MATERNAL-FETAL

EVIDENCE BASED
GUIDELINES
Series in Maternal-Fetal Medicine
About the Series

Published in association with the Journal of Maternal-Fetal and Neonatal Medicine, the series in Maternal-Fetal Medicine keeps read-
ers up to date with the latest clinical therapies to improve the health of pregnant patients and ensure a successful birth. Each volume
in the series is prepared separately and typically focuses on a topical theme. Volumes are published on an occasional basis, depending
on the emergence of new developments.

Maternal-Fetal Evidence Based Guidelines, Fourth Edition

Vincenzo Berghella

Obstetric Evidence Based Guidelines, Fourth Edition

Vincenzo Berghella

Maternal-Fetal and Obstetric Evidence Based Guidelines, Two Volume Set, Fourth Edition
Vincenzo Berghella

The Long-Term Impact of Medical Complications in Pregnancy: A Window into Maternal and Fetal Future Health
Eyal Sheiner

Operative Obstetrics, 4E
Joseph J. Apuzzio, Anthony M. Vintzileos, Vincenzo Berghella, Jesus R. Alvarez-Perez

Placenta Accreta Syndrome

Robert M. Silver

Neurology and Pregnancy: Clinical Management

Michael S. Marsh, Lina Nashef, Peter Brex

Fetal Cardiology: Embryology, Genetics, Physiology, Echocardiographic Evaluation, Diagnosis, and Perinatal Management of
Cardiac Diseases, Third Edition
Simcha Yagel, Norman H. Silverman, Ulrich Gembruch

New Technologies and Perinatal Medicine: Prediction and Prevention of Pregnancy Complications
Moshe Hod, Vincenzo Berghella, Mary D’Alton, Gian Carlo Di Renzo, Eduard Gratacos, Vassilios Fanos

Problem-Based Obstetric Ultrasound, Second Edition

Amar Bhide, Asma Khalil, Aris T Papageorghiou, Susana Pereira, Shanthi Sairam, Basky Thilaganathan

Recurrent Pregnancy Loss: Causes, Controversies and Treatment, Third Edition

Howard Carp

For more information about this series please visit: https://www.crcpress.com/Series-in-Maternal-Fetal-Medicine/book-series/

CRCSERMATFET
MATERNAL-FETAL
EVIDENCE BASED
GUIDELINES

FOURTH EDITION

Edited by
Vincenzo Berghella, MD, FACOG
Director, Division of Maternal-Fetal Medicine
Director, Maternal-Fetal Medicine Fellowship Program
Professor, Department of Obstetrics & Gynecology
Sidney Kimmel Medical College of Thomas Jefferson University
Philadelphia, PA, USA
Fourth edition published 2022
by CRC Press
6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742

and by CRC Press

2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN

© 2022 Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, LLC

This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts
have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal
responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any
views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do
not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is
intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the
medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufac-
turer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any
information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly
urged to consult the relevant national drug formulary and the drug companies’ and device or material manufactur-
ers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials
mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a
particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own profes-
sional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to
trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permis-
sion to publish in this form has not been obtained. If any copyright material has not been acknowledged please write
and let us know so we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or
utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including pho-
tocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission
from the publishers.

For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the
Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are
not available on CCC please contact mpkbookspermissions@tandf.co.uk

Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for
identification and explanation without intent to infringe.

ISBN: 978-0-367-56702-6 (hbk)

ISBN: 978-0-367-56705-7 (pbk)
ISBN: 978-1-003-09906-2 (ebk)
DOI: 10.1201/9781003099062

Typeset in Warnock Pro

by KnowledgeWorks Global Ltd.
 I dedicate this fourth edition to my father, Andrea Berghella, who passed away at 87 in January 2019.
He was and remains my professional inspiration and guiding light. The bright light of his lighthouse,
to use a metaphor, keeps on shining inside my mind and heart, and leading me onwards and upwards.
To Federica, Andrea, Pietro, Mamma, Anna, and Michele, for giving me
the serenity, love, and strength at home now, then, and in the future to
fulfill my dreams and spend my talents as best as possible.
To all those who loved the prior editions
To the health of mothers and babies
And, as I often toast – To the next generation!
 CONTENTS

Introduction............................................................................................................................................................................................................................ x
How to “Read” This Book.................................................................................................................................................................................................. xii
Contributors....................................................................................................................................................................................................................... xiii
List of Abbreviations........................................................................................................................................................................................................ xvii

1. Hypertensive Disorders............................................................................................................................................................................................1
Amanda Roman

2. Cardiac Disease.........................................................................................................................................................................................................26
Preethi Pirlamarla and Gregary D. Marhefka

3. Obesity.........................................................................................................................................................................................................................35
Rebekah Jo McCurdy

4. Pregestational Diabetes..........................................................................................................................................................................................57
F. Weston Loehr, A. Dhanya Mackeen, and Michael J. Paglia

5. Gestational Diabetes................................................................................................................................................................................................66
A. Dhanya Mackeen, Richard S. Vigh, and Kajal Angras

6. Hypothyroidism........................................................................................................................................................................................................78
Alessandra Livi

7. Hyperthyroidism.......................................................................................................................................................................................................86
Alessandra Livi

8. Prolactinoma..............................................................................................................................................................................................................92
Matteo Antonio Ucci

9. Nausea/Vomiting of Pregnancy and Hyperemesis Gravidarum................................................................................................................99

Rupsa C. Boelig and Sofia Guidi

10. Intrahepatic Cholestasis of Pregnancy............................................................................................................................................................111

Ginevra Salsi

11. Inflammatory Bowel Disease..............................................................................................................................................................................117

Priyadarshini Koduri

12. Alimentary Tract Diseases..................................................................................................................................................................................129

Ryan Lamm, Arturo J. Rios-Diaz, Priyadarshini Koduri, and Francesco Palazzo

13. Pregnancy after Liver and Other Transplantation......................................................................................................................................137

Guillermo Gurza and Adam Bodzin

14. Maternal Anemia....................................................................................................................................................................................................144

Ashley E. Benson and Marcela C. Smid

15. Sickle Cell Disease..................................................................................................................................................................................................153

Zimeng Gao

16. Von Willebrand Disease.......................................................................................................................................................................................161

Melody Safarzadeh

17. Urinary Tract Disease...........................................................................................................................................................................................166

Giuseppe Chiossi

18. Headache...................................................................................................................................................................................................................182
Stephen Silberstein and Shuhan Zhu

vii
viii Contents

19. Seizures......................................................................................................................................................................................................................187
Sally Mathias and Meriem Bensalem-Owen

20. Other Neurologic Diseases in Pregnancy.......................................................................................................................................................193

Loralei L. Thornburg and Meredith L. Birsner

21. Mood Disorders...................................................................................................................................................................................................... 203

Madeleine A. Becker, Tal E. Weinberger, and Leigh J. Ocker

22. Smoking.................................................................................................................................................................................................................... 223

Jorge E. Tolosa, Niyazi Kilic, and David M. Stamilio

23. Substance Use Disorders......................................................................................................................................................................................232

Neil S. Seligman

24. Intimate Partner Violence and Trauma Informed Care in Pregnancy................................................................................................ 257
Johanna Quist-Nelson and Amy Weil

25. Racism and Racial Disparity in Obstetrics.....................................................................................................................................................262

Ukachi N. Emeruwa, Emily Rosenthal, and Allison S. Bryant

26. Respiratory Diseases: Asthma, Pneumonia, Influenza, Tuberculosis, and COVID-19....................................................................269

Aref T. Senno and Ryan K. Brannon

27. Systemic Lupus Erythematosus..........................................................................................................................................................................297

Maria A. Giraldo-Isaza and Bettina F. Cuneo

28. Antiphospholipid Syndrome.............................................................................................................................................................................. 309

Michael Miller, Arthur Jason Vaught, and Torre Halscott

29. Inherited Thrombophilia.....................................................................................................................................................................................315

Guillermo Gurza

30. Venous Thromboembolism and Anticoagulation........................................................................................................................................324

Alexandra V. Ramirez

31. Hepatitis A............................................................................................................................................................................................................... 340

Rebecca Pierce-Williams, Neil Silverman, Steven K. Herrine, and Danielle Tholey

32. Hepatitis B................................................................................................................................................................................................................ 343

Laura Felder, Zimeng Gao, and Danielle Tholey

33. Hepatitis C............................................................................................................................................................................................................... 350

Rebecca Pierce-Williams, Neil Silverman, Raja Dhanekula, Jonathan M. Fenkel, and Danielle Tholey

34. HIV..............................................................................................................................................................................................................................359
Jenani Jayakumaran and William R. Short

35. Gonorrhea................................................................................................................................................................................................................ 367

A. Marie O’Neill

36. Chlamydia.................................................................................................................................................................................................................372
Molly A. Amero and Shawn Mattson

37. Syphilis.......................................................................................................................................................................................................................377
A. Marie O’Neill

38. Trichomonas............................................................................................................................................................................................................ 384

Tino Tran

39. Group B Streptococcus..........................................................................................................................................................................................387

Stephanie Thomas
Contents ix

40. Vaccinations.............................................................................................................................................................................................................393
Joshua H. Barash and Edward M. Buchanan

41. Trauma...................................................................................................................................................................................................................... 400

Danielle M. Prentice and Lauren A. Plante

42. Critical Care.............................................................................................................................................................................................................412

Jaimie Maines and Lauren A. Plante

43. Amniotic Fluid Embolism................................................................................................................................................................................... 433

Zaid Diken, Antonio F. Saad, and Luis D. Pacheco

44. Cancer........................................................................................................................................................................................................................ 441

Elyce Cardonick, Charlotte Maggen, and Puja Patel

45. Dermatoses of Pregnancy.................................................................................................................................................................................... 458

Hannah J. Anderson, Dana Correale, and Jason B. Lee

46. Multiple Gestations............................................................................................................................................................................................... 469

Edward J. Hayes and Michelle R. Hayes

47. Fetal Growth Restriction..................................................................................................................................................................................... 482

Juliana Gevaerd Martins and Alfred Abuhamad

48. Fetal Macrosomia.................................................................................................................................................................................................. 500

Sipika Tyagi

49. Cytomegalovirus.................................................................................................................................................................................................... 504

Timothy J. Rafael

50. Toxoplasmosis..........................................................................................................................................................................................................511
Corina N. Schoen and Elizabeth A. Morgan

51. Parvovirus.................................................................................................................................................................................................................516
Timothy J. Rafael

52. Herpes.........................................................................................................................................................................................................................520
Timothy J. Rafael

53. Varicella.....................................................................................................................................................................................................................525
Timothy J. Rafael

54. Fetal and Neonatal Alloimmune Thrombocytopenia.................................................................................................................................529

Leen Al-Hafez

55. Hemolytic Disease of the Fetus and Newborn...............................................................................................................................................536

Pedro Argoti, Ana M. Angarita, and Giancarlo Mari

56. Nonimmune Hydrops Fetalis..............................................................................................................................................................................552

Chelsea DeBolt, Katherine Connolly, Mary E. Norton, and Joanne Stone

57. Fetal Death............................................................................................................................................................................................................... 564

Emily A. Oliver and Uma M. Reddy

58. Antepartum Testing.............................................................................................................................................................................................. 572

Nora Graham

59. Sonographic Assessment of Amniotic Fluid: Oligohydramnios and Polyhydramnios....................................................................589

Ariel T. Levy
Index.....................................................................................................................................................................................................................................599
 INTRODUCTION
Welcome to the fourth edition of our evidence-based books on
obstetrics and maternal-fetal medicine! I am indebted for your
support! I can’t believe how much praise we have received for
these companion volumes. Your words of encouragement have
kept me and all the wonderful collaborators going on strong for
15 years! It has been extremely worthwhile, and fulfilling. You
are making me happy! In return, I hope we are helping you and
your patients toward ever better evidence-based care of preg-
nant women and their babies, and therefore better outcomes.
Indeed, most maternal and perinatal morbidities and mortalities
throughout the world are improving.
To me, pregnancy has always been the most fascinating and
exciting area of interest, as care involves not one, but at least two
persons—the mother and the fetus—and leads to the miracle of
a new life. I was a third-year medical student when, during a lec-
ture, a resident said: “I went into obstetrics because this is the
easiest medical field. Pregnancy is a physiologic process, and
there isn’t much to know. It is simple.” I knew from my “classical”
background that “obstetrics” means to “stand by, stay near,” and
that indeed pregnancy used to receive no medical support at all.
After more than 31 years of practicing obstetrics, I now know that
although physiologic and at times simple, obstetrics and mater-
nal-fetal medicine can be the most complex of the medical fields:
pregnancy is based on a different physiology than non-pregnant
women and can include medical disease, required surgery, etc. It
is not so simple. In fact, ignorance can kill; in this case with the
health of the woman and her baby both at risk. Too often, I have
gone to a lecture, journal club, rounds, or other didactic event to
hear presented only one or a few articles regarding the subject,
without the presenter reviewing the pertinent best review of the
total literature and data. It is increasingly difficult to read and
acquire knowledge of all that is published, even just in obstetrics,
with over 3000 scientific manuscripts published monthly on this
subject. Some residents or even authorities would state at times
that “there is no evidence” on a topic. We indeed used to be the
field with the worst use of randomized trials [1]. As the best way
to find something is to look for it, my coauthors and I searched
for the best evidence. On careful investigation, indeed there are
data on almost everything we do in obstetrics, especially on our
interventions. Indeed, our field is now the pioneer for a number of
meta-analyses and extensions of work for evidence-based reviews
[2]. Obstetricians are now blessed with lots of data and should
make the best use of it.
The goals of this book are to summarize the best evidence
available in the obstetrics and maternal-fetal medicine literature,
and make the results of randomized controlled trials (RCTs) and
meta-analyses of RCTs easily accessible to guide clinical care.
The intent is to bridge the gap between knowledge (the evidence)
and its easy application. To reach these goals, we reviewed all
trials on effectiveness of interventions in obstetrics. Millions
of pregnant women have participated in thousands of properly
conducted RCTs. The efforts and sacrifice of mothers and their
fetuses for science should be recognized at least by the physicians’
awareness and understanding of these studies. Some of the trials
have been summarized in over 600 Cochrane reviews, with hun-
dreds of other meta-analyses also published in obstetrical topics
(Table I.1). All the Cochrane reviews, as well as other meta-anal-
yses and trials in obstetrics and maternal-fetal medicine, were
reviewed and referenced. The material presented in single trials
x
TABLE I.1: Obstetrical Evidence
• Over 600 current Cochrane reviews
• Hundreds of other current meta-analyses
• Thousands of RCTs
• Millions of pregnant women randomized
or meta-analyses is too detailed to be readily translated to advice
for the busy clinician who needs to make dozens of clinical deci-
sions a day. Even the Cochrane Library, the undisputed leader for
evidence-based medicine efforts, has been criticized for its lack of
flexibility and relevance in failing to be more easily understand-
able and clinically readily usable [3]. It is the gap between research
and clinicians that needed to be filled, making sure that proven
interventions are clearly highlighted, and are included in today’s
care. Just as all pilots fly planes under similar rules to maximize
safety, all obstetricians should manage all aspects of pregnancy
with similar, evidenced-based rules. Indeed, only interventions
that have been proven to provide benefit should be used rou-
tinely. On the other hand, primum non nocere: interventions that
have clearly been shown to not be helpful or indeed harmful to
mother and/or baby should be avoided. Another aim of the book
is to make sure the pregnant woman and her unborn child are
not marginalized by the medical community. In most circum-
stances, medical disorders of pregnant women can be treated as
non-pregnant adults. Moreover, there are several effective inter-
ventions for preventing or treating specific pregnancy disorders.
Evidence-based medicine is the concept of treating patients
according to the best available evidence. While George Bernard
Shaw said: “I have my own opinion, do not confuse me with the
facts,” this can be a deadly approach, especially in medicine, and
compromise two or more lives at the same time in obstetrics
and maternal-fetal medicine. What should be the basis for our
interventions in medicine? Meta-analyses provide a comprehen-
sive summary of the best research data available. As such, they
provide the best guidance for “effective” clinical care [4]. It is
unscientific and unethical to practice medicine, teach, or con-
duct research without first knowing all that has already been
proven [4]. In the absence of trials or meta-analyses, lower level
evidence is reviewed. This book aims at providing a current sys-
tematic review of all the best evidence, so that current practice
and education, as well as future research can be based on the full
story from the best-conducted research, not just the latest data or
someone’s opinion (Table I.2).
These evidence-based guidelines cannot be used as a “cook-
book,” or a document dictating the best care. The knowledge
from the best evidence presented in the guidelines needs to be
integrated with other knowledge gained from clinical judgment,
TABLE I.2: Goals of This Book
• Improve the health of women and their children
• “Make it easy to do it right”
• Implement the best clinical care based on science (evidence), not opinion
• Education
• Develop lectures
• Decrease disease, use of detrimental interventions, and therefore costs
• Reduce medicolegal risks
Introduction
individual patient circumstances, and patient preferences, to lead
to best medical practice. These are guidelines, not rules. Even the
best scientific studies are not always perfectly related to any given
individual, and clinical judgment must still be applied to allow
the best “particularization” of the best knowledge for the indi-
vidual, unique patient. Evidence-based medicine informs clinical
judgment, but does not substitute it. It is important to under-
stand, though, that greater clinical experience by the physician
actually correlates with inferior quality of care if not integrated
with knowledge of the best evidence [5]. The appropriate treat-
ment is given in only 50% of visits to general physicians [5]. At
times, limitations in resources may also limit the applicability of
the guidelines, but should not limit the physician’s knowledge.
Guidelines and clinical pathways based on evidence not only
point to the right management, but also can decrease medicolegal
risk [6]. We aimed for brevity and clarity. Suggested management
of the healthy or sick mother and child is stated as straightfor-
wardly as possible, for everyone to easily understand and imple-
ment (Table I.3). If you find the Cochrane reviews, scientific
TABLE I.3: This Book Is For
• Obstetricians
• Midwives
• Family medicine and others (practicing obstetrics)
• Residents
• Nurses
• Medical students
• Maternal-fetal medicine attendings
• Maternal-fetal medicine fellows
• Other consultants on pregnancy
• Lay persons who want to know “the evidence”
• Politicians responsible for health care
xi
manuscripts, and other publications difficult to “translate” into
care of your patients, this book is for you. We wanted to prevent
information overload.
On the other hand, “everything should be made as simple as
possible, but not simpler” (Albert Einstein). Key management
points are highlighted at the beginning of each guideline and in
bold in the text. The chapters are divided in two volumes, one on
obstetrics and one on maternal-fetal medicine; cross references to
chapters in Obstetric Evidence Based Guidelines have been noted
in the text where applicable. Please contact me (vincenzo.ber-
ghella@jefferson.edu) for any comments, criticisms, corrections,
missing evidence, etc.
I have the most fun discovering the best ways to alleviate dis-
comfort and disease. The search for the best evidence for these
guidelines has been a wonderful, stimulating journey. Keeping up
with evidence-based medicine is exciting. The most rewarding
part, as a teacher, is the dissemination of knowledge. I hope, truly,
that this effort will be helpful to you, too.
References
1. Cochrane AL. 1931–1971: A critical review, with particular reference to
the medical profession. In: Medicines for the Year 2000. London: Office of
Health Economics, 1979:1–11. [Review]
2. Dickersin K, Manheimer E. The Cochrane collaboration: evaluation of
health care and services using systematic reviews of the results of random-
ized controlled trials. Clinic Obstet Gynecol 1998;41:315–331. [Review]
3. Summerskill W. Cochrane collaboration and the evolution of evidence.
Lancet 2005;366:1760. [Review]
4. Chalmers I. Academia’s failure to support systematic reviews. Lancet
2005;365:469. [III]
5. Arky RA. The family business—to educate. NEJM 2006;354:1922–1926.
[Review]
6. Ransom SB, Studdert DM, Dombrowski MP, et al. Reduced medico-legal
risk by compliance with obstetric clinical pathways: a case-control study.
Obstet Gynecol 2003;101:751–755. [II-2]
 HOW TO “READ” THIS BOOK
The knowledge from randomized controlled trials (RCTs) and
meta-analyses of RCTs is summarized and easily available for clini-
cal implementation. Key management points are highlighted at the
beginning of each guideline, and in bold in the text. Relative risks and
95% confidence intervals from studies are quoted sparingly. Instead,
the straight recommendation for care is made if one intervention is
superior to the other, with the percent improvement often quoted to
assess degree of benefit. If there is insufficient evidence to compare
to interventions or managements, this is clearly stated.
References: Cochrane reviews with 0 RCT are not referenced,
and, instead of referencing a meta-analysis with only one RCT,
the actual RCT is usually referenced. RCTs that are already
included in meta-analyses are not referenced for brevity, and
because they can be easily accessed by reviewing the meta-analy-
sis. If new RCTs are not included in meta-analysis, they are obvi-
ously referenced. Each reference was reviewed and evaluated for
quality according to a modified method as outlined by the U.S.
Preventive Services Task Force (www.ahrq.gov):
xii
I Evidence obtained from at least one properly designed ran-
domized controlled trial.
II-1 Evidence obtained from well-designed controlled trials
without randomization.
II-2 Evidence obtained from well-designed cohort or case-con-
trol analytic studies, preferably from more than one center
or research group.
II-3 Evidence obtained from multiple time series with or with-
out the intervention. Dramatic results in uncontrolled
experiments could also be regarded as this type of evidence.
III (Review) Opinions of respected authorities, based on clini-
cal experience, descriptive studies, or reports of expert
committees.
These levels are quoted after each reference. For RCTs and
meta-analyses, the number of subjects studied is stated and,
sometimes, more details are provided to aid the reader to under-
stand the study better.

Alfred Abuhamad
Department of Obstetrics and Gynecology
Eastern Virginia Medical School
Virginia Beach, Virginia
Leen Al-Hafez
Department of Obstetrics and Gynecology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Molly A. Amero
Department of Obstetrics and
Gynecology
Thomas Jefferson University
Philadelphia, Pennsylvania
Hannah J. Anderson
Department of Dermatology and
Cutaneous Biology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Ana M. Angarita
Obstetrics and Gynecology
Philadelphia, Pennsylvania
Kajal Angras
Department of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine
Geisinger
Danville, Pennsylvania
Pedro Argoti
Maternal-Fetal Medicine
University of Tennessee Health Science
Center
Memphis, Tennessee
Joshua H. Barash
Department of Family and Community
Medicine
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Madeleine A. Becker
Department of Integrative Medicine and
Nutritional Sciences
Department of Psychiatry and Human
Behavior
Sidney Kimmel Medical College
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Meriem Bensalem-Owen
Department of Neurology/Epilepsy
Program
University of Kentucky
Lexington, Kentucky
CONTRIBUTORS
Ashley E. Benson
Division of Maternal-Fetal Medicine
University of Utah Health
Salt Lake City, Utah
Meredith L. Birsner
Maternal and Fetal Medicine
St. Luke’s University Health Network
Bethlehem, Pennsylvania
Adam Bodzin
Department of Surgery
Sidney Kimmel Medical College
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Rupsa C. Boelig
Maternal-Fetal Medicine
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Ryan K. Brannon
Patient Safety and Quality Management
Division
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Allison S. Bryant
Maternal-Fetal Medicine
Massachusetts General Hospital
Boston, Massachusetts
Edward M. Buchanan
Department of Family and Community
Medicine
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Elyce Cardonick
Department of Obstetrics and
Gynecology
Cooper University Health Care
Camden, New Jersey
Giuseppe Chiossi
Department of Obstetrics and Gynecology
Modena Policlinico Hospital
University of Modena and Reggio Emilia
Modena, Italy
Katherine Connolly
Obstetrics and Gynecology
UCSF Medical Center
San Francisco, California
Dana Correale
Cheshire Dermatology (Private Practice)
Cheshire, Connecticut
Bettina F. Cuneo
Cardiology and Pediatrics
Children’s Hospital Colorado
Aurora, Colorado
Chelsea DeBolt
Department of Obstetrics, Gynecology,
and Reproductive Science
Mount Sinai Health System and Icahn
School of Medicine at Mount Sinai
New York, New York
Raja Dhanekula
Department of Transplant Hepatology
Baylor Scott and White
Austin, Texas
Zaid Diken
Department of Obstetrics/Gynecology
Division of Maternal-Fetal Medicine
The University of Texas Medical Branch
Galveston, Texas
Ukachi N. Emeruwa
Department of Obstetrics and
Gynecology
Division of Maternal-Fetal Medicine
New York Presbyterian Hospital
New York, New York
Laura Felder
Department of Obstetrics and
Gynecology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Jonathan M. Fenkel
Jefferson Hepatitis C Center
Jefferson University Hospital
Philadelphia, Pennsylvania
Zimeng Gao
Department of Obstetrics and
Gynecology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Maria A. Giraldo-Isaza
Maternal-Fetal Medicine
Florida Perinatal Associates
Tampa, Florida
Nora Graham
Obstetrics and Gynecology
Inova Health System
Alexandra, Virginia
xiii
xiv Contributors

Sofia Guidi Ariel T. Levy Shawn Mattson

Dipartimento Scienze della Salute della
Donna e del Bambino e di Sanità
Pubblica
Fondazione Policlinico Universitario “A.
Gemelli” IRCCS-Università Cattolica
del Sacro Cuore
Rome, Italy
Guillermo Gurza
Department of Obstetrics and
Gynecology
Instituto Nacional de Perinatología
Mexico City, Mexico
Torre Halscott
Maternal-Fetal Medicine and Critical
Care Medicine
The Johns Hopkins University School of
Medicine
Baltimore, Maryland
Edward J. Hayes
Maternal-Fetal Medicine
Aurora Bay Care Medical Center
Green Bay, Wisconsin
Michelle R. Hayes
Neonatal-Perinatal Medicine
Green Bay, Wisconsin
Steven K. Herrine
Transplant Hepatology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Jenani Jayakumaran
Department of Obstetrics and Gynecology
Thomas Jefferson University
Philadelphia, Pennsylvania
Niyazi Kilic
Department of Obstetrics and Gynecology
St. Luke’s University Hospital Network
Bethlehem, Pennsylvania
Priyadarshini Koduri
Obstetrics and Gynecology
Advocate Illinois Masonic Medical
Center
Chicago, Illinois
Ryan Lamm
Family Medicine
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Jason B. Lee
Department of Dermatology and
Cutaneous Biology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Department of Obstetrics and Department of Obstetrics and Gynecology
Gynecology Thomas Jefferson University Hospital
Division of Maternal-Fetal Medicine Philadelphia, Pennsylvania
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania Rebekah Jo McCurdy
Obstetrics and Gynecology and Maternal-
Alessandra Livi Fetal Medicine
Department of Medical and Surgical Jefferson University Physicians
Sciences Philadelphia, Pennsylvania
Sant’Orsola-Malpighi University Hospital
University of Bologna Michael Miller
Bologna, Italy Center for Preventive Cardiology
University of Maryland School of Medicine
F. Weston Loehr Baltimore, Maryland
Department of Obstetrics and Gynecology
University of Virginia Elizabeth A. Morgan
Charlottesville, Virginia Department of Pathology
Brigham and Women’s Hospital
A. Dhanya Mackeen Springfield, Massachusetts
Department of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine Mary E. Norton
Geisinger Obstetrics, Gynecology and Reproductive
Danville, Pennsylvania Sciences
University of California San Francisco
Charlotte Maggen San Francisco, California
Department of Oncology
KU Leuven Leigh J. Ocker
Leuven, Belgium Department of Psychiatry and Human
and Behavior
Department of Obstetrics and Prenatal Thomas Jefferson University Hospital
Medicine Philadelphia, Pennsylvania
University Hospitals Brussels
Brussels, Belgium Emily A. Oliver
Maternal-Fetal Medicine
Jaimie Maines Thomas Jefferson University Hospital
Obstetrics and Gynecology Philadelphia, Pennsylvania
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania A. Marie O’Neill
Department of Obstetrics and Gynecology
Gregary D. Marhefka Jefferson Washington Township Hospital
Internal Medicine Turnersville, New Jersey
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania Luis D. Pacheco
Department of Obstetrics/Gynecology
Giancarlo Mari Division of Maternal-Fetal Medicine
Maternal-Fetal Medicine and
Cleveland Clinic Department of Anesthesiology
Cleveland, Ohio Division of Surgical Critical Care
The University of Texas Medical Branch
Juliana Gevaerd Martins Galveston, Texas
Department of Obstetrics and
Gynecology Michael J. Paglia
Eastern Virginia Medical School Division of Maternal-Fetal Medicine
Virginia Beach, Virginia Geisinger
Danville, Pennsylvania
Sally Mathias
Department of Neurology/Epilepsy Francesco Palazzo
Program Department of Surgery
University of Kentucky Jefferson Methodist Hospital and Thomas
Lexington, Kentucky Jefferson University Hospital
Philadelphia, Pennsylvania
Contributors
Puja Patel
Department of Obstetrics and Gynecology
Cooper Medical School at Rowan
University
Camden, New Jersey
Rebecca Pierce-Williams
Obstetrics and Gynecology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Preethi Pirlamarla
Cardiology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Lauren A. Plante
Obstetrics and Gynecology
Delaware County Memorial Hospital
Drexel Hill, Pennsylvania
Danielle M. Prentice
Obstetrics and Gynecology
Penn State Hershey Medical Center and
Penn State College of Medicine
Hershey, Pennsylvania
Johanna Quist-Nelson
Obstetrics and Gynecology
University of North Carolina
Chapel Hill, North Carolina
Timothy J. Rafael
Department of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine
North Shore University Hospital
Manhasset, New York
Alexandra V. Ramirez
Internal Medicine
Hennepin County Medical Center
St. Paul, Minnesota
Uma M. Reddy
Maternal-Fetal Medicine
Yale School of Medicine
New Haven, Connecticut
Arturo J. Rios-Diaz
Department of Surgery
Thomas Jefferson University
Philadelphia, Pennsylvania
Amanda Roman
Maternal-Fetal Medicine
Thomas Jefferson University
Philadelphia, Pennsylvania
Emily Rosenthal
Obstetrics and Gynecology
Boston University Medical School
Boston, Massachusetts
Antonio F. Saad
Department of Obstetrics/Gynecology
Division of Maternal-Fetal Medicine
and
Department of Anesthesiology
Division of Surgical Critical Care
The University of Texas Medical Branch
Galveston, Texas
Melody Safarzadeh
Department of Obstetrics and Gynecology
Sidney Kimmel Medical College
Thomas Jefferson University
Philadelphia, Pennsylvania
Ginevra Salsi
Obstetrics and Gynaecology
Department of Medical and Surgical
Sciences
University of Bologna
Bologna, Italy
Corina N. Schoen
Department of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine
University of Massachusetts-Baystate
Medical Center
Springfield, Massachusetts
Neil S. Seligman
Division of Maternal-Fetal Medicine
Strong Memorial Hospital
University of Rochester
Rochester, New York
Aref T. Senno
Obstetrics and Gynecology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
William R. Short
Obstetrics and Gynecology and Division
of Infectious Diseases
Perelman School of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Stephen Silberstein
Department of Neurology
Boston University School of Medicine
Boston, Massachusetts
Neil Silverman
Center for Fetal Medicine and Obstetrics
and Gynecology
UCLA School of Medicine
Los Angeles, California
Marcela C. Smid
Division of Maternal-Fetal Medicine
University of Utah Health
Salt Lake City, Utah
xv
David M. Stamilio
Division of Maternal-Fetal Medicine
Wake Forest School of Medicine
Winston-Salem, North Carolina
Joanne Stone
Department of Obstetrics, Gynecology,
and Reproductive Science
Mount Sinai Health System and Icahn
School of Medicine at Mount Sinai
New York, New York
Danielle Tholey
Digestive Health Institute
Jefferson University Hospital
Philadelphia, Pennsylvania
Stephanie Thomas
Obstetrics and Gynecology
Thomas Jefferson University Hospital and
Jefferson Surgery Center at The Navy
Yard
Philadelphia, Pennsylvania
Loralei L. Thornburg
Department of Obstetrics and
Gynecology
University of Rochester
Rochester, New York
Jorge E. Tolosa
Department of Obstetrics and
Gynecology
Division of Maternal-Fetal Medicine
St. Luke’s University Health Network
Bethlehem, Pennsylvania
and
Division of Maternal-Fetal Medicine
Oregon Health & Science University
Portland, Oregon
Tino Tran
Crozer Medical Associates Obstetrics and
Gynecology
Chester, Pennsylvania
Sipika Tyagi
Obstetrics and Gynecology
Jefferson Stratford Hospital
Stratford, New Jersey
Matteo Antonio Ucci
Department of Medicine and Aging
Sciences
D’Annunzio University of Chieti-Pescara
Chieti, Italy
Arthur Jason Vaught
Obstetrics and Gynecology
The Johns Hopkins University School of
Medicine
Baltimore, Maryland
xvi Contributors

Richard S. Vigh Tal E. Weinberger

Department of Obstetrics and Gynecology Department of Psychiatry and Human
Division of Maternal-Fetal Medicine Behavior
Geisinger Thomas Jefferson University
Danville, Pennsylvania Philadelphia, Pennsylvania

Amy Weil Shuhan Zhu

Ambulatory Care Center Department of Neurology
UNC Medical Center Boston University School of Medicine
University of North Carolina Boston, Massachusetts
Chapel Hill, North Dakota

The publishers would also like to thank the following contributors to the previous edition for any material used in this edition:

James A. Airoldi Elisabeth J.S. Kunkel Kelly M. Orzechowski

Laura Carlson Augusto Lauro Leonardo Pereira

Nahida Chakhtoura Dawnette Lewis Sarah Poggi

Ann Chandy Melisa Lott Shane Reeves

Suneet P. Chauhan Lucio Mandala Sharon Rubin

Melissa Chu Lam Tracy A. Manuck Joya Sahu

Jeffrey Ecker Amber S. Maratas Jacques E Samson

Henry L. Galan Ignazio R. Marino Kathryn Shaia

Maran Gooding Maria Teresa Mella Nazanin E Silver

Ibrahim A. Hammad M. Kathryn Menard Robert M Silver

Christopher R. Harman Rebeccca J. Mercier Giuliana Simonazzi

Paniz Heidari Srikanth Nagalla Robert A Strauss

Katherine Husk Mariam Naqvi Danielle L Tate

Sushma Jwala A. Marie O’Neill Oscar A Viteri

 LIST OF ABBREVIATIONS

Ab antibody EKG (synonym of EDC) electrocardiogram

AC abdominal circumference FBS fetal blood sampling
ACA anticardiolipin antibody FDA Food and Drug Administration
ACOG American College of Obstetricians and FFN fetal fibronectin
Gynecologists FGR fetal growth restriction
ACS acute chest syndrome FHR fetal heart rate
ADR autosomic dysreflexia FISH fluorescent in situ hybridization
AF amniotic fluid FLM fetal lung maturity
AFI amniotic fluid index FOB father of baby
AFP alpha-fetoprotein FPR false positive rate
AFV amniotic fluid volume FTS first trimester screening
Ag antigen FVL factor V Leiden
AIDS acquired immune deficiency syndrome g grams
ALT alanine aminotransferase GA gestational age
ANA antinuclear antibodies GBS group B streptococcus
aPT activated prothrombin time GDM gestational diabetes mellitus
APS antiphospholipid syndrome GI gastrointestinal
aPTT activated partial thromboplastin time HAART highly active antiretroviral therapy
AROM artificial rupture of membranes HAV hepatitis A virus
ART assisted reproductive technologies HBV hepatitis B virus
ARV antiretroviral therapy HBsAg hepatitis B surface antigen
ASA aspirin HCG human chorionic gonadotropin
ASD atrial septal defect Hct hematocrit
AST aspartate aminotransferase HCV hepatitis C virus
AT III antithrombin III HG hyperemesis gravidarum
AZT ziduvudine Hgb hemoglobin
bid “bis in die,” i.e., twice per day HIE hypoxic-ischemic encephalopathy
BPD biparietal diameter HIV human immunodeficiency virus
BPD bronchopulmonary dysplasia HR heart rate
BPP biophysical profile HSV herpes simplex virus
BMI body mass index HTN hypertension
BP blood pressure IBD inflammatory bowel disease
CAP community-acquired pneumonia ICU intensive care unit
CBC complete blood count ICP intrahepatic cholestasis of pregnancy
CCB calcium channel blocker IUGR intrauterine growth restriction (synonym
CDC Centers for Disease Control and Prevention of FGR)
CF cystic fibrosis IV intravenous
CHD congenital heart defect IVH intraventricular hemorrhage
CL cervical length IUT intrauterine transfusion
CMV cytomegalovirus L&D labor and delivery floor
CNS central nervous system LA lupus anticoagulant
COX cyclooxygenase Lab laboratory
CRL crown-rump length LFT liver function tests
CSE combined spinal epidural LMP last menstrual period
CSF cerebrospinal fluid LBW low birth weight (infants)
CT computerized tomography LMW low molecular weight
CVS chorionic villus sampling LMWH low-molecular-weight heparin
DASH Dietary Approaches to Stop Hypertension LR likelihood ratio
DES diethylstilbestrol MAS meconium aspiration syndrome
DIC disseminated intravascular coagulation MCA middle cerebral artery
DM diabetes mellitus MCV mean corpuscular volume
DNA deoxyribonucleic acid MOM multiple of the median
DRVVT dilute Russell’s viper venom time MRI magnetic resonance imaging
DV ductus venosus MTHFR methylenetetrahydrofolate reductase
DVP deepest vertical pocket MVP maximum vertical pocket
DVT deep vein thrombosis NA not available
ECV external cephalic version NAIT neonatal alloimmune thrombocytopenia
EDC estimated date of confinement NEC necrotizing enterocolitis
EDD estimated date of delivery NIH National Institutes of Health

xvii
xviii List of Abbreviations

NIH nonimmune hydrops RCT randomized controlled study

NRFS nonreassuring fetal status RDS respiratory distress syndrome
NRFHR nonreassuring fetal heart rate RNA ribonucleic acid
NRFHT nonreassuring fetal heart testing ROM rupture of membranes
NSAIDs nonsteroidal anti-inflammatory drugs RPR rapid plasma regain
NT nuchal translucency RR respiratory rate
NTD neural tube defects Rx treatment
NST nonstress test SAB spontaneous abortion
n/v nausea and/or vomiting SC subcutaneous
OR operating room SCI spinal cord injury
ORA oxytocin receptor agonist SDP single deepest pocket
PC protein C SIDS sudden infant death syndrome
PCR polymerase chain reaction SLE systemic lupus erythematosus
PE pulmonary embolus SPTB spontaneous preterm birth
PFT pulmonary function tests SSRI selective serotonin reuptake inhibitor
PGM prothrombin gene mutation STD sexually transmitted diseases (synonym
PID pelvic inflammatory disease of STI)
PL pregnancy loss STI sexually transmitted infections
PNC prenatal care STS second-trimester screening
po “per os,” i.e., by mouth SVR sustained virologic response
PPH postpartum hemorrhage TB tuberculosis
PRCD planned repeat cesarean delivery TG Toxoplasma gondii
PS protein S tid three times per day
PT prothrombin time TOL trial of labor
PTB preterm birth TRAP twin reversal arterial perfusion
PTT partial thromboplastin time TRH thyrotropin-releasing hormone
PPD postpartum depression TSH thyroid-stimulating hormone
PPROM preterm premature rupture TSI thyroid-stimulating immune globulins
of membranes TTTS twin-twin transfusion syndrome
pRBC packed red blood cells TVU transvaginal ultrasound
PROM preterm rupture of membranes UA umbilical artery
PSV peak systolic velocity UFH unfractionated heparin
PTL preterm labor UPC urinary protein creatinine ratio
PTU propylthiouracil U/S (or u/s) ultrasound
PUBS percutaneous umbilical blood sampling USPSTF United States Preventative Services Task
PVH periventricular hemorrhage Force
PVR pulmonary vasculature resistance VBAC vaginal birth after caesarean
qd once a day VDRL venereal disease research laboratory
qid four times per day VSD ventricular septal defect
qhs before bedtime VTE venous thromboembolism
QS quadruple screen WHO World Health Organization
RBC red blood cell
1
HYPERTENSIVE DISORDERS
Amanda Roman
Chronic hypertension
Key points
• Chronic hypertension (CHTN) is defined as either a his-
tory of hypertension preceding the pregnancy or a blood
pressure (BP) ≥140/90 prior to 20 weeks’ gestation.
• Severe CHTN has been defined as systolic blood pres-
sure (SBP) ≥160 mmHg or diastolic blood pressure (DBP)
≥110 mmHg.
• High-risk CHTN has been defined in pregnancy as that
associated with secondary hypertension, target organ
damage (left ventricular dysfunction, retinopathy, dys-
lipidemia, microvascular disease, prior stroke), mater-
nal age >40, previous pregnancy loss, SBP ≥180, or DBP
≥110 mmHg.
• Maternal complications of CHTN include worsening
HTN; superimposed pre-eclampsia; severe pre-eclampsia;
eclampsia, HELLP (Hemolysis, Elevated Liver enzymes
and Low Platelet count) syndrome; cesarean delivery, and
(uncommonly) pulmonary edema, hypertensive enceph-
alopathy, retinopathy, cerebral hemorrhage, and acute
renal failure.
• Fetal complications of CHTN: Fetal growth restriction
(FGR); oligohydramnios; placental abruption; preterm
birth (PTB); and perinatal death.
• Prevention (mostly preconception) consists of exercise,
weight reduction, proper diet, and restriction of sodium
intake.
• In addition to history and physical examination, initial
evaluation may include liver function tests (LFTs), plate-
let count, creatinine, urine analysis, 24-hour urine for
total protein (and creatinine clearance). Women with
high-risk, severe, or long-standing HTN may need an
electrocardiogram (EKG) and echocardiogram, as well. If
hypertension is newly diagnosed and has not been evalu-
ated previously, a medical consult may be indicated to
assess for possible etiologic factors (renal artery stenosis,
pheochromocytoma, hyperaldosteronism, etc.).
• There is insufficient evidence to assess bed rest for man-
aging CHTN in pregnancy.
• Blood pressure decreases physiologically in the first and sec-
ond trimester in pregnancy, with its nadir at 16–18 weeks
of gestation, especially in women with CHTN. As blood
pressure is usually <140/90 mmHg at the first visit for
hypertensive women, often antihypertensive drugs do
not need to be increased. BP will usually increase again
in the third trimester, leading to workup for pre-eclampsia
and, if absent, restarting of antihypertensive drugs.
• Antihypertensive medications in pregnancy are recom-
mended in cases with severe HTN: SBP ≥160 or DBP
DOI: 10.1201/9781003099062-1
≥100 on two occasions. The goal is usually to maintain a
BP of around 140–150/90–100 mmHg. With end-organ
damage such as renal disease, diabetes with vascular
disease, or left ventricular dysfunction, these thresh-
olds should probably be lowered to <140/90.
• On the basis of limited trial data, labetalol and nifedip-
ine are the current antihypertensive drugs most used
by experts. Labetalol dosing can start at 100 mg twice a
day, with a maximum dose of 2400 mg a day. Nifedipine
is started at 10 mg twice a day, or 30 mg XL once a day,
with a maximum dose of 120 mg/day. Angiotensin-
converting enzyme (ACE) inhibitors are contraindicated
in pregnancy.
Diagnosis/Definition
Chronic hypertension in pregnancy (CHTN) is defined as
either a history of hypertension preceding the pregnancy
or a blood pressure ≥140/90 prior to 20 weeks’ gestation
(Table 1.1). Though controversial, the 5th Korotkoff sound is used
for the diastolic reading. Careful consideration should be taken
to appropriate BP measuring technique. Blood pressure measure-
ments can be obtained using a manual or an automated cuff with
the patient in the right upper arm, sitting position, resting for at
least 10 minutes, avoid caffeinated beverages and use of appro-
priate size cuff. Severe CHTN is defined as SBP ≥160 mmHg
or DBP ≥110 mmHg. Guidelines from the American College of
Cardiology (ACC) and the American Heart Association (AHA)
have changed the criteria for diagnosing hypertension in non-
pregnant adults [1]. These recommendations include classifying
blood pressure into four categories: (1) normal (SBP <120 mmHg
and DBP <80 mmHg); (2) elevated (SBP of 120–129 mmHg and
DBP <80 mmHg); (3) stage 1 hypertension (SBP of 130–139 mmHg
or DBP of 80–89 mmHg); and (4) stage 2 hypertension (SBP of
≥140 mmHg or DBP of ≥90 mmHg) (Table 1.2). These changes
were made to assist in clinical and public health decision mak-
ing and reflect data to suggest modifiable long-term cardiovas-
cular risk even in the elevated and stage 1 hypertension ranges.
However, ACOG continue their recommendation for diagnosis of
SBP of ≥140 mmHg or DBP of ≥90 mmHg [2].
Home blood pressure monitoring
Telehealth, using text-based technology platform to support
home blood pressure monitoring, have shown to be a potential
solution for improving care in women with hypertensive disor-
ders [3]. Women perceived the telehealth remote intervention was
a safe, easy to use and an overall satisfying method for antepar-
tum and postpartum blood pressure monitoring [4]. However, the
home blood pressure devices are sold without formal validation
of accuracy, and reviewing for equipment adequacy, especially
cuff size and teaching appropriate technique are limitations of
this clinical practice [5].
1
2 Maternal-Fetal Evidence Based Guidelines

TABLE 1.1: Definitions and Diagnostic Criteria for Hypertensive Disorders of Pregnancy
Chronic hypertension in pregnancy
Either a history of hypertension (HTN) preceding the pregnancy with or without antihypertensive medication or a blood pressure ≥140/90 prior to 20
weeks’ gestation

Gestational hypertension
Sustained (on at least two occasions, 6 hr apart) BP ≥140/90 after 20 wk, without proteinuria, other signs or symptoms of pre-eclampsia, or a prior
history of HTN.

Pre-eclampsia without severe features (‘mild pre-eclampsia’)

Sustained (at least twice, 6 hr but not >7 days apart) BP ≥ 140/90 mmHg and proteinuria (≥300 mg in 24 hr in a woman without prior proteinuria)
after 20 wk of gestation in a woman with previously normal blood pressure

Superimposed pre-eclampsia
One or more of the following criteria:

• New onset of proteinuria (≥300 mg in 24 hr, without prior proteinuria) after 20 weeks in a woman with chronic HTN or sudden increase in
proteinuria in a woman with known proteinuria before or early in pregnancy.
• A sudden increase in hypertension previously well controlled or escalation of antihypertensive medication to control BP.

Superimposed pre-eclampsia with severe features

One or more of the following criteria:

• Severe range of BP (≥160/110 mmHg) despite escalation of antihypertensive medication

• Platelet count <100,000/mm3
• Increased hepatic transaminases (AST and/or ALT) two times of the upper limit of normal concentration at a particular laboratory
• New onset or worsening renal insufficiency (creatinine ≥1.1 mg/dL or a doubling of the serum creatinine)
• Pulmonary edema
• Persistent neurological symptoms (e.g. headache, visual changes)

Pre-eclampsia with severe features (‘severe pre-eclampsia’)

Pre-eclampsia, with any one of the following criteria:

• BP ≥160/110 mmHg (two occasions, >4 hr apart)

• Thrombocytopenia (platelets <100,000/mm3), and/or evidence of microangiopathic hemolytic anemia
• Increased hepatic transaminases (AST and/or ALT) two times of the upper limit of normal concentration at a particular laboratory
• Progressive renal insufficiency (creatinine ≥1.1 mg/dL or a doubling of the serum creatinine or oliguria (<500 mL urine in 24 hr) in absence of
other renal disease.
• Persistent headache or other cerebral or visual disturbances (including grand mal seizures)
• Persistent epigastric (or right upper quadrant) pain
• Pulmonary edema or cyanosis

HELLP syndrome
Tennessee Classification (most commonly used)

• Hemolysis as evidenced by an abnormal peripheral smear in addition to either serum LDH >600 IU/L, or total bilirubin ≥1.2 mg/dL (≥20.52
μmol/L)
• Elevated liver enzymes, as evidenced by an AST or ALT two times of the upper limit of normal concentration at a particular laboratory
• Platelets <100,000 cells/mm3.

If all the criteria are met, the syndrome is defined “complete”; if only one or two criteria are present, the term “partial HELLP” is preferred.

Subclassification: Mississippi HELLP Classification System

• Class 1: HELLP syndrome (severe thrombocytopenia): Platelet count ≤50,000 cells/mm3 + LDH >600 IU/L and AST or ALT ≥70 IU/L
• Class 2: HELLP syndrome (moderate thrombocytopenia): Platelet count >50,000 but ≤100,000 cells/mm3 + LDH >600 IU/L and AST or ALT
≥70 IU/L
• Class 3: HELLP syndrome (mild thrombocytopenia): Platelet count >100,000 but ≤150,000 cells/mm3 + LDH >600 IU/L and AST or ALT
≥40 IU/L

Eclampsia

• Seizures (grand mal) in the presence of pre-eclampsia and/or HELLP syndrome.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; hr, hours; HELLP, hemolysis, elevated liver enzymes, low platelets; LDH,
lactase dehydrogenase; wk, weeks.
Hypertensive Disorders
TABLE 1.2: Categories of BP in Adults (Individuals with
Systolic and Diastolic Readings in Two Categories
Should Be Designated to the Higher Category),
Based on an Average of Two or More Careful
Readings Obtained on Two or More Occasions
Category Systolic (mmHg) Diastolic (mmHg)
Normal <120 and <80
Elevated 120–129 and <80
Hypertension stage 1 130–139 or 80–89
Hypertension stage 2 ≥140 or ≥90
Source: From Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the
prevention, detection, evaluation, and management of high blood pres-
sure in adults: a report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guidelines. J Am Coll
Cardiol 2018;71:e127–248. Ref. [1], with permission.
Epidemiology/Incidence
CHTN occurs in about 1–5% of pregnant women. CHTN in preg-
nancy is the second leading cause of maternal mortality in the
United States, accounting for about 15% of such deaths. The rate
of maternal CHTN increased by 67% from 2000 to 2009, with
the largest increase (87%) among African American women. This
increase is largely secondary to obesity and advance maternal age
[6]. Hypertensive disorders such as CHTN, gestational hyperten-
sion, pre-eclampsia with or without severe features, or HELLP
syndrome occur in 12–22% of pregnancies.
Etiology/Basic pathophysiology
CHTN mostly develops as a complex quantitative trait affected by
both genetic and environmental factors. Most women have essen-
tial or primary hypertension, around 10% may have underlying
renal, vascular or endocrine disease.
Classification
Severe CHTN in pregnancy has been defined as SBP ≥160 mmHg,
or DBP ≥110 mmHg, at least two measurements 4 hours apart [7].
High-risk CHTN has been defined in pregnancy as that associ-
ated with secondary hypertension, target organ damage (left
ventricular dysfunction, retinopathy, dyslipidemia, maternal
age >40 years, microvascular disease, prior stroke), previous
loss, SBP ≥180 mmHg or DBP ≥110 mmHg or other maternal
diseases like obesity [8] and/or diabetes mellitus. For gesta-
tional HTN, see later in this chapter.
Risk factors/Associations
Renal disease (most common cause of secondary CHTN); colla-
gen vascular disease; antiphospholipid syndrome; diabetes; and
other disorders such as thyrotoxicosis, Cushing’s disease, hyper-
aldosteronism, pheochromocytoma, or coarctation of the aorta.
Complications
Maternal
Worsening CHTN, superimposed pre-eclampsia (20–50%) [9,
10] with or without severe features, eclampsia, HELLP syn-
drome, gestational diabetes and cesarean delivery. Pulmonary
3
edema, hypertensive encephalopathy, retinopathy, cerebral
hemorrhage, and acute renal failure were five- to six-fold higher
than normotensive women, but more common with women with
severe uncontrolled CHTN [2].
Fetal
Growth restriction (8–15%); oligohydramnios, placental
abruption (0.7–1.5%, about a two-fold increase), PTB (12–34%),
and perinatal death (two- to four-fold increase). Most of the
preterm deliveries are indicated due to maternal or fetal compli-
cation rather than spontaneous preterm deliveries. All of these
complications have higher incidences with severe or high-risk
CHTN.
Implications of new ACC/AHA guidelines
The new guidelines recommendations for non-pregnant adults
were made to suggest modifiable long-term cardiovascular risk
even in the stage 1 hypertension (SBP 130–139 mmHg or SBP
80–89 mmHg). Secondary analysis of a RCT of low-dose aspi-
rin in the prevention of pre-eclampsia evaluated the outcomes in
the placebo patients with non-pregnant stage 1 hypertension and
they had higher risk of pre-eclampsia (15.3% vs. 5.4%, RR: 2.66,
95% CI 1.56–4.54, P < .001), gestational diabetes, (6.1% vs. 2.5%,
P = .03) and indicated preterm birth (4.2% vs. 1.1%, P=.01) [11].
However, low-dose aspirin, did not appear to lower the risk of
pre-eclampsia or other adverse outcomes in this group of women.
Similar findings were seen in retrospective studies, 1318 (63.0%)
normotensive women versus 772 (37.0%) stage I hypertensive after
20 weeks the risk of any pre-eclampsia (aRR: 2.41 [2.02–2.85]) and
pre-eclampsia with severe features aRR: 2.93 (1.76–4.79) [12].
Management
Principles
Pregnancy is characterized by increased blood volume, decreased
colloid oncotic pressure (see also Chapter 3, Obstetric Evidence
Based Guidelines). Physiologic BP decrease in first and second
trimester may mask CHTN.
Initial evaluation/Workup
History. Antihypertensive drugs, prior workup, end-organ dam-
age, prior obstetrical history, family history of renal or cardiac
disease.
Physical examination. Blood pressure, cardiac murmurs,
edema.
Laboratory tests. Baseline values may be useful to be able to
diagnose secondary causes of CHTN and to compare them in
cases of possible superimposed pre-eclampsia: Liver function test
(LFT), platelets, creatinine, urine analysis, 24-hour urine for
total protein (and creatinine clearance), antinuclear antibodies
(ANA), anticardiolipin antibody (ACA), and lupus anticoagulant
(LA) (see also Chapter 23). An early glucose challenge test may be
indicated. Coagulation studies (especially fibrinogen) are usually
not indicated, except in specific severe cases. Creatinine clear-
ance (mL/min) is calculated as follows:
Urine creatinine(mg/dL) × Total urine volume(mL)
Serum(mg/dL) × 1440minutes
Other tests. Maternal EKG, echocardiogram, and ophthal-
mological examination are suggested, especially in women with
long-standing, high-risk, or severe hypertension. Renal ultra-
sound to rule out polycystic kidney disease or obstructive disease
4 Maternal-Fetal Evidence Based Guidelines
causing renal failure may be considered in cases of suspected
obstructive uropathy, or strong family history of kidney disease.
Also consider toxicology studies, as alcohol, amphetamines,
Ecstasy (MDMA and derivatives), and cocaine are associated
with hypertension.
Workup
It is important to identify cardiovascular risk factors or any
reversible cause of hypertension, and assess for target organ dam-
age or cardiovascular disease. Reversible causes include chronic
kidney disease, coarctation of the aorta, Cushing’s syndrome,
drug-induced/related causes, pheochromocytoma, hyperaldo-
steronism, renovascular hypertension (renal artery stenosis),
thyroid/parathyroid disease, and sleep apnea. If hypertension is
newly diagnosed and has not been evaluated previously, a medi-
cal consult may be indicated to assess for any of these factors.
Secondary hypertension, target organ damage (left ventricular
dysfunction, retinopathy, dyslipidemia, renal disease, microvas-
cular disease, prior stroke), maternal age >40 years, previous loss,
SBP ≥180 or DBP ≥110 mmHg are associated with higher risks in
pregnancy.
Prevention
In women with mild hypertension, gestational hyperten-
sive disorders, or a family history of hypertensive disorders,
30 minutes of exercise three times a week may decrease DBP,
as per a very small trial [13]. Maintaining ideal body weight
and preconception weight reduction is recommended if over-
weight or obese women. A proper diet should be rich in fruits,
vegetables, and low-fat dairy foods, with reduced saturated and
total fats. Restriction of sodium intake to <2.4 g sodium daily
intake, recommended for essential hypertension, is beneficial
in non-pregnant adults. Use of alcohol and tobacco is strongly
discouraged.
Screening/Diagnosis
Initial BP evaluation may help to identify women with chronic
hypertension, while third-trimester blood pressure readings aid
in pre-eclampsia screening. A BP of ≥120/80 mmHg in the first
or second trimester is not normal, and associated with later
risks of pre-eclampsia (Table 1.3). Blood pressure should be
taken properly. Appropriate measurement of BP includes using
Korotkoff phase V, appropriate cuff size (length 1.5 × upper-arm
circumference, or a cuff with a bladder that encircles ≥80% of the
arm), and position, so that the woman’s arm is at the level of the
heart (sitting up), at rest.
TABLE 1.3: Selected Clinical Risk Factors
for Pre-Eclampsia
Primiparity
Primipaternity
Previous pre-eclamptic pregnancy
Chronic hypertension
Chronic renal disease
History of thrombophilia
In vitro fertilization
Family history of pre-eclampsia
Pregestational diabetes mellitus
Obesity
Systemic lupus erythematosus
Advanced maternal age (>40 years)
Preconception counseling
There are significant risks associated with hypertension and pre-
eclampsia in pregnancy. All women should be counseled appro-
priately regarding the possible complications and preventive and
management strategies for hypertensive disorders in pregnancy.
ACE inhibitors and angiotensin type II (AII) receptor antagonists
should be discontinued. Some beta-blockers need to be replaced.
A complete evaluation and workup, as described earlier, should
be done, especially if she has a several-year history of hyperten-
sion and/or hypertension never fully evaluated. Modifiable asso-
ciated factors should be identified and treated. Baseline tests can
also be obtained for later comparison. Abnormalities should be
addressed and managed appropriately (see specific chapters). If,
for example, serum creatinine (Cr) is >1.4 mg/dL, the woman
should be aware of increased risks in pregnancy (pregnancy/
fetal loss, reduced birth weight, preterm delivery, and accelerated
deterioration of maternal renal disease). Even mild renal disease
(Cr = 1.1–1.4 mg/dL) with uncontrolled HTN is associated with
10 times higher risk of fetal loss (see Chap. 17).
Ambulatory blood pressure monitoring. Often BP monitoring
at home is suggested in pregnancies with CHTN. At present, the
possible advantages and risks of ambulatory blood pressure mon-
itoring during pregnancy, in particular in hypertensive pregnant
women, cannot be defined. Two feasibility small RCTs have been
published (n = 191) [14, 15], larger RCT are needed to support the
use of ambulatory BP monitoring during pregnancy [16].
Three RCTs are underway, two in United Kingdom and one
in The Netherlands. BP-PRESELF RCT: To assess whether home
blood pressure monitoring (HBPM) in women with a history of
pre-eclampsia or HELLP but not CHTN, is a valuable tool for
the early detection of hypertension. Women are randomized
between HPBM or “usual care.” The primary outcome is feasibil-
ity and usability of HBPM after 1 year of follow-up. Secondary
outcomes will be the effectiveness of HPBM to detect hyperten-
sion, the efficacy of BP treatment, quality of life, health-related
symptoms, work ability, and lifestyle behavior. The results of
this study will provide better strategies for timely detection and
prevention of hypertension in women after PE/HELLP [17]. Two
linked trials aim to evaluate whether BP self-monitoring in preg-
nancy improves the detection of elevated BP (BUMP 1, n = 2262)
and whether self-monitoring reduces SBP in women with CHTN
(BUMP 2, n = 512) [18]. Participants will be randomized to self-
monitoring with telemonitoring or usual care. HOTEL trial: The
aim of this study is to compare the effects on patient safety, sat-
isfaction, and cost-effectiveness of hospital care (n = 208) versus
telemonitoring (n = 208) (as an obstetric care strategy in high-
risk pregnancies requiring daily monitoring). Eligible pregnant
women are >26+0 weeks of singleton gestation requiring moni-
toring because of pre-eclampsia (hypertension with proteinuria),
FGR, PPROM without contractions, recurrent decreased fetal
movements or a history of IUFD in a previous pregnancy [19].
Therapy
Lifestyle changes and bed rest. There are no trials to assess life-
style changes other than bed rest in pregnancy. Weight reduction
is not recommended. The diet should be rich in fruits, vegetables,
low-fat dairy foods, with reduced saturated and total fats and
with sodium intake restricted to <2.4-g sodium daily.
There is insufficient evidence to demonstrate any differences
between bed rest (in or out of the hospital) for reported outcomes
overall. Compared with routine activity at home, some bed rest
in hospital for nonproteinuric hypertension is associated with
Hypertensive Disorders
a 42% reduced risk of severe hypertension and a borderline 47%
reduction in risk of PTB in one trial [20]. The trial did not address
possible adverse effects of bed rest. Three times more women in
the bed rest group opted not to have the same management in
future pregnancies, if the choice is given. There are no significant
differences for any other outcomes [20].
Antihypertensive drugs
Common types
• Labetalol (alpha- and beta-blocker): On the basis of limited
trial data (see “Effectiveness’), labetalol is the current drug
of choice of many experts [7, 21, 22]. Labetalol has an addi-
tional arteriolar vasodilating action that lowers peripheral
resistance. It has a rapid onset of action (within 2 hours).
Dosing can start at 100 mg twice a day, with maximum
dose of 2400 mg a day in 2–3 divided doses. As with other
drugs, generally a different agent should not be added until
maximum doses of the first drug are achieved. Labetalol
has been associated with elevated liver enzymes in rare
cases (which may be confused with HELLP syndrome), as
well as lethargy, fatigue, sleep disorders, orthostatic hypo-
tension, and bronchoconstriction. Labetalol should be
avoided in women with asthma, heart disease, or conges-
tive heart failure.
• Calcium channel blockers: Calcium channel blockers
are frequently used as first or second option for CHTN
in pregnancy. There is no known association with birth
defects, with reassuring long-term follow-up of babies
up to 1.5 years. Nifedipine is not associated with adverse
perinatal outcome [23]. Nifedipine can be started at 10 mg
twice a day, with maximum dose 120 mg/day. Long-acting
nifedipine XL can be started at 30 mg, with 120 mg as
maximum dose. Very rare cases of neuromuscular block-
ade have been reported when nifedipine is used simultane-
ously with magnesium sulfate. This blockade is reversible
with 10% solution of calcium gluconate. Although amlo-
dipine is widely used in non-pregnant individuals with
hypertension, there are sparse data of its use in pregnancy
[24]. Common side effects of nifedipine and amlodipine
include dizziness, headache, peripheral edema, flushing,
tachycardia, and rash. Other calcium antagonists such as
verapamil and diltiazem have been used. Common side
effects of verapamil and diltiazem are: Dizziness, head-
ache, edema, constipation, bradycardia, slow atrioventric-
ular conduction, hearth failure, lupus like rash. They need
to be used with caution in women who are also taking a
beta blocker.
• Beta-blockers: The safety of beta-adrenergic blockers is
somewhat controversial due to reports of premature labor,
FGR, neonatal apnea, bradycardia, and hypoglycemia in
pregnancy compared to placebo, and with higher mortality
in non-pregnant adults compared to other agents, should
probably be avoided. There is insufficient evidence to
assess if other drugs in this class (or even other classes) are
associated with the same effect (see “Effectiveness”).
• Diuretics: Women who use diuretics from early in preg-
nancy do not have the physiologic increase in plasma vol-
ume, which poses a theoretical concern since pre-eclampsia
is associated with reduced plasma volume. Nonetheless,
the reduction in plasma volume associated with diuretics
has not been associated with adverse effects on outcomes.
5
Diuretics are not contraindicated in pregnancy, except in
settings where uteroplacental perfusion is already reduced
(i.e., pre-eclampsia and FGR). This is usually the drug of
first choice for some non-pregnant adults and should be
considered as a secondary option in pregnant women.
Women already taking a thiazide or thiazide-like diuretic
who become pregnant can generally continue taking it. The
initial dose of hydrochlorothiazide is usually 12.5 mg twice
a day, with a maximum dose of 50 mg/day. Dose should be
adjusted to prevent hypokalemia. Other diuretics like furo-
semide maybe indicated in women with cardiomyopathy,
history of heart failure or with moderate or severe renal
impairment. Careful electrolyte evaluation should be done
on patient on diuretics.
• ACE inhibitor (or AII receptor antagonists): These drugs are
contraindicated in the first trimester because they might
be associated with a twofold increase in malformations,
and are contraindicated also later in pregnancy because
they are associated with FGR, oligohydramnios, neonatal
renal failure, and neonatal death. Postpartum complica-
tions include oliguria and anuria.
• Methyldopa (Aldomet): This drug was the preferred first-
line agent historically, and the most studied. It is associated
with stable uteroplacental blood flow and fetal hemodynam-
ics, and no long-term adverse effects are seen in exposed
children (up to 7.5 years; best documentation of fetal safety
of any antihypertensive drug). It is a mild antihypertensive
agent and has a slow onset of action (3–6 hours). Liver dis-
ease is a contraindication. Initial dose is usually 250 mg
two to three times a day, with highest dose 500 mg four
times a day (2 g/day). Can be associated with significant
dry mouth, drowsiness, and sedation, when high doses are
required to control blood pressure.
Effectiveness
Mild-to-moderate HTN. Mild-to-moderate HTN is usually
defined in the trials as a SBP of 140–159 mmHg or a DBP of
90–109 mmHg. A Cochrane review published on 2018 included
58 trials (5909 women) to evaluate the management in pregnant
women with mild-to-moderate hypertension (all diagnoses
included), antihypertensive drugs versus placebo were associ-
ated with a 50% reduction in the risk of developing severe
hypertension, but no differences in the risk of developing
pre-eclampsia, PTB < 37 weeks, small for gestational age
(SGA), perinatal death (including miscarriage), or any other
outcomes [25]. Of the included studies, only 10 had dedicated
inclusion of women with CHTN: Similar to the overall find-
ings, in this subgroup of women there was a 43% reduction in
the risk of developing severe hypertension but no changes in
other maternal or perinatal outcome. Beta-blockers and calcium
channel blockers, used together instead of methyldopa, have a
30% reduction in the risk of an episode of severe hypertension
and a 27% overall risk of developing proteinuria/pre-eclampsia.
However, there is insufficient evidence to conclude that one
antihypertensive is better than another [25]. Other meta-
analyses have suggested that women receiving beta-blockers
(atenolol, propranolol) had a significant 38% increase risk in
SGA birth weight and a threefold increase in birth weight <5th
percentile [22, 26–28]. Pooling of randomized controlled tri-
als indicated that no agent significantly affected the incidence
of pre-eclampsia, preterm delivery or perinatal death. The inci-
dence of severe range hypertension and placental abruption were
6 Maternal-Fetal Evidence Based Guidelines

significantly lower with nifedipine and methyldopa. A recent TABLE 1.4: Antihypertensive Medications for Urgent Blood
multicenter international RCT compared “less tight control” to Pressure Control in the Hospital
“tight control” of BP for pregnant women with mild to moderate
Drug Dose Comments
hypertension [14]. The study reported outcomes for 987 women
who were enrolled at 14–33 weeks of gestation; participants had Labetalol 10–20 mg IV, then Considered first-line agent
either chronic (75%) or gestational (25%) nonproteinuric hyper- 20–80 mg every Tachycardia is less common
tension. Women were randomized to either less tight control 20–30 minutes to a and fewer adverse effects
(target DBP 100 mmHg) or tight control (target DBP 85 mmHg) maximum dose of 300 mg, Contraindicated in patients
during pregnancy. The primary outcome of pregnancy loss or or with asthma, heart disease,
need for high-level neonatal care for ≥48 hours did not differ Constant infusion or congestive heart failure
between groups (31.4% vs. 30.7%). The frequency of severe hyper- 1–2 mg/min IV
tension was higher with less-tight control but was not associ- Hydralazine 5 mg IV or IM, then Higher or frequent dosage
ated with any adverse pregnancy outcome such as pre-eclampsia, 5–10 mg IV every associated with maternal
abruption, or composite of “serious maternal complications”. The 20–40 min or hypotension, headaches, and
overall risk of SGA (<10th percentile) was not different between Constant infusion fetal distress—maybe more
groups, aOR:0.78;(0.56–1.08). In the subgroup with chronic 0.5–10 mg/hour common than other agents
hypertension, the risk of SGA was 33% lower with less-tight con- Nifedipine 10–20 mg orally, repeat in May observe tachycardia and
trol (13.9% vs. 19.7%; aOR:0.66; 95% CI 0.44–1.00), although this 30 minutes if needed; then headaches
study was underpowered to examine subgroup differences [29]. 10–20 mg every 2–6 hours
In absence of strong evidence of benefits and risks of pharma-
Source: Adapted from Ref. 7.
cologic treatment and SGA, management of pregnant women Abbreviations: IM, intramuscular; IV, intravenously.
with mild-to-moderate chronic hypertension remains uncertain
[7, 21]. An ongoing RCT, Chronic Hypertension and Pregnancy
(CHAP) Project (ClinicalTrials.gov Identifier: NCT02299414) renal complications. The goal is to maintain BP around 140–
will evaluate the benefits and harms of pharmacologic treatment 150/90–100 mmHg.
of mild CHTN in pregnancy (<160/110 mmHg) compared to the There are two indications of antihypertensive medications for
ACOG recommended standard during pregnancy of no treat- women with CHTN: (1) acute lowering of severe HTN in the hos-
ment unless BP is severe. pital (Table 1.4), or (2) chronic treatment in outpatient setting
The task force of hypertension in pregnancy recom- (Table 1.5). Based on finding of the Cochrane systematic review
mends that women with mild to moderate hypertension [30], there is no clear evidence that one antihypertensive is
(SBP ≥140 mmHg but <160 mmHg or DBP ≥90 mmHg but preferable to the others for improving outcome for women
<110 mmHg) without end organ damage should not be treated with very high blood pressure during pregnancy. Therefore,
with pharmacologic agents [1]. the choice of antihypertensive should depend on the expe-
In women with known CHTN well controlled on antihyper- rience and familiarity of an individual clinician with a
tensive medications, discontinuation of the medication during
the first trimester is a reasonable alternative as blood pressure is
TABLE 1.5: Oral Antihypertensive Medications in Pregnant
usually <140/90 at the first visit. Often BP will increase again in
Patients (Outpatient)
the third trimester, leading to workup for pre-eclampsia, and, if
pre-eclampsia is absent, antihypertensive drugs can be restarted. Drug Dosage Comments
For women with CHTN and end-organ damage (renal dis- Labetalol 200–2400 mg/day Well tolerated
ease, diabetes with vascular disease, or left ventricular dys- orally in two or Partial bronchoconstrictive
function), these thresholds should probably be lowered to three divided effects
<140/90 mmHg to avoid progression of the disease during doses Avoid in patients with asthma
pregnancy and associated complications. and congestive heart failure
Severe HTN. Severe HTN is defined as SBP ≥160 mmHg or
Nifedipine 30–120 mg/day Do not use sublingual form
DBP ≥110 mmHg [7]. There is insufficient evidence to assess
orally of a slow
benefits and risks of different antihypertensive drugs for severe
release preparation
CHTN, as most studies that address this question have not be
Methyldopa 0.5–3 g/day orally in Childhood safety data up to
limited to women with CHTN but also have included gesta-
two to three 7 years of age
tional HTN and pre-eclampsia. A Cochrane systematic review
divided doses May not be as affective in
of 35 trials, 3573 women, evaluated the drug treatment for
control of severe
severe HTN during pregnancy [30]. Drug therapy was initiated
hypertension
for DBP ≥100–110 mmHg mostly during the third trimester.
Thiazide diuretics Depends of the Second-line agent
They included few women with CHTN but subgroup analysis
agent Risk of hypokalemia
was not performed. The Task Force of hypertension in preg-
nancy recommends to start antihypertensive therapy at SBP Angiotensin- Associated with fetal
>160 mmHg or DBP >105 mmHg on at least two occasions, converting anomalies
with a goal for SBP between 120 and 60 mmHg and DBP enzyme inhibitors/ Contraindicated in pregnancy
between 80 and 105 mmHg, avoiding overly aggressive BP angiotensin and preconception period
lowering due to concerns of decreased uteroplacental blood receptor blockers Postpartum oliguria and
flow [1]. This is to decrease the risk of cerebrovascular acci- anuria
dents, and cardiovascular (e.g., congestive heart failure) and Source: Adapted from Ref. [7].
Hypertensive Disorders
particular drug and on what is known about adverse maternal
and fetal side effects. Three drugs (high-dose diazoxide [31],
ketanserin, and nimodipine) have serious disadvantages and
so should probably be avoided for women with very high blood
pressure during pregnancy.
Antepartum testing
Increased perinatal morbidity and mortality is mainly attributed
to severe CHTN and high risk CHTN with end organ damage or
secondary HTN. The risk of FGR with uncomplicated CHTN is 8%
to 15%, while with severe and high risk CHTN the risk increases
up to 40%. Early detection of FGR can decrease the risk of still-
birth by 20% [32], and the addition of umbilical artery Doppler on
those with suspected FGR decreases perinatal mortality by 29%
[33]. Initial dating ultrasound, preferably in the first trimester
(FTS at 11–14 weeks), anatomy ultrasound at around 18 to 20
weeks, and ultrasound for growth at 28–32 weeks are suggested
for women with uncomplicated CHTN and every month after
anatomy ultrasound on those with severe and high risk CHTN
(see also Chapter 4).
Antenatal testing (usually with weekly nonstress tests) is sug-
gested starting around 32 weeks, especially if poorly controlled,
severe HTN, high risk CHTN, FGR, or superimposed pre-
eclampsia is indicated. Umbilical artery Doppler is recommended
in cases of FGR (see Chap. 44). For uterine artery Doppler, see
section “Pre-eclampsia.”
Delivery
Often PTB (either spontaneous or iatrogenic) occurs because
of complications. In the uncomplicated pregnancy with CHTN,
the pregnancy should probably be delivered by the estimated
date of confinement (EDC). Unfortunately, there are no RCT
evaluating timing of delivery for women with chronic HTN. In
a large population-based cohort study, among women with oth-
erwise uncomplicated chronic hypertension, delivery at 38 or
39 weeks appears to provide the optimal trade-off between the
risk of adverse fetal and adverse neonatal outcomes. The ACOG
Committee of opinion recommends that women with isolated,
uncomplicated CHTN off medications can be delivered between
38 0/7 to 39 6/7 weeks of gestation, while of those on medications
they can be delivered earlier from 37 0/7. In women with CHTN
on medications requiring frequent adjustment of antihyperten-
sive medications consider late preterm delivery starting at 36
0/7 weeks of gestation. No amniocentesis for fetal lung maturity
is needed [34]. Consider late steroid administration for women
diagnosed with superimposed pre-eclampsia with severe features
between 34 0/7 and 36 0/7 weeks [35]. The risk of stillbirth is sig-
nificantly higher at 41 weeks [36].
Anesthesia
See section “Pre-eclampsia,” and also Chapter 11, Obstetric
Evidence Based Guidelines.
Postpartum/Breastfeeding
Methyldopa, labetalol, beta-blockers, calcium channel blockers,
and most other agents are safe with breastfeeding, with the pos-
sible exception of ACE inhibitors, because even low concentra-
tions in breast milk could affect neonatal renal function.
7
Gestational hypertension
Definition
Gestational hypertension (GHTN), formerly known as preg-
nancy-induced hypertension, is defined as sustained (on at least
two occasions, 6 hours apart) BP ≥140/90 after 20 weeks, without
proteinuria, other signs or symptoms of pre-eclampsia, or a prior
history of HTN. Severe GHTN is defined similarly, except that
the cutoffs are ≥160/110 mmHg (Table 1.1).
Incidence
About 6–17% healthy nulliparous women develop GHTN.
Complications
Progression to pre-eclampsia usually is seen in 1–3 weeks.
Severe GHTN is associated with higher morbidities than mild
pre-eclampsia, with incidences of abruption, PTB, and SGA,
similar to severe pre-eclampsia. If GHTN develops before 30
weeks or is severe, there is a high (50%) rate of progression to
pre-eclampsia.
Antenatal management
GHTN is usually associated with good outcomes, similar to low-
risk pregnant women [37], so that close surveillance for devel-
opment of pre-eclampsia, but no other intervention, is usually
needed. Before 37 weeks, in the absence of severe GHTN, pre-
eclampsia with severe features or preterm labor, and in the
presence of reassuring fetal testing, expectant management is
suggested. Outpatient management with close surveillance of
maternal symptoms, BP (suggest daily as outpatient with per-
sonal BP cuff), proteinuria, and laboratory tests is suggested.
Antihypertensive medications for BP <160/110 mmHg, or bed
rest are not recommended. Antepartum surveillance also should
include daily fetal kick counts, ultrasonography fetal growth
assessment every 3–4 weeks, BPP or modified BPP every week
starting at the onset of diagnosis.
Severe GHTN usually requires admission to the hospital at diag-
nosis to increase maternal fetal surveillance. Antihypertensive
medications are recommended in women with SBPs ≥160 mmHg
or DBPs ≥110 mmHg to avoid maternal complications (stroke,
cardiac failure, pulmonary edema, renal impairment, and death).
Drugs of choice for both oral or intravenous administration, and
doses, are described in Tables 1.4 and 1.5 (same recommenda-
tions as discussed earlier in the CHTN section).
Delivery
For women at or beyond 37 weeks with GHTN, delivery is rec-
ommended, rather than continued observation. Compared to
expectant management, induction of labor in women with mostly
(about 66%) gestational hypertension (or pre-eclampsia without
severe features) at 36–41 weeks’ gestation is associated with a
trend for lower incidence of maternal complications (e.g., HELLP,
severe HTN, and pulmonary edema) (RR 0.81, 95% CI 0.63–1.03),
and lower incidence of neonatal pH <7.05 with induction of labor
≥37 weeks [38]. Trends were seen for benefit of induction asso-
ciated with less cesarean delivery and maternal ICU admission.
Magnesium sulfate for seizure prophylaxis is not indicated in
GHTN. Women with severe GHTN requiring antihyperten-
sive medications should be managed as pre-eclampsia with
severe features (see “Pre-eclampsia”). If any of the criteria for
severe features of pre-eclampsia are present, delivery is indicated
at 34 weeks or after (see “Pre-eclampsia”).
8 Maternal-Fetal Evidence Based Guidelines
Postpartum management of women with GHTN requires con-
tinue observation of BPs for 72 hours postpartum and outpatient
follow up in 7–10 days, as there is an increased risk of postpartum
pre-eclampsia/eclampsia and CHTN in these women [1].
Pre-eclampsia
Key points
• Pre-eclampsia is defined as sustained (at least twice, 6 hours
but not >7 days apart) new onset of SBP ≥140 mmHg or
DBP ≥90 mmHg and new onset of proteinuria (≥300 mg
in 24 hours or protein creatinine ratio ≥0.3, or dipstick
reading of more than 1+ (only if other methods are not
available), after 20 weeks of gestation in a woman with
previously normal blood pressure.
• Pre-eclampsia can be diagnosed as well if there is new
onset of SBP ≥140 mmHg or DBP ≥90 mmHg in absence
of proteinuria but with new onset of any of the follow-
ing: Platelets <100,000/mm3, serum creatinine level
≥1.1 mg/dL or doubling of the previous creatinine level
in absence of other renal disease, elevated aspartate ami-
notransferase (AST) and/or alanine aminotransferase
(ALT) twice the reference level, pulmonary edema or per-
sistent headache or other cerebral or visual disturbances.
• Superimposed pre-eclampsia (in a woman with known
well controlled CHTN) is defined as the new onset of
proteinuria (≥300 mg in 24 hours or protein/creatinine
ratio ≥0.3) after 20 weeks or significant increase in preex-
isting proteinuria or sudden exacerbation of BPs or wors-
ening HTN requiring increased dose of antihypertensive
medications on more than two occasions.
• Pre-eclampsia with severe features (“severe pre-eclampsia”)
is defined as pre-eclampsia with any of the following: SBP
≥160 mmHg or DBP ≥110 mmHg or higher in two occa-
sions at least 4 hours apart while in bed rest, platelets
<100,000/mm3, progressive renal disease as diagnosed by
elevated serum creatinine level ≥1.1 mg/dL or doubling of
the previous creatinine level in absence of other renal dis-
ease, impaired liver function as indicated by elevated AST
and/or ALT twice the reference level, severe right upper
quadrant or epigastric pain not accounted by other etiolo-
gies, pulmonary edema, or new onset of persistent head-
ache or other cerebral or visual disturbances.
• HELLP syndrome is defined as hemolysis, elevated liver
enzymes (AST or ALT) twice the reference level, and
platelets <100,000/mm3.
• Eclampsia is defined as new onset of grand mal seizures
in the presence of pre-eclampsia and/or HELLP syndrome.
Eclampsia can occur before, during and after labor.
• Maternal complications of pre-eclampsia include (mater-
nal) HELLP syndrome, disseminated intravascular coag-
ulation (DIC), pulmonary edema, abruptio placentae,
renal failure, cardiac failure, seizures (eclampsia), cere-
bral hemorrhage, liver hemorrhage, and maternal death.
• Fetal complications of pre-eclampsia include: FGR, PTB,
perinatal death, hypoxemia, or neurologic injury.
• Low-dose aspirin (75–150 mg/day) given to women
with risk factors for pre-eclampsia is associated with a
17% reduction in the risk of pre-eclampsia, a small (8%)
reduction in the risk of PTB <37 weeks, a 10% reduc-
tion in SGA babies, and a 14% reduction in perinatal
deaths.
• If low-dose aspirin is given anyway because of a history
of pre-eclampsia, then uterine artery Doppler screening
may not be necessary or beneficial. It is recommended to
start low-dose aspirin early (≤16 weeks) in women with
high risk for pre-eclampsia, as it is associated with a 90%
reduction in severe pre-eclampsia, a 69% reduction in
gestational hypertension, and a 49% reduction in intra-
uterine growth restriction (IUGR).
• Calcium supplementation is associated with a 35% reduc-
tion in the incidence of high blood pressure and a 55%
reduction in the risk of pre-eclampsia. This effect is
greatest in women with low baseline calcium intake or high
risk of pre-eclampsia, in which calcium supplementation
(1.5–2 g/day) may be indicated.
• Antioxidant therapy with vitamin C 1000 mg/day and
vitamin E 400 IU/day starting in the early second tri-
mester is not associated with a reduction in risk of pre-
eclampsia. Antioxidant therapy is not recommended for
prevention of pre-eclampsia.
• Diuretics or dietary salt restriction during pregnancy
diuretics are not associated with reduction in the incidence
of pre-eclampsia.
• Bed rest or the restriction of other physical activity should
not be used for the primary prevention of pre-eclampsia
and its complications.
• In women with risk factors for pre-eclampsia the baseline
values should be obtained at first prenatal visit: Complete
history and physical examination (BP), AST and ALT,
platelets, creatinine, 24-hour urine for total protein (and
creatinine clearance), and/or protein/creatinine ratio.
• Indications for delivery: Pre-eclampsia without severe
features at ≥37 weeks. Pre-eclampsia with severe features
(severe pre-eclampsia) at ≥34 weeks warrants expeditious
delivery after maternal stabilization. Before 34 weeks,
delivery within 48 hours after completion of corticoste-
roid administration is suggested for uncontrollable BP in
spite of continuing increase in antihypertensive drugs, per-
sistent headache and/or visual/CNS symptoms, epigastric
pain, vaginal bleeding, persistent oliguria, preterm labor,
PPROM, platelets <100,000/mm3 or elevated liver enzymes
(partial or complete HELLP syndrome), non-reassuring
fetal heart rate, or reversed umbilical artery end-diastolic
flow ≥32 weeks. Immediate delivery even before completion
of steroids is recommended in case of eclampsia, pulmonary
edema, acute renal failure, DIC, suspected abruptio pla-
centae, or non-reassuring fetal status.
• Magnesium is the drug of choice for prevention of
eclampsia, it is superior to phenytoin and diazepam.
Magnesium is associated with a 59% reduction in the
risk of eclampsia, a 36% reduction in abruption, and a
non-­statistically significant but clinically important 46%
reduction in maternal death. The reduction is similar
regardless of severity of pre-eclampsia, with about 400
women who need to be treated to prevent eclampsia for mild
pre-eclampsia, 71 for severe pre-eclampsia, and 36 for pre-
eclampsia with central nervous system (CNS) symptoms.
• Magnesium is recommended in women with pre-
eclampsia with severe features. The intravenous route is
Hypertensive Disorders
recommended, initiating with a loading dose of 4–6 g fol-
lowed by maintenance dose of 1–2 g/hour, usually given
at least in active labor and 24 hours postpartum, with-
out mandatory serum monitoring. When cesarean delivery
is indicated, it is recommended to continue magnesium
during the procedure, as discontinuing magnesium may
increase the risk of postpartum eclampsia.
• Antihypertensive drugs for the treatment of pre-eclampsia
with severe HTN (SBP ≥160 and/or DBP ≥110) are usu-
ally labetalol, nifedipine, or hydralazine.
• Antihypertensive therapy may decrease progression to
severe hypertension by 50%, but there is no effect on the
risk of developing severe pre-eclampsia may also be associ-
ated with impairment of fetal growth.
• There is insufficient evidence to recommend the use of
dexamethasone or other steroids for therapy specific for
HELLP syndrome.
• In about 15% of cases, hypertension or proteinuria may
be absent before eclampsia. A high index of suspicion
for eclampsia should be maintained in all cases of hyper-
tensive disorders in pregnancy, in particular those with
CNS symptoms (e.g. headache and visual disturbances).
• In eclampsia (see “Eclampsia”), the first priorities are air-
way, breathing, and circulation.
• Women with prior pre-eclampsia or its complications
are not only at increased risk of recurrence, but also at
increased risk of cardiovascular disease in the future.
Diagnoses/Definitions
Pre-eclampsia
Sustained (at least twice, 6 hours but not >7 days apart) BP ≥140 or
≥90 mmHg and new onset of proteinuria (≥300 mg in 24 hours
or urinary protein creatinine ratio (UPC) ≥0.3) after 20 weeks
of gestation in a woman with previously normal blood pressure
and normal protein in the urine (Table 1.1) [7, 39, 40]. BP should be
measured with adequate cuff size, position of the heart at arm level,
and with calibrated equipment. The accuracy of dipstick urinalysis
with a 1+ (0.1 g/L) threshold in the prediction of significant protein-
uria by 24-hour urine is poor [41]. Pre-eclampsia without severe
features (“mild pre-eclampsia”) is usually defined as pre-eclampsia
not meeting severe criteria (see “Pre-eclampsia with severe fea-
tures”). “Toxemia” is a lay term. The “30–15 rule” and edema have
been eliminated as criteria to diagnose pre-eclampsia [40].
Superimposed pre-eclampsia
One or more of the following criteria:
• New onset of proteinuria (≥300 mg in 24 hours, without
prior proteinuria) after 20 weeks in a woman with chronic
HTN
• Sudden increase in proteinuria in a woman with known
proteinuria before or early in pregnancy.
• A sudden increase in hypertension previously well controlled
or escalation of antihypertensive medication to control BP.
Superimposed pre-eclampsia with severe features
One or more of the following are present
• Severe range of BP (≥160/110 mmHg) despite escalation of
antihypertensive medication
• Platelet count <100,000/mm3
9
• Increased hepatic transaminases (AST and/or ALT) two
times of the upper limit of normal concentration at a par-
ticular laboratory
• New onset or worsening renal insufficiency (creatinine
≥1.1 mg/dL or a doubling of the serum creatinine.
• Pulmonary edema
• Persistent neurological symptoms (e.g. headache, visual
changes)
Severe pre-eclampsia or pre-eclampsia
with severe features
Any of the following criteria:
• BP ≥160/110 mmHg (two occasions, ≥4 hours apart)
• Thrombocytopenia, Platelets <100,000/mm3 (and/or evi-
dence of microangiopathic hemolytic anemia)
• Increased hepatic transaminases (AST and/or ALT) two
times of the upper limit of normal concentration at a par-
ticular laboratory
• Progressive renal insufficiency (creatinine ≥1.1 mg/dL or
a doubling of the serum creatinine or oliguria (<500 mL
urine in 24 hours) in absence of other renal disease.
• Persistent headache or other cerebral or visual distur-
bances (including grand mal seizures)
• Persistent epigastric (or right upper quadrant) pain
• Pulmonary edema or cyanosis
Proteinuria ≥5 g/24 hours was removed as criteria of severe
pre-eclampsia as expectant management was not associated with
worsening maternal or neonatal outcome, and resolution of renal
dysfunction occurred in all women after delivery [42, 43].
HELLP syndrome
HELLP syndrome can have an antepartum or postpartum onset
and it is associated with increased maternal morbidity and mor-
tality. For HELLP syndrome to be diagnosed, there must be
micro-angiopathic hemolysis, thrombocytopenia, and abnor-
malities of liver function. There is no consensus, however, on the
classification criteria and the specific thresholds of hematologic
and biochemical values to use in establishing the diagnosis of
HELLP syndrome. The following criteria are most commonly
used (Tennessee Classification): Hemolysis as evidenced by an
abnormal peripheral smear in addition to either serum lactate
dehydrogenase (LDH) >600 IU/L, or total bilirubin ≥1.2 mg/dL
(≥20.52 μmol/L); elevated liver enzymes, (AST and/or ALT) two
times of the upper limit of normal concentration at a particu-
lar laboratory, and platelets <100,000 cells/mm3 [44]. If all the
criteria are met, the syndrome can be also called “complete”; if
only one or two criteria are present, the term “partial HELLP” is
preferred.
Eclampsia
New onset of grand mal seizures in the presence of pre-eclampsia
and/or HELLP syndrome.
Symptoms
Persistent headache or other cerebral or visual disturbances,
altered mental status (including grand mal seizures), persis-
tent epigastric (or right upper quadrant) pain, severe range BPs.
Massive proteinuria and/or edema maybe present.
10
Epidemiology/Incidence
In healthy nulliparous women, about 7% (most occur at term and
are mild).
Etiology/Basic pathophysiology
Pre-eclampsia is a systemic disease of unknown etiology. It
is associated with endothelial disease, with vasospasm and
sympathetic over activity. Trophoblastic invasion by the
placenta into the spiral arteries of the uterus is incomplete,
resulting in reduced perfusion. Hypoxia, free radicals, oxi-
dative stress, and activation of endothelium are characteris-
tic. Thromboxane (which is associated with vasoconstriction,
platelet aggregation, and decreased uteroplacental blood flow)
is increased, while prostacyclin (which has opposite effects) is
decreased. FGR is also theorized to develop as a result of defec-
tive placentation and the imbalance between prostacyclin and
thromboxane.
• Alterations of the immune response.
• Vascular: Vasospasm and subsequent hemoconcentration
are associated with contraction of intravascular space; cap-
illary leak and decreased colloid oncotic pressure may pre-
dispose to pulmonary edema.
• Cardiac: Usually reduced cardiac output, decreased plasma
volume, increased systemic vascular resistance.
• Hematological: Thrombocytopenia and hemolysis with
HELLP syndrome (also elevated LDH), disseminated intra-
vascular coagulation (DIC).
• Hepatic: Elevated AST, ALT; subcapsular hematoma and
liver rupture.
• CNS: Eclampsia, intracranial hemorrhage, headache,
blurred vision, scotomata, hyperreflexia, temporary
blindness.
• Renal: Vasospasm, hemoconcentration, and decreased
renal blood flow resulting in oliguria (rarely leading to
acute tubular necrosis, possibly leading to acute renal fail-
ure), proteinuria and hematuria.
• Fetal: Impaired uteroplacental blood flow [FGR, oligohy-
dramnios, abruption, and nonreassuring fetal heart rate
testing (NRFHT)].
Classification
See without severe features (“mild”) versus with severe features
(“severe”), discussed earlier.
Risk factors/Associations
Nulliparity, limited sperm exposure, primipaternity, “dangerous
father” (for pre-eclampsia), donor eggs and/or sperm, multifetal
gestation, prior pre-eclampsia, chronic HTN, diabetes, vascular
and connective tissue disease, nephropathy, anti-phospholipid
syndrome (APS), obesity, insulin resistance, young maternal age
or advanced maternal age, African American race, family his-
tory of pre-eclampsia, maternal low birth weight, low socioeco-
nomic status, increased soluble fms-like tyrosine kinase 1 (sFlt-1),
reduced placental growth factor, and higher fetal cells in mater-
nal circulation. A change in partner is usually associated with a
protective effect if prior pregnancy had pre-eclampsia. Previous
pregnancy with same partner seems to be protective, albeit for
Maternal-Fetal Evidence Based Guidelines
a short (one to three years) time. Smoking is associated with
decreased incidence of pre-eclampsia. The presence of inherited
thrombophilias such as factor V Leiden, prothrombin 20210, and
MTHFR has not been associated with pre-eclampsia when the
best studies (prospective, large, etc.) are evaluated (see Chap. 27,
and Table 27.3). While antiphospholipid antibodies, in particu-
lar ACA, are associated with an increased risk of pre-eclampsia,
screening is not suggested as no therapy has been evaluated in
these cases (see Chap. 26).
Prediction
Despite the variety of methods studied, there are still no sensitive
prediction tests for pre-eclampsia shown to alter outcome. No
single test or combination of tests reliably predicts pre-eclampsia,
early onset of pre-eclampsia or progression of GHTN or mild pre-
eclampsia into severe pre-eclampsia.
Uterine artery Doppler velocimetry has been studied, espe-
cially in pregnant women who are at high risk for pre-eclampsia
[45]. Abnormal uterine artery Doppler findings in the second
trimester have a sensitivity of 20–60%, and a positive predic-
tive value of 6–40%, depending on prevalence of pre-eclampsia.
According to recent meta-analyses, an increased pulsatility index
alone or combined with notching is the best predictor of pre-
eclampsia in women with risk factors (positive likelihood ratios =
21.0 in high-risk women), but it is not so predictive in low-risk
population (positive likelihood ratio = 7.5) [46]. Uterine artery
Doppler evaluation alone has a low predictive value for the devel-
opment of early onset of pre-eclampsia. Furthermore, the studies
included in the metaanalysis are heterogeneous in severity of dis-
ease and outcomes, timing of uterine artery Doppler assessment,
and inclusion of other screening tests.
A variety of blood tests to predict the risk of pre-eclampsia have
been studied. Some of the metabolites that have been proposed
as early biochemical markers of pre-eclampsia are beta-human
chorionic gonadotropin ( β-hCG), α-fetoprotein; first-trimester
serum levels of the biomarkers placental protein-13 (PP-13),
pregnancy-associated plasma protein-A (PAPP-A), soluble Flt-1
(soluble vascular endothelial growth factor receptor-1), placental
growth factor (PlGF), vascular endothelial growth factor (VEGF),
and soluble endoglin. Some of these markers are altered 4–5
weeks prior to the onset of pre-eclampsia and cannot be detected
earlier in pregnancy. An algorithm developed by logistic regres-
sion that combined the logs of uterine artery pulsatility index,
mean arterial pressure, PAPP-A, serum-free PlGF, body mass
index, and presence of nulliparity or previous pre-eclampsia
revealed that at a 5% false-positive rate, the detection rate for
early pre-eclampsia was 93.1%; more impressively, the positive LR
was 16.5, and the negative LR was 0.06 [47]. However, none of
these studies have demonstrated improvement in maternal or
fetal outcome or both in women who undergone uterine artery
Doppler assessment or biomarker testing or both. Some of these
biomarkers are not approved in the United States by the FDA, and
they are not endorsed by the ACOG [48].
Currently, there is no reliable predictive test for pre-eclampsia.
Further research is needed to identify the ideal timing of uterine
artery Doppler and the possible combination with other predic-
tors of pre-eclampsia, such as measurement of maternal serum
biomarkers, to improve perinatal outcomes. Complete medi-
cal history and physical exam to evaluate for risk factors and
strict surveillance and education are currently the only strat-
egies for clinical prediction.
Hypertensive Disorders
Complications
Complications depend on gestational age at time of diagnosis, sever-
ity of disease, presence of other medical conditions, and, of course,
management. Most cases of mild pre-eclampsia, at term, do not con-
vey significant risks. Rates of complications for severe pre-eclampsia
are given in the following subsections in parenthesis [49].
Maternal
HELLP syndrome (20%), DIC (10%), pulmonary edema (2–5%),
abruptio placentae (1–4%), renal failure (1–2%), seizures
(eclampsia) (<1%), cerebral hemorrhage (<1%), liver hemor-
rhage (<1%), death (rare).
Fetal/Neonatal
PTB (15–60%), FGR (10–25%), perinatal death (1–2%), hypox-
emia-neurologic injury (<1%), long-term cardiovascular mor-
bidity (rate unknown—fetal origin of adult disease).
Management
For management algorithms, see Figures 1.1 and 1.2) [49–52].
Principles
Pre-eclampsia is one of the most common, and perhaps most typ-
ical, obstetric complications. The only interventions associated
Maternal and Fetal Findings
• >=37 0/7 weeks
or
• >=37 0/7 weeks with:
º Labor or rupture of membranes
º Abnormal maternal-fetal test results
º Ultrasound EFW > 5th%
º Suspected abruptio placenta
NO
< 37 0/7 weeks
Inpatient or outpatient management
• Maternal evaluation: twice weekly
• Fetal evaluation
º With pre-eclampsia: twice weekly NST
º With gestational hypertension: weekly NST
• >=37 0/7 weeks
• Worsening maternal or fetal condition
• Labor or premature rupture of membranes
FIGURE 1.1 Suggested management of gestational hypertension and pre-eclampsia without severe features. (Adapted from Ref. 7.)
11
with significant prevention of pre-eclampsia are antiplatelet
agents, primarily low-dose aspirin, and calcium supplementation.
It is important to understand that pre-eclampsia’s only cure is
delivery. As such, pre-eclampsia is a temporary disease, which
resolves usually 24–48 hours after delivery. Remember that there
are two patients: Delivery is always good for the mother, but not
always for the baby, especially if very premature. In general, most
patients with pre-eclampsia are otherwise healthy.
Prevention
Aspirin. Aspirin acts to inhibit thromboxane synthesis while
maintaining vascular wall prostacyclin synthesis, which could
theoretically improve uteroplacental blood flow and fetal
growth.
Compared to placebo or no treatment, antiplatelet agents such
as low-dose aspirin (75–150 mg/day) given to women with risk
factors for pre-eclampsia (especially early onset or severe pre-
eclampsia in previous pregnancies) are associated with a 17%
reduction in the risk of pre-eclampsia [53]. Low-dose aspirin is
also associated with a small (8%) reduction in the risk of PTB
<37 weeks, a 10% reduction in SGA babies, and a 14% reduc-
tion in perinatal deaths [53].
Compared to placebo, low-dose aspirin (81 mg/day) initi-
ated between 6 0/7 and 13 6/7 weeks of pregnancy, in low risk
nulliparous women with singleton viable pregnancy signifi-
cantly decreased PTB <37 weeks by 11%, perinatal mortality
YES
• Delivery
• Prostaglandins if needed for
YES
12 Maternal-Fetal Evidence Based Guidelines

• Observe in labor and delivery for first 24–48 hours

• Corticosteroids, magnesium sulfate prophylaxis, and
• antihypertensive medications
• Ultrasonography, monitoring of fetal heart rate, symptoms, and
laboratory tests

Contraindications of continued expectant management

YES
Delivery once maternal
condition is stable
• Eclampsia
• Pulmonary edema
• Disseminated intravascular coagulation
• Uncontrollable severe hypertension
• Nonviable fetus
• Abnormal fetal test results
• Abruptio placentae
• Intrapartum fetal demise

Are there additional expectant complications?

• >= 33 5/7 weeks of gestation
YES • Persistent symptoms
Corticosteroids for fetal • HELLP or partial HELLP syndrome
maturation • Fetal growth restriction (less than fifth percentile)
Delivery after 48 hours
• Severe oligohydramnios
• Reversed end-diastolic flow (umbilical artery Doppler studies)
• Labor or premature rupture of membranes
• Significant renal dysfunction

Expectant management
• Facilities with adequate maternal and neonatal intensive care resources
• Fetal viability–33 6/7 weeks
• Inpatient only and stop magnesium sulfate
• Daily maternal–fetal tests
• Vital signs, symptoms, and blood tests
• Oral antihypertensive drugs

YES • Achievement of 34 0/7 weeks of gestation

• New-onset contraindications to expectant management
Deliver
• Abnormal maternal–fetal test results
• Labor or premature rupture of membranes

FIGURE 1.2 Suggested management of severe pre-eclampsia <34 weeks. (Adapted from Ref. 7.)
Hypertensive Disorders
by 14%, early PTB < 34 weeks by 25% and most importantly
decreased PTB < 34 weeks associated with hypertensive disor-
ders by 62% [54].
Compared with trials using 75 mg or less of aspirin, there is a
significant reduction in the risk of pre-eclampsia in trials using
higher doses (e.g. 150 mg). Although there is evidence that
higher doses of aspirin may be more effective, this requires care-
ful evaluation as risks may also be increased [53]. Low-dose aspi-
rin use has been shown to be safe for the fetus, even in the first
trimester [54, 55].
There is some evidence that the earlier low-dose aspirin is
started in pregnancy, the greater the benefits are, as shown in a
meta-analysis of 34 RCTs [56]. Low-dose aspirin initiated before
16 weeks is associated with a significant decrease in the incidence
of gestational hypertension (69%), pre-eclampsia (53%), severe
pre-eclampsia (90%), IUGR (54%), and PTB (78%) in women iden-
tified to be at risk for pre-eclampsia, therefore it is recommended
to start prior to 16 weeks of gestation. However, two other meta-
analyses (Cochrane [53] and USPSTF [57] found no difference in
outcome when the gestational age at the initiation of ASA was
evaluated. There is still a benefit when ASA is started later in preg-
nancy, however there is no information of its benefit when started
after 28 weeks. According to ACOG [7, 58], indications for low-
dose aspirin include only women with a history of early onset
pre-eclampsia/superimposed pre-eclampsia plus delivery at <34
0/7 weeks of gestation or pre-eclampsia in >1 pregnancy; ACOG
and SMFM supports the more expansive USPSTF criteria. Low-
dose aspirin (81 mg/day) prophylaxis is recommended in women
at high risk of pre-eclampsia and should be initiated between 12
weeks and 28 weeks of gestation (optimally <16 weeks) and con-
tinued daily until delivery. Low-dose aspirin prophylaxis should
be considered for women with more than one of several moderate
risk factors for pre-eclampsia. Women at risk of pre-eclampsia are
defined based on the presence of one or more high-risk factors:
Multifetal gestation; CHTN; type I or II diabetes mellitus; renal
disease; and autoimmune disease (antiphospholipid syndrome,
systemic lupus erythematosus). The American Heart Association
and American Stroke Association recommend low-dose aspirin
>12th week of gestation until delivery to women with CHTN or
history of pre-eclampsia [59].
There is concern that low-dose aspirin will not prevent pre-
eclampsia in women with CHTN. A retrospective cohort (n =
457) showed that despite 70% adhesion to guidelines, superim-
posed pre-eclampsia, small for gestational age, and preterm birth
were not significantly decreased after implementation of 81-mg
aspirin initiated between 12 and 16 weeks of gestation [10]. A sub
analysis of the ASPRE trial (daily aspirin 150 mg starting at 11–14
weeks of gestation) [60, 61] including only women with CHTN,
there was no significant difference in pre-eclampsia diagnosed
<37 weeks of gestation: 10.2% (5/49) in the aspirin group and 8.2%
(5/61) in the placebo group (aOR, 1.29; 95% CI, 0.33–5.12), even
with >90% compliance. The low sample size of these subgroups
of women may have affected this outcome, as the subgroup of
CHTN was 110/1620 (6.7%).
Further studies on the dosing, timing, and evaluation of the
efficacy of aspirin in pre-eclampsia prevention are needed on
women with CHTN, as they have a significant risk of develop-
ing superimposed pre-eclampsia and adverse outcomes. Using a
greater dose of aspirin, 150 mg, or 162 mg (2 tablets), as suggested
by the International Federation of Gynecology and Obstetrics
(FIGO) recommendation, may be an option [62]. The efficacy of
preconception initiation of aspirin at different doses needs to be
13
studied in a high-risk population. The impact of maternal BMI
on the appropriate dose of aspirin requires pharmacokinetic
studies.
Low-dose aspirin appears to be of little or no benefit in
women who already have developed pre-eclampsia [63–65].
Aspirin does not prevent progression to severe features and
may increase the risk of bleeding in patients with the HELLP
syndrome.
Prevention with abnormal uterine Doppler ultrasound.
Impedance to flow in the uterine arteries normally decreases as
pregnancy progresses. Increased impedance for gestational age
reflects high downstream resistance due to defective differentia-
tion of trophoblast, leading to pre-eclampsia and placental insuf-
ficiency. Abnormal uterine artery Doppler in the second trimester
has been associated with an increased risk of pre-eclampsia. The
only intervention studied if this screening test is abnormal is low-
dose aspirin. If low-dose aspirin is given anyway because of a
history of pre-eclampsia or other risk factors for pre-eclampsia
like CHTN (see “Chronic hypertension”), then uterine artery
Doppler screening may not be necessary or beneficial.
A meta-analysis of nine RCTs (n = 1317) comparing low-dose
(50–150 mg/day) aspirin to placebo or no treatment in women
with abnormal uterine Doppler ultrasound at 14–24 weeks
reveals that pre-eclampsia is decreased by 52% when aspirin
treatment starts before 16 weeks, with no significant reduction
when started later in pregnancy. Early start of the treatment in
women with abnormal uterine Doppler also significantly reduces
the incidence of severe pre-eclampsia by 90%, gestational
hypertension by 69%, and IUGR by 49% [66]. There are insuf-
ficient data to assess other important outcomes, such as abrup-
tion and perinatal death.
The combination of abnormal uterine artery Doppler at 22 and
24 weeks of gestation and low-dose aspirin in nulliparous women
without risk factors for pre-eclampsia versus no Doppler and pla-
cebo was evaluated a large French trial [67] trying to assess this
intervention had a different study design from the others; this
trial is not included in the meta-analysis. Women in this trial are
randomized to having the uterine Doppler examination between
22 and 24 week of gestation and always getting aspirin if abnor-
mal, or not receiving the Doppler screening. This trial confirmed
the predictive value of uterine artery Doppler for pre-eclampsia,
but failed to demonstrate the value of routine screening followed
by low-dose aspirin therapy for a positive test compared to rou-
tine prenatal care [67]. The late initiation of treatment reported
in this trial may explain the negative results obtained, confirm-
ing that aspirin treatment may be not effective in preventing pre-
eclampsia if started late in pregnancy A meta-analysis including
only women with abnormal uterine artery Doppler at first tri-
mester were randomized to low-dose aspirin versus placebo at or
before 16 weeks of gestation (3 trials, 346 women); the analysis
showed that aspirin reduced the risk of pre-eclampsia by 40% and
severe pre-eclampsia by 70% [68]. This data required further inves-
tigation as the sample size were small and they included some
women with increased risk for pre-eclampsia as CHTN, preges-
tational diabetes, etc.
A 2017 multicenter, double-blind, placebo-controlled trial was
conducted including 1776 women with singleton pregnancies who
were considered high risk for preterm pre-eclampsia based on a
combination of maternal factors, mean arterial pressure (MAP),
uterine-artery pulsatility index, maternal serum pregnancy-asso-
ciated plasma protein A (PAPP-A) and placental growth factor
(PlGF) during their visit between 11 0/7 weeks through 13 6/7
14
weeks of gestation. Patients received either aspirin (150 mg/day)
or placebo from 11–14 weeks of gestation until 36 weeks of gesta-
tion. Preterm pre-eclampsia was decreased by 62% in the aspirin
group (OR, 0.38; 95% CI, 0.20 to 0.74; P = 0.004) [60].
Heparin. A meta-analysis including eight studies comparing
heparin (alone or in combination with dipyridamole or low-dose
aspirin) versus no treatment showed no significant differences
in the risk of developing pre-eclampsia in women at risk of pla-
cental dysfunction. The use of heparin was associated with 60%
reduction in risk of perinatal mortality, 54% and 28% reduction in
preterm birth before 34 and 37 weeks’ gestation respectively, and
50% reduction in SGA. However, there is no information regard-
ing serious adverse events in infants and long-term childhood
outcomes [69]. Further trials are needed to evaluate the poten-
tial benefits of heparin in preventing pre-eclampsia. Therefore,
LMWH is not recommended at this time as prophylaxis for
recurrence for women with a history of pre-eclampsia [70, 71].
Calcium. Compared with placebo or no treatment, calcium
supplementation is associated with a 35% reduction in the inci-
dence of high blood pressure and a 55% reduction in the risk
of pre-eclampsia, as shown in a meta-analysis of 13 studies,
15,730 women [72]. The reduction is greater among women at
high risk of developing hypertension (78%), and in those with low
baseline calcium intake (64%). Although the risk of pre-eclampsia
is reduced, this is not clearly reflected in any reduction in severe
pre-eclampsia, eclampsia, or admission to intensive care. One
of the largest trials reported no reduction in the rate or severity
of pre-eclampsia, and no delay in its onset [73]. Optimum dos-
age and the effect on some substantive outcomes require further
investigation.
Calcium supplementation is also associated with a 24% reduc-
tion in the risk of PTB overall, and by 55% in women at high risk
of pre-eclampsia. There is no evidence of any effect on admis-
sion to NICU, fetal death or death before discharge from hospi-
tal. The risk ratio of the composite outcome “maternal death or
severe morbidity” is reduced by 20% for women receiving calcium
supplementation. Maternal death alone was not significantly dif-
ferent. In one study, childhood systolic blood pressure >95th per-
centile is reduced by 41%.
Overall, these results support the use of calcium supplemen-
tation during pregnancy, especially for women at high risk
of developing pre-eclampsia and for those with low dietary
intake [72]. For most studies the intervention was 1.5–2 g/day
of calcium. Nonetheless, some experts still doubt calcium ben-
efit in this settings, as the data and the selection factors are not
homogeneous (e.g. several different risk factors for pre-eclampsia
included) and final results are mostly due to influence of smaller
and lower quality studies [74].
Antioxidant therapy. Pre-eclampsia has been associated in
some studies (but not in others) with oxidative stress. Anti-
oxidative therapy (in particular vitamins C and E) has been tested
as a preventative intervention. Evidence from a meta-analysis
of 10 trials does not support routine antioxidant supplementa-
tion during pregnancy to reduce the risk of pre-eclampsia and its
complications [75]. Comparing antioxidant use with placebo or
no treatment, there is no significant difference in the risk of
pre-eclampsia, PTB, SGA infants, or fetal or neonatal death. Two
more recent meta-analysis confirmed previous results [76–78],
which do not show any maternal or fetal benefit, including no
reduction in pre-eclampsia, eclampsia, or gestational hyperten-
sion, among high- and low-risk women receiving daily supple-
mentation with 1000 mg of vitamin C and 400 IU of vitamin E,
Maternal-Fetal Evidence Based Guidelines
starting in the early second trimester. In one of the trials [78] the
intervention is associated with an increased risk of fetal loss or
perinatal death, PROM, and PPROM (an increased risk of PPROM
is observed in another previous trial) [79]. Given these results,
antioxidant therapy should not be recommended for preven-
tion of pre-eclampsia. In two studies where women already
had pre-eclampsia [80, 81], antioxidants were not associated
with any clinical benefit.
Magnesium. There is insufficient evidence to assess magne-
sium as a preventive intervention for pre-eclampsia.
Diuretics. There is insufficient evidence to support the use of
diuretics on prevention of pre-eclampsia and its complications.
Diuretics for preventing pre-eclampsia are not associated with
benefits, but have adverse effects and so their use for this purpose
cannot be recommended [82].
Salt intake. Compared to advice to continue a normal diet,
advice to reduce dietary salt intake is associated with similar out-
comes, including incidence of pre-eclampsia [83]. In the absence
of evidence that advice to alter salt intake during pregnancy has
any beneficial effect for prevention of pre-eclampsia or any other
outcome, either reliance on the non-pregnancy data on beneficial
salt restricted diet or personal preference can guide salt intake.
Fish oil. The use of omega-3 fatty acids contained in fish oil is
not associated with significant prevention of pre-eclampsia in a
meta-analysis of four studies [84].
Garlic. There is not enough evidence to recommend increased
garlic intake for preventing pre-eclampsia and its complications
[85].
Rest/Exercise. There is insufficient evidence to support recom-
mending rest or reduced activity to women for preventing pre-
eclampsia and its complications [86]. It has been suggested that
exercise may help prevent pre-eclampsia in women at moderate-
to-high risk, but current evidence is insufficient to draw reliable
conclusions about this effect [87].
Progesterone. There is insufficient evidence for reliable con-
clusions about the effects of progesterone for preventing pre-
eclampsia and its complications. Therefore, progesterone should
not be used for this purpose in clinical practice at present [88].
Nitric oxide. There is insufficient evidence to draw reliable con-
clusions about whether nitric oxide donors and precursors pre-
vent pre-eclampsia or its complications [89].
Preconception counseling
Preventive measures are as per chronic hypertension, identifica-
tion of secondary CHTN, decrease weight, as described earlier,
plus avoidance of risk factors, if feasible.
Diagnosis
Diagnosis is described earlier (see Table 1.1).
History
Headache; blurry vision, “spots in front of eyes”; abdominal pain.
Physical examination
Vital signs (BP, HR, RR, O2 saturation, urinary output), auscultate
lungs: Look for pulmonary edema, RUQ tenderness, edema (espe-
cially if hands, face, lower abdomen; excessive quick weight gain),
increased reflexes. Period when hypertension is first documented
(before or after 20 weeks) is important.
Workup
Laboratory tests: CBC (hemoconcentration/hemolysis, plate-
let count), AST and ALT, creatinine, 24-hour urine for total
Hypertensive Disorders
protein (and creatinine clearance). It is important to know the
baseline values of these tests in the woman when either not preg-
nant or at least in the beginning of the pregnancy to be able to
compare in women being evaluated for pre-eclampsia or its com-
plications. Therefore, these tests should be obtained at first pre-
natal visit in women with significant risk factors (e.g., chronic
hypertension, diabetes, renal disease, collagen disorders, APS,
prior pre-eclampsia, and HELLP). Coagulation studies (especially
fibrinogen) can be obtained only in severe cases. Uric acid is nei-
ther sensitive nor specific, and has not been shown to be helpful
in management. Repeat laboratory tests can be performed at least
once a week or as clinically indicated. Fetal assessment: Dating
ultrasound, biometry (to rule out IUGR), if IUGR is diagnosed
include umbilical artery Doppler, amniotic fluid, non-stress test,
biophysical profile as needed.
Evaluate for symptoms and laboratory tests to distinguish pre-
eclampsia from superimposed pre-eclampsia in patients with
chronic HTN, and to assess disease progression and severity.
Counseling
Delivery (the only definite treatment) is always appropriate for
the mother, but may not be so for the fetus. The woman should
be instructed on the signs and symptoms of pre-eclampsia and
severe pre-eclampsia. The management plan should always con-
sider gestational age, maternal and fetal status, and presence of
labor or PPROM. Expectant management aims to palliate the
maternal condition to allow fetal maturation and cervical ripen-
ing. Consider corticosteroid administration to accelerate fetal
lung maturity between 24 and 33 6/7 weeks. Consider late steroid
administration for women diagnosed with pre-eclampsia with
severe features between 34 0/7 and 36 0/7 weeks [35]. BP (sev-
eral times a day), urine for protein, fluid input and output, weight,
laboratory tests (as discussed earlier), and fetal status should be
closely monitored.
Admission
Management of gestational hypertension or pre-eclampsia with-
out severe features (proteinuric and nonproteinuric hyperten-
sion) in day care units has similar clinical outcomes and costs
but greater maternal satisfaction compared to hospital admis-
sion [90–92]. Admission for 24 hours observation is acceptable to
establish diagnosis and rule out severe features. Hospitalization
may be indicated in cases in which the woman is unreliable.
Admission is indicated in cases of pre-eclampsia with severe fea-
tures (Figure 1.2).
Magnesium prophylaxis
Magnesium is the drug of choice for prevention of eclampsia;
it is superior to phenytoin and diazepam. Compared with placebo
or no anticonvulsant, magnesium sulfate is associated with a 59%
reduction in the risk of eclampsia (number needed to treat for
an additional beneficial outcome: 100), a 36% reduction in abrup-
tion, and a non-statistically significant but clinically important
46% reduction in maternal death [93].
The reduction of the risk of eclampsia is consistent across
the subgroups. In particular, the reduction is similar regard-
less of severity of pre-eclampsia. As eclampsia is more common
among women with severe pre-eclampsia than among those with
mild pre-eclampsia, the number of women who would need to
be treated to prevent one case of eclampsia is greater for (mild)
pre-eclampsia without severe features (i.e. 400 for mild pre-
eclampsia, 71 for severe pre-eclampsia, and 36 in those with
15
CNS symptoms) [94]. In women with mild pre-eclampsia, the
incidence of eclampsia may be only <1/200, and magnesium has
not been shown to affect perinatal outcome, possibly because
too few (n = 357) women with mild pre-eclampsia have been
enrolled in the two specific trials [94]. In women with severe
pre-eclampsia the incidence of eclampsia decreases 61%, from
2% in the placebo group to 0.6% in the magnesium group
(four trials) [93, 94].
Magnesium is also associated with trend for a 33% decrease in
abruption in women with severe pre-eclampsia. Women allocated
to magnesium sulfate have a small increase (5%) in the risk of
cesarean section. There is no overall difference in the risk of fetal
or neonatal death.
Side effects, in particular flushing, occur in 24% of women on
magnesium, compared to 5% of controls. Almost all the data on
side effects and safety come from studies that used either the
intramuscular (IM) regimen for maintenance therapy, or the
intravenous (IV) route with 1 g/hour for around 24 hours. One
trial compared a low-dose regimen with a standard-dose regimen
over 24 hours. This study was too small for any reliable conclu-
sions about the comparative effects [95]. Other toxicities and
their associated magnesium serum levels are shown in Table 1.3.
Intravenous administration is preferable, where there are
appropriate resources, as side effects and injection site prob-
lems are lower. Magnesium is recommended in women with
pre-eclampsia with severe features, and usually given at least in
active labor initiating with a loading dose of 4–6 g followed by
maintenance dose of 1–2 g/hour, and for 12–24 hours postpar-
tum, but can be given for a shorter or longer period depending
on the severity of pre-eclampsia (maintenance dose depends on
renal function and maternal urine output). Three trials compared
short maintenance regimens postpartum (e.g. 12 hours) with
continuing for 24 hours after the birth, but even taken together
these trials were too small for any reliable conclusions [95]. Most
trials managed magnesium without serum monitoring, but with
clinical monitoring of respiration, tendon reflexes, and urine out-
put. If serum levels are used, Table 1.6 shows the correlations
with side effects. Monitoring of patellar reflexes can be used to
avoid toxicity. The use of higher doses and longer duration cannot
be supported by trial data. Magnesium sulfate for pre-eclampsia
prophylaxis does not significantly affect labor but is associated
with higher use of oxytocin [96].
Compared to phenytoin, magnesium sulfate is associated with
a 92% better reduction in the risk of eclampsia, with a 21%
increased risk of cesarean section [93]. Compared to nimodip-
ine, magnesium sulfate is associated with a 67% better reduc-
tion in the risk of eclampsia. There is insufficient evidence on
other agents, such as diazepam or methyldopa [93].
Magnesium sulfate does not appear to affect blood loss intra-
partum and postpartum in women with pre-eclampsia. A recent
meta-analysis including five trials showed that the incidence of
postpartum hemorrhage was similar between the two groups
TABLE 1.6: Maternal Serum Magnesium Concentrations
Associated with Toxicity
mmol/L mEq/L mg/dL
Loss of patellar reflexes 3.5–5 7–10 8.5–12
Respiratory depression 5–6.5 10–13 12–16
Altered cardiac conduction >7.5 >15 >18
Cardiac arrest >12.5 >25 >30
16
(magnesium sulfate: 17% vs. no magnesium sulfate: 18%, RR 0.97,
95% CI 0.88–1.06). There was no statistical difference between any
of the other blood loss outcomes reported in the included studies.
The rate of eclampsia with magnesium sulfate was decreased by
60% when compared to placebo. Magnesium sulfate, therefore,
should be continued during CD, given the benefit of seizure pro-
phylaxis without any increased risk of hemorrhage [97].
Plasma volume expansion
Blood plasma volume increases gradually in women during preg-
nancy. The increase is usually greater for women with multiple
pregnancies and less for those with small babies. Plasma volume
is reduced in women with pre-eclampsia. There is insufficient
data to assess any effect of plasma volume expansion on outcomes
in women with pre-eclampsia. Three small trials compared a col-
loid solution with no plasma volume expansion. For every out-
come reported, the confidence intervals are very wide and cross
the no-effect line [98].
Antihypertensive therapy
Patients with SBP consistently ≥160 mmHg and/or DBP ≥110
(severe HTN) should be placed on antihypertensive medication;
this includes those women with pre-eclampsia or its complica-
tions (HELLP, etc.). As stated earlier in this chapter, it is appro-
priate to initiate therapy at lower blood pressures in patients
with evidence of end-organ damage (renal, cardiovascular, etc.)
and diabetes. Target BP should be 140–150 mmHg systolic and
about 90 mmHg diastolic. ACE inhibitors are contraindicated in
pregnancy. Any patient requiring antihypertensive agents may
be placed on home BP monitoring if managed as an outpatient.
There are no trials on this intervention in pre-eclampsia.
Most antihypertensive drugs are effective at reducing blood
pressure, with little evidence that one is any better or worse than
another [2, 30, 99]. Types of medications for acute management of
hypertension include the following (Table 1.4).
• Labetalol: 20 mg IV bolus, then 40, 80, 80 mg as needed,
every 10 minutes (maximum 220 mg total dose).
• Hydralazine: 5 to 10 mg IV (or IM) every 20 minutes. Change
to another drug if no success by 30 mg (maximum dose).
Hydralazine may be associated with more maternal side
effects and NRFHT than IV labetalol or oral nifedipine [100].
• Nifedipine: 10 to 20 mg orally, may repeat in 30 minutes.
This drug is associated with diuresis when used postpar-
tum. Nifedipine and magnesium sulfate can probably be
used simultaneously.
• Sodium nitroprusside (rarely needed): Start at 0.25 μ/kg/
min to a maximum of 5 μ/kg/min.
Antiplatelet agents
Five trials compared antiplatelet agents with placebo or no anti-
platelet agent for the treatment of pre-eclampsia. There are insuf-
ficient data for any firm conclusions about the possible effects
of these agents when used for treatment of pre-eclampsia [101]
(meta-analysis, now withdrawn).
Antepartum testing
Antenatal testing (usually with non-stress tests) is done at diag-
nosis and repeated once or twice weekly; twice weekly for FGR
or oligohydramnios. Umbilical artery Doppler ultrasound is rec-
ommended at least weekly if FGR is present. Ultrasound for fetal
Maternal-Fetal Evidence Based Guidelines
growth and amniotic fluid assessment should be performed at
diagnosis and every 3 weeks if still pregnant.
Anesthesia
(See also Chapter 11 of Obstetric Evidence Based Guidelines)
Regional anesthesia is preferred, but contraindicated with coagu-
lopathy or platelets <75,000/mm3. Patients with hypertension may
benefit from epidural analgesia, as it may improve uterine perfu-
sion through several pathways (localized neuraxial vasodilatory
effect, reduced catecholamine release). Epidural analgesia is the
analgesia of choice in hypertensive pregnant women. Patients
with hypertension, pre-eclampsia, and eclampsia are at increased
risk for hemodynamic instability during both labor and surgical
anesthesia. Some, but not all studies, have found a higher inci-
dence of hypotension in parturients receiving a spinal versus epi-
dural. Methods to prevent hypotension should be employed. The
prevention, rather than treatment, of hypotension has been asso-
ciated with better outcomes for the fetus. In women with severe
pre-eclampsia, a careful approach is necessary for either regional
or general anesthesia. Provided this is followed, they are associ-
ated with similar, good outcomes in a small trial [102]. Women
with severe pre-eclampsia who must undergo general anesthesia
are at risk for an extremely exaggerated hypertensive response
to intubation and often benefit from pretreatment with an anti-
hypertensive, such as labetalol, immediately prior to induction.
Prophylaxis with magnesium sulfate for pre-eclampsia/eclampsia
can potentiate neuromuscular blockade in patients receiving gen-
eral anesthesia, so care must be taken in using intermediate- to
long-acting nondepolarizing muscle relaxants.
Delivery
Timing
Before 37 weeks, in the absence of severe criteria, or preterm
labor, and in the presence of reassuring fetal testing, expectant
management is suggested, with delivery for development of any
severe criteria (see “Pre-eclampsia with severe features”).
Compared to expectant management, induction of labor in
women with gestational hypertension or pre-eclampsia without
severe features at 36–41 weeks’ gestation is associated with a 29%
reduction in composite maternal outcome (e.g. HELLP, severe
HTN, severe pre-eclampsia, eclampsia, abruptio placenta and pul-
monary edema) and lower incidence of neonatal pH <7.05 with
induction of labor ≥37 weeks, but no differences in rates of neo-
natal complications or cesarean delivery [38].
Therefore, women with gestational hypertension without
severe blood pressure and pre-eclampsia without severe fea-
tures delivery at 37 0/7 weeks of gestation or at diagnosis is
recommended. Women with gestational hypertension with
severe blood pressure and pre-eclampsia with severe features
delivery at 34 0/7 weeks of gestation or at diagnosis is recom-
mended (Figures 1.1 and 1.2).
Mode
Vaginal delivery is preferred, with induction of labor if neces-
sary. Women with GHTN or pre-eclampsia without severe features
benefit most from induction if the cervix is unfavorable [103].
With severe pre-eclampsia, the chances of a successful induc-
tion vary from 34% to over 90% in different studies [104–110].
Table 1.7 shows the rate of cesarean delivery in induced labors at
different gestational ages, and should be helpful with counseling
Hypertensive Disorders 17

TABLE 1.7: Rate of Cesarean Delivery in Induced Labors in • Magnesium sulfate for maternal seizure prevention
Women with Severe Pre-Eclampsia at 24–34 Weeks’ • Expectant management no more than 34 weeks
Gestation • Delivery by 34 weeks
• Close postpartum BPs surveillance for first 72 hours
24–28 wk 28–32 wk 32–34 wk
• Close follow up 7–10 days after delivery
Author % (n) % (n) % (n)
Nassar [86] 68 (13/19) 55 (47/86) 38 (15/40) Pre-eclampsia with severe features
Blackwell [83] 96 (26/27) 65 (33/51) 31 (23/73) See also section “Pre-eclampsia.”
Alanis [80] 93 (14/15) 53 (84/158) 31 (34/109)
Mashiloane [85] 35 (14/40) Diagnostic criteria
OVERALL 87 (53/61) 53 (178/335) 32 (72/222) The diagnosis of pre-eclampsia with severe features is made if
Abbreviation: wk, weeks.
one or more of the following are present: (1) BP ≥160/110 mm
on two occasions at least 4 hours apart while the patient is on
bed rest (unless antihypertensive therapy is initiated before this
and management. If the woman is stable and accepts this low time); (2) thrombocytopenia ≥100,000 platelets/mL; (3) impaired
incidence of success, induction may be reasonable, especially in liver function AST or ALT twice normal concentration, severe
a woman desiring a large family, if management includes a clear persistent right upper quadrant or epigastric pain unresponsive
end point for delivery (e.g. within 24 hours). to medication and not accounted for by alternative diagnoses, or
both; (4) progressive renal insufficiency (serum creatinine con-
Hemodynamic monitoring centration >1.1 mg/dL or a doubling of the serum creatinine con-
Invasive hemodynamic monitoring in pre-eclamptic women, even centration in the absence of other renal disease); (5) pulmonary
with severe cardiac disease, renal disease, refractory HTN, pul- edema; (6) cerebral or visual disturbances (Table 1.1).
monary edema, or unexplained oliguria, is usually unnecessary, Severe proteinuria (>5 grams) has been eliminated from the
especially since Swan–Ganz catheters have been associated with consideration of pre-eclampsia as a severe feature because several
complications and no improvements in outcomes in non-pregnant studies indicated that expectant management was not associ-
critically ill adults (see Chap. 20). There are no trials on this inter- ated with worse maternal or fetal outcome. [42, 113, 114]. As fetal
vention in pregnancy. growth restriction is managed similarly in pregnant women with
and without pre-eclampsia, it has been removed as well as criteria
Pre-eclampsia complications of severe features of pre-eclampsia.

Superimposed pre-eclampsia Management

Prognosis may be much worse for mother and fetus than with
either diagnosis (chronic hypertension or pre-eclampsia) alone.
Complications are similar to pre-eclampsia, but more common
and severe (e.g. PTB 50–60%, FGR 15%, abruption 2–5%, peri-
natal death 5%). There are no specific trials to guide manage-
ment, therefore management should follow as per pre-eclampsia
(Figures 1.1 and 1.2), with even more caution given the higher
morbidity and mortality [111, 112].
Management
Management of CHTN with superimposed pre-eclampsia
without severe features [7]:
• Antihypertensive medications for SBP >160 mmHg or
>105 mmHg
• Maintain BPs between >120/80 mmHg and <160/105 mmHg
• Consider outpatient management in selected population
with easy access to the health system [111]
• Home BPs measurements
• Close follow-up in clinic every week with NST
• Fetal growth evaluation every 3 weeks
• Delivery no less than 37 weeks
• Close postpartum BPs surveillance for first 72 hours
• Close follow up 7–10 days after delivery
Management of CHTN with superimposed pre-eclampsia
with severe features:
• Admission to the hospital for evaluation
• Antihypertensive medications for SBP >160 mmHg or
>105 mmHg
Magnesium sulfate. See the section “Pre-eclampsia” (Figure. 1.2).
Plasma volume expansion. The addition of plasma volume
expansion as a temporizing treatment does not improve mater-
nal or fetal outcome in women with early preterm severe pre-
eclampsia [115].
Timing of delivery (Figure 1.2). In the presence of pre-eclampsia
with severe features at ≥34 weeks, expeditious delivery is rec-
ommended, given the high maternal incidence of complications
with expectant management. Timing the delivery of a very pre-
mature infant <34 weeks in the presence of severe pre-eclampsia
is a difficult clinical decision. When the mother’s life is in danger,
there is no doubt that delivery is the only correct course of action.
This situation is rare. More usually, the risks of maternal morbid-
ity if the pregnancy is continued have to be constantly balanced
against the hazards of prematurity to the fetus if it is delivered
too early. The options are expeditious delivery, delivery after
competition of corticosteroids or expectant management to
improve perinatal outcome, but there are only three trials com-
paring these approaches at 28–34 weeks [116–118] In general, an
interventionist approach with immediate delivery before 48
hours and before completion of corticosteroid administra-
tion (“aggressive management”) is suggested with eclampsia,
pulmonary edema, DIC, abruptio placentae, abnormal fetal
testing, uncontrollable BP in spite of continuing increase in
antihypertensive drugs, fetal demise or non-viable fetus. Delivery
after 48 hours, after completion of corticosteroids, is sug-
gested in women with persistent headache and/or visual/
CNS symptoms, epigastric pain, renal dysfunction (Cr >1.1,
double creatinine value or persistent oliguria), preterm labor,
PROM, AST/ALT more than two fold normal value, platelets
<100,000/mm3 (partial or complete HELLP syndrome), severe
18 Maternal-Fetal Evidence Based Guidelines

oligohydramnios, or reversed umbilical artery end-diastolic TABLE 1.8: Differential Diagnosis of HELLP Syndrome
flow ≥32 weeks [50, 119].
Acute fatty liver of pregnancy (AP)
There are insufficient data for reliable conclusions comparing
Lupus flare: Exacerbation of systemic lupus erythematosus
these policies for outcome for the mother. For the baby, there is
Thrombotic thrombocytopenic purpura (TTP)
insufficient evidence for reliable conclusions about the effects on
fetal or neonatal death. Babies whose mothers are allocated to Hemolytic uremic syndrome (HUS)
interventionist groups have 2.3-fold more hyaline membrane Immune thrombocytopenic purpura (ITP)
disease and 5.5-fold more necrotizing enterocolitis, and are Thrombophilias (e.g. antiphospholipid syndrome)
32% more likely to need admission to the neonatal intensive Severe folate deficiency
care unit (NICU) than those allocated to an expectant policy Cholangitis/cholecystitis/pancreatitis/ruptured bile duct
[119]. Nevertheless, babies allocated to the interventionist policy Gastric ulcer
are 64% less likely to be SGA. There are no statistically significant Cardiomyopathy
differences between the two strategies for any other outcomes. Dissecting aortic aneurysm
In observational studies expectant care of severe pre-eclampsia Systemic viral sepsis (herpes, cytomegalovirus)
<34 weeks is associated with pregnancy prolongation of 7–14 SIRS/sepsis
days, and few serious maternal complications (<5%), similar to
Hemorrhagic or hypotensive shock
interventionist care [120].
Stroke in pregnancy or puerperium
Expectant management. Expectant management (prolong-
ing pregnancy beyond 48 hours) is possible only if none of Paroxysmal nocturnal hemoglobinuria
the conditions described earlier is present. At any time during Pheochromocytoma
expectant management, the development of any sign described Advanced embryonal cell carcinoma of the liver
earlier necessitates delivery (Figure 1.2) [50]. Expectant manage- Acute cocaine intoxication
ment is not recommended beyond 34 weeks, because maternal Myasthenia gravis
risks outweigh perinatal benefits. Pseudocholinesterase deficiency
Expectant management of severe pre-eclampsia remote from
Source: Adapted from Ref. [44].
term warrants hospitalization at a tertiary facility [121], daily
antenatal testing, and laboratory studies at frequent intervals,
with the decision to prolong pregnancy determined day to day.
Expectant management was associated with increased risk of concurrent with the syndrome or other disorders altogether. The
abruptio placentae and SGA in an RCT from Latin America [118]. diseases that may imitate HELLP syndrome and that have to be
In cases of severe HTN, such as those with severe pre-eclampsia, considered in the differential diagnosis are shown in Table 1.8 [44].
in which expectant management is appropriate, we suggest add-
ing labetalol 200–800 mg orally every 8 hours to the antihyper- Signs and symptoms
tensive therapy described earlier. An alternative is nifedipine The presenting symptoms are usually right upper abdominal
10–20 mg orally every 4–6 hours (Table 1.5). quadrant or epigastric pain, nausea, and vomiting. Headache
Women with renal disease, systemic lupus erythematosus, and visual symptoms can occur. Malaise or viral syndrome–like
insulin-dependent diabetes, or multiple gestations require very symptoms may be present with advanced HELLP syndrome. It
careful management if expectantly managed. Massive protein- is important to note that 15% have no hypertension and 13% no
uria, even >10 g in 24 hours, is not associated per se with worse proteinuria (Table 1.9) [125].
maternal or neonatal outcomes compared with proteinuria of <10
or even <5 g, and so should probably not be a criterion for delivery Complications
by itself. The presence of FGR requires even closer monitoring, Complications (Table 1.10) of HELLP syndrome are somewhat
is associated with worse outcomes, but is usually not in itself a similar in incidence and severity to those of severe pre-eclampsia,
criterion for delivery [122, 123]. once gestational age is controlled [125]. If profound hypovolemic
shock occurs, suspect liver hematoma. If confirmed, liver hema-
HELLP syndrome toma is best managed conservatively. Contributing factors to
Epidemiology
HELLP syndrome is a severe manifestation of pre-eclampsia
and complicates approximately 0.5–0.9% of all pregnancies and TABLE 1.9: Signs and Symptoms of HELLP Syndrome
10–20% of cases with severe pre-eclampsia [124]. Approximately
72% of cases are diagnosed antepartum, and 28% postpartum (of Condition Frequency (%)
which 80% <48 hours, and 20% ≥48 hours postpartum). Of the Hypertension 85
antepartum cases, about 70% occur 28–36 weeks, 20% >37 weeks, Proteinuira 87
and about 10% <28 weeks. HELLP syndrome detected before fetal Right upper quadrant or epigastric pain 40–90
viability may identify a pregnancy complicated by partial mole/ Nausea or vomiting 30–85
triploidy, trisomy 13, anti-phospholipid syndrome, autoantibod- Headaches 35–60
ies to angiotensin AT(1)-receptor, or severe preterm pre-eclampsia
Visual Changes 10–20
with “mirror” syndrome [44].
Mucosal bleeding 10
Diagnosis Jaundice 5
See earlier in this chapter and Table 1.1. Patients presumptively Source: Adapted from Ref. 125.
diagnosed with HELLP syndrome can have other disorders Abbreviation: HELLP, Hemolysis, Elevated Liver enzymes and a Low Platelet count.
Hypertensive Disorders 19

TABLE 1.10: Complications of HELLP Syndrome Management

Complication Frequency (%)
See Figure 1.3 for management [126].
Workup. Laboratory tests as per severe pre-eclampsia, plus
Maternal death 1 peripheral smear evaluation.
Adult respiratory distress syndrome (ARDS) 1 Corticosteroids. Eleven trials (550 women) have assessed cor-
Laryngeal edema 1–2 ticosteroids versus placebo/no treatment for HELLP syndrome,
Liver failure or hemorrhage 1–2 and are summarized in a meta-analysis [127]. The dose of dexa-
Acute renal failure 3 methasone was usually 10-mg IV every 6–12 hours for two to
Pulmonary edema 6–8 three doses, followed by 5- to 6-mg IV 6–12 hours later for two
Pleural effusions 10–15 to three more doses. There is no difference in the risk of mater-
Abruptio placentae 10–15
nal death, maternal death or severe maternal morbidity, or
perinatal/infant death. The only significant effect of treatment
Disseminated intravascular coagulopathy 10–15
on individual outcomes is improved platelet count: This effect is
Marked ascites 10–15
strongest if the treatment is started antenatally.
Perinatal death 7–20
In two trials comparing dexamethasone with betametha-
PTB 70 sone, there is no clear evidence of a difference between groups
Source: Adapted from Ref. 125. in respect to perinatal morbidity or mortality. Maternal death
Abbreviations: HELLP, Hemolysis, Elevated Liver enzymes and Low Platelets; PTB, and severe maternal morbidity is not reported. Regarding platelet
preterm birth. count, dexamethasone is superior to betamethasone, when treat-
ment is commenced both antenatally and postnatally [128, 129].
deaths of women with HELLP syndrome are, in order of decreas- The two largest and only placebo-controlled trials [130, 131]
ing frequency, stroke, cardiac arrest, DIC, adult respiratory dis- failed to show any significant difference between dexamethasone
tress syndrome, renal failure, sepsis, hepatic rupture, and hypoxic and placebo with respect to duration of hospitalization, recovery
encephalopathy [44]. time for laboratory or clinical parameters, complications, or need

Refer to tertiary care facility (< 35 weeks)

Admit to labor and delivery area
IV magnesium sulfate
Antihypertensives if BP ≥ 160/105

24–34 weeks ≥34 weeks

< 23 weeks

Fetal non-reassuring status

Maternal non-reassuring status
Eclampsia
DIC
NO
Renal failure
Complete
Abruptio placentae
Pulmonary edema steroid course
Suspect liver hematoma (24–48 hours latency)

YES

Delivery

FIGURE 1.3 Suggested management of HELLP syndrome. (Adapted from Ref. 126.)
20
for blood transfusion. These results remained unchanged, even
following analysis stratified according to whether the patients
were still pregnant or postpartum. A subgroup analysis accord-
ing to the severity of disease shows a shorter platelet recovery and
duration of hospitalization in the subgroup with class 1 HELLP
who received dexamethasone [94].
There is only one randomized placebo-controlled trial evaluat-
ing the effect of prolonged administration of high-dose predniso-
lone in 31 pregnant women with early-onset (<30 weeks) HELLP
syndrome, during expectant management (mean prolongation
of about 7 days) [132]. The results show a reduced risk of recur-
rent HELLP syndrome exacerbations (presence of at least two of
the following three criteria: Right upper abdominal or epigastri-
cal pain, a platelet count decrease below 100,000/mm3, and an
increase of AST/ALT more than two fold normal value) in the
prednisolone group as compared to the placebo group (hazard
ratio 0.3, 95% CI 0.3–0.9). Nevertheless, expectant management
for >48 hours in women with HELLP syndrome, even with early
onset, is not recommended.
Given no significant improvements in important maternal and
fetal outcomes, there is still insufficient evidence to recom-
mend the routine use steroids for therapy specific for HELLP
syndrome, and this approach should be considered experimental.
The use of corticosteroids may be justified in clinical situations in
which increased rate of recovery in platelet count is considered
clinically worthwhile.
Anesthesia
Regional anesthesia is usually allowed by anesthesiologists in
cases with platelet counts ≥75,000/mm3. General anesthesia may
be safer in cases with lower platelet counts.
Delivery
Timing (Figure 1.3). Prompt delivery is indicated if HELLP is
diagnosed at ≥34 weeks, or even earlier if multiorgan dysfunction,
DIC, liver failure or hemorrhage, renal failure, possible abruption,
or NRFHT are present. Delivery can only be delayed for a maxi-
mum of 48 hours between 24 and 33 6/7 weeks to give steroids
for fetal maturity, but even this management is not tested in tri-
als. Although some women may have improvement in laboratory
values in these 48 hours, delivery is still indicated in most cases.
Mode. Mode of delivery should generally follow obstetrical
indications, with HELLP syndrome not being an indication for
cesarean per se. No randomized trial compared maternal and
neonatal outcome after vaginal delivery or cesarean section in
women with HELLP syndrome. Counseling and management
should include the information that the incidence of cesarean
delivery in trials of labor with HELLP at <30 weeks is high.
With a platelet count <100,000/mm3, a drain may be indicated
under and/or over the fascia in cases of cesarean delivery.
Eclampsia
Incidence
The incidence is about 2–3 cases per 10,000 births in Europe and
other developed countries, and 16–69 cases per 10,000 births in
developing countries [133]. The onset can be antepartum (40–
50%), intrapartum (20–35%), or postpartum (10–40%). Late post-
partum eclampsia (>48 hours but <4 weeks after delivery) is rare,
but can occur.
Definition
Eclampsia is the occurrence of new onset of ≥1 grand mal
seizure(s) in association with pre-eclampsia.
Maternal-Fetal Evidence Based Guidelines
Complications
The risk of maternal death is around 1–2% in the developed
world and up to 10% in developing countries. An estimated
50,000 women die each year worldwide having had an eclamptic
convulsion. Perinatal mortality is 6–12% in the developed world
and up to 25% in developing countries. Other complications are
similar and possibly more severe than severe pre-eclampsia cases
(maternal—abruption 7–10%, DIC 7–11%, HELLP 10–15%, pul-
monary edema 3–5%, renal failure 5–9%, aspiration pneumonia
2–3%, cardiopulmonary arrest 2–5%; perinatal—PTB 50%) [94].
Management
Principles. In about 15% of cases, hypertension or proteinuria
may be absent before eclampsia. A high index of suspicion for
eclampsia should be maintained in all cases of hypertensive
disorders in pregnancy, in particular those with CNS symp-
toms (headache, visual disturbances). Up to 50% or more of
cases of eclampsia, occurring in women with no diagnosis of pre-
eclampsia, or only mild disease, preterm or before hospitaliza-
tion, may not be preventable.
The first priorities are airway, breathing, and circulation.
Multidisciplinary care is essential, as several people are needed
for immediate stabilization. Interventions include airway assess-
ment and placing the patient in the lateral decubitus position
(to avoid aspiration). Maintain oxygenation with supplemen-
tal oxygen via 8–10 L/min mask. Obtain vital signs and assess
pulse oximetry. Supportive care includes inserting a tongue blade
between the teeth (avoiding inducing a gag reflex), and preventing
maternal injury.
Workup. Cerebral imaging is usually not necessary for the diag-
nosis and management of most women with eclampsia. It might
be helpful in cases complicated by neurologic deficits, coma,
refractory to magnesium, or seizures >48 hours after delivery.
Therapy. Magnesium sulfate is the drug of choice to treat
eclampsia and prevent recurrent convulsions, as it is associ-
ated with maternal and fetal/neonatal benefits compared to all
interventions against which it has been tested. The standard
intravenous regimen widely used in many countries consists in
a loading dose of 4 g, followed by an infusion of 1 g/hour [95].
Increasing the loading dose to 6 g and the infusion rate to 2 g/
hour has also been suggested [94].
Trials comparing alternative treatment regimens (loading dose
alone vs. loading dose plus maintenance therapy for 24 hours or
low-dose regimen vs. a standard-dose regimen over 24 hours) are
too small for reliable conclusions [95].
Serum monitoring of magnesium levels is not absolutely neces-
sary. The effectiveness and safety of magnesium sulfate has been
demonstrated with clinical monitoring alone [95].
Trials comparing magnesium sulfate with other anticonvul-
sants for treating eclampsia demonstrate that it is more effective
than diazepam, phenytoin, or lytic cocktail [134–136].
Magnesium versus diazepam. Compared with diazepam, mag-
nesium sulfate is associated with reductions in maternal death
by 41%, in further convulsions from eclampsia by 57%, in Apgar
scores <7 at 5 minutes by 30%, in the need of intubation at the
place of birth by 33%, and in length of stay in special care baby
unit >7 days by 34% [134]. There was no clear difference in peri-
natal deaths.
Magnesium versus phenytoin. Compared with phenytoin, mag-
nesium sulfate is associated with reduction in maternal compli-
cations such as the recurrence of convulsions by 66%, maternal
death by 50% (nonsignificant because of small numbers: RR 0.50,
Hypertensive Disorders
95% CI 0.24–1.05), pneumonia by 56%, ventilation by 32%, and
admission to the intensive care unit by 33%. For the baby, mag-
nesium sulfate is associated with 27% fewer admissions to a spe-
cial care baby unit, and 23% fewer babies who died or were in
special baby care unit for >7 days [135].
Magnesium versus lytic cocktail. Lytic cocktail is usually a
mixture of Thorazine (chlorpromazine), Phenergan (prometha-
zine), and Demerol (meperidine). Compared to a lytic cocktail,
magnesium sulfate is associated with a 86% reduction in mater-
nal death and a 94% reduction in subsequent convulsions.
Magnesium sulfate is also associated with 88% less maternal
respiratory depression and 94% less coma, without any clear
difference in the risk of neonatal death [136].
Other issues About 10% of women will have a second seizure
even after receiving magnesium sulfate. In that case, another
bolus of 2 g of magnesium sulfate can be then given intrave-
nously over 3–5 minutes, and, rarely, if another convulsion
occurs, sodium amobarbital 250-mg IV over 3–5 minutes is nec-
essary [94].
Blood pressure should be maintained at about 140–159/90–
109 by antihypertensive agents, as described for pre-eclampsia.
Antepartum testing
NRFHT occurs in many cases of eclampsia, but usually resolves
spontaneously in 3–10 minutes by fetal in utero resuscitation
with maternal support. Therefore, NRFHT is not an indication
for immediate cesarean delivery in case of eclampsia, unless it
continues >10–15 minutes despite normal maternal oxygenation.
Delivery
Delivery should occur expeditiously, but only when the mother
is stable. This requires a multidisciplinary, efficient, and timely
effort.
Postpartum management
Eclampsia prophylaxis. Magnesium should be continued for at
least 12 hours, and often for about 24 hours or at least improve-
ment in maternal urinary output (e.g., >100 mL/hour). In some
cases of severe pre-eclampsia, eclampsia, HELLP or continuing
oliguria, or other complications, magnesium may need to be
continued for >24 hours. Pre-eclampsia can worsen postpartum.
Edema always worsens, and the woman should be aware of this.
Eclampsia can still occur, especially in the first 48 hours post-
delivery, but even up to ≥14 days postpartum.
Management of hypertension. There are no reliable data to
guide management of women who are hypertensive postpartum
or at increased risk of becoming so. Women should be informed
that they will require long-term surveillance (and possible ther-
apy) for hypertension at their postpartum visit.
For prevention in women who had antenatal pre-eclampsia,
there is insufficient data to assess outcomes comparing furose-
mide or nifedipine with placebo/no therapy [137]. Compared to
no therapy, postpartum furosemide 20 mg orally for 5 days does
not affect any outcomes in women with mild or superimposed
pre-eclampsia [138]. In women with severe pre-eclampsia, this
intervention normalizes blood pressure more rapidly and reduces
the need for antihypertensive therapy, but does not affect the inci-
dence of delayed complications or the length of hospitalization
[138]. L-Arginine therapy does hasten recovery in postpartum
pre-eclampsia [139]. Therefore, for women with antenatal hyper-
tension, even that of pre-eclampsia, it is unclear whether or not
they should routinely receive postpartum anti-hypertensive
therapy. Although blood pressure peaks on day 3–6 postpartum,
21
whether or not routine postpartum treatment can prevent tran-
sient severe maternal hypertension and/or prolongation of mater-
nal hospital stay has not been established [137].
For treatment, there is insufficient data to assess the antihy-
pertensive studied: These are oral timolol or hydralazine com-
pared with oral methyldopa for treatment of mild-to-moderate
postpartum hypertension, and oral hydralazine plus sublingual
nifedipine compared with sublingual nifedipine [137]. Oral nife-
dipine (10 mg every 8 hours short-acting or 30 mg daily long-
acting; maximum dose 120 mg/day) is a reasonable choice, with
ACE inhibitors for women with diabetes or nephropathy. If
a clinician feels that hypertension is severe enough to treat,
the agent used should be based on his/her familiarity with the
drug.
Long-term counseling
Since a history of early-onset hypertensive disorders of preg-
nancy increases the risk of recurrence in subsequent pregnan-
cies, long-term counseling should involve review of recurrence,
and preventive measures (see “Complications”). The risk of com-
plications in the subsequent pregnancy depends on how early in
gestation and how severe the complications were, other underly-
ing medical conditions, age of the woman at future pregnancy,
same versus different partner, and many other variables (see sec-
tion “Risk Factors”). Several studies tried to identify prediction
tests for recurrent hypertensive disease in pregnancy, but there
is insufficient evidence to assess the clinical usefulness of these
tests [140].
In a large cohort study, the recurrence risk of pre-eclampsia
is around 15% in the second pregnancy for women who had had
pre-eclampsia in their first pregnancy and 30% for women who
had pre-eclampsia in the previous two pregnancies [141, 142]. In a
systematic review of seven studies, the pooled risk of recurrence
of hypertension, pre-eclampsia, or HELLP syndrome resulting
in a delivery before 34 weeks is 7.8% [143]. In two recent large
cohort studies, the recurrence rate of pre-eclampsia associated
with delivery before 34 weeks’ gestation is 6.8% and 17%, respec-
tively [142, 144].
Women with a history of the HELLP syndrome have an
increased risk of at least 20% (range 5–52%) that some form of
hypertension will recur in a subsequent gestation [124], about 5%
for recurrence of HELLP, 30–40% of PTB, 25% of SGA, and up to
5–10% of perinatal death [145].
Moreover, women with prior pre-eclampsia and related
hypertensive disorders are at increased risk of cardiovascular
disease in the future, even premenopause if the pre-eclampsia
occurred early in pregnancy, is recurrent, associated with IUGR,
or as a multipara, or in menopause if it happened at term in a pri-
mipara. These cardiovascular risks equal the risk associated with
obesity or smoking. In 2011, the American Heart Association
added pre-eclampsia to risk factors to cardiovascular disease. For
prevention of this cardiovascular disease and its complications,
early intervention is suggested [146].
References
1. Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ABC/ACPM/
AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detec-
tion, evaluation, and management of high blood pressure in adults: a report
of the American College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127–248.
[Level III]
22
2. ACOG Practice Bulletin No. 203. Chronic hypertension in pregnancy.
American College of Obstetricians and Gynecologists’ Committee on
Practice Bulletins—Obstetrics. Obstet Gynecol 2019;133(1):e26–e50.
[Level III]
3. Fazal N, Webb A, Bangoura J, et al., Telehealth: improving maternity services by
modern technology. BMJ Open Qual 2020;9(4):e000895. [Evidence II-3]
4. Thomas NA, Drewry A, Passmore SR, et al. Patient perceptions, opinions
and satisfaction of telehealth with remote blood pressure monitoring post-
partum. BMC Pregnancy Childbirth 2021;21(1):153. doi: 10.1186/s12884-
021-03632-9. [Secondary analysis II-1]
5. Akpolat T, Aydogdu T, Erdem E, et al. Inaccuracy of home sphygmoma-
nometers: a perspective from clinical practice. Blood Press Monit 2011;16:
168–171. [Level II-3]
6. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2009. Natl
Vital Stat Rep 2011;60:1–70. [Level II-3]
7. American College of Obstetricians and Gynecologists. Hypertension
in pregnancy. Report of the American College of Obstetricians and
Gynecologists’ task force on hypertension in pregnancy. Obstet Gynecol
2013;122(5):1122–1131.
8. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl
J Med 1999;341:427.
9. Sibai BM, Lindheimer M, Hauth J, et al. Risk factors for pre-eclampsia,
abruptio placentae, and adverse neonatal outcomes among women with
chronic hypertension. National Institute of Child Health and Human
Development Network of Maternal–Fetal Medicine Units. N Engl J Med
1998;339:667–671. [Secondary analysis RCT n = 193.I]
10. Banala C, Moreno S, Cruz Y, et al. Impact of the ACOG guideline regarding
low-dose aspirin for prevention of superimposed pre-eclampsia in women
with chronic hypertension. Am J Obstet Gynecol. 2020;223(3):419.e1–419.
e16. [Level II-2]
11. Sutton EF, Hauspurg, A, Caritis, SN. et al. Maternal outcomes associated
with lower range stage 1 hypertension. Obstet Gynecol 2018;132:843.
[Evidence: secondary analysis RCT, n = 2947. I]
12. Porcelli BA, Diveley, E, Meyenburg, K. et al. A new definition of gestational
hypertension? New-onset blood pressures of 130 to 139/80 to 89 mm Hg
after 20 weeks of gestation. Am J Obstet Gynecol 2020;223(3):442.e1–442.
e7. [Evidence: retrospective cohort study, n = 2090. II-2]
13. Yeo S, Steele NM, Chang MC. Effect of exercise on blood pressure in preg-
nant women with a high risk of gestational hypertensive disorders. J Reprod
Med 2000;45(4):293–298. [RCT, n = 16; I]
14. Rhodes CA, Beevers, DG, Churchill, D. A randomized trial of ambula-
tory blood pressure monitoring versus clinical blood pressure measure-
ment in the management of hypertension in pregnancy. A feasibility study.
Pregnancy Hypertens 2018;11:142–144. [Evidence: Feasibility RCT n = 91, I]
15. Cairns AE, Tucker, KL, Leeson, P, et al. Self-Management of Postnatal
Hypertension: The SNAP-HT Trial Hypertension. 2018;72(2):425–432.
[Evidence: Feasibility RCT n = 100, I]
16. Bergel E, Carroli G, Althabe F. Ambulatory versus conventional methods
for monitoring blood pressure during pregnancy. Cochrane Database Syst
Rev 2002;(2):CD001231. [Review; III]
17. Hella EC, van der Heijden, OWH, de Boer, K, et al. Blood pressure after
PRE-eclampsia/HELLP by SELF monitoring (BP-PRESELF): rationale and
design of a multicenter randomized controlled trial. BMC Womens Health
2020;20(1):41. [RCT: Level I]
18. Greig D., Franssen, M, Tucker, KL, et al. Blood pressure monitoring in high-
risk pregnancy to improve the detection and monitoring of hypertension
(the BUMP 1 and 2 trials): protocol for two linked randomised controlled
trials. BMJ Open 2020;10(1):e034593. [RCT: Level I]
19. van den Heuvel Josephus FM, Ganzevoort W, De Haan-Jebbink JM, et al.
Hospital care versus telemonitoring in high-risk pregnancy (HOTEL): study
protocol for a multicentre non-inferiority randomised controlled trial. BMJ
Open 2019;9(10):e031700. [RCT: Level I]
20. Meher S, Abalos E, Carroli G. Bed rest with or without hospitalisa-
tion for hypertension during pregnancy. Cochrane Database Syst Rev
2005;(4):CD003514. [Meta-analysis; 4 RCTs, n = 449; I]
21. Committee SP. SMFM Statement: benefit of antihypertensive therapy for
mild-to-moderate chronic hypertension during pregnancy remains uncer-
tain. Am J Obstet Gynecol 2015;213(1):3–4. [Review III]
22. Bellos I, Pergialiotis P, Papapanagiotou A, et al. Comparative efficacy and
safety of oral antihypertensive agents in pregnant women with chronic
hypertension: a network metaanalysis. Am J Obstet Gynecol. 2020.
[Review III]
23. Gruppo di Studio Ipertensione in Gravidanza. Nifedipine versus expectant
management in mild to moderate hypertension in pregnancy. Br J Obstet
Gynaecol 1998;105(7): 718–722. [II-1]
Maternal-Fetal Evidence Based Guidelines
24. Ahn HK, Nava-Ocampo AA, Han JY, et al. Exposure to amlodipine in the
first trimester of pregnancy and during breastfeeding. Hypertension in
Pregnancy 2007;26(2):179-87. [II-2]
25. Abalos E, Duley L, Steyn DW, Gialdini C. Antihypertensive drug therapy
for mild to moderate hypertension during pregnancy. Cochrane Database
Syst Rev 2018;10(10):CD002252. [I]
26. Magee LA, Duley L. Oral beta-blockers for mild to moderate hyperten-
sion during pregnancy. Cochrane Database Syst Rev 2003; (3):CD002863.
[Meta-analysis; 29 RCTs, n = 2500; I]
27. von Dadelszen P, Ornstein MP, Bull SB, et al. Fall in mean arterial pressure
and fetal growth restriction in pregnancy hypertension: a meta-analysis.
Lancet 2000;355(9198):87–92. [Evidence: Meta-analysis 14 RCTs, I]
28. Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use dur-
ing pregnancy and the risk of major congenital malformations or small-for-­
gestational-age newborns. Birth defects research Part B, Developmental
and reproductive toxicology 2010;89(2):147–154. [Evidence: II-2]
29. Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of
hypertension in pregnancy. N Engl J Med 2015;372(5):407–417. [Evidence:
RCT, I]
30. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure
during pregnancy. Cochrane Database Syst Rev 2013;7:CD001449. [Meta-
analysis; 24 RCTs, n = 2949]
31. Hennessy A, Thornton CE, Makris A. A randomised comparison of hydral-
azine and mini-bolus diazoxide for hypertensive emergencies in pregnancy:
the PIVOT trial. Aust N Z J Obstet Gynaecol 2007;47(4):279–285. [RCT,
n = 124, hydralazine vs mini-bolus diazoxide; not included in Cochrane by
Duley; I]
32. Imdad A, Yakoob MY, Siddiqui S, Bhutta ZA. Screening and triage of intra-
uterine growth restriction (IUGR) in general population and high risk
pregnancies: a systematic review with a focus on reduction of IUGR related
stillbirths. BMC Public Health 2011;11(Suppl 3):S1. [Review]
33. Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound
in normal pregnancy. Cochrane Database Syst Rev 2010;(8):CD001450.
[Meta-analysis]
34. Medically indicated late-preterm and early-term deliveries: ACOG
Committee Opinion, Number 818. Obstet Gynecol 2021;137(2):e29–e33.
[ Review III]
35. Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal beta-
methasone for women at risk for late preterm delivery. N Engl J Med
2016;374(14):1311–1320. [RCT, I]
36. Hutcheon JA, Lisonkova S, Magee LA. Optimal timing of delivery in
pregnancies with pre-existing hypertension. BJOG 2011;118 (1):49–54.
[Population-based cohort study, n = 171,669; II-2]
37. Sibai BM. Diagnosis and management of gestational hypertension and pre-
eclampsia. Obstet Gynecol 2003;102(1):181–192. [Review; III]
38. Koopmans CM, Bijlenga D, Groen H. Induction of labour versus expect-
ant monitoring for gestational hypertension or mild pre-eclampsia after
36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised con-
trolled trial. Lancet 2009;374(9694):979–988. [RCT, n = 756; I]
39. ACOG Practice Bulletin. Diagnosis and management of pre-eclampsia and
eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99(1):159–167.
[Review III]
40. Program, National High Blood Pressure Education. Report of the
national high blood pressure education program working group on high
blood pressure in pregnancy. Am J Obstet Gynecol 2000;183(1):S1–S22.
[Guideline]
41. Waugh JJ, Clark TJ, Divakaran TG. Accuracy of urinalysis dipstick tech-
niques in predicting significant proteinuria in pregnancy. Obstet Gynecol
2004;103(4):769–777. [Review; III]
42. Schiff E, Friedman SA, Kao L, Sibai BM. The importance of urinary protein
excretion during conservative management of severe pre-eclampsia. Am J
Obstet Gynecol 1996;175:1313–1316. [66 cases]
43. Newman MG, Robichaux AG, Stedman CM, et al. Perinatal outcomes in
pre-eclampsia that is complicated by massive proteinuria. Am J Obstet
Gynecol 2003;188:264–268.
44. Martin JN Jr., Rose CH, Briery CM. Understanding and managing HELLP
syndrome: the integral role of aggressive glucocorticoids for mother and
child. Am J Obstet Gynecol 2006;195(4):914–934. [Review; III]
45. Rath W, Fischer T. The diagnosis and treatment of hypertensive disorders of
pregnancy: new findings for antenatal and inpatient care. Dtsch Arztebl Int
2009;106(45):733–738. [Review; III]
46. Cnossen JS, Morris RK, ter Riet G. Use of uterine artery Doppler ultraso-
nography to predict pre-eclampsia and intrauterine growth restriction: a
systematic review and bivariable meta-analysis. CMAJ 2008;178(6):701–
711. [Meta-analysis, 74 studies, n = 79,547; I]
Hypertensive Disorders
47. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-
trimester prediction of hypertensive disorders in pregnancy. Hypertension
2009;53:812–818.
48. American College of Obstetricians and Gynecologists. First-trimester risk
assessment for early-onset pre-eclampsia. Committee opinion no. 638.
Obstet Gynecol 2015;126:e25–7.
49. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365(9461):
785–799. [Review; III]
50. Haddad B, Sibai BM. Expectant management in pregnancies with severe
pre-eclampsia. Semin Perinatol 2009;33(3):143–151. [Review; III]
51. Sibai BM. Expectant management of pre-eclampsia. OBG Management
2005;3:18–36. [Review; III]
52. Sibai BM, Barton JR. Expectant management of severe pre-eclampsia
remote from term: patient selection, treatment, and delivery indications.
Am J Obstet Gynecol 2007;196(6):514–519. [Review; III]
53. Duley L, Henderson-Smart DJ, Meher S. Antiplatelet agents for prevent-
ing pre-eclampsia and its complications. Cochrane Database Syst Rev
2007;(2):CD004659. [Meta-analysis; 59 RCTs, n = 37,560; I]
54. Hoffman MK, Goudar SS, Kodkany BS, et al. Low-dose aspirin for the pre-
vention of preterm delivery in nulliparous women with a singleton preg-
nancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.
Lancet 2020;395(10220):285–293. [RCT, I]
55. Kozer E, Nikfar S, Costei A. Aspirin consumption during the first trimes-
ter of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet
Gynecol 2002;187(6):1623–1630. [Meta-analysis; 22 RCTs; I]
56. Bujold E, Roberge S, Lacasse Y. Prevention of pre-eclampsia and intrauterine
growth restriction with aspirin started in early pregnancy: a meta-analysis.
Obstet Gynecol 2010;116(2 pt 1):402–414. [Meta-analysis; 34 RCTs, n =
11,348; I]
57. Henderson JT, Whitlock EP, O’Conner E, Senger CA, Thompson JH,
Rowland MG. Low-dose aspirin for the prevention of morbidity and mor-
tality from pre-eclampsia: a systematic evidence review for the U.S. preven-
tive services task force [internet]. Rockville (MD): Agency for Healthcare
Research and Quality (US); 2014 April Available from http://www.ncbi.nlm.
nih.gov/books/NBK196392/
58. ACOG Committee Opinion No. 743. Low-dose aspirin use during preg-
nancy. Obstet Gynecol 2018;132(1):e44–e52. [Review; III]
59. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the preven-
tion of stroke in women: a statement for healthcare professionals from
the American Heart Association/American Stroke Association. Stroke
2014;45(5):1545.
60. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnan-
cies at high risk for preterm pre-eclampsia. N Engl J Med 2017;377:613–622.
[RCT, I]
61. Poon LC, Wright D, Rolnik DL, et al. Aspirin for Evidence-Based Pre-
eclampsia Prevention trial: effect of aspirin in prevention of preterm pre-
eclampsia in subgroups of women according to their characteristics and
medical and obstetrical history. Am J Obstet Gynecol 2017;217:585 e1–585
e5. [Secondary analysis RCT, N-110, I]
62. Poon LC, Shennan A, Hyett JA, et al. The International Federation of
Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic
guide for first-trimester screening and prevention. Int J Gynaecol Obstet
2019;145(Suppl 1):1–33. [Review III]
63. Dekker GA, Sibai BM. Low-dose aspirin in the prevention of pre-eclampsia
and fetal growth retardation: rationale, mechanisms, and clinical trials. Am
J Obstet Gynecol. 1993;168(1 Pt 1):214.
64. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative
Group. CLASP: a randomised trial of low-dose aspirin for the prevention
and treatment of pre-eclampsia among 9364 pregnant women. Lancet
1994;343(8898):619.
65. Schiff E, Barkai G, Ben-Baruch G, Mashiach S. Low-dose aspirin does
not influence the clinical course of women with mild pregnancy-induced
hypertension. Obstet Gynecol 1990;76(5 Pt 1):742.
66. Bujold E, Morency AM, Roberge S. Acetylsalicylic acid for the prevention of
pre-eclampsia and intra-uterine growth restriction in women with abnor-
mal uterine artery Doppler: a systematic review and meta-analysis. J Obstet
Gynaecol Can 2009;31(9):818–826. [Meta-analysis; 9 RCTs, n = 1317; I]
67. Subtil D, Goeusse P, Houfflin-Debarge V. Randomised comparison of
uterine artery Doppler and aspirin (100 mg) with placebo in nulliparous
women: the Essai Regional Aspirine Mere-Enfant study (Part 2). BJOG
2003;110(5):485–491. [RCT, n = 1253; I]
68. Villa PM, Kajantie E, Räikkönen K, et al. Aspirin in the prevention of pre-
eclampsia in high-risk women: a randomised placebo-controlled PREDO
Trial and a meta-analysis of randomised trials., PREDO Study Group BJOG
2013;120(1):64.
23
69. Dodd JM, McLeod A, Windrim RC, Kingdom J. Antithrombotic therapy for
improving maternal or infant health outcomes in women considered at risk
of placental dysfunction. Cochrane Database Syst Rev 2013;7:CD006780.
70. Rey E, Garneau P, David M. Dalteparin for the prevention of recurrence
of placental-mediated complications of pregnancy in women without
thrombophilia: a pilot randomized controlled trial. J Thromb Haemost
2009;7(1):58–64. [RCT, n = 116; I]
71. Bates SM, Greer IA, Pabinger I. Venous thromboembolism, thrombo-
philia, antithrombotic therapy, and pregnancy: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest 2008;133(Suppl 6):844S–886S. [Guidelines]
72. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Torloni MR. Calcium sup-
plementation during pregnancy for preventing hypertensive disorders and
related problems. Cochrane Database Syst Rev 2014;6:CD001059. [Meta-
analysis; 13 RCTs, n = 15,730; I]
73. Levine RJ, Hauth JC, Curet LB. Trial of calcium to prevent pre-eclampsia. N
Engl J Med 1997;337(2):69–76.
74. Sibai BM. Calcium supplementation during pregnancy reduces risk of high
blood pressure, pre-eclampsia and premature birth compared with pla-
cebo? Evid Based Med 2011;16(2):40–41. [Review; III]
75. Rumbold A, Duley L, Crowther CA. Antioxidants for preventing pre-
eclampsia. Cochrane Database Syst Rev 2008;(1):CD004227. [Meta-
analysis; 10 RCTs, n = 6533; I]
76. Basaran A, Basaran M, Topatan BSO. Combined vitamin C and E supple-
mentation for the prevention of pre-eclampsia: a systematic review and
meta-analysis. Obstet Gynecol Surv 2010;65(10):653. [9 studies]
77. Conde-Agudelo A, Romero R, Kusanovic JP, Hassan SS. Supplementation
with vitamins C and E during pregnancy for the prevention of pre-eclampsia
and other adverse maternal and perinatal outcomes: a systematic review
and metaanalysis. Am J Obstet Gynecol 2011;204(6):503.e1. [Nine trials
involving a total of 19,810 women]
78. Xu H, Perez-Cuevas R, Xiong X. An international trial of antioxidants
in the prevention of pre-eclampsia (INTAPP). Am J Obstet Gynecol
2010;202(3):239. [RCT, n = 2363; I]
79. Spinnato JA, Freire S, Pinto e Silva JL. Antioxidant supplementation and
premature rupture of the membranes: a planned secondary analysis. Am J
Obstet Gynecol 2008;199(4):433–438. [RCT, n = 697; I]
80. Stratta P, Canavese C, Porcu M, et al. Vitamin E supplementation in pre-
eclampsia. Gynecol Obstet Invest 1994;37(4):246.
81. Gülmezoğlu AM, Hofmeyr GJ, Oosthuisen MM. Antioxidants in the treat-
ment of severe pre-eclampsia: an explanatory randomised controlled trial.
Br J Obstet Gynaecol 1997;104(6):689.
82. Churchill D, Beevers GD, Meher S. Diuretics for preventing pre-eclampsia.
Cochrane Database Syst Rev 2007;(1):CD004451. [Meta-analysis; 5 RCTs,
n = 1836; I]
83. Duley L, Henderson-Smart D, Meher S. Altered dietary salt for prevent-
ing pre-eclampsia, and its complications. Cochrane Database Syst Rev
2005;(4):CD005548. [Meta-analysis; 2 RCTs, n = 603; I]
84. Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin pre-
cursor, supplementation for pregnancy uncomplicated by pre-eclampsia
or intrauterine growth restriction. Cochrane Database Syst Rev 2006;3:
CD003402. [Meta-analysis; 6 RCTs, n = 2783; I]
85. Meher S, Duley L. Garlic for preventing pre-eclampsia and its complica-
tions. Cochrane Database Syst Rev 2006;3:CD006065. [Meta-analysis;
1 RCT, n = 100; I]
86. Meher S, Duley L. Rest during pregnancy for preventing pre-eclampsia
and its complications in women with normal blood pressure. Cochrane
Database Syst Rev 2006;(2):CD005939. [Meta-analysis; 2 RCT, n = 106; I]
87. Meher S, Duley L. Exercise or other physical activity for prevent-
ing pre-eclampsia and its complications. Cochrane Database Syst Rev
2006;(2):CD005942. [Meta-analysis; 2 RCTs, n = 45]
88. Meher S, Duley L. Progesterone for preventing pre-eclampsia and its
complications. Cochrane Database Syst Rev 2006;(4):CD006175. [Meta-
analysis; 2 RCTs, n = 296; I]
89. Meher S, Duley L. Nitric oxide for preventing pre-eclampsia and its compli-
cations. Cochrane Database Syst Rev 2007;(2):CD006490. [Meta-analysis,
6 RCTs, n = 310]
90. Kroner C, Turnbull D, Wilkinson C. Antenatal day care units versus hospi-
tal admission for women with complicated pregnancy. Cochrane Database
Syst Rev 2001;(4):CD001803. [Meta-analysis; 1 RCT, n = 54]
91. Tuffnell DJ, Lilford RJ, Buchan PC. Randomised controlled trial of day care
for hypertension in pregnancy. Lancet 1992;339(8787):224–227. [RCT, n =
54; included in Cochrane by Kroner; I]
92. Turnbull DA, Wilkinson C, Gerard K. Clinical, psychosocial, and economic
effects of antenatal day care for three medical complications of pregnancy:
24
a randomised controlled trial of 395 women. Lancet 2004;363(9415):
1104–1109. [RCT, n = 395; not included in Cochrane by Kroner; I]
93. Duley L, Gulmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and
other anticonvulsants for women with pre-eclampsia. Cochrane Database
Syst Rev 2010;11:CD000025. [Meta-analysis; 15 RCTs, n = 11,444; I]
94. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet
Gynecol 2005;105(2):402–410. [Review; III]
95. Duley L, Matar HE, Almerie MQ. Alternative magnesium sulphate regi-
mens for women with pre-eclampsia and eclampsia. Cochrane Database
Syst Rev 2010;(8):CD007388. [Meta-analysis; 6 RCTs, n = 866; of which 2
compared regimens for women with eclampsia and 4 for women with pre-
eclampsia; I]
96. Witlin AG, Friedman SA, Sibai BM. The effect of magnesium sulfate ther-
apy on the duration of labor in women with mild pre-eclampsia at term: a
randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol
1997;176(3):623–627. [RCT, n = 135; I]
97. Graham NM, Gimovsky AC, Roman A, et al. J Blood loss at cesarean
delivery in women on magnesium sulfate for pre-eclampsia. Matern Fetal
Neonatal Med 2015 September 2:1–5. [Epub ahead of print]
98. Duley L, Williams J, Henderson-Smart DJ. Plasma volume expansion for
treatment of women with pre-eclampsia. Cochrane Database Syst Rev
2000;(2):CD001805. [Meta-analysis; 3 RCTs, n = 61; I]
99. ACOG Committee Opinion No. 623. Emergent therapy for acute-onset,
severe hypertension during pregnancy and the postpartum period. Obstet
Gynecol 2015;125:521–525 [Guideline]
100. Magee LA, Cham C, Waterman EJ. Hydralazine for treatment of severe
hypertension in pregnancy: meta-analysis. BMJ 2003;327(7421):955–960.
[Meta-analysis; 1 RCTs, n = 893, of which eight compared hydralazine with
nifedipine and five with labetalol; I]
101. Knight M, Duley L, Henderson-Smart DJ. Withdrawn: antiplate-let agents
for preventing and treating pre-eclampsia. Cochrane Database Syst Rev
2007;(2):CD000492. [Meta-analysis; 42 RCTs, n = 32,000; I]
102. Wallace DH, Leveno KJ, Cunningham FG. Randomized comparison of gen-
eral and regional anesthesia for cesarean delivery in pregnancies compli-
cated by severe pre-eclampsia. Obstet Gynecol 1995;86(2):193–199. [RCT,
n = 80; I]
103. Tajik P, van der Tuuk K, Koopman CM. et al. Should cervical favorability
play a role in the decision for labour induction in gestational hypertension
or mild pre-eclampsia at term? An exploratory analysis from the HYPITAT
trial. BJOG 2012;119:1123–1130 [Secondary analysis of RCT]
104. Alanis MC, Robinson CJ, Hulsey TC. Early-onset severe pre-eclampsia:
induction of labor vs. elective cesarean delivery and neonatal outcomes. Am
J Obstet Gynecol 2008;199(3):262–266. [Level II-3]
105. Alexander JM, Bloom SL, McIntire DD. Severe pre-eclampsia and the very
low birth weight infant: is induction of labor harmful? Obstet Gynecol
1999;93(4):485–488. [Level III]
106. Berkley E, Meng C, Rayburn WF. Success rates with low dose misoprostol
before induction of labor for nulliparas with severe pre-eclampsia at vari-
ous gestational ages. J Matern Fetal Neonatal Med 2007;20(11):825–831.
[Level III]
107. Blackwell SC, Redman ME, Tomlinson M. Labor induction for the preterm
severe pre-eclamptic patient: is it worth the effort? J Matern Fetal Med
2001;10(5):305–311. [Level III]
108. Hall DR, Odendaal HJ, Steyn DW. Delivery of patients with early
onset, severe pre-eclampsia. Int J Gynaecol Obstet 2001;74(2):143–150.
[Level III]
109. Mashiloane CD, Moodley J. Induction or caesarean section for preterm pre-
eclampsia? J Obstet Gynaecol 2002;22(4):353–356. [Level III]
110. Nassar AH, Adra AM, Chakhtoura N. Severe pre-eclampsia remote from
term: labor induction or elective cesarean delivery? Am J Obstet Gynecol
1998;179(5):1210–1213. [Level III]
111. Schoen CN, Moreno, SC, Graham, NM, et al. 786: Is outpatient manage-
ment safe for women with superimposed pre-eclampsia without severe fea-
tures? Am J Obstet Gynecol 2016;214(1):S411.
112. Schoen, C, Odell, L, Moreno, SC, et al. Predictors of progression of preterm
pre-eclampsia without severe features to severe disease. Obstet Gynecol.
2016;127:73S. [ACOG abstract]
113. Hall DR, Odendaal HJ, Steyn DW. Grové D. Urinary protein excretion and
expectant management of early onset, severe pre-eclampsia. Int J Gynaecol
Obstet 2002;77(1):1 [74 cases]
114. von Dadelszen P, Payne B, Li J, et al. Prediction of adverse maternal out-
comes in pre-eclampsia: development and validation of the full PIERS
model. PIERS Study Group. Lancet 2011;377(9761):219. [Review; III]
115. Ganzevoort W, Rep A, Bonsel GJ. A randomised controlled trial compar-
ing two temporising management strategies, one with and one without
Maternal-Fetal Evidence Based Guidelines
plasma volume expansion, for severe and early onset pre-eclampsia. BJOG
2005;112(10):1358–1368. [Meta-analysis; 2 RCTs, n = 216; I]
116. Odendaal HJ, Pattinson RC, Bam R. Aggressive or expectant management
for patients with severe pre-eclampsia between 28 to 32 weeks’ gestation: a
randomized controlled trial. Obstet Gynecol 1990;76(6):1070–1075. [RCT,
n = 28; included in Cochrane by Churchill, 2002; I]
117. Sibai BM, Mercer BM, Schiff E. Aggressive versus expectant management of
severe pre-eclampsia at 28 to 32 weeks’ gestation: a randomized controlled
trial. Am J Obstet Gynecol 1994;171(3):818–822. [RCT, n = 95; included in
Cochrane by Churchill, 2002; I]
118. Vigil-Degraxia, Tejada, Calle Minaca, et al. Expectant management of
severe pre-eclampsia remote from term: the MEXPRE Latin Study, a ran-
domized multicenter trial. Am J Obstet Gynecol 2013;209:425.e1–8 [RCT,
n = 267]
119. Churchill D, Duley L. Interventionist versus expectant care for severe pre-
eclampsia before term. Cochrane Database Syst Rev 2002;(3):CD003106.
[Meta-analysis; 2 RCTs, n = 133; I]
120. Magee LA, Yong PJ, Espinosa V. Expectant management of severe pre-
eclampsia remote from term: a structured systematic review. Hypertens
Pregnancy 2009;28(3):312–347. [Review; 72 studies; III]
121. American College of Obstetricians and Gynecologists and Society for
Maternal–Fetal Medicine, Menard MK, Kilpatrick S, Saade G, Hollier LM,
Joseph GF Jr, Barfield W, Callaghan W, Jennings J, Conry J. Levels of mater-
nal care. Am J Obstet Gynecol 2015;212(3):259–71.
122. Publications Committee, Society for Maternal-Fetal Medicine, Sibai BM.
Evaluation and management of severe pre-eclampsia before 34 weeks’ ges-
tation. Am J Obstet Gynecol 2011;205(3):191–198.
123. Society for Maternal-Fetal Medicine Publications Committee, Berkley E,
Chauhan SP, Abuhamad A. Doppler assessment of the fetus with intra-
uterine growth restriction. Am J Obstet Gynecol. 2012;206(4):300–308.
Erratum in: Am J Obstet Gynecol. 2015 Feb;212(2):246. Am J Obstet
Gynecol 2012 Jun;206(6):508.
124. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues
and management. A review. BMC Pregnancy Childbirth 2009;9:8. [Review;
III]
125. Sibai BM. A practical plan to detect and manage HELLP syndrome. OBG
Management 2005;4:52–69. [Review; III]
126. Sibai BM. Diagnosis, controversies, and management of the syndrome of
hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol
2004;103(5 pt 1):981–991. [Review; III]
127. Woudstra DM, Chandra S, Hofmeyr GJ. Corticosteroids for HELLP
(hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy.
Cochrane Database Syst Rev 2010;(9):CD008148. [Meta-analysis; 11 RCTs,
n = 550; I]
128. Isler CM, Barrilleaux PS, Magann EF. A prospective, randomized trial com-
paring the efficacy of dexamethasone and betamethasone for the treatment
of antepartum HELLP (hemolysis, elevated liver enzymes, and low platelet
count) syndrome. Am J Obstet Gynecol 2001;184(7):1332–1337. [RCT,
n = 40. Dexamethasone versus betamethasone; I]
129. Isler CM, Magann EF, Rinehart BK. Dexamethasone compared with beta-
methasone for glucocorticoid treatment of postpartum HELLP syndrome.
Int J Gynaecol Obstet 2003;80(3):291–297. [RCT, n = 36; Dexamethasone
versus betamethasone I]
130. Fonseca JE, Mendez F, Catano C. Dexamethasone treatment does not
improve the outcome of women with HELLP syndrome: a double-blind,
placebo-controlled, randomized clinical trial. Am J Obstet Gynecol
2005;193(5):1591–1598. [RCT, n = 132; I]
131. Katz L, de Amorim MM, Figueiroa JN. Postpartum dexamethasone for
women with hemolysis, elevated liver enzymes, and low platelets (HELLP)
syndrome: a double-blind, placebo-controlled, randomized clinical trial.
Am J Obstet Gynecol 2008;198(3):283–288. [RCT, n = 105;I]
132. van Runnard Heimel PJ, Huisjes AJ, Franx A. A randomised placebo-­
controlled trial of prolonged prednisolone administration to patients with
HELLP syndrome remote from term. Eur J Obstet Gynecol Reprod Biol
2006;128(1–2):187–193. [RCT, n = 31; I]
133. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol
2009;33(3):130–137. [Review; III]
134. Duley L, Henderson-Smart DJ, Walker GJ. Magnesium sulphate versus
diazepam for eclampsia. Cochrane Database Syst Rev 2010;12:CD000127.
[Meta-analysis; 7 RCTs, n = 1396; I]
135. Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phe-
nytoin for eclampsia. Cochrane Database Syst Rev 2010;(10):CD000128.
[Meta-analysis; 7 RCTs, n = 972; I]
136. Duley L, Gulmezoglu AM, Chou D. Magnesium sulphate versus lytic cock-
tail for eclampsia. Cochrane Database Syst Rev 2010;(9):CD002960.
Hypertensive Disorders
137. Magee L, Sadeghi S. Prevention and treatment of postpartum hypertension.
Cochrane Database Syst Rev 2005;(1):CD004351. [Meta-analysis; 6 RCTs: 3
RCTs on prevention, n = 315; 3 RCTs on treatment, n = 144; I]
138. Ascarelli MH, Johnson V, McCreary H. Postpartum pre-eclampsia man-
agement with furosemide: a randomized clinical trial. Obstet Gynecol
2005;105(1):29–33. [RCT, n = 264; I]
139. Hladunewich MA, Derby GC, Lafayette RA. Effect of L-arginine therapy
on the glomerular injury of pre-eclampsia: a randomized controlled trial.
Obstet Gynecol 2006;107(4):886–895. [RCT, n = 45;I]
140. Sep S, Smits L, Prins M. Prediction tests for recurrent hypertensive dis-
ease in pregnancy, a systematic review. Hypertens Pregnancy 2010;29(2):
206–230. [Review, 33 studies; III]
141. Van Oostwaard MF, Langenveld J, Schiut E, et al. Recurrence of hyperten-
sive disorders of pregnancy: an individual patient data Metaanalysis. AJOG
2015;212:624.e1–17 [II-1]
142. Hernandez-Diaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and
subsequent pregnancies: prospective cohort study. BMJ 2009;338:b2255.
[Cohort analytic study, n = 763,795; II-2]
25
143. Langenveld J, Jansen S, van der Post J. Recurrence risk of a delivery before
34 weeks of pregnancy due to an early onset hypertensive disorder: a sys-
tematic review. Am J Perinatol 2010;27(7):565–571. [Meta-analysis;
7 RCTs, n = 2188; I]
144. Langenveld J, Buttinger A, van der Post J. Recurrence risk and prediction of
a delivery under 34 weeks of gestation after a history of a severe hyperten-
sive disorder. BJOG 2011;118 (5):589–595. [Cohort analytic study, n = 211;
II-2]
145. Chames MC, Haddad B, Barton JR. Subsequent pregnancy outcome in
women with a history of HELLP syndrome at < or = 28 weeks of gestation.
Am J Obstet Gynecol 2003;188(6):1504–1507. [II-2]
146. Magnussen EB, Vatten LJ, Smith GD. Hypertensive disorders in pregnancy
and subsequently measured cardiovascular risk factors. Obstet Gynecol
2009;114(5):961–970. [Observational study, n = 15,065; II-3]
2
CARDIAC DISEASE
Preethi Pirlamarla and Gregary D. Marhefka
Key points
• Pregnancy is characterized by predictable physiologic
changes including decreased systemic vascular resistance,
increased intravascular volume, increased cardiac output,
and hypercoagulability, all of which can severely exacer-
bate pre-existing or newly diagnosed cardiac disease.
• In the prenatal period or during gestation, a useful scheme
to risk stratify pregnant patients is the World Health
Organization classification of maternal cardiovascular
risk, from class I to IV.
• Severe pulmonary hypertension, severe cardiomyopa-
thy (ejection fraction < 30%) or previous peripartum
cardiomyopathy, severe symptomatic aortic stenosis,
Marfan syndrome with aortic root > 4.5 cm, and bicus-
pid aortic valve with aortic aneurysm > 5 cm constitute
class IV conditions with extremely high risk of morbid-
ity or mortality with pregnancy.
• For many cardiac conditions, especially severe pulmo-
nary hypertension and severe aortic stenosis, relative
hypervolemia rather than fluid restriction, and avoid-
ance of hypotension are the key intrapartum man-
agement principles. Mitral stenosis and some cases of
cardiomyopathy are the main exceptions to this principle.
• Though rare, coronary artery disease events are more
common in pregnant patients than age matched non-preg-
nant patients, and are more likely due to spontaneous coro-
nary artery dissection and coronary artery disease without
obstruction, than classic atherosclerotic coronary artery
disease.
• Women with congenital heart disease should have a fetal
echocardiogram at around 22 weeks.
Background
Pre-existing or newly diagnosed maternal cardiac diseases por-
tend a higher risk for peripartum cardiovascular complications,
neonatal complications, and maternal mortality. In fact, despite
being relatively uncommon, cardiovascular diseases are the
most common cause of pregnancy related deaths, more than
historically common causes like infection and hemorrhage [1].
Four main risk factors are associated with maternal cardio-
vascular mortality: race, age, hypertension, and obesity [2].
Congestive heart failure, valvular heart disease, systemic and
pulmonary hypertensive disorders in pregnancy, congenital
heart disease, and even ischemic heart disease are important
pre-existing or newly diagnosed maternal disorders that can be
associated with high mortality and are discussed in this chap-
ter. The physiologic changes associated with pregnancy can
contribute to exacerbations of any these cardiovascular dis-
eases during gestation. Acute onset or decompensation of any
of these conditions in pregnancy, or any associated complications
26
like arrhythmias, warrant special attention and thoughtful
management strategies. Patients with pre-existing or newly
diagnosed cardiovascular disease should be referred to a car-
dio-obstetrics team [3]. These referrals can be initiated by any
of the following: primary care practitioners, emergency depart-
ment providers, obstetricians/gynecologists, and cardiovascular
disease specialists. The cardio-obstetrics team can include obste-
tricians, cardiologists, maternal fetal medicine specialists, with
ad-hoc additions of anesthesiologists, geneticists, neurologists,
nurses, and pharmacists when deemed appropriate.
Symptoms/Signs
The physiologic changes of pregnancy can often lead to symp-
toms and signs that are difficult to distinguish from exacerba-
tion of pre-existing or new onset cardiovascular disease (see
Chap. 3 in Obstetric Evidence Based Guidelines). Symptoms and
signs include fatigue, reduced physical exertional capacity,
palpitations, resting shortness of breath, dyspnea on exer-
tion, chest pain, tachycardia, distended neck veins, right or
left sided gallops, pathologic murmurs, rales and edema. It is
estimated that 25% or more of maternal deaths could be pre-
vented if cardiovascular diseases were considered by health
care practitioners in the differential diagnosis of many of
these symptoms and signs [2]. Maintaining a high clinical index
of suspicion along with diligent history and physical examination
are the first steps in identifying these conditions and to mitigate
untoward complications. Table 2.1 shows clues to differentiating
physiologic pregnancy findings from potentially pathologic car-
diovascular disease findings.
Epidemiology/Incidence
For years cardiac disease complicated only 1–4% of all pregnan-
cies in the United States, yet cardiovascular diseases are respon-
sible for the majority of maternal deaths. In an update from 2017,
evaluating data from 2009 pregnancy-related deaths from
2010–2013 reported to the Centers for Disease Control, more
than 25% were deemed cardiovascular in nature (cardiovascu-
lar conditions – not including cardiomyopathy – in 15.5%, and
cardiomyopathy in another 11%) [1]. The four risk factors identi-
fied by the American College of Obstetrics and Gynecology for
maternal cardiovascular mortality are non-Hispanic black race,
age > 40 years old, hypertension, and obesity [2]. In the devel-
oped world, important acquired cardiac diseases are in large part
caused by poor diet, inactivity, obesity, smoking, hyperlipidemia,
diabetes, and hypertension. The incidence of pregnancies in heart
disease is also increasing due to a higher number of survivors of
congenital heart disease into adulthood and an increasing mater-
nal age. In the Western world, congenital heart disease makes
up 80% of pregnancies in patients with pre-existing cardiac dis-
ease, with a low risk of mortality (0.5%), but significant risk of
DOI: 10.1201/9781003099062-2
Cardiac Disease
TABLE 2.1: Symptoms and Signs of Pregnancy and Cardiac Disease
Normal
Fatigue Mild
Palpitations Rare
Dyspnea With heavy exertion only
Chest pain Reflux related, resolves with
treatment
Heart rate (bpm) <90
Systolic BP (mm Hg) 90–140
Jugular venous None
distension (JVD)
Gallop Soft S3, absence of symptoms
Murmur Soft systolic murmur
Lungs Clear
Edema Mild
Source: Adapted from Ref. [41].
Abbreviations: JVD: jugular venous distension, BP: blood pressure, S3: S3 murmur, S4: S4 murmus, bpm: beats per minute.
morbidity (11%, mainly in the form of arrhythmias and heart fail-
ure) [4]. Cardiac diseases are a leading cause of admission of
the peripartum patient to an intensive care unit [5].
Genetics
There are a handful of autosomal dominant cardiac conditions, for
which the mother would ideally have sought prenatal screening
to discuss potential transmission to children. These syndromes
include hypertrophic cardiomyopathy, inherited arrhythmias like
long QT, Marfan, Noonan, William, Holt-Oram, and DiGeorge
(22q11 deletion) [6]. Certain genetic aortopathies are at higher
risk for progressive aneurysm formation, dissection and extra-
cardiac manifestations, which vary based on etiology. Genetic
causes of aortopathy can contribute to intracellular pathology
(ACTA2, FLNA, MYLK, PRKG1, MYH11, SKI, SMAD3,4 and
TGFβR1,2) or those that affect the extracellular matrix (BGN,
COL1A1, COL3A1, 5A1, FBN1, 2, LOX, MFAP5, PLOD1, PRKG1,
and TGFβ1,2,3). Other genetic conditions to consider with well-
known associated aortopathies are bicuspid aortic valve and
Turner’s syndrome (XO) [7]. As an ad-hoc member of the cardio-
obstetrics team, a geneticist can assist in determining risk profiles.
Etiology/Basic pathophysiology/
Pregnancy considerations
The main function of the heart is to provide oxygen (and other nutri-
ents), and remove carbon dioxide (and other wastes) to and from all
end organs of the body, which include the uterus and fetus during
pregnancy. The chief determinants of oxygen delivery include the
amount carried by the blood (determined by the amount of hemo-
globin and degree of saturation) and the delivery of that blood: pri-
marily cardiac output (determined by preload, afterload, cardiac
contractility, and heart rate). Any disease process or pregnancy
physiology that interferes with this main function of the heart can
result in maternal and fetal morbidity and mortality.
27
Concerning Needs Evaluation
Mild to moderate Severe
Occasional, no associated Frequent and/or associated with
symptoms presyncope or syncope
Moderate exertion At rest or with minimal exertion,
significant orthopnea or
paroxysmal nocturnal dyspnea
Atypical At rest or with minimal exertion
90–120 >120
140–160 <90 with symptoms or >160
≥2 cm above clavicle
S3 with symptoms, or S4
Loud systolic murmur, any
diastolic murmur
Rales, wheezing
Moderate Severe
Five principal physiologic changes of pregnancy can compli-
cate cardiac disease during pregnancy [8]. See also Chapter 3,
Obstetric Evidence Based Guidelines.
1. Decreased systemic vascular resistance (SVR). Systemic vas-
cular resistance decreases in pregnancy due to estrogen and
progesterone mediated vasodilation as well as the high flow
and low resistance circuit in the uteroplacental circulation [9].
Though overall well tolerated in patients with normal cardiac
function, this change in afterload can lead to adverse effects
in patients with pre-existing cardiac history. One such group
of patients are those with ventricular septal defects (VSDs).
VSDs result in the shunting of blood from the left ventricle
to the right ventricle due to the difference in the right and
left system pressure gradients. Over time, shunting results
in pulmonary hypertension that can approach systemic
blood pressures. Pregnancy, with its associated 20% decrease
in SVR, can allow pulmonary pressures to equal or exceed
systemic pressures resulting in a reversal of this shunt. This
would result in deoxygenated right ventricular blood enter-
ing the left ventricle, resulting in decreased oxygen delivery
to the body and even cyanosis and death [10]
2. Increase in intravascular volume. During pregnancy, there
is a sharp increase in the circulating plasma volume at
50–70% of pre-pregnancy volume [9] This occurs through-
out pregnancy and is maximal by 32 weeks’ gestation. This
volume increase can be poorly tolerated in women with
pre-existing cardiomyopathy or left ventricular dysfunc-
tion, leading to heart failure exacerbations and persistently
elevated filling pressures.
3. Postpartum increase in intravascular volume from “auto-
transfusion” of blood from the contracted uterus and mobi-
lization of third spaced fluid. Women with mitral stenosis
have restricted left ventricular filling. This postpartum
vascular load could result in pulmonary edema.
4. Hypercoagulability. This well-characterized pregnancy
adaptation can dramatically heighten the risk for
28 Maternal-Fetal Evidence Based Guidelines

thromboembolism in at-risk patients. Pregnant women TABLE 2.3: A Statement from the American Heart Association:
with artificial mechanical heart valves, for example, can World Health Organization Classification of
develop fatal thromboses despite adequate anticoagulation Maternal Cardiovascular Risk
as a result of this physiology [11].
I No increase in • Uncomplicated mild PS, small PDA,
5. Marked increase in cardiac output during parturition.
maternal mortality, mild MVP
This increase occurs during pregnancy, and is both neces-
no or mild increase • Repaired ASD, VSD, PDA, APVD
sary for and partly “worsened” by labor and delivery and
morbidity • Isolated atrial or ventricular ectopic
the postpartum volume shift described earlier. In women
complexes
whose cardiac output is fixed and very dependent on pre-
II Small increase in • Uncomplicated unrepaired ASD,
load, like aortic stenosis, these volume shifts are poorly
mortality, moderate VSD
tolerated. A negative volume shift from postpartum hem-
increase in • Repaired TOF
orrhage can result in a precipitous drop in cardiac output
morbidity • Uncomplicated arrhythmias
and lead to inadequate coronary and cerebral perfusion [6].
II–III Moderate increase • Mild LV dysfunction (LVEF
in mortality and 45–55%)
Understanding these pathophysiologic interactions form the
morbidity • HCM
basis for understanding, anticipating, and managing patients
• Native or tissue valvular disease
with cardiac disease during pregnancy.
• Marfan without aortic aneurysm
• BV small aortic aneurysm <4.5 cm
Classification • Repaired coarctation
III Significantly • Mechanical valve
Patients with heart disease are symptomatically classified by their
increased mortality • Systemic RV
clinical functional class (New York Heart Association [(NYHA]
or severe morbidity • Fontan circulation
system) (Table 2.2). Women who have pre-pregnant NYHA III
• Unrepaired cyanotic CHD
or IV functional capacity tend to tolerate pregnancy poorly,
• Other complex CHD
but even less symptomatic women are at risk during pregnancy
• Marfan aortic aneurysm 4–4.5 cm
because up to 40% of those who develop congestive heart failure
• BV medium aortic aneurysm
during gestation begin their pregnancy without symptoms (class
4–4.5 cm
I), and 15–55% of pregnant women with heart disease show dete-
rioration by this system [12]. IV Extremely high • PH, any cause
mortality or severe • Severe LV dysfunction (LVEF < 30%,
morbidity NYHA III-IV)
Risk factors • Previous peripartum CM with LV
dysfunction
Predictors of maternal complications include prior car-
• Severe mitral stenosis
diac events, NYHA class III or IV symptoms (Table 2.2), left
• Severe symptomatic aortic stenosis
sided obstructions (mitral stenosis, aortic stenosis), mechani-
• Marfan aortic aneurysm > 4.5 cm
cal heart valve, Marfan syndrome, aortic root dilatation, and
• BV large aortic aneurysm >5 cm
significant left ventricular systolic dysfunction. The modified
• Severe coarctation
World Health Organization (WHO) classification (Table 2.3) is
an effective method to stratify cardiovascular risk in pregnant Source: Adapted from Ref. [7].
Abbreviations: PS: pulmonic stenosis, PDA: patent ductus arteriosus, MVP: mitral
valve prolapse, ASD: atrial septal defect, VSD: ventricular septal defect, APVD:
TABLE 2.2: New York Heart Association Classification of anomalous pulmonary venous drainage, TOF: Tetralogy of Fallot, LV: left ventricle,
Heart Failure Symptoms EF: ejection fraction, HCM: hypertrophic cardiomyopathy, BV: bicuspid valve, RV:
right ventricle, CHD: congenital heart disease, PH: pulmonary hypertension, NYHA:
Class I New York Heart Association, CM: cardiomyopathy.
No symptoms or limitations.
Ordinary physical activity does not cause undue fatigue, dyspnea, or
palpitations.
women with congenital heart disease; this model integrates
knowledge about maternal risk, including known contraindi-
Class II
cations for pregnancy which are not addressed in other risk
Slight limitation of physical activity.
scores, as well as known predictors found in other studies,
Comfortable at rest.
underlying heart disease, and other morphological and clinical
Ordinary physical activity (e.g., carrying heavy packages) may result in
variables [6]. Expert knowledge is sometimes required for use
fatigue, palpitations, or dyspnea.
of this model, especially when choosing between WHO class II
Class III
and III.
Marked limitation of physical activity.
Comfortable at rest.
Less than ordinary physical activity (e.g., getting dressed) leads to Complications
symptoms.
Today, with proper management, maternal mortality is pre-
Class IV
dominantly restricted to patients with severe pulmonary
Severe limitation of physical activity.
hypertension, coronary artery disease (CAD), cardiomyopa-
Symptoms of heart failure or angina are present at rest and worsen
thy, endocarditis, and sudden arrhythmia [6]. These groups
with any activity.
can be used to determine general treatment principles. Neonatal
Cardiac Disease
complications mostly derive from preterm birth, miscarriage,
and growth restriction.
Management
Pre-conception counseling
A multi-disciplinary cardio-obstetrics team is crucial in
pre-conception counseling for women with pre-existing car-
diovascular conditions to facilitate shared decision making
with the patient at every stage of the process. As discussed
earlier, the cardio-obstetrics team can include obstetricians,
cardiologists, maternal fetal medicine specialists, with ad-
hoc additions of anesthesiologists, geneticists, neurologists,
nurses, and pharmacists when appropriate. Previously referred
to, Table 2.3 classifies cardiovascular risk by the WHO. Risk
categories range from I to IV, with an example of class I being
isolated atrial or ventricular ectopic complexes which do not
portend an increased risk, to a class IV example of significant
pulmonary hypertension from any cause which portends an
extremely high risk of cardiovascular mortality. Other pro-
hibitive conditions include severe left ventricular dysfunc-
tion, severe left-sided heart obstruction, and significant aortic
aneurysms associated with bicuspid aortic valve and Marfan
syndrome [6]. Most women with these high risk conditions are
recommended to avoid pregnancy, but may present after con-
ception and still benefit from evaluation and management by
a cardio-obstetrics team. Discussion of contraceptive plan-
ning is also advised in these high risk patients. Pre-conception
counseling is also a time to review all cardiovascular medi-
cations for contraindications, such as teratogenic angiotensin
converting enzyme inhibitors that will require alternatives. In
a retrospective study of 15,000 patients < 45 years of age, 178
women underwent percutaneous coronary intervention from
2008 to 2017 in a British tertiary care facility. Of these, only 2
women (1.1%) had chart documentation of counseling on preg-
nancy risks of cardiac medications [13].
Prenatal care/Antepartum testing
The pregnant woman with pre-existing or newly diagnosed
cardiovascular disease should have a careful medical history
obtained including assessment of functional class, and a complete
physical exam conducted including oxygen saturation, to assess
for signs of decompensation. In certain situations brain natri-
uretic peptides and/or echocardiography should be obtained
to assess chamber dimensions, ventricular function, valvular
function, estimated pulmonary artery systolic pressure, and aor-
tic dimensions. Echocardiography may not always satisfactorily
estimate pulmonary artery systolic pressure, and in select cases,
pulmonary artery catheter placement may rarely be required for
confirmation. Echocardiography would also be recommended in
disproportionate or unexplained dyspnea or in the case of patho-
logic murmurs (loud systolic or any diastolic murmurs). Women
with congenital heart disease should be offered fetal echo-
cardiography around 22 weeks which can identify the majority
of congenital heart disease defects [14]. In pregnancy, the heart
tends to rotate leftward from the gravid abdomen 15–20° on an
electrocardiogram. Other findings include non-specific ST and
T wave changes, Q wave and T wave inversion in lead III, attenu-
ated Q wave in aVF, and inverted T waves in right precordial leads
V1–V3. Other changes may mimic left ventricular hypertrophy
and other structural heart disease.
29
General management
Certain general principles apply to women with general and cer-
tain cardiovascular diseases:
1. Cardio-obstetrics team. Collaborative care of pregnant
patients with cardiovascular conditions includes obstetri-
cians, cardiologists, maternal fetal medicine specialists,
with ad-hoc additions of anesthesiologists, geneticists,
neurologists, nurses, and pharmacists when deemed
appropriate.
2. Antepartum activity restriction. Activity restriction may
be appropriate in certain conditions such as symptom-
atic mitral stenosis and severe pulmonary hypertension to
avoid exacerbating symptoms [6]. Strict bed rest should be
avoided to prevent venous thromboembolic disease.
3. Treat co-existing medical conditions. Medical conditions
like anemia, hypertension, and thyroid disease should be
identified and treated according to standard guidelines to
minimize morbidity.
4. Labor in the lateral decubitus position. Labor in the left
decubitus position has been recommended for years
to reduce inferior vena cava compression by the gravid
uterus and maximize blood return and cardiac output [15].
Magnetic resonance imaging in late pregnancy does show
a supine increase in collateral venous blood flow from infe-
rior vena cava compression, with a reduction in cardiac
output and aortic blood flow [16].
5. Epidural anesthesia. Labor is painful with its physiologic
response being tachycardia, hypertension, and tachypnea.
The associated increase in cardiac output and myocardial
oxygen demand could prove problematic for the parturient
cardiac patient. Epidural anesthesia can reduce the pain,
thereby reducing the detrimental effects of the anticipated
physiologic response. Attention to judicious hydration is
paramount to avoid excessive hypotension from vasodi-
lation and reduced preload that may occur with epidural
anesthesia. Care should also be taken to avoid inadvertent
anesthetic placement intrathecally or intravascularly, as
inappropriate dosing could result in complications [17].
Epidural anesthesia is contraindicated in the fully antico-
agulated patient.
6. Bacterial endocarditis prophylaxis. Prophylactic anti-
biotics are not recommended for routine vaginal or
cesarean delivery by American or European guidelines
on infectious endocarditis. However, in women with con-
genital heart disease such as Eisenmenger syndrome and
cyanotic heart disease, guidelines suggest it is reasonable
to prophylax 30 minutes before delivery since the conse-
quences of endocarditis in this high-risk population could
be quite life threatening [18, 19].
7. Cesarean delivery is reserved for usual obstetrical indi-
cations and in some specific instances in the cardiac
patient. Cesarean delivery is preferred in vasculopathies
like Marfan and Loeys-Dietz syndromes if the aorta is >
4.5 cm, or in bicuspid valve-associated aortopathy when
the aorta is > 5 cm, and in all aortic diameters in patients
with Ehlers-Danlos Type IV. Likewise, patients with severe
pulmonary hypertension and severe left-sided obstruc-
tive disorders like severe aortic stenosis or hypertrophic
cardiomyopathy with obstruction should be considered
for cesarean section. In severe orthopnea associated with
severe heart failure, the parturient patient may best be
30
managed with cesarean section. Lastly, fully anticoagu-
lated patients on warfarin should undergo cesarean sec-
tion in order to reduce fetal hemorrhage risks [17]. Arterial
line blood pressure monitoring should be considered in all
high-risk cardiac patients.
8. Invasive hemodynamic monitoring with a pulmonary artery
catheter is used less often than in the past. As previously
described, postpartum relief of uterine obstruction of the
inferior vena cava and the anticipated “auto-transfusion”
of blood from the uterus can lead to hemodynamic com-
promise in multiple conditions. Select patients with severe
pulmonary hypertension, heart failure, severe aortic ste-
nosis, myocardial ischemia, coronary artery dissection or
aortic dissection, may be best managed with a pulmonary
artery catheter [17].
9. Cardiac arrest. Management of pregnant patients with
cardiac arrest should focus first on the patient with ces-
sation of fetal monitoring during maternal resuscitation.
Particular attention to the airway is important due to a
reduced physiologic pulmonary reserve during pregnancy.
Cardiopulmonary resuscitation with chest compressions,
defibrillation and medications are no different than in
non-pregnant patients. Intravenous or intraosseous lines
should preferentially be placed in the upper extremities
as access from the lower extremities may not allow suffi-
cient systemic circulation due to compression of the gravid
uterus on the inferior vena cava. Therapeutic hypothermia
protocol when deemed clinically appropriate may be con-
sidered on a case by case basis with continuous fetal moni-
toring [20].
10. Postpartum contraceptive management is imperative.
Cardiac conditions with increased risk during pregnancy
include complicated valvular heart disease, uncontrolled
hypertension >160/110 mm Hg, ischemic heart disease,
and peripartum cardiomyopathy. In part, some of the con-
ditions mentioned require teratogenic medications. If not
already discussed antepartum, the postpartum period is
an opportune time to plan contraceptive management [21].
Patients with WHO class III and IV conditions indicated
in Table 2.3 should be considered the highest risk patients
and be counseled on avoiding future repeat pregnancy.
Pregnancy management of specific diseases
Palpitations
Palpitations are more commonly felt in pregnancy. This may be
due to an increased awareness due to a combination of hemo-
dynamic, hormonal and autonomic changes during pregnancy
[22]. Workup should be similar to the non-pregnant patient, with
careful history focusing on timing duration, exertional or non-
exertional, associated symptoms such as chest pain and shortness
of breath, and associated syncope. In addition, a detailed social
history including caffeine intake, smoking, alcohol consumption,
and illicit drug use should be sought after. Testing with thyroid
function tests, electrocardiogram, echocardiogram and Holter
monitoring should be done in select cases. The most commonly
associated findings are premature atrial and ventricular com-
plexes, and are usually benign.
Ventricular septal defects
Repaired or small, restrictive VSDs are considered low risk WHO
class I or II conditions, respectively (Table 2.3). Pregnancy out-
comes are usually good. Since many congenital heart disease
Maternal-Fetal Evidence Based Guidelines
conditions can be associated with other anomalies, scrutiny
for these co-existing findings is important. If VSDs are associ-
ated with significant pulmonary hypertension, outcomes will be
dependent on the degree of pulmonary hypertension and should
be treated accordingly.
Pulmonary hypertension
Pulmonary hypertension is a term used to describe a heterog-
enous group of diseases that are characterized by a mean pul-
monary artery pressure (mPAP) of greater than 25 mmHg.
The WHO differentiates pulmonary hypertension disorders by
classifying them into a 5-group system with treatment dictated
by the etiology (Table 2.4) [9]. WHO group I pulmonary hyper-
tension, defined as pulmonary arterial hypertension, is marked
by progressive pulmonary vascular remodeling leading to right
ventricular hypertrophy, worsening right ventricular failure,
and eventual death. In patients without pulmonary hyperten-
sion, pulmonary vasculature responds to pregnancy with dila-
tation and recruitment of non-perfused vessels, leading to an
overall reduction in pulmonary vasculature resistance (PVR)
[9]. This ability to dilate and recruit is compromised in patients
with pulmonary hypertension, leading to an inability to accom-
modate the increase in cardiac output. The consequences of this
includes significant elevation in mPAP and PVR, increase in RV
afterload and eventual RV failure. Additionally, progressive RV
failure can lead to right to left shunting, leading to increased
hypoxia. Pregnancy in women with pulmonary hypertension,
particularly pre-capillary pulmonary arterial hypertension,
carries a dismal prognosis, with mortality upwards of 50%.
Thus, pregnancy in such patients should be strongly advised
against. However, should pregnancy occur, early referral to an
experienced pulmonary hypertension team should be pursued, as
management of such patients requires a multidisciplinary, team-
based approached. Patients with pulmonary hypertension should
be followed at least monthly throughout the course of their preg-
nancy. Special attention should be paid as the patient approaches
the second trimester, as volume expansion and increase in car-
diac output occurs the greatest during this time [9]. As the patient
progresses to the third trimester, follow up frequency should be
increased to every two weeks, with serial echocardiograms to
monitor RV function. Symptoms should be managed with
TABLE 2.4: World Health Organization Pulmonary
Hypertension Classification
Group Type Examples
1 Primary Idiopathic, connective tissue
disorders, congenital heart disease
2 Secondary to left Left ventricular systolic or diastolic
heart disease heart failure, aortic or mitral
valvulopathy
3 Secondary to lung Chronic obstructive pulmonary
disease artery disease, emphysema,
interstitial lung disease,
obstructive sleep apnea
4 Secondary to Chronic pulmonary emboli
thromboembolic
disease
5 Multifactorial Sarcoidosis, chronic hemolytic
anemia
Source: Adapted from Ref. [9].
Cardiac Disease
diuretics (furosemide being the diuretic of choice) and sup-
plemental oxygen as needed. Route of delivery for women with
severe pulmonary hypertension remains controversial. While
vaginal delivery is associated with less risk of hemorrhage, infec-
tion, and venous thromboembolism, maneuvers used during
vaginal delivery, such as Valsalva, can increase intrathoracic pres-
sures and decreases in venous return and RV preload [9]. However,
emergency cesarean without proper cardiac anesthesia person-
nel or maternal hemodynamic monitoring is associated with an
increased risk of complications. Scheduled cesarean can allow
optimization of delivery conditions with multidisciplinary team
involvement and resources [23]. During labor and delivery, the
patient should have continuous monitoring with pulse oxim-
etry, intra-arterial line, and central venous pressure monitor-
ing [9]. In select cases, invasive hemodynamic monitoring can be
beneficial to monitor RV function during delivery. Regardless of
the route of delivery, care should be taken to avoid hypotension
and hypercarbia which can accentuate RV failure.
Coarctation of the aorta
Coarctation is defined as a discrete narrowing of the aorta.
Though there are anatomical variations, this narrowing typically
occurs distal to the subclavian artery. Generally, they are discov-
ered incidentally during evaluation for hypertension, and can be
associated with other congenital heart defects, including bicuspid
aortic valve or septal defects. The effects of untreated coarcta-
tion are varied, with uncontrolled hypertension being the most
common, and can lead to adverse neonatal effects such as blunted
growth and abruption placentae [23]. The most detrimental
effect, however, is aortic dissection or ruptured aorta, which
can occur secondary to longstanding hypertension and changes
to the intimal walls [23]. There are few data regarding manage-
ment of coarctation in pregnancy patients. In cases of isolated
coarctation, if surgically or percutaneously corrected, maternal
outcomes are favorable. Women with smaller aortic dimensions
are more likely to experience hypertensive complications related
to pregnancy, and conversely, those with larger aortic dimensions
have a lower risk of adverse cardiovascular, obstetric, and fetal/
neonatal events. When evaluating a patient with coarctation, a
full evaluation with echocardiogram and cardiovascular mag-
netic resonance imaging should be performed to evaluate for co-
existing congenital defects [24].
Tetralogy of Fallot
Tetralogy of Fallot consists of VSD, pulmonic stenosis, right ven-
tricular hypertrophy, and overriding aorta. Historically corrected
lesions do well, but uncorrected ones are still associated with high
maternal mortality [25]. Because of the VSD-associated shunting
in uncorrected cases, hypotension, myocardial depressants,
and bradycardia should be avoided [26].
Mitral valve stenosis
In an international prospective pregnancy registry, rheumatic
mitral valve disease was present in 390 patients with 75% from
developing countries. Mitral stenosis was severe by the current
definition, mitral valve area < 1.5 cm2 in 161 patients (~40%).
There was one death, but ~50% developed heart failure. Even
in those with mild mitral stenosis, 16% developed heart failure.
Thirty percent of heart failure occurred in the first week postpar-
tum (in part secondary to the increase in preload). In a subset of
pregnant patients with moderate to severe mitral regurgitation,
23% developed heart failure [27]. Beta-blockers are an important
31
mainstay of medical therapy in significant mitral stenosis, as
higher heart rates are associated with increased mitral valve gra-
dients and thereby pulmonary venous hypertension and heart
failure. Tachycardia should be avoided. This is particularly
relevant if atrial fibrillation ensues because not only is the rapid
ventricular response poorly tolerated, but also the loss of atrial
contraction. Peak heart rate and cardiac output during pregnancy
occur at 28–32 weeks’ gestation. The best time to intervene on
symptomatic mitral stenosis is after the fourth month [14]. Mitral
valve balloon valvuloplasty is preferred if rheumatic, no signifi-
cant mitral regurgitation and an appropriately low Wilkins score
is determined. Invasive hemodynamic monitoring via pulmonary
artery catheterization may be appropriate in certain situations.
Avoid decreases in systemic vascular resistance and increases in
pulmonary vascular resistance. Echocardiography is important
in determining mitral valve area, concomitant mitral regur-
gitation, biventricular function, and estimating pulmonary
artery pressure.
Aortic stenosis
Aortic stenosis in a younger pregnancy age patient is most often
due to bicuspid aortic valve, which can also be associated with
both aortopathy and coarctation of the aorta. Aortic stenosis
is a fixed outflow obstruction of the left ventricle and is there-
fore sensitive to preload and hypotension which can result
in hemodynamic collapse if not recognized and treated early.
Complications can occur in up to 10% of aortic stenosis patients,
with heart failure reported as high as 42% in one report; mor-
tality is rare (<1%) [6]. Progressively increasing volume and car-
diac output during pregnancy, as well as, postpartum increases
in preload are what lead to heart failure from acute pulmonary
edema in severe aortic stenosis. In highly symptomatic patients,
aortic valve balloon valvuloplasty may be considered if no sig-
nificant aortic regurgitation. If too late, invasive hemodynamic
monitoring with a pulmonary artery catheter may prove useful in
the peripartum period. Due to a genetic predisposition for bicus-
pid aortic valve, fetal echocardiography or postpartum pediatric
echocardiography should be offered.
Pulmonic stenosis
Congenital pulmonic stenosis is a valvulopathy in which survival
to adulthood is common. In general, pulmonic stenosis is well
tolerated during pregnancy. In patients with severe pulmonic ste-
nosis with severe right ventricular failure or symptoms, pulmonic
valve balloon valvuloplasty should be considered prior to con-
ception in the absence of significant regurgitation, or in highly
symptomatic pregnant patients [18]. Pulmonic stenosis can also
be seen in surgically managed transposition of the great arteries
and tetralogy of Fallot.
Mechanical heart valves
Women with mechanical heart valves are at increased risk
of adverse outcomes in pregnancy including valve throm-
bosis (4.7%), hemorrhage (23.1%), and death (1.4%), making
pre-pregnancy counseling and centralization of care impera-
tive [11]. Those women who anticipate ultimately needing valve
replacement surgery should be encouraged to complete child-
bearing before valve replacement. For women with mechanical
heart valves, optimal anticoagulation during pregnancy is con-
troversial. The highest risk is with first-generation mechanical
valves (Starr–Edwards, Bjork–Shiley) in the mitral position,
followed by second-generation valves (St. Jude) in the aortic
32
position. These women need to be therapeutically antico-
agulated throughout pregnancy and postpartum, with blood
levels frequently (usually weekly) checked to ensure therapeutic
levels of anticoagulation. Options for anticoagulation in pregnant
patient with mechanical valves include warfarin, low-molecular-
weight heparin, and unfractionated heparin. Direct oral anti-
coagulants are contraindicated in mechanical valves. Warfarin
is well known to be associated with embryopathy, but less so in
doses < 5 mg [18]. Therapeutic warfarin therapy at delivery neces-
sitates a cesarean delivery to minimize hemorrhaging. If using
a low molecular weight heparin, thromboembolism is increased
so anti-Xa levels should be monitored to ensure efficacy during
pregnancy [6]. See Chap. 30.
Marfan syndrome
Marfan syndrome is an autosomal dominant connective tis-
sue disorder associated with aortopathy. Pregnancy associated
increases in heart rate and cardiac output can increase the risk
of aortic enlargement and dissection in these patients. In the
pre-conception period, patients with Marfan syndrome should
have an echocardiogram and genetic counseling. In Table 2.3,
Marfan syndrome without aortic root enlargement is a WHO
class II-III condition with a moderate increase in maternal mor-
bidity and mortality, whereas an aortic root measuring 4–4.5
cm is a WHO class III condition (significantly increased
risk), and if measuring >4.5 cm is a WHO class IV condition
(extremely high risk). In pregnancy, hypertension should be
avoided and early beta-blocker initiated. Avoiding positive ino-
tropic agents is also important. Epidural anesthesia in the peri-
partum period can reduce hemodynamic stress (watch for dural
ectasia, present in about 90% of patients with Marfan syndrome).
If cesarean delivery is required, retention sutures should be con-
sidered because of generalized connective tissue weakness [26].
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac con-
dition that is characterized by an abnormally hypertrophied
left ventricle without a secondary cause. There are over a dozen
genetic variants that have been described and can have variable
penetrance. The histological features of HCM include myocardial
disarray as well as fibrosis. The area of myocardium impacted can
also be variable, with hypertrophy of the basal interventricular
septum often being the most severe. One third of patients with
hypertrophic cardiomyopathy can also have obstruction of the
left ventricular outflow tract, which when provoked, can lead to
decreased stroke volume and cardiac output [28]. Patients with
HCM are at increased risk of ventricular arrhythmias and sud-
den cardiac death. Additionally, patients with an obstructive left
ventricular outflow tract gradient are intolerant of hypotension,
hypovolemia, tachycardia and inotropes, as these can worsen the
gradient [29]. Despite the complications of HCM, pregnancy is
generally well tolerated. The decrease in SVR of pregnancy can
worsen outflow obstruction. Also, tachycardia decreases dia-
stolic filling time, compromising cardiac output. However, these
adverse effects are somewhat offset by the increase in circulating
blood volume [28]. Peripartum management focuses on avoid-
ing tachycardia (treatment with beta-blockade), hypovolemia,
and hypotension [30, 31].
Peripartum cardiomyopathy
Peripartum cardiomyopathy (with EF < 45%) is defined as occur-
ring during the last 4 weeks of pregnancy or within 5 months
Maternal-Fetal Evidence Based Guidelines
postpartum (peaks at 2 months postpartum), without other
cause. The incidence is 1/3000 to 4000 live births. Risk factors
are older maternal age, multiparity, African American race,
multiple gestations, and hypertensive disorders of pregnancy.
Serial echocardiography, medical management (digoxin,
diuretics, hydralazine and/or beta-blockers in pregnancy; and
angiotensin converting enzyme inhibitors, angiotensin recep-
tor blockers, or combination angiotensin receptor blockers
with a neprilysin inhibitor postpartum), anticoagulation if
EF is <35%, and possible intrapartum pulmonary artery cath-
eterization in severely decompensated patients may be needed
for management [4, 26, 32–34]. The addition of bromocriptine to
standard heart failure therapy appears to improve left ventricular
EF and a composite clinical outcome in women with acute severe
peripartum cardiomyopathy, but the number of patients studied
was too small to make any recommendation [35]. The majority
of patients with peripartum cardiomyopathy have favorable out-
comes. Severity of left ventricular dysfunction and the degree of
left ventricular enlargement at presentation are associated with
less likelihood of recovery of ventricular function [36]. Regarding
future pregnancies after a diagnosis of peripartum cardiomy-
opathy, persistent dilated cardiomyopathy with abnormal EF
predicts a high risk (19%) of mortality and symptoms of car-
diac failure (44%) with subsequent gestation, and should be
discouraged. Of women with EF < 25%, 57% require a cardiac
transplant or are on a transplant list because of progressive
symptoms of heart failure at a mean of 3.4 years of follow-up
postpartum [37]. Even women with “normal” echocardio-
grams (EF ≥ 45–50%) after recovering from peripartum car-
diomyopathy can have persistent “subclinical” low contractile
reserve, with up to 21% risk of developing symptoms of CHF,
but no mortality reported in one study [33, 38].
Dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is characterized by abnormal
cardiac structure and function in the absence of other known
causes. In dilated cardiomyopathy, cardiac structure is abnormal
with left ventricular dilatation. Dilated cardiomyopathy differs
from peripartum cardiomyopathy in timing of diagnosis; while
peripartum cardiomyopathy developed within the last month of
pregnancy to the first five months after birth, dilated cardiomy-
opathy is pre-existing. As discussed previously, plasma volume
increases throughout the course of pregnancy. Patients with pre-
existing DCM can be intolerant of this increase in volume. This
increase in volume, plus the need for cessation of neurohormonal
blockade therapy used in heart failure due their risk of teratoge-
nicity, can precipitate heart failure exacerbations in patients with
DCM. It is imperative to monitor patients for symptoms of heart
failure (orthopnea, bendopnea, paroxysmal nocturnal dyspnea)
and differentiate from symptoms of normal pregnancy, partic-
ularly towards the end of gestation when circulating volume is
highest (Table 2.1) [39]. Pregnancy in patients with pre-existing
cardiomyopathy carries a high rate of morbidity and mortality,
with adverse events including progression of cardiomyopathy,
ventricular and atrial arrhythmias, and sudden cardiac death, and
can occur in as high as 60% of patients with DCM [39]. Therefore,
pre-pregnancy counseling is imperative, as well as close, frequent
follow-up with serial echocardiography as often as monthly to
monitor for symptoms [40]. Management of patients with DCM
should be team based and multidisciplinary, with Advanced
Heart Failure and high-risk Maternal Fetal Medicine collaborat-
ing care as part of the cardio-obstetrics team. As with pulmonary
Cardiac Disease
hypertension, labor and delivery should be planned through a
multidisciplinary approach. The patient should have continu-
ous monitoring with pulse oximetry, intra-arterial line, and
central venous pressure monitoring [9]. In select cases, inva-
sive hemodynamic monitoring with a pulmonary artery catheter
can be beneficial to monitor biventricular filling pressures. In
patients with DCM, vaginal delivery with regional anesthesia
is preferred with plan for cesarean section as back up if neces-
sary [39].
Coronary artery disease
The third trimester and postpartum period are when most coro-
nary events occur, with atherosclerosis accounting for <50% of
patients, and spontaneous coronary artery dissection and acute
myocardial infarction without obstructive coronary artery
disease accounting for the majority. Though rare, risk of acute
myocardial infarction is increased in pregnancy compared to
non-pregnant patients by 3 to 4 times, with mortality rates ~5%
[7]. Acute ST-segment elevation myocardial infarction (STEMI)
should be managed similarly in pregnancy as in non-preg-
nancy, with percutaneous coronary intervention (PCI) pre-
ferred with appropriate lead shielding of the fetus. Attention to
non-selective contrast injections, avoidance of deeply seating the
coronary catheter and low pressure injections are favored to avoid
iatrogenically causing a coronary artery dissection if not already
present [6]. When PCI is not available for STEMI, then thrombo-
lytic therapy can be carefully considered with an expected risk of
bleeding. In non-STEMI, pregnant patients should be managed
similarly to standard of care in non-pregnancy; however, conser-
vative approaches without coronary angiography to minimize
risk of iatrogenic complications is favored in lower risk, stable
patients. Aspirin and clopidogrel are the preferred antiplatelet
agents, and heparin and beta-blockers are also utilized with
relative safety. Traditional risk factors apply to pregnancy and
ischemic heart disease as in non-pregnancy, including unhealthy
diet, inactivity, obesity, smoking, hyperlipidemia, diabetes and
hypertension, which also comprises hypertensive disorders of
pregnancy like pre-eclampsia.
Conclusion
With medical and surgical advances, and advancing maternal
age, heart disease complicating pregnancy is increasingly com-
mon. Understanding the physiologic changes of pregnancy and
their effect on specific cardiac conditions forms the basis for
management during pregnancy. Pre-pregnant cardiovascular
assessment and counseling should be a primary goal. Heightened
awareness to optimize cardiac status close perinatal surveillance
and a coordinated management cardio-obstetrics team are criti-
cal to improve maternal and fetal outcome.
References
1. Creanga AA, Syverson C, Seed K, et al. Pregnancy-related mortality in the
United States, 2011–2013. Obstet Gynecol 2017;130:366–373. [III]
2. American College of Obstetricians and Gynecologists. Practice Bulletin
No. 212: Pregnancy and heart disease. Obstet Gynecol 2019;133:e320–e356.
[Review]
3. Magun E, DeFilippis EM, Noble S, et al. Cardiovascular care for pregnant
women with cardiovascular disease. J Am Coll Cardiol 2020;76:2102–2113.
[I]
4. Elkayam U, Goland S, Pieper PG, et al. High-risk cardiac disease in preg-
nancy part II. J Am Coll Cardiol 2016;68:502–516. [Review]
33
5. Small MJ, James AH, Kershaw T, et al. Near-miss maternal mortality:
cardiac dysfunction as the principal cause of obstetric intensive care unit
admissions. Obstet Gynecol 2012;119:250–255. [I]
6. Elkayam U, Goland S, Pieper PG, et al. High-risk cardiac disease in preg-
nancy part I. J Am Coll Cardiol 2016;68:396–410. [Review]
7. Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular considerations in
caring for pregnant patients a scientific statement from the American Heart
Association. Circulation 2020;141:e884–e903. [Review]
8. American College of Obstetricians and Gynecologists. ACOG Technical
Bulletin No. 168: Cardiac disease in pregnancy 1992. Int J Gynaecol Obstet
1993;41:298–306. [Review]
9. Hemnes A, Kiely D, Cockrill B, et al. Statement on pregnancy in pulmonary
hypertension from the Pulmonary Vascular Research Institute. Pulm Circu
2015;5:435–465. [I]
10. Sinnenberg RJ. Pulmonary hypertension in pregnancy. South Med J
1980;3:1529–1531. [V]
11. Van Hagen IM, Roos-Hesselink JW, Ruys TP, et al. Pregnancy in women
with a mechanical heart valve: data of the European Society of Cardiology
registry of pregnancy and cardiac disease (ROPAC). Circulation
2015;132(2):132–142. [I]
12. Sciscione AC, Callen NA. Pregnancy and contraception: congenital heart
disease in adolescents and adults. Cardiol Clin 1993;11:701–709. [II]
13. Morgan H, Nana M, Kinnaird T. Preconception counselling for women on
cardiovascular medications. Eur Heart J 2019;40:3436–3437. [III]
14. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC guide-
lines for the management of cardiovascular diseases during pregnancy
the task force for the management of cardiovascular diseases during preg-
nancy of the European Society of Cardiology (ESC). Eur Heart J 2018;39:
3165–3241. [I]
15. Ueland K, Novy MJ, Peterson EN, et al. Maternal cardiovascular dynamics
IV. The influence of gestational age on maternal cardiovascular response to
posture and exercise. Am J Obstet Gynecol 1969;104:856. [IV]
16. Humphries A, Mirjalili SA, Tarr GP, et al. The effect of supine positioning
on maternal hemodynamics during late pregnancy. J Matern Fetal Neonatal
Med 2019;32:3923–3930. [IV]
17. Arendt KW, Lindley KJ. Obstetric anesthesia management of the patient
with cardiac disease. Int J Obstet Anesth 2019;37:73–85. [Review]
18. Canobbio MM, Warnes CA, Aboulhosn J, et al. Management of preg-
nancy in patients with complex congenital heart disease. Circulation.
2017;135:e50–e87. [I]
19. Lancellotti P, Antunes MJ, Bongiorni MG, et al. 2015 ESC guidelines for
the management of infective endocarditis. Eur Heart J 2015;36:3075–
3123. [I]
20. Kikuchi J, Deering S. Cardiac arrest in pregnancy. Semin Perinatol
2018;42:33–38. [Review]
21. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for
contraceptive use, 2016. MMWR Recomm Rep 2016;65:1–104. [I]
22. Jarvis S, Nelson-Piercy C. Common symptoms and signs during pregnancy.
Obstet Gynaecol Reproduct Med 2014;24:245–249. [Review]
23. Beauchesne L, Connolly H, Ammash N, et al. Coarctation of the aorta: out-
come of pregnancy. J Am Coll Cardiol 2001;36:6. [III]
24. Jimenez-Juan L, Krieger EV, Valente AM, et al. Cardiovascular magnetic
resonance imaging predictors of pregnancy outcomes in women with
coarctation of the aorta. Eur Heart J Cardiovasc Imaging 2014;15:299–306.
[III]
25. Shime J, Mocarski EJM, Hastings D, et al. Congenital heart disease in
pregnancy: short and long term implications. Am J Obstet Gynecol
1987;156:313–322. [III]
26. Foley MR. Cardiac disease. In: Dildy GA, Belfort MA, Saade GR, et al.
eds. Critical Care Obstetrics. 4th ed. Molden, MA: Blackwell Publishing
Company, 2004;252–274. [Review]
27. van Hagen IM, Thorne SA, Taha N, et al. Pregnancy outcomes in women
with rheumatic mitral valve disease results from the registry of pregnancy
and cardiac disease. Circulation 2018;137:806–816. [I]
28. Marian A, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogen-
esis, clinical manifestations, diagnosis, and therapy. Circ Res 2017;121:749–
770. [Review]
29. Goland S, van Hagen IM, Elbaz-Greener, G, et al. Pregnancy in women
with hypertrophic cardiomyopathy: data from the European Society of
Cardiology initiated Registry of Pregnancy and Cardiac disease (ROPAC).
Eur Heart J 2017;38:2683–2690. [I]
30. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA
2002;287:1308–1320. [Review]
31. Fairley CJ, Clarke JT. Use of esmolol in a parturient with hypertrophic
obstructive cardiomyopathy. Br J Anaesth 1995;74:801–804. [V]
34
32. Demakis JG, Rahimtoola SH, Sutton GC, et al. Natural course of peripar-
tum cardiomyopathy. Circulation 1971;44:1053–1061. [II]
33. Lampert MB, Weinert L, Hibbard J, et al. Contractile reserve in patients
with peripartum cardiomyopathy and recovered left ventricular function.
Am J Obstet Gynecol 1997;176: 189–195. [II]
34. Witlin AG, Mabie WC, Sibai BM. Peripartum cardiomyopathy: an ominous
diagnosis. Am J Obstet Gynecol 1997;176:182–188. [III]
35. Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bromocriptine in the
treatment of acute severe peripartum cardiomyopathy: a proof-of-concept
pilot study. Circulation 2010;121:1465–1473. [I]
36. McNamara DM, Elkayam, U, Alharethi R, et al. Clinical outcomes for peri-
partum cardiomyopathy in North America. J Am Coll Cardiol 2015;66:
905–914. [I]
Maternal-Fetal Evidence Based Guidelines
37. Elkayam U. Risk of subsequent pregnancy in women with a history of
peripartum cardiomyopathy. J Am Coll Cardiol 2014;64:1629–1636.
[Review]
38. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of
subsequent pregnancies in women with peripartum cardiomyopathy.
N Eng J Med 2001;344:1567–1571. [III]
39. Schaufelberger M. Cardiomyopathy and pregnancy. Heart 2019;105:
1543–1551. [Review]
40. Grewal J, Siu SC, Ross HJ, et al. Pregnancy outcomes in women with dilated
cardiomyopathy. J Am Coll Cardiol 2009;55:45–52. [II]
41. Thorne S. Pregnancy and native heart valve disease. Heart 2016;102:
1410–1417. [Review]
3
OBESITY
Rebekah Jo McCurdy
Key points
• The preconception visit may be the single most impor-
tant health care visit when viewed in the context of its
effect on pregnancy. Height in meters and weight in
kilograms should be recorded for all women at each
doctor visit to allow for calculation of BMI. The BMI
category should be reviewed with the patient, high-
lighting potential risks and mitigation strategies, and
making sure she understands if her category is not
normal.
• Obesity is a risk factor for cardiovascular disease; diabetes;
hypertension; stroke; osteoarthritis; gall stones; increased
incidence of endometrial, breast, or colon cancer; car-
diomyopathy; hepatic steatosis; obstructive sleep apnea;
urinary tract infections; other complications; and, most
importantly, mortality. Prepregnancy obesity and exces-
sive gestational weight gain are associated with increased
risk of childhood obesity (and other chronic diseases) for
offspring.
• Preconception weight loss with diet, exercise, behav-
ior change, and, if necessary, pharmacotherapy or bar-
iatric surgery is recommended. Weight loss of at least
5–10% will help reduce the incidence of obesity-related
comorbidities.
• Preconception (and at first prenatal visit), check BP with an
appropriately sized cuff, fasting lipid profile (preconcep-
tion only), blood glucose (including a hemoglobin A1c),
thyroid function tests, and overnight polysomnogram
for those with sleep concerns. In patients with obesity
with multiple risk factors (such as diabetes, chronic hyper-
tension, maternal age >40 years, high-risk racial groups)
and/or symptoms, it is advisable to consider an EKG and
an echocardiogram.
• Women with BMI ≥40 kg/m2 or ≥35 kg/m2 with comorbidi-
ties are candidates for bariatric surgery in the preconcep-
tion or interconception period. Incidences of gestational
diabetes and hypertension are reduced after gastric bypass
surgery, especially if BMI is reduced to <30 kg/m2. Pregnant
patients with a history of bariatric surgery can be started
on vitamin B12, folate, iron, and calcium if deficient.
• Obesity is strongly correlated with impaired fertility, mis-
carriage, congenital malformations, gestational diabetes,
hypertension, pre-eclampsia, stillbirth, macrosomia, anes-
thesia complications, labor abnormalities, cesarean birth,
wound infection, and thromboembolism.
• A patient-centered discussion with education about
obesity and maternal and perinatal outcomes is
recommended.
• Optimal gestational weight gain in women with obe-
sity remains unclear. Some data suggest no weight gain
may be best for or even some weight loss in obese
DOI: 10.1201/9781003099062-3
(especially class III obesity) gravidas for optimal obstet-
ric outcomes.
• Serial fetal growth ultrasounds should be performed
starting at 28–32 weeks.
• For women undergoing a cesarean delivery, the sub-
cutaneous layer should be closed with sutures if depth
is >2 cm and the subcuticular layer should be closed
with suture in order to reduce wound infection and
separation.
• Early mobilization 4–6 hours after delivery even if
cesarean, and graduated compression stockings during
and after cesarean are recommended. Each institution
is encouraged to develop a postpartum anticoagulation
guideline that accounts for BMI. It is reasonable to con-
sider anticoagulation in all women with obesity who also
have additional risk factors, such as cesarean delivery.
• Postpartum, women should be encouraged and helped to
return to a normal BMI, through counseling, diet, exer-
cise, and breastfeeding.
Definition and classification
Obesity is defined as BMI ≥30 kg/m2, with additional distinctions
made between classes I, II, and III or by specific BMI categories
when describing risks and outcomes. Other terms for categoriz-
ing obesity are in use, with the Centers for Disease Control and
Prevention (CDC) utilizing the term “severe obesity” to define
those with BMIs ≥40.0 kg/m2. In general, it is preferable to uti-
lize the specific BMI or the class categories as assigned by the
National Academy of Medicine. (Table 3.1) [1]. BMI is defined
as weight in kilograms divided by height in meters squared. It
is a simple clinical tool, with online calculators available (www.
nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm).
Increasing severity of class of obesity in pregnancy is associated
with greater risks of adverse perinatal outcomes (Table 3.2) [2–51]
and other health risks (Table 3.3). In discussing weight, patients
prefer to avoid terms such as “fatness”, “obesity”, and “large size”
and prefer terms such as “weight”, “BMI”, “weight problem”, and
“excess weight” [52]. The American College of Obstetricians and
Gynecologists (ACOG) recommends that terms “patients with
obesity” be used instead of “obese patients”, and likewise, provid-
ers should be aware of their own implicit biases regarding weight
[53]. Shared decision-making and patient engagement/ patient
centered care are key in mitigating the effects of excess weight
prior to, during, and after pregnancy, thus every attempt should
be made to avoid patient alienation in discussing weight, which
can be a sensitive topic associated with stigma [54]. A system-
atic review highlighted that women with obesity appear to be
equally dissatisfied when weight is not addressed as when it is
addressed in negative manner [55]. Conversations and interven-
tions must consider the social environment in which decisions
about weight take place [56].
35
36 Maternal-Fetal Evidence Based Guidelines

TABLE 3.1: The International Classification of Epidemiology/Incidence

Adult Underweight, Overweight, and
Obesity According to BMI, WHO WHO describes obesity as “one of the most blatantly visible,
yet neglected, public-health problems that threatens to over-
Classification BMI (kg/m2)
whelm both more and less developed countries.” As of 2016,
Underweight <18.5 the WHO estimates that more than 1.9 billion adults are over-
Normal range 18.5–24.9 weight, including 650 million who are obese [18]. By 2030, over
Overweight 25.0–30.0 2.16 billion people worldwide are projected to be overweight
Obese ≥30.0 with an additional 1.12 billion people projected to be obese.
Obese class I 30.0–34.9 Costs per capita in the United States were estimated to be nearly
Obese class II 35.0–39.9
$7000 yearly, with direct costs per capita suggested to be greater
than $171,000 over a lifetime [43, 57, 58]. At all ages and through-
Obese class III ≥40.0
out the world, women are generally found to have higher mean
Source: Adapted from American College of Obstetricians and BMI and higher rates of obesity than men, although recent data
Gynecologists. Obesity in pregnancy, Practice from the CDC notes that this difference no longer exist in the
Bulletin No. 156. Obstet Gynecol (Reaffirmed 2018).
United States [3, 59]. These numbers are increasing as the obesity
2015;126:e112–1F26. Ref. [2], with permission.
epidemic explodes on the public health stage.

TABLE 3.2: Complications of Obesity Related to Pregnancy (see also text) [4–60, 62–68]
Risk (%) or OR Comments Ref.
Infertility OR 1.7–2 [4, 5, 321]
Miscarriage rates OR 1.31 [7, 321, 322]
Recurrent miscarriage OR 1.75, (1.24=2.47) [6, 322]
Decreased live birth rate following IVF OR 0.85 (0.82–0.87) [39, 41]

Prenatal/Medical
Chronic hypertension OR 2–3 [8, 321]
Gestational hypertension OR 2.5–3.2 [9, 323]
Pre-eclampsia OR 3.15 (2.69–3.35) Risk increases with increasing [10, 15, 323]
class of obesity
Gestational diabetes OR 1.4–20 [321, 323]
Venous thromboembolism OR 1.30–2.65 [321]
Obstructive sleep apnea OR 1.12 [324]
Respiratory issues (e.g. asthma OR 1.3 [26]
exacerbations)
Depression OR 1.12 OR 4.9 class III [325]
Urinary tract infections OR 1.4 [4]
Urinary Incontinence OR 1.53 (1.28–1.83) Includes overweight [326]

Obstetric
Spontaneous pregnancy loss OR 1.7 [2, 7]
Indicated preterm birth OR 1.3 Includes overweight [327]
Spontaneous preterm birth OR 1.24 [327]
Lower accuracy of ultrasound 25–48% detection Progressively worse with [226]
Residual anomaly risk after increasing BMI
ultrasound in obese 1%
Difficulty with fetal testing (e.g. FH No definite recommendation [11]
monitoring) for invasive monitoring
Failure to progress OR 2.6 Class II [328]
Induction of labor OR 2.2 [8]
Fetal distress OR 1.3 Class II (BMI >35) [328]
Lower success of TOLAC OR 0.53–2.0 Excessive weight gain lowers [83, 84]
success—Class III
Rupture/dehiscence after TOLAC OR 5.6 [84]
Postterm birth (less likely to go into OR 1.7 Increasing incidence with [13, 329]
spontaneous labor) increasing BMI
Obesity 37

TABLE 3.2 (Continued): Complications of Obesity Related to Pregnancy (see also text) [4–60, 62–68]
Risk (%) or OR Comments Ref.
Lower rates of breastfeeding (Failure to OR 2.6 Class III [4]
start and sustain)
Late prenatal care OR 1.56 [8]

Fetus/Neonate
Congenital fetal defects
Neural tube defects OR 1.7–2.8 OR 3–4 class II–III [29, 32, 330]
Congenital heart disease OR 1.3–1.5 Increases with increasing BMI [33, 49, 51, 78, 330]
Cleft lip/palate OR 1.13 (1.04–1.23) [78, 330, 331]
Anorectal atresia OR 1.5 [78, 330]
Hydrocephalus OR 1.7 [78]
Limb reduction defects OR 1.3 [330]
Down syndrome 1.12–1.56 [332]
IUGR 2.1 [333]
Gastroschisis OR 0.17 Reduced risk in the obese [330]
Macrosomia (>4000 g) OR 1.7–2.36 [4, 8, 22, 99, 149]
Birth injury, shoulder dystocia OR 1.51–3.1 Associated most with [12, 47, 99]
macrosomia
Low Apgar scores OR 1.4 (1.27-1.54) Increases with increasing [4, 50, 334]
obesity class
Fetal death OR 2.0–3.6 [40, 41–43]
Neonatal mortality OR 1.15-1.3 OR 3.4 class III [16, 330]
Childhood obesity BMI >95 percentile and OR 1.62–4.47 Increases with increasing [4, 24, 27, 146, 335, 336]
metabolic syndrome levels of obesity and GWG
Cerebral palsy Class I OR 1.31 (1.15–1.50) [45, 48]
Class II OR 1.65 (1.34–2.02)
Class III OR 2.37 (1.91–2.94)
Autism spectrum disorder OR 1.47 (1.24–1.74) [32]
NICU admission OR 1.28–1.34 [8, 12]

Intrapartum
Earlier admission
Longer labor 7 hours (obese) versus 5.4 hours Slow labor to 7 cm [23, 337]
(normal)
Anesthesia complications 8.4% composite morbidity 6/8 maternal deaths were in [249, 251, 252]
obese gravida (45)
Chorioamnionitis in setting of PPROM HR 1.6 (1.1–2.1) [25]
Difficult regional anesthesia placement OR 19.4 [338]
Difficult intubations (general anesthesia) OR 2.1 [338]
Need for cesarean delivery OR 1.46–3.0 47% in class II–III (especially [9, 12, 17, 23, 323]
failure to progress)
Increase operative time >60 min; OR 9.3 [251, 338]
Emergency cesarean OR 4.7 [338]
Wound infections/disruptions OR 2.24–3.4 [8, 255]
Hemorrhage OR 5.2 Morbid obesity >300 lb [338]
Postpartum hemorrhage OR 1.4–2.11 [8, 337, 339]
Longer hospitalization OR 1.48 [8]
ICU admissions OR 3.8 BMI >50 [340]
Hormonal contraceptive failure OR 1.91 BMI >25; limited studies, may [300, 302]
still be the best if used
properly
Postpartum
Breastfeeding initiation difficulty OR 1.49 (1.33–1.67) [30]
Abbreviations: OR, odds ratio; IVF, in vitro fertilization; NTD, neural tube defect; CHD, congenital heart disease; TOLAC, trial of labor after cesarean; GWG, gestational
weight gain; BMI, body mass index.
38
TABLE 3.3: Future Health Risks Associated with Obesity
• Premature death • Cancer
• Type II diabetes • High cholesterol
• Metabolic syndrome • Hirsutism
• Heart disease • Stress incontinence
• Stroke • Surgical risk
• Hypertension • Osteoarthritis
• Gallbladder disease • Asthma
• Sleep apnea • Social stigma
• Depression
The prevalence of overweight, and women with obesity aged
20–74 continues to increase since 1960. As of 2017–2018, the
prevalence of obesity and extreme obesity in women was 41.9%
and 11.5%, respectively, compared to 15.8% and 1.4% in 1960 [3,
60, 61]. Population data indicates that 50% of women are over-
weight or obese at the start of pregnancy [62].
There are racial differences with non-Hispanic black women
having the highest prevalence of obesity (56.9%) when com-
pared to Hispanic (43.7%), non-Hispanic white (39.8%), and non-­
Hispanic Asian (17.2%) women [3].
Genetics
A heritability of about 50–90% for obesity has been shown when
comparing monozygotic twins with dizygotic twins, however the
role of environmental influences is complex. Multiple genes and
associated mutations have been proposed in the role of the devel-
opment of obesity, including both mono-allelic as well as dozens
of polygenic contributors [63–67]. The role of chromosome 2p21
with serum leptin levels in human pregnancies has been identi-
fied in some ethnic groups [63]. The risk of childhood obesity is
significantly increased if one parent is obese, but the risk is even
higher if both parents are affected (adjusted odds ratio [aOR]
10.4, 95% confidence interval [CI] 5.1–21.3) [68]. Maternal obe-
sity results in in utero programming and childhood obesity due
to the effects of a maternal high-fat diet leading to insulin resis-
tance, hyperinsulinemia, and increased fat accumulation in the
offspring.
Etiology/Basic pathophysiology
White adipose tissue produces proteins with endocrine function
called adipokines. A state of relative hypoxia occurs in the adi-
pocytes in obesity, which sets a chronic inflammatory response,
causing the release of adipokines. Leptin, adiponectin, resistin,
and ghrelin are the most studied adipokines [69]. The name leptin
is derived from the Greek, which means the “thinning factor.”
Leptin is a neuroendocrine hormone that acts as a satiety factor,
inducing a reduction in food intake and an increase in energy
utilization [70]. Leptin is produced by the adipocytes, placenta,
and fetal adipose tissue. Endometrium and ovarian follicles also
have leptin receptors. Adiponectin is an endogenous insulin
sensitizer that is present in lower circulating concentrations in
obesity [70].
Maternal leptin levels increase throughout pregnancy
from 6 weeks onward and decrease rapidly after parturition.
Conversely, adiponectin levels appear to decrease throughout
pregnancy and are especially low in patients with prepregnancy
Maternal-Fetal Evidence Based Guidelines
obesity [70]. High levels of serum leptin in pregnancy are similar
to that seen in obesity [71]. Leptin appears to be an independent
regulator of fetal growth, and leptin levels are a marker for fetal
fat mass. The majority of leptin (98%) produced by the placenta is
released into maternal circulation. The increased level of leptin
seen in obesity and pregnancy stimulates increased production of
cytokines such as interleukin-6, interleukin-1, and alpha tumor
necrosis factor that lead to a chronic inflammatory state, further
resulting in structural and vascular damage [72, 73]. Epigenetic
modification in the preimplantation stage, alteration in very early
metabolism of the embryo, and endometrial abnormalities seen
on biopsy in patients with obesity could explain at least partially
the low implantation rates, birth defects, and fetal growth aber-
rations [61].
Risk factors
Women who are older, multiparous, from lower socioeconomic
backgrounds; those with limited resource environment (espe-
cially with food insecurities or poor nutrition options); unsafe
neighborhoods for unrestricted physical activity; lack of access to
medical care, minority status; and a family history of obesity, are
all at risk for obesity in general and for its associated complica-
tions in pregnancy [73].
Pregnancy complications
Table 3.2 summarizes the long list of pregnancy complications
associated with obesity in pregnancy. The higher the patient’s
BMI, the greater the chance of complications. Similar compli-
cations are seen among women with obesity in developed coun-
tries as well as low- and middle-income countries [37].
Obesity is associated with an increased risk of congenital
anomalies as well as a decreased ability to detect these anom-
alies. Maternal obesity is an independent risk factor for congeni-
tal heart defects (CHD) with an aOR of 1.15 (95% CI 1.00–1.32)
for class I obesity and 1.31 (95% CI 1.11–1.56) for class II obesity
[33, 49, 51, 74–77]. Prepregnancy BMI > 25 kg/m2 and increasing
levels of obesity are associated with several phenotypes of CHD
such as conotruncal defects, total anomalous pulmonary venous
return, hypoplastic left heart syndrome, right ventricular outflow
tract defects, and septal defects [74, 76]. Maternal obesity (BMI
>30 kg/m2) also increases the risk for other congenital anoma-
lies including neural tube defects (NTD) (OR 4.08; 95% CI 1.87–
7.75), hydrocephaly, orofacial clefts (OR 1.90; 95% CI 1.27–2.86),
anal atresia, hypospadias, cystic kidney, talipes, omphalocele, and
diaphragmatic hernia [29, 77, 78]. Neural tube defects may be due
to folate deficiency or local endometrial and placental factors,
leading to altered angiogenesis related to leptin or altered carbo-
hydrate metabolism with undetected hyperglycemia. This higher
rate of anomalies persists in women with obesity even after con-
trolling for diabetes. Ultrasound for detection of anomalies
may result in suboptimal images 20–50% of the time. Serum
screening for aneuploidy is also less reliable in women with obe-
sity [36].
Excluding women with hypertension, the risk of pre-eclampsia
is doubled with each 5–7 kg/m2 increase in prepregnancy BMI
[10]. When compared to a BMI of 21 kg/m2, the risk is doubled
with a BMI of 26 kg/m2 and almost tripled when the BMI is
>30 kg/m2 [79, 80]. Women with class III obesity had higher inci-
dence of pre-eclampsia, antepartum stillbirth, cesarean delivery,
instrumental delivery, shoulder dystocia, meconium aspiration,
Obesity
fetal distress, early neonatal death, and large babies as compared
to normal-weight women [79, 80].
Increased BMI is a risk factor for impairment of carbohydrate
tolerance. Fasting and postprandial plasma insulin concentra-
tions are higher in obese pregnant women than in those who are
not obese.
Each 1-unit increase in pregravid BMI (5 lbs) increases the risk
of cesarean delivery by about 7% [81]. Success rates of vaginal
birth are low in the obese population and infectious morbidity
such as chorioamnionitis is increased particularly after labor
[82–85]. Antepartum complications of obesity largely account
for this higher cesarean delivery rate, as well as macrosomia-
associated cephalopelvic disproportion, nonreassuring fetal
testing, and failed induction. Operative risks are also high in
patients with obesity including increased total operative time,
blood loss, endometritis, and wound disruptions and infec-
tions [2]. Fetal deaths are mostly unexplained and are thought
to be secondary to placental dysfunction and related comorbidi-
ties [86, 87]. Suggested pathophysiological mechanisms include
placental dysfunction, placental inflammation, impaired glucose
tolerance and insulin resistance, and excessive hyperlipidemia.
Furthermore, the incidence of abnormal cord blood pH and low
APGAR scores is increased in those with obesity [50].
Prepregnancy obesity and excessive gestational weight gain
are associated with indicated preterm birth (such as for that
of pre-eclampsia with severe features), while obesity seems
to protect against spontaneous preterm birth [13, 34, 88–92].
Nulligravid women with obesity are likely at greater risk than the
multiparous women.
Obstructive sleep apnea (OSA) has a higher incidence in
women with obesity especially with neck circumference >38 cm.
OSA has been associated with pre-eclampsia, gestational diabe-
tes, pulmonary hypertension [93]. It is also associated with fetal
heart rate decelerations during periods of maternal hypoxia.
Lower Apgar scores, low birth weight, and increased admission
to neonatal intensive care unit are seen in infants of women
with obesity with OSA [94]. OSA may complicate anesthesia and
postoperative care [18–20]. Continuous positive airway pressure
(CPAP) has been shown to improve blood pressure control in
pregnant women with chronic hypertension [95].
Prepregnancy obesity is an independent risk factor for large for
gestational age (LGA) fetuses and macrosomia and is correlated
with increasing categories of obesity and gestational weight gain.
Maternal excess weight with BMI >25 kg/m 2 before pregnancy
has been shown to be a determinant of fetal macrosomia (OR
2.0; 95% CI 1.72, 2.32) [96]. Macrosomic fetuses are at high risk
for childhood obesity and adult metabolic syndrome. Excessive
weight gain during pregnancy can increase the risk of macroso-
mia by 30%; although lifestyle modification during pregnancy
may have a significant impact on neonatal adipose tissue depo-
sition, although not other anthropometric measurements [22,
96–98]. The incidence of shoulder dystocia remains undefined,
with some reporting a higher incidence and others no difference
in the obese population versus the non-obese. Shoulder dystocia
is associated with birth weight rather than increasing levels of
obesity [47, 99, 100].
Obesity is associated with greater healthcare usage with
more prenatal visits with physicians, fetal testing, obstetrical
ultrasound, medications, telephone calls, longer length of stay,
increased cesarean deliveries, and medical conditions associated
with obesity [57]. It is estimated that 5.7% of the total U.S. health
expenditure is from obesity-related illness [58].
39
Close to 300,000 deaths annually are attributed to a diag-
nosis of obesity. About 24% deaths in adult women aged
25–64 years are due to obesity, and obesity is a key risk factor
for maternal mortality. Outcome reporting however remains
variable, with many key outcomes not reported in clinical tri-
als [21].
Preconception care/Prevention
Preconception evaluation
The preconception visit may be the single most important
healthcare visit when viewed in the context of its effect on
pregnancy (see Chap. 1, Obstetric Evidence Based Guidelines).
Height in meters and weight in kilograms should be recorded
for all women at each visit to allow for calculation of BMI
(Figure 3.1). Identification and awareness by both patient and
healthcare worker of obesity is the first step in prevention of
complications and appropriate management. The BMI category
should be reviewed with the patient, making sure she under-
stands the implications of her specific BMI (Table 3.1). A nice
review of the current literature and preconception management
of women with obesity is available [100].
Once obesity is confirmed, a waist circumference can be mea-
sured at the end of expiration, at the level of the iliac crest. This, as
well as the exact BMI, should be documented. A risk assessment
of cardiovascular disease by taking BP with an appropriately-
sized cuff, dyslipidemia by obtaining a fasting lipid profile and
diabetes evaluation with a fasting blood sugar, underlying thy-
roid disease with thyroid function tests, and OSA requiring a
standard overnight polysomnogram should be initiated. In
patients with obesity with chronic hypertension or type II dia-
betes, an EKG and an echocardiogram should be considered
[2, 42]. A resting heart rate should be obtained for all precon-
ception and prenatal visits and if >110 on two subsequent vis-
its, evaluation for underlying cardiac disease should likewise be
completed (Figure 3.2). Women with obesity are more likely to
experience congestive heart failure and cardiomyopathy. Family
history should be elicited. History of weight cycling is important
and indicates poor compliance that may be associated with an
increased risk of comorbidities.
Discussion and education about obesity and its comorbidi-
ties and poor perinatal outcomes should be provided (con-
sider giving a copy of Tables 3.2 and 3.3). Providers should be
aware that current information available on websites for patients
and providers is variable and may not be credible, including
governmental websites [101]. An assessment should be made to
see if the patient is ready for intervention with diet and exercise
(Table 3.4). Motivational interviewing is defined as a “directive,
client-centered counseling style for eliciting behavior change by
helping clients explore and resolve ambivalence” (see OARS in
Table 3.5) [102, 103]. A easily used acronym is OARS and clini-
cians should focus on assisting the women they are caring for
with identifying small, achievable goals that are important to her
(with close follow-up to review successes, barriers, and develop
new goals) [104].
Women with increased BMI are known to have a threefold
greater risk of infertility due to disturbances in the hypotha-
lamic-pituitary axis, menstrual cycle alterations, and anovula-
tion. An abnormal BMI is associated with significantly reduced
live-birth rate and increased miscarriage rate after IVF treatment.
Fertilization rates and clinical pregnancy rates are reported to be
lower in obese women [105–107].
40 Maternal-Fetal Evidence Based Guidelines

Prepregnancy/preconception workup

http://www.nhlbisupport.com/bmi

Calculate BMI (kg/m2)

25–29.9 30–34.9 35–39.9 =>40

Overweight Class I obesity Class II obesity Class III obesity

With Co-Morbidities
Motivational assessment

Yes No Bariatric surgery

Start diet and physical activity Periodic weight assessment referral

Success No

Provide support for Drug therapy

Weight loss Diet
Maintenance Physical activity

FIGURE 3.1 Algorithm for preconception management of women with obesity.

The most effective intervention in the adult obese population is
diet, physical activity, and behavior modification. The most impor-
tant interventions in the management of obesity in reproductive
age women are weight reduction prior to conception, and pre-
vention of excessive gestational weight gain (Table 3.6).
Prepregnancy weight reduction
Diet
Use of a low-calorie diet that creates a deficit of 500–1000 kcal/
day will cause a weight loss of 1–2 lb/week and a 10% weight loss
over 6 months. There is good evidence that such a weight loss can

TABLE 3.4: Stages of Change Model to Assess Readiness for Weight Loss
Stage Characteristic Appropriate Intervention Sample Dialog
Precontemplation Unaware of problem, no Provide information about “Would you be open to some information about the health
interest in change health risks and benefit of aspects of obesity? When would be a good time to raise
weight loss this topic in the future?”
Contemplation Aware of problem, beginning to Help resolve ambivalence; “What are some of the benefits of weight loss? What might
think of changing discuss barriers you need to change to achieve weight loss?”
Preparation Realizes benefits of making Teach behavior modification; “What might you do to reduce some of the calories you eat
changes and thinking about provide education and to increase your activity during the day? Can I provide
how to change some additional information for this effort?”
Action Actively taking steps toward Provide support and guidance, “Congratulations on your efforts, particularly XYZ! What
change with a focus on the long term problems have you had? How have you solved them?”
Maintenance Initial treatment goals reached Relapse control “What situations continue to tempt you to overeat? What
can be helpful for the next time you face the situation?”
Source: Modified from ACOG Committee Opinion No. 423 (Ref. 341).
Obesity 41

SYMPTOMS VITAL SIGNS RISK FACTORS PHYSICAL EXAM

NYHA class ≥ II *
• Resting HR ≥110 bpm • Age ≥40 years ABNORMAL FINDINGS
Suggestive of Heart Failure • Systolic BP ≥140 mm Hg • African American Heart: Loud murmur or
• Dyspnea • RR ≥24 • Pre-pregnancy obesity Lung: Basilar crackles
• Mild orthopnea • Oxygen sat ≤96% (BMI ≥35)
• Tachypnea • Pre-existing diabetes
• Asthma unresponsive • Hypertension
to therapy
• Substance use (nicotine,
Suggestive of Arrhythmia:
• Palpitations cocaine, alcohol,
methamphetamines) NO
• Dizziness/syncope
Suggestive of Coronary • History of chemotherapy YES
Artery Disease:
• Chest pain
• Dyspnea

Consultation indicated:
≥ 1 Symptom + ≥ 1 Vital Signs Abnormal + ≥ 1 Risk Factor or
ANY COMBINATION ADDING TO ≥ 4 MFM and Primary
Care/Cardiology

Obtain: EKG and BNP

• Echocardiogram +/- CXR if HF or valve disease is suspected, or if the BNP levels are elevated
• 24 hour Holter monitor, if arrhythmia suspected
• Referral to cardiologist for possible treadmill echo vs. CTA vs. alternative testing if postpartum
Consider: CXR, CBC, Comprehensive metabolic profile, Arterial blood gas, Drug screen, TSH, etc.
Follow-up within 1 week
Results abnormal

CVD highly suspected

Results negative

Signs and symptoms resolved

Reassurance and routine follow-up

FIGURE 3.2 Cardiac screening algorithm. (Modified from California Department of Public Health, 2017. Developed in partner-
ship between ACOG with California Maternal Quality Care Collaborative Cardiovascular Disease in Pregnancy and Postpartum
Taskforce. www.CMQCC.org has further details [42].) Abbreviations: NIHA, New York Heart Association; HR, heart rate; BP, blood
pressure; RR, respiratory rate; BMI, body mass index; MFM, maternal-fetal medicine; EKG, electrocardiogram; BNP, brain natriuretic
peptide; CXR, chest x-ray; HF, heart failure; CTA, computed tomographic angiography; CBC, complete blood count; TSH, thyroid
stimulating hormone; CVD, cardiovascular disease.

TABLE 3.5: OARS Acronym for Motivational Interviewing TABLE 3.6: Suggested Management of the Pregnant Woman
Acronym Task Technique Goal with Obesity

O Open- Ask questions that encourage To understand a Preconception

Ended a thought-provoking patient’s barriers Calculate and record BMI and category
Questions response and expectations Review history and comorbidities
Engage in a two-way dialogue Counseling of pregnancy complications (show, review, and give a copy
A Affirmative Recognize and support the To promote a of Table 3.2)
Statements patient’s personal and collaborative Counseling of medical long-term complications (show, review, and
specific strengths, successes, relationship give a copy of Table 3.3)
and efforts to change Glucose screen with 2-hour glucose tolerance test or Hemoglobin A1c
R Reflective Utilize reflective listening and To validate the Consider lipid screening
Listening respond thoughtfully by patient’s point of Counsel and plan regarding weight loss and exercise before
paraphrasing view considering pregnancy—behavior modification
Confirm that the patient has Nutrition counseling
been heard Exercise counseling
S Summary Utilize concise statements that To identify Document blood pressure
Statements recount and clarify the specific action Baseline 24-hour urine for proteinuria; LFTs, platelets
patient’s statements steps Evaluation for possible long-term complications (especially if BMI >35)
Source: See further Ref. 104. Echocardiogram
(Continued)
42 Maternal-Fetal Evidence Based Guidelines

TABLE 3.6 (Continued): Suggested Management of the Obese
Gravida
EKG
Sleep apnea evaluation
Consider referral to bariatric surgery program
Pregnancy
1st trimester
All recommendations as Preconception, except weight loss
Confirm pregnancy with a 1st trimester ultrasound for dating
Nuchal translucency and serum screening for chromosomal
abnormalities
Early 1-hour glucose screen
Review weight gain goals (Table 3.8) and address throughout
prenatal care
2nd/3rd trimester
Counsel regarding limitations of fetal ultrasound
Consider fetal growth ultrasound in 3rd trimester (e.g. 32 weeks)
Repeat as needed if suspected macrosomia
Repeat 1-hour glucose screen if negative in 1st trimester
Encourage Fetal Kick Counts, consider antepartum testing if BMI
≥ 35 kg/m2
Anesthesia consult in 3rd trimester
Intrapartum
Secure early venous access
Ultrasound to confirm fetal presentation
Early placement of regional anesthesia with extra-long spinal/epidural
needles and fiberoptic bronchoscope, consider ultrasound guidance
Ensure appropriate blood products are available
Application of FSE if unable to evaluate FHT externally
Appropriately sized blood pressure cuff
Large speculums
OR tables that accommodate patient weight
Lithotomy stirrups with capacity of 230 kg (i.e. Yellofins® Stirrups and
Yellofins Elite®, respectively, Allen Medical Systems, Action, MA,USA)
Long instrument tray
Closure of subcutaneous layer ≥2 cm with sutures during cesarean
Closure of subcuticular layer with stitches
Appropriately sized graduated compression stockings
Extra staffing to assist with patient transfer
Labor beds and stretchers rated patients with obesity
Bariatric wheelchairs
Postpartum
Incentive spirometry
Graduated compression stockings and prophylactic enoxaparin until
ambulation
Early mobilization and hydration
Compression boots and/or prophylactic enoxaparin during
prolonged bed rest
75-mg, 2-hour glucose challenge test >6 weeks postpartum
Referral to nutritional and behavioral counselors for weight loss
Contraceptive counseling
Encourage breastfeeding
Establish a plan for postpartum weight loss
Source: Adapted From Ref. 111.
Routine screening offered to all pregnant women (e.g. sequential screening) not
included.
Abbreviations: BMI, body mass index; LFT, liver function test; DM, diabetes mellitus;
AROM, artificial rupture of membranes; IUPC, intrauterine pressure catheter; FSE,
fetal scalp electrode; FHT, fetal heart tracing.
be sustained over long periods of time, at least one year. This level
of weight loss will improve the BP, lipid profile, and blood glucose
levels. Patients can be referred to nutritionist or can visit websites
such as www.choosemyplate.gov/.
Physical activity
Exercise contributes only modestly to weight loss, but it increases
cardiorespiratory fitness and helps with all weight loss mainte-
nance programs. Moderate exercise for 30–45 minutes for at
least 3–5 days initially and followed by accumulation of at
least 30 minutes daily on most days should be an integral part
of weight loss and weight maintenance. For some patients with
more sedentary lifestyles, smaller exercise goals may be needed at
first, such as a daily walk.
Behavior therapy
Specific strategies include self-monitoring of eating habits and
physical activity, stress management, stimulus control, problem
solving, contingency management, cognitive restructuring, and
social support. Emerging mHealth interventions (such as mobile
phone apps) show promise in motivating weight loss, but further
follow-up studies are needed [108, 109].
Pharmacotherapy
Weight loss drugs should only be used when concomitant
lifestyle modifications have not obtained sufficient results.
Currently available medications include orlistat, phentermine-
topirimate, naltrexone-buproprion, and liraglutide. The effi-
cacy of these medications is modest and side effects are often
present [110–113]. Indications for use are BMI >30 kg/m 2 or
BMI >27 kg/m 2 with comorbidities despite maximal efforts at
diet, exercise, and behavior therapy. Weight loss produced by
medications has not been shown to be any better than weight
loss through lifestyle modification in reducing related comor-
bidities. Weight loss pharmacotherapy is contraindicated in
pregnancy.
Bariatric surgery
Women with BMI >40 kg/m2 or BMI >35 kg/m2 with comor-
bidities are candidates for bariatric surgery when diet, physi-
cal activity, and behavior modification (and possible drug
therapy) have failed (Figure 3.1; Table 3.7). The weight loss fol-
lowing surgery is in the range of 10–105 kg and is sustained for as
long as 8 years. Approximately 80% of bariatric surgery recipients
are of reproductive age [114].
Bariatric surgery procedures are generally categorized
into three groups: 1) restrictive procedures 2) malabsorp-
tive procedures and 3) restrictive and malabsorptive pro-
cedures. Restrictive procedures (e.g. laparoscopic adjustable
gastric banging [LAGB], sleeve gastrectomy) reduce gastric
capacity, which consequently restricts energy intake [115–117].
Malabsorptive procedures (e.g. biliopancreatic diversion, jeju-
noileal bypass) cause weight loss by restricting absorption of
nutrients; however, these procedures are rarely performed, as
they have been associated with long-term complications like
hepatic failure [118, 119]. Lastly, malabsorptive and restric-
tive procedures (e.g. Roux-en-Y gastric bypass) reduce stomach
capacity causing malabsorption and a restriction of food intake.
Intragastric balloon appears to have little benefit in weight loss
therapy over diet, behavior modification, and motivation [120].
Adjustable gastric band management during pregnancy is not
well defined, but almost 20% may need adjustment or removal
of band for nausea and vomiting [121].
Obesity
TABLE 3.7: Special Considerations for Preconception and
Prenatal Care after Bariatric Surgery
• Preconception
• Fertility often resumes after bariatric surgery
• Bariatric surgery should not be considered a treatment for
infertility
• Oral contraception is often ineffective because of potential
malabsorption; consider injectable forms of hormonal
contraception as needed. Use reliable contraception until period
of maximal weight loss (at least 12 months) is over
• Consider waiting 12 months or until maximum weight loss
achieved after bariatric surgery before conception
• Evaluate and treat comorbidities
• Prenatal
• Monitor for nutritional deficiencies (especially after Roux-en-Y) such
as
• Vitamin B12 (if needed, 500–1000 μg daily)
• Folate (up to 5 mg daily)
• Iron (check ferritin)
• Vitamin D (if needed, do not exceed pregnancy RDA of 400 IU
maximum)
• Calcium (if needed, 1200 mg calcium citrate)
• Be aware that nausea, vomiting, abdominal pain, etc., may be signs of
bariatric surgery complications such as intestinal obstruction, GI
hemorrhage, anastomic leaks, hernias, band erosions and migrations,
and can even lead to maternal death. Early consultation with
bariatric surgeon is suggested.
• Avoid glucola screening given risk of dumping syndrome for those
with a history of malabsorptive procedures. Use fasting and 2-hour
postprandial blood sugar monitoring as an alternative.
• If BMI is still 30 kg/m2, risks remain as in Table 3.2 and 3.3, and
management in general as in Table 3.6.
• Bariatric surgery is not an indication for cesarean delivery.
A weight maintenance program consisting of diet, physical
activity, and behavior therapy should be a priority after the
initial 6–12 months of weight loss therapy. Lifelong medical
surveillance after surgical therapy is a necessity. Almost 20% of
patients who undergo bariatric surgery experience some compli-
cation, although they are usually minor and the postoperative
mortality is <1%. There is a 5% failure rate from use of OCP fol-
lowing bariatric surgery [122]. After the surgical procedure, there
is typically a rapid weight loss in the first 6–18 months [123].
Thus, pregnancy during this period may be complicated by nutri-
tional deficiencies that could be detrimental to the growing fetus
[124–127]. Patients should be advised to delay pregnancy for at
least 12 months or until significant weight loss is completed
[2, 128]. There is little evidence to support the duration of delay
for conception with regard to birth weight, cesarean delivery,
or congenital malformation. Weight loss usually plateaus after
12–18 months.
Prognosis for a future pregnancy depends mostly on the
BMI that has been attained. There is significant decrease in
incidence of gestational diabetes (OR 0.31; 95% CI 0.15–0.65),
hypertensive disorders (OR 0.42; 95% CI 0.23–0.78), and mac-
rosomia (OR 0.40; 95% CI 0.24–0.67) following bariatric sur-
gery, especially for women capable of starting the pregnancy
with a BMI <30 kg/m2, compared to before bariatric surgery or
to obese women who have not had bariatric surgery [115, 121,
128–133]. Often the studies are not matched for BMI, a major
43
shortcoming. There does not appear to be any clear increased
(secondary to nutrient deficiencies) or decreased (secondary to
lower maternal BMI) association with incidence of birth defects
after completion of bariatric surgery [134].
Nutritional supplementation should be recommended
because there is good evidence of increased incidences of mater-
nal and neonatal deficiencies of vitamin B12, vitamin D, iron,
and calcium in women post-bariatric surgery (Table 3.7) [135].
Preconception issues mentioned earlier should be reviewed,
including an increased likelihood of small-for-gestational age
newborns among bariatric surgery recipients (OR 2.16; 95% CI
1.28–3.66) [115, 129, 130] as well as possible increased risk of
stillbirth or neonatal death (Table 3.7) [129]. Patients with bar-
iatric surgery should be started on vitamin B12, folate, iron,
and calcium if deficient [128]. Vitamin D supplement 10 mg
daily during pregnancy and breastfeeding can be recommended
as per the Royal College of Obstetricians and Gynaecologists
(RCOG) guidelines [136]. Uncertainty remains regarding
whether supplementation with vitamin K is warranted, but it is
known that women with major malabsorptive surgeries are at
increased risk for vitamin K deficiency [137]. A bariatric surgeon
should be involved during prenatal care, should gastric band need
some adjustments. Seemingly insignificant or normal prenatal
complaints warrant attention as patients who have had bariatric
surgery are at risk for postoperative complications. Specifically,
the triad of epigastric pain and/or nausea and vomiting in a preg-
nant patient with a history of a Roux-en-Y bypass must be taken
seriously as this can indicate an internal hernia [138]. During
pregnancy, patients who present with signs and symptoms of
intestinal obstruction, perforation, or hemorrhage should have a
CT scan done to establish diagnosis since this can be associated
with 20% maternal mortality.
Folic acid supplementation and
other necessary vitamins
Proper general preconception care should be provided (Figure 3.1;
Chapter 1, Obstetric Evidence Based Guidelines). Since almost
50% pregnancies are unplanned, all patients capable of child-
bearing should be placed on folic acid 0.4–0.8 mg (400–800 μg)
supplementation at least 1 month before conception, and con-
tinue daily supplements through the first 2–3 months of preg-
nancy [139]. Folate levels have been noted to be low in the obese
population [140]. Although obesity is considered a risk factor
for a NTD, the folic acid supplementation in the United States
has remained the same [139]. However, both the RCOG [136]
and the Society of Obstetricians and Gynaecologists of Canada
(SOGC) [11] have recommended a dose of 5 mg daily for the
obese population (BMI >35 kg/m 2) starting from 1–3 months
preconception through the first trimester. The use of pericon-
ception multivitamins has not been associated with reduction
of the increased risk of CHD in the overweight and obese popu-
lation. Drug history should be reviewed to identify any potential
teratogens.
Prenatal care
Preconception management, except for large weight loss, should
be followed (Table 3.6) [141]. Alternative models for delivery of
prenatal care (such as a clinical carepath) may be helpful in opti-
mizing provision of care. Clinical evidence should be reviewed
frequently as significant research is ongoing in the field of opti-
mizing care of women with obesity during pregnancy [142, 143].
44
Ideal weight gain
The total weight of an average fetus, placenta, and amniotic fluid
at term is about 4–5 kg. In the last 20 years, both the Institute of
Medicine (IOM) and ACOG have suggested 5–9 kg (11–20 lbs) as
total weight gain in pregnancy for women with obesity [144]. This
suggestion does not account for differences in class of obesity.
Significant weight loss during pregnancy is not recommended
by ACOG and IOM; but incidence of small for gestational age
births in those with obesity (especially class II and III) who lose
weight during pregnancy is still less than 10% (normal), so that
the benefits of losing some weight (e.g. less pre-eclampsia, dia-
betes, macrosomia, etc.) are not outweighed by any risks [145].
Most women with obesity exceed these guidelines, with African
American women and those with lower educational attainment
more likely to exceed guidelines [146–148].
More recent data suggest that lower weight gain in the obese
gravida is associated with maternal and fetal benefits, including
appropriate fetal growth [147, 149–152]. For women with obe-
sity, weight gain has limited if any benefit. The lowest risks
for mother and baby seem to occur with weight gain of 0–9 lb
for class II women with obesity (or even some minimal weight
loss), and weight loss of 0–9 lb for class III women with obesity
[153]. On the basis of these data, new guidelines should be consid-
ered for women with obesity (Table 3.8). Lifestyle interventions
have been shown to reduce the amount of weight gained dur-
ing pregnancy, particularly if provided by primary care provid-
ers [154]. Follow-up of two randomized controlled trials did not
demonstrate any difference for maternal lifestyle interventions
on child neurobehavioral development at 3–6 years of life [155].
A nutritional consult may be sought to prevent excessive gesta-
tional weight gain. Dieticians who utilized “Healthy Conversation
Skills” were better received by participants [156]. Charts to out-
line the patient’s progress should be a permanent part of the
prenatal record. Excessive weight retention self-perpetuates the
obesity cycle for subsequent pregnancies [149]. Almost three-
fourths of all women will weigh more at a subsequent pregnancy
[157]. Self-weighing has not been shown to be effective in reduc-
ing obstetric complications [158].
Diet
A balanced diet, rich in high fiber and complex carbohydrates,
with low glycemic intake, is suggested. Specific focus on reduc-
tion in sweets, snacks, and sugar-sweetened beverages appears to
be more useful in avoiding excessive weight gain than adherence
to a specific diet [159]. Up to 5 mg of folic acid should be contin-
ued from the pre-pregnancy period until at least 10 weeks’ ges-
tation [11, 136]. Education about weight gain, healthy eating,
and exercise decreases the percentage of women who exceed
weight gain recommendations [160, 161], The evidence for ante-
natal dietary and lifestyle interventions in overweight and obese
pregnant women to decrease complications is still insufficient
to make recommendations, although some trials show promise
TABLE 3.8: Weight Gain Suggestions for Overweight and Obese Women
Prepregnancy Weight Category Our Suggested Total Weight Gain Range (lb)
Overweight (BMI 25–29.9 kg/m2) 6–20 (2.7–9.0 kg) (2.0–16.0 kg)
Class I Obesity (BMI 30–34.9 kg/m2) 5–15 (2.3–6.8 kg) (2.0–6.0 kg)
Class II Obesity (BMI 35–39.9 kg/m2) –9 to 9 (–4.0 to 4.0 kg) (loss to 4 kg)
Class III Obesity (BMI > 40 kg/m2) –15 to 0 (–6.8 to 0 kg) (0–6.0 kg)
Source: Adapted from Refs. 122, 149, 328, 335.
Abbreviation: IOM, Institute of Medicine.
Maternal-Fetal Evidence Based Guidelines
in reducing weight gain and improving lipid profiles [162–165].
Dietary and exercise counseling did result in increased vitamin
D levels compared to women who did not receive this counsel-
ing [166]. Likewise, partial meal replacement resulted in an
improvement in micronutrient deficiencies [167] and a random-
ized trial suggests that this coupled with a lifestyle intervention
also resulted in less excessive weight gain [168]. Probiotics and/
or fish oil supplementation does not appear to lower the risk of
gestational diabetes mellitus or improve mental health among
women with obesity [169–172]. Furthermore, women with obe-
sity have an attenuated response to omega-3 fatty acid supple-
mentation during pregnancy [173]. Myo-inositol supplementation
when started at the completion of the first trimester did show a
decreased incidence of gestational diabetes mellitus in one ran-
domized trial [174]. Women with obesity tend to have lower levels
of serum vitamins and a majority did not reach adequate vitamin
D intake, thus supplementation may be considered [175]. Neither
diet or exercise showed a benefit in decreasing the incidence of
hypertensive disorders of pregnancy in one study [176].
Exercise
Physical activity during pregnancy is successful in restrict-
ing gestational weight gain, and may reduce the incidence of
the development of gestational diabetes [161, 177–183]. An RCT
among 300 overweight and obese pregnant women showed that
30 minutes of cycling, at least 3 times weekly, resulted in a lower
incidence of gestational diabetes (22.0% in the cycling group
versus 40.6% in the usual activity group; [184]). Physical activ-
ity intervention assessed by pedometer is associated with lower
gestational weight gain compared to controls [185]. Physical
activity should be encouraged as per ACOG recommendations
[186]. Supervised exercise during pregnancy did not improve
psychological wellbeing, although this may be due to low adher-
ence to the program [187]. Exercise for women with obesity is not
associated with an increased incidence of preterm birth [181].
Lifestyle interventions may have limited benefit in certain groups
of women, such as those with early gestational diabetes mellitus,
however this warrants further study [188]. In addition, lifestyle
interventions may have greater benefit in disadvantaged women,
such as those of low socioeconomic status, but this has not been
replicated in all studies [189, 190].
Medication
Metformin given in obese non-diabetic pregnant women
decreased maternal weight gain (4.6 kg versus 6.3 kg in con-
trol group) as well as the need for cesarean delivery (39.8% with
Metformin versus 62.9% in control group); however, this is not
yet a standard of care given lack of efficacy in some trials as well
as gastrointestinal side effects [191–194]. In addition, there is
some evidence, however low-quality, that metformin may reduce
the risk of hypertensive disorders of pregnancy, particularly in
women with obesity who also carry a diagnosis of gestational
IOM Recommendations (lb)
15–25 (6.8–11.4 kg)
11–20 (5–9.1 kg)
11–20 (5–9.1 kg)
11–20 (5–9.1 kg)
Obesity
diabetes [195]. Furthermore, metformin administered to obese
pregnant women does not prevent the development of ges-
tational diabetes mellitus nor did it prevent increasing birth
weights [196, 197].
Counseling/Coaching
Coaching programs have shown some efficacy in reducing
excessive weight gain, improving overall activity level in preg-
nancy, and increasing knowledge regarding weight gain goals,
even when administered via telehealth or through electronic-
based applications [198–203]. However, other brief behavioral
interventions delivered in clinic settings or online have not pre-
vented excessive weight gain [204, 205]. In addition, group pre-
natal care has not been shown to be associated with less risk for
excessive weight gain, although outcomes reported in a system-
atic review are inconsistent and deserve further study [206].
Mental health and related issues
A significant proportion of pregnant women with obesity also
have concomitant depression and anxiety as well as adverse
childhood experiences [207, 208]. The relationship between these
diagnoses and the development of obesity is unclear. However,
given the underutilization of mental health resources, screening
for depression and anxiety and referrals to appropriate special-
ists is appropriate and recommended. Underlying psychologi-
cal disorders are associated with increasing weight gain during
pregnancy, as do weight-related cognitions such as underlying
concerns about weight gain, negative body image, and perceived
barriers to healthy eating [209–211]. Depression has not been
shown to have an adverse impact on adherence to lifestyle inter-
ventions, and thus, these should be recommended regardless of
the concurrent presence of depression [212]. Homeopathic treat-
ment of overweight and obese pregnant women with underlying
mental health disorders does not appear to influence weight gain
during pregnancy [213].
In addition, women with obesity may struggle with insomnia
and poor sleep quality for a multitude of reasons, including men-
tal health concerns as obstructive sleep apnea. One RCT noted
an improvement for obese pregnant patients with insomnia with
a behavioral sleep intervention compared to standard care [214].
Baseline screening
Diabetic screening (see Chap. 5) should be done at the first
visit. If this is negative, it should be repeated at 24–28 weeks. A
recent trial calls this practice into question however, noting no
difference in composite perinatal outcomes [215]. Baseline data
to evaluate renal function and liver status, such as liver function
tests (LFTs), 24-hour urine for protein and creatinine clear-
ance, can be obtained. Reassessment of risk and the need for
EKG and echocardiogram can be made (see Table 3.2). Excess
weight has an effect on biochemical serum aneuploidy screening,
so an adjustment has to be made according to maternal weight to
achieve similar detection rates as in other women.
Office accommodations
Equipment in the office or clinic to accommodate the needs of
this population, such as wide chairs, sit-on weighing scales,
tables, and large BP cuffs, should be available [2]. The professional
team should undertake a discussion of pregnancy, maternal,
and fetal outcomes. Educational materials should be provided.
Pharmacotherapy for obesity is contraindicated in pregnancy.
While the RCOG recommends more frequent prenatal visit every
3 weeks from 24–32 weeks and then every 2 weeks till delivery,
45
there is insufficient level I data to make this an evidence-based
recommendation [216].
Aspirin for pre-eclampsia prevention
Women with obesity have higher rates of pre-eclampsia, however
women with obesity receiving low-dose aspirin for pre-eclampsia
prevention may demonstrate less blocking of the production of
thromboxane A 2, a potent mediator of vasoconstriction. ACOG
considers obesity to be a moderate risk factor for the develop-
ment of pre-eclampsia and if additional risk factors are present,
daily 81 mg aspirin can be considered in this population [217].
There are not yet clear recommendations on whether women with
obesity should receive greater doses of aspirin for pre-eclampsia
prevention, however studies are ongoing [218, 219].
Fetal ultrasound
Gestational age should be established with early (e.g. first tri-
mester is optimal) ultrasound (see Chap. 4, Obstetric Evidence
Based Guidelines).
The ability to obtain a nuchal translucency (NT) is significantly
decreased with increasing BMI. In women with Class II obesity,
the failure rate for NT is 7.8% compared to 1.0% in normal weight
gravida [220]. Multiple techniques can be used by the ultrasonog-
rapher to improve visualization including changing ultrasound
probes to improve resolution and penetration, adjusting the tis-
sue harmonics index and frequency, increasing the gain, elevating
the patient’s pannus, placing the patient on their side, or scanning
through the umbilicus [221].
A detailed fetal survey is recommended between 20–22
weeks to rule out any fetal anomalies. Women with obesity
have a higher rate of congenital heart defects among their off-
spring, with increasing rates as the class of obesity rises (OR
1.15, 95% CI 1.11–1.20 for class I, OR 1.26, 95% CI 1.18–1.34
for class II, and 1.42, 95% CI 1.33–1.51 for class III obesity)
[49]. Ultrasound detection of fetal abnormalities is limited in
women with obesity because of the increased depth of abdomi-
nal adipose tissue and increased angle of insonation [222–224].
This leads to lower prenatal detection of fetal anomalies via
ultrasonography (aOR 0.77; 95% CI 0.60–0.99) [225]. For nor-
mal BMI, overweight, and class I, II, and III obesity, detection
with standard ultrasonography was 66%, 49%, 48%, 42%, and
25%, respectively, and with targeted ultrasonography 97%, 91%,
75%, 88%, and 75%, respectively [226]. Obese gravida should
also be counseled that the ultrasound duration will be longer
with a high likelihood of having to return for repeat ultrasounds
[220]. Women with a BMI >35 kg/m 2 should be considered
to undergo a screening fetal echo between 20 and 24 weeks.
Because obese gravidas are at an increased risk for LGA infants,
and fetal growth is difficult to assess clinically, ultrasounds
are recommended every 4 weeks from 28–36 weeks to assess
fetal growth and amniotic fluid [227].
Antepartum fetal testing
There is insufficient evidence that fetal heart rate testing would
benefit the perinatal outcomes in the obese population, however,
since the risk of fetal demise is high, antepartum testing may be
considered. Fetal kick counts are also encouraged and a recent
meta-analysis noted that women with obesity are more likely to
present with decreased fetal movement, but themselves do not
have impaired perception of fetal movement, thus decreased
movement should be taken seriously as both decreased move-
ment and obesity are associated with poor pregnancy out-
comes [228].
46
Prevention of preterm birth
See Chap. 18 for detailed prevention of preterm birth. Compared
to normal weight women, women with obesity had longer cervi-
cal lengths and a lower incidence of spontaneous preterm birth,
however, a screening cervical length is recommended at the time
of the detailed fetal survey (20–22 weeks) to identify those with a
short cervix who may benefit from progesterone therapy, and cer-
clage if they also have a prior preterm birth [229]. The efficacy of
17-alpha hydroxyprogesterone caproate (17-OHP) to prevent pre-
term birth in the obese population has not been proven, however
there is evidence to support utilizing vaginal progesterone over
IM administration of 17-OHP [230]. Furthermore, if a cervical
cerclage is indicated in general, it remains indicated in the obese
population as efficacy of cervical cerclage is not different in this
population, although ideal placement may require special atten-
tion to proper patient positioning in the operating room [231].
Administration of preterm steroids
A secondary analysis of the antenatal late preterm steroids (ALPS)
trial did not show any decrease in efficacy of betamethasone for
prevention of late preterm neonatal respiratory morbidity [232].
Intrapartum care
A multidisciplinary approach to the intrapartum management
of an obese gravida should be undertaken. The RCOG recom-
mends that women with a pre-pregnancy BMI of ≥ 30 kg/m2 have
an informed and clearly documented discussion about the pos-
sible complications that can occur as a result of obesity [233].
The hospital facility should be notified so that appropriate equip-
ment, pneumatic compression devices, beds, transfer equipment,
hoists, wide corridors, and stretchers are available. Early venous
access is suggested. The obese gravida is at an increased risk for
induction of labor (26.2% in normal weight and 34.4% in women
with obesity), failed induction (13% in normal weight versus 29%
in women with obesity), prolonged first stage of labor (up to
5 hour difference, while second stage length is not dependent on
BMI), greater oxytocin requirements, operative vaginal deliv-
eries, failed anesthesia, and postpartum hemorrhage (2–3-
fold increase) [234–243].
There may be limitations to monitoring uterine contrac-
tions and fetal heart rate in labor. Invasive toco-monitoring may
become necessary if there are no other contraindications. Active
management of the third stage would help reduce the incidence of
postpartum hemorrhage.
Mechanical cervical ripening for induction is association with
similar obstetric outcomes for women with obesity compared to
normal weight women, however maternal satisfaction with the
process is less for women with obesity [244].
For the neonate, there is an increased risk of shoulder dysto-
cia (two- to threefold increase), malpresentation, lower Apgar
scores, and greater risk of NICU admission [50].
Vaginal birth after cesarean (VBAC) section rates are also lower
in women with obesity with a failure rate of 45% compared to 30%
in non-obese gravida with a greater risk of uterine rupture [245].
A planned cesarean section in the morbidly obese does not
decrease maternal or neonatal morbidity and is not recom-
mended [246]. A scheduled cesarean at 39 weeks, however,
should be discussed with the patient if the estimated fetal
weight is >4500 g in a diabetic patient and >5000 g in a non-
diabetic obese patient [2]. See also Chapters 7–15 in Obstetric
Evidence Based Guidelines.
Maternal-Fetal Evidence Based Guidelines
Anesthesia
If an anesthesia consult was not obtained antepartum, then it
should be obtained early in labor. Regional anesthesia is the
anesthetic of choice. A combined spinal epidural is preferred.
Distorted anatomic landmarks, difficult maternal positioning,
and excessive layers of adipose tissue make regional anesthesia
more challenging. Obesity is associated with increased regional
anesthesia failure rates, higher incidences of dural puncture, and
greater need for general anesthesia [44, 247]. More attempts at
placement of epidural and spinal have to be made in the obese
population as compared to the non-obese. The initial failure rate
of epidural catheter placement can be as high as 42% in the mor-
bidly obese. Use of limited ultrasound can reduce the amount of
time needed for lumbar epidural placement (Tubinis et al., RCT,
n = 150, 6.9 versus 9.5 minutes, with less needle passes needed
[87.5% success in first placement with ultrasound versus 52.5%
without ultrasound [248].
Women with obesity can be a challenge because of related
OSA and asthma. Positioning and placement of the panniculus
can impair respiratory function [249]. In a morbidly obese patient
(BMI > 40 kg/m2) undergoing a planned cesarean delivery, the
overall conductive anesthesia complication rate is about 8%.
General anesthesia in the obese pregnant woman also poses its
own challenges including difficult endotracheal intubation due to
excessive tissue and edema and intraoperative respiratory events
from failed or difficult intubation [250]. General anesthesia is
used more frequently in patients with obesity and intraoperative
hypotension can be a problem [251]. Of about 1% maternal deaths
that were anesthesia related, 75% were noted to be obese [252]. The
incidence of partially obliterated oropharyngeal anatomy among
obese parturients is double that among non-obese parturients.
This leads to an increased risk of difficult intubations, gastric
aspiration, and difficulty in maintaining adequate mask ven-
tilation [249]. Mask ventilation tends to be difficult because of
low chest wall compliance and increased intra-abdominal pres-
sure. The anesthesiologist should have long epidural needles,
and equipment such as a laryngeal mask ventilation, fiberoptic
guidance, and/or ultrasound available for these challenging cases
[2, 253]. In addition, women with obesity undergoing a cesarean
delivery with spinal anesthesia who received a phenylephrine
infusion (compared to bolus dosing) had less nausea and vom-
iting [254]. See also Chapter 12 in Obstetric Evidence Based
Guidelines.
Cesarean delivery
Obesity is a risk factor for complications from cesarean section.
As BMI increases, the time from incision to delivery and total
operative time also increases.
Increased operative time leads to worse outcomes [255, 256].
Wound complications (separation and infection) are as high as
30% in women with obesity compared to a 3–17% overall popula-
tion risk with the vast majority occurring 8–10 days post cesarean
section [257]. Tissue oxygenation is poor in the obese population.
Increased oxygen supplementation perioperatively may enhance
wound healing, as per non-pregnancy data, but there is insuf-
ficient evidence to recommend it in the obese obstetric popula-
tion [258–261]. (See also Chap. 14 in Obstetric Evidence Based
Guidelines.)
Surgical techniques that have been proven to reduce wound
infection and separation include: Closure of the subcutane-
ous layer with suture if the depth is >2 cm and subcuticular
closure with suture over staples [262–264], although a recent
Obesity
RCT in class III women with obesity found no difference between
suture and staples [265]. One RCT suggests that interrupted
subcutaneous sutures may be more effective in prevention of
wound complications than continuous closure of the subcuta-
neous space [266]. Another RCT (n = 169) suggests that closure
with interrupted subcuticular sutures may be more effective in
preventing wound complications when compared to a continuous
subcuticular suture [267]. A more controversial recommendation
includes placement of the skin incision either vertically or trans-
verse, although a transverse skin incision is likely preferred
and associated with less morbidity [268, 269]. This decision
should be individualized as this may differ depending on the cat-
egory and type (e.g. central) of obesity. Placing the incision above
the panniculus, which at times means above the umbilicus, may
be necessary in the woman with severe obesity.
Use of a barrier self-retaining retractor to optimize exposure
in obese pregnant women undergoing a cesarean delivery was not
associated with any change in surgical site infections compared
to non-use of this retractor, thus use can be left to the discretion
of the surgeon [270].
Prophylactic antibiotics should be administered (e.g. with
cefazolin 2 g IV) at least 30 minutes prior to the skin incision.
Some studies suggest that 4 g of IV cefazolin leads to higher tissue
concentrations than 2 g, which may result in decreased surgical
site infections and endometritis [271–273]. A double-blind RCT
demonstrated that although 3 g of cefazolin administered preop-
eratively results in significantly higher adipose tissue concentra-
tions at the time of hysterotomy and fascial closure and greater
umbilical cord blood concentrations compared to 2 g, both doses
achieved sufficient adipose tissue concentrations to provide
prophylaxis against Gram-positive and Gram-negative bacteria
[274]. Other recent studies have produced conflicting data in
regard to reaching adequate adipose tissue concentrations with
higher doses of prophylactic cefazolin (2 g versus 3 g) in women
with obesity [275, 276]. Further studies are needed to evaluate
alterations in maternal dosing before changing the currently
recommended dose of 2 g.
Negative pressure wound therapy does not decrease the
incidence of wound complications in women with obesity and
appears to increase the risk of skin reactions for the group receiv-
ing negative pressure therapy, as studied so far [277–280]; how-
ever, some studies have shown some benefit [281]. Likewise, silver
nylon dressings did not confer a benefit over gauze [282].
Postpartum
Venous thromboembolism
Women with obesity have an up to fourfold increased risk of
venous thromboembolism compared to normal weight women
[283]. Because of this increased risk, ACOG recommends early
mobilization and placement of pneumatic compression devices
before surgery, in all cases of anticipated prolonged labor,
and then continued until ambulation is established postpar-
tum [284, 285]. More recently, non-RCT evidence supports the
use of pharmacologic thrombophrophylaxis for 7 days post-
partum in women with obesity with additional risk factors for
thromboembolism (age >35, weight >80 kg, ≥para 4, pre-
eclampsia, immobility >4 days prior to surgery, major illness,
emergency cesarean section, current infection, antiphos-
pholipid syndrome, prior thromboembolic event, or family
history of thromboembolism) or in all women who are class
III obese (BMI >40 kg/m2) [286–288]. Two studies suggest
47
that weight-based dosing of low-dose heparin, e.g. enoxaparin
(0.5 mg/kg SQ every 12 hours) to be better than traditional pro-
phylactic dosing (40 mg SQ daily) [289, 290]. Women who meet
criteria for pharmacologic prophylaxis should at the very least be
started on enoxaparin (lovenox) 40 mg SQ daily while hospital-
ized, although weight-based dosing is also acceptable. See also
Chapter 30.
Other complications
In the postpartum period, women with obesity are also at
a greater risk of requiring longer hospital stays, resulting in
increased medical costs, maternal ICU admissions (OR 3.50; 95%
CI 2.72–4.51), wound infections (OR 3.4; 95%CI 1.4–1.8), post-
partum endometritis, emergency department visits (aOR 2.2;
95% CI 1.03–4.9) and maternal death (OR 2.9; 95% CI 1.1–8.1)
[237, 238, 255, 291]. Specifically, one study found that for every
9091 obese pregnant patients, 1 patient will experience death at
delivery hospitalization. About 24% deaths in adult women aged
25–64 years are due to obesity [292]. Because of these increased
postpartum risks, special care should be given to the postpartum
obese patient by experienced physicians and nursing staff.
Psychological implications
Compared to normal weight women, obese gravida are at an
increased risk of depression during pregnancy and postpar-
tum (OR 1.43; 95% CI 1.27–1.61 and OR 1.30; 95% CI 1.20–1.42,
respectively). They are also at an increased risk for anxiety (OR
1.68; 95% CI 1.34–2.12) [293]. The patient should be provided
with resources for counseling and social work prior to discharge
home with consideration to have them return sooner than the
routine 6-week postpartum visit.
Breastfeeding
Women should be strongly encouraged and helped to return to
a normal BMI, through counseling, diet, exercise, and breast-
feeding. Breastfeeding is encouraged since it benefits both the
mother and infant. In particular, it helps accelerate the return to
pre-pregnancy weight and decreases the risk of chronic diseases
such as type II diabetes, and breast and ovarian cancer. For the
infant, breastfeeding reduces the risk of obesity [294, 295].
Women with obesity are less likely to initiate breastfeeding, or
exclusively breastfeed compared to normal weight women [296].
In order to increase the rates of breastfeeding, women with obe-
sity would benefit from consultation with a lactation specialist
[297]. It is unclear if a certain type of support (provision of breast
pump, group counseling, face-to-face versus telephone, among
others) is more beneficial than others, and additional studies need
to be completed [298].
Contraception
The contraceptive intrauterine device (IUD), implant, depot
medroxyprogesterone acetate (DMPA) injectable contraception,
and the progestin-only contraceptive pills appear to be as effec-
tive in women with and without obesity and should be encouraged
for postpartum use. Some studies indicate that oral hormonal
contraception may not be as effective as in the non-obese;
however, others do not confirm this finding [299–302]. The CDC
list combined hormonal contraceptives as recommendation class
I (advantages generally outweigh theoretical or proven risks) and
the other forms of contraception (copper or levonorgestere IUD,
implant, DMPA, and progesterone only pills as recommendation
class I (no restrictions) [303]. Oral contraceptives may also not
be as effective in women who undergo bariatric surgery because
48
of the malabsorptive effects. Pregnancy rates are high after
weight loss surgery; therefore, effective contraception should
be discussed prior to the procedure [304]. Additionally, body
weight >90 kg is a risk factor for failure of the contraceptive
patch and other options should be prioritized [301]. Finally,
the DMPA injection has been associated with weight gain and
women with obesity should be aware of this potential effect (and
may be less motivated to utilize this method). This may be one of
the underlying reasons that women with obesity are more likely
to use LARCs (long-acting reversible contraceptives) compared
to their non-obese counterparts [305]. Further studies looking at
both weight and BMI and association with contraceptive efficacy
are needed [302].
Emergency contraception with levonorgesterel (and pos-
sible ulipristal acetate) is less effective in women with obesity
than those who are non-obese, however this should not restrict
access to this method, but should prompt additional counseling
[306, 307].
Long-term maternal and offspring risks
Obesity during pregnancy is an independent risk factor for long-
term cardiovascular morbidity (aHR 2.6; 95% CI 2.0–3.4),
specifically ischemic stroke (aHR 2.63; 95% CI 1.41–1.91) and
myocardial infarction (aHR 1.89; 95% CI 1.25–2.84). There is a
greater risk of all-cause mortality in women with obesity (HR
1.35; 95% CI 1.02–1.77) compared to women of normal pregnancy
BMI [308–311].
Offspring of obese mothers are at increased risk for sig-
nificant health conditions later in life as a result of in utero pro-
gramming, which may work through environmental, genetic,
and epigenetic mechanisms. The biggest risks include obesity,
lower childhood cognitive scores, autism (OR 1.58; 95% CI
1.26–1.98), type II diabetes mellitus/abnormal glucose toler-
ance, increased blood pressure, cancer, and cardiovascular
disease, as well as potential renal injury (Table 3.2) [32, 38, 45,
308, 312–320]. The key is to identify and intervene early and to
potentially reverse the known future adverse consequences asso-
ciated with maternal obesity.
Future
Future research should assess the degree of intensiveness and
contact with a healthcare provider during management with diet
and exercise, drug therapy to target different biological pathways
to obesity, the mechanisms of fetal macrosomia and fetal demise
secondary to obesity, and childhood obesity, among many others.
Reducing maternal pre-pregnancy obesity and excessive gesta-
tional weight retention will help alleviate the obesity epidemic.
Food industry companies, insurance companies, public educa-
tion, school education, tax breaks, premium breaks, fitness pro-
grams, and many others should work together to end this vicious
cycle, leading to now earlier mortality than previous generations
because of obesity.
Patient resources
• American Obesity Association – www.obesity.org
• MyPlate – MyPlate.gov
• National Heart, Lung, and Blood Institute. Obesity educa-
tion initiative www.nhlbi.nih.gov/about/oei/index.htm
• Weight-control Information Network – www.win.niddk.
nih.gov
Maternal-Fetal Evidence Based Guidelines
References
1. World Health Organization. Obesity: preventing and managing the
global epidemic. Geneva, Switzerland: World Health Organization: WHO
Technical Report Series 2000;894:1–253. [III: Review]
2. American College of Obstetricians and Gynecologists. Obesity in preg-
nancy, Practice Bulletin No. 156. Obstet Gynecol (Reaffirmed 2018).
2015;126:e112–1F26. [III: Review]
3. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity and
severe obesity among adults: United States, 2017–2018. NCHS Data Brief
No. 360. 2020 February Retrieved on 8 December 2020 from https://
w w w.cdc.gov/nchs/products/databriefs/db360.htm#:~:text=The%20
age%2Dadjusted%20prevalence%20of%20severe%20obesity%20among%20
U.S.%20adults,60%20and%20over%20(5.8%25) (2017–2018 NHANES Survey
and Physical Exam, n = 8704). [III: Review]
4. Nohr EA, Timpson NJ, Anderson CS, et al. Severe obesity in young women
and reproductive health: the Danish National Birth Cohort. PLOS ONE
2009;4(12):e8444. [II-2:Danish National Birth Cohort, prospective cohort,
n = 4901, obese BMI > 30 kg/m 2, n = 2451]
5. Bolumar F, Olsen J, Rebagliato M, et al. Body mass index and delayed con-
ception: a European Multicenter Study on Infertility and Subfecundity. Am
J Epidemiol 2000;151:1072–1079. [II-2: European multicenter prospective
study, n = 4.035]
6. Cavalcante MB, Sarno M, Peixoto AB, Júnior EA, Barini R. Obesity and
recurrent miscarriage: a systematic review and meta-analysis. J Obstet
Gynaecol Res 2019;45(1):30–38. [II-2: Meta-analysis, 6 studies]
7. Metwally M, Ong KJ, Ledger WL, et al. Does high body mass index increase
the risk of miscarriage after spontaneous and assisted conception? A meta-
analysis of the evidence. Fertil Steril 2008;90:714–726. [II-2: 16 studies
meta-analysis n = 5545, BMI > 25]
8. Sebire NJ, Jolly M, Harris JP, et al. Maternal obesity and pregnancy outcome:
a study of 287,213 pregnancies in London. Int J Obes 2001;25:1175–1182.
[II-3: UK observational study 1989–1997, n = 287,213; BMI > 30 kg/m 2, n =
31,276]
9. Weiss JL, Malone FD, Emig D, et al., Obesity, obstetric complications and
cesarean delivery rate—a population-based screening study. FASTER
Research Consortium. Am J Obstet Gynecol 2004;190:1091–1097. [II-1:
Prospective multicenter population-based screening study, n = 16,102; BMI
30–35 kg/m 2, n = 1473; BMI > 35 kg/m 2, n = 877]
10. Poorolajal J, Jenabi E. The association between body mass index and pre-
eclampsia: a meta-analysis. J Matern Fetal Neonatal Med 2016;29(22):3670–
3676. [II-2: Meta-analysis, 23 studies, n = 1,387,599)
11. Davies GAL, Maxwell C, McLeod L, et al. Obesity in pregnancy. SOGC
clinical practice guidelines. Int J Gynaecol Obstet 2010;110(2):165–173. [III:
Clinical guideline, 79 references]
12. Crane JM, Murphy P, Burrage L, et al. Maternal and perinatal out-
comes of extreme obesity in pregnancy. J Obstet Gynaecol Can
2013;35(7):606e11. [II-2: Population based cohort study, n = 5788; BMI
> 50 kg/m 2 n = 71]
13. Stotland NE, Washington AE, Caughey AB. Prepregnancy body mass index
and the length of gestation at term. Am J Obstet Gynecol 2007;197(4):378.
e371–378.e375. [II-2: Retrospective study, US, one center, n = 9336]
14. Ovesen P, Rasmussen S, Kesmodel U. Effect of prepregnancy maternal over-
weight and obesity on pregnancy outcome. Obstet Gynecol 2011;118(2 Pt
1):305e12. [II-2: Danish Medical Birth Registry, prospective cohort 2004–
2010, n = 369,347]
15. Samuels-Kalow ME, Funai EF, Buhimschi C, et al. Prepregnancy body
mass index, hypertensive disorders of pregnancy, and long-term maternal
mortality. Am J Obstet Gynecol 2007;197(5): 490.e1e6. [II-2: Retrospective
cohort study, n = 13,722]
16. Aune D, Saugstad OD, Henriksen T, et al. Maternal body mass index and
the risk of fetal death, stillbirth, and infant death: a systematic review and
meta-analysis. JAMA 2014;311(15):1536e46. [II-3: Meta-analysis: 38 stud-
ies, n = 10,147 fetal deaths, n = 16,274 stillbirths, n = 4311 perinatal deaths,
n = 11,294 neonatal deaths, and n = 4983 infant deaths were included]
17. Bautista-Castano I, Henriquez-Sanchez P, Aleman-Perez N, et al. Maternal
obesity in early pregnancy and risk of adverse outcomes. PLOS ONE
2013;8(11):e80410. [II-2: Population-based cohort study, single-center
study, n = 6887]
18. World Health Organization. Obesity and overweight. Geneva, Switzerland:
World Health Organization: 2020. WHO Fact Sheet. Updated 2020. [III:
Review]
19. Álvarez-Bueno C, Cavero-Redondo I, Lucas-de la Cruz L, Notario-Pacheco
B, Martínez-Vizcaíno V. Association between pre-pregnancy overweight
and obesity and children’s neurocognitive development: a systematic review
Obesity
and meta-analysis of observational studies. Int J Epidemiol 2017;46(5):
1653–1666. [II-2; Meta-analysis, 15 observational studies]
20. Barbosa L, Boaviagem A, Moretti E, Lemos A. Multiparity, age, and over-
weight/obesity as risk factors for urinary incontinence in pregnancy: a sys-
tematic review and meta-analysis. Int Urogynecol J 2018;29(10):1413–1427.
[II-2; Meta-analysis, 13 studies]
21. Dadouch R, Faheim M, Susini O, Sedra S, Showell M, D’Souza R. Variation
in outcome reporting in studies on obesity in pregnancy – a systematic
review. Clin Obes 2019;9(6):e12341. [I; Systematic Review, 70 included clini-
cal trials]
22. Dai R-X, He X-J, Hu C-L. Maternal pre-pregnancy obesity and the risk of
macrosomia: a meta-analysis. Arch Gynecol Obstet 2018;297(1):139–145.
[II-2; Meta-analysis, 16 cohort studies]
23. Ellis JA, Brown CM, Barger B, Carlson NS. Influence of maternal obesity
on labor induction: a systematic review and meta-analysis. J Midwifery
Womens Health 2019;64(1):55–67. [II-2; Systematic Review and meta-­
analysis, 10 studies]
24. Golab BP, Santos S, Voerman E, Lawlor DA, Jaddoe VWV, Gaillard R.
Influence of maternal obesity on the association between common preg-
nancy complications and risk of childhood obesity: an individual partici-
pant data meta-analysis. Lancet Child Adolesc Health 2018;2(11):812–821.
[II-2; Meta-analysis, 34 studies, n = 160, 757 mother-infant pairs].
25. Hadley EE, Discacciati A, Constatine MM, et al. Maternal obesity is associ-
ated with chorioamnionitis and earlier indicated preterm delivery among
expectantly managed women with preterm premature rupture of mem-
branes. J Matern Fetal Neonatal Med 2019;32(2):271–278. [II-1; Secondary
Analysis of RCT, n = 164 cases of PPROM].
26. Hendler I, Schatz M, Momirova V, et al. for the National Institute of Child
Health and Human Development Maternal–Fetal Medicine Units Network.
Association of obesity with pulmonary and nonpulmonary complications
of pregnancy in asthmatic women. Obstet Gynecol 2006;108:77–82. [II-2,
Secondary analysis of prospective cohort, n = 2566]
27. Heslehurst N, Vieira R, Akhter Z, et al. The association between maternal
body mass index and child obesity: a systematic review and meta-analysis.
PLOS Med 2019;16(6):e1002817. [II-2; Systematic review and meta-analysis,
79 studies, n = 88,872]
28. Hibbard JU, Gilbert S, Landon MB, et al. for the National Institute of Child
Health and Human Development Maternal–Fetal Medicine Units Network.
Trial of labor or repeat cesarean delivery in women with morbid obesity
and previous cesarean delivery. Obstet Gynecol 2006;108(1):125–133. [II-2:
Multicenter, prospective study, n = 28,442]
29. Huang H-Y, Chen H-L, Feng L-P. Maternal obesity and the risk of neural tube
defects in offspring: a meta-analysis. Obes Res Clin Pract 2017;11(2):188–
197. [II-2; Meta-analysis, 22 studies, n = 1,758,832]
30. Huang Y, Ouyang Y-Q, Redding SR. Maternal prepregnancy body
mass index, gestational weight gain, and cessation of breastfeeding:
a systematic review and meta-analysis. Breastfeeding Med. Jul/Aug
2019;14(6):366–374. [II-2; Systematic review and meta-analysis, 30 stud-
ies, n = 170,109 women]
31. Kawasaki M, Arata N, Miyazaki C, Mori R, Kikuchi T, Ogawa Y, Ota E.
Obesity and abnormal glucose tolerance in offspring of diabetic mothers: a
systematic review and meta-analysis. PLOS ONE 2018;13(1):e0190676. [II-
2; Meta-analysis, 20 observational studies]
32. Li Y-M, Ou J-J, Liu L, Zhang D, Zhao J-P, Tang S-Y. Association between
maternal obesity and autism spectrum disorder in offspring: a meta-­
analysis. J Autism Dev Disord 2016;46(1):95–102. [II-2; Meta-analysis,
5 observational studies]
33. Liu X, Ding G, Yang W, et al. Maternal body mass index and risk of con-
genital heart defects in infants: a dose-response meta-analysis. BioMed
Research International. 2019 July 7;1–14. [II-2; IPD Meta-analysis, 19 stud-
ies, n = 2,416,546]
34. Lutziv O, Mah J, Beyene J, McDonald SD. The effects of morbid obesity on
maternal and neonatal health outcomes: a systematic review and meta-
analyses. Obes Rev 2015;16(7):531–46. [II-2; Meta-analysis, 59 studies].
35. Prodromidou A, Frountzas M, Perrea D, Vlachos GD, Pergialiotis V. The
impact of obesity on cervical cerclage efficacy: a systematic review of the
literature. J Neonatal Perinatal Med 2016;9(1):59–65. [II-2; Meta-analysis, 3
studies]
36. Racusin D, Stevens B, Campbell G, Aagaard-Tillery K. Obesity and the risk
and detection of fetal malformations. Semin Perinatol 2012;36(3):213–221.
[III; Review]
37. Rahman MM, Abe SK, Kanda M, et al. Maternal body mass index and risk of
birth and maternal health outcomes in low- and middle-income countries:
a systematic review and meta-analysis. Obes Rev 2015;16(9):758–770. [II-2;
Meta-analysis, 42 studies]
49
38. Sanchez CE, Barry C, Sabhlok A, et al. Maternal pre-pregnancy obe-
sity and child neurodevelopmental outcomes: a meta-analysis. Obes Rev
2018;19(4):464–484. [II-2; Meta-analysis, 41 studies]
39. Sermondade N, Huberlant S, Bourhis-Lefebvre V, et al. Female obesity
is negatively associated with live birth rate following IVF: a systematic
review and meta-analysis. Hum Reprod Update 2019;25(4):439–451. [II-2;
Systematic review and meta-analysis, 21 studies]
40. Steinig J, Nagl M, Linde K, Zietlow G, Kersting A. Antenatal and postna-
tal depression in women with obesity: a systematic review. Arch Womens
Ment Health 2017;20(4):569–585. [II-2; Systematic review, 14 observational
studies]
41. Supramaniam PR, Mittal M, McVeigh E, Lim LN. The correlation between
raised body mass index and assisted reproductive treatment outcomes:
a systematic review and meta-analysis of the evidence. Reprod Health
2018;15(1):34. [II-2; Meta-analysis, 49 studies]
42. Task Force on Pregnancy and Heart Disease, American College of
Obstetricians and Gynecologists. Pregnancy and Heart Disease, Practice
Bulletin Number 212. Obstet Gynecol 2019;133(5):e320–e356. [III; Review]
43. Tremmel M, Gerdtham U-G, Nilsson PM, Saha S. Economic burden of obe-
sity: a systematic literature review. IJERPH 2017;14:435. [III; Review]
44. Uyl N, de Jonge E, Uyl-de Groot C, van der Marel C, Duvekot J. Difficult
epidural placement in obese and non-obese pregnant women: a system-
atic review and meta-analysis. Int J Obstet Anesth 2019;40:52–61. [II-2;
Systematic Review, 8 studies, 44,401 participants]
45. Xiao D, Qu Y, Huang L, Wang Y, Li X, Mu D. Association between maternal
overweight or obesity and cerebral palsy in children: a meta-analysis. PLOS
ONE 2018;13(10):e0205733. [II-2; Systematic Review, 8 studies]
46. Yamazaki M, Dwyer K, Sobhan M, et al. Effect of obesity on the effective-
ness of hormonal contraceptives: an individual participant data meta-­
analysis. Contraception 2015;92(5):445–52. [I; Meta-analysis, 7 Phase
3 clinical trials]
47. Zhang C, Wu Y, Li S, Zhang D. Maternal prepregnancy obesity and the risk
of shoulder dystocia: a meta-analysis. BJOG 2018;125(4):407–413. [II-2;
Meta-analysis, 20 observational studies, n = 2,153,898]
48. Zhang J, Peng L, Chang Q, et al. Maternal obesity and risk of cerebral palsy
in children: a systematic review and meta-analysis. Dev Med Child Neurol
2019;61(1):31–38. [II-2; Meta-analysis, 5 cohort studies, n = 7919, 288 par-
ticipants with 12, 324 cases of cerebral palsy]
49. Zheng Z, Yang T, Chen L, et al. Increased maternal body mass index is asso-
ciated with congenital heart defects: an updated meta-analysis of obser-
vational studies. Int J Cardiol 2018;273:112–120. [II-2; Meta-analysis, 29
studies, n = 6,467,422 participants with 99,205 participants with congenital
heart disease]
50. Zhu T, Tang J, Zhao F, Qu Y, Mu D. Association between maternal obe-
sity and offspring APGAR score or cord pH: a systematic review and meta-
analysis. Sci Rep 2015;5:18386. [II-2; Meta-analysis, 11 cohort studies, n =
2,586,265]
51. Zhu Y, Chen Y, Feng Y, Yu D, Mo X. Association between maternal body
mass index and congenital heart defects in infants: a meta-­ a nalysis.
Congenit Heart Dis 2018;13(2):271–281. [II-2; Meta-analysis, n = 17
studies]
52. Volger S, Vetter ML, Dougherty M, et al. Patients’ preferred terms for
describing their excess weight: discussing obesity in clinical practice.
Obesity (Silver Spring) 2012;20(1):147–150. [II-3; Prospective survey, n =
390]
53. American College of Obstetricians and Gynecologists, Committee
on Ethics. Ethical considerations for the care of patients with obesity,
Committee Opinion No 763. Obstet Gynecol 2019;133(1):e90–e96. [III;
Review]
54. Olander EK, Berg M, McCourt C, Carlström E, Dencker A. Person-centered
care in interventions to limit weight gain in pregnant women with obe-
sity – a systematic review. BMC Pregnancy Childbirth 2015;15:50. (II-2;
Systematic review, 10 studies)
55. Jones C, Jomeen J. Women with a BMI ≥30 kg/m 2 and their experience of
maternity care: a meta ethnographic synthesis. Midwifery 2017;53:87–95.
[II-3; Systematic review, 12 qualitative studies]
56. Vanstone M, Kandasamy S, Giacomini M, DeJean D, McDonald SD.
Pregnant women’s perceptions of gestational weight gain: a systematic
review and meta-synthesis of qualitative research. Matern Child Nutr
2017;13(4):e12374. [II-3; Qualitative meta-analysis, 42 studies]
57. Kelly T, Yang W, Chen C, et al. Global burden of obesity in 2005 and pro-
jections to 2030. Inter J Obes 2008;32:1431–1437. [II-3: Pooling analysis of
representative population samples from 106 countries]
58. Han J, Lawlor D, Kimm S. Childhood obesity. The Lancet 2010;375(9727):
1737–1748. [III: Review]
50
59. James WPT, Jackson-Leach R, Ni Mhurchu C. Overweight and obesity (high
body mass index). In: Ezzati TM, ed. Comparative quantification of health
risks global and regional burden of disease attributable to selected major
risk factors. Vol 1. Geneva: World Health Organization 2004:497–596. [III:
Review]
60. Fryar C, Carroll M, Ogden C. Prevalence of overweight, obesity, and extreme
obesity among adults: United States, 1960–1962 through 2011–2012.
Division of Health and Nutrition Examination Surveys. September 2012:
1–8. https://www.cdc.gov/nchs/data/hestat/obesity_adult_13_14/obesity_
adult_13_14.pdf [III: Review]
61. Jungheim ES, Moley KH. Current knowledge of obesity’s effects in the pre-
and periconceptional periods and avenues for future research. Am J Obstet
Gynecol 2010;203(6):525–530. [III: Review]
62. Scheil W, Scott J, Catcheside B, et al. Pregnancy outcome in South Australia
2012. Adelaide: Pregnancy Outcome Unit, SA Health, Government of South
Australia, 2014. [III: Review]
63. Barsh GS, Farooqi IS, O’Rahilly S. Genetics of body-weight regulation.
Nature 2000;404:644–651. [III: Review]
64. Choquet H, Meyre D. Genetics of obesity: what have we learned? Curr
Genomics 2011;12(3): 169–179. [III; Expert Review]
65. Kaur Y, de Souza RJ, Gibson WT, Meyre D. A systematic review of genetic
syndromes with obesity. Obesity Reviews 2017;18(6):603–634. [II-2;
Systematic Review, 161 studies included]
66. Willer CJ, Speliotes EK, Loos RJ, for the Genetic Investigation of
Anthropometric Traits Consortium, et al. Six new loci associated with
body mass index highlight a neuronal influence on body weight regulation.
Nat Genet 2009;41:25–34. [II-3: Meta-analysis: 15 genome-wide association
studies for BMI (n > 32,000) and followed up top signals in 14 additional
cohorts (n > 59,000)]
67. Savona-Ventura, C. The inheritance of obesity. Best Prac Res Clin Ob
2015;29(3):300–308. [III: Review]
68. Reilly JJ, Armstrong J, Dorosty AR, et al. for the Avon Longitudinal Study of
Parents and Children Study Team. Early life risk factors for obesity in child-
hood: cohort study. BMJ 2005;330 (7504):1357. [II-2: Prospective cohort
observational study, n = 8234]
69. Metwally M, Ledger WL, Li TC. Reproductive endocrinology and clinical
aspects of obesity. Ann N Y Acad Sci 2008;1127:140–146. [III: Review]
70. Luo, ZH. Maternal and fetal leptin, adiponectin levels and associations with
fetal insulin sensitivity. Obesity 2013;21:210–216. [II-2: Prospective cohort
study, n = 248].
71. Kratzsch J, Hockel M, Kiess W. Leptin and pregnancy outcome. Curr Opin
Obstet Gynecol 2000;12:501–505. [III: Review]
72. Hauguel-de Mouzon S, Lepercq J, Catalano P. The known and unknown
of leptin in pregnancy. Am J Obstet Gynecol 2006;194(6):1537–1545. [III:
Review]
73. American College of Obstetricians and Gynecologists, ACOG Committee
on Health Care for Underserved Women. Challenges for overweight and
obese urban women. Obstet Gynecol 2014;123(3):726–730. [III: Review]
74. Gilboa SM, Correa A, Botto LD, et al. and the National Birth Defects
Prevention Study. Association between prepregnancy body mass index and
congenital heart defects. Am J Obstet Gynecol 2010;202(1):51.e1–51.e10.
[II-2: US population-based observational study, n = 11,113]
75. Brite J, Laughon SK, Troendle J, Mills J. Maternal overweight and obesity and
risk of congenital heart defects in offspring. Int J Obes 2014;38(6):878–882.
[II-2: Cohort study, the Consortium on Safe Labor, n = 121, 815 deliveries
with 1388 infants with CHD]
76. Waller DK, Shaw GM, Rasmussen SA, et al. Prepregnancy obesity as
a risk factor for structural birth defects. Arch Pediatr Adolesc Med
2007;161:745–750. [II-2: Case-control, National Birth Defects Prevention
Study, n = 10,249]
77. Rankin J, Tennant PW, Stothard KJ, Bythell M, Summerbell CD, Bell R.
Maternal body mass index and congenital anomaly risk: a cohort study. Int
J Obes 2010;34:1371–1380. [II-2: prospective cohort study, n = 682]
78. Blomberg MI, Källén B. Maternal obesity and morbid obesity: the risk
for birth defects in the offspring. Birth Defects Res A Clin Mol Teratol
2010;88(1):35–40. [II-2: Swedish Medical Health Registries, n = 1,049,582]
79. Schummers L, Hutcheon JA, Bodnar LM, Lieberman E, Himes KP. Risk of
adverse pregnancy outcome by prepregnancy body mass index. a popula-
tion-based study to inform prepregnancy weight loss counseling. Obstet
Gynecol 2015;125(1):133–143. [II-2: Population-based cohort study, n =
226,958]
80. Swank M, Marshall N, Caughey A, et al. Pregnancy outcomes in the super
obese stratified by weight gain above and below Institute of Medicine
guidelines. Obstet Gynecol 2014;124(6)1105–1110. [II-2: Retrospective
cohort study, n = 1034]
Maternal-Fetal Evidence Based Guidelines
81. Santangeli L, Sattar N, Huda S. Impact of maternal obesity on perinatal and
childhood outcomes. Best Prac Res Cli Ob 2014;29:438–448. [III: Review]
82. Hadley EE, Discacciati A, Constatine MM, et al. Maternal obesity is associ-
ated with chorioamnionitis and earlier indicated preterm delivery among
expectantly managed women with preterm premature rupture of mem-
branes. J Matern Fetal Neonatal Med 2019;32(2):271–278. [II-1; Secondary
Analysis of RCT, n = 164 cases of PPROM]
83. Gabor J, Gyamfi C, Gyamfi P, et al. Effect of body mass index and exces-
sive weight gain on success of vaginal birth after cesarean delivery. Obstet
Gynecol 2005;106:741–746. [II-2 : Retrospective study, n = 1213]
84. Hibbard JU, Gilbert S, Landon MB, et al. for the National Institute of Child
Health and Human Development Maternal–Fetal Medicine Units Network.
Trial of labor or repeat cesarean delivery in women with morbid obesity
and previous cesarean delivery. Obstet Gynecol 2006;108(1):125–133. [II-2:
Multicenter, prospective study, n = 28,442]
85. Brost BC, Goldenberg RL, Mercer BM, et al. The Preterm Prediction Study:
association of cesarean section with increases in maternal weight and body
mass index. Am J Obstet Gynecol 1997;177(2):333–337. [II-2: Prospective
study, n = 2809]
86. Nohr EA, Bech BH, Davies MJ, et al. Prepregnancy obesity and fetal
death: a study within the Danish National Birth Cohort. Obstet Gynecol
2005;106(2):250–259. [II-2: Retrospective, population-based cohort study,
n = 54,505]
87. Chu SY, Kim SY, Lau J, et al. Maternal obesity and risk of stillbirth: a meta-
analysis. Am J Obstet Gynecol 2007;197(3):223–228. [II-3: Meta-analysis of
9 observational studies]
88. Hendler I, Goldenberg RL, Mercer BM, et al. for the National Institute of
Child Health and Human Development, Maternal–Fetal Medicine Units
Network, National Institutes of Health. The preterm prediction study: asso-
ciation between maternal body mass index and spontaneous and indicated
preterm birth. Am J Obstet Gynecol 2005;192(3):882–886. [II-1: US 10 cen-
ters, prospective observational study, n = 2910, BMI >30 kg/m 2, n = 597]
89. Salihu HM, Lynch O, Alio AP, et al. Obesity subtypes and risk of sponta-
neous versus medically indicated preterm births in singletons and twins.
Am J Epidemiol 2008;168(1):13–20. [II-2: US population cohort study, n =
459,913]
90. Dietz PM, Callaghan WM, Cogswell ME, et al. Combined effects of pre-
pregnancy body mass index and weight gain during pregnancy on the risk
of preterm delivery. Epidemiology 2006;17:170–177. [II: Prospective obser-
vational cohort (PRAMS) US study 21 states, n = 113,019]
91. Ehrenberg HM, Iams JD, Goldenberg RL, et al. for the Eunice Kennedy
Shriver National Institute of Child Health and Human Development
(NICHD), Maternal–Fetal Medicine Units Network. Maternal obesity,
uterine activity, and the risk of spontaneous preterm birth. Obstet Gynecol
2009;113:48–52. [II: US multicenter, case control, n = 253]
92. Faucher MA, Hastings-Tolsma M, Song JJ, Willoughby DS, Bader SG.
Gestational weight gain and preterm birth in obese women: a systematic
review and meta-analysis. BJOG 2016;123(2):199–206. [II-2; Meta-analysis,
six studies]
93. Boujeily G, Ankner G. Sleep-disordered breathing in pregnancy. Clin Chest
Med 2011;32: 175–189. [III: Review]
94. Chen YH, Kang JH, Lin CC, Wang IT, Keller, JJ, Lin HC. Obstructive sleep
apnea and risk of adverse pregnancy outcomes. Am J Obstet Gynecol
2012;206(20):136. e131–135. [II-2: Cross-sectional study, n = 218,776
women, n = 791 had been diagnosed with OSA]
95. Poyares, D. Guilleminault C. Pre-eclampsia and nasal CPAP: Part 2:
Hypertension during pregnancy, chronic snoring, and early CPAP nasal
intervention. Sleep Medicine 2007;9:15–21. [I: Randomized control trial,
n = 16]
96. Gaudet, L. Ferraro ZM, Wen SW, Walker M. Maternal obesity and occur-
rence of fetal macrosomia: a systematic review and meta-analysis. BioMed
Research International 2014;640291. [II-3: Meta-analysis: 30 studies, multi-
center, multi-country review, n = 162,183 obese patients versus normal or
underweight control group n = 1,072,397].
97. Dodd JM, Deussen AR, Mohamad I, et al. The effect of antenatal life-
style advice for women who are overweight or obese on secondary mea-
sures of neonatal body composition: the LIMIT randomized trial. BJOG
2016;123(2):244–253. [I; RCT, n = 970 neonates].
98. Grivell RM, Yelland LN, Deussen A, Crowther CA, Dodd JM. Antenatal
dietary and lifestyle advice for women who are overweight or obese and
the effect on fetal growth and adiposity: the LIMIT randomized trial. BJOG
2016 January;123(2):233–243. [I; RCT, n = 1847]
99. Robinson H, Tkatch S, Mayes DC, et al. Is maternal obesity a predictor of
shoulder dystocia? Obstet Gynecol 2003;101(1):24–27. [II-2: Canada, case
control study, n = 45,877]
Obesity
100. Price SA, Sumithran P, Nankervis A, Permezel M, Proietto J. Preconception
management of women with obesity: a systematic review. Obes Rev
2019;20(4):510–526. [II-2; Systematic Review, 13 included studies]
101. Al Watter BH, Pidgeon C, Learner H, Zamora J, Thangaratinam S. Online
health information on obesity in pregnancy: a systematic review. Eur J
Obstet Gynecol Reprod Biol 2016;206:147–152. [II-2; Systematic review,
53 websites]
102. National Institutes of Health. Clinical guidelines on the identification, eval-
uation, and treatment of overweight and obesity in adults—the Evidence
Report 1998. Obes Res 1998:6(suppl 2):51S–209S. [III: Review]
103. American College of Obstetricians and Gynecologists. Motivational inter-
viewing: a tool for behaviour change. ACOG Committee Opinion No.423.
Obstet Gynecol 2009;113:234–236. [III: Review]
104. Madson MB, Loignon AC, Lane C. Training in motivational interviewing: a
systematic review. J Subst Abuse Treat 2009;36(1):101–109. [II-2; Systematic
review, 27 studies]
105. Vural F, Vural B, Çakıroğlu Y. The role of overweight and obesity in
in vitro fertilization outcomes of poor ovarian responders. BioMed
Research International 2015;2015:781543. [II-2: Retrospective cohort
study: single center design, normal weight (18.5–24.9 kg/m 2 , n = 96);
Group 2 was overweight (25.0–29.9 kg/m 2 , n = 52); and Group 3 was obese
(≥30.0 kg/m 2 , n = 40)]
106. Supramaniam PR, Mittal M, McVeigh E, Lim LN. The correlation between
raised body mass index and assisted reproductive treatment outcomes:
a systematic review and meta-analysis of the evidence. Reprod Health
2018;15(1):34. (II-2; meta-analysis, 49 studies]
107. Sermondade N, Huberlant S, Bourhis-Lefebvre V, et al. Female obesity
is negatively associated with live birth rate following IVF: a systematic
review and meta-analysis. Hum Reprod Update 2019;25(4):439–451. [II-2;
Systematic review and meta-analysis, 21 studies]
108. Wang Y, Xue H, Huang Y, Huang L, Zhang D. A systematic review of appli-
cation and effectiveness of mHealth interventions for obesity and diabe-
tes treatment and self-management. Adv Nutr 2017;8(3):449–462. [II-2;
Systematic Review, 24 studies]
109. Flores Mateo G, Granado-Font E, Ferre-Grau C, Montana-Carreras X.
Mobile phone apps to promote weight loss and increase physical activity: a
systematic review and meta-analysis. J Med Internet Res 2015;17(11):e253.
[II-2; meta-analysis, 12 studies]
110. Bray GA, Tartaglia LA. Medicinal strategies in the treatment of obesity.
Nature 2000;404:672–677. [III: Review]
111. Perrio MJ, Wilton LV, Shakir SAW. The safety profiles of orlistat and
sibutramine: results of prescription-event monitoring studies in England.
Obesity (Silver Spring) 2007;15(11):2712–2722. [II-2: Observational cohort
study, n = 28,357].
112. Jull AB, Ni Mhurchu C, Bennett DA, et al. Chitosan for overweight or
obesity. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.:
CD003892. [II-3: meta-analysis]
113. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a system-
atic and clinical review. JAMA 2014;311(1):74–86. [II-2; systematic review,
21 studies]
114. Ducarme G, Parisio L, Santulli P, et al. Neonatal outcomes in pregnancies
after bariatric surgery: a retrospective multi-centric cohort study in three
French referral centers. J Matern Fetal Neonatal Med 2013;26(3):275–278.
[II-2: Retrospective cohort study, multi-center study, laparoscopic adjust-
able gastric banding (LAGB, n = 63) or Roux-en-Y gastric bypass (RYGB,
n = 31), BMI class (n = 72 women with BMI ≥ 30 kg/m 2)]
115. Yi X, Li Q, Zhang J, et al. A meta-analysis of maternal and fetal outcomes
of pregnancy after bariatric surgery. Int J Gynaecol Obstet 2015;130(1):3–9.
[II-3:Meta-analysis, 21 cohort studies reviewed]
116. Guelinckx I, Devlieger R, Vansant G. Reproductive outcome after bariat-
ric surgery: a critical review. Hum Reprod Update 2009;15(2):189–201.
[III: Review]
117. Buchwald H, Oien D. Metabolic/bariatric surgery worldwide 2008. Obes
Surg 2009;19(12):1605–1611. [III: Review]
118. Scopinaro N, Gianetta E, Civalleri D, Bonalumi U, Bachi V. Bilio-pancreatic
bypass for obesity: II.Initial experience in man. Br J Surg 1979;66(9):618–620.
[II-2: Prospective cohort study in initial patients undergoing bilio-­
pancreatic bypass, n = 18]
119. Livingston EH. Obesity and its surgical management. Am J Surg
2002;184(2):103–113. [III: Review]
120. Fernandes MAP, Atallah AN, Soares BG, et al. Intragastric balloon for obe-
sity. Cochrane Database Syst Rev 2007;(1):CD004931. [II-3: Meta-analysis,
9 RCTs, n = 395, high level of bias, nonpregnant participants]
121. Maggard M, Li Z, Yermilov I, et al. Bariatric surgery in women of reproduc-
tive age: special concerns for pregnancy. Evid Rep Technol Assess (Full Rep)
51
2008;(169):1–51. [III: Review 57 studies; 23 case reports, 21 case series, 12
cohort, 1 case control]
122. Robinson JA, Burke AE. Obesity and hormonal contraceptive efficacy.
Women’s Health (Lond) 2013;9(5):453–466. [III: Review]
123. Wax J, Cartin A, Wolff R, et al. Pregnancy following gastric bypass for
morbid obesity: effect of surgery-to-conception interval on maternal and
neonatal outcomes. Obes Surg 2008;18(12):1517–1521. [II-2: Retrospective
cohort study, n = 50]
124. Agnolo C, Cyr C, Montigny F, et al. Pregnancy after bariatric surgery:
obstetric and perinatal outcomes and the growth and development of chil-
dren. Obes Surg 2015; Published online April 20, 2015. [II-2: Retrospective
cross-sectional study, n = 19]
125. Parikh R, Lavoie M, Wilson L, Maranda L, Leung K, Simas TM. Timing of
pregnancy after bariatric surgery. Obstet Gynecol 2014;123(Suppl. 1):165S.
[II-2: Retrospective cohort study, n = 52]
126. Martin LF, Finigan KM, Nolan TE. Pregnancy after adjustable gastric band-
ing. Obstet Gynecol 2000;95(6 Pt 1):927–930. [II-1: Clinical trial evaluating
adjustable gastric banding, n = 359 obese women]
127. Wittgrove AC, Jester L, Wittgrove P, Clark GW. Pregnancy following
gastric bypass for morbid obesity. Obes Surg 1998;8(4):461–464. [II-2:
Retrospective cohort study, n = 41]
128. American College of Obstetricians and Gynecologists. Bariatric sur-
gery and pregnancy. ACOG Practice Bulletin No. 105. Obstet Gynecol
2009;113:1405–1413. [III: Review]
129. Johannson K, Cnattinius S, Naslund I, et al. Outcomes of pregnancy after
bariatric surgery. N Engl J Med 2015;372:814–824. [II-2: Retrospective
cohort study using Swedish Medical Birth Register, n = 628,778, women
who had undergone bariatric surgery n = 1755]
130. Adams T, Hammoud A, Davidson L, et al. Maternal and neonatal outcomes
for pregnancies before and after gastric bypass surgery. Int J Obes (Lond)
2015;39(4):686–694. [II-2: Retrospective matched-control cohort study,
RYGB (group 1; n = 295 matches) and women with pregnancies after RYGB
(group 2; n = 764 matches)]
131. Catalano PM. Management of obesity in pregnancy. Obstet Gynecol
2007;109:419–433. [III: Review]
132. Al-Nimr RI, Hakeem R, Moreschi J, et al. Effects of bariatric surgery on
maternal and infant outcomes of pregnancy – an evidence analysis cen-
ter systematic review. J Acad Nutr Diet 2019;119(11):1921–1943. [II-2;
Systematic review, 13 studies, n = 11,584 women]
133. Kwong W, Tomlinson G, Feig DS. Maternal and neonatal outcomes after bariat-
ric surgery: a systematic review and meta-analysis: do the benefits outweigh
the risks? Am J Obstet Gyencol 2018;218(6):573–580. [II-2; meta-analysis,
20 cohort studies, n = 2.8 million, of whom 8364 had bariatric surgery]
134. Benjamin RH, Littlejohn S, Mitchell LE. Bariatric surgery and birth defects:
a systematic literature review. 2018;32(6):533–544. [II-2; Systematic review,
15 studies]
135. Shekelle PG, Morton SC, Maglione MA, et al. Pharmacological and surgical
treatment of obesity. Evid Rep Technol Assess (Summ) 2004;(103):1–6. [II-3:
Meta-analysis: 28 trials of orlistat; 147 total studies for surgery, 89 for weight
loss analysis, 134 for mortality analysis, 128 for complication analysis]
136. Centre for Maternal and Child Enquiries/Royal College of Obstetricians
and Gynaecologists. Management of women with obesity in pregnancy.
RCOG Guidelines. 2010. [III: Clinical guideline, 77 references]
137. Sherf-Dagan S, Goldenshluger A, Azran C, Sakran N, Sinai T, Ben-Porat
T. Vitamin K – what is known regarding bariatric surgery patients: a sys-
tematic review. Surg Obes Relat Dis 2019;15(8):1402–1413. [II-2; Systematic
Review and Meta-analysis, 4 studies, n = 83]
138. Dave DM, Clarke KO, Manicone JA, Kopelan AM, Saber AA. Internal
hernias in pregnant females with Roux-en-Y gastric bypass: a systematic
review. Surg Obes Relat Dis 2019;15:1633–1640. [II-2; Systematic Review,
27 studies, n = 59 patients]
139. U.S. Preventive Services Task Force. Folic acid for the prevention of neural
tube defects: U.S. Preventive Services Task Force recommendation state-
ment. Ann Intern Med 2009;150(9):626–631. [III: 5 studies from 1995-2008;
RCT = 1]
140. Mojtabai R. Body mass index and serum folate in childbearing women. Eur
J Epidemiol 2004;19:1029–1036. [II-1: US population based cohort study
National Health and Nutrition Examination Survey (NHANES) from 1988
to 1994 and 1999 to 2000, n = 5018]
141. Ghaffari N, Srinivas SK, Durnwald CP. The multidisciplinary approach to
the care of the obese parturient. Am J Obstet Gynecol 2015;318–325. [III:
Review]
142. McDonald SD, Viaje KA, Rooney RA, et al. A clinical carepath for obese
pregnant women: a pragmatic pilot cluster randomized controlled trial. J
Matern Fetal Neonatal Med 2019;32(23):3915–3922. [I; RCT, n = 189]
52
143. Carlson NS, Leslie SL, Dunn A. Antepartum care of women who are obese
during pregnancy: systematic review of the current evidence. J Midwifery
Womens Health 2018;63(3):259–272. [II-2; Systematic Review, 63 studies]
144. Rasmussen KM, Yaktine AL, for Institute for Medicine and National
Research Council (US) Committee to Reexamine IOM Pregnancy Weight
Guidelines. Weight gain during pregnancy: reexamining the guidelines.
Washington, DC: National Academic Press 2009. [III: Consensus Report]
145. Kapadia MZ, Park CK, Beyene J, Giglia L, Maxwell C, McDonald SD.
Can we safely recommend gestational weight gain below the 2009 guide-
lines in obese women? A systematic review and meta-analysis. Obes Rev
2015;16(3):189–206. [II-2; Meta-analysis, 18 cohort studies]
146. O’Brien EC, Segurado R, Geraghty AA, et al. Impact of maternal educa-
tion on response to lifestyle interventions to reduce gestational weight gain:
individual participant data meta-analysis. BMJ Open 2019;9(8):e0256020.
[I; IPD of 21 RCTs, n = 5183 participants]
147. Herring SJ, Albert JJ, Darden N, et al. Targeting pregnancy-related weight
gain to reduce disparities in obesity: baseline results from the Healthy
Babies trial. Contemp Clin Trials 2019;87:105822. [I; RCT, n = 262]
148. Rogozińska E, Zamora J, Marlin N, et al. Gestational weight gain outside
the Institute of Medicine recommendations and adverse pregnancy out-
comes: analysis using individual participant data from randomized trials.
BMC Pregnancy Childbirth 2019:19(1):322. [I; IPD of 33 RCTs, n = 4429
participants]
149. Siega-Riz AM, Viswanathan M, Moos MK, et al. A systematic review of
outcomes of maternal weight gain according to the Institute of Medicine
recommendations: birthweight, fetal growth, and postpartum weight
retention. Am J Obstet Gynecol 2009;201(4):339.e1–e14. [III: Systematic
review of 35 studies from 1990 to 2007]
150. Savage JS, Hohman EE, McNitt KM, et al. Uncontrolled eating during
pregnancy predicts fetal growth: the Healthy Mom Zone Trial. Nutrients
2019;11(4):899. [I; RCT, n = 27]
151. Xu Z, Wen Z, Zhou Y, Li D, Luo Z. Inadequate weight gain in obese women
and the risk of small for gestational age (SGA): a systematic review and
meta-analysis. J Maternal Fetal Neonatal Med 2017;30(3):357–367. [II-2;
Meta-analysis, 13 studies]
152. Faucher MA, Barger MK. Gestational weight gain in obese women by class
of obesity and select maternal/newborn outcomes: a systematic review.
Women Birth 2015;28(3):e70–79. [II-2; Systematic review, 10 studies]
153. Kominiarek MA, Seligman NS, Dolin C, et al. Gestational weight gain and
obesity: is 20 pounds too much? Obstet Gynecol 2013;209:e1–11. [II-1:
Prospective cohort study, high weight gain was associated with increased
large for gestational age infants (class I OR, 2.4; 95% CI, 1.9–2.9; class II OR,
1.7; 95% CI, 1.3–2.1; class III OR, 1.6; 95% CI, 1.3–2.1) n = 20,950]
154. Yeo S, Walker JS, Caughey MC, Ferraro AM, Asafu-Adjei J. What character-
istics of nutrition and physical activity interventions are key to effectively
reducing weight gain in obese or overweight pregnant women? A systematic
review and meta-analysis. Obes Rev 2017;18(4):385–399. [I; Meta-analysis,
32 RCTs, n-5869 obese/overweight women]
155. Menting MD, van de Beek C, Rono K, et al. Effects of maternal lifestyle
interventions on child neurobehavioral development: follow-up of ran-
domized controlled trials. Scand J Psychol 2019;60(6):548–558. [I; 2 RCTs,
n = 521]
156. Jarman M, Adam L, Lawrence W, Barker M, Bell RC. Healthy conversa-
tions skills as an intervention to support healthy gestational weight gain:
experience and perceptions from interventions deliverers and participants.
Patient Educ Couns 2019;102(5):924–931. [I; RCT, n = 70]
157. Gore S, Brown DM, Smith-West D. The role of postpartum weight reten-
tion in obesity among women: a review of evidence. Ann Behav Med
2003;26:149–159. [III: Review]
158. McCarthy EA, Walker SP, Ugoni A, Lappas M, Leong O, Shub A. Self-
weighing and simple dietary advice for overweight and obese pregnant
women to reduce obstetric complications without impact on quality of life:
a randomized controlled trial. BJOG 2016;123(6):965–973. [I; RCT, n = 382]
159. Renault KM, Carlsen EM, Nørgaard K, et al. Intake of sweets, snacks
and soft drinks predicts weight gain in obese pregnant women: detailed
analysis of the results of a randomized controlled trial. PLOS ONE
2015:10(7):e0133041. [II-1; Secondary analysis of RCT, n = 425]
160. Polley BA, Wing RR, Sims CJ. Randomized controlled trial to prevent
excessive weight gain in pregnant women. Int J Obesity Relat Metab Disord
2002;26:1494–1502. [I: RCT, n = 120]
161. Shieh C, Cullen DL, Pike C, Pressler SJ. Intervention strategies for prevent-
ing excessive gestational weight gain: systematic review and meta-analysis.
Obes Rev 2018;19(8):1093–1109. [I; Meta-analysis, 23 RCTs included]
162. Okesene-Gafa KAM, Li M, McKinlay CJD, et al. Effect of antenatal
dietary interventions in maternal obesity on pregnancy weight-gain and
Maternal-Fetal Evidence Based Guidelines
birthweight: Healthy Mums and Babies (HUMBA) randomized trial. Am J
Obstet Gynecol 2019;221(2):152.e1–152.e13. [I; RCT, n = 230]
163. Harreiter J, Simmons D, Desoye G, et al. Nutritional lifestyle intervention in
obese pregnant women, including lower carbohydrate intake, is associated
with increased maternal free fatty acids, 3-B-hydroxybutyrate, and fasting
glucose concentrations: a secondary factorial analysis of the European mul-
ticenter randomized controlled DALI Lifestyle Intervention Trial. Diabetes
Care 2019;42(8):1380–1389. [II-1; secondary analysis RCT, n = 436]
164. Mills HL, Patel N, White SL, et al. The effect of lifestyle intervention in
obese pregnant women on gestational metabolic profiles: findings from the
UK Pregnancies Better Eating and Activity Trial (UPBEAT) randomised
controlled trial. BMC Med 2019;17(1):15. [I; RCT, n = 1158]
165. Flynn AC, Dalrymple K, Barr S, et al. Dietary interventions in overweight
and obese pregnant women: a systematic review of the content, deliv-
ery, and outcomes of randomized controlled trials. Nutr Rev 2016;74(5):
312–328. [I; Systematic Review, 13 RCTs]
166. Tanvig MH, Jensen DM, Andersen MS, Ovesen PG, Jorgensen JS, Vinter
CA. Vitamin D levels were significantly higher during and after lifestyle
intervention in pregnancy: a randomized controlled trial. Acta Obstet
Gynecol Scand 2020;99(3):350–356. [1; RCT, n = 360]
167. Phelan S, Abrams B, Wing RR. Prenatal intervention with partial meal
replacement improves micronutrient intake of pregnant women with obe-
sity. Nutrients 2019;11(5):1071. [II-1; Secondary analysis RCT, n = 211]
168. Phelan S, Wing RR, Brannen A, et al. Randomized controlled clinical trial
of behavioral lifestyle intervention with partial meal replacement to reduce
excessive gestational weight gain. Am J Clin Nutr 2018;107(2):183–194.
[I; RCT, n = 257]
169. Pellonpera O, Mokkala K, Houttu N, Vahlberg T, Koivuniemi E, Tertti K,
Ronnemaa T, Laitinen K. Efficacy of fish oil and/or probiotic interven-
tion on the incidence of gestational diabetes mellitus in an at-risk group
of overweight and obese women: a randomized, placebo-controlled,
double-blind clinical trial. Diabetes Care 2019;42(6):1009–1017. [1; RCT,
n = 439]
170. Dawe JP, McCowan LME, Wilson J, Okesene-Gafa KAM, Serlachius AS.
Probiotics and maternal mental health; a randomised controlled trial
among pregnant women with obesity. Sci Rep 2020;10(1):1291. [1; RCT,
n = 230]
171. Asgharian H, Homayouni-Rad A, Mirghafourvand M, Mohammad-
Alizadeh-Charandabi S. Effect of probiotic yoghurt on plasma glucose in
overweight and obese pregnant women; a randomized controlled clinical
trial. Eur J Nutr 2020;59(1):205–215. [I; RCT, n = 130]
172. Calloway LK, McIntyre HD, Barrett HL, et al. Probiotics for the prevention
of gestational diabetes mellitus in overweight and obese women; findings
from the SPRING double-blind randomized controlled trial. Diabetes Care
2019;42(3):364–371. [1; RCT, n = 411]
173. Monthé-Drèze C, Penfield-Cyr A, Smid MC, Sen S. Maternal pre-pregnancy
obesity attenuates response to omega-3 fatty acids supplementation during
pregnancy. Nutrients 2018;10(12):1908. [II-1; Secondary analysis of MFM
Units RCT, n = 556 participants]
174. D’Anna R, Di Benedetto A, Scilipoti A, et al. Myo-inositol supplementation
for prevention of gestational diabetes in obese pregnant women: a random-
ized controlled trial. Obstet Gynecol 2015;126(2):310–315. [1; RCT, n = 220]
175. Karlsson T, Andersson L, Hussain A, et al. Lower vitamin D status in obese
compared with normal-weight women despite higher vitamin D intake in
early pregnancy. Clin Nutr 2015;34(5):892–8. [1; RCT, n = 105].
176. Syngelaki A, Campos MS, Roberge S, Andrade W, Nicolaides KH. Diet and
exercise for pre-eclampsia prevention in overweight and obese pregnant
women: systematic review and meta-analysis. J Matern Fetal Neonatal Med
2019;32(20):3495–3501. [1; Meta-analysis, 23 RCTs, n = 7236]
177. Du M-C, Ouyang Y-Q, Nie X-F, Huang Y, Redding SR. Effects of physical
exercise during pregnancy on maternal and infant outcomes in overweight
and obese pregnant women: a meta-analysis. Birth 2019;46(2):211–221.
[1; Systematic review and meta-analysis, 13 RCTs, n = 1439]
178. Peaceman AM, Clifton RG, Phelan S, et al. Lifestyle interventions limit
gestational weight gain in women with overweight or obesity: LIFE-Moms
prospective meta-analysis. Obesity (Silver Spring) 2018;26(9):1396–1404.
[1; meta-analysis, 7 RCTs, n = 1150]
179. Daly N, Farren M, McKeating A, O’Kelly R, Stapleton M, Turner MJ. A
medically supervised pregnancy exercise intervention in obese women:
a randomized controlled trial. Obstet Gynecol 2017;130(5):1001–1010.
[1; RCT, n = 88]
180. Rogozińska E, Marlin N, Jackson L, et al. Effects of antenatal diet and
physical activity on maternal and fetal outcomes: individual patient data
meta-analysis and health economic evaluation. Health Technol Assess
2017;21(41):1–158. [II-2; Meta-analysis, 33 studies, n = 9320 women]
Obesity
181. Magro-Malosso ER, Saccone G, Di Mascio D, Di Tommaso M, Berghella
V. Exercise during pregnancy and risk of preterm birth in overweight and
obese women: a systematic review and meta-analysis of randomized con-
trolled trials. Acta Obstet Gynecol Scand 2017;96(3):263–273. [1; Meta-
analysis, 9 RCTs, n = 1502]
182. Muktabhant B, Lawrie TA, Lumbiganon P, Laopaiboon M. Diet or exer-
cise, or both, for preventing excessive weight gain in pregnancy. Cochrane
Database Syst Rev 2015;CD007145. [I; Systematic review, 65 RCTs, 11,444
women]
183. Garnaes KK, Mørkved S, Salvesen Ø, Moholdt T. Exercise training and
weight gain in obese pregnant women: a randomized controlled trial (ETIP
Trial). PLOS Med 2016;13(7):e1002079. [1; RCT, n = 91]
184. Wang C, Wei Y, Zhang X, et al. A randomized clinical trial of exercise dur-
ing pregnancy to prevent gestational diabetes mellitus and improve preg-
nancy outcome in overweight and obese pregnant women. Am J Obstet
Gynecol 2017;216(4):340–351. [1; RCT, n = 300]
185. Renault KM, Norgaard K, Nilas L, et al. The treatment of obese pregnant
women (TOP) study: a randomized controlled trial of the effect of physical
activity intervention assessed by pedometer with or without dietary inter-
vention in obese pregnant women. Am J Obstet Gynecol 2014;210:134.e1–9.
[I: RCT, n = 389]
186. American College of Obstetricians and Gynecologists. Exercise during
pregnancy and the postpartum period. ACOG Committee Opinion No.267.
Ostet Gynecol 2002;99:171–173. [III: Review]
187. Garnaes KK, Helvik AS, Stafne SN, et al. Effects of supervised exercise
training during pregnancy on psychological well-being among overweight
and obese women: secondary analyses of the ETIP-trial, a randomised con-
trolled trial. BMJ Open 2019;9(11):e028252. [I; RCT, n = 91]
188. Vinter CA, Tanbig MH, Christensen MH, et al. Lifestyle intervention
in Danish obese pregnant women with early gestational diabetes mel-
litus according to WHO 2013 criteria does not change pregnancy out-
comes: results from the LiP (Lifestyle in Pregnancy) study. Diabetes
Care 2018;41(10):2079–2085. (II-1; Secondary Analysis of RCT, n-90
with early GDM]
189. Cahill AG, Haire-Joshu D, Cade WT, et al. Weight control program and
gestational weight gain in disadvantaged women with overweight or
obesity: a randomized clinical trial. Obesity (Silver Spring) 2018;26(3):
485–491. [I; RCT, n = 267]
190. Chang M-W, Brown R, Nitzke S. Results and lessons learned from a preven-
tion of weight gain program for low-income overweight and obese young
mothers: Mothers in Motion. BMC Public Health 2017;17(1):182. [I; RCT,
n = 612]
191. Syngelaki A, Nicolaides KH, Balani J, et al. Metformin versus pla-
cebo in obese pregnant women without diabetes mellitus. N Engl J Med
2016;374(5):434–43. [I; RCT, n = 400]
192. Baptistella do Nascimento I, Barbosa Sales W, Dienstmann G, et al.
Metformin for prevention of cesarean delivery and large-for-gestational-age
newborns in non-diabetic obese pregnant women: a randomized clinical
trial. Arch Endocrinol Metab. May–Jun 2020;64(3):290–297. [I; RCT, n = 357]
193. Dodd JM, Louise J, Deussen AR, Grivell RM, Dekker G, McPhee AJ,
Hague W. Effect of metformin in addition to dietary and lifestyle advice
for pregnant women who are overweight or obese, the GRoW random-
ized, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol
2019;7(1):15–24. [I; RCT, n = 524]
194. Dodd JM, Grivell RM, Deussen AR, Hague WM. Metformin for women
who are overweight or obese during pregnancy for improving maternal and
infant outcomes. Cochrane Database Syst Rev 2018;7(7):CD010564. [I; 3
RCTs, n = 1099]
195. Kalafat E, Sukur YE, Abdi A, Thilaganathan B, Khalil A. Metformin for pre-
vention of hypertensive disorders of pregnancy in women with gestational
diabetes or obesity: systematic review and meta-analysis of randomized tri-
als. Ultrasound Obstet Gynecol 2018;52(6):706–714. [I; Meta-analysis,
15 RCTs]
196. Sales WB, Baptistella do Nascimento I, Dienstmann G, Ramos de Souza
ML, Dutra da Silva G, Silva JC. Effectiveness of metformin in the prevention
of gestational diabetes mellitus in obese pregnant women. Rev Bras Ginecol
Obstet 2018;40(4):180–187. [I; RCT, n = 164]
197. Chiswick C, Reynolds RM, Denison F, et al. Effect of metformin on mater-
nal and fetal outcomes in obese pregnant women (EMPOWaR): a random-
ized, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol
2015;3(10):778–786. [I; RCT, n = 449]
198. Ferrera A, Hedderson MM, Brown SD, et al. A telehealth lifestyle inter-
vention to reduce excess gestational weight gain in pregnant women with
overweight or obesity (GLOW): a randomised, parallel-group, controlled
trial. Lancet Diabetes Endocrinol 2020;8(6):490–500. [I; RCT]
53
199. Van Horn L, Peaceman A, Kwasny M, et al. Dietary approaches to stop
hypertension diet and activity to limit gestational weight: maternal off-
spring metabolics family intervention trial, a technology enhanced ran-
domized trial. Am J Prev Med 2018;55(5):603–614. [I; RCT, n = 281]
200. Abdel-Aziz SB, Hegazy IS, Mohamed DA, El Kasem MMA, Hagag SS. Effect
of dietary counseling on preventing excessive weight gain during preg-
nancy. Public Health 2018;154:172–181. [I; RCT, n = 200]
201. Sanda B, Vistad I, Sagedal LR, Haakstad LAH, Lohne-Seiler H, Torstveit
MK. Effect of a prenatal lifestyle intervention on physical activity level in late
pregnancy and the first year postpartum. PLOS ONE 2017;12(11):e0188102.
[I; RCT, n = 606]
202. Lau Y, Klainin-Yobas P, Htun TP, et al. Electronic-based lifestyle interven-
tions in overweight or obese perinatal women: a systematic review and
meta-analysis. Obes Rev 2017;18(9):1071–1087. [I; Meta-analysis, 14 RCTs]
203. Skouteris H, McPhie S, Hill B, et al. Health coaching to prevent excessive
gestational weight gain: a randomized-controlled trial. Br J Health Psychol
2016;21(1):31–51. [I; RCT, n = 261]
204. Daley A, Jolly K, Jebb SA, et al. Effectiveness of a behavioural intervention
involving regular weighing and feedback by community midwives within
routine antenatal care to prevent excessive gestational weight gain: POPS2
randomised controlled trial. BMJ Open 2019;9(9):e030174. [I; RCT, n = 656]
205. Olson CM, Groth SW, Graham ML, Reschke JE, Strawderman MS,
Fernandez ID. The effectiveness of an online intervention in preventing
excessive gestational weight gain: the e-moms roc randomized controlled
trial. BMC Pregnancy Childbirth 2018;18(1):148. [I; RCT, n = 1689]
206. Kominiarek MA, Lewkowitz AK, Carter E, Fowler SA, Simon M. Gestational
weight gain and group prenatal care: a systematic review and meta-analysis.
BMC Pregnancy Childbirth 2019;19(1):18. [II-2; Systematic Review & Meta-
analysis, 15 studies, n = 13,779 participants]
207. Steinig J, Nagl M, Linde K, Zietlow G, Kersting A. Antenatal and postna-
tal depression in women with obesity: a systematic review. Arch Womens
Ment Health 2017;20(4):569–585. [II-2; Systematic review, 14 observational
studies]
208. Nagl M, Linde K, Stepan H, Kersting A. Obesity and anxiety during preg-
nancy and postpartum: a systematic review. J Affect Disord 2015;186:
293–305. [II-2; Systematic review, 13 studies]
209. Faria-Schützer DB, Surita FG, Nascimento SL, Vieira CM, Turato E.
Psychological issues facing obese pregnant women: a systematic review. J
Matern Fetal Neonatal Med 2017;30(1):88–95. [II-2; Systematic review, 3
qualitative studies, 5 quantitative studies]
210. Hartley E, McPhie S, Skouteris H, Fuller-Tyszkiewicz M, Hill B. Psychosocial
risk factors for excessive gestational weight gain: a systematic review.
Women Birth 2015;28(4):e99–e109. [II-2; Systematic review, 12 studies]
211. Kapadia MZ, Gaston A, Van Blyderveen S, et al. Psychological antecedents
of excess gestational weight gain: a systematic review. BMC Pregnancy
Childbirth 2015;15:107. [II-2; Systematic review, 35 studies]
212. Molyneaux E, Begum S, Briley AL, Seed PT, Howard LM, Poston L. Do
elevated symptoms of depression predict adherence and outcomes in the
UPBEAT randomized controlled trial of a lifestyle intervention for obese preg-
nant women? BMC Pregnancy Childbirth 2018;18(1):378. [I; RCT, n = 1555]
213. Costa De Vilhena E, Ayres de Castilho E. Homeopathic treatment of over-
weight and obesity in pregnant women with mental disorders: a double-
blind, controlled clinical trial. Altern Ther Health Med 2016;22(S3):14–22.
[I; RCT, n = 134]
214. Cain MA, Brumley J, Louis-Jacques A, Drerup M, Stern M, Louis JM. A
pilot study of a sleep intervention delivered through group prenatal care
to overweight and obese women. Behav Sleep Med 2020;18(4):477–487. [I;
RCT, n = 53]
215. Harper LM, Jauk V, Longo S, Biggio JR, Szychowski JM, Tita AT. Early ges-
tational diabetes screening in obese women: a randomized controlled trial.
Am J Obstet Gynecol 2020;222(5):495.e1–495.e8. [I; RCT, n = 962]
216. Centre for Maternal and Child Enquiries/Royal College of Obstetricians
and Gynaecologists. Management of women with obesity in pregnancy.
RCOG Guidelines. 2010. [III: Clinical guideline, 77 references]
217. American College of Obstetricians and Gynecologists, Committee on
Obstetric Practice. Low-dose aspirin use during pregnancy, Committee
Opinion No 743. Obstet Gynecol 2018;132(1):e44–e52. [III; Review]
218. Finneran MM, Gonzalez-Brown VM, Smith DD, Landon MB, Rood KM.
Obesity and laboratory aspirin resistance in high-risk pregnant women
treated with low-dose aspirin. Am J Obstet Gynecol 2019;220(4):385.e1–
385.e6. [II-1; Secondary analysis of multi-center trial, n = 1002 patients]
219. Cantu JA, Jauk VR, Owen J, et al. Is low-dose aspirin therapy to prevent
pre-eclampsia more efficacious in non-obese women or when initiated early
in pregnancy? J Matern Fetal Neonatal Med 2015;28(10):1128–1132. [II-1;
Secondary analysis of RCT, n = 2503]
54
220. Aagaard-Tillery KM, Flint Porter T, Malone FD, Nyberg DA, Collins J.
Influence of maternal BMI on genetic sonography in the FaSTER trial.
Prenat Diagn 2010;30:14–22. [II-2: Prospective cohort, n = 8555]
221. Tsai PJS, Loichinger M, Zalud I. Obesity and the challenges of ultra-
sound fetal abnormality diagnosis. Best Practice Res Clin Obstet Gynecol
2015;29:320–327. [III: Review]
222. Tsai LJ, Ho M, Pressman EK, et al. Ultrasound screening for fetal aneu-
ploidy using soft markers in the overweight and obese gravida. Prenat Diagn
2010:30:821–826. [II-2: Retrospective review, n = 5690]
223. Maxwell C, Dunn E, Tomlinson G, et al. How does maternal obesity affect
the routine fetal anatomic ultrasound? J Matern Fetal Neonatal Med
2010;23:1187–1192. [II-2: Retrospective review, n = 100]
224. Fuchs F, Houllier M, Voulgaropoulos A, et al. Factors affecting feasibil-
ity and quality of second-trimester ultrasound scans in obese pregnant
women. Ultrasound Obstet Gynecol 2013;41:40–46. [II-2: Prospective
study, n = 283]
225. Best KE, Tennant PW, Bell R, et al. Impact of maternal body mass index on
the antenatal detection of congenital anomalies. BJOG 2012;119(12):1503–
1511. [II-2: Population-based register study, n = 3096]
226. Dashe JS, McIntire DD, Twickler DM. Effect of maternal obesity on the
ultrasound detection of anomalous fetuses. Obstet Gynecol 2009;113:1001–
1007. [II-2: Retrospective cohort study, n = 11,210]
227. Harper LM, Jauk VC, Owen J, et al. The utility of ultrasound surveil-
lance of fluid and growth in obese women. Am J Obstet Gynecol
2014;211(5):524:e1-8. [II-2: Retrospective cohort, n = 1164]
228. Bradford BF, Thompson JMD, Haezell AEP, Mccowan LME, McKinlay
CJD. Understanding the associations and significance of fetal movements
in overweight or obese pregnant women: a systematic review. Acta Obstet
Gynecol Scand 2018;97(1):13–24. [II-2; Meta-analysis, 19 observational
studies]
229. Venkatesh KK, Manuck TA. Maternal body mass index and cervical length
among women with a history of spontaneous preterm birth. J Matern Fetal
Neonatal Med 2020;33(5):825–830. [II-1; Secondary analysis of MFMU
RCT, n = 356]
230. Heyborn KD, Allshouse AA, Christopher Carey J. Does 17-alpha hydroxy-
progesterone caproate prevent recurrent preterm birth in obese women?
Am J Obstet Gynecol 2015;213(6):844.e1–6. [II-1; Secondary analysis of
RCT, n = 443]
231. Prodromidou A, Frountzas M, Perrea D, Vlachos GD, Pergialiotis V. The
impact of obesity on cervical cerclage efficacy: a systematic review of the
literature. J Neonatal Perinatal Med 2016;9(1):59–65. [II-2; Meta-analysis,
3 studies]
232. Bicocca MJ, Blackwell SC, Sibai BM. Does prepregnancy weight or mater-
nal BMI at betamethasone administration impact late preterm respiratory
morbidity. Am J Perinatol 2020;37(4):365–369. [II-1; Secondary analysis of
RCT, n = 2822]
233. Royal College of Obstetricians and Gynecologists. CMAE/RCOG Joint
Guideline. Management of women with obesity in pregnancy. England
and Wales: Centre for Maternal and Child Enquiries. Royal College of
Obstetricians and Gynecologists; 2010. [III: Review]
234. Kbayashi N, Lim BH. Induction of labour and intrapartum care in obese
women. Best Prac Res Cl Ob 2015;29:394–405. [III: Review]
235. Arrowsmith S, Wray S, Quenby S. Maternal obesity and labor com-
plications following induction of labor in prolonged pregnancy. BJOG
2011;118:578–588. [II-2: Retrospective cohort, n = 29, 224]
236. Wolfe KB, Rossi RA, Warshak CR. The effect of maternal obesity on the
rate of failed induction of labor. Am J Obstet Gynecol 2011;205(125):1–7.
[II-2: Population based cohort study, Ohio Department of Health birth
certificate data, n = 279,521]
237. Wolfe H, Timofeev J, Tefera E, et al. Risk of caesarean in obese nulliparous
women with unfavorable cervix: elective induction vs. expectant manage-
ment at term. Am J Obstet Gynecol 2014;210:e1–5. [II-2: Retrospective
cohort, n = 470]
238. Tonidandel A, Booth J, D’Angelo R, Harris L, Carlhall S, Kallen K, Blomberg
M. Maternal body mass index and duration of labor. Eur J Obstet
Gynecol Repro Biol 2013;17:49–53. [II-2: Historical prospective cohort
study, n = 63,829]
239. Soni S, Chivan N, Cohen WR. Effect of maternal body mass index on oxy-
tocin treatment for arrest of dilatation. J Perinat Med 2013;41(5):517–521.
[II-2: Retrospective analysis, n = 118]
240. Vinayagam D, Chandraharan E. Clinical study: the adverse impact of
maternal obesity on intrapartum and perinatal outcomes. International
Scholarly Research Network. Obstet Gynecol 2012. Article ID 939762. [II-2:
Retrospective case-control analysis, the study group (BMI > 40) n = 100
women and a control group (BMI 20 – 25) n = 100]
Maternal-Fetal Evidence Based Guidelines
241. Poobalan AS, Aucott LS, Gurun T, et al. Obesity as an independent
risk factor for elective and emergency cesarean delivery in nulliparous
women-systematic review and meta-analysis of cohort studies. Obes Rev
2009;10:28–35. [II-3: Meta-analysis, n = 209,193]
242. Clark-Ganheart CA, Reddy UM, Kominiarek MA, et al. Pregnancy out-
comes among obese women and their offspring by attempted mode of deliv-
ery. Obstet Gynecol 2015;126(5): 985–993. [II-2: retrospective cohort study,
n = 47,372]
243. Ellis JA, Brown CM, Barger B, Carlson NS. Influence of maternal obesity
on labor induction: a systematic review and meta-analysis. J Midwifery
Womens Health 2019;64(1):55–67. [II-2; Systematic Review and meta-­
analysis, 10 studies]
244. Anabusi S, Mei-Dan E, Hallak M, Walfisch A. Mechanical labor induction
in the obese population: a secondary analysis of a prospective randomized
trial. Arch Gynecol Obstet 2016;293(1):75–80. [II-1; Secondary analysis of
RCT, n = 181]
245. Belogolovkin V, Crisan L, Lynch O, et al. Neonatal outcomes of successful
VBAC among obese and super obese mothers. J Matern Fetal Neonatal Med
2012;25:714–718. [II-2: Missouri maternally linked cohort data, n = 30,017]
246. Subramaniam A, Jauk VC, Goss AR, et al. Mode of delivery in women with
class II obesity: planned cesarean compared with induction of labor. Am J
Obstet Gynecol 2014;211:700.e1–9. [II-2: Retrospective cohort study, n = 661]
247. Tan T, Sia AT. Anesthetic considerations in the obese gravida. Semin
Perinatol 2011;35:350–355. [III: Review]
248. Li M, Ni X, Xu Z, Shen F, Song Y, Li Q, Liu Z. Ultrasound-assisted technol-
ogy versus the conventional landmark location method in spinal anesthesia
for cesarean delivery in obese parturients: a randomized controlled trial.
Anesth Analg 2019;129(1):155–161. [I; RCT, n = 80]
249. Saravanakumar K, Rao SG, Cooper GM. The challenges of obesity and
obstetric anaesthesia. Curr Opin Obstet Gynecol 2006;18:631–635.
[III: Review]
250. Obestetric Anaesthetic Association and the Association of Anaesthetists
of Great Britain and Ireland) (Royal College of Obstetricians and
Gynecologists. CMAE/RCOG Joint Guideline. Management of women with
obesity in pregnancy. England and Wales: Centre for Maternal and Child
Enquiries. Roycal College of Obstetricians and Gynecologists; 2010.
[III: Review].
251. Vricella LK, Louis JM, Mercer BM, et al. Anesthesia complications dur-
ing scheduled cesarean delivery for morbidly obese women. Am J Obstet
Gynecol 2010;203(3):276.e1–e5. [II-2: Retrospective cohort study, n = 578]
252. Mhyre JM, Riesner MN, Polley LS, et al. A series of anesthesia-related mater-
nal deaths in Michigan, 1985–2003. Anesthesiology 2007;106:1096–1104.
[II-2: Michigan Maternal Mortality Surveillance 1985–2003, retrospective
study, n = 855]
253. Tonidandel A, Booth J, D’Angelo R, Harris L, Tonidandel S. Anesthetic
and obstetric outcomes in morbidly obese parturients: a 20 year follow-
up retrospective cohort study. Inl J Obstet Anesthesia 2014; 23P357–364.
[II-2: Retrospective cohort, n = 460]
254. George RB, McKeen DM, Dominguez JE, Allen TK, Doyle PA, Habib AS.
A randomized trial of phenylephrine infusion versus bolus dosing for nau-
sea and vomiting during cesarean delivery in obese women. Can J Anaesth
2018;65(3):254–262. [I; RCT, n = 160]
255. Stamilio DM, Scifres CM. Extreme obesity and postcesarean maternal
complications. Obstet Gynecol 2014;124(2 Pt 1):227e32. [II-2: Retrospective
cohort analysis of a previous randomized control trial, n = 585]
256. Girsen AI, Osmundson SS, Naqvi M, et al. Body mass index and opera-
tive times at cesarean delivery. Obstet Gynecol 2014;124(4):684–689.
[II-2: Cohort study, Maternal Fetal Medicine Units Network Cesarean
Registry, n = 21,372]
257. Alanis MC, Villers MS, Law TL, et al. Complications of cesarean delivery
in the massively obese parturient. Am J Obstet Gynecol 2010;203:271.e1–7.
[II-2: Retrospective cohort, n = 194]
258. Kabon B, Nagele A, Reddy D, et al. Obesity decreases perioperative tissue
oxygenation. Anesthesiology 2004;100:274–280. [Clinical investigation,
n = 46]
259. Scifres CM, Leighton BL, Fogertey PJ, et al. Supplemental oxygen for the
prevention of postcesarean infectious morbidity: a randomized controlled
trial. Am J Obstet Gynecol 2011;205:267.e1–9. [I: RCT, n = 585]
260. Gardella C, Goltra LB, Laschansky E, et al. High-concentration supplemen-
tal perioperative oxygen to reduce the incidence of postcesarean surgical
site infection. Obstet Gynecol 2008;112(3):545–552. [I: double-blind RCT,
n = 143]
261. Duggal N, Poddatoori V, Noroozkhani S, et al. Perioperative oxygen supple-
mentation and surgical site infection after cesarean delivery: a randomized
trial. Obstet Gynecol 2013;122(1)79–84. [I: RCT, n = 831]
Obesity
262. Hellums EK, Lin MH, Ramsey PS. Prophylactic subcutaneous drainage for
prevention of wound complications after cesarean delivery – a metaanaly-
sis. Am J Obstet Gynecol 2007;197:229–235. [II-3: Meta-analysis, 6 RCTs
included]
263. Dahlke JD, Mendez-Figueroa H, Rouse DJ, et al. Evidence-based surgery
for cesarean delivery: an updated systematic review. Am J Obstet Gynecol
2013;294–306. [III: Systematic Review, 73 RCTs, 10 metaanalyses and/or
systematic reviews, and 12 Cochrane reviews]
264. Mackeen AD, Schuster M, Berghella V. Suture versus staples for skin clo-
sure after cesarean: a metaanalysis. Am J Obstet Gynecol 2015;212(5):621.
e1010. [II-3: Meta-analysis, 12 RCTs, n = 3112]
265. Zaki MN, Wing DA, McNulty JA. Comparison of staples vs subcuticu-
lar suture in class III obese women undergoing cesarean: a random-
ized controlled trial. Am J Obstet Gynecol 2018;218(4):451.e1–451.e8.
[I; RCT, n = 242]
266. Alalfy M, Elgazzar A, Fares T, et al. Effect of subcutaneous tissue closure
technique in cesarean section on postoperative wound complications
in obese Egyptian women. J Matern Fetal Neonatal Med 2019;32(15):
2452–2459. [I; RCT, n = 397]
267. Maged AM, Mohesen MN, Elhalwagy A, et al. Subcuticular interrupted
versus continuous skin suturing in elective cesarean section in obese
women: a randomized controlled trial. J Matern Fetal Neonatal Med
2019;32(24):4114–4119. [I; RCT, n = 169]
268. Marrs C, Blackwell S, Hester A, et al. Pfannenstiel versus vertical skin inci-
sion for cesarean delivery in women with class III obesity: a randomized
trial. Am J Perinatol 2019;36(1):97–104. [I; RCT, n = 91]
269. McCurdy RJ, Felder LA, Saccone G, et al. The association of skin incision
placement during cesarean delivery with wound complications in obese
women: a systematic review and meta-analysis. J Matern Fetal Neonatal
Med 2020;1–13. [II-2; Meta-analysis, 15 studies, n = 8960].
270. Scolari Childress KM, Gavard JA, Ward DG, Berger K, Gross GA. A barrier
retractor to reduce surgical site infections and wound disruptions in obese
patients undergoing cesarean delivery: a randomized controlled trial. Am J
Obstet Gynecol 2016;214(2):285.e1–285e.10. [I; RCT, n = 301]
271. Use of Prophylactic Antibiotics in Labor and Delivery. ACOG Practice
Bulletin No. 120. American College of Obstetricians and Gynecologists.
Obstet Gynecol 2011;117:1472–1483. [III: Review]
272. Pevzner L, Swank M, Krepel C, et al. Effects of maternal obesity on tissue
concentrations of prophylactic cefazolin during cesarean delivery. Obstet
Gynecol 2011117(4):877–882. [II: descriptive study with prospective collec-
tion, n = 29]
273. Stitely M, Sweet M, Slain D, et al. Plasma and tissue cefazolin concentra-
tions in obese patients undergoing cesarean delivery and receiving differing
pre-operative doses of drug. Surg Infect 2013;14(5):455–459. [I: RCT, n = 23]
274. Young OM, Shaik IH, Twedt R, et al. Pharmacokinetics of cefazolin prophy-
laxis in obese gravidae at time of cesarean delivery. Am J Obstet Gynecol
2015;213:541.e1–7. [I: Double-blind RCT, n = 26]
275. Swank ML, Wing DA, Nicolau DP, McNulty JA. Increase 3-gram cefazo-
lin dosing for cesarean delivery prophylaxis in obese women. Am J Obstet
Gynecol 2015;213(3):415.e1–8 [II-2: Prospective cohort, n = 28]
276. Maggio L, Nicolau DP, DaCosta M, et al. Cefazolin prophylaxis in obese
women undergoing cesarean delivery: a randomized controlled trial.
Obstet Gynecol 2015;125(5):1205–1210) [I: double-blind RCT, n = 57]
277. Tuuli MG, Liu J, Tita ATN, et al. Effect of prophylactic negative pressure
wound therapy vs standard wound dressing on surgical-site infection in
obese women after cesarean delivery: a randomized clinical trial. JAMA
2020;324(12):1180–1189. [I; RCT, n = 1624]
278. Hussamy DJ, Wortman AC, McIntire DD, Leveno KJ, Casey BM, Roberts
SW. Closed incision negative pressure therapy in morbidly obese women
undergoing cesarean delivery: a randomized controlled trial. Obstet
Gynecol 2019;134(4):781–789. [I; RCT, n = 677]
279. Wihbey KA, Joyce EM, Spalding ZT, et al. Prophylactic negative pressure
wound therapy and wound complication after cesarean delivery in women
with class II or III obesity: a randomized controlled trial. Obstet Gynecol
2018;132(2):377–384. [I; RCT, n = 166]
280. Smid MC, Dotters-Katz SK, Grace M, et al. Prophylactic negative pres-
sure wound therapy for obese women after cesarean delivery; a systematic
review and meta-analysis. Obstet Gynecol 2017;130(5).969–978. [I; Meta-
analysis, 10 studies, 5 of which were RCTs]
281. Hyldig N, Vinter CA, Kruse M, et al. Prophylactic incisional negative pres-
sure wound therapy reduces the risk of surgical site infection after caesar-
ean section in obese women: a pragmatic randomized clinical trial. BJOG
2019;126(5):628–635. [I; RCT, n = 876]
282. Connery SA, Yankowitz J, Odibo L, Raitano O, Nikolic-Dorschel D, Louis
JM. Effect of using silver nylon dressings to prevent superficial surgical site
55
infection after cesarean delivery: a randomized clinical trial. Am J Obstet
Gynecol 2019;221(1):57.e1–57.e7. [I; RCT, n = 657]
283. Robinson HE, O’Connell CM, Joseph KS, McLeod NL. Maternal outcomes in
pregnancies complicated by obesity. Obstet Gynecol 2005;106:1357–1364.
[II-2: Population-based cohort study, Nova Scotia Atlee Perinatal Database,
n = 142,404]
284. American College of Obstetricians and Gynecologists. Thromboembolism
in pregnancy. Practice Bulletin No. 123. Obstet Gynecol 2011;118:718–729.
[III:Review]
285. Tepper NK, Boulet SL, Whiteman MK, et al. Postpartum venous thrombo-
embolism: incidence and risk factors. Obstet Gynecol 2014;123(5):987–996.
[II-2: Truven Health MarketScan Commercial and Multi-State Medicaid
databases, n = 2456 venous thromboebolisms]
286. Cavazza S, Rainaldi MP, Adduci A, Palareti G. Thromboprophylaxis follow-
ing cesarean delivery: one site prospective pilot study to evaluate the appli-
cation of a risk score model. Throm Res 2012;129:28–31. [II-2: n = 501]
287. Royal College of Obstetricians and Gynaecologists. Reducing the risk of
thrombosis and embolism during pregnancy and the puerperium. Green-
top Guideline No. 37a. London: RCOG; 2009. [III: Review]
288. Drife J. Deep venous thrombosis and pulmonary embolism in obese women.
Best Pract Res Cl Ob 2015:29;365–376. [III: Review]
289. Overcash RT, Somers AT, LaCoursiere Y. Enoxaparin Dosing after cesarean
delivery in morbidly obese women. Obstet Gynecol 2015;125(6):1371–1376.
[II-2: Prospective sequential cohort study, n = 42]
290. Stephensen ML, Serra AE, Neeper JM, Caballero DC, McNulty J. A ran-
domized controlled trial of differing doses of postcesarean enoxaparin
thromboprophylaxis in obese women. J Perinatol 2016;36(2):95–99. [I; RCT,
n = 84].
291. Campbell KH, Savitz D, Werner EF, et al. Maternal Morbidity and Risk of
Death at Delivery Hospitalization. Obstet Gynecol 2013;122(3):627–633.
[II-2: Restrospective cohort, Birth certificate data and the Statewide
Planning and Research Cooperative System database, n = 1,084,862 live
singleton births and n = 132 maternal deaths]
292. Flegal KM, Williamson DF, Pamuk ER, et al. Estimating deaths attributable
to obesity in the United States. Am J Public Health 2004;94:1486–1489. [III:
Review]
293. Molyneaux E, Poston L, Ashurst-Williams S, Howard LM. Obesity and
mental disorders during pregnancy and postpartum: a systematic review
and meta-analysis. Obstet Gynecol 2014;123(4):857–867. [II-3: Meta-
analysis, 62 studies, n = 540,373]
294. Verret-Chalifour J, Giguere Y, Forest JC, et al. Breastfeeding Initiation:
impact of obesity in a large Canadian perinatal cohort study. PLOS ONE
10(2):e0117512. [II-2: Retrospective cohort, n = 7866]
295. Rothberg BEG, Magriples U, Kershaw TS, Rising SS, Gestational weight gain
and subsequent postpartum weight loss among young, low-income, ethnic
minority women. Am J Obstet Gynecol 2011;204:1–11. [II-2: Retrospective
cohort, n = 427]
296. Garcia AH, Voortman T, Baena CP, et al. Maternal weight status, diet,
and supplement use as determinants of breastfeeding and complemen-
tary feeding: a systematic review and meta-analysis. Nutr Rev 2016
August;74(8):490–516. [II-2; Meta-analysis, 81 studies]
297. Baker JL, Michaelson KF, Sorenson TIA, Rasmussen KM. High prepregnant
body mass index is associated with early termination of full and any breast-
feeding in Danish women. Am J Clin Nutr 2007;86:404. [II-2: Retrospective
cohort, n = 37,459]
298. Fair FJ, Ford GL, Soltani H. Interventions for supporting the initiation
and continuation of breastfeeding among women who are overweight or
obese. Cochrane Database Syst Rev 2019;CD012099. [I; Systematic Review,
7 RCTs, n = 831]
299. Merki-Feld GS, Skouby S, Serfaty D, et al. European Society of Contraception
Statement on Contraception in Obese Women. Eur J Contracep Repr
2015;20(1):19–28. [III: Review]
300. Dragoman MV, Simmons KB, Paulen ME, Curtis KM. Combined hormonal
contraceptive (CHC) use among obese women and contraceptive effective-
ness: a systematic review. Contraception 2017;95(2):117–129. [II-2]; Meta-
analysis, 15 studies]
301. Yamazaki M, Dwyer K, Sobhan M, et al. Effect of obesity on the effective-
ness of hormonal contraceptives: an individual participant data meta-
analysis. Contraception 2015;92(5):445–452. [I; Meta-analysis, 7 Phase
3 clinical trials]
302. Lopez LM, Bernholc A, Chen M, et al. Hormonal contraceptives for con-
traception in overweight or obese women. Cochrane Database Syst Rev
2016;(8):CD008452. [I; Systematic Review, 17 studies, n = 63,813]
303. Curtis, KM, Tepper, NK, Jatlaoui, TC. U.S. Medical Eligibility Criteria for
Contraceptive Use, 2016. MWWR Recomm Rep 2016;65(3):1–108.
56
304. Merhi ZO. Revisiting optimal hormonal contraception following bariatric
surgery. Contraception 2013;87(2):131–133. [III: Review]
305. Bhuva K, Kraschnewski JL, Lehman EB, Chuang CH. Does body mass
index or weight perception affect contraceptive use? Contraception
2017;95(1):59–64. [II-2; Retrospective Cohort, n = 987]
306. Festin MPR, Peregoudov A, Seuc A, Kiarie J, Temmerman M. Effect of BMI
and body weight on pregnancy rates with LNG as emergency contracep-
tion: analysis of four WHO HRP studies. Contraception 2017;95(1):50–54.
[I; Meta-analysis, 4 RCTs, n = 6873 women]
307. Jatlaoui TC, Curtis KM. Safety and effectiveness data for emergency contra-
ceptive pills among women with obesity: a systematic review. Contraception
2016;94(6):605–611. [II-2; Systematic review, four studies]
308. Yaniv-Salem S, Shoham-Vardi I, Kessous R, Pariente G, Sergienko R, Sheiner
E. Obesity in pregnancy: what’s next? Long-term cardiovascular morbid-
ity in a follow-up period of more than a decade. J Matern Fetal Neonatal
Med 2016 February 16;29(4):619–623. [II-2: Population based retrospective
cohort, n = 46,688]
309. Schmiegelow MD, Anderson C, Kober L, et al. Prepregnancy obesity and
associations with stroke and myocardial infarction in women in the years
after childbirth: A nationwide cohort study. Circulation 2014;113:330–337.
[II-2: Cohort, Danish Medical Birth Register, n = 273, 101]
310. Mongraw-Chaffin ML, Anderson CA, Clark JM, Bennett WL. Prepregnancy
body mass index and cardiovascular disease mortality: the Child Health and
Development Studies. Obesity 2014;22(4):1149–1156. [II-2: Retrospective
cohort, California Vital Status Records, n = 1839]
311. Lee KK, Raja EA, Lee AJ, et al. Maternal Obesity during pregnancy associ-
ated with premature mortality and major cardiovascular events in later life.
Hypertension 2015;66(5):938–944. [II-2: Retrospective cohort, n = 18,873]
312. Krakowiak P, Walker CK, Bremer AA, et al. Maternal metabolic conditions
and risk for autism and other neurodevelopmental disorders. Pediatrics
2012;129(5):e1121–e1128. [II-2: Population-based cohort study, n = 517
ASD, n = 172 DD, n = 315 controls]
313. Reynolds RM, Allan KM, Raja EA, et al. Maternal obesity during pregnancy
and premature mortality from cardiovascular event in adult offspring: fol-
low-up of 1,323,275 person years. BMJ 2013;347:f453. [II-2: Record linkage
cohort analysis, Aberdeen Maternity and Neonatal databank, n = 37,709]
314. Starling AP, Brinton JT, Glueck DH, et al. Associations of maternal BMI and
gestational weight gain with neonatal adiposity in the health start study.
Am J Clin Nutri 2015;101:302–309. [II-2: Prospective cohort, n = 1132]
315. Eriksson JG, Sandboge S, Salonen MK, et al. Long-term consequences of
maternal overweight in pregnancy on offspring later health: Findings from
the Helsinki Birth Cohort Study. Ann Med 2014;46:434–438. [II-2: Cohort
study, Helsinki Birth Cohort Study, n = 13,345]
316. Jansen MAC, Dalmeijer GW, Saldi SR, et al. Pre-pregnancy paren-
tal BMI and offspring blood pressure in infancy. Eur J Prev Cardiol
October;26(15):1581–1590. [I; RCT, n = 587 infants]
317. Lee YQ, Collins CE, Gordon A, Rae KM, Pringle KG. The relationship
between maternal obesity and diabetes during pregnancy on offspring
kidney structure and function in humans: a systematic review. J Dev Orig
Health Dis 2019;10(4):406–419. [II-2; Systematic Review, 9 studies]
318. Nyrnes SA, Garnaes KK, Salvensen O, Timilsina AS, Moholdt T, Ingul CB.
Cardiac function in newborns obese women and the effect of exercise during
pregnancy: a randomized controlled trial. PLOS ONE 2018;13(6):e0197334.
[I; RCT, n = 55]
319. Kawasaki M, Arata N, Miyazaki C, Mori R, Kikuchi T, Ogawa Y, Ota E.
Obesity and abnormal glucose tolerance in offspring of diabetic mothers:
a systematic review and meta-analysis. PLOS ONE 2018;13(1):e0190676.
[II-2; Meta-analysis, 20 observational studies]
320. Álvarez-Bueno C, Cavero-Redondo I, Lucas-de la Cruz L, Notario-
Pacheco B, Martínez-Vizcaíno V. Association between pre-pregnancy
overweight and obesity and children’s neurocognitive development: a sys-
tematic review and meta-analysis of observational studies. Int J Epidemiol
2017;46(5):1653–1666. [II-2; Meta-analysis, 15 observational studies]
321. Yogev Y, Catalano P. Pregnancy and obesity. Obstet Gynecol Clin North Am
2009;36:285–300. [III; Review]
322. Boots C, Stephenson M. Does obesity increase the risk of miscarriage
in spontaneous conception: a systematic review. Semin Reprod Med
2011;29(6):507–513. [II-2: 6 retrospective studies meta-analysis, BMI >
28 kg/m 2, n = 3800]
323. Athukorala C, Rumbold A, Wilson K, et al. The risk of adverse preg-
nancy outcomes in women who are overweight or obese. BMC Pregnancy
Childbirth 2010;10(1):10–56. [I: Australian Collaborative Trial of
Maternal-Fetal Evidence Based Guidelines
Supplements, secondary analysis n = 1661; BMI > 25 kg/m 2 n = 446, BMI >
30 kg/m 2 n = 272]
324. Louis JM, Auckley D, Sokol RJ, et al. Maternal and neonatal morbidities asso-
ciated with obstructive sleep apnea complicating pregnancy. Am J Obstet
Gynecol 2010;202(3):261.e1–261.e5. [II-3: Retrospective cohort, n = 114]
325. Ma J, Xiao L. Obesity and depression in US women: results from the 2005–
2006 National Health and Nutritional Examination Survey. Obesity (Silver
Spring) 2010;18:347–353. [II-2: Population-based study, n = 1875, average
age 48 years]
326. Barbosa L, Boaviagem A, Moretti E, Lemos A. Multiparity, age, and over-
weight/obesity as risk factors for urinary incontinence in pregnancy: a sys-
tematic review and meta-analysis. Int Urogynecol J 2018;29(10):1413–1427.
[II-2; Meta-analysis, 13 studies]
327. McDonald SD, Han Z, Mulla S, et al. on behalf of the Knowledge Synthesis
Group. Overweight and obesity in mothers and risk of preterm birth
and low birth weight infants: systematic review and metaanalyses. BMJ
2010;341:c3428. doi:10.1136/bmj.c3428. [II-2; Systematic review and meta-
analysis, cohort studies, n = 64, case control studies, n = 20]
328. Bianco AT, Smilen SW, Davis Y, et al. Pregnancy outcome and weight
gain recommendations for the morbidly obese woman. Obstet Gynecol
1998;91:97–102. [II-2, U.S. retrospective cohort study, n = 11,926]
329. Heslehurst N, Vieira R, Hayes L, et al. Maternal body mass index and
post-term birth: a systematic review and meta-analysis. Obes Rev
2017;18(3):293–308. [II-2; Meta-analysis, 39 studies]
330. Stothard KJ, Tennant PWG, Bell R, et al. Maternal overweight and obesity
and risk of congenital anomalies a systematic review and meta-analysis.
JAMA 2009;301:636–650. [II-2: Systematic review 39 studies mostly from
the US, meta-analysis 18 studies]
331. Blanco R, Colombo A, Suazo J. Maternal obesity is a risk factor for orofacial
clefts: a meta-analysis. Br J Oral Maxillofac Surg 2015;53(8):699–704. [II-2;
Meta-analysis, 8 studies]
332. Hildebrand E, Kallen B, Josefsson A, et al. Maternal obesity and risk of
down syndrome in the offspring. Prenat Diagn 2014;34(4):310e5. [II-2: pop-
ulation-based cohort study, Study Group I n = 1,568,604, Study Group II n =
10,224]
333. Gupta M, Lauring J, Kunselman AR, et al. Fetal growth restriction may
be underestimated in obese patients. Obstet Gynecol 2014;123(Suppl.
1):98se9s. [II-2: Retrospective cohort study comparing n = 150 normal
weight (BMI < 25 kg/m 2 ) and n = 150 obese (BMI > 30 kg/m 2 )]
334. Sekhavat L, Fallah R. Could maternal pre-pregnancy body mass index affect
Apgar score? Arch Gynecol Obstet 2013;287(1):15e8. [II-2: Retrospective
cohort study, single-center, n = 3120]
335. Voerman E, Santos S, Inskip H. et al (LifeCycle Project – Maternal
Obesity and Childhood Outcomes Study Group). Association of gesta-
tional weigh gain with adverse maternal and infant outcomes. JAMA
2019;321(17):1702–1715. [II-2; Systematic review and meta-analysis,
25 cohort studies, 196,670 women]
336. Voerman E, Santos S, Patro Golab B, et al. Maternal body mass index,
gestational weight gain, and the risk of overweight and obesity across
childhood: an individual participant data meta-analysis. PLOS Med
2019;16(2):e1002744. [II-2; Systematic review and meta-analysis, 37 studies,
n = 162,129 mothers and children]
337. Vahratian A, Zhang J, Troendle JF, et al. Maternal prepregnancy over-
weight and obesity and the pattern of labor progression in term nulliparous
women. Obstet Gynecol 2004;104(5 pt 1):943–951. [II-2: US prospective
cohort study, n = 612]
338. Perlow JH, Morgan MA. Massive maternal obesity and perioperative cesar-
ean morbidity. Am J Obstet Gynecol 1994;170:560–565. [II-2: n = 43 patients
>300 lb]
339. Fyfe EM, Thompson JM, Anderson NH, et al. Maternal obesity and postpar-
tum haemorrhage after vaginal and caesarean delivery among nulliparous
women at term: a retrospective cohort study. BMC Pregnancy Childbirth
2012;12:112. [II-2: Retrospective cohort study, National Women’s Health
Clinical Database, n = 11,363].
340. Knight M, Kurinczuk JJ, Spark P, et al. On behalf of the UK obstetric sur-
veillance system extreme obesity in pregnancy in the United Kingdom.
Extreme obesity in pregnancy in the United Kingdom. Obstet Gynecol
2010;115:989–997. [II-2: Population-based cohort study, BMI > 50 kg/m 2 ,
n = 665]
341. American College of Obstetricians and Gynecologists, Committee on
Health Care for Underserved Women. Motivational interviewing: a tool for
behavior change, no 423. Obstet Gynecol 2009;113:243–246. [III; Review]
4
PREGESTATIONAL DIABETES
F. Weston Loehr, A. Dhanya Mackeen, and Michael J. Paglia
Key points
• The prevalence of pregestational diabetes mellitus is
increasing, particularly in minority populations.
• Poorly controlled diabetes in pregnancy is associated with
increased risks of first-trimester miscarriage, congenital
malformations (especially cardiac defects and CNS anom-
alies), fetal death, preterm birth, pre-eclampsia, ketoacido-
sis, polyhydramnios, macrosomia, operative (both vaginal
and cesarean) delivery, birth injury (including brachial
plexus), delayed lung maturity, respiratory distress syn-
drome, jaundice, hypoglycemia, hypocalcemia, perinatal
mortality, and long-term consequences for the children
such as obesity, type II diabetes, and lower IQ.
• Preconception counseling should include weight loss,
exercise, appropriate diet, and optimization of blood
sugar control. Normalization of glucose levels (hemoglo-
bin A1c <6%) prevents most, if not all, of the complica-
tions of diabetes in pregnancy.
• In pregestational diabetics, fasting glucose <95 mg/dL and
2-hour postprandial ≤120 mg/dL (or 1-hour postpran-
dial ≤140 mg/dL) should be achieved and maintained at all
times with diet, exercise, and insulin therapy as necessary.
• There is insufficient evidence to guide the use of continuous
glucose monitoring in women with pregestational diabetes,
with recent data showing maternal and perinatal benefits.
• There is insufficient evidence to assess the efficacy of oral
hypoglycemic agents in pregestational diabetes.
• Diabetic ketoacidosis is treated with aggressive hydra-
tion and intravenous insulin.
• In pregestational diabetics with good glycemic control,
timing of delivery is about 39 0/7–39 6/7 weeks; cesarean
delivery may be offered if estimated fetal weight is ≥4500 g.
Diagnosis/Definition
Diabetes mellitus (DM) is defined as a metabolic abnormality
characterized by elevated circulating glucose. The diagnoses
of diabetes and impaired glucose tolerance outside of preg-
nancy are established on the basis of formal laboratory crite-
ria (Table 4.1) [1–3]. As different countries use either mmol/L or
mg/dL for glucose values, a comparison is provided in Table 4.2.
Symptoms
Often asymptomatic, but classic symptoms of uncontrolled dia-
betes are polydipsia, polyuria, and polyphagia.
Epidemiology/Incidence
The prevalence of pregestational DM continues to
increase in many high-income countries. The prevalence of
DOI: 10.1201/9781003099062-4
diabetes in reproductive-aged women has been reported at 4.5%
[4]. Pregestational DM was noted to complicate 0.9% of all preg-
nancies in the United States in 2018 [5]. Hispanic and African
American women had greater relative increase in incidence of
pregestational DM from 1999 to 2014 [6]. Type I diabetes was
more prevalent in non-Hispanic white women and type II dia-
betes was more prevalent in Hispanic and African American
women [6].
Basic pathophysiology
The etiology of the disease varies and includes a primary insu-
lin production defect, insulin receptor abnormalities, end-organ
insulin resistance, and diabetes secondary to another disease
process, such as cystic fibrosis [3]. Type I diabetics are insulin
deficient, secondary to the autoimmune destruction of the pan-
creatic islet beta-cells [3]. These individuals develop disease early
in life, require insulin replacement, and become acutely symp-
tomatic with ketoacidosis if no therapy is initiated. In contrast,
type II diabetics continue to produce insulin but at diminished
levels. They are often hyperinsulinemic, at least in the early
stages; relative hypo-insulinemia may (or may not) develop later
[3]. Insulin resistance is the cardinal feature of type II diabetics
and many exhibit insulin resistance at the level of the end-organ
receptor. The onset of disease is usually later in life, the course is
gradual but progressive, and the disease is linked to obesity [3].
This is rapidly changing with time, type II diabetes is now being
seen at earlier ages, including childhood and adolescence. Both
groups can be further subclassified on the basis of the presence
of vascular complications, such as hypertension, renal disease,
and retinopathy. The same physiologic changes of pregnancy
that cause gestational diabetes (see Chap. 5) also complicate the
achievement of optimal glucose control in the pregestational dia-
betic. In a meta-analysis, women with type II diabetes had a 1.5×
increased risk of perinatal mortality, decreased risk of diabetic
ketoacidosis, and decreased cesarean delivery rate as compared to
those with type I diabetes; however, there were no significant dif-
ferences between the two groups in the frequency of major con-
genital malformation, stillbirth, or neonatal mortality [7].
Classification
To facilitate the management of these patients, the classification
of diabetes has undergone recent revisions to reflect the physi-
ology and implications of the disease process. Classification as
type I and type II diabetes (as defined earlier) is still commonly
used, especially in non-pregnant patients. Presence of vascular
diseases, defined as chronic hypertension (HTN), renal insuffi-
ciency, retinopathy, coronary artery disease, or prior cerebrovas-
cular accident, is a better predictor of adverse pregnancy outcome
than is White’s classification [8, 9]. Therefore, White’s classifica-
tion is no longer recommended for management.
57
58 Maternal-Fetal Evidence Based Guidelines

TABLE 4.1: Criteria for the Diagnosis of Diabetes Mellitus in maturity; respiratory distress syndrome; jaundice (because of
the Non-Pregnant State polycythemia), hypoglycemia, hypocalcemia, and polycythemia
in the neonates (all related to elevated glucose levels and con-
Impaired Fasting
sequent hyperinsulinemia antenatally); and perinatal mortality
Glucose or Impaired
[16, 17]. Long-term follow-up has shown increased infant adi-
Normal Values Glucose Tolerance Diabetes Mellitus [85]
posity and higher rates of obesity, type II DM, and lower IQ in
FPG: <100 mg/dL FPG: 100–125 mg/dL FPG: ≥126 mg/dL children of mothers with poorly controlled DM during preg-
75-g, 2-hour OGTT: 75-g, 2-hour OGTT: (7.0 mmol/L)a nancy [16–21].
2-hour PG 2-hour PG 75-g, 2-hour OGTT:
<140 mg/dL 140–199 mg/dL 2-hour PG
Hemoglobin A1c ≥200 mg/dL
Pregnancy considerations
5.7–6.4% (11.1 mmol/L)a It is always important to consider the effect of maternal disease
Hemoglobin A1c on pregnancy and, conversely, the effect of pregnancy on mater-
≥6.5%a nal end organs, (Table 4.3) especially because pregestational dia-
Symptoms of betes affects the micro- and macrovascular systems. Diabetic
hyperglycemia and retinopathy is the leading cause of blindness in reproductive
PG (without regard years. Background retinopathy is characterized by retinal micro-
to time since last aneurysms and dot-blot hemorrhages, and proliferative retinopa-
meal) ≥200 mg/dL thy by neovascularization. Proliferative diabetic retinopathy may
(11.1 mmol/L) progress as tightened glycemic control is achieved [22]. However,
Source: Data from Ref. [85]. clinicians should not be deterred from achieving optimal glu-
a Unless unequivocal hyperglycemia is present, the diagnosis of diabetes mellitus cose control as the risk of subsequent progression of retinopathy
should be confirmed on a separate day by any of these three tests. is overall decreased as compared to patients not managed with
Abbreviations: FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; PG, intensive therapy [22]. Diabetic nephropathy occurs in 5–10%
plasma glucose. of pregestational diabetics and can progress to end-stage renal
disease, especially in women with creatinine of ≥1.4 mg/dL or
24-hour proteinuria of ≥3 g (see Chap. 17). Proteinuria increases
Risk factors/Associations in diabetic patients as they approach term, particularly in those
who have baseline nephropathy. Women with baseline nephropa-
Obesity, hypertension, advanced maternal age, non-white race,
thy are at increased risk of iatrogenic preterm birth and utero-
family history (type II diabetes), and metabolic syndrome, among
placental insufficiency. Progression of renal insufficiency is not
others are associated risk factors for diabetes.
clearly linked to the physiologically increased glomerular filtra-
tion rate of pregnancy, although those with nephrotic range pro-
Complications teinuria and moderate to severe renal insufficiency may progress
to end-stage renal disease [23, 24]. Diabetic neuropathy is not
Incidence of complications is inversely proportional to glu-
worsened, per se, in pregnancy, although decreased gastrointesti-
cose control, with minimal complications if glucose control
nal motility related to progesterone and mechanical factors may
is optimal [10]. Pedersen first proposed that the exaggerated
exacerbate underlying gastroparesis [24]. The presence of HTN
fetal response to insulin is provoked by fetal hyperglycemia
(in 5–10% of women with pregestational DM) further increases
that results from maternal hyperglycemia [11]. Poorly con-
the risks of pre-eclampsia, fetal growth restriction, and fetal
trolled DM is associated with increased risks of the following:
death [23]. Progression of cardiovascular disease in the diabetic
first-trimester miscarriage; congenital malformations [12–14]
pregnant patient has not been reported, but symptomatic coro-
(most common malformations are cardiac defects and CNS
nary artery disease is a contraindication to pregnancy in these
anomalies, especially neural tube defects [15]; most pathog-
diabetic women [24].
nomonic are sacral agenesis/caudal regression); intrauterine
fetal demise; preterm birth (both iatrogenic and spontaneous);
pre-eclampsia; ketoacidosis; polyhydramnios; macrosomia
TABLE 4.3: Diabetes Workup in Pregnancy
(increased fetal insulin acts as growth factor; the degree of
macrosomia is correlated with fasting and postprandial blood Workup
glucose values outside of the suggested parameters); operative • Careful history (review of glucose control and therapy; history of
delivery (both vaginal and cesarean) and birth injury (includ- end-organ disease)
ing brachial plexus) (both related to macrosomia); delayed lung
• Laboratory tests (preconception or first trimester if feasible):
• Hemoglobin A1c
TABLE 4.2: Glucose Equivalents • Metabolic profile (glucose, creatinine)
• Urine culture: repeat each trimester
mmol/L mg/dL
• 24-hour urine collection for protein and creatinine clearance
5.9 105 • TSH for type I diabetics
6.7 120 • Consider EKG, especially if concomitant hypertension
7.8 140 • Consider ophthalmologic consult to assess for any retinopathy,
8.0 144 especially if long-standing or poorly controlled diabetes mellitus
11.0 198
Abbreviations: EKG, electrocardiogram; TSH, thyroid-stimulating hormone.
Pregestational Diabetes
Management
See Table 4.4.
TABLE 4.4: Management of Pregestational Diabetes
Preconception Counseling
• Weight loss
• Exercise
• Glucose testing
• Treatment of hyperglycemia as appropriate
• Strict glucose control
Preconception evaluation (Table 4.5)
• Normalization of the hemoglobin A1c to within 1% of normal (<6%)
• Evaluate the presence of vascular disease
• Ophthalmologic exam with retinal evaluation
• 24-hour urine for protein and creatinine clearance
• EKG
• Nutritional counseling (Table 4.7)
• 30–35 kcal/kg/day if normal weight
• Institute glucose testing to include fasting and postprandial values
(Table 4.8)
• Incorporate exercise regimen
• Start or refine insulin regimen (Figures 5.1 and 5.2)
Antepartum management
• Insulin therapy adjusted by weight and pregnancy trimester as
guided by glucose monitoring (Tables 4.8 and 5.4; Figures 5.1
and 5.2)
• Viability/dating scan
• Fetal surveillance and antepartum testing (Table 4.11)
• Alpha-fetoprotein screening at 16–20 weeks
• Detailed anatomic survey at 18–20 weeks
• Fetal echocardiogram (at 14–16 weeks especially if hemoglobin
A1c >8%) and at 20–22 weeks
• Serial ultrasounds for growth in the second and third trimester
• Antenatal assessments with NST or BPP weekly or twice weekly
from 32–35 6/7 weeks, then twice weekly until delivery
– Start at 28 weeks if diabetes is poorly controlled
Intrapartum management (Figure 4.1)
• Trial of labor unless clinical or ultrasound estimated fetal weight
greater than 4500 g
• Delivery at: 39 0/7–39 6/7 weeks if pregestational diabetes is well
controlled; 37 0/7–38 6/7 weeks if pregestational diabetes is
complicated by vascular disease; 34 0/7–39 6/7 weeks
(individualized to situation) if diabetes is poorly controlled [76]
• IV insulin therapy to maintain blood sugar between 70 and
110 mg/dL
• IV dextrose solution if blood sugars fall <70 mg/dL or with
development of ketonuria
• For scheduled cesarean section, administer the dose of long-acting
insulin in PM and withhold the AM short-acting dose
• Monitor blood glucose hourly
Postpartum management
• Reduce the antepartum insulin dose by half and administer it with
the resumption of oral intake
• Supplement breastfeeding mothers with extra 500 kcal compared to
non-pregnant levels
Abbreviations: BPP, biophysical profile; EKG, electrocardiogram; NST, non-stress
test, IV, intravenous.
59
Principles
Strict glycemic control, aiming for HgbA1c of < 6%.
Workup
See Table 4.3.
Prevention
Weight loss, exercise, and optimization of blood sugar control can
prevent most, if not all, of the complications of DM in pregnancy.
Preconception counseling
The care of the pregestational diabetic patient is best instituted
in the preconception period. The objectives of pre-pregnancy
care are shown in Table 4.5. The frequency of maternal hospital-
izations, length of NICU admission, congenital malformations,
preterm delivery, and perinatal mortality are reduced in women
with DM who seek consultation in preparation for pregnancy;
unfortunately, only about one-third of these women receive such
consultation [25, 26].
The evaluation should emphasize the importance of tight
glycemic control, with normalization of the hemoglobin A1c
(aim for at least <6.0%) (Tables 4.4–4.6) [8, 27, 28]. Decreased
spontaneous miscarriage, congenital anomalies, and other com-
plications have been demonstrated in multiple studies, includ-
ing randomized controlled trials (RCTs), when optimal glucose
control is attained via multiple daily insulin doses adjusted to
glucose monitoring ≥4 times per day [29, 30]. Optimal glucose
control also prevents future obesity, DM, and its complications
in the offspring. In addition to advocating the use of at least 400 µg
of folic acid for at least 1 month prior to conception, this consul-
tation affords the opportunity to screen for end-organ damage
(Table 4.3). Women with end-organ damage (vascular com-
plications) are at an increased risk of pre-eclampsia, but not of
congenital malformations or other neonatal complications [31].
Women aged 35–39 are at an increased risk of having a small
for gestational age (SGA) fetus or an intrauterine fetal demise
[32]. Ophthalmologic evaluation, EKG, and renal evaluation via
a 24-hour urine collection for total protein and creatinine clear-
ance will ascertain end-organ damage and determine ancillary
pregnancy risks. As 40% of young women with type I diabetes have
hypothyroidism, the thyroid-stimulating hormone (TSH) should
also be checked. Proliferative retinopathy should be treated with
laser before pregnancy. Women compliant with insulin pumps
may continue this regimen. Sexually active diabetic adolescents
benefit from preconception counseling [33, 34].
Prenatal care
Optimizing health outcomes can be achieved by a combina-
tion of diet, exercise, glucose monitoring, and insulin therapy.
Women with type I DM and glucose levels of >200 mg/dL should
check their urine ketones and immediately alert their health care
TABLE 4.5: The Objectives of Diabetes Pre-Pregnancy Care
• Patient education
• Assessment of patient’s medical condition
• Optimize glycemic control (hemoglobin A1c <6% prior to conception)
• Folic acid supplementation (at least 400 μg) for at least 1 month prior
to conception
60 Maternal-Fetal Evidence Based Guidelines

Check blood sugar on admission

< 70 mg/dL 70–99 mg/dL ≥100 mg/dL

D5NS D5NS D5NS

No insulin Consider insulin Start insulin infusion:
Blood Sugar (mg/dL) Initial Insulin dose (U/hr)
100–140 1.0
141–180 1.5
> 180 2.0

No insulin Start insulin at 0.5 U/hr Check accuchecks at least hourly.

< 70 70–99 100–140 ≥ 140

mg/dL mg/dL mg/dL mg/dL

Stop insulin by No change insulin

insulin 0.5–1 U/hr in insulin by 0.5–1

Accucheck every 1–2 hours Accucheck hourly

Please note:
• These are suggestions and patients should be managed on a case by case basis
• Insulin should be mixed as follows: Mix 10 units of short-acting insulin in 1000 mL of D5NS
• Intravenous fluids should be infused at a rate of 100–150 cc/h (2.5 mg/kg/min)
• If patients persistently have blood sugars > 180 mg/dL, consider Normal Saline (NS) instead of D5NS and evaluate for DKA
• We suggest having two lines, one running NS and one running D5NS, so that rate of NS infusion can be changed as per L&D needs and D5NS can be
consistently infused

FIGURE 4.1 Intrapartum management of diabetes (GDMA2 and pregestational). (Adapted from Refs. [8, 39].) Abbreviations: DKA,
diabetic ketoacidosis; L&D, labor and delivery; NS, normal saline; D5NS, 5% dextrose normal saline.

provider if positive [8]. A glass of milk is preferable to juice for
hypoglycemia. Glucagon should be immediately available.
Diet
Nutritional requirements are adjusted on the basis of maternal
body mass index (BMI); women with normal BMI require 30–35
kcal/kg/day (Table 4.7) [8]. Individuals with <90% of their ideal
body weight (IBW) may increase this by an additional 5 kcal/kg/
day, while those >120% of their IBW should decrease this value
to 24 kcal/kg/day [8]. The content should be distributed as 45%
complex high-fiber carbohydrates, 20% protein, and 35% primar-
ily unsaturated fats (Table 4.6) [8, 25]. The calories are distributed
over three meals and three snacks with breakfast receiving the
smallest allotment at 15% and the other two meals receiving near
equal distribution. Saccharin, aspartame, acesulfame-K, malto-
dextin, and sucralose may be used safely in moderate amounts.
Carbohydrate counting and help of a registered dietitian may
provide benefit, but these two interventions have been insuffi-
ciently studied in pregnancy [35].
Exercise
Moderate exercise decreases the need for insulin therapy in type
II diabetics by increasing the glucose uptake in skeletal mus-
cle, and therefore, should be strongly encouraged for diabetic
patients, though it is important to take into consideration any
pre-existing comorbidities, including class III obesity [36].

TABLE 4.6: Risk of Congenital TABLE 4.7: Diabetic Diet

Malformations Based on 30–35 kcal/kg/day (usually 2000–2400
Hemoglobin A1c kcal/day)
HbA1c (%) Risk
3 meals and 3 snacks
<7 No increased risk Composition
7–10 3–7% Carbohydrate (complex) 45%
10–11 8–10% Protein 20%
≥11 10–20% or more Fat (<10% saturated) 35%
Note: See further Ref. [28]. Source: Data from Ref. [8].
Pregestational Diabetes
TABLE 4.8: Target Venous Plasma Glucose Levels
Fasting 60–90 mg/dL
Preprandial 60–100 mg/dL
One-hour postprandial ≤140 mg/dL
Two-hour postprandial ≤120 mg/dL
3 AM 60–90 mg/dL
Source: Adapted from Ref. [39].
Glucose monitoring
Frequent home glucose monitoring, both pre- and post-­prandially,
has been associated with enhanced glucose control and shorter
interval to achieve target blood sugars. Capillary blood glucose
(“fingerstick”) measurements using a glucometer should be
obtained at least four times a day—fasting and 2 hours (or 1 hour)
postprandial [37, 38]. There are no RCTs comparing 1- versus
2-hour postprandial glucose monitoring in pregnancy. Target
levels are in Table 4.8 [39]. Some women will require another
assessment at 3 AM for prevention of hypoglycemic episodes.
Glycosylated hemoglobin A1c <6% is normal [40]. Hemoglobin
A1c of 6% reflects a mean glucose level of 120 mg/dL; each 1%
increment in hemoglobin A1c is equal to a change in mean glu-
cose level of 30 mg/dL. There is evidence that blood sugars (and
hemoglobin A1c measurements) should be maintained within
normal limits throughout gestation and not just in a particular
trimester to decrease the risk of poor pregnancy outcomes [41].
While earlier studies [42, 43] suggested some benefit to continu-
ous glucose monitoring (CGM), more recent studies showed
no improvement in glycemic control or in maternal/fetal out-
comes in women using CGM (measurements every 10 seconds
for up to 288 measurements daily) intermittently (for 6 days at
various time points in pregnancy), versus routine monitoring
[44] or constant continuous monitoring [45, 46] In the latest
meta-analysis of RCTs, CGM may reduce hypertensive dis-
orders of pregnancy (pre-eclampsia and gestational HTN) (RR
0.58, 95% CI 0.39–0.85), but not pre-eclampsia alone (RR 0.65,
95% CI 0.39–1.08), cesarean section (RR 0.94, 95% CI 0.75–1.18),
large-for-gestational age (RR 0.84, 95% CI 0.57–1.26), perinatal
mortality (RR 0.82, 95% CI 0.05–12.61), or mortality or morbid-
ity composite (RR 0.80, 95% CI 0.61–1.06) possibly due to small
numbers. CGM appears to reduce neonatal hypoglycemia (RR
0.66, 95% CI 0.48–0.93). Therefore at this point no clear strong
recommendation regarding CGM in pregnancy can be made
[47]. A recent RCT showed improved neonatal outcomes in preg-
nant patients with type 1 DM who used CGM and capillary glu-
cose monitoring versus those using capillary glucose monitoring
alone [48].
Oral hypoglycemic agents
There may be a role for oral hypoglycemic agents in women with
preconception diabetes. Previously, in women on oral hypogly-
cemic control before pregnancy, insulin therapy had been sug-
gested for glucose control. Occasionally, a woman well controlled
on either glyburide or metformin pre-pregnancy and a normal
hemoglobin A1c can be managed by continuing these medica-
tions, as long as glycemic control remains optimal [30, 49, 50].
Recent studies evaluating oral hypoglycemic agents in pre-
existing diabetic women have used metformin. Two studies have
shown benefits of incorporating metformin into an insulin regi-
men [51, 52]. Improved maternal glycemic control and reduced
neonatal hypoglycemia, respiratory distress syndrome, and NICU
61
admission was noted when metformin was added to an insulin
regimen in women with poor control despite daily insulin dose
of ≥1.12 units/kg [52]. The addition of metformin to an insu-
lin regimen in women with well-controlled type II DM showed
improved glycemic control, lower insulin doses, and less risk
of birth-weight >97%, however there was a slight increase in SGA
neonates [53].
Insulin
Multiple-dose insulin (MDI) injection therapy is the mainstay
in the management of pregestational diabetes. All subcutaneous
insulin types have been approved during pregnancy.
A review of the types of insulin, their onset, and duration of
action are listed in Table 4.9. Women, particularly those new to
insulin therapy, need to be counseled about the differences in the
various insulins, in order to use them to their greatest efficacy.
Close monitoring with at least weekly contact with a provider is
suggested to maximize insulin adjustment. The goals of therapy
are shown in Table 4.8 [39]. Both fasting and postprandial blood
sugars are correlated with fetal macrosomia, especially elevated
postprandials (see Chap. 5) [54, 55]. Hypoglycemia can cause
significant maternal morbidities, but has not been associated
with embryopathy [56]. Glucagon should be available for home
use in emergency situations.
Though satisfactory glucose control may be obtained solely
with an intermediate-acting insulin rather than a short-acting
insulin [57], we suggest optimizing metabolic control with one
evening injection of long-acting insulin (e.g., insulin glargine),
and meal-time (three daily) injections of short-acting insulin
(e.g., lispro or aspart) (Figures 5.1 and 5.2). Glargine cannot be
mixed in the same syringe with other insulins. Intermediate-
acting insulin (e.g., neutral protamine Hagedorn [NPH]) twice
daily can also be used, instead of insulin glargine. Studies have
shown that short-acting insulin is as effective as regular insulin
and may result in improved postprandial glucose control and less
preterm deliveries [58, 59]. Insulin lispro should be given imme-
diately before eating. As compared to two daily insulin injec-
tions, additional doses are associated with improved glycemic
control [60]. A meta-analysis of cohort studies comparing insu-
lin glargine to NPH did not reveal any significant differences in
outcomes including infant birth weight, congenital anomalies,
and respiratory distress [61]. A large randomized trial including
310 pregnancies compared insulin detemir with NPH and found
no differences between maternal HgbA1c, the frequency of major
hypoglycemic episodes [62], early fetal loss, congenital anomalies,
or adverse events [63]. Insulin analogs have not been associated
with an increased risk of congenital anomalies [64].
Falling insulin requirements has been associated with devel-
oping fetoplacental compromise [65]. Falling insulin requirement
TABLE 4.9: Types of Insulin and Their Pharmacokinetics
Type Onset Peak Duration
Lispro/aspart 15–30 min 0.5–3 hours ≤5 hours
Regular 30 min 2.5–5 hours 4–12 hours
NPH 1–2 hours 4–12 hours 14–24 hours
Detemir 3–4 hours 3–9 hours 6–23 hours (dose
dependent)
Glargine 3–4 hours None 24 hours
Note: See further Ref. [86].
62
≥15% confers an increased risk for pre-eclampsia, SGA fetus,
preterm delivery, placental abruption, and preterm birth [65].
Subcutaneous insulin pump therapy (continuous subcutane-
ous insulin infusion therapy [CSII]) may be continued in women
already compliant with this mode of therapy. In non-pregnant
adults, women compliant with insulin pumps have increased sat-
isfaction, decreased episodes of severe hypoglycemia, and better
control of hyperglycemia [8]. Basal infusion rates tend to increase
and carbohydrate-to-insulin ratios decrease during the course
of pregnancy [66, 67]. There is currently insufficient evidence to
recommend CSII versus MDI in pregnant women not already on
pumps [68, 69]. An observational study suggested that MDI ther-
apy has better glycemic outcomes and better maternal and neo-
natal outcomes than pump therapy [70]. In women who do use
CSII during pregnancy, closed-loop insulin delivery appears to
keep blood sugars in the appropriate range more so than sensor-
augmented therapy [71]. Inhaled insulin has been tested in non-
pregnant adults, but there are yet insufficient data for pregnancy
management [72].
Carbohydrate counting and the use of an insulin-to-­carbohydrate
ratio of 1 unit of insulin for every 15 g of carbohydrate in early
gestation can allow for greater flexibility in eating, but has not
been studied in a trial. As pregnancy advances with its concomi-
tant increased insulin resistance, an increased ratio is required
with 1 unit covering a lower amount of carbohydrates, for exam-
ple, 1 unit/3 g of carbohydrate [66].
Useful sample calculations for the total daily insulin require-
ment and insulin regimen are in Table 5.4 and Figures 5.1 and 5.2.
Very tight versus tight control
There are limited data to assess the effect of moderate-tight versus
very tight glycemic control in women with type I pregestational
diabetes, but there is some evidence to suggest very tight control
(either fasting and 2-hour postprandial <5.6 mmol/L or fasting
<4.4 mmol/L and 1.5-hour postprandial <6.7 mmol/L) improves
neonatal metabolic outcomes including hypoglycemia [73].
Loose control (fasting blood glucose above 7.0 mmol/L) is
associated with increased incidences of pre-eclampsia, cesar-
ean deliveries, and infants that were large for gestational age
[74]. There are no data to assess the clinical impact for prevention
of significant long-term neonatal morbidity. Patients with type I
diabetes may have increased susceptibility to hypoglycemia dur-
ing pregnancy than in the pre-pregnant state; early pregnancy
hypoglycemia was not associated with an increased risk of early
pregnancy loss or malformations which is consistent with other
studies [56].
Diabetic ketoacidosis
Diabetic ketoacidosis occurs in 5–10% of pregnant women with
pregestational type I diabetes. It is defined by elevated glucose
(usually >250 mg/dL, though no definitive cutoff exists in preg-
nancy), positive serum ketones, and acidosis. Risk factors include
type I diabetes, new-onset diabetes, infections (e.g., urinary or
respiratory tract infections), poor compliance, insulin pump fail-
ure, and treatment with beta-mimetics or steroids [8]. Symptoms
include abdominal pain, nausea, vomiting, and altered sensorium.
Laboratory tests should include an arterial blood gas (pH <7.3),
electrolytes (serum bicarbonate <15 mEq/L and elevated anion
gap), serum and urinary ketones (elevated). Aggressive hydra-
tion, intravenous insulin, and correction of the underlying
Maternal-Fetal Evidence Based Guidelines
etiology are the most important interventions, with close
electrolyte (especially glucose and potassium) monitoring
(Table 4.10) [8, 75]. Fetal mortality may be up to 10%, even with
aggressive management.
Antepartum testing
Fetal surveillance is required to determine whether congeni-
tal anomalies are present and minimize perinatal mortality
(Table 4.11). The nature of this surveillance is by convention and
expert consensus rather than supported by well-performed trials.
Because of the increased risk of birth defects, particularly cardiac
and neural tube defects, patients should be offered alpha-feto-
protein screening at 16–18 weeks gestation, targeted ultrasonog-
raphy at 18–20 weeks, and fetal echo-cardiography at 20–22
weeks. Some suggest an earlier first anatomic fetal sonographic
survey, at around 14–16 weeks, as well early fetal echocardiog-
raphy at this time, especially in women with poor glycemic con-
trol in the first trimester (e.g., hemoglobin A1c >10 mg/dL). Serial
ultrasounds in the third trimester to evaluate fetal growth and
frequent prenatal visits to review glucose control are also advo-
cated. The use of fetal surveillance with nonstress test (NST) and/
or biophysical profile is recommended by expert opinion [25], but
the frequency and nature of the testing cannot be determined,
since there is no randomized trial to direct effective screening.
TABLE 4.10: Management of Diabetic Ketoacidosis in
Pregnancy
IV hydration: Use isotonic saline (0.9% NS)
• First hour: Give 1 L NS
• Hours 2–4: 0.5–1 L NS/hour
• Thereafter (24 hour): Give 250 mL/hour 0.45% NS until 80% deficit
corrected
• Body water deficit = {[0.6 body weight (kg)] + [1–(140/serum
sodium)]} ≈ 100 mL deficit/kg body weight
Insulin: Mix 50 units of regular insulin in 500 mL of NS and flush IV
tubing prior to infusion
• Loading: 0.2–0.4 units/kg
• Maintenance: 2–10 units/hour
• Continue insulin therapy until bicarbonate and anion gap normalize
Potassium replacement: Maintain serum K+ at 4–5 mEq/L
• If K+ is initially normal or reduced, consider an infusion of up to
15–20 mEq/hour
• If K+ is elevated, do not add supplemental potassium until levels are
within normal range, then add 20–30 mEq/L
Phosphate: Consider replacement if serum phosphate <1.0 mg/dL or if
cardiac dysfunction present or patient obtunded
Bicarbonate: If pH is <7.1, add one ampule (44 mEq) of bicarbonate to
1 L of 0.45% NS
Laboratory tests: Check arterial blood gas on admission; check serum
glucose, ketones, and electrolytes every 1–2 hours until normal
• Consider doubling insulin infusion rate if serum glucose does not
decrease by 20% within the first 2 hours
• When blood glucose reaches 250 mg/dL, change IVF to D5NS
• Continue insulin drip until ketosis resolves and the first
subcutaneous dose of insulin is administered
Source: Adapted from Refs. [8, 75].
Abbreviations: NS, normal saline; IVF, intravenous fluids; K+, potassium; kg, kilo-
grams; D5NS, 5% dextrose normal saline.
Pregestational Diabetes
TABLE 4.11: Antepartum Testing
A. Assessment of viability and exact GA: first-trimester ultrasound
B. Detection of congenital malformations
a. If hemoglobin A1c is elevated, consider transvaginal ultrasound at
about 14 weeks to rule out structural defects, including cardiac
b. Maternal serum alpha-fetoprotein level at 16 weeks
c. Level II ultrasound at 18–20 weeks
d. Fetal echocardiogram at 20–22 weeks
C. Assessment of fetal growth
a. Serial growth ultrasounds in third trimester every 3–4 weeks
D. Assessment of fetal well-being
a. Maternal assessment of fetal activity (“fetal kick counts”)
b. Once or twice weekly NSTs/BPPs starting at 32 weeks until 36
weeks, then twice weekly until delivery. Begin at 32 weeks if
maternal glycemic control is satisfactory, fetal growth is
appropriate, and there are no coexisting maternal medical or
obstetric complications. Begin earlier (~28 weeks) with increased
frequency if the aforementioned conditions are not met.
Abbreviations: NST, nonstress tests; BPP, biophysical profile.
For women with good glycemic control, antepartum testing can
start at 32 weeks with once or twice weekly NSTs, increased to
twice weekly at 36 weeks, and continued until delivery [8]. For
women with poor glycemic control, antepartum testing may need
to begin earlier [8].
Delivery
Timing
Timing of delivery in women with pregestational DM in good
control is usually at about 39 0/7–39 6/7 week, as perinatal mor-
tality increases after 40 weeks. In women with pregestational
diabetes and pregnancy complicated by vascular complications,
poor glucose control or prior stillbirth, delivery should occur
between 36 0/7–38 6/7 weeks [76]. In general, indicated delivery
before 39 weeks, if truly indicated, should not require assess-
ment of fetal maturity. If assessment of fetal maturity is done,
laboratory tests are interpreted as in nondiabetic patients, with
phosphatidylglycerol ≥3% accepted by most authorities as the lab
value indicating the least risk for fetal respiratory insufficiency
in diabetic women; patients should be cautioned that a positive
test does not preclude infant morbidities. Compared to expectant
management until 42 weeks, induction of labor at 38 completed
weeks in women with insulin-dependent diabetes (of which >90%
were gestational) is associated with reduced incidences of macro-
somia [77, 78]. However, the sample size was too small to evaluate
the impact on perinatal mortality, which is a concern in women
with diabetes who are delivered prior to 39 weeks [77].
Mode
Mode of delivery is generally vaginal. Cesarean is indicated if
estimated fetal weight is ≥4500 g (see Chap. 48) [8]. The diag-
nosis of macrosomia is inexact by ultrasound and clinical estima-
tion, confounding the ability to make a clear recommendation.
Induction for macrosomia is not recommended due to lack of evi-
dence for benefit [79, 80].
Intrapartum glucose management
The usual subcutaneous long-acting (e.g., glargine) or interme-
diate-acting insulin (e.g., NPH) is given at bedtime the evening
63
before delivery, while the usual subcutaneous morning insulin
is withheld on the day of delivery. Intrapartum management
(Figure 4.1) [39] is targeted to maintain maternal glucose lev-
els between 70 and 110 mg/dL. Often the insulin require-
ment is decreased because of the energy requirements of labor.
Intravenous insulin, dextrose solution, frequent (usually every
hour) glucose monitoring, and evaluation of urinary ketones are
required to prevent a catabolic state and the development of keto-
acidosis. Once active labor begins or glucose is <70 mg/dL, IV
5% dextrose at 125 cc/hour can be started. Once glucose level is
≥100 mg/dL, short-acting (e.g., lispro or regular) IV insulin should
be started. IV 5% dextrose and insulin infusions should be sepa-
rate, and often should occur at the same time, to prevent ketonu-
ria. Adjustments to the basal infusion rates are based on hourly
fingerstick blood sugars while in labor. The use of the insulin
pump, maintaining the basal rate, rather than using an IV insulin
infusion, is an accepted alternative. A small RCT did not show
any benefit to using real-time continuous glucose monitoring
versus hourly monitoring during labor to reduce the likelihood
of neonatal hypoglycemia [81]. A closed loop delivery system can
keep blood sugars in target range during labor, delivery and post-
partum without any increase in maternal or neonatal outcomes
[82]. Use of software-guided insulin dosing systems may intra-
partum glucose control without increasing hypoglycemia [83].
With cesarean delivery, use of a single injection of long-acting
insulin, an IV insulin infusion, or subcutaneous pump at a low
basal rate are equal alternatives, until oral intake is assured and
more standard dosing can be reinstituted. Insulin requirements
are diminished postpartum and are generally half of the antepar-
tum requirement.
Anesthesia
No specific adjustments necessary.
Postpartum/Breastfeeding
Usual diabetic diet should be restarted after delivery, with one
half of the predelivery dose or the full pre-pregnancy dose (if
this achieved euglycemia) restarted [39]. If food intake cannot
be restarted soon, then glucose levels of >140 mg/dL should be
treated with proper coverage. In an RCT among women with
pregestational and gestational DM, antenatal breast milk expres-
sion was safe and associated with exclusive breastfeeding of the
neonate shortly after delivery [84]. Breastfeeding has increased
maternal caloric demands and an additional 500 kcal/day needs
to be added to the diet to avoid hypoglycemia. All forms of con-
traception are available to diabetics, providing they have no
contraindications such as hypertension or vascular disease (see
Chap. 28, Obstetrics Evidence Based Guidelines).
Future
New therapeutic approaches include pancreatic islet cell
transplant.
References
1. Galernau F, Inzucchi SE. Diabetes mellitus in pregnancy. Obstet Gynecol
Clinic North America 2004;31:907–933 [Review]
2. American Diabetes Association. Report of the expert committee on the
diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26
(Suppl 1):S5–S20. [Review, guideline]
64
3. American Diabetes Association. Classification and diagnosis of diabetes:
standards of medical care in diabetes—2020. Diabetes Care 2020;43(Suppl
1):S14–S31. [Review, guideline]
4. Azeez O, Kulkarni A, Kuklina EV, Kim SY, Cox S. Hypertension and diabe-
tes in non-pregnant women of reproductive age in the United States. Prev
Chronic Dis 2019;16:E146. Published 2019 Oct 24. [Case control]
5. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK. Births: final data for
2018. Natl Vital Stat Rep 2019;68(13):1–47. [Data review]
6. Peng TY, Ehrlich SF, Crites Y, et al. Trends and racial and ethnic disparities
in the prevalence of pregestational type 1 and type 2 diabetes in Northern
California: 1996–2014. Am J Obstet Gynecol. 2017;216(2):177.e1–177.e8.
[Cohort study, n = 665,428]
7. Balsells M, Garcia-Patterson A, Gich I, Corcoy R. Maternal and fetal out-
come in women with type 2 versus type 1 diabetes mellitus: a systematic
review and meta-analysis. J Clin Endocrinol Metab 2009;94(11):4284–4291.
[Meta-analysis, 33 RCTs, n ≥ 11,000]
8. American College of Obstetricians and Gynecologists’ Committee
on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 201:
Pregestational diabetes mellitus. Obstet Gynecol 2018;132(6):e228–e248.
[Review, guideline]
9. Cormier CM, Martinez CA, Refuerzo JS, et al. White’s classification of
diabetes in pregnancy in the 21st century: is it still valid? Am J Perinatol
2010;27(5):349–352. [II-2]
10. Jovanovic L, Druzin M, Peterson CM. Effect of euglycemia on the outcome
of pregnancy in insulin-dependent diabetic women as compared with nor-
mal control subjects. Am J Med 1981;71(6):921–927. [II-2]
11. Pedersen J. Diabetes and pregnancy. Blood sugar of newborn infants dur-
ing fasting and glucose adminitration. Nordisk Medicin 1952;2:1049.
[Level III]
12. Correa A, Giloba SM, Besser LM, et al. Diabetes mellitus and birth defects.
Am J Obstet Gynecol 2008;199(3):237.e1–237.e9. [Review]
13. Ludvigsson JF, Neovius M, Söderling J, et al. Periconception glycaemic con-
trol in women with type 1 diabetes and risk of major birth defects: popula-
tion based cohort study in Sweden. BMJ 2018;362:k2638. Published 2018
July 5. [Retrospective cohort study, n = 2458]
14. Tinker SC, Gilboa SM, Moore CA, et al. Specific birth defects in pregnan-
cies of women with diabetes: National Birth Defects Prevention Study,
1997–2011. Am J Obstet Gynecol 2020;222(2):176.e1–176.e11. [Case con-
trol, n = 42,454]
15. Yazdy MM, Liu S, Mitchell AA, Werler MM. Maternal dietary glycemic
intake and the risk of neural tube defects. Am J Epidemiol 2010;171(4):407–
414. [Case control, n = 1394]
16. Tyrala EE. The infant of the diabetic mother. Obstet Gynecol Clin North
Am 1996;23(1):221–241. [Review]
17. Boulet SL, Alexander GR, Salihu HM, Pass M. Macrosomic births in
the United States: determinants, outcomes, and proposed grades of risk.
Am J Obstet Gynecol 2003;188(5):1372–1378. [Case control, n = 8.2 million]
18. Van Assche FA, Holemans K, Aerts L. Fetal growth and consequences for
later life. J Perinat Med 1998;26(5):337–346. [Review]
19. Rizzo T, Metzger BE, Burns WJ, Burns K. Correlations between antepartum
maternal metabolism and child intelligence. N Engl J Med 1991;325(13):
911–916. [Observational, n = 223]
20. Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in pregnancy on
offspring: follow-up research in the Pima Indians. J Matern Fetal Med
2000;9(1):83–88. [II-3]
21. Logan KM, Gale C, Hyde MJ, et al. Diabetes in pregnancy and infant adipos-
ity: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed
2017;102(1):F65–F72. [Metanalysis, 35 observational studies]
22. Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L,
Siebert C. The effect of intensive treatment of diabetes on the development
and progression of long-term complications in insulin-dependent diabetes
mellitus. N Engl J Med 1993;329(14):977–986. [RCT, n = 1441]
23. Simpson LL. Maternal medical disease: risk of antepartum fetal death.
Semin Perinatol 2002;26(1):42–50. [Data review]
24. Kitzmiller JL, Block JM, Brown FM, et al. Managing preexisting diabetes for
pregnancy: summary of evidence and consensus recommendations for care.
Diabetes Care 2008;31(5):1060–1079. [Review]
25. Koerenbrot CC, Steinberg A, Bender C, et al. Preconception care: a system-
atic review. Matern Child Health J 2002(6):75–88. [Review of seven studies
addressing the value of preconceptional care in the diabetic patient]
26. Wahabi HA, Fayed A, Esmaeil S, et al. Systematic review and meta-
analysis of the effectiveness of pre-pregnancy care for women with
diabetes for improving maternal and perinatal outcomes. PLOS ONE
2020;15(8):e0237571. Published 2020 August 18. [Metanalysis, 1 RCT, 34
cohort studies, 1 case control study]
Maternal-Fetal Evidence Based Guidelines
27. Jensen DM, Korsholm L, Ovesen P, et al. Peri-conceptional A1c and risk of
serious adverse pregnancy outcome in 933 women with type 1 diabetes.
Diabetes Care 2009;32(6):1046–1048. [Prospective, n = 933]
28. Guerin A, Nisenbaum R, Ray JG. Use of maternal GHb concentration to
estimate the risk of congenital anomalies in the offspring of women with
prepregnancy diabetes. Diabetes Care 2007;30(7):1920–1925. [II-2]
29. Diabetes Control Complications Trial Research Group. Pregnancy out-
comes in the diabetes control and complications trial. Am J Obstet Gynecol
1996;174(4):1343–1353. [RCT, n = 180]
30. Tieu J, Middleton P, Crowther CA. Preconception care for diabetic women
for improving maternal and infant health. Cochrane Database Syst Rev
2010;12:CD007776. [1 RCT, n = 53]
31. Samii L, Kallas-Koeman M, Donovan LE, et al. The association between vas-
cular complications during pregnancy in women with Type 1 diabetes and
congenital malformations. Diabet Med 2019;36(2):237–242. [Observational
retrospective cohort, n = 232]
32. Walker AR, Waites BT, Caughey AB. The impact of extremes of maternal
age on maternal and neonatal pregnancy outcomes in women with pre-
gestational diabetes mellitus. J Matern Fetal Neonatal Med 2020;33(3):
437–441. [Retrospective cohort study, n = 1.58 million]
33. Fischl AF, Herman WH, Sereika SM, et al. Impact of a preconception
counseling program for teens with type 1 diabetes (READY-girls) on
patient-provider interaction, resource utilization, and cost. Diabetes Care
2010;33(4):701–705. [RCT, n = 88]
34. Charron-Prochownik D, Ferons-Hannan M, Sereika S, Becker D.
Randomized efficacy trial of early preconception counseling for diabetic
teens (READY-girls). Diabetes Care 2008;31(7):1327–1330. [RCT, n = 53]
35. McCance DR, Holmes VA, Maresh MJ, et al. Vitamins C and E for pre-
vention of pre-eclampsia in women with type 1 diabetes (DAPIT): a ran-
domised placebo-controlled trial. Lancet 2010;376(9737):259–266. [RCT,
n = 761]
36. ACOG Committee Opinion No. 650: Physical Activity and Exercise During
Pregnancy and the Postpartum Period. Obstet Gynecol 2015;126(6):
e135–e142. [Review, guideline]
37. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus prepran-
dial blood glucose monitoring in women with gestational diabetes mellitus
requiring insulin therapy. N Engl J Med 1995;333(19):1237–1241.
38. Landon MB, Gabbe SG. Gestational diabetes mellitus. Obstet Gynecol
2011;118(6):1379–1393.
39. Landon MB, Catalano PM, Gabbe SG. Diabetes mellitus complicating preg-
nancy. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: Normal and
Problem Pregnancies 5th ed. Elsevier; 2007:976–1005. [Review]
40. Gabbe SG, Graves CR. Management of diabetes mellitus complicating preg-
nancy. Obstet Gynecol 2003;102(4):857–868. [III]
41. Damm P, Mersebach H, Rastam J, et al. Poor pregnancy outcome in
women with type 1 diabetes is predicted by elevated HbA1c and spikes of
high glucose values in the third trimester. J Matern Fetal Neonatal Med
2014;27(2):149–154. [RCT, n = 322]
42. Murphy HR, Rayman G, Lewis K, et al. Effectiveness of continuous glucose
monitoring in pregnant women with diabetes: randomised clinical trial.
BMJ 2008;337:a1680. [RCT, n = 71]
43. McLachlan K, Jenkins A, O’Neal D. The role of continuous glucose monitor-
ing in clinical decision-making in diabetes in pregnancy. Aust N Z J Obstet
Gynaecol 2007;47(3):186–190. [Descriptive study, n = 68]
44. Secher AL, Ringholm L, Andersen HU, et al. The effect of real-time continu-
ous glucose monitoring in pregnant women with diabetes: a randomized
controlled trial. Diabetes Care 2013;36(7):1877–1883. [RCT, n = 149]
45. Petrovski G, Dimitrovski C, Bogoev M, et al. Is there a difference in
pregnancy and glycemic outcome in patients with type 1 diabetes
on insulin pump with constant or intermittent glucose monitoring?
A pilot study. Diabetes Technol Ther 2011;13(11):1109–1113. [pilot RCT,
n = 25]
46. Kristensen K, Ögge LE, Sengpiel V, et al. Continuous glucose monitoring in
pregnant women with type 1 diabetes: an observational cohort study of 186
pregnancies. Diabetologia 2019;62(7):1143–1153. [Observational cohort,
n = 186]
47. Jones LV, Ray A, Moy FM, Buckley BS. Techniques of monitoring blood
glucose during pregnancy for women with pre-existing diabetes. Cochrane
Database Syst Rev 2019;5(5):CD009613. Published 2019 May 23. [Meta-
analysis, RCT = 12]
48. Feig DS, Donovan LE, Corcoy R, et al. Continuous glucose monitoring in
pregnant women with type 1 diabetes (CONCEPTT): a multicentre inter-
national randomized controlled trial. [published correction appears in
Lancet. 2017 Nov 25;390(10110):2346] Lancet 2017;390(10110):2347–2359.
[RCT, n = 325]
Pregestational Diabetes
49. Tieu J, Coat S, Hague W, Middleton P. Oral anti-diabetic agents for
women with pre-existing diabetes mellitus/impaired glucose tolerance
or previous gestational diabetes mellitus. Cochrane Database Syst Rev
2010;(10):CD007724. [Meta-analysis, RCTs = 0]
50. Tieu J, Crowther CA, Middleton P. Dietary advice in pregnancy for pre-
venting gestational diabetes mellitus. Cochrane Database Syst Rev
2008;(2):CD006674. [Meta-analysis, 2 RCTs, n =82]
51. Balsells M, Garcia-Patterson A, Sola I, et al. Glibenclamide, metformin, and
insulin for the treatment of gestational diabetes: a systematic review and
meta-analysis. BMJ 2015;350:h102. [Meta-analysis, 15 RCTs, n = 2,509]
52. Ibrahim MI, Hamdy A, Shafik A, et al. The role of adding metformin in
insulin-resistant diabetic pregnant women: a randomized controlled trial.
Arch Gynecol Obstet 2014;289(5):959–965. [RCT, n = 90]
53. Feig DS, Donovan LE, Zinman B, et al. Metformin in women with type 2
diabetes in pregnancy (MiTy): a multicenter, international, randomised,
placebo-controlled trial. Lancet Diabetes Endocrinol 2020;8(10):834–844.
[RCT, n = 502]
54. Durnwald CP, Mele L, Spong CY, et al. Glycemic characteristics and neo-
natal outcomes of women treated for mild gestational diabetes. Obstet
Gynecol 2011;117(4):819–827. [Secondary analysis, RCT, n = 460]
55. Prutsky GJ, Domecq JP, Wang Z, et al. Glucose targets in pregnant women
with diabetes: a systematic review and meta-analysis. J Clin Endocrinol
Metab 2013;98(11):4319–4324. [Meta-analysis, 34 RCTs, n = 9,433]
56. Rosenn BM, Miodovnik M, Holcberg G, Khoury JC, Siddiqi TA, et al.
Insulin-dependent diabetes mellitus. Obstet Gynecol 1995;85(3):417–422.
[Prospective, n = 84]
57. Nor Azlin MI, Nor NA, Sufian SS, et al. Comparative study of two insu-
lin regimes in pregnancy complicated by diabetes mellitus. Acta Obstet
Gynecol Scand 2007;86(4):407–408. [RCT, n = 68]
58. Hod M, Damm P, Kaaja R, et al. Fetal and perinatal outcomes in type 1
diabetes pregnancy: a randomized study comparing insulin aspart
with human insulin in 322 subjects. Am J Obstet Gynecol 2008;198(2):
186.e1–186.e7. [RCT, n = 322]
59. Mathiesen ER, Kinsley B, Amiel SA, et al. Maternal glycemic control and
hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insu-
lin aspart versus human insulin in 322 pregnant women. Diabetes Care
2007;30(4):771–776. [RCT, n = 322]
60. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times
daily insulin dose regimens for diabetes in pregnancy: randomised con-
trolled trial. BMJ 1999;319(7219):1223–1227. [RCT, n = 392]
61. Pollex E, Moretti ME, Koren G, Feig DS. Safety of insulin glargine use in
pregnancy: a systematic review and meta-analysis. Ann Pharmacother
2011;45(1):9–16. [meta-analysis, n = 702]
62. Mathiesen ER, Hod M, Ivanisevic M, et al. Maternal efficacy and safety out-
comes in a randomized, controlled trial comparing insulin detemir with
NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care
2012;35(10):2012–2017. [RCT, n = 310]
63. Hod M, Mathiesen ER, Jovanovic L, et al. A randomized trial comparing
perinatal outcomes using insulin detemir or neutral protamine Hagedorn
in type 1 diabetes. J Matern Fetal Neonatal Med 2014;27(1):7–13. [RCT, n =
310]
64. Wang H, Wender-Ozegowska E, Garne E, et al. Insulin analogues use in
pregnancy among women with pregestational diabetes mellitus and risk
of congenital anomaly: a retrospective population-based cohort study.
BMJ Open 2018;8(2):e014972. Published 2018 February 24. [Retrospective
cohort study, n = 1661]
65. Padmanabhan S, Lee VW, Mclean M, et al. The association of falling insulin
requirements with maternal biomarkers and placental dysfunction: a pro-
spective study of women with preexisting diabetes in pregnancy. Diabetes
Care 2017;40(10):1323–1330. [Prospective cohort study, n = 158]
66. Mathiesen JM, Secher AL, Ringholm L, et al. Changes in basal rates and
bolus calculator settings in insulin pumps during pregnancy in women
with type 1 diabetes. J Matern Fetal Neonatal Med 2014;27(7):724–728.
[Prospective, n = 27]
67. Abell SK, Suen M, Pease A, et al. Pregnancy outcomes and insulin require-
ments in women with type 1 diabetes treated with continuous subcutane-
ous insulin infusion and multiple daily injections: cohort study. Diabetes
Technol Ther 2017;19(5):280–287. [Retrospective cohort study, n = 139]
68. Farrar D, Tuffnell DJ, West J. Continuous subcutaneous insulin infusion
versus multiple daily injections of insulin for pregnant women with diabe-
tes. Cochrane Database Syst Rev 2007;(3):CD005542.[Meta-analysis, RCT
2, n = 60]
65
69. Mukhopadhyay A, Farrell T, Fraser RB, Ola B. Continuous subcutaneous
insulin infusion vs intensive conventional insulin therapy in pregnant dia-
betic women: a systematic review and metaanalysis of randomized, con-
trolled trials. Am J Obstet Gynecol 2007;197(5):447–456. [Meta-analysis, 6
RCTs or quasi-RCTs, n = 213]
70. Feig DS, Corcoy R, Donovan LE, et al. Pumps or multiple daily injec-
tions in pregnancy involving type 1 diabetes: a prespecified analysis of
the CONCEPTT randomized trial. Diabetes Care 2018;41(12):2471–2479.
[Secondary analysis of RCT, n = 248]
71. Stewart ZA, Wilinska ME, Hartnell S, et al. Closed-loop insulin deliv-
ery during pregnancy in women with type 1 diabetes. N Engl J Med
2016;375(7):644–654. [RCT, n = 20]
72. Hollander PA, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insu-
lin (exubera) compared with subcutaneous insulin therapy in patients
with type 2 diabetes: results of a 6-month, randomized, comparative trial.
Diabetes Care 2004;27(10):2356–2362. [RCT, n = 299]
73. Walkinshaw SA. Very tight versus tight control for diabetes in pregnancy.
Cochrane Database of Syst Rev 2007;2. [meta-analysis; 2 RCTs, n = 182]
74. Middleton P, Crowther CA, Simmonds L. Different intensities of glycaemic
control for pregnant women with pre-existing diabetes. Cochrane Database
Syst Rev 2012;8:CD008540. [Meta-analysis, 3 RCTs, n = 233]
75. Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care
Med 2005;33(10 Suppl):S347–S353. [Review]
76. American College of Obstetricians and Gynecologists’ Committee on
Obstetric Practice, Society for Maternal-Fetal Medicine. Medically
Indicated Late-Preterm and Early-Term Deliveries: ACOG Committee
Opinion, Number 831. Obstet Gynecol. 2021;138(1):e35–e39. [Review,
guideline]
77. Boulvain M, Stan C, Irion O. Elective delivery in diabetic pregnant women.
Cochrane Database Syst Rev 2001;(2). [Meta-analysis, 1 RCT, n = 200]
78. Kjos SL, Henry OA, Montoro M, Buchanan TA, Mestman JH. Insulin-
requiring diabetes in pregnancy: a randomized trial of active induction of
labor and expectant management. Am J Obstet Gynecol 1993;169:611–615.
[RCT, n = 200]
79. Sanchez-Ramos L, Bernstein S, Kaunitz AM. Expectant management ver-
sus labor induction for suspected fetal macrosomia: a systematic review.
Obstet Gynecol 2002;100(5(1)):997–1102. [Meta-analysis, 9 observational
studies, 2 RCTs, 3751 subjects]
80. Committee on Practice Bulletins—Obstetrics. Macrosomia: ACOG
Practice Bulletin, Number 216. Obstet Gynecol 2020;135(1):e18–e35.
[Review, guideline]
81. Cordua S, Secher AL, Ringholm L, et al. Real-time continuous glu-
cose monitoring during labour and delivery in women with type 1 dia-
betes – observations from a randomized controlled trial. Diabet Med
2013;30(11):1374–1381. [Observational]
82. Stewart ZA, Yamamoto JM, Wilinska ME, et al. Adaptability of closed
loop during labor, delivery, and postpartum: a secondary analysis of
data from two randomized crossover trials in type 1 diabetes pregnancy.
Diabetes Technol Ther 2018;20(7):501–505. [Secondary analysis of two
RTC, n = 32]
83. Dinglas C, Muscat J, Adams T, et al. Software-guided insulin dosing
improves intrapartum glycemic management in women with diabetes
mellitus. Am J Obstet Gynecol 2018;219(2):191.e1–191.e6. [Retrospective
cohort study, n = 33]
84. Forster DA, Moorhead AM, Jacobs SE, et al. Advising women with dia-
betes in pregnancy to express breastmilk in late pregnancy (Diabetes
and Antenatal Milk Expressing. [DAME]): a multicentre, unblinded, ran-
domised controlled trial. Lancet 2017;389(10085):2204–2213. [RCT, n =
635]
85. AD Association. Management of diabetes in pregnancy: standards of
medical care in diabetes-2018. Diabetes Care 2018;41(Suppl 1):S137–S143.
[Review, guideline]
86. Drug result page: MICROMEDEX®. 2015. http://www.micromedexsolutions.
com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/
CS/3F59D1/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/
A04EE9/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/
PFActionId/evidencexpert.DoIntegratedSearch?SearchTerm=Insulin+
Human+Regular&fromInterSaltBase=true&false=null&false=null&=null#.
Accessed 12/3/2015.
5
GESTATIONAL DIABETES
A. Dhanya Mackeen, Richard S. Vigh, and Kajal Angras
Key points
• Poorly controlled gestational diabetes mellitus (GDM)
in pregnancy is associated with increased risks of fetal
death, preterm birth, pre-eclampsia, polyhydramnios, mac-
rosomia, operative (both vaginal and cesarean) delivery
and birth injury (including brachial plexus), delayed lung
maturity, respiratory distress syndrome, jaundice, hypo-
glycemia, hypocalcemia, and perinatal mortality.
• Prevention of GDM can be achieved with optimization of
maternal health and body mass index prior to pregnancy.
Routine intake of dietary supplements to prevent GDM
cannot be recommended at this time.
• Women with risk factors should be screened prior to con-
ception or at the first prenatal visit. If the early screen is
negative, a repeat screen should be performed at 24–28
weeks. Optimization of blood glucose control with diet
and insulin to achieve fasting glucose ≤95 mg/dL and
2-hour postprandial glucose <120 mg/dL (or 1-hour
postprandial <140 mg/dL) is associated with reduced
macrosomia, perinatal morbidity and maternal comorbidi-
ties, including hypertensive disorders of pregnancy and
depression.
• Pharmacologic therapy should be initiated if during the
2-week monitoring period, one or two measurements are
above limits.
• Insulin is the preferred drug when medical management
is indicated; insulin is superior to glyburide as it results
in less fetal macrosomia and less neonatal hypoglycemia.
Compared to glyburide, metformin is preferred, given
lower maternal weight gain and neonatal birth weight. In
select patients, metformin may be an acceptable adjunct
therapy to insulin therapy. Many women will fail metfor-
min monotherapy. Women with GDM who are obese, have
a high fasting glucose, or need pharmacologic therapy early
in pregnancy may be more suitable for insulin therapy, or
may require insulin as an adjunct to metformin therapy.
In women whose total insulin dose is ≥1.12 IU/kg, the
addition of metformin has been shown to improve glyce-
mic control.
• Smartphone-based daily feedback improves patient com-
pliance and glycemic control, while also decreasing insulin
requirements.
• In GDM, exercise is associated with a similar rate of
macrosomia as compared to insulin, improvement in
cardiovascular fitness and improvement in glycemic con-
trol when done in combination with diet as compared to
diet alone.
• Breastfeeding decreases the risk of GDM progression to
type II diabetes.
• Women with GDM should be screened for diabetes
4–12 weeks postpartum and every 1–3 years thereafter.
66
Screening/Diagnosis
Gestational diabetes mellitus (GDM) refers to hyperglycemia
that is first recognized or diagnosed during pregnancy [1]. If
hyperglycemia is detected before 20 weeks, pregestational diabe-
tes is probably present. It is important to screen for GDM and
to optimize glycemic control in order to reduce hyperglycemia-
associated complications [2–7]. A1GDM refers to those whose
are euglycemic with diet and lifestyle modifications alone while
A2GDM refers to those who require medication for blood glucose
optimization.
Who to screen
The population who should be offered screening has not been
uniformly identified [8]. Low-risk women in whom screening
may not be necessary (selective screening) must meet all of the
following criteria: age <25 years, ethnic origin of low-risk (not
Hispanic, African, Native American, south or east Asian, or
Pacific Islander), BMI <25 kg/m2, no personal history of glucose
intolerance or family history of diabetes, and no previous his-
tory of adverse obstetric outcomes associated with GDM [1–5, 9].
However, universal screening is most commonly adopted and
is endorsed by the United States Preventative Services Task Force
(USPSTF) [10]. The risk of developing GDM is directly associated
with pre-pregnancy BMI [11].
How to screen
The optimal way to screen for GDM remains controversial [12],
and generally can be performed with either a one-step or two-
step process. Two-step screening is more cost-effective than
one-step screening [13, 14] and is supported by the American
College of Obstetrics and Gynecology (ACOG) [1]. However,
as those diagnosed using one-step screening are at increased
risk of adverse pregnancy outcomes, and a meta-analysis shows
improved maternal and perinatal outcomes with one-step
compared to two-step screening [18], the evidence is sup-
portive of one-step screening in an effort to decrease associ-
ated morbidities (Table 5.1).
One-step process
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO)
study was a large, multicenter study that revealed increased inci-
dences of pre-eclampsia, preterm delivery, shoulder dystocia/birth
injury, large for gestational age (LGA) infants, neonatal intensive
care unit (NICU) admission, and hyperbilirubinemia in women
with glucose levels >75 mg/dL (fasting), 133 mg/dL (1-hour), or
109 mg/dL (2-hour) after a one-step screen [15]; many of these
findings were confirmed by meta-analyses [16, 17]. On the basis
of the HAPO study, the International Association of Diabetes
and Pregnancy Study Group (IADPSG) suggested the 75 g, one-
step screening process, using one abnormal value as criteria for
diagnosis: fasting >5.1 mmol/L (92 mg/dL), 1-hour >10.0 mmol/L
DOI: 10.1201/9781003099062-5
Gestational Diabetes 67

TABLE 5.1: Recommendations Regarding Screening

Screening
Organization Year Recommendation Screening Process Diagnostic Process
ACOG 2018 Universal screening 2 Step process: 50 g, 1-hour GCT GCT: ≥130, 135,140 mg/dLa GTT: > 2
then 100 g, 3-hour GTT abnormal values on CCC or NDDGb
ADA 2020 Universal screening either the 1 Step or 2 Step process Same as IADPSG and ACOG (CCC)
FIGO 2015 Universal screening 1 Step process: 75 g, 2-hour GTT > 1 abnormal value: fasting:
92–125 mg/dL 1-hour: > 180 mg/dL
2-hour: 153–199 mg/dL
IADPSG 2020 Universal screening 1 Step process: 75 g, 2-hour GTT > 1 abnormal value: fasting: ≥92 mg/dL
1-hour: ≥180 mg/dL 2-hour: ≥153 /dL
NICE 2015 Women with risk 1 Step process: 75 g, 2-hour GTT Fasting: > 5.6 mmol/liter (100 mg/dL)
factors 2-hour: > 7.8 mmol/liter (140 mg/dL)
TES 2013 Universal screening 1 Step process: 75 g, 2-hour GTT Same as FIGO
USPSTF 2014 Universal screening either the 1 Step or 2 Step process Either ACOG or FIGO
WHO 2016 Not specified 1 Step process: 75 g, 2-hour GTT Same as FIGO
Abbreviations: ACOG, American College of Obstetrics and Gynecology; ADA, American Diabetes Association; CCC, Carpenter-Coustan Criteria; FIGO, The International
Federation of Gynecology and Obstetrics; GCT, glucose challenge test; GTT, glucose tolerance test; IADPSG, International Association of Diabetes and Pregnancy Study
Groups; NDDG, National Diabetes Data Group; NICE, National Institute for Health and Care Excellence; TES, The Endocrine Society; USPTF, United States Preventative
Services Task Force; WHO, World Health Organization.
a We use 135 mg/dL
b See Table 5.2.

(180 mg/dL), 2-hour >8.5 mmol/L (153 mg/dL) [5, 18]. This values on these tests establish the diagnosis of GDM. Women
approach diagnoses twice as many women as having GDM as diagnosed by either Carpenter-Coustan’s stricter criteria increase
compared to the two-step process generally employed in North by about 50% the number of women with a diagnosis of GDM
America [19, 20]. compared to the National Diabetes Data Group (NDDG) crite-
ria [27] and these pregnancies have elevated incidences of mac-
Two-step process rosomia and neonatal insulinemia [28]. Therefore, as there is
The first (screening) step involves a 50 g, 1-hour oral glucose associated morbidity even when applying the lower cutoffs, we
load (glucose challenge test, GCT), applied in the non-fasting suggest using the Carpenter–Coustan criteria. In fact, there is
state [21], with a venous glucose value obtained 1-hour after con- evidence to suggest that hyperglycemia below the cutoff of even
sumption. Glucose polymer solutions are better tolerated than the Carpenter–Coustan criteria can result in poor pregnancy
monomeric solutions [22]. While studies have compared different outcomes [15, 29].
GDM screening approaches including glucose polymer, glucose If one abnormal value in the GTT is present, the patient
monomer, candy bar, jelly beans [23] or candy twists [24], there should be counseled to avoid excess glucose consumption; fast-
is insufficient evidence to compare the effects of these different ing and 2-hour postprandial glucose samples or a repeat 3-hour
ways to glucose load, and the subsequent management of GDM, GTT can be obtained 3–4 weeks later. Studies have shown that
thereafter [13]. in these women, better glycemic control (either with diet,
A positive result on the first part of the screening test is vari- exercise, insulin and/or nutritional counseling) was associ-
ably defined at the following thresholds: 130, 135, or 140 mg/dL. ated with less neonatal complications and decreased incidence
The lowest threshold identifies 90% of gestational diabetics, but of LGA and cesarean delivery (CD), as compared to no interven-
subjects 20–25% of those screened to the second diagnostic test. tions [30–34].
In contrast, the highest threshold has a lower sensitivity of 80%,
but subjects fewer women (14–18%) to further testing. ACOG When to screen
recommends that one of these 3 cutoff values be used [1]. The To balance sensitivity and specificity with adequate treatment
cutoff used by many is ≥135 mg/dL. Over 80% of women with duration, women should be screened at 24–28 weeks. However,
values ≥200 mg/dL on the GCT will fail the glucose tolerance test the incidence of GDM (related to placental mass and hormone
(GTT); many use this cutoff as diagnostic of GDM [25].
For those with GCT results greater than the chosen threshold TABLE 5.2: Criteria for Standard 100 g Oral Glucose
and lower than 200 mg/dL, definitive diagnosis of GDM is made Tolerance Test to Diagnose Gestational Diabetes
based on the results of the second (confirmatory) step involving
National Diabetes Carpenter–Coustan
the 100 g, 3-hour oral glucose tolerance test (GTT), adminis-
Data Group Criteria
tered after an overnight fast (8–14 hours), ideally following 3 days
of unrestricted diet (including carbohydrate loading) and activity mg/dL mmol/L mg/dL mmol/L
[26]. During the test, the patient remains seated and refrains from Fasting 105 5.8 95 5.3
smoking. 1-hour 190 10.6 180 10.0
Unfortunately, the criteria to establish diagnosis by this test are
2-hour 165 9.2 155 8.6
not universally accepted. The two competing criteria and their
3-hour 145 8.0 140 7.8
diagnostic levels are listed in Table 5.2. Two or more abnormal
68
TABLE 5.3: Risk Factors for GDM
History of gestational diabetes
BMI >40 kg/m2
BMI >25 kg/m2 PLUS physical inactivity
Pre-existing hypertension or metabolic syndrome
Prior unexplained stillbirth
Prior infant with congenital anomaly (if not screened in that pregnancy)
Prior macrosomic infant
Family history of diabetes mellitus
Chronic use of steroids
Age >35 years
Non-white ethnicity
Excessive gestational weight gain
Polycystic ovarian syndrome
Hypothyroidism
Sleep disordered breathing
Vitamin D deficiency
Use of 17-alpha hydroxyprogesterone caproate
Glycosuria
Known impaired glucose metabolism
production) increases with gestational age. Women with risk
factors (Table 5.3) should be screened prior to conception or
at the first prenatal visit. About 5–10% of women with these risk
factors will have early GDM, and these represent 40% of all GDM
cases diagnosed later at 24–28 weeks [35]. If the early screen
is negative, a repeat screen should be performed at 24–28
weeks. Typically, if a patient fails the early GCT and passes the
early GTT, the GTT can be offered at 24–28 weeks [36]. If GDM
is diagnosed before 20 weeks, counseling and management
should be as for pregestational diabetes.
Incidence
The incidence of GDM in the United States is about 6% [37], rep-
resenting one of the most common obstetric medical complica-
tions. A recent meta-analysis of RCTs revealed an incidence of
4% with two-step, and 8% with one-step GDM screening [18].
The incidence depends on the screening strategy used, with some
suggesting that stricter criteria would result in 18% of pregnant
women being diagnosed with GDM [15, 18]. Of all cases of diabe-
tes in pregnancy, 87% are GDM [37].
Pathophysiology
The pathophysiology of GDM is insulin resistance caused by
increased maternal and placental production of human placental
lactogen, progesterone, growth hormone, cortisol, and prolactin.
Increased body weight and caloric intake also contribute to the
insulin resistance associated with pregnancy, and may offset the
normally increased insulin production in the pregnant woman
[38]. Women with GDM have been found to have lower basal islet
cell function, in addition to increased insulin resistance, when
compared to a non-diabetic cohort. The combination of the two
factors contributes to the development of GDM. This insulin
resistance and decreased insulin production persists in the post-
partum state and increases the risk of type II diabetes in this pop-
ulation. Low adiponectin levels may be a predictive biomarker for
the development of GDM in obese women, but further studies are
needed to ascertain the utility of this before clinical application
Maternal-Fetal Evidence Based Guidelines
[39, 40]. Specific genes related to GDM and response to therapy
are under investigation [41, 42].
Risk factors/Associations
Age ≥35 years at delivery [43], increased maternal pre-pregnancy
BMI and excessive gestational weight gain [44, 45], pre-existing
hypertension, metabolic syndrome, family history of type II DM,
non-white ethnicity, and previous macrosomia are well estab-
lished risk factors, among others, for GDM (Table 5.3). ACOG
endorses early screening in women with BMI ≥25 kg/m2 who
are also physically inactive, have high cholesterol, or a history
of cardiovascular disease [1]. In addition, singleton pregnan-
cies conceived by assisted reproductive technology (ART) are
1.5 times more likely to develop GDM compared to pregnancies
conceived spontaneously [46]. Patients with polycystic ovarian
syndrome, hypothyroidism, sleep disordered breathing, and vita-
min D deficiency are also at an increased risk of developing GDM
[47, 48]. The use of 17-alpha hydroxyprogesterone caproate has
been shown to increase the risk of developing GDM [49]. There is
inconclusive evidence to determine the association between vagi-
nal progesterone and the risk of GDM.
Complications
The incidence of complications is inversely proportional
to glucose control. In poorly controlled GDM, increased glu-
cose in the mother causes abnormal glucose metabolism, while
in the fetus it causes hyperinsulinemia, and its associated con-
sequences. Maternal complications are hypertensive disorders
including pre-eclampsia, preterm delivery, operative vaginal
delivery and CD. Fetal/neonatal complications include congeni-
tal malformations (OR 1.2–1.4) [50], macrosomia, LGA neonate,
and birth injury (confounded by maternal obesity; both related
to macrosomia) [1, 6, 15, 51, 52]. Treatment of even mild GDM
reduced birth-weight percentiles and neonatal fat mass [53].
Elevated fasting glucose is associated with fetal macrosomia
and with elevated C-peptide (which is correlated with increased
fetal fat deposition) [54]. In addition to transient neonatal hypo-
glycemia and jaundice, children of women with GDM are at an
increased risk of being overweight and developing metabolic syn-
drome [55, 56].
Prevention
There is insufficient evidence to support the benefit of a low-
glycemic diet [57], or a diet with adequate (not excessive) caloric
intake, especially in the preconception period, in preventing
GDM [58, 59]. However, some data note a 15–30% reduction in
the incidence of GDM by an early intervention with the adoption
of the Dietary Approaches to Stop Hypertension (DASH) or
Mediterranean diets [59]. Structured moderate physical exer-
cise programs during pregnancy decrease the risk of GDM and
diminish maternal weight gain [60–62]. Although one systematic
review [63] did not find a benefit, more recent systematic reviews
and meta-analyses have suggested that both diet and exercise
are preventative of GDM [59, 64].
Myo-inositol has also been shown to be safe and effective
in preventing GDM. Myo-inositol (2 g b.i.d.) decreases insulin
resistance [65] and reduces the incidence of GDM in both high-
risk and low-risk patient populations [59, 66]. Of the types of
Gestational Diabetes
stereoisomers, myo-inositol has demonstrated the most benefit
compared to D-chiro-inositol [67]. Furthermore, myo-inositol
supplementation started in the first trimester has been shown to
reduce the risk of preterm delivery and macrosomia in patients
who are at high-risk for GDM [66, 68].
The benefit of vitamin D, calcium, omega-3 fatty acid, or pro-
biotic supplementation for the prevention of GDM is limited by
low-quality evidence [59, 69–71].
Treatment of GDM
The treatment of GDM consists of diet, exercise, and glucose
monitoring (Table 5.4). Medications such as insulin and/or oral
hypoglycemic agents are reserved for use when glycemic con-
trol is not achieved with diet and exercise. Compared to usual
prenatal care, treatment in women with GDM is associated with
significantly decreased incidences of pre-eclampsia and birth
weight >4000 g, perinatal morbidity (shoulder dystocia, bone
fracture, nerve palsy) and mortality [3, 6, 72, 73]. The incidence
of CD is not significantly affected [3]..
Lifestyle modifications
Diet
Dietary therapy consists of approximately 30 kcal/kg/day for the
average patient and ±5 kcal/kg/day for underweight and over-
weight women, respectively [25]. Calories should be divided
between 3 meals and 2–3 snacks: 33–40% carbohydrate, 20%
TABLE 5.4: Management of Gestational Diabetic Gravida
Preconception Prevention
• Weight loss
• Exercise
Antepartum Management
• Nutritional counseling for dietary control
• Fingerstick blood sugar assessments: fasting values should be
<95 mg/dL and 2-hour postprandial values should be <120 mg/dL
(or 1-hour postprandial values should be <140 mg/dL)
• Exercise program
• Insulin (or oral hypoglycemic agent), if diet not sufficient to
optimize blood sugars
• Fetal surveillance A2GDM: starting at 32 weeks
Intrapartum Management (see Figure 4.1)
• Delivery
• A1GDM: at 39 weeks
• A2GDM: between 39 0/7 and 39 6/7 weeks
• CD if EFW >4500 g
• Frequent glucose assessment
• A1GDM: every 4-hour
• A2GDM: Every 1-hour
• Target blood sugars 70–110 mg/dL
• IV insulin therapy if blood sugars greater than target blood sugars or
with ketonuria
• IV saline infusion at 125 cc/hour unless ketonuric, then add 5%
dextrose solution to keep blood sugar in target range
Postpartum management
• Standard 75 g glucose challenge test at 6 week postpartum visit (see
Figure 5.3 and Table 4.1)
Abbreviations: NSTs, non-stress tests; EFW, estimated fetal weight; IV, intravenous.
69
protein, and 40% unsaturated fat [1]. Since about 30–40% of ges-
tational diabetics fail to achieve glucose control with diet alone,
other interventions may be necessary. Dietary counseling has
been shown to improve dietary intake in patients at risk for GDM
[74], and may result in lower neonatal birth-weight (133 g) and
decreased incidence of LGA [75]. While a diet with a low-glyce-
mic index (e.g., decreased consumption of white bread, processed
cereals and potatoes) was felt to decrease the need for insulin in
women with GDM [76], this recommendation was recently chal-
lenged by a larger study which showed no benefit [77]. There are
no differences in neonatal and adverse pregnancy outcomes for
women on a low glycemic index diet versus a high fiber diet [78];
and a low glycemic index diet compared to healthy eating did not
result in differences in birth-weight, fetal percentile, or ponderal
index [79]. The DASH diet has demonstrated improved glucose
tolerance, lipid profile, diastolic blood pressure, serum insulin
level and decreased insulin requirement in small RCTs; however,
large trials are needed to further assess its effectiveness [80–82].
An oil-rich diet (45–50 g sunflower oil daily) versus a low-oil diet
(20 g daily) did not influence pregnancy outcomes [83].
Exercise
Thirty minutes of moderate-intensity aerobic exercise performed
5 times per week is beneficial for women with or at risk for GDM
[1, 84]. In small RCTs of women with GDM, exercise (as defined
by 30 minutes of non-weight-bearing activity at 50% of aerobic
capacity) has been associated with decreased gestational weight
gain in obese gravidas [85], a similar rate of macrosomia com-
pared to insulin [86], improvement in glycemic control when
done in conjunction with diet compared to diet alone [87, 88],
and improvement in cardiovascular fitness [89]. Although exer-
cise later in pregnancy did not decrease the risk of developing
GDM, it did reduce the GDM-related risk of neonatal macroso-
mia [84]. Improvement in maternal triglycerides [90, 91], insulin
sensitivity [90], and post-prandial glucose [91] have been demon-
strated with exercise in pregnancy. Diet or exercise, or both, dur-
ing pregnancy can reduce the risk of excessive gestational weight
gain and decreases maternal hypertension [92]. The combined
interventions have been shown to decrease neonatal respiratory
morbidity. The amount and safety of exercise requires further
research for the creation of safe guidelines [92]. If an exercise pro-
gram is to be prescribed, early counseling regarding frequency
and healthy practices is important to combat declining physical
activity as pregnancy progresses [93–95]. Due to low compliance
with exercise programs [96, 97], the evidence supporting the ben-
eficial effects of exercise in women with GDM with regards to
maternal and neonatal outcome varies [4]. Overall, data seems to
show that exercise is beneficial in this population, though the
frequency and intensity of the regimen must be individualized
and should take into consideration the patient’s comorbidities.
Glucose monitoring
Using a glucometer, four glucose values are recorded daily:
fasting as well as 1-hour or 2-hour postprandial measure-
ments after meals. Although not in widespread use, continuous
glucose monitoring reveals more postprandial hyperglycemia
than just checking 2-hour postprandial values [98, 99]. Target
goals (euglycemia) are fasting glucose values between 60 and
95 mg/dL and postprandial values at 1-hour <120 mg/dL or
2-hour <140 mg/dL (we use fasting and 2-hour values) [1]. No
trial has shown clear superiority of 1-hour compared to 2-hour
postprandial monitoring [1]. If diet and exercise interventions are
70
sufficient, a 1–2 week period of glucose monitoring should dem-
onstrate all glucose values to be within target limits. If, during
the 2-week monitoring period, 1 or 2 measurements are above
limits, pharmacologic therapy should be initiated [100].
Compared to pre-prandial monitoring, postprandial moni-
toring is associated with improvement in glycosylated hemo-
globin, less CD for labor dystocia, smaller birth-weights, and
less neonatal hypoglycemia [101]. Since the risk of macrosomia
appears to be linked with postprandial hyperglycemia, following
these limits appears to be reasonable, and are what trials have
tested [6, 7, 30]. A fasting glucose ≤90 mg/dL in the third tri-
mester may be associated with a lower risk of macrosomia [102].
If all values are within normal limits for extended periods, less
frequent monitoring can be considered: measuring the four
glucose values every other day was non-inferior to daily measure-
ments and increased compliance with glucose measurements
[103]. Electronically reminding patients to transmit their blood
glucose log data to their providers increased maternal reporting
of blood sugars, though it did not influence maternal glucose val-
ues or infant birth-weight [104]. In contrast, use of a smartphone-
based daily feedback system improved patient compliance and
glycemic control in women with GDM, while also decreasing
the number who eventually required treatment with insulin
[105]. There is insufficient evidence to assess the utility of apply-
ing ultrasound parameters in addition to maternal blood glucose
measurements to guide the medical management of GDM [106].
In pregnant women with GDM who also receive antepartum
corticosteroids for fetal indications, hyperglycemia is a common
occurrence. An expert review outlining various patient scenarios
for managing hyperglycemia associated with antepartum corti-
costeroid administration is available [107].
Pharmacologic management
Oral hypoglycemic agents
Oral hypoglycemic agents are overall considered safe in preg-
nancy, but have demonstrated transplacental passage, have
limited long-term neonatal safety data, are less effective than
insulin at achieving euglycemia, especially in obese women
and those with fasting hyperglycemia. These agents are not
FDA-approved for the treatment of GDM; therefore, insulin is
overall superior to oral agents for prevention of GDM-related
complications [108].
Glyburide
Glyburide is a second-generation sulfonylurea. While glyburide
was previously considered as efficacious as insulin [109, 110],
recent evidence suggests that insulin is superior to glyburide
with lower maternal weight gain, lower neonatal birth-
weight, less fetal macrosomia, and less neonatal hypoglyce-
mia [111–117]. Other trials comparing placebo with glyburide
have not shown improvement in perinatal outcomes [118–120].
Approximately 10–20% of women taking glyburide do not achieve
euglycemia, especially those with obesity [121]. If an oral hypo-
glycemic agent is chosen, metformin is preferred to glyburide
[111]. If used, glyburide is started at 2.5 mg orally in the morning,
with a maximum dose of 20 mg daily.
Metformin
Metformin (Glucophage) is a biguanide. It is commonly used
in women with polycystic ovarian syndrome to treat infertility
related to anovulation. The incidences of miscarriage and GDM
Maternal-Fetal Evidence Based Guidelines
are decreased in women who are continued on this medication in
pregnancy [122]; however, this may be misleading as metformin
use may mask the development of GDM. The provider may con-
sider discontinuing metformin 2 days before GDM screening (the
half-life of metformin is 6.2 hours). No metformin-attributable
birth defects or adverse outcomes in this patient population have
been reported [1, 122, 123].
Compared to glyburide, those treated with metformin had less
maternal weight gain, lower neonatal birth-weights, less macroso-
mia, and fewer LGA infants [111, 117]. Glyburide combined with
metformin reduced the need for insulin [124].
Compared to insulin therapy, metformin (± insulin, if neces-
sary) is associated with more preterm birth [117, 125], but less
gestational hypertension [117, 125], maternal [126] and neo-
natal hypoglycemia [111, 117, 125, 127–131]. Though metfor-
min decreases the risk of macrosomia/LGA at birth, by 18–24
months of age metformin-exposed infants weigh 1 pound more
than their insulin-exposed peers [115, 116]. About one-third
of patients fail metformin treatment. Women with GDM
who are obese, have a high fasting glucose, or need phar-
macologic therapy early in pregnancy (e.g., <24 weeks) may
be more suitable for insulin therapy or may require insulin
as an adjunct to metformin therapy [132]. In women whose
total insulin dose is ≥1.12 IU/kg, the addition of metformin
has been shown to improve glycemic control, decrease mater-
nal hypoglycemia, reduce neonatal hypoglycemia, and decrease
NICU admission [133]. Metformin offers no benefit for post-
partum weight loss compared to placebo [134].
In summary, if an oral hypoglycemic agent is chosen, it appears
that metformin should be preferred over glyburide. In addi-
tion, consideration can be given to the addition of metformin
to an insulin regimen as an alternative to increasing the insulin
dose.
Insulin
Useful sample calculations for the total daily insulin require-
ment and insulin regimen are provided in Table 5.5 [135–137]
and Figures 5.1 and 5.2; these are applicable for women who have
hyperglycemia throughout the day. Targeted insulin therapy can
be utilized for those who are consistently hyperglycemic at a spe-
cific time of day, e.g., fasting [1].
As with pregestational DM, insulin glargine/detemir, neutral
protamine Hagedorn (NPH), and insulin lispro can be used for
glucose control. Compared to regular insulin, insulin lispro is
associated with a lower incidence of maternal hypoglycemic epi-
sodes in women with GDM [138]. The choice of insulin aspart
versus insulin lispro does not appear to affect the rate of CD [139].
Although early studies did not demonstrate benefit [140], it has
been clearly established that in women with GDM, compared to
no treatment or diet only, diet and glucose monitoring, with
TABLE 5.5: Total Insulin Requirements
Trimester Units/kg/day
1 0.7–0.8
2 0.8–1.0
3 0.9–1.2
Source: Refs. [135–137].
Note: Patients with multifetal gestations or who have
received steroids or betamimetics often require
higher doses.
Gestational Diabetes
1/3 with
breakfast
1/2 Insulin
Lispro or 1/3 with lunch
Aspart
Total Daily
1/3 with dinner
Insulin Dose
1/2 Insulin Dose in the
Glargine evening
FIGURE 5.1 Distribution of insulin dose throughout the day if
using insulin glargine and lispro/aspart.
insulin if needed, are associated with reduced birth trauma
(bone fracture or nerve palsy) or perinatal death [3, 6], reduced
macrosomia [141] and shoulder dystocia; and similar incidences
of CD, NICU admission, and neonatal hypoglycemia [142]. Mood
and quality of life are improved and the incidence of depres-
sion decreases with the above interventions and the optimiza-
tion of glycemic control [6]. Neonatal outcomes are not affected
by the initiation of treatment (in the form of nutrition counseling,
diet, or insulin) anytime between 24 and 30 weeks [143]. There
does not appear to be a difference between insulin and oral anti-
diabetic pharmacological therapy for various maternal outcomes,
including CD, postnatal weight retention, or the risk of develop-
ing type II diabetes, though there may be increased hypertensive
disorders of pregnancy (though not defined by the study) in those
treated with insulin. Similarly, there is no difference for neonatal
outcomes, including LGA, serious perinatal morbidity or mortal-
ity, neonatal hypoglycemia, neonatal adiposity, or rates of dis-
ability in later childhood, such as mild developmental delay or
hearing or visual impairment [144].
Insulin can be readily titrated to control very high maternal
glucose levels, whereas the dose ceiling for metformin is reached
much sooner. Up to one-half of patients receiving metformin
monotherapy will be forced to augment or transition to insu-
lin due to poor maternal glucose control [145]. The FDA has not
approved metformin or glyburide for the management of GDM
[146, 147]. Metformin crosses the placenta. In contrast, insulin
2/3 NPH insulin
2/3 in AM
1/3 Insulin Lispro
or Aspart
Total Daily
Insulin Dose
1/2 NPH insulin
1/3 in PM
1/2 Insulin Lispro
or Aspart
FIGURE 5.2 Distribution of insulin dose throughout the day if
using NPH and insulin lispro/aspart.
71
does not cross the placenta and its century-long history of use
provides an extensive record of safety data. Therefore, compared
to insulin, long-term prospective follow-up data for neurodevel-
opmental outcomes for metformin and other non-insulin phar-
macologic agents is more limited [148]. Finally, there is a paucity
of non-inferiority trials that compare insulin to metformin.
Nutritional supplementation
Minerals and vitamins have been investigated as a treatment for
GDM. Selenium supplementation improves glucose metabolism,
inflammation, and oxidative stress [149]. Zinc supplementation
improves various parameters associated with glucose metabo-
lism [150]. Calcium with vitamin D may have beneficial effects
on glucose metabolism, lipid profiles [151, 152], and biomarkers
of oxidative stress [151]. Additionally, vitamin D reduces poly-
hydramnios, hyperbilirubinemia, and the need for maternal or
infant hospitalization [153]. Vitamin C supplementation reduces
maternal oxidative stress, while also improving neonatal blood
sugar stability [154].
Other dietary supplements have also been investigated as a
treatment for GDM. Probiotic treatment has not been shown to
change perinatal outcomes [155–157]. Myo-inositol for the treat-
ment of GDM modestly lowers BMI, offers a small reduction in
fasting blood sugar levels, reduces the need to initiate insulin
in order to achieve glycemic control, and reduces birth-weight
[158, 159]. Omega-3 fatty acid supplementation improves glu-
cose metabolism but does not change perinatal outcomes [160,
161]. Cod liver oil improves glucose metabolic indices as well as
inflammation [162].
Given the current number of studies available for each supple-
ment and the overall quality of the evidence, routine intake of
these supplements cannot be recommended outside of an
investigational setting.
Antepartum testing and ultrasound assessment
Antepartum fetal surveillance:
• Euglycemic with diet only (A1GDM): While there is limited
data, fetal surveillance may not be necessary [1].
• Hyperglycemic or medication-assisted (A2GDM): Consider
management similar to pregestational diabetics: fetal sur-
veillance starting at 32 weeks; continued until delivery at
39 weeks (see Chap. 4).
Ultrasound assessment of fetal weight is commonly employed,
but because of the inherent inaccuracy of predicting macrosomia,
it has not been supported by any studies, despite the application
of customized or normalized population growth curves [163].
Delivery
Timing, mode, and lung maturity
Compared to expectant management until 41–42 weeks, induc-
tion of labor (IOL) at 38 weeks in women with insulin-depen-
dent diabetes (of which >90% were gestational) is associated
with reduced incidences of macrosomia [2, 164] but increased
risk of neonatal intensive care unit admission [165]. Data are
insufficient to evaluate the impact on perinatal mortality,
which is a concern in women with diabetes who are delivered
prior to 39 weeks [2]. Two studies (in A1GDM and A2GDM)
support IOL prior to 40 weeks as it reduces the risk of CD
[165, 166] and current evidence suggests delivery prior to EDC
for those with A2GDM.
72 Maternal-Fetal Evidence Based Guidelines

In women requiring medication, management is usually sim-
ilar to that of the pregestational diabetic, and delivery is advo-
cated at 39 0/7–39 6/7 weeks. In general (truly), indicated delivery
before 39 weeks, should not require assessment of fetal maturity.
If assessment of fetal lung maturity is performed, laboratory tests
are interpreted as in non-diabetic patients, with the addition of
phosphatidylglycerol ≥3% accepted by most authorities as the lab
value indicating the least risk for fetal respiratory insufficiency
in diabetic women. Patients should be cautioned that a positive
test does not preclude infant morbidities. While recognizing
that macrosomia remains a difficult antenatal diagnosis to make
both clinically and by ultrasound, cesarean is recommended for
fetuses estimated to be >4500 g (see Chapter 48). Operative deliv-
ery should be avoided in women with a prolonged second stage of
labor and when fetal weight is estimated to be >4000 g [1].
Intrapartum glucose management
Intrapartum glucose management requires frequent assessment
of blood glucose levels during labor (see Figure 4.1). For patients
who have required insulin therapy, hourly assessments of blood
sugars should be performed to maintain levels between 70 and
120 mg/dL. Intravenous insulin may be necessary to maintain the
glucose levels, but is seldom required in these patients. Patients
managed with diet alone may not need as frequent evaluations
during labor and can have assessments every 4 hours. Glucose
measurements every 4 hours compared to hourly measurements
are not associated with improved neonatal glucose concentra-
tions during the first 24 hours of life [167].
Anesthesia
No specific adjustments are necessary, unless the woman is
obese.
Immediate postpartum/Breastfeeding
In the postpartum period, women with GDM do not, in general,
require medication to control their blood sugars. Blood sugars
can be assessed if pregestational diabetes is suspected. Because
these women have an increased risk of developing frank diabetes,
screening with a 75 g glucose challenge or other standard non-
pregnant modality (see Table 4.1) is advocated at 4–12 weeks
postpartum (Figure 5.3) [1] and every 1–3 years, thereafter
[168–172]. Screening rates are improved when reminder letters
are sent directly to patients [173], but not when providers receive
reminders in the electronic health record [174]. Postpartum
screening can be accomplished by either the obstetrician with
referral if values are abnormal, or by referral for the screening to
a medicine specialist. CD and excessive gestational weight gain
(in those with GDM) may be associated with an increase in symp-
toms of depression at 6 weeks postpartum [175].
Breastfeeding, diet, and exercise should be encouraged, par-
ticularly in obese women. Multiple meta-analyses (including
observational studies) showed that breastfeeding decreased
the risk of progression to type II diabetes; the longer the
duration of breastfeeding, the greater the reduction in risk
[176–178]. All forms of contraception are available to diabetics,
provided they have no contraindications, such as hypertension or
vascular disease.
Long-term risks
Approximately 30% of women will develop metabolic syndrome
[179]. Pre-pregnancy obesity and fasting glucose >100 mg/dL are
associated with increased risks of developing metabolic syndrome
[180]. Women whose pregnancies were complicated by GDM
have a 10-fold higher risk of developing diabetes during their life-
time [181]; the risks are approximately 20% at 10 years, 30% at
20 years, 40% at 30 years, 50% at 40 years and 60% at 50 years
[182]. Women who are obese, diagnosed with GDM early in ges-
tation, and have significantly abnormal screening results during
and after pregnancy have the highest chance of adult-onset dia-
betes. For those with normal glucose assessment at 6–12 weeks
postpartum, a Mediterranean lifestyle intervention with nutri-
tion education and monitored physical activity were less likely to
develop glucose disorders within 3 years (42.8% vs. 56.8%) [183].
GDM increases the risk of developing non-alcoholic fatty liver

Gestational diabetes

FPG or 75-g 2 hr OGTT at 6–12 weeks postpartum

Diabetes mellitus Impaired fasting glucose or IGT or both Normal

Assess glycemic status

Refer for diabetes management Consider referral for management
every 3 years
Advocate for healthy diet and exercise that promote weight
Weight loss and physical
loss
activity counseling as
Consider metformin if combined impaired fasting glucose needed
and IGT

Yearly assessment of glycemic status

FIGURE 5.3 Postpartum screening of patients who had GDM. (Adapted from Ref. [1].) Abbreviations: FPG, fasting plasma glucose;
OGTT, oral glucose tolerance test; IGT, impaired glucose tolerance.
Gestational Diabetes
disease by 2.5–3-fold [184] and of cardiovascular events by 2-fold
[185] as compared to those who did not have GDM.
Some suggest that women with an abnormal GCT result are
also at increased risk of metabolic derangements later in life,
despite a normal GTT [186]. Counseling regarding diet and exer-
cise, maintenance of normal BMI, and surveillance with periodic
screening are indicated.
References
1. American College of Obstetricians and Gynecologists. Gestational diabetes
mellitus. Practice Bulletin No. 190. Obstet Gynecol 2018;131(2):e49–e64.
[Review, Guideline, III]
2. Boulvain M, Stan C, Irion O. Elective delivery in diabetic pregnant women.
Cochrane Database Syst Rev 2001;2(2):1–18.CD001997. [Meta-analysis, 1
RCT, n = 200]
3. Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane
Database Syst Rev 2009;(3):1–47.CD003395 [Meta-analysis, 8 RCTs, n =
1418]
4. Ceysens G, Rouiller D, Boulvain M. Exercise for diabetic pregnant women.
Cochrane Database Syst Rev 2006;3:CD004225. [Meta-analysis, 4 RCTs, n
= 114]
5. American Diabetes Association. Diagnosis and classification of diabetes
mellitus. Diabetes Care 2011;34(Supp 1):S62–69. [Review, Guideline, III]
6. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS, et al.
Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.
N Engl J Med 2005;352(24):2477–2486. [RCT, n = 1000]
7. Bancroft K, Tuffnell DJ, Mason GC, Rogerson LJ, Mansfield M. A ran-
domised controlled pilot study of the management of gestational impaired
glucose tolerance. Br J Obstet Gynaecol 2000;107(8):959–963. [RCT, n = 68]
8. Tieu J, McPhee AJ, Crowther CA, Middleton P, Shepherd E. Screening for
gestational diabetes mellitus based on different risk profiles and settings
for improving maternal and infant health. Cochrane Database Syst Rev
2017;8(8):CD007222. [Meta-analysis, 2 RCTs, n = 4523]
9. Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden
DR, et al. Summary and recommendations of the Fifth International
Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care
2007;30(Suppl 2):S251–260. [Review, Guideline, III]
10. Summaries for patients. Screening for gestational diabetes mellitus: U.S.
Preventive Services Task Force recommendation statement. Ann Intern
Med 2014;160(6):414–420. [Review, Guideline, III]
11. Torloni MR, Betran AP, Horta BL, Nakamura MU, Atallah AN, Moron AF,
et al. Prepregnancy BMI and the risk of gestational diabetes: a systematic
review of the literature with meta-analysis. Obes Rev 2009;10(2):194–203.
[Meta-analysis of 59 cohorts and 11 case–controls with 671,945 women]
12. Farrar D, Duley L, Dowswell T, Lawlor DA. Different strategies for diagnos-
ing gestational diabetes to improve maternal and infant health. Cochrane
Database Syst Rev 2017;8(8):CD007122. [Meta-analysis, 7 RCTs, n = 1420]
13. Tieu J, McPhee AJ, Crowther CA, Middleton P. Screening and subsequent
management for gestational diabetes for improving maternal and infant
health. Cochrane Database Syst Rev 2014;(2):CD007222. [Meta-analysis of
3 RCTs and 1 quasi-RCT, n = 3972]
14. Meltzer SJ, Snyder J, Penrod JR, Nudi M, Morin L. Gestational diabetes
mellitus screening and diagnosis: a prospective randomised controlled
trial comparing costs of one-step and two-step methods. BJOG 2010;117(4):
407–415. [RCT, n = 1500]
15. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR,
Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy
outcomes. N Engl J Med 2008;358(19):1991–2002. [Prospective, n = 25,505,
II-2]
16. Hosseini E, Janghorbani M. Systematic review and meta-analysis of diag-
nosing gestational diabetes mellitus with one-step or two-step approaches
and associations with adverse pregnancy outcomes. Int J Gynaecol Obstet
2018;143(2):137–144. [Meta-analysis, 9 RCTs, n = 41,663]
17. Saccone G, Khalifeh A, Al-Kouatly HB, Sendek K, Berghella V. Screening
for gestational diabetes mellitus: one step versus two step approach.
A meta-analysis of randomized trials. J Matern Fetal Neonatal Med
2020;33(9):1616–1624. [Meta-analysis, 4 RCTs, n = 2582]
18. Coustan DR, Lowe LP, Metzger BE, Dyer AR, International Association of
Diabetes and Pregnancy Study Groups. The Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) study: paving the way for new diagnostic cri-
teria for gestational diabetes mellitus. Am J Obstet Gynecol 2010;202(6):
654.e1–654.e6. [Review, III]
73
19. Brody SC, Harris R, Lohr K. Screening for gestational diabetes: a summary
of the evidence for the U.S. preventative services task force. Obstet Gynecol
2003;101:380–392. [Review, III]
20. Yeral MI, Ozgu-Erdinc AS, Uygur D, Seckin KD, Karsli MF, Danisman AN.
Prediction of gestational diabetes mellitus in the first trimester, compari-
son of fasting plasma glucose, two-step and one-step methods: a prospec-
tive randomized controlled trial. Endocrine 2014;46(3):512–518. [RCT, n =
486]
21. Coustan DR, Widness JA, Carpenter MW, Rotondo L, Pratt DC, Oh W.
Should the 50-gram, one hour plasma glucose screening test for gestational
diabetes be administered in the fasting or fed state? Am J Obstet Gynecol
1986;154(1031–1035) [n = 72, II-2]
22. Murphy NJ, Meyer BA, O’Kell RT, Hogard ME. Carbohydrate sources
for gestational diabetes mellitus screening. A comparison. J Reprod Med
1994;39(12):977–981. [RCT, n = 108]
23. Lamar ME, Kuehl TJ, Cooney AT, Gayle LJ, Holleman S, Allen SR. Jelly
beans as an alternative to a fifty gram glucose beverage for gestational dia-
betes screening. Am J Obstet Gynecol 1999;181:1154–1157. [RCT, n = 160]
24. Racusin DA, Antony K, Showalter L, Sharma S, Haymond M, Aagaard KM.
Candy twists as an alternative to the glucola beverage in gestational dia-
betes mellitus screening. Am J Obstet Gynecol 2015;212(4):522.e1–522.e5.
[Prospective cohort, n = 20, II-2]
25. Gabbe SG, Graves CR. Management of diabetes mellitus complicating preg-
nancy. Obstet Gynecol 2003;102(4):857–868. [Review, III]
26. Carpenter MW, Coustan DR. Criteria for screening tests for gestational dia-
betes. Am J Obstet Gynecol 1982;144(7):768–773. [Prospective cohort, n =
381, II-2]
27. Harper LM, Mele L, Landon MB, Carpenter MW, Ramin SM, Reddy
UM, et al. Carpenter-Coustan Compared With National Diabetes Data
Group Criteria for Diagnosing Gestational Diabetes. Obstet Gynecol
2016;127(5):893–898. [Secondary analysis of RCT, n = 958]
28. Magee MS, Walden CE, Benedetti TJ, Knopp RH. Influence of diagnostic
criteria on the incidence of gestational diabetes and perinatal morbidity.
JAMA 1993;269(5):609–615. [Observational study, n = 2015, II-2]
29. Sevket O, Ates S, Uysal O, Molla T, Dansuk R, Kelekci S. To evaluate the
prevalence and clinical outcomes using a one-step method versus a two-step
method to screen gestational diabetes mellitus. J Matern 2014;27(1):36–41.
[RCT, n = 786]
30. Langer O, Anyaegbunan A, Brustman L, Divon M. Management of women
with one abnormal oral glucose tolerance test value reduces adverse out-
come in pregnancy. Am J Obstet Gynecol 1989;161:593–599. [RCT, n = 272]
31. Deveer R, Deveer M, Akbaba E, Engin-Ustun Y, Aydogan P, Celikkaya
H, et al. The effect of diet on pregnancy outcomes among pregnant with
abnormal glucose challenge test. Eur Rev Med 2013;17(9):1258–1261. [RCT,
n = 100]
32. Kokanali MK, Tokmak A, Kaymak O, Cavkaytar S, Bilge U. The effect of
treatment on pregnancy outcomes in women with one elevated oral glucose
tolerance test value. Ginekol Pol 2014;85(10):748–753. [RCT, n = 411]
33. Grant SM, Wolever TM, O’Connor DL, Nisenbaum R, Josse RG. Effect of
a low glycaemic index diet on blood glucose in women with gestational
hyperglycaemia. Diabetes Res Clin Pract 2010;91(1):15–22. [RCT, n = 38]
34. Berggren EK, Mele L, Landon MB, Spong CY, Ramin SM, Casey B, et al.
Perinatal outcomes in Hispanic and non-Hispanic white women with mild
gestational diabetes. Obstet Gynecol 2012;120(5):1099–1104. [Secondary
analysis, RCT, n = 1535]
35. Meyer WJ, Carbone J, Gauthier DW, Gottmann DA. Early gestational glu-
cose screening and gestational diabetes. J Reprod Med 1996;41:675–679.
[Retrospective cohort, n = 329, II-2]
36. Mackeen AD, Loehr FW, Nordberg C, Bringman JJ. 490: Consider perform-
ing 3-hour GTT when rescreening for GDM in pregnancy. Am J Obstet
Gynecol 2019;220(1):S329. [Retrospective cohort, n = 490, II-2]
37. Deputy NP, Kim SY, Conrey EJ, Bullard KM. Prevalence and Changes in
Preexisting Diabetes and Gestational Diabetes Among Women Who Had
a Live Birth - United States, 2012-2016. MMWR Morb Mortal Wkly Rep
2018;67(43):1201–1207. [Review, III]
38. American Diabetes Association. Gestational diabetes mellitus. Diabetes
Care 2004;(Suppl 1):S88–S90. [Review, III]
39. Maitland RA, Seed PT, Briley AL, Homsy M, Thomas S, Pasupathy D, et al.
Prediction of gestational diabetes in obese pregnant women from the UK
Pregnancies Better Eating and Activity (UPBEAT) pilot trial. Diabet Med
2014;31(8):963–970. [RCT, n = 106]
40. Iliodromiti S, Sassarini J, Kelsey TW, Lindsay RS, Sattar N, Nelson SM.
Accuracy of circulating adiponectin for predicting gestational diabetes:
a systematic review and meta-analysis. Diabetologia 2016;59(4):692–699.
[Meta-analysis, 11 RCTs, n = 2865]
74
41. Bo S, Gambino R, Menato G, Canil S, Ponzo V, Pinach S, et al. Isoleucine-to-
methionine substitution at residue 148 variant of PNPLA3 gene and meta-
bolic outcomes in gestational diabetes. Am J Clin Nutr 2015;101(2):310–318.
[RCT, n = 200]
42. Wojcik M, Zieleniak A, Mac-Marcjanek K, Wozniak LA, Cypryk K. The
elevated gene expression level of the A(2B) adenosine receptor is associated
with hyperglycemia in women with gestational diabetes mellitus. Diabetes/
Metab Res Rev 2014;30(1):42–53. [Prospective, n = 117, II-2]
43. Li Y, Ren X, He L, Li J, Zhang S, Chen W. Maternal age and the risk of ges-
tational diabetes mellitus: a systematic review and meta-analysis of over
120 million participants. Diabetes Res Clin Pract 2020;162:108044. [Meta-
analysis, 24 observational studies, n = 127,275,067, II-2]
44. Yao D, Chang Q, Wu QJ, Gao SY, Zhao H, Liu YS, et al. Relationship
between maternal central obesity and the risk of gestational diabetes melli-
tus: a systematic review and meta-analysis of cohort studies. J Diabetes Res
2020;2020:6303820 [Meta-analysis, 11 observational studies, n = 27,675,
II-2]
45. Brunner S, Stecher L, Ziebarth S, Nehring I, Rifas-Shiman SL, Sommer
C, et al. Excessive gestational weight gain prior to glucose screening and
the risk of gestational diabetes: a meta-analysis. Diabetologia 2015;58(10):
2229–2237. [Meta-analysis, 1 secondary analysis and 7 observational stud-
ies, n = 13,748, II-2]
46. Bosdou JK, Anagnostis P, Goulis DG, Lainas GT, Tarlatzis BC, Grimbizis
GF, et al. Risk of gestational diabetes mellitus in women achieving single-
ton pregnancy spontaneously or after ART: a systematic review and meta-­
analysis. Hum Reprod Update 2020;26(4):514–544. [Meta-analysis, 38
observational studies, n = 1,934,494, II-2]
47. Giannakou K, Evangelou E, Yiallouros P, Christophi CA, Middleton
N, Papatheodorou E, et al. Risk factors for gestational diabetes: an
umbrella review of meta-analyses of observational studies. PLOS ONE
2019;14(4):e0215372. [Meta-analysis of meta-analyses, 30 meta-analyses of
observational studies, n = sum total not provided in source, II-2]
48. Zhang Y, Gong Y, Xue H, Xiong J, Cheng G. Vitamin D and gestational dia-
betes mellitus: a systematic review based on data free of Hawthorne effect.
BJOG 2018;125(7):784–793. [Meta-analysis, 25 RCTs and 87 observational
studies, n = 58,304, II-2]
49. Pergialiotis V, Bellos I, Hatziagelaki E, Antsaklis A, Loutradis D, Daskalakis
G. Progestogens for the prevention of preterm birth and risk of develop-
ing gestational diabetes mellitus: a meta-analysis. Am J Obstet Gynecol
2019;221(5):429–436.e5. [Meta-analysis, 4 RCT and 7 observational
cohorts, n = 512, II-2]
50. Balsells M, Garcia-Patterson A, Gich I, Corcoy R. Major congenital mal-
formations in women with gestational diabetes mellitus: a systematic
review and meta-analysis. Diabetes/Metab Res Rev 2012;28(3):252–257.
[Meta-analysis, 17 RCTs, n>500,000]
51. Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, et al.
A multicenter, randomized trial of treatment for mild gestational diabetes.
N Engl J Med 2009;361(14):1339–1348. [RCT, n = 958]
52. Lamminpää R, Vehviläinen-Julkunen K, Gissler M, Selander T, Heinonen
S. Pregnancy outcomes in women aged 35 years or older with gestational
diabetes – a registry-based study in Finland. J Matern Fetal Neonatal Med
2016;29(1):55–59. [Observational study, n = 283,324, II-2]
53. Bahado-Singh RO, Mele L, Landon MB, Ramin SM, Carpenter MW, Casey
B, et al. Fetal male gender and the benefits of treatment of mild gesta-
tional diabetes mellitus. Am J Obstet Gynecol 2012;206(5):422.e1–422.e5.
[Secondary analysis, RCT, n = 932]
54. Durnwald CP, Mele L, Spong CY, Ramin SM, Varner MW, Rouse DJ, et al.
Glycemic characteristics and neonatal outcomes of women treated for mild
gestational diabetes. Obstet Gynecol 2011;117(4):819–827. [Secondary
analysis, RCT, n = 460]
55. Maftei O, Whitrow MJ, Davies MJ, Giles LC, Owens JA, Moore VM.
Maternal body size prior to pregnancy, gestational diabetes and weight
gain: associations with insulin resistance in children at 9-10 years. Diabet
Med 2015;32(2):174–180. [Prospective cohort, n = 443, II-2]
56. Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, Lauenborg
J, et al. Overweight and the metabolic syndrome in adult offspring of
women with diet-treated gestational diabetes mellitus or type 1 diabetes.
J Clin Endocrinol Metab 2009;94(7):2464–2470. [Retrospective cohort,
n = 309, II-2]
57. Tieu J, Crowther CA, Middleton P. Dietary advice in pregnancy for pre-
venting gestational diabetes mellitus. Cochrane Database Syst Rev
2008;(2):CD006674. [Meta-analysis, 2 RCTs, n = 82]
58. Kibret KT, Chojenta C, Gresham E, Tegegne TK, Loxton D. Maternal
dietary patterns and risk of adverse pregnancy (hypertensive disorders of
pregnancy and gestational diabetes mellitus) and birth (preterm birth and
Maternal-Fetal Evidence Based Guidelines
low birth weight) outcomes: a systematic review and meta-analysis. Public
Health Nutr 2018:1–15. [Meta-analysis, 21 observational studies, n = (total
subject sample size not reported), II-2]
59. Griffith RJ, Alsweiler J, Moore AE, Brown S, Middleton P, Shepherd E,
et al. Interventions to prevent women from developing gestational diabetes
mellitus: an overview of Cochrane reviews. Cochrane Database Syst Rev
2020;6(6):CD012394. [Meta-analysis; combined diet and exercise interven-
tion: 19 RCTs, n = 6633; myo-inositol: 3 RCTs, n = 502; vitamin D: 2 RCTs,
n = 446; probiotics: 2 RCTs, n = 225]
60. Sanabria-Martinez G, Garcia-Hermoso A, Poyatos-Leon R, Alvarez-Bueno
C, Sanchez-Lopez M, Martinez-Vizcaino V. Effectiveness of physical activ-
ity interventions on preventing gestational diabetes mellitus and exces-
sive maternal weight gain: a meta-analysis. BJOG 2015;122(9):1167–1174.
[Meta-analysis, 13 RCTs, n = 2873]
61. Russo LM, Nobles C, Ertel KA, Chasan-Taber L, Whitcomb BW. Physical
activity interventions in pregnancy and risk of gestational diabetes mel-
litus: a systematic review and meta-analysis. Obstet Gynecol 2015;125(3):
576–582. [Meta-analysis; 10 RCTs, n = 3401]
62. Ming WK, Ding W, Zhang CJP, Zhong L, Long Y, Li Z, et al. The effect of
exercise during pregnancy on gestational diabetes mellitus in normal-
weight women: a systematic review and meta-analysis. BMC Pregnancy
Childbirth 2018;18(1):440-018-2068-7. [Meta-analysis, 8 RCTs, n = 3256]
63. Bain E, Crane M, Tieu J, Han S, Crowther CA, Middleton P. Diet and exer-
cise interventions for preventing gestational diabetes mellitus. Cochrane
Database Syst Rev 2015;(4):CD010443. doi(4):CD010443. [Meta-analysis, 11
RCTs, n = 3744]
64. Guo XY, Shu J, Fu XH, Chen XP, Zhang L, Ji MX, et al. Improving the
effectiveness of lifestyle interventions for gestational diabetes prevention:
a meta-analysis and meta-regression. BJOG 2019;126(3):311–320. [Meta-
analysis, 47 RCTs, n = 15,745]
65. Corrado F, D’Anna R, Di Vieste G, Giordano D, Pintaudi B, Santamaria A,
et al. The effect of myoinositol supplementation on insulin resistance in
patients with gestational diabetes. Diabetic Med 2011;28(8):972–975. [RCT,
n = 69]
66. Vitagliano A, Saccone G, Cosmi E, Visentin S, Dessole F, Ambrosini G,
et al. Inositol for the prevention of gestational diabetes: a systematic review
and meta-analysis of randomized controlled trials. Arch Gynecol Obstet
2019;299(1):55–68. [Meta-analysis, 5 RCTs, n = 965]
67. Celentano C, Matarrelli B, Pavone G, Vitacolonna E, Mattei PA, Berghella
V, et al. The influence of different inositol stereoisomers supplementation in
pregnancy on maternal gestational diabetes mellitus and fetal outcomes in
high-risk patients: a randomized controlled trial. J Matern Fetal Neonatal
Med 2020;33(5):743–751. [RCT, n = 180]
68. Santamaria A, Alibrandi A, Di Benedetto A, Pintaudi B, Corrado F,
Facchinetti F, et al. Clinical and metabolic outcomes in pregnant women
at risk for gestational diabetes mellitus supplemented with myo-inositol:
a secondary analysis from 3 RCTs. Am J Obstet Gynecol 2018;219(3):300.
e1–300.e6. [Meta-analysis, secondary analysis of 3 RCTs, n = 595]
69. Corcoy R, Mendoza LC, Simmons D, Desoye G, Adelantado JM, Chico A,
et al. The DALI vitamin D randomized controlled trial for gestational dia-
betes mellitus prevention: no major benefit shown besides vitamin D suf-
ficiency. Clin Nutr 2020;39(3):976–984. [RCT, n = 220]
70. Wickens KL, Barthow CA, Murphy R, Abels PR, Maude RM, Stone PR, et al.
Early pregnancy probiotic supplementation with Lactobacillus rhamnosus
HN001 may reduce the prevalence of gestational diabetes mellitus: a ran-
domised controlled trial. Br J Nutr 2017;117(6):804–813. [RCT, n = 390]
71. Yap C, Cheung NW, Gunton JE, Athayde N, Munns CF, Duke A, et al.
Vitamin D supplementation and the effects on glucose metabolism during
pregnancy: a randomized controlled trial. Diabetes Care 2014;37(7):1837–
1844. [RCT, n = 158]
72. Horvath K, Koch K, Jeitler K, Matyas E, Bender R, Bastian H, et al. Effects of
treatment in women with gestational diabetes mellitus: systematic review
and meta-analysis. BMJ 2010;340:c1395. [Meta-analysis, 5 RCTs, n = 2999]
73. Landon MB, Gabbe SG. Gestational diabetes mellitus. Obstet Gynecol
2011;118(6):1379–1393. [Review, III]
74. Kinnunen TI, Puhkala J, Raitanen J, Ahonen S, Aittasalo M, Virtanen
SM, et al. Effects of dietary counselling on food habits and dietary intake
of Finnish pregnant women at increased risk for gestational diabetes - a
secondary analysis of a cluster-randomized controlled trial. Matern Child
Nutr 2014;10(2):184–197. [Secondary analysis, RCT, n = 399]
75. Luoto R, Kinnunen TI, Aittasalo M, Kolu P, Raitanen J, Ojala K, et al.
Primary prevention of gestational diabetes mellitus and large-for-gesta-
tional-age newborns by lifestyle counseling: a cluster-randomized con-
trolled trial. PLOS Medicine/Public Library of Science 2011;8(5):e1001036.
[RCT, n = 399]
Gestational Diabetes
76. Moses RG, Barker M, Winter M, Petocz P, Brand-Miller JC. Can a low-­
glycemic index diet reduce the need for insulin in gestational diabetes mel-
litus? A randomized trial. Diabetes Care 2009;32(6):996–1000. [RCT, n = 63]
77. Moreno-Castilla C, Hernandez M, Bergua M, Alvarez MC, Arce MA,
Rodriguez K, et al. Low-carbohydrate diet for the treatment of gesta-
tional diabetes mellitus: a randomized controlled trial. Diabetes Care
2013;36(8):2233–2238. [RCT, n = 152]
78. Louie JC, Markovic TP, Perera N, Foote D, Petocz P, Ross GP, et al. A ran-
domized controlled trial investigating the effects of a low-glycemic index
diet on pregnancy outcomes in gestational diabetes mellitus. Diabetes Care
2011;34(11):2341–2346. [RCT, n = 99]
79. Moses RG, Casey SA, Quinn EG, Cleary JM, Tapsell LC, Milosavljevic M,
et al. Pregnancy and Glycemic Index Outcomes study: effects of low gly-
cemic index compared with conventional dietary advice on selected preg-
nancy outcomes. Am J Clin Nutr 2014;99(3):517–523. [RCT, n = 576]
80. Asemi Z, Tabassi Z, Samimi M, Fahiminejad T, Esmaillzadeh A. Favourable
effects of the Dietary Approaches to Stop Hypertension diet on glucose tol-
erance and lipid profiles in gestational diabetes: a randomised clinical trial.
Br J Nutr 2013;109(11):2024–2030. [RCT, n = 34]
81. Asemi Z, Samimi M, Tabassi Z, Esmaillzadeh A. The effect of DASH diet
on pregnancy outcomes in gestational diabetes: a randomized controlled
clinical trial. Eur J Clin Nutr 2014;68(4):490–495. [RCT, n = 52]
82. Asemi Z, Samimi M, Tabassi Z, Naghibi Rad M, Rahimi Foroushani A,
Khorammian H, et al. Effect of daily consumption of probiotic yoghurt on
insulin resistance in pregnant women: a randomized controlled trial. Eur J
Clin Nutr 2013;67(1):71–74. [RCT, n = 70]
83. Wang H, Jiang H, Yang L, Zhang M. Impacts of dietary fat changes on preg-
nant women with gestational diabetes mellitus: a randomized controlled
study. Asia Pac J Clin Nutr 2015;24(1):58–64. [RCT, n = 84]
84. Barakat R, Pelaez M, Lopez C, Lucia A, Ruiz JR. Exercise during pregnancy
and gestational diabetes-related adverse effects: a randomised controlled
trial. Br J Sports Med 2013;47(10):630–636. [RCT, n = 420]
85. Vinter CA, Jorgensen JS, Ovesen P, Beck-Nielsen H, Skytthe A, Jensen DM.
Metabolic effects of lifestyle intervention in obese pregnant women. Results
from the randomized controlled trial ‘Lifestyle in Pregnancy’ (LiP). Diabet
Med 2014;31(11):1323–1330. [RCT, n = 304]
86. Bung P, Bung C, Artal R, Khodiguian N, Fallenstein F, Spatling L.
Therapeutic exercise for insulin-requiring gestational diabetics: effects on
fetus – results of a randomized prospective longitudinal study. J Perinat
Med 1993;21:125–137. [RCT, n = 41]
87. Jovanovic-Peterson L, Durak EP, Peterson CM. Randomized trial of diet
versus diet plus cardiovascular conditioning on glucose levels in ges-
tational diabetes mellitus. Am J Obstet Gynecol 1989;161(2):415–419.
[RCT, n = 33]
88. Ruchat SM, Davenport MH, Giroux I, Hillier M, Batada A, Sopper MM,
et al. Effect of exercise intensity and duration on capillary glucose
responses in pregnant women at low and high risk for gestational diabetes.
DiabetesMetab Res Rev 2012;28(8):669–678. [RCT, n = 46]
89. Avery MD, Leon AS, Kopher RA. Effects of a partially home-based exer-
cise program for women with gestational diabetes. Obstet Gynecol 1997;89:
10–15. [RCT, n = 33]
90. van Poppel MN, Oostdam N, Eekhoff ME, Wouters MG, van Mechelen W,
Catalano PM. Longitudinal relationship of physical activity with insulin
sensitivity in overweight and obese pregnant women. J Clin Endocrinol
Metab 2013;98(7):2929–2935. [Prospective, Longitudinal, n = 24]
91. Bo S, Rosato R, Ciccone G, Canil S, Gambino R, Poala CB, et al. Simple
lifestyle recommendations and the outcomes of gestational diabetes. A 2 ×
2 factorial randomized trial. Diabetes Obes Metab 2014;16(10):1032–1035.
[RCT, n = 400]
92. Muktabhant B, Lawrie TA, Lumbiganon P, Laopaiboon M. Diet or exer-
cise, or both, for preventing excessive weight gain in pregnancy. Cochrane
Database of Syst Rev 2015(6. [Meta-analysis, 49 RCTs, n = 11,444]).
93. Korpi-Hyovalti E, Heinonen S, Schwab U, Laaksonen DE, Niskanen L. Effect
of intensive counselling on physical activity in pregnant women at high risk
for gestational diabetes mellitus. A clinical study in primary care. Prim
Care Diabetes 2012;6(4):261–268. [RCT, n = 54]
94. Harrison CL, Lombard CB, Strauss BJ, Teede HJ. Optimizing healthy ges-
tational weight gain in women at high risk of gestational diabetes: a ran-
domized controlled trial. Obesity (Silver Spring) 2013;21(5):904–909. [RCT,
n = 203]
95. Aittasalo M, Raitanen J, Kinnunen TI, Ojala K, Kolu P, Luoto R. Is intensive
counseling in maternity care feasible and effective in promoting physical
activity among women at risk for gestational diabetes? Secondary analysis
of a cluster randomized NELLI study in Finland. Int J Behav Nutr Phys Act
2012;9:104. [Secondary analysis, RCT, n = 399]
75
96. Oostdam N, van Poppel MN, Wouters MG, Eekhoff EM, Bekedam DJ,
Kuchenbecker WK, et al. No effect of the FitFor2 exercise programme on
blood glucose, insulin sensitivity, and birthweight in pregnant women who
were overweight and at risk for gestational diabetes: results of a randomised
controlled trial. BJOG 2012;119(9):1098–1107. [RCT, n = 121]
97. Stafne SN, Salvesen KA, Romundstad PR, Eggebo TM, Carlsen SM,
Morkved S. Regular exercise during pregnancy to prevent gestational dia-
betes: a randomized controlled trial. Obstet Gynecol 2012;119(1):29–36.
[RCT, n = 702]
98. Kestila KK, Ekblad UU, Ronnemaa T. Continuous glucose monitoring ver-
sus self-monitoring of blood glucose in the treatment of gestational diabetes
mellitus. Diabetes Res Clin Pract 2007;77(2):174–179. [RCT, n = 71]
99. McLachlan K, Jenkins A, O’Neal D. The role of continuous glucose monitor-
ing in clinical decision-making in diabetes in pregnancy. Aust N Z J Obstet
Gynaecol 2007;47(3):186–190. [Descriptive study, n = 68]
100. Caissutti C, Saccone G, Khalifeh A, Mackeen AD, Lott M, Berghella V.
Which criteria should be used for starting pharmacologic therapy for man-
agement of gestational diabetes in pregnancy? Evidence from randomized
controlled trials. J Matern Fetal Neonatal Med 2019;32(17):2905–2914.
[Meta-analysis, 15 RCTs, n = 4307]
101. de Veciana M, Major CA, Morgan MA, Asrat T, Tooney JS, Lien JM,
Evans AT. Postprandial versus preprandial blood glucose monitoring in
women with gestational diabetes mellitus requiring insulin therapy. NEJM
1195;333:1237–1241. [RCT, n = 66]
102. Prutsky GJ, Domecq JP, Wang Z, Carranza Leon BG, Elraiyah T, Nabhan M,
et al. Glucose targets in pregnant women with diabetes: a systematic review
and meta-analysis. J Clin Endocrinol Metab 2013;98(11):4319–4324. [Meta-
analysis, 34 RCTs, n = 9433]
103. Mendez-Figueroa H, Schuster M, Maggio L, Pedroza C, Chauhan SP, Paglia
MJ. Gestational diabetes mellitus and frequency of blood glucose monitor-
ing: a randomized controlled trial. Obstet Gynecol 2017;130(1):163–170.
[RCT, n = 293]
104. Homko CJ, Deeb LC, Rohrbacher K, Mulla W, Mastrogiannis D, Gaughan
J, et al. Impact of a telemedicine system with automated reminders on out-
comes in women with gestational diabetes mellitus. Diabetes Technol Ther
2012;14(7):624–629. [RCT, n = 80]
105. Miremberg H, Ben-Ari T, Betzer T, Raphaeli H, Gasnier R, Barda G, et al.
The impact of a daily smartphone-based feedback system among women
with gestational diabetes on compliance, glycemic control, satisfaction, and
pregnancy outcome: a randomized controlled trial. Am J Obstet Gynecol
2018;218(4):453.e1–453.e7. [RCT, n = 120]
106. Rao U, de Vries B, Ross GP, Gordon A. Fetal biometry for guiding the
medical management of women with gestational diabetes mellitus for
improving maternal and perinatal health. Cochrane Database Syst Rev
2019;9(9):CD012544. [Meta-analysis, 3 RCTs, n = 524]
107. Dashora U, Murphy HR, Temple RC, Stanley KP, Castro E, George S,
et al. Managing hyperglycaemia during antenatal steroid administration,
labour and birth in pregnant women with diabetes. Diabet Med 2018;35(8):
1005–1010. [Review, Guideline, III]
108. Hebert MF, Ma X, Naraharisetti SB, Krudys KM, Umans JG, Hankins GD,
et al. Are we optimizing gestational diabetes treatment with glyburide?
The pharmacologic basis for better clinical practice. Clin Pharmacol Ther
2009;85(6):607–614. [n = 106, II-2]
109. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A compari-
son of glyburide and insulin in women with gestational diabetes mellitus.
N Engl J Med 2000;343(16):1134–1138. [RCT, n = 404]
110. Tempe A, Mayanglambam RD. Glyburide as treatment option for gesta-
tional diabetes mellitus. J Obstet Gynaecol Res 2013;39(6):1147–1152. [RCT,
n = 64]
111. Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I, Corcoy R.
Glibenclamide, metformin, and insulin for the treatment of gestational dia-
betes: a systematic review and meta-analysis. BMJ 2015;350:h102. [Meta-
analysis, 15 RCTs, n = 2509]
112. Zeng YC, Li MJ, Chen Y, Jiang L, Wang SM, Mo XL, et al. The use of
glyburide in the management of gestational diabetes mellitus: a meta-
analysis. Adv Med Sci 2014;59(1):95–101. [Meta-analysis, 5 RCTs,
n = 674]
113. Song R, Chen L, Chen Y, Si X, Liu Y, Liu Y, et al. Comparison of glyburide
and insulin in the management of gestational diabetes: a meta-analysis.
PLOS ONE 2017;12(8):e0182488. [Meta-analysis, 10 RCTs, n = 1194]
114. Helal KF, Badr MS, Rafeek ME, Elnagar WM, Lashin ME. Can glyburide be
advocated over subcutaneous insulin for perinatal outcomes of women with
gestational diabetes? A systematic review and meta-analysis. Arch Gynecol
Obstet 2020;301(1):19–32. [Meta-analysis, 11 RCTs and 13 observational
cohort studies, n = 24,517]
76
115. Tarry-Adkins JL, Aiken CE, Ozanne SE. Comparative impact of pharma-
cological treatments for gestational diabetes on neonatal anthropom-
etry independent of maternal glycaemic control: a systematic review and
meta-analysis. PLOS Med 2020;17(5):e1003126. [Meta-analysis, 33 RCTs,
n = 4944]
116. Jiang YF, Chen XY, Ding T, Wang XF, Zhu ZN, Su SW. Comparative efficacy
and safety of OADs in management of GDM: network meta-analysis of ran-
domized controlled trials. J Clin Endocrinol Metab 2015;100(5):2071–2080.
[Meta-analysis, 18 RCTs, n = 2800]
117. Guo L, Ma J, Tang J, Hu D, Zhang W, Zhao X. Comparative efficacy and
safety of metformin, glyburide, and insulin in treating gestational dia-
betes mellitus: a meta-analysis. J Diabetes Res 2019;2019:9804708.
[Meta-analysis, 41 RCTs, n = 7703]
118. Lain KY, Garabedian MJ, Daftary A, Jeyabalan A. Neonatal adiposity fol-
lowing maternal treatment of gestational diabetes with glyburide compared
with insulin. Am J Obstet Gyn 2009;200:501.e1–501.e6. [RCT, n = 83]
119. Casey BM, Duryea EL, Abbassi-Ghanavati M, Tudela CM, Shivvers SA,
McIntire DD, et al. Glyburide in women with mild gestational diabetes: a
randomized controlled trial. Obstet Gynecol 2015;126(2):303–309. [RCT,
n = 375]
120. Brown J, Martis R, Hughes B, Rowan J, Crowther CA. Oral anti-diabetic
pharmacological therapies for the treatment of women with gestational dia-
betes. Cochrane Database Syst Rev 2017;1(1):CD011967. [Meta-analysis, 11
RCTs, n = 1487]
121. Langer O, Yogev Y, Xenakis EMJ, Brustman L. Overweight and obese in ges-
tational diabetes: the impact on pregnancy outcomes. Am J Obstet Gynecol
2005;192:1768–76. [Prospective cohort, II-2]
122. De Leo V, Musacchio MC. The administration of metformin during preg-
nancy reduces polycystic ovary syndrome related gestational complica-
tions. Eur J Obstet Gynecol Reprod Biol 2011;157:63–66. [Prospective
cohort, n = 208]
123. Wouldes TA, Battin M, Coat S, Rush EC, Hague WM, Rowan JA.
Neurodevelopmental outcome at 2 years in offspring of women randomised
to metformin or insulin treatment for gestational diabetes. Arch Dis Child
Fetal Neonatal Ed 2016;101(6):F488–F493. [Prospective cohort, n = 211,
II-2]
124. Nachum Z, Zafran N, Salim R, Hissin N, Hasanein J, Gam Ze Letova Y,
et al. Glyburide versus metformin and their combination for the treatment
of gestational diabetes mellitus: a randomized controlled study. Diabetes
Care 2017;40(3):332–337. [RCT, n = 104]
125. Bao LX, Shi WT, Han YX. Metformin versus insulin for gestational diabe-
tes: a systematic review and meta-analysis. J Matern Fetal Neonatal Med
2019:1–13. [Meta-analysis, 17 RCTs, n = 2828]
126. Hickman MA, McBride R, Boggess KA, Strauss R. Metformin compared
with insulin in the treatment of pregnant women with overt diabetes: a ran-
domized controlled trial. Am J Perinatol 2013;30(6):483–490. [RCT, n = 28]
127. Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational
diabetes: a meta-analysis. PLOS ONE 2013;8(5):e64585. [Meta-analysis,
5 RCTs, n = 1270]
128. Kalafat E, Sukur YE, Abdi A, Thilaganathan B, Khalil A. Metformin for pre-
vention of hypertensive disorders of pregnancy in women with gestational
diabetes or obesity: systematic review and meta-analysis of randomized
trials. Ultrasound Obstet Gynecol 2018;52(6):706–714. [Meta-analysis, 15
RCTs, n = 3124]
129. Li G, Zhao S, Cui S, Li L, Xu Y, Li Y. Effect comparison of metformin
with insulin treatment for gestational diabetes: a meta-analysis based on
RCTs. Arch Gynecol Obstet 2015;292(1):111–120. [Meta-analysis, 11 RCTs,
n = 2712]
130. Feng Y, Yang H. Metformin – a potentially effective drug for gestational
diabetes mellitus: a systematic review and meta-analysis. J Matern Fetal
Neonatal Med 2017;30(15):1874–1881. [Meta-analysis, 12 RCTs and 5
observational or retrospective case-control studies, n = 2946 trials in RCTs
and total subject sample size not reported in remaining studies]
131. Kitwitee P, Limwattananon S, Limwattananon C, Waleekachonlert O,
Ratanachotpanich T, Phimphilai M, et al. Metformin for the treatment of
gestational diabetes: an updated meta-analysis. Diabetes Res Clin Pract
2015;109(3):521–532. [Meta-analysis, 8 RCTs, n = 1712]
132. Ijas H, Vaarasmaki M, Morin-Papunen L, Keravuo R, Ebeling T, Saarela T,
et al. Metformin should be considered in the treatment of gestational dia-
betes: a prospective randomized trial. BJOG 2011;118(7):880–885. [RCT,
n = 100]
133. Ibrahim MI, Hamdy A, Shafik A, Taha S, Anwar M, Faris M. The role
of adding metformin in insulin-resistant diabetic pregnant women: a
randomized controlled trial. Arch Gynecol Obstet 2014;289(5):959–965.
[RCT, n = 90]
Maternal-Fetal Evidence Based Guidelines
134. Refuerzo JS, Viteri OA, Hutchinson M, Pedroza C, Blackwell SC, Tyson JE,
et al. The effects of metformin on weight loss in women with gestational
diabetes: a pilot randomized, placebo-controlled trial. Am J Obstet Gynecol
2015;212(3):389.e1–389.e9. [RCT, n = 79]
135. ACOG Practice Bulletin. Pregestational diabetes mellitus. Obstet Gynecol
2005;105:675–684. [Review, Guideline, III]
136. Jovanovic L, Druzin M, Peterson CM. Effect of euglycemia on the outcome
of pregnancy in insulin-dependent diabetic women as compared with nor-
mal control subjects. Am J Med 1981;71(6):921–927. [Prospective cohort,
n = 104, II-2]
137. Langer O, Anyaegbunam A, Brustman L, Guidetti D, Levy J, Mazze R.
Pregestational diabetes: insulin requirements throughout pregnancy.
Am J Obstet Gynecol 1988;159(3):616–621. [II-2]
138. Jovanovic L, Ilic S, Pettitt DJ, Hugo K, Gutierrez M, Bowsher RR, et al.
Metabolism and immunologic effects of insulin lispro in gestational diabe-
tes. Diabetes Care 1999;22:1422–1427. [RCT, n = 42]
139. Martis R, Crowther CA, Shepherd E, Alsweiler J, Downie MR, Brown
J. Treatments for women with gestational diabetes mellitus: an over-
view of Cochrane systematic reviews. Cochrane Database Syst Rev
2018;8(8):CD012327. [Meta-analysis, 3 RCTs, n = 410]
140. Garner P, Okun N, Keeley E, Wells G, Perkins S, Sylvain J, et al. A random-
ized controlled trial of strict glycemia control and tertiary level obstetric
care versus routine obstetric care in the management of gestational diabe-
tes: a pilot study. Am J Obstet Gynecol 1997;177(1):190–195. [RCT, n = 300]
141. Thompson DJ, Porter KB, Gunnells DJ, Wagner PC, Spinnato JA.
Prophylactic insulin in the management of gestational diabetes. Obstet
Gynecol 1990;7(6):960–964. [RCT, n = 108]
142. Gojnic M, Perovic M, Pervulov M, Ljubic A. The effects of adjuvant insulin
therapy among pregnant women with IGT who failed to achieve the desired
glycemia levels by diet and moderate physical activity. J Matern Fetal
Neonatal Med 2012;25(10):2028–2034. [RCT, n = 280]
143. Palatnik A, Mele L, Landon MB, Reddy UM, Ramin SM, Carpenter MW,
et al. Timing of treatment initiation for mild gestational diabetes mellitus
and perinatal outcomes. Am J Obstet Gynecol 2015;213(4):560.e1–560.e8.
[RCT, n = 958]
144. Brown J, Grzeskowiak L, Williamson K, Downie MR, Crowther CA. Insulin
for the treatment of women with gestational diabetes. Cochrane Database
Syst Rev 2017;11(11):CD012037. [Meta-analysis, 53 RCTs, n = 7381]
145. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, MiG trial investi-
gators. Metformin versus insulin for the treatment of gestational diabetes.
N Engl J Med 2008;358(19):2003–2015. [RCT, n = 751]
146. Kimber-Trojnar Z, Marciniak B, Patro-Malysza J, Skorzynska-Dziduszko K,
Poniedzialek-Czajkowska E, Mierzynski R, et al. Is glyburide safe in preg-
nancy? Curr Pharm Biotechnol 2014;15(1):100–112. [Review, III]
147. Lautatzis ME, Goulis DG, Vrontakis M. Efficacy and safety of metformin
during pregnancy in women with gestational diabetes mellitus or polycystic
ovary syndrome: a systematic review. Metabolism 2013;62(11):1522–1534.
[Review, III]
148. Society of Maternal-Fetal Medicine (SMFM) Publications Committee.
SMFM Statement: pharmacological treatment of gestational diabetes.
Am J Obstet Gynecol 2018;218(5):B2–B4. [Review, Guideline, III]
149. Asemi Z, Jamilian M, Mesdaghinia E, Esmaillzadeh A. Effects of selenium
supplementation on glucose homeostasis, inflammation, and oxidative
stress in gestational diabetes: randomized, double-blind, placebo-controlled
trial. Nutrition 2015;31(10):1235–1242. [RCT, n = 70]
150. Li X, Zhao J. The influence of zinc supplementation on metabolic status in
gestational diabetes: a meta-analysis of randomized controlled studies. J
Matern Fetal Neonatal Med 2019:1–6. [Meta-analysis, 5 RCTs, n = 263]
151. Asemi Z, Karamali M, Esmaillzadeh A. Effects of calcium-vitamin D co-
supplementation on glycaemic control, inflammation and oxidative stress
in gestational diabetes: a randomised placebo-controlled trial. Diabetologia
2014;57(9):1798–1806. [RCT, n = 54]
152. Asemi Z, Hashemi T, Karamali M, Samimi M, Esmaillzadeh A. Effects of
vitamin D supplementation on glucose metabolism, lipid concentrations,
inflammation, and oxidative stress in gestational diabetes: a double-blind
randomized controlled clinical trial. Am J Clin Nutr 2013;98(6):1425–1432.
[RCT, n = 54]
153. Rodrigues MRK, Lima SAM, Mazeto GMFDS, Calderon IMP, Magalhães
CG, Ferraz GAR, et al. Efficacy of vitamin D supplementation in gestational
diabetes mellitus: systematic review and meta-analysis of randomized tri-
als. PLOS ONE 2019;14(3):e0213006. [Meta-analysis, 6 RCTs, n = 456]
154. Maged AM, Torky H, Fouad MA, GadAllah SH, Waked NM, Gayed AS,
et al. Role of antioxidants in gestational diabetes mellitus and relation to
fetal outcome: a randomized controlled trial. J Matern Fetal Neonatal Med
2016;29(24):4049–4054. [RCT, n = 200]
Gestational Diabetes
155. Pan J, Pan Q, Chen Y, Zhang H, Zheng X. Efficacy of probiotic supplement
for gestational diabetes mellitus: a systematic review and meta-analysis. J
Matern Fetal Neonatal Med 2019;32(2):317–323. [Meta-analysis, 6 RCTs,
n = 830]
156. Zhang J, Ma S, Wu S, Guo C, Long S, Tan H. Effects of probiotic supple-
ment in pregnant women with gestational diabetes mellitus: a systematic
review and meta-analysis of randomized controlled trials. J Diabetes Res
2019;2019:5364730. [Meta-analysis, 11 RCTs, n = 719]
157. Taylor BL, Woodfall GE, Sheedy KE, O’Riley ML, Rainbow KA, Bramwell
EL, et al. Effect of probiotics on metabolic outcomes in pregnant women
with gestational diabetes: a systematic review and meta-analysis of ran-
domized controlled trials. Nutrients 2017;9(5):461. [Meta-analysis, 4 RCTs,
n = 288]
158. Brown J, Crawford TJ, Alsweiler J, Crowther CA. Dietary supplementation
with myo-inositol in women during pregnancy for treating gestational dia-
betes. Cochrane Database Syst Rev 2016;9(9):CD012048. [Meta-analysis, 2
RCTs, n = 142]
159. Fraticelli F, Celentano C, Zecca IA, Di Vieste G, Pintaudi B, Liberati M,
et al. Effect of inositol stereoisomers at different dosages in gestational dia-
betes: an open-label, parallel, randomized controlled trial. Acta Diabetol
2018;55(8):805–812. [RCT, n = 80]
160. Gao L, Lin L, Shan N, Ren CY, Long X, Sun YH, et al. The impact of omega-3
fatty acid supplementation on glycemic control in patients with gestational
diabetes: a systematic review and meta-analysis of randomized controlled
studies. J Matern Fetal Neonatal Med 2020;33(10):1767–1773. [Meta-
analysis, 7 RCTs, n = 478]
161. Li F, Pei L, Huang G, Ye H. Influence of omega-3 fatty acid and vitamin
co-supplementation on metabolic status in gestational diabetes: a meta-
analysis of randomized controlled studies. Eur J Obstet Gynecol Reprod
Biol 2020;247:191–197. [Meta-analysis, 4 RCTs, n = 250]
162. Yang S, Lin R, Si L, Li Z, Jian W, Yu Q, et al. Cod-liver oil improves metabolic
indices and hs-CRP levels in gestational diabetes mellitus patients: a dou-
ble-blind randomized controlled trial. J Diabetes Res 2019;2019:7074042.
[RCT, n = 550]
163. Costantine MM, Mele L, Landon MB, Spong CY, Ramin SM, Casey B, et al.
Customized versus population approach for evaluation of fetal overgrowth.
Am J Perinatol 2013;30(7):565–572. [RCT, n = 491]
164. Kjos SL, Henry OA, Montoro M, Buchanan TA, Mestman JH. Insulin-
requiring diabetes in pregnancy: a randomized trial of active induction of
labor and expectant management. Am J Obstet Gynecol 1993;169:611–5.
[RCT, n = 200]
165. Melamed N, Ray JG, Geary M, Bedard D, Yang C, Sprague A, et al. Induction
of labor before 40 weeks is associated with lower rate of cesarean deliv-
ery in women with gestational diabetes mellitus. Am J Obstet Gynecol
2016;214(3):364.e1–364.e8. [Retrospective cohort, n = 8392, II-2]
166. Sutton AL, Mele L, Landon MB, Ramin SM, Varner MW, Thorp JM, Jr,
et al. Delivery timing and cesarean delivery risk in women with mild ges-
tational diabetes mellitus. Am J Obstet Gynecol 2014;211(3):244.e1–244.e7.
[Secondary analysis, RCT, n = 679]
167. Hamel MS, Kanno LM, Has P, Beninati MJ, Rouse DJ, Werner EF.
Intrapartum glucose management in women with gestational diabetes mel-
litus: a randomized controlled trial. Obstet Gynecol 2019;133(6):1171–1177.
[RCT, n = 76]
168. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of
type 2 diabetes: a systematic review. Diabetes Care 2002;25(10):1862–1868.
[Review, III]
169. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus
after gestational diabetes: a systematic review and meta-analysis. Lancet
2009;373(9677):1773–1779. [20 cohort studies (retrospective and prospec-
tive), n = 675,455, II-2]
170. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Report of the expert committee on the diagnosis and classification of diabe-
tes mellitus. Diabetes Care 2003;26 (Suppl 1):S5–20. [Review, Guideline, III]
77
171. The Royal Australian and New Zealand College of Obstetricians and
Gynaecologists. College statement. Diagnosis of gestational diabetes mel-
litus. Melbourne: RANZCOG, 2008. [Review, Guideline, III]
172. American Diabetes Association. 13. Management of diabetes in pregnancy.
Diabetes Care 2017;40(Suppl 1):S114–S119. [Review, Guideline, III]
173. Olmos PR, Borzone GR, Berkowitz L, Mertens N, Busso D, Santos JL,
et al. Preventive letter: doubling the return rate after gestational diabetes
mellitus. Matern Child Health J 2015;19(5):939–944. [RCT, n = 468]
174. Zera CA, Bates DW, Stuebe AM, Ecker JL, Seely EW. Diabetes screening
reminder for women with prior gestational Diabetes: a randomized con-
trolled trial. Obstet Gynecol 2015;126(1):109–114. [RCT, n = 847]
175. Nicklas JM, Miller LJ, Zera CA, Davis RB, Levkoff SE, Seely EW. Factors
associated with depressive symptoms in the early postpartum period
among women with recent gestational diabetes mellitus. Matern Child
Health J 2013;17(9):1665–1672. [RCT, n = 71]
176. Ma S, Hu S, Liang H, Xiao Y, Tan H. Metabolic effects of breastfeed in
women with prior gestational diabetes mellitus: a systematic review and
meta-analysis. Diabetes Metab Res Rev 2019;35(3):e3108. [Meta-analysis,
23 observational studies, n ≥ 11,000, II-2]
177. Feng L, Xu Q, Hu Z, Pan H. Lactation and progression to type 2 diabetes
in patients with gestational diabetes mellitus: a systematic review and
meta-analysis of cohort studies. J Diabetes Investig 2018;9(6):1360–1369.
[Meta-analysis, 13 observational studies, n = 122,877, II-2]
178. Tanase-Nakao K, Arata N, Kawasaki M, Yasuhi I, Sone H, Mori R, et al.
Potential protective effect of lactation against incidence of type 2 diabetes
mellitus in women with previous gestational diabetes mellitus: a systematic
review and meta-analysis. Diabetes Metab Res Rev 2017;33(4):e2875. [Meta-
analysis, 5 observational studies, n = 3408, II-2]
179. Varner MW, Rice MM, Landon MB, Casey BM, Reddy UM, Wapner RJ, et al.
Pregnancies after the diagnosis of mild gestational diabetes mellitus and
risk of cardiometabolic disorders. Obstet Gynecol 2017;129(2):273–280.
[Prospective observational cohort, n = 483, II-2]
180. Akinci B, Celtik A, Yener S, Yesil S. Prediction of developing metabolic
syndrome after gestational diabetes mellitus. Fertil Steril 2010;93(4):
1248–1254. [Prospective, n = 164, II-2]
181. Vounzoulaki E, Khunti K, Abner SC, Tan BK, Davies MJ, Gillies CL.
Progression to type 2 diabetes in women with a known history of gesta-
tional diabetes: systematic review and meta-analysis. BMJ 2020;369:m1361.
[Meta-analysis, 20 observational studies, n = 1,332,273, II-2]
182. Li Z, Cheng Y, Wang D, Chen H, Chen H, Ming WK, et al. incidence
rate of type 2 diabetes mellitus after gestational diabetes mellitus: a sys-
tematic review and meta-analysis of 170,139 women. J Diabetes Res
2020;2020:3076463. [Meta-analysis, 28 observational studies, n = 170,139,
II-2]
183. Pérez-Ferre N, Del Valle L, Torrejón MJ, Barca I, Calvo MI, Matía P, et al.
Diabetes mellitus and abnormal glucose tolerance development after ges-
tational diabetes: a three-year, prospective, randomized, clinical-based,
Mediterranean lifestyle interventional study with parallel groups. Clin
Nutr 2015;34(4):579–585. [RCT, n = 260]
184. Lavrentaki A, Thomas T, Subramanian A, Valsamakis G, Thomas N, Toulis
KA, et al. Increased risk of non-alcoholic fatty liver disease in women with
gestational diabetes mellitus: a population-based cohort study, systematic
review and meta-analysis. J Diabetes Complications 2019;33(10):107401.
[Meta-analysis, 3 observational studies, n = 42,385, II-2]
185. Kramer CK, Campbell S, Retnakaran R. Gestational diabetes and the risk
of cardiovascular disease in women: a systematic review and meta-analysis.
Diabetologia 2019;62(6):905–914. [Meta-analysis, 9 observational studies,
n = 5,390,591, II-2]
186. Retnakaran R, Qi Y, Sermer M, Connelly PW, Hanley AJ, Zinman B. An
abnormal screening glucose challenge test in pregnancy predicts post-
partum metabolic dysfunction, even when the antepartum oral glucose
tolerance test is normal. Clin Endocrinol (Oxf) 2009;71(2):208–214.
[Observational study, n = 259, II-3]
6
HYPOTHYROIDISM
Alessandra Livi
Key points
• Hypothyroidism is characterized by inadequate thyroid
hormone production, and usually requires for diagnosis
elevated thyroid-stimulating hormone (TSH) and low
free thyroxine (FT4) [or free triiodothyronine (FT3)].
• Subclinical hypothyroidism requires for diagnosis an
elevated TSH but normal FT4.
• Hashimoto’s thyroiditis is the most common cause of
hypothyroidism in pregnancy, with thyroid peroxidase
antibodies in >90% of these women.
• Untreated or partially-treated hypothyroidism is associ-
ated with increased risk of pre-eclampsia, abruption, pre-
term birth, low birth weight, fetal death, and long-term
impaired psychomotor function.
• All physiologic changes and placental transfer should be
known by the physician caring for thyroid disease in preg-
nancy (Table 6.1).
• Women at high risk for hypothyroidism (Table 6.3)
should be screened with TSH and FT4, and with thy-
roid peroxidase antibodies (TPOAb) if TSH is >2.5
mU/L.
• Goal of levothyroxine treatment in pregnancy is maternal
serum TSH between the lower limit (often 0.5 mU/L)
and 2.5 mU/L. Most women with hypothyroidism need
an increase in thyroxine replacement dose.
• In women with overt hypothyroidism, TSH and FT4 lev-
els should be checked preconceptionally, at first prenatal
visit in first trimester, 4 weeks after altering the doses,
(therefore, every 4 weeks until TSH is normal, especially
in the first 20 weeks), and at least every trimester in
pregnancy.
• Iodine supplementation in a population with high levels
of endemic cretinism results in a reduction in deaths dur-
ing infancy and early childhood, with decreased endemic
cretinism at 4 years of age and better psychomotor devel-
opment scores between 4 and 25 months of age.
• There is no evidence that screening and treatment of
subclinical hypothyroidism during pregnancy improves
maternal or fetal outcomes.
• Screening and treating for hypothyroxinemia is also
unnecessary, as it is not associated with any maternal or
child benefits.
• Every woman with a thyroid nodule should have fine-nee-
dle aspiration and TSH checked.
Clinical hypothyroidism
Definitions
Clinical (or overt) hypothyroidism: Inadequate thyroid hormone
production of any cause. Usually requires elevated TSH and low
FT4 (or FT3) (see Figure 6.1 for basic thyroid evaluation).
78
Subclinical hypothyroidism: Elevated TSH and normal FT4.
Elevated TSH reflects the sensitivity of the hypothalamic-­
pituitary axis to small decreases in thyroid hormone; as the thy-
roid gland fails, the TSH level may rise above the upper limit of
normal while the FT4 is still within the normal range.
Hypothyroxinemia: Normal TSH and low FT4.
TSH is also called thyrotropin, T4 is also called thyroxine, T3 is
also called triiodothyronine; FT4 stands for free T4.
Incidence
One percent in general population; about 0.2–1% in pregnant
women [1–3]. There is an increased incidence with concurrent
autoimmune disease, that is, 5–8% incidence in patients with
type 1 diabetes [4]. Up to 25% of patients with type I diabetes
develop postpartum thyroid dysfunction [4]. In the United States,
10–15% of pregnant women are iodine deficient (urinary iodine
concentration <5 μg/dL) [5].
Signs/Symptoms
Thyroid disease may be masked by hypermetabolic state of
pregnancy. The most common signs include dry skin, weak-
ness, facial puffiness, and mild-to-moderate weight gain [6].
Fatigue, constipation, cold intolerance, muscle cramps, insom-
nia, hair loss, goiter, prolonged relaxation phase of deep ten-
don reflexes, carpal tunnel syndrome, intellectual slowness,
voice changes, myxedema, and (extremely rarely) coma are less
common.
Pathophysiology
The thyroid maintains the metabolism in cells by stimulating
transcription and translation. It also stimulates oxygen consump-
tion and regulates lipid and carbohydrate metabolism, and is nec-
essary for normal growth and maturation. The thyroid is under
the control of TSH from the anterior pituitary. TSH induces thy-
roid growth, differentiation, and iodine metabolism.
The majority (>99%) of hypothyroidism cases are due to pri-
mary thyroid abnormality. Secondary hypothyroidism is pituitary
in origin following irradiation or hypophysectomy or Sheehan’s
syndrome (postpartum pituitary necrosis). Tertiary hypothyroid-
ism (hypothalamic) is rare.
Hashimoto’s thyroiditis is the most common cause of hypo-
thyroidism in pregnancy. It is a chronic autoimmune lympho-
cytic thyroiditis, characterized by antithyroid antibodies (thyroid
peroxidase antibodies [TPOAb] 90%, thyroglobulin antibodies
20–50%), and usually firm, painless goiter as a presenting symp-
tom [7]. TPOAb are present in 6% of the general population. Less
common causes are subacute viral thyroiditis; iodine deficiency
(median urinary iodine level <100 μg/L); “burned-out” Graves’
disease, after radioiodine therapy, thyroidectomy, or antithy-
roid drugs; other head and neck surgery; other radiation therapy
to the head, neck, or chest area; medications—lithium, iodine,
amiodarone; rarely hypothalamic dysfunction, that is, Sheehan’s
syndrome.
DOI: 10.1201/9781003099062-6
 Hypothyroidism 79

TABLE 6.1: Thyroid Physiology Changes in Pregnancy and periods [12]. Selenoproteins act as antioxidants and decrease
Transplacental Passage thyroid inflammation in autoimmune thyroiditis by reducing
TPOAb titers. Up to 30% of women with TPOAb develop per-
Change in Placental
manent hypothyroidism following postpartum thyroid dysfunc-
Pregnancy Transfer
tion [13]. This may suggest a preventive role of selenomethionine
Thyroid-binding globulin (TBG) ↑ + supplementation in autoimmune thyroid dysfunction.
Total thyroxine (TT4) ↑ –(minimal)
Total triiodothyronine (TT3) ↑ – Preconception
In a small RCT, it was shown that preconception adjustment with
Resin triiodothyronine uptake ↓ –
increased dosage of levothyroxine supplementation in hypothy-
(RT3U)
roid women of reproductive age results in better control by TSH
Thyroid-stimulating hormone – –
and FT4 at first prenatal visit [14].
(TSH)
Free thyroxine (FT4) – ++ Pregnancy considerations
Free triiodothyronine (FT3) – ++ Anatomy/Radiology
TRH – –(<1%) In pregnancy, moderate glandular hyperplasia, and increased vas-
Iodide ↓ ++ cularity in the thyroid are physiologic. Thyroid volume by ultra-
Thyroid-stimulating – ++ sound increases a mean of 18% during pregnancy and returns to
immunoglobulin (TSI) normal size in the postpartum period [5, 15]. Any significant
goiter should be worked up.
Antithyroid peroxidase antibody ↓ ++
Levothyroxine replacement NA –(minimal) Maternal physiology
Thioamide (PTU or NA ++ Several changes occur, as shown in Table 6.1 (see Chap. 3,
methimazole) therapy Obstetric Evidence Based Guidelines). Thyroid-binding globulin
Free thyroxine index (FTI) – NA (TBG) increases about 200% secondary to estrogen-stimulated
hepatocyte production and altered glycosylation, which inhibits
degradation. High levels of HCG, which peak at 10–12 weeks,
Complications have some TSH-like activity and stimulate thyroid hormone
Untreated or partially treated clinical hypothyroidism is associ- secretion, which in turn suppresses TSH. A reduction of the
ated with increased risk of infertility, miscarriage, pre-eclamp- TSH reference occurs during pregnancy, especially during the
sia (44%), abruption (19%), preterm birth (PTM), low birth first trimester. From the late first trimester (weeks 7–12), there is
weight (31%), or fetal death (12%) [8–10]. Fetal goiter does not a downward shift both of the lower reference range of TSH (that
develop in women with hypothyroidism, unless they had previ- can be reduced by 0.4 mU/L) and of the upper reference (reduced
ous hyperthyroidism and thyroid-stimulating immunoglobulins by 0.5 mU/L). This corresponds to a TSH upper reference limit of
(TSIs) are still >200%. Infants whose mothers had serum FT4 4 mU/L.
below 10th percentile may have a high incidence of impaired In the second and third trimester the TSH reference range
psychomotor function [11]. gradually rise, but it remains lower than in non-pregnant status.
Normal TSH levels in pregnancy are shown in Table 6.2. TSH
Management suppression is even more marked for twins, which are character-
Prevention ized by higher HCG concentrations than singleton pregnancies
Recently, trace element selenium has been shown to reduce the [16]. Even if the TSH concentrations decrease in all populations,
incidence of hypothyroidism during pregnancy and postpartum substantial variations exist according to BMI, geography and
ethnicity.
Peripheral metabolism of thyroid hormones is also altered by
placental deiodinases, more in second half of pregnancy [17].
PRIMARY NTI or Pt. on SECONDARY Throughout pregnancy there is an approximate 30–50% increase
HIGH

HYPERTHYROID LEVOTHYROXINE HYPERTHYROID in T4 requirements [18, 19]. Plasma iodide levels decrease during
FREE THYROXINE or FT4

pregnancy because of fetal use of iodide and increased maternal

renal clearance of iodide [20]. Pregnancy does not appear to alter
the course of thyroid cancer [21].
NORMAL

SUB-CLINICAL SUB-CLINICAL
EUTHYROID
HYPERTHYROID HYPOTHYROID
Fetal thyroid physiology
In the fetus, the small amount of thyroxine that crosses the pla-
centa provides all the thyroid hormone until 10–12 weeks. Before
12 weeks (time period for initiation of fetal brain development),
SECONDARY NON THYROID PRIMARY
LOW

HYPOTHYROID ILLNESS - NTI HYPOTHYROID the fetus is entirely dependent on maternal transfer of thyroid
hormones. Upon the beginning of activation of the fetal hypo-
thalamic/pituitary-thyroid axis at this gestational age, the fetal
LOW NORMAL HIGH thyroid begins to concentrate iodine and synthesize iodothyro-
THYROID STIMULATING HORMONE - TSH nines. At 18–20 weeks, the fetal thyroid is controlled by fetal pitu-
itary TSH and mature hormone synthesis begins. TSH, T4, and
FIGURE 6.1 Basic thyroid evaluation. Abbreviations: NTI, T3 all begin to increase throughout gestation, as there seems to
non-thyroid illness; Pt, patient. be minimal negative feedback mechanism [20].
80 Maternal-Fetal Evidence Based Guidelines

TABLE 6.2: Thyroid-Stimulating Hormone Percentiles TABLE 6.3: Indications for Screening for Thyroid Dysfunction
According to Gestational Age in Singleton Pregnancies in Pregnancy
Gestational 2.5th 50th 97.5th Personal history of thyroid disfunction
Age (week) Percentile Percentile Percentile Symptoms or sign of thyroid disfunction
Known thyroid antibody positivity
6 0.23 1.36 4.94
Presence of goiter or palpable thyroid nodules
7 0.14 1.21 5.09
History of head or neck irradiation or prior thyroid surgery
8 0.09 1.01 4.93
Age >30
9 0.03 0.84 4.04
Type 1 diabetes or other autoimmune disease
10 0.02 0.74 3.12 History of pregnancy loss, preterm delivery or infertility
11 0.01 0.76 3.65 Multiple prior pregnancies (≥2)
12 0.01 0.79 3.32 Family history of thyroid disease (autoimmune thyroid disease or
13 0.01 0.78 4.05 thyroid disfunction)
14 0.01 0.85 3.33 Morbid obesity (BMI ≥ 40 kg/m2)
15 0.02 0.92 3.40 Medications (use of amiodarone, lithium or recent administration of
16 0.04 0.92 2.74 iodinated radiologic contrast)
17 0.02 0.98 3.32 Residing in an area of known moderate to severe iodine insufficiency
18 0.17 1.07 3.48
Source: Adapted from Refs. [3, 23].
19 0.22 1.07 3.03
20 0.25 1.11 3.20
21 0.28 1.21 3.04 and Table 6.4). Hypothyroidism in pregnancy is mainly (>99%)
22 0.26 1.15 4.09 primary. Elevated TSH and normal FT4 are consistent with
23 0.25 1.08 3.02 subclinical hypothyroidism (see later in this chapter).
24 0.34 1.13 2.99 Euthyroid women, but with increased risk for hypothyroidism
25 0.30 1.11 2.82 (Table 6.3), should be monitored with serum TSH measurement
26 0.20 1.07 2.89 every 4 weeks until midgestation and then at least once near 30
27 0.36 1.11 2.84 weeks’ gestation [23].
28 0.30 1.03 2.78 When available, population-based trimester-specific refer-
29 0.31 1.07 3.14 ence range for TSH are recommended for the evaluation of thy-
roid function in pregnancy [23]. Reference range determinations
30 0.20 1.07 3.27
should only include TPOAb-negative pregnant women with no
31 0.23 1.06 2.81
known thyroid disease and optimal iodine intake. Normal refer-
32 0.31 1.07 2.98
ence range for TSH in pregnancy among the American popula-
33 0.31 1.20 5.25 tion is shown in Table 6.2.
34 0.20 1.18 3.18 If population-specific reference ranges are not available, an
35 0.30 1.20 3.41 upper reference limit for TSH of 4.0 mU/L may be used [23].
36 0.33 1.31 4.59 TPOAb is present in not only 90% women with Hashimoto’s
37 0.37 1.35 6.40 thyroiditis but also 2–17% of unselected pregnant women. It
38 0.23 1.16 4.33 crosses the placenta and may increase the risk of adverse preg-
39 0.57 1.59 5.14 nancy outcomes, such as spontaneous abortion [30], preterm
≥40 0.38 1.68 5.43 delivery, perinatal complications, lower offspring QI, and post-
partum thyroid dysfunction [23, 31–34]. Moreover, TPOAb lev-
Source: Adapted from Ref. [16].
els >50 IU/mL have been shown to be associated with increased
risk of abruption [35]. Women with TPOAb positivity, compared
to those who are TPOAb negative, seems to present increased
Placenta physiology risk for adverse pregnancy outcomes, even when thyroid func-
It is important to be aware of which molecules cross the placenta tion is identical. As a consequence, the American Thyroid
and can affect the fetus. FT4, FT3, thyrotropin-releasing hor-
mone, iodine, TSI, and TPOAb cross the placenta (Table 6.1)
[22]. TSH does not cross. The placenta rapidly deiodinases mater-
TABLE 6.4: Primary vs. Secondary Hypothyroidism
nal T4 and T3 to the inactive reverse-T3.
Primary hypothyroidism
Screening/Diagnosis TSH ↑
Universal screening for hypothyroidism in pregnancy is not usu- FT4 ↓
ally recommended [3, 23–26]. At the first prenatal visit, women Antithyroglobulin +/–
should be verbally screened for any history of thyroid dysfunc- Antithyroid peroxidase +/–
tion. Women at high risk for thyroid dysfunction should be
Secondary hypothyroidism
screened in the first trimester of pregnancy (Table 6.3) [27].
TSH ↓
Tests used for screening and diagnosis include TSH (most sen-
sitive) [28, 29] and FT4. Elevated TSH, and either low FT4 or FT4 ↓
low FT3, is consistent with clinical hypothyroidism (Figure 6.1 Abbreviations: TSH, thyroid-stimulating hormone; FT4, free thyroxine.
Hypothyroidism 81

Possible testing and treatment for thyroid disfunction in pregnancy

TSH < 2.5th percentile TSH 0.1–2.5 mU/L TSH 2.5–10 mU/L TSH ≥10 mU/L
or <0.1 mU/L

See thyrotoxicosis No further workup Treat with

section Levothyroxine

TPOAb TPOAb
positive negative

TSH 2.5 mU/L-ULRR TSH ULRR-10 mU/L TSH 2.5 mU/L-ULRR TSH ULRR-10 mU/L
or 2.5–4 mU/L or 4–10 mU/L or 2.5–4 mU/L or 4–10 mU/L

Consider treatment with Consider treatment with

Treat with Levothyroxine No treatment
Levothyroxine Levothyroxine

FIGURE 6.2 Possible testing and treatment for thyroid dysfunction in pregnancy. (Adapted from Ref. [23].) Abbreviation: ULRR:
upper limit of reference range.

Association proposed an alternative approach to consider both
TSH and TPOAb status to decide about levothyroxine treatment
(Figure 6.2) [23].
Therefore, euthyroid women with positive TPOAb status
present a higher risk of hypothyroidism during pregnancy: in
these women, TSH concentrations should be measured every
4 weeks through midpregnacy [23].
Measuring TPOAb or thyroglobulin antibodies is important
for diagnosis, but serial levels are usually not indicated since
treatment does not alter them.
Treatment
Goal
Maternal serum TSH between the lower limit of the refer-
ence range (usually 0.6 mU/L) and 2,5 mU/L. Serum TSH level
should be measured approximately every 4 weeks, especially
while adjusting therapy [3, 23].
Interestingly, there are really no RCTs on treatment of overt
hypothyroidism in pregnancy. Two trials of 30 and 48 hypothy-
roid women, respectively, compared levothyroxine doses, but
both trials reported only biochemical outcomes [36].
Thyroxine replacement
Dose
Pre-existing hypothyroidism Approximately 45–85% of hypo-
thyroid women need up to 45% increase in thyroxine replace-
ment dose during pregnancy because of increased metabolism
of thyroxine, weight gain, increased T4 pool, high serum TBG,
placental deiodinase activity, and transfer of T4 to fetus [37, 38].
Hypothyroid women who become pregnant should consider
increasing the replacement dosage by 20–30% at the time of a
positive pregnancy test and contact their physician [32].
New diagnosis Levothyroxine replacement therapy can be
started at 1–2 µg/kg daily or approximately 100 µg/day, then
adjusted by monitoring TSH levels [3, 23]. Thyroxine replacement
will need to be increased as in pre-existing disease.
Ferrous sulfate and calcium carbonate interfere with T4
absorption and should be taken at a different time of day from
thyroxine therapy [39]. Therefore, pregnant women should
space their levothyroxine and prenatal vitamin by at least 2 to
3 hours. Carbamazepine, phenytoin, and rifampin can increase
the clearance of T4. It takes approximately 4 weeks for thyrox-
ine therapy to alter TSH level. Not only under replacement (see
earlier in this chapter) but also over replacement (pregnancy loss,
low birth weight) should be avoided [40].
Type
Levothyroxine Levothyroxine is the recommended thyroid
replacement therapy in pregnant hypothyroid women. Other thy-
roid preparations such as T3 or desiccated thyroid extract should
be avoided during pregnancy [3, 23].
Iodine supplement Iodine supplementation in a population
with high levels of endemic cretinism results in a reduction
of the condition with no apparent adverse effects [41]. Iodine
supplementation is associated with a reduction in deaths dur-
ing infancy and early childhood, with decreased endemic cre-
tinism at 4 years of age, and better psychomotor development
scores between 4 and 25 months of age. About 10–15% of the
U.S. population has iodine deficiency, which can manifest as sub-
clinical hypothyroidism, or with normal TSH and low T4. A daily
dose of 150 μg of iodine is recommended for women planning
a pregnancy, 250 μg daily during pregnancy and breast-feed-
ing [23, 42].
82
Antepartum management
• Among hypothyroid women, TSH and FT4 levels should
be checked preconception, at first prenatal visit in first
trimester, 4 weeks after altering the doses, (therefore,
every 4 weeks until TSH is normal, especially in first 20
weeks), and at least every trimester in pregnancy.
• Fetal heart rate should be assessed at each visit by doptone
to rule out fetal bradycardia <120.
• Antepartum testing is not recommended if euthyroid;
weekly non-stress tests beginning at about 32 weeks can be
considered for clinically hypothyroid patients.
• Ultrasound is not recommended if euthyroid; monthly ultra-
sound can be considered for fetal growth, thyroid circumfer-
ence [43], and fetal heart rate if clinically hypothyroid.
• Important to inform pediatrician at time of delivery.
Postpartum
Immediately post-delivery, the dosage of levothyroxine should
be reduced to the pre-pregnancy dose, and TSH levels should be
measured 6 weeks postpartum, and follow-up with medical doc-
tor/endocrinologist. In some women who become hypothyroid
during pregnancy, there is no necessity of levothyroxine replace-
ment therapy postpartum: in these women, levothyroxine could
be discontinued after delivery, especially if the daily dose is
≤50 µg. TSH serum level should be evaluated in 6 weeks [23].
Neonatal
The incidence of iodine-deficient congenital hypothyroidism is
1/4000 births, 5% identified at birth by clinical symptoms, oth-
ers by newborn screening. The United States screens all new-
borns. If discovered and treated in the first few weeks of life,
near-­normal growth and intelligence are expected [44, 45]. The
majority of cases are due to agenesis/dysgenesis of fetal thyroid,
dyshormonogenesis, or iodine deficiency. Fetuses are protected
in utero by small quantity of maternal T4 that crosses placenta.
Neonatal issues include neuropsychological abnormalities, deaf-
ness, respiratory difficulties, growth failure, lethargy, and hypo-
tonia and myxedema of the larynx and epiglottis.
Subclinical hypothyroidism
Incidence
Two to five percent of pregnant women [46–48].
Diagnosis
Elevated TSH and normal FT4.
Screening and management
Routine screening for subclinical hypothyroidism is currently not
recommended since treatment of subclinical hypothyroidism has
not been demonstrated to improve maternal or fetal outcomes [3,
23, 26]. Previously some observational studies have shown that
subclinical hypothyroidism can been associated with impaired
neurodevelopment in offspring [11]; as well as increased inci-
dences of preterm birth, abruption, severe pre-eclampsia, gesta-
tional diabetes, respiratory distress syndrome, and admission to
intensive care nursery [46, 49–51], but not consistently shown by
other studies [47, 52]. In a large randomized controlled trial (RCT),
levothyroxine supplementation given to asymptomatic women
screened and identified to have a TSH ≥97.5th percentile was
associated with a similar IQ and cognitive outcomes in their chil-
dren at 3 years of age, compared to placebo [26]. Follow-up of the
Maternal-Fetal Evidence Based Guidelines
children of this study through age 9 years confirmed the absence of
neurodevelopmental improvement in offspring of women treated
with levothyroxine [53]. Similarly, in another large RCT, levothy-
roxine supplementation given to asymptomatic women screened
and identified to have a TSH ≥4 mU/mL and a normal free T4
(0.86–1.9 ng/dL) was associated with a similar IQ and c­ ognitive
outcomes in their children at 5 years of age, compared to placebo
[54, 55]. Therefore, currently, there is no evidence that screen-
ing and treatment of subclinical hypothyroidism during preg-
nancy improves maternal or fetal outcomes [23, 26, 53, 55, 56].
However, pregnant women with sub-clinical hypothyroidism
and TPOAb seem to have increased risk of pregnancy complica-
tions: in this group levothyroxine therapy could be beneficial,
especially in reducing miscarriages [34, 57–59]. Therefore, accord-
ing to the American Thyroid Association, pregnant women with
TSH concentration >2.5 mU/L could be evaluated for TPOAb sta-
tus and decision about levothyroxine treatment should consider
TPOAb status (Figure 6.2) [23, 32, 60].
Moreover, women with subclinical hypothyroidism and
TPOAb frequently progress to overt hypothyroidism, and may
develop hyperlipidemia and atherosclerotic heart disease [61]: in
these women, TSH concentrations should be measured every 4
weeks through midpregnacy.
Hypothyroxinemia
Incidence
The incidence of hypothyroxinemia is about 1.3% in pregnant
women [52].
Diagnosis
Normal TSH and low FT4.
Screening and management
Universal screening to detect isolated low T4 concentrations in
pregnancy is not recommended [23].
Available data from prospective non-randomized studies, suggest
an association between hypothyroxinemia in pregnancy, higher risk
of preterm delivery and reduced cognitive development of the off-
spring [33, 62, 63], but not consistently shown by other studies [64].
Moreover, no studies exist in which levothyroxine administra-
tion has been shown to improve these effects. On the contrary,
there are at least two large RCTs showing no benefit from screen-
ing and treating isolated hypothyroxinemia in pregnancy. In a
RCT, levothyroxine supplementation given to asymptomatic
women screened and identified to have a free T4 below the
2.5th percentile was associated with a similar IQ and cogni-
tive outcomes in their children at 3 years of age, compared to
placebo [26]. In another RCT, levothyroxine supplementation
given to asymptomatic women screened and identified to have
a normal TSH (0.08–3.99 mU/mL) and a low free T4 (<0.86
ng/dL) was associated with a similar IQ and cognitive out-
comes in their children at 5 years of age, compared to placebo
[54]. Therefore, there is evidence that screening and treating
for hypothyroxinemia in pregnancy is unnecessary, as it is not
associated with any maternal or child benefits [23].
TPO-antibodies only
Some women are euthyroid, but have been identified to have
TPOAb. In a RCT of euthyroid pregnant women with thyroid per-
oxidase antibodies, levothyroxine therapy significantly reduced
Hypothyroidism
the rate of PTB compared to placebo, while the incidence of pre-
eclampsia was similar [36, 57]. However, in two subsequent trials,
levothyroxine therapy did not reduce the rate of PTB or improve
other pregnancy outcomes among euthyroid women with TPOAb
positive status, compared with either no treatment or placebo [65,
66]. Therefore, routine thyroid screening and/or treatment for
TPOAb in asymptomatic euthyroid women is not suggested.
A trial of 169 TOP-positive, euthyroid women compared the
trace element selenomethionine (selenium) with placebo and no
significant differences were seen for either pre-eclampsia (RR
1.44; 95% CI 0.25–8.38) or preterm birth (RR 0.96; 95% CI 0.20–
4.61) [36], but there was an improvement (decrease) in postpar-
tum thyroiditis [12].
Thyroid nodule
Incidence
Totally, 5–10% of thyroid tumors are neoplastic. Thyroid cancer
occurs in 1/1000 pregnant women with palpable thyroid nodule.
Diagnosis
Ultrasound was used to define dominant nodule, followed by fine-
needle aspiration for nodules >1 cm, which has a 95% diagnostic
accuracy in pregnancy [67]. Radioisotope scanning is contraindi-
cated in pregnancy. Serum TSH and FT4 should be checked.
Thyroid surgery
For malignancy diagnosed on fine-needle aspiration, neck explo-
ration should be performed ideally either in the second trimester
or postpartum [67]. Neck irradiation for malignancy should be
deferred until after pregnancy.
Postpartum thyroiditis
Definition
Autoimmune inflammation of the thyroid gland that presents
as new-onset painless hypothyroidism, transient thyrotoxico-
sis, or thyrotoxicosis followed by hypothyroidism within 1 year
postpartum.
Incidence
Occurs in 5% of women in the United States who do not have a
history of thyroid disease [68], and may occur after delivery or
pregnancy loss.
Risk factors
Postpartum depression, high serum TPOAb concentration, his-
tory of Graves’ disease, other autoimmune disorders. All patients
with depression, including postpartum depression, should be
screened for thyroid disfunction [23].
Etiology
Subacute lymphocytic thyroiditis or postpartum exacerbation of
chronic lymphocytic thyroiditis.
Diagnosis
Documentation of new-onset abnormal levels of TSH and/or FT4
within the first postpartum year. All women with symptoms of
thyroid dysfunction or who develop a goiter postpartum should
be evaluated with TSH, FT4. If the diagnosis is unclear, a TPOAb
level should be measured. Women with highest levels of TSH and
TPOAb have the highest risk for developing permanent hypothy-
roidism [69].
83
Three clinical presentations
1. Transient hyperthyroidism followed by recovery—28%
2. Transient hyperthyroidism, followed by transient or rarely
permanent hypothyroidism—28%
3. Transient or permanent hypothyroidism—44%
Management
Most women do not require treatment. Treatment is based on
symptoms.
If symptomatic, thyrotoxicosis should be treated with a beta-
adrenergic antagonist drug, typically required for a few weeks.
Antithyroid medications are not recommended [23]. Transient
hypothyroidism is treated with thyroxine (25–75 mcg/day) for
6–12 months [3].
Recurrence risk
Risk of recurrence is 70% [70].
Risk of developing permanent primary hypothyroidism in the
5- to 10-year period following an episode of postpartum thyroid-
itis is markedly increased. Annual TSH level should be performed
in them [71].
References
1. Montoro MN. Management of hypothyroidism during pregnancy. Clin
Obstet Gynecol 1997;40(1):65–80. [II-2]
2. Klein RZ, Haddow JE, Faix JD, et al. Prevalence of thyroid deficiency in
pregnant women. Clin Endocrinol (Oxf) 1991;35(1):41–46. [II-2]
3. American College of Obstetricians and Gynecologists. Practice Bulletin
No. 223: Thyroid disease in pregnancy. Obstet Gynecol. 2020;135(6):e261
–e274. [Review, guideline]
4. Alvarez-Marfany M, Roman SH, Drexler AJ, Robertson C, Stagnaro-Green
A. Long-term prospective study of postpartum thyroid dysfunction in
women with insulin dependent diabetes mellitus. J Clin Endocrinol Metab
1994;79(1):10–16. [II-2]
5. Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition
in the United States. Trends and public health implications: iodine
excretion data from National Health and Nutrition Examination
Surveys I and III (1971–1974 and 1988–1994). J Clin Endocrinol Metab
1998;83(10):3401–3408. [II-2]
6. Rakel RE. Textbook of Family Practice. 6th ed. Philadelphia: WB Saunders;
2002. [Review]
7. Weetman AP, McGregor AM. Autoimmune thyroid disease: developments
in our understanding. Endocr Rev 1984 Spring;5(2):309–355. [III]
8. Reid SM, Middleton P, Cossich MC, Crowther CA. Interventions for clinical
and subclinical hypothyroidism in pregnancy. Cochrane Database Syst Rev
2010;(7):CD007752. [Review]
9. Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal
outcome in hypothyroid pregnancies. Obstet Gynecol 1993;81(3):349–353.
[II-2]
10. Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating preg-
nancy. Obstet Gynecol 1988;72(1):108–112. [II-3]
11. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine con-
centrations during early pregnancy are associated with impaired psycho-
motor development in infancy. Clin Endocrinol (Oxf) 1999;50(2):149–155.
[II-2]
12. Negro R, Greco G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. The influ-
ence of selenium supplementation on postpartum thyroid status in preg-
nant women with thyroid peroxidase autoantibodies. J Clin Endocrinol
Metab 2007;92(4):1263–1268. [RCT, n = 169]
13. Premawardhana LD, Parkes AB, Ammari F, et al. Postpartum thyroid-
itis and long-term thyroid status: prognostic influence of thyroid per-
oxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab
2000;85(1):71–75. [II-2]
14. Rotondi M, Mazziotti G, Sorvillo F, et al. Effects of increased thyroxine
dosage pre-conception on thyroid function during early pregnancy. Eur J
Endocrinol 2004;151(6):695–700. [RCT, n = 25]
15. Rasmussen NG, Hornnes PJ, Hegedus L. Ultrasonographically determined
thyroid size in pregnancy and post partum: the goitrogenic effect of preg-
nancy. Am J Obstet Gynecol 1989;160(5 Pt 1):1216–1220. [II-3]
84
16. Dashe JS, Casey BM, Wells CE, et al. Thyroid-stimulating hormone in
singleton and twin pregnancy: importance of gestational age-specific refer-
ence ranges. Obstet Gynecol 2005;106(4):753–757. [II-3]
17. Glinoer D, de Nayer P, Bourdoux P, et al. Regulation of maternal thyroid
during pregnancy. J Clin Endocrinol Metab 1990;71(2):276–287. [II-3]
18. Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen
PR. Timing and magnitude of increases in levothyroxine require-
ments during pregnancy in women with hypothyroidism. N Engl J Med
2004;351(3):241–249. [II-2]
19. Glinoer D. The regulation of thyroid function in pregnancy: pathways
of endocrine adaptation from physiology to pathology. Endocr Rev
1997;18(3):404–433. [III]
20. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N
Engl J Med 1994;331(16):1072–1078. [III]
21. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer diag-
nosed in pregnant women. J Clin Endocrinol Metab 1997;82(9):2862–2866.
[II-2]
22. Bajoria R, Fisk NM. Permeability of human placenta and fetal mem-
branes to thyrotropin-stimulating hormone in vitro. Pediatr Res
1998;43(5):621–628. [II-3]
23. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American
Thyroid Association for the diagnosis and management of thyroid dis-
ease during pregnancy and the postpartum. Thyroid. 2017;27(3):315–389.
[Review, guideline]
24. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dys-
function during pregnancy and postpartum: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 2012;97(8):2543–2565. [Review,
guideline]
25. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green
A. Universal screening versus case finding for detection and treatment of
thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab
2010;95(4):1699–1707. [II-2]
26. Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and
childhood cognitive function. N Engl J Med 2012;366(6):493–501. [RCT,
n = 794]
27. Gharib H, Cobin RH, Dickey RA. Subclinical hypothyroidism during
pregnancy: position statement from the American Association of Clinical
Endocrinologists. Endocr Pract 1999;5(6):367–368. [Review, guideline]
28. American Association of Clinical Endocrinologists, editor. AACE clini-
cal practice guidelines for evaluation and treatment of hyperthyroidism
and hypothyroidism. American Association of Clinical Endocrinologists.
Jacksonville, FL: American Association of Clinical Endocrinologists. 1996.
[Review, guideline]
29. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association
guidelines for detection of thyroid dysfunction. Arch Intern Med
2000;160(11):1573–1575. [Review, guideline]
30. Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Alvarez-Marfany
M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive
assays for thyroid autoantibodies. JAMA 1990;264(11):1422–1425. [II-3]
31. Kuijpens JL, Pop VJ, Vader HL, Drexhage HA, Wiersinga WM. Prediction
of postpartum thyroid dysfunction: can it be improved? Eur J Endocrinol
1998;139(1):36–43. [II-2]
32. Dickens LT, Cifu AS, Cohen RN. Diagnosis and management of thy-
roid disease during pregnancy and the postpartum period. JAMA
2019;321(19):1928–1929. [Review, guideline]
33. Korevaar TI, Schalekamp-Timmermans D, de Rijke YB, et al.
Hypothyroxinemia and TPO-antibody positivity are risk factors for
premature delivery: the generation R study. J Clin Endocrinol Metab
2013;98:4382–4390. [II-2]
34. Negro R, Schwartz A, Gismondi R, et al. Increased pregnancy loss
rate in thyroid antibody negative women with TSH levels between 2.5
and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab
2010;95(9):E44–E48. [I]
35. Haddow JE, McClain MR, Palomaki GE, et al. Thyroperoxidase and thy-
roglobulin antibodies in early pregnancy and placental abruption. Obstet
Gynecol 2011;117(2 Pt 1):287–292. [II-2]
36. Reid SM, Middleton P, Cossich MC, Crowther CA, Bain E. Interventions
for clinical and subclinical hypothyroidism pre-pregnancy and during
pregnancy. Cochrane Database Syst Rev 2013;5:CD007752. [Meta-analysis;
4 heterogeneous RCTs]
37. Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine
during pregnancy in women with primary hypothyroidism. N Engl J Med
1990;323(2):91–96. [II-2]
38. Kaplan MM. Management of thyroxine therapy during pregnancy. Endocr
Pract 1996;2(4):281–286. [III]
Maternal-Fetal Evidence Based Guidelines
39. Brent GA. Maternal hypothyroidism: recognition and management.
Thyroid 1999;9(7):661–665. [III]
40. Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss associated
with excess thyroid hormone exposure. JAMA 2004;292(6):691–695. [II-3]
41. Mahomed K, Gulmezoglu AM. Maternal iodine supplements in areas
of deficiency. Cochrane Database Syst Rev 2007;(3):CD000135. [Meta-
analysis: 3 RCTs, n = 1551]
42. WHO Secretariat, Andersson M, de Benoist B, Delange F, Zupan J.
Prevention and control of iodine deficiency in pregnant and lactating women
and in children less than 2-years-old: Conclusions and recommendations of
the technical consultation. Public Health Nutr 2007;10(12A):1606–1611.
[Review]
43. Ranzini AC, Ananth CV, Smulian JC, Kung M, Limbachia A, Vintzileos
AM. Ultrasonography of the fetal thyroid: Nomograms based on biparietal
diameter and gestational age. J Ultrasound Med 2001;20(6):613–617. [II-2]
44. Glorieux J, Dussault J, Van Vliet G. Intellectual development at age 12 years
of children with congenital hypothyroidism diagnosed by neonatal screen-
ing. J Pediatr 1992;121(4):581–584. [II-2]
45. Rovet JF, Ehrlich RM, Sorbara DL. Neurodevelopment in infants and pre-
school children with congenital hypothyroidism: etiological and treatment
factors affecting outcome. J Pediatr Psychol 1992;17(2):187–213. [II-2]
46. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and preg-
nancy outcomes. Obstet Gynecol 2005;105(2):239–245. [II-2]
47. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal
thyroid hypofunction and pregnancy outcome. Obstet Gynecol
2008;112(1):85–92. [II-1]
48. Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid disease
in pregnancy. Obstet Gynecol Clin North Am 2010;37(2):173–193. [III]
49. Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of
subclinical thyroid disease to the incidence of gestational diabetes. Obstet
Gynecol 2012;119(5):983–988. [II-3]
50. Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG.
Subclinical thyroid disease and the incidence of hypertension in pregnancy.
Obstet Gynecol 2012;119(2 Pt 1):315–320. [II-3]
51. Korevaar TI, Derakhshan A, Taylor PN, et al. Association of thyroid
function test abnormalities and thyroid autoimmunity with preterm
birth: a systematic review and meta-analysis. Consortium on thyroid and
pregnancy – Study group on preterm birth. JAMA 2019;322(7):632–641.
[Systematic review an meta-analysis]
52. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF.
Perinatal significance of isolated maternal hypothyroxinemia identified in
the first half of pregnancy. Obstet Gynecol 2007;109(5):1129–1135. [II-2]
53. Hales C, Taylor PN, Channon S, et al. Controlled antenatal thyroid screen-
ing II: effect of treating maternal suboptimal thyroid function on child con-
dition. J Clin Endocrinol Metab 2018;103:1583–1591. [II-2]
54. Casey B. Effect of maternal subclinical hypothyroidism or hypothyroxemia
on IQ in offspring. AJOG 2016;214(January, Issue 1, Supplement):S2. [RCT,
n = 677 for subclinical hypothyroidism; n = 526 for hypothyroxinemia]
55. Casey BM, Thom EA, Varner MW, et al. Treatment of subclinical
hypothyroidism or Hypothiroxinemia in pregnancy. N Engl J Med
2017;376(9):815–825. [I]
56. Cappola AR, Casey BM. Thyroid function test abnormalities during preg-
nancy. JAMA 2019;322:617–619.
57. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H.
Levothyroxine treatment in euthyroid pregnant women with autoimmune
thyroid disease: effects on obstetrical complications. J Clin Endocrinol
Metab 2006;91(7):2587–2591. [RCT, n = 115]
58. Lepoutre T, Debiève F, Gruson D, et al. Reduction of miscarriages through
universal screening and treatment of thyroid autoimmune disease. Gynecol
Obstet Invest 2012;74:265–273. [III]
59. Liu H, Shan Z, Li C, et al. Maternal subclinical hypothyroidism, thyroid
autoimmunity, and the risk of miscarriage: a prospective cohort study.
Thyroid 2014;24:1642–1649. [II-2]
60. L. Cooper DS, Pearce EN. Subclinical hypothyroidism and hypothyroxin-
emia in pregnancy – Still no answers. N Engl J Med 2017;376(9):876–877.
[Review]
61. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med
2003;348(26):2646–2655. [III]
62. Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid func-
tion during early pregnancy and cognitive functioning in early childhood:
the generation R study. J Clin Endocrinol Metab 2010;95:4227–4234. [II-2]
63. Korevaar TI, Muetzel R, Medici M, et al. Association of maternal thyroid
function during early pregnancy with offspring IQ and brain morphology
in childhood: a population-based prospective cohort study. Lancet Diabetes
Endocrinol 2016;4:35–43.
Hypothyroidism
64. Craig WY, Allan WC, Kloza EM, et al. Mid-gestational maternal free thy-
roxine concentration and offspring neurocognitive development at age two
years. J Clin Endocrinol Metab 2012;97:E22–28. [II-2]
65. Wang H, Gao H, Chi H, et al. Effect of levothyroxine on miscarriage among
women with normal thyroid function and thyroid autoimmunity undergo-
ing in vitro fertilization and embryo transfer: a randomized clinical trial.
JAMA. 2017;318:2190–2198. [I]
66. Dhillon-Smith R, Middleton LJ, Sunner KK, et al. Levothyroxine in women
with thyroid peroxidase antibodies before conception. N Engl J Med.
2019;380:1316–1325. [I]
67. Tan GH, Gharib H, Goellner JR, van Heerden JA, Bahn RS. Management of
thyroid nodules in pregnancy. Arch Intern Med 1996;156(20):2317–2320.
[II-2]
85
68. Gerstein HC. How common is postpartum thyroiditis? A methodologic
overview of the literature. Arch Intern Med 1990;150(7):1397–1400. [III]
69. Lucas A, Pizarro E, Granada ML, Salinas I, Foz M, Sanmarti A. Postpartum
thyroiditis: epidemiology and clinical evolution in a nonselected popula-
tion. Thyroid 2000;10(1):71–77. [II-2]
70. Lazarus JH, Ammari F, Oretti R, Parkes AB, Richards CJ, Harris B.
Clinical aspects of recurrent postpartum thyroiditis. Br J Gen Pract
1997;47(418):305–308. [II-3]
71. Azizi F. The occurrence of permanent thyroid failure in patients with sub-
clinical postpartum thyroiditis. Eur J Endocrinol 2005;153(3):367–371.
[II-2]
7
HYPERTHYROIDISM
Alessandra Livi
Key points
• Hyperthyroidism occurs in 0.2–0.7% of pregnancies.
• Graves’ disease accounts for 95% of women with
hyperthyroidism.
• Untreated hyperthyroidism is associated with increased
risks of spontaneous pregnancy loss, preterm birth, pre-
eclampsia, fetal death, abruption, fetal growth restric-
tion (FGR), neonatal Graves’ disease, as well as maternal
congestive heart failure and thyroid storm.
• Hyperemesis gravidarum (HG) can be associated with
gestational transient biochemical thyrotoxicosis (low,
usually undetectable thyroid-stimulating hormone [TSH],
and elevated T4), but this biochemical change always
resolves spontaneously. Therefore, there should be no test-
ing, follow-up, or treatment for biochemical thyrotoxi-
cosis in women with HG.
• Clinical hyperthyroidism is diagnosed by suppressed
TSH and elevated serum-free thyroxine (FT4). Thyroid-
stimulating immunoglobulin (TSI) can be obtained, as
positive TSI is consistent with Graves’ disease, and val-
ues >200–500% indicate higher risk for fetal/neonatal
hyperthyroidism.
• Goal of treatment is to keep FT4 in high normal range.
Measure TSH and FT4 every 4 weeks until FT4 is consis-
tently in the high normal range, and then every trimester.
• Main treatment is with either propylthiouracil (PTU) or
methimazole. Because of the very rare teratogenic effects
of methimazole, and the hepatotoxicity of PTU, PTU can
be used through 16 weeks’ gestation followed by switch-
ing over to methimazole in the second trimester for the
rest of the pregnancy.
• Radioiodine is absolutely contraindicated in pregnancy.
• Thyroid storm is initially diagnosed clinically and treated
aggressively with PTU, saturated solution of potassium
iodide (SSKI), dexamethasone, and propranolol.
Definitions
Hyperthyroidism
Hyperfunctioning thyroid gland results in thyrotoxicosis. It usu-
ally implies low TSH and high T4 (or T3).
Graves’ disease
An autoimmune disease causing hyperthyroidism, characterized
by production of thyroid-stimulating immunoglobulins (TSIs)
or thyroid-stimulating hormone-binding inhibitory immu-
noglobulins (TBIIs). TSI coexists with TBII 30% of the time [1].
TSIs stimulate thyrotropin receptor. Instead, TBII can stimulate
or inhibit TSH receptor [2]. TBIIs are seen in 30% of patients
with Graves’ disease and in 10% of patients with autoimmune
Hashimoto’s thyroiditis. TBII disappear and patients achieve
euthyroidism in 40% of the cases. Therefore, TBII assays have not
86
been developed for clinical use because of higher costs involved
in developing TBII assays as compared to the number of patients
who would benefit from them.
TRAb (TSH receptor antibodies) is a broader term used to
include both TSI and TBII. TRAb assays, in general, measure
TSIs as TBII assays have not been established so far [3].
Thyrotoxicosis
Clinical and biochemical state that results from an excess pro-
duction or exposure to thyroid hormone, from any etiology.
Gestational thyrotoxicosis
Biochemical tests consistent with hyperthyroidism during preg-
nancy, but not a disease.
Thyroid storm
Severe, acute, life-threatening exacerbation of the signs/symp-
toms of hyperthyroidism.
Subclinical hyperthyroidism
Sustained TSH <0.1 mU/L with normal FT4 and free triiodo-
thyronine (FT3), in the absence of nonthyroidal illness.
Signs/Symptoms
Symptoms (may mimic hypermetabolic state of pregnancy):
nervousness, tremor, frequent stools, excessive sweating, heat
intolerance, insomnia, palpitations, decreased appetite, pruritus,
decreased exercise tolerance, shortness of breath, eye symptoms
of frequent lacrimation, double vision, and retro-orbital pain.
Physical examination
Hypertension, goiter, tachycardia (>100 bpm, that does not
decrease with Valsalva), wide pulse pressure, weight loss, oph-
thalmopathy (lid lag, lid retraction), and dermopathy (localized,
pretibial myxedema). Goiter occurs only with iodine deficiency or
thyroid disease, and must be considered pathological.
Incidence
Hyperthyroidism occurs in about 0.2–0.7% of pregnancies [4–6].
Etiology
Graves’ disease accounts for 95% of women with hyperthy-
roidism. It can be associated with diffuse thyromegaly or infiltra-
tive ophthalmopathy. Non-Graves’ hyperthyroidism accounts for
5% of women with hyperthyroidism, and can be associated with
gestational trophoblastic neoplasia [4, 7], toxic nodular and mul-
tinodular goiter [5], hyperfunctioning thyroid adenoma, subacute
thyroiditis, extra thyroid source of thyroid hormone (e.g., struma
ovarii), iodine-induced hyperthyroidism, thyrotropin receptor
activation [8], or viral thyroiditis.
DOI: 10.1201/9781003099062-7
Hyperthyroidism
Of women with hydatidiform mole or choriocarcinoma,
50–60% may have severe hyperthyroidism, which is primarily
treated with evacuation of the mole or therapy directed against
the choriocarcinoma.
Basic physiology/Pathophysiology
See also hypothyroid guidelines (see Chap. 6). Ninety-five per-
cent of cases are due to TSIs [8] stimulating excess thyroid hor-
mone production from the thyroid gland (Graves’ disease). These
IgG antibodies bind to and activate the G-protein-coupled thyro-
tropin receptor, which then stimulates follicular hypertrophy and
hyperplasia, as well as increases thyroid hormones production,
T3 more than T4 [2]. Women with Graves’ disease have 40–50%
remission of the disease in 12–18 months [9].
Complications
Untreated hyperthyroidism preconception or in pregnancy is
associated with increased risks of spontaneous pregnancy
loss, preterm birth, pre-eclampsia, abruption, fetal death,
FGR, low birth weight, maternal congestive heart failure, and
thyroid storm [4, 5, 8, 10–14]. Neonatal Graves’ disease can
affect neonates of women with Graves’ disease. Fetal thyro-tox-
icosis is a possibility in women with Graves’ disease. Long-term
uncontrolled hyperthyroidism, even subclinical, is associated
with increased maternal risk for atrial fibrillation, dementia,
Alzheimer’s, and hip fractures.
On the contrary, subclinical hyperthyroidism has not been
associated with adverse pregnancy outcomes [15].
Management
Pregnancy considerations
See also hypothyroid guidelines in Chapter 6, including tables.
High levels of HCG, which peak at 10–12 weeks, have some
TSH-like activity, and stimulate thyroid hormone secretion,
which in turn suppresses TSH. Normal TSH levels in pregnancy
are shown in Table 6.2. TSH suppression is even more marked
for twins. Because of pregnancy physiologic changes, hyperthy-
roidism typically ameliorates during third trimester, but may
worsen postpartum.
Gestational transient biochemical thyrotoxicosis is char-
acterized by low, usually undetectable TSH, and elevated T4: it
may occur in about 1–3% of pregnancies and is secondary to high
serum HCG, especially during the period of highest serum HCG
concentrations (10–12 weeks) [16]. It is often associated with
hyperemesis gravidarum (HG), which is defined as severe nau-
sea and vomiting associated with ketonuria and 5% weight loss
(see Chap. 9) [17].
Therefore, no testing, follow-up, or treatment for thyroid
disease in women with HG should be initiated, since there is
no true thyroid disease, and the biochemical hyperthyroidism
always spontaneously resolves [10]. Women with signs or symp-
toms of hyperthyroidism from before pregnancy can be tested,
regardless of HG.
Women of childbearing age should have an average iodine
intake of 150 μg/day. During pregnancy and breastfeeding,
women should increase their daily iodine intake to 250 μg on
average [18–20]. Most prenatal vitamins have at least 200 μg in
them. In the United States, 10–15% of pregnant women are iodine
deficient.
87
Screening/Diagnosis
Women with signs/symptoms consistent with hyperthyroid-
ism should be screened with serum TSH and FT4 [21, 22].
Clinical hyperthyroidism is diagnosed by suppressed TSH
and elevated serum FT4. FT3 is measured in patients with
suppressed TSH but normal FT4 measurements (5% of hyper-
thyroid women): FT3 elevation indicates T3 thyrotoxicosis.
Among patients with suppressed TSH and elevated FT4/FT3,
it is essential to detect the cause. Medical history and physical
examination are important to identify signs of Graves’ disease
such as absence of prior history of thyroid disfunction, no signs
of Graves’ disease, mild and self-limited symptoms, and pres-
ence of emesis are suggestive for the diagnosis of transient ges-
tational thyrotoxicosis.
TSI can be obtained in women with clinical hyperthyroidism
at the first prenatal visit [18–24]. A positive TSI is consistent with
Graves’ disease. Presence of TSI differentiates Graves’ disease
from gestational thyrotoxicosis (biochemical tests consistent
with hyperthyroidism during pregnancy, but no disease) [5, 11, 13,
17, 25, 26]. In patients with HG, routine measurements of thyroid
function are not recommended unless other overt signs of hyper-
thyroidism are evident (see Chap. 9). TSI values ≥200–500%
indicate higher risk for fetal/neonatal hyperthyroidism, and
can help fetal and neonatal management. Unfortunately, there
is no standard test for TSI, often making comparisons between
different laboratories or studies impossible.
Women with thyroid surgery/ablation in the past who con-
tinue to produce antibodies (i.e., TSI) warrant assessment of
maternal TSI level as these antibodies are associated with fetal/
neonatal Graves’ disease [23].
If maternal TSI level is elevated in early pregnancy, repetition
should occur at weeks 18–22. If TSI level is elevated at weeks
18–22, TSI measurement should be performed in the third tri-
mester, in order to identify neonates with augmented risk of thy-
roid disfunction who could need for additional monitoring [27].
Treatment
There are no randomized controlled trails (RCTs) regarding
management of hyperthyroidism in pregnancy [28]. Goal is to
control symptoms of hyperthyroidism without causing fetal
hypothyroidism, keeping FT4 slightly above or in high normal
range, regardless of TSH levels, with lowest possible dose of thi-
onamide. Propylthiouracil (PTU) >200 mg/day may result in fetal
goiter [29], while keeping the FT4 in upper non-pregnant refer-
ence range [30, 31] minimizes the risk of fetal hypothyroidism. It
may be helpful to measure TSH and FT4 every 4 weeks until
FT4 is consistently in the high normal range. Then measure-
ments every trimester may be obtained. Dosing may need to be
decreased as pregnancy advances, and about 30% can discontinue
antithyroid therapy and still remain euthyroid [27, 32].
Pregnancy outcomes have not been shown to improve with
treatment of maternal subclinical hyperthyroidism and may
result in unnecessary exposure of the fetus to antithyroid drugs
[4, 15, 25, 32]. Identification and treatment of subclinical hyper-
thyroidism during pregnancy are unwarranted [15].
In case of gestational transient thyrotoxicosis and/or HG, the
appropriate management consists in supportive therapy, correc-
tion of dehydration and hospitalization if necessary. Antithyroid
drugs are not recommended because serum T4 usually returns
to normal by 14–18 weeks’ gestation. Use of antithyroid drugs in
88
the first trimester increases the risk of birth defect and does not
improve obstetric outcomes. β-blockers may be considered [27,
32–35].
Thionamides
Either PTU or methimazole (MMI), both thionamides, can be
used to treat overt hyperthyroidism during pregnancy. The choice
of medication depends on trimester of pregnancy, response to
prior therapy, and whether the thyrotoxicosis in predominantly
FT4 or FT3.
Propylthiouracil
PTU can be started at 100–600 mg daily, divided into three
doses, depending on clinical severity. Typical PTU daily dose in
average patient is 200–400 mg [27, 32]. It might take 6–8 weeks to
get adequate effect, with initial clinical response in as little as 2–3
weeks. Usual doses are 50–150 mg every 8 hours, with require-
ments usually inversely proportional to gestational age (decrease
as pregnancy advances) [35].
Methimazole
MMI can be started at 5–30 mg daily, according to laboratory
values and severity of symptoms: typical daily dose in average
patient is 10–20 mg/daily. MMI can be generally given once a
day; it can be administrated twice a day in case of severe hyper-
thyroidism. It is an acceptable alternative as it is equally effec-
tive. In fact, in non-pregnant women, methimazole is often
preferred to PTU, as the longer half-life often allows once-
daily dosing (compared to three times a day for PTU) [27, 32].
Efficacy of methimazole may be superior to PTU with fewer side
effects [2]. However, MMI administration during first trimester
of pregnancy has been associated with a twofold increased risk
of fetal malformation compared with PTU, even if the terato-
logic risks of aplasia cutis and esophageal and choanal atresia
are extremely rare [4, 9, 36–41]. There is no significant differ-
ence between PTU and methimazole in normalizing maternal
TSH or on neonatal thyroid function, which might imply that
transplacental transfer is similar [37]. Because of the very rare
teratogenic effects of methimazole, and the dual mechanism of
action of PTU, PTU is generally prescribed for control of hyper-
thyroidism through 16 weeks of pregnancy. During second and
third trimester, both PTU and MMI can be used [9, 27, 32]. In
2009, US FDA had issued a safety alert on hepatotoxicity asso-
ciated with PTU. Therefore, in order to balance methimazole
embryopathy with PTU induced hepatotoxicity, societies have
suggested that PTU can be used through 16 weeks’ gestation
and then followed by switching over to methimazole in sec-
ond trimester [32, 35] for the rest of the pregnancy. In case of
switch, the equivalent dose of MMI to PTU is approximately 1:20
(e.g., 5 mg MMI = 100 mg PTU).
Mode of action
Both PTU and methimazole compete for peroxidase, blocking
organification of iodide, and so decreasing thyroid hormone syn-
thesis. PTU also inhibits peripheral T4 to T3 conversion, and is
therefore thought to work faster with less transplacental crossing
than methimazole [2]. For this reason, PTU is used preferentially
for FT3-predominant thyrotoxicosis [32, 35].
Side effects
Maternal. Agranulocytosis (granulocytes <250/mL) is the
most serious side effect and occurs in 0.1–0.4% of cases. Risk
factors are older gravidas and higher doses. It presents with
Maternal-Fetal Evidence Based Guidelines
fever, sore throat, malaise, or gingivitis. If hyper-thyroid women
treated with thionamides present with sore throat and fever,
discontinue therapy and check a white blood count [9]. Other
side effects (all with incidence of <5%) are thrombocytopenia,
hepatitis, lupus-like syndrome, vasculitis, rash, hives, pruritus,
nausea, vomiting, arthritis, anorexia, drug fever, and loss of
taste or smell [9, 42].
Fetal/Neonatal. As PTU and methimazole both cross the pla-
centa, they may cause fetal hypothyroidism. Transient hypo-
thyroidism may cause goiter secondary to suppression of fetal
pituitary-thyroid axis. This, however, rarely requires therapy. IQ
scores of children exposed to thionamide in utero are normal
compared to non-exposed siblings [43, 44].
Radioiodine
Radioiodine therapy is often used in the United States as the first-
or second-line (after thionamides) therapy. The goal of radio-
iodine therapy is induced hypothyroidism in order to prevent
a recurrence of Graves’ disease. This goal is achieved in about
80% of patients [2]. All women of reproductive age should have a
pregnancy test immediately before this treatment. It is generally
recommended that women do not attempt conception for 6–12
months after radioiodine treatment [2]. As the half-life for radio-
iodine is 8 days, reassurance can be provided to women who pres-
ent with conception more than 4 weeks from therapy.
This therapy is absolutely contraindicated in pregnancy.
Fetal thyroid tissue will be ablated after 10 weeks. If given after
10 weeks, termination should be presented as an option. If given
prior to 10 weeks, radioiodine does not appear to cause congeni-
tal hypothyroidism [45–47]. Breast feeding should be avoided for
120 days after this therapy.
Beta-blocker
Propranolol is the preferred β-blocker in pregnancy and can be
initiated at 10–40 mg orally every 6–8 hours. Beta-blockers are
useful for rapid control of adrenergic symptoms of thyrothoxico-
sis, until thionamide takes effect (4–6 weeks). This therapy does
not alter synthesis or secretion of the thyroid hormone. The goal
is to keep the maternal heart rate at 80–90 bpm, without palpi-
tations. Prolonged therapy can lead to fetal side effects such as
FGR, fetal bradycardia, hypoglycemia, and subnormal response
to hypoxemic stress. In the majority of patients, therapy could be
discontinued in 2–6 weeks [27, 32].
Surgery
This is the least-often used treatment. Thyroidectomy may be
indicated for women who (1) cannot tolerate thionamide; (2) need
persistently high doses of antithyroid drugs; (3) are noncompli-
ant with antithyroid drugs; (4) goiter resulting in compressive
symptoms; or (5) have other indications similar to non-pregnant
women. If indicated, second trimester is the optimal time for sur-
gery [48–50].
Iodine
Short-term use is safe for symptomatic relief [51], while use for
longer than 2 weeks may cause fetal goiter [52].
Antepartum testing
• The fetal heart rate can be assessed for at least 1 minute
at each visit by doptone to rule out fetal tachycardia >180.
• Thyroid function testing with TSH and FT4 should be per-
formed at least every trimester.
Hyperthyroidism
• Weekly NSTs can begin at 32–34 weeks, especially in
women with uncontrolled hyperthyroidism or elevated
TSIs.
• Ultrasound can assess fetal heart rate, thyroid (for goi-
ter), and growth. If clinically hyperthyroid, ultrasounds
every 4 weeks for growth may be indicated. If FGR or fetal
tachycardia is present, fetal thyroid circumference can be
assessed [53]. The sensitivity and specificity of fetal thyroid
ultrasound at 32 weeks are 92% and 100%, respectively, for
the diagnosis of clinically relevant fetal thyroid dysfunc-
tion [54].
• The fetus is at risk from either hypothyroidism from trans-
placental passage of antithyroid drugs, or from hyperthy-
roidism from TSI. The presence of a fetal goiter would
point to fetal thyroid dysfunction, but not distinguish
between these two possibilities. Fetal blood sampling
is rarely indicated, but can be considered if high mater-
nal TSI (200–500% normal), and fetal signs suggestive of
severe thyroid disease, that is, fetal hydrops, goiter, tachy-
cardia, cardiomegaly, FGR, or history of prior fetus with
hyperthyroidism [55, 56]. Fetal hyperthyroidism should
not be feared or tested for if TSIs are <130% (normal
range). If the fetus is hypothyroid, injection of thyroxine
in amniotic fluid is a possible intervention [57]. If fetus is
hyperthyroid, maternal treatment with thionamide to pre-
vent fetal effects may be indicated even if maternal T4 is
low or normal [58].
• It is important to inform the pediatrician at time of deliv-
ery of maternal diagnosis and drug therapy.
Neonate
Neonates born to mothers with Graves’ disease should be fol-
lowed closely by a pediatrician for the possibility of transient neo-
natal hyperthyroidism [54, 59, 60]. Neonatal Graves’ disease can
affect 2–5% neonates of women with Graves’, unrelated to mater-
nal thyroid function, secondary to transplacental transfer of TSI
or TBII. The risk is high if the TSI index is ≥5, or ≥200–500% [61].
Signs are tachycardia (>160 bpm), goiter, FGR, advanced bone
age, craniosynostosis, hydrops, later motor difficulties, hyperac-
tivity, or failure to thrive [61]. Neonates of women who have been
treated surgically or with radioactive iodine before pregnancy
and still have TSI are at highest risk for neonatal Graves’ disease
since thionamide therapy is not present to counteract this effect.
On the other hand, fetal and neonatal complications can also
arise from thionamide treatment of the disease, as, when this is
excessive, signs of hypothyroidism can occur.
Postpartum
Both PTU and methimazole are considered safe [62]. Only small
amounts of PTU cross into breast milk, while higher amounts
of methimazole are present in breast milk [32, 63]. Of pregnant
patients in remission from Graves’ disease, 75% will either relapse
postpartum or develop postpartum thyroiditis [9].
TSH should be performed 3 and 6 months postpartum in
women known to have thyroid peroxidase antibodies (TPO-Ab)
[64, 65]. Annual TSH level should be performed in women with
a history of postpartum thyroiditis as they have a markedly
increased risk of developing permanent primary hypothyroidism
in the next 5- to 10-year period following the episode of postpar-
tum thyroiditis [66–69].
89
Thyroid nodule
Incidence of hyroide nodules in reproductive-aged women is
reported to be 1–2% [70]. Evaluation of the thyroid nodule in
pregnancy includes obtaining complete history and physical,
TSH, and neck ultrasound. If there is sonographic evidence of
hypoechoic pattern, irregular margins, or micro calcifications,
malignancy should be suspected [71]. If there is suspicion for
malignancy, fine-needle aspiration and histologic evaluation for
malignancy should be performed [72]. For thyroid cancer in preg-
nancy, see Chap. 44.
Thyroid storm
Incidence
A rare hypermetabolic, acute life-threatening condition in preg-
nancy, which occurs in 1% of hyperthyroid women.
Precipitating factors
Labor, infection, pre-eclampsia, severe anemia, surgery.
Signs/Symptoms
Fever, tachycardia disproportionate to fever, mental status
change, vomiting, diarrhea, dehydration, cardiac arrhythmia,
congestive heart failure [5, 73], and rarely seizures, shock, stupor,
and coma.
Diagnosis
It initially should be made clinically with a combination of signs
and symptoms. Confirmatory labs include increased FT4 (or
increased FT3) and very low/undetectable TSH.
Treatment
PTU, SSKI, dexamethasone, and propranolol should be given as
shown in Table 7.1 [32]. The saturated solution of potassium iodide
and sodium iodide block the release of thyroid hormone from
TABLE 7.1: Suggest Possible Treatment of Thyroid Storm in
Pregnant Women
1. Propylthiouracil (PTU), 1000 mg orally, immediately, even before
laboratory tests are back; then 200 mg orally every 6 hours. If oral
administration is not possible, use methimazole rectal
suppositories.
2. Starting 1–2 hours after PTU administration, saturated solution of
potassium iodide (SSKI), 5 drops orally every 8 hours; or sodium
iodide, 500–1000 mg intravenously every 8 hours; or Lugol’s
solution, 10 drops every 8 hours; or lithium carbonate, 300 mg
orally every 6 hours.
3. Consider dexamethasone, 2 mg intravenously every 6 hours for
four doses; or hydrocortisone, 100 mg intravenously every 8 hours
for three doses.
4. Propranolol, 20–80 mg orally every 4–6 hours; or propranolol,
1–2 mg intravenously every 5 minutes for a total of 6 mg, then
1–10 mg intravenously every 4 hours.
5. If the patient has a history of severe bronchospasm, consider:
• Reserpine, 1–5 mg intramuscularly every 4–6 hours.
• Guanethidine, 1 mg/kg orally every 12 hours.
• Diltiazem, 60 mg orally every 6–8 hours.
6. Phenobarbital, 30–60 mg orally every 6–8 hours as needed for
extreme restlessness.
Source: Adapted from Ref. [32].
90
the gland. Dexamethasone decreases thyroid hormone release
and peripheral conversion of T4 to T3. Propranolol inhibits the
adrenergic effects of excessive thyroid hormone. Supportive
measures include IV fluids with glucose, acetaminophen (as
antipyretic), and oxygen, as needed. Fetal monitoring and mater-
nal cardiac monitoring are recommended [24]. Delivery in the
presence of a thyroid storm should be avoided if possible, with
maternal treatment leading to in utero fetal resuscitation. The
underlying cause, for example, infection, should be treated.
Resources
• National Graves’ Disease Foundation (http://www.ngdf.
org)
• American Thyroid Association Alliance for Patient Education
(http://www.thyroid.org/patients/patients.html)
• Thyroid Foundation of Canada (http://www.thyroid.ca)
References
1. Amino N, Izumi Y, Hidaka Y, et al. No increase of blocking type anti-thyro-
tropin receptor antibodies during pregnancy in patients with Graves’ dis-
ease. J Clin Endocrinol Metab 2003;88(12):5871–5874. [II-3]
2. Brent GA. Clinical practice. Graves’ disease. N Engl J Med
2008;358(24):2594–2605. [III]
3. Zophel K, Roggenbuck D, Schott M. Clinical review about TRAb assay’s his-
tory. Autoimmun Rev 2010;9(10):695–700. [III, Review]
4. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dys-
function during pregnancy and postpartum: an Endocrine Society clini-
cal practice guideline. J Clin Endocrinol Metab 2007;92(8 Suppl):S1–47.
[Review]
5. Mestman JH. Hyperthyroidism in pregnancy. Best Pract Res Clin
Endocrinol Metab 2004;18(2):267–288. [Review]
6. Dong AC, Stagnaro-Green A. Differences in diagnostic criteria mask
the true prevalence of thyroid disease in pregnancy: a systematic review
and meta-analysis. Thyroid 2019;29:278–289. [Systematic review and
meta-analysis]
7. Palmieri C, Fisher RA, Sebire NJ, Smith JR, Newlands ES. Placental-site tro-
phoblastic tumour: an unusual presentation with bilateral ovarian involve-
ment. Lancet Oncol 2005;6(1):59–61. [III]
8. Marx H, Amin P, Lazarus JH. Hyperthyroidism and pregnancy. BMJ
2008;336(7645):663–667. [Review]
9. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352(9):905–917. [III,
Review]
10. LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol
Metab Clin North Am 2006;35(1):117–136, vii. [Review]
11. Davis LE, Lucas MJ, Hankins GD, Roark ML, Cunningham FG.
Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol
1989;160(1):63–70. [II-2]
12. Mestman JH. Diagnosis and management of maternal and fetal thyroid dis-
orders. Curr Opin Obstet Gynecol 1999;11(2):167–175. [III, Review]
13. Millar LK, Wing DA, Leung AS, Koonings PP, Montoro MN, Mestman JH.
Low birth weight and pre-eclampsia in pregnancies complicated by hyper-
thyroidism. Obstet Gynecol 1994;84(6):946–949. [II-2]
14. Phoojaroenchanachai M, Sriussadaporn S, Peerapatdit T, et al. Effect of
maternal hyperthyroidism during late pregnancy on the risk of neonatal
low birth weight. Clin Endocrinol (Oxf) 2001;54(3):365–370. [II-3]
15. Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG.
Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol
2006;107(2 Pt 1):337–341. [II-2]
16. Yeo CP, Khoo DH, Eng PH, Tan HK, Yo SL, Jacob E. Prevalence of gesta-
tional thyrotoxicosis in Asian women evaluated in the 8th to 14th weeks of
pregnancy: correlations with total and free beta human chorionic gonado-
trophin. Clin Endocrinol (Oxf) 2001;55(3):391–398. [II-2]
17. Goodwin TM, Montoro M, Mestman JH. Transient hyperthyroidism
and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol
1992;167(3):648–652. [III]
18. Glinoer D. Pregnancy and iodine. Thyroid 2001;11(5):471–481. [Review]
19. Glinoer D. Feto-maternal repercussions of iodine deficiency during preg-
nancy. An update. Ann Endocrinol (Paris) 2003;64(1):37–44. [Review]
Maternal-Fetal Evidence Based Guidelines
20. Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the United
States. Trends and public health implications: iodine excretion data from
National Health and Nutrition Examination Surveys I and III (1971-1974 and
1988-1994). J Clin Endocrinol Metab 1998;83(10):3401–3408. [II-2]
21. American Association of Clinical Endocrinologists. AACE Clinical
Practice Guidelines for Evaluation and Treatment of Hyperthyroidism and
Hypothyroidism. Jacksonville, Florida; 1996. [Review]
22. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association
guidelines for detection of thyroid dysfunction. Arch Intern Med
2000;160(11):1573–1575. [III]
23. Weetman AP. Graves’ disease. N Engl J Med 2000;343(17):1236–1248. [III,
Review]
24. Ecker JL. Thyroid function and disease in pregnancy. Curr Probl Obstet
Gynecol Fertil 2000(23):109–122. [III]
25. Tan JY, Loh KC, Yeo GS, Chee YC. Transient hyperthyroidism of hypereme-
sis gravidarum. BJOG 2002;109(6):683–688. [III]
26. Goodwin TM, Montoro M, Mestman JH, Pekary AE, Hershman JM. The
role of chorionic gonadotropin in transient hyperthyroidism of hypereme-
sis gravidarum. J Clin Endocrinol Metab 1992;75(5):1333–1337. [II-2]
27. Alexander EK, Pearce EN, Brent GA, et al. 2017 guidelines of the American
Thyroid Association for the diagnosis and management of thyroid dis-
ease during pregnancy and the postpartum. Thyroid. 2017;27(3):315–389.
[Review, guideline]
28. Earl R, Crowther CA, Middleton P. Interventions for hyperthyroid-
ism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev
2013;11:CD008633. [Meta-analysis; 0 RCTs]
29. Hamburger JI. Thyroid nodules in pregnancy. Thyroid 1992 Summer;2(2):
165–168. [III]
30. Momotani N, Noh J, Oyanagi H, Ishikawa N, Ito K. Antithyroid drug ther-
apy for Graves’ disease during pregnancy. Optimal regimen for fetal thyroid
status. N Engl J Med 1986;315(1):24–28. [II-2]
31. Mortimer RH, Tyack SA, Galligan JP, Perry-Keene DA, Tan YM. Graves’
disease in pregnancy: TSH receptor binding inhibiting immunoglobu-
lins and maternal and neonatal thyroid function. Clin Endocrinol (Oxf)
1990;32(2):141–152. [II-3]
32. American College of Obstetricians and Gynecologists. Practice Bulletin No.
223: thyroid disease in pregnancy. Obstet Gynecol 2020;135(6):e261–e274.
[Review, guideline]
33. Bouillon R, Naesens M, Van Assche FA, et al. Thyroid function in patients
with hyperemesis gravidarum. Am J Obstet Gynecol 1982;143:922–926.
[II-3]
34. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol
2006;108:1283–1292. [III]
35. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association
guidelines for diagnosis and management of hyperthyroidism and other
causes of thyrotoxicosis. Thyroid 2016;26:1343–1421. [Review, guideline]
36. Wing DA, Millar LK, Koonings PP, Montoro MN, Mestman JH. A compari-
son of propylthiouracil versus methimazole in the treatment of hyperthy-
roidism in pregnancy. Am J Obstet Gynecol 1994;170(1 Pt 1):90–95. [II-2]
37. Momotani N, Noh JY, Ishikawa N, Ito K. Effects of propylthiouracil and
methimazole on fetal thyroid status in mothers with Graves’ hyperthyroid-
ism. J Clin Endocrinol Metab 1997;82(11):3633–3636. [II-2]
38. Clementi M, Di Gianantonio E, Pelo E, Mammi I, Basile RT, Tenconi R.
Methimazole embryopathy: delineation of the phenotype. Am J Med Genet
1999;83(1):43–46. [III]
39. Di Gianantonio E, Schaefer C, Mastroiacovo PP, et al. Adverse effects of
prenatal methimazole exposure. Teratology 2001;64(5):262–266. [II-2]
40. Yoshihara A, Noh J, Yamaguchi T, et al. Treatment of Graves’ disease with
antithyroid drugs in the first trimester of pregnancy and the prevalence of
congenital malformation. J Clin Endocrinol Metab 2012;97(7):2396–2403.
[II-3]
41. Laurberg P, Andersen SL. Antithyroid drug use in pregnancy and birth
defects: Why some studies find clear associations, and some studies report
none. Thyroid 2015;25(11):1185–1190. [III]
42. Abraham P, Avenell A, Watson WA, Park CM, Bevan JS. Antithyroid drug
regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst Rev
2005;(2):CD003420. [Meta-analysis, Review]
43. Burrow GN, Klatskin EH, Genel M. Intellectual development in children
whose mothers received propylthiouracil during pregnancy. Yale J Biol Med
1978;51(2):151–156. [II-2]
44. Eisenstein Z, Weiss M, Katz Y, Bank H. Intellectual capacity of sub-
jects exposed to methimazole or propylthiouracil in utero. Eur J Pediatr
1992;151(8):558–559. [II-2]
45. Berg GE, Nystrom EH, Jacobsson L, et al. Radioiodine treatment of hyper-
thyroidism in a pregnant women. J Nucl Med 1998;39(2):357–361. [II-3]
Hyperthyroidism
46. Evans PM, Webster J, Evans WD, Bevan JS, Scanlon MF. Radioiodine
treatment in unsuspected pregnancy. Clin Endocrinol (Oxf) 1998;48(3):
281–283. [II-3]
47. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the
American Thyroid Association for the diagnosis and management of
thyroid disease during pregnancy and postpartum. Thyroid 2011;21(10):
1081–1125. [III]
48. Stice RC, Grant CS, Gharib H, van Heerden JA. The management of Graves’
disease during pregnancy. Surg Gynecol Obstet 1984;158(2):157–160. [II-3]
49. Burrow GN. The management of thyrotoxicosis in pregnancy. N Engl J Med
1985;313(9):562–565. [Review]
50. Brodsky JB, Cohen EN, Brown BW, Jr, Wu ML, Whitcher C. Surgery during
pregnancy and fetal outcome. Am J Obstet Gynecol 1980;138(8):1165–1167.
[II-2]
51. Nohr SB, Jorgensen A, Pedersen KM, Laurberg P. Postpartum thyroid dys-
function in pregnant thyroid peroxidase antibody-positive women living in
an area with mild to moderate iodine deficiency: is iodine supplementation
safe? J Clin Endocrinol Metab 2000;85(9):3191–3198. [II-2]
52. Momotani N, Hisaoka T, Noh J, Ishikawa N, Ito K. Effects of iodine on thy-
roid status of fetus versus mother in treatment of Graves’ disease compli-
cated by pregnancy. J Clin Endocrinol Metab 1992;75(3):738–744. [II-2]
53. Ranzini AC, Ananth CV, Smulian JC, Kung M, Limbachia A, Vintzileos
AM. Ultrasonography of the fetal thyroid: nomograms based on biparietal
diameter and gestational age. J Ultrasound Med 2001;20(6):613–617. [II-2]
54. Luton D, Le Gac I, Vuillard E, et al. Management of Graves’ disease during
pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol
Metab 2005;90(11):6093–6098. [II-3]
55. Nachum Z, Rakover Y, Weiner E, Shalev E. Graves’ disease in pregnancy:
prospective evaluation of a selective invasive treatment protocol. Am J
Obstet Gynecol 2003;189(1):159–165. [II-2]
56. Kilpatrick S. Umbilical blood sampling in women with thyroid disease in
pregnancy: Is it necessary? Am J Obstet Gynecol 2003;189(1):1–2. [III]
57. Hanono A, Shah B, David R, et al. Antenatal treatment of fetal goiter: a ther-
apeutic challenge. J Matern Fetal Neonatal Med 2009;22(1):76–80. [II-3]
58. Peleg D, Cada S, Peleg A, Ben-Ami M. The relationship between maternal
serum thyroid-stimulating immunoglobulin and fetal and neonatal thyro-
toxicosis. Obstet Gynecol 2002;99(6):1040–1043. [II-2]
59. McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and
hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992
Summer;2(2):155–159. [Review]
91
60. Mitsuda N, Tamaki H, Amino N, Hosono T, Miyai K, Tanizawa O. Risk
factors for developmental disorders in infants born to women with Graves’
disease. Obstet Gynecol 1992;80(3 Pt 1):359–364. [III]
61. Becks GP, Burrow GN. Thyroid disease and pregnancy. Med Clin North Am
1991;75(1):121–150. [III, Review]
62. Committee on Drugs. Transfer of drugs and other chemicals into human
milk. Pediatrics 2001;108(3):776–789. [Review]
63. Briggs GG, Freeman RK, Yaffe SJ. eds. Drugs in Pregnancy and Lactation: A
Reference Guide to Fetal and Neonatal Risk. 6th ed.: Lippincott Williams &
Wilkins; 2001. [II-2]
64. Premawardhana LD, Parkes AB, John R, Harris B, Lazarus JH. Thyroid
peroxidase antibodies in early pregnancy: utility for prediction of post-
partum thyroid dysfunction and implications for screening. Thyroid
2004;14(8):610–615. [II-2]
65. Stagnaro-Green A. Clinical review 152: Postpartum thyroiditis. J Clin
Endocrinol Metab 2002;87(9):4042–4047. [Review]
66. Azizi F. The occurrence of permanent thyroid failure in patients with sub-
clinical postpartum thyroiditis. Eur J Endocrinol 2005;153(3):367–371.
[II-3]
67. Premawardhana LD, Parkes AB, Ammari F, et al. Postpartum thyroid-
itis and long-term thyroid status: prognostic influence of thyroid per-
oxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab
2000;85(1):71–75. [II-1]
68. Othman S, Phillips DI, Parkes AB, et al. A long-term follow-up of postpar-
tum thyroiditis. Clin Endocrinol (Oxf) 1990;32(5):559–564. [II-2]
69. Tachi J, Amino N, Tamaki H, Aozasa M, Iwatani Y, Miyai K. Long term
follow-up and HLA association in patients with postpartum hypothyroid-
ism. J Clin Endocrinol Metab 1988;66(3):480–484. [II-2]
70. Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid disease
in pregnancy. Obstet Gynecol Clin North Am 2010;37(2):173–193. [III]
71. Gharib H, Papini E, Paschke R, et al. American Association of Clinical
Endocrinologists, Associazione Medici Endocrinologi, and European
Thyroid Association medical guidelines for clinical practice for the diag-
nosis and management of thyroid nodules: Executive Summary of recom-
mendations. J Endocrinol Invest 2010;33(5):287–291. [III]
72. Bartolazzi A, Gasbarri A, Papotti M, et al. Application of an immunodi-
agnostic method for improving preoperative diagnosis of nodular thyroid
lesions. Lancet 2001;357(9269):1644–1650. [II-3]
73. Sheffield JS, Cunningham FG. Thyrotoxicosis and heart failure that compli-
cate pregnancy. Am J Obstet Gynecol 2004;190(1):211–217. [III]
8
PROLACTINOMA
Matteo Antonio Ucci
Key points
• Diagnosis: elevated prolactin and MRI-proven pituitary
adenoma.
• Preconception: treat with dopamine agonist (bro-
mocriptine or cabergoline) aiming to normalize prolactin
and decrease size of adenoma, continuing therapy up to
positive pregnancy test. Discourage pregnancy until those
aims have been achieved, and any neurologic or visual
symptoms or suprasellar involvement have been resolved.
• Maternal risk is adenoma enlargement; this occurs in
pregnancy in 2–2.5% of microadenomas and about 20–30%
of macroadenomas with no prior surgery or irradiation,
and in 4.7% with prior surgery/irradiation.
• Bromocriptine and cabergoline have been shown to be
safe for the fetus.
• Cabergoline has been shown to be more effective than
bromocriptine in non-pregnant adults and should prob-
ably be the drug of choice in pregnancy as well. Compared
to cabergoline, bromocriptine has the following advantages:
cheaper, more pregnancy safety data, no association with
cardiac-valve disease; but its disadvantages include twice
daily (versus twice weekly) dosing, and more side effects.
• Management depends on the size of adenoma:
• Microadenoma (<1 cm): Consider stopping dopamine
agonist in pregnancy, especially if normal pre-preg-
nancy prolactin and stable microadenoma >2 years.
During the pregnancy, the woman should be asked
about headaches and changes in vision at each visit
(at least every three months). The decision to treat
with dopamine agonist is based on symptoms (e.g.,
headache) and signs (e.g., abnormal visual field
examination) only. Prolactin levels should not be
checked since they physiologically (10-fold) increase in
pregnancy.
• Macroadenoma (≥1 cm): Dopamine agonist should
be continued. Other experts suggest consideration for
stopping dopamine agonist with macroadenoma within
the sellar boundaries. Monitoring as per microade-
noma, plus formal visual field testing every 3 months.
Transsphenoidal surgery suggested usually only if max-
imal dopamine agonist therapy is ineffective.
• Postpartum: Continue dopamine agonist therapy in those
with macroadenomas. A prolactin level and MRI 6–8
weeks postpartum can be performed to assess for regres-
sion/remission, although prolactin levels may not nor-
malize until 6 months postpartum. Continue dopamine
agonist in women with microadenomas and elevated pro-
lactin. Consider stopping therapy in women with microad-
enomas, stable >2 years, normal prolactin, and on low-dose
therapy. If on dopamine agonist therapy, women should be
advised against breastfeeding.
92
Diagnosis/Definition
Pituitary adenomas producing prolactin (prolactinomas, or lacto-
troph adenomas) are diagnosed by sustained non-pregnant eleva-
tion of serum prolactin (usually >40 μg/L × 2; normal prolactin
non-pregnant: <20 μg/L) and radiographic (best is MRI) evidence
of pituitary adenoma. Rule out other causes of prolactinemia
(Table 8.1) [1, 2] and macroprolactinemia (a condition where more
than 60% of circulating prolactin is made up of macroprolactin,
a complex formed by IgG and monomeric prolactin that result in
elevate serum prolactin but has low biological activity and usually
requires no treatment) in all asymptomatic patients [3, 4].
Symptoms
Before pregnancy, galactorrhea in 80% of women and irregular
menses (e.g., oligomenorrhea). With macroadenoma headaches
and visual field defects can be present.
Epidemiology/Incidence
Prolactinomas account for about 40–60% of pituitary tumors.
They are the most common type of secretory pituitary tumor. The
relative prevalence of prolactinomas range from 10–54 cases per
100,000 person-year [5, 6].
Etiology/Basic pathophysiology
These adenomas produce prolactin. Outside of pregnancy, pro-
lactin levels parallel tumor size fairly closely. Increased prolactin
usually causes infertility because of the inhibitory effect of pro-
lactin on secretion of GNRH, which in turn inhibits the release
of LH and FSH, thus impairing gonadal steroidogenesis and ovu-
lation, and thereby conception. Sometimes the mass effect of a
macroadenoma can also lead to infertility. Prolactinomas are
usually benign and nonhereditary.
Classification
Microadenoma: <10 mm; macroadenoma: ≥10 mm.
Complications
Mother
The principal risk is the increase in adenoma size sufficient to
cause neurologic symptoms, most importantly visual impair-
ment or also headaches. In women with lactotroph adenomas
who become pregnant, the hyperestrogenemia of pregnancy may
increase the size of the adenoma. This should be distinguished
from increase in pituitary (overall) size, which is physiologic in
pregnancy. The risk that the adenoma increase will be clinically
DOI: 10.1201/9781003099062-8
Prolactinoma
TABLE 8.1: Etiology of Hyperprolactinemia
Physiologic:
Coitus, exercise, pregnancy, lactation, nipple stimulation, stress, sleep
Pathologic
Pituitary disease:
Prolactinomas, acromegaly, Cushing disease, empty sella syndrome,
lymphocytic hypophysitis, plurihormonal adenoma
Hypothalamic disease:
Pituitary stalk damage by trauma/section, infiltration/compression by
tumors (craniopharyngiomas, dysgerminomas, meningiomas,
metastases, etc.) or other lesions such as Rathke’s cyst, infiltrative
disorders (histiocytosis, sarcoidosis, etc.), irradiation
Systemic disease:
Chest wall lesion ( trauma, surgery, herpes zoster, etc.), cirrhosis, chronic
renal failure, hypothyroidism, PCOS, adrenal insufficiency,
pseudocyesis, epileptic seizures
Ectopic production:
Renal cell carcinoma, ovarian teratomas, gonadoblastoma, non-Hodgkin
lymphoma, uterine cervical carcinoma, colorectal adenocarcinoma, etc.
Medications:
• Antipsychotics (typical and atypical)
• Antidepressants (tricyclic, SSRIs, SNRIs, MOA-I)
• Antihypertensive drugs (verapamil, α-methyldopa, reserpine,
intravenous labetalol)
• Prokinetic agents (metoclopramide, domperidone)
• Antihistamines (H2)
• Estrogens
• Anesthetics
• Opiates
Idiopathic:
Macroprolactinemia (the presence of macroprolactin, a bigger isoform of
prolactin, elevate serum prolactin level without symptoms and need for
treatment)
Source: Adapted from Refs. [2–4].
Abbreviations: SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin and
noradrenaline reuptake inhibitors; MOA-I, monoamine oxidase inhibitors; PCOS,
polycystic ovarian syndrome.
important depends on the size of the adenoma before preg-
nancy. The risk of a clinically important increase in the size of a
lactotroph microadenoma during pregnancy is small. Because of
enlargement, about 2–2.5% of pregnant women with microad-
enomas develop neurologic symptoms [7, 8], such as headaches
and/or a visual field abnormality, and about 1% diabetes insipidus.
With macroadenomas, with no prior surgery or irradiation neu-
rologic symptoms occur in about 20–30% or higher of pregnant
women [7, 8] and in 4.7% of macroadenomas with prior surgery/
irradiation [7], and diabetes insipidus in about 1–2% [9–11]. Long-
term hyperprolactinemia may lead to decrease in bone density,
which again increases (not back to normal levels) after normal
prolactin levels are re-established [1].
Rarely a pituitary macroadenoma can be accompanied by
hyponatremia [12] possibly due to a local mechanical stress [12,
13]. In such cases in a pregnant woman consider the possibility of
pre-eclampsia, because it has recently been associated with hypo-
natremia in a newly defined pre-eclampsia presentation named
PALS – pre-eclampsia and low sodium [14].
93
Fetus
The main potential risk to the fetus is from dopamine agonist
treatment of hyperprolactinemia. As dopaminergic neurons form
early in fetal development, dopamine represents a key component
of motor and cognitive development, and both bromocriptine
and cabergoline cross the placenta [7, 15, 16]. Administration
of bromocriptine during the first months of pregnancy does not
harm the fetus (over 6000 pregnancies reported) [7, 8, 17–19].
Data available about the use of bromocriptine later in pregnancy
are less, but no adverse events have been reported. Cabergoline
use in pregnancy is probably safe as well (over 1000 pregnancies
reported), but less experience is reported in comparison to bro-
mocriptine (see also preconception counseling) [7, 15, 16, 19–23].
Because of the long half-life of cabergoline, concerns were raised
about use in pregnancy induction (i.e. achieving pregnancy in a
previously infertile woman) [15], however use of cabergoline in
early pregnancy has not been associated with negative outcomes
and thus far, there is no evidence to suggest an increased risk of
major malformations beyond the baseline risk [7, 15, 16, 19, 22,
23]. There are however, limited data available about use of caber-
goline throughout pregnancy [5, 7, 15].
Pregnancy considerations
The ability to treat prolactinomas successfully with dopamine
agonists in >90% of patients allows most women with this disor-
der to become pregnant. The theoretical basis for an increase in
size of the pituitary during pregnancy is that hyperestrogenemia
causes lactotroph hyperplasia. Secondary to estrogen causing lac-
totroph hyperplasia, there is a progressive increase in pituitary
size throughout pregnancy, as assessed by MR imaging, so that
the volume during the third trimester is more than double of that
in non-pregnant women [24].
Pregnancy-related management
Principles
Effect of pregnancy on disease
The whole pituitary enlarges in pregnancy and the prolactinoma
itself can enlarge. Prolactin levels are physiologically elevated
in pregnancy and cannot be used for management. Serum lev-
els of prolactin in non-pregnant patients with prolactinomas are
usually proportional to the tumor mass [4], but this relation is lost
in pregnancy, particularly if dopamine agonists are discontinued
early in pregnancy [3, 19]. Prolactin levels do not correlate well
with symptoms in both non-pregnant and pregnant patients with
prolactinomas [25].
Effect of disease on pregnancy
No obstetrical effects unless major surgery is needed.
Workup
In pregnancy
• Prolactin levels are not helpful in pregnancy.
• MRI is more effective in revealing small tumors and the
extension of large tumors compared to CT scan [1].
• Visual field testing is indicated in women with macroad-
enomas (see Figure 8.1).
In non-pregnant woman
If an elevated prolactin is detected, this should be repeated.
If still elevated, then a head MRI is performed, even in
cases of mild hyperprolactinemia. At initial diagnosis,
94 Maternal-Fetal Evidence Based Guidelines

PRECONCEPTION

- Dopamine agonist therapy aiming to normalize prolactin and shrink adenoma

- Discourage pregnancy until neurologic/visual symptoms resolved
- MRI (gadolinium-enhanced) before pregnancy

PREGNANCY

MICROADENOMA (<1 cm) MACROADENOMA (>1 cm)

- Stop dopamine agonist
**Especially if stable
adenoma ≥24 months**
- Ask regarding visual symptoms,
headache at each visit
- Continue dopamine agonist
- Ask regarding visual symptoms
headache at each visit
symptomatic

symptomatic - Visual field exam every 3 months

Yes Yes
Abnormal

- Head MRI
- Consider restart/increase dopamine agonist therapy or
change to cabergoline
- Endocrine/Neuro-ophthalmology consult
- Transsphenoidal surgery only if maximal dopamine agonist
therapy ineffective (Table 8.4)

FIGURE 8.1 Management of prolactinoma in pregnancy (see also Table 8.3).

thyroid-stimulating hormone and free T4, renal and hepatic Bromocriptine (Parlodel)
function should be assessed [25]. Dose: Started at 0.625 mg po qhs with snack for one week. Then
add 1.25 mg qam for one week, and increase by 1.25 mg. So
Treatment at 4 weeks, a total of 5 mg total dose (split 2.5 mg ql2h) is
The primary therapy for all prolactinomas is a dopamine agonist. reached and prolactin rechecked. Usually a total of 5–7.5 mg
The dopamine agonists approved in the United States are bro- (split ql2h) total dose is required. It can also be used intravagi-
mocriptine and cabergoline (see Figure 8.1). Dose recommenda- nally (same dose, less side effects, minimal vaginal irritation).
tions and side effects are listed in Tables 8.2 and 8.3 [25]. Mechanism of action: Dopamine agonist (dopamine inhibits
lactotroph receptors, so less prolactin is produced, and the
size of tumors is decreased); ergot derivative.
TABLE 8.2: Dose and Side Effect Profiles for Dopamine
Agonists Approved for Use in the United States
TABLE 8.3: Indications for Therapy in Patients with
Medication Dose Side Effects of Both Drugsa Prolactinomas
Bromocriptine Initial: 0.625–1.25 mg Nausea, headaches, dizziness Main indication in pregnancy
daily; usual range for (postural hypotension), nasal Macroadenoma
maintenance dose: congestion, constipation
2.5–10.0 mg daily Infrequent: fatigue, anxiety, Pregnant and non-pregnant
depression, alcohol intolerance Enlarging microadenoma
Rare: cold-sensitive vasospasm, Bothersome galactorrhea
psychosis Gynecomastia
Cabergoline Initial: 0.25–0.5 mg Possible: cardiac-valve Acne and hirsutism
weekly; usual range abnormalities (reported with
for maintenance dose: cabergoline) Non-pregnant
0.25–3.0 mg weekly Infertility
Oligomenorrhea or amenorrhea
Source: Modified from Ref. [25].
a More common with bromocriptine. Source: Modified from Ref. [25].
Prolactinoma
Evidence for effectiveness: See later in this chapter.
Safety in pregnancy: Safe (FDA category B); breastfeeding is
contraindicated.
Side effects: Nausea, hypotension, and depression (less if ther-
apy initiated at night).
Cabergoline (Dostinex)
Dose: Start at 0.25 mg twice weekly, increase monthly to nor-
mal prolactin. Usual required dose is 0.25–0.5 mg twice
weekly; maximum dose should be 1 mg twice weekly.
Mechanism of action: Dopamine agonist (see earlier in this
chapter); ergot derivate; high affinity for lactotroph dopa-
mine receptors.
Evidence for effectiveness: See later in this chapter.
Safety in pregnancy: Safe (FDA category B); breastfeeding is
contraindicated.
Side effects: Associated with heart-valve disease in very high
doses.
Preconception counseling
Treatment of women with lactotroph adenomas outside of preg-
nancy is based on the size of the tumor, presence/absence of
gonadal dysfunction, and woman’s desire regarding fertility [1].
Indications for therapy in adults with prolactinoma are listed in
Table 8.3 [25]. Treatment should begin before conception with
advice to the woman and her partner about the risks of preg-
nancy to her and the fetus. When a dopamine agonist is needed
to lower the serum prolactin concentration to permit ovulation,
counselling should include the fact that bromocriptine has
larger safety data, while cabergoline (Dostinex) has less data
in pregnancy (although all reassuring thus far). Malformation
and other pregnancy outcomes seems to not have increased [5,
7]. Bromocriptine normalizes prolactin levels in >80% of women
with microadenomas, restoring menses and fertility in >90%.
Compared to cabergoline, bromocriptine has the following
advantages: it is cheaper, there are more pregnancy safety data,
and there is no association with heart-valve disease; but its dis-
advantages include twice daily (vs. twice weekly) dosing, less
effective at normalizing prolactin levels, and more side effects
[25]. If a woman cannot tolerate bromocriptine, cabergoline
should be recommended; 70% of patients who do not have a
response to bromocriptine respond to cabergoline. Overall, cab-
ergoline is effective in inducing pregnancy at a high rate, even in
cases that have been traditionally considered difficult to treat,
such as those with large tumor size, bromocriptine resistance,
or bromocriptine intolerance [26]. There are however, substan-
tial numbers of women (approximately 18%), who are resistant
to cabergoline and will require higher doses to achieve nor-
malization of prolactin levels and to ovulate [19]. Quinagolide
(pergolide) should not be recommended because it is not FDA
approved to treat hyperprolactinemia, has not been well stud-
ied during pregnancy, and has been associated with cardiac
valvular defects [27]. In non-pregnant adults with prolactino-
mas, prolactin levels and MRI should be checked after diagnosis
and stabilization once a year for 3 years, and then about every
2 years if the patient’s condition is stable. In patients with nor-
mal prolactin for ≥2 years on low-dose therapy, some consider
stopping the dopamine agonist therapy. The risk of enlargement
over time in untreated patients is about 20% [25]. With micro-
prolactinomas, surgery has a high likelihood of cure and gives
the opportunity to become pregnant without dopamine agonist
medication. In macroprolactinomas, pre-pregnancy debulking
95
significantly reduces the risk of symptomatic enlargement dur-
ing pregnancy [28].
Microadenomas
A woman who has a lactotroph microadenoma should be told
that the risk of clinically important enlargement of her adenoma
during pregnancy is very small (2–2.5%) and that it should not
be a deterrent to becoming pregnant. She should also be told
that bromocriptine or cabergoline will likely be effective if symp-
toms do occur. If she is willing to take this small risk of enlarge-
ment, she should be given bromocriptine or cabergoline before
pregnancy in whatever dosage is necessary to lower her serum
prolactin concentration to normal. Bromocriptine is the drug
associated with the greater experience. When the serum prolac-
tin concentration is normal and menses have occurred regularly
for a few months, the woman can attempt to become pregnant.
Before pregnancy, the dopamine agonist should be tapered to the
lowest effective dose, and can be discontinued before pregnancy
if used for >24 months with normal prolactin levels, as about
25% of patients maintain normal levels even off of medication;
although most need to restart it.
Macroadenomas
A woman who has a lactotroph macroadenoma should be advised
of the relatively higher risk of clinically important tumor enlarge-
ment during pregnancy [9–11]. A macroadenoma is an absolute
indication for therapy (dopamine agonist, followed together
with endocrinologist), in non-pregnant or pregnant women.
Doses of dopamine agonists sufficient to control the macroad-
enoma are usually higher (bromocriptine 7.5–10 mg/daily; cab-
ergoline 0.5–1 mg twice weekly) than with microadenomas. The
goals of treatment are to decrease prolactin levels and symptoms,
to decrease and stabilize the tumor mass, and to prevent head-
aches and cranial nerve compression [25]. Before pregnancy, the
dopamine agonist should be carefully tapered to lowest effec-
tive dose. This may take weeks to years. Advice and monitoring
depend on the size of the adenoma.
• If the macroadenoma does not elevate the optic chiasm
or extend behind the sella, treatment with bromocrip-
tine or cabergoline for a sufficient period to shrink it sub-
stantially should reduce the chance of clinically important
enlargement during pregnancy [9, 29]. As with treatment
with dopamine agonists, this risk is likely only somewhat
increased compared with microadenomas [19]. Once suffi-
cient decrease in size has occurred, the woman can attempt
to become pregnant.
• If the adenoma is very large or elevates the optic chi-
asm, pregnancy should be strongly discouraged until the
adenoma has been adequately treated and it shrinks within
sellar boundaries [5, 30]. Despite ongoing treatment with
dopamine agonists, large macroadenomas, particularly
those with extension beyond the sella, have a 23% risk of
undergoing clinically significant increase in size during
pregnancy [19]. If the macroadenoma extends behind the
sella, the woman should undergo visual field examination
and testing of anterior pituitary function. Transsphenoidal
surgery may be necessary and perhaps postoperative
radiation. Postoperative treatment with bromocriptine
or cabergoline may also be helpful in reducing adenoma
size further and lowering the serum prolactin concentra-
tion to normal. Such a regimen reduces the chance that
96
symptomatic expansion will occur during pregnancy [9,
10], but it may still occur. Cabergoline has the potential for
use as the primary therapeutic agent for macroadenomas,
even those that extend beyond the sella, and may prevent
the need for traditional combination therapy with surgery,
radiotherapy, and bromocriptine [26] Cabergoline has been
shown to be more effective than bromocriptine in non-
pregnant adults and should probably be the drug of choice
in pregnancy as well as bromocriptine.
• Pregnancy should be discouraged in a woman whose
macroadenoma is unresponsive to bromocriptine and
cabergoline, even if it is not elevating the optic chiasm,
until the size has been greatly reduced by transsphenoidal
surgery, because medical treatment would not likely be
effective if the adenoma enlarges during pregnancy.
Prenatal care
See also “Preconception Counseling.”
Microadenoma
Bromocriptine, and probably cabergoline, are safe in pregnancy.
They can be discontinued as soon as pregnancy has been con-
firmed if the patient who has a normal prolactin and a recent
reassuring (adenoma <1 cm) MRI so desires. The risk of clinically
significant tumor enlargement during pregnancy is about 2–2.5%
for microprolactinomas [7].
During the pregnancy, the woman should be asked about
headaches and changes in vision at each visit (or at least every
3 months). Formal visual field test every 3 months can be per-
formed, but are not absolutely necessary. If symptoms related to
tumor growth as headache and/or visual impairment occur, sellar
MRI without contrast and visual field testing with neurooph-
talmologic evaluation must be performed. [5, 7, 30]. MRI in the
first trimester is safe for the fetus [31, 32]. Gadolinium may be
retained in the body for months to years after administration.
Gadolinium should be avoided in pregnancy because when used
as contrast media has been shown a slightly increased risk of
stillbirth or neonatal death when exposed at any point dur-
ing pregnancy (17.6 per 1000 in exposed fetuses vs. 6.9 per 1000
fetuses not exposed) but no significant difference was seen in
infants exposed during only the first trimester, suggesting that
exposure during the second or third trimester may have a higher
risk. To note that fetuses exposed to gadolinium during the first
trimester had an increased risk of childhood diagnosis of a
broad set of rheumatological, inflammatory, or infiltrative
skin conditions (125.8 per 1000 person-years in exposed fetuses
vs. 93.7 per 1000 person-years in fetuses not undergoing MRI).
There is no significant difference regarding nephrogenic systemic
fibrosis and the risk of congenital anomalies between exposed
and non-exposed infants. [31, 32]. The decision to treat with
dopamine agonist is based on symptoms (e.g. headache) and
signs (e.g. abnormal visual filed examination) only. It should
not be based on prolactin levels. In fact, prolactin levels should
not be checked since they physiologically increase (about 10-fold)
in pregnancy. If no symptoms occur, serum prolactin can be mea-
sured about 2 months after delivery or cessation of nursing, and
if it is similar to the pretreatment value, the drug can be resumed.
Macroadenoma
The dopamine agonist should be continued during preg-
nancy in most cases. In these patients, discontinuation of
Maternal-Fetal Evidence Based Guidelines
TABLE 8.4: Indication for Neurosurgery in Patients with
Prolactinomas
Pregnant or non-pregnant
Increasing tumor size despite optimal medical therapy
Dopamine agonist-resistant macroadenoma
Pituitary apoplexy
Inability to tolerate necessary dopamine agonist therapy
Persistent chiasmal compression despite optimal medical therapy
Medically unresponsive cystic prolactinoma
Cerebrospinal fluid leak during administration of dopamine agonist
Macroadenoma in a patient with a psychiatric condition for which
dopamine agonists are contraindicated
Infertility patients
Dopamine agonist-resistant microadenoma, if ovulation induction is not
appropriate
Macroadenoma in proximity to optic chiasm despite optimal medical
therapy (pre-pregnancy debulking recommended)
Source: Modified from Ref. [25].
the drug usually leads to expansion of the adenoma [1]. Some
experts suggest consideration for stopping dopamine agonist
with macroadenoma within the sellar boundaries because data
on dopamine agonist therapy used throughout the gestation are
scarce [5, 7]. Monitoring during pregnancy should be similar to
that described earlier for women with microadenomas, except
for the fact that formal visual field testing every 3 months
should be performed [5]. The risk of clinically significant
tumor enlargement during pregnancy is about 30% for macrop-
rolactinomas [25].
A perceived change in vision should be assessed by a neuro-
ophthalmologist, and an MRI without gadolinium should be per-
formed if an abnormality consistent with a pituitary adenoma is
confirmed. If the adenoma has enlarged to a degree that could
account for the symptoms, the woman should be treated with
higher doses of bromocriptine throughout the remainder of the
pregnancy, which will usually decrease the size of the adenoma
and alleviate the symptoms [33, 34]. If the adenoma does not
respond to bromocriptine, cabergoline may be successful [35]. If
cabergoline is not successful, transsphenoidal surgery could be
considered in the second trimester if vision is severely compro-
mised; in comparison, surgery for persistent visual symptoms in
the third trimester should be deferred until delivery, if possible.
Surgery is recommended only if medical therapy is ineffective.
Indications for neurosurgery in a patient with prolactinoma are
listed in Table 8.4 [25]. Surgical cure rates are <50% with mac-
roadenomas, with up to 80% of these patients experiencing recur-
rent hyperprolactinemia [25].
Antepartum testing
None needed (except if other indications present).
Delivery
No special precautions.
Anesthesia
No special precautions.
Prolactinoma
Postpartum
A prolactin level and a gadolinium-enhanced MRI can be per-
formed 6–8 weeks postpartum. Prolactin levels may not normal-
ize until 6 months postpartum [25]. Varying rates of remission
have been reported after postpartum, ranging from 10% to
almost 70%. Particularly those with smaller adenoma size ini-
tially and/or normalization of pituitary MRI following pregnancy
have a higher chance of remission [22, 30]. The mechanisms of
tumor regression/remission are unknown, but proposed mecha-
nisms include changes in estrogen and/or dopamine status fol-
lowing pregnancy or autoinfarction of the tumor [16, 26]. All
women with macroadenomas and those with microadenomas
and elevated prolactin should be continued/started on dopamine
agonist therapy, with endocrine follow-up. In women stable for
over 2 years with microadenoma with normal prolactin and low
dose of therapy, consideration can be given to stopping therapy
[25]. If therapy is stopped, close follow-up is necessary, as even in
stable patients with normal prolactin, recurrence of hyperprolac-
tinemia is >30% for microprolactinomas and >50% for macropro-
lactinomas [25]. Other methods of contraception can be used, but
oral estrogen-containing pills are also probably safe [25].
Breastfeeding
A microadenoma is not a contraindication to nursing. If the
woman has no neurologic symptoms at the time of delivery and
there was no symptomatic tumor enlargement in pregnancy, nurs-
ing should not be of substantial risk [30], as breastfeeding does not
appear to increase the risk of tumor enlargement and hyperpro-
lactinemia recurrence [16]. If the woman decides to breastfeed
the dopamine agonist therapy is usually not be resumed until
breastfeeding ends [30] and there is no need to limit duration of
breastfeeding. [36]. If she does have neurologic symptoms at the
time of delivery or if they develop during nursing, she should be
treated with a dopamine agonist. Since dopamine agonists sup-
press lactation, if dopamine agonists are necessary, the women on
these drugs should be advised against breastfeeding.
I thank Katherine Husk, who wrote the previous version of this
chapter, which was fundamental in writing the current one.
References
1. Schlechte JA. Prolactinoma. N Engl J Med 2003;349:2035–2041. [III; review]
2. Molitch ME. Diagnosis and treatment of pituitary adenomas: A review.
JAMA. 2017;317(5):516–524.
3. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of
hyperprolactinoemia: an Endocrine Society clinical practice guideline. J
Clin Endocrinol Metab 2011;96(2):273–288. [III]
4. Vilar L, Vilar CF, Lyra R, Freitas MDC. Pitfalls in the diagnostic evaluation
of hyperprolactinemia. Neuroendocrinology. 2019;109(1):7–19. [III; review]
5. Glezer A, Bronstein MD. Prolactinomas in pregnancy: Considerations
before conception and during pregnancy. Pituitary 2020;23(1):65–69. [III
review, long term follow up with bromocriptine: two studies no impair-
ments in 1052 children up to 9 years, one study reported 1 idiopathic hydro-
cephalus, 1 tuberous sclerosis, 1 precocious puberty in 70 children followed
up to 20 years; with cabergoline: two studies, no abnormality in 5 and
83 children followed up to 20 years and 12 years respectively]
6. Melmed S. Pituitary-tumor endocrinopathies. N Engl J Med 2020;382(10):
937–950. [III; review]
7. Huang W, Molitch ME. Pituitary tumors in pregnancy. Endocrinol Metab
Clin North Am 2019;48(3):569–581. [III expert review; bromocriptine
in early pregnancy (<6 weeks) no malformation in 6272 pregnancies, use
throughout pregnancy 1 cryptorchidism, 1 congenital talipes in 100 preg-
nancies; cabergoline in early pregnancy (<6 weeks) no malformation in 1061
97
pregnancies, use throughout pregnancy 1 preterm birth (36 weeks), 1 fetal
death related to pre-eclampsia in 15 pregnancies]
8. Jean WC, Felbaum DR. Fertility, pregnancy, and prolactinoma: a survey
of pituitary surgeons’ view and review of the literature. J Clin Neurosci
2017;42:198–203. [III]
9. Gemzell C, Wang CF. Outcome of pregnancy in women with pituitary ade-
noma. Fertil Steril 1979;31:363. [A survey of 25 physicians in 1979 revealed
that they had seen a total of 91 pregnancies in 85 women with lactotroph
microadenomas and 46 women with lactotroph macroadenomas were fol-
lowed during 56 pregnancies]
10. Molitch ME. Management of prolactinomas during pregnancy. J Reprod
Med 1999;44:1121. [III; review]
11. Kupersmith MJ, Rosenberg C, Kleinberg D. Visual loss in pregnant women
with pituitary adenomas. Ann Intern Med 1994;121:473. [II-3]
12. Saito T, Watanabe Y, Yuzawa M, et al. SIADH is only an atypical clinical
feature in a patient with prolactinoma. Intern Med 2007;46(10):653–656.
13. Sato H, Takahashi H, Kanai G, et al. Syndrome of inappropriate secretion of
antidiuretic hormone caused by pituitary macroadenoma with hemangio-
matous stroma. Tokai J Exp Clin Med 2011;36(4):128–133.
14. Powel JE, Rosenthal E, Roman A, Chasen ST, Berghella V. Pre-eclampsia
and low sodium (PALS): a case and systematic review. Eur J Obstet Gynecol
Reprod Biol 2020;249:14–20.
15. Glezer A, Bronstein MD. Prolactinomas, cabergoline, and pregnancy.
Endocrine 2014;47:64–69. [III; review]
16. Auriemma RS, Perone Y, Di Sarno A, et al. Results of a single-center 10-year
observational survey study on recurrence of hyperprolactinemia after preg-
nancy and lactation. J Clin Endocrinol Metab 2013;98:372–379. [II-3; n =
143 pregnancies, 91 patients]
17. Turkalj I, Braun P, Krupp P. Surveillance of bromocriptine in pregnancy.
JAMA 1982;247:1589. [The manufacturer of bromocriptine, surveyed physi-
cians known to prescribe bromocriptine. The survey evaluated 1410 preg-
nancies in 1335 women who took the drug during pregnancy, primarily
during the first month [5]. The incidence of spontaneous abortions (11.1%)
and major (1%) and minor (2.5%) congenital malformations was similar to
that in the general population. Only eight women had taken bromocriptine
after the second month of pregnancy]
18. Molitch ME. Pregnancy and the hyperprolactinemic woman. N Engl J Med
1985;23:1364–1370. [II-c; safety of bromocriptine]
19. Molitch ME. Management of the pregnant patient with a prolactinoma. Eur
J Endocrinol 2015;172(5):R205–R213. [III; review]
20. Robert E, Musatti L, Piscitelli G, et al. Pregnancy outcome after treatment
with the ergot derivative, cabergoline. Reprod Toxicol 1996;10:333. [II-3;
n = 226]
21. Ricci E, Parazzini F, Motta T, et al. Pregnancy outcome after cabergoline
treatment in early weeks of gestation. Reprod Toxicol 2002;16:791–793. [II-
3; cabergoline safety proven in 61 pregnancies]
22. Domingue M-E, Devuyst F, Alexopoulou O, Corvilain B, Maiter D. Outcome
of prolactinoma after pregnancy and lactation: a study on 73 patients. Clin
Endocrinol 2014;80:642–648. [II-3; n = 73]
23. Lebbe M, Hubinont C, Bernard P, Maiter D. Outcome of 100 pregnan-
cies initiated under treatment with cabergoline in hyperprolactinae-
mic women. Clin Endocrinol 2010;73:236–242. [II-3; cabergoline safety
proven in 100 pregnancies]
24. Gonzalez JG, Elizondo G, Saldivar D, et al. Pituitary gland growth during
normal pregnancy: an in vivo study using magnetic resonance imaging. Am
J Med 1988;85:217. [II-3]
25. Klibanski A. Prolactinomas. N Engl J Med 2010;362:1219–1226. [III]
26. Ono M, Miki N, Amano K, et al. individualized high-dose cabergoline ther-
apy for hyperprolactinemic infertility in women with micro- and macrop-
rolactinomas. J Clin Endocrinol Metab 2010;95(6):2672–2679.
27. Flowers CM, Racoosin JA, Lu SL, et al. The US Food and Drug
Administration’s registry of patients with Pergolide-associated valvular
heart disease. Mayo Clin Proc 2003;78:730. [II-3]
28. Honegger J, Nasi-Kordhishti I, Aboutaha N, Giese S. Surgery for prolactino-
mas: a better choice?. Pituitary 2020;23(1):45–51. [III; review]
29. Ahmed M, Al-Dossary E, Woodhouse NJY. Macroprolactinomas with
suprasellar extension: effect of bromocriptine withdrawal during one or
more pregnancies. Fertil Steril 1992;58:492. [II-2]
30. Cocks Eschler D, Javanmard P, Cox K, Geer EB. Prolactinoma through the
female life cycle. Endocrine 2018;59(1):16–29. [III; review]
31. Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association
between MRI exposure during pregnancy and fetal and childhood outcomes.
JAMA 2016;316(9):952–961. [II-2; cohort study, 1737 first trimester MRI,
397 gadolinium MRI any trimester. Gadolinium in first trimester has
increased risk of childhood rheumatological, inflammatory, or infiltrative
98
skin conditions 125.8 per 1000 person-years in exposed fetuses vs. 93.7
per 1000 person-years in fetuses not undergoing MRI].
32. Mervak BM, Altun E, McGinty KA, Hyslop WB, Semelka RC, Burke LM.
MRI in pregnancy: indications and practical considerations. J Magn Reson
Imaging 2019;49(3):621–631. [III; gadolinium has increased risk of stillbirth
or neonatal death (17.6 per 1000 in exposed fetuses vs. 6.9 per 1000 fetuses
not exposed), but no difference if exposed only in first trimester].
33. Konopka P, Raymond JP, Merceron RE, et al. Continuous administration of
bromocriptine in the prevention of neurological complications in pregnant
women with prolactinomas. Am J Obstet Gynecol 1983;146:935. [II-3]
Maternal-Fetal Evidence Based Guidelines
34. Van Roon E, van der Vijver JC, Gerretsen G, et al. Rapid regression of a
suprasellar extending prolactinoma after bromocriptine treatment during
pregnancy. Fertil Steril 1981;36:173. [II-3]
35. Liu C, Tyrrell JB. Successful treatment of a large macroprolactinoma with
cabergoline during pregnancy. Pituitary 2001;4:179. [II-3]
36. Davanzo R. Controversies in breastfeeding. Front Pediatr 2018;6:278.
[III; review]
9
NAUSEA/VOMITING OF PREGNANCY AND HYPEREMESIS GRAVIDARUM
Rupsa C. Boelig and Sofia Guidi
Key points
• Diagnosis of hyperemesis gravidarum is nausea and
vomiting ≥3 times a day, with large ketones in urine
or acetone in blood (dehydration, fluid, and electrolytes
changes), and weight loss of >3 kg or >5% pre-pregnancy
weight, having excluded other diagnoses.
• Do not test for thyroid-stimulating hormone (TSH) in
women with nausea/vomiting or hyperemesis gravi-
darum, unless they have preexisting history/symptoms of
hyperthyroidism.
• For prevention, start prenatal vitamins before
conception.
• Start treating nausea and vomiting early, to prevent hyper-
emesis gravidarum.
• Therapies proven to improve nausea and vomiting of
pregnancy and/or hyperemesis gravidarum are (in
approximate order of increasing risk/invasiveness/potency)
(Figure 9.1):
• Acupressure
• Ginger capsules
• Vitamin B6 with doxylamine
• Metoclopramide
• Ondansetron
• Promethazine
Diagnosis/Definition
Nausea and vomiting of pregnancy (NVP) can be quite variable
and symptoms can range from mild to severe (hyperemesis gravi-
darum, HG). Mild symptoms include intermittent nausea, odor
and food aversion, retching, and vomiting
Hyperemesis gravidarum (HG) or severe nausea/vomiting
is generally defined as intractable n/v ≥3 times a day, with
signs of dehydration (large ketonuria, high urine specific
gravity, or electrolyte imbalance), and weight loss of >3 kg or
>5% pre-pregnancy weight, having excluded other diagnoses
(Table 9.1).
Epidemiology/Incidence
Nausea and vomiting are common in early pregnancy; approx-
imately 50–80% will experience nausea and 50% vomiting.
HG, in contrast, affects only 0.3–1% of pregnancies [1–3]. The
onset is about 4–6 weeks, peak 8–12 weeks, resolution <20
weeks. HG is the most common indication for hospital admis-
sion in the first trimester of pregnancy and second to preterm
labor throughout the entire pregnancy. Of the cases, 60%
resolve by the end of the first trimester, and 91% have complete
resolution by 20 weeks [3]. For symptoms presenting after 9
weeks, alternative diagnoses should be carefully considered
(Table 9.1) [4, 5].
DOI: 10.1201/9781003099062-9
Genetics
More common in first-degree relatives (daughters, sisters, mono-
zygotic more than dizygotic twins). Daughters born to mothers
with HG have a three times higher risk of future development [6].
Etiology
Hypotheses:
1. Gastrointestinal (GI) motility decreases in pregnancy
because of increasing levels of progesterone (but not par-
ticularly in HG; probably secondary phenomenon).
2. Hormones (hCG, thyroxine, cortisol, etc.) trigger chemo-
receptor trigger zone (CTZ), in brainstem-vomiting center.
3. CTZ more sensitive to hormones.
4. Abnormalities in vestibulo-ocular reflex pathway [7].
5. N/v correlates with the rise and fall of hCG. It has been
theorized that hCG stimulates the ovary to produce more
estrogen, which is known to increase n/v [3].
6. Helicobacter pylori (IgG 90.5% in HG patients, 47.5% in
controls [8]; no randomized controlled trials (RCTs) exist
for treatment of H. pylori in HG) [2, 8].
7. Possible psychologic predisposition, associated with
unwanted, unplanned pregnancies, or excessive life stress-
ors (and conversion disorder) [4, 9]. Of women with HG
report, 85% have poor support by partner.
8. Some have also postulated that n/v is evolutionary, to pro-
tect the fetus from teratogenic exposures since time frame
correlates with the period of organogenesis [4]
9. There is likely a strong genetic component involved in HG
as the recurrence risk is significantly greater in women
with a history of HG, however the influence of paternity
remains controversial [10–12].
Classification
A pregnancy-unique quantification of emesis/nausea (PUQE)
index has been proposed, validated, and recently slightly modi-
fied. Scores from this index can be associated to quality of life
measurements [4], but it is seldom used clinically [13–15].
Management is based on clinical severity as well as a woman’s
perception of severity and desire for treatment.
Risk factors/Associations
Risk factors include young maternal age; nulliparity; prior HG
(recurrence in about 67%); prior molar pregnancy; obesity;
African- American race; female fetus; history of motion sickness,
migraines, or psychiatric illness; preexisting hyperthyroidism,
diabetes, GI disorders, or asthma; conditions associated with high
hCG levels (larger placental mass as in multiple pregnancy, molar
99
100 Maternal-Fetal Evidence Based Guidelines

TABLE 9.1: Differential Diagnosis of Nausea and Vomiting of Complications

Pregnancy
Maternal
Gastrointestinal conditions
Mild cases are not associated with significant complications. For
• Gastroparesis/lleus
moderate to severe cases or HG, some women may experience sig-
• Gastroenteritis nificant psychosocial morbidity resulting in depression or decision
• Cyclic vomiting syndrome to terminate (2.9% incidence of termination with HG in Sweden) [4,
• Achalasia 16, 20]. A meta-analysis shows a significant increase in anxiety and
• Biliary tract disease depression that may extend to the postnatal period [21]. Moderate
• Hepatitis to severe cases are also associated with higher healthcare costs, eco-
• Intestinal obstruction nomic burden due to time lost from work, and need for hospital-
• Peptic ulcer disease/H. pylori ization [4]. Rare complications include Wernicke’s encephalopathy
• Pancreatitis (vitamin Bl deficiency; permanent neurologic disability or maternal
• Appendicitis death), peripheral neuropathies (vitamin B6 and B12 deficiency),
• Inflammatory bowel disease
central pontine myelinolysis, splenic avulsion, esophageal rupture,
pneumothorax, or acute tubular necrosis. In extreme and very rare
Genitourinary tract conditions
cases of HG, maternal death can occur [4].
• Pyelonephritis
• Uremia Fetal/Neonatal
• Ovarian torsion Minimal complications (e.g., no increase in FGR) are found in
• Kidney stones NVP [4]. HG, however, is associated with a higher incidence
• Degenerating uterine fibroids of fetal growth restriction (especially if severe HG), low birth
Metabolic diseases weight, small for gestational age, gestational hypertension, and
• Diabetic ketoacidosis preterm delivery [17, 22]. If symptoms continue into late second
• Porphyria trimester or third trimester, the RCOG guidelines suggest to offer
• Addison’s disease
women serial scans to monitor fetal growth [23]. HG is not asso-
ciated with an increased risk of congenital malformation, and
• Hyperthyroidism
fetal death is very rare [4, 22].
• Hyperparathyroidism
NVP and HG are also associated with lower incidence of
Neurologic disorders
pregnancy loss thought to be secondary to robust placental
• Pseudotumor cerebri
synthesis [24].
• Vestibular lesions
• Migraines
• Tumors of the central nervous system Pregnancy management
• Lymphocytic hypophysitis
Miscellaneous Principles
• Drug toxicity or intolerance Prevention is better than treatment; that is, intervening early
• Psychologic in nausea/vomiting is helpful in preventing worsening symp-
Pregnancy-related conditions toms [25]. HG is a diagnosis of exclusion: See Table 9.1 for dif-
• Acute fatty livery of pregnancy ferential diagnosis. N/v tends to be undertreated by both some
physicians and some patients, although safe and effective thera-
• Pre-eclampsia
pies exist. Approximately 10% of patients with n/v during preg-
• Trophoblastic disease
nancy will require medication [3].
Source: From Ref. [5] with permission.
Workup
pregnancy, Trisomy 21), and high estradiol levels. Women who Differential diagnostic possibilities should be ruled out, espe-
experienced n/v related to estrogen exposure (i.e. oral contra- cially prior to the diagnosis of HG (see Table 9.1) [4, 5].
ceptive pill) outside pregnancy were more likely to experience
History and review of systems
NVP [4]. Smoking has been associated with a lower incidence
Special attention should be made to severity of n/v, weight loss,
of HG, possibly because it is associated with lower levels of
prior GI diagnosis, and stressors—dietary, physical, and psycho-
hCG and estradiol [4, 16, 17], confirmed also by a meta-
logic. Abdominal pain, fever, and headache/migraine, are atypical
analysis [18].
complaints of a patient with n/v of pregnancy.
A related condition symptomatically is ptyalism, defined by
sialorrhea or excessive salivation; although little is known about Physical exam
this condition. The diagnosis is salivation >1900 mL/day, and the Special attention is made to vital signs, signs of dehydration, goi-
etiologic hypothesis is stimulation by starch (possibly pica). It is ter, and can include abdominal and neurologic examinations.
characterized by the inability to swallow rather than excessive
production of saliva. No therapy (gum, lozenges, small meals, Labs
anticholinergics, ganglion-blocking agents, oxyphenonium bro- • Serum (especially for severe cases): Electrolytes, BUN, cre-
mide, etc.) has been studied appropriately or shown to be effi- atinine, glucose, LFTs, amylase, lipase, acetone (quantita-
cacious in pregnancy. Check hydration, nutrition, psychologic tive hCG not helpful in management)
status, and other issues as per NVP [19]. • Urine: Ketones, specific gravity
Nausea/Vomiting of Pregnancy and Hyperemesis Gravidarum 101

• Thyroid-stimulating hormone (TSH): No need to send TSH
(60–70% of HG have “transient biochemical hyperthyroid-
ism of pregnancy” with decreased TSH and increased free
thyroid index; this is secondary to hCG-stimulating thy-
roxine synthesis from pituitary; always resolves spontane-
ously in 1–10 weeks [26, 27]; only test if pregnant woman
has a history of thyroid disease or goiter).
Radiologic
Fetal ultrasound (to assess for molar pregnancy, multiple gesta-
tion, etc.).
Treatment
Figure 9.1 illustrates a suggested stepwise approach to the man-
agement of NVP and HG. Several interventions are available
for treatment of n/v and HG (Table 9.2) [1, 2]. It is suggested to
intervene early with n/v. A combination of interventions is often
necessary. For HG, consider starting at least at step 3, but still
consider implementing steps 1 and 2 as appropriate. Any under-
lining/concomitant GI disorder (reflux, ulcer, anorexia, etc.)
should be treated appropriately.
Consults
For refractory cases consider nutrition, gastroenterology, and/or
psychiatry consultation depending on history.
Treatment
Figure 9.1 shows a suggested stepwise therapeutic approach.
Step 1: Prevention
Prenatal multivitamin before/at conception
Vitamin B6 found in prenatal multivitamins (MVI) has been
shown to reduce the incidence of n/v [28], and the early use

1. Prevention
a) Prenatal vitamins started 3 months prior to conception
b) For patients with a history of HG: prophylactic therapy with B6 and doxylamine

2. N/V, No Sign of Dehydration or Weight Loss; Tolerating PO

a) Non-pharmacologic interventions (may be used in conjunction with other therapies):
i. Ginger
ii. Acupressure
iii. Dietary modifications: small meals, increased protein, avoiding noxious stimuli
b) Pharmacologic interventions:
i. Vitamin B6
ii. Vitamin B6 and doxylamine
iii. Add H2 blocker or PPI for symptoms of reflux
ADD

3. No Improvement OR Signs of Dehydration or Weight Loss; Tolerating PO

a) Metoclopramide
b) AND/OR ondansetron
c) AND/OR promethazine

4. Signs of Dehydration or Weight Loss; Not Tolerating PO

ADD
a) Inpatient assessment:
i. Urine analysis for ketones, specific gravity
ii. Serum studies: electrolytes, creatinine
iii. Rule out other possible etiologies (See Table 9.1)
b) IV rehydration:
i. D5 or normal saline rehydration
ii. Consider the addition of thiamine repletion in severe cases to prevent Wernicke's encephalopathy
c) Pharmacotherapy with IV ondansetron, metoclopramide, or promethazine either individually or in
combination. If responsive, transition to oral or rectal formulation for continued outpatient management.
d) If refractory HG despite all above therapies: consider steroid course (>10 weeks' gestation), consider Gl
and/or nutrition consult.

ADD
5. No Improvement, Continued Weight Loss; Not Tolerating PO
a) Enteral nutrition; if unsuccessful, then:
b) Parenteral nutrition

FIGURE 9.1 Management of nausea and vomiting of pregnancy and hyperemesis gravidarum. Proceed through steps in a progres-
sive, additive fashion. Therapies in BOLD have consistently demonstrated efficacy in randomized controlled trials for treatment of
NVP and/or HG. Therapies in ITALICS have demonstrated efficacy in at least 1 RCT in pregnancy although results may be mixed.
N/V: nausea and/or vomiting. Abbreviations: PO, per os/by mouth; IV, intravenous; NVP, nausea and vomiting of pregnancy; HG,
hyperemesis gravidarum.
102 Maternal-Fetal Evidence Based Guidelines

TABLE 9.2: Selected Pharmacologic Treatment of NVP and HG

Agent Dose Side Effects FDA Category Comments
Ginger extract 125–250 mg tid/qid, po Reflux, heartburn C Step 2a; OTC availability,
food supplement
Vitamin B6 (pyridoxine) 10–25 mg q8h po, do not exceed 100 mg A Step 2b; recommended as
qd first-line pharmacologic
intervention
Vitamin B6 – doxylamine Pyridoxine, 10–25 mg q8h, po; Sedation A Steps 1, 2b;
doxylamine, 25 mg qhs, 12.5 mg bid Recommended as
prn, po; Diclegis (10 mg/10 mg) start first-line pharmacologic
2–4 tabs qd-tid intervention. May be
taken prophylactically if
history of HG
Other Antihistamines Sedation, dizziness, May be helpful for relief of
(H1-receptor drowsiness, vestibular type
antagonists) anticholinergic effects symptoms
• Diphenhydramine 25–50 mg q4–6h prn; po, IV, IM B
(Benadryl) Maximum: 100 mg/dose, 400 mg/day
• Meclizine (Bonine, 25–50 mg q6h, po; maximum: B
Antivert) 100 mg/24 hour
• Hydroxyzine (Atarax, 25–100 mg q6–8h prn, po/IM; C
Vistaril) maximum:
600 mg/24 hour
• Dimenhydrinate 50–100 mg q4–6h, po/pr/IM or B
(Dramamine) 50 mg (in 50 cc saline over
20 minutes) q4–6h IV (not to exceed
400 mg/day, or 200 mg/day if also
doxylamine
H2 receptor antagonists B Step 2b; for patients with
reflux, H. pylori
• Cimetidine (Tagamet) 1600 mg qd divided bid/qid
• Famotidine (Pepcid) 20–40 mg bid, po/IV
• Ranitidine (Zantac) 75–150 mg prn, po (maximum 2
tabs/24 hour); 50 mg q6h IM/IV
Proton Pump Inhibitors B Step 2b; Second line for
(PPIs) reflux symptoms
• Omeprazole (Prilosec) 20–40 mg qd, po (maximum
80 mg/day)
• Pantoprazole (Protonix) 40 mg bid, po
• Esomeprazole (Nexium) 20–40 mg qd, po/NG/IV (maximum:
80 mg/day)
• Lansoprazole (Prevacid) 15–30 mg qd, po
Dopamine2—antagonists Sedation, Step 3
anticholinergic effects
• Metoclopramide 10–20 mg q6–8 hour, po/IM/IV; Tardive dyskinesia with B Step 3. Also available as
(Reglan) 1–2 mg/kg IV increased duration of subcutaneous pump
use (>12 weeks) and therapy, benefit pump
high total cumulative therapy is questionable.
dose.
• Trimethobenzamide 300 mg tid/qid, po; 200 mg tid/qid, IM C Dopamine antagonist
(Tigan) directly to emetic center
CTZ
• Droperidol (Inapsine) 0.625–2.5 mg over 15 minutes, then 1.25 Black box warning of C Give with benadryl to
or 2.5 mg IM q3–4h prn, IM or torsades prevent extrapyramidal
continuous IV at 1–1.25 mg/hour symptoms
(maximum: 2.5 mg/dose, slow push
over 2–5 minutes, repeat doses with
caution
Nausea/Vomiting of Pregnancy and Hyperemesis Gravidarum 103

TABLE 9.2 (Continued): Selected Pharmacologic Treatment of NVP and HG

Agent Dose Side Effects FDA Category Comments
5-HT3 (Seratonin) receptor Constipation, diarrhea, Step 3
antagonist headache, fatigue,
mild sedation.
• Odansetron (Zofran) 4–8 mg tid/qid po; 4–8 mg over B Also available as an oral
15 minutes q6–8h IV; or 1 mg/hour dissolving tablet, and as a
continuous for 24 hours subcutaneous pump.
Benefit of pump therapy
is questionable
Phenothiazines (D2- Sedation; ↓BP if given Step 3
receptor antagonists) too quickly,
Parkinson’s tremors,
rash, anticholinergic
side effects, tardive
dyskinesia
• Promethazine 12.5–25 mg q4–6h, po/pr/IM/IV Severe tissue injury C May have similar or
(Phenergan) (maximum: 50 mg/dose po/IM; with undiluted IV use reduced efficacy with
25 mg/dose IV) more side effects
compared to
ondansetron and
metoclopramide
• Prochlorperazine 5–10 mg q4–6h; po/IM/IV/ D/c if unexplained C
maleate (Compazine; buccal, 10–25 mg q6h pr decrease in WBCs
Bukatel) (maximum:10 mg/dose,
40 mg/day)
Glucocorticoids Increased risk of cleft C Step 4: for HG refractory
lip if used before 10 to other medications.
weeks gestation RCTs with mixed data
on benefit. May be
useful in refractory
cases and decrease rate
of readmission. Initial
therapy for 3 days, if
successful, may be
tapered over 1–2 weeks,
or for recurrent
symptoms continued for
maximum of 6 weeks for
maximum duration,
with tapered dose if
possible. If no
improvement after
72 hour, discontinue.
• Methylprednisolone • 16 mg PO TID
• Prednisolone • 5–20 mg PO qd-TID PO
• Methylprednisolone • 125 mg IV × 1 followed by oral taper
• Hydrocortisone • 300 mg IV qd
Notes: BOLD: Therapies consistently demonstrating efficacy in RCTs in pregnancy; ITALICS: Therapies with efficacy demonstrated in at least 1 RCT in pregnancy, although
results may be mixed. Therapies listed without bold or italics have no RCTs proving efficacy in pregnancy.
Food and Drug Administration (FDA) categories are as follows: A, controlled studies show no risk; B, no evidence of risk in humans; C, risk cannot be ruled out; D, positive
evidence of risk; and X, contraindicated in pregnancy (http://www.fda.gov/).
Abbreviations: NVP, nausea and vomiting of pregnancy; HG, hyperemesis gravidarum; RTC, randomized controlled trial; PO, per os; IV, intravenous; IM, intramuscular; PR,
per rectum; NG, nasogastric; qd, once daily; bid, twice a day; tid, three times a day; qid, four times a day; qhs, quaque hora somni or given at bedtime; q“X”h, given every “X”
hours; prn, pro re nata or take as needed; OTC, over the counter medication; min, minute; BP, blood pressure; WBCs, white blood cells; SubQ, subcutaneous; GI, gastrointes-
tinal; CTZ, chemoreceptor trigger zone; d/c, discontinue.
104
(prior to 6 weeks) of prenatal vitamin was associated with a
decreased rate of vomiting [29].
Doxylamine/Vitamin B6
One randomized controlled trial (RCT) found that in women
with a history of HG, preemptive therapy with 10 mg doxyl-
amine and 10 mg pyridoxine (Diclectin, delayed release) up
to 4 tabs daily resulted in a significant decrease in recurrence
of HG [30].
Step 2a: Non-pharmacologic interventions
Lifestyle/Dietary changes
Avoid odor/food triggers. Stop medications (e.g., iron, large vita-
mins) producing n/v. Counsel regarding safety and efficacy of
treatment; provide reassurance regarding outcomes (see later
in the chapter). There is no evidence that rest improves n/v. Diet
includes frequent, small meals: Eat only one spoonful, wait, eat
again, and so on; avoid an empty stomach; eat crackers in the
morning upon waking; avoid fatty greasy spicy foods; ginger
ale; prefer protein. One small nonrandomized prospective study
found that protein-predominant meals produced decreased nau-
sea compared to carbohydrate or fat predominant meals [31], but
prolonged high-protein diet is associated with higher incidences
of preterm birth and fetal death.
Acupressure wristbands
In the treatment of NVP, acupressure at P6 Neiguan point [32–39]
(Brands: Seaband; Bioband) has been associated with improved
nausea or symptom relief in one RCT and with no improvement
in others when compared to placebo [1]. An RCT showed no sig-
nificant difference between P6 acupressure versus vitamin B6
therapy in nausea/vomiting of pregnancy [40]. A double-blind
RCT shows that 12-hour daily use of an acupressure band at
the P6 Neiguan point for 3 days, significantly reduces the symp-
toms of nausea, vomiting, retching, and ketonuria, and leads to a
shorter hospital stay compared to the use of an otherwise identi-
cal non-stimulating wristband [41].
In the treatment of HG, there are three RCTs, one with cross
over design, comparing acupressure versus placebo. The results
could not be combined for meta-analysis; however, the individ-
ual studies demonstrated improved nausea and a decreased
number of antiemetics were required [2, 42–45]. There are no
pregnancy safety or breastfeeding concerns [2]. This intervention
therefore can be considered either prior to (in mild cases), or as an
adjunct to, pharmaceutical interventions.
Acustimulation wristbands
Acustimulation at P6 Neiguan point [46, 47] (Brand: Relief
Band Device, Woodside Biomedical—http://www.reliefband.
com). This device for noninvasive nerve electric stimulation
was associated with less n/v and higher weight gain compared
to placebo [46, 47], but in the largest RCT, the assessment of
the outcomes was not blinded and the study was industry-
sponsored by the makers of the device [47]. A systematic review
[48] of the clinical trials states that, despite some evidence that
correlate acustimulation with a reduced combined outcome
of nausea, vomiting, and ketones in the case of HG, it’s pre-
mature to conclude on the beneficial effect of this technique.
This is due to the moderate quality of the studies, with respect
to blinding and to the non-significant results found in other
included studies. There are limited pregnancy safety or breast-
feeding concerns.
Maternal-Fetal Evidence Based Guidelines
Auricular acupressure
One randomized controlled trial on the use of auricular acupres-
sure found no significant benefit in either symptom improvement
or number of antiemetic drugs needed as compared to controls
[49]. There are no pregnancy safety or breastfeeding concerns.
Acupuncture
In the treatment of NVP, one trial found acupuncture to be equiv-
alent to a sham procedure in the treatment of nausea of preg-
nancy [50]. Another trial found benefit of acupuncture compared
to control in improvement of nausea, but not vomiting, although
the sham procedure had some beneficial effect as well [51]. In the
condition of HG, acupuncture was found to be as similar to meto-
clopramide in the reduction of nausea and vomiting [52]. There
does not appear to be a benefit with the use of acupuncture in
the treatment of NVP or HG in pregnancy [1, 2, 4]
Ginger
Ginger use has been suggested as an early therapy in outpatients
[4, 53]. Side effects include reflux and heartburn. There have
been several RCTs examining ginger for the treatment of NVP.
A Cochrane review demonstrated benefit of ginger compared
to placebo [1]. A recent meta-analysis shows a significant effect
of ginger on relieving NVP symptoms and nausea, but not on
vomiting. In addition, it states that ginger is more effective than
vitamin B6 in the treatment of NVP, even though there were no
significant differences [54].
Regarding HG, one RCT found benefit with the use of gin-
ger in HG; however, it was small (30 women), and a cross-over
design [55].
Comparing it to other individual therapies, there was not found
to be a significant difference in benefit with ginger versus chamo-
mile, dimenhydrinate, or metoclopramide [1, 56–58].
Other non-pharmacologic interventions
Regarding other non-pharmacologic interventions for n/v,
there were two studies on oils versus placebo in NVP. One
study on mint oil found no significant difference in severity
of nausea and vomiting, and one study on lemon oil found no
difference in overall PUQE score but did show a significant
reduction of symptoms from baseline to day three [59, 60]. One
study on chamomile found that it improved symptoms after
1 week [56].
In the setting of HG, progressive muscle relaxation with
pharmacotherapy versus pharmacotherapy alone had better
global improvement scores [61]. Midwife-led outpatient care
had similar clinical outcomes but with decreased hours of hos-
pital admission [62]. A holistic care plan versus standard medical
therapy alone had a shorter length of hospital stay but no signifi-
cant improvement in quality of life measures, nausea and vomit-
ing severity, or cost [63].
There are no RCTs on hypnosis although there are case reports
of some benefit [4, 64]. There is insufficient evidence of benefit to
suggest this as a therapy for NVP or HG.
In summary, ginger may be considered as an effective
non-pharmacologic intervention in the settling of mild
nausea and vomiting. Acupressure (by wristband and other
means) may also be a beneficial adjunct. Acupuncture does
not appear to be beneficial, and there is limited data to sup-
port the use of other non-pharmacologic interventions such as
nerve stimulation, muscle relaxation, hypnotherapy, and other
dietary supplements.
Nausea/Vomiting of Pregnancy and Hyperemesis Gravidarum
Step 2b: Pharmacologic interventions
Vitamin B6
In the treatment of NVP, B6 has been associated with decrease
in nausea, not in vomiting [1, 65, 66]. However, when used in
women hospitalized for HG, it does not seem to affect n/v by itself
[67]. A RCT comparing vitamin B6 and quince fruit syrup in 76
women with mild-to-moderate NVP, found quince to have sig-
nificant effects on NVP symptoms compared to vitamin B6 [68].
According to the RCOG guidelines, pyridoxine alone is not rec-
ommended for NVP and HG [23].
Doxylamine and vitamin B6
Doxylamine is an antihistamine that has been studied in com-
bination with vitamin B6. This combination (formerly known
as Bendectin and now available as Diclegis in the United States,
Diclectin in Canada, Debendox in the United Kingdom) is safe,
with no evidence of teratogenicity (proven with over 200,000
exposures, by far the most for any other drug in pregnancy), and
effective (>70% decrease in n/v) [3, 4]. The published evidence
on the efficacy of doxylamine and pyridoxine is limited [1]. The
“Benedectin Antinausent 8-way” study is a 1970s unpublished
study that has been referred to in support of the use in combi-
nation of doxylamine and pyridoxin. It was subsequently ana-
lyzed and was found to have questionable data integrity and
other methodological concerns. The claims of the efficacy of this
combination based on this trial need to be revisited [69]. ACOG
suggests the use of Doxylamine in combination to vitamin B6, as
it is effective and to use it as first-line therapy [4]. Doxylamine
and vitamin B6 are associated with decrease in both n/v when
used together compared to no therapy or placebo [70–73]. A
double-blind RCT showed Diclectin (an available doxylamine-
pyridoxine delayed-release preparation) to significantly improve
n/v and quality of life compared to placebo [73].
Other antihistamines (histamine-1
receptor antagonists)
Other antihistamines are generally safe and used mostly for the
relief of vestibular-like symptoms. There may be an increased rel-
ative risk, but small absolute risk of septal defects [74–76]; these
include diphenhydramine, meclizine, hydroxyzine, and dimen-
hydrinate. An RCT showed that dimenhydrinate is as effective
as ginger in the treatment of n/v with fewer side effects [57], and
another demonstrated the benefit of hydroxyzine over placebo
for nausea relief [77]. No RCTs exist for the other histamine-1
receptor antagonists (H1RAs) to assess their effectiveness for n/v
in pregnancy or HG.
Histamine-2 receptor antagonists
Cimetidine, famotidine, ranitidine, and nizatidine are approved
for use in pregnancy to treat symptoms of heartburn, acid reflux,
and H. pylori, which can exacerbate n/v. They may be added if
symptoms are present. No RCTs exist regarding their effective-
ness for NVP or HG. A meta-analysis showed no increased risk
of congenital malformations, risk of spontaneous abortions, or
preterm delivery compared to controls [78]. In intractable cases
of n/v with positive H. pylori serology, a non-randomized study
suggested benefit with triple therapy of ranitidine/flagyl/ampicil-
lin [79].
Proton- pump inhibitor
Common proton- pump inhibitors (PPIs) used in pregnancy are
omeprazole, pantoprazole, esomeprazole, and lansoprazole. These
105
can be used in conjunction with or separately from histamine-2
receptor antagonists (H2RAs) for heartburn and reflux, and H.
pylori infections. In a recent review [80], a meta-analysis [81] and
a cohort study [82] showed that there is no evidence to suggest
that the use of PPIs anytime during pregnancy increases the over-
all risk of birth defects, preterm delivery, or spontaneous abor-
tion. There are no RCTs on this intervention for NVP or HG.
In summary given its well demonstrated safety and efficacy,
vitamin B6 with doxylamine should be considered first-line
pharmacotherapy for the treatment of NVP [4, 53]. If symp-
toms of reflux, heartburn, or H. pylori are present, H2RAs and
PPIs can also be considered.
Step 3: Antiemetic therapy
Of the three commonly prescribed antiemetics, metoclopramide,
promethazine, and ondansetron, only metoclopramide was
studied in a placebo controlled RCT, the remainder were studied
RCTs comparing one therapy with another. Less commonly used
and much less studied, thiethylperazine and fluphenazine-pyri-
doxine were also studied in placebo-controlled trials [1, 2]. In a
Cochrane review ondansetron, metoclopramide, and prometha-
zine were not found to have significant differences compared to
each other in regards of symptomatic relief; the differences were
mostly seen in the side effects [2].
Metoclopramide (Dopamine-2 antagonist)
Metoclopramide (Reglan) is safe in pregnancy without increased
risk of teratogenicity, preterm birth, low birth-weight, or peri-
natal mortality [83–85]. In the setting of NVP, an RCT compar-
ing metoclopramide to placebo found improved n/v [58]. An
RCT showed that metoclopramide (with one IM shot of 50 mg
of pyridoxine) is superior in decreasing vomiting and subjective
improvement compared to monotherapy with either prochlor-
perazine or promethazine [86]. Compared with ondansetron,
there was similar improvement in nausea, but worse with vomit-
ing [87].
Two recent RCTs compared metoclopramide and ondansetron
in the setting of HG and one found similar improvement in symp-
toms, but also found that there was an increased rate of drowsi-
ness and dry mouth in the metoclopramide group The other
RCT found improved vomiting with ondansetron [88–89]. A
recent RCT of inpatient HG patients showed that metoclopramide
10-mg IV q8h had similar efficacy and decreased drowsiness, diz-
ziness, and dystonia when compared to IV promethazine [90].
The use of metoclopramide together with a variety of pheno-
tiazine medications (e.g. promethazine, prochlorperazine, or
chlorpromazine) can lead to an increased risk of extrapyramidal
effects (e.g. Tardive dyskinesia) or rarely, neuroleptic malignant
syndrome [4].
A subcutaneous Reglan pump is an alternative mode of admin-
istering the drug, not yet tested in any pregnancy RCT. It is not
necessarily cost-effective compared to inpatient management or
home care, and may have significant side effects; thus it is not
recommended for routine use in the management of NVP or HG
[4, 91, 92].
Ondansetron (5-HT3 receptor antagonist)
Ondansetron (Zofran) is a serotonin 5-hydroxytryptamine-3
receptor antagonist. Although one study found an association
between first trimester ondansetron use and cardiac anoma-
lies, especially septal defects, and another with cleft palate, the
absolute risk was still quite low; other much larger studies have
106
demonstrated its safety in pregnancy [93–96]. A recent review
[97] and a meta-analysis [98] showed that there is not a significant
increase of major congenital malformations with Ondansetron
use. The review found a small increase in oral clefts (3 additional
clefts per 10,000 women treated; adjustable RR, 1.24) but not car-
diac malformations. The absolute risk to any fetus is low [4].
Ondansetron must be prescribed with care as there is a risk
of QT prolongation that could lead to potentially fatal arrhyth-
mias. As such, the FDA has recommended it not be prescribed
in IV doses >16 mg, and care should be taken to avoid other QT
prolonging medications [4]. Ondansetron when used with pheno-
tiazine medications (e.g. chlorpromazine) may lead to a potential
cardiac risk of QT prolongation [4].
In the treatment of NVP, women treated with ondansetron
versus metoclopramide had similar levels of nausea, but had
reduced vomiting [87]. Ondansetron was found to be superior
to pyridoxine and doxylamine in improvement of n/v [99].
In the setting of HG, there was no significant difference
when compared with promethazine in reduction of nausea or
in adverse effects [100]. There are two RCTs comparing ondan-
setron and metoclopramide in the setting of HG. One study
found similar efficacy in control of nausea with improved vom-
iting with ondansetron [89], the other found similar effects on
n/v but reduced side effects with ondansetron [88]. There is
limited evidence to support the use of subcutaneous pump of
ondansetron. There are no RCTs comparing subcutaneous with
oral or IV administration. Although there may be some symp-
tom improvement with a subcutaneous pump, a significant
number of women experience complications with 25% stopping
treatment related to complications [91, 92]. Given the limited
data on benefit and the significant side effects, the use of sub-
cutaneous pumps is not recommended [4].
Promethazine (phenothiazines)
Phenothiazines (prochlorperazine [Compazine], promethazine
[Phenergan]) appear to be safe in pregnancy. A case-control
study of promethazine showed no evidence of increase risk/rate
of congenital anomalies in humans [95, 101]. Phenothiazines are
often used in addition to or instead of antihistamines. The level
1 evidence for effectiveness is limited. As stated earlier, metoclo-
pramide (with one IM shot of 50 mg of pyridoxine) is superior
in decreasing vomiting and subjective improvement compared
to monotherapy with either prochlorperazine or promethazine in
NVP [86], it had similar efficacy with reduced side effects in HG
[90]. Compared to ondansetron, there was no difference in sever-
ity of nausea in the setting of HG [100]. Two studies compared
promethazine and corticosteroids in patients with HG. One study
[102] found a decreased rate of hospital readmission with cortico-
steroids, the other study [103] found an increase in n/v at 48 hours
but not after 17 days with prednisolone [2].
Other phenothiazines have been studied in the setting of NVP
although they are not commonly used and their safety is not
established. Thiethylperazine demonstrated improved symptoms
compared to placebo, and fluphenzine-pyridoxine was not statis-
tically significantly better than placebo in another [1, 104, 105].
Beside the oral and the IV routes, promethazine is available
also as rectal suppositories and this administration may be ben-
eficial when the patient does not tolerate the oral route [4].
In summary, if n/v persists despite steps 1–2, consider add-
ing metoclopramide or ondansetron. Phenothiazine (pro-
methazine) therapy may be added as well, although it may not
be as effective and has more side effects.
Maternal-Fetal Evidence Based Guidelines
Step 4: Inpatient assessment and treatment
Inpatient management
Admit if HG diagnosis is confirmed, woman is not tolerating
oral intake, and failed outpatient management. Some suggest
just brief ER visits for severe cases needing emergent hydration.
Home infusion services should be used as much as safely possible.
Admission by itself does not improve HG, and should be limited.
According to the RCOG guidelines, thromboprophylaxis with
low-molecular-weight heparin should be proposed to women
admitted with HG. It can be discontinued upon discharge [23].
Other etiologies of n/v should be ruled out (Table 9.1), and workup
should be initiated as described in “Pregnancy Management” ear-
lier. Outpatient treatment compared to the inpatient one is more
cost-effective for the treatment of NVP, day care treatment is a
valid alternative for these patients [106].
Intravenous fluid hydration
IVF can be used if dehydration is present. Volume should be
adequate to replenish loss and ongoing loss through vomiting.
IV rehydration may be done with normal saline, lactated ring-
ers, or dextrose normal saline along with electrolytes as needed.
In severe cases, thiamine should be replete to prevent the devel-
opment of Wernicke’s encephalopathy. Add thiamine 100 mg qd
for 2–3 days, then multivitamins to IV fluids. Hypertonic solu-
tions should be avoided; rapid overcorrection of hyponatremia
may cause central pontine myelinolysis. According to the RCOG
guidelines, thiamine supplementation (oral or IV) should be
given to every women admitted with prolonged vomiting, espe-
cially before dextrose administration or PN [23].
One RCT compared dextrose saline with normal saline and
found that although there was improved nausea at hours 8 and
16 after treatment with dextrose saline, by 24 hours there was
no difference in nausea score, quality of life, or length of hospital
stay [107].
Diet
One RCT compared early ad lib feeding compared to 12 hours
enforced fasting during admission for HG and found no benefit
with enforced fasting, but improved adherence and patient sup-
port of early feeding, suggesting delayed oral intake is not neces-
sary during inpatient admission for HG [108].
Additional pharmacologic therapy
Corticosteroids
Safety data on corticosteroids include possible increased inci-
dence of oral cleft if used <10 weeks [4].
RCTs on the use of corticosteroids in the treatment of HG
have had mixed results. A meta-analysis on this was limited
by the difference in inclusion criteria and definition of HG.
Compared with placebo, the addition of corticosteroids to
other antiemetic therapy does not appear to improve symp-
toms, but may reduce hospital readmission rate [2]. One
small RCT found decreased episodes of emesis compared to
metoclopramide [109]. Two RCTs compared steroids with pro-
methazine and one found increased side effects and delayed
response compared to promethazine [103], and the other found
decreased readmission associated with corticosteroids [102].
Adrenocorticotropic hormone (ACTH) is not beneficial [110].
Corticosteroids are not recommended for the treatment of
NVP, but may be considered for a short course (up to 3 days)
in refractory cases of HG after 10 weeks’ gestation. Usual
dosing is methylprednisolone 16 mg po/IV tid, prednisolone
Nausea/Vomiting of Pregnancy and Hyperemesis Gravidarum
20 mg po bid, or hydrocortisone 300 mg IV qd. For patients who
do respond, this 3-day course may be followed with a 1–2 week
taper. ACOG suggests that patients who initially responded
and then develop recurrent vomiting after the taper may be
continued on an effective dose for up to 6 weeks, although this
is not based on any specific trial data [4].
Benzodiazepines
Do not use diazepam, a category D drug, because of possible fetal
effects, despite one trial on its efficacy [111].
Clonidine
Clonidine is a centrally acting alpha-2 adrenergic agonist com-
monly used as an anti-hypertensive agent. It has been studied in
the prevention of post-operative nausea and vomiting. One small
cross over design RCT (N = 12) evaluated transdermal cloni-
dine in addition to other anti-emetic therapy for the treatment
of refractory HG and found subjective and objective improve-
ment in measures of nausea and vomiting. Of note on this small
study, it was also reported one patient whose pregnancy course
was complicated by central venous catheter associated sepsis
[112]. Given this small limited study, there is insufficient data
on safety or efficacy to recommend clonidine for the treatment
of NVP or HG.
In summary, for patients with dehydration, weight loss,
and inability to tolerate PO, consider admission for IV rehy-
dration, beginning treatment with the IV formulation of
the antiemetics in step 3. Multiple combinations and dos-
ing can be used. In the rare cases in which these are not suc-
cessful, one may proceed with a short course of corticosteroids.
Benzodiazepines are not recommended because of adverse fetal
effects and limited data on benefit. Clonidine may be effective
but is not recommended given the limited data on its benefits
and safety.
Step 5: Nutritional supplementation
Women hospitalized for HG can eat according to their prefer-
ence, since satisfaction, vomiting, and nausea are not signifi-
cantly different between immediate oral feeding and 12-hour
fasting regimens [108]. If weight loss or dehydration persist
(e.g. over 5–7 days despite aggressive inpatient therapy), con-
sider consulting gastroenterology and possibly psychiatry as
well. In addition, supplement with either enteral (EN) or par-
enteral nutrition (PN) in conjunction with a nutrition con-
sult. There are no RCTs comparing nasogastric (NG) tube or
PN [4].
Enteral nutrition
Enteral nutrition requires a nasogastric (NG) tube. There are
several types (e.g. Dobbhoff 8 Fr) of NG tubes, with insufficient
evidence to assess effectiveness of one versus the other. This
intervention is best used for persistent n/v, with no response to
antiemetic therapy. One large retrospective cohort study com-
pared EN with IVF and PN. They found the EN resulted in similar
weight gain and pregnancy outcomes despite the fact that they
had significantly greater weight loss on admission [113]. A ran-
domized clinical trial found early enteral tube feeding in women
with HG did not improve maternal and perinatal outcomes and
was poorly tolerated by patients [114].
Since PN is associated with several possible complications, the
NG tube should be tried first, as tolerated [4]. A small case series
of three patients demonstrated the feasibility and safety of endo-
scopically placed jejunostomy tubes in the setting of refractory
107
HG, and this may be an area for further study [115]. Enteral nutri-
tion may be poorly tolerated and complicated by tube dislodge-
ment requiring replacement.
Nutritional goals should be developed in conjunction with a
nutrition consult. Specific nutritional requirements will depend
on individual factors such as degree of weight loss and severity
of nausea and vomiting. In general, the Harris-Benedict equation
for women may be used to calculated basal energy expenditure,
with an additional 300 calories added to meet the additional
demands in pregnancy [116]. The weight used in the calculation
may be current weight or pre-pregnancy weight depending on the
degree of weight loss.
Nutrition (Harris–Benedict equation)
• Basal Metabolic Rate = 655.1 + [9.56 × wt(kg)] + [1.85 ×
ht(cm)] – [4.68 × age(year)]
• Activity Factor: 1.2 to 1.9 (for sedentary activity level to
extremely demanding activity level)
• (Basal Metabolic Rate × Activity Factor) + 300 = Daily
caloric requirement in pregnancy
• Start at 25 mL/hour, increase by 25 mL/hour until goal.
Then consolidate to give over 8–12 hours overnight rather
than continuously over 24 hours.
Parenteral nutrition
Several catheters and regimens are possible (peripherally
inserted central catheter [PICC], midline IV, etc.). Like enteral
nutrition, parenteral nutrition (PN) should be managed in con-
junction with a nutrition consult. Generally PN is associated
with a high incidence of catheter complications, for example,
infection leading to sepsis, (about 25%) thrombosis/occlusion,
and dislodgement/mechanical failure, with mixed reports on
maternal or neonatal benefit, and no RCTs assessing its efficacy
[117–121]. Peripheral catheters have high morbidity, and central
catheters have central access complications. Other complica-
tions include pneumothorax, cholestasis, preterm birth, and fetal
death. This is an expensive therapy to be used only when HG is
refractory to treatment, with significant weight loss (>5%), and
failure of enteral nutrition.
In summary, for patients that are admitted with HG refrac-
tory to steps 1–4, order a nutrition consult and consider
enteral over parenteral nutrition.
Other issues
If persistent weight loss or dehydration (e.g. over 5–7 days despite
aggressive inpatient therapy), consider consulting gastroen-
terology, and either enteral or parenteral nutrition. Consider
psychiatric consult in severe, refractory-to-therapy cases. It
is suggested in a meta-analysis [21], to provide, when appropri-
ate, psychological care for the psychological morbidity of HG.
Psychotherapy was evaluated in a RCT including 86 women with
moderate NVP. Forty-three women were treated with pyridoxine
hydrochloride and intensive mindfulness-based cognitive ther-
apy and 43 with medical therapy alone. The first group had sta-
tistical and clinical significant improvements in NVP symptoms,
anxiety/depression symptoms, and pregnancy distress, compared
to the medical therapy alone group. Psychotherapy can be used
as a complementary treatment option for women with moderate
NVP [122]. Woman can be discharged home on IV fluids and/or
parenteral nutrition (PN) as long as stable, not losing weight, or
other factors.
108
Postpartum
The risk of recurrence of HG [2, 4, 10] is about 15% (vs. 0.7% in
controls without prior HG). The risk may be reduced by a change
in paternity [10].
References
1. Matthews A, Haas DM, Omathuna DP, Dowswell T. Interventions for nau-
sea and vomiting in early pregnancy. Cochrane Database Syst Rev 2015:9.
[Review]
2. Boelig RC, Barton SJ, Saccone G, Kelly AJ, Edwards SJ, Berghella V.
Interventions for treating hyperemesis gravidarum. Cochrane Database
Syst Rev 2016;(5):CD010607. [Meta-analysis or RCTs]
3. Niebyl JR. Nausea and vomiting in pregnancy. N Engl J Med 2010;363:
1544–1550. [Review]
4. American College of Obstetrics and Gynecology. Nausea and vomit-
ing of pregnancy. ACOG Practice Bulletin No. 189. Obstet Gynecol
2018;131(1):e15–e30. [III]
5 Goodwin TM, Hyperemesis gravidarum. Obstet Gynecol Clin North Am
2008;35(3): 401–417. [Review]
6. Vikanes A, Skjaerven R, Grijbovski AM, et al. Recurrence of hypereme-
sis gravidarum across generations: a population based cohort study. BMJ
2010;340:c2050. [II-2]
7. Goodwin TM, Nwankwo OA, O’Leary LD, et al. The first demonstration
that a subset of women with hyperemesis gravidarum has abnormalities
in the vestibuloocular reflex pathway. Am J Obstet Gynecol 2008;199:
417.el–117.e9. [II-3]
8. Sandven I, Abdelnoor M, Nesheim BI, et al. Helicobacter pylori infec-
tion and hyperemesis gravidarum: a systematic review and meta-analysis
of case-control studies. Acta Obstet Gynecol Scand 2009;88:1190–1200.
[Meta-analysis, 25 case-control studies, 3425 pts total, 1970 controls]
9. El-Mallakh RS, Liebowitz NR, Hale MS. Hypermesesis gravidarum as con-
version disorder. J Nerv Ment Dis 1990;178(10):655–659. [II-3]
10. Trogstad LI, Stoltenberg C, Magnus P, et al. Recurrence risk in hyperemesis
gravidarum. BJOG 2005;112(12):1641–1645. [II-3]
11. Einsarson TR, Navioz Y, Maltepe C, et al. Existence and severity of nau-
sea and vomiting in pregnancy (NVP) with different partners. J Obstet
Gynaecol 2007;27(4) 360–362. [II-3]
12. Fejzo MS, Ching CY, Schoenberg FP, et al. Change in paternity and recur-
rence of hyperemesis gravidarum. JMFNM 2011;25(8):1241–1245 [II-2]
13. Koren G, Boskovic R, Hard M, et al. Motherisk-PUQE (pregnancy-unique
quantification of emesis and nausea) scoring system for nausea and vomit-
ing of pregnancy. Am J Obstet Gynecol 2002;186(Suppl 5):s228–s231. [II-3]
14. Lacasse A, Rey E, Ferreira E, et al. Validity of a modified Pregnancy-
Unique Quantification of Emesis and Nausea (PUQE) scoring index to
assess severity of nausea and vomiting of pregnancy. Am J Obstet Gynecol
2008;198(l):71.el–71.e7. [II-3]
15. Ebrahimi N, Maltepe C, Bournissen G, et al. Nausea and vomiting of
pregnancy, using the 24-hour pregnancy-unique quantification of emesis
(PUQE-24) Scale. J Obstet Gynaecol Can 2009;31(9):803–807. [II-3]
16. Fell DB, Dodds L, Joseph KS, et al. Risk factors for hyperemesis gravidarum
requiring hospital admission during pregnancy. Obstet Gynecol 2006;107(2
Pt 1):277–284. [II-2]
17. Temming L, Franco A, Istwan N, et al. Adverse pregnancy outcomes in
women with nausea and vomiting of pregnancy. J Matern Fetal Neonatal
Med 2014;27(1):84–88. [II-2]
18. Jenabi E, Fereidooni B. The association between maternal smoking and
hyperemesis gravidarum: a meta-analysis. J Matern Fetal Neonatal Med
2017;30(6):693–697. [Meta-analysis]
19. Van Dinter MC. Ptyalism in pregnant women. J Obstet Gynecol Neonatal
Nurs 1991;20:206–209. [Review]
20. Poursharif B, Korst LM, Macqibbon KW. Elective pregnancy termination
in a large cohort of women with hyperemesis gravidarum. Contraception
2007;76(6):451–455. [II-3]
21. Mitchell-Jones N, Gallos I, Farren J, et al. Psychological morbidity asso-
ciated with hyperemesis gravidarum: a systematic review and meta-
analysis. BJOG Int J Obstet Gynaecol. 2017;124(1):20–30. [Review and
meta-analysis]
22. Veenendaal MV, van Abeelen AF, Painter RC, et al. Consequences of hyper-
emesis gravidarum for offspring: a systematic review and meta-analysis.
BJOG 2011;118(11):1302–1313. [Meta-analysis: 24 studies (cohort, case
control, and cross sectional)]
Maternal-Fetal Evidence Based Guidelines
23. Royal College of Obstetricians & Gynaecologists. The management of nau-
sea and vomiting of pregnancy and hyperemesis gravidarum. Green-top
Guideline No. 69. 2016.
24. Hinkle SN, Mumford SL, Grantz KL, et al. Association of nausea and vomit-
ing during pregnancy with pregnancy loss: A secondary analysis of a ran-
domized clinical trial. JAMA Intern Med 2016;176(11):1621.
25. Brent R. Medical, social, and legal implications of treating nausea and vom-
iting of pregnancy. Am J Obstet Gynecol 2002;186:s262–s266. [Review]
26. Goodwin TM, Montoro M, Mestman JH. Transient hyperthyroidism
and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol
1992;167:648–652. [II-3]
27. Goodwin TM, Mestman J. Transient hyperthyroidism of hyperemesis grav-
idarum. Contemp Obstet Gynecol 1996;6:65–78. [II-3, and review]
28. Czeizel AE, Dudas I, Fritz G, et al. The effect of periconceptional multi-
vitamin-mineral supplementation on vertigo, nausea and vomiting. Arch
Gynecol Obstet 1992;251:181–185. [RCT, n = 48]
29. Emelianova S, Mazzotta P, Einarson A, Koren G. Prevalence and severity of
nausea and vomiting of pregnancy and effect of vitamin supplementation.
Clin Invest Med 1999;22(3):106–110. [II-2]
30. Maltepe C, Koren G. Preemptive treatment of nausea and vomiting of
pregnancy: results of a randomized controlled trial. Obstet Gynecol Int
2013;2013:809787. [RCT, n = 59]
31. Jednak MA, Shadigian EM, Kim MS, et al. Protein meals reduce nausea and
gastric slow wave dysrhythmic activity in first trimester pregnancy. Am J
Physiol 1999;277(4 Pt 1):G855–61. [II-3]
32. Murphy PA. Alternative therapies for nausea and vomiting of pregnancy.
Obstet Gynecol 1998;91:149–155. [Meta-analysis; 10 RCTs; 7 RCTs on
acupressure]
33. Dundee JW, Sourial FB, Ghaly RG, et al. P6 acupressure reduces morning
sickness. J Royal Soc Med 1988;81(8):456–457. [RCT]
34. Hyde E. Acupressure therapy for morning sickness. A controlled clinical
trial. J Nurse Midwifery 1989;34(4):171–178. [RCT]
35. de Aloysio D, Penacchioni P. Morning sickness control in early preg-
nancy by Neiguan point acupressure. Obstet Gynecol 1992;80(5):852–
854. [RCT]
36. Bayreuther J, Lewith GT, Pickering R. A double-blind cross-over study to
evaluate the effectiveness of acupressure at pericardium 6 (P6) in the treat-
ment of early morning sickness (EMS). Com-plem Ther Med 1994;2:70–76.
[RCT, n = 23]
37. Belluomini J, Litt RC, Lee KA, et al. Acupressure for nausea and vomit-
ing of pregnancy: a randomized, blinded study. Obstet Gynecol 1994;84(2):
245–248. [RCT]
38. O’Brien B, Relyea MJ, Taerum T. Efficacy of P6 acupressure in the treat-
ment of nausea and vomiting during pregnancy. Am J Obstet Gynecol
1996;174:708–715. [RCT]
39. Werntoft E, Dykes AK. Effect of acupressure on nausea and vomiting during
pregnancy. J Reprod Med 2001;46:835–839. [RCT, n = 60]
40. Jamigorn M, Phupong V. Acupressure and vitamin B6 to relieve nausea
and vomiting in pregnancy: a randomized study. Archives Gynecol Obstet
2007;276(3):245–249. [RCT, n = 66]
41. Adlan A-S, Chooi KY, Mat Adenan NA. Acupressure as adjuvant treatment
for the inpatient management of nausea and vomiting in early pregnancy:
A double-blind randomized controlled trial: Acupressure: Adjuvant treat-
ment for NVP. J Obstet Gynaecol Res 2017;43(4):662–668. [I, RCT, n: 60
acupressure, n:60 placebo]
42. Shin HS, Song YA, Seo S. Effect of Neiguan point (P6) acupressure on keto-
nuria, nausea, and vomiting in women with hyperemesis gravidarum. J Adv
Nurs 2007;59:510–519. [RCT, n = 66]
43. Habek D, Barbir A, Habek JC, et al. Success of acupuncture and acupres-
sure of the pc 6 acupoint in the treatment of hyperemesis gravidarum.
Forschende Komplementarmedizin und Klassische Naturheilkunde
2004;11(1):20–23. [RCT, n = 36]
44. Mamo J, Mamo D, Pace M, Felice D. “Evaluation of sea-band acupressure
device for early pregnancy nausea and vomiting.” 27th British Congress
of Obstetrics and Gyneaecology; 1995 July 4–7; Dublin, Ireland. 1995:283.
[RCT, n = 38]
45. Heazell A, Thornaycroft J, Walton V, et al. Acupressure for the inpatient
treatment of nausea and vomiting in early pregnancy: a randomized con-
trolled trial. Am J Obstet Gynecol 2006;194:815–820. [RCT, n = 80]
46. Evans AT, Samuels SN, Marshall C, et al. Suppression of pregnancy-induced
nausea and vomiting with sensory afferent stimulation. J Repro Med
1993;38:603–606. [RCT, n = 23]
47. Rosen T, de Veciana M, Miller HS, et al. A randomized controlled trial of
nerve stimulation for relief of nausea and vomiting in pregnancy. Obstet
Gynecol 2003;102:129–135. [RCT, n = 230]
Nausea/Vomiting of Pregnancy and Hyperemesis Gravidarum
48. Van den Heuvel E, Goossens M, Vanderhaegen H, Sun HX, Buntinx F.
Effect of acustimulation on nausea and vomiting and on hyperemesis in
pregnancy: a systematic review of Western and Chinese literature. BMC
Complement Altern Med. 2015;16(1):13. [II-3, Review]
49. Puangsricharern A, Mahasukhon S. Effectiveness of auricular acupressure
in the treatment of nausea and vomiting in early pregnancy. J Med Assoc
Thai 2008;91(11):1633–1638. [RCT, n = 98]
50. Knight B, Mudge C, Openshaw S, et al. Effect of acupuncture on nausea
of pregnancy: a randomized, controlled trial. Obstet Gynecol 2001;97:
184–188. [RCT, n = 55]
51. Smith C, Crowther C, Beilby J. Acupuncture to treat nausea and vomiting
in early pregnancy: a randomized controlled trial. Birth 2002;29:1–9. [RCT,
n = 593]
52. Neri I, Allais G, Schiapparelli P, et al. Acupuncture versus pharmacological
approach to reduce hyperemesis gravidarum discomfort. Minverva Ginecol
2005;57(4)471–475.
53. Arsenault MY, Lane CA, MacKinnon CJ, et al. The management of nausea
and vomiting of pregnancy. J Obstet Gynaecol Can 2002;24(10):817–831.
[III]
54. Hu Y, Amoah AN, Zhang H, et al. Effect of ginger in the treatment of nausea
and vomiting compared with vitamin B6 and placebo during pregnancy: a
meta-analysis. J Matern Fetal Neonatal Med 2020;1–10. [Meta-analysis]
55. Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of
hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1991;38(1):
19–24. [RCT, n = 30, cross-over design]
56. Modares M, Besharat S, Rahimi K, et al. Effect of ginger and chamomile
capsules on nausea and vomiting in pregnancy. J Gorgan Univ Med Sci
2012;14(1):46–51. [RCT n = 70]
57. Pongrojpaw D, Somprasit C, Chanthasenanont A. A randomized com-
parison of ginger and dimenhydrinate in the treatment of nausea
and vomiting in pregnancy. J Med Assoc Thai 2007;90(9):1703–1709.
[RCT n = 170]
58. Mohammadbeigi R, Shahgeibi S, Soufizadeh N, et al. Comparing the effects
of ginger and metoclopramide on the treatment of pregnancy nausea. Pak J
Biol Sci 2011;14(16):817–820. [RCT n = 68]
59. Pasha H, Behmanesh F, Mohsenzadeh F, et al. Study of the effect of mint
oil on nausea and vomiting during pregnancy. Iran Red Crescent Med J
2012;14(11):727–730. [RCT, n =]
60 Kia PY, Safajou F, Shahnazi M, Nazemiyeh H. “The effect of lemon inhala-
tion aromatherapy on nausea and vomiting of pregnancy: a double-blind
randomised controlled clinical trial.” Unpublished data, reported in
Matthew 2014 (ref 1). [RCT n = 100]
61. Gawande S, Vaidya M, Tadke R, Kirpekar V. Progressive muscle relaxation
in hyperemesis gravidarum. J SAFOG 2011;3(1):28–32. [RCT, n = 30]
62. McParlin C, Carrick-Sen D, Steen IN, et al. Hyperemesis in pregnancy
study: a randomised controlled trial of midwife-led “outpatient” care. Arch
Dis Child Fetal Neonatal Ed 2008;93. [RCT, n = 53]
63. Fletcher SJ, Waterman H, Nelson I, et al. The effectiveness and cost-effec-
tiveness of a holistic assessment and individualised package of care of
women with hyperemesis gravidarum: randomised controlled trial. BJOG
2013;120(Suppl s1):552–553. [RCT, n = 273]
64. McCormack D. Hypnosis for hyperemesis gravidarum. J Obstet Gynaecol
2010;30(7):647–653.
65. Sahakian V, Rouse D, Sipes S, et al. Vitamin B6 is effective therapy for nau-
sea and vomiting of pregnancy: a randomized double-blind placebo-con-
trolled study. Obstet Gynecol 1991;78:33. [RCT, n = 59; vitamin B6 25-mg
orally q8h × 72 hours versus placebo]
66. Vutyavanich T, Wongtrangan S, Ruangsri RA. Pyridoxine for nausea and
vomiting of pregnancy: a randomized, double-blind, placebo-controlled
trial. Am J Obstet Gynecol 1995;173:881–884. [RCT, n = 342; vitamin B6
30-mg orally q8h versus placebo]
67. Tan PC, Yow CM, Omar ST. A placebo-controlled trial of oral pyridox-
ine in hyperemesis gravidarum. Gynecol Obstet Invest 2009;77:151–157.
[RCT, n = 92]
68. Jafari-Dehkordi E, Hashem-Dabaghian F, Aliasl F, et al. Comparison of
quince with vitamin B6 for treatment of nausea and vomiting in pregnancy:
a randomised clinical trial. J Obstet Gynaecol 2017;37(8):1048–1052 [RCT,
n:40 quince, n:36 vitamin B6]
69. Zhang R, Persaud N. 8-Way randomized controlled trial of Doxylamine,
Pyridoxine and Dicyclomine for nausea and vomiting during pregnancy:
restoration of unpublished information. Mintzes B, editor. PLOS ONE.
2017;12(1):e0167609.
70. Geiger CJ, Fahrenbach DM, Healey FJ. Bendectin in the treatment of
nausea and vomiting in pregnancy. Obstet Gynecol 1959;14:688–690.
[RCT, n = 110]
109
71. McGuiness BW, Binns DT. “Debendox” in pregnancy sickness. J R Coll Gen
Pract 1971;21:500–503. [RCT, n = 81]
72. Wheatley D. Treatment of pregnancy sickness. Br J Obstet Gynecol
1977;84:444–447. [RCT, n = 56]
73. Koren G, Clark S, Hankins GDV, et al. Effectiveness of delayed-release dox-
ylamine and pyridoxine for nausea and vomiting of pregnancy: a random-
ized placebo controlled trial. Am J Obstet Gynecol 2010;203:571.el–571.e7.
[RCT, n = 256]
74. Seto A, Einarson T, Koren G. Pregnancy outcome following first trimes-
ter exposure to antihistamines: meta-analysis. Am J Perinatol 1997;14(3):
119–124. [Meta-analysis, 24 controlled studies, >20,000 patients]
75. Smedts HP, de Jonge L, Bandola SJ, et al. Early pregnancy exposure to
antihistamines and risk of congenital heart defects: results of two case-
control studies. Eur J Epidemiol 2014;29(9):653–661. [II-2, 2 case-control
studies]
76. Gilboa SM, Ailes EC, Rai RP, Anderson JA, Honein MA. Antihistamines
and birth defects: a systematic review of the literature. Expert Opin Drug
Saf 2014;13(12):1667–1698. [Review, III]
77. Erez S, Schifrin BS, Dirim O. Double-blind evaluation of hydroxyzine as an
antiemetic in pregnancy. J Reprod Med. 1971;7(1):35–37. [RCT, n = 150]
78. Gill SK, O’Brien L, Koren G. The safety of histamine 2 (H2) blockers in preg-
nancy: a meta-analysis. Dig Dis Sci 2009;54(9):1835–1838. [II-3, n = 2398
patients]
79. Mansour GM, Nashaat EH. Role of Helicobacter pylori in the pathogen-
esis of hyperemesis gravidarum. Arch Gynecol Obstet 2010. DOI 10.1007/
s00404-010-1759-8. [II-l, n = 160]
80. Majithia R, Johnson DA. Are proton pump inhibitors safe during pregnancy
and lactation? Evidence to date. Drugs 2012;72(2):171–179. [Review]
81. Gill SK, O’Brien L, Einarson TR, et al. The safety of proton pump inhibitors
(PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol 2009;104:1541–
1545. [Meta-analysis]
82. Pasternak B, Hviid A. The use of proton-pump inhibitors in early pregnancy
and the risk of birth defects. N Engl J Med 2010;363:2114–2123. [II-2]
83. Matok I, Gorodischer R, Karen G, et al. The safety of metoclo-pramide use
in the first trimester of pregnancy. N Engl J Med 2009;360:2528–2535. [II-2,
n = 3458]
84. Berkovitch M, Mazzota P, Greenberg R, et al. Metoclopramide for nausea
and vomiting of pregnancy: a prospective multicenter international study.
Am J Perinatol 2002;19:311–316. [II-2, n = 175 neonates exposed in 1st tri-
mester to metoclopramide]
85. Pasternak B, Svanstrom H, Molgaard-Nielsen D, Melbye M, Hviid A.
Metoclopramide in pregnancy and risk of major congenital malformations
and fetal death. JAMA. 2013;310(15):1601–1611. [II-2, case-control, 28,486
cases versus 113,698 control]
86. Bsat F, Hoffman DE, Seubert DE. Comparison of three outpatient regi-
mens in the management of nausea and vomiting in pregnancy. J Perinatol
2003;23:531–535. [RCT, n = 169]
87. Ghahiri AA, Abdi F, Mastoo R, Ghasemi M. The effect of ondansetron and
metoclopramide in nausea and vomiting of pregnancy. J Isfahan Med Sch
2011;29(131). [RCT, n = 70]
88. Abas MN, Tan PC, Azmi N, Omar SZ. Ondansetron compared with meto-
clopramide for hyperemesis gravidarum: a randomized controlled trial.
Obstet Gynecol 2014;123(6):1272–1279. [RCT, n = 160]
89. Kashifard M, Basirat Z, Kashifard M, et al. Ondansetron or metoclo-
pramide? Which is more effective in severe nausea and vomiting of preg-
nancy? A randomized trial double blind study. Clin Exp Obstet Gynecol
2013;40(1)127–130. [RCT, n = 83]
90. Tan PC, Khine PP, Vallikkannu N, et al. Promethazine compared with
metoclopramide for hyperemesis gravidarum: a randomized control trial.
Obstet Gynecol 2010;115:975–981. [RCT, n = 149]
91. Reichmann JP, Kirkbride MS. Reviewing the evidence for using continuous
subcutaneous metoclopramide and ondansetron to treat nausea and vomit-
ing during pregnancy. Manag Care 2012;21(5):44–47. [Review]
92. Klauser CK, Fox NS, Istwan N, et al. Treatment of severe nausea and
vomiting of pregnancy with subcutaneous medications. Am J Perinatol
2011;28(9):715–721[II-3]
93. Einarson A, Maltepe C, Navioz Y, et al. The safety of ondansetron for nau-
sea and vomiting of pregnancy: a prospective comparative study. BJOG
2004;111:940–943. [II-2, n = 176 women with ondansetron exposure]
94. Danielsson B, Wikner BN, Kallen B. Use of ondansestron during preg-
nancy and congential malformations in the infant. Reprod Toxicol 2014;50:
134–137. [II-2, n = 1349 infants with exposure]
95. Anderka M, Mitchell AA, Louik C, et al. Medications used to treat nau-
sea and vomiting of pregnancy and the risk of selected birth defects. Birth
Defects Res A Clin Mol Teratol 2012;94(1):22–30. [II-3]
110
96. Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy and risk
of adverse fetal outcomes. N Engl J Med 2013;368(9):814–823. [II-2, 1848
exposed women, 7396 control]
97. Huybrechts KF, Hernández-Díaz S, Straub L, et al. Association of maternal
first-trimester ondansetron use with cardiac malformations and oral clefts
in offspring. JAMA 2018;320(23):2429. [II2]
98. Kaplan YC, Richardson JL, Keskin-Arslan E, et al. Use of ondansetron dur-
ing pregnancy and the risk of major congenital malformations: A systematic
review and meta-analysis. Reprod Toxicol 2019;86:1–13. [Meta-analysis]
99. Oliveira LG, Capp SM, You WB, Riffenburgh RH, Carstairs SD. Ondansetron
compared with doxylamine and pyridoxine for treatment of nausea in preg-
nancy: a randomized controlled trial. Obstet Gynecol 2014;124(4):735–742.
[RCT, n = 36; ondansetron 4 m PO versus 25 mg pyridoxine plus 12.5 mg
doxylamine]
100. Sullivan CA, Johnson CA, Roach H, et al. A pilot study of intravenous
ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:
1565–1568. [RCT, n = 30; ondansetron 10-mg IV versus promethazine
50-mg IV, both q8h]
101. Bartfai Z, Kocsis J, Puno EH, et al. A population based case-control tera-
tologic study of promethazine use during pregnancy. Reprod Toxicol
2008;25:276–285. [II-3]
102. Safari HR, Fassett MJ, Souter IC, et al. The efficacy of methyl-prednisolone
in the treatment of hyperemesis gravidarum: a randomized, double-blind,
controlled study. Am J Obstet Gynecol 1998;179:921–924. [RCT, n = 40]
103. Ziaei S, Hosseiney FS, Faghihzadeh S. The efficacy of low dose prednisolone
in the treatment of hyperemesis gravidarum. Acta Obstet Gynecol Scand
2004;83:272–275. [RCT, n = 80]
104. Newlinds JS. Nausea and vomiting in pregnancy: a trial of thiethylperzine.
Med J Aust 1964;15(1): 234–236. [RCT, n = 164]
105. Price JJ, Barry MC. A double blind study of fluphenazine with pyridoxine.
Pa Med J 1964;67:37–40. [RCT, n = 78]
106. Murphy A, McCarthy FP, McElroy B, et al. Day care versus inpatient man-
agement of nausea and vomiting of pregnancy: cost utility analysis of a ran-
domised controlled trial. Eur J Obstet Gynecol Reprod Biol 2016;197:78–82.
107. Tan PC, Norazilah MF, Omar SZ. Dextrose saline compared with normal
saline rehydration of hyperemesis gravidarum: a randomized controlled
trial. Obstet Gynecol 2013;121(2 Pt 1):291–298. [RCT, n = 202]
108. Tan P, Abdussyukur S, Lim B, et al. Twelve-hour fasting compared with
expedited oral intake in the initial inpatient management of hyper-
emesis gravidarum: a randomised trial. BJOG Int J Obstet Gynaecol
2020;127(11):1430–1437. [RCT, n: 80 expedited oral intake, n:80 twelve-
hour fasting]
109. Bondok RS, El Sharnouby NM, Eid HE, et al. Pulsed steroid therapy is an
effective treatment for intractable hyperemesis gravidarum. Crit Care Med
2006;34:2781–2783. [RCT, n = 40]
Maternal-Fetal Evidence Based Guidelines
110. Ylikorkala O, Kauppila A, Ollanketo ML. Intramuscular ACTH or placebo
in the treatment of hyperemesis gravidarum. Acta Obstet Gynecol Scand
1979;58(5):453–455. [RCT, n = 32]
111. Ditto A, Morgante G, la Marca A, et al. Evaluation of treatment of hyper-
emesis gravidarum using parenteral fluid with or without diazepam. A ran-
domized study. Gynecol Obstet Invest 1999;48:232–236. [RCT, n = 50]
112. Maina A, Arrotta M, Cicogna L, et al. Transdermal clonidine in the treat-
ment of severe hyperemesis. A pilot randomised control trial: CLONEMESI.
BJOG 2014;121(12):1556–1562. [RCT, n = 12]
113. Stokke G, Gjelsvik BL, Flaatten KT, Birkeland E, Flaatten H, Trovik J.
Hyperemesis gravidarum, nutritional treatment by nasogastric tube feed-
ing: a 10-year retrospective cohort study. Acta Obstet Gynecol Scand
2015;94(4):359–367. [II-3, n = 107 parenteral nutrition, n = 10 parenteral
nutrition, n = 273 intravenous fluids]
114. Grooten IJ, Koot MH, van der Post JA, et al. Early enteral tube feed-
ing in optimizing treatment of hyperemesis gravidarum: the Maternal
and Offspring outcomes after Treatment of HyperEmesis by Refeeding
(MOTHER) randomized controlled trial. Am J Clin Nutr 2017;ajcn158931.
[RCT]
115. Garg S, Contag S, Dutta S. Emerging role of endoscopically placed jejunos-
tomy tubes in the management of severe hyperemesis gravidarum: a case
series. Gastrointest Endosc 2014;79(4):685–688.
116. Hsu JJ, Clark-Glena R, Nelson DK, et al. Nasogastric enteral feeding in
the management of hyperemesis gravidarum. Obstet Gynecol 1996;88:
343–346. [II-3]
117. Russo-Stieglitz KE, Levine AB, Wagner BA, et al. Pregnancy outcome
in patients requiring parenteral nutrition. J Matern Fetal Med 1999;8:
164–167. [II-2]
118. Folk JJ, Leslie-Brown HF, Nosovitch JT, et al. Hyperemesis gravidarum:
outcomes and complications with and without total parenteral nutrition.
J Reprod Med 2004;49:497–502. [II-2, n = 166]
119. Holmgren C, Aagaard-Tillery KM, Silver RM, et al. Hyperemesis in preg-
nancy: an evaluation of treatment strategies with maternal and neonatal
outcomes. Am J Obstet Gynecol 2008;198(1):56. [II-2]
120. Nuthalapaty FS, Beck MM, Mabie WC. Complications of central venous
catheters during pregnancy and postpartum: a case series. Am J Obstet
Gynecol 2009;201:311.el–311.e5. [II-3]
121. Peled Y, Melamed N, Hiersch L, Pardo J, Wiznitzer A, Yogev Y. The impact of total
parenteral nutrition support on pregnancy outcome in women with hyper-
emesis gravidarum. J Matern Fetal Neonatal Med 2014;27(11):1146–1150.
[II-2, n = 122 cases of HG with TPN, n = 1797 controls without HG]
122. Faramarzi M, Yazdani S, Barat S. An RCT of psychotherapy in women with
nausea and vomiting of pregnancy. Hum Reprod 2015;dev248. [RCT, n:43
pyridoxine hydrochloride and intensive mindfulness-based cognitive ther-
apy, n:43 pyridoxine hydrochloride]
10
INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Ginevra Salsi
Key points
• The diagnosis of intrahepatic cholestasis of pregnancy
(ICP) is defined as first onset of pruritus in the second or
third trimester, elevated serum bile acids >10 μmol/L,
and spontaneous relief of signs and symptoms within 4
weeks after delivery.
• ICP is diagnosed once all other forms of liver disease and
cholestasis have been excluded.
• ICP should be classified by bile acid levels: 11–39
μmol/L: mild; 40–99 μmol/L: moderate; ≥100 μmol/L:
severe.
• Complications of untreated, usually severe ICP, include
spontaneous preterm birth, meconium, nonreassuring
fetal heart tracing, fetal death, neonatal death, and post-
partum hemorrhage.
• The increased incidence of stillbirth exceeds that of the
general population once total bile acid concentration is
>100 μmol/L. Fetal deaths occur mostly ≥36 weeks.
• Ursodeoxycholic acid (UDCA) is the current treatment
of choice for ICP: it shows mainly a reduction in pruritus
but the size of the effect is probably small. It is associated
with improvements with maternal pruritus, bile acids, and
transaminases.
• Vitamin K 10 mg by mouth once a day at onset of ICP or
34 weeks has been suggested for prevention of postpartum
hemorrhage, but there is insufficient evidence for a strong
recommendation.
• There are several reports of sudden fetal death within
24 hours of a reactive nonstress test (NST), and
insufficient evidence for a recommended fetal test-
ing protocol. Most experts do non-stress tests or
biophysical profiles weekly, but there is no evidence for
benefit.
• Women with intrahepatic cholestasis of pregnancy and
singleton pregnancies should be managed on the basis of
their peak bile acid concentration.
• Because bile acids can change rapidly with advancing ges-
tation, regular monitoring of serum total bile acids (e.g.,
weekly especially in third trimester) is suggested to reas-
sess risk; most studies use the peak level for prognosis and
management.
• For women with total bile acid concentration of ≥100
μmol/L, delivery should probably occur by 35 0/7–36
6/7 weeks of gestation.
• In women with bile acid concentrations of 40–99 μmol/L,
delivery should probably occur around 37 0/7–37 6/7
weeks.
• For women with bile acid level of < 40 μmol/L, consider-
ing the risk of prematurity and the low risk of intrauterine
demise due to cholestasis, it is possible to wait until 38
0/7–38 6/7 weeks of gestation.
DOI: 10.1201/9781003099062-10
Historic notes
Old names such as “benign jaundice of pregnancy” or “idiopathic
jaundice of pregnancy” should no longer be used.
Diagnosis/Definition
Intrahepatic cholestasis of pregnancy (ICP) is diagnosed when
otherwise unexplained pruritus occurs in pregnancy with ele-
vated total bile acids (TBA) >10 μmol/L, often with elevations
in serum alkaline phosphatase and aminotransferases, which all
resolve after delivery [1]. TBA should be done fasting [2]. In the
setting of normal bile acids, some accept the diagnosis of pruri-
tus and abnormal transaminases [3]. Other names used in the lit-
erature are gestational cholestasis or obstetric cholestasis. Other
causes of pruritus and liver disfunction should be excluded.
Differential diagnosis may include hepatitis A, B, and C, Epstein–
Barr and cytomegalovirus, autoimmune liver disease, gallbladder
stones, tumors of the hepatobiliary tract, and a number of causes
with elevated hepatic enzymes specified to pregnancy (e.g. pre-
eclampsia, HELLP syndrome and acute fatty liver) (Figure 10.1;
Table 10.1) [4–7]. Women with persistent unexplained pruritus
and normal biochemical tests should have liver function tests
repeated every 1–2 weeks [1].
Symptoms
ICP is characterized by mild to severe pruritus usually starting
after 30 weeks, which often resolves within 48 hours following
delivery [4]. The pruritus of ICP is typically worse at night, is
often widespread through the whole body, and may be most
severe in the palms of the hands and/or soles of the feet [1, 8].
Mild jaundice, if present (incidence of 14–25%), typically develops
1–4 weeks after onset of pruritus with mildly elevated serum lev-
els of conjugated bilirubin. Insomnia, fatigue, anorexia, malaise,
weight loss, epigastric discomfort, steatorrhea, gallstones, chole-
cystitis, vitamin K deficiency, and dark urine are other signs and
symptoms associated with ICP [4].
Incidence/Epidemiology
ICP is the most common liver disease during pregnancy, affect-
ing 0.2–2% of pregnancies worldwide [9]. The prevalence of ICP
in pregnant women varies according to geographical location and
population, as genetic and environmental factors play a role in its
manifestation. Following studies from past decades, in countries
of North America, Southern Europe, Asia, and Australia, the
range of ICP was between 0.01% and 0.1%, in some countries
of South America between 1.5% and 4.0%, and in Scandinavian
countries, the reported prevalence was 1.5%. Chile, Bolivia,
Finland, Sweden, and Portugal are among the most affected
countries in the world [2]. It commonly occurs in late second and
111
112 Maternal-Fetal Evidence Based Guidelines

Cutaneous No eruptions
eruptions

Pregnancy related Nonpregnancy related

• Pruritic urticarial papules • Atopic or contact dermatitis
and plaques of pregnancy • Scabies
• Prurigo of pregnancy • Psoriasis Elevated bile Normal bile acids
• Pruritic folliculitis of pregnancy • Urticaria acids
• Herpes gestationis*

Elevated LFTs Normal LFTs

Acute symptoms Chronic symptoms

Intrahepatic
cholestasis Refer for other
Primary
of pregnancy Acute fatty differentials
sclerosing Primary liver
Cholestasis cholangitis biliary of pregnancy
Viral hepatitis
cirrhosis

Nonalcoholic HELLP
fatty liver syndrome
disease

FIGURE 10.1 Workup and differential diagnosis of pruritus during pregnancy. Abbreviations: LFT, liver function tests; HELLP,
Hemolytic anemia, Elevated Liver enzymes, and Low Platelet count.

TABLE 10.1: Selected Differential Diagnoses of Pregnant Women with Pruritus

Intrahepatic
Cholestasis of Primary Sclerosing Primary Biliary Acute Fatty Liver
Pregnancy Viral Hepatitis Cholangitis Cirrhosis of Pregnancy
Common trimester Third Any Any Any Second, third
presentation
Clinical features Severe pruritis, Nausea, vomiting, Insidious and Fatigue, intermittent Nausea, vomiting,
jaundice jaundice, prolonged intermittent jaundice, pruritis, RUQ pain, abdominal pain,
abdominal pain and fatigue, pruritis, anorexia, and jaundice mental status
fluctuating jaundice abdominal pain jaundice changes, +/– pre-
and pruritis eclampsia, +/– HTN
Laboratory findings Alkpho nl or elevated Alkpho nl Alkpho 3–5× nl Alkpho 3–4 × nl Alkpho nl
Trans elevated, Trans 1000 to 2000 Trans 4–5× nl Trans <3× nl Trans nl or moderately
sometimes to 1000 U/L; ALT >AST elevated
U/L
Bilirubin: mildly Bilirubin: nl or mildly Bilirubin: nl or mildly Bilirubin: Early stage: Bilirubin: elevated
elevated elevated elevated nl, then increases
slowly, may exceed
>20 mg/dL
Pathology Mutation in multidrug Viral infection; Idiopathic, associated Autoimmune Often idiopathic, some
resistance-3 gene; sequalae from acute with IBS; inflammatory patients with inherited
environmental hepatitis can lead to cholangiographic destruction of LCHAD deficiency;
factors cholestasis findings of multifocal intralobular bile most common in
structuring an ectasia ducts. primiparous and
of biliary tree multiple gestations
Bx: Bland changes Bx: Marked Bx: Thickened, fibrotic Bx: Ductopenia: Bx: Microvesicular fatty
typical of cholestasis inflammation duct wall absence of liver disease
of liver biopsy interlobular bile ducts
>50% portal tracts
Treatments with Ursodeoxycholic acid Supportive measures Ursodeoxycholic acid, Ursodeoxycholic acid, Delivery
reported benefit (first-line therapy); treat underlying, liver steroids
on symptoms SAMe transplant
Source: Adapted from Refs. [30, 31].
Abbreviations: Alkpho, alkaline phosphatase; Bx, biopsy; HTN, hypertension; LCHAD, Long-chain 3-hydroxyacyl CoA dehydrogenase; nl, normal; RUQ, right upper quad-
rant; SAMe, S-adenosylmethionine; Trans, transaminases.
Intrahepatic Cholestasis of Pregnancy
third trimester, rapidly resolves within 4 weeks after delivery,
and is associated with adverse pregnancy outcomes [1, 10].
Genetics
About 15–30% of women presenting with ICP have a family his-
tory of intrahepatic cholestasis (IC), but most cases are not related
to known mutations of familial IC. Genetic predisposition is
shown in high-prevalence regions such as Chile and Scandinavia.
Family clustering, prevalence of ethnic and geographic varia-
tions, and recently demonstrated mutations in gene coding for
hepatobiliary transport proteins further indicate a genetic pre-
disposition in ICP. There are many genetic variations described,
which occur at different chromosomal locations: ATP8B1 at 18q
21–22, ABCB4 at 7q21, and ABCB11 at 2q24 [11]. Genetic predis-
position may lead to altered cell membrane composition of bile
ducts and hepatocytes, as well as the subsequent dysfunction of
biliary canalicular transporters. Mutations in the hepatic phos-
pholipid transporter (MDR3/ABCB4), amniophospholipid trans-
porter (ATP8B1/FIC1), and bile salt export pump (BSEP/ABCB11)
have been found in patients with ICP. These genetic mutations are
more frequent in women who developed severe ICP [4, 8].
Etiology/Basic pathophysiology
ICP is associated with a rise in conjugated bile salts, particularly
the tauroconjugates of cholic and chenodeoxycholic acid. Bile acids
are the end product of hepatic cholesterol metabolism. The meta-
bolic demand of pregnancy increases the demand for and exceeds
hepatic capacity for cholesterol metabolism in susceptible individ-
uals. Bile acids such as glycocholic and taurocholic acid increase in
serum and cause itching [7]. Bile acids are inherently cytotoxic and
thus their metabolism is tightly regulated. In ICP the transport of
bile salts from liver to the gallbladder and intestine is disrupted,
leading to compensatory transport of bile salts from hepatocytes
into the blood [9]. An increase in bile acid serum concentration is
thought to play a primary role in the onset of the typical chole-
static pruritus [8]; however, the correlation between the bile acid
serum concentration and severity of pruritus is poor. Moreover,
the increased passage of bile acids through the placental barrier
appears to be toxic for the fetus during ICP [2].
The underlying mechanisms of obstetric complications (pre-
term delivery, meconium passage, fetal distress and fetal death)
are poorly understood [12]. First, research in animals has shown
a detrimental effect of high bile acid levels on cardiomyocytes,
which cause arrhythmias [13]. Such potentially lethal arrhyth-
mias in the fetus could explain the increased incidence of still-
birth. Second, a vasoconstrictive effect of bile acids on human
placental chorionic veins has been shown, possibly explaining
the occurrence of fetal distress, asphyxia and death [3]. Finally
several studies have shown bile acid to increase the sensitivity
and expression of oxytocin receptors in the human myometrium,
possibly clarifying the mechanism behind spontaneous preterm
labor in pregnancies that are complicated by ICP [14, 15].
Classification
ICP should be classified by bile acid levels: 11–39 μmol/L: mild;
40–99 μmol/L: moderate; ≥100+μmol/L: severe. A bile acid
level of ≥40 μmol occurs in about 20% of ICP cases. Complications
occur mainly with severe ICP [16, 17]. In particular, the increased
113
incidence of stillbirth only seems to exceed those of the general
population once total bile acid concentrations are of 100 μmol/L
or more [18].
Risk factors/Associations
Most often the disease seems to affect women with a history of
ICP during previous pregnancies or a history of cholestasis asso-
ciated with the use of oral contraceptives, in-vitro fertilization,
with a family or personal history of biliary disease, with hepatitis
C viral infection, twin pregnancies, or women with in vitro fertil-
ization pregnancies. The risk of acquiring ICP is higher in women
over the age of 35 years [2]. The likelihood of ICP recurring during
a subsequent pregnancy is about 60% [10]. Several environmental
factors have been reported to play a role in the etiology of ICP in
genetically susceptible individuals: high maternal serum copper
and low maternal serum selenium and zinc. Interestingly, ICP is
more common in some countries during the winter, when natural
selenium levels are lower. Deficiency of vitamin D has been also
reported in women with ICP [2, 4].
Complications (without treatment)
ICP is associated with increased rates of spontaneous and iat-
rogenic preterm birth, meconium-stained amniotic fluid, and
neonatal unit admission [18]. Concerning the risk of stillbirth,
increased incidence of stillbirth only exceeds those of the gen-
eral population once total bile acid concentrations are of ≥100
μmol/L; the stillbirth prevalence after 24 weeks of gestation was
3.4% women with ICP compared with 0.3–0.4% from pooled
national average data among included countries. Instead, if total
bile acid concentrations remain <100 μmol/L stillbirth rates
seem similar to the general population (0.13–0.28%). These
data are consistent to other recent findings [19].
Complications of untreated ICP include: preterm birth (PTB)
(15–44%), passage of meconium (25–45%), non-reassuring fetal
heart testing (NRFHT) 5–15%, fetal death (2–10%), neonatal death
(1–2%) and postpartum hemorrhage (20–22%) [3]. Spontaneous
preterm birth (SPTB) occurs mostly at 32–36 weeks. The risk of
SPTB is higher (8–9%) for bile acid concentrations ≥4 μmol/L
than for patients with bile acids lower than 40 μmol/L (6–7%) [18].
Fetal deaths (stillbirths) occur mostly ≥36 weeks [18]. The eti-
ology of fetal deaths is unclear. Fetal compromise increased by
1–2% for each additional μmol/L of bile acid concentration in one
study; compared with control pregnancies, these rates increased
significantly at bile acid levels ≥40 micromoles/L [18]. In a recent
multicenter retrospective cohort study, bile acids ≥40 μmol/L were
associated with increased risk of meconium-stained amniotic
fluid, while bile acids ≥100 μmol/L were associated with increased
risk of stillbirth [19]. No increase in perinatal deaths has occurred
in recent series with treatment and delivery by 37–38 weeks [13,
20]. Subclinical steatorrhea may occur along with fat malabsorp-
tion. This condition may lead to vitamin K deficiency, resulting in
a prolonged prothrombin time and postpartum hemorrhage [20].
Pregnancy considerations
Up to 50% of women recall pruritus during pregnancy, but few
have elevated bile acids. Bile acids may initially be normal, later
increasing at an average of 3 weeks after symptoms of pruritus. Of
ICP diagnoses, 80–86% are made after 30 weeks.
114 Maternal-Fetal Evidence Based Guidelines

Pregnancy management/Evaluation TABLE 10.2: Delivery Timing for ICP According to

Principles
Management of ICP depends in part on the level of peak
bile acids, with bile acids >=100 associated with most
complications.
Workup
Laboratory evaluation includes bile acids (with serial mea-
surement if initially negative and high clinical suspicion) and
transaminases, such as AST and ALT (which are elevated in
approximately 60% of cases). GGT is not necessary, but is elevated
in 30% of cases. Serum bilirubin is elevated in about 25% of cases
of ICP, rarely exceeding 6 mg/dL. [4]. Hepatitis C antibody can be
checked, especially in the presence of risk factors for the infec-
tion, as ICP is more common in these women. In the appropriate
clinical setting, right upper quadrant ultrasound can be used to
investigate the possibility of biliary obstruction (10% have cho-
lelithiasis) (Figure 10.1; Table 10.1) [4–7]. Once bile acids are >10
and diagnosis of ICP is made, bile acids can be repeated serially
(e.g. weekly, or monthly, or just at 34–36 weeks) to assess any
change in classification among mild, moderate, vs severe disease.
Postnatal resolution of symptoms and biochemical abnormalities
is required to confirm the diagnosis [1].
Management
See Figure 10.2; Table 10.2.
Prevention
No preventive measures have been proposed.
Bile Acid Levels
Suggested Gestational Age
Peak Bile Acid Level (μmol/L) at Delivery (weeks)
11–39 (mild) 38 0/7–38 6/7
40–99 (moderate) 37 0/7–37 6/7
≥100 (severe) 35 0/7–36 6/7
Therapy
Ursodeoxycholic acid (Ursodiol)
Mechanism of action for ursodiol, which is a hydrophilic bile acid
that inhibits intestinal absorption of other bile acids, enhances
excretory hepatocyte function and choleretic activity, stabilizes
hepatocyte cell membranes and dilutes toxic bile acids in the
enterohepatic circulation [13]. Ursodiol may also allow for trans-
port of bile acids out of fetal compartment. After treatment, urso-
deoxycholic acid (UDCA) becomes the main component of the
total bile acid measurement, thus reducing the proportion of cho-
lic acid, that has been repeatedly implicated in the pathogenesis
of fetal complications [21].
Safety. FDA pregnancy category B.
Dose. Ten to 25 mg/kg orally divided in two doses daily. The
standard starting does is 300 mg to 500 mg orally twice a day.
Side effects. Headache, diarrhea and constipation, all reported
in less than 25% of patients. UDCA is generally well tolerated by
pregnant women [22].
Effectiveness. Compared to placebo, UDCA was tradition-
ally associated with decreased pruritus, a significantly
greater reduction in bile acids and transaminases, and

Intrahepatic Cholestasis
of Pregnancy

Bile Acids Bile Acids

<40 µmol/L ≥40 µmol/L

UDCA UDCA
10 mg/kg/day 10 mg/kg/day

Symptoms Symptoms Symptoms Symptoms

Improve Persist Persist Improve

• Continue UCDA treatment

• Continue UCDA treatment Repeat Bile Acids Repeat Bile Acids • Antenatal testing
• Antenatal testing • Deliver by 37 0/7 – 37 6/7 weeks
• Deliver at 38 0/7 – 38 6/7 weeks
<40 µmol/L ≥40 µmol/L
• Deliver by 35 0/7 – 36 6/7 weeks
if BA > 100 µmol/L

• Increase UCDA to maximum of 15 mg/kg/day

• Increase UCDA to maximum of 15 mg/kg/day
• Antenatal testing
• Antenatal testing
• Deliver by 37 0/7 – 37 6/7 weeks
• Deliver at 38 0/7 – 38 6/7 weeks
• Deliver by 35 0/7 – 36 6/7 weeks if BA >100 µmol/L

FIGURE 10.2 Treatment algorithm. (Adapted from Refs. [3, 4, 8].) Abbreviations: UDCA, ursodeoxycholic acid; SAMe,
S-adenosylmethionine.
Intrahepatic Cholestasis of Pregnancy
lower incidence of total preterm birth but not SPTB [23–
26]. However, a recent Cochrane meta-analysis concluded that
UDCA probably shows a reduction in pruritus, but the size
of the effect is small; for most pregnant women and clini-
cians, the reduction may fall below the minimum clinically
worthwhile effect. There may be a place for it in offering
a test period to a woman for managing pruritus if itching
is severe. The evidence was unclear for other adverse fetal
outcomes (stillbirth, fetal distress/asphyxial events), due to
very low-certainty evidence [22].
S-Adenosylmethionine
S-adenosylmethionine (SAMe) is a methyl donor which is thought
to improve bile flow and biliary lipid metabolism. The dose should
be 500 mg orally twice a day, or 800 to 900 mg IV infusion once a
day. Compared to placebo, one trial showed significantly greater
improvements in pruritus, bile salts, and liver enzymes with
SAMe [22]. Compared to UDCA, SAMe is less effective at
improving pruritus, bile acids, transaminases, and bilirubin
[23, 26–28]. SAMe is not commonly used by itself given the toler-
ability and therapeutic superiority of UDCA [22].
UDCA and SAMe
Compared to placebo, UDCA and SAMe resulted in greater
improvements in pruritus, bile salts, and selected liver function
assays; however, combined UDCA and SAMe were no more effec-
tive than UDCA alone in regard to improvement in pruritus [26–28].
Other therapies
• Dexamethasone. Compared to dexamethasone, UDCA is
associated with a greater reduction in bile acids and liver
enzymes, with improved pruritus only in women with
severe ICP [22]. Dexamethasone should not be first-line
therapy for treatment of ICP, nor should it be used outside
of a randomized controlled trial without a thorough con-
sultation with the woman [1].
• Cholestyramine. Cholestyramine is an anion exchange
resin that binds to bile acids and decreases their absorption
in the ileum. Compared to UDCA, cholestyramine had a
lower effect on pruritus and liver function. No significant
differences were observed in fetal outcomes and caesar-
ean section rates. Cholestyramine use was found to have
a greater number of adverse effects [22]. Cholestyramine
should not be taken with other medications because
of potential interference with their absorption. Safety:
FDA pregnancy category C. Dose: 8 g orally once a day.
Significant side effects include a decrease in intestinal
absorption of fat-soluble vitamins A, D, E, and K, increased
intestinal gas, diarrhea and poor palatability. No studies
support the use of vitamin K supplementation to decrease
risks associated with deficiency [29].
• Guar gum. Guar gum is a type of dietary fiber that decreases
the bile acid pool by binding to bile acids in the intestinal
lumen [6] Safety: FDA pregnancy category B. Compared to
placebo, there are no differences in pruritus, bile salts, ges-
tational age at birth or fetal/neonatal outcomes [23].
• Activated charcoal. Activated charcoal is a highly porous car-
bon compound. It is widely used to treat acute poisoning fol-
lowing oral ingestion, where it binds to the toxin and prevents
its absorption from the stomach and intestine. It can effec-
tively adsorb bile salts in vitro. Safety: FDA class C. Compared
to no treatment, the reduction in bile salts was greater with
115
charcoal, but there was no difference in pruritus or fetal/neo-
natal outcomes in a very small RCT [22].
• Hydroxyzine. Hydroxyzine antagonizes central and periph-
eral histamine-1 receptors. Safety: FDA pregnancy cat-
egory C; dose: 25–100 mg as needed every 6 hours orally.
Hydroxyzine might improve tolerance to persistent itch-
ing, but this is not based on RCT data [21]. Antihistamines
may provide some sedation at night but do not have a sig-
nificant impact on pruritus.
• Vitamin K. Vitamin K (FDA pregnancy category C) 10 mg
once a day at onset of ICP or 34 weeks has been suggested
for prevention of postpartum hemorrhage, but there is
insufficient evidence for a strong recommendation [7].
Women should be advised than when prothrombin time is
prolonged, the use of water-soluble vitamin K (for example,
menadiol sodium phosphate) in dose of 5–10 mg daily may
be indicated [4].
Conclusion
UDCA monotherapy is the current treatment of choice and
should be used as the first line of therapy for ICP. UDCA has been
demonstrated to be equal or superior in safety, efficacy, cost-
effectiveness, and convenience compared to other therapies.
Although UDCA has not been shown to prevent the
adverse outcomes of ICP, there is no other effective treat-
ment for this condition, and there is a small reduction in
maternal itching [22].
There is insufficient evidence to recommend that SAMe, guar
gum, activated charcoal, dexamethasone, cholestyramine, Salvia,
Yinchenghao decoction, Danxioling and Yiganling, alone or in
combination are effective in treating women with ICP [22].
Antepartum testing
No RCT specifically addresses fetal surveillance and its frequency
in ICP. No specific method of antenatal fetal monitoring for the
prediction of fetal death can be recommended. Even if maternal
detection of movements is simple, its role in monitoring preg-
nancy complicated by ICP has not been assessed. Ultrasound and
cardiotocography are not reliable methods for preventing fetal
death in ICP. Daily kick counts, and non-stress tests (NSTs) once
per week starting at diagnosis (usually on or after 32 weeks) have
been proposed, but there are several reports of fetal death after
reactive NST [30, 31]. Despite this, expert opinion suggests that
continuous fetal monitoring in labor should be offered [1].
Once ICP is diagnosed, it is reasonable to repeat bile acids, in
particular if <100 μmol/L, serially until delivery, to determine
peak level for management. Most studies use the highest bile
acid level for prognosis and management (Figure 10.2). Some
suggest to also repeat liver function tests serially until deliv-
ery, but these levels usually do not determine delivery timing
and management [1].
Delivery
Stillbirths in ICP have been reported across all gestations, but the
majority of unexplained fetal deaths occur after 37 weeks [8].
Since the increased stillbirth rates only exceed those of the
general population once total bile acid concentrations are of ≥100
μmol/L, women with ICP and singleton pregnancies should
be managed on the basis of their peak bile acid concentra-
tion. Because bile acids can change rapidly with advancing
116
gestation, regular monitoring of serum levels (e.g. weekly) is
needed to reassess risk [18].
• In women with total bile acid concentrations of ≥100
μmol/L, delivery should probably occur by 35 0/7–36
6/7 weeks of gestation
• In women with bile acid concentrations <100 μmol/L,
Royal College of Obstetricians and Gynaecologists
(RCOG) recommends offering induction of labour after
37+0 weeks, considering the risks connected to prematu-
rity and with women being informed of the increased risk
of perinatal morbidity from early intervention [1]. This
recommendation is consistent with more recent studies
that have reconsidered the risk of stillbirth that, for TBA
<100 μmol/L is similar to the one of the general popula-
tion. Minimal variations have been proposed according to
a further stratification upon bile acid levels:
• In women with bile acid concentrations of 40–99
μmol/L, delivery should probably occur around 37
0/7–37 6/7 weeks
• For women with bile acid level of <40, it is possible
to wait for delivery until 38 0/7–38 6/7 weeks of ges-
tation (Figure 10.2; Table 10.2) [1, 18, 32–34]
The guidelines published in 2011 by the RCOG open discus-
sion with women about the scarce evidence supporting early term
delivery to minimize stillbirth risk.
Although the American College of Obstetricians and Gyne­
cologists and the Society for Maternal Fetal Medicine endorsed
active management of ICP-affected pregnancies, RCOG reported
that active management of ICP should be replaced by individual
management decisions according to the evidence concerning
the known perinatal risk of early term birth versus the small but
unknown risk of ICP-associated term stillbirth [35].
References
1. Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis.
Green-top Guideline No. 43; April 2011. [Guideline; III]
2. Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile
acids or serum bile acid profile, or both, for the diagnosis of intrahepatic
cholestasis of pregnancy. Cochrane Database Syst Rev 2019;(7). Article No.
CD012546. doi: 10.1002/14651858.CD012546.pub2. [I]
3. Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. Vasoconstrictive
effect of bile acids on isolated human placental chorionic veins. Eur J Obstet
Gynecol Reprod Biol 1991;42:211–215. [II-3]
4. Ozkan S, Ceylan Y, Ozkan OV, Yildirim S. Review of a challenging clini-
cal issue: Intrahepatic cholestasis of pregnancy. World J Gastroenterol
2015;21(23):7134–7141. [Review; III]
5. Cappell M. Hepatic disorders severely affected by pregnancy: medical and
obstetric management. Med Clin North Am 2008;92(4):739–760. [II-2]
6. Cappell M. Hepatic disorders mildly to moderately affected by pregnancy:
medical and obstetric management. Med Clin North Am 2008;92(4):
717–737. [II-2]
7. Feldman M, Friedman L, Brandt L. Gastrointestinal and Liver Disease 9th
ed. Philadelphia, PA: Saunders, 2010. [Review]
8. Pathak B, Sheibani L, Lee R. Cholestasis of pregnancy. Obstet Gynecol Clin
North Am 2010;37(2):269–282. [II-3]
9. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet
Gynecol 2014;124(1):120–133. [Review; III]
10. Piechota J, Jelski W. Intrahepatic cholestasis in pregnancy: Review of the
literature. J Clin Med. 2020;9(5):1361. [II-2]
11. Floreani A, Gervasi MT. New insights on intrahepatic cholestasis of preg-
nancy. Clin Liver Dis 2016;20(1):177–89. [Review; III]
12. Brouwers L, Koster MP, Page-Christiaens GC et al. Intrahepatic ­cholestasis
of pregnancy: maternal and fetal outcomes associated with elevated bile
acid levels. Am J Obstet Gynecol 2015;212(1):100.e1–7. [II-2]
Maternal-Fetal Evidence Based Guidelines
13. Gorelik J, Shevchuk A, de Swiet M, et al. Comparison of the arrhythmogenic
effects of tauro- and glycoconjugates of cholic acid in an in vitro study of rat
cardiomyocytes. BJOG 2004;111(8):867–870. [II-2]
14. Israel EJ, Guzman ML, Campos GA. Maximal response to oxytocin of the
isolated myometrium from pregnant patients with intrahepatic cholestasis.
Acta Obstet Gynecol Scand 1986;65:581–582. [II-3]
15. German AM, Kato S, Carvajal JA, et al. Bile acids increase response and
expression of human myometrial oxytocin receptor. Am J Obstet Gynecol
2003;189:577–582. [II-3]
16. Sentilhes L, Bacq Y. The intrahepatic cholestasis of pregnancy. J Obstet
Gynecol Reprod Biol 2008;37(2):118–126. [II-3]
17. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N
Engl J Med 1998;339(17):1217–1227. [Review; nonpregnant]
18. Ovadia C, Seed PT, Sklavounos A, et al. Association of adverse perinatal
outcomes of intrahepatic cholestasis of pregnancy with biochemical mark-
ers: results of aggregate and individual patient data meta-analyses. Lancet
2019;393:899–909 [I]
19. Puljic A, Kim E, Page J, et al. The risk of infant and fetal death by each addi-
tional week of expectant management in intrahepatic cholestasis of preg-
nancy by gestational age. Am J Obstet Gynecol 2015;212:667. [III]
20. Saleh M, Abdo K. Intrahepatic cholestasis of pregnancy: review of the lit-
erature and evaluation of current evidence. J Womens Health 2007;16(6):
833–841. [II-3]
21. Manna LB, Ovadia C, Loevgren-Sandblom A, et al. Enzymatic quantifica-
tion of total serum bile acids as a monitoring strategy for women with intra-
hepatic cholestasis of pregnancy receiving ursodeoxycholic acid treatment:
a cohort study. BJOG 2019;126:1633–1640.
22. Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG.
Pharmacological interventions for treating intrahepatic cholestasis of preg-
nancy. Cochrane Database Syst Rev 2020,(7). Article No. CD000493. doi:
10.1002/14651858.CD000493.pub3. [I]
23. Roncaglia N, Locatelli A, Arreghini A, et al. A randomized controlled trial
of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of
gestational cholestasis. BJOG 2004;111:17–21. [RCT, n = 46]
24. Diaferia A, Nicastri PL, Tartagni M, et al. Ursodeoxycholic acid therapy
in pregnant women with cholestasis. Int J Gynaecol Obstet 1996;52(2):
133–140. [RCT, n = 16]
25. Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment of
cholestasis of pregnancy: a randomized, double-blind study controlled with
placebo. J Hepatol 2000;27(6):1022–1028. [RCT, n = 15]
26. Nicastri PL, Diaferia A, Tartagni M, et al. A randomised placebo-controlled
trial of ursodeoxycholic acid and S-adenosylmethio-nine in the treatment
of intrahepatic cholestasis of pregnancy. BJOG 1998;105(11):1205–1207.
[RCT; UDCA = 8; SAMe = 8; both = 8; placebo = 8; RCT, n = 32; I]
27. Gurung V, Middleton P, Milan SJ, Hague W, Thornton JG. Interventions for
treating cholestasis in pregnancy. Cochrane Database Syst Rev. 2013 Jun
24;2013(6):CD000493. doi: 10.1002/14651858.CD000493.pub2. Update in:
Cochrane Database Syst Rev. 2020 Jul 27;7:CD000493. PMID: 23794285;
PMCID: PMC7043272
28. Zhan L, Liu XH, Qi HB, et al. Ursodeoxycholic acid and S-adenosylmethionine
in the treatment of intrahepatic cholestasis of pregnancy: a multi-centered
randomized controlled trial. Eur Rev Med Pharmacol Sci 2015;19(19):3770–
3776. [RCT, n = 135; I]
29. Glantz A, Marschall HU, Lammert F, et al. Intrahepatic cholestasis of preg-
nancy: a randomized controlled trial comparing dexamethasone and urso-
deoxycholic acid. Hepatology 2005;2(6):1399–1405. [RCT, n = 130]
30. Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis.
Obstet Gynecol 1999;94:189–193. [II-2]
31. Alsulyman O, Ouzounian J, Ames-Castro M. Intrahepatic cholestasis of
pregnancy: perinatal outcome associated with expectant management. Am
J Obstet Gynecol 1996;175:957–960. [II-2]
32. Palmer KR, Xiaohua L, Mol BW. Management of intrahepatic cholestasis in
pregnancy. Lancet. 2019;393(10174):853–854. [III]
33. Di Mascio D, Quist-Nelson J, Riegel M, et al. Perinatal death by bile acid lev-
els in intrahepatic cholestasis of pregnancy: a systematic review. J Matern
Fetal Neonatal Med. 2019:1–9. doi: 10.1080/14767058.2019.1685965.
[Review, III]
34. Geenes V, Chappell LC, Seed PT, et al. Association of severe intrahepatic
cholestasis of pregnancy with adverse pregnancy outcomes: a prospective
population-based case-control study. Hepatology 2014;59:1482. [II-1]
35. Mohan M, Antonios A, Konje J, Lindow S, Ahmed Syed M, Akobeng A.
Stillbirth and associated perinatal outcomes in obstetric cholestasis: a
systematic review and meta-analysis of observational studies. Eur J Obstet
Gynecol Reprod Biol X. 2019;3:100026. [II-2]
11
INFLAMMATORY BOWEL DISEASE
Priyadarshini Koduri
Key points
• Inflammatory bowel disease (IBD) refers to Crohn’s disease
(CD) and ulcerative colitis (UC).
• Pathogenesis of IBD is not well known, although both envi-
ronmental and genetic factors play a role.
• If one parent has UC, the risk of the offspring developing
UC is 1.6%; if one parent has CD, risk goes up to as high
as 5.2%. With both parents having IBD, the offspring’s risk
goes up to 36%.
• Complications from IBD can be from intestinal or extra-
intestinal manifestations.
• Women with IBD should be encouraged to plan concep-
tion when they have achieved steroid-free remission,
and when their nutritional status is optimized. Clinical
remission is defined as normal bowel form and number
without bleeding or abdominal pain. Endoscopic remission
indicates healing of the mucosa.
• Women with UC should be up-to-date on relevant can-
cer screening and all women with IBD should be up-to-
date on vaccinations.
• Smoking cessation is an extremely important factor in
keeping women with CD quiescent.
• The majority of women with quiescent disease at the time
of conception will remain quiescent during pregnancy
while active disease typically remains active.
• CD has been associated with first-trimester miscarriage,
preterm birth <37 weeks, low birth-weight, VTE (venous
thromboembolism), depression and anxiety. It may be
associated with stillbirth and SGA infants.
• UC is associated with preterm birth <37 weeks. It may be
associated with an increased risk of congenital anomalies,
SGA and stillbirth.
• Increased disease activity is associated with increased risk
of adverse pregnancy outcomes.
• The risk of a flare of IBD during pregnancy (33%) is sim-
ilar to when they are not pregnant.
• Multiple medications are available for management
of IBD and the majority are safe for use in pregnancy.
Most women will require ongoing therapy in pregnancy
to control bowel inflammation. Co-management with
a gastroenterologist is essential. Aminosalicylates,
biologics, and immunomodulator medications can be
continued in pregnancy. Continuation of anti-integrin
agents requires careful counseling due to the limited
safety profiles of these medications in pregnancy and
lactation. Third trimester dosage adjustments and neo-
natology consultation should be planned with the use
of biologics. Monotherapy for maintenance therapy is
preferred.
• Goals of therapy are to achieve symptomatic relief,
improve quality of life, and attain steroid-free
remission.
DOI: 10.1201/9781003099062-11
• Steroids may be used for treatment of flares but should
be avoided for maintenance therapy.
• Surgical management for UC during pregnancy is only
indicated in cases of massive hemorrhage, fulminant coli-
tis unresponsive to medical management, perforation, or
strongly suspected/known carcinoma. Colectomy in preg-
nancy is historically associated with high perinatal mortal-
ity, but more recent outcomes are reassuring.
• Ileal pouch–anal anastomosis does not confer additional
maternal or fetal morbidity. Long-term pouch function is
not affected by pregnancy or mode of delivery.
• Serial growth surveillance and third trimester antenatal
surveillance is recommended in women with active dis-
ease. Women in remission are recommended to have a sin-
gle third trimester growth ultrasound but may not require
antenatal surveillance.
• Mode of delivery in IBD remains controversial with
no randomized controlled trials available to provide
guidance. Limited evidence suggests that in women
with IBD, vaginal delivery is appropriate in quiescent
or absent perianal disease (abscess/fistula). A cesarean
delivery may be performed for women with active peri-
anal disease such as perianal abscess or fistula.
• Mode of delivery does not impact development of IBD in
children.
• Thromboprophylaxis postpartum is recommended, par-
ticularly post-cesarean section.
• Pregnancy and breastfeeding may have a mitigating effect
on the course of IBD in the years following delivery.
Background
Inflammatory bowel disease (IBD) primarily refers to Crohn’s dis-
ease (CD) and ulcerative colitis (UC). Crohn’s disease and ulcer-
ative colitis are chronic systemic inflammatory diseases that affect
women of reproductive age. They have a protracted relapsing and
remitting course that extends over years. Although they share
several common features, there are distinct differences between
the two conditions summarized in Table 11.1. Differentiating
between UC and CD, may be challenging in 5–15% of patients
when disease is limited to the colon [1, 2]. These patients are clas-
sified as having indeterminate colitis or IBD-unspecified.
Crohn’s disease
Definition
CD is a systemic inflammatory disease that mainly manifests as
chronic, transmural, granulomatous inflammation of the gas-
trointestinal system. Any part of the GI tract can be affected.
Although it commonly involves the colon and terminal ileum,
the rectum may be involved in up to 50% of patients [1]. While the
disease is progressive in a majority of those affected, the location
of disease typically stays stable [3].
117
118 Maternal-Fetal Evidence Based Guidelines

TABLE 11.1: Comparison of Ulcerative Colitis and Crohn’s TABLE 11.2: Extraintestinal Manifestations of IBD
Disease
Dermatologic Erythema Nodosum
Feature Ulcerative Colitis Crohn’s Disease
Pyoderma gangrenosum
Extent of inflammation Limited to mucosa Involves all layers Aphthous stomatitis
(transmural) Pyostomatitis vegetans
Intestine involved Colon only All segments of the Sweet’s syndrome
gastrointestinal Anal skin tags
tract; terminal ileum Musculoskeletal Osteopenia/osteoporosis
most common
Osteomalacia
Rectal involvement Always Sometimes
Increased risk of fractures in hips,
Pattern of spread Contiguous Patchy, skip lesions wrist, spine, and ribs
Granulomas No Yes (sometimes)
Peripheral arthritis
Fistula No Yes
Axial arthropathies
Strictures No Yes
Ocular Conjunctivitis
Abscess No Yes
Uveitis
Perianal disease No Yes
Scleritis/episcleritis
Bloody diarrhea Yes Maybe
Genitourinary Nephrolithiasis
Ileal disease on No Yes
Ureteral obstruction
computed
Fistulas
tomography
Hepatobiliary/pancreatic Primary sclerosing cholangitis
Increased colon cancer Yes Maybe (if colonic
Cholelithiasis
risk involvement)
Pancreatitis
Cure with surgery Yes No
Thromboembolic Increased risk of venous and arterial
Percent of patients 20% 70%
who will need Thromboses
surgery Hyperhomocysteinemia
Hematologic Anemia
Pulmonary/cardiovascular Chronic bronchitis
Diagnosis Bronchiectasis
There are no pathognomonic features associated with CD and Endocarditis/myocarditis
a single gold standard for the diagnosis of CD is not available. Pleuropericarditis
Diagnosis is made clinically. It requires integration of history, Reactive amyloidosis
physical examination, laboratory evaluation, and a combination Abbreviation: IBD, inflammatory bowel disease.
of endoscopic, radiographic, and histologic findings document-
ing the focal, asymmetric, and transmural features of the disease
(Table 11.1). The diagnosis is largely dependent on the find- Epidemiology/Incidence
ing of chronic discontinuous intestinal inflammation often The incidence of CD varies by geographical region, but has been
with granulomatous changes [3, 4]. Fecal calprotectin may help rising worldwide over the past several decades. The incidence of
differentiate inflammatory bowel disease from irritable bowel CD in developed Western countries, including the United States,
syndrome but is not validated in the pregnant population [1, 3]. is estimated at 7 per 100,000 population [6]. Disease frequency
Routine use of genetic testing or serologic markers is not indi- is two to four times higher in Jewish populations. The peak age of
cated [1, 3]. A diagnosis of CD is rarely made for the first time onset is in the second and third decades of life. Smoking is associ-
during pregnancy [5]. ated with a 2-fold increased risk of CD [1].

Signs/Symptoms Etiology/Basic pathophysiology

Manifestations of CD in pregnancy are similar to those in
the non-pregnant state. Typical symptoms include chronic or
intermittent diarrhea, abdominal pain often in the right lower
quadrant and worse postprandially, weight loss, fever, and rectal
bleeding. Acute ileitis may mimic appendicitis. Additional clini-
cal features include anemia, pallor, anorexia, palpable abdominal
mass/tenderness, perianal fissures, fistula, or abscess. Perianal
manifestations are unique to CD and perianal fistulizing CD is
seen in up to 25% of patients [3].
Extraintestinal symptoms are not uncommon and may
involve a variety of organ systems (Table 11.2). Many of these
manifestations are also seen in UC. CD has a weak association
with many other immune mediated diseases such as asthma,
chronic bronchitis, multiple sclerosis, pericarditis, psoriasis,
celiac disease, and rheumatoid arthritis [3].
Etiology remains unclear. Multiple susceptibility loci on numerous
chromosomes have been identified. Familial clustering and genetic
anticipation have been confirmed [7]. However, these loci only
explain ~20% of the heritability of CD, emphasizing the importance
of other factors. Testing for susceptibility variants is not yet clin-
ically useful because no one variant has a high enough frequency in
the CD population. The current hypothesis is that IBD results from
a response to environmental triggers (infection, smoking, drugs,
or other agents) in genetically susceptible individuals, resulting in a
chronic dysregulation of mucosal immune function [8].
Complications
Maternal
Women with active disease or with history of surgery related
to IBD have an increased risk of infertility [9–11]. Women with
Inflammatory Bowel Disease
disease in remission or who have never had surgery have fertil-
ity rates similar to the general population. IBD is an independent
risk factor for VTE during pregnancy and the postpartum period
[3, 12]. Depression and anxiety are common in IBD patients [1].
Complications can also arise directly from CD, such as serosal
adhesions, partial and complete small bowel obstruction, fistula
formation, perforation with resulting peritonitis, abscess forma-
tion, malabsorption, and perianal disease. Up to a half of patients
with CD develop an intestinal complication within 20 years of
diagnosis [3].
Also, complications may arise from any extraintestinal mani-
festations (Table 11.2).
Fetal
Women with CD appear to be at increased risk for adverse preg-
nancy outcomes. Several population-based studies and two
meta-analyses demonstrate an increased risk of preterm birth,
cesarean delivery, and low birth-weight infants [9, 13–17].
The risk of preterm birth may be higher in women who require
oral systemic steroids. Oral systemic steroids may also increase
the risk of pre-eclampsia with severe features [18]. Retrospective
studies suggest there may be an increased risk of first-trimester
miscarriage in women with CD when compared to controls [19].
However, this association has not been consistently demonstrated
in large population based cohort studies [18, 20]. The association
with congenital anomalies remains questionable [9, 17]. The data
regarding the risk of small for gestational age (SGA) infants and
stillbirth are inconsistent, but two recent meta-analyses suggest
an increased risk [9, 17].
Pregnancy considerations
Effect of pregnancy on CD
Pregnant women with CD are no more likely to flare compared to
non-pregnant women with CD [21]. Pregnancy may have a positive
effect on disease activity as lower rates of relapse are observed in
the three years following pregnancy [22, 23]. Lower rates of stenosis
and/or resection have also been noted in women with CD who have
been pregnant during their disease course [24].
Effect of CD on pregnancy
Regardless of disease activity, women with CD are at risk for
adverse pregnancy outcomes that have been previously out-
lined. Multiple studies demonstrate a direct association between
increasing disease activity and increased risk of adverse preg-
nancy outcomes [18, 25–27].
Management
Principles
Only 20–30% of patients with CD will have a non-progressive
course [3]. The majority of pregnant women will need ongoing
therapy to control bowel inflammation. Management is best
guided by a multidisciplinary team that includes a gastroenterol-
ogist, obstetrician and maternal-fetal medicine specialist [3, 28].
Treatment of CD during pregnancy is similar to therapy in a non-
pregnant patient. Management decisions are guided by disease
activity, IBD related complications, medication risk and disease
prognosis. Medical therapy is used to either induce or maintain
remission. Patients who achieve remission should be considered
candidates for maintenance therapy.
The goals of therapy are to achieve symptomatic relief,
improve quality of life, and attain steroid-free remission.
More objective goals of therapy have been identified in the
119
non-pregnant population including endoscopic confirmation of
mucosal healing and monitoring markers like fecal calprotectin
[1, 3, 28]. The use of fecal calprotectin has not yet been validated
in pregnancy [28].
Most medications used in the management of CD are con-
sidered safe for use in pregnancy and have not been shown
to be teratogenic. They fall into one of several categories:
Aminosalicylates, antibiotics, corticosteroids, immunomodula-
tors/immunosuppressants, and biologics. More recently, com-
plementary and alternative therapies have also been employed
including cannabinoids, herbal therapies, and elimination diets.
Women maintained in remission should continue their pre-
pregnancy medications throughout their pregnancy, unless they
are on clearly teratogenic agents. Termination of pregnancy is not
a therapeutic option for CD as there is no evidence that termina-
tion results in improved disease activity [29].
Workup
When a woman presents with symptomatic colitis and relapse is
suspected, it is important to rule out infectious causes including
Clostridium difficile colitis. Clostridium difficile may have a more
fulminant course in patients with IBD [1]. Although imaging and
colonoscopy/sigmoidoscopy may be indicated in the initial diag-
nosis of CD, they are often not necessary for workup of a relapse.
If imaging is needed, MRI and ultrasound are preferable to com-
puted tomography to avoid fetal radiation exposure. Gadolinium
should be avoided. Flexible sigmoidoscopy without sedation can
be safely performed if needed [28, 30]. A full colonoscopy can be
performed with anesthesia and fetal monitoring if appropriate
and if it will change management [28, 30].
Differential diagnosis
Differential diagnosis for ulcerative colitis includes infectious
colitis (bacterial, fungal, viral, or protozoan), diverticulitis,
ischemic colitis, solitary rectal ulcer syndrome, nonsteroidal
­
anti-inflammatory drug (NSAID)-related colitis.
Preconception counseling
Preconception counseling is associated with healthier lifestyle
changes, improved medication compliance, and lower risk of
relapse during pregnancy [31]. Counseling should include input
from a multidisciplinary team that includes a gastroenterolo-
gist, obstetrician, and maternal-fetal medicine provider. Women
should ideally be in steroid-free remission for 3–6 months
before pregnancy is planned [4, 30, 32]. Clinical remission
is defined as normal bowel form and number (presence of
formed stool and absence of diarrhea) without bleeding or
abdominal pain [33]. Endoscopic remission indicates healing
of the mucosa. Remission may also include normalization of
markers of inflammation and radiologic tests [3].
The clinical course of CD during pregnancy depends on CD
activity at the time of conception [4, 30, 32–34]. Quiescent
disease at the time of conception (either spontaneous or
on therapy) typically remains quiescent in two-thirds of
patients during pregnancy while active disease remains
active in up to 70% of patients. Improvement during preg-
nancy is only noted in 30% [35]. In a recent meta-analysis, 46%
of patients with active disease at time of conception remained
active while only 23% of women who were in remission at the
time of conception relapsed [26].
Contraceptive options with an emphasis on LARC (long-
active reverasable contraception) should be reviewed as part of
120 Maternal-Fetal Evidence Based Guidelines

a pre-conception discussion. Some authors recommend avoiding Therapy

estrogen containing contraceptive options due to the increased Treatment of CD is based on disease location, severity, and
risk of VTE in the IBD population [30]. extraintestinal complications. Pharmacologic therapy is the
The risk of infertility in patients with CD who have not any mainstay of treatment. The goal of therapy is to maintain stable
IBD–related surgery appears to be similar to the general popula- disease activity. Monotherapy is preferable. Table 11.3 summa-
tion. Active disease is associated with increased risk of infertility rizes the pregnancy recommendations for commonly used drugs
[11]. Although referral for ART (assisted reproductive technolo- in the therapy of IBD.
gies) should be individualized, it is not unreasonable to refer
women after 6 months of unsuccessful attempts [30].
The likelihood of a child developing CD should be discussed TABLE 11.3: Selected Medications Used in Inflammatory
with parents, although pregnancy should never be discouraged Bowel Disease
due to this reason. The risk is estimated at 5.2% if one parent Lactation
has CD and 36% if both parents have IBD [34, 36]. Drug Class/Name Pregnancy Risk Compatibility
Nutritional status should be optimized. CBC, folate, vita-
min B12, and iron should be assessed and appropriate replace- Aminosalicylates
ment initiated if indicated [30, 33]. Sulfasalazine Low risk; women should Likely compatible
Counsel women on avoidance of exacerbating factors like take 2-mg folic acid
smoking and NSAID use [3, 30]. Women should also be advised daily
to avoid alcohol, opioids, and recreational drug use including Mesalamine Low risk Likely compatible
marijuana [30]. Olsalazine Low risk Likely compatible
Ensure vaccinations are up to date. Women on immunosup- Balsalazide Limited information Limited information
pressants should be immunized against influenza and pneumo-
coccal infections. Under appropriate circumstances they should Immunomodulators/Immunosuppressants
also receive tetanus and meningococcal vaccines [37]. Live vac- Azathioprine Likely low risk Likely compatible
cinations may be given at least 4 weeks before starting and at a 6-Mercaptopurine Likely low risk Likely compatible
minimum of 3 months after stopping, but not while receiving Cyclosporine Moderate risk Not compatible
immunosuppressive therapy [1]. Methotrexate Contraindicated; Not compatible;
Medication regimens should be finalized with a multi-­ teratogenic teratogenic
disciplinary team. The greatest risk of flare occurs when women Thalidomide Contraindicated; Not compatible;
discontinue medications [33]. Effective maintenance medications teratogenic teratogenic
should be continued if they are not teratogenic. This includes ami-
nosalicylates, immunomodulators, and biologics. Corticosteroids Anti-TNF agents
are not appropriate as maintenance therapy and use should be Infliximab Low risk Likely compatible
limited to flares [1, 28, 30]. Adalimumab Likely low risk Likely compatible
Women on methotrexate (MTX) should discontinue use at Certolizumab Likely low risk Likely compatible,
least 3 months but ideally 6 months before conception [28, 30, 33]. data limited
Women on sulfasalazine should be on 2 mg/d of folic acid [28].
Anti-Integrin agents
Prenatal care Natalizumab Likely low risk, limited Likely compatible,
Co-management with a gastroenterologist is recommended data, use with caution data limited, use
for medication management and appropriate management of any with caution
flares. A colorectal surgeon should also be part of the multi-dis- Vedolizumab Limited data, use with Likely compatible,
ciplinary team if there is history of any IBD related surgery. Early caution data limited, use
evaluation and treatment of iron and vitamin B12 deficiency is with caution
recommended [30]. Mental health support should be offered for Ustekinumab Limited data, use with Compatibility
depression and anxiety if needed [1]. Women should be advised to caution unknown, use with
gain weight in accordance with the current Institute of Medicine caution
guidelines. Assistance from a nutritionist may be helpful.
Oral Janus Kinase Inhibitors
Insufficient weight gain in pregnancy is associated with increased
Tofacitinib Limited data, not Limited data, not
risk of SGA infants, FGR (fetal growth restriction), and preterm
recommended compatible
birth [38, 39]. Women should be reassured that other than castor
oil, most stool softeners are safe for use in pregnancy. Corticosteroids
While a single third trimester growth ultrasound is sufficient Prednisone Low risk; avoid use in Likely compatible
for women in remission, serial growth surveillance every 4 weeks first trimester
should be instituted in women with more active disease [30].
Antibiotics
Similarly, women with more active disease should also be offered
Metronidazole Likely low risk, avoid use Compatibility
antenatal surveillance in the third trimester [30].
in first trimester unknown, avoid
Women should be assessed for active perianal disease in
long-term use
the third trimester. Perianal disease evidenced by a fistula,
Quinolones Moderate risk Likely safe
abscess, anal fissure or anal stenosis, increases the risk of a
higher-order perineal laceration and will impact delivery plan- Vancomycin Low risk Likely safe
ning [40]. Abbreviations: IBD, inflammatory bowel disease; TNF, tumor necrosis factor.
Inflammatory Bowel Disease
Aminosalicylates
Sulfasalazine, mesalamine, balsalazide, and olsalazine are in this
category. Drugs in this category have limited placental transfer
and are generally considered safe for use in pregnancy and in
breastfeeding. Aminosalicylates have not been shown to be tera-
togenic in humans [41–45]. They have not been shown to be asso-
ciated with stillbirth, spontaneous abortion, preterm delivery, or
low birth-weight [41].
Because of the possible antifolate effects of sulfasalazine, women
on sulfasalazine are recommended to take 2-mg folic acid/day in
the prenatal period and throughout the pregnancy [28, 30].
Corticosteroids
Prednisone and budesonide are commonly used to treat flares.
Due to pregnancy risks and long-term health risks, corticoste-
roids are not appropriate for maintenance therapy [3, 30]. First
trimester exposure is associated with an increased risk of orofa-
cial clefting, and use during this time period should be avoided
or limited to the lowest effective dose. Corticosteroid use is also
associated with an increased risk of low birthweight, gestational
diabetes, and preterm birth [33, 46, 47]. Budesonide is generally
safe in pregnancy and with breastfeeding. Prednisone is generally
safe with breastfeeding, but women on high doses should avoid
breastfeeding within 4 hours of taking their dose to minimize
possible neonatal effects. High-dose prednisone confers risk of
diabetes (early glucola is warranted) and PPROM. A steroid taper
is recommended when used for more than 1 week. Stress dose
steroids are indicated only in special circumstances.
Antibiotics
Metronidazole and quinolones have been used in the manage-
ment of IBD mainly to treat pouchitis and perianal disease.
Vancomycin has been advocated for treatment of C. difficile. First
trimester metronidazole use is associated with a small increased
risk of cleft lip and palate. Use during the first trimester and while
breastfeeding is not recommended [48]. Quinolones have a high
affinity for bone tissue and cartilage. Animal studies show carti-
lage damage in weight-bearing joints after quinolone exposure.
Although risk with exposure is minimal, alternative therapies
should be used in pregnancy when available [34]. While ciproflox-
acin is excreted in breast milk, it is considered compatible with
breastfeeding. Augmentin, another antibiotic used commonly in
the management of both perianal and luminal CD, can be used
safely during pregnancy and with breastfeeding. Vancomycin can
be used safely during pregnancy and with breastfeeding.
Immunomodulators/Immunosuppressants
Azathioprine/6-mercaptopurine
Mercaptopurine and azathioprine are used to maintain remis-
sion in steroid-dependent patients with IBD [49, 50]. Azathioprine
and 6-mercaptopurine should ideally not be started for the first
time in pregnancy due to prolonged response time and the small
risk of severe side effects [1, 33, 48]. Combination therapy with a
biologic is best avoided [48]. Women taking an immunomodula-
tor should not receive live attenuated vaccines [3].
Data regarding safety of thiopurines in pregnancy is con-
flicting. Multiple case series and cohort studies have not dem-
onstrated an increased risk of congenital anomalies, suggesting
that these drugs are safe for use in pregnancy [51–57]. However,
a large population-based cohort study and meta-analyses dem-
onstrated an increased risk of congenital anomalies in neonates
born to women using thiopurines [25, 58, 59]. Data regarding the
121
risk of preterm delivery, low birth-weight, and SAB is also con-
flicting. While a multicenter study and meta-analysis did not sug-
gest an increased risk of adverse pregnancy outcomes, a recent
meta-analysis demonstrated an increased risk of stillbirth, fetal
growth restriction, and preterm birth [25, 60, 61].
Current guidelines suggest that thiopurines have a low risk
profile in pregnancy and recommend that women who conceive
on these medications should continue them during pregnancy
[28, 30, 48]. Women should be counseled not to stop 6-mercapto-
purine before conceiving as that may actually increase the risk of
fetal loss [62]. Several series suggest that azathioprine/6-mercap-
topurine are compatible with breastfeeding [32, 63, 64].
Methotrexate
MTX is clearly teratogenic and use is contraindicated in preg-
nancy and in women considering pregnancy. Use in pregnancy or
during organogenesis (6–8 weeks after conception) is associated
with methotrexate embryopathy. Exposure later in pregnancy
may be associated with fetal toxicity and/or mortality. Women
considering pregnancy should discontinue MTX 3–6 months
before attempting conception [28, 30, 33, 34]. MTX is contraindi-
cated in breastfeeding.
Cyclosporin
Cyclosporin should preferably not be initiated during pregnancy
[53, 54]. It has not been found to be teratogenic in humans [65–67].
However, it is associated with SGA, preterm birth, hypertension
and seizures [67, 68]. Breastfeeding is not recommended because
of potential neonatal nephrotoxicity and immunosuppression [69].
Thalidomide
Thalidomide has been successfully used in the treatment of some
patients with CD [70]. Use in pregnancy and while breastfeed-
ing is unequivocally contraindicated because of its well-known
teratogenic effects.
Biologics
Anti-tumor necrosis factors
These drugs are used for both induction and maintenance of
remission. Women who conceive while on a maintenance
anti-TNF agent should continue their medication during
pregnancy [28, 30]. Continued biologic therapy during preg-
nancy is associated with reduced disease activity and fewer
antenatal and postpartum flares [30]. It is crucial to confirm
vaccination history before starting a biological agent. The use
of live attenuated vaccines should be avoided in women receiv-
ing biological agents [3].
Infliximab: Infliximab is a tumor necrosis factor (TNF)-alpha
inhibitor approved for use in patients with IBD [71–73]. Several
studies and a meta-analysis have documented the safety of inf-
liximab in pregnancy and have shown no increased risk of
congenital anomalies, or other adverse pregnancy or postna-
tal outcomes [74–82]. There are concerns regarding increased
drug transfer across the placenta in the third trimester and high
newborn drug levels [83, 84]. Cord blood concentrations of inf-
liximab and adalimumab are significantly higher than maternal
levels and they remain detectable for up to 1 year [48]. Elevated
newborn drug levels may in theory increase the neonatal infec-
tious complications or response to vaccines, although this has not
been demonstrated clinically [82, 85, 86]. This concern has led to
a recommendation to avoid live vaccines for the first 6 months of
life [48, 78].
122
Recommendations pertaining to third trimester continua-
tion of anti-TNF agents are mixed. The European Crohn’s and
Colitis Organization (ECCO) suggests discontinuing anti-TNF
agents at 22–24 weeks to minimize any adverse neonatal effects
[32]. However, evidence for adverse neonatal effects is lack-
ing. Systematic reviews and a meta-analysis have not shown an
increased risk of congenital malformations, miscarriage or neo-
natal infections [78, 87, 88]. Many societal guidelines and expert
opinion support women remaining on anti-TNF agents through
the third trimester but with an adjusted dose to achieve the low-
est effective serum concentration by delivery [1, 28, 30]. A neo-
natology or pediatric consultation can be offered to address
vaccination concerns. Infliximab appears to be compatible with
breastfeeding [28, 30, 32, 76, 77, 86, 89].
Adalimumab: Use of adalimumab in pregnancy does not appear
to be associated with an increased risk of congenital anomalies
or other adverse pregnancy outcomes [78, 90–92]. Similar to inf-
liximab, concerns regarding third trimester use and newborn
drug levels exist. Third trimester drug dosage adjustments can
be made similar to infliximab to limit neonatal exposure. A pedi-
atric and/or neonatology consultation can be offered to address
vaccination concerns. Adalimumab appears to be compatible
with breastfeeding [28, 30, 86, 89].
Certolizumab: Certolizumab is an anti-TNF agent with
decreased placental transfer compared to infliximab and adali-
mumab. It has not been associated with congenital anomalies or
other adverse outcomes [78, 93]. It has not been detected in breast
milk and while data is limited, it appears to be compatible with
breastfeeding [86, 94].
Anti-integrin agents
Natalizumab: This is a humanized IgG4 monoclonal antibody
approved for treatment of CD. Data regarding safety in pregnancy
is limited, but the Natalizumab Pregnancy Exposure Registry does
not demonstrate an association with adverse pregnancy outcomes
[95]. As with all biologics, there is a theoretical concern with the
effect of the drug on the neonatal immune system and response
to vaccines. A neonatology or pediatric consultation should be
obtained to discuss the vaccination plan. Data is limited but natal-
izumab appears to be compatible with breastfeeding [86].
Vedolizumab: This is a humanized monoclonal IgG1 antibody
approved for use in CD. There is limited data to support the safety
of vedolizumab use in pregnancy [96, 97]. Similar to natalizumab,
there are concerns regarding effects on the neonatal immune sys-
tem response. To alleviate these concerns, consideration can be
given to administer the last dose 6–10 weeks before delivery [97].
While vedolizumab appears to be compatible with breastfeed-
ing, data is very limited and warrants careful counseling [96, 97].
Pediatric or neonatology consultation can be offered to discuss
vaccination risks.
Ustekinumab: This is a IgG1 monoclonal anti-IL 12-23 anti-
body more commonly used for psoriasis but now approved for
CD. Data regarding safety in pregnancy is limited to case series
and registry data [98, 99]. While ustekinumab may be contin-
ued during pregnancy, the limited safety data necessitates care-
ful counseling [30]. There is limited data to support safety of
ustekinumab with breastfeeding and recommendations are
conflicting [30, 86, 100].
Oral janus kinase inhibiting agents
Tofacitinib: This drug is used mostly in rheumatoid arthritis and
appears to be effective in treating UC. Safety data for pregnancy
Maternal-Fetal Evidence Based Guidelines
and lactation is inadequate and tofacitinib is not recommended
for use in pregnancy or with breastfeeding [85, 101].
Miscellaneous agents
Naltrexone: This is an opioid antagonist used in low doses to
induce remission [102]. There is insufficient evidence to deter-
mine safety or efficacy in the non-pregnant population and no
data yet on use in pregnant women with IBD.
Complementary and alternative therapies
Fecal microbiotia transplantation: FMT is an emerging therapy,
but further study is needed before it can be recommended for
treatment of IBD [3]. Studies in pregnancy are lacking.
Diet: Exclusive enteral nutrition (EEN) may be effective in
inducing remission in adult CD patients [1]. Studies in pregnancy
are lacking.
Herbal supplements, probiotics, acupuncture: A recent system-
atic review showed benefit of probiotics added to a standard UC
medication regimen in induction therapy [103]. However, there is
insufficient high quality evidence to support routine probiotic use
for induction or maintenance of remission in IBD [1]. Curcumin,
the main active ingredient in turmeric, and fish oil have received
attention for anti-inflammatory properties. Fish oil does not
appear to have any benefit in management of CD [104]. Curcumin
may be helpful when added to a standard medication regimen for
UC, but further high quality studies are needed before routine
use is recommended [105].
Cannabis: Cannabis and cannabinoids have been used for pain
control. There is not enough high quality evidence to determine
benefit and/or efficacy [106, 107]. ACOG recommends against
cannabis use in pregnancy and with breastfeeding [108].
In summary, most pregnant women with CD can be man-
aged by continuing non-teratogenic pre-pregnancy main-
tenance medications including immunomodulators and
biologics. Continuation of anti-integrin agents requires care-
ful counseling due to limited safety profiles in pregnancy.
Third trimester dosage adjustments and neonatology consul-
tations should be planned with the use of biologics in preg-
nancy. Steroid use should be limited to inducing remission.
Antepartum testing
A single third trimester growth ultrasound is advised in women
who are in remission, while serial growth surveillance should be
offered to women with active or more severe disease [30]. Third
trimester antenatal surveillance is advised in women with greater
disease activity [30].
Delivery
No randomized controlled trials exist to determine the best form
of delivery for women with CD. By current practice, in the absence
of active or perianal disease, the mode of delivery should be
dictated by obstetric indications [28, 30, 32]. Cesarean delivery
does not appear to protect against a flare [35, 109, 110]. A cesar-
ean delivery should be performed in women with active peri-
anal disease defined as perianal abscess or fistula [28, 32, 33,
111, 112]. A third trimester perineal examination can help assess
for perianal disease. Episiotomy or perineal trauma should be
avoided as it places women with CD at further risk for perineal
disease [30, 113]. Mode of delivery does not appear to influence
the development of IBD in offspring [114].
Thromboprophylaxis (e.g., with low-molecular-weight heparin)
is recommended for women postpartum during hospitalization
Inflammatory Bowel Disease
but even up to 6 weeks in select patients, particularly for those
women undergoing a cesarean delivery [28, 30, 32].
Postpartum/Breastfeeding
Breastfeeding is not associated with an increased risk of disease
flare and may even be protective against a flare in the year follow-
ing delivery [115, 116].
Ulcerative colitis
Definition
UC is a chronic idiopathic systemic disease characterized by
mucosal inflammation that usually involves the rectum and
extends proximally to involve all or part of the colon. The major-
ity of patients have disease limited to the rectum or left colon at
diagnosis, while 25% of patients with limited disease have exten-
sion over time [117]. Disease extension occurs most commonly
within the first 10 years after diagnosis and it is augmented if the
disease is not well controlled [117].
Diagnosis
A diagnosis of UC is typically suspected on clinical grounds. It
is confirmed by proctosigmoidoscopy or colonoscopy, histol-
ogy of biopsy specimens, and by a negative stool exam ruling
out infectious causes including C. difficile [3]. Alternative causes
of diarrhea (infectious and non-infectious) should be ruled out
before a definitive diagnosis can be made.
Classification
The disease can be classified based on disease extent (proctitis,
left-sided colitis or extensive colitis) and by disease severity [3,
4]. Table 11.4 outlines criteria used to determine disease severity.
Determining disease severity is essential for management deci-
sions and for determining prognosis and long risk of colectomy
[1]. Fecal calprotectin can help differentiate IBD from irritable
bowel syndrome. It can also be used as a proxy for disease activity
and response to treatment. However, use of fecal calprotectin has
not been validated in pregnancy [1].
Signs/Symptoms
The manifestations of UC are similar in pregnant and non-preg-
nant women. The disease course is characterized by periods of
remission and relapse. Extension of colonic disease can occur
with time. Common symptoms include bloody diarrhea, rectal
TABLE 11.4: Montreal Classification of Extent and Severity
of Ulcerative Colitis
E1 (proctitis) Inflammation limited to the rectum
E2 (left-sided; distal) Inflammation limited to the splenic flexure
E3 (pancolitis) Inflammation extends to the proximal splenic
flexure
S0 (remission) No symptoms
S1 (mild) Four or less stools per day (with or without
blood), absence of systemic symptoms,
normal inflammatory markers
S2 (moderate) Four stools per day, minimum signs of
systemic symptoms
S3 (severe) Six or more bloods per day, pulse rate
≥90 beats per min, Temperature ≥37.5°C,
Hemoglobin concentration <105g/L, ESR
≥30 mm/hour
123
bleeding, mucous, urgency, tenesmus and abdominal cramping
[3, 4]. In severe disease, liquid stool with blood, pus, and fecal
matter may be experienced. Generalized symptoms may include
anorexia, nausea, vomiting, fever, and weight loss. Acute severe
ulcerative colitis (ASUC) is characterized by ≥6 bowel move-
ments per day and at least one systemic sign including tachycar-
dia, fever, anemia, or inflammatory markers [1, 3]. Severe pain
and tympany on abdominal exam suggests toxic megacolon, a
potentially lethal complication. Signs of peritonitis may suggest
perforation. Similar to CD, extraintestinal manifestations are not
uncommon (Table 11.2).
Epidemiology/Incidence
The incidence of UC varies by geographical location but is
increasing worldwide [3]. It is most common in Western
nations and incidence in the United States is estimated at 8 to
12/100,000 population per year [37]. UC can develop at age
but diagnosis peaks at ages 15–30 years [3]. Appendectomy
for appendicitis in childhood and smoking are associated with
reduced severity and risk of UC while smoking cessation may
increase the risk of UC [4].
Etiology/Basic pathophysiology
The etiology of UC remains unknown. The pathogenesis is cur-
rently thought to be similar to CD (see section “Etiology/Basic
Pathophysiology” described earlier for CD).
Complications
Maternal
Massive hemorrhage typically from erosions in the colon (1%),
ASUC (15–25%), toxic megacolon (5%), perforation (rare, but fatal
in 15% of cases), and strictures (5–10%) [1]. All patients with UC
are at an increased risk of colorectal cancer and that risk is fur-
ther increased depending on disease duration, extent, and sever-
ity [4]. After 10 years, the colon cancer risk is estimated at 0.5–1%
per year, necessitating colonoscopic surveillance every 1–3 years
[3, 37]. IBD is an independent risk factor for VTE during preg-
nancy and postpartum [3, 12]. Anxiety and depression are com-
mon in IBD patients [26]. Complications may also arise from any
existing extraintestinal manifestations (Table 11.2).
In women with an ileal pouch–anal anastomosis (IPAA),
pregnancy is considered safe and is not associated with an
increased frequency of adverse pregnancy outcomes or pouch
complications [118–120]. Vaginal delivery appears to be safe, and
if there is transient anal dysfunction postpartum it tends to be
transient [119]. Pouch function does not appear to be impacted
by vaginal delivery and it returns to pre-pregnancy function
within 6 months post-delivery independent of mode of delivery
[119]. Nonetheless, some experts suggest consideration of a cesar-
ean delivery in women with an IPAA due to the potential risk of
anal sphincter injury and subsequent fecal incontinence [28].
Potential pouch complications reported in pregnancy include
small bowel obstruction (2.8% antenatally, 6.8% postpartum),
pouchitis (1.8%), and perianal abscess (0.4%) [121].
Fetal
UC is associated with preterm birth [9, 17, 122]. The risk of
preterm birth may be higher in women who require systemic
steroids and they may also be at increased risk for severe pre-
eclampsia [18]. Evidence regarding other adverse pregnancy
outcomes is inconsistent. Several studies suggest that UC is
not associated with low birth-weight, fetal growth restriction,
124
SGA, or stillbirth [9, 112, 123, 124]. However, a recent meta-
analysis demonstrated an increased risk of SGA and stillbirth
in women with IBD [17]. While some population-based stud-
ies and a meta-analysis suggest that UC may be associated with
congenital anomalies, specifically limb deficiencies, obstruc-
tive urinary abnormalities, and multiple anomalies these find-
ings have not been replicated in other studies [9, 18, 123, 125].
Similar to CD, increased disease activity in pregnancy appears
to be associated with worse pregnancy outcomes [18, 25]. The
presence of an IPAA does not confer additional fetal morbidity
or mortality [118, 119].
Pregnancy considerations
Effect of pregnancy on UC
Pregnant women with UC are just as likely to flare as non-preg-
nant women [4, 126]. Flares complicate up to 35% of pregnan-
cies [127]. Pregnancy may result in fewer relapses in the years
following delivery in women with UC [25, 128].
In women with an IPAA, there may be transient worsening of
pouch function during the pregnancy or postpartum, but long-
term function is preserved regardless of mode of delivery [119].
Long-term pouch function in women who have had a vaginal
delivery is similar to women who had a cesarean delivery follow-
ing IPAA [118, 129].
Effect of UC on pregnancy
See section “Complications: Fetal.”
Management
General principles
Treatment of UC during pregnancy is similar to therapy in a
non-pregnant patient. Treatment decisions are guided by dis-
ease extent, severity, and prognosis. The goal of therapy is to
either induce or maintain steroid-free remission. There is no
standardized definition of remission, but a reasonable approach is
to aim for improvement of symptoms, endoscopic findings dem-
onstrating mucosal healing, and reduced disease impact without
continued steroid use [3]. Fecal calprotectin is suggested as a sur-
rogate for endoscopy in non-pregnant patients but use in preg-
nancy has not been validated [1].
Workup
See section “Workup” described earlier for CD.
Differential diagnosis
The differential diagnosis for ulcerative colitis includes infectious
diarrhea (bacterial, fungal, viral or protozoan), diverticulitis, ischemic
colitis, solitary rectal ulcer syndrome, and NSAID-related colitis.
Preconception counseling
• Preconception counseling is associated with healthier life-
style changes, improved medication compliance and lower
risk of relapse during pregnancy [31].
• Women should be encouraged to optimize the medical
management before conception and optimize nutritional
status (see section “Crohn’s Disease”). Care and counseling
should be administered by a multidisciplinary team that
includes a gastroenterologist, obstetrician, maternal-fetal
medicine specialist and colorectal surgeon if the woman
has an IPAA or ostomy.
• Women should ideally conceive when the disease is qui-
escent as they then have a relapse risk similar to the gen-
eral population [4].
Maternal-Fetal Evidence Based Guidelines
• Reassure patients that in the absence of IBD related sur-
gery, women with UC appear to have similar fertility com-
pared to the general population [32].
• Discontinue known teratogenic drugs. Women on metho-
trexate should discontinue methotrexate 3–6 months
before attempting pregnancy. Women on sulfasalazine
should take 2-mg folic acid daily at least one month prior to
conceiving and through the pregnancy.
• Ensure access to mental health support for treatment of
depression or anxiety.
• Women should be up-to-date on relevant cancer screen-
ing as advised by their gastroenterologist.
• CBC, folate, vitamin B12 and iron should be assessed and
appropriate replacement initiated if indicated [30, 33].
• Counsel on the risk of inheritance of UC. The risk is esti-
mated at 1.6% if the mother has UC and 36% if both have
IBD [51].
• Review of vaccination history is important. Women
on immunosuppressants should be immunized against
influenza and pneumococcal infections. Under appropri-
ate circumstances, they should also receive tetanus and
meningococcal vaccines [37].
Prenatal care
Many aspects of prenatal care are shared with CD. See section
“Prenatal Care” under CD. Pregnancy should be managed in part-
nership with a gastroenterologist. A colorectal surgeon should
also be included if the woman has a history of an ileal pouch–anal
anastomosis or ostomy.
Although the data are conflicting regarding the increased risk
of congenital anomalies, a careful anatomical survey is recom-
mended. A single third trimester growth ultrasound is recom-
mended in women with IBD in remission, but serial growth
surveillance is recommended in women with active disease [30].
Antenatal surveillance should be instituted in women with more
active disease or higher disease severity [30].
Therapy
Treatment for UC is individualized based on disease severity and
extent of colonic involvement. Many of the medications used
to maintain remission or treat acute relapses are similar to the
medications used in CD. (See section “Therapy”, under CD, and
Table 11.3.) Fecal microbiotia transplantation is an emerging ther-
apy, but further study is needed before it can be recommended for
treatment of UC [3]. In summary, most pregnant women with UC
can be managed by continuing non-teratogenic pre-pregnancy
maintenance medications including immunomodulators and
biologics. Continuation of anti-integrin agents requires careful
counseling due to limited safety profiles in pregnancy. Third
trimester dosage adjustments and neonatology consultations
should be planned with the use of biologics in pregnancy.
Steroid use should be limited to inducing remission.
Surgery
Despite medical management, approximately 15–30% of all
patients with UC will eventually require or elect to undergo
surgical intervention [119]. Operative options include abdomi-
nal colectomy or total proctocolectomy with either a perma-
nent end ileostomy or an ileal pouch–anal anastomosis (IPAA)
that restores gastrointestinal continuity. Although surgery in
pregnancy comes with risk of miscarriage and preterm labor,
the risk of continued acute disease represents a greater risk [32].
Inflammatory Bowel Disease
Indications for surgery are similar in pregnant and non-­
pregnant patients and if warranted, surgery should not be
delayed due to pregnancy.
Colectomy. The likelihood of colectomy depends on disease
severity and presence of deep colonic ulcerations on admission
[130]. Indications for colectomy are acute colitis with evidence of
actual or impending perforation, hemorrhage, chronic UC refrac-
tory to medical therapy, presence of carcinoma, non-adenoma-
like dysplasia-associated lesion or mass of high grade dysplasia,
and presence of a stricture in the background of a long standing
disease [119].
Urgent or emergent surgery typically involves a total or sub-
total colectomy with a temporary ileostomy without removal of
the rectal stump. Subsequent proctectomy, IPAA, and ileostomy
closure is performed when the patient recovers [119, 130].
Historically, colectomy in pregnancy for fulminant UC has
been associated with a high fetal mortality rate (49%) and con-
cerning maternal mortality rate (22%) [131]. However, a more
recent case series of women with fulminant UC undergoing total
colectomy demonstrated no maternal or fetal mortality, which is
consistent with other reports published after 1987 [132].
Ileal pouch–anal anastomosis
Total proctocolectomy with IPAA is the standard of care for elec-
tive surgery. It involves resection of the large intestine and cre-
ation of an ileal J-pouch, which is attached to a rectal muscle cuff.
It helps patients maintain quality of life after colectomy because
it maintains intestinal continuity and the function of defecation.
IPAA is considered curative for UC.
IPAA can be done abdominally or laparoscopically. Both
approaches have similar lengths of hospital stay, reoperation,
readmission, morbidity, and mortality rates [133]. Women with
an IPAA have a 3-fold increase in infertility and lower rates of
conception compared to non-surgical controls [119]. The laparo-
scopic approach to IPAA is associated with a lower rate of infer-
tility compared to the open approach and is preferred if future
pregnancy is desired [134, 135].
Antepartum testing
See “Crohn’s Disease: Antepartum Testing.”
Delivery
Similar to CD, mode of delivery should be dictated by obstet-
ric indications. A vaginal delivery is considered safe for women
with an IPAA, although cesarean delivery can be considered
due to the potential for fecal incontinence [28, 118, 119, 136].
Thromboprophylaxis (e.g., with low-molecular-weight heparin)
is recommended for women postpartum during hospitalization
but even up to 6 weeks in select patients, particularly for those
women undergoing a cesarean delivery [28, 30, 32].
Postpartum/Breastfeeding
Breastfeeding may have a protective effect on the disease course
of UC [137].
References
1. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. British
Society of Gastroenterology consensus guidelines on the management of
inflammatory bowel disease in adults. Gut 2019;68(Suppl 3):s1–s106. [III]
2. Langagergaard V, Pedersen L, Gislum M, Norgard B, Sorensen HT. Birth
outcome in women treated with azathioprine or mercaptopurine during
pregnancy: A Danish nationwide cohort study. Aliment Pharmacol Ther
2007;25(1):73–81. [II-2]
125
3. Lichtenstein GR, Jr. EVL, Isaacs K, Regueiro MD, Gerson LB, Sands
B. ACG clinical guideline: Management of Crohn’s disease in adults.
Am J Gastroenterol 2018;113:481–517. [III]
4. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de
Acosta M, et al. Third European evidence-based consensus on diagno-
sis and management of ulcerative colitis. part 1: definitions, diagnosis,
extra-intestinal manifestations, pregnancy, cancer surveillance, sur-
gery, and ileo-anal pouch disorders. J Crohns Colitis 2017;11(6):649–
670. [III]
5. Hill J, Clark A, Scott NA. Surgical treatment of acute manifestations of
Crohn’s disease during pregnancy. J R Soc Med 1997;90(2):64–66. [II-3]
6. Lichtenstein GR, Hanauer SB, Sandborn WJ, Practice Parameters
Committee of American College of G. Management of Crohn’s disease in
adults. Am J Gastroenterol 2009;104(2):465–483; quiz 4, 84. [III]
7. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet 2012;380(9853):
1590–1605. [III]
8. Carter MJ, Lobo AJ, Travis SP, IBD Section BSoG. Guidelines for the man-
agement of inflammatory bowel disease in adults. Gut. 2004;53(Suppl
5):V1–V16. [III]
9. Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, et al. A meta-
analysis on the influence of inflammatory bowel disease on pregnancy. Gut.
2007;56(6):830–837. [I]
10. Rajaratnam SG, Eglinton TW, Hider P, Fearnhead NS. Impact of ileal
pouch-anal anastomosis on female fertility: meta-analysis and systematic
review. Int J Colorectal Dis. 2011;26(11):1365–1374. [I]
11. Ban L, Tata LJ, Humes DJ, Fiaschi L, Card T. Decreased fertility rates in 9639
women diagnosed with inflammatory bowel disease: A United Kingdom
population-based cohort study. Aliment Pharmacol Ther. 2015;42(7):
855–866. [II-2]
12. Kim YH, Pfaller B, Marson A, Yim HW, Huang V, Ito S. The risk of venous
thromboembolism in women with inflammatory bowel disease during
pregnancy and the postpartum period: A systematic review and meta-
analysis. Medicine (Baltimore). 2019;98(38):e17309. [I]
13. Fonager K, Sorensen HT, Olsen J, Dahlerup JF, Rasmussen SN. Pregnancy
outcome for women with Crohn’s disease: a follow-up study based on link-
age between national registries. Am J Gastroenterol 1998;93(12):2426–
2430. [III]
14. Kornfeld D, Cnattingius S, Ekbom A. Pregnancy outcomes in women with
inflammatory bowel disease–a population-based cohort study. Am J Obstet
Gynecol 1997;177(4):942–946. [II-2]
15. Baird DD, Narendranathan M, Sandler RS. Increased risk of preterm
birth for women with inflammatory bowel disease. Gastroenterology
1990;99(4):987–994. [II-2]
16. Reddy D, Murphy SJ, Kane SV, Present DH, Kornbluth AA. Relapses of
inflammatory bowel disease during pregnancy: in-hospital manage-
ment and birth outcomes. Am J Gastroenterol 2008;103(5):1203–1209.
[II-2]
17. O’Toole A, Nwanne O, Tomlinson T. Inflammatory bowel disease
increases risk of adverse pregnancy outcomes: a meta-analysis. Dig Dis Sci
2015;60(9):2750–2761. [I]
18. Boyd HA, Basit S, Harpsoe MC, Wohlfahrt J, Jess T. Inflammatory
bowel disease and risk of adverse pregnancy outcomes. PLOS ONE
2015;10(6):e0129567. [II-2]
19. Mayberry JF, Weterman IT. European survey of fertility and pregnancy in
women with Crohn’s disease: a case control study by European collabora-
tive group. Gut 1986;27(7):821–825. [II-2]
20. Bortoli A, Pedersen N, Duricova D, D’Inca R, Gionchetti P, Panelli MR, et al.
Pregnancy outcome in inflammatory bowel disease: prospective European
case-control ECCO-EpiCom study, 2003-2006. Aliment Pharmacol Ther
2011;34(7):724–734. [II-2]
21. Nielsen OH, Andreasson B, Bondesen S, Jacobsen O, Jarnum S. Pregnancy
in Crohn’s disease. Scand J Gastroenterol 1984;19(6):724–732. [II-2]
22. Agret F, Cosnes J, Hassani Z, Gornet JM, Gendre JP, Lemann M, et al.
Impact of pregnancy on the clinical activity of Crohn’s disease. Aliment
Pharmacol Ther 2005;21(5):509–513. [II-3]
23. Castiglione F, Pignata S, Morace F, Sarubbi A, Baratta MA, D’Agostino L,
et al. Effect of pregnancy on the clinical course of a cohort of women with
inflammatory bowel disease. Ital J Gastroenterol 1996;28(4):199–204. [II-2]
24. Riis L, Vind I, Politi P, Wolters F, Vermeire S, Tsianos E, et al. Does preg-
nancy change the disease course? A study in a European cohort of patients
with inflammatory bowel disease. Am J Gastroenterol 2006;101(7):
1539–1545. [II-2]
25. Broms G, Granath F, Linder M, Stephansson O, Elmberg M, Kieler H.
Birth outcomes in women with inflammatory bowel disease: effects
of disease activity and drug exposure. Inflamm Bowel Dis 2014;20(6):
1091–1098. [II-2]
126
26. Abhyankar A, Ham M, Moss AC. Meta-analysis: the impact of disease
activity at conception on disease activity during pregnancy in patients
with inflammatory bowel disease. Aliment Pharmacol Ther 2013;38(5):
460–466. [I]
27. Norgard B, Hundborg HH, Jacobsen BA, Nielsen GL, Fonager K. Disease
activity in pregnant women with Crohn’s disease and birth outcomes: a
regional Danish cohort study. Am J Gastroenterol 2007;102(9):1947–1954.
[II-2]
28. Nguyen GC, Seow CH, Maxwell C, Huang V, Leung Y, Jones J, et al. The
Toronto consensus statements for the management of inflammatory bowel
disease in pregnancy. Gastroenterology 2016;150(3):734–757. [III]
29. Mottet C, Juillerat P, Gonvers JJ, Froehlich F, Burnand B, Vader JP, et al.
Pregnancy and Crohn’s disease. Digestion 2005;71(1):54–61. [III]
30. Mahadevan U, Robinson C, Bernasko N, Boland B, Chambers C,
Dubinsky M, et al. inflammatory bowel disease in pregnancy clini-
cal care pathway: A report from the American Gastroenterological
Association IBD Parenthood Project Working Group. Gastroenterology
2019;156(5):1508–1524. [III]
31. de Lima A, Zelinkova Z, Mulders AG, van der Woude CJ. Preconception
care reduces relapse of inflammatory bowel disease during pregnancy. Clin
Gastroenterol Hepatol 2016;14(9):1285–1292 e1. [II-2]
32. van der Woude CJ, Ardizzone S, Bengtson MB, Fiorino G, Fraser G,
Katsanos K, et al. The second European evidenced-based consensus on
reproduction and pregnancy in inflammatory bowel disease. J Crohns
Colitis 2015;9(2):107–124. [III]
33. Mahadevan U, Matro R. Care of the pregnant patient with inflammatory
bowel disease. Obstet Gynecol 2015;126(2):401–412. [III]
34. Mahadevan U. Pregnancy and inflammatory bowel disease. Med Clin
North Am 2010;94(1):53–73. [III]
35. Rogers RG, Katz VL. Course of Crohn’s disease during pregnancy and
its effect on pregnancy outcome: a retrospective review. Am J Perinatol
1995;12(4):262–264. [II-3]
36. National Association for Colitis and Crohn’s Disease. Pregnancy and IBD:
NACC Information Sheet. 2018. p. 1–13. [III]
37. Kornbluth A, Sachar DB, Practice Parameters Committee of the American
College of G. Ulcerative colitis practice guidelines in adults: American
College Of Gastroenterology, Practice Parameters Committee. Am J
Gastroenterol 2010;105(3):501–523; quiz 24. [III]
38. Bengston M-B, Aamodt G, Mahadevan U, Vatn MH. Inadequate gestational
weight gain, the hidden link between maternal IBD and adverse pregnancy
outcomes: Results from the Norweigan Mother and Child Cohort Study.
Inflammatory Bowel Disease 2017;23(7):1225–1233. [II-2]
39. Bengtson M-B, Martin CF, Aamodt G, Vatn MH, Mahadevan U. Inadequate
gestational weight gain predicts adverse pregnancy outcomes in mothers
with inflammatory bowel disease: results from a prospective us pregnancy
cohort. Dig Dis Sci 2017;62:2063–2069. [II-2]
40. Hatch Q, Champagne BJ, Maykel JA, Davis BR, Johnson EK, Bleier JS, et al.
Crohn’s disease and pregnancy: the impact of perianal disease on delivery
methods and complications. Dis Colon Rectum 2014;57(2):174–178. [II-2]
41. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Pregnancy outcome in women
with inflammatory bowel disease following exposure to 5-aminosalicylic
acid drugs: a meta-analysis. Reprod Toxicol 2008;25(2):271–275. [I]
42. Mogadam M, Dobbins WO, 3rd, Korelitz BI, Ahmed SW. Pregnancy in
inflammatory bowel disease: effect of sulfasalazine and corticosteroids on
fetal outcome. Gastroenterology 1981;80(1):72–76. [II-3]
43. Norgard B, Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. Population-
based case control study of the safety of sulfasalazine use during pregnancy.
Aliment Pharmacol Ther 2001;15(4):483–486. [II-2]
44. Diav-Citrin O, Park YH, Veerasuntharam G, Polachek H, Bologa M,
Pastuszak A, et al. The safety of mesalamine in human pregnancy: a
prospective controlled cohort study. Gastroenterology 1998;114(1):
23–28. [II-2]
45. Marteau P, Tennenbaum R, Elefant E, Lemann M, Cosnes J. Foetal out-
come in women with inflammatory bowel disease treated during pregnancy
with oral mesalazine microgranules. Aliment Pharmacol Ther 1998;12(11):
1101–1108. [II-2]
46. Norgard B, Pedersen L, Christensen LA, Sorensen HT. Therapeutic drug
use in women with Crohn’s disease and birth outcomes: a Danish nation-
wide cohort study. Am J Gastroenterol 2007;102(7):1406–1413. [II-2]
47. Bandoli G, Palmsten K, Forbess Smith CJ, Chambers CD. A review of sys-
temic corticosteroid use in pregnancy and the risk of select pregnancy and
birth outcomes. Rheum Dis Clin North Am 2017;43(3):489–502. [III]
48. Mahadevan U, McConnell RA, Chambers CD. Drug safety and risk of
adverse outcomes for pregnant patients with inflammatory bowel disease.
Gastroenterology 2017;152(2):451–462. [III]
Maternal-Fetal Evidence Based Guidelines
49. Chande N, Patton PH, Tsoulis DJ, Thomas BS, MacDonald JK. Azathioprine
or 6-mercaptopurine for maintenance of remission in Crohn’s disease.
Cochrane Database Syst Rev 2015; (10):CD000067. [I]
50. Hazlewood GS, Rezaie A, Borman M, Panaccione R, Ghosh S, Seow CH,
et al. Comparative effectiveness of immunosuppressants and biologics for
inducing and maintaining remission in Crohn’s disease: a network meta-
analysis. Gastroenterology 2015;148(2):344–354 e5; quiz e14-5. [I]
51. Gisbert JP, Linares PM, McNicholl AG, Mate J, Gomollon F. Meta-analysis:
the efficacy of azathioprine and mercaptopurine in ulcerative colitis.
Aliment Pharmacol Ther 2009;30(2):126–137. [I]
52. Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI.
6-Mercaptopurine in the management of inflammatory bowel disease:
short- and long-term toxicity. Ann Intern Med 1989;111(8):641–649. [III]
53. Alstead E. Fertility and pregnancy in inflammatory bowel disease. World J
Gastroenterol 2001;7(4):455–459. [III]
54. Alstead EM. Inflammatory bowel disease in pregnancy. Postgrad Med J
2002;78(915):23–26. [III]
55. Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The
safety of 6-mercaptopurine for childbearing patients with inflammatory
bowel disease: a retrospective cohort study. Gastroenterology 2003;124(1):
9–17. [II-2]
56. Moskovitz DN, Bodian C, Chapman ML, Marion JF, Rubin PH, Scherl
E, et al. The effect on the fetus of medications used to treat pregnant
inflammatory bowel-disease patients. Am J Gastroenterol 2004;99(4):
656–661. [II-2]
57. Polifka JE, Friedman JM. Teratogen update: azathioprine and 6-mercapto-
purine. Teratology 2002;65(5):240–261. [III]
58. Mozaffari S, Abdolghaffari AH, Nikfar S, Abdollahi M. Pregnancy out-
comes in women with inflammatory bowel disease following exposure to
thiopurines and antitumor necrosis factor drugs: a systematic review with
meta-analysis. Hum Exp Toxicol 2015;34(5):445–459. [I]
59. Cleary BJ, Kallen B. Early pregnancy azathioprine use and pregnancy out-
comes. Birth Defects Res A Clin Mol Teratol 2009;85(7):647–654. [III]
60. Casanova MJ, Chaparro M, Domenech E, Barreiro-de Acosta M, Bermejo
F, Iglesias E, et al. Safety of thiopurines and anti-TNF-alpha drugs during
pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol
2013;108(3):433–440. [II-2]
61. Gonzalez-Suarez B, Sengupta S, Moss AC. Impact of inflammatory bowel
disease activity and thiopurine therapy on birth weight: A meta-analysis.
World J Gastroenterol 2017;23(45):8082–8089. [I]
62. Zlatanic J, Korelitz BI, Rajapakse R, Kim PS, Rubin SD, Baiocco PJ, et al.
Complications of pregnancy and child development after cessation of treat-
ment with 6-mercaptopurine for inflammatory bowel disease. J Clin
Gastroenterol 2003;36(4):303–309. [II-2]
63. Moretti ME, Verjee Z, Ito S, Koren G. Breast-feeding during maternal use of
azathioprine. Ann Pharmacother 2006;40(12):2269–2272. [III]
64. Sau A, Clarke S, Bass J, Kaiser A, Marinaki A, Nelson-Piercy C. Azathioprine
and breastfeeding: is it safe? BJOG 2007;114(4):498–501. [III]
65. Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke
JF. National transplantation Pregnancy Registry–outcomes of 154 preg-
nancies in cyclosporine-treated female kidney transplant recipients.
Transplantation 1994;57(4):502–506. [III]
66. Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, Gulati R, McGrory
CH, et al. Report from the National Transplantation Pregnancy Registry
(NTPR): outcomes of pregnancy after transplantation. Clin Transpl
2005:69–83. [III]
67. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after
cyclosporine therapy during pregnancy: a meta-analysis. Transplantation
2001;71(8):1051–1055. [I]
68. Paziana K, Del Monaco M, Cardonick E, Moritz M, Keller M, Smith B, et al.
Ciclosporin use during pregnancy. Drug Saf 2013;36(5):279–294. [III]
69. American Academy of Pediatrics Committee on Drugs. Transfer of
drugs and other chemicals into human milk. Pediatrics 2001;108(3):
776–789. [III]
70. Ehrenpreis ED, Kane SV, Cohen LB, Cohen RD, Hanauer SB. Thalidomide
therapy for patients with refractory Crohn’s disease: an open-label trial.
Gastroenterology 1999;117(6):1271–1277. [II-1]
71. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel
JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I ran-
domised trial. Lancet 2002;359(9317):1541–1549. [I]
72. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al.
Infliximab for induction and maintenance therapy for ulcerative colitis.
N Engl J Med 2005;353(23):2462–2476. [II-1]
73. Gisbert JP, Gonzalez-Lama Y, Mate J. Systematic review: Infliximab therapy
in ulcerative colitis. Aliment Pharmacol Ther 2007;25(1):19–37. [I]
Inflammatory Bowel Disease
74. O’Donnell S, O’Morain C. Review article: use of antitumour necrosis factor
therapy in inflammatory bowel disease during pregnancy and conception.
Aliment Pharmacol Ther 2008;27(10):885–894. [III]
75. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen
DM, et al. Serious infections and mortality in association with thera-
pies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol
2006;4(5):621–630. [II-2]
76. Mahadevan U, Kane S, Sandborn WJ, Cohen RD, Hanson K, Terdiman
JP, et al. Intentional infliximab use during pregnancy for induction or
maintenance of remission in Crohn’s disease. Aliment Pharmacol Ther
2005;21(6):733–738. [II-2]
77. Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR.
Outcome of pregnancy in women receiving infliximab for the treat-
ment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol
2004;99(12):2385–2392. [III]
78. Narula N, Al-Dabbagh R, Dhillon A, Sands BE, Marshall JK. Anti-TNF
alpha therapies are safe during pregnancy in women with inflammatory
bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis
2014;20(10):1862–1869. [I]
79. Shihab Z, Yeomans ND, De Cruz P. Anti-Tumour Necrosis Factor alpha
Therapies and Inflammatory Bowel Disease Pregnancy Outcomes: A Meta-
analysis. J Crohns Colitis 2016;10(8):979–988. [I]
80. Lichtenstein GR, Feagan BG, Mahadevan U, Salzberg BA, Langholff W,
Morgan GJ, et al. Pregnancy Outcomes Reported During the 13-Year
TREAT Registry: A Descriptive Report. Am J Gastroenterol 2018;113:
1678–1688. [III]
81. Duricova D, Dvorakova E, Hradsky O, Mitrova K, Durilova M, Kozeluhova
J, et al. Safety of anti-TNF-alpha therapy during pregnancy on long-term
outcome of exposed children: A controlled, multicenter observation.
Inflamm Bowel Dis 2019;25(4):789–796. [II-1]
82. Chaparro M, Verreth A, Lobaton T, Gravito-Soares E, Julsgaard M,
Savarino E, et al. Long-term safety of in utero exposure to anti-TNFalpha
drugs for the treatment of inflammatory bowel disease: results
from the Multicenter European TEDDY Study. Am J Gastroenterol
2018;113(3):396–403. [II-2]
83. Zelinkova Z, de Haar C, de Ridder L, Pierik MJ, Kuipers EJ, Peppelenbosch
MP, et al. High intra-uterine exposure to infliximab following mater-
nal anti-TNF treatment during pregnancy. Aliment Pharmacol Ther
2011;33(9):1053–1058. [III]
84. Vasiliauskas EA, Church JA, Silverman N, Barry M, Targan SR, Dubinsky
MC. Case report: evidence for transplacental transfer of maternally
administered infliximab to the newborn. Clin Gastroenterol Hepatol
2006;4(10):1255–1258. [III]
85. Beaulieu DB, Ananthakrishnan AN, Martin C, Cohen RD, Kane S,
Mahadevan U. Use of biologic therapy by pregnant women with inflam-
matory bowel disease does not affect infant response to vaccines. Clin
Gastroenterol Hepatol 2018;16(1):99–105. [II-2]
86. Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure concen-
trations of infants breastfed by women receiving biologic therapies for
inflammatory bowel diseases and effects of breastfeeding on infections and
development. Gastroenterology 2018;155(3):696–704. [II-2]
87. Marchioni RM, Lichtenstein GR. Tumor necrosis factor-alpha inhibitor
therapy and fetal risk: a systematic literature review. World J Gastroenterol
2013;19(17):2591–2602. [I]
88. Nielsen OH, Loftus EV, Jr., Jess T. Safety of TNF-alpha inhibitors during
IBD pregnancy: a systematic review. BMC Med 2013;11:174. [I]
89. Sammaritano LR, Bermas BL, Chakravarty EE, Chambers C, Clowse MEB,
Lockshin MD, et al. 2020 American College of Rheumatology Guideline for
the management of reproductive health in rheumatic and musculoskeletal
diseases. Arthritis Rheumatol 2020;72(4):529–556. [III]
90. Vesga L, Terdiman JP, Mahadevan U. Adalimumab use in pregnancy. Gut
2005;54(6):890. [III]
91. Mishkin DS, Van Deinse W, Becker JM, Farraye FA. Successful use of adali-
mumab (Humira) for Crohn’s disease in pregnancy. Inflamm Bowel Dis
2006;12(8):827–828. [III]
92. Chambers CD, Johnson DL, Xu R, Luo Y, Lopez-Jimenez J, Adam MP, et al.
Birth outcomes in women who have taken adalimumab in pregnancy: A
prospective cohort study. PLOS ONE 2019;14(10):e0223603. [II-2]
93. Clowse ME, Forger F, Hwang C, Thorp J, Dolhain RJ, van Tubergen A, et al.
Minimal to no transfer of certolizumab pegol into breast milk: results from
CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic
study. Ann Rheum Dis 2017;76(11):1890–1896. [II-2]
94. Clowse ME, Wolf DC, Forger F, Cush JJ, Golembesky A, Shaughnessy L,
et al. Pregnancy outcomes in subjects exposed to certolizumab pegol. J
Rheumatol 2015;42(12):2270–2278. [II-2]
127
95. Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M. Evaluation
of pregnancy outcomes from the Tysabri(R) (natalizumab) pregnancy
exposure registry: a global, observational, follow-up study. BMC Neurol
2016;16(1):150. [III]
96. Bye WA, Jairath V, Travis SPL. Systematic review: the safety of vedolizumab
for the treatment of inflammatory bowel disease. Aliment Pharmacol Ther
2017;46(1):3–15. [I]
97. Gisbert JP, Chaparro M. Safety of new biologics (vedolizumab and
ustekinumab) and small molecules (tofacitinib) during pregnancy: A
review. Drugs 2020;80(11):1085–1100. [III]
98. Venturin C, Nancey S, Danion P, Uzzan M, Chauvenet M, Bergoin C, et al.
Fetal death in utero and miscarriage in a patient with Crohn’s disease under
therapy with ustekinumab: case-report and review of the literature. BMC
Gastroenterol 2017;17(1):80. [III]
99. Mahadevan U, Naureckas S, Sharma B, Szapary P, Busse C, Kimball A.
Pregnancy outcomes in women exposed to Ustekinumab. Gastroenterology
2018;154(6):588–589. [III]
100. Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E,
Chambers C, et al. The EULAR points to consider for use of antirheumatic
drugs before pregnancy, and during pregnancy and lactation. Ann Rheum
Dis 2016;75(5):795–810. [III]
101. Clowse ME, Feldman SR, Isaacs JD, Kimball AB, Strand V, Warren RB, et al.
Pregnancy outcomes in the tofacitinib safety databases for rheumatoid
arthritis and psoriasis. Drug Saf 2016;39(8):755–762. [III]
102. Parker CE, Nguyen TM, Segal D, MacDonald JK, Chande N. Low dose nal-
trexone for induction of remission in Crohn’s disease. Cochrane Database
Syst Rev 2018;4:CD010410. [I]
103. Ghouri YA, Richards DM, Rahimi EF, Krill JT, Jelinek KA, DuPont AW.
Systematic review of randomized controlled trials of probiotics, prebiot-
ics, and synbiotics in inflammatory bowel disease. Clin Exp Gastroenterol
2014;7:473–487. [I]
104. Feagan BG, Sandborn WJ, Mittmann U, Bar-Meir S, D’Haens G, Bradette
M, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn
disease: the EPIC Randomized Controlled Trials. JAMA 2008;299(14):
1690–1697. [I]
105. Kumar S, Ahuja V, Sankar MJ, Kumar A, Moss AC. Curcumin for main-
tenance of remission in ulcerative colitis. Cochrane Database Syst Rev
2012;10:CD008424. [I]
106. Kafil TS, Nguyen TM, MacDonald JK, Chande N. Cannabis for the
treatment of Crohn’s disease. Cochrane Database Syst Rev 2018;11:
CD012853. [I]
107. Kafil TS, Nguyen TM, MacDonald JK, Chande N. Cannabis for the
treatment of ulcerative colitis. Cochrane Database Syst Rev 2018;11:
CD012954. [I]
108. Committee on Obstetric Practice. Committee Opinion No. 722: mari-
juana use during pregnancy and lactation. Obstet Gynecol 2017;130(4):
e205–e209. [III]
109. Smink M, Lotgering FK, Albers L, de Jong DJ. Effect of childbirth on the
course of Crohn’s disease; results from a retrospective cohort study in the
Netherlands. BMC Gastroenterol 2011;11:6. [II-2]
110. Cheng AG, Oxford EC, Sauk J, Nguyen DD, Yajnik V, Friedman S, et al.
Impact of mode of delivery on outcomes in patients with perianal Crohn’s
disease. Inflamm Bowel Dis 2014;20(8):1391–1398. [II-2]
111. Ilnyckyji A, Blanchard JF, Rawsthorne P, Bernstein CN. Perianal Crohn’s
disease and pregnancy: role of the mode of delivery. Am J Gastroenterol
1999;94(11):3274–3278. [II-2]
112. Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA.
Pregnancy outcomes in women with inflammatory bowel disease: a large
community-based study from Northern California. Gastroenterology
2007;133(4):1106–1112. [II-2]
113. Brandt LJ, Estabrook SG, Reinus JF. Results of a survey to evalu-
ate whether vaginal delivery and episiotomy lead to perineal involve-
ment in women with Crohn’s disease. Am J Gastroenterol 1995;90(11):
1918–1922. [II-2]
114. Bruce A, Black M, Bhattacharya S. Mode of delivery and risk of inflam-
matory bowel disease in the offspring: systematic review and meta-
analysis of observational studies. Inflamm Bowel Dis 2014;20(7):
1217–1226. [I]
115. Moffatt DC, Ilnyckyj A, Bernstein CN. A population-based study of breast-
feeding in inflammatory bowel disease: initiation, duration, and effect
on disease in the postpartum period. Am J Gastroenterol 2009;104(10):
2517–2523. [II-2]
116. Klement E, Cohen RV, Boxman J, Joseph A, Reif S. Breastfeeding and risk of
inflammatory bowel disease: a systematic review with meta-analysis. Am J
Clin Nutr 2004;80(5):1342–1352. [I]
128
117. Singh S, Feuerstein JD, Binion DG, Tremaine WJ. AGA technical review on
the management of mild-to-moderate ulcerative colitis. Gastroenterology
2019;156(3):769–808 e29. [III]
118. McLeod RS. Ileal pouch anal anastomosis: pregnancy–before, during and
after. J Gastrointest Surg. 2008;12(12):2150–2152. [III]
119. Ross H, Steele SR, Varma M, Dykes S, Cima R, Buie WD, et al. Practice
parameters for the surgical treatment of ulcerative colitis. Dis Colon
Rectum 2014;57(1):5–22. [III]
120. Hahnloser D, Pemberton JH, Wolff BG, Larson D, Harrington J, Farouk R,
et al. Pregnancy and delivery before and after ileal pouch-anal anastomosis
for inflammatory bowel disease: immediate and long-term consequences
and outcomes. Dis Colon Rectum 2004;47(7):1127–1135. [II-2]
121. Seligman NS, Sbar W, Berghella V. Pouch function and gastrointestinal
complications during pregnancy after ileal pouch-anal anastomosis. J
Matern Fetal Neonatal Med 2011;24(3):525–530. [III]
122. Norgard B, Fonager K, Sorensen HT, Olsen J. Birth outcomes of women with
ulcerative colitis: a nationwide Danish cohort study. Am J Gastroenterol
2000;95(11):3165–3170. [II-2]
123. Dominitz JA, Young JC, Boyko EJ. Outcomes of infants born to mothers
with inflammatory bowel disease: a population-based cohort study. Am J
Gastroenterol 2002;97(3):641–648. [II-2]
124. Molnar T, Farkas K, Nagy F, Lakatos PL, Miheller P, Nyari T, et al.
Pregnancy outcome in patients with inflammatory bowel disease accord-
ing to the activity of the disease and the medical treatment: a case-control
study. Scand J Gastroenterol 2010;45(11):1302–1306. [II-2]
125. Norgard B, Puho E, Pedersen L, Czeizel AE, Sorensen HT. Risk of congenital
abnormalities in children born to women with ulcerative colitis: a popula-
tion-based, case-control study. Am J Gastroenterol 2003;98(9):2006–2010.
[II-2]
126. Nielsen OH, Andreasson B, Bondesen S, Jarnum S. Pregnancy in ulcerative
colitis. Scand J Gastroenterol 1983;18(6):735–742. [III]
Maternal-Fetal Evidence Based Guidelines
127. Caprilli R, Gassull MA, Escher JC, Moser G, Munkholm P, Forbes A, et al.
European evidence based consensus on the diagnosis and management of
Crohn’s disease: special situations. Gut 2006;55(Suppl 1):i36–58. [III]
128. Dubinsky M, Abraham B, Mahadevan U. Management of the pregnant IBD
patient. Inflamm Bowel Dis 2008;14(12):1736–1750. [III]
129. Ravid A, Richard CS, Spencer LM, O’Connor BI, Kennedy ED, MacRae HM,
et al. Pregnancy, delivery, and pouch function after ileal pouch-anal anas-
tomosis for ulcerative colitis. Dis Colon Rectum 2002;45(10):1283–1288.
[II-2]
130. Ordas I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative
colitis. Lancet 2012;380(9853):1606–1619. [III]
131. Dozois EJ, Wolff BG, Tremaine WJ, Watson WJ, Drelichman ER, Carne
PW, et al. Maternal and fetal outcome after colectomy for fulminant ulcer-
ative colitis during pregnancy: case series and literature review. Dis Colon
Rectum 2006;49(1):64–73. [III]
132. Ilnyckyj A. Surgical treatment of inflammatory bowel diseases and preg-
nancy. Best Pract Res Clin Gastroenterol 2007;21(5):819–834. [III]
133. Ahmed Ali U, Keus F, Heikens JT, Bemelman WA, Berdah SV, Gooszen HG,
et al. Open versus laparoscopic (assisted) ileo pouch anal anastomosis for
ulcerative colitis and familial adenomatous polyposis. Cochrane Database
Syst Rev 2009;(1):CD006267. [I]
134. Bartels SA, D’Hoore A, Cuesta MA, Bensdorp AJ, Lucas C, Bemelman WA.
Significantly increased pregnancy rates after laparoscopic restorative procto-
colectomy: a cross-sectional study. Ann Surg 2012;256(6):1045–1048. [II-2]
135. Beyer-Berjot L, Maggiori L, Birnbaum D, Lefevre JH, Berdah S, Panis Y. A
total laparoscopic approach reduces the infertility rate after ileal pouch-
anal anastomosis: a 2-center study. Ann Surg 2013;258(2):275–282. [II-2]
136. Hou JK, Mahadevan U. A 24-year-old pregnant woman with inflammatory
bowel disease. Clin Gastroenterol Hepatol 2009;7(9):944–947. [III]
137. Friedman S, Regueiro MD. Pregnancy and nursing in inflammatory bowel
disease. Gastroenterol Clin North Am 2002;31(1):265–273, xii. [III]
12
ALIMENTARY TRACT DISEASES
Ryan Lamm, Arturo J. Rios-Diaz, Priyadarshini Koduri, and Francesco Palazzo
Key points
• Symptomatic gallstones are common in pregnant women,
but acute cholecystitis is uncommon.
• Pregnancy and the postpartum period increase the risk
of gallstones and acute cholecystitis.
• Biliary colic is the most common symptom associated with
gallstones.
• Acute cholecystitis can be differentiated from biliary colic
based on constant right upper quadrant or epigastric pain,
Murphy’s sign, and evidence of inflammation with sys-
temic signs.
• Diagnosis of cholelithiasis or acute cholecystitis is based
on characteristic signs, symptoms, and ultrasonographic
findings.
• Acute cholecystitis is associated with significant maternal
and fetal risks.
• Laparoscopic cholecystectomy is recommended for
pregnant patients with acute cholecystitis.
• Cholecystectomy is unequivocally recommended in
women with sepsis, ileus, or perforation.
• Endoscopic retrograde cholangiopancreatography
(ERCP) and magnetic resonance cholangiopancrea-
tography (MRCP) are considered safe in pregnancy.
Pregnancy is a risk factor for post-ERCP pancreatitis.
• Early ERCP and laparoscopic cholecystectomy is rec-
ommended for choledocholithiasis and biliary pancre-
atitis in pregnancy.
• Laparoscopic appendectomy is recommended for acute
appendicitis in pregnancy.
Cholelithiasis
Diagnosis/Definition
Cholelithiasis is the presence of gallstones in the gallbladder. A
diagnosis of cholelithiasis may be incidental or may be suspected
on the basis of classic symptoms with confirmation on ultrasound.
Symptoms
Up to 50% of pregnant women with cholelithiasis are asymptom-
atic [1]. The most common symptom reported is biliary colic—
recurrent pain in the right upper quadrant or epigastrium that
is sudden in onset and may radiate to the interscapular area or
right scapula. Biliary colic results from obstruction of the cystic
or common bile duct. The resulting increased intraluminal pres-
sure is unrelieved by repeated gallbladder contractions. While
nausea and vomiting often accompany biliary colic, the common
triad of bloating, nausea, and heartburn is only weakly associated
with the presence of gallstones [2].
Epidemiology/Incidence
Gallstones are fairly common and are found in up to 20% of
women under age 40 in autopsy series [3]. Gallstones have been
DOI: 10.1201/9781003099062-12
reported in 7% of nulliparous women and 20% of multi-parous
women [4]. Biliary sludge, which is a precursor to gallstones, is
seen in up to 30% of pregnant women [2]. Gallbladder disease is
the second most-common indication for non-obstetrical surgery
in pregnancy [5]. Increasing physical activity to moderate or vig-
orous levels did not decrease the incidence of sludge or gallstones
in one trial [6].
Etiology/Pathophysiology
Gallstones form by concretion or accretion of normal or abnormal
bile constituents. Increased biliary secretion of cholesterol and
gallbladder hypomotility contributes to gallstone formation. There
are three major types of gallstones: Cholesterol, pigmented, and
mixed. Cholesterol and mixed stones constitute the majority of
gallstones seen (80%) while pigment stones constitute the rest [3].
Risk factors/Associations
Common risk factors for cholelithiasis are listed in Table 12.1.
Pregnancy is associated with an increased risk of cholelithi-
asis likely due to decreased gallbladder motility and increased
lithogenicity of bile [1, 7]. Increased risk for cholelithiasis may
remain up to five years postpartum [8]. While the incidence of
gallstones or sludge may increase with advancing gestation,
regression in the postpartum period is not uncommon [9–13].
Differential diagnosis
Acute cholecystitis (should be suspected if fever, chills, tachy-
cardia, or other systemic signs accompany persistent right upper
quadrant/epigastric pain), appendicitis, pancreatitis, peptic ulcer
disease, pyelonephritis, hemolysis, elevated liver enzymes, low
platelet count (HELLP) syndrome, acute fatty liver disease, or
hepatitis.
Complications
Maternal
Cholecystitis, cholangitis, choledocholithiasis, pancreatitis, or
ileus.
Fetal
No reports suggest an increased fetal risk associated with biliary
colic or the presence of gallstones.
Management
Principles
Conservative management may be an option at least initially in an
attempt to avoid surgery. However, more recent evidence suggests
having a lower threshold for surgical intervention given the
safety of the laparoscopic approach and potentially improved
fetal outcomes particularly in the second trimester [4, 14, 15].
Retrospective and survey-based studies suggest that conservative
management of symptomatic cholelithiasis is associated with an
increased symptom recurrence, hospitalizations and emergency
room visits [16–18].
129
130
TABLE 12.1: Risk Factors for Cholelithiasis
Cholesterol and mixed gallstones
Race/Ethnicity: North American Indians, Hispanics
Obesity
Rapid weight loss (e.g., post gastric bypass)
Female sex hormones (e.g., oral contraceptive pills)
Ileal resection
Advancing age
Gallbladder hypomotility
Diet: High calorie, high fat
Pigment stones
Ethnicity: Asian
Chronic hemolysis
Alcoholic cirrhosis
Chronic biliary tract infection, parasitic infection
Workup
Laboratory investigations: Complete blood count, full hepatic
function panel, serum amylase, and lipase.
Imaging: Ultrasound is the most useful and sensitive test
for detecting sludge and gallstones even as small as 2 mm [3, 19].
Classic sonographic findings suggestive of gallstones include acous-
tic shadowing of opacities in the gallbladder lumen that change with
the patient’s position. The false-negative and false-positive rates for
ultrasound in gallstone patients are estimated at 2–4% [3].
Therapy
All pregnant women with symptomatic cholelithiasis should be
admitted to the hospital for observation. Although it is gener-
ally accepted that women without systemic symptoms should
be conservatively managed initially in an effort to avoid surgery,
this view was challenged in a retrospective review of 58 preg-
nant women with gallbladder disease, excluding those with acute
cholecystitis [20]. Compared to women surgically managed,
women who were conservatively managed had twice the rate
of obstetric complications [20]. However, this difference was not
statistically significant and the obstetric complications were not
directly linked to gallbladder disease.
Conservative management should be attempted initially for
about 24 hours. This typically includes bowel rest with NPO, intra-
venous hydration, and use of opioid analgesics. Surgical consulta-
tion should be obtained. Indications for surgical management in
symptomatic women without acute cholecystitis include wors-
ening of symptoms, inability to tolerate oral intake, increasing
abdominal tenderness, and patient preference.
Pregnancy considerations
Biliary colic alone does not appear to increase the risk of adverse
obstetric outcome.
Labor and delivery issues
Mode of delivery is not impacted by the presence of gallstones.
Cesarean section should be performed for obstetric indications.
Acute cholecystitis
Diagnosis/Definition
Acute cholecystitis is inflammation of the gallbladder. A diagnosis
of acute cholecystitis should be made on the basis of characteris-
tic history and physical examination. The 2018 Tokyo Guidelines
diagnostic criteria can be followed to make a diagnosis of acute
Maternal-Fetal Evidence Based Guidelines
TABLE 12.2: 2018 Tokyo Guidelines for Diagnosing Acute
Cholecystitis
A. Local signs of inflammation etc.
(1) Murphy’s sign, (2) RUQ mass/pain/tenderness
B. Systemic signs of inflammation etc.
(1) Fever, (2) elevated CRP, (3) elevated WBC count
C. Imaging findings
Imaging findings characteristic of acute cholecystitis
Suspected diagnosis: One item in A + one item in B
Definite diagnosis: One item in A + one item in B + C
Source: Adapted from Ref. [21], [III].
Abbreviations: RUQ, right upper quadrant; CRP, c-reactive protein; WBC, white blood cell.
cholecystitis (Table 12.2) [21]. Murphy’s sign is a physical exami-
nation finding of increased abdominal rigidity on inspiration and
right upper quadrant tenderness. This sign can also be elicited on
a right upper quadrant ultrasound examination with visualiza-
tion of the gallbladder being compressed. This sign is pathogno-
monic for acute cholecystitis, but may not always be present on
exam, depending on gestational age and body habitus.
Classification
Table 12.3 summarizes the 2018 Tokyo Guidelines criteria used
to grade the severity of acute cholecystitis [21].
Symptoms
Symptoms suggestive of acute cholecystitis are similar in the
pregnant and non-pregnant state. Common signs and symptoms
TABLE 12.3: 2018 Tokyo Guidelines for Severity Grading for
Acute Cholecystitis
Grade III (severe) acute cholecystitis
“Grade III” acute cholecystitis is associated with dysfunction of any one
of the following organs/systems:
1. Cardiovascular dysfunction: Hypotension requiring treatment with
dopamine ≥5 μg/kg per min, or any dose of norepinephrine
2. Neurological dysfunction: Decreased level of consciousness
3. Respiratory dysfunction: PaO2/FiO2 ratio <300
4. Renal dysfunction: Oliguria, creatinine >2.0 mg/dl
5. Hepatic dysfunction: PT-INR >1.5
6. Hematological dysfunction: Platelet count <100,000/mm3
Grade II (moderate) acute cholecystitis
“Grade II” acute cholecystitis is associated with any one of the following
conditions:
1. Elevated WBC count (>18,000/mm3)
2. Palpable tender mass in the right upper abdominal quadrant
3. Duration of complaints >72 ha
4. Marked local inflammation (gangrenous cholecystitis,
pericholecystic abscess, hepatic abscess, biliary peritonitis,
emphysematous cholecystitis)
Grade I (mild) acute cholecystitis
“Grade I” acute cholecystitis does not meet the criteria of “Grade III” or
“Grade II” acute cholecystitis. It can also be defined as acute
cholecystitis in a healthy patient with no organ dysfunction and mild
inflammatory changes in the gallbladder, making cholecystectomy a
safe and low-risk operative procedure
Source: Adapted from Ref. [21], [III].
Alimentary Tract Diseases
include constant right upper quadrant pain or tenderness,
fever, tachycardia, leukocytosis, anorexia, nausea, vomiting,
and inability to tolerate oral intake. Jaundice and signs consis-
tent with peritonitis may also be present. In women with super-
imposed bacterial infection, sepsis may also be apparent.
Epidemiology/Incidence
Although cholelithiasis is fairly common in pregnancy, acute
cholecystitis is relatively uncommon. It is estimated to compli-
cate 0.1% of all pregnancies [22].
Etiology/Pathogenesis
The majority of cases of acute cholecystitis result from obstruc-
tion of the cystic duct by gallstones [2, 23]. Inflammation of the
gallbladder results from three factors: Mechanical inflammation
from increased intraluminal pressure, resulting in ischemia of the
gallbladder wall and mucosa, chemical inflammation from release
of tissue factors, and bacterial inflammation. Bacterial inflamma-
tion may play a role in 20% of all patients with acute cholecys-
titis [23]. Characteristic bacteria involved include Escherichia
coli, Klebsiella, Streptococcus faecalis, Staphylococcus, and
Clostridium [3, 23].
Risk factors/Associations
See earlier section “Cholelithiasis.”
Complications
Maternal
Maternal risks include sepsis, cholangitis, pancreatitis, empyema of
the gallbladder, gangrene and perforation, fistula formation, gall-
stone ileus, porcelain gallbladder with associated increased risk of
gallbladder cancer. In addition, patients treated non-operatively
were more likely to require re-admission (18.7% vs. 10.7%) and
require Cesarean sections (OR 3.18) [24].
Fetal
Fetal death occurred in 7% of women treated conservatively ver-
sus 2% of women treated with laparoscopic cholecystectomy [14].
In patients treated non-operatively, there was an increased risk of
preterm delivery (OR 3.2), first-trimester miscarriage, and poor
fetal growth (OR 6.55) [24].
Pregnancy considerations
Principles
The appropriate and optimal management of pregnant women
with acute cholecystitis remains controversial. Risks of con-
servative management include risk to the fetus from recurrent
relapses, malnutrition, and other complications that may result
from complicated gallbladder disease. However, surgery is not
without maternal or fetal risk either. Management decisions for
the pregnant woman with acute cholecystitis should be made in
conjunction with a general surgeon to ensure optimal manage-
ment for both mother and fetus.
Workup
Laboratory investigations: Complete blood count, full hepatic
function panel, serum amylase, and lipase.
Imaging: Ultrasound is the image modality of choice in
pregnancy for diagnosing cholecystitis. Classic sonographic
findings suggestive of acute cholecystitis are similar in pregnant
and non-pregnant women. They include a thickened gallbladder
wall (>3–5 mm), pericholecystic fluid, gallstones, and a sono-
graphic Murphy’s sign [2, 25].
131
However, ultrasound is insensitive in diagnosing choledocholi-
thiasis (presence of an obstructing gallstone in the common bile
duct). If choledocholithiasis is suspected on the basis of a dilated
biliary tree, abnormal liver tests or pancreatitis, further diagnos-
tic modalities should be employed, namely MRCP or ERCP. See
“Choledocholithiasis” section.
Management
All women with suspected acute cholecystitis should be hospi-
talized and a surgical consultation should be obtained. If acute
cholecystitis is confirmed, patients have been historically treated
with conservative management for about 24 hours as an initial
option. Traditionally, conservative therapy would include
nothing per os (NPO)/bowel rest, intravenous hydration, opi-
oid analgesia, and broad-spectrum antibiotics in women with
systemic symptoms for 12 to 24 hours [2].
However, more recent studies have shown that maternal and
fetal complications were significantly higher for patients
treated conservatively and that patients treated conservatively
were more likely to be-admitted with complications [24, 26]. In
addition, a majority of patients (40–70%) who are treated con-
servatively relapse during the pregnancy and approximately
27% of women who failed conservative management required
cholecystectomy [27]. Since 2008 management trends displayed
a trend towards early surgical treatment, with up to 60% of
pregnant patients being treated with laparoscopic cholecys-
tectomy [28–30]. Cholecystectomy is unequivocally recom-
mended in women with sepsis, ileus, or perforation.
Patient should be placed in the left lateral position to avoid
aortocaval compression. Perioperative fetal assessment is recom-
mended [22]. In previable pregnancies, fetal heart tones should
be obtained pre- and post-procedure. Viable pregnancies should
at minimum be assessed with a period of continuous fetal heart
rate and contraction monitoring before and after the procedure.
A neonatology consultation should be obtained pre-operatively.
Due to the risk of preterm delivery, steroids for fetal lung matu-
rity should be administered to women with viable premature
fetuses. Care should be taken to avoid high intraperitoneal pres-
sures, using the open technique for umbilical port insertion and
using electrocautery away from the uterus [31].
Other surgical approaches have been described. There is a more
recent technique, called NOTES (Natural Orifice Transluminal
Endoscopic Surgery), in which surgery is performed via a natural
occurring orifice. There are no reports of a NOTES cholecystec-
tomy performed during pregnancy. Percutaneous cholecystos-
tomy tube placement is a technique whereby the gallbladder is
decompressed with a pigtail catheter placed under ultrasound
guidance. It is a helpful management alternative in patients who
cannot safely undergo surgery or who have contraindications to
anesthesia. However, with the safety and acceptance of laparo-
scopic cholecystectomy, the role of percutaneous cholecystos-
tomy is not well defined in pregnancy. A few case series and
observational studies have suggested that it can be performed
safely in all trimesters [32–34]. Peroral endoscopic gallbladder
drainage (transmural or trans-papillary) has not been described
in the pregnant population.
The safety and possible efficacy of a short course of indo-
methacin in the second trimester to attempt to reverse the
gallbladder inflammation has been reported, but is not rec-
ommended [22]. Indomethacin use should be avoided after 32
weeks to avoid premature closure of the ductus arteriosus and
oligohydramnios.
132
Labor and delivery considerations
Acute cholecystitis or history of cholecystectomy during the
pregnancy should not impact mode of delivery. Cesarean section
should be reserved for obstetric indications.
Choledocholithiasis
Diagnosis/Definition
Presence of gallstone(s) impacted in the common bile duct.
Diagnosis often made in conjunction with acute cholecystitis (see
earlier section), but can be present alone. Typically detected using
hepatic function panel and ultrasound.
Symptoms
Symptoms can be similar to those of acute cholecystitis and
are similar in the pregnant and non-pregnant state. Common
signs and symptoms include right upper quadrant tenderness
which can be colicky or constant. Anorexia, nausea, vomit-
ing, and inability to tolerate oral intake may also be present.
Jaundice and signs consistent with peritonitis may also be pres-
ent. In women with superimposed bacterial infection, sepsis may
also be apparent indicative of cholangitis. In this case you may see
fever, tachycardia, leukocytosis.
Epidemiology/Incidence
Choledocholithiasis occurs in roughly 1 in 1000 pregnant women
[35, 36].
Etiology/Pathophysiology
Choledocholithiasis is a sequela of cholelithiasis, for which
the etiology, risk factors, and pathophysiology is described
earlier. Specifically, choledocholithiasis results from gall-
stones migrating from the gallbladder through the cystic
duct to the common bile duct where they become impacted
and obstruct the flow of bile from the liver to the small
intestine.
Risk factors/Associations
See section on “Cholelithiasis.”
Differential diagnosis
See section on “Cholelithiasis.”
Complications
Maternal
Maternal complications include sepsis, cholangitis, pancreatitis,
empyema of the gallbladder, gangrene and perforation, fistula for-
mation, gallstone ileus.
Fetal
Although exact risk to the fetus is unknown due to low rates of
disease, the development of cholangitis can lead to fetal death and
other adverse obstetric outcomes [36].
Management
Principles
All women with suspected choledocholithiasis should be hos-
pitalized and a surgical consult as well as a gastroenterology
consult should be obtained. Focus should be spent on whether
the patient is showing signs of superimposed infection or toxic-
ity and a low threshold for the initiation of broad-spectrum anti-
biotics should be obtained as this poses the greatest risk to the
mother and fetus.
Maternal-Fetal Evidence Based Guidelines
Workup
Laboratory investigations: Complete blood count, full hepatic
function panel, serum amylase, and lipase.
Imaging: Ultrasound again is the initial image modality of
choice in pregnancy for diagnosing choledocholithiasis which
will show a dilated common bile duct (CBD) and sometimes
the presence of a stone within the CBD. CBD size greater than
6 mm is suspicious for choledocholithiasis, but should be cor-
related with patient history, physical, and laboratory findings
to make the diagnosis [37].
MRCP: Considering the safety of MRI in pregnancy, MRCP is
likely safe in pregnancy. MRCP and ERCP have been shown to
have similar diagnostic accuracy for choledocholithiasis in the non-­
pregnant population [38]. Nonetheless, there are no clear guidelines
for use of MRCP in pregnancy. In doses several times the human
dose, paramagnetic contrast agents have been associated with fetal
abnormalities and increased risk of miscarriage in animals [39, 40].
Safety of contrast agents during breastfeeding remains unknown.
Therapy
ERCP followed by sphincterotomy and stone extraction is now
the most common treatment modality for symptomatic cho-
ledocholithiasis. In cases of acute cholecystitis, a cholecystectomy
may be performed after an ERCP to prevent recurrence of obstruc-
tion. A large retrospective meta-analysis [41] and several small ret-
rospective studies support the safety of ERCP in pregnancy when
performed by an experienced endoscopist [42–49]. A large retro-
spective matched-cohort study showed that ERCP associated com-
plications of perforation, cholecystitis and post-sphincterotomy
hemorrhage were rare in both pregnant and non-pregnant women
[50]. However, pregnant women were found to have a significantly
higher incidence of post-ERCP pancreatitis compared to non-­
pregnant women (12% vs. 5%, P < 0.001). More recent studies have
shown that the rates of post-ERCP pancreatitis in pregnancy are
decreasing and cases are usually mild [51, 52]. Pregnancy complica-
tions were rare and rates of maternal mortality, fetal distress and
fetal loss were comparable to national averages [53]. Interestingly,
pregnant women post-ERCP had lower rates of preterm labor com-
pared to the national average [50]. ERCP is best performed in the
second trimester to minimize obstetric risks [43]. Fetal radiation
exposure during an ERCP can vary depending on procedure time
and fluoroscopy time. Although there is a correlation between fluo-
roscopy time and fetal radiation exposure, this relationship is not
entirely linear [48]. In a series of 17 patients undergoing ERCP, fetal
radiation doses were <200 mrad when fluoroscopy time was limited
to less than one minute [48]. Effort should be made to minimize
fluoroscopy time, using shielding under the pelvis and over the
lower part of the abdomen. Modifying techniques to minimize
fluoroscopy time have successfully been used to decrease fetal radi-
ation exposure to negligible levels [53]. Non-radiation ERCP has
been successfully performed during pregnancy without resultant
adverse pregnancy outcomes [35, 54–57]. However, the small num-
ber of reported procedures limits conclusions regarding safety of
the procedure in pregnancy and this should only be attempted by
experienced endoscopists using this technique, with recommen-
dations favoring fluoroscopic-guided ERCP [57]. Fetal monitoring
before and after ERCP is recommended.
Labor and delivery issues
Choledocholithiasis during the pregnancy should not impact
mode of delivery. Cesarean section should be reserved for obstet-
ric indications.
Alimentary Tract Diseases
Biliary pancreatitis
Diagnosis/Definition
Cholelithiasis, gallstones, which migrate through the biliary sys-
tem and block either the common bile duct and/or pancreatic duct
preventing pancreatic enzymes from entering the small intestine
and causing inflammation of the pancreas, or pancreatitis.
Symptoms
Symptoms can be similar to those experienced in cholelithiasis
and acute cholecystitis (see respective earlier sections of this
chapter). In addition, can have symptoms of classic pancreatitis
including cramping epigastric pain, nausea, and emesis.
Epidemiology/Incidence
Biliary pancreatitis is the most common cause of pancreatitis in
pregnant patients [58]. Although the exact incidence is unknown,
studies estimated the rate of all pancreatitis in pregnancy to be
around 1 in 1000 to 10,000 [59]. One study showed the etiology of
pancreatitis in pregnancy was cholelithiasis in 96% of cases [60].
Etiology/Pathophysiology
See section titled “Cholelithiasis.” Specifically, there is an
obstruction, by one or more gallstone(s), to the normal flow of
pancreatic enzymes into the small intestine causing inflamma-
tion of the pancreas.
Classification
Ranson’s criteria is commonly used to determine severity of
acute pancreatitis and the associated mortality (Table 12.4) [61].
Risk factors/Associations
See the “Cholelithiasis” section.
TABLE 12.4: Ranson’s Criteria for Acute Pancreatitis Severity
and Associated Mortality
Ranson’s criteria on admission (one point for each of the following):
• Age >55 years
• White blood cell count >16,000 cells mm–3
• Blood glucose >11 mmol l–1
• Serum AST >250 IU l–1
• Serum LDH >350 IU l–1
Ranson’s criteria after 48 hours of admission (one point for each of
the following):
• Hypocalcemia (serum calcium <2.0 mmol l–1)
• Fall in hematocrit by >10%
• Hypoxemia (PO2 <60 mmHg)
• Increase in BUN to >1.98 mmol l–1 after IV fluid hydration
• Base deficit (negative base excess) >4 mmol l–1
• Sequestration of fluids >6 l
Interpretation
• If the score ≥3, severe pancreatitis likely
• If the score <3, severe pancreatitis is unlikely
Or
• Score 0–2: 2% mortality
• Score 3–4: 15% mortality
• Score 5–6: 40% mortality
• Score 7–8: 100% mortality
Source: Adapted from Ref. [61].
133
Differential diagnosis
See the “Cholelithiasis” section. Others include autoimmune
pancreatitis and alcoholic pancreatitis although these etiologies
are much less common in the pregnant population.
Complications
Maternal
One study found outcomes comparable between non-pregnant
and pregnant patients with most cases of biliary pancreatitis
being mild or moderate (85%) with a mortality rate of 0.8% [62].
The 15% of cases that progress to severe are associated with mor-
tality rates of up to 25% as well as significant hospital length of
stays sometimes requiring operative interventions and ICU level
care [62].
Fetal
Except in severe cases of pancreatitis secondary to cholelithia-
sis where maternal health is detrimentally affected, few obstetric
specific adverse outcomes are reported in the literature.
Management
Principles
Determination of cause of pancreatitis should be the early focus
as treatment algorithm differs depending on etiology. With bili-
ary pancreatitis being the most common etiology, diagnostic test-
ing should be ordered accordingly.
Workup
Laboratory investigations: Complete blood count, full hepatic
function panel, serum amylase, and lipase.
Imaging: Ultrasound can help detect the presence of gallstones
within the gallbladder; however, CT scan is the gold standard to
detect inflammation, fluid, or necrosis in the pancreas in the non-
pregnant patient. Given the risks of CT scan, abdominal MRI
is recommended in pregnant patients when biliary pancreati-
tis is suspected as it can provide information on pancreatic
edema, pseudocysts, or hemorrhage around the pancreas and
it can also help to determine whether the common bile duct/
main pancreatic duct are clear or not when persistent cho-
lestasis occurs [61].
Therapy
All patients with suspected biliary pancreatitis should be admitted
to the hospital with a general surgery consult and a gastroenter-
ology consult. As in acute cholecystitis, conservative management
has classically been employed to treat biliary pancreatitis. This
includes keeping the patient NPO, IV fluids, and broad-spectrum
antibiotics if signs of sepsis such as fever and leukocytosis are
present. This has recently been challenged given the relative safety
of ERCP and laparoscopic cholecystectomy (see earlier sections),
and with the information that recurrence is common in patients
treated conservatively (up to 70%) [61]. Current recommenda-
tions are early ERCP with sphincterotomy in the first and third
trimester and subsequent laparoscopic cholecystectomy in the
second trimester or post-delivery for the third trimester for biliary
pancreatitis [61, 63, 64]. Recent retrospective database reviews have
shown that this is not happening in practice with pregnant patients
receiving less ERCP and laparoscopic cholecystectomy than their
non-pregnant counterparts and as a result have an increased risk
of readmission (OR 1.96) [65].
In patients with severe pancreatitis, supportive care and some-
times endoscopic, image-guided, or operative drainage may
be necessary, but there are only a few reports of these cases in
134
pregnant patients and mortality is high, even in non-pregnant
patients, careful consideration with general surgery consultant
input is recommended for these cases.
Labor and delivery issues
Biliary pancreatitis during the pregnancy should not impact
mode of delivery. Cesarean section should be reserved for obstet-
ric indications.
Appendicitis
Diagnosis/Definition
Inflammation and infection of the appendix. Diagnosis is usu-
ally made with a CT scan in the non-pregnant patient, however
abdominal MRI is often used in the pregnant patient, and by
classic symptoms of RLQ pain which may have originated near
the umbilicus, nausea, anorexia, and emesis. Sometimes fever
and leukocytosis are present.
Symptoms
RLQ pain which may have originated near the umbilicus, nausea,
anorexia, and emesis. Fever is common, sometimes reported as
chills felt at home.
Epidemiology/Incidence
Acute appendicitis is reported as high as 41 per 10,000 patients
and is the most common non-obstetric surgical problem in
pregnancy [66]. It most often occurs during the second trimes-
ter [66].
Etiology/Pathophysiology
Although exact pathophysiology is unknown, acute inflamma-
tion of the appendix is thought to occur from blockage of the
lumen of the appendix by a fecalith, fecal matter, and/or lymphoid
hyperplasia which decreases blood flow and allows bacteria to
multiply leading to infection [67]. Perforation is thought to occur
when intra-luminal pressure exceeds the capacity of the diseased
appendiceal lumen and extravasation of intra-luminal contents
occurs, sometimes leading to abscess formation and/or peritoni-
tis known as complicated appendicitis.
Risk factors/Associations
No specific risk factors for the development of acute appen-
dicitis in pregnant patients exists; however, some evidence
that pregnant patients are actually at decreased risk for acute
appendicitis compared to non-pregnant patient equivalents
exists [68]. Although supported by weak evidence, risk factors
for the development of acute appendicitis in the non-pregnant
patient include family history of acute appendicitis and diag-
nosis of cystic fibrosis; these can likely be applied to the preg-
nant patient as well [69].
Differential diagnosis
Gastroenteritis, acute cholecystitis, peptic ulcer disease, GERD.
Complications
Maternal
Sepsis, perforation, peritonitis
Fetal
Preterm delivery rate is reported to be as high as 30% and fetal
loss as high as 20%, most frequently reported with complicated,
perforated appendicitis [70, 71].
Maternal-Fetal Evidence Based Guidelines
Management
Principles
Management should focus on accurate diagnosis and whether or
not it is perforated as treatment algorithm differs.
Workup
Laboratory investigations: Complete blood count with differential.
Imaging: CT scan with IV contrast is the gold standard for acute
appendicitis diagnosis in non-pregnant patients. MRI should be
used in the pregnant patient as it can reduce the need for CT
scan by 50% and successfully diagnose acute appendicitis in
90% of pregnant patients who present with acute abdominal
pain [69, 72–76]. Trans-abdominal ultrasound may also be used
as an initial test, but is often equivocal and has a lower sensitiv-
ity than abdominal MRI [77]. In patients with equivocal imag-
ing studies and unconvincing history, physical, and laboratory
evidence for acute appendicitis, delay for repeat testing during
the same hospital stay does not put the patient or the fetus at
increased risk [77].
Therapy
All patients with suspected acute appendicitis should be hospi-
talized and surgical consultation should be obtained. Patients
should be made NPO and placed on IV fluids and appropriate
antibiotics. Similar to pre-cholecystectomy, peri-­operative
fetal assessment is recommended. Previable fetuses should
have fetal heart tones documented with Doppler pre- and
post-procedure. Viable fetuses should at minimum have a
period continuous fetal heart rate and contraction moni-
toring pre- and post-procedure. Antenatal corticosteroids
for fetal maturity should be administered pre-operatively
to women with viable premature fetuses and a neonatology
consultation should be obtained. Laparoscopic appendec-
tomy is currently recommended by many major surgical
and obstetric societies for the treatment of acute, uncom-
plicated appendicitis in pregnant patients during any
trimester when indicated [29, 31, 78, 79]. It has been
shown to decrease operative times, length of stay, and postop-
erative complications when compared to open appendectomy
[71, 80].
For pregnant patients with complicated, perforated appen-
dicitis no formal recommendations specifically exist. As such,
guidelines for the non-pregnant patient should likely be fol-
lowed. These include immediate operative intervention for
signs of sepsis, peritonitis, or free perforation [81]. If patient
does not have any of these signs conservative management of
NPO, IV fluids, and antibiotics may be employed with opera-
tive intervention reserved for clinical deterioration [81]. If an
abscess is identified, the role of percutaneous drainage (tim-
ing/modality of insertion) is not well defined in the pregnant
population, but is utilized in the non-pregnant population
[82]. Delayed appendectomy is not specifically defined in the
pregnant patient population, but recommended after a 4–6
week delay in the non-pregnant patient [83]. Any clinical deci-
sion making in these cases should include a multi-disciplinary
approach, utilizing the obstetric, general surgery, and interven-
tional radiology teams’ input.
Labor and delivery issues
Acute appendicitis or history of appendectomy during the preg-
nancy should not impact mode of delivery. Cesarean section
should be reserved for obstetric indications.
Alimentary Tract Diseases
Other alimentary tract etiologies
Common pathologies requiring surgical intervention may pres-
ent in the pregnant patient such as incarcerated hernias, bowel
obstructions, medically refractory inflammatory bowel disease
(IBD) (see Chap. 11), and diverticulitis, among others. Careful
consideration with surgical, obstetrical, and gastroenterologi-
cal consultants’ input should be taken when proceeding with
conservative versus operative management in this patient pop-
ulation. In IBD specifically, it is recommended to treat patients
with immunomodulators and anti-tumor necrosis factor medi-
cations, as these medications have a favorable side effect profile
for the pregnant patient [84]. Common indications for surgical
intervention identified for medically refractory IBD include per-
forated small bowel or unremitting pain [85]. In a meta-analysis,
surgical interventions resulted in a rate of 50% preterm labor
when performed in the first and second trimester and a rate of
100% preterm labor in the third; however, no maternal or fetal
mortality was reported [85]. Additionally, incidence is low and no
formal recommendations exist for these pathologies specific to
the pregnant patient.
References
1. Ramin KD, Ramsey PS. Disease of the gallbladder and pancreas in preg-
nancy. Obstet Gynecol Clin North Am 2001;28(3):571–580. [III]
2. Gilo NB, Amini D, Landy HJ. Appendicitis and cholecystitis in pregnancy.
Clin Obstet Gynecol 2009;52(4):586–596. [III]
3. Paumgartner G, Greenberger, NJ, Diseases of the gallbladder and bile
ducts. Harrison’s Principles of Internal Medicine. Vol. 15th ed. 2001,
New York:McGraw-Hill. [III]
4. Swisher SG, et al. Biliary disease during pregnancy. Am J Surg
1994;168(6):576–579;discussion 580-1. [II-3]
5. Ellington SR, et al. Recent trends in hepatic diseases during pregnancy
in the United States, 2002-2010. Am J Obstet Gynecol 2015;212(4):
524 e1–527. [II-3]
6. Ko CW., et al. Physical activity, maternal metabolic measures, and the inci-
dence of gallbladder sludge or stones during pregnancy: a randomized trial.
Am J Perinatol 2014;31(1):39–48. [I]
7. Everson GT. Gastrointestinal motility in pregnancy. Gastroenterol Clin
North Am 1992;21(4):751–776. [III]
8. Thijs C, Knipschild P, Leffers P. Pregnancy and gallstone disease: an
empiric demonstration of the importance of specification of risk periods.
Am J Epidemiol 1991;134(2):186–195. [II-2]
9. Maringhini A, et al. Sludge and stones in gallbladder after pregnancy.
Prevalence and risk factors. J Hepatol 1987;5(2):218–223. [II-3]
10. Tsimoyiannis EC., et al. Cholelithiasis during pregnancy and lactation.
Prospective study. Eur J Surg 1994;160(11):627–631. [II-3]
11. Ko CW, et al. Incidence, natural history, and risk factors for biliary sludge
and stones during pregnancy. Hepatology 2005;41(2):359–365. [II-3]
12. Basso L, et al. A study of cholelithiasis during pregnancy and its relation-
ship with age, parity, menarche, breast-feeding, dysmenorrhea, oral con-
traception and a maternal history of cholelithiasis. Surg Gynecol Obstet
1992;175(1):41–46. [II-2]
13. Valdivieso V, et al. Pregnancy and cholelithiasis: pathogenesis and natu-
ral course of gallstones diagnosed in early puerperium. Hepatology
1993;17(1):1–4. [II-3]
14. Jelin EB, et al. Management of biliary tract disease during pregnancy: A
decision analysis. Surg Endosc 2008;22(1):54–60. [II-3]
15. Barone JE, et al. Outcome study of cholecystectomy during pregnancy.
Am J Surg 1999;177(3):232–236. [II-3]
16. Othman MO, et al. Conservative management of cholelithiasis and its
complications in pregnancy is associated with recurrent symptoms and
more emergency department visits. Gastrointest Endosc 2012;76(3):
564–569. [II-2]
17. Jorge AM, et al. Non-operative management of symptomatic cholelithiasis
in pregnancy is associated with frequent hospitalizations. J Gastrointest
Surg 2015;19(4):598–603. [II-3]
18. Veerappan A, et al. Delaying cholecystectomy for complicated gallstone
disease in pregnancy is associated with recurrent postpartum symptoms.
J Gastrointest Surg 2013;17(11):1953–1959. [II-3].
135
19. Shea JA, et al. Revised estimates of diagnostic test sensitivity and speci-
ficity in suspected biliary tract disease. Arch Intern Med 1994;154(22):
2573–2581. [II-3]
20. Dhupar R, Smaldone GM, Hamad GG, Is there a benefit to delaying cho-
lecystectomy for symptomatic gallbladder disease during pregnancy? Surg
Endosc 2010;24(1):108–112. [II-3]
21. Yokoe M, et al. Tokyo Guidelines 2018: diagnostic criteria and severity
grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci
2018;25(1):41–54. [III]
22. Dietrich CS, 3rd, Hill CC, Hueman M. Surgical diseases presenting in preg-
nancy. Surg Clin North Am 2008;88(2):403–419, vii-viii. [III]
23. Indar AA, Beckingham IJ. Acute cholecystitis. BMJ 2002;325(7365):
639–643. [III]
24. Rios-Diaz AJ, et al. Is it safe to manage acute cholecystitis nonoperatively
during pregnancy?: A nationwide analysis of morbidity according to man-
agement strategy. Annals of Surgery 2020;272(3):449–456. [II-2]
25. Baron TH, Grimm IS, Swanstrom LL. Interventional approaches to gall-
bladder disease. N Engl J Med 2015;373(4):357–365. [III]
26. Athwal R., et al. Surgery for gallstone disease during pregnancy does not
increase fetal or maternal mortality: a meta-analysis. Hepatobiliary Surg
Nutr 2016;5(1):53–57. [I]
27. Date RS, Kaushal M, Ramesh A, A review of the management of gall-
stone disease and its complications in pregnancy. Am J Surg 2008;196(4):
599–608. [III]
28. Pearl JPet al. Guidelines for the use of laparoscopy during pregnancy.
Society of American Gastrointestinal and Endoscopic Surgeons. 2017 [cited
2020. October 8]; Available from: https://www.sages.org/publications/
guidelines/guidelines-for-diagnosis-treatment-and-use-of-laparoscopy-
for-surgical-problems-during-pregnancy/. [III]
29. Yumi H. Guidelines for diagnosis, treatment, and use of laparoscopy for sur-
gical problems during pregnancy. This statement was reviewed and approved
by the Board of Governors of the Society of American Gastrointestinal and
Endoscopic Surgeons (SAGES), September 2007. It was prepared by the
SAGES Guidelines Committee. Surg Endosc 2008;22(4):849–861. [III]
30. Cheng V, et al. Surgical trends in the management of acute cholecystitis
during pregnancy. Surg Endosc 2020:1–8 [II-2]
31. ACOG Committee Opinion No. 775: Nonobstetric Surgery During
Pregnancy. Obstet Gynecol 2019;133(4):e285–e286. [III]
32. Allmendinger N, et al. Percutaneous cholecystostomy treatment of
acute cholecystitis in pregnancy. Obstet Gynecol 1995;86(4 Pt 2):
653–654. [III]
33. Chiappetta Porras LT, et al. Minimally invasive management of acute bili-
ary tract disease during pregnancy. HPB Surg 2009;2009:829020. [III]
34. Caliskan K. The use of percutaneous cholecystostomy in the treat-
ment of acute cholecystitis during pregnancy. Clin Exp Obstet Gynecol
2017;44(1):11–13. [II-3]
35. Sethi, S, Thosani N, Banerjee S. Radiation-free ERCP in pregnancy: A
“sound” approach to leaving no stone unturned. Dig Dis Sci 2015;60(9):
2604–2607. [III]
36. Petrov MS, Savides TJ. Systematic review of endoscopic ultrasonography
versus endoscopic retrograde cholangiopancreatography for suspected
choledocholithiasis. Br J Surg 2009;96(9):967–974. [III]
37. Freitas ML, Bell RL, Duffy AJ. Choledocholithiasis: evolving standards for
diagnosis and management. World J Gastroenterol 2006;12(20):3162–3167.
[III]
38. Kaltenthaler EC, et al. MRCP compared to diagnostic ERCP for diagno-
sis when biliary obstruction is suspected: a systematic review. BMC Med
Imaging 2006;6:9. [I]
39. ACOG Committee Opinion. Number 299, September 2004 (replaces No.
158, September 1995). Guidelines for diagnostic imaging during pregnancy.
Obstet Gynecol 2004;104(3):647–651. [III]
40. Kanal E, et al. American College of Radiology White Paper on MR
Safety: 2004 update and revisions. AJR Am J Roentgenol 2004;182(5):
1111–1114. [III]
41. Azab M, et al. Safety of endoscopic retrograde cholangiopancreatogra-
phy (ERCP) in pregnancy: A systematic review and meta-analysis. Saudi J
Gastroenterol 2019;25(6):341–354. [II-2]
42. Chong VH, Jalihal A. Endoscopic management of biliary disorders during
pregnancy. Hepatobiliary Pancreat Dis Int 2010;9(2):180–185. [II-3]
43. Al-Hashem H, et al. Biliary disease in pregnancy with an emphasis on the
role of ERCP. J Clin Gastroenterol 2009;43(1):58–62. [III]
44. Gupta R., et al. Safety of therapeutic ERCP in pregnancy - an Indian experi-
ence. Indian J Gastroenterol 2005;24(4):161–163. [II-3]
45. Jamidar PA., et al. Endoscopic retrograde cholangiopancreatography in
pregnancy. Am J Gastroenterol 1995;90(8):1263–1267. [II-3]
136
46. Tham TC, et al. Safety of ERCP during pregnancy. Am J Gastroenterol
2003;98(2):308–311. [II-3]
47. Tang SJ, et al. Safety and utility of ERCP during pregnancy. Gastrointest
Endosc 2009;69(3 Pt 1):453–461. [II-3]
48. Kahaleh M, et al. Safety and efficacy of ERCP in pregnancy. Gastrointest
Endosc 2004;60(2):287–292. [II-3]
49. Friedel D, et al. Gastrointestinal endoscopy in the pregnant woman. World
J Gastrointest Endosc 2014;6(5):156–167. [III]
50. Inamdar S, et al. Pregnancy is a risk factor for pancreatitis after endoscopic
retrograde cholangiopancreatography in a national cohort study. Clin
Gastroenterol Hepatol 2016;14(1):107–114. [II-2]
51. Arce-Lievano E., et al. Endoscopic retrograde cholangiopancreatography
results for the treatment of symptomatic choledocholithiasis in pregnant
patients: A recent experience at a secondary care hospital in Mexico City.
Rev Gastroenterol Mex 2021;86:21–27. [II-2]
52. Cappell MS, Stavropoulos SN, Friedel D. Systematic review of safety and
efficacy of therapeutic endoscopic-retrograde-cholangiopancreatography
during pregnancy including studies of radiation-free therapeutic endo-
scopic-retrograde-cholangiopancreatography. World J Gastrointest Endosc
2018;10(10):308–321. [III]
53. Smith I, et al. Safety of endoscopic retrograde cholangiopancreatogra-
phy in pregnancy: Fluoroscopy time and fetal exposure, does it matter?
World J Gastrointest Endosc 2013;5(4):148–153. [III]
54. Wu W, et al. Non-radiation endoscopic retrograde cholangiopancrea-
tography in the management of choledocholithiasis during pregnancy.
Dig Endosc 2014;26(6):691–700. [III]
55. Uomo G., et al. Endoscopic treatment of acute biliary pancreatitis in preg-
nancy. J Clin Gastroenterol 1994;18(3):250–252. [II-3]
56. Simmons DC, et al. Endoscopic retrograde cholangiopancreatography
(ERCP) in pregnancy without the use of radiation. Am J Obstet Gynecol
2004;190(5):1467–1469. [II-3]
57. Ersoz G, et al. Nonradiation ERCP with endoscopic biliary sphincterotomy
plus papillary balloon dilation for the treatment of choledocholithiasis dur-
ing pregnancy. Surg Endosc 2016;30(1):222–228. [III]
58. Juo YY, et al. Cumulative financial burden of readmissions for biliary pan-
creatitis in pregnant women. Obstet Gynecol 2018;132(2):415–422. [II-2]
59. Eddy JJ, et al. Pancreatitis in pregnancy. Obstet Gynecol 2008;112(5):
1075–1081. [III]
60. Gonzalez-Gonzalez JA., et al. The impact of pregnancy on the outcome of
biliary acute pancreatitis. Rev Gastroenterol Mex 2020;85:416–420. [II-2]
61. Ducarme G, et al. Acute pancreatitis during pregnancy: a review. J Perinatol
2014;34(2):87–94. [III]
62. Freeman ML, et al. Interventions for necrotizing pancreatitis: sum-
mary of a multidisciplinary consensus conference. Pancreas 2012;41(8):
1176–1194. [III]
63. Mali P, Pancreatitis in pregnancy: etiology, diagnosis, treatment, and out-
comes. Hepatobiliary Pancreat Dis Int 2016;15(4):434–438. [II-2]
64. Yin BL, Fu XD. A clinical analysis of acute pancreatitis in pregnancy.
Hepatobiliary Pancreat Dis Int 2017;16(3):323–325. [III].
65. Luthra, AK, et al. Endoscopic intervention and cholecystectomy in preg-
nant women with acute biliary pancreatitis decrease early readmissions.
Gastrointest Endosc 2019;89(6):1169–1177 e10. [II-2]
Maternal-Fetal Evidence Based Guidelines
66. Lee SH, et al. Laparoscopic appendectomy versus open appendectomy for
suspected appendicitis during pregnancy: a systematic review and updated
meta-analysis. BMC Surg 2019;19(1):41. [I]
67. Miranda R, Johnston AD, O’Leary JP. Incidental appendectomy: frequency
of pathologic abnormalities. Am Surg 1980;46(6):355–357. [III]
68. Zingone F, et al. Risk of acute appendicitis in and around pregnancy: a
population-based cohort study from England. Ann Surg 2015;261(2):
332–337. [III]
69. Becker P, Fichtner-Feigl S, D Schilling Clinical management of appendicitis.
Visc Med 2018;34(6):453–458. [III]
70. Park SH, et al. Laparoscopic appendectomy performed during preg-
nancy by gynecological laparoscopists. Eur J Obstet Gynecol Reprod Biol
2010;148(1):44–48. [III]
71. Prodromidou A, et al. Outcomes after open and laparoscopic appendec-
tomy during pregnancy: A meta-analysis. Eur J Obstet Gynecol Reprod Biol
2018;225:40–50. [II-2].
72. Aguilera F, Gilchrist BF, Farkas DT. Accuracy of MRI in diagnosing appen-
dicitis during pregnancy. Am Surg 2018;84(8):1326–1328. [III]
73. Al-Katib S, Sokhandon F, Farah M. MRI for appendicitis in pregnancy: is
seeing believing? clinical outcomes in cases of appendix nonvisualization.
Abdom Radiol (NY) 2016;41(12):2455–2459. [II-2]
74. Burns M, et al. Utility of magnetic resonance imaging for the diagnosis of
appendicitis during pregnancy: A Canadian experience. Can Assoc Radiol J
2017;68(4):392–400. [II-2]
75. Donlon NE, et al. Should MRI be the imaging modality of choice in sus-
pected appendicitis during pregnancy? Ir Med J 2019;112(10):1018. [III]
76. Schwulst SJ, Son M. Diagnostic imaging in pregnant patients with sus-
pected appendicitis. JAMA 2019;322:455–456. [III]
77. Tankel J, et al. Delaying laparoscopic surgery in pregnant patients with an
equivocal acute appendicitis: a step-wise approach does not affect maternal
or fetal safety. Surg Endosc 2019;33(9):2960–2966. [II-2]
78. Ball E, et al. Evidence-based guideline on laparoscopy in pregnancy:
Commissioned by the British Society for Gynaecological Endoscopy (BSGE)
endorsed by the Royal College of Obstetricians & Gynaecologists (RCOG).
Facts Views Vis Obgyn 2019;11(1):5–25. [III]
79. Frountzas M, et al. Is the laparoscopic approach a safe choice for the man-
agement of acute appendicitis in pregnant women? A meta-analysis of
observational studies. Ann R Coll Surg Engl 2019;101(4):235–248. [I]
80. Cox TC, et al. Laparoscopic appendectomy and cholecystectomy versus open:
a study in 1999 pregnant patients. Surg Endosc 2016;30(2):593–602. [II-2]
81. Oliak D, et al. Initial nonoperative management for periappendiceal
abscess. Dis Colon Rectum 2001;44(7):936–941. [II-2]
82. Dong Y., et al. [Meta-analysis of laparoscopic surgery versus conservative
treatment for appendiceal abscess]. Zhonghua Wei Chang Wai Ke Za Zhi
2018 December 1;21(12):1433–1438. [II-2]
83. Kristo G, Itani KMF. Settling the controversy-appendectomy as the crite-
rion for appendicitis diagnosis. JAMA Surg 2019;154(3):207–208. [III]
84. Winter, R, Norgard BM, Friedman S. Treatment of the pregnant patient with
inflammatory bowel disease. Inflamm Bowel Dis 2016;22(3):733–744. [III]
85. Killeen S, Gunn J, Hartley, J. Surgical management of complicated and med-
ically refractory inflammatory bowel disease during pregnancy. Colorectal
Dis 2017;19(2):123–138. [III]
13
PREGNANCY AFTER LIVER AND OTHER TRANSPLANTATION
Guillermo Gurza and Adam Bodzin
Key points
• The best outcomes in pregnancy after liver transplant
occur in patients with:
• Good general health ≥1 year since transplant
• Minimal or no proteinuria (<1 gram/24 hour)
• Creatinine <1.5 mg/dL
• Well-controlled or no hypertension
• No evidence of recent graft rejection
• Stable immunosuppressive regimen and liver function
• Potential maternal and fetal complications include pre-
term birth, pre-eclampsia, fetal growth restriction, and
low birth-weight.
• Pregnancy in and of itself does not affect previously stable
hepatic allograft function.
• The effect of comorbid conditions (i.e., diabetes, hyper-
tension) should be considered and their management
optimized.
• Transplant recipients should have their baseline kidney
function (creatinine, 24-hour urine collection for total
protein) assessed.
• Maintenance of current immunosuppression in pregnancy
is usually recommended, except for mycophenolic acid
products, for which fetal risks should be discussed and
alternatives sought.
• Summary of management options in Table 13.4.
Pregnancy after liver transplantation
Introduction and historic notes
Since the first human liver transplant performed in 1963 by Thomas
Starzl (University of Colorado) [1], many advances in surgical tech-
niques and immunosuppressive therapy have helped to increase
the number of women who undergo allogenic organ transplanta-
tion each year. In 1978, Walcott [2] documented the first known
pregnancy in a liver transplant recipient, which resulted in a suc-
cessful delivery with both mother and infant in excellent health.
Many times, a transplanted organ normalizes a woman’s hormonal
imbalance and restores fertility, thus offering the prospect of preg-
nancy and providing many women with end-stage organ disease
a chance to conceive and bear children. As a result, among trans-
plant recipients, a higher survival rate and a return to a good qual-
ity of life have been achieved. In 1991, the National Transplantation
Pregnancy Registry (NTPR) was established at Thomas Jefferson
University in Philadelphia, Pennsylvania, to analyze pregnancy
outcomes in solid-organ transplant recipients [3].
Definition/Symptoms and signs
of end-stage liver disease
End-stage liver disease (ESLD): Any hepatic disease that jeop-
ardizes the survival or that seriously modifies the quality of life of
the patient, and for which the transplant is the only therapy, since
no other therapy exists to provide a chance of recovery.
DOI: 10.1201/9781003099062-13
Liver transplantation (LTx): Treatment of choice for all non-
neoplastic end-stage liver diseases and for selected patients with
non-resectable hepatobiliary malignancies.
Before undergoing LTx, some patients remain in robust clini-
cal condition with compensated liver disease with hepatocellular
carcinoma (HCC). There may be individual variations in terms of
hospital care requirements including those in multi-system organ
failure with intensive care needs. As the liver disease progresses,
symptoms such as encephalopathy, weakness, lethargy, and mal-
nutrition become more frequent. Additionally, intractable asci-
tes, GI bleeding, peripheral edema, anorexia, jaundice, pruritus
and cholestasis, bacterial peritonitis, and other infections may
also develop.
Indications
Non-alcoholic steatohepatitis is the leading cause of LTx in
women across different ethnic groups, followed by alcoholic liver
disease and chronic hepatitis C virus infection [4]. In women of
childbearing age, autoimmune hepatitis appears to be the leading
cause of LTx, with drug-induced liver failure also being a com-
mon etiology in women of such age group [5].
Epidemiology
Approximately 35.5% of patients who undergo LTx are women,
and about 75% of female recipients are of reproductive age [4, 6].
The incidence indicates that more than 14,000 women of repro-
ductive age are living in the United States after liver transplanta-
tion (LTx), and another 500 undergo LT each year [5, 7].
Pathophysiology
Women with decompensated liver disease commonly have men-
strual dysfunction: Infertility is common in women with ESLD
because of hypothalamic-pituitary-gonadal dysfunction which
decreases ovulation [8–10] and affects up to 50% of these patients.
In fact, menstrual abnormalities may be the first signs of liver dis-
ease in females with unknown liver disease. In the cirrhotic state,
hypothalamic-pituitary dysfunction is associated with inad-
equate response to the gonadotropin-releasing hormone agonists
and clomiphene citrates as well as diminished gonadotrophin
release relative to the reduced levels of circulating sex steroids
[10]. Furthermore, serum levels of estradiol and testosterone are
increased in patients with porto-systemic shunts. Thus, preg-
nancy in decompensated cirrhosis is very uncommon. A suc-
cessful transplant almost uniformly leads to a prompt return
to normal menstrual cycles and to reproductive functions
because of the recovery of the gonadotrophic function [10–13]. In
70–95% of LTx recipients, normalization of the menstrual cycle
occurs during the first year after transplant with some reports
of menstruation after the first month of transplantation [14–17].
This is an important component of the restoration of normality
of life for patients of childbearing age, and is demonstrated by the
increasing number of post-transplantation pregnancies reported
worldwide [12–30].
137
138 Maternal-Fetal Evidence Based Guidelines

Preconception counseling and timing of pregnancy
Pregnancy after liver transplant should be considered as a
high-risk pregnancy and monitored closely by a team of trans-
plant hepatologists and experts in obstetrics and maternal-fetal
medicine. Female liver transplant recipients who are planning to
become pregnant should be counseled on contraception and
optimal timing of pregnancy, proper vaccinations, and risks
associated with immunosuppressive therapy.
For this reason, an appropriate contraceptive plan should be
recommended. Oral contraceptives are relatively contraindi-
cated in women with liver transplant because of many theoretical
complications such as the risk of thromboembolism, cholesta-
sis, exacerbated hypertension, and interference in cyclosporine
metabolism [9]. Regarding use of intrauterine devices, there is no
increased risk for infection, specifically pelvic inflammatory dis-
ease, in immunocompromised patients compared to the general
population [31–34]; therefore, the use of IUD should be recom-
mended among transplant patients.
Many medications used for post-transplant immunosuppres-
sion have potential effects during pregnancy and breastfeeding.
The risks and benefits of each medication should be reviewed
with patients contemplating pregnancy, and regimens should
be tailored accordingly (see later in this chapter).
Ideally, patients should be vaccinated prior to transplan-
tation against influenza, pneumococcus, hepatitis B, and
tetanus. Alternatively, they should be vaccinated pre-pregnancy.
Immunity to rubella is especially important in female transplant
recipients of childbearing age because of the risks for congenital
rubella syndrome if these patients contract rubella while preg-
nant [35].
The optimal timing of conception post-transplant is controver-
sial, but current recommendations suggest waiting for at least
1 year after transplantation based on rejection risks, and to
allow stabilization of allograft function and immunosuppressive
regimen [9, 10, 26]. Of note, the shortest interval from (ortho-
topic liver transplantation) OLTx to conception reported in the
literature is 3 weeks [30]. Immunosuppressive agents are usu-
ally minimalized at one-year post liver transplantation and risk
of allograft rejection is lower at that time. Furthermore, renal
and liver functions tend to stabilize during that period making
it ideal to delay pregnancy until the patient is on a maintenance
immunosuppression 1–2 years after transplantation to minimize
fetal exposure to high doses of immunosuppressants. When
choosing the timing of pregnancy after OLTx, several factors
should be considered:
a. Good general health ≥1 year since transplant
• Risk of acute graft rejection
• Risk of acute infection that might impact the fetus
(cytomegalovirus [CMV] acute infection is most com-
mon within 6–12 months post-transplant)
b. Proteinuria and creatinine level
• None or minimal proteinuria (<1 g/24 hour)
• Serum creatinine <1.5 mg/dL
c. Rejection and immunosuppression
• No evidence of recent graft rejection (in the past year)
• Stable immunosuppression regimen (stable dosing)
d. Stable liver function
e. Maternal age
f. Medical compliance
Comorbidity and risk factors
The outcome in liver transplant recipients from selected publi-
cations is shown in Table 13.1. The main comorbidity, risk fac-
tors about patient, graft and fetus complications described in the
English literature are also described later in this chapter.
Hepatitis virus reactivation
Even if autoimmune hepatitis is the most frequent reason for
transplantation among young female recipients who may become
pregnant after transplant, a reactivation of viral hepatitis is con-
sidered one of the most serious risks for both mother and child.
For hepatitis B, for example, vertical transmission is reported
between 10–20% of HBsAg-positive (HBeAg-negative) non-­
transplant mothers without immunoprophylaxis. It is rec-
ommended to vaccinate and give IVIG to all newborns born
to HBsAg-positive women within 12 hours of birth, as the
hepatitis B virus (HBV) neonatal infection risks with these
interventions decreases to less than 10% (see Chap. 32) [36].
The rate of maternal-fetal HCV transmission in OLTx recipients
is still unclear, requiring additional analysis. In HIV-negative women
with chronic HCV infection, the risk of vertical transmission was
5.8%. On the other hand, the risk of vertical transmission in HIV-
positive women was 10.8% [37]. A well-documented risk factor for
HCV vertical transmission is a high maternal viral load. Therefore,
special attention should be given to patients with high viral load
post-transplant (see Chap. 33). The paradigm of HCV infection is

TABLE 13.1: Fetal and Maternal Outcomes in Liver Transplant Recipients from Selected Studies
No. of Live Birth Spontaneous Graft Cesarean Birth Weight Maternal Neonatal
Author Pregnancies Rate (%) Abortions (%) Preterm (%) Dysfunction (%) Rate (%) <2500 g (%) Deaths (%) Deaths (%)
Alvaro E 30 66.6 26.6 NA 10 42 NA 0 6
Armenti VT 205 73 19 35 7 35 34 0 0
Dashpande NA 450 76.9 6.2 39.4 NA 44.6 NA NA NA
Christopher V 71 71 19 NA 17 40 20 4 NA
Coffin CS 20 70 5 27 5 38 NA 0 6
Dei Malatesta MF 285 78 NA 31 10 43 23 4 4
Jabiry- Zieniewicz Z 39 100 0 31 8 80 20 0 0
Jain AB 49 100 0 4 25 47 9 10 6
Nagy S 38 63 NA 29 17 46 17 17 0
Sibanda N 16 69 13 50 NA 62 57 NA NA
Total 1203 76.7 7.95 30.8 12.37 47.76 25.7 4.3 3.1
Source: Adapted from Ref. [14].
Pregnancy after Liver and Other Transplantation
changing, however, making it less common given the introduction of
direct-acting antiviral therapies to the liver community.
Hypertension and renal insufficiency
Immunosuppressive regimens using calcineurin inhibitors
(cyclosporine and tacrolimus) are most common and have an
association with an increased incidence of hypertension and renal
insufficiency in post-transplantation. The pathogenesis is related
to endothelial cell dysfunction and decrease endogenous nitric
oxide production, causing renal dysfunction and hypertension;
the side effect for the post-LTx pregnant women is an increased
incidence of pre-eclampsia [8, 27]. The same treatment with cal-
cium channel blockers used in the non-transplant population is
recommended [38].
Diabetes
The estimated incidence rates at 12 months post-transplant are
2–52% for kidney transplants, 9–21% for liver transplants, and
approximately 20% for lung transplants [39]. The annual report
published by NTPR in 2017, reported an incidence of 8% among
LTx recipients [3]. Immunosuppressive therapies play an impor-
tant role depending on the regimen of choice. Most agree that
there is a benefit to limit steroid use if possible and to reduce
calcineurin inhibitors to the minimum dose necessary. The
management of new onset diabetes mellitus (NODM) is essen-
tially similar to that of diabetes in the non-transplant popula-
tion. NODM is associated with obesity, insulin resistance, insulin
secretory defect, and subsequent development of type 2 diabetes
in the offspring. Modern treatment protocols during pregnancy
include strict glycemic control by a combination of diet and
medications (Chapters 4 and 5). Traditionally, insulin therapy has
been considered the gold standard for management of diabetes,
because of its efficacy in achieving better glucose control and the
fact that it does not cross the placenta [40].
Cytomegalovirus acute infection
Cytomegalovirus (CMV) infection represents a serious viral
infection often occurring within 6–12 months post-transplant.
Unfortunately, it is deleterious in early pregnancy given its cau-
sality of congenital malformation (microcephaly, cerebral palsy,
sensorineural deafness) or congenital liver disease with an inci-
dence of 10–15% of infected pregnancies. It is advisable to screen
all transplant recipients with CMV IgG and IgM. If IgM posi-
tive, avidity testing should be performed (Chapter 49). The use
of antiviral agents in the management of CMV infection during
pregnancy remains controversial (Chapter 49) [10].
Acute cellular rejection
Acute cellular rejection (ACR) rate in the post-LTx pregnancies is
reported between 2% and 15% [3, 10, 29, 41] and occurs during
the earlier phases of pregnancy. Immunosuppression should
be maintained and monitored during pregnancy by serum
levels, as a reduction or discontinuation may lead to rejection
of the transplanted organ. When acute rejection is suspected,
a liver allograft biopsy is strongly recommended and should
follow a duplex ultrasound of the graft to exclude an anatomic
source of graft dysfunction [42]. The ACR treatment includes
adjustment of immunosuppressive medications, use of high dose
steroids, and consideration of thymoglobulin in the setting of
steroid-resistant rejection. Patients that present with ACR, are
more likely to experience poorer pregnancy outcomes; therefore,
they should be advised to delay pregnancy until graft and immu-
nosuppression are minimalized and stable [17].
139
Infra-renal aortic graft
One death due to aortic graft clotting by external compression
from the gravid uterus has been reported [38]. For this reason,
patients with infra-renal aortic graft should be monitored with
duplex ultrasonography during pregnancy.
Infections
Even though the rate of infections appears to be similar in the
transplant population compared to the general population, a
recent study reported an increase in the rate of genitourinary
tract infections (5.3% vs. 1.4%, respectively) [43].
Anemia
Anemia is one of the most common complications in LTx recipi-
ents. Pregnancy physiologic changes, state of immunosuppres-
sion, and iron deficiency are responsible for this association. A
population-based study showed an anemia rate of 23% in trans-
plant patients, compared to 9.5% in non-transplant patients [43].
Pregnancy complications (Table 13.1)
Preterm birth and low birth weight
The risk of prematurity is up to 50% and mean gestational age
ranges between 36 and 37 weeks [3, 6, 7, 26]. The risk of prematu-
rity in KTx recipients is 51%, and 39% in OLTx patients with low
birth weight present in 41% and 30% in kidney and liver trans-
plant patients, respectively [3].
Intrauterine growth restriction
In a recent study, the incidence of intrauterine growth restriction
(IUGR) was found to be 31.3% and 19.2% in RTx and LTx recipi-
ents, respectively [44].
Pre-eclampsia
The incidence of hypertension and pre-eclampsia is approxi-
mately 20% in OLTx recipients and seems to occur mainly in
patients taking cyclosporine, probably because of the related
endothelial cell dysfunction, and less commonly with tacroli-
mus [3, 6–8, 29, 38]. As seen in Table 13.5, the incidence of pre-
eclampsia in LTx recipients is approximately 24%, whereas in KTx
recipients is close to 31% [3]. The management of pre-eclampsia is
the same as in the non-transplant population (Chapter 1).
Abnormal blood chemistry and liver function tests
In most series, pruritus and cholestasis seem to be the most fre-
quent symptoms described in pregnancies after LTx. Differential
diagnosis including ACR as well as bile duct obstruction should
be considered in all cases. HELLP syndrome and anemia have
been reported [5, 7].
Immunosuppression therapy:
Drugs and their side effects
There is no consensus on the optimal maintenance regimen for
transplant pregnant recipients; however, the fact remains is some
immunosuppression is unavoidable. All immunosuppressive
medications cross the placenta and enter into fetal circulation
and could potentially have effects in utero. Despite the fact that
immunosuppressive agents such as azathioprine, cyclosporine, and
mycophenolic acid were teratogenic in animals, the risk of birth
defects was not statistically different between those who received
immunosuppressive medications and those who did not. Patients
treated with calcineurin inhibitors (cyclosporine or tacrolimus)
should continue to have serial blood tests in pregnancy to fol-
low medication levels while assessing hepatic and renal function
140
TABLE 13.2: Historic FDA Classification of Risk of Immuno­
suppressive Drug in Pregnancy
Drugs Pregnancy Category
Corticosteroids B
Cyclosporin C
Sirolimus C
Tacrolimus C
Azathioprine D
Mycophenolate mofetil D
and avoiding unnecessary toxicity. Azathioprine has been asso-
ciated with lymphopenia, hypogammaglobulinemia and thymic
hypoplasia in children. Nevertheless, these complications tend to
regress shortly after birth [17]. Cyclosporine use has a moderate
risk of IUGR [17, 45]. Recent studies have reported an association
between administration of mycophenolic acid products (MPA)
(myco-phenolate mofetil [MMF] and enteric-coated myco-
pheno-late sodium [EC-MPS]) and increased risk of adverse out-
comes in pregnancy including a specific pattern of birth defects. In
2007, the package inserts of MMF and EC-MPS included a change
from pregnancy category C to category D [46–49]. The warning
states that females of potential childbearing should use contracep-
tion while taking MPA since its use during pregnancy is associated
with increased rates of pregnancy loss and congenital malforma-
tions. Patients should ideally use two methods of contraception
for at least 4 weeks before initiating MMF, during treatment and
for 12 weeks after discontinuation [17]. Pregnancy outcomes with
exposure to sirolimus, an m-TOR inhibitor, remain limited with
three liver recipients with three pregnancies (two live births, one
spontaneous abortion) reported to the NTPR [3].
Belatacept is an immunosuppressant agent that works as a selec-
tive T-cell co-stimulator blocker. It was approved for use in kidney
transplant recipients in 2011. The Food and Drug Administration
(FDA) has not approved its use during pregnancy [50]; however, case
reports of uncomplicated pregnancies in KTx recipients have been
published since it was first used in two pregnant patients in 2018 [51].
Again in 2020, a successful pregnancy was reported in a woman with
two previous LTx in the setting of belatacept use [52].
The FDA classification of risk medication and their categories
in pregnancy is reported in Table 13.2. Selected immunosuppres-
sive drugs and their side effects are reported in Table 13.3.
Workup and management
A summary of the suggested key points is in Table 13.4.
TABLE 13.3: Selected Immunosuppressive Agents and Their
Side Effects
Immunosuppressant Side Effect
Prednisone a Glucose intolerance
Azathioprinea Leukopenia
Cyclosporinea,b Hypertension, nephrotoxicity
Tacrolimusa,b Hypertension, nephrotoxicity, neurotoxicity,
glucose intolerance, myocardial hypertrophy
Mycophenolate mofetil GI disturbance
Sirolimusa,b Leukopenia, thrombocytopenia, hyperlipidemia
Abbreviation: GI, gastrointestinal.
a There have been no known teratogenic effects.
b Follow with blood levels.
Maternal-Fetal Evidence Based Guidelines
TABLE 13.4: Pregnancy after Liver Transplantation: Man­
agement Options
Pre-pregnancy
• Patients should defer conception for at least 1 year after
transplantation, with adequate contraception
• Assessment of graft function (organ specific):
• Recent liver biopsy
• Proteinuria (24-hour collection for total protein)
• Hepatitis B and C status (HBsAg; Hep. C antibody)
• CMV, toxoplasmosis, herpes simplex status (IgG, IgM)
• Maintenance immunosuppression options:
• Azathioprine
• Cyclosporine
• Tacrolimus
• Corticosteroids
• Mycophenolate mofetil (avoid as feasible)
• Enteric-coated mycophenolate sodium (avoid as feasible)
• Sirolimus
• The effect of comorbid conditions (i.e., diabetes, hypertension)
should be considered and their management optimized
• Vaccinations should be given if needed (i.e., rubella, etc.) (see
Chap. 40)
• Explore etiology of original disease
• Discuss genetic issues, if relevant
• Discuss the effect of pregnancy on renal allograft function
• Discuss the risks of intrauterine growth restriction, preterm birth,
low birth weight, etc.
Prenatal
• Pregnancy in and of itself does not affect previously stable allograft
function
• Accurate early diagnosis and dating of pregnancy
• Baseline laboratory tests should include:
a. Liver enzymes (ALT and AST)
b. Creatinine and bilirubin
c. Immunosuppression medication (e.g., cyclosporine or tacrolimus)
level
d. 24-hour urinary protein and creatinine clearance
e. Urine analysis and urine culture
f. CMV, HSV, and Toxoplasma IgM and IgG
g. HBsAg, HBsAb, HepCAb
Timing of repeat laboratory testing of at least tests (a–e) should be once
every trimester until 32 weeks.
• Fetal surveillance
• Monitor for hypertension and nephropathy
• Careful surveillance for pre-eclampsia
• Early screening for gestational diabetes
Labor and Delivery
• Vaginal delivery is optimal; cesarean delivery for obstetric
reasons
Postnatal
• Monitor immunosuppressive drug levels for at least 1 month
postpartum, especially if dosages increased during pregnancy
• Surveillance for rejection with biopsy if it is suspected
• Breastfeeding discussion
• Contraception counseling
Pregnancy after Liver and Other Transplantation 141

In case of elevations of liver function tests and/or bilirubin, an
ACR should be ruled out. Evaluation of rejection includes liver
ultrasound with Doppler to exclude anatomic sources of graft
dysfunction. Liver biopsy to diagnose rejection is not contra-
indicated in pregnancy. Because of an increased risk of carbo-
hydrate intolerance caused by the administration of prednisone
or tacrolimus, patients should be screened with glucose toler-
ance tests in the first trimester, followed by routine screening
between 24 and 28 weeks.
Antepartum testing
A dating ultrasound should be performed in the first trimes-
ter. Ultrasound study should be performed every trimester, with
detailed fetus anatomy in the second trimester and serial assess-
ment of fetal growth in the third trimester [3, 19, 25, 53]. Weekly
nonstress tests can begin at 32 weeks, unless medical or obstetric
complications indicate earlier testing.
Labor and delivery issues
Patients who have received steroids during the antepartum period
in the equivalent of more than 20 mg of prednisone for more than
3 weeks should receive “stress dose” steroids (i.e., hydrocortisone
100 mg IV every 8 hours × 24 hours). Vaginal delivery at term is
the preferred method of delivery, and cesarean delivery should be
performed only for obstetric indications [3].
Breastfeeding
Data collected from the NTPR [3] indicated no adverse
outcomes in infants who were breastfed during maternal
cyclosporine use. Azathioprine seems also to be safe with
breastfeeding. Nevertheless, mothers may be discouraged to
breastfeed in the first few months post-transplantation when
immunosuppressive therapy is at high serum levels. The
American Academy of Pediatrics advises that breastfeeding
mothers can use prednisone and other glucocorticoids safely.
In a study where whole blood tacrolimus concentration was
measured in ­ neonates, the tacrolimus concentration was
undetectable [54], thus ­m aternal tacrolimus therapy may be
compatible with breast feeding [55].
Pregnancy after other transplantations
For pregnancy after renal transplantation, please see Chap. 17.
Table 13.5 shows pregnancy outcomes in kidney, kidney/pan-
creas, liver, heart, lung recipients for comparison [3]. Female
heart transplant recipients are able to maintain pregnancy with

TABLE 13.5: Pregnancy Outcomes among Solid-Organ Transplant Recipients

Kidney–
Kidney Liver Pancreas Heart Lung
Female recipients 1100 281
63 92 33
Mean age at first transplant (years) 24 ± 6.3 21 ± 9
30 ± 3.4 20 ± 8.8 27 ± 6.5
Mean transplant-conception interval (years) 5.4 ± 4.3 8.1 ± 6.9
4.2 ± 3.2 7.5 ± 5.9 3.9 ± 3
During Pregnancy
Primary immunosuppressant CsA Tac Other CsA Tac Other CsA Tac Other CsA Tac Other CsA Tac Other
45% 31% 24% 37% 60% 3% 41% 59% <1% 47% 53% 0% 23% 77% 0%
Hypertension treated 48% 22% 57% 46% 52%
Diabetes treated 8% 8% 4% 9% 34%
Pre-eclampsia 31% 24% 42% 27% 15%
Rejection 1% 4.50% 5% 9% 16%
After Pregnancy
Postpartum rejection 1.30% 5.00% 4.40% 7% 14.00%
Graft loss within 2 years of pregnancy outcome 5.6% (111 losses) 3% (17 losses) 11% (12 losses) 2% (3 losses) 7% (3 losses)
OUTCOMES 2062 579 12 165 46
Live births 75% 69% 69% 67% 59%
Neonatal deaths 1.40% 1.00% 1.00% 0 11%
Miscarriages 18% 23% 26% 26% 28%
Stillbirths 2% 1% 0% 1% 0%
Ectopic pregnancies 1% 1% 2% 1% 2%
LIVE BIRTHS 1515 402 83 111 27
Mean gestational age (weeks) 35.9 ± 3.4 36.6 ± 3.4 34.2 ± 3.1 36.3 ± 3.4 34.3 ± 5
Premature (<37 weeks) 51% 39% 76% 41% 56%
Early preterm (<34 weeks) 21% 15% 42% 18% 30%
Mean birth-weight (g) 2571 ± 762 2733 ± 792 2130 ± 724 2600 ± 688 2185 ± 850
Low (<2500 g) 41% 30% 63% 37% 59%
Very low (<1500 g) 10% 9% 20% 8% 19%
Cesarean section 52% 43% 69% 42% 41%
Birth defects 4.50% 4.60% 1.30% 8% 3.90%
Adequate graft function at last follow-up 68% 82% 47% 64% 70%
Source: Adapted from Ref. [3].
Abbreviations: Cyclosporine or its modified form (CsA); tacrolimus (Tac); sirolimus, everolimus, mycophenolic acid products, or belatacept (Other).
142
the majority resulting in a live birth. Of note, not all heart rejec-
tions are treated as some are low- grade. Maternal survival, inde-
pendent of pregnancy related events, should be considered as part
of pre-pregnancy planning.
By comparison, lung recipients have a higher incidence of more
significant rejection as well as graft loss in the peripartum period
with smaller newborn. Successful pregnancy is possible post-lung
transplantation; however, analyses of a larger number of cases
may help to identify trends in pregnancy after lung transplanta-
tion. Whether long-term maternal survival is impacted by preg-
nancy warrants further study.
Intestinal transplantation has shown steady improvements
in graft and patient survival over the past 20 years and is rapidly
becoming more established worldwide [35, 56]. The first preg-
nancy after intestinal transplant was described in 2006 [36, 57],
followed later by other reports [58–61] with 100% success rate.
Specifically to this procedure, there are two factors affecting the
transplant to be considered in case of pregnancy: Higher need
of immunosuppressants and absorptive function of transplanted
bowel. Close monitoring of renal function and of the graft by
endoscopies with biopsies must be performed during the preg-
nancy in order to prevent episodes of rejection or enteritis, pre-
serving the fetus by temporary malnutrition.
Uterine transplantation has become an available treatment for
women born with congenital uterine agenesis (Mayer-Rokitansky-
Küster-Hauser syndrome) and women with a non-functional
uterus. The first reported case of a successful pregnancy follow-
ing uterine transplantation was published in Sweden in 2013. The
uterine transplant recipient became pregnant 1 year after trans-
plantation by embryo transfer and delivered a healthy male baby.
Throughout her pregnancy she received tacrolimus, azathioprine
and corticosteroids [62]. In the United States, the first success-
ful pregnancy following uterus transplant was reported in 2018
where the patient was placed on tacrolimus and mycophenolic
acid that was later replaced with azathioprine. Successful embryo
transfer was performed at 6 months post-transplantation with
eventual delivery of a healthy male baby at 33 weeks of gestation
following a planned cesarean [63].
References
1. Starzl TE, Marchioro TL, Von Kaulla KN, et al. Homotransplantation of the
liver in humans. Surg Gynecol Obstet 1963;117:659–676. [III]
2. Walcott WO, Derick DE, Jolley JJ, et al. Successful pregnancy in a liver
transplant patient. Am J Obstet Gynecol 1978;132: 340–341. [III]
3. Coscia L, Daly T, Nathan H, Armenti D, Kliniewski D, Constantinescu S,
Moritz M. Transplant Pregnancy Registry International. Transplantation
2017 August 1;101:S64. [II-2]
4. Noureddin M, Vipani A, Bresee C, et al. NASH leading cause of liver trans-
plant in women: updated analysis of indications for liver transplant and eth-
nic and gender variances. Am J Gastroenterol 2018;113(11):1649–1659. [II-2]
5. Kamarajah SK, Arntdz K, Bundred J, Gunson B, Haydon G, Thompson F.
Outcomes of pregnancy in recipients of liver transplants. Clin Gastroenterol
Hepatol 2019;17(7):1398–1404.e1. [II-2]
6. Jabiry-Zieniewicz Z, Cyganek A, Luterek K, et al. Pregnancy and delivery
after liver transplantation. Transplant Proc 2005;37:1197–1200. [III]
7. Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes of liver
transplant recipients: a systematic review and meta-analysis. Liver Transp
2012;18:621–629. [II-3]
8. Nagy S, Bush MC, Berkowitz R, et al. Pregnancy outcome in liver transplant
recipients. Obstet Gynecol 2003;102(1):121–128. [II-2] [III]
9. McKay DB, Josephson MA, Armenti VT, et al. Reproduction and transplan-
tation: report on the AST Consensus Conference on Reproductive Issues
and Transplantation. Am J Transplant 2005;5:1592–1599. [III]
10. Armenti VT, Herrine SK, Radomski JS, et al. Pregnancy after liver trans-
plantation. Liver Transpl 2000;6:671–685. [III]
Maternal-Fetal Evidence Based Guidelines
11. Van Thiel DH, Lester R. The effect of chronic alcohol abuse on sexual func-
tion. Clin Endocrinol Metab 1979;8:499–510. [III]
12. Bonanno C, Dove L. Pregnancy after liver transplantation. Semin Perinatol
2007;31:348–353. [III]
13. Cundy TF, O’Grady JG, Williams R. Recovery of menstruation and preg-
nancy after liver transplantation. Gut 1990;31: 337–338. [III]
14. Jabiry-Zieniewicz Z, Kaminski P, Bobrowska K, Pietrzak B, Wielgos M,
Smoter P, Zieniewicz K, Krawczyk M. Menstrual function in female liver
transplant recipients of reproductive age. Transplant Proc 2009;41(5)
1735–1739. [II-2]
15. de Koning ND, Haagsma EB. Normalization of menstrual pattern
after liver transplantation: consequences for contraception. Digestion
1990;46(4):239–41. [II-2]
16. Mass K, Quint EH, Punch MR, Merion RM. Gynecological and reproduc-
tive function after liver transplantation. Transplantation 1996;62(4):476–9.
[II-2]
17. Rahim MN, Long L, Penna L, Williamson C, Kametas NA, Nicolaides
KH, Heneghan MA. Pregnancy in Liver Transplantation. Liver Transpl
2020;26(4):564–581. [II-2]
18. Parolin MB, Rabinovitch I, Urbanetz AA, et al. Impact of successful liver
transplantation on reproductive function and sexuality in women with
advanced liver disease. Transplant Proc 2004;36:943–944. [III]
19. Christopher V, Al-Chalabi T, Richardson PD, et al. Pregnancy outcome
after liver transplantation: a single-center experience of 71 pregnancies in
45 recipients. Liver Transpl 2006;12:1138–1143. [II-3]
20. Hammound GM, Almashhrawi AA, Ahmed KT, et al. Liver diseases in
pregnancy: liver transplantation in pregnancy. World J Gastroenterol
2013;19:7647–51. [III]
21. Dei Malatesta MF, Rossi M, Rocca B, et al. Pregnancy after liver transplan-
tation: report of 8 new cases and review of the literature. Transpl Immunol
2006;15:297–302. [III]
22. Pan GD, Yan LN, Li B, et al. A successful pregnancy following liver trans-
plantation. Hepatobiliary Pancreat Dis Int 2007;6:98–100. [III]
23. Jankovic Z, Stamenkovic D, Duncan B, et al. Successful outcome after
technically challenging liver transplant during pregnancy. Transplant Proc
2007;39:1704–1706. [III]
24. Jabiry-Zieniewicz Z, Bobrowska K, Pietrzak B. Mode of delivery in women
after liver transplantation. Transplant Proc 2007;39:2796–2799. [III]
25. Heneghan MA, Selzner M, Yoshida EM, et al. Pregnancy and sexual func-
tion in liver transplantation. J Hepatol 2008;49:507–519. [III]
26. Surti B, Tan J, Saab S. Pregnancy and liver transplantation. Liver Int
2008;28:1200–1206. [III]
27. Coffin CS, Shaheen AA, Burak KW, et al. Pregnancy outcomes among liver
transplant recipients in the United States: a nationwide case-control analy-
sis. Liver Transpl 2010;16:56–63. [III]
28. Cash WJ, Knisely AS, Waterhouse C, et al. Successful pregnancy after liver
transplantation in progressive familial intrahepatic cholestasis, type 1.
Pediatr Transplant 2010;15:E174–176. [III]
29. Armenti VT, Constantinescu S, Moritz MJ, et al. Pregnancy after trans-
plantation. Transplant Rev 2008;22:223–240. [III]
30. Laifer SA, Darby MJ, Scantlebury VP, et al. Pregnancy and liver transplan-
tation. Obstet Gynecol 1990;76:1083–1088. [III]
31. Sarkar M, Bramham K, Moritz MJ, Coscia L. Reproductive health in
women following abdominal organ transplant. Am J Transplant 2018;18(5):
1068–1076. [II-2]
32. Ramhendar T, Byrne P. Use of the levonorgestrel-releasing intrauter-
ine system in renal transplant recipients: a retrospective case review.
Contraception 2012;86(3):288–289. [II-2]
33. Huguelet PS, Sheehan C, Spitzer RF, Scott S. Use of the levonorgestrel
52-mg intrauterine system in adolescent and young adult solid organ trans-
plant recipients: a case series. Contraception 2017;95(4):378–381. [II-2]
34. Juliato CRT, Stahlschmidt P, Fernandes A, Monteiro I, Bahamondes L. A
case series on the use of levonorgestrel 52 mg intrauterine system after
organ transplant. Contraception 2018;98(3):252–254.
35. Kim YJ, Kim SI. Vaccination strategies in patients with solid organ
transplant: evidences and future perspectives. Clin Exp Vaccine Res
2016;5(2):125–131 [II-3]
36. Lai CL, Ratziu V, Yuen MF, et al. Viral hepatitis B. Lancet 2003;362:
2089–2094. [II-2]
37. Society for Maternal-Fetal Medicine (SMFM), Hughes BL, Page CM, Kuller
JA. Hepatitis C in pregnancy: screening, treatment, and management. Am J
Obstet Gynecol 2017;217(5):B2–B12. [III]
38. Jain AB, Reyes J, Marcos A, et al. Pregnancy after liver transplantation
with tacrolimus immunosuppression: a single center’s experience update at
13 years. Transplantation 2003;76:827–832. [III]
Pregnancy after Liver and Other Transplantation
39. Marchetti P. New-onset diabetes after liver transplantation: from patho-
genesis to management. Liver Transpl 2005;11:612–620. [III]
40. Homko CJ, Sivan E, Reece AE. Is there a role for oral antihyper-glycemics
in gestational diabetes and type 2 diabetes during pregnancy? Treat
Endocrinol 2004;3:133–139. [III]
41. Kanzaki Y, Kondoh E, Kawasaki K, et al. Pregnancy outcomes in liver trans-
plant recipients: A 15-year single-center experience. J Obstet Gynaecol Res
2016;42(11):1476–1482. [II-2]
42. Choudhary NS, Saigal S, Bansal RK, et al. Acute and chronic rejection after
liver transplantation: What a clinician needs to know. J Clin Exp Hepatol
2017;7(4):358–366. [III]
43. Ghazali S, Czuzoj-Shulman N, Spence AR, et al. Pregnancy outcomes in
liver transplant patients, a population-based study. J Matern Fetal Neonatal
Med 2017;30(3):261–266. [II-2]
44. Cyganek A, Pietrzak B, Kociszewska-Najman B, et al. Intrauterine growth
restriction in pregnant renal and liver transplant recipients: risk factors
assessment. Transplant Proc 2014;46(8):2794–2797. [II-2]
45. Rayes N, Neuhaus R, David M, et al. Pregnancies following liver transplan-
tation–how safe are they? A report of 19 cases under cyclosporine A and
tacrolimus. Clin Transplant 1998;12(5):396–400. [II-3]
46. Anderka MT, Lin AE, Abuelo DN, et al. Reviewing the evidence for myco-
phenolate mofetil as a new teratogen: case report and review of the litera-
ture. Am J Med Genet A 2009;149A:1241–1248. [II-1]
47. Sifontis NM, Coscia LA, Constantinescu S, et al. Pregnancy outcomes in
solid organ transplant recipients with exposure to mycophenolate mofetil
or sirolimus. Transplantation 2006;82:1698–1702. [III]
48. Roche Laboratories. Mycophenolate Mofetil Package Insert. Nutley, NJ:
Roche Laboratories, 2009. [II-3]
49. Novartis Pharmaceuticals Corp. Mycophenolic Acid Package Insert. East
Hanover, NJ: Novartis Pharmaceuticals, 2009. [II-3].
50. Vincenti F, Blancho G, Durrbach A, et al. Ten-year outcomes in a random-
ized phase II study of kidney transplant recipients administered belatacept
4-weekly or 8-weekly. Am J Transplant 2017;17(12):3219–3227. [I]
143
51. Combs J, Kagan A, Boelkins M, et al. Belatacept during pregnancy in
renal transplant recipients: two case reports. Am J Transplant 2018;18(8):
2079–2082. [II-3]
52. Klintmalm GB, Gunby RT Jr. Successful Pregnancy in a Liver Transplant
Recipient on Belatacept. Liver Transpl 2020;26(9):1193–1194. [II-3]
53. Mastrobattista JM, Gomez-Lobo V, Society for Maternal-Fetal Medicine.
Pregnancy after solid organ transplantation. Obstet Gynecol 2008;112:
919–932. [III]
54. Gouraud A, Bernard N, Millaret A, et al.. Follow-up of tacrolimus breastfed
babies. Transplantation 2012;94(6):e38–40. [II-2]
55. Armenti VT, Moritz MJ, Davison JM. Breastfeeding and tacrolimus: is it a
reasonable approach? Expert Rev Clin Immunol 2013;9(7):623–626. [III]
56. Abu-Elmagd K. The concept of gut rehabilitation and the future of visceral
transplantation. Nat Rev Gastroenterol Hepatol 2015;12:108–120. [III]
57. Kosmach-Park B, Doshi B, Seward L, et al. Successful pregnancy following
intestine transplant in a long term survivor. Am J Transplant 2006;6(Suppl
2):855. World Transplant Congress, Boston 2006. [III]
58. Gomez-Lobo V, Landy HJ, Matsumoto C, et al. Pregnancy in an intestinal
transplant recipient. Obstet Gynecol 2012;120:497–500. [III]
59. Kosmach-Park B, Costa G, Mazariegos G. Reproductive health and out-
comes following intestine transplantation. XIII ISBTS Annual Small Bowel
Transplant Symposium, Oxford (UK) 2013. [III]
60. Srivastava R, Clarke S, Gupte GL, et al. Successful pregnancy outcome fol-
lowing triple organ transplantation (small intestine, liver and pancreas).
Eur J Obstet Gynecol Reprod Biol 2012;163:238–239. [III]
61. Marcus EA, Wozniak LJ, Venick RS, et al. Successful term pregnancy in
an intestine-pancreas transplant recipient with chronic graft dysfunc-
tion and parenteral nutrition dependence: a case report. Transplant Proc
2015;47:863–867. [III]
62. Brännström M, Johannesson L, Bokström H, et al. Live birth after uterus
transplantation. Lancet 2015;385(9968):607–616. [II-3]
63. Testa G, McKenna GJ, Gunby RT Jr, et al. First live birth after uterus trans-
plantation in the United States. Am J Transplant 2018;18(5):1270–1274. [II-3]
14
MATERNAL ANEMIA
Ashley E. Benson and Marcela C. Smid
Key points
• Screening all pregnant women with Hgb and mean cor-
puscular volume (MCV) for acquired and inherited ane-
mias is recommended.
• Anemia in pregnancy is defined as a hemoglobin (Hgb)
<11 g/dL and hematocrit (Hct) <33% in the first or
third trimesters and Hgb <10.5 g/dL and Hct <32% in
the second trimester. For African- American women, rec-
ommend lowering cutoffs for Hgb and Hct by 0.8 g/dL and
2%, respectively.
• Key laboratory tests for the workup of anemia in pregnancy
include a complete blood count (CBC) with MCV, red
blood cell distribution width (RDW), serum ferritin level,
and hemoglobin electrophoresis. Workup of anemia in
pregnancy is described in Figures 14.1–14.3.
• Individuals of African, Mediterranean, and Southeast
Asian descent are at increased risk of hemoglobinopathies
and/or inherited anemia. All women who identify as hav-
ing African ancestry should be offered hemoglobin elec-
trophoresis [1]. Women of Mediterranean and Southeast
Asian descent should be screened with CBC and MCV. If
abnormal, further workup is recommended.
• The most common cause of anemia in pregnancy is iron
deficiency. Iron deficiency anemia in pregnancy is variably
defined as serum ferritin <15–30 µg/L with an Hgb <11 g/
dL and Hct <33%.
• Universal preventative oral iron supplementation dur-
ing pregnancy, with or without folate, is associated with
a reduced risk of maternal anemia and iron deficiency
at term.
• Iron deficiency anemia is associated with adverse peri-
natal outcomes including preterm birth, low birth-weight,
and perinatal mortality, although the evidence regarding
the reduction of adverse outcomes with treatment of iron
deficiency anemia in pregnancy are lacking due to a paucity
of studies.
• Treatment of iron deficiency anemia with oral iron treat-
ment in pregnancy is associated with a reduction in the
number of women with hemoglobin <11 g/dL and a
greater mean hemoglobin level.
• IV iron should be considered in women with iron
deficiency anemia with Hgb <9 g/dL, those who can-
not tolerate oral iron or those in their third trimester of
pregnancy.
• Severe anemia from any etiology (Hgb <7 mg/dL) is
associated with poor perinatal outcomes and increased
perinatal and maternal mortality. Transfusion may be
considered.
For sickle cell disease, see Chapter 15; for von Willebrand disease,
see Chapter 16; for care of Jehovah’s Witness pregnant women,
see Chapter 9 in Obstetric Evidence Based Guidelines.
144
Definition
Maternal anemia is defined by hemoglobin (Hgb) <11 g/
dL and hematocrit (Hct) <33% in the first or third trimesters
and <10.5 g/dL and Hct <32% in the second trimester [1, 2]. The
Institute of Medicine and the Centers for Disease Prevention and
Control (CDC) suggest that iron deficiency anemia in pregnancy
should be defined as serum ferritin <15 µg/L with an Hgb <11 g/
dL and Hct <33% [4]. However, recent studies suggest that using a
ferritin <30 µg/L improves the specificity and sensitivity for diag-
nosing iron deficiency [5–7]. However, research on pregnancy-
specific cutoffs are lacking [8].
Symptoms
Usually asymptomatic, unless hemoglobin <6 to 7 g/dL. Iron
deficiency is associated with symptoms of fatigue, headache, hair
loss, poor concentration, pica (including pagophagia), restless
legs syndrome, and reduced physical performance.
Prevalence
Worldwide, 38–42% of pregnant women are anemic with estimates
ranging from 22% in high resource areas to 56% in Africa [9, 10]. In
the United States, 5% of pregnant women are anemic; 18% are iron
deficient with prevalence increasing from 7% in the first trimester
to 28% in the third trimester. African American women (30%) and
Mexican-American women (24%) have a higher prevalence of iron
deficiency anemia compared to white women (14%) [11].
Genetics
Worldwide, 7% of the population are carriers for important hemo-
globin disorders [9]. In the United States, approximately, 1:12
African Americans have the sickle cell trait, 1:300 have a form of
sickle cell disease, and 1:600 have sickle cell anemia [12, 13].
See Tables 14.1–14.3 for types of hemoglobins. Tables 14.4 and
14.5 describe the types of hemoglobinopathies and their clini-
cal significance. Cis-α-thalassemia is common among women
in Southeast Asian ancestry; β-thalassemia is common among
women of Mediterranean, Asian, Middle Eastern, Hispanic, and
West Indian ancestry. However, self-identified ethnicity is not a
good predictor of risk as ethnic background may be assumed or
not known [2].
Etiology/Pathophysiology
Pregnant women undergo normal physiologic hemodynamic
changes, which must be understood to correctly identify those
who may benefit from additional testing and interventions. Total
red blood cell (RBC) mass and plasma both increase, however the
plasma increase (40–60%) is proportionally greater than the RBC
DOI: 10.1201/9781003099062-14
Maternal Anemia 145

*First and third trimesters- hematocrit <33% Or hemoglobin <11.0 g/dL

*Second trimester—hematocrit <32% OR Hgb <10.5 g/dL
*Choose algorithm based on the Mean Corpuscular Volume (MCV)

Normal MCV High MCV

Low MCV
(80–100 fL) (>100 fL)
(<80 fL)
*go to Figure 14.2 *go to Figure 14.3

Low ferritin Low normal ferritin Normal or high ferritin

(<15–30 ng/mL) (30–40 ng/mL) (>40 ng/mL)

Recheck ferritin
& transferrin saturation (TSAT)
Hemoglobin
Iron Deficiency <15–30 ng/mL or >30 ng/mL electrophoresis
TSAT <20%

Normal and Asian or African

ethnicity SS = sickle cell
SA = sickle trait
See Table 14.5 for A2 >3.5% = beta
treatment options thalassemia

DNA analysis to
assess for alpha-
Ring sideroblasts on thalassemia
peripheral smear No thalassemia
Hemoglobinopathy

YES NO

Begin folate (1 mg/day) w/PNV

Sideroblastic Chronic
Anemia Disease

Draw paternal CBC and

hemoglobin electrophoresis

Hematology Consider erythropoietin treatment if

consult renal disease, Hct <25% or risks for Consider referral for genetic
perinatal hemorrhage. counseling.

FIGURE 14.1 Evaluation of anemia in pregnancy. Algorithms for diagnosing anemia generally fail in the presence of more than
one cause. Abbreviations: fL, fentoliters; hgb, hemoglobin; MCV, mean corpuscular volume; TSAT, transferrin serum iron saturation;
PNV, prenatal vitamins; hct, hematocrit.

increase (15–30%), resulting in a lowering of the Hgb concentra-
tion compared to non-pregnant adults. Hgb 11–12 g/dL and Hct
32–33% are normal pregnancy related ranges.
Anemia may be inherited or acquired. Table 14.6 describes
anemia by its pathophysiological mechanism. Anemia in preg-
nancy can be cause by decreased red blood cell production
(nutritional deficiencies including iron, vitamin B12, folate,
decreased absorption, chronic disease, infection, bone marrow
suppression, hormonal deficiencies), increased red blood cell
destruction (inherited hemolytic anemias, acquired hemolytic
anemias) and blood loss.
While this chapter focuses on anemia, the CDC notes that preg-
nant women with Hb concentration of greater than 15.0 g/dL or a
Hct of greater than 45.0%, particularly in the second trimester, are
at increased risk of poor perinatal outcomes (fetal growth restric-
tion, preterm birth, fetal death) [2]. Increased Hb in the second or
third trimester likely indicates poor blood volume expansion and
should not be considered an indication of adequate iron stores.
146 Maternal-Fetal Evidence Based Guidelines

Normal MCV
(80–100 fL)

Reticulocyte count,
Ferritin, B12, RBC folate

Reticulocyte count <3% Reticulocyte count >3%

RDW Normal RDW Elevated Direct Direct

(12–15%) (>15%) Coombs (–) Coombs (+)

*G6PD deficiency
Autoimmune
*Hemoglobinopathies hemolytic
Low levels of Normal levels
*Microangiopathic anemia
*Infections ferritin, B12, of ferritin, B12,
anemias (HUS, TTP)
*Medications RBC folate RBC folate
*Spherocytocsis
*Rental disease *Elliptocytosis
*Aplastic anemia
Mixed Chronic Consider
disorder Disease rheumatology
Consider consult
hematology
Consider Treat per consult
hematology deficiency Consider erythropoietin treatment
consult protocols

FIGURE 14.2 Normocytic anemia (MCV 80–100). Abbreviations: fL, femtoliters; MCV, mean corpuscular volume; RDW, red blood
cell distribution width; RBC, red blood cell; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.

High MCV Iron deficiency anemia

(>100 fL)
B12, RBC folate levels
*B12 deficiency: <100 pg/mL
*Folate deficiency: RBC
folate <150 ng/mL3
Vitamin Deficiency
Folate
Folic Acid 1 mg/d in 1 mg Vitamin B12 IM Q
addition to prenatal
vitamin
Iron deficiency anemia is the most common cause of anemia dur-
ing pregnancy due to the nutrient demands required for the fetus
and for maternal red blood cell mass expansion (Figure 14.4). Total
iron loss associated with pregnancy and lactation is approximately
1 g. The typical diet in high resource areas includes 15 mg of ele-
mental iron per day. The recommended daily intake of ferrous
iron during pregnancy is 27 mg (present in most prenatal vita-
mins) and 10 mg during lactation [14].
Risk factors
Risk factors for iron deficiency or iron deficiency anemia include
diet poor in iron-rich food, a diet poor in iron absorption enhanc-
ers (vitamin C rich foods), a diet rich in foods that diminish iron
absorption (dairy, soy products, coffee, spinach), pica (eating
nonfood substances such as clay), gastrointestinal compromise
B12 affecting absorption (e.g., celiac disease, Crohn’s disease, bariat-
ric surgery), short pregnancy interval, parity ≥2, multiple gesta-
tion, low socioeconomic status and history of blood loss (heavy
wk × 8 weeks then menses, postpartum hemorrhage). Though iron deficiency ane-
monthly
mia from ongoing blood loss from the gastrointestinal system is

TABLE 14.1: Types of Hemoglobins

Recheck CBC in 1 month
Hgb A1 2 α-chains 2 β-chains Major adult hemoglobin
Refer to medicine service HgbA2 2 α-chains 2 δ-chains Minor adult hemoglobin
postpartum for etiologic HgbF 2 α-chains 2 γ-chains Fetal hemoglobin
testing
Hgb H — 4 β-chains α-Thalassemia major (-/-α)
Hgb Barts — 4 γ-chains Hydrops fetalis (-/-)
FIGURE 14.3 Macrocytic anemia (MCV > 100). Abbreviations: Hgb Gower 2 ε-chains 2 ς-chains Embryonic hemoglobin
fL, femtoliters; MCV, mean corpuscular volume; RBC, red blood
cell; d, day; wk, week; IM, intramuscular; q, every. Abbreviation: Hgb, hemoglobin.
Maternal Anemia 147

TABLE 14.2: Types of α-Thalassemia TABLE 14.5: Hematological Studies and Clinical Severity of
Thalassemias
Clinical
Nomenclature Genotype Disease Clinical
Condition Hb Level HbA2 HbF Other Hg Severity
Silent carrier –/α/α/α – Asymptomatic
heterozygous α+-thalassemia Homozygotes
α-Thalassemia α – /α – (trans) Mild anemia α-Thalassemia Severely 0 0 80% Hb Barts, Hydrops
trait Homozygous α+-thalassemia Similar to low remainder fetalis
Common among those with β-thalassemia HbH
black African heritage minor β+- Thalassemia Very low Variable Variable Some HbA Moderately
Or severe
– /α α (cis) Cooley
Heterozygous α0 thalassemia anemia
Common among those with β0- Thalassemia Severely Variable High No HbA Severe
Asian heritage low Cooley
Hemoglobin H α –/– – Severe anemia
disease α+-thalassemia/α0- Hgb H hemolytic δβ0- Thalassemia Low 0 100% No HbA Thalassemia
(α-Thalassemia thalassemia anemia intermedia
major) Heterozygotes
Hydrops fetalis – –/ – – Lethal in utero α-Thalassemia Normal Normal Normal 1–2% Hb Normal
Bart’s disease Homozygous α0-thalassemia without silent carrier Barts at
80% Hgb Barts/ 20% Hgb H transfusions birth
α-Thalassemia Low to Normal Normal 5% Hb Barts Very mild
Because there are two α-chains on each chromosome 16, the possibility exists for trait normal at birth
four different disease states (unlike β-thalassemias, where only two disease states are HbH disease Low Normal Normal 3–30% Hb H Thalassemia
found). in adult; 35% intermedia
HbH at birth
TABLE 14.3: Types of β-Thalassemia β+- Thalassemia Mildly low Elevated Elevated None Mild
to low
β-Thalassemia trait: One β chain affected β/β°
β0- Thalassemia Mildly low Elevated Very None Mild
Cooley anemia: Both β chains affected β°/β°
to low elevated
β° absence of β chain production → causes more severe anemia
β+ decrease in β chain production → causes milder anemia

trimester is more consistently associated with adverse peri-

TABLE 14.4: Hemoglobin Electrophoresis Patterns in natal outcomes, compared to anemia diagnosed in the third
Common Hemoglobinopathies trimester [20, 24]. Severe maternal anemia is associated with
abnormal fetal cerebral profusion and decreased amniotic
Condition HbA HbS HbC HbF HbA2
fluid [25]. Severe maternal anemia (Hgb <7 g/dL) is associated
Normal 95–98 0 0a
<1 2.5 ± 0.2 with maternal cardiovascular compromise and increased
Beta-thalassemia minor 90–95 0 0 1–3 >3.5 risk of maternal death (aOR 2.36, 95% CI 1.6–3.48) [26–28].
Sickle cell trait 50–60 35–45a 0 <2 <3.5
Sickle-beta(+) thalassemia 5–30 65–90 0 2–10 >3.5
Sickle-beta(0) thalassemia 0 80–92 0 2–15 >3.5 TABLE 14.6: Anemia Characterized by Mechanism
Sickle-HbC disease 0 45–50 45–50 1–8 <3.5
Dilutional (expansion Pregnancy
Homozygous sickle cell disease 0 85–95 0 2–15 <3.5 of plasma volume) Hyperglobinemia
Source: Adapted from Schrier 2015. An introduction to human hemoglobin Massive splenomegaly
­mutations. UptoDate. Decreased red blood Iron deficiency
a May be as low as 21 with sickle cell trait in presence of alpha thalassemia.

Abbreviation: Hb: hemoglobin. cell production Vitamin B12 deficiency

Folic acid deficiency
Bone marrow disorder or suppression
less common in women of reproductive age, when iron deficiency
Low levels of erythropeietin
is recognized during pregnancy, all possible causes should be
Hypothyroidism
considered.
Increased red blood Inherited: Sickle cell, thalassemia major, hereditary
cell destruction spherocytosis
Complications Acquired: Autoimmunie hemolytic, throbotic
thrombocytopenia purpura, hemolytic uremic
Observational studies suggest that maternal anemia and iron
syndrome, malaria
deficiency anemia are associated with poor perinatal outcomes
Increased loss Hemorrhage
including increased risk of low birth-weight, preterm birth
Gastrointestinal bleed
and perinatal death [15–23]. Maternal anemia in the first
148 Maternal-Fetal Evidence Based Guidelines

Iron deficiency anemia identified 3rd trimester or

Hgb < 10
1st or 2nd trimester

- Treat with oral ferrous sulfate (325 mg orally daily) in addition to prenatal
vitamin and 250 mg Vitamin C supplementation
- If taken with meals or antacids, may decrease absorption
- Consider Colace 100 mg PO BID if constipation present

If poor tolerance, consider every other day

oral dosing or IV iron

Recheck hematocrit in 4 weeks

No anemia Persistent anemia

Maintain -Assess compliacne

supplementation -Consider change to IV iron
with ferrous sulfate -Perform stool guaic
325 mg PO Q day -Nutrition consult
-Consider pica

Good compliance; negative

stool guiac

Consider IV iron

FIGURE 14.4 Treatment of iron deficiency anemia. Abbreviations: hgb, hemoglobin; po, orally; bid, twice a day; q, every; IV,
intravenous.

Maternal anemia is also associated with caesarean section
and need for blood transfusion [29, 30] postpartum depres-
sion [31], impaired maternal postpartum cognition [32], poor
mother-infant interaction and infant cognitive function [33].
Furthermore, isolated maternal iron deficiency (without con-
comitant anemia) is associated with neonatal iron deficiency
[34–36] increasing the risk of cognitive dysfunction detectable
into adolescence [37, 38].
Microcytic anemia
Diagnosis
An approach to determining the cause of maternal anemia is out-
lined in Figures 14.1–14.3. Anemia can be the result of more than
one cause, and in such instances an algorithmic approach to
the diagnosis may be incomplete.
• All individuals of African ancestry should have a
hemoglobin electrophoresis. See Tables 14.4–14.5.
Solubility testing is inadequate for screening since it
fails to identify other important hemoglobinopathies
[2, 42]. If documented results from a prior hemoglobin
electrophoresis can be obtained, this test should not be
repeated.
• Hgb <10.5–11 g/dL and MCV <80 um3 represents a micro-
cytic anemia (Figure 14.1).
• If not previously available, obtain ferritin level, which has
the highest sensitivity and specificity for diagnosing iron
deficiency in anemic patients [5, 7, 17].
• Obtain Hgb electrophoresis to assess for a hemoglobin-
opathy (Table 14.4).

Workup Normocytic anemia

• Initial evaluation: CBC with Hbg/Hct and MCV and
ferritin. This initial anemia screening is recommended
for all pregnant women (Figure 14.1) [1]. The American
Society of Hematology advocates for universal screen-
ing with ferritin [39], ACOG and British Society for
Haematology only in women with risk factors [1, 8, 40],
while the USPSTF recommends only evaluating ferritin
in women with anemia [41].
• If Hgb 10.5–11 g/dL and MCV ≥80–100 um3, obtain
reticulocyte count to determine if anemia is secondary
to underproduction or hemolysis, and obtain a history to
identify any evidence of active bleeding, medication expo-
sure, chronic disease, glucose-6-phosphate dehydrogenase
(G6PD) deficiency, or a family history of RBC disorders
(Figure 14.2).
• Obtain ferritin, vitamin B12 and RBC folate.
Maternal Anemia 149

TABLE 14.7: Hematological Studies of Anemias • A genetic consult should be obtained for all patients with
inherited disorders. Attempt to obtain a paternal blood
Anemia of Iron Thalassemia
sample for hemoglobin electrophoresis prior to the genetic
Chronic Deficiency alpha/beta
consult. DNA testing for alpha-globin abnormalities is
Marker Disease Anemia Trait or HbE
available.
Hemoglobin Normal to Normal to Normal to
decreased decreased decreased Prevention
MCV Normal to Decreased Decreased
decreased can be <70 Daily and intermittent iron supplementation are associated
RDW Normal to Increased Normal with prevention of low hemoglobin at term and at 6 weeks
increased to >15 postpartum. Insufficient evidence exists, however, that oral
Transferrin Decreased Decreased Normal supplementation results in a significant reduction of adverse
saturation perinatal outcomes including low birth weight, preterm birth, or
Ferritin No change to Decreased Normal infection [43, 44]. Most of the RCTs provided very limited infor-
increased mation about the clinical outcomes for women or their neonates.
Intermittent iron supplementation appears to produce similar
Abbreviations: MCV, mean corpuscular volume; RDW, red blood cell distribution width.
maternal and neonatal outcomes as daily supplementation with
fewer side effects [43, 44].
• If high reticulocyte counts (≥3), then anemia may be sec- Except in women with hemochromatosis or other genetic dis-
ondary to hemolysis or blood loss. Consider (1) periph- orders, there is little evidence of morbidity associated with iron
eral blood smear and haptoglobin (decreased), (2) direct supplementation. Common side effects of oral supplementation
Coombs (suggests autoimmune hemolytic anemia), (3) include constipation and gastrointestinal upset. The recom-
Hgb electrophoresis to rule out SS or SC disease, and (4) mended daily allowance of ferrous iron during pregnancy is
hemoccult or other tests if other sources of blood loss are 27 mg, which is present in most prenatal vitamins [1]. Table 14.9
suggested by history. lists elemental iron content of available iron supplements.
• If low reticulocyte count (<3), then anemia is secondary Folate supplementation is associated with increased or main-
to underproduction. Assess red cell distribution width tained serum folate levels and red cell folate levels compared to
(RDW) and follow algorithm. placebo or no supplementation. Folate supplementation is associ-
ated with a reduction in the proportion of women with mega-
Macrocytic anemia loblastic anemia but no difference in pre-delivery hemoglobin,
• If Hgb 10.5–11 g/dL and MCV >100 um3, obtain vitamin serum folate or RBC folate levels. Compared to placebo, folate
B12 and RBC folate level (Figure 14.3). supplementation is associated with increase in mean birth-
• Anemia of chronic disease is usually associated with nor- weight, but no difference in preterm birth or stillbirth/neona-
mocytic anemia (about 20% are associated with microcytic tal death. Based on available data, there is insufficient evidence
anemia) (Table 14.7). Causes include chronic liver disease, to conclude if folate supplementation has any substantial effect on
thyroid disease, uremia, chronic infections, and malignan- maternal or neonatal outcomes [45].
cies. Workup may include liver function tests (LFTs), blood
urea nitrogen (BUN) and creatinine, thyroid-stimulating
hormone (TSH), and any tests for malignancy or chronic Therapy
infection indicated by patient history and risk factors. Also Compared to placebo, oral iron treatment in pregnancy is asso-
check serum iron, serum B12, and RBC folate to rule out ciated with a reduction in the number of pregnant women with
combined deficiencies. Normal pregnancy specific values anemia in the second trimester and greater mean hemoglobin and
can be found in Table 14.8. ferritin levels. However, there is insufficient evidence to assess
• A nutrition consult should be obtained for patients with change in clinical outcomes, including preterm birth, low
B12, folate, and iron deficiencies. birth-weight or maternal morbidity in treatment of anemia
with oral supplementation [46]. Intermittent (e.g., every other
day) oral regimens produce similar maternal and infant benefits
TABLE 14.8: Trimester Specific Pregnancy Reference Ranges as daily supplementation, but are associated with reduced the
(2.5 and 97.5 Percentile) risk of high levels of Hgb [43] and fewer gastrointestinal (GI) side
First Second Third
Trimester Trimester Trimester
TABLE 14.9: Iron Supplements
Serum ferritin level (ng/mL) 6–130 2–230 0–116
Preparation Elemental Iron Content
Total iron-binding capacity μg/dL 278–403 Not reported 359–609
Transferrin saturation (%) Not reported 10–44 5–37 Ferrous fumarate 106 mg per 325 mg tablet
Plasma iron level (μg/dL) 72–113 44–178 30–193 Ferrous sulfate 65 mg per 325 mg tablet
Folate (RBC) (ng/mL) 137–589 94–828 109–663 Ferrous gluconate 34 mg per 300 mg tablet
Folate (serum) (ng/mL) 2.5–15.0 0.8–24.0 1.4–20.7 Iron dextran 50 mg/mL, IM or IV
B12 (cobalamin) pg/mL 118–438 130–656 99–526 Ferric gluconate 12.5 mg/mL IV
MCV μm3 81–96 82–97 81–99 Iron sucrose 20 mg/mL IV
Ferric carboxymaltose 750 mg IV; 1500 mg maximum
Abbreviation: MCV, mean corpuscular volume; RBC, red blood cell.
150
effects (e.g., constipation, nausea, and abdominal cramps) which
are common with oral iron treatments. Compared with standard
oral preparations, controlled release iron preparations are
associated with a diminished frequency of constipation.
Compared to oral administration, intravenous (IV) routes
of administration are associated with better hematologic indi-
ces (including higher mean Hgb and ferritin levels), improved
compliance and quality of life metrics, higher birth-weight, and
acceptable safety profiles [47–55]. IV iron should be considered
in pregnant women that fail to respond to oral iron, those with
severe anemia, or newly diagnosed iron deficiency anemia
(e.g., Hgb <9–10 g/dL) in the third trimester [1, 8, 40]. When
IV iron preparations are used, and the safety profile of different
preparations should be considered. Concern for anaphylactic
reactions with high molecular weight IV dextran and long infu-
sion times with iron polymaltose reduces their clinical use, par-
ticularly given limited information in pregnancy. Low molecular
weight IV iron dextran offers an improved safety profile and is
inexpensive, however, does require long infusion times Ferric
carboxymaltose is associated with higher mean Hgb and ferritin
levels, compared to IV sucrose, with comparable safety profiles
and requiring only one infusion of 750 mg of iron in 15 minutes
[29, 56, 57]. We recommend the use of 750 mg of IV ferric car-
boxymaltose or 1000 mg of IV low molecular weight iron rec-
ognizing the trade-offs of increased cost and increased infusion
time, respectively.
There are insufficient data to assess the effects of other forms of
prevention or therapy, including self-donation during pregnancy.
Antepartum testing
Consider growth ultrasound in the third trimester given associa-
tion with anemia and low birth-weight, although there is limited
evidence to support this practice.
Delivery and anesthesia
Prepare team regarding increased risk in the event of hemor-
rhage. Consider having blood available for possible transfusion in
cases of severe anemia, for example, Hgb <8 g/dL.
Postpartum/Breastfeeding
Intravenous iron (IV) was compared to oral iron in 15 trials
among postpartum anemic women with Hgb<12 g/dL [58]. Hgb
concentrations were higher at 6 weeks postpartum and GI side
effects were fewer. Overall the safety profile was reassuring with
an anaphylaxis rate of 0.6% [58, 59]. Iron sucrose and ferric car-
boxymaltose were the IV preparations used most frequently in
the included trials. Single dose IV iron isomaltoside was also
associated with significant reduction in physical fatigue within 12
weeks following postpartum hemorrhage when compared to oral
iron supplementation [60]. Use of IV iron for postpartum anemia
is also associated with improved physical performance and qual-
ity of life [59]. To date, there are insufficient data comparing
the various IV iron formulations to each other in pregnant
individuals. We favor the use of 750 mg IV ferric carboxy-
maltose or 1000 mg IV low molecular weight iron for their ease
of availability, recognizing the trade-offs of cost and time, and
encourage institutional individualization based on preparation
availability.
Maternal-Fetal Evidence Based Guidelines
One study evaluated red blood cell transfusion versus non-
intervention. General fatigue improved significantly more in the
transfusion group at 3 days but no difference between groups
was seen at 6 weeks. Overall, there is insufficient evidence to
conclude that blood transfusion significantly benefits women
postpartum when compared to the risk of immunological sen-
sitization with blood transfusion. There may also be a role for
IV iron in women with postpartum anemia who fail to tolerate or
respond to oral iron.
Hematological indices (Hgb and Hct) show some improve-
ment when erythropoietin was compared to iron only, or iron
and folate, but not when compared with placebo [61]. When
compared with oral iron therapy only, erythropoietin increased
the likelihood of lactation at discharge from hospital in one very
small trial.
Given that postpartum anemia is associated with several com-
plications, including decreased ability to fully engage in child-
care, household tasks, and exercise, as well as altered cognition,
mood and productivity, preventive measures for iron-deficiency
postpartum anemia may be considered, although there is insuf-
ficient evidence to recommend this approach.
References
1. American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 95: anemia in pregnancy. Obstet Gynecol 2008;112(1):201.
[Review]
2. Yip R, Parvanta I, Cogswell ME, McDonnell SM, Bowman BA, Grummer-
Strawn LM, et al. Recommendations to prevent and control iron defi-
ciency in the United States. Morbidity and Mortality Weekly Report:
Recommendations and Reports. 1998:1–29. https://www.cdc.gov/mmwr/
preview/mmwrhtml/00051880.htm [Review]
3. Institute of Medicine Committee on the Prevention, Detection, and
Management of Iron Deficiency Anemia among U.S. Children and Women
of Childbearing Age In: Earl R, Woteki CE, editors. Iron Deficiency Anemia:
Recommended Guidelines for the Prevention, Detection, and Management
Among U.S. Children and Women of Childbearing Age. Washington, DC:
National Academies Press (US) Copyright 1993 by the National Academy of
Sciences. All rights reserved. 1993. [Review]
4. WHO. Nutritional anaemias: tools for effective prevention and control.
World Health Organization; 2017. https://apps.who.int/iris/bitstream/
handle/10665/259425/9789241513067-eng.pdf [Review]
5. Daru J, Allotey J, Peña-Rosas JP, Khan KS. Serum ferritin thresholds for the
diagnosis of iron deficiency in pregnancy: a systematic review. Transfus
Med 2017;27(3):167–174. [Systematic Review, 76 trials]
6. Seid, MH, Derman, RJ Baker, JB Banach W, Goldberg C, Rogers, R. Ferric
carboxymaltose injection in the treatment of postpartum iron deficiency
anemia: a randomized controlled clinical trial. Am J Obstet Gynecol
2008;199(4):435–e1. [RCT, n = 291]
7. Van den Broek NR, Letsky EA, White SA, Shenkin A. Iron status in preg-
nant women: which measurements are valid? Br J Haematol 1998;103(3):
817–824. [II-1]
8. Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J, BSH
Committee. UK guidelines on the management of iron deficiency in preg-
nancy. Br J Haematol 2020;188(6):819–830. [Review]
9. McLean E, Cogswell M, Egli I, Wojdyla D, De Benoist B. Worldwide preva-
lence of anaemia, WHO vitamin and mineral nutrition information system,
1993–2005. Public Health Nutr 2009;12(04):444–454. [Review]
10. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca
F, et al. Global, regional, and national trends in haemoglobin concentration
and prevalence of total and severe anaemia in children and pregnant and
non-pregnant women for 1995–2011: a systematic analysis of population-
representative data. Lancet Glob Health 2013;1(1):e16–e25. [Systematic
review; 107 countries]
11. Mei Z, Cogswell ME, Looker AC, Pfeiffer CM, Cusick SE, Lacher DA, et al.
Assessment of iron status in US pregnant women from the National Health
and Nutrition Examination Survey (NHANES), 1999-2006. Am J Clin Nutr
2011;93(6):1312–1320. [IIc]
12. Motulsky AG. Frequency of sickling disorders in U.S. blacks. N Engl J Med
1973;288(1):31–33. [IIc]
Maternal Anemia
13. World Health Organization. Genomics and World Health: Report of the
Advisory Committee on Health Research. 2002. [Review]
14. Institute of Medicine Panel on Micronutrients. Dietary Reference Intakes
for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine,
Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. A
report of the panel on micronutrients and of interpretation and uses of
dietary reference intakes, and the standing committee on the scientific
evaluation of dietary reference intakes. National Academy Press; 2001.
[Review]
15. Alwan NA, Cade JE, McArdle HJ, Greenwood DC, Hayes HE, Simpson
NA. Maternal iron status in early pregnancy and birth outcomes: insights
from the Baby’s Vascular health and Iron in Pregnancy study. Br J Nutr
2015;113(12):1985–1992. [IIb]
16. Garn SM, Keating MT, Falkner F. Hematological status and pregnancy out-
comes. Am J Clin Nutr 1981;34(1):115–117. [III]
17. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and manage-
ment of iron-restricted erythropoiesis. Blood 2010;116(23):4754–4761.
[Review]
18. Klebanoff MA, Shiono PH, Selby JV, Trachtenberg AI, Graubard BI. Anemia
and spontaneous preterm birth. Am J Obstet Gynecol 1991;164(1 Pt 1):
59–63. [IIb]
19. Scholl TO, Hediger ML. Anemia and iron-deficiency anemia: compilation of
data on pregnancy outcome. Am J Clin Nutr 1994;59(Suppl. 2):492S–500S.
[III]
20. Murphy JF, O’Riordan J, Newcombe RG, Coles EC, Pearson JF. Relation of
haemoglobin levels in first and second trimesters to outcome of pregnancy.
Lancet 1986;1(8488):992–995.[III]
21. Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs iron deficiency:
increased risk of preterm delivery in a prospective study. Am J Clin Nutr
1992;55(5):985–988. [IIb]
22. Singh K, Fong YF, Arulkumaran S. Anaemia in pregnancy – a cross-­
sectional study in Singapore. Eur J Clin Nutr 1998;52(1):65–70. [III]
23. Zhou LM, Yang WW, Hua JZ, Deng CQ, Tao X, Stoltzfus RJ. Relation of
hemoglobin measured at different times in pregnancy to preterm birth
and low birth weight in Shanghai, China. Am J Epidemiol 1998;148(10):
998–1006. [III]
24. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia,
prenatal iron use, and risk of adverse pregnancy outcomes: systematic
review and meta-analysis. BMJ (Clinical Research Ed) 2013;346:f3443.
[Meta-analysis, 48 trials, n = 17,793]
25. Carles G, Tobal N, Raynal P, Herault S, Beucher G, Marret H, et al.
Doppler assessment of the fetal cerebral hemodynamic response to mod-
erate or severe maternal anemia. Am J Obstet Gynecol 2003;188(3):
794–799. [III]
26. Brabin BJ, Hakimi M, Pelletier D. An analysis of anemia and pregnancy-
related maternal mortality. J Nutr 2001;131(2S-2):604S–14S. [Systematic
review; n > 10,000]
27. Daru J, Zamora J, Fernández-Félix BM, Vogel J, Oladapo OT, Morisaki
N, et al. Risk of maternal mortality in women with severe anaemia dur-
ing pregnancy and postpartum: a multilevel analysis. Lancet Glob Health
2018;6(5):e548–e554. [II-3]
28. Geelhoed D, Agadzi F, Visser L, Ablordeppey E, Asare K, O’Rourke P,
et al. Maternal and fetal outcome after severe anemia in pregnancy in rural
Ghana. Acta Obstet Gynecol Scand 2006;85(1):49–55. [IIb]
29. Auerbach M, James SE, Nicoletti M, Lenowitz S, London N, Bahrain HF,
Derman R, Smith S. Results of the First American Prospective Study of
Intravenous Iron in Oral Iron-Intolerant Iron-Deficient Gravidas. Am J
Med 2017;130:1402–1407. [II-1]
30. Drukker L, Hants Y, Farkash R, Ruchlemer R, Samueloff A, Grisaru-
Granovsky S. Iron deficiency anemia at admission for labor and delivery is
associated with an increased risk for Cesarean section and adverse mater-
nal and neonatal outcomes. Transfusion 2015;55:2799–2806. [II-2]
31. Corwin EJ, Murray-Kolb LE, Beard JL. Low hemoglobin level is a risk factor
for postpartum depression. J Nutr 2003;133(12):4139–4142. [III]
32. Beard JL, Hendricks MK, Perez EM, Murray-Kolb LE, Berg A, Vernon-
Feagans L, et al. Maternal iron deficiency anemia affects postpartum emo-
tions and cognition. J Nutr 2005;135(2):267–272. [RCT, n = 81]
33. Perez EM, Hendricks MK, Beard JL, Murray-Kolb LE, Berg A, Tomlinson
M, et al. Mother-infant interactions and infant development are altered
by maternal iron deficiency anemia. J Nutr 2005;135(4):850–855. [RCT,
n = 81]
34. Juul SE, Derman RJ, Auerbach M. Perinatal iron deficiency: implications for
mothers and infants. Neonatology 2019;115(3):269–274. [Review]
35. Shao J, Lou J, Rao R, Georgieff, MK, Kaciroti, N, Felt, BT, Zhao, Z-T, Lozoff
B. Maternal serum ferritin concentration is positively associated with
151
newborn iron stores in women with low ferritin status in late pregnancy. J
Nutr 2012;142:2004–2009. [II-2]
36. Georgieff MK. Iron deficiency in pregnancy. Am J Obstet Gynecol
2020;223(4):516–524. [Review]
37. Congdon EL, Westerlund A, Algarin CR, Peirano PD, Gregas, M, Lozoff,
B, Nelson, CA. Iron deficiency in infancy is associated with altered neural
correlates of recognition memory at 10 years. J Pediatr 2012;160:1027–1033.
[II-3]
38. Lozoff B, Jimenez E, Smith JB. Double burden of iron deficiency in infancy
and low socioeconomic status: a longitudinal analysis of cognitive test
scores to age 19 years. Arch Pediatr Adolesc Med 2006;160:1108–1113.
[II-3]
39. Breymann C, Auerbach M. Iron deficiency in gynecology and obstetrics:
clinical implications and management. Hematology Am Soc Hematol Educ
Program 2017;2017(1):152–159. [Review]
40. Muñoz M, Peña-Rosas JP, Robinson S, Milman N, Holzgreve W,
Breymann C, et al. Patient blood management in obstetrics: manage-
ment of anaemia and haematinic deficiencies in pregnancy and in
the post-partum period: NATA consensus statement. Transfus Med
2018;28(1):22–39. [Review]
41. Siu AL. screening for iron deficiency anemia and iron supplementation
in pregnant women to improve maternal health and birth outcomes: U.S.
Preventive Services Task Force recommendation statement. Ann Intern
Med 2015;163(7):529–536. [Review]
42. American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 78: hemoglobinopathies in pregnancy. Obstet Gynecol
2007;109:229–237. [Review]
43. Cantor AG, Bougatsos C, Dana T, Blazina I, McDonagh M. Routine
iron supplementation and screening for iron deficiency anemia in
pregnancy: a systematic review for the U.S. Preventive Services Task
Force. Ann Intern Med 2015;162(8):566–576. [Meta-analysis, 11 trials,
n > 2000]
44. Peña-Rosas JP, De-Regil LM, Gomez Malave H, Flores-Urrutia MC,
Dowswell T. Intermittent oral iron supplementation during pregnancy.
Cochrane Database Syst Rev 2015;2015(10):CD009997. [Meta-analysis, 21
trials, n = 5490]
45. Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid supplementa-
tion during pregnancy for maternal health and pregnancy outcomes.
Cochrane Database Syst Rev 2013;3:CD006896. [Meta-analysis, 31 trials,
n = 17,771]
46. Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for
iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev
2011;(10):CD003094. [Meta-analysis, 23 trials, n = 3198]
47. Al RA, Unlubilgin E, Kandemir O, Yalvac S, Cakir L, Haberal A. Intravenous
versus oral iron for treatment of anemia in pregnancy: a randomized trial.
Obstet Gynecol 2005;106(6):1335–1340.
48. Bayoumeu F, Subiran-Buisset C, Baka NE, Legagneur H, Monnier-
Barbarino P, Laxenaire MC. Iron therapy in iron deficiency anemia in
pregnancy: intravenous route versus oral route. Am J Obstet Gynecol
2002;186(3):518–522. [RCT, n = 50]
49. Breymann C, Milman N, Mezzacasa A, Bernard R, Dudenhausen J; FER-
ASAP investigators. Ferric carboxymaltose vs. oral iron in the treatment of
pregnant women with iron deficiency anemia: an international, open-label,
randomized controlled trial (FER-ASAP). J Perinat Med 2017;45(4):443–
453. [RCT, n = 252]
50. Froessler B, Cocchiaro C, Saadat-Gilani K, Hodyl N, Dekker G. Intravenous
iron sucrose versus oral iron ferrous sulfate for antenatal and postpartum
iron deficiency anemia: a randomized trial. J Matern Fetal Neonatal Med
2013;26(7):654–659. [II-b]
51. Govindappagari S, Burwick RM. Treatment of iron deficiency anemia in
pregnancy with intravenous versus oral iron: systematic review and meta-
analysis. Am J Perinatol 2019;36(4):366–376. [Meta-analysis, 11 trials, n =
1190]
52. Khalafallah A, Dennis A, Bates J, Bates G, Robertson IK, Smith L,
et al. A prospective randomized, controlled trial of intravenous versus
oral iron for moderate iron deficiency anaemia of pregnancy. J Intern Med
2010;268(3):286–95. [RCT, n = 200]
53. Khalafallah AA, Hyppa A, Chuang A, Hanna F, Wilson E, Kwok C, et al. A
prospective randomised controlled trial of a single intravenous infusion of
ferric carboxymaltose vs single intravenous iron polymaltose or daily oral
ferrous sulphate in the treatment of iron deficiency anaemia in pregnancy.
Semin Hematol 2018;55(4):223–234. [RCT, n = 256]
54. Kochhar PK, Kaundal A, Ghosh P. Intravenous iron sucrose versus oral iron
in treatment of iron deficiency anemia in pregnancy: a randomized clinical
trial. J Obstet Gynaecol Res 2013;39(2):504–510. [RCT, n = 100]
152
55. Lewkowitz AK, Gupta A, Simon L, Sabol BA, Stoll C, Cooke E, et al.
Intravenous compared with oral iron for the treatment of iron-deficiency
anemia in pregnancy: a systematic review and meta-analysis. J Perinatol
2019;39(4):519–532. [Meta-analysis, 20 trials, n = 2716]
56. Christoph P, Schuller C, Studer H, Irion O, De Tejada BM, Surbek D.
Intravenous iron treatment in pregnancy: comparison of high-dose ferric
carboxymaltose vs. iron sucrose. J Perinatol 2012;40(5):469–474. [II-2]
57. Jose A, Mahey R, Sharma JB, Bhatla N, Saxena R, Kalaivani M, Kriplani A.
Comparison of ferric Carboxymaltose and iron sucrose complex for treat-
ment of iron deficiency anemia in pregnancy- randomised controlled trial.
BMC Pregnancy Childbirth 2019;19(1):54. [RCT, n = 100]
58. Sultan P, Bampoe S, Shah R, Guo N, Estes J, Stave C, Goodnough LT,
et al. Oral vs intravenous iron therapy for postpartum anemia: a systematic
Maternal-Fetal Evidence Based Guidelines
review and meta-analysis. Am J Obstet Gynecol 2019;221(1):19–29.e3.
[Meta-analysis, 15 trials, n = 2182]
59. Daniilidis A, Panteleris N, Vlachaki E, Breymann C, Assimakopoulos
E. Safety and efficacy of intravenous iron administration for uterine
bleeding or postpartum anaemia: a narrative review. J Obstet Gynaecol
2018;38(4):443–447. [Review]
60. Holm C, Thomsen LL, Norgaard A, Langhoff-Roos J. Single-dose intrave-
nous iron infusion or oral iron for treatment of fatigue after postpartum
haemorrhage: a randomized controlled trial. Vox Sang 2017;112(3):219–
228. [RCT, n = 196]
61. Markova V, Norgaard A, Jorgensen KJ, Langhoff-Roos J. Treatment for
women with postpartum iron deficiency anaemia. Cochrane Database Syst
Rev 2015;8:CD010861. [Meta-analysis, 22 trials, n = 2858]
15
SICKLE CELL DISEASE
Zimeng Gao
Key points
• Sickle cell disease is an autosomal recessive disease
resulting from an alteration in the structure of hemoglo-
bin producing hemoglobin S (HbS). It is characterized by
chronic hemolytic anemia and vaso-occlusive events.
• Diagnosis is made by hemoglobin electrophoresis.
• Severe complications during pregnancy and adverse
pregnancy outcomes are most commonly experienced by
women with HbSS and HbSβ0 genotypes.
• Complications may include pregnancy loss, fetal growth
restriction, preterm birth, pre-eclampsia, placental abnor-
malities, anemia, painful crises, UTI and other infections,
thromboembolic events, acute chest syndrome (ACS), alloim-
munization, postpartum infections, and maternal mortality.
• Pneumococcal and influenza vaccines are important
prevention interventions.
• Hydroxyurea (also known as hydroxycarbamide) is rec-
ommended for adults with sickle cell disease, in particular
for those with three or more crises per year, pain or chronic
anemia interfering with daily life, or severe or recurrent
episodes of ACS. Data in pregnancy is limited; however
available case series do not appear to demonstrate an
increased risk of congenital malformations. If hydroxyurea
was beneficial prior to pregnancy, its continual use could
be considered during pregnancy.
• Painful crises are managed with narcotic (preferably mor-
phine) therapy and IV fluids. Antibiotics should be added
if the woman is febrile, has an infection, or has ACS; oxy-
gen should be added if the woman has low oxygen satura-
tion to maintain O2 saturation ≥95%.
• Prophylactic blood transfusions can be beneficial to
improve maternal and perinatal outcomes. Initiate pro-
phylactic transfusions in the third trimester, performed
every 3–4 weeks for a Hgb goal of 9–12 g/dL and HbS
<35%. Blood transfusions are indicated for symptomatic
or orthostatic anemia, hemoglobin <6 g/dL or hematocrit
<25%, acute stroke, ACS, or multiple organ failure.
• In the 10% of patients with sickle cell disease who develop ACS,
a chest X-ray is necessary. Antibiotics (usually cephalosporin
and a macrolide) aimed at infectious pathogen(s) in pulmonary
tree, and bronchodilators are the mainstay of therapy.
Historic notes
Sickle cell disease was first described in 1910 by Drs. Irons and
Herrick. In 1949, Linus Pauling described the molecular structure of
sickle cell hemoglobin by protein electrophoresis. In 1956, Ingram
and Hunt discovered the single amino acid change in sickle cell
hemoglobin [1]. In the 1960s, the median survival age in the United
States for those with sickle cell disease was estimated to be 42 years for
men and 48 years for women [2]. During the past two decades, improve-
ments in medical care and earlier detection (especially through
DOI: 10.1201/9781003099062-15
newborn screening) have led to better survival rates (life span is still
about two or three decades shorter), improved quality of life, and
better pregnancy outcomes in women with sickle cell disease [3, 4].
Pathophysiology
Hemoglobin provides the oxygen-carrying capacity of erythro-
cytes, and exists as a tetramer of two α and two β protein subunits
(α2β2), also known as hemoglobin A (HbA). Hemoglobin has nor-
mal variants which differ by their protein subunits and are present
in most adult red blood cells. In most adults without hemoglo-
binopathy, 96–97% of circulating hemoglobin is HbA (α2β2), with
2–3% of hemoglobin A2 (α2δ2), and 0–1% hemoglobin F (α2γ2).
An abnormal variant of hemoglobin is HbS, which occurs
because of a single nucleotide mutation in which valine is substi-
tuted for glutamic acid at position 6 (E6V substitution). This substi-
tution replaces a hydrophobic amino acid in place of a hydrophilic
amino acid in the β-globin gene. This mutation does not change the
morphology of hemoglobin under normal oxygen concentration,
but allows HbS to polymerize when in conditions of low oxygen
concentration. This polymerization triggers a cascade of repeated
injury to the red-cell membrane, which causes the red blood cell to
assume a characteristic sickle shape. The sickled red blood cells are
brittle, causing increased hemolysis and difficulty passing through
small capillaries, leading to vessel occlusion and ischemia. This tis-
sue ischemia leads to acute and chronic pain, as well as to end-
organ damage. As vaso-occlusion can occur in any vessel, this is a
systemic disease that can affect multiple organs. The life span of a
sickle cell is about 10–20 days compared to the 120 days life span of
a normal red blood cell. This chronic hemolysis contributes to the
anemia [1, 5, 6]. Dehydration, infection, decrease in oxygen ten-
sion, and acidosis, are common triggers of cell sickling and sickle
cell crisis. Sickle cell crisis is a term used to label several different
and independent acute conditions occurring in patients with sickle
cell disease (vaso-occlusive crisis, aplastic crisis, hemolytic crisis).
Sickle cell disease describes a group of inherited disorders char-
acterized by the presence of HbS. Sickle cell disease is associated
with a mild to moderate chronic anemia. The term sickle cell dis-
ease includes sickle cell anemia (HbSS) (70% of cases), hemo-
globin S combined with hemoglobin C (HbSC) (most of the
remaining cases), hemoglobin S combined with β-thalassemia
(HbSβ+ or HbSβ0), and other double heterozygous conditions
causing sickling and thus, clinical disease (e.g., hereditary per-
sistence of fetal hemoglobin (HgS/HPHP), and hemoglobin E
(HbS/HbE) [7]. The clinical manifestations vary among these
genotypes, with HbSβ0 usually with a similar severe phenotype
as HbSS, HbSC associated with intermediate disease, and HbSβ+,
HbSHPHP, and HbSE with mild or symptom-free disease [1, 5].
The term sickle cell anemia includes HbSS, and also HbSβ0 (due
to its similar phenotype). The sickle cell trait is the heterozygous
inheritance of HgbS and is characterized by benign clinical course
without anemia, with protection against malaria [8].
153
154 Maternal-Fetal Evidence Based Guidelines

Epidemiology/Incidence
Sickle cell disease occurs in about 1 in 600 African Americans,
and affects between 70,000 and 100,000 Americans. The sickle
cell trait occurs in 1 in 12 African Americans and affecting 1 in
365 American-American births annually in the United States [9].
Worldwide, over 300,000 infants were born with sickle cell ane-
mia in 2010, with a majority of affected infants born in Nigeria,
Democratic Republic of the Congo, and India [10]. HbSS accounts
for 60–70% of sickle cell disease in the United States. The prevalence
of sickle cell disease and sickle cell trait is highest in West Africa
(25% of the population have one mutation), Mediterranean, Saudi
Arabia, India, South and Central America, and Southeast Asia [1, 5].
chance of having sickle cell disease, 50% chance of having sickle
cell trait, and 25% chance of being unaffected [5]. As noted ear-
lier, other forms of sickle cell disease result from co-inheritance
of HbS with other abnormal β-globin chain variants, the most
common forms being sickle hemoglobin C disease (HbSC) and
two types of sickle β-thalassemia (HbSβ+ thalassemia and HbSβ0
thalassemia). Inheriting one HbS gene results in sickle cell trait,
while inheriting two HbS genes results in sickle cell disease.
Diagnosis
The diagnosis is made by hemoglobin electrophoresis through
the detection of HbS. In all 50 U.S. states, newborns are screened
for sickle cell disease at birth.

Genetics/Inheritance Symptoms
Sickle cell disease has an autosomal recessive inheritance pat- 1. Hematologic
tern. Concordant with an autosomal recessive pattern of inheri- • Chronic hemolytic anemia—fatigue, pallor, shortness
tance, if both parents carry one HbS gene, the fetus has a 25% of breath

Neurologic

Transient ischemic attacks

Hematologic
Cerebrovascular accidents
Chronic hemolytic anemia Seizures
Aplastic crisis Hemorrhagic stroke
Splenic infarctions Orbital infarction
Vaso-occlusive episodes

Pulmonary
Cardiac
Acute chest syndrome
Cardiomegaly
Chronic restrictive lung
Systolic murmur
disease
High output failure
Pulmonary hypertension

Renal Gastrointestinal

Papillary necrosis Hepatopathy

Nephrotic syndrome Cholelithiasis

Renal infarction Mesenteric vaso-

occlusion
Pyelonephritis
Cholangiopathy

Infections

Urinary tract infections Skeletal

Osteomyelitis Avascular necrosis of

humeral or femoral head
Pneumonia
Leg ulcerations
Endometritis

FIGURE 15.1 Symptoms of sickle cell disease.

Sickle Cell Disease 155

• Aplastic crisis—severe anemia and reticulocytope- TABLE 15.1: Complications: Effects of Sickle Cell Disease on
nia. It is the most common hematologic crisis during Pregnancy
pregnancy
Complication HBSS HBSC HBSβ0
• Splenic infarctions—patients with sickle cell anemia
have effective hyposplenism and have increased risk of Pregnancy loss (mostly 7–36% [8,11,12] 9% [12]
infection first trimester)
• Acute vaso-occlusive episodes—pain involving the Fetal death No increase [8,11] No increase [8,11]
chest, lower back, abdomen, head, and bones/extremi- Fetal growth 45% [11] 21% [11]
ties. Exacerbated by cold, infection, stress, dehydra- restriction (FGR)
tion, alcohol, and fatigue Small for gestational 21% [13]
• Dactylitis (inflammation of fingers and/or toes) often age (SGA) a
the first symptom of sickle cell disease (see Figure 15.1) Acute anemia 4% [13] 15% [13]
Painful crisesb 20–50% [8,11,13] 19–26% [11,13]
2. Pulmonary Urinary tract infections 15% [8]
• Acute chest syndrome is a serious complication of
Preterm birth 45% [11,13]c 22% [11]
sickle cell disease presents with chest pain, dyspnea,
Pre-eclampsia 10% [11,14] 3%
tachypnea, fever, cough, leukocytosis, and pulmonary
Alloimmunizationd 24% [21] 6% [21] 4% [21]
infiltrates. It is usually a result of infection, vaso-
occlusion, or bone marrow embolization Antepartum 62% [11] 26% 2.8 [11]
• Chronic restrict lung disease as a consequence of admissionse
chronic vaso-occlusive damage Postpartum infectionsf 1.4% [14]
• Pulmonary hypertension % is reported if available in the source study.
3. Renal a Pre-eclampsia and acute anemia episodes are risk factors for SGA. High hemoglo-

• Papillary necrosis with hematuria, nephrotic syn- bin F levels are protective for fetal growth [13].
drome, renal infarction, pyelonephritis, hyposthenu- b There is no difference in the rate of painful episodes before, during and after preg-

ria, and renal medullary carcinoma nancies [13].

4. Infections
• Urinary tract infections, osteomyelitis, pneumonia,
endometritis
• Organisms include encapsulated organisms such as
Streptococcus pneumoniae, Hemophilus influenza,
Staphylococcus, gram-negative organisms, Salmonella,
c The mean gestational age at delivery is 34–37 weeks [11, 13].
d Percentages reflect women that were not randomized to prophylactic transfusions;
there were no differences in alloimmunization among women with HbSS that were
randomized to prophylactic transfusions and controls (29% vs. 21%). Any woman
with sickle cell disease is at increased risk for Rh and other antibodies if she has had
blood transfusions in the past.
e Because of all the aforementioned complications, in particular painful crises, and

and mycoplasma
5. Neurologic
• Transient ischemic attacks, cerebrovascular accidents,
seizures, coma, hemiparesis, hemianesthesia, visual
field changes, and cranial nerve palsy
increased incidences of infections in general, women with sickle cell disease in
pregnancy are at increased risk for hospitalization.
f More likely to have postpartum infections secondary to endometritis or pyelone-
phritis. The effect is listed as Odds Ratio compared to the general African-
American population. No increased risk for postpartum hemorrhage [8, 11].

• Orbital infarction
6. Cardiac
on sickle cell disease—Table 15.2 [11, 14, 15]. Stroke occurs in
• Cardiomegaly, systolic murmur, high output failure
24% of women with sickle cell disease by age 45. Venous throm-
7. Gastrointestinal
boembolism in 25% of women with sickle cell disease by age 30
• Hepatopathy, cholelithiasis, mesenteric vaso-occlu-
[12]. During pregnancy of women with sickle cell disease, about
sion, cholangiopathy
• Can present as abdominal pain, fever, hepatomegaly,
hyperbilirubinemia, and increased liver function tests
8. Skeletal TABLE 15.2: Complications: Effects of Pregnancy on Sickle
• Avascular necrosis most often occurs in the humeral Cell Disease
and femoral heads and is characterized by pain Complication HbSS
• Leg ulcerations
Maternal mortality 0.5–2.1% [8, 13, 14]

Complications Acute chest syndrome 7–20% [8, 13]

Thromboembolic events 2.5% [14]
Pregnancy in women with sickle cell disease is complicated by Cerebral vein thrombosis 4.9% [14]
both the underlying disease and the physiologic changes and Pyelonephritis 1.3% [14]
adaptations of pregnancy, which may compound or exacerbate Pneumonia 9.8% [14]
organ damage. Despite this, most women can achieve a success- Sepsis 6.8% [14]
ful pregnancy: The majority tends to deliver beyond 28 weeks’ SIRS 12.6% [14]
gestation with a >80% live birth rate, although 50% will require Pulmonary hypertension 6.3% [14]
transfusion or medically indicated hospitalization and 75% will
No. of blood transfusions 22.5% [14]
have a pain crisis during the pregnancy [11].
Postpartum infection 1.4% [14]
Several complications have been reported: Effects of sickle cell
disease on pregnancy—Table 15.1 [11–15]; effects of pregnancy % is reported if available in the source study.
156
50–70% require hospitalization and 30–40% blood transfusion
[13]. A retrospective analysis in 2019 compared postpartum
outcomes of almost 7 million deliveries of women in the United
States with and without sickle cell disease, finding that pregnant
women with sickle cell disease were more than two times as likely
to die in the hospital (OR 2.16; 95% CI 1.15–4.04), 27% as likely
to be readmitted 30 days postpartum (OR 1.27, CI 1.13–1.43),
and 92% as likely to be readmitted 90 days postpartum (OR 1.92;
CI: 1.75–2.11) [16]. The study found that women with SCD have
increased rates of sickle cell-associated complications, including
deep venous thrombosis, urinary tract infections, sepsis/shock,
supraventricular arrhythmias, cardiac arrest, myocardial infarc-
tion, stroke, pulmonary embolism, pneumonia, and acute renal
failure.
Pregnancy management
Principles
Management of a pregnant woman with sickle cell disease
requires multidisciplinary team approach, involving providers
from hematology, blood bank, primary care, obstetrics and/or
maternal fetal medicine, and any other involved specialists (e.g.,
providers from pulmonology, cardiology, nephrology, neurology,
pain management, and social services).
Workup
For diagnosis: Hemoglobin electrophoresis.
For a crisis: Hemoglobin, hemoglobin electrophoresis, urine
culture, and culture of any other possible infectious source;
blood gas if hypoxia is present.
Preventive care
Pneumococcal and influenza vaccines. Avoid triggers (espe-
cially infections). Optimize hemoglobin status by educating on
good nutrition and prescribe vitamins/folic acid/iron as needed,
establish plan for home medication regimen, and educate on
analgesia safety in pregnancy.
Preconception
Patients are no longer counseled to avoid pregnancy. Counseling
should consist of a review of the effects of sickle cell disease on
pregnancy, highlighting an increased risk for hospital admis-
sions, pain crises, infections, severe anemia, maternal mortality,
pre-eclampsia and other maternal complications (Tables 15.1 and
15.2) [11, 14–18]. The discussion should also entail the effects of
sickle cell disease on the fetus, which include early pregnancy
loss, growth restriction, and perinatal mortality, as well as a risk
for inherited hemoglobinopathies. Preventive care should be
emphasized, such as avoidance of dehydration and cold environ-
ments. Try to optimize hemoglobin status by prescribing 5-mg
folic acid and a prenatal vitamin that does not contain iron [4,
19]. Additional iron supplementation should be avoided due to
the state of chronic hemolysis and repeated blood transfusions
that result in excessive iron stores in most patients with sickle
cell anemia [20]. Discuss medication use during pregnancy and
change/stop teratogenic medications (ACE inhibitors, iron che-
lators, and possibly hydroxyurea). Hydroxyurea (also known as
hydroxycarbamide) is recommended for adults with sickle cell
disease, in particular for those with three or more crises per year,
pain or chronic anemia interfering with daily life, or severe or
recurrent episodes of ACS. Vaccinate as needed (see section on
“Preventive Care”).
Maternal-Fetal Evidence Based Guidelines
Genetic counseling for women with sickle cell disease, with
possible pre-implantation genetic diagnosis for those at risk of
having a baby with sickle cell anemia, can be offered. Evaluated
of the fetus for sickle cell disease or other hemoglobinopathies
can be completed with chorionic villus biopsy at 10–13 weeks of
gestation or amniocentesis at ≥15 weeks of gestation. While clini-
cal trials of fetal sickle cell disease detection with cell-free DNA is
underway, this testing is not commercially available [21].
Allogenic hematopoietic stem cell transplantation has been
done with some success, almost exclusively in children, with bone
marrow cells from HLA-identical siblings, and is associated with
a 92–94% survival and 82–86% event-free survival [22]. Despite
rare reports of successful pregnancies in these women, almost all
become infertile after the chemotherapy.
Prenatal care
1. Initial visit: Medical (assess for chronic organ dam-
age, especially pulmonary hypertension, renal disease,
retinopathy, and congestive heart failure), obstetrical,
transfusion, and social history; nutritional assessment;
discuss precipitating factors for painful crises and prior
successful pain management. Counseling regarding risks
(Tables 15.1 and 15.2), nutrition, hydration, and preventa-
tive care. Low-dose aspirin may be considered as the U.S.
Preventative Services Task Force recommends the use of
aspirin 81 mg/day starting early in pregnancy, i.e., first tri-
mester, in women who are at high risk for pre-eclampsia.
There are no trials specifically on this preventive inter-
vention in this population, and we do not routinely offer
it. Maternal-fetal medicine, and hematology consults can
be considered.
2. Initial laboratory studies: CBC, reticulocyte count, Hb
electrophoresis, ferritin, bilirubin, liver function tests,
hepatitis A, B, and C, HIV, BUN, creatinine, urine protein
(by protein/creatinine ratio or 24 hour urine), urine cul-
ture, antibody screen, rubella antibody titer, VDRL, tuber-
culosis skin test, Pap smear as appropriate, chlamydia and
gonorrhea cultures.
3. Offer laboratory evaluation to father of the baby (CBC,
hemoglobin electrophoresis). Offer genetic counseling if
father is positive for HbS. If father is positive for HbS,
offer prenatal diagnosis via chorionic villous sampling
or amniocentesis through direct DNA analysis (poly-
merase chain reaction). Interestingly, the vast majority
of women at risk of an affected fetus decline prenatal
diagnosis.
4. Serial urine cultures every 4–8 weeks.
5. CBC every trimester.
6. Folate supplementation of 5 mg daily plus prenatal vita-
min without iron [4, 17]. Women with sickle cell disease
tend to be iron overloaded due to a state of chronic hemo-
lysis and repeated blood transfusions and do not require
additional iron [20]. Avoid iron supplementation unless
there is a documented iron deficiency with laboratory
values.
7. Prophylactic penicillin should be continued in preg-
nancy if the patient had been taking it prior to pregnancy
for functional hyposplenism. Penicillin has a safe mater-
nal-fetal profile in pregnancy, but there is no available evi-
dence that starting prophylactic penicillin in pregnancy
has improved benefits.
8. Pneumococcal, influenza, and meningococcal vaccines.
Sickle Cell Disease
9. Recommend first-trimester ultrasound for more accu-
rate dating, which will aid in screening for growth
restriction later during pregnancy. Ultrasound at 18–20
weeks for a detailed anatomy scan, and then growth
scans starting at 28–32 weeks as clinically indicated. A
guideline from the United Kingdom recommends repeat
growth ultrasounds at weeks 28, 32, and 36 as well as
regular monitoring of fetal well-being with NSTs or
BPPs in the third trimester given the possibility of pla-
cental ischemia in setting of vaso-occlusive disease in
sickle cell anemia [19].
10. Some recommend maternal echocardiogram, especially if
there exists signs of pulmonary hypertension [23].
11. For patients with multiple red cell alloantibodies and an
anticipated need for a blood transfusion, consider to have
phenotypically matched units of PRBC identified.
12. Rescreen for red cell alloantibodies in third trimester,
especially if blood transfusions were indicated during
pregnancy [24].
Therapy
1. Painful crisis (diagnosis made by patient reported history,
often no physical or laboratory finding).
• Narcotics: Morphine or hydromorphone are the pre-
ferred agents for acute pain management. Consider
using a patient-controlled analgesia (PCA) system
for severe pain. Oral controlled-release morphine is
as effective as intravenous morphine in non-pregnant
adults. Ask women regarding which narcotic or other
pain medication works best for them, and implement
as appropriate. After 28–32 weeks, avoid NSAIDs
due to a premature narrowing or closure of the duc-
tus arteriosis, which are safe and effective earlier in
pregnancy. Prescribe stool softeners with narcotic
use [25].
• Intravenous fluids: Effective in non-pregnant adults.
Adequate fluid intake is 60 mL/kg/24 hour in adults
[25]. Consider running intravenous fluids at a rate of
150 cc/hour. Monitor fluid balance.
• Antibiotics: Broad-spectrum antibiotics should be
used if patient is febrile (T >38°C), or if there is evi-
dence of infection. A third generation cephalosporin
is typically given, with addition of a macrolide (e.g.,
azithromycin or erythromycin) if chest symptoms are
present [25].
• Oxygen: Use only for ACS or if O2 saturation is less
than patient’s known state or <95% [4] (such treatment
is ineffective in non-pregnant patients and may be so in
pregnant women as well) [25].
• Incentive spirometry should be used by women hos-
pitalized for vaso-occlusive crises.
• Venous thromboembolism (VTE) prophylaxis:
Should be considered for pregnant women with sickle
cell disease who are admitted for inpatient antepartum
management. Sickle cell disease is a thrombophilic
process and pregnant women with sickle cell disease
are at increased risk of developing VTEs, especially in
states of reduced ambulation.
• Labor and delivery: There is no need to alter
general recommendations for labor and delivery
in women in sickle cell crisis. A crisis is not an
157
indication for cesarean delivery or other special
intervention. Close monitoring of mother and fetus
for adequate oxygenation is paramount. Pain during
labor can be managed with narcotics, regional anes-
thesia, or local anesthesia via pudendal block [26].
Pediatricians should be aware of any chronic nar-
cotic use in pregnancy, as such is a risk for neonatal
withdrawal.
2. Anemia
• Transfusions: The role of prophylactic transfusions
in pregnant women with sickle cell disease has been
controversial in setting of limited data. In a random-
ized control trial of 72 pregnant women with sickle
cell disease, prophylactic transfusions and indi-
cated transfusions was associated with no signifi-
cant difference in perinatal outcome [27]. Patients
who received prophylactic transfusions experienced
decreased the number of painful crisis (14% vs. 50%)
[27]. However, a recent meta-analysis of 12 studies
(1291 patients) found that prophylactic transfusions
were associated with reduced maternal mortality
(OR 0.23; 95% CI 0.06–0.91), perinatal mortality (OR
0.43; CI 0.19–0.99), and neonatal death (OR 0.26; CI
0.07–0.93) [28].
Prophylactic transfusions start in the third tri-
mester, performed every 3–4 weeks for a Hgb goal of
9–12 g/dL and HbS <35%. Disadvantages of prophy-
lactic transfusion include increase in volume overload,
acute hemolytic and non-hemolytic reactions, transfu-
sional iron overload, costs, number of hospitalizations,
and risk of alloimmunization [10, 27].
Indications for transfusions are any woman who
is symptomatic or orthostatic from anemia, and/or
with a hemoglobin <6 g/dL or hematocrit <25%,
or with acute stroke or chest syndrome or multiple
organ failure.
Sickle cell crisis is not an absolute indication
to transfusion. Persistent crises are an indication to
transfusion to avoid recurrence. If blood transfusion
is indicated, it should always be leukodepleted and
matched for Rh and Kell antigens.
Goal of transfusion are usually: Hematocrit
>35%, HbA1 >40%, and HbS <35%.
There is insufficient evidence to compare exchange
versus regular blood transfusions for sickle cell disease
in pregnancy. For a hematocrit <15%, a direct trans-
fusion is always preferable. For a hematocrit >15%, an
exchange transfusion can be considered.
A serum ferritin level of >1000 ng/mL is sugges-
tive of iron overload, and is a contraindication to
iron supplementation.
• Iron, folic acid, and multivitamins: Only prescribe
iron if patient is deficient (avoid iron overload).
• Hydroxyurea (hydroxycarbamide): In non-pregnant
women, hydroxyurea has been shown to decrease
the number and severity of painful crises and to
improve overall survival [29]. Data in pregnancy is
limited; however available case series do not appear
to demonstrate an increased risk of congenital
malformations [30–32]. If felt to be beneficial for
management, its use could be considered during
pregnancy.
158
Alloimmunization
If the antibody screen is positive as a result of sensitization from
past transfusions, follow recommendations in Chapter 52. The
antigen status of the father of the pregnancy should be tested, as
he often does not carry the offending antigen, with the maternal
antibody usually acquired by prior transfusions. Bilirubin level
(Delta OD450) in amniotic fluid of women with sickle cell dis-
ease is unreliable for detecting fetal anemia, as maternal hemoly-
sis and hyperbilirubinemia increase fetal and AF bilirubin levels.
Fetal anemia may be assessed by middle cerebral artery Doppler
(see Chap. 55).
Antenatal testing
There are no prospective studies on the use of antepartum
testing in sickle cell disease women [13]. Repeat growth ultra-
sounds can be completed at 28, 32, and 36 weeks, as well as
regular monitoring of fetal well-being with weekly NSTs start-
ing at 32 weeks [19].
Delivery
It is safe for patients to deliver vaginally. Inductions and cesar-
ean deliveries should be reserved for obstetrical indications [4].
While some have proposed delivery around 37 weeks [13], there
is no strong evidence for delivery before 39 0/7 and 39 6/7 weeks,
unless complications (e.g., pre-eclampsia) occur. There is one case
report of a sickle cell crisis triggered by induction of labor with a
prostaglandin [33]. Some recommend prophylactic transfusion
before a cesarean delivery to avoid precipitating a crisis because
of blood loss in patients with hemoglobin 7–8 g/dL or less [26].
During labor, mothers should be kept adequately oxygenated with
O2 saturation ≥95% and the implementation of continuous fetal
heart monitoring.
Anesthesia
There are no contraindications to anesthesia (IV, regional, or gen-
eral) [4].
Postpartum
During the postpartum period, early ambulation and ade-
quate hydration is encouraged. Compression boots and incen-
tive spirometry should be used. Guidelines from the Royal
College Obstetricians and Gynecologists recommend admin-
istration of prophylactic LMWH for 7 days after discharge in
women with sickle cell disease following vaginal delivery and
for 6 weeks postpartum following cesarean delivery [34, 35].
Though U.S. guidelines are more lenient, the American College
of Obstetricians and Gynecologists does recommend consid-
eration of pharmacologic prophylaxis in women after cesar-
ean birth if additional risk factors are present; thus, it seems
prudent to consider postpartum prophylaxis with LMWH in
women with sickle cell disease after cesarean birth or if addi-
tional risk factors are present [36]. Decision-making regarding
VTE prophylaxis in women after a vaginal birth should con-
sider risk factors in addition to sickle cell disease (e.g., age,
obesity); those with several risk factors may warrant chemo-
prophylaxis. Anemia should be assessed and transfusion only if
Maternal-Fetal Evidence Based Guidelines
indicated (see earlier in this chapter). Breastfeeding is encour-
aged. A study of 16 lactating women on hydroxyurea found that
the amount of hydroxyurea secreted into breast milk over a
24-hour period was 3.4% of the maternal weight adjusted dose,
showing a low hydroxyurea profile in breastmilk and relative
safety of use in breastfeeding women on hydroxyurea [37].
About 5–6% of neonates of mothers with sickle cell disease can
have neonatal withdrawal syndrome, due to maternal chronic
opioid use [38].
Contraception
Progestin-containing contraception agents are safe among
women with sickle cell disease; these include depot medroxypro-
gesterone acetate (DMPA), etonogestrel implants and the levo-
norgestrel intrauterine device [39, 40]. The copper intrauterine
device system is a safe, effective, and excellent choice in these
women. A 2012 systematic review of eight studies found no evi-
dence that either combined or progestin-only hormonal contra-
ception in women with sickle cell disease increased their rate of
complications [41].
Acute chest syndrome
Definition
New pulmonary infiltrate of at least one complete lung seg-
ment with alveolar consolidation and excluding atelecta-
sis; and presence of chest pain, temp T >38.5°C, tachypnea,
wheezing, or cough. Hypoxia, decreasing hemoglobin levels,
and progressive pneumonia are frequent. Mostly associated
with pulmonary fat embolism and pulmonary infection, with
3–10% chance of death, related to pulmonary embolism and
pneumonia.
Incidence
Acute chest syndrome develops in about 10% of women with
sickle cell disease.
Pathophysiology
Cause of ACS remains mainly unknown. Infection leading to
sickle crisis, anemia, hypoxia, and vaso-occlusion with ischemic
damage are the most common associations.
Symptoms
Chest pain, pain in arms and legs, dyspnea, fever, etc.
Complications
ACS is one of the most common causes of death (3–10%) among
those with sickle cell disease. Neurologic complications, prob-
ably secondary to CNS hypoxia, occur in about 20% of patients.
Pulmonary emboli and infarction can also occur.
Workup
For ACS, obtain chest X-ray, sputum culture, nasopharyngeal
sample and/or culture of bronchoscopy washings (Chlamydia
pneumoniae and Mycoplasma pneumoniae are the most common
pathogens).
Therapy
Antibiotics (usually cephalosporin and a macrolide) aimed at
infectious pathogen(s) in pulmonary tree, and bronchodilators
Sickle Cell Disease
(even if no evidence of reactive airway disease). Blood trans-
fusions (especially in hypoxic and/or anemic women), oxy-
gen (15% need mechanical ventilation), and pain control as
needed [40].
Sickle cell trait
Pregnant women with sickle cell trait should be screened with
a hemoglobin electrophoresis if this has not been done before,
and testing of the father and genetic counseling should be
offered. They are at increased risk of urinary tract infections,
and therefore should have a urine culture at first prenatal visit
and in every trimester. Asymptomatic bacteriuria should be
treated.
HbSC disease
HbC is due to a single nucleotide substitution (A for G) in the
6th codon of the β-globin gene (making it a Hb C gene) in chro-
mosome 11, leading to substitution of lysine for glutamic acid on
the β-globin chain, resulting in βc globin. Of African Americans,
1% are carriers (trait). Diagnosis is by electrophoresis. No disease
with trait only.
HbSC occurs in about 1/833 African Americans. About
40–60% have same clinical course as HbSS disease, while others
have milder disease. Preventive and prenatal management should
be as for HbSS.
HbS-/βTHAL
There are two types of sickle cell-β thalassemia, and they are
classified according to the amounts of beta globin chain pres-
ent. Women with HbSβ0 have complete absence of beta globin,
and are clinically similar to HbSS (hemoglobin electrophoresis:
Absent HbA; elevated HbA2 and HbF). Women with HbSβ+ have
reduced amounts of beta globin (hemoglobin electrophoresis:
Low HbA; elevated HbA2 and HbF) and are typically managed
similar to women with HbSS, but tend to have a milder disease
[42, 43].
Hemoglobin E
Prevalent in Southeast Asia. No increase in mortality; may have
slight decrease in birth-weight and increase in abruption.
References
1. Rust OA, Perry KG. Pregnancy complicated by sickle hemoglobinopathy.
Clin Obstet Gynecol 1995;38(3):472–484. [Review]
2. Serjeant GR, Higgs DR, Hambleton IR. Elderly survivors with homozygous
sickle cell disease. N Engl J Med 2007;356(6):642–643. [III]
3. World Health Organization. Sickle Cell Anaemia: Report by the Secretariat.
59th World Health Assembly; 2006. [III]
4. ACOG Committee on Obstetrics. ACOG Practice Bulletin No. 78: hemo-
globinopathies in pregnancy. Obstet Gynecol 2007;109(1):229–237. [III]
5. Rappaport VJ, Velazquez M, Williams K. Hemoglobinopathies in preg-
nancy. Obstet Gynecol Clin North Am 2004;31(2):287–317, vi. [Review]
6. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004;364(9442):
1343–1360. [Review]
7. Serjeant GR. The emerging understanding of sickle cell disease. Br J
Haematol 2001;112(1):3–18. [Review]
8. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. NEJM 2017;376:1561–
1573. [Review; III]
159
9. Centers for Disease Control and Prevention. Data and statistics on sickle
cell disease; December 2020. [III]
10. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease.
Lancet 2017; S0140-6736 (17):30193–30199. [Review; III]
11. Serjeant GR, Loy LL, Crowther M, Hambleton IR, Thame M. Outcome
of pregnancy in homozygous sickle cell disease. Obstet Gynecol
2004;103(6):1278–1285. [II-2]
12. Naik RP, Streiff MB, Haywood C, Nelson JA, Lanzkron S. Venous thrombo-
embolism in adults with sickle cell disease: a serious and under-recognized
complication. Am J Med 2013;126(5):443–449. [II-2]
13. Ngô C, Kayem G, Habibi A, et al. Pregnancy in sickle cell disease:
maternal and fetal outcomes in a population receiving prophylac-
tic partial exchange transfusions. Eur J Obstet Gynecol Reprod Biol
2010;152(2):138–142. [II-3]
14. Sun PM, Wilburn W, Raynor BD, Jamieson D. Sickle cell disease in preg-
nancy: twenty years of experience at Grady Memorial Hospital, Atlanta,
Georgia. Am J Obstet Gynecol 2001;184(6):1127–1130. [II-2]
15. Milner PF, Jones BR, Döbler J. Outcome of pregnancy in sickle cell ane-
mia and sickle cell-hemoglobin C disease. An analysis of 181 pregnan-
cies in 98 patients, and a review of the literature. Am J Obstet Gynecol
1980;138(3):239–245. [II-3]
16. Bae E, Tangel V, Liu N, et al. Inpatient mortality and postpartum readmis-
sion rates in sickle cell disease pregnancies: a multistate analysis, 2007–
2014. J Matern Fetal Neonatal Med 2019. [I]
17. Smith JA, Espeland M, Bellevue R, Bonds D, Brown AK, Koshy M. Pregnancy
in sickle cell disease: experience of the Cooperative Study of Sickle Cell
Disease. Obstet Gynecol 1996;87(2):199–204. [II-2]
18. Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated
with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008;199(2):125.
e1–5. [III]
19. Bennett L, Chapman C, Davis B, et al. Pregnancy, contraception and fertil-
ity. In: Standards for the Clinical Care of Adults with Sickle Cell Disease in
the UK. London: Sickle Cell Society. 2008. [III]
20. Abudu OO, Macaulay K, Oluboyede OA. Serial evaluation of iron stores
in pregnant Nigerians with hemoglobin SS or SC. J Natl Med Assoc
1990;82:41. [II-2]
21. van Campen J, Silcock L, Yau S, et al. A novel non-invasive prenatal sickle
cell disease test for all at-risk pregnancies. Br J Haematol 2020;190:119.
[II-2]
22. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle
cell disease: summary of the 2014 evidence-based report by expert panel
members. JAMA 2014;312(10):1033–1048. [III]
23. Klings ES, Machado RF, Barst RJ, et al. An official American Thoracic
Society clinical practice guideline: diagnosis, risk stratification, and man-
agement of pulmonary hypertension of sickle cell disease. Am J Respir Crit
Care Med 2014;189(6):727–740. [III]
24. Okusanya BO, Oladapo OT. Prophylactic versus selective blood trans-
fusion for sickle cell disease in pregnancy. Cochrane Database Syst Rev
2013;12:CD010378. [I]
25. Rees DC, Olujohungbe AD, Parker NE, et al. Guidelines for the man-
agement of the acute painful crisis in sickle cell disease. Br J Haematol
2003;120(5):744–752. [II-3]
26. Firth PG, Head CA. Sickle cell disease and anesthesia. Anesthesiology
2004;101(3):766–785. [Review]
27. Koshy M, Burd L, Wallace D, Moawad A, Baron J. Prophylactic red-cell
transfusions in pregnant patients with sickle cell disease. A randomized
cooperative study. N Engl J Med 1988;319(22):1447–1452. [RCT, n=72]
28. Malinowski AK, Shehata N, D’Souza R, Kuo KHM, et al. Prophylactic trans-
fusion for pregnant women with sickle cell disease: a systematic review and
meta-analysis. Blood 2015;126(21):2424–2435. [I: n=1291]
29. Rees DC, Williams TN, Gladwin MT. Sickle cell disease. Lancet
2010;376(9757):2018–2031. [Review]
30. Ballas SK, McCarthy WF, Guo N, et al. Exposure to hydroxyurea and
pregnancy outcomes in patients with sickle cell anemia. J Natl Med Assoc
2009;101(10):1046–51. [II-2]
31. Jackson N, Shukri A, Ali K. Hydroxyurea treatment for chronic myeloid leu-
kaemia during pregnancy. Br J Haematol 1993;85(1):203–204. [II-2]
32. Liebelt EL, Balk SJ, Faber W, et al. NTP-CERHR expert panel report on the
reproductive and developmental toxicity of hydroxyurea. Birth Defects Res
B Dev Reprod Toxicol 2007;80(4):259–366. [III]
33. Faron G, Corbisier C, Tecco L, Vokaer A. First sickle cell crisis triggered
by induction of labor in a primigravida. Eur J Obstet Gynecol Reprod Biol
2001;94(2):304–306. [II-3]
34. RCOG. Green-top Guideline No. 37a: Reducing the Risk of Venous
Thromboembolism during Pregnancy and the Puerperium. 2015.
160
https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.
pdf [III]
35. Green-top Guideline No. 61: Management of Sickle Cell Disease in
Pregnancy. Green-top Guideline No. 61; 2011. [III]
36. James A, Committee on Practice Bulletins—obstetrics. Practice Bulletin
No. 123: thromboembolism in pregnancy. Obstet Gynecol 2011;118(3):718–
729. [III]
37. Ware RE, Marahatta A, Ware JL, et al. Hydroxyurea exposure in lactation:
A pharmacokinetics study (HELPS). J Pediatr 2020;222:236–239. [II-2]
38. Kellogg A, Rose CH, Harms RH, Watson WJ. Current trends in narcotic use
in pregnancy and neonatal outcomes. Am J Obstet Gynecol 2011;204(3):259.
e1–4. [II-3]
39. WHO. Medical Eligibility Criteria for Contraceptive Use. 4th ed. 2010.
http://whqlibdoc.who.int/publications/2010/9789241563888_eng.pdf. [III]
Maternal-Fetal Evidence Based Guidelines
40. Manchikanti A, Grimes DA, Lopez LM, Schulz KF. Steroid hormones for
contraception in women with sickle cell disease. Cochrane Database Syst
Rev 2007;(2):CD006261. [I]
41. Haddad LB, Curtis KM, Legardy-Williams JK, Cwiak C, Jamieson DJ.
Contraception for individuals with sickle cell disease: a systematic review
of the literature. Contraception 2012;85(6):527–537. [I]
42. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease.
Rates and risk factors. N Engl J Med 1991;325(1):11–16. [II-3]
43. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in
sickle cell disease: incidence and risk factors. The Cooperative Study of
Sickle Cell Disease. Blood 1994;84(2):643–649. [II-3]
16
VON WILLEBRAND DISEASE
Melody Safarzadeh
Key points
• It is difficult to establish a diagnosis of type 1 von
Willebrand disease (VWD) in pregnant women. The
diagnostic workup includes: (1) prolonged bleeding
time; (2) low levels of factor VIII; (3) decreased von
Willebrand factor (vWF) antigen (Ag); (4) decreased
ristocetin cofactor activity. Be aware of physiologic
increase in factor VIII and vWF levels in pregnancy.
• Workup therefore includes these key labs: Factor VIII,
vWFAg, ristocetin cofactor activity or von Willebrand
activity, and bleeding time.
• Desmopressin acetate (DDAVP) responsiveness should
be tested preconception, or in the second or third trimester.
• Aim to achieve vWF, factor VIII, and ristocetin cofactor
levels of ≥50 IU/dL (associated with lower risk of bleeding
complications).
• Prophylactic therapies for VWD depend on type and
include DDAVP (for type 1), vWF/factor VIII concen-
trates (Humate P, Alphanate SD/HT), platelet trans-
fusion, and/or adjuvant therapy with antifibrinolytic
amino acids (aminocaproic acid and tranexamic acid).
• If possible, avoid fetal scalp electrode or fetal scalp sam-
pling, pudendal blocks, and operative vaginal deliveries
as the fetus can have up to a 50% chance of being affected.
Historic notes
Von Willebrand Disease (VWD) was first described in 1926 by a
Finnish pediatrician, Erik von Willebrand. He also reported that
the condition was inherited in an autosomal dominant fashion
and improved with blood transfusions.
Diagnosis/Definition
VWD is an inherited bleeding disorder characterized by quantita-
tive or qualitative defects in vWF, which facilitates platelet adhe-
sion and aggregation, and is a carrier of factor VIII. Diagnosis of
VWD is complex (Table 16.1) [1–7]. VWD is usually associated
with a prolonged bleeding time and with frequently normal aPT
and aPTT (aPTT is only prolonged in patients with severe VWD
due to decreased factor VIII levels). For type 1 VWD the most
important laboratory tests are:
• vWF Ag (von Willebrand factor antigen; an immunoreac-
tive protein) (decreased)
• Factor VIII (decreased)
• Ristocetin cofactor activity (binding of vWF Ag to the
platelet membrane glycoprotein Iba mediated by the anti-
biotic ristocetin) (decreased), or von Willebrand activity
(this test uses a monoclonal antibody against the glycopro-
tein Ib binding site of vWF) (decreased)
DOI: 10.1201/9781003099062-16
As a patient progresses through pregnancy, many of the values
used for diagnosis are normal due to the procoagulant state of
pregnancy, thus diagnosis cannot be made reliably. For distin-
guishing types (Table 16.1) also send multimeric analysis and fac-
tor VIII binding assay. Factor VIII levels are best (but not that
good) at predicting surgical/soft-tissue bleeding.
Symptoms
Obtain a thorough medical and family history, and perform a
physical examination. Abnormal bleeding symptoms include
epistaxis, gingival bleeding and bleeding after dental pro-
cedures, prolonged bleeding after minor cuts, ecchymoses,
gastrointestinal bleeding, joint bleeding, menorrhagia, post-
partum hemorrhage, delayed postpartum hemorrhage, and
postoperative bleeding [8].
Epidemiology/Incidence
Most common inherited bleeding disorder affecting males and
females of all ethnic groups and 0.1–1% of the general popula-
tion [9].
Genetics
Usually autosomal inheritance pattern (Table 16.2). vWF is a
large multimeric glycoprotein encoded on the short arm of chro-
mosome 12, and synthesized and released from the endothelium
and megakaryocytes [9]. There are over 250 mutations of all types
known.
Etiology/Basic pathophysiology
Quantitative (types 1 and 3) or qualitative (type 2) deficiency in
vWF (also known as factor VIII cofactor). This cofactor is critical
for normal platelet adhesion and aggregation at the site of vascu-
lar injury (Figure 16.1) [1–7].
Classification
Type 1: (>80%) Autosomal Dominant. Partial quantitative
deficiency (mild-moderate) of vWF with decreased factor
VIII [5-30 IU/dL (nl 50–150 IU/dL)] and ristocetin cofac-
tor levels.
Type 2: (15–20%) Autosomal Dominant. Qualitative defect
of vWF.
a. Decreased vWF function due to decrease in intermedi-
ate- and high-molecular weight vWF multimers
b. vWF gain-of-function mutation resulting in increased
affinity for platelet receptor, glycoprotein 1b (moderate-­
severe thrombocytopenia)
M and N types are uncommon.
161
162 Maternal-Fetal Evidence Based Guidelines

TABLE 16.1: Common Laboratory Findings in von Willebrand Disease

von Willebrand Factor
von Willebrand Factor Ristocetin Cofactor Low-Dose Ristocetin-
von Willebrand Ristocetin Cofactor Activity/von Willebrand Induced Platelet
Subtype Factor Antigen Activity Factor Antigen (ratio) Factor VIII Aggregation Multimer Assay
Type 1 Low Low >0.5–0.7 Low or normal No reaction Normal
Type 2A Low Low <0.5–0.7 Low or normal No reaction Decrease in large
multimers
Type 2B Low Low <0.5–0.7 Low or normal Positive Decrease in large
multimers
Type 2M Low Low <0.5–0.7 Low or normal No reaction Normal
Type 2N Normal to low Normal to low >0.5–0.7 Low No reaction Normal
Type 3 Absent Absent Low No reaction Absent
Source: Adapted from Ref. [4].

Type 3: (<5%) Autosomal Recessive. Virtually complete
quantitative deficiency characterized by undetectable vWF
and ristocetin cofactor levels, and markedly low factor VIII
(most severe form) [9].
Acquired: During certain disease states.
Complications
There is an increased risk of both primary (within 24 hours of
delivery) and secondary (>24 hours after delivery) postpartum
hemorrhage. VWD does not impair fertility or increase preg-
nancy loss.
Pregnancy considerations
vWF and factor VIII levels increase progressively during preg-
nancy, and may be normal at term, even in patients with VWD.
Patients with type 2 VWD experience an increase in dysfunc-
tional vWF Ag without an increase in vWF activity. Patients with
type 3 VWD do not experience a rise in vWF or factor VIII during
pregnancy [10].
Pregnancy management
Principles
Treat as you would in non-pregnant adults.
Workup (labs)
See the section “Diagnosis” above (Tables 16.1 and 16.2).
Management
Preconception counseling: Obtain a thorough history and per-
form a physical examination. Order baseline laboratory tests
(see workup above). Hematology consult is recommended, and
genetic counseling should be offered. If patient has type 1 VWD
with factor VIII levels <50 IU/dL, types 2 or 3 VWD, or a history
of severe bleeding, consider care in a high-risk center with close
collaboration with hematology.

TABLE 16.2: Mechanism, Inheritance, and Treatment for Different Types of von Willebrand Disease
Type Mechanism Inheritance Treatment Second-Line Therapy
1 Quantitative (partial) decrease VWF Autosomal dominant DDAVP Factor VIII/VWF
concentrates
2 Qualitative/functional defect VWF Autosomal dominant
A Platelet-dependent VWF – absence Autosomal dominant Factor VIII/VWF concentrates DDAVP
of large or intermediate size
multimers
B Large multimers absent (increase in Autosomal dominant None
binding with platelets and VWF)
M Autosomal dominant Factor VIII/VWF concentrates DDAVP
N Defect in binding of VWF with Autosomal dominant Factor VIIII/VWF concentrates DDAVP
platelets
3 Severe or absent VWF and Factor Autosomal recessive Factor VIII/VWF concentrates
VIII deficiency (without alloantibodies)
Recombinant factor VIII (with
alloantibodies )
Acquired Occurs in disease states such as Increased clearance of Treatment of underlying Desmopressin, plasma
cancer, valvular heart disease (AS), VWF from plasma condition concentrates, IVIg
thrombocythemia, autoimmune
diseases
Abbreviations: vWF, von Willebrand factor; DDAVP, 1-deamino-8-D-arginine vasopressin.
Von Willebrand Disease 163

A Collagen receptor
GPIb/IX

Nonactivated
Platelet GPIIb/IIIa

Initial platelet Platelet rolling Platelet activation

tethering and adhesion
torque

Activated
GPIIb/IIIa

Endothelial cells

vWF
Collagen
fibril

Fibrinogen
ADP

TXA2

Thrombin

FIGURE 16.1 Platelet adhesion and activation at the site of vascular injury. (A) Endothelial cells within an intact vessel wall prohibit
circulating platelets and their membrane glycoprotein GpIb, nonactivated GpIIb/IIIa, and collagen receptors from interacting with von
Willebrand factor and collagen fibrils within the subendothelial extracellular matrix. Once the vessel wall is damaged, von Willebrand fac-
tor and collagen fibrils within the subendothelial extracellular matrix become exposed to flowing blood and shear forces. von Willebrand
factor can then bind to exposed collagen and uncoil. At first, von Willebrand factor only interacts with platelet receptor GpIb (initial plate-
let tethering). This interaction has a fast dissociation rate, and platelets continue to move in the direction of blood flow (platelet rolling).
Platelet collagen receptors then proceed to bind to exposed collagen, which leads to platelet adhesion and activation. Platelet activation
causes a conformational change of GpIIb/IIIa that enhances its affinity for von Willebrand factor. This enhanced affinity, along with plate-
let rolling, allows for platelet binding to the vessel wall. (B) GpIIb/IIIa-von Willebrand factor binding also facilitates interactions between
platelets, leading to the formation of a platelet plug (also mediated by fibrinogen). (From Ref. [17] with permission.)
164 Maternal-Fetal Evidence Based Guidelines

Prenatal care. First trimester: See “Preconception Counseling”
if not done yet. Prenatal diagnosis, including chorionic villus sam-
pling and amniocentesis, is possible (prophylaxis with DDAVP
or vWF/factor VIII concentrates is safe and can reduce the risk
of bleeding during antenatal procedures); Second/third trimes-
ter: Recommend anesthesia consult and test response to DDAVP
if not done yet. Third trimester: Monitor clotting factor levels.
Develop birth plan (anesthesia, potential prophylactic measures,
avoidance of invasive procedures such as operative vaginal deliv-
ery, etc.). Aim to achieve vWF, factor VIII, and ristocetin cofactor
levels of ≥50 IU/dL (associated with lower risk of bleeding com-
plications) [2, 6, 7].
Therapy (Table 16.2 and Figure 16.2)
VIII from endothelial cells within 30–60 minutes, and high
plasma concentrations last for 6–8 hours [11]. Recommend
test-dose infusion to determine pattern of response and duration
[11]. Safe in pregnancy for mother and fetus (does not cross the
placenta) [2], and during breastfeeding (Category B).
If not responsive to DDAVP: vWF/factor VIII concentrates
such as alphanate and humate-P (preferred over cryoprecipitate
because there are no infectious disease concerns). Usual load-
ing dose for these 2 vWF/factor VIII concentrates is 40–60 IU/
kg. Alternatives, especially for treatment of hemorrhage more
so than prophylaxis, are cryoprecipitate (fibrinogen and vWF)
or fresh frozen plasma (monitor for signs of volume overload).
Applies to all of the above: Limited data regarding safety, but
probably safe. Counsel regarding blood product precautions.

Type 1
DDAVP [desmopressin acetate, i.e. 1-deamino-8-D-arginine vaso-
pressin: Synthetic vasopressin (antidiuretic hormone) analog]
0.3 mcg/kg IV over 30 minutes (maximum dose: 25–30 mcg).
Also available subcutaneously (0.3 mcg/kg) or intranasally (fixed
dose of 300 mcg in subjects >50 kg and 150 mcg in subjects <50 kg)
[11]. This treatment promotes the release of vWF and factor
Type 2A
Preferred therapy is vWF/factor VIII concentrates (alphanate,
humate-P, etc.).
Type 2B
Replacement with vWF/factor VIII concentrates or recombinant
vWF. DDAVP is relatively contraindicated as it may exacerbate

• Check CBC, aPTT, PT

Operative vaginal delivery
• Check FVIII levels
only if necessary.
• Check VWF:RCo Assay
Avoid pudendal blocks and
• Type and cross packed red blood cells
episiotomies if possible.
as needed

Type 1 VWD: Type 2 VWD: Type 3 VWD:

• DDAVP* if FVIII or VWD:RCo • DDAVP* if response • VWF concentrates (if FVIII

<50 IU/dL.
Follow FVIII and VWF:RCo daily
(titrate infusions accordingly).
• Maintain levels of both >50
IU/dL during labor, delivery,
and up to 5 days postpartum.
documented on test does
(mainly 2A)
• VWF concentrates (if FVIII
or VWF:RCo <50 IU/dL).
Follow FVIII and VWF:RCo
daily (titrate infusions
accordingly).
• Maintain levels of both
>50 IU/dL during labor,
delivery, and up to 5
days postpartum.
or VWF:RCo < IU/dL). Follow
FVIII and VWF:RCo daily
(titrate infusions accordingly).
• Maintain levels of both
>50 IU/dL during labor,
delivery, and up to 5
days postpartum.

If prolonged treatment
with DDAVP, consider adding
VWF concentrates. Continue close follow-up of FVIII and VWF:RCo levels for
up to 2 weeks postpartum (especially if cesarean section)
and provide prophylaxis accordingly to avoid late
postpartum hemorrhage.

FIGURE 16.2 Peripartum management of von Willebrand disease (Adapted from Ref. [4].) * Avoid hypotonic solutions at time of
delivery if using DDAVP in order to prevent hyponatremia. Abbreviations: vWF, von Willebrand factor; DDAVP, 1-deamino-8-D-arginine
vasopressin; vWF:RCo, von Willebrand factor ristocetin cofactor activity; CBC, complete blood count; aPTT, activated partial
thromboplastin time.
Von Willebrand Disease
thrombocytopenia. Recommend platelet transfusion to count
>50 × 109/L along with antifibrinolytic therapy (tranexamic acid
or aminocaproic acid) [12].
Type 3
Without alloantibodies: vWF/factor VIII concentrates; with
alloantibodies: Recombinant factor VIII. Does not respond to
DDAVP. Consider platelet transfusion if indicated, along with
adjuvant antifibrinolytic therapy [9].
Antepartum testing
Not indicated unless other complications present (no known
direct fetal risks).
Delivery (Figure 16.2)
Types 1 and 2: If vWF levels are ≥50 IU/dL, there is very low risk
of increased bleeding with vaginal or cesarean delivery. If lower,
prophylactically administer DDAVP (if DDAVP responder)
or concentrates/blood products (see above, according to type)
at time of delivery (if possible, 1 hour before) and 12 hours
thereafter (then as needed).
Type 3: Treat daily as above starting before delivery.
Oxytocin administration should be carefully monitored as
fluid retention can be a side effect of both oxytocin and DDAVP,
and can lead to life-threatening hyponatremia. Consideration
should be given to oxytocin and misoprostol (400 mcg buc-
cally), oxytocin and methergine, or carbetocin, as these are all
more effective at preventing postpartum hemorrhage than oxy-
tocin alone [13]. In addition, tranexamic acid prophylaxis (1 g
IV or 10 mg/kg) can also be considered [14]. As the fetus can
have up to a 50% chance of having VWD, fetal scalp electrode,
fetal scalp sampling, and operative vaginal delivery should be
avoided.
Anesthesia
There is a risk of spinal or epidural-site hematoma in patients
with bleeding disorders. Neuraxial anesthesia can be considered
for types 1 and 3 VWD if factor VIII, vWF, and ristocetin cofac-
tor levels are ≥50 IU/dL, and there is no evidence of coagulation
defect (aPTT level is normal) [9]. There is little data regarding the
safety of neuraxial anesthesia for patients with type 2B VWD [12].
Postpartum/Breastfeeding
There is an increased risk of both primary (within 24 hours of
delivery) and secondary (>24 hours after delivery) postpartum
hemorrhage. vWF and factor VIII levels return to baseline 1–3
weeks following delivery, thus close monitoring and additional
doses of DDAVP or vWF/factor VIII concentrates may be war-
ranted [15]. Oral antifibrinolytic therapy can also be used to
prevent delayed postpartum bleeding [11]. Patients with type
2B VWD also have an increased risk of morbidity related to pri-
mary and secondary postpartum hemorrhage as well as severe
thrombocytopenia [16]. Products that inhibit platelet adhe-
sion, such as nonsteroidal anti-inflammatory drugs, should be
avoided [8]. As the neonate has up to a 50% chance of having
VWD, circumcision should be delayed until VWD status is
determined [8].
165
Future
vWF produced by recombinant DNA techniques; gene therapy.
Rare/Related
Glanzman disease (congenital thrombasthenia): Congenital bleed-
ing disorder defined by defective or quantitatively abnormal gly-
coprotein (GP) IIb/IIIa receptors (Figure 16.1). Diagnosis: Bleeding
and abnormal platelet aggregation in response to stimuli, pro-
longed bleeding times, and normal platelet counts [3]. Four preg-
nancies in the world’s literature up to 1978, very few, if any, since.
References
1. Mannucci P. Treatment of von Willebrand disease. NEJM 2004;
351:683–694. [Review]
2. James AH. Von Willebrand disease. Obstet Gynecol Survey 2006;61:
136–145. [Review]
3. Newman PJ, Seligsohn U, Lyman S, et al. The molecular genetic basis of
Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in
Israel. Proc Natl Acad Sci USA 1991;88:3160–3164. [II-3]
4. Pacheco LD, Constantine MM, Saade GR, Mucowski S, Hankins GDV,
Sciscione AC. Von Willebrand disease and pregnancy: a practical approach
for the diagnosis and treatment. Am J Obstet Gynecol 2010;(203):194–200.
[Review]
5. Kadir RA, Lee CA, Sabin CA, Pollard D, Economides DL. Pregnancy
in women with von Willebrand’s disease or factor XI deficiency. BJOG
1998;105:314–321. [II-3]
6. Lipe BC, Dumas MA, Ornstein DL. Von Willebrand disease in pregnancy.
Hematol Oncol Clin N Am 2011;25:335–358. [Review]
7. Chi C, Kadir RA. Inherited bleeding disorders in pregnancy. Best Pract Res
Clin Obstet Gynaecol 2012;26:103–117. [Review]
8. Von Willebrand disease in women. Committee Opinion No. 580.
American College of Obstetricians and Gynecologists. Obstet Gynecol
2013;122:1368–1373. [Committee Opinion; III]
9. Makhamreh MM, Kass SL, Russo ML, et al. Type 3 von Willebrand disease
in pregnancy: A systematic literature review. Am J Perinatol 2019; Online
ahead of print. [Review; II-3]
10. Punt MC, Waning ML, Mauser-Bunschoten EP, et al. Maternal and neo-
natal bleeding complications in relation to peripartum management in
women with von Willebrand disease: A systematic review. Blood Reviews
2020;39:100633. [Review; II-2]
11. Castaman G and James PD. Pregnancy and delivery in women with von
Willebrand disease. Eur J Haematol 2019;103:73–79. [Review; III]
12. Pishko AM, Levine LD, Cines DB. Thrombocytopenia in pregnancy:
Diagnosis and approach to management. Blood Reviews 2020;40:100638
[Review; III]
13. Gallos ID, Williams HM, Price MJ, et al. Uterotonic agents for preventing
postpartum haemorrhage: a network meta-analysis. Cochrane Database
Syst Rev 2018;4(4) Update in: Cochrane Database Syst Rev. 2018 Dec 19;12.
[Meta-analysis; n ≥ 89,000]
14. Simonazzi G, Bisulli M, Saccone G, et al. Tranexamic acid for preventing
postpartum blood loss after cesarean delivery: a systematic review and
meta-analysis of randomized controlled trials. Acta Obstet Gynecol Scand
2016;95(1):28–37. [Meta-analysis; 9 RCTs]
15. Winikoff R, Scully MF, Robinson KS. Women and inherited bleeding disor-
ders – A review with a focus on key challenges for 2019. Transfus Apher Sci
2019;58:613–622. [Review; III]
16. Makhamreh MM, Russo ML, Karl T, et al. Type 2B von Willebrand disease
in pregnancy: A systematic literature review. Semin Thromb Hemost 2020.
2021 Mar;47(2):201–216. doi: 10.1055/s-0041-1723799. Epub 2021 Feb 26.
PMID: 33636751. [Review; III]
17. Berger J, Schwartz J, Ramachandran S, et al. Review of von Willebrand dis-
ease and acquired von Willebrand syndrome for patients undergoing car-
diac surgery. J Cardiothorac Vasc Anesth 2019;33(12):3446–3457.
17
URINARY TRACT DISEASE
Giuseppe Chiossi
Key points
• The frequency of complications in pregnancies with mater-
nal renal disease is directly proportional to the severity of
renal dysfunction, typically correlated with the initial cre-
atinine level.
• Pregnancy-related acute kidney injury (AKI) is associated
with maternal death, longer intensive care unit stays, cesar-
ean delivery (CD), preterm birth, stillbirth and perinatal
death, and lower birth weight, but it usually resolves with
no long-term consequences on maternal renal function
• Pregnant women with chronic kidney disease (CKD) have
a higher risk of pre-eclampsia, CD, preterm birth, still-
birth, and perinatal death, as well as lower birthweights
than healthy controls. Higher CKD stages are associated
with worse pregnancy outcomes. A definitive association
between pregnancy and further loss of renal function has
not been demonstrated; however, mothers with mild renal
insufficiency are unlikely to experience disease progression
in pregnancy, as opposed to those with more advanced CKD
stages. In women with creatinine ≥1.4 mg/dL, about 10% will
have progressive renal deterioration. Creatinine >2.3 mg/dL
may be regarded as a contraindication to pregnancy.
• Women with end-stage renal disease (ESRD) on dialysis
should be counseled preconceptionally that they should
receive a renal transplant and then wait 1–2 years before
attempting pregnancy. Women on dialysis or with a
recently transplanted kidney should be maintained on
effective contraception. If pregnant, counseling should
include review of the very high rates of the above compli-
cations. Intensive (>36 hour/week) hemodialysis signifi-
cantly improves fetal outcomes in ESRD patients.
• Live birth rates in women after renal transplantation are
≥80%, when pregnancy is adequately planned.
• Patients with CKD, ESRD, and renal transplant recipients
should receive low-dose aspirin to reduce their incidence
of pre-eclampsia.
• Workup of patients with kidney disease includes a mini-
mum of serum creatinine, blood urea nitrogen, electro-
lytes as well as 24-hour urine collection for protein and
creatinine clearance. A blood pressure target of less than
140/90 mmHg is also recommended.
• Pelvic floor muscle training among continent pregnant
women decreased the rate of urinary incontinence in
late pregnancy, and up to 6 months postpartum. Pelvic
floor muscle training after childbirth is effective in pre-
vention and treatment of urinary incontinence.
• Asymptomatic bacteriuria should be assessed for at the
first prenatal visit and treated promptly as 20–40% of
women will develop pyelonephritis if left untreated.
• Creatinine >2.4 mg/dL may be regarded as a contrain-
dication to pregnancy.
166
Physiologic renal changes in pregnancy
Pregnancy is marked by vasodilation, occurring soon after con-
ception. This results in a drop in blood pressure, an increase in
cardiac output, and an increase in renal blood flow as well as
glomerular filtration rate (GFR). Likely causes include increased
progesterone, nitric oxide, relaxin, and estrogen. Functionally,
there is increased renal plasma flow that peaks 60–80% in second
trimester and then falls to 50–60% above baseline during third
trimester. GFR increases 30% during the first trimester and peaks
at 50% above pre-pregnancy values in the second trimester [1].
Creatinine (Cr) and urea productions remain unchanged, result-
ing in a drop in serum Cr and urea (BUN) levels to mean values
of 0.6 and 9 mg/dL, respectively. Near term, a 15–20% decrease
in GFR occurs (Chapter 3, Obstetric Evidence Based Guidelines)
[2, 3]. Ideally, evaluation of renal function in pregnancy should
be based on GFR, with Cr clearance probably the best way to
approximate GFR (normal values; Table 17.1) [4]. Hyperfiltration
and changes in glomerular permeability account for an increase
in protein excretion from 60–90 mg/d to 180–250 mg/d during
the course of normal pregnancy, as measured by a 24-hour urine
collection. As a consequence of this physiologic increase in pro-
teinuria, the threshold for elevated proteinuria in pregnancy has
been set at a higher level of protein excretion of 300 mg/d. The use
of spot urine protein-creatinine ratio (P/Cr) has gained favor
in pregnancy to quantify proteinuria in order to diagnose pre-
eclampsia, which is typically characterized by a P/Cr > 0.3 g/g.
There may be increased P/Cr in the absence of hypertension or
kidney disease, a phenomenon known as isolated proteinuria,
present in as many as 15% of pregnancies [1].
There is also an increase in the size of the kidneys and
urinary collecting system. Kidney length increases approxi-
mately 1 cm and volume increases 30% [5]. The combina-
tion of smooth muscle relaxation due to progesterone and
mechanical compression by the enlarging uterus can cause
physiologic hydronephrosis and retention of urine in the col-
lecting system during pregnancy, which may be confused with
an obstructive uropathy. Mild hydronephrosis, particularly
common on the right, may be present and physiologic in >90%
of normal pregnancies [6].
Acute kidney injury
Definition
Acute kidney injury (AKI) is characterized by a rapid decrease
in renal function over hours or days, resulting in an increase in
metabolic waste products, increasing serum Cr and BUN levels,
and eventually, a decrease in urine output. An accepted definition
of AKI during pregnancy is challenging in view of the physiologi-
cal changes in GFR with gestation, and frequent lack of baseline
Cr levels. The international definitions of AKI are not validated
for use in pregnancy, and there is potential for pregnant women
DOI: 10.1201/9781003099062-17
Urinary Tract Disease 167

TABLE 17.1: Normal Ranges of Renal Functions during • Serial or comparative measurements of serum Cr and
Pregnancy BUN, evaluation of serum electrolytes, full blood count
and liver function tests.
Non-pregnant 1st 2nd 3rd
• Urine electrolyte evaluation and urinalysis. Frequently,
Adult Trimester Trimester Trimester
in cases of intrinsic renal injury, renal concentration of
Creatinine 0.5–0.9 0.4–0.7 0.4–0.8 0.4–0.9 urinary electrolytes is impaired because of damage to the
(mg/dL) renal post-glomerular nephron, accounting for a different
Glomerular 106–132 131–166 135–170 117–182 pattern of urinary electrolyte concentration as opposed to
Filtration Rate prerenal azotemia. The fractional excretion of Na [FENa
(ml/min) = (urine Na+/serum Na+)/(urine creatinine/serum cre-
Source: From Callaghan WM, Creanga AA, et al. Severe maternal morbidity
atinine) × 100%)] reflects the relative conservation of this
among delivery and postpartum hospitalizations in the United States. electrolyte. FENa in prerenal AKI is <1 unless the patient
Obstet Gynecol 2012;120(5):1029e36. Ref. [9], with permission. receives chronic diuretic therapy. In intrinsic AKI, FENa
is usually >1. Commonly seen urinary and laboratory val-
with AKI to have Cr levels falling within the “normal range” for ues in AKI are outlined in Table 17.3.
non-pregnant women despite a significant drop in GFR. • Microscopic urinary sediment: Prerenal AKI is typically
We propose in Table 17.2 the KDIGO (Kidney Disease: associated with hyaline casts, while intrinsic AKI is associ-
Improving Global Outcomes) definition of AKI [7]. ated with cellular (epithelial cells) or granular casts, as the
sediment is reflective of nephron disruption.
Epidemiology • Assessment of proteinuria using the urinary dipstick
According to the International Society of Nephrology, 1% of AKI is method, 24-hour urine collection, and P/Cr ratio on a ran-
pregnancy related; however, the burden is highest in lower-income dom sample.
countries where 3.1% cases of AKI were found to be pregnancy • Ultrasound to rule out urinary tract obstructions.
related compared to 0.3% of cases in high income countries [8]. • Second level examinations are represented by MRI or
However, more recent data show that pregnancy-related AKI is CT scans, to evaluate the entire urinary tract, especially
increasing in the United States from 2.3/10,000 deliveries in 1998 to if ultrasound is not conclusive. CT is usually performed
4.5/10,000 deliveries in 2008 [9]. These trends may be explained by a if MRI is not available due to radiation exposure. Kidney
higher prevalence of risk factors for obstetric complications such as biopsy can also be performed if indicated.
obesity, hypertension, diabetes, and advanced maternal age.
Prerenal AKI
Classification and clinical approach FENa in prerenal AKI is <1. It is the result of decreased renal
to AKI in pregnancy perfusion, often due to intravascular volume depletion, but also
As in non-pregnant patients, AKI can be divided into prerenal, from decreased cardiac output. Sustained prerenal azotemia
intrinsic (renal), or postrenal causes; however, renal failure is results in acute tubular necrosis (ATN), which is the most com-
frequently a multimodal process due to more than one insult. mon cause of intrinsic AKI. Early in pregnancy, hyperemesis
Evaluation of pregnant patients with AKI includes: gravidarum or other gastrointestinal illnesses with vomiting or
diarrhea are frequent causes of AKI secondary to profound vol-
• History and physical examination. ume depletion. Obstetric hemorrhage from abortion, placenta
• Assessment of urine output as oliguria is indicative of previa, placental abruption, uterine rupture, or postpartum uter-
renal dysfunction. ine atony may account for prerenal ischemia and decrease renal
perfusion. Sepsis may also lead to hypotension and AKI [10, 11].
TABLE 17.2: KIDGO Definition of AKI
Renal AKI
Stage Serum Creatinine Urine Output In intrinsic AKI, FENa is usually >1. Acute renal failure may
result from a variety of intrinsic renal diseases. Different com-
1 1.5–1.9 baseline <0.5 ml/Kg/hour for
ponents of the kidney may be involved depending on the specific
Or 6–12 hours
disease process: Involvement of the glomeruli is characteristic of
≥0.3 mg/dl (≥26.5 μmol/l) increase
2 1.5–1.9 baseline <0.5 ml/Kg/hour for
12 hours
TABLE 17.3: Urine and Laboratory Values in AKI
3 3 baseline <0.3 ml/Kg/hour for
Or 24 hours Prerenal AKI Intrinsic AKI
Increase to ≥4 mg/dl (≥353.6 μmol/l) Or BUN: Creatinine ratio >20:1 10:1
Or Anuria for ≥12 hours Urine Na+ (mEq/L) <20 >40
Initiation of renal replacement therapy
Fractional excretion of Na+ (FENa+) <1% >2%
Or
Urine osmolality (mosm/kg H2O) >500 <350
In patients <18 decrease in eGFR to
Urine sp gr >1.020 1.010
<35 ml/min per 1.73 m2
Urine sediment Bland Granular casts, renal
Source: From KDIGO. Clinical practice guideline for acute kidney injury. Kidney tubular epithelial
Int Off J Int Soc Nephrol 2012;2(1):1e138. i–iv, Available from: http://
cells
www.kdigo.org/index.php. Ref. [7], with permission.
Abbreviation: KDIGO, Kidney Disease: Improving Global Outcomes. Source: Modified from Vijaian et al. 2019, Ref. [11].
168
TABLE 17.4: AKI According to Different Intrinsic Renal Diseases
Acute Tubular
Necrosis
Urine sediment Brown granular casts
Proteinuria <2 g/day
FENa+ >2%
Hypertension Uncommon
Systemic Hypotension, sepsis,
manifestations hemorrhage
Source: Modified from Vijaian et al. 2019, Ref. [11].
glomerulonephritis, renal tubules are mainly damaged in ATN,
and the interstitium is the primary area of injury in acute inter-
stitial nephritis [10, 11]. Examination of the urinary sediment can
provide valuable clues to the diagnosis (Table 17.4).
Acute tubular necrosis
Early AKI results from moderate renal ischemia and is usu-
ally a mild form of disease that is reversible if renal perfusion is
restored. When renal ischemia is prolonged and persistent, acute
tubular necrosis (ATN) develops. The combination of paren-
chymal edema and the sloughing of necrotic tubular epithelium
into the tubule obstructs the tubular lumen, leading to resultant
decreased GFR and granular casts in the urinary sediment. The
final stage is represented by renal cortical necrosis (now rarely
seen in societies with access to health care) that follows severe
renal ischemia with disintegration of both glomeruli and tubules
in the renal cortex [10, 11]. Although rare in pregnancy, ATN may
also result from a variety of toxic exposures, including aminogly-
cosides, radiographic contrast, heavy metals, chemotherapeutic
agents, and nonsteroidal anti-inflammatory agents. Moreover,
pigment-induced ATN may occur in cases of rhabdomyolysis
or massive hemolysis. Acute tubular necrosis has three phases:
Initiation, maintenance, and recovery, which depend on the
severity of insult and proportion of unaffected residual nephrons.
Urinalysis typically reveals muddy brown granular casts and
renal tubular epithelial cells. In light of impaired renal tubular
function, laboratory evaluation reveals a high urinary sodium
excretion as well as urine that is neither concentrated nor diluted.
Acute tubular necrosis may be either oliguric (urine output <400
mL/day) or non-oliguric (>400 mL/day). The recovery phase is
typically characterized by polyuria with eventual return of renal
function.
Acute glomerulonephritis
Numerous causes of acute glomerulonephritis (GN) may account
for AKI in pregnancy, such as post-streptococcal GN, mem-
branoproliferative GN, idiopathic rapidly progressive (or cres-
centic) GN, as well as secondary glomerular disorders such as
lupus nephritis, systemic vasculitis, and bacterial endocarditis
[10, 11]. Acute glomerulonephritis usually manifest as nephritic
syndrome characterized by reduced kidney function, non-
nephrotic proteinuria (<3.5 g/24 hours), hematuria with red cell
casts, hypertension, and edema. A common mode of presenta-
tion, represented by the acute post-streptococcal GN, is oliguria,
Maternal-Fetal Evidence Based Guidelines
Acute Interstitial
Nephritis Acute Glomerulonephritis
Hematuria, pyuria, Hematuria, renal tubular cells RBC
eosinophils, WBC casts casts, oval fat bodies
<2 g/day Variable
• 0.15–2 g/day mild forms
• >2 g/day severe forms
• possible nephrotic syndrome
>2% <1%
Uncommon Common
Fever, skin rash, new Collagen-vascular disease, infection
medication
cola-colored urine, weight gain, edema, and hypertension over a
few days [10, 11].
Acute interstitial nephritis
Acute interstitial nephritis (AIN) is characterized by inflamma-
tory infiltration within the renal interstitial parenchyma and
peritubular space. AIN has been associated with exposure to
medications (nonsteroidal anti-inflammatory agents, diuretics,
beta-lactamic antibiotics, antacids), infections, and autoimmune
disorders. Drug exposure is the most common cause of AIN in
pregnancy: The risk of the disease increases after 2 weeks of treat-
ment although there is no direct association with the medication
dose. Nonsteroidal anti-inflammatory agents may produce both
AIN and ATN by drug reaction and ischemia-mediated tubular
dysfunction, respectively. Pyelonephritis also may cause AKI by
AIN or ATN, the latter in the setting of hypovolemia and prer-
enal AKI. AIN typically presents with modest proteinuria (<2 g/
day), pyuria, eosinophiluria, hematuria, and white blood cell casts
on urinalysis. Systemic manifestations may include fever, rash,
arthralgias, and other signs of a hypersensitivity reaction espe-
cially when AIN is due to medication exposure [10, 11].
Thrombotic microangiopathies
Thrombotic thrombocytopenic purpura (TTP) and hemolytic
uremic syndrome (HUS) are characterized by thrombi of fibrin
and/or platelets developing in the organ microvasculature (pri-
marily the brain and kidney), accounting for organ damage and
microangiopathic hemolytic anemia [10, 11]. Histologic findings
in the kidney show endothelial cell swelling, subendothelial pro-
tein deposits, and double contouring of the basement membrane.
Postrenal AKI
It is uncommon in pregnancy, when it is usually due to obstruc-
tion of the urethra or both ureters by the gravid uterus (particu-
larly in cases of multiple pregnancies or polyhydramnios), kidney
stones, or extrinsic compression.
Pre-eclampsia and AKI
About 40% of AKI in pregnancy is due to pre-eclampsia with
severe features and HELLP syndrome. One percent of women
with pre-eclampsia and 3–15% of those diagnosed with HELLP
syndrome will develop AKI [1]. Patients with pre-eclampsia
are predisposed to AKI due to reduced intravascular volume,
resulting in a prerenal kidney perfusion state and oliguria.
Urinary Tract Disease 169

Less commonly, renal afferent arteriolar vasospasm or depressed Treatment of AKI

myocardial function are responsible for the underlying patho-
physiological process. The histologic lesion pathognomonic of
pre-eclampsia is glomeruloendotheliosis. The lesion is character-
ized by decreased glomerular size and increased cytoplasmic vol-
ume, which account for reduced capillary lumen diameter leading
to prerenal AKI and ATN. Finally, vasoconstriction, as well as
inflammatory and coagulation cascades activation typical of pre-
eclampsia, are further risk factors for AKI [10, 11]. Renal biopsies
performed on 16 patients with persistent AKI after HELLP syn-
drome showed histopathology consistent with thrombotic micro-
angiopathies (TMA), ATN, or acute renal cortical necrosis [12].
The exclusion of pre-eclampsia/HELLP syndrome from the dif-
ferential diagnosis of TMA is challenging in the pregnant patient,
as outlined in Table 17.5.
Renal biopsy
Renal biopsy is rarely indicated in pregnancy. A systematic review
of 39 studies provided data for 243 biopsies performed during
pregnancy: The main indication was to differentiate glomeru-
lonephritis from pre-eclampsia, and the results led to changes
in therapy in 66% of cases. The risk of complications follow-
ing renal biopsy in pregnancy is 7% compared to that of 1%
after delivery, with a 2% risk of major bleeding, particularly
for renal biopsies performed in the second trimester. Overall,
renal biopsy should be performed in pregnancy if results are
expected to change management during pregnancy or change
the timing of delivery [13].
Supportive measures
Drugs that may cause further renal damage should be stopped
(such as non-steroidal anti-inflammatory drugs, or aminoglyco-
side antibiotics). Medications (i.e., antibiotics) may also need dose
adjustment according to the degree of renal impairment. The load-
ing dose of magnesium sulfate can be administered safely even in
renal shut-down. Regular assessment of serum magnesium con-
centrations and deep tendon reflexes, as well as lower constant
infusion rates (e.g., 1 g/hour), are often indicated [10, 11].
Fluid balance
Replacement of blood and fluid losses is mandatory to maintain
adequate blood pressure levels and ensure sufficient renal perfusion;
however, an excessive fluid infusion in patients with oliguria from
renal AKI such as ATN or pre-eclampsia may result in fluid overload,
causing serious iatrogenic problems. When the diagnosis of AKI is
associated with persistent oliguria, increasing serum BUN and Cr,
strict fluid balance (strict Input/Output, I&O) and biochemical
monitoring must be instituted. The diet should decrease the amount
of potassium and phosphate, and provide high-quality proteins.
Serum potassium levels should be carefully checked due to the dan-
gers of hyperkalemia and attention should also be given to the acid-
base balance due to the danger of metabolic acidosis [1, 10, 11].
Pharmacological therapies
Loop diuretics are rarely harmful and may assist in fluid man-
agement in cases of volume overload, especially within the first

TABLE 17.5: AKI in Different Disease Processes

Pre-Eclampsia/
HELLP AFLP TTP HUS Lupus Flare

Timing
2nd trimester + + ++ + +
3rd trimester ++ ++ + + +
Postpartum + 0 + ++ +

Signs and Symptoms

Fever 0 0 + + ++
HTN +++ ++ + + 0 to +++
Neurologic symptoms + + ++ 0 0 to +++
Purpura 0 0 ++ ++ 0

Laboratory Abnormalities
Hemolysis + to +++ 0 to + +++ ++ to +++ 0 tp +
Schistocytes 0 to ++ 0 to + +++ ++ to +++ 0
Elevated LFTs ++ to +++ ++ to +++ 0 to + 0 to + 0
Elevated LDH ++ to +++ + to ++ +++ ++ to +++ 0 to +
Low platelet ++ to +++ + to ++ +++ ++ to +++ + to ++
Factor V N or ↓ ↓ N N N
Total bilirubin + ++ to +++ + to ++ + to ++ 0 to +
AKI 0 to ++ + 0 to ++ ++ to +++ 0 to +++
DIC 0 to + + to +++ 0 0 0
Hypoglycemia 0 to + + to +++ 0 0 0
ADAMTS 13 activity Detectable NA Undetectable Detectable Detectable
Source: Modified from Vijaian et al. 2019, Ref. [11].
Abbreviations: HTN, hypertension; LFT, liver function tests; TTP, Thrombotic thrombocytopenic purpura; HUS, hemolytic uremic
syndrome.
170 Maternal-Fetal Evidence Based Guidelines

TABLE 17.6: Stages of Chronic Kidney Disease

Stage 1 2 3 4 5
Function Normal a Mildly impaired Moderately impaired Severely impaired End-stage kidney failure
GFR ≥90 60–89 30–59 15–29 <15 or on dialysis
Disease progression 7.6% progress 12.6% progress 16.2% progress to 20% require 20% of non-dialyzed
in pregnancy to stage 2 to stage 3 stage 4 dialysis patients require dialysis
Source: Adapted from Ref. [69].
a Kidney damage already present, as indicated by urinalysis, structural abnormalities, or genotype, but not otherwise clinically evident.

48 hours of the diagnosis of AKI. Increased mortality and poorer
renal outcomes were associated with diuretic use in critically
ill patients with AKI [14], while a large multicenter prospec-
tive cohort study demonstrated no difference in mortality rates
according to diuretic use [15], as converting oliguric to non-oli-
guric AKI does not improve outcomes per se. When considering
renal causes of pregnancy-related AKI, it is of critical importance
to initiate disease specific treatments. TMA are treated with
serial plasma exchange; glomerulonephritis and lupus flares are
often treated with steroids and immunosuppressants, while in
cases of pre-eclampsia or HELLP syndrome prompt delivery is
the only cure along with adequate supportive measures. In most
cases, AKI will respond to supportive measures, but when this
approach is unsuccessful or patients present late in the course
of their illness, dialysis may be necessary. The literature on
renal replacement in pregnancy primarily involves women with
chronic kidney disease and therefore requires extrapolation to
pregnancy-related AKI [10, 11].
Pregnancy considerations and outcomes
A systematic review and meta-analysis of maternal and fetal out-
comes of pregnancy-related AKI including almost 6000 preg-
nancies in 11 studies from a variety of settings (data from China,
France, Tunisia, Morocco, and Turkey) showed that pregnancy-
related AKI is associated with a higher risk of maternal death
(OR 4.5; 95%CI 2.7–7.3), stillbirth and perinatal death (OR 3.39;
95%CI 2.76–4.18), longer intensive care unit stays (weighted
mean difference 2.13 days, 95%CI 1.43–2.83), lower birth weight
(weighted mean difference −740 g; 95%CI −1180 to −310), lower
gestational age at delivery (weighted mean difference −0.7 weeks;
95%CI −1.21 to −1.19), delivery by cesarean section (OR 1.49
95%CI 1.37–1.61) and other outcomes such as placental abrup-
tion, or HELLP syndrome [16]. Of note, definitions of pregnancy-
related AKI in the included studies varied considerably.
In terms of renal outcomes, previously AKI was thought to be
an entirely reversible syndrome. However, there is mounting evi-
dence outside of pregnancy that AKI leads to an increased risk of
CKD [17]. There are limited data available on to pregnancy-related
AKI, but in the majority of cases, AKI appears to be revers-
ible, with rates of renal recovery reported between 60% and
90% [18]. Follow-up of women who have an episode of pregnancy-
related AKI is also important, particularly among those with a
renal etiology such as pre-eclampsia. At 6 months postpartum,
proteinuria secondary to pre-eclampsia resolves in more than
95% of women [19]. Therefore, women with persistent postpar-
tum proteinuria warrant further monitoring, as underlying renal
disease was found in >70% when renal biopsy if performed due
to persistent postpartum proteinuria [20]. The 6-week postnatal
check offers adequate opportunity for follow-up of these patients,
assessing proteinuria with dipstick urine testing in the office and
prescribing repeat renal function.
Chronic kidney disease
Definition
Chronic kidney disease (CKD), previously known as chronic renal
insufficiency or chronic renal failure, is the result of a heteroge-
neous group of disorders leading to a progressive impairment of
renal function. CKD is classified according to glomerular filtra-
tion rate (GFR) into five stages, the most severe of which (end-
stage renal disease or ESRD) is characterized by insufficient renal
function to sustain life, requiring dialysis or kidney transplanta-
tion (Table 17.6) [21]. Without proper treatment, ESRD is fatal.
Older studies used serum Cr to classify CKD, although the rela-
tionship between serum Cr and CKD stage in pregnancy is not as
predictable as in the non-pregnant state. (Table 17.7). However,
first trimester (or preconception) Cr can still be used to estimate
prognosis in pregnancy (Table 17.8).
TABLE 17.7: CKD Definitions
Degree of CKD Serum Cr (mg/dl) Cr Clearance (ml/min) Stage of CKD
Mild <1.4 >70 1–2
Moderate 1.4–2.4 40–70 2–3
Severe >2.4 <40 3–4

TABLE 17.8: Rate of Complications According to Degree of Renal Insufficiency (%)

Perinatal Decline in
Creatinine PTB Pre-Eclampsia HTN FGR Mortality Live Birth Renal Function
<1.4 20 11 25 24 9 >90 16
1.4–2.8 36–60 42 56 31–37 7 >90 50
>2.8 73–86 86 56 43–57 36 N/A 40
Dialysis 48–84 20 100 50–80 60 40–50 N/A
Renal transplant 52–75 23–37 47–63 20–66 7 74–80 14
Source: From Refs. [14, 22–26].
Abbreviations: PTB, preterm birth; HTN, hypertension; FGR, fetal growth restriction; N/A, not available.
Urinary Tract Disease
Symptoms
Besides symptoms related to the specific cause of CKD, edema,
fatigue, weakness, headaches, and loss of appetite are common.
As renal disease progresses to ESRD, symptoms of uremia such as
nausea, vomiting, bad breath, and pruritus may develop as toxic
metabolites, normally filtered out of the blood by the kidneys,
build up to harmful levels. Urine output depends on the degree of
renal impairment and therefore affects micturition. Impairment
of renal function also accounts for anemia, altered bone min-
eral metabolism, acid-base and electrolyte imbalances that may
account for specific clinical manifestations.
Epidemiology
The overall incidence of CKD in the general obstetric population
is 0.03–0.4% [22].
Complications
Prognosis is directly related to the degree of renal damage
(Table 17.8) [14, 22–26]. The best outcomes are in women with
preconception serum creatinine levels below 2 mg/dL and dia-
stolic blood pressure of 90 mmHg or less, although women with
only mild renal insufficiency may still be at increased risk for
adverse outcomes [1, 6, 27]. Creatinine clearance below 70 mL/
min prior to conception is associated with poor outcomes even
when serum creatinine levels are in the minimal dysfunction cat-
egory [28]. Needing more than one antihypertensive medication
for optimal control is associated with a significant decrease in live
birth rate [20]. Proteinuria (>1 g/24 hour) and reduced GFR (<40
mL/min) in combination are risk factors for progression of renal
disease to end stage, and also predict a shorter time to dialysis
therapy and lower birth weight [29].
Infertility: Conception with GFR <25 mL/min is rare second-
ary to alterations in hypothalamic-pituitary-adrenal (HPA)
axis [30].
Hypertension: Incidence of hypertension increases from 28%
at baseline to approximately 50% by the third trimester
[21].
Proteinuria: Urinary protein excretion >3 g in 24 hours increases
from approximately 25–41% during pregnancy [21].
Pre-eclampsia: Increased incidence. Diagnosis is difficult
because of the high frequency of baseline hypertension and
proteinuria.
Preterm labor: Incidence as high as 85% [31].
Low birth weight: 66% [31].
Perinatal mortality: 10% to 20% [20, 21].
Cost: Women with chronic renal disease have increased
median cost of pregnancy [4].
Effects of pregnancy on CKD
Pregnancy has the potential to accelerate disease progression and
decrease time to ESRD according to the severity of the underlying
renal disease. In those with mild renal insufficiency, significant
renal function loss is unlikely, while among those with more
advanced CKD, are at risk of further loss of kidney function
(Table 17.8). In a 1996 study on women with advanced CKD≤
there were 59 pregnancies in women with moderate renal insuffi-
ciency (1.4–2.4 mg/dL) and 15 pregnancies in women with severe
renal insufficiency (greater than 2.4 mg/dL) noting worsening
renal function that persisted at 6 months postpartum in 31% of
the patients, with 23% of this subgroup progressing to ESRD by
6 months postpartum [23].
171
A 2015 systematic review evaluated the effect of pregnancy on
kidney function of women with CKD as opposed to those without
the disease. Of the 23 studies identified, eight reported 216 renal
outcomes in 1268 participants. Renal outcomes were defined as
doubling of serum Cr levels, 50% decrement in Cr clearance, or
ESRD. The study found no association between CKD and decrease
in renal function [24]. In 2015, in 504 pregnancies in women with
CKD the likelihood for loss of kidney function increased with
each successive stage of CKD. Respectively 7.6%, 12.6%, and
16.2% of the patients in CKD stage 1, 2, and 3 progressed to
the next stage of CKD, while 20% of patients with stage 4 and 5
required dialysis [25]. The risk for loss of renal function in preg-
nancy depends not only on the CKD stage, but also on concomi-
tant factors such as hypertension and proteinuria. Inadequately
treated hypertension may contribute to further renal damage,
even in women with only moderate renal insufficiency. Further,
when proteinuria exceeds 1 g/d in combination with significantly
compromised GFR (less than 40 mL/min), there is accelerated
GFR loss postpartum [26].
Effects of CKD on pregnancy
A 2015 systematic review and meta-analysis included 23 studies
and examined adverse pregnancy outcomes in 506,340 pregnan-
cies enrolled in 14 studies, comparing women with chronic kid-
ney disease to healthy controls. Women with CKD had a higher
risk of pre-eclampsia (OR 10.4, 95% CI 6.3–17.1), preterm deliv-
ery (OR 5.7, 95% CI 3.3–10.0), small for gestational age (SGA)
or low birth weight infant (OR 4.9, 95% CI 3.0–7.8), cesarean
delivery (OR 2.7, 95% CI 2.0–3.5), and failed pregnancy (includ-
ing fetal and neonatal death, OR 1.8, 95% CI 1.0–3.1) [24].
Again, worsening of pregnancy outcomes depends on the degree
of CKD; as women progress through the stages of renal insuffi-
ciency, the risk of adverse outcomes increases accordingly [25].
Women with more advanced CKD are also more likely to have
higher rates of concomitant hypertension and proteinuria, which
further increases the risk of adverse pregnancy outcomes [26].
Management
Multidisciplinary care that includes nephrologists, maternal-
fetal medicine specialists, anesthesiologists, and neonatologists
is the ideal in the management of pregnancies with CKD, given
the higher risks of complications.
Workup
Serum creatinine, BUN, and electrolytes as well as 24-hour
urine collection for protein and creatinine clearance. A
24-hour urine >300-mg protein is considered abnormal and cor-
relates roughly to 1+ proteinuria on a urine dipstick. Urine dip-
stick should not be the only testing for women with suspected
renal disease, as this can miss up to 1 in 11 hypertensive pregnant
women with actual proteinuria [32]. A 24-hour urine collection
has long been the gold standard, although a random protein-
creatinine ratio has been shown to accurately predict baseline
proteinuria in early pregnancy [33, 34]. Renal biopsy should be
reserved to those whose diagnosis is in question, particularly in
those with sudden deterioration in renal function for no known
reason, as it may change the management in up to 66% of cases
[35]. It is generally recommended only before 32 weeks of preg-
nancy, as delivery after 32 weeks may be accomplished with
relatively good outcomes for the neonate after which the biopsy
may be performed. Severe renal disease may increase the risk
172
of complications from the renal biopsy. A skilled physician and
ultrasound guidance should be used in the performance of a renal
biopsy in a pregnant individual [10].
Preconception
Ideally, pre-pregnancy counseling by a multidisciplinary team is
recommended for patients with CKD, to discuss the risks associ-
ated with pregnancy according to the CKD stage. Prior to concep-
tion CKD patients should be advised on the importance of [27]:
• Discontinuation of teratogenic medications: ACE
inhibitors and ARB should be stopped prior to con-
ception or at most before 8 weeks of gestation.
Immunosuppressants such as mycophenolate mofetil,
methotrexate, and cyclophosphamide should be discon-
tinued, and patients should be switched to agents consid-
ered acceptable in pregnancy.
• Control of blood pressure (<140/90 mmHg) with preg-
nancy-appropriate medications such as labetalol, nifedip-
ine, or hydralazine.
• Optimization of glycemic control in diabetic patients
(see Chapters 4 and 5) [27].
• Waiting for at least 6 months of disease quiescence prior to
conceiving if CKD is due to SLE or vasculitis [27].
• Renal transplant before pregnancy for patients with
CKD stages IV or V (in general creatinine >2.4 mg/dL).
Prenatal care
Termination of pregnancy generally will not improve renal func-
tion, and, in women with advanced CKD who demonstrate pro-
gression with no evidence of fetal deterioration and controllable
hypertension, expectant management with initiation of dialy-
sis may be considered. Instead, a significantly rapid and severe
decline in renal function is an indication for preterm delivery or
termination of pregnancy.
Hypertension
Hypertension increases the risk pre-eclampsia, preterm deliv-
ery, and fetal growth restriction [26]. Ideally, blood pressure
control should be optimized before pregnancy. No random-
ized controlled trials exist to establish optimal blood pressure
targets among pregnant patients with CKD. A blood pressure
target of less than 140/90 mmHg has been recommended for
women with CKD as hypertension may lead to further kidney
damage [26].
Proteinuria
The degree of proteinuria has been associated with progression
of underlying renal disease during pregnancy and adverse preg-
nancy outcomes [26]. Management of proteinuria for diseases
typically treated with immunosuppression (i.e., lupus nephritis,
vasculitis, membranous nephropathy, minimal change disease)
include prednisone, azathioprine, and the calcineurin inhibitors.
All patients with lupus nephritis should receive hydroxychlo-
roquine during pregnancy (see Chap. 27). It should be initiated
in women with SLE not taking the medication and it should be
continued in those already on it because discontinuation during
pregnancy has been associated with flares. Hydroxychloroquine
also leads to decreased risks of SGA neonates, and drops by
50% the risk of congenital heart block in mothers who are anti-
Sjögren’s syndrome–related antigen A positive [26].
Peripheral edema from severe proteinuria may be incapacitat-
ing. Conservative therapy includes elevation of the extremities
Maternal-Fetal Evidence Based Guidelines
and use of compression stockings and, but often careful use of
loop diuretics (i.e., furosemide) is necessary; in extreme cases,
albumin infusions also have been used. Hypoalbuminemia is
associated with a significantly increased risk of venous throm-
boembolic disease. Limited data suggest that thrombopro-
phylaxis with low molecular weight heparin (LMWH) should
be prescribed throughout pregnancy and 6 weeks postpartum
to women with nephrotic syndrome [26], to those with severe
proteinuria and a serum albumin level <2.0–2.5 g/dL, or to
mothers with lesser degrees of proteinuria and with additional
risk factors, including prolonged periods of immobility or obe-
sity. Proteinuria associated with renal diseases at higher risks
of thrombosis (i.e., membranous nephropathy and vasculitis)
should also prompt thromboprophylaxis in pregnancy [26].
Pre-eclampsia prevention
As pregnant women with CKD are at high risk for the develop-
ment of pre-eclampsia, aspirin should be initiated before 16
weeks of gestation; usually starting at 12 weeks [28]. The recent
ASPRE trial (Combined Multimarker Screening and Randomized
Patient Treatment with Aspirin for Evidence-Based Pre-eclampsia
Prevention) suggests that perhaps a higher dose (i.e., 150 mg)
may be more effective [29]. The benefit of vitamin D and calcium
supplementation in pregnancy for risk reduction of pre-eclampsia
and gestational hypertension was assessed by a meta-analysis of
27 randomized controlled trials including approximately 28,000
women. Calcium, vitamin D, and calcium plus vitamin D low-
ered the risk of pre-eclampsia when compared with placebo,
with pooled RRs (95% CI) of 0.5 (0.4–0.7), 0.5 (0.2–0.9), and 0.5
(0.3–0.8), respectively [30]. The World Health Organization rec-
ommends daily supplementation with 1.5–2 g of oral elemental
calcium in populations with low dietary intake for the preven-
tion of pre-eclampsia, but vitamin D supplementation requires
further study.
Prenatal visits
Patients may be seen every 2–4 weeks until 32 weeks’ gestation,
after which they may need to be seen weekly because of the mark-
edly increased risk for severe pre-eclampsia. Careful monitoring
of blood pressure and proteinuria for early detection of hyper-
tension and superimposed pre-eclampsia should be performed at
every visit.
Laboratory tests
Evaluation of renal function should include a 24-hour creati-
nine clearance and protein excretion at least at the first visit
in early pregnancy, and, depending on severity of renal insuf-
ficiency, each trimester. Similarly, evaluation of serum electro-
lytes (sodium, potassium, chloride, bicarbonate), hemoglobin
and hematocrit should be monitored according to the severity
of the disease. Frequent (i.e., monthly) urine culture should
also be done for early detection of asymptomatic bacteriuria or
confirmation of urinary tract infection. Renal biopsy is rarely
performed in pregnancy, as the diagnosis of CKD generally pre-
cedes conception. Indications for renal biopsy may include
new-onset nephrotic syndrome, significant glomerular disease
where in confirmation of diagnosis will affect treatment choice,
or a sudden deterioration in renal function. Beyond approxi-
mately 30 weeks of gestation, however, the risks of kidney
biopsy may supersede its benefits, owing to technical challenges
associated with a gravid uterus and the potential for coexistent
pre-eclampsia.
Urinary Tract Disease
Other therapies
• Avoidance of nephrotoxic agents for any CKD stage, such
as the tocolytic indomethacin, nonsteroidal anti-inflam-
matory medications for postpartum pain control, or
gentamicin.
• Renal dosing of medications filtered and/or excreted by the
kidneys (i.e., magnesium sulfate, antibiotics). Magnesium
is not contraindicated, but should be used with extreme
caution, begun at 1 to 2 g/hour, possibly without a bolus, or
just giving boluses (no continuous infusion rate) as needed.
Evaluation for side effects of magnesium should occur at
least hourly and magnesium levels should be checked often
(e.g., every 2–4 hours) in labor to adjust the dose. Calcium
gluconate should be available. Clinicians should be aware
of the increased risk of pulmonary edema in women with
CKD and pre-eclampsia [27].
• Metfomin may cause metabolic acidosis in patients with
CKD: It can be used in women with a pre-pregnancy GFR
>30 ml/min/1.73 m2 and stable renal function during gesta-
tion [27].
• Anemia prevention with oral or IV iron supplementation,
in addition to erythropoietin-stimulating agents when
necessary.
• Treatment of hypocalcemia and hyperphosphatemia due to
secondary hyperparathyroidism with oral calcium carbon-
ate supplementation, binders, or both as well as vitamin D
analogues.
• Treatment of maternal acidosis with sodium bicarbonate
to maintain serum pH >7.2 and avoid fetal acidemia. If the
treatment is unsuccessful dialysis should be initiated.
• Prevention and treatment of electrolyte abnormalities.
Low potassium diet should be initiated.
Antepartum testing
Serial (i.e., monthly) ultrasound for fetal growth are recom-
mended, as well as antenatal testing (i.e., non-stress tests, or bio-
physical profile scores) beginning weekly at ≥32 weeks [31].
Delivery
Delivery should be performed in a tertiary care center, especially
in advanced CKD stages. In the absence of maternal or fetal com-
promise, consideration should be given to delivery at or near
term, with cesarean delivery reserved for standard obstetric indi-
cations [26].
Postpartum/Breastfeeding
Little is known about the quantities of immunosuppressive
agents in breast milk. While small series have shown little toxic-
ity, caution should be used when recommending breastfeeding to
patients taking these agents [36].
Long-term renal prognosis
When kidney dysfunction is mild, pregnancy does not appear
to adversely alter the natural history with the possible excep-
tion of a few disorders [20]. In women with moderate to severe
renal insufficiency (maternal serum creatinine ≥1.4 mg/dL),
10% of patients will have progressive renal deterioration at
12 months postpartum [21]. Mild renal insufficiency: Typically
successful pregnancy outcomes with no adverse effect on the course
of their disease [20]. Instead, with moderate and severe renal insuf-
ficiency prognosis is more guarded. Deterioration in renal function
is seen in 43%, of which 10% do not improve postpartum [21].
173
Clinical presentation and disorders
accounting for CKD
Nephrotic syndrome
Definition
Nephrotic syndrome (NS): Defined by >3.5 g of proteinuria in
24 hours in non-pregnant adults [37]. A condition caused by any
disease that damages the kidneys’ filtering system, the glomeruli.
Because of the decrease in oncotic pressure in pregnant women,
nephrotic syndrome is associated with hypoalbuminemia, edema,
venous thromboembolism, and hypercholesterolemia.
Although most cases of nephrotic syndrome are associated
with CKD; such clinical presentation may also accompany AKI as
in minimal change disease [37].
General
The most common causes of adult nephrotic syndrome outside of
pregnancy are focal glomerulosclerosis, membranous nephropa-
thy, and minimal-change disease [38].
Epidemiology/incidence
Nephrotic syndrome occurs in 0.012–0.025% of all pregnan-
cies [37].
Workup
Newly diagnosed nephrotic syndrome in early pregnancy has
been associated with hydatidiform molar pregnancies; therefore,
this should be evaluated [34, 38, 39]. If the diagnosis is made prior
to pregnancy, histologic diagnosis can help direct treatment. In
most cases of stable disease, renal biopsy can be deferred until
postpartum if histologic diagnosis is not already made. Renal
biopsy in pregnancy is considered a safe option, especially if the
results are expected to potentially change management [40, 41].
The presence of proteinuria >1 g in combination with GFR <40
mL/min is predictive of worse prognosis in pregnancy [29]. For
this reason, patients with newly diagnosed proteinuria prior
to 20 weeks gestation (1+ or greater on urine dipstick on two
samples at least 6 hours but no more than 7 days apart) [8]
should have a 24-hour urine collection for both protein and
creatinine clearance, in order to estimate GFR [42]. Testing
for proteinuria on urine dipstick is associated with a high
false positive rate and contamination (blood, semen, deter-
gents, etc.).
Complications
Nephrotic syndrome rarely causes complications in pregnancy in
the absence of hypertension and abnormal renal function. Most
of the literature on nephrotic syndrome in pregnancy is based on
case reports; therefore, the incidence of specific complications is
unknown.
Specific diseases
Membranous nephropathy is associated with increased fetal
demise, preterm delivery (43%), hypertension, and a decline in
maternal renal function [43].
Prenatal care, fetal monitoring,
and labor management
A similar approach to antepartum and intrapartum care can be
used for patients with chronic renal insufficiency (see preceding
section). Patients should be managed with a multidisciplinary
approach, in conjunction with a perinatologist, nephrologist, and
neonatologist.
174
Management
It may be necessary to treat nephrotic syndrome with steroids,
which requires early and repeat screening for gestational diabetes
mellitus (GDM). Thromboprophylaxis should be considered for
women with proteinuria >5 g/day [44].
Long-term prognosis
Relates to the specific diagnosis. Most evidence suggests that
pregnancy does not worsen or accelerate the overall disease pro-
cess in women with primary glomerular disease, at least at 5-year
follow-up [45]. The exception to this appears to be women with
membranous glomerulonephritis, who do worse after experienc-
ing a pregnancy.
Vasculopathies
Patients with vasculopathy from scleroderma and polyarteritis
nodosa should be discouraged from pregnancy, because of high
maternal and fetal morbidity and mortality [1, 13, 14].
Lupus nephritis
Patients with lupus nephritis do well when the disease is in
remission for 6 months prior to conception, with a live birth rate
up to 95% [15, 16]. Rates of preterm delivery and pre-eclamp-
sia are based on degree of renal insufficiency. Total live birth
rate for all lupus patients is 58–95% [15, 17]. Low complement
levels at conception are predictive of adverse pregnancy out-
comes (RR 19), while use of low-dose aspirin during pregnancy
is associated with a decrease in adverse outcomes (RR 0.11)
[16]. Presence of antiphospholipid antibodies is also associated
with increased risk [18]. In addition, the risk of lupus flare is
increased in patients with >1 g of proteinuria or GFR <60 mL/
min (see Chap 25) [16].
Dialysis in ESRD
Preconception principles/Counseling
Women with ESRD on dialysis have impaired fertility second-
ary to suppression of hypothalamic-pituitary-adrenal (HPA) axis
function, leading to anovulation and amenorrhea. Fertility rates
are improving with advances in dialysis, the use of more biocom-
patible membranes, increased use of erythropoietin, and intensi-
fication of dialysis prescription. Published rates of fertility range
from 1–7%, although the highest documented pregnancy inci-
dence is 15.6% in intensively dialyzed patients [46].
Dialysis-dependent patients with ESRD should be offered con-
traception [47]. Patients on dialysis should be counseled pre-
conceptionally that they should strongly consider receiving a
renal transplant and then wait for 1–2 years before attempting
pregnancy [48]. Live births in women on dialysis during preg-
nancy has improved from 23% in the 1970’s and 1980’s in the
1970’s and 1980’s [49] to about 50% in 1994 [21], to 79% in 1998
[50], and to 92% in 2002 [47]. Synthesis of data from published
cohorts since 2000 equates to a live birth rate of 78% (range
61–89%), at a mean gestational age at delivery of 34 weeks
(range 27–35 weeks), with 46% of babies being small for ges-
tational age (range 14–80%), and a risk of perinatal death of
18% [51]. A systematic review revealed an overall live birth rate
of 82% and a positive relationship between number of hours
on dialysis and improved outcomes, with a decreased risk
of preterm delivery and SGA infants [25]. Such findings were
confirmed by numerous cohort studies, demonstrating a trend
of improved pregnancy outcomes with longer dialysis time
Maternal-Fetal Evidence Based Guidelines
in pregnancy [51]. Dialysis patients are at increased risk of pre-
eclampsia, with rates ranging from 14–19%. Heterogeneity in the
estimate is due to the difficulty in making a diagnosis of super-
imposed pre-eclampsia in the context of pre-existing hyperten-
sion and/or proteinuria/anuria [51]. Preconception counseling is
recommended to enable informed, value congruent choices for
dialysis patients and their partners.
Of note, in dialysis patients, serum levels of B-human chorionic
gonadotropin may be borderline elevated in women who are not
pregnant; an ultrasound should be used to confirm the diagnosis
of pregnancy [48].
Pregnancy management
• Counseling regarding complications (see earlier in this
chapter) should be reviewed. Because of the incidence of
complications, termination may be discussed, as well as
the possibility of a better outcome after renal transplant
[47]. Maternal health should be optimized prior to con-
ception as for CKD patients, antenatal care should also
follow the same recommendations for pregnant women
with CKD.
• For successful outcomes in pregnant women on dialy-
sis, the key is coordination of multidisciplinary care to
maintain blood pressure control, fluid balance, and ade-
quate nutrition. There is an overall >80% likelihood of fetal
survival [50].
• Discontinuation of teratogenic medications and calcimi-
metic drugs (i.e., cinalcalcet, etelcalcetide), given the lim-
ited data on their use in pregnancy.
• Double the dose of water soluble vitamins (i.e., vitamin C,
vitamin B complex) [44, 51].
• Add folic acid 5 mg/day [44, 51].
• Recommend daily protein intake of 1.5–1.8 g/kg/day
(amino acids can be lost daily in the dialysate), diet can
be unrestricted, including liberalized dietary phosphate
[44, 51].
• The results of the first trimester screening must be
interpreted with caution because analyte serum levels
are altered in an unpredictable manner in cases of renal
compromise: Beta-HCG is partially cleared by the kidneys,
PAPP-A concentration is higher in patients on hemodialy-
sis. NIPT can be attempted [44, 51].
• Cervical length should be evaluated in the second trimester
at around 20 weeks, as cervical insufficiency appears to be
more prevalent among ESRD women on hemodialysis [32].
• Asymptomatic bacteriuria in dialysis patients should be
treated for two weeks, and suppression may be given for
the remainder of the pregnancy [34].
• Avoid maintenance infusion of magnesium sulfate, serum
levels should be checked after the initial IV bolus [44, 51].
Dialysis
ESRD patients are usually on dialysis prior to conception, while
in a minority of patient CKD progresses to require dialysis during
pregnancy. Indications for commencement of dialysis in the non-
pregnant population include symptomatic uremia, evidence of
protein-energy wasting, and the inability to safely manage meta-
bolic abnormalities and/or volume overload with medical therapy.
Current practice remains variable: From automatic commence-
ment of dialysis when urea is >47 mg/dl (>17 mmol/L) [35], to the
consideration of dialysis only for women with progressive loss of
renal function and a urea consistently >56 mg/dl (>20 mmol/L) [52].
Urinary Tract Disease
However, in the context of pregnancy, the fetotoxicity of urea
(BUN) is likely to precede any maternal indications for dialy-
sis, although the absolute level at which the provision of dialysis
improves pregnancy outcome remains unknown: Historical
studies have shown significantly increased perinatal mortality at
serum BUN concentrations above the current standards used to
initiate or target dialysis.
Intensive (>36 hours/week – usually 6–7 times/week)
hemodialysis (HD) in pregnancy facilitates gradual excess
fluid removal with less hemodynamic variation, and accounts
for improved fetal outcomes compared to standard dialysis
(<20 hours/week). A continuous association between increased
dialysis provision and improved fetal outcomes is shown at
>20 hours/week and >36 hours per week. Expert consensus sug-
gests 36 hours as a minimum target for hemodialysis provi-
sion in pregnancy [51]. An alternative approach to guide the
intensification of dialysis uses the serum BUN, recommending
pre-dialysis targets of less than 35 mg/dl (<12.5 mmol/L) [51].
A large contemporary cohort study showed that BUN is corre-
lated with adverse fetal outcomes: A midweek predialysis BUN
>35 mg/dl (>12.5 mmol/L) had a sensitivity of 88% and an OR of
6.4 (CI: 1.4–30) for adverse fetal outcome [53].
Hemodynamic stability during dialysis is fundamental: The
post-dialysis blood pressure target is <140/90 mmHg whilst
avoiding intra-dialytic hypotension (<120/70 mmHg).
LMWH or UFH can be safely used in pregnancy to prevent
clotting of the hemodialysis circuit, although doses may need to
be increased along with gestational age. For women receiving an
intensified regimen there may be a need to use increased dialysate
concentrations of potassium (3 mEq/L), calcium (1.5 mmol/L),
phosphate, and magnesium [51].
Peritoneal dialysis (PD) offers potential benefits for preg-
nancy including continuous ultrafiltration, avoidance of hemo-
dynamic fluctuation, and no requirement for anticoagulation.
However, progressive distension of the uterus may necessitate
reduced dialysate volumes and affect catheter position leading
to concern about the capacity to intensify dialysis requirements
in pregnancy. Incidence of pregnancy is lower for women on PD
compared to hemodialysis; moreover, reports have suggested
that, despite comparable rates of preterm delivery, PD is asso-
ciated with a higher rate of SGA infants and maternal infec-
tions than HD. HD therefore remains the modality of choice
in pregnancy, with most experts advocating a switch from PD to
HD in pregnancy in order to facilitate controlled intensification
of dialysis [51].
Other HD suggestions include:
• Avoid excessive fluid shifts. Ensure minimal fluctuations
and limit volume changes.
• Alter heparin regimen near delivery if possible.
• Use maternal dry weight to base HD volume.
• Obtain a nutritional consult [48].
• Keep bicarbonate 22–26 mEq/L.
• Keep hemoglobin 11–12 mg/dL with erythropoietin
(can be given in pregnancy, does not cross the placenta).
Because of resistance to erythropoietin in pregnancy, the
dose must be increased by as much as 50% to maintain the
target hemoglobin [54]. Anemia is associated with worse
neonatal outcomes [25].
• Replace calcium (>2 g/day), phosphorus.
• Dialysate: May need more potassium, less calcium.
• Adequate calorie and protein supply needs to be assured.
175
Antepartum testing
Fetal surveillance should include serial evaluations of amni-
otic fluid volume, as high maternal BUN levels may account for
osmotic diuresis in the fetus and cause polyhydramnios. Increased
amounts of amniotic fluid may therefore prompt intensification
of the dialysis dose. Close antepartum fetal surveillance is war-
ranted because of risk of FGR and fetal heart rate abnormalities.
Labor and delivery
Timing and mode of delivery are based on obstetric indications.
Induction of labor is often considered at term to avoid spontane-
ous labor in anticoagulated patients.
Neonatology
Neonatologists should be available at the time of delivery:
Neonates born with high BUN and Cr levels often experience
osmotic diuresis, resulting in volume contraction and electrolyte
abnormalities. Intrauterine hypercalcemia may result in postna-
tal hypocalcemia and tetany [33].
Postpartum
Most women return to pre-pregnancy dialysis regimens and have
uncomplicated postpartum recoveries. Postpartum care must
address contraception. A renal transplant should precede future
pregnancies.
Renal transplantation
Principles
Management should be at a center with a transplant nephrolo-
gist, and requires attention toward serial assessment of renal
function, diagnosis and treatment of rejection, blood pres-
sure control, and control of anemia. There is an overall success
of pregnancy (live births) in women after renal transplantation
of >90% [55]. Fertility can normalize soon after transplantation,
so patients should be maintained on contraception until ready
to attempt a pregnancy. If graft function is adequate and stable,
pregnancy does not cause accelerated graft demise [56]. However,
one case-control study suggested that graft function is adversely
affected by pregnancy [57]. At 10-year follow-up, graft survival
was 69% in pregnant patients and 100% in non-pregnant controls.
Complications
Slightly increased incidences of fetal growth restriction, prema-
ture rupture of membranes, preterm delivery, and pre-eclampsia.
Preconception counseling
Kidney transplantation (KT) allows the hypothalamic-pituitary-
ovarian axis compromised in CKD to normalize, resulting in
ovulation and regular menstrual cycles within weeks postop-
eratively. Estimates indicate that the proportion of women with
renal transplants who become pregnant is approximately 2–5%
[26]. The most cited requirements to identify the best candidates
for pregnancy after KT are:
• Normal or good kidney function (serum Cr <1.5 mg/dl, GFR
>60 ml/min). Creatinine >2.4 mg/dL may be regarded as
a contraindication to pregnancy as all transplant patients
with a creatinine >2.3 mg/dL experienced progression of
renal failure requiring retransplant or dialysis within
2 years of pregnancy [26].
• Absent or scarce proteinuria (< 300–500 mg/day).
176 Maternal-Fetal Evidence Based Guidelines

• No or well-controlled hypertension (treated in mono- accelerated by superimposed pre-eclampsia [39]. Fortunately,

therapy and without organ damage). Discontinue ACE
inhibitors.
• Low-dose immunosuppression with drugs allowed in preg-
nancy. Potentially teratogen drugs should be discontinued
for at least 6 weeks prior to conception.
• No rejection episodes in the previous year.
• No recent UTIs.
• Avoidance of conception in the first year after transplant as
recommended by the American Society of Transplantation
Guidelines, although experts suggest to wait at least 2 years
after KT [58]. A retrospective analysis of 729 pregnan-
cies showed that pregnancy in both the first and second
post-transplant years was associated with higher rates
of allograft failure from any cause censored for death
(hazard ratio 1.3, 95% CI 1.04–1.50 and hazard ratio 1.3,
95% CI 1.06–1.50, respectively), as opposed to pregnancy
in the third post-transplant year [36]. On the other hand,
live birth rates tend to be higher in the first 2 years post-
transplantation: A meta-analysis of outcomes in 4706
pregnancies in KT recipients indicated a higher live birth
rate (80%) with a mean interval between transplant and
pregnancy of less than 2 years compared with intervals of
2–3 years, 3–4 years, and more than 4 years (live birth rates
64%, 76%, and 75%, respectively) [37]. However, for those
conceiving less than 2 years post-transplant, higher risks of
other adverse pregnancy outcomes, including pre-eclampsia,
gestational diabetes, cesarean delivery, and preterm birth,
were reported [37].
Effects of pregnancy on KT
Potential loss of graft function due to the hemodynamic effects
of pregnancy presents a significant concern, but women can be
reassured that overall long-term graft function and survival
is usually not significantly affected by pregnancy, as shown in
a recent meta-analysis [38]. However, when allograft function
before pregnancy is impaired, pregnancy may hasten graft
loss. For serum Cr levels >1.5 mg/dL, there is a greater likeli-
hood of postpartum graft dysfunction, which may be further
episodes of acute rejection are rare in kidney recipients, with
rates of only 4.2% [37].
Effects of KT on pregnancy
Pregnancy outcomes after KT are better than those in women
undergoing dialysis, but they are worse than the ones noted in
the general obstetric population. A systematic review and meta-
analysis on 6712 pregnancies from 4174 KT recipients showed the
following rates of adverse pregnancy outcomes: Miscarriages
(15.4%), stillbirths (5.1%), pre-eclampsia (21.5%), gestational
diabetes (5.7%), gestational hypertension (24.1%), cesarean
section (62.6), and preterm delivery (43.1%). The mean gesta-
tional age at delivery was 34.9 weeks, while the mean birth-weight
was 2470 g [40]. Patients maintained on calcineurin inhibitors
(i.e., cyclosporine, tacrolimus) and prednisone are at a higher
risk of gestational diabetes and may require insulin therapy for
glycemic control during pregnancy. Although never specifically
studied in this population, aspirin should be prescribed for pre-
eclampsia prevention because KT patients are at higher risk of
this complication. Finally, the chronically immunosuppressed
woman is at risk for opportunistic infections, being UTI the most
frequent [41, 42].
Prenatal care
Pregnancy in KT are considered high risk and should be followed
by an integrated multidisciplinary team including a transplant
physician, nephrologist, diabetologist, and a maternal-fetal medi-
cine specialist. Knowledge of what immunosuppressive agents
can be used in pregnant KT patients, in order to avoid teratogenic
medications. Azathioprine and steroids are the most often
employed and best known drugs. Tacrolimus and cyclosporine
are also frequently used in pregnancy. Mycophenolate mofetil
is to be avoided as teratogenic, while only few studies have con-
sidered the use of m-Tor inhibitors, Rituximab, and Simulect in
pregnancy, whose use is also discouraged (Table 17.9). Levels of
calcineurin inhibitors (i.e cyclosporine, tacrolimus) should be
checked monthly (consider twice monthly in the first and second
trimester), to adjust doses when levels decrease [41, 42].

TABLE 17.9: Immunosuppressive Agents Commonly Used and Their Side Effects
Agent Characteristics Side Effects FDA Rating
Steroids Utilized in pregnancy Higher risks of PROM, gestational diabetes and C
No major malformations noted, labiopalatoschisis does infections. Neonatal adrenal insufficiency,
not appear to be an issue according to latest research thymic hypoplasia have also been reported
Azathioprine Recommended in pregnancy Leukopenia (maintain maternal white blood D
Purine inhibitor: It is teratogen in animal models but not count >7500 pL)
in humans as the fetal liver does not activate the drug
Cyclosporine A Utilized in pregnancy Hypertension, nephrotoxicity (watch for drug C
Calcineurin inhibitor. It is not teratogen in humans interactions) intrauterine growth retardation
Tacrolimus Utilized in pregnancy Hypertension, nephrotoxicity, neurotoxicity, C
Calcineurin inhibitor glucose intolerance, myocardial hypertrophy,
hyperkalemia, neonatal anuria
Mycophenolate mofetil To be avoided in pregnancy May cause severe cardiovascular and limb and D
IMP dehydrogenase inhibitor: The medication should cranial malformations, including (microtia,
be discontinued for at least 6 weeks prior to auditory canal atresia, cleft lip and palate, and
conceiving micrognathia) malformations in humans
m-Tor inhibitors To be avoided in pregnancy. Very few studies on their Teratogen in animals C
use in pregnancy
Urinary Tract Disease
Lab work
This includes monthly assessment of CBC, BUN, serum creati-
nine, electrolytes, serum urate, 24-hour urine collection for
creatinine clearance and protein levels, and urine specimen
for culture. Initial labs should also include serum serologies for
cytomegalovirus, toxoplasmosis, and herpes simplex virus (IgM
and IgG for each) as well as LFTs, albumin, total proteins, vita-
min D, folate, and B12. Patients on prednisone or tacrolimus are
at risk of glucose intolerance and should undergo early screening
for gestational diabetes. Due to the considerable risk for UTIs,
monthly urine cultures are recommended to promptly treat
asymptomatic bacteriuria [41, 42].
Antenatal visits
Their main goal is to assess fetal wellbeing and to identify and
treat complications, including acute rejection, hypertension, ane-
mia, and coagulation disorders. Visits should be planned every
2–4 weeks up to 32 weeks and weekly thereafter. The frequency of
antenatal appointments should increase in case of hypertension,
reduced kidney function or proteinuria. Follow up should also
include nephrology consultations every 2–4 weeks. Management
of hypertension should follow recommendations for pregnant
CKD patients (see earlier in this chapter).
KT graft rejection
Transplant rejection is a rare event in pregnancy. Factors that
increase risk include increased number of episodes of rejection
during the year prior to conception, maternal serum creati-
nine >2 mg/dL, proteinuria >500 mg/dL, and graft dysfunc-
tion during pregnancy [42]. Clinical hallmarks include fever,
oliguria, deteriorating renal function, renal enlargement, and
tenderness. Renal ultrasound and biopsy for diagnosis is neces-
sary before aggressive anti-rejection therapy is begun.
Labor and delivery
Operative records from transplant surgery should be available
for obstetricians, to better locate the transplanted kidney and the
ureter in case of caesarean delivery. Women who have received
steroids for long periods during the antepartum period,
i.e., 20 mg or more of prednisone or equivalent for more
than 3 weeks, should receive “stress dose” steroids in labor.
Notification of the use of immunosuppressants to the pediatri-
cian is important for proper follow-up of the neonate.
Lower urinary tract infection
Definitions
Lower urinary tract infections (UTI) can be asymptomatic or symp-
tomatic. Asymptomatic bacteriuria is usually defined as the isola-
tion of bacteria in at least 100,000 colony forming units (CFU) per
mL of cultured urine, in the absence of signs or symptoms of a UTI
[43]. Cystitis is defined as significant bacteriuria with associated
bladder mucosal invasion, complicating 1–2% of pregnancies [43].
Symptoms
UTI may manifests with dysuria, urgency, frequency, abdominal
or suprapubic pan as well as fever.
Microbiologic etiology
Microorganisms associated with both symptomatic and asymp-
tomatic bacteriuria are Escherichia coli, accounting for >80% of
cases, Staphylococcus saprophyticus, Klebsiella, Enterobacter,
Proteus, Enterococcus, group B Streptococcus [43].
177
Screening
All pregnant women should be screened at the first prenatal visit
for asymptomatic bacteriuria. The prevalence of such condition
in pregnancy ranges between 2% and 15% [45]. If asymptomatic
bacteriuria goes untreated in pregnancy, 20–40% of patients will
develop pyelonephritis, compared to 3% of women who are treated
[45]. A recent meta-analysis involving over 2000 women enrolled
in 15 studies showed that antibiotic treatment compared with pla-
cebo or no treatment may reduce the incidence of pyelonephritis
(average risk ratio (RR) 0.24, 95%CI 0.13–0.41) may be associated
with a reduction in the incidence of preterm birth (RR 0.34, 95%
CI 0.13–0.88), and low birth weight (RR 0.64, 95% CI 0.45–0.93)
[45]. Women with risk factors for urinary tract infections (UTIs)
(DM, GDM, neurogenic bladder, prior frequent UTIs, sickle cell
disease or trait) should be screened every trimester.
Complications
Pregnant women with asymptomatic bacteriuria are at increased
risk for symptomatic infections and pyelonephritis. UTIs in
pregnancy have also been associated with other adverse obstetri-
cal outcomes such as pre-eclampsia, preterm birth, and low birth-
weight [43]. Treatment of asymptomatic bacteriuria helps prevent
these complications (see Chapters 2 and 18, Obstetric Evidence
Based Guidelines).
Prevention
Daily intake of 10–16 oz of cranberry juice decreases the inci-
dence of recurrent E. coli UTIs. Lactobacillus GG drink does not
have any benefit [47].
Diagnosis
A threshold of ≥100,000 colony-forming units (CFUs) per mil-
liliter of the same bacterial strain on two consecutive voided
specimens is the indication for treatment [48]. The detection of
≥100,000 CFU/mL in a single voided midstream urine sample is
accepted as an adequate and more practical alternative, although
there is only an 80% probability the woman has true bacteriuria;
this increases to 95% if two or more consecutive cultures are
positive for the same organism [59]. Additionally, asymptomatic
bacteriuria may be defined as >100,000 CFU/ml of a single recog-
nized uropathogen when the specimen was obtained with a cath-
eterized specimen [48]. Because the performance of rapid urine
screening tests in pregnancy is poor, quantitative culture remains
the gold standard for diagnosis. Group B Streptococcus should
be appropriately treated at any concentration (see Chap. 18,
Obstetric Evidence Based Guidelines). It is important to avoid
contamination by cleansing the perineum and then collecting
“mid-stream” urine.
Dipstick urinalysis is easily available in the office, it is fast and
inexpensive, and it is usually the first urine test performed. It per-
mits the analysis of leukocyte esterase, nitrite, and red blood
cells, which increase in UTIs. In pregnancy, the pooled sensi-
tivity for either leukocyte esterase or nitrite is 73% with 89%
specificity [50]. Microscopic urinalysis is performed with man-
ual or automated light microscopy. The presence of leukocytes
(pyuria: >5–10 WCB/high power field [hpf]) or bacteria (bacteri-
uria: >15 bacteria/hpf) in the urine can be helpful in diagnosing
UTIs. In pregnancy, bacteriuria of >20 WBC/hpf was found
to have sensitivity and specificity of 78% and 92% [50]. One
or two bacteria per hpf on an unspun catheterized urine speci-
men, or >20 bacteria per hpf on spun urine, closely correlates with
>100,000 cfu/ml of bacteria on urine culture.
178
Treatment
Treatment recommendations for uncomplicated UTIs (including
asymptomatic bacteriuria) include:
• Nitrofurantoin monohydrate/macrocrystals 100 mg
twice daily
• Amoxicillin 500 every 8 hours or 875 mg every 12 hours
• Amoxicillin-clavulanate 500 every 8 hours or 875 mg
every 12 hours
• Cephalexin 500 mg every 6 hours
• Cefpodoxime 100 mg every 12 hours
• Trimetoprim-sulfamethoxazole 160/800 mg every
12 hours
Treatment should consider any allergies, and microorganism
sensitivities in culture. Almost 20–40% of cases of E. coli show
resistance to Ampicillin and Amoxicillin, so their use is not
optimal when this organism is detected; fosfomycin is a useful
alternative. Trimetoprim-sulfamethoxazole should be avoided
in the first trimester as it antagonizes folic acid, while nitrofu-
rantoin can cause hemolytic anemia in G6PD deficiency at term.
The standard duration of treatment in pregnancy is 7 days
(including cases of asymptomatic bacteriuria), except for recur-
rent infections where treatment should last for 10–14 days
[43]. Suppressive therapy (once a day of nitrofurantoin 50 mg,
amoxicillin 250 mg, or cephalexin 250 mg) is indicated after
two UTIs or one episode of pyelonephritis.
Follow-up
A test of cure is necessary [49]. If urine culture remains posi-
tive, another antibiotic regimen is recommended according to the
bacteria sensitivity profile, together with assessment of patients’
compliance. Intramuscular treatment can be given if compliance
remains an issue.
Upper urinary tract infection
(Pyelonephritis)
Definition
Pyelonephritis is defined by significant bacteriuria with associ-
ated inflammation of renal parenchyma, calices, pelvis. It usually
involves ascent of infecting microbes from the bladder.
Symptoms
It manifests with dull back or flank pain, associated with fever,
chills, nausea, vomiting and CVA tenderness on physical exam.
Incidence
It may affect as many as 1–2% of all pregnant women.
Complications
Anemia is the most common complication associated with pyelo-
nephritis, while bacteremia, sepsis, ARDS, and preterm labor are
less common.
Diagnosis
Symptoms and signs are indicative of the diagnosis, that needs to
be confirmed by a positive urine culture with ≥ 100,000 CFU/mL.
Pyuria or the presence of leukocyte casts are also consistent with
the diagnosis. Urinary dipstick testing for leukocyte esterase and
nitrites is often positive. Pathogens causing pyelonephritis are the
same that cause lower UTIs [54, 60].
Maternal-Fetal Evidence Based Guidelines
Management
Urine culture sensitivity is crucial to assure adequate antibiotic
coverage. Workup should include CBC, electrolytes, serum
Cr, LFTs, and urinalysis. Endotoxin-mediated hemolysis, elec-
trolytes abnormalities, and AKI may be encountered. Blood cul-
tures can be obtained when pyelonephritis is suspected, although
the value of this practice has been questioned [61]. Ultrasound
scan, which usually reveals dilation of pyelocalyceal systems,
is usually reserved for patients that do not respond to the ini-
tial antibiotic treatment, as it allows to exclude complications
such as renal abscess, ureter obstruction, or other abdominal
infections.
In pregnancy, usually pyelonephritis involves inpatient treat-
ment, at least in the first 48 hours, especially when mothers
are >24 weeks’ gestation. Intravenous antimicrobial therapy
is usually continued until the patient is afebrile for 24 (some
prefer 48) hours and symptoms have improved; afterwards, the
patient is treated with oral antibacterials for a total of 10–14
days. Antibiotic suppression is recommended for the remain-
ing of the pregnancy. Usually the treatment is initiated empir-
ically and verified after obtaining the microbial sensitivity
test results. In case of fever persisting for more than 48 hours,
blood and urine cultures should be repeated, and any possible
causes of treatment failure (perirenal abscess, lithiasis, congeni-
tal or acquired structural changes within the urinary tract) have
to be carefully considered via ultrasound and other means.
Standard initial IV antibiotic regimens include
• Ceftriaxone: 1–2 g every 24 hours
• Cefazolin: 1–2 g every 6–8 hours
Alternative initial IV regimens include
• Cefepime: 1 g every 24 hours
• Aztreonam: 1 g every 8–12 hours
• Ampicillin: 1–2 g every 6 hours + gentamicin 5–7 mg/Kg
every 24 hours
Immunocompromised patients, patients with severe clinical
presentations such as high fever with chills, persistent vomiting,
significant dehydration or clinical signs of sepsis (tachycardia,
tachypnea or hypotension), or patients with urinary stasis should
be treated with
• Piperacillin/Tazobactam: 3.375 g every 6 hours
• Ticarcillin/clavulanic acid: 3.1 g every 6 hours
• Ertapenem: 1 g every 24 hours
• Meropenem: 0.5 g every 8 hours
Cephalexin is usually administered orally when intrave-
nous antibiotic treatment is discontinued [54, 60]. Appropriate
hydration of the patient is a very important part of the treatment,
urinary output is monitored. A test of cure is recommended.
Urinary nephrolithiasis
Incidence
Nephrolithiasis is also called renal calculi or stones. The reported
incidence of renal stone disease in the pregnant population varies
widely, with rates of hospitalization ranging from 0.03–0.8% [62].
Up to 12% of the general population has had a urinary stone dur-
ing their lifetime, with recurrence rates approaching 50%. Given
Urinary Tract Disease
the low incidence, it is unclear if the occurrence of nephrolithiasis
is or is not increased in pregnancy, with some authors reporting
an incidence as high as 1/200.
Risk factors
Nephrolithiasis is more common in Caucasians, second and third
trimester, right side, recurrent UTIs, gout, prior renal stones or
renal disease, family history.
Complications
There is a higher risk of pyelonephritis, preterm birth, premature
rupture of membranes, SGA among pregnant women with renal
colic from nephrolithiasis [59, 63].
Diagnosis
A typical presentation for renal colic includes flank pain and
hematuria. Additional symptoms may include nausea, vomiting,
or abdominal pain. Renal ultrasound is the first-line imaging
modality for pregnant women with suspected nephrolithiasis,
with sensitivity in stone detection that varies widely from
29–95%. Indirect ultrasound signs indicative of nephrolithiasis
are indicated by hydronephrosis (in case of physiologic hydrone-
phrosis ureteral dilation extends only to the level of the iliac ves-
sels, beyond which the ureter tapers, and absence of ureteral jet.
MRI, and in particular magnetic resonance urography (MRU),
has been recommended as the second-line imaging technique for
pregnant patients. Helical CT is the gold standard for detec-
tion of nephrolithiasis, with a 96% sensitivity and 100% specific-
ity [55]. Despite that the radiation dose from CT lies below the
exposures associated with fetal harm, ACOG supports its use
only when deemed necessary and US or MRI are not available [56,
63]. Abdominal plain-film x-ray and intravenous pyelography are
uncommonly used in contemporaneous practice due to growing
use of cross-sectional imaging modalities; moreover they lead to
radiation exposure to the fetus [59, 63].
Management
Supportive management is recommended as the first-line
approach to the pregnant stone patient without overt infection.
This includes hydration, anti-emetics, and adequate anal-
gesia, with acetaminophen and narcotics if needed, with
reported rates of spontaneous stone passage of 23–85% (usu-
ally >65–70%) in pregnancy. In cases where initial urinalysis or
presentation is equivocal for infection, observation with antibi-
otic therapy can be practiced. Up to 17% of women admitted
for nephrolithiasis and renal colic have concomitant pyelone-
phritis, but the true rate of progression to febrile infection during
a trial of conservative management remains unknown. The role of
medical expulsive therapy with alpha 1 selective antagonists (i.e.,
tamsulosin, off label use) or calcium channel blockers in preg-
nancy is poorly studied. Only a few small studies addressed the
use of alphablockers in pregnancy with heterogeneous results.
Indications for intervention among pregnant patients include
intractable symptoms (i.e., uncontrolled pain, nausea, vomit-
ing), obstructing stone with infection, progressive hydrone-
phrosis, obstruction of a solitary kidney, bilateral ureteral
obstruction, or severe hydronephrosis indicating high-grade
obstruction. Ureteral stenting remains a valid option. Stents are
generally placed under anesthesia, with US guidance and min-
imal or no fluoroscopy. Rates of complications in pregnancy
are as high as 16%, including removal due to patients’ intoler-
ance, failure, migration or preterm labor. Stent exchanges every
4–6 weeks are recommended due to higher rates of encrustation
179
in pregnancy. US-guided nephrostomy tube placement can also
be performed in pregnancy: Tube revision or exchange (every 4–6
weeks) are often performed in pregnancy due to higher risks of
calcification or occlusion. Ureteroscopy with lithotripsy or bas-
keting may represent a definitive treatment for kidney stones even
in pregnancy, with complication rates of 4–8%. Though percu-
taneous nephrolithotomy and shockwave lithotripsy have been
successfully performed in the pregnant patient, these treatment
approaches are not currently recommended due to higher compli-
cation rates. Ultimately, consideration of the type of intervention
requires shared decision making with the patient, and a multi-
disciplinary team including specialists in urology, maternal-fetal
medicine, and anesthesiology. Postpartum follow up with urol-
ogy is recommended among women experiencing renal colic in
pregnancy [59, 63].
Prevention of urinary incontinence
Incidence
Urinary incontinence has been reported to occur in 5–40% of
pregnant and postpartum women [57].
Prevention
A recent systematic review and meta-analysis showed that pel-
vic floor muscle training among continent pregnant women
decreased the rate of urinary incontinence in late pregnancy
(62% less, risk ratio (RR) 0.38 95%CI 0.2–0.7, 6 trials, 624 women),
and up to 6 months postpartum (29% less, RR 0.71 95%CI 0.54–
0.95), but not later. Pelvic floor muscle training in incontinent
pregnant women does not seem to improve the rate of urinary
incontinence, or affect fecal incontinence [64]. Group training
with a physiotherapist for 60 minutes once per week and twice
daily at home for a period of 12 weeks between 20 and 36 weeks
holding the pelvic floor muscle contraction 6–8 seconds each
time (for ~10 times) with rest periods of 6 seconds is one accepted
and effective intervention [65]. Pelvic floor muscle training
after childbirth is effective in prevention and treatment of
urinary incontinence [65, 66].
Postpartum urinary retention
Definition
Absence of spontaneous micturition six hours post vaginal deliv-
ery or six hours after catheter removal (after cesarean delivery). A
residual <50 mL is normal and >200 mL is abnormal [67].
Incidence
The incidence rate is 0.2–3% [67].
Risk factors
Risk factors for postpartum urinary retention are nulliparity,
prolonged stages of labor, epidural anesthesia, operative or cesar-
ean delivery.
Management
There are no trials to assess any intervention. Oral analgesia,
standing and walking, warm bath, and/or immersing hands in
cold water may help. If bladder volume by ultrasound <400 mL,
wait; if >400 mL, intermittent catheterization every 4–6 hours
until the woman is able to void and then the first residual volume
is <150 mL is usually recommended and preferable to indwell-
ing catheterization. Pharmacologic treatment should be avoided.
180
If the woman has still retention upon discharge and/or after
48 hours, self-catheterization should be taught. Prophylactic anti-
biotics are indicated in women who require catheterization. There
are no clear long-term sequelae of postpartum urinary retention.
Complete resolution of voiding dysfunction is expected within 28
days with no increased risk for long-term voiding abnormalities.
Higher postvoid residual volumes at 72 hours after delivery are
predictive of a longer time to full recovery [67].
Microscopic hematuria in pregnancy
Definition
Microscopic hematuria: 5–10 red blood cells per high power field
in a spun catheterized specimen.
Incidence
Incidence is 3% during pregnancy, 2–16% in non-pregnant popu-
lation [68].
Differential diagnosis
Pseudohematuria: May be present from excessive consump-
tion of beets, berries, rhubarb, or food coloring, as well as certain
laxatives and medications.
Acute renal disease: Hematuria may be sole presentation; dif-
ferential diagnosis includes HELLP syndrome, hemolytic uremic
syndrome, thrombotic thrombocytopenic purpura, pre-eclampsia
with severe features, renal cortical necrosis, acute pyelonephritis,
acute fatty liver of pregnancy, or urinary tract obstruction [68].
Chronic renal disease: As discussed earlier.
Infectious renal disease: Pyelonephritis, cystitis, urethritis.
Trauma in pregnancy: Hematuria may be the presenting sign in
a pregnant patient who is a victim of domestic violence.
Placental pathology: If the placenta invades the bladder (pla-
centa percreta), hematuria may result.
Uncommon causes of hematuria in pregnancy: Youssef syn-
drome (vesicouterine fistula), hydatidiform mole (either with
malignancy or renal failure), hemangiomas, arteriovenous mal-
formations, renal vein thrombosis, nutcracker syndrome (com-
pression of left renal vein leading to increased pressure gradient
and hematuria).
Risk factors for significant disease
• Age >40 years
• Smoking history
• History of gross hematuria
• Occupational exposure to chemicals or dyes (benzenes or
aromatic amines)
• Previous urologic disease (e.g., chronic cystitis or bacterial
infections)
• History of irritative voiding symptoms
• Analgesic abuse
• History of pelvic irradiation
• Cyclophosphamide exposure
Management
• Repeat dipstick: If negative, no need for further workup.
• Evaluate for vaginal bleeding possibly contaminating urine
specimen
• Send for microscopy: If abnormal casts or dysmorphic
RBCs, consider nephrology consultation for glomerular
etiology
• Urine culture: If positive, treat with appropriate antibiotics
• Urine cytology: If positive, cystoscopy is recommended
Maternal-Fetal Evidence Based Guidelines
• Obtain renal ultrasound to look for pathological basis for
hematuria
• Renal biopsy reserved for sudden deterioration of renal
function, relatively safe in pregnancy
References
1. Gonzalez Suarez ML, Kattah A, et al. Renal disorders in pregnancy: core
curriculum 2019. Am J Kidney Dis 2019;73(1):119–130. Published online
2018 Aug 16. [Review]
2. Milne JE, Lindheimer MD, Davison JM. Glomerular heteroporous mem-
brane modeling in third trimester and postpartum before and during
amino acid infusion. Am J Physiol Renal Physiol 2002;282(1):F170–175.
[Cohort study III]
3. Vidaeff AC, Yeomans ER, Ramin SM. Pregnancy in women with renal dis-
ease. Part I: general principles. Am J Perinatol 2008;25(7):385–397. [Review]
4. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and
laboratory studies: a reference table for clinicians. Obstet Gynecol
2009;114(6):1326–1331. [Systematic Review]
5. Wide-Swensson D, Strevens H, Willner J. Antepartum percutaneous renal
biopsy. Int J Gynaecol Obstet 2007;98(2):88–92. [Cohort study III]
6. Tsai YL, Seow KM, et al. Comparative study of conservative and surgi-
cal management for symptomatic moderate and severe hydronephrosis in
pregnancy: a prospective randomized study. Acta Obstet Gynecol Scand
2007;86(9):1047–1050 [RCT I]
7. KDIGO. Clinical practice guideline for acute kidney injury. Kidney Int Off
J Int Soc Nephrol 2012;2(1):1e138. i–iv, Available from: http://www.kdigo.
org/index.php. [Clinical guidelines]
8. Mehta RL, Burdmann EA, et al. Recognition and management of acute kid-
ney injury in the International Society of Nephrology 0by25 Global Snapshot:
a multinational cross-sectional study. Lancet 2016;387(10032):2017e25.
[Cross sectional study III]
9. Callaghan WM, Creanga AA, et al. Severe maternal morbidity among deliv-
ery and postpartum hospitalizations in the United States. Obstet Gynecol
2012;120(5):1029e36. [Cohort study III].
10. Hall DR, Conti-Ramsden F. Acute kidney injury in pregnancy including
renal disease diagnosed in pregnancy. Best Pract Res Clin Obstet Gynaecol
2019;57:47–59. [Review]
11. Vijayan M, Avendano M, Chinchilla KA, Jim B. Acute kidney injury in preg-
nancy. Curr Opin Crit Care 2019;25(6):580–590 [Review]
12. Ye W, Shu H, et al. Renal histopathology of prolonged acute kidney injury
in HELLP syndrome: a case series and literature review. Int Urol Nephrol
2019;51(6):987–994. [Review]
13. Piccoli GB, Daidola G, et al. Kidney biopsy in pregnancy: evidence for coun-
selling? A systematic narrative review. BJOG An Int J Obstet Gynaecol
2013;120(4):412e27. [Systematic review]
14. Mehta RL, Mehta RL, et al. Diuretics, mortality, and nonrecovery of renal
function in acute renal failure. J Am Med Assoc 2002;288(20):2547e53.
[Cohort study III]
15. Uchino S, Doig GS, et al. Diuretics and mortality in acute renal failure. Crit
Care Med 2004;32(8):1669e77. [Cohort study III]
16. Liu Y, Ma X, et al. Pregnancy outcomes in patients with acute kidney injury
during pregnancy: a systematic review and meta-analysis. BMC Pregnancy
Childbirth 2017;17(1):235. [Systematic Review]
17. Coca SG, Singanamala S, et al Chronic kidney disease after acute kidney
injury: a systematic review and metaanalysis. Kidney Int 2012;81(5):442e8.
[Systematic Review]
18. Stratta P, Besso L, et al. Is pregnancy-related acute renal failure a disappear-
ing clinical entity? Ren Fail 1996;18(4):575e84. [Review]
19. Kaze FF, Njukeng FA, et al. Post-partum trend in blood pressure levels, renal
function and proteinuria in women with severe pre-eclampsia and eclamp-
sia in Sub-Saharan Africa: a 6-months cohort study. BMC Pregnancy
Childbirth 2014;14:134. [Cohort study II-2]
20. Unverdi S, Ceri M, et al. Postpartum persistent proteinuria after pre-
eclampsia: a single-center experience. Wien Klin Wochenschr 2013;
125(3e4):91e5 [Cohort study III]
21. Levey AS, Coresh J, et al. National Kidney Foundation practice guidelines
for chronic kidney disease: evaluation, classification, and stratification.
Ann Intern Med 2003;139(2):137–147. [Systematic Review]
22. Piccoli GB, Alrukhaimi M, et al. World Kidney Day Steering Committee.
What we do and do not know about women and kidney diseases; ques-
tions unanswered and answers unquestioned: reflection on World Kidney
Day and International Woman’s Day. Physiol Int 2018;105:1–18. [Clinical
guidelines]
Urinary Tract Disease
23. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or
severe renal insufficiency. N Engl J Med 1996;335:226–232. [Cohort study III]
24. Zhang JJ, Ma XX, et al. A systematic review and meta-analysis of outcomes
of pregnancy in CKD and CKD outcomes in pregnancy. Clin J Am Soc
Nephrol 2015;10:1964–1978. [Systematic review]
25. Piccoli GB, Minelli F, et al. Pregnancy in dialysis patients in the new millen-
nium: a systematic review and meta-regression analysis correlating dialysis
schedules and pregnancy outcomes. Nephrol Dial Transpl 2015;31:1905–
1934. [Systematic review]
26. Hui D, Hladunewich MA Chronic kidney disease and pregnancy. Obstet
Gynecol 2019;133(6):1182–1194. [Review]
27. Wiles K, Chappell L, at al. Clinical practice guideline on pregnancy and
renal disease. BMC Nephrol. 2019;20(1):401.
28. ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During
Pregnancy. Obstet Gynecol 2018;132(1):e44–e52. [Clinical guidelines]
29. Rolnik DL, Wright D, et al. Aspirin versus placebo in pregnancies at high
risk for preterm pre-eclampsia. N Engl J Med 2017;377:613–22. [RCT I]
30. Khaing W, Vallibhakara SA, et al. Calcium and vitamin D supplementation
for prevention of pre-eclampsia: a systematic review and network meta-
analysis. Nutrients 2017;9:E1141. [Systematic review]
31. ACOG. Practice Bulletin 145: antepartum fetal surveillance. Obstet Gynecol
2014;124(1):182–92. and Lactation. Obstet Gynecol. 2017;130(4):e210-e216.
32. Hladunewich MA, Hou S, Odutayo A, et al. Intensive hemodialysis associ-
ates with improved pregnancy outcomes: a Canadian and United States
cohort comparison. J Am Soc Nephrol 2014;25(5):1103–1109. [Cohort
Study III]
33. Blowey DL, Warady BA. Neonatal outcome in pregnancies associated with
renal replacement therapy. Adv Ren Replace Ther 1998;5(1):45–52. [Review]
34. Romao JE, Jr, Luders C, et al. Pregnancy in women on chronic dialysis.
A single-center experience with 17 cases. Nephron 1998;78(4):416–422.
[Cohort study III]
35. Sato JL, De Oliveira L, Kirsztajn GM, Sass N. Chronic kidney disease in preg-
nancy requiring first-time dialysis. Int J Gynaecol Obstet 2010;111:45e8.
[Cohort study III]
36. Rose C, Gill J, et al. Timing of pregnancy after kidney transplantation and
risk of allograft failure. Am J Transpl 2016;16:2360–2367. [Cohort study III]
37. Deshpande NA, James NT, et al. Pregnancy outcomes in kidney trans-
plant recipients: a systematic review and meta-analysis. Am J Transpl
2011;11:2388–2404. [Systematic Review]
38. Van Buren MC, Schellekens A, et al. Long term graft survival and graft
function following pregnancy in kidney transplant recipients: a system-
atic review and meta-analysis Transplantation 2020;104(8):1675–1685.
[Systematic review]
39. Bramham K, Nelson-Piercy C, et al. Pregnancy in renal transplant recipi-
ents: a UK national cohort study. Clin J Am Soc Nephrol 2013;8:290–298.
[Cohort study III]
40. Shah S, Venkatesan RL, et al. Pregnancy outcomes in women with kid-
ney transplant: Metaanalysis and systematic review. BMC Nephrol
2019;20(1):24. [Systematic review]
41. Nadhusudan V, Pavlakis M. Pregnancy and the kidney transplant recipient.
Curr Opin Nephrol Hypertens 2017;26(6):494–500 [Review].
42. Cabiddu G, Spotti D, et al. A best-practice position statement on pregnancy
after kidney transplantation: focusing on the unsolved questions. The
Kidney and Pregnancy Study Group of the Italian Society of Nephrology.
Kidney and Pregnancy Study Group of the Italian Society of Nephrology. J
Nephrol. 2018;31(5):665–681. [Clinical guidelines]
43. Kalinderi K, Delkos D, et al. Urinary tract infection during pregnancy:
current concepts on a common multifaceted problem. J Obstet Gynaecol.
2018;38(4):448–453. [Review]
44. Tagren J, Nadel M, Hladunewich MA. Pregnancy and end stage renal dis-
ease. Blood Purif 2018;45:194–200 [Review]
45. Smaill FM, Vazquez JC. Antibiotics for asymptomatic bacteriuria in preg-
nancy. Cochrane Database Syst Rev 2019;2019(11):CD000490. [Systematic
review]
46. Barua M, Hladunewich, et al. Successful pregnancies on nocturnal home
hemodialysis. Clin J Am Soc Nephrol 2008;3:392–396. [Cohort study III]
181
47. Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari
M. Randomised trial of cranberry-lingonberry juice and Lactobacillus
GG drink for the prevention of urinary tract infections in women. BMJ
2001;322(7302):1571. [RCT]
48. Nicolle LE, Bradley S, et al. Infectious Diseases Society of America guide-
lines for the diagnosis and treatment of asymptomatic bacteriuria in adults.
Clin Infect Dis 2005;40(5):643–654. [Review]
49. Ennis M, Callaway L, Lust K. Adherence to evidence-based guidelines
for the management of pyelonephritis in pregnancy. Aust N Z J Obstet
Gynaecol 2011;51(6):505–509. [Cohort study]
50. Chu CM, Lowder JL. Diagnosis and treatment of urinary tract infections
across age groups. Am J Obstet Gynecol 2018;2019(1):40–51. [Systematic
Review]
51. Wiles K, de Oliveira L. Dialysis in pregnancy. Best Pract Res Clin Obstet
Gynaecol 2019;57:33–46. [Review]
52. Hladunewich M, Schatell D. Intensive dialysis and pregnancy. Hemodial Int
2016;20:339e48. [Review]
53. Luders C, Titan SM, et al. Risk factors for adverse fetal outcome in hemo-
dialysis pregnant women. Kidney Int Rep 2018. 3(5):1077–1088 [Cohort
study III]
54. Matuszkiewicz-Rowinska J, Malyszko J, et al. Urinary tract infections in
pregnancy: old and new unresolved diagnostic and therapeutic problems.
Arch Med Sci 2015;11(1):67–77 [Review]
55. Teichman JM. Clinical practice. Acute renal colic from ureteral calculus. N
Engl J Med 2004;350(7):684–693. [Review]
56. Jain C. ACOG Committee Opinion No. 723: Guidelines for diagnostic imag-
ing during pregnancy. Obstet Gynecol 2019;133(1):186. [Clinical guidelines]
57. Kontiokari T, Sundqvist K, et al. Randomised trial of cranberry-lingonberry
juice and Lactobacillus GG drink for the prevention of urinary tract infec-
tions in women. BMJ 2001;322(7302):1571. [RCT I]
58. McKay DB, Josephson MA, et al. Reproduction and transplantation: report
on the AST Consensus Conference on reproductive issues and transplanta-
tion. Am J Transpl 2005;5:1592–1599. [Clinical guidelines]
59. Semins MJ, Matlaga BR. Kidney stones during pregnancy. Nat Rev Urol
2014;11(3):163–168. [Review]
60. Jolley AJ, Wing DA. Pyelenephritis in pregnancy. An update on treatment
options for optimal outcomes. Drugs 2010;70(13):1643–1655. [Review]
61. Gomi H, Goto Y, Laopaiboon M, Usui R, Mori R. Routine blood cultures in
the management of pyelonephritis in pregnancy for improving outcomes.
Cochrane Database Syst Rev 2015;2:CD009216. [Systematic Review]
62. Rosenberg E, Sergienko R, et al. Nephrolithiasis during pregnancy:
characteristics, complications, and pregnancy outcome. World J Urol
2011;29(6)743–747 [Cohort study III]
63. Dai JC, Nicholson TM, et al. Nephrolithiasis in pregnancy: treating for two.
Urology 2020;S0090-4295(20)31019–0 [Review]
64. Woodley SJ, Lawrenson P, et al. Pelvic floor muscle training for prevent-
ing and treating urinary and faecal incontinence in antenatal and postna-
tal women. Cochrane Database Syst Rev 2020;5(5):CD007471. [Systematic
review]
65. Morkved S, Bo K, Schei B, Salvesen KA. Pelvic floor muscle training dur-
ing pregnancy to prevent urinary incontinence: a single-blind randomized
controlled trial. Obstet Gynecol 2003;101(2):313–319. [RCT I]
66. Morkved S, Bo K. Effect of postpartum pelvic floor muscle training in pre-
vention and treatment of urinary incontinence: a one-year follow up. BJOG
2000;107(8):1022–1028. [RCT follow-up]
67. Groutz A, Levin I, et al. Protracted postpartum urinary retention: the
importance of early diagnosis and timely intervention. Neurourol Urodyn
2011;30(1):83–86. [Cohort study III]
68. Sandhu KS, LaCombe JA, et al. Gross and microscopic hematuria: guidelines
for obstetricians and gynecologists. Obstet Gynecol Surv 2009;64(1):39–49.
[III]
69. National Kidney Foundation, K/DOQI Clinical practice guidelines for
chronic kidney disease: evaluation, classification and stratification,
National Kidney Foundation, Inc., 2006, available at: https://www.kidney.
org/sites/default/files/docs/ckd_evaluation_classification_stratification.
pdf [clinical guidelines]
18
HEADACHE
Stephen Silberstein and Shuhan Zhu
Key points
• Most causes of headache in pregnancy are not due to
ominous causes, but to migraine or tension-type headache.
• Migraines affect up to 18% of pregnant women; most of
whom have an existing diagnosis pre-pregnancy.
• Most patients with migraine without aura, and many with
migraine with aura, improve during pregnancy, particu-
larly during the second and third trimester.
• New-onset headache in pregnancy requires a thorough neu-
rological evaluation that may include neuroradio graphic
studies and/or cerebrospinal fluid (CSF) analysis.
• Some worrisome disorders that cause headache occur more
commonly in pregnant women. These include sub-arachnoid
hemorrhage, stroke, pituitary tumor or apoplexy, and cere-
bral venous thrombosis.
• Education about avoiding specific food, caffeine, and
alcohol triggers for migraine may reduce the need for
both preventive and acute medications. Pregnant patients
with headache should avoid skipping meals, optimize
sleep and exercise habits, and consider yoga, medita-
tion, or biofeedback as an adjunctive migraine preventive
modality.
• Some acute and preventive medication can be used with
caution in pregnancy; few are absolutely contraindicated.
• Patients who are unknowingly pregnant and who have
taken medications in the nonsteroidal anti-inflammatory
class or the triptan class early in pregnancy can be reas-
sured that drugs of these classes have not been shown to
increase the incidence of teratogenicity.
• For acute treatment of primary headache, acetamino-
phen alone (preferably) or with codeine (for refractory
headache) should be the first choice during all trimesters.
Naproxen and ibuprofen are safe and well tolerated in
pregnancy, but should be avoided after 28 weeks. Severe
unrelenting migraine responds well to parenteral anti-
emetics, such as metoclopramide and prochlorperazine.
Beta-blockers (such as propranolol or metoprolol) or low-
dose tricyclics (amitriptyline) can be considered as a
prophylactic medication for the pregnant patient whose
headache frequency requires daily preventive medication,
and for whom non-pharmacologic approaches to headache
prophylaxis have failed.
• The new class of migraine preventives based on CGRP
monoclonal antibody antagonists lacks safety data for
pregnancy and therefore should be avoided, especially
given the long half-life of these medications.
Background/Epidemiology
The relationship between headache and pregnancy is of concern
for two reasons: First, primary headache disorders (migraine or
tension-type headaches) are far more common in women than
182
men, and the impact of headache in women is directly affected
by reproductive life events. One-year migraine prevalence is 18%
in women in the United States. It has a peak incidence following
menarche in young girls, is most prevalent in the reproductive
age of 20–50, is commonly exacerbated by menses, influenced by
hormonal contraception and replacement therapy, and is often
improved following menopause. Migraine, particularly migraine
without aura, generally improves with pregnancy and worsens in
the postpartum period.
Pregnancy has been a common exclusion criterion for con-
trolled clinical trials. Therefore, data on the safety of drugs used
for primary headache types in pregnant women, such as migraine
and tension-type headache, are scant. Yet, in a survey of drug
utilization by the World Health Organization, 68% of pregnant
women took some form of medication.
Clinicians should be particularly vigilant regarding second-
ary headaches associated with pregnancy such as stroke, cerebral
venous thrombosis, pituitary apoplexy, and posterior reversible
encephalopathy associated with eclampsia [1].
Diagnosis
Diagnostic criteria as per the International Headache Society are
shown in Table 18.1 [2].
Diagnostic considerations for headache in pregnancy
Some secondary causes of headache are (because of another,
often ominous, disorder):
• Cortical venous thrombosis or cranial sinus thrombosis
• Subarachnoid hemorrhage
• Pre-eclampsia or eclampsia associated with elevated blood
pressure (associated with reversible cerebral vasoconstric-
tion syndrome [RCVS])
• Stroke
• Idiopathic intracranial hypertension (pseudotumor cerebri)
• Pituitary tumor and pituitary apoplexy
• Headache associated with trauma to the head or neck,
or to infection or disease of the meninges, sinuses, eyes,
or ears
Some primary causes of headache:
• Migraine with and without aura
• Tension-type headache
• Trigeminal autonomic cephalgias (cluster headache)
• Cough headache
Red flags suggesting a secondary (ominous) headache:
• Sudden-onset (thunderclap) headache
• Secondary risk factors (HIV, systemic cancer)
DOI: 10.1201/9781003099062-18
Headache
TABLE 18.1: International Headache Society Criteria for the
Diagnosis of Migraine
Migraine without Aura
A. At least five attacks fulfilling criteria B–D
B. Headache duration of 4–72 hour (untreated or unsuccessfully
treated)
C. Headache with at least two of the following:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe pain intensity
4. Aggravation by routine physical activity
D. During headache at least one of the following:
1. Nausea and/or vomiting
2. Photophobia and phonophobia
E. Not better accounted for by another diagnosis
Migraine with Aura
A. At least two attacks fulfilling criteria B and C
B. One or more of the following fully reversible aura symptoms:
1. Visual
2. Sensory
3. Speech and/or language
4. Motor
5. Brainstem
6. Retinal
C. At least two of the following four characteristics:
1. At least one aura symptom spreads gradually over ≥5 minutes,
and/or two or more symptoms occur in succession
2. Each individual aura symptom lasts 5–60 minutes
3. At least one aura symptom is unilateral
4. The aura is accompanied, or followed within 60 minutes, by
headache
D. Not better accounted for by another diagnosis, and transient
ischemic attack has been excluded
Tension-Type Headache
A. At least 10 episodes occurring on <1 day/mo on average and
fulfilling criteria B–D
B. Headache lasting from 30 min to 7 days
C. Headache that has at least two of the following characteristics
1. Bilateral location
2. Pressing/tightening (nonpulsatile) quality
3. Mild or moderate intensity
4. Not aggravated by routine physical activity
D. Both of the following:
1. No nausea or vomiting
2. No more than one of photophobia or phonophobia
E. Not better accounted for by another diagnosis
Source: Adapted from Ref. [2].
• Headache associated with systemic symptoms (fever, weight
loss, meningeal signs, papilledema) or focal neurologic
signs (confusion, impaired alertness, or incoordination)
• New, different, or progressively worsening headache
• Positional headache that occurs only in the upright posture
and is relieved with recumbency (CSF leak)
Epidemiology/Pathophysiology
In the past year, 18% of women and 6% of men had a migraine
headache, but nearly half of these patients remain undiag-
nosed. It is estimated that an even greater number of women
183
(approximately 40%) suffer from episodic or chronic tension-
type headache. Migraine usually improves during pregnancy,
but a first migraine can occur, typically in the first trimester. The
elevated and sustained levels of plasma estrogens are felt to be
protective during pregnancy and the fall in estrogen at the onset
of menses is a factor in menstrual-associated migraine. Estrogens
are known to increase pain thresholds in animal studies [3]
and endogenous opioids also increase as pregnancy progresses.
Migraine often recurs postpartum, usually within three to 6 days.
The pathophysiology of migraine is complex. Even less is
known about the genesis of tension-type headache. Migraine aura
has been shown to be due to cortical spreading depression (CSD)
[4]. CSD is a spreading decrease in electrical activity that moves
across the cerebral cortex at 2–3 mm/min. It is characterized
by shifts in cortical steady state potential, transient increases in
potassium, nitric oxide, and glutamate, and transient increases in
CBF, followed by sustained decreases. Functional MRI studies of
patients with migraine show that a period of hyperemia precedes
the oligemia present during the migraine aura and the headache
itself can begin before hyperemia, while blood flow in the cere-
bral cortex is still reduced. Headache likely results from activa-
tion of meningeal and blood vessel nociceptors combined with a
change in central pain modulation. Headache and its associated
neurovascular changes are subserved by the trigeminal system.
Stimulation results in the release of substance P and calcitonin
gene related peptide (CGRP) from sensory C-fiber terminals and
neurogenic inflammation [5]. Neurogenic inflammation sensi-
tizes nerve fibers (peripheral sensitization), which now respond
to previously innocuous stimuli, such as blood vessel pulsations,
partly causing the pain of migraine. Central sensitization of tri-
geminal nucleus caudalis neurons can also occur. Central sen-
sitization may play a key role in maintaining the headache. The
migraine aura can trigger headache: CSD activates trigemino-
vascular afferents. This replaces the older theories of migraine
pathophysiology of aura caused by vasoconstriction and head-
ache caused by vasodilation.
Genetics
Migraine is a group of familial disorders with a genetic compo-
nent. Familial hemiplegic migraine (FHM) is a group of auto-
somal dominant disorders associated with attacks of migraine,
with and without aura, and hemiparesis [6]. FHM1 accounts for
approximately two-thirds of cases and is due to at least 10 dif-
ferent missense mutations in the CACNA1A gene, which codes
for the α1-subunit of a voltage dependent P/Q Ca2+ channel.
FHM2 results from a new mutation in the α2-subunit of the
Na/K pump. FHM3 is due to a missense mutation in gene SCN1A
(Glnl489Lys), which encodes an α1-subunit of a neuronal voltage-
gated Na+ channel (Navl.l)
Pregnancy considerations
Effect of pregnancy on the disorder
Several retrospective studies of the course of migraine in preg-
nancy have been performed [7, 8]. Most women with migraine
improve during pregnancy, women without aura more commonly
than women with aura, generally by the second and third trimes-
ter. Women whose migraines began during the menarche and
those with menstruation-associated migraine are more likely
to have headaches recede during pregnancy [1]. Large prospec-
tive trials are now available. The MIGRA study prospectively
184 Maternal-Fetal Evidence Based Guidelines

reviewed headache and migraine during pregnancy and puerpe- Pharmacological acute therapy for headache
rium. Over 2000 pregnant women with headache participated, Preface: In 2015, the Federal Drug Administration (FDA)
with 208 fulfilling IHS criteria for a diagnosis of migraine. There replaced the pregnancy risk categories of A/B/C/D/X for pharma-
was a significant decrease in the frequency of migraine during cologic agents in favor of more detailed explanatory paragraphs.
pregnancy, specifically during the second and third trimes- Although this system has been updated, many publications and
ters [9]. physicians continue to refer to this system for its ease of use.
Therefore, the FDA risk categories have been retained for this
Effect of the disorder on pregnancy publication.
Previously, women with migraine were not believed to have an Acute migraine treatments in nonpregnant women include,
increased incidence of teratogenicity, toxemia, stillbirths, or among others, simple analgesics (acetaminophen, aspirin), non-
miscarriage compared with controls [10]; however, with addi- steroidal anti-inflammatory drugs (NSAIDs), opioids, ergot alka-
tional prospective and retrospective studies, it is more clear that loids, isometheptene caffeine-barbiturate combinations, and
migraine disease is associated with some risks during pregnancy. triptans (Table 18.2).
A study from Taiwan found that, compared with unaffected Migraine typically improves as pregnancy progresses.
mothers, women with migraines were at increased risk of having However, in the first trimester, when headache often worsens,
low-birth-weight preterm babies, pre-eclampsia, and delivery by concern arises as to the potential effect of acute medication on
caesarean. [11]. A 2009 prospective cohort study in Italy found embryogenesis. The situation is particularly poignant as many
that migraine was a risk factor for subsequent development of women, unknowingly pregnant, will have used acute medications
hypertensive disorders during pregnancy, though there were no to treat migraine or tension-type headache in the very early days
significant associations with low birthweight, fetal loss or prema- or weeks after conception.
ture delivery [12]. Additional studies in various populations have Acetaminophen is the drug most commonly taken during
also replicated similar associations with higher rates of preterm pregnancy. There is no evidence of any teratogenic effect [17–19]
delivery, pre-eclampsia, and low birthweight [13, 14]. (FDA B) and is considered first line for treatment of migraine and
other pain throughout pregnancy [20].
Management Antiemetic medicines, such as metoclopramide (FDA B), pro-
methazine (FDA C), and prochlorperazine (FDA C), are effec-
Evaluation of headache in pregnancy tive parenterally for the head pain itself, in addition to the nausea
Headache in pregnancy should be evaluated in the same manner and vomiting that can accompany migraine. These are gener-
as any other time, with the awareness of specific disorders that ally considered safe for use during pregnancy. Intravenous or
are more frequent or only occur with pregnancy. When evaluat-
ing pregnant patients with headache, physicians should first eval-
TABLE 18.2: Proposed Management of Primary Headache in
uate for possible dangerous secondary causes before assessing for
Pregnancy
primary headache disorders.
The clinician should be alert to the warning signs of ominous Non-pharmacologic Recommended for all pregnant women
headache. Certain conditions that cause worrisome headache are methods Ideally should be discussed as pre-conception
more common in pregnancy. Headache that presents in a sud- Optimize sleep, nutrition, planning
den (thunderclap) fashion may indicate subarachnoid hemor- exercise. Education,
rhage, particularly if associated with a change in consciousness counselling, reassurance
or focal neurologic signs. Sudden headache can also accompany Analgesic FDA Cata Before 28 weeks After 28 weeks
pre-eclampsia (consider RCVS) or pituitary apoplexy. The risk of Acetaminophen B First line First line
venous or sinus thrombosis is also increased in the puerperium Ibuprofen B Ibuprofen used more NOT
and can present with seizure, precipitous headache, vomiting or Naproxen B commonly, RECOMMENDED,
focal signs. If intracranial pressure is elevated due to intracranial naproxen also all NSAIDs are FDA
hemorrhage or venous thrombosis, papilledema may be seen on considered low risk category D in 3rd
examination. trimester
Whether or not to obtain a CT or an MRI as part of the evaluation Anti-emetic
of headache in pregnancy depends on the degree of suspicion for an Metoclopramide B Anti-emetic class generally safe, effective for
ominous cause of headache. Generally speaking, head CT and MRI Promethazine C nausea and migraine pain, can be given
without contrast are safe in pregnancy, although the decision to Prochlorperazine C intravenously and in combination with an
obtain the study should be based on the risk of missing a structural appropriate analgesic
or serious cause of headache without the study. Gadolinium, used Opioid
as a contrast agent for MRI, does cross the placenta [15] and is gen-
Meperidine B Recommend short Limit opioids during
erally avoided in pregnancy due to lack of proven safety. However,
Codeine C opiate courses if other late pregnancy to
if an intracerebral bleed, mass lesion, or meningitis is suspected,
Morphine C medications maximized reduce neonatal
the benefit of CT, MRI, or MRA far outweighs the potential risks,
withdrawal
including the risk of gadolinium. Gadolinium was deemed safe by
Others
the European Society of Radiology, as after gadolinium contrast
Caffeine C May be combined appropriate analgesic
media no effect on the fetus has been reported in the literature [16].
Recently, gadolinium has been reported as not safe in pregnancy. Prednisone C Recommend short courses of steroids, limit to
Lumbar puncture to diagnose meningitis or hemorrhage may be Dexamethasone C 3–6 day courses to reduce risk of fetal side
delayed until CT of the brain without contrast is obtained to avoid effects
the risk of herniation if a mass or cerebral edema is suspected. a U.S. Food and Drug Administration Pregnancy Category.
Headache
intramuscular antiemetics, with fluid replacement, are effective
in aborting status migrainosus or severe headache in the emer-
gency room or urgent care center. A randomized control trial in
2018 [21] showed that in patients who are refractory to oral acet-
aminophen, intravenous treatment with metoclopramide and
diphenhydramine was more effective than oral codeine in head-
ache relief at 30 minutes, 1 hour and 12 hours.
Nonsteroidal anti-inflammatories (NSAIDs) NSAIDs are
not associated with teratogenicity but do have other known
associated risks. In the first trimester, some studies have some
an association in NSAID use and miscarriage while some have
not [22, 23]. In the third trimester, NSAIDs should be avoided
due to risk of premature ductus arteriosus closure and neonatal
pulmonary hypertension, and oligohydramnios [24]. Due to the
possible risks in the first trimester and known risks in the third
trimester, NSAID use is may be safer to limit to the second tri-
mester only.
Caffeine is a category C drug and may be used alone or in
combination with NSAID or acetaminophen, depending on the
gestational age. The caffeine content of one cup of drip coffee
is approximately 100 mg [25]; consumption of up to 200 mg of
caffeine a day is generally considered low risk during pregnancy
[26, 27].
Meperidine (FDA B), codeine (FDA C) and morphine (FDA
C) may be used with the caveat that chronic use, particularly dur-
ing late pregnancy can result in neonatal withdrawal syndromes
[1]. Prednisone or dexamethasone may be used for intractable
migraine though chronic exposure can result in fetal adrenal sup-
pression and other complications [1].
Ergotamine and dihydroergotamine are category X, and should
be avoided in pregnant women. Ergots are abortifacients and have
been shown to cause fetal distress and birth defects.
The triptans are 5-HT IB/ID receptor agonists effective in
treating migraine headache and the accompanying symptoms
of photosensitivity, nausea, and vomiting. The data obtained
from close to 20 years of prospective monitoring of pregnancies
exposed to sumatriptan and naratriptan have not shown a sub-
stantial increase in the risk of all major birth defects. However,
the size of the registry is currently insufficient to evaluate the
risk of specific defects or to permit definitive conclusions of the
risks associated with sumatriptan or naratriptan [28]. The trip-
tan class is category C, and is not recommended for use in preg-
nancy. Nevertheless, on the basis of the pregnancy registry, if a
patient has unwittingly taken sumatriptan prior to knowledge
of her pregnancy, reassurance is appropriate given the lack of
teratogenicity of this drug. It is not known whether this positive
outcome may also be extrapolated to other medications in the
triptan class.
Calcitonin gene-related peptide (CGRP) receptor antag-
onists: Known as the “gepants”, these include ubrogepant and
rimegepant, which received FDA approval in 2019 and 2020
respectively. Animal studies have shown adverse effects from
both drugs and is not recommended for patients who are
pregnant. There is little registry data due to the newness of
these drugs.
Peripheral nerve blocks performed at the greater occipital
nerves, lesser occipital nerves or branches of the trigeminal nerve
with lidocaine anesthetics is generally considered low risk for
pregnant patients and the developing fetus.
The literature for pregnancy outcomes after local anesthetic
exposure comes largely from the dental field. A prospective,
comparative observational study in Israel followed 210 pregnant
185
patients who received local anesthetic for dental procedures
and found no difference in rates of miscarriages, gestational age
at delivery, or birth weight [29]. Both the American College of
Obstetrics and Gynecologists [30, 31] categorize the use of local
anesthetic for dental procedures to be safe during pregnancy.
A retrospective study of peripheral blocks involving 13
patients, some of whom received repeated blocks, showed
improvement in immediate pain reduction with no serious
adverse effects [32].
Non-pharmacologic headache prophylaxis
Education about avoiding specific food, caffeine, and alcohol
triggers for migraine may reduce reliance on both preventive
and acute medications. Pregnant patients with headache should
avoid skipping meals, optimize sleep and exercise habits, and
consider meditation or yoga. Relaxation training and thermal
biofeedback, combined with relaxation techniques and cog-
nitive behavioral therapies, have been subjected to rigorous,
well-designed, randomized clinical trials, and show efficacy in
migraine prevention [33]. In contradistinction, evidence-based
therapy recommendations for acupuncture, hypnosis, and chi-
ropractic manipulation for headache prevention are not yet
available.
Pharmacological headache prophylaxis
Clinicians should be encouraged to treat headaches in early preg-
nancy with acute medications such as acetaminophen or low doses
of codeine. Preventive therapy should be reserved for women
whose headaches continue to worsen throughout pregnancy.
There are no prospective randomized clinical trials of migraine
prophylactic drugs in pregnant women. Non-pharmacologic thera-
pies should be initiated first.
Whenever a second comorbid condition exists with migraine,
it is advisable to use one drug to treat both conditions. Examples
include migraine and epilepsy, wherein an anticonvulsant
may be effective to treat both conditions, and migraine and
depression, for which a selective serotonin reuptake inhibitor
(SSRI), such as fluoxetine (category B), may similarly permit
monotherapy.
Propranolol or metoprolol are the drugs of choice as head-
ache preventive during pregnancy [1]. Verapamil (calcium chan-
nel blocker) may also be beneficial [34]. Valproic acid should be
avoided for headache prophylaxis because of its potential for
causing neural tube defects. The use of topiramate and gabapen-
tin should be restricted for headache prophylaxis in view of their
potential association with fetal defects, although these drugs can
be very effective for non-pregnant migraineurs.
Tricyclic antidepressant amitriptyline is considered category
C, at low doses (10–25 mg) a day has not been associated with
adverse outcomes during pregnancy. Clinicians should consider
tapering the dose in the weeks before delivery to reduce risk of
neonatal sedation [35].
Nutraceutical such as magnesium oxide may also be con-
sidered during pregnancy. The recommended daily amount is
350-400 mg of elemental magnesium [36]. Oral supplementation
at such a dose is generally accepted to be safe for use in pregnancy.
Non-invasive transcutaneous electrical nerve stimulation
(TENS) with the Cefaly device has been studied for both acute
and preventive treatment of migraine [37, 38], and has been mar-
keted as safe for pregnancy based on data for use of TENS for back
pain during pregnancy [39]. Limitations for this device is cost and
lack of insurance coverage.
186
References
1. MacGregor E. Headache in pregnancy. Continuum (Minneap Minn)
2014;20(1):128–147 [Review].
2. Headache Classification Committee of the International Headache S. The
International Classification of Headache Disorders, 3rd edition (beta ver-
sion). Cephalalgia 2013;33(9):629–808.
3. Dawson-Basoa M, Gintzler A. 17-Beta-estradiol and progesterone modu-
late an intrinsic opioid analgesic system. Brain Res 1993;601(1-2):241–245.
[II-3].
4. Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev
Neurol 2013;9(11):637–644.
5. Dimitriadou V, Buzzi MG, Theoharides TC, Moskowitz MA. Ultrastructural
evidence for neurogenically mediated changes in blood vessels of the rat
dura mater and tongue following antidromic trigeminal stimulation.
Neuroscience 1992;48(1):187–203. [II -2].
6. Silberstein S, Dodick D. Migraine genetics: part II. Headache
2013;53(8):1218–1229. [Review].
7. Loder E, Silberstein S. Headaches in woman. In: Silberstein SD, Lipton RB,
Dodick DW, eds. Wolff’s Headache and Other Head Pain. 8th ed. New York:
Oxford University Press, 2008:691–710. [Review]
8. Burch R. Epidemiology and treatment of Menstrual Migraine and
Migraine during pregnancy and lactation: A narrative review. Headache
2020;60(1):200–216.
9. Kvisvik E, Stovner L, Helde G, Bovim G, Linde M. Headache and migraine
during pregnancy and puerperium: the MIGRA-study. J Headache Pain
2011;12(4):443–451.
10. Wainscott G, Sullivan F, Volans G, Wilkinson M. The outcome of preg-
nancy in women suffering from migraine. Postgrad Med J 1978;54(628):
98–102. [II-2].
11. Chen H, Chen S, Chen Y, Lin H. Increased risk of adverse pregnancy out-
comes for woman with migraines: a nationwide population-based study.
Cephalalgia 2010;30(4):443–448. [II-2].
12. Facchinetti F, Allais G, Nappi R, D’Amico R, Marozio L, Bertozzi L, et al.
Migraine is a risk factor for hypertensive disorders in pregnancy: a prospec-
tive cohort study. Cephalalgia 2009;29(3):286–292 [II-3].
13. Grossman TB, Robbins MS, Govindappagari S, Dayal AK. Delivery
Outcomes of Patients with Acute Migraine in Pregnancy: A Retrospective
Study. Headache 2017;57(4):605–611.
14. Skajaa N, Szepligeti SK, Xue F, Sorensen HT, Ehrenstein V, Eisele O,
et al. Pregnancy, birth, neonatal, and postnatal neurological outcomes after
pregnancy with migraine. Headache 2019;59(6):869–879.
15. Schwartz R. Neurodiagnostic imaging of the pregnant patient. In: Deinsky
O, Feldmann E, Hainline B, eds. Neurologic Complications of Pregnancy.
New York: Raven Press, 1994:243–248. [Review]
16. Webb J, Thomsen H, Morcos S. The use of iodinated and gadolinium
contrast media during pregnancy and lactation. Eur Radiol 2005;15(6):
1234–1240. [Review].
17. Rebordosa C, Kogevinas M, Horvath-Puho E, Norgard B, Morales M,
Czeizel AE, et al. Acetaminophen use during pregnancy: effects on risk for
congenital abnormalities. Am J Obstet Gynecol 2008;198(2):178 e1–7.
18. Feldkamp ML, Meyer RE, Krikov S, Botto LD. Acetaminophen use in preg-
nancy and risk of birth defects: findings from the national birth defects pre-
vention study. Obstet Gynecol 2010;115(1):109–115.
19. Servey J, Chang J. Over-the-counter medications in pregnancy. Am Fam
Physician 2014;90(8):548–555.
20. Bisson DL, Newell SD, Laxton C, Royal College of O, Gynaecologists.
Antenatal and Postnatal Analgesia: Scientific Impact Paper No. 59. BJOG
2019;126(4):e114–e24.
Maternal-Fetal Evidence Based Guidelines
21. Childress KMS, Dothager C, Gavard JA, Lebovitz S, Laska C, Mostello DJ.
Metoclopramide and Diphenhydramine: A Randomized Controlled Trial
of a Treatment for Headache in Pregnancy when Acetaminophen Alone Is
Ineffective (MAD Headache Study). Am J Perinatol 2018;35(13):1281–1286.
22. Daniel S, Koren G, Lunenfeld E, Bilenko N, Ratzon R, Levy A. Fetal expo-
sure to nonsteroidal anti-inflammatory drugs and spontaneous abortions.
CMAJ 2014;186(5):E177–E182.
23. Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs
during pregnancy and risk of miscarriage: population based cohort study.
BMJ 2003;327(7411):368.
24. Morris J, Rosen D, Rosen K. Nonsteroidal anti-inflammatory agents in neo-
nates. Paediatr Drugs 2003;5(6):385–405. [Review].
25. United States Department of Agriculture Agricultural Research
Service National Nutrient Database for Standard Reference Release 28. In:
usda.gov (online). Available at: http://ndb.nal.usda.gov/ndb/foods/show/
4277?fgcd=&manu=&lfacet=&format=&count=&max=35&offset=&sort=
&qlookup=14209. Accessed August 17, 2020. [Review].
26. Jahanfar S, Jaafar SH. Effects of restricted caffeine intake by mother on
fetal, neonatal and pregnancy outcomes. Cochrane Database Syst Rev
2015;(6):CD006965.
27. Maslova E, Bhattacharya S, Lin SW, Michels KB. Caffeine consumption
during pregnancy and risk of preterm birth: a meta-analysis. Am J Clin
Nutr 2010;92(5):1120–1132.
28. Cunnington M, Ephross S, Churchill P. The safety of sumatriptan and
naratriptan in pregnancy: what have we learned? Headache 2009;49(10):
1414–1422. [Review].
29. Hagai A, Diav-Citrin O, Shechtman S, Ornoy A. Pregnancy outcome after
in utero exposure to local anesthetics as part of dental treatment: A pro-
spective comparative cohort study. J Am Dent Assoc 2015;146(8):572–580.
30. Oral Health Topics: Pregnancy: American Dental Association; [cited 2020
September 26, 2020].
31. American College of O, Gynecologists Women’s Health Care P, Committee
on Health Care for Underserved W. Committee Opinion No. 569: oral
health care during pregnancy and through the lifespan. Obstet Gynecol
2013;122(2 Pt 1):417–422.
32. Govindappagari S, Grossman TB, Dayal AK, Grosberg BM, Vollbracht S,
Robbins MS. Peripheral nerve blocks in the treatment of migraine in preg-
nancy. Obstet Gynecol 2014;124(6):1169–1174.
33. Campbell JK, Penzien DB, Wall EM, and the US Headache Consortium.
Evidence-based guidelines for migraine headache: behavioral and physi-
cal treatments. In: AOA.net (online). Available at: http://tools.aan.com/
professionals/practice/pdfs/gl0089.pdf. Accessed September 26, 2020. [Review].
34. Silberstein S, Freitag F, Bigal M. Migraine treatment. In: Silberstein SD,
Lipton RB, Dodick DW, eds. Wolff’s Headache and Other Head Pain. 8th ed.
New York: Oxford University Press, 2008:177–292. [Review].
35. MacGregor EA. Migraine in pregnancy and lactation. Neurol Sci 2014;35
(Suppl 1):61–64.
36. Food and Nutrition Board, Institute of Medicine. Magnesium. Dietary
Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and
Fluoride. Washington, DC: National Academy Press; 1997:190–242.
37. Chou DE, Shnayderman Yugrakh M, Winegarner D, Rowe V, Kuruvilla D,
Schoenen J. Acute migraine therapy with external trigeminal neurostimula-
tion (ACME): A randomized controlled trial. Cephalalgia 2019;39(1):3–14.
38. Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M,
Gerard P, et al. Migraine prevention with a supraorbital transcutaneous
stimulator: a randomized controlled trial. Neurology 2013;80(8):697–704.
39. Keskin EA, Onur O, Keskin HL, Gumus, II, Kafali H, Turhan N.
Transcutaneous electrical nerve stimulation improves low back pain dur-
ing pregnancy. Gynecol Obstet Invest 2012;74(1):76–83.
19
SEIZURES
Sally Mathias and Meriem Bensalem-Owen
Key points
• Epilepsy is a chronic neurological condition characterized
by recurrent unprovoked seizures. The most important
diagnostic tool is the history.
• Approximately 0.3–0.7% of all pregnancies are among
women with epilepsy.
• For the majority of the patients, seizure frequency remains
unchanged during pregnancy. Status epilepticus is rare
during pregnancy.
• Fetal loss, perinatal death, congenital anomalies (4–8%,
or about twice the baseline risk), low birth weight, pre-
maturity, induction, developmental delay, and child-
hood epilepsy have been reported in the past to be more
frequent, but more recent data do not confirm an increase
in these complications.
• Supplemental folic acid (0.4 up to 4 mg daily, usually
2–4 mg) may be given to all women of childbearing age
taking antiepileptic drugs (AEDs) prior to conception and
continued during pregnancy. There is insufficient pub-
lished information to address the dosing of folic acid.
• Counsel women with seizures or epilepsy about the risk
of AED-associated teratogenicity and neurodevelopmental
delay, folic acid supplementation, possible changes in sei-
zure frequency during pregnancy, importance of medica-
tion compliance and AED level monitoring, inheritance
risks for seizures, and breastfeeding. Encourage enrol-
ment in a pregnancy registry.
• In general, the best choice for therapy is the AED that best
controls the seizures. Monotherapy at the lowest possible
dose of the AED most efficient in controlling seizures
should be the goal. All treatment decisions involve a dis-
cussion of benefits and harms of treatment options.
• Carbamazepine, phenobarbital, primidone, phenytoin,
valproate, and topiramate are FDA category D drugs,
and should be avoided if possible. Currently levetiracetam
(Keppra) and lamotrigine (Lamictal) are common choices
for AED in pregnancy, but other safe choices are available
as well.
• Optimize AED therapy and complete AED changes if
possible at least 6 months before planned conception.
• Seizure freedom for at least 9 months prior to preg-
nancy is probably associated with a high likelihood of
remaining seizure-free during pregnancy.
• Stopping or changing an AED during pregnancy for the
sole purpose of reducing teratogenicity is not advised.
• Prenatal testing should include first-trimester ultrasound,
alpha-fetoprotein (AFP) levels, anatomy and echocar-
diographic ultrasounds, and if needed amniocentesis for
amniotic fluid AFP and acetylcholinesterase.
• As pregnancy progresses, both total and nonprotein
bound plasma concentrations of some AEDs may decline.
DOI: 10.1201/9781003099062-19
• Monitor AED levels through the eighth postpartum week.
• There is insufficient evidence to support or refute a ben-
efit of prenatal vitamin K supplementation for reducing
the risk of hemorrhagic complications in the newborns
of women with epilepsy.
• There is possibly a substantial increased risk preterm
birth for women with epilepsy who smoke.
• Encourage breastfeeding and monitor for sedation or
feeding difficulties, which can be caused by certain AEDs,
usually those with low protein binding.
• Emphasize that >90% of women with epilepsy have suc-
cessful pregnancies and deliver healthy babies.
Background
Recommendations and guidelines presented in this chapter are in
large part based on the updated companion Practice Parameters
of the Quality Standards Subcommittee and Therapeutics and
Technology Assessment Subcommittee of the American Academy
of Neurology, American Epilepsy Society, the updated Epilepsy
Quality Measurement Set and the report from the International
League Against Epilepsy Task Force on Women and Pregnancy
[1–5].
Diagnoses/Definitions
Seizures result from an abnormal paroxysmal discharge of a
group of cerebral neurons. Epilepsy is a chronic neurological
condition. Epilepsy is defined as at least two unprovoked (or
reflex) seizures occurring greater than 24 hours apart or one
unprovoked (or reflex) seizure and a probability of further sei-
zures similar to the general recurrence risk after two unpro-
voked seizures, occurring over the next 10 years, or diagnosis
of an epilepsy syndrome [6]. The most important diagnostic tool
is the history. The examination is very often normal unless the
patient has a structural brain lesion. The history should include
the following information:
• The presence or absence of an aura, which is a recurrent
stereotypic abnormal sensation or experience. The aura is
a focal seizure without impairment of awareness according
to the newly proposed classification of seizures and epilep-
sies [7].
• Seizure description by an eyewitness, including duration.
• Postictal phase, description, and duration.
• Exacerbating factors.
• Birth history, especially when the seizure onset is in the
neonatal period or early childhood.
• History of febrile convulsions, central nervous system
infections, head trauma with loss of consciousness or
known structural lesion in the brain.
• Family history.
187
188
Ancillary tests include EEG, laboratory tests as indicated by
the history, and imaging of the brain. MRI of the head is more
sensitive than CT scan for detecting subtle lesions. EEG poses no
risk to the fetus, so workup for diagnosis should proceed in preg-
nancy just as in nonpregnant adults.
Symptoms
In focal seizures (previously called partial-onset seizures), some
patients may experience a subjective feeling, called aura. The par-
ticular site of the brain affected determines usually the symptom-
atology and/or the clinical expression of the seizure.
Epidemiology/Incidence
Epilepsy occurs in 0.5–0.8% of the general population, with
5% of people reporting a seizure at some time in their life.
Approximately 1 in 26 people will develop epilepsy at some point
in their lives [8]. The prevalence of epilepsy in the United States
indicates that approximately 1.5 million women with epilepsy are
of childbearing age. Approximately 0.3–0.7% of all pregnancies
are among women with epilepsy [9].
Etiology/Basic pathophysiology
Paroxysmal discharges of neurons occur when the threshold for
firing of neuronal membranes is reduced. The pathophysiology of
epileptic disorders is not very well understood. Structural abnor-
malities of neuronal transmitter receptors, channelopathies,
excessive excitatory activity, cortical remodeling, and loss of
inhibitory neuronal activity have all been implicated as possible
mechanisms.
Classification
The International League Against Epilepsy (ILAE) proposed a
new operational classification for seizures and epilepsies in 2017
[7]. Depending on their onset, seizures are classified as focal,
generalized, or unknown. Focal seizures can be further sub-
divided into seizures with or without impairment of awareness,
previously known as simple partial or complex partial seizures
(CPS). Focal onset seizures are further divided into motor onset
or non-motor onset based on clinical features. When aware-
ness is preserved the patient may either experience focal motor
or sensory manifestations or experience a subjective feeling,
called aura. Auras can be olfactory, gustatory, sensory, auditory,
visual, vertiginous sensations, or psychic experiences (such as
déja vu). Focal seizures with impairment of consciousness can
evolve into bilateral convulsive seizure (also known as second-
arily generalized seizure). The prototype for generalized seizures
is the generalized tonic clonic (GTC) seizure. However, general-
ized onset seizures are further divided into motor (main subtypes
being tonic-clonic, clonic, tonic, atonic myoclonic) and nonmo-
tor (main subtype being absence seizure). The most common
unknown onset epilepsy is epileptic spasms.
Risk factors/Associations
Risk factors for seizures are numerous, but could include malfor-
mations of cortical development, head trauma, central nervous
system infections, family history, complicated febrile convulsions,
Maternal-Fetal Evidence Based Guidelines
and possibly history of difficult birth (anoxia or trauma) or com-
plicated (fetal infections and/or preterm birth) pregnancy.
Complications
Women with epilepsy of childbearing age should be informed of
the risks associated with antiepileptic drug (AED) use prior to
conception [3], and that seizures may be harmful to mother and
fetus [4]. A recently published retrospective cohort study evalu-
ated the effect of pregnancy planning in women with epilepsy on
seizure control during pregnancy and on maternal and neonatal
outcomes. Planned pregnancies had a significantly greater pro-
portion of patients receiving AED monotherapy and of not using
valproic acid. This group also had a lower frequency of seizures
during pregnancy as well as a significantly lower likelihood of
altering their AED regimen during pregnancy [10].
Maternal complications
The American Academy of Neurology (AAN) reviewed the sci-
entific literature and published practice parameters in 2009,
which stated that probably no substantially increased risk
exists of cesarean delivery, late pregnancy bleeding, or preterm
labor and delivery in women with epilepsy who are taking anti-
epileptic drugs [1–3]. There is insufficient evidence to support
or refute an increased risk of pre-eclampsia, gestational hyper-
tension, spontaneous abortion, a change in seizure frequency
or an increased risk of status epilepticus in pregnant women
with epilepsy. Only class IV studies could be found on this
subject. On the basis of class II studies, seizure freedom for at
least 9 months prior to pregnancy is probably associated with
a high likelihood (84–92%) of remaining seizure-free during
pregnancy. Women can injure themselves during convulsive
seizures.
Fetal complications
GTC seizures increase the risk of hypoxia and acidosis as well as
injury from blunt trauma. Generalized seizures but not focalsei-
zures occurring during labor can affect fetal heart rate. According
to a recent study, women with epilepsy on AED therapy and expe-
riencing more than one GTC seizure during pregnancy had an
overall five-times higher preterm birth risk, a shorter gestational
age, and a reduced birthweight in boys [11]. Fetal loss (1.3–14%)
and perinatal death (1.3–7.8%), congenital malformations
anomalies (4–8%, or about twice the baseline risk), low birth-
weight (7–10%), preterm birth (4–11%), induction, develop-
mental delay, and childhood epilepsy can be associated with in
utero exposure to AEDs. There is insufficient evidence to deter-
mine whether the risk of neonatal hemorrhagic complications in
the newborns of women with epilepsy taking AEDs is substan-
tially increased. Evidence is inadequate to determine whether
prenatal vitamin K in women with epilepsy reduces the risk of
hemorrhagic complications in the newborns.
Congenital malformations are more common among off-
spring of women on AEDs (5%) than among offspring of
untreated patients (3%).
Major congenital malformations include neural tube
defects (NTDs), congenital heart disease, cleft lip/palate and
urogenital defects. Minor congenital malformations include
coarse hair, epicanthal folds, small nail beds, and skin tags. Most
common congenital malformations, which differ for different
AEDs, are cardiac, neural tube, craniofacial, and involving the
fingers.
Seizures 189

Epilepsy and pregnancy registries have been operational Management

for more than 20 years and were developed in order to bet-
ter understand the risks of birth defects associated with AED
treatment, and more importantly, to systematically study the
range of birth defects resulting from use of each AED [12].
Two class I studies, including one from the U.K. Epilepsy and
Pregnancy Registry, revealed that exposure during the first tri-
mester to valproic acid monotherapy is associated with a greater
risk for major congenital malformations than carbamazepine
monotherapy [13, 14]. Valproic acid as part of polytherapy was
associated with greater risk than polytherapy without valproic
acid [13].
Data from the North American Antiepileptic Drug (NAAED)
Pregnancy Registry indicate that the rate of major malforma-
tions is 9.3% with valproate, 5.6% with phenobarbital, 5.1%
with topiramate, 2.9% with carbamazepine, 2.6% with phe-
nytoin, 2.3% with lamotrigine, and 2.3% with levetiracetam
[15]. Valproic acid is associated with neural tube defects, oral
clefts, hypospadias, poor cognitive outcome, and cardiac mal-
formations [16]. Exposure to phenytoin, carbamazepine, topira-
mate and lamotrigine was associated with oral clefts. Avoidance
of phenobarbital may reduce the risk of cardiac malformations.
Principles
Effect of pregnancy on disease: Increase in hepatic cytochrome
P450 enzyme activity and renal clearance causes the concentra-
tion of some AEDs to fall. Decreased protein binding results
in higher levels of unbound biologically active AEDs and
may cause toxicity (Table 19.1). On the basis of current studies,
there is insufficient evidence to support or refute an increased
risk of a change in seizure frequency or status epilepticus during
pregnancy.
Preconception counseling
Also include in first prenatal visit:
1. Conception should be deferred until seizures are well con-
trolled on minimum dose of medication.
2. Monotherapy is preferable. Good compliance with AEDs
is essential to avoid any seizures. Currently levetiracetam
(Keppra) and lamotrigine (Lamictal) are common choices
for AED in pregnancy, but other safe choices are available
as well.

TABLE 19.1: Pharmacokinetic Profile of the Most Commonly Used AEDs

Pregnancy Category Protein
Mechanism by FDA (prior to 2015) Binding (%) Adverse effects

First-generation AEDs
Phenytoin (Dilantin)
Carbamazepine (Tegretol)
Valproic acid (Depakote,
Depakene)
Ethosuximide (Zarontin)
Na D 90 Rash, ataxia, hirsutism, gingival hypertrophy,
osteoporosis
Ca, GABA D 75 Rash, diplopia, sexual dysfunction, osteoporosis
Na, GABA D 85–95 Weight gain, tremor, hair loss, encephalopathy,
hepatotoxicity, pancreatitis, polycystic ovaries
T-type Ca C 0 Nausea, vomiting, anorexia, rash

Second-, third-, and fourth-generation AEDs

Gabapentin (Neurontin)
Pregabalin (Lyrica)
Lamotrigine (Lamotrigine)
Levetiracetam (Keppra)
Oxcarbazepine(Trileptal)
Tiagabine (Gabatril)
Topiramate (Topiramate)
Zonisamide (Zonegran)
Lacosamide (Vimpat)
Rufinamide (Banzel)
Vigabatrin (Sabril)
Eslicarbazepine (Aptiom)
Clobazam (Onfi)
Perampanel (Fycompa)
Cannabidiol (Epidiolex)
Cenobamate (Xcopri)
Abbreviation: DRESS, drug reaction with eosinophilia and system symptoms.
Ca C 0 Weight gain, edema, myoclonus
Ca C 0 Increased appetite, confusion, somnolence
Na, Glutamate C 55 Rash, aseptic meningitis, arrhythmias
SV2a C 0 Behavioral changes, asthenia
Na, Ca C 40 Hyponatremia, diplopia, rash
GABA reuptake C 96 Encephalopathy, status epilepticus
Multiple D 10 Renal stones, speech difficulties, paresthesias, weight
loss, acidosis, closed-angle glaucoma
Na, T-Ca C 40–60 Renal stones, weight loss, paresthesias, contraindicated
if history of allergy to sulfa drugs
Na (slow C 15 Dizziness, nausea, vomiting, double vision
inactivation)
Na C 34 Headaches, drowsiness, dizziness, vomiting
GABA C 0 Visual field loss, somnolence, headaches, dizziness
Na C <40 Dizziness, disturbance in gait and coordination
GABA C 80–90 Somnolence, lethargy, ataxia
AMPA C 95–96 Psychiatric and behavioral reactions (aggression,
Unknown No data >94 hostility, homicidal ideation in higher doses),
Na, GABA No data 60 dizziness, somnolence, fatigue, weight gain
Hepatotoxicity, somnolence, fatigue, decrease appetite,
diarrhea
Somnolence, dizziness, fatigue, diplopia, QT
shortening, DRESS
190
3. Inform women with epilepsy that infants exposed in utero
to AED have a 4–8% risk of congenital malformation,
most notably neural tube defects, cardiac and craniofa-
cial defects, compared to 2–3% for the general population.
Epilepsy pregnancy registries have been operational for
more than 20 years, and collected an impressive amount
of data. Carbamazepine, phenobarbital, primidone,
phenytoin, topiramate, and valproate have increased
rates of malformations and should be avoided if pos-
sible at least in the first trimester. Recent pregnancy data-
bases have suggested that valproate is significantly more
teratogenic than carbamazepine, and the combination of
valproate with lamotrigine and valproate with carbam-
azepine is particularly teratogenic [15–17]. A recent study,
that included the largest sample to date with monotherapy
management, demonstrated a four- to fivefold increased
risk of early neurodevelopmental disorders associated with
exposure to valproate during pregnancy. The risk was still
present at low doses and was noted for exposure in the
second and third trimester [18]. If Valproate is used, high
plasma levels (>70 µg/mL) should be avoided unless neces-
sary to control seizures, and the drug should be given in
divided doses three or four times daily. To date the most
comprehensive prospective study of cognitive development
reported IQ in children exposed to low dose of valproate
comparable to IQ in children exposed to other antiepilep-
tic drugs [18]. Lamotrigine has been associated with facial
clefts, however lowest rates of MCMs were seen when
lamotrigine dose was <300 mg/day [19].
4. Seizure freedom for at least nine months prior to pregnancy
is probably associated with a high likelihood of remaining
seizure-free during pregnancy.
5. Consider neurological consultation regarding the pos-
sibility of tapering off and stopping anticonvulsant medi-
cations if the patient has been seizure-free for greater
than two years and has a normal EEG. The patient should
be observed for 6–12 months off AED before attempting
conception.
6. Preconception folic acid supplementation (usually 2–4 mg)
may be considered to reduce the risk of major congenital
malformations.
7. Driving privileges should be suspended for several months
after a seizure; the exact length varies depending on the
state [20].
8. Home/Work: Avoid baths, take showers instead. Avoid
manipulation of heavy machinery or working at heights
[20].
9. Enzyme-inducing AEDs enhance the metabolism of
oral contraceptives, therefore decreasing their efficacy.
Pregnancies should be planned.
10. Emphasize that 90% of women with epilepsy have suc-
cessful pregnancies and deliver healthy babies [21].
Prenatal counseling
At the first prenatal visit and during pregnancy as necessary,
counsel women with seizures or epilepsy regarding all of the
aforementioned preconception issues. In addition, discuss the
following:
• In the majority of women with epilepsy, pregnancy has no
effect on the seizure frequency. If seizures are well con-
trolled, they are likely to remain so during pregnancy [22].
Maternal-Fetal Evidence Based Guidelines
• Although no AED is specifically indicated for use in
pregnant women, the AED that renders the patient
seizure-free and side effect-free should be the drug
of choice during pregnancy. Currently levetiracetam
(Keppra) and lamotrigine (Lamictal) are common choices
for AED in pregnancy, but other safe choices are available
as well.
• The risk-to-benefit ratio must be considered when select-
ing a drug.
• There is a risk of AED-associated teratogenicity and neuro-
development delay.
• Importance of medication compliance and AED level
monitoring during pregnancy. The plasma AED concen-
tration fluctuates during pregnancy due to several physi-
ologic reasons, including increase in glomerular filtration
rate, which leads to increased renal clearance, increased
volume of distribution, enhanced hepatic metabolism/
absorption of AED, hepatic enzyme induction by steroid
hormones and decreased protein binding [23]. Therefore,
levels should be measured on highly protein bound AEDs
(Table 19.1).
• In a retrospective population-based study a tenfold increase
in mortality was noted in pregnancy in women with epi-
lepsy compared to women without epilepsy. The etiology
for mortality was not found, thus leaving many questions
answered. Most of these deaths were Sudden Unexpected
Death in Epilepsy (SUDEP) demonstrating the importance
of complete seizure control and a heightened clinical atten-
tion for these pregnancies [24, 25].
• Breastfeeding issues (see later in this chapter).
• Inheritance risks for seizures.
• Child care issues [26].
• Educate patients about various pregnancy registries
and encourage enrolment to a registry. The goal of any
registry is to gather and publish information on the rate of
major malformations in infants whose mothers had taken
AED’s during pregnancy, and to determine the safety of
seizure medications. The North American Anti-Epileptic
Drug Pregnancy Registry enrolls pregnant women with
epilepsy from the U.S. and Canada (e.g. www.aedpreg-
nancyregistry.org). Likewise, every region has its own
pregnancy registry, and newer AED manufacturers have a
registry of their own.
Prenatal care
• Supplemental folic acid (usually 2–4 mg/day) in women
with epilepsy before they become pregnant is recom-
mended to reduce the risk of major congenital malforma-
tions. A recent study showed that use of periconceptional
folate in pregnant women with epilepsy taking AEDs was
associated with higher Full-Scale IQ in children at 3 and
6 years of age, and hence better cognitive development [27].
• A first-trimester ultrasound is indicated for exact dating.
• Anatomic ultrasound at 11–13 weeks can identify most
severe defects, such as anencephaly.
• Prenatal testing for neural tube defects with alpha-­
fetoprotein levels at 15–18 weeks’ gestation (up to 21 weeks).
• If appropriate, amniocentesis for amniotic fluid alpha-feto-
protein and acetylcholinesterase levels.
• Ultrasound at 16–20 weeks’ gestation can assess ana-
tomic anomalies such as orofacial clefts, heart defects, and
caudal neural tube defects.
Seizures
• Fetal echocardiogram at about 22 weeks.
• An ultrasound for growth at >32 weeks is not mandatory.
• Neonates should receive vitamin K, 1 mg IM at birth. The
benefit of prenatal maternal vitamin K therapy is unknown,
with no trial available for assessment.
Therapy
• Multidisciplinary communication between the primary
care provider, obstetrician, geneticist, and neurologist/epi-
leptologist for counseling and management of seizures and
epilepsy during pregnancy is crucial.
• There is no trial that indicates which AED is safest dur-
ing pregnancy. The ideal AED is one that best controls the
seizures. The following AEDs result in major congenital
malformations: Carbamazepine, phenobarbital, primi-
done, phenytoin, valproate, and topiramate (Table 19.1).
These six AEDs should therefore be avoided if possible,
by using a different therapy beginning in the preconception
period. Switching and abruptly stopping of AEDs are to be
avoided. Currently levetiracetam (Keppra) and lamotrigine
(Lamictal) are common choices for AED in pregnancy, but
other safe choices are available as well.
• Regarding AED therapy, at the beginning of pregnancy it
is recommended that the patient is on monotherapy with
the AED of choice for the seizure type, achieving optimal
seizure control, at the lowest effective dose.
• Monitoring the serum levels of lamotrigine, carbamaze-
pine, and phenytoin during pregnancy should be consid-
ered and monitoring of levetiracetam and oxcarbazepine
(as monohydroxy derivative) levels may be considered.
Free levels (serum or saliva) are available for carbamaze-
pine, valproic acid, phenobarbital, and phenytoin. Avoid
high peak levels by spreading out the total daily dose into
multiple smaller doses. Studies provide some evidence sup-
porting active monitoring of AED levels during pregnancy,
particularly of lamotrigine, as changes in lamotrigine lev-
els were associated with increased seizure frequency [28].
It seems reasonable to individualize this monitoring for
each patient, with the aim of maintaining a level close
to preconception level, presumably the one at which
the woman with epilepsy was doing well with seizure
control. One study showed that during pregnancy the
clearance of lamotrigine increases with a peak of 94% in
the third trimester; hence, frequent adjustments of the
dose are required during pregnancy [21].
• AEDs have effects on sodium, potassium, or calcium chan-
nels. They also can affect neurotransmitters enhancing the
inhibitory neurotransmitter, gamma-aminobutyric acid
(GABA), or inhibiting the excitatory glutamate.
• North American AED Pregnancy Registry: Phone number
1-888-233-2334; www.aedpregnancyregistry.org.
Delivery
AEDs should be continued in labor, and in the immediate
postpartum period. Women should be encouraged to bring
their own AEDs to the delivery and medications should be taken
at their usual times during labor [29]. Consider intravenous for-
mulations of AEDs if these cannot be taken orally. A recent study
found that women with epilepsy on polytherapy versus mono-
therapy had an increased risk of cesarean section [29]. There
191
is possibly a substantial increased risk of preterm birth or
women with epilepsy who smoke [30].
Postpartum/Breastfeeding
Breastfeeding is not contraindicated. The greater the protein
binding of AED (Table 19.1), the lower is its concentration in breast
milk. Breastfeeding is not contraindicated in patients on anti-
convulsant medications unless excess neonatal sedation occurs.
Monitor newborns or infants for sedation when breastfeeding
mothers with seizures take low-protein-bound AEDs. The AED
concentration profiled in breast milk follows the plasma concen-
tration curve. The total amount of drug transferred to infants via
breast milk is usually much smaller than the amount transferred
via the placenta during pregnancy. However, as drug elimination
mechanisms are not fully developed in early infancy, repeated
administration of a drug via breast milk may lead to accumula-
tion in the infant. Extended release formulations of AEDs should
be avoided. It appears that there are no adverse effects of AED
exposure via breast milk on cognition and development observed
at 3 years and 6 years [31, 32].
Valproic acid, phenobarbital, phenytoin, and carbamazepine
may be considered as not transferring into breast milk to as great
an extent as, for example, levetiracetam, gabapentin, lamotrigine,
and topiramate.
For most AEDs, the pharmacokinetics in the mother will
return to prepregnancy levels within 10–14 days after deliv-
ery. Monitor AED levels through the eighth postpartum week
and adjust doses accordingly to avoid toxicity. Sleep depriva-
tion may exacerbate seizures, and should therefore be avoided.
Women with epilepsy should not bathe their child while they
are alone at home. Women with frequent seizures or myoclonus
should avoid stair climbing while carrying the baby and a por-
table changing pad placed on the floor should be used for chang-
ing. New mothers should avoid using a carrier in front or on their
back. A portable carrier with handles is a safer alternative in the
event of a seizure and subsequent fall [26]. Since enzyme-inducing
AEDs (Table 19.1) lower estrogen concentrations by 40–50%,
thereby compromising contraceptive effectiveness, hormonal
contraceptives prescribed to women with epilepsy on these AEDs
should contain ≥50 μg of ethinyl estradiol [33]. Oral contracep-
tives induce lamotrigine metabolism requiring adjustment of its
dose [34].
Managing women with epilepsy during pregnancy can be
challenging. Counseling is essential during the preconcep-
tual period, during pregnancy, and in the postpartum period.
Knowledge of the risks associated with epilepsy and AEDs is
crucial. Antiepileptic drug levels and the doses adjusted during
pregnancy and in the postpartum period should be carefully
monitored. Most women with epilepsy have uncomplicated preg-
nancies with normal outcomes.
References
1. Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update:
management issues for women with epilepsy—focus on pregnancy (an
evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-
feeding: report of the Quality Standards Subcommittee and Therapeutics
and Technology Assessment Subcommittee of the American Academy of
Neurology and American Epilepsy Society. Neurology 2009;73(2):142–149.
[Guideline; III]
2. Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management
issues for women with epilepsy—focus on pregnancy (an evidence-based
192
review): I. Obstetrical complications and change in seizure frequency:
report of the Quality Standards Subcommittee and Therapeutics and
Technology Assessment Subcommittee of the American Academy of
Neurology and American Epilepsy Society. Neurology 2009;73:126–132.
[Guideline; III]
3. Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update:
Management issues for women with epilepsy—focus on pregnancy (an
evidence-based review): II. Teratogenesis and perinatal outcomes: report
of the Quality Standards Subcommittee and Therapeutics and Technology
Assessment Subcommittee of the American Academy of Neurology and
American Epilepsy Society. Neurology 2009;73:133–141. [Guideline; III]
4. Fountain NB, Van Ness PC, Bennett A, et al. Quality improvement
in neurology: epilepsy update quality measurement set. Neurology
2015;84(14):1483–1487. [Guideline; III]
5. Tomson T, Battino D, Bromley R, et al. Management of epilepsy in preg-
nancy: A report from the International League Against Epilepsy Task Force
on Women and Pregnancy. Epileptic Disord 2019;21:497–517. [III]
6. Fisher R, Acevedo C, Arzimanoglou A, et al. A practical clinical definition
of epilepsy, Epilepsia 2014;55:475–482. [Review]
7. Fisher RS, Cross JH, French JA, et al. Operational classification of sei-
zure types by the International league against epilepsy: Position paper
of the ILAE commission for classification and terminology. Epilepsia
2017;58(4):522–530. [III]
8. Institute of Medicine Committee on the Public Health Dimensions of
the Epilepsies; England MJ, Liverman CT, Schultz AM, Strawbridge LM.
Epilepsy Behav 2012;25(2):266–276. [Review]
9. MacDonald SC, Bateman BT, McElrath TF. Mortality and morbidity dur-
ing delivery hospitalization among pregnant women with epilepsy in the
United States. JAMA Neurol 2015;72:981–88. [II-2]
10. Abe K, Hamada H, Yamada T, et al. Impact of planning of pregnancy in
women with epilepsy on seizure control during pregnancy and on maternal
and neonatal outcomes. Seizure 2014;23:112–116. [II-3]
11. Rauchenzauner M, Ehrensberger M, Rieschi M, et al. Generalized tonic-
clonic seizures and antiepileptic drugs during pregnancy – a matter of
importance for the baby? J Neurol 2013;260:484–488. [II-3]
12. Meador KJ, Pennell PB, Harden CL, et al. Pregnancy registries in epilepsy:
a consensus statement on health outcomes. Neurology 2008;71:1109–1117.
[II–3]
13. Morrow J, Russell A, Guthrie E, et al. Malformations risks of antiepilep-
tic drugs in pregnancy: a prospective study from the UK Epilepsy and
Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77(2):193–198.
[II–2]
14. Wide K, Winbladh B, Kallen B. Major malformations in infants exposed
to antiepileptic drugs in utero, with emphasis on carbamazepine and val-
proic acid: a nation-wide, population-based register study. Acta Paediatr
2004;93(2):174–176. [II–2]
15. The North American Pregnancy Registry newsletter. www.aedpregnan-
cyregistry.org/wp-content/uploads/The-NA-AED-Pregnancy-Registry-
AES-2019.pdf [II-3]
16. Wyszynski DF, Nambisan M, Surve T, et al. and for the Antiepileptic Drug
Pregnancy Registry. Increased rate of major malformations in offspring
exposed to valproate during pregnancy. Neurology 2005;64(6):961–965. [II–3]
Maternal-Fetal Evidence Based Guidelines
17. Tomson T, Battino D, Craig J, et al. ILAE Commission on therapeutic strat-
egies. Pregnancy registries: differences, similarities, and possible harmoni-
zation. Epilepsia 2010;51(5):909–915. [III]
18. Meador KJ, Baker GA, Browning N, et al. NEAD Study Group. Fetal antiepi-
leptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a
prospective observational study. Lancet Neurol 2013;12(3):244–252. [II-3]
19. Holmes LB, Baldwin EJ, Smith CR, et al. Increased frequency of isolated
cleft palate in infants exposed to lamotrigine during pregnancy. Neurology
2008;70(22 pt 2):2152–2158. [II–2]
20. Dean P. Safety issues for women with epilepsy. In: Morrell MJ, Flynn K, eds.
Women with Epilepsy. 1st ed. Cambridge: University Press, 2005:263–268.
[II–3]
21. McAuley JW, Anderson GD. Treatment of epilepsy in women of repro-
ductive age: pharmacokinetic considerations. Clin Pharmacokinet
2002;41:559–579. [II–3]
22. La Neve A, Boero G, Francavilla T, et al. Prospective, case–control study
on the effect of pregnancy on seizure frequency in women with epilepsy.
Neurol Sci 2015;36:79–83. [II-1]
23. Leppik IE, Rask CA. Pharmacokinetics of antiepileptic drugs during preg-
nancy. Semin Neurol 1988;8(3):240–246. [Review]
24. Edey S, Moran N, Nashef L. SUDEP and epilepsy-related mortality in preg-
nancy. Epilepsia 2014;55(7):e72–74. [II-2]
25. MacDonald SC, Bateman BT, McElrath TF, Hernández-Díaz S. Mortality
and morbidity during delivery hospitalization among pregnant women with
epilepsy in the United States. JAMA Neurol 2015;72(9):981–988. [II-3]
26. Callanan M. Parenting for women with epilepsy. In: Morrell MJ, Flynn
K eds. Women with Epilepsy. 1st ed. Cambridge: University Press, 2005:
228–234. [III]
27. Meador KJ, Pennell PB, May RC, et al. Effects of periconceptional folate on
cognition in children of women with epilepsy: NEAD study. Neurology.
2020;94(7):e729–e740 [II-2]
28. Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clear-
ance, therapeutic drug monitoring, and seizure frequency. Neurology
2008;70:2130–2136. [II–3]
29. Thomas SV, Syam U, Devi SJ. Predictors of seizures during pregnancy in
women with epilepsy. Epilepsia 2012;53(5):e85–88. [II-2]
30. Viale L, Allotey J, Cheong-See F, et al, for EBMCONNECT Collaboration.
Epilepsy in pregnancy and reproductive outcomes: a systematic review
and meta-analysis. Lancet 2015; published online August 26. http://dx.doi.
org/10.1016/S0140-6736(15)00045-8. [Review; II-1]
31. Hvas CL, Henriksen TB, Ostergaard JR, et al. Epilepsy and pregnancy:
effect of antiepileptic drugs and lifestyle on birth weight. BJOG 2000;107:
896–902. [II–3]
32. Meador KJ, Baker GA, Browning N, et al. For the Neurodevelopmental
effects of Antiepileptic drugs (NEAD) study group. Breastfeeding in
children of women taking antiepileptic drugs: cognitive outcomes at age
6 years. JAMA Pediatric 2014;168:729–736. [II-2]
33. Harden CL, Leppik I. Optimizing therapy of seizures in women who use
oral contraceptives. Neurology 2006;67:S56–S58. [II–3]
34. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce
lamotrigine metabolism: evidence from a double-blind, placebo-controlled
trial. Epilepsia 2007;48:484–489. [RCT]
20
OTHER NEUROLOGIC DISEASES IN PREGNANCY
Loralei L. Thornburg and Meredith L. Birsner
This chapter reviews several common neurological conditions in
pregnancy. Some topics such as headache (Chapter 18), seizure
disorder (Chapter 19) and stroke (Chapter 42) are addressed in
their own chapters.
Topics covered include:
i. General approach to neurology disease in pregnancy
ii. Spinal cord injury
iii. Guillain–Barré Syndrome
iv. Aneurysm
v. Myasthenia Gravis
I. General approach to neurologic
disease in pregnancy
Key points
• Specific recommendations for each disease need to
be addressed in a multidisciplinary fashion with the
patient’s goals at the center, by a multidisciplinary team
including ob/gyn, MFM, neurology, and other specialists
as dictated by the patient’s underlying disease and specific
manifestations.
• The physiology of pregnancy can alter the maternal toler-
ance of neurology disease as well as care for her disease,
and therefore providers should follow symptoms closely for
deterioration.
• Specific disease states are addressed individually, but as
a general approach, the patient with neurologic disease
should receive all usual obstetric care, as well as all the
typical neurologic care, including imaging; however, she
may require additional monitoring, testing or evaluation.
• If medication adjustments are needed, the goal should
be control maternal disease, while minimizing risk to
the fetus, using the lowest dose of the least teratogenic
medication.
Overall, most neurologic diseases will require a multidisciplinary
approach and care planning between teams. Therefore, a gen-
eral approach for ALL neurologic disease is reviewed first in this
chapter, with specifics for each disease state to follow.
Pregnancy management
Preconception counseling
Patients with neurologic disease who are contemplating preg-
nancy should undergo preconception counseling. Most neuro-
logic disease does not affect fertility, and those wishing to avoid
pregnancy should use contraception. If a disease is congenital or
hereditary in origin, this should additionally include then genetic
DOI: 10.1201/9781003099062-20
counseling. All patients should take the standard of at least
400 mg of folic acid preconception.
Women with congenital spinal lesions such as meningomy-
elocele should be made aware of the increased risk of spinal
cord lesions to their offspring and placed on 4 mg/day of folic
acid prior to conception [1]. All other patients should take the
standard of at least 400 mg of folic acid preconception.
Antenatal management of neurologic disease
All patients with neurologic disease should be monitored for
ongoing changes in disease state and care individualized to their
specific manifestations. Neurologic specialists or other disease
state specialists should see these patients regularly and be part of
the multidisciplinary care team.
All patients with mobility challenges secondary to neurologic
disease should meet with PT/OT to review home care, assistive
devices, and aids that can be helpful as pregnancy progresses.
Even if a patient did not use assistive devices prior to pregnancy,
many of those patients that have baseline weakness/limitations
in mobility may need to temporarily or intermittently use wheel-
chairs or additional assistive devices as abdominal size and weigh
increases. PT/OT can similarly aid in planning for infant care,
and determination of best options for adaptive equipment both in
and after pregnancy.
Psychological challenges
Non-pregnant people with neurological disorders are at increased
risk for depression [2]. During the perinatal period these patients
have a markedly increased risk of depression, and therefore fre-
quent screening is recommended [3, 4].
Delivery and delivery planning
Neurologic diseases are a heterogeneous group of disorders that
require coordination of care and delivery planning by a multidisci-
plinary team to assure the best possible outcome. Multidisciplinary
care plans are critical for these patients given the complex manifes-
tations of disease [5]. These care plans are proven to decrease the
length of hospital stay, rate of in-hospital complications, hospital-
ization costs, improve documentation, and enhance patient care [6].
Anesthesia
Many patients with neurological and neuromuscular disease
will have concerns that necessitate pre-delivery aesthesia con-
sultation. Those with involvement of respiratory musculature
and pulmonary sufficiency may require additional cardiopul-
monary testing or monitoring prior to or during labor. Some
conditions may make placement of regional aesthesia unsafe
or technically challenging, and therefore anesthesia should
evaluate these patients in the second trimester to assess risks
and address anesthetic planning. Patients with hereditary neu-
rologic diseases like Klippel-Trenaunay or von Hippel-Lindau
193
194
syndromes that are at risk for epidural or subdural hemangio-
mas may need MRI evaluation to determine the safety of neur-
axial anesthesia [7].
Postpartum care and breastfeeding
Many autoimmune-based neurological conditions are at risk for
worsening during the postpartum period. Others, such as sei-
zure disorders, are exacerbated by sleep disturbance, a common
occurrence in the perinatal period. Therefore, close follow up in
the postpartum period, as well as counseling of patients and sup-
port people to help assure that they are aware of symptoms to
watch for is important.
The concept of patients with chronic disease, especially those
with limited mobility or those using assistive devises becoming
parents frequently generates negative societal reactions; however,
research has demonstrated that the children of patients with SCI
have the same attitudes towards their parents, gender roles and
family functioning when compared to peers [8].
A number of peer support groups have developed ingenious
solutions for parenting and societal barriers faced by patients
with neuromuscular limitations, and most patients are able to
effective parent with some degree of assistance (e.g. https://
sciparenting.com/tips-tricks/). Prenatal discussion and planning
can help facilitate a successful transition to parenthood.
Breastfeeding should be encouraged, although assistance may
be needed depending on level of injury. Pre-delivery planning for
this, including consultation with lactation support teams, lacta-
tion physicians, and optimization of medications for breastfeed-
ing is recommended.
Contraception: Most neuromuscular diseases do not affect fer-
tility, therefore, use of contraception should be offered to those
patients at risk of pregnancy after delivery. Oral contraceptive pills
are generally considered safe for most neuromuscular conditions,
however, avoidance of estrogen is recommended by some authors
and for those with active thrombotic risks [9–11]. Progesterone-
only pills, transdermal patches, intramuscular medroxyproges-
terone injections, condoms and spermicide, and intrauterine
devices are all acceptable alternatives. Of note, some neuroepi-
lepics and other neurologic medications can interfere with the
function of oral contraceptives, and discussion of each patient’s
contraceptive options should therefore be individualized.
II. Spinal cord injury and
autonomic dysreflexia
Key points
• Spinal cord injury (SCI) in pregnancy is associated with
increased risks of urinary tract infections, preterm birth,
increased spasticity, and falls. The most worrisome, poten-
tially fatal complication is autonomic dysreflexia (ADR).
• Antenatal management pre-existing SCI includes screen-
ing for asymptomatic bacteriuria, aggressive treat-
ment of urinary tract infections, stool softeners and a
high-fiber diet; routine skin exams, frequent position
changes, and minimizing risk of falls. There is insufficient
data at this time to recommend universal pharmacologic
thromboprophylaxis.
• ADR affects up to 85% of patients with any spinal lesion
at or above the level of T6 (including prior neural tube
Maternal-Fetal Evidence Based Guidelines
defect repair, traumatic injury, transverse myelitis, or
Guillain–Barré). The most common sign of ADR is sys-
temic hypertension. Symptoms are synchronous with
any lower body stimulus, including uterine contractions.
Delivery and labor are a key stimuli that can trigger ADR.
Prevention involves avoidance of triggers (constipation,
catheterization, exams, etc.), and for labor, early neuraxial
anesthesia. Hypertension may be treated also with antihy-
pertensive agents that have a rapid onset and short dura-
tion of action, with first-line antihypertensive therapy for
ADR including nifedipine and labetolol.
• For SCI patients with baseline pulmonary insufficiency,
additional hemodynamic monitoring in labor may be
necessary.
Diagnosis/Definition
Spinal cord injury (SCI) is injury to the spinal cord, either by
trauma or disease, that results in a variety of pathologies. While
SCI can occur following trauma to the spinal cord, it can also be
due to a variety of pathologies including neural tube defect repair,
traumatic injury, transverse myelitis, or Guillain–Barré syndrome.
Epidemiology/Incidence
Approximately 17,730 new spinal cord injuries occur per year in
the United States [12]; women comprise approximately 20% of
injuries, with nearly half occurring in persons between the ages
of 16 and 30 years [13]. Each year about 2000 women with SCI will
become pregnant [12]. While new acute SCI during pregnancy is
rare, SCI pre-existing pregnancy is relatively more common.
Classification
SCI is classified by its etiology and the level of the lesion. The
higher is the functional level of the lesion, the higher the risk for
complications and other medical conditions.
Complications
Complications for pre-existing SCI included: Urinary tract com-
plications (59%), dysreflexia (27%), worsened spasticity (22%),
and thrombosis (8%) were the most common complications ante-
natally, and postpartum depression (35%) was the most com-
mon postpartum complication (18). The risk of preterm birth is
between 8% and 13% (2–5). Anemia can occur in 12% of women
with SCI, especially with history of chronic pyelonephritis, decu-
bitus, and/or renal failure. The most worrisome, potential fatal
complication is autonomic dysreflexia (ADR).
Pregnancy management
Patients with pre-existing SCI who are contemplating pregnancy
should undergo preconception counseling. SCI does not affect
fertility, and those wishing to avoid pregnancy should use con-
traception counselling [14]. If the spinal cord lesion is congeni-
tal or hereditary in origin this should additionally include then
genetic counseling. Women with congenital spinal lesions such
as meningomyelocele should be made aware preconception of
the increased risk of spinal cord lesions to their offspring and
placed on 4 mg/day of folic acid [15].
Other Neurologic Diseases in Pregnancy
In general patients with preexisting SCI are probably at no
greater risk than the general obstetric population for either
congenital malformations or fetal death [16]. In contrast to
patients with SCI antecedent to pregnancy, patients who suffer
traumatic SCI during pregnancy may be at risk for spontaneous
abortion, fetal malformation, abruptio placenta, or direct
fetal injury [17].
Prenatal care
Acute SCI during pregnancy
Acutely, SCI results in neurogenic shock or “spinal shock” because
of the loss of sympathetic innervation. This typically presents
with hypotension, bradycardia, and hypothermia because of
unmitigated parasympathetic effects. Traumatic SCI in preg-
nancy should be treated exactly as those outside of pregnancy,
including assuring adequate volume resuscitation and pres-
sor support, appropriate surgery (as needed) for trauma related
events. For some patients, administration of methyl-prednisolone
within 8 hours of traumatic SCI may improve neurologic recovery
[18]. The risk of deep venous thrombosis and pulmonary embo-
lism is greatest within 8 weeks, and prophylactic anticoagulation
should be considered during this period [19]. In rare cases, acute
SCI may result from acute hemorrhage, malignancy, or aggressive
hemangiomas. In those cases, embolization or decompressive
surgery may be necessary during pregnancy [7, 20].
Antenatal management of pre-existing SCI
Pregnancy in women with SCIs should be managed by a multidis-
ciplinary team approach involving specialists, which may include
an obstetrician with experience in caring for women with dis-
abilities, maternal-fetal medicine subspecialists, anesthesiolo-
gists, spinal rehabilitation physicians, nurses, physiotherapists,
occupational therapists, lactation consultants, pediatricians, and
neonatologists [14].
Urinary: Virtually all patients with SCIs suffer from neu-
rogenic lower urinary tract dysfunction, and various bladder
evacuation modes include indwelling catheters, intermittent
self-catheterization, Credé maneuver (extrinsic manual compres-
sion on the bladder), and spontaneous voiding [21]. Continuous
indwelling catheterization appears to have a near 100% incidence
of UTI in SCI patients, so self, intermittent catheterization,
every 4–6 hours may be preferable, if possible. Lidocaine during
Foley catheter placement may reduce the risk of ADR.
Recurrent UTIs and/or sepsis are common complications of
SCI. Frequent urinary cultures are recommended, at least
once per trimester. Urinary tract infections and pyelonephri-
tis are the most common reason for hospitalization of women
with SCIs during pregnancy [22]; symptoms of urinary tract
infection may not be typical among paitents with SCIs [23] and
may include autonomic dysreflexia and increased spasticity.
Given the increased risk of medical complications in pregnant
people with SCIs, practitioners should treat UTI in pregnant
people with SCIs just as they would in all pregnant women, but
may consider prescribing a longer course of antibiotics [14].
Frequent urinary cultures or antibiotic suppression with
nitrofurantoin should be considered [14, 24, 25], although
there is a paucity of data to guide optimal genitourinary care in
pregnancy [21].
Gastrointestinal: Stool softeners and a high-fiber diet are
advised to prevent constipation.
Dermatology: Pressure sores occur in 6–15% of pregnant peo-
ple with SCIs [22], and ulcers most commonly occur over ischial
195
and sacral areas [26]. Routine skin exams for any evidence of
decubitus ulcers at each visit, and frequent position changes.
Wheelchairs or other assistive devices may need to be resized
or fitted with extra padding. Supplemental vitamin D (2000 IU
daily) is recommended [27].
Pulmonary: Impaired pulmonary function may be present in
women with high thoracic or cervical spine lesions, usually above
the T5 level [28]. Diminished respiratory volumes from upward
displacement of the diaphragm by the enlarging gravid uterus is
particularly problematic for patients with tetraplegia, in whom the
diaphragm is the primary muscle of respiration [29]. For patients
with borderline function, ventilatory support and meticulous
attention to pulmonary care is necessary during pregnancy and
delivery, and antenatally, isolated or serial pulmonary function
testing as well as specialty involvement or co-management from
respiratory therapists or pulmonary medicine specialists may be
warranted [14]. Supine tilted positioning is suggested for labor.
Thromboembolic: Despite an incidence of venous thromboem-
bolism reported as high as 8% [30] there are insufficient data at
this time to recommend universal administration of pharma-
cologic thromboprophylaxis during pregnancy. However, range
of motion exercises and thrombolytic stockings should be consid-
ered for all patients, and consideration can be given to mechani-
cal or pharmacologic prophylaxis after patient counseling and
depending on other risk factors and local protocols [14]. Patients
suffering acute SCI during pregnancy should receive pharmaco-
logic thromboprophylaxis on the basis of the high rate of deep
venous thromboses reported in non-pregnant patients during
this time period [19].
Hematology: Screen for and treat anemia aggressively.
General support: Spasticity and muscle contractions frequently
complicate SCI. A regular program of a range of motion exercises
in lower extremities, leg elevation, and exercises to increase upper
body strength is recommended, as are social support services [24,
31]. All patients should meet with PT/OT to review home care,
assistive devices, and aids that can be helpful as abdominal size
increases and interferes with transfers. PT/OT can similarly aid
in planning for infant care and determination of best options for
adaptive equipment both in and after pregnancy.
Autonomic dysreflexia: ADR is the most serious complica-
tion impacting obstetric management, affecting about 85% of
patients with lesions at or above the level of T6 (above sym-
pathetic outflow and above the upper level of greater splanch-
nic flow) [9, 32]. It is potentially fatal. It is attributed to loss of
hypothalamic control over sympathetic spinal reflexes of somatic
or visceral sensory impulses still active distal to the level of the
lesion [33]. The most common sign of ADR is systemic hyper-
tension (vasoconstriction), which is which is variable in severity
but can be severe. Clinical manifestations include hyperthermia,
piloerection, diaphoresis, increased extremity spasticity, pupil
dilation, nasal congestion, respiratory distress, bradycardia (most
common) or tachycardia or cardiac arrhythmia, extreme fear and
anxiety, headache, loss of consciousness, intracranial bleed, con-
vulsions, and even death. Symptoms are typically synchronous
with uterine contractions. BP rises with contractions, then nor-
malizes in between.
ADR may be mistaken for pre-eclampsia, but several findings
may help differentiate the two conditions (see Table 20.1); a poten-
tial distinguishing factor is that the hypertension of autonomic
dysreflexia occurs during contractions and resolves between
them, whereas the hypertension of pre-eclampsia is unrelated to
uterine contractions [14].
196
TABLE 20.1: Differentiation of Pre-Eclampsia from Autonomic Dysreflexia during Labor
Disorder Onset Hypertension Symptoms
Pre-eclampsia Variable Mild or severe Independent of Could see elevated creatinine or Positive for
independent of uterine contractions uric acid or liver functions,
uterine contractions
Autonomic Acute Mild or severe Synchronous with
dysreflexia synchronous with uterine contractions
uterine contractions
Source: Adapted from Ref. [28], with permission.
a Not helpful in acute setting.
Triggers: Afferent stimuli (usually distension) from hollow vis-
cus (bladder, bowel, uterus) or skin (irritation or temp change)
below level of the spinal cord lesion. These include tight clothing
or constrictive devices, uterine contractions, cervical manipula-
tion/pelvic examinations, fundal massages, cold stirrups, inser-
tion of speculum, manipulation of urinary catheters, catheter
obstruction, external uterine compression during an ultrasound
exam, constipation, and decubitus ulcers.
Preventive management of ADR in susceptible patients
includes:
1. Routine bladder catheterization with topical anesthetic.
2. Avoidance of constipation with bowel regimen.
3. Pelvic exams: Minimize to when absolutely necessary and
shorten to minimal duration; consider pudendal block or
topical anesthetic (lidocaine) prior to exams. Avoid cold
stirrups or speculums if possible.
4. Neuraxial anesthesia at the onset of labor is not only
necessary but may be life-saving [34]. Although pain per-
ception is impaired in people with SCIs at or above T10,
neuraxial anesthesia is the treatment of choice to reduce
the risk of autonomic dysreflexia because it blocks neuro-
logic stimuli arising from the pelvic organs [35].
Treatment of ADR (Figure 20.1)
1. Remove offending stimulus. Expedite delivery if in sec-
ond stage with forceps or vacuum; If autonomic dysreflexia
during labor cannot be controlled, cesarean birth may be
necessary (this should be discussed with patient prior to
labor) [14].
2. Positioning: Tilt head upward/move patient as upright as
possible; induces beneficial pooling of blood in the abdo-
men and lower extremity vessels thereby causing reduction
in arterial blood pressure [32]; loosen tight clothing.
3. Antihypertensive therapy—rapid onset and short
duration of action (such as nifedipine or labetolol) [32].
Consult with anesthesiologist or intensivist for optimal
treatment.
4. Prepare for rebound hypotension after stimulus is
removed. If hypotension occurs, reverse positioning by
lowering head of the bed (Trendelenburg) as well as rais-
ing legs into the air.
Antepartum testing: No specific testing is recommended unless
there are associated pregnancy concerns that would otherwise
warrant antepartum assessment.
Maternal-Fetal Evidence Based Guidelines
Laboratory Urine Dipstick Treatment
Intravenous magnesium
protein sulfate
decreased platelets
Normal laboratory values Positive for Remove offending
norepinephrinea stimulus; initiate acute
anti-hypertensive
therapy
Ascertainment and preparation
for (preterm or term) labor
Patients with spinal cord transection above T10, especially
above T6, may have painless labor, and are at risk for unat-
tended delivery. Even with lower levels, if transection is com-
plete, patients may not perceive contractions as traditionally
described. Instead symptoms that are related through the sym-
pathetic nervous system may alert patients to labor, including
abdominal or leg spasms, shortness of breath, or increased
spasticity, and therefore these should be reviewed with patients,
including how to perform uterine palpation techniques for
themselves and partners. It is reasonable to consider induc-
tion and/or inpatient hospitalization, especially if patients are
dilated and have (>T6) high lesions (because of possible unat-
tended delivery with ADR).
Psychological challenges: Successful pregnancy outcomes relies
on multidisciplinary team coordination with providers from
high-risk obstetrics, anesthesiology, and spinal cord injury ser-
vice when possible [24, 36]. Patients should have an anesthesia
consult, with a plan for neuraxial anesthesia at onset of labor.
Professional support from a multidisciplinary team that focuses
on patient empowerment and the degree of controllability can
make the pregnancy experience a positive one [37]. Depression
is commonly associated with SCI and treatment options include
cognitive behavioral therapy, acupuncture, and selected antide-
pressants (some increase spasticity concerns) [38].
Delivery
Patients with spinal cord transection above the level of T10 are
at risk for unattended delivery secondary to unrecognized con-
tractions. Consider inpatient hospitalization for patients with
advanced cervical dilation because of the risk of unattended
delivery, or for patients with spinal cord lesions above the level of
T6 because of the high risk of ADR [25, 39].
Labor is the period during which ADR is most likely to arise.
Therefore, there should be a plan for delivery in a unit capable
of invasive hemodynamic monitoring. Appropriate antihyper-
tensive therapy should be available—using similar agents to
those for other hypertensive events of pregnancy—typically
short-acting nifipine and labetolol as preferred agents. For
those with baseline pulmonary insufficiency, further hemody-
namic monitoring should be considered including telemetry.
Body temperature should be closely monitored, without assum-
ing that temperature increases are due to intra-amniotic infec-
tion, as ADR may cause thermo-disregulation. A Foley catheter
may be placed (with lidocaine) to avoid bladder distension or
Other Neurologic Diseases in Pregnancy 197

Signs and Symptoms of Autonomic Dysreflexia

hypertension, piloerection, headache, nasal congestion,
anxiety, prickling sensation in skull, reactive sinus
bradycardia, sinus tachycardia, or cardiac arrhythmias

Consider multidisciplinary consultation

Initial management and awareness*

Place urinary catheter Check blood pressure

If overdistended – drain 500 mL initially and then
250 mL every 10–15 mins to avoid hypotension
If blood pressure elevated
• Sit patient upright
Assessment for other potential stimuli or • Remove tight clothing and
sources or causes compression socks

NO
If blood pressure remains elevated
Stimulus found? • Oral nifedipine
• Intravenous labetalol

YES

Stimulus is ongoing or cannot be removed Stimulus removed • Supportive care until AD resolves
(eg, labor, infection, fracture) or resolved • Monitor for 4 hours
• Place epidural with goal of T10 level while • If symptomatic
laboring or treating hypotension develops
• Treatment of stimulus toward resolution with stimulus resolution—
• Minimize stimulus lie flat and elevate legs

FIGURE 20.1 Initial recognition and management of autonomic dysrefexi. (From Ref. [14] with permission.) *Distended bladder is
common in patients with SCIs and can lead to hypertension or ADR. Health care professionals should be aware that a urinary catheter
may be needed and should regularly assess for bladder distention in patients with SCI.

repeated catheterizations. Patients should change position and
have frequent skin examinations. Episiotomy should be avoided,
not only because it is not beneficial in general, but also because it
is a possible trigger for ongoing ADR in the postpartum period.
The rate of spontaneous vaginal delivery and need for assisted
vaginal delivery depends on the level of the spinal cord lesion.
Approximately 70% of SCI patients (similar to general population)
will be delivered by cesarean, but it is unclear if this is related to
SCI or provider/patient preference [14].
Anesthesia
Epidural anesthesia should be administered early in labor
[32, 40]. This is to prevent ADR, with a goal for T10 level. Pre-
hydration is extremely important, as SCI patients are at increased
risk for post-placement hypotension.
Postpartum care and breastfeeding
Children of women with SCI when compared with peers have the
same attitudes towards their parents, gender roles, and family
functioning [8]. A number of peer support groups have developed
ingenious solutions for parenting and societal barriers faced by
patients with SCI (example: https://sciparenting.com/tips-tricks/).
In addition to routine postpartum care, obstetrician–gyne-
cologists and other obstetric care professionals should ensure
that perineal and cesarean wounds are examined appropri-
ately because of concerns for delayed wound healing in patients
with SCI; healthcare professionals should also be aware of and
able to counsel patients about common postpartum medica-
tions, experiences, and procedures, such as bladder distension
and fundal massage, which may increase the risk of autonomic
dysreflexia [14]. The use of pharmacologic thromboprophy-
laxis of SCI patients during the puerperium is controversial.
Breastfeeding should be encouraged, although assistance may
be needed depending on level of injury. Although breastfeeding
may be possible, data suggest that SCI, particularly at or above
T6, can disrupt lactation and is associated with shorter breast-
feeding duration. Additional support may be needed to facilitate
breastfeeding/chestfeeding in patients with SCIs who desire to
do so and are physiologically capable of doing so [14]. Oral con-
traceptive pills appear to be safe [9, 10] although some authors
discourage their use [11]. Progesterone-only pills, intramuscular
medroxyprogesterone injections, condoms and spermicide, and
intrauterine devices are all acceptable alternatives.
Depression, suicide, alcoholism, and a wide variety of other
mental health problems all occur at higher rates in women with
SCIs [41]; screening and treatment for postpartum depression
198 Maternal-Fetal Evidence Based Guidelines

and other maternal mental health disorders are especially impor- and immune triggers have been implicated in this disease, with
tant in this population [14]. Campylobacter jejuni often cited as one of the most common.

III. Guillain–Barré syndrome Pregnancy management

Key points
• Polyneuropathy with progressive weakness, with similar
challenges to SCI.
• General anesthesia carries increased risk, especially if
succinylcholine is utilized for acute hyperkalemia.
• For acute cases, corticosteroids, plasmapheresis and IVIG
should be given and are considered safe in pregnancy.
Diagnosis/Definition
Guillain–Barré syndrome (GBS) is an acute inflammatory poly-
neuropathy resulting in progressive, symmetric, typically ascend-
ing muscle weakness (Figure 20.2), hypo- or areflexia, prominent
sensory symptoms including pain but relatively mild sensory loss,
variable autonomic, respiratory or cranial nerve dysfunction, and
albuminocytologic dissociation (increased protein and normal
cell count) in cerebrospinal fluid.
Epidemiology/Incidence
Guillain–Barré syndrome is typically “triggered” by a systemic illness
2–4 weeks prior to onset of symptoms. A wide variety of infections
With many of the features of SCI in common, pregnant patients
with Guillain–Barré syndrome face similar challenges and over-
all management is similar [42]. Although patients will in general
recover function, the time course of this can be highly variable.
Up to 20% of patients remain non-ambulatory at 6 months after
onset, and many patient experience long-term fatigue and pain.
The risk of UTI and DVTG are both increased in good data on this
population, while extreme muscle weakness can lead to paralysis
and the need for ventilatory support. A multidisciplinary team
approach is highly recommended.
Guillain–Barré syndrome is a potentially lethal condition
in pregnancy, with a maternal mortality of 10% and up to 35%
requiring ICU admission; it affects the nervous system with acute
onset of symmetric ascending weakness and may result in frank
respiratory failure and autonomic dysfunction; the diagnosis is
clinical, and most patients recall symptoms of a respiratory or
gastrointestinal illness in the weeks preceding the onset of weak-
ness. Clinical characteristics include: New onset of progres-
sive ascending symmetric weakness, hyporeflexia or areflexia
of involved limbs, prodromal symptoms of respiratory, febrile,
or gastrointestinal illness; mild sensorial manifestations; cra-
nial nerve impairment (facial weakness, ocular anomalies, bul-
bar weakness), pain, and autonomic dysfunction (labile blood
pressure, arrhythmias). The risk of UTI and thromboembolism
are both increased in this population, while extreme muscle

* Fetal heart tracing, biophysicial profile.

† We recommend consulting the Centers for Disease Control and Prevention for the most recent guidelines for
screening and management.
‡ With forced vital capacity and negative inspiratory pressure monitoring.
§ Evaluate for fetal central nervous system involvement.
?- If respiratory failure, inability to clear secretions, or autonomic instability (hyper- or hypotension, arrhythmias,
sweating, flushing, ileus). IVIG, intravenous immunoglobulin; PT, physical therapy; OT, occupational therapy;
PCR, polymerase chain reaction.

Acute onset of ascending symmetrical weakness

and hyporeflexia with no other alternative etiology

• Admit patient to labor and
delivery or similar intermediate
care unit
• Start plasmapheresis or IVIG
without delay
• Viable pregnancies: If Zika virus infection suspected
lntermittent antenatal testing*
• Venous thromboembolism
prophylaxis Serology or serum or amniotic
• Aggressive pain management fluid PCR†
• Aggressive PT and OT
• Frequent assessment of
Serial fetal ultrasounds
respiratory status‡
recommended§
• Frequent evaluation for
autonomic dysfunction
• Avoid bowel or bladder
distention

Transfer to intensive care unit?

FIGURE 20.2 Management of Guillain–Barré syndrome. (From Ref. [66] with permission.)
Other Neurologic Diseases in Pregnancy
weakness can lead to paralysis and the need for ventilatory sup-
port. Supportive measures include venous thromboembolism
prophylaxis, aggressive physical therapy, pressure ulcer preven-
tion, enteral nutrition, and respiratory support. The mainstay
of management comprises plasmapheresis or administration
of intravenous immunoglobulins which should be considered
in cases involving severe or worsening weakness; intravenous
immunoglobulin is administered either as 1 g/kg per day for
2 days or 0.4 g/kg per day for 5 consecutive days (both will provide
a total dose of 2 g/kg per day); there is no evidence to support
the use of a second course if the patient continues to deteriorate
after completion of treatment, and steroids are not indicated.
Treatment with vasopressors, fluids, antihypertensive agents,
atropine, and even temporary pacemakers may be rarely required,
though in the absence of end-organ damage, many hypertensive
episodes will not require treatment. Delivery can often be accom-
plished by neuraxial anesthesia and passive or assisted second
stage. The use of general anesthesia can be particularly dangerous
in these patients, specifically in regards to the need for avoidance
of succinylcholine, risk of hyperkalemia, autonomic instability,
and the challenges of extubation in severely weakened patients. A
multidisciplinary team approach is highly recommended.
Preconception counseling
This will be specific to the patient’s current function, remain-
ing disease, and associated respiratory status. Specific attention
should be focused on anesthesia risks, need for assistance with
care during pregnancy and postpartum period depending on
functional status, very similarly to SCI patients.
Acute Guillain–Barré syndrome during pregnancy
Guillain–Barré syndrome is a clinical diagnosis, and many of
the presenting symptoms can be initially subtle before pro-
gressing to rapidly progressive paralysis. The differential is
wide, and in the event of new symptoms, a throughout workup
of a CNS disorders, acute neuropathies, etc., is warranted. Once
the diagnosis has been established, the safety and effective-
ness of plasmapheresis (aka plasma exchange) and/or IVIG
to treat GBS is clear and are considered first-line therapy for
this diagnosis. Both of these are safe during pregnancy. Timely
immunotherapy and comprehensive support are critical to
improving recovery [43]. Inpatient monitoring with close mon-
itoring of respiratory status is necessary, as respiratory failure
and dysautonomia are common [44]. While most patients will
improve, prognosis is variable and mortality 2–10% [45]. If
acute Guillain–Barré syndrome occurs in late pregnancy, pre-
term labor has been reported [46]. Delivery or pregnancy ter-
mination does not alter the course or prognosis of the disease,
and should be reserved for obstetrical indications. For those
with respiratory failure in late pregnancy, delivery may help
to reduce physiology changes/pressures on the diaphragm, but
will not alter the course of GBS disease.
Antepartum testing: No specific testing is recommended.
Plasmapheresis can increase fluid shifts, and some experts rec-
ommend fetal monitoring for viable patients during this therapy.
Delivery
Delivery can often be accomplished by regional anesthesia and
passive or assisted second stage. Guillain–Barré syndrome does
not necessitate cesarean delivery, although operative assistance
may be needed as weakness in the abdominal muscles is common.
199
This can also lead to challenges with recovery and limit ability to
maintain respiratory status after a caesarean delivery.
Anesthesia
The use of general anesthesia can be particularly dangerous in
Guillain–Barré syndrome patients, specifically in regards to the
need for avoidance of succinylcholine, risk of hyperkalemia, auto-
nomic instability, and the challenges of extubation in severely
weakened patients.
IV. Intracranial aneurysm
Key points
• The rate of rupture in pregnancy is fortunately low, with
1–10/100,000 pregnancies affected.
• Intervention outside of pregnancy is typically reserved
for those with aneurysm >7 mm, but when planning preg-
nancy, intervention could be considered between 3–6 mm.
Epidemiology/Incidence
Approximately 1–6% of the population have an intracranial aneu-
rysm, with a higher prevalence in patients over age 30 of Japanese,
Finnish, Korean, and Chinese descent [47, 48]. Overall, approxi-
mately 1.8% of patients ageing 16–22 carry a diagnosis of cerebral
aneurysm. Polycystic kidney disease, Marfans and Ehlers-Danlos
are all associated with increased risk as well. While overall rate of
hemorrhage is low, rupture is associated with morbidity/mortal-
ity of 20–30% [49, 50].
Classification and rupture risk
Aneurysms outside of pregnancy are typically classified by size,
with those <7 mm having the lowest risk of rupture, while those
greater than that have a risk of rupture correlated with size
(Table 20.2) [51]. However, for pregnancy, data suggest that >90%
of those that ruptured were >6 mm, suggesting this may be a bet-
ter cutoff for patients during pregnancy [52].
Pregnancy management
Acute rupture
The rate of rupture in pregnancy is fortunately low, with
1–10/100,000 pregnancies affected, with the majority occurring
antepartum (92%) [53], and most commonly in the third trimester
(80%) [54]. Mortality in these events is 3–7% [52]. If rupture is sus-
pected, imaging should proceed as per usual standards regardless of
gestational age, including use of CT, MRI and/or contrasts as needed.
If confirmed, standard therapies should be offered, with a focus on
maximizing cognitive outcomes. The treatment team should consist
of a multidisciplinary approach involving neurosurgeons, anesthe-
siologists, neurointensivists, MFM, and obstetrics and gynecology.
TABLE 20.2: Five-Year Rupture Risk by Size of the Aneurysm
<7 mm 7–12 mm 13–24 mm >25 mm
Anterior circulation Negligible 2.6% 14.5% 40%
Posterior circulation 2.5% 14.5% 18.4% 50%
200
Prenatal care
Routine pregnancy care, with through evaluation of new neuro-
logic symptoms or changes.
Antepartum testing: No specific testing is recommended.
Delivery
Typically vaginal delivery is possible, and does not appear to
increase risk of the rupture [55], although a shortened second
stage may be preferable [56]. For large and unstable aneurysms
delivery by caesarean may be reasonable to minimize vascular
shifts and maximize blood pressure control.
Anesthesia
No changes to care is typically necessary in unruptured aneu-
rysm. However, for those with known aneurysm, rupture during
pregnancy and/or prior aneurysmal clipping, consultation prior
to delivery with the anesthesia team is recommended. For those
with hereditary syndromes associated with aneurysms, routine
imaging may be recommended.
V. Myasthenia gravis
Diagnosis/Definition
Myasthenia gravis is an acquired autoimmune disorder charac-
terized by weakness of skeletal muscle due to antibodies against
the nicotinic acetylcholine receptor (AchR Ab) itself, or muscle-
specific tyrosine-kinase (MuSK), lipoprotein receptor-related
protein 4 (LRP4) and agrin involved in clustering of AchRs within
the postsynaptic membrane and structural maintenance of the
neuromuscular synapse.
Epidemiology/Incidence
MG is more common in women, with an incidence peaking
around the third decade, making it therefore common in repro-
ductive-aged people.
Classification
For patients with MG, weakness typically involves ocular (dip-
lopia and ptosis), bulbar (speech and swallowing) and proximal
muscles of the shoulder and hip girdle. Symptoms fluctuate and
the weakness is fatigable, typically worse at the end of the day
or with exercise. Symptoms are exacerbated by pregnancy, infec-
tions, medications, and anesthesia.
Pregnancy management
Preconception counseling
For most patients, the counseling will focus on specific disease
manifestations and the effects on pregnancy. However, early
pregnancy and postpartum period are typically times of flare, and
patients should expect increased fatigability and symptoms dur-
ing these times. Pregnancy does not appear to affect the course of
MG, or increase the risk of pregnancy loss [57].
Prior to attempting pregnancy, optimization of myasthenic
status is imperative to minimize the need for immunosuppressive
Maternal-Fetal Evidence Based Guidelines
therapy (with associated risks). The majority of MG patients that
are in remission prior to pregnancy do not require immunosup-
pression during pregnancy.
Immunotherapy and pyridostigmine are the mainstays of ther-
apy for MG. Thymectomy has also been recommended. While
this has been shown to reduce the likelihood of neonatal myas-
thenia in the infant [58], it does not improve other pregnancy
outcome measures (such as severity of symptoms, use of medica-
tion and complications with delivery) and therefore should not be
recommended for pregnancy planning alone [59].
Prenatal care
Routine pregnancy care is recommended, with close follow up to
assess for changes in symptoms. Monitoring respiratory status in
later pregnancy is recommended.
Typically medications that are managing symptoms well
should be continued in pregnancy, with discussion of risk of these
medications to the fetus. Uncontrolled MG is a significant risk
to maternal respiratory status and health, which will also affect
the pregnancy, and the risk/benefits must be carefully consid-
ered. Pyridostigmine is considered safe in pregnancy at doses
<600 mg/day, while IV choline esterase inhibitors may produce
uterine contractions and are typically avoided [60].
Antepartum testing: No specific testing is recommended.
Delivery
Patients with MG are at increased risk for complications in labor,
including protracted labor and fetal distress. Status prior to
delivery does not appear to predict complications, and may even
occur in those without symptoms. Vaginal delivery is recom-
mended, with caesarean reserved for obstetrical complications,
although assisted delivery may be necessary. As the third stage of
labor involves active use of the striated muscle, patients with MG
are prone to early fatigue and assisted second stage may be war-
ranted. During labor, use of IV anticholinesterase medications
(such as neostigmine) may be necessary due to limited parenteral
absorption to help prevent muscular (particularly respiratory
muscle) fatigue [61].
Medication safety and MG risks
during pregnancy and labor
Patients with MG can have increased complications with a num-
ber of commonly utilized medications and events in pregnancy.
Magnesium sulfate is contraindicated due to its neuromuscular
blocking effects. Infection can exacerbate MG symptoms, and
therefore patient with flare should be checked carefully for com-
mon pregnancy infections (like urinary tract infection) as well as
providers should watch MG symptoms carefully when chorioam-
nionitis or endometritis is diagnosed. Fluoroquinolones are also
contraindicated due to their potential to provoke MG flare. When
patients are in a flare, steroids (such as for fetal lung maturity) can
further worsen a flare, and should be given after other therapy
(such as IVIG or plasmapheresis) has already been started.
Anesthesia
Epidural/spinal analgesia/anesthesia is preferred, as patients
with MG are particularly sensitive to depolarizing agents used
for general anesthesia, and may have prolonged extubation
times [62].
Other Neurologic Diseases in Pregnancy
Postpartum care and breastfeeding
Infants of patients with MG are at risk of neonatal MG, with
10–20% experiencing this complication [57–59]. Symptoms
include difficulties in feeding, swallowing, breathing, or hypoto-
nia of the newborn, and typically develop between 12–48 hours
after birth. Therefore, infants should remain in the hospital
post-delivery for at least 48 hours to assure neonatal transition,
and that there is no evidence of respiratory depression [61, 63].
Thymectomy, which has been used as a therapy for MG, may also
decrease the risk of these complications in the infant.
In rare cases, infants of patients with MG can develop arthro-
gryposis multiplex congenita (non-progressive contractures
over 2 joints), which in severe forms can lead to fetal or neona-
tal demise or neonatal death [64]. This complication is unfor-
tunately independent of maternal disease status or symptoms.
Serial ultrasound for women with MG that develop this com-
plication will typically show poor fetal movement with contrac-
tures and associated polyhydramnios in severe cases. The risk
of recurrent arthrogryposis multiplex congenita is increased in
patients who develop this complication [64, 65].
References
1. Wilson RD, Genetics Committee, Motherisk. Pre-conceptional vitamin/
folic acid supplementation 2007: the use of folic acid in combination with
a multivitamin supplement for the prevention of neural tube defects and
other congenital anomalies. J Obstet Gynaecol Can 2007;29(12):1003–1013.
[II-B]
2. Bulloch AG, Fiest KM, Williams JV, et al. Depression–a common disor-
der across a broad spectrum of neurological conditions: a cross-sectional
nationally representative survey. Gen Hosp Psychiatry 2015;37(6):507–512
[II-A]
3. Bjork MH, Veiby G, Reiter SC, et al. Depression and anxiety in women with
epilepsy during pregnancy and after delivery: a prospective population-
based cohort study on frequency, risk factors, medication, and prognosis.
Epilepsia 2015;56(1):28–39. [II-A]
4. Reiter SF, Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Psychiatric comor-
bidity and social aspects in pregnant women with epilepsy - the Norwegian
mother and child cohort study. Epilepsy Behav 2013;29(2):379–385. [II-B]
5. Fausett MB, Propst A, Van Doren K, Clark BT. How to develop an effective
obstetric checklist. Am J Obstet Gynecol 2011;205(3):165–170. [II-B]
6. Rotter T, Kinsman L, James E, et al. Clinical pathways: effects on pro-
fessional practice, patient outcomes, length of stay and hospital costs.
Cochrane Database Syst Rev 2010(3):CD006632. [II-B]
7. Vercauteren M, Waets P, Pitkanen M, Forster J. Neuraxial techniques in
patients with pre-existing back impairment or prior spine interventions: a
topical review with special reference to obstetrics. Acta Anaesthesiol Scand
2011;55(8):910–917. [III-Review]
8. Signore C, Spong CY, Krotoski D, Shinowara NL, Blackwell SC. Pregnancy
in women with physical disabilities. Obstet Gynecol 2011;117(4):935–947.
[III-Review]
9. Verduyn WH. Spinal cord injured women, pregnancy and delivery.
Paraplegia 1986;24(4):231–240. [II-B]
10. Jackson AB, Wadley V. A multicenter study of women’s self-reported
reproductive health after spinal cord injury. Arch Phys Med Rehabil
1999;80(11):1420–1428. [II-B]
11. Sipski ML. The impact of spinal cord injury on female sexuality, men-
struation and pregnancy: a review of the literature. J Am Paraplegia Soc
1991;14(3):122–126. [III-Review]
12. National Spinal Cord Injury Statistical Center: Spinal cord injury facts
and figures at a glance. 2019; https://www.nscisc.uab.edu/Public/Facts%20
and%20Figures%202019%20-%20Final.pdf. Accessed March 3, 2021. [II-B]
13. National Spinal Cord Injury Statistical Center: Complete public version of
the 2018 annual statistical report for the spinal cord injury model systems.
2018; https://www.nscisc.uab.edu/public/2018%20Annual%20Report%20-
%20Complete%20Public%20Version.pdf. Accessed march 3, 2021. [II-B]
14. Obstetric management of patients with spinal cord injuries: ACOG
Committee Opinion, Number 808. Obstet Gynecol 2020;135(5):e230–
e236. [IV]
201
15. Hughes SJ, Short DJ, Usherwood MM, Tebbutt H. Management of the preg-
nant woman with spinal cord injuries. Br J Obstet Gynaecol 1991;98(6):
513–518. [II–B]
16. Goller H, Paeslack V. Pregnancy damage and birth-complications in the
children of paraplegic women. Paraplegia 1972;10(3):213–217. [II–B]
17. Atterbury JL, Groome LJ. Pregnancy in women with spinal cord injuries.
Nurs Clin North Am 1998;33(4):603–613. [Review; III]
18. Gilson GJ, Miller AC, Clevenger FW, Curet LB. Acute spinal cord injury and
neurogenic shock in pregnancy. Obstet Gynecol Surv 1995;50(7):556–560.
[II–B]
19. Sugarman B. Medical complications of spinal cord injury. Q J Med
1985;54(213):3–18. [II–B]
20. Slimani O, Jayi S, Fdili Alaoui F, et al. An aggressive vertebral hemangioma
in pregnancy: a case report. J Med Case Rep 2014;8:207. [II–B]
21. Pannek J, Bertschy S. Mission impossible? Urological management of
patients with spinal cord injury during pregnancy: a systematic review.
Spinal Cord 2011;49(10):1028–1032. [III- review]
22. Le Liepvre H, Dinh A, Idiard-Chamois B, et al. Pregnancy in spinal cord-
injured women, a cohort study of 37 pregnancies in 25 women. Spinal Cord
2017;55(2):167–171. [II–B]
23. Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the
management of asymptomatic bacteriuria: 2019 Update by the Infectious
Diseases Society of America. Clin Infect Dis 2019;68(10):1611–1615.[IV]
24. Skowronski E, Hartman K. Obstetric management following traumatic
tetraplegia: case series and literature review. Aust N Z J Obstet Gynaecol
2008;48(5):485–491. [III- review]
25. Greenspoon JS, Paul RH. Paraplegia and quadriplegia: special consider-
ations during pregnancy and labor and delivery. Am J Obstet Gynecol
1986;155(4):738–741. [III- review]
26. Bertschy S, Bostan C, Meyer T, Pannek J. Medical complications during
pregnancy and childbirth in women with SCI in Switzerland. Spinal Cord
2016;54(3):183–187. [II–B]
27. Dorner B, Posthauer ME, Thomas D, National Pressure Ulcer Advisory P.
The role of nutrition in pressure ulcer prevention and treatment: National
Pressure Ulcer Advisory Panel white paper. Adv Skin Wound Care
2009;22(5):212–221. [III- review]
28. Pereira L. Obstetric management of the patient with spinal cord injury.
Obstet Gynecol Surv 2003;58(10):678–687. [III- review]
29. Burns AS, Jackson AB. Gynecologic and reproductive issues in women
with spinal cord injury. Phys Med Rehabil Clin N Am 2001;12(1):183–199.
[III- review]
30. Ghidini A, Healey A, Andreani M, Simonson MR. Pregnancy and women
with spinal cord injuries. Acta Obstetricia et Gynecologica Scandinavica
2008;87(10):1006–1010. [III- review]
31. Ditunno JF, Jr., Formal CS. Chronic spinal cord injury. NEJM
1994;330(8):550–556. [III- review]
32. Krassioukov A, Warburton DE, Teasell R, Eng JJ, Spinal Cord Injury
Rehabilitation Evidence Research T. A systematic review of the manage-
ment of autonomic dysreflexia after spinal cord injury. Arch Phys Med
Rehabil 2009;90(4):682–695. [III- review]
33. Berghella V, Spector T, Trauffer P, Johnson A. Pregnancy in patients with
preexisting transverse myelitis. Obstet Gynecol 1996;87(5 Pt 2):809–812.
[III- case report]
34. McCunniff DE, Dewan D. Pregnancy after spinal cord injury. Obstet
Gynecol 1984;63(5):757–758. [IV]
35. Kang AH. Traumatic spinal cord injury. Clin Obstet Gynecol 2005;48(1):
67–72. [IV]
36. Engel S, Ferrara G. Obstetric outcomes in women who sustained a spinal
cord injury during pregnancy. Spinal Cord 2013;51(2):170–171. [II-B]
37. Tebbet M, Kennedy P. The experience of childbirth for women with spi-
nal cord injuries: an interpretative phenomenology analysis study. Disabil
Rehabil 2012;34(9):762–769. [II-B]
38. Olkin R. Disability and depression. In: Welner SL HF, ed. Welenr’s Guide to
the Care of Women with Disabilities. Philadelphia, PA: Lippincott, Williams
& Wilkins; 2004:279–299 [III- review]
39. Wanner MB, Rageth CJ, Zach GA. Pregnancy and autonomic hyperreflexia
in patients with spinal cord lesions. Paraplegia 1987;25(6):482–490. [II-B]
40. Baker ER, Cardenas DD. Pregnancy in spinal cord injured women. Arch
Phys Med Rehabil 1996;77(5):501–507. [III- review]
41. Cesario SK. Spinal cord injuries. Nurses can help affected women & their
families achieve pregnancy birth. AWHONN Lifelines 2002;6(3):224–232.
[III- review]
42. Chan LY, Tsui MH, Leung TN. Guillain-Barre syndrome in pregnancy.
Acta Obstetricia et Gynecologica Scandinavica 2004;83(4):319–325.
[III-Review]
202
43. Hughes RA, Wijdicks EF, Barohn R, et al. Practice parameter: immuno-
therapy for Guillain-Barre syndrome: report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology
2003;61(6):736–740. [IV]
44. Leonhard SE, Mandarakas MR, Gondim FAA, et al. Diagnosis and
management of Guillain-Barre syndrome in ten steps. Nat Rev Neurol
2019;15(11):671–683. [IV]
45. Verboon C, van Doorn PA, Jacobs BC. Treatment dilemmas in Guillain-
Barre syndrome. J Neurol Neurosurg Psychiatry 2017;88(4):346–352.
[III- review]
46. Lozier M, Adams L, Febo MF, et al. Incidence of Zika Virus Disease by Age
and Sex - Puerto Rico, November 1, 2015-October 20, 2016. MMWR Morb
Mortal Wkly Rep 2016;65(44):1219–1223. [II-B]
47. Agarwal N, Guerra JC, Gala NB, et al. Current treatment options for cere-
bral arteriovenous malformations in pregnancy: a review of the literature.
World Neurosurg 2014;81(1):83–90. [III- review]
48. HR W. Youmans and Winn Neurological Surgery. 7 ed. Philadelphia, PA:
Elsevier; 2017. [III- review]
49. Molyneux AJ, Kerr RS, Yu LM, et al. International subarachnoid aneurysm
trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143
patients with ruptured intracranial aneurysms: a randomised comparison
of effects on survival, dependency, seizures, rebleeding, subgroups, and
aneurysm occlusion. Lancet 2005;366(9488):809–817. [I-RTC]
50. McDougall CG, Spetzler RF, Zabramski JM, et al. The Barrow Ruptured
Aneurysm Trial. J Neurosurg 2012;116(1):135–144. [I-RTC]
51. Wiebers DO, Whisnant JP, Huston J, 3rd, et al. Unruptured intracranial
aneurysms: natural history, clinical outcome, and risks of surgical and
endovascular treatment. Lancet 2003;362(9378):103–110. [II-B]
52. Barbarite E, Hussain S, Dellarole A, Elhammady MS, Peterson E. The man-
agement of intracranial aneurysms during pregnancy: a systematic review.
Turkish Neurosurg 2016;26(4):465–474. [II-B]
53. Dias MS, Sekhar LN. Intracranial hemorrhage from aneurysms and
arteriovenous malformations during pregnancy and the puerperium.
Neurosurgery 1990;27(6):855–865; discussion 865-856. [III- review]
Maternal-Fetal Evidence Based Guidelines
54. Lv X, Liu P, Li Y. Pre-existing, incidental and hemorrhagic AVMs in preg-
nancy and postpartum: Gestational age, morbidity and mortality, manage-
ment and risk to the fetus. Interv Neuroradiol 2016;22(2):206–211. [II-B]
55. Kim YW, Neal D, Hoh BL. Cerebral aneurysms in pregnancy and deliv-
ery: pregnancy and delivery do not increase the risk of aneurysm rupture.
Neurosurgery 2013;72(2):143–149; discussion 150. [II-A]
56. Greenberg M. Handbook of Neurosurgery. 8 ed. New York, NY: Thieme;
2016. [III- review]
57. Batocchi AP, Majolini L, Evoli A, Lino MM, Minisci C, Tonali P. Course
and treatment of myasthenia gravis during pregnancy. Neurology
1999;52(3):447–452. [II-B]
58. Djelmis J, Sostarko M, Mayer D, Ivanisevic M. Myasthenia gravis in preg-
nancy: report on 69 cases. Eur J Obstet Gynecol Reprod Biol 2002;104(1):
21–25. [II-B]
59. Hoff JM, Daltveit AK, Gilhus NE. Myasthenia gravis in pregnancy and birth:
identifying risk factors, optimising care. Eur J Neurol 2007;14(1):38–43. [II-B]
60. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance
for management of myasthenia gravis: Executive summary. Neurology
2016;87(4):419–425. [IV]
61. Ciafaloni E, Massey JM. The management of myasthenia gravis in preg-
nancy. Seminars in Neurology 2004;24(1):95–100. [III- review]
62. Almeida C, Coutinho E, Moreira D, Santos E, Aguiar J. Myasthenia gra-
vis and pregnancy: anaesthetic management – a series of cases. Eur J
Anaesthesiol 2010;27(11):985–990. [III- review]
63. Ciafaloni E, Massey JM. Myasthenia gravis and pregnancy. Neurol Clin
2004;22(4):771–782. [III- review]
64. Vincent A, Newland C, Brueton L, et al. Arthrogryposis multiplex con-
genita with maternal autoantibodies specific for a fetal antigen. Lancet
1995;346(8966):24–25. [III- case report]
65. Midelfart Hoff J, Midelfart A. Maternal myasthenia gravis: a cause for
arthrogryposis multiplex congenita. J Child Orthop 2015;9(6):433–435.
[III- review]
66. Pacheco LD, Saad AF, Hankins GDV, Chiosi G, SaadeG. Guillain-Barré syn-
drome in pregnancy. Obstet Gynecol 2016 November;128(5):1105–1110.
21
MOOD DISORDERS
Madeleine A. Becker, Tal E. Weinberger, and Leigh J. Ocker
Key points
• Depression is twice as common in women as in men, and
rates are highest during the childbearing years.
• Depression is one of the most common complications
during pregnancy and in the postpartum period.
• Postpartum blues is a temporary, common condition,
affecting up to 75% of new mothers.
• Postpartum depression occurs in approximately 6–17%
of women.
• Psychotherapy is considered first-line treatment to
manage depression and anxiety during pregnancy and
in the postpartum period.
• Electroconvulsive therapy (ECT) may be an effective option
for severe or refractory perinatal depression.
• Untreated maternal depression has been associated with
an increased risk of preterm birth, low birth weight, and
other complications in infants and children.
• Practice guidelines recommend universal screening
of pregnant and postpartum women for depression
and anxiety at least once during the perinatal period
using a standardized, validated tool. Screening must
be followed by referral and treatment with appropriate
behavioral health resources when indicated.
• Postpartum psychosis affects about 0.1–0.2% of women,
and is considered to be a strong predictor of bipolar
disorder.
• Onset of symptoms of postpartum psychosis is often
sudden, with peak prevalence of symptom onset
between postpartum days 1–3.
• Women with a previous history of postpartum psycho-
sis are at extremely high risk in subsequent pregnancies.
• Bipolar disorder is often misdiagnosed as major depres-
sive disorder.
• The risk of postpartum affective episodes is very high
among women with bipolar disorder.
• The impact of maternal psychiatric depression, related
comorbidities, and other risk factors on neonatal out-
come has been difficult to evaluate independently of
medication effects.
• The SSRIs have been associated with poor neonatal
adaptation syndrome. Many studies demonstrate no
teratogenic risk, and a few demonstrate a slightly higher
risk (and low absolute risk) of some congenital malforma-
tions. SSRIs have also been associated with small increases
in association with preterm birth, persistent pulmonary
hypertension of the newborn, and spontaneous abortion
in some studies. Effects of confounding by indication may
account at least partially for these findings. Some recent
studies have also found a small increase in pre-eclampsia
and postpartum hemorrhage that may be associated with
antidepressant use.
DOI: 10.1201/9781003099062-21
• If medications are necessary during pregnancy, the
minimal number of medications should be used at
the lowest effective dose. Suboptimal dosing exposes
the fetus to both partially treated depression as well as
medication.
• Based on the current data, paroxetine has a small but
higher risk of cardiac malformations than other seroto-
nergic antidepressants and alternatives should be used
as first-line treatment if possible.
• Individual decisions about medication management dur-
ing pregnancy should take into account multiple factors,
such as severity of maternal illness, frequency of mood
episodes, efficacy of past medication trials, and strength of
maternal support system.
• The relative risk of Ebstein’s anomaly is significantly
higher with lithium exposure than the general popula-
tion risk; however, the absolute risk remains small.
• The risk for major congenital anomalies in infants
exposed to valproic acid in utero is estimated to be
about 10.9%. Cognitive deficits, learning difficulties,
and autism spectrum disorder have been repeatedly
reported. This medication should be avoided in women
of childbearing potential.
• Data regarding first trimester exposure to quetiapine,
olanzapine, and aripiprazole are reassuring and do
not suggest a clinically meaningful increased risk of
teratogenicity.
• All psychotropic medications cross the placenta and
can enter breast milk.
• Most SSRIs produce low infant levels and should be
continued in breastfeeding mothers who need to take
antidepressant medications.
Depression in pregnancy and postpartum
Definitions and epidemiology
Symptoms of peripartum depression are the same as those of
major depressive disorder (MDD), and include depressed mood,
insomnia, anhedonia, suicidal ideation, guilt, worthlessness,
fatigue, impaired concentration, change in appetite, and change
in motor activity. The DSM-5 categorizes “peripartum onset” as
a specifier of MDD, applied to the first 4 weeks after childbirth
(ICD-10 coding permits classifications of postpartum mental dis-
orders up to 6 weeks after childbirth) [1]. In practice, many clini-
cians consider depression to be “postpartum depression” (PPD)
for a much longer period than this, generally for up to 1 year after
childbirth [2]. Symptoms that are most prevalent tend to be sleep
disturbance, anxiety, irritability, and feelings of anxiety about the
baby [2].
One in 20 non-pregnant women of childbearing age experience
major depression [3]. Women have a much higher prevalence of
depression (8.7%) compared with men (5.3%) [4]. In women, the
203
204
highest rates of major depression occur during the childbearing
years, between the ages of 25 and 44. Depression is one of the
most common complications during pregnancy and in the post-
partum period [5]. Prevalence varies and range from 6–12.9% and
are higher in low income countries [2]. In a recent large meta-
analysis, global prevalence of postpartum depression was found
to be approximately 17.7% [6]. Suicide is a significant cause of
mortality in the postpartum period and suicide accounts for up
to 20% of postpartum deaths [7, 8].
Postpartum blues or “the baby blues” is a common condi-
tion, affecting up to 75% of new mothers. It is characterized by
tearfulness, mood lability, irritability, and anxiety. Symptoms are
typically mild and begin around postpartum day 2–4. They do
not seriously impair functioning and resolve spontaneously, usu-
ally in about 2 weeks [9, 10]. Symptoms may initially be difficult
to distinguish from postpartum depression, which is more persis-
tent and pervasive, lasting 2 weeks and often longer. Women with
postpartum blues may be at increased risk for the subsequent
development of postpartum depression and warrant close follow
up after delivery [2].
Postpartum psychosis is much less common than postpar-
tum depression, commonly assumed to affect about 0.1–0.2% of
women in the general population [11]. A recent review reported
an incidence of 0.89–2.6 per 1000 births across several countries,
which is consistent with the earlier frequently cited statistic [12].
Postpartum psychosis is characterized by mood lability, agita-
tion, confusion, thought disorganization, hallucinations, and
disturbed sleep. Postpartum psychosis has been associated with
an increased risk of suicide, infant neglect, and infanticide [13],
and is considered a psychiatric emergency. Postpartum psycho-
sis is considered to be a strong predictor of the development
of bipolar disorder. The DSM5 does not recognize postpartum
psychosis as a distinct clinical entity, and often women present-
ing with a first episode of postpartum psychosis will be given a
diagnosis of bipolar disorder [1]. In a recent meta-analysis, recur-
rence of psychotic symptoms outside of the postpartum period
in women with a history of single episode postpartum psychosis
was tracked for a mean follow-up period of 16 years, to attempt
to clarify how many would subsequently develop symptoms con-
sistent with bipolar disorder. In this group, 56.7% of women went
on to experience recurrent non-postpartum episodes consistent
with bipolar disorder, while 43.5% experienced no recurrence or
recurrences isolated to the postpartum period [14]. Therefore,
while the risk of postpartum psychosis ultimately declaring itself
to be the first episode of a chronic bipolar illness is extremely
high, the concept of isolated postpartum psychotic illness appears
to be a distinct clinical entity requiring further study.
Risk factors
The strongest risk factor for depression during pregnancy
is a history of major depressive disorder. Women with a his-
tory of anxiety disorder, postpartum depression, or other previ-
ous psychiatric disorders are also at an increased risk for PPD.
Other risk factors include young or advanced maternal age, low
socioeconomic status, being single, prior pregnancy termina-
tions, anemia, and gestational diabetes [15]. Social isolation, poor
social support, high parity, unintended pregnancy, and exposure
to trauma, domestic violence, and birth complications, are also
factors that have been associated with PPD [16–18].
A recent systematic review and meta-analysis found that women
with severe or recurrent depression who discontinue antidepres-
sant medications during pregnancy are also at risk for relapse.
Maternal-Fetal Evidence Based Guidelines
There was a two-fold higher risk of relapse for patients with severe
depression (chronic course of depressive illness, multiple episodes
or history of suicide attempts) compared with those that continued
medication. This review did not find this risk of recurrence to be
greater for those with only mild or moderate depression [19].
Biological factors may also predict PPD. Hypothalamic-
pituitary-adrenal dysregulation, stress, inflammatory processes,
and genetic predisposition are all risk factors [20]. Hormonal fac-
tors also have been implicated in PPD. Timing of symptom onset
in PPD coincides with a precipitous drop in steroid hormone
levels, including estrogen and progesterone. However, studies
attempting to demonstrate this relationship have been inconclu-
sive, with some showing a correlation between steroid hormone
levels and PPD, and others failing to demonstrate this relation-
ship [21]. It has been proposed that PPD may not be related to an
abnormality in steroid hormone levels, but rather, to a sensitivity
of a certain vulnerable subset of women to normal fluctuations in
steroid hormone levels, such as those that occur postpartum [22].
Complications of depression in pregnancy
Untreated depression during pregnancy has been found to
have multiple adverse effects on the mother, fetus, newborn,
and child. Untreated maternal depression during pregnancy has
been associated with poorer maternal physical and psychological
health and with a worse quality of life. Women with depression
also experience more difficulties in their social relationships, and
have an increased risk of using alcohol, tobacco, and illicit drugs.
Overall, women with depression tend to have a shorter duration
of breastfeeding and more associated problems with breastfeed-
ing, as well as poorer maternal care, and increased prevalence of
suicidal ideation [23].
A pooled study of neonatal outcomes in women with
untreated depression (defined by using DSM5 criteria and
valid screening tools) during pregnancy (not treated with
therapy or antidepressants), compared with women without
depression, found that those with untreated depression had
significant risks of two key perinatal outcomes, preterm birth
and low birth weight [24], which is noted repeatedly in the lit-
erature [25, 26]. These are also the two leading causes of infant
morbidity and mortality [27].
Untreated gestational depression and depressive symptoms
during pregnancy have been found to have other negative effects
on the developing fetus including hyperactivity and irregular fetal
heart rate. Newborns of depressed mothers have been found to have
increased cortisol and norepinephrine levels, decreased dopamine
levels, altered EEG patterns, reduced vagal tone, stress/depressive-
like behaviors, and increased rates of premature deaths and neo-
natal intensive care unit admission. Children of mothers that were
depressed during pregnancy have shown increased salivary cortisol
levels, internalizing and externalizing problems, as well as central
adiposity [28]. A recent population based study, which followed
children for ten years after birth, found that severe maternal depres-
sive symptoms in the peripartum period and especially in the post-
partum period may impact child brain development, with smaller
white and gray matter, as compared with children whose mothers
had no symptoms of depression [29]. Postpartum depression can
also impact infant cognitive development, emotional and language
development, as well as increase risk for emotional problems and
symptoms of attention deficit hyperactivity disorder [30]. Perinatal
depression, and especially antenatal depression, has also been asso-
ciated with the risk of depression in adolescence and adulthood in
affected offspring [31].
Mood Disorders
Bipolar disorder in pregnancy
and postpartum
Definitions and epidemiology
Bipolar disorder is a psychiatric illness characterized by episodes
of depression alternating with sustained episodes of elevated
mood and/or irritability, which are classified as either “mania” or
“hypomania.” Hypomania is an attenuated form of mania with no
associated functional impairment. Both mania and hypomania
are associated with increased energy, decreased need for sleep,
rapid speech and/or thoughts, distractibility, impulsivity, mood
lability, and grandiosity. “Mood swings” are not adequate for a
diagnosis of bipolar disorder; rather, a patient must have a syn-
drome characterized by sustained symptoms lasting for several
days to weeks.
Bipolar disorder, type I (BAD I) is a severe form of bipolar
disorder defined by at least one lifetime manic or mixed episode.
Mixed episodes are characterized by simultaneous manic and
depressive symptoms. The lifetime prevalence estimate is 1% for
BAD I [32]. Men and women are affected at equal rates. Bipolar
disorder, type II (BAD II) is characterized by episodes of depres-
sion and hypomania. The lifetime prevalence estimate is 1.1%
for BAD II. Women with BAD II outnumber men by a ratio of
approximately 2:1 [33]. The average age of onset of bipolar disor-
der is in the late teens to early twenties, placing affected women
at high risk for mood episodes during their reproductive years.
Hormonal fluctuations associated with reproductive events have
been demonstrated to affect the course of bipolar disorder, with
vulnerable periods occurring during the luteal phase of the men-
strual cycle and during perimenopause, in addition to the post-
partum period [34].
Risk factors
Extremely high susceptibility to mood episodes in the postpar-
tum period, is a unique feature of bipolar disorder [35]. In a recent
analysis of postpartum relapse risk in women with bipolar disor-
der, overall relapse risk was found to be 35%. However, when risk
was stratified by maintenance versus continuation of prophylac-
tic mood stabilizing medication, postpartum relapse rates were
found to be significantly higher among those who discontinued
their maintenance mood stabilizer regimen during pregnancy
(66%) than in those who maintained it (23%) [36].
Specific risk factors for postpartum psychosis have been iden-
tified. Family history of postpartum psychosis increases the risk
of a postpartum psychotic episode [33]. Women with a previous
history of postpartum psychosis are at extremely high risk in
subsequent pregnancies [37]. A strong association between pri-
miparity and risk of postpartum psychosis has been identified;
this may be related to prophylactic strategies being implemented
faster and more aggressively in women who have had previous
deliveries affected by postpartum psychosis [38]. As opposed to
non-psychotic postpartum depression, studies have consistently
found no association between stressful life events and onset of
postpartum psychosis [35].
Timing of symptoms
Onset of symptoms in women with postpartum psychosis is often
sudden. The peak prevalence of symptom onset is between
postpartum days 1 to 3 [33]. In a large retrospective study, 94%
of episodes of mania or psychotic depression occurring in women
with BAD I occurred within the first 4 weeks after delivery, while
the onset of nonpsychotic depression was later in the postpartum
205
period [39]. Women with bipolar disorder have a 23-fold greater
risk of psychiatric admission within 30 days of delivery com-
pared to non-postpartum women with bipolar disorder [40].
Approximately 50% of episodes of postpartum psychosis are the
first manifestation of bipolar disorder; with sudden onset and
precipitous worsening of symptoms [35].
Complications of bipolar disorder in pregnancy
Unplanned pregnancy and voluntary termination of pregnancy
may occur more frequently in women with BAD [41]. Adverse
neonatal outcomes, such as preterm delivery, severe large for
gestational age birth-weight, neonatal morbidity (such as RDS,
sepsis, and neonatal abstinence syndrome) congenital malfor-
mations, and neonatal hospital readmission, have been found
to be more common among women with a history of hospital-
ization for bipolar disorder. The cause of the higher percentage of
adverse outcomes in this population is unknown; potential expla-
nations include direct physiological effect of psychiatric illness,
health care and lifestyle behaviors related to mood symptoms, or
effects of psychiatric medication [42].
Exposure to bipolar disorder during pregnancy has been asso-
ciated with premature birth, low birthweight, and behavioral
disturbances in the children of women with untreated illness
[43]. However, in contrast, a recent study comparing the infants
of women with bipolar disorder with and without treatment with
unaffected controls found similar pregnancy outcomes across
all three groups, except for decreased head circumference in the
infants of mothers with untreated bipolar disorder [44].
Based on current literature, questions regarding the indepen-
dent effect of pregnancy on the course of bipolar disorder can-
not be answered; the effect of medication discontinuation during
pregnancy is clear. Multiple studies have found higher risk of
recurrence in women who discontinue maintenance mood stabi-
lizers. However, as these studies are conducted at centers special-
izing in the management of perinatal mood disorders, they likely
select for women with more severe psychopathology, which may
contribute to the high recurrence risk [45]. Perinatal affective epi-
sodes are more often depressive rather than manic or hypomanic
[45] and, after occurring in one pregnancy, tend to recur in sub-
sequent pregnancies [46]. The proportion of women experiencing
mood episodes during pregnancy was found to be approximately
22.7% in one large study, and was similar for women with BAD
I and BAD II [47]. Younger age at illness onset was found to be
strongly associated with perinatal illness [47]. Maintenance of
mood stability during pregnancy is crucial, as recurrence of
symptoms during this time strongly predicts the onset of post-
partum episodes [48].
Screening
Screening recommendations
Regular screening of maternal mental health disorders allows
for recognition, early intervention and facilitates appropriate
management and referral processes, and can prevent or decrease
adverse outcomes [49]. The U.S. Preventive Services Task
Force (USPSTF), the American College of Obstetricians and
Gynecologists (ACOG) and the American College of Nurse-
Midwives, National Institute for Health Care Excellence
(NICE) guidelines all recommend universal screening of
pregnant and postpartum women for depression as one com-
ponent of quality obstetric care. Screening should occur at
least once during the perinatal period for depression and
206 Maternal-Fetal Evidence Based Guidelines

anxiety symptoms using a standardized, validated tool [50– Name:

53]. Consistent screening can reduce stigma and normalizes the Address:
process for patients [49]. If a patient screens positive for depres- Baby’s Age:
sion and/or anxiety during pregnancy, additional evaluations
As you have recently had a baby, we would like to know how you are
should occur. In addition, full assessment of mood and emotional
feeling. Please UNDERLINE the answer which comes closest to how
well-being (including screening for postpartum depression and
you have felt IN THE PAST 7 DAYS, not just how you feel today.
anxiety with a validated instrument) should be conducted during
the comprehensive postpartum visit for each patient. Screening 1. I have been able to laugh and see the funny side of things.
should be implemented with adequate systems in place to ensure As much as I always could
accurate diagnosis, effective treatment, and appropriate follow-up Not quite so much now
[51, 52]. The American Academy of Pediatrics recommends that Definitely not so much now
pediatricians screen mothers for PPD at the infant’s 1-, 2-, and Not at all
4-month well-child visit. It has been suggested that PPD screen- 2. I have looked forward with enjoyment to things.
ing be implemented at the 1-, 2-, 4-, and 6-month well-child visits As much as I ever did
and that, pediatricians coordinate with prenatal providers when Rather less than I used to
mothers are diagnosed with prenatal depression [54]. Definitely less than I used to
Although underutilized, telephone and internet use for screen- Hardly at all
3. * I have blamed myself unnecessarily when things went wrong.
ing for perinatal depression [55] is a feasible model when mental
Yes, most of the time
health services are not easily available or accessible. Accessibility
Yes, some of the time
to tele-psychiatry services for obstetric patients show promise
Not very often
for reaching a greater breadth of patients where mental health
No, never
resources are scarce [49, 56]. 4. I have been anxious or worried for no good reason.
Updated NICE guidelines recommend asking questions about No, not at all
depression and anxiety, as follows: Hardly ever
Yes, sometimes
• During the past month have you often been bothered by Yes, very often
having little interest or pleasure in doing things? 5. * I have felt scared or panicky for not very good reason.
• During the past month have you been bothered by having Yes, quite a lot
little interest or pleasure in doing things? Yes, sometimes
• During the past have you been nervous, anxious or feeling No, not much
on edge? No, not at all
• During the past month have you not been able to stop or 6. Things have been getting on top of me.
control worrying? Yes, most of the time I haven’t been able to cope at all
Yes, sometimes I haven’t been coping as well as usual
If a woman answers yes to any of these questions, further No, most of the time I have coped quite well
assessment is needed [53]. The Patient Health Questionnaire 9 No, I have been coping as well as ever
(PHQ-9) and the Edinburgh Postnatal Depression Scale (EPDS) 7. I have been so unhappy that I have had difficulty sleeping.
Yes, most of the time
(Figure 21.1) are simple screening tools and have both been vali-
Yes, sometimes
dated in perinatal populations [49]. The EPDS is short and easy to
Not very often
administer. It is a self-administered scale, consisting of 10 ques-
No, not at all
tions assessing mood and anxiety symptoms experienced by the
8. * I have felt sad or miserable.
mother over the seven days prior to evaluation. Both scales are
Yes, most of the time
short and can be completed in about 5 minutes [51]. Yes, quite often
Not very often
Misclassification of BAD as MDD is No, not at all
common in the general population 9. * I have been so unhappy that I have been crying.
This can lead to inappropriate treatment, and consequent lack Yes, most of the time
of improvement or worsening of the patient’s psychiatric condi- Yes, quite often
tion. Some markers of bipolar depression (as opposed to unipolar, Only occasionally
or major depression) include atypical symptoms (i.e., increased No, never
sleep or appetite), psychotic depression, early age of symptom 10. * The thought of harming myself has occurred to me.
onset, treatment resistance to antidepressants, and a family his- Yes, quite often
tory of bipolar disorder [57]. Hypomania often is overlooked Sometimes
in the general psychiatric population, as patients often dismiss Hardly ever
symptoms that do not disrupt (or even enhance) their function- Never
ing. Clinicians may not inquire about episodes of elevated mood. Response categories are scored 0, 1, 2, and 3 according to
Hypomania after delivery may be misconstrued as normal joy increased severity of the symptoms. Items marked with an aster-
related to the birth of a child [32]. isk (*) are reverse scored (i.e., 3, 2, 1, and 0). The total score is cal-
There are no screening instruments specifically designed to culated by adding together the scores for each of the ten items.
detect mood episodes in patients with bipolar disorder, before or
after delivery. Commonly used screening instruments, such as FIGURE 21.1 Edinburgh Postnatal Depression Scale (EPDS).
the EPDS, have not been validated in postpartum women with (Adapted from Ref. [40].)
Mood Disorders
BAD [32]. Of all the screening instruments for BAD used in the
general population, the Mood Disorders Questionnaire (MDQ)
has been most widely studied, both in psychiatric settings as well
as primary care and community settings.
No screening instrument is intended to replace a thorough clin-
ical history and evaluation. A history of a mental health disorder,
and a history of psychiatric treatment during either a previous
pregnancy or at any time, are other well-established risk factors
for perinatal depression. Any patient who has a positive screen
for symptoms of mood disorder should be referred in a timely
fashion for mental health evaluation. Immediate screening by a
mental health professional is warranted for suspected suicidal
ideation or homicidal ideation toward the baby, as well as for any
concern for postpartum psychosis. The incidence of infanticide in
women with postpartum psychosis with depressive features has
been estimated to be as high as 4.5%, with lower rates (less than
1%) in postpartum psychotic episodes without overt depressive
symptoms [58]. Emergent intervention (such as psychiatric hospi-
talization) may be necessary to address immediate safety issues.
It is recommended that there is a response plan in place for refer-
ral for treatment for patients with a positive screen [49]. Because
perinatal mood and anxiety disorders are common and can be
complex, the initial response to a positive screening result should
focus on determining maternal and infant (and other children’s)
safety and then following a management algorithm [49].
Thyroid function tests and a complete blood count are useful
for identifying other medical conditions that can present with
symptoms of depression. Prompt psychiatric consultation should
be obtained when depression is suspected, especially when symp-
toms are severe or when psychotic or suicidal features are pres-
ent. The presence of psychosis, or suicidal, or homicidal ideation
or intent should be considered an emergency.
Management of mood disorders
General considerations
Psychotherapy is effective and should be first-line intervention for
treatment for patients with depression during pregnancy. This is
in line with the current NICE guidelines (National Institute for
Health and Care Excellence [NICE] guideline on antenatal and
postnatal mental health) and in most practice guidelines [59]
which advise clinicians to offer psychotherapy to every pregnant
woman with a history of mild to severe depression [49, 53, 60].
Cognitive behavioral therapy and interpersonal psychotherapy
have both been found to be effective for treatment of depression
in this population [61].
Psychopharmacology
All psychotropic medications cross the placenta and can enter
breast milk [46]. Fetal exposure to either maternal depression
or antidepressants carries some risk to the developing fetus [62].
Many women, up to 50%, discontinue medications during preg-
nancy mainly because of fear of fetal exposure [19]. Individual
decisions about medication management during pregnancy
should take into account multiple factors, such as severity of
maternal illness, frequency of mood episodes, risk of relapse,
efficacy of past medication trials or alternative treatments and
strength of maternal support system. When symptoms are severe,
or there is a high risk of relapse, consideration of antidepressant
medications is important [63]. In general, a single medication
(monotherapy) is preferable to multiple medications [64].
Treatment with the lowest effective dose is recommended,
207
keeping in mind that suboptimal dosing exposes the fetus to both
medication as well as maternal depression. Decision to use medi-
cation during pregnancy should balance the risks of medication
exposure to the fetus against the risks (to both mother and fetus)
of untreated maternal illness [65].
Antidepressants
The most commonly prescribed medications for depression are
the selective serotonin reuptake inhibitors (SSRIs) [3]. These
are the most studied of all the antidepressants in pregnancy.
However, many studies have included other antidepressant
medications in their trials, since many include serotonergic
mechanisms. There have been very few studies comparing anti-
depressant medications to each other or to other treatments
during the perinatal period, so it is difficult to draw conclusions
about the comparative effectiveness of individual antidepressants
for treating depression during pregnancy or during the postpar-
tum period [66]. Additionally, the potential impact of mater-
nal psychiatric depression, related comorbidities, and other
risk factors on neonatal outcomes has been difficult to evalu-
ate independently of medication effects. In some studies, the
SSRIs have been associated with a slightly higher risk of congeni-
tal malformations, in particular cardiac malformations, although
the majority of studies demonstrate no major teratogenic effect.
SSRIs have been associated with poor neonatal adaptation syn-
drome, a temporary condition with no reported long-term
sequelae. There is also a possible association between SSRIs and
preterm birth as well as persistent pulmonary hypertension of the
newborn, although confounding by indication may be a potential
contributor to these findings. SSRIs have been linked to autism
spectrum disorders, although a confounding effect of depression
appears to be primarily responsible for the association with these
disorders, rather than exposure to SSRIs. The need for continu-
ing or initiating medications during pregnancy should always
be balanced against the history of severity of depression in the
mother and any known risk of exposure of the fetus or nurs-
ing infant. If using antidepressant medications during preg-
nancy, the lowest effective dose of medication should be used
to minimize exposure risk to the fetus [65] (Table 21.1).
Teratogenicity
Several large systematic reviews recently and in the past years
found no substantial increase in prevalence of cardiovascular
defects [67, 68] or congenital malformations for either the SSRIs
or for the serotonin and norepinephrine reuptake inhibitors
(SNRIs), and these medications are not considered to be major
teratogens [69–74]. However, some more recent large reviews
have found a small but increased risk of various congenital defects
associated with antidepressant use [75], particularly cardiac
defects [65, 76–78]. A recent multicenter case-control National
Birth Defects Prevention Study found associations between
maternal antidepressant use and some specific birth defects,
including cardiac defects and some degree of higher risk for other
defects, among women taking antidepressants who were exposed
during early pregnancy compared with those exposed outside of
early pregnancy. This study found that venlafaxine was associ-
ated with the highest number of defects, although the number
of exposed infants was too small (n=11) to draw any reliable con-
clusions [79]. Associations between the SSRIs and specific heart
defects were largely attenuated when compared with women
who took antidepressants outside of early pregnancy, which sug-
gest that the elevated associations between heart defects and
TABLE 21.1: Antidepressants in Pregnancy and Lactation

208
Neurodevelopmental
Class Medication Teratogenicity Neonatal Effects Effects Breastfeeding
Selective Citalopram SSRIs as a class: Possible increased risk of preterm birth, low birth weight, Conflicting reports of an RID: <1–7% [227]
serotonin (Celexa®) Some studies have found a small and small for gestational age in SSRI exposed increase in autism Infant serum concentration low in several
reuptake increased risk of congenital pregnancies, [76, 90–93, 96] although difficult to separate spectrum disorder or studies [202, 207]
inhibitors malformations, most commonly effects from confounding by indication [92, 93, 95] ADHD in offspring in One reported case of infant serum level of
cardiac defects, although Length of gestational age in treated vs. untreated some studies [76, 118, >10%, which authors defined as elevated [202,
difficult to separate effects from unlikely to be clinically significant [96] 120–123]; and many 207, 227]
confounding by indication [65, Possible association with increased risk of pre- studies have found that
75–78] eclampsia [110, 111] this association is no
Other studies have not found a Conflicting reports of PPHN in infants exposed to longer significant when
substantial risk [67, 68, 73, 74]. SSRIs after 20 weeks’ gestation [65, 100, 101, 104–106] underlying maternal
Not generally considered Poor neonatal adaptation (PNAS) jitteriness, tremor, psychiatric disorder is
substantial teratogens [65, autonomic instability, respiratory distress, which is accounted for [118,
75–78] self-limited [108, 109] 122–127]
Some studies have found small increased risk of
spontaneous abortion in the first trimester, results
may be confounded by indication or other
uncontrolled variables [98, 99]
Possible increased risk of postpartum hemorrhage with
third trimester exposure [82, 112–116]

Fluoxetine As above As above As above RID: 7–>10% [227]

(Prozac®, Prozac Infant plasma concentration variable and higher
Weekly®, than with most other SSRIs [202, 207] Less
Sarafem®) favored in treatment naive patients because of
long-acting active metabolite [227]; most

Maternal-Fetal Evidence Based Guidelines

studies without adverse effects in exposed
infants [202, 207, 227]
Sertraline As above As above As above RID: 2% [227]
(Zoloft®) Infant serum concentration low to undetectable
[202, 207]
Escitalopram As above As above As above RID: 1.7% [227]
(Lexapro®) Limited data, but infant exposure not expected
to cause adverse effects in breastfed infants
[202, 207, 227]. One case of necrotizing
enterocolitis reported in breastfed newborn,
but causality not established [227]
Fluvoxamine As above As above As above RID: 1–2% [227]
(Luvox®, Luvox Limited data; infant plasma levels variable [202,
CR®) 207, 227]
TABLE 21.1 (Continued): Antidepressants in Pregnancy and Lactation

Mood Disorders
Neurodevelopmental
Class Medication Teratogenicity Neonatal Effects Effects Breastfeeding
Paroxetine Some, studies have found an As above As above RID: <1–5% [227]
(Paxil®, Paxil CR®, increased risk of cardiac Infant serum concentration low to undetectable
Pexeva®) malformations compared other [202, 207, 227]
SSRIs as well as increased risk
of malformations [65, 74, 76, 78]
Serotonin- Venlafaxine Risks of birth defects small and Theoretical as above for SSRIs [83] Studies have not shown Limited data, mean infant dose is 6.4% of
norepinephrine (Effexor®, Effexor comparable to SSRIs. Most Has been associated with an increased risk of adverse effects maternal levels; no adverse effects noted [227]
reuptake XR®, Venlafaxine evidence finds no increased risk hypertension during pregnancy and possible small
inhibitors ER) [72, 83] increased risk of postpartum hemorrhage [83]

Duloxetine Risks of birth defects small and As above, for SSRIs. Additionally, may be associated No studies to date Very limited data available; one study showed
(Cymbalta®) comparable to SSRIs [82] with small increased risk of postpartum hemorrhage RID of 0.82% [227]
Most evidence finds no increased [82]
risk [72]

Other Mirtazapine Risks of birth defects small and As above for SSRIs No studies to date Limited data available, one study showed RID of
(Remeron®, comparable to SSRIs [85] Possible increased risk of pre-term birth in found in 0.8%, low to undetectable infant levels; no
Remeron SolTab®) Other studies found no increased some studies [84] adverse events noted [227]
risk [84]

Trazadone Generally considered as above
(Desyrel®, Oleptro®, for SSRIs.
Trazorel®) Studies looking at Trazodone
separately in pregnancy have
not found an increased risk of
major malformations [228]
Bupropion Most studies have not identified
(Budeprion SR, an increased risk of major
Budeprion XL, malformations [87–89]
Buproban Has been associated with small
Wellbutrin®, increased risk of cardiac defects
Wellbutrin SR®, in first trimester in some studies
Wellbutrin XL®, but may be confounded by
Zyban®) indication for smoking cessation
[86, 89]
Brexanolone Not for use during pregnancy
(Zulresso®)
Abbreviation: RID, weight adjusted relative infant dose, or % of weight adjusted maternal dose ingested by the infant.
As above for SSRIs
Few studies, but appears to have few adverse effects
when studies looked specifically at Bupropion in
pregnancy [229]
No data available Limited data available indicating low infant
levels; no adverse effects expected [227]
No data available Limited data available indicating low infant
levels and no expected adverse effects;
however, given little reported use in breastfed
newborn infants and case reports of a possible
seizure in breastfed 6 month olds, another
drug may be preferred, depending on
circumstances [227]
Low oral bioavailability
RID 1.3%
No adverse effects noted, but very little data
Not recommended at this time [227, 230, 231]

209
210
antidepressants may be confounded by the underlying condition.
Another review evaluating SNRI exposure analyzed data for 3186
venlafaxine exposed infants and 668 duloxetine exposed infants
and demonstrated no significant association with an increased
risk of congenital malformations [72]. Another large population
based cohort study, which included sibling controlled analyses,
found no substantial increase in prevalence of overall cardiac
birth defects among infants exposed to SSRIs or venlafaxine in
utero [73]. A large recent comprehensive systematic review and
meta-analysis of cohort studies including more than 9 million
births found small increased risks of multiple congenital mal-
formations, including cardiac defects, in infants born to mothers
with exposure to SSRIs during early pregnancy. Again, however,
authors noted that absolute risks are extremely small and inter-
pretation of the results is complex as it is difficult to completely
separate effects from confounding by indication. There was insuf-
ficient evidence to estimate fetal outcomes for a dose-response
analysis of SSRIs use during pregnancy. Results of these large
reviews suggest a generally small risk, not considered to be a sub-
stantial teratologic effect of the SSRIs [75].
Women exposed to paroxetine in the first trimester may carry
a higher risk (1.5- to 2-fold) for cardiac malformations than the
other SSRIs [65, 74, 76, 78] which is supported by past studies
and which led to the FDA to issue a warning in 2005 regarding
its use in early pregnancy. These malformations primarily con-
sist of atrial or ventricular septal defects. Other studies also show
an increase in congenital malformations for paroxetine and also
fluoxetine [65, 80, 81]. There are also large cohort studies that
demonstrate no association between paroxetine or fluoxetine and
cardiovascular malformations [68].
However, based on currently available data in early pregnancy,
avoidance of paroxetine is advised if effective alternative treatment
is available, because of the slightly higher, though still small, risk
compared with other SSRIs [65]. Given the findings, it is impos-
sible to completely rule out the possibility that SSRIs may lead to
a slight increase in risk of congenital malformations. However, the
associations from the studies show that the absolute risk of any
of these malformations, if present, would still be extremely small.
Most of these large studies do not differentiate between anti-
depressants and include the SNRIs and other antidepressants as
a group. However, when looking at the data for the SNRIs (venla-
faxine and duloxetine) separately, most studies have found either
a small increased risk, similar to the SSRIs [82] or no increased
risk of malformations [83]. Most studies looking at the safety of
mirtazapine have not found an association with an increased risk
of neonatal malformations [84]. Other studies have found that it
may carry a small risk similar to the SSRIs [85].
Bupropion has been associated with a small risk of increased car-
diac defects in the first trimester, but studies may be confounded by
indication for smoking cessation as well as depression [86]. Other
studies found no increased rate of major malformations [87–89].
Taking the entirety of the literature into account, results associat-
ing major organ malformations with in utero antidepressant expo-
sure should be interpreted with caution. Major depression is itself
associated with multiple co-morbidities and behaviors that can
influence pregnancy and infant outcomes and depression during
pregnancy also increases risk of adverse pregnancy outcomes. These
co-morbidities and confounds have generally not been controlled for
in many of these studies. These factors may therefore contribute at
least in part to these findings. The small risk found in these studies
must be balanced against the considerable known risks incurred by
the infant exposed to untreated maternal depression [65, 75].
Maternal-Fetal Evidence Based Guidelines
Preterm birth
Numerous studies have demonstrated an association between
SSRIs, as well as other antidepressants, and preterm delivery [76,
90–93]. An increase in preterm birth has also been found when
comparing in utero exposure of antidepressant use in depressed
women to women with untreated depression and also compared
with controls with no depression [94]. The association appears
to be attenuated with the combination of antidepressant use and
maternal depression [92, 93, 95]. There has also been an associa-
tion between both preterm birth and low birth weight [24]; how-
ever, other systematic reviews did not find that the risk of low
birth weight differs between antidepressant-treated pregnant
women and untreated depressed women [76, 96]. It is important
to note the potential role of confounding by maternal depres-
sion as well as severity of depression symptoms in the mother
could potentially influence the risk of preterm birth as well.
Women who receive SSRIs during pregnancy are likely to have
had more severe depression and therefore have been at higher
risk for PTB than the control group with untreated depression.
It is not known whether, in the absence of treatment, the out-
come of the antidepressant-exposed pregnancies could have
been even worse [94].
Spontaneous abortion
Some studies have found small increased risk of spontaneous
abortion in women exposed to antidepressants in the first tri-
mester [97–99]. Results may be confounded by indication or other
uncontrolled variables [98, 99]. Confounding by maternal depres-
sion and other lifestyle factors may at least partially explain the
association, so results should be interpreted cautiously.
Persistent pulmonary hypertension of the newborn
Persistent pulmonary hypertension of the newborn (PPHN)
involves right-to-left shunting of blood through the fetal ductus
arteriosus and foramen ovale and results in neonatal hypoxia. If
this is severe, it can result in right heart failure and is fatal in
approximately 10% of cases.
Exposure to selective serotonin reuptake inhibitors and sero-
tonin norepinephrine reuptake inhibitors during (more frequently
late >20 weeks) pregnancy has been associated with an increased
risk for PPHN compared to women with no exposure [65, 100],
According to the studies demonstrating increased risk, this risk
remains low but significant [101] at approximately 2.9 cases per
1000 live births compared with 1.8/1000 in unexposed mothers.
One possible mechanism is high serotonin levels in the fetal lungs
leading to vasoconstriction and increased pulmonary vascular
resistance [102]. Sertraline may have a lower risk for PPHN com-
pared to other selective serotonin reuptake inhibitors [103].
Other large studies demonstrate no significant association
between perinatal SSRI exposure and PPHN [104–106]. It is
important to consider that that other factors such as obesity,
smoking, premature birth, and delivery by caesarean section,
all known risk factors for PPHN, are more common in women
with depression; therefore, it is possible that the association with
PPHN may be confounded, at least in part, by factors related to
the underlying depressive disorder [107, 108].
Poor neonatal adaptation syndrome
Antidepressant exposure late in pregnancy has also been asso-
ciated with transient neonatal complications which have been
referred to collectively as poor neonatal adaptation syndrome
(PNAS). Symptoms may include jitteriness, tremor, tachypnea,
Mood Disorders
hypoglycemia, temperature instability, weak cry, poor tone, and
mild respiratory distress [109]. It is not clear whether the mecha-
nism is a withdrawal syndrome or related to medication toxic-
ity [62, 70]. The syndrome has been described to occur in up to
30% of infants that have had serotonergic antidepressant expo-
sure (both SSRIs and SNRIs). Symptoms usually occur in the first
neonatal days and generally resolve in a period of two weeks or
less [108, 109].
Pre-eclampsia
A recent, large, prospective cohort study found that there is also
a possible association between early pregnancy exposure to anti-
depressants and an increased risk of pre-eclampsia. The SSRIs
and SNRIs as well as anxiolytics have all been associated with this
risk. Antidepressant-mediated vasoconstriction may contribute
to pre-eclampsia by increasing peripheral vascular resistance and
blood pressure elevation. Further studies are needed in this area
[110, 111].
Postpartum hemorrhage
Exposure to antidepressants, especially SSRIs and close to the
time of delivery have been associated with a small but significant
increased risk of postpartum hemorrhage [112–114]. Other stud-
ies have found that SNRIs also are associated with an increased
risk [82, 115]. The underlying mechanism of this effect is thought
to be the inhibition of serotonin uptake into platelets, as sero-
tonin plays an important role in the process of vasoconstriction
and platelet aggregation [116].
Autism spectrum disorders and
neurodevelopmental effects
Multiple studies have found an association with first trimes-
ter exposure to SSRIs, as well as maternal depression, and an
increased risk of autism spectrum disorders (ASD) compared
with unexposed women [76, 117–121]. Several meta-analyses
looking at exposure to SSRIs in utero found an association with
increased risk of developing ASD [122] as well as other mental
or behavioral disorders (e.g., attention deficit hyperactivity dis-
order [ADHD], mental retardation, mood disorder, depression,
anxiety disorder, speech disorders) [123]. The authors noted that
the results do not necessarily represent a causal relationship and
are likely affected by residual confounding by indication, which
may account for some (or all) of the observed positive associa-
tions [122, 123].
Adjustment for confounders in many of the studies found that
associations between in utero exposure to antidepressants and
physical, neurodevelopmental, and psychiatric outcomes may be
primarily associated with underlying maternal disorder [118, 124].
A large review did, however, find an increase in affective disor-
ders in children of mothers taking antidepressants during preg-
nancy, even after these adjustments [124]. Additionally, two large
studies from Denmark and Sweden found no association between
antidepressant exposure and autism spectrum disorders after
controlling for confounding factors and looking at sibling stud-
ies [95, 125]. Furthermore, a recent large systematic review found
no consistent evidence linking antidepressants in pregnancy to
neurocognitive developmental deficits in infants or preschool
children. This review did find some studies associating maternal
depression with an increased risk of ASD [126]. At this time, there
is no clear ­evidence of a detrimental effect of antidepressant use
during ­pregnancy on neurodevelopmental and neurobehavioral
outcomes [127].
211
Brexanolone
Brexanolone, a soluble IV formulation of the neuroactive ste-
roid allopregnanolone, is the first medication approved by the
FDA specifically for the treatment of postpartum depression.
Allopregnanolone, a progesterone metabolite, is a potent alloste-
ric modulator of GABAa receptors and has been shown to have
significant effects on anxiety and depression in animal mod-
els. Allopregnanolone levels change in parallel with progester-
one, reaching highest concentrations in the third trimester and
decreasing abruptly after childbirth [128, 129]. Brexanolone dos-
ing was designed to be comparable to allopregnanolone levels in
the third trimester. Brexanolone is administered as a continuous
60-hour infusion, with a gradual decrease in dose until the infu-
sion is stopped, allowing for a slow rather than abrupt decrease in
allopregnanolone levels in a population which may be vulnerable
to rapid hormonal fluctuation.
In three trials women receiving brexanolone had a greater
reduction in depressive symptoms compared to placebo at the pri-
mary endpoint of 60 hours and in many endpoints up to 30 days
post-infusion. In one of the three trials, brexanolone no longer sep-
arated from placebo at the 30-day endpoint; Of the patients who
had a response at 60 hours, 94% did not relapse at day 30 [130, 131].
Limitations include no data beyond the 30-day endpoint and the
fact that all clinical trials to date have been industry-sponsored.
Brexanolone, while generally well-tolerated, has been associated
with excessive sedation/pre-syncope/syncope in a very small subset
of patients, leading the FDA to mandate strict monitoring require-
ments including continuous pulse oximetry and monitoring for
sedation every 2 hours while awake. While receiving the infusion,
patients must be accompanied during all interactions with their
children. Use of this medication requires registration through the
drug company’s risk evaluation and mitigation strategy (REMS)
program [132]. These requirements, in addition to the considerable
cost of treatment, may ultimately lead to obstacles in the routine
implementation of brexanolone for the treatment of PPD.
Ketamine
Research on the use of ketamine for prevention of postpartum
depression is limited, and at the time of this publication, no
systematic reviews currently exist. Two RCTs examining the
effect of ketamine administered in a single dose for prevention
of PPD in patients undergoing elective caesarean deliveries with
spinal anesthesia showed conflicting results. One such study of
patients with no history of psychiatric illness receiving one sub-­
dissociative IV dose of ketamine administered during caesarean
section exhibited no significant difference in PPD measures at
3 days or 6 weeks following delivery compared to patients who
received placebo [163]. In a second such study of patients with or
without antenatal depressive symptoms (assessed by EDPS), with
or without antenatal suicidal ideation, and varying levels of stress
during pregnancy (assessed by a 30-item Pregnancy Pressure
Scale) receiving ketamine administered 10 minutes following
delivery demonstrated significantly lower rates of postpartum
blues at 4–6 days postpartum and postpartum depression at
6–8 weeks postpartum compared to standard postpartum care,
with the prophylactic effect of ketamine on depression symptoms
appearing greater in patients with a history of moderate stress,
depressive symptoms, and suicidal ideation in the antenatal
period. Exclusion criteria of subjects in the second study included
“unstable psychiatric disorders” not further defined [164]. Further
212
research on the efficacy of ketamine for the prevention of PPD is
needed to establish recommendations on use.
Mood stabilizers
Lithium
Lithium is associated with an increased risk of Ebstein’s anomaly, a
cardiac defect characterized by congenital displacement of the tri-
cuspid valve toward the apex of the right ventricle. In the general
population, the risk of Ebstein’s anomaly is 1:20,000. Lithium is often
stopped during or in anticipation of pregnancy because of concern
about this risk. However, lithium’s teratogenic risk has likely been
overestimated [133]. A recent meta-analysis seeking to assess the
risk of neonatal exposure to lithium concluded that the odds ratio
of any cardiac anomaly in lithium-exposed infants was 1.86; risk
was found to be dose dependent with lithium doses >900 mg posing
greater risk [134, 135]. While the relative risk of Ebstein’s anomaly
is significantly higher with prenatal lithium exposure, the absolute
risk still remains small, and has been estimated to be approximately
1:1,500 [136]. Additionally, as previously established, lithium was
found to be an effective strategy for prophylaxis against postpartum
mood episodes. Lithium was found to have a favorable risk-benefit
ratio, with a number needed to treat (NNT) of 3 for prevention of
mood episode relapse, and a number needed to harm (NNH) of 33
for risk of any congenital anomaly [134]. Individual cases of infant
arrhythmia, nephrogenic diabetes insipidus, thyroid dysfunc-
tion, hypotonia, hypoglycemia, and hyperbilirubinemia have been
reported with lithium exposure; these problems are generally tran-
sient and with no long-term sequelae. Lithium-exposed infants may
have poor respiratory effort and/or cyanosis at delivery. Neonatal
hypotonicity, bradycardia, cyanosis, and hypoglycemia can be pre-
ventable if lithium is discontinued immediately before delivery;
however, this should be carefully considered, given the high risk of
postpartum mood episodes in women with bipolar disorder [137].
Lithium is distributed in total body fluid volume, and levels can
be affected by vomiting and changes in sodium intake [41]. Thyroid
function should be monitored during pregnancy because of the
possibility of lithium-induced thyroid toxicity. In the last trimes-
ter, renal excretion of lithium increases by 30–50% [137], which
may necessitate a dose increase at this time. Decreasing the dose of
lithium at delivery may theoretically be necessary to avoid maternal
lithium toxicity associated with decrease in vascular volume occur-
ring at delivery; however, this is observed infrequently in practice.
Adequate hydration should be maintained during labor [41].
Many experts recommend continuing lithium during preg-
nancy in women with severe symptoms who have had a good
response to lithium [136, 138]. Many “lithium responders” have
a uniquely positive response to this medication; other mood sta-
bilizers are not interchangeable. However, given the small risk of
Ebstein’s anomaly, some patients with less frequent, less severe
episodes may be able to discontinue lithium during pregnancy or
at least during the first trimester. When the decision is made to
discontinue lithium, the drug should be tapered slowly (over the
course of >15 days) as rapid discontinuation of lithium is associ-
ated with higher frequency of and reduced latency to recurrence
of symptoms [139]. Prenatal screening, including high-resolution
ultrasound and fetal echocardiography, should be conducted in
pregnant women with first-trimester lithium exposure [136, 138].
Valproic acid
Congenital anomalies seen with valproic acid (VPA) include neu-
ral tube defects (NTDs), cardiovascular anomalies, limb defects,
and hypospadias. About 1–2% of exposed infants present with
Maternal-Fetal Evidence Based Guidelines
NTDs [140]. Lumbosacral meningomyelocele is the most com-
mon NTD associated with VPA exposure, likely representing a
drug effect on neural crest closure [41]. This defect occurs 10 to
20 times more frequently in VPA-exposed infants than in the
general population [140].
In a systematic review and meta-analysis of data on the occur-
rence of major congenital malformations in children exposed to
antiepileptic drug (AED) monotherapy during pregnancy, valpro-
ate was found to be associated with a significantly higher mal-
formation rate than nine other AEDs, including carbamazepine,
oxcarbazepine, and lamotrigine, which are also utilized in the
treatment of bipolar disorder. Valproate was specifically associ-
ated with a greater risk of neural tube, cardiac, orofacial/cranio-
facial, and skeletal and limb malformations, compared to other
AEDS. The absolute risk of major malformations with valproate
was found to be 10.93%, with magnitude of risk demonstrating
dose dependence [141, 142].
A specific combination of facial dysmorphic features has been
described in infants exposed to VPA in utero; this same syndrome
was later described in children of women using other AEDs (includ-
ing carbamazepine) during pregnancy. This syndrome is known as
the “antiepileptic drug syndrome” and is characterized by intrauter-
ine growth retardation, long and thin upper lip, shallow philtrum,
epicanthal folds, and midfacial hypoplasia with flat nasal bridge,
small upturned nose, and down-turned angles of the mouth [140].
In infants exposed to VPA in utero, these features are often associ-
ated with other major anomalies and developmental delay.
Cognitive deficits, learning difficulties, and autism spectrum
disorder have been repeatedly reported in children exposed to
VPA in utero. In a population-based study of all children born in
Denmark from 1996–2006, perinatal valproate use was associ-
ated with a significantly increased risk of autism spectrum dis-
orders and childhood autism [143]. In a systematic review and
meta-analysis, perinatal valproate exposure was found to be the
only AED significantly associated with cognitive delay, language
delay, psychomotor delay, and autism/dyspraxia [144]. In another
study utilizing French national healthcare databases, exposure
to VPA was associated with almost threefold increased risks of
neurodevelopmental disorder, more than fourfold increased risk
of pervasive neurodevelopmental disorders, and threefold risk of
intellectual disability [145]. Teratogenicity and cognitive effects
related to prenatal VPA exposure are likely dose dependent, with
doses greater than 800–1000 mg associated with significantly
greater risk [145]. Polytherapy with VPA and other anticonvul-
sants results in a higher rate of teratogenicity than monotherapy
with VPA alone [140].
In summary, valproic acid should generally not be used dur-
ing pregnancy or in women of childbearing potential. In 2013,
the FDA issued a drug safety communication stating that val-
proic acid is contraindicated for the treatment of migraine during
pregnancy and that it should “only be prescribed if other medica-
tions are not effective in treating the condition or are otherwise
unacceptable” for the treatment of epilepsy and bipolar disorder.
Women of childbearing age must be informed of the increased
risk for decreased IQ in children exposed to valproate in utero
[146]. In 2018, the European Commission approved a ban on the
use of valproate-containing medications for migraine and bipo-
lar disorder during pregnancy and a ban on using these medica-
tions to treat epilepsy during pregnancy “unless there is no other
effective treatment available.” Women of childbearing potential
are required to be enrolled in a pregnancy prevention program
before valproate can be prescribed [147].
Mood Disorders
Carbamazepine and oxcarbazepine
Rates of malformations with carbamazepine exposure range
from 2.2% to 5.4% in different large AED pregnancy registries.
A recent Cochrane Review evaluating perinatal carbamazepine
exposure in women with epilepsy found a relative risk of 2 versus
unexposed, unaffected (without seizure disorder) women [141].
Carbamazepine is associated with a risk of NTDs of 0.5–1%.
Recent data suggest that carbamazepine exposure may not cause
cognitive impairment [145]. Malformation rates are consistently
higher with VPA than with carbamazepine [141, 148]. Pregnancies
exposed to high doses of carbamazepine (>1000 mg) resulted in
a higher rate of malformations than lower doses (<400 mg) [149].
Data on malformation rates with oxcarbazepine exposure are
still limited. The EURAP registry, an international registry of
women with epilepsy on AED monotherapy at the time of con-
ception, reports on the largest dataset of oxcarbazepine-exposed
pregnancies currently available. In 333 oxcarbazepine-exposed
pregnancies, the malformation rate was found to be 3%, which is
reassuringly within the commonly accepted general population
rate [148, 150]. Oxcarbazepine does not produce the same toxic
epoxide metabolite as carbamazepine and thus, authors speculate
that oxcarbazepine may be less harmful to the developing fetus
[41]. Plasma concentrations of oxcarbazepine may decrease dur-
ing pregnancy [151], which may necessitate dose adjustment.
Lamotrigine
The reproductive safety data regarding lamotrigine is reassur-
ing compared to other treatments for BAD. While some earlier
studies reported increased risk of cleft lip and/or cleft palate in
infants exposed to lamotrigine in utero [152], more recent data
do not substantiate this association. In a recent meta-analysis,
no association between perinatal lamotrigine use and adverse
neonatal outcomes (including congenital malformations, miscar-
riage, stillbirth, and pre-term delivery) was found. Some studies
included in this analysis reported a correlation between higher
doses of lamotrigine and rate of congenital malformations, while
others did not support this association [153]. In a review of studies
evaluating effects of perinatal antiepileptic exposure on neurode-
velopmental outcome, no adverse effect on IQ or specific cogni-
tive skills was demonstrated for lamotrigine [154]. Lamotrigine
clearance is increased during pregnancy, which may necessi-
tate dose increases to maintain therapeutic effect. However, the
extent to which pregnancy affects lamotrigine pharmacokinetics
is highly variable, and can vary significantly between individual
patients [155]. After delivery, lamotrigine clearance returns rap-
idly to baseline, requiring careful monitoring, and possible dose
adjustment to avoid toxicity [156].
Second generation antipsychotics
In a large study utilizing a nationwide Medicaid database, preg-
nancies exposed to first generation antipsychotics and individual
second generation antipsychotics (aripiprazole, quetiapine, olan-
zapine, ziprasidone and risperidone) were compared to unex-
posed pregnancies. No increased risk of cardiac malformations
or overall congenital malformations was found for any of the
individual agents, with the exception of risperidone, which dem-
onstrated a relative risk of 1.26 for both cardiac malformations
and overall congenital malformations compared to unexposed
pregnancies, after correction for potential confounders, includ-
ing indication. This small increase in risk with risperidone should
be interpreted with caution and requires replication [157]. There
is currently substantial reassuring data regarding first trimester
213
exposure to quetiapine, olanzapine, and aripiprazole which do
not suggest a clinically meaningful increased risk of teratogenic-
ity. While no adverse outcomes are apparent from the literature,
data regarding other pregnancy outcomes such as miscarriage,
preterm delivery, small for gestational age, neonatal adaptation,
and neurodevelopmental outcomes after perinatal second gener-
ation antipsychotic exposure are insufficient as yet to draw defini-
tive conclusions [158, 159].
In a meta-analysis evaluating effects of perinatal antipsy-
chotic treatment on neurodevelopmental outcomes, results
were inconsistent, with the most consistent finding being a
transient delay in motor development at 6 months after in utero
antipsychotic exposure. However, this result was based on only
two studies [160].
The association between second generation antipsychotics and
metabolic complications such as weight gain, diabetes mellitus
and hyperlipidemia has been well-documented. However, in a
recent literature review on association of second generation anti-
psychotics and gestational diabetes, no association between the
use of second generation antipsychotics and gestational diabetes
was found, when confounding variables, including indication,
were taken into account [161]. Recent literature has also demon-
strated a twofold risk of type II diabetes mellitus associated with
the diagnosis of bipolar disorder or schizophrenia, compared
with unaffected controls [162].
Non-pharmacologic management
of mood disorders
Psychotherapy
Psychotherapeutic interventions are considered first-line treat-
ment to manage depression and anxiety during pregnancy and
depression in the postpartum period [165]. A meta-analysis of
psychosocial interventions showed that women receiving such
treatment were less likely to be depressed at one year postpartum
than those who did not receive such care [2]. Interpersonal ther-
apy (ITP) and cognitive behavioral therapy (CBT), which are both
time-limited, problem-focused, evidence-based psychotherapies,
have demonstrated positive effects in multiple trials for women
with mild to moderate unipolar major depression in the postpar-
tum period [2, 165–169] and are often viewed as preferable treat-
ment options for women who choose not to take medications or
for mild to moderate depression [165]. Both CBT and ITP have
been found to be effective for treatment of perinatal depression as
well [170–172]. Interpersonal therapy has been shown to be par-
ticularly effective in reducing depressive symptoms and preva-
lence of depressive episodes [171].
Efficacy of CBT has been demonstrated even when adminis-
tered by a therapist via internet-based platforms [2, 173, 174],
which offers potential options for patients when accessibility is
limited by geography, time constraints, lack of childcare, or other
considerations. CBT can be delivered in individual or group
settings [175], demonstrating the breadth of its potential use to
promote accessibility and fit to the patient. Psychotherapeutic
interventions may afford additional value when delivered by
nurses and other non-physician healthcare practitioners as
they may allow greater accessibility and cost-effectiveness [165].
Conducting therapy in a group setting may lead to group support
for postpartum women in overcoming common challenges with
a newborn and changing lifestyle. When cost and time serve as
barriers, therapeutic modalities in remote format (e.g., computer
214
and internet-based or telephone based) can save substantial time
and cost in travel [176].
Exercise
Exercise represents a safe strategy for improving psychological
wellbeing throughout pregnancy. There is good evidence that
shows that physical activity reduces the symptoms of depression
during pregnancy and can be an additional preventive measure
for minimizing risk for perinatal depression [177–181]. Physically
active women may have a lower risk of developing depression com-
pared to non-active women. In addition, exercise has been shown
to have an impact on reducing both level of anxiety and stress, as
well as increasing overall quality of life [182]. Evidence supports
a recommendation of healthy lifestyle including regular physical
activity for pregnant and postpartum women. A meta-analysis of
RCTs showed that physical activity has a beneficial effect regard-
less of frequency, type, or intensity of the activity [183]. Studies
of both physical activity and yoga as interventions for preg-
nant and postpartum women with depression have shown
significant reductions in depressive symptoms as measured by
both EPDS and Quick Inventory of Depressive Symptomatology
(QIDS) and support antenatal yoga as a safe practice [184, 185].
Additionally, studies of mindfulness-based interventions showed
positive effect in reduction of depressive symptoms [186], further
supporting the role of both yoga and mindfulness-based therapies
in pregnant and postpartum women.
Healthy women who are not already doing vigorous-intensity phys-
ical activity should get at least 2 hours and 30 minutes (150 minutes)
of moderate-intensity aerobic activity a week, divided throughout
the week. Women who regularly engage in vigorous-intensity aero-
bic activity or high amounts of activity can continue their activity
provided that their condition remains unchanged and they talk to
their healthcare provider about their activity level throughout their
pregnancy. If women were previously inactive, addition of activity
should be gradual, and spread throughout the week. Modifications
to some exercises may be required, and hyperthermia and exposure
to excess heat, as in “hot yoga,” should be avoided. Women should
also ensure adequate hydration and caloric intake [187, 188].
Diet
Multiple studies have shown an inverse relationship between
healthy diet patterns and perinatal anxiety and depression [189,
190]. Evidence suggests that certain overall dietary patterns dur-
ing pregnancy may be protective for healthy outcomes, such as a
lower risk of preterm birth [191]. These protective dietary patterns
are higher in vegetables; fruits; fiber; nuts, legumes, and seeds;
and seafood, and lower in processed meats and fried foods [190].
In addition to reducing adverse perinatal outcomes, a systematic
review of dietary patterns in association with perinatal depression
and anxiety found an inverse relationship between diets consisting
of whole foods, fruits, vegetables, fish and seafood and perinatal
depression and anxiety [166, 189]. A review examining the bidi-
rectional association between maternal depression and diet found
a protective effect of healthy varied diets consisting mostly of
non-meat protein, fish, fruits, vegetables and dairy and general
health consciousness against depression symptoms during the
pre- and postnatal periods. Additionally, there is an association
between eating disorders and postnatal depression [191].
Electroconvulsive therapy
Electroconvulsive therapy (ECT) is an effective option for severe
or refractory perinatal depression and should be considered
Maternal-Fetal Evidence Based Guidelines
when patients are treatment resistant or when depression is
life threatening as in cases of high suicide risk, psychotic fea-
tures, catatonia, or significant physical decline [192]. ECT is also
recommended for patients with bipolar disorder who have not
responded to three medication trials or are at imminent risk to
themselves [193]. ECT in pregnancy has risks similar to that of
the general population, including nausea and vomiting, myal-
gias, headaches, confusion, and memory loss. The most common
maternal adverse events with ECT are premature contractions
and preterm labor, seen most frequently in the second and
third trimesters and with relatively low prevalence. Literature
describes preterm labor risk of 3.5%, which is not clearly
increased by ECT, and uterine contractions risk of 0.6–24%, with
no significant consequences to mother or fetus. The most com-
mon fetal adverse event with ECT is cardiac arrhythmia, specifi-
cally postictal irregular fetal heart, tonic phase fetal bradycardia,
or reduced heart rate variability. Congenital anomalies have not
been associated with ECT [192]. Similar to the general popula-
tion, some medical conditions are associated with increased
risk with ECT, and specific consideration should be given when
assessing for safety of ECT, including severe or unstable car-
diovascular disease, space-occupying intracranial lesion with
evidence of elevated intracranial pressure, recent cerebral hem-
orrhage or stroke, unstable or bleeding vascular aneurysm, and
severe pulmonary condition [194].
Transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation (rTMS) is a
non-invasive modality of treatment that delivers electrical
stimuli through the scalp to modulate cortical activity and is
FDA-approved for patients in the general population who have
failed to respond to at least one antidepressant. TMS represents
a particularly important option for the pregnant population as
it does not carry pharmacologic effects and is less invasive than
other neurostimulatory treatment options, such as ECT [195].
Studies of TMS used in pregnant women have demonstrated that
TMS is well tolerated and effective, with most women achieving
some response and approximately one third reaching remission –
without adverse pregnancy or fetal outcomes. Of note, estimates
of fetal exposure to electrical fields in TMS would likely be well
below the threshold of potential harm [176]. Studies [2, 196] exam-
ining the effect of TMS on postpartum depression showed signif-
icant decreases in Hamilton Depression Rating Scale (HDRS) and
EPDS scores [197] and low dropout [198], which supports TMS as
a promising treatment in pregnant and postpartum women, but
more studies are needed with larger numbers of subjects.
Lactation considerations
Given the high rate of psychiatric illness during and after preg-
nancy, all postpartum patients who may be at risk for psychiatric
illness should be evaluated to determine whether medication is
necessary. All psychiatric medications are lipid soluble and are
passed into breast milk, however, infant exposure through lacta-
tion is generally considerably lower than exposure in utero [199].
Over the last 10 years, various indices have been developed in
order to evaluate the safety of SSRIs during breastfeeding [200].
Several studies have examined the extent of drug exposure that
occurs to nursing infants whose mothers take psychotropic medi-
cations, however, the available literature continues to be repre-
sented largely by case reports or studies with small sample sizes
and there is an overall low quality of the current literature on this
topic [200]. Additionally, most studies lack accurate evaluation
Mood Disorders
and analysis of potential confounding factors, such as mother’s
habits (e.g., cigarette smoking and other concomitant drugs pre-
scribed) and prenatal drug exposure [201].
A commonly used index is the ratio of infant drug (RID) level
(kg/day) to the average maternal plasma drug level (kg/day). A
value below 10% is generally considered safe during lactation
[202, 203]. This index, however, does not take into account differ-
ences in the infant’s ability to metabolize drugs which is also an
important determinant of plasma level [201].
During the postpartum period, in addition to concerns about
medication passage into breast milk, important considerations
include the impact of breastfeeding during the night, and sleep
disruption in patients with maternal mental illness. Sleep depri-
vation can be extremely destabilizing particularly in women with
bipolar disorder.
Antidepressants
Overall, there are few reports of adverse effects in infants exposed
to the SSRIs. Among the SSRIs, only occasional mild to moder-
ate short-term side effects and no adverse long-term effects were
described for most of these medications [201]. Fluoxetine has
been found to have higher plasma levels in infants, likely due to
its long-half-life, however, few adverse effects have been reported
[204]. There is much less data on the SNRIs. Venlafaxine has been
reported to have a higher RID (although variable) than other
SSRIs, but still below 10% [201]. Both venlafaxine and duloxetine
show no clear causality between infant adverse reactions and
drug concentrations in milk [201, 205].
When the use of antidepressant medication is indicated in a
nursing woman, the drugs that should be preferred as first-line
choice in a treatment-naive patient are paroxetine and sertra-
line, because of their good safety profiles as reported in exposed
infants. However, if a woman has been stable on an antide-
pressant throughout her pregnancy, preference is usually to
remain on that same medication postpartum, as evidence sug-
gests that most infant SSRI levels are compatible with breastfeed-
ing. The postpartum period, a period of significant vulnerability
for women with mood disorders, is generally an inappropriate
time to stop an effective medication and try another that has not
been previously used or demonstrated to be helpful in a partic-
ular patient. These findings are in line with the recommenda-
tions of most authoritative guidelines [46, 200, 201, 203]. For the
tricyclic antidepressants, nortriptyline is the preferred choice
[201, 206]. Although most antidepressant drugs do not pose a
risk to the nursing infant; consideration to the individual risk/
benefit is necessary in each individual patient. Medications with
longer half-lives are less preferred options as first-line treatment
as they may accumulate in the infants, especially those that are
premature or those with underlying medical conditions [199,
207]. Overall, positive benefits of breastfeeding outweigh possi-
ble adverse side effects of antidepressant drugs [206]. Long-term
effects of infant exposure to SSRIs through nursing have been
less well studied [206].
Mood stabilizers
Lithium
Data regarding lithium’s compatibility with breastfeeding is
derived from several case series. Historically, lithium use dur-
ing lactation has been discouraged due to reports of high infant
levels [208]. More recent data demonstrates significantly lower
infant levels, no overt adverse effects, and laboratory abnormali-
ties that are rare, minor and transient [209]. However, infants
215
may be more susceptible to both dehydration and lithium tox-
icity because of their immature kidney function and potential
for rapid dehydration. While many experts will still discour-
age breastfeeding in women maintained on lithium, others may
support it for women who are reliable and motivated, with close
monitoring of the infant.
Valproic acid
Breastfeeding data concerning valproic acid is derived from
case reports, case series, and a few open label studies. Although
valproic acid is contraindicated during pregnancy for the treat-
ment for bipolar disorder, it is generally considered compatible
with breastfeeding, with extremely low levels found in breast
milk [209]. Breastfed infants of mothers exposed to valproic acid
in utero and through breast milk (for the treatment of epilepsy)
demonstrated no additional cognitive deficits at ages 3 and 6 com-
pared to those with perinatal exposure who did not breastfeed
[210, 211]. One adverse event of thrombocytopenia and anemia
in an exposed infant was reported, which resolved immedi-
ately when breastfeeding was discontinued [212]. Otherwise, no
clear adverse reactions in breastfed infants have been reported.
Theoretically, breastfed infants could be at risk for hepatotoxicity
related to valproic acid, and therefore should be monitored for
jaundice and other signs of liver damage [213].
Carbamazepine and oxcarbazepine
Data on infant exposure is limited. In a recent prospective
cohort study, representing a larger sample size than previously
available for carbamazepine and oxcarbazepine, infant-to-
mother concentrations were found to be low [214]. However, in
two case reports of infants exposed during both pregnancy and
lactation, carbamazepine was associated with infant hepatotox-
icity [215, 216].
Lamotrigine
Lamotrigine is excreted in relatively high levels in breast milk.
Infant serum levels are approximately 30% of maternal levels,
likely because of slow, immature elimination in infants. This has
resulted in some concern about the safety of lamotrigine during
breastfeeding. However, despite this, no clinically relevant adverse
effects have been consistently described. One case report of apnea
that resolved with the discontinuation of breastfeeding, and one
case of toxicity have been reported, and some infants have dem-
onstrated mild thrombocytosis of no clinical significance [217].
Breastfed infants of mothers exposed to lamotrigine in utero and
through breast milk (for the treatment of epilepsy) demonstrated
no cognitive deficits at ages 3 and 6, compared to those with peri-
natal exposure who did not breastfeed [210, 218]. It is reasonable
for mothers taking lamotrigine to breastfeed if desired, given rare
and generally mild adverse effects related to exposure, despite high
milk concentration of this drug, as long as the infant is monitored
closely. Some authors recommend monitoring serum lamotrigine
levels in breastfeeding infants [217] (Table 21.2).
Second generation antipsychotics
Available data supports the use of most second generation anti-
psychotics (SGAs) during lactation, with minimal concentrations
of active metabolites found in breast milk. The SGA with the larg-
est breastfeeding data set is olanzapine, which demonstrates low
infant plasma concentrations and low relative infant dose, with
one infant under 4 months of age with relatively high serum
­levels. Generally, no adverse effects have been reported [209].
TABLE 21.2: Mood Stabilizers in Pregnancy and Lactation

216
Medication Teratogenicity Neonatal Toxicity Breastfeeding Comments
Lithium Increased risk of Ebstein’s anomaly but absolute risk is small, Individual cases of transient Infants may be more susceptible to both High-resolution ultrasound and
(Eskalith®, Lithobid®) estimated at 1:1500 [24] arrythmia, nephrogenic dehydration and lithium toxicity because of their fetal echocardiography at 16–18
diabetes insipidus, thyroid immature kidney function and potential for rapid weeks’ gestation [48]
dysfunction, hypotonia, dehydration Favorable risk/ benefit ratio in
hypoglycemia, and women who are “lithium
hyperbilirubinemia [137] responders”
Valproic acid Absolute risk of major malformations with valproate of 10.93%, None noted Considered compatible with breastfeeding; low Should generally not be used during
(Depakene®, Stavzor®)/ with magnitude of risk demonstrating dose dependence [141, 142] infant serum levels [193] pregnancy or in women of
Divalproex sodium 1–2% risk of NTDs [140] childbearing potential
(Depakote®, Risk of facial dysmorphic features “antiepileptic drug syndrome”
Depakote ER®, [140]
Depakote Sprinkles®) Increased risk of cognitive deficits and ASD [143–145]
Carbamazepine Risk of NTD 0.5–1%; overall risk of major malformations None noted Infant-to-mother concentrations found to be low [214]
(Carbatrol®, Equetro®, 2.2–5.4% [48, 128] In two case reports of infants exposed during both
Tegretol®, Tegretol pregnancy and lactation, carbamazepine was
XR®) associated with infant hepatotoxicity [215, 216]
Oxcarbazepine Available teratogenic information is reassuring but database is None noted Limited data Levels may decrease during
(Trileptal®) too small to draw definitive conclusions [128] pregnancy [46]
Lamotrigine While some earlier studies reported increased risk of cleft lip and/ None noted High infant exposure, approximately 30% of Changes in clearance during
(Lamictal®, Lamictal or cleft palate in infants exposed to lamotrigine in utero [152], maternal levels [193] pregnancy and after delivery may
XR®) more recent data do not substantiate this association [153] Hypothetical risk of SJS in the newborn [177, 178] necessitate dose adjustment in
No adverse effect on IQ or specific cognitive skills was some women [155]
demonstrated for lamotrigine [154] Safety data are reassuring compared
to other treatment options [137]
Atypical antipsychotics Substantial reassuring data regarding first trimester exposure to Insufficient results to Minimal concentrations of active metabolites of most
Olanzapine quetiapine, olanzapine, and aripiprazole, which do not suggest a draw definitive SGAs found in breastmilk

Maternal-Fetal Evidence Based Guidelines

(Zyprexa®, Zyprexa clinically meaningful increased risk of teratogenicity conclusions Olanzapine: has the largest data set and demonstrates
Zydis®) Transient delay in motor low infant plasma concentrations, low RID, and
Risperidone development seen in two generally no adverse effects reported [209]
(Risperdal®, Risperdal studies [160] Quetiapine: Case reports and series demonstrate very
M-Tab®) low infant exposure and no adverse events [209]
Quetiapine Risperidone: Case reports demonstrated higher
(Seroquel®, Seroquel breastmilk levels than those found with quetiapine
XR®) or olanzapine, but low or undetectable infant levels,
Aripiprazole and no adverse effects reported [209]
(Abilify®, Abilify Aripiprazole: Available cases do not demonstrate
Discmelt®) adverse effects. May be associated with reduced milk
Ziprasidone production due to decreased prolactin release [221]
(Geodon®) Clozapine: variable levels in infant serum;
Clozapine hypothetical risk of agranulocytosis [185]
(Clozaril®, FazaCIo®)
Abbreviations: NTD, neural tube defects; ASD, autistic spectrum disorder; SJS, Steven’s Johnson Syndrome; LGA, large for gestational age; EPS, extrapyramidal symptoms.
Mood Disorders
Data regarding quetiapine is derived from case reports and series,
demonstrating very low infant exposure and no adverse events
[209]. A recent small study utilizing a highly sensitive analytical
method demonstrated quetiapine exposure during lactation to be
less than 0.2% of the mother’s weight adjusted dose [219]. Only case
reports are available for risperidone, with higher levels excreted
into breast milk than those found with quetiapine or olanzapine,
but with low or undetectable infant levels, and no adverse effects
reported [209, 220–222]. Available cases of infant exposure to
aripiprazole during lactation do not demonstrate adverse effects.
Maternal aripiprazole treatment may be associated with reduced
milk production due to decreased prolactin release [221].
There are very few studies published on the safety of clozap-
ine. In one case report, clozapine was shown to have relatively
high accumulation in breast milk [223]. In an infant exposed
to clozapine both prenatally and during breastfeeding, delayed
speech acquisition may have been attributable to clozapine [224].
Although no cases have been reported of agranulocytosis in nurs-
ing infants, it is a theoretical risk [225]. Decisions regarding clo-
zapine use during lactation should be made on a case by case basis,
as clozapine is generally reserved for the most treatment resistant
patients who have likely tried and failed other agents [226].
The authors suggest using the LactMed database to ensure the
most up-to-date information on a particular medication. This
database of the NIH includes information on the levels of medica-
tions in breast milk and infant blood, and possible adverse effects
in the nursing infant [227].
Conclusions
Psychotherapy is considered first-line treatment for depression
during pregnancy and in the postpartum period. In patients with
moderate to severe depression, or in those who have previously
responded well to medication, pharmacotherapies along with psy-
chotherapy should be considered firstline. Patients should be pro-
vided with information and advised that no decision is risk-free
when considering the risks of fetal exposure to untreated mater-
nal depression versus risks of antidepressant exposure. Decisions
about the risks and benefits of treatment versus lack of treatment
during pregnancy should be made on an individual basis with each
patient. Factors including illness severity, history of disorder, social
situation and patient preference should guide decision-making. For
some women, therapy alone may be effective for mild to moder-
ate depression. For others, careful consideration should be given to
treatment with medications [62]. Given the negative consequences
of untreated or partially treated perinatal or postpartum depression
on child development, maintaining maternal euthymia should be a
priority. Caution is advisable in making decisions about whether to
continue or stop treatment with SSRIs during pregnancy. Stopping
treatment in mothers with major depression could be more harm-
ful for the infant than continuing use of SSRIs.
Women with bipolar disorder are particularly vulnerable
to mood episodes in the postpartum period. In women with
a known history of bipolar disorder, medication maintenance
during pregnancy and postpartum is often warranted. Mood
stabilizers are not generally interchangeable and their risk/ben-
efit profiles are also individualized. The only mood stabilizing
medication which is unequivocally contraindicated in preg-
nancy is valproic acid. Treatment decisions should be made on
an individualized basis, and maintenance of euthymia should
again be prioritized.
217
References
1. APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed.
American Psychiatric Association; 2013. [Committee guidelines, III]
2. Stewart DE, Vigod S. Postpartum depression. N Engl J Med
2016;375(22):2177–2186. [Review, III]
3. Guo N, Robakis T, Miller C, Butwick A. Prevalence of depression
among women of reproductive age in the United States. Obstet Gynecol
2018;131(4):671–679. [Cohort, II-2]
4. NIMH. Major Depression [Internet]. [cited 2020 Oct 13]. Available from:
https://w w w.nimh.nih.gov/health/statistics/major-depression.shtml
[Committee report, III]
5. Screening for Perinatal Depression | ACOG [Internet]. [cited 2020 Oct
13]. Available from: https://www.acog.org/clinical/clinical-guidance/
committee-opinion/articles/2018/11/screening-for-perinatal-depression
[Committee report, III]
6. Hahn-Holbrook J, Cornwell-Hinrichs T, Anaya I. Economic and health pre-
dictors of national postpartum depression prevalence: a systematic review,
meta-analysis, and meta-regression of 291 studies from 56 countries. Front
Psychiatry 2017;8:248. [Review, III]
7. Lindahl V, Pearson JL, Colpe L. Prevalence of suicidality during preg-
nancy and the postpartum. Arch Womens Ment Health 2005;8(2):77–87.
[Review, III]
8. Palladino CL, Singh V, Campbell J, Flynn H, Gold KJ. Homicide and suicide
during the perinatal period: findings from the national violent death report-
ing system. Obstet Gynecol 2011;118(5):1056–1063. [Cohort, II-2]
9. Howard LM, Molyneaux E, Dennis C-L, Rochat T, Stein A, Milgrom
J. Non-psychotic mental disorders in the perinatal period. Lancet
2014;384(9956):1775–1788. [Literature review of studies that included
RCTs and observational studies, III]
10. Rezaie-Keikhaie K, Arbabshastan ME, Rafiemanesh H, Amirshahi M,
Ostadkelayeh SM, Arbabisarjou A. Systematic review and meta-analysis of
the prevalence of the maternity blues in the postpartum period. J Obstet
Gynecol Neonatal Nurs 2020;49(2):127–136. [Review, III]
11. Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and
lactation. Ann Pharmacother 2004;38(7–8):1265–71. [Review, III]
12. VanderKruik R, Barreix M, Chou D, et al. The global prevalence of post-
partum psychosis: a systematic review. BMC Psychiatry 2017;17(1):272.
[Review, III]
13. Spinelli MG. A systematic investigation of 16 cases of neonaticide. Am J
Psychiatry 2001;158(5):811–813. [Case series, II-3]
14. Gilden J, Kamperman AM, Munk-Olsen T, Hoogendijk WJG, Kushner
SA, Bergink V. Long-term outcomes of postpartum psychosis: a sys-
tematic review and meta-analysis. J Clin Psychiatry 2020;81(2).
[Review, III]
15. Räisänen S, Lehto SM, Nielsen HS, Gissler M, Kramer MR, Heinonen S.
Risk factors for and perinatal outcomes of major depression during preg-
nancy: a population-based analysis during 2002-2010 in Finland. BMJ Open
2014;4(11):e004883. [Cross-sectional study, II-3]
16. Katon W, Russo J, Gavin A. Predictors of postpartum depression. J Womens
Health (Larchmt) 2014;23(9):753–9. [Prospective cohort, II-2]
17. Mercier RJ, Garrett J, Thorp J, Siega-Riz AM. Pregnancy intention and
postpartum depression: secondary data analysis from a prospective cohort.
BJOG 2013;120(9):1116–22. [Prospective cohort, II-2]
18. Verreault N, Da Costa D, Marchand A, Ireland K, Dritsa M, Khalifé S. Rates
and risk factors associated with depressive symptoms during pregnancy
and with postpartum onset. J Psychosom Obstet Gynaecol 2014;35(3):84–
91. [Prospective cohort, II-2]
19. Bayrampour H, Kapoor A, Bunka M, Ryan D. The risk of relapse of depres-
sion during pregnancy after discontinuation of antidepressants: a system-
atic review and meta-analysis. J Clin Psychiatry 2020;81(4). [Review, III]
20. Yim IS, Tanner Stapleton LR, Guardino CM, Hahn-Holbrook J, Dunkel
Schetter C. Biological and psychosocial predictors of postpartum depres-
sion: systematic review and call for integration. Annu Rev Clin Psychol
2015;11(1):99–137. [Review, III]
21. Walton N, Maguire J. Allopregnanolone-based treatments for postpartum
depression: Why/how do they work? Neurobiol Stress 2019;11:100198.
[Review, III]
22. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR.
Effects of gonadal steroids in women with a history of postpartum depres-
sion. Am J Psychiatry 2000;157(6):924–930. [Controlled trial, II-1]
23. Slomian J, Honvo G, Emonts P, Reginster J-Y, Bruyère O. Consequences
of maternal postpartum depression: A systematic review of maternal and
infant outcomes. Womens Health (Lond Engl) 2019;15:1745506519844044.
[Review, III]
218
24. Jarde A, Morais M, Kingston D, et al. Neonatal outcomes in women with
untreated antenatal depression compared with women without depression:
a systematic review and meta-analysis. JAMA Psychiatry 2016;73(8):826–
837. [Review, III]
25. Szegda K, Markenson G, Bertone-Johnson ER, Chasan-Taber L. Depression
during pregnancy: a risk factor for adverse neonatal outcomes? A critical
review of the literature. J Matern Fetal Neonatal Med 2014;27(9):960–967.
[Data largely obtained from prospective cohort studies, II-2]
26. Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. The impact of
maternal depression during pregnancy on perinatal outcomes: a systematic
review and meta-analysis. J Clin Psychiatry 2013;74(4):e321–e341. [Cohort
studies were analyzed, II-2]
27. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes
of preterm birth. Lancet 2008;371(9606):75–84. [Review, III]
28. Gentile S. Untreated depression during pregnancy: short- and long-term
effects in offspring. A systematic review. Neuroscience 2017;342:154–66.
[Review, III]
29. Zou R, Tiemeier H, van der Ende J, et al. Exposure to maternal depressive
symptoms in fetal life or childhood and offspring brain development: a
population-based imaging study. Am J Psychiatry 2019;176(9):702–710.
[Cohort, II-2]
30. Glover V. Maternal depression, anxiety and stress during pregnancy and
child outcome; what needs to be done. Best Pract Res Clin Obstet Gynaecol
2014;28(1):25–35. [Literature review and expert opinion, III]
31. Tirumalaraju V, Suchting R, Evans J, et al. Risk of depression in the adoles-
cent and adult offspring of mothers with perinatal depression: a systematic
review and meta-analysis. JAMA Netw Open 2020;3(6):e208783. [Review,
III]
32. Sharma V. Management of bipolar II disorder during pregnancy and
the postpartum period–Motherisk Update 2008. Can J Clin Pharmacol
2009;16(1):e33–41. [Review, III]
33. Chessick CA, Dimidjian S. Screening for bipolar disorder during pregnancy
and the postpartum period. Arch Womens Ment Health 2010;13(3):233–
248. [Review, III]
34. Sharma V, Sharma P, Sharma S. Managing bipolar disorder during preg-
nancy and the postpartum period: a critical review of current practice.
Expert Rev Neurother 2020;20(4):373–383. [Review, III]
35. Jones I, Chandra PS, Dazzan P, Howard LM. Bipolar disorder, affective psy-
chosis, and schizophrenia in pregnancy and the post-partum period. Lancet
2014;384(9956):1789–1799. [Literature review and discussion of prospec-
tive cohort studies, III]
36. Wesseloo R, Kamperman AM, Munk-Olsen T, Pop VJM, Kushner SA,
Bergink V. Risk of postpartum relapse in bipolar disorder and postpar-
tum psychosis: a systematic review and meta-analysis. Am J Psychiatry
2016;173(2):117–127. [Review, III]
37. Robertson E, Jones I, Haque S, Holder R, Craddock N. Risk of puerperal and
non-puerperal recurrence of illness following bipolar affective puerperal
(post-partum) psychosis. Br J Psychiatry 2005;186:258–259. [Prospective
cohort study, II-2]
38. Di Florio A, Jones L, Forty L, et al. Mood disorders and parity - a clue to the
aetiology of the postpartum trigger. J Affect Disord 2014;152–154:334–339.
[Case-control study, II-2]
39. Di Florio A, Forty L, Gordon-Smith K, et al. Perinatal episodes across the mood
disorder spectrum. JAMA Psychiatry 2013;70(2):168–175. [Cohort, II-2]
40. Sharma V, Sharma S. Peripartum management of bipolar disorder: what
do the latest guidelines recommend? Expert Rev Neurother 2017;17(4):
335–344. [Review, III]
41. Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar dis-
order during pregnancy and the postpartum period. Am J Psychiatry
2004;161(4):608–620. [Review, III]
42. Mei-Dan E, Ray JG, Vigod SN. Perinatal outcomes among women with
bipolar disorder: a population-based cohort study. Am J Obstet Gynecol
2015;212(3):367.e1–8. [Cohort study, II-2]
43. Sharma V, Pope CJ. Pregnancy and bipolar disorder: a systematic review.
J Clin Psychiatry 2012;73(11):1447–1455. [Review of largely prospective
observational data, II-2]
44. Wisner KL, Sit D, O’Shea K, et al. Bipolar disorder and psychotropic
medication: Impact on pregnancy and neonatal outcomes. J Affect Disord
2019;243:220–225. [Prospective study, II-2]
45. Salim M, Sharma V, Anderson KK. Recurrence of bipolar disorder during
pregnancy: a systematic review. Arch Womens Ment Health 2018;21(4):
475–479. [Review, III]
46. ACOG Committee on Practice Bulletins–Obstetrics. ACOG Practice
Bulletin: Clinical management guidelines for obstetrician-gynecol-
ogists number 92, April 2008 (replaces practice bulletin number 87,
Maternal-Fetal Evidence Based Guidelines
November 2007). Use of psychiatric medications during pregnancy and
lactation. Obstet Gynecol 2008;111(4):1001–1020. [Committee report, III]
47. Viguera AC, Tondo L, Koukopoulos AE, Reginaldi D, Lepri B, Baldessarini
RJ. Episodes of mood disorders in 2,252 pregnancies and postpartum peri-
ods. Am J Psychiatry 2011;168(11):1179–1185. [Retrospective observational
study, II-2]
48. Einarson A, Boskovic R. Use and safety of antipsychotic drugs during preg-
nancy. J Psychiatr Pract 2009;15(3):183–192. [Review, III]
49. Kendig S, Keats JP, Hoffman MC, et al. Consensus bundle on mater-
nal mental health: perinatal depression and anxiety. Obstet Gynecol
2017;129(3):422–430. [Committee report, III]
50. American College of Nurse-Midwives. Position statement: depression in
women. Division of Women’s Health Policy and Leadership. 2013;Clinical
Standards and Documents Section. [Committee report, III]
51. American College of Obstetricians and Gynecologists (ACOG). ACOG
Committee Opinion No. 757: screening for perinatal depression. Obstet
Gynecol 2018;132(5):e208–212. [Committee report, III]
52. Siu AL, US Preventive Services Task Force (USPSTF), Bibbins-Domingo
K, Grossman DC, Baumann LC, et al. Screening for depression in adults:
US preventive services task force recommendation statement. JAMA
2016;315(4):380–387. [Committee report, III]
53. Howard LM, Megnin-Viggars O, Symington I, Pilling S, Guideline
Development Group. Antenatal and postnatal mental health: summary of
updated NICE guidance. BMJ 2014;349:g7394. [Committee report, III]
54. Earls MF, Yogman MW, Mattson G, Rafferty J, Committee on Psychosocial
Aspects of Child and Family Health. Incorporating recognition and
management of perinatal depression into pediatric practice. Pediatrics
2019;143(1):e20183260. [Committee report, III]
55. Martínez-Borba V, Suso-Ribera C, Osma J. The use of information and com-
munication technologies in perinatal depression screening: A systematic
review. Cyberpsychol Behav Soc Netw 2018;21(12):741–752. [Review, III]
56. Worley LLM, Wise-Ehlers A. Telepsychiatry in Obstetrics. Obstet Gynecol
Clin North Am 2020;47(2):333–340. [Review, III]
57. Ghaemi SN. Why antidepressants are not antidepressants: STEP-BD,
STAR*D, and the return of neurotic depression. Bipolar Disord
2008;10(8):957–968. [Review, III]
58. Brockington I. Suicide and filicide in postpartum psychosis. Arch Womens
Ment Health 2017;20(1):63–69. [Review, III]
59. Molenaar NM, Kamperman AM, Boyce P, Bergink V. Guidelines on treat-
ment of perinatal depression with antidepressants: An international review.
Aust N Z J Psychiatry 2018;52(4):320–327. [Review, III]
60. O’Connor E, Senger CA, Henninger ML, Coppola E, Gaynes BN.
Interventions to prevent perinatal depression: evidence report and system-
atic review for the US preventive services task force. JAMA 2019;321(6):588–
601. [Review, III]
61. van Ravesteyn LM, Lambregtse-van den Berg MP, Hoogendijk WJG,
Kamperman AM. Interventions to treat mental disorders during preg-
nancy: A systematic review and multiple treatment meta-analysis. PLOS
ONE 2017;12(3):e0173397. [Review, III]
62. Suri R, Lin AS, Cohen LS, Altshuler LL. Acute and long-term behavioral
outcome of infants and children exposed in utero to either maternal
depression or antidepressants: a review of the literature. J Clin Psychiatry
2014;75(10):e1142–1152. [Literature review, III]
63. O’Hara MW, Engeldinger J. Treatment of postpartum depression: recom-
mendations for the clinician. Clin Obstet Gynecol 2018;61(3):604–614.
[Review, III]
64. Menon SJ. Psychotropic medication during pregnancy and lactation. Arch
Gynecol Obstet 2008;277(1):1–13. [Review, III]
65. Alwan S, Friedman JM, Chambers C. Safety of selective serotonin reup-
take inhibitors in pregnancy: A review of current evidence. CNS Drugs
2016;30(6):499–515. [Review, III]
66. Molyneaux E, Telesia LA, Henshaw C, Boath E, Bradley E, Howard LM.
Antidepressants for preventing postnatal depression. Cochrane Database
Syst Rev 2018;4:CD004363. [Review of RCTs, I]
67. Wang S, Yang L, Wang L, Gao L, Xu B, Xiong Y. Selective Serotonin
Reuptake Inhibitors (SSRIs) and the Risk of Congenital Heart Defects: A
Meta-Analysis of Prospective Cohort Studies. J Am Heart Assoc 2015;4(5):
e001681. [Review of prospective cohort studies, II-2]
68. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy
and the risk of cardiac defects. N Engl J Med 2014;370(25):2397–2407.
[Cohort study of 949,504 women, II-2]
69. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, National
Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibi-
tors in pregnancy and the risk of birth defects. N Engl J Med 2007;356(26):
2684–2692. [Cross-sectional study, n = 6582, II-3]
Mood Disorders
70. Yonkers KA, Blackwell KA, Glover J, Forray A. Antidepressant use in preg-
nant and postpartum women. Annu Rev Clin Psychol 2014;10:369–392.
[Literature review of largely observational studies, including prospective
cohort studies, II-2]
71. Nordeng H, van Gelder MMHJ, Spigset O, Koren G, Einarson A, Eberhard-
Gran M. Pregnancy outcome after exposure to antidepressants and the
role of maternal depression: results from the Norwegian mother and child
cohort study. J Clin Psychopharmacol 2012;32(2):186–194. [Cohort study,
II-2]
72. Lassen D, Ennis ZN, Damkier P. First-trimester pregnancy exposure to venla-
faxine or duloxetine and risk of major congenital malformations: a systematic
review. Basic Clin Pharmacol Toxicol 2016;118(1):32–36. [Review, III]
73. Furu K, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibi-
tors and venlafaxine in early pregnancy and risk of birth defects: popula-
tion based cohort study and sibling design. BMJ 2015;350:h1798. [Cohort
study, II-2]
74. Ban L, Gibson JE, West J, et al. Maternal depression, antidepressant pre-
scriptions, and congenital anomaly risk in offspring: a population-based
cohort study. BJOG 2014;121(12):1471–1481. [Cohort study, II-2]
75. Gao S-Y, Wu Q-J, Sun C, et al. Selective serotonin reuptake inhibitor use
during early pregnancy and congenital malformations: a systematic review
and meta-analysis of cohort studies of more than 9 million births. BMC
Med 2018;16(1):205. [Review of cohort studies, II-2]
76. Fitton CA, Steiner MFC, Aucott L, et al. In utero exposure to antidepres-
sant medication and neonatal and child outcomes: a systematic review. Acta
Psychiatr Scand 2020;141(1):21–33. [Review, III]
77. Gentile S. Early pregnancy exposure to selective serotonin reuptake inhibi-
tors, risks of major structural malformations, and hypothesized teratogenic
mechanisms. Expert Opin Drug Metab Toxicol 2015;11(10):1585–1597.
[Expert guidance, III]
78. Bérard A, Zhao J-P, Sheehy O. Antidepressant use during pregnancy and the
risk of major congenital malformations in a cohort of depressed pregnant
women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open
2017;7(1):e013372. [Cohort study, II-2]
79. Anderson KN, Lind JN, Simeone RM, et al. Maternal use of specific antide-
pressant medications during early pregnancy and the risk of selected birth
defects. JAMA Psychiatry 2020;1246–1255 [Case-control study, II-2]
80. Myles N, Newall H, Ward H, Large M. Systematic meta-analysis of indi-
vidual selective serotonin reuptake inhibitor medications and congenital
malformations. Aust N Z J Psychiatry 2013;47(11):1002–1012. [Review, III]
81. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA, National Birth
Defects Prevention Study. Specific SSRIs and birth defects: Bayesian
analysis to interpret new data in the context of previous reports. BMJ
2015;351:h3190. [Review, III]
82. Huybrechts KF, Bateman BT, Pawar A, et al. Maternal and fetal out-
comes following exposure to duloxetine in pregnancy: cohort study. BMJ
2020;368:m237. [Cohort, II-2]
83. Richardson JL, Martin F, Dunstan H, et al. Pregnancy outcomes following
maternal venlafaxine use: A prospective observational comparative cohort
study. Reprod Toxicol 2019;84:108–113. [Cohort, II-2]
84. Smit M, Dolman KM, Honig A. Mirtazapine in pregnancy and lactation
- A systematic review. Eur Neuropsychopharmacol 2016;26(1):126–135.
[Review, III]
85. Winterfeld U, Klinger G, Panchaud A, et al. Pregnancy outcome following
maternal exposure to mirtazapine: a multicenter, prospective study. J Clin
Psychopharmacol 2015;35(3):250–259. [Cohort, II-2]
86. Hendrick V, Suri R, Gitlin MJ, Ortiz-Portillo E. Bupropion use during preg-
nancy: a systematic review. Prim Care Companion CNS Disord 2017;19(5).
[Review, III]
87. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression
during pregnancy: a report from the American Psychiatric Association
and the American College of Obstetricians and Gynecologists. Gen Hosp
Psychiatry 2009;31(5):403–413. [Review, III]
88. Chun-Fai-Chan B, Koren G, Fayez I, et al. Pregnancy outcome of women
exposed to bupropion during pregnancy: a prospective comparative study.
Am J Obstet Gynecol 2005;192(3):932–936. [Prospective case-control, II-1]
89. Cole JA, Modell JG, Haight BR, Cosmatos IS, Stoler JM, Walker AM.
Bupropion in pregnancy and the prevalence of congenital malforma-
tions. Pharmacoepidemiol Drug Saf 2007;16(5):474–484. [Retrospective
study, II-3]
90. Huang H, Coleman S, Bridge JA, Yonkers K, Katon W. A meta-analysis
of the relationship between antidepressant use in pregnancy and the
risk of preterm birth and low birth weight. Gen Hosp Psychiatry 2014
Feb;36(1):13–18. [Meta-analysis including prospective and retrospective
observational studies, II-2]
219
91. Ross LE, Grigoriadis S, Mamisashvili L, et al. Selected pregnancy and deliv-
ery outcomes after exposure to antidepressant medication: a systematic
review and meta-analysis. JAMA Psychiatry 2013;70(4):436–443. [Studies
reviewed are largely cohort studies, II-2]
92. Huybrechts KF, Sanghani RS, Avorn J, Urato AC. Preterm birth and antide-
pressant medication use during pregnancy: a systematic review and meta-
analysis. PLOS ONE 2014;9(3):e92778. [Analysis of largely prospective and
retrospective cohort studies, II-2]
93. Chang Q, Ma X-Y, Xu X-R, Su H, Wu Q-J, Zhao Y-H. Antidepressant use in
depressed women during pregnancy and the risk of preterm birth: a sys-
tematic review and meta-analysis of 23 cohort studies. Front Pharmacol
2020;11:659. [Review of cohort studies, II-2]
94. Eke AC, Saccone G, Berghella V. Selective serotonin reuptake inhibitor
(SSRI) use during pregnancy and risk of preterm birth: a systematic review
and meta-analysis. BJOG 2016;123(12):1900–1907. [Review, III]
95. Sujan AC, Rickert ME, Öberg AS, et al. Associations of maternal antide-
pressant use during the first trimester of pregnancy with preterm birth,
small for gestational age, autism spectrum disorder, and attention-def-
icit/hyperactivity disorder in offspring. JAMA 2017;317(15):1553–1562.
[Retrospective cohort study, II-2]
96. Mitchell J, Goodman J. Comparative effects of antidepressant medica-
tions and untreated major depression on pregnancy outcomes: a systematic
review. Arch Womens Ment Health 2018;21(5):505–516. [Review, III]
97. Nakhai-Pour HR, Broy P, Bérard A. Use of antidepressants during preg-
nancy and the risk of spontaneous abortion. CMAJ 2010;182(10):1031–1037.
[Case-control, II-2]
98. Wu P, Velez Edwards DR, Gorrindo P, et al. Association between first trimes-
ter antidepressant use and risk of spontaneous abortion. Pharmacotherapy
2019;39(9):889–898. [Cohort, II-2]
99. Kjaersgaard MIS, Parner ET, Vestergaard M, et al. Prenatal antidepressant
exposure and risk of spontaneous abortion – a population-based study.
PLOS ONE 2013;8(8):e72095. [II-2]
100. Grigoriadis S, Vonderporten EH, Mamisashvili L, et al. Prenatal exposure
to antidepressants and persistent pulmonary hypertension of the newborn:
systematic review and meta-analysis. BMJ 2014;348:f6932. [Analysis of
cohort and case-control studies, II-2]
101. ‘t Jong GW, Einarson T, Koren G, Einarson A. Antidepressant use in preg-
nancy and persistent pulmonary hypertension of the newborn (PPHN): a
systematic review. Reprod Toxicol 2012;34(3):293–297. [Review, III]
102. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-
reuptake inhibitors and risk of persistent pulmonary hypertension of the
newborn. N Engl J Med 2006;354(6):579–587. [Retrospective cohort - con-
trol, II-2]
103. Masarwa R, Bar-Oz B, Gorelik E, Reif S, Perlman A, Matok I. Prenatal expo-
sure to selective serotonin reuptake inhibitors and serotonin norepineph-
rine reuptake inhibitors and risk for persistent pulmonary hypertension of
the newborn: a systematic review, meta-analysis, and network meta-analysis.
Am J Obstet Gynecol 2019;220(1):57.e1–57.e13. [Review, III]
104. Wilson KL, Zelig CM, Harvey JP, Cunningham BS, Dolinsky BM,
Napolitano PG. Persistent pulmonary hypertension of the newborn is
associated with mode of delivery and not with maternal use of selec-
tive serotonin reuptake inhibitors. Am J Perinatol 2011 Jan;28(1):19–24.
[Case-control study, II-2]
105. Wichman CL, Moore KM, Lang TR, St Sauver JL, Heise RH, Watson
WJ. Congenital heart disease associated with selective serotonin reup-
take inhibitor use during pregnancy. Mayo Clin Proc 2009;84(1):23–27.
[Retrospective study, n = 808 and 24,406 controls, II-2]
106. Andrade SE, McPhillips H, Loren D, et al. Antidepressant medica-
tion use and risk of persistent pulmonary hypertension of the newborn.
Pharmacoepidemiol Drug Saf 2009;18(3):246–252. [Retrospective cohort-
control study, n = 1104 and 1104 controls, II-2]
107. Occhiogrosso M, Omran SS, Altemus M. Persistent pulmonary hyper-
tension of the newborn and selective serotonin reuptake inhibitors:
lessons from clinical and translational studies. Am J Psychiatry 2012
Feb;169(2):134–140. [Review, III]
108. Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use in pregnancy:
a critical review focused on risks and controversies. Acta Psychiatr Scand
2013 Feb;127(2):94–114. [Review, III]
109. Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. The effect of pre-
natal antidepressant exposure on neonatal adaptation: a systematic review
and meta-analysis. J Clin Psychiatry 2013;74(4):e309–320. [Review of
cohort and case-control studies, II-2]
110. Youash S, Sharma V. Depression, antidepressants and hypertensive disor-
ders of pregnancy: A systematic review. Curr Drug Saf 2019;14(2):102–108.
[Review, III]
220
111. Bernard N, Forest J-C, Tarabulsy GM, Bujold E, Bouvier D, Giguère Y.
Use of antidepressants and anxiolytics in early pregnancy and the risk of
pre-eclampsia and gestational hypertension: a prospective study. BMC
Pregnancy Childbirth 2019;19(1):146. [Prospective cohort, II-2]
112. Palmsten K, Hernández-Díaz S, Huybrechts KF, et al. Use of antidepres-
sants near delivery and risk of postpartum hemorrhage: cohort study of low
income women in the United States. BMJ 2013;347:f4877. [Cohort, II-2]
113. Grzeskowiak LE, McBain R, Dekker GA, Clifton VL. Antidepressant use in
late gestation and risk of postpartum haemorrhage: a retrospective cohort
study. BJOG 2016;123(12):1929–1936. [Cohort, II-2]
114. Ford JB, Morris JM. Peripartum antidepressant use is associated with an
increased risk of postpartum haemorrhage. Evid Based Med 2014;19(2):79.
[Cohort, II-2]
115. Hanley GE, Smolina K, Mintzes B, Oberlander TF, Morgan SG. Postpartum
hemorrhage and use of serotonin reuptake inhibitor antidepressants in
pregnancy. Obstet Gynecol 2016;127(3):553–561. [Cohort, II-2]
116. Heerdink ER. Antidepressants and postpartum haemorrhage. BMJ
2013;347:f5194. [Expert opinion, III]
117. Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental
depression, maternal antidepressant use during pregnancy, and risk of
autism spectrum disorders: population based case-control study. BMJ
2013;346:f2059. [Case-control, II-2]
118. Morales DR, Slattery J, Evans S, Kurz X. Antidepressant use during preg-
nancy and risk of autism spectrum disorder and attention deficit hyperactiv-
ity disorder: systematic review of observational studies and methodological
considerations. BMC Med 2018;16(1):6. [Review, III]
119. Kaplan YC, Keskin-Arslan E, Acar S, Sozmen K. Prenatal selective serotonin
reuptake inhibitor use and the risk of autism spectrum disorder in children:
A systematic review and meta-analysis. Reprod Toxicol 2016;66:31–43.
[Review, III]
120. Brown HK, Ray JG, Wilton AS, Lunsky Y, Gomes T, Vigod SN. Association
between serotonergic antidepressant use during pregnancy and
autism spectrum disorder in children. JAMA 2017;317(15):1544–1552.
[Retrospective cohort study, II-2]
121. Kim JY, Son MJ, Son CY, Radua J, Eisenhut M, Gressier F, et al.
Environmental risk factors and biomarkers for autism spectrum disorder:
an umbrella review of the evidence. Lancet Psychiatry 2019;6(7):590–600.
[Review, III]
122. Halvorsen A, Hesel B, Østergaard SD, Danielsen AA. In utero exposure
to selective serotonin reuptake inhibitors and development of mental
disorders: a systematic review and meta-analysis. Acta Psychiatr Scand
2019;139(6):493–507. [Review, III]
123. Kobayashi T, Matsuyama T, Takeuchi M, Ito S. Autism spectrum disorder
and prenatal exposure to selective serotonin reuptake inhibitors: a system-
atic review and meta-analysis. Reprod Toxicol 2016;65:170–178. [Review,
III]
124. Rommel A-S, Bergink V, Liu X, Munk-Olsen T, Molenaar NM. Long-term
effects of intrauterine exposure to antidepressants on physical, neurodevel-
opmental, and psychiatric outcomes: a systematic review. J Clin Psychiatry
2020;81(3). [Review, III]
125. Sørensen MJ, Grønborg TK, Christensen J, et al. Antidepressant expo-
sure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol
2013;5:449–459. [Cohort study, II-2]
126. Araujo JSA de, Delgado IF, Paumgartten FJR. Antenatal exposure to antide-
pressant drugs and the risk of neurodevelopmental and psychiatric disor-
ders: a systematic review. Cad Saude Publica 2020 Jan 31;36(2):e00026619.
[Review, III]
127. Prady SL, Hanlon I, Fraser LK, Mikocka-Walus A. A systematic review
of maternal antidepressant use in pregnancy and short- and long-term
offspring’s outcomes. Arch Womens Ment Health 2018;21(2):127–140.
[Review, III]
128. Zheng W, Cai D-B, Zheng W, et al. Brexanolone for postpartum depres-
sion: a meta-analysis of randomized controlled studies. Psychiatry Res
2019;279:83–89. [Review of three RCTs, I]
129. Kanes SJ, Colquhoun H, Doherty J, et al. Open-label, proof-of-concept
study of brexanolone in the treatment of severe postpartum depression.
Hum Psychopharmacol 2017;32(2): e2576. [Proof of concept, open label
study, II-2]
130. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547
injection) in post-partum depression: a randomised controlled trial. Lancet
2017;390(10093):480–489. [RCT, I]
131. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection
in post-partum depression: two multicentre, double-blind, randomised,
placebo-controlled, phase 3 trials. Lancet 2018;392(10152):1058–1070.
[RCT, I]
Maternal-Fetal Evidence Based Guidelines
132. Brexanolone (zulresso) for postpartum depression. JAMA. 2019 July
2;322(1):73–74. [Committee report, III]
133. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR.
Lithium toxicity profile: a systematic review and meta-analysis. Lancet
2012;379(9817):721–728. [Review and analysis of seven cohort studies,
seven case-control studies, and 48 case reports, II-2]
134. Fornaro M, Maritan E, Ferranti R, et al. Lithium exposure during preg-
nancy and the postpartum period: a systematic review and meta-analysis of
safety and efficacy outcomes. Am J Psychiatry 2020 January 1;177(1):76–92.
[Review, III]
135. Patorno E, Huybrechts KF, Bateman BT, et al. Lithium use in pregnancy and
the risk of cardiac malformations. N Engl J Med 2017;376(23):2245–2254.
[Cohort study, II-2]
136. Ornoy A, Weinstein-Fudim L, Ergaz Z. Antidepressants, antipsychotics,
and mood stabilizers in pregnancy: what do we know and how should we
treat pregnant women with depression. Birth Defects Res 2017;109(12):933–
956. [Review, III]
137. Pinelli JM, Symington AJ, Cunningham KA, Paes BA. Case report and
review of the perinatal implications of maternal lithium use. Am J Obstet
Gynecol 2002;187(1):245–249. [Review, III]
138. Hermann A, Gorun A, Benudis A. Lithium use and non-use for preg-
nant and postpartum women with bipolar disorder. Curr Psychiatry Rep
2019;21(11):114. [Review, III]
139. Viguera AC, Whitfield T, Baldessarini RJ, et al. Risk of recurrence in women
with bipolar disorder during pregnancy: prospective study of mood stabi-
lizer discontinuation. Am J Psychiatry 2007;164(12):1817–1824; quiz 1923.
[Prospective cohort, n = 89, II-2]
140. Ornoy A. Valproic acid in pregnancy: how much are we endangering the
embryo and fetus? Reprod Toxicol 2009;28(1):1–10. [Review, III]
141. Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy
in pregnancy: congenital malformation outcomes in the child. Cochrane
Database Syst Rev 2016;11:CD010224. [Review, III]
142. Andrade C. Valproate in pregnancy: recent research and regulatory
responses. J Clin Psychiatry 2018;79(3). [Review, III]
143. Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate expo-
sure and risk of autism spectrum disorders and childhood autism. JAMA
2013;309(16):1696–1703. [Cohort study, II-2]
144. Veroniki AA, Rios P, Cogo E, et al. Comparative safety of antiepileptic drugs
for neurological development in children exposed during pregnancy and
breast feeding: a systematic review and network meta-analysis. BMJ Open
2017;7(7):e017248. [Review, III]
145. Blotière P-O, Miranda S, Weill A, et al. Risk of early neurodevelopmental
outcomes associated with prenatal exposure to the antiepileptic drugs most
commonly used during pregnancy: a French nationwide population-based
cohort study. BMJ Open 2020;10(6):e034829. [Cohort study, II-2]
146. U.S. Food and Drug Administration. FDA Drug Safety Communication:
Valproate Anti-seizure Products Contraindicated for Migraine Prevention
in Pregnant Women due to Decreased IQ Scores in Exposed Children |
FDA [Internet]. [cited 2020 Oct 4]. Available from: https://www.fda.gov/
drugs/drug-safety-and-availability/fda-drug-safety-communication-
valproate-anti-seizure-products-contraindicated-migraine-prevention
[Committee report, III]
147. European Medicines Agency. Valproate and related substances | European
Medicines Agency [Internet]. [cited 2020 Oct 4]. Available from: https://
www.ema.europa.eu/en/medicines/human/referrals/valproate-related-
substances-0 [Committee report, III]
148. Andrade C. Major congenital malformations associated with exposure to
antiepileptic drugs during pregnancy. J Clin Psychiatry 2018;79(4). [Expert
opinion, III]
149. Campbell E, Kennedy F, Russell A, et al. Malformation risks of antiepilep-
tic drug monotherapies in pregnancy: updated results from the UK and
Ireland epilepsy and pregnancy registers. J Neurol Neurosurg Psychiatr
2014;85(9):1029–1034. [Prospective observational study, II-2]
150. Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major con-
genital malformations with eight different antiepileptic drugs: a prospec-
tive cohort study of the EURAP registry. Lancet Neurol 2018;17(6):530–538.
[Prospective cohort study, II-2]
151. Battino D, Tomson T. Management of epilepsy during pregnancy. Drugs
2007;67(18):2727–2746. [Review, III]
152. Holmes LB, Baldwin EJ, Smith CR, et al. Increased frequency of isolated
cleft palate in infants exposed to lamotrigine during pregnancy. Neurology
2008;70(22 Pt 2):2152–2158. [Prospective cohort, II-2]
153. Pariente G, Leibson T, Shulman T, Adams-Webber T, Barzilay E, Nulman I.
Pregnancy outcomes following in utero exposure to lamotrigine: a system-
atic review and meta-analysis. CNS Drugs 2017;31(6):439–450. [Review, III]
Mood Disorders
154. Haskey C, Galbally M. Mood stabilizers in pregnancy and child developmen-
tal outcomes: A systematic review. Aust N Z J Psychiatry 2017;51(11):1087–
1097. [Review, III]
155. Sabers A. Algorithm for lamotrigine dose adjustment before, during, and
after pregnancy. Acta Neurol Scand 2012;126(1):e1–4. [Expert recommen-
dation, III]
156. de Haan GJ, Edelbroek P, Segers J, et al. Gestation-induced changes
in lamotrigine pharmacokinetics: a monotherapy study. Neurology
2004;63(3):571–573. [Case series, n = 12, II-3]
157. Huybrechts KF, Hernández-Díaz S, Patorno E, et al. Antipsychotic use in
pregnancy and the risk for congenital malformations. JAMA Psychiatry
2016;73(9):938–946. [Cohort study, II-2]
158. Damkier P, Videbech P. The safety of second-generation antipsychotics dur-
ing pregnancy: a clinically focused review. CNS Drugs 2018;32(4):351–366.
[Review, III]
159. Newport DJ, Calamaras MR, DeVane CL, et al. Atypical antipsychotic
administration during late pregnancy: placental passage and obstetrical
outcomes. Am J Psychiatry 2007;164(8):1214–1220. [Prospective observa-
tional study, II-2]
160. Poels EMP, Schrijver L, Kamperman AM, et al. Long-term neurodevelop-
mental consequences of intrauterine exposure to lithium and antipsychot-
ics: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry
2018;27(9):1209–1230. [Review, III]
161. Uguz F. Antipsychotic use during pregnancy and the risk of gesta-
tional diabetes mellitus: A systematic review. J Clin Psychopharmacol
2019;39(2):162–167. [Review, III]
162. Vancampfort D, Mitchell AJ, De Hert M, et al. Prevalence and predictors of
type 2 diabetes mellitus in people with bipolar disorder: a systematic review
and meta-analysis. J Clin Psychiatry 2015;76(11):1409–1490. [Review, III]
163. Xu Y, Li Y, Huang X, Chen D, She B, Ma D. Single bolus low-dose of ket-
amine does not prevent postpartum depression: a randomized, double-
blind, placebo-controlled, prospective clinical trial. Arch Gynecol Obstet
2017;295(5):1167–1174. [RCT, I]
164. Ma J-H, Wang S-Y, Yu H-Y, et al. Prophylactic use of ketamine reduces
postpartum depression in Chinese women undergoing cesarean section☆.
Psychiatry Res 2019;279:252–258. [RCT, I]
165. Li C, Sun X, Li Q, Sun Q, Wu B, Duan D. Role of psychotherapy on antenatal
depression, anxiety, and maternal quality of life: a meta-analysis. Medicine
(Baltimore) 2020;99(27):e20947. [Review, III]
166. Peñalver Bernabé B, Maki PM, Dowty SM, et al. Precision medicine in peri-
natal depression in light of the human microbiome. Psychopharmacology
(Berl) 2020;237(4):915–941. [Review, III]
167. Li Z, Liu Y, Wang J, Liu J, Zhang C, Liu Y. Effectiveness of cognitive behav-
ioural therapy for perinatal depression: a systematic review and meta-anal-
ysis. J Clin Nurs 2020;29(17–18):3170–3182. [Review, III]
168. Huang L, Zhao Y, Qiang C, Fan B. Is cognitive behavioral therapy a bet-
ter choice for women with postnatal depression? A systematic review and
meta-analysis. PLOS ONE 2018;13(10):e0205243. [Review, III]
169. Nillni YI, Mehralizade A, Mayer L, Milanovic S. Treatment of depression,
anxiety, and trauma-related disorders during the perinatal period: a sys-
tematic review. Clin Psychol Rev 2018;66:136–148. [Review, III]
170. Nguyen J. A literature review of alternative therapies for postpartum
depression. Nurs Womens Health 2017;21(5):348–359. [Review, III]
171. Sockol LE. A systematic review and meta-analysis of interpersonal psycho-
therapy for perinatal women. J Affect Disord 2018;232:316–328. [Review,
III]
172. Sockol LE, Epperson CN, Barber JP. A meta-analysis of treatments for peri-
natal depression. Clin Psychol Rev 2011;31(5):839–849. [Review, III]
173. Lau Y, Htun TP, Wong SN, Tam WSW, Klainin-Yobas P. Therapist-
supported internet-based cognitive behavior therapy for stress, anxiety, and
depressive symptoms among postpartum women: a systematic review and
meta-analysis. J Med Internet Res 2017;19(4):e138. [Review, III]
174. Roman M, Constantin T, Bostan CM. The efficiency of online cognitive-
behavioral therapy for postpartum depressive symptomatology: a system-
atic review and meta-analysis. Women Health 2020;60(1):99–112. [Review,
III]
175. Stamou G, García-Palacios A, Botella C. Cognitive-behavioural therapy and
interpersonal psychotherapy for the treatment of post-natal depression: a
narrative review. BMC Psychol 2018;6(1):28. [Review, III]
176. Johansen SL, Robakis TK, Williams KE, Rasgon NL. Management of peri-
natal depression with non-drug interventions. BMJ 2019;364:l322. [Review,
III]
177. Kołomańska-Bogucka D, Mazur-Bialy AI. Physical activity and the occur-
rence of postnatal depression-a systematic review. Medicina (Kaunas)
2019;55(9): 560. [Review, III]
221
178. Nakamura A, van der Waerden J, Melchior M, Bolze C, El-Khoury F,
Pryor L. Physical activity during pregnancy and postpartum depression:
Systematic review and meta-analysis. J Affect Disord 2019;246:29–41.
[Review, III]
179. Dipietro L, Evenson KR, Bloodgood B, Sprow K, Troiano RP, Piercy
KL, et al. Benefits of physical activity during pregnancy and postpar-
tum: an umbrella review. Med Sci Sports Exerc 2019;51(6):1292–1302.
[Review, III]
180. Pritchett RV, Daley AJ, Jolly K. Does aerobic exercise reduce postpartum
depressive symptoms? a systematic review and meta-analysis. Br J Gen
Pract 2017;67(663):e684–691. [Review, III]
181. McCurdy AP, Boulé NG, Sivak A, Davenport MH. Effects of exercise on
mild-to-moderate depressive symptoms in the postpartum period: a meta-
analysis. Obstet Gynecol 2017;129(6):1087–1097. [Review, III]
182. Kołomańska D, Zarawski M, Mazur-Bialy A. Physical activity and depres-
sive disorders in pregnant women-a systematic review. Medicina (Kaunas)
2019;55(5): 212. [Review, III]
183. Poyatos-León R, García-Hermoso A, Sanabria-Martínez G, Álvarez-Bueno
C, Cavero-Redondo I, Martínez-Vizcaíno V. Effects of exercise-based inter-
ventions on postpartum depression: A meta-analysis of randomized con-
trolled trials. Birth 2017;44(3):200–208. [Review, III]
184. Eustis EH, Ernst S, Sutton K, Battle CL. Innovations in the treatment of
perinatal depression: the role of yoga and physical activity interventions
during pregnancy and postpartum. Curr Psychiatry Rep 2019;21(12):133.
[Review, III]
185. Kwon R, Kasper K, London S, Haas DM. A systematic review: The effects
of yoga on pregnancy. Eur J Obstet Gynecol Reprod Biol 2020;250:171–177.
[Review, III]
186. Gómez-Sánchez L, García-Banda G, Servera M, Verd S, Filgueira A, Cardo
E. [Benefits of mindfulness in pregnant women]. Medicina (B Aires) 2020;80
Suppl 2:47–52. [Review, III]
187. Physical activity and exercise during pregnancy and the postpartum period:
ACOG Committee Opinion, No. 804. Obstet Gynecol 2020;135(4):e178–
188. [Committee report, III]
188. Current Guidelines | health.gov [Internet]. [cited 2020 Oct 15]. Available
from: https://health.gov/our-work/physical-activity/current-guidelines
[Committee guidelines, III]
189. Silva DFO, Cobucci RN, Gonçalves AK, Lima SCVC. Systematic review of
the association between dietary patterns and perinatal anxiety and depres-
sion. BMC Pregnancy Childbirth 2019;19(1):212. [Review, III]
190. Opie RS, Uldrich AC, Ball K. Maternal postpartum diet and postpartum
depression: a systematic review. Matern Child Health J 2020;24(8):966–978.
[Review, III]
191. Khan R, Waqas A, Bilal A, Mustehsan ZH, Omar J, Rahman A. Association
of maternal depression with diet: a systematic review. Asian J Psychiatr
2020;52:102098. [Review, III]
192. Ward HB, Fromson JA, Cooper JJ, De Oliveira G, Almeida M.
Recommendations for the use of ECT in pregnancy: literature review and
proposed clinical protocol. Arch Womens Ment Health 2018;21(6):715–
722. [Review, III]
193. Clark CT, Wisner KL. Treatment of peripartum bipolar disorder. Obstet
Gynecol Clin North Am 2018;45(3):403–417. [Review, III]
194. Tess A, Smetana GW. Medical consultation for electroconvulsive therapy.
UpToDate 2021. [III]
195. Klomjai W, Katz R, Lackmy-Vallée A. Basic principles of transcranial mag-
netic stimulation (TMS) and repetitive TMS (rTMS). Ann Phys Rehabil
Med 2015;58(4):208–213. [Review, III]
196. Cole J, Bright K, Gagnon L, McGirr A. A systematic review of the safety
and effectiveness of repetitive transcranial magnetic stimulation in the
treatment of peripartum depression. J Psychiatr Res 2019;115:142–150.
Review, III]
197. Peng L, Fu C, Xiong F, et al. Effects of repetitive transcranial magnetic stim-
ulation on depression symptoms and cognitive function in treating patients
with postpartum depression: a systematic review and meta-analysis of
randomized controlled trials. Psychiatry Res 2020;290:113124. [Review of
RCTs, I]
198. Ganho-Ávila A, Poleszczyk A, Mohamed MMA, Osório A. Efficacy of
rTMS in decreasing postnatal depression symptoms: a systematic review.
Psychiatry Res 2019;279:315–322. Review, III]
199. Eberhard-Gran M, Eskild A, Opjordsmoen S. Use of psychotropic medica-
tions in treating mood disorders during lactation: practical recommenda-
tions. CNS Drugs 2006;20(3):187–198. [Review, III]
200. den Besten-Bertholee D, van der Meer DH, Ter Horst PGJ. Quality of lacta-
tion studies investigating antidepressants. Breastfeed Med 2019;14(6):359–
365. [Review, III]
222
201. Orsolini L, Bellantuono C. Serotonin reuptake inhibitors and breastfeed-
ing: a systematic review. Hum Psychopharmacol 2015 Jan;30(1):4–20.
[Review, III]
202. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepres-
sant levels in lactating mothers, breast milk, and nursing infants. Am J
Psychiatry 2004;161(6):1066–1078. [Meta-analysis, II-2]
203. Hale TW, Kendall-Tackett K, Cong Z, Votta R, McCurdy F. Discontinuation
syndrome in newborns whose mothers took antidepressants while pregnant
or breastfeeding. Breastfeed Med 2010;5(6):283–288. [Cohort study, II-2]
204. Rowe H, Baker T, Hale TW. Maternal medication, drug use, and breastfeed-
ing. Child Adolesc Psychiatr Clin N Am 2015 Jan;24(1):1–20. [Review, III]
205. Schoretsanitis G, Augustin M, Saßmannshausen H, Franz C, Gründer G,
Paulzen M. Antidepressants in breast milk; comparative analysis of excre-
tion ratios. Arch Womens Ment Health 2019;22(3):383–390. [Cohort, II-2]
206. Davanzo R, Copertino M, De Cunto A, Minen F, Amaddeo A. Antidepressant
drugs and breastfeeding: a review of the literature. Breastfeed Med
2011;6(2):89–98. [Review, III]
207. Sachs HC, Committee on drugs. The transfer of drugs and therapeu-
tics into human breast milk: an update on selected topics. Pediatrics
2013;132(3):e796–809. [Committee report, III]
208. Schou M, Amdisen A. Lithium and pregnancy. 3. Lithium inges-
tion by children breast-fed by women on lithium treatment. Br Med J
1973;2(5859):138. [II-3]
209. Pacchiarotti I, León-Caballero J, Murru A, et al. Mood stabilizers and
antipsychotics during breastfeeding: Focus on bipolar disorder. Eur
Neuropsychopharmacol 2016;26(10):1562–1578. [Review, III]
210. Meador KJ, Baker GA, Browning N, et al. Effects of breastfeeding in chil-
dren of women taking antiepileptic drugs. Neurology 2010;75(22):1954–
1960. [Prospective case-control study, II-2]
211. Meador KJ. Breastfeeding and antiepileptic drugs. JAMA 2014;311(17):1797–
1798. [Prospective cohort study, II-2]
212. Stahl MM, Neiderud J, Vinge E. Thrombocytopenic purpura and anemia in
a breast-fed infant whose mother was treated with valproic acid. J Pediatr
1997;130(6):1001–1003. [II-3]
213. Anderson PO. Antiepileptic drugs during breastfeeding. Breastfeed Med
2020;15(1):2–4. [Review, III]
214. Birnbaum AK, Meador KJ, Karanam A, et al. Antiepileptic drug expo-
sure in infants of breastfeeding mothers with epilepsy. JAMA Neurol
2020;77(4):441–450. [Prospective cohort study, II-2]
215. Frey B, Schubiger G, Musy JP. Transient cholestatic hepatitis in a neonate
associated with carbamazepine exposure during pregnancy and breast-
feeding. Eur J Pediatr 1990;150(2):136–138. [II-3]
216. Frey B, Braegger CP, Ghelfi D. Neonatal cholestatic hepatitis from carbam-
azepine exposure during pregnancy and breast feeding. Ann Pharmacother
2002;36(4):644–647. [II-3]
Maternal-Fetal Evidence Based Guidelines
217. Dalili H, Nayeri F, Shariat M, Asgarzadeh L. Lamotrigine effects on breast-
fed infants. Acta Med Iran. 2015;53(7):393–394. [Review, III]
218. Meador KJ, Baker GA, Browning N, et al. Breastfeeding in children of
women taking antiepileptic drugs: cognitive outcomes at age 6 years. JAMA
Pediatr 2014;168(8):729–736. [Prospective cohort study, II-2]
219. Yazdani-Brojeni P, Tanoshima R, Taguchi N, et al. Quetiapine excretion
into human breast milk. J Clin Psychopharmacol 2018;38(4):362–364.
[Prospective cohort study, II-2]
220. Sprague J, Wisner KL, Bogen DL. Pharmacotherapy for depression and
bipolar disorder during lactation: A framework to aid decision making.
Semin Perinatol 2020;44(3):151224. [Review, III]
221. Cuomo A, Goracci A, Fagiolini A. Aripiprazole use during pregnancy, peri-
partum and lactation. A systematic literature search and review to inform
clinical practice. J Affect Disord 2018;228:229–237. [Review, III]
222. Werremeyer A. Ziprasidone and citalopram use in pregnancy and
lactation in a woman with psychotic depression. Am J Psychiatry
2009;166(11):1298. [II-3]
223. Barnas C, Bergant A, Hummer M, Saria A, Fleischhacker WW. Clozapine
concentrations in maternal and fetal plasma, amniotic fluid, and breast
milk. Am J Psychiatry 1994;151(6):945. [Case report, II-3]
224. Mendhekar DN. Possible delayed speech acquisition with clozapine ther-
apy during pregnancy and lactation. J Neuropsychiatry Clin Neurosci
2007;19(2):196–197. [Case report, II-3]
225. Gentile S. Infant safety with antipsychotic therapy in breast-feeding: a sys-
tematic review. J Clin Psychiatry 2008;69(4):666–673. [Review, III]
226. Mehta TM, Van Lieshout RJ. A review of the safety of clozapine during
pregnancy and lactation. Arch Womens Ment Health 2017;20(1):1–9. [Case
report, II-3]
227. Drugs and Lactation Database (LactMed) [Internet]. 2006 [cited
2020 Oct 22]. Available from: https://www.ncbi.nlm.nih.gov/books/
NBK501922/#IX-S [Expert guidelines, III]
228. Einarson A, Bonari L, Voyer-Lavigne S, et al. A multicentre prospective
controlled study to determine the safety of trazodone and nefazodone use
during pregnancy. Can J Psychiatry 2003;48(2):106–110. [Controlled trial,
II-1]
229. Ornoy A. Pharmacological treatment of attention deficit hyperactivity dis-
order during pregnancy and lactation. Pharm Res 2018;35(3):46. [Review,
III]
230. Association of Women’s Health, Obstetric and Neonatal Nurses. Maternal
and newborn safety during the administration of brexanolone: AWHONN
practice brief number 10. Nurs Womens Health 2020;24(6):468–469.
[Committee report, III]
231. Frieder A, Fersh M, Hainline R, Deligiannidis KM. Pharmacotherapy of
postpartum depression: current approaches and novel drug development.
CNS Drugs 2019;33(3):265–82. [Review, III]
22
SMOKING
Jorge E. Tolosa, Niyazi Kilic, and David M. Stamilio
Key points
• Smoking is the most significant preventable risk factor
associated with low birth weight, preterm birth, perinatal
death, and other perinatal and maternal complications.
• Smoking cessation in pregnancy reduces the incidences
of low birth weight, preterm birth, and perinatal death.
• Comprehensive screening for women who smoke in
pregnancy is necessary by asking if she smokes; if no,
you need to ask if she smoked in the last year; if no, ask
if she uses electronic cigarettes (vaping), or other forms
of nicotine use such as hookahs, snus, lozenges, chew-
ing gum, or skin patches. If the answer to any of these
three questions is yes, counseling and intervention are
necessary.
• Counseling with behavioral and educational interven-
tions is associated with the highest cessation rates
(Tables 22.1–22.4).
• Pharmacotherapies are either contraindicated, or their
safety and efficacy is insufficiently studied in pregnancy.
• Nicotine replacement therapies are safe and effective in
the general population, but there is insufficient evidence
for recommending them in pregnant smokers.
• Nicotine replacement therapy is associated with known
adverse fetal effects.
• The greatest risk of relapse occurs in the postpartum
period.
• There is insufficient evidence to recommend specific
interventions to prevent relapse in pregnant and post-
partum women.
Historic notes
The twentieth century saw the rise of the manufactured cigarette
and its popularity grew [1]. People continue to smoke despite
known adverse effects [1].
Diagnosis/Definition
Tobacco dependence is a chronic addictive condition that requires
repeated intervention for cessation.
Epidemiology/Incidence
Approximately 176 million adult women are daily smokers world-
wide with the majority living in high income countries. There is
a very concerning trend towards increased rates of tobacco use,
smoked and smokeless, in low- and middle-income countries
[1]. In 2019 in the United States, nearly 13 of every 100 adult
women smoked [2]. The incidence of smoking in pregnancy in
the United States was 7.2% in 2016 a reduction from 12.3% in 2010
[3]. Estimated smoking rates during pregnancy among reproduc-
tive age women vary in different countries from 0.1–50% [4].
DOI: 10.1201/9781003099062-22
By race, the highest prevalence of smoking occurs among those
reporting multiple races and being white. The lowest prevalence
occurs among Hispanics and Asian Pacific Islander women [5].
Women are more likely to stop smoking in pregnancy than
in any other time in their lives [6]. Up to 46% of women who
smoke, stop smoking soon after learning about their preg-
nancy and before their first antenatal visit or during pregnancy
[7, 8]. Pregnancy can help motivate women to quit smoking. Of
those who quit smoking in pregnancy 50–60% relapse within
the first 4 months postpartum [3, 8]. Over 300 million people
around the world, the vast majority of whom live in South Asia,
use smokeless tobacco products. Its use in high income coun-
tries remains stable (not including use of vaporized nicotine deliv-
ery systems) [1]. Regional variations ranging from 6% (Congo) to
33.5% (Orissa, India) exist among low- and middle-income coun-
tries [9]. Among high-income countries, both the United States
and Sweden have seen increases in smokeless tobacco use that may
offset decreases in cigarette consumption [10, 11].
Genetics
• Maternal genotype may affect the risk of low birth weight
in cigarette smokers [12].
• The CYP1A1, CYP2A6, and GSTT1 genes encode enzymes
active in metabolism and elimination of toxic substances in
cigarette smoke [12–14].
• In women who smoked, heterozygous variants of CYP1A1
and absence of GSTT1 genes resulted in significantly
greater reductions in birth weight.
Etiology/Basic pathology
• Tobacco smoke has more than 7000 chemicals, hundreds
of which are toxic and negatively affect almost all organ
systems [1]. Nicotine and carbon monoxide are docu-
mented fetal neurotoxins and major compounds of tobacco
smoke [15].
• Other toxic compounds include: Ammonia, polycyclic aro-
matic hydrocarbons, hydrogen cyanide, vinyl chloride, and
nitrogen oxide.
• Smoking may result in damage to fetal genetic material [16].
Nicotine
• Crosses the placenta and can be detected in the fetal cir-
culation at levels that exceed maternal circulation levels by
15% [17].
• Amniotic fluid levels are 88% higher than maternal
plasma levels [17].
• Causes for impaired fetal oxygen delivery: Vasoconstriction
and changes in capillary volume and villous membrane con-
tribute to abnormal gas exchange within the placenta [18].
• Fetal central nervous system effects: Abnormalities in cell
proliferation and differentiation lead to decreased number
223
224
TABLE 22.1: Multiple-Choice Questionnaire Improves Initial
Disclosure Rates of Smoking/Tobacco/E-cigarette Use
A. I have never smoked or I have smoked less than 100 cigarettes in my
lifetime.
B. I stopped smoking before I found out I was pregnant, and I am not
smoking now.
C. I stopped smoking after I found out I was pregnant, and I am not
smoking now.
D. I smoke some now, but I cut down on the number of cigarettes I
smoke since I found out I was pregnant.
E. I smoke regularly now, about the same as before I found out I was
pregnant.
F. Do you use any other tobacco product like the e-cigarette/vaping,
hookah, mods or pods? (If yes, inquire about details as above)
If the patient responds to B or C, reinforce her decision to quit,
congratulate her on success of quitting, and encourage her to remain
smoke free.
If the patient responds to D or E, she should be classified as a smoker.
Document in the chart and proceed to the other 5As of the 5A
framework: Ask, Advise Assess, Assist, and Arrange.
Source: From McCowan LM, Dekker GA, Chan E, et al. Spontaneous preterm
birth and small for gestational age infants in women who stop smoking
early in pregnancy: prospective cohort study. BMJ 2009;338:b1081. Ref.
[41], with permission.
TABLE 22.2: The “5 Rs” for Smokers Who Are Unwilling to
Quit Smoking
1. Relevance: Motivational information to a patient is more effective if
it is relevant to a patient’s personal circumstances (i.e., smoking can
cause adverse effects in pregnancy).
2. Risks: Stress the acute and long-term risks of smoking. Try to
associate it with the patient’s current health or illnesses.
3. Rewards: Ask the patient to identify potential benefits of smoking.
4. Roadblocks: Identify barriers or impediments to quitting and note
treatment options that could address the barriers.
5. Repetition: Repeat the motivational intervention at each visit.
Source: From Ref. [23], in the public domain.
TABLE 22.3: The “5 As” for Patients Who Are Willing to Quit
Smoking
1. .Ask: Tobacco status is inquired and documented. A multiple-choice
question method (Table 22.1) improves disclosure.
2. Advise: Urge all tobacco users to quit in a clear, strong, personalized
manner. Review risks associated with continued smoking.
3. Assess: Determine the patient’s willingness to quit in the next 30
days. If unwilling, the provider should ask and advise at each
subsequent office visit.
4. Assist: Provide smoking cessation materials and provide support.
Help the patient develop a plan and provide practical counseling.
Pharmacotherapy may be considered for the general population of
smokers, although there are insufficient data on safety and efficacy in
pregnancy.
5. Arrange: Provide follow-up contact, either in person or by telephone
soon after the quit date, and further follow-up encounters as needed.
Congratulate success during each visit. Review circumstances if a
relapse occurred and use it as a learning experience for the patient.
Consider referral or more intensive treatment. Assess
pharmacotherapy use and problems.
Source: From Ref. [23], in the public domain.
Maternal-Fetal Evidence Based Guidelines
TABLE 22.4: Smoking Cessation Counseling (Skills Training
and Problem-Solving Techniques)
1. Identify activities that increase risk of smoking or relapse.
2. Explore coping skills and describe the time and nature of withdrawal.
3. Tell patients they may experience anxiety, frustration, depression,
and intense cravings for cigarettes.
4. Withdrawal symptoms become manageable in a few weeks.
5. Make lifestyle changes to reduce stress and improve quality of life.
6. Minimize time spent in the company of smokers.
7. Provide as much information to the patient as possible: Supplement
discussions with pamphlets, booklets, videos, hotlines (1-800-QUIT-
NOW), internet, or support groups (www.smokefree.gov, www.
smokefreefamilies.org).
Source: From Ref. [23], in the public domain.
of cells and eventually altered synaptic activity. Nicotine
not only affects multiple transmitter pathways and influ-
ences the development of the fetal brain, but also affects
eventual programming and synaptic competence [17].
• Studies have been focused on short-term developmen-
tal fetal effects such as sympathetic activation, leading to
increased fetal heart rate and reduction in fetal breath-
ing movement. However, animal studies suggest that
fetal exposure to nicotine alone impacts the incidence
of late-onset diseases including type II diabetes, obesity,
hypertension, neurobehavioral deficits, and respiratory
dysfunction [19].
Carbon monoxide
• Crosses the placenta rapidly and can be detected in the
fetal circulation at levels that exceed maternal circula-
tion levels by 15% [15, 17].
• Exposure causes formation of carboxyhemoglobin.
Carboxyhemoglobin is cleared slowly from the fetal cir-
culation and diminishes tissue oxygenation via competi-
tive inhibition with oxyhemoglobin. There is a left shift of
the oxyhemoglobin dissociation curve, causing decreased
availability of oxygen to the fetus [17].
• A 10% maternal carboxyhemoglobin concentration would
result in a decrease of available oxygen supply to the fetus
akin to a 60% reduction in blood flow.
Carcinogens
• More than 69 carcinogens have been identified in smoked
tobacco products, compounds that are toxic to rapidly
dividing cells.
• Levels of cyanide and at least one tobacco-specific carcino-
gen are higher in smokers [15, 17].
Risk factors
• Social disadvantage and lower education [5, 20]
• High parity
• Low levels of social support and/or being without a partner
• Exposure to domestic violence
• Having a partner that smokes or exposure to second-hand
smoke at home
• Depression, coexisting emotional/psychiatric problems,
substance abuse
• Job strain
• Poor coping skills
Smoking
• Younger maternal age
• Fear of weight gain and dissatisfaction with female body
image
Spontaneous quitters usually smoke less, are more likely to have
stopped smoking before, are more likely to have a non-smoker part-
ner or have more support and encouragement at home for quitting,
and have stronger beliefs about the dangers of smoking [6].
Complications
Smoking is the most modifiable risk factor associated with
adverse pregnancy outcomes [8, 15, 21–23].
• Congenital anomalies: There is sufficient evidence to infer
a causal relationship between maternal smoking in early
pregnancy and orofacial clefts and suggestive evidence of a
possible association with clubfoot, gastroschisis and atrial
septal defects [24].
• Low birth weight (LBW): Women who smoke are more
likely to have a low-birth weight baby (<2500 g) with rela-
tive risk (RR) of 1.3–10. The mean birth weight deficit
is 200 to 300 g by term [2]. Up to 19% of term LBW has
been attributed to smoking [25], including environmen-
tal tobacco smoke exposure in pregnancy [26]. Low birth
weight causes a substantial economic burden [3].
• Preterm birth: Women who smoke are 1.3 to 2.5 times more
likely to have a preterm delivery. It is estimated that up to
5–8% of preterm births may be attributed to smoking [25].
• Pregnancy loss: Women who smoke are 1.2 to 3.4 times
more likely to have an early pregnancy loss.
• Premature rupture of membranes (PROM): Smoking
increases PROM risk by at least 2-fold (RR of 1.9–4.2).
• Pre-eclampsia: Smoking in the second trimester of preg-
nancy is associated with a reduced incidence of pre-
eclampsia. The mechanism for the risk reduction has not
been elucidated [27].
• Placental abruption: Smoking increases the rate of abrup-
tion (RR of 1.4–2.5).
• Placenta previa: Smoking is associated with a higher rate of
placenta previa (RR of 1.4–4.4).
• Fetal death: Large case-control and cohort studies sug-
gest a fetal death RR of 1.2–1.4 associated with cigarette
smoking.
• Postnatal morbidities: Increased risk of sudden infant death
syndrome (SIDS), respiratory infections, reactive airway dis-
eases, otitis media, bronchiolitis, short stature, hyper-activ-
ity, obesity, and decreased school performance. Up to 34% of
cases of SIDS have been attributed to smoking [25].
• Smoking-caused health costs include annual expenditures
for health and developmental problems of infants and
children caused by being exposed to smoking in utero or
being exposed to second-hand smoke during pregnancy or
by children being exposed to parents smoking after birth.
Annual healthcare expenditures solely from secondhand
smoke exposure are estimated at $6.03 billion [28]. Not
included here are costs from smokeless or spit tobacco use,
adult secondhand smoke exposure, or pipe/cigar smoking.
• Maternal lifetime complications: Atherosclerotic dis-
ease, lung cancer, chronic obstructive pulmonary disease,
increased risk of ectopic pregnancy, premature menopause,
infertility, osteoporosis, among others [24].
225
Smokeless tobacco complications
Study of adverse outcomes related to use of smokeless tobacco
has been limited. One study of the Swedish Medical Birth
Registry reports an increased risk of stillbirth with an adjusted
odds ratio (OR) of 1.6 [CI 1.1–2.3] [29]. This finding had been
previously reported in India [30]. Maternal snuff use (OR 1.58;
95% CI: 1.14–2.21) has been associated with an increased risk of
extremely preterm birth [31].
Electronic cigarettes (e-cigarettes) in pregnancy
Although the prevalence of e-cigarette use has increased con-
siderably since their U.S. market introduction in 2007, cur-
rently there are very limited data on the safety and efficacy of
e-­cigarettes in pregnant patients. Electronic delivery systems
are noncombustible products, which include e-cigarettes and
vaping products, vaporizers, hookah pens, vape pens, mod or
pod systems, and e-pipes [8]. In addition to nicotine, e-cigarettes
contain nitrosamines, diethylene glycol, and variable amounts
of trace metals, including arsenic, chromium, cadmium, nickel,
and lead. Contents, including nicotine amount, of the e-cigarette
vapor vary considerably among the multitude of products [32].
• Pregnancy and maternal effects of the non-nicotine vapor
contents, including those from liquid flavorants, are
unknown.
• Although e-cigarette nicotine pregnancy effects have not
been studied, there is an abundance of animal research
that provides evidence that prenatal nicotine exposure
has deleterious effects to offspring, including lung disease,
central nervous system abnormalities that produce adverse
cognitive and neurologic outcomes, stress-induced cardiac
defects, high blood pressure, and reduced fertility [32].
• In non-pregnant patients there are limited observational
data and one clinical trial, indicating that e-cigarettes may
assist in reducing cravings and the number of cigarettes
smoked per day, but efficacy has not been studied in preg-
nant patients [33–35].
• Misconceptions about e-cigarettes are common among
pregnant women, including a belief (in 43%) that e-cigarettes
are safer to the fetus than traditional cigarettes. These mis-
conceptions could pose risks to both maternal and child
health [36].
• Approximately two thirds of adults who use e-cigarettes
continue smoking cigarettes, known as dual use [8]. These
data support a recommendation for asking specifically
if the pregnant woman who reports smoking now, or not
smoking now or in the last year, is using the e-cigarette or
vaping.
• A survey indicates that misconceptions exist among
obstetric providers, with 29% responding that e-cigarettes
are safer than traditional cigarettes and 14% reporting that
e-cigarettes have no adverse health effects [37].
• The U.S. Centers for Disease Control and Prevention
(CDC) recently issued an advisory notice about a multi-
state outbreak of non-infectious severe pulmonary dis-
ease associated with e-cigarette and vaping product use.
It was found that tetrahydrocannabinol (THC)-containing
e-­cigarettes, or vaping products and those containing
vitamin E acetate are strongly linked to the outbreak. A
recommendation for immediate discontinuation of use of
any form of e-­cigarette use or vaping needs to be made by
the healthcare provider [8, 38].
226
Pregnancy considerations
• Pregnancy is a unique opportunity for medical inter-
vention and may be the only time women seek medical
attention.
• Concerns over the dangers of smoking to the fetus may
serve as a motivation for smoking cessation.
• Behavioral interventions such as contingency manage-
ment, (use of incentives), and other support/reward
programs have demonstrated efficacy in pregnancy
[20, 23, 39].
• The safety and efficacy of existing pharmacotherapies
remain uncertain in pregnancy [6, 8, 23, 24].
Principles
• Goal: Cessation of tobacco product use preconceptionally,
during pregnancy, postpartum, and for a lifetime.
• Tobacco dependence treatments are both clinically and
cost effective relative to other medical disease prevention
interventions [23].
• Women who quit smoking by the third trimester have
birthweights similar to those of nonsmokers [40].
• Smoking cessation in pregnancy could prevent 19% of
low-birth weight births, and 5–8% of preterm deliveries
[25]. Smoking in the third trimester has the greatest impact
on birth weight, while smoking cessation in the first and
second trimesters results in birth weights similar to those
of non-smokers [41, 42].
Management
• Document smoking status at each initial prenatal visit
(Table 22.1) [42]. For tobacco users, document smoking
status at each follow-up prenatal visit.
• The patient should also be asked about the use of any other
tobacco product, e-cigarette/vaping, hookah, mods, or
pods.
• Comprehensive screening for women who smoke in
pregnancy is necessary by asking if she smokes; if no,
you need to ask if she smoked in the last year; if no, ask
if she uses electronic cigarettes. If the answer to any of
these three questions is yes, counseling and interven-
tion are necessary.
• While most pregnant women do disclose their smoking,
urine cotinine testing can aid in uncovering the few
who do not disclose, which may help in managing smok-
ing cessation [43]. Biochemical verification of smoking
status is an important component to the research setting
and may also help to guide intervention in the clinical
setting [44–46].
• Smoking cessation programs are helpful compared to no
intervention at all [6].
• Most smokers make many attempts to quit before success
is achieved. First-time quitters need to be aware of this
trend [23].
• Explore reasons for previous failures: Assess for non-
adherence to therapy and improper use of cessation aides
in the past [23].
• Assess for psychosocial comorbidities that may affect
smoking cessation [47].
Maternal-Fetal Evidence Based Guidelines
• Address second-hand tobacco exposures.
• Comprehensive tobacco control programs including mass
media campaigns are effective in changing smoking
behavior in adults [48].
• Other political and social interventions such as smok-
ing taxation, smoking bans in public and other places,
bans on tobacco advertising and promotion, increases
in retail prices, anti-smoking advocacy, and other public
policies are effective in smoking cessation [49]. For exam-
ple, smoke-free legislation such as smoking bans in work-
places, public places, or both, is associated with significant
reductions in preterm births and child hospital admission
for asthma [50].
Therapy
Assessment for intervention
• Assess and document tobacco use and status at every
visit. This increases the likelihood of smoking-related
discussions between patients and healthcare providers
and increase cessation rates (Table 22.1). There is insuffi-
cient evidence (no RCTs) to assess the effect of an objec-
tive method to assess smoking status (e.g. a breath carbon
monoxide monitor or cotinine measurement use system-
atically) alone in pregnant women [46].
• The five-step assessment (the 5Rs) can be used to address
the patient who reports unwillingness to initiate smoking
cessation (Table 22.2) [23].
• The five-step intervention (the 5As) is recommended
in clinical practice to help pregnant women quit smok-
ing if they verbalize a desire to quit in the next 30 days
(Table 22.3) [23]. Use of the 5As is endorsed by The
American College of Obstetricians and Gynecologists [8],
the National Cancer Institute, and the British Thoracic
Society.
Counseling
• Simple advice has a small, but positive, effect on cessation
rates [51].
• All healthcare providers should give clear, strong, and
personalized advice to every patient to quit smoking as
evidence demonstrates that a 3-minute intervention
raises abstinence rates [23].
• Disclosure rates improve 40% if a multiple-choice format
for disclosure is used rather than a yes/no format (Table
22.1) [42].
• Oral and written advice at each prenatal visit regarding
the risk of smoking for mother and fetus, and a plan to quit
are effective (Table 22.4) [23].
• On the basis of >88 randomized controlled trials with
>28,000 women participants use of support and reward
techniques to help quit smoking have been associated with
a 23% decrease in continued smoking late in pregnancy
[52–54].
• Voucher-based contingency management is a promising
mode of therapy as it has been associated with increased
abstinence rates and improved neonatal birthweights
[20, 38]. Financial incentives significantly increase rates
of smoking cessation [55]. For example, serial vouchers
($68–$274, up to a total of $548) provided for validated
abstinence were associated with more smokers stopping
Smoking
smoking (22.5%) compared to controls (8.6%) [56]. In par-
ticular, reward-based programs (e.g. $800 for smoking ces-
sation) are much more frequently accepted by individuals
who smoke than deposit-based programs (e.g. refundable
deposit of $150 plus $650 in reward payments), leading
to higher rates of sustained abstinence from smoking.
However, among the select minority of smokers (14%) who
would accept either a deposit-based or a reward-based pro-
gram, individuals were more likely to quit smoking in the
deposit-based program [57].
• There is a strong dose-response relationship between the
duration and frequency of counseling and its effective-
ness [23]. Videos, self-help manuals, self-help guides,
and telephone calls are other examples of effective smok-
ing cessation interventions [8].
• Women who received psychosocial interventions had an
18% reduction in preterm births and infants with low birth
weight [7].
• Telephone hotlines (aka, QUITLINE; 1-800-QUIT-NOW)
and web information (www.smokefree.gov; www.smoke-
freefamilies.org) sites are helpful and increase efficiency in
implementing smoking cessation care in the clinical office.
Patient uptake of QUITLINE assistance is improved with
provider encouragement for its use and with proactive
referral by the provider (with patient consent), rather than
passively providing the phone number to a patient.
• Interventions to increase smoking cessation among the
partners of pregnant women, with the additional aim of
facilitating cessation by the women themselves, have been
insufficiently studied [6]. Nonetheless, from studies includ-
ing non-pregnant women, partner smoking cessation
counseling and intervention should be performed dur-
ing pregnancy.
Pharmacotherapies
Nicotine replacement therapy
• General
• Nicotine replacement therapy (NRT) includes patches,
gums, inhalers, lozenges, and nasal spray.
• NRT is a part of an effective strategy to promote smok-
ing cessation in the general non-pregnant population
(Table 22.5) [58]. All of the commercially available forms
of NRT (gum, transdermal patch, nasal spray, inhaler,
and sublingual tablets/lozenges) can help people who
TABLE 22.5: Nicotine Replacement Therapy
Only Recommended in the General Non-pregnant Population
Nicotine Replacement Dosing Regimen
Nicotine patch: Nicoderm DQ: 21 mg/day for 6 weeks, then
Nicoderm DQ or 14 mg/day for 2 weeks, then 7 mg/day for 2
Nicotrol weeks. Nicotrol: Single-dose patch for 16 hour/
day for 6 weeks (no tapering recommended)
Nicotine gum or lozenge Start on quit date: 2 mg tab if <25 cigarettes per
day or 4 mg tab if >25 cigarettes per day
Nicotine nasal spray 1–2 doses per hour × 3 mo. Most patients
require from 7–40 sprays over 24 hour
Nicotine inhaler 10 mg cartridges used over 20 min. 6–16
cartridges per day
227
make a quit attempt to increase their chances of suc-
cessfully stopping smoking. NRTs increase the rate of
quitting by about 50–70%, regardless of setting. Quit
rates are increased 43% with nicotine gum (4 mg more
effective than 2 mg), and 66% with the patch. Nicotine
inhaler, tablets/lozenges, and nasal spray are associated
with 90–100% increase in quit rates. All of these effects
were largely independent of the duration of therapy, the
intensity of additional support provided or the setting
in which the NRT was offered [58].
• In pregnancy, NRT may help with nicotine withdrawal,
has not yet been shown to have a significant advantage
over other types of interventions, and has not been
proven to effectively reduce smoking rates in pregnant
smokers [52, 59]. A recent systematic review reported that
pregnant women who use nicotine replacement therapy
instead of smoking reduce their nicotine exposure [60].
• In pregnancy, some studies show that NRT is associ-
ated with a trend for benefit [61–64], but safety/efficacy
concerns remain [8, 52].
• There is a risk of adverse effects of nicotine on the fetus
through alterations in the uterine, placental, or cere-
bral blood flow [15–17, 52].
• Animal studies suggest nicotine may be toxic to the
developing central nervous system [15–17, 52].
• The American College of Obstetricians and
Gynecologists cautions that the use of NRT should
only be undertaken with close supervision and after
careful consideration and discussion with the patient
of the known risk of continued smoking and the pos-
sible risks of NRT [8].
• There is insufficient evidence to assure safety or
efficacy of NRT in pregnancy, with unclear ratio of
risks and benefits [6, 8, 52, 65].
• Biomarkers such as plasma, urine, or salivary nicotine,
thiocyanate, carboxyhemoglobin, or cotinine may be
useful to monitor NRT use in pregnancy [44–46].
• Nicotine gum
• FDA labels it as associated with known adverse effect
on fetus in animal models.
• Nicotine gum 2 mg was associated with a nonsignifi-
cant increase in smoking cessation from 10–13%, and
significantly increased birth weights and gestational
age at birth, compared to placebo [66].
Advantages Disadvantages
Over-the-counter, Local skin irritation in up to 50% of users,
easy dosing insomnia with 24 hour dosing. 30–60 min
required for maximal effect
Over-the-counter, Low nicotine levels, multiple dosing
satisfy oral behavior
Rapid and higher Initial adverse effects may include throat
nicotine levels and nasal irritation, discouraging use
Substitutes for Low nicotine levels
smoking behavior
228
• Nicotine patch
• FDA classifies it as a drug with known human risk in
pregnancy.
• Nicotine patches during pregnancy have been associ-
ated with nonsignificant effects on smoking cessation
in pregnant smokers [63, 64, 66, 67]. Multiple meta-­
analyses of studies on other nicotine replacement ther-
apies in pregnancy indicate that there is insufficient
evidence that NRT (mostly patch) is effective or safe
in prenatal smoking cessation [52, 68, 69]. Myung et al.
concluded that there is a 13% mean abstinence rate in
their meta-analysis; they included seven studies of which
one is s a prospective study of bupropion, one is a quasi
RCT that studied use of a multimodal intervention, and
the other five were RCTs of NRT that did not show an
effect [69]. Adding a nicotine patch (15 mg per 16 hours)
to behavioral cessation support for women who smoked
during pregnancy did not significantly increase the rate
of abstinence from smoking until delivery or the risk of
adverse pregnancy or birth outcomes [65]. No signifi-
cant effect on birth-weight or preterm birth were asso-
ciated with nicotine patch use [61, 63, 67].
• Nicotine inhaler, tablets/lozenges, and nasal sprays
• FDA classifies it as a drug with known human risk in
pregnancies.
• There is insufficient evidence to assess the safety and
effectiveness of nicotine inhaler, tablets/lozenges, and
nasal spray. A RCT of nicotine inhaler in pregnancy,
showed no difference in biochemically validated smok-
ing cessation rates between groups. A reduction in
preterm birth was observed in the group exposed to
nicotine [45].
• Electronic cigarettes
• There are insufficient data on the safety and smok-
ing cessation efficacy of electronic cigarettes during
pregnancy, with no RCTs or well-designed observa-
tional studies in pregnant patients. Based on the lack
of human data for safety and efficacy and potential for
fetal harm from nicotine, electronic cigarettes are not
recommended in pregnant or breastfeeding patients.
Bupropion HCl (Zyban®, Wellbutrin®)
• FDA classifies it as a drug in pregnancy with no known
adverse fetal effects.
• Had an FDA black box warning relating to the risk of seri-
ous maternal neuropsychiatric events including suicide,
which was removed in 2016 [8].
• In controlled clinical trials, this antidepressant increased
success for moderate to heavy smokers >15 cigarettes/day
by 50–100% in the general population of non-pregnant
smokers [6].
• One small RCT on the use of sustained release bupropion
in pregnancy compared to placebo, showed a reduction in
smoking cessation and reduced cravings, but did not reduce
abstinence at the end of the intervention or treatment [70].
A recently published systematic review found no evidence
that bupropion may be an effective aid for smoking cessa-
tion during pregnancy, and there was little evidence evalu-
ating its safety in this population [71].
• Dose: 300 mg/day (in two divided doses to minimize side
effects). Start 2 weeks prior to anticipated quit date and
continue up to 7–12 weeks [72].
Maternal-Fetal Evidence Based Guidelines
• Advantages: Non-nicotine, may be used in combination
with patch for greater efficacy, provides therapy for comor-
bid depression.
• Disadvantages: Contraindicated if history of seizures, head
trauma, alcohol abuse, or anorexia. Multiple-drug interac-
tions with anti-HIV medications.
Varenicline (Chantix®)
• FDA indicates there are no adequate or well-controlled
studies in pregnant women.
• Had an FDA black box warning relating to the risk of seri-
ous neuropsychiatric events including suicide, which was
removed in 2016 [8].
• Varenicline is a partial nicotine agonist sharing structural
similarity with nicotine and competitively binds nicotine
acetylcholine receptors.
• In non-pregnant populations, a meta-analysis of nine ran-
domized trials shows that varenicline increased abstinence
over placebo at 6 months or longer [RR 2.33 (CI 1.95–2.80)],
over bupropion at 1 year [RR 1.52 (CI 1.22–1.88)], and over
NRT at 1 year [RR 1.31 (CI 1.01–1.71)] [67].
• There are no published clinical trials to assess the safety
and efficacy of varenicline as a smoking cessation inter-
vention in pregnancy [59].
• As varenicline shares close structural similarity to nico-
tine and occupies identical receptor sites and safety data
are non-existent, it is not advisable to use varenicline dur-
ing gestation and lactation.
• Disadvantages: Risk of serious neuropsychiatric events; risk
of angioedema and serious skin reactions; twofold increase
in adverse effects of nausea, vomiting, vivid dreams, and
constipation compared to placebo.
Combination therapies
More studies are needed to determine whether combination ther-
apy of NRT or other pharmaceutical in combination with behav-
ioral modification, such as contingency management, increases
efficacy or safety [64, 73, 74].
NOT recommended
• Clonidine: Limited efficacy. Not superior to placebo. Side
effects include drowsiness, fatigue, and dry mouth [75]
• Nortriptyline (a tricyclic agent): Some benefit as a second-
line agent in non-pregnant patients [76]
• Moclobemide (a monoamine oxidase inhibitor): Some bene-
fit but not FDA approved. Uncertain safety in pregnancy [76]
• Serotonin reuptake inhibitors: Not effective [77]
• Opioids: Naloxone and naltrexone. Not effective [77]
Alternative treatments
• Acupuncture: There is no clear evidence that acupuncture,
acupressure, laser therapy, or electrostimulation are effec-
tive at smoking cessation [78].
• Hypnosis and meditation have been insufficiently studied
in pregnant smokers to make a recommendation [8].
• Stages of change or feedback known as the transtheoretical
model of behavior change assesses an individual’s readiness
to act on a new healthier behavior, and provides strategies,
or processes of change to guide the individual through the
stages of change to action and maintenance. It is composed
of the following constructs: Stages of change, processes of
change, self-efficacy, decisional balance and temptation; it
has not shown benefit [6].
Smoking
Breastfeeding
• Abstinence increases breastfeeding initiation and duration
[79–81].
• Breastfed infants of smoking mothers have urinary coti-
nine levels 50 times higher than breastfed infants of non-
smoking mothers and levels are 10 times higher among
bottle-fed infants of women who smoke [22]. Mothers
unable to quit smoking in the postpartum period should
still be encouraged to breastfeed. Mothers should be coun-
seled to avoid smoking at home [74].
• Incentive-based programs for tobacco cessation may
increase duration of breastfeeding [60].
Postpartum
• Of those who quit smoking, 50–60% relapse in the first
4 months after delivery [3, 8], likely due to period of great
stress and emotional fluctuations.
• Risk factors for relapse include depression, family members
who smoke, pre-pregnancy tobacco use, and low weight
gain in pregnancy [71].
• Effective strategies for preventing relapse have not yet
been identified [38, 71], but smoking cessation inter-
ventions should be continued, in collaboration with
primary physicians and other healthcare personnel
(Table 22.5).
Prevention
Relapse prevention
• Insufficient evidence to support use of any specific inter-
ventions for helping smokers who have successfully quit for
a short time and prevent relapse [81].
• It may be more efficient to focus efforts on initial cessation
attempts [6, 82].
• Biochemical markers may be used to monitor abstinence
once cessation has occurred: Carbon monoxide and uri-
nary cotinine [22, 45]. More research is needed to validate
this method [6].
Reduce initiation of smoking
Prevent sale of tobacco to young people, prohibit smoking in pub-
lic places, increase tobacco taxation, workplace smoking cessa-
tion programs, ban on tobacco sponsorship of sports and cultural
events [6, 48, 49, 83].
Reduce pregnancy complications of smoking
Vitamin C 1000 mg and vitamin E 400 IU supplementation has
been associated with a reduction in placental abruption and
preterm birth among smokers [84]. The use of omega-3 supple-
mentation in pregnancy has been associated with a lower risk of
spontaneous preterm birth in smokers (RR 0.56, 95%CI; 0.36–
0.87), in a secondary analysis of an RCT to test this intervention
to reduce recurrence of preterm birth [85].
Reduce consequences of smoking in newborn
Supplemental vitamin C 500 mg/day started before 22 weeks
by smokers who decline to quit, improves newborn pulmonary
function tests and decreases wheezing through 1 year in the off-
spring [44].
229
Future
• Development of clinical trials needed to determine safety
and efficacy of pharmacologic therapies such as nicotine
replacement, bupropion, and varenicline [6–8, 59].
• Clinical trials of alternative interventions such as contin-
gency management to reduce tobacco use, and use of bio-
chemical markers of exposure to tobacco in pregnancy and
the postpartum period, including populations in low- and
middle-income countries [86].
• Existing tobacco surveillance practices should be modified
to include screening and intervention for use of smokeless
tobacco and electronic cigarettes.
• Continued investigations should include an anti-nicotine
vaccine; initial trials have not been successful; and new
pharmaceutical approaches.
References
1. Eriksen M P, Ross H, et al. The Tobacco Atlas. 5th ed. Atlanta, GA: American
Cancer Society, 2015. [Epidemiologic data]
2. Cornelius ME, Wang TW, Jamal A, Loretan C, Neff L. Tobacco product
use among adults – United States, 2019. MMWR Morb Mortal Wkly Rep
2020;69 (46):1736–1742. [Accessed 19 November 2020] [Epidemiologic
data]
3. Drake P, Driscoll AK, Mathews TJ. Cigarette smoking during pregnancy:
United States, 2016. NCHS Data Brief No. 305. Hyattsville, MD: National
Center for Health Statistics; 2018. [Epidemiologic data]
4. WHO Report on the Global Tobacco Epidemic, 2009: Implementing smoke-
free environments, World Health Organization, 2009. [III]
5. Cornelius ME, Wang TW, Jamal A, Loretan C, Neff L. Tobacco product
use among adults – United States, 2019. MMWR Morb Mortal Wkly Rep,
2020;69(46):1736–1742. [accessed 2020 November 19]. [Epidemiologic
data]
6. U.S. Department of Health and Human Services. Women and Smoking: A
Report of the Surgeon General. Rockville: U.S. Department of Health and
Human Services, Public Health Service, Office of the Surgeon General,
2001. [Epidemiologic data]
7. Chamberlain C, O’Mara-Eves A, Porter J, Coleman T, Perlen SM, Thomas
J, McKenzie JE. Psychosocial interventions for supporting women to stop
smoking in pregnancy. Cochrane Database Syst Rev 2017;(2):CD001055. [88
trials > 28,000 women] [II-3]
8. ACOG. Smoking cessation during pregnancy. ACOG Committee Opinion
No. 807. Obstet Gynecol 2020;135(5):e221–e229. [Guideline] [III]
9. England LJ, Kim YS, Tomar SL, et al. Non-cigarette tobacco use
among women and adverse pregnancy outcomes. Acta Obstet Gynecol
2010;89:454–464. [Review] [III]
10. Swedish National Board of Health and Welfare. Available at: www.social-
styrelsen.se/publikationer2008/2008-125-18. Accessed 2/16/2011. [II-2]
11. Connolly GN, Alpert HR. Trends in the use of cigarettes and other tobacco
products, 2000–2007. JAMA 2008;299:2629–2630. [II-3]
12. Wang X, Zuckerman B, Pearson C, et al. Maternal cigarette smoking,
metabolic gene polymorphism, and infant birthweight. JAMA 2002;287:
195–202. [II-2, n = 741]
13. Tyndale RF. Genetics of alcohol and tobacco use in humans. Ann Med
2003;35:94–121. [Review] [III]
14. Aagaard-Tillery K, Spong KY, Thom E, et al. Pharmacogenomics of mater-
nal tobacco use: metabolic gene polymorphisms and risk of adverse preg-
nancy outcomes. Obstet Gynecol 2010;115:568–577. [II-2, n = 1004]
15. Dempsey DA, Benowitz NL. Risks and benefits of nicotine to aid smoking
cessation in pregnancy. Drug Safety 2001;24:277–322. [Review] [III]
16. Chica RA, Ribas I, Giraldo J, et al. Chromosomal instability in amniocytes
from fetuses of mothers who smoke. JAMA 2005;293:1212–1222. [II-1]
17. Andres RL, Day MC. Perinatal complications associated with maternal
tobacco use. Semin Neonatol 2000;5:231–241. [II-2]
18. Burton GJ, Palmer ME, Dalton KJ. Morphometric differences between the
placental vasculature of non-smokers, smokers, and ex-smokers. BJOG
1989;96(8):907–915. [II-3]
19. Bruin JE, Hertzel CG, Holloway AC. Long-term consequences of fetal and
neonatal nicotine exposure: a critical review. Toxicol Sci 2010;116:364–374.
[Review] [III]
230
20. Heil SH, Scott TL, Higgins ST. An overview of principles of effective treat-
ment of substance use disorders and their potential application to pregnant
cigarette smokers. Drug Alcohol Depend 2009;104(suppl 1): S106–S114.
[Review] [III]
21. Castles A, Adams EK, Melvin CL, et al. Effects of smoking during preg-
nancy: five meta-analyses. Am J Prev Med 1999;16(3):208–215. [Meta-
analyses, 34 articles] [III]
22. Rodriguez D, Kathuria H. Cigarette and tobacco products in pregnancy:
impact on pregnancy and the neonate. UpToDate. 2019. www.uptodate.
com/contents/cigarette-and-tobacco-products-in-pregnancy-impact-
onpregnancy-and-the-neonate.. [Review] [III]
23. Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and Dependence:
2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department
of Health and Human Services, Public Health Service, 2008. [Guideline]
[III]
24. U.S. Department of Health and Human Services. The Health Consequences
of Smoking: 50 Years of Progress. A Report of the Surgeon General. Atlanta,
GA: U.S. Department of Health and Human Services, Centers for Disease
Control and Prevention, National Center for Chronic Disease Prevention
and Health Promotion, Office on Smoking and Health, 2014. Printed with
corrections, January 2014. [Review] [III]
25. Dietz PM, England LJ, Shapiro-Mendoza CK, et al. Infant morbidity and
mortality attributable to prenatal smoking in the U.S. Am J Prev Med
2010;39(1):45–52. [II-2]
26. Heggard HK, Kjaergaad H, Moller LF, et al. The effect of environmental
tobacco smoke during pregnancy on birthweight. Acta Obstet Gynecol
Scand 2006;85(6):675–681. [II-2]
27. Karumanchi SA, Levine RJ How does smoking reduce the risk of pre-
eclampsia? Hypertension 2010;55(5): 1100–1101. [Review] [III]
28. Health care costs updated to 2009 dollars, based on data in Behan, DF,
et al., Economic effects of environmental tobacco smoke, Society of
Actuaries, Accessed March 31, 2005, www.soa.org/resources/research-
reports/2000-2006/research-economic-effect/[Review] [III]
29. Wikstrom AK, Cnattingius S, Stephansson O. Maternal use of Swedish
snuff (snus) and risk of stillbirth. Epidemiology 2010;21(6):772–778. [II-2]
30. Gupta PC, Subramoney S. Smokeless tobacco use and risk of stillbirth a
cohort study in Mumbai, India. Epidemiology 2006;17: 47–51. [II-1]
31. Dahlin S, Gunnerbeck A, Wikstrom AK, Cnattingius S, Edstedt Bonamy
AK. Maternal tobacco use and extremely premature birth - a population-
based cohort study. BJOG. 2016;123(12):1938–1946. [II-2, Population based
cohort study, n = 1,371,274 births].
32. Suter MA, Mastrobattista J, Sachs M, Aagaard K. Is there evidence for
potential harm of electronic cigarette use in pregnancy? Birth Defects Res
A 2015;103:186–195. [II-3]
33. Siegel MB, Tanwar KL, Wood KS.. Electronic cigarettes as a smoking-cessation:
tool results from an online survey. Am J Prev Med 2011;40:472–475. [II-3]
34. Polosa R, Caponnetto P, Morjaria JB, et al. Effect of an electronic nicotine
delivery device (e-Cigarette) on smoking reduction and cessation: a pro-
spective 6-month pilot study. BMC Public Health 2011;11:786. [II-1]
35. Caponnetto P, Campagna D, Cibella F, et al. Efficiency and safety of an elec-
tronic cigarette (ECLAT) as tobacco cigarettes substitute: a prospective
12- month randomized control design study. PLOS ONE 2013;8(6): e66317.
[RCT, n = 300] [I]
36. Mark KS, Farquhar B, Chisolm BM, Coleman-Cowger VH, Terplan M.
Knowledge, attitudes, and practice of electronic cigarette use among preg-
nant women J Addict Med 2015;9:266–272 [II-3]
37. England LJ, Anderson BL, Tong VTK, et al. Screening practices and atti-
tudes of obstetricians-gynecologists toward new and emerging tobacco
products. Am J Obstet Gynecol 2014;211:695. e1–7. [II-3]
38. Centers for Disease Control and Prevention. Outbreak of Lung Injury
Associated with the Use of e-Cigarette, or Vaping, Products. Atlanta, GA:
CDC; 2019. Available at https://www.cdc.gov/tobacco/basic_information/e-
cigarettes/severe-lung-disease.html. Updated February 25, 2020.[III]
39. Heil SH, Higgins ST, Bernstein IM. Effects of voucher-based incentives
on abstinence from cigarette smoking and fetal growth among pregnant
women. Addiction 2008;103(6):1009–1018. [RCT, n = 82 pregnant tobacco
users] [I]
40. Wallace JL, Aland KL, Blatt K, Moore E, DeFranco EA, Modifying the risk
of recurrent preterm birth: influence of trimester-specific changes in smok-
ing behaviors. Am J Obstet Gynecol 2017;216(3):310.e1–310.e8. [II-2]
41. McCowan LM, Dekker GA, Chan E, et al. Spontaneous preterm birth and
small for gestational age infants in women who stop smoking early in preg-
nancy: prospective cohort study. BMJ 2009;338:b1081. [II-2, n = 2504]
42. Mullen PD, Carbonari JP, Tabak ER, et al. Improving disclosure of smoking
by pregnant women. Am J Obstet Gynecol 1991;165(2):409–413. [II-3]
Maternal-Fetal Evidence Based Guidelines
43. Swamy GK, Reddick KL, Brouwer RJ, et al. Smoking prevalence in early
pregnancy: comparison of self-report and anonymous urine cotinine test-
ing. J Matern Fetal Neonatal Med 2011;24(1):86–90. [II-3]
44. McEvoy CT, Schilling D, Clay N, et al. Vitamin C supplementation for preg-
nant smoking women and pulmonary function in the newborn infants. A
randomized clinical trial. JAMA 2014;311:2074–82. [RCT, n = 179] [I].
45. Oncken C, Dornelas EA, Kuo C-L, Sankey HZ, Kranzler HR, Mead EL,
Thurlow SD. Randomized trial of nicotine inhaler for pregnant smokers.
ACOG 2019;(1)10–18. [RCT: n = 137] [I]
46. Tolosa JE, Sherman A, Stamilio DM, McEvoy CT. Tobacco and nicotine expo-
sure prevention in pregnancy: a priority to improve perinatal and maternal
outcomes. Am J Obstet Gynecol MFM. 2019;1(1):19–23. [Review] [III]
47. Kleber HD, Weiss RD, Anton RF Jr, et al. Treatment of patients with sub-
stance use disorders, second edition. American Psychiatric Association.
Am J Psychiatry 2007;164(4 suppl):5–123. [Guideline] [III]
48. Bala MM, Strzeszynski L, Topor Madry R, Cahill K. Mass media inter-
ventions for smoking cessation in adults. Cochrane Database of Syst Rev
2013;(6):CD004704. [Meta-analysis; 11 “Mass media campaigns”] [II-3]
49. Ali MK, Koplan JP. Promoting health through tobacco taxation. JAMA
2010;303(4):357–358. [Review III]
50. Been JV, Nurmatov UB, Cox B, et al. Effect of smoke-free legislation on
perinatal and child health: a systematic review and meta-analysis. Lancet
2014;383(9928):1549–1560. [Meta-analysis, 11 studies] [II-3]
51. Stead LF, Buitrago D, Preciado N, Sanchez G, Hartmann-Boyce J, Lancaster
T. Physician advice for smoking cessation. Cochrane Database Syst Rev
2013;(5):CD000165 [Meta-analysis; 41 trials, n = 31,000 nonpregnant par-
ticipants] [III]
52. Lumley J, Chamberlain C, Dowswell T, Oliver S, Oakley L, Watson
L. Interventions for promoting smoking cessation during pregnancy.
Cochrane Database Syst Rev 2009;(3):CD001055. DOI: 10.1002/14651858.
CD001055.pub3
53. Sexton M, Hebel JR. A clinical trial of change in maternal smoking and its
effect on birthweight. JAMA 1984;251(7):911–915. [RCT n = 935] [I]
54. Donatelle RJ, Prows SL, Champeau D, et al. Randomised controlled trial
using social support and financial incentives for high risk pregnant smok-
ers: Significant Other Supporter (SOS) program. Tob Control 2000;9(suppl
3):iii67–iii69. [RCT n = 220] [I]
55. Volpp KG, Troxel AB, Pauly MV, et al. A randomized, controlled trial of
financial incentives for smoking cessation. N Engl J Med 2009;360:699–709.
[RCT, n = 878 nonpregnant adults] [I]
56. Tappin D, Bauld L, Purves D, et al. Financial incentives for smoking cessa-
tion in pregnancy: randomised controlled trial. BMJ 2015;350:h134. [RCT,
n = 612] [I]
57. Halpern SD, French B, Small DS, et al. Randomized trial of four financial
incentive programs for smoking cessation. NEJM 2015;372:2108–2117.
[RCT, n = 2538] [I]
58. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. Nicotine
replacement therapy versus control for smoking cessation. Cochrane
Database Syst Rev 2018;5(5):CD000146. [Meta-analysis; 136 trials, n =
64,640, non-pregnant women adults, men and women] [III]
59. Oncken CA, Kranzler HR. What do we know about the role of pharmaco-
therapy for smoking cessation before or during pregnancy? Nicotine Tob
Res 2009;11:1265–1273. [Review] [III]
60. Taylor L, Claire R, Campbell K, Coleman-Haynes T, Leonardi-Bee J,
Chamberlain C, Berlin I, Davey MA, Cooper S, Coleman T. Fetal safety of
nicotine replacement therapy in pregnancy: systematic review and meta-
analysis. Addiction 2020;116(2):239–277. [Meta-analysis] [III]
61. Pollack KJ, Oncken CA, Lipkus IM, et al. Nicotine replacement and
behavioral therapy for smoking cessation in pregnancy. Am J Prev Med
2007;33:297–305. [RCT, n = 181] [I]
62. Wisborg K, Henriksen TB, Secher NJ. A prospective intervention study of
stopping smoking in pregnancy in a routine antenatal care setting. BJOG
1998;105(11):1171–1176. [RCT, n = 250] [I]
63. Kapur B, Hackman R, Selby P, et al. Randomized, double blind, placebo-
controlled trial of nicotine replacement therapy in pregnancy. Curr Ther
Res 2001;62(4):274. [RCT, n = 30] [I]
64. Hegaard H, Hjaergaard H, Moller L, et al. Multimodel intervention raises
smoking cessation rate during pregnancy. Acta Obstet Gynecol Scand
2003;82:813–819. [RCT] [I]
65. Coleman T, Cooper S, Thornton JG, et al. Smoking, Nicotine, and Pregnancy
(SNAP) Trial Team. A randomized trial of nicotine-replacement therapy
patches in pregnancy. N Engl J Med 2012;366(9):808–818. [RCT, n = 1051] [I]
66. Oncken C, Dornelas E, Greene J, et al. Nicotine gum for pregnant smokers:
a randomized controlled trial. Obstet Gynecol 2008;112:859–867. [RCT, n =
194] [I]
Smoking
67. Wisborg K, Henriksen TB, Jespersen LB, et al. Nicotine patches for pregnant
smokers: a randomized controlled study. Obstet Gynecol 2000;96:967–971.
[RCT, n = 250] [I]
68. Coleman T, Chamberlain C, Cooper S, Leonardi-Bee J. Efficacy and safety
of nicotine replacement therapy for smoke cessation in pregnancy: sys-
tematic review and meta-analysis. Addiction 2011;106(1):52–561. [Meta-
analysis] [III]
69. Myung S, Ju W, Jung H, Park C, Oh S, Seo H, Kim H. Efficacy and safety of
pharmacotherapy for smoking cessation among pregnant smokers: a meta-
analysis. BJOG 2012;119:1029–1039. [Meta-analysis] [III]
70. Nanovskaya TN, Oncken C, Fokina VM, Feinn R, Clark SM, West H, Jain
SK, Ahmed MS, Hankins GDV. Bupropion sustained release for pregnant
smokers: a randomized, placebo-controlled trial. Am J Obstet Gynecol
2017;216(4), 420.e1–9. [RCT, n = 65] [I]
71. Claire R, Chamberlain C, Davey MA, Cooper SE, Berlin I, Leonardi Bee J,
Coleman T. Pharmacological interventions for promoting smoking cessa-
tion during pregnancy. Cochrane Database Syst Rev 2020;(3): CD010078.
[Meta-analysis, 11 trials, n = 2412] [I]
72. Simon JA, Duncan C, Carmody TP, et al. Bupropion for smoking cessation: a
randomized trial. Arch Intern Med 2004;164 (16):1797–1803. [RCT n = 244] [I]
73. Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T.
Nicotine receptor partial agonists for smoking cessation. Cochrane
Database Syst Rev 2016;(5):CD006103. DOI: 10.1002/14651858.CD006103.
pub7 [Meta-analysis; 2 trials cytisine n = 937; 27 trials varenicline n =
12,625] [III]
74. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-
release bupropion, a nicotine patch, or both for smoking cessation. N Engl J
Med 1999;340(9):685–691. [RCT n = 893] [I]
75. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation.
Cochrane Database Syst Rev 2004;(3):CD000058. [Meta-analysis] [III]
76. Howes S, Hartmann-Boyce J, Livingstone-Banks J, Hong B, Lindson N.
Antidepressants for smoking cessation. Cochrane Database Syst Rev
2020;CD000031. [Meta-analysis; 115 studies] [III]
77. David SP, Lancaster T, Stead LF, Evins AE, Prochaska JJ. Opioid antagonists
for smoking cessation. Cochrane Database Syst Rev 2013;6(6):CD003086
[Meta-analysis, 8 trials n > 1200] [III]
231
78. White AR, Rampes H, Liu JP, Stead LF, Campbell J. Acupuncture and
related interventions for smoking cessation. Cochrane Database Syst Rev
2014;(1):CD000009. DOI: 10.1002/14651858.CD000009.pub4 [Metanalysis:
38 studies] [III]
79. Higgins TM, Higgins ST, Heil SH, et al. Effects of cigarette smoking cessa-
tion on breastfeeding duration. Nicotine Tob Res 2010;12(5):483–488. [II-1,
n = 158]
80. Gartner L, Morton J, Lawrence RA, et al. American academy of pediatrics
policy statement: breastfeeding and the use of human milk. Pediatrics
2005;115(2):496–506. [Guideline] [III]
81. Soloman LJ, Higgins ST, Heil SH, et al. Predictors of postpartum relapse to
smoking. Drug Alcohol Depend 2007;90(2–3):224–227. [II-3, n = 87]
82. Livingston-Banks J, Norris E, Hartmann-Boyce J, West R, Jarvis M, Hajek
P. Relapse prevention interventions for smoking cessation. Cochrane
Database Syst Rev 2099; CD003999. [Meta-analysis, 77 studies n = 67,285]
[III]
83. Cahill K, Lancaster T. Workplace interventions for smoking cessation.
Cochrane Database Syst Rev 2014; (2):CD003440. [Meta-analysis, 57 stud-
ies] [III]
84. Abramovici A, Gandley RE, Clifton RG, Leveno KJ, Myatt L, Wapner RJ,
Thorp JM Jr, Mercer BM, Peaceman AM, Samuels P, Sciscione A, Harper
M, Saade G, Sorokin Y. for the Eunice Kennedy Shriver National Institute
of Child Health Human Development Maternal-Fetal Medicine Units
Network. Prenatal vitamin C and E supplementation in smokers are asso-
ciated with reduced placental abruption and preterm birth: a secondary
analysis. BJOG 2015;122:1740–1747. [Secondary analysis of RCT, n = 9969]
[I]
85. Kuper SG, Abramovici AR, Jauk VC, Harper LM, Biggio JR, Tita AT. The
effect of omega-3 supplementation on pregnancy outcomes by smoking sta-
tus. Am J Ob Gyn 2017;217(4):476.e1–6. [RCT, n = 851] [I]
86. Oncken CA, Dietz PM, Tong VT, et al. Prenatal tobacco prevention and ces-
sation interventions for women in low- and middle-income countries. Acta
Obstet Gynecol Scand 2010;89(4):442–453. [Review] [III]
23
SUBSTANCE USE DISORDERS
Neil S. Seligman
Key points
• Estimates of the incidence of drug abuse during pregnancy,
based from a large national survey was 5.8% but varies from
0.4–27%. Polysubstance abuse (including tobacco and alco-
hol) is common.
• All pregnant patients should be screened for illicit drug
using tools such as the 4 Ps (Table 23.3). Urine drug
screening tests for the presence of substances in the urine
and cannot diagnose substance use disorder. Urine drug
screening should only be performed with consent.
• Many states have laws which consider substance use during
pregnancy child abuse and a few consider it to be grounds
for civil commitment.
• Screening, brief intervention, and referral to treatment,
otherwise known as the “SBIRT” model, is recommended.
Several online resources and free applications are available
for this.
• Promoting preconception behavioral change, or ideally
strategies to prevent initiation of substance use, is pre-
ferred over drug abuse treatment during pregnancy.
Marijuana
• Marijuana is the most commonly used drug during preg-
nancy; approximately 2–5% pregnant patients use mari-
juana. Marijuana use is becoming more common due to
legalization, perceived safety, use of marijuana to treat rou-
tine discomforts of pregnancy.
• Conflicting evidence exists regarding the risk of preterm
birth but in a recent study of more than 9000 patients,
preterm birth was more common among patients using
marijuana even after controlling for other factors such
as tobacco use. Marijuana use during pregnancy may
increase the risk of stillbirth and sudden infant death
syndrome.
• Marijuana is believed to alter fetal brain development by
binding to opioid receptors in the central nervous system
which are present as early as the 14th week of gestation but
long-term effects are unclear.
Opioids
• Infections (including hepatitis, HIV, endocarditis, and oth-
ers) account for the majority of complications related to
parenteral opioid use.
• Neonatal withdrawal from opioids occurs in 60% (26–
95%) of exposed neonates.
• Opioid agonist therapy with either methadone or
buprenorphine is the standard treatment for opioid
use disorder. Replacement therapy diminishes the risks of
obstetrical complications and increases utilization of pre-
natal care, among other benefits. The dose of medication is
titrated to the lowest dose that effectively prevents with-
drawal symptoms.
232
• Recent evidence demonstrates that withdrawal is not
inherently dangerous to the fetus but nonetheless, detoxi-
fication (a.k.a. withdrawal or tapering) is not advised due to
a high risk of relapse (23–53%).
• For patients taking either methadone or buprenorphine,
breastfeeding is encouraged and may have a favorable
effect on neonatal opioid withdrawal.
Cocaine
• Systemic effects of cocaine include hypertension, tachy-
cardia, and mydriasis. Pregnancy is associated with
increased sensitivity of the cardiovascular system to the
harmful effects of cocaine such as arrhythmias and myo-
cardial infarction.
• Cocaine readily crosses the placenta causing uterine
artery vasospasm and vasoconstriction. The resultant
decreased uteroplacental blood flow uteroplacental insuffi-
ciency and may lead to fetal acidosis, hypoxia, and distress.
Vasoconstriction is also believed to be the pathophysiology
of some of the congenital anomalies that occur following
intrauterine cocaine exposure.
• Interventions for cocaine dependence primarily involve
psychosocial therapies; currently, there are no Food
and Drug Administration (FDA)-approved pharmaco-
therapies for treatment of cocaine dependence during
pregnancy.
Amphetamines
• Amphetamines are a group of synthetic stimulants that are
structurally similar to biogenic amines; effects are simi-
lar to cocaine. Methamphetamine is the most commonly
abused amphetamine.
• The incidence of methamphetamine use during preg-
nancy varies from 0.1–1.0% but may be up to 5.2% in
some high prevalence areas. Ecstasy use among pregnant
patients varies from 0.6–8.8% in the United Kingdom
but is much less common in the United States. Despite
a recent epidemic, the use of synthetic cathinones (“bath
salts”) during pregnancy is not well characterized.
• Regional anesthesia can cause profound hypotension and
vasopressors should be used with caution. Inhaled anes-
thetic agents which sensitive the myocardium to endog-
enous catecholamines should be avoided.
Others
• Isolated or primary benzodiazepine use disorder is uncom-
mon. Most of the data on pregnancy outcomes comes
from patients taking prescribed benzodiazepines and
z-hypnotics.
• Abrupt discontinuation can lead to seizures, delirium,
autonomic instability, and suicidal ideation. Patients
should be monitored for changes in vital signs and may
require tapering with a long-acting benzodiazepine.
DOI: 10.1201/9781003099062-23
Substance Use Disorders
• Phencyclidine (PCP) is associated with a higher incidence
of intrauterine growth restriction, low birth weight, and
small for gestational age infants. Developmental effects,
including impaired fine motor skills, neurological effects,
behavioral problems, inconsolability and sleep distur-
bances have been noted.
• An increased risk of limb reduction defects, central ner-
vous system anomalies, and neural tube defects has been
reported in association with lysergic acid diethylamide
(LSD) use.
Background
Substance use disorder (SUD) is a chronic medical illness. In gen-
eral, continued use of harmful substances is not intended to harm
the fetus but rather a response to acute psychological or physical
need [1]. In current terminology, the term “substance use disor-
der” has replaced “abuse” and “addiction” (Table 23.1). There is no
safe pattern of illicit substance use.
Incidence
Despite well-established risks, the prevalence of illicit sub-
stance use by reproductive age females has steadily increased.
TABLE 23.1: Definitions
• Substance use: Use of any type of substance, including both licit and
illicit substances
• Substance misuse: The use of substances for non-medical purposes in a
way in which it is harmful to health
• Substance use disorder: Defined by the DSM-V as variable consumption
resulting in significant impairment or distress including: (1) social or
interpersonal consequences, (2) failure to fulfill obligations at work,
school, or home, (3) physically hazardous situations, (4) tolerance, (5)
withdrawal, (6) substance is taken in larger amounts and for longer
than was expected, (7) persistent desire or unsuccessful efforts to cut
down, (8) excessive time is spent in obtaining or using the substance,
(9) important work, recreation, or social life activities are reduced or
given up, (10) substance use is continued despite knowledge of the
adverse consequences, (11) craving or strong desire or urge to use a
specific substance
• Mild: 2–3 of the above within a 12 month period; replaces “abuse”
• Moderate (4–5) or severe (>6): Of the above within a 12 month
period; replaces “substance dependence”
• Physical dependence: A state of neurological adaptation that is
manifested by a drug class-specific withdrawal syndrome that can be
produced by abrupt cessation, rapid dose reduction, decreasing blood
level of the drug, and/or administration of an antagonist
• Psychological dependence: A subjective sense of need for a specific
psychoactive substance, either for its positive effects or to avoid
negative effects associated with its abstinence
• Tolerance: A decrease in response to a drug dose with continued use
• Substance abuse: A term in the DSM referring to a category of
psychoactive substance-related disorders but no longer recommended
for use because of pejorative connotations
• Addiction: A treatable, chronic medical disease involving complex
interactions among brain circuits, genetics, the environment, and an
individual’s life experiences; behaviors that become compulsive and
often continue despite harmful consequences is characteristic
Source: Adapted from Refs. [235–237].
233
The most current estimates of use in the general population are
available from the 2019 National Survey on Drug Use and Health
(NSDUH) [2]:
• 57.2 million Americans (1 in 6 people; 20.8%) aged 12 and
older used illicit drugs in the past year. 35.8 million used
illicit drugs in the past month (13%).
• 8.3 million (3%) were diagnosed with illicit drug use
disorder.
• Most commonly used illicit drugs were marijuana, psycho-
therapeutic drugs, hallucinogens, and cocaine.
• Substance abuse is lower in females (18%; 46.3% overall)
than in males (23.8%) but the gender inequality is decreas-
ing [3].
During pregnancy substance use ranges from 0.4–27%
depending on the population surveyed, based on patient inter-
views and urine toxicology testing at the initial prenatal visit and
delivery [4]. According to the 2019 NSDUH [2]:
• 5.8% of pregnant patients aged 15–44 years old
reported current (past month) illicit drug corresponding
to >200,000 infants born annually exposed to illicit drugs
in utero.
• Illicit drug use during pregnancy is more prevalent among
younger females (18–25 years old: 10.5% vs. 26–44 years
old: 3%).
• Fewer pregnant patients reported current drug use dur-
ing the third trimester compared to the first or second
trimester (3.3% vs. 9.7% and 4.9%, respectively).
Substance use disorder is the most commonly missed and
undertreated diagnosis during pregnancy. Survey-based esti-
mates may underestimate substance abuse by as much as 50%
or more. In a study of universal screening for substance abuse in
an inner city population, 19% of pregnant patients screened posi-
tive for one or more substances at the time of admission to labor
and delivery, of which, only 32.6% gave a history of drug use [5].
Risk factors
Childhood trauma is associated with development of psychiat-
ric disorders, violence in personal relationships, and economic
instability later in life and also plays a role in the development
of SUD [3]. All these characteristics are common among preg-
nant patients that use illicit drugs. The presence of psychopa-
thology (e.g., anxiety, depression, PTSD, bipolar disorder) is
common and may impede optimal management. These patients
also tend to be younger (highest risk is among those <25 years
old), have less education (high school or less), lower income
(household income below the poverty level), and have a family
history of SUD [3]. Substance use increases the risk of sexually
transmitted infections, including hepatitis C and HIV, endo-
carditis, and tuberculosis through needle sharing, risky sexual
behaviors (e.g., unprotected intercourse, sex with multiple
partners, trading drugs for sex, and prostitution), and incar-
ceration (resulting from the purchase and sale of illicit drugs,
prostitution, or theft). The use of more than one substance, par-
ticularly alcohol and tobacco, at the same time (polysubstance
abuse), is present in >50% of pregnancies by patients using
substances. Factors that may heighten the suspicion of drug
abuse are shown in Table 23.2.
234
TABLE 23.2: Common Signs and Symptoms That Should
Indicate a High Risk of Drug Use
• No prenatal care, limited prenatal care (3 or less prenatal visits prior to
28 weeks gestation) or late prenatal care (initiation of prenatal care
after the first trimester)
• Multiple missed prenatal care appointments
• Impaired school or work performance
• History of unexplained adverse obstetrical or neonatal outcomes (e.g.,
abruption)
• Children with neurodevelopmental problems
• Children not currently living in the home or involvement by child
protective services
• Medical history of substance abuse or substance-abuse-related
problems
• Past or current treatment with either methadone or buprenorphine
• Family history of substance abuse
• Frequent encounters with law enforcement
• Partners who have a history of substance abuse
• Homelessness
• Physical stigmata of substance use (track marks, related infections) or
withdrawal
• History of physical or sexual abuse
• Sudden behavioral changes or inappropriate behavior, including
disorientation, somnolence, loose associations, unfocused anger
• Signs or symptoms of preterm labor or abruption
• Severe hypertension (blood pressure >160/110 mmHg)
• Unexplained vaginal bleeding or fetal demise
Workup
Screening is the use of brief self-report instruments to identify
substance use. All pregnant patients should be screened for
the use of illicit substances, tobacco, and alcohol [6–8]. In fact,
since substance use by reproductive age females represents possi-
ble teratogenic exposures, all females over 12 years old should be
screened [9]. Obtaining a history of drug abuse may be facilitated
by creating a private, safe, nonjudgmental atmosphere. Patients
should be informed that screening is universal and answers are
confidential. They should also be told that the intent of screening
is to allow treatment for substance use and ensure appropriate
prenatal care [6, 8]. Maternal history alone may not be sufficient
when there is a high suspicion of substance abuse. Reluctance to
admit substance use may stem from fear of legal repercussions
and involvement of child protective services. Providers should
address misinformation and dispel any myths about the risks
and ramifications of substance use including the laws regarding
disclosure of substance use disorder in their state [6]. Twenty-
three states and the District of Columbia consider substance use
during pregnancy a form of child abuse and three states con-
sider it grounds for civil commitment. Twenty-five states and the
District of Columbia have laws requiring mandatory reporting of
suspected prenatal drug use and eight states require testing for
prenatal drug exposure if drug use is suspected. In some states
positive toxicology at birth may result in the newborn being
removed from the home. Criminalization of addiction in preg-
nancy is both ineffective and ethically inappropriate [1]. Under
the federal Child Abuse Prevention and Treatment Act (CAPTA)
and Comprehensive Addiction and Recovery Act (CARA) states
are required to have policies and procedures to address the needs
of infants affected by substance use or withdrawal symptoms
Maternal-Fetal Evidence Based Guidelines
TABLE 23.3: 4 Ps
1. Parents: Did any of your parents have a problem with alcohol or other
drug use?
2. Partner: Does your partner have a problem with alcohol or drug use?
3. Past: In the past, have you had difficulties in your life because of
alcohol or other drugs, including prescription medications?
4. Present: In the past month have you drunk any alcohol or used other
drugs?
Scoring: Any “yes” should trigger further questions.
Source: Adapted from Refs. [83, 238].
from drug use including a requirement to notify child protective
services of such infants for the purpose of helping the newborn
and their family rather than serving as an allegation of child
abuse.
Options for the evaluation of illicit substance use include
interview, questionnaires, and chemical tests. Use of open-
ended questions and motivational interviewing techniques
may be helpful [10]. The “4 Ps” is a frequently recommended
screening tool for pregnant patients (Table 23.3). SURP-P (spe-
cifically designed for pregnant patients), T-ACE, TWEAK (spe-
cific to alcohol), CAGE-AID, CRAFFT (for patients 26 years or
younger), NIDA Quick Screen, and DAST are other available
options. None of these have been proven to be both highly sen-
sitive and specific [11].
Testing is analysis of a biologic specimen to determine whether
an individual has used a specific drug. Self-report alone under-
estimates the prevalence of substance abuse however, routine
drug screening is not currently recommended. “Screening” for
the presence of a substance in a biologic specimen should not
be confused with “screening” for SUD. Toxicology screening
cannot diagnose SUD, or its severity, nor can it determine fre-
quency, amount, or route of use [12]. Chemical tests for samples
of maternal blood, hair, saliva, sweat, or urine, or fetal/neonatal
specimens (amniotic fluid, cord blood, meconium, blood, hair,
or urine) are available for most illicit substances. While not
legally required, most organizations recommend obtaining
consent before obtaining these tests. Urine toxicology, often
referred to as “urine drug screen (UDS)”, is the most commonly
used laboratory test. The substances included and sensitivity
are variable; providers should be aware of the substances
being assessed and the strengths and limitations of this test.
False-negative test results can occur when the drug is present
at less than detectable levels, ingestion occurred too recently
for the substance to appear in the urine, when sufficient time
has passed to allow complete drug clearance (Table 23.4), with
dilute urine, or adulteration of the specimen. False positive
results can be as high as 5% [12]. For example, labetalol may
create a false positive result for amphetamines [13]. Secondary
testing is required to confirm positive UDS results. Not all
substances can be detected with a typical UDS (Table 23.5)
[12]. For example, more specific testing may be required for
synthetic opioids such as oxycodone. Testing is also not read-
ily available for synthetic cannabinoids. The physician should
also be aware of the limitations of neonatal testing. Drugs may
be present in meconium for months, making it difficult to dif-
ferentiate between the occasional user, continued substance
use, and patients on treatment (e.g., methadone) with no recent
substance use.
When maternal history and/or laboratory tests are positive for
illicit drug use, a complete drug history should be obtained for
Substance Use Disorders 235

TABLE 23.4: Length of Time Drugs Are The initial evaluation of pregnant patients with a history of
Present in Urine SUD presenting to the labor and delivery unit for any reason
should include a UDS, ideally with consent.
Opioids
Codeinea 2–3 days
Morphinea 2–3 days Management
Heroina 1–2 day
Methadone 3 days In general, pregnant patients are highly motivated to decrease
Cocainea <1 day
or stop using illicit substances to avoid potential negative
Benzoylecgonine (metabolite) a 2–5 days
consequences for the fetus. Pregnant patients who acknowl-
edge their use of illicit substances should be counseled and
Amphetamines
offered treatment as necessary [14]. Identifying patients with
D-amphetaminea 2–3 days
SUD, providing feedback and advice (a.k.a. brief intervention)
D-methamphetaminea 2–3 days
and referral to treatment, as needed is known as the “SBIRT”
MDMA 2 days
model. Various online resources (e.g., https://www.samhsa.
Benzodiazepines
gov/sbirt) and apps (e.g., SBIRT for Health Professionals) are
Diazepam/nordiazepama 10–30 days freely available to help. Treatment options include psychoso-
Lorazepam 3–5 days cial treatments [4] such as motivational interviewing [10],
Midazolam 2 days cognitive behavioral therapies, 12-step approaches, com-
Single use 3 days munity/social network approaches, contingency manage-
Chronic use 6 weeks ment, pharmacologic therapies, and inpatient treatment.
Marijuanaa Neither contingency management strategies (rewards for
Occasional (1–2 times a week) 3 days good behavior) or motivational interviewing-based tech-
Moderate (4–6 times a week) 5–7 days niques were effective in improving retention or abstinence
Heavy (daily use) 10–15 days of pregnant patients in illicit drug treatment programs [15].
Chronic use daily use >30 days The introduction of CARA in 2016 requires a Plan of Safe Care
a Detected by most urine drug screens using enzyme
which addresses the needs of the family. It is helpful to have a
immunoassays. social worker integrated in the care team to assist in meeting
this obligation.
each substance. The acronym “DRUG” may be useful to remem-
ber the components of the drug history. Prevention
Drug name The prevention of drug abuse is paramount to drug abuse treat-
Route (e.g., intravenous, oral) ment. Prevention strategies are focused on increasing pub-
Used how much, how often lic awareness of the harmful effects of drug use through
Gotten how (e.g., prostitution, theft) advertising campaigns, school programs, and encouraging
parents to educate their children. Physicians should take
an active role in drug abuse prevention by routinely counsel-
TABLE 23.5: Drugs Not Typically Detected ing their patients about the negative consequences of drug
in a UDS abuse.
Opioids
Oxycodone Preconception counseling
Fentanyl
Methadone Substance use is an important component of the history in
Tramadol female patients seeking preconception counseling because
Cocaine fetal drug exposure is preventable. Patients with a positive his-
Amphetamines tory and/or laboratory testing for substance abuse should be
MDMA counseled about the reproductive effects of the specific sub-
Synthetic stimulants (e.g., bath salts) stances along with the risks and benefits of pharmacological
Gamma-hydroxybutarate and non-pharmacologic treatment. They should be encouraged
to postpone conception until after initiating or completing
Benzodiazepines
drug treatment. Because of the reproductive risks of certain
Lorazepam
pharmacological treatments, reliable methods of contracep-
Clonazepam
tion should be encouraged. Anovulatory cycles and infertil-
Non-benzodiazepine hypnotics
ity are more common in substance-abusing female patients,
Marijuana
especially with opioid use; however, it should be stressed that
Synthetic cannabinoids (e.g., spice) pregnancy can definitely occur without adequate contracep-
Ketamine tion. There is some evidence that pre-pregnancy health
Hallucinogens promotion is associated with a positive effect on mater-
Mescaline (peyote) nal behavior change (specifically binge drinking) but more
Psilocybin (mushrooms) research is needed (see Obstetric Evidence Based Guidelines,
Source: Adapted from Ref. [239]. Chapter 1) [16].
236
TABLE 23.6: Elements of the Initial Evaluation
• History of drug sequelae (thrombophlebitis, bacterial endocarditis,
hepatitis)
• Psychosocial history (abuse, domestic violence, depression/ anxiety/
bipolar, inpatient psych admission)
• Thorough drug history (what, how much, how often, how obtained,
taken how)
• Review of state prescription drug monitoring program data
• Observation for signs and symptoms of intoxication or withdrawal
• Assessment of nutritional status
• Physical exam (sequelae of drug use: track marks, skin lesions from
intradermal injection aka “skin popping”, abscess scars, dentition)
• Dating ultrasound
• Laboratory evaluation: CBC with differential, basic metabolic panel,
liver function tests, hepatitis B and C antibody, RPR, blood type and
antibody screen, HIV (with counseling), urinalysis and culture, UDS
(with consent), TB skin test, gonorrhea, chlamydia, wet mount
(trichomonas)
Prenatal care
Providers must be aware of the specific needs of the pregnant
substance abuser. Components of the history and physical
exam and the recommended laboratory evaluation are shown in
Table 23.6. Because of the frequent association with poor nutrition,
they may benefit from nutritional counseling. Continued positive
drug screens may warrant ultrasound and non-stress test (NST)
surveillance. Whether referral to a maternal-fetal medicine special-
ist is required depends on physician experience and the presence of
other comorbidities. Regardless, treatment of substance-abusing
pregnant patients requires a multidisciplinary team. A collab-
orative approach involving the obstetric provider, substance use
treatment provider, and mental health provider is essential. Where
available, referral to specialized programs integrating, addiction
treatment, obstetrical and medical care, social services, and psy-
chiatric support may be beneficial [1, 12].
Marijuana (cannabis);
synthetic cannabinoids
Historic notes
Cannabis has been used for medicinal purposes for thousands
of years and is among the earliest non-food-bearing plants cul-
tivated by humans [17]. In humans, endogenous cannabinoids
(endocannabinoids) play an important role in pregnancy implan-
tation and maintenance. From 1850 to 1942, marijuana was listed
in the U.S. Pharmacopeia and prescribed for several obstetrical
and gynecological indications including: menstrual cramps, labor
pain, and uterine hemorrhage. As of 2020, marijuana is legal for
medical use in 33 states and recreational use in 15 states but
still illegal at the federal level and mandated reporting laws
have not caught up with state laws.
Diagnosis/definition
Cannabis (marijuana) contains more than 400 chemicals. The
primary active chemical is tetrahydrocannabinol (THC), a can-
nabinoid, of which there are more than 60. Marinol (dronabinol),
a synthetic preparation of delta-9-THC, is indicated for treatment
of anorexia and weight loss in patients with AIDS and of nau-
sea and vomiting associated with chemotherapy. Dried cannabis
Maternal-Fetal Evidence Based Guidelines
leaves contain up to 12% THC. Some common street names for
marijuana include Pot, Grass, Herb, Weed, Mary Jane, Reefer,
Skunk, Boom, Gangster, Kif, Chronic, and Ganja. Marijuana is
most commonly smoked but can also be taken orally. “Spice” or
“K2” refers to marijuana alternatives made from dried plant
material mixed with synthetic cannabinoids.
Symptoms
The symptoms of marijuana intoxication include euphoria, tachy-
cardia, conjunctival congestion, and anxiety [18].
Epidemiology/Incidence
Marijuana is the most commonly used illicit drug in the United
States and the most commonly used illicit drug during preg-
nancy and usage continues to increase. Of patients who use illicit
drugs during pregnancy, 75–80% use marijuana [19]. The preva-
lence of marijuana use during pregnancy ranges from 2% to 28%
(typically 2–5%) [8]. Eight states participating in the Pregnancy
and Risk Assessment Monitoring System (PRAMS) collected data
on marijuana use in 2017. The weighted prevalence of self-reported
marijuana use was 4.2% (range 2.6–12.1% by state) [20]. The actual
rate is probably much higher since urine toxicology detects more
than twice as many pregnant patients compared to self-report.
Usage varies significantly by age with the highest rates of use
among young adults 18–25 years old [21]. Among young, urban,
socioeconomically disadvantage females the rate of marijuana use
during pregnancy is as high as 18–25% [8].
Marijuana use increased 62% among pregnant patients
between 2002–2014 [21]. Some of the increase in prenatal
marijuana use can be attributed to legalization and increased
societal acceptance of marijuana. [22]. Legalization can inadver-
tently imply safety. Among marijuana users, 62% indicated they
would increase use during pregnancy if marijuana was legalized.
In 2015, 65.4% of pregnant patients using marijuana reported
no risk [23] which may be the reason that 34–60% of marijuana
users continue use during pregnancy [8]. Marijuana is also being
increasingly used as a treatment for common pregnancy symp-
toms and is viewed by some as a safer and more natural alterna-
tive to prescription medications. Nausea, anxiety, and pain are
some of the reasons stated for marijuana use. Between 2009–2016
the prevalence of marijuana use by patients with nausea and vom-
iting of pregnancy in California increased from 6.5% to 11.1% [24].
Among pregnant patients reporting marijuana use, 18.1% met
criteria for abuse or dependence [25]. Admission for treatment of
marijuana use is increasing. Marijuana was the primary drug in
6% of pregnant patients admitted for substance abuse treatment
in 1992 compared to 20% in 2012 [26].
Etiology/Basic pathophysiology
Tetrahydrocannabinol crosses the placenta and can be detected
in fetal tissues for several weeks after use [27]. Fetal plasma lev-
els are approximately 10% of maternal levels but greater exposure
can result from repetitive use [8]. Chronic marijuana use alters
uterine artery blood flow [28] and may decrease uteroplacental
perfusion [29]. Compared to cigarettes, smoking marijuana is
associated with five-fold higher levels of carbon monoxide [30].
When taken in combination, marijuana can potentiate the effects
of other illicit drugs.
Risk factors/Associations
Patients who use marijuana during pregnancy are less likely to use
folic acid and are more likely to be younger, non-Hispanic White,
Substance Use Disorders
single, nulliparous, underweight, have lower levels of educa-
tion (<12 years) and income (<$20,000), receiving Medicaid
and WIC, late to prenatal care, and be victims of intimate part-
ner violence (8.1% before pregnancy; 3.2% during pregnancy)
[8, 20]. At least one third of pregnant marijuana users also
use another substance [31]. Alcohol (14.2%; binge drinking:
2.9%) and tobacco (43%) use is 2–3 times more likely among
marijuana users [32]. Marijuana use during pregnancy is more
likely in patients living in a states where marijuana has been
legalized or decriminalized [33].
Complications
Limitations of the current research on the effects of marijuana
use during pregnancy include ascertainment (e.g., self-report),
frequent use of other substances (especially tobacco), sociode-
mographic differences, and recent increase in prevalence of
prenatal marijuana use. The risk of obstetrical and/or neona-
tal complications may increase in relation to the amount of
marijuana used and quantification is lacking in most studies.
Although it is difficult to separate the effects of marijuana from
its contextual associations of use, subtle effects could have a large
impact because exposure is so frequent [34]. Additionally, much
of the research was performed during a period in which mari-
juana potency was four-fold less than it is today. Recently, two
large meta-analyses were published (Conner 2016: n = 31 studies,
7851 exposed patients; Gunn 2016: n = 24 studies). These studies
reached different conclusions about the effect prenatal marijuana
use possibly owing to the fact each included some studies that
were not included in the other [35, 36]. Medicinal marijuana
should not be prescribed or condoned during pregnancy
[8]. Little is known about the reproductive risks of synthetic
cannabinoids.
• Congenital anomalies: There is no obvious pattern of
malformations associated prenatal exposure to marijuana
[37]. One study reported an increased incidence of anen-
cephaly with first trimester marijuana use (OR 2.5; 95% CI
1.3–4.9) which may reflect less frequent use of supplemen-
tal folic acid [8].
• Obstetrical complications: Frequent marijuana use is
associated with a small reduction in length of gesta-
tion but whether marijuana use is an independent risk
factor for preterm birth (PTB) is controversial. No asso-
ciation between marijuana and PTB was found in either
meta-analysis except in a subgroup group with moderate
to heavy use (at least weekly, RR 2.04; 95% CI 1.32–3.17)
[30, 36]. The risk of PTB in these patients may be due
to tobacco use. Conner et al. showed no association with
PTB in an analysis stratified for concomitant tobacco use
(marijuana alone: RR 1.25; 95% CI 0.63–2.5). However, a
large study published after these meta-analyses included
more than 9000 pregnant marijuana users. In this cohort,
the PTB rate was 12% versus 6.1%. In a subanalysis using
a matched cohort the risk of PTB was lower (10.2% versus
7.2%; RR 1.41; 95% CI 1.36–1.47) but still significant [38].
Two contemporary, but much smaller (n=119 and n=211
marijuana users), studies had conflicting results [39, 40].
Another concern is stillbirth. An increased risk of IUFD
was reported in one of the meta-analyses (RR 1.74) but
could not adjust for smoking [35]. However, in an NICHD
Stillbirth Collaborative Research Network study which
used biochemical tests on umbilical cord specimens to
237
confirm exposure; the effect persisted after adjusting for
confounding exposures including tobacco (OR 2.34; 95%
CI 1.13–4.81) [41]. Another study including patients with
biochemically validated marijuana use compared users of
tobacco cigarettes only, cannabis only, and co-use. In the
cannabis only group, the OR of stillbirth was 14.3 (95%
CI 1.3–161.5) [42]. An increased risk of NICU admission
was reported in one of the meta-analyses (OR 2.02; 95%
CI 1.27–3.21) [36] but results of subsequent studies have
been mixed [38–40, 43].
• Fetal/neonatal morphometrics: Gunn et al. demonstrated
a higher odds of low birth weight (LBW) (1.77; 95% CI
1.04–3.01) with a pooled mean difference of 109 grams.
Findings of the Generation R study were similar, with con-
tinued marijuana use associated with a 172 gram (95% CI
–208 to –35 g) reduction in mean birth weight [44]. The
effects of marijuana on fetal growth may be dose depen-
dent. In the meta-analysis by Conner et al., an association
with LBW was only seen among moderate-heavy marijuana
users (RR 1.90; 95% CI 1.44–2.45). Marijuana use during
the first 18 weeks only was associated with a smaller, but
still significant reduction in weight (–95.4 g; 95% CI –168 to
–23 g). As with the other outcomes reviewed, some or all of
the difference in birth weight may be due to cigarette smok-
ing. No difference in birthweight was found after adjusting
for cigarette smoking in one study but not in another study
using matched population cohorts [32, 45]. The effect, if
any, on small for gestational age (SGA), length, and head
circumference (approximately –0.5 cm) is small [19, 38, 43,
46, 47].
• Neonatal withdrawal: There is no well described neonatal
withdrawal from marijuana however increased tremor,
irritability, and hand-to-mouth activity have been
reported in some studies [41].
• Long-term neonatal outcome: Exposure to marijuana
through second-hand smoke is a risk factor for sudden
infant death syndrome [48, 49]. Cannabinoid receptors
in the fetal central nervous system (CNS), present as early
as 14 weeks, play a role in normal brain development by
regulating differentiation of neurons and glia, guiding
axonal migration and synaptogenesis [37]. Marijuana is
believed to alter fetal brain development by binding
these receptors leading to changes in synaptic structure
and function and thus altered behavior, a predilection for
adult neuropsychiatric disorders, and early onset mari-
juana use [46, 49, 50]. The main findings from longitudi-
nal studies of perinatal marijuana exposure are: impaired
mental development at nine months, increased aggression
and inattention at 18 months (in girls), impaired memory
and decreased verbal scores at 36–48 months, increased
anxiety and depression, increased externalizing behavior
(e.g., impulsivity, hyperactivity) at 6–10 years, impaired
abstract and visual reasoning at 10 years, impaired
visuoperceptual functioning at 9–12 years, and altered
visuo-spatial memory at 18–22 years [51]. Despite this,
there is still uncertainty about the association between
prenatal marijuana use and childhood neurodevelop-
mental outcomes.
Therapy
Currently, there is no approved pharmacotherapy for marijuana
abuse.
238
Antepartum testing
The role of antepartum surveillance for marijuana exposure is
insufficiently studied to make recommendations.
Anesthesia
Drugs affecting maternal heart rate and blood pressure should
be used with caution. Adverse interactions have been reported
between marijuana and drugs such as propranolol [52]. Likewise,
during cesarean section under general anesthesia, the combina-
tion of marijuana and certain inhaled anesthetics can result in
pronounced myocardial depression [52]. If general anesthesia is
planned, the airway effects of chronic smoke inhalation should be
considered [52]. Cross-tolerance to opioids and benzodiazepines
may make dosing difficult [52].
Postpartum/Breastfeeding
THC levels in breast milk are between 0.8–2.5% of the mater-
nal dose [37]. Concentrations in breast milk are related to the
amount and frequency of marijuana use. Reported effects of
marijuana use during breastfeeding include sedation, lethargy
and less frequent and shorter feedings [53]. There are conflict-
ing studies about exposure to THC in breastmilk and motor
development [37]. The American Academy of Pediatrics (AAP),
American College of Obstetricians and Gynecologist (ACOG),
and Academy of Breastfeeding Medicine (ABM) strongly advise
that patients should not use marijuana while breastfeeding as
it may be hazardous to the infant and nursing mother [26, 49, 53,
54]. If discontinuation is not possible, patients should be encour-
aged to limit use as much as possible [37].
Opioids: Heroin and prescription
opioid analgesics
Historic notes
Opioids are among the world’s oldest known drugs. Opium is
the dried “latex” of the opium poppy, which is grown mainly in
Southeast Asia. Use of opium for its therapeutic benefits pre-
dates recorded history. Historically, opium has incited significant
social, political, and economic strife. Opium contains morphine,
codeine, and thebaine (converted chemically into oxycodone,
oxymorphone, nalbuphine, naloxone, naltrexone, and buprenor-
phine). Opium can also be converted into heroin, a highly addic-
tive and rapid-acting opioid with a short half-life. Its origin dates
back to 1874 when it was first introduced as a cure for morphine
addiction [6, 55]. Opioid maintenance therapy was adopted in the
1960s as a treatment for heroin addiction [1].
Diagnosis/Definition
Opioids are chemicals that bind to the opioid receptor. The
term “opiate” refers to the naturally occurring alkaloids
(morphine, codeine, heroin) found in opium. Street names
for heroin in the United States include Big H, Black Tar, Chiva,
Hell Dust, Horse, Negra, and Smack. Opioids can be taken orally,
sniffed, smoked, absorbed through the skin, or injected (most
common route of administration for heroin). Heroin may be “cut”
with adulterants such as quinine, cornstarch, or powdered baby
formula. Heroin’s short half-life requires use multiple times per
day to avoid withdrawal. The diagnosis of opioid use disorder
(OUD) is based on specific criteria defined by the Diagnostic and
Statistical Manual of Mental Disorder, Fifth Edition (DSM-5),
and is graded as mild (2–3), moderate (4–5), or severe (6 or more)
depending on the number of recurring symptoms (Table 23.7).
Maternal-Fetal Evidence Based Guidelines
TABLE 23.7: DSM-5 Criteria for Diagnosis of Opioid
Use Disorder
Opioids are often taken in larger amounts or over a longer period of time
than intended.
There is a persistent desire or unsuccessful efforts to cut down or control
opioid use.
A great deal of time is spent in activities necessary to obtain the opioid,
use the opioid, or recover from its effects.
Craving, or a strong desire to use opioids.
Recurrent opioid use resulting in failure to fulfill major role obligations at
work, school or home.
Continued opioid use despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of opioids.
Important social, occupational or recreational activities are given up or
reduced because of opioid use.
Recurrent opioid use in situations in which it is physically hazardous.
Continued use despite knowledge of having a persistent or recurrent
physical or psychological problem that is likely to have been caused or
exacerbated by opioids.
aTolerance, as defined by either of the following:
a. A need for markedly increased amounts of opioids to achieve
intoxication or desired effect
b. Markedly diminished effect with continued use of the same amount
of an opioid
Withdrawal, as manifested by either of the following:
a
c. The characteristic opioid withdrawal syndrome
d. The same (or a closely related) substance are taken to relieve or avoid
withdrawal symptoms
Source: Adapted from Ref. [237].
a Criteria not met for those taking opioid solely as under medical supervision
Severity: Mild: 2–3 symptoms. Moderate: 4–5 symptoms. Severe: 6 or more
symptoms.
Symptoms
Opioids reduce pain but can also cause a sense of euphoria
which can lead to misuse. However, opioids also can affect mul-
tiple organ systems (e.g., sedation, hypotension, constipation,
urinary retention, sedation, miosis). Withdrawal presents as
abdominal cramps, restlessness, insomnia, mydriasis, tachycar-
dia, tachypnea, hypertension, lacrimation, rhinorrhea, yawning,
piloerection, drug craving, irritability, and anxiety. Withdrawal
symptoms may start within 4–6 hours and last up to 1 week
(longer for methadone) [6]. The Clinical Opioid Withdrawal Scale
(COWS) is a validated and freely available tool to determine the
severity of withdrawal and guide treatment (Table 23.8). Opioid
overdose, the most serious complication, presents with respira-
tory depression, miotic pupils, pulmonary edema, obtundation,
and/or coma. Overdose because of opioids is usually managed by
securing an airway, supporting respiration, and administration of
naloxone (Narcan).
Epidemiology/Incidence
The United States is amidst an opioid epidemic. Between 1999
and 2014 the prevalence of OUD quadrupled reaching 6.5/1000
delivery hospitalizations. While no state has been exempt from
the rise in OUD the prevalence varies from 0.7 to 48.6/1000 [56].
Other estimates indicate that 5.6–12/1000 pregnant patients
reported misuse of prescription opioid analgesics [12, 57].
Heroin use more than doubled from 2004– 2005 through 2012–
2013, along with the rise in prescription opioid misuse, but has
Substance Use Disorders 239

TABLE 23.8: Clinical Opioid Withdrawal Scale (COWS)

Resting Pulse Rate (beats/minute) GI Upset
Measured after patient is sitting or lying for one minute Over last 1/2 hour
0 pulse rate 80 or below 0 no GI symptoms
1 pulse rate 81–1 00 1 stomach cramps
2 pulse rate 101–120 2 nausea or loose stool
4 pulse rate greater than 1 20 3 vomiting or diarrhea
5 multiple episodes of diarrhea or vomiting
Sweating Tremor
Over past 1/2 hour not accounted for by room temperature or Observation of outstretched hands
patient activity 0 no tremor
0 no report of chills or flushing 1 tremor can be felt, but not observed
1 subjective report of chills or flushing 2 slight tremor observable
2 flushed or observable moistness on face 4 gross tremor or muscle twitching
3 beads of sweat on brow or face
4 sweat streaming off face
Restlessness Yawning
Observation during assessment Observation during assessment
0 able to sit still 0 no yawning
1 reports difficulty sitting still, but is able to do so 1 yawning once or twice during assessment
3 frequent shifting or extraneous movements of legs/arms 2 yawning three or more times during assessment
5 unable to sit still for more than a few seconds 4 yawning several times/minute
Pupil size Anxiety or Irritability
0 pupils pinned or normal size for room light 0 none
1 pupils possibly larger than normal for room light 1 patient reports increasing irritability or anxiousness
2 pupils moderately dilated 2 patient obviously irritable or anxious
5 pupils so dilated that only the rim of the iris is visible 4 patient so irritable or anxious that participation in the
assessment is difficult
Bone or Joint Aches Gooseflesh Skin
If patient was having pain previously, only the additional 0 skin is smooth
component attributed to opiates withdrawal is scored 3 piloerection of skin can be felt or hairs standing up on
0 not present arms
1 mild diffuse discomfort 5 prominent piloerection
2 patient reports severe diffuse aching of joints/muscles
4 patient is rubbing joints or muscles and is unable to sit still
because of discomfort
Runny Nose or Tearing Total Score
Not accounted for by cold symptoms or allergies
0 not present
1 nasal stuffiness or unusually moist eyes
2 nose running or tearing
4 nose constantly running or tears streaming down cheeks
Score: 5–12 = Mild; 13–24 = Moderate; 25–36 = Moderately severe; More than 36 = Severe withdrawal
Source: Adapted from Ref. [240].
Choose the score that best represents the patient’s symptoms. Rate on just the relationship to opioid withdrawal (i.e., consider factors that
would otherwise raise the patient’s score and are not due to withdrawal).

since returned to baseline levels (5/10,000 in 2016–2017) [58]. Risk factors/Associations

Oxycodone and hydrocodone are the most commonly abused
prescription opioid analgesics. Among pregnant patients misus-
ing opioids, 46% reported receiving those opioids from their own
doctor [59]. In 2012, of 21553 pregnant substance use treatment
admissions, 23% reported heroin use and 28% reported non-her-
oin opioid misuse [60]. In tandem with the rise in OUD, Neonatal
Opioid Withdrawal Syndrome (NOWS) increased five-fold
from 2004 to 2014 (14.4/1000 births in a Medicaid population;
5/1000 births overall) [6, 61]. Presently, maintenance medica-
tions for OUD (e.g., buprenorphine) account for the majority of
NOWS. Opioid misuse decreases during pregnancy reaching the
lowest rate in the third trimester.
Many pregnant patients with OUD are younger (68%, 12–25 years
old), unmarried (18–77%), poorly educated (20–38% finished high
school), lower income (44%, <$20K), report fair to poor health
(22%), have no or government health insurance (75%) [55, 62]. The
percentage who do not receive prenatal care is as high as 80% [55].
Polysubstance abuse (particularly tobacco [95%], alcohol, mari-
juana, and benzodiazepines), concomitant mental illness (e.g.,
depression and/or anxiety 26–30%), domestic violence, a history
of physical or sexual assault (40–70%), and self-reported stress
are common [62, 63]. Despite these associations, patients who
use opioids during pregnancy are a diverse group; OUD affects
patients of all backgrounds.
240
Complications
Although females tend to use smaller amounts of heroin and are
less likely to inject it compared to males [63], determining whether
there has been parenteral opioid use (particularly needle shar-
ing) is important since it accounts for much of the obstetrical
issues. Of concern are infections, especially hepatitis B, hepa-
titis C, and HIV. Other sequelae include, but are not limited to,
bacteremia/sepsis, cellulitis, endocarditis, tuberculosis/pneu-
monia, and sexually transmitted infections [64]. However, the
greatest risk is maternal mortality. Opioids accounted for 10% of
pregnancy-associated deaths (4.2 deaths/100000 live births in
2016) [65]. The rise in overdose deaths can be partially attributed
to adulteration of heroin with fentanyl often without the knowl-
edge of the user. Illicitly manufactured fentanyl, a synthetic
opioid 50-100 times more potent than morphine, is used to cut
heroin because of potency, low cost and ease of smuggling (largely
from China) [66].
Recent literature on obstetrical complications pertains mainly
to patients receiving medications for opioid use disorder (MOUD).
For this section, these studies were largely excluded. Few studies
have independently evaluated non-supervised or “street” metha-
done or misuse of prescription opioid analgesics. Complications
related to illicit opioid use and prescribed opioids when used as
directed use may not be comparable. It is important to keep in
mind that opioids are themselves a treatment for OUD.
• Congenital anomalies: There is no established increased
risk of congenital anomalies or pattern of malformations
related to fetal opioid exposure [1]. A recent systematic
review identified 30 studies which included an unexposed
comparison group. Significant associations were reported
for oral clefts (n = 3 case-control studies), congenital heart
disease (ventricular and atrial septal defects: n = 3 case-
control studies, n = 6 cohort studies, CHD), spina bifida (n
= 2 case-control studies), and clubbed foot (n = 2 cohort
studies). Uncertainty remains about the teratogenicity of
opioids because of the variety of exposures (including: her-
oin, reported “opioid abuse”, urinalysis positive for opioids,
and MOUD) and lack of high quality studies [67]. Under
the previous FDA medication labeling system, most pre-
scription opioid analgesics are category B and C.
• Obstetrical complications: Heroin use is associated with
a six-fold increase in obstetric complications [68]. When
the results of four observational studies are averaged, the
rate of preterm birth (PTB) is 28% (range 17–45%) among
pregnant patients addicted to heroin [69]. The incidence
of meconium staining ranges from 21–46% compared to
12–13.8% in drug-free controls [55]; however some stud-
ies have reported no difference. Additionally, there are
higher rates of abruption and stillbirth [6]. A retrospec-
tive cohort study examining the effect of the type of nar-
cotic used demonstrated rates of “fetal distress” between
47% and 52% for pregnant patients abusing unsupervised
methadone, heroin, and polydrug abuse [70]. Respiratory
distress may be less common because of fetal stress from
repeated episodes of withdrawal.
• Fetal/neonatal morphometrics: Heroin use is associated with
decreased birth weight. In a retrospective study, mean
birth weight of infants exposed to heroin during pregnancy
was lower than controls (2490 g vs. 3176 g) [71]. Combining
the results of four controlled studies yielded similar
results (mean 2553 g; –691 g compared to controls) [55].
Maternal-Fetal Evidence Based Guidelines
It is not entirely clear whether this is entirely due to heroin
or is secondary to other aspects related to heroin addic-
tion (e.g., malnutrition and smoking). One theory is that
heroin affects birth weight by lowering fetal plasma leptin
levels. Likewise, intrauterine growth restriction (IUGR)
and LBW are more common [6]. Averaging the results
from controlled studies, the rate of LBW is 41% (vs. 26%
in methadone, p ≤0.01 and 19% in drug-free controls, p ≤
0.0025) [55], much of which is due to a higher incidence
of IUGR (20% vs. 4%) [72], and SGA infants (18% vs. 12%
in methadone and 5% in drug-free controls) [55]. Chronic
opioid exposure sufficient enough to result in NOWS (87%
MOUD) was associated with a 1 cm decrease in average
head circumference (HC) compared to matched controls
[73]. In this study, the proportion with HC <10th percentile
and <3rd percentile was also higher in infants with NOWS.
• Neonatal withdrawal: Approximately 60% of opioid-
exposed neonates develop NOWS (range 26–95%) with
an average length of stay of 16.9 days (vs. 2.1 days with-
out NOWS) [74]. The reason why some infants develop
withdrawal is not well understood. A number of factors are
known to affect the risk of NOWS including polysubstance
abuse, and genetic and epigenetic factors to name a few but
MOUD dose (either methadone or buprenorphine) does
not influence the rate of NOWS [75, 76]. Co-prescription
of psychotropic medications also appears to be a factor
(1 psychotropic RR 1.37; 95% CI 1.26–1.49, 2 or more RR
2.05; 95% CI 1.77–2.37) [77]. Symptoms typically appear
within the first 72 hours after birth but can occur any
time within the first 2 weeks [6]. NOWS is characterized
by CNS hyperirritability, feeding difficulties, respiratory
distress, and autonomic symptoms [64, 78]. A study of a
small group of preterm neonates suggests that increased
cholinergic tone (leading to increased clearance time) and
increased lower esophageal sphincter tone is the reason
for feeding difficulties in infants with fetal opioid expo-
sure [79]. The most serious, life-threatening sequela of
NOWS is seizures. Up to 30% of opioid-exposed neonates
will demonstrate abnormalities on electroencephalo-
gram and historically 2–11% will have overt seizures [80].
However, in the current era of treatment for NOWS, sei-
zures are extremely rare. There are several scoring sys-
tems to measure the severity of NOWS, the most common
of which was proposed by Finnegan [81]. Neonates with
high NOWS scores (e.g., a cumulative Finnegan score of
≥24) may be candidates for replacement therapy (usually
neonatal opium solution, morphine, clonidine, or pheno-
barbital, but buprenorphine has also been recently studied
with promising results) [82].
• Long-term neonatal outcome: With the exception of meth-
adone, data on long-term outcome of infants with in utero
exposure to opioids are limited [83]. Video-taped interac-
tions between opioid dependent female parents and their
infants at four months showed, lower quality global rat-
ings of interaction quality compared to non–drug-exposed
dyads [78]. Studies have also reported greater body tension,
poorer coordination, increased temper, impulsivity, aggres-
siveness, poorer self-confidence, and impaired memory
and perception [84] Significant difference in cognitive,
psychomotor, or behavioral development was found in
a meta-analysis of five studies (218 infants and 224 pre-
school children) of infants whose main exposure was
Substance Use Disorders
illicit heroin [85, 86]. Magnetic resonance imaging (MRI)
of older children exposed to opioids in utero has shown
changes in cortical white matter microstructure and
reduced regional cerebral volumes compared to matched
controls [87]. Whether this is due to opioid exposure before
birth, other confounding exposures (e.g., polysubstance
use, smoking) or other postnatal exposure (e.g., parenting,
genetics) is unclear but a similar pattern is seen in MRI
imaging studies of opioid exposed newborns [87, 88]. The
finding of reduced volume of multiple brain structures
is consistent with finding of smaller mean HC and vali-
dates concerns about the potential effects on neurode-
velopmental outcome.
Therapy
Opioid agonist treatment with either methadone or buprenor-
phine is the standard treatment for opioid-use disorder with
dependence. The incidence of obstetrical complications is
lower among females undergoing treatment [6]. Randomized
controlled trials (RCTs) demonstrate an approximately three-fold
reduction in heroin use and a three-fold increase in retention in
treatment relative to non-pharmacological treatment [4, 89]. In
pregnancy, the maternal and fetal benefits are extensive and,
among others, include preventing complications of illicit drug
use (e.g., acquiring and vertically transmitting hepatitis C and
HIV), encouraging prenatal care and drug treatment, reducing
criminal activity, and avoiding other risks associated with drug
culture [6]. Long-term studies have shown that pregnant patients
enrolled in opioid maintenance therapy rarely resume illicit sub-
stance use and can maintain a relatively normal family life [1].
Opioid replacement is only one aspect of a comprehensive drug
treatment program however the addition of adjuvant psychosocial
treatments may not significantly improve treatment outcomes [90].
Two approaches to pharmacological treatment are mainte-
nance and detoxification. Maintenance therapy is the preferred
approach during pregnancy. The goal of maintenance therapy
is substitution of a licit opioid in quantities sufficient to pre-
vent symptoms of withdrawal and drug craving. Detoxification
(sometimes called “withdrawal” or “tapering”); however,
aims to replace illicit opioids with progressively lower doses of
a licit opioid until treatment is no longer required. Historically,
detoxification has been associated with miscarriage, stillbirth,
and alterations in fetal catecholamine levels. A meta-analysis,
including 14 studies (n = 1097 pregnancies), evaluated fetal loss
with detoxification. In 12 studies reporting a loss rate “during”
detoxification, there was only one loss in 888 pregnancies which
is not increased compared to the background rate [91]. In a simi-
lar metaanalysis (15 studies; n = 1126 pregnancies) the total fetal
loss rate was 1.24% in the detoxification group versus 1.95%
in the comparison group; most were unrelated to detoxifica-
tion [92]. While this seemingly supports the safety of detoxifica-
tion, these studies only measured “life-threatening” fetal stress.
Long-term neurodevelopmental harm may occur due to epigen-
etic programming from repeated episode of in utero stress related
to withdrawal [93]. Relapse rates average 35% (range 23–53%)
with detoxification leading to the typical recommendation for
maintenance; however, discontinuation rates of 23–34% among
pregnant patients enrolled in an opioid agonist treatment pro-
gram also cannot be ignored [83, 87]. These two approaches to
therapy have not been compared in RCTs of pregnant patients
and these studies will not likely be done soon due to ethical con-
cerns. Detoxification may be appropriate if the patient declines
241
MOUD or treatment is unavailable and should be accompanied
by behavioral health follow-up [6]. Patients who opt for detoxi-
fication after informed consent should not be shamed or penal-
ized in any way for their decision nor should they be prevented
from returning to maintenance therapy if they cannot tolerate
further dose reductions. Pregnant patients are given priority in
opioid maintenance programs. A list of providers can be found
at: https://findtreatment.samhsa.gov/TreatmentLocator/faces/
quickSearch.jspx.
Methadone
Methadone (FDA category C), a long-acting synthetic μ receptor
agonist. Four RCTs have shown that methadone maintenance
decreases illicit opioid use, criminal activity, and mortality
rates in non-pregnant heroin-addicted adults [94]. Typical
initial stabilization doses range from 10 to 30 mg with the dose
increased in 5 to 10 mg increments thereafter. The most appro-
priate methadone dose is controversial. Doses of at least 60 mg
are more effective than lower doses [4]. We recommend titrat-
ing the daily methadone dose to achieve the dose that effec-
tively prevents symptoms of withdrawal and drug cravings.
As a result of the physiologic changes that occur during preg-
nancy (decreased plasma levels and increased clearance) dose
increases are often needed in the later part of pregnancy to
prevent withdrawal. A methadone trough level may be useful
in guiding dose adjustments as symptomatic pregnant patients
have significantly lower mean methadone levels than asymptom-
atic pregnant patients (0.18 mg/L vs. 0.24 mg/L) [95]. Likewise,
trough levels >0.3 mg/L in symptomatic pregnant patients should
be clinically correlated to UDS results because of the possibil-
ity of withdrawal from other illicit substances. Rarely, split daily
dosing may be required because of rapid metabolism [6]. Caution
should be taken when prescribing other medications to pregnant
patients on methadone because of the potential for drug-drug
interactions. For example, both methadone and the commonly
prescribed antibiotic metronidazole increase the QTc interval,
which can lead to potentially fatal ventricular arrhythmias. The
rate of continued illicit substance abuse is 15–36% in some stud-
ies and this continued substance abuse may attenuate some of the
beneficial effects of drug treatment programs [69, 96].
The most common neonatal sequela of opioid exposure is
NOWS but methadone, like other opioids, has been associated
with decreased birth weight and HC [97] as well as jaundice
and thrombocytosis. Less commonly recognized is the effect
of methadone on the developing visual system. In a systematic
review of 12 studies (n=275 methadone-exposed vs. 128 unex-
posed), strabismus and nystagmus was present in approximately
50% of methadone-exposed neonates and differences were also
noted in visual evoked potentials [98]. Neither the long-term
effects nor the independent effect of other illicit substances are
clear. Maternal smoking, which is prevalent in this patient group,
has been associated with strabismus, optic nerve hypoplasia, and
decreased retinal nerve fiber layer thickness [99, 100].
Buprenorphine
Buprenorphine (Subutex, FDA category C) is a partial μ recep-
tor agonist and ĸ receptor antagonist. Randomized trials dem-
onstrate that buprenorphine increases treatment retention (RR
1.21–1.52) and decreases heroin use [3, 60] in non-pregnant
adults compared to methadone. Effectiveness during pregnancy
is similar to methadone [12]. The main advantages of buprenor-
phine are lower risk of overdose (“ceiling effect”) and respiratory
242
depression, fewer drug interactions, that it does not require
supervised daily administration [6]. Buprenorphine can be
prescribed by any physician with the appropriate credentialing
which improves accessibility and confidentiality and decreases
the social stigma [1]. On the other hand, induction is more dif-
ficult, and some patients express dissatisfaction likely due to
partial μ receptor agonist properties. Unlike methadone, dose
changes during pregnancy are less common.
The MOTHER Study randomized patients to either metha-
done or buprenorphine. The study found no difference in the
rate of neonatal treatment for NOWS (57% vs. 47%; p = 0.26) but
buprenorphine was associated with significantly lower doses of
morphine for treatment of NOWS (mean total amount 1.1 vs.
10.4 mg), shorter duration of treatment for NOWS (4.1 vs. 9.9
days), and shorter neonatal hospital stay (10.0 vs. 17.5 days) [96].
A limitation of the trial was a markedly higher attrition rate from
the buprenorphine treatment arm than from the methadone
arm (18% vs. 33%, p = 0.02). The Cochrane Systematic Review of
maintenance agonist treatments for opiate-dependent pregnant
patients, was updated in 2020 to include the MOTHER Study.
Compared to methadone, buprenorphine was not associated with
a difference in dropout (RR 0.66; 95% CI 0.37–1.20), continued
illicit heroin use (RR 1.81; 95% CI 0.70–4.68), rate of neonatal
treatment for NOWS (RR 1.19; 95% CI 0.87–1.63) or mean dura-
tion of treatment for NOWS (MD 0.00; 95%CI -0.03 to 0.03) [101].
Suboxone is a combination of buprenorphine and naltrex-
one in a 4:1 ratio. The addition of naltrexone is meant to deter
parenteral use and lowers the risk of diversion. Previous guide-
lines recommended use of the buprenorphine monoproduct dur-
ing pregnancy due to the theoretical risk of naloxone exposure
and withdrawal from misuse. A recent systematic review (n=5
studies, 291 buprenorphine-naloxone exposed dyads) dem-
onstrated similar pregnancy outcomes compared to other
MOUD [102]. As additional data becomes available supporting
the safety of the combination product, its use during pregnancy
is likely to continue to increase. There is no reason to preferen-
tially start a pregnant patient on the monoproduct or switch to
the monoproduct in a patient previously stable on the combina-
tion product.
Buprenorphine is available as an implant (Probuphine) and a
monthly extended-release subcutaneous injection. There are
no adequate or well-controlled studies of these formulations in
pregnant patients; however, the risks should be comparable to
buprenorphine in other forms and there is no reason to remove
the implant if a patient conceives while using it.
Other treatments
Other treatments for opioid-addicted pregnant patients, includ-
ing oral slow-release morphine, heroin-assisted treatment, and
L-A-acetylmethadol (LAAM), are of historical interest only.
Heroin-assisted treatment combines methadone with injectable
heroin and was used in patients with a history of addiction for
more than two years, failure of at least two alternative treatments,
and risk of further physical or social decline. Experience with
“heroin-assisted” treatment in pregnancy is limited to two case
series with a total of five pregnant patients. The authors observed
a higher birth weight compared to pregnant patients treated
with methadone alone [103]. LAAM is a μ receptor agonist with
a longer half-life than methadone. It was taken off the market in
2003 because of QT interval prolongation and the risk of poten-
tially life-threatening ventricular arrhythmias. Clonidine, an
α-agonist antihypertensive medication, has been used alone or
Maternal-Fetal Evidence Based Guidelines
in addition to other medications for mild withdrawal. Clonidine
prevents withdrawal symptoms through its α2-agonist proper-
ties. Naltrexone is an opioid receptor antagonist. Research con-
sists of two retrospective studies totaling 189 patients [104, 105].
Outcomes were similar to those of other MOUD but one study
found an increased risk of urogenital anomalies. While evidence
is insufficient to justify initiation of naltrexone during preg-
nancy it may be continued for those already taking it after
discussion of the potential risks but will make postpartum pain
management challenging since opioids will be ineffective.
In summary, treatments other than methadone or buprenor-
phine have limited evidence for safety and efficacy and should
be avoided in most cases.
Antepartum testing
Reports of an increased risk of intrauterine fetal demise (IUFD)
associated with intravenous opiate abuse [64] have led some
authors to suggest weekly fetal monitoring beginning at 32 weeks.
However, for pregnant patients in a treatment program who
have repetitively negative UDS, antepartum testing should
be reserved for standard obstetrical indications (e.g., IUGR).
Opiates are associated with decreases in baseline, variability,
and accelerations due to decreased movement reduced integra-
tion between heart rate and motor activity [106]. Ideally, to avoid
misinterpretation, pregnant patients on methadone or other pre-
scribed narcotics should have nonstress test (NST) or biophysical
profile (BPP) scheduled before or at least four to six hours after a
dose of methadone.
Delivery
As per common obstetric practices.
Anesthesia
MOUD should be continued throughout labor and delivery
as it is not part of the labor analgesia. Similarly, complaints of
pain should be taken seriously and not assumed to be drug seek-
ing behavior. Opioid antagonists or agonist-antagonists can
precipitate acute withdrawal [107]. Examples of these drugs are
Nubain®, Talwin®, Stadol®, and Narcan®. If any of these drugs are acci-
dentally given, withdrawal can also be reversed with any opioid
[107]. Regional anesthesia is safe. However, hypotension may occur
more frequently because of concomitant malnutrition and/or liver
disease. If general anesthesia becomes necessary, poor dentition,
airway burns, chronic lung disease, and decreased gastric empty-
ing may result in airway compromise [12]. Peripheral intravenous
access can be difficult in chronic intravenous drug abusers.
Unlike vaginal delivery, pregnant patients with OUD have
increased pain following cesarean section and opioid require-
ments are 30–100% greater than opioid-naïve patients however,
adequate postpartum analgesia can be obtained using scheduled
NSAIDs and higher opioid doses in conjunction with continued
MOUD [107–110]. Dosing of other opioid analgesics for pain con-
trol during labor and postpartum can be challenging because of
recent use or tolerance from chronic receptor stimulation [111]
Chronic opioid use also leads to hyperalgesia. Leveraging the
analgesic properties of buprenorphine by increasing the daily
dose and giving it as divided doses three to four times a day
can often achieve postpartum pain control after cesarean sec-
tion with minimal need for additional opioids [112]. The use of
transversus abdominus plane blocks (TAP) reduces postoperative
analgesia use and can be particularly helpful in achieving pain
control in this population.
Substance Use Disorders
Postpartum/Breastfeeding
Methadone or buprenorphine should be continued during the
immediate peripartum period. Oversedation from methadone
because of changes in volume of distribution and hepatic clear-
ance is rare in practice [113]. Dose reductions should be based on
clinical signs and symptoms rather than protocol and are rarely
needed in routine practice.
The AAP strongly advises against heroin while breastfeeding
as it may be hazardous to the infant and nursing mother [54].
Tremors, restlessness, vomiting, and poor feeding have been
reported in breastfed infants of patients using heroin [53]. Breast-
feeding is not contraindicated in patients taking opioids for acute
(e.g., oxycodone for postoperative pain) or chronic pain.
For those patients taking methadone, breastfeeding should
be encouraged, irrespective of dose, assuming the patient is
enrolled in a treatment program and remains abstinent [6, 49, 53,
54]. Potential benefits include improved maternal-infant bond-
ing and favorable effects on NOWS [49] [83–87]). However,
close observation is warranted since lethargy, respiratory diffi-
culty, and poor weight have also been observed [53]. Methadone
levels in human milk are <3% of the maternal weight-adjusted
dose and infant plasma concentrations are <3% of the mater-
nal trough concentration. With such low exposure, it is not
clear whether the favorable effects of breastfeeding on NOWS are
related to methadone in breast milk or the act of breastfeeding
itself [114].
Likewise, breastfeeding should also be encouraged while
taking buprenorphine [6]. While this contradicts the package
labeling, the amount of buprenorphine is breast milk is also
low. Infant exposure is <2.4% of the maternal weight-adjusted
dose [53] which is unlikely to have any negative effects on devel-
opment [49]. Similar to methadone, buprenorphine also appears
to have favorable effects on NOWS [49].
Cocaine (benzoylmethylecognine)
Historic notes
The leaves of the South American erythroxylon coca plant have
been consumed to increase energy and reduce fatigue and hunger
since as early as 3000 B.C. [115]. Cocaine was purified in 1862 by
Albert Neiman and while Sigmund Freud first introduced cocaine
into modern medicine in 1884 with his treatise “On Coca,” its use
as a topical anesthetic (cocaine-saturated saliva) dates back thou-
sands of years. Cocaine is still used in some ophthalmologic
procedures. Coca-Cola® contained cocaine until 1903; today the
soft drink still contains a non-narcotic extract prepared from the
coca plant.
Diagnosis/Definition
As a hydrochloride, cocaine (also known as Snow) is sold in the
form of a powder, or as granules or crystals. Crack, or crack
cocaine, is cocaine returned to its pure, alkalinized form by
heating it with baking soda and water. The name “Crack” comes
from the characteristic sound made during the “cooking” pro-
cess [115]. This form of cocaine is also called Rock, or Freebase.
Cocaine can be injected, snorted, or smoked (in cigarettes or with
marijuana). Inhalation is the preferred route of administration by
crack users.
Symptoms, signs and cardiopulmonary complications
Cocaine produces a brief euphoria by interfering with pre-synaptic
neurotransmitter uptake, thereby increasing sympathomimetic
243
neurotransmitters (serotonin, norepinephri (serotonin, norepi-
nephrine, and dopamine) [116]. Systemic effects include hyper-
tension (mean rise 25 mmHg systolic and 6 mmHg diastolic),
tachycardia (mean increase 20 beats per minute), and dilated
pupils [115]. More severe consequences include arrhythmias,
hypotension, myocardial infarction, seizures, stroke, gastroin-
testinal ischemia, thrombosis, hyperthermia, and sudden death.
Pulmonary complications of smoking crack include interstitial
pneumonitis, spontaneous pneumothorax, and “crack lung”
which is characterized by acute dyspnea, hypoxia, fever, hemop-
tysis, and respiratory failure. The active metabolites may have
delayed activity. The combination of cocaine and alcohol pro-
duces cocaetheylene which increases the risk of cardiac events
40-fold and sudden death 25-fold.
Pregnancy is associated with increased sensitivity of the
cardiovascular system to cocaine [117, 118]. Plasma cholinester-
ase activity, the enzyme responsible for metabolizing cocaine, is
decreased during pregnancy, which prolongs the adverse effects
of cocaine [119]. Additionally, other physiologic changes during
pregnancy (increased oxygen demand and limited or decreased
supply because of increases in heart rate, blood pressure and left
ventricular contractility) [116] increase the cardiopulmonary
toxicity of cocaine [119, 120].
Cocaine use may present as the constellation hypertension,
proteinuria, and edema, and therefore may be confused for pre-
eclampsia. Withdrawal symptoms from cocaine include drug
craving, fatigue, and mental depression.
Epidemiology/Incidence
Cocaine use peaked in the 1980s (8–17% in urban hospitals) [121]
and has since declined. From 1993 to 1995, cocaine use dur-
ing pregnancy was 9.1% at four urban centers by self-report or
positive meconium (3.4% history and positive meconium) [122].
According to another study, in the late 1990s, the prevalence
of cocaine use by pregnant patients was approximately 0.28%
(1/10th of overall drug use during pregnancy) [123]. More
recently, estimates in Brazil range from 1.7% (2002; third tri-
mester hair analysis of pregnant teens) to 4.6% (1999; meconium
and self-report) whereas estimates in Spain are 6.4% (2010; third
trimester hair analysis of pregnant teens) [124, 125]. Overall,
cocaine use decreases from the first to the third trimester but
relapse is common [126].
Etiology/Basic pathophysiology
Cocaine readily crosses the placenta and can be detected in fetal
blood and tissues. The myometrium, placenta and membranes
act as a reservoir for cocaine and its metabolites resulting in sus-
tained release and prolonged exposure [127]. The maternal and
fetal sequelae of cocaine are related to the effects of cocaine on
the cardiovascular system [120, 128]. Uterine artery vasospasm
and vasoconstriction in response to cocaine-mediated increases
in norepinephrine results in decreased uteroplacental blood flow
and uteroplacental insufficiency, which can lead to fetal acidosis,
hypoxia, and distress. Furthermore, cocaine metabolites cause fetal
oxidative stress and further contribute to the morbidity of prenatal
cocaine use [125]. Increased maternal plasma norepinephrine
also stimulates uterine contractions as do the β-agonist prop-
erties of cocaine [123], an effect that has been reproduced in vitro
[129]. Uterine contractions and acute vasoconstriction of vessels
in the placental bed are thought to be the mechanisms of abrup-
tion related to cocaine use [119, 130]. Cocaine can potentiate the
effects of or be potentiated by other drugs. Cocaine is metabolized
244
through the liver hence preexisting liver disease may potentiate
its’ effects. Cocaethylene is a biologically active substance with
unknown reproductive effects [120].
Risk factors/Associations
As with other substances, female patients who use cocaine are
more likely to use other illicit substances, tobacco, and/or alco-
hol. Cocaine use during pregnancy is more common among
Black patients compared with the racial distribution of other
substances. Pregnant patients who use cocaine also tend to be
older, have less than a high school education, higher gravidity,
and are more likely to have had a prior abortion [121]. Poverty,
poor nutrition, depression, physical abuse, poor social support,
and sexually transmitted infections have also been associated
with cocaine use.
Maternal and perinatal complications
• Congenital anomalies: Cocaine use alone (RR 1.7; 95% CI
1.12–2.60) or in addition to other drugs (RR 2.10; 95% CI
1.42–3.09) during pregnancy is associated with a higher
rate of congenital malformations which is likely the
effect of factors other than cocaine itself [122, 131, 132].
The overall rate of malformations is 10% [115]. A similar
association was not found with crack cocaine use (OR 0.91;
95% CI 0.39–2.11) [133]. Vasoconstriction leads to dis-
ruption of the fetal bowel (atresia, infarction, perforation,
necrotizing enterocolitis in the neonate), CNS (microceph-
aly in 16%, porencephaly), structural or functional CHD
(arrhythmias, conduction abnormalities, etc.), and/or limb
(reduction). Exposure to cocaine has been suggested in the
etiology of hydranencephaly [120, 134].
• Obstetrical complications: Miscarriage, shorter gesta-
tion (cocaine: –1.47 weeks 95% CI95% CI –1.97 to –0.98
weeks), PTB (cocaine: OR 3.38; 95% CI 2.72–4.21, crack:
OR 2.22; 95% CI 1.59-3.10), PPROM (cocaine alone: RR
1.85: 95% CI 1.35–2.52, cocaine with other drugs: RR 3.18:
95% CI 1.61–6.29), abruption (cocaine alone: RR 4.55:
95% CI 3.19–6.50, cocaine with other drugs: RR 4.95; 95%
CI 2.08–11.81, crack: OR 2.03; 95% CI 1.66–2.48), pre-­
eclampsia, stillbirth (cocaine: 18.2%) [135], meconium
staining of the amniotic fluid and fetal heart rate abnor-
malities are the most frequently cited obstetrical compli-
cations of cocaine and crack cocaine use [18, 120, 121, 132,
133, 136, 137]. Unsurprisingly, patients who use cocaine
during pregnancy are four times more likely to require
emergent delivery. Precipitous delivery is also common
(13.4%) [138]. Unlike cocaine, crack was not associated with
stillbirth [133]. Pregnant patients presenting with PPROM
in association with cocaine exhibit more advanced cervi-
cal dilation and shorter latency [139, 140]. Body packing,
the ingestion of multiple packets of cocaine for the purpose
of smuggling, can cause serious complications if a packet
ruptures and at least one case of perimortem cesarean sec-
tion has been reported in this situation [141]. Cocaine use
increases vertical transmission of HIV four-fold [142].
• Fetal/neonatal morphometrics: Cocaine and crack cocaine
are associated with decreased birth weight (cocaine:
–492 g; 95% CI –562 to –421 g), LBW (cocaine: OR 3.66; 95%
CI 2.90–4.63, crack: OR 2.80; 95% CI 2.39–3.27), IUGR,
SGA infants (cocaine: OR, 3.23; 95% CI 2.43–4.30, crack:
OR 4.00; 95% CI 1.74–9.18), decreased HC (cocaine: –1.21
to –1.72 cm, crack: –1.65 cm; 95% CI –3.12 to –0.19 cm),
Maternal-Fetal Evidence Based Guidelines
and decreased length (cocaine: –2.17 to –2.57 cm) [104,
107, 114]. Poor placental perfusion and appetite suppres-
sion leading to poor maternal weight gain are hypothesized
to cause the observed changes in growth. Head circumfer-
ence continues to lag during the first 2 years of life among
children born with microcephaly.
• Neonatal withdrawal: Abrupt discontinuation of cocaine at
birth results in a constellation of symptoms, best described
as “neonatal toxicity”. These symptoms include jitteri-
ness/tremulousness (OR 2.17; 95% CI 1.44–3.29), high
pitched cry (OR 2.44; 95% CI 1.06–5.66), irritability (OR
1.81; 95% CI 1.18–2.80), excessive suck (OR 3.58; 95% CI
1.63–7.88), hyperalertness (OR 7.78; 95% CI 1.72–35.06),
and autonomic instability (OR 2.64; 95% CI 1.17–5.95) and
typically occur in the first 2–3 days of life [122]. Dystonic
movements, abnormal sleep, poor feeding, vomiting, diar-
rhea, sneezing, hyperactive Moro reflex, tachypnea, hyper-
tonia, and convulsions have also been reported.
• Long-term neonatal outcome: Initial studies reported
adverse neurological consequences of antenatal cocaine
exposure (so-called “crack babies”); however, more recent
studies have found that much of the effect is related to co-
occurring exposures and associated sociodemographic
factors (e.g., poverty). Nonetheless, cocaine is not without
consequence. Cocaine stimulates increases in dopamine,
serotonin, and norepinephrine in the fetal brain leading
to changes in neuronal organization, cell organiza-
tion, and cell differentiation which alters brain devel-
opment [143]. Brain MRI of these children shows lesser
total gray matter especially in the prefrontal and frontal
regions [144]. Microcephaly is a poor prognostic factor.
Children followed up to 15 years demonstrate attention
and behavioral problems, particularly poorer external-
izing behaviors like aggression, risk taking, and delin-
quency [145]. Internalizing behaviors (e.g., depression,
anxiety, withdrawal) are also more common. These behav-
iors may, at least in part, explain the increased incidence
of teen substance use and abuse/dependence in teens with
prenatal cocaine exposure [146]. Some, but not all stud-
ies, have found deficits in language (due to differences in
auditory comprehension), learning and cognition includ-
ing short-term memory, executive function learning, visual
spatial/math skills, problem solving, abstract reasoning,
and attention (e.g., ADHD) [145]. Cocaine also has effects
on the visual system. Strabismus and refractive errors are
more likely among children prenatally exposed to cocaine.
Cases of permanent eyelid edema have also been reported.
In follow-up of children at 15 years, antenatal exposure to
cocaine was associated with reduced weight, height, and
HC. Reports of obesity are likely explained by poor mater-
nal nutrition and LBW, which has been linked to later
excessive weight gain.
Therapy
There are currently no FDA-approved pharmacologic therapies
available for detoxification or maintenance of cocaine depen-
dence. Interventions for cocaine dependence primarily involve
psychosocial therapies (e.g., cognitive behavioral therapy, moti-
vational interviewing). Very few interventions have been specifi-
cally studied in pregnancy. Treatment programs for cocaine have
a favorable impact on pregnancy outcome; rates of PTB and LBW
were decreased by 67% and 84% [128]. Motivational enhancement
Substance Use Disorders
therapy was compared to “usual” counseling for pregnant
patients abusing cocaine in a randomized trial that found no dif-
ference in treatment utilization. The use of motivational incen-
tives, also known as voucher-based contingency management,
was studied in a small, RCT of pregnant patients abusing cocaine.
Treatment retention and abstinence from cocaine was high in
both groups and there was a trend toward increased attendance at
prenatal care visits (p = 0.077) [147]. In a separate study, motiva-
tional interviewing was associated with a significant reduction
in neonatal intensive care unit admission (NICU) and length of
stay and cost savings amounted to $5000 per mother/infant pair
above the cost of the program [148]. A recent pilot study demon-
strated that progesterone may have some promise as a treatment
for cocaine use disorder in postpartum patients [149].
Withdrawal from cocaine is usually mild, if present, and not
life threatening for the mother or fetus. Benzodiazepines can
be given to relieve symptoms [123]. Rarely, psychotic symptoms
during withdrawal may require treatment with antipsychotic
medications.
Antepartum testing
The role of antepartum testing (ultrasound and NST or BPP) for
cocaine use is insufficiently studied to make recommendations.
Based on expert opinion, weekly antenatal testing is recom-
mended starting at 32 weeks [150].
Anesthesia
Regional anesthesia should be used with caution because of
combative behavior, altered perception of pain, cocaine-induced
thrombocytopenia, and ephedrine-resistant hypotension (usually
responds to phenylephrine). The perception of pain may con-
tinue despite adequate spinal/epidural anesthesia levels [134].
Hydralazine is the drug of choice for management of cocaine-
induced hypertension, but treatment with labetalol plus nitro-
glycerin may be a reasonable alternative [52, 111]. Propranolol
should be avoided because of the potential for unopposed
α-adrenergic stimulation however labetalol is generally consid-
ered safe. The use of general anesthesia also presents challenges;
all volatile anesthetics can cause arrhythmia and increased
systemic vascular resistance [52, 111].
Postpartum/Breastfeeding
The AAP strongly advises against cocaine use while breastfeed-
ing as it may be hazardous to the infant and nursing mother [54].
Cocaine intoxication, seizures, irritability, vomiting, diarrhea,
and tremulousness has been reported in breastfed infants of
patients using cocaine [53].
Amphetamines: Amphetamine,
methamphetamine, 3,4-
methylenedioxymethamphetamine
(ecstasy), cathinones (khat, “bath salts”)
Historic notes
Amphetamines were first synthesized in 1887 [151]. Amphetamine
is FDA approved (schedule II) for the treatment of atten-
tion-deficit hyperactivity disorder (ADHD) and narcolepsy.
The more potent stimulant, methamphetamine (schedule II),
is FDA approved for the treatment of ADHD and obesity.
Methamphetamine is easily made from over-the-counter cold
medications and addiction can occur after as little as one use
245
[152]. Ecstasy, which is chemically similar to methamphetamine,
was patented in 1912 [153]. In the 1970s, psychotherapists used
ecstasy to enhance “openness” with their patients [153]. Ecstasy
was classified as a schedule I drug in 1985 [153]. Khat is a shrub
(Catha edulis) native to the Southwestern Arabian Peninsula and
Eastern Africa. Chewing khatpyy has been chewed for centuries
because of stimulant and euphoric effects. The active ingredi-
ent is β-ketoamphetamine, a cathinone with properties that are
similar to amphetamine [154]. Bath salts are a group of synthetic
cathinones (naturally occurring alkaloids which are chemically
similar to amphetamines) with amphetamine-like stimulant
properties. Bath salts, sometimes also sold as “jewelry cleaner”,
“phone screen cleaner”, or “plant food”, get their name from the
resemblance of the white or beige crystalline powder to the real
thing [154]. Bath salts are not detected on routine urine drug
screens.
Diagnosis/Definition
Amphetamines are a group of synthetic stimulants which are
structurally similar to norepinephrine [155]. Amphetamines
increase levels of norepinephrine, serotonin, and dopamine
by increasing release and blocking re-uptake [156]. Street
names for amphetamines include Dexies (dextroampheamine),
Bennies (Benzedrine), Speed, Ice, and Crystal (methamphet-
amine). Bath salts are often call Blizzard, Cloud 9, Ivory
Wave, or Meow [154]. Amphetamines can be injected,
snorted, smoked (78.3% for methamphetamines), or taken
orally or anally [157]. Ecstasy is typically taken as a pill but is
also found in a powder form referred to as “Molly”. Gamma-
hydroxybutyrate (GHB) is sometimes referred to as “Liquid
Ecstasy” but is chemically and pharmacologically unrelated
to 3,4-methylenedioxymethamphetamine.
Symptoms, signs and organ toxicity
Symptoms of amphetamine and synthetic cathinone intoxication
include increased energy, alertness, sleeplessness, euphoria,
exhilaration, emotional openness, reduction of negativity,
and decreased inhibition anxiety, agitation, violent behav-
ior, tachycardia, hypertension, hyperthermia, diaphoresis,
dilated pupils [158]. Other systemic effects include tachycardia,
hypertension, dilated pupils, tremor, agitation, confusion, and
hyperactivity [155]. Rarely, at high doses, toxicity mimicking
that of cocaine, including paranoia, psychosis, delirium, violent
behavior, serotonin syndrome, hyponatremia, hypertension, reti-
nal damage, cardiac arrhythmia, myocardial infarction, cardio-
myopathy, rhabdomyolysis, hyperthermia, seizure, shock, stroke,
and death [154, 155].
The alpha- and beta-adrenergic properties of amphetamines
are responsible for the cardiovascular effects of amphetamines.
Release of serotonin is responsible for some of the hallucino-
genic effects of amphetamines [155]. Amphetamine use can dam-
age brain structures including the grey matter, temporal lobe, and
basal ganglia. Methamphetamine abuse can cause toxic hepatitis,
which presents similarly to acute viral hepatitis. Consequences
of long-term methamphetamine use include anxiety, confusion,
insomnia, memory loss, weight loss, dental problems (“meth
mouth”), depression, violence, paranoia, hallucinations, and
formication [156]. Symptoms of amphetamine and synthetic
cathinone withdrawal are mild and not life-threatening (e.g.,
depression, insomnia) but some users have reported symptoms
of psychological dependence (e.g., drug cravings) weeks after
discontinuation.
246
Ecstasy produces symptoms of euphoria, intimacy, and
decreased anxiety. Methylenedioxyproalevone, a constituent of
bath salts, can cause hypertension and acute neurological, car-
diovascular, and psychiatric symptoms.
Epidemiology/Incidence
Amphetamines are the most abused prescription medication
[159] and are overall the second most commonly abused drug
worldwide. They are one of the most addictive substances even
after a single use. Despite similarity with cocaine, the greater
popularity of amphetamines is likely related to longer half-
life, greater sympathomimetic effects, lower cost, and greater
accessibility [160]. Amphetamine-related deliveries doubled
from 2008–2009 to 2014–2015 from 1.2% to 2.4% [161]. 1% of
reproductive age female patients reported prescription amphet-
amine misuse [162]. In recent years, hospitalization for amphet-
amine abuse by pregnant women has increased 2-3 fold [157, 163].
Methamphetamine, the most commonly abused amphetamine,
is an escalating problem in the United States and other parts of
the world [153, 156, 164]. The reported incidence of metham-
phetamine use during pregnancy is between 0.1–1.0%, and up
to 5.2% in the highest use areas [165, 166]. Methamphetamine
use during pregnancy is significantly more common in rural
counties and the poorest zip codes, and in the West, Midwest,
and Southern United States [161]. Methamphetamine accounts
for nearly a quarter of drug treatment admissions during preg-
nancy [157]. The rate of ecstasy exposure during pregnancy is
less clear. Ecstasy is one of the most widely used illicit drugs in
the United Kingdom where the rate of self-reported use ranged
from 0.6% to 8.8% in 2004 [153]. In the United States, ecstasy use
peaked in 2001 and has since declined. There has been a recent
epidemic of bath salt use but prevalence in pregnancy is not well
characterized.
Etiology/Basic pathophysiology
Methamphetamine crosses the placenta and is detectable in
fetal tissues. Studies of methamphetamine in pregnant sheep
suggest that vasoconstriction may be one of the mechanisms
that leads to obstetrical and neonatal complications [167].
Vasoconstriction in turn leads to chronic hypoxia as evidenced
by increased placental weight and surface area, larger placenta-
to-birthweight ratio, and increased intrauterine passage of meco-
nium observed in studies of human subjects [168]. Abruption is
thought to be due to amphetamine-mediated platelet activa-
tion and uterine contractions [13]. Methamphetamine causes
oxidative DNA damage which is postulated to be the cause of
reduced volume of several brain structures and associated neuro-
developmental deficits [169].
Risk factors/Associations
In general, poor health and nutrition, infection with HIV and
hepatitis C, psychosocial issues (e.g., history of trauma), mental
health conditions (e.g., schizophrenia, PTSD), low rates of access-
ing care, and involvement in the criminal justice system are
common among those with amphetamine use disorder. Other
characteristics of amphetamine using mothers include late ini-
tiation of prenatal care, fewer prenatal care visits, lower SES, less
education, less likely to have private insurance, less likely to have
social support, and are more likely to be homeless, victims of
domestic violence, involved in criminal activity, have comorbid
psychiatric conditions, and engage in risky sexual behavior [170].
Pregnant methamphetamine users are more likely to be young,
Maternal-Fetal Evidence Based Guidelines
white (although an increasing proportion are Hispanic), and
unmarried [156]. As with most illicit substances, polysubstance
abuse is common. Patients who use ecstasy during pregnancy
are more likely to be younger (mean 23.2 years vs. 31.2 years,
p < 0.0001), report that the pregnancy was unplanned (84% vs. 54%,
p < 0.05), use alcohol (66% vs. 31%, p < 0.0001), smoke cigarettes
(54% vs. 20%, p < 0.0001), and use other illicit drugs during preg-
nancy compared to nonusers [170, 171].
Complications
Given that amphetamines and cocaine have similar effects on
the CNS, both agents produce similar effects during pregnancy
and are often combined in studies. Amphetamines concentrate
in the fetus at levels that eventually exceed those in the mother
[13]. Proving an association between amphetamines and adverse
outcomes is difficult because of multiple accompanying con-
founders. This section does not consider the risks of prescription
stimulants taken as directed. There is limited data on the obstet-
ric and neonatal effects of synthetic cathinones but the effects
would be expected to be similar to amphetamines or natural
cathinones. Except for congenital anomalies, the obstetrical and
neonatal complications of ecstasy use are insufficiently studied.
• Congenital anomalies: A variety of birth defects have
been reported in association with periconceptional use of
amphetamines. Vasoconstriction, a common property of
stimulants, is believed to play a role in the pathogenesis
of gastroschisis which has been reported in association
with pre-pregnancy methamphetamine use (OR 7.15; 95%
CI 1.4–38.0) [172]. However, the best available evidence
suggests that exposure to amphetamines, excluding
ecstasy, during pregnancy is unlikely to cause congeni-
tal anomalies [156, 160]. Likewise, prescription stimulants
do not appear to increase the risk of congenital anoma-
lies. Data from the United Kingdom National Teratology
Information Service demonstrated a 15% rate of congeni-
tal anomalies after prenatal ecstasy exposure (expected
2–3%). Among these malformations, talipes equinovarus
occurred more frequently than expected (all three female,
38/1000; 95% CI 8.0–109.0/1000 vs. expected 3:1 male pre-
dominance, 1/1000) [173]. There was also a trend toward
higher-than-expected rates of congenital heart disease
(26/1000; 95% CI 3.0–90.0/1000 vs. expected 5–10/1000).
Chemical additives used to expand drug volume (e.g.,
talc, inositol, methylsulfonylmethane) pose an unknown
risk of congenital anomalies [156]. Khat does not appear to
increase the risk of congenital anomalies [162, 174].
• Obstetrical and neonatal complications: Studies of amphet-
amine-exposed patients have shown increased risks of PTB
(OR 4.11; 95% CI 3.05–5.55), LBW (OR 3.97; 95% CI 2.45–
6.43) and SGA (OR 5.79; 95% CI 1.39–24.06) [175]. Mean
difference in birthweight was –279 grams (95% CI –485 to
–74 g). In a study using deliveries from 2004–2015 in the
National Inpatient Sample amphetamine exposure (defined
by ICD-9 for amphetamine dependence, use, or poisoning)
was associated with a two times higher incidence of pre-
eclampsia as compared to other hospital deliveries (9.3%
versus 4.8%) [161]. In a meta-analysis of case-control stud-
ies (8 studies) evaluating outcomes in pregnancies (n = 626)
complicated specifically by methamphetamine use there
was a small reduction in length of gestation (–0.9 weeks
95% CI –0.11 to –1.69 weeks) but no difference in other
Substance Use Disorders
obstetrical outcomes [176]. More recently a cohort study
of methamphetamine-exposed newborns in the Czech
Republic showed a similar decrease in length of gestation
(–0.9 weeks) but the finding was no longer significant after
adjusting for confounding factors [177]. These findings
contrast with an earlier study not included in the meta-
analysis. Complications that occurred significantly more
frequently included gestational hypertension (OR 1.8; 95%
CI 1.6–2.0), pre-eclampsia (OR 2.7; 95% CI 2.4–3.0), IUFD
(OR 5.1; 95% CI 3.7–7.2), abruption (OR 5.5; 95% CI 4.9-
6.3), PTB (OR 2.9; 95% CI 2.7–3.1), neonatal death (OR 3.1;
95% CI 2.3–4.2) and infant death (OR 2.5; 95% CI 1.7–3.7)
[160]. Amphetamine use during pregnancy is also associ-
ated with increased severe maternal morbidity and mortal-
ity (3.8% vs. 1.6%) and higher delivery costs (average $1100
difference) [161]. The effects of khat include PTB (OR 6.0;
95% CI 1.53–23.53), gestational hypertensive disorders,
fetal distress, perinatal mortality, and NICU admission
(OR 6.0; 95% CI 1.53–23.53) [174].
• Fetal/neonatal morphometrics: There is a consistent asso-
ciation between stimulant exposure and reduction in birth-
weight. A systematic review of 10 studies demonstrated a
279 g decrease in mean birthweight (95% CI –485 to –74g)
and increases in LBW (OR 3.97 95% CI95% CI 2.45–6.43),
and SGA (OR 5.79; 95% CI 1.39–24.06) among amphet-
amine-addicted pregnant patients [175]. Exposure to meth-
amphetamine specifically was associated with similar
reduction in birthweight (–215 g; 95% CI –0.11 to –1.69 g)
[176] in the meta-analysis mentioned earlier. The difference
was 285 g in the Czech cohort study but only 63 g after
adjusting for confounding factors [177]. IUGR, SGA (OR
2.05–3.5), LBW (OR 2.0), and decreased HC (–0.88 cm;
95% CI –0.48 to –1.28 cm), and length (–0.94 cm; 95% CI
–0.55 to –1.32 cm) [160, 167, 176]. Chewing khat increased
the risk of LBW (OR 8.94 95% CI 1.83–43.59) [174].
• Neonatal withdrawal: Neonatal withdrawal from amphet-
amines is characterized by abnormal sleep, poor feeding,
tremors, hypertonia, agitation, and tachypnea. Other new-
born findings include abnormal tone.
• Long-term neurodevelopmental outcome: Prenatal expo-
sure to amphetamines is associated with developmental
delays that are evident well beyond infancy. In a longitudi-
nal follow-up study in Sweden, the children demonstrated
deficits in behavior and school performance including
language, mathematics, and physical fitness at age 14 years
[178]. Earlier follow-up of these children showed increased
sleepiness, characteristics of autism, speech abnormali-
ties, and stranger anxiety by 1 year old, lower IQ at 4 years
old, and aggressive behavior and difficulty with peers at
8 years old [179]. This study included a relatively small sam-
ple and lacked a control group. EEG abnormalities, sensory
deficits, reduced attention, personality disorders, and poor
adaptation have also been reported. Correspondingly,
neuroimaging abnormalities are present within the first
2 months of life in neonates exposed prenatally to meth-
amphetamine [180, 181]. The IDEAL study examined
developmental outcomes of methamphetamine-exposed
children vs. matched controls. These children were more
likely to have poorer motor performance at 1 to 2 years
and behavioral problems, including emotional reactivity,
anxiety/depression, externalizing behavior (i.e. “lash-
ing out”) and ADHD, at 3 to 5 years [179, 182]. Further
247
follow-up of these same children at showed a much higher
likelihood of cognitive problems (OR 2.8; 95%CI 1.2–6.5)
at 7.5 years old [179] placing them at risk of poor academic
achievement and behavioral problems. MRI studies of chil-
dren up to 16 years old with prenatal exposure to metham-
phetamine showed smaller brain structures correlating
with impairment in executive functioning (e.g., attention
deficit) and verbal memory [183]. A cohort of infants fol-
lowed up to 24 months demonstrated fine and gross motor
deficits following in utero exposure to ecstasy [184].
Therapy
There are currently no FDA-approved medications available for
detoxification or maintenance of amphetamine dependence.
Nonetheless, these patients should be referred for treatment since
psychosocial interventions (e.g., cognitive behavioral therapy)
can be beneficial; due to the intensive schedule a residential cen-
ter may be preferred.
Antepartum testing
The role of antepartum surveillance for exposure to amphet-
amines is insufficiently studied to make recommendations. Based
on expert opinion, weekly antenatal testing is recommended
starting at 32 weeks [150].
Anesthesia
Sympathectomy caused by regional anesthesia can result in
profound hypotension in patients using amphetamines, and
vasopressors should be used with caution [52]. Small doses of
benzodiazepines may be useful for agitation. Dosing of general
anesthetics may be altered by acute and chronic amphetamine
use [52]. Inhalation agents which sensitive the myocardium to
endogenous catecholamines and should be avoided [52].
Postpartum/Breastfeeding
The AAP and ACOG strongly advise that patients should
not ingest amphetamines while breastfeeding [54, 156].
Amphetamines can decrease breast milk supply by inhibiting
prolactin release [156]. Additionally, amphetamines concentrate
in breastmilk resulting in levels 2.8–7.5 times higher than in
maternal plasma [156]. Adverse effects on the neonate have been
reported (irritability, poor sleep, hypertension, tachycardia, sei-
zures) [53, 54]. Infant fatality from continued methamphet-
amine use during breastfeeding has been reported [53]. Like
amphetamines, ecstasy is also concentrated in breast milk [53].
At prescription doses, methylphenidate levels in breast milk are
very low (relative infant dose 0.7%; <10% is generally considered
acceptable for breastfeeding) [185]. Patients who use khat and in
large quantities while breastfeeding report a high rate of a history
of child dying however it is unclear if the is due to khat or other
sociodemographic factors [186].
Benzodiazepines
Historic notes
Benzodiazepines have been studied as a potential treatment for
threatened abortion, preterm labor, pre-eclampsia, and as an
adjunct for pain management in labor. The term “Z-hypnotics”
refers to a group of medications that are both structurally simi-
lar to benzodiazepines and have a similar mechanism of action.
These are sometimes also referred to as “benzodiazepine-like” or
“benzodiazepine-related” medications.
248
Diagnosis/Definition
Benzodiazepines are a group of compounds formed through the
fusion of a benzene and a diazepine ring. They are categorized by
half-life as short, medium, and long acting. Street names for ben-
zodiazepines include Benzos, Downers, Nerve Pills, and Tranks.
Benzodiazepines are usually taken orally.
Symptoms
Benzodiazepines are sedative drugs, used mainly for the treat-
ment of anxiety, and have the potential for addiction. They act on
the GABA type A receptor inhibiting postsynaptic signaling.
Epidemiology/Incidence
At one time, benzodiazepines were the most commonly pre-
scribed drugs in pregnancy with up to 40% of pregnant patients
having been prescribed medication for anxiety [187]. More recent
estimates are much lower. Among privately insured pregnant
patients between 2006–2011, 2.7% were prescribed a benzodiaz-
epine or benzodiazepine-like medication [188] but in the National
Birth Defects Prevention Study dataset, the rate was much lower
(0.8%); this difference is likely attributable to the exclusion of ben-
zodiazepine-like medications [189]. Globally, the estimated rate
of benzodiazepine use during pregnancy is similar (1.9%; 95% CI
1.6–2.2%) [190]. The most commonly prescribed medications in
this class are lorazepam and zolpidem [190]. The incidence of illicit
benzodiazepine use is less clear but according to the 2019 NSDUH
1.8% of females 12 and older reported benzodiazepine misuse.
Etiology/Basic pathophysiology
Benzodiazepines cross the placenta with placental transfer
increasing as gestational age increases. Fetal and neonatal con-
centration vary between benzodiazepines. Whereas diazepam
levels in the neonate are one- to three-fold higher than those of
the mother, neonatal levels of midazolam are lower than those of
the mother [187].
Risk factors/Associations
Prescription benzodiazepine exposure in Swedish females is
associated with older age, higher incidence of smoking, less edu-
cation, and use of other psychoactive drugs [191]. Benzodiazepine
misuse, in isolation, is relatively uncommon and as such it is
not clear whether patient characteristics are similar to those who
use prescribed benzodiazepines.
Complications
A clear understanding of the effects benzodiazepines is limited
by significant heterogeneity between studies: benzodiazepines
studied as a class versus individual agents; effect of the underlying
medical condition (e.g., epilepsy) or obstetrical complication (e.g.,
pre-eclampsia); prescribed use of therapeutic doses versus illicit
use; chronic versus intermittent use; concomitant use of other
psychoactive drugs, illicit substances, tobacco, or alcohol. Mental
health conditions are independently associated with adverse birth
outcomes and can be difficult to differentiate from the effect of
the treatment. Most of the literature reflects outcomes in patients
using prescribed benzodiazepines however, to the extent possible,
this section considers the risks of benzodiazepines misuse. There is
essentially no data on z-hypnotics and pregnancy outcomes.
• Congenital anomalies: Early reports suggested an increased
risk of cleft lip and palate, but the absolute risk of oral cleft
from prenatal benzodiazepine exposure was increased by
only 0.01%, from 6 in 10,000 to 7 in 10,000 [192]. More
Maternal-Fetal Evidence Based Guidelines
recent meta-analyses have shown that prenatal benzodi-
azepine use is not associated with an increase in major
malformations [193–195]. Considering benzodiazepines
individually rather than as a class, the OR for anal atre-
sia was 6.15 (95% CI 2.44–15.74) following exposure to
lorazepam [195] while alprazolam was associated with an
increased risk of anophthalmia/microphthalmia (aOR 4.0
95% CI 1.2–13.1) and esophageal atresia or stenosis (aOR
2.7 95% CI 1.2–13.1) [189].
• Obstetrical and neonatal complications: Early preg-
nancy exposure to benzodiazepines is associated with
an increased risk of miscarriage (aOR 1.85; 95% CI 1.61–
2.12) [196]. An increased risk of PTB has been reported
in several studies (OR 2.03; 95% CI 1.11–3.69); exposure
in late pregnancy is associated with greater risk (early
exposure: aOR, 1.48 95% CI 1.26–1.75; late exposure
aOR 2.57; 95% CI 1.92–3.43) [197–199]. Increased risks
of cesarean section (OR 2.45; 95% CI 1.36–4.40), NICU
admission (OR 2.02 95% CI 1.11–3.66), and neonatal ven-
tilatory support (OR 2.85 95% CI 1.17–6.94) have also
been reported and remained after controlling for a pri-
mary diagnosis of anxiety or other mental health condi-
tions [200, 201].
• Fetal/neonatal morphometrics: Gestational age at delivery
appears to be the main driver of differences in birth weight
(e.g., increased LBW) [199]. On the other hand, small HC
was increased (OR 3.89; 95% CI 1.25–12.03) even after
using a propensity score to adjust for potential confound-
ing by multiple factors [200].
• Neonatal withdrawal: Neonatal withdrawal from ben-
zodiazepines is characterized by hypoventilation, irri-
tability, hypertonicity, and “floppy infant syndrome”
(hypotonia, lethargy, poor respiratory effort, and feed-
ing difficulties). Other withdrawal symptoms include
irritability, sleep disturbance, restlessness, hyperre-
flexia, tremulousness, jitteriness, and gastrointesti-
nal symptoms (diarrhea and vomiting) [202]. Symptoms
of withdrawal may be delayed, not occurring until day
12 to 21, and may last for several months [202]. We rec-
ommend, if clinically feasible, limiting administration of
benzodiazepines to pregnant patients, especially those
on methadone maintenance therapy. Benzodiazepine use
by these patients is associated with more severe neonatal
NOWS [76, 80, 94, 203]. In a multivariate analysis, the
mean length of treatment was two weeks longer among
neonates exposed to methadone and benzodiazepines
versus methadone alone [76].
• Long-term neonatal outcome: There is a paucity of long-
term data however, benzodiazepines have been available
for >40 years and there is no significant evidence of a
harmful effect on brain development [202, 204]. At 18
months, compared to children born to a parent without
a psychiatric disorder, benzodiazepine-exposed (mainly
diazepam) children (n = 17) showed impaired fine motor
skills and abnormal tone and patterns of movement (e.g.,
walking) [205]. However, in a group of children exposed to
benzodiazepines and z-hypnotics at a median of 5.1 years
(n = 283), only gross motor and communication skills defi-
cits were noted but not to an extent that was clinically rel-
evant [206]. There does not appear to be any impact on fine
motor skills, ADHD symptoms, internalizing or external-
izing behaviors, or cognition [206–208].
Substance Use Disorders
Therapy
Abrupt discontinuation of benzodiazepines taken continu-
ously (i.e., three to four times per day) for more than 3–4
weeks may result in withdrawal [209]. Mild symptoms include
tremor, diaphoresis, tachycardia, other vitals sign changes.
More serious symptoms include seizure, delirium, autonomic
instability, and suicidal ideation. Patients taking benzodiaz-
epines infrequently should be reassessed for benzodiazepine
withdrawal if they have changes in vital signs (systolic blood
pressure ≥150 mmHg, diastolic blood pressure ≥100 mmHg,
pulse >110 beats/min, temperature >101°F, or SpO2 <96%) or
symptoms of anxiety or agitation. Consultation is suggested
for patients who are dependent on benzodiazepines (i.e., use
of benzodiazepine at therapeutic doses for ≥4 weeks). Typically
scheduled tapering is done with a longer-acting benzodiaze-
pine (e.g., clonazepam) to reduce the risk of benzodiazepine
withdrawal seizure. Protocols based on objective measures
(e.g., vitals signs), symptoms, and subjective complaints such
as the Clinical Institute Withdrawal Assessment of Alcohol
Scale, Revised can be used instead of, or in addition to, taper-
ing. There are no published guidelines for detoxification dur-
ing pregnancy. Likewise, there are currently no FDA-approved
medications available for maintenance of benzodiazepine
dependence.
Antepartum testing
The role of antepartum surveillance for benzodiazepine exposure
is insufficiently studied to make a recommendation.
Postpartum/Breastfeeding
Approximately 0.1% to 11% of the weight adjusted maternal
benzodiazepine dose is transferred to the breast milk and is drug
specific [173]. Nonetheless, most prescription benzodiazepines
are “moderately safe” (lactation risk category L3) during breast-
feeding and few adverse events are reported [210]. However, CNS
depression, accumulation of metabolites, and prolonged half-life
in the neonate have been noted [53]. Sedation may be more likely
when multiple CNS depressant medications are taken together
[202]. Patients are strongly advised to refrain from nonmedical
use of benzodiazepines while breastfeeding [49, 54].
Phencyclidine
Historic notes
Phencyclidine (PCP) was developed as an anesthetic agent,
marketed under the name Sernyl, due to its ability to produce
effective anesthesia and analgesia with minimal respiratory and
cardiovascular depression. Sernyl was removed from the market
in 1965 because of a high incidence of postoperative delirium,
agitation, and violence but PCP remained in use by veterinar-
ians until it became illegal in 1978 [211]. The dissociative anes-
thetic ketamine is a derivative of PCP [211].
Diagnosis/Definition
The chemical name of PCP is 1-(1-phenylcyclohexyl) piperi-
dine. PCP is available as a crystalline powder (“Angel Dust”),
tablet (“PeaCe Pills”), crystals, or liquid (“Whack”) and is most
commonly smoked (73%) or snorted (13%) but can also be swal-
lowed (12%) or injected (2%) [212]. The use of PCP as an animal
tranquilizer led to the names “Hog” and Elephant”. Other street
names include: Ozone, Rocket Fuel, Boat, Tic Tac, Zoom, and
Embalming Fluid. Tobacco or marijuana cigarettes dipped in
249
PCP are referred to as “Dippers”, “Shermans”, “Fry”, “Super Grass”
or “Wets” [213]. These cigarettes are sometimes also dipped in
embalming fluid (the formaldehyde preservative).
Symptoms
The typical dose of PCP is 1–10 mg but injection produces
effects at much lower doses (i.e., 0.25 mg) [213]. Doses greater
than 20 mg may cause serious complications (e.g., seizures,
coma) [211]. Most female patients who abuse PCP do so only
occasionally and a typical dose is 5 mg. Chronic use may
lead to habituation and the need for doses as high as 100 mg
to achieve the same feeling [214]. In more than 50% of adult
patients, PCP intoxication is characterized by violent behav-
ior, nystagmus, tachycardia, hypertension, anesthesia, and
analgesia [213]. Other neurologic findings may include bizarre
actions, lack of judgement, decreased pain sensation, dis-
orientation, confusion, hallucinations, and acute psychosis.
Although CNS stimulation is more common, some patients
may also exhibit CNS depression. More serious complications
include rhabdomyolysis (and hyperkalemia), seizures, hyper-
tensive crisis, intracranial hemorrhage, cardiopulmonary
arrest, and coma. Death from PCP intoxication is rare and
mostly secondary to trauma. PCP released from lipid stores
and adipose tissue can lead to recurrent symptoms for months
after initial use [211].
Epidemiology/Incidence
PCP emerged as a drug abuse in San Francisco during the 1960s
but was not widely used until the 1970s. PCP abuse declined in
the late 1980s and 1990s. In the early 1980s, PCP use by preg-
nant patients in Cleveland ranged from 5.8% (by testing) to
6.4% (by history) [215, 216]. In the beginning of the 2000s PCP
had reemerged as a drug of abuse, but use appears to be leveling
off. According to the 2019 NSDUH, lifetime PCP was reported
by 2.2% of individuals ages 12 or over (approximately 73,000
people) though almost none reported use within the past year
[217]. PCP abuse is most common among young adults and high
school students. According to the 2017 Monitoring The Future
survey, 1.1% of 12 graders reported PCP use [2]. Given these
statistics, PCP use by pregnant patients is expected to be
rare.
Etiology/Basic pathophysiology
The symptoms of PCP intoxication result from its effects
on multiple sites in the CNS. Primarily, PCP is an N-methyl
D-aspartate (NMDA) receptor antagonist but it also stimu-
lates sigma opioid receptors and prevents reuptake of biogenic
amines (dopamine, norepinephrine, and serotonin). Increases
in catecholamines leads to sympathomimetic effects also seen
with cocaine [211, 213]. PCP crosses the placenta and can be
detected in amniotic fluid, umbilical cord blood [218–220], and
neonatal urine [221]. Concentrations in the fetus may exceed
maternal levels [55, 120, 164].
Risk factors/Associations
The rate of concomitant tobacco use ranges from 43% to 84%
[222–224]. The majority of PCP users also abuse other illicit
drugs (e.g., cocaine) and alcohol; the trend is similar among preg-
nant patients.
Pregnancy complications
There is a high rate of polysubstance abuse by women using PCP,
which limits the ability to tease out the obstetrical and neonatal
250
effects PCP abuse. The use of matched, non drug exposed con-
trols was infrequent.
• Congenital anomalies: Although there were early case
reports of infants exposed antenatally to PCP born with
dysmorphic facial features [216, 225], microcephaly [221],
and cerebellar malformations, no increased rate of con-
genital malformations has been reported in a literature
review totaling 206 neonates with prenatal PCP exposure
[226].
• Obstetrical complications: The rate of PTB among PCP-
exposed neonates was 20–22% [222, 225].
• Fetal/neonatal morphometrics: Prenatal exposure to PCP
has not been consistently shown to affect birth weight,
length, or HC [215, 223, 224]. However, higher-than-
expected rates of IUGR (32%) [222], LBW (30%) [225], and
SGA (17%) [225] have been reported.
• Neonatal withdrawal: Neonatal withdrawal from PCP
is characterized by neurological (e.g., tremor, abnormal
tone, and hypertonic reflexes) and gastrointestinal (e.g.,
emesis and diarrhea) symptoms, irritability, exaggerated
responses to auditory and tactile stimuli, lethargy and
rapid shifts in consciousness [214, 215, 221, 224, 225,
227]. Symptoms of withdrawal were reported in 55% of
22 infants with exposure to PCP alone [176]. Symptoms
of withdrawal can be managed conservatively (e.g.,
swaddling), by acidification of the urine, or when med-
ications are indicated, with phenobarbital, diazepam, or
paregoric.
• Long-term neonatal outcome: Studies of long-term neu-
rodevelopmental outcome are limited by small size and
dropout rates of over 50%. Attachment disorder has been
described during the first year of life [225]. At 12 to 18
months of age, exposed infants demonstrated impaired
fine motor skills [227]. Caretakers reported behavioral
problems (e.g., temper tantrums and oppositional
behaviors), inconsolability, and sleep disturbances
[225, 227].
Therapy
Mild symptoms can be managed with supportive care by plac-
ing the individual in a dark, quiet environment with as little
stimulation as possible. Benzodiazepines are the preferred
agent (e.g., lorazepam, diazepam) for patients requiring chemi-
cal sedation. PCP-induced hypertension and hyperthermia, may
also improve with benzodiazepines [211]. Additional symptoms
and their pharmacologic treatments are as follows: Convulsions
are treated with benzodiazepines, hypertension with antihyper-
tensives (e.g., hydralazine), fever/hyperthermia with antipyret-
ics, and severe rigidity and rhabdomyolysis with dantrolene [55,
228]. Antipsychotics and other drugs with anticholinergic
effects should be used cautiously [213]. Physical restraints may
increase the risk of rhabdomyolysis [213]. There are currently no
FDA-approved medications available for detoxification or main-
tenance of PCP dependence.
Antepartum testing
The role of antepartum surveillance is insufficiently studied to
make recommendations. However, hypertension in response to
moderate to high doses of PCP may be an indication for NSTs
and/or ultrasound to estimate fetal weight [55].
Maternal-Fetal Evidence Based Guidelines
Postpartum/Breastfeeding
PCP is present in breast milk [218, 219] in sufficient quantities to
cause intoxication [53]. The AAP and ABM advise that women
should not use PCP while breastfeeding [49, 53, 54].
Hallucinogens: Lysergic acid
diethylamide, psilocybin (magic
mushrooms), peyote (mescaline)
Historic Notes
Naturally occurring hallucinogens have been used for centu-
ries as part of religious and cultural activities. LSD, the proto-
typical synthetic hallucinogen, was synthesized in 1938 by the
chemist Albert Hofmann who recognized its hallucinogenic
capabilities when he was accidentally exposed. LSD is cur-
rently being studied as a treatment for a variety of psychiat-
ric indications.
Diagnosis/Definition
The active ingredients in psilocybin and peyote are psilocin (N,
N-dimethyl-4-phosphoryloxytryptamine) and 3,4,5-trimethoxy-
pheneylamine. LSD is an ergot (rye fungus) derivative. Street
names are as follows:
• LSD: Acid, Trips, Microdots, Dots, Blotters (or named by
the design on the blotting paper), Mellow or Tabs
• Psilocybin: Magic Mushrooms, Shrooms, Magics, Blue
Meanies, Liberty Caps, Golden Tops, Mushies
• Peyote: Buttons, Cactus, Mesc, Peyoto
LSD can be taken orally as a tablet, capsule or liquid applied to
blotter paper, sniffed, injected, or smoked. Psilocybin and peyote
are usually taken orally; peyote can also be smoked.
Symptoms
Hallucinogens principally alter sensory perceptions, mood,
and thought patterns. On occasion neuropsychiatric symp-
toms may be unpleasant (i.e., “bad trip”) and rarely hallucino-
gen intoxication may lead to psychosis. Vital sign abnormalities
are uncommon but may include increased blood pressure and
heart rate. Most symptoms are mild and self-limited, but
cases of hyperthermia and serotonin syndrome have been
reported.
Epidemiology/Incidence
According to the 2019 NSDUH, 10% of persons ages 12 or older
reported lifetime use of LSD while 0.9% reported use within
the past year [217]. Only 0.2% of reproductive age women aged
15–44 years reported hallucinogen use in the past month. There
has been a significant increase in hallucinogen use among
adults including a 56% increase in LSD use from 2015–2018
[229]. Among pregnant patients screened for inclusion in a
study of prenatal methamphetamine exposure, <0.5% used hal-
lucinogens [166]. In Europe, the rate of LSD and hallucinogenic
mushroom use is 0.4–2.0% (7.5% in the United Kingdom) and
0.2–12.8%, respectively [230].
Etiology/Basic pathophysiology
Most hallucinogens act primarily as serotonin agonists [231].
However, the exact cause of the hallucinations is not well known.
Many hallucinogens also produce sympathomimetic effects.
Substance Use Disorders
Complications
The effects of hallucinogen exposure on obstetrical neonatal out-
come are not well studied.
• Congenital anomalies: Evidence that LSD causes DNA
damage in vitro raises concerns about its potential as a
teratogen [232]. In a literature review including 162 preg-
nancies with parental LSD use before or during pregnancy,
there were 7 anomalies (4.3%) not attributable to other
causes. Limb reduction defects accounted for 5 of the 7
anomalies; a higher-than-expected incidence (1.78/1000)
[233]. Another series of 148 pregnancies, including speci-
mens from spontaneous and induced abortions, with
parental LSD use showed a 9.6% rate of major anomalies
that were mainly CNS (hydrocephalus and arteriovenous
malformations) and neural tube defects. Eye abnormali-
ties have also been reported [231]. Because of lack of appro-
priate controls and potential confounding by use of other
illicit substances, tobacco, and alcohol, a cause-and-effect
relationship cannot be established [233, 234]. There are
no reports of human teratogenesis from psilocybin or
peyote.
• Obstetrical and neonatal complications: There is
no evidence that LSD, or other hallucinogens, are
associated with any adverse obstetrical or neonatal
outcomes.
• Long-term neonatal outcome: Follow-up of children, whose
parents used LSD, to 2.5 years old showed no growth or
developmental abnormalities [234].
Therapy
In most cases, supportive care is all that is necessary.
Benzodiazepines are the first-line treatment for acute agita-
tion. Antipsychotics medications like haloperidol may be added
if psychotic features are present. Rarely, severe hyperthermia may
require medically induced paralysis. There are currently no FDA-
approved medications available for detoxification or maintenance
of hallucinogen dependence.
Antepartum testing
The role of antepartum surveillance is insufficiently studied to
make recommendations. However, hyperthermia and serotonin
syndrome may be an indication for fetal monitoring.
Postpartum/Breastfeeding
Hallucinogen use while breastfeeding has not been well studied
however, in general, ongoing illicit drug use is not compatible
with breastfeeding [49, 53].
References
1. Kremer ME, Arora KS. Clinical, ethical, and legal considerations in preg-
nant women with opioid abuse. Obstet Gynecol 2015;126(3):474–478.
[Review; III]
2. Center for Behavioral Health Statistics and Quality. Results from the 2019
National Survey on Drug Use and Health: Detailed tables. Rockville, MD:
Substance Abuse and Mental Health Services Administration; 2020.
[Survey; III]
3. Cook JL, Green CR, de la Ronde S, et al. Epidemiology and effects of sub-
stance use in pregnancy. JOGCe 2017;39(10):906–915. [Review; III]
4. Rayburn WF, Bogenschutz MP. Pharmacotherapy for pregnant women with
addictions. Am J Obstet Gynecol 2004;191(6):1885–1897. [Review; III]
5. Azadi A, Dildy III GA. Universal screening for substance abuse at the time
of parturition. Am J Obstet Gynecol 2008;198(5):e30–e32. [II-3]
251
6. American College of Obstetricians and Gynecologists. Committee Opinion
No. 711: Opioid use and opioid use disorder in pregnancy. 2017;130(2):
e83–e94. [III]
7. American College of Obstetricians and Gynecologists. Committee
Opinion No. 633: Alcohol abuse and other substance use disorders: ethical
issues in obstetric and gynecologic practice. Obstet Gynecol 2015;125(6):
1529–1537. [III]
8. American College of Obstetricians and Gynecologists Committee on
Obstetric Practice. ACOG Committee Opinion No. 722: Marijuana use
during pregnancy and lactation. Obstet Gynecol 2017;130(4):e205. [III]
9. National Institute on Drug Abuse. Screening for drug use in general medi-
cal settings: resource guide. Updated version NIDA. 2012. [III]
10. American College of Obstetricians and Gynecologists. Committee Opinion
No. 423: Motivational interviewing: a tool for behavioral change. Obstet
Gynecol 2009;113(1):243–246. [III]
11. Ondersma SJ, Chang G, Blake-Lamb T, et al. Accuracy of five self-report
screening instruments for substance use in pregnancy. Addiction.
2019;114(9):1683–1693. [III]
12. Jones HE, Deppen K, Hudak ML, et al. Clinical care for opioid-using preg-
nant and postpartum women: the role of obstetric providers. Am J Obstet
Gynecol 2014;210(4):302–310. [Review; III]
13. Oei JL, Kingsbury A, Dhawan A, et al. Amphetamines, the pregnant woman
and her children: a review. J Perinatol 2012;32(10):737–747. [Review; III]
14. Kuczkowski KM. The effects of drug abuse on pregnancy. Curr Opin Obstet
Gynecol 2007;19(6):578–585. [Review; III]
15. Terplan M, Ramanadhan S, Locke A, Longinaker N, Lui S. Psychosocial
interventions for pregnant women in outpatient illicit drug treatment
programs compared to other interventions. Cochrane Database Syst Rev
2015(4). [Systematic Review; I]
16. Whitworth M, Dowswell T. Routine pre-pregnancy health promotion for
improving pregnancy outcomes. Cochrane Database Syst Rev 2009(4).
[Systematic Review; I]
17. Childers SR, Breivogel CS. Cannabis and endogenous cannabinoid systems.
Drug Alcohol Depend 1998;51(1–2):173–87. [Systematic Review; I]
18. Kuczkowski K. Marijuana in pregnancy. Ann Acad Med Singapore
2004;33:336–339. [III]
19. de Moraes Barros MC, Guinsburg R, de Araújo Peres C, Mitsuhiro S,
Chalem E, Laranjeira RR. Exposure to marijuana during pregnancy alters
neurobehavior in the early neonatal period. J Pediat 2006;149(6):781–787.
[Review; III]
20. Ko JY, Coy KC, Haight SC, et al. Characteristics of marijuana use during
pregnancy—eight states, pregnancy risk assessment monitoring system,
2017. MMWR 2020;69(32):1058. [Survey; III]
21. Brown QL, Sarvet AL, Shmulewitz D, Martins SS, Wall MM, Hasin DS.
Trends in marijuana use among pregnant and nonpregnant reproductive-
aged women, 2002–2014. JAMA 2017;317(2):207–209. [III]
22. Gnofam M, Allshouse AA, Stickrath EH, Metz TD. Impact of marijuana
legalization on prevalence of maternal marijuana use and perinatal out-
comes. Am J Perinatol 2020;37(01):059–065. [II-2]
23. Jarlenski M, Koma JW, Zank J, Bodnar LM, Bogen DL, Chang JC. Trends in
perception of risk of regular marijuana use among US pregnant and nonpreg-
nant reproductive-aged women. Am J Obstet Gynecol 2017;217(6):705. [III]
24. Young-Wolff KC, Sarovar V, Tucker L-Y, et al. Trends in marijuana use
among pregnant women with and without nausea and vomiting in preg-
nancy, 2009–2016. Drug Alcohol Depend 2019;196:66–70. [III]
25. Ko JY, Farr SL, Tong VT, Creanga AA, Callaghan WM. Prevalence and pat-
terns of marijuana use among pregnant and nonpregnant women of repro-
ductive age. Am J Obstet Gynecol 2015;213(2):201.e1-.e10. [II-2]
26. Martin CE, Longinaker N, Mark K, Chisolm MS, Terplan M. Recent trends
in treatment admissions for marijuana use during pregnancy. J Addict Med
2015;9(2):99–104. [II-3]
27. Kozer E, Koren G. Effects of prenatal exposure to marijuana. Can Fam
Physician 2001;47(2):263–264. [III]
28. El Marroun H, Tiemeier H, Steegers EA, et al. A prospective study on
intrauterine cannabis exposure and fetal blood flow. Early Hum Dev
2010;86(4):231–236. [II-2]
29. Cornelius MD, Taylor PM, Geva D, Day NL. Prenatal tobacco and mari-
juana use among adolescents: effects on offspring gestational age, growth,
and morphology. Pediatrics 1995;95(5):738–743. [II-2]
30. Conner SN, Carter EB, Tuuli MG, Macones GA, Cahill AG. Maternal mari-
juana use and neonatal morbidity. Am J Obstet Gynecol 2015;213(3):422.
e1-.e4. [II-2]
31. Goler N, Conway A, Young-Wolff KC. Data are needed on the poten-
tial adverse effects of marijuana use in pregnancy. American College of
Physicians; 2018. [III]
252
32. Ko JY, Tong VT, Bombard JM, Hayes DK, Davy J, Perham-Hester KA.
Marijuana use during and after pregnancy and association of prenatal
use on birth outcomes: a population-based study. Drug Alcohol Depend
2018;187:72–78. [II-2]
33. Short VL, Hand DJ, Gannon M, Abatemarco DJ. Maternal character-
istics associated with preconception marijuana use. Am J Prev Med
2020;59(4):555–561. [III]
34. Jobe AH. Marijuana effects on neurobehavior of newborns. J Pediat
2006;149(6):A1. [III]
35. Conner SN, Bedell V, Lipsey K, Macones GA, Cahill AG, Tuuli MG.
Maternal marijuana use and adverse neonatal outcomes. Obstet Gynecol
2016;128(4):713–723. Meta-analysis; I]
36. Gunn J, Rosales CB, Center K, et al. Prenatal exposure to cannabis and
maternal and child health outcomes: a systematic review and meta-analysis.
BMJ Open 2016;6(4). Meta-analysis; I]
37. Metz TD, Borgelt LM. Marijuana use in pregnancy and while breastfeeding.
Obstet Gynecol 2018;132(5):1198. [Review; III]
38. Corsi DJ, Walsh L, Weiss D, et al. Association between self-reported pre-
natal cannabis use and maternal, perinatal, and neonatal outcomes. JAMA
2019;322(2):145–152. [II-2]
39. Klebanoff MA, Wilkins DG, Keim SA. Marijuana use during pregnancy and
preterm birth: a prospective cohort study. Am J Perinatol 2020. [II-2]
40. Rodriguez CE, Sheeder J, Allshouse AA, et al. Marijuana use in young
mothers and adverse pregnancy outcomes: a retrospective cohort study.
BJOG 2019;126(12):1491–1497. [II-2]
41. Varner MW, Silver RM, Hogue CJR, et al. Association between still-
birth and illicit drug use and smoking during pregnancy. Obstet Gynecol
2014;123(1):113. [III]
42. Coleman-Cowger VH, Oga EA, Peters EN, Mark K. Prevalence and associ-
ated birth outcomes of co-use of Cannabis and tobacco cigarettes during
pregnancy. Neurotoxicol Teratol 2018;68:84–90. [II-2]
43. Warshak C, Regan J, Moore B, Magner K, Kritzer S, Van Hook J. Association
between marijuana use and adverse obstetrical and neonatal outcomes.
J Perinatol 2015;35(12):991–995. [II-2]
44. El Marroun H, Tiemeier H, Steegers EA, et al. Intrauterine cannabis expo-
sure affects fetal growth trajectories: the Generation R Study. J Am Acad
Child Adolesc Psychiatry 2009;48(12):1173–1181. [II-2]
45. Bailey BA, Wood DL, Shah D. Impact of pregnancy marijuana use on birth
outcomes: results from two matched population-based cohorts. J Perinatol
2020:1–6. [II-2]
46. American College of Obstetricians and Gynecologists. Committee Opinion
No. 637: Marijuana use during pregnancy and lactation. Obstet Gynecol
2015;126:234–238. [III]
47. Bada HS, Reynolds EW, Hansen WF. Marijuana use, adolescent pregnancy,
and alteration in newborn behavior: How complex can it get? J Pediat
2006;149(6):742–745. [Comment; III]
48. Scragg R, Mitchell E, Ford R, Thompson J, Taylor B, Stewart A. Maternal
cannabis use in the sudden death syndrome. Acta Paediatr 2001;90(1):
57–60. [II-2]
49. Reece-Stremtan S, Marinelli KA, Academy of Breastfeeding Medicine. ABM
clinical protocol# 21: Guidelines for breastfeeding and substance use or sub-
stance use disorder, revised 2015. Breastfeed Med. 2015;10(3):135–141. [III]
50. Day N, Goldschmidt L, Day R, Larkby C, Richardson G. Prenatal marijuana
exposure, age of marijuana initiation, and the development of psychotic
symptoms in young adults. Psychol Med 2015;45(8):1779. [II-3]
51. Calvigioni D, Hurd YL, Harkany T, Keimpema E. Neuronal substrates and
functional consequences of prenatal cannabis exposure. Eur Child Adolesc
Psychiatry 2014;23(10):931–941. [Review; III]
52. Kuczkowski KM. Anesthetic implications of drug abuse in pregnancy. J Clin
Anesth 2003;15(5):382–394. [Review; III]
53. Sachs HC. The transfer of drugs and therapeutics into human breast milk:
an update on selected topics. Pediatrics 2013;132(3):e796–e809. [III]
54. Eidelman AI, Schanler RJ. Breastfeeding and the use of human milk.
Pediatrics 2012;129(3):e827–e41. [III]
55. Christopher GJ, Woods Jr JR. Cocaine, heroin, and phencyclidine: obstetric
perspectives. Clin Obstet Gynecol 1993;36(2):279–301. [Review; III]
56. Haight SC, Ko JY, Tong VT, Bohm MK, Callaghan WM. Opioid use dis-
order documented at delivery hospitalization—United States, 1999–2014.
MMWR 2018;67(31):845. [III]
57. Wilbourne P, Wallerstedt C, Dorato V, Curet LB. Clinical management
of methadone dependence during pregnancy. J Perinat Neonatal Nurs
2001;14(4):26–45. [Review; III]
58. Vanderziel A, Parker MA, Alshaarawy O. Trends in heroin use among
women of reproductive age in the United States, 2004–2017. Addict Behav
2020;110:106518. [Survey; III]
Maternal-Fetal Evidence Based Guidelines
59. Kozhimannil KB, Graves AJ, Jarlenski M, Kennedy-Hendricks A, Gollust
S, Barry CL. Non-medical opioid use and sources of opioids among preg-
nant and non-pregnant reproductive-aged women. Drug Alcohol Depend
2017;174:201–208. [Survey; III]
60. Smith K, Lipari R. Women of childbearing age and opioids. The CBHSQ
Report: Substance Abuse and Mental Health Services Administration (US);
2017. [Review; III]
61. Winkelman TN, Villapiano N, Kozhimannil KB, Davis MM, Patrick SW.
Incidence and costs of neonatal abstinence syndrome among infants with
Medicaid: 2004–2014. Pediatrics 2018;141(4). [II-2]
62. Kozhimannil KB, Graves AJ, Levy R, Patrick SW. Nonmedical use of pre-
scription opioids among pregnant US women. Women’s Health Issues
2017;27(3):308–315. [Survey; III]
63. Jones HE, Kraft WK. Analgesia, opioids, and other drug use during preg-
nancy and neonatal abstinence syndrome. Clin Perinatol 2019;46(2):
349–366. [Review; III]
64. Kaltenbach K, Berghella V, Finnegan L. Opioid dependence during
pregnancy: effects and management. Obstet Gynecol Clin North Am
1998;25(1):139–151. [Review; III]
65. Gemmill A, Scd MVK, Alexander MJ. Trends in pregnancy-associated
mortality involving opioids in the United States, 2007–2016. Am J Obstet
Gynecol 2019;220(1):115–116. [III]
66. Kennedy L, Coelho M. “Absolutely the worst drug I’ve ever seen”: Risk, gov-
ernance, and the construction of the illicit fentanyl “crisis.” Theor Criminol
2020;24(4):612–632. [Review; III]
67. Lind JN, Interrante JD, Ailes EC, et al. Maternal use of opioids during
pregnancy and congenital malformations: a systematic review. Pediatrics
2017;139(6). [Systematic Review; I]
68. Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment
with opioid analgesics and risk for birth defects. Am J Obstet Gynecol
2011;204(4):314.e1-.e11. [II-2]
69. Almario CV, Seligman NS, Dysart KC, Berghella V, Baxter JK. Risk factors
for preterm birth among opiate-addicted gravid women in a methadone
treatment program. Am J Obstet Gynecol 2009;201(3):326.e1–.e6. [II-2]
70. Stimmel B, Goldberg J, Reisman A, Murphy RJ, Teetsz K. Fetal outcome in
narcotic-dependent women: the importance of the type of maternal nar-
cotic used. Am J Drug Alcohol Abuse 1982;9(4):383–395. [II-2]
71. Kandall SR, Albin S, Lowinson J, Berle B, Eidelman AI, Gartner LM.
Differential effects of maternal heroin and methadone use on birthweight.
Pediatrics 1976;58(5):681–685. [II-2]
72. Doberczak TM, Thornton JC, Bernstein J, Kandall SR. Impact of maternal
drug dependency on birth weight and head circumference of offspring. Am
J Dis Child 1987;141(11):1163–1167. [II-2]
73. Towers CV, Hyatt BW, Visconti KC, Chernicky L, Chattin K, Fortner KB.
Neonatal head circumference in newborns with neonatal abstinence syn-
drome. Pediatrics 2019;143(1). [II-2]
74. Patrick SW, Davis MM, Lehmann C, Cooper WO. Increasing incidence and
geographic distribution of neonatal abstinence syndrome: United States
2009 to 2012. J Perinatol 2015;35(8):650–655. [II-2]
75. Cleary BJ, Donnelly J, Strawbridge J, et al. Methadone dose and neonatal
abstinence syndrome—systematic review and meta-analysis. Addiction
2010;105(12):2071–2084. [Meta-analysis; I]
76. Seligman NS, Almario CV, Hayes EJ, Dysart KC, Berghella V, Baxter JK.
Relationship between maternal methadone dose at delivery and neonatal
abstinence syndrome. J Pediat 2010;157(3):428–433.e1. [II-2]
77. Huybrechts KF, Bateman BT, Desai RJ, et al. Risk of neonatal drug with-
drawal after intrauterine co-exposure to opioids and psychotropic medica-
tions: cohort study. BMJ 2017;358:j3326. [II-2]
78. Kaltenbach K, Silverman N, Wapner R. Methadone maintenance during
pregnancy. In: State Methadone Treatment Guidelines. Rockville, MD:
US Department of Health and Human Services, 1992. 85–93. [Review; III]
79. Hart BJ, Viswanathan S, Jadcherla SR. Persistent feeding difficulties among
infants with fetal opioid exposure: mechanisms and clinical reasoning.
J Mater Fetal Neonat Med 2019;32(21):3633–3639. [II-2]
80. Oei J, Lui K. Management of the newborn infant affected by maternal opi-
ates and other drugs of dependency. J Paediatr Child Health 2007;43(1-2):9–
18. [Review; III]
81. Finnegan LP, Connaughton Jr JF, Kron RE, Emich JP. Neonatal abstinence syn-
drome: assessment and management. Addict Dis 1975;2(1-2):141–158. [II-3]
82. Kraft WK, Gibson E, Dysart K, et al. Sublingual buprenorphine for treat-
ment of neonatal abstinence syndrome: a randomized trial. Pediatrics
2008;122(3):e601–e607. [RCT, n = 26; I]
83. American College of Obstetricians and Gynecologists. Committee Opinion
No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet
Gynecol 2012;119(5):1070–1076. [III]
Substance Use Disorders
84. Viteri OA, Soto EE, Bahado-Singh RO, Christensen CW, Chauhan SP, Sibai
BM. Fetal anomalies and long-term effects associated with substance abuse
in pregnancy: a literature review. Am J Perinatol 2015;32(05):405–16. [III]
85. Baldacchino A, Arbuckle K, Petrie DJ, McCowan C. Neurobehavioral
consequences of chronic intrauterine opioid exposure in infants and pre-
school children: a systematic review and meta-analysis. BMC Psychiatry
2014;14(1):104. Meta-analysis; I]
86. Baldacchino A, Arbuckle K, Petrie DJ, McCowan C. Erratum: neurobehav-
ioral consequences of chronic intrauterine opioid exposure in infants and
preschool children: a systematic review and meta-analysis. BMC Psychiatry
2015;15(1):1–4. [Meta-analysis; I]
87. Caritis SN, Panigrahy A. Opioids affect the fetal brain: reframing the detox-
ification debate. Am J Obstet Gynecol 2019;221(6):602–8. [Review; III]
88. Merhar SL, Kline JE, Braimah A, et al. Prenatal opioid exposure is associ-
ated with smaller brain volumes in multiple regions. Pediatr Res 2020:1–6.
[II-2]
89. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance ver-
sus placebo or methadone maintenance for opioid dependence. Cochrane
Database Syst Rev 2014(2). [Systematic Review; I]
90. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial combined with ago-
nist maintenance treatments versus agonist maintenance treatments alone
for treatment of opioid dependence. Cochrane Database Syst Rev 2011(10).
Systematic Review; I]
91. Towers CV, Terry P, Rackley B, Hennessy M, Visconti K. Fetal outcomes
with detoxification from opioid drugs during pregnancy: a systematic
review. Am J Perinatol 2020;37(07):679–688. [Systematic Review; I]
92. Terplan M, Laird HJ, Hand DJ, et al. Opioid detoxification during preg-
nancy: a systematic review. Obstet Gynecol 2018;131(5):803. [Systematic
Review; I]
93. McCarthy JJ, Leamon MH, Finnegan LP, Fassbender C. Opioid dependence
and pregnancy: minimizing stress on the fetal brain. Am J Obstet Gynecol
2017;216(3):226–231. [Review; III]
94. Berghella V, Lim PJ, Hill MK, Cherpes J, Chennat J, Kaltenbach K.
Maternal methadone dose and neonatal withdrawal. Am J Obstet Gynecol
2003;189(2):312–317. [II-2]
95. Drozdick III J, Berghella V, Hill M, Kaltenbach K. Methadone trough levels
in pregnancy. Am J Obstet Gynecol 2002;187(5):1184–1188. [II-2]
96. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after
methadone or buprenorphine exposure. N Engl J Med 2010;363(24):2320–
2331. [RCT, n=131; I]
97. Hayes E, Seligman N, Horowitz K, et al. 252: Dose-response relationship
between maternal methadone dose and decreased neonatal head circumfer-
ence. Am J Obstet Gynecol 2007;197(6):S81. [II-2]
98. Monnelly VJ, Hamilton R, Chappell FM, Mactier H, Boardman JP.
Childhood neurodevelopment after prescription of maintenance metha-
done for opioid dependency in pregnancy: a systematic review and meta-
analysis. Dev Med Child Neurol 2019;61(7):750–760. [Meta-analysis; I]
99. Torp-Pedersen T, Boyd HA, Poulsen G, et al. In-utero exposure to smok-
ing, alcohol, coffee, and tea and risk of strabismus. Am J Epidemiol
2010;171(8):868–875. [II-2]
100. Nita M, Grzybowski A. Smoking and eye pathologies. A systemic review.
Part II. Retina diseases, uveitis, optic neuropathies, thyroid-associated
orbitopathy. Curr Pharm Des 2017;23(4):639–654. {Systematic Review; I]
101. Minozzi S, Amato L, Jahanfar S, Bellisario C, Ferri M, Davoli M.
Maintenance agonist treatments for opiate-dependent pregnant women.
Cochrane Database Syst Rev 2020(11). [Systematic Review; I]
102. Link HM, Jones H, Miller L, Kaltenbach K, Seligman NS. Buprenorphine-
naloxone use in pregnancy: a systematic review and metaanalysis. Am J
Obstet Gynecol MFM 2020;2(3):1–12. [Meta-analysis; I]
103. Kashiwagi M, Arlettaz R, Lauper U, Zimmermann R, Hebisch G. Methadone
maintenance program in a Swiss perinatal center:(I): Management and out-
come of 89 pregnancies. Acta Obstet Gynecol Scand 2005;84(2):140–144.
[II-3]
104. Kelty E, Hulse G. A retrospective cohort study of birth outcomes in neonates
exposed to naltrexone in utero: a comparison with methadone-, buprenor-
phine-and non-opioid-exposed neonates. Drugs 2017;77(11):1211–1219.
[II-2]
105. Towers CV, Katz E, Weitz B, Visconti K. Use of naltrexone in treating opi-
oid use disorder in pregnancy. Am J Obstet Gynecol 2020;222(1):83.e1–e8.
[II-2]
106. Jansson LM, DiPietro J, Elko A. Fetal response to maternal methadone
administration. Am J Obstet Gynecol 2005;193(3):611–617. [II-2]
107. Meyer M, Wagner K, Benvenuto A, Plante D, Howard D. Intrapartum and
postpartum analgesia for women maintained on methadone during preg-
nancy. Obstet Gynecol 2007;110(2):261–266. [II-2]
253
108. Jones HE, O’Grady K, Dahne J, et al. Management of acute postpartum pain
in patients maintained on methadone or buprenorphine during pregnancy.
Am J Drug Alcohol Abuse 2009;35(3):151–156. [II-2]
109. Höflich AS, Langer M, Jagsch R, et al. Peripartum pain management in opi-
oid dependent women. Eur J Pain 2012;16(4):574–584. [II-2]
110. Meyer M, Paranya G, Norris AK, Howard D. Intrapartum and postpartum
analgesia for women maintained on buprenorphine during pregnancy. Eur
J Pain 2010;14(9):939–943. [II-2]
111. Kuczkowski KM. The cocaine abusing parturient: a review of anesthetic
considerations. Canadian Journal of Anesthesia 2004;51(2):145–154.
[Review; III]
112. Caritis SN, Bastian JR, Zhang H, et al. An evidence-based recommendation
to increase the dosing frequency of buprenorphine during pregnancy. Am J
Obstet Gynecol 2017;217(4):459.e1–.e6. [III]
113. Pace CA, Kaminetzky LB, Winter M, et al. Postpartum changes in metha-
done maintenance dose. J Subst Abuse Treat 2014;47(3):229–232. [II-3]
114. Liu AJ, Nanan R. Methadone maintenance and breastfeeding in the neona-
tal period. Pediatrics 2008;121(4):869. [III]
115. Cain MA, Bornick P, Whiteman V. The maternal, fetal, and neona-
tal effects of cocaine exposure in pregnancy. Clin Obstet Gynecol
2013;56(1):124–132. [III]
116. Hernandez M, Birnbach DJ, Van Zundert AA. Anesthetic management
of the illicit-substance-using patient. Current Opinion in Anesthesiology
2005;18(3):315–324. [Review; III]
117. Woods Jr JR, Plessinger MA. Pregnancy increases cardiovascular toxicity to
cocaine. Am J Obstet Gynecol 1990;162(2):529–533. [II-2]
118. Plessinger MA, Woods Jr JR. Maternal, placental, and fetal patho-
physiology of cocaine exposure during pregnancy. Clin Obstet Gynecol
1993;36(2):267–278. [Review; III]
119. Gaither K. Cocaine abuse in pregnancy: an evolution from panacea to pan-
demonium. South Med J 2008;101(8):783–784. [Editorial; III]
120. Plessinger MA, Woods Jr JR. Cocaine in pregnancy: recent data on maternal and
fetal risks. Obstet Gynecol Clin North Am 1998;25(1):99–118. [Review; III]
121. Day NL, Cottreau CM, Richardson GA. The epidemiology of alcohol, mari-
juana, and cocaine use among women of childbearing age and pregnant
women. Clin Obstet Gynecol 1993;36(2):232–245. [Review; III]
122. Bauer CR, Langer JC, Shankaran S, et al. Acute neonatal effects of cocaine
exposure during pregnancy. Arch Pediatr Adolesc Med 2005;159(9):824–
834. [II-2]
123. Bhuvaneswar CG, Chang G, Epstein LA, Stern TA. Cocaine and opioid use
during pregnancy: prevalence and management. Prim Care Companion J
Clin Psychiatry 2008;10(1):59. [Review; III]
124. Mitsuhiro SS, Chalem E, Barros MM, Guinsburg R, Laranjeira R. Teenage
pregnancy: use of drugs in the third trimester and prevalence of psychiatric
disorders. Braz J Psychiatry 2006;28(2):122–125. [III]
125. Parcianello RR, Mardini V, Ceresér KMM, et al. Increased cocaine
and amphetamine-regulated transcript cord blood levels in the new-
borns exposed to crack cocaine in utero. Psychopharmacology (Berl)
2018;235(1):215–222. [II-2]
126. Latuskie KA, Leibson T, Andrews NC, Motz M, Pepler DJ, Ito S. Substance
use in pregnancy among vulnerable women seeking addiction and parent-
ing support. Int J Ment Health Addict 2019;17(1):137–150. [III]
127. De Giovanni N, Marchetti D. Cocaine and its metabolites in the placenta:
a systematic review of the literature. Reprod Toxicol 2012;33(1):1–14.
[Systematic Review; I]
128. Hull L, May J, Farrell-Moore D, Svikis DS. Treatment of cocaine abuse dur-
ing pregnancy: translating research to clinical practice. Current Psychiatry
Reports 2010;12(5):454–461. [Review; III]
129. Monga M, Weisbrodt NW, Andres RL, Sanborn BM. The acute effect of
cocaine exposure on pregnant human myometrial contractile activity. Am
J Obstet Gynecol 1993;169(4):782–785. [II-3]
130. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol
2006;108(4):1005–16. [Review; III]
131. Cressman AM, Natekar A, Kim E, Koren G, Bozzo P. Cocaine abuse during
pregnancy. JOGC 2014;36(7):628–631. [Review; III]
132. Addis A, Moretti ME, Syed FA, Einarson TR, Koren G. Fetal effects of
cocaine: an updated meta-analysis. Reprod Toxicol 2001;15(4):341–369.
[Meta-analysis; I]
133. Dos Santos JF, Cavalcante Cd MB, Barbosa FT, et al. Maternal, fetal and
neonatal consequences associated with the use of crack cocaine during the
gestational period: a systematic review and meta-analysis. Arch Gynecol
Obstet 2018;298(3):487–503. [Meta-analysis; I]
134. Meyer KD, Zhang L. Short-and long-term adverse effects of cocaine abuse
during pregnancy on the heart development. Ther Adv Cardiovasc Dis
2009;3(1):7–16. [Review; III]
254
135. Martinez A, Larrabee K, Monga M. Cocaine is associated with intrauter-
ine fetal death in women with suspected preterm labor. Am J Perinatol
1996;13(03):163–166. [II-2]
136. Gouin K, Murphy K, Shah PS. Effects of cocaine use during pregnancy on
low birthweight and preterm birth: systematic review and metaanalyses.
Am J Obstet Gynecol 2011;204(4):340. e1–. e12. [Meta-analysis; I]
137. Bingol N, Fuchs M, Diaz V, Stone RK, Gromisch DS. Teratogenicity of
cocaine in humans. J Pediatr 1987;110(1):93–6. [II-2]
138. Chasnoff IJ, Burns KA, Burns WJ. Cocaine use in pregnancy: perinatal mor-
bidity and mortality. Neurotoxicol Teratol 1987;9(4):291–3. [II-2]
139. Delaney DB, Larrabee KD, Monga M. Preterm premature rupture of
the membranes associated with recent cocaine use. Am J Perinatol
1997;14(05):285–288. [II-2]
140. Dinsmoor MJ, Irons SJ, Christmas JT. Preterm rupture of the membranes
associated with recent cocaine use. Am J Obstet Gynecol 1994;171(2):305–
309. [II-2]
141. Cordero DR, Medina C, Helfgott A. Cocaine body packing in pregnancy.
Ann Emerg Med 2006;48(3):323–325. [II-3]
142. Bulterys M, Landesman S, Burns DN, Rubinstein A, Goedert JJ. Sexual
behavior and injection drug use during pregnancy and vertical transmis-
sion of HIV-1. J Acquir Immune Defic Syndr 1997;15(1):76–82. [II-3]
143. Minnes S, Min MO, Short EJ, et al. Executive function in children with prenatal
cocaine exposure (12–15 years). Neurotoxicol Teratol 2016;57:79–86. [II-2]
144. Grewen K, Burchinal M, Vachet C, et al. Prenatal cocaine effects on brain
structure in early infancy. Neuroimage 2014;101:114–123. [II-2]
145. Richardson GA, Goldschmidt L, Larkby C, Day NL. Effects of prena-
tal cocaine exposure on adolescent development. Neurotoxicol Teratol
2015;49:41–48. [II-2]
146. Minnes S, Min MO, Kim J-Y, et al. The association of prenatal cocaine expo-
sure, externalizing behavior and adolescent substance use. Drug Alcohol
Depend 2017;176:33–43. [II-2]
147. Elk R, Mangus L, Rhoades H, Andres R, Grabowski J. Cessation of cocaine
use during pregnancy: Effects of contingency management interventions on
maintaining abstinence and complying with prenatal care. Addict Behav
1998;23(1):57–64. [RCT, n = 12; I]
148. Svikis DS, Golden AS, Huggins GR, et al. Cost-effectiveness of treatment
for drug-abusing pregnant women. Drug Alcohol Depend 1997;45(1-2):105–
113. [III]
149. Yonkers KA, Forray A, Nich C, et al. Progesterone for the reduction of
cocaine use in post-partum women with a cocaine use disorder: a ran-
domised, double-blind, placebo-controlled, pilot study. The Lancet
Psychiatry 2014;1(5):360–367. [RCT, n=50; I]
150. Izquierdo LA, Yonke N. Fetal surveillance in late pregnancy and during
labor. Obstet Gynecol 2014;41(2):307–315. [Review; III]
151. Berman S, O’Neill J, Fears S, Bartzokis G, London ED. Abuse of amphet-
amines and structural abnormalities in brain. Ann N Y Acad Sci
2008;1141:195. [Review; III]
152. Anglin MD, Burke C, Perrochet B, Stamper E, Dawud-Noursi S. History of
the methamphetamine problem. J Psychoactive Drugs 2000;32(2):137–141.
[Review; III]
153. Skelton MR, Williams MT, Vorhees CV. Developmental effects of 3, 4-meth-
ylenedioxymethamphetamine: a review. Behav Pharmacol 2008;19(2):91.
[Review; III]
154. Chomchai S, Phuditshinnapatra J, Mekavuthikul P, Chomchai C. Effects of
unconventional recreational drug use in pregnancy. Seminars Fetal Neonat
Med 2019;24(2):142–148. [Review; III]
155. Plessinger MA. Prenatal exposure to amphetamines: risks and adverse out-
comes in pregnancy. Obstet Gynecol Clin North Am 1998;25(1):119–138.
[Review; III]
156. American College of Obstetricians and Gynecologists Committee on
Health Care for Underserved Women. Committee Opinion No. 479:
Methamphetamine abuse in women of reproductive age. Obstet Gynecol
2011;117(3):751–755. [III]
157. Terplan M, Smith EJ, Kozloski MJ, Pollack HA. Methamphetamine use
among pregnant women. Obstet Gynecol 2009;113(6):1285–1291. [II-3]
158. Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI. The pharmacol-
ogy and clinical pharmacology of 3, 4-methylenedioxymethamphetamine
(MDMA, “ecstasy”). Pharmacol Rev 2003;55(3):463–508. [Review; III]
159. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring the
future: national survey results on drug use, 1975–2006. Volume I: Secondary
School Students. NIH Publication No. 07-6205. National Institute on Drug
Abuse (NIDA). 2007. [Survey; III]
160. Gorman MC, Orme KS, Nguyen NT, Kent III EJ, Caughey AB. Outcomes in
pregnancies complicated by methamphetamine use. Am J Obstet Gynecol
2014;211(4):429.e1–.e7. [II-2]
Maternal-Fetal Evidence Based Guidelines
161. Admon LK, Bart G, Kozhimannil KB, Richardson CR, Dalton VK,
Winkelman TN. Amphetamine-and opioid-affected births: incidence,
outcomes, and costs, United States, 2004–2015. Am J Public Health
2019;109(1):148–154. [III]
162. Smid MC, Metz TD, Gordon AJ. Stimulant use in pregnancy: an under-
recognized epidemic among pregnant women. Clin Obstet Gynecol
2019;62(1):168–184. [Review; III]
163. Cox S, Posner SF, Kourtis AP, Jamieson DJ. Hospitalizations with amphet-
amine abuse among pregnant women. Obstet Gynecol 2008;111(2):341–
347. [III]
164. Good MM, Solt I, Acuna JG, Rotmensch S, Kim MJ. Methamphetamine
use during pregnancy: maternal and neonatal implications. Obstet Gynecol
2010;116(2):330–334. [II-2, n = 276]
165. Della Grotta S, LaGasse LL, Arria AM, et al. Patterns of methamphetamine
use during pregnancy: results from the Infant Development, Environment,
and Lifestyle (IDEAL) Study. Matern Child Health J 2010;14(4):
519–527. [II-2]
166. Arria AM, Derauf C, LaGasse LL, et al. Methamphetamine and other
substance use during pregnancy: preliminary estimates from the Infant
Development, Environment, and Lifestyle (IDEAL) study. Matern Child
Health J 2006;10(3):293. [II-3]
167. Nguyen D, Smith LM, LaGasse LL, et al. Intrauterine growth of infants
exposed to prenatal methamphetamine: results from the infant devel-
opment, environment, and lifestyle study. J Pediatrics 2010;157(2):
337–339. [II-2]
168. Carter RC, Wainwright H, Molteno CD, et al. Alcohol, methamphet-
amine, and marijuana exposure have distinct effects on the human
placenta. Alcoholism: Clinical and Experimental Research 2016;40(4):
753–764. [III]
169. Wells PG, Bhatia S, Drake DM, Miller-Pinsler L. Fetal oxidative stress
mechanisms of neurodevelopmental deficits and exacerbation by ethanol
and methamphetamine. Birth Defects Research (Part C) Embryo Today:
Reviews 2016;108(2):108–130. [Review; III]
170. Derauf C, LaGasse LL, Smith LM, et al. Demographic and psychosocial
characteristics of mothers using methamphetamine during pregnancy:
preliminary results of the infant development, environment, and lifestyle
study (IDEAL). Am J Drug Alcohol Abuse 2007;33(2):281–289. [II-2]
171. Ho E, Karimi-Tabesh L, Koren G. Characteristics of pregnant women who
use ecstasy (3, 4-methylenedioxymethamphetamine). Neurotoxicol Teratol
2001;23(6):561–567. [II-2]
172. Garey JD, Lusskin SI, Scialli AR. Teratogen update: amphetamines. Birth
Defects Research 2020;112(15):1171–1182. [Review; III]
173. McElhatton P, Bateman D, Evans C, Pughe K, Thomas S. Congenital anoma-
lies after prenatal ecstasy exposure. The Lancet 1999;354(9188):1441–1442.
[II-3]
174. Abdel-Aleem M. Khat chewing during pregnancy: an insight on an ancient
problem impact of chewing khat on maternal and fetal outcome among
Yemeni pregnant women. J Gynecol Neonatal Biology 2015;1(2):1–4. [II-2]
175. Ladhani NNN, Shah PS, Murphy KE, Knowledge synthesis group on deter-
minants of preterm/lbw births. Prenatal amphetamine exposure and birth
outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol
2011;205(3):219.e1–.e7. [Meta-analysis; I]
176. Kalaitzopoulos D-R, Chatzistergiou K, Amylidi A-L, Kokkinidis DG, Goulis
DG. Effect of methamphetamine hydrochloride on pregnancy outcome: a
systematic review and meta-analysis. J Addict Med 2018;12(3):220–226.
[Meta-analysis; I]
177. Gabrhelík R, Skurtveit S, Nechanská B, Handal M, Mahic M, Mravčík V.
Prenatal methamphetamine exposure and adverse neonatal outcomes: a
nationwide cohort study. Eur Addict Res 2020:1–10. [II-2]
178. Cernerud L, Eriksson M, Jonsson B, Steneroth G, Zetterstrom R.
Amphetamine addiction during pregnancy: 14-year follow-up of growth
and school performance. Acta Paediatr 1996;85(2):204–208. [II-2]
179. Diaz SD, Smith LM, LaGasse LL, et al. Effects of prenatal methamphet-
amine exposure on behavioral and cognitive findings at 7.5 years of age. J
Pediat 2014;164(6):1333–1338. [II-2]
180. Warton FL, Taylor PA, Warton CM, et al. Prenatal methamphetamine
exposure is associated with corticostriatal white matter changes in neo-
nates. Metab Brain Dis 2018;33(2):507–522. [II-2]
181. Warton FL, Meintjes EM, Warton CM, et al. Prenatal methamphetamine
exposure is associated with reduced subcortical volumes in neonates.
Neurotoxicol Teratol 2018;65:51–59. [II-2]
182. Wouldes TA, LaGasse LL, Huestis MA, DellaGrotta S, Dansereau LM,
Lester BM. Prenatal methamphetamine exposure and neurodevelopmen-
tal outcomes in children from 1 to 3 years. Neurotoxicol Teratol 2014;
42:77–84. [II-2]
Substance Use Disorders
183. Chang L, Smith LM, LoPresti C, et al. Smaller subcortical volumes and
cognitive deficits in children with prenatal methamphetamine exposure.
Psychiatry Research: Neuroimaging 2004;132(2):95–106. [II-2]
184. Singer LT, Moore DG, Min MO, et al. Motor delays in MDMA (ecstasy) exposed
infants persist to 2 years. Neurotoxicol Teratol 2016;54:22–28. [II-2]
185. Bolea-Alamanac BM, Green A, Verma G, Maxwell P, Davies SJ.
Methylphenidate use in pregnancy and lactation: a systematic review of
evidence. Br J Clin Pharmacol 2014;77(1):96–101. [Systematic Review; I]
186. Omer MIA, Al Mansoub M, Omer R, Omer R, Shadli M, Williams R. The
effect of qat chewing and other factors on breast-feeding and child survival
in a Yemeni society. Sudanese Journal of Paediatrics 2011;11(2):14. [III]
187. McElhatton PR. The effects of benzodiazepine use during pregnancy and
lactation. Reprod Toxicol 1994;8(6):461–475. [Review; III]
188. Hanley GE, Mintzes B. Patterns of psychotropic medicine use in pregnancy
in the United States from 2006 to 2011 among women with private insur-
ance. BMC Pregnancy Childbirth 2014;14(1):242. [II-2]
189. Tinker SC, Reefhuis J, Bitsko RH, et al. Use of benzodiazepine medica-
tions during pregnancy and potential risk for birth defects, National Birth
Defects Prevention Study, 1997–2011. Birth Defects Research 2019;111(10):
613–620. [Survey; III]
190. Bais B, Molenaar NM, Bijma HH, et al. Prevalence of benzodiazepines and
benzodiazepine-related drugs exposure before, during and after pregnancy:
a systematic review and meta-analysis. J Affect Disord 2020.
191. Wikner BN, Stiller CO, Källén B, Asker C. Use of benzodiazepines and ben-
zodiazepine receptor agonists during pregnancy: maternal characteristics.
Pharmacoepidemiol Drug Saf 2007;16(9):988–994. [II-2]
192. Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic
management of psychiatric illness during pregnancy: dilemmas and guide-
lines. Am J Psychiatry 1996. [III]
193. Enato E, Moretti M, Koren G. The fetal safety of Benzodiazepines: An updated
meta-analysis (vol 33, pg 46, 2011). JOGC 2011;33(4):319. [Meta-analysis; I]
194. Grigoriadis S, Graves L, Peer M, et al. Benzodiazepine use during pregnancy
alone or in combination with an antidepressant and congenital malforma-
tions: systematic review and meta-analysis. J Clin Psychiatry 2019;80(4).
195. Bellantuono C, Tofani S, Di Sciascio G, Santone G. Benzodiazepine expo-
sure in pregnancy and risk of major malformations: a critical overview.
Gen Hosp Psychiatry 2013;35(1):3–8. [Review; III]
196. Sheehy O, Zhao J-P, Bérard A. Association between incident exposure to
benzodiazepines in early pregnancy and risk of spontaneous abortion.
JAMA Psychiatry 2019;76(9):948–957. [II-2]
197. Ogawa Y, Takeshima N, Furukawa TA. Maternal exposure to benzodiazepine
and risk of preterm birth and low birth weight: A case-control study using a
claims database in Japan. Asia-Pacific Psychiatry 2018;10(3):e12309. [II-2]
198. Wikner BN, Stiller CO, Bergman U, Asker C, Källén B. Use of benzodiaz-
epines and benzodiazepine receptor agonists during pregnancy: neonatal
outcome and congenital malformations. Pharmacoepidemiol Drug Saf
2007;16(11):1203–1210.
199. Huitfeldt A, Sundbakk LM, Skurtveit S, Handal M, Nordeng H. Associations
of maternal use of benzodiazepines or benzodiazepine-like hypnotics dur-
ing pregnancy with immediate pregnancy outcomes in Norway. JAMA
Network Open 2020;3(6):e205860. [II-2]
200. Freeman MP, Góez-Mogollón L, McInerney KA, et al. Obstetrical and neo-
natal outcomes after benzodiazepine exposure during pregnancy: results
from a prospective registry of women with psychiatric disorders. Gen Hosp
Psychiatry 2018;53:73–79. [II-2]
201. Yonkers KA, Gilstad-Hayden K, Forray A, Lipkind HS. Association of panic
disorder, generalized anxiety disorder, and benzodiazepine treatment
during pregnancy with risk of adverse birth outcomes. JAMA Psychiatry
2017;74(11):1145–1152. [II-2]
202. American College of Obstetricians and Gynecologists. Use of psychi-
atric medications during pregnancy and lactation. Obstet Gynecol
2008;111(4):1001–1020. [III]
203. Sutton LR, Hinderliter SA. Diazepam abuse in pregnant women on meth-
adone maintenance: implications for the neonate. Clin Pediatr (Phila)
1990;29(2):108–111. [II-3]
204. Organization of Teratology Information Specialists. Benzodiazepines and
Pregnancy. 2016. [Review; III]
205. Laegreid L, Hagberg G, Lundberg A. Neurodevelopment in late infancy after
prenatal exposure to benzodiazepines-a prospective study. Neuropediatrics
1992;23(02):60–67. [II-2]
206. Lupattelli A, Chambers CD, Bandoli G, Handal M, Skurtveit S, Nordeng
H. Association of maternal use of benzodiazepines and z-hypnotics dur-
ing pregnancy with motor and communication skills and attention-deficit/
hyperactivity disorder symptoms in preschoolers. JAMA Network Open
2019;2(4):e191435. [II-2]
255
207. Sundbakk LM, Wood M, Gran JM, Nordeng H. Impact of prenatal exposure
to benzodiazepines and z-hypnotics on behavioral problems at 5 years of
age: A study from the Norwegian Mother and Child Cohort Study. PLOS
ONE 2019;14(6):e0217830. [II-2]
208. El Marroun H, White T, Verhulst FC, Tiemeier H. Maternal use of anti-
depressant or anxiolytic medication during pregnancy and childhood
neurodevelopmental outcomes: a systematic review. Eur Child Adolesc
Psychiatry 2014;23(10):973–992. [Systematic Review; I]
209. Shyken JM, Babbar S, Babbar S, Forinash A. Benzodiazepines in pregnancy.
Clin Obstet Gynecol 2019;62(1):156–167. [Review; III]
210. Kelly LE, Poon S, Madadi P, Koren G. Neonatal benzodiazepines exposure
during breastfeeding. J Pediatrics 2012;161(3):448–451. [II-3]
211. Journey JD, Bentley TP. Phencyclidine (PCP) Toxicity. StatPearls 2019.
[Review; III]
212. McCarron MM, Schulze BW, Thompson GA, Conder MC, Goetz WA.
Acute phencyclidine intoxication: incidence of clinical findings in 1,000
cases. Ann Emerg Med 1981;10(5):237–242. [II-3]
213. Bey T, Patel A. Phencyclidine intoxication and adverse effects: a clinical
and pharmacological review of an illicit drug. Cal J Emerg Med 2007;8(1):9.
[Review; III]
214. Golden NL, Kuhnert BR, Sokol RJ, Martier S, Bagby B. Phencyclidine use
during pregnancy. Am J Obstet Gynecol 1984;148(3):254–259. [II-2]
215. Golden NL, Kuhnert BR, Sokol RJ, Martier S, Williams T. Neonatal mani-
festations of maternal phencyclidine exposure. J Pediat Med 1987. [II-2]
216. Golden NL, Sokol RJ, Rubin IL. Angel dust: possible effects on the fetus.
Pediatrics 1980;65(1):18–20. [II-3]
217. Quality CfBHSa. Results from the 2019 National Survey on Drug Use and
Health: Detailed Tables. Substance Abuse and Mental Health Services
Administration, Rockville, MD 2020.
218. Nicholas JM, Lipshitz J, Schreiber EC. Phencyclidine: its transfer across
the placenta as well as into breast milk. Am J Obstet Gynecol 1982;143(2):
143–146. [II-3]
219. Kaufman K, Petrucha R, Pitts JF, Weekes M. PCP in amniotic
fluid and breast milk: case report. J Clin Psychiatry 1983;44(7):269–270.
[II-3]
220. Kaufman KR, Petrucha RA, Pitts FN, Kaufman ER. Phencyclidine in umbil-
ical cord blood: Preliminary data. Am J Psychiatry 1983. [II-3]
221. Strauss AA, Modanlou HD, Bosu SK. Neonatal manifestations of maternal
phencyclidine (PCP) abuse. Pediatrics 1981;68(4):550–552. [II-3]
222. Tabor BL, Smith-Wallace T, Yonekura ML. Perinatal outcome associated
with PCP versus cocaine use. Am J Drug Alcohol Abuse 1990;16(3-4):
337–348. [II-2]
223. Mvula M, Miller JJ, Ragan F. Relationship of phencyclidine and pregnancy
outcome. J Reprod Med 1999;44(12):1021–1024. [II-2]
224. Chasnoff IJ, Burns WJ, Hatcher RP, Burns KA. Phencyclidine: Effects on the
fetus and neonate. Dev Pharmacol Ther 1983;6:404–408. [II-2]
225. Wachsman LW, Schuetz S, Chan LS, Wingert WA. What happens to
babies exposed to phencyclidine (PCP) in utero? Am J Drug Alcohol Abuse
1989;15(1):31–39. [II-3]
226. Fico TA, VanderWende C. Phencyclidine during pregnancy: Behavioral
and neurochemical effects in the offspring. Ann NY Acad Sci 1989.
[II-3]
227. Howard J, Kropenske V, Tyler R. The long-term effects on neurodevelop-
ment in infants exposed prenatally to PCP. Phencyclidine: An Update.
64: Department of Health and Human Services, Public Health Service,
Alcohol …; 1986. p. 237–251. [II-3]
228. McCarron MM. Phencyclidine intoxication. NIDA Res Monogr
1986;64:209–217. [II-3]
229. Yockey RA, Vidourek RA, King KA. Trends in LSD use among US adults:
2015-2018. Drug Alcohol Depend 2020:108071. [Survey; III]
230. Madgula RM, Groshkova T, Mayet S. Illicit drug use in pregnancy:
effects and management. Expert Rev Obstet Gynecol 2011;6(2):179–192.
[Review; III]
231. Holbrook BD, Rayburn WF. Teratogenic risks from exposure to illicit drugs.
Obstet Gynecol 2014;41(2):229–239. [Review; III]
232. Illinois Teratogen Information Service. ITIS Newsletters: the effects of
hallucinogen use during pregnancy 2000. Available from: http://fetal-
exposure.org/the-effects-of-hallucinogen-use-during-pregnancy.
233. Long SY. Does LSD induce chromosomal damage and malformations? A
review of the literature. Teratology 1972;6(1):75–90. [Review; III]
234. Jacobson CB, Berlin CM. Possible reproductive detriment in LSD users.
J Am Med Assoc 1972;222(11):1367–1373. [II-2]
235. Cunningham C, Edlund FM, Fishman M, et al. The ASAM National
Practice Guideline for the Treatment of Opioid Use Disorder: 2020
Focused Update.
256
236. Polak K, Kelpin S, Terplan M. Screening for substance use in preg-
nancy and the newborn. In Semin Fetal Neonatal Med 2019 April
1;24(2):90–94.
237. American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders, 5th ed. (DSM-5). Washington, DC: American Psychiatric
Pub; 2013.
238. Ewing H. A practical guide to intervention in health and social services with
pregnant and postpartum addicts and alcoholics: theoretical framework,
Maternal-Fetal Evidence Based Guidelines
brief screening tool, key interview questions, and strategies for referral to
recovery resources. Martinez, CA: The Born Free Project, Contra Costa
County Department of Health Services 1990.
239. Dyer EM, Salehian S. How to interpret urine toxicology tests. Arch Dis
Child Educ Pract 2020 April 1;105(2):84–88.
240. Wesson DR, Ling W. The clinical opiate withdrawal scale (COWS).
J Psychoactive Drugs. 2003 June 1;35(2):253–259.
24
INTIMATE PARTNER VIOLENCE AND TRAUMA INFORMED CARE IN PREGNANCY
Johanna Quist-Nelson and Amy Weil
Key points
• Intimate partner violence (IPV) is “any behavior within an
intimate relationship that causes physical, psychological,
or sexual harm to those in the relationship.”
• Trauma informed care (TIC) is wholistic sensitive care that
attends to past or ongoing experiences of trauma.
• The risk of IPV increases during pregnancy.
• Screening for IPV during pregnancy should be univer-
sal; each patient should be asked each trimester.
• Patients should be screened without a partner or family
member present.
• Screening may be verbally or with a standardized written tool.
• Important signs of IPV can be absence from or lateness to
prenatal care.
• Often patients who are experiencing IPV may present with
avoidance behavior or extreme anxiety related to pelvic exams.
• For known trauma survivors, special consideration should
be given to avoid re-traumatization with repeat exams and
interventions.
• Referral and supportive counseling are likely to benefit
women.
• Offering and supporting lactation in a postpartum woman
should be done with care for patients who are victims of
IPV to avoid re-traumatization.
• Postpartum or post-abortion contraception should be offered
to patients to assist in avoiding unplanned pregnancies.
However, clinicians should always avoid reproductive coercion
in the contraception counseling.
Historic and cultural notes
Intimate partner violence (IPV) has been present throughout
human history, with the earliest complex societies recording laws that
sanctioned men treating women, particularly their wives, with vio-
lence [1]. Worldwide, terminology often refers to gender-based vio-
lence (GBV) and includes the state as well as more intimate partners,
primarily focused on women. In this chapter, we will discuss IPV pri-
marily against women within pregnancy and postpartum as women
carry “the overwhelming global burden of IPV” [2]. It is also notable
that IPV may occur at higher rates in lesbian, gay, bisexual, transgen-
der, questioning, intersex, asexual, and ally (LGBTQIAA) relation-
ships [3]. We recommend that providers give consideration to the
possibility of IPV in each pregnant person and individualize care [4].
Definitions
The WHO defines IPV as “any behavior within an intimate rela-
tionship that causes physical, psychological, or sexual harm
to those in the relationship” [5]. An intimate partner may be
a spouse, boyfriend/girlfriend, dating partner, or ongoing sexual
partner [6]. Some examples of IPV are included in Table 24.1
although other examples of IPV do exist.
DOI: 10.1201/9781003099062-24
The term domestic violence is often used in conjunction with IPV
but is a broader term to reference abuse of any member of a house-
hold including child or elder abuse. Thus, the term IPV will be used
throughout this chapter. Trauma informed care (TIC) is wholistic
sensitive care that attends to past or ongoing experiences of trauma.
Symptoms and signs
The risk of IPV increases during pregnancy [7]. Patients living
with IPV may present with myriad manifestations ranging from
absence from scheduled visits, to somatic complaints, observable
injuries, pregnancy specific manifestations, psychological distress,
or no obvious signs or symptoms with or without disclosure. For
this reason, universal screening of patients who do not disclose
ongoing IPV outright is important, especially as it normalizes pro-
viders’ role in assisting patients and the clinical setting as a place
of safety. It is common for a patient not to acknowledge ongoing
IPV outright. Stigma, shame, lack of recognition of dynamics, may
all be at play. Past or ongoing IPV should be considered in several
situations (Table 24.2) including absence from prenatal care or
extreme anxiety relating to pelvic exams [4].
It is notable in one meta-analysis that injuries or Petechiae
to the face, neck or head had a higher association with IPV in
women when compared to injuries to the upper or lower extremi-
ties, though so called ‘defensive’ injuries to the forearms may
be seen. Petechiae and other head and neck manifestations may
reflect strangulation, which is a life-threatening injury [8].
Epidemiology/Incidence
The World Health Organization (WHO) released a compre-
hensive report on IPV which detailed that outside of pregnancy
20–75% of women have experienced one emotionally abusive act
from a partner in their lifetime, while between 13–61% report
experiencing physical violence by a partner [9].
Within pregnancy, rates of IPV have been estimated to be as
high as 20% [10]. In the WHO report cited earlier, greater than
5% of pregnant women were victims of IPV worldwide. Of these
women, approximately 50% reported first incidence of IPV during
pregnancy [9]. It should be noted that surveys of this type run the
risk of underreporting due to perceived stigma and safety con-
cerns. Anonymous telephone surveys regarding IPV have shown
even higher numbers affected [11].
Screening
Role of obstetric providers in screening
and providing trauma informed care
Screening for IPV during pregnancy should be universal;
each patient should be asked each trimester. Obstetric pro-
viders are positioned to screen women who are highest risk of
IPV and provide trauma informed care (TIC), wholistic sensitive
257
258 Maternal-Fetal Evidence Based Guidelines

TABLE 24.1: Examples of Intimate Partner Violence
Physical Violence
Hitting, pushing, punching, scratching, choking, shaking, burning, use
weapons or restraints
Sexual Violence
Sexual violence, including rape, forced sexual intercourse, and other
forms of sexual coercion
Noncontact unwanted sexual experiences including unwanted exposure
to sexual situation, verbal or behavioral harassment, unwanted filming,
taking or disseminated photographs of a sexual nature
Psychological
Emotional (psychological) abuse, such as insults, belittling, constant
humiliation, name-calling
Intimidation such as threats of harm, threats to take away children
Controlling behaviors, including isolating a person from family and friends
Controlling behaviors such as monitoring a person’s movements; and
restricting access to financial resources, employment, education or
medical care
Controlling behaviors or coerced pregnancy termination or coerced
pregnancy continuation
Stalking
Defined as a pattern of repeated unwanted attention that causes concern
for one’s own safety
Source: Adapted from Centers for Disease Control and Prevention (Ref. [6]).
TABLE 24.3: Six Principles of Trauma Informed Approach
Safety
Truthworthiness and transparency
Peer support
Collaboration and mutuality
Empowerment and choice
Culture, historical and gender issues
Source: From CDC, in the public domain: (https://www.cdc.gov/cpr/infographics/
6_principles_trauma_info.htm).
to all patients during pregnancy [14]. The American College of
Obstetricians and Gynecologists (ACOG) recommends screen-
ing in each trimester as well as postpartum [15]. In one RCT, non-­
pregnant women who were screened experienced less depression
and improved quality-of-life than those who were not screened [16].
Evidence-based screening
Importantly, patients should be screened without a partner or
family member present. A meta-analysis of [13] trials and more
than 14,000 women demonstrated no harms associated with
screening and suggested that pregnant women may be more
likely to disclose IPV then non-pregnant people [17]. Screening
should routinely occur alone, not in the presence of the patient’s
partner or family. If patient is screened verbally, providers should
screen with framing statements to explain the routine nature of
the questions [4].

Screening tools
care that attends to past or ongoing experiences of trauma [12]. Patients may prefer written screening tools over verbal screening
TIC allows survivors to rebuild a sense of control and empower- [18]. There are several validated written or clinician-administered
ment. General principle of TIC is summarized by the four Rs: (1) screening tools available. Table 24.4 shows those screening tools
Realize the prevalence of traumatic events and impact of trauma; that are rated as accurately detecting IPV by the U.S. Preventive
(2) Recognize the signs and symptoms of trauma; (3) Respond by Task Force. One written screening tool HARK (Humiliation,
integrating knowledge about trauma into policies, procedures,
and practices; and (4) Seek to actively Resist re-traumatization.
There are six principles to providing TIC listed in Table 24.3. TABLE 24.4: Validated Screening Tools Rated as Accurate by
It is notable that providing TIC is not amenable to a checklist the U.S. Preventative Service Task Force
or formulaic approach, but that these principles can be imple- Name of Tool Sensitivity Specificity Description
mented broadly in every patient interaction and apply especially
to screening. Humiliation, Afraid, 81 95 4-item self-report
There are multiple ways to train providers to implement TIC. Rape, Kick survey based off of
One example of an introductory session from health profession- Instrument (HARK) AAS
als is available on MedEdPortal [13]. Hurt/Insult/ 86–96 91–99 4-item survey, either
Threaten/Scream self-report or
Evidence for screening (HITS) staff-administered,
Screening is recommended by U.S. Preventive Service Task Force excluding sexual
as well as multiple other organizations and should be universal violence
Extend Hurt/Insult/ Includes additional item
TABLE 24.2: Possible Symptoms and Signs of IPV Threaten/Scream assessing frequency of
(E-HITS) sexual violence
A women who is absent from or late to prenatal care or experiences trauma
Partner Violence 49–71 80–94 3-item staff-
during her pregnancy [7].
Screen (PVS) administered survey,
Persistent pain that cannot be explained by underlying condition [39]
assesses violence,
Anxiety and depression as up to 60% of patients with depression have a current safety,
history of IPV [4]. excluding sexual abuse
Marks on neck, facial petechiae, neck swelling [8] Woman Abuse 89–96 55 8-item self-report survey
Hoarseness, sore throat, respiratory disturbance or accidental injury to Screening Tool including emotional
the neck [8] (WAST) and sexual abuse
Disassociation from pelvic exams [34].
Source: From Lutgendorf M. Intimate partner violence and women’s health.
Avoidance behavior or extreme anxiety related to pelvic exams [4]. Obstet Gynecol 2019;134(3):470–480. Ref. [4], with permission.
Abbreviation: IPV, intimate partner violence. Abbreviation: AAS, abuse assessment screen.
Intimate Partner Violence and Trauma Informed Care in Pregnancy
Afraid, Rape, Kick) instrument is a four-item self-report survey that
can be easily scored [19]. These items are available online and can
be adopted into routine clinical practice. If a tool is self-reported,
consideration should be made to the patient’s level of literacy. For
staff-administered surveys the questions may be routinely asked
by staff or clinicians during their initial prenatal visit and each
trimester. All survey results or verbal screening results should be
included in the prenatal record. While not specific to pregnancy,
some have proposed screening at the workplace to capture those
who do not seek medical attention [20].
Etiology/Basic pathophysiology
The etiology of IPV is complex and includes risk factors, as well
as the perpetrator’s own experience of violence with their family,
community, and society, which can lead to a cycle of generational
violence [7]. It is generally accepted that one form of IPV occurs
in a cyclic nature with a tension building phase, a battering phase,
and a honeymoon phase where the perpetrator may engage in
behaviors to rectify or justify behavior or blame the victim [21].
Mutual IPV has also been seen and may not always follow this
same pattern.
Risk factors/Associations
There is a complex network of associations increasing the risk of
IPV divided into social, community, relationship, and individual
risk factors [6]. Societal level risk factors include traditional gen-
der roles, structural violence including systemic racism, xeno-
phobia, homophobia, and transphobia, and general acceptance
of violence for conflict resolution [7, 22]. Community risk factors
include poverty, poor social cohesion, weak social capital defined
as institutions, relationships, and norms that shape the quality
and quantity of a society’s social interactions [23]. Noting these
factors as causal does not fully take into account how the risks
for individuals at each level may be caused/worsened by factors,
such as historical and community precedents that intersect with
each other; all need to be addressed in order to decrease/mitigate
IPV in individuals. One large meta-analysis showed that the sin-
gle greatest, modifiable risk factor is unplanned pregnancy [24],
which may occur spontaneously, but may also result from repro-
ductive coercion or sexual assault.
Complications of unplanned
pregnancy in the setting of IPV
• Risk of maternal death; reported rates range from 0.97–
10.6 per 100,000 live births [25].
• Homicide from IPV may be at highest risk in the first tri-
mester [26].
• The risk of perinatal death is increased (OR 3.18, 95% CI
1.88–5.38) [27] with 60% of these deaths may be attributed
to exposure of IPV.
• The overall rate of pregnancy complications is increased,
such as increased risk of miscarriage, preterm labor, pre-
term birth, placental abruption, low birthweight, uterine
rupture [28, 29].
Management
General principles
Although IPV can increase in severity of violence during preg-
nancy or postpartum [30] the overarching principle is that
patients want caregivers to be nonjudgmental, compassionate,
259
and confidential [31]. Delivery of such care is well summarized
by the six principles of trauma informed care as outlined in
Table 24.3.
Notably, pregnancy is a time of regular appointments that
afford time for follow-up and intervention [4]. Thus, not all
of the support and goals are necessarily established in one
interaction.
There are many principles of TIC that can be applied to a his-
tory and physical exam [32]. These include being seated as much
as possible to decrease power differential between provider and
patients and encouraging all in attendance to also be seated. Prior
to the exam, ask if there is a part of the physical exam that they
feel anxious about, or if there is anything you can do to make
them feel more comfortable. During the physical exam it is
important to ask the patient for permission before moving on to
the next part of the physical exam. It is recommended that the
provider does not shift the clothing out of the way, but rather ask
the patient to do so. Lastly, determine if alternate measures can
be taken for examinations such as offering a self-swab rather than
a speculum [32].
Prevention
True primary prevention would require interventions on a
societal level that focus on sex inequality as well as structural
factors including systemic racism, heterosexism and xeno-
phobia, and general acceptance of violence for conflict resolu-
tion [33].
Applying the TIC principles mentioned earlier with each
patient may also decrease the risk of retraumatizing patients with
their interactions and provide daily prevention [34].
When faced with individual clinical situations, we may assist
our patients in avoiding unplanned pregnancies [24] by provid-
ing patient-centered counseling about birth control meth-
ods as well as access to safe, confidential abortion care [35].
Additionally, assisting our patients with interventions outlined
later once IPV is disclosed may allow patients to avoid future
episodes of IPV or at least to reduce their risks and cope with
strength.
Preconception counseling
The principles regarding universal screening for all patients for
IPV and providing appropriate TIC includes in the preconcep-
tion period.
Prenatal care
Intervention services
In providing TIC, a provider should guide a survivor to under-
stand what choices they have and to build a safety plan to
respond to dangerous situations that may ensue [4]. Evidence
from randomized controlled trials regarding screening, referral,
and supportive counseling all are likely to benefit those who are
survivors of IPV [36].
At no point should a provider confront the perpetrator or
instruct a patient to leave a situation as both actions increase
danger for survivors. Hearing the patients’ voice and offering
choices and support as well as referral if patients are inter-
ested are much preferred and safer strategies.
In many states in the United States providers may be mandated
reporters of violence if a deadly weapon (gun, knife, or in some
circumstances, hands) is used or there are child witnesses.
Once IPV is recognized, providers should continue to use
trauma informed interview and exam practices, as they should
260
TABLE 24.5: Resources for Patients and Clinicians
Websites
Futures without Violence: www.futureswithoutviolence.org
National Coalition against Domestic Violence: https://ncadv.org/
National Network to End Domestic Violence: https://nnedv.org/
National Resource Center on Domestic Violence: https://www.nrcdv.org/
Office on Violence against Women: https://www.justice.gov/ovw
Hotlines
National Domestic Violence Hotline: 1-800-799-SAFE (7233)
Rape Abuse & Incest National Network RAINN Hotline: 1-800-656-
HOPE (4673)
Source: From ACOG Committee Opinion No. 518: intimate partner violence.
Obstet Gynecol 2012;119(2 Pt 1):412–417. Ref. [21], with permission.
be doing universally. Additional assistance may be needed from
within or outside of the clinical setting, including community
agencies keyed to assist IPV survivors. This referral depends on
patients being agreeable; it also refers to what local resources are
available that could include 1) psychological support 2) relo-
cation support or legal support if the patient is amenable.
Evidence-based interventions may also include home visitation
or behavior counseling [14].
It is also notable that a Cochrane Review of 33 psychological
trials suggested that for non-pregnant women who experience
IPV, psychological therapies probably reduce depression and
may reduce anxiety [37]. These include body based modalities
such has mindful breathing, which can also aid in labor and
delivery.
There are several systems of support and resources that vary by
hospital system, country, and location. Table 24.5 lists websites
that may be of use to clinicians within the United States.
Antepartum testing
Decisions about additional antepartum appointments or testing
should only be undertaken in discussions of risk and benefit with
the patient. Additional appointments could lead to fear, concern,
or blame in some relationships. Alternatively, visits can provide
additional opportunities for confidential support, referral, and
safety planning.
As there is evidence of an increased risk of fetal death, antena-
tal surveillance with non-stress tests could be considered at
or after 32 weeks. Given the reports of low birthweight in infants
affected by IPV during their pregnancy, a third trimester growth
scan could be considered.
Delivery
Recommendations for delivery timing should be according to
other obstetrical risk factors and indications. It is imperative that
special considerations be made to avoid re-traumatization with
repeat exams and interventions [7, 12, 38].
There may be special considerations to planning of the pres-
ence of a partner on labor and delivery. It is also key to assure
safety for parent and child if the perpetrator is a partner and there
is an ongoing threat. In some cases, especially if charges have
been pressed, the partner may be “trespassed,” not permitted to
enter the institution to assure safety. Knowledge of one’s local
institutional policies may be helpful in these situations.
Maternal-Fetal Evidence Based Guidelines
Anesthesia
It is reasonable to consider discussing the benefits and risks of an
early epidural for comfort with exams and interventions that may
occur during the birthing process as well as respecting patient
wishes for a natural birth. As always, giving the patient maximum
control of decision-making while maintaining safety for parent
and child will help with healing.
Postpartum/Breastfeeding
Patients who have experienced IPV may be sensitive to breast
manipulation and exposure required for breastfeeding. It is rec-
ommended that there be training for nursing and lactation con-
sultants to avoid retraumatized by breast manipulation during
breastfeeding [38]. Clinicians should have more flexibility when
it comes to strongly encouraging breastfeeding if it is associated
as a trigger or retraumatizing for the patient.
Future (postpartum counseling,
recurrence risks, etc.)
The WHO has provided 15 recommendations to decrease IPV
and violence against women that providers can encourage and
incorporate into their practices [2]. These include:
• Promoting gender equality and women’s human rights.
• Decreasing systemic violence including systemic racism,
xenophobia, and violence against persons who identify as
LGBTQIAA.
• Enhance capacity and establish systems for data collection
to monitor violence against women, and the attitudes and
beliefs that perpetuate it.
• Use reproductive health services as entry points for identi-
fying and supporting women in abusive relationships, and
for delivering referral or support services.
References
1. Clay C, Chandrika P, Senecal C. Envision women in world history,
Prehistory-1500, Volume 1. McGraw Hill. 2009. [Historical Reference]
2. World Health Organization; WHO multi-country study on women’s health
and domestic violence against women. 2005. Available at: https://www.
who.int/reproductivehealth/publications/violence/24159358X/en/.
Retrieved June 17, 2020. [Review]
3. Walters ML, Chen J, Breiding MJ. The National Intimate Partner and Sexual
Violence Survey (NISVS): 2010 findings on victimization by sexual orien-
tation. Available at: https://www.cdc.gov/violenceprevention/pdf/nisvs_
sofindings.pdf. Retrieved June 18, 2020. [Review]
4. Lutgendorf M. Intimate partner violence and women’s health. Obstet
Gynecol 2019;134(3):470–480. [Review]
5. World Health Organization; Understanding and addressing violence
against women. 2012. Available at: https://www.who.int/reproductivehealth/
topics/violence/vaw_series/en/. Retrieved June 17, 2020. [Review]
6. Center for Disease Control and Prevention. Intimate partner violence. 2019.
Available at: https://www.cdc.gov/violenceprevention/intimatepartnervi-
olence/riskprotectivefactors.html. Accessed: June 18, 2020. [Review]
7. Zolotor A, Denham AC, Weil A. Intimate partner violence. Prim Care
2009;36(1):167–179. [Review]
8. Armstrong M Jr, Strack GB. Recognition and documentation of strangula-
tion crimes: a review. JAMA Otolaryngol Head Neck Surg 2016;142(9):891–
897. [II-2]
9. García-Moreno C, Jansen HA, Ellsberg M, Heise L, Watts C. WHO multi-
country study on women’s health and domestic violence against women.
World Health Organization; 2005. Accessed: June 18, 2020. [Review]
Intimate Partner Violence and Trauma Informed Care in Pregnancy
10. Gazmararian JA, Lazorick S, Spitz AM, Ballard TJ, Saltzman LE, Marks
JS. Prevalence of violence against pregnant women. JAMA 1996;275(24):
1915–1920. [II-2]
11. Center for Disease Control and Prevention. The National Intimate Partner
and Sexual Violence Survey. 2010-2012 State Report. Available at: https://
www.cdc.gov/violenceprevention/pdf/nisvs-statereportbook.pdf. Accessed
October 26, 2020. [Review]
12. Sperlich M, Seng JS, Li Y, Taylor J, Bradbury-Jones C. Integrating trauma-
informed care into maternity care practice: conceptual and practical issues.
J Midwifery Womens Health 2017;62(6):661–672. [Review]
13. Schrier MW, Rougas SC, Schrier EW, Elisseou S, Warrie S. Intimate partner
violence screening and counseling: an introductory session for health care
professionals. MedEdPORTAL 2017;13:10622. [Education Training]
14. Feltner C, Wallace I, Berkman N et al. Screening for intimate partner
violence, elder abuse, and abuse of vulnerable adults: evidence report
and systematic review for the US Preventive Services Task Force. JAMA
2018;320(16):1688–1701. [Guideline]
15. American College of Obstetricians and Gynecologists. Special Issues in
Women’s Health. Washington, DC: American College of Obstetricians and
Gynecologists; 2005. [Guideline]
16. MacMillian H, Wathen CN, Jamieson E, et al. Screening for intimate
partner violence in health care settings: a randomized trial. JAMA
2009;302(5):493–501. [I]
17. O’Doherty L, Hegarty K, Ramsay J, Davidson LL, Feder G, Taft A. Screening
women for intimate partner violence in healthcare settings. Cochrane
Database Syst Rev 2015;2015(7):CD007007. [Meta-analysis, I]
18. MacMillian H, Wathen CN, Jamieson E, et al. Approaches to screening for
intimate partner violence in health care settings: a randomized trial. JAMA
2006;296(5):530–536. [I]
19. Sohal H, Eldridge S, Feder G. The sensitivity and specificity of four ques-
tions (HARK) to identify intimate partner violence: a diagnostic accuracy
study in general practice. BMC Fam Pract 2007;8:49. [II-2]
20. Adhia A, Gelaye B, Friedman LE, Marlow LY, Mercy JA, Williams MA.
Workplace interventions for intimate partner violence: a systematic review.
J Workplace Behav Health 2019;34(3). doi: 10.1080/15555240.2019.1609361.
PMID: 32322182; PMCID: PMC7176402. [Meta-analysis, I]
21. ACOG Committee Opinion No. 518: intimate partner violence. Obstet
Gynecol 2012;119(2 Pt 1):412–417. [Guideline]
22. Waltermaurer E, Watson CA, McNutt LA. Black women’s health: the
effect of perceived racism and intimate partner violence. Violence Against
Women 2006;12(12):1214-1222. [II-3]
23. Zolotor AJ, Runyan DK. Social capital, family violence, and neglect.
Pediatrics 2006;117(6):e1124–1131. [II-2]
24. Yakubovich AR, Stöckl H, Murray J, et al. Risk and protective factors for inti-
mate partner violence against women: systematic review and meta-analyses
of prospective-longitudinal studies. Am J Public Health 2018;108(7):e1–e11.
[Meta-analysis, II-1]
261
25. Cliffe C, Miele M, Reid S. Homicide in pregnant and postpartum women
worldwide: a review of the literature. J Public Health Policy 2019;40(2):180–
216. [Review]
26. Cheng D, Horon IL. Intimate-partner homicide among pregnant and post-
partum women. Obstet Gynecol 2010;115(6):1181–1186. [II-2]
27. Pastor-Moreno G, Ruiz-Pérez I, Henares-Montiel J, Petrova D. Intimate
partner violence during pregnancy and risk of fetal and neonatal death: a
meta-analysis with socioeconomic context indicators. Am J Obstet Gynecol
2020;222(2):123–133.e5. [Meta-analysis, II-2]
28. El Kady D, Gilbert WM, Xing G, Smith LH. Maternal and neonatal out-
comes of assaults during pregnancy. Obstet Gynecol 2005;105(2):357–363.
[II-1]
29. Janssen PA, Holt VL, Sugg NK, Emanuel I, Critchlow CM, Henderson AD.
Intimate partner violence and adverse pregnancy outcomes: a population-
based study. Am J Obstet Gynecol 2003;188(5):1341–1347. [II-2]
30. Brownridge DA, Taillieu TL, Tyler KA, Tiwari A, Ko Ling Chan, Santos SC.
Pregnancy and intimate partner violence: risk factors, severity, and health
effects. Violence Against Women 2011;17(7):858–881. [II-1]
31. Feder GS, Hutson M, Ramsay J, et al. Women exposed to intimate part-
ner violence: expectations and experiences when they encounter health
care professionals: a meta-analysis of qualitative studies. Arch Intern Med
2006;166(1):22–37. [II-3]
32. Ravi A, Little V. Providing trauma-informed care. Am Fam Physician
2017;95(10):655–657. [Guideline]
33. Chisholm CA, Bullock L, Ferguson JEJ 2nd. Intimate partner violence and
pregnancy: epidemiology and impact. Am J Obstet Gynecol 2017;217(2):141–
144. [Review]
34. Gerber MR, ed. Trauma-Informed Healthcare Approaches: A Guide for
Primary Care. Boston, MA: Springer, 2019. [Book Chapter]
35. Drew LB, Mittal M, Thoma ME, Harper CC, Steinberg JR. Intimate part-
ner violence and effectiveness level of contraceptive selection post-abortion
[published online ahead of print, 2019 Nov 14]. J Womens Health (Larchmt)
2019. [II-3]
36. Daley D, McCauley M, van der Broek N. Interventions for women who
report domestic violence during and after pregnancy in low- and middle-
income countries: a systematic literature review. BMC Pregnancy
Childbirth 2020;20:141 [Meta-analysis, I]
37. Hameed M, O’Doherty L, Gilchrist G, et al. Psychological therapies for
women who experience intimate partner violence. Cochrane Database Syst
Rev 2020;7(7):CD013017. [Meta-analysis, I]
38. Montgomery E. Feeling safe: a metasynthesis of the maternity care needs
of women who were sexually abused in childhood. Birth 2013;40(2):88–95.
[II-3]
39. Walker N, Beek K, Chen H, Shang J, et al. The experiences of persistent
pain among women with a history of intimate partner violence: a system-
atic review. Trauma Violence Abuse 2020. doi: 10.1177/1524838020957989.
Epub ahead of print. PMID: 32945245. [II-2]
25
RACISM AND RACIAL DISPARITY IN OBSTETRICS
Ukachi N. Emeruwa, Emily Rosenthal, and Allison S. Bryant
Key points
• Race is a social construct developed without consider-
ation for a specific genetic or biological attribute, and
yet it seems inextricably linked to health outcomes, of
which maternal health outcomes are no exception. Women
of color often have less favorable reproductive health
outcomes than do their White counterparts.
• As a lived experience, racism is woven into the foundation
of obstetrics, and research and narratives show that these
experiences have persisted in modern-day form in the
practice of what has been termed obstetric racism.
• Obstetric racism lies at the intersection between obstet-
ric violence and medical racism and is defined as the
mechanism and practices of subordination to which Black
women and Black people’s reproduction are subjected that
track along histories of anti-Black racism. Obstetric rac-
ism includes, but is not limited to, coercion to perform
procedures, neglectful or dismissive treatment, lapses
in diagnosis, and causing pain, all of which contribute to
the threat to maternal health and neonatal outcomes.
• In addition to individually mediated racism, meted out
at an interpersonal level, exist societal-level barriers
that impact perinatal outcomes for women of color. The
complex relationship between racial disparities and these
systemic factors has also been shown to be mediated by
racism at internalized, institutional, and structural levels.
Internalized racism is defined as acceptance by members
of the stigmatized races of negative messages about their
own abilities and intrinsic worth; institutionalized rac-
ism as the policies, practices, and procedures of institu-
tions that result in differential access to goods, services,
and opportunities of society by race; and structural rac-
ism as the system of social structures (e.g. public policies
and institutions) that produce and perpetuate cumulative,
durable, race-based inequalities. In other words, higher
poverty rates, lower educational attainment, dispropor-
tionate incarceration, toxic habits, and lower access to
nutritional food faced by women of color serve as seem-
ingly independent risk factors for poor outcomes, but are
importantly a function of institutionally sanctioned racial-
ized constraints and abuses.
• Non-Hispanic Black women are three to four times
more likely to die from pregnancy-related complica-
tions than non-Hispanic White women.
• Pregnancy-related mortality ratio (PRMR) is 40.8 per
100,000 live births for Black women compared to 12.7
per 100,000 live births for White women.
• While disparities in poverty, educational attainment,
and other social determinants of health have tradition-
ally been offered as explanations for these differences,
statistics consistently demonstrate evidence to the
262
contrary. In particular, Black women with the highest
levels of educational attainment have maternal death
rates 1.6 times higher than White women with the low-
est levels of educational attainment.
• An overwhelming body of peer-reviewed literature com-
piled by the National Academy of Medicine (formerly
the Institute of Medicine) into a report at Congressional
request found strong evidence that racial bias plays a role
in the lower quality of care that patients of color receive
compared to White patients. The report identified dis-
crimination, stereotyping, and clinical uncertainty as
key factors that mediated the relationship between race
and quality of care.
• Internalized racism has been shown to take a physi-
ologic toll on Black women’s mental, emotional, and physi-
cal health and has been directly linked to higher rates of
chronic disease and adverse birth outcomes.
• Cardiovascular disease is among the risk factors dispro-
portionately experienced by Black women linking them to
higher rates of maternal mortality.
• Though little data exist to evaluate interventions for reduc-
ing racial disparities in maternal mortality, expert opinion
and recommendations targeting the theorized, evidence-
based mechanisms propose a number of individual and
system-level interventions. These include implementation
of standardized, evidence-based quality care bundles
and metrics for improvement; diverse representation
of researchers and project leads; accurate measurement
and communication of disparities; education of provid-
ers about racial disparities, the importance of shared
decision-making and cultural competency; and implicit
bias training for providers.
• One well-studied intervention has been the provision of
continuous intrapartum support. Based on a Cochrane
Review that demonstrated improved pregnancy outcomes
for women allocated to continuous one-to-one support
during labor compared to usual care, including lower
cesarean delivery rates, provision and support of doulas
to advocate for Black women within the system may be a
promising link in closing the racial mortality gap.
• Non-Hispanic Black patients in the United States have
double the rate of preterm birth compared to non-His-
panic White patients.
• Preterm birth recurs in Black patients at 4 times the rate of
White patients.
• Group prenatal care, which incorporates social support
into regular care, has been associated with decreased risk
of preterm birth and reduction of racial disparity associ-
ated with preterm birth for Black patients.
• Suggested interventions for reducing disparities include
standardized protocols for end-organ evaluation during
prenatal care, prescription of low-dose aspirin according
DOI: 10.1201/9781003099062-25
Racism and Racial Disparity in Obstetrics
to United States Preventive Services Task Force (USPSTF)
guidelines, and implementation of care bundles, and
postpartum text-based blood pressure monitoring.
• Women of color are more likely to experience socioeco-
nomic and structural barriers to accessing prenatal care
in the form of conflict with work schedules and childcare,
transportation availability, and finances.
• As concluded by the former Institute of Medicine in 2002,
a substantial body of peer-reviewed literature supports the
notion that women of color receive lower quality care,
even when controlling for access-related factors.
• A retrospective cohort study found that the degree of per-
ceived racial microaggressions is correlated with delayed
or no entry into prenatal care, an effect that persisted after
controlling for other potential sociodemographic factors.
• Interventions to reduce disparities in prenatal care include
home visits, the adoption of accountable care organiza-
tions, and screening for social determinants of health,
group prenatal care, which has been cited by patients
as allowing for self-advocacy and community, as well as
increasing provider diversity, which allows for improved
cultural humility and for greater patient-provider racial
concordance.
• A systematic review of the literature found that patient-
provider racial concordance was associated with better
communication but that providers can overcome barri-
ers inherent in racially discordant interactions through
training and early development of competent, patient-
centered communication.
• Hispanic and non-Hispanic Black patients received less
opioid analgesia while admitted, and had lower odds of
receiving an opioid prescription at discharge as com-
pared to White patients, despite having higher odds of
reporting a pain score of 5 or greater.
• A standardized protocol for postpartum pain manage-
ment, improvement of patient-provider communication
through shared decision-making, and efforts to increase
diversity among providers could reduce racial disparity in
postpartum pain control.
Background
Race is a social construct developed without consideration
for a specific genetic or biological attribute, and yet it seems
inextricably linked to health outcomes, of which maternal health
outcomes are no exception. We use “Black” and “White” through-
out the text to capture the racial identity of women of varying
ethnic backgrounds. Women of color (i.e. non-White women)
often have less favorable reproductive health outcomes than
do their White counterparts [1].
Furthermore, racial disparities in maternal health outcomes
exist even after accounting for comorbidities, education, income,
and access [2], leaving the necessary consideration of the lived
experience of race, i.e. racism, as a unique risk factor for poor
outcomes, rather than as a proxy for other concepts.
Racism, deemed one of “America’s earliest tradition[s]” [3], has
been used as a way of devaluing those classified as non-European,
and in the 1800s gained affirmation in “scientific” works that
served to reinforce White supremacy [3, 4]. As a lived experi-
ence, racism is woven into the foundation of obstetrics, ranging
from medical experimentation to nonconsensual procedures to
263
the degradation of enslaved women coerced to serve as instru-
ments for nurturing White offspring at the expense of their
own. Research and narratives show that these experiences have
persisted in modern-day form in the practice of what has been
termed obstetric racism [5]. Obstetric racism lies at the intersec-
tion between obstetric violence and medical racism and is defined
as the mechanism and practices of subordination to which Black
women and Black people’s reproduction are subjected that track
along histories of anti-Black racism [5, 6]. Obstetric racism
includes, but is not limited to, coercion to perform procedures,
neglectful or dismissive treatment, lapses in diagnosis, and
causing pain, all of which contribute to the threat to maternal
health and neonatal outcomes.
In addition to individually mediated racism meted out at an
interpersonal level, exist societal-level barriers that impact
perinatal outcomes for women of color. The complex relationship
between racial disparities and these systemic factors has also
been shown to be mediated by racism at internalized, institu-
tional, and structural levels [7–9]. Internalized racism is defined
as acceptance by members of the stigmatized races of negative
messages about their own abilities and intrinsic worth; institu-
tionalized racism as the policies, practices, and procedures of
institutions that result in differential access to goods, services,
and opportunities of society by race; and structural racism as the
system of social structures (e.g. public policies and institutions)
that produce and perpetuate cumulative, durable, race-based
inequalities [7, 10, 11]. In other words, higher poverty rates,
lower educational attainment, disproportionate incarcera-
tion, toxic habits, and lower access to nutritional food faced
by women of color serve as seemingly independent risk factors for
poor outcomes, but are importantly a function of institutionally
sanctioned racialized constraints and abuses [2, 4, 8]. Therefore, it
bears acknowledging systemic racism as a ubiquitous risk factor
impacting many maternal health crises.
As a result of these perpetuated ideologies and practices,
maternal race differentially impacts minorities, and, in par-
ticular, Black women, compared to White women in regards to
maternal health. Crises facing current day Black mothers in par-
ticular range from disproportionately higher preterm birth rates
and maternal mortality rates to increased risk of hypertensive
disorders of pregnancy and their associated complications to
lower utilization of prenatal care, among many other disparities.
Black women bear the brunt of these disparities with consistently
worse outcomes than White women, though other racial minori-
ties share the burden in various domains related to pregnancy
outcomes, maternal outcomes and obstetric care [1].
Historically, the attribution of racial disparities to biological
differences has impeded the development of interventions to
combat and address individual and structural racism in the effort
to improve health outcomes. With the acknowledgment of the
lived experience of race as an independent risk factor in affect-
ing maternal outcomes, a growing body of literature has begun to
explore and offer critical solutions to the threats posed by racism.
This paradigm shift allows health providers and investigators to
remove disproportionate emphasis on individual behaviors and
instead, simultaneously target the compounding structural and
systemic barriers that had previously been neglected in a more
comprehensive approach to reducing perinatal morbidity and
mortality. Paramount to these efforts is the development of vali-
dated instruments to define, measure, and evaluate racism and
its association with poor outcomes, after which the utility of
264
interventions designed to modify and eliminate racist practices
and policies can be adequately assessed.
What follows in this chapter is a discussion of several dis-
parities in obstetric care, outcomes, and how racism serves as an
attributable independent risk factor for each. Table 25.1 shows a
summary of possible intervention to decrease racial disparities
in obstetrics.
Maternal mortality
Over the past three decades, as maternal mortality rates in the
United States have been on the rise, the racial disparity in mater-
nal mortality has continued to widen [1, 12].
Epidemiology
Data from CDC’s Pregnancy Mortality Surveillance System
(PMSS) for 2007–2016 demonstrate that non-Hispanic Black
women are three to four times more likely to die from preg-
nancy-related complications than non-Hispanic White
women [13]. This disparity has persisted for over a century, and
in fact widened over the last hundred years, with non-Hispanic
Black women having the fastest increase in maternal deaths.
TABLE 25.1: Possible Interventions to Decrease Racial
Disparities in Obstetrics
Disparity Intervention
Maternal mortality Continuous one-to-one intrapartum
support by a doula
Implementation of standardized,
evidence-based quality care bundles
and metrics for improvement
Diverse representation of researchers
and project leads
Accurate measurement and
communication of disparities
Education of providers about racial
disparities, the importance of shared
decision-making and cultural
competency
Implicit bias training for providers
Preterm birth Group prenatal care
Hypertensive disorders Standardized protocols for end-organ
of pregnancy and the evaluation during prenatal care
postpartum period Prescription of low-dose aspirin
according to USPSTF guidelines
Implementation of hypertension care
bundles
Text-based blood pressure monitoring in
the postpartum period
Prenatal care Group prenatal care
Increasing provider diversity and
patient-provider racial concordance
Provider training in patient-centered
communication
Home visits, the adoption of accountable
care organizations, and screening for
social determinants of health
Anesthesia and analgesia Standardized protocols
Increased provider diversity
Provider-training in patient-centered
communication
Maternal-Fetal Evidence Based Guidelines
The 2007–2016 PMSS reported a pregnancy-related mor-
tality ratio (PRMR) of 40.8 per 100,000 live births for Black
women compared to 12.7 per 100,000 live births for White
women. American Indian/Alaskan Native women similarly
faced disproportionately higher death rates with a PRMR
of 29.7 per 100,000 live births. Hispanic women and Asian/
Pacific Islander women experienced death rates comparable
to White women (PRMR 11.5 and 13.5 per 100,000 live births,
respectively).
While disparities in poverty, educational attainment, and
other social determinants of health have traditionally been
offered as explanations for these differences, statistics con-
sistently demonstrate evidence to the contrary. In particular,
Black women with the highest levels of educational attain-
ment have maternal death rates 1.6 times higher than White
women with the lowest levels of educational attainment [13].
A retrospective study using nationwide surveillance data that
adjusted for education and other sociodemographic and repro-
ductive risk factors also found that the Black-White disparity
in pregnancy-related mortality could not be accounted for, and
in fact, was minimally altered by these traditional measures
[14]. Additionally, state- and national-level data reveal that for-
eign-born women have better birth outcomes than their U.S.-
born racial/ethnic counterparts, despite less education and
later prenatal care initiation, yet for Black women specifically,
foreign-born women have significantly higher rates of mater-
nal mortality than White women in the United States [1, 15].
Taken together, these data point away from a proposed genetic
or environmental basis for race as a cause of disparities and
toward a shared lived experience in the United States, perhaps
with a dose-response relationship.
Also striking is that the Black-White gap in maternal death is
inversely related to the absolute risk for maternal death, whereby
among women with less than a high school diploma, with over-
all higher absolute risks of death, the Black-White disparity ratio
is 1.8, whereas among college graduates or higher, the disparity
ratio is 5.2. This suggests that the socio-demographic factors that
are protective for White women do not confer the same protec-
tion for Black women.
Mechanisms
Applying a racial justice lens to understanding disparate health
outcomes offers several mechanisms by which race as a lived
experience serves as an independent risk factor.
Interpersonal discrimination
influencing quality of care
An overwhelming body of peer-reviewed literature compiled
by the National Academy of Medicine (formerly the Institute
of Medicine) into a report at Congressional request found
strong evidence that racial bias plays a role in the lower qual-
ity of care that patients of color receive compared to White
patients [7, 16]. The report identified discrimination, stereo-
typing, and clinical uncertainty as key factors that medi-
ated the relationship between race and quality of care. It also
implicated structural factors (e.g. tiered systems with unequal
healthcare quality), understood here as structural racism, in
the creation of constraints that activate bias and stereotypes.
Further studies have found that these interpersonal biases lead
to detrimental issues such as dismissal and denial of care, ineq-
uitable subspecialty care and patient mistrust, and fear of pro-
viders and the system [2, 17].
Racism and Racial Disparity in Obstetrics
Structural racism impacting social
determinants of health
Further research has broadened the understanding of how sys-
temic-level racial bias negatively impacts health outcomes by
causing racial disparities in known social determinants of health.
A U.S. Department of Housing and Urban Development study
found that White individuals were favored over identically quali-
fied Black individuals in 22% of rental housing test cases, and over
Hispanics in 26% of cases, contributing to housing disparities
[18]. Audit studies of employment discrimination confirm similar
patterns [19]. These policies perpetuate the concentration of pov-
erty, housing insecurity, and food insecurity in racial minority
communities.
Internalized trauma deteriorating physiologic states
Internalized racism has been shown to take a physiologic toll
on Black women’s mental, emotional, and physical health and
has been directly linked to higher rates of chronic disease and
adverse birth outcomes [20]. In 1992, Geronimus proposed the
theory of “weathering” to describe how daily stressors of rac-
ism can create ongoing and persistent trauma with deleterious
physiologic effects, and researchers subsequently demonstrated
an association between the stress of racism, increased levels of
cortisol and inflammation, and such physiologic effects as car-
diovascular reactivity [21–23]. Cardiovascular disease is among
the risk factors disproportionately experienced by Black women
linking them to higher rates of maternal mortality [1]. In 2006,
Geronimus et al. found that Black women in particular have
higher allostatic load scores – an algorithmic measurement of
stress-associated associated body chemicals and their cumulative
effect on the body’s systems – than White women and Black men,
concluding that “persistent racial differences in health may be
influenced by the stress of living in a race-conscious society” and
highlighting the intersectionality of discrimination that makes
Black women particularly vulnerable to its deleterious health
effects [24]. Intersectionality, a term coined by Black feminist
scholar Kimberlé Crenshaw in 1989, refers to the way in which
different types of discrimination interact to create a uniquely
compounded form of oppression [25]. The theory of intersection-
ality counteracts the treatment of individual identities (e.g. racial
identity and gender identity) as mutually exclusive categories of
experience. In doing so, intersectionality captures and highlights
the experience of those who are multiply burdened by interlock-
ing systems of power.
Interventions
While multiple factors contribute to racial disparities in mater-
nal mortality, the exclusion of the complex contribution of rac-
ism to the phenomenon has left the health system ill-equipped
to close the gap. Though little data exist to evaluate interven-
tions for reducing racial disparities in maternal mortality,
expert opinion and recommendations targeting the theorized,
evidence-based mechanisms propose a number of individual
and system-level interventions. These include implementa-
tion of standardized, evidence-based quality care bundles
and metrics for improvement; diverse representation of
researchers and project leads; accurate measurement and
communication of disparities; education of providers
about racial disparities, the importance of shared decision-
making and cultural competency; and implicit bias train-
ing for providers [26, 27]. Additionally, engaging in activism
to spark policy change and hold our systems and institutions
265
accountable may play a key role in addressing maternal death
disparities [27, 28].
One well-studied intervention has been the provision of con-
tinuous intrapartum support. Based on a Cochrane Review that
demonstrated improved pregnancy outcomes for women allo-
cated to continuous one-to-one support during labor compared
to usual care, including lower cesarean delivery rates, provision
and support of doulas to advocate for Black women within the
system may be a promising link in closing the racial mortality
gap [29].
Preterm birth
Epidemiology
Non-Hispanic Black patients in the United States have double
the rate of preterm birth compared to non-Hispanic White
patients. Accordingly, prematurity is the leading cause of infant
mortality among Black infants. Increased psychosocial stress in
Black pregnant patients, due to the chronic and intergenerational
effects of systemic racism, has been postulated as the la contrib-
uting cause to this disparity [30]. Specific sequelae of systemic
racism that are associated with increased risk of preterm birth
include income inequality and resulting poverty, neighborhood
poverty, redlining, and unequal access to preventive healthcare
and prenatal care [30, 31].
Notably, however, there is increased risk of preterm birth
among Black patients even after adjusting for socioeconomic
and maternal medical factors. That foreign-born Black patients
do not have similarly increased risk of preterm birth suggests
that the particular manifestations of systemic racism existing in
the United States, and the resulting chronic stress, may have a
dose-response relationship, with shorter duration of exposure for
foreign-born patients resulting in less disparity [30–32].
Preterm birth recurrence risk
Preterm birth recurs in Black patients at 4 times the rate of White
patients [33]. There may also be an increased risk of intergenera-
tional recurrence; a population-based study showed that mothers
born at less than 34 weeks themselves were at the highest risk for
a preterm birth at less than 34 weeks [34].
Supplemental progesterone administration has been a mainstay
for the prevention of recurrent preterm birth for over a decade.
Unfortunately, there are racial disparities in use of this interven-
tion, including initiation by 20 weeks and consistency of use. In
a retrospective cohort study of 472 women who were eligible for
supplemental intramuscular progesterone, non-Hispanic Black
women were significantly more likely to have >1 missed dose or
initiation later than 20 weeks gestation as compared to women in
other ethnic and racial groups (67.6% versus 32.4%). In this study,
there was a significant interaction between non-Hispanic Black
race and public insurance. Of note, during the majority of the
study period, the state Medicaid did not cover home administra-
tion of supplemental progesterone, which may have contributed
to this disparity and requires further study [35].
Interventions
Group prenatal care, which incorporates social support into
regular care, has been associated with decreased risk of preterm
birth and reduction of racial disparity associated with preterm
birth for Black patients. The postulated mechanism is stress
reduction through social support [36]. A systematic review and
meta-analysis did not find a difference in preterm birth rates
as compared to traditional prenatal care. However, when the
266
authors limited the analysis to high quality studies, there was a
significantly reduced rate of preterm birth among Black women
receiving group prenatal care [37].
Hypertensive disorders
Numerous studies have found racial disparity in both diagnosis of
hypertensive disorders of pregnancy and deaths related to hyper-
tensive disorder, with non-Hispanic Black patients at highest risk
[38–40].
Diagnosis
A ten-year longitudinal, population-based study of pregnan-
cies in New York State showed a markedly increased risk of pre-
eclampsia among Black patients residing in New York City, which
was not associated with neighborhood poverty level. Rates of
pre-eclampsia were higher among Black patients as compared to
White patients throughout urban areas of New York State, and
the disparity increased over time [38].
Morbidity
National data from 1988–1997 revealed that Black women more
likely to suffer severe complications from hypertensive disorders
of pregnancy, including need for mechanical ventilation and
blood transfusion [40]. Hospital readmission due to postpartum
hypertension is twice as likely among Black patients as compared
to White patients [41, 42].
Mortality
National data from 1979–1992 showed that Black patients were
3.1 times as likely to die from pre-eclampsia or eclampsia as
White women. Although prenatal care reduced the risk of death
from a hypertensive disorder of pregnancy, a significant racial
disparity was seen among those receiving prenatal care [43].
Interventions
Suggested interventions for reducing disparities include stan-
dardized protocols for end-organ evaluation during prenatal
care, prescription of low-dose aspirin according to USPSTF
guidelines, and implementation of care bundles to improve
quality of care among hospitals [44]. With regard to postpartum
hypertension, a secondary analysis of a randomized controlled
trial of text-based blood pressure monitoring in the postpartum
period showed no re-admissions for hypertension in any patient
in the texting arm, whereas three out of four re-admissions in the
standard arm were for Black patients. The authors suggest this
may be an effective way to reduce racial disparity [45].
Prenatal care
Insufficient and delayed prenatal care have been linked to adverse
pregnancy outcomes. While the factors affecting prenatal care
utilization are complex, discrimination has been linked to its dif-
ferential use [46, 47].
Epidemiology
Early and adequate antenatal care are thought to promote healthy
pregnancies and healthy behaviors during pregnancy through
screening and management of risk factors and comorbidities
[26]. Population-level analysis of Center for Disease Control and
Prevention data from 2005–2014 shows that four or fewer pre-
natal visits (i.e. insufficient prenatal care), as well as second or
third trimester initiation of prenatal care (i.e. delayed prena-
tal care) are associated with increased risk of maternal mortal-
ity. Observational data revealing a decline in Black maternal
Maternal-Fetal Evidence Based Guidelines
mortality rates associated with provision of prenatal care by pub-
lic health departments supports this finding [48]. Insufficient and
delayed prenatal care are also associated with such outcomes as
preterm birth and severe maternal morbidity, smoking and alco-
hol consumption, insufficient weight gain, and no breastfeeding,
which are in part attributable to structural racism [2, 8, 26, 47,
49]. National data have consistently demonstrated that the timing
and receipt of prenatal care varies by race and ethnicity [1, 26].
Data from the U.S. Department of Health in Human Services in
2012 showed the highest rate of first trimester care utilization for
White and Asian women (79% and 78%, respectively), followed
by multiracial and Hispanic women (71% and 69%, respectively),
and finally, the lowest for Black, American Indian/Alaska Native,
and Native Hawaiian/other Pacific Island women (64%, 59%, and
55%, respectively) [26]. In addition to the myriad of social factors
contributing to differential utilization of prenatal care, studies
show that for Black and Hispanic women, it is linked to discrimi-
nation, which they experience at three times higher odds than
White women [47].
Access to care
Women of color are more likely to experience socioeconomic
and structural barriers to accessing prenatal care in the form
of conflict with work schedules and childcare, transportation
availability, and finances [2]. At the system level, residential seg-
regation contributes to an imbalance between the concentration
of health risks in majority-minority communities versus the con-
centration of providers in predominantly White communities,
and this in turn contributes to inequities in access to obstetric
care [7]. Additionally, minorities are less likely to be referred to
subspecialists during pregnancy, even when indicated, which has
been shown by population data to be related to maternal mortal-
ity ratios [17, 26].
Quality of care
As concluded by the former Institute of Medicine in 2002, a sub-
stantial body of peer-reviewed literature supports the notion that
women of color receive lower quality care, even when control-
ling for access-related factors [16]. The Listening to Mothers
III Survey revealed that 40% of women reported communication
issues in prenatal care [50]. A systematic review found that Black
patients report poorer patient-physician communication than
White patients, which has been shown in some populations to
impact disparities in treatment and information exchange and
may play a key role in dismissive treatment, lapses in diagnosis,
and dissatisfaction with care [51].
Experience with care
National birth certificate data reveal that 10% of Black women
received late prenatal care starting in the third trimester, com-
pared to 4% of White women [47]. A retrospective cohort study
found that the degree of perceived racial microaggressions
is correlated with delayed or no entry into prenatal care, an
effect that persisted after controlling for other potential sociode-
mographic factors [52]. This is consistent with a 2017 report on
Black experiences that found that over one fifth of Black patients
have avoided seeking necessary medical care to prevent potential
discrimination [53].
Interventions
Many proposed interventions to reduce disparities in prena-
tal care focus on mitigating the downstream effects of barriers
Racism and Racial Disparity in Obstetrics
imposed by structural inequities. These include home visits, the
adoption of accountable care organizations, and screening
for social determinants of health [47]. Interventions that more
directly target the underlying contributions of the lived experi-
ences of race include group prenatal care, which has been cited
by patients as allowing for self-advocacy and community, as well
as increasing provider diversity, which allows for improved
cultural humility and for greater patient-provider racial con-
cordance [47, 51]. A systematic review of the literature found that
patient-provider racial concordance was associated with bet-
ter communication but that providers can overcome barriers
inherent in racially discordant interactions through training
and early development of competent, patient-centered com-
munication [51].
Anesthesia and analgesia
Racial disparity exists in both intrapartum and postpartum pain
control [54–57].
Neuraxial anesthesia during labor
Multiple studies have demonstrated racial disparity in use of
neuraxial anesthesia during labor. A review of over 29,000
state of Georgia Medicaid recipients found that epidural rates
were lower for Black, Hispanic, and Asian patients than for
non-Hispanic White patients [54]. Similarly, a review of the
New York State Perinatal Database found that Hispanic and
Black patients were less likely to receive epidural anesthesia
for labor, after adjustment for clinical, socioeconomic, and
provider factors [55]. Differences in epidural usage may be
due in part to cultural differences in patient preference for
birthing style and differences in view of labor and delivery as a
medical process vs. a normal physiologic life event, and type of
provider (physician vs. midwife) [54]. Further study is needed
to determine whether equal rates of epidural usage are an opti-
mal outcome.
Neuraxial anesthesia for cesarean delivery
Black women have higher rates of general anesthesia for
cesarean delivery than do White women. This disparity remains
significant after controlling for patient-level factors such as age,
body mass index, and multiple gestation [56]. There are provider-
and systems-level factors that may contribute to these disparities,
including provider bias, type of provider, availability of anesthe-
sia services, and access to interpreter services [56].
Postpartum analgesia
A retrospective cohort study of all deliveries over 1 year at a sin-
gle tertiary care center found that Hispanic and non-Hispanic
Black patients received less opioid analgesia while admitted,
and had lower odds of receiving an opioid prescription at dis-
charge as compared to White patients, despite having higher
odds of reporting a pain score of 5 or greater. The authors sug-
gest that a standardized protocol for postpartum pain manage-
ment could reduce racial disparity in the future [57].
Interventions
Although there are no high quality studies evaluating interven-
tions for reducing racial disparity with regard to intrapartum
and postpartum pain management, suggested interventions
include development of standardized protocols, improve-
ment of patient-provider communication through shared
decision-making, and efforts to increase diversity among
providers.
267
References
1. Bryant AS, Worjoloh A, Caughey AB, Washington AE. Racial/ethnic dis-
parities in obstetric outcomes and care: prevalence and determinants. Am J
Obstet Gynecol 2010;202(4):335–343. [Literature review; 1 RCT, n = 891] [I]
2. St Clair M. “Disbelieving Black Women to Death”; the “Double Jeopardy”:
Racism and Sexism Affects Black Women’s Access to and Quality of Care
During Pregnancy, Birth, and Postpartum. 2020. [II-2]
3. Boyd RW, Lindo EG, Weeks LD, McLemore MR. On racism: a new standard
for publishing on racial health inequities. Health Affairs Blog 2020;10. [III]
4. Ford CL, Airhihenbuwa CO. Critical race theory, race equity, and pub-
lic health: toward antiracism praxis. Am J Public Health 2010;100(S1):
S30–S35. [III]
5. Davis D-A. Obstetric racism: the racial politics of pregnancy, labor, and
birthing. Medical Anthropology 2019;38(7):560–573. [II-3]
6. Bridges K. Reproducing Race: An Ethnography of Pregnancy as a Site of
Racialization. University of California Press, Berkeley, CA. 2011. [II-3]
7. Smedley BD. The lived experience of race and its health consequences.
Am J Public Health 2012;102(5):933–935. [III]
8. Taylor J, Jackson B. Factors affecting alcohol consumption in black women.
Part II. Int J Addict 1990;25(12):1415–1427. [II-3]
9. Chae DH, Lincoln KD, Adler NE, Syme SL. Do experiences of racial dis-
crimination predict cardiovascular disease among African American
men? The moderating role of internalized negative racial group attitudes.
Soc Sci Med 2010;71(6):1182–1188. [II-2]
10. Jones CP. Invited commentary: “Race,” Racism, and the practice of epidemi-
ology. Am J Epidemiol 2001;154(4):299–304. [III]
11. Liu SY, Fiorentini C, Bailey Z, Huynh M, McVeigh K, Kaplan D. Structural
Racism and Severe Maternal Morbidity in New York State. Clin Med
Insights 2019;12. https://doi.org/10.1177/1179562X19854778. [II-2]
12. Kassebaum NJ, Barber RM, Bhutta ZA, et al. Global, regional, and national
levels of maternal mortality, 1990–2015: a systematic analysis for the Global
Burden of Disease Study 2015. Lancet 2016;388(10053):1775–1812. [II-3]
13. Petersen EE, Davis NL, Goodman D, et al. Racial/ethnic disparities in preg-
nancy-related deaths—United States, 2007–2016. MMWR Morb Mortal
Wkly Rep 2019;68(35):756–762. [II-3]
14. Saftlas AF, Koonin LM, Atrash HK. Racial disparity in pregnancy-related
mortality associated with livebirth: can established risk factors explain it?
Am J Epidemiol 2000;152(5):413–419. [II-2]
15. Creanga AA, Berg CJ, Syverson C, Seed K, Bruce FC, Callaghan WM. Race,
ethnicity, and nativity differentials in pregnancy-related mortality in the
United States: 1993–2006. Obstet Gynecol 2012;120(2 Pt 1):261–268. [II-3]
16. Nelson A. Unequal treatment: confronting racial and ethnic disparities in
health care. J Natl Med Assoc 2002;94(8):666. [III]
17. Van Ryn M, Fu SS. Paved with good intentions: do public health and human
service providers contribute to racial/ethnic disparities in health? Am J
Public Health 2003;93(2):248–255. [Literature review and hypothesized
causal model; 1 RCT, n = 156]. [I]
18. Turner MA, Ross SL, Galster GC, Yinger J. Discrimination in Metropolitan
Housing Markets: National Results from Phase I HDS 2000. Washington,
DC: The Urban Institute. 2002. [II-1]
19. Pager D. The mark of a criminal record. Am J Sociol 2003;108(5):937–975.
[RCT, n = 350]. [I]
20. Lu MC, Halfon N. Racial and ethnic disparities in birth outcomes: a life-
course perspective. Matern Child Health J 2003;7(1):13–30. [II-2]
21. Geronimus AT. The weathering hypothesis and the health of African-
American women and infants: evidence and speculations. Ethn Dis
1992;2(3):207–221. [II-2]
22. Seeman TE, Singer B, Wilkinson CW, McEwen B. Gender differences in
age-related changes in HPA axis reactivity. Psychoneuroendocrinology
2001;26(3):225–240. [II-1]
23. Roy MP, Steptoe A, Kirschbaum C. Life events and social support as mod-
erators of individual differences in cardiovascular and cortisol reactivity. J
Pers Soc Psychol 1998;75(5):1273. [II-2]
24. Geronimus AT, Hicken M, Keene D, Bound J. “Weathering” and age pat-
terns of allostatic load scores among blacks and whites in the United States.
Am J Public Health 2006;96(5):826–833. [II-3]
25. Crenshaw K. Demarginalizing the intersection of race and sex: a black femi-
nist critique of antidiscrimination doctrine, feminist theory and antiracist
politics. u Chi Legal f 1989:139. [III]
26. Howell EA. Reducing disparities in severe maternal morbidity and mor-
tality. Clin Obstet Gynecol 2018;61(2):387–399. [Literature review; 1 RCT,
n = 1047]. [I]
27. Taylor JK. Structural racism and maternal health among black women. J
Law Med Ethics 2020;48(3):506–517. [III]
268
28. ACOG Committee Opinion No. 649: Racial and ethnic disparities in
obstetrics and gynecology. Obstet Gynecol 2015;126(6):e130–134. [1 RCT,
n = 524].
29. Bohren MA, Hofmeyr GJ, Sakala C, Fukuzawa RK, Cuthbert A. Continuous
support for women during childbirth. Cochrane Database Syst Rev 2017(7).
[Meta-analysis; 26 RCTs, n = 15,858]. [I]
30. Reagan PB, Salsberry PJ. Race and ethnic differences in determinants
of preterm birth in the USA: broadening the social context. Soc Sci Med
2005;60(10):2217–2228. [II-2]
31. Mendez DD, Hogan VK, Culhane JF. Institutional racism, neighborhood
factors, stress, and preterm birth. Ethn Health 2014;19(5):479–499. [II-2]
32. Kramer MR, Hogue CR. What causes racial disparities in very preterm
birth? A biosocial perspective. Epidemiol Rev 2009;31:84–98. [II-2]
33. Kistka ZA, Palomar L, Lee KA, et al. Racial disparity in the frequency
of recurrence of preterm birth. Am J Obstet Gynecol 2007;196(2):
131 e131–136. [II-2]
34. Smid MC, Lee JH, Grant JH, et al. Maternal race and intergenerational
preterm birth recurrence. Am J Obstet Gynecol 2017;217(4):480 e481–480
e489. [II-2]
35. Yee LM, Liu LY, Sakowicz A, Bolden JR, Miller ES. Racial and ethnic dis-
parities in use of 17-alpha hydroxyprogesterone caproate for prevention of
preterm birth. Am J Obstet Gynecol 2016;214(3):374 e371–376. [II-2]
36. Picklesimer AH, Billings D, Hale N, Blackhurst D, Covington-Kolb S. The
effect of CenteringPregnancy group prenatal care on preterm birth in a low-
income population. Am J Obstet Gynecol 2012;206(5):415 e411–417. [II-2]
37. Carter EB, Temming LA, Akin J, et al. Group prenatal care compared with
traditional prenatal care: a systematic review and meta-analysis. Obstet
Gynecol 2016;128(3):551–561. [Meta-analysis; 4 RCTs, 10 observational
studies, n = 10,321]. [I]
38. Tanaka M, Jaamaa G, Kaiser M, et al. Racial disparity in hypertensive dis-
orders of pregnancy in New York State: a 10-year longitudinal population-
based study. Am J Public Health 2007;97(1):163–170. [II-2]
39. Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and
maternal mortality. Curr Opin Obstet Gynecol 2013;25(2):124–132. [II-2]
40. Zhang J, Meikle S, Trumble A. Severe maternal morbidity associated with
hypertensive disorders in pregnancy in the United States. Pregnancy
Hypertens 2003;22(2):203–212. [II-2]
41. Chornock R, Iqbal SN, Kawakita T. Racial disparity in postpartum readmis-
sion due to hypertension among women with pregnancy-associated hyper-
tension. Am J Perinatol 2020. [II-2]
42. Aziz A, Gyamfi-Bannerman C, Siddiq Z, et al. Maternal outcomes by
race during postpartum readmissions. Am J Obstet Gynecol 2019;220(5):
484 e481–484 e410. [II-2]
43. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from pre-
eclampsia and eclampsia. Obstet Gynecol 2001;97(4):533–538. [II-2]
Maternal-Fetal Evidence Based Guidelines
44. Jain JA, Temming LA, D’Alton ME, et al. SMFM special report: putting the
“M” back in MFM: Reducing racial and ethnic disparities in maternal mor-
bidity and mortality: A call to action. Am J Obstet Gynecol 2018;218(2):
B9–B17. [II-2]
45. Hirshberg A, Sammel MD, Srinivas SK. Text message remote monitoring
reduced racial disparities in postpartum blood pressure ascertainment.
Am J Obstet Gynecol 2019;221(3):283–285. [RCT, n = 206] [I]
46. Yan J. The effects of prenatal care utilization on maternal health and health
behaviors. Health Economics 2017;26(8):1001–1018. [II-2]
47. Gadson A, Akpovi E, Mehta PK. Exploring the social determinants of racial/
ethnic disparities in prenatal care utilization and maternal outcome. Semin
Perinatol 2017;41(5):308–317. [Literature review; 4 systematic reviews,
1 RCT] [I]
48. Bekemeier B, Grembowski D, Yang YR, Herting JR. Local public health
delivery of maternal child health services: are specific activities associated
with reductions in black–white mortality disparities? Matern Child Health
J 2012;16(3):615–623. [II-3]
49. Griswold MK, Crawford SL, Perry DJ, et al. Experiences of racism and
breastfeeding initiation and duration among first-time mothers of the
black women’s health study. J Racial Ethn Health Disparities 2018;5(6):
1180–1191. [II-2]
50. Declercq ER, Sakala C, Corry MP, Applebaum S, Herrlich A. Listening to
mothers SM III. New Mothers Speak Out 2013:2013. [II-3]
51. Shen MJ, Peterson EB, Costas-Muñiz R, et al. The effects of race and racial
concordance on patient-physician communication: a systematic review of
the literature. J Racial Ethn Health Disparities 2018;5(1):117–140. [II-2]
52. Slaughter-Acey JC, Sneed D, Parker L, Keith VM, Lee NL, Misra DP.
Skin tone matters: Racial microaggressions and delayed prenatal care.
Am J Prev Med 2019;57(3):321–329. [II-2]
53. NPR RWJF, Harvard TH Chan Sch. Public Health. Discrimination in
America: Experiences and Views of African Americans. In: 2017. [II-3].
https://media.npr.org/assets/img/2017/10/23/discriminationpoll-african-
americans.pdf.
54. Rust G, Nembhard WN, Nichols M, et al. Racial and ethnic disparities in
the provision of epidural analgesia to Georgia Medicaid beneficiaries dur-
ing labor and delivery. Am J Obstet Gynecol 2004;191(2):456–462. [II-2]
55. Glance LG, Wissler R, Glantz C, Osler TM, Mukamel DB, Dick AW. Racial
differences in the use of epidural analgesia for labor. Anesthesiology
2007;106(1):19–25; discussion 16–18. [II-2]
56. Lange EMS, Rao S, Toledo P. Racial and ethnic disparities in obstetric anes-
thesia. Semin Perinatol 2017;41(5):293–298. [II-2]
57. Badreldin N, Grobman WA, Yee LM. Racial disparities in postpartum pain
management. Obstet Gynecol 2019;134(6):1147–1153. [II-2]
26
RESPIRATORY DISEASES
Asthma, Pneumonia, Influenza, Tuberculosis, and COVID-19
Aref T. Senno and Ryan K. Brannon
Asthma
Key points
• Asthma is characterized by airway obstruction, inflamma-
tion, and increased responsiveness to stimuli. When spi-
rometry, history, and physical exam findings are consistent
with asthma, other possible diagnoses must be excluded.
• Asthma is classified as intermittent, mild persistent,
moderate persistent, and severe persistent by symptoms
and peak expiratory flow rate (PEFR) or spirometry.
• Asthma, especially if untreated or inadequately treated, is
associated with increased risks of preterm birth, low birth-
weight, small for gestational age, neonatal hospitalization,
and perinatal mortality. If asthma is adequately treated and
not severely persistent, it is usually not associated with a sig-
nificant increase in adverse maternal and perinatal outcomes.
• Pregnancy has a variable effect on asthma severity, with
about two thirds improved and one third worsened.
• The management of asthma in pregnant women should fol-
low the same guidelines as for other nonpregnant patients.
• Management is based on objective measurements of pul-
monary function and the frequency/severity of symptoms
(Table 26.1). The management plan should include use of
environmental control measures, adequate pharmacother-
apy, and patient education regarding symptoms, manage-
ment, and compliance.
• Inhalation therapy is preferred to systemic treatments,
with inhaled corticosteroids, NOT inhaled β-agonists,
the mainstay of therapy.
• Prostaglandin F2α analogues (Carboprost) should be
avoided. Ergonovine and indomethacin, sometimes used in
obstetric care, may worsen bronchospasm.
Epidemiology
Asthma affects approximately 8% of pregnant women in the United
States [1]. Among U.S. women aged 18–44, 5% reported an asthma
attack within the preceding 12 months. However, 12–14% had
received a diagnosis of asthma at some point during their lifetimes [1].
Etiology/Basic pathophysiology
Asthma is defined by the National Asthma Education and
Prevention Program (NAEPP) as a “common chronic disorder
of the airways that is complex and characterized by variable and
recurring symptoms, airflow obstruction, bronchial hyperre-
sponsiveness, and an underlying inflammation” [2]. The etiology
of asthma is complex and multi-faceted. While bronchospasm
DOI: 10.1201/9781003099062-26
is often the cause of acute asthma attacks, airway inflammation
with edema and cellular remodeling are significant contributors
to disease burden. Increased airway responsiveness to stimuli is
characteristic.
Diagnosis
Diagnosis is characterized by: (1) episodic symptoms of airway
obstruction and/or hyperresponsiveness; (2) airflow obstruction
is at least partially reversible; or (3) alternative explanations have
been excluded. Indicators that suggest a diagnosis of asthma include
wheezing, history of recurrent cough, chest tightness or difficulty
in breathing; worsening of symptoms with exercise, viral infection,
exposure to animal fur or feathers, mold, pollen, house dust mites,
tobacco or wood smoke, changes in weather, airborne chemicals or
dusts; or worsening of symptoms at night. Physical examination is
not always reliable, and may include thoracic hyper-expansion or
chest deformity, hunching of shoulders or use of accessory muscles,
audible wheezing or a prolonged expiratory phase, increased nasal
discharge or nasal polyps, or any manifestation of an allergic skin
condition. The more indicators present, the more likely the diagno-
sis. However, the absence of wheezing does not exclude a diagnosis
of asthma. A clinical suspicion of asthma should be confirmed with
the use of spirometry. Forced vital capacity (FVC), forced expi-
ratory volume (FEV1), and their ratio (FEV1/FVC) are measured
before and after administration of a short-acting bronchodilator.
Reduced FEV1 (<80% predicted) or FEV1/FVC (<0.7) confirms
airflow limitation. An increase in FEV1 ≥ 12% from baseline or
≥10% of predicted FEV1 following short-acting bronchodilator
inhalation meets criteria for partial reversibility [2].
When spirometry, history, and physical exam findings are
consistent with asthma, other possible diagnoses must be
excluded such as chronic obstructive pulmonary disease, con-
gestive heart failure, pulmonary embolus, laryngeal or vocal cord
dysfunction, and mechanical airway obstruction.
Symptoms
Wheezing, shortness of breath, coughing, chest tightness, diffi-
culty in breathing, and dyspnea.
Classification
Asthma severity, that is, the intrinsic intensity of the disease, is
classified into four stages (Table 26.1) [2]. Severity is most eas-
ily measured in a patient who is not receiving long-term control
therapy. Severity can also be measured, once asthma control is
achieved, by the amount of medication required to maintain con-
trol (Tables 26.2–26.4).
269
270 Maternal-Fetal Evidence Based Guidelines

TABLE 26.1: Classification of Asthma Severity

Intermittent Mild Persistent Moderate Persistent Severe Persistent
Symptoms ≤2 times a week >2 times a week Daily Continuous
but <1 time a day
Asymptomatic between Exacerbations occur ≥2 times a week Frequent exacerbations
exacerbations
Pulmonary function Normal PEFR between FEV1 or PEFR 60% to 80% of predicted FEV1 or PEFR <60% of
exacerbations predicted
FEV1 or PEFR in ≥ 80% ≥80%
relation to predicted
PEFR variability <20% 20% to 30% >30% >30%
Nocturnal awakening ≤2 times a month >2 times a month >1 time a week Nightly awakenings
Interference with None Mild Some interference with normal Limitations of physical
daily activities activities but rare severe exacerbation activity
Treatment Step 1 Step 2 Step 3 or Step 4 Step 5 or Step 6
Source: From Ref. [2] in the public domain.
Abbreviations: NAEPP, National Asthma Education and Prevention Program; PEFR, peak expiratory flow rate; FEV1, forced expiratory volume in one second.

TABLE 26.2: Typical Medications and Dosages for Long-Term Control during Pregnancy
Dosage
Medication Low Dose Medium Dose High Dose
Inhaled corticosteroid
Beclomethasone CFC 42 or 84 μg/puff 168–504 μg TDD 504–840 μg TDD >840 μg TDD
Beclomethasone HFA 40 or 80 μg/puff 80–240 μg TDD 240–480 μg TDD >480 μg TDD
Budesonide dry powder 200 μg/puff 200–600 μg TDD 600–1200 μg TDD >1200 mg TDD
Flunisolide 250 μg/puff 500–1000 μg TDD 1000–2000 μg TDD >2000 μg TDD
Fluticasone Metered dose inhaler: MDI: 88–264 μg TDD MDI: 264–660 μg TDD MDI: >660 μg TDD
44, 88, 220 μg/puff
Dry powder inhaler: 50, 100, DPI: 100–300 μg TDD DPI: 300–750 μg TDD DPI: >750 μg TDD
250 mg/inhalation
Triamcinolone acetonide 100 μg/puff 400–1000 μg TDD 1000–2000 μg TDD >2000 μg TDD
Systemic corticosteroid How supplied Daily dose (all three drugs are Short burst to achieve
dosed the same) control (all dosed the same)
Methylprednisolone Tablets: 2,4,8,16,32 mg 7.5–60 mg daily 40–60 mg/day
Prednisolone Tablets: 5 mg Syrup: 5 mg/5 mL, As a single dose in AM As a single dose, or as two
15 mg/5 mL divided doses
Prednisone Tablets: 1,2.5,5,10,20,50 mg Oral Every other day as needed for For 3–10 days
solution: 5 mg/mL control
Long-acting β-agonist (LABA): Not for symptom relief, and not used alone; use with inhaled corticosteroids
Salmeterol MDI: 21 μg/puff MDI: 2 puffs q12h
DPI: 50 μg/blister DPI: 1 blister q12h
Formoterol DPI: 12 μg per single-use capsule 1 capsule q12h
Combination: LABA plus inhaled corticosteroid
Fluticasone/salmeterol DPI: Fluticasone dose varies 100, 250 or One inhalation twice daily Fluticasone dose depends on
500 μg /puff; asthma severity
Salmeterol always 50 μg/puff
Budesonide/Formoterol HFA MDI: Budesonide dose varies 80, Two inhalations twice daily; as Budesonide dose depends on
160 µg/puff; formoterol always 4.5 µg/puff needed for exacerbations asthma severity
Cromolyn MDI: 1 mg/puff MDI: 2–4 puffs, 3–4 × daily Or
Nebulizer 20 mg/amp 1 ampule nebulized 3–4 × daily
Leukotriene receptor antagonists
Montelukast 10 mg tablet 10 mg nightly
Zafirlukast Tablet, 10 or 20 mg 40 mg daily
Theophylline Liquids; sustained-release tablets; Starting dose 10 mg/kg/day Maximum dose 800 mg/day;
capsules serum drug monitoring,
5-12 μg/mL is therapeutic
Source: From Ref. [2] in the public domain.
Abbreviations: TDD, total daily dose; NAEPP, National Asthma Education and Prevention Program; PEFR, peak expiratory flow rate; FEV1, forced expiratory volume in one
second; CFC, chlorofluorocarbons; HFA, hydrofluoroalkane; MOI, metered-dose inhaler; DPI, dry powder inhaler.
Respiratory Diseases 271

TABLE 26.3: Quick-Relief Short-Acting β-agonists (SABAs)

Medication How Provided Dose (all same)
Albuterol CFC 90 μg/puff (200 puffs/canister) Two puffs 5 min before anticipated exercise
Albuterol HFA 90 μg/puff (200 puffs/canister) OR
Pirbuterol CFC 200 μg/puff (400 puffs/canister) Two puffs q4-6h, as needed
Levalbuterol HFA 45 μg/puff (200 puffs/canister)
Source: From Ref. [2] in the public domain.
Abbreviations: CFC, chlorofluorocarbons; HFA, hydrofluoroalkane.

Pregnancy complications
Asthma poses risks to both the mother and fetus. Evidence
regarding maternal complications has been mixed, but large
retrospective studies observed increased rates of hypertensive
disorders of pregnancy, postpartum hemorrhage, and cesar-
ean delivery [3, 4]. Meta-analyses examining fetal outcomes
have repeatedly identified an association between asthma and
increased risks of congenital malformations, preterm birth, low
birthweight, small for gestational age, neonatal hospitalization,
and perinatal mortality [5–8]. The risk of some maternal and
fetal complications may be reduced with better asthma control,
highlighting the importance of medical management. The risk of
preterm labor and preterm delivery is reduced when asthma is
well controlled [9, 10]. A relationship has been reported between
decreased FEV1 during pregnancy and increased risk of low birth-
weight and prematurity [11]. In addition, women who required
hospitalization for asthma during pregnancy, or who reported
their asthma control to be poor during pregnancy, were at higher
risk for preterm birth, though not for growth restriction [10].

TABLE 26.4: Medications for Asthma Exacerbations during Pregnancy

Medication Dose Comment
ICS-LABA
Budesonide plus formoterol
MDI: 80 µg/4.5 µg, 160 µg/4.5 µg 1 puff as needed; Repeat up to 12 times per
day
Short-acting inhaled β-agonist
Albuterol nebulizer solutions 5 mg/mL, or Nebulizer: 2.5–5 mg q 20 minutes × 3 Dilute to minimum of 3 mL, use gas flow
2.5 mg/3 mL, 1.25 mg/mL doses; follow with 2.5–10 mg q1–4h as 6–8 L/minutes
needed or 10–15 mg/hour continuously
MDI: 90 mg/puff MDI: 4–8 puffs q20 minutes up to 4 hour; MDI is as effective as nebulizer if patient is
then q1–4h as needed able to coordinate
Levalbuterol nebulizer solutions 1.25 mg/3 1.25–2.5 mg q 20 minutes × 3 doses, then
mL, 0.63 mg/3 mL 1.25–5 mg q1–4h as needed, or
5–7.5 mg/hour continuously
Bitolterol, pirbuterol Has not been studied in severe
exacerbations
Injected β-agonists
Epinephrine 1:1000 (1 mg/mL) 0.3–0.5 mg sq q20 minutes × 3 doses No proven advantage of injection over
aerosol
Terbutaline 1 mg/mL 0.25 mg sq q20 minutes × 3 doses No proven advantage of injection over
aerosol
Anticholinergics
Ipratropium bromide Nebulizer solution Nebulizer: 0.5 mg q30 min × 3 doses, then Not as first-line monotherapy. May mix in
0.25 mg/mL q2–4h as needed nebulizer with albuterol
Ipratropium plus albuterol Nebulizer Nebulizer: 3 mL q30 min × 3 doses, then
solution: Each 3-mL vial contains 0.5-mg q2–4h as needed
ipratropium bromide þ 2.5-mg albuterol
MDI: Each puff contains 18-μg ipratropium 4–8 puffs as needed
bromide þ 90-μg albuterol
Systemic corticosteroids
Prednisone (dose all three the same) 120–180 mg/day,
in three or four divided doses × 48 hour
Methylprednisolone 60–80 mg/day until
Prednisolone PEFR reaches 70% of predicted or 70% of
personal best
272
Large studies indicate that therapy tailored according to asthma
severity can result in excellent infant and maternal outcomes [9,
12]. There are no randomized prospective trials comparing preg-
nancy outcomes in treated and untreated asthmatics. Women
who decrease their asthma medication during pregnancy deliver
infants of lower birthweight and slightly shorter gestational age
than those who either increase their medication or make no
change [13].
Pregnancy considerations
Pregnant women are less likely than others to receive appropri-
ate asthma care [14]. Pregnant women are equally likely to be
admitted for an asthma attack but are less likely to receive cor-
ticosteroids in the emergency department (ED), and those who
are sent home are less likely to be prescribed outpatient ste-
roids. Pregnant women are far more likely than non-­pregnant
counterparts to report ongoing symptoms 2 weeks after an
ED visit, perhaps because of the difference in steroid use [14].
Adherence to treatment with inhaled corticosteroids has been
reported to be poor in many studies. For example, women
reported to decrease their use of inhaled corticosteroids dur-
ing early pregnancy, as compared with their use of these agents
in the 20 weeks before their last menstrual period; this may be
due to their reported concern regarding the safety of inhaled
corticosteroids during pregnancy [5].
Pregnancy has a variable effect on asthma severity, which may
improve, worsen, or remain unchanged. In general, about two
thirds of asthmatics have symptomatic improvement, and one
third have worsening symptoms [1, 15]. Most exacerbations
occur between 24 and 36 weeks, while the fewest symptoms
occur at term. Of patients with mild disease, 2% were hospital-
ized during pregnancy, 13% were noted to have an exacerbation,
and 13% had symptoms at time of delivery [11]. For patients with
moderate asthma, 7% were hospitalized, and 26% had an exac-
erbation during pregnancy with 21% symptomatic at delivery.
Among severe asthmatics, 27% were hospitalized, 52% had an
exacerbation during pregnancy, and 46% of severe asthmatics
were symptomatic at delivery [11]. A number of factors have been
proposed as predictors of disease worsening during pregnancy
(smoking, carrying a female fetus, worsening of rhinitis) but stud-
ies are inconsistent [16–18].
Management
Principles
The management of asthma in pregnant women should follow
the same guidelines as for non-pregnant patients. The goal is
to maintain asthma control during pregnancy. In 2004, the
National Asthma Education and Prevention Program (NAEPP)
stated, “it is safer for pregnant women with asthma to be
treated with asthma medications than it is for them to have
asthma symptoms and exacerbations” [19]. Recommendations
for asthma management and control are available from the
2007 NAEPP Guidelines [2], the NAEPP update on managing
asthma in pregnancy [19], the 2020 NAEPP Guidelines update
on selected topics [20], the American College of Obstetricians
and Gynecologists (ACOG) [21], and the 2020 Global Initiative
for Asthma (GINA) Report [22]. As is true for many guidelines,
recommendations may be made based on consensus or expert
opinion rather than on level I evidence. A 2014 Cochrane Review
Maternal-Fetal Evidence Based Guidelines
TABLE 26.5: Environmental Control Measures for Asthma
Management
Reduce or eliminate allergens
Cockroaches
Pollen
Mold
Animal dander
House dust mites
Encase mattresses and pillows in allergen-impermeable covers
Remove carpets from bedroom
Reduce indoor humidity
Eliminate or reduce exposure to tobacco smoke
Reduce exposure to indoor and outdoor pollutants
Wood-burning stoves, fireplaces
Unvented stoves or heaters
Irritants such as perfumes and cleaning products
concluded that “no firm conclusions about optimal interven-
tions for managing asthma in pregnancy can be made” [23].
Prevention
Eliminate or mitigate asthma triggers. Environmental control
measures are shown in Table 26.5.
Preconception care
Multidisciplinary care is recommended for preparation of preg-
nancy and during pregnancy. Education regarding prognosis, com-
plications, and management of asthma therapy should be reviewed
with the patient. Asthma therapy should not change in pregnancy
compared to the non-pregnant state, but should still aim for maxi-
mal relief of symptoms and best pulmonary function through
attentive patient compliance with suggested management.
Prenatal care
Achieving and maintaining asthma control requires four compo-
nents of care:
1. Use of objective measures of lung function such as PEFR, to
ascertain severity, assess asthma control, and to monitor
therapy.
2. Control of environmental factors and comorbid conditions
to eliminate or mitigate asthma triggers.
3. Pharmacotherapy aimed at preventing or reversing airway
inflammation typical of asthma, in addition to the treat-
ment of acute exacerbations.
4. Patient education regarding symptoms, management, and
compliance.
Workup of asthma control
Asthma control should be assessed on a regular basis (at least at
each prenatal visit) by review of symptoms, medications used,
and quality of life over the preceding weeks. The peak expira-
tory flow (PEF) can be measured by peak flow meters, which
are portable, inexpensive, and disposable. Both FEV1 and PEF
remain unchanged in pregnancy in the normal state. Predicted
PEF values are based on age, gender, and height. For women,
they range from 380–550 L/min. Each pregnant woman
should establish her personal best during quiescent asthma.
Respiratory Diseases
PEF >80% of personal best are normal; values between 50%
and 80% are intermediate; values <50% are associated with
severe asthma exacerbation. Daily peak flow monitoring using
an inexpensive home meter is advisable in cases of moderate
or severe asthma, in order to identify pre-symptomatic airflow
obstruction, which may require escalation of therapy. Outcomes
have not been proven to be different when symptom-based moni-
toring is used rather than PEF monitoring [2]. Objective measures
can be valuable for patients with a history of exacerbations, when
evaluating a change in therapy, or for patients whose perception
of airflow is poor. PEF results should be recorded in a log and
brought to each prenatal visit.
Therapy
General
Inhalation therapy is preferred to systemic treatments because of
direct delivery to airway and fewer side effects. Spacer devices
can increase delivery to the lungs and minimize oral absorption.
For all except the intermittent type of asthma, inhaled cortico-
steroids, NOT inhaled β-agonists, are the mainstay of therapy.
All asthmatic patients should have access to a combination
inhaled corticosteroid (ICS)-formoterol or short-acting β-
agonist (SABA) such as an Albuterol inhaler for immediate
relief of symptoms.
Use of one or more canisters of β-agonist per month indicates
inadequate asthma control. Gain control as quickly as possible;
a short course of oral steroids may be helpful. Review symptoms
monthly. Other indicators of a need for stepped-up therapy are
symptoms more than twice per week; three or more nighttime
awakenings related to asthma symptoms; and limitation or inter-
ference with normal activity. Stepdown therapy may be attempted
only if symptoms are well controlled. However, given the risks of
asthma and low risk of medications (SABA, ICS, long-acting β-
agonist [LABA]), step-down should be performed following deliv-
ery in most cases [22].
An individualized action plan should be generated for an asth-
matic patient. This incorporates frequent self-assessment, a daily
self-management plan, long-term self-management plan, and an
asthma action plan based on symptoms, peak flow, and medica-
tions used. The action plan allows patients to step-up therapy at
home with exacerbations, and provides criteria for contacting the
physician or seeking care in an ED. Sample action plans can be
found online at:
• https://www.nhlbi.nih.gov/health/public/lung/asthma/
asthma_actplan.pdf
• https://www.cdc.gov/asthma/actionplan.html
If symptoms are not adequately controlled, review compliance,
inhalation technique, and environmental control. If no room for
improvement in these areas, step up to the next level of therapy.
At step 3 or 4 (moderate or severe persistent disease), if patient
required >2 bursts of oral systemic corticosteroids in one year, or
has an exacerbation requiring hospitalization, refer to an asthma
specialist.
Goals
• No limitations at school or work
• Normal or near-normal pulmonary function assessed by
PEF (or FEV1)
273
• Prevent hypoxemia
• Minimal-to-none exacerbations, chronic symptoms, use of
short-term β-agonists, or medication side effects
Suggested medications
A stepwise approach to manage asthma is recommended to gain
and maintain control (Figure 26.1). Usual drug doses are shown in
Table 26.2. Medications for exacerbation are shown in Tables 26.3
and 26.4 (all tables are adapted from the NAEPP) [2]. Algorithms
for home and hospital management of exacerbation can be found
in the NAEPP guidelines (Figures 26.2 and 26.3) [2]. Number
of medications, potency of medications, and frequency of use
increase with increasing asthma severity. On the basis of clini-
cal trials, medications are considered to be “preferred” or “alter-
native” at each step of therapy. For patients who are not already
taking long-term control medications, assess asthma severity and
initiate therapy according to level of severity. For patients who
are already taking long-term control medications, assess asthma
control and step-up therapy if the patient’s asthma is not well
controlled on current therapy. In general, using SABA or ICS-
formoterol >2 days a week indicates the need for starting or
increasing long-term control medications.
Intermittent asthma: Although exacerbations/symptoms may
be infrequent, these episodes can be severe. These patients require
no daily medication (step 1) but will need access to rapid-acting
medication. Quick relief can be provided in the form of an ICS-
formoterol or SABA inhaler as needed. There is some evidence
that ICS-formoterol may be preferred to SABA for exacerbations
for intermittent as well as all higher steps of asthma [22]. In the
event of exacerbation, PEFR 50% to 80% of predicted should be
treated with an inhaled ICS-formoterol or SABA inhaler imme-
diately. Values <50% require the same therapy and immediate
visit to an emergency room. However, rescue inhaler use twice
per week or more should elicit step-up in therapy and a reclassi-
fication of severity. These patients can have severe exacerbations
interrupting long periods of normal lung function, in which case
systemic steroids may be required.
Mild persistent asthma: Treat with a daily low-dose ICS or
as needed ICS-formoterol. Alternative therapies include inhaled
cromolyn, leukotriene receptor antagonist (LTRA), low-dose ICS
whenever SABA taken, or sustained-release theophylline adjusted
to serum level of 5–12 μg/mL (step 2).
Moderate persistent asthma: Treat with a daily low-dose ICS-
LABA (step 3). If necessary, give a medium-dose ICS-LABA (step
4). Alternative therapies include low-dose or medium-dose inhaled
corticosteroid in combination with either theophylline or a LTRA.
Severe persistent asthma: These patients require both a
medium-dose ICS-LABA and long-acting muscarinic antago-
nist (LAMA) with as needed SABA (step 5) and may also require
oral corticosteroids (step 6); when feasible, oral corticosteroids
should be discontinued, and control maintained with inhaled
agents. The patient may benefit from phenotypic assessment and
consideration of add-on therapy such as tiotropium, anti-IgE,
anti-IL5/5R, or anti-IL4R.
Alternative therapy includes a high-dose ICS and sustained-
release theophylline titrated to therapeutic serum levels, as dis-
cussed earlier.
Inhaled steroids
Anti-inflammatory agents decrease edema and secretions in the
bronchioles. Indications are shown in Figure 26.1. They are used
274 Maternal-Fetal Evidence Based Guidelines

Intermittent
Asthma Management of Persistent Asthma in Individuals Ages 12+ Years

STEP 5 STEP 6
STEP 2 STEP 3 STEP 4
Treatment STEP 1

PRN SABA Daily low-dose ICS Daily and PRN Daily and PRN Daily medium-high Daily high-dose
and PRN SABA combination combination dose ICS-LABA + ICS-LABA +
Preferred or low-dose ICS- medium-dose LAMA and oral systemic
PRN concomitant formoterol ICS-formoterol PRN SABA corticosteroids +
ICS and SABA PRN SABA

Daily LTRA* and Daily medium- Daily medium- Daily medium-high

PRN SABA dose ICS and PRN dose ICS-LABA or dose ICS-LABA
or SABA daily medium-dose or daily high-dose
Cromolyn,* or or ICS + LAMA, and ICS + LTRA,* and
Nedocromil,* or Daily low-dose PRN SABA PRN SABA
Zileuton,* or ICS-LABA, or daily or
Theophylline,* and low-dose ICS + Daily medium-
PRN SABA LAMA, or daily dose ICS + LTRA,*
Alternative
low-dose ICS + or daily medium-
LTRA,* and dose ICS +
PRN SABA Theophylline,* or
or daily medium-dose
Daily low-dose ICS ICS + Zileuton,*
+ Theophylline* or and PRN SABA
Zileuton,* and
PRN SABA
Steps 2-4: Conditionally recommend the use of subcutaneous Consider adding Asthma Biolog'ics
immunotherapy as an adjunct treatment to standard pharmacotherapy (e.g .. anti-lgE. anti-ILS, anti-ILSR,
in individuals ≥ 5 years of age whose asthma is controlled at the anti-IL4/ IL13)**
initiation. build up, and maintenance phases of immunotherapy

Assess Control

• First check adherence, inhaler technique, environmental factors, and comorbid conditions.
• Step up if needed; reassess in 2-6 weeks
• Step down if possible (if asthma is well controlled for at least 3 consecutive months)

Consult with asthma specialist if Step 4 or higher is required. Consider consultation at Step 3.

Control assessment is a key element of asthma care. This involves both impairment and risk. Use of objective measures,
self-reported control, and health care utilization are complementary and should be employed on an ongoing basis,
depending on the individual's clinical situation.

FIGURE 26.1 Stepwise approach for management of asthma in individuals ages 12 years and older. (From Ref. [20] with permis-
sion.) Abbreviations: SABA, short-acting β-agonists; LTRA, leukotriene receptor antagonist; LABA, long-acting β-agonist; GERD,
gastroesophageal reflux disease; ICS, inhaled corticosteroid.

not for acute relief, but for long-term management (4 weeks for
maximal benefit). Inhaled corticosteroids are the most con-
sistently effective long-term control medication at all steps
of care for persistent asthma. If a β-agonist (e.g., albuterol)
is used two times a week, inhaled steroid therapy should be
started. Most of the data on inhaled steroids in human pregnancy
come from budesonide (Pulmicort) [17]. Inhaled beclomethasone
is associated with improved FEV1 and fewer side effects compared
to oral theophylline in the only trial comparing them in preg-
nancy [24]. In a large, double-blind, randomized trial, treatment
with low-dose budesonide had no adverse effects on the outcome
of pregnancy [23]. There is no evidence of increased rates of con-
genital malformations with the use of inhaled corticosteroids in
pregnancy [7, 19]. Nor is there an effect on fetal growth, preterm
birth, rates of gestational hypertension, pre-eclampsia, and peri-
natal mortality [10, 11, 25–27]. A meta-analysis concludes that
they are safe in pregnancy [28].
β-Agonists
β-Agonists relax bronchiolar smooth muscle. There is no con-
sistent evidence of increased rates of congenital malformations
with the use of β-agonists in pregnancy [19] despite a recent case-
control study suggesting an increased risk of gastroschisis when
bronchodilators were used during the periconception period [29].
Without having adjusted for severity of maternal asthma, it would
be premature to conclude that β-agonists correlate with gastros-
chisis. Use of inhaled β-agonists does not appear to increase peri-
natal risks in pregnant asthmatic patients (including gestational
Respiratory Diseases 275

Assess Severity
Measure PEF: Value <50% personal best or predicted suggests severe exacerbation
Note signs and symptoms: Degrees of cough, breathlessness, wheeze, and chest tightness correlate
imperfectly with severity of exacerbation
Accessory muscle use and suprasternal retractions suggest severe exacerbation

Initial Treatment
SABA: up to 3 treatments of 2–4 puffs by MDI at 20-minute intervals or single nebulizer treatment
ICS-Formoterol: up to 6 treatments of 1 puff by MDI at 1–3 minute intervals

Good Response Incomplete Response Poor Response

Mild Exacerbation
PEF>80% predicted or personal best.
No wheezing or shortness of breath.
Response to SABA sustained for 4
hours. Appropriate fetal activity.*
Moderate Exacerbation
PEF 50–80% predicted or personal best.
Persistent wheezing and shortness of
breath.
Decreased fetal activity.*
Severe Exacerbation
PEF <50% predicted or personal best.
Marked wheezing and shortness of
breath.
Decreased fetal activity.*

Treatment: Treatment: Treatment:

- May continue SABA every 3-4 hours
for 24–48 hours.
- For patients on ICS, no longer
recommend short term increase in dose
- Add on oral corticosteroid - Add oral corticosteroid
- Continue SABA - Repeat SABA or ICS-Formoterol
immediately.
- If distreass is severe and
nonresponsive, call your clinician
immediately and proceed to emergency
department; consider calling ambulance
or 911.

Contact clinician for followup Contact clinician urgently (this day) for
instructions. instructions. Proceed to emergency department.

FIGURE 26.2 Management of asthma exacerbations during pregnancy and lactation: Home treatment. (From Ref. [19] with permis-
sion.) *Fetal activity is monitored by observing whether fetal kick counts decrease over time. Abbreviations: PEF, peak expiratory flow;
MDI, mtered dose inhaler; SABA, short-acting β-agonists; ICS, inhaled corticosteroid.

hypertension, preterm birth, low birth weight, fetal growth, and
small for gestational age) [10, 11].
Short-acting β-agonists: Produces rapid, relatively short-dura-
tion bronchodilation. Regularly scheduled, daily, chronic use of
SABA is not recommended. The onset of action is <5 minutes,
with a duration of only 4–6 hours.
Long-acting β-agonists: Produce bronchodilation for at
least 12 hours after a single dose. They are not to be used as
monotherapy for long-term control of asthma. Instead, they
are used in combination with inhaled corticosteroids for
both immediate treatment of exacerbations and long-term
control/prevention of symptoms in moderate or severe per-
sistent asthma. Only formoterol-budesonide (Symbicort) has
been evaluated as a rescue inhaler. LABAs have been shown to
be more effective than leukotriene receptor antagonists
(LTRAs) or theophylline as add-on therapy to inhaled corti-
costeroids [2].
Cromolyn
Cromolyn sodium is a nonsteroidal anti-inflammatory agent
used for chronic management of asthma, not acute exacerba-
tions (4 weeks for maximal benefit). There is no evidence of
increased rates of congenital malformations with the use of
cromolyn in pregnancy [19]; this is a safe drug in pregnancy, as
is nedocromil.
Theophylline
Theophylline has a long record of use in pregnancy and no
teratogenic effects are known; however, the narrow therapeutic
window and potential for maternal and fetal toxicity mandates
close monitoring of serum levels. Low-dose theophylline is an
alternative to a LABA when inhaled corticosteroids do not suf-
fice to control symptoms, but this is not a preferred therapy [2].
GINA guidelines now recommend against the regular use of
theophylline.

Combination of inhaled corticosteroids and long- Leukotriene receptor antagonists

acting β-agonists (fixed-drug combination) Limited human data are available on the use of LTRA during
Fluticasone and salmeterol (Advair) combination is more effec- pregnancy. Several small studies have not shown an increase
tive than either drug alone in non-pregnant trials. in the rate of major malformations in offspring of women who
276 Maternal-Fetal Evidence Based Guidelines

Initial Assessment
History, physical examination (auscultation, use of accessory muscles, heart rate, respiratory rate), PEF or FEV1, oxygen saturation, and other tests as indicated
Initiate fetal assessment (consider continuous electronic fetal monitoring and/or biophysical profile if pregnancy has reached fetal viability)

FEV1 or PEF ≥50%
Short-acting inhaled beta2-agonist by MDI or
nebulizer, up to three doses in first hour
Oxygen to achieve O2 saturation ≥95%
Oral systemic corticosteroid if no immediate
response or if patient recently took oral
systemic corticosteroid
FEV1 or PEF <50% (Severe Exacerbation)
High-dose short-acting inhaled beta2-agonist by
nebulization every 20 minutes or continuously
for 1 hour + inhaled ipratropium bromide
Oxygen to achieve O2 saturation >95%
Oral systemic corticosteroid
Impending or Actual Respiratory Arrest
Intubation and mechanical ventilation with
100% O2
Nebulized short-acting inhaled beta2-agonist +
inhaled ipratropium bromide
Intravenous corticosteroid

Repeat Assessment
Symptoms, physical examination, PEF, O2 saturation, other tests as needed Admit to hospital intensive care
Continue fetal assessment (See box below)

Moderate Exacerbation Severe Exacerbation

FEV1 or PEF 50%–80% predicted/personal best FEV1 or PEF <50% predicted/personal best
Physical exam: moderate symptoms Physical exam: severe symptoms at rest, accessory
Short-acting inhaled beta2-agonist every muscle use, chest retraction
60 minutes History: high-risk patient
Systemic corticosteroid No improvement after initial treatment
Short-acting inhaled beta2-agonist hourly or
Oxygen to maintain O2 saturation >95%
continuously + inhaled ipratropium bromide
Continue treatment 1–3 hours, provided there is
Oxygen
improvement
Systemic corticosteroid

Good Response Incomplete Response Poor Response

FEV1 or PEF ≥70% FEV1 or PEF ≥50% but <70% FEV1 or PEF <50%
Response sustained 60 minutes after last Mild or moderate symptoms PC02 >42 mmHg
treatment Continue fetal assessment Physical exam: symptoms severe, drowsiness,
No distress confusion
Physical exam: normal Continue fetal assessment
Reassuring fetal status

Individualized Decision re:

Hospitalization

Discharge Home Admit to Hospital Ward Admit to Hospital Intensive Care

Continue treatment with short-acting inhaled Short-acting inhaled beta2-agonist + inhaled Short-acting inhaled beta2-agonist hourly or
beta2-agonist ipratropium bromide continuously + inhaled ipratropium bromide
Continue course of oral systemic corticosteroid Systemic (oral or intravenous) corticosteroid Intravenous corticosteroid
Initiate or continue inhaled corticosteroid until Oxygen Oxygen
review at medical followup
Patient education Monitor FEV1 or PEF, O2 saturation, pulse Possible intubation and mechanical ventilation
– Review medicine use Continue fetal assessment until patient stabilized Continue fetal assessment until patient stabilized
– Review/initiate action plan
– Recommend close medical followup

Improve

Discharge Home
Continue treatment with short-acting inhaled
beta2-agonist
Continue course of oral systemic corticosteroid
Initiate or continue inhaled corticosteroid until
review at medical followup
Patient education
– Review medicine use
– Review/initiate action plan
– Recommend close medical followup

FIGURE 26.3 Management of asthma exacerbations during pregnancy and lactation: Emergency department and hospital-based
care. (From Ref. [19] with permission.) Abbreviations: FEV1, forced expiratory volume in 1 second; MDL, metered-dose inhaler; PCO2,
carbon dioxide partial pressure; PEF, peak expiratory flow.
Respiratory Diseases
took LTRA during pregnancy [30, 31]. Mean birth weight was
lower, and risk of low birthweight and fetal distress was higher
in the montelukast-exposed group, a difference that may have
been related to asthma severity rather than drug effect. In
nonpregnant individuals, these drugs are less effective than
inhaled corticosteroids, and do not add much benefit to women
already on inhaled steroids. They do not reduce the risk of exac-
erbation requiring systemic steroids, and are associated with
modest improvement in PEF, with very modest decrease in use
of rescue SABAs [32]. These drugs may be considered during
pregnancy for women who had a good response to them prior
to pregnancy, but they are not a preferred option when initiat-
ing therapy. Montelukast and zafirlukast are safe in pregnancy
[33, 34]. Zileuton, a 5-lipoxygenase inhibitor, has been advised
against in pregnancy based on animal data: Human data are
lacking [19].
Anticholinergics
Anticholinergics such as LAMAs inhibit muscarinic cholin-
ergic receptors and reduce intrinsic vagal tone of the airway.
Ipratropium bromide provides additive benefit to SABA in mod-
erate or severe exacerbations in the emergency care setting, not
the hospital setting.
Oral Corticosteroids
Oral corticosteroids are indicated when combinations of
inhaled steroids, β-agonists, and cromolyn do not control
asthma. Oral steroid use in the first trimester is associated
with a possible increased risk of cleft lip (with or without cleft
palate) from the background rate of 0.1–0.3%, a small excess
risk. The use of oral corticosteroids during pregnancy is asso-
ciated with an increase in incidence of gestational diabetes,
pre-eclampsia, preterm delivery, and low birthweight. These
outcomes may be attributed to either the drug or the sever-
ity of the disease process. Available data do not allow for the
distinction [11].
Intravenous corticosteroids may be indicated in severe asthma
exacerbation.
Status asthmaticus
Recommendations for management are either anecdotal or
extrapolated from management of status asthmaticus outside of
pregnancy [35, 36].
Acute treatment of asthma
The treatment of an acute asthma exacerbation should be the
same, in general, as in non-pregnant adults. Oxygen, aerosolized
albuterol and ipratropium, as well as systemic steroids should be
initiated, as described earlier [37].
Antepartum testing
No specific indication.
Delivery
Asthma medications should be continued in labor. Although
asthma is typically quiescent during labor and delivery, PEF
should be measured upon admission, and again every 12 hours
in labor.
277
The theory of giving stress doses of steroids in labor or peri-
operatively is poorly supported by research (see Chapter 27).
Individuals receiving long-term corticosteroids have not, in ran-
domized studies, proven incapable of endogenous steroid produc-
tion perioperatively. A recent systematic review concludes that
there is no need to add stress-dose steroids in the perioperative
period, as long as patients continue to get their usual daily dose of
steroids. This would exclude patients with primary adrenal failure
or other primary dysfunction of the hypothalamic-pituitary axis,
who would still require additional glucocorticoid coverage. Based
on studies involving other surgical patients, adrenal crisis would
be unexpected in labor. It may be appropriate to continue stan-
dard daily steroid dosing during labor for women who are on
oral steroid therapy, without adding additional stress doses.
Blood pressure should be carefully monitored when administer-
ing oral steroids due to a common side effect of hypertension [38].
Prostaglandin E1 (Misoprostol) and E2 (Dinoprostone)
are bronchodilators and do not cause asthma exacerbations.
Prostaglandin F2α (Carboprost) should be avoided, as it can
cause bronchospasm. Ergonovine, methylergonovine, and non-
steroidal anti-inflammatory drugs (NSAIDs) may precipitate
bronchospasm.
Anesthesia
No specific changes; as a rule, regional anesthetics are preferred
to general.
Postpartum/Breastfeeding
The use of prednisone, theophylline, antihistamines, inhaled cor-
ticosteroids, β2-agonists, and cromolyn is not contraindicated for
breastfeeding [14]. Breastfeeding does not protect against asthma
in offspring [39]. Although nonsteroidal anti-inflammatory drugs
(NSAIDs) may precipitate bronchospasm in some asthmatics, the
risk in the general asthmatic population is less than 1%. Thus,
it is reasonable to treat patients during the postpartum period
with NSAIDs especially if they have not previously exhibited an
adverse reaction.
Pneumonia
Key points
• The presence of an infiltrate on chest X-ray confirms the
diagnosis of pneumonia.
• Complications of community-acquired pneumonia (CAP)
include mechanical ventilation, maternal mortality, low
birthweight infant, and perinatal mortality.
• Prompt administration of antibiotics without delay and
appropriate antibiotic therapy are the most important
principles for effective management.
• Hospitalization is indicated when a pregnant woman with
CAP has coexisting medical conditions such as malig-
nancy, renal failure, immunosuppression, cerebrovascular
disease, diabetes, or valvular heart disease, respiratory rate
(RR) ≥ 30, diastolic blood pressure (BP) ≤ 60, systolic BP
≤ 90, heart rate (HR) ≥ 125, altered mental status, partial
pressure carbon dioxide (PaCO2) < 60 on room air, pres-
ence of a pleural effusion, hematocrit < 30, arterial pH <
7.35, or multilobe involvement.
278
• Most cases of low-risk CAP in pregnancy can be treated
with a macrolide or amoxicillin, while patients requir-
ing hospitalization can be treated with a macrolide and
a β-lactam.
• Antibiotic therapy should not be changed within the first
72 hours unless clinical deterioration is overt or organism
sensitivities become available.
Epidemiology
The attack rate for CAP is no different among pregnant women
than among women of reproductive age who are not pregnant,
approximately 1.5 per 1000 [40]. Pregnant women hospitalized
with CAP have lower severity scores than their non-pregnant
counterparts; this may reflect either a tendency for the disease
process to be less severe or a lower threshold for hospitaliza-
tion during pregnancy. Pneumonia incidence is evenly distrib-
uted throughout pregnancy; that is, there is no specific period of
vulnerability.
Etiology/Basic pathophysiology
Etiology is usually bacterial infection, with a minority con-
tribution of viral and fungal infection of the lungs. Following
the COVID-19 pandemic, viral etiology has become a major
contributor to global CAP burden and is discussed separately.
Streptococcus pneumoniae (5–30%) and Mycoplasma pneu-
moniae (5–30%) are the most common pathogens, but dozens
of different organisms can cause pneumonia (Table 26.6) [41,
42]. In CAP, the causative agent is identified in only 40–60% of
cases [43].
TABLE 26.6: Pathogens Isolated in Patients with Community-
Acquired Pneumonia
Bacterial
• Common: Streptococcus pneumoniae, Mycoplasma pneumoniae,
Haemophilus influenza, Staphylococcus aureus, Chlamydophila
pneumoniae and psittaci
• Less common: Pseudomonas aeruginosa, Legionella spp., Klebsiella
spp., Moraxella catarrhalis, Bordetella pertussis, Escherichia coli,
Enterobacter spp., Serratia spp.
Viral
• Common: Influenza A and B and varicella-zoster virus
• Less common: Adenovirus species, enteroviruses (echovirus,
coxsackievirus, poliovirus), Epstein–Barr virus, cytomegalovirus,
respiratory syncytial virus (common in children), parainfluenza
virus, human metapneumovirus, herpes simplex virus,
coronaviruses, measles virus, hantavirus
Fungal
• Uncommon: Histoplasma capsulatum, Coccidioides immitis,
Cryptococcus neoformans, Blastomyces hominis, Aspergillus spp.,
Candida spp., Mucormycotic fungi
Other Causes
• Uncommon: Mycobacterium tuberculosis, Pneumocystis jirovecii,
Toxoplasma gondii, Ascaris lumbricoides, Strongyloides stercoralis,
Coxiella burnetii, Rickettsia rickettsii
Source: From Ref. [42], with permission.
Maternal-Fetal Evidence Based Guidelines
Risk factors
Smoking, alcohol, chronic lung disease (asthma, chronic obstruc-
tive pulmonary disease, bronchiectasis, restrictive lung disease),
chronic co-morbidities (diabetes mellitus, chronic heart failure,
immunocompromised state), aspiration (seizure, stroke, esopha-
geal dysmotility), and crowded living conditions.
Diagnosis
Pneumonia is an infectious process of the lower respiratory
tract, which should be suspected if a patient presents with new
respiratory symptoms of cough, dyspnea, or sputum produc-
tion, particularly if fever and abnormal breath sounds are also
present. The presence of an infiltrate on chest x-ray confirms
the diagnosis. Chest x-ray and computed tomography (CT) are
both safe imaging modalities in pregnancy; radiation exposure
from these modalities is far below the 5 Rad per pregnancy limit
needed to cause fetal malformations or induce pregnancy loss
[44]. Radiographic findings such as lobar consolidation, inter-
stitial infiltrates, cavitary lesions, or ground glass opacities may
suggest specific etiology. However, radiographic findings alone
should not dictate class of treatment without further workup. In
most cases, clinical signs and symptoms do not distinguish one
pathogen from another.
Classification
Pneumonia is classified by setting of infection: (1) community
acquired pneumonia (CAP): Acute infection acquired outside of
the hospital, (2) hospital acquired pneumonia (HAP): Acquired
48 hours or more after admission to the hospital, (3) ventilator-
associated pneumonia (VAP): Acquired 48 hours or more after
endotracheal intubation. The category of healthcare-associated
pneumonia introduced in the 2005 American Thoracic Society/
Infectious Diseases Society of America (ATS/IDSA) guide-
lines have since been abandoned due to likely over-treatment
of antibiotic-sensitive organisms. The vast majority of cases of
pneumonia in pregnant women in clinical practice and in the
literature are cases of CAP.
The Pneumonia Severity Index (PSI) stratifies CAP by comor-
bidity and risk of mortality [45]. Most pregnant patients with
CAP will fall into subset I; this is a group that, if non-pregnant,
would be appropriately treated as outpatients. There are, however,
no reliable data as to inpatient versus outpatient therapy in
pregnancy.
Symptoms
Cough, dyspnea, sputum production, pleuritic chest pain, and/or
fever.
Pregnancy considerations
Women hospitalized for CAP during pregnancy appear to be less
ill than their non-pregnant counterparts, measured by either
severity score or length of stay, but this likely reflects a tendency
to hospitalize for less severe disease because of the pregnancy.
The rate of preterm delivery is higher among women with a diag-
nosis of pneumonia than among those with upper-tract respira-
tory infection or with no respiratory infection [46]. In addition,
Respiratory Diseases
the risk of placental abruption is twice as high among pregnant
women hospitalized for pneumonia compared to a control group
without respiratory disease [47].
Approximately 2% of pregnant women with pneumonia
require intubation and mechanical ventilation [48]. The risk
of maternal mortality with CAP was 2.9% from reports in the
1990s [49]. Among women hospitalized for pneumonia dur-
ing pregnancy, the risk of delivering a small-for-gestational-age
infant is increased relative to controls, although this may be con-
founded by different health behaviors in the two groups. Rates of
preterm birth and perinatal mortality are increased after preg-
nancy complicated by pneumonia, though not to statistical sig-
nificance. Term and preterm premature rupture of membranes
have been shown to be increased in women with viral and bacte-
rial pneumonia [50].
Management
Principles
Prompt administration of antibiotics without delay and appropri-
ate antibiotic therapy are the most important principles for effec-
tive management.
Prevention
Pneumococcal vaccine prevents 71% of cases of CAP and 32%
of related mortality in non-pregnant adults [41]. For details
on recommended pneumococcal and influenza vaccines, see
Chapter 40.
Workup
Assess severity of illness by physical findings (blood pressure,
respiratory rate, mental status, state of hydration) and by radio-
graphic findings (e.g., multi-lobar involvement and pleural effu-
sion). Laboratory testing for a specific cause is controversial
and frequently nonrevealing. The IDSA and the ATS have rec-
ommended that diagnostic testing be initiated to determine the
cause of CAP if the results would change treatment decisions, for
example antimicrobial regimens. This would be most useful in
areas of high antibiotic resistance or if unusual pathogens are sus-
pected. A list of clinical indications for more extensive diagnos-
tic testing can be found in the IDSA/ATS Consensus Guidelines
[45]. Routine diagnostic tests to identify an etiologic diagnosis
are optional for the mildly ill, but patients with severe CAP
should have the following diagnostic tests: Blood cultures,
urinary antigen assays for Legionella spp. and S. pneumoniae,
and expectorated sputum/endotracheal aspirate culture.
Additionally, if empiric treatment for methicillin-­ resistant S.
aureus (MRSA) or Pseudomonas aeruginosa is initiated (or
patient has history of prior MRSA or P. aeruginosa infection),
then blood and sputum cultures should be obtained regardless
of severity of disease. During influenza season, the patient should
additionally be tested for influenza as co-infection with bacterial
pneumonia is common.
Blood culture is positive in 5–11% of cases; positive blood cul-
tures are more common in those with severe CAP [51]. Blood
cultures should ideally be obtained before antibiotic adminis-
tration. Procalcitonin has been proposed as a method to distin-
guish bacterial and viral infections. While higher procalcitonin
levels have been associated with bacterial infections, there has
not be a level determined to adequately rule out bacterial pneu-
monia, and thus should not be used to guide antibiotic admin-
istration [52].
279
Treatment
Hospitalization
The initial management decision after diagnosis is to determine
the site of care, that is, outpatient, hospital floor, or intensive care
unit (ICU). There are no trials addressing benefits of outpatient
versus inpatient care for the pregnant woman with pneumonia.
Keeping this in mind, physicians may still begin treatment deci-
sions by using a prediction tool for increased mortality, such as
the PSI, combined with clinical judgment [45]. The PSI was devel-
oped to assist physicians in identifying patients at a higher risk of
complications and who are more likely to benefit from hospital-
ization, that is, those with comorbidities, hypoxemia, alteration
in vital signs, etc. The PSI has not been validated in pregnancy.
Direct admission to ICU is required for patients with septic shock
requiring vasopressors, or with acute respiratory failure requir-
ing intubation and mechanical ventilation.
The majority of obstetrical patients will fail to qualify as high
risk by these criteria. Retrospectively, applying ATS guidelines in
place at the time of the study (similar to discussed earlier), only
25% of pregnant patients with a diagnosis of CAP could have been
assigned to outpatient care [48]. A 23-hour observation period
might be useful in deciding whether inpatient treatment is war-
ranted in the pregnant patient.
Antibiotics
There are no trials to determine which antibiotic regimen is most
beneficial for the pregnant woman with pneumonia. No pub-
lished treatment guidelines alter therapy for pneumonia because
of pregnancy. Antibiotic selection should take into account the
common causes of CAP, local antibiotic resistance patterns, clini-
cal presentation, comorbid conditions, and recent antibiotic use.
Fluoroquinolones are generally avoided in pregnancy because of
concerns about interference with cartilage formation in the fetus.
Tetracyclines are also avoided because of concerns about denti-
tion. However, depending on drug allergies and microbiologic
sensitivities, it may be necessary to alter these preferences. Initial
choice of antimicrobial treatment is empirical. The ATS/IDSA
recommended outpatient regimens for adults with CAP are (for
those with no comorbidities or risk factors for MRSA or P. aeru-
ginosa) amoxicillin or doxycycline or macrolide, if local pneumo-
coccal resistance is under 25% and (for those with comorbidities)
combination therapy with amoxicillin/clavulanate or cephalo-
sporin AND macrolide or doxycycline OR monotherapy with
respiratory fluoroquinolone; where possible, exclude quinolones
and tetracyclines (see further Ref. [52]). The ATS/IDSA recom-
mended inpatient regimens for adults with CAP are (for those
with non-severe pneumonia) β-lactam + macrolide or respiratory
fluoroquinolone and (for those with severe pneumonia) β-lactam
+ macrolide or respiratory fluoroquinolone; where possible,
exclude quinolones and tetracyclines (see further Ref. [52] for
modifications for prior respiratory isolation or recent hospital-
ization and parenteral antibiotics).
Most cases of low-risk CAP in pregnancy can be treated
with a macrolide or amoxicillin, while patients requiring hos-
pitalization can be treated with a macrolide and a β-lactam.
Uncommon pathogens do exist and should be considered if
response to therapy is inadequate or incomplete.
Typical responses to therapy include defervescence in
2–4 days, with resolution of leukocytosis in the same time
period. The chest x-ray may take longer to clear, as may the
auscultatory findings. Antibiotic therapy should not be
280
changed within the first 72 hours unless clinical deterio-
ration is overt or organism sensitivities become available.
There is no evidence in non-pregnant adults that intravenous
and oral therapy differ in efficacy. Patients should be switched
from intravenous to oral therapy when hemodynamically sta-
ble and improving clinically, able to ingest medications, and
have a normally functioning GI tract. If the pathogen and
sensitivities are known, the narrowest spectrum agent should
be chosen for oral therapy, but in most cases, this will not
be possible. When switching to oral agents, choose the same
medication or the same class when possible. The ATS/IDSA
recommend discharge to home the same day that clinical
stability is achieved (afebrile, no tachypnea nor tachycar-
dia, normotensive, normoxemic, normal mental status, and
able to tolerate oral intake) and the switch to oral agents
is made. Inpatient observation while receiving oral therapy is
not necessary. A follow-up inpatient chest x-ray is not recom-
mended [52].
There are inadequate data to determine the best dura-
tion of antimicrobial treatment for CAP. With older agents,
a duration of 10–14 days is commonly prescribed, but newer
agents have longer half-lives and therefore may be curative
over shorter courses of therapy. Current recommendations for
non-pregnant adults is to continue therapy for a minimum of 5
days. Extended therapy should be considered for patients with
meningitis, endocarditis, or with uncommon pathogens (fun-
gal, TB, etc.). Patients with suspected MRSA or P. aeruginosa
should be treated for at least 7 days. Prior to discontinuation
of therapy, patient should have stable and normal vital signs,
normal mentation, and be able to eat. If unable to meet clini-
cal stability, consider longer duration of therapy or switching
classes of antibiotics. Oxygen support should be provided as
needed.
Antepartum testing
No specific indication.
Delivery
No specific changes.
Anesthesia
No specific changes.
Postpartum/Breastfeeding
No specific changes.
Influenza
Key points
• Trivalent inactivated influenza vaccine is recommended
for all pregnant and postpartum women.
• In addition to the protective effect of vaccination on
women themselves, infants born to vaccinated mothers
have fewer episodes of influenza, fever, and respiratory
illness in their first 6 months of life.
Maternal-Fetal Evidence Based Guidelines
• Influenza antiviral medications should be started as soon
as possible after symptom onset, ideally within 48 hours
of symptom onset. Treatment should not be delayed for
laboratory confirmation of influenza.
• Risk of severe illness and mortality because of influenza
appear to be higher among pregnant women.
Epidemiology
Annual epidemics of influenza typically occur during the late
fall through early spring: In the Northern Hemisphere, flu sea-
son starts in September or October and may continue as late as
May. In addition to seasonal influenza, epidemics or pandemics
arise unpredictably. The pattern of emergence is usually in the
Southern Hemisphere first, during the austral winter, where sea-
sonal influenza peaks in August. A systematic review examining
the incidence of influenza among pregnant patients showed that
rates varied widely across regions and years. Estimates of serol-
ogy-confirmed influenza cases range from 483 to 1097 cases per
10,000 pregnant women [53–55]. Symptomatic cases however
tend to be far less. In the United States, symptomatic influenza
ranged from 0.1 to 6.6 cases per 10,000 pregnancies during the
2009 pandemic [56, 57].
Etiology/Basic pathophysiology
Influenza illnesses are caused by infection with one of the three
types of circulating RNA viruses: A, B, or C [58]. While B and C
are almost exclusive to humans, A is avian in origin, although
capable of infecting a range of warm-blooded animals. Both A
and B types cause seasonal epidemic human disease, although
only Influenza A is known to cause pandemics. Influenza C may
cause mild symptoms but is not known to cause epidemics.
High mutation rates and the potential for cross-species genetic
re-assortment are characteristic of influenza A [44]. Influenza A
is subtyped by its surface antigens hemagglutinin (H) and neur-
aminidase (N). New influenza A subtypes have the potential to
cause a pandemic, as demonstrated most recently in the 2009
H1N1 pandemic. The 2009 pandemic influenza A (H1N1) virus
contained a combination of gene segments that had not been
reported previously in animals or humans.
Influenza is spread by aerosolized droplets. The incubation
period for influenza is 1–4 days; patients are likely infectious one
day before symptom onset.
Symptoms
Infection with influenza virus can range from asymptomatic
infection to uncomplicated upper respiratory tract disease to
serious complicated illness such as secondary bacterial pneu-
monia, sepsis, and organ failure. Symptoms include fever, cough,
sore throat, nasal congestion or rhinorrhea, headache, myalgia,
and malaise.
Diagnosis
A variety of laboratory tests are available (Table 26.7). Testing
should occur if the result would influence clinical management.
Antigen-based rapid testing is most commonly used during influ-
enza season, but positive predictive value is poor when influenza
prevalence is low.
Respiratory Diseases 281

TABLE 26.7: Influenza Virus Testing Methods

Methoda Types Detected Acceptable Specimensb Test Time CLIA Waivedc
Rapid influenza diagnostic tests d A and B NP swab, aspirate or wash, nasal
e
<15 minutes Yes/No
(antigen detection) swab, aspirate or wash, throat
swab
Rapid molecular assay (influenza viral A and B NPe swab, nasal swab 15–30 minutesf Yes/Nof
RNA or nucleic acid detection)
Immunofluorescence, direct (DFA) or A and B NPd swab or wash, bronchial 1-4 hours No
indirect (IFA) florescent antibody wash, nasal or endotracheal
staining (antigen detection) aspirate
RT-PCRg (singleplex and multiplex; A and B NPe swab, throat swab, NPe or Varies (1 to No
real-time and other RNA-based) and bronchial wash, nasal or 8 hours, varies
other molecular assays (influenza endotracheal aspirate, sputum by the assay)
viral RNA or nucleic acid detection)
Rapid cell culture (shell vials; cell A and B NPe swab, throat swab, NPe or 1-3 days No
mixtures; yields live virus) bronchial wash, nasal or
endotracheal aspirate, sputum;
(specimens placed in VTMh)
Viral tissue cell culture (conventional; A and B NPe swab, throat swab, NPe or 3–10 days No
yields live virus) bronchial wash, nasal or
endotracheal aspirate, sputum
(specimens placed in VTM8)
Source: CDC – https://www.cdc.gov/flu/professionals/diagnosis/table-testing-methods.htm – in the public domain.
a Serologic (antibody detection) testing is not recommended for routine patient diagnosis and cannot inform clinical management. A single acute serum specimen for sea-

sonal influenza serology is uninterpretable and should not be collected. Serological testing for detection of antibodies to seasonal influenza viruses is useful for research
studies and requires collection of appropriately timed acute and convalescent serum specimens and testing of paired sera at specialized research or public health
laboratories.
b Approved clinical specimens vary by influenza test. Consult the manufacturer’s package insert for the approved clinical specimens for each test (see Ref. [167]).

c Clinical Laboratory Improvement Amendments (CLIA) of 1988. http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.htmlexternal icon.

d Chromatographic- and/or fluorescence-based lateral flow and membrane-based immunoassays. Some approved rapid influenza diagnostic assays utilize an analyzer reader

device.
e NP, nasopharyngeal.

f Rapid molecular assays can provide results in approximately 15–30 minutes.

g Reverse transcription polymerase chain reaction, including FDA-approved test systems, reference laboratory testing using ASR or lab-developed reagents. Some approved

molecular assays can produce results in approximately 60–80 minutes.

h VTM, Viral transport media.

Complications H1N1 influenza [64]. Some studies have observed moderately

Complications are largely maternal. In influenza pandemics,
the maternal mortality case–fatality ratio is higher than that of
the general population. In the most recent influenza pandemic
(2009), pregnant women, who represented approximately 1% of
the U.S. population, accounted for 5% of deaths from the 2009
influenza A (H1N1) [57, 59]. In a case series from the 2009 H1N1
pandemic, 7% of deaths occurred in the first trimester, 27% in the
second, and 64% in the third trimester [46]. This study is con-
sistent with previous pandemics and seasonal influenza studies,
which usually suggest that the risk of influenza complications
is higher in the second and third trimester of pregnancy than
in the first trimester [60, 61].
Transplacental passage of influenza virus appears to be rare
[49]. The effect of influenza on perinatal outcomes is inconsis-
tent. In most studies, there are no significant differences in mode
of delivery, duration of delivery admission, episodes of preterm
labor, and adverse perinatal outcomes between the influenza
and non-influenza groups [62, 63]. Infants born to women with
laboratory-confirmed seasonal influenza during pregnancy do
not have higher rates of low birthweight or lower Apgar scores
[53, 55]. A meta-analysis of neonatal outcomes did not identify
significant increases in preterm birth, except in cases of severe
increased risk of fetal death; however, the only high-quality stud-
ies are from the H1N1 pandemic [65, 66]. Severe maternal illness,
such as overt respiratory failure, is associated with significantly
worse perinatal outcome than in most seasonal or even pandemic
influenza [67–69].
Although pregnancy outcomes do not seem to be significantly
affected, there is evidence that maternal exposure to influenza
may lead to increased rates of congenital anomalies. One meta-
analysis showed that maternal exposure to influenza in the first
trimester led to a two-fold increase in congenital malformations.
This included a significant increase in neural tube defects, hydro-
cephaly, congenital heart defects, aortic valve atresia/stenosis,
ventricular septal defect, cleft lip, digestive system malformation,
and limb reduction deficits [70].
Pregnancy considerations
Changes in the immune, respiratory, and cardiovascular systems
result in pregnant women being more severely affected. Pregnant
women are at higher risk for severe complications and death from
influenza, both H1N1 influenza and seasonal influenza.
During periods of seasonal flu, pregnant women account for
excess healthcare visits related to respiratory complaints and
282
excess hospitalizations (above what would be expected outside of
pregnancy); this is true for both healthy women and those with
chronic conditions. The rate of hospitalization for seasonal influ-
enza among healthy non-pregnant women in Canada is nearly 10
times as high among healthy pregnant women. This difference
in influenza hospitalization persists among women with comor-
bidities, thought their rate of hospitalization is overall higher
[71]. Pregnant women are at increased risk for hospitalization
during influenza season, and those hospitalized for respiratory
illness stay longer [59, 71, 72]. During the 2009 H1N1 influenza
pandemic, pregnant and postpartum women with H1N1 influ-
enza had a 7 times higher risk of admission to the ICU than
non-­pregnant women in the same age group; After 20 weeks of
pregnancy the relative risk of ICU admission was 13 times higher
[69]. The severity of disease is demonstrated by utilization of
extracorporeal membrane oxygenation (ECMO). Sixteen per-
cent of all ECMO interventions for respiratory failure in H1N1
in Australia and New Zealand were performed on pregnant or
postpartum patients, whom conventional mechanical ventilation
could not adequately oxygenate [73].
Management
Prevention
Annual influenza vaccination is the most effective method for
preventing influenza infection and its complications [74]. The
vaccine is reformulated yearly to cover the strains predicted to
be in circulation and as a result has varying levels of efficacy.
Large-scale studies examining vaccine efficacy in pregnancy are
lacking, but a review of available evidence found vaccine efficacy
of 41–91.5% reduction in laboratory-confirmed influenza [75].
The trivalent inactivated vaccine (TIV) for individuals is recom-
mended for women who are pregnant, postpartum, or breast-
feeding during the influenza season. TIV contains noninfectious
killed viruses and cannot cause influenza. It can be given in any
trimester of pregnancy. A meta-analysis examining the timing of
influenza vaccine delivery showed a greater immune response is
created later in pregnancy and that vaccination later in pregnancy
led to increased maternal transfer of antibodies [76]. However, the
optimal timing of influenza vaccine has not yet been determined
and should thus be administered at the start of the influenza sea-
son, regardless of gestational age. There is no clear evidence of
fetal harm after TIV administration to pregnant women [77] and
no difference in rate of preterm birth and cesarean delivery [62]. In
fact, influenza vaccination in the first trimester is not associated
with an increase in major malformations rates and is associated
with a decrease in stillbirth rates [78]. In addition to the protec-
tive effect of vaccination on women themselves, infants born to
vaccinated mothers have fewer episodes of influenza, fever, and
respiratory illness in their first 6 months of life [79], which may
represent antibody transfer [80]. The live attenuated influenza
vaccine (given intranasally), like other live-virus vaccines, should
not be given during pregnancy (see also Chapter 40).
Each season, influenza vaccines are reformulated. Vaccination
providers may check updated information at the Centers for
Disease Control and Prevention (www.cdc.gov/flu), Food and Drug
Administration (https://www.fda.gov/vaccines-blood-biologics/
safety-availability-biologics/inf luenza-virus-vaccine-safety-
availability), or World Health Organization (WHO) (https://
www.who.int/influenza/vaccines/virus/recommendations/en/).
However, national health authorities approve the specific compo-
sition and formulation of yearly vaccines for individual countries.
Maternal-Fetal Evidence Based Guidelines
Prophylaxis after suspected exposure
Chemoprophylaxis after exposure to influenza is recommended
for individuals at high risk of complications from influenza, which
would include pregnant and women up to 14 days postpartum
[81]. For household exposures, a 7–10 day course of either osel-
tamivir 75 mg once daily, or zanamivir as two 5-mg inhalations
once daily are recommended. If symptoms begin, chemoprophy-
laxis dosing should be increased to therapeutic dosing. There are
no RCTs of post-exposure influenza prophylaxis among pregnant
women. The efficacy of oseltamivir prophylaxis has been called
into question after a reanalysis of data obtained directly from the
manufacturer showing a 55% decrease in symptomatic influenza
cases, but no significant reduction in transmission or asymptom-
atic cases [82].
Therapy
The neuraminidase inhibitors, oseltamivir and zanamivir, are
modestly effective against both influenza A (including H1N1)
and influenza B. Although the manufacturer has conducted no
studies to assess safety of these medications for pregnant women,
available risk-benefit data suggest that pregnant women with
suspected or confirmed influenza should receive prompt
antiviral therapy. Information about peramivir in preg-
nancy is limited to a handful of cases treated under the FDA’s
Emergency Use Authorization, and no recommendation can
be made about this drug.
The standard therapeutic dose for oseltamivir is 75 mg twice
daily for 5 days [83]. Oseltamivir is the preferred agent for treat-
ment in pregnancy due to decreased lung volume in pregnancy.
The standard therapeutic dose for zanamivir is two inhalations
(10 mg) twice daily for 5 days; this drug should be avoided in case
of chronic respiratory disease, including asthma. If oseltamivir
resistance is suspected, use zanamivir. The standard therapeu-
tic dose for peramivir is 600 mg IV given over 15–30 minutes.
Adamantane anti-viral agents including amantadine and
rimantadine were historically used in treatment of Influenza A.
However, treatment of influenza with these medications has been
abandoned due to high rates of resistance.
Treatment should be started as soon as possible, preferably
within the first 48 hours. Delayed treatment of antiviral therapy
has been associated with more severe illness and death in both
seasonal influenza and the H1N1 pandemic, whereas early initia-
tion of treatment has been associated with reduced duration of
illness, severity, mortality, and incidence of complications [59, 67,
84–86]. Laboratory confirmation of influenza virus infection
is not necessary for the initiation of treatment.
Several systematic reviews of neuraminidase inhibitors in
non-pregnant adults [86–88] appeared to show an advantage
for oseltamivir compared to placebo in reduction of symptoms
(HR = 1.20; 95% CI, 1.06, 1.35), with a reduction in duration of
illness of about 1 day. These reviews, however, have been called
into question because of concerns of reporting bias. Most recent
reviews have revealed that oseltamivir, compared to placebo,
shortened the time to alleviation of symptoms by 16 hours,
had no effect on hospital admission, and did not affect the
risk of developing objectively verified pneumonia or any other
complication deemed significant [85].
Epidemiologic data from the 2009–2010 pandemic showed that
among pregnant women, later initiation of antiviral treatment (≥4
days after symptoms began) was associated with higher rates of
hospital admission, ICU admission, and mechanical ventilation,
Respiratory Diseases
compared to those who began treatment earlier. Women who
received no antiviral drug had no increased risk of hospital admis-
sion but were more likely to be admitted to ICU and to receive
mechanical ventilation, compared to those who began antiviral
therapy at less than 4 days after symptom onset. “Late” or no
treatment was also associated with higher risk of death, though
mortality was, surprisingly, higher with late treatment than with
no treatment, perhaps reflecting a small number of events [59].
There is limited evidence regarding the safety of oseltamivir
use in pregnancy. A single cotyledon perfused placental model
showed that oseltamivir is extensively metabolized by the pla-
centa [89] with minimal accumulation of the metabolite on the
fetal side. In a population of 90 Japanese women who received
oseltamivir during pregnancy, the incidence of malformation
(1.1%) was similar to the incidence of major malformations in the
general population [90]. A retrospective cohort study of 239 preg-
nant women in Texas demonstrated no association of antepar-
tum exposure to amantadine, rimantadine, or oseltamivir with
adverse fetal outcomes [91]. As of 2020, the CDC continues to
recommend oral oseltamivir for treatment of pregnant and
postpartum women suspected of having influenza, and states
that the decision to start antiviral treatment should not wait
for laboratory confirmation, since “laboratory testing can delay
treatment and because a negative rapid influenza diagnostic test
does not rule out influenza” [92].
Antepartum testing
No evidence for specific recommendations.
Delivery
No evidence for specific recommendations.
Postpartum/Breastfeeding
Whether influenza viruses are passed into human milk is not
known; however, respiratory droplets are believed to be the main
mode of viral transmission. Because of the protective benefits of
breast milk for infants, continuation of breastfeeding is recom-
mended while the mother is receiving treatment for influenza
infection. The concentration of oseltamivir found in breast milk
equates to much lower doses than the therapeutic dose given to
infants [93]. Inhalational zanamivir accumulates to a negligible
concentration in breast milk. Breastfeeding should not be discon-
tinued due to zanamivir use. It is not known whether peramivir
is found in breast milk.
Tuberculosis
Key points
• Definitive diagnosis of active infection is based on cul-
ture (of suspected site: Sputum for pulmonary TB) for
Mycobacterium tuberculosis. Sputum culture is also
important for drug sensitivity testing.
• Diagnosis of latent tuberculosis infection is based on a
positive tuberculin test (called tuberculin skin testing, TST,
or purified protein derivative, PPD), or interferon gamma-
release assay (IGRA), and the absence of signs, symptoms,
283
or proof of active disease. The choice of diagnostic test is
based on available resources and specific populations.
• Pregnancy does not influence the progression from latent
to active disease.
• The treatment for latent tuberculosis infection in preg-
nancy is Isoniazid 300 mg daily for 6–9 months.
• Treatment of active tuberculosis consists of an initial two-
month phase of therapy, including isoniazid, rifampin,
ethambutol, and possibly pyrazinamide. Directly observed
therapy is usually recommended. Isoniazid and rifampin
are continued for an additional four months. Treatment
for active tuberculosis is not altered by pregnancy.
Epidemiology
TB is rare in high-income countries, with, for example, approxi-
mately 9000 new cases in the United States in 2019. This is
consistent with a rate of 2.7 cases per 100,000 persons [94]. In
comparison, there were 7.0 million new TB cases in 2018 world-
wide, and 1.5 million deaths; TB is one of the top three causes
of death for women of reproductive age [95]. Human immuno-
deficiency virus (HIV) coinfection (about 8.6% of incident cases
worldwide) accounts for a significant portion of the tuberculosis
burden. The national incidence of TB in pregnancy in the UK in
2008 was estimated at 4 per 100,000 maternities [96]. All but one
of the TB patients in this study were non-Western immigrants,
and half had extrapulmonary disease. Few had undergone tuber-
culin skin testing, despite recommendations to the contrary.
Etiology/Basic pathophysiology
TB is a bacterial infection due to Mycobacterium tuberculosis.
The pathogenesis of tuberculosis infection and disease in preg-
nant women is similar to that in nonpregnant women. Infection
is primarily pulmonary, though extrapulmonary spread is com-
mon. Spread (by airborne droplets) is facilitated by the ability
of these small particles to remain airborne for hours after being
emitted from an infected respiratory tract. Once inhaled, M.
tuberculosis may (1) be cleared from the body, (2) produce an
active infection, (3) produce an asymptomatic latent infection,
or (4) reactivate into an active infection months to years later.
When M. tuberculosis is taken up by alveolar macrophages, the
infection may either be contained by granuloma formation or
may progress to active disease [97]. Most patients develop cell-
mediated immunity, which is demonstrated by conversion of
the tuberculin skin test (TST), and which constitutes latent
tuberculosis infection. In some patients, the replication of M.
tuberculosis cannot be contained, and active disease occurs.
Latent tuberculosis infection can spontaneously develop into
active tuberculosis, especially in individuals with risk factors.
Pulmonary disease is the most common but not the only form
of active tuberculosis. Twenty percent of cases (extrapulmo-
nary tuberculosis) can manifest as meningitis, osteitis, genito-
urinary involvement, or disseminated disease.
Risk factors/Associations
HIV is the most important risk factor. Poorly controlled diabe-
tes, renal failure, malignancy, steroids, malnutrition, and vitamin
A or D deficiency are other risk factors for acquiring active M.
tuberculosis infection [97].
284 Maternal-Fetal Evidence Based Guidelines

TABLE 26.8: Indications for Tuberculin Skin Testing in
Pregnancy (Risk Factors for Progression from Latent
to Active Disease)
Recent conversion
Household contacts of persons with infectious pulmonary TB
Recent immigration from parts of the world with high rates of TB
Homelessness
HIV infection
Living or working in institutional setting in which TB is common
(hospital, jail, homeless shelter)
Injection drug use
Renal failure on hemodialysis
Diabetes
Solid organ transplantation
Certain cancers; certain surgeries such as gastrectomy or jejunal bypass
High-dose corticosteroids for prolonged periods (lower limit not known)
Significantly underweight/poor nutrition
Symptoms (of active disease)
Cough, lethargy, dyspnea, malaise, fever, night sweats, and weight
loss. Hemoptysis is a late finding.
Screening
Targeted tuberculin testing in individuals at increased risk for
developing M. tuberculosis infection who would benefit from
treatment of latent tuberculosis infection is recommended. The
WHO recommends that systematic TB screening should be per-
formed as a part of routine prenatal care when TB in the general
population is equal to or greater than 100 cases per 100,000 peo-
ple. Testing is otherwise discouraged among persons without
risk factors (Table 26.8). Persons at increased risk for develop-
ment of active disease are those who were recently infected (i.e.,
converted from a positive to a negative skin test within the pre-
ceding 2 years), as well as those who have latent infection plus an
increased risk of progression to overt disease. Table 26.8 displays
a non-exhaustive list of indications for testing in pregnancy. A
decision to test is a decision to treat. Therefore, do not screen
unless prepared to treat.
Tuberculin skin testing (TST) is the method historically used
to detect both latent and active disease. TST can be performed
safely in pregnant women, and pregnancy does not alter the
response to the TST [98]. Using standardized purified protein
derivative (PPD), 0.1 mL (5 tuberculin units) is administered
intradermally in the volar surface of the forearm. The reaction is
read 48 to 72 hours after the injection, although reading is accu-
rate up to a week after challenge. CDC interpretation of PPD
results is shown in Table 26.9; however, national guidelines may
vary based on local prevalence.
Selective immunological testing (IGRA) for tuberculosis
antigens, performed on whole blood, is an alternative to TST.
IGRA appears to correlate better with recent TB exposure, is
less likely to be affected by prior BCG vaccination, is more spe-
cific, at least as sensitive, is less likely to produce a false-positive
result, and may be a better predictor of progression, compared
to TST [99, 100]. Data in pregnancy are encouraging. A trial in
Kenya of cryopreserved specimens obtained from HIV-positive
pregnant women suggest that positive IGRA testing correlated
strongly with the development of active TB postpartum [101]. A
cross-­sectional study in India showed that more pregnant women
tested positive with IGRA than with TST, which may reflect
higher sensitivity for latent tuberculosis infection [102].
IGRA may be used to screen adults in any situation in which
TST would be considered, including women with prior BCG vac-
cine [94]. Currently there are no studies that strongly support the
use of one test versus the other. While both tests are acceptable
options for the diagnosis of TB, the ability to make a diagnosis in
one visit with the IGRA does provide some logistical advantages.
ATS/IDSA recommends IGRA over TST in populations who are
likely to be infected and are at low to intermediate risk of progres-
sion to active disease. Additionally, IGRA is preferred in those
who have previously received the Bacille Calmette-Guérin (BCG)
vaccination and those who historically have poor rates of return
for TST reading. TST and IGRA are equally preferred in high risk
of progression groups [103].
A positive TST or IGRA should be followed by assessment of
active disease. Chest x-ray and perhaps additional testing is indi-
cated to differentiate latent from active infection, as the therapy is
different. Radiographic findings suggesting tuberculosis include
upper lobe infiltrate, cavitary lesions, and hilar adenopathy. The
screening algorithm is shown in Figure 26.4.

TABLE 26.9: Classification of the Tuberculin Skin Test Reaction

An induration of ≥5 mm is considered An induration of ≥10 mm is considered An induration of ≥15 mm is considered
positive in positive in positive in

• People living with HIV
• Recent contact of a person with
infectious TB disease
• Chest x-ray findings suggestive of
previous TB disease
• Organ transplants
• Other immunosuppressed people (e.g.,
patients on prolonged therapy with
corticosteroids ≥ 15 mg per day of
prednisone or those taking TNF-a
antagonists)
Source: From CDC – https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm – in the public domain.
• People born in countries where TB disease is • No known risk factors for TB
common (including Mexico)
• People who abuse drugs
• Mycobacteriology laboratory workers
• People who live or work in high-risk
congregate settings
• Medical conditions at high risk for TB (e.g.,
diabetes mellitus and severe kidney disease)
• Low body weight (<90% of ideal body weight)
• Children younger than 5 years of age
• Infants, children, and adolescents exposed to
adults in high-risk categories
Respiratory Diseases
Patient with risk factors for LTBI or progression to active tuberculosis
TST/QuantiFERON-TB gold test
Positive
Normal chest X-ray findings/symptoms Abnormal chest X-ray findings/symptoms
Treat for LTBI Evaluate for active TB
FIGURE 26.4 Tuberculosis screening algorithm. (From Ref. [168].) Abbreviations: TB, tuberculosis; LTBI, latent TB infection; TST,
tuberculin skin test; Rx, therapy.
Diagnosis
Diagnosis of latent TB is made when a TST or IGRA is positive,
in the absence of disease (thus no symptoms, x-ray findings sug-
gestive of active disease, bacilli on smear, or positive culture).
Definitive diagnosis of active TB is still made by culture (of sus-
pected site, e.g., sputum) for M. tuberculosis. Sputum culture is
required both for definitive diagnosis and for drug sensitivity test-
ing [96], although both false-positive and false-negative results
have been reported. Growth generally occurs in 7 to 21 days
but may take 6 weeks or longer. The most widely used method
to detect respiratory TB in most disease-endemic countries is
sputum smear microscopy of acid-fast bacilli due to its low cost
and relatively fast speed. Sputum smear can be falsely negative
even in active disease (15–20% of cases). Drawbacks include low
sensitivity (especially in children and in HIV-positive individu-
als), inability to determine drug susceptibility, and variable per-
formance depending on operator training and skill. Additionally,
a fully automated nucleic acid amplification test (NAAT) for TB
case detection with additional rifampin resistance testing. In
a multinational study of about 1500 nonpregnant adults, this
assay identified 98% of patients with smear-positive and culture-­
positive TB (including more than 70% of patients with smear-
negative and culture-positive disease) and correctly identified
98% of bacteria that were resistant to rifampin [104]. The effect
of pregnancy on this test has not been extensively studied, but it
is counterintuitive to assume pregnancy would affect test perfor-
mance. When assessing for active disease, three sputum samples
should ideally be collected for evaluation by all three modalities.
Pregnancy considerations
Tuberculosis attack rates appear to be comparable in the preg-
nant and non-pregnant states. Presentation is similar among
both pregnant and non-pregnant patients, but diagnosis may be
delayed in pregnancy because of the ubiquity of constitutional
complaints during early pregnancy. Pregnancy is not known to
influence the progression from latent to active disease, nor has
it been shown to affect the response to treatment. Pregnancy is
not associated with higher (or lower) prevalence of anergy com-
pared to other HIV-negative adults.
There has been some conflicting data on the effect of TB on
maternal and neonatal outcomes. A meta-analysis of maternal
285
Negative
Contact with person who has active TB
Repeat TST/QuantiFERON-TB gold test after 12 weeks
Positive Negative
High-risk patient
Continue Rx
and neonatal outcomes in active TB patients revealed a significant
increase in maternal morbidity, maternal anemia, cesarean delivery,
preterm birth, low birthweight, birth asphyxia, and neonatal death
[105]. Additionally, several of these outcomes were more pronounced
when treatment was started late in pregnancy. Extrapulmonary TB
was associated with worse outcomes. In a population-based study in
Taiwan, women known to have TB during pregnancy—all of whom
were treated—demonstrated an absolute increase of 2–3% in the rate
of low-birthweight babies, with no difference in preterm births, com-
pared to controls [106]. An earlier case-control study from India sug-
gested higher rates of both preterm birth and small for gestational
age newborns among women undergoing treatment for pulmonary
TB, compared to matched controls [107], but a later Indian case-con-
trol study found no difference in perinatal outcome [108].
Congenital TB, which is very rare, is associated with maternal
HIV infection, tuberculous endometritis, and miliary tuberculo-
sis [109]. It can occur hematogenously via the placenta and umbil-
ical vein or by fetal aspiration or ingestion of infected amniotic
fluid. Neonatal TB develops following exposure of an infant to
the mother’s aerosolized respiratory sections. This is more com-
mon than congenital TB, and diagnosis of neonatal TB can lead
to diagnosis of previously unrecognized TB in the mother [110].
Pregnancy management
Principles
Management of M. tuberculosis infection in pregnancy should
be multidisciplinary, with involvement of obstetrician, maternal-
fetal medicine, and infectious diseases specialists.
Management
Prevention
The BCG vaccine is a live attenuated vaccine commonly admin-
istered at birth for the prevention of TB. When administered
to TB-naïve children, BCG vaccine prevents >70% M. tuber-
culosis infections and reduces >85% of TB death in children
[111]. Although the efficacy of the BCG vaccine begins to decline
after 15–20 years, several studies have shown that partial protec-
tion may last for several decades [112, 113]. Large-scale studies of
booster BCG vaccines have not shown any benefit towards pre-
vention of TB [114, 115]. BCG should not be administered during
pregnancy due to theoretical re-activation.
286
People living with HIV (PLHIV) are at significantly increased
risk for active TB. The WHO recommends that PLHIV who are
TST unknown or positive with low likelihood of active TB should
complete TB preventative therapy regardless of immunosuppres-
sion, highly active anti-retroviral therapy (HAART) participa-
tion, or prior TB treatment [116]. Recommended preventative
therapy is daily isoniazid for at least 36 months. A meta-analysis
of isoniazid preventative therapy identified a 35% reduction in
TB across all HIV patients and a 52% pooled relative risk reduc-
tion in TB in TST-positive HIV patients [117]. However, a recent
randomized control trial published after the WHO guidelines
assessing timing of initiation of preventative therapy in PLHIV on
HAART found that postpartum initiation was non-inferior and
led to less hepatotoxicity than initiation at 28 weeks [77]. These
findings suggest that patients with HIV on HAART may consider
deferring treatment to postpartum if not already started on pre-
ventative therapy when pregnancy is detected.
Therapy
Latent tuberculosis infection
For most patients, treatment of latent TB should be deferred 2–3
months postpartum. Patients at high risk for activation of latent
TB, such as recently exposed and HIV positive patients should
undergo treatment of latent TB during pregnancy. These groups
are also at increased risk for transplacental spread of tubercle
bacilli and thus for congenital tuberculosis, which implies that
treatment for latent infection in these cases should be especially
expeditious and compliant. Advantages of beginning treatment
during pregnancy include better compliance and less loss to fol-
low-up. When possible, treatment should ideally be completed
prior to pregnancy. A decision analysis suggests that antepartum
treatment of latent tuberculosis infection is more efficient at pre-
venting additional cases of TB within the population [118].
The preferred treatment for latent tuberculosis infection in
pregnancy is isoniazid 5 mg/kg up to 300 mg daily for 6–9
months [110]. An alternative twice weekly isoniazid regimen
(15 mg/kg up to 900 mg) can be used but must be performed
under directly observed therapy (DOT). Coadministration of
Pyridoxine 25–50 mg/day is advisable because isoniazid can
interfere with pyridoxine metabolism and thereby precipitate
peripheral neuropathy. Isoniazid is 60%–90% effective in reduc-
ing the risk of progression from tuberculosis latent infection to
active disease. The most important but rare (1/1000) side effect
of isoniazid is drug induced hepatotoxicity; the concern that this
may be more common among pregnant women (which prompted
a consideration of routinely deferring treatment to the puerpe-
rium) is based on a single investigation in which five cases of
isoniazid hepatitis were identified among nearly 4000 pregnant
women [119]: Statistical significance was absent. Age >35 years
is no longer considered a contraindication to isoniazid use [98].
Pregnant and postpartum women should have pretreatment
liver transaminases and bilirubin function tests, and if these
are normal, isoniazid can be started. Liver function tests should
be obtained monthly. Isoniazid should be discontinued in a
symptomatic or jaundiced patient if alanine aminotransferase
(ALT) is more than three times the upper limit of normal, and in
an asymptomatic patient if ALT is more than five times the upper
limit of normal [120].
Alternative regimens are not well studied in pregnancy. A
4-month course of daily rifampin, (3–4)-month course of daily
isoniazid/rifampin, and 3-month course of weekly isoniazid/
Maternal-Fetal Evidence Based Guidelines
rifapentine all showed similar rates of reduction in progression
to active TB in largely non-pregnant patients [121]. Rifampin has
been well tolerated in pregnancy in treatment of active disease
and may be considered for treatment of latent TB when isoniazid
is poorly tolerated. A recent examination of 126 pregnancies with
accidental exposure to a 3-month course of isoniazid/rifapentine
found similar rates of pregnancy loss and congenital malforma-
tions [122]. While this may become a future treatment strategy in
pregnancy due to its shorter course, there is not enough data to
currently support this treatment regimen in pregnancy.
Active tuberculosis infection
Tuberculosis treatment is not altered by pregnancy. Although
latent TB treatment may be deferred to the postpartum period,
there is no defensible argument for deferring treatment of
active disease during pregnancy. Pregnant women who are
untreated pose an infection risk to the population at large as well
as to their own infants. To guide treatment, sputum samples for
smear microscopy and culture should be obtained at monthly
intervals until two consecutive negative months are observed.
Monotherapy is not recommended for active TB due to
rapid progression of drug resistance. Combination therapy for
six months or more can cure >95% of patients (Tables 26.10 and
26.11) [99]. The treatment regimen is two-part. The initial inten-
sive phase kills actively growing bacilli, shortening the time the
individual is infectious to others. The following continuation
phase is aimed at microbiologic cure. The preferred treatment
for new patients with active TB is an initial two-month phase
of isoniazid, rifampin, pyrazinamide, and ethambutol. Drugs
may be given as fixed-dose combinations. Strict adherence to the
regimen is important in minimizing drug resistance; for this rea-
son, directly observed therapy is usually recommended. For the
following 4 months, isoniazid and rifampin are continued. In
settings where isoniazid resistance is high and the patient’s strain
of TB has not been tested for isoniazid resistance, the 4-month
continuation phase should also include ethambutol. The CDC
differs from WHO recommendations due to unknown effects
of pyrazinamide during pregnancy. The CDC recommends a
2-month intensive phase of isoniazid, rifampin, and ethambu-
tol followed by a 7-month continuation phase of Isoniazid and
rifampin. However, ATS/IDSA recommend individualized dis-
cussion regarding risks and benefits of including Pyrazinamide
given widespread use globally and endorsement by WHO [123].
Treatment regimens and alternatives are available from the
Centers for Disease Control and Prevention, the American
Thoracic Society, the National Institute for Clinical Excellence,
and the WHO. Those interested in these topics may bookmark
the CDC’s Find TB Resources website at https://findtbresources.
cdc.gov/, which contains links to these sites.
TABLE 26.10: Recommended Daily Doses of First-Line Anti-
Tuberculosis Pharmacotherapy (Adults)
Isoniazid 4–6 mg/kg Maximum 300 mg
Rifampin 8–12 mg/kg Maximum 600 mg
Pyrazinamide 20–30 mg/kg
Ethambutol 12–18 mg/kg
Source: From Ref. [166], with permission.
Daily dosing is optimal. Dosing three times a week instead of daily is an alternative
for HIV-negative patients, assuming that therapy is directly observed. In the case of
three times weekly treatment, doses of isoniazid, pyrazinamide, and ethambutol are
higher than listed here.
Respiratory Diseases 287

TABLE 26.11: WHO-Recommended Tuberculosis Treatment Regimens

Tuberculosis Treatmenta
Treatment Category Patients Initial Phase Continuation
I New cases of smear-positive pulmonary TB; or 2 mo H3R3Z3E3 or 2 mo 4 mo H3R3
severe extrapulmonary TB; or severe H3R3Z3S3
smear-negative pulmonary TB; or severe
concomitant HIV disease
II Previously treated smear-positive pulmonary 2 mo HRZE or 2 mo 4 mo HR
TB; relapse; treatment failure; treatment after HRZS
default
2 mo H3R3Z3E3S3/1 mo 5 mo
H3R3Z3E3
H3R3E3
III New cases of smear-negative pulmonary TB, or 2 mo HRZES/1 mo 5 mo HRE
with less severe forms of extrapulmonary TB HRZE
2 mo H3R3Z3E3 4 mo H3R3
4 mo HR
Source: Compiled from Ref. [166].
a Subscript refers to the number of doses per week; for daily dosing, no subscript.

Abbreviations: H, Isoniazid; R, rifampicin; Z, Pyrazinamide; S, streptomycin; E, Ethambutol.

Drug resistance tuberculosis gateway that provides links to epidemiology and to

Multi drug-resistant (MDR) TB—resistant to isoniazid and
rifampin—accounts for about 1% of isolates in the United States
in 2019 [124]. Worldwide, MDR TB and rifampin-resistant TB
accounted for 3.4% of new cases and 18% of previously treated cases,
although in some areas of the Russian Federation >50% of previ-
ously treated TB is at least rifampin resistant [95]. Approximately
5–10% of MDR TB strains are believed to be extensively drug-
resistant (XDR): Resistant to isoniazid, rifampin, one fluoroqui-
nolone, and one of three injectable second-line agents. Pregnant
women with MDR TB should be treated despite the limited safety
data because of the grave health and public health implications.
TB strains that are known to be resistant to one or more of the
first-line drugs are treated with alternative agents, for example,
capreomycin, cycloserine, fluoroquinolones, para-aminosalicy-
late, thiacetazone, amoxicillin-clavulanic acid, clofazimine, or
clarithromycin. Most second-line agents are Category C with the
exception of bedaquiline and Meropenem which are Category B
and aminoglycosides which are Category D. Kanamycin, strepto-
mycin, and amikacin, which are ototoxic, have been associated
with hearing loss in newborns whose mothers were treated during
pregnancy. Ethionamide not only worsens nausea associated with
pregnancy but has also been associated with congenital anoma-
lies in animal studies: The WHO recommends against its use in
pregnancy, if possible [101]. For all the second-line drugs, well-
designed controlled studies in pregnant women are unavailable.
The literature on treatment of drug-resistant TB during preg-
nancy is limited to case reports or case series [102–105]. Therapy
of MDR TB during pregnancy should be driven by microbiologic
susceptibility patterns (obtained by direct culture or local anti-
biograms) modified where possible by fetal concerns. The WHO
suggests that treatment of drug-resistant TB may be delayed until
the second trimester after a discussion with the patient of the
risks and benefits. The individual practitioner is unlikely to make
independent decisions about the treatment of MDR TB, as this
is a role commonly filled by the health authority. More extensive
discussion of MDR/XDR TB treatment can be found under the
ATS/IDSA treatment guidelines [123]. The WHO maintains a
treatment of tuberculosis: www.who.int/tb/en/.
Coinfection with TB and HIV during pregnancy
This is a large and growing public health problem, directly affect-
ing global maternal mortality [106], which is nevertheless beyond
the scope of this chapter. The interested reader is referred to a
review of the topic [125] and to online resources at CDC (www.
cdc.gov/tb/default.htm).
Infection control issues
Women with active pulmonary tuberculosis are infectious, but
if the organism is sensitive, 2 weeks of multidrug therapy ren-
ders them noninfectious, so special precautions are not neces-
sary thereafter. If the duration of therapy is shorter, or if MDR
tuberculosis is present or suspected, the mother must be isolated
in a negative pressure room for labor, and personal protective
equipment should be worn by staff. Measures for the infant may
include prophylactic Isoniazid, BCG vaccination, or—in cases of
MDR or XDR tuberculosis—separation from the mother.
Antepartum testing
No specific indication.
Delivery
Cord blood and placenta should be tested for acid-fast bacilli.
Postpartum/Breastfeeding
Maternal tuberculosis treatment is not altered by breastfeed-
ing. Pyridoxine (1–2 mg/kg/day) should be administered to the
breastfeeding infant even if the infant is not receiving Isoniazid
therapy [108, 110]. Neonate should undergo TST, chest x-ray, lum-
bar puncture, and M. tuberculosis smear and culture if mother
had TB during pregnancy. If TB is suspected in the child, the
child should be adequately treated.
288
COVID-19
Key points
• At the time of publication, the SARS-CoV-2 pandemic was
still rapidly evolving. Refer to national and international
guidelines to find the most up to date information regard-
ing prevention, treatment, and management.
• The destruction of the endothelium of pulmonary capil-
laries causes significant recruitment of macrophages and
neutrophils, resulting in a characteristic pulmonary edema
and development of acute respiratory distress syndrome
(ARDS).
• Pregnancy is a risk factor for requiring more intensive
care, mechanical ventilation and perhaps maternal death
compared to non-pregnant women. Once infected, the
severity of disease peaks about 7–10 days after onset of
symptoms.
• Nucleic acid amplification testing (NAAT) to detect
viral RNA has become the most common means of rapid
diagnosis.
• Preterm delivery is 3 times higher in COVID-positive
mothers compared to COVID-negative mothers, especially
those with severe or critical COVID-19 infection.
• Patients should be counseled on preventative measures
including wearing face masks, social distancing, and
avoiding contact with COVID-positive or suspected
cases.
• Universal rapid testing should be considered a priority for
admitted mothers to labor and delivery given implications
for healthcare workers as well as for neonates.
• COVID-19 transmission to the neonate following delivery
is overall rare (about 2–3%) and is rarely symptomatic; it
seems to have no perinatal consequences.
• Women planning to conceive, pregnant, and post-
partum even while breastfeeding should be actively
encouraged to get vaccinated. Most pregnancy safety
data available as of this writing come from the messen-
ger ribonucleic acid (mRNA) vaccines from Pfizer and
Moderna.
For the most up to date information:
• ht t p s ://w w w.who .int /e me r ge nc i e s/di s e a s e s/nove l -
coronavirus-2019
• https://www.cdc.gov/coronavirus/2019-ncov/index.html
• https://www.nih.gov/coronavirus
Epidemiology
In late 2019 a novel respiratory virus was reported in main-
land China. Now known as Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2), the virus rapidly spread globally
with millions infected within a few short months. At the time
of publication, the virus has spread to every continent except for
Antarctica. Within the first 10 months of the pandemic, approx-
imately 37 million confirmed cases and over 1 million deaths
were reported. These figures likely underrepresent the true
burden of disease. One seroprevalence study in the United States
found that actual infection rates were 6 to 24 times the reported
case totals [126].
Maternal-Fetal Evidence Based Guidelines
Etiology/Basic pathophysiology
SARS-CoV-2 is a single-stranded RNA virus, which enters host
cells via the angiotensin converting enzyme-2 (ACE2) receptor
[127]. The virus initially infects epithelial cells of the nasal and
bronchial surfaces as well as pneumocytes. Replication continues
in lymphocytes, causing profound lymphopenia as well as endo-
thelial cells, leading to destruction of the epithelial-endothelial
layer. The destruction of the endothelium of pulmonary capil-
laries causes significant recruitment of macrophages and neu-
trophils, resulting in a characteristic pulmonary edema and
development of acute respiratory distress syndrome (ARDS)
[128]. Severe infection is complicated by activation of the coagu-
lation cascade, which results in microthrombi across the body.
This has led to increased rates of deep venous thrombosis, pul-
monary embolism, and arterial thrombotic complications. One
study in examining fatalities in Wuhan found that 71% met crite-
ria for disseminated intravascular coagulation [129].
The spectrum of disease caused by SARS-CoV-2 virus is
referred to as coronavirus disease 2019 (COVID-19). The pri-
mary mode of transmission is person-to-person. Infection spreads
mainly via respiratory droplets, direct contact, and indirect
contact (via fomites). When spread via respiratory droplets, most
transmission occurs within 6 feet, although some cases have
been reported at longer distances in enclosed spaces [130]. The
incubation period from time of exposure to symptom onset is
approximately 5 days, with 99% of cases reporting symptoms
within 2 weeks of exposure [131]. Once symptoms begin, most
patients are infectious for about 7–10 days. However, approxi-
mately 44% of cases are transmitted prior to symptom onset,
starting up to 12 days prior to symptom onset [132]. While pri-
marily a pulmonary disease, secondary renal and hepatic damage
are common in severe disease [133, 134].
Symptoms
Approximately 15.6% of patients infected with SARS-CoV-2 are
asymptomatic at time of diagnosis [135]. However, about half of
patients who are asymptomatic at time of diagnosis may develop
symptoms in the future. Most patients develop symptoms
2–14 days following exposure. The most common symptoms of
COVID-19 are fever (83.3%), cough (60.3%), and fatigue (38.0%)
[136]. Other commonly reported symptoms include chills, short-
ness of breath, muscle or body aches, headache, anosmia, ageusia,
sore throat, congestion, nausea, vomiting, and diarrhea.
Risk factors/Associations
Several risk factors for severe disease have been well documented
that do not apply to the pregnant population including male sex and
age >65 [137]. Comorbid conditions associated with severe disease
include cardiovascular disease, diabetes mellitus, smoking, obesity,
chronic kidney disease, chronic lung disease, cancer, organ trans-
plant, and sickle cell disease [138, 139]. Pregnancy may not be a risk
factor for acquiring COVID-19 but may be a risk factor for requiring
more intensive care compared to non-pregnant women [140].
Diagnosis
COVID-19 symptoms are often non-specific and can present
similarly to other viral respiratory infections such as influenza
and respiratory syncytial virus (RSV). Laboratory and imaging
Respiratory Diseases
findings may aid in diagnosis when there is a clinical suspi-
cion for COVID-19. COVID-19 is associated with elevations in
CRP, LDH, ESR, and bilirubin. Lymphopenia, leukopenia, and
hypoalbuminemia have also been reported [141]. Radiologic
findings, when present, most commonly present as bilateral
multi-lobar ground glass opacification [142]. When seen on
CT, lesions are commonly located peripherally or posteriorly.
These findings on CT scan are highly sensitive (91.9%) but lack
specificity (25.1%) [143].
There have been numerous diagnostic tests developed by pri-
vate companies and government agencies worldwide with varying
degrees of accuracy. There currently is no gold standard diagnos-
tic test for COVID-19, although NAAT to detect viral RNA has
become the most common means of rapid diagnosis. Sample
sites include the sputum, nasopharynx, throat, saliva, urine,
stool, and blood. Nasopharyngeal swab displays high levels of
sensitivity when compared to other sample sites, although ante-
rior nares, oropharyngeal, saliva, and mid-turbinate swabs are
acceptable depending on type of test used [144, 145]. NAAT usu-
ally results in 15 minutes to 8 hours, although turnaround time
is dependent upon laboratory capacity and volume. Accuracy of
testing varies across different NAAT used globally, but sensitivity
and specificity are high (>95% and >99%, respectively) [146, 147].
Viral RNA—and thus a positive NAAT—may persist for up to 6
weeks following symptom onset, although infectiousness does
not necessarily persist over this time period [148].
Antigen tests have additionally been developed with the goal
of providing rapid, point-of-care testing. Antigen-based testing
has had mixed results, with poor average sensitivity of 56% (range
0–94%) but with excellent sensitivity (99.5%) [146]. However, anti-
gen-based testing may improve over time and provide a low-cost,
rapid alternative to NAAT.
Pregnancy considerations
Data on COVID effects on pregnancy continues to evolve. One
initial report estimated a higher incidence of infection in preg-
nant patients compared to other reproductive-age females (9%
vs. 5%) [149]. However, these figures likely over-estimate the pro-
portion of pregnant patients as universal testing was adopted at
many labor and delivery units, pregnancy information was miss-
ing from a large proportion of patients, and pregnant patients
have significantly more interaction with the healthcare system
than other women of childbearing age. When pregnant women
do contract COVID-19, they may be at increased risk for
ICU admission and invasive mechanical ventilation [140].
Co-morbid conditions including obesity, hypertension, pre-ges-
tational diabetes, and advanced maternal age increased the risk
of severe disease. The effect on mode of delivery is unclear. A
meta-analysis examining mode of delivery varied significantly by
region. Cesarean delivery was performed in 90% of Chinese, 40%
of U.S., and 38% of European COVID-positive deliveries [150].
It is unclear whether these differences highlight regional differ-
ences in mode of delivery or severity of infection. Preterm deliv-
ery was 3 times higher in COVID-positive mothers compared
to COVID-negative mothers. Higher rates of low-birthweight
neonates have also been reported, although it is unclear if this
is solely due to prematurity or other factors [150]. NICU admis-
sion occurred in 25% of COVID-positive deliveries, elevated from
baseline. This may be in part due to increased rates of preterm
delivery and voluntary separation rather than neonatal effects
from possible COVID infection [140]. Death from COVID-19
289
infection may be higher for a pregnant woman than a similar
non-pregnant woman [140, 150].
Vertical transmission
The risk of vertical transmission seems to be small. Of 936 neo-
nates born to COVID-positive mothers, approximately 3.2% were
found to have positive nasopharyngeal NAAT [151]. There were
2.9% found to have positive serologic NAAT. In cases where verti-
cal transmission has been suspected, there does not seem to be
significant short-term neonatal effects. The possible long-term
complications from intra-uterine transmission are still unknown.
Management
Prevention
Vaccine
Women planning to conceive, pregnant—in any trimes-
ter—and postpartum even while breastfeeding should be
actively encouraged and recommended to get vaccinated
for COVID-19 infection. At the time of publication, several
dozen COVID-19 vaccines are currently in varying stages of
development. While vaccine development usually takes years,
several vaccines were approved for use globally within the first
year of COVID-19. The long-term impact regarding side effects,
adverse events, and immunity will likely be largely unknown,
in part due to this expedited process. Most pregnancy safety
data available as of this writing come from the messenger
ribonucleic acid (mRNA) vaccines from Pfizer and Moderna.
mRNA is quickly metabolized in human cells after stimulat-
ing antibody production. As a result, mRNA never enters the
nucleus and therefore does not change maternal or fetal genetic
material. Moreover, greater than 30,000 pregnancies have been
self-reported to the CDC’s V-safe After Vaccination Health
Checker as of this writing. This registry has data on 275 com-
pleted pregnancies [152]. The CDC’s Vaccine Adverse Event
Reporting System (VAERS) has data on 154 pregnancies. No
excess in side effects or adverse events has been observed com-
pared with the CDC national birth data.
Masking and physical distancing
Prevention of transmission is one of the best methods of
reducing mortality and morbidity. Several behavioral, com-
munity, and institutional practices have been adopted to reduce
the likelihood of transmission. Patients should be counseled on
preventative measures including wearing face masks, physi-
cal distancing, and avoiding contact with COVID-positive or
suspected cases. A meta-analysis of different behavioral meth-
ods found that consistent face mask usage resulted in significant
reduction in risk of transmission (OR = 0.15). More significant
associations were identified with medical masks and N95 respira-
tors [153]. However, one meta-analysis of face mask usage found
no difference in viral transmission (including COVID-19) when
comparing medical masks to N95 respirators, suggesting that N95
may not be specifically necessary for healthcare workers [154].
Prevention of transmission of infectious particles is maximized
when wearing a non-medical mask over a medical mask and per-
forming knot tying of the ear loops proximal to the mask [155].
When possible, patients should remain at least 6 feet from other
individuals per CDC guidelines. Physical distancing reduces risk
of transmission (OR = 0.18) at 1-meter separation, with increasing
effectiveness at greater distances [153]. If a patient does come into
contact with a known COVID case, she should self-quarantine for
290 Maternal-Fetal Evidence Based Guidelines

14 days. Testing can be performed at 5–7 days after contact, but
negative testing does not shorten quarantine.
Screening
All levels of care including outpatient antepartum care, inpatient
antepartum care, labor and delivery, and inpatient postpartum
should screen for COVID-19. Screening at minimum may include
a symptom and contact screen. Universal rapid testing should be
considered a priority for admitted mothers to labor and deliv-
ery given implications for healthcare workers as well as for
neonates. The labor process is naturally an aerosolizing procedure
given the amount of exertional effort required to have a vaginal
delivery and various breathing techniques commonly employed.
In one prospective cohort study, 78.6% of COVID-positive patients
identified through universal screening at a New York City labor
and delivery were asymptomatic at time of diagnosis [156].
Classification
Illness severity is classified according to NIH guidelines and
adapted in Table 26.12 [157]. Management and therapy should be
tailored to disease classification. Classification is independent of
pregnancy.
Therapy
Treatment strategies for COVID-19 are currently in development.
Evidence for the use of these strategies is largely based on stud-
ies among the general population without many or any pregnant
patients. Comprehensive discussion of known and unknown risks
and benefits of any treatment strategy with respect to maternal
and fetal effects should occur. However, the National Institutes of
Health (NIH) recommends that no potential treatment be with-
held due to theoretical concerns for safety. Treatment of any
patient with moderate illness should be in conjunction with an
infectious disease physician, maternal fetal medicine physician,
and/or critical care physician. NIH treatment guidelines are sum-
marized in Figure 26.5.
Antiviral therapy
Remdesivir is an IV prodrug of an adenosine analog, which binds
the viral RNA-dependent RNA polymerase to inhibit replication.
Remdesivir is available through Emergency Use Authorization
(EUA) by the FDA and supply is limited globally. A large RCT
identified shorter time to clinical recovery compared to pla-
cebo (11 days vs. 15 days) [158]. A post-hoc analysis suggested that
there may be a survival benefit for this group. When supplemen-
tary oxygen is required via a high-flow device, non-invasive venti-
lation, or invasive mechanical ventilation, Remdesivir should only
be administered in combination with dexamethasone and not as
mono-therapy. Optimal duration of treatment is not clear, though
5 and 10-day courses have been proposed. Gastrointestinal side
effects including nausea, vomiting and diarrhea are most com-
mon. Dosing is suggested at 200 mg IV over 30–120 minutes for
1 dose, followed by 100 mg IV on day 2 onwards. Transaminase
elevations may occur. Additionally, PT prolongation may occur.
The drug vehicle, SBECD may cause renal toxicity. Both liver
and renal function tests should be collected prior to initiation of
therapy and should be evaluated during the treatment course.

TABLE 26.12: NIH COVID-19 Severity Classification

Illness Severity Features
Asymptomatic/Pre-Symptomatic None
Mild Illness Fever, cough, sore throat, malaise,
headache, muscle pain, nausea,
vomiting, diarrhea, loss of taste/smell
Moderate Illness Features of mild illness with
shortness of breath, dyspnea
Evidence of lower respiratory tract
disease on exam or imaging.
Severe Illness Same as Moderate Illness
Critical Illness May be associated with ARDS, septic
shock, distributive shock, cardiac
dysfunction, elevation of
inflammatory cytokines. Cardiac,
hepatic, renal, central nervous
system, or thrombotic
complications may occur
Persistent Symptoms/Illness Persistent symptoms including
after Recovery fatigue, joint pain, chest pain,
palpitations, shortness of breath,
worsened quality of life, anxiety,
and depression that persist beyond
post-intensive care syndrome seen
in patients without COVID-19
Source: From Ref. [157] in the public domain.
Respiratory Function
Normal
Do not have shortness of breath,
dyspnea, or abnormal imaging
Evidence of lower respiratory
tract disease on exam or
imaging. SpO2 values remain
≥94%
SpO2 values <94% on room air,
PaO2/FiO2 <300 mmHg,
respiratory rate >30 breaths/
min, lung infiltrates >50%
Possible permanent loss of
pulmonary function
Treatment
Expectant management,
quarantine
Outpatient supportive care
Close monitoring is
recommended. If bacterial
pneumonia/sepsis are suspected,
administer empiric antibiotics.
Supplemental oxygen,
Dexamethasone, Remdesivir
Mechanical ventilation,
dexamethasone, tocilizumab,
avoid remdesivir if mechanical
ventilation
Expectant management,
pulmonary rehabilitation, lung
transplant in most severe cases
Respiratory Diseases 291

DISEASE SEVERITY PANEL'S RECOMMENDATIONS

There are insufficient data to recommend either for or against any

specific antiviral or antibody therapy. SARS-CoV-2 neutralizing
antibodies (bamlanivimab or casirivimab plus imdevimab) are
Not Hospitalized, available through EUAs for outpatients who are at high risk of
Mild to Moderate COVID-19 disease progression.a
The Panel recommends against the use of dexamethasone or
other corticosteroids (AIII).b

The Panel recommends against the use of dexamethasone (Alla)

Hospitalized but Does Not Require
Supplemental Oxygen
or other corticosteroids (AIII).b
There are insufficient data to recommend either for or against the
routine use of remdesivir. For patients at high risk of disease
progression, the use of remdesivir may be appropriate.

Use one of the following options:

Hospitalized and Requires
Supplemental Oxygen
(But Does Not Require Oxygen Delivery
Through a High-Flow Device,
Noninvasive Ventilation, Invasive
Mechanical Ventilation, or ECMO)
• Remdesivirc,d (e.g., for patients who require minimal
supplemental oxygen) (BIIa)
• Dexamethasonee plus remdesivirc,d (e.g., for patients who
require increasing amounts of supplemental oxygen) (BIII)f,g
• Dexamethasonee (e.g., when combination therapy with
remdesivir cannot be used or is not available) (BI)

Hospitalized and Requires Oxygen Use one of the following options:

Delivery Through a High-Flow Device • Dexamethasonee,g (AI)
or Noninvasive Ventilation • Dexamethasonee plus remdesivirc,d (BIII)f,g

Hospitalized and Requires Invasive

Dexamethasonee (AI)h
Mechanical Ventilation or ECMO

FIGURE 26.5 Pharmacologic treatment of COVID-19 based on disease severity. (From Ref. [157], in the public domain.)
Abbreviations: Rating of recommendations: A, strong; B, moderate; C, optional. Rating of evidence: I, one or more randomized trials
without major limitations; IIa, other randomized trials or subgroup analyses of randomized trials; IIb, nonrandomized trials or obser-
vational cohort studies; III, expert opinion. ECMO, extracorporeal membrane oxygenation.

Several other antiviral medications have been proposed.
Chloroquine and hydroxychloroquine with or without azithro-
mycin were not found to decrease mortality and moreover were
associated with an increased median hospital stay compared to
standard of care at that time. Patients were also more likely to
require mechanical intubation and die [153]. These treatment
strategies are not recommended for treatment of COVID-19.
Immune-based therapy
Immunomodulatory medications are the most effective treatment
for moderate to critical illness, targeting the significant inflam-
matory response that often leads to ARDS and death in severe
COVID-19 infections. The only current immunomodulatory
agent approved for COVID-19 treatment is dexamethasone. A
randomized control trial in the UK showed a significant reduc-
tion in mortality for patients requiring mechanical ventilation
(29.1% vs. 41.4%). A smaller, but still significant reduction in mor-
tality was seen for patients requiring oxygen supplementation
but not requiring mechanical ventilation (23.3% vs. 26.2%) [159].
Dexamethasone however should not be used in patients who do
not require supplemental oxygen. Prednisone, methylpredniso-
lone, or hydrocortisone can all be considered as alternatives to
dexamethasone when dexamethasone is not available. When
used as alternatives these steroids can reduce fetal exposure to
glucocorticoids compared to dexamethasone, but mortality ben-
efit is less clear. Dosing for dexamethasone is 6 mg IV or oral daily
for up to 10 days, though fetal lung maturity dosing (6 mg every
12 hours for 4 doses) followed by standard dosing can be consid-
ered if steroids for fetal lung maturity are indicated.
Tocilizumab is an anti-interleukin-6 (IL-6) receptor anti-
body which may be beneficial for a limited group of patients.
Tocilizumab has been shown to improve survival and reduce hos-
pital stay length in critically ill patients [160, 161]. Patients show-
ing rapid decline in pulmonary function should be considered
candidates for tocilizumab therapy. A single IV dose of 8 mg/kg
of actual body weight up to 800 mg in combination with standard
292
dexamethasone should be considered. There is insufficient safety
data for tocilizumab in pregnancy.
Several immune therapies are currently being evaluated for use.
Convalescent plasma is currently the most common immune-
based therapy utilized and is available under EUA. Convalescent
plasma is derived from plasma from individuals with previously
laboratory-confirmed COVID-19, containing antibodies with
potential activity against SARS-CoV-2. Preliminary data is over-
all mixed and of low-quality. Some studies have shown a mor-
tality benefit. The largest study to date of convalescent plasma
recruited over 56,000 patients and identified a 7-day 21% mor-
tality reduction when low antibody titer plasma was used and a
45% mortality reduction when high antibody titer plasma was
initiated within 72 hours of diagnosis. Additionally, safety data
from this study was overall reassuring with low rates of adverse
reactions [162].
Adjunctive therapy
As noted earlier, patients with COVID-19 have been shown to be
at risk for thromboembolic events. Pregnancy is a pro-thrombotic
state. However, no high-quality studies have examined thrombopro-
phylaxis in pregnancy with COVID-19. Thromboprophylaxis should
be initiated for the same reasons as non-pregnant patients admitted
to the hospital. Antithrombotic therapy started for other indications
should be continued if diagnosed with COVID-19. Routine antico-
agulation is not recommended but may be considered for patients
at high risk of venous thromboembolic events or are critically ill.
Low-molecular weight heparin is preferred in pregnancy.
Antepartum testing
No specific indication.
Delivery
Labor and delivery policies to reduce transmission
As discussed previously, a significant number of pregnant
women are potentially asymptomatic carriers of SARS-CoV-2.
Additionally, delivery is a potentially aerosolizing process
whether delivery mode is vaginal or cesarean. Policies should aim
to reduce transmission to healthcare workers and transmission to
patients. These policies should include evidence-based commu-
nity strategies such as hand hygiene, face mask usage when pos-
sible, and social distancing. Social distancing within labor and
delivery has been controversial as many labor and delivery units
have opted to reduce support persons or ban them completely.
Labor and delivery units should form policies to encourage social
distancing while recognizing the known benefits of support per-
sons during the labor process.
Prior to scheduled admission for cesarean delivery, induction
of labor, or other obstetric indications, patients should be tested
for COVID-19. When patients are admitted unexpectedly (in labor,
rupture of membranes, etc.), universal screening with rapid testing
should be considered if testing resources are available.
In general, delivery timing should be determined by maternal
indications and not necessarily changed by COVID-19 diagnosis.
Postpartum/Breastfeeding
In the early stages of the pandemic, several guidelines called for
limited maternal contact with the newborn in an abundance
of caution when neonatal effects were still largely unknown.
Maternal-Fetal Evidence Based Guidelines
Growing evidence now suggests that COVID-19 transmission
to the neonate following delivery is overall rare (about 2–3%)
and is rarely symptomatic [163]. As a result, recommendations
limiting contact were largely curtailed. While efforts should be
made to reduce overall contact by maintaining 6 feet of distance
when possible, wearing a face mask, and using hand hygiene, the
patient should be enabled to perform skin-to-skin and room-
in if she is healthy enough to care for her newborn independently.
It is unclear whether SARS-CoV-2 may be transmitted via breast
milk. A WHO case series identified SARS-CoV-2 viral particles in
3 of 46 mother-infant dyads. 1 of 3 of those neonates developed
COVID-19, though the source of infection is unclear (vertical
transmission, respiratory droplets, etc.) [164]. Additionally, the
presence of viral RNA does not necessarily demonstrate that
infectious particles are transmitted. The American Academy
of Pediatrics (AAP) recommends that COVID-positive mothers
who desire breastfeeding continue to breastfeed given the known
benefits [165]. When breastfeeding occurs, the mother should
wear a medical mask and perform hand hygiene.
References
1. Kwon HL, Triche EW, Belanger K, Bracken MB. The epidemiology of asthma
during pregnancy: prevalence, diagnosis, and symptoms. Immunol Allergy
Clin North Am 2006;26(1):29–62. [III]
2. National Asthma Education and Prevention Program. Expert panel report
3: guidelines for the diagnosis and management of asthma: National Heart
Lung and Blood Institute. 2007 August. [Guideline]
3. Tata LJ, Lewis SA, McKeever TM, Smith CJ, Doyle P, Smeeth L, et al. A
comprehensive analysis of adverse obstetric and pediatric complications in
women with asthma. Am J Respir Crit Care Med 2007;175(10):991–7. [II-3]
4. Mendola P, Laughon SK, Männistö TI, Leishear K, Reddy UM, Chen Z,
et al. Obstetric complications among US women with asthma. Am J Obstet
Gynecol 2013;208(2):127.e1–e8. [II-3]
5. Enriquez R, Wu P, Griffin MR, Gebretsadik T, Shintani A, Mitchel E, et al.
Cessation of asthma medication in early pregnancy. Am J Obstet Gynecol
2006;195(1):149–53. [II-2]
6. Murphy V, Namazy J, Powell H, Schatz M, Chambers C, Attia J, et al.
A meta‐analysis of adverse perinatal outcomes in women with asthma.
BJOG 2011;118(11):1314–23. [II-2]
7. Murphy V, Wang G, Namazy J, Powell H, Gibson P, Chambers C, et al.
The risk of congenital malformations, perinatal mortality and neonatal
hospitalisation among pregnant women with asthma: a systematic review
and meta‐analysis. BJOG 2013;120(7):812–22. [II-1]
8. Namazy JA, Murphy VE, Powell H, Gibson PG, Chambers C, Schatz M.
Effects of asthma severity, exacerbations and oral corticosteroids on peri-
natal outcomes. Eur Respir J 2013;41(5):1082–90. [II-2]
9. Schatz M, Dombrowski M, Wise R, Momirova V, Landon M, Mabie W, et al.
The relationship of asthma medication use to perinatal outcomes. J Allergy
Clin Immunol 2004;113(6):1040–5. [II-2]
10. Bakhireva LN, Schatz M, Jones KL, Chambers CD, Group OoTISCR. Asthma
control during pregnancy and the risk of preterm delivery or impaired fetal
growth. Ann Allergy Asthma Immunol 2008;101(2):137–43. [II-3]
11. Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W,
et al. Spirometry is related to perinatal outcomes in pregnant women with
asthma. Am J Obstet Gynecol 2006;194(1):120–6. [II-3]
12. Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer
BP. Asthma symptoms, severity, and drug therapy: a prospective study of
effects on 2205 pregnancies. Obstet Gynecol 2003;102(4):739–52. [II-2]
13. Olesen C, Thrane N, Nielsen GL, Sørensen HT, Olsen J. A population-based
prescription study of asthma drugs during pregnancy: changing the inten-
sity of asthma therapy and perinatal outcomes. Respiration 2001;68(3):
256–61. [II-2]
14. Cydulka RK, Emerman CL, Schreiber D, Molander KH, Woodruff PG, Camargo
Jr CA. Acute asthma among pregnant women presenting to the emergency
department. Am J Respir Crit Care Med 1999;160(3):887–92. [II-3]
15. Schatz M, Harden K, Forsythe A, Chilingar L, Hoffman C, Sperling W,
et al. The course of asthma during pregnancy, post partum, and with
successive pregnancies: a prospective analysis. J Allergy Clin Immunol
1988;81(3):509–17. [II-3]
Respiratory Diseases
16. Kircher S, Schatz M, Long L. Variables affecting asthma course during
pregnancy. Ann Allergy Asthma Immunol 2002;89(5):463–6. [II-3]
17. Gluck JC, Gluck PA. The effect of pregnancy on the course of asthma.
Immunol Allergy Clin North Am 2000;20(4):729–43. [II-3]
18. Beecroft N, Cochrane G, Milburn HJ. Effect of sex of fetus on asthma
during pregnancy: blind prospective stud. Br Med J 1998;317(7162):
856–7. [II-3]
19. Busse WW. NAEPP expert panel report: managing asthma during preg-
nancy: recommendations for pharmacologic treatment—2004 update. J
Allergy Clin Immunol 2005;115(1):34–46. [Guideline]
20. Cloutier MM, Baptist AP, Blake KV, Brooks EG, Bryant-Stephens T,
DiMango E, et al. 2020 Focused updates to the asthma management
guidelines: a report from the National Asthma Education and Prevention
Program Coordinating Committee Expert Panel Working Group. J Allergy
Clin Immunol 2020;146(6):1217–70. [Guideline]
21. Dombrowski MP, Schatz M. ACOG practice bulletin: clinical manage-
ment guidelines for obstetrician-gynecologists number 90, February 2008:
asthma in pregnancy. Obstet Gynecol 2008;111(2 Pt 1):457–64. [III]
22. Global Initiative for Asthma. Global Strategy for Asthma Management and
Prevention. 2020. Available from www.ginasthma.org.
23. Bain E, Pierides KL, Clifton VL, Hodyl NA, Stark MJ, Crowther CA, et al.
Interventions for managing asthma in pregnancy. Cochrane Database Syst
Rev 2014;(10). [II-1]
24. National Heart Lung and Blood Institute. Draft needs assessment report
for potential update of the Expert Panel Report 3 (2007): guidelines for the
diagnosis and management of asthma. 2015. [III]
25. Dombrowski MP, Schatz M, Wise R, Thom EA, Landon M, Mabie W,
et al. Randomized trial of inhaled beclomethasone dipropionate versus
theophylline for moderate asthma during pregnancy. Am J Obstet Gynecol
2004;190(3):737–44. [I, n = 385]
26. Silverman M, Sheffer A, Diaz PV, Lindmark B, Radner F, Broddene M,
et al. Outcome of pregnancy in a randomized controlled study of patients
with asthma exposed to budesonide. Ann Allergy Asthma Immunol
2005;95(6):566–70. [I, n = 313]
27. Namazy J, Schatz M, Long L, Lipkowitz M, Lillie MA, Voss M, et al. Use of
inhaled steroids by pregnant asthmatic women does not reduce intrauterine
growth. J Allergy Clin Immunol 2004;113(3):427–32. [II-2]
28. Martel M-J, Rey É, Beauchesne M-F, Perreault S, Lefebvre G, Forget
A, et al. Use of inhaled corticosteroids during pregnancy and risk of
pregnancy induced hypertension: nested case-control study. Br Med J
2005;330(7485):230. [II-2]
29. Breton M-C, Beauchesne M-F, Lemière C, Rey É, Forget A, Blais L. Risk of
perinatal mortality associated with inhaled corticosteroid use for the treat-
ment of asthma during pregnancy. J Allergy Clin Immunol 2010;126(4):
772–7.e2. [II-2]
30. Rahimi R, Nikfar S, Abdollahi M. Meta-analysis finds use of inhaled corti-
costeroids during pregnancy safe: a systematic meta-analysis review. Hum
Exp Toxicol 2006;25(8):447–52. [I]
31. Lin S, Munsie JPW, Herdt-Losavio ML, Bell E, Druschel C, Romitti
PA, et al. Maternal asthma medication use and the risk of gastroschisis.
Am J Epidemiol 2008;168(1):73–9. [II-2]
32. Bakhireva LN, Jones KL, Schatz M, Klonoff-Cohen HS, Johnson D, Slymen
DJ, et al. Safety of leukotriene receptor antagonists in pregnancy. J Allergy
Clin Immunol 2007;119(3):618–25. [II-2]
33. Sarkar M, Koren G, Kalra S, Ying A, Smorlesi C, De Santis M, et al.
Montelukast use during pregnancy: a multicentre, prospective, comparative
study of infant outcomes. Eur J Clin Pharmacol 2009;65(12):1259–64. [II-2]
34. Ducharme FM. Addition of anti‐leukotriene agents to inhaled corticoste-
roids for chronic asthma. Cochrane Database Syst Rev 2004(1). [Review]
35. Siddiqui AK, Gouda H, Multz AS, Steinberg H, Kamholz SL. Ventilator
strategy for status asthmaticus in pregnancy: a case-based review. J Asthma
2005;42(3):159–62. [II-3].
36. Elsayegh D, Shapiro JM. Management of the obstetric patient with status
asthmaticus. J Intensive Care Med 2008;23(6):396–402. [II-3]
37. Lazarus SC. Emergency treatment of asthma. N Engl J Med 2010;363(8):
755–64. [III]
38. Marik PE, Varon J. Requirement of perioperative stress doses of corticoste-
roids: a systematic review of the literature. Arch Surg 2008;143(12):1222–6.
[Review]
39. Rust GS, Thompson CJ, Minor P, Davis-Mitchell W, Holloway K, Murray V.
Does breastfeeding protect children from asthma? Analysis of NHANES III
survey data. J Natl Med Assoc 2001;93(4):139. [II-3]
40. Jin Y, Carriere KC, Marrie TJ, Predy G, Johnson DH. The effects of com-
munity-acquired pneumonia during pregnancy ending with a live birth.
Am J Obstet Gynecol 2003;188(3):800–6. [II-2]
293
41. File Jr TM. Community-acquired pneumonia. Lancet 2003;362(9400):
1991–2001. [Review]
42. Sheffield JS, Cunningham FG. Community-acquired pneumonia in preg-
nancy. Obstet Gynecol 2009;114(4):915–22. [Review]
43. Goodnight WH, Soper DE. Pneumonia in pregnancy. Crit Care Med
2005;33(10):S390–S7. [Review]
44. Toppenberg KS, Hill DA, Miller DP. Safety of radiographic imaging during
pregnancy. Am Fam Physician 1999;59(7):1813. [III]
45. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al.
A prediction rule to identify low-risk patients with community-acquired
pneumonia. N Engl J Med 1997;336(4):243–50. [II-3]
46. Bánhidy F, Ács N, Puhó EH, Czeizel AE. Maternal acute respiratory infec-
tious diseases during pregnancy and birth outcomes. Eur J Epidemiol
2008;23(1):29–35. [II-2]
47. Getahun D, Ananth CV, Peltier MR, Smulian JC, Vintzileos AM. Acute
and chronic respiratory diseases in pregnancy: associations with placental
abruption. Am J Obstet Gynecol 2006;195(4):1180–4. [II-2]
48. Yost NP, Bloom SL, Richey SD, Ramin SM, Cunningham FG. An appraisal
of treatment guidelines for antepartum community-acquired pneumonia.
Am J Obstet Gynecol 2000;183(1):131–5. [II-3]
49. Bloom SL, Ramin S, Cunningham FG. A prediction rule for community-
acquired pneumonia. N Engl J Med 1997;336(26):1913–4. [Meta-analysis in
letter to the editor].
50. Getahun D, Ananth CV, Oyelese Y, Peltier MR, Smulian JC, Vintzileos AM.
Acute and chronic respiratory diseases in pregnancy: associations with
spontaneous premature rupture of membranes. J Matern Fetal Neonatal
Med 2007;20(9):669–75. [II-2]
51. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean
NC, et al. Infectious Diseases Society of America/American Thoracic
Society consensus guidelines on the management of community-acquired
pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2):S27–S72. [Guideline]
52. Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al.
Diagnosis and treatment of adults with community-acquired pneumonia.
An official clinical practice guideline of the American Thoracic Society
and Infectious Diseases Society of America. Am J Respir Crit Care Med
2019;200(7):e45–e67. [Guideline]
53. Griffiths P, Ronalds C, Heath R. A prospective study of influenza infections
during pregnancy. J Epidemiol Community Health 1980;34(2):124–8. [II-2]
54. Hardy JM, Azarowicz EN, Mannini A, Medearis Jr DN, Cooke RE. The effect
of Asian influenza on the outcome of pregnancy, Baltimore, 1957–8. Am J
Public Health Nations Health 1961;51(8):1182–8. [II-3]
55. Irving W, James D, Stephenson T, Laing P, Jameson C, Oxford J, et al.
Influenza virus infection in the second and third trimesters of pregnancy: a
clinical and seroepidemiological study. BJOG 2000;107(10):1282–9. [II-2]
56. Doyle TJ, Goodin K, Hamilton JJ. Maternal and neonatal outcomes among
pregnant women with 2009 pandemic influenza A (H1N1) illness in Florida,
2009–2010: a population-based cohort study. PLOS ONE 2013;8(10):
e79040. [II-3]
57. Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL,
Biggerstaff MS, et al. H1N1 2009 influenza virus infection during preg-
nancy in the USA. Lancet 2009;374(9688):451–8. [II-3]
58. Taubenberger JK, Morens DM. Influenza: the once and future pandemic.
Public Health Rep 2010;125(Suppl 3):15–26. [Review]
59. Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM,
et al. Pandemic 2009 influenza A (H1N1) virus illness among pregnant
women in the United States. J Am Med Assoc 2010;303(15):1517–25. [II-3]
60. Dodds L, McNeil SA, Fell DB, Allen VM, Coombs A, Scott J, et al. Impact
of influenza exposure on rates of hospital admissions and physician visits
because of respiratory illness among pregnant women. Can Med Assoc J
2007;176(4):463–8. [II-2]
61. Tamma PD, Steinhoff MC, Omer SB. Influenza infection and vaccination in
pregnant women. Expert Rev Respir Med 2010;4(3):321–8. [III]
62. Hartert TV, Neuzil KM, Shintani AK, Mitchel Jr EF, Snowden MS, Wood
LB, et al. Maternal morbidity and perinatal outcomes among pregnant
women with respiratory hospitalizations during influenza season. Am J
Obstet Gynecol 2003;189(6):1705–12. [II-2]
63. Ács N, Bánhidy F, Puhó E, Czeizel AE. Pregnancy complications and deliv-
ery outcomes of pregnant women with influenza. J Matern Fetal Neonatal
Med 2006;19(3):135–40. [II-2]
64. Fell DB, Savitz D, Kramer MS, Gessner B, Katz M, Knight M, et al. Maternal
influenza and birth outcomes: systematic review of comparative studies.
BJOG 2017;124(1):48–59. [Review]
65. Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M. Perinatal out-
comes after maternal 2009/H1N1 infection: national cohort study. Br Med
J 2011;342. [II-2]
294
66. Håberg SE, Trogstad L, Gunnes N, Wilcox AJ, Gjessing HK, Samuelsen SO,
et al. Risk of fetal death after pandemic influenza virus infection or vaccina-
tion. N Engl J Med 2013;368(4):333–40. [II-3]
67. Louie JK, Acosta M, Jamieson DJ, Honein MA. Severe 2009 H1N1 influ-
enza in pregnant and postpartum women in California. N Engl J Med
2010;362(1):27–35. [II-3]
68. Multicenter Study. Critical illness due to 2009 A/H1N1 influenza in preg-
nant and postpartum women: population based cohort study. Br Med J
2010;340(Mar18 3):c1279–c. [II-2]
69. Oluyomi-Obi T, Avery L, Schneider C, Kumar A, Lapinsky S, Menticoglou
S, et al. Perinatal and maternal outcomes in critically ill obstetrics patients
with pandemic H1N1 Influenza A. J Obstet Gynaecol Can 2010;32(5):
443–7. [II-3]
70. Luteijn J, Brown M, Dolk H. Influenza and congenital anomalies: a system-
atic review and meta-analysis. Hum Reprod 2014;29(4):809–23. [Review and
Meta-analysis]
71. Schanzer DL, Langley JM, Tam TW. Influenza-attributed hospitalization
rates among pregnant women in Canada 1994–2000. J Obstet Gynaecol
Can 2007;29(8):622–9. [II-2]
72. Cox S, Posner SF, McPheeters M, Jamieson DJ, Kourtis AP, Meikle S.
Hospitalizations with respiratory illness among pregnant women during
influenza season. Obstet Gynecol 2006;107(6):1315–22. [III]
73. The Australia New Zealand Extracorporeal Membrane Oxygenation
Influenza Investigators. Extracorporeal membrane oxygenation for 2009
influenza a(H1N1) acute respiratory distress syndrome. J Am Med Assoc
2009;302(17):1888–95. [II-3]
74. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–82. [III]
75. Manske JM. Efficacy and effectiveness of maternal influenza vaccina-
tion during pregnancy: a review of the evidence. Matern Child Health J
2014;18(7):1599–609. [Review]
76. Cuningham W, Geard N, Fielding JE, Braat S, Madhi SA, Nunes MC, et al.
Optimal timing of influenza vaccine during pregnancy: a systematic review
and meta‐analysis. Influenza Other Respi Viruses 2019;13(5):438–52.
[Review and Meta-analysis]
77. Gupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, et al.
Isoniazid preventive therapy in HIV-infected pregnant and postpartum
women. N Engl J Med 2019;381(14):1333–46. [I, n = 956]
78. Sheffield JS, Greer LG, Rogers VL, Roberts SW, Lytle H, McIntire DD, et al.
Effect of influenza vaccination in the first trimester of pregnancy. Obstet
Gynecol 2012;120(3):532–7. [II-1]
79. Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, et al.
Effectiveness of maternal influenza immunization in mothers and infants.
N Engl J Med 2008;359(15):1555–64. [I, n = 340]
80. Steinhoff MC, Omer SB, Roy E, Arifeen SE, Raqib R, Altaye M, et al.
Influenza immunization in pregnancy antibody responses in mothers and
infants. N Engl J Med 2010;362(17):1644. [III]
81. Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG,
et al. Seasonal influenza in adults and children—diagnosis, treatment, che-
moprophylaxis, and institutional outbreak management: clinical practice
guidelines of the Infectious Diseases Society of America. Clin Infect Dis
2009:1003–32. [Guideline]
82. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ.
Oseltamivir for influenza in adults and children: systematic review of clini-
cal study reports and summary of regulatory comments. Br Med J 2014;348
[Review]
83. World Health Organization. WHO guidelines for pharmacological man-
agement of pandemic (H1N1) 2009 influenza and other influenza viruses.
2009. [Guideline]
84. Aoki FY, Macleod MD, Paggiaro P, Carewicz O, El Sawy A, Wat C, et al.
Early administration of oral oseltamivir increases the benefits of influenza
treatment. J Antimicrob Chemother 2003;51(1):123–9. [II-2]
85. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oselta-
mivir treatment on influenza-related lower respiratory tract complications
and hospitalizations. Arch Intern Med 2003;163(14):1667–72. [I]
86. Nicholson K, Aoki F, Osterhaus A, Trottier S, Carewicz O, Mercier C,
et al. Efficacy and safety of oseltamivir in treatment of acute influ-
enza: a randomised controlled trial. Lancet 2000;355(9218):1845–50.
[I, n = 726]
87. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D,
et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir
in treating acute influenza: a randomized controlled trial. J Am Med Assoc
2000;283(8):1016–24. [I, n = 726]
88. Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for
preventing and treating influenza in healthy adults: systematic review and
meta-analysis. Br Med J 2009;339. [Review]
Maternal-Fetal Evidence Based Guidelines
89. Worley KC, Roberts SW, Bawdon RE. The metabolism and transplacen-
tal transfer of oseltamivir in the ex vivo human model. Infect Dis Obstet
Gynecol 2008;2008. [II-1]
90. Tanaka T, Nakajima K, Murashima A, Garcia-Bournissen F, Koren G, Ito
S. Safety of neuraminidase inhibitors against novel influenza A (H1N1)
in pregnant and breastfeeding women. Can Med Assoc J 2009;181(1–2):
55–8. [Review]
91. Greer LG, Sheffield JS, Rogers VL, Roberts SW, McIntire DD, Wendel GD.
Maternal and neonatal outcomes after antepartum treatment of influenza
with antiviral medications. Obstet Gynecol 2010;115(4):711–6. [II-2]
92. Centers for Disease Control and Prevention. Recommendations for obstet-
ric health care providers related to use of antiviral medications in the
treatment and prevention of influenza. Influenza: Flu. Centers for Disease
Control and Prevention. 2016 October; 21. [Guideline]
93. Wentges-van Holthe N, van Eijkeren M, van der Laan JW. Oseltamivir and
breastfeeding. Int J Infect Dis 2008;12(4):451. [III]
94. Schwartz NG, Price SF, Pratt RH, Langer AJ. Tuberculosis—United States,
2019. Morbidity and Mortality Weekly Report 2020;69(11):286. [III]
95. Annabel B, Anna D, Hannah M. Global Tuberculosis Report 2019. Geneva:
World Health Organization. 2019:7–9. [III]
96. Knight M, Kurinczuk J, Nelson‐Piercy C, Spark P, Brocklehurst P.
Tuberculosis in pregnancy in the UK. BJOG 2009;116(4):584–8. [III]
97. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet
2003;362(9387):887–99. [Review]
98. American Thoracic Society. Targeted tuberculin testing and treatment of latent
tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221–S47. [Review]
99. National Collaborating Centre for Chronic Conditions, Centre for Clinical
Practice at NICE. Tuberculosis: clinical diagnosis and management of
tuberculosis, and measures for its prevention and control. 2011. [Review]
100. Lighter-Fisher J, Surette A-M. Performance of an interferon-gamma release
assay to diagnose latent tuberculosis infection during pregnancy. Obstet
Gynecol 2012;119(6):1088–95. [II-2]
101. Jonnalagadda S, Payne BL, Brown E, Wamalwa D, Obimbo EM, Majiwa
M, et al. Latent tuberculosis detection by interferon γ release assay dur-
ing pregnancy predicts active tuberculosis and mortality in human immu-
nodeficiency virus type 1-infected women and their children. J Infect Dis
2010;202(12):1826–35. [III]
102. Mathad JS, Bhosale R, Sangar V, Mave V, Gupte N, Kanade S, et al. Pregnancy
differentially impacts performance of latent tuberculosis diagnostics in a
high-burden setting. PLOS ONE 2014;9(3):e92308. [III]
103. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond
E, et al. Official American Thoracic Society/Infectious Diseases Society
of America/Centers for Disease Control and Prevention clinical practice
guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis
2017;64(2):e1–e33. [Guideline]
104. Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, et al.
Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J
Med 2010;363(11):1005–15. [II-2]
105. Sobhy S, Babiker ZO, Zamora J, Khan KS, Kunst H. Maternal and perina-
tal mortality and morbidity associated with tuberculosis during pregnancy
and the postpartum period: a systematic review and meta‐analysis. BJOG
2017;124(5):727–33. [Review and Meta-analysis]
106. Lin HC, Lin HC, Chen SF. Increased risk of low birthweight and small
for gestational age infants among women with tuberculosis. BJOG
2010;117(5):585–90. [II-3]
107. Jana N, Vasishta K, Jindal S, Khunnu B, Ghosh K. Perinatal outcome in
pregnancies complicated by pulmonary tuberculosis. Int J Gynaecol Obstet
1994;44(2):119–24. [II-2]
108. Tripathy S. Tuberculosis and pregnancy. Int J Gynaecol Obstet
2003;80(3):247–53. [II-1]
109. American Thoracic Society. CDC; Infectious Diseases Society of America:
Treatment of tuberculosis. MMWR 2003;52(11):1–77. [Review]
110. Laibl VR, Sheffield JS. Tuberculosis in pregnancy. Clin Perinatol
2005;32(3):739–47. [Review]
111. Rodrigues LC, Diwan VK, Wheeler JG. Protective effect of BCG against
tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J
Epidemiol 1993;22(6):1154–8. [Meta-analysis]
112. Nguipdop-Djomo P, Heldal E, Rodrigues LC, Abubakar I, Mangtani P.
Duration of BCG protection against tuberculosis and change in effective-
ness with time since vaccination in Norway: a retrospective population-
based cohort study. Lancet Infect Dis 2016;16(2):219–26. [II-2]
113. Mangtani P, Nguipdop-Djomo P, Keogh RH, Sterne JA, Abubakar I,
Smith PG, et al. The duration of protection of school-aged BCG vaccina-
tion in England: a population-based case–control study. Int J Epidemiol
2018;47(1):193–201. [II-2]
Respiratory Diseases
114. Karonga Prevention Trial Group. Randomised controlled trial of single
BCG, repeated BCG, or combined BCG and killed Mycobacterium lep-
rae vaccine for prevention of leprosy and tuberculosis in Malawi. Lancet
1996;348(9019):17–24. [I, n = 121,020]
115. Rodrigues LC, Pereira SM, Cunha SS, Genser B, Ichihara MY, de Brito SC,
et al. Effect of BCG revaccination on incidence of tuberculosis in school-
aged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet
2005;366(9493):1290–5. [I, n = 200,771]
116. World Health Organization. Latent tuberculosis infection: updated and
consolidated guidelines for programmatic management. World Health
Organization; 2018. Report No. 9241550236. [Guideline]
117. Ayele HT, van Mourik MS, Debray TP, Bonten MJ. Isoniazid prophylac-
tic therapy for the prevention of tuberculosis in HIV infected adults: a
systematic review and meta-analysis of randomized trials. PLOS ONE
2015;10(11):e0142290. [Review and Meta-analysis]
118. Boggess KA, Myers ER, Hamilton CD. Antepartum or postpartum isonia-
zid treatment of latent tuberculosis infection. Obstet Gynecol 2000;96(5):
757–62. [III]
119. Franks AL, Binkin NJ, Snider Jr DE, Rokaw WM, Becker S. Isoniazid hepa-
titis among pregnant and postpartum Hispanic patients. Public Health Rep
1989;104(2):151. [II-3]
120. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al.
An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J
Respir Crit Care Med 2006;174(8):935–52. [III]
121. Pease C, Hutton B, Yazdi F, Wolfe D, Hamel C, Quach P, et al. Efficacy and
completion rates of rifapentine and isoniazid (3HP) compared to other
treatment regimens for latent tuberculosis infection: a systematic review
with network meta-analyses. BMC Infect Dis 2017;17(1):1–11. [Review and
Meta-analysis]
122. Moro RN, Scott NA, Vernon A, Tepper NK, Goldberg SV, Schwartzman K, et al.
Exposure to latent tuberculosis treatment during pregnancy. The PREVENT
TB and the iAdhere trials. Ann Am Thor Soc 2018;15(5):570–80. [II-3]
123. Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, et al.
Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA
clinical practice guideline. Am J Respir Crit Care Med 2019;200(10):e93–
e142. [Guideline]
124. Centers for Disease Control and Prevention. Trends in tuberculosis, 2019. 2020.
[II-3]. https://www.cdc.gov/tb/statistics/reports/2019/national_data.htm
125. Adhikari M, Ed. Tuberculosis and tuberculosis/HIV co-infection in preg-
nancy. Seminars in Fetal and Neonatal Medicine. 2009: Elsevier. [III]
126. Havers FP, Reed C, Lim T, Montgomery JM, Klena JD, Hall AJ, et al.
Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States,
March 23–May 12, 2020. JAMA Intern Med 2020;180(12):1576–86. [II-3]
127. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen
S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is
blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271–80.
e8. [II-3]
128. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings
of COVID-19 associated with acute respiratory distress syndrome. Lancet
Respir Med 2020;8(4):420–2. [II-3]
129. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associ-
ated with poor prognosis in patients with novel coronavirus pneumonia. J
Thromb Haemost 2020;18(4):844–7. [II-2]
130. Setti L, Passarini F, De Gennaro G, Barbieri P, Perrone MG, Borelli M,
et al. Airborne transmission route of COVID-19: why 2 meters/6 feet of
inter-personal distance could not be enough. Multidisciplinary Digital
Publishing Institute; 2020. [III]
131. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The
incubation period of coronavirus disease 2019 (COVID-19) from publicly
reported confirmed cases: estimation and application. Ann Intern Med
2020;172(9):577–82. [II-3]
132. He X, Lau EH, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics
in viral shedding and transmissibility of COVID-19. Nat Med 2020;26(5):
672–5. [II-3]
133. Zhang C, Shi L, Wang F-S. Liver injury in COVID-19: management and
challenges. Gastroenterol Hepatol (NY) 2020;5(5):428–30. [III]
134. Ronco C, Reis T. Kidney involvement in COVID-19 and rationale for
extracorporeal therapies. Nature Reviews Nephrology 2020;16(6):308–10.
[Review]
135. He J, Guo Y, Mao R, Zhang J. Proportion of asymptomatic coronavi-
rus disease 2019: A systematic review and meta‐analysis. J Med Virol
2021;93(2):820–30. [Review and Meta-analysis]
136. Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T, et al. Clinical character-
istics of coronavirus disease 2019 (COVID-19) in China: a systematic review
and meta-analysis. J Infect 2020;80(6):656–65. [Review and Meta-analysis]
295
137. Zheng Z, Peng F, Xu B, Zhao J, Liu H, Peng J, et al. Risk factors of critical &
mortal COVID-19 cases: A systematic literature review and meta-analysis.
J Infect 2020. [Review and Meta-analysis]
138. Wang B, Li R, Lu Z, Huang Y. Does comorbidity increase the risk of
patients with COVID-19: evidence from meta-analysis. Aging (Albany NY)
2020;12(7):6049. [Meta-analysis]
139. Xu L, Mao Y, Chen G. Risk factors for 2019 novel coronavirus disease
(COVID-19) patients progressing to critical illness: a systematic review
and meta-analysis. Aging (Albany NY) 2020;12(12):12410. [Review and
Meta-analysis]
140. Allotey J, Stallings E, Bonet M, Yap M, Chatterjee S, Kew T, et al. Clinical
manifestations, risk factors, and maternal and perinatal outcomes of coro-
navirus disease 2019 in pregnancy: living systematic review and meta-
analysis. Br Med J 2020;370. [Meta-analysis and review]
141. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E,
Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical,
laboratory and imaging features of COVID-19: A systematic review
and meta-analysis. Travel Med Infect Dis 2020;34:101623. [Review and
Meta-analysis]
142. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus
disease 2019 (COVID-19): a systematic review of imaging findings in 919
patients. Am J Roentgenol Radium Ther 2020;215(1):87–93. [Review]
143. Böger B, Fachi MM, Vilhena RO, de Fátima Cobre A, Tonin FS, Pontarolo R.
Systematic review with meta-analysis of the accuracy of diagnostic tests for
COVID-19. Am J Infect Control 2020. [Review]
144. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2
viral load in upper respiratory specimens of infected patients. N Engl J Med
2020;382(12):1177–9. [II-3]
145. Centers for Disease Control and Prevention. Interim guidelines for col-
lecting and handling of clinical specimens for COVID-19 Testing. 2020.
[Guideline]
146. Dinnes J, Deeks JJ, Adriano A, Berhane S, Davenport C, Dittrich S, et al.
Rapid, point‐of‐care antigen and molecular‐based tests for diagnosis
of SARS‐CoV‐2 infection. Cochrane Database Syst Rev 2020;(8).
[Review]
147. Nalla AK, Casto AM, Huang M-LW, Perchetti GA, Sampoleo R, Shrestha
L, et al. Comparative performance of SARS-CoV-2 detection assays using
seven different primer-probe sets and one assay kit. J Clin Microbiol
2020;58(6). [II-3]
148. Xiao AT, Tong YX, Zhang S. Profile of RT-PCR for SARS-CoV-2: a pre-
liminary study from 56 COVID-19 patients. Clin Infect Dis 2020;71(16):
2249–51. [II-3]
149. Ellington S, Strid P, Tong VT, Woodworth K, Galang RR, Zambrano
LD, et al. Characteristics of women of reproductive age with laboratory-­
confirmed SARS-CoV-2 infection by pregnancy status—United States,
January 22–June 7, 2020. MMWR 2020;69(25):769. [II-3]
150. Dubey P, Reddy S, Manuel S, Dwivedi AK. Maternal and neonatal characteristics
and outcomes among COVID-19 infected women: an updated systematic review
and meta-analysis. Eur J Obstet Gynecol 2020. [Review and Meta-analysis]
151. Kotlyar AM, Grechukhina O, Chen A, Popkhadze S, Grimshaw A, Tal O,
et al. Vertical transmission of coronavirus disease 2019: a systematic review
and meta-analysis. Am J Obstet Gynecol 2021;224(1):35–53 e3. [Review and
Meta-analysis]
152. Shimabukuro T. COVID-19 vaccine safety update. Advisory Committee on
Immunization Practices (ACIP) 2021. [III]
153. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ, et al.
Physical distancing, face masks, and eye protection to prevent person-
to-person transmission of SARS-CoV-2 and COVID-19: a systematic
review and meta-analysis. Lancet 2020;395(10242):1973–87. [Review and
Meta-analysis]
154. Bartoszko JJ, Farooqi MAM, Alhazzani W, Loeb M. Medical masks vs N95
respirators for preventing COVID‐19 in healthcare workers: A systematic
review and meta‐analysis of randomized trials. Influenza Other Respi
Viruses 2020;14(4):365–73. [Review]
155. Brooks JT, Beezhold DH, Noti JD, Coyle JP, Derk RC, Blachere FM, et al.
Maximizing fit for cloth and medical procedure masks to improve perfor-
mance and reduce SARS-CoV-2 transmission and exposure, 2021. MMWR
2021;70(7):254.
156. Prabhu M, Cagino K, Matthews KC, Friedlander RL, Glynn SM, Kubiak JM,
et al. Pregnancy and postpartum outcomes in a universally tested popula-
tion for SARS‐CoV‐2 in New York City: a prospective cohort study. BJOG
2020;127(12):1548–56. [II-2]
157. National Institutes of Health. COVID-19 treatment guidelines panel. coro-
navirus disease 2019 (COVID-19) treatment guidelines. Available at https://
www.covid19treatmentguidelines.nih.gov/. [Guideline]
296
158. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al.
Remdesivir for the treatment of Covid-19—preliminary report. N Engl J
Med 2020. [I, n = 1062]
159. Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L. RECOVERY
Collaborative Group. Dexamethasone in hospitalized patients with covid-
19—preliminary report. N Engl J Med [I, n = 2104]
160. Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, Arabi YM,
et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-
19. N Engl J Med 2021. [I, n = 755]
161. Horby PW, Pessoa-Amorim G, Peto L, Brightling CE, Sarkar R, Thomas
K, et al. Tocilizumab in patients admitted to hospital with COVID-19
(RECOVERY): preliminary results of a randomised, controlled, open-label,
platform trial. Medrxiv 2021. [I, n = 4116]
162. Emergency Use Authorization Request for Convalescent Plasma for the
Treatment of Patients With COVID-19. Health and Human Services/
Assistant Secretary for Preparedness Response; 2020. [III]. https://www.
fda.gov/media/141481/download
Maternal-Fetal Evidence Based Guidelines
163. Walker KF, O’Donoghue K, Grace N, Dorling J, Comeau JL, Li W, et al.
Maternal transmission of SARS‐COV‐2 to the neonate, and possible routes
for such transmission: A systematic review and critical analysis. BJOG
2020;127(11):1324–36. [Review]
164. World Health Organization. Breastfeeding and COVID-19: Scientific brief.
2020. https://apps.who.int/iris/handle/10665/332639 [III]
165. American Academy of Pediatrics. Breastfeeding guidance post hospital dis-
charge for mothers or infants with suspected or confirmed SARS-CoV-2
infection. 2020. [Guideline]
166. World Health Organization, Stop TB Initiative. Treatment of tuberculosis:
guidelines, fourth ed. World Health Organization; 2010. [Guideline]
167. Leland et al. Approved respiratory specimens vary among FDA cleared
influenza assays. Clin Micro Rev 2007;20: 49–78.
168. Jasmer RM, Nahid P, Hopewell PC. Latent tuberculosis infection. N Engl J
Med 2002; 347:1860–1866. [Review].
27
SYSTEMIC LUPUS ERYTHEMATOSUS
Maria A. Giraldo-Isaza and Bettina F. Cuneo
Key points
• Diagnosis: More than 4/11 American College of Rheuma­
tology (ACR) criteria OR 4/17 Systemic Lupus International
Collaborating Clinics (SLICC) criteria with at least one
clinical criteria and one immunologic criteria or lupus
nephritis by renal biopsy in the presence of ANA or anti ds-
DNA antibodies OR ANA >1:80 plus additive criteria score
of ≥10 points at any time per the European League against
Rheumatism (EULAR)/American College of Rheumatology
(ACR) criteria.
• Preconception counseling: With the exception of cardiac
neonatal lupus erythematosus (C-NLE), fetal-neonatal and
maternal complications are primarily seen in systemic
lupus erythematosus (SLE) patients with active disease
periconception or patients with hypertension, renal,
heart, lungs or brain disease, or antiphospholipid, or
SSA/SSB antibodies. Therefore, it is recommended to
screen for all above, and to start pregnancy with SLE in
remission. Optimize medical therapy (usually with hydroxy-
chloroquine) preconception.
• Laboratory workup: CBC with platelets, transaminases,
creatinine, BUN, anti-Ro/SSA and anti-La/SSB) antibod-
ies, anticardiolipin antibodies (ACA), lupus anticoagulant
(LA) or dilute Russell’s viper venom time (DRVVT), anti-
beta-2 glycoprotein-I, anti-ds DNA, C3, C4, CH50, urine
sediment, 24-hour urine for total protein and creatinine
clearance or spot urine protein to creatinine ratio.
• Repeat laboratories at least every trimester to evaluate
disease activity.
• Currently hydroxychloroquine (Plaquenil) is the saf-
est and most effective therapy for SLE pregnant women
who need therapy. If stable with no recent flares on
hydroxychloroquine, it is recommended to continue it
in pregnancy and postpartum. If not previously taking,
consider initiating hydroxychloroquine for prevention
of flares and complications, unless contraindicated.
• Low-dose aspirin (usually 81 mg or up to 150 mg daily),
should be initiated between 12 and 16 weeks for preven-
tion of pre-eclampsia.
• Women with anti-SSA or anti-SSA/SSB antibodies have
about a 2% risk of C-NLE. Recurrence rate of C-NLE is
18% if prior affected pregnancy.
• Hydroxychloroquine is recommended for C-NLE pre-
vention in women with positive anti-SSA with a prior
child with C-NLE. There is insufficient data to recom-
mend hydroxychloroquine in women with positive anti-
SSA or anti-SSA/SSB antibodies with prior child without
cardiac neonatal lupus, but it is possibly beneficial.
• Fetal echocardiography surveillance is suggested in women
with positive anti-SSA or anti-SSA/SSB from 16 to 26 weeks
gestation. Women with fetuses who develop N-CLE should
DOI: 10.1201/9781003099062-27
be managed and delivered at a tertiary care center with the
availability of immediate neonatal pacing.
• For women with Antiphospholipid Syndrome (APS), see
Chapter 28.
Diagnosis
SLE is a chronic multisystemic immunologic disease supported by
the presence of autoantibodies in patients with clinical manifesta-
tions. Diagnostic criteria from several societies (American College
of Rheumatology-ACR, Systemic Lupus International Collaborating
Clinics-SLICC and the European League against Rheumatism-
EULAR/ACR) have been published. ACR criteria were developed
in 1982 and revised in 1997: Need ≥4/11 criteria to make diagno-
sis of SLE—either serially or simultaneously (Table 27.1) [1]. The
ACR criteria were revised and validated to reflect new knowledge
and attempt to reflect better clinical and immunologic aspects of
the disease. The 2012 validated SLICC diagnosis needs 4/17 crite-
ria, with at least one clinical criteria and one immunologic criteria
OR lupus nephritis by renal biopsy in the presence of ANA or anti
ds-DNA antibodies (Table 27.2) [2]. The SLICC criteria were found
to have better sensitivity (96.7% versus 82.8%), but less specific-
ity (83.7% versus 93.4%) when compared to the ACR criteria. The
EULAR/ACR criteria were developed in 2019 to improve the
detection of early onset disease [3]. An antinuclear antibody (ANA)
titer ≥1:80 on HEp cells or equivalent test at any time is required as
entry criteria PLUS additive criteria score of ≥10 points at any time.
Additive criteria include clinical and immunologic parameters. At
least one clinical criterion is needed (Table 27.3). This classification
was found to have a sensitivity of 96.1% and specificity of 93.4%.
Currently, the EULAR/ACR diagnostic criteria are used and
acceptable considering higher sensitivity and specificity.
Symptoms
See diagnostic criteria in Tables 27.1–27.3. Other symptoms and
signs include general (fatigue, fever, malaise, weight loss); GI
(anorexia, ascites, vasculitis); thrombosis, Raynaud’s phenom-
enon, among others.
Epidemiology/Incidence
Incidence is 1:700 to 2000 general population (1:200 in African
Americans). 90% in women. 1/500 in childbearing age.
Table 27.4 provides a list of incidence of abnormal laboratory
tests and their association with SLE. 25% of SLE patients meet
criteria for antiphospholipid syndrome (APS) (see Chap. 28).
Etiology/Basic pathophysiology
Autoantibody (Ab) to fixed tissue antigen (Ag) in vessel wall,
nucleus, cytoplasmic membranes, etc.; Ag-Ab complexes in serum.
297
298 Maternal-Fetal Evidence Based Guidelines

TABLE 27.1: American College of Rheumatology – ACR TABLE 27.3: The European League against Rheumatism
Diagnostic Criteriaa (EULAR)/American College of Rheumatology (ACR)
1. Malar rash Diagnostic Criteriaa
2. Discoid rash Clinical Criteria (points) Immunologic Criteria (points)
3. Photosensitivity
4. Oral ulcers – painless Entry criteria (ANA) titer ≥1:80 on HEp cells or equivalent test
5. Arthritis: Nonerosive, involving two or more peripheral joints Fever (2) Anti-cardiolipin antibodies or anti
6. Serositis: Pleuritis or pericarditis Leukopenia (3) B2 glycoprotein 1 antibodies or
7. Renal disorder: Persistent proteinuria >0.5 g/day, or cellular casts Thrombocytopenia (4) Lupus
8. Neurologic disorder: Seizure or psychosis Autoimmune hemolysis (4) anticoagulant (2)
9. Immunologic disorder: Positive lupus erythematosus cell Delirium (2) Low Complement C3 or C4 (3)
preparation, or anti-double-stranded (ds) DNA, or anti-Smith (SM) Psychosis (3) Low Complement C3 and C4 (4)
antibody, or false-positive serologic test for syphilis Seizures (5) Anti-ds DNA OR anti-Smith
10. Hematologic disorder: Hemolytic anemia with reticulocytosis, or Non scarring alopecia (2) antibodies (6)
leukopenia <4000/mm3, or lymphopenia <1500/mm3, or Oral ulcers (2)
thrombocytopenia <100,000/mm3 Subacute cutaneous OR
11. Antinuclear antibodies (ANA) in abnormal titers discoid lupus (4)
a For diagnosis, need ≥4/11 criteria, either serially or simultaneously. Acute cutaneous lupus (6)
Pleural or pericardial
TABLE 27.2: Systemic Lupus International Collaborating effusion (5)
Clinics – SLICC Diagnostic Criteriaa Acute pericarditis (6)
Joint involvement (6)
Clinical Criteria Immunologic Criteria
Proteinuria >0.5 g/24 hour (4)
Acute cutaneous lupus: Malar lupus rash, ANA (laboratory reference) Renal biopsy Class II or V
bullous lupus, toxic epidermal necrolysis, lupus nephritis (8)
maculopapular lupus rash, photosensitivity Renal biopsy Class III or IV
Subacute cutaneous lupus lupus nephritis (10)
Chronic cutaneous lupus: Classic, Anti-ds DNA (laboratory a For diagnosis, need antinuclear antibody (ANA) titer ≥1:80 on HEp cells or equiv-
hypertrophic, panniculitis, mucosal, lupus reference or ELISA twice
alent test at any time required as entry criteria PLUS additive criteria score of ≥10
erythematous tumidus, chilblains, discoid/ laboratory reference)
points at any time. Additive criteria include clinical and immunologic (laboratory)
lichen planus
domains. At least one clinical criterion is needed.
Oral ulcers: Not explained by other causes. Anti-Smith Abbreviations: ANA, antinuclear antibodies; anti-ds DNA, anti-double stranded
Non-scarring alopecia: Not explained by Antiphospholipid antibody: DNA.
other causes Lupus anticoagulant OR false
positive RPR OR medium/
high titer of Ig G, Ig M, or Ig
A anticardiolipin, Ig G, Ig M,
or Ig A b2 glycoprotein TABLE 27.4: Selected Laboratory Tests for SLE
Synovitis: Swelling/effusion = or >2 joints Low complement: C3, C4, or Prevalence in
OR tenderness = or >2 joints with = or CH50
Test SLE Patients Associations/comments
>30 minutes morning stiffness
Serositis: Pleurisy, pleural effusions or Direct coombs without ANA 95% Not specific or
pleural rub >1 day OR pericardial pain, hemolytic anemia pathognomonic
pericardial effusions, pericardial rub or Anti-double- 70% Clinical activity and flares;
pericarditis by EKG >1 day stranded (ds) DNA renal
Renal: 500 mg protein/24 hour by urine Anti-Ro (SSA) 40% Neonatal lupus, C-NLE,
protein/creatinine or 24 hour urine antibodies Sjogren’s syndrome
protein OR RBC casts
Anti-La (SSB) 15% Neonatal lupus, Sjogren’s
Neurologic: Seizures, psychosis,
antibodies syndrome
mononeuritis multiple, myelitis, peripheral
Anticardiolipin 50% APS (see Chap. 28),
or cranial neuropathy, acute confusional
antibodies (ACA) thrombosis
state not explained by other causes
Hemolytic anemia Lupus anticoagulant 26% FGR, fetal death,
Leukopenia (<4000/mm3) OR lymphopenia (LA) pre-eclampsia
(<1000/mm3) not explained by other causes Anti-SM 20% Specific for SLE
Thrombocytopenia (<100,000/mm3) not Anti-RNP 40% Neonatal lupus, mixed
explained by other causes connective tissue disorder
a For diagnosis, need 4/17 criteria, with at least one clinical criteria and one immu-
Anticentromere 90% in CREST variant of
nologic criteria, OR lupus nephritis by renal biopsy in the presence of ANA or anti scleroderma
ds-DNA antibodies. Abbreviations: SLE, systemic lupus erythematosus; ANA, antinuclear antibodies;
Abbreviations: ANA, antinuclear antibodies; Anti-ds DNA, anti-double-stranded (ds) APS, antiphospholipid syndrome; Anti-SM, Anti-Smith; Anti-RNP, anti-ribonucleo-
DNA; ELISA, enzyme linked immunosorbent assay; RBC, red blood cell; RPR, rapid protein; CREST, calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclero-
plasm regain; Ig, Immunoglobulin. dactyly, and telangiectasia.
Systemic Lupus Erythematosus 299

Complications kidney transplants for other indications [13]. (see Chapters 13

and 17). Overall rate of renal flare is about 16% [14]. Proteinuria
Maternal (>500 mg –1 g/day) and GFR <60 ml/min increase the risk of
Complications include hypertension (4–20%), pre-eclampsia renal flares [15]. Pregnancy can worsen renal function. Mild renal
(8–20%), eclampsia (0.5–1%), preterm birth (20–50%) (spon- insufficiency (creatinine <1.4 mg/dl): Usually successful preg-
taneous—preterm premature rupture of membranes [PPROM] nancy outcome, no irreversible effect renal function. Moderate-
and preterm labor [PTL]—and indicated), cesarean section (30– severe renal insufficiency (creatinine >1.4 mg/dl): Increased risk
40%), lupus flare (20–30%), nephritis (10–20%); hematologic of OB complications, 43% worsening renal function, 10% irre-
complications including thrombocytopenia (4%), anemia (13%), versible renal deterioration [16]. Renal biopsy might be indicated
antepartum bleeding (2%), blood transfusion (3%) [4–6]. There in selected women. Pregnancy by itself does not contraindicate
is also increased risk (1–2%) for infections, thrombosis, and renal biopsy.
maternal death when compared with non-SLE pregnant women
[6]. However, maternal mortality rate has improved over the last Management
18 years in the United States (442 per 100,000 admissions for
1998–2000 to <50 per 100,000 for 2013–2015) [7]. Indicated pre- Principles
term delivery occurs in 70% of SLE pregnancy women, mostly due Over 85–90% of women without end-organ disease or antiphos-
to pre-eclampsia or high disease activity [8]. Increased risk of dia-
pholipid antibodies (APAs) do well, and take home babies. Goal:
betes is associated to treatment with steroids during pregnancy. Pregnancy with SLE in remission. Start pregnancy with SLE in
remission.
Fetal/neonatal To achieve this, usually need to optimize medical therapy
Fetal and neonatal risks are an increased incidence of first-­ preconception, usually with hydroxychloroquine. Most
trimester spontaneous pregnancy loss (10–20%), fetal death drugs are safe (see later), and should be continued throughout
(1–5%), fetal growth restriction (FGR) (5–20%), and neonatal pregnancy.
lupus (including C-NLE) (see later) [4–6] Independent risk fac-
tors for pregnancy loss in SLE women are proteinuria (≥500 mg in Workup
24 hours), APS, thrombocytopenia (≤150,000/mm3), and hyper- Baseline prenatal laboratory tests in a woman with known SLE
tension (≥140/90 mmHg) [9]. should include the following (Table 27.5): CBC with platelets/
With the exception of C-NLE, these adverse outcomes are differential count, transaminases, creatinine, blood urea
primarily seen in SLE patients with active disease periconcep-
tion, or in patients with hypertension, renal, cardiac, pulmo-
nary or neurologic disease, or antiphospholipid antibodies.
APS is associated with most fetal deaths in SLE. Renal disease TABLE 27.5: Proposed Management of SLE
is present in 50% of SLE patients. Lupus nephritis and APS are Preconception
associated with higher incidence of PTL and hypertensive disor-
ders. The complications discussed earlier may also be seen more • Start pregnancy in remission (at least >6 months)
frequently in multiple pregnancies with SLE. • Evaluate end organ damage/prior laboratory
• Assess concurrent comorbidities (HTN, APS)
• Optimize medications (usually hydroxychloroquine 200 bid),
Pregnancy considerations counsel regarding side effects
• Discontinue teratogenic medications
Effect of pregnancy on SLE • Counseling maternal and fetal complications and need for C-NLE
Pregnancy usually does not affect long-term prognosis of SLE. surveillance
Incidence of flares varies widely, depending on the definition of • Baseline laboratory evaluation: CBC with platelets/differential count,
flare, patient selection, and clinical status at conception. About transaminases, creatinine, blood urea nitrogen, anti-Ro (SSA),
50% of patients will have measurable lupus activity during preg- anti-La (SSB), ACA, LA, anti-beta 2-glycoprotein-I, anti-ds DNA,
nancy. The overall rate of lupus flare is about 26.5% [4]. In patients C3, C4, CH 50, urine sediment, 24-hour urine for total protein and
with inactive or mild to moderate disease activity at conception creatinine clearance or spot urine protein to creatinine ratio.
the rate of severe flare is only 3% [10]. Continuation of hydroxy- • Screen for diabetes if risk factors (long-term steroids)
chloroquine is important to prevent flares. If stopped, there is a • Discontinue NSAIDs if having difficulty to conceive
2.5 times higher risk of flare compared to placebo [11, 12].
Flares can occur in any trimester, but are most common in Antepartum
late pregnancy and postpartum. Most flares in pregnancy are
• Multi-disciplinary management (OB, MFM, rheumatology,
mild to moderate, musculoskeletal, cutaneous and hematologic.
nephrology, etc.)
Prednisone ≥20 mg is usually only required for severe flares.
• Continue hydroxychloroquine (usually 200 mg bid) to control
maternal disease. Consider starting if not previously taking
Effect of SLE on pregnancy
• Initiate hydroxychloroquine >200 mg/d (usually 200 mg bid) prior to
Increased incidence of complications (see earlier in the chap-
10 weeks if positive anti-SSA or anti-SSA/SSB antibodies and prior
ter). If renal SLE, 50% have hypertension, 10–30% worsening but
child with C-NLE. Consider in those with positive anti-SSA or
usually reversible renal disease. If creatinine ≥1.3 mg/dL, and/
anti-SSA/SSB antibodies without prior affected child
or creatinine clearance <50 mL/min, and/or proteinuria >3 g in
• Initiate aspirin 81 mg prior to 16 weeks’ gestation
24 hour preconception, there is small risk of irreversible renal
• Baseline laboratory evaluation (same as preconception)
deterioration. Patients with SLE that undergo kidney transplant
have a pregnancy outcome similar to those patients that have (Continued)
300
TABLE 27.5 (Continued): Proposed Management of SLE
• Repeat laboratory tests every trimester: CBC with platelets/
differential count, urinalysis, anti-ds DNA, C3, C4, 24-hour urine for
total protein and creatinine clearance or spot urine protein to
creatinine ratio
• Screen for diabetes if risk factors (e.g. on steroids)
• 1st trimester ultrasound for dating
• Ultrasound at 18–20 weeks for fetal anatomic survey
• Serial growth ultrasounds every 3–4 weeks
• Fetal echocardiograms from 16–26 weeks occurring every week and
every other week from 28-34 weeks if a previous offspring with
C-NLE and every other week if no previous offspring with C-NLE
• Consider treatment with dexamethasone or dexamethasone and
intravenous immune globulin (IVIG) for fetal first- and second-
degree AV block with continued therapy based on clinical response
• Isolated third-degree AV block is irreversible and the decision to
treat or not treat should be on a case- by- case basis, especially with
extranodal findings and after discussion with parents
• Antenatal testing weekly starting at 32 weeks, earlier as clinically
indicated
• Surveillance for pre-eclampsia, worsening kidney disease
• Evaluation by pediatric cardiologist if C-NLE
• For APS, see Chap. 28
Intrapartum
• Delivery at 39 0/7 – 39 6/7 weeks if no earlier indications
• Stress dose of steroids, if indicated
• Vaginal delivery ideal, cesarean section for OB indications/unable to
monitor fetal heart rate because of C-NLE
• Delivery at Level 3 NICU, pediatric cardiologist /pacemaker
availability if C-NLE with low ventricular rate
• Notify pediatric of SLE, especially if maternal SSA or SSA/SSB antibodies
Postpartum
• Contraception counseling
• Breastfeeding counseling
• Long-term follow-up
Abbreviations: HTN, hypertension; APS, anti-phospholipid syndrome; ACA, anticar-
diolipin antibody; LA, lupus anticoagulant; Anti-ds DNA, anti-double stranded
DNA; NSAIDs, nonsteroidal anti-inflammatory drugs; OB, obstetrician; MFM,
maternal fetal medicine; C-NLE, cardiac neonatal lupus erythematosis; C3, comple-
ment C3; C4, Complement C4; NICU, neonatal intensive care unit; SLE, systemic
lupus erythematous.
nitrogen (BUN), anti-Ro (SSA), anti-La (SSB), ACA, LA, anti-
beta 2-glycoprotein-I, anti-ds DNA, C3, C4, CH 50, urine sedi-
ment, 24-hour urine for total protein and creatinine clearance
or spot urine protein to creatinine ratio. Repeat every trimester to
assess disease activity: CBC with platelets/differential count, uri-
nalysis, anti-ds DNA, C3, C4, 24-hour urine for total protein and
creatinine clearance or spot urine protein to creatinine ratio [17].
Differential diagnosis to distinguish SLE flare from pre-
eclampsia includes the following: C3, C4 (↓ in SLE), and anti-ds
DNA (↑ in SLE), urine sediment (red and white cells and cellular
casts seen in SLE). Gestational age (GA) at onset of symptoms is
also helpful, with pre-eclampsia usually only after 20 weeks.
Preconception counseling
Preconception, antepartum, intrapartum, and postpartum care
are summarized in Table 27.5. Evaluate by history, physical exam,
Maternal-Fetal Evidence Based Guidelines
and laboratory tests. Obtain records. Discuss current medications.
To ensure pregnancy is conceived with SLE quiescent, encourage
patient to wait at least six months without flares/active disease
before attempting conception. Review diagnosis, risks and compli-
cations, and management with patient and family. Discuss contra-
ception. If stable with no recent flares on hydroxychloroquine,
it is recommended to continue it in pregnancy and postpartum.
Consider initiating hydroxychloroquine, if not previously tak-
ing. Keep steroids, if needed, at lowest possible efficacious dose.
Substitute teratogenic medications (e.g., mycophenolate mofetil)
with safe medications prior to conception. Consider multidisci-
plinary management with rheumatologist/nephrologist if lupus
nephritis. Based on baseline renal function, counsel regarding risks
of progression of renal disease and irreversible renal damage (see
Chap. 17). Women with creatinine >2.5 mg/dL should be coun-
seled regarding trying not to get pregnant, and the alternatives
of renal transplant, surrogacy, and/or adoption.
Prenatal care
For women with positive antiphospholipid antibody, see Chap. 28.
Treatment decisions are based on the past obstetric history and
any history of prior thromboembolic events. Identify and manage
risk factors for early pregnancy loss. The use of medications to
treat or suppress SLE flares will need to be evaluated on an indi-
vidual basis. If patients have been maintained on medication(s)
throughout the pregnancy, these should be continued through
the postpartum period. Counsel women regarding avoiding
excessive sun exposure or fatigue.
Therapy (Table 27.6)
Hydroxychloroquine sulfate (Plaquenil)
Hydroxychloroquine sulfate was originally an antimalarial drug.
400 mg orally daily or divided bid. Maximum dose 5 mg/kg/
day. Safe in pregnancy [18]. No increased risk of miscarriage,
stillbirth, pregnancy loss, and congenital anomalies (including
ocular abnormalities) in exposed pregnancies when compared
to non-exposed group [19–21]. This is currently the safest and
most effective therapy for SLE pregnant women who need
therapy. Important not to stop drug periconception [11, 19,
22]. Hydroxychloroquine therapy is desirable in all pregnant
SLE patients, for maternal and fetal benefit. If stable with no
recent flares on hydroxychloroquine, it is recommended to
continue it in pregnancy and postpartum. If not previously
taking, consider initiating hydroxychloroquine therapy,
unless contraindicated. Hydroxychloroquine >200 mg/d ini-
tiated prior to 10 weeks and continued through pregnancy
decreases C-NLE recurrence by greater than 50% in women
with prior affected offspring [23–25]. See CHB Prevention later
in the chapter. Compatible with breastfeeding.
NSAIDs (Nonsteroidal anti-inflammatory drugs)
Safe up to 28–30 weeks. Non-selective NSAIDs preferred over
COX 2 selective NSAIDs as limited data available to assess the
safety of cyclooxygenase (COX 2) selective NSAIDs in pregnancy.
Longer time to achieve conception is associated with the use of
NSAIDs preconception. Limited data in the literature has shown
a delayed in follicular rupture in patients taking NSAIDs. Based
on this concern, consider discontinuing NSAIDs in those patients
having difficulty to conceive [26–28]. Side effects include fetal
ductal closure and oligohydramnios, especially after 30 weeks
[29]. Non selective NSAIDs are compatible with breastfeeding.
Systemic Lupus Erythematosus 301

TABLE 27.6: Medications

Type of Medication Drug Recommendation
Immunosuppressive Agents Hydroxychloroquine Low risk
Increased risk of flares if stopped
Reduces recurrence of C-NLE
NSAIDs Non-selective COX inhibitors Safe up to 28–30 weeks
Discontinue preconception if having difficulty
conceiving as associated with delay in follicular rupture
NSAIDs COX2-selective NSAIDs Avoid as possible. Insufficient data to support its use
NSAIDs Low-dose aspirin Safe in pregnancy. Begin at 12–16 weeks for prevention
(50–150 mg) of pre-eclampsia
Corticosteroids Short-acting corticosteroids: Continue in pregnancy if efficacious
Prednisone Keep <10–20 mg/d as possible
Corticosteroids Fluorinated corticosteroids: Not for treatment of lupus activity
Dexamethasone and Betamethasone Consider its use for C-NLE
Immunosuppressive Agents Azathioprine Continue in pregnancy if efficacious
Keep <2 mg/kg/day
Immunosuppressive Agents: Certolizumab Likely safe all trimesters, minimal placental transfer
TNF inhibitors
Immunosuppressive Agents: Infliximab Likely safe in 1st and 2nd trimester based on limited
TNF inhibitor Etanercept data, long term effects unknown. Consider
Adalimumab discontinuation in the 3rd trimester
Golimumab
Immunosuppressive Agents: Rituximab Avoid as possible
TNF inhibitors
Immunosuppressive Agents: Anakira Insufficient data to recommend use in pregnancy. Use
TNF inhibitors Ustekinumab alternative TNF inhibitor
Tocilizumab
Secukinumab
Abatacept
Belimumab
Immunosuppressive Agents: Tacrolimus Likely safe based on limited data
Calcineurin inhibitors Cyclosporine Limited data in the literature. Use only if benefits
outweigh the risks
Immunoglobulin Compatible with pregnancy
Immunosuppressive Agents Leflunomide Avoid, not safe in pregnancy
Cholestyramine washout recommended if detectable
levels periconceptionally
Immunosuppressive Agents Methotrexate Contraindicated, teratogenic
Immunosuppressive Agents Cyclophosphamide Avoid, not safe in pregnancy
Use only under life-threatening conditions in 2nd and
3rd trimester
Immunosuppressive Agents Mycophenolate Avoid, not safe in pregnancy
mofetil
Intravenous immune IVIG May improve outcome of C-NLE especially with
globulin extranodal findings
Abbreviations: C-NLE, cardiac neonatal lupus erythematosis; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factors.

Low-dose aspirin (usually 81 mg, up to 150 mg daily)
should be initiated between 12 and 28 weeks gestation (ide-
ally 12–16 weeks) and taken for the duration of the pregnancy
for prevention of pre-eclampsia [30]. The use of low-dose
aspirin (60–150 mg) decreases the risk of pre-eclampsia
by 24% (RR 0.76; CI 0.62–0.95). For women with SLE, the
American College of Obstetricians and Gynecologists and
The U.S. Preventive Services Task Force recommend a dose of
81 mg daily based on tablet availability on the United States
and proven benefit on the studies included in the USPFTS
analyses [31, 32]. Additional studies have suggested using a
higher dose of 150 mg; however, this remains controversial
at this time [33].
Azathioprine (Azasan, Imuran)
Daily 50–100 mg orally or divided bid. Increase after 6–8 weeks.
Keep dose <2 mg/kg/day. Safe in pregnancy [7, 34]. FGR association
is probably due to SLE, not azathioprine. It induces chromo-
somal breaks, which disappear as infant grows. Compatible with
breastfeeding.
302
Corticosteroids
Mechanism of action is that it lowers antibody levels. Compatible
with pregnancy. For treatment of flares, usually need ≥60 mg/day
for 3 weeks.
Short-acting steroids (such as prednisone): These are metabo-
lized by the placenta with minimal to no placental transfer. Try
to keep maintenance doses <10–20 mg/day. Consider adding
steroid-sparing medications. For treatment of flares, usually need
≥60 mg/day for 3 weeks. Controversy exists regarding its associa-
tion with oral clefts when used in the first trimester. While some
authors suggested an increased risk of oral clefts (3.4-fold risk)
[35], a follow-up large study did not find such association [36].
High doses have a risk of diabetes (perform early screening for
diabetes), PPROM, hypertension, and FGR. Taper if used more
than 7 days. Side effects include increased bone loss, especially
together with heparin (give calcium).
Fluorinated corticosteroids (such as dexamethasone and beta-
methasone): These cross the placenta and should not be used to
treat lupus activity. Only use them for C-NLE. Increased risk of
FGR, oligohydramnios, and maternal complication with pro-
longed used [37–39]. See C-NLE later in the chapter.
Recommendations for perioperative stress dose of steroids are
not evidence based and limited consensus exists. In general, there
is no need for stress steroids peripartum. The usual oral daily
dose should be given peripartum. Until further data are available,
stress dose of steroids are suggested in women taking predni-
sone ≥20 mg daily or equivalent dose of a different steroid given
for >3 weeks, those with clinical features of Cushing syndrome,
and those with established diagnosis of adrenal insufficiency
by laboratory testing. Patients taking any dose of steroids for <3
weeks, prednisone <5 mg daily or equivalent dose of a different ste-
roid, or prednisone <10 mg every other day are at low risk for HPPA
suppression and do not need stress dose steroids peripartum. Less
agreement exists regarding approach to patients at intermediate
risk. Some will continue the usual morning dose and monitor for
clinical signs of adrenal insufficiency, others perform preoperative
diagnostic testing and others support therapy [40–45].
This is to prevent Addisonian collapse, manifested as general
malaise, nausea/vomiting, and skin changes, which is extremely
rare. If used, stress dose of steroids can be given as hydrocorti-
sone 100 mg IV when patient is in active labor or prior to induc-
tion of anesthesia if cesarean delivery, followed by hydrocortisone
50 mg IV q8h for 24 hours. Usual oral dose should be restarted
postpartum. If unexplained refractory hypotension, consider
secondary hypotension and treat as needed. Steroids are com-
patible with breastfeeding. Avoid breastfeeding for 4 hours if
taking prednisone ≥20 mg daily or equivalent dose of a different
steroid, otherwise discard breast milk.
Biologic agents – tumor necrosis factors inhibitors
(TNF inhibitors)
Earlier data suggested possible association with VACTERL (ver-
tebral, anorectal, cardiac, tracheoesophageal fistula, renal, limb
defects) anomaly [46], however this has not been replicated by
follow-up analyses [47–49].
Certolizumab pegol: Likely safe in pregnancy. No increased risk
of birth defects or adverse outcomes with the use of Certolizumab.
Certolizumab does not cross the placenta as it does not have the
antibody FC-region that facilitates the passage of immunoglobu-
lins through the placenta. Therefore, its use appears to be accept-
able during the entire pregnancy [50, 51].
Maternal-Fetal Evidence Based Guidelines
Etanercept, Infliximab, Adalimumab: Likely safe in first and
early second trimester based on limited data, long-term effects
unknown. Consider discontinuation, if feasible, in the second to
third trimester (infliximab, adalimumab at 20 weeks and etaner-
cept at 32 weeks) due to concern for levels of the drug in the neo-
nate which can increase the risk of infectious complications [17,
34, 52]. This association, however, remains controversial. A recent
study found similar rates of serious infections in the offspring of
exposed to TNF factor inhibitor compared to those non exposed
(2% exposed versus 1.9% non-exposed group) [53]. Live vaccines
should be avoided in neonates and for at least 6 months when there
is known exposure to TNF inhibitors during pregnancy [54, 55].
Rituximab: Less data available with Rituximab, so avoid as
possible. Reported decreased white blood cell counts in newborns
exposed in utero. If benefits outweigh risks, continue during peri-
conception and only in severe life threatening maternal condition
during pregnancy [34, 56].
Other TNFs (anakinra, ustekinumab, tocilizumab, secukinumab,
abatacept, belimumab): Consider alternative TNF use. Insufficient
data to assess risk profile in pregnancy.
TNFs compatible with breastfeeding: Certolizumab, etaner-
cept, infliximab, adalumimab.
Tacrolimus
This is a calcineurin inhibitor (CNI), used often in immunosup-
pression for transplant patients. Safe in pregnancy. Used most
often for acute flare or maintenance of lupus nephritis. Keep at
lowest effective dose. Transient neonatal elevation of the potas-
sium and creatinine level has been frequently observed after in
utero exposure to tacrolimus. Association with preterm delivery
and low birth weight, but possibly this association is due to the
underlying disease [34, 57–62]. Compatible with breastfeeding.
Cyclosporine
Not used anymore much for SLE in pregnancy. Calcineurin
inhibitor (CNI). Limited data in the literature. Use only if benefits
outweigh the risks in patients not responding to other therapy.
No increased risk of congenital anomalies. Association with low
birth weight, maternal diabetes, hypertension and kidney graft
rejection likely related to disease and not cyclosporine [63–65].
Compatible with breastfeeding.
Immunoglobulin
Safe in pregnancy, but usually not necessary for SLE in pregnancy.
If indicated, use as 0.5 g/kg initiated after positive pregnancy
test until 33 weeks of gestation (placental transfer increases after
30–32 weeks). It has been associated in a nonrandomized study
with decrease in the rate of miscarriage in patients with history
of recurrent pregnancy loss (25% pregnancy loss in non-treated
group versus 0% in treated group) with or without associated
APS, decrease in doses of concomitant medications including
prednisolone, decrease in lupus activity, and improvement in
laboratory values (anti-ds DNA, anti-Ro, and anti-LA antibod-
ies) [66]. Insufficient data for recommendation; further studies
are needed [34]. Compatible with breastfeeding.
Leflunomide
Antimetabolite, blocks pyrimidine synthesis by inhibiting the
dihydroorotate dehydrogenase. Avoid as no data available and
long half-life of its metabolite, teriflunomide, is of concern. Wait
2 years after discontinuation of therapy to attempt conception.
Cholestyramine washout is recommended if detectable levels
Systemic Lupus Erythematosus
prior to a planned pregnancy or once pregnant to accelerate clear-
ance. This is achieved with a level of <0.02 mg/L documented in 2
occasions 14 days apart. The risk of congenital anomalies does not
appear increased in those pregnancies exposed to leflunomide
following cholestyramine washout [67].
Other agents
Acetaminophen or paracetamol: Safe throughout pregnancy.
Usually not as effective as other therapies.
Cyclophosphamide, methotrexate, and mycophenolate mofetil:
Avoid; not safe in pregnancy, known teratogenics. Discontinue
at least 1–3 months prior to conception.
Plasmapheresis: Last resort, consult rheumatology.
Antepartum testing
Accurate gestational age assessment is important; therefore, a
first-trimester ultrasound examination is indicated. Perform
fetal anatomic survey between 18 and 20 weeks and fetal echo-
cardiogram at 16 or 17 weeks. For women with anti-SSA or
anti-SSA/SSB antibodies and a prior child with C-NLE, echo-
cardiograms have been recommended every week from 16 to 26
weeks and every other week from 26 to 34 weeks. For women
with anti-SSA or anti-SSA/SSB antibodies and no previously
affected children, echocardiograms have been recommended
weekly or biweekly from 16 to 26 weeks; however, recommenda-
tions for echocardiographic surveillance may be changing in the
next 5 years (see section on C-NLE). Fetal growth can be evalu-
ated throughout the pregnancy with ultrasound examinations
every 4 weeks. Patients in whom disease activity is quiescent,
and there is no evidence of hypertension, renal disease, FGR, or
pre-eclampsia, can begin weekly fetal testing at 32–36 weeks’
gestation [68]. Patients with active disease, antiphospholipid anti-
bodies, renal disease, hypertension, or FGR can begin antepar-
tum testing earlier.
Delivery
Delivery is recommended at 39 0/7–39 6/7 weeks, if no earlier
indications. A trial of labor is preferred, and cesarean delivery
should be reserved for obstetrical indications or if the fetus has
developed C-NLE rendering heart rate monitoring inconclusive.
Stress dose steroids are indicated only if prednisone ≥20 mg daily
or equivalent dose of a different steroid is given for >3 weeks,
clinical features of Cushing syndrome, and established diag-
nosis of adrenal insufficiency by laboratory testing. See section
“Corticosteroids.”
Postpartum/Breastfeeding
Flares are more common. Continue, and consider increasing, SLE
therapies. Breastfeeding is usually safe depending on medications.
Cardiac neonatal lupus erythematosis
Neonatal lupus erythematosus (NLE) occurs in 1–2% of babies
born to mothers with anti-SSA or anti-SSA/SSB antibodies. The
female to male ratio of affected offspring is 14:1. All but the car-
diac manifestations of NLE are transient, last up to 16 weeks. It
is caused by passage of maternal Ig G (anti-Ro/SSA and anti-La/
SSB) antibodies through the placenta and occurs regardless of
maternal diagnosis or symptoms of lupus or other auto-immune
303
disease. Non-cardiac manifestations include cutaneous (pho-
tosensitive annular erythematous rash), hematologic (anemia,
thrombocytopenia, pancytopenia), and hepatic (elevated liver
enzymes, cholestasis, fulminant liver disease) findings. The car-
diac manifestations are permanent and include congenital atrio-
ventricular (AV) block, dilated cardiomyopathy and endocardial
fibroelastosis. These finding, whether isolated or occurring
together, are known as cardiac neonatal lupus erythematosus
(C-NLE).
Etiology and pathogenesis
SSA/Ro-SSB/La antibodies cross the placenta and bind to surface
cardiomyocytes triggering inflammation, remodeling and fibro-
sis. Two hypotheses have been proposed.
Apoptosis Hypothesis: Cells undergoing physiologic apoptosis
expose intracellular antigens (SSA/Ro and SSB/La ribonucleopro-
teins) to the surface of the cardiomyocyte. An immune complex
is then formed between the apoptotic cell and the SSA/Ro anti-
bodies or SSA/SSB antibodies. Following phagocytosis by mac-
rophages, these immune complexes ligate to Toll like receptors
(TLC) 7/8 triggering an inflammatory response leading to secre-
tion of cytokines (such as type I interferon) which promotes car-
diac fibrosis.
Calcium Channel Hypothesis: Cross reactivity of L-type cal-
cium channels with anti-/SSA or anti-SSA/SSB antibodies has
also been proposed as a mechanism altering calcium homeosta-
sis leading to conduction abnormalities. This might also lead to
pathogenic apoptosis and subsequent inflammation and fibrosis
[69–73].
Anti-SSA/Ro with or without anti-SSB/La antibodies are caus-
ative in C-NLE. SSB/La antibodies alone are associated with
<0.5% of C-NLE. High levels of anti-Ro/SSA antibodies are neces-
sary but not sufficient for the development of C-NLE. Results from
a research laboratory found that a level of ≥50 U/ml of anti-Ro
antibodies correlated with risk of C-NLE while fetuses of mothers
with anti-Ro levels < 50U/ml did not develop C-NLE [74]. Testing
for specific amino acids regions within the Ro52 antibody might
be incorporated in the future and the specific Ro52/p200 might
play a role in predicting those patients at higher risk for C-NLE.
Counseling
The risk of C-NLE is about 2% in mothers with positive anti-SSA
or anti-SSA/SSB antibodies and no prior affected pregnancy. It
increases to 10–15% if prior child with cutaneous lupus and 18% if
prior child with cardiac–NL, but the risk does not decrease with
a previously unaffected child. Anti-SSA or anti-SSA/SSB posi-
tive mothers with thyroid disease have a higher risk of NC-NLE
as compared with mothers whose babies born in spring [108].
It is estimated that approximately 40% of patients with SLE
have anti-Ro/SSA antibodies. C-NLE is most likely to occur
between 18- and 24 weeks gestation and rarely after 26 weeks’
gestation [75, 80]. Third-degree AV block may be associated with
congestive heart failure (hydrops), and in 18%, fetal or neonatal
demise [77]. If third-degree AV block is associated with dilated
cardiomyopathy, mortality is 50%. Poor prognostic factors in
utero include diagnosis at <20 weeks’ gestation, hydrops, ventric-
ular rate <50 bpm, left ventricular failure. A permanent cardiac
pacemaker is needed in almost all survivors, and in 60–70% of
affected children by 3 months of age [77]. In the current era, the
10-year survival rate of liveborns with normal cardiac function is
86% but falls to 23.1% if dilated cardiomyopathy is present at birth
[109]. Cardiac transplant action occurs in 7–19% [98, 110].
304
Management
Prenatal care evaluation
Fetal echocardiography has been the mainstay of prenatal sur-
veillance for anti-SSA or anti-SSA/SSB antibody positive preg-
nancies. The purpose of the fetal echocardiogram is to evaluate
the mechanical consequences of AV conduction and to assess
extranodal findings of C-NLE such as EFE, effusions, and AV
valve insufficiency.
The fetal mechanical PR (also called the AV) interval is lon-
ger by 18–20 ms than the concurrently measured electrical time
intervals because it incorporates the isovolumic contraction time
and intra-atrial conduction times [111]. The AV interval is mea-
sured from the onset of the atrial contraction to the onset of ven-
tricular contraction using simultaneous mitral inflow and aortic
outflow Doppler waveforms. While an AV interval of 150 ms has
previously been the cut off for first-degree AV block, newer data
suggest an AV interval of ≥170 ms may be a more accurate defi-
nition of first-degree AV block [81, 96]. Published recommenda-
tions suggest weekly or biweekly fetal echocardiograms from
16 to 28 weeks [82]; however, not only may this protocol not be
cost effective due to the rarity of C-NLE, but also Doppler/M-
mode tracings of diagnostic quality may not be easy to obtain or
interpret. Furthermore, even weekly echocardiograms occur too
infrequently to detect first- or second-degree AV block [83, 87].
The technique of ambulatory fetal heart rate and rhythm moni-
toring (FHRM) is gaining favor as an adjunct to fetal echocar-
diography [88, 112]. Because of its frequency, FHRM is able to
detect changes in rhythm and rate that occur over hours rather
than weeks. Identifying the transition period of “emergent” third-
degree AV block by a change in rhythm from regular to irregular
allows for rapid treatment that can restore normal rhythm [113].
Echocardiography is still the only technique to detect extranodal
findings of C-NLE, but its role in surveillance for conduction sys-
tem disease may be challenging.
Prevention
A non-randomized study suggested that hydroxychloroquine
>200 mg/day (common dose 200 mg bid) initiated prior to
10 weeks and continued through pregnancy decreases C-NLE
recurrence in women with prior affected offspring by 64% [23]. A
follow-up study showed a decreased recurrence of CHB of greater
than 50% (from 18% to 7.4%) when hydroxychloroquine 400 mg/d
was given to anti-Ro/SSA antibody positive women with or with-
out SSB antibodies with a prior affected child [25].
While data are insufficient to recommend the use of hydroxy-
chloroquine to decrease the risk of C-NLE in anti-Ro/SSA or
anti-Ro/SSA and anti-La/SSB antibody positive women without
affected offspring, the 2020 American College of Rheumatology
(ACR) Guideline for the Management of Reproductive Health in
Rheumatic and Musculoskeletal Diseases (RMD) “conditionally”
recommends hydroxychloroquine to all women with posi-
tive anti- SSA or anti-SSA/SSB antibodies in pregnancy [3]. A
cohort study showed decreased risk by 28%, but statistical signifi-
cance was no longer seen after multivariable analyses [24]. IVIG
is ineffective for recurrence prevention [89, 90].
Therapy
Controversy exits regarding the management of C-NLE because
data are retrospective, and treatment is based on institutional
preference. The hypothesis that inflammation precedes fibrosis
in the pathogenesis of C-NLE supports the therapeutic effects
Maternal-Fetal Evidence Based Guidelines
of fluorinated steroids such as dexamethasone as well as intra-
venous immune globulin. These medications have been judged
on success in two categories: restoring normal AV conduction
and improving outcome. While third-degree AV block is irre-
versible, treating emergent third-degree AV block can halt pro-
gression or restore normal rhythm. Improved outcomes include
fewer fetuses with dilated cardiomyopathy and more survivors.
Those who advocate IVIG and/or dexamethasone in the presence
of third-degree AV block believe that the treatment will prevent
or improve myocardial disease. Dexamethasone 8 mg/day for
10–14 days than 4 mg/day for the remainder of pregnancy or
weaning the dose after 32 weeks has been proposed to treat
fetuses with first- and second-degree AV block to normalize
AV conduction or to prevent progression to complete heart block.
While some continue to advocate its use (including the 2020 ACR
Guideline for the Management of Reproductive Health in RMD),
others question the risk/benefits and even discourage its use [17,
37, 77, 78, 83, 84, 87, 91–100].
The risks and benefits, as well as the limited data supporting
treatment and expectant management should be openly dis-
cussed with the family whose fetus has any sign of C-NLE, be
it conduction system or myocardial disease. The side effects of
dexamethasone (oligohydramnios, fetal growth restriction,
maternal diabetes) are well known and significant; some can be
reduced if the dexamethasone is weaned after 30 or 32 weeks of
gestation [114]. Further studies are needed to evaluate the long-
term effects of steroids therapy on neurocognitive development
[37–39].
First-degree AV block: The decision to treat is not straight for-
ward since first-degree AV block has progressed and improved
both with and without treatment, and before and after delivery
[96, 115]. Probably the most important consideration has been
previously mentioned, that is to use an accurate definition of
first-degree AV block. FHRM should provide assurance that an
AV interval of 150–170 ms is not progressing to second-degree
AV block. An exception may be made if signs of extranodal
C-NLE are present with an AV interval of 150–170 ms. More
should be understood of the natural history of Second-degree
AV block: Definitive conclusions regarding the efficacy of IVIG
and/or fluorinated steroids cannot be made from available data
as regression, stabilization, and progression have all been dem-
onstrated in the literature [37, 78, 84, 91, 93, 96–100], both with
and without treatment. Second-degree heart block can progress
to third-degree AV block, alternatively it can spontaneously
improve or improve with treatment. Retrospective data from
non-randomized studies have shown the rates of progression to
third-degree AV block in the steroid treated group compared
to the non-treated group were 52% versus 73%, respectively.
The rates of regression (to sinus rhythm, first-degree AV block or
intermitted first-/second-degree AV block) in the steroid treated
group compared to the non-treated group were 25% versus 23%,
respectively [93]. The 2020 ACE Guideline for the Management
of Reproductive Health in RMD also recommends the use of
steroids for the treatment of first- and second-degree AV
block. Once therapy is initiated, consider follow up fetal echo-
cardiogram on a weekly basis and daily ambulatory FHRM to
assess the benefits of therapy [17, 94, 95].
Two recent meta-analyses questioned the efficacy and risk/
benefit of fluorinated corticosteroids for the treatment of C-NLE
including second- and third-degree AV block. The first meta-
analysis reported a downgrade of congenital heart block of 9.5%
in the treated patients compared to 1.8% in the non-treated
Systemic Lupus Erythematosus
patients. However, this publication concluded that rates of fetal
and neonatal death and pacemaker placement were not statisti-
cally different between the treated and non-treated groups and
showed increased risk of oligohydramnios, fetal growth restric-
tion, and maternal complication. Therefore, the authors discour-
aged the use of steroids in the management of C-NLE. However,
by not analyzing second- and third-degree AV block separately,
the strength of the authors’ conclusions is weakened [37]. The
other meta-analysis discouraging the use of steroids did not
demonstrate an improvement in survival, progression of incom-
plete heart block, extra-nodal disease and pacemaker placement.
The rate of progression of second-degree AV block in the steroid
treated group compared to the non-treated group was 52.4% ver-
sus 63.1%, respectively. However, only 42 fetuses were included
in this subgroup analysis. Survival in the steroid treated group
compared to the non-treated group was 86.8% versus 86.7%,
respectively. Pacemaker placement in the steroid treated group
compared to the non-treated group was 70.24% versus 76.3%,
respectively. Extra-nodal disease in the steroid treated group
compared to the non-treated group was present or occurred in
24.2% versus 21%, respectively [100].
Third-degree AV block: The use of steroids is not beneficial in
the absence of myocardial dysfunction.
Third-degree AV block is considered to be irreversible.
Some experts will still consider therapy in fetuses with asso-
ciated extra nodal disease (such as endocardial fibroelasto-
sis and dilated cardiomyopathy) or hydrops. However, this
remains an area of controversy [84, 98, 99, 101, 102].
Meta-analyses of non-randomized clinical trials evaluated the
use of steroids in fetuses with third-degree AV block. The rates of
regression to second or first-degree AV block in the steroid treated
group compared to the non-treated group were 3% versus 4.3%,
respectively. Pacemaker placement in the steroid treated group
compared to the non-treated group was 71.5% versus 57.8%,
respectively. Mortality rates of the non-hydropic fetuses in the
steroid treated group compared to the non-treated group were
8.9% versus 12%, respectively. Mortality rates of the hydropic
fetuses in the steroid treated group compared to the non-treated
group were 76.2% versus 23.8%, respectively. Improvement or
resolution of hydrops in the steroid treated group compared to
the non-treated group was 76% versus 23.3%, respectively [101].
While some studies suggested steroids improved long-term
survival [50], others have failed to demonstrate that treatment
with fluorinated steroids once third-degree AV block is detected,
fail to, improve survival or, decrease the need of pacemaker place-
ment [78, 95, 98, 99, 101].
There is a potential benefit of IVIG (1 g/kg, 1–3 doses) to
improve survival rates and decrease the need of cardiac trans-
plant in fetuses/neonates with cardiomyopathy and/or endo-
cardial fibroelastosis [92].
Other therapies: A combination of plasmapheresis, IVIG, and
betamethasone suggests possible benefit in reverting second
degree block to first-degree AV block or sinus rhythm. Those with
third-degree AV block did not change. Data are still limited and
further studies are needed to assess the efficacy of these combi-
nation therapies [103]. Beta-mimetics, usually given as adjuvant
therapy, remains an area of further research but has been found
to increase ventricular and atrial rates and prolong gestation [72].
The STOP BLOQ (Surveillance and Treatment to stop AV
block likely to occur quickly) clinical trial, currently under-
way, will (1) determine if risk stratification by antibody titers
is valid; (2) define the role of ambulatory FHRM and fetal
305
echocardiography in the surveillance for fetal AV block; and
(3) determine if maximum anti-inflammatory treatment
(IVIG plus dexamethasone) during the period of emergent
third-degree AV block can prevent progression or restore nor-
mal rhythm for surveillance.
Delivery
Women with fetuses with CHB should be managed and deliv-
ered at a tertiary care center with the availability of immedi-
ate neonatal pacing. While trial of labor (TOL) by repeated scalp
sampling to assure fetal well-being has been attempted, most
fetuses with C-NLE undergo Cesarean delivery.
Contraception
IUDs are a safe and most effective option in women with
SLE taking immunosuppressive medications. Caution is
advised with the initiation of injectable Depot medroxypro-
gesterone acetate in women with SLE with platelets <50,000.
Combination oral contraceptives (pill or vaginal ring) are safe
for women with mild/stable lupus who do not have antiphos-
pholipid antibodies and/or cardiovascular risk factors (as
determined by the U.S. Medical Eligibility Criteria [USMEC]
for contraceptive use). Progestin only pills or IUDs are accept-
able options for women with SLE with moderate or severe
disease activity (such as vascular disease, nephritis) and/or
antiphospholipid antibodies. Combined oral contraceptives
are contraindicated in women with antiphospholipid antibod-
ies. Avoid a transdermal estrogen-progestin patch in all SLE
patients [17, 104–107].
References
1. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The
1982 revised criteria for the classification of systemic lupus erythematosus.
Arthritis Rheum 1982;25(11):1271–7. [III]
2. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al.
Derivation and validation of the systemic lupus international collaborating
clinics classification criteria for systemic lupus erythematosus. Arthritis
Rheum 2012;64(8):2677–86. [II-2]
3. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman
R, et al. 2019 European League Against Rheumatism/American college of
rheumatology classification criteria for systemic lupus erythematosus. Ann
Rheum Dis 2019;78(9):1151–9. [III]
4. Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic VD. A sys-
tematic review and meta-analysis of pregnancy outcomes in patients with
systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol
2010;5(11):2060–8. [II-2]
5. Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the
United States for women with systemic lupus erythematosus and rheuma-
toid arthritis. Arthritis Rheum 2006;54(3):899–907. [II-2]
6. Clowse ME, Jamison M, Myers E, James AH. A national study of the compli-
cations of lupus in pregnancy. Am J Obstet Gynecol 2008;199(2):127 e1–6.
[II-2]
7. Mehta B, Luo Y, Xu J, Sammaritano L, Salmon J, Lockshin M, et al. Trends
in maternal and fetal outcomes among pregnant women with systemic
lupus erythematosus in the United States: a cross-sectional analysis. Ann
Intern Med 2019;171(3):164–71. [II-2]
8. Eudy AM, Jayasundara M, Haroun T, Neil L, James AH, Clowse MEB.
Reasons for cesarean and medically indicated deliveries in pregnancies in
women with systemic lupus erythematosus. Lupus 2018;27(3):351–6. [II-2]
9. Clowse ME, Magder LS, Witter F, Petri M. Early risk factors for pregnancy
loss in lupus. Obstet Gynecol 2006;107(2 Pt 1):293–9. [II-2]
10. Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, et al.
Predictors of pregnancy outcomes in patients with lupus: a cohort study.
Ann Intern Med 2015;163(3):153–63. [II-2]
11. Canadian Hydroxychloroquine Study G. A randomized study of the effect
of withdrawing hydroxychloroquine sulfate in systemic lupus erythemato-
sus. N Engl J Med 1991;324(3):150–4. [I, RCT: n = 47]
306
12. Eudy AM, Siega-Riz AM, Engel SM, Franceschini N, Howard AG, Clowse
MEB, et al. Effect of pregnancy on disease flares in patients with systemic
lupus erythematosus. Ann Rheum Dis 2018;77(6):855–60. [II-2]
13. McGrory CH, McCloskey LJ, DeHoratius RJ, Dunn SR, Moritz MJ, Armenti
VT. Pregnancy outcomes in female renal recipients: a comparison of
systemic lupus erythematosus with other diagnoses. Am J Transplant
2003;3(1):35–42. [II-2]
14. Huong DL, Wechsler B, Vauthier-Brouzes D, Beaufils H, Lefebvre G, Piette
JC. Pregnancy in past or present lupus nephritis: a study of 32 pregnancies
from a single centre. Ann Rheum Dis 2001;60(6):599–604. [II-2]
15. Imbasciati E, Tincani A, Gregorini G, Doria A, Moroni G, Cabiddu
G, et al. Pregnancy in women with pre-existing lupus nephritis: pre-
dictors of fetal and maternal outcome. Nephrol Dial Transplant
2009;24(2):519–25. [II-2]
16. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or
severe renal insufficiency. N Engl J Med 1996;335(4):226–32. [II-2]
17. Sammaritano LR, Bermas BL, Chakravarty EE, Chambers C, Clowse MEB,
Lockshin MD, et al 2020 American College of Rheumatology Guideline for
the management of reproductive health in rheumatic and musculoskeletal
diseases. Arthritis Rheumatol 2020;72(4):529–56. [Guideline, III]
18. Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong DL, Sebbough D,
Wechsler B, et al. Safety of hydroxychloroquine in pregnant patients with
connective tissue diseases: a study of one hundred thirty-three cases com-
pared with a control group. Arthritis Rheum 2003;48(11):3207–11. [II-2]
19. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus
pregnancy. Arthritis Rheum 2006;54(11):3640–7. [II-2]
20. Costedoat-Chalumeau N, Amoura Z, Huong DL, Lechat P, Piette JC. Safety
of hydroxychloroquine in pregnant patients with connective tissue diseases.
Review of the literature. Autoimmun Rev 2005;4(2):111–5. [Review, III]
21. Gaffar R, Pineau CA, Bernatsky S, Scott S, Vinet E. Risk of ocular anomalies
in children exposed in utero to antimalarials: a systematic literature review.
Arthritis Care Res (Hoboken) 2019;71(12):1606–10. [Review, III]
22. Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, et al.
Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-
controlled study. Lupus 2001;10(6):401–4. [I, RCT: n = 20]
23. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim
MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with
a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac mani-
festations of neonatal lupus. Circulation 2012;126(1):76–82. [II-2]
24. Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, et al.
Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac
manifestations of neonatal lupus in fetuses of mothers with systemic
lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis
2010;69(10):1827–30. [II-2]
25. Izmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, Clancy R,
Copel JA, et al. Hydroxychloroquine to prevent recurrent congenital
heart block in fetuses of Anti-SSA/Ro-Positive mothers. J Am Coll Cardiol
2020;76(3):292–302. [II-1]
26. Brouwer J, Hazes JM, Laven JS, Dolhain RJ. Fertility in women with rheuma-
toid arthritis: influence of disease activity and medication. Ann Rheum Dis
2015;74(10):1836–41. [II-2]
27. Uhler ML, Hsu JW, Fisher SG, Zinaman MJ. The effect of nonsteroidal anti-
inflammatory drugs on ovulation: a prospective, randomized clinical trial.
Fertil Steril 2001;76(5):957–61. [I, RCT: n = 24]
28. Pall M, Friden BE, Brannstrom M. Induction of delayed follicular rupture
in the human by the selective COX-2 inhibitor rofecoxib: a randomized
double-blind study. Hum Reprod 2001;16(7):1323–8. [I, RCT: n = 13]
29. Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME. Nonsteroidal
antiinflammatory drugs during third trimester and the risk of prema-
ture closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother
2006;40(5):824–9. [I]
30. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al.
Prevention of pre-eclampsia and intrauterine growth restriction with aspi-
rin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010;116
(2 Pt 1):402–14. [I]
31. ACOG Committee Opinion No. 743: Low-dose aspirin use during preg-
nancy. Obstet Gynecol2018;132(1):e44–e52. [III]
32. LeFevre ML, Force USPST. Low-dose aspirin use for the prevention of
morbidity and mortality from pre-eclampsia: U.S. Preventive Services
Task Force recommendation statement. Ann Intern Med 2014;161
(11):819–26. [III]
33. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco
Matallana C, et al. Aspirin versus Placebo in Pregnancies at High Risk
for Preterm Pre-eclampsia. N Engl J Med 2017;377(7):613–22. [I, RCT:
n = 1776]
Maternal-Fetal Evidence Based Guidelines
34. Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E,
Chambers C, et al. The EULAR points to consider for use of antirheumatic
drugs before pregnancy, and during pregnancy and lactation. Ann Rheum
Dis 2016;75(5):795–810. [Review, III]
35. Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett
L, et al. Birth defects after maternal exposure to corticosteroids: prospec-
tive cohort study and meta-analysis of epidemiological studies. Teratology
2000;62(6):385–92. [II-2]
36. Hviid A, Molgaard-Nielsen D. Corticosteroid use during pregnancy and
risk of orofacial clefts. CMAJ 2011;183(7):796–804. [II-2]
37. Michael A, Radwan AA, Ali AK, Abd-Elkariem AY, Shazly SA, Middle-East
O, et al. Use of antenatal fluorinated corticosteroids in management of
congenital heart block: systematic review and meta-analysis. Eur J Obstet
Gynecol Reprod Biol X 2019;4:100072. [Review, III]
38. Kelly EN, Sananes R, Chiu-Man C, Silverman ED, Jaeggi E. Prenatal anti-Ro
antibody exposure, congenital complete atrioventricular heart block, and
high-dose steroid therapy: impact on neurocognitive outcome in school-age
children. Arthritis Rheumatol 2014;66(8):2290–6. [II-2]
39. Breur JM, Visser GH, Kruize AA, Stoutenbeek P, Meijboom EJ. Treatment
of fetal heart block with maternal steroid therapy: case report and
review of the literature. Ultrasound Obstet Gynecol 2004;24(4):467–72.
[Review, III]
40. Marik PE, Varon J. Requirement of perioperative stress doses of corticoste-
roids: a systematic review of the literature. Arch Surg 2008;143(12):1222–6.
[Review, III]
41. Kelly KN, Domajnko B. Perioperative stress-dose steroids. Clin Colon
Rectal Surg 2013;26(3):163–7. [Review, III]
42. Liu MM, Reidy AB, Saatee S, Collard CD. Perioperative steroid management:
approaches based on current evidence. Anesthesiology 2017;127(1):166–72.
[Review, III]
43. Woodcock T, Barker P, Daniel S, Fletcher S, Wass JAH, Tomlinson JW,
et al. Guidelines for the management of glucocorticoids during the peri-
operative period for patients with adrenal insufficiency: guidelines from
the Association of Anaesthetists, the Royal College of Physicians and the
Society for Endocrinology UK. Anaesthesia 2020;75(5):654–63. [Review,
III]
44. Groleau C, Morin SN, Vautour L, Amar-Zifkin A, Bessissow A. Perioperative
corticosteroid administration: a systematic review and descriptive analysis.
Perioper Med (Lond) 2018;7:10. [Review, III]
45. Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer
GD, et al. Diagnosis and treatment of primary adrenal insufficiency: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab
2016;101(2):364–89. [Guideline, III]
46. Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment
of tumor necrosis factor antagonists during pregnancy: a review of the
Food and Drug Administration database. J Rheumatol 2009;36(3):635–41.
[Review, III]
47. Crijns HJ, Jentink J, Garne E, Gispen-de Wied CC, Straus SM, de Jong-
van den Berg LT, et al. The distribution of congenital anomalies within
the VACTERL association among tumor necrosis factor antagonist-
exposed pregnancies is similar to the general population. J Rheumatol
2011;38(9):1871–4. [II-2]
48. Chambers C, Koren G, Tutuncu ZN, Johnson D, Jones KL. Are new
agents used to treat rheumatoid arthritis safe to take during pregnancy?
Organization of teratology information specialists (OTIS) study. Can Fam
Physician 2007;53(3):409–12. [Review, III]
49. Chambers C, Johnson DL, Kiernan E. Approach to evaluating preg-
nancy safety of anti-rheumatic medications in the OTIS MotherToBaby
pregnancy studies: what have we learned? Rheumatology (Oxford)
2018;57(suppl_5):v34–v9. [III]
50. Clowse MEB, Scheuerle AE, Chambers C, Afzali A, Kimball AB, Cush JJ,
et al. Pregnancy outcomes after exposure to Certolizumab Pegol: updated
results from a pharmacovigilance safety database. Arthritis Rheumatol
2018;70(9):1399–407. [II-2]
51. Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA,
et al. Placental transfer of anti-tumor necrosis factor agents in pregnant
patients with inflammatory bowel disease. Clin Gastroenterol Hepatol
2013;11(3):286–92; quiz e24. [III]
52. Chambers CD, Johnson DL, Xu R, Luo Y, Lopez-Jimenez J, Adam MP, et al.
Birth outcomes in women who have taken adalimumab in pregnancy: a pro-
spective cohort study. PLOS ONE 2019;14(10):e0223603. [II-2]
53. Vinet E, De Moura C, Pineau CA, Abrahamowicz M, Curtis JR, Bernatsky
S. Serious infections in rheumatoid arthritis offspring exposed to
tumor necrosis factor inhibitors: a cohort study. Arthritis Rheumatol
2018;70(10):1565–71. [II-2]
Systemic Lupus Erythematosus
54. Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K, et al.
BSR and BHPR guideline on prescribing drugs in pregnancy and breast-
feeding-Part I: standard and biologic disease modifying anti-rheumatic
drugs and corticosteroids. Rheumatology (Oxford) 2016;55(9):1693–7.
[Guideline, III]
55. Heller MM, Wu JJ, Murase JE. Fatal case of disseminated BCG infection
after vaccination of an infant with in utero exposure to infliximab. J Am
Acad Dermatol 2011;65(4):870. [III]
56. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes
after maternal exposure to rituximab. Blood 2011;117(5):1499–506. [II-2]
57. Kainz A, Harabacz I, Cowlrick IS, Gadgil SD, Hagiwara D. Review of the
course and outcome of 100 pregnancies in 84 women treated with tacroli-
mus. Transplantation 2000;70(12):1718–21. [II-3]
58. Kainz A, Harabacz I, Cowlrick IS, Gadgil S, Hagiwara D. Analysis of 100
pregnancy outcomes in women treated systemically with tacrolimus.
Transpl Int 2000;13 (Suppl 1):S299–300. [II-3]
59. Jain A, Venkataramanan R, Fung JJ, Gartner JC, Lever J, Balan V, et al.
Pregnancy after liver transplantation under tacrolimus. Transplantation
1997;64(4):559–65. [II-2]
60. Jain AB, Reyes J, Marcos A, Mazariegos G, Eghtesad B, Fontes PA, et al.
Pregnancy after liver transplantation with tacrolimus immunosuppres-
sion: a single center’s experience update at 13 years. Transplantation
2003;76(5):827–32. [II-2]
61. Webster P, Wardle A, Bramham K, Webster L, Nelson-Piercy C, Lightstone
L. Tacrolimus is an effective treatment for lupus nephritis in pregnancy.
Lupus 2014;23(11):1192–6. [II-3]
62. Westbrook RH, Yeoman AD, Agarwal K, Aluvihare V, O’Grady J, Heaton
N, et al. Outcomes of pregnancy following liver transplantation: The King’s
College Hospital experience. Liver Transpl 2015;21(9):1153–9. [II-2]
63. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after
cyclosporine therapy during pregnancy: a meta-analysis. Transplantation
2001;71(8):1051–5. [II-2]
64. Paziana K, Del Monaco M, Cardonick E, Moritz M, Keller M, Smith B, et al.
Ciclosporin use during pregnancy. Drug Saf 2013;36(5):279–94. [Review, III]
65. Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke
JF. National transplantation Pregnancy Registry–outcomes of 154 preg-
nancies in cyclosporine-treated female kidney transplant recipients.
Transplantation 1994;57(4):502–6. [II-2]
66. Perricone R, De Carolis C, Kroegler B, Greco E, Giacomelli R, Cipriani P,
et al. Intravenous immunoglobulin therapy in pregnant patients affected
with systemic lupus erythematosus and recurrent spontaneous abortion.
Rheumatology (Oxford) 2008;47(5):646–51. [II-2]
67. Chambers CD, Johnson DL, Robinson LK, Braddock SR, Xu R, Lopez-
Jimenez J, et al. Birth outcomes in women who have taken leflunomide dur-
ing pregnancy. Arthritis Rheum 2010;62(5):1494–503. [II-2]
68. Practice Bulletin No. 145: antepartum fetal surveillance. Obstet Gynecol
2014;124(1):182–92. [III]
69. Clancy RM, Markham AJ, Reed JH, Blumenberg M, Halushka MK, Buyon
JP. Targeting downstream transcription factors and epigenetic modifica-
tions following Toll-like receptor 7/8 ligation to forestall tissue injury in
anti-Ro60 associated heart block. J Autoimmun 2016;67:36–45. [II-2]
70. Clancy RM, Halushka M, Rasmussen SE, Lhakhang T, Chang M, Buyon
JP. Siglec-1 Macrophages and the contribution of IFN to the development
of autoimmune congenital heart block. J Immunol 2019;202(1):48–55.
[II-2]
71. Hedlund M, Thorlacius GE, Ivanchenko M, Ottosson V, Kyriakidis N,
Lagnefeldt L, et al. Type I IFN system activation in newborns exposed to
Ro/SSA and La/SSB autoantibodies in utero. RMD Open 2020;6(1). [II-2]
72. Pruetz JD, Miller JC, Loeb GE, Silka MJ, Bar-Cohen Y, Chmait RH. Prenatal
diagnosis and management of congenital complete heart block. Birth
Defects Res 2019;111(8):380–8. [Review, III]
73. Izmirly PM, Buyon JP, Saxena A. Neonatal lupus: advances in understand-
ing pathogenesis and identifying treatments of cardiac disease. Curr Opin
Rheumatol 2012;24(5):466–72. [Review, III]
74. Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E. The importance
of the level of maternal anti-Ro/SSA antibodies as a prognostic marker
of the development of cardiac neonatal lupus erythematosus a prospec-
tive study of 186 antibody-exposed fetuses and infants. J Am Coll Cardiol
2010;55(24):2778–84. [II-2]
75. Brito-Zeron P, Izmirly PM, Ramos-Casals M, Buyon JP, Khamashta MA.
The clinical spectrum of autoimmune congenital heart block. Nat Rev
Rheumatol 2015;11(5):301–12. [Review, III]
76. Izmirly PM, Llanos C, Lee LA, Askanase A, Kim MY, Buyon JP. Cutaneous
manifestations of neonatal lupus and risk of subsequent congenital heart
block. Arthritis Rheum 2010;62(4):1153–7. [II-2]
307
77. Izmirly PM, Saxena A, Kim MY, Wang D, Sahl SK, Llanos C, et al. Maternal
and fetal factors associated with mortality and morbidity in a multi-
racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus.
Circulation 2011;124(18):1927–35. [II-2]
78. Eliasson H, Sonesson SE, Sharland G, Granath F, Simpson JM, Carvalho JS,
et al. Isolated atrioventricular block in the fetus: a retrospective, multina-
tional, multicenter study of 175 patients. Circulation 2011;124(18):1919–26.
[II-2]
79. Buyon JP, Hiebert R, Copel J, Craft J, Friedman D, Katholi M, et al.
Autoimmune-associated congenital heart block: demographics, mortality,
morbidity and recurrence rates obtained from a national neonatal lupus
registry. J Am Coll Cardiol 1998;31(7):1658–66. [II-2]
80. Saxena A, Izmirly PM, Bomar RP, Golpanian RS, Friedman DM, Eisenberg
R, et al. Factors associated with long-term cardiac dysfunction in neonatal
lupus. Ann Rheum Dis 2020;79(2):217–24. [III]
81. Van Bergen AH, Cuneo BF, Davis N. Prospective echocardiographic evalua-
tion of atrioventricular conduction in fetuses with maternal Sjogren’s anti-
bodies. Am J Obstet Gynecol 2004;191(3):1014–8. [II-3]
82. Donofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Sklansky MS,
Abuhamad A, et al. Diagnosis and treatment of fetal cardiac disease: a
scientific statement from the American Heart Association. Circulation
2014;129(21):2183–242. [III]
83. Friedman DM, Kim MY, Copel JA, Davis C, Phoon CK, Glickstein JS, et al.
Utility of cardiac monitoring in fetuses at risk for congenital heart block:
the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study.
Circulation 2008;117(4):485–93. [II-1]
84. Friedman DM, Kim MY, Copel JA, Llanos C, Davis C, Buyon JP. Prospective
evaluation of fetuses with autoimmune-associated congenital heart block
followed in the PR Interval and Dexamethasone Evaluation (PRIDE) Study.
Am J Cardiol 2009;103(8):1102–6. [II-1]
85. Wojakowski A, Izbizky G, Carcano ME, Aiello H, Marantz P, Otano L. Fetal
Doppler mechanical PR interval: correlation with fetal heart rate, gesta-
tional age and fetal sex. Ultrasound Obstet Gynecol 2009;34(5):538–42.
[II-2]
86. Nii M, Hamilton RM, Fenwick L, Kingdom JC, Roman KS, Jaeggi ET.
Assessment of fetal atrioventricular time intervals by tissue Doppler and
pulse Doppler echocardiography: normal values and correlation with fetal
electrocardiography. Heart 2006;92(12):1831–7. [II-2]
87. Rein AJ, Mevorach D, Perles Z, Gavri S, Nadjari M, Nir A, et al. Early diag-
nosis and treatment of atrioventricular block in the fetus exposed to mater-
nal anti-SSA/Ro-SSB/La antibodies: a prospective, observational, fetal
kinetocardiogram-based study. Circulation 2009;119(14):1867–72. [II-1]
88. Cuneo BF, Sonesson SE, Levasseur S, Moon-Grady AJ, Krishnan A,
Donofrio MT, et al. Home monitoring for fetal heart rhythm during anti-Ro
pregnancies. J Am Coll Cardiol 2018;72(16):1940–51. [III]
89. Friedman DM, Llanos C, Izmirly PM, Brock B, Byron J, Copel J, et al.
Evaluation of fetuses in a study of intravenous immunoglobulin as preven-
tive therapy for congenital heart block: results of a multicenter, prospective,
open-label clinical trial. Arthritis Rheum 2010;62(4):1138–46. [II-1]
90. Pisoni CN, Brucato A, Ruffatti A, Espinosa G, Cervera R, Belmonte-Serrano
M, et al. Failure of intravenous immunoglobulin to prevent congenital heart
block: findings of a multicenter, prospective, observational study. Arthritis
Rheum 2010;62(4):1147–52. [II-2]
91. Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK.
Transplacental fetal treatment improves the outcome of prenatally diag-
nosed complete atrioventricular block without structural heart disease.
Circulation 2004;110(12):1542–8. [II-2]
92. Trucco SM, Jaeggi E, Cuneo B, Moon-Grady AJ, Silverman E, Silverman
N, et al. Use of intravenous gamma globulin and corticosteroids in the
treatment of maternal autoantibody-mediated cardiomyopathy. J Am Coll
Cardiol 2011;57(6):715–23. [II-2]
93. Ciardulli A, D’Antonio F, Magro-Malosso ER, Manzoli L, Anisman P,
Saccone G, et al. Maternal steroid therapy for fetuses with second-degree
immune-mediated congenital atrioventricular block: a systematic review
and meta-analysis. Acta Obstet Gynecol Scand 2018;97(7):787–94. [III]
94. Clowse MEB, Eudy AM, Kiernan E, Williams MR, Bermas B, Chakravarty
E, et al. The prevention, screening and treatment of congenital heart block
from neonatal lupus: a survey of provider practices. Rheumatology (Oxford)
2018;57(suppl_5):v9–v17. [III]
95. Izmirly P, Saxena A, Buyon JP. Progress in the pathogenesis and treat-
ment of cardiac manifestations of neonatal lupus. Curr Opin Rheumatol
2017;29(5):467–72. [Review, III]
96. Jaeggi ET, Silverman ED, Laskin C, Kingdom J, Golding F, Weber R.
Prolongation of the atrioventricular conduction in fetuses exposed
to maternal anti-Ro/SSA and anti-La/SSB antibodies did not predict
308
progressive heart block. A prospective observational study on the effects of
maternal antibodies on 165 fetuses. J Am Coll Cardiol 2011;57(13):1487–92.
[III]
97. Saleeb S, Copel J, Friedman D, Buyon JP. Comparison of treatment with fluo-
rinated glucocorticoids to the natural history of autoantibody-associated
congenital heart block: retrospective review of the research registry for
neonatal lupus. Arthritis Rheum 1999;42(11):2335–45. [II-2]
98. Eronen M, Siren MK, Ekbad H., et. al. Short and long term outcome of chil-
dren with congenital complete heart block diagnosed in utero or as a new-
born. Pediatrics. 2000 Jul: 106 (1 Pt 1): 86–91.
99. Izmirly PM, Saxena A, Sahl SK, Shah U, Friedman DM, Kim MY, et al.
Assessment of fluorinated steroids to avert progression and mortality in
anti-SSA/Ro-associated cardiac injury limited to the fetal conduction sys-
tem. Ann Rheum Dis 2016;75(6):1161–5. [II-2]
100. Hoxha A, Mattia E, Zanetti A, Carrara G, Morel N, Costedoat-Chalumeau
N, et al. Fluorinated steroids are not superior to any treatment to amelio-
rate the outcome of autoimmune mediated congenital heart block: a sys-
tematic review of the literature and meta-analysis. Clin Exp Rheumatol
2020;38(4):783–91. [Review, III]
101. Ciardulli A, D’Antonio F, Magro-Malosso ER, Saccone G, Manzoli L,
Radolec M, et al. Maternal steroid therapy for fetuses with immune-medi-
ated complete atrioventricular block: a systematic review and meta-analy-
sis. J Matern Fetal Neonatal Med 2019;32(11):1884–92. [III]
102. Shinohara K, Miyagawa S, Fujita T, Aono T, Kidoguchi K. Neonatal lupus
erythematosus: results of maternal corticosteroid therapy. Obstet Gynecol
1999;93(6):952–7. [II-2]
103. Ruffatti A, Cerutti A, Favaro M, Del Ross T, Calligaro A, Hoxha A, et al.
Plasmapheresis, intravenous immunoglobulins and bethametasone – a
combined protocol to treat autoimmune congenital heart block: a prospec-
tive cohort study. Clin Exp Rheumatol 2016;34(4):706–13. [II-2]
104. Sanchez-Guerrero J, Uribe AG, Jimenez-Santana L, Mestanza-Peralta M,
Lara-Reyes P, Seuc AH, et al. A trial of contraceptive methods in women
with systemic lupus erythematosus. N Engl J Med 2005;353(24):2539–49.
[I, RCT: n = 162]
Maternal-Fetal Evidence Based Guidelines
105. Petri M, Kim MY, Kalunian KC, Grossman J, Hahn BH, Sammaritano LR,
et al. Combined oral contraceptives in women with systemic lupus erythe-
matosus. N Engl J Med 2005;353(24):2550–8. [I, RCT: n = 183]
106. Galzote RM, Rafie S, Teal R, Mody SK. Transdermal delivery of combined
hormonal contraception: a review of the current literature. Int J Womens
Health 2017;9:315–21. [Review, III]
107. ACOG Practice Bulletin No. 206: Use of hormonal contracep-
tion in women with coexisting medical conditions. Obstet Gynecol
2019;133(2):e128–e50. [III]
108. Spence, D Hornberger L. et al. J Rheumatol 2006,;33 (1):167-170 and
Ambrosi A, Salomonson S et. al. An Rheum Dis 20122012;71(3)224–40.
109. Morel N, Levesque K, Maltret A, et.al. Incidence, risk factors and mor-
tality of neonatal and late-onset dilated cardiomyopathy associated with
cardiac neonatal lupus. Int J Cardio. 2017; Dec1;248:260–263.
110. Lopes LM, Tavares GMP, Damiano AP, et.al;. Perinatal outcome of fetal
atrioventricular block: one-hundred-sixteen cases from a single institu-
tion. Circulation 2008 Sept 16;118 (12):128–75.
111. Cuneo BF, Bitant S, Strasburger JF, Kaizer AM, Wakai RTAssessment
of atrioventricular conduction by echocardiography and magnetocar-
diography in normal and anti-Ro/SSA-antibody-positive pregnancies.
Ultrasound Obstet Gynecol. 2019 Nov;54(5):625–633.
112. Cuneo BF, Moon-Grady AJ, Sonesson SE, et. al. Heart sounds at home:
feasibility of an ambulatory fetal heart rhythm surveillance program for
anti-SSA positive pregnancies. J. Perinatol 2017 Mar;37(3):226–230.
113. Cuneo BF, Ambrose SE, Tworetzky W. Detection and successful treatment
of emergent anti-SSA-mediated fetal atrioventricular block. Am J Obstet
Gynecol 2016 Oct 2155(4):527–8.
114. Cuneo BF, Lee, M, Roberson D, et. al. A management strategy for fetal
immune-mediated atrioventricular block. J. Matern Fetal Neonatal Med.
2019 Dec;23(12):1400–5.
115. Sonesson SE, AmbrosiA, Wahren-Herlenius M. Benefits of echocardio-
graphic surveillance in pregnancies at risk of congenital heart block:
­single center study of 212 anti-Ro52-positive pregnancies. Ultrasound
Obstet Gyneol 2019 Jul;54(1):87–95.
28
ANTIPHOSPHOLIPID SYNDROME
Michael Miller, Arthur Jason Vaught, and Torre Halscott
Key points
• The diagnosis of antiphospholipid syndrome (APS)
requires the presence of at least one clinical and one labo-
ratory criteria (Tables 28.1 and 28.2).
• APS is associated with venous thromboembolism
(VTE), early onset pre-eclampsia, early pregnancy loss,
fetal growth restriction (FGR), fetal death, preterm
birth, and other complications.
• Therapy should be as follows:
• For APS with ≥3 unexplained consecutive pregnancy
losses at <10 weeks or ≥1 fetal loss >10 weeks: Low-
dose ASA and prophylactic heparin (either unfrac-
tionated or low molecular weight).
• For APS with VTE during the current pregnancy:
Therapeutic anticoagulation with heparin.
• For APS with VTE prior to pregnancy: Prophylactic
anticoagulation with heparin.
• There are no trials to assess therapy for APS with a his-
tory of pre-eclampsia and/or FGR prior to 34 weeks’
gestation.
• If utilizing anticoagulation, regional anesthesia may need
to be delayed until ≥4–24 hours after the last dose depend-
ing on the specific medication and dose.
Historic notes
Lupus anticoagulant (LA) was first described in early 1950s as
prolonging certain clotting assays. A few years later, LA was
found to be associated with the false-positive test for syphilis and,
paradoxically, thrombosis.
Diagnosis
The diagnosis of APS requires the presence of at least one clini-
cal (Table 28.1) and one laboratory (Table 28.2) criteria [1, 2].
Abnormal laboratory tests must occur on more than two occa-
sions, ≥12 weeks apart. The two tests must occur within a 5-year
time frame. There are no time limits on the interval between the
clinical and laboratory events. Once the diagnosis is established
by the criteria above, subsequent negative results decrease, but do
not eliminate the risks of complications.
Antiphospholipid antibody testing
Antiphospholipid antibodies (APAs) are directed against phos-
pholipids, and include anticardiolipin antibodies (ACAs), LA, and
anti-beta-2 glycoprotein-I (B2GP-I) (Table 28.2). LA is a double
misnomer. LA is seen in many patients without systemic lupus
erythematosus (SLE), and is associated with thrombosis, not anti-
coagulation (see Chapter 27). ACAs strongly correlate with LA
and thrombosis. ACAs require the presence of plasma phospho-
lipids-binding protein B2 glycoprotein I to bind to cardiolipin. In
DOI: 10.1201/9781003099062-28
contrast, ACAs from patients with syphilis or other infections are
B2 glycoprotein I independent. Approximately 80% of patients
with LA have ACAs, while 20% of patients with ACAs are also
positive for LA [2]. Substantial interlaboratory variation when
testing the same sera remains a serious problem, therefore a
laboratory confirmation should ideally come from the same
facility and/or methodology.
Symptoms
Clinical manifestations of APS may include any organ system,
including vascular (arterial or venous), cardiac, cutaneous, endo-
crine/reproductive, gastrointestinal, hematologic, neurologic,
obstetrical, ophthalmologic, pulmonary, renal, and others.
Epidemiology/Incidence
Up to 11% of healthy controls with uncomplicated pregnan-
cies have APAs, with a median prevalence of about 2%. APAs
have a very poor positive predictive value for adverse obstetric
outcomes, and a causal relationship between APAs and a single
clinical event can be difficult to prove, given that many of the
studied adverse obstetric outcomes are common. Of SLE patients,
25% to 35% have APS (see Chapter 27). ACAs are present in 15%
women with recurrent miscarriage; LA is found in 8% of patients
with recurrent miscarriage. In women with mid-trimester fetal
loss, LA is seen in up to 30%. Of definite APS patients, 70% have
both ACAs and LA.
Etiology/Basic pathophysiology
APAs are theorized to cause pregnancy loss by thrombosis of pla-
cental vessels, interference with coagulation factors (reduce levels
of annexin V), inhibition of proliferation of trophoblasts, comple-
ment activation, or other yet unknown mechanisms. However,
given that asymptomatic healthy women with APAs who do not
meet criteria for APS have little to no increased risk, mere pres-
ence of APAs is insufficient to cause these adverse pregnancy out-
comes [3].
Classification
Primary APS refers to patients with APS but no other autoim-
mune disorders. Secondary APS refers to patients with other
autoimmune disorders (e.g., SLE) [2].
Complications
Maternal
• Venous, and arterial, thromboembolism: Risk is 5% to
12% in pregnancy; there are no adequate cohort or case-
control studies to validate these estimates of VTE with
309
310
TABLE 28.1: Clinical Criteria for Diagnosis of Antiphospholipid
Syndrome
1. Vascular thrombosis
One or more clinical episodes of arterial, venous, or small vessel
thrombosis, in any tissue or organ. Thrombosis must be confirmed
by objective criteria (e.g., imaging or Doppler studies or
histopathology).
And/or
2. Pregnancy morbidity
A. One or more unexplained deaths of a morphologically normal
fetus at or beyond the 10th week of gestation, with normal fetal
morphology documented by ultrasound or by direct examination
of the fetus.
And/or
B. One or more premature births of a morphologically normal
neonate before the 34th week of gestation because of:
Eclampsia or severe pre-eclampsia, or features consistent with
placental insufficiency (e.g., abnormal Doppler flow, abnormal
fetal testing, SGA <10%, oligohydramnios).
And/or
C. Three or more unexplained consecutive spontaneous
abortions before the 10th week of pregnancy, after exclusion of
maternal anatomic or hormonal abnormalities, paternal and
maternal chromosomal causes.
Source: Modified from Refs. [1, 2].
Abbreviations: AFI, amniotic fluid index; SGA, small for gestational age.
APS pregnant women [4]. It was found that 0.5% to 2% of
asymptomatic non-pregnant people, incidentally found
to have APAs, have thromboses each year. Most throm-
botic events are venous (65–70%). Arterial thromboses can
occur in atypical sites such as the retina, the subclavian
artery, or the middle cerebral artery (the most common
vessel involved when a stroke occurs in these patients).
TABLE 28.2: Laboratory Criteria for the Diagnosis of
Antiphospholipid Syndrome
1. Lupus anticoagulant present in plasma, on two or more occasions
at least 12 weeks apart. Examples are lupus anticoagulant, DRVVT,
or aPTT test. Testing is ideally performed before the patient is
treated with anticoagulants.
And/or
2. Anticardiolipin antibody of IgG and/or IgM isotype in serum or
plasma, present as >40 GPL or MPL, or >99th percentile, on two or
more occasions, at least 12 weeks apart.
And/or
3. Anti-B2 glycoprotein-I of IgG and/or IgM isotype in serum or
plasma (in titer >40 GPL or MPL, or >99th percentile for a normal
population as defined by the laboratory performing the test), present
on two or more occasions, at least 12 weeks apart.
Source: Modified from Refs. [1, 2].
Abbreviations: aPTT, activated partial thromboplastin time; DRVVT, dilute Russell’s
viper venom time.
Maternal-Fetal Evidence Based Guidelines
• Pre-eclampsia: Incidence of pre-eclampsia is increased,
and ranges from 18–48% among women with APS. There
is a statistically significant association especially between
pre-eclampsia and ACA [4].
• Autoimmune thrombocytopenia: Risk is 40% to 50%.
Thrombocytopenia secondary to APAs is difficult to distin-
guish from ITP, and is treated in a similar fashion. Heparin-
induced thrombocytopenia (less with low-­molecular-weight
heparin [LMWH]) can also occur, as well as lupus flare in
patients with coexisting SLE.
• Other medical complications: APS is also associated
with autoimmune hemolytic anemia, livedo reticularis,
cutaneous ulcers, chorea gravidarum, multi-infarct
dementia, and transverse myelitis. These complications,
while associated with APS, are insufficient for clinical
diagnosis of APS.
• Rarely, catastrophic APS, resulting in progressive throm-
boses, multiorgan failure, and death may occur.
Fetal
• Pregnancy loss and fetal death: These complications can
occur in any trimester, and be recurrent. About 5–20% of
women with recurrent pregnancy losses have APAs [2].
While all APAs are associated with pregnancy loss and
fetal death, early pregnancy loss has been associated in a
review with both ACA and LA; recurrent first trimester
with ACA; second trimester with LA; third trimester with
ACA [4]. ACA IgM, ACA IgG, and anti-beta-2-microglob-
ulin-I are present in about 6%, 5%, and 2% of stillbirths,
respectively, compared to 3%, 1%, and 0.6% of live births,
respectively (3- to 5-fold increased risk for stillbirth) [5].
• FGR (in particular with ACA) [4].
• Preterm birth (33%, secondary to gestational hyperten-
sion or placental insufficiency, either spontaneous or
iatrogenic).
• Placental abruption (not associated with ACA or LA in a
review) [4].
Furthermore, adverse maternal and perinatal outcomes
increase with a greater number of positive antibody types.
Those with triple positive results as compared to single positive
antibody (LA only) have the following risks: Stillbirth (45% vs.
7.4%), pre-eclampsia with severe features (25% vs. 0%), without
severe features (55% vs. 11.1%), fetal growth restriction (70.0% vs.
25.9%); the chance of a successful live birth in such patients is 30%
as compared to 79.6% [6].
Pregnancy considerations
The likelihood of complications is lower if pregnancy starts
when APS is “quiescent” without symptoms and with unde-
tectable or lower levels of APAs. Complications are more fre-
quent and severe if APS is active with high levels of APAs. As with
other autoimmune disorders, APS can exacerbate postpartum:
Fever, pulmonary infiltrates, pleural effusion, occasionally renal,
pulmonary complications, VTE; rarely DIC and mortality.
Management
Principles
Multidisciplinary management with a rheumatologist or inter-
nal medicine specialist is recommended.
Antiphospholipid Syndrome
Who to screen
Women with clinical criteria for APS (Table 28.1) should be
screened for ACA, LA, and B2GP-I. Other conditions associ-
ated with APS include autoimmune thrombocytopenia, amauro-
sis fugax, livedo reticularis, systemic lupus erythematosus, and
a false-positive rapid plasma reagin (RPR) testing result. These
conditions are not considered clinical criteria for APS, therefore,
testing individuals for the presence of APA with these isolated
conditions is not recommended. Testing women without clinical
features of APS may lead to management dilemmas; this problem
can be avoided by testing only individuals who meet clinical cri-
teria for APS [2].
How to screen
Laboratory tests include ACA (IgG and IgM), LA, and B2GP-I
(IgG and IgM) tests (Table 26.2). Initial positive results should be
confirmed after a minimum of 12 weeks. Testing for APAs other
than LA, ACA, and B2GP-I is not clinically useful in the diagnosis
of APS and should not be performed. As APS may occur concom-
itantly with systemic lupus erythematosus (SLE), it is reasonable
to test for SS-A (Ro) and SS-B (La) antibodies in such patients as
well, given the association of these with SLE and their potential
impact for a gestation.
Prevention
There is currently no known preventive strategy for the diagnosis
of APS itself.
Therapy
Evidence
• Aspirin alone: Compared to placebo or usual care, low-dose
aspirin alone is not associated with improvement in out-
comes in pregnant women with APS [7–9]. The summary
relative risk for recurrent pregnancy loss is 1.05 (95% CI
0.66–1.68) [10]. A more recent meta-analysis showed a sum-
mary risk for live birth rate of 0.97 (95% CI 0.80–1.16) [11]
• Combination of unfractionated heparin (UFH) and
low-dose aspirin in APS patients with recurrent first-tri-
mester losses is associated with significant reduction in
early pregnancy loss (OR 0.26, 95% CI 0.14–0.48; number
needed to treat 4) [10, 12–14] compared to low-dose aspirin
alone. Low molecular weight heparin (LMWH) did not
show a benefit when combined with aspirin (OR 0.70, 95%
CI 0.34–1.45) [15, 16]. This could be attributed to the lower
efficacy of LMWH or to several other parameters such as
the paucity of studies on LMWH and small study samples,
low cutoff threshold for APAs positivity, coexistence of
other thrombophilic disorders within the same study, or
late entry into the studies that may preclude many early
losses, nonacceptance of randomization, and the crossover
from assigned treatments [15, 16]. These five studies have
been reviewed and published as a systematic review [17].
• Four studies have evaluated UFH plus low-dose aspirin
compared with just low-dose aspirin. A meta-analysis
showed improved live birth rates in the UFH with the aspi-
rin group (RR 1.60, 95% CI 1.31, 1.94) [11].
• Eight studies have evaluated LMWH with low-dose aspi-
rin compared with just low-dose aspirin. A meta-analysis
showed improved live birth rates in the LMWH with
aspirin group (RR 1.23, 95% CI 1.12, 1.36) [11].
• Two small RCTs have directly compared UFH plus low-dose
aspirin with LMWH plus low-dose aspirin. Both studies
311
found similar obstetric outcomes, suggesting that LMWH
has similar efficacy to comparable to UFH [17–19]. An
additional small open-label RCT randomized women with
APS and recurrent abortion to receive LMWH plus low-dose
aspirin or UFH plus low-dose aspirin and found no significant
difference in live birth rates (80% vs. 66.7%, p = 0.243) [20].
• The addition of glucocorticoids does not improve obstetric
outcomes. One small study compared aspirin + prednisone
vs. aspirin + placebo. The live birth rate was similar between
groups (65% vs. 56%, p = 0.19) [21]. Another study of aspi-
rin + prednisone vs aspirin also found no difference in live
birth rates. (RR 0.85, 95% CI 0.53, 1.36) [21, 22]. However,
both trials had significantly increased adverse effects. Both
studies found an increased risk of preterm delivery in the
prednisone group [21, 22]. Hypertension (13% vs. 5%, p =
0.05) and gestational diabetes (15% vs. 5%, p = 0.02) were
also found to be more common in the prednisone group
[22]. In another study, when compared to heparin and low-
dose aspirin, prednisone and low-dose aspirin were asso-
ciated with no difference in pregnancy loss rates, but the
prednisone group was again associated with a significantly
higher rate of preterm birth [23].
• Severe and/or resistant APS and alternative therapy:
• IVIG: In women already on heparin and aspirin, the
addition of IVIG does not affect pregnancy loss rates in
a very small trial, but is associated with a significantly
higher preterm birth rate [24]. This therapy is very
expensive, but is the only treatment shown to lower
anticardiolipin levels.
• Hydroxychloroquine: Theoretical benefits have been
suggested, as HCQ reverses platelet activation induced
by APA. A retrospective study found that HCQ was
associated with higher live birth rates (67% vs. 57%, p =
0.05). However the study was limited by its retrospec-
tive nature and differing prevalence of SLE in the two
groups [25]. A multicenter, RCT evaluating HCQ vs.
placebo is currently underway [26].
• Plasma exchange: Limited case reports and a small
case series have investigated the role of therapeutic
plasma exchange in improving pregnancy outcomes
among women who have failed first-line therapy. The
largest report included 18 women who received pred-
nisone (10 mg/day) and plasma exchange (3×/week),
and reported a 100% live birth rate, but the major-
ity had at least one major complication such as PTB
(22%), oligohydramnios (16%), fetal growth restriction
(11%), and/or pre-eclampsia (5%) [27]. Additional stud-
ies are needed before this strategy can be routinely
recommended.
Actual therapy (Table 28.3)
• APS with early (usually <10 weeks) recurrent pregnancy
loss: Low-dose aspirin (ASA) and prophylactic heparin
(either UFH or LMWH, although most data in UFH) [10,
28, 29].
Therapy is usually begun once fetal viability is estab-
lished, but there is insufficient evidence regarding best
time of initiation of therapy. Low-dose aspirin is usu-
ally about 75–100 mg daily (and some experts recom-
mend starting it even preconception in severe cases) [28].
Dose for prophylactic UFH is usually: 5000–7500 U first
trimester, 7500–10,000 U second trimester, 10,000 U
312 Maternal-Fetal Evidence Based Guidelines

TABLE 28.3: Suggested Prophylaxis for APS during Pregnancy and Postpartum Based on Selected Clinical Scenarios
Antepartum Postpartum
APS characterized by laboratory criteria Low-dose aspirin with either: LMWH and low-dose aspirin
and fetal loss (≥3 recurrent consecutive
• UFH 5000–7500 U first trimester; 7500–10,000 U
first trimester miscarriages or ≥1
second trimester; 10,000 U third trimester SQ q12h
unexplained fetal loss >10 weeks), but no
history of arterial or venous thrombosis or

• LMWH, e.g., enoxaparin (Lovenox) 30–40 mg SQ

APS characterized by laboratory criteria
and obstetric morbidity of ≥1 preterm
deliveries of a morphologically normal
infant <34 weeks due to placental
insufficiency (IUGR or severe pre-
eclampsia), but no history of arterial or
venous thrombosis
Laboratory criteria for APS, but no clinical
criteria for APS
APS with previous arterial or venous
thrombosis
q12h or dalteparin (Fragmin) 5000 U SQ q12h
• Clinical surveillance and low-dose aspirin • Clinical surveillance
or or
• Low-dose aspirin and UFH or LMWH in cases of • Low-dose aspirin and UFH or
recurrent placental insufficiency, or evidence of LMWHa
extensive decidual inflammation, vasculopathy,
and/or thrombosis on placental pathologya
Clinical surveillance • Clinical surveillance, or
• Postpartum anticoagulation only
if family history of thrombosis
Low-dose aspirin with either Warfarin (lifelong)
• UFH 5000–7500 U first trimester; 7500–10,000 U
second trimester; 10,000 U third trimester SQ q12h

or

• LMWH, e.g., enoxaparin (Lovenox) 30–40 mg SQ

q12h or dalteparin (Fragmin) 5000 U SQ q12h
a There is no level 1 evidence for this management, but it may be considered in select cases and in consultation with maternal-fetal medicine.
Abbreviations: APS, antiphospholipid syndrome; LMWH, low-molecular-weight heparin; SQ, subcutaneous; UFH, unfractionated heparin.

third trimester SQ q12h. Dose for prophylactic LMWH
is usually: Enoxaparin (Lovenox) 30–40 mg SQ q12h or
dalteparin (Fragmin) 5000 U SQ q12h. One may adjust
prophylaxis in high-risk cases to a heparin (anti-Xa) level
range of 0.2 to 0.4. Anti-Xa level is usually drawn 4 hours
after injection. Anti-Xa levels have not been adequately
evaluated prospectively to show a reduction in the inci-
dence of complications.
• APS with VTE during the current pregnancy:
Therapeutic anticoagulation [28, 29].
Therapeutic intravenous UFH doses need to be adjusted
to keep activated partial thromboplastin time (aPTT) two
to three times normal. Therapeutic LMWH is usually
enoxaparin 1 mg/kg q12h SQ, or dalteparin 200 U/kg
q12h SQ. Therapeutic LMWH must be adjusted to heparin
(anti-Xa) level 0.5 to 1.2. After initial therapy, subcutane-
ous therapeutic LMWH or UFH should be continued for
a minimum total duration of six months. Anticoagulation
should also be used for 6 weeks postpartum. Postpartum
anticoagulation could be at therapeutic doses if the VTE
occurred late in pregnancy, or it could be at prophylactic
doses if the VTE occurred early in pregnancy.
• APS with VTE in a prior pregnancy: Prophylactic hepa-
rin (either UFH or LMWH) both in the antepartum and
postpartum period (six weeks) [28, 29].
Therapy is usually begun once fetal viability is estab-
lished, but there is insufficient evidence regarding best
time of initiation of therapy. Low-dose aspirin is usually
about 75–100 mg daily. Prophylactic UFH dose is usually
5000–7500 U first trimester, 7500–10,000 U second tri-
mester, 10,000 U third trimester SQ q12h. Prophylactic
LMWH dose are usually enoxaparin (Lovenox) 30 to 40 mg
SQ q12h, or dalteparin (Fragmin) 5000 U SQ q12h. One
may adjust prophylaxis in high-risk cases to a heparin
(anti-Xa) level range of 0.2 to 0.4. Anti-Xa level is usually
drawn 4 hours after injection. Anti-Xa levels have not been
adequately evaluated prospectively to show a reduction in
the incidence of complications.
• APS with late fetal death: Treatment trials have not
shown a significant benefit at this time. The two trials that
addressed this issue had some weaknesses, and thus no rec-
ommendations can be made at this time [15, 16].
• APS with a medically indicated preterm birth sec-
ondary to early onset intrauterine growth restriction
(IUGR) or severe pre-eclampsia: There are no treatment
trials to assess any therapy, and recommendations are
based primarily on expert opinion. Some experts have sug-
gested prophylaxis similar to that shown in Table 28.3 [29].
Clinical surveillance alone is a reasonable strategy given
the lack of evidence in this group of women [2].
Other issues with therapy
Heparin is associated with a 5% decrease in bone mass density
and, therefore, osteoporosis. Supplemental calcium (calcium
gluconate/carbonate 1500 mg daily) and vitamin D, as well
as resistance exercise, should be encouraged. Idiosyncratic
thrombocytopenia known as heparin-induced thrombocy-
topenia (HIT) occurs in <5% of women on heparin therapy,
Antiphospholipid Syndrome
is usually mild, and starts usually 3 to 15 days after initiation
of therapy. HIT is less common with LMWH. If on heparin
(either type), consider checking an anti-Xa level at least once
in 3 weeks after initiating heparin. Check platelet counts ini-
tially and then weekly in the first three weeks to assure that
there is no evidence of HIT. There is no evidence to assess
warfarin therapy for women with extreme thrombotic histo-
ries, including recurrent thromboses or cerebral thrombosis
(see also Chapter 27).
Antepartum testing
• Early ultrasound is essential for accurate dating.
• Detailed fetal anatomic survey ultrasound at 18–20 weeks
and follow-up ultrasounds approximately every 4–6 weeks
for growth, fluid volume, and (if necessary) Doppler evalu-
ation of the fetus.
• Fetal surveillance testing (e.g., NSTs and/or BPPs) start-
ing at 32 weeks. The optimal regimen for fetal testing is
unclear, and the entire clinical scenario must be consid-
ered when determining the optimal testing regimen for an
individual patient.
Preparations for delivery
• If on full anticoagulation dosing of LMWH, switch to an
equivalent dosing of UFH at 36 weeks to allow regional
anesthesia. Specific medications utilizing prophylactic
dosing may be continued until the appropriate amount of
hours prior to a planned delivery.
• Delivery should be considered at 39 0/7–39 6/7 weeks ges-
tation to control timing of anticoagulation discontinuation
• Anticoagulation should be discontinued 4–24 hours prior
to planned induction of labor or cesarean section, depend-
ing on specific medication and dosing (see Chapter 27).
Delivery
Consider sending the placenta to pathology, to check for
decreased placental weight, ischemic-hypoxic changes—infarc-
tions, decidual and fetal thrombi, chronic villitis.
Anesthesia
If on intravenous UFH, regional anesthesia can be administered
usually 4–6 hours after the dose, or at least when the aPTT is
within normal limits. For subcutaneous UFH, timing is depen-
dent on dose as follows with 2–3 times daily dosing: 5000 units
(4–6 hours), 7500–10,000 (12 hours), and >10,000 units (24 hours)
[30]. If on LMWH, regional anesthesia should be delayed until
≥12–24 hours after the last dose (prophylactic vs. therapeutic
dosing), since there is a risk of spinal hematoma if regional anes-
thesia is performed within that timeframe. That is why a woman
on LMWH might be switched off LMWH an onto UFH weeks
before any chance of labor or delivery (usually around 36 weeks if
no other risk of preterm birth).
Postpartum/Breastfeeding
• In women with APS based on recurrent embryonic loss <10
weeks, the use of anticoagulation in the postpartum period
has not been shown to be helpful.
313
• In women with APS based on fetal loss ≥10 weeks and no
thrombotic events, anticoagulation for 6 weeks is usually
recommended in the United States [2] (only 3–5 days in the
United Kingdom).
• Women with APS based on prior thrombotic events should
remain on lifelong anticoagulation therapy, and postpar-
tum, should be switched to warfarin therapy. Warfarin
therapy is safe in breastfeeding women. An INR of 2.0–3.0
is desirable in general.
Estrogen-containing contraceptives are relatively contraindi-
cated, as they further increase the VTE risk.
It is imperative that women with APS be followed closely by
a medical or hematological specialist after pregnancy. Women
with APS based on obstetric history and no history of thrombosis
have an increased postpartum risk of deep venous thrombosis
(adjusted hazard ratio [aHR] 1.85, 95% CI 1.50–2.28, annualized
rate 1.46%) and stroke (aHR 2.10, 95% CI 1.08–4.08, annual-
ized rate 0.17%) [31]. Additionally, about 10% with APS will later
develop SLE [2].
References
1. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus state-
ment on an update of the classification criteria for definite antiphospholipid
syndrome (APS). J Thromb Haemost 2006;4:295–306. [Review]
2. ACOG Practice Bulletin No. 132. Antiphospholipid syndrome. Obstet
Gynecol 2012;120(6):1514–21. [Review]
3. Infante-Rivard C, David M, Gauthier G, Rivard GE. Lupus anticoagulants,
anticardiolipin antibodies, and fetal loss: A case-control study. N Engl J
Med 1991 October 10;325(15):1063–6. [II; Case-Control, n = 55].
4. Robertson L, Wu O, Langhorne S, et al. Thromphilia in pregnancy: a sys-
tematic review. Br J Haematol 2006;132:171–196. [Review]
5. Silver RM, Parker CB, Reddy UM, et al. Antiphospholipid antibodies in
stillbirth. Obstet Gynecol 2013;122:641–57. [II-1; Case-Control, n = 2129]
6. Saccone G, Berghella V, Maruotti GM, et al. Pregnants (pregnancy in
women with antiphospholipid syndrome) working group. Antiphospholipid
antibody profile based obstetric outcomes of primary antiphospholipid
syndrome: the pregnants study. Am J Obstet Gynecol. 2017 May;216(5):525.
e1–525.e12. [II-1; Cohort, n = 750]
7. Pattison NS, Chamley LW, Birdsall M, et al. Does aspirin have a role
in improving pregnancy outcome for women with the antiphospho-
lipid syndrome? A randomized controlled trial. Am J Obstet Gynecol
2000;183:1008–1012. [I; RCT, n = 50]
8. Cowchock S, Reece EA. Do low-risk pregnant women with antiphospholipid
antibodies need to be treated? Am J Obstet Gynecol 1997;176:1099–1100.
[I; RCT, n = 19]
9. Tulppala M, Marttunen M, Soderstrom-Anttila V, et al. Low-dose aspirin
prevention of miscarriage in women with unexplained or autoimmune
related recurrent miscarriage: effect on prostacyclin and thromboxane
A2 production. Hum Reprod 1997;12:1567–1572. [I; RCT, n = 66]
10. Empson M, Lassere M, Craig JC, et al. Recurrent pregnancy loss with
antiphospholipid antibody: a systematic review of therapeutic trials. Obstet
Gynecol 2002;99:135–144. [Meta-analysis; 10 RCTs, n = 627]
11. Lu C, Liu Y, Jiang HL. Aspirin or heparin or both in the treatment of recur-
rent spontaneous abortion in women with antiphospholipid antibody syn-
drome: a meta-analysis of randomized controlled trials. J Matern-Fetal
Neonat Med 2019;32(8):1299–311. [Meta-analysis; 19 RCTs, n = 1251]
12. Rai R, Cohen H, Dave M, et al. Randomised controlled trial of aspirin and
aspirin plus heparin in pregnant women with recurrent miscarriage associ-
ated with phospholipids antibodies. BMJ 1997; 314:253–257. [I; RCT, n = 90]
13. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy
loss: treatment with heparin and low dose aspirin is superior to low-dose
aspirin alone. Am J Obstet Gynecol 1996;174:1584–1589. [I; RCT, n = 50]
14. Goel N, Tuli A, Choudhry R. The role of aspirin versus aspirin and heparin
in cases of recurrent abortions with raised anticardiolipin antibodies. Med
Sci Monit 2006;12:CR132–CR136. [I; RCT, n = 72]
15. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome
in pregnancy: a randomized controlled trial of treatment. Lupus 2002;
100:408–413. [I; RCT, n = 98]
314
16. Laskin CA, Spitzer KA, Clark CA, et al. Low molecular weight heparin and
aspirin for recurrent pregnancy loss: results from the randomized, con-
trolled HepASA Trial. J Rheumatol 2009;36:279–287. [I; RCT, n = 88]
17. Ziakas P, Pavlou M, Voulgarelis M. Heparin treatment in antiphospho-
lipid syndrome with recurrent pregnancy loss. Obstet Gynecol 2010;115:
1256–1262. [Review]
18. Noble LS, Kutteh WH, Lashey N, et al. Antiphospholipid antibodies asso-
ciated with recurrent pregnancy loss: prospective, multicenter, controlled
pilot study comparing treatment with low-molecular-weight heparin versus
unfractionated heparin. Fertil Steril 2005;83:684–690. [I; RCT, n = 50]
19. Stephenson MD, Ballem PJ, Tsang P, et al. Treatment of antiphospholipid
antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing
low molecular weight heparin to unfractionated heparin. J Obstet Gynaecol
Can 2004;26:729–734. [I; RCT, n = 26]
20. Fouda UM, Sayed AM, Abdou AM, Ramadan DI, Fouda IM, Zaki MM.
Enoxaparin versus unfractionated heparin in the management of recurrent
abortion secondary to antiphospholipid syndrome. Int J Gynaecol Obstet.
2011;112(3):211–5. [I; RCT, n = 60]
21. Silver RK, MacGregor SN, Sholl JS, et al. Comparative trial of prednisone
plus aspirin vs. aspirin alone in the treatment of anticardiolipin antibody
positive obstetric patients. Am J Obstet Gynecol 1993;169:1411–1417. [I;
RCT, n = 39]
22. Laskin CA, Bombardier C, Hannah ME, et al. Prednisone and aspirin in
women with autoantibodies and unexplained recurrent fetal loss. N Engl J
Med 1997;337:148–153. [I; RCT, n = 202]
23. Cowchock FS, Reece EA, Balaban D, et al. Repeated fetal losses associated
with antiphospholipid antibodies: a collaborative randomized trial com-
paring prednisone with low-dose heparin treatment. Am J Obstet Gynecol
1992;166:1318–1323. [I; RCT, n = 45]
Maternal-Fetal Evidence Based Guidelines
24. Branch DW, Peaceman AM, Druzin M, et al. A multicenter placebo-con-
trolled pilot study of intravenous immune globulin treatment of antiphos-
pholipid syndrome during pregnancy. The Pregnancy Loss Study Group.
Am J Obstet Gynecol 2000;182:122–127. [I; RCT, n = 16]
25. Sciascia S, Hunt BJ, Talavera-Garcia E, Lliso G, Khamashta M, Cuadrado
MJ. The impact of hydroxychloroquine treatment on pregnancy out-
come in women with antiphospholipid antibodies. Am J Obstet Gynecol.
2016;214(2):273–e1. [II; Cohort, n = 96]
26. Schreiber K, Breen K, Cohen H, et al. HYdroxychloroquine to Improve Pregnancy
Outcome in Women with AnTIphospholipid Antibodies (HYPATIA) pro-
tocol: a multinational randomized controlled trial of hydroxychloroquine
versus placebo in addition to standard treatment in pregnant women with
antiphospholipid syndrome or antibodies. Semin Thromb Hemost. 2017
September;43(6):562–571. [I; RCT, n = enrolling, goal of >328]
27. El-Haieg AU, Zanati MF, El-Foual FM. Plasmapheresis and pregnancy out-
come in patients with antiphospholipid syndrome. Int J Gynaecol Obstet.
2007;99(3):236. [III; Case series, n = 18]
28. Bates S, Greer I, Pabinger I, et al. Venous thromboembolism, thrombophilia
antithrombotic therapy and pregnancy. Chest 2008;133:844–886. [Review]
29. Ruiz-Irastorza G, Crowther M, Branch W, et al. Antiphospholipid syn-
drome. Lancet 2010;376:1498–1509. [Review]
30. Leffert, Lisa, Butwick, Alexander, et al. The Society for Obstetric Anesthesia
and Perinatology Consensus Statement on the Anesthetic Management
of Pregnant and Postpartum Women Receiving Thromboprophylaxis or
Higher Dose Anticoagulants. Anesth Analg. 2018;126(3):928–944. [Review]
31. Gris JC, Bouvier S, Molinari N, et al. Comparative incidence of a
first thrombotic event in purely obstetric antiphospholipid syn-
drome with pregnancy loss: the NOH-APS observational study. Blood.
2012;119(11):2624–32. [II; Case-control, n = 1592]
29
INHERITED THROMBOPHILIA
Guillermo Gurza
Key points
• Inherited thrombophilias are genetic conditions that
increase the risk of thromboembolism.
• The risk of thrombotic events is affected by numerous
factors including thrombophilia, personal history of deep
vein thrombosis (DVT), family history of DVT, surgery, age
over 35 years, high parity, high body mass index, smoking,
trauma, and immobilization.
• The prevalence and thrombogenic potential of the inher-
ited thrombophilias are shown in Tables 29.1 and 29.2.
• Venous thromboembolism (VTE) is associated with fac-
tor V Leiden (FVL), prothrombin 20210A gene mutation
(PGM), antithrombin III (ATIII) deficiency, decreased
protein C (PC) and protein S (PS) in retrospective
cohort studies.
• The presence of inherited thrombophilias has been
weakly associated with adverse pregnancy outcomes
such as stillbirth, pre-eclampsia, and fetal growth restric-
tion in retrospective studies. However, there has been
no or minimal association in several large prospective
studies.
• Fetal carriage of inherited thrombophilia mutations also
have been weakly associated with adverse pregnancy out-
comes but quality data are lacking.
• Screening for inherited thrombophilias:
• Universal screening for inherited thrombophilias is
not recommended.
• It is recommended to screen any pregnant woman
with a prior personal history of VTE, as this could
affect anticoagulation recommendations, especially if
the event was “unprovoked.” Screening should include
FVL, PGM, ATIII, PS and PC, although ATIII, PC
and PS deficiencies are rare in the absence of a fam-
ily history of VTE.
• In a woman with VTE in the current pregnancy,
screening can be performed for FVL, PGM, and ATIII.
PC and PS assessment is less reliable in pregnancy.
• In an otherwise healthy pregnant woman with no
personal history of VTE or adverse pregnancy out-
comes, but whose first-degree relative has a genetic
thrombophilia or VTE, there is insufficient evidence
to recommend for or against any type of screening.
Given a lack of proven benefit, screening such women
is not advised. In an otherwise healthy pregnant
woman with a prior adverse pregnancy outcome but
no major risk factors for VTE, there is insufficient evi-
dence to support thrombophilia screening.
• Treatment for inherited thrombophilias and related
conditions:
• If PC, PS, heterozygous FVL, or PGM are detected in
a woman with prior VTE, prophylactic anticoagula-
tion is reasonable.
DOI: 10.1201/9781003099062-29
• If homozygous FVL or PGM or an ATIII deficiency
or a compound heterozygote is detected in a woman
with a prior VTE, full therapeutic anticoagulation is
reasonable although prophylactic anticoagulation may
be adequate.
• In a woman with a prior personal history of a VTE
and a recurring etiology (e.g. estrogen containing
oral contraceptives or pregnancy), prophylactic
anticoagulation is recommended.
• Among women with a nonrecurring cause for the
prior VTE (e.g. orthopedic surgery) and no throm-
bophilia, the risk of recurrent antepartum VTE is
low; therefore, routine antepartum prophylaxis with
heparin may not be warranted. Anticoagulation
could still be given postpartum.
• Thromboprophylaxis is not advised for women with
thrombophilia in hopes of improving obstetric
outcomes.
See also Chapters 27, 28, and 30.
Historic notes
Antithrombin deficiency and dysfibrinogenemia, the first inher-
ited thrombophilias to be described (1965), were discovered in
studies of families in which several members were affected by
venous thrombosis [1, 2]. Later, heterozygous deficiencies of pro-
tein C (PC) [3] and protein S (PS) [4] were identified as causes of
inherited thrombophilia. In 1993, resistance to activated PC, the
most common cause of inherited thrombophilia, was discovered
[5, 6]. In most cases, it results from a mutation of the factor V
gene (G1691A), resulting in an abnormal factor V protein, termed
factor V Leiden (FVL) [7]. In 1996, the G20210A mutation of the
prothrombin gene was found to be another cause of thrombo-
philia [8].
Definition
Inherited thrombophilias are genetic conditions that increase
the risk of VTE [9].
Epidemiology/Incidence
VTE is one of the leading causes of pregnancy-related maternal
morbidity and mortality in the developed world [10]. Estimates for
the incidence of thrombotic events occurring during pregnancy
and the puerperium vary from 0.2 to 2 per 1000 births [10, 11].
During pregnancy, women have a fivefold increased risk of VTE
compared with non-pregnant women [11], and cesarean delivery
carries a fivefold higher risk of thrombosis relative to vaginal
delivery [12, 13]. The incidence of thrombotic events is equal in
the antepartum and postpartum periods. However, the rate of
VTE per day is relatively higher postpartum. Also, the increased
315
316
TABLE 29.1: Prevalence of Different Thrombophilias in the
General and At-Risk Population
Prevalence in Prevalence in
General Patients with History
Population (%) of Thrombosis (%)
Factor V Leiden (heterozygous) 1–15 10–50
Prothrombin gene (heterozygous) 2–5 6–18
ATIII deficiency 0.02 1–3
Protein S deficiency 0.1–1.3 1–5
Protein C deficiency 0.2–0.4 3–5
Hyperhomocysteinemia 5 10
MTHFR (C677T heterozygous) 5–14 – V polypeptide (factor V Q506). The resultant amino acid sub-
Source: From Refs. [15, 16].
risk may persist for up to 12 weeks after delivery [14]. Antepartum
risk is equally divided for each trimester [11]. Pulmonary embo-
lism is more common postpartum [11].
Up to 50% of women who have thrombotic events dur-
ing pregnancy possess an underlying congenital or acquired
thrombophilia [15]. The frequency of major inherited throm-
bophilias varies substantially within healthy populations and
among patients with previous venous thrombosis (Table 29.1) [16,
17]. The most common inherited thrombophilias are heterozy-
gosity for the FVL gene mutation, the prothrombin G20210A gene
mutation (PGM), and the thermolabile variant of methylenetetra-
hydrofolate reductase (C677T MTHFR), the most common cause
of hyper-homocysteinemia. However, this latter thrombophilia is
only weakly associated with VTE [18]. Less common thrombo-
philias include autosomal-dominant deficiencies of antithrom-
bin, PC, and PS. Factor V Leiden and the G20210A mutation in
the prothrombin gene are common among Caucasians but are
less common among Asians and Africans [18, 19]. The prevalence
of different thrombophilias in the general and at-risk popula-
tions are shown in Table 29.1 [15, 16, 20]. A recent prospective
cohort study of the factor V Leiden noted a carrier rate of 6.1% in
Caucasians, 0.8% in African Americans, 1.7% in Hispanics, and
1.9% in others [21].
Etiology/Basic pathophysiology
Changes in the coagulation system, an increase in venous stasis,
and vascular injury at delivery (Virchow’s triad) substantially
increase the risk of developing VTE in pregnancy compared
with the nonpregnant state [10]. Changes in the coagulation
system during pregnancy include increases in fibrinogen and
factors II, VII, VIII, IX, X, and XII, an increase in the activity of
the fibrinolytic inhibitors as evidenced by increases in plasmin-
ogen-activator inhibitor 1 (PAI-1) and 2 (PAI-2), a decrease in PS
activity (because of estrogen-induced decreases in total PS and
increases in the complement 4b binding protein, which binds
PS), and an increase in resistance to activated PC in the second
and third trimesters (see Chapter 3, Obstetric Evidence Based
Guidelines) [22]. In approximately 50% of patients with a heredi-
tary thrombophilia, the initial thrombotic event occurs in the
presence of an additional risk factor such as pregnancy, personal
or family history, high body mass index, smoking, oral contra-
ceptive use, orthopedic trauma, immobilization, or surgery
[23, 24]. Histologic examination of uteroplacental vessels and
intervillous architecture from pathologic pregnancies typically
Maternal-Fetal Evidence Based Guidelines
display increased fibrin deposition, thrombosis, and hypoxia-
associated endothelial and trophoblast changes [25]. However,
these findings are not consistent in placentas of women with
thrombophilias [26].
Genetics/classification of each inherited
thrombophilia (Tables 29.1 and 29.2)
Factor V Leiden
The FVL mutation arises from a (G to A) mutation in nucleotide
1691 of the factor V gene’s 10th exon, resulting in a substitu-
tion of a glutamine for an arginine at position 506 in the factor
stitution impairs the inactivation of factor Va by the complex
activated PC and PS. This defect is termed the FVL mutation
and is primarily inherited in an autosomal-dominant fash-
ion. It is the most common cause of activated PC resistance.
Its prevalence is about 5–10% in Europeans, 3% in African
Americans, and rare in Asian and African populations (Table
27.1). Homozygosity for the mutation, although rare, confers a
far higher risk of thromboembolism. Compound heterozygotes
(FVL heterozygotes and prothrombin gene heterozygotes; see
later in the chapter) should be treated similar to homozygous
women [18, 19].
Prothrombin G20210A
Heterozygosity for a mutation in the promoter of the prothrom-
bin gene (G20210A) leads to increased (150–200%) circulating
levels of prothrombin and an increased risk of thromboembo-
lism. Homozygosity for the prothrombin mutation confers a risk
of thrombosis equivalent to that of FVL homozygosity. It is inher-
ited in an autosomal-dominant fashion [19].
Antithrombin III
Antithrombin III (ATIII) deficiency is the most thrombogenic
of the inherited thrombophilias with a 70–90% lifetime risk of
thromboembolism. Deficiencies in AT result from numerous
point mutations, deletions, and insertions, and are usually inher-
ited in an autosomal-dominant fashion. Because the prevalence
of AT deficiency is low, 1/1000 to 1/5000, it is only present in 1%
of patients with thromboembolism [19]. The appropriate thresh-
old for abnormally low activity is <60%.
Protein C
PC is a vitamin K–dependent polypeptide synthesized primarily
in the liver. Activated PC combines with free PS to inhibit fac-
tors V and VIII (see Figure 30.1). PC levels can be decreased by
warfarin. PC deficiency can result from numerous mutations,
which have highly variable procoagulant sequelae, making it
extremely difficult to predict which patients with PC or PS defi-
ciencies will develop thromboembolism [19]. The inheritance
is autosomal dominant. PC deficiency is best diagnosed by a
functional assay activity cutoff of <50%, found in only 0.3%
of the population.
Protein S
PS is a vitamin K–dependent polypeptide synthesized pri-
marily in the liver. PS is present in plasma in its free (40%)
and bound (60%) forms, but it is the free form that is func-
tional. PS functions as a cofactor with PC (see Figure 28.1). PS
deficiency has three distinct phenotypes: (1) type I, marked
by reduced total and free immunoreactive forms; (2) type
Inherited Thrombophilia 317

II, characterized by normal free immunoreactive levels but Complications

reduced activated protein C (APC) cofactor activity; and (3)
type III, in which there is normal total immunoreactive but VTE
reduced free immunoreactive levels. The inheritance is auto- The thrombogenic potential of inherited thrombophilias and
somal dominant. Protein S decreases normally by about the estimated probability of thrombosis per pregnancy in
40% during pregnancy, and thus screening during pregnancy affected individuals are shown in Table 29.2 [16, 17, 44, 45]. If a
is not recommended. The decrease in pregnancy is due to woman is a heterozygote for both FVL and PGM, the probability
estrogen-induced decreases in total PS and increases in the of thrombosis per pregnancy is estimated as 4.6% [44]. Data from
complement 4b binding protein, which binds PS. A free PS older case-control studies show significant associations between
antigen <55% in non-pregnant women should be detected thrombophilias and VTE in women with no personal history [14]
at least twice to document PS deficiency, and best correlates as well as in those with prior VTE [45]. In a prospective study [29],
with PS mutations. If screening in pregnancy is performed, the frequency of FVL in women with a history of thrombosis was
cutoff values in the second and third trimesters of <30% and higher than expected, (15% vs. 2%), but not for MTHFR (about
<24%, respectively, may be valid [27]. 505 in cases and controls). In another prospective study [46],
pregnant women with a single previous episode of VTE without
MTHFR/Homocysteinemia antepartum anticoagulation had a 2.4% antepartum recurrence
The most common form of genetic hyper-homocysteinemia of VTE. There were no recurrences in the 44 women who had
results from the production of a thermolabile variant of methy- no evidence of thrombophilia and who also had a previous
lenetetrahydrofolate reductase (MTHFR) with reduced enzy- episode of thrombosis that was associated with a nonrecur-
matic activity (T mutation) [28]. The gene encoding for this ring risk factor. However, the small numbers of women meeting
variant contains an alanine-to-valine substitution at amino acid these criteria do not allow a definitive conclusion that there is
677 (C677T) [29]. The responsible mutation is common, with a no increased risk of recurrent thrombosis. Among the 51 women
population frequency for homozygosity estimated between 5% with abnormal laboratory results or a previous episode of idio-
and 14% [30, 31]. A MTHFR polymorphism at A1298C is less com- pathic thrombosis, or both, 5.9% had an antepartum recurrence
mon. Homozygosity for the thermolabile variant of MTHFR (TT of VTE. [46]. Although there was no association between
genotype) is a relatively common cause of mildly elevated plasma thrombophilias and VTE in several prospective studies in
homocysteine levels in the general population, often occurring in asymptomatic women, they included too few individuals to
association with low serum folate levels [32, 33]. Increased blood make conclusions regarding the risk of VTE [20, 47].
levels of homocysteine may reflect deficiency of folate, vitamin A recent retrospective study gathered data on 243 women
B6, and/or vitamin B12 [34–37]. Plasma folate and B12 levels, in with a history of VTE in a previous pregnancy. The study found
particular, are strong determinants of the homocysteine con- that in women ≥35 years, the individual probability of gesta-
centration. Homocysteine levels are inversely related to folate tional VTE was as follows: 0.7% for heterozygous FVL; 3.4% for
consumption, reaching a stable baseline level when folate intake homozygous FVL; 0.6% for heterozygous prothrombin G20210A;
exceeds 400 mg/day [38, 39]. Vitamin B6 is a weaker determinant
[39]. Isolated MTHFR mutations (in the setting of normal
homocysteine levels) are not associated with increased risk
of VTE, and therefore, should not be categorized as thrombo- TABLE 29.2: Risk of VTE with Different Thrombophilias
philias [11, 40, 41]. VTE Risk per
Pregnancy
VTE
Classification Potential No History Prior % of All
High-risk types: (RR of VTE) (%) VTE (%) VTE
Factor V Leiden 5–7 0.5–3.1 10 40
• AT deficiency heterozygote
• FVL homozygous Factor V Leiden 25 2.2–14.0 17 2
• PGM homozygous homozygote
• Compound heterozygote FVL and PGM Prothrombin gene 3–9 0.4–2.6 >10 17
heterozygote
Low-risk types:
Prothrombin gene 25 2–4 >17 0.5
homozygote
• FVL heterozygous
FVL/prothrombin 84 4-8.2 >20 1–3
• PGM heterozygous
compound heterozygote
• Protein C deficiency
Antithrombin III activity 50–100 0.2–11.6 40 1
• Protein S deficiency
<60%
Protein C activity <50% 10–13 0.1–1.7 4–17 14
Risk factors/Associations Protein S free antigen 2–10 0.3-6.6 0–22 3
The risk of thrombotic events is affected by numerous factors <55%
including thrombophilia, personal history of DVT, family his- Hyperhomocysteinemia 3–6 0.2 NA <5%
tory of DVT, surgery, age over 35 years, high parity, high body (>16 mM)
mass index, smoking, edema, proteinuria, tissue trauma, and Source: From Refs. [44, 83].
immobilization [42, 43]. Abbreviation: VTE, venous thromboembolism; RR, risk ratio.
318
8.2% for compound heterozygotes for FVL and prothrombin
G20210A; 9.0% for antithrombin deficiency; 1.1% for protein C
deficiency; and 1.0% (0.7%) for protein S deficiency [48].
A 2017 meta-analysis of 36 studies found that the absolute risk
of VTE exceeded 3% only for women with antithrombin, pro-
tein C, and protein S deficiencies, or homozygosity for factor V
Leiden. All women with antithrombin, protein C, and protein S
deficiency included in this meta-analysis had a family history of
VTE, which is an additional risk factor for VTE [49].
Adverse pregnancy outcome (Table 29.3)
To assess the true association between thrombophilias and preg-
nancy complications, prospective cohort studies are preferred over
retrospective cohort and case-control studies. Meta-analyses of
retrospective cohort and case-control studies show associations
between various thrombophilias and adverse pregnancy outcomes
[50–57]. Confounders were assessed and included ethnicity, genetic
testing only, and severity of illness [58]. Thrombophilias tended to be
more strongly associated with later pregnancy loss (e.g. after 10 or 20
weeks) gestation than early pregnancy loss [50, 51]. However, there
was no association found between thrombophilias and adverse preg-
nancy outcomes in several prospective cohort studies. In a large mul-
ticenter study in the United States conducted through the MFMU,
neither the FVL or prothrombin gene mutations were related to
pregnancy loss (any trimester), placental abruption, pre-eclampsia,
or fetal growth restriction [21, 59]. In another large case-control
study, there was no significant association between pre-eclampsia
and four different thrombophilias (FVL, prothrombin gene muta-
tion, MTHFR C677T mutation, or homocysteine) [60].
Seven prospective cohort studies are noted in the most cur-
rent literature. All were performed in low-risk women, which
should be distinguished from women with thromboembolism
and/or obstetric complications.
In the first study, there was no association between the factor
V Leiden mutation or the prothrombin G20210A mutation and
pregnancy loss, pre-eclampsia, abruption, or SGA neonates in a
low-risk, prospective cohort [21, 59].
In the second study, some associations between thrombophil-
ias and adverse outcomes were noted [61]:
• Women who carried the prothrombin gene mutation had
an odds ratio (OR) of 3.58 (95% confidence interval [CI]
1.20–10.61, p = 0.02) for the development of the composite
primary outcome (abruption, stillbirth, or neonatal death).
• Homozygous carriers of the MTHFR 1298 polymorphism
had an odds ratio of 0.26 (95% CI 0.08–0.86, p = 0.03) for
the composite outcome, denoting a protective effect.
• None of the other polymorphisms studied showed a signifi-
cant association with the composite outcome.
TABLE 29.3: Associations between Inherited Thrombophilias and Adverse Pregnancy Outcomes
Factor V
First trimester loss No [18, 57, 60, 63] Yes [58]
Second or third trimester loss No [18, 57, 60, 63] Yes [56]
IUGR No [18, 56–58, 60, 63]
Pre-eclampsia No [18, 54, 56–58, 60, 63]
Placental abruption No [18]
Source: From Refs. [18, 54–58, 60, 61, 63].
Based on prospective cohort studies and large case-control studies.
Abbreviations: PT, prothrombin; MTHFR (C677T), methylenetetrahydrofolate reductase.
Maternal-Fetal Evidence Based Guidelines
• Placental abruption was significantly associated with pro-
thrombin gene mutation (OR 12.15, 95% CI 2.45–60.39,
p = 0.002).
• FVL conferred an increased risk of stillbirth (OR 8.85, 95%
CI 1.60–48.92, p = 0.01).
In the third study, there was no association between FVL and pre-
eclampsia, intrauterine growth restriction, or pregnancy loss. FVL
was associated with birthweights >90th percentile (OR 1.81; 95% CI
1.04–3.31) and neonatal death (OR 14.79; 95% CI 2.71–80.74) [62].
In the fourth study, the frequency of FVL and MTHFR was no
higher in those who subsequently developed pre-eclampsia or
intrauterine growth retardation, and none of the screened popu-
lation developed thrombosis [63].
In the fifth study, the APC-resistant subgroup did not differ
from the non–APC-resistant subgroup in terms of pregnancy
complications, but was characterized by an eightfold higher risk
of VTE (3/270 vs. 3/2210), a lower rate of profuse intrapartum
hemorrhage (3.7% vs. 7.9%) (p = 0.02), and less intrapartum blood
loss (340 mL vs. 361 mL) (p = 0.04) [64].
In the sixth study, women with hyper-homocysteinemia had severe
pre-eclampsia (2/35 vs. 5/714, p < 0.01) and stillbirth (2/35 vs. 10/714,
p < 0.05) more frequently than normo-homocysteinemia [65].
The seventh study was performed in three tertiary care centers
in Canada. Women were assessed for thrombophilias in the early
second trimester of pregnancy. Placenta-mediated pregnancy
complications occurred in 11.64% of women testing positive for
thrombophilias compared to 11.23% in those testing negative (RR
1.04; 95% CI 0.81–1.33) [66].
A 2006 meta-analysis of 26 studies of 2120 women with unex-
plained recurrent pregnancy loss and 2949 controls did not find
that the MTHFR C677T genotype was a risk factor for this out-
come, except in a Chinese population [67]. In summary, there are
no consistent results from these prospective cohort studies, with
most showing no or little association between thrombophil-
ias and adverse pregnancy outcomes. Importantly, the vast
majority of women with thrombophilias and no prior adverse
pregnancy outcomes have uncomplicated normal pregnan-
cies. Accordingly, such women should not be screened for
thrombophilias and should be reassured regarding pregnancy.
Other than the potential for selection bias in case-control
studies, it is unclear why results differ in retrospective and
prospective studies. At worst, thrombophilias should be con-
sidered a minor “risk factor” rather than a “cause” of obstetric
complications. It also seems that women with thrombophilias
and prior adverse pregnancy outcomes comprise a different
population than those with no prior complications. Indeed,
the obstetric history is more predictive of subsequent obstet-
ric risk than the thrombophilia.
PT 20210 MTHFR (C677T)
No [55, 63] No [58]
No [55, 56, 63] No [56] Yes [61]
No [55, 56, 63] No [56, 58]
No [54–56, 63] No [54, 56, 58] Yes [61]
No [55] Yes [56] No [56]
Inherited Thrombophilia
Fetal thrombophilias
Fetal carriage of thrombophilic mutations may also have adverse
clinical consequences. A case-control study evaluated abortuses
for the presence of FVL [68]. The mutation was present more fre-
quently among abortuses than in unselected pregnancies. If the
placenta showed >10% infarction, the fetus was 10 times more
likely to have the mutation than when the placenta was normal.
Carriers of multiple or homozygous thrombophilic defects were
at increased risk of having a birthweight in the lowest quartile
or lowest decile in a retrospective study [69]. In a prospective
study [21], there was no statistical significance between fetal
thrombophilia and any adverse pregnancy outcome. However,
fetal FVL mutation carriage was associated with more frequent
pre-eclampsia among African American women and Hispanic
women compared to Caucasian women.
Dose dependency of thrombophilia
A case-control study nested in the European Prospective Cohort
on Thrombophilia (EPCOT) compared 571 women with throm-
bophilia, with 395 control patients, and reported an increased
risk of fetal loss (miscarriage and stillbirth) among the former
patients (29.4% vs. 23.5%; p = 0.04) [70]. The risk of loss was
greater after 28 weeks than at or before 28 weeks (OR 3.6; 95% CI
1.4–9.4 vs. OR 1.27; 95% CI 0.94–1.71). The highest risk for still-
birth was observed in women with combined thrombophilic
defects and antithrombin and PC deficiencies. This suggests
that often single genetic defects, such as FVL, may not lead to
thrombosis, but rather it is the presence of multiple defects that
causes a problem.
In another study [71], the FVL homozygous genotype increased
the risk of late fetal loss. However, the overall likelihood of a positive
outcome was high in women who were homozygous for factor V.
Management
Screening (Table 29.4)
The decision to perform screening should be influenced by the
following:
• Prevalence of the risk factor in the studied popula-
tion (e.g. personal and family history of thrombosis or
thrombophilia)
• If the information gathered will impact clinical manage-
ment in the short and long term.
TABLE 29.4: Who to Consider Screening (or No Screening)
for Inherited Thrombophilias
Screen for
Prior VTE with nonrecurrent etiology Factor V, PT 20210; ATIII; PC; PS
Prior VTE with recurrent etiology Factor V; PT 20210; ATIII; PC; PS
VTE in current pregnancy Factor V; PT 20210; ATIII; PC
General population No screening
Relative with inherited thrombophilia No screening
but no personal history of VTE
Prior adverse pregnancy outcome No screening
Abbreviations: VTE, venous thromboembolism; PT, prothrombin; PC, protein C; PS,
protein S; ATIII, antithrombin III.
319
There is insufficient evidence to support universal screen-
ing, given the overall low prevalence of thrombophilias in the
general population, and the low prevalence of VTE and adverse
pregnancy outcomes, even in women with thrombophilias.
In women with acute venous thromboembolism during their
pregnancy, thrombophilia screening has limited value since the
results in general do not change the management of the disease.
Screening should be considered after the end of pregnancy and
once the use of anticoagulants has stopped [72]
In a small prospective study [70], pregnant women with a
single previous episode of VTE without antepartum anticoagu-
lation had a 2.4% antepartum recurrence of VTE. There were no
recurrences in the 44 women who had no evidence of throm-
bophilia and who also had a previous episode of thrombosis
that was associated with a nonrecurring risk factor. However,
there have been numerous subsequent exceptions with recurrent
VTE in this population. Nonetheless, they are at lower risk than
women with VTE and thrombophilias. Among the 51 women
with abnormal laboratory results or a previous episode of idio-
pathic thrombosis, or both, 5.9% had an antepartum recurrence
of VTE. In an otherwise healthy pregnant woman with no
personal history of VTE, but whose first-degree relative has a
genetic thrombophilia or prior VTE, there is insufficient evi-
dence to recommend for or against screening. Thrombophilia
screening in this population is advised by some authorities [18].
However, given a lack of proven benefit, we do not advise screen-
ing such women. [72–74].
In an otherwise healthy pregnant woman with a prior
adverse pregnancy outcome but no major risk factors for VTE,
there is insufficient evidence to support screening either ante-
partum or postpartum. Screening for MTHFR mutations is not
recommended.
Diagnosis
It is important to be cognizant of potential inaccuracy when
testing for thrombophilias. In general, DNA- or antibody-
based tests are reliable in most circumstances. However, some
clotting assays may be affected by anticoagulant therapy,
pregnancy, and other conditions. Table 29.5 describes testing of
thrombophilias. The following are some potential causes of false-
positive results when testing for thrombophilias [73]:
• Hyperhomocysteinemia: Deficiencies of folic acid, vitamin
B12, or vitamin B6; older age, renal failure, smoking
• Protein C activity: Pregnancy, liver disease, childhood, use
of oral anticoagulants, vitamin K deficiency, disseminated
intravascular coagulation (DIC), the presence of antibodies
against PC
• Protein S total and free antigen: Pregnancy, liver disease,
childhood, use of oral anticoagulants, vitamin K deficiency,
DIC, use of oral contraceptives, nephrotic syndrome, the
presence of antibodies to PS
• Antithrombin III activity: Liver disease, use of heparin
therapy, nephrotic syndrome, DIC
Treatment
The primary goal of clinical management is to reduce the risk
of VTE. As with many pregnancy-related conditions, there are
few data from properly designed clinical trials to guide evi-
dence-based management. Accordingly, recommendations
are based on observational studies and extrapolation of
data derived from non-pregnant populations. Expert-based
320 Maternal-Fetal Evidence Based Guidelines

TABLE 29.5: Testing Characteristics for Different Inherited Thrombophilias

Is Testing Reliable Is Testing Reliable during Is Testing Reliable with
Thrombophilia Testing Method during Pregnancy? Acute Thrombosis? Anti-Coagulation?
Factor V Leiden Mutation Activated protein C resistance Yes Yes No
assay (second generation)
If abnormal: DNA analysis Yes Yes Yes
Prothrombin G20210A mutation DNA analysis Yes Yes Yes
Protein C deficiency Protein C activity (<65%) Yes No No
Protein S deficiency Functional assay (<55%) Noa No No
Antithrombin deficiency Antithrombin activity (<60%) Yes No No
Source: Adapted from Ref. [83].
a If screening in pregnancy is necessary, cutoff values for free protein S antigen levels in the second and third trimesters have been identified at less than 30% and less than

24%, respectively.

recommendations from the most recent ACOG bulletin are
shown in Table 29.6. Treatment can be divided in “Prevention of
VTE,” and “Prevention of obstetrical complications.”
Prevention of VTE
Among women with a nonrecurring cause for the prior VTE
and no thrombophilia, the risk of recurrent antepartum VTE is
low; therefore, routine antepartum prophylaxis with heparin
may not be warranted. Prophylactic anticoagulation should still
be given postpartum, especially if there is a cesarean delivery. If
moderate risk thrombophilias such as PC, PS, heterozygous
FVL, or PGM are detected in this group of women, prophy-
lactic anticoagulation is advised. If high-risk thrombophilias
such as homozygous FVL or PGM, a compound heterozygote,
or ATIII deficiency is detected, full therapeutic anticoagu-
lation is recommended. An elevated homocysteine and a low
folate, B6, or B12 level should prompt replacement.
In a woman with a prior personal history of a VTE and no prior
sporadic precipitating event (e.g. unprovoked, oral contracep-
tives, or pregnancy), prophylactic anticoagulation antepartum
and postpartum is usually recommended. Full anticoagulation
is advised in women with high-risk thrombophilias. An elevated
homocysteine and a low folate, B6, or B12 level should prompt
replacement.
In a woman with a VTE in the current pregnancy, full anti-
coagulation is typically advised for 3–6 months duration.
At that time, women with low-risk thrombophilias are then
given prophylactic doses of anticoagulation through 6 weeks

TABLE 29.6: Recommended Thromboprophylaxis for Pregnancies Complicated by Inherited Thrombophiliasa

Clinical Scenario
Low-risk thrombophilia without previous
c Surveillance without anticoagulation Surveillance without anticoagulation therapy or postpartum
VTE
Low-risk thrombophiliac with a family
history (first-degree relative) of VTE
Low-risk thrombophiliac with a single
previous episode of VTE—Not receiving
long-term anticoagulation therapy
High-risk thrombophiliad without previous
VTE
High-risk thrombophiliad with a single
previous episode of VTE or an affected
first-degree relative—Not receiving
long-term anticoagulation therapy
Thrombophilia with two or more episodes of
VTE—Not receiving long-term
anticoagulation therapy
Thrombophilia with two or more episodes of
VTE—Receiving long-term anticoagulation
therapy
Source: Adapted from Ref. [83].
a Postpartum treatment levels should be equal to antepartum treatment.
Antepartum Management Postpartum Management
therapy prophylactic anticoagulation therapy if the patient has
additional risks factorsb
Surveillance without anticoagulation Postpartum prophylactic anticoagulation therapy or
therapy or prophylactic LMWH/UFH intermediate-dose LMWH/UFH
Prophylactic or intermediate-dose Postpartum prophylactic anticoagulation therapy or
LMWH/UFH intermediate-dose LMWH/UFH
Prophylactic or intermediate-dose Postpartum prophylactic anticoagulation therapy or
LMWH/UFH intermediate-dose LMWH/UFH
Prophylactic, intermediate-dose, or Postpartum prophylactic anticoagulation therapy, or
adjusted-dose LMWH/UFH intermediate or adjusted-dose LMWH/ UFH for 6 weeks
(therapy level should be equal to the selected antepartum
treatment)
Intermediate-dose or adjusted-dose Postpartum anticoagulation therapy with intermediate-dose or
LMWH/UFH adjusted dose LMWH/UFH for 6 weeks (therapy level should
be equal to the selected antepartum treatment)
Adjusted-dose LMWH/UFH Resumption of long-term anticoagulation therapy. Oral
anticoagulants may be considered postpartum based upon
planned duration of therapy, lactation, and patient preference.

b First-degree relative with a history of a thrombotic episode or other major thrombotic risk factors (e.g. obesity, prolonged immobility, cesarean delivery).

c Low-risk thrombophilia: Factor V Leiden heterozygous; prothrombin G20210A heterozygous; protein C or protein S deficiency.

d High-risk thrombophilias include factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for factor V Leiden and prothrombin

G20210A mutation, or antithrombin deficiency.

Abbreviations: LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism.
Inherited Thrombophilia
postpartum. Those with high-risk thrombophilias (homozy-
gous FVL, homozygous PGM, compound heterozygote, ATIII
deficiency) or recurrent VTE are treated with full anticoagu-
lant doses through 6 weeks postpartum and often for life.
Prevention of obstetrical
complications (see Table 30.5)
On balance, anticoagulant therapy in women with thrombophil-
ias does not appear to be efficacious for improving obstetric out-
comes. However, there are scant high-quality data and definitive
conclusions cannot be made. A prospective randomized, non-
blinded non–placebo-controlled randomized trial evaluated the
effect of thromboprophylaxis in women with one unexplained
pregnancy loss at ≥10th week of amenorrhea and either hetero-
zygous FVL mutation, prothrombin G20210A mutation, or PS
deficiency (free antigen <55%) [69]. Women were given 5-mg folic
acid daily before conception, to be continued during pregnancy,
and either low-dose aspirin 100 mg daily or LMWH enoxa-
parin 40 mg starting at 8 weeks. LMWH was associated with a
higher (86% vs. 29%) incidence of a healthy live birth, and lower
incidence of low birthweight (10% vs. 30%). No significant side
effects of the treatments could be evidenced in patients or new-
borns. This trial led to enthusiasm about the potential benefits
of thromboprophylaxis. However, this was not a blinded trial
and outcomes in untreated women were considerably worse than
expected. Thus, results should be interpreted with caution.
Since that time, results have not been as encouraging. A ret-
rospective, non-randomized study noted no improvement in
pregnancy outcomes in women with thrombophilias who were
and were not treated with thromboprophylaxis [75]. A cohort
study showed that in women with a thrombophilia (heterozy-
gous factor V, activated PC resistance, MTHFR 677 TT genotype,
PS deficiency, heterozygous prothrombin 20210, antithrombin II
deficiency, hyper-homocysteinemia, and/or PC deficiency) and a
history of ≥3 first trimester losses, ≥2 second trimester losses,
or a fetal death in the third trimester, enoxaparin 40 mg/day
was associated with an approximate 80% rate of live births, simi-
lar to enoxaparin 80 mg/day [76]. Recent meta-analyses and
reviews also found no increase in live birth rates in women with
thrombophilias and pregnancy loss treated with anticoagulant
therapy [77, 78]. The FRUIT trial compared low-dose aspirin with
and without dalteparin in 139 women with thrombophilia and
prior adverse pregnancy outcome. Dalteparin decreased the risk
of recurrent hypertensive disease prior to 34 weeks’ gestation
(risk reduction 8.7% [95% CI 1.9–15.5%]) but had no effect on fetal
growth [79, 80].
Finally, a recent, large, multi-center, multi-national study, the
TIPPS trial, compared antepartum prophylactic dalteparin ver-
sus no dalteparin for the prevention of pregnancy complications
in 289 women with thrombophilia [81]. There was no difference
in adverse obstetric outcomes between groups. There also was a
similar rate of major bleeding although minor bleeding was more
common in the dalteparin group [81]. Taken together, these data
do NOT support the use of thromboprophylaxis in women with
thrombophilias in order to improve pregnancy outcomes.
Hyperhomocysteinemia
There are no trials to assess interventions for the pregnant woman
with hyper-homocysteinemia. It might be reasonable to suggest
safe therapy aimed to normalize the homocysteine level, with
folic acid 4 mg once a day, in addition to vitamin B6 25 mg 3–4
times a day and vitamin B12 100 mg once a day, but counseling
321
should emphasize that this therapy has not been tested in trials
in pregnant women. This therapy has been tested in the non-
pregnant population. The vitamins and thrombosis (VITRO)
study investigated the effect of homocysteine lowering by daily
supplementation of B vitamins on the risk reduction of DVT and
pulmonary embolism (PE) [82]. The results did not show that
homocysteine lowering by vitamin B supplementation prevents
recurrent venous thrombosis, even though homocysteine levels
were lowered back to the normal range with therapy.
For antepartum testing, delivery, anesthesia, and postpar-
tum/breastfeeding, see Chapter 30.
References
1. Egeberg O. Inherited antithrombin III deficiency causing thrombophilia.
Thromb Diath Haemorrh 1965;13:516–530. [II-3]
2. Beck EA, Charache P, Jackson DP. A new inherited coagulation disor-
der caused by an abnormal fibrinogen (“fibrinogen Baltimore”). Nature
1965;208:143–145. [II-3]
3. Griffin JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in con-
genital thrombotic disease. J Clin Invest 1981;68:1370–1373. [II-3]
4. Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with
a partial deficiency of protein S. N Engl J Med 1984;311:1525–1528. [II-2]
5. Koeleman BP, Reitsma PH, Bertina RM. Familial thrombophilia: a complex
genetic disorder. Semin Hematol 1997;34:256–264. [II-2]
6. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a
previously unrecognized mechanism characterized by poor anticoagulant
response to activated protein C: prediction of a cofactor to activated protein
C. Proc Natl Acad Sci USA 1993;90:1004–1008. [II-3]
7. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagula-
tion factor V associated with resistance to activated protein C. Nature
1994;369:64–67. [II-2]
8. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation
in the 3’-untranslated region of the prothrombin gene is associated with
elevated plasma prothrombin levels and an increase in venous thrombosis.
Blood 1996;88:3698–3703. [II-2]
9. Lockwood CJ. Inherited thrombophilias in pregnant patients. Prenat
Neonat Med 2001;6:3–14. [Review]
10. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet
1999;353:1258–1265. [Review]
11. Practice bulletin No. 113. Inherited thrombophilias in pregnancy.
American College of Obstetricians and Gynecologists. Obstet Gynecol
2010;116:212–222. [Review]
12. Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a
population study. Obstet Gynecol 1999;94:595–599. [II-2]
13. Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and
gynaecology: the Scottish experience. Scott Med J 1996;41:83–86. [II-2]
14. Kamel H, Navi BB, Sriram N, et al. Risk of a thrombotic event after the 6
week postpartum period. N Engl J Med 2014;370:1307–1315. [II-2]
15. Grandone E, Margaglione M, Colaizzo D, et al. Genetic susceptibility to
pregnancy-related venous thromboembolism: roles of factor V Leiden,
prothrombin G20210A, and methylenetetrahydrofolate reductase C677T
mutations. Am J Obstet Gynecol 1998;179:1324–1328. [II-2]
16. Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum
Genet 2001;109:369–384. [II-2]
17. Haverkate F, Samama M. Familial dysfibrinogenaemia and thrombo-
philia. Report on a study of the SSC Subcommittee on fibrinogen. Thromb
Haemost 1995;73:151–161. [II-2]
18. American College of Obstetricians and Gynecologists Women’s Health
Care Physicians. ACOG Practice Bulletin Number 138: Inherited throm-
bophilias in pregnancy. Obstet Gynecol 2013 September;122:706–717.
[Review]
19. Lockwood C. Inherited thrombophilias in pregnant patients: detection and
treatment paradigm. Obstet Gynecol 2002;99:333–341. [Review]
20. Dautaj A, Krasi G, Bushati V, Precone V, Gheza M, Fioretti F, Sartori M,
Costantini A, Benedetti S, Bertelli M. Hereditary thrombophilia. Acta
Biomed 2019;90(10-S):44–46. [III]
21. Dizon-Townsend D, Miller C, Sibai B, et al. The relationship of the factor
V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet
Gynecol 2005;106:517–524. [II-2]
22. Lockwood CJ. Heritable coagulopathies in pregnancy. Obstet Gynecol Surv
1999;54:754. [Review]
322
23. Walker MC, Garner PR, Keely EJ, et al. Changes in activated protein C resis-
tance during normal pregnancy. Am J Obstet Gynecol 1997;77:162. [II-3]
24. De Stefano V, Leone G, Mastrangelo S, et al. Clinical manifestations and
management of inherited thrombophilia: retrospective analysis and follow-
up after diagnosis of 238 patients with congenital deficiency of antithrom-
bin III, protein C, protein S. Thromb Haemost 1994;72:352–358. [II-3]
25. Middledorp S, Henkens CM, Koopman MM, et al. The incidence of venous
thromboembolism in family members of patients with factor V Leiden
mutation and venous thrombosis. Ann Intern Med 1998;128:15–20. [II-2]
26. Kingdom JC, Kaufmann P. Oxygen and placental villous development: ori-
gins of fetal hypoxia. Placenta 1997;18:613–621. [II-3]
27. Many A, Schreiber L, Rosner S, et al. Pathologic features of the placenta
in women with severe pregnancy complications and thrombophilia. Obstet
Gynecol 2001;98(6):1041–1044.[II-3]
28. Paidas MJ, Ku DH, Lee MJ, et al. Protein Z, protein S levels are lower in
patients with thrombophilia and subsequent pregnancy complications. J
Thromb Haemost 2005;3:497–501. [II-2]
29. Kang SS, Wong PWK, Susmano A, et al. Thermolabile methylenetetrahy-
drofolate reductase: an inherited risk factor for coronary artery disease. Am
J Hum Genet 1991;48:536. [II-3]
30. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular
disease: a common mutation in methylenetetrahydrofolate reductase. Nat
Genet 1995;10:111. [II-3]
31. Gallagher PM, Meleady R, Shields DC, et al. Homocysteine and risk of
premature coronary heart disease: evidence for a common gene mutation.
Circulation 1996;94:2154. [II-3]
32. Guttormsen AB, Ueland PM, Nesthus I, et al. Determinants and vitamin
responsiveness of intermediate hyperhomocysteinemia (40 mmol/L). J Clin
Invest 1996;98:2174. [II-3]
33. Harmon DL, Woodside JV, Yarnell JW, et al. The common “thermolabile”
variant of methylenetetrahydrofolate reductase is a major determinant of
mild hyperhomocysteinemia. QJM 1996;89:571. [II-3]
34. Kluijtmans LA, Young IS, Boreham CA, et al. Genetic and nutritional
factors contributing to hyperhomocysteinemia in young adults. Blood
2003;101:2483. [II-3]
35. Robinson K, Arheart K, Refsum H, et al. for the European COMCAC
Group. Low circulating folate and vitamin B6 concentrations. Risk fac-
tors for stroke, peripheral vascular disease, and coronary artery disease.
Circulation 1998;97:437. [II-2]
36. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and
supplements in relation to risk of coronary heart disease among women.
JAMA 1998;279:359. [II-2]
37. Voutilainen S, Rissanen TH, Virtanen J, et al. Low dietary folate intake is
associated with an excess incidence of acute coronary events: The Kuopio
Ischemic Heart Disease Risk Factor Study. Circulation 2001;103:2674. [II-1]
38. Vermeulen EG, Stehouwer CD, Twisk JW, et al. Effect of homocysteine-
lowering treatment with folic acid plus vitamin B6 on progression of sub-
clinical atherosclerosis: a randomised, placebo-controlled trial. Lancet
2000;355:517. [RCT n = 158] [I]
39. Selhub J, Jacques PF, Wilson PW, et al. Vitamin status and intake as pri-
mary determinants of homocysteinemia in an elderly population. JAMA
1993;270:2693. [II-1]
40. Ubbink JR, Vermaak WJ, van der Merwe A, et al. Vitamin B-12, vitamin
B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J
Clin Nutr 1993;57:47. [II-2]
41. McColl MD, Ellison J, Reid F, et al. Prothrombin 20210, MTHFR C677T
mutations in women with venous thromboembolism associated with preg-
nancy. BJOG 2000;107:565–569. [III]
42. Ziakas PD, Poulou LS, Pavlou M, Zintzaras E. Thrombophilia and venous
thromboembolism in pregnancy: a meta-analysis of genetic risk. Eur J
Obstet Gynecol and Reprod Biol 2015;191:106–11. [II-2]
43. Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gestational
venous thromboembolism. Best Pract Res Clin Haematol 2003;16:243.
[Review]
44. British Society of Hematology. Investigation and management of heritable
thrombophilia. Br J Haematol 2001;114:512. [Review]
45. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V
mutations in women with a history of thrombosis during pregnancy and the
puerperium. N Engl J Med 2000;342:374–380. [II-2]
46. Simioni P, Tormene D, Prandoni P, et al. Pregnancy related recurrent events
in thrombophilic women with previous venous thromboembolism. Thromb
Haemost 2001;86:929. [II-2]
47. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin
in pregnant women with a history of venous thromboembolism. N Engl J
Med 2000;343:1439–1444. [II-1, n = 125]
Maternal-Fetal Evidence Based Guidelines
48. Gerhardt A, Scharf RE, Greer IA, Zotz RB. Hereditary risk factors for
thrombophilia and probability of venous thromboembolism during preg-
nancy and the puerperium. Blood. 2016;128(19):2343–2349. [II-2]
49. Croles FN, Nasserinejad K, Duvekot JJ, Kruip MJ, Meijer K, Leebeek FW.
Pregnancy, thrombophilia, and the risk of a first venous thrombosis: sys-
tematic review and Bayesian meta-analysis. BMJ 2017;359:j4452. [Review]
50. Robertson L, Wu O, Langhorne S, et al. Thrombophilia in pregnancy: a sys-
tematic review. Br J Haematol 2006;132:171–196. [Review]
51. Rey E, Kahn SR, David M, et al. Thrombophilic disorders and fetal loss: a
meta-analysis. Lancet 2003;361:901. [II-2]
52. Howley HE, Walker M, Rodger MA. A systematic review of the associa-
tion between factor V Leiden or prothrombin gene variant and intrauterine
growth restriction. Am J Obstet Gynecol 2005;192:694. [II-2]
53. Lin J, August P Genetic Thrombophilias and pre-eclampsia: a meta-­
analysis. Obstet Gynecol 2005;105:182–192. [II-2]
54. Roque H, Paidas MJ, Funai EF, et al. Maternal thrombophilias are not asso-
ciated with early pregnancy loss. Thromb Haemost 2004;91:290. [II-2]
55. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of
thrombophilia polymorphisms with intrauterine growth restriction. N
Engl J Med 2002;347:1. [II-2]
56. Prochazka M, Happach C, Marsal K, et al. Factor V Leiden in pregnancies
complicated by placental abruption. BJOG 2003;110:462–466. [II-2]
57. Facco F, You W, Grobman W. Genetic thrombophilias and intrauterine
growth restriction. A meta-analysis. Obstet Gynecol 2009;113:1206–1216.
[Review]
58. Kist W, Janssen, N, Kalk, J et al. Thrombophilias and adverse pregnancy
outcome – a confounded problem. Thromb Haemost 2008;99:77–85.[II-3]
59. Silver R, Zhao Y, Spong Y, et al. Prothrombin gene G20210A mutation and
obstetric complications. Obstet Gynecol 2010;115:14–20.[II-2]
60. Kahn S, Platt R, McNamara H, et al. Inherited thrombophilia and pre-
eclampsia within a multicenter cohort: the Montreal Pre-eclampsia study.
Am J Obstet Gynecol 2009;200:151–159.[II-3]
61. Said JM, Higgins J, Moses E, et al. Inherited thrombophilia polymor-
phisms and pregnancy outcomes in nulliparous women. Obstet Gynecol
2010;115:5–13.[II-2]
62. Clark P, Walker I, Govan L, et al. The GOAL study: a prospective exami-
nation of the impact of factor V Leiden and ABO(H) blood groups on
haemorrhagic and thrombotic pregnancy outcomes. Br J Haematol
2008;140:236–240.[II-2]
63. Murphy RP, Donoghue R, Nallen R. Prospective evaluation of the risk
conferred by factor V Leiden and thermolabile methylenetetrahydrofolate
reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol
2000;20:266–270. [II-2]
64. Lindqvist PG, Svensson PJ, Marsal K, et al. Activated protein C resistance
(FVQ506) and pregnancy. Thromb Haemost 1999;81:532–537. [II-2]
65. Murakamis S, Matsubara N, Miyakaw S, et al. The relation between
homocysteine concentration and methylenetetrahydrofolate reductase
genetic polymorphism in pregnant women. J Obstet Gynaecol Res 2001;27:
349–352. [II-2]
66. Rodger MA, Walker MC, Smith GC, et al. Is thrombophilia associated with
placenta-mediated pregnancy complications? A prospective cohort study. J
Thromb Haemost 2014;12:469–78. [II-2]
67. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism
and the risk of unexplained recurrent pregnancy loss: a meta-analysis.
Fertil Steril 2006;86(6):1716–22. [I]
68. Dizon-Townson DS, Meline L, Nelson LM, et al. Fetal carriers of the factor
V Leiden mutation are prone to miscarriage and placental infarction. Am J
Obstet Gynecol 1997;177:402. [II-2]
69. von Kries R, Junker R, Oberle D, et al. Foetal growth restriction in children
with prothrombotic risk factors. Thromb Haemost 2001;86:1012. [II-2]
70. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women
with heritable thrombophilia. Lancet 1996;348:913–916. [II-2]
71. Biron-Andréani C, Bauters A, Le Cam-Duchez V, et al. Factor V Leiden
homozygous genotype and pregnancy outcomes. Obstet Gynecol
2009;114:1249–1253.[II-2]
72. Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N
Engl J Med 2008;359(19):2025–33 [II-2]
73. Stevens SM, Woller SC, Bauer KA, et al. Guidance for the evaluation
and treatment of hereditary and acquired thrombophilia. J Thromb
Thrombolysis 2016;41(1):154–64 [I]
74. Seligsohn U, Lubetsky A. Medical progress: genetic susceptibility to venous
thrombosis. N Engl J Med 2001;344:1222–1231. [Review]
75. Warren JE, Simonsen SE, Branch DW, et al. Thromboprphylaxis and preg-
nancy outcome in asymptomatic women with inherited thrombophilias.
Am J Obstet Gynecol 2009;200:e1–5.[II-2]
Inherited Thrombophilia
76. Brenner B, Hoffman R, Carp H, et al. Efficacy and safety of two doses of
enoxaparin in women with thrombophilia and recurrent pregnancy loss:
the LIVE-ENOX study. J Thromb Haemost 2005;3:227–229. [II-2]
77. de Jong PG, Kaandorp S, Di Nisio M, et al. Aspirin and/or heparin for
women with unexplained recurrent miscarriage with or without inher-
ited thrombophilia. Cochrane Database Syst Rev 2014;2014(7):CD004734.
[Review]
78. Areia AL, Fonseca E, Areia M, Moura P. Low-molecular weight heparin plus
aspirin versus aspirin alone in pregnant women with hereditary thrombo-
philia to improve live birth date; meta-analysis of randomized controlled tri-
als. Arch Gynecol Obstet 2015;DOI 10.1007/s00404-015-3782-2. [Review; I]
79. de Vries JI, van Pampus MG, Hague WM, et al. Low-molecular weight
heparin added to aspirin in the prevention of recurrent early-onset pre-­
eclampsia in women with inheritable thrombophilia in the FRUIT-RCT. J
Thromb Haemost 2012;10:64–72. [I]
323
80. Abheiden CNH, Van Hoorn ME, Hague WM, et al. Does low molecular
weight heparin influence fetal growth or uterine and umbilical arterial
Doppler in women with a history of early-onset uteroplacental insufficiency
and an inheritable thrombophilia? Secondary randomized controlled trial
results. BJOG 2015;DOI: 10.1111/1471-0528.13421. [I]
81. Rodger MA, Hague WM, Kingdom J, et al. Antepartum dalteparin versus
no antepartum dalteparin for the prevention of pregnancy complications in
pregnant women with thrombophilias (TIPPS): a multinational open-label
randomized trial. Lancet 2014;384:1673–83. [I]
82. den Heijer M, Willems H, Blom H, et al. Homocysteine lowering by B vita-
mins and the secondary prevention of deep vein thrombosis and pulmo-
nary embolism: a randomized, placebo-controlled, double-blind. Blood
2007;109:139–144.[RCT, n = 325] [I]
83. ACOG Practice Bulletin No. 197: Inherited thrombophilias in pregnancy.
Obstet Gynecol 2018;132(1):e18–e34. [Review]
30
VENOUS THROMBOEMBOLISM AND ANTICOAGULATION
Alexandra V. Ramirez
Key points
• Venous thromboembolism is one of the leading causes of
pregnancy-related maternal morbidity and mortality in
high-income countries.
• The most risk factors that increase the chance of VTE are:
Pregnancy, increased parity, prior thromboembolism,
age of 35 years or more, increased maternal weight,
instrumented-assisted deliveries or cesarean section,
prolonged immobilization, smoking, and the presence
of an acquired or inherited thrombophilia.
• Compressive ultrasonography is the primary modality for
the diagnosis of deep vein thrombosis (DVT) in pregnancy.
• The ventilation/perfusion (V/Q) scan or a computed
tomography pulmonary angiography (CTPA) are fairly
equivalent first-line imaging tests for the diagnosis of
pulmonary embolism (PE) in pregnant patients although
some experts favor V/Q scans.
• The three anticoagulants typically used are unfraction-
ated heparin (UFH), low-molecular-weight heparin
(LMWH), and warfarin.
• Platelet counts should be checked 5 days after the initia-
tion of UFH and periodically for the first 3 weeks of hepa-
rin therapy.
• LMWH is at least as effective and safe as UFH for the
treatment of patients with acute DVT, and for the preven-
tion of DVT. LMWH and UFH do not cross the placenta,
and are safe for the fetus. The incidences of bleeding,
osteopenia, and heparin-induced thrombocytopenia with
LMWH are probably decreased compared to UFH in preg-
nant patients. Pregnant women may require higher doses
and the risks could be dose related. The dosing of LMWH
in pregnancy remains controversial.
• Warfarin derivatives cross the placenta and have the
potential to cause both bleeding in the fetus and terato-
genicity. Warfarin use is believed to be safe in the first 6
weeks of gestation, but has been associated with warfarin
embryopathy in 4–5% of fetuses when maternal expo-
sure occurs between 6 and 9 weeks gestation.
• In the pregnant patient with acute VTE, either thera-
peutic LMWH throughout pregnancy or intravenous
UFH for at least five days, followed therapeutic UFH or
LMWH for a minimum of 6 months, is the recommended
approach. Anticoagulants should be administered for at
least 6 weeks postpartum.
• There are three general approaches to the antepartum
management of pregnant patients with previous VTE:
UFH, LMWH, or close surveillance.
• Among women with a nonrecurring cause for the prior
VTE and no thrombophilia, the risk of recurrent antepar-
tum VTE is low, and therefore routine antepartum prophy-
laxis with heparin is not warranted. However postpartum
low-dose prophylaxis is still recommended.
324
• If there is a potential recurring cause, prophylactic anti-
coagulation is recommended
• In pregnant women with a prior VTE with history of a
low-risk thrombophilia (heterozygous Factor V or pro-
thrombin gene, protein C or S), prophylactic anticoagu-
lation is recommended.
• Therapeutic anticoagulation is recommended for prior
VTE and high-risk thrombophilia (ATIII deficiency,
homozygous factor V or prothrombin gene, or com-
pound heterozygote).
• Therapeutic anticoagulation should be used in pregnant
women if the woman has recurrent VTE episodes, life-
threatening thrombosis, or thrombosis while receiving
chronic anticoagulation. Filters of the inferior vena cava
should be considered in these situations as well.
• It is recommended that pregnant patients with recurrent
early pregnancy losses and antiphospholipid syndrome
(APS) who do not have a history of VTE receive prophy-
lactic regimen of heparin and low-dose aspirin, and that
those with previous VTE and APS receive a similar prophy-
lactic dose of heparin.
• In pregnant women with mechanical heart valves, it
appears reasonable to use one of these regimens: (1) thera-
peutic LMWH (or UFH) between 6 and 10 weeks and close
to term only, and vitamin K antagonists (VKAs) at other
times; (2) VKAs throughout pregnancy (lowest VTE risk);
and (3) therapeutic LMWH throughout pregnancy.
Definition
Venous thromboembolism (VTE) refers to a condition in which
blood clots inappropriately, and includes deep vein thrombosis
([DVT], when a clot forms in the deep veins of the body; 75–80%
of VTE cases), and pulmonary embolism ([PE] when a clot in the
deep veins breaks free and is carried to the arteries of the lung;
20–25% of VTE cases). Approximately 50% occur during preg-
nancy, and 50% occur during the postpartum period [1].
Symptoms
The two most common initial symptoms (80% of pregnant patients
with DVT) are unilateral pain and edema of an extremity [2].
Other symptoms include discoloration and calor of the leg. Pain
with foot dorsiflexion (Homans’ sign) is neither sensitive nor spe-
cific in non-pregnant patients, but data are lacking in patients who
are pregnant. Compared with the non-pregnant patient, in whom
distal vein thrombosis is more common, most events in preg-
nancy are iliofemoral and patients may manifest with unusual
symptoms such as isolated buttock, groin, flank, or abdominal pain
[3]. PE is not detected clinically in 70–80% of patients in whom it is
detected postmortem. Approximately 30% of apparently isolated
episodes of PE are associated with asymptomatic DVT, and in
patients presenting with symptomatic DVT, the incidence of
DOI: 10.1201/9781003099062-30
Venous Thromboembolism and Anticoagulation
asymptomatic PE ranges 40–50% [4,5]. Most patients who die
of PE die within 30 minutes of the event, reinforcing the need
for rapid and accurate diagnosis [4]. Clinical presentation of
PE can range from low-grade pyrexia, dyspnea, tachypnea, chest
pain, or hemoptysis to cardiovascular collapse. Due to common
nonspecific symptoms during pregnancy, diagnosis of VTE can
be challenging. Clinical suspicion of DVT is confirmed in 10% of
pregnant patients compared with 25% of non-pregnant patients,
and PE is confirmed in only 4% of pregnant patients [6].
Epidemiology and incidence
VTE is one of the leading causes of pregnancy-related maternal
morbidity and mortality in high-income countries. VTE com-
plicates ~1.2 of every 1000 deliveries [7,8] Fatal PE accounts for
9.8% of all pregnancy related deaths in the United States [9].
Due to physiological and anatomical changes normally associ-
ated with pregnancy, the risk of VTE in women during pregnancy
and immediately postpartum is higher than women who are the
same age not pregnant. The risk of VTE is increased 5-fold dur-
ing pregnancy and 60-fold during the first 3 months after birth
[10]. A systematic review to evaluate the risk of VTE during the
postpartum period demonstrated a substantially higher risk dur-
ing the first 6 weeks postpartum with a gradual decline with every
week after delivery; however, it is not entirely clear from these data
exactly when a women’s risk of VTE returns to baseline levels [11].
This risk might persist until at least 12 weeks postpartum [12].
While the relative risk of VTE is greatly increased, the absolute
risk is estimated at around 1–2 in 1000 pregnancies [13,14].
Although much of the evidence suggests incidence is equally dis-
tributed throughout all trimesters, a recent study suggested an
exponential increase in the risk across the duration of pregnancy
[15]. The highest risk is in the puerperium likely because of the
addition of trauma to the pelvic vessels during delivery. Unlike the
non-pregnant women in which distal DVT is more common, the ana-
tomic distribution of DVT in pregnant women differs from that for
12
11
– ≠9
– ≠ 8
–ATIII – ≠ 10
–
≠ 2 (prothrombin)
≠ 1 fibrinogen
FIGURE 30.1 Coagulations cascade and some pregnancy changes. –↑↓, change in pregnancy; ◻, vitamin K-dependent; –, negative
feedback
325
non-pregnant patients. In addition to what was previously known –
that left-sided DVT is more common in pregnancy – this study
also found that proximal DVT restricted to the femoral or iliac
veins is also more common (>60% of cases) [16]. PE occurs in 15%
of untreated DVTs with a mortality rate of 1% and in 4.5% of
treated DVTs with a mortality rate of 1% [17]. Death from PE
occurs about every 1.1–1.5 per 100,000 pregnancies [18].
Genetics
Thrombophilic disorders can be inherited or acquired. About
50% of patients with thrombosis have an identifiable under-
lying genetic disorder [19]. Approximately 50–60% of patients
with a hereditary basis for thrombosis, or a thrombophilia, do
not experience a thrombotic event until one other risk factors is
present [20]. Tables 29.1–29.4 summarize the prevalence, risk of
VTE, testing characteristics, and management for the different
inherited thrombophilias (see Chap. 29) [21].
Antiphospholipid syndrome (APS) is the most important
acquired thrombophilia of pregnancy and is defined by specific
levels of circulating antiphospholipid antibodies and one of the
clinical criteria, which include vascular thrombosis or recur-
rent miscarriages, unexplained death of a fetus after 10 weeks of
gestation or premature birth before 34 weeks due to eclampsia
or pre-eclampsia (see Chap. 28) [21]. Current evidence does not
support inherited thrombophilia or APS screening [22]. However
expert opinion suggest screening may be considered in cases of
personal history of VTE that was associated with a noncurrent
risk factor (e.g., fractures, surgery, and prolonged immobiliza-
tion) or a first-degree relative with a high-risk thrombophilia [23].
Etiology/Basic pathophysiology
The coagulation cascade is briefly and schematically shown
in Figure 30.1. Pregnancy is associated with marked altera-
tions in the proteins of the coagulation and fibrinolytic systems
7
Ø Protein S
–
–Protein C
– Protein S
5
13
Clot
326 Maternal-Fetal Evidence Based Guidelines

TABLE 30.1: Changes in the Normal Functioning of the TABLE 30.2: Conditions Associated with Increased Risks for
Coagulation System during Pregnancy VTE (Pregnant and Non-Pregnant Women)
Coagulant Factors Change in Pregnancy Previous VTE
Thrombophilia
Procoagulants
Advancing age
Fibrinogen Increased
Obesity
Factor VII Increased
Surgery
Factor VIII Increased
Factor X Increased • Cesarean delivery: Especially when complicated by postpartum
Von Willebrand factor Increased hemorrhage or infections
Plasminogen activator inhibitor-1 Increased Trauma
Plasminogen activator inhibitor-2 Increased Smoking
Factor II No change Active cancer
Factor V No change Acute medical illnesses; e.g., acute myocardial infarction, heart failure,
Factor IX No change respiratory failure, infection
Anticoagulants Sickle cell disease
Free Protein S Decreased Inflammatory bowel disease
Antiphospholipid syndrome
Protein C No change
Dyslipoproteinemia
Antithrombin III No change
Nephrotic syndrome
Paroxysmal nocturnal hemoglobinuria
Myeloproliferative diseases
(Table 30.1) [23–25]. (See Obstetric Evidence Based Guidelines,
Behçet’s syndrome
Chapter 3.) A tendency for excessive clotting seems to be an
Varicose veins
adaptive mechanism to prevent excessive bleeding at delivery.
Superficial vein thrombosis
At delivery, about 120 spiral arteries are denuded while carry-
Congenital venous malformation
ing about 12% of the woman’s cardiac output every minute. Much
Long-distance travel
of the prevention in bleeding is due to myometrial contraction,
Prolonged bed rest
but there are also marked increased clotting capacity, impaired
Immobilization
fibrinolysis, and decreased natural anticoagulant activity in
Limb paresis
pregnancy. Pregnancy and postpartum are characterized by the
Chronic care facility stay
presence of the three components of Virchow’s triad, which con-
Pregnancy/puerperium
tribute to the increased risk of VTE:
Oral contraceptives
Hormone replacement therapy
1. Hypercoagulable blood: Increased clotting potential,
Heparin-induced thrombocytopenia
decreased anticoagulant activity and decreased fibrinolysis
Other drugs
occurs during pregnancy to prepare for the hemostatic chal-
lenges of delivery. Mechanisms driving this state include: • Chemotherapy
• Increase in the levels of fibrinogen (factor II) and factor • Tamoxifen
V, VII, VIII, IX, X and XII levels [26]. The generation of • Thalidomide
fibrin also increases markedly. • Antipsychotics
• The anticoagulant activity of protein S is decreased by
about 40% although the levels of protein C remain nor- Central venous catheter
mal [27]. Vena cava filter
• Thrombus dissolution (fibrinolysis) is decreased from Intravenous drug abuse
increased plasminogen activator inhibitor type 1 and Source: Adapted from Refs. [4, 13].
2 activity and decreased tissue plasminogen activator
activity [26]. thrombophilia; approximated in 20–50% of cases of VTE in preg-
2. Venous stasis: Caused by progesterone induced venodi- nancy are associated with an inherited or acquired thrombo-
lation, venous compression by the gravid uterus, com- philia. Cesarean is an independent risk factor for VTE, with an
pression of the left iliac vein by the right iliac artery and estimated incidence of approximately 3 cases per 1000, a four-
immobilization. A 50% reduction of the legs venous flow fold increased risk as compares with vaginal delivery [4]. Other
velocity occurs by weeks 25–29 of gestation [5]. risk factor include age ≥35 years, multiparity, obesity, multiple
3. Vascular damage: Due to venous distention, vaginal, pregnancies, assisted vaginal delivery, immobilization, smoking,
assisted vaginal and cesarean deliveries [28]. and the presence of inherited or acquired thrombophilia (see
Chaps. 28 and 29) [18, 30].
Risk factors/Associations
Complications
Risks factors are shown in Table 30.2, with the most common
in pregnancy including a personal history of thrombosis [4] DVT: Risk of PE, post-thrombotic syndrome (PTS) due to
(15–25% of all cases of VTE are recurrent events) [29]. The sec- thrombotic obstruction, incomplete recanalization, and/
ond most important individual risk factor is the presence of a or permanent damage to the venous valves resulting in
Venous Thromboembolism and Anticoagulation
valvular reflux and venous hypertension. Severe PTS may result
in venous ulcers. PTS may occur in as many as 60% of patients
after acute DVT involving the iliac, and/or femoral vein seg-
ments. In a study, 42% of women with lower extremity DVT
developed PTS, which was severe in 7% [5]. In women with a
history of pregnancy-related DVT in the lower limb, the preva-
lence of PTS was 42%. Of women with a pregnancy-related PE,
24% reported PTS [13, 31].
PE: Risk of death, pulmonary hypertension, and right ventricu-
lar failure [32]. Evidence on the association between a pregnancy-
related PE and subsequent chronic thromboembolic pulmonary
hypertension (CTPH) is limited. A large prospective cohort study
observed a CTPH incidence of 3.8% after an acute first episode of
PE. In the subgroup of patients with a transient risk factor, including
pregnancy, no increased risk for CTPH was observed [13].
Management
Principles
Given the paucity of data regarding diagnosis and treatment in
pregnancy, most data are derived from the non-pregnant general
population
Diagnosis
A full history and physical examination should be the initial
steps in the diagnoses of DVT or PE, but objective testing is
essential because clinical assessment alone is unreliable and
the consequences of misdiagnosis are serious. To diagnose VTE,
clinical suspicion must remain high. Only about 25% of patients
who present with symptoms of DVT have a definitive diagnosis
of DVT on objective testing [33]. However, in symptomatic preg-
nant women, DVT and PE appear less prevalent due to the fact
that symptoms such as lower extremity edema, chest pain and
dyspnea can be common in pregnancy. The prevalence of DVT
is about 8% in pregnant women with suspected DVT, and the
prevalence of PE is about 5% in pregnant women with sus-
pected PE [34]. A concern with diagnostic tests has been the
potential side effects of fetal radiation exposure. Epidemiologic
studies have shown that exposure to radiation of less than a
cumulative dose of 5 rads has not been associated with signifi-
cant risk for fetal injury [35]. The diagnostic tests shown in Table
30.3 are all below the safe limit. Some case-controlled studies,
however, have shown a slight increase of childhood cancers.
The fetus is especially sensitive to radiation between 8 and 15
weeks, during which there is rapid neuronal development and
migration. Radiation exposure higher than 100 mGy during this
TABLE 30.3: Radiation Exposures of Diagnostic Tests for
VTE
Test Radiation Exposure (rads)
Chest X-ray 0.001
Perfusion scan 0.018
Ventilation scan 0.019
Helical CT 0.005
Limited venography 0.050
Pulmonary angiography 0.221
Compression u/s None
MRI None
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging.
327
period may lead to mental retardation, microcephaly, and intra-
uterine growth restriction [5, 36,37].
Deep vein thrombosis
During pregnancy, thrombosis most frequently begins in the
veins of the calf or in the iliofemoral segment of the deep venous
system and has a striking predilection for the left leg (85–90%)
[38–40], possibly because of the compressive effects on the left
iliac vein by the right iliac artery where they cross [41]. While
clinical assessment using clinical decision, rules has been demon-
strated to be very successful in assigning pretest probability out-
side of pregnancy, the studies deriving and validating this model
did not include pregnant patients [42].
In non-pregnant women D-dimer can also be used in combi-
nation with the clinical probability score to diagnose DVT [43].
However, D-Dimer values increase progressively throughout
pregnancy limiting its utility [44]. Although a low D-dimer
may be helpful in ruling out DVT, a positive (high) D-dimer
result will be common in pregnancy and always require con-
firmatory testing [45]. Compressive ultrasonography is now
the primary modality for the diagnosis of DVT in pregnancy
(Figure 30.2) [4, 46]. This method is noninvasive and there is
no radiation exposure to the fetus. It has a sensitivity of 97%
and a specificity of 94% for the diagnosis of proximal DVT in
non-pregnant patients [47,48]. The sensitivity and specificity is
lower for distal DVT (i.e., DVT isolated to the paired calf veins,
peroneal, anterior tibial and posterior tibial veins) and for iliac
vein thrombosis [49]. When iliac vein thrombosis is suspected,
the available options include: (1) venography, (2) magnetic
resonance imaging, and (3) pulse Doppler and/or direct visu-
alization of the iliac vein [48]. In cases of confirmed DVT with
compression ultrasonography, treatment should be initiated.
In cases of negative results and no suspicion of iliac vein pro-
cess, surveillance is recommended. When tests are negative or
equivocal and there is suspicion of thrombosis, patients can
either have additional imaging studies such as venography
Suspected lower extremity
DVT
Compression
ultrasonography of
lower extremities
Negative Equivocal Positive
with no suspected with continued
other VTE suspected VTE
Additional imaging studies (e .g. venography)
Negative Positive
Surveillance without
Anticoagulation
anticoagulation
FIGURE 30.2 Diagnosis of deep vein thrombosis during preg-
nancy. (Adapted from Ref. [6].)
328 Maternal-Fetal Evidence Based Guidelines

or serial noninvasive testing, or presumptive anticoagulation
therapy started [49].
Pulmonary embolism
The accurate diagnosis of PE in pregnancy is imperative. If undi-
agnosed, it can be fatal, whereas treating patients with antico-
agulation can expose them to unnecessary risks of such therapy.
The approach to diagnosing PE in pregnancy is similar to that
of the non-pregnant patient. An approach using D-dimer has
been suggested (YEARS algorithm) (Figure 30.3) [50] or an
alternative one without using D-dimer can be used (Figure 30.4).
If the clinical features are compatible with PE, V/Q scan is one
of the tests of choice [51]. If the test is normal, PE is excluded. If a
segmental defect in perfusion with normal ventilation (high prob-
ability lung scan) is seen, the diagnosis of PE is confirmed [34].
About 40–60% of V/Q scans are diagnostic (either high probability
or normal). Patients with non-diagnostic lung scans can undergo
compression ultrasound or CT pulmonary angiography (CTPA). A
limitation of V/P scan in the non-pregnant population is that most
scans are non-diagnostic, in which the incidence of PE varies widely
from 10 to 30%. In pregnant patients, however, fewer patients will
have non-diagnostic scans likely due to less concomitant respira-
tory disease and hyper-dynamic pulmonary circulation [52]. The
prevalence of inconclusive test results for both imaging techniques
is relatively high due to the physiological changes during pregnancy
and therefore specifically designed protocols for pregnant women
may be required. In a study, the pooled rate of an inconclusive result
with V/Q scanning was 14% and with CTPA is was 12% [13].
CTPA is also an available additional first-line imaging test.
It is usually preferred in non-pregnant patients for several rea-
sons: (1) the specificity is higher than V/Q (>90% vs. 10%); (2) CTPA
may identify alternative diagnosis as cause of the symptoms; and
(3) CTPA is more widely accessible [53]. Despite its advantages,
the sensitivity and specificity of CTPA can be affected by the
location of the embolus. CTPA is more sensitive for the detec-
tion of central arteries and can miss sub-segmental emboli [54].
CTPA has also been associated with increased risk of breast can-
cer [55]. Regardless of the method chosen for diagnosing PE, both
are not associated with high dose radiation exposure to the fetus,
the lowest exposure being with Helical CT 0.0033–0.02 mGy for
the first trimester, 0.0079–0.0767 mGy for the second trimester,
0.0513–0.1308 mGy for the third trimester; when compared to
V/Q Approx. 0.32–0.64 mGy [4]. Doppler US of the lower extrem-
ities can also be initially performed because the diagnosis of DVT
may confirm PTE indirectly and the therapy is the same for both
conditions [56].
Pulmonary angiography remains the gold standard for ruling
out PE. This test requires expertise for performance and inter-
pretation and is invasive. Thus, it is held in reserve for patients in
whom the diagnosis cannot be made or excluded on the basis of
less invasive testing.
The American Thoracic Society and the Society of Thoracic
Radiology (ATS/STR) clinical practice guidelines for the evalua-
tion of suspected PE in pregnancy suggest that chest x-ray (CXR)
be used as an initial evaluation, with progression to V/Q scan if
the CXR is normal and CTPA if the CXR is abnormal [57].

Clinical signs of DVT

Compression US of
symptomatic leg

Normal compression US Abnormal compression US

+ADDITIONAL YEARS CRITERIA? Initiate anticoagulation

* Hemoptysis treatment
* PE as most likely diagnosis

No YEARS criteria and 1–3 YEARS criteria and No YEARS criteria and 1–3 YEARS criteria and
D-dimer <1000 ng/ml D-dimer <500ng/ml D-dimer ≥1000 ng/ml D-dimer ≥ 500ng/ml

PE ruled out Perform CT PA

Withhold anticoagulation Initiate anticoagulation
treatment treatment if CT PA indicates PE

FIGURE 30.3 Pregnancy-adapted algorithm for the management of suspected acute pulmonary embolism. (Adapted from Ref. [50].)
Abbreviations: CT, computed tomography; US, ultrasonography; DVT, deep vein thrombosis; PE, pulmonary embolism; PA, pulmo-
nary angiography.
Venous Thromboembolism and Anticoagulation 329

Suspected PE

Ventilation perfusion
scan
CTPA

High probability Nondiagnostic Normal Positive

PE excluded
Treat PE CUS

DVT present DVT absent

Treat PE Serial CUS Pulmonary

angiography

Negative Positive Negative

PE excluded Treat PE PE excluded

FIGURE 30.4 Workup for suspected pulmonary embolus. (Adapted from Ref. [4].) Abbreviations: CTPA, computerized tomography
pulmonary angiogram; PE, pulmonary embolism; CUS, conventional ultrasound; DVT, deep vein thrombosis.

Management: Clinical scenarios, to DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in

and anticoagulation
Despite an increased risk of DVT/PE associated with pregnancy
and the postpartum period, routine anticoagulation therapy is not
currently recommended due to possible complications that can
arise with this therapy [58,59]. Anticoagulation (Table 30.4) [4] is
recommended in those patients with an acute thromboembolism
or with risk factors including a prior history of DVT/PE or a diag-
nosed thrombophilia. Table 30.5 [4] shows proposed manage-
ment of patients based on risk factors for VTE in pregnancy.
The anticoagulants that have been evaluated for the preven-
tion and treatment of VTE in pregnancy include heparin and
heparin-like compounds (UFH, LMWH, heparinoids and pen-
tasaccharide) and coumadin derivatives (warfarin). In recent
years, direct oral anticoagulants (DOACs) have replaced VKAs
as first choice for the treatment of VTE. There is currently little
evidence about the safety of DOACs during pregnancy. Animal
models have shown that DOACs pass the placenta and are also
found in breastmilk. In a review of 223 women who were exposed
pregnancy, congenital abnormalities were observed in 7 of the
137 live-born children, with 3 considered as embryopathy [13].
The International Society on Thrombosis and Hemostasis (ISTH)
recommends against the use of DOACs during pregnancy [13].
UFH and LMWH are the anticoagulants most often used given
their safety and efficacy during pregnancy.
Unfractionated heparin
The word heparin derives from the Greek hepar, meaning liver,
the organ where it was first isolated from. Unfractionated hepa-
rin (UFH) exerts its anticoagulation action by two mechanisms of
action: 1) stimulation of anti-thrombin III (ATIII) activity; which
inhibits factor 2, 9, 10, and 11 [2] and direct factor 10 inhibition
[60]. It does not cross the placenta and is safe for the fetus; how-
ever, it has been associated with adverse effects in the mother
including bleeding, skin reactions, heparin-induced thrombocy-
topenia (HIT), and osteoporosis [61].
The rate of major maternal bleeding in pregnant patients
treated with UFH therapy is about 2%, which is consistent with
330 Maternal-Fetal Evidence Based Guidelines

TABLE 30.4: Anticoagulation Regimen Definitions
Anticoagulation
Regimen Anticoagulation Dosage
Prophylactic Enoxaparin, 40 mg SC once daily
LMWHa Dalteparin, 5000 units SC once daily
Tinzaparin, 4500 units SC once daily
Nadroparin, 2850 units SC once daily
Intermediate- Enoxaparin, 40 mg SC every 12 hours
dose LMWH Dalteparin, 5000 units SC every 12 hours
Adjusted-dose Enoxaparin, 1 mg/kg every 12 hours
(therapeutic) Dalteparin, 200 units/kg once daily
LMWHb Tinzaparin, 175 units/kg once daily
Dalteparin, 100 units/kg every 12 hours
Target an anti-Xa level in the therapeutic range of
0.6–1.0 units/mL 4 hours after last injection for
twice-daily regimen; slightly higher doses may be
needed for a once-daily regimen.
Prophylactic UFH, 5000–7500 units SC every 12 hours in first
UFH trimester
UFH, 7500–10,000 units SC every 12 hours in the
second trimester
UFH, 10,000 units SC every 12 hours in the third
trimester, unless the aPTT is elevated
Adjusted-dose UFH, 10,000 units or more SC every 12 hours in
(therapeutic) doses adjusted to target aPTT in the therapeutic
UFHb range (1.5–2.5 3 control) 6 hours after injection
Postpartum Prophylactic, intermediate, or adjusted dose LMWH
anticoagulation for 6–8 weeks as indicated. Oral anticoagulants may
be considered postpartum based upon planned
duration of therapy, lactation, and patient
preference.
Surveillance Clinical vigilance and appropriate objective
investigation of women with symptoms suspicious
of deep vein thrombosis or pulmonary embolism.
VTE risk assessment should be performed
prepregnancy or early in pregnancy and repeated if
complications develop, particularly those
necessitating hospitalization or prolonged
immobility.
Source: Modified from Ref. [4].
a Although at extremes of body weight, modification of dose may be required.
platelets and lead to life threatening arterial and venous throm-
bosis. It should be suspected with a fall in platelet count >50%
from baseline or <100,000/µL, antibodies to heparin, skin lesions
at the injection site, and systemic reaction after IV injection 5–15
days after commencing heparin [59]. It should be differentiated
from a transient thrombocytopenia that can occur with initia-
tion of UFH due to platelet clumping. Platelet counts should be
checked about 5 days after initiation of UFH and periodi-
cally for the first 2 weeks. Definitive laboratory data using HIT
antibody testing (e.g., immunoassay and sometimes functional
assay) may not be available for several days, and it may be nec-
essary to make a presumptive diagnosis of HIT while awaiting
these data. In pregnant women who are diagnosed with HIT and
require anticoagulation, alternative options include use of the
heparinoid, danaparoid sodium (does not cross the placenta but
unavailable in the United States [65], or fondaparinux, a syn-
thetic pentasaccharide and selective factor Xa inhibitor. A retro-
spective study comparing fondaparinux with enoxaparin found
no effects of fondaparinux on mother or infant; however, some
anticoagulant activity has been detected in umbilical cord blood
of exposed infants [66–68]. Therefore the use of fondaparinux
during the first trimester is not recommended [13].
Fondaparinux has been recommended by the Pregnancy and
Thrombosis Working Group as an alternative for patients with
HIT [69] or cases of severe cutaneous allergy to heparin. Small
case series and case reports have shown fondaparinux to be safe,
but it is important to recognize that most of these involve expo-
sure during second and third trimesters [5].
Heparin-induced osteoporosis
Symptomatic vertebral fractures have been reported to occur in
about 2–3% of heparin-treated patients and significant reduc-
tions in bone mineral density in up to 30% of patients receiving
long-term UFH [70]. In a systematic review of 2777 pregnant
women on heparin, only one case (0.04%) of osteoporotic fracture
was identified [13]. The mean bone loss is about 5% with unclear
reversibility. LMWH has a lower risk of osteopenia than UFH.
Low-molecular-weight heparin
LMWH has become the anticoagulant of choice during preg-
nancy. LMWH exerts its anticoagulation action by stimulation
of antithrombin III activity, inhibiting in particular factor 10 (not

b Also referred to as weight adjusted, full treatment dose.

Abbreviations: aPTT, activated partial thromboplastin time; INR, international nor-
malized ratio; LMWH, low-molecular-weight heparin; SC, subcutaneously; UFH,
unfractionated heparin; VTE, venous thromboembolism.
the reported rates of bleeding associated with heparin therapy
in non-pregnant patients [62] and with warfarin [63]. UFH half-
life is about 1.5 hours. This short half-life makes it the pre-
ferred anticoagulation around the time of delivery or surgery.
The anticoagulant effect lasts for about 8–12 hours and its effect
can be reversed with protamine sulfate if necessary. PTT can be
obtained to verify clearance. Recent UFH administration is not a
contraindication to regional anesthesia as long as the PTT is not
prolonged.
Heparin-induced thrombocytopenia
Approximately 3% of non-pregnant patients receiving UFH
acquire heparin-induced thrombocytopenia (HIT) [64]. HIT
is very rare in pregnancy and is an adverse reaction to heparin in
which antibodies to platelets form. These antibodies can activate
factor 2). Multiple studies have found LMWH to be more effec-
tive, associated with lower risk of hemorrhagic complications and
with lower mortality than UFH in the treatment if DVT in non-
pregnant women [71,72]. In a Cochrane Review of 22 studies with
over 8000 patients with DVT and PE, LMWH was associated
with lower rates of VTE recurrence or extension, lower mor-
tality, and less bleeding during the initial treatment period
[73]. Also the risk of HIT is substantially lower with LMWH,
as well as the risk of heparin-induced osteoporosis [74] and
there are fewer allergic skin reactions. The other advantage is
a longer plasma life and a more predictable response than UFH
[75]. LMWH does not cross the placenta and studies have sup-
ported its safety on maternal and fetal outcomes [76].
The dosing of LMWH remains controversial. The anticoagu-
lant effect of LMWH lasts for 18–24 hours. Pregnant women may
require increases in dalteparin dose of 10–20% compared with
doses of non-pregnant women to reach the target anti-Xa levels
[77–79]. Anticoagulation with LMWH may need to be monitored
in pregnant women and the dose adjusted to reach the target
Xa level, which decreases the logistical and financial ben-
efits of LMWH. The therapeutic anti-Xa level for adjusted-dose
Venous Thromboembolism and Anticoagulation 331

TABLE 30.5: Recommended Pharmacologic Thromboprophylaxis in Pregnancy and the Postpartum Period
Clinical Scenario Antepartum Management Postpartum Management
No history of VTE, no thrombophilia Surveillance without
d Surveillance without anticoagulation therapy or postpartum
anticoagulation therapy anticoagulation therapy if the patient has additional risks factorsc
VTE diagnosed during pregnancy Adjusted-dose LMWH/UFH Adjusted-dose LMWH/UFH for a minimum 6 weeks postpartum.
Longer duration of therapy may be indicated depending on the
timing of VTE during pregnancy. Oral anticoagulation may be
considered based upon planned duration of therapy, lactation,
and patient preference
Single provoked VTE (precipitated by specific event Surveillanced without Surveillance without anticoagulation therapy or postpartum
such as surgery, trauma or immobility unrelated to anticoagulation therapy prophylactic anticoagulation therapy if the patient has additional
estrogen or pregnancy due to a transient (resolved) risks factorsc
risk factor, no thrombophilia
History of single unprovoked VTE (no identified Prophylactic or Prophylactic or intermediate-dose or adjusted-dose LMWH/UFH
precipitating factor present; included prior VTE in intermediate-dose or regimen for 6 weeks postpartum
pregnancy or associated with hormonal adjusted-dose LMWH/
contraception), not on long-term anticoagulation UFH
Low-risk thrombophiliaa without previous VTE Surveillanced without Surveillance without anticoagulation therapy or postpartum
anticoagulation therapy prophylactic anticoagulation therapy if the patient has additional
risks factorsc
Low-risk thrombophiliaa with a family history Surveillanced without Postpartum prophylactic anticoagulation therapy or intermediate-
(first-degree relative) of VTE anticoagulation therapy or dose LMWH/UFH
prophylactic LMWH/UFH
Low-risk thrombophiliab with a single previous Prophylactic or Postpartum prophylactic anticoagulation therapy or intermediate-
episode of VTE—not receiving long-term intermediate-dose LMWH/ dose LMWH/UFH
anticoagulation therapy UFH
High-risk thrombophiliab without previous VTE Prophylactic or intermediate Postpartum prophylactic anticoagulation therapy or intermediate-
LMWH or UFH dose LMWH/UFH
High-risk thrombophiliab with a single previous episode Prophylactic, intermediate- Postpartum prophylactic anticoagulation therapy, or intermediate
of VTE—or an affected first-degree relative—not dose, or adjusted-dose or adjusted-dose LMWH/UFH for 6 weeks (therapy level should
receiving long-term anticoagulation therapy LMWH/UFH be equal to the selected antepartum treatment)
Two or more episodes of VTE—not receiving Intermediate-dose, or Postpartum anticoagulation therapy with intermediate-dose or
long-term anticoagulation therapy (regardless adjusted-dose LMWH/ adjusted-dose LMWH/UFH for 6 weeks (therapy level should be
thrombophilia) UFH equal to the selected antepartum treatment)
Two or more episodes of VTE—receiving long-term Adjusted-dose LMWH/UFH Resumption of long-term anticoagulation therapy. Oral
anticoagulation therapy, (regardless thrombophilia) anticoagulants may be considered postpartum based upon
planned duration of therapy, lactation, and patient preference
Source: From American College of Obstetrics and Gynecology Practice Bulletin No. 196: Thromboembolism in pregnancy: correction. Obstet Gynecol 2018;132(4):1068.
[Review]. Ref. [4], with permission.
a Low-risk thrombophilia: Factor V Leiden heterozygote; prothrombin G20210A mutation heterozygote; protein C or protein S deficiency, antiphospholipid antibody.

b High-risk thrombophilias include Factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for factor V Leiden and prothrombin

G20210A mutation, or antithrombin deficiency.

c First- degree relative with a history of a thrombotic episode, or other major thrombotic risk factors (eg, obesity, prolonged immobility, cesarean delivery).

d VTE risk assessment should be performed pre-pregnancy or early in pregnancy and repeated if complications develop, particularly those necessitating hospitalization or

prolonged immobility.
Abbreviations: LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism.

therapy is 0.5–1.2 U/mL. The target anti-Xa level for prophylac-
tic dose therapy is 0.2–0.4 U/mL. To achieve these levels, often
dosing every twelve hours is necessary even for prophylaxis in
pregnancy. Twice-daily dosing of enoxaparin may be necessary to
maintain anti–Xa activity above 0.1 IU/mL throughout a 24-hour
period in pregnant women [8, 70, 72] Enoxaparin 40 mg every
12 hours (instead of once daily) has been suggested for prophylac-
tic anticoagulation in women at or above 90 kg [8]. It is not known
whether a specific minimum level of anti-Xa activity is neces-
sary throughout the day to prevent thrombosis in pregnancy or
whether maintaining a specific minimum level of anti-Xa activity
for only a portion of the day is sufficient. Anti-Xa levels may be
used especially for obese and for renal disease patients [8].
Warfarin (Coumadin)
Vitamin K derives its name from the German word koagula-
tion. Warfarin derivatives are vitamin K antagonists (VKA), and
inhibit vitamin K dependent factors (2, 7, 9, 10, Protein C and S).
VKA crosses the placenta and can cause bleeding and terato-
genicity in the fetus [80]. Warfarin is believed to be safe in the
first 6 weeks of gestation, but has been associated with warfa-
rin embryopathy in 4–5% of fetuses when maternal exposure
332
between 6 and 9 weeks. Warfarin embryopathy is characterized
by skeletal (stippled epiphyses), nasal, and limb (hypoplasia)
involvement. Bleeding in the fetus can occur in all trimesters.
Warfarin also increases the risk of fetal loss in the first trimester
[13]. The risk of fetal cerebral hemorrhage in women on warfarin
appears to be greatest around the time of delivery; therefore, if deliv-
ery unexpectedly is necessary while a woman is receiving a vitamin
K antagonist, cesarean delivery may be required and the neonate
may require administration of vitamin K and fresh frozen plasma
[4]. There are cases in which warfarin is the preferred anticoagula-
tion despite its risks. These may include women with mechanical
heart valves, those who have a recurrence while receiving heparin,
and those with contraindications to heparin therapy. In a system-
atic review of observational studies between 1966 and 1997 that
reported outcome with various anticoagulant regimens in preg-
nant women with mechanical prosthetic heart valves, VKA were
associated with the lowest risk of valve thrombosis and sys-
temic embolism (3.9%), and UFH regimen group were associated
with the highest [81]. In pregnant women with mechanical heart
valves, it appears reasonable to use one of these regimens: 1) thera-
peutic LMWH (or UFH) between 6 and 10 weeks and close to term
only, and vitamin K antagonists (VKAs) at other times; 2) VKAs
throughout pregnancy (lowest VTE risk); or 3) therapeutic LMWH
throughout pregnancy. The VKA regimen throughout pregnancy
has been said to be best for pregnant women with low maintenance
warfarin doses (<=5 mg/day); the LMWH/VKA regimen might be
reasonable for pregnant women with high maintenance warfarin
doses, and the LMWH only regimen could be used for pregnant
women who refuse VKAs [82]. Patient should understand the risks
and benefits and options before making a decision. Warfarin does
not induce an anticoagulant effect in the breast-fed infant when
the drug is given to a nursing mother [83,84]. Therefore, the use
of warfarin in breastfeeding women who require postpartum
anticoagulant therapy is safe.
Aspirin
Low-dose aspirin (60–150 mg) can be administered safely during
the second and third trimesters in women at risk for hypertensive
complications and/or fetal growth restriction (FGR) [85,86]. The
safety of higher doses of aspirin and/or aspirin ingestion during
the first trimester remains uncertain, with potential reported
complications during the first trimester including birth defects
(e.g., gastroschisis) and bleeding.
Treatment of new onset DVT
and PE in pregnancy
There are no RCTs for treatment of DVT specific to pregnant
women. Therapeutic doses are recommended in patients with
an acute VTE [87]. As previously mentioned, LMWH is the pre-
ferred option. Weight adjusted doses are used for the treat-
ment of acute VTE and requirements may alter as pregnancy
progresses because the volume of distribution of LMWH changes
and glomerular filtration rate increased in the second trimester.
Eighty-one bid or daily regimens (1.5 mg/kg) can be used, with-
out a risk of recurrence with the once daily dosing versus the bid
regimen [88]. Table 30.6 shows recommended heparin doses. It is
not clear whether adjustment of dosing is necessary, however,
based on conclusions of some small studies, dose can be increased
to maintain a therapeutic anti-Xa LMWH levels in the range
of 0.6–1.0 units/ml and slightly higher doses may be needed for
a once daily regimen. Measurement of anti-Xa levels can be
done every 1–3 months, 4–6 hours after injection. Patients
Maternal-Fetal Evidence Based Guidelines
are usually converted to a subcutaneous therapeutic dose of
UFH in the last month of pregnancy. In this case, aPTT should
be obtained 6 hours after injection and dose modified to achieve
an aPTT of 1.2–2.5 [28]. Platelets should be checked for HIT in
cases of UFH, but data is less clear regarding LMWH [89,90].
Intravenous UFH may be preferred in cases where delivery, sur-
gery or thrombolysis (indicated for severe PE with hemodynamic
compromise) [91] is necessary. Other options for treatment of
life threatening PE include catheter assisted-thrombus removal
and surgical embolectomy. Embolectomy has been associated
with a 20–40% incidence of fetal loss, so this treatment should be
restricted to cases in which the women’s life is endangered [92].
TABLE 30.6: Anticoagulation Regimen Definitions
Anticoagulation Regimens
Management Type Dosage
Prophylactic Enoxaparin, 40 mg SC onceb daily
LMWHa Dalteparin, 5000 units SC once daily
Tinzaparin, 4500 units SC once daily
Nadroparin, 2850 units SC one daily
Therapeutic LMWHc Enoxaparin, 1 mg/kg every 12 hours
(Also referred to as Dalteparin, 200 units/kg once daily
weight-adjusted, Tinzaparin, 175 units/kg once daily
full-treatment dose) Dalteparin, 100 units/kg every 12 hours
Mini-dose UFH, 5000 units SC every 12 hours
prophylactic UFH
Prophylactic UFH UFH, 5000–10,000 units SC every 12 hours
UFH, 5000–7500 units SC every 12 hours in first
trimester
UFH, 7500–10,000 units SC every 12 hours in the
second trimester
UFH, 10,000 units SC every 12 hours in the third
trimester, unless the aPTT is elevated
Therapeutic UFH UFH, 10,000 units or more SC every 12 hours in
(Also referred to as doses adjusted to target aPTT in the therapeutic
weight-adjusted, range (1.5–2.5, 6 hours after injection)
full-treatment dose)
Postpartum Prophylactic LMWH/UFH for 4–6 weeks
anticoagulation or
Vitamin K antagonists for 4–6 weeks with a target
INR of 2.0–3.0, with initial UFH or LMWH therapy
overlap until the INR is 2.0 or more for 2 days
Surveillanced Clinical vigilance and appropriate objective
investigation of women with symptoms
suspicious of deep vein thrombosis or
pulmonary embolism. VTE risk assessment
should be performed prepregnancy or early in
pregnancy and repeated it complications
develop, particularly those necessitating
hospitalization or prolonged immobility.
Source: From American College of Obstetrics and Gynecology Practice Bulletin
No. 196: Thromboembolism in pregnancy: correction. Obstet Gynecol
2018;132(4):1068. [Review]. Ref. [4], with permission.
a Although at extremes of body weight, modification of dose may be required.
b Advocate twice a day.
c An anti-Xa level in the therapeutic range of 0.6–1.0 units/mL for twice-daily regi-
men; slightly higher doses may be needed for a once-daily regimen.
d Vigilance and appropriate objective investigation of women with symptoms suspi-
cious of deep vein thrombosis or pulmonary embolism may be needed.
Abbreviations: LMWH, low molecular weight heparin; SC, subcutaneously; UFH,
unfractionated heparin; aPTT, activated partial thromboplastin time; INR, interna-
tional normalized ratio.
Venous Thromboembolism and Anticoagulation
Duration of therapeutic anticoagulation treatment after an
acute episode of VTE in pregnancy and postpartum should
be minimum 3 months, with many experts recommending
6 months [87]. Controversy exists on whether the dose of LMWH
or UFH can be reduced after the initial therapeutic anticoagu-
lation. Some suggest continuation of therapeutic doses during
pregnancy and postpartum, while others have proposed lowering
the dose to an intermediate dose regimen [93] or 75% of a full-
treatment dose [94], which has been successfully used in patients
at high risk, such as cancer patients.
Women with antithrombin deficiency, antiphospholipid anti-
bodies, homozygous or combined thrombophilias, or previous
VTE may benefit from indefinite anticoagulation, but this should
be decided by an internist after pregnancy [94]. Long-term, low-
intensity warfarin therapy is associated with an about 50% pre-
vention of recurrent VTE, major hemorrhage or death in patients
with a prior idiopathic VTE [95].
Inferior vena cava (IVC) filters should be restricted to women
with proven VTE and either recurrent PE despite adequate antico-
agulation or contraindications to anticoagulation [56]. Suprarenal
placement is recommended. Careful evaluation should be under-
taken since filter placement is associated with complications such
as migration, filter fracture, and IVC perforation [56].
In the initial management of DVT, the leg should be elevated
and a gradual elastic compression stocking applied to reduce
edema. Traditionally it was thought that mobilization could
dislodge an unstable thrombus and cause PE. Randomized con-
trolled trials have shown the opposite. Early ambulation with
leg compression does not increase PE or thrombus propaga-
tion, and leg pain and edema improve faster [94].
The use of thrombolytic agents during pregnancy has been
limited to life-threatening situations because of the risk of sub-
stantial maternal bleeding, especially at the time of delivery
and immediately postpartum [96]. The risk of placental abrup-
tion and fetal death due to these drugs is currently unknown.
Systemic thrombolysis must be considered in pregnant patients
with life-threatening hemodynamic instability due to massive
PE. A recent literature review summarized 23 case reports on
the use of systematic thrombolysis as a treatment for massive
PE in pregnant patients. No maternal deaths occurred, and fetal
deaths were reported in 2 of 23 (9%) cases. Bleeding complica-
tions were reported in 9 of 23 (39%) cases of which 5 of 23 (22%)
were major bleeding. The authors concluded that thrombolysis
is beneficial with a relatively low risk of complications [13]. The
2018 American Society of Hematology guideline suggests
administering systemic thrombolytic therapy in addition to
anticoagulant therapy in pregnant women with acute PE and
life-threatening hemodynamic instability [13].
Embolectomy, another treatment option when conservative
treatment fails, is indicated to prevent death in patients who are
hemodynamically unstable despite anticoagulation and treat-
ment with vasopressors [92]. Embolectomy has been associated
with a 20–40% incidence of fetal loss [97], so this treatment must
be restricted to cases in which the woman’s life is endangered.
Prevention of VTE
Avoidance of risk factors (Table 30.2) is the key to the preven-
tion of VTE and its complications. Preconception counseling
should review preventative measures, as well as review in detail
any prior history of VTE or known thrombophilia. In general, for
a pregnant patient with a prior VTE, prophylactic anticoagulation
is recommended, but this can be modified based on the cause of
333
the VTE and the presence of a thrombophilia. See Table 30.5 for
further recommendations.
Women with a history of VTE (with or without thrombophilia)
are believed to have a higher risk of recurrence in subsequent
pregnancies. Estimates of the rate of recurrent venous thrombo-
sis during pregnancy in women with a history of VTE have varied
between 1% and 10% [98–101]. The higher of these estimates has
prompted recommendation for anticoagulant prophylaxis during
pregnancy and the postpartum period in women with a history
of VTE. However, the risk is likely to be lower than has been sug-
gested by some of these studies because they were retrospective,
with the possibility of significant bias. The recurrence of VTE is
dramatically influenced by risk factors, in particular the presence
of thrombophilias (Table 30.2 and Chapter 29).
There are very few randomized controlled trials (RCTs) for the
prevention of VTE in pregnancy (both antepartum and postpar-
tum). The sample sizes of all trials are small and often cannot be
combined.
For antenatal prophylaxis, none of the RCTs included in the
latest Cochrane Review reported on maternal mortality, and
no differences were detected for the other primary outcomes of
symptomatic thromboembolic events, symptomatic PE and symp-
tomatic DVT when LMWH or UFH was compared with no treat-
ment/placebo or when LMWH was compared with UFH [102].
The RR for symptomatic VTE was antenatal LMWH/UFH versus
no heparin, RR 0.33; 95% confidence interval (CI) 0.04–2.99 (two
trials, 56 women); and antenatal LMWH versus UFH, RR 0.47; 95%
CI 0.09–2.49 (four trials, 404 women). No differences were shown
when antenatal LMWH or UFH was compared with no treat-
ment/placebo for any secondary outcomes. Antenatal LMWH was
associated with fewer adverse effects sufficient to stop treatment
(RR 0.07; 95% CI 0.01–0.54; two trials, 226 women), and fewer fetal
losses (RR 0.47; 95% CI 0.23–0.95; three trials, 343 women) when
compared with UFH. In two trials, antenatal LMWH compared
with UFH was associated with fewer bleeding episodes (defined in
one trial of 121 women as bruises >1 inch (RR 0.18, 95% CI 0.09–
0.36); and in one trial of 105 women as injection site hematomas
of ≥2 cm, bleeding during delivery or other bleeding (RR 0.28; 95%
CI 0.15–0.53). The results for these secondary outcomes should be
interpreted with caution, being derived from small trials that were
not of high methodological quality [102].
In general, in pregnant women with a prior VTE, prophylactic
anticoagulation can be used. This may be modified based on the
cause of the first VTE and the presence of a thrombophilia. If
the prior VTE was related to a non-recurrent cause (i.e. bro-
ken bone and immobilization) and the thrombophilia workup
is negative, the risk of recurrence is very low, and prophylaxis
may be avoided, especially in women without other risk factors
except pregnancy. In fact the risk of recurrence was 0% in 44 such
women followed without antepartum anticoagulation [103].
Approximately 50–80% of gestational VTE’s are associated
with heritable thrombophilia (Chapter 29). Given that the back-
ground rate of VTE during pregnancy is approximately 1:1000,
the absolute risk of VTE remains modest for the majority of these
thrombophilias, except antithrombin deficiency, homozygosity
for the factor V Leiden mutation and for the prothrombin muta-
tion, and combined defects. The absolute risk of pregnancy-associ-
ated VTE has been reported to range from 9–16% in homozygotes
for the factor V Leiden mutation [104–107]. Double heterozygosity
for the factor V Leiden and prothrombin gene mutations has been
reported to have an absolute risk of pregnancy-associated VTE of
4.0% (95% CI 1.4–16.9) [108]. These data suggest that women with
antithrombin deficiency, homozygosity for the factor V Leiden
334
mutation or the prothrombin mutation as well as double hetero-
zygotes, should be managed more aggressively than those with
other low risk inherited thrombophilias, and thus adjusted-dose
therapeutic anticoagulation is recommended for prior DVT
and a high risk thrombophilia (AT III deficiency, homozygous
factor V or prothrombin gene mutation, or double heterozygote).
Therapeutic anticoagulation may also be used in pregnant women
if the woman has had recurrent VTE episodes, life-threatening
thrombosis, or thrombosis while receiving chronic anticoagula-
tion. Filters in the inferior vena cava should be considered in this
situation as well. In pregnant women with a history of a prior VTE
with history of a low risk thrombophilia (heterozygous factor V
or prothrombin gene, protein C or S) prophylactic anticoagula-
tion is recommended. Persistent antiphospholipid antibodies are
associated with an increased risk of VTE during pregnancy and the
puerperium. It has been suggested that pregnant patients with the
antiphospholipid syndrome who do not have a history of venous
thrombosis receive a low-dose prophylactic regimen of heparin,
as well as those with previous thrombosis (Chapter 28) [70]. The
antepartum management of pregnant women with known throm-
bophilia and no prior VTE remains controversial because of our
limited knowledge of the natural histories of various thrombo-
philias and a lack of trials of VTE prophylaxis. Prospective data
is lacking regarding the issue of the incidence of VTE in a large
group of pregnant women with known thrombophilia and no
prior VTE. Currently, there is no evidence to suggest prophylactic
low-dose anticoagulation in this group. If there is a very strong
family history of VTE (especially at young ages), consideration can
be made for low-dose prophylactic anticoagulation. Individualized
risk assessment should be performed in this situation.
TIPPS is the first large international randomized controlled
trial designed to resolve the clinical effect of antepartum LMWH
(dalteparin) on adverse pregnancy outcomes in women at the
highest risk of these outcomes (i.e., women with both throm-
bophilia and a history of either adverse pregnancy outcomes or
venous thromboembolism). The results of this study are negative:
Following the randomization of 292 women, antepartum dalte-
parin did not significantly reduce the incidence of adverse preg-
nancy outcomes. LMWH is ineffective in preventing a wide range
of clinically important adverse pregnancy outcomes in women
with thrombophilia. Only postpartum thromboprophylaxis is
suggested for women with anything but the most serious cases of
thrombophilia (see Chap. 29) [109].
Prophylaxis in women with
mechanical heart valves
Women who anticipate ultimately needing valve replacement
surgery should be encouraged to complete childbearing before
valve replacement. The highest risk for VTE is with first genera-
tion mechanical valves (Starr-Edwards, Bjork-Shiley) in the mitral
position, followed by second generation valves (St Jude) in the
aortic position (Chapter 2). These women need to be therapeu-
tically anticoagulated throughout pregnancy and postpar-
tum, with blood levels frequently (usually weekly) checked to
ensure therapeutic levels of anticoagulation. Pregnant women
with prosthetic heart valves pose a problem because of the lack of
trials regarding the efficacy and safety of antithrombotic therapy
during pregnancy. There is insufficient data to make definitive
recommendations about optimal anticoagulation in pregnant
patients with mechanical heart valves.
Maternal-Fetal Evidence Based Guidelines
There are in general three regimens that can be considered:
(1) therapeutic LMWH (or UFH) between 6 and 10 weeks and
close to term only, and vitamin K antagonists (VKAs) at other
times; (2) VKAs throughout pregnancy (lowest VTE risk); and (3)
therapeutic LMWH throughout pregnancy. Before any of these
approaches is used, it is crucial to explain the risks/benefits care-
fully to the patient.
In a review, VKAs throughout pregnancy was the regimen
associated with the lowest risk of valve thrombosis/systemic
embolism (3.9%); using UFH only between 6 weeks and 12 weeks’
gestation was associated with an increased risk of valve throm-
bosis (9.2%) [110]. This analysis suggests that VKAs are more
efficacious than UFH for thromboembolic prophylaxis of women
with mechanical heart valves in pregnancy; however, coumarins
increase the risk of embryopathy. In the first trimester couma-
rin is associated with a 10–15% teratogenic risk (nasal hypoplasia,
optic atrophy, digital anomalies, mental impairment). European
experts have recommended warfarin therapy throughout preg-
nancy in view of the reports of poor maternal outcomes with
heparin and their impression that the risk of embryopathy with
coumarin derivatives has been overstated [111]. If coumarin is
used, the dose should be adjusted to attain a target INR of 3.0
(range 2.5–3.5).
A common option utilizes LMWH during the first trimester
to minimize teratogenesis, warfarin for the majority of preg-
nancy (12–36 weeks), and LMWH, or unfractionated heparin
to prepare for delivery and allow for epidural anesthesia, in the
last month. While this may be efficacious, fetal risk is not com-
pletely eliminated. Substituting VKAs with heparin between 6
weeks and 10 weeks reduces the risk of fetopathic effects, but
possibly subjects the woman to an increased risk of thromboem-
bolic complications. The reported high rates of thromboembo-
lism with UFH might be explained by inadequate dosing and/or
the use of an inappropriate target therapeutic range.
The use of weight-adjusted therapeutic UFH warrants careful
monitoring and appropriate dose adjustment. A target aPTT ratio
of at least twice the control should be attained [112]. If used, SC
UFH should be initiated in high doses, usually every 8 hours, and
adjusted to prolong a 6-hour post-injection aPTT into the thera-
peutic range (usually 60–80 seconds); strong efforts should be
made to ensure an adequate anticoagulant effect. LMWH use in
pregnant women with prosthetic heart valves has been associated
with treatment failures [113–116], and the use of LMWH for this
indication has recently become controversial due to a warning
from a LMWH manufacturer regarding their safety in this situ-
ation [117]. If used, LMWH should be administered twice daily
and dosed to achieve anti-Xa levels of 1.0 to 1.2 U/mL 4–6 hours
(peak) after SC injection, with trough 0.6–0.7.
Extrapolating from data in non-pregnant patients with mechan-
ical valves receiving warfarin therapy [118], for some high-risk
women, the addition of low-dose aspirin, 75–162 mg/day, can
be considered in an attempt to reduce the risk of thrombosis, rec-
ognizing that it increases the risk of bleeding.
The largest systematic review and meta-analysis to date
regarding the effectiveness and safety of the four updated
anticoagulation regimens in pregnant women with MPHVs
(mechanical prosthetic heart valves) included data from 51
studies and 1538 women with 2113 pregnancies in a five-decade
span [82]. The analytical results revealed that the VKA regi-
men may be the best option for mothers with maintenance
warfarin doses of <5 mg/day, especially for pregnant women
with high thromboembolic risk factors, such as older valve
Venous Thromboembolism and Anticoagulation 335

designs, position (mitral and tricuspid valve), atrial fibrilla-
tion, or history of thromboembolism. Compared with patients
in the high-dose subgroup, the rate of warfarin embryopathy
was significantly lower in patients in the low-dose subgroup.
The maintenance warfarin dose could be reduced by adopting
relatively low INR levels (median INR <2.5) in pregnant women
with a mechanical bi-leaflet valve, especially the lowest throm-
bogenic risk bi-leaflet (Carbomedics and On-X Prosthetic
Heart Valve; St Jude Medical, St Paul, MN). Three reports
that adopted low INR levels (1.5–2.5) in pregnant women with
MPHVs showed good maternal and fetal results. In those cases
where maintenance warfarin doses are higher than 5 mg/day, a
heparin/VKA/heparin regimen might be a reasonable choice.
Substitution of a VKA with UFH or LMWH during the first
trimester of pregnancy can be a good option due to a decrease
in the risk of adverse fetal outcomes, since UFH and LMWH do
not cross the placental barrier.
When pregnant women require high VKA maintenance
doses, the heparin/VKA/heparin regimen is recommended.
However, this regimen is associated with an increase in the risk
of maternal major thromboembolic events. Another indication of
LMWH is for pregnant women who refuse VKAs [82].
Antepartum testing
No specific recommendations for antepartum testing.
Delivery and anesthesia
For women on anticoagulation, a planned delivery, either through
induction of labor or by cesarean delivery, may optimize timing
of events and prevent the risks of an unplanned delivery. Patients
can be recommended to withhold anticoagulation 12–24 hours
(depending on the type of heparin used) prior to induction or
scheduled cesarean delivery (Table 30.7). Women are usually
converted to UFH near term (e.g., 36 weeks), with the purpose of
preventing the rare possibility of an epidural or spinal hematoma
with regional anesthesia [119]. If regional anesthesia is planned
and/or desired, UFH is usually stopped about 12 hours before the
start of induction or cesarean delivery. The American Society of
Regional Anesthesia and Pain Medicine Guidelines support the
use of neuraxial anesthesia in patients receiving 5000 units
of UFH bid, but safety is unknown in higher doses, when indi-
vidualized evaluation is recommended on a case-by-case basis. If
spontaneous labor occurs after adjusted UFH doses occur, aPTT
should be obtained and if prolonged, reversal can be performed
with protamine sulfate [34]. For LMWH, the American Society of
Regional Anesthesia and Pain Medicine guidelines recommend
withholding neuraxial anesthesia for 10–12 hours after a pro-
phylactic dose of LMWH or 24 hours after the last therapeutic
dose of LMWH [119].
For women nor receiving regional anesthesia, if vaginal or
cesarean delivery occurs more than 4 hours after a prophylactic
dose of UFH, the patient is not at significant risk of hemorrhagic
complications.
Pneumatic compression devices are recommended in patients
in whom anticoagulation therapy has been temporarily withheld
during delivery [4].
In cases where VTE was diagnosed within 2–4 weeks prior
to delivery therapeutic LMWH can be changed to therapeu-
tic intravenous UFH in hospital >24 hours before delivery,
and UFH discontinued about 4 hours before the expected
time of delivery or when obtaining neuraxial analgesia [13].
Intravenous UFH can be reversed with protamine if necessary.
Removable filters can be placed to provide protection from PE
during the time anticoagulation is stopped [34].
In women with mechanical heart valves, therapeutic antico-
agulation can be continued IV (half-life: 1 ½ hour) until active
labor, and then stopped during active labor and for delivery, with
therapeutic heparin restarted about 6–12 hours after delivery, and

TABLE 30.7: Timing of Neuraxial Anesthesia in Relation to Pharmacologic Anticoagulation

Dosage Regimen Intrapartum, Elective Procedure Intrapartum, Urgent/Emergent Procedure Postpartum
UFH prophylaxis Hold dose for 12 hours and assess Hold dose for 12 hours and assess coagulation Wait at least 1 hour after neuraxial
(7500 units SC twice coagulation status before status before administering neuraxial blockade and catheter removal
daily or 10,000 units SC administering neuraxial anesthesia anesthesia. However, in urgent cases with before restarting heparin
twice daily) greater competing risks from general
anesthesia, placement of neuraxial anesthesia
may be appropriate
UFH adjusted-dose Hold dose for 24 hours and assess If at least 24 hours since last dose and aPTT Wait at least 1 hour after neuraxial
(10,000 units per dose coagulation status before within normal limits or undetectable anti-Xa, blockade or catheter removal
or 20,000 units per day) administering neuraxial anesthesia likely low risk for neuraxial blockade before restarting heparin
Low-dose LMWH Wait 12 hours after last dose before Insufficient data to make a recommendation for Wait at least 12 hours after
prophylaxis neuraxial blockade placement of neuraxial blockade less than neuraxial blockade and at least
12 hours from last dose of LMWH. In high risk 4 hours after catheter removal to
situations in which intervention is needed, restart LMWH prophylaxis
risks of general anesthesia may outweigh risks
of spinal epidural hematoma
LMWH intermediate- Wait 24 hours after last dose before If less than 24 hours, insufficient evidence to Consider waiting at least 24 hours
dose or adjusted-dose neuraxial blockade recommend proceeding with neuraxial after neuraxial blockade and at
blockade least 4 hours after catheter removal
to restart LMWH anticoagulation
Source: From American College of Obstetrics and Gynecology Practice Bulletin No. 196: Thromboembolism in pregnancy: correction. Obstet Gynecol 2018;132(4):1068.
[Review]. Ref. [4], with permission.
Abbreviations: LMWH, low-molecular-weight heparin; SC, subcutaneously; UFH, unfractionated heparin.
336
warfarin restarted in an overlapping fashion (to avoid paradoxical
thrombosis) 24–36 hours after delivery (the night after delivery).
Extensive counseling on all these options and risks is required.
Prophylaxis after cesarean delivery
Available data suggests that the risk of VTE is higher after a
cesarean section (especially emergent surgery) than after vagi-
nal delivery [120]. The presence of additional risk factors for preg-
nancy-associated VTE (for example, prior VTE, thrombophilia,
age >35 years, obesity, prolonged bed rest, and concomitant acute
medical illness) may exacerbate this risk. Clinical judgment
should be used to decide on anticoagulation after cesarean sec-
tion, taking into account all of the patients risk factors.
For post-caesarean/postnatal prophylaxis, only one RCT
comparing 5-day versus 10-day LMWH after caesarean section
reported on maternal mortality, observing no deaths. No dif-
ferences were seen across any of the comparisons for the other
primary outcomes (symptomatic thromboembolic events, symp-
tomatic PE and symptomatic DVT). The RRs for symptomatic
thromboembolic events were: Post-cesarean LMWH/UFH versus
no heparin, RR 1.30; 95% CI 0.39–4.27 (four trials, 840 women);
post-cesarean LMWH versus UFH, RR 0.33; 95% CI 0.01–7.99
(three trials, 217 women); post-cesarean 5-day versus 10-day
LMWH, RR 0.36; 95% CI 0.01 to 8.78 (one trial, 646 women);
postnatal UFH versus no heparin, RR 0.16; 95% CI 0.02–1.36 (one
trial, 210 women). For prophylaxis after cesarean section, in one
trial (of 580 women), women receiving UFH and physiotherapy
were more likely to have bleeding complications than women
receiving physiotherapy alone (RR 5.03; 95% CI 2.49–10.18) [102].
Use of pneumatic compression device after cesarean deliv-
ery has been shown to provide a VTE risk reduction similar to
universal prophylaxis with heparin while reducing the risks asso-
ciated with anticoagulation [121]. Routine anticoagulation is not
recommended in the universal population in the United States,
but it is currently in the UK and other countries. For patients with
additional risk factors from VTE, individual risk assessment may
require prophylaxis with LMWH or UFH [88]. In women under-
going cesarean delivery with BMI >50 kg/m2, previous VTE, or
two or more additional risk factors for VTE (such as smoking,
multiple gestation, BMI >30 kg/m2, prolonged immobility, and
infection), adding to mechanical prophylaxis pharmacologi-
cal VTE prophylaxis, with either enoxaparin 40 mg daily or UH
5000 every 12 hours, should be considered. This pharmacological
prophylaxis can start post-operatively, at 6–12 hours, after con-
cerns for hemorrhage have decreased, and can continue until full
ambulation [122]. In certain cases, for example women with anti-
thrombin deficiency, anti-thrombin concentrates can be used [4].
(See Obstetric Evidence Based Guidelines, Chapter 14.)
Postpartum management of anticoagulation
To minimize bleeding complications, anticoagulation with UFH
or LMWH should be restarted 4–6 hours after a vaginal deliv-
ery or 6–12 hours after cesarean delivery and no sooner than
2 hours after epidural removal [111]. Some suggest resumption of
LMWH after delivery after 12–24 hours for prophylactic dose, and
24 hours postpartum when restarting higher doses of LMWH, pro-
vided blood loss is normal [4, 13]. Pneumatic compression devices
should be left in place until patient is ambulating and anticoagula-
tion is restarted. It has been proposed that anticoagulant therapy
Maternal-Fetal Evidence Based Guidelines
should be continued for at least 6 weeks postpartum and to allow
a total duration of treatment of at least 3 months after a VTE [88].
Women who require more than 6 weeks of therapeutic antico-
agulation postpartum can be bridged to warfarin, which is safe
during breastfeeding [123]. Warfarin can be started with a 5 mg
dose. If desired, warfarin can be started in an overlapping fashion
(to avoid paradoxical thrombosis) 24–36 hours after delivery (the
night after delivery). Daily testing of the International Normalized
Ratio (INR) is recommended starting day 2 of warfarin therapy
and subsequent doses titrated to maintain the INR between 2.0
and 3.0. Heparin should be continued for the first 5–7 days and
can be discontinued once the INR is greater than 2.0 for at least
24 hours [124]. In general, postpartum anticoagulation should be
at levels at or higher those antepartum (Table 30.5).
Breastfeeding is safe while on anticoagulation (with either
UFH, LMWH, or warfarin).
Thrombophilia testing should be considered once anticoagu-
lation has been discontinued, and only if this will influence the
patient’s future management [125].
Contraception
Combined estrogen-progestin oral contraceptives have been
associated with higher efficacy than progestin only pills, but have
the disadvantage of an increased risk of VTE. This risk has been
attributed to the estrogen component. In women taking estrogen-
containing oral contraceptives the risk of VTE increases 39-fold
to 99-fold among those heterozygous for factor V Leiden and
prothrombin G20210A mutations [126]. A meta-analysis of eight
observational studies assessing the risk of VTE in women pre-
scribed progestin-oral contraception showed no increased risk
compared with non-users of hormonal contraception [127]. In a
sub-analysis of women prescribed injectable progestins, there was
a two-fold increase in thrombotic risk. The type of progestin might
influence this risk, with newer progestins such as desogestrel,
gestodene, and norgestimate associated with a greater risk than
older ones such as levonorgestrel, lynestrenol, and noresthister-
one [128–130]. The risk of VTE of the general population increases
two- to three-fold in users of CEPCs (combined estro-progestin
contraception) with norethisterone, levonorgestrel, or norgesti-
mate, and of six-fold in users of CEPCs containing desogestrel,
gestodene, drospirenone, or cyproterone acetate [131].
Better contraceptive options for women at risk for VTE include
the intrauterine device (including those with estrogen), and
progestin implants. Barrier methods of contraception are also
safe, but less effective [132].
References
1. Kesieme E, Chinenye K, Jebbin N, Irekpita E, Dongo A. Deep vein thrombo-
sis: a clinical review. J Blood Med 2011;2:59–69. [Review]
2. James A. Venous thromboembolism in pregnancy. Asterioscler Thromb
Vasc Biol 2009;29:326–331. [Review]
3. Rodger M. Evidence based for the management of venous thromboembo-
lism in pregnancy. Hematology 2010. [Review]
4. American College of Obstetrics and Gynecology Practice Bulletin No.
196: Thromboembolism in pregnancy: correction. Obstet Gynecol
2018;132(4):1068. [Review]. Data from Leffert L, Butwick A, Carvalho B,
Arendt K, Bates SM, Friedman A, et al. The Society for Obstetric Anesthesia
and Perinatology consensus statement on the anesthetic management of
pregnant and postpartum women receiving thrombo-prophylaxis or higher
dose anticoagulants. Members of the SOAP VTE Taskforce. Anesth Analg
2018;126:928–44.
Venous Thromboembolism and Anticoagulation
5. Devis P, Knuttinen MG. Deep venous thrombosis in pregnancy: incidence,
pathogenesis and endovascular management. Cardiovasc Diagn Ther
2017;7(Suppl 3):S309–S319. [Review]
6. Dresang L, Fontaine P, Leeman L, King V. Venous thromboembolism dur-
ing pregnancy. Am Fam Physician 2008;77(12): 1709–1716. [Review]
7. Bates SM, Rajasekhar A, Middeldorp S, McLintock C, et al. American
Society of Hematology 2018 guidelines for management of venous throm-
boembolism: venous thromboembolism in the context of pregnancy. Blood
Adv 2018;2(22):3317–3359. [Review]
8. Geer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet
1999;353:1258–1265. [Review]
9. CDC. Pregnancy mortality surveillance system. 2016. [Review]
10. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ, Dogge CJM.
Pregnancy, the postpartum period and prothrombotic defects:
risks of venous thrombosis in the MEGA study. J Thromb Haemost
2008;6940:632–637. [II-2]
11. Jackson E, Curtis K, Gaffield M. Risk of venous thromboembolism dur-
ing the postpartum period. A systematic review. Obstet Gynecol 2011;117:
691–703. [Review]
12. Kamel H, Navi BB, Siriam N, Hovsepian DA, Devereux RB, Elkind MS. Risk
of thrombotic event after the 6-week postpartum period. N Engl J Med
2014;370(14):1307. [II-3]
13. Wiegers HMG, Middeldorp S. Contemporary best practice in the man-
agement of pulmonary embolism during pregnancy. Ther Adv Respir Dis
2020;14 [Review]
14. Lussana F, Coppens M, Cattaneo M, Middeldorp S. Pregnancy-related
venous thromboembolism: risk and the effect of thromboprophylaxis.
Thromb Research 2012;129:673–680. [Review]
15. Virkus, RA, Lokkegaard EC, Bergholt T, Mogensen U, Langhoff-Ross
J, Lidegaard O. Venous thromboembolism in pregnant and puerperal
women in Denmark 1995–2005. A national cohort study. Thromb Haemost
2011;106(2):204–309. [II-2]
16. Chan WS, Spencer F, Ginsberg J. Anatomic distribution of deep vein throm-
bosis in pregnancy. CMAJ 2010;182[7):657–660. [Review]
17. Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteris-
tics and timing of objectively diagnosed venous thromboembolism during
pregnancy. Obstet Gynecol 1999;94:730–734 [II-2]
18. Marik P, Plante L. Venous thromboembolic disease and pregnancy. N Engl
J Med 2008;359:2025–2033. [III]
19. Grandone E, Margaglione M, Colaizzo D, et al. Genetic susceptibil-
ity to pregnancy-related thromboembolism: roles of factor V Leiden,
Prothrombin G20210A, and methylenetetrahydrofolate reductase C677T
mutations. Am J Obstet Gynecol 1998;179:1324–1328. [II-2]
20. National Institutes of Health Consensus Development Conference.
Prevention of venous thrombosis and pulmonary embolism. JAMA
1986;256:744–749. [Review]
21. AOCG Practice Bulletin. Antiphosphlipid Syndrome. December 2012.
[Review]
22. Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, Walker ID,
Greaves M, Brenkel I, Regan L, Greer IA. Thrombophilia in pregnancy: a
systematic review. Br J Haematol 2006;132:171–196. [Review]
23. AOCG Practice Bulletin. Inherited Thrombophilias in Pregnancy.
September 2013. [Review]
24. Lockwood CJ. Heritable coagulopathies in pregnancy. Obstet Gynecol Surv
1999;54:754. [Review]
25. Walker MC, Garner PR, Keely EJ, et al. Changes in activated protein C resis-
tance during normal pregnancy. Am J Obstet Gynecol 1997;77:162. [II-3]
26. Rosenkranz A, Hiden M, Leschnik B, et al. Calibrated automated throm-
bin generation in normal uncomplicated pregnancy. Thromb Haemost
2008;99:331–337. [II-3]
27. Clark P, Brennand J, Conkie JA, et al. Activated protein C sensitivity, pro-
tein C, protein S and coagulation in normal pregnancy. Thromb Haemost
1998;79:1166–1170. [II-3]
28. AOCG Practice Bulletin Thromboembolism in pregnancy. August 2011.
[Review]
29. Pabinger I, Grafenhofer H, Kyrle Pam Quehenberger P, Mannhalter C,
Lechner K, et al. Temporary increase in the risk of recurrence during
pregnancy in women with a history of venous thromboembolism. Blood
2002;100:1060–1062. [II-3]
30. Investigation and Management of heritable thrombophilia. Br J Haematol
2001;114–512. [Review]
31. Henke PK, Camerota AJ. An update on etiology, prevention and therapy of
post thrombotic syndrome. J Vasc Surg 2011;53(2):500–509 [II-3]
32. Benotti JR, Ockene IS, Alpert JS, Dalen JE. The clinical profile of unresolved
pulmonary embolism. Chest 1983;84 (6):669. [II-3]
337
33. Hirsh J, Lee A. How we diagnose and treat deep vein thrombosis. Blood
2002;99:3102–3110. [II-2]
34. Bates, S, Ginsberg J. How we manage venous thromboembolism during
pregnancy. Blood 2002:3470–3478. [II-2]
35. Pabinger I, Grafnhofer H. Thrombosis during pregnancy: risk factors, diag-
nosis and treatment. Pathophysiol Haemost Thromb 2002;32:322–324. [II-3]
36. Doll R, Wakefield R. Risk of childhood cancer from fetal radiation. Br J
Radiol 1997;70:130–139. [II-2]
37. Ginsberg JS, Hirsh J, Ranbow AJ, Coates G. Risks to the fetus of radiologic
procedures used in the diagnosis of maternal venous thromboembolic dis-
ease. Thromb Haemost 1989;61:189–196. [II-3]
38. Bergqvist D, Hedner U. Pregnancy and venous thromboembolism. Acta
Obstet Gynecol Scand 1983;62:449–453. [Review]
39. Bergqvist A, Bergqvist D, Hallbook T. Deep vein thrombosis during
pregnancy: a prospective study. Acta Obstet Gynecol Scand 1983;62:
443–448. [II-1]
40. Hull RD, Raskob GE, Carter CJ. Serial impedance plethysmography in
pregnant patients with clinically suspected deep-vein thrombosis: clinical
validity of negative findings. Ann Intern Med 1990;112:663–667. [II-2]
41. Cockett FB, Thomas ML, Negus D. Iliac vein compression: its relation to
iliofemoral thrombosis and the post-thrombotic syndrome. BMJ 1967;2:
14–16. [II-2]
42. Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have
deep vein thrombosis? JAMA 2006;295:199–207. [III]
43. Bates S, Jaeschke R, Stevens S, Goodacre S, Wells P, Stevenson M, et al.
Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis,
9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012 February;141(Suppl 2):e351S–e418S.
[Review]
44. Kjellberg U, Anderson NE, Rosen S, Tenghorn L, Hellgren M. APC resis-
tance and other haemostatic variables during pregnancy and puerperium.
Thromb Haemost 1999;81:527–531. [II-3]
45. Michiels JJ, Freyburger G, van der Graaf F, Janssen M, Oortwijn W, Van
Beek E. Strategies for the safe and effective exclusion and diagnosis of
deep vein thrombosis by sequential use of clinical score, D-dimer testing,
and compression ultrasonography. Semin Thromb Hemost 2000;26(6):
657–667. [II-3]
46. Nijkeuter M, Ginsberg JS, Huisman MV. Diagnosis of deep vein thrombo-
sis and pulmonary embolism in pregnancy: a systematic review. J Thromb
Haemost 2006;4:496–500. [Systematic Review]
47. Kearon C, Julian JA, Newman TE, et al. Noninvasive diagnosis of deep vein
thrombosis: McMaster diagnostic imaging practice guidelines initiative.
Ann Intern Med 1998;128:663–677. [Review]
48. Chan WS, Ginsberg JS. Diagnosis of deep vein thrombosis and pulmonary
embolism in pregnancy. Thromb Res 2002;107:85–91. [II-2]
49. Heijboer C, Beuler HR, Lensing AQ, et al. A comparison of real time diag-
nosis of deep vein thrombosis in symptomatic outpatients. N Engl J Med
1993;329:1365–1369. [II-2]
50. Van der Pol LM, Tromeur C, Bistervels IM, Ni Ainle F, Artemis Study
Investigators. Pregnancy-adapted YEARS algorithm for diagnosis of sus-
pected pulmonary embolism. N Engl J Med 2019;380(12):1139–1149. [II-1]
51. Bourjely G, Paidas M, Khalil H, et al. Pulmonary embolism in pregnancy.
Lancet 2010;375:500–512. [Review]
52. Chan WS, Ray JG, Murray S, et al. Suspected pulmonary embolism in
pregnancy: clinical presentation, results of lung scanning and subse-
quent maternal and pediatric outcomes. Arch Intern Med 2002;162:
1170–1175. [II-2]
53. Roy PM, Meyer G, Vielle B, et al. Appropriateness of diagnostic manage-
ment and outcomes of suspected pulmonary embolism. Ann Intern Med
2006;144:157–164. [Review]
54. Goodman LR, Curtin JJ, Mewissen MW, et al. Detection of pulmonary
embolism in patients with unresolved clinical and scintigraphic diagnosis:
helical CT vs angiography. Am J Roentgenol 1995;164:1369–1374. [II-2]
55. Remy-Jardin M, Remy. Spiral CT angiography of the pulmonary circulation.
Radiology 1999;212:615–636. [Review]
56. Greer I. A. Thrombosis in pregnancy: updates in diagnosis and manage-
ment. Hematology 2012;203–207. [Review]
57. Leung AN, Bull TM, Jaeschke R, Lockwood CJ, et al. ATS/STR Committee
on Pulmonary Embolism in Pregnancy. An official American Thoracic
Society/Society of Thoracic Radiology clinical practice guideline: evalua-
tion of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care
Med 2011;184(10):1200–1208. [Review]
58. Tooher R, Gates S, Dowswell T, Davis LJ. Prophylaxis for venous throm-
boembolic disease in pregnancy and the early postnatal period. Cochrane
Database Syst Rev 2010;(5). [Review]
338
59. Che Yaakob CA, Dzarr AA, Ismail AA, Zuky Nik Lah NA, Ho JJ.
Anticoagulant therapy for deep vein thrombosis (DVT) in pregnancy.
Cochrane Database of Syst Rev 2010;(6). [Review]
60. Hirsh J, Anand S, Halperin J, Fuster V. Mechanism of action and pharma-
cology of unfractioned heparin. Arterioscler, Thromb, Vas Biol 2001;
21:1094–1096. [II-3]
61. Nelson-Piercy C. Hazards of heparin: allergy, heparin-induced thrombocy-
topenia and osteoporosis. Bailliere’s Clin Ob Gy 1997;11:489–509. [II-2]
62. Hull RD, Delmore TJ, Carter CJ, et al. Adjusted subcutaneous heparin vs
warfarin sodium in the long-term treatment of venous thrombosis. N Engl J
Med 1982;306:189–194. [II-1]
63. Hull RD, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant
therapy in the treatment of proximal-vein thrombosis. N Engl J Med
1982;307:1676–1681. [II-3]
64. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytope-
nia in patients treated with low molecular weight heparin or unfractioned
heparin. N Engl J Med 1995;332:1330–1335. [II-2]
65. Greinacher A, Eckhart T, Mussmann J, Mueller-Eckhardt C. Pregnancy
complicated by heparin associated thrombocytopenia: management by
a prospectively in vitro selected heparinoid (Org 10172). Thromb Res
1993;71:123–126. [II-3]
66. Widmer M, Blum J, Hofmeyr GJ, Carroli G, Abdel-Aleem H, Lumbiganon
P, et al. Misoprostol as an adjunct to standard uterotonics for treatment of
postpartum haemorrhage: a multicenter, double-blinded randomised trial.
Lancet 2010;375:1808–1813. [I]
67. Knol, HM, Schultinge L, Erwich JJHM, Meijer K. Fondaparinux as an
alternative anticoagulant therapy during pregnancy. J Thromb Haemost
2010;8:1876–1879. [Review]
68. Dempfle CE. Minor transplacental passage of fondaparinux in vivo. N Engl
J Med 2004;350:1914–1915. [Review]
69. Duhl AJ, Paidas MJ, Ural SH, Branch W, Casele H, Cox-Gill J, et al.
Pregnancy and Thrombosis working group. Antithrombotic therapy and
pregnancy: consensus report and recommendations for prevention and
treatment of venous thromboembolism and adverse pregnancy outcomes.
Am J Obstet Gynecol 2007;197:457 e1–21. [Review]
70. Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during preg-
nancy. Chest 2001;119:122–131. [Review]
71. Dolovich I, Ginsberg JS. Low molecular weight heparin in the treatment of
venous thromboembolism: an updated meta-analysis. Vessels 1997;3:4–11.
[Review]
72. Gold MK, Dembitzer AD, Doyle RI, Hastie TJ, Garber AM. Low molecu-
lar weight heparins compared with unfractioned heparin for treatment of
acute deep venous thrombosis. A meta-analysis of randomized controlled
trials. Ann Intern Med 1999;130:800–809. [Meta-Analysis]
73. Van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose sub-
cutaneous low molecular weight heparins versus adjusted dose unfrac-
tioned heparin for venous thromboembolism. Cochrane Database Syst Rev
2004;(4). [Review]
74. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for throm-
bophrophylaxis and treatment of venous thromboembolism in preg-
nancy: a systematic review of safety and efficacy, Blood 2005;106:401–407.
[Review]
75. Weitz J. Low-molecular-weight heparins. N Engl J Med 1997;337:688–698.
[Review]
76. Nelson-Piercey C, Letsky EA, de Michaeal Swiet. Low-molecular-
weight heparin for obstetric thromboprophylaxis: experience of sixty-
nine pregnancies in sixty-one women at high risk. Am J Obstet Gynecol
1997;176(5):1062–1068. [II-2]
77. Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that
dalteparin requirements increase in pregnancy to maintain therapeutic lev-
els of anticoagulation. Am J Obstet Gynecol 2004;191:1024–1029. [II-1]
78. Casele HL, Laifer SA, Wolkers DA, et al. Changes in the pharmacokinetics
of the low-molecular-weight heparin enoxaparin sodium during pregnancy.
Am J Obstet Gynecol 1999;181:1113–1117. [II-2]
79. Sephton V, Farquharson RG, Topping J, et al. A longitudinal study of mater-
nal dose response to low molecular weight heparin in pregnancy. Obstet
Gynecol 2003;101:1307–1311. [II-2]
80. Hall JAG, Paul RM, Wilson KM. Maternal and fetal sequelae of anticoagula-
tion during pregnancy. Am J Med 1980;68:122–140. [II-3]
81. Han WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with
mechanical heart valves: a systematic review of the literature. Arch Intern
Med 2000;160(2):191–196. [Review]
82. Xu Z, Fan J, Luo X, Zhang WB, et al. Anticoagulation regimens during preg-
nancy in patients with mechanical heart valves: A systematic review and
meta-analysis. Can J Cardiol 2016;32(10):1248.e1–1248.e9. [Review]
Maternal-Fetal Evidence Based Guidelines
83. Orme L’E, Lewis M, de Swiet M, et al. May mothers given warfarin breast-
feed their infants? BMJ 1977;1:1564–1565. [II-3]
84. McKenna R, Cole ER, Vasan V. Is warfarin sodium contraindicated in the
lactating mother? J Pediatr 1983;103:325–327. [II-3]
85. Imperiale TF, Petrulis AS. A metanalysis of low dose aspirin for preven-
tion of pregnancy induced hypertensive disease. JAMA 1991;266:260–264.
[Review]
86. CLASP Collaborative Group. CLASP: a randomized trial of low dose aspirin
for the prevention of pre-eclampsia among 9,364 pregnant women. Lancet
1994;343:619–629. [I]
87. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous thromboembo-
lism, thrombophilia, antithrombotic therapy, and pregnancy: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
8th ed. American College of Chest Physicians. Chest 2008;133:844S–886S.
[Review].
88. Knight M, UKOSS. Antenatal pulmonary embolism: risk factors, manage-
ment and outcomes. BJOG 2008;115(4):453–461. [Review]
89. Warketin TE, Greinacher A, Koster A, Lincoff AM. Treatment and pre-
vention of heparin-induced thrombocytopenia: American College of
Chest Physicians evidence-based clinical guidelines, 8th ed. Chest
2008;133:340S–80S. Erratum: Chest. 2011 May;139(5):1261. Dosage error
in article text. [Review]
90. Walenga JM, Prechel M, Jeske WP, Bakhos M. Unfractioned heparin com-
pared with low molecular weight heparin as related to heparin-induced
thrombocytopenia. Curr Opin Pulm Med 2005;11:385–391. [Review].
91. Jaff MR, McMurtry MS, Archer SI, Cushman M, Goldenberg N, Goldhaber
SZ, et al. American Heart Association Council on Cardiopulmonary,
Critical Care. Management of massive and submassive pulmonary embo-
lism, iliofemoral deep vein thrombosis, and chronic thromboembolic
pulmonary hypertension: a scientific statement from the American Heart
Association. Circulation 2011;123:1788–1830. [Review]
92. Ahearn GS, Hadjiliadis D, Govert JA, et al. Massive pulmonary embolism
during pregnancy successfully treated with recombinant tissue plasmino-
gen activator: a case report and review of treatment options. Arch Intern
Med 2002;162:1221–1227. [Review]
93. Monreal M, Lafoz E, Olive A, delRio Im Vedia C, Comparison of subcutane-
ous unfractioned heparin with low-molecular-weight heparin (Fragmin) in
patients with venous thromboembolism and contraindications to couma-
rin. Thromb Haemost 1994;7(1):7–11. [II-1]
94. Aschwanden M, Labs KH, Engel H, Schob A, Jeannerret C, Mueller-
Brand J, et al. Acute deep vein thrombosis: early mobilization does
not increase the frequency of pulmonary embolism. Thromb Haemost
2001;85:42–46. [II-3]
95. Greenfield LJ, Cho KJ, Proctor MC, et al. Late results of suprarenal
Greenfield vena cava filter placement. Arch Surg 1992;127:967–969. [II-2]
96. Riedel M. Acute pulmonary embolism 2: treatment. Heart 2001;
85:351–360. [Review]
97. De Swiet M, Floyd E, Letsky E. Low risk of recurrent thromboembolism in
pregnancy. Br J Hosp Med 1987;38:264. [Review]
98. Howell R, Fidler J, Letsky E, et al. The risk of antenatal subcutaneous hepa-
rin prophylaxis: a controlled trial. BJOG 1983;90:1124–1128. [II-1]
99. Badaracco MA, Vessey M. Recurrent venous thromboembolic disease and
use of oral contraceptives. BMJ 1974;1:215–217. [II-2]
100. Tengborn L. Recurrent thromboembolism in pregnancy and puerperium: is
there a need for thromboprophylaxis? Am J Obstet Gynecol 1989;160:90–
94. [II-2]
101. Pettila V, Kaaja R, Leinonen P, et al. Thromboprophylaxis with low molecu-
lar weight heparin (dalteparin) in pregnancy. Thromb Res 1999;96:275–282.
[II-2]
102. Bain E, Wilson A, Tooher R, Gates S, Davis LJ, Middleton P. Prophylaxis
for venous thromboembolic disease in pregnancy and the early postnatal
period. Cochrane Database Syst Rev 2014;(2). [Meta-analysis; 19 RCTs, n ≥
2600]. [Review]
103. Middledorp S, Van der Meer J, Hamulyak K, et al. Counseling women
with factor V Leiden homozygosity: use absolute instead of relative risks.
Thromb Haemost 2001;87:360–361. [Review]
104. Middledorp S, Libourel EJ, Hamulyak K, et al. The risk of pregnancy-related
venous thromboembolism in women who are homozygous for factor V
Leiden. Br J Haematol 2001;113:553–555. [II-2]
105. Martinelli I, Legnani C, Bucciarelli P, et al. Risk of pregnancy-related
venous thrombosis in carriers of severe inherited thrombophilia. Thromb
Haemost 2001;86:800–803. [II-2]
106. Pabinger I, Nemes L, Rintelen C, et al. Pregnancy-associated risk for venous
thromboembolism and pregnancy outcome in women homozygous for fac-
tor V Leiden. Hematol J 2000;1:37–41. [II-2]
Venous Thromboembolism and Anticoagulation
107. Hill NCW, Hill JG, Sargent JM, et al. Effect of low dose heparin on blood loss
at caesarean section. BMJ 1988;296:505–506. [II-3]
108. Brill-Edwards. Safety of withholding heparin in pregnant women with a
history of venous thromboembolism. N Engl J Med 2000;343:1439–1444.
[II-2]
109. Gibson PS, Nerenberg KA. TIPPing practice away from anticoagulation in
pregnancy. Lancet 2014;384(9955):1648–1649. [I]
110. Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve pros-
theses. Br Heart J 1994;71:196–201. [II-2]
111. Brill-Edwards P, Ginsberg JS, Johnston M, et al. Establishing a therapeutic
range for heparin. Ann Intern Med 1993;119:104–109. [II-2]
112. Arnaout MS, Kazma H, Khalil A, et al. Is there a safe anticoagulation pro-
tocol for pregnant women with prosthetic valves? Clin Exp Obstet Gynecol
1998;25:101–104. [II-2]
113. Leyh RG, Fischer S, Ruhparwar A, et al. Anticoagulation for prosthetic
heart valves during pregnancy: is low-molecular-weight heparin an alterna-
tive? Eur J Cardiothorac Surg 2002;21:577–579. [II-2]
114. Mahesh B, Evans S, Bryan AJ. Failure of low molecular-weight heparin in
the prevention of prosthetic mitral valve thrombosis during pregnancy:
case report and review of options for anticoagulation. J Heart Valve Dis
2002;11:745–750. [II-3]
115. Lev-Ran O, Kramer A, Gurevitch J, et al. Low-molecular-weight hepa-
rin for prosthetic heart valves: treatment failure. Ann Thorac Surg 2000;
69:264–265. [II-3]
116. Lovenox Injection. Bridgewater, NJ: Aventis Pharmaceuticals, 2004.
[Review]
117. Turpie AGG, Gent M, Laupacis A, et al. A comparison of aspirin with pla-
cebo in patients treated with warfarin after heart-valve replacement. N Engl
J Med 1993;329:524–529. [I]
118. Anderson DR, Ginsberg JS, Burrows R, et al. Subcutaneous heparin ther-
apy during pregnancy: a need for concern at the time of delivery. Thromb
Haemost 1991;63:248–250. [II-2]
119. Horlocker TT. Low molecular weight heparin and neuraxial anesthesia.
Thromb Res 2001;101:141–154. [II-3]
120. Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a
population study. Obstet Gynecol 1999;94:595–599 [II-2]
339
121. Quinones J, James D, Stamilio D, Lawrence Cleary K, Macones G.
Thromboprophylaxis after cesarean delivery. A Decision Analysis. Obstet
Gynecol 2005;106(4):733–740. [Review]
122. Society for Maternal Fetal Medicine (SMFM), Varner MW.
Thromboprophylaxis for cesarean delivery. Cont Obstet Gynecol 2011;
6:30–33. [Review].
123. Orme ML, Lewis PJ, de Swiet M, Serlin MJ, Sibeon R, Baty JD, et al.
May mothers given warfarin breastfeed their infants? Br Med J 1977;1:
1564–1565. [II-3]
124. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. British
Committee for Standards in Haeatology Guidelines on oral anticoagulation
with warfarin 4th ed. Br J Haematol 2011;154:311–324. [Review]
125. Thromboembolic Disease in Pregnancy and the Puerperium: Acute
Management. Green-top Guideline No. 37b, April 2015. [Review]
126. Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated
with hormonal contraceptives and hormone replacement therapy: a clinical
review. Arch Intern Med 2004;164:1965–1976. [Review]
127. Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing
the risk of venous thromboembolic events in women taking progestin-only
contraception: a meta-analysis. BMJ 2012 August 7;345:e4944. [Review]
128. Lidegaard O, Lokkegaard E, Svendsen AL, Agger C. Hormonal contracep-
tion and risk of venous thromboembolism: a national follow-up study. BMJ
2009;339:b2921. [II-3]
129. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ,
Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects
of estrogen dose and progestogen type, results of the MEGA case-control
study, BMJ 2009;339. [II-2]
130. Kemmeren JM, Algra A, Gorbee DE. Third generation oral contracep-
tives and risk of venous thrombosis: meta-analysis BMJ 2001;323:131–134.
[Review]
131. Fruzzetti F, Cagnacci A. Venous thrombosis and hormonal contraception:
what’s new with estradiol-based hormonal contraceptives? Open Access J
Contracept 2018;9:75–79. [II-1]
132. Centers for Disease Control and Prevention (CDC). U S. medical eligibil-
ity criteria for contraceptive use, 2010. MMWR. Recommendations and
reports: MMWR Recomm Rep 2010;59(RR-4):1–86. [Review]
31
HEPATITIS A
Rebecca Pierce-Williams, Neil Silverman, Steven K. Herrine, and Danielle Tholey
Key points
• The vast majority of hepatitis A virus (HAV) infections
are self-limited.
• There is no perinatal transmission of HAV.
• The inactivated HAV vaccine can be safely used for pre-
vention, including during pregnancy if a patient is at risk
for HAV exposure.
• Exposed pregnant women can receive immune globulin
injections, which are >85% effective in preventing HAV
infection if given within 2 weeks of exposure.
• Therapy of acute HAV infection in pregnancy is supportive.
Diagnosis
According to 2019 criteria by the Council of State and Territorial
Epidemiologists, acute hepatitis A is defined by clinical and
laboratory criteria [1, 2]. The clinical criteria include the acute
development of viral hepatitis-like symptoms, such as jaundice,
abdominal pain, nausea, vomiting, fever, headache, anorexia,
malaise or dark urine, along with the following:
• Jaundice, or bilirubin ≥3.0 mg/dL OR elevated serum ala-
nine aminotransferase (ALT) >200 IU/L
• When a more likely diagnosis is not present
The laboratory criteria include one of the following:
• Anti-hepatitis A virus (anti-HAV) immunoglobulin M
(IgM) positive OR
• Nucleic acid amplification test (NAAT) positive for HAV
RNA
Acute HAV is confirmed when a patient meets the clinical cri-
teria and is anti-HAV IgM positive or has had contact with some-
one with laboratory confirmed HAV in the 15–50 days prior to
symptoms, or, if HAV RNA was detected by NAAT.
Symptoms
Symptoms for HAV include fever, malaise, decreased appetite,
nausea, abdominal discomfort, dark urine, and jaundice.
Epidemiology/Incidence
Although HAV is a reportable disease, it remains underreported,
and the estimated number of United States cases in 2018 was
approximately 24,900 [3]. With the introduction of a vaccine,
the United States incidence (new cases) declined more than
95%, from 11.7 cases per 100,000 population in 1996 to 0.4 cases
per 100,000 population in 2011 [4]. Subsequently, there was a
sharp increase in cases from 2016 to 2018, up to just under 4 cases
340
per 100,000 persons, a 294% increase [5]. Though the virus is
typically transmitted via contaminated food, the increase
in recent years has been attributed to person-to-person out-
breaks among those experiencing homelessness or reporting
drug use. Worldwide, geographic areas can be characterized
by high, intermediate, or low levels of endemicity (Figure 31.1).
Levels of endemicity are related to hygienic and sanitary condi-
tions in the geographic areas. HAV infection is common (high
or intermediate endemicity) throughout the developing world,
where infections most frequently are acquired during early child-
hood and usually are asymptomatic or mild. In areas of high
endemicity, adults are usually immune and epidemics of hepatitis
A are uncommon.
Of the viral hepatitides, the incidence of hepatitis A in preg-
nancy is quite low. In a retrospective review of patients hospital-
ized during an urban United States epidemic, of the 256 patients
hospitalized with acute HAV, only four were pregnant [6]. Similar
low rates have been found in other countries, such as Ireland [7],
where out of over 13,000 deliveries, one woman was affected by
HAV during pregnancy; and Israel, where in a retrospective review
of over 79,000 deliveries, 13 cases of HAV were identified [8].
Genetics
Hepatitis A is a small RNA virus within the genus Hepatovirus,
and of the Picornavirus family.
Etiology/Basic pathophysiology
Hepatitis A is usually transmitted through fecal-oral contact
with infected persons or contaminated food and/or water.
Most cases in the United States are directly transmitted through
person-to-person or sexual contacts during outbreaks. The
average incubation period is 28 (15–50) days, with peak infectivity
2 weeks prior to an abrupt symptom onset [9, 10]. HAV infection
can be symptomatic (adults) but also asymptomatic (mostly chil-
dren <6 years of age). The vast majority of cases are self-limited
(1–2 weeks), though severe cases can last months [11]. Relapse can
occur (up to 20% of cases), though the symptoms are often milder,
and the average duration is 4.7 weeks, with reported durations up
to 4 months [12]. Anti-HAV IgM usually appears 5–10 days before
symptoms present, and can persist for 3–12 months [10].
Risk factors/Associations
Increased risk of acquiring HAV infection, or risk of more severe
disease, is associated with:
• Poor hygiene and sanitation
• Homelessness
• Men who have sex with men
• Drug use
DOI: 10.1201/9781003099062-31
Hepatitis A 341

Pacific Ocean
Atlantic Ocean

Indian Ocean

Estimated hepatitis A
virus prevalence
High
Intermediate
Low
Very low

FIGURE 31.1 Endemicity of hepatitis A in the world. (From El-Kamary SKS. Viral hepatitis. In: R, Edward, Hill D, Solomon T,
Aronson NET, editor. Hunter’s Tropical Medicine and Emerging Infectious Diseases. 10th ed. Elsevier; 2020. p. 308–24. [III]. Ref. [19],
with permission.)

• Unvaccinated travelers to countries with high or interme- Pregnancy management

diate endemicity
• Occupational exposure, such as persons who work with
non-human primates
• Persons living in certain group settings or who are
incarcerated
• Persons with chronic liver disease
• Persons with human immunodeficiency virus (either due
to lack of prior infection, lack of vaccination, or lack of
seroconversion)
• Age over 40 years
Complications
Of those infected, 11–22% with HAV require hospitalization. The
overall mortality rate 0.3%, but increases to at least 1.8% in those
over the age of 50 years and those with chronic liver disease [4].
Rare complications include liver failure, nephrotic syndrome,
glomerulonephritis, vasculitis, and aplastic anemia. A chronic
carrier state does not exist.
Pregnancy considerations
Acute HAV in pregnancy has been associated with complications
including preterm labor, premature rupture of membranes, and
placental abruption [8]. Perinatal transmission is not expected
to occur, as it has only been reported in rare cases [13, 14].
Workup
In those presenting with symptoms of viral hepatitis, testing
should include HAV, as well as hepatitis B and C (see Hepatitis B
and C guidelines). See also section “Diagnosis”. Additional labo-
ratory testing should include liver enzymes (aspartate and ala-
nine aminotransferase) and bilirubin.
Prevention/Preconception counseling
The best method for preventing HAV is through vaccination. As
of 2020, according to the US Centers for Disease Control and
Prevention, vaccination is recommended during pregnancy
if a patient is at risk for HAV exposure, or at risk of severe
illness (See section “Risk Factors/Associations”) [15]. Havrix
(Glaxo Smith Kline) and Vaqta (Merck) are single-antigen inac-
tive vaccines given through intramuscular (IM) injection, on a
2-dose schedule (see Table 31.1). Combination hepatitis A and
B vaccination Twinrix (Glaxo Smith Kline) can also be given if
also non-immune to hepatitis B virus. Dosing and schedules for
those >18 years of age can be found in Table 31.1. Duration of
immunity after vaccination (or infection) is unknown and may
be lifelong [15].
Women should also be counseled to avoid fecal-oral contamina-
tion by washing all foods and keeping hands clean. HAV in foods
can be inactivated by heating to >185°F for 1 minute [9]. Children
are a potential source of infection and are often asymptomatic.
342 Maternal-Fetal Evidence Based Guidelines

TABLE 31.1: Hepatitis A Prophylaxis Vaccination Dosing and References

Schedule, >18 Years of Age
1. Council of State and Territorial Epidemiologists. Public Health Reporting
Vaccine Dosage and Route Schedule and National Notification for Hepatitis A [Internet]. 2019. Available from:
https://cdn.ymaws.com/www.cste.org/resource/resmgr/2018_position_
Hepatitis A 1 mL (1440 ELISA units 0, 6–12 months statements/18-ID-07.pdf [III]
(Havrix) inactivated HAV), IM 2. Centers for Disease Control and Prevention. Hepatitis A, Acute 2019 Case
Hepatitis A 1 mL (50 units HAV 0, 6–18 months Definition [Internet]. National Notifiable Diseases Surveillance System
(NNDSS). 2019. https://cdn.ymaws.com/www.cste.org/resource/resmgr.
(Vaqta) antigen), IM
Available from: wwwn.cdc.gov/nndss/conditions/candida-auris/case-­
Combined 1 mL (720 ELISA units 0, 1 month, 6 months definition/2019/ [III]
Hepatitis A & inactivated HAV + 20 µg OR, accelerated schedule: 3. Centers for Disease Control and Prevention. Viral hepatitis surveillance—
B (Twinrix) HBsAg), IM 0, 7 days, 21–30 days; United States, 2018 [Internet]. Viral Hepatitis. 2018. Available from: https://
www.cdc.gov/hepatitis/statistics/2018surveillance/HepA.htm [III]
Booster at 12 months
4. Murphy TV, Denniston MM, Hill HA, et al. Progress toward eliminating
Source: Adapted from Ref. [15]. hepatitis A disease in the United States. MMWR Suppl 2016;65:29–41. [III]
Abbreviations: ELISA, enzyme-linked immunosorbent assay; HAV, hepatitis A virus; 5. Foster MA, Hofmeister MG, Kupronis BA, et al. Increase in hepatitis
A virus infections—United States, 2013–2018. Morb Mortal Wkly Rep
HBsAg, hepatitis B surface antigen; IM, intramuscular.
2019;68:413–15. [III]
6. Willner IR, Uhl MD, Howard SC, Williams EQ, Riely CA, Waters B. Serious
hepatitis A: an analysis of patients hospitalized during an urban epidemic
Having a child under 3 years of age in the home is associated with
in the United States. Ann Intern Med 1998;128(2):111–4. [II-3]
an increased risk of transmission (odds ratio 8.8; 95% CL: 2.1,36; 7. O’Donoghue K, Byrne BM. Antenatal detection of abnormal liver func-
P = .002) [16]. tion tests: a marker for poor perinatal outcome. J Obstet Gynaecol (Lahore)
2000;20(5):475–8. [II-3]
Prenatal care 8. Elinav E, Ben-Dov IZ, Shapira Y, et al. Acute hepatitis A infection in preg-
nancy is associated with high rates of gestational complications and pre-
Therapy
term labor. Gastroenterology 2006;130(4):1129–34. [II-3]
Acute infection 9. ACOG Practice Bulletin No. 86. Viral hepatitis in pregnancy. Obstet
No antiviral therapy is available at present. Supportive therapies Gynecol 2007;941–55. [III]
can be offered as outpatient. Pregnant women should be hospital- 10. Desai AN, Kim AY. Management of Hepatitis A in 2020–2021. JAMA
2020;324(4):383–4. [III]
ized in the rare case of severe dehydration, encephalopathy, or
11. Centers for Disease Control and Prevention. CDC Yellow Book 2020: Health
coagulopathy. Household contacts and sexual partners should Information for International Travel. New York: Oxford University Press,
receive HAV prophylaxis as needed. 2017. [Guidelines; III]
Post-exposure prophylaxis (PEP) should be given to unvacci- 12. Glikson, M, Galun E, Oren R, Tur-Kaspa R SD. Relapsing hepati-
nated pregnant women within 2 weeks of close personal or sexual tis A. Review of 14 cases and literature survey. Medicine (Baltimore)
1992;71(1):14–23. [II-3]
contact. The first dose of the HAV vaccine should be given, with 13. McDuffie RS, Bader T. Fetal meconium peritonitis after maternal hepatitis
the second dose 6 months later for long-term immunity. The com- A. Am J Obstet Gynecol 1999;180(4):1031–2. [II-3]
bination hepatitis A and B vaccine, Twinrix, is not recommended 14. Leikin E, Lysikiewicz A, Garry D TN. Intrauterine transmission of hepatitis
for PEP [15]. Immune globulin (one dose of GamaSTAN 0.1 mL/ A virus. Obs Gynecol 1996;88(4 pt 2):690–1. [II-3]
15. Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of hepatitis A
kg intramuscular injection) can be considered during pregnancy
virus infection in the United States: recommendations of the advisory
and is safe [17]. HAV immune globulin prevents HAV infection in committee on immunization practices, 2020. MMWR Recomm Rep
80–90% of cases, if given within 2 weeks of exposure [18]. 2020;69(5):1–38. [III]
16. Staes CJ, Schlenker TL, Risk I, et al. Sources of infection among persons
Antepartum testing with acute hepatitis A and no identified risk factors during a sustained
Not indicated. community-wide outbreak. Pediatrics 2000;106(4). [II-3]
17. Centers for Disease Control and Prevention. Supplementary text 1. pro-
vider guidance on risk assessment and clinical decision-making for hepa-
Delivery titis a postexposure prophylaxis. Supplements: Update: Recommendations
Follow obstetrical indications. of the advisory committee on immunization practices for use of hepa-
titis A vaccine for postexposure prophylaxis and for preexposure pro-
Anesthesia phylaxis for international travel. MMWR Morb Mortal Wkly Rep 2018;
No particular precautions necessary. 67(43):1216–20. [III]
18. Winokur PL, Stapleton JT. Immunoglobulin prophylaxis for hepatitis A.
Clin Infect Dis 1992;14(2):580–6. [III]
Postpartum/Breastfeeding
19. El-Kamary SKS. Viral hepatitis. In: R, Edward, Hill D, Solomon T, Aronson
Breastfeeding is not contraindicated, but good hygiene practices NET, editor. Hunter’s Tropical Medicine and Emerging Infectious Diseases.
should be maintained. 10th ed. Elsevier; 2020. p. 308–24. [III]
32
HEPATITIS B
Laura Felder, Zimeng Gao, and Danielle Tholey
Key points
• Universal precautions, proper hygiene and avoidance of
high-risk behavior where contact with potentially infec-
tious body fluids may occur (blood, semen, and saliva)
should be employed by individuals to avoid acquiring hepa-
titis B virus (HBV) infection.
• HBV vaccine should be administered preconception or
early in pregnancy to every reproductive age woman who
is non-immune to infection.
• All women should be screened for HBV infection during
pregnancy by testing for the presence of HBsAg.
• HBV is a reportable infection and should be reported to
local departments of health.
• Vertical transmission of HBV can occur in up to 95% of
women with HBeAg+ in the absence of neonatal HBV vac-
cination and HBIg.
• Vertical transmission occurs in approximately 10% of
women who are HBsAg+, but HBeAg– in the absence of
neonatal immunoprophylaxis.
• In pregnant women with HBV infection, HBV viral load
testing should be performed in the third trimester.
• In pregnant women with HBV infection and viral load
>200,000 IU/mL or >6–8 log 10 (106-8) copies/mL, HBV-
targeted maternal antiviral therapy (e.g. tenofovir)
should be initiated in pregnancy to decrease the risk of
vertical transmission.
• About 90% of newborns infected with HBV develop
chronic HBV without intervention, with 25% of chronic
HB carriers eventually dying of related complications (cir-
rhosis, hepatocellular cancer).
• Hepatitis B vaccine and HBIg should be given within
12 hours of birth to all newborns of HBsAg positive
mothers or those with unknown or undocumented
HBsAg status, regardless of whether maternal antiviral
therapy has been given during pregnancy.
• Breastfeeding is not contraindicated for mothers
with HBV, as long as the newborn receives appropri-
ate immunoprophylaxis and the mother does not have
cracked or bleeding nipples.
• Mode of delivery for women with HBV infection should be
based on obstetric indications.
Epidemiology/Incidence
An estimated 2 billion people worldwide have been infected with
HBV [1]. Approximately, 90% of adults exposed to HBV spontane-
ously clear the virus while about 10% develop chronic HBV infec-
tion. Risk of developing chronic HBV is dependent on the presence
or absence of a mature immune system and thus is age dependent.
Specifically, chronic infection occurs in 90% of newborns who
are infected before 1 year of age, 30–50% of children infected
between 1 and 5 years of age and less than 5% of healthy adults [1, 2].
DOI: 10.1201/9781003099062-32
In 2015, the World Health Organization (WHO) estimated that
257 million individuals worldwide had chronic HBV infection
(Figure 32.1) [3]. Most patients acquire the infection at birth or in
the first 1–2 years of life. Those that develop chronic infection are at
risk for significant morbidity and mortality. In 2018, over 800,000
cases of liver cancer were newly diagnosed worldwide and more
than 50% of them were due to HBV infection [4, 5]. Over 800,000
people die each year globally from complications related to HBV
infection, largely hepatocellular carcinoma and hepatic failure [1].
The HBV vaccine is about 95% effective against infection [1].
More than 90 countries have initiated universal vaccination mak-
ing the worldwide eradication of HBV a distinct possibility. In
fact, the fight to end HBV is a goal established by the UN Agenda
for Sustainable Development and the World Health Assembly
aims to eradicate the disease by 2030.
Highly endemic areas, defined as an HBV prevalence over 8%
of the population, include many countries in Sub-Saharan Africa,
Southeast Asia, and the Western Pacific [6]. In some countries,
the adult prevalence rate is over 20%. China has the highest abso-
lute number of individuals currently infected with HBV, over 80
million people [7]. Low prevalence areas include much of North
America, Western Europe, and Australia with rates below 0.7%
[1]. In endemic areas where universal childhood HBV vaccina-
tion has been instituted, such as China, subsequent decreases in
HBsAg carrier rates were associated with up to 90% reductions
in the incidence of chronic liver disease and hepatocellular carci-
noma in children and adolescents [8].
The absolute annual incidence of acute HBV infection has
decreased in the United States from 8000 to 3500 cases per
year over the 2000–2017 interval. However, this likely under-
represents the actual number of cases as not all HBV cases are
reported, despite being a reportable infection. Recently, the rate
of HBV infection has stabilized at 1.1 cases/100,000 population
in the United States, down from 9.6 cases/100,000 in 1982 [9, 10].
However, rates of neonatal vaccination at birth remain below tar-
get, at only 73.6% as reported by the CDC [11].
Genetics
HBV is a small partially double-stranded DNA virus in the family
of Hepadinaviridae. Humans are its only known host and viral
replication occurs within hepatocytes. Diagnosis and determina-
tion of disease stage relies on detection of three distinct antigens
(Ag), or antibodies (Ab) directed against these antigens (core Ag,
surface Ag, envelope Ag). Ten different HBV genotypes exist
(A–J), corresponding to varying disease courses and prognoses.
For example, patients with HBV genotype C carry a higher risk of
developing hepatocellular carcinoma.
• Antigens
• “c” core
• “s” surface – indicates infection. If present >6 months,
chronic HBV infection
343
344 Maternal-Fetal Evidence Based Guidelines

High: ≥ 8%
High Intermediate: 5%–7%
Low intermediate: 2%–4%
Low: < 2%
No data available

FIGURE 32.1 Worldwide prevalence of chronic hepatitis B virus infection. (From Schweitzer A, Horn J, Mikolajczyk RT, Krause G,
Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965
and 2013. Lancet 2015;386(10003):1546–55. [Review, III]. Ref. [6], with permission.)

•
“e” envelope – connotes higher viral replication and
therefore increased infectivity
• Antibodies
• “s” immune
• “c” core – appears at onset of symptoms in acute HBV
and persists for life. Indicates previous infection (if
HBsAb+) or chronic infection (If HBsAb is negative
with positive HBsAg). Can have isolated HBcAb posi-
tive in “window” period or as a false positive
Diagnosis/Definition
Adults (see Table 32.1)
Acute: HBsAg+, HBcAb+, HBcIgM+, HBsAb–
Chronic: HBsAg+ >6 months, HBcAb+, HBcIgM–, HBsAb– [4]
Screening for hepatitis B is performed with enzyme immuno-
assays directed against HBsAg. If positive, additional labs includ-
ing HBcAb and HBeAg are indicated to determine the stage of
infection (acute versus chronic) and infectivity, respectively.

TABLE 32.1: Interpretation of the Hepatitis B Panel

HBsAg Anti-HBc Anti-HBc IgM Anti-HBs Interpretation Vertical Transmissiona
− − − − Susceptible 0%
− + − + Immune because of natural infection 0%
− − − + Immune because of hepatitis B vaccination 0%
+ + + − Acutely infected First trimester: 10%
Third trimester: 80%–90%
HBeAg−: 10%–20%
HBeAg+: 90%
+ + − − Chronically infected HBeAg−: 2%–10%
HBeAg+: 80%–90%
− + − − Four interpretations possible: 0%
1. May be recovering from acute HBV infection
2. May be distantly immune and test is not sensitive
enough to detect very low level of anti-HBs in serum
3. May be susceptible with false-positive anti-HBc
4. May have recently acquired hepatitis B and has
not yet mounted a serum response
Source: Adapted from Ref. [2].
a Assuming HIV negative, and no HB vaccine and immunoprophylaxis of neonate.
Hepatitis B
HBV viral DNA is detected by polymerase chain reaction (PCR)
in blood, but additional body fluids are also infectious including
semen, vaginal secretions, and saliva. When considering HBV
infection, the initial differential diagnosis also includes hepatitis
A or C viruses (HAV, HCV), cytomegalovirus (CMV), Epstein–
Barr virus (EBV), varicella zoster virus (VZV), coxsackie B virus,
herpes simplex virus (HSV), rubella, autoimmune hepatitis, and
drug or herbal induced hepatotoxicity.
Infants
The diagnosis in infants is made by detection of persistent (e.g.
>9 months of age) HBsAg. Like in adults, HBsAb is attributable
to newborn vaccination while HBcAb arises only as the result of
HBV infection.
Symptoms
Only 30–50% of acutely infected adult patients have symptom-
atic HBV infection [12]. Symptoms are typically non-specific and
insidious in onset, including loss of appetite, malaise, nausea,
vomiting, abdominal pain, or fever. Jaundice is an uncommon
finding.
Etiology/Basic pathophysiology
Initial HBV exposure is followed by an incubation period of 60–90
days (depending on the degree of viral exposure) before labora-
tory changes occur (Table 32.1 and Figure 32.2). The presence of
HBsAb indicates immunity, whether it results from vaccination
or from prior infection that has resolved. HBcAb arises only as a
result of natural infection, and coexists with HBsAb in individu-
als who have cleared their past infection. In contrast, HBsAb and
HBsAg do not coexist in standard clinical testing, since HBsAb is
the neutralizing antibody for the antigen.
Classification
See Table 32.1.
Risk factors/Associations
Transmission occurs with mucosal exposure to infected blood
or other bodily fluids such as semen, saliva, or vaginal fluids. The
greatest source of chronic HBV infection worldwide is perina-
tal transmission from HBV-infected mothers. However, in the
United States sexual contact with persons infected with HBV and
injection drug use account for the majority of new cases. Risk fac-
tors include intravenous drug use (IVDU), history of sexually trans-
mitted diseases (STDs), multiple sex partners, household contacts,
institutionalization/incarceration, chronic conditions such as dia-
betes mellitus or other chronic liver diseases, and need for hemodi-
alysis. Infection that occurs as a result of an HBV-infected blood
transfusion is rare, with a risk of about 1 in 300,000 [14]. HBV-
infected patients are more likely to be infected with HIV and HCV,
so patients with HBV should always be screened for coinfection.
Complications
The outcome of acute HBV infection is age-dependent. While
most acute infections are asymptomatic or mildly symptomatic,
some portion will develop hepatitis, or in some cases fulminant
disease leading to death or liver transplantation. The risk of acute
345
disease that is symptomatic increases with age however the risk
of developing chronic infection decreases with age. About 95%
of neonates, 20–30% of children age 1–5 years old, and 5% of
adults develop chronic infection [1].
Individuals chronically infected with HBV are often asymp-
tomatic without evidence of liver dysfunction. The 5-year inci-
dence of progression to cirrhosis is 8–20% and once present,
liver failure occurs within 5 years in 20% of these individuals [15].
Hepatocellular carcinoma develops in 2–5% of individuals
with chronic HBV annually [16]. Disease progression, complica-
tions, and mortality are influenced by co-existent medical condi-
tions, duration of HBV infection, HBV genotype, and geographic
location at the time of infection. The age-adjusted mortality
rate in the United States in 2016 was 0.45 per 100,000 people as
reported by the CDC [17].
Pregnancy considerations
Vertical transmission may occur by transplacental route, or
more commonly, at the time of delivery when there is exposure of
neonatal mucus membranes and maternal blood and other bodily
fluids. Vertical transmission is influenced by the presence
of the HBeAg and occurs in about 10% of children born to
HBsAg+/HBeAg– mothers, if no neonatal immunoprophylaxis
is given. In woman who are also HBeAg+, the risk for verti-
cal transmission increases to 75% (with some studies reporting
rates over 90%) in the absence of appropriate immunoprophy-
laxis (HBIg and immunization). Rates of vertical transmission
are reduced to 1% and 6%, respectively, when both HBIg and
immunization occur at or shortly after birth [18]. While the use
of both HBIg and the HBV vaccine neonatally has had a dramatic
impact on rates of perinatal HBV transmission, concern persists
regarding the proportion of newborns who are infected despite
receiving appropriate neonatal immunoprophylaxis. HBIG
and vaccine failure is largely restricted to newborns of women
with very high HBV viral loads (e.g. >200,000) and positive
HBeAg, but the reported rate is variable. A prospective cohort
of over 60,000 women with a 6.5% HBV infection rate, showed a
3.5% risk of immunoprophylaxis failure while others report fail-
ure rates up to 15% [5, 19].
Historically, the risk of vertical transmission of HBV was
not thought to be higher in HBV-infected women undergo-
ing amniocentesis compared to HBV-infected women who did
not [1]. However, two recent cohort series have demonstrated
an increased risk of in utero infection after amniocentesis
in women with viral titers >7 log 10 copies/mL, compared to
those women with titers below that cutoff (50% versus 4%, OR
21.3, p = 0.006 and 10.81% versus 0%, p = 0.004) [20, 21]. There
are insufficient data to assess the risk of in utero infection related
to chorionic villus sampling in HBV-infected women [2, 5]. Such
emerging data may have an impact on counseling surrounding
invasive prenatal testing as data accumulate from more series
using maternal HBV viral load as a predictor of procedural risk.
In general, the course of pregnancy does not appear to be
altered by HBV infection (same incidences of pregnancy loss,
congenital anomalies, etc.). An exception is in cases of acute third-
trimester HBV infection (where preterm birth is more likely) or
cases where maternal cirrhosis is present [22, 23]. Hepatic flares
can occur at any point in pregnancy but are most common in the
postpartum period, occurring in as many as 25% of cases [24]. For
this reason, women with chronic HBV should be carefully moni-
tored by a hepatologist for a minimum of 6 months postpartum.
346 Maternal-Fetal Evidence Based Guidelines

HBsAg Anti-HBs

HBV DNA

HBeAg Anti-HBe

Anti-HBc lgM
Alanine aminotransferase

Anti-HBc lgG

Symptoms
1000

HBsAg

HBV DNA

HBeAg HBeAg or anti-HBe

Anti-HBc lgM
Alanine aminotransferase

Anti-HBc lgG

Symptoms
1000

0
0 1 2 3 4 5 6 12 24 36 48
Months after HBV infection

FIGURE 32.2 Hepatitis B virus (HBV) markers during natural course resolved acute HBV infection (A) and transition of acute
to chronic HBV infection (B). A subset of chronic patients might seroconvert from HBeAg to anti-HBe despite persistence of
HBV DNA. (From Trepo C, Chan HLY, Lok A. Hepatitis B virus infection. Lancet 2014;384:2053–63. [Review]. Ref. [13], with
permission.)
Hepatitis B
Management
Principles
The main goal of management is prevention of vertical trans­
mission.
Prevention/Preconception counseling
Universal precautions, proper hygiene and avoidance of high-risk
behavior where contact with potentially infectious body fluids
may occur (blood, semen, and saliva) should be employed by indi-
viduals to avoid acquiring HBV infection.
The HBV vaccine may be administered preconception or
in pregnancy to any reproductive age woman who is suscep-
tible to infection (HBsAg– and HBsAb–). It should especially
be considered for women with risks factors for infection such as
those with prior STDs, HIV+, HepC+, and IVDU (for full list see
Risk factors/ Associations).
Universal maternal screening with HBsAg is recommended
at the first prenatal or preconception visit. Repeat testing in
the early third trimester for high-risk groups may be consid-
ered (see risk factors/Associations).
Workup
The following labs should be ordered if HBsAg returns posi-
tive: HBsAb, HBcAb, HBcIgM, HBeAg, HBeAb, and HBV
DNA. See Table 32.1 for interpretation of diagnosis and disease
stage. HBV DNA by quantitative PCR is recommended in the
late second trimester or early third trimester for women diag-
nosed with chronic HBV infection. The viral load can inform
counseling regarding the risk of intrauterine infection/neonatal
immunization failure, and treatment with maternal antiviral
therapy in pregnancy to decrease the risk of fetal infection.
Antepartum and immediate postpartum care
Maternal antiviral therapy should be recommended for very high
maternal viral loads, which is discussed in subsequent text. All
newborns of HBsAg+ women should receive HBIg and HBV vac-
cine within 12 hours of birth, regardless of whether maternal
antiviral therapy was used during pregnancy. With implementa-
tion of this algorithm in the United States, the rate of HBV infec-
tion decreased 96% in children between 1990 and 2005 [25].
Women who are chronically HBV infected (HBsAg+) should
also be screened for prior hepatitis A virus infection (test:
HAV-IgG) and vaccinated if non-immune, since co-infection
with other hepatitis viruses has additive morbidity.
Prenatal care
Immunization and treatment
Main intervention therapies
Hepatitis B vaccine Series of two or three IM injections in del-
toid muscle over 6 months of recombinant DNA; 95% seroconver-
sion (HBsAb+ and immune) rate. It is safe in pregnancy and for
neonate [26]. Three vaccines are available:
1. Recombivax HB (Merck and Co, Inc., NJ, U.S.): Adults
>20 years old = 10 µg (1 mL) ×3; <20 years old 5 µg (0.5 mL)
×3; 11–15 years old = 10 µg (1.0 mL) ×2
2. Engerix-B (Smith Kline Beecham Biologicals, Belgium):
Adults >20 years old – 20 µg (1 mL) ×3; <20 years old = 10
µg (0.5 mL) ×3
3. Heplisav: Adults ≥18 years old = 20 µg (0.5 mL); limited
data available on safety of administration in pregnancy.
347
Doses are different for immunocompromised individuals or
those on hemodialysis.
There is also one combination (HAV and HBV) vaccine avail-
able for adults (Twinrix) [1].
HBIg Immunoglobulins specific for HB (0.06 mL/kg IM for
adult; 0.5 mL for neonate). It is safe in pregnancy and for neonate
[25, 27].
Nucleoside/Nucleotide analogs HBV viral load is directly
related to the risk of disease progression in infected adults.
Randomized controlled trials have shown that use of antivirals in
HBV-infected adults can lower viremia and, in turn, lower long-
term disease risks. Some of the single-agent antivirals studied are
those used to treat HIV infection, specifically lamivudine and
tenofovir. One of the earlier non-pregnant adult trials using lami-
vudine demonstrated significantly less progression of hepatic
fibrosis and cirrhosis over 32 months compared to placebo, but
was complicated by significant rates of drug resistance which
occurred in a high proportion of patients [28]. Subsequent tri-
als using tenofovir and entecavir, another reverse transcriptase
inhibitor, showed sustained viral suppression below detectable
levels and reversal of hepatic histopathology with lower levels of
resistance in non-pregnant adults [29]. More recent reports have
demonstrated that in chronically infected non-pregnant adults,
tenofovir monotherapy has maintained HBV-DNA suppres-
sion while used for up to 6 years of continuous treatment, with
no evidence of tenofovir resistance, even in patients whose virus
became resistant to lamivudine [30] (see Table 32.2).
In pregnancy, studies have examined the effect of lamivudine,
telbivudine, and tenofovir on maternal viral loads and vertical
transmission rates, extrapolating from data already present on
maternal HIV treatment. The preferred first-line therapy rec-
ommended by the American Association for the Study of Liver
Diseases (AASLD) and the European Association for the Study
of the Liver (EASL) for all pregnant women in the third trimester
with a viral load greater than >106 –108 copies/mL or 200,000 IU/
mL is tenofovir disoproxil fumarate (TDF) [15, 31]. Treatment
is also recommended for pregnant women with chronic HBV and
other treatment indications such as cirrhosis.
Early studies evaluating the efficacy of lamivudine starting at
24–32 weeks of gestation through 4 weeks postpartum resulted
in a significant 80% decrease in intrauterine fetal HBV infection
(OR 0.2 [0.10–0.39]; p <0.001) [32]. A 2016 meta-analysis of 26
TABLE 32.2: FDA Pregnancy Category of Hepatitis B Drugs
Drug Class Pregnancy Category
Interferon alfa-2b Interferon C
Peginterferon alfa Interferon C
Lamivudine nucleoside C
analogue
Adefovir dipivoxil Nucleotide C
analogue
Entecavir Nucleoside C
analogue
Telbivudine Nucleoside B
analogue
Tenofovir Nucleotide B
analogue
Source: Adapted from Ref. [42].
348
studies including over 3600 women similarly showed decreased
maternal viral loads at delivery (risk ratio 0.3, 95% CI 0.2–0.5) and
decreased risk of HBV vertical transmission with third trimester
lamivudine or telbivudine use (risk ratio 0.3; 95% CI 0.2–0.4) [33].
However, because of concerns about viral resistance, TDF is the
preferred antiviral in pregnancy.
Two recent randomized controlled studies have shown a sig-
nificant decrease in maternal viral loads when TDF is used in
the third trimester of pregnancy. In one study including only
pregnant women with VL >200,000 IU/mL, 68% of women
in the TDF treatment arm and only 2% of women in the pla-
cebo arm had VL less than 200,000 IU/mL at delivery. Rates of
child infection, as measured at 28 weeks postpartum, were 5%
in the treatment group compared to 18% in the control group
(p = 0.007) [34]. In the second study including only women
with HBeAg positivity (regardless of HBV VL), the number
of women with VL >200,000 IU/mL decreased significantly
at delivery in the treatment group to 12% compared to 90%
in the placebo group; however, the decrease in child infection
was non-significant (0 versus 2% (p = 0.12) [35]. Both studies
utilized universal co-administration of HBV vaccine and HBIg
at birth. Despite differences in the child immunoprophylaxis
failure rates between these studies, TDF treatment in the third
trimester is still recommended by the AASLD and EASL, and
the NICE guidelines from the UK currently support offering
TDF in the third trimester of pregnancy when the VL is greater
than 107 IU/mL [36].
Newer treatment agents such as tenofovir alafenamide (TAF)
are available, but there are limited data on use in pregnancy.
Clinical trials are ongoing, evaluating the safety and efficacy
of TAF in reducing vertical transmission of HBV in pregnancy.
Early data do not suggest an increased risk of congenital malfor-
mation after use in pregnancy [37]. At this time, TAF is not yet
recommended for pregnant women.
Safety
In general, antiretroviral agents are thought to be safe for use in
pregnancy. The antiretroviral pregnancy registry has shown a
similar rate of birth defects among women using antiretrovirals
in their first trimester or in the third trimester, as the baseline
rate of birth defects (about 3%) [38–40].
Special conditions
• Acute Hepatitis B in pregnancy: Diagnosis is based on con-
version from HBsAg– to HBsAg+. All labs described ear-
lier should be evaluated. Outpatient supportive therapy is
sufficient for most individuals. Consider hospitalization for
severe anemia, diabetes mellitus, severe dehydration, coag-
ulopathy, significantly elevated bilirubin, or mental status
changes which could be a harbinger of acute liver failure.
Consider nucleoside/nucleotide, and/or HBIg therapy.
Vitamin K 10 mg IM (or po) q8h × 3 can be given to preg-
nant women with coagulopathy. Mortality is about 1% [2].
Sexual, needle, and household contacts should be informed
by the patient.
• Exposure to HB in pregnancy: Check all labs as discussed
previously (see Table 32.1). If HBsAg– and HBsAb–, give
HBIg and begin the HBV vaccine series (preferably within
24 hours of exposure): This combination will prevent 75%
of transmission [27]. Must give HBIg within 14 days of
sexual contact. Repeat HBIg within one month if blood or
mucous membrane exposure [27].
Maternal-Fetal Evidence Based Guidelines
Antepartum testing
Not generally indicated.
Delivery
Route of delivery should be based on obstetrical indications
as cesarean delivery has not been shown to decrease the risk of
vertical transmission [2, 5]. Similarly, invasive procedures during
labor such fetal scalp electrode and episiotomy should be used as
needed based on general obstetric indications [2]. While theoreti-
cally they may seem to increase the risk of vertical transmission,
routine use of HBIg and HBV vaccination is thought to mitigate
this risk.
Anesthesia
No particular precautions are necessary for chronic HBV infec-
tion unless patient has known cirrhosis or acute HBV infection.
In these situations, liver function testing should be performed
to assess coagulation function prior to administering regional
anesthesia.
Postpartum/Breastfeeding
Breastfeeding is not contraindicated, as long as the neonate
receives HBIg and HBV vaccine as discussed previously and
maternal nipples are not cracked or bleeding [2, 41].
Rare/Related
Hepatitis D virus: Incomplete RNA virus, which can super-
infect 20–25% of chronic HBV-infected patients. As HDV
requires the HBV machinery to replicate, the HDV cannot exist
without HBV. HDV infection worsens chronic HBV infection,
so that 25% may die from disease [2]. If HBV is prevented, HDV
infection is prevented, too. HDV has no effect on pregnancy or
fetus/neonate.
References
1. World Health Organization. Hepatitis B vaccines: WHO position paper –
July 2017. Wkly Epidemiol Rec 2017;92(27):369–92. [Review, III]
2. American College of Obstetricians and Gynecologists. Viral hepati-
tis in pregnancy. ACOG Practice Bulletin No. 86. Obstet Gynecol 2007;
110(4):941–56. [Review, III]
3. World Health Organization. Hepatitis B. https://www.who.int/news-room/
fact-sheets/detail/hepatitis-b (Accessed on July 27, 2020). [Review, III]
4. World Health Organization, Global Cancer Organization, International
Agency for Research on Cancer. Liver. https://gco.iarc.fr/today/data/fact-
sheets/cancers/11-Liver-fact-sheet.pdf (Accessed on July 27, 2020). [Review,
III]
5. Dionne-Odom J, Tita AT, Silverman NS, Society for Maternal-Fetal
Medicine (SMFM. # 38: Hepatitis B in pregnancy screening, treatment, and
prevention of vertical transmission. AJOG 2016;214(1):6–14. [Review, III]
6. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of
worldwide prevalence of chronic hepatitis B virus infection: a systematic
review of data published between 1965 and 2013. Lancet 2015;386(10003):
1546–55. [Review, III]
7. Razavi-Shearer D, Gamkrelidze I, Nguyen MH, Chen DS, Van Damme P,
Abbas Z, et al. Global prevalence, treatment, and prevention of hepatitis B
virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol
2018;3(6):383–403. [Original Research, II-3]
8. Chiang CJ, Yang YW, You SL, Lai MS, Chen CJ. Thirty-year outcomes
of the national hepatitis B immunization program in Taiwan. JAMA
2013;310(9):974–976. [Original Research, II-2]
Hepatitis B
9. CDC. Surveillance data for viral hepatitis – United States, 2013–2017.
Atlanta, GA: US Department of Health and Human Services, CDC; 2019.
https://www.cdc.gov/hepatitis/statistics/2017surveillance/TablesFigures-
HepB.htm#tabs-1-1 (Accessed on July 27, 2020). [Review, III]
10. Schillie S, Vellozzi C, Reingold A, Harris A, Haber P, Ward JW, et al.
Prevention of hepatitis B virus infection in the United States: recommen-
dations of the Advisory Committee on Immunization Practices. MMWR
Recommend Rep 2018;67(1):1. [Review, III]
11. CDC. National Progress Report 2020 Goal: Increase the percentage
of infants who receive hepatitis B vaccine with 3 days of birth to 85.0%.
https://www.cdc.gov/hepatitis/policy/NationalProgressReport-HepB-
IncreaseVacinations.htm#:~:text=The%20percentage%20of%20infants%20
receiving,annual%20target%20of%2078.7%25%20coverage (Accessed
July 27, 2020). [Review, III]
12. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B:
special emphasis on disease progression and prognostic factors. J Hepatol
2008;48(2):335–52. [Review, III]
13. Trepo C, Chan HLY, Lok A. Hepatitis B virus infection. Lancet
2014;384:2053–63. [Review]
14. American Red Cross. Risks and complications. https://www.redcrossblood.
org/donate-blood/blood-donation-process/what-happens-to-donated-
blood/blood-transfusions/risks-complications.html#:~:text=The%20
odds%20of%20catching%20hepatitis,is%20approximately%201%20in%20
350%2C000 (Accessed on July 27, 2020). [Review, III]
15. European Association for the Study of the Liver. EASL 2017 clinical prac-
tice guidelines on the management of hepatitis B virus infection. J Hepatol
2017;67(2):370–98. [Review, III]
16. Raffetti E, Fattovich G, Donato F. Incidence of hepatocellular carcinoma in
untreated subjects with chronic hepatitis B: a systematic review and meta-
analysis. Liver Int 2016;36:1239–51. [Review, III]
17. CDC. National Progress Report 2020 Goal: Reduce the rate of hepati-
tis B-related deaths to 0.48 per 100,000 population. https://www.cdc.
gov/hepatitis/policy/NationalProgressReport-HepB-ReduceDeaths.
htm#:~:text=The%20age%2Dadjusted%20hepatitis%20B,goal%20of%20
0.48%20per%20100%2C000 (Accessed on July 27, 2020). [Review, III]
18. Isaacs D, Kilham HA, Alexander S, Wood N, Buckmaster A, Royle J. Ethical
issues in preventing mother-to-child transmission of hepatitis B by immun-
isation. Vaccine 2011;29(37):6159–62. [II-2]
19. Zhang L, Gui X, Wang B, Ji H, Yisilafu R, Li F, et al. A study of immuno-
prophylaxis failure and risk factors of hepatitis B virus mother-to-infant
transmission. Eur J Pediat 2014;173(9):1161–8. [Original Research, II-2]
20. Han Z, Zhang Y, Bai X, Yin Y, Xu C, Hou H. Mother-to-child transmission
of hepatitis B virus after amniocentesis: a retrospective matched cohort
study. Prenat Diagn 2019;39(6):431e40. [Original Research, II-2]
21. Yi W, Pan CQ, Hao J, Hu Y, Liu M, Li L, Liang D. Risk of vertical transmis-
sion of hepatitis B after amniocentesis in HBs antigen-positive mothers. J
Hepatol 2014;60:523–9. [Original Research, II-2]
22. Wong SF, Chan LY, Yu V, Ho LC. Hepatitis B carrier and perinatal out-
come in singleton pregnancy. Am J Perinatol 1999;16(09):485–8. [Original
Research, II-2]
23. Shaheen AA, Myers RP. The outcomes of pregnancy in patients with cir-
rhosis: a population‐based study. Liver Intern 2010;30(2):275–83. [Original
Research, II-2]
24. Giles M, Visvanathan K, Lewin S, Bowden S, Locarnini S, Spelman T,
Sasadeusz J. Clinical and virological predictors of hepatic flares in preg-
nant women with chronic hepatitis B. Gut 2015;64(11):1810–5. [Original
Research, II-2]
25. Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L,
et al. A Comprehensive immunization strategy to eliminate transmission
349
of hepatitis B virus infection in the United States; recommendations of the
Advisory Committee on Immunization Practices (ACIP); Immunization of
adults; Part II. [Review, III]
26. CDC. Hepatitis B Questions and Answers for Health Professionals. https://
www.cdc.gov/hepatitis/hbv/hbvfaq.htm#D4 (Access on July 27, 2020).
[Review, III]
27. Schillie S, Murphy TV, Sawyer M, Ly K, Hughes E, Jiles R, et al. CDC guid-
ance for evaluating health-care personnel for hepatitis B virus protection
and for administering postexposure management. MMWR Recommend
Rep 2013;62(RR-10):1. [Review, III]
28. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee C-Z, Yuen H, et al. Lamivudine
for patients with chronic hepatitis B and advanced liver disease. N Engl J
Med 2004;351:1521–31 [RCT, I]
29. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term
entecavir therapy results in the reversal of fibrosis/cirrhosis and continued
histological improvement in patients with chronic hepatitis B. Hepatology
2010;52:886–93. [Original Research, II-1]
30. Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, et al.
No detectable resistance to tenofovir disoproxil fumarate after 6 years of
therapy in patients with chronic hepatitis B. Hepatology 2014;59:434–42.
[Original Research, II-2]
31. Terrault NA, Lok AS, McMahon BJ, Chang KM, Hwang JP, Jonas MM,
et al. Update on prevention, diagnosis, and treatment of chronic hepati-
tis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67(4):1560–99.
[Review, III]
32. Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to
interrupt in utero transmission of hepatitis B virus: a systematic review and
meta-analysis. Obstet Gynecol 2010;116(1):147–59. [Review, III]
33. Brown Jr RS, McMahon BJ, Lok AS, Wong JB, Ahmed AT, Mouchli MA, et al.
Antiviral therapy in chronic hepatitis B viral infection during pregnancy:
a systematic review and meta-analysis. Hepatology 2016;63(1):319e33.
[Review, III]
34. Pan CQ, Duan Z, Dai E, Zhang S, Han G, Wang Y, et al. Tenofovir to pre-
vent hepatitis B transmission in mothers with high viral load. N Engl J Med
2016;374(24):2324–34. [RCT, I]
35. Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Khamduang W,
Tierney C, et al. Tenofovir versus placebo to prevent perinatal transmission
of hepatitis B. N Engl J Med 2018;378(10):911–23. [RCT, I]
36. NICE. Hepatitis B (chronic): diagnosis and management. Clinical guideline
[CG165]. 2013. [Review, III]
37. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral
Pregnancy Registry Interim Report for 1 January 1989 through 31 July 2019.
Wilmington, NC: Registry Coordinating Center. 2019. [II-3]. http://apregistry.
com/forms/exec-summary.pdf
38. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral
Pregnancy Registry Interim Report for 1 January 1989 through 31 July 2018.
Wilmington, NC: Registry Coordinating Center; 2017. www.APRegistry.
com (Accessed on May 24, 2019). [II-3]
39. Greenup A-J, Tan PK, Nguyen V, Glass A, Davison S, Chatterjee U, et al.
Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent
perinatal transmission of hepatitis B virus. J Hepatol 2014;61:502–07 [II-2]
40. Chen H-L, Lee C-N, Chang C-H, Ni Y-H, Shyu M-K, Chen S-M, et al. Efficacy
of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant
transmission of hepatitis B virus. Hepatology 2015;62:375–86. [RCT, I]
41. Hill JB, Sheffield JS, Kim MJ, Alexander JM, Sercely B, Wendel GD. Risk of
hepatitis B transmission in breast-fed infants of chronic hepatitis B carriers.
Obstet Gynecol 2002; 99:1049–52. [Original Research, II-2]
42. Piratvisuth T. Optimal management of HBV infection during pregnancy.
Liver Intern 2013; 188–94. [Review, III]
33
HEPATITIS C
Rebecca Pierce-Williams, Neil Silverman, Raja Dhanekula, Jonathan M. Fenkel, and Danielle Tholey
Key points
• Chronic hepatitis C virus (HCV) infection is defined as a
reactive HCV antibody with detectable HCV RNA for
>6 months duration.
• Rates of HCV have increased in recent years, likely due to
the continued opioid epidemic.
• In 2018, HCV was a contributing or underlying cause of
over 15,000 deaths in the United States.
• Complications of chronic HCV infection include cirrho-
sis, liver failure, and hepatocellular carcinoma.
• Chronic HCV-related liver disease and hepatocellular
carcinoma (liver cancer) are among the most common
indications for liver transplantation in the United States;
rates of HCV-related transplants are decreasing due to
high cure rates with the recent advent of direct-acting
antivirals.
• HCV is primarily acquired via infected blood-to-blood
contact, but mother-to-infant (MTCT, or vertical trans-
mission) can also occur.
• Reported transmission rates are 5.8% when a mother is
HCV-RNA positive and HIV negative.
• Rates increase to approximately 11% when a mother is
both HCV-RNA and HIV positive.
• MTCT is most commonly diagnosed by the presence of
HCV antibody and/or HCV RNA in the infant after 18
months of age.
• In women of reproductive age with chronic HCV, treatment
before conception with direct-acting antivirals should be
strongly considered.
• Universal screening for hepatitis C is recommended for
all pregnant women, at the start of each pregnancy.
• All women should be counseled on risk factors for HCV
(Table 33.1).
• Recommended workup and management for pregnant
women with HCV (Box 33.1) includes viral load and gen-
otype, assessment of liver function, evaluation of immu-
nity to hepatitis A and B (and vaccination if non-immune),
HIV status, staging imaging such as abdominal ultrasound
or postpartum liver elastography (FibroScan®) and con-
sultation with hepatologist and maternal-fetal medicine
provider.
• In HCV-positive, but HIV-negative women, cesarean deliv-
ery should be reserved for obstetrical indications.
• Breastfeeding is not a risk factor for MTCT of HCV in non-
HIV infected women.
• In women of reproductive age with chronic HCV, treat-
ment before conception should be strongly considered with
as short as an 8–12-week regimen of direct-acting antivi-
ral agents (DAAs), particularly if they have advanced liver
fibrosis, compensated cirrhosis, severe extra-hepatic com-
plications of HCV, or prior children infected with HCV via
MTCT.
350
• Women with cirrhosis should be counseled about the
increased risks of pregnancy (pre-eclampsia, cesarean sec-
tion, hemorrhage, maternal and neonatal death, preterm
delivery, low birthweight).
• Pregnancy should be managed by a maternal-fetal
medicine provider in conjunction with a hepatologist.
• Historically, treatment consisted of pegylated interferon
(PEG-IFN), ribavirin and protease inhibitors. Ribavirin is
contraindicated in pregnancy due to teratogenicity con-
cerns. Treatment has changed dramatically since 2011 with
the development of DAAs.
• For any genotype, in a treatment-naïve patient with-
out cirrhosis, the preferred therapy is either 8 weeks
of glecaprevir/pibrentasvir or 12 weeks of sofosbuvir/
velpatasvir.
• Treatments are associated with few and mild side
effects (headache, nausea, fatigue, insomnia).
• Ongoing research into HCV treatment (ledipasvir/
sofosbuvir) during pregnancy is promising, as many
women could be cured while receiving prenatal care.
– Until treatment in pregnancy is approved, women
should be referred to a hepatologist in the postpar-
tum treatment for antiviral therapy and long-term
follow-up.
BOX 33.1 RECOMMENDED
WORKUP AND MANAGEMENT FOR
PREGNANT WOMEN WITH HCV
• Initial evaluation
• Hepatitis C quantitative RNA (“viral load”) and
HCV genotype
• Screen for other infections
– HIV, hepatitis A (total Ab) and B (HBsAg
and HBsAb), other sexually transmitted
infections (i.e. gonorrhea, chlamydia,
syphilis).
– Vaccination for hepatitis A and
B is recommended during preg-
nancy if non-immune, as patients
with chronic HCV infection are at
an increased risk of liver failure if
they become infected with other
forms of viral hepatitis
• Liver function assessment
– AST, ALT, total bilirubin, albumin,
platelet count, prothrombin time/INR
– Liver ultrasound to evaluate for cirrhosis
• Consultation with hepatologist
– This can be deferred to postpartum if
HCV-RNA negative
DOI: 10.1201/9781003099062-33
Hepatitis C
– Treatment should be considered post-
partum for those with a detectable viral
load
– Review of risk reducing behaviors
• Consultation with maternal-fetal medicine (ide-
ally preconception, or with initiation of prenatal
care or diagnosis of HCV)
• Antepartum care
• Counseling on genetic screening and/or testing
– If testing is desired, amniocentesis is
preferred
• Third trimester ultrasound for fetal growth
• Intrapartum care
• When possible, avoid prolonged rupture of
membranes
• Avoid use of fetal scalp electrodes
• Cesarean delivery reserved for obstetric indications
• Postpartum care
• Encourage breastfeeding, as long as contraindi-
cations are not present
– Referral to lactation professional, as needed
• Appropriate contraception, with consideration
of other comorbidities
• Vaccination against hepatitis A and B, if non-
immune and not vaccinated during pregnancy
• Hepatology follow-up
– Liver elastography (FibroScan®) for eval-
uation of cirrhosis and staging
– Assessment of HCV RNA level
– In the absence of spontaneous clearance,
treatment should be planned
• Appropriate pediatric follow-up and testing
TABLE 33.1: Risk Factors for Hepatitis C Virus Infection
Risk Factor Odds Ratioa
Injection drug use
Blood transfusion
Sex with partner who injects drugs
Incarceration >3 days
Religious scarification
Stuck or cut with a bloody object
Body piercings
Immunoglobulin injection
History of multiple sexually transmitted infections
HIV infection
Hepatitis B infection
Sexual partner with HIV, HBV, or HCV infection
Men who have sex with men
Intranasal drug use
Unregulated tattooing
Recipient of organ transplants
Unexplained elevated transaminases
History of hemodialysis
Participant in in vitro fertilization programs from
anonymous donors
a Odd ratios from Murphy EL et al. NHLBI Retrovirus Epidemiology Donor Study
(REDS) [31].
351
Diagnosis
Adults
The initial differential diagnosis of acute hepatitis includes
hepatitis A, B, or C virus (HAV, HBV, or HCV), cytomegalovirus
(CMV), Epstein–Barr, varicella (VZV), coxsackie B, herpes (HSV),
rubella, and autoimmune hepatitis. HCV RNA is most often
detected via PCR of a blood sample, but has also been detected
in feces, seminal fluid, saliva, and GI tract [1, 2]. HCV RNA can
be detected at 1–2 weeks post-exposure, and anti-HCV antibod-
ies by 12 weeks post-exposure [1, 2]. Acute HCV is diagnosed
with positive HCV RNA polymerase chain reaction (PCR)
and negative anti-HCV antibody from blood; however, positive
anti-HCV antibodies does not exclude a diagnosis of acute HCV.
If test results within the past 6 months were negative for HCV
RNA and anti-HCV antibody, acute hepatitis is most likely. Most
patients will have a marked elevation in transaminases and some
will also have hyperbilirubinemia.
Chronic HCV infection is confirmed with detectable HCV
RNA for >6 months [3, 4]. Chronic HCV infection often follows
a progressive course over many years and can ultimately result in
cirrhosis, liver failure, HCC, and the need for liver transplantation.
Children
Mother-to-child transmission (MTCT) is most commonly
diagnosed by the presence of anti-HCV antibody in the infant
at or after 18 months of age. Antibody testing should not be per-
formed sooner, due to the potential presence of maternal anti-
bodies in neonatal circulation. HCV RNA PCR testing can be
performed at 2 months of age, if required. If anti-HCV antibody
positive, HCV RNA testing should be completed after age 3 years
to diagnose chronic HCV [5].
According to a retrospective cohort study by Kushner et al., of
194 births in 151 pregnant women with HCV and cirrhosis, only
42% of children were tested for HCV antibodies, and only 21%
of those were tested at 1–2 years of age. These data highlight the
significant room for improvement in the care of not only women
with HCV, but also their offspring [6].
49.6
10.9
Symptoms
6.3 Most (about 75%) patients with HCV infection are asymptom-
2.9 atic or have only mild nonspecific symptoms. Among those who
2.8 have symptoms, the most frequent complaint is fatigue; other
2.1 less common manifestations include nausea, abdominal pain,
2.0 anorexia, fever, myalgias, arthralgias, and weight loss [7]. A
1.6 number of extrahepatic conditions have been associated with
chronic HCV infection [8–10]. (See Figure 33.1.)
Additionally, HCV has a significant impact on quality of life in
adults, as well as diminished cognitive, social and psychological
functioning. Adults with HCV may also suffer from increased rates
of anxiety and depression [11, 12]. HCV has significant impact on
pediatric development including impaired executive function com-
pared to unaffected children, physical and emotional limitations,
and diminished overall health. Parents of children with HCV also
experience significant emotional distress and worry [12, 13].
Natural history
Reports on the natural history of HCV suggest spontaneous
clearance (anti-HCV antibody positive, HCV RNA negative)
rates of 20–50% [14], though recent data suggests prevalence
352 Maternal-Fetal Evidence Based Guidelines

• Symptomatic mixed cryoglobulinemia

Autoimmune Diseases
• Polyarteritis nodosa

• Raynaud phenomenon
Cutaneous Conditions • Purpura
• Porphyria cutanea tarda

• Sicca symptoms
Rhemnatic Symptoms
• Arthralgias

• Sensory neuropathy
Neurologic Symptoms
• Motoro neuropathy

• Membranoproliferative glomerulonephritis
Renal Disease
• Renal insufficiency

• Type II diabetes mellitus

Other
• Depression

FIGURE 33.1 Extrahepatic conditions associated with hepatitis C virus. (See further Refs. [8–10].)

of clearance up to 68.7% [15, 16]. For those who achieve clear-
ance most will do so within 6 months of acute infection [5, 14].
Spontaneous clearance is more common in women, those with
symptomatic disease and hyperbilirubinemia [15, 16].
Chronic infection, which occurs in 50–80% of those
infected, results in chronic inflammation of the liver, which heals
with scar tissue formation or fibrosis, and ultimately cirrhosis in
a subset of patients, although the rate of disease progression is
variable. In those with progressive disease (i.e. cirrhosis or bridg-
ing fibrosis), the incidence of hepatocellular carcinoma (HCC) is
1–4% per year [17]. Risk factors for HCV associated HCC include
high HCV RNA levels, elevated ALT (>45 IU/mL) and genotype
1 [17]. Those who develop cirrhosis are at risk of decompensa-
tion, with development of ascites, jaundice, encephalopathy, and
death; however, many people with compensated cirrhosis remain
stable for years (Figure 33.2). Liver-related mortality in those
with HCV ranges from 1–14%, though these events are likely
underreported [4, 18].
With regard to MTCT, according to a multicenter, prospec-
tive study, rates of spontaneous clearance, asymptomatic chronic
infection, and active chronic infection in children are approxi-
mately 20%, 50%, and 30%, respectively [19].
Epidemiology
Worldwide, it is estimated that chronic HCV affects 71 million
individuals [20]. As of 2016, it is estimated that 2.4 million peo-
ple (1% of the population) in the United States have chronic
HCV, and 4.1 million people (1.7%) are HCV antibody positive
[21]. Rates of HCV have increased in recent years, likely due to
the continued opioid epidemic. There were an estimated 50,300
new U.S. infections in 2018 [21, 22]. The largest increase was seen

Stable chronic
infection
30–60%

Chronic
Slow fibrosis
infection
progression
50–80%
20–33% Decompensation:
Infection with Compensated
HCV cirrhosis HCC, ascites,
Spontaneous (5–25% jaundice, bleeding,
clearance Rapid fibrosis encephalopathy,
chronically
20–50% progression death
infected)
11–25% (4–8%)

FIGURE 33.2 Natural history of hepatitis C. (From Refs. [4, 5, 14, 17, 75, 76].) Abbreviations: HCV, hepatitis C virus; HCC, hepato-
cellular carcinoma.
Hepatitis C
in the 20–39-year age group. An estimated 52% of people who
inject drugs are infected with HCV [23]. Among reproductive
age women, a prevalence of 1–1.6% has been reported [24,
25]. The true prevalence is difficult to ascertain, as populations
including incarcerated and those experiencing homelessness are
not included in the National Health and Nutrition Examination
Survey assessment of disease prevalence. Between 2011 and 2014
in the United States, the percentage of children born to mothers
with HCV increased 68% and there was a 22% increase in detec-
tion in women of childbearing age.
Chronic HCV is one of the most common chronic liver diseases
and a leading cause for liver transplantation. Chronic HCV infection
is usually slowly progressive and may not result in clinically appar-
ent liver disease in many patients. Approximately 5–25% of chroni-
cally infected individuals develop cirrhosis over a 10- to 20-year
period of time [4]. In 2018, HCV was a contributing or underlying
cause of over 15,000 deaths in the United States [26, 27].
Genetics
HCV is a single-stranded RNA virus, with striking genetic het-
erogeneity, including 7 genotypes and 67 subtypes [28]. In the
United States, approximately 75% of infections are caused by
genotype 1 [29]. Current treatments are targeted to specific gen-
otypes and subtypes; however, more recently several pangeno-
typic antivirals have been developed.
Pathogenesis and risk factors
HCV is primarily acquired via infected blood-to-blood con-
tact, but mother-to-child transmission (MTCT, vertical
transmission) can occur [30]. Table 33.1 delineates risk fac-
tors associated with HCV acquisition [31]. In the United States,
the primary risk factor for HCV infection is injection drug use
(IDU) [5]. Although transfusion of blood products used to be a
major cause of transmission in the United States, since the imple-
mentation of blood screening in 1992, the risk has dramatically
decreased and is now less than one case per 2 million units
transfused [27]. Additional risk factors include intranasal drug
use, men who have sex with men (MSM), HIV infection, unregu-
lated tattooing or body piercing, history of incarceration, organ
recipient (especially before 1992), occupational exposure (i.e.
needle stick injury), and chronic hemodialysis [5]. Personal care
items such as razors, toothbrushes, and nail clippers can also
present household risk for HCV infection through infected blood.
Sexual contact is a very uncommon source of HCV infection, with
the exception of HIV positive MSM. Infection with other sexually
transmitted infections (STIs) and sexual behaviors that are more
likely to cause a breach of the mucosal barrier, such as anal receptive
intercourse, may be more likely to transmit HCV [32]. The preva-
lence of HCV infection in monogamous, heterosexual relationships
with an HCV infected partner (HIV negative) is 1–3% [32, 33]. As
with HIV, in vitro fertilization (IVF) with intracytoplasmic sperm
injection (ICSI) after sperm washing can decrease the risk of trans-
mission from an HCV-infected male partner [34, 35].
Mother-to-child transmission
HCV infects an estimated 3.26 million children age 1–19 (0.13%)
worldwide, with a prevalence of 0.05–0.32% in the United States
[36, 37]. Table 33.2 summarizes transmission rates compiled from
77 studies and 383 cases of mother-to-infant transmission cases [19,
38–41]. MTCT rates depend on detectable HCV and co-infection
353
TABLE 33.2: Rate of Vertical Transmission (MTCT) of
Hepatitis C
Rate (%)
Anti-HCV only (RNA negative) 0–3
Viremic (HCV RNA positive) 4–6
HIV positive 19–25
HIV negative 3–6
Anti-HCV and IDU 7-9
Anti-HCV and no IDUa 3-7
Source: Adapted from Refs. [30, 38–41].
a Women with history of IDU, but no use in pregnancy, and women with no history
of IDU.
Abbreviations: MTCT, mother-to-child transmission; HCV, hepatitis C virus; RNA,
ribonucleic acid; IDU, injection drug use.
with human immunodeficiency virus (HIV). With undetect-
able HCV RNA, vertical transmission rarely occurs. The risk
with detectable HCV RNA is approximately 6% if the mother is
HIV-negative. In the setting of co-infection with HIV, the risk is
increased, up to 11% [30]; however, studies on women receiving
combination antiretroviral therapy in the setting of HCV/HIV co-
infection report rates of transmission ranging from 4–9% [42, 43].
In addition to HIV co-infection, risk factors for MTCT include
high HCV viral load, prolonged rupture of membranes (greater
than 6 hours) and use of internal monitoring devices (i.e. uterine
monitors and fetal scalp electrodes) [30, 38]. Correlation between
HCV RNA titers and transmission are unpredictable, though some
studies suggest increased transmission beyond 105 copies/mL [39].
Amniocentesis does not appear to significantly increase the
risk of MTCT [20], but very few studies have addressed this. If
amniocentesis is requested, transplacental needle insertion
should be avoided when possible. There are no data regard-
ing chorionic villus sampling (CVS) and in utero transmission.
Therefore, appropriate counseling should be undertaken if an
HCV-infected woman requests CVS, and the availability of
amniocentesis should be discussed as a potentially less-invasive
and vasodisruptive procedure [44].
There is no association between gestational age and risk of
transmission. Vertical transmission does not correlate with
mode of delivery in non-HIV-infected pregnant women; how-
ever, data are limited to observational studies and randomized
controlled trials have not been identified [19, 45]. Cesarean deliv-
ery should be considered only for obstetrical reasons. Exception
could be given to women co-infected with HIV and HCV, as one
retrospective study on MTCT of HCV showed that this sub-
group of women was 60% less likely to vertically transmit HCV if
delivered via cesarean [46].
Breastfeeding is not a risk factor for MTCT of HCV in non-
HIV infected women [47]. The safety of breastfeeding operates
on the assumption that traumatized, cracked, or bleeding nipples
are not present. Breastfeeding is not recommended in women
with HCV/HIV co-infection [5].
Management
Prevention
There is no HCV vaccine available. Risk factors for HCV
(Table 33.1) should be avoided and risk reduction counseling
should be performed for HCV infected patients. Prevention of
354
complications of liver disease includes avoidance of alcohol and
hepatotoxic medicines (i.e. acetaminophen and certain herbal
remedies) [5]. Obesity has also been associated with increased
progression of liver fibrosis in those with HCV [48]; therefore,
counseling should include an emphasis on maintaining a healthy
diet and regular exercise.
Principles
Effect of pregnancy on hepatitis C
Pregnancy does not affect the clinical course of chronic HCV.
There is an improvement in biochemical markers of liver dam-
age (i.e. ALT) in HCV-positive women during pregnancy, with
a rise postpartum [49, 50]. HCV-RNA levels have been shown
to increase throughout pregnancy and then return to baseline
postpartum [50]. Some studies have shown rates of spontaneous
clearance of up to 25%; therefore, viral load should be assessed in
the postpartum period prior to initiating therapy [51, 52].
Effect of hepatitis C on pregnancy
Chronic active hepatitis in the pregnant woman is associated
with an increased incidence of preterm delivery, fetal growth
restriction, small for gestational age, neonatal need for
assisted ventilation, and neonatal intensive care unit admis-
sion [23–25]; however, data may be confounded by other factors,
such as maternal substance use (i.e. drug, alcohol, tobacco use)
[53–55]. Outcomes are worse for those with cirrhosis and por-
tal hypertension and include increased risks of pre-eclampsia,
preterm delivery, cesarean delivery, low birthweight, and mater-
nal and neonatal death [5, 56].
Pregnant women with HCV are also at an increased risk of
intrahepatic cholestasis of pregnancy (ICP) with an odds ratio
of 20.40 (95% CI, 9.39–44.33, I2 = 55%) compared to women with-
out HCV [57]. Symptoms of ICP should prompt a workup includ-
ing serum bile acids and transaminase levels.
Screening
Previously, screening for HCV in pregnancy was reserved for
those with risk factors for transmission. In 2018, a study by Rose
et al. suggested that risk-based screening might miss a propor-
tion of women with active HCV who should be linked to care, and
that universal screening is cost-effective [58]. Subsequently, the
American Association for the Study of Liver Diseases (AASLD)
and the Infectious Diseases Society of America (IDSA) have rec-
ommended universal screening for HCV in each pregnancy
[5]. Universal screening recommendations, with the exception of
those living in areas with a prevalence of <1%, have since been
endorsed by the U.S. Centers for Disease Control (CDC) and the
U.S. Preventative Services Task Force (USPSTF) [59, 60]. In April
2020, the American College of Obstetricians and Gynecologists
(ACOG) released a practice advisory on the new recommenda-
tions and is reviewing guidance for an updated practice bulletin
[61]. Screening should be completed with HCV-antibody test,
reflexing to HCV RNA PCR.
Workup
Any woman who tests positive for anti-HCV antibody should have
HCV RNA quantitative evaluation (via PCR) performed. An
HCV genotype is also recommended, as treatment is tailored to
the genotype and subtype. She should be screened for co-infection
with HIV (HIV antibody) and hepatitis A and B (hepatitis B sur-
face antigen), as well as other STIs. Patients with chronic HCV
infection are at high risk of liver failure if they are infected with
other forms of viral hepatitis. Screening for immunity to hepatitis
Maternal-Fetal Evidence Based Guidelines
A (hepatitis A total antibody) and hepatitis B (hepatitis B sur-
face antibody), and vaccinating if non-immune, is also recom-
mended. Blood tests to measure liver function include aspartate
aminotransferase (AST), alanine aminotransferase (ALT), bili-
rubin, platelet count and international normalized ratio (INR).
Imaging of the liver to evaluate for cirrhosis can be completed
with ultrasound during pregnancy, or liver elastography precon-
ception or postpartum. Patients with cirrhosis should receive the
pneumococcal vaccination [5]. A hepatology referral is recom-
mended for assessment of disease severity, counseling on risk
reduction behaviors, and treatment.
Preconception and pregnancy counseling
Multidisciplinary care should be initiated prior to pregnancy,
including the hepatologist and maternal-fetal medicine (MFM)
provider (See Box 33.1). This co-management is especially impor-
tant in women with cirrhosis. In women of reproductive age with
HCV, treatment before conception should be strongly consid-
ered to reduce the risk of MTCT (see section “Treatment”). If not
treated prior to pregnancy, the postpartum or interpregnancy
interval is an ideal time to initiate therapy.
Counseling should include a review of the effect of pregnancy
on HCV and vice versa, risk factors known to increase MTCT
(see “Mother-to-Child Transmission”), and reassurance for fac-
tors known not to increase transmission. Counseling on genetic
screening and testing should include education on non-invasive
screening methods (i.e. Sequential Screen, cell free fetal DNA)
and if testing is desired, amniocentesis should be recommended
over CVS. Counseling should also include other possible com-
plications, management, and postpartum follow-up for mother
and baby. Women with cirrhosis should be counseled about the
increased risks of pregnancy (pre-eclampsia, cesarean section,
hemorrhage, maternal and neonatal death, preterm delivery, low
birth weight) [5, 56].
Other disease specific counseling tips include: Avoid sharing
personal care items such as toothbrushes and dental or shaving
equipment, and cover any bleeding wound in order to keep their
blood away from others. Patients should be counseled on cessa-
tion of illicit drugs and alcohol, and be referred to appropriate
treatment programs. Those who continue to inject drugs should
be counseled to avoid reusing or sharing syringes, needles, water,
and cotton or other paraphernalia; to clean the injection site with
a new alcohol swab; and to dispose safely of syringes and needles
after one use. In those not yet immune to hepatitis A or B, vac-
cinations can be given prior to or during pregnancy.
HCV-infected patients should be counseled that the risk of sex-
ual transmission is low and that the infection itself is not a reason
to change sexual practices; however, barrier protection, such as
condoms, can be used to further decrease the risk of transmis-
sion. Safe sex practices such as barrier protection or abstinence
are recommended for those with multiple partners [32].
Treatment
Treatment of the non-pregnant patient
The main goal of treatment for HCV is cure. This is typically
defined as a sustained virologic response (SVR), with unde-
tectable HCV RNA (<25 IU/mL) at 12 weeks after completing
therapy. Cure of HCV leads to a decrease in all-cause mortal-
ity, liver-related mortality, liver complications including HCC, as
well as improving symptoms and mortality rates associated with
extrahepatic manifestations of HCV [29, 30].
Hepatitis C
Guidance from the AASLD, IDSA, and International Antiviral
Society–US (IAS, U.S.) outlines designation of highest priority
for treatment, high priority, and persons at elevated risk of trans-
mitting HCV, in order to guide treatment [62]. While treatment
is recommended for all persons with either acute or chronic
HCV (with the exception of those with a short life expectancy not
expected to be improved by treatment or liver transplantation),
eligibility criteria amongst medical insurance coverage plans
varies widely. The highest priority group includes those with
advanced fibrosis or cirrhosis, organ transplant, and significant
extrahepatic manifestations (essential mixed cryoglobulinemia
with end-organ vasculitis, membranoproliferative glomerulone-
phritis etc.). High priority includes HIV-1 and/or HBV coinfec-
tion, stage 2 fibrosis, type II diabetes mellitus, porphyria cutanea
tarda and other coexisting liver disease. Reproductive age women
with HCV planning childbearing are considered elevated risk of
transmission, along with MSM, IDU, HCV-infected healthcare
workers, hemodialysis patients, and incarcerated persons [62].
Pretreatment assessment (including evaluation for advanced
fibrosis), as well as monitoring during and after therapy, should
occur under the care of a hepatologist.
Historically, treatment regimens for HCV consisted of
pegylated interferon (PEG-IFN), ribavirin, and protease inhibi-
tors. In 2011, the first direct-acting antiviral agents (DAAs) were
introduced (telaprevir and boceprevir) and since then progres-
sive generations of DAAs have proved to be superior with regard
to effectiveness, patient tolerance, and duration of therapy. The
three classes of DAAs include NS3/4A protease inhibitors, NS5B
nucleoside analog polymerase inhibitors, and nonstructural
(NS5A) protein inhibitors [60]. First-line therapy now consists
of a short course (8–12 weeks) of DAAs. For any genotype, in
a treatment-naïve patient without cirrhosis, the preferred ther-
apy is either 8 weeks of glecaprevir/pibrentasvir, or 12 weeks
of sofosbuvir/velpatasvir. If cirrhosis is present, genotypes 1
thru 6 can be treated with glecaprevir/pibentasvir for 8 weeks.
Combination sofosbuvir/velpatasvir for 12 weeks can be used in
genotypes 1, 2, 4, 5, or 6 in this group. Genotype 1, the most com-
mon in the United States, can also be treated with 12 weeks of
ledipasvir/sofosbuvir [5]. Genotype 3 remains a challenging geno-
type, with increased rates of HCC, and current guidance recom-
mends treatment with sofosbuvir, ribavirin, and PEG-IFN for 12
weeks, or sofosbuvir plus ribavirin for 24 weeks [62]. These com-
binations have very few and generally mild side effects includ-
ing headache, nausea, fatigue, and insomnia, and has not been
shown to be associated with an increased risk of serious adverse
events [63–65]. Many therapies and combinations exist, and the
AASLD/IDSA “HCV Guidance: Recommendations for Testing,
Managing, and Treating Hepatitis C” can be referenced for addi-
tional information [5].
Treatment of the pregnant patient
Pregnancy is a unique opportunity to not only cure the mother
of her HCV, but also to prevent her child from becoming
infected, while the mother is established in regular medical
care. Additionally, many women would reportedly be willing to
undergo therapy during pregnancy for the benefit of reducing
MTCT [66].
The safety profile of DAA regimens make them particularly
attractive for potential use in pregnancy. The short duration (12
weeks or less for most patients) is also an attractive duration for use
during the third trimester. Combination ledipasvir/sofosbuvir has
not been shown to cause fetal harm in animal studies. A recent
355
clinical trial on the pharmacokinetics of ledipasvir/sofosbuvir
during pregnancy in women with genotype 1 HCV infection
showed promising results [67]. In this open-label, phase 1 trial,
nine women received a 12-week course of the combination ther-
apy, starting at 23 weeks, with outcomes compared to a historical
reference group (non-pregnant). There was no difference between
groups in the primary outcome of systemic plasma exposure of
ledipasvir and sofosbuvir; however, exposure to the metabolite
of sofosbuvir, GS-331007 (which is renally cleared), was lower in
the pregnant group, likely due to the increased glomerular filtra-
tion rate in pregnancy. The cure rate (HCV RNA undetectable
12 weeks after end of treatment) was 100%, and there were
no adverse maternal or neonatal events related to the treatment
exposure. Though this study was small, it has opened up the pos-
sibility for the future of HCV treatment in pregnancy.
Sufficient information on the safety and efficacy of DAAs in
the pregnant population has not been established, and there-
fore, their use is not yet recommended. Additional research
is ongoing and of extreme importance. One observational pilot
study in India (manuscript not yet peer-reviewed) examined 21
pregnant women treated with ledipasvir/sofosbuvir and found
SVR in all women at 12 weeks post-therapy, no signs of MTCT at
6 months of age, and no congenital malformations [68]. Another
observational study of the course of HCV in pregnancy and treat-
ment with sofosbuvir/velpatasvir postpartum, and after cessation
of breastfeeding, is currently ongoing [69]. If a woman becomes
pregnant while on a DAA, consultation with a hepatologist and
an MFM provider should occur before recommending discon-
tinuation of therapy, to allow discussion of the risks and benefits
of completing treatment.
Historically, before DAAs where available, interferon (IFN)
and ribavirin were used in non-pregnant adults for HCV treat-
ment. IFN alpha has been used in pregnancy for the treatment of
conditions such as essential thrombocythemia or chronic myelo-
cytic leukemia, and is unlikely to cause congenital malformations
or other adverse effects [70]. IFN was combined with ribavirin in
order to obtain SVR. Ribavirin is contraindicated in pregnancy
due to its potential teratogenic effects. IFN and ribavirin should
not be used in pregnancy for treatment of HCV.
In summary, currently, DAAs treatment should start post-
partum in women with HCV, under the direction of a hepa-
tologist previously consulted during pregnancy.
Antepartum testing
Due to the risk of fetal growth restriction associated with HCV in
pregnancy, a third trimester ultrasound for fetal growth should
be considered. In those with cirrhosis or portal hypertension,
as the risk of growth restriction is further increased, consider-
ation could be given to more frequent growth ultrasounds (i.e.
monthly) in the third trimester. Antepartum fetal surveillance
(i.e. non-stress tests) are not indicated for HCV infection alone.
Intrapartum management
When possible, prolonged rupture of membranes and the use
of fetal scalp electrodes should be avoided in labor. In HCV-
positive women not co-infected with HIV, mode of delivery does
not affect vertical transmission, and cesarean delivery should
be reserved for obstetrical indications. In HCV- and HIV-co-
infected women, mode of delivery should be cesarean delivery if
the HIV viral load is ≥1000 [22].
356
Anesthesia
In the setting of stable, chronic HCV with normal baseline INR,
repeat evaluation of coagulation studies are not required prior
to neuraxial anesthesia. With regard to platelet count, if routine
assessment in pregnancy was normal, the decision to obtain
an intrapartum platelet count prior to neuraxial anesthesia is
at the discretion of the anesthesia provider. With acute hepati-
tis or a high likelihood of cirrhosis (coinfection with HCV and
HIV, excessive alcohol consumption, or the combination of con-
genitally acquired HCV and advanced maternal age), coagula-
tion factors should be repeated prior to initiation of neuraxial
anesthesia.
Postpartum management
Breastfeeding
As mentioned previously, breastfeeding should be encouraged
in women with HCV, as long as other contraindications do not
exist (i.e. HIV). Referral to a lactation professional should be
provided to all women, as needed [71].
Contraception
A reliable form of contraception recommended for all patients
to prevent unplanned and undesired pregnancies, and to allow
for adequate inter-pregnancy intervals. Appropriate initiation
of timing depends on the chosen method, medical comorbidi-
ties, and breastfeeding plans. In the absence of comorbid condi-
tions, combined hormonal contraceptives (CHCs) should not be
started within one month after delivery due to the risk of venous
thromboembolism. For women who choose to breastfeed, most
obstetricians recommend delaying initiation of CHCs until
approximately 6 weeks postpartum to allow for the establishment
of breastmilk production; however, these recommendations are
based on limited evidence of fair to poor quality [72].
According to the U.S. Medical Eligibility Criteria for
Contraceptive Use (U.S. MEC), all forms of pharmacologic con-
traception are acceptable in the setting of chronic HCV, as well
as mild, compensated cirrhosis (U.S. MEC category 1); however,
in the setting of acute hepatitis or flare initiation of estrogen
containing contraceptives should be avoided (U.S. MEC cat-
egory 3/4), as potential risks outweigh benefits of use. In cases
of decompensated cirrhosis the copper-containing intrauterine
device (Cu-IUD) is preferred (category 1), while the levonorgestrel
IUD (LNG-IUD) and progestin only contraceptives (i.e. etonoges-
trel implant, depo medroxyprogesterone acetate, progestin-only
pills) are U.S. MEC category 3. In this subgroup of patients, use
of estrogen containing contraception is contraindicated (U.S.
MEC category 4). In women with a history of ICP, non-estrogen
containing contraceptives are preferred (U.S. MEC category 1);
however, CHCs remain an acceptable option (U.S. MEC category
2), with the exception of those women who have experienced cho-
lestasis related to CHC use (U.S. MEC category 3) [73].
The option of sterilization, along with risks and benefits of the
various procedures, should be reviewed with women who have
completed childbearing. It is important to review male steriliza-
tion, via vasectomy, as a safer option, with a lower failure rate
than female sterilization (0.15% in first year), and less cost [74].
Vaccination
If immunization has not occurred antenatally in the non-immune
woman, hepatitis A and B vaccines (or their combination) should
be given postpartum, even if breastfeeding [26].
Maternal-Fetal Evidence Based Guidelines
Long-term follow-up
In the postpartum period, women with HCV should follow up
with a hepatologist and complete an assessment of the HCV
RNA level, and liver elastography (FibroScan®) for evaluation of
cirrhosis and staging. As mentioned previously, some women
may experience spontaneous clearance in the postpartum
period [51, 52]. If spontaneous clearance has not occurred, treat-
ment should be initiated. Timing of treatment is also dependent
on breastfeeding status. In those who chose not to breastfeed,
treatment can be initiated at any time. Currently the DAAs are
not approved for use while breastfeeding, so delaying treat-
ment until the woman and baby have completed breastfeeding
is acceptable.
References
1. Marcellin P. Hepatitis C: the clinical spectrum of the disease. J Hepatol
Suppl 1999;31(1):9–16. [III]
2. Lingala S, Ghany MG. Natural history of hepatitis C. Gastroenterol Clin
North Am 2015;44(4):717–34. [III]
3. Maheshwari A, Ray S, Thuluvath PJ. Acute hepatitis C. Lancet (London)
2008;372(9635):321–32. [III]
4. Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis
2005;9(3):383–98. [III]
5. AASLD/IDSA. HCV Guidance: Recommendations for Testing, Managing,
and Treating Hepatitis C. AASLD/IDSA. 2020. pp. 1–18. Available from:
http://w w w.hcvguidelines.org/full-report/hcv-testing-and-linkage-
care [III]
6. Kushner T, Djerboua M, Terrault N, Flemming J. Low adherence to infant
HCV testing guidelines among pregnant women with HCV cirrhosis.
Hepatology 2020;72(Suppl 1):36A. [II-2]
7. Corey KE, Ross AS, Wurcel A, Schulze zur Wiesch J, Kim AY, Lauer GM,
et al. Outcomes and treatment of acute hepatitis C virus infection in a
United States population. Clin Gastroenterol Hepatol 2006;4(10):1278–82.
[II-3]
8. Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, et al.
Extrahepatic manifestations associated with hepatitis C virus infection.
A prospective multicenter study of 321 patients. The GERMIVIC. Groupe
d’Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur
le Virus de l’Hepatite C. Medicine (Baltimore) 2000;79(1):47–56. [III]
9. Cacoub P, Comarmond C, Domont F, Savey L, Desbois AC, Saadoun D.
Extrahepatic manifestations of chronic hepatitis C virus infection. Ther
Adv Infect Dis 2016;3(1):3–14. [III]
10. Gumber SC, Chopra S. Hepatitis C: a multifaceted disease. Review of extra-
hepatic manifestations. Ann Intern Med 1995;123(8):615–20. [III]
11. Spiegel BMR, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F.
Impact of hepatitis C on health related quality of life: a systematic review
and quantitative assessment. Hepatology 2005;41(4):790–800. [II-1]
12. Rodrigue JR, Balistreri W, Haber B, Jonas MM, Mohan P, Molleston JP, et al.
Impact of hepatitis C virus infection on children and their caregivers: qual-
ity of life, cognitive, and emotional outcomes. J Pediatr Gastroenterol Nutr
2009;48(3):341–7. [II-1]
13. Nydegger A, Srivastava A, Wake M, Smith AL, Hardikar W. Health-related
quality of life in children with hepatitis C acquired in the first year of life. J
Gastroenterol Hepatol 2008;23(2):226–30. [II-2]
14. Kamal SM. Acute hepatitis C: a systematic review. Am J Gastroenterol
2008;103(5):1283–98. [III]
15. Seo S, Silverberg MJ, Hurley LB, Ready J, Saxena V, Witt D, et al. Prevalence
of spontaneous clearance of hepatitis C virus infection doubled from 1998
to 2017. Clin Gastroenterol Hepatol 2020;18(2):511–3. [II-3]
16. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer
A, et al. Acute hepatitis C: High rate of both spontaneous and treatment-
induced viral clearance. Gastroenterology 2003;125(1):80–8. [II-2]
17. Zamor PJ, Russo MW. Impact of hepatitis C virus eradication on hepatocel-
lular carcinoma rates. Clin Liver Dis 2017;10(3):75–8. [III]
18. Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality
among persons in care with hepatitis C virus infection: the chronic hepati-
tis cohort study (CHeCS), 2006–2010. Clin Infect Dis 2014;58(8):1055–61.
[II-2]
19. European Paediatric Hepatitis C Virus Network. Three broad modalities in
the natural history of vertically acquired hepatitis C virus infection. Clin
Infect Dis 2005;41(1):45–51. [II-2]
Hepatitis C
20. Hepatitis C Fact Sheet [Internet]. World Health Organization. 2020.
Available from: https://www.who.int/news-room/fact-sheets/detail/­
hepatitis-c [III]
21. Hofmeister MG, Rosenthal EM, Barker LK, Rosenberg ES, Barranco MA,
Hall EW, et al. Estimating prevalence of hepatitis C virus infection in the
United States, 2013-2016. Hepatology 2019;69(3):1020–31. [II-3]
22. Centers for Disease Control and Prevention. Acute Hepatitis C, 2018 2018.
Available from: https://www.cdc.gov/hepatitis/statistics/2018surveillance/
HepC.htm#Figure3.1 [III]
23. Degenhardt L, Peacock A, Colledge S, Leung J, Grebely J, Vickerman P, et al.
Global prevalence of injecting drug use and sociodemographic character-
istics and prevalence of HIV, HBV, and HCV in people who inject drugs: a
multistage systematic review. Lancet Glob Heal 2017;5(12):e1192–207. [III]
24. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter
MJ. The prevalence of hepatitis C virus infection in the United States, 1999
through 2002. Ann Intern Med 2006;144(10):705–14. [II-3]
25. Prasad MR, Honegger JR. Hepatitis C virus in pregnancy. Am J Perinatol
2013;30(2):149–59. [III]
26. Centers for Disease Control and Prevention. Viral hepatitis surveillance—
United States, 2018. Viral Hepatitis. 2018. Available from: https://www.cdc.
gov/hepatitis/statistics/2018surveillance/HepA.htm [III]
27. Centers for Disease Control and Prevention. Viral hepatitis, Q&As for
health professionals. 2020. Available from: https://www.cdc.gov/hepatitis/
hcv/hcvfaq.htm#ref03 [III]
28. Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, et al.
Expanded classification of hepatitis C virus into 7 genotypes and 67 sub-
types: updated criteria and genotype assignment web resource. Hepatology
2014;59(1):318–27. [III]
29. Gordon SC, Trudeau S, Li J, Zhou Y, Rupp LB, Nerenz DR, et al. Race, age,
and geography impact hepatitis C genotype distribution in the United
States. J Clin Gastroenterol 2019;53(1):40–50. [III]
30. Benova L, Mohamoud YA, Calvert C, Abu-Raddad LJ. Vertical transmission
of hepatitis C virus: systematic review and meta-analysis. Clin Infect Dis
2014;59(6):765–73. [I]
31. Murphy EL, Bryzman SM, Glynn SA, Ameti DI, Thomson RA, Williams
AE, et al. Risk factors for hepatitis C virus infection in United States blood
donors. NHLBI Retrovirus Epidemiology Donor Study (REDS). Hepatology
2000;31(3):756–62. [II-2]
32. Terrault NA. Sexual activity as a risk factor for hepatitis C. Hepatology
2002;36(5 Suppl 1):S99–105. Available from: http://www.ncbi.nlm.nih.gov/
pubmed/12407582 [II-3]
33. Terrault NA, Dodge JL, Murphy EL, Tavis JE, Kiss A, Levin TR, et al. Sexual
transmission of hepatitis C virus among monogamous heterosexual cou-
ples: The HCV partners study. Hepatology 2013;57(3):881–9. [II-3]
34. Pasquier C, Daudin M, Righi L, Berges L, Thauvin L, Berrebi A,
et al. Serodiscordant couples wishing to have children. AIDS 2000;14(14):
2093–9. [II-2]
35. Mencaglia L, Falcone P, Lentini GM, Consigli S, Pisoni M, Lofiego V,
et al. ICSI for treatment of human immunodeficiency virus and hepatitis
C virus-serodiscordant couples with infected male partner. Hum Reprod
2005;20(8):2242–6. [II-2]
36. Schmelzer J, Dugan E, Blach S, Coleman S, Cai Z, DePaola M, et al. Global
prevalence of hepatitis C virus in children in 2018: a modelling study.
Lancet Gastroenterol Hepatol 2020;5(4):374–92. [II-2]
37. El-Shabrawi MH, Kamal NM. Burden of pediatric hepatitis C. World J
Gastroenterol 2013;19(44):7880–8. [III]
38. Mast EE, Hwang L, Seto DSY, Nolte FS, Nainan O V., Wurtzel H,
et al. Risk factors for perinatal transmission of hepatitis C virus (HCV)
and the natural history of HCV infection acquired in infancy. J Infect Dis
2005;192(11):1880–9. [II-2]
39. Yeung L. Mother-to-infant transmission of hepatitis C virus. Hepatology
2001;34(2):223–9. [III]
40. European Paediatric Hepatitis C Virus Network. A significant sex—but not
elective cesarean section—effect on mother-to-child transmission of hepa-
titis C virus infection. J Infect Dis 2005;192(11):1872–9. [II-1]
41. Airoldi J, Berghella V. Hepatitis C and pregnancy. Obstet Gynecol Surv
2006;61(10):666–72. [III]
42. Checa Cabot CA, Stoszek SK, Quarleri J, Losso MH, Ivalo S, Peixoto MF,
et al. Mother-to-child transmission of hepatitis C virus (HCV) among HIV/
HCV-coinfected women. J Pediatric Infect Dis Soc 2013;2(2):126–35. [II-2]
43. Snijdewind IJ., Smit C, Schutten M, Nellen FJB, Kroon FP, Reiss P, et al.
Low mother-to-child-transmission rate of hepatitis C virus in cART treated
HIV-1 infected mothers. J Clin Virol 2015;68:11–5. [II-2]
44. Hughes BL, Page CM, Kuller JA. Hepatitis C in pregnancy: screening, treat-
ment, and management. Am J Obstet Gynecol 2017;217(5):B2–12. [III]
357
45. McIntyre PG, Tosh K, McGuire W. Caesarean section versus vaginal
delivery for preventing mother to infant hepatitis C virus transmission.
Cochrane Database Syst Rev 2006;(4). [III]
46. European Paediatric Hepatitis C Virus Network. Effects of mode of deliv-
ery and infant feeding on the risk of mother-to-child transmission of
hepatitis C virus. European Paediatric Hepatitis C Virus Network. BJOG
2001;108(4):371–7. [II-2]
47. Recommendations for prevention and control of hepatitis C virus (HCV)
infection and HCV-related chronic disease. Centers for Disease Control
and Prevention. MMWR Recomm Rep 1998;47(RR-19):1–39 [III]
48. Ortiz V, Berenguer M, Rayón JM, Carrasco D, Berenguer J. Contribution
of obesity to hepatitis C-related fibrosis progression. Am J Gastroenterol
2002;97(9):2408–14. [II-2]
49. Conte D, Fraquelli M, Prati D, Colucci A, Minola E. Prevalence and clini-
cal course of chronic hepatitis C virus (HCV) infection and rate of HCV
vertical transmission in a cohort of 15,250 pregnant women. Hepatology
2000;31(3):751–5. [II-2]
50. Gervais A, Bacq Y, Bernuau J, Martinot M, Auperin A, Boyer N, et al.
Decrease in serum ALT and increase in serum HCV RNA during pregnancy
in women with chronic hepatitis C. J Hepatol 2000;32(2):293–9. [II-2]
51. Hashem M, Jhaveri R, Saleh DA, Sharaf SA, El-Mougy F, Abdelsalam L, et al.
Spontaneous viral load decline and subsequent clearance of chronic hepati-
tis C virus in postpartum women correlates with favorable interleukin-28B
gene allele. Clin Infect Dis 2017;65(6):999–1005. [II-2]
52. Hattori Y, Orito E, Ohno T, Sugauchi F, Suzuki S, Sugiura M, et al. Loss
of hepatitis C virus RNA after parturition in female patients with chronic
HCV infection. J Med Virol 2003;71(2):205–11. [II-2]
53. Pergam SA, Wang CC, Gardella CM, Sandison TG, Phipps WT, Hawes SE.
Pregnancy complications associated with hepatitis C: data from a 2003–
2005 Washington state birth cohort. Am J Obstet Gynecol 2008;199(1):38.
e1–38.e9. [II-2]
54. Huang Q-T, Hang L-L, Zhong M, Gao Y-F, Luo M-L, Yu Y-H. Maternal HCV
infection is associated with intrauterine fetal growth disturbance: a meta-
analysis of observational studies. Medicine (Baltimore) 2016;95(35):e4777.
[II-2]
55. Connell LE, Salihu HM, Salemi JL, August EM, Weldeselasse H, Mbah AK.
Maternal hepatitis B and hepatitis C carrier status and perinatal outcomes.
Liver Int 2011;31(8):1163–70. [III]
56. Puljic A, Salati J, Doss A, Caughey AB. Outcomes of pregnancies compli-
cated by liver cirrhosis, portal hypertension, or esophageal varices. J Matern
Fetal Neonatal Med 2016;29(3):506–9. [II-2]
57. Wijarnpreecha K, Thongprayoon C, Sanguankeo A, Upala S, Ungprasert
P, Cheungpasitporn W. Hepatitis C infection and intrahepatic cholesta-
sis of pregnancy: a systematic review and meta-analysis. Clin Res Hepatol
Gastroenterol 2017;41(1):39–45. [I]
58. Rose M, Myers J, Evans J, Prince A, Espinosa A. Hepatitis C virus risk-based
vs. universal screening among pregnant women: implementation and cost-
effectiveness analysis. Hepatology 2018;68(S1):1–183. [II-1]
59. US Preventive Services Task Force, Owens DK, Davidson KW, Krist AH,
Barry MJ, Cabana M, et al. Screening for hepatitis C virus infection in ado-
lescents and adults: US Preventive Services Task Force Recommendation
Statement. JAMA 2020; Available from: http://www.ncbi.nlm.nih.gov/
pubmed/32119076 [III]
60. Schillie S, Wester C, Osborne M, Wesolowski L, Ryerson AB. CDC recom-
mendations for hepatitis C screening among adults—United States, 2020.
MMWR Recommend Rep. 2020;69(2):1. [III]
61. American College of Obstetricians & Gynecologists. Screening for hepati-
tis C virus infection. Practice Advisory. 2020. Available from: https://www.
acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/04/
screening-for-hepatitis-c-virus-infection [III]
62. Terrault N, Monto A, Stinchon MR, Rusie E, Moreo K. New therapies,
evidence, and guidance in hepatitis C management: expert practices
and insights from an educational symposium at the AMCP 27th Annual
Meeting Expo. J Manag care Spec Pharm 2015;21(9):S1–14. [III]
63. Medeiros T, Salviato C de M, do Rosário NF, Saraiva G do N, Esberard EBC,
Almeida JR, et al. Adverse effects of direct acting antiviral-based regimens
in chronic hepatitis C patients: a Brazilian experience. Int J Clin Pharm
2017;39(6):1304–11. [II-3]
64. Werner CR, Schwarz JM, Egetemeyr DP, Beck R, Malek NP, Lauer UM,
et al. Second-generation direct-acting-antiviral hepatitis C virus treat-
ment: Efficacy, safety, and predictors of SVR12. World J Gastroenterol
2016;22(35):8050–9. [II-1]
65. McGlynn EA, Adams JL, Kramer J, Sahota AK, Silverberg MJ, Shenkman E,
et al. Assessing the safety of direct-acting antiviral agents for hepatitis C.
JAMA Netw open 2019;2(6):e194765. [II-2]
358
66. Kushner T, Cohen J, Tien PC, Terrault NA. Evaluating women’s prefer-
ences for hepatitis C treatment during pregnancy. Hepatol Commun
2018;2(11):1306–10. [II-2]
67. Chappell CA, Scarsi KK, Kirby BJ, Suri V, Gaggar A, Bogen DL, et al. Ledipasvir
plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1
pharmacokinetic study. The Lancet Microbe 2020;1(5):e200–8. [I]
68. Yattoo GN, Dar G, Kaushik S, Gulzar GM, Sodhi JS, Laway M,
et al. Treatment of chronic hepatitis C in pregnancy: an observational
pilot study. SSRN Electron J 2019. Available from: https://www.ssrn.com/
abstract=3424200 [II-1]
69. Transmission of chronic hepatitis C in pregnancy. Clinicaltrials.gov. 2020.
Available from: https://clinicaltrials.gov/ct2/show/NCT03570112 [Clinical
trial in process]
70. Yazdani Brojeni P, Matok I, Garcia Bournissen F, Koren G. A systematic review of
the fetal safety of interferon alpha. Reprod Toxicol 2012;33(3):265–8. [III]
71. American College of Obstetricians and Gynecologists’ Committee on
Obstetric Practice, Breastfeeding Expert Work Group. Committee Opinion
Maternal-Fetal Evidence Based Guidelines
No. 658: Optimizing support for breastfeeding as part of obstetric practice.
Obstet Gynecol 2016;127(2):e86–92. [III]
72. Tepper NK, Phillips SJ, Kapp N, Gaffield ME, Curtis KM. Combined hor-
monal contraceptive use among breastfeeding women: an updated system-
atic review. Contraception 2016;94(3):262–74. [III]
73. Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB,
et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR
Recommend Rep. 2016;65(3):1–103. [III]
74. American College of Obstetricians and Gynecologists’ Committee on
Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 208: benefits
and risks of sterilization. Obstet Gynecol 2019;133(3):e194–207. [III]
75. Ryder SD, Irving WL, Jones DA, Neal KR, Underwood JC, Trent Hepatitis C
Study Group. Progression of hepatic fibrosis in patients with hepatitis C: a
prospective repeat liver biopsy study. Gut 2004;53(3):451–5. [II-2]
76. Richardson MM, Powell EE, Barrie HD, Clouston AD, Purdie DM, Jonsson
JR. A combination of genetic polymorphisms increases the risk of progres-
sive disease in chronic hepatitis C. J Med Genet 2005;42(7):e45. [II-2]
34
HIV
Jenani Jayakumaran and William R. Short
Key points
• Identification of HIV infection during pregnancy is
essential for the prevention of perinatal transmission.
Therefore, universal screening is recommended in the
first trimester or at entry into prenatal care. An opt-out
approach has been shown to increase acceptance rates for
HIV testing in pregnant women and is the recommended
approach to universal prenatal screening.
• Screening should be repeated preferably before 36 weeks
in cases of high-risk behavior, high-prevalence area, or
in a patient who previously declined testing.
• Rapid testing is recommended for previously untested
women presenting in labor, or those expected to be deliv-
ered for maternal or fetal indications before results of con-
ventional testing can be obtained. If a rapid HIV test result
is positive, antiretroviral prophylaxis should be offered
without waiting for the results of the confirmatory conven-
tional tests.
• The goal of HIV treatment in pregnancy is to prevent ver-
tical transmission primarily by reducing maternal viral
load to <1000 copies/mL or below the limit of detection
of the assay.
• Rate of perinatal transmission is directly correlated to
maternal viral load, but other factors also appear to
play a role. Perinatal transmission can occur at any HIV
RNA level, including in women with an undetectable
viral load.
• All women with HIV should be offered combination anti-
retroviral therapy (ART) regardless of clinical or immu-
nological diagnosis to maximally suppress viral replication,
reduce the risk of perinatal transmission, and minimize
the risk of development of resistant virus. See chart later in
this chapter for current preferred regimen and doses.
• Plasma HIV-1 RNA levels should be monitored serially, at
least initially, and every trimester, to assess both effec-
tiveness of ART and options for best mode of delivery.
• Women with a viral load >1000 copies/mL should be
counseled regarding the benefit of planned cesarean
delivery at 38 weeks with zidovudine infusion prior to
reduce the risk of transmission.
• With effective antiretroviral therapy leading to undetect-
able viral load (see Table 34.1), planned cesarean delivery
for viral load ≥1000 copies/mL, and formula feeding, the
risk of perinatal transmission is reduced to <2%.
Historical notes
The first cases of what would soon thereafter be called AIDS
were reported in homosexual males on June 5, 1981. In 1994,
the PACTG-076 regimen of antepartum and intrapartum AZT
administered to the mother and then to the newborn for six
DOI: 10.1201/9781003099062-34
weeks resulted in a reduction of maternal-infant transmission of
HIV-1 from 25.5% to 8% [1].
Diagnosis
Diagnosis is made when a screening antigen/antibody immu-
noassay that detects HIV-1 and HIV-2 antibodies and HIV-1 p24
antigen is positive. This may be repeated depending on regulatory
authorities and is followed by a supplemental antibody immuno-
assay that differentiate HIV-1 and HIV-2 antibodies. Specimens
that are reactive on initial antigen/antibody immunoassay but
non-reactive or indeterminate on the antibody differentiation
immunoassay should be tested with an HIV-1 nucleic acid test
(NAT). A positive test indicated acute HIV-1 infection. A nega-
tive HIV-1 NAT in combination with a non-reactive or indeter-
minate HIV-1 antibody differentiation immunoassay indicates a
false positive on the initial immunoassay. A negative HIV-1 NAT
and repeatedly non-reactive or indeterminate HIV-2 immunoas-
say should have repeat testing in 2–4 weeks or testing with a dif-
ferent supplemental HIV-2 test [2].
Rapid testing may be used in the outpatient setting but is more
commonly used for any woman who arrives to a labor and delivery
with undocumented HIV status during the current pregnancy.
A positive rapid test should be followed by the earlier described
testing algorithm starting with the antigen/antibody immunoas-
say. If a rapid test is positive for a patient in labor, antiretroviral
prophylaxis should be started while waiting for the confirmatory
test results [3]. The sensitivity and specificity of each of the avail-
able rapid testing assays ranges from 95% to 100% [4], while the
positive predictive value depends on the prevalence of disease in
the population. In a population with low prevalence of disease,
the positive predictive value is low while the false-positive rate
is high. For example, with a prevalence of disease of ~1% in the
population, the positive predictive value of the test may be as low
as 60%.
Epidemiology
The total number of cases of HIV/AIDS in adolescents and adults
worldwide is currently estimated to be 36.2 million, with approxi-
mately 50% of those cases occurring in women [5]. There is great
variation in distribution and prevalence from region to region as
shown in Table 34.2. While the number of new HIV infections
continues to decline gradually, almost 50% occur in eastern and
southern Africa. HIV infection in this area is mostly related to
heterosexual transmission within serodifferent marital or cohab-
itating relationships [6]. In the United States, an estimated 1.2
million people are living with HIV, 19% of new HIV/AIDS cases
are among women [7]. Black and Hispanic women have been dis-
proportionately affected, accounting for 75% of the diagnoses of
HIV infections among females in 2018. Heterosexual contact is
the major mode of transmission among females accounting for
359
360 Maternal-Fetal Evidence Based Guidelines

TABLE 34.1: Possible Preferred Regimens prophylactic treatment in women who are aware of their status
presents an additional risk for perinatal transmission.
Preferred dual- Tenofovir disoproxil fumarate/emtricitabine
nucleoside reverse Tenofovir disoproxil fumarate/lamivudine
transcriptase inhibitors Abacavir/lamivudine Pathophysiology
(NRTI)-these used in
combination with HIV primarily infects T lymphocytes that express the CD4 anti-
either INSTI or PI (not gen, resulting in a progressive loss of these cells and impairment
used alone) * all dosed of cellular immunity as well as humoral immunity. When CD4
once daily lymphocytes are sufficiently depleted there is the progression to
AIDS, characterized by the development of opportunistic infec-
Preferred integrase 1. Abacavir/lamivudine/dolutegravir once daily
tions and malignancies.
inhibitors (INSTI)
or

2. One of the preferred dual-NRTI plus either Classification

Dolutegravir 50 mg daily The CDC classification is based on clinical and laboratory evalu-
or ations (Table 34.3). There are five stages: 0, 1, 2, 3, or unknown.
Raltegravir 400 mg twice daily If a patient has a negative HIV test within 6 months of the first
Preferred protease One of the preferred dual-NRTI plus either HIV infection diagnosis, they are stage 0 and remain stage 0 until
inhibitors (PI) Darunavir 600 mg/ritonavir 100 mg twice daily 6 months after diagnosis. The patient has AIDS once a stage-3
Or defining opportunistic illness has been diagnosed regardless of
Atazanavir 300 mg/ritonavir 100 mg daily CD4 count. If none of the stages apply, the stage is unknown [10].

Risk factors
91% in Black/African American, 87% in Hispanic/Latino, and 65% Risk of perinatal transmission is closely related to viral load (VL)
in White females in the United States [7]. Worldwide, heterosexual at the time of delivery [11–13]. Other risk factors include low
contact is also the predominant mode of transmission in women, CD4+ T-lymphocyte count, lack of ARV therapy, biologic pheno-
followed by intravenous drug use with sharing of needles [8]. type of the virus, substance abuse, prolonged duration of mem-
More than 90% of pediatric HIV/AIDS cases result from brane rupture, HCV coinfection, sexually transmitted infections
perinatal transmission/breastfeeding. In developed countries, (STIs), preterm birth, and chorioamnionitis [14–17]. Risk factors
continued perinatal transmission can be attributed to a lack of for maternal infection include unprotected sexual contact with
awareness among pregnant women about their HIV status, the an person without HIV, sharing drug needles or syringes, sexual
increase in HIV infection among women of childbearing age, contact with someone whose HIV status is unknown, transfu-
absent or delayed prenatal care especially in women using illicit sions of contaminated blood or blood components. The presence
drugs, acute or primary infection in late pregnancy or in women of ulcerating or non-ulcerating STIs including syphilis, genital
who are breastfeeding, poor adherence to prescribed antiretro- herpes, chlamydial infection, gonorrhea, or bacterial vaginosis
viral (ARV) regimens, and lack of full implementation of routine increases susceptibility to HIV infection during sex with infected
universal prenatal HIV counseling and testing [5]. Perinatal diag- partners. There is no evidence that HIV is spread through sweat,
nosis of HIV has declined in the United States by 41% from 2012 tears, urine, feces, or by insect bites such as mosquito bites.
to 2016; however, 1814 children under the age of 13 are living with
perinatal HIV [9]. In undeveloped countries, the lack of access to
Complications
Maternal
TABLE 34.2: Regional HIV and AIDS Statistics and Features Increased risks of chorioamnionitis, postpartum endometritis,
in 2018 and wound infection have been reported. The risk of peripartum
Adults and Adults and Adult and infection is inversely proportional to the CD4+ count at the time
Children Children Child of delivery.
Living Newly Infected Deaths Due
Region with HIV with HIV to AIDS
TABLE 34.3: HIV Infection Stage Based on Age-Specific
Eastern and southern Africa 20.6 million 800,000 310,000
CD4+ T-Lymphocyte Count or CD4+ T-Lymphocyte
Western and central Africa 5.0 million 280,000 160,000
Percentage of Total Lymphocytes
Middle East and north Africa 240,000 20,000 8400
Asia and the Pacific 5.9 million 310,000 200,000 Age on Date of CD4+ T-Lymphocyte Test
Latin America 1.9 million 100,000 35,000 <1 year 1–5 years ≥6 years
Caribbean 340,000 16,000 6700
Stage Cells/µL % Cells/µL % Cells/µL %
Eastern Europe and central 1.7 million 150,000 38,000
Asia 1 ≥1500 ≥34 ≥1000 ≥30 ≥500 ≥26
Western and central Europe 2.2 million 68,000 13,000 2 750–1499 26–33 500–999 22–29 200–499 14–25
and North America 3 <750 <26 <500 <22 <200 <14
Source: Adapted from Ref. [5]. Source: From Ref. [10].
HIV 361

Fetal TABLE 34.4: Initial Antiretroviral Therapy in Pregnancy

Possible increased risk of preterm delivery if on a protease inhibi- Drug Regimen Notes
tor (PI) containing regimen, but no increased risk of FGR, still-
birth, or low Apgar scores [18–20]. Preferred Abacavir + 1. Once daily dosing
dual NRTI lamivudine 2. Abacavir should not be used in
backbones patients who test positive for
Pregnancy considerations HLA-B*5701 due to risk of
hypersensitivity reaction
Effect of pregnancy on disease
Tenofovir disoproxil 1. Once-daily dosing
Pregnancy has no clear effect on HIV progression. A transient
fumarate + 2. Tenofovir disoproxil fumarate has
but clinically insignificant decrease in the CD4+ T-lymphocyte
emtricitabine potential renal toxicity—caution
count has been described; however recent studies have shown no
Tenofovir disoproxil in patients with renal insufficiency
difference [21].
fumarate +
Effect of disease on pregnancy lamivudine
Perinatal transmission can occur antepartum (25–40%), intrapar-
tum (60–75%), or postpartum with breastfeeding (14%). Perinatal Preferred Dolutegravir 1. Once daily dosing
transmission appears closely related to VL. There is a strong corre- INSTI 2. Lower resistance rate
lation between high maternal VL at delivery and risk of transmission, regimens 3. Rapidly decreases viral load
but transmission has occurred at all levels of VL [22]. Transmission Raltegravir 1. Twice daily dosing
rates are about 1.2% on HAART, 10.4% on AZT monotherapy, and 2. Rapidly decreases viral load
25% on no antiretrovirals (ARVs) [12]. There is also an increased risk 3. Do not take within 2 hours of
of pre-eclampsia in HIV-infected patients [23]. prenatal vitamin to maximize
absorption
Pregnancy management Preferred PI Atazanavir/ritonavir 1. Once daily dosing
regimens 2. Associated with maternal
Screening hyperbilirubinemia, recommend
All states in the United States allow opt-out approach HIV test- neonatal bilirubin monitoring
ing during pregnancy although specific regulations may vary 3. Cannot be administered with PPIs
from state to state. Given the effectiveness of intervention, stan- Darunavir/ritonavir 1. Twice daily dosing
dard serologic testing with counseling is recommended for
Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; INSTI, integrase
all pregnant women at the initiation of prenatal care with a strand transferase inhibitor; PI, protease inhibitor.
screening antigen/antibody immunoassay, which if positive is
followed by a confirmatory supplemental antibody immunoassay
that differentiate HIV-1 and HIV-2 antibodies. Screening should
be repeated before 36 weeks in the case of high-risk behavior, on ARV therapy. Preconception counseling should include the
high-prevalence area, incarcerated, have signs or symptoms following [24]:
consistent with acute HIV or previously declined testing [3].
Rapid testing is recommended for previously untested women • Initiate or modify ARV therapy, avoiding potentially tera-
presenting in labor, or those expected to be delivered for maternal togenic agents and working towards maximal viral sup-
or fetal indications before results of conventional testing can be pression before attempting conception
obtained. If a rapid HIV test result is positive, ARV prophylaxis • Opportunistic infection prophylaxis as indicated by CD4
should be offered without waiting for the results of the confirma- count
tory conventional tests [3]. • Appropriate immunizations
• Optimize maternal nutritional status, initiating folic acid
Principles supplementation
The goal of HIV therapy is to achieve a HIV RNA level <1000 • Screen for and treat sexually transmitted infections (STIs)
copies/mL or below the limit of detection of the assay. The risk of • Screen for psychological and substance abuse disorders.
perinatal transmission can be <2% with effective ARV therapy • Encourage elimination of alcohol, tobacco and other drugs.
(Table 34.4), planned cesarean delivery (CD) as appropriate, and Provide appropriate counseling and treatment as needed
formula feeding. ARV therapy is recommended in pregnancy • Advise how to optimize the chance of conception while
predominantly to decrease maternal VL and thereby decrease the minimizing the risk of sexual transmission using pre-
risk of perinatal transmission and to improve maternal health. exposure prophylaxis (PrEP)
Combination ARV therapy is indicated in pregnancy regard- • Provide information about contraception to decrease like-
less of clinical or immunological status. When combination lihood of unplanned pregnancy
ARV therapy is not available, or the patient chooses not to under-
take this therapy, several short-course peripartum drug regimens
have been shown to significantly decrease the risk of vertical Prenatal Care
transmission to ~10%. Care in pregnancy should be multidisciplinary, with close col-
laboration between the obstetrician, maternal-fetal medicine,
Preconception counseling pediatric, and infectious disease specialists. A specialist with
Many HIV-positive women enter pregnancy aware of their diag- experience in the treatment of pregnant women with HIV infec-
nosis, and more than half of these women enter the first trimester tion should be involved in the prenatal care.
362
Initial prenatal visit history
• Complete medical and obstetric/gynecologic history at
first prenatal visit.
• Document history of prior or current ARV use.
• Evaluation for symptoms of AIDS should include fever,
night sweats, weight loss, a new persistent dry cough, diar-
rhea, refractory vaginal candidiasis, oral candidiasis, and
new outbreaks of herpes.
• Assess need for antimicrobial prophylaxis against oppor-
tunistic infections such as pneumocystis pneumonia (PCP)
if CD4 count <200 cells/µL
Physical examination: Complete physical exam at initial visit
including ultrasound confirmation of gestational age. During
subsequent visits, screen for HIV disease progression. With CD4
<200 cells/mm3, specifically evaluate for thrush, HSV, lymphade-
nopathy, or a rash.
Labs: Baseline (and follow-up) laboratory investigations should
include the following:
• Hepatitis A antibody.
• Patients with no evidence of immunity or infection
may be vaccinated in pregnancy after discussing risks
versus benefit [25].
• Hepatitis B surface antigen and antibody, hepatitis B core
antibody.
• Patients with no evidence of immunity or infection
should begin hepatitis B immunization series [25].
• Hepatitis C antibody.
• CBC with differential, liver, and renal profile to be repeated
each trimester to monitor for ART toxicity.
• VDRL/RPR, gonorrhea, and chlamydia testing.
• Tuberculosis screening.
• Treatment of asymptomatic latent TB infection in
pregnancy remains controversial [26].
• Toxoplasmosis [27].
• Early diabetes screening of patients maintained on prote-
ase inhibitors (PI) as there is an association with glucose
intolerance.
• Pap smear (most abnormal Pap smears require colposcopy).
• CD4 cell count (should be monitored at the initial visit and
at least every trimester).
• Pregnancy is associated with a decline in CD4 count
likely due to increased plasma volume. CD4 cell per-
centage remains unchanged [28].
• Plasma HIV RNA levels (should be monitored at the initial
visit, 2–4 weeks after initiating or changing therapy, monthly
until HIV RNA levels are undetectable, and then at 34–36
weeks’ gestation to make a decision regarding mode of delivery).
• The VL should decrease by 1–2 logs within 4 weeks of
starting therapy.
• Resistance testing should be performed prior to starting
ART, in women who enter pregnancy with a HIV RNA
level above the threshold for resistance testing on therapy,
in women with suboptimal viral suppression after initia-
tion of therapy, and in women with a persistently detect-
able plasma VL on therapy which previously suppressed
the virus to below the assay level of detection. Genotyping
is preferable to phenotyping because it is less expensive, it
has a faster turnaround time, and a greater sensitivity for
detecting mixtures of wild-type and resistant virus.
• HLA B-5701 testing if abacavir use is anticipated [29].
Maternal-Fetal Evidence Based Guidelines
Counseling
• Discuss risk of transmission and factors that modify those
risks.
• Discuss risk and benefits of ART for both the patient and
the fetus.
• Educate on safe sex practices with condoms and partner
PrEP.
Antiretroviral therapy
All pregnant women with HIV should receive ARV for treat-
ment of maternal HIV as well as prevent perinatal transmis-
sion (Table 34.4). The risk of perinatal transmission declines
with ART given at all time points (antepartum, intrapartum, and
postnatally to the neonate) and with decreasing levels of mater-
nal HIV RNA. For these reasons the importance of adherence to
ARV drug regimens should be highlighted during counseling.
Treatment protocols must be individualized for each patient.
Resistance to therapeutic agents and regimen failure are com-
monly related to patient noncompliance. Therefore, regimens are
tailored to maximize compliance. Patients with detectable virus
should have drug resistance testing but ART should be initiated
prior to the availability of those results [24].
Specific ARV treatments preferred for use in pregnancy in treat-
ment naïve women are outlined in Table 34.2. The preferred initial
regimens have clinical trial data that have demonstrated efficacy
and durability with acceptable toxicity and pregnancy-specific
pharmacokinetic data to guide dosing. These three drug treat-
ments include a dual nucleoside reverse transcriptase inhibitor
(NRTI) combination with either a ritonavir-boosted prote-
ase inhibitor (PI) or an integrase strand transferase inhibitor
(INSTI). Zidovudine monotherapy and two-drug ARV regimens
are not recommended for use in pregnant women [30]. Women
already on fully suppressive ART regiments when pregnancy
occurs should continue those regimens unless they are not rec-
ommended in adults or there are concerns about safety or efficacy
in pregnancy. Pharmacokinetic changes in pregnancy may lead to
lower plasma levels of drugs which may require increased doses,
boosting or more frequent viral load monitoring [24].
At the time of this publication, dolutegravir (DTG) exposure
around conception has been associated with increased signal of
infant neural tube defects in a study conducted in Botswana and
the Panel on Treatment of Pregnant Women with HIV infection
and Prevention of Perinatal Transmission recommends DTG as a
preferred drug for pregnant women irrespective of trimester and
an alternative drug for women who are trying to conceive [24].
The study has continued and with additional exposures, the sig-
nal has continued to decline.
Medications/combinations to avoid
Cobicistat is not recommended for use in pregnancy as cobicistat
has been shown to reduce other drug levels in the second and
third trimester.
Monitor for side effects [18, 29, 31]
Nucleoside reverse transcriptase inhibitor—AZT: Indications of
toxicity that require interrupting or stopping AZT include hemo-
globin <8 g/dL, absolute neutrophil count <750 cells/mm3, AST
or ALT >5 times the upper limit of normal. Potential toxicities
that may affect the neonate must be considered. Animal data have
noted an association between AZT use and squamous tumors in
rats in later life. NRTI use has rarely been linked to mitochondrial
toxicity in neonates.
HIV 363

Protease inhibitor—hyperglycemia: New-onset diabetes melli-
tus or exacerbation of existing diabetes mellitus, hyperglycemia,
and diabetic ketoacidosis have been reported in patients taking
PIs. However, a recent meta-analysis has shown no significant
association between HIV-positivity and GDM [32]. Pregnant
women taking PIs should undergo the same routine diabetes
screening at 24–28 weeks although some experts recommend
early screening [29]. Amprenavir solutions should be avoided
because of potential propylene glycol toxicity.
Nucleoside analogue drugs—mitochondrial toxicity and clini-
cal disorders: Clinical disorders include neuropathy, cardiomyop-
athy, myopathy, pancreatitis, hepatic steatosis, and lactic acidosis
which could be confused with HELLP syndrome or acute fatty
liver of pregnancy. Monitor liver enzymes and electrolytes in the
third trimester. Fatalities due to lactic acidosis during pregnancy
or in the early postpartum period have been reported in women
on ART regimens that included the combination of d4T and ddI.
Non-nucleoside reverse transcriptase inhibitor—nevirapine—
rash and hepatotoxicity: The risk is higher in women especially if
CD4>250 cells/mm3. Women entering pregnancy on an effective
nevirapine (NVP)-containing regimen may continue.
NVP: Pregnant women on NVP should have transaminase levels
monitored especially in the first 18 weeks of treatment. If the patient
is symptomatic with even mildly elevated transaminase levels, or
asymptomatic with severely elevated levels, NVP should be stopped
and avoided in the future. Efavirenz—animal teratology studies
demonstrated increased incidence of neural tube defects.
Prophylaxis for opportunistic infections
See Table 34.5.
Immunizations
Although HIV infection is primarily a disease of cell-mediated
immunity, humoral immunity is also impaired in HIV-positive
individuals. Serologic response to vaccination may be subopti-
mal, especially in advanced disease. Live virus vaccines have his-
torically been withheld from HIV-positive individuals because
of the risk of contracting the disease from the vaccine. Vaccines
should be administered early in the course of HIV infection if
possible to increase the likelihood of adequate responses and to
minimize the risk of disseminated infection from live vaccines in
immunocompromised patients.
All patients should receive the following vaccines prior to or
during pregnancy [25]:
• Pneumococcal
• Hepatitis A

TABLE 34.5: Prophylaxis for Opportunistic Infections

Infection Indication First-Line Tx Alternate Tx
Pneumocystis • CD4 count <200 Trimethoprim-sulfamethoxazole TMP-SMZ one DS tablet 3 times/week
jiroveci • CD4 count between 200 and 250 when (TMP-SMZ) one DS tablet Dapsone 50 mg bid or 100 mg daily
pneumoniaa frequent monitoring is not possible daily Dapsone 50 mg daily with pyrimethamine 50 mg
• CD4 % <14 TMP-SMZ one SS tablet daily + leucovorin 25 mg weekly
Dapsone 200 mg with pyrimethamine 75 mg +
leucovorin 25 mg weekly
Atovaquone 1500 mg daily
Aerosolized pentamidine 300 mg monthly
Toxoplasmic CD4 < 100 cells/mL and seropositive for Trimethoprim-sulfamethoxazole TMP-SMZ one DS tablet 3×/week
encephalitisb Toxoplasma gondii IgG (TMP-SMZ) one DS tablet TMP-SMZ one SS tablet daily
daily Dapsone 50 mg po daily + leucovorin 25 mg po
weekly and pyrimethamine 50 mg weekly
Dapsone 200 mg po + leucovorin 25 mg po
weekly and pyrimethamine 75 mg weekly
Atovaquone 1500 mg daily with or without
pyrimethamine 25 mg + leucovorin 10 mg
Disseminated Primary prophylaxis not recommended in
Mycobacterium pregnant women and adolescents who are
avium complex taking ART
Mycobacterium PPD ≥5 mm INH 300 mg po + pyridoxine Rifapentine po + INH 900 mg po + pyridoxine
tuberculosis OR 50 mg po daily for 9 months 50 mg po weekly for 12 weeks (only for pts
Prior positive PPD without adequate treatment receiving raltegravir based regimens)
OR
Contact with person with active TB regardless
of PPD status
Varicella zoster Varicella nonimmune and exposed to Varicella Zoster immune
virus chickenpox or shingles globulin—5 vials (1.25 μL each)
within 48–96 hours of exposure
Source: Adapted from Ref. [29].
a Primary and secondary prophylaxis should be discontinued after sustained response to HAART with a CD4 count >200 cells/pL for >6 months.

b Discontinue primary prophylaxis after sustained response to HAART with CD4 count >200 cells/pL for >6 months. Discontinue secondary prophylaxis when initial therapy

completed and asymptomatic with sustained CD4 count >200 cells/pL for >6 months.
Abbreviations: DS, double strength; SS, single strength; po, orally; TB, tuberculosis; ART, antiretroviral therapy; INH, isoniazide.
364
• Hepatitis B
• Influenza (annually)
• Tetanus and diphtheria (during every pregnancy, prefer-
ably during the third trimester)
• Inactivated polio
• Meningococcal
Patients who are rubella or varicella nonimmune and have a
CD4 count >200 should be offered MMR or varicella vaccination
respectively in the postpartum period [33, 34].
If risk of exposure to yellow fever is high and CD4 count is
>200 cells/µL, yellow fever vaccine may be administered; how-
ever, serologic response may be as low as 35% [35].
BCG vaccine should not be administered to HIV-infected
women or their newborns—even if the risk of acquiring TB is high.
Disseminated BCG has been reported after immunization [36].
Aneuploidy screening
There is limited evidence on the effect of HIV infection on prena-
tal aneuploidy screening. Currently, serum screening appears not
affected sufficiently to alter its accuracy. Routine counseling should
occur regarding noninvasive prenatal aneuploidy screening [37].
Antepartum testing
Ultrasound evaluation should be performed for the usual obstet-
ric indications including confirmation of gestational age and
assessing fetal anatomy [38]. Invasive procedures such as amnio-
centesis, chorionic villus sampling, and cordocentesis indicated
for diagnostic or therapeutic purposes may place the fetus at
increased risk of transmission of the HIV virus, and appropri-
ate counseling with review of indication for these interventions
is recommended. Among women on HAART, no perinatal trans-
missions have been reported after amniocentesis, but a small
risk of transmission cannot be ruled out [39]. If an amniocentesis
is planned, it should be performed after initiation of an effec-
tive combination ART regimen and when the VL is nondetect-
able avoiding traversing the placenta.
Preterm premature rupture of membranes
The risks of prematurity-related morbidity/mortality must be
balanced against the risk of vertical transmission with pro-
longed rupture of membranes. If preterm premature rupture of
membranes (PPROM) occurs prior to 34 weeks, expectant man-
agement with administration of corticosteroids for fetal lung
maturity and antibiotics for latency is recommended. Perinatal
transmission is not related to the duration of rupture of mem-
branes prior to delivery [40]. At a gestational age ≥34 weeks the
patient should be delivered, and mode of delivery will be depen-
dent on viral load. Consultation with a neonatologist should be
sought if considering delivery prior to 34 weeks without the ben-
efit of steroids as prognosis is dependent on resources available
for care of the preterm infant [14, 17].
Delivery
Maintain universal body fluid precautions for all deliveries. Inform
pediatrician of mother’s status. Bulb suction baby at delivery and
wash off maternal secretions as soon as possible after birth.
Maternal-Fetal Evidence Based Guidelines
Use the most recent VL level to counsel regarding mode of
delivery. Risk of perinatal transmission with persistently unde-
tectable VL on ARV therapy is <2% regardless of mode of delivery.
Honor the woman’s decision regarding mode of delivery. Women
with a VL >1000 copies/mL should be counseled regarding
the potential benefit of scheduled CD at 38 weeks to reduce
the risk of transmission [24]. Continue HAART therapy as usual
and initiate AZT infusion for 3 hours prior to CD and continue
until cord is clamped. Women with a low CD4 count may be
at increased risk of complications after CD. All women should
receive prophylactic antibiotics about 30 minutes before incision
to reduce the risk of postpartum infection [41].
Women with a recent VL <1000 copies/mL can be counseled
that trial of labor and vaginal delivery does not significantly
increase the very low (<2%) risk of perinatal transmission.
Prolonged membrane rupture is not a risk factor for perinatal
transmission [42, 43].
Intrapartum care
Induction of labor should be reserved for obstetric indications.
Admit in early labor and augment labor to expedite delivery.
Continue the oral HAART regimen; administer intravenous
AZT in labor with loading and maintenance dosing continuously
until the umbilical cord is clamped in all patients with viral load
>1000 copies/mL. AZT may be considered for women with HIV
RNA between 50–999 copies/mL but there is inadequate data and
the decision should be made on a case-by-case basis. AZT is not
required for patients’ who have been adherent to their ART regi-
ment and HIV RNA is less than 50 copies/mL during late preg-
nancy or near delivery [24].
Delay amniotomy; however, it is not contraindicated and may
be used to augment labor later in the active phase. Avoid inva-
sive fetal monitoring, intrauterine pressure catheter (IUPC), fetal
scalp electrode (FSE), fetal blood sampling (FBS), episiotomy, for-
ceps, or vacuum delivery [44, 45].
Breastfeeding
Women with HIV who have access to an adequate supply of infant
formula or other suitable source of nutrition should not breastfeed
[24]. If access to an alternate nutrition source is not sufficient to
completely replace breastfeeding, then exclusive breastfeeding is
preferable to alternating breastfeeding/formula-feeding regimens.
Any woman considering breastfeeding should be aware of her HIV
status. While women with HIV on ART in high income countries
have decreased postnatal transmission, this risk increases when
ART is stopped [46–49]. Furthermore, the frequency of monitor-
ing the mother and infant in these situations remains unclear [50].
However, in resource limited settings, mothers on ART should
breastfeed for 12–24 months [51]. A decision not to breastfeed may
raise issues regarding confidentiality of a mother’s HIV diagnosis
and requires sensitivity and supportive interventions [52, 53].
Maternal postpartum care
It is crucial to establish ongoing primary care for HIV. Long-term
planning is essential to ensure that the woman does not fall out of
the health care system. Rubella and varicella vaccines should be
administered postpartum to those women with CD4 count > 200
[33, 34]. Following delivery, the patient should continue ART and
HIV
any plans for modifying treatment should be made in consulta-
tion with her and her HIV care provider.
Family planning is critical to the prevention of perinatal
transmission. If long-acting reversible contraception is desired,
this should be placed prior to hospital discharge or during the
postpartum visit. Condom use should be strongly encouraged.
Monitor for gynecological manifestations associated with disease
progression.
Follow-up of infants
Even in high resource countries, there continues to be perinatal
transmission [54].The baby should be bathed soon after delivery
to remove potentially infectious maternal secretions. Baseline
CBC followed by AZT prophylaxis and referral to an HIV special-
ist are recommended. HIV diagnostic testing to establish or rule
out HIV infection as early as possible is suggested. Initiate PCP
prophylaxis at 4–6 weeks (until there are two consecutive nega-
tive HIV results). Long-term follow-up of HIV and ARV exposed
infants is important [55, 56].
Diagnosis of HIV infection in the infant
Establishing the diagnosis of HIV infection in the neonate is com-
plicated by the presence of transplacentally acquired maternal
antibodies, which makes serologic testing unreliable. The mean
time to clear maternal antibodies is 10.3 months, but it can take
up to 18 months [57].
For this reason, virologic tests such as NATs, HIV DNA PCR
and related RNA qualitative or quantitative assays should be
used. HIV virologic testing should be performed at a minimum
age of 14–21 days, 1–2 months, and 4–6 months. Some experts
also test at birth especially if there is poor control in pregnancy.
HIV may be presumptively excluded with two or more negative
tests with one at ≥14 days and another at ≥1 month of age. Many
experts confirm HIV-negative status with an HIV antibody test
at 12–18 months [58].
References
1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant
transmission of human immunodeficiency virus type 1 with zidovudine
treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group.
N Engl J Med 1994;331(18):1173–80. [I]
2. 2018 Quick reference guide: Recommended laboratory HIV testing
algorithm for serum or plasma specimens. https://stacks.cdc.gov/view/
cdc/50872 [III]
3. ACOG Committee Opinion No. 752: Prenatal and perinatal human immu-
nodeficiency virus testing. Obstet Gynecol 2018;132(3):e138–e142. [III]
4. Hurt CB, Nelson JAE, Hightow-Weidman LB, Miller WC. Selecting an
HIV test: a narrative review for clinicians and researchers. Sex Transm Dis
2017;44(12):739–46. [III]
5. Nations U. UN AIDS Data 2019. 2019. Accessed April 21, 2020. https://www.
unaids.org/sites/default/files/media_asset/2019-UNAIDS-data_en.pdf [III]
6. Dunkle KL, Stephenson R, Karita E, et al. New heterosexually trans-
mitted HIV infections in married or cohabiting couples in urban
Zambia and Rwanda: an analysis of survey and clinical data. Lancet
2008;371(9631):2183–91. [II-2]
7. CDC. HIV Surveillance Report, 2018 (Preliminary). Vol. Volume 30.
November 2019. Accessed April 21, 2020. http://www.cdc.gov/hiv/library/
reports/hiv-surveillance.html [III]
8. Beyrer C. HIV epidemiology update and transmission factors: risks and risk
contexts–16th International AIDS Conference epidemiology plenary. Clin
Infect Dis 2007;44(7):981–7. doi:10.1086/512371. [III]
9. CDC. Preventing Perinatal HIV transmission Accessed April 21, 2020,
https://www.cdc.gov/hiv/group/gender/pregnantwomen/index.html [III]
365
10. Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI.
Revised surveillance case definition for HIV infection—United States, 2014.
MMWR: Recommend Rep 2014;63(3):1–10. [III]
11. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral
strategies for the treatment of pregnant HIV-1-infected women and pre-
vention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr
2002;29(5):484–94. [III]
12. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human
immunodeficiency virus type 1 RNA and the risk of perinatal trans-
mission. Women and Infants Transmission Study Group. N Engl J Med
1999;341(6):394–402. [II-2]
13. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal trans-
mission of human immunodeficiency virus type 1 in women treated with
zidovudine. N Engl J Med 1999;341(6):385–93. [II-2]
14. International Perinatal HIV Group. Duration of ruptured membranes and
vertical transmission of HIV-1: a meta-analysis from 15 prospective cohort
studies. AIDS 2001;15(3):357–68. [II-2]
15. Chi BH, Mudenda V, Levy J, Sinkala M, Goldenberg RL, Stringer JS. Acute
and chronic chorioamnionitis and the risk of perinatal human immunodefi-
ciency virus-1 transmission. Am J Obstet Gynecol 2006;194(1):174–81. [II-1]
16. Minkoff H, Burns DN, Landesman S, et al. The relationship of the duration
of ruptured membranes to vertical transmission of human immunodefi-
ciency virus. Am J Obstet Gynecol 1995;173(2):585–9. [II-2]
17. Landesman SH, Kalish LA, Burns DN, et al. Obstetrical factors and the
transmission of human immunodeficiency virus type 1 from mother
to child. The Women and Infants Transmission Study. N Engl J Med
1996;334(25):1617–23. [II-2]
18. Tuomala RE, Shapiro DE, Mofenson LM, et al. Antiretroviral therapy
during pregnancy and the risk of an adverse outcome. N Engl J Med
2002;346(24):1863–70. [II-2]
19. Cotter AM, Garcia AG, Duthely ML, Luke B, O’Sullivan MJ. Is antiretroviral
therapy during pregnancy associated with an increased risk of preterm deliv-
ery, low birth weight, or stillbirth? J Infect Dis 2006;193(9):1195–201. [II-2]
20. Combination antiretroviral therapy and duration of pregnancy. AIDS
2000;14(18):2913–20. [II-2]
21. Wall KM, Rida W, Haddad LB, et al. Pregnancy and HIV disease progres-
sion in an early infection cohort from five African countries. Epidemiology
2017;28(2):224–32. [II-2]
22. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human
immunodeficiency virus type 1 by pregnant women with RNA virus loads
<1000 copies/ml. J Infect Dis 2001;183(4):539–45. [II-2]
23. Sansone M, Sarno L, Saccone G, et al. Risk of pre-eclampsia in human
immunodeficiency virus-infected pregnant women. Obstet Gynecol
2016;127(6):1027–32. [II-2]
24. Panel on Treatment of Pregnant Women with HIV Infection and Prevention
of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs
in Transmission in the United States. 2020. Accessed April 22, 2020. https://
files.aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf [III]
25. ACOG Committee Opinion No. 741: Maternal immunization. Obstet
Gynecol 2018;131(6):e214–e217. [III]
26. Targeted tuberculin testing and treatment of latent tuberculosis infection.
American Thoracic Society. MMWR Recommend Rep 2000;49(Rr-6):1–51. [III]
27. Practice bulletin no. 151: Cytomegalovirus, parvovirus B19, varicella zoster,
and toxoplasmosis in pregnancy. Obstet Gynecol 2015;125(6):1510–25. [III]
28. Tuomala RE, Kalish LA, Zorilla C, et al. Changes in total, CD4+, and CD8+
lymphocytes during pregnancy and 1 year postpartum in human immu-
nodeficiency virus-infected women. The Women and Infants Transmission
Study. Obstet Gynecol 1997;89(6):967–74. [II-2]
29. Mofenson LM. U.S. Public Health Service Task Force recommendations
for use of antiretroviral drugs in pregnant HIV-1-infected women for
maternal health and interventions to reduce perinatal HIV-1 transmission
in the United States. MMWR Recommend Rep 2002;51(RR-18):1–38; quiz
CE1-4. [III]
30. Fowler MG, Qin M, Fiscus SA, et al. Benefits and risks of antiretroviral ther-
apy for perinatal HIV prevention. N Engl J Med 2016;375(18):1726–37. [I]
31. Senise JF, Castelo A, Martínez M. Current treatment strategies, complica-
tions and considerations for the use of HIV antiretroviral therapy during
pregnancy. AIDS Rev 2011;13(4):198–213. [III]
32. Soepnel LM, Norris SA, Schrier VJ, et al. The association between HIV, anti-
retroviral therapy, and gestational diabetes mellitus. Aids 2017;31(1):113–
25. [II-2]
33. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS. Prevention of measles,
rubella, congenital rubella syndrome, and mumps, 2013: summary recom-
mendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recommend Rep 2013;62(RR-04):1–34. [III]
366
34. Marin M, Güris D, Chaves SS, Schmid S, Seward JF. Prevention of varicella:
recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recommend Rep 2007;56(RR-4):1–40. [III]
35. Staples JE, Gershman M, Fischer M. Yellow fever vaccine: recommenda-
tions of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recommend Rep 2010;59(RR-7):1–27. [III]
36. O’Brien KL, Ruff AJ, Louis MA, et al. Bacillus Calmette-Guerin complica-
tions in children born to HIV-1-infected women with a review of the litera-
ture. Pediatrics 1995;95(3):414–8. [III]
37. LaVigne KA, Seligman NS, Berghella V. Offering aneuploidy screening to
HIV-positive women: routine counselling or not? BJOG 2011;118(7):775–8.
[III]
38. Practice Bulletin No. 175: Ultrasound in pregnancy. Obstet Gynecol
2016;128(6):e241–e256. [III]
39. Mandelbrot L, Jasseron C, Ekoukou D, et al. Amniocentesis and mother-to-
child human immunodeficiency virus transmission in the Agence Nationale
de Recherches sur le SIDA et les Hépatites Virales French Perinatal Cohort.
Am J Obstet Gynecol 2009;200(2):160.e1–9. [II-2]
40. Alvarez JR, Bardeguez A, Iffy L, Apuzzio JJ. Preterm premature rupture of
membranes in pregnancies complicated by human immunodeficiency virus
infection: a single center’s five-year experience. J Mat Fed Neonatal Med
2007 January 1;20(12):853–7. [II-2]
41. ACOG Practice Bulletin No. 199: Use of prophylactic antibiotics in labor
and delivery. Obstet Gynecol 2018;132(3):e103–e119. [III]
42. Cotter AM, Brookfield KF, Duthely LM, Gonzalez Quintero VH, Potter JE,
O’Sullivan MJ. Duration of membrane rupture and risk of perinatal trans-
mission of HIV-1 in the era of combination antiretroviral therapy. Am J
Obstet Gynecol 2012;207(6):482.e1–5. [II-2]
43. Peters H, Byrne L, De Ruiter A, et al. Duration of ruptured membranes and
mother-to-child HIV transmission: a prospective population-based sur-
veillance study. BJOG 2016;123(6):975–81. doi:10.1111/1471-0528.13442.
[II-2]
44. Mandelbrot L, Mayaux MJ, Bongain A, et al. Obstetric factors and mother-
to-child transmission of human immunodeficiency virus type 1: the French
perinatal cohorts. SEROGEST French Pediatric HIV Infection Study Group.
Am J Obstet Gynecol 1996;175(3 Pt 1):661–7. [II-2]
45. ACOG Committee Opinion No. 751: Labor and delivery management of
women with human immunodeficiency virus infection. Obstet Gynecol
2018;132(3):e131–e137. [III]
46. Bispo S, Chikhungu L, Rollins N, Siegfried N, Newell ML. Postnatal HIV
transmission in breastfed infants of HIV-infected women on ART: a sys-
tematic review and meta-analysis. J Int AIDS Soc 2017;20(1):21251. [II-2]
Maternal-Fetal Evidence Based Guidelines
47. Gamell A. Is breastfeeding for HIV-positive mothers now recommendable?
Swiss Med Wkly 2018;148:w14655. [III]
48. Kahlert C, Aebi-Popp K, Bernasconi E, et al. Is breastfeeding an equipoise
option in effectively treated HIV-infected mothers in a high-income set-
ting? Swiss Med Wkly 2018;148:w14648. [III]
49. White AB, Mirjahangir JF, Horvath H, Anglemyer A, Read JS. Antiretroviral
interventions for preventing breast milk transmission of HIV. Cochrane
Database Syst Rev 2014;(10):Cd011323. [I]
50. Waitt C, Low N, Van de Perre P, Lyons F, Loutfy M, Aebi-Popp K. Does
U=U for breastfeeding mothers and infants? Breastfeeding by mothers on
effective treatment for HIV infection in high-income settings. Lancet HIV
2018;5(9):e531–e536. [III]
51. World Health Organization. WHO Guideline: Updates on HIV and Infant
Feeding: The Duration of Breastfeeding, and Support from Health Services
to Improve Feeding Practices Among Mothers Living with HIV. 2016.
52. Dunn DT, Newell ML, Ades AE, Peckham CS. Risk of human immu-
nodeficiency virus type 1 transmission through breastfeeding. Lancet
1992;340(8819):585–8. [II-2]
53. Tess BH, Rodrigues LC, Newell ML, Dunn DT, Lago TD. Infant feeding and
risk of mother-to-child transmission of HIV-1 in São Paulo State, Brazil.
São Paulo Collaborative Study for Vertical Transmission of HIV-1. J Acquir
Immune Defic Syndr Hum Retrovirol 1998;19(2):189–94. [II-2]
54. Taylor AW, Nesheim SR, Zhang X, et al. Estimated perinatal HIV infec-
tion among infants born in the United States, 2002–2013. JAMA Pediatr
2017;171(5):435–42. [II-2]
55. Siberry GK. Preventing and managing HIV infection in infants, children,
and adolescents in the United States. Pediatrics in Review 2014;35(7):268–
86. [III]
56. Stringer J. Turning the page on perinatal human immunodeficiency virus.
Obstet Gynecol 2017;130(3):495–96. [III]
57. Louisirirotchanakul S, Kanoksinsombat C, Likanonsakul S, Sunthornkachit
R, Supanit I, Wasi C. Patterns of anti-HIV IgG3, IgA and p24Ag in peri-
natally HIV-1 infected infants. Asian Pac J Allergy Immunol 2002;20(2):
99–104. [II-3]
58. Schneider E, Whitmore S, Glynn KM, Dominguez K, Mitsch A, McKenna
MT. Revised surveillance case definitions for HIV infection among adults,
adolescents, and children aged <18 months and for HIV infection and AIDS
among children aged 18 months to <13 years–United States, 2008. MMWR
Recommend Rep 2008;57(RR-10):1–12. [III]
35
GONORRHEA
A. Marie O’Neill
Key points
• Gonorrhea has been associated with an increased risk of
spontaneous abortion, preterm birth, early rupture of
fetal membranes, chorioamnionitis, and perinatal mortal-
ity, as well as neonatal conjunctivitis leading to blindness,
increased HIV transmission, and postpartum infection.
• Prevention strategies shown to be effective include use of
condoms, screening high-risk populations, early diag-
nosis and treatment, and partner notification and treat-
ment without clinical assessment.
• There is insufficient evidence to recommend screening of
low-risk pregnant women.
• Pregnant women at high risk for gonorrhea are those of
age <25 years, with prior sexually transmitted infec-
tion (STI), having multiple sexual partners, having a
partner with a past history of any STIs, sex work, drug
use, or inconsistent condom use. These women should be
screened in pregnancy for gonorrhea.
• Definitive diagnosis requires isolation by culture or posi-
tive nucleic acid amplification test.
• Because of the potential for concomitant infection, testing
for Chlamydia trachomatis, syphilis, HIV, and hepatitis
B is recommended.
• First-line treatment for gonorrhea in pregnancy in the
United States and most of Western Europe is ceftriaxone
250 mg IM plus a single dose of azithromycin 1 g orally.
Due to increasing drug resistance single-agent therapy is
no longer considered adequate.
• Patients presenting with preterm premature rupture of
membranes and having active gonorrheal infection can be
managed expectantly as long as prompt treatment for gon-
orrhea is instituted.
• The emergence of multi-drug resistant organisms is
causing a worldwide crisis in the treatment of gonorrhea
and of all STIs. The prevalence of multi-drug resistant gon-
orrhea is greatest in low and middle income countries, but
is increasing in all countries. Overuse and inappropriate
use of antibiotics in healthcare and farming is a major and
preventable contributor to the emergence of drug resistant
organisms. Responsible use of antibiotics must become a
priority for all healthcare professionals.
• If test of cure is positive, susceptibility testing of isolate
prior to retreating is recommended.
• Suspected treatment failure should be reported to the
health department promptly. Consult an infectious dis-
ease specialist or health department for testing and treat-
ment recommendations in all cases of suspected treatment
failure.
• In the United States, the Gonococcal Isolate Surveillance
Program (GISP) monitors antimicrobial susceptibilities of
N. gonorrhoeae strains obtained from urethral specimens,
DOI: 10.1201/9781003099062-35
and establishes evidence-based therapies. An enhanced
program, eGISP, developed in 2017, has added isolates
obtained from pharyngeal and anal sites to its surveillance
protocol. https://www.cdc.gov/std/gisp/
• In Europe the Euro-GASP (Gonococcal Antimicrobial
Surveillance Programme) monitors Neisseria gonorrhoeae
susceptibility with participation of all member states
https://www.ecdc.europa.eu/en/about-us/partnerships-
and-networks/disease-and-laboratory-networks/euro-
gasp. And the World Health Organization (WHO) GASP
network is a collaborative worldwide network of regional
and subregional reference laboratories dedicated to
monitoring gonococcal antimicrobial resistance world-
wide https://www.who.int/reproductivehealth/topics/rtis/
gasp_network/en/.
Epidemiology/Incidence
Worldwide, the World Health Organization’s (WHO) most
recent estimate reports that there were approximately 86.9 mil-
lion new cases of gonorrhea in 2016. The incidence in people
aged 15–49 years is approximately 26/1000 in men and 20/1000
in women [1]. The highest incidences of gonorrhea and its com-
plications occur in developing countries. As a result of a national
gonorrhea control program implemented in the United States in
1970s, the national rate of gonorrheal infection decreased >75%
in the following three decades with a 40-year low being reported
in 2009. In 2018, there were 583,405 cases of gonorrhea reported
to the Centers for Disease Control (CDC), which represents
an increase of 82.6% since 2009, and a 5% increase from 2017.
Approximately 58,000 of these infections occurred in pregnant
women. The CDC estimated that fewer than half of all infec-
tions are reported, and the true rate is estimated to be over one
million cases annually [2]. The incidence is substantially lower
in all countries of Western Europe than in the United States, but
high and rising rates have been documented in Eastern Europe.
In the United States, gonorrhea disproportionately affects African
Americans with the reported rate of infection in this population
being 6.9 times greater than that in Whites; however, this dispar-
ity is decreasing as a result of significantly lower increase in infec-
tion rate among Blacks. From 2014–2018, the rate of gonorrhea
increased in all races with 119.5% increase among multiracial per-
sons, 99.4% among Asians, 90.3% among Native Hawaiians/Other
Pacific Islanders, 89.1% among Whites, 66% among American
Indians/Alaska natives, and 38.8% among Blacks [2, 3]. Due to a
wide variation in antenatal STI screening practices data on preva-
lence rates of curable STIs in pregnancy in various global regions
is limited. Available data on mean prevalence of gonorrhea in
pregnant women in low- and middle-income countries reports
rates of 4.6% in southern Africa, 2.3% in east Africa, 2.8% in
Asia, and 0.3% in Latin America [4].
367
368
Etiology
Neisseria gonorrhoeae is a gram-negative diplococcus that pri-
marily infects non-ciliated, columnar or cuboidal epithelium of
the endocervix, urethra, rectum, or pharynx. Gonococci are obli-
gate human pathogens and can survive only briefly outside of the
human reservoir.
Pathophysiology/Transmission
Neisseria gonorrhoeae is easily transmitted during oral, vaginal,
or anal sex. The transmission rate from male to female during
vaginal intercourse is approximately 50% per contact, rising to
90% after three exposures [5, 6]. The incubation period for N.
gonorrhoeae is on average 2–7 days, but may vary between 1 and
14 days. Vertical transmission to the infant occurs in 30–47%
cases if cervical infection is present at the time of delivery.
The eye is the most common site of neonatal infection, but dis-
seminated gonococcal infection or gonococcal arthritis may also
occur in the newborn [7, 8]. The vast majority of vertical trans-
mission occurs during vaginal delivery; however, transmission
has been reported after cesarean delivery in patients with rup-
tured membranes.
Symptoms
The clinical manifestations of gonorrhea are unchanged in preg-
nant women, except that pelvic inflammatory disease (PID) and
perihepatitis are uncommon after the first trimester. Cervical
infection is asymptomatic in up to 80% of women [9]. When
symptoms are present they include a purulent or mucopurulent
cervical exudate, edema, easily induced cervical or endocervi-
cal bleeding. Urethral infection is present in 70–90% of women
who have gonococcal cervicitis—most will present with dysuria
[9, 10]. Neisseria gonorrhoeae does not cause vaginitis, however
coinfection with bacterial vaginosis, trichomonas, or C. tracho-
matis is common and often causes abnormal vaginal discharge.
Pharyngeal infection is typically asymptomatic, but may cause
exudative pharyngitis and cervical lymphadenopathy. This occurs
in 10–20% of women with cervical gonorrhea [11, 12]. Rectal
infection is typically asymptomatic, but may cause anal pruritus,
mucopurulent discharge, and sometimes pain, tenesmus, and
bleeding. This occurs in about 40% of women with cervical gon-
orrhea [9]. Disseminated gonococcal infection occurs in 0.5–3%
of infected individuals, and usually causes septic arthritis accom-
panied by a rash of hemorrhagic papules and pustules [13]. There
are conflicting reports as to whether pregnancy is a risk factor for
disseminated infection; however, a recent publication reports an
incidence of 0.04–0.09% in pregnancy [14].
Complications
• Gonorrhea has been associated with an increased risk of
spontaneous abortion, preterm birth, early rupture of
fetal membranes, chorioamnionitis, and perinatal mor-
tality, It is not clear if these complications are a direct
result of gonococcal infection, or if infection is a marker
for other high-risk factors [15–18].
• Vertical transmission to the infant can cause conjunctivi-
tis, which if left untreated may result in blindness. Prior
to routine prophylaxis of all infants at the time of birth,
approximately 25% of congenital blindness in the United
Maternal-Fetal Evidence Based Guidelines
States was caused by gonorrheal conjunctivitis, and it
remains a major cause of congenital blindness in underde-
veloped countries [7, 8].
• Epidemiologic and biologic studies provide strong evidence
that gonococcal infections facilitate the transmission of
HIV infection which has major implications for the preg-
nancy [18–20].
• Women with active cervical infection at the time of deliv-
ery are at increased risk for postpartum infection [15, 17].
Management
Prevention
Condoms, when used correctly and consistently, provide a high
degree of protection from gonorrheal infection, as well as from
other STIs [21]. Other important practices for prevention of gon-
orrhea are screening to identify asymptomatic cases in high-
risk populations, early diagnosis and treatment, and partner
notification and treatment. Several recent randomized trials
reported a reduction in the rate of reinfection with an expe-
dited approach to partner therapy (EPT) whereby partners
are treated without a clinical assessment. In this approach, the
patient delivers either medication or prescriptions to their partner
[22–25]. The legal status of such an approach varies in the United
States with some states prohibiting EPT. Legal status should be
verified prior to providing EPT. Another complicating factor in
providing EPT is the most recent recommendation of combina-
tion intramuscular and oral medications as first-line treatment
for uncomplicated gonorrhea in the United States. Evaluation
of all sex partners from the previous 60 days and treatment
with the recommended regimen (ceftriaxone 250 mg IM plus
a single dose of azithromycin 1 g orally) is the best course of
action. However, if this is not possible, EPT with oral cefixime
400 mg and azithromycin 1gram should be considered, as not
treating partners is significantly more harmful than is the use of
oral EPT for gonorrhea [24, 25].
Screening (Table 35.1)
There is no evidence that screening low-risk pregnant women
is beneficial. Screening pregnant women at high risk for gonor-
rhea may prevent other complications associated with gonococ-
cal infection during pregnancy. Risk factors include age <25,
prior STI, multiple sexual partners, having a partner with a
past history of any STI, sex work, drug use, or inconsistent
condom use. Because N. gonorrhoeae can cause infection at a
variety of body sites, the decision of which sites to test should
be guided by sexual history and physical exam findings [26–31].
Diagnosis (Table 35.1)
Isolation of N. gonorrhoeae by culture is the historic mainstay of
gonorrhea diagnosis, however this method is somewhat limited
by the difficulty of maintaining viability of organisms during
transport and storage from a variety of settings in which screen-
ing programs are established and the time delay from specimen
collection to result reporting [5, 26]. In most laboratories, culture
has been replaced by nucleic acid amplification tests (NAATs),
including ligase (LCR), polymerase chain reaction (PCR), tran-
scription-mediated amplification (TMA), and strand-displace-
ment amplification (SDA) [26–31]. The sensitivity, specificity, and
ease of specimen collection and transport with NAAT technology
is better than that of any other test available, and these tests have
been shown to be cost effective in preventing sequelae due to
Gonorrhea 369

TABLE 35.1: Screening and Diagnostic Tests for Gonorrhea

Sensitivity Specificity Advantages Disadvantages
NAAT 96.7% compared 98% • High sensitivity • Most expensive option
to culture • Is the current gold standard for screening and • No isolate preserved for forensics or
diagnosis sensitivity testing
• Approved for testing on voided urine • Highest false-positive rate when
• Approved for testing on liquid-based pap persons at low risk are tested
medium • Limited to cervical or urine specimens
• Rapid results • Nonviable organisms or contaminants
• Specimen less affected by handling and transport will give false-positive result

Currently the preferred testing method for rectal and

oropharyngeal specimens if lab is CLIA compliant

Culture 80–90% 100% • Can obtain specimen from any potentially • Organism is especially fastidious—can
infected site be difficult to grow in culture
• Preserves and isolate for antimicrobial sensitivity • Overgrowth of contaminating
testing and forensics microorganisms can give a false-
negative result
• Organism can be rendered nonviable
during transport if incorrect media
used or delay in transport
• 48–72 hours to complete

Gram stain 40–60% compared 70–90% • Rapid results • Least sensitive/specific

to culture • Negative predictive value is 99–100% • Higher false-negative rate results in
• In setting of limited resources can be used for more failure to treat
screening with follow-up testing of screen
positives
Non-NAAT 92.1% compared 99% • Inexpensive • Nonviable organisms or contaminants
to culture • Rapid results will give false-positive result
• Specimen less affected by handling and transport • Limited to cervical specimens
• NOT RECOMMENDED
Source: From Refs. [26–31].
Abbreviation: NAAT, nucleic acid amplification test; CLIA, clinical laboratory improvement amendments.

N. gonorrhea infection [26]. A significant limitation of these tests
is the risk of specimen contamination—the presence of a single
viable or non-viable organism will lead to a positive test result,
therefore workflow and lab cleaning procedures are of extreme
importance [31]. Non-NAAT testing utilizing DNA probes is
available but is NOT recommended due to significantly lower sen-
sitivity [30]. For NAAT testing a self-collected or clinician-
collected vaginal swab is the preferred specimen type; however,
a first catch voided urine or endocervical swab is acceptable
for most available assays; confirm specimen requirements for
each assay used [30]. NAAT tests are not FDA approved for use
on rectal, pharyngeal, or conjunctival specimens; however, most
labs have developed performance specifications for using NAATs
on these specimens and they are currently the recommended
testing method for rectal and oropharyngeal specimens with the
caveat that the testing lab must be in compliance with the Clinical
Laboratory Improvement Amendments (CLIA) for test modifica-
tions [28–30]. Conjunctival specimens should be cultured. Some
assays can detect C. trachomatis or N. gonorrhoeae in a single
specimen. Several of these combined assays do not differentiate
between the two organisms, so a positive result should be followed
by tests for each organism to obtain an organism-specific result
[31]. Clinicians who perform STI screening tests should be aware
of the prevalence of STIs in the population being screened and
have a conceptual understanding of positive predictive value and
the impact of screening low-risk individuals with a test that has
limited specificity. The positive predictive value of nucleic acid-
based tests is <60% when the prevalence of infection in the popu-
lation is <1%. Routine test of cure is not recommended except in
cases where an alternate treatment is used to treat pharyngeal
infections; then a test of cure by either culture or NAAT is rec-
ommended in 14 days [31, 32]. Because of the continued increase
in antibiotic resistant strains, suspected treatment failures must
be evaluated with culture rather than a NAAT so that antibi-
otic sensitivity can be evaluated [31, 32].
Treatment
Due to increasing multi-drug resistance, awareness of local
antimicrobial resistance data is of utmost importance in the
treatment of gonorrhea. The Gonococcal Isolate Surveillance
Project (GISP) of the CDC and the European Gonococcal
Antimicrobial Surveillance Programs (Euro-GASP) have reported
resistance to penicillin, tetracyclines, and fluoroquinolones. From
2006–2012, the minimum concentrations of cefixime needed to
inhibit in vitro growth of the N. gonorrhoeae strains circulating in
the United States and many other countries increased, suggesting
that the susceptibility may be decreasing [32–37]. In 2018, based
on isolates collected from all EU Member States, Euro-GASP
370 Maternal-Fetal Evidence Based Guidelines

results revealed that compared to 2017 azithromycin susceptibil- that includes azithromycin [32, 33]. Patients should be advised
ity decreased, and three N. gonorrhoeae isolates were resistant to to abstain from sexual activity for 7 days after treatment and
ceftriaxone. In that 1-year time period ciprofloxacin resistance until all partners are adequately treated and complete 7 days of
significantly increased and cefixime resistance remained stable abstinence to prevent transmission and reinfection.
[38]. In addition, treatment failures with cefixime or other oral Allergic reactions to first-generation cephalosporins occur
cephalosporins have been reported in Asia, Europe, South Africa, in only <2.5% of persons with a history of penicillin allergy
and Canada [32–37]. In 2017 the GISP in the United States was and are uncommon with third-generation cephalosporins (e.g.,
expanded to conduct N. gonorrhoeae surveillance in non-urethral ceftriaxone and cefixime). Use of ceftriaxone or cefixime is
isolates. The expanded GISP or eGISP includes pharyngeal, rectal, contra-indicated in persons with a history of an IgE-mediated
and endocervical isolates and was established to help understand penicillin allergy (e.g., anaphylaxis, Stevens-Johnson syndrome,
if pharyngeal and/or rectal environments may select for or pro- and toxic epidermal necrolysis). Data are limited regarding
mote antimicrobial resistance. Updates can be found at https:// alternative regimens for treating gonorrhea among persons who
www.cdc.gov/std/gisp/ [39]. have either a cephalosporin or IgE-mediated penicillin allergy.
Current CDC recommendations for treatment are presented Spectinomycin can be considered for treatment of urogenital
in Table 35.2. Currently, only one regimen consisting of dual and anorectal gonorrhea, however it is not widely available. An
treatment with ceftriaxone and azithromycin is recommended infectious disease specialist should be consulted for advisement
for treatment of gonorrhea in the United States, but as resistance in treating persons with cephalosporin or IgE-mediated penicil-
patterns change so too will treatment recommendations. There lin allergy [43, 44]. Updates can be found at www.cdc.gov/STD/
are no published trials evaluating this regimen in a pregnant pop- treatment/ [33].
ulation, however efficacy of cephalosporins in a pregnant popu- For uncomplicated gonococcal infection treated with
lation has previously been demonstrated [40–42]. Dual therapy the recommended regimen, a test of cure is not necessary.
using two antimicrobials with different mechanisms of action However, if alternate treatment regimens are used, consider per-
(e.g., a cephalosporin plus azithromycin) is expected to improve forming a test of cure with either a NAAT or culture two weeks
treatment efficacy and potentially slow the emergence and spread after completing the treatment. If NAAT is used and returns a
of resistance to cephalosporins. Persons infected with N. gonor- positive result obtain culture for susceptibility testing prior
rhoeae are frequently coinfected with C. trachomatis. Of women to retreatment.
who have endocervical gonorrhea, 35–50% are coinfected If a patient fails the recommended treatment regimen, a cul-
with C. trachomatis, so there is a longstanding recommenda- ture should be obtained for antimicrobial susceptibility test-
tion that persons treated for gonococcal infection also be treated ing. Treatment is considered to have failed if the patient reports
with a regimen that is effective against uncomplicated genital C. ongoing symptoms despite compliance with medication regimen,
trachomatis infection, further supporting the use of dual therapy simultaneous treatment of her partner, and no sexual activity
without barrier protection after completing treatment. It is dif-
TABLE 35.2: Current CDC Recommendations for Treatment ficult to exclude reinfection as the cause of a positive result on
of Gonorrhea Infection repeat testing. In the United States, clinicians should contact
their local or state health department or the CDC for guidance
Site of Infection Recommended Alternate
and assistance in follow-up testing and treatment of these patients
Cervix/urethra/ Ceftriaxone 250 mg IM Spectinomycin 2 g IM to minimize risk or promoting antimicrobial drug resistance as
rectum single dose (99.1% efficacy) single dose if allergic part of the ongoing GISP. In European countries, the European
PLUS to cephalosporins Centre for Disease Prevention and Control (ECDC) should be
Azithromycin 1 g PO single (98.2% efficacy)a made aware of apparent treatment failures [34, 35].
dose Patients presenting with preterm premature rupture of mem-
Pharynx Ceftriaxone 250 mg IM Spectinomycin 2 g IM branes who are found to have active gonorrheal infection can be
single dose (99% efficacy) single dose (only managed expectantly as long as treatment for gonorrhea is initi-
PLUS 50% efficacy)a ated promptly [40].
Azithromycin 1 g orally in a Because of the potential for concomitant infection, testing for
single dose C. trachomatis, syphilis, HIV, and hepatitis B is recommended.
Conjunctiva Ceftriaxone 1 g IM in a
Expedited partner single dose Cefixime 400 mg PO
therapy (EPT) PLUS single dose References
Azithromycin 1 g orally in a PLUS 1. WHO. Prevalence and incidence of selected sexually transmitted infec-
single dose Azithromycin 1 g PO tions, Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis and tricho-
Ceftriaxone 250 mg IM single doseb monas vaginalis. Methods and results used by WHO to generate 2016
single dose estimates. Geneva, World Health Organization, 2019. Bull World Health
Organ 2019;97:548–562. [Epidemiologic data]
PLUS 2. Centers for Disease Control and Prevention. Sexually Transmitted Disease
Azithromycin 1 g PO single Surveillance 2018. Atlanta: U.S. Department of Health and Human Services;
dose 2019. [Epidemiologic data]
3. Satterwhite CL, Torrone E, Meites E, et al. Sexually transmitted infections
Source: From Refs. [31, 32]. among US women and men: prevalence and incidence estimates, 2008. Sex
Abbreviations: CDC, Center for Disease Control; PO, by mouth; IM, intramuscular. Transm Dis 2013;40(3):187–193.[Epidemiologic data]
a Consultation with an infectious disease specialist is recommended prior to treat-
4. Joseph Davey DL, Shull HI, Billings JD, Wang D, Adachi K, Klausner JD.
ment with an alternate regimen. Prevalence of curable sexually transmitted infections in pregnant women
b Oral regimen for expedited partner treatment is considered appropriate ONLY in low- and middle-income countries from 210 to 2015. Sex Transm Dis
when partner cannot present for first-line IM/PO regimen. 2016;43(7):450–458.[Epidemologic data]
Gonorrhea
5. Handsfield HH, Sparling FP. Neisseria gonorrhoeae. In: Mandell GL, Bennett
JE, Dolin R, eds. Principles and Practices of Infectious Diseases. 6th ed.
Philadelphia, USA: Churchill and Livingstone, Inc., 2005:2514–2527. [Review]
6. Lin JS, Donegan SP, Heeren TC, et al. Transmission of Chlamydia tra-
chomatis and Neisseria gonorrhoeae among men with urethritis and their
female sex partners. J Infect Dis 1998;178(6):1707–1712. [II-2]
7. Fransen L, Nsanze H, Klauss V, et al. Ophthalmia neonatorum in Nairobi,
Kenya: the roles of Neisseria gonorrhoeae and Chlamydia trachomatis. J
Infect Dis 1986;153(5):862–869. [II-3]
8. Galega FP, Heymann DL, Nasah BT. Gonococcal ophthalmia neonato-
rum: the case for prophylaxis in tropical Africa. Bull World Health Organ
1984;62(1):95–98. [Review]
9. McCormack WM, Stumacher RJ, Johnson K, et al. Clinical spectrum of
gonococcal infection in women. Lancet 1977;1(8023):1182–1185. [Review]
10. Brunham RC, Paavonen J, Stevens CE, et al. Mucopurulent cervicitis—
the ignored counterpart in women of urethritis in men. N Engl J Med
1984;311(1):1–6. [II-2]
11. Wiesner PJ. Gonococcal pharyngeal infection. Clin Obstet Gynecol
1975;18(1):121–129. [II-2]
12. Wiesner PJ, Tronca E, Bonin P, et al. Clinical spectrum of pharyngeal gono-
coccal infection. N Engl J Med 1973;288(4):181–185. [II-3]
13. Holmes KK, Counts GW, Beaty HN. Disseminated gonococcal infection.
Ann Intern Med 1971;74(6):979–993. [II-3]
14. Phupong V, Sittisomwong T, Wisawasukmongchol W. Disseminated gono-
coccal infection during pregnancy. Arch Gynecol Obstet 2005;273(3)
:185–186. [II-3]
15. Edwards LE, Barrada MI, Hamann AA, et al. Gonorrhea in pregnancy. Am
J Obstet Gynecol 1978;132(6):637–641. [II-3]
16. Schulz KF, Cates W Jr., O’Mara PR. Pregnancy loss, infant death, and
suffering: legacy of syphilis and gonorrhea in Africa. Genitourin Med
1987;63(5):320–325. [II-3]
17. McGregor JA, French JI, Richter R, et al. Antenatal microbiologic and
maternal risk factors associated with prematurity. Am J Obstet Gynecol
1990;163(5 pt 1):1465–1473. [II-2]
18. Alger LS, Lovchik JC, Hebel JR, et al. The association of Chlamydia tra-
chomatis, Neisseria gonorrhoeae, and group B streptococci with preterm
rupture of the membranes and pregnancy outcome. Am J Obstet Gynecol
1988;159(2):397–404. [II-2]
19. Fox KK, Whittington WL, Levine WC, et al. Gonorrhea in the United
States, 1981-1996. Demographic and geographic trends. Sex Transm Dis
1998;25(7):386–393. [Epidemiologic data]
20. Cohen MS, Hoffman IF, Royce RA, et al. Reduction of concentration of
HIV-1 in semen after treatment of urethritis: implications for prevention of
sexual transmission of HIV-1. AIDSCAP Malawi Research Group. Lancet
1997;349(9069):1868–1873. [II-2]
21. Paz-Bailey G, Koumans EH, Sternberg M, et al. The effect of correct and
consistent condom use on chlamydial and gonococcal infection among
urban adolescents. Arch Pediatr Adolesc Med 2005;159(6):536–542. [II-2]
22. Golden MR, Whittington WL, Handsfield HH, et al. Effect of expedited
treatment of sex partners on recurrent or persistent gonorrhea or chlamyd-
ial infection. N Engl J Med 2005;352(7):676–685. [II-2]
23. Kissinger P, Mohammed H, Richardson-Alston G, et al. Patient-delivered
partner treatment for male urethritis: a randomized, controlled trial. Clin
Infect Dis 2005;41(5):623–629. [RCT]
24. American College of Obstetricians and Gynecologists Committee Opinion
No. 632. Expedited partner therapy in the management of gonorrhea and
chlamydial infection. Obstet Gynecol 2015;125:1526–1528.[III]
25. Centers for Disease Control and Prevention. Guidance on the use of expe-
dited partner therapy in the treatment of gonorrhea. Updated August 20,
2015. [Review]
371
26. Crotchfelt KA, Welsh LE, DeBonville D, et al. Detection of Neisseria
gonorrhoeae and Chlamydia trachomatis in genitourinary specimens
from men and women by a coamplification PCR assay. J Clin Microbiol
1997;35(6):1536–1540. [II-2]
27. Koumans EH, Black CM, Markowitz LE, et al. Comparison of methods for
detection of Chlamydia trachomatis and Neisseria gonorrhoeae using com-
mercially available nucleic acid amplification tests and a liquid pap smear
medium. J Clin Microbiol 2003;41(4):1507–1511. [II-2]
28. Martin DH, Cammarata C, Van Der Pol B, et al. Multicenter evaluation of
AMPLICOR and automated COBAS AMPLICOR CT/NG tests for Neisseria
gonorrhoeae. J Clin Microbiol 2000;38(10):3544–3549. [II-2]
29. Bachmann LH, Johnson RE, Cheng H, Markowitz LE, Papp JR, Hook EW
III. Nucleic acid amplification tests for diagnosis of Neisseria gonorrhea
oropharyngeal infections. J Clin Microbiol 2009;47:902–907. [II-2]
30. Bachmann LH, Johnson RE, Cheng H, et al. Nucleic acid amplification tests
for diagnosis of Neisseria gonorrheae and Chlamydia trachomatis rectal
infections. J Clin Microbiol 2010;48:1827–1832. [II-2]
31. Papp JR, Schachter J, Gaydos C, Van Der Pol B, Recommendations for the
Laboratory-Based Detection of Chlamydia trachomatis and Neisseria gon-
orrheae. MMWR Recommend Rep 2014 March 14;63.1. [Review]
32. Centers for Disease Control and Prevention (CDC). Update to CDC’s sexu-
ally transmitted Diseases treatment Guidelines, 2010: Oral cephalosporins
no longer no longer a recommended treatment for gonococcal infections.
MMWR 2012;61:590–594. [III]
33. Centers for Disease Control and Prevention. Sexually Transmitted
Disease Surveillance 2013: Gonococcal Isolate Surveillance Project (GISP)
Supplement and Profiles. Atlanta: U.S. Department of Health and Human
Services; 2015. [Review]
34. Unemo M, Golparian D, Syversen G, et al. Two cases of verified clinical fail-
ures using internationally recommended first-line cefixime for gonorrhea
treatment, Norway, 2010. Euro Surveill 2010;15:19721. [III]
35. Ison CA, Hussey J, Sankar KN, et al. Gonnorrhoes treatment failures
to cefixime and azithromycin in England, 2010. Euro Surveill 2011;16:
19833. [III]
36. Ohnishi M, Saika T, Hoshina S, et al. Ceftriaxone-resistant Neisseria gonor-
rhoeae. Japan Emerg Infect Dis 2011;17:148–149. [III]
37. Allen VG, Mitterni L, Seah C, et al. Neisseria gonorrhoeae treatment fail-
ure and susceptibility to cefixime in Toronto, Canada. JAMA 2013;309:
163–170. [III]
38. European Center for Disease Prevention and Control. Gonococcal
Antimicrobial Susceptibility Surveillance in Europe, Results Summary,
2018. Stockholm: ECDC; 2020.
39. Pham C, Raphael B, St Cyr S, Torrone E. Gonococcal Isolate Surveillance
Project (GISP) and Enhanced GISP (eGISP) Protocol. Center for Disease
Control and Prevention. January 2020.
40. Maxwell GL, Watson WJ. Preterm premature rupture of membranes:
results of expectant management in patients with cervical cultures positive
for group B streptococcus or Neisseria gonorrhoeae. Am J Obstet Gynecol
1992;166(3):945–949. [II-3]
41. Ramus RM, Sheffield JS, Mayfield JA, et al. A randomized trial that com-
pared oral cefixime and intramuscular ceftriaxone for the treatment of gon-
orrhea in pregnancy. Am J Obstet Gynecol 2001;185(3):629–632. [RCT]
42. Brocklehurst P. Antibiotics for gonorrhea in pregnancy. Cochrane Database
Syst Rev 2002;(2):CD000098. [Meta analysis; 2 RCTs, n = 346]
43. Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to
cephalosporins among patients allergic to penicillins. Clin Exp Allergy
2001;31:438–443. [II-2]
44. Romano A, Gaeta F, Valluzzi RL, et al. IgE-mediated hypersensitivity to
cephalosporins: cross-reactivity and tolerability of penicillins, mono-
bactams, and carbapenems. J Allergy Clin Immunol 2010;126:994–999.
[II-2]
36
CHLAMYDIA
Molly A. Amero and Shawn Mattson
Key points
• Untreated maternal genital Chlamydia trachomatis has
been associated with increased preterm premature rup-
ture of membranes, preterm birth, low birth weight,
endometritis, and decreased perinatal survival.
• Neonatal infection is associated with neonatal conjuncti-
vitis and pneumonitis.
• Prevention strategies shown to be effective include
condoms, screening to identify asymptomatic cases in
high-risk populations, early diagnosis and treatment,
and partner notification and treatment without a clini-
cal assessment (expedited partner treatment).
• Screening and treatment of women at risk for chlamydial
infection improves pregnancy outcome.
• Risk factors for acquiring chlamydial infection include age
<25 years old, new sex partner, multiple sex partners,
a sex partner who has other partners, sex partner with
sexually transmitted infection (STI), inconsistent con-
dom usage, previous or coexisting STI, and exchanging
money for sex or drugs.
• The Centers for Disease Control and Prevention (CDC)
recommends screening for chlamydia for all pregnant
women under 25, and those 25 or older with risk factors
(new or multiple sex partners, sex partner with concur-
rent partners, or sex partners who have an STI). Repeat
screening in the third trimester is recommended for
women under 25, or for older women with continued
risk factors present.
• A nucleic acid amplification test (NAAT) (e.g., LCR or
PCR) screening test, confirmed by another NAAT test,
achieves highest predictive accuracy for the diagnosis of
maternal genital chlamydial infection, and is therefore the
gold standard.
• Azithromycin 1 g orally as a single dose is the pre-
ferred treatment of maternal genital chlamydial infection.
Partner notification and treatment without a clinical
assessment increase the rates of partner treatment, and
decrease the rates of maternal reinfection for various STIs,
and is therefore supported.
• A test of cure approximately 3 weeks after completion of
therapy with a recommended regimen and repeat testing
in the third trimester, as well as testing for Neisseria gon-
orrheae, syphilis, HIV, and hepatitis B are recommended
for those women with positive testing earlier in pregnancy.
Background
The major sexually transmitted diseases caused by C. tracho-
matis are cervicitis, urethritis, proctitis, and lymphogranuloma
venerum (LGV). Chlamydia trachomatis is also a significant
pathogen causing conjunctivitis in both the newborn and in sexu-
ally active adolescents and adults.
372
Epidemiology/Incidence
Globally, it is estimated that there are over 127 million new cases
of chlamydial infections annually [1]. The incidence of chlamydial
infections in the United States and worldwide continues to rise
annually. In 2018, there were over 1.7 million reported cases
of chlamydia in the United States and over 1.1 million of these
cases were diagnosed in women [2]. Higher rates among women
compared to men likely reflects more frequent screening, and
the increase in the number of cases reported annually is thought
to be due in part to expansion of screening programs for at-risk
women.
The age-specific rate for genital chlamydial infection is high-
est in the 15- to 24-year-old age category. The rate of chlamydia
in African American females in the United States is five times
higher than the rate among white females [2]. Estimates of the
prevalence of chlamydia in pregnancy in the United States vary
widely, ranging from 2.8% to 19%, with the highest prevalence
tending to be found in urban populations [3, 4]. The prevalence
of chlamydia varies significantly across the world; sample rates of
genital C. trachomatis infection in pregnant women are shown in
Table 36.1 [5].
Extragenital chlamydial infections are less common, however
still represent a public health issue. Ocular trachoma, a chronic
keratoconjunctivitis caused by C. trachomatis, is rare in high-
income countries, however it is responsible for visual impairment
or blindness in 1.9 million people, with Africa being the most
affected continent. As of 2020, ten countries have been validated
by the World Health Organization for achieving elimination of
trachoma [6].
LGV occurs sporadically in developed countries but is
endemic in Africa, India, Southeast Asia, South America, and the
Caribbean. LGV infection is more common in patients with HIV
coinfection and with men who have sex with men (MSM).
Symptoms
Chlamydia trachomatis infections can be divided into four
clinical categories:
• Classic ocular trachoma
• Other ocular and genital diseases in adults
• LGV
• Perinatal infection—primarily conjunctivitis and
pneumonia
In pregnant women, genital infection including LGV, and
conjunctivitis are the most clinically significant.
Maternal genital infection
The clinical manifestations of C. trachomatis are unchanged in
pregnant women, except that pelvic inflammatory disease and
perihepatitis are uncommon after the first trimester. About
DOI: 10.1201/9781003099062-36
Chlamydia 373

TABLE 36.1: Rates of Chlamydial Pathophysiology/Etiology

Infection in Pregnant Women
Chlamydia trachomatis is an obligate intracellular pathogen
Country %
that exhibits morphologic and structural similarities to gram-
Papua New Guinea 26 negative bacteria. The organism has a unique life cycle that
India 17 includes an extracellular infectious form and an intracellular rep-
Cape Verde 13 licative form. The target cells of C. trachomatis are the squamo-
Iceland 8 columnar epithelial cells of the endocervix and upper genital
Tanzania 6 tract, the conjunctiva, urethra, and rectum.
Thailand 5.7 Target cells of the trachoma biovar of C. trachomatis are the
squamo-columnar epithelial cells of the endocervix and upper
United States 5
genital tract, conjunctiva, urethra, and rectum. The LGV biovar of
Italy 2.7
C. trachomatis penetrates breaks in the skin or infects epithelial
Brazil 2.1
cells of the mucous membranes of the genital tract or rectum. It is
Source: Data from Ref. [5]. then carried by lymphatic drainage to the regional lymph nodes,
where it multiplies inside mononuclear phagocytes. C. trachoma-
tis serovars D through K cause conjunctivitis in neonates as well
as in adults. The incubation for C. trachomatis is variable depend-
70–90% of women with cervical or urethral C. trachomatis ing on the type of infection, but in general is 7–21 days. Infection
infection are asymptomatic. with C. trachomatis confers little protection against reinfection,
and the limited protection that is conferred is short lived.
Cervicitis/Urethritis
Mucopurulent cervicitis that may be perceived as vaginal dis-
charge, cervical edema and friability, dysuria if urethritis present, Transmission
and low abdominal pain if upper genital tract infection present.
• Chlamydia trachomatis is readily transmitted during vagi-
Proctitis/Proctocolitis nal, oral, or anal sex, and mother-to-infant transmission
Results from anal intercourse or secondary spread of secretions commonly occurs at delivery.
from the cervix. • The risk of acquisition of C. trachomatis with a single epi-
sode of sexual intercourse with an infected partner is not
• Serovars D through K—anal pruritus and a mucous rec- known. However, it appears to be substantially less than
tal discharge that may become mucopurulent. The infec- that for N. gonorrhoeae [7].
tion remains superficial, is limited to the rectum, and • Between 22% and 44% of infants born to infected women
closely resembles gonococcal proctitis. Infection is often develop neonatal conjunctivitis [8]. In the United States,
asymptomatic. the rate of neonatal chlamydial conjunctivitis between
• LGV strains—rectal pain, tenesmus, rectal bleeding, and 2014 and 2018 was relatively stable at 1.4–2.3 cases per
fever. The disease extends into the colon. The rectal and 100,000 live births [2].
colonic mucosa become ulcerated, and a granulomatous • Between 11% and 20% of infants born to infected mothers
inflammatory process occurs in the bowel wall, with both develop pneumonia caused by C. trachomatis [9].
noncaseating granulomas and crypt abscesses. Sinus tract
formation can lead to rectovaginal fistulas in women. Complications/Risks
Chlamydial conjunctivitis Untreated maternal genital C. trachomatis has been associated
Chlamydia is the most common cause of chronic follicular con- to be an independent risk factor for the statistically significant
junctivitis. Common manifestations are a unilateral or bilateral increase in preterm premature rupture of membranes, pre-
asymmetric conjunctivitis associated with moderate hyperemia term birth, low birth weight, endometritis, and decreased
and mucopurulent discharge. perinatal survival when compared to either treated women or
controls without the infection [10, 11]. Successful treatment is
LGV therefore associated with prevention of premature rupture of
LGV is often a difficult diagnosis to make because it is not membranes and small-for-gestational-age infants [12]. Treatment
thought of in the differential and because of its relative rarity early in pregnancy with sustained eradication is associated with
among women. better outcomes compared to diagnosis and treatment later in
pregnancy [13]. Neonatal infection acquired from an infected
• The first stage is the formation of a primary lesion—a small maternal genital tract at the time of delivery is associated with
papule or herpetiform ulcer—usually on genital mucosa or neonatal conjunctivitis and pneumonitis.
adjacent skin and causes little or no symptoms.
• The secondary stage occurs days to weeks later and is char- Management
acterized by painful inguinal lymphadenopathy and sys-
temic symptoms. Prevention
• The third stage manifests as hypertrophic chronic granu- Condoms, when used correctly and consistently, provide a high
lomatous enlargement with ulceration of the external geni- degree of protection from chlamydia and other STIs [14]. Other
talia. Lymphatic obstruction may also lead to elephantiasis important practices for prevention of chlamydia are screen-
of the genitalia. ing to identify asymptomatic cases in high-risk populations,
374
early diagnosis and treatment, and partner notification and
treatment. Expedited partner treatment (EPT) is an approach to
therapy where the patient delivers either medication or prescrip-
tions to their partner without requiring the partner to present for
clinical assessment. EPT is known to increase the rates of partner
treatment, and to decrease the rates of maternal reinfection for
various STIs [15, 16]; however, the impact on specifically chla-
mydial reinfection is uncertain [17–19]. The American College of
Obstetricians and Gynecologists (ACOG) supports the provision
of EPT for prevention of gonorrhea and chlamydial reinfection
[20]. As of 2020, in the United States, EPT for chlamydial infec-
tion is permissible in 45 states, potentially allowable in 4 states,
and prohibited in 1 state (South Carolina) [21].
Screening
There is no trial to assess the efficacy of universal or risk-based
screening for chlamydial genital infection in pregnancy. The
CDC recommends screening for chlamydia for all pregnant
women under 25, and those 25 or older with risk factors (new
or multiple sex partners, sex partner with concurrent part-
ners, or sex partners who have an STI). Repeat screening in
the third trimester is recommended for women under 25, or
for older women with continued risk factors present [22]. Both
ACOG and the American Academy of Pediatrics (AAP) recom-
mend universal chlamydia screening in the first trimester with
repeat screening in the third trimester only if the patient is under
25 or risk factors are present (Table 36.2) [23]. Risk factors for
acquiring chlamydial infection include age <25 years old, new
sex partner, multiple sex partners, a sex partner who has other
partners, sex partner with STI, inconsistent condom usage,
previous or coexisting STI, and exchanging money for sex or
drugs [24].
Diagnosis
A nucleic acid amplification test (NAAT) (e.g., ligase chain
reaction [LCR] or polymerase chain reaction [PCR]) screening
test, confirmed by another NAAT test, achieves highest predic-
tive accuracy for the diagnosis of maternal genital chlamydia
infection [25, 26]. Therefore, NAAT testing is the gold standard
for the diagnosis of maternal genital chlamydial infection.
• Anti-Chlamydia IgM is uncommon in adults with genital
tract infection. The prevalence of anti-Chlamydia IgG is
high in sexually active adults (30–60%), even in those who
do not have an active infection, and is probably due to past
TABLE 36.2: Recommendations for Chlamydial Screening in
Pregnancy
First Trimester Third Trimester
Under 25 Universal screening Universal repeat screening
(ACOG, CDC, AAP) (ACOG, CDC, AAP)
25 or older • Universal screening Screening when risk factors
(ACOG, AAP) present (ACOG, CDC, AAP)
• Screening when risk
factors present (CDC)a
Source: From Refs. [22–24].
Abbreviations: ACOG, American College of Obstetricians and Gynecologists; CDC,
Center for Disease Control; AAP, American Academy of Pediatrics.
a Risk factors defined as new sex partner, multiple sex partners, a sex partner who
has other partners, sex partner with STI, inconsistent condom usage, previous or
coexisting STI, and exchanging money for sex or drugs.
Maternal-Fetal Evidence Based Guidelines
infection. The sensitivity, specificity, and predictive values
of serologies are not high enough to make them clinically
useful in the diagnosis of active disease. Thus, chlamydial
serologies are not recommended for diagnosis of active
disease except in suspected cases of LGV.
• When endocervical culture is compared with endocervi-
cal DFA, EIA, and PCR, nonculture tests have a higher
sensitivity, even in a population with a prevalence rate as
low as 4.3% [27, 28].
• Clinicians who perform STD screening tests should be
aware of the prevalence of STDs in the population being
screened and have a conceptual understanding of positive
predictive value and the implications of screening low-
risk individuals with a test that has limited specificity. In
low-prevalence populations (<5% infected), a significant
proportion of positive test results are false-positives. For
example, with a prevalence of 3%, out of 1000 patients 30
are infected. A test with a sensitivity of 80% and a speci-
ficity of 99% detects 24 of the infected people but falsely
identifies 10 uninfected as infected. The positive predictive
value in this example is 70%.
• The CDC recommended confirming positive screening
tests for C. trachomatis when positive predictive values are
<90%.
• A positive result on a nonculture test should be consid-
ered presumptive evidence of infection in a low-prev-
alence population. Consideration should be given to
performing an additional test after a positive screening
test and requiring that both the screening test and addi-
tional test be positive to make a diagnosis of C. tracho-
matis infection.
• Except for using culture to obtain an isolate, a non-NAAT
should not be used as an additional test after a NAAT
because of the lower sensitivity of the non-NAAT.
• The majority of commercial NAATs have been cleared by
the Food and Drug Administration (FDA) to detect C. tra-
chomatis in endocervical swabs and urine from women.
• Two prospective studies compared LCR NAAT performed
on voided urine to endocervical culture in pregnant
women, and found the LCR NAAT to be more sensitive [29,
30]; voided urine NAAT has been shown to be equivalent
to endocervical NAAT in pregnant women [31].
• Commercial NAAT performed with vaginal swabs are
equivalent to cervical swabs in detecting chlamydia [28],
and one trial has found them to be equivalent in pregnant
women [32].
• Patient-collected vaginal swabs are accurate and have been
found to have a sensitivity of 92% and specificity of 98%
for chlamydia when compared to specimens collected by a
healthcare provider [28, 33]; however, only one small trial
has assessed their performance in pregnant patients [34].
Treatment
• Azithromycin, or amoxicillin, (in order of preference) are
accepted treatments of maternal genital chlamydial infec-
tion. (Table 36.3). Azithromycin has the highest efficacy,
highest compliance, and fewest reported side effects in
pregnant women [35–39].
• Amoxicillin is associated with similar efficacy to eryth-
romycin in achieving a negative test of cure, and is better
tolerated in pregnant women than erythromycin [40–43].
Chlamydia
TABLE 36.3: Treatment of Chlamydial Infection in Pregnancy
Recommended Alternate
Cervicitis/ Azithromycin Amoxicillin 500 mg orally three
urethritis/ 1 g orally single times a day for 7 days
proctitis dose
Conjunctivitis Azithromycin
1 g orally single
dose
Source: See further Ref. [22].
• While in vitro studies suggest that C. trachomatis may
have resistance to amoxicillin, two randomized trials have
demonstrated that it is efficacious in pregnant patients
[44, 45]. Amoxicillin is less expensive than azithromycin.
However, since azithromycin is a single dose and amoxicil-
lin requires a thrice-daily dosing for a seven day course,
compliance with amoxicillin is often lower than with
azithromycin [44].
• Clindamycin may be considered if azithromycin, and
amoxicillin are contraindicated or not tolerated [45, 46].
• Doxycycline has been shown to have a 100% cure rate com-
pared to 97% in azithromycin, though noninferiority of
azithromycin was not able to be established [47]. Although
doxycycline is one treatment of choice in non-pregnant
women, it is not recommended in pregnancy because it
may cause permanent discoloration in developing fetal
teeth.
• Treatment for LGV and conjunctivitis caused by C. tracho-
matis has not been studied in pregnancy. Recommendations
are based on treatment recommendations in non-pregnant
populations.
• Concurrent treatment for gonorrhea is not indicated unless
a positive test for this organism is obtained. Because of the
potential for concomitant infection, testing for N. gon-
orrheae, syphilis, HIV, and hepatitis B is recommended.
Treatment of sexual partners may decrease reinfection rates
[16–18]. Common partner-management options include partner
notification (partners are notified and instructed to seek evalu-
ation and treatment) and patient-delivered partner therapy
(PDPT) (partner is provided with either medication or prescrip-
tions directly via the index patient). As discussed previously,
expedited partner therapy is supported by ACOG and recom-
mended for partner treatment and prevention of reinfection.
ACOG recommends that patients inform all partners from
the two months prior to diagnosis of infection. For those
who are unwilling or unable to seek treatment, PDPT should be
offered. Depending on provider preference, this usually entails
filling the patient’s prescription with enough medication to treat
the partner, or they may prefer to directly prescribe to the part-
ner. The partner should also be encouraged to seek medical care
and screening for additional STIs. The patient should abstain
from unprotected intercourse with the partner for 7 days after
they have both completed treatment. EPT should not be used in
cases where intimate partner violence is suspected, and disclo-
sure of the infection would endanger the patient [20].
A follow-up test of cure is recommended in pregnant women
treated for chlamydia. If a nucleic acid-based test is used, fol-
low-up testing should be performed at least three weeks post-
treatment because nonviable organisms may remain present for
375
some days after successful treatment and can give a false-positive
test result. Repeat testing in the third trimester of pregnancy
is recommended for women who test positive earlier in preg-
nancy to reduce transmission to the neonate at birth [23, 24].
One prospective study of cervical chlamydial infection in
women presenting with preterm premature rupture of mem-
branes who were conservatively managed and not treated for
Chlamydia showed no effect on duration of latency and no
increase in the incidence of chorioamnionitis or early endome-
tritis [48].
References
1. Report on global sexually transmitted infection surveillance, 2018. Geneva:
World Health Organization; 2018. [Epidemiologic data]
2. CDC Sexually Transmitted Disease Surveillance, 2018. Atlanta, GA. US
Department of Health and Human Services. Dec 2019. [Epidemiologic data]
3. CDC Sexually Transmitted Disease Surveillance, 2011. Atlanta, GA. US
Department of Health and Human Services. Dec 2012. [Epidemiologic data]
4. Berggren EK, Patchen L. Prevalence of Chlamydia trachomatis and
Neisseria gonorrhoeae and repeat infection among pregnant urban adoles-
cents. Sex Transm Dis 2011;38(3):172–174. [II-2]
5. World Health Organization. Global Prevalence and Incidence of Selected
Curable Sexually Transmitted Infections. Geneva: World Health
Organization, 2001. (Epidemiologic data)
6. World Health Organization. Trachoma. 2020. Available from: https://www.
who.int/news-room/fact-sheets/detail/trachoma [Epidemiologic data]
7. Lycke E, Lowhagen GB, Hallhagen G, et al. The risk of transmission of geni-
tal Chlamydia trachomatis infection is less than that of genital Neisseria
gonorrhoeae infection. Sex Transm Dis 1980;7(1):6–10. [II-2]
8. Hammerschlag MR, Roblin PM, Gelling M, et al. Use of polymerase chain
reaction for the detection of Chlamydia trachomatis in ocular and naso-
pharyngeal specimen from infants with conjunctivitis. Pediatr Infect Dis J
1997;16(3):293–297. [II-2]
9. Schachter J, Grossman M, Sweet RL, et al. Prospective study of peri-
natal transmission of Chlamydia trachomatis. J Am Med Assoc
1986;255(24):3374–3377. [II-2]
10. Ryan GM Jr., Abdella TN, McNeeley SG, et al. Chlamydia trachomatis
infection in pregnancy and effect of treatment on outcome. Am J Obstet
Gynecol 1990;162(1):34–39. [II-2]
11. Olson-Chen C, Balaram K, Hackney DN. Chlamydia trachomatis and
adverse pregnancy outcomes: meta-analysis of patients with and without
infection. Matern Child Health J 2018;22:812–821. [Meta-Analysis, 56 pro-
spective or retrospective cohort studies, n = 614,892; II-2]
12. Cohen I, Veille JC, Calkins BM. Improved pregnancy outcome fol-
lowing successful treatment of chlamydial infection. J Am Med Assoc
1990;263(23):3160–3163. [II-2]
13. Folger AT. Maternal Chlamydia trachomatis infections and preterm birth:
the impact of early detection and eradication during pregnancy. Matern
Child Health J 2014;18(8):1795–1802. [II-3]
14. Paz-Bailey G, Koumans EH, Sternberg M, et al. The effect of correct and
consistent condom use on chlamydial and gonococcal infection among
urban adolescents. Arch Pediatr Adolesc Med 2005;159(6):536–542. [II-2]
15. Schillinger JA, Kissinger P, Calvet H, et al. Patient-delivered partner treat-
ment with azithromycin to prevent repeated Chlamydia trachomatis
infection among women: a randomized, controlled trial. Sex Transm Dis
2003;30(1):49–56. [RCT, n = 1787; I]
16. Golden MR, Kerani RP, Stenger M, et al. Uptake and population-level
impact of expedited partner therapy (EPT) on Chlamydia trachomatis and
Neisseria gonorrhoeae: the Washington State community-level randomized
trial of EPT. PLOS Med 2015;12(1). [RCT, n = 24 health jurisdictions; I]
17. Golden MR, Whittington WL, Handsfield HH, et al. Effect of expedited
treatment of sex partners on recurrent or persistent gonorrhea or chlamyd-
ial infection. N Engl J Med 2005;352(7):676–685. [II-2]
18. Ferreira A, Young T, Mathews C, Zunza M, Low N. Strategies for partner
notification for sexually transmitted infections, including HIV. Cochrane
Database Syst Rev 2013;(10). [Meta-Analysis, 26 RCT, n > 17,000; I]
19. Trelle S, Shang A, Nartey L, Cassell JA, Low N. Improved effectiveness
of partner notification for patients with sexually transmitted infections:
systematic review. BMJ 2007;334(7589):354. [Meta-analysis, 14 RCT, n >
12,000; I]
20. American College of Obstetricians and Gynecologists Committee Opinion
Number 737. Expedited partner therapy. June 2018. [Review; III]
376
21. Centers for Disease Control and Prevention. Legal status of expedited part-
ner therapy. Accessed on 10/11/2020 at http://www.cdc.gov/std/ept/legal/
default.htm [Review; III]
22. Centers for Disease Control and Prevention. Sexually Transmitted Diseases
Treatment Guidelines, 2015. Atlanta, GA: US Department of Health and
Human Services. June 2015. [Guideline]
23. American Academy of Pediatrics and American College of Obstetricians
and Gynecologists. Guidelines for Perinatal Care. 8th ed. Washington, DC:
American College of Obstetricians and Gynecologists, 2017. [Guideline]
24. U.S. Preventative Services Tasks Force. Final recommendation statement:
chlamydia and gonorrhea: screening. September 2014. [Guideline]
25. Dille BJ, Butzen CC, Birkenmeyer LG. Amplification of Chlamydia trachomatis
DNA by ligase chain reaction. J Clin Microbiol 1993;31(3):729–731. [II-3]
26. Ossewaarde JM, Rieffe M, Rozenberg-Arska M, et al. Development and
clinical evaluation of a polymerase chain reaction test for detection of
Chlamydia trachomatis. J Clin Microbiol 1992;30(8):2122–2128. [II-3]
27. Thejls H, Gnarpe J, Gnarpe H, et al. Expanded gold standard in the diag-
nosis of Chlamydia trachomatis in a low prevalence population: diagnostic
efficacy of tissue culture, direct immunofluorescence, enzyme immunoas-
say, PCR and serology. Genitourin Med 1994;70(5):300–303. [II-2]
28. Papp JR, Schachter J, Gaydos CA, Van Der Pol B. Centers for Disease
Control and Prevention. Recommendations for the laboratory–based detec-
tion of Chlamydia trachomatis and Neisseria gonorrhoeae 2014. MMWR
2014;63(0):1–19. [Review III]
29. Andrews WW, Lee HH, Roden WJ, et al. Detection of genitourinary tract
Chlamydia trachomatis infection in pregnant women by ligase chain reac-
tion assay. Obstet Gynecol 1997;89(4):556–560. [II-3]
30. Gaydos CA, Howell MR, Quinn TC, et al. Use of ligase chain reaction with
urine versus cervical culture for detection of Chlamydia trachomatis in an
asymptomatic military population of pregnant and nonpregnant females
attending Papanicolaou smear clinics. J Clin Microbiol 1998;36(5):1300–
1304. [II-2]
31. Roberts SW, Sheffield JS, McIntire DD, Alexander JM. Urine screen-
ing for Chlamydia trachomatis during pregnancy. Obstet Gynecol
2011;117(4):883–885. [II-2]
32. Witkin SS, Inglis SR, Polaneczky M. Detection of Chlamydia trachomatis
and Trichomonas vaginalis by polymerase chain reaction in introital speci-
mens from pregnant women. Am J Obstet Gynecol 1996;175(1):165–167.
[II-2]
33. Davies D, Shepherdson N, Wertzler, K. How accurate are patient-collected
vaginal gonorrhea and chlamydia swabs in detecting infection? Evidence-
Based Pract 2017;20(10):10. [III]
34. Oakeshott P, Hay P, Hay S, Steinke F, Rink E, Thomas B, Oakeley P, Kerry
S. Detection of Chlamydia trachomatis infection in early pregnancy using
self-administered vaginal swabs and first pass urines: a cross-sectional
community-based survey. Br J Gen Pract 2002;52(483):830–832. [II-3]
35. Adair CD, Gunter M, Stovall TG, et al. Chlamydia in pregnancy: a ran-
domized trial of azithromycin and erythromycin. Obstet Gynecol
1998;91(2):165–168. [RCT, n = 106]
Maternal-Fetal Evidence Based Guidelines
36. Bush MR, Rosa C. Azithromycin and erythromycin in the treatment
of cervical chlamydial infection during pregnancy. Obstet Gynecol
1994;84(1):61–63. [II-2]
37. Edwards MS, Newman RB, Carter SG, et al. Randomized clinical trial of
azithromycin vs erythromycin for the treatment of Chlamydia cervicitis in
pregnancy. Infect Dis Obstet Gynecol 1996;4:333–337. [RCT, n = 140]
38. Rosenn MF, Macones GA, Silverman NS. Randomized trial of erythromy-
cin and azithromycin for treatment of chlamydial infection in pregnancy.
Infect Dis Obstet Gynecol 1995;3:241–244. [RCT, n = 48]
39. Pitsouni E, Iavazzo C, Athanasiou S, Falagas ME. Single-dose azithro-
mycin versus erythromycin or amoxicillin for Chlamydia trachomatis
infection during pregnancy: a meta-analysis of randomised controlled
trials. Int J Antimicrob Agents 2007;30(3):213–221. [Meta-Analysis, 8
RCT, n > 500]
40. Alary M, Joly JR, Moutquin JM, et al. Randomised comparison of amoxycil-
lin and erythromycin in treatment of genital chlamydial infection in preg-
nancy. Lancet 1994;344(8935):1461–1465. [RCT, n = 210]
41. Silverman NS, Sullivan M, Hochman M, et al. A randomized, pro-
spective trial comparing amoxicillin and erythromycin for the treat-
ment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol
1994;170(3):829–832. [RCT, n = 74]
42. Magat AH, Alger LS, Nagey DA, et al. Double-blind randomized study
comparing amoxicillin and erythromycin for the treatment of Chlamydia
trachomatis in pregnancy. Obstet Gynecol 1993;81(5 pt 1):745–749. [RCT,
n = 143]
43. Turrentine MA, Troyer L, Gonik B. Randomized prospective study com-
paring erythromycin, amoxicillin, and clindamycin for the treatment
of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol
1995;2:205–209. [RCT, n = 174]
44. Kacmar Jl, Cheh E, Montagno A, Peipert JF A randomized trial of azithro-
mycin versus amoxicillin for the treatment of Chlamydia trachomatis in
pregnancy. Infect Dis Obstet Gynecol 2001;9(4):197–202. [RCT n = 39]
45. Jacobson GF, Autry AM, Kirby RS, Liverman EM, et al. A randomized
controlled trial comparing amoxicillin and azithromycin for the treat-
ment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol
2001;184(7):1352–1354; discussion 1354–1356. [RCT, n = 129]
46. Brocklehurst P, Rooney G. Interventions for treating genital Chlamydia
trachomatis infection in pregnancy. Cochrane Database Syst Rev 2009;4.
[Meta-analysis, 11 RCT, n > 300]
47. Geisler W, Uniyal A, Lee J, et al. Azithromycin versus doxycycline for uro-
genital Chlamydia trachomatis infection. N Engl J Med 2015;373:2512–
2521. [I, RCT, n = 310]
48. Ismail MA, Pridjian G, Hibbard JU, et al. Significance of positive cervical
cultures for Chlamydia trachomatis in patients with preterm premature
rupture of membranes. Am J Perinatol 1992;9(5–6):368–370. [II-3]
37
SYPHILIS
A. Marie O’Neill
Key points
• Between 2012 and 2018 the prevalence of syphilis in preg-
nant women worldwide remained stable while the rate of
congenital syphilis decreased. However, rates of both syph-
ilis in reproductive age women and of congenital syphilis
increased several-fold in the United States during that time.
• Limited prenatal care and lack of adequate maternal
treatment despite timely diagnosis account for over half
of missed opportunities to prevent congenital syphilis.
• Prenatal screening and treatment of pregnant women for
syphilis is cost-effective, even in areas of low prevalence
of the disease (<0.1%).
• All pregnant women should be screened with a sero-
logic test for syphilis at the first prenatal visit. Women
who are at high risk, live in areas of high syphilis mor-
bidity, or are previously untested should be screened at
28 weeks and again at delivery.
• Penicillin (parenteral penicillin G, 2.4 million units IM,
either once or repeated weekly for 3 weeks depending on
stage) remains the only recommended treatment for syph-
ilis in pregnancy.
• Pregnant women with a penicillin allergy should be
desensitized and then treated with penicillin.
• Staging of disease and penicillin dosing are not altered by
pregnancy.
• Current treatment regimens are based on more than
50 years of clinical experience with penicillin, expert opin-
ion, and observational clinical studies rather than on ran-
domized clinical trials.
Definition
Treponema pallidum is the causative agent of syphilis.
Incidence/Epidemiology
Worldwide, it is estimated that more than 6.3 million new
cases of syphilis occur annually [1]. In 2016, the World Health
Organization (WHO) estimated there were over 1 million active
syphilis infections in pregnant women for a prevalence of
approximately 0.69% worldwide. More than 90% of new cases
occur in developing countries with the greatest burden of disease
is seen in sub-Saharan Africa and Southeast Asia. Approximately
80% of infected women have had at least one antenatal visit, how-
ever approximately 57% were not screened or treated and 16%
were screened but not treated. Approximately 21% of affected
women did not receive prenatal care [2, 3]. Since 1989, the newly
independent states of the former Soviet Union have experienced a
43-fold increase in reported cases with rises proportionally larger
among reproductive-aged women [4].
Each year at least half a million infants are born with
congenital syphilis worldwide, and another half million
DOI: 10.1201/9781003099062-37
pregnancies result in spontaneous abortion, stillbirth, or
early neonatal death as a result of maternal infection [3].
The rate of primary and secondary syphilis in the United
States declined by 89.7% between 1990 and 2000 to a rate of 2.1
cases/100,000 population, the lowest rate since reporting began in
1941. However, the rate has increased almost every year since with
a case rate of 10.8/100,000 population reported in 2018. Between
2014 and 2018 the case rate in reproductive age women increased
by 172.7%. The number of cases of congenital syphilis in the
United States essentially mirrors the case rate of primary and
secondary syphilis in reproductive age women. Congenital syphi-
lis decreased from 446 cases (10.5/100,000 live births) in 2008 to
334 cases (8.4/100,000) in 2012. However the rate of congenital
syphilis subsequently increased with 1306 cases (33.1/100,000)
reported in 2018 which is a 291% increase since 2012 [5–7]. Syphilis
disproportionately affects African Americans with the reported
rate of infection in this population being 5.4 times greater than
that in Whites, and 57% of infants with congenital syphilis being
born to Black women [5–7]. The Syphilis Elimination Effort (SEE)
is a national initiative launched by the Centers for Disease Control
and Prevention (CDC) in 1999 to reduce or eliminate syphilis in
the United States. Updates on the progress of this project can be
found at www.cdc.gov/stopsyphilis/.
In 2007, the WHO launched the Initiative for Global
Elimination of Congenital Syphilis with a goal of achieving a pre-
natal screen rate of >/= 90%, providing adequate treatment to >/=
90% of seropositive women and their partners, and decreasing
rate of congenital syphilis to <50 cases/100,000 live births [2].
Pathophysiology and transmission
Treponema pallidum is a gram-negative spirochete unable to sur-
vive outside the human host, and therefore has never been grown
in culture. Unlike most other infectious diseases, it is rarely if
ever diagnosed by isolation and characterization of the causative
organism. Treponema pallidum can survive in the human host
for several decades.
Treponema pallidum is easily transmitted by sexual contact,
and an overwhelming majority of cases are transmitted by sexual
intercourse. Endemic syphilis is transmitted non-venerally by
close contact with an active lesion and occurs in communities liv-
ing under poor hygiene conditions. Syphilis is rarely transmitted
during transfusion of blood or blood products or through needle
sharing by intravenous drug abusers. The organism generally
enters the body through small breaches in epithelial surfaces of
genital, anorectal, oropharyngeal, or other cutaneous sites; how-
ever; penetration of intact mucous membranes can occur. Once
inside the body it rapidly disseminates. The incubation period for
T. pallidum averages 3 weeks, but can range 10–90 days. During
the incubation period infected patients have, by definition,
neither clinical nor serologic evidence of disease but are poten-
tially infectious. The period of greatest infectivity is early in the
377
378
disease when a chancre, mucous patch, or condyloma latum is
present. Infectivity decreases over time, and after 4 years it is very
unlikely that an untreated individual will spread syphilis, even
by sexual contact. The risk of infection during a single sexual
encounter with an infected individual is up to 60% depending
on the stage of disease, and approaches 100% after five sexual
encounters [8].
Fetal syphilis occurs as a result of transplacental passage of
the spirochete that enters fetal circulation causing infection.
Neonates may acquire syphilis at the time of delivery by contact
with infectious maternal secretions, blood, or genital lesions.
Perinatal transmission may occur during any stage of maternal
disease; however, it is most common in cases of maternal pri-
mary, secondary, or early latent syphilis with up to 83% of fetuses
and newborns being affected [9].
Symptoms and classification
Syphilis has been called “the great pretender” because of the myriad
of clinical manifestations it can produce. It is a chronic, systemic
infection characterized by several stages. The immune response
to T. pallidum plays a significant role in the manifestations of all
stages of syphilis. Much of the pathology observed in the disease
is attributable to vascular abnormalities caused by proliferative
endarteritis that occurs in all stages of syphilis. The pathophysiol-
ogy of the endarteritis is not known, although the scarcity of trepo-
nemes and the intense inflammatory infiltrate suggest that the
immune response plays a role in the development of these lesions.
Manifestations of syphilis are not altered by pregnancy.
Incubation period
Asymptomatic with no serologic evidence of disease.
Transmission can occur during this period.
Primary syphilis
• Symptoms develop at the site of initial treponemal invasion
as a result of local replication of the organism.
• Treponemes also spread throughout the body by hemato-
logic and lymphatic dissemination, even before the appear-
ance of the chancre.
• Regional adenopathy often develops within the first week
and usually consists of several discrete nontender, rubbery
nodes. Inguinal adenopathy is often bilateral.
• Primary lesions are papular, but rapidly ulcerate to form a
chancre.
• The classic chancre is a solitary, painless lesion with raised,
firm, everted edges, central ulceration, and a granular base.
However, up to 40% of individuals have multiple chancres
[10–12].
• The most common site is the labia or cervix in females, but
primary lesions may also occur on the lips, breasts, mouth,
and anus [10–12].
• Without treatment, the local lesion spontaneously
resolves within 3–6 weeks [10–13].
• Approximately 25% of individuals will have an adequate
immune response and the infection will be spontaneously
cleared [8, 10–12].
Secondary syphilis
• If the primary infection is untreated, secondary syphi-
lis develops 2–8 weeks later in approximately 75% of
untreated individuals [8, 10–12].
Maternal-Fetal Evidence Based Guidelines
• Secondary infection demonstrates a wide diversity in phys-
ical features involving virtually any organ and is often not
thought of early in the diagnostic process.
• Generally begins with a nonspecific constitutional ill-
ness that commonly includes a sore throat, low-grade
fever, myalgias, and generalized lymphadenopathy.
• Skin rashes are the classic and most commonly recognized
lesions, but the appearance is highly variable, and differen-
tial diagnosis is often challenging [10–12].
• Rash is often initially macular and nonpruritic, and
becomes papular by three months [10–12].
• Rash frequently involves the palms of the hands and soles
of the feet, and may be accompanied by mucous patches
in the mouth, pharynx, or cervix and condyloma lata in
the anogenital region or axilla. Condyloma lata are hyper-
trophic lesions resembling flat warts that occur in moist
areas [10–12].
• Individuals are highly contagious during this stage, espe-
cially upon contact with mucous patches or condyloma lata
[8, 10, 11].
• Secondary disease lasts for an average of 3.6 months and
spontaneously resolves. Approximately 25% of individuals
experience a relapse of secondary disease during the first
year of infection [8, 10–12].
Latent syphilis
• In latent syphilis, by definition, there are no clinical stig-
mata of active disease, although disease remains detect-
able by positive specific treponemal serologic tests
[FTA-ABS (fluorescent treponemal antibody absorption) or
MHA-TP (microhemagglutination assay for T. pallidum)].
Latent syphilis is further subdivided into stages based on
the duration of infection: Early latent, late latent, and latent
of unknown duration [8, 10–13].
Early latent syphilis/Early non-
primary non-secondary
• In 2018, the CDC revised case definition and nomenclature
and adopted the term “early non-primary non-secondary”
to replace “early latent” [6].
• Early latency is defined as the time period within one year
of initial infection.
• Ninety percent of relapse occurs during this time period;
mucocutaneous lesions are most common. Patient is infec-
tious while lesions are present [8, 10–13].
• Patients are believed to be potentially infectious in the
absence of lesions.
• Vertical transmission of infection may occur.
Late latent syphilis/Unknown duration or late
• In 2018, the CDC revised case definition and adopted the
term “unknown duration or late” to replace “late latent
syphilis” [6].
• Initial infection has occurred greater than 1 year previ-
ously or there is insufficient evidence to conclude the infec-
tion was acquired within the previous 12 months [5].
• Associated with host resistance to reinfection [5, 8].
• Sexual transmission is unlikely [8, 13].
• Transplacental infection of the fetus can occur, but is less
likely than with earlier stages of disease. 9]
• Infection via blood transfusion is possible [13].
Syphilis
Late benign syphilis (tertiary syphilis)
• Without treatment at earlier stages of disease, tertiary
syphilis eventually develops in 30–40% of infected patients
[8, 10–12].
• Usually becomes clinically manifest after a period of
15–30 years of untreated infection [10–13].
• Characteristic manifestations of tertiary disease include
cardiovascular and gummatous lesions [10–13].
• Cardiovascular syphilis typically presents as inflamma-
tory lesions of the cardiovascular system—especially aor-
titis [10–13].
• Gummas are granulomatous, nodular lesions that can
occur in a variety of organs, most commonly skin and bone.
• In patients with untreated syphilis, about 10% develop car-
diovascular syphilis, 16% develop gummatous syphilis, and
6.5% develop symptomatic neurosyphilis [10–13].
• The diagnosis of late syphilis is confounded by the lack of sen-
sitivity of the nontreponemal tests in these conditions [13].
• If a patient suspected of having late syphilis has a non-
reactive nontreponemal test, a confirmatory treponemal
test should be performed [6, 8].
• Approximately one-third of patients will remain seroreac-
tive for decades, but will not develop clinical manifesta-
tions of tertiary syphilis [12, 13].
• Treatment of tertiary syphilis achieves a microbiologic
cure, but many of the clinical manifestations will be irre-
versible [10–13].
Neurosyphilis
• The diagnosis of neurosyphilis is made at any stage of
disease when both clinical and laboratory criteria are
met [8, 13].
• Treponema pallidum disseminates widely after initial
infection. Examination of cerebrospinal fluid will reveal
evidence of infection [elevated lymphocytes and protein,
positive VDRL (Venereal Disease Research Laboratory)] in
approximately 15% of patients with primary syphilis, and
as many as 40% of patients with secondary syphilis [8, 12].
• Many patients with cerebrospinal fluid (CSF) evidence of
infection will be asymptomatic in the early stages of dis-
ease [12, 13].
• Persistence of CSF abnormalities for more than 5 years in
the untreated patient is highly predictive of the develop-
ment of clinical neurosyphilis [12, 13].
• Clinical evidence of central nervous system infection with
T. pallidum includes the following:
• Acute syphilitic meningitis
• Meningovascular syphilis/seizures/stroke syndrome
• General paresis/dementia/depression/memory loss/
change in personality
• Argyle Robertson pupils—small fixed pupils that
do not react to light but do react to convergence-
accommodation
• Tabes dorsalis—paresthesias, abnormal gait, shooting
pains in the extremities or trunk, diminished periph-
eral reflexes, loss of position and vibration senses
• Laboratory evidence of neurosyphilis includes a reactive
serologic test for syphilis and a reactive VDRL in the CSF
[12, 13].
• The CSF-VDRL is a highly specific test, but has a sensitiv-
ity of only about 30% [13].
379
• Treponemal-specific testing of CSF is helpful only when
negative—this rules out neurosyphilis. IgG antibodies cross
the blood-brain barrier and can give a positive result in the
absence of neurosyphilis, so a positive treponemal-specific
test is not helpful in making the diagnosis [12, 13].
• CSF examination is essential in patients with signs or
symptoms of neurologic involvement at any stage of T. pal-
lidum infection, and is also recommended in all patients
with untreated syphilis of unknown duration or of
duration greater than 1 year [12, 13].
• CSF evaluation should include a cell count, protein level,
and VDRL. Elevated lymphocytes and protein, positive
VDRL are typical findings [13].
• Treatment of neurosyphilis achieves a microbiologic cure,
but many of the neurologic manifestations will be irrevers-
ible [13].
Risk factors
Risk factors for maternal infection include: Multiple sexual part-
ners, unprotected sex, sex in exchange for money or drugs, pres-
ence of other sexually transmitted infections, African American
race, spending time in a correctional facility.
The single most significant risk factor for congenital syphi-
lis infection is the maternal stage of disease. With early-stage
disease (primary, secondary, and early latent), up to 83% of fetuses
and newborns are affected [9].
Complications
• Untreated syphilis can profoundly affect pregnancy out-
come resulting in spontaneous abortion, stillbirth, non-
immune hydrops fetalis, preterm birth, or perinatal
morbidity and mortality. Fetal syphilis has similar com-
plications and manifestations to those seen in neonatal
syphilis: Hepatomegaly, ascites, elevated transaminases,
anemia, and thrombocytopenia are common [9].
• The longer the interval between infection and pregnancy,
the more benign the outcome for the infant [13].
• In general, infection during early gestation ends in spon-
taneous abortion or stillbirth; infection in late gestation
results in full-term delivery of an infant with congenital
syphilis; while infection in the distant past often results in
an unaffected infant [12].
• The greatest risk of stillbirth caused by congenital syphilis
occurs at 24–32 weeks’ gestation [14].
• Rates of vertical transmission in untreated women based
on stage of disease [14]:
• 70–100% in primary syphilis
• 40% in early latent syphilis
• 10% in late latent disease
Management
Prevention
Important practices for prevention of syphilis are early diagnosis
and treatment, partner notification and treatment, and screening
to identify asymptomatic cases in high-risk populations.
In the United States, missed opportunities to diagnose and
treat maternal syphilis has led to a rapid increase in the num-
ber of cases of congenital syphilis over the past decade. In 2018,
380 Maternal-Fetal Evidence Based Guidelines

lack of adequate maternal treatment despite timely diagnosis was
identified in 30.7% cases and lack of prenatal care in 28.2% of
cases [14, 15]. For women who require three dose treatment regi-
men, if subsequent dose is not administered within 7 days, the
course of treatment should be restarted to ensure adequate drug
levels are sustained for the duration of treatment [15].
Screening (Table 37.1)
• Most pregnant women with syphilis are asymptomatic and
can only be identified through serological screening.
• Prenatal screening and treatment programs are limited or
nonexistent in many developing countries where the inci-
dence and burden of disease is greatest.
• Screening all pregnant women for syphilis and appro-
priately treating those found to be reactive effectively
reduces complications associated with infection during
pregnancy [15, 18].
• In the United States, serologic screening during pregnancy
has been legislated since the 1930s; however, only 90% of
states currently have statutes requiring antepartum syphi-
lis screening [19]. Of those states with mandatory screen-
ing, 76% require one prenatal test early in pregnancy, and
24% require repeat screening in the third trimester. The
most cost-effective approach is to screen all pregnant
women at their initial prenatal visit, and to repeat screen-
ing in the third trimester in those women with significant
risk factors [20].
• The CDC and American College of Obstetricians and
Gynecologists (ACOG) recommend screening all preg-
nant women with a serologic test at the first prenatal
visit. Women who are at high risk, live in areas of high
syphilis morbidity, or are previously untested should be
screened at 28 weeks and again at delivery [8, 20].
• The genus Treponema includes T. carateum, the causative
agent of pinta, and T. pallidum. The latter species is subdi-
vided into three subspecies: T. pallidum subspecies pallidum,
which causes syphilis; T. pallidum subspecies pertenue, which
causes yaws; and T. pallidum subspecies endemicum, which
causes bejel. The subspecies causing pinta, yaws, and bejel are
morphologically and serologically indistinguishable from
T. pallidum (syphilis), so there is no test in current clinical use
which can differentiate one of these treponemal infections
from another. The transmission of yaws, pinta, or bejel is not
via sexual contact and the clinical course of each disease is sig-
nificantly different, which differentiates them from syphilis.
• Serologic testing remains the mainstay for screening
and laboratory diagnosis of secondary, latent, and tertiary
syphilis. These tests include nontreponemal and trepone-
mal antibody detection.
• Nontreponemal tests are useful for screening. These
include the Rapid Plasma Reagin (RPR) card test and the
VDRL.
• Nontreponemal tests are also useful for monitoring treat-
ment as titers drop over time, and often revert to negative;
however, with repeated infection complete seroreversion
may not occur.
• There is no gold standard for syphilis testing. Traditional
algorithm was performance of a nontreponemal test with
reflex to a treponemal test for confirmation. Because non-
treponemal tests are manual assays and therefore more
labor-intensive reverse algorithms are becoming more
commonly employed in a number of labs. Treponemal test-
ing is automated and high throughput testing is possible
and is more cost effective. A positive result is followed by a
nontreponemal test. A discordant result is then followed by
a different treponemal test [6].

TABLE 37.1: Screening Tests for Syphilis

Sensitivity Specificity
(%) (%) Advantages Disadvantages
Serology 85.5 97.1 • Relatively inexpensive • Not useful in primary disease
• Rapid • RPR and VDRL detect antigens
• Technically simple NOT specific to treponemes
Dark-field 80 99–100 • Useful in evaluating lesions of • Not widely available—requires
microscopy primary disease special equipment and an
• Immediate diagnosis if positive experienced operator
findings
ICS 84.1–95.3 92 • Point-of-care testing • Slightly lower sensitivity than
• Inexpensive other methods
• Can be used in the most resource-
poor settings
PCR 95.8 95.7 • In trials PCR does differentiate • Expensive
syphilis from other treponematoses
• Considered a valid test for primary • Investigational—not yet
Point of care 98.2 97.3 and secondary infection available for clinical use

Inexpensive, rapid result reduces risk of Positive result should be confirmed

patient lost to follow up with diagnostic testing
Source: Adapted from Refs. [16–18].
Abbreviations: ICS, immunochromatographic strip; PCR, polymerase chain reaction; RPR, rapid plasma reagin; VDRL, Venereal Disease
Research Laboratory.
Syphilis
• Point of care testing is now being used, primarily in
resource poor settings. Syphilis Health Check is the only
point of care test currently FDA approved. It was approved
in 2011, and received waver from the Clinical Laboratory
Improvement Amendment (CLIA) to allow the test to be
used by untrained personnel and outside of conventional
lab settings in 2015. It is a rapid immunochromatographic
test that qualitatively screens for antibodies to T. pallidum
in serum, plasma, or whole blood. It can be performed on
a fingerstick whole blood specimen, and yields result in
12 minutes. It is a screening test, so positive results should
be followed up with confirmatory diagnostic testing. If
confirmatory testing is not possible, immediate treat-
ment of screen positive women and their partners has the
potential to reduce transmission to the fetus and to sexual
contacts. A number of logistical and technical problems
have been reported with this approach, and so far no clear
reduction in perinatal death has been observed. More tri-
als are needed to adequately assess the risks and benefits of
this strategy [21].
Diagnosis
• Treponemal tests are used to confirm the diagnosis. These
include the serum FTA-ABS and the MHA-TP tests.
• Treponemal tests remain reactive for many years in over
85% of persons adequately treated, and they give a false-
positive result in about 1% of the general population, and
should therefore not be used for screening [22].
• Serologic tests are generally not reactive until several weeks
after the appearance of the primary lesion, and therefore
are not useful in diagnosing primary syphilis.
• Dark-field microscopy and direct fluorescent-antibody
testing for T. pallidum (DFA-TP) are diagnostic options for
primary syphilis.
• Dark-field microscopy is the most specific technique
for diagnosing syphilis when an active chancre or con-
dyloma latum is present. Its sensitivity is limited by the
experience of the operator performing the test, the num-
ber of live treponemes in the lesion, and the presence of
nonpathologic treponemes in oral or anal lesions. Given
the inherent difficulties of dark-field microscopy, nega-
tive examinations on three different days are necessary
before a lesion may be considered negative for T. palli-
dum [23].
• A new screening test that consists of an immunochromato-
graphic strip (ICS) impregnated with treponemal anti-
gen which tests blood obtained by finger prick and offers
immediate results is available [17]. It has been found to be
cost-effective, and has the potential to have a significant
impact on the epidemiology of this disease in undeveloped,
resource-poor countries.
• The complete genome of T. pallidum has been sequenced,
and specific PCR primers have been developed; however,
PCR is not yet available for routine clinical use [24, 25].
Workup
• Lumbar puncture is indicated with
• Neurologic/ophthalmologic signs
• Aortitis/gummas
• Treatment failure/treatment with agent other than
penicillin
381
• HIV infection
• Titer >1:32
• Cerebral spinal fluid with a positive VDRL is diagnostic for
neurosyphilis
Treatment
• The efficacy of penicillin for the treatment of syphilis was
well established through clinical experience before the
value of randomized controlled clinical trials was recog-
nized. Therefore, almost all the recommendations for the
treatment of syphilis are based on the opinions of persons
having knowledge about STDs and are reinforced by case
series, clinical trials, and more than 50 years of clinical
experience (Table 37.2).
• While erythromycin, azithromycin, and ceftriaxone are
routinely used to treat syphilis in nonpregnant patients,
they have not been shown to reliably cure maternal infec-
tion or prevent congenital syphilis [26].
• Parenteral penicillin G is the only therapy with docu-
mented efficacy for syphilis during pregnancy. The success
of therapy is >98% [27].
• The highest risk of fetal treatment failure exists with
maternal secondary syphilis [27].
• High VDRL titers at treatment and delivery, earlier mater-
nal stage of syphilis, the interval from treatment to deliv-
ery, and delivery of an infant at ≤36 weeks’ gestation are
associated with the delivery of a congenitally infected neo-
nate after adequate treatment for maternal syphilis [28].
• Pregnant women with syphilis in any stage who report
penicillin allergy should be evaluated to determine the
TABLE 37.2: Treatment of Syphilis
Primary syphilis Benzathine penicillin G 2.4 million units IM in a
single dose
Secondary syphilis Benzathine penicillin G 2.4 million units IM in a
single dose
Early latent syphilis Benzathine penicillin G 2.4 million units IM in a
single dose
Late latent syphilisa Benzathine penicillin G 2.4 million units IM each
at 1-week intervals × 3 weeks
7.2 million units total
Tertiary syphilis Benzathine penicillin G 2.4 million units IM each
at 1-week intervals × 3 weeks
7.2 million units total
Neurosyphilis Aqueous crystalline penicillin G 18–24 million
units per day, administered as 3–4 million units
IV every 4 hour or continuous infusion, for 10–14
days
OR
Procaine penicillin 2.4 million units IM once daily
PLUS
Probenecid 500 mg orally four times a day, both
for 10–14 days
Source: See further Ref. [26].
a Or syphilis of unknown duration.
382 Maternal-Fetal Evidence Based Guidelines

TABLE 37.3: Oral Desensitization Protocol for Follow-up after treatment

Patients with a Positive Skin Test
Penicillin V Cumulative
Suspension Dose No. Units Dose (Units)
1 100 100
2 200 300
3 400 700
4 800 1500
5 1600 3100
6 3200 6300
7 6400 12,700
8 12,000 24,700
9 24,000 48,700
10 48,000 96,700
11 80,000 176,700
12 160,000 336,700
13 320,000 656,700
14 640,000 1,296,700
Source: Adapted from Ref. [29].
Note: Observation period: 30 minutes before parenteral
administration of penicillin. Interval between doses,
15 minutes; elapsed time, 3 hours and 45 minutes;
cumulative dose, 1.3 million units.
need for desensitization and treated with penicillin
(Table 37.3) [29].
• Women with a penicillin reaction other than anaphylaxis
should undergo skin testing. Those with a history of ana-
phylaxis or a positive skin test to one of the penicillin deter-
minants should be desensitized and treated with penicillin.
• Desensitization is a straightforward, relatively safe pro-
cedure that can be done orally or intravenously. Oral
desensitization is regarded as safer, and is easier to per-
form. Patients should be desensitized in a hospital setting
because serious IgE-mediated allergic reaction can rarely
occur. Desensitization is typically completed in approxi-
mately 4 hours, after which the first treatment dose of peni-
cillin is administered. After desensitization, patients must
be maintained on a penicillin regimen for the duration of
therapy if multiple weekly doses are indicated by stage of
disease.
• The Jarisch–Herxheimer reaction is an acute febrile
reaction frequently accompanied by headache, myalgias,
and other symptoms that usually occurs within the first
24 hours after any therapy for syphilis. It occurs most often
in early disease—especially primary—and is thought to
represent massive lysis of treponemes. The reaction begins
within 1–2 hours of treatment, peaks at 8 hours, and
typically resolves within 24–48 hours. It occurs in up to
45% of pregnant women treated for syphilis. The Jarisch–
Herxheimer reaction may induce labor or cause fetal dis-
tress in pregnant women; however, these concerns should
not prevent or delay therapy.
• Ultrasonography provides a noninvasive means to evaluate
the fetus for signs of syphilis. Abnormal findings indicate a
risk for obstetric complications and fetal treatment failure
[30, 31].
• Sexual contacts must be elicited, tracked, and treated
(by law in the United States).
• Nontreponemal antibody serologic titers should be checked
at 1, 3, 6, 12, and 24 months following treatment [13].
• Among patients with primary and secondary syphi-
lis, a fourfold decline (two dilutions) by 6 months and
an eightfold decline (four dilutions) by 12 months are
expected.
• Among patients with early latent syphilis, a fourfold
decline by 12 months is expected.
• Titers that show a fourfold rise or do not decrease appro-
priately suggest either treatment failure or reinfection. The
treatment regimen should be repeated in these cases.
• It is important that the same testing method (RPR or
VDRL) be used for all follow-up examinations since titers
may vary by one to two dilutions if different tests are used.
• Patients with neurosyphilis should have repeat CSF evalu-
ation every 6 months for the first 2 years, or until the CSF
shows no evidence of disease [13, 24].
• Treponemal tests usually stay positive for life.
Neonatal congenital syphilis
Neonatal congenital syphilis can be completely asymptomatic
at birth, or may present with a number of characteristic clini-
cal findings including maculopapular rash, hepatosplenomegaly,
osteochondritis/periostosis (do X-ray of long bones: 95% of these
infants will have osteochondritis), jaundice, ascites/hydrops,
petechiae/purpura, lymphadenopathy, chorioretinitis, anemia,
thrombocytopenia, hyperbilirubinemia, elevated liver enzymes,
reactive syphilis serologic tests in blood/cerebral spinal fluid.
Congenital syphilis carries a significantly increase risk for peri-
natal death; up to 40% of infants born to women with untreated
syphilis are stillborn or die shortly after birth. Without treat-
ment, symptoms may develop weeks to years later. Of congenitally
affected babies, >50% are born to mothers with late or no prenatal
care, and the majority of cases are preventable [28, 30–32].
Diagnosing congenital syphilis can be difficult as the transpla-
cental transfer of maternal nontreponemal and treponemal IgG
can complicate interpretation of reactive serologic test results
in the neonate. A confirmed case of congenital syphilis is an
infant in whom T. pallidum is identified by darkfield microscopy,
fluorescent antibody, or other specific stain in specimen from
suspicious lesion, placenta, umbilical cord, or autopsy specimen.
A presumptive case is an infant of a mother with untreated
syphilis, relapse/reinfection, inadequately treated, treated <1
month before delivery, without a good history of treatment, with-
out fourfold decrease in titers, or without enough serologic fol-
low-up [26, 28, 30–32].
All neonates born to mothers with reactive nontreponemal
and treponemal test results should be evaluated with a quanti-
tative nontreponemal serologic test (RPR or VDRL) performed
specifically on serum and should have a thorough physical exam.
Neonates with proven, highly probable, or possible congenital
syphilis should also have a lumbar puncture with CSF analysis
for VDRL, cell count, and protein. Neonates with proven, highly
probable, or possible congenital syphilis need to be treated with
a 10-day course of penicillin, either intravenous aqueous crys-
talline penicillin G or intramuscular procaine penicillin G. For
cases in which the mother received adequate treatment >4 weeks
prior to delivery and congenital syphilis is less likely, a single
dose of intramuscular benzathine penicillin G can be considered
[26, 27, 30–32]. All neonates with reactive nontreponemal tests
Syphilis
should be followed closely with a physical examination and repeat
quantitative nontreponemal testing every 2–3 months until the
test becomes nonreactive [27, 28]. The importance of universal
screening in early pregnancy and repeat testing in the third tri-
mester and at delivery in all high-risk women followed by appro-
priate treatment cannot be overstated.
References
1. Rowley J, Vander Hoorn S, Korenromp E, et al. Global and regional esti-
mates of the prevalence and incidence of four curable sexually transmitted
infections in 2016. WHO Bulletin June 2019. [Epidemiologic data]
2. World Health Organization Department of Reproductive Health and
Research. The Global Elimination of Syphilis: Rationale and Strategy for
Action. Geneva: World Health Organization, 2007. [Epidemiologic data]
3. Korenromp EL, Rowley J, Alonso M, et al. Correction: global burden
of maternal and congenital syphilis and associated adverse birth out-
comes—Estimates for 2016 and progress since 2012. PLOS ONE 2019;14(7)
e0219613.
4. Borisenko KK, Tichonova LI, Renton AM. Syphilis and other sexu-
ally transmitted infections in the Russian federation. Int J STD AIDS
1999;10(10):665–668. [Epidemiologic data]
5. Centers for Disease Control and Prevention. Sexually Transmitted Disease
Surveillance, 2014. Atlanta, GA: U.S. Department of Health and Human
Services, 2015. [Review]
6. Centers for Disease Control and Prevention. Sexually Transmitted Disease
Surveillance, 2018. Atlanta, GA: U.S. Department of Health and Human
Services, 2019.
7. Centers for Disease Control and Prevention. STD’s and Pregnancy Fact
Sheet. Atlanta, GA: Department of Health and Human Services, 2018.
[Review]
8. Garnett GP, Aral SO, Hoyle DV, et al. The natural history of syphilis.
Implications for the transmission dynamics and control of infection. Sex
Transm Dis 1997;24(4):185–200. [Review]
9. Hollier LM, Harstad TW, Sanchez PJ, et al. Fetal syphilis: clinical and labo-
ratory characteristics. Obstet Gynecol 2001;97(6):947–953. [II-2]
10. Clark EG, Danbolt N. The Oslo study of the natural history of untreated
syphilis; an epidemiologic investigation based on a restudy of the Boeck-
Bruusgaard material; a review and appraisal. J Chronic Dis 1955;2(3):
311–344. [II-2]
11. Danbolt N, Clark EG, Gjestland T. The Oslo study of untreated syphilis; a
re-study of the Boeck-Bruusgaard material concerning the fate of syphi-
litics who receive no specific treatment; a preliminary report. Acta Derm
Venereol 1954;34(1–2):34–38. [II-2]
12. Rockwell DH, Yobs AR, Moore MB Jr. The Tuskegee study of untreated syph-
ilis; the 30th year of observation. Arch Intern Med 1964;114:792–798. [II-2]
13. Singh AE, Romanowski B. Syphilis: review with emphasis on clinical, epi-
demiologic, and some biologic features. Clin Microbiol Rev 1999;12(2):187–
209. [Review]
383
14. Fiumara NJ. Review of congenital syphilis. Sex Transm Dis 1984;11(1):
49–50. [Review]
15. Kimball A, Torrone E, Miele K, et al. Missed opportunities for prevention of
congenital syphilis – United States, 2018. MMWR Morb Mortal Wkly Rep
2020;69:661–665. [Epidemiologic data]
16. Montoya PJ, Lukehart SA, Brentlinger PE, et al. Comparison of the diagnos-
tic accuracy of a rapid immunochromatographic test and the rapid plasma
reagin test for antenatal syphilis screening in Mozambique. Bull World
Health Organ 2006;84(2):97–104. [II-3]
17. Young H. Syphilis serology. Dermatol Clin 1998;16(4):691–698. [II-3]
18. United States Preventive Services Task Force. Screening for Syphilis
Infection: Recommendation Statement. Rockville, MD: Agency for
Healthcare Research and Quality, 2004. [Guideline]
19. Hollier LM, Hill J, Sheffield JS, et al. State laws regarding prenatal syphi-
lis screening in the United States. Am J Obstet Gynecol 2003;189(4):
1178–1183. [Review]
20. American College of Obstetricians and Gynecologists and American
Academy of Pediatrics. Guidelines for Perinatal Care. 7th ed. Elk Grove
Village (IL): AAP; Washington, DC: ACOG, 2012. [III]
21. Tucker JD, Bu J, Brown LB, et al. Accelerating worldwide syphilis screen-
ing through rapid testing: a systematic review. Lancet Infect Dis 10;(6):
381–386. [Review]
22. Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpreta-
tion of tests for syphilis. Clin Microbiol Rev 1995;8(1):1–21. [II-3]
23. Cummings MC, Lukehart SA, Marra C, et al. Comparison of methods
for the detection of Treponema pallidum in lesions of early syphilis. Sex
Transm Dis 1996;23(5):366–369. [II-1]
24. Liu H, Rodes B, Chen CY, et al. New tests for syphilis: rational design of a
PCR method for detection of Treponema pallidum in clinical specimens
using unique regions of the DNA polymerase I gene. J Clin Microbiol
2001;39(5):1941–1946. [II-2]
25. Serwin AB, Kohl PK, Chodynicka B. The centenary of Wassermann reac-
tion—the future of serological diagnosis of syphilis, up-to-date studies.
Przegl Epidemiol 2005;59(3):633–640. [Review]
26. Centers for Disease Control and Prevention. Sexually transmitted diseases
treatment guidelines 2015. Morb Mort Wkly Rep 2015;64(RR-):36–37.
[Guidelines]
27. Alexander JM, Sheffield JS, Sanchez PJ, et al. Efficacy of treatment for syphi-
lis in pregnancy. Obstet Gynecol 1999;93(1):5–8. [II-2]
28. Sheffield JS, Sanchez PJ, Morris G, et al. Congenital syphilis after mater-
nal treatment for syphilis during pregnancy. Am J Obstet Gynecol
2002;186(3):569–573. [II-2]
29. Wendel GD Jr., Stark BJ, Jamison RB, et al. Penicillin allergy and
desensitization in serious infections during pregnancy. N Engl J Med
1985;312(19):1229–1232. [II-2]
30. Wendel GD Jr., Sheffield JS, Hollier LM, et al. Treatment of syphilis in preg-
nancy and prevention of congenital syphilis. Clin Infect Dis 2002;35(Suppl
2):S200–S209. [II-2]
31. Adhikari EH. Syphilis in pregnancy. Obstet Gynecol 2020;135(5):1121–1135.
32. Rubin R. Why are mothers still passing syphilis to their babies? JAMA
2019;321(8):729–731.
38
TRICHOMONAS
Tino Tran
Key points
• Pregnant women colonized with Trichomonas vaginalis
in the second trimester have a higher risk of delivering
an infant with low birth weight or delivering before
term, but unfortunately metronidazole treatment has
been associated with an increased risk of preterm birth.
Trichomonas vaginalis infection is a risk factor for sexual
transmission of HIV-1, with a twofold increase reported.
• Condoms, when used correctly and consistently, provide a
high degree of protection from many STIs, including T.
vaginalis infection.
• There is no evidence that identifying asymptomatic T. vagi-
nalis is beneficial in reducing the associated risk of preterm
delivery or delivery of a low-birth weight infant. Therefore,
there is insufficient evidence to recommend screening
of asymptomatic pregnant women, and some evidence
that treatment of these patients may in fact be harmful.
• Diagnosis by PCR and NAAT from vaginal secretions is the
gold standard in diagnosis of T. vaginalis in pregnancy.
• Metronidazole as a single 2-g oral dose, or 500 mg twice
a day for 7 days, at any gestational age is the treatment of
choice for symptomatic T. vaginalis infection.
• Concurrent treatment of sexual partners or referral for
treatment can be suggested to prevent reinfection.
Epidemiology/Incidence
Worldwide, it is estimated that the incidence of trichomoniasis
is 240 million new cases annually between men and women. The
prevalence worldwide was estimated to be around 156 million,
or 5.3%, up from 5.0% in 2012 [1]. Developing countries account
for a disproportionate number of cases. Trichomoniasis affects
approximately 3.7 million non-pregnant and 80,000 preg-
nant women in the United States annually [2]. The frequency
of infection in European women is similar. The World Health
Organization (WHO) estimates 78 million new infections annu-
ally in Africa [3]. In contrast to bacterial sexually transmitted
infections (STIs), such as Neisseria gonorrhoeae and Chlamydia
trachomatis, T. vaginalis infection rates are as high or higher in
middle-aged women when compared to adolescents. Incidence is
highest among women with multiple sexual partners, and in pop-
ulations with high rates of other sexually transmitted infections.
Symptoms/Signs
The clinical manifestations of trichomoniasis are unchanged
in pregnant women. Infection is asymptomatic in up to 50%
of women. The most common symptoms include vulvovaginal
pruritus (7–11%), vaginal discharge (10–17%), dysuria (30–50%),
and dyspareunia (10–50%). The most common signs are copious
vaginal discharge (50–75%) (yellow/green in 5–20%, frothy in
384
10–50%), inflammation of vaginal mucosa (40–75%), vulvar ery-
thema (10–20%) and abdominal pain (1–5%) [4].
Pathophysiology/Etiology
Trichomoniasis is caused by the protozoan T. vaginalis, which
had been previously thought to be a harmless commensal.
Trichomonas vaginalis can infect the vagina and the Skene’s
glands of the urethra along with the urethra itself. Less com-
mon sites of infection include the cervix, bladder, and Bartholin’s
gland. The incubation period for T. vaginalis is 4–7 days on
average, but ranges from 2 to 28 days. The mechanism on how
trichomoniasis infection causes preterm labor is unknown.
Some studies have linked infection to a maternal inflammatory
response. This was demonstrated by findings of elevated cervical
interleukin-9 and vaginal defensing in pregnant asymptomatic
patients which causes a neutrophilic response to release mixed
metalloproteinases [5].
Transmission
Trichomonas vaginalis is easily transmitted during vaginal inter-
course. The organism will survive for several hours in moist envi-
ronment outside the host and is rarely transmitted non-­venerally.
The transmission rate from male to female during vaginal inter-
course has been reported to be 66–100% [6]. Vertical transmis-
sion to a female infant occurs in 2–17% if vaginal infection is
present at the time of delivery [7].
Complications/Risks
Pregnant women colonized with T. vaginalis in the second tri-
mester had a 30–40% higher risk of delivering an infant with
low birth weight or delivering before term, and a 40% higher
risk of giving birth to an infant who was both preterm and of low
birth weight [8]. In a meta-analysis, infection with Trichomonas
yielded an increased relative risk of 1.42 for preterm birth, 1.41
for preterm premature rupture of membranes, and 1.51 for small
for gestational age [5]. In pregnant women with T. vaginalis,
unfortunately, metronidazole treatment, as given in the trial
(two 2-g doses given 48 hours apart at 16–23 weeks, which is
twice the usual dose for treatment) has been associated with
an 80% increase of preterm birth compared to no treatment,
with the majority of the increase in preterm delivery attributed
to spontaneous preterm labor [9–11]. The proposed mechanism
for treatment with metronidazole causing preterm labor is that
lysis of dying trichomonads elicits an inflammatory response
that triggers labor (see also Chapter 18, Obstetric Evidence Based
Guidelines) [9–11]. Other non-randomized studies have not
shown this association. A retrospective study found no asso-
ciation between metronidazole use and increase risk of preterm
birth, low birth weight, or congenital abnormalities [12]. Another
DOI: 10.1201/9781003099062-38
Trichomonas 385

retrospective cohort of 4274 women diagnosed with Trichomonas the sensitivity of this method is low. Providers using wet mount
found treatment was not associated with an increased risk of pre- to diagnose trichomoniasis should also attempt to interpret slides
term birth, and may even be protective (HR 0.69, CI 0.52–0.92, immediately as decreases in sensitivity have been found with
p = 0.010) [13]. slides interpreted >1 hour after retrieval [17].
Trichomonas vaginalis infection is a risk factor for sexual Isolation of T. vaginalis by culture was the prior gold standard,
transmission of HIV-1 in women. Studies from Africa have but the greater cost and longer time to diagnosis make this an
suggested that T. vaginalis infection approximately doubles the underutilized diagnostic option. Commonly used culture media
rate of HIV transmission [14]. The proposed mechanism for this include [18, 19]:
increased risk is twofold: Local infiltration of large number of
leukocytes including CD4+ lymphocytes—the primary target Modified Diamond’s broth media Sensitivity 95%
of HIV infection—and disruption in the integrity of the vaginal InPouch™ transport and test system Sensitivity 87%
mucosa allowing access to viral particles. HIV-positive women Modified Columbia agar Sensitivity 98%
who become infected with T. vaginalis have been shown to shed
more HIV virus in their vaginal secretions, and therefore pose a To increase the detection rate in a high-risk population without
higher risk for transmission. substantially increasing cost, culture could be performed on those
Epidemiologic studies of T. vaginalis infection in the neonatesymptomatic patients with a negative wet mount. Conventional
have reported vertical transmission rates ranging from 2% to 17% Pap smear is not considered accurate for the identification of
[7], causing vaginal, urinary, and respiratory infection in theseT. vaginalis. Confirmatory testing is necessary for those cases
neonates. reported by Pap: Sensitivity = 60–70%, specificity = 88%. Liquid-
based Pap smear is accurate for the identification of T. vaginalis
Management and warrants treatment without further testing; however, the sen-
sitivity is low (61.4%) [20]. Clinicians who perform STI screening
Prevention tests should be aware of the prevalence of STIs in the population
Condoms, when used correctly and consistently, provide a being screened and have a conceptual understanding of positive
high degree of protection from many STIs, including tricho- predictive value and the impact screening low-risk individuals has
monas [15]. Most cases of reinfection result from sexual contact with a test that has limited specificity (Table 38.1) [21–23].
with an untreated partner. Adequate treatment of sexual part- Nucleic acid-based (polymerase chain reaction [PCR] and
ners has been shown to decrease reinfection [16]. NAAT) tests are currently considered the gold standard for
detection of trichomonads. PCR and nucleic acid amplification
Screening tests that can be performed as rapid point of care testing are com-
There is no evidence that identifying asymptomatic T. vagi- mercially available in the United States. Recently, multiple assays
nalis in the general population is beneficial in reducing such as the APTIMA T. Vaginalis assay (Hologic Gen-Probe, San
the associated risk of preterm delivery or delivery of a low- Diego CA) and the BD Probe tec TV Qx has been FDA cleared for
birth weight infant. However, all women with HIV should detection of T. vaginalis from vaginal, cervical, or urine speci-
be screened for trichomoniasis as there is a high rate of co-­ mens for women. The sensitivity and specificity of NAAT test-
infection (up to 53%). Treatment of trichomoniasis in women ing has been found to be as high as 95.3–99% and 95.2–99%,
with concomitant HIV has been shown to decrease genital tract respectively. [24]. Rapid swabs for trichomoniasis are also readily
viral shedding and load [17]. available and can be read as quickly as 10 minutes, having similar
sensitivities and specificities [25].
Diagnosis
Wet mount preparation of vaginal secretions suspended in nor- Treatment
mal saline with microscopic observation of motile trichomonads The nitroimidazoles are the only class of drugs useful for the
is the most commonly utilized method of diagnosing trichomo- oral or parenteral treatment of trichomoniasis. In randomized
niasis in women. Cost is minimal with wet preparation however, clinical trials, oral nitroimidazoles have resulted in parasitologic

TABLE 38.1: Screening/Diagnostic Tests for Trichomonas vaginalis Obtained via Vaginal Swab
Sensitivity (%) Specificity (%) Advantages Disadvantages
Wet mount 62–80 >99 • Rapid results • Low sensitivity compared to culture
• Inexpensive • Sensitivity and specificity are strongly dependent
on the skills and experience of the microscopist
and also on the quality of the sample
• High specificity
Culture 95 100 • High sensitivity and • Organism can be rendered nonviable if incorrect
specificity media used or delay in transport
• 3–7 days to complete
• Not available in most clinical labs
PCR/NAAT 95 98 • Results available more • Most expensive option
quickly than with culture
Source: Adapted from Refs. [20–22].
Abbreviations: PCR, polymerase chain reaction; NAAT, nucleic acid amplification test.
386
cure rates of 90–95%. Metronidazole and tinidazole are most
commonly used. Metronidazole can be given as a single 2-g
oral dose, or 500 mg twice a day for 7 days, and can be given
to symptomatic women at any gestational age [10]. Twice daily
dosing may be more effective than the single oral dose in all
patients (RR 0·55, 95% CI 0·34–0·70; p <0·0001) [26]. In patients
with co-infection with HIV, studies have shown the twice a day
dosing to be more effective and thus should be the treatment of
choice. All patients, regardless of HIV status, should also be re-
screened for a test of cure within 3 months of initial infection
[17, 27]. This is due to the high levels of ongoing infection found
in pregnant women [28] and can be done as soon as 2 weeks with
PCR amplification. Multiple studies and meta-analyses have not
demonstrated an association between metronidazole use during
pregnancy and teratogenic or mutagenic effects in infants [29, 30,
31]. Tinidazole is given as a single 2-g oral dose. Its use is con-
tra-indicated in the first trimester of pregnancy. Metronidazole
resistance is increasingly common. The CDC estimated that 5%
of clinical isolates of T. vaginalis exhibit some degree of met-
ronidazole resistance. An escalated dosing regimen of metro-
nidazole 2 g daily for 3–5 days has been successful in some cases
of resistant infection, but in general not more than a single 2-g
dose should be given to prevent possible increase in preterm
birth [10]. Tinidazole is effective in treating up to 60% of met-
ronidazole-resistant T. vaginalis infections. Concurrent treat-
ment of sexual partners is recommended to prevent reinfection.
Concurrent treatment via expedited partner treatment (EPT) has
been proposed for treatment of trichomoniasis but has not shown
in randomized trials to decrease reinfection rates versus partner
referral [16, 32]. Currently, no clear evidence-based recommen-
dations for EPT exist [17]. In those rare cases with a confirmed
metronidazole allergy, patients should go through desensitization
of their allergy before being treated with metronidazole [33].
References
1. Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea,
trichomoniasis and syphilis: global prevalence and incidence estimates,
2016. Bull World Health Organ 2019;97(8):548–62P. [III]
2. Satterwhite CL, Torrone E, Meites E, et al. Sexually transmitted infections
among US women and men: prevalence and incidence estimates, 2008. Sex
Transm Dis 2013;40:187–93. [III]
3. Gerbase AC, Mertens TE. Sexually transmitted diseases in Africa: time for
action. Afr Health 1998;20(3):10–12. [Review, III]
4. Sutton M, Sternberg M, Koumans EH, McQuillan G, Berman S, Markowitz
L. The prevalence of Trichomonas vaginalis infection among reproduc-
tive-age women in the United States, 2001-2004. Clin Infect Dis 2007;45:
1319–26. [Level II-3]
5. Silver BJ, Guy RJ, Kaldor JM, et al. Trichomonas vaginalis as a cause of peri-
natal morbidity: a systematic review and meta-analysis. Sex Transm Dis
2014;41(6):369–76 [Meta-analysis; 11 studies]
6. Krieger JN. Trichomoniasis in men: old issues and new data. Sex Transm
Dis 1995;22(2):83–96. [II-3]
7. Danesh IS, Stephen JM, Gorbach J. Neonatal Trichomonas vaginalis infec-
tion. J Emerg Med 1995;13(1):51–54. [II-3]
8. Cotch MF, Pastorek JG II, Nugent RP, et al. Trichomonas vaginalis associ-
ated with low birth weight and preterm delivery. The Vaginal Infections and
Prematurity Study Group. Sex Transm Dis 1997;24(6):353–60. [II-2]
9. Klebanoff MA, Carey JC, Hauth JC, et al. National Institute of Child Health
and Human Development Network of Maternal-Fetal Medicine Units.
Failure of metronidazole to prevent preterm delivery among pregnant
women with asymptomatic Trichomonas vaginalis infection. N Engl J Med
2001;345(7):487–93. [RCT; I]
10. Gulmezoglu AM, Azhar M. Interventions for trichomoniasis in pregnancy.
Cochrane Database Syst Rev 2011;2011(5). [Meta-analysis; two RCTs; n =
842, (II-1)]
Maternal-Fetal Evidence Based Guidelines
11. Ross SM, Van Middelkoop A. Trichomonas infection in pregnancy: does it
affect outcome? S Afr Med J 1983;63:566–67. [RCT; n = 225; 2 g metronida-
zole × 1 dose to women and their partners, (II-1)]
12. Koss C, Baras D, Lane S, et al. Investigation of metronidazole use during
pregnancy and adverse birth outcomes. Antimicrob Agents Chemother
2012;56:4800–05. [II-1]
13. Mann JR, DMcDermott S, Zhou L et al. Treatment of trichomoniasis in
pregnancy and preterm birth: an observational study. J Women’s Health
2009;18(4):493–97. [II-2]
14. Laga M, Manoka A, Kivuvu M, et al. Non-ulcerative sexually transmitted
diseases as risk factors for HIV-1 transmission in women: results from a
cohort study. AIDS 1993;7(1):95–102. [II-2]
15. Paz-Bailey G, Koumans EH, Sternberg M, et al. The effect of correct and
consistent condom use on chlamydial and gonococcal infection among
urban adolescents. Arch Pediatr Adolesc Med 2005;159(6):536–42.
[II-3]
16. Schwebke JR, Desomnd RA. A randomized controlled trial of partner noti-
fication methods for prevention of Trichomonas in women. Sex Transm Dis
2010;37:392–96. [RCT, n = 484, (II-1)]
17. Workowski KA, Bolan GA; Centers for Disease Control and Prevention.
Sexually transmitted diseases treatment guidelines, 2015. MMWR
Recomm Rep. 2015 Jun 5;64(RR-03):1-137.
18. Borchardt KA, Zhang MZ, Shing H, et al. A comparison of the sensitiv-
ity of the InPouch TV, diamond’s and trichosel media for detection of
Trichomonas vaginalis. Genitourin Med 1997;73(4):297–98. [II-2]
19. Stary A, Kuchinka-Koch A, Teodorowicz L. Detection of Trichomonas vagi-
nalis on modified Columbia agar in the routine laboratory. J Clin Microbiol
2002;40(9):3277–80. [II-2]
20. Lara-Torre E, Pinkerton JS. Accuracy of detection of Trichomonas vagina-
lis organisms on a liquid-based Papanicolaou smear. Am J Obstet Gynecol
2003;188(2):354–56. [II-2]
21. Radonjic IV, Dzamic AM, Mitrovic SM, et al. Diagnosis of Trichomonas
vaginalis infection: the sensitivities and specificities of microscopy, cul-
ture and PCR assay. Eur J Obstet Gynecol Reprod Biol 2006;126:116–20.
[II-2]
22. Aslan DL, Gulbahce HE, Stelow EB, et al. The diagnosis of Trichomonas
vaginalis in liquid-based pap tests: correlation with PCR. Diagn Cytopathol
2005;32(6):341–44. [II-3]
23. Patel SR, Wiese W, Patel SC, et al. Systematic review of diagnostic tests for
vaginal trichomoniasis. Infect Dis Obstet Gynecol 2000;8(5–6):248–57.
[Review, II-1]
24. Hollman D, Coupey SM, Fox AS, et al. Screening for Trichomonas vaginalis
in high-risk adolescent females with a new transcription-mediated nucleic
acid amplification test (NAAT): associations with ethnicity, symptoms, and
prior and current STIs. J Pediatr Adolesc Gynecol 2010;23:312–6. [II-2]
25. Gaydos CA, Schwebke J, Dombrowski J, et al. Clinical performance of the
Solana® point-of-care trichomonas assay from clinician-collected vaginal
swabs and urine specimens from symptomatic and asymptomatic women.
Expert Rev Mol Diagn 2017;17(3):303–6. [II-2]
26. Kissinger P, Muzny CA, Mena LA, et al. Single-dose versus 7-day-dose met-
ronidazole for the treatment of trichomoniasis in women: an open-label,
randomised controlled trial. Lancet Infect Dis 2018;18(11):1251–9. [II-1]
27. Lazenby GB, Thompson L, Powell AM, et al. Unexpected high rates of per-
sistent Trichomonas vaginalis infection in a retrospective cohort of treated
pregnant women. Sex Transm Dis 2019;46(1):2–8. [II-2]
28. Sheehy O, Santos F, Ferreira E, et al. The use of metronidazole during preg-
nancy: a review of evidence. Curr Drug Saf 2015;10(2):170–9. [Review; II]
29. Kissinger P, Mena L, Levison J, et al. A randomized treatment trial: sin-
gle versus 7-day dose of metronidazole for the treatment of Trichomonas
vaginalis among HIV-infected women. J Acquir Immune Defic Syndr
2010;55:565–71. [RCT, N-270, (II-1)]
30. Burtin P, Taddio A, Ariburnu O, et al. Safety of metronidazole in pregnancy:
a meta-analysis. Am J Obstet Gynecol 1995;172(2 pt 1):525–29. [Meta-
analysis, III]
31. Sorensen HT, Larsen H, Jensen ES, et al. Safety of metronidazole during
pregnancy: a cohort study of risk of congenital abnormalities, preterm
delivery and low birth weight in 124 women. J Antimicrob Chemother
1999;44(6):854–56. [II-2]
32. Kissinger P, Schmidt N, Mohammed H, et al. Patient-delivered partner
treatment for Trichomonas vaginalis infection: a randomized controlled
trial. Sex Transm Dis 2006;33:445–50. [II-1]
33. Helms DJ, Mosure DJ, Secor WE, Workowski KA. Management of
Trichomonas vaginalis in women with suspected metronidazole hypersen-
sitivity. Am J Obstet Gynecol 2008;198:370.e1–7. [Level II-3]
39
GROUP B STREPTOCOCCUS
Stephanie Thomas
Key points
• Asymptomatic group B streptococcus (GBS) colonization
in the pregnant patient is associated with an incidence
of neonatal GBS disease of 1–2% without intervention.
Neonatal disease is divided into early onset and late-
onset, with possible complications including sepsis, pneu-
monia, meningitis, and less frequently focal infections
and death.
• Major risk factors for neonatal GBS sepsis are preterm
delivery, prolonged rupture of membranes (≥18 hours),
and temperature ≥100.4°F (≥38°C).
• Universal prenatal screening with intrapartum antibi-
otic treatment as indicated is more effective than a risk
factor-based strategy for prevention of early onset GBS dis-
ease. There is no known effective preventative strategy for
late-onset disease.
• Patients with GBS bacteriuria (of any colony count) in
the current pregnancy or who had a prior infant with
GBS sepsis are candidates for intrapartum antibiotic
prophylaxis (IAP), and should be the only two groups not
screened in the third trimester.
• Screening involves collecting an anovaginal specimen
at 36 0/7 to 37 6/7 weeks (labeled penicillin-allergic if
appropriate).
• Patients who are GBS positive are treated with penicil-
lin in labor. Ampicillin is a reasonable alternative. If the
patient is penicillin-allergic but not at high risk for ana-
phylaxis, cefazolin is the agent of choice. For the patient
at high risk for anaphylaxis to penicillin and with a cul-
tured isolate sensitive to both clindamycin and erythro-
mycin, treatment with clindamycin is indicated. If the
culture is resistant to either clindamycin or erythromy-
cin, or if sensitivities are unknown, then treatment with
vancomycin is recommended.
• If intraamniotic infection is suspected, broad-spectrum
antibiotic therapy should include coverage for GBS (e.g.,
ampicillin and gentamicin) and should replace GBS
prophylactic therapy.
Background
GBS (Streptococcus agalactiae) is an encapsulated gram-positive
coccus that colonizes the vagina and gastrointestinal tract of
some patients. Infection with GBS is a cause of morbidity and
mortality in pregnant and postpartum patients as well as in neo-
nates. Neonates acquire the organism as a result of vertical trans-
mission from the maternal genital tract in utero or usually at
delivery after rupture of membranes. GBS disease in the neonate
is divided into early onset and late-onset disease (Table 39.1).
Early-onset disease presents within the first 6 days of life and
often is observed within 24 hours of delivery. Late-onset disease
DOI: 10.1201/9781003099062-39
presents between 7 days and 3 months after birth, most com-
monly at 3–4 weeks of age. Infections in the infant can be local-
ized or systemic.
Symptoms
In the pregnant patient, GBS colonization is usually asymptom-
atic. Symptoms of neonatal GBS disease include breathing prob-
lems, poor feeding, irritability, extreme drowsiness, unstable
temperature (low or high), weakness, and listlessness (in late
onset). The clinical presentation in early onset disease does not
differentiate GBS as the etiology from other pathogens [1].
Epidemiology/Incidence
GBS is a major cause of infectious morbidity among infants.
In the United States, it is the most common cause of serious
neonatal bacterial sepsis, including neonatal meningitis. The
prevalence of asymptomatic GBS anovaginal colonization in
pregnant patients is about 20%, with a range of 10–30% [1–5].
GBS colonization during pregnancy can be transient or persis-
tent. Roughly half of patients who are colonized during one preg-
nancy will have GBS colonization during a subsequent pregnancy
[6, 7]. Usually 40–75% of neonates born to colonized patients are
colonized themselves (see Figure 39.1) [2]. As a result of preven-
tion efforts, employing screening, and antibiotic prophylaxis, the
incidence of early onset GBS sepsis fell in the United States from
1.8 cases per 1000 live births in the 1990s to 0.23 per 1000 live
births in 2015 [8].
Risk factors/Associations
For early onset GBS disease, risk factors include anovaginal GBS
colonization during the intrapartum period, preterm delivery
(though >80% of affected neonates were delivered at term),
prolonged rupture of membranes (ROM) (≥18 hours), tem-
perature ≥100.4°F (≥38°C), birth of a previous infant with inva-
sive GBS disease, intra-amniotic infection, young maternal age,
African American race, Hispanic ethnicity, and GBS bacteriuria
during pregnancy [9]. Diabetes or anovaginal GBS colonization
in a previous pregnancy are not risk factors for early onset GBS
disease, though GBS colonization in a previous pregnancy is a
risk factor for recurrent GBS colonization [10].
Complications
GBS can cause urinary tract infections, intraamniotic infections,
endometritis, and bacteremia in the pregnant patient. In the fetus,
it can be associated with stillbirth. Neonatal early onset disease
presents with breathing difficulty, shock, pneumonia, and occa-
sionally meningitis [1]. Late-onset disease is commonly charac-
terized by bacteremia and meningitis; less frequently it presents
387
388 Maternal-Fetal Evidence Based Guidelines

TABLE 39.1: Early versus Late-Onset GBS Characteristics Maternal GBS Colonization
10–30%
Early Onset Late Onset
Definition Occurs <1 week ≥1 week
Usual timing of 24–48 hour ≥1 week
manifestation after birth Newborn non-colonized Newborn colonized
Incidence (of all neonatal 80% (without 20% (without prophylaxis); 50% 50%
GBS sepsis) prophylaxis); 50% 50% (screen and treat)
(screen and treat)
Most common/ Sepsis, pneumonia Meningitis, localized Asymptomatic Early-onset neonatal sepsis
predominant clinical (meningitis infections (ears, eyes, ≥98% ≤2%*
signs/symptoms 10–30%)
breasts, bone, joints, skin,
FIGURE 39.1 GBS infection: maternal to infant transmission.
etc.)
* With treatment (anogenital screening at 36–37 weeks’ gestation
Serotype III (95%) and intrapartum prophylaxis if GBS positive), 0.4% of colonized
Case-fatality ratio Overall = 5% <2% neonates will develop early-onset GBS sepsis. Without treatment,
Full-term = 2–3% 2% of colonized neonates will develop early-onset GBS sepsis.
<33 week = 30%
Long-term morbidity If meningitis—15–50% can
have neurologic sequelae the pregnancy or with a prior infant with GBS disease are also
given intrapartum treatment. Over 20% of neonates with early
onset GBS sepsis are born to patients without risk factors. While
this was a popular strategy in the past, it is less effective than a
with focal infections such as osteomyelitis, septic arthritis, or
screening-based strategy [12]. It leads to both unnecessary pro-
cellulitis. Neonatal death occurs in 4–6% of cases of early onset
phylaxis in some GBS negative patients and lack of prophylaxis in
disease. Mortality is higher among preterm infants—20% to 30%
others [15]. A risk factor-based strategy is still recommended in the
if <33 weeks’ gestation—compared with 2–3% among full-term
United Kingdom, with the latest guideline published September
infants (see Table 39.1) [1].
2017 [16]. Listed reasons from the Royal College of Obstetricians
and Gynaecologists for not adopting universal screening include
Management limited data on the impact of a universal screening strategy on
mortality, concerns about maternal anaphylaxis, development of
Several approaches to the prevention of early onset GBS neo- antibiotic resistance, and increased medicalization of the perina-
natal infection have been studied or devised [11]. There are no tal period. A 2020 systematic review and meta-analysis compared
randomized trials that compare the efficacy of these approaches, a universal screening strategy to a risk factor-based strategy and
probably because they would have to include >100,000 screened found lower incidences of early onset GBS disease without an
pregnancies to show a difference in early onset GBS sepsis, given increase in antibiotic administration, calling into question the
the current incidence of the disease (<0.5%). concern about antibiotic overuse with universal screening [17].
Universal prenatal screening and Universal maternal treatment
intrapartum treatment There is insufficient data to evaluate universal treatment of all
A universal screening-based strategy is more effective than pregnant patients during birth.
a risk factor-based strategy [12, 13]. With a universal screen-
ing strategy, risk factor-based treatment is applied for those with Neonatal (screening and) treatment only
an unknown GBS status at the time of impending delivery. After Screening and/or treatment of just the neonate without some
the Centers for Disease Control and Prevention (CDC) recom- form of in utero prophylaxis is a much inferior approach than
mended this screening strategy compared to the risk factor– the prenatal screening approaches just described (screening or
based strategy in 2002, the incidence of early onset GBS sepsis in risk factor-based). Neonatal treatment only is “too little too late,”
the United States declined from 0.47/1000 live births (1999–2001) as 40% of neonates with GBS are already bacteremic at birth.
to 0.23/1000 live births (2015) [8, 14]. This approach of screening Evaluation of neonates born to GBS-positive patients who were
for GBS colonization and intrapartum treatment does not affect not treated or to patients with risk factors is imperative [18].
incidence of late-onset GBS sepsis. A screening-based strategy
is recommended in the United States (see Figure 39.2) (see section Future directions: Maternal vaccination
“Screening” for more details) [1, 9]. Vaccination against GBS is a potential method of preventing the
morbidity and mortality caused by GBS infection. GBS vaccines
Intrapartum treatment based on risk have been investigated as a tool to reduce anogenital colonization
factors without prenatal screening and prevent transmission to the neonate. However, a licensed vac-
Under this strategy, universal prenatal screening is not performed. cine is not yet available [1]. GBS capsular polysaccharide (CPS)-
Instead, risk factors are assessed at the time of admission for deliv- based protein conjugate vaccines have been tested in phase I and II
ery to determine which patients receive prophylactic antibiotic trials [19–21]. They were shown to be safe and well-tolerated, and
therapy. Risk factors used for this strategy are gestational age <37 the antibody response was persistent for over a year in the patient
and 0/7 weeks, intrapartum temperature of ≥100.4°F (≥38°C), with passive protection passed on to the neonate [22]. Bacterial
or ROM ≥18 hours [1]. Patients with GBS bacteriuria during surface proteins are another target in vaccine development [20].
Group B Streptococcus
Vaginal and rectal GBS screening cultures at 36–37 weeks gestation for all pregnant patients
(unless patient had GBS bacteriuria during the current pregnancy or a previous infant with
invasive GBS disease)
Intrapartum prophylaxis indicated
• Previous infant with invasive GBS disease
• GBS bacteriuria (>10,000 CFU) during current
pregnancy
• Positive GBS screening culture during current
pregnancy (unless cesarean birth with intact
membranes prior to labor)
• Intrapartum NAAT positive for GBS
• Unknown GBS status (culture not done, incomplete,
or results unknown) and any of the followinga:
• Delivery at <37 weeks gestation
• Amniotic membrane rupture ≥18 hours
• Intrapartum temperature ≥100.4°F (≥38 . 0°C)b
• Known GBS positive status in a previous
pregnancy
FIGURE 39.2 Indications for intrapartum antibiotic prophylaxis to prevent perinatal GBS disease under a universal prenatal
screening strategy based on combined vaginal and rectal cultures collected at 36 0/7 to 37 6/7 weeks’ gestation from all pregnant
patients. (Modified from Ref. [1].)
a If an intrapartum nucleic acid amplification test (NAAT) is negative and any of the following risk factors are present, then intrapartum prophylaxis
is indicated.
b If amnionitis is suspected, broad-spectrum antibiotic therapy that includes an agent known to be active against GBS should replace GBS prophylaxis.
c Optimal timing 36–37 weeks’ gestation.
A phase III randomized trial recording neonatal disease events
after vaccination is needed [1, 23]. Vaccination is the only strat-
egy that would have the potential to protect against late-onset
disease, which current strategies do not cover.
Screening
As anogenital GBS colonization is the primary risk factor for early
onset neonatal GBS infection, prenatal screening can help iden-
tify neonates at risk. Because colonization can be intermittent,
a swab done earlier in pregnancy is less predictive of intrapar-
tum status and early onset GBS disease than a culture performed
within 5 weeks of birth. In 2019, ACOG updated its recommended
timing for GBS screening to 36 0/7 to 37 6/7 weeks gestation [9].
The rationale for the change from 35 to 36 weeks’ gestation was
that intrapartum antibiotic prophylaxis (IAP) is recommended
as a default for preterm deliveries with unknown GBS status and
that this will provide a valid result for gestations up to 41 weeks.
Patients with GBS bacteriuria in the current pregnancy or who
had a prior infant with GBS sepsis are candidates for IAP, and
should not be screened [1]. Notably, cultures obtained after pro-
phylactic antibiotic administration may not accurately reflect
GBS status [24].
Prenatal screening is primarily performed via GBS culture
from a vaginal-rectal swab. Sampling the lower vagina, fol-
lowed by the anorectal area gives the highest yield of GBS
[1]. ACOG recommends that rectal sampling include swabbing
internal to the anal sphincter. However, vaginal-rectal swabs,
during which >70% of women report at least mild pain, do not
389
Intrapartum prophylaxis not indicated
• Previous pregnancy with a positive GBS
screening culture (unless colonization
status is unknown during current
pregnancy)
• Cesarean delivery performed in the
absence of labor or membrane rupture
(regardless of maternal GBS culture
status)
• Negative vaginal and rectal GBS
screening culture in late gestationc
during the current pregnancy, regardless
of intrapartum risk factors
increase GBS detection rates compared to vaginal-perianal swabs
in one study [25]. The swab is transported in special medium (e.g.,
Amies or Stuart’s without charcoal), which maintains GBS viabil-
ity at room temperature for several days. It is labeled “penicillin
allergy” when applicable. The swab is incubated using a selective
enrichment broth media (e.g., Todd-Hewitt with antibiotics) over
18–24 hours and then cultured on blood agar plates. For penicil-
lin-allergic patients, clindamycin and erythromycin disk suscep-
tibility is performed [1].
Nucleic acid amplification testing (NAAT) is used by some lab-
oratories for GBS testing. When performed after an 18–24 hour
incubation step, rates for GBS detection are equivalent to those of
standard culture. Rapid NAAT has also been used as a point-of-
care test for patients in labor, though the sensitivity of the test is
reduced without the incubation step [9, 26]. Whether performed
after an incubation step or not, NAAT does not allow for sus-
ceptibility testing for those patients with penicillin allergies. For
patients who present in labor at term with an unknown GBS sta-
tus and without risk factors for early onset GBS disease, use of
NAAT has adequate specificity (92–99%) to guide IAP [27–30].
Intrapartum prophylaxis
The incidence of early onset GBS infection is reduced with use
of IAP in patients colonized with GBS. Treatment is associated
with a 90% decreased incidence of infant colonization and 83%
decreased incidence of early onset GBS disease [31]. Without IAP,
early onset disease will occur in 1–2% of neonates who experience
vertical transmission of GBS (see Table 39.2) [9].
390 Maternal-Fetal Evidence Based Guidelines

TABLE 39.2: Recommended Regimens for Intrapartum such as amniotomy, should not be withheld solely to achieve
Antimicrobial Prophylaxis for Perinatal GBS 4 hours of IAP prior to delivery [9].
Disease Preventiona Penicillin is the first-line agent for intrapartum GBS prophy-
laxis (Table 39.2). For patients with a penicillin allergy who are
Recommended Penicillin G, 5 million units IV
not at high risk for anaphylaxis, cefazolin is recommended.
initial dose, then 3 million units IV
For the patient at high risk for anaphylaxis to penicillin with
every 4 hours until delivery
a cultured isolate sensitive to both clindamycin and erythro-
Alternative Ampicillin, 2 g IV initial dose, then
mycin, treatment with clindamycin is indicated. If the cul-
1 g IV every 4 hours until delivery
ture is resistant to either clindamycin or erythromycin, or if
If penicillin allergicb
sensitivities are unknown, then treatment with vancomycin
Patients not at high risk for Cefazolin, 2 g IV initial dose, then is recommended [1]. If intra-amniotic infection is suspected,
anaphylaxis 1 g IV every 8 hours until delivery broad-spectrum antibiotic therapy (e.g., ampicillin and gen-
Patients at high risk for anaphylaxisc tamicin) is recommended; this replaces GBS prophylactic
GBS susceptible to clindamycin Clindamycin, 900 mg IV every therapy. Penicillin allergy skin testing is safe in pregnancy and
and erythromycind 8 hours until delivery can be considered for patients with unclear allergy histories.
GBS resistant to clindamycin Vancomycin, 20 mg/kg IV every Most patients with a stated penicillin allergy are not truly allergic
or erythromycin or 8 hours until delivery, [9]. Such testing may decrease the costs and potential morbidity
susceptibility unknown maximum of 2 g per single dose of treating a patient with alternative antibiotics over the course of
Source: Modified from Ref. [1]. her lifetime [33].
a Broader-spectrum agents, including an agent against GBS, are necessary for treat- For patients with threatened preterm delivery, see Figure 39.3.
ment of intraamniotic infection. In brief, such patients should be tested for GBS if their status is
b History of penicillin allergy should be assessed to determine whether a high risk unknown and treated with IAP if unknown status or if known
for anaphylaxis, angioedema, respiratory distress, or urticaria is present. GBS positive. If preterm labor stalls, IAP can be discontinued.
c Clindamycin and erythromycin susceptibility testing should be performed on pre-
Patients with preterm premature rupture of membranes at or
natal GBS isolates from penicillin-allergic patients at high risk for anaphylaxis. after 34 weeks who are colonized with GBS should be counseled
d Resistance to erythromycin is often, but not always, associated with clindamycin
to proceed with delivery [34].
resistance. If a strain is resistant to erythromycin, but appears susceptible to
Newborns of patients undergoing cesarean delivery before
clindamycin, it may still have inducible resistance to clindamycin. Treatment with
labor or ROM have an extremely low risk for early onset GBS
erythromycin is not recommended.
disease. Antibiotic prophylaxis is not recommended in this cir-
cumstance. However, patients planning to be delivered by cesar-
The highest efficacy is seen when antibiotics are given ean should still undergo screening for GBS, in case they present
≥4 hours before delivery. A retrospective study evaluating the in labor or with ROM.
timing of antibiotic prophylaxis found a smaller but still benefi- Adverse consequences of prophylaxis are anaphylaxis to
cial decrease in early onset sepsis if antibiotics were administered penicillin (4–40/100,000), development of drug resistance,
2 hours prior to delivery [32]. Indicated obstetric interventions, and potential alterations to the neonatal gut microbiome [35].

Onset of labor or at <37 weeks gestation with significant risk for

imminent preterm delivery

No GBS culture GBS+ GBS negative

within 5 weeks

Obtain vaginal
and rectal GBS Intrapartum
culture and prophylaxis No GBS
initiate GBS prophylaxisa
prophylaxis
Progressing in labor?
Culture negative
No Yes

Stop antibioticsa Stop antibioticsb Continue GBS prophylaxis

until delivery

FIGURE 39.3 Algorithm for GBS prophylaxis for patients with threatened preterm delivery. This algorithm is not an exclusive
course of management. Variations that incorporate individual circumstances or institutional preferences may be appropriate. (See
further Ref. [43].)
a If delivery has not occurred within 4 weeks, a vaginal and rectal GBS screening culture should be repeated, and the patient should be managed as
described, based on the result of the repeat culture.
b GBS prophylaxis at onset of true labor.
Group B Streptococcus
Signs of clinical No
illness
Yes
Blood cultures
Empiric antibioticsa
FIGURE 39.4 One option for early-onset GBS sepsis assessment in infants born ≥35 weeks gestation. (Adapted from Ref. [42].)
a Consider lumbar puncture and CSF culture before initiation of empiric antibiotics for infants who are at the highest risk of infection, especially
those with critical illness. Antibiotics should be administered promptly and not deferred because of procedure delays.
b Adequate GBS IAP is defined as the administration of penicillin G, ampicillin, or cefazolin ≥4 hours before delivery.
Additionally, there are concerns about increased rates of neo-
natal infection from agents other than GBS, but this has been
challenged by a large multi-center observational study by the
CDC which showed no increase in gram-negative early onset
sepsis after adoption of a universal screening strategy [36].
Vaginal chlorhexidine has not been shown to be associated
with reductions in neonatal early onset GBS disease or mortality
[37]. The lack of efficacy may be due to insufficient data (type II
error).
GBS bacteriuria
Antibiotics should not be used before the intrapartum period
to treat asymptomatic maternal GBS colonization, except in
the case of GBS bacteriuria, which is defined as 10 5 or more
CFU/mL. Asymptomatic patients with GBS bacteriuria at
27–31 weeks’ gestation have decreased preterm birth (PTB) <37
weeks when treated with penicillin 1 million IU three times per
day for 6 days compared to placebo [38]. Such treatment is not
expected to eliminate GBS from the maternal genitourinary or
gastrointestinal tracts. There is no evidence that antepartum
treatment of asymptomatic patients with lower concentrations
of GBS in their urine improves maternal or neonatal outcomes
[9, 39]. Every urine specimen sent in pregnancy should be
labeled “pregnant” to alert the laboratory to report any isola-
tion of GBS. GBS identified in the urine at any concentration
is a marker for heavy maternal colonization and is an indi-
cation for IAP [1, 40].
Antepartum testing
No specific indication for GBS carriers.
Delivery
IAP is described in Figure 39.2 and Table 39.2. There is insuf-
ficient evidence to assess whether digital vaginal examinations
or intrauterine fetal monitoring affect incidence of GBS sepsis
[1]. Per ACOG, GBS colonization is not a contraindication for
clinically indicated vaginal exams, amniotomy, or intrauterine
monitoring [9]. There seems to be no increase in GBS sepsis in
pregnancies undergoing stripping of membranes [41], but none of
the studies reported screening or results for GBS.
391
Maternal No GBS IAP No
intrapartum indicated?
temperature
Routine
Yes newborn care
Yes
Adequate GBS
Yes
IAP givenb?
No
Clinical observation
Neonatal management
In 2019, the American Academy of Pediatrics (AAP) updated its
recommendations for evaluation and management of infants at
risk for GBS disease. For infants born at or above 35 weeks’ gesta-
tion, three different risk assessment approaches are acceptable.
See Figure 39.4 for one such approach, and see the AAP publica-
tion for further information, including recommendations for care
of at-risk infants born below 35 weeks’ gestation [42].
References
1. Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B strepto-
coccal disease—revised guidelines from CDC, 2010. Division of Bacterial
Diseases, National Center for Immunization and Respiratory Diseases,
Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep
2010;59(RR–10):1–36. [Review/guideline; Accessible at: http://www.cdc.
gov/groupbstrep]
2. Regan JA, Klebanoff MA, Nugent RP. The epidemiology of GBS coloniza-
tion in pregnancy. Vaginal infections and prematurity study group. Obstet
Gynecol 1991;77(4):604–610. [II-2]
3. Anthony BF, Okada DM, Hobel CJ. Epidemiology of group B Streptococcus:
longitudinal observations during pregnancy. J Infect Dis 1978;137:524–530.
[II-3]
4. Dillon HC Jr., Gray E, Pass MA, et al. Anorectal and vaginal carriage of
group B streptococci during pregnancy. J Infect Dis 1982;145:794–799.
[II-3]
5. Boyer KM, Gadzala CA, Kelly PD, et al. Selective intrapartum chemo-
prophylaxis of neonatal group B streptococcal early-onset disease. II.
Predictive value of prenatal cultures. J Infect Dis 1983;148:802–809.
[II-2]
6. Turrentine MA, Colicchia LC, Hirsch E, et al. Efficiency of screening for the
recurrence of antenatal group B streptococcus colonization in a subsequent
pregnancy: a systematic review and meta-analysis with independent patient
data. Am J Perinatol 2016;33:510–7. [Meta-analysis; II-3]
7. Rottenstreich M, Rotem R, Srebnik N, et al. The recurrence risk of group
B streptococcus in consecutive deliveries. J Matern Fetal Neonatal Med
2020;33(13):2263–2268. [II-2]
8. Nanduri SA, Petit S, Smelser C, et al. Epidemiology of invasive early-onset
and late-onset group B streptococcal disease in the United States, 2006
to 2015: multistate laboratory and population-based surveillance. JAMA
Pediatr 2019;173(3): 224–233. [II-2]
9. American College of Obstetrics and Gynecologists. Prevention of early-
onset group B streptococcal disease in newborns. Committee Opinion No.
797. Obstet Gynecol 2020;135:e51–72. [Guideline; III]
392
10. Page-Ramsey SM, Johnstone SK, Kim D, Ramsey PS. Prevalence of
group B Streptococcus colonization in subsequent pregnancies of group
B Streptococus-colonized versus noncolonized women. Am J Perinatol
2013;30:383–388. [II-2]
11. Rouse DJ, Goldenberg RL, Oliver SP, et al. Strategies for the prevention
of early-onset neonatal group B streptococcal sepsis: a decision analysis.
Obstet Gynecol 1994;83:483–494. [Decision analysis]
12. Schrag SJ, Zell ER, Lyndfield R, et al. A population-based comparison of
strategies to prevent early-onset group B streptococcal disease in neonates.
N Engl J Med 2002;347:233–239. [II-1]
13. Locksmith GJ, Clark P, Duff P. Maternal and neonatal infection rates with
three different protocols for prevention of group B streptococcal disease.
Am J Obstet Gynecol 1999;180:416–422. [II-1]
14. Centers for Disease Control and Prevention. Active Bacterial Core
Surveillance Report, Emerging Infections Program Network, Group B
Streptococcus, 2013.
15. Johansen NR, Kjærbye-Thygesen A, Jønsson S, et al. Prevalence and treat-
ment of group B streptococcus colonization based on risk factors ver-
sus intrapartum culture screening. Eur J Obstet Gynecol Reprod Biol
2019;240:178–181. [III]
16. Hughes RG, Brocklehurst P, Steer PJ, et al on behalf of the Royal College
of Obstetricians and Gynaecologists. Prevention of early-onset neona-
tal group B streptococcal disease. Green-top Guidelines No. 36. BJOG
2017;124:e280–e305. [Guideline; III]
17. Hasperhoven GF, Al-Nasiry S, Bekker V, et al. Universal screening versus
risk-based protocols for antibiotic prophylaxis during childbirth to prevent
early-onset group B streptococcal disease: a systematic review and meta-
analysis. BJOG 2020;127(6):680–691. [Meta-analysis; II-2]
18. Puopolo KM, Madoff LC, Eichenwald EC. Early-onset group B strepto-
coccal disease in the era of maternal screening. Pediatrics 2005;115(5):
1240–1246. [II-2]
19. Paoletti LC, Mafoff LC. Vaccines to prevent neonatal GBS infection. Semin
Neonatal 2002;7(4):315–323. [Review]
20. Song JY, Lim JH, Lim S, et al. Progress toward a group B streptococcal vac-
cine. Hum Vaccin Immunother 2018;14:2669–81. [Review; III]
21. Hillier SL, Ferrieri P, Edwards MS, et al. A phase 2, randomized, control
trial of group B streptococcus (GBS) type III capsular polysaccharide-­
tetanus toxoid (GBS III-TT) vaccine to prevent vaginal colonization with
GBS III. Clin Infect Dis 2019;68(12):2079–2086. [I]
22. Lin FY, Philips III JB, Azimi PH. Level of maternal antibody required to pro-
tect neonates against early onset disease caused by group B Streptococcus
type Ia: a multicenter, seroepidemiology study. J Infect Dis 2001;184:
1022–1028. [II-2]
23. Law MR, Palomaki G, Alfiveric Z, et al. The prevention of neonatal group B
streptococcal disease: a report by a working group of the medical screening
society. J Med Screen 2005;12:60–68. [III]
24. Mackay G, House MD, Bloch E, Wolfberg AJ. A GBS culture collected
shortly after GBS prophylaxis may be inaccurate. J Mat Fetal Neonatal Med
2012;25(6):736–8. [II-2]
25. Jamie WE, Edwards RK, Duff P. Vaginal-perianal compared with vaginal-
rectal cultures for identification of group B Streptococcus. Obstet Gynecol
2004;104:1058–1061. [II-2]
26. El Helali N, Habibi F, Azria E, et al. Point-of-care intrapartum group B
streptococcus molecular screening: effectiveness and costs. Obstet Gynecol
2019;133:276–81. [II-3]
Maternal-Fetal Evidence Based Guidelines
27. Chan WSW, Chua SC, Gidding HF, et al. Rapid identification of group B
streptococcus carriage by PCR to assist in the management of prelabour
rupture of membranes in term pregnancy. Aust N Z J Obstet Gynaecol
2014;54(2):138–145. [II-2]
28. Poncelet-Jasserand E, Forges F, Varlet M-N, et al. Reduction of the use of
antimicrobial drugs following the rapid detection of Streptococcus agalac-
tiae in the vagina at delivery by real-time PCR assay. BJOG 2013;120:1098–
1109. [II-2]
29. Young BC, Dodge LE, Gupta M, et al. Evaluation of a rapid, real-time
intrapartum group B streptococcus assay. Am J Obstet Gynecol 2011;205:
37231–6. [II-2]
30. Abdelazim IA. Intrapartum polymerase chain reaction for detec-
tion of group B streptococcus colonization. Aust N Z J Obstet Gynaecol
2013;53:236–242. [II-2]
31. Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal Group B
streptococcal colonization. Cochrane Database Syst Rev 2014;6:CD007467.
[Three RCTs, n = 488 infants. Overall poor-quality RCTs]
32. Turrentine MA, Greisinger AJ, Brown KS, et al. Duration of intrapartum
antibiotics for group B streptococcus on the diagnosis of clinical neonatal
sepsis. Inf Dis Obstet Gynecol 2013;2013:525878. [II-2]
33. Desai SH, Kaplan MS, Chen Q, Macy EM. Morbidity in pregnant women
associated with unverified penicillin allergies, antibiotic use, and group B
streptococcus infections. Perm J 2017;21:16-080. [II-2]
34. Tajik P, van der Ham DP, Zafarmand MH, et al. Using vaginal Group B
streptococcus colonization in women with preterm premature rupture of
membranes to guide the decision for immediate delivery: a secondary anal-
ysis of the PPROMEXIL trials. BJOG 2014;121:1263–1273. [I]
35. Seedat F, Geppert J, Stinton C, et al. Universal antenatal screening for
group B streptococcus may cause more harm than good. BMJ 2019;364:l463.
[Review/opinion; III]
36. Schrag SJ, Farley MM, Petit S, et al. Epidemiology of invasive early-onset
neonatal sepsis, 2005 to 2014. Pediatrics 2016;138:e20162013. [II-2]
37. Ohlsson A, Shah VS, Stade BC. Vaginal chlorhexidine during labour to
prevent early-onset neonatal group B streptococcal infection. Cochrane
Database Syst Rev 2014;12:CD003520. [Meta-analysis; five RCTs, n = 2190]
38. Thomsen AC, Morup L, Hansen KB. Antibiotic elimination of group-B
streptococci in urine in prevention of preterm labour. Lancet 1987;591–593.
[RCT; n = 69]
39. Khalil MR, Uldbjerg N, Moller JK, Thorsen PB. Group B streptococci cul-
tured in urine during pregnancy associated with preterm delivery: a selec-
tion problem? J Matern Fetal Neonatal Med 2019;32(19):3176–3184. [II-2]
40. Perez-Moreno MO, Pico-Plana E, Grande-Armas J, et al. Group B strep-
tococcal bacteriuria during pregnancy as a risk factor for maternal
intrapartum colonization: a prospective cohort study. J Med Microbiol
2017;66:454–60. [II-2]
41. Boulvain M, Stan CM, Irion O. Membrane stripping for induction of labor.
Cochrane Database Syst Rev 2010. [Meta-analysis]
42. Puopolo KM, Lynfield R, Cummings JJ, American Academy of Pediatrics,
Committee on Fetus and Newborn, Committee on Infectious Diseases.
Management of infants at risk for Group B streptococcal disease. Pediatrics
2019;144(2):e20191881. [Guideline; III]
43. National Institute for Health and Clinical Excellence: Antibiotics for early-
onset neonatal infection. CG149. London: National Institute for Health and
Clinical Excellence, 2012. [Review/guideline; available at: www.nice.org/
uk/cg149]
40
VACCINATIONS
Joshua H. Barash and Edward M. Buchanan
Key points
• Evaluation of a woman’s immune status should occur in
the preconception period. Optimally, immunization with
indicated vaccines should occur prior to pregnancy.
• Immunity to rubella, varicella, influenza, and hepatitis B
should be determined and vaccination should be adminis-
tered as necessary in the preconception period.
• Nonetheless, in most cases, vaccines should be admin-
istered to pregnant women believed to be at high risk for
acquiring a vaccine-preventable illness, as there is no vac-
cine that is more dangerous to a pregnant woman or her
fetus than the disease it is designed to prevent.
• Recombinant, inactivated, and subunit vaccines, as well as
toxoids, and immunoglobulins pose no threat to a develop-
ing fetus.
• Inactivated influenza vaccine should be given to all
pregnant women during the influenza season. The live
attenuated form of the vaccine (intranasal spray) should
not be given during pregnancy.
• Hepatitis B vaccine can be safely given in pregnancy.
• Tdap vaccine should be administered to all pregnant
women in every pregnancy regardless of previous vac-
cination history. Optimal timing of Tdap vaccination is
27–36 weeks’ gestation.
• Live, attenuated vaccines are contraindicated in preg-
nancy because of the theoretical concern for fetal infec-
tion. However, if inadvertent vaccination occurs during
pregnancy, no adverse fetal outcomes have been described
with rubella, varicella, or BCG vaccination.
• Rubella and varicella immunity should be determined in
all women of childbearing age. MMR (measles-mumps-
rubella) and varicella vaccination should be avoided in
pregnancy as they are live attenuated vaccines, and admin-
istered to all nonimmune women in the preconception
or postpartum period.
• The m-RNA COVID vaccines (e.g. Pfizer, Moderna)
as well as other selected COVID vaccines are safe and
should be recommended in pregnant women, in any tri-
mester, as well as during lactation.
• Breastfeeding does not adversely affect immunization
and is not a contraindication for any vaccine, with the
exception of smallpox vaccine.
• No vaccine is 100% safe and 100% effective in non-preg-
nant or pregnant adults.
Historical notes
Vaccination is one of the most cost-effective and clinically suc-
cessful medical interventions available. The incidence of vac-
cine-preventable diseases drops precipitously upon initiating an
effective vaccination program within a population [1]. A strategic
DOI: 10.1201/9781003099062-40
approach to vaccinating women of childbearing age and their
close contacts is critical to preventing infectious prenatal compli-
cations, fetal embryopathy, and neonatal disease. Immunization
prior to conception or at specific windows of opportunity during
pregnancy, create disease specific interventions to protect a preg-
nant woman, her offspring, or both [2].
Pregnancy and vaccine-preventable diseases
Pregnancy is an important part of the life cycle when certain
infections can play a particularly destructive role. Pregnancy
creates a relative immune suppression, which places a woman
at greater risk of complications from illnesses such as influenza
and varicella. Likewise, maternal infections with such viruses as
varicella and rubella can cause a spectrum of fetal effects includ-
ing congenital anomalies, fetal morbidities, and even fetal death.
Finally, neonates are highly susceptible to complications from
vaccine preventable diseases at a time when they do not receive
full protection from vaccination themselves. Vaccination of an
individual induces immunity, a process known as active immu-
nization. Maternal vaccination also provides protection of the
neonate through passive immunization, in which maternal
antibodies (IgG) are transmitted transplacentally, particu-
larly in the last 4–6 weeks of gestation [3]. An additional benefit
may occur with the passage of antibodies (IgA) via breast milk.
In addition, by immunizing close contacts of a newborn, the risk
of exposure to disease is reduced, a strategy known as cocooning.
General guidelines for
vaccination and pregnancy
Preconception
Evaluation of a woman’s immune status should occur in the
preconception period. Optimally, immunization with indi-
cated vaccines should occur prior to pregnancy. For the repro-
ductive age female, preconception evaluation of immunity to
rubella, varicella, and hepatitis B are particularly beneficial
for the health of the woman and her offspring (Tables 40.1–41.4)
[1–59]. If live, attenuated vaccines are administered, the
patient should avoid pregnancy for 4 weeks because of the
theoretical concern for transplacental infection of the fetus [4].
Family members of a newborn should be immunized against
influenza. Through cocooning, this gives additional protec-
tion to individuals at high risk of complications from influ-
enza. Likewise, the need for pertussis booster should be
assessed in close contact of a newborn as family members are
the most common source of neonatal infections [5].
Pregnancy
If a woman is pregnant at the time of evaluation, careful selection
of appropriate vaccinations should be made on the basis of the
clinical situation to reduce morbidity from high-risk infections.
Recombinant, inactivated, and subunit vaccines, as well as toxoids
393
394 Maternal-Fetal Evidence Based Guidelines

TABLE 40.1: Recommended for All Women of Childbearing Age (Preconception, Postpartum, and Considered Safe in
Pregnancy)
Vaccine Vaccine Type Dosing Regimen Indications/Comments
Influenza [23, 24] Inactivated subunit Annually Vaccinate all adults and children >6 months. Pregnant women
Trivalent-inactivated (IM injection) should be immunized during the influenza season at any gestation.
vaccine (TIV) Do not administer live vaccine (LAIV, FluMist) during pregnancy
Tetanus/diphtheria Toxoids Booster every 10 years after primary Uncertain history or incomplete primary series, administer
Td [26] series completed three-dose primary series (Td):

• Vaccines given at 0, 4 weeks, and 6–12 months.

• Tdap should replace one dose of Td, preferably during the
late second or third trimester of pregnancy [28]
Tdap [26] Toxoids/acellular Single dose of Tdap to replace one No history of prior Tdap vaccination:
Td booster
• Tdap should be administered as a one-time booster
regardless of interval since the last tetanus or
diphtheriatoxoid containing vaccine

Tdap and pregnancy:

• Women who have not received Tdap should receive it during

pregnancy, preferably between 27–36 weeks gestation [28]
Hepatitis B [36] Recombinant Pre-exposure prophylaxis: Exposure to blood in workplace, dialysis/ESRD patients, current
or history of injection drug use, more than 1 sexual partner in
• Three-dose series: 0, 1, and 4 monthsa
the past 6 months, other sexually transmitted infections,
• Third dose at least 2 months after
hepatitis C, household contact or sexual partner of person with
second dose AND at least 4 months
chronic hepatitis B, health care personnel, travel to area of high
after initial dose
prevalence for >6 monthb
Postexposure prophylaxis:

• Either vaccinate, give HBIG or both

(depends on exposure type, vaccine
status, time from exposure)

COVID-19 [60–62] mRNA Two-dose series The m-RNA vaccines (e.g., Pfizer; Moderna) are safe and should
be recommended in pregnant women, in any trimester, as well
• Second dose 3–4 weeks after first
as during lactation [62]
dose

Human papilloma Recombinant Three-dose series Although HPV vaccine has not been causally associated with
(HPV) [38, 39] adverse outcomes during pregnancy (category B), it is not
• Second dose 1–2 months after the
recommended during pregnancy
first dose
If a woman becomes pregnant after starting the series, the
• Third dose 6 months after the initial
remainder of the series should be delayed until after delivery
dose
No interventions are needed if a dose is inadvertently
administered during pregnancy
a Special dosing required for dialysis and immunocompromised patients.
b Diseases related to travel, available at: http://www.cdc.gov/travel/content/diseases.aspx.

and immunoglobulins, pose no threat to a developing fetus [6, 7].
These medications may be administered at any time in pregnancy
although delaying until the second trimester will avoid false asso-
ciations with adverse events in the first trimester. Live, attenuated
vaccines are contraindicated in pregnancy because of the theo-
retical concern for fetal infection. However, if inadvertent vaccina-
tion occurs during pregnancy, no adverse fetal outcomes have been
described with rubella, varicella, or BCG vaccination [8–13].
Specific vaccines
Influenza
Inactivated influenza vaccine should be administered
in any trimester during the flu season to reduce the risk
that infection poses to a pregnant woman (Table 40.1) [14].
Close contacts of the pregnant woman should also be immu-
nized. Pregnant women and young infants are at significant
increased risk for serious sequelae of influenza. During preg-
nancy, women have a fourfold increased rate of serious illness
and hospitalization [15]. The increased morbidity related to
influenza during pregnancy is related to physiologic changes
that include decreased pulmonary volume, increased car-
diac output, and suppression of cell-mediated immunity [16].
Likewise, newborns have higher rates of hospitalization, mor-
bidity, and mortality due to influenza compared to other age
groups [17]. Multiple studies demonstrate that influenza vac-
cination during pregnancy reduces the incidence of infection
and disease complications for women and their offspring,
including risk of hospitalization and death [18–21]. Influenza
vaccine has been routinely administered during pregnancy
Vaccinations 395

TABLE 40.2: Recommended for Pregnant Women at Significant Risk for Exposure
Vaccine Subtype Dosing Regimen Indications/Comments
Hepatitis A Inactivated Pre-exposure prophylaxis: Chronic liver disease, clotting disorders requiring clotting factor
[40, 41] precipitates, illicit drug users (both injection and noninjection),
• Two-dose vaccine series, second dose
men who have sex with men, travel/live/work in endemic areas
6–18 month after the first dose
Unvaccinated persons in contact with an infected person (both
Postexposure prophylaxis: sexual and household contacts), members of child care centers with
an infected employee or child, to be considered for hospital workers
• Either vaccinate, give IG or both in close contact with infected patients
depending on exposure type, age, health
statusa
Pneumococcal Polysaccharide Single dose Smoking (adults 19 year and older), chronic pulmonary disease
[37] including smoking, asthma, chronic liver disease, chronic
alcoholism, chronic cardiovascular disease, chronic renal failure or
nephrotic syndrome, functional or anatomic asplenia (e.g., sickle
cell disease or splenectomy), diabetes mellitus, immunosuppressive
conditions (e.g., HIV) [42]
One-time revaccination after 5 year Chronic renal failure or nephrotic syndrome, functional or anatomic
asplenia (e.g., sickle cell disease or splenectomy), chronic high-dose
steroids, immunosuppressive conditions [42]
Rabies [43–45] Inactivated Pre-exposure prophylaxis: Veterinary workers, persons having frequent contact with animal
species at risk for rabies,b spelunkers, travelers to areas where dog
• Three doses: days 0, 7, 21, or 28
rabies is enzootic and rapid access to medical care may not be
Test Ab titer every 6 month for continuous available
exposure or every 2 year for intermittent Indicated for any wound/scratch/bite caused by a possibly rabid
exposure animalb
Multiple studies on the vaccine and RIG in pregnant women failed
• Booster vaccination if titer < acceptable to show an elevated risk, vaccine felt to be overall safe in
level pregnancy [43, 44]
Postexposure prophylaxis:

• Not previously vaccinated:

Single dose of rabies immune globulin

(RIG) + four doses of vaccine on days 0,
3, 7, and 14c

• If previously vaccinated: one dose of

vaccine immediately, and repeat 3 days
later
Meningococcal Polysaccharide, Single dose, revaccination after 5 year Anatomic or functional asplenia, terminal complement component
[46–50] conjugate, recommended if continued high risk for deficiency, military recruits, boarding school or college students,
recombinant infection travel or reside in endemic or epidemic area
Safety data with the quadrivalent polysaccharide vaccine in
pregnancy is limited; however, more safety data is available for the
polysaccharide than the conjugated version of the vaccine. Of note,
conjugated vaccine has not been associated with any increase risk
of adverse effects when given inadvertently in pregnancy. No
pregnancy data exists for Serogroup B meningococcal vaccines
Polio (IPV, Inactivated Three-dose primary series if not previously Travel to or live in areas where polio is endemic or epidemic, lab
inactivated Completed worker who might handle poliovirus, health care workers who
polio vaccine) might care for polio infected persons, unvaccinated adults whose
• Second dose 1–2 months after first dose
[51] children will receive OPV
• Third dose 6–12 months after second
dose • IPV is used exclusively for routine vaccination in the United
States and other nations where polio is not endemic. OPV is still
Booster—if risk of exposure and primary
used for outbreaks [51]
series completed more than 10 year
• Pregnancy: Vaccination should be avoided on theoretical
previously:
grounds, but if at increased risk for infection, IPV can be
• Single dose of IPV administered. No adverse effects have been found in pregnant
women or their fetuses
(Continued)
396 Maternal-Fetal Evidence Based Guidelines

TABLE 40.2 (Continued): Recommended for Pregnant Women at Significant Risk for Exposure
Vaccine Subtype Dosing Regimen Indications/Comments
Polio (OPV, Live If less than 4 weeks available to immunize, a dOPV has a risk of causing vaccine-related paralytic poliomylitis. It is
oral polio single dose of OPV may be given [22] used in countries endemic for polio where the superior secretory
vaccine) Three-dose primary series and booster immunity in the gastrointestinal tract induced by OPV is an
recommendations are same as discussed advantage. OPV is the only product available in many developing
earlier nations and should be used in pregnancy as indicated. No adverse
effects have been found to mother/fetus
Anthrax [52] Inactivated, Pre-exposure: 5 IM doses (0 week, 4 week, 6 Pre-exposure: Military personnel in high risk areas, persons who
acellular month, 12 month, and 18 month (IM)) + perform high risk laboratory work, handle animal product/hides
vaccine annual booster to maintain immunity and unable to adhere to standards of prevention (Although, likely
safe in pregnancy, CDC recommends deferment in vaccine
administration in pregnant persons even if high risk of exposure)
Postexposure: Three doses SC (0, 2, 4 week) Postexposure: Given to persons exposed including pregnant and
with 60-day antimicrobial postexposure breast-feeding women, children <18 year decided case by case
prophylaxis
Japanese Inactivated Three-dose series Travelers with significant risk of exposure based on destination,
encephalitis duration of travel, season, and activities [53]
• 0, 7, and 30 days
[53]
Typhoid Live attenuated Oral: three-dose series Given to those at high risk: travel to or live in area where typhoid is
OralTY21a Polysaccharide endemic, close contact of typhoid carrier, lab exposure to
• One dose every 2 days
injectable Vi Inactivated Salmonella typhi bacteria. Information on safety in pregnancy is
whole-cell Injection Vi not available, on theoretical grounds avoid vaccination in
vaccine pregnancy
• Single dose Given to those at high risk: live in or travel to area where yellow fever
Inactivated injection is endemic, or lab exposure to the virus. Not well studied in
pregnancy, pregnant women who must travel to areas where risk of
• Two doses 4 week apart yellow fever infection is high should be vaccinated
Yellow fever Live virus Single dose
[54–56]
• Booster every 10 year for continued risk/
exposure
a Recommendations for hepatitis A postexposure prophylaxis: www.cdc.goV/mmwr/preview/mmwrhtml/mm5641a3.htm#box.
b Animals at high risk for carrying rabies: https://www.cdc.gov/rabies/exposure/animals/other.html.
c For persons with immunosuppression, rabies postexposure prophylaxis should be administered using all five doses of vaccine on days 0, 3, 7, 14, and 28.

d Diseases related to travel.

Abbreviation: IG, immunoglobulin.

since 1957. No study to date has shown an adverse conse-
quence of inactivated influenza vaccine in pregnant women
or their offspring [22–24].
Td/Tdap
Td (tetanus toxoid, reduced inactivated diphtheria toxoid) is a
tetanus vaccine containing diphtheria toxoid as well (Table 40.1).
Tetanus in newborn infants, once common, is prevented if the
mother has been immunized, because the immune mother passes
antibodies to the fetus across the placenta. Maternal tetanus
toxoid vaccination has been shown to be up to 98% effective in
preventing neonatal tetanus [25]. Td effectiveness in preventing
neonatal deaths was 62% [26]. The WHO estimates that 1.5 mil-
lion cases of neonatal tetanus have been prevented since a 1989
initiative to eliminate maternal and neonatal tetanus.
Tdap vaccine (tetanus toxoid, reduced inactivated diphthe-
ria toxoid, and acellular pertussis) was first licensed in 2005
and now recommended for use in persons age ≥ 7 years old
(Table 40.1). Pertussis protection was added to Td vaccine due
to a resurgence of pertussis cases worldwide. Family members
with pertussis are the source of infection in 75% of cases in early
infancy, when complications and fatalities are high [27]. Infants
less than 12 months old account for most of the morbidity and
mortality related to pertussis [28].
Tdap administration is recommended for all women in each
pregnancy as early as possible between 27 and 36 weeks gesta-
tion, regardless of previous immunization timing. With peak
maternal antibody titers occurring at least 2 weeks after vacci-
nation, this timing allows for maximal transplacental antibody
passage to the fetus during the third trimester [29] Consequently,
the newborn will benefit from passive immunity to pertussis until
active immunization takes effect via the childhood immunization
program schedule. This strategy, recommended by the CDC since
2013, has demonstrated a vaccine effectiveness for newborn pro-
tection from pertussis of 90–93% [30–32].
Hepatitis B
Hepatitis B is a serious problem in pregnancy because of the
possibility of vertical transmission to the neonate (see Chap. 32;
Table 40.1). Vertical transmission occurs in up to 90% of infected
women depending on their viral status, and 90% of the chil-
dren who become infected develop chronic infection [33–35].
Nonimmune women at high risk for HBV infection during preg-
nancy should be immunized. This includes women who have had
Vaccinations 397

TABLE 40.3: Not Recommended in Pregnancy

Vaccine Type Dosing Regimen Comments
Varicella Live attenuated Two-dose series Not given to pregnant women or women planning to
become pregnant within 4 week
• Second dose 4–8 week after first
Initiate series in the immediate postpartum period to
Postexposure prophylaxis those women determined to be varicella nonimmune
on prenatal evaluation
• Varicella zoster immune globulin (VZIG) within VZIG and IVIG are safe in pregnancy and breastfeeding
96 hour of exposure to varicella or herpes zoster Acyclovir in Pregnancy Registry was completed in 1999.
• If VZIG is not available: Data on 124,748 exposures in pregnancy did not find an
• IVIG can be used at a dose of 400 mg/kg association with any adverse pregnancy outcome [57]
given IV as a single dose

OR

• Closely monitor for development of disease and

treat with acyclovir if disease develops
MMR Live attenuated Single dose Not given to pregnant women or women planning to
(measles- become pregnant within 4 week
mumps- Administer this MMR vaccine in the immediate
rubella) postpartum period to those women determined to be
rubella nonimmune on prenatal evaluation
BCG Live attenuated Single dose Consider giving to healthcare workers in areas where drug
resistant strains of TB persist. No harmful fetal effects
have been associated with BCG, but its use is not
recommended in pregnancy [8]
Smallpox Live attenuated Single inoculation Pregnant women, or women planning to become pregnant
[58, 59] Immunity decreases 3–5 years after vaccination within 4 week should not be vaccinated in the absence of
Postexposure prophylaxis: exposure to active disease
Vaccination within 3 days of exposure will Close contacts of pregnant women or women planning to
completely prevent or significantly modify become pregnant within 4 week should not be vaccinated
smallpox in the vast majority of persons. unless exposed to active disease—exposure to the
Vaccination 4–7 days after exposure likely offers resulting lesion can cause vaccinia viral infection in the
some protection from disease or decreases severity pregnant woman and/or fetus
CDC’s Advisory Committee on Immunization Practices does not recommend preventive use of vaccinia immune globulin (VIG) for pregnant women. However, if a woman
has a complication from smallpox vaccine that could be treated with VIG, she should receive it while pregnant [30, 31].

more than one sexual partner in the past 6 months, illicit drug
TABLE 40.4: Vaccination Clinical Guide Summary
users (both injected and non-injected substances), those with an
Preconception Pregnancy Postpartumg HBsAg-positive sex partner, and those being evaluated or treated
Influenzaa Any trimester Influenzaa
for a sexually transmitted disease [36]. Women at risk should also
be counseled on safe sexual practices to prevent HBV infection.
MMRb Influenzaa; COVID MMRb
HBV is also spread through oral secretions. Therefore, women
Varicellab Gestational age 27–36 weeks Varicellab
with HBsAg-positive household members should also be vacci-
Td/Tdap Tdape Tdaph
nated [36].
HPVc Maternal indications Benefit HPVc
> Risk Streptococcus pneumoniae
Hepatitis Bd Hepatitis B Hepatitis Bd In Table 40.2, pneumococcal vaccine indications are presented,
Pneumococcald Pneumococcal Pneumococcald which includes maternal asthma and smoking. Although studies
Meningococcald Meningococcalf Meningococcald have investigated a potential protective effect against pneumo-
Hepatitis Ad Hepatitis A Hepatitis Ad coccal disease of the newborn through maternal immunization, a
COVID COVID recent Cochrane Review concludes there is insufficient evidence
to assess this outcome [37]. At the present time, pneumococcal
See Table 40.2 for further details about travel vaccines or vaccines related to high-risk
vaccination is recommended for maternal indications only.
conditions.
a Administer one dose of inactivated vaccine during influenza season.

b If demonstrated non-immune, preconception advise to avoid pregnancy for 4 weeks.

c Age 13–26 years.
d When maternal indications are present.
e Administer every pregnancy regardless of vaccination history.
f Tetravalent polysaccharide preferred based on safety data [21].
g Postpartum vaccines listed are not contraindicated in breastfeeding [32].
h If not already given intrapartum.
COVID-19
Several vaccines are available against SARS-CoV-2, the virus
responsible for COVID-19 infections. COVID-19 infection is
associated with higher incidence of hospitalization, mechanical
ventilation, intensive care unit admission, maternal death, com-
pared to COVID-19 in non-pregnant reproductive age women
[60], and higher incidences of preterm birth, stillbirth, and other
398
adverse perinatal outcomes, especially with critical COVID-19
infection [61]. The m-RNA vaccines (e.g. Pfizer, Moderna) are
safe and should be recommended in pregnant women, in any
trimester, as well as during lactation [62]. Withholding FDA-
approved vaccines from this population based on theoretical risks
would be unethical [62]. FDA-approved vaccines should not be
withheld from women solely based on their pregnancy or lacta-
tion status when they otherwise meet criteria for vaccination
[62]. Withholding vaccine violates ethical principle of autonomy,
as well as beneficence and justice [62]. Live-attenuated vaccines
should not be administered in pregnancy.
Contraindications to vaccination
The only true contraindication applicable to all vaccines is a his-
tory of a severe allergic reaction after a prior dose of vaccine or to a
vaccine component, unless the recipient has been desensitized. An
extensive listing of vaccine components, their use, and the vaccines
that contain each component is available from CDC’s National
Immunization Program website at www.cdc.gov/vaccines/.
References
1. Roush SW, Murphy TV, Vaccine-Preventable Disease Table Working Group.
Historical comparisons of morbidity and mortality for vaccine-preventable
diseases in the United States. JAMA 2007;298(18):2155–63. [Review]
2. Abu-Raya B, Edwards KM. Optimizing the timing of vaccine administra-
tion during pregnancy. JAMA 2019;321(10):935–6. [Review]
3. Insel RA. Maternal immunization to prevent neonatal infections. N Engl J
Med 1988;319(18):1219–20. [Review]
4. Centers for Disease Control and Prevention and Advisory Committee
on Immunization Practices (ACIP). Guidelines for vaccinating pregnant
women. Available at: www.cdc.gov/vaccines/pubs/downloads/b_preg_
guide pdf [Accessed 2020, 29]. [Guideline]
5. Liang JL, Tiwari T, Moro P, Messonnier NE, Reingold A, Sawyer M, et al.
Prevention of pertussis, tetanus, and diphtheria with vaccines in the united
states: recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Recomm Rep 2018;67(2):1–44. [Guideline]
6. Ezeanolue E, Harriman K, Hunter P, Kroger A, Pellegrini C. General best
practice guidelines for immunization: best practices guidance of the
Advisory Committee on Immunization Practices (ACIP). National Center
for Immunization and Respiratory Diseases 2019. [Guideline]
7. Gynecologists American College of Obstetricians and ACOG
Committee Opinion, No. 741. Maternal immunization. Obstet Gynecol.
2018;131(741):e214–7. [Guideline]
8. Representatives Liaison The role of BCG vaccine in the prevention and con-
trol of tuberculosis in the united states a joint statement by the Advisory
Council for the Elimination of Tuberculosis and the Advisory Committee
on Immunization Practices. MMWR Recommend Rep 1996;45:1–18.
[Guideline]
9. Bar-Oz B, Levichek Z, Moretti ME, Mah C, Andreou S, Koren G. Pregnancy
outcome following rubella vaccination: a prospective controlled study. Am
J Med Genet A 2004;130A(1):52–4. [RCT]
10. Bart SW, Stetler HC, Preblud SR, Williams NM, Orenstein WA, Bart KJ,
et al. Fetal risk associated with rubella vaccine: an update. Rev Infect Dis
1985;7(Suppl 1):S95–102. [Review]
11. Centers for Disease Control (CDC). Rubella vaccination during preg-
nancy—United States, 1971-1988. MMWR Morb Mortal Wkly Rep
1989;38(17):289–93. [Review]
12. Sheppard S, Smithells RW, Dickson A, Holzel H. Rubella vaccination and
pregnancy: preliminary report of a national survey. Br Med J (Clin Res Ed)
1986;292(6522):727. [Survey]
13. Wilson E, Goss MA, Marin M, Shields KE, Seward JF, Rasmussen SA, et al.
Varicella vaccine exposure during pregnancy: data from 10 Years of the
pregnancy registry. J Infect Dis 2008;197(Suppl 2):S178–84. [II-2]
14. Mak TK, Mangtani P, Leese J, Watson JM, Pfeifer D. Influenza vaccination
in pregnancy: current evidence and selected national policies. Lancet Infect
Dis 2008;8(1):44–52. [Review]
15. MacDonald NE, Riley LE, Steinhoff MC. Influenza immunization in preg-
nancy. Obstet Gynecol 2009;114(2 Pt 1):365–8. [Review]
Maternal-Fetal Evidence Based Guidelines
16. Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, Omer SB.
Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol
2009;201(6):547–52. [Review]
17. Munoz FM. Influenza virus infection in infancy and early childhood.
Paediatr Respir Rev 2003;4(2):99–104. [Review]
18. Poehling KA, Szilagyi PG, Staat MA, Snively BM, Payne DC, Bridges CB,
et al. Impact of maternal immunization on influenza hospitalizations in
infants. Am J Obstet Gynecol 2011;204(6 Suppl 1):S141–8. [II-2]
19. Benowitz I, Esposito DB, Gracey KD, Shapiro ED, Vázquez M. Influenza
vaccine given to pregnant women reduces hospitalization due to influenza
in their infants. Clin Infect Dis 2010;51(12):1355–61. [Review]
20. Dabrera G, Zhao H, Andrews N, Begum F, Green H, Ellis J, et al. Effectiveness
of seasonal influenza vaccination during pregnancy in preventing influenza
infection in infants, England, 2013/14. Euro Surveill 2014;19(45):20959.
[Review]
21. Madhi SA, Cutland CL, Kuwanda L, Weinberg A, Hugo A, Jones S, et al.
Influenza vaccination of pregnant women and protection of their infants. N
Engl J Med 2014;371(10):918–31. [Review]
22. ACOG and Gynecologists American College of Obstetricians Committee
Opinion no. 732. Influenza vaccination during pregnancy. Obstet Gynecol
2018 April. [Guideline]
23. Munoz FM, Jackson LA, Swamy GK, Edwards KM, Frey SE, Stephens I, et al.
Safety and immunogenicity of seasonal trivalent inactivated influenza vac-
cines in pregnant women. Vaccine 2018;36(52):8054–61. [RCT]
24. Grohskopf LA, Alyanak E, Broder KR, Walter EB, Fry AM, Jernigan DB.
prevention and control of seasonal influenza with vaccines: recommenda-
tions of the advisory committee on immunization practices - United States,
2019-20 Influenza Season. MMWR Recommend Rep 2019;68(3):1–21.
[Guideline]
25. Havers FP, Moro PL, Hunter P, Hariri S, Bernstein H. Use of tetanus tox-
oid, reduced diphtheria toxoid, and acellular pertussis vaccines: updated
recommendations of the advisory committee on immunization practices
– United States, 2019. MMWR Morb Mortal Wkly Rep 2020;69(3):77–83.
[Guideline]
26. Demicheli V, Barale A, Rivetti A. Vaccines for women to prevent neonatal
tetanus. Cochrane Database Syst Rev 2005;(4):CD002959. [Meta-analysis]
27. Bisgard KM, Pascual FB, Ehresmann KR, Miller CA, Cianfrini C, Jennings
CE, et al. Infant pertussis: who was the source? Pediatr Infect Dis J
2004;23(11):985–9. [RCT]
28. Centers for Disease Control and Prevention (CDC). Updated recommen-
dations for use of tetanus toxoid, reduced diphtheria toxoid, and acellu-
lar pertussis vaccine (Tdap) in pregnant women–Advisory Committee on
Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep
2013;62(7):131–5. [Review]
29. Munoz FM, Bond NH, Maccato M, Pinell P, Hammill HA, Swamy GK, et al.
Safety and immunogenicity of tetanus diphtheria and acellular pertussis
(Tdap) immunization during pregnancy in mothers and infants: a random-
ized clinical trial. JAMA 2014;311(17):1760–9. [CCT]
30. Terranella A, Asay GRB, Messonnier ML, Clark TA, Liang JL. Pregnancy
dose Tdap and postpartum cocooning to prevent infant pertussis: a deci-
sion analysis. Pediatrics 2013;131(6):e1748–56.
31. Dabrera G, Amirthalingam G, Andrews N, Campbell H, Ribeiro S, Kara E,
et al. A case-control study to estimate the effectiveness of maternal per-
tussis vaccination in protecting newborn infants in England and Wales,
2012–2013. Clin Infect Dis 2015;60(3):333–7.
32. Amirthalingam G, Andrews N, Campbell H, Ribeiro S, Kara E, Donegan K,
et al. Effectiveness of maternal pertussis vaccination in England: an obser-
vational study. Lancet 2014;384(9953):1521–8. [Review]
33. Gupta I, Ratho RK. Immunogenicity and safety of two schedules of hepatitis
B vaccination during pregnancy. J Obstet Gynaecol Res 2003;29(2):84–6.
[Review]
34. Levy M, Koren G. Hepatitis B vaccine in pregnancy: maternal and fetal
safety. Am J Perinatol 1991;8(3):227–32. [Guideline]
35. Munoz FM, Jamieson DJ. Maternal immunization. Obstet Gynecol
2019;133(4):739–53. [Meta-analysis]
36. Schillie S, Vellozzi C, Reingold A, Harris A, Haber P, Ward JW, et al.
Prevention of hepatitis B virus infection in the united states: recommen-
dations of the advisory committee on immunization practices. MMWR
Recomm Rep 2018;67(1):1–31. [Guideline]
37. Chaithongwongwatthana S, Yamasmit W, Limpongsanurak S, Lumbiganon
P, Tolosa JE. Pneumococcal vaccination during pregnancy for prevent-
ing infant infection. Cochrane Database Syst Rev 2015;1:CD004903.
[Meta-analysis]
38. Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL,
et al. Pregnancy and infant outcomes in the clinical trials of a human
Vaccinations
papillomavirus type 6/11/16/18 vaccine: a combined analysis of five random-
ized controlled trials. Obstet Gynecol 2009;114(6):1179–88. [Guideline]
39. Markowitz LE, Dunne EF, Saraiya M, Chesson HW, Curtis CR, Gee J, et al.
Human papillomavirus vaccination: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Recomm Rep
2014;63(RR-05):1–30. [Guideline]
40. Nelson NP, Weng MK, Hofmeister MG, Moore KL, Doshani M, Kamili S,
et al. Prevention of hepatitis A virus infection in the United States: recom-
mendations of the advisory committee on immunization practices, 2020.
MMWR Recomm Rep 2020;69(5):1–38. [Review]
41. Duff B, Duff P. Hepatitis A vaccine: ready for prime time. Obstet Gynecol
1998;91(3):468–71. [Guideline]
42. Centers for Disease Control and Prevention (CDC), Advisory Committee
on Immunization Practices. Updated recommendations for prevention of
invasive pneumococcal disease among adults using the 23-valent pneumo-
coccal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep.
2010;59(34):1102–6. [II-3]
43. Chabala S, Williams M, Amenta R, Ognjan AF. Confirmed rabies exposure
during pregnancy: treatment with human rabies immune globulin and
human diploid cell vaccine. Am J Med 1991;91(4):423–4. [Review]
44. Sudarshan MK, Madhusudana SN, Mahendra BJ. Post-exposure prophy-
laxis with purified vero cell rabies vaccine during pregnancy–safety and
immunogenicity. J Commun Dis 1999;31(4):229–36. [Guideline]
45. Manning SE, Rupprecht CE, Fishbein D, Hanlon CA, Lumlertdacha B,
Guerra M, et al. Human rabies prevention–United States, 2008: recommen-
dations of the Advisory Committee on Immunization Practices. MMWR
Recommend Rep 2008;57(RR-3):1–28. [Guideline]
46. Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner
HC, et al. Prevention and control of meningococcal disease: recommen-
dations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recommend Rep 2013;62(RR-2):1–28. [Review]
47. Adam I, Abdalla MA. Is meningococcal polysaccharide vaccine safe during
pregnancy? Ann Trop Med Parasitol 2005;99(6):627–8. [II-2]
48. Shahid NS, Steinhoff MC, Roy E, Begum T, Thompson CM, Siber GR.
Placental and breast transfer of antibodies after maternal immunization
with polysaccharide meningococcal vaccine: a randomized, controlled
evaluation. Vaccine 2002;20(17–18):2404–9. [Review]
49. Zheteyeva Y, Moro PL, Yue X, Broder K. Safety of meningococcal polysac-
charide-protein conjugate vaccine in pregnancy: a review of the Vaccine
Adverse Event Reporting System. Am J Obstet Gynecol 2013;208(6):478.
e1–6. [Guideline]
50. MacNeil JR, Rubin L, Folaranmi T, Ortega-Sanchez IR, Patel M, Martin
SW. Use of serogroup B meningococcal vaccines in adolescents and young
adults: recommendations of the advisory committee on immunization
399
practices, 2015. MMWR Morb Mortal Wkly Rep 2015;64(41):1171–6.
[Guideline]
51. Prevots DR, Burr RK, Sutter RW, Murphy TV. Poliomyelitis prevention in
the United States. Updated recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Recommend Rep 2000;49(RR-
5):1–22. [Guideline]
52. Bower WA, Schiffer J, Atmar RL, Keitel WA, Friedlander AM, Liu L, et al.
Use of anthrax vaccine in the united states: recommendations of the advi-
sory committee on immunization practices, 2019. MMWR Recommend
Rep 2019;68(4):1–14. [Guideline]
53. Hills SL, Walter EB, Atmar RL, Fischer M, ACIP Japanese Encephalitis
Vaccine Work Group. Japanese encephalitis vaccine: recommendations of
the advisory committee on immunization practices. MMWR Recommend
Rep 2019;68(2):1–33. [II-3]
54. Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus
infection after immunization in pregnancy. J Infect Dis 1993;168(6):
1520–3. [II-2]
55. Nasidi A, Monath TP, Vandenberg J, Tomori O, Calisher CH, Hurtgen X,
et al. Yellow fever vaccination and pregnancy: a four-year prospective study.
Trans R Soc Trop Med Hyg 1993;87(3):337–9. [II-2]
56. Nishioka S de A, Nunes-Araújo FR, Pires WP, Silva FA, Costa HL. Yellow
fever vaccination during pregnancy and spontaneous abortion: a case-con-
trol study. Trop Med Int Health 1998;3(1):29–33. [Guideline]
57. Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown Z, Alexander
ER, et al. Pregnancy outcomes following systemic prenatal acyclovir expo-
sure: Conclusions from the international acyclovir pregnancy registry,
1984–1999. Birth Defects Res Part A Clin Mol Teratol 2004;70(4):201–7.
[Guideline]
58. Cono J, Casey CG, Bell DM, Centers for Disease Control and Prevention.
Smallpox vaccination and adverse reactions. Guidance for clinicians.
MMWR Recomm Rep 2003;52(RR-4):1–28. [Guideline]
59. CDC. Pregnancy guidelines and recommendations by vaccine. Available
from: https://www.cdc.gov/vaccines/pregnancy/hcp-toolkit/guidelines.
html [Accessed October 6, 2020] [Guideline]
60. Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, et al.
Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19)
during pregnancy: a systematic review and meta-analysis. Am J Obstet
Gynecol MFM 2020;2(2):100107. [Meta-analysis]
61. Pierce-Williams RAM, Burd J, Felder L, Khoury R, Bernstein PS, Avila K,
et al. Clinical course of severe and critical coronavirus disease 2019 in hos-
pitalized pregnancies: a United States cohort study. Am J Obstet Gynecol
MFM 2020;2(3):100134. [II-2]
62. Craig AM, Hughes BL, Swamy GK. Coronavirus disease 2019 vaccines in
pregnancy. Am J Obstet Gynecol MFM 2020;3(2):100295. [III]
41
TRAUMA
Danielle M. Prentice and Lauren A. Plante
Key points
• Trauma during pregnancy is a common complication, and
accounts for a significant fraction of maternal deaths as
well as perinatal mortality.
• Changes in physiology related to pregnancy must be borne
in mind when managing trauma care.
• Care of the pregnant trauma patient:
• There is no level I evidence to dictate the initial care
of the traumatized pregnant patient, the type and
duration of monitoring, the type of testing required, or
the follow-up care of ongoing pregnancy after trauma.
• Initial maternal stabilization takes priority over
fetal assessment.
• Transfer to a trauma center should be considered for
severe cases. This decision is usually made at the scene.
• Multidisciplinary approach is important, as obstetri-
cian, maternal-fetal specialist, trauma surgeon, inten-
sivist, anesthesiologist, neonatologist and others may
need to be involved.
• Maternal stabilization: As part of the advanced
trauma life support (ATLS) primary survey, mater-
nal stabilization takes precedence over fetal evalua-
tion, which is a component of the secondary survey.
• Appropriate radiologic or other studies should not
be withheld because of pregnancy.
• Ultrasound, fetal monitoring, tocodynamometer (con-
traction) monitoring, and blood testing for fetomater-
nal hemorrhage can be considered in the management
of the pregnant patient with trauma.
• After hospital discharge following trauma, there remains
an increased probability of worse perinatal outcome.
Ongoing fetal assessment may be indicated, although the
exact type of surveillance has not been established.
Definition
Trauma includes both intentional harm and accidents. Intentional
harm encompasses assault, blunt force trauma, and penetrating
trauma. Accidents include, predominantly, motor vehicle crashes
and falls.
Incidence
Incidence of trauma in pregnancy is unclear, and both the burden
and the breakdown of cause vary by region and socioeconomic
factors. A commonly quoted figure of 8% from the U.S. is of uncer-
tain reliability [1, 2]. Estimates vary widely: from 8% (any physi-
cal trauma) to 0.2–2% (evaluation for trauma) to 0.4–2/10,000
(hospitalization for trauma) [3–5]. A population-based study in
Sweden, using both the national birth registry and the national
traffic accident registry, calculated a ratio of 207 motor vehicle
collisions (MVC) per 100,000 pregnancies [6]. The probability of
400
hospital admission after maternal trauma increases with increas-
ing gestational age [7]; trauma is most commonly reported in the
third trimester [8]. Domestic violence against pregnant patients
ranges from 4–9% [9]. Published figures are probably affected by
reporting bias and undercounting of the total number of injuries.
Not all cases of maternal trauma are seen at a trauma center, or
even referred to a hospital. Available literature on trauma is gener-
ally biased toward more serious injury whenever data are collected
from hospital visits or admissions rather than from traffic records.
Registry information is sometimes available, though these reg-
istries do not collect information on the fetus or newborn, nor
on the pregnancy outcome. For example, in the United States,
the National Trauma Data Bank, maintained by the American
College of Surgeons, maintains a voluntary nationwide registry;
individual states may also collect data, whether mandatory or vol-
untary. In a recent analysis drawn from the Pennsylvania Trauma
Systems Registry across all accredited trauma centers in the state,
the Pennsylvania Trauma Outcome Study (PTOS) was queried to
compare outcomes among pregnant and non-pregnant patients
showed that although pregnant trauma patients had, on aver-
age, a significantly lower injury severity score (8.9 versus 10.9), a
higher Glasgow Coma Score, and were more likely to have experi-
enced only minor injury (69% versus 59%), they were nevertheless
seen to have a higher risk of mortality (3.7% versus 2.9%), most
attributed to a dead-on-arrival status. Rates of violent injury at
the hands of others were higher for pregnant patients, while sui-
cide was lower. The disadvantage in mortality compared to the
non-pregnant group may be attributed to the greater burden of
violence inflicted on the pregnant group, as violent trauma was
associated with a 3.14-fold increase in mortality compared to
non-violent trauma [10]. In contrast, an analysis of the National
Inpatient Sample (NIS) demonstrates that, among patients admit-
ted to hospital following MVC, pregnant patients had a lower risk
of fracture, open wounds, intracranial, internal and spinal cord
injury, transfusion, operations (other than those coded as geni-
tourinary, a grouping that includes cesarean) and death than a
matched group of non-pregnant controls [11]. This may represent
either a difference in the type or severity of MVC in which a preg-
nant patient is involved, a difference in seatbelt use, or a differ-
ential willingness on the part of physicians to admit a pregnant
patient for observation even with minor or no discernable injury.
The NIS dataset also showed that 3.8% of MVC involved pregnant
patients, though it could not show the overall incidence of MVC
in pregnancy. Motor vehicle crashes involving pregnant patients
are, roughly, evenly distributed by trimester [12, 13].
Etiology/Basic pathophysiology
Causes of trauma in pregnancy in the United States:
• 73% motor vehicle collision, including auto versus pedestrian
(MVC; 3–4% of all MVC involve a pregnant patient) [11, 14]
• 12% assault
DOI: 10.1201/9781003099062-41
Trauma
TABLE 41.1: Prevalence by Trauma Type
Trauma Type Prevelance (per 100,000)
Blunt (MVC, slips and falls) 260
Penetrating 3.3
Domestic violence 8307
Suicide 2 patient is discharged home undelivered.
Homicide 3.3
Source: Modified from Ref. [2].
Abbreviation: MVC, motor vehicle collision.
• 9% fall
• 2% bicycle
• <1% suicide
• 3% other (unintentional)
These reflect American data and cannot be taken as univer-
sally representative. By way of comparison, assault accounted for
more than half of admissions of pregnant patients to a metro-
politan trauma service in South Africa [15]. A systematic review
covering international literature published between 1990 and
2012 estimated the incidence of each trauma type in pregnancy.
(Table 41.1): domestic violence was an order of magnitude higher
than MVC, which in turn was an order of magnitude higher than
slips and falls. Domestic violence is by far the leading cause of
trauma related to pregnancy, which implies that asking about
interpersonal or intimate partner violence (IPV) is no less impor-
tant than counseling on seat belt use.
Prognostic factors
More severe injury predisposed pregnant patients to a worse
pregnancy outcome (see Box 41.1). Drug use and shock at
admission are also correlated with worse outcome, though to a
lesser extent [3, 16]. Individual risk factors associated with fetal
demise include penetrating injury, severity of injury, maternal
hypotension, and need for laparotomy [15, 17].
In cases of minor trauma (ISS = 0), classically described risk
factors such as Kleihauer-Betke, fibrinogen <200, contraction
pattern by tocodynamometer, direct abdominal trauma, placenta
location, and abdominal pain are not reliable predictors of adverse
pregnancy outcomes [18]. While the evaluation of each patient
should be individualized, extensive evaluation measures that are
routine in practice may be reconsidered in cases of minor trauma
in pregnancy.
BOX 41.1: FACTORS ASSOCIATED WITH
WORSE PREGNANCY OUTCOME
• Higher degree of severity, e.g., Injury Severity
Score >9 (For an online calculator of Injury
Severity Score (ISS), see https://www.mdcalc.
com/injury-severity-score-iss)
• Lactate >2 mmol/L
• Altered mental status at admission (Glasgow
Coma Score <8)
• Lack of proper seat belt use
• Severe head injury
• Injury to thorax, abdomen, lower extremities, or
spine
401
Complications
Complications are more common if there is severe injury (ISS ≥9)
[4], or if the patient is delivered during the hospitalization for
trauma [5]. Delayed complications may occur even when there is
no injury diagnosed at the time of hospitalization and when the
Maternal death
Maternal mortality associated with trauma is about 0.1–1.4%
[3, 5]: this is 10–100 times increased over the background U.S.
maternal mortality ratio. Among pregnant patients hospitalized
after trauma, the case fatality rate is 2–4% [10, 19–23].
Trauma is a leading cause of maternal death, as about 27%
of maternal deaths are injury related [24]. As an aside, these
figures are not always counted in maternal mortality statistics,
since commonly used definitions of maternal mortality ratio and
pregnancy-related death specifically exclude those deaths arising
from “accidental” or “incidental” causes [25]. Of these deaths, the
largest fraction is attributed to MVCs (44%), followed by homi-
cide (31%), unintentional injuries (13%), and suicide (10%). Data
from the Pregnancy Mortality Surveillance System in the 1990s
suggested that the majority of pregnancy-associated homicides
occurred in the postpartum period [24], but figures drawn a
decade later from the National Violent Death Reporting System
showed that 77% of pregnancy-associated homicides occurred, in
fact, during pregnancy [26]. Trauma and other forms of violence
are also the leading cause of death in non-pregnant patients of
reproductive age.
Hospitalization
Patients in the third trimester are more likely to be admitted to
the hospital than patients in the first or second trimester [12]; 3%
of all trauma admissions are pregnant [27].
Transfusion
Transfusion percentages are 0.6–4%.
Hysterectomy
Hysterectomies occur in about 0.5–2% of pregnant trauma
patients. They may be indicated in cases of penetrating injury
to the uterus or in cases of uterine rupture, resulting from blunt
force trauma when surgical repair is not reasonable [28] or in
cases where coagulopathy follows placental abruption.
Fetal/Neonatal outcomes
In a meta-analysis of 19 observational studies with information
on over 3 million pregnant patients after MVC, the pooled inci-
dence of perinatal death was 6.6 per 1000 patients, most of which
were stillbirths rather than neonatal deaths; no information was
available on the gestational age at which MVC occurred [29]. The
pooled rate of perinatal death, in this meta-analysis, was not sig-
nificantly different from the comparison group not exposed to
MVC, nor was the rate of preterm delivery, premature rupture of
membranes, or cesarean delivery. Placental abruption was higher,
however, with an odds ratio 1.43 [29].
Smaller observational studies: Nonreassuring fetal testing:
5–20%; preterm birth (PTB) <37 weeks: 14–20% [4]. There is a
difference in outcome between those patients who deliver dur-
ing the hospitalization for trauma compared to those who are
discharged undelivered: patients who remain undelivered at the
time of discharge after MVC generally have good pregnancy out-
comes [30].
402
Placental abruption
Placental abruption is the most common adverse event in preg-
nancy resulting from blunt abdominal trauma [31]. It occurs in
1–13% of traumas [32]. Fetal mortality rates in the third tri-
mester may be as high as 54% [33]. The major mechanism of
placental abruption due to trauma is thought to be due to a shear-
ing force at the uterine-placental interface. Severity of maternal
injury does not reliably correlate with abruption [32]. The time
course of placental abruption is usually delayed, on average
2–6 hours after the trauma and up to 24 hours [7].
In a small study of placental histology following trauma after
20 weeks’ gestation, 85% of placentas examined showed a patho-
logic finding such as retroplacental hemorrhage (38%) or intervil-
lous thrombus, compared to 40% of the control placentas [34].
These changes were found anywhere from 1–16 weeks after the
inciting trauma.
Uterine rupture
Uterine rupture is uncommon, occurring in less than 1% of
pregnant trauma patients. It is most likely to occur in patients
with previous cesarean deliveries. However, maternal mortality
reaches 10% and fetal mortality reaches 100% when uterine rup-
ture occurs during a trauma [30].
Pelvic fracture
Incidence of fracture during pregnancy related to trauma is less
than 1%. Of these fractures, 1–20 are pelvic fractures [35]. Despite
the low incidence, sustaining a pelvic fracture in pregnancy due
to trauma is associated with increased morbidity and mortality
in both the mother and the fetus [36]. Pelvic fractures are not a
contraindication to vaginal delivery [37].
Fetal injury
Very few cases have been reported of fetal injury from maternal
gunshot or stab wounds, and of fetal fractures, visceral ruptures,
and intracranial hemorrhage after blunt trauma. Penetrating
abdominal injury, which, in the second half of pregnancy, usually
involves the uterus, is associated with fetal death in up to 73% of
cases [38], and has been proposed as an indication to explore the
abdomen or effect cesarean delivery.
Fetal death
The fetal death rate is 0.4–1.5%. The rate of fetal death among
patients hospitalized for trauma is about 11% [19–23]. About
5/1000 fetal deaths can be attributed to trauma, or approximately
4 traumatic fetal deaths per 100,000 live births [39]. The single
most salient risk factor for fetal death is maternal death. The
majority (>80%) of these fetal deaths in the United States are asso-
ciated with MVC, while 6% are related to firearms and another
3% to falls: this does not mean that MVC is uniquely lethal to
fetuses, only that it is more common than other mechanisms
of injury. Less than half of fetal deaths are designated as due to
placental injury (42%), 20% as placental abruption. Fetal death
is more likely in cases of maternal death, hemorrhagic shock, or
no seat belt use. Aside from maternal death, the most significant
associations with fetal death after blunt trauma are maternal
ejection from a vehicle, maternal tachycardia (HR >110), mater-
nal ISS >9, and fetal bradycardia (FHR <120) [40]. However, even
minor maternal injuries from MVC have been associated with
fetal death. Swedish data showed the risk of fetal death to be 93%
with fatal maternal injury, 5% with major maternal injury, and
1% with minor maternal injury, but because there are so many
Maternal-Fetal Evidence Based Guidelines
more minor injuries, these still contributed significantly to fetal
outcome statistics [6]. The odds ratio for fetal demise was 3.55
among all patients involved in a motor vehicle crash; excluding
early pregnancy losses, the odds ratio for fetal death was 2.49
when only third-trimester crashes were taken into account. In
a retrospective study, the risk of stillbirth, but not of placental
abruption, preterm birth, or preterm premature rupture of mem-
branes, was decreased by seat belt use [41].
Neonatal death
Highly related to preterm birth, neonatal death percentages range
from 0.4–1.5%.
Special considerations for
complications from assault
The rate of hospitalization for assault during pregnancy is 0.04–
0.1% [42, 43]. In California, 46% of assaults were related to an
unarmed fight, 12% to firearms or bomb, and 9% to stab injuries.
Patients assaulted during pregnancy had higher rates of preterm
delivery, low birth weight, placental abruption, stillbirth, and
uterine rupture compared to patients who were never hospital-
ized for assault during pregnancy. Thirteen percent of patients
hospitalized after assault delivered during the hospitalization.
These patients had worse outcomes than either patients who
were not assaulted, or patients who were assaulted but discharged
undelivered [42]. In New Zealand, assault during pregnancy and
assault after pregnancy were both associated with long-term dan-
ger for patients, including injury and death within a 5-year period
[43].
Intimate-partner violence is a leading cause of trauma in preg-
nancy. Non-pregnant rates of domestic violence are 5239/100,000
patients, while pregnant rates are 8307/100,000 live births. This
accounts for a 58% increase during pregnancy [44]. In fact, 20.1%
of pregnant patients report physical or sexual abuse [45] although
due to underreporting, it is thought the figure can be as high as
40% [46]. Adverse outcomes include acute placental abruption,
preterm labor and delivery, premature rupture of membranes,
fetal growth restriction, and fetal death [47]. Fetal morbidity and
mortality directly correlates to the severity of maternal injury
[45]. Sadly, over a 15-year period in Maryland, homicide was
the leading cause of pregnancy-associated maternal death, most
often perpetrated by a current or former intimate partner, and
most often by gunshot [48].
Pregnancy considerations
Causes of trauma in pregnancy differ from non-pregnant trauma
in that more are attributed to intimate partner violence and motor
vehicles and fewer to other causes. Pregnancy is generally protec-
tive in relation to suicide. Compared to patients of the same age
who are not pregnant, pregnant patients who sustained trauma
were younger, had lower ISS and lower mortality (1% versus 4%),
had shorter length of stay, and lower rates of alcohol and drug
use; however, 12% had been drinking and 20% had been using
drugs [12]. A crash rate of 13/1000 person-years was calculated
for pregnant patients aged 15 to 39, which is half the rate for non-
pregnant patients in this age group (26/1000) [12].
In 11% of pregnancy trauma cases [27], the pregnancy status
was unknown at admission to the receiving trauma team, and in
two-thirds of those the pregnancy was newly diagnosed by serum
Trauma
hCG screening—that is, the status had possibly not been known
by the patient either. Of those pregnancies newly diagnosed by
the trauma team and not previously known to the patient, fetal
mortality was 100%, including both spontaneous and elective
abortion. Incidental pregnancies that were discovered by trauma
team and already known to the patient carried a 25% probabil-
ity of fetal mortality [27]. One-third of the non-survivors in the
newly diagnosed group were elective terminations, in which
the patients reported they were fearful of nonspecific damage
because of either injury or radiation [27].
Pregnancy management
Prevention of injury
Seat belts
Rates of seat belt use are now similar among pregnant and
non-pregnant individuals involved in MVCs, based on the
National Automotive Sampling System/Crashworthiness Data
System: approximately two-thirds used a lap and shoulder belt
[13]. Three-point seat belts should always be worn, with the
shoulder belt over the shoulder, collar bone, and across the
chest, between the breasts, and the lap belt as low as possible
under the abdomen and the uterus. Seat belts save maternal
lives by preventing ejection. In an observational study of 680
pregnant patients after MVC, injury severity scores were signifi-
cantly higher among those who were unrestrained (7 versus 13),
and the unrestrained were more likely to require emergency sur-
gery (14% versus 10%) and a longer hospital stay than those who
had been restrained [49].
Correct seat belt use is also associated with better fetal out-
comes: an in-depth physical and mechanical analysis of 57 MVCs
involving pregnant patients demonstrated adverse fetal outcomes
(death or damage) in 29% of correctly seat belted, 50% of improp-
erly restrained, and 80% of unrestrained patients. [50]. However,
severity of the crash was an independent predictor of poor fetal
outcome: 85% of severe crashes (≥30 mph) in this sample were
followed by fetal death, direct fetal injury, uterine rupture, or
preterm delivery. A large study which linked birth records with
state crash records in North Carolina concluded that the risk of
stillbirth was tripled when a crash involved an unbelted preg-
nant driver, compared to a belted pregnant driver [51]. Seat belt
restraints also have a protective role in low-velocity collisions.
Impact testing using a crash-test dummy modeled to represent
a patient at 30 weeks of pregnancy demonstrated two to three
times higher peak abdominal pressure when the dummy was
unrestrained compared to properly belted [52].
Air bags
A cohort study in Washington State cross-referenced State Patrol
crash data with birth certificate and fetal death certificate data
and found no statistically significant differences in maternal
or fetal outcomes among 198 patients whose airbag deployed
compared to 622 patients whose airbag did not deploy [53]. The
rates of preterm labor and of fetal death were higher in the
no-­airbag group, and the lack of statistical significance may be a
function of small numbers. In the North Carolina study, the rate
of placental abruption was 58% higher when the pregnant driver’s
vehicle was not equipped with airbags [51], though rates of pre-
term birth and stillbirth were not significantly different.
In a case series of 30 patients past 20 weeks of pregnancy
who were hospitalized after crashes in which their air bags
deployed, 67% of whom were also restrained with a seat belt, 90%
403
had obstetrical signs or symptoms at admission (contractions,
abdominal pain, abnormal fetal heart rate, or vaginal bleeding,)
but there was only one fetal death. All with a live fetus were dis-
charged home undelivered, after a mean length of stay of 24 hours,
though unfortunately most were lost to follow-up [54]. On the
available evidence, no definitive statement can be made as
to the utility or safety of air bags specifically in pregnancy,
but since they save maternal lives, they would, on balance, be
expected to save fetal lives.
Intimate partner violence
Prevention is key. ACOG recommends screening for intimate
partner violence at the initial prenatal visit, at least once per tri-
mester, and again in the postpartum period. ACOG also encour-
ages gun safety and firearm restrictions as a way of reducing
pregnancy-associated homicide [55, 56].
Care of the pregnant trauma patient
There are no trials assessing effectiveness of initial care and inter-
ventions for the pregnant patient following trauma, including the
type and duration of monitoring, the type of testing required,
or the follow-up care of ongoing pregnancy after trauma. The
Society of Obstetricians and Gynaecologists of Canada has
recently released guidelines for care of the pregnant trauma
patient [57]. Guidelines have also been published by the Eastern
Association for the Surgery of Trauma [7], and the American
College of Surgeons includes a section on trauma in pregnancy
in the Advanced Trauma Life Support (ATLS) course and manual
[58]. These recommendations are level II and level III, given lack
of randomized trials in pregnancy.
Pre hospital decision making
Often, pregnant trauma patients are first met in the field by emer-
gency medical personnel. Personnel should not deviate from the
standard protocol for assessing patients upon arrival just because
the patient is pregnant. Initial focus should always be on maternal
stability. Once maternal stability is ensured, focus may be shifted
to the fetus [59].
The CDC has provided guidelines for the field triage of injured
patients, last updated in 2011. With that update, a special consid-
eration for pregnancy greater than 20 weeks was added for imme-
diate transport to the nearest trauma center or hospital capable
of timely and thorough initial management of potentially serious
injuries [60].
Local and regional medical units should have established pro-
tocols for triaging and transporting patients to the closest hos-
pital that can stabilize the patient. The emergency department
should be notified of the incoming trauma. It is essential that the
pregnancy status and gestational age be conveyed prior to arrival
so the appropriate obstetrical and neonatal care teams can be in
place [46].
In the United States, trauma center levels range from I to IV, I
being the highest level of care. Designation is made at the state or
local level and verification is provided by the American College of
Surgeons. For a hospital to qualify as a level I trauma center, an
obstetrician must be immediately available. Patients with major
injuries or involved in a serious trauma are often transported to
Level I or II trauma centers [61].
Transport to these institutions may be effected via ground or
air. A retrospective study analyzing the American College of
Surgeons National Trauma Data Bank showed that in cases where
injury severity score was greater than 15 after blunt or penetrating
trauma, survival to discharge was significantly improved in those
404 Maternal-Fetal Evidence Based Guidelines

who were transported via air support, after controlling for multiple
variables [62]. More evidence is needed on how this may directly
impact pregnant trauma patients. However, limited transport data
in pregnancy suggests that air support is a safe method for trans-
port in obstetrical transport, despite concerns about in-transit
delivery of a preterm or distressed neonate: this is a rare event [63].
Given the importance of maternal stabilization, air transport
should not be precluded due to pregnancy status.
Workup and management
An algorithm for evaluation and management of trauma in
pregnancy, specifically, is shown in Figure 41.1 [2]. Electronic
resources are also available, online at www.myatls.com, and as
the MyATLS app for smartphones: search iPhone’s AppStore or
GooglePlay for Android devices. Most importantly, emergency
departments, trauma service units, and maternity units should
have a guideline in place for trauma in pregnancy [46].

Assess Maternal Status

- Cardiac arrest
- Unresponsive
- Loss of airway/respiratory arrest
- BP <80/40 mm Hg or HR <50 or >140 bpm
- If fetus viable, FHR <110 or > 160 bpm

PRESENT ABSENT

Advanced life support Maternal injury greater than minor

Airway/Cervical spine control bruising, lacerations or contusions
Breathing
Circulation PRESENT ABSENT
Disability
Exposure
Consultation with trauma team; notify NICU
Supplemental O2 Consider trauma team consultaion Brief fetal assessment
Displace uterus to left if GA >20 weeks IV Access No lab evaluation required
IV Access (2 peripheral lines) Labs: CBC, Coagulation profile, type & screen; No radiologic imaging
Labs: CBC, Coagulation profile, type & KB if Rh (-) required
screen; KB if Rh (-), type & cross Viable fetus: fetal monitoring for 4 hours – Patient counseling on
Viable fetus: continuous FHR monitoring Ctxs <6/hour consider discharge signs/symptoms abruption
Previable fetus: FHR via Doppler Ctxs ≥6/hour consider admission
Tocometer if concern for abruption Previable fetus: FHR via Doppler
Tocometer if concern for abruption

Once the patient is stable

Fetal Ultrasound +/– Biophysical Profile
Consider other labs - chemistries, urinalysis, urine toxicology screen
Radiologic assessment/Peritoneal lavage/F.A.S.T. U/S Imaging (if indicated)

MVA Slips/Falls Burns DV/IPV Penetrating trauma Toxic exposure

Determine Assess for Aggressive Assess for Level of entry Agent and GA at
whether abdominal fluid depression determines affected exposure guides
patient was trauma and resuscitation and suicide organ; gravid uterus maternal therapy and
wearing extremities for Consider risk may protect from counseling
seatbelt fractures/ delivery if visceral injury
ligament damage burn area
>50%

FIGURE 41.1 Management algorithm for trauma in pregnancy. (From Mendez-Figueroa H, Dahlke JD, Vrees RA, Rouse DJ. Trauma in
pregnancy: an updated systematic review. Am J Obstet Gynecol 2013;208(4):321.e1–9 [Systematic review, Level III]. [2] with permission.)
Abbreviations: BP, blood pressure; CBC, complete blood cell count; Ctxs, contractions; DV, domestic violence; FAST, focused assess-
ment with sonography for trauma; FHR, fetal heart rate; GA, gestational age; HR, heart rate; IPV, intimate partner violence; ISS, injury
severity score; IV, intravenous; KB, Kleihauer-Betke; MVA, motor vehicle accident; NICU, neonatal intensive care unit; O2, oxygen;
U/S, ultrasound.
Trauma
TABLE 41.2: Maternal Stabilization after Trauma in
Pregnancy
• Airway
• Breathing
• Circulation
• Disability (neurological evaluation)
• Exposure, environmental control (undress the patient, look
everywhere for injuries, but keep them warm)
• (Fetus)
Source: Modified from Ref. [41].
Stabilization
The American College of Surgeons [7], the American College
of Obstetricians and Gynecologists [1], and the Society of
Obstetricians and Gynaecologists of Canada [58], are unanimous
in declaring that maternal stabilization takes priority over
fetal assessment. The ATLS algorithm lays out, in order, assess-
ment and stabilization as shown in Table 41.2. Traditionally,
trauma has been managed by the “ABCs.” These are addressed
briefly, in regard to pregnant patients especially, in the following
subsections [59].
Airway: Airway edema is more common in pregnant patients,
so smaller endotracheal tube size is required. Airway
reflexes are not changed in pregnancy, but longer gastric
emptying times and diminished function of the lower
esophageal sphincter leave pregnant patients more prone
to aspiration of gastric contents [59].
Breathing: In pregnancy, minute ventilation is increased and
functional residual capacity is decreased, so periods of
apnea or hypopnea lead more quickly to hypoxemia [59].
Circulation: Physiologic changes in pregnancy include
increased cardiac output, expanded plasma volume,
peripheral vasodilation, and a decrease in systolic and
diastolic blood pressure. As a result, the signs of hypovo-
lemia are seen later in pregnant patients because of these
compensatory mechanisms. Tachycardia and narrowed
pulse pressure are late findings as pregnant patients prog-
ress through the stages of hypovolemic shock. Fetal heart
rate should be evaluated as an additional vital sign. A nor-
mal fetal heart rate suggests normal uterine perfusion,
while an abnormal FHR may reflect compromised perfu-
sion and function as an early warning sign of decreased
circulatory volume. Maintenance of left uterine displace-
ment is important in maintaining preload and cardiac
output after mid-pregnancy because of the effect of the
gravid uterus on compressing the inferior vena cava. If
the patient is visibly pregnant to the prehospital provider,
the supine position should be avoided [59]. Recently, there
has been some discussion about changing this algorithm
to “CAB”. This is based on the recent shift in cardiopul-
monary resuscitative efforts from “ABC” to “CAB,” priori-
tizing perfusion through chest compressions, which has
led to better outcomes. There is also evidence that early
intubation may lead to worse outcomes, due to decrease
in perfusion relating to hypotension and decreased car-
diac output. A recent retrospective study evaluated
trauma management comparing the traditional “ABC”
405
method to the “CAB” made popular in cardiopulmonary
resuscitation. Surprisingly, it found that 55% of patients
were transfused prior to intubation despite the emphasis
of airway over circulation in the ATLS algorithm; thus it
appears that multiple centers are already addressing cir-
culation before breathing. Prospective, multicenter trials
are needed to determine if this method is superior to the
traditional algorithm [64].
After maternal stabilization, history (medical/surgical/
pregnancy history, gestational age, trauma mechanism, etc.),
should be obtained, a thorough physical examination should
be performed (including vital signs, signs of trauma, uterine
tenderness, speculum examination, and bimanual exam), and
available records (e.g., ultrasounds, laboratory tests) should be
reviewed. Problems with history or physical examination, how-
ever, must be borne in mind. In severe trauma, history may be
unobtainable if the patient’s neurologic status is compromised;
information may be obtained from family members or emer-
gency responders as an alternative. The absence of uterine
tenderness cannot be construed as the absence of uterine
or placental injury. Speculum/manual exam may be difficult
or impossible if the patient is in c-spine immobilization or has
pelvic fractures [59].
The focused abdominal sonogram for trauma (FAST) is com-
monly undertaken as part of initial assessment in the Emergency
Department. This is a quick 4-quadrant ultrasound to look for
free fluid in the abdomen and pelvis; sensitivity is reported to
be 80% and specificity 100% in the pregnant patient following
blunt-force abdominal trauma [51]. The FAST scan, though not
originally designed for fetal assessment, presents an obvious
opportunity to ascertain fetal cardiac activity and other relevant
factors.
Evaluation and diagnostic studies
Appropriate studies should not be withheld because of
pregnancy.
1. CT is recommended for evaluation of hemodynamically
stable patients with associated neurological injury, mul-
tiple nonabdominal injury, or equivocal physical exami-
nation. Patients with a negative CT should nonetheless be
admitted for observation [65] (radiation concerns, see later
in this chapter and Tables 41.3–41.5) [77].
2. Blunt abdominal trauma
a. FAST ultrasound: The maternal abdomen can be eval-
uated for the presence of intraperitoneal blood with
TABLE 41.3: Estimates of Fetal Radiation Dose for the
Following Examinations
Examination Mean Fetal Dose (mGy) Maximum Fetal Dose (mGy)
Skull <0.01 <0.01
Chest <0.01 <0.01
Abdomen 1.4 4.2
Thoracic spine <0.01 <0.01
Lumbar spine 1.7 10
Pelvis 1.1 4
IVP 1.7 10
Source: From Ref. [48], with permission.
406 Maternal-Fetal Evidence Based Guidelines

TABLE 41.4: Estimates of Fetal Radiation Exposure with 6. Traumatic brain injury: head CT is generally required.
Computed Tomography Broad-spectrum prophylactic antibiotics if penetrating
brain injury [7]
CT Examination Mean Fetal Dose (mGy) Maximum Fetal Dose (mGy)
7. Spine trauma suspected: immobilization and imaging,
Head <0.005 <0.005 generally CT [7]
Chest 0.06 0.96 8. Special pregnancy-specific evaluations/studies:
Abdomen 8.0 49
Lumbar spine 2.4 8.6 a. Fetal ultrasound: While there is insufficient formal evi-
Pelvis 25 79 dence to assess the effectiveness of performing a fetal
Pelvimetry 0.2 0.4 ultrasound in the patient with trauma in pregnancy, it
is near-universal and is without risk as long as it does
Source: From Ref. [48], with permission.
not delay definitive maternal care. Assessment of fetus,
AFV, and placenta by ultrasound may be beneficial for
diagnostic peritoneal lavage (DPL) or with ultrasound; management. Ultrasound is insufficiently sensitive to
the FAST scan has supplanted DPL in most institu- detect placental abruption unless it involves >50% of
tions. [7, 66]. FAST scan has 80% sensitivity and 100% the placenta, so that a negative ultrasound does not
specificity for intra-abdominal injury in the pregnant exclude abruption, especially since abruption may
patient following blunt abdominal trauma [66]. If DPL develop days after the initial trauma.
is elected, it is typically performed with an open tech- b. Fetal monitoring: There is insufficient evidence to
nique in pregnancy. Both these techniques can be per- assess fetal monitoring and especially its duration in
formed quickly, therefore are suitable for evaluation of the patient with trauma in pregnancy. Assessment of
an unstable patient, and avoid transport and ionizing fetal status may be beneficial as the fetoplacental unit is
radiation altogether. often one of the most sensitive “organs” to be affected
b. Exploratory laparotomy is indicated for a positive by maternal circulatory compromise. If fetal monitor-
DPL [65] and in most cases of a positive FAST scan. ing is to be undertaken, continuous monitoring is prob-
Suspicion of uterine rupture is also an indication for ably preferable to intermittent. More than one-third
laparotomy [57]. of third trimester patients with trauma have omi-
nous findings on monitoring [22]. The fact that mater-
3. In hemodynamically stable patients with positive FAST nal and fetal outcomes are worse in patients who do not
scan, follow-up CT scan may be considered so as to iden- have electronic monitoring in some reports [22] reflects
tify the source: some solid viscus injuries may be managed the team priorities (more severely injured mothers
nonoperatively [65]. require interventions that preclude fetal monitoring, or
4. Penetrating abdominal wound: Single preoperative electronic monitoring is deemed of low priority).
dose of broad-spectrum antibiotic [65]. Laparotomy is c. Tocodynamometer or contraction monitoring: An
indicated if: hypotension is present with a penetrating oft-cited study [33] found that at >20 weeks’ gestation,
abdominal wound; gunshot wound to abdomen; bleeding >90% of pregnant patients with trauma presenting for
from GI or GU tract after penetrating trauma; peritonitis; evaluation demonstrate some uterine contractions in
evisceration; free air. The pregnant uterus tends to shield first four hours, with uterine activity decreasing over
maternal viscera, so stab wounds to the abdomen are less time. Within the first hour, 64% were contracting with
likely to injure bowel unless the site is the upper abdomen. a frequency of every five minutes or more, declining to
In contrast, the fetus is often injured. As is true outside 29% by hour 4. Patients without contractions or whose
of pregnancy, the trajectory of a bullet or other missile contractions never exceeded q10 minute frequency
is unpredictable and therefore laparotomy is generally were discharged at the end of four hours, and none
indicated. had abruption [33]. Those who had been contracting
5. Open fractures: Prophylactic antibiotics with gram- at more than q11 minute frequency were all kept for
positive coverage, administered as soon as possible after at least 24 hours. There was one placental abruption
injury [7]. at six hours, resulting in emergent delivery for fetal
distress, and among the patients hospitalized beyond
24 hours, there was a 40% delivery rate, with one still-
born infant. Total abruption rate was 8% [33]. Practice
TABLE 41.5: Threshold Doses by Gestational Age for the
guidelines vary for duration of monitoring. The Eastern
Appearance of Embryo/Fetus Death or Congenital
Association for the Surgery of Trauma recommends
Malformation
a minimum of 6 hours of continuous monitoring [7].
Embryo/Fetus Congenital ACOG does not give a clear recommendation, but sug-
Weeks from LMP Death Malformation gests a minimum of 6 hours [1] Society of Obstetricians
No threshold at conception and Gynecologists of Canada recommend 4 hours if
4 to 7 250–500 mGy 200 mGy
normal FHT and physical examination are present,
but extend to 24 hours of monitoring in the presence
7 to 9 500 mGy 500 mGy
of uterine or abdominal tenderness, vaginal bleeding,
9 to 23 >500 mGy Very few observed
contractions more frequently than 10 minutes, non-
23 to term >1000 mGy Very few observed reassuring fetal heart tones, fibrinogen <200 g/L, or
Source: From Ref. [77], with permission. other high-risk factors [57]. From these data comes
Trauma
the common recommendation for monitoring at
least four hours after maternal trauma [57, 67].
Others have recommended a minimum of six hours of
monitoring, acknowledging that the best duration of
monitoring is unknown [7]. In nearly 5% of trauma
in pregnancy cases, fetal compromise or placental
abruption becomes evident only after prolonged
monitoring (6–48 hours or more) [68].
d. The Kleihauer–Betke (KB) test assesses presence of
fetal red blood cells in the maternal circulation. It has
been proposed as an adjunct to predict preterm labor
after trauma [69]. A study of 233 patients found that
20% of pregnant trauma patients who had KB drawn
had positive results, although the test proved neither
sensitive nor specific for a poor outcome [68]: 96% of
patients with a positive KB (defined as >0.01 mL of fetal
blood in the maternal circulation) had preterm con-
tractions, half of whom also had cervical change, while
none of those with a negative test had any contractions
during the period of surveillance, which encompassed
a minimum of four hours. A smaller study evaluating
73 patients with KB after trauma calculated the like-
lihood ratio of a positive KB for predicting preterm
labor as greater than 20 [69]; none of the KB-negative
patients had contractions. The authors proposed that if
the KB were negative, duration of monitoring could be
limited to the time it took to get the test back, that is,
1–2 hours. While the test is inexpensive and simple to
perform, it has been criticized for its subjectivity and
lack of reproducibility [70]. Using known admixtures
of fetal and maternal blood, KB testing overestimates
the volume of fetomaternal hemorrhage and has been
demonstrated to vary more than 10-fold with repeat
testing of a single sample [70]. Research has shown
that substitution of flow cytometry (using a fluores-
cence-activated cell sorter) or monoclonal antibod-
ies to Hb F as a test for fetomaternal hemorrhage may
more reliably determine hemorrhage [71]
e. Rh status must be tested after maternal trauma. Rh
negative patients should receive Rh immune globulin
after maternal trauma of any degree, since even minor
maternal trauma may be associated with maternofetal
hemorrhage sufficient to cause sensitization. ACOG
currently recommends KB testing in all pregnant
trauma patients who are Rh negative [72]. This helps
to determine the correct dose of Rh immune globulin
needed to prevent rhesus isoimmunization [72].
f. Coagulation studies (e.g., fibrinogen, D-dimer, PT,
and PTT): there is no evidence of benefit of routine
coagulation studies, unless massive hemorrhage has
occurred or is expected.
g. Admission: admission to the hospital for longer
observation (≥24 hours) should be considered for
patients with uterine tenderness, continued abdom-
inal pain, a high-risk mechanism of injury (such as
auto versus pedestrian or high-speed crash), persis-
tent (>4/hour) contractions, rupture of membranes,
positive KB, bleeding, abnormal fetal heart rate
tracing [57].
The indication for tetanus prophylaxis does not change dur-
ing pregnancy. All traumatic wounds are at risk for development
407
of tetanus, and passive immunization should be considered in all
cases, with human tetanus immune globulin 250 units given
IM. [7].
Mass transfusion protocol
In severe trauma rapid correction and stabilization of blood loss
has become paramount. Given this, mass transfusion protocols
(MTP) have become more popular. Through military literature
and clinical trials that show survival benefit, a 1:1:1 ratio of plate-
lets, plasma, and packed red blood cells has become the most
common mass transfusion protocol. In fact, it has been shown to
improve outcomes [73].
Radiation in the pregnant trauma patient
Estimates of fetal radiation dose for the following examina-
tions are shown in Table 41.3 [50]. Gray is the unit of mea-
surement for absorbed dose of radiation; it is defined as 1 J
of energy deposited in 1 kg of material. This has replaced the
rad or roentgen-absorbed dose, which is the dose delivered
to an object of 100 ergs of energy per gram of material. One
Gray = 100 rads (or, 1 rad = 10 mGy). Teratogenic effects are
of no concern until after 5 to 10 mGy. Plain radiographs of
the spine and chest can be performed in pregnancy with mini-
mal radiation exposure to the fetus, with abdomen and pelvis
shielding. The American College of Radiology states that there
is no “safe” amount of radiation, but note that many patients
are exposed to higher levels of radiation in their everyday life
than they would be exposed to with imaging. These lifestyle
factors include living at altitude and air travel. They consider
that some radiological examinations expose a pregnant uterus
to so low a dose that pregnancy does not affect the decision to
proceed [74]: these include chest x-ray in the first and second
trimester, x-ray or CT of the extremities, and any imaging of
the head or neck. With CT scanning, the total radiation dose
to the fetus depends on the site imaged, the machine and tech-
nique used, and on the distance between cuts.
Estimates of fetal radiation exposure with computed tomog-
raphy (CT) are shown in Table 41.4 [75]. Since the actual fetal
dose given in a procedure may be as much as 10-fold higher than
the published mean dose, depending on the patient’s size and the
technique used, actual dose should be ascertained wherever
possible by contacting the institution’s radiation physicists for
dosimetry. The ACR suggests that unused personnel monitors
for radiation dose could be placed above and below the patient’s
pelvis so as to document the uterine dose [74]. The proxy for fetal
radiation dose is uterine dose.
Most data pertaining to the effects of radiation on the fetus
are derived from observational studies of patients exposed to
large amounts of radiation in disasters such as Japan’s Hiroshima
bombing and Chernobyl nuclear power plant disaster [76].
The consequences of radiation exposure in pregnancy include
pregnancy loss, malformation, developmental delay, and carcino-
genesis [77]. Timing and dose of radiation exposure determines
outcome. These thresholds based on gestation age are shown in
Table 41.5 [77]. Concerns have also been raised about the pos-
sibility of cancer induction in children exposed to intrauterine
radiation. Because childhood cancers are rare events, even a dou-
bling or quadrupling of the risk has little impact on cancer deaths.
Excess risk of fatal childhood cancer attributed to fetal exposure
with typical diagnostic procedures range from 1 in 30,000 to 1 in
1700. The derived risk is estimated at 1 excess case per 33,000 per
mGy of exposure. The highest risks, which remain quite small on
408
a population basis, are seen with the highest exposures, for exam-
ple, CT of the pelvis as shown in Table 41.3 [75]. This concern
is not a reason to routinely offer termination of pregnancy [75,
78]. Recent estimates of conceptus radiation dose with a single
anteroposterior chest radiograph (assuming an average maternal
size: dose increases with increasing maternal size) range from
0.0021–0.0028 mGy in the first trimester to 0.1–5.9 mGy in the
second and 0.1–1.9 mGy in the third trimester [79]. This corre-
sponds to an excess risk of childhood cancer of approximately 10
per million.
Concerns have also been raised about the possibility of cancer
induction in children exposed to intrauterine radiation. Unlike
death or malformation, the induction of cancers is believed to
be a dose-response rather than threshold phenomenon. Because
childhood cancers are rare events, even a doubling or quadru-
pling of the risk has little impact on cancer deaths. Excess risk of
fatal childhood cancer attributed to fetal exposure with typical
diagnostic procedures range from 1 in 30,000 to 1 in 1700. The
derived risk is estimated at 1 excess case per 33,000 per mGy of
exposure. The highest risks, which remain quite small on a popu-
lation basis, are seen with the highest exposures, for example, CT
of the pelvis [75]. This concern is not a reason to routinely offer
termination of pregnancy [75, 78]. Recent estimates of concep-
tus radiation dose with a single anteroposterior chest radiograph
(assuming an average maternal size: dose increases with increas-
ing maternal size) range from 0.0021–0.0028 mGy in the first tri-
mester to 0.1–5.9 mGy in the second and 0.1–1.9 mGy in the third
trimester [79]. This corresponds to an excess risk of childhood
cancer of approximately 10 per million.
Ultrasound and magnetic resonance imaging (MRI) do not uti-
lize radiation energy and are not associated with adverse effects
on the embryo or fetus. MRI is used infrequently in the setting
of trauma.
Iodinated contrast medium is not known to be harmful to
fetuses: it is not teratogenic and does not suppress fetal thyroid
function. The American College of Radiology states, “We do not
recommend withholding the use of iodinated contrast agents in
pregnant or potentially pregnant patients when it is needed for
diagnostic purposes” [80].
Unfortunately, pregnant patients are less likely to undergo
recommended imaging after trauma [81], a situation one author
group has called “radiation fear,” and which can only be decried.
Cardiopulmonary resuscitation
Indications for beginning cardiopulmonary resuscitation (CPR)
are no different in pregnant patients. Algorithms for treatment,
including drugs and defibrillation, are unchanged by the fact
of pregnancy [82]. After mid-pregnancy, left uterine displace-
ment should be effected so as to avoid caval compression: this
may be done with a wedge under the right hip, manual displace-
ment of the uterus from above, or with a human wedge in which
the patient’s right hip is lifted onto a rescuer’s knees. The 2015
American Heart Association (AHA) guidelines advocate man-
ual uterine displacement in preference to the other techniques
because of easier access for defibrillation and airway management
and the potential for more effective chest compressions when the
patient is not tilted [82]. Survival among pregnant patients under-
going CPR in the emergency department after traumatic injury
has been reported as 17% in a national administrative dataset,
worse than age-matched non-pregnant controls [83].
Maternal-Fetal Evidence Based Guidelines
Prenatal care
If the pregnant patient who has had trauma can be discharged
undelivered, she should be counseled that abruption, PTB, and
other complications can occur even days to weeks after dis-
charge of a stable patient after trauma [5, 18]. Even if they have
been discharged from the hospital, patients who suffered trauma
in pregnancy should be aware that a normal baby outcome cannot
be guaranteed. The optimal strategy for ongoing pregnancy sur-
veillance is not known, but heightened suspicion for pregnancy
complications is reasonable.
Antepartum testing
There is no trial to assess effectiveness of testing in this population.
Delivery
There are no specific recommendations as to delivery of patients
who have had some trauma earlier in pregnancy, which is a more
common situation than the one of catastrophic trauma.
If efforts to resuscitate the pregnant patient having had major
trauma are unsuccessful and there is no return of spontaneous cir-
culation, perimortem cesarean delivery (PMCD), also known
as resuscitative hysterotomy (RH) should be performed for
patients at later gestational ages. The gestational age at which this
intervention should be undertaken is subject to dispute, prob-
ably reflecting confusion about the purpose of PMCD: the goal
has sometimes been understood as fetal salvage and sometimes
as an adjunct to maternal resuscitation. If aortocaval compres-
sion by the gravid uterus impedes venous return to the heart or
renders chest compressions ineffective, and PMCD alleviates
both by emptying the uterus, it may allow for return of sponta-
neous circulation. Intervention for the sake of the fetus does not
make sense before viability—depending on local practice, much
before 24 weeks—but intervention for maternal resuscitation may
be considered even at earlier gestational ages. Some have advo-
cated PMCD in such circumstances if the uterus extends to the
fundus or above, corresponding to about 20 weeks in a single-
ton pregnancy, since the potential for aortocaval compression is
present. The 2015 AHA guidelines [82] are circumspect, stating:
“Not every pregnant patient in cardiac arrest is a candidate for
PMCD; the decision depends on whether the gravid uterus is
thought to interfere with maternal hemodynamics.”
While no trials exist, it has been reported that the best fetal
outcomes occur with delivery within 4–5 minutes after arrest,
and higher fetal mortality rates occurring at greater than
10 minutes of cardiopulmonary arrest [84]. Data are quite lim-
ited, however. A review of literature published from 1980 to 2010
turned up a total of 94 cases of maternal cardiac arrest: in 87% of
viable pregnancies, PMCD was undertaken with an average time
from arrest to delivery of 16 minutes [85]. Very few were delivered
in under 4 minutes; neonatal survival was noted to occur even
when arrest-to-delivery times were appreciably longer. Return of
spontaneous circulation in the mother was more common with-
out PMCD (93%) than after PMCD (54%) but the odds of mater-
nal survival were 5-fold higher when PMCD occurred less than
10 minutes from arrest. The authors of this review stated that
PMCD clearly contributed to maternal survival in 32% of cases,
and in no case was it deleterious to maternal survival. Overall
neonatal survival after PMCD was 64%, even when deliv-
ery occurred more than 10 minutes after maternal arrest.
Trauma
A surveillance project in the UK has been collecting data on all
cardiac arrests in pregnancy over a 3-year period, including infor-
mation on PMCD, but results have not yet been published [86]
Time should not be wasted moving a patient to any other loca-
tion for PMCS, nor should preparations be extensive. To quote
the 2015 AHA guidelines [82]: “The only equipment needed to
start a PMCD is a scalpel.”
Anesthesia
No specific recommendations regarding anesthesia for delivery
in patients who have sustained trauma earlier in pregnancy.
Postpartum/Breastfeeding
No specific recommendations.
References
1. American College of Obstetricians (Webb) Gynecologists. Obstetric
aspects of trauma management. ACOG Educational Bulletin No. 251, 1998,
Washington DC: ACOG. [Level III evidence. Expert opinion. The American
College of Obstetricians and Gynecologists quotes trauma rates of 1 in 12
pregnancies, but it is unclear how the figure was obtained.]
2. Mendez-Figueroa H, Dahlke JD, Vrees RA, Rouse DJ. Trauma in pregnancy:
an updated systematic review. Am J Obstet Gynecol 2013;208(4):321.e1–9
[Systematic review, Level III]
3. Ikossi DG, Lazar AA, Morabito D, et al. Profile of mothers at risk: an analy-
sis of injury and pregnancy loss in 1195 trauma patients. J Am Coll Surg
2005;200:49–56. [Level II-2. Cohort. The American College of Surgeons
maintains a National Trauma Data Bank (NTDB)—data collected from
130 trauma centers in the United States, including level I, level II, and level
III facilities. Review of the NTDB between 1994 and 2001 compared 1195
female admissions that were additionally coded as pregnant to a control
group of 76,126 injured patients in the same age group. Since during this
time there were approximately 27 million live births in the United States
(NCHS) that equates to four trauma center admissions per 100,000 live
births.]
4. Schiff MA, Holt VL. Pregnancy outcomes following hospitalization
for motor vehicle crashes in Washington State from 1989 to 2001. Am J
Epidemiol 2005;161:503–10. [Level II-2. Cohort. State of Washington hos-
pitalizations for MVA in pregnancy from 1989 to 2001, n = 625]
5. El Kady D, Gilbert WM, Anderson J, et al. Trauma during pregnancy: an
analysis of maternal and fetal outcomes in a large population. Am J Obstet
Gynecol 2004;190(6):1661–68. [Level II-2. Cohort. California: 10,316
patients who sustained trauma during a pregnancy of at least 20 weeks’ ges-
tation identified via a statewide hospital discharge database from 1991 to
1999]
6. Kvarnstrand L, Milsone I, Lekander T, Druid H, Jacobsson B. Maternal
fatalities, fetal and neonatal deaths related to motor vehicle crashes during
pregnancy: a national population-based study. Acta Obstet Gynecol Scand
2008;87:946–52. [Level II-2. Cohort]
7. Barraco RD, Chiu WC, Clancy TV, et al. EAST Practice Management
Guidelines Work Group. Practice management guidelines for the diagno-
sis and management of injury in the pregnant patient: the EAST Practice
Management Guidelines Workgroup. J Trauma 2010;69(1):211–14. [III,
Review]
8. Melamed N, Aviram A, Silver M, et al. Pregnancy course and outcome
following blunt trauma. J Matern Fetal Neonatal Med. 2012;25(9):1612–7.
[Retrospective cohort study, II-3]
9. Saltzman LE, Johnson CH, Gilbert BC, et al. Physical abuse around the time
of pregnancy: an examination of prevalence and risk factors in 16 states.
Matern Child Health J 2003;7(1):31–43. [II-3]
10. Deshpande NA, Kucirka LM, Smith RN, Oxford CM. Pregnant trauma
victims experience nearly 2-fold higher mortality compared with their
nonpregnant counterparts. Obstetric Anesthesia Digest. 2018;38(3):126–7.
[Retrospective cohort study, II-2]
11. Azar T, Longo C, Oddy L, Abenhaim HA. Motor vehicle collision-related
accidents in pregnancy. J Obstet Gynaecol Res 2015;41:1370–76. [Level II-2.
Cohort, retrospective; administrative dataset]
409
12. Weiss HB, Strotmeyer S. Characteristics of pregnant women in motor
vehicle crashes. Inj Prev 2002;8:207–10. [1995–1999 National Automotive
Sampling System Crashworthiness Data System, drawn from police-
reported traffic accidents] [Review, III]
13. Manoogian S. Comparison of pregnant and non-pregnant occupant crash
and injury characteristics based on national crash data. Accid Anal Prev
2015;69–76. [Level II-2. Administrative dataset]
14. Hyde LK, Cook LJ, Olson LM, et al. Effect of motor vehicle crashes on
adverse fetal outcome. Obstet Gynecol 2003;102:279–286. [II-3]
15. Wall SL, Figueirido F, Laing GL, Clarke DL. The spectrum and outcome of
pregnant trauma patients in a metropolitan trauma service in South Africa.
Injury 2014;45:1220–3. [Level III. Case series]
16. Aboutanos SZ, Aboutanos MB, Dompokowski D, et al. Predictors of fetal
outcome in pregnant trauma patients: a five-year institutional review. Am
Surg 2007;73(8):824–7. [II-3]
17. Petrone P, Talving P, Browder T, et al. Abdominal injuries in pregnancy:
a 155-month study at two level 1 trauma centers. Injury 2011;42(1):47–49.
[II-3]
18. Cahill AG, Bastek JA, Stamilio DM, et al. Minor trauma in pregnancy—is
the evaluation warranted? Am J Obstet Gynecol 2008;198:208.e1–208.e5.
[II-2. Prospective cohort of 256 complete records of patients with minor
trauma. Rate of positive KB at presentation 2.8%. Adverse pregnancy out-
come in this cohort consisted of 19.2% with no statistically significant asso-
ciation of any single predictor variable or in combination.]
19. Corsi PR, Rasslan S, de Oliveira LB, et al. Trauma in pregnant patients:
analysis of maternal and fetal mortality. Injury 1999;30:239–43. [II-3. Fetal
death: Corsi’s 315; Shah’s 14% if you don’t count elective abortions; Rogers
was 9%; Warner’s—a fairly small study—was 6%; and Theodorou’s 18%.
Maternal death: Corsi 12%, Shah 9%, Rogers 4%, and Warner 3%]
20. Shah KH, Simons RK, Holbrook T, et al. Trauma in pregnancy: maternal
and fetal outcomes. J Trauma 1998;45:83–86. [II-3]
21. Rogers FB, Rozycki GS, Osler TM, et al. A multi-institutional study of fac-
tors associated with fetal death in injured pregnant patients. Arch Surg
1999;134:1274–77. [II-3]
22. Warner MW, Salfinger SG, Rao S, et al. Management of trauma during preg-
nancy. ANZ J Surg 2004;74:125–28. [II-3]
23. Theodorou DA, Velmahos GC, Souter I, et al. Fetal death after trauma in
pregnancy. Am Surg 2000;66:809–12. [II-3]
24. Chang J, Berg CJ, Saltzmann LE, et al. Homicide: a leading cause of injury
deaths among pregnant and postpartum patients in the United States,
1991–1999. Am J Public Health 2005;95:471–77. [Level II-3. Administrative
dataset. Pregnancy Mortality Surveillance System, established in 1989 by
the Center for Disease Control, identified 7342 deaths among patients who
were pregnant or within one year postpartum]
25. Health statistics and information systems. World Health Organization.
https://www.who.int/healthinfo/statistics/indmaternalmortality/en/.
[cited 2020 August 27]. Also cite: Pregnancy mortality surveillance sys-
tem. Centers for Disease Control and Prevention. https://www.cdc.gov/
reproductivehealth/maternal-mortality/pregnancy-mortality-surveillance-
system.htm.
26. Palladino CL, Singh V, Campbell J, Flynn H, Gold KJ. Homicide and suicide
during the perinatal period. Obstet Gynecol 2011;118:1056–63. [Level II-3.
Administrative dataset]
27. Boccichio GV, Napolitano LM, Hann J, et al. Incidental pregnancy in
trauma patients. J Am Coll Surg 2001;192:566–69. [II-3]
28. Brown HL. Trauma in pregnancy. Obstet Gynecol 2009;114 (1):147–60. [III,
Review]
29. Amezcua-Prieto C, Ross J, Rogozińska E, et al. Maternal trauma due to
motor vehicle crashes and pregnancy outcomes: a systematic review and
meta-analysis. BMJ Open. 2020 October 1;10(10):e035562. [Systematic
review and meta-analysis, I]
30. Vivian-Taylor J, Roberts CL, Chen JS, Ford JB. Motor vehicle accidents
during pregnancy: a population-based study. BJOG 2012;119(4):499–503.
[Retrospective cohort study, II-2]
31. Tsuei BJ. Assessment of the pregnant trauma patient. Injury 2006;37(5):367–
73. [Review, III]
32. Pearlman MD, Tintinalli JE, Lorenz RP. A prospective controlled study
of outcome after trauma during pregnancy. Am J Obstet Gynecol
1990;162:1502–10. [II-2; n = 60. Recommendations for at least four hours of
monitoring]
33. Rogers FB, Rozycki GS, Osler TM, et al. A multi-institutional study of fac-
tors associated with fetal death in injured pregnant patients. Arch Surg
1999;134(11):1274–7. [Multi-institutional retrospective cohort study, II-2])
34. Knoop B van der, Voorn J van der, Nikkels PGJ, et al. Placental histol-
ogy after minor trauma in pregnancy: a pilot study. Pediatr Dev Pathol
410
[Internet]. 2018 September 12 [cited 2020 November 2]; Available from:
https://journals.sagepub.com/doi/10.1177/1093526618799292 [prospective
study, II-1]
35. El Kady D, Gilbert WM, Xing G, Smith LH. Association of maternal fractures
with adverse perinatal outcomes. Am J Obstet Gynecol 2006;195(3):711–6.
[Retrospective cohort study, II-3]
36. Tejwani N, Klifto K, Looze C, Klifto CS. Treatment of pregnant patients
with orthopaedic trauma. J Am Acad Orthop Surg 2017;25(5):e90–101.
[Review, III]
37. Leggon RE, Wood GC, Indeck MC. Pelvic fractures in pregnancy: factors
influencing maternal and fetal outcomes. J Trauma 2002;53(4):796–804.
[Review, III]
38. Petrone P, Talving P, Browder T, et al. Abdominal injuries in pregnancy: 1
155-month study at two level 1 trauma centers. Injury 2011;42:47–9. [Level
III. Case series]
39. Weiss HB, Songer TJ, Fabio A. Fetal deaths related to maternal injury.
JAMA 2001;286:1863–68. [Level III. Administrative data. Fetal death cer-
tificates in 16 U.S. States, 1995–1997]
40. Curet MJ, Schermer CR, Demarest GB, et al. Predictors of outcome in
trauma during pregnancy: identification of patients who can safely be
monitored for less than 6 hours. J Trauma 2000;49:18–24. [Level III. Case
series. Eight years’ experience at a large level I trauma center; 271 pregnant
patients who were admitted after blunt trauma; reviewed delivery outcomes
in approximately half]
41. Vladutiu CJ, Weiss HB. Motor vehicle safety during pregnancy. Am J Lifest
Med. 2012;6(3):241–9. [Review, III]
42. El Kady D, Gilbert WM, Xing G, et al. Maternal and neonatal outcomes of
assaults during pregnancy. Obstet Gynecol 2005;105:357–63. [II-3, n = 2070
pregnant patients hospitalized following an assault]
43. Gulliver PJ, Dixon RS. Immediate and long-term outcomes of assault
in pregnancy. Austr NZ J Obstet Gynaecol 2014;54:256–62. [Level II-2.
Case-control]
44. Alhusen, J. L., Ray, E., Sharps, P., & Bullock, L. Intimate partner violence
during pregnancy: maternal and neonatal outcomes. J Womens Health
2015;24(1):100–6. https://doi.org/10.1089/jwh.2014.4872.
45. Sakamoto J, Michels C, Eisfelder B, Joshi N. Trauma in pregnancy. Emerg
Med Clin North Am 2019;37(2):317–38. [Review, III]
46. Greco PS, Day LJ, Pearlman MD. Guidance for evaluation and management
of blunt abdominal trauma in pregnancy. Obstet Gynecol 2019;134(6):
1343–57. [Review, III]
47. Meuleners LB, Lee AH, Janssen PA, Fraser ML. Maternal and foetal out-
comes among pregnant women hospitalised due to interpersonal violence:
A population based study in Western Australia, 2002–2008. BMC Preg
Childbirth. 2011;11(1):70. [Retrospective cohort study, II-2])
48. Cheng D, Horon IL. Intimate-partner homicide among pregnant and
postpartum patients. Obstet Gynecol 2010;115:1181–6. [Level III. Case
series]
49. Schellenberg M, Ruiz NS, Cheng V, et al. The impact of seat belt use in preg-
nancy on injuries and outcomes after motor vehicle collisions. J Surg Res.
2020 October 1;254:96–101. [Large retrospective cohort study, II-2]
50. Klinich KD, Flannagan CAC, Rupp JD, et al. Fetal outcome in motor-vehicle
crashes: effects of crash characteristics and maternal restraint. Am J Obstet
Gynecol 2008;198:450.e1–450.e9. [II-3]
51. Vladutiu CJ, Marshall SW, Poole C, Casteel C, Menard MK, Weiss HB.
Adverse pregnancy outcomes following motor vehicle crashes. Am J Prev
Med 2013;45:629–36. [II-2. Cohort]
52. Motozawa Y, Hitosugi M, Abe T, et al. Effects of seat belts worn by pregnant
drivers during low-impact collisions. Am J Obstet Gynecol 2010;203:62.
e1–62.e8. [II-3]
53. Schiff MA, Mack CD, Kaufman RP, et al. The effect of air bags on pregnancy
outcomes in Washington State, 2002–2005. Obstet Gynecol 2010;115:85–
92. [II-2]
54. Metz TD, Abbott JT. Uterine Trauma in pregnancy after motor vehicle
crashes with airbag deployment: a 30-case series. J Trauma 2006;61:658–61.
[II-3]
55. American College of Obstetricians and Gynecologists. Committee on
Health Care for Underserved Patients. Intimate Partner Violence, February
2012. Available from: https://www.acog.org/clinical/clinical-guidance/
committee-opinion/articles/2012/02/intimate-partner-violence. [III.
Expert opinion]
56. American College of Obstetricians and Gynecologists Statement of
Policy. Gun Violence and Safety. February 2014. [cited 2015 September
25]. Available from: http://www.acog.org/-/media/Statements-of-
Polic y/Public/2014GunViolenceA ndSa fet y.pd f ?dmc=1&ts =201509
25T2306541535. [Guideline, III]
Maternal-Fetal Evidence Based Guidelines
57. Jain V, Chari R, Maslovitz S, Farine D, et al. Guidelines for the management
of a pregnant trauma patient. J Obstet Gynaecol Can 2015;37:553–74. [III.
Guideline. Expert opinion, evidence-based where possible]
58. American College of Surgeons, ACS Committee on Trauma. Advanced
Trauma Life Support. ATLS Student Course Manual, 9th edition. Chicago,
IL: ACS, 2012. [Guideline, III]
59. Advanced Trauma Life Support [Internet]. American College of Surgeons.
[cited 2020 November 2]. Available from: https://www.facs.org/quality-­
programs/trauma/atls. [Guidelines, III]
60. Sasser SM, Hunt RC, Sullivent EE, et al. Guidelines for field triage of injured
patients. recommendations of the national expert Panel on field triage.
MMWR Recomm Rep 2009;58(RR-1):1–35. [Guidelines, III]
61. Resources for Optimal Care of the Injured Patient 2014/Resources
Repository [Internet]. American College of Surgeons. [cited 2020 November
2]. Available from: https://www.facs.org/quality-programs/trauma/tqp/
center-programs/vrc/resources. [Guidelines, III]
62. Michaels D, Pham H, Puckett Y, Dissanaike S. Helicopter versus ground
ambulance: review of national database for outcomes in survival in
transferred trauma patients in the USA. Trauma Surg Acute Care Open
2019;4(1):e000211. [Large retrospective cohort study, II-2].
63. Shipway T, Johnson E, Bell S, Martin J, Clark P. A case review: in-flight
births over a 4-year period in the northern territory, Australia. Air Med J
2016;35(5):317–20. [Retrospective case series, III])
64. Ferrada P, Callcut RA, Skarupa DJ, et al. Circulation first – the time
has come to question the sequencing of care in the ABCs of trauma; an
American Association for the Surgery of Trauma multicenter trial. World J
Emerg 2018 February 5;13(1):8 [Retrospective cohort study, II-3]
65. Hoff WS, Holevar M, Nagy KK, et al. Practice management guidelines for
the evaluation of blunt abdominal trauma: The EAST Practice Management
Guidelines Work Group. J Trauma 2002;53:602–15. [III. Guideline. Expert
opinion]
66. Brown MA, Sirlin CB, Farahmand N, et al. Screening sonography in preg-
nant patients with blunt abdominal trauma. J Ultrasound Med 2005;24:
175–79. [II-3]
67. American College of Emergency Physicians. Trauma in the obstetric
patient: a bedside tool. [cited 2015 September 20]. Available from: www.
acep.org/Clinical—Practice-Management/Trauma-in-the-Obstetric-
Patient–A-Bedside-Tool/. [Guideline, III]
68. Dahmus MA, Sibai BM. Blunt abdominal trauma: are there any predic-
tive factors for abruptio placentae or maternal-fetal distress? Am J Obstet
Gynecol 1993;169:1054–59. [II-2; 1988–1991; 233 patients >20 weeks’ ges-
tation admitted after noncatastrophic abdominal trauma. Unusually, in
this population assaults and falls each outnumbered motor vehicle acci-
dents. Duration of monitoring ranged from 0 to 120 hours, with a mean of
13 hours]
69. Muench MV, Baschat AA, Reddy UM, et al. Kleihauer–Betke testing is
important in all cases of maternal trauma. J Trauma 2004;57:1094–98. [II-2]
70. Ochsenbein-Imhof N, Ochsenbein AF, Seifert B, et al. Quantification of
fetomaternal hemorrhage by fluorescence microscopy is equivalent to flow
cytometry. Transfusion 2002;42:947–53. [II-3]
71. Bromilow IM, Duguid JK. Measurement of feto-maternal haemorrhage: a
comparative study of three Kleihauer techniques and tow flow cytometry
methods. Clin Lab Haematol 1997;19(2):137–42. [Non-randomized con-
trolled experiment, II-1]
72. Practice Bulletin No. 181 Summary: Prevention of Rh D alloimmunization.
Obstet Gynecol 2017;130(2):481–3. [Guidelines, III]
73. Dente CJ, Shaz BH, Nicholas JM, et al. Improvements in early mortality and
coagulopathy are sustained better in patients with blunt trauma after insti-
tution of a massive transfusion protocol in a civilian level I trauma center. J
Trauma 2009;66(6):1616–24. [II-2]
74. American College of Radiology and Society for Pediatric Radiology. ACR-
SPR Practice parameter for imaging pregnant or potentially pregnant ado-
lescents and patients with ionizing radiation. Amended 2014 (Resolution
39.) [cited 2015 September 25]. Available from: http://www.acr.org/~/media
/9E2ED55531FC4B4FA53EF3B6D3B25DF8.pdf. [Guideline, III]
75. Health Protection Agency, the Royal College of Radiologists and the
College of Radiographers. Protection of pregnant patients during diag-
nostic medical exposures to ionizing radiation: advice from the Health
Protection Agency, the Royal College of Radiologists and the College of
Radiographers. 2009. [cited November 20, 2010]. Available from: https://
www.ipem.ac.uk/Portals/0/Images/Protection%20of%20pregnant%20
patients.pdf. [Review, III]
76. De Santis M, Cesari E, Nobili E, Straface G, Cavaliere AF, Caruso A.
Radiation effects on development. Birth Defects Res C Embryo Today
2007;81(3):177–82. [Review, III]]
Trauma
77. Yoon I, Slesinger TL. Radiation exposure in pregnancy. In: StatPearls
[Internet]. Treasure Island, FL: StatPearls Publishing; 2019. [cited 2020
November 2]. Available from: http://www.ncbi.nlm.nih.gov/books/
NBK551690/. [Review, III]
78. American College of Obstetricians and Gynecologists. Committee on
Obstetric Practice. Guidelines for diagnostic imaging during pregnancy and
lactation. ACOG Committee Opinion No. 723. October 2017. Available from:
https://www.acog.org/clinical/clinical-guidance/committee-opinion/
articles/2017/10/guidelines-for-diagnostic-imaging-during-pregnancy-
and-lactation. [III]
79. Damilakis J, Perisinakis K, Prassopoulos P, et al. Conceptus radiation dose and
risk from chest screen-film radiography. Eur Radiol 2003;13:406–12. [II-2]
80. ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast
Media—V10.1, 2015. http://www.acr.org/~/media/ACR/Documents/PDF/
QualitySafety/Resources/Contrast%20Manual/2015_Contrast_Media.pdf
[Guideline, III]
81. Shakerian R, Thomson BN, Judson R, Skandarajah AR. Radiation fear:
impact on compliance with trauma imaging guidelines in the pregnant
patient. J Trauma Acute Care Surg 2015;78:88–93. [39% got no imaging; in
the high-risk mechanism group, compliance with imaging guidelines only
19%!] [Level II-3. Cross-sectional]
411
82. Jeejeebhoy FM, Zelop CM, Lipman S, et al. On behalf of the American
Heart Association Emergency Cardiovascular Care Committee, Council
on Cardiopulmonary Critical Care, Perioperative and Resuscitation,
Council on Cardiovascular Diseases in the Young, and Council on
Clinical Cardiology. Cardiac arrest in pregnancy: a scientific statement
from the American Heart Association. Circulation 2015;132: 1747–73
[Guideline, III]
83. Lavecchia M, Abenhaim HA. Cardiopulmonary resuscitation in the
emergency department. Resuscitation 2015;91:104–7 [Level II-2. Cohort,
retrospective]
84. Katz VL, Dotters DJ, Droegemueller W. Perimortem cesarean delivery.
Obstet Gynecol 1986;68:571–76. [III]
85. Einav S, Kaufman N, Sela HY. Maternal cardiac arrest and perimor-
tem cesarean delivery: evidence or expert-based? Resuscitation 2012;83
:1191–1200. [III]
86. National Perinatal Epidemiology Unit. UK Obstetric Surveillance Project.
[cited 2015 September 24]. https://www.npeu.ox.ac.uk/ukoss/current-­
surveillance/cap?highlight=YTozOntpOjA7czo3OiJjYXJkaWFjIjtpOjE7cz
o2OiJhcnJlc3QiO2k6MjtzOjE0OiJjYXJkaWFjIGFycmVzdCI7fQ== [Level
II-2. Cohort]
42
CRITICAL CARE
Jaimie Maines and Lauren A. Plante
Key points
• In the developed world, <1% of maternity admissions
require admission to intensive care, but up to 5% require
admission to intermediate care or high-­ dependency
unit.
• Most maternal admissions to ICU are postpartum.
• Antepartum admission to ICU is associated with high
rates of preterm birth.
• Standard of care for acute respiratory distress syn-
drome is a low-tidal-volume strategy, though this has
not been formally tested in pregnancy.
• Delayed recognition and treatment of sepsis increases
mortality.
Background
The field of maternal critical care remains insufficiently
researched. While many recommendations in critical care are
based on good evidence, little is specifically focused on preg-
nant or postpartum women. Much of this chapter will, perforce,
address general critical care, extrapolating to maternal critical
care whenever possible.
Incidence
In the developed world, between 1 and 8/1000 obstetric admis-
sions are managed in an intensive care unit (ICU) [1–16].
Among this population, the risk of death ranges from 2–11%, a
figure that, while better than average ICU mortality in a general
population, is orders of magnitude higher than the maternal mor-
tality ratio in the developed world.
Figures on ICU admission do not include women with similarly
life-threatening conditions who are treated within the confines
of a labor and delivery unit or specialized obstetric care unit.
Another 1–5% of all women admitted for delivery require this
type of care [17–19].
Definitions of maternal mortality (and related terms), and
severe maternal morbidity (sometimes called near-miss mortality)
are shown in Table 42.1. Audits of near-miss maternal mortality
or severe acute maternal morbidity have been used to quantitate
life-threatening conditions and therefore constitute a proxy for
intensive care utilization. In Scotland, severe morbidity and near-
miss events were recorded in 4/1000 deliveries, although only
one-third of these ended up in ICU [8]. Severe maternal morbidity
occurred in 4/1000 deliveries between 1991 and 2001 in Canada
[20], but increased to 14/1000 between 2003 and 2007 [21]. This
increase in Canadian figures may represent differential classifica-
tion, different datasets, or a real increase in severe acute maternal
morbidity over time. Analysis of year-by-year data shows a steady
increase in rates of acute renal failure, assisted ventilation, and
major obstetrical hemorrhage in Canada [22]. Admission to ICU
412
was reported in 2.4/1000 deliveries in the Netherlands, but only
one-third of women with serious maternal morbidity were cared
for in the ICU [16]. Population-based estimates in the United
States show an increase of 45% in the proportion of women with
severe maternal morbidity during delivery hospitalizations over a
10-year period, from 101 (per 10,000 delivery hospitalizations) in
2006 to 147 per 10,000 in 2015 (Figure 42.1) [23]. With 4 million
births per year in the United States [24], these figures imply more
than 58,000 episodes of severe acute maternal morbidity per
year among pregnant and postpartum women in this country.
The need for maternal critical care appears to be increasing
in the developed world, driven largely by an increase in both the
rate of postpartum hemorrhage and the risk of adverse outcomes
among women with postpartum hemorrhage [25–27]. One may
predict that the need will continue to rise in parallel with a rising
cesarean rate [28, 29].
Studies on the importance of social determinants of health
have highlighted the racial and ethnic disparities among women
who experience severe maternal morbidity. Using 2015 U.S. data,
when compared with White women, severe maternal morbid-
ity was 110% more likely among Black women, 40% more likely
among Hispanic women, and 20% more likely among Asian/
Pacific Islander women. In addition, Black women were three
times more likely than White women to die as a result of child-
birth [23]. More than half of pregnancy-related mortality is
thought to be preventable, some of which is facility-related [30].
Levels of critical care
An intensive care unit is defined as:
an organized system for the provision of care to critically
ill patients that provides intensive and specialized medi-
cal and nursing care, an enhanced capacity for monitoring,
and multiple modalities of physiologic organ support to
sustain life during a period of acute organ system insuf-
ficiency [31].
A system of critical care requires physical space, technology
for organ support and monitoring, a trained and interdisciplin-
ary work force, and specific services it can deliver, both within
the hospital and as a component in a larger healthcare system. In
addition to individual patient-care services, it provides research,
professional education, and disaster response. Suggested equip-
ment is shown in Table 42.2.
The World Federation of Societies of Intensive and Critical
Care Medicine (WFSICCM) describes a framework for levels of
critical care [31].
Level 1 (primary) ICU
Basic care, with a nurse-to-patient ratio higher than that in a gen-
eral ward. Physicians have critical care experience, as do nurses,
but not necessarily formal training. Physicians are not on-site
DOI: 10.1201/9781003099062-42
Critical Care 413

TABLE 42.1: Definitions of Maternal Mortality (and Related Terms) and Severe Maternal Morbidity (or Near-Miss Maternal
Mortality)
Definition Reference
Maternal Death of a woman while pregnant or within 42 days of World Health Organization and CDC, both ICD-9 and ICD-10
Mortality termination of pregnancy, irrespective of the duration (Source: Hoyert DL. Maternal mortality and related concepts.
and the site of the pregnancy, from any cause related to National Center for Health Statistics. Vital Health Stat 3(33). 2007
or aggravated by the pregnancy or its management, but http://www.cdc.gov/nchs/data/series/sr_03/sr03_033.pdf
not from accidental or incidental causes Accessed 11/3/15)
Pregnancy- Death while pregnant or within 42 days of termination of Same as above
related deaths pregnancy, regardless of cause of death
Direct obstetric Death resulting from obstetric complications (pregnancy, Same as above
deaths labor, puerperium)
Indirect obstetric Death resulting from previous existing disease, or disease Same as above
deaths developed during pregnancy, not due to direct obstetric
causes, but aggravated by physiology of pregnancy
Late maternal Death from direct OR indirect obstetric causes, >42 days Same as above
deaths but <1 year after termination of pregnancy
Severe maternal A woman who nearly died but survived a complication Pattinson R, Sale L, Souza JP, van den Broek N, Rooney C, on behalf
morbidity that occurred during pregnancy, childbirth, or within 42 of the WHO Working Group on Maternal Mortality and
days of termination of pregnancy Morbidity Classifications. Bull World Health Org 2009; 87: 734
Severe maternal A woman receiving 4 or more units of red blood cells Joint Commission (JCAHO) as: (http://www.acog.org/About-
morbidity and/or ICU admission ACOG/News-Room/Statements/2015/Severe-Maternal-
Morbidity-Clarification-of-the-New-Joint-Commission-Sentinel-
Event-Policy; also http://www.jointcommission.org/assets/1/23/
jconline_February_4_151.PDF. Accessed 11/4/15)

150
Any severe maternal 146.6
morbidity
45 percent
increase
125
Number of Deliveries Involving Severe Maternal
Morbidity per 10,000 Delivery Hospitalizations

121.1

101.3
54 percent
100 increase
Blood transfusion
(with or without other indicators
78.9 of severe maternal morbidity)a
75

24 percent
50 increase
41.9
33.8
Other severe maternal morbidity
25 (with or without blood transfusion)a

0
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Year

FIGURE 42.1 Trends in U.S. delivery hospitalizations involving severe maternal morbidity, 2006–2015. (From Fingar KR, Hambrick
MM, Heslin KC, Moore JE. Trends and disparities in delivery hospitalizations involving severe maternal morbidity, 2006–2015.
Statistical brief #243. September 2018. Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. https://
www.hcup-us.ahrq.gov/reports/statbriefs/sb243-Severe-Maternal-Morbidity-Delivery-Trends-Disparities.jsp. Accessed 11/21/2020.
Ref. [23], with permission.)
414
TABLE 42.2: Equipment and Support That an ICU Should Be
Prepared to Provide
• Continuous ECG monitoring (with high/low alarms), all patients
• Continuous arterial pressure monitoring (invasive and noninvasive)
• Central venous pressure monitoring
• Transcutaneous oxygen monitoring or pulse oximetry for all patients
receiving supplemental oxygen
• Airway equipment, including laryngoscopes and endotracheal tubes
• Ventilatory equipment: Ambu bags, ventilators, oxygen, compressed air
• Emergency resuscitation equipment
• Equipment to support hemodynamically unstable patients: Infusion
pumps, blood/fluid warmers, pressure bags, blood filters
• Beds with removable headboard and adjustable position; various
specialty beds
• Adequate lighting for bedside procedures
• Suction
• Cooling/warming blankets
• Scales
• Temporary pacemakers (transcutaneous and transvenous)
• Temperature monitoring devices
• Pulmonary artery pressure monitoring
• Cardiac output monitoring
• Continuous and intermittent dialysis and ultrafiltration
• Peritoneal dialysis
• Capnography
• Fiberoptic bronchoscopy
• Intracranial pressure monitoring
• Continuous EEG monitoring capability
• Positive and negative pressure isolation rooms
• Immediate access to information (medical books, journals; drug
information, poison control; personnel phone and page numbers;
patient lab and test data; medical record information)
around the clock. Monitoring capabilities are noninvasive (e.g.,
continuous ECG monitoring, pulse oximetry) and organ support
is limited. Respiratory support is limited to supplemental oxygen
provided noninvasively, although some short-term mechani-
cal ventilation can be undertaken. It accepts patients only from
within the hospital, has no plan for surge capacity, and requires
a transfer agreement with higher-level centers to accept patients
beyond this scope.
Level 2 (secondary) ICU
Nurses have special qualifications, and the nurse-to-patient ratio
should not be more than 1:3. Physicians have specialty train-
ing (e.g., medicine, surgery, anesthesiology) and may have ICU
training. Allied health professionals are part of the ICU team.
Monitoring, in addition to the noninvasive capabilities above,
includes invasive technologies such as arterial and central lines.
Blood gas analysis is immediately available. These units can han-
dle endotracheal intubation, positive-pressure ventilation, vaso-
active infusions, and renal replacement therapies. Level 2 ICUs
are referral centers for local hospitals.
Level 3 (tertiary) ICU
This is the highest level care for the critically ill patient. Nurses
have specialized training, nurse-to-patient ratio is ideally 1:1 or 1:2.
Physicians have specialty critical care training and coverage is
Maternal-Fetal Evidence Based Guidelines
round the clock (although a qualified nurse practitioner or criti-
cal care physician trainee may provide some of that coverage).
Allied health staff are part of the team. The full suite of ICU
monitoring and support is available, and additional services such
as invasive neurologic monitoring or extracorporeal membrane
oxygenation may be supported. Isolation facilities and a surge
or disaster plan are needed; Level 3 units are the regional refer-
ral center for critical care. In most cases these will be teaching
hospitals.
An alternative to the ICU is the intermediate care unit
(IMCU) or high-dependency unit (HDU) [32]. Patients who
require frequent monitoring of vital signs or frequent nursing
interventions but do not need specific ICU life-support treat-
ments may be admitted to such a unit. The intermediate care unit
is staffed at lower nursing levels and includes less complex tech-
nology than the ICU, which makes it less expensive to run, frees
up beds in the ICU, and has been associated with greater family
satisfaction. Intermediate care units include post-ICU step-down
units, telemetry units for cardiac patients, etc.
Low-risk monitor patients are those predicted to be at low
risk of requiring active life-saving treatment such as mechanical
ventilation or vasopressors. The most frequent monitoring ser-
vices deployed in the care of such patients in the ICU are ECG
(>99%), intra-arterial BP monitoring (51%), and pulse oxim-
etry (33%), and the most frequent labor-intensive nursing inter-
ventions were intake/output measurement, hourly vital signs, and
hourly neurologic checks [33].
When planning obstetric critical care services, the intermedi-
ate care unit is a good approximation of the type and acuity of
services generally needed. However, experience in 2009–2010
with novel influenza and most recently in 2019–2020 with SARS
Co-V2 should remind us that pregnant women are at higher risk
of respiratory failure in some circumstances, and a contingency
plan for epidemic and pandemic respiratory infections must be
made, including provision of invasive and noninvasive ventilatory
support [34–37].
A similar schema for levels of critical care comes from the
Intensive Care Society (ICS) in the United Kingdom [38]. Level 0
refers to normal ward care, Level 1 to patients with single-organ
failure (i.e., noninvasive ventilation or vasopressor support and
at risk of deterioration), Level 2 to patients with multiple-organ
failure (i.e., noninvasive ventilatory and pressure support or renal
replacement therapy), and Level 3 to patients requiring more
advanced organ support (i.e., mechanical ventilation) [38]. The
Maternal Critical Care Working Group, convened in 2018, and
explicitly adapted the ICS guidelines to maternal care [39]. The
Obstetric Care Consensus document published by the American
College of Obstetricians and Gynecologists and the Society for
Maternal-Fetal Medicine issued guidance on levels of maternal
care which is different still; critical care services are mentioned
as a component of Level III and Level IV maternal care (see later
text and Table 42.3) [40].
Organization of obstetric
critical care services
If the discipline of critical care is young, that of obstetric critical
care is younger still. There are no evidence-based recommen-
dations published specifically for critical care in pregnancy.
As such, information regarding critical care in pregnancy is based
on recommendations from (non-pregnant) adult critical care and
Critical Care 415

TABLE 42.3: Levels of Maternal Care: (A) Level III and (B) Level IV (ACOG and SMFM)h
(A) Level III
Level III (Subspecialty Care)
Definition Level II facility plus care of more complex maternal medical conditions, obstetric complications, and fetal conditions
Capabilities Level II facility capabilities plus

• In-house availability of all blood components

• Computed tomography scan, magnetic resonance imaging, maternal echocardiography, and nonobstetric ultrasound
imaging services and interpretation readily available at all timesa
• Specialized obstetric ultrasound and fetal assessment, including Doppler studies, with interpretation readily available at
all timesa
• Basic interventional radiology (capable of performing uterine artery embolization) readily available at all timesa
• Appropriate equipment and personnel physically present at all timesg onsite to ventilate and monitor women in labor and
delivery until they can be safely transferred to the ICU
• Onsite medical and surgical ICUs that accept pregnant women and women in the postpartum period. The ICUs have
adult critical care providers physically present at all times.g An MFM is readily available at all timesa to actively
communicate or consult for all obstetric patients in the ICU
• Documented mechanism to facilitate and accept maternal transfers/transports
• Provide outreach education and patient transfer feedback to I and II designated facilities to address maternal care quality issues
• Provide perinatal system leadership if acting as a regional center (for example, in areas where IV facilities are not
available) (see Level IV)

Healthcare providers Level II healthcare providers plus

• Nursing leaders and adequate number of RNs who have special training and experience in the management of women
with complex and critical maternal illnesses and obstetric complications
• Board-certifiedf OB-GYN physically presentg at all times
• An MFM with inpatient privileges readily available at all timesa either onsite, by phone, or by telemedicine. Timing of
need to be onsite is directed by urgency of clinical situation. However, MFM must be able to be onsite to provide direct
care within 24 hours
• Director of maternal-fetal medicine service is a board-certified MFM
• Director of obstetric service is a board-certified OB-GYN or MFM
• Board-certified anesthesiologistf physically presentg at all times
• Director of obstetric anesthesia services is board-certified anesthesiologist with obstetric anesthesia fellowship training or
experience in obstetric anesthesia
• Full complement of subspecialists, such as subspecialists in critical care, general surgery, infectious disease, hematology,
cardiology, nephrology, neurology, gastroenterology, internal medicine, behavioral health, and neonatology, readily
available for inpatient consultation at all timesa

(B) Level IV (ACOG and SMFM)

Level IV (Regional Perinatal Healthcare Centers)
Definition Level III facility plus on-site medical and surgical care of the most complex maternal conditions and critically ill pregnant
women and fetuses throughout antepartum, intrapartum, and postpartum care

Capabilities Level III facility capabilities plus

• On-site medical and surgical care of complex maternal conditions with the availability of critical care unit or ICU beds
• On-site ICU care for obstetric patients with primary or co-management by maternal-fetal medicine team.
Co-management includes at least daily rounds by an MFM with interaction with the ICU team and other subspecialists
with daily documentation. In some settings, the ICU is in an adjoining or connected building, which is acceptable as long
as maternal-fetal medicine care is as noted earlier. If the woman must be transported by ambulance to the ICU, this is not
considered onsite
• Perinatal system leadership, including facilitation of collaboration with facilities in the region, analysis and review of system
perinatal outcome and quality data, provision of outreach education and assistance with quality improvement as needed

Healthcare providers Level III healthcare providers plus

• Maternal-fetal medicine care team with expertise to manage highly complex, critically ill, or unstable maternal patients. A
board-certified MFM attending with full inpatient privileges is readily available at all timesa for consultation and
management. This includes co-management of ICU-admitted obstetric patients
• Nursing Service Line leadership with advanced degree and national certification
• Continuous availability of adequate numbers of RNs who have experience in the care of women with complex medical
illnesses and obstetric complications with close collaboration between critical care nurses and obstetric nurses with
expertise in caring for critically ill women
(Continued)
416 Maternal-Fetal Evidence Based Guidelines

TABLE 42.3 (Continued): Levels of Maternal Care: (A) Level III and (B) Level IV (ACOG and SMFM)h
• Board-certified anesthesiologist with obstetric anesthesia fellowship training or experience in obstetric anesthesia
physically present at all timesg
• At least one of the following adult subspecialties readily available at all times for consultation and treatment as needed
onsite: Neurosurgery, cardiac surgery, or transplant. If the facility does not have all three subspecialties available, there
should be a process in place to transfer women to a facility that can provide the needed service
Source: From American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine. Obstetric Care Consensus No. 9. Levels of maternal care.
Obstet Gynecol 2019; 134:e41–e55. Ref. [40], with permission.
a Readily available at all times: The specific person should be available 24 hours a day, 7 days a week for consultation and assistance, and able to be physically present onsite

within a time frame that incorporates maternal and fetal or neonatal risks and benefits with the provision of care. Further defining this time frame should be individualized
by facilities and regions, with input from their obstetric care providers. If referring to the availability of a service, the service should be available 24 hours a day, 7 days a week
unless otherwise specified.
b Available at https://safehealthcareforeverywoman.org/patient-safety-bundles.

c See also emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. ACOG Committee Opinion No. 767. American College of

Obstetricians and Gynecologists. Obstet Gynecol 2019;133:e174–80.

d Midwives who meet international Confederation of Midwives standards, such as certified nurse-midwives (CNMs) and certified midwives (CMs) and who are legally recog-

nized to practice within the jurisdiction of the state.

e Scope of practice for nurse anesthetists and anesthesiologist assistants may vary by state.

f Also includes physicians who have completed residency training and are eligible for board certification according to applicable board policies.
g Physically present at all times: The specific person should be onsite in the location where the perinatal care is provided, 24 hours a day, 7 days a week.

h These guidelines are limited to maternal needs. Consideration of fetal or neonatal needs and the appropriate level of care should occur following existing guidelines. In fact,

levels of maternal care and levels of neonatal care may not match within facilities. Additionally, these are guidelines, and local issues will affect systems of implementation
for regionalized maternal care, perinatal care, or both.
Abbreviations: CMs, certified midwives; CNMs, certified nurse-midwives; ICU, intensive care unit; MFM, maternal-fetal medicine subspecialists; OB-GYNs, obstetrician-
gynecologists; RNs, registered nurses.

expert opinion [41, 42]. There is limited research available regard-
ing critical care in pregnancy; in fact, with rare exceptions (such
as the RECOVERY trial in the UK, https://www.recoverytrial.
net/), pregnant women are specifically excluded from critical care
trials. As there are unique issues that arise when the pregnant
patient becomes sick, there is a need for additional research in
this area. The interested practitioner must extrapolate from the
general critical care literature instead, or rely on expert opinion.
Hemorrhage and hypertension are, consistently, the most
common causes of admission from obstetrical services to
intensive care [1–16, 18, 43–58]. The majority of these patients
require monitoring and only simple interventions. The degree
of nursing care involved, while higher acuity than on most gen-
eral wards, is well within the abilities of most labor and delivery
nurses in a specialty or subspecialty care facility, that is, levels of
maternal care II and III, as described by the American College
of Obstetricians and Gynecologists and Society for Maternal-
Fetal Medicine [40]. The intermediate care unit or HDU is also
designed to provide care of this type.
A smaller number of obstetrical patients have nonobstetric
causes for ICU admission, such as trauma, sepsis, respiratory
illness, cardiovascular disease, neurologic disorders, diabetic
ketoacidosis, overdose/poisoning, and the like; these amount
to 20–30% of the total [10, 12–15, 18]. Most obstetric patients
who are admitted to ICU are sent there postpartum rather
than undelivered [10, 11, 14, 15]. The preponderance of post-
partum over antepartum admissions may stem from postpar-
tum vulnerability (e.g., postpartum hemorrhage, postpartum
decompensation of cardiac disease) or to ascertainment bias;
obstetricians may be reluctant to transfer, or intensivists to
accept, a patient whose fetus must be considered in manage-
ment. In the case of an “obstetrical ICU” existing within a
L & D unit, there is a higher percentage of both antepartum
admissions and primary medical (nonobstetric) admissions
[7, 18]. This may reflect a lower threshold for admission to the
obstetrical ICU (as no transfer or travel is involved); a need to
justify the continuation of the service; or a preference to trans-
fer out postpartum patients; L & D beds are a scarce commodity,
and a postpartum patient requiring intensive care ties up space
and personnel when she could be adequately cared for outside
of the obstetric unit.
Most obstetrical services would be unable to implement
a full-service obstetrical ICU. Both the technology and the
personnel mandated by ICU guidelines are impracticable. The
HDU or intermediate care unit, however, is a reasonable model
for much of obstetric critical care. Published experience, albeit
limited, is encouraging. A high-volume public hospital in Dallas,
Texas, admitted 1.7% of maternity cases to a five-bed obstetrics
intermediate care unit, usually postpartum (80%), with a mean
length of stay less than 24 hours [18]. Of these 500 women, 15%
subsequently were transferred to a full-service medical or sur-
gical ICU, most for mechanical ventilation. A referral mater-
nity hospital in Dublin, Ireland, opened a “high-dependency” or
intermediate care unit [17]. Prior to debut of the HDU, patients
requiring intensive care services (0.1% of maternity admissions)
were transferred out to another hospital with a medical/surgical
ICU. After the obstetric HDU was established, the referral rate
to the offsite ICU dropped by 50%, but the HDU was busier than
one might have expected; 1% of maternity patients were admit-
ted thereto, a 10-fold increase in the percentage of patients who
were managed as higher acuity. The question as to whether this
represents underutilization of needed services before the advent
of the obstetric intermediate care unit, or overutilization after,
cannot be answered. In a large women’s hospital in Birmingham,
United Kingdom, without an on-site ICU, a three-bed HDU
within the delivery suite accommodated between 1% and 5% of
all obstetric patients; the percentage steadily increased over time
[19]. Among women admitted to this HDU, 3.5% were then trans-
ferred out to intensive care.
The American College of Obstetricians and Gynecologists,
jointly with the Society for Maternal-Fetal Medicine, produced
an Obstetric Care Consensus on levels of maternal care, the
Critical Care
stated goal being a reduction in maternal morbidity and mortal-
ity, including the reduction of existing disparities and the deliv-
ery of risk-appropriate care [40]. This Obstetric Care Consensus
focuses on the regionalization of maternal care to allow for rela-
tionships between facilities that provide differing levels of care.
These established relationships should facilitate consultation and
transfer of care when maternal risk warrants. These recommen-
dations are based on data from studies suggesting that hospital
delivery volume, healthcare provider volume, and hospital level
of care can affect maternal outcomes [40]. Critical care ser-
vices are specifically mentioned in Levels III and IV facilities
(Table 42.3). Level III facilities are expected to have:
an on-site intensive care unit…and critical care providers
onsite to actively collaborate with maternal-fetal special-
ists at all times. Equipment and personnel with expertise
must be available onsite to ventilate and monitor women
in the labor and delivery unit until they can be safely trans-
ferred to the ICU.
The concept of critical care in pregnancy is more explicitly
spelled out in the description of Level IV facilities, which are to
be regional perinatal healthcare centers:
A level IV facility is distinct from a level III facility in the
approach to the care of pregnant women and women in the
postpartum period with complex and critical illnesses. In
addition to having ICU care onsite for obstetric patients,
a level IV facility must have…a maternal-fetal medicine
care team that has the expertise to assume responsibility
for pregnant women and women in the postpartum period
who are in critical condition or have complex medical con-
ditions. The maternal-fetal medicine team collaborates
actively in the co-management of all obstetric patients who
require critical care and ICU services. This includes co-
management of ICU-admitted obstetric patients…The team
should be led by a board-certified maternal-fetal medicine
subspecialist with expertise in critical care obstetrics…
The maternal-fetal medicine team must have expertise in
critical care at the physician level, nursing level, and ancil-
lary services level… There should be institutional support
for the routine involvement of a maternal-fetal medicine
care team with the critical care units and specialists.…The
director of obstetric services is a board-certified maternal-
fetal medicine subspecialist or a board-certified obstetri-
cian-gynecologist with expertise in critical care obstetrics.
The American College of Critical Care Medicine states, “The
Physician Director should meet guidelines for the definition of
an intensivist and the practice of critical care medicine” [59].
The definition of an intensivist is one that few obstetricians
or maternal-fetal medicine specialists would be able to meet,
since it includes not only skills, interest, and availability but also
completion of an approved training program in critical care
medicine. Decades ago, Mabie suggested several ways in which
an obstetrician might obtain exposure to critical care training
[50]: A critical care fellowship, an additional residency in inter-
nal medicine, or a maternal-fetal medicine fellowship. A more
recent plea to put the “M” back into MFM [60] resulted in a new
American Board of Obstetrics and Gynecology (ABOG) require-
ment for MFM fellows to complete 1 month of ICU training, which
cannot be considered adequate in itself. Critical care medicine
417
fellowships in the United States run 12 months under the aegis of
anesthesiology or surgery (both of which are open to individuals
who have completed residency in OB-GYN), or 2 years after com-
pletion of an emergency medicine or internal medicine residency,
or 3 years after a pediatric residency. A review of obstetric critical
care training around the world, from the standpoint of OB-GYN,
anesthesiology, and intensive care medicine, concluded that it
could not be considered adequate anywhere [61]. Having acquired
formal training would, furthermore, be insufficient if there is not
enough clinical material to maintain skills and expertise: This is
an even higher hurdle. Regionalization of obstetric care would
allow for concentration of women who need it, to centers with
expertise in maternal critical care, and support maintenance of
skills among those practitioners.
Recommendations for nursing care in an ICU [59] state
that all nurses working in critical care should complete a clini-
cal and didactic course in critical care before taking on patient
responsibilities, participate in continuing education, and assume
nurse-to-patient ratios either 1:2 or based on patient acuity. High
nurse-to-patient ratios are already standard on labor/delivery units
and would, therefore, be rather easy to implement in establishing
an obstetric critical care unit. As discussed earlier, acquiring and
maintaining critical care skills would be considerably more diffi-
cult as this requires a considerable volume of critical care patients.
ACOG and SMFM have recommended that nursing services in
maternal III hospitals have “continuously available … RNs with
special training and “expertise in managing women with complex
maternal illnesses,” and that IV facilities should also have “nurs-
ing leadership [with] expertise in maternal intensive and critical
care” [40].
Competence in core procedural skills is expected of any phy-
sician practicing in critical care [62]; see Box 42.1.
Some critical care techniques are used less frequently now
than in the past. Utilization of the pulmonary artery catheter
dropped by two-thirds in the first decade of the 21st century [63],
after demonstration that its use is not associated with improve-
ment in outcomes. Noninvasive methods of ventilation have
replaced mechanical ventilation in some cases. More recent
competencies for critical care training and practice now also
include point-of-care ultrasound imaging (lung, abdomen, and
heart, as well as procedural guidance), advanced airway manage-
ment, bronchoscopy, and thoracentesis [64, 65]. As some tech-
niques are phased out, new ones appear; thus, the list here can
only be taken as a snapshot of current critical care practice. Skill
maintenance may not be feasible unless alternative means are
sought, such as simulation-based or supervised experience.
BOX 42.1: SOME CORE PROCEDURAL
SKILLS FOR ICU PRACTICE (SEE REF. [62])
1. Maintenance of airway (non-intubated patient)
2. Ventilation (bag and mask)
3. Endotracheal intubation
4. Management of pneumothorax
5. Arterial puncture; insertion of an arterial line
6. Central venous cannulation
7. Pulmonary artery catheterization (insertion,
maintenance, interpretation)—little used now
8. ECG interpretation
9. Cardioversion, defibrillation
418
Considerations in transfer (interhospital)
The maternal and fetal unit are intimately connected. This must be
considered when determining the level of care for both maternal
and neonatal needs when transfer is necessary. Preterm delivery
may occur concurrently with critical illness, because of underly-
ing medical or obstetric conditions, spontaneous preterm labor,
or iatrogenic interventions. One case-control study [6] found
36 weeks was the mean gestational age achieved by antepartum
patients admitted to ICU. In earlier series of respiratory failure
in pregnancy, median gestational age achieved was 31–32 weeks
[66, 67]; recent series of coronavirus-associated respiratory fail-
ure show that 75–80% of women delivered preterm, at a median
gestational age ranging from 31–34 weeks [68–71]. The Mayo
series of 93 antepartum admissions to ICU reported that one-
third resulted in fetal losses and one-half in preterm births [72].
Thus, it would appear prudent that a pregnant woman requir-
ing ICU services, after achieving a gestational age compatible
with extra-uterine viability, should be managed in a facility
with both adult and neonatal ICU capability. Because some
hospitals maintain adult intensive care services but no maternity
services, and others, specifically women’s hospitals, do not have
adult intensive care, arrangements should be in place for seam-
less transfer to a facility that maintains appropriate levels of
care for mothers and neonates. Guidelines for perinatal trans-
fers have advocated antenatal over neonatal transfer where fea-
sible. In the event that maternal transport is unsafe or impossible,
alternative arrangements for neonatal transport must be made.
Transfer in cases of critical illness is more complex than the
usual perinatal transfer. The transport process increases risk of
morbidity and mortality for the critically ill [73], and therefore
cannot be embarked upon lightly. Once the decision to transfer has
been made and the patient (or her designated decision-maker) has
consented, she should be transferred as expeditiously as possible
to the receiving facility that has agreed to accept her. If the patient
is unstable, she should be stabilized and/or resuscitated to the best
possible condition prior to transport, albeit with the understand-
ing that complete stabilization may not be possible outside of the
receiving facility. Transport may be by ground or air, based on the
urgency of the patient’s condition, the distance between facilities,
weather conditions, potential interventions during transport, and
equipment or personnel available. The minimum monitoring
of a critically ill patient during transport includes continu-
ous pulse oximetry and ECG as well as regular assessment of
vital signs [73]. Patients who already have arterial or central lines
should have those monitored as well. Women who are mechani-
cally ventilated must have the endotracheal tube position con-
firmed and secured before transport and must be assessed for
adequacy of oxygenation and ventilation. All critically ill patients
must have secure venous access before transport.
Opinion, but no data, guides us as to additional monitoring
during transport of the critically ill obstetric patient. Patients at
high risk of delivering en route should be held at the initial hospi-
tal until delivered, since there is unlikely to be access to both the
patient’s head and her vagina in tight transport quarters, most
transport teams lack expertise in delivery and neonatal resus-
citation, and a dedicated neonatal transport team can be sum-
moned for the newborn if the mother was not transferred prior
to delivery. There is little benefit in tocodynamometry during the
transport process, as any information obtained would not likely
be acted upon in the setting of transport. Fetal monitoring during
transport may be feasible to perform but is of unproven utility.
Maternal-Fetal Evidence Based Guidelines
Because fetal monitoring equipment takes up space in tight quar-
ters and there is little or nothing the transport team can do en
route for an ominous tracing, it seems preferable to avoid fetal
monitoring when transporting a critically ill obstetric patient.
Transport should not be delayed due to inability to provide fetal
monitoring as optimization of maternal status will optimize fetal
status. Simple measures such as left uterine displacement and
supplemental oxygen should be routine during transport of the
critically ill pregnant patient.
Admission to intensive care
Hemorrhage and hypertension are the most common reasons for
transfer to ICU. Most maternal ICU admissions are postpartum
rather than antepartum. Level II and III maternity units [40]
may be able to care for such patients on the labor and delivery
unit, particularly if an intermediate care unit or HDU is located
there. Level I facilities, however, should consider transfer either
to a higher-level perinatal center or to the ICU at their own facil-
ity. In cases where both obstetric and critical care services are at
the most basic level, transfer of such patients to another facility
may be the best approach. A small number of OB-GYN specialty
hospitals exist in the United States [74]; these usually have limited
critical care support or consultation available in-house and should
have a low threshold for transfer. Obstetrics services in such hos-
pitals should have a set of site-specific guidelines established at
the hospital level. While ICU beds are a scarce resource, objec-
tive clinical parameters, potential for clinical deterioration, need
for high-acuity interventions, and need for clinical critical care
expertise should be considered in determining need for transfer
of care to a higher level unit or facility.
In any center, a decision to transfer to ICU should be made on
the basis of need for site-specific care. An obstetric service should
adopt guidelines for transfer based on the level of care required,
modified by the level of care that could be provided on the labor
floor or within an existing obstetric intermediate care unit.
Necessary care must not be withheld while awaiting transfer.
The Maternal Critical Care Working Group has called for equity
of care for pregnant and puerperal women with critical illness,
meaning that the same standard of care applies for both their
obstetric and critical care needs, regardless of where that care
must be delivered [39].
The National Partnership for Maternal Safety has identi-
fied bedside triggers that should prompt immediate evaluation
and consideration for escalation in the level of care [75] (see
Table 42.4). Adoption of maternal early warning criteria, coupled
TABLE 42.4: Maternal Early Warning Criteria (National
Partnership for Maternal Safety)
Systolic blood pressure (mmHg) <90 or >160
Diastolic blood pressure (mmHg) >100
Heart rate (beats per min) <50 or >120
Respiratory rate (breaths per min) <10 or >30
Oxygen saturation on room air, at sea level, % <95
Maternal agitation, confusion of unresponsiveness
Patient with pre-eclampsia reporting non-remitting
headache or shortness of breath
Source: From Mhyre JM. D’Oria R, Hameed AB, et al. The maternal early warning
criteria: a proposal from the National Partnership for Maternal Safety.
Obstet Gynecol 2014; 124:782–786. Ref. [75], with permission.
Critical Care
with an appropriate clinical pathway, has been shown to decrease
severe acute maternal morbidity [76]. An adaptation of this or a
similar tool could simplify the process of triage to ICU or HDU
[77]. Other early warning systems exist [78], and can predict
the likelihood of ICU admission, but unlike the Maternal Early
Warning Criteria, they do not take into account the physiologic
changes of pregnancy.
Logistics
The Maternal Critical Care Working Group provides useful guid-
ance about service organization, competencies, and workforce
development [39]. This document is indispensable to anyone con-
templating setting up maternal critical care services.
Zeeman proposed a “blueprint” for obstetric critical care [18,
79], that is, an intermediate care unit in the obstetric setting. She
lists as advantages the “concurrent availability of expert obstetric
care and critical care management … the option of continuous
fetal monitoring with on-hand expertise in its interpretation …
the advantages of keeping mother and infant together combined
with the improved continuity of antenatal and postnatal care”
[79]. This seems indisputable for units that are big enough to keep
up expertise. For lower-volume centers, however, it is not always
feasible, and for even the largest services, there will be patients
who are best treated in a full-service ICU.
Better outcomes are demonstrated in a general medical/
surgical ICU population when specialized ICU physicians staff
the unit. High-intensity ICU physician staffing (either a closed
ICU model or mandatory intensivist consultation) is associated
with lower ICU mortality, lower hospital mortality, and decreased
length of stay in both ICU and hospital, compared to models in
which intensivist consultation is optional [80]. Although there
are limited data specifically addressing the critical care obstetric
patient, it would seem to follow that intensivist input would also
improve outcomes in this population [81, 82]. ICU admission has
been demonstrated to reduce maternal mortality by as much
as 80% among women with critical illness [83].
If a patient who is still pregnant requires critical care ser-
vices, the first question to answer is: Where is she best cared
for? If the pregnancy is early or the duration of ICU services is
anticipated to be lengthy, the labor floor is not likely the best
location. If she is in active labor, the labor floor is probably the
best choice. Most patients will not fall into these two clear cat-
egories. Factors affecting the decision of where to admit will then
include degree of instability, interventions required, staffing and
expertise available, anticipated duration of ICU stay, probability
of delivery, access for family, etc.
The obstetrician transferring a patient to an ICU must be
familiar with the types of units available within the facility, that
is, general medical/surgical ICU or specialty unit (cardiothoracic,
neurologic/neurosurgical, etc.), and understand whether the ICU
is open, closed, or hybrid/transitional [84]. In an open unit, any
physician can write orders or perform procedures; management
or consultation by an intensivist is not mandatory. In a closed ICU,
only the critical care staff writes orders and manages patients; the
primary team gives over control. The hybrid or transitional model
allows all physicians to write orders but requires an on-site criti-
cal care physician to consult, round on, or co-manage all patients
in the unit. As discussed earlier, involving the intensivist has
been shown to improve outcome.
Critical care requires a multidisciplinary approach [59] to
achieve best outcomes. The ICU team is comprised of physicians,
419
nurses, pharmacists, and respiratory therapists. In the case of
maternal critical care, the ICU team must also include obstetri-
cians, obstetric/perinatal nurses, and pediatricians. The obstetric
and pediatric parties commonly consist of subspecialty-trained
physicians in maternal-fetal medicine and neonatology.
When an undelivered patient is transferred to ICU, efforts
should be made to map out the anticipated course of her condi-
tion or disease, look ahead to possible complications, and set
parameters for delivery. Delivery parameters will depend on
gestational age and shared decision-making with the patient, if pos-
sible, and her family. In general, pre-viable delivery or pregnancy
termination is considered in circumstances where the mother’s
life is threatened by continuing the pregnancy. Following viability,
both maternal and fetal/neonatal factors should be considered in
planning whether to continue the pregnancy, how to implement
antepartum surviellance, and how to effect delivery. Modifications
of physical and laboratory assessment related to pregnancy must
be known and taken into account; the obstetrician will be more
familiar with these than the intensivist. The plan should be clear
to the medical team and to the patient’s family, and to the patient
herself if she is able to understand. The risk-benefit balance for a
given intervention will change as pregnancy progresses, so it is
important to revisit the care plan on a regular basis.
Fetal monitoring will often, but not always, be appropriate. If
plans are made for fetal monitoring outside of the labor and deliv-
ery unit, the team should strategize about the type and frequency
of monitoring as well as the expected interventions. It is not
appropriate to commit to continuous fetal monitoring unless the
strip can be interpreted in real time by someone qualified to read
it and empowered to take corrective action. In some cases this
will entail an obstetric or perinatal nurse at the bedside in ICU.
Alternatively, remote access monitoring can be used to transmit
the tracing to a display on the obstetrical unit. Changes in the
fetal monitor tracing often reflect alterations in maternal
physiology rather than in the fetal status, and thus may func-
tion as an early warning system for derangements in maternal
end-organ status (acid-base balance, volume status, etc.). This
means that the usual trigger response on the labor floor—that is,
delivery in the setting of a non-reassuring fetal tracing—must be
suppressed long enough to look for alternate explanations for a
change in fetal status. Often, optimization of maternal status will
improve fetal status and avoid reflex delivery in a compromised
patient that could ultimately result in worse outcomes for both
mother and neonate.
The plan for delivery should be made long before delivery is
imminent, and address the preferred location for delivery, mode
of delivery, requirement for analgesia or anesthesia, and access
for the neonatal team. It must also include alternatives in case
matters do not go as anticipated. It must be understood that the
plan for delivery is subject to change as maternal and fetal sta-
tus change and gestation progresses. Frequent reassessment of
the plan for delivery should occur with multi-disciplinary input.
Communication is critical in caring for obstetric patients in ICU.
The patient in an HDU or intermediate care unit on the
labor floor can easily be delivered there. Many critically ill
obstetric patients will, however, be elsewhere. Advantages of
vaginal delivery in ICU include ready availability of critical care
interventions and staff, plus avoidance of potentially destabiliz-
ing transport. Disadvantages include lack of space to conduct
delivery, unfamiliarity of critical care personnel with obstetric
management, space constraints for the pediatric team and equip-
ment, and inadequate privacy. The alternative, transport to L&D,
420
ensures familiarity with obstetric issues but unfamiliarity with
critical care issues. The process of transport itself is risky for a
critically ill patient [73].
When considering delivery in ICU, the increased likelihood
of instrumental delivery must be kept in mind. Patients with
trans-laryngeal intubation cannot close the glottis to push and,
therefore, may have a prolonged second stage, often requiring
delivery via vacuum or forceps. Most of these patients are sedated
and incapable of cooperating with a coached second stage.
Patients with cardiac, respiratory, or neuromuscular compromise
are at risk of decompensation during labor, especially in second
stage. Women with altered mental status may not tolerate pain or
obstetric manipulation. Pain relief cannot be forgone in ICU even
when a patient cannot verbalize discomfort, but patients may
not qualify for regional analgesia techniques because of issues
with positioning, hemodynamic instability, or coagulopathy.
Intravenous analgesia is, of course, an alternative to epidural, but
is not as effective in protecting a medically fragile patient from
hemodynamic derangements associated with pain. Close collabo-
ration between the critical care physician, anesthesiologist, and
the obstetric physician is necessary to provide a safe environment
for these medically complex patients.
Cesarean delivery in ICU is fraught with hazards. The ICU
does allow for some surgical procedures performed under local
anesthesia with deep sedation, such as tracheostomy, percuta-
neous gastrostomy, insertion of vena cava filters, or diagnostic
laparoscopy [85–88]. Some cardiothoracic units allow emergency
re-exploration in ICU for bleeding or tamponade rather than re-
transport back to the operating room (OR) [89]; laparotomy has
been performed at the bedside when patients have been deemed
too unstable for transport to OR, though with high mortality
rates [90]. Rates of bedside laparotomy, usually for damage con-
trol or abdominal compartment syndrome, have risen in some
Level 3 ICUs [91]. Disadvantages of performing cesarean in the
ICU include inadequate space for anesthetic and surgical equip-
ment (to say nothing of required neonatal resuscitation gear),
inadequate lighting, unfamiliarity of attendant personnel with
the operation, the accumulation of a crowd of onlookers, and the
risk of nosocomial infection with drug-resistant organisms; ICUs
have the highest rates of healthcare-associated infections in a
hospital [92, 93]. Obstetric patients in ICU should have a route
to an operating room mapped in the event that urgent cesarean
delivery is necessary. This route should be known to all taking
care of the patient. In the special, and thankfully rare, condition
of perimortem cesarean, these concerns would be ignored; the
primary goal of perimortem cesarean delivery in the ICU is as a
component of cardiopulmonary resuscitation, to maximize the
odds of achieving return of spontaneous circulation.
Role of OB-GYN
In an intermediate care unit on a labor/delivery floor, the lead
physician will typically be an obstetrician-gynecologist, with or
without subspecialty maternal-fetal medicine training; some-
times this function will be fulfilled instead by an obstetric anes-
thesiologist. The team leader would coordinate and manage the
patient’s care, in addition to providing hands-on care as neces-
sary. It is essential that the lead physician be readily available to
the critically ill obstetric patient and that coverage arrangements
are adequate, in order to avoid interference with prompt deliv-
ery of care. When other specialty consultation is required, the
lead physician must coordinate and integrate such consultation
Maternal-Fetal Evidence Based Guidelines
as appropriate. He/she must also be able to clearly decide when
the patient’s condition is no longer appropriate for intermediate
care and then transfer up for intensive care or down for routine
ward care.
When obstetric patients are transferred to the ICU, the
obstetrician’s role will depend on the ICU model (open or
closed) and the patient’s status (antepartum or postpar-
tum). The OB-GYN’s anxiety about a patient in the ICU is easily
matched by the ICU team’s anxiety about a fetus in the uterus,
and even in a closed unit, the obstetrician’s input is welcomed.
Decisions about care for a pregnant patient in the ICU should
be made in concert by the multidisciplinary team and should
involve the patient and her family insofar as this is feasible. No
matter what the ICU model, the obstetrician should continue
to see the patient and consult with the primary ICU team
daily, offering pregnancy-specific knowledge necessary to give
the best care to these complex patients. The normal physiology
of pregnancy affects all maternal organ systems. These changes
affect the way in which maternal vital signs, imaging studies,
and lab values are interpreted and how resuscitation is pro-
vided. Cardiovascular changes result in a dilutional anemia and
increased cardiopulmonary resuscitation circulation demands.
Pregnant patients are susceptible to third spacing of fluids due
to decreased systemic vascular resistance, colloid oncotic pres-
sure, and pulmonary capillary wedge pressure. The decreased
peristalsis and gastroesophageal sphincter tone increase the risk
of aspiration of gastric contents. The increased shunting of blood
to the uteroplacental unit serves as a reservoir for blood during
cardiopulmonary resuscitation which can have a negative impact
on the ability to resuscitate a pregnant woman. Chest wall com-
pliance is decreased during pregnancy which results in a need for
increased force of chest compressions during cardiopulmonary
resuscitation [42]. An understanding of how pregnant physiology
is different from non-pregnant physiology is necessary in iden-
tifying women at risk for maternal morbidity and mortality and
ensuring timely implementation of critical care when necessary.
Physicians who deal with the critically ill are familiar with the
difficulties of informed consent and with the frequent need to
identify a designated decision-maker. This is not typically a prob-
lem with which obstetricians have much experience, but in criti-
cal care obstetrics the designated decision-maker must assume
the role for both mother and fetus when the woman herself can-
not. Even if a woman has previously made her wishes known with
a living will or advance directive, state law varies; advance direc-
tives may be specifically invalidated if a patient is pregnant [94].
The hospital ethics committee may be called upon for guidance
as needed.
Fetal surveillance is often employed when a pregnant patient
is admitted to ICU. The obstetrician who is used to reviewing
fetal heart rate tracings as an indicator of fetal status should con-
sider that the fetal heart rate tracing reflects maternal end-organ
(uteroplacental) perfusion and maternal acid-base status as well.
If baseline variability disappears or decelerations are seen, a rea-
son should be sought in maternal physiology, such as hypoten-
sion, acidemia, or compression of the inferior vena cava by the
gravid uterus in supine position. Correction of these factors may
result in improvement of the tracing.
The potential for preterm delivery is high in the ICU [66–72].
Attempts to suppress preterm contractions are ill-advised in the
case of critical illness in pregnancy; aside from the equivocal
efficacy of tocolytic drugs, preterm labor may represent an adap-
tive response. No drug is devoid of side effects, which must be
Critical Care
carefully monitored in the setting of critical illness (tachycardia
and decreased BP with beta-agonists, effects on platelet function
and renal perfusion with indomethacin, magnesium’s effects on
cardiac function, etc.). But because of the potential for preterm
birth, the threshold for administration of a course of antenatal
corticosteroids to promote fetal lung maturity should be low.
Corticosteroids are often given in an ICU setting for reasons such
as sepsis and spinal cord injury; it may be feasible to substitute
betamethasone or dexamethasone for the usual hydrocortisone
in these circumstances in order to obtain additional fetal benefit.
If a patient is transferred to the ICU postpartum, the obste-
trician’s role becomes simpler medically, although the patient
and family may have concerns regarding any obstetrical event
that precipitated transfer. Anger, dissatisfaction, or legal action
often follow a perceived bad outcome; in case of a postpartum
complication or condition requiring critical care, the obstetrician
may bear the brunt of questions. This is likely to be stressful even
when there has been no evident error, as the fear of litigation is
prominent in such cases [95].
The medical issues with a postpartum admission to the ICU
typically relate to uncertainty (on the part of the primary ICU
team) about vaginal bleeding, evaluation of fever, therapies such
as magnesium, and feasibility of breast-feeding, especially com-
patibility with various medications. There may be surgical issues
such as re-exploration or reclosure of incisions. Under some
circumstances the OB-GYN will be the advocate for bringing
together the critically ill mother and her new baby.
Critical care tools and techniques
When critical care is required during pregnancy, maternal stabili-
zation is of primary importance, as the stability of the fetoplacen-
tal unit is dependent on maternal health. Maternal interventions
should not be withheld due to unwarranted fetal concerns.
Hemodynamic monitoring
Central venous catheters can be used to administer medica-
tions, fluids, and monitor changes to central venous pressure in
response to interventions. Arterial catheters allow for instan-
taneous and continuous blood pressure monitoring and arterial
blood gas analysis. Due to the gravid uterus and proximity of
the femoral vessels to the areas involved in vaginal and cesarean
delivery, access via the femoral artery and vein should generally
be avoided. Some critical care techniques (e.g., the pulmonary
artery or Swan-Ganz catheter) have largely disappeared from
critical care practice [63]. Noninvasive or minimally invasive
hemodynamic monitors have become more common.
Mechanical ventilation
Airway management in pregnancy is complicated by physical
and hormonal changes that occur during pregnancy. The grow-
ing uterus leads to compression of the intra-abdominal contents,
including the stomach. This, in combination with the relaxation
of the gastroesophageal sphincter induced by progesterone, leads
to an increased risk of aspiration during intubation attempts.
Decreased functional residual capacity and increased oxygen
demand speed desaturation. Airway edema and increased breast
size can make direct laryngeal visualization and endotracheal
intubation difficult [42].
Pregnancy physiology is marked by a compensated respiratory
alkalosis. Arterial blood gases in pregnancy should be interpreted
in light of this physiology. A higher PaCO2 in pregnancy, even
421
TABLE 42.5: Arterial Blood Gas (ABG) Changes in Pregnancy
Pregnancy State
Non-Pregnant
ABG Measurement State First trimester Third trimester
pH 7.40 7.42–7.46 7.43
PaO2 (mmHg) 93 105–106 101–106
PaCO2 (mmHg) 37 28–29 26–30
Serum HCO3 (mEq/L) 23 18 17
Source: From Hegewald MJ, Crapo RO, Respiratory physiology in pregnancy, Clin
Chest Med 2011; 32: 1–13, with permission.
within a range that may still be considered normal in the non-
pregnant individual, should be concerning for maternal respira-
tory failure (Table 42.5). Intubation and mechanical ventilation
should be considered early when there are signs of respiratory
compromise. The increased minute ventilation and decreased
functional residual capacity seen in pregnancy can result in
significant hypoxemia quickly in the pregnant patient [42].
Noninvasive methods of ventilation (high-flow nasal cannula,
bilevel positive airway pressure [BiPAP], continuous positive
airway pressure [CPAP]) have replaced mechanical ventila-
tion in some cases.
Point of care ultrasound
Competencies for critical care training and practice now include
ultrasound imaging of the lung, abdomen, and heart, as well as
ultrasound procedural guidance [64, 65]. Point of care ultrasound
(POCUS) at the patient’s bedside can be used to predict fluid
responsiveness by assessing the collapsibility of the inferior vena
cava. It can also be used to assess left ventricular function during
systole and diastole.
Lung ultrasound (LUS) plays an increasingly important role in
the ICU; it can diagnose pneumothorax, pneumonia, pleural effu-
sion, pulmonary edema, and help with lung recruitment maneu-
vers and titrating levels of positive end-expiratory pressure [96]. It
is also helpful in managing hypotensive patients, since it can dis-
tinguish “wet” from “dry” lung and therefore determine whether
fluids or vasopressors are preferred [97]. Specific applications of
LUS in pregnancy have been demonstrated in both pre-eclampsia
[98] and COVID-19 [99, 100]. Obvious advantages of LUS over
computed tomography (CT) are the absence of ionizing radia-
tion and the ability to image at the bedside rather than requiring
transport.
The combination of LUS and transthoracic echocardiography
(TTE) has proven helpful in assessing fluid responsiveness in
severe pre-eclampsia; extravascular lung water is greater and fluid
responsiveness less likely in women with severe pre-eclampsia as
compared to normal controls [98]. This technology is promising for
a rational approach to fluid management in severe pre-eclampsia.
LUS has also been shown to be of benefit in the recent COVID-19
pandemic [99, 100]. Lung ultrasound has proven to be an accu-
rate imaging method in pregnant women for the detection of
pneumonia and other pulmonary pathologies. See Box 42.2 and
Figure 42.2 for a description of the findings of COVID-19 pneu-
monia on LUS [101].
Transthoracic echocardiography
Transthoracic echocardiography (TTE) can assess myocardial
contractility and systolic and end-diastolic ventricular volumes
in maternal critical illness, and assist in determining the cause
of tachycardia and/or hypotension. Dennis described a rapid
422
6 3
5 2
8 10
4 1
7
FIGURE 42.2 The fourteen anatomic landmarks for lung ultrasound. (From Moro F, Buonsenso D, Moruzzi MC, et al. How to perform
lung ultrasound in pregnant women with suspected COVID-19. Ultrasound Obstet Gynecol 2020; 55: 593–598. Ref. [101], with permission.)
BOX 42.2: LUNG ULTRASOUND FINDINGS
OF COVID-19 PNEUMONIA (SEE REF. [101])
1. Patchy distribution of interstitial artefactual signs
2. Small subpleural consolidations (focal or lobar)
with associated areas of white lung and occa-
sional air bronchograms
3. Thickening of pleural line with pleural irregular-
ity (pleural line regular or irregular)
4. B-lines—vertical, discrete, laser-like hyperechoic
reverberation artifacts, focal or confluent, arising
from the pleural line, occur due to extra-alveolar
fluid collection and A-lines—horizontal lines in
recovery phase
5. Ground-glass appearance of lung; these patterns
extend to multiple areas of lung surface leading to
peripheral lung disease and mild pleural effusion
and pneumothorax in rare cases
obstetric screening echocardiographic scan (ROSE scan) in preg-
nant women for bedside diagnosis and monitoring response to
treatment [102]. She listed clinical questions which could quickly
be answered via TTE (see Box 42.3).
BOX 42.3: CLINICAL QUESTIONS
ANSWERABLE WITH TTE (SEE REF. [102])
• What is the volume status?
• Are there regional wall motion abnormalities?
• What is the left ventricular contractility?
• What is the right ventricular size and contractility?
• Is right ventricular outflow tract obstruction
present?
• Is there pericardial tamponade?
• What is the fetal heart rate?
Maternal-Fetal Evidence Based Guidelines
12 14
11 13
9
Lung ultrasound and TTE can be used together for dynamic
real-time assessment of hemodynamics: TTE evaluates intra-
vascular volume, fluid responsiveness, and cardiac contractility,
while lung ultrasound quantifies extravascular lung water.
Specific conditions for which
critical care may be required
Reviews of severe acute maternal morbidity [1–16, 43–58] sug-
gest the following conditions are of most concern: Hemorrhage,
eclampsia, cardiac arrest, pulmonary edema, respiratory fail-
ure, renal failure, sepsis, shock (multiple types), cerebrovas-
cular event, coma, anesthetic complications (e.g., aspiration,
difficult/failed intubation), and other cardiac conditions. Most
obstetricians will be familiar with hemorrhage, pre-eclampsia,
and eclampsia—in fact, more familiar than most intensivists—
and these conditions are frequently handled on a labor and deliv-
ery unit without transfer to ICU. The remainder of the chapter
will address a few critical care topics with which the obstetrician
may be less familiar. With the understanding that critical care
medicine, like any other branch of medicine, is constantly evolv-
ing, current evidence-based practice in critical care is described
later.
Acute respiratory distress syndrome
and mechanical ventilation
The acute respiratory distress syndrome (ARDS) is a nonspe-
cific response of the lung to a variety of inciting events. It is the
extreme form of a spectrum of acute lung injury (ALI) and has
been defined as “a syndrome of inflammation and increased per-
meability that is associated with a constellation of clinical, radiol-
ogy, and physiologic abnormalities that cannot be explained by,
but may coexist with, left atrial or pulmonary capillary hyperten-
sion” [103]. In other words, ARDS is a type of non-­cardiogenic
pulmonary edema. Inflammation due to activation of neutro-
phils is thought to be the responsible mechanism of the patho-
physiology of ARDS. Pro-inflammatory mediators function
to increase vascular permeability which then further leads to
disruption of normal lung vasculature and resultant increased
Critical Care
inflammation and ultimate lung damage. The increased capillary
permeability results from damage to the capillary and alveolar
epithelium. Fluid removal from the alveolar space is impaired,
leading to alveolar damage and further inflammation [104]. As a
result of the inflammation and increased vascular permeability,
there is a reduction in the remaining physical size of the lungs,
leading to poor compliance and resistance to expansion.
Criteria for ARDS diagnosis were last revised in 2012 [105].
The timing required for diagnosis of ARDS is onset of the respi-
ratory distress within one week of a known clinical inciting
event or in the setting of current respiratory symptoms that
acutely worsen. Chest x-ray or chest CT should show bilateral
opacities. Echocardiogram should be considered to rule out car-
diac failure or fluid overload as the cause of respiratory failure.
ARDS can then be separated into mild, moderate, and severe dis-
ease based on levels of oxygenation (mild: 200 mmHg < PaO2/
FiO2 ≤ 300 mmHg with PEEP or CPAP ≥ 5 cm H2O; moderate:
100 mmHg < PaO2/FiO2 ≤ 200 mmHg with PEEP ≥ 5 cm H2O;
and severe: PaO2/FiO2 ≤ 100 mmHg with PEEP ≥ 5 cm H2O; see
further Ref. [105]).
ARDS is an uncommon disorder in pregnancy, with an inci-
dence frequently quoted from case series as between 1/3000 and
1/6000 deliveries [66, 106]. More recent population-level data,
however, show that ARDS was coded in six delivery hospitaliza-
tions and three postpartum hospitalizations per 10,000 deliveries
in 2008–2009 [107]. Not only is this much higher than the esti-
mates from old case series, but the incidence appears to be rising
with time, as figures from the same dataset in 1998–1999 were
3.6 (delivery hospitalizations) and 1.1 (postpartum hospitaliza-
tions) per 10,000 deliveries. Data from Canada, however, showed
a rate of ARDS of 0.6 per 10,000 among pregnancy hospitaliza-
tions from 2003–2007 [108]. It is possible that this represents not
an epidemiologic difference in North America, but a difference
in data capture; U.S. data relied on ICD-9 codes and Canadian
on ICD-10. ARDS itself is not always captured in administra-
tive datasets, but may be approximated by the number of cases
of mechanical ventilation. In the Netherlands, between 2004 and
2006, 291 women of the 358,874 who delivered required mechan-
ical ventilation, for a rate of about 8 per 10,000 [16]. In a cohort
of 2808 obstetric patients in the National Inpatient Sample data-
base with a diagnosis of ARDS [109] the rate of ARDS requiring
mechanical ventilation rose from 36.5 cases per 100,000 live
births in 2006 to 59.6 cases per 100,000 live births in 2012, with
an overall mortality rate of 9%.
ARDS figures are affected by pandemic respiratory infections.
Among pregnant women with H1N1 influenza, the rate of ARDS
was nearly twice as high as among non-pregnant women (9.7% vs.
5.4%) [110]; the severity is demonstrated in a report from Australia
and New Zealand in which extracorporeal membrane oxygen-
ation (ECMO) was required in 45% of pregnant or postpartum
women with severe H1N1 respiratory disease [111]. Literature on
the SARS-CoV-2 pandemic is emerging. While pregnant women
do not appear to be at increased risk of contracting the COVID-
19 virus, they are at an increased risk of adverse outcomes if they
do become infected. In a recent systematic review and meta-
analysis, of 2567 pregnancies complicated by SARS-Co-V2 in
eight countries, ICU admission was required in 7% of patients,
with 3.4% patients undergoing intubation and mechanical ven-
tilation. Maternal mortality was uncommon, with an incidence
of 1% [112]. The U.S. Centers for Disease Control and Prevention
reported on 23,434 pregnant women with laboratory-confirmed
SARS-CoV-2 infection, of whom 10.5 per 1000 were admitted to
423
ICU (a rate 3 times as high as their non-pregnant counterparts),
2.9 per 1000 required invasive mechanical ventilation (relative
risk 2.9), 0.7 per 1000 required ECMO (relative risk 2.3), and 1.5
per 1000 died (relative risk 1.7) [37].
The mortality rate for ARDS among obstetric patients was
estimated to be 24–44% in older case series [66, 106, 113, 114],
and 33% in a more recent series [115]; neither is greatly differ-
ent from the general population case-fatality rate of 38% [116].
A review of Canadian hospital admissions between 1991 and
2002, however, found that the case-fatality rate among obstet-
ric patients with ARDS in the absence of any major pre-existing
condition was only 6% [20], and between 2003 and 2007, the
case-fatality rate was under 3% [21]. More recently, a U.S. series
found the mortality rate was 9–14% in pregnant patients under-
going mechanical ventilation for ARDS, with longer duration of
mechanical ventilation associated with increased mortality [109];
additional factors associated with higher mortality were renal or
hepatic failure, amniotic fluid embolism, and influenza or puer-
peral infection.
In managing ARDS in pregnancy, many authorities recom-
mend maintaining maternal SpO2 > 95%, or PaO2 >60 mmHg,
in an effort to promote fetal well-being, but it is unclear what
evidence supports this recommendation. The physiology of
the maternal, fetal, and placental unit is such that the gradient
between maternal and fetal oxygen content drives transfer of
oxygen to the fetus. Because the oxygen content of fetal blood is
quite low, the gradient is easily preserved; normal fetal umbilical
venous pO2 is only 31–42 mmHg [117]. Oxygen delivery to the
fetus and to fetal organs, as to the adult, is the product of blood
flow and oxygen content. Adaptive strategies in the fetus include
higher affinity of fetal hemoglobin for oxygen, and high cardiac
output relative to size.
There is one experimental trial of deliberate hypoxia in human
pregnancy [118]. Ten women with normal pregnancies near term
were exposed to a hypoxic gas mixture with an FiO2 approxi-
mately 0.1 (50% room air, 50% nitrogen) for 10 minutes, during
which time maternal oxygen saturation (SpO2) decreased by 15%.
Fetal heart rate baseline and variability, umbilical artery Doppler
indices, and middle cerebral artery Doppler indices did not
change during experimental maternal hypoxia. Direct sampling
of fetal blood was not performed in this study. In a series of 29
pregnant women requiring mechanical ventilation in pregnancy,
six had oxygen saturation values below 90% (83–88%), none of
whom suffered stillbirth or other pregnancy loss [119]. Longer-
term outcomes of the infants were not described in either study.
Positive-pressure ventilation is the mainstay of treatment for
ARDS, but may cause further damage to the lung through baro-
trauma, volutrauma, and atelectrauma. After the publication of
the ARDSNet trial in 2000, which demonstrated better survival
with low-tidal-volume ventilation [120], strategies for mechani-
cal ventilation changed from normalizing arterial blood gases to
limiting ventilator-induced lung injury. This lower-tidal-volume
strategy allows hypercapnia and respiratory acidosis while mini-
mizing inflation pressures and stretch-induced lung injury. In the
ARDSNet multicenter randomized controlled trial, the use of
lower tidal volumes in mechanical ventilation (6 ml/kg pre-
dicted body weight vs. 12 ml/kg) was associated with lower
mortality and more ventilator-free days in non-pregnant
adults [120] in a general medical-surgical ICU population.
There are few studies on prolonged mechanical ventilation
in the pregnant patient. Unlike the non-pregnant population,
there are no randomized controlled trials of lung-protective
424
or lower-tidal-volume-ventilation strategies for pregnant
women with ARDS. In case series from the era preceding low-
tidal-volume ventilation for ARDS, barotrauma rates were high
in obstetric patients who were mechanically ventilated: 36–44%
[66, 106]. This compares unfavorably with the background rate
of barotrauma of 11% among non-obstetric patients ventilated
with “traditional” tidal volumes in ARDS [120]. There is, however,
no head-to-head trial among pregnant patients with ARDS. In a
recent case series on mechanical ventilation in pregnancy, not all
ventilated for ARDS, the mean tidal volume was 7.7 mL/kg of pre-
dicted body weight [119], which was higher than the ARDSNet
recommendation for tidal volumes (approximately 6 ml/kg.)
When contemplating a low-tidal-volume ventilation strategy
for pregnant women with ARDS, the maternal PaCO2 must be
considered. The resultant permissive hypercapnia and acido-
sis in low-volume-ventilation may potentially be detrimental in
the pregnant population. CO2 transfer from fetus to the mother
across the placenta requires a gradient; in this case the higher
PCO2 of fetal blood diffuses across the placental interface to
the lower PCO2 of maternal blood. High maternal PCO2, as in
permissive hypercapnia, would be expected to impede transfer
and result in fetal acidemia. In a small trial of CO2 rebreathing
in 35 healthy pregnant women, a rise in the maternal end-tidal
CO2 as high as 60 torr was associated with a loss of fetal heart
rate variability in 57% of fetuses monitored, this being a proxy
for fetal acidemia; 90% of fetuses thus affected normalized the
tracing posttest [121]. A few case reports describe women with
status asthmaticus during pregnancy in whom permissive hyper-
capnia was implemented so as to decrease the risk of barotrauma
[122, 123]. In most cases, there appeared to be no immediate or
long-term ill effects on the fetuses, but one of six exhibited a non-
reassuring fetal heart rate tracing after seven days of permissive
hypercapnia and was therefore delivered.
Maternal acidemia does affect fetal acid-base status, which
suggests that continuous fetal monitoring could be useful in the
mechanically ventilated patient, specifically in determining the
lower acceptable limits of maternal pH (Table 42.5). This is an
example of using the fetal heart rate tracing as another mater-
nal vital sign. We suggest that a pregnant woman ventilated
with a low-tidal-volume strategy should have the fetal heart
rate tracing continuously monitored once viability has been
reached, and if the tracing is suspicious for fetal acidemia, con-
sider increasing minute ventilation by increasing frequency
or tidal volume (to increase maternal pH, decrease PCO2), or
switch to airway pressure release ventilation (ARPV). There is
a small case series of ARPV in pregnancy, an alternative lung-
protective strategy, in which the lungs were kept inflated to a
high PEEP (28–33 cm H2O) interrupted for brief periods with
low PEEP (8–10 cm H2O). This was well tolerated by mothers and
fetuses, and maternal oxygenation immediately improved [124].
Delivery does not improve maternal survival in ARDS [66,
67, 125]. Neonatal survival, however, is tightly linked to gesta-
tional age at delivery; this would imply a fetal benefit to continu-
ing rather than interrupting pregnancy, assuming maternal and
fetal condition permits. Delivery may, however, reduce maternal
oxygen requirement and/or increase total respiratory system
compliance [67, 119], and it may make prone positioning easier.
The use of extracorporeal membrane oxygenation (ECMO) as
an adjunct for refractory ARDS has been increasing in the past
decade or two. Both the H1N1 and SARS-CoV-2 pandemics have
been accompanied by a rise in demand for ECMO. Resorting to
ECMO during pregnancy and the peripartum period has also
Maternal-Fetal Evidence Based Guidelines
increased, and mortality has decreased, over time. Analysis of the
Extracorporeal Life Support Organization Registry from 1997 to
2017 (n = 280, most venovenous ECMO) showed that mortality
dropped from about 54% to about 27% [126]. A significant risk of
hemorrhagic complications, not all attributed to cannulation, is
still associated with ECMO in these patients.
Sepsis
Sepsis, a leading cause of maternal death in the era before the
introduction of aseptic technique and antibiotics, remains a
threat. Global estimates suggest that obstetric (direct) infections
are the third most common cause of maternal mortality, repre-
senting 10.7% of maternal deaths [127].
The criteria and classification systems for sepsis were redefined
in 2016. It is important to bear in mind that sepsis is a clinical
syndrome without a gold-standard diagnostic test.
Sepsis is not simply infection. It is currently defined as “life-
threatening organ dysfunction caused by a dysregulated host
response to infection” [128]. Old categories of “systemic inflamma-
tory response syndrome” and “severe sepsis” have been discarded.
The only other category remaining in the Sepsis-3 classification
is septic shock, defined as “a subset of sepsis in which profound
circulatory, cellular, and metabolic abnormalities are associated
with a greater risk of mortality than with sepsis alone” [128].
Because there is no diagnostic test, the clinician should score
organ dysfunction according to a standard Sequential Organ
Failure Assessment (SOFA) score; see Table 42.6. The SOFA score
requires both clinical and laboratory assessment. A 2-point rise
from baseline is considered positive; if the baseline is not known,
it is assumed to be zero. For the clinician at the bedside, the quick
SOFA (qSOFA) score is a screening tool applicable without lab
testing (see Table 42.7). A qSOFA score of 2 or 3 requires further
evaluation.
The diagnosis of septic shock is predicated on hypotension
requiring vasopressors to maintain mean arterial pressure ≥
65mmHg and a serum lactate level > 2 mmol/L despite adequate
fluid resuscitation [129].
Neither the SOFA nor the qSOFA score has been validated
in pregnancy, and there are physiologic reasons to suspect that
they may not perform well, particularly in relating to the BP cri-
terion. Healthy pregnant women may have a normal systolic BP
< 100mmHg. The Society of Obstetric Medicine Australia New
Zealand (SOMANZ), recognizing that neither the SOFA nor
qSOFA score account for the normal physiology of pregnancy,
have proposed a modified screening tool for sepsis in pregnancy;
see Tables 42.8 and 42.9 [130]. Further work is needed before
these tools can be fully implemented.
The diagnosis of sepsis may be more challenging in obstet-
ric patients, particularly when normal alterations in pregnancy
physiology are taken into account. Blood pressure in normal preg-
nancy tends to be lower and heart rate higher, and leukocytosis is
common both in the third trimester and in labor [110]. Thus, the
specificity of usual criteria for sepsis has been called into ques-
tion. The more salient problem, however, would be the possibility
of under-recognition of sepsis in pregnancy and the puerperium.
In a series of maternal deaths from sepsis in the state of Michigan
between 1999 and 2006, only 18% were febrile at presentation,
and 25% were never febrile during hospitalization [131].
When reading the literature on sepsis in pregnancy, bear in
mind that definitions have been variable; many equated sep-
sis and bacteremia, some used nonstandard definitions, almost
Critical Care 425

TABLE 42.6: Sequential Organ Failure Assessment (SOFA) Score

Score
System 0 1 2 3 4
Respiratory
(PaO2/FiO2, mmHg) >400 <400 <300 <200, with <100, with
respiratory support respiratory support
Coagulation
Platelets (100,000 per ml) >150 <150 <100 <50 <20
Liver
Bilirubin mg/dl (µmol/L) <1.2 (20) 1.2–1.9 (20–32) 2.0–5.9 (33–101) 6.0–11.9 (102–204) >12.0 (204)
Cardiovascular MAP>70mmHg MAP <70 On dopamine <5 On dopamine 5.1–15 mcg/kg/ On dopamine >15, or
mcg/kg/minute minute, or epinephrine <0.1 epinephrine >0.1, or
or any dose mcg/kg/minute or norepinephrine >0.1
dobutamine norepinephrine <0.1 mcg/kg/
minute
Central nervous system (CNS)
Glasgow Coma Scale (GCS) 15 13–14 10–12 6–9 <6
Renal
Serum creatinine, mg/dL (µmol/L) <1.2 (110) 1.2–1.9 (110–170) 2.0–3.4 (171–299) 3.5–4.9 (300–440) >5.0 (440)
Urine output, ml/day <500 <200
Source: Adapted from Ref. [128].
Note: Organ dysfunction is identified as an acute increase in total SOFA score of at least 2 points above the patient’s baseline, due to infection; baseline is assumed to be
0 unless preexisting organ dysfunction precedes infection.

TABLE 42.7: Quick Sequential Organ Failure (qSOFA) Score: none used current Sepsis-3 criteria. Several recent publications
A Score of 2 or 3 Is Abnormal and Requires Further describe the epidemiology of maternal sepsis and suggest that
Investigation rates of the most severe forms of sepsis are increasing among
pregnant and postpartum patients [132, 133]. The World Health
1 point for each of: Organization carried out the largest cross-sectional study yet to
• Respiratory rate ≥22/minute address the epidemiology of maternal sepsis [134], aligning the
• Altered mentation case definition with Sepsis-3. The Global Maternal Sepsis Study
• Systolic BP ≤100 mmHg (GLOSS) collected data on 2850 women with suspected or con-
firmed infection in 713 health facilities in 52 countries during a
Source: Adapted from Ref. [128].
single week, including antepartum, intrapartum, postpartum,
and post-abortion cases [134]. The incidence of infection was
TABLE 42.8: Obstetrically Modified SOFA Score 70.4 hospitalized women per 1000 live births overall, with 10.9
System Parameter Score
infection-related severe maternal outcomes per 1000 live births.
Sepsis may be obstetric (direct) or non-obstetric (indirect).
0 1 2 Obstetric sepsis includes uterine infection, both chorioamnion-
Respiration itis and endometritis, septic abortion, and wound infection. In
PaO2/FiO2 ≥400 300 to ≤400 300 addition, sepsis may follow invasive procedures such as amnio-
Coagulation centesis, chorionic villus sampling, cervical cerclage, or percu-
Platelets, ×106/L ≥150 100–150 <100 taneous umbilical blood sampling. Common indirect causes of
Liver sepsis include influenza-like illness, meningitis, and urinary and
Bilirubin (μmol/L) ≤20 20–32 >32 respiratory infections. The UK Obstetric Surveillance System
Cardiovascular (UKOSS) reported on all cases of severe maternal sepsis in
MAP (mmHg) MAP ≥70 MAP<70 Vasopressors
required
Central nervous system Alert Rousable Rousable by TABLE 42.9: Obstetrically Modified Quick SOFA Score
by voice pain Parameter Score
Renal
0 1
Creatinine (μmol/L) ≤90 90–120 ≥120
Systolic blood pressure ≥90 mmHg ≤90 mmHg
Source: Bowyer L, Robinson HL, Barrett H, et al. SOMANZ guidelines for the Respiratory rate Less than 25 breaths/min 25 breaths/min or greater
investigation and management of sepsis in pregnancy. Aust NZ Obstet
Altered mentation Alert Not alert
Gynaecol 2017; 57:540–551. Ref. [130], with permission.
Abbreviations: FiO2, fraction of inspired oxygen, expressed as a decimal; MAP, mean Source: Bowyer L, Robinson HL, Barrett H, et al. SOMANZ guidelines for the
arterial pressure; mmHg, millimeters of mercury; PaO2, partial pressure of oxygen, in investigation and management of sepsis in pregnancy. Aust NZ Obstet
mmHg; SOFA, Sequential (sepsis-related) Organ Failure Assessment score. Gynaecol 2017; 57:540–551. Ref. [130], with permission.
426 Maternal-Fetal Evidence Based Guidelines

TABLE 42.10: Modified Early Obstetric Warning System Variables: Normal and Trigger
Ranges
Variable
Normal range for “Amber” (caution)
MEOWS vital signs components pregnancy trigger “Red” (urgent) trigger
Respiratory rate (breaths/min) 10–20 21–30 <10 or >30
Temperature (°C) 37–38 35–36 <35 or >38
Heart rate (beats/min) 51–99 40–50 or 100–120 <40 or >120
Systolic blood pressure (mmHg) 101–149 90–100 or 150–160 <90 or >160
Diastolic blood pressure (mmHg) <80 80–90 >90

Other components
Oxygen saturation (%) ≥90 No trigger <90
Looks unwell No Yes No trigger
Neurologic response Fully responsive Responsive to voice Responsive only to
pain or unresponsive
Pain scorea 0–1 2–3 No trigger
Amniotic fluid Clear No trigger Green
Lochia Light to moderate No trigger Heavy or foul
with no odor
Passed urine (yes/no) Yes No trigger No trigger
Dipstick proteinuria Negative or trace No trigger >2+
Source: From Ryan HM, Jones MA, Payne BA, et al. Validating the performance of the Modified Early Obstetric Warning
System multivariable model to predict maternal intensive care unit admission. J Obstet Gynaecol Can 2017;
39(9): 728–733. Ref. [140], with permission.
a The “pain score” assesses pain on movement, deep breathing, or coughing as follows: 0 for no pain at rest or on move-
ment, 1 for no pain at rest but slight pain on movement, 2 for intermittent pain at rest and moderate pain on movement,
and 3 for intermittent pain at rest and moderate pain on movement.

2011–2012, determining that 20% of cases arose from the geni-
tal tract, 34% from the urinary tract, 9% were respiratory in ori-
gin, and in 30% the source remained unidentified [135]. In the
GLOSS study, among the 80% of infections for which a source
was identified, approximately 28% were urinary, 30% were uter-
ine (evenly divided between chorioamnionitis and endometritis),
about 15% derived from skin or soft tissue, and 9% were respira-
tory. Infection-related severe maternal outcome which includes
maternal death or near misses were noted to arise more com-
monly from endometritis and respiratory infections [134]. The
abortion-related severe maternal outcome (maternal death or
near miss) rate has been reported at approximately 14% [134], but
in the developed world, this condition is seen almost exclusively
where abortion is illegal.
Maternal survival is better in obstetric than non-obstetric
causes of sepsis [135, 136], which may reflect either expedited
awareness and treatment or the amenability of the uterus to
source control. During influenza-like pandemics, as in the H1N1
pandemic in 2009–2010 and the SARS-CoV2 pandemic in 2019–
2020, respiratory causes of sepsis become more prominent among
pregnant women, as among the population generally. See Chapter
26 for a more detailed discussion of influenza in pregnancy.
In the non-pregnant population, efforts have been made to
implement quality improvement initiatives for sepsis recognition
and treatment, including quick identification tools, treatment
bundles and protocols, and checklists which facilitate appropri-
ate monitoring of vital signs, lab studies, and medications. Time
is of utmost importance in sepsis, as delay in recognition of sep-
sis and initiation of appropriate antibiotics contributes to death
[137]. In sepsis and septic shock, each hour of delay in initiation
of appropriate antibiotics leads to an increase in mortality [137,
138]. A review of maternal deaths due to sepsis revealed a delay
in antibiotics in 73% and a delay in escalation of care (e.g., con-
sultation with infectious disease specialist or transfer to critical
care) in 53% [131]. Similarly, a review of maternal deaths in the
United Kingdom identified a delay in recognition or management
in 70% of maternal deaths from sepsis [139]; sadly, two-thirds of
those delays occurred in the obstetric unit. A repeated theme in
quality improvement initiatives is to “think sepsis” when caring
for a pregnant, postpartum, or post-abortion patient who pres-
ents with warning signs [139]. Ryan recently validated the perfor-
mance of a Modified Early Obstetric Warning System (MEOWS)
to predict ICU admission in an obstetric population [140] (see
Table 42.10). The National Partnership for Maternal Safety has
proposed a similar system for identifying patients who need more
thorough assessment, not exclusively for sepsis (Table 42.4) [75].
The Surviving Sepsis Campaign (SSC) [141] is a multiorgani-
zational effort to improve mortality in sepsis and septic shock,
based on best available evidence; not tested or evaluated in preg-
nancy, but in the absence of pregnancy-specific guidelines, we
must extrapolate as best we can. It proposes therapeutic goals
and recommends care bundles (see Table 42.11). Adherence
to these goals has been shown to improve mortality in sep-
tic shock [142]. SSC guidelines, originally codified in 2003, have
gone through several revisions since then. A guideline to care for
adults with critical COVID-19 was released in 2020 [143].
The 2016 guidelines for management of sepsis in adults are
outlined later in this chapter. [141]. There is no specific evidence
for or against these guidelines in a pregnant or postpartum
patient. There are no randomized trials on sepsis specific to
Critical Care
TABLE 42.11: Surviving Sepsis Campaign Care Bundle
HOUR-1 BUNDLE: INITIAL RESUSCITATION FOR SEPSIS AND
SEPTIC SHOCK
1. Measure lactate level.a
2. Obtain blood cultures before administering antibiotics.
3. Administer broad-spectrum antibiotics.
4. Begin rapid administration of 30 mL/kg crystalloid for hypotension
or lactate ≥ 4 mmol/L.
5. Apply vasopressors if hypotensive during or after fluid resuscitation
to maintain a mean arterial pressure ≥ 65 mmHg.
Source: From Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign:
International Guidelines for Management of Sepsis and Septic Shock:
2016. Crit Care Med 2017; 45(3):486–552. Ref. [141], with permission. ©
2019 the Society of Critical Care Medicine and the European. Society of
Intensive Care Medicine. All Rights Reserved. survivingsepsis.org.
a Remeasure lactate if initial lactate elevated (>2 mmol/L).
the obstetric population. In most trials, pregnant patients are
explicitly barred from enrollment. This exclusion results in a lack
of sepsis management guidelines specific to obstetrics.
Table 42.11 summarizes the most important elements of
SSC for adults. The 2016 guidelines recommend fluid resus-
citation and antibiotic administration be undertaken within
3 hours of the diagnosis, though a 2018 modification recom-
mends shortening the time to 1 hour (https://www.sccm.org/
SurvivingSepsisCampaign/Guidelines/Adult-Patients. accessed
11/21/2020).
1. Sepsis and septic shock are medical emergencies.
Treatment and resuscitation should begin immediately.
At least 30 mL/kg of IV crystalloid should be given
within the first 3 hours in the setting of sepsis-induced
hypoperfusion. Following this initial fluid resuscita-
tion, additional fluids be guided by frequent reassess-
ment of hemodynamic status. Prior guidelines did list
specific goals of therapy with regard to central venous
pressure (CVP), mixed venous oxygen saturation and urine
output, but more recent data has suggested that care should
be specific for each patient and dynamic rather than static
measurements of response to fluid resuscitation are pre-
ferred. An initial target mean arterial pressure (MAP) of
65 mmHg is recommended in patients with septic shock
requiring vasopressors and resuscitation should be to nor-
malize lactate in patients with elevated lactate levels as a
marker of tissue hypoperfusion. In pregnancy, however,
this fluid recommendation may be overly aggressive, since
not all patients are fluid responders, and since the col-
loid oncotic pressure is lower and consequently the risk of
precipitating pulmonary edema is higher. The Society for
Maternal-Fetal Medicine recommends initially adminis-
tering 1–2 L crystalloid and then using dynamic measures
of fluid responsiveness to guide further therapy, e.g., pas-
sive leg raising, pulse-pressure variation, or POCUS [144].
2. Appropriate routine microbiologic cultures (always
including two sets of blood cultures, both aerobic and
anaerobic) should be obtained before starting antimi-
crobial therapy in patients with suspected sepsis or
septic shock as long as there is no delay in initiation
of antimicrobial therapy. Sterilization of cultures can
occur within minutes to hours of initiation of appropri-
ate antimicrobials, which may alter results if cultures
427
are not obtained prior to antibiotic administration. This
should also apply in the obstetric population. One study in
Finland described this specific policy for obstetric patients;
2% (of over 40,000) were cultured for fever and had broad-­
spectrum antibiotics instituted immediately. Bacteremia
was confirmed in 5% of cases; only 1 of the 798 patients cul-
tured developed septic shock, for an incidence of 0.1% [145].
3. Administration of empiric broad-spectrum IV anti-
microbials should be initiated within 1 hour for both
sepsis and septic shock. Initial therapy should be aimed
at covering all likely pathogens, including bacterial, fungal,
and viral sources. Empiric antimicrobial therapy should
be evaluated daily and de-escalated once pathogen iden-
tification and sensitivities are established and/or there is
adequate clinical improvement. Specific regimens for iden-
tified pathogens are not provided here, being both beyond
the scope of this chapter and subject to rapid change
as organisms evolve resistance. Usual resources may be
consulted, or consultation may be sought from an expert
in infectious disease. Total duration of therapy should
usually be 7–10 days, though may need to be longer if
Staphylococcus aureus bacteremia, slow clinical response,
undrainable focus of infection, etc. Broad-spectrum cover-
age is appropriate in OB patients; in a large study of peri-
partum sepsis, more than 40 organisms were cultured,
including aerobic gram-positive and gram-negative as well
as anaerobic bacteria [145]. When narrowing coverage,
consideration should be given to whether transplacental
coverage is needed; some drugs do not cross placenta well
and result in inadequate fetal treatment, such as azithro-
mycin in the treatment of syphilis [146].
4. The specific anatomic source of infection should be iden-
tified or excluded as soon as possible and any required
source control intervention (drainage, removal of cath-
eter, debridement) be implemented as soon as medically
and logistically practical after the diagnosis is made in
order to effect source control. The intervention under-
taken should be the one with the least potential for physio-
logic derangement, e.g., percutaneous rather than surgical
drainage of an abscess. There are limited data specific to
pregnancy. Up to half of sepsis cases in pregnant/post-
partum women localize to the uterus [135, 147, 148], and
would therefore require the uterus be emptied. There are
no data on antibiotics without delivery for women diag-
nosed with clinical sepsis attributed to intra-amniotic
infection. Women with a diagnosis of subclinical intra-
amniotic infection, treated with antibiotics alone in the
hope of delaying delivery to a more favorable gestational
age, have had pregnancy prolonged by days to weeks, with
the only maternal morbidity being a 3% rate of postpartum
endometritis [149] but with an infant death rate of 33% and
major infant morbidity >75%. It should be emphasized
that patients with subclinical chorioamnionitis, who
typically present with preterm labor or membrane rup-
ture, are unlikely to come to the ICU; if these nonseptic
patients cannot be managed without delivery, there is
no argument for managing clinical chorioamnionitis
expectantly. There is no evidence for deferring source con-
trol in pregnancy.
In addition to the recommendations for initial resuscitation
and antimicrobial treatment, SSC weighs in on hemodynamic
428
support and adjunctive therapy in severe sepsis and septic
shock, as follows:
1. Crystalloid as the fluid of choice for initial resuscitation
and subsequent intravascular volume replacement. If
colloid resuscitation is elected in pregnancy, use albumin
rather than hydroxyethyl starch, because of evidence of
harm with hydroxyethyl starch (HES) [141].
2. Vasopressor therapy should be used to target initial
mean arterial pressure > 65mmHg. The goal is to main-
tain tissue perfusion even if hypovolemia has not yet
been resolved. Supplemental clinical endpoints are also
important: BP, mental status, urine output, blood lactate.
Norepinephrine is the vasopressor of choice in severe
sepsis and septic shock [141].
No data exist to make a recommendation about the lower
limit of mean arterial pressure in pregnancy, but since
mean arterial pressure is normally lower in pregnancy
[121], a target MAP ≥ 65 may be too stringent. Although
MAP is approximately 4–5mmHg lower in pregnancy,
one cannot extrapolate a target of 60 mmHg instead. The
uteroplacental circulation does not autoregulate, and com-
promised placental perfusion is expected to affect the fetus.
Use of clinical endpoints, as described earlier, is crucial in
making a decision for an individual patient; if the patient
is still pregnant, the electronic fetal heart rate tracing may
help with individualization of target MAP. There is little
data as to use of vasopressors in septic pregnancy in par-
ticular. Norepinephrine has been studied, in a randomized
trial, as an agent to maintain maternal BP during cesarean
under spinal anesthesia [150]. Compared to the commonly
used agent phenylephrine, norepinephrine maintained BP
equally well, with a more favorable chronotropic profile and
a higher cardiac output. There was no difference in Apgar
scores or cord gases; a significantly lower concentration of
epinephrine in the cord blood of norepinephrine-exposed
than phenylephrine-exposed infants suggested at least
the possibility of decreased physiologic stress. Though the
dose used in this study was constrained to a maximum of
5 μ/minute and the duration of fetal exposure generally
less than 30 minutes, which are both less than would be
required in septic shock, this study nevertheless repre-
sents early evidence that norepinephrine does not seem
to impair uteroplacental perfusion in and of itself. This
supports preclinical work that showed, in a dual-perfused
single-cotyledon model of human placenta, no change in
fetal perfusion with administration of norepinephrine [151].
3. Trial of dobutamine in either myocardial dysfunction
(high filling pressures and low cardiac output) or ongo-
ing hypoperfusion despite adequate intravascular vol-
ume and MAP [141]. Normal cardiac output in pregnancy
is increased and the systemic vascular resistance decreased
[152]; thus, it is unclear what would constitute a “low” car-
diac output in pregnancy. It probably requires clinical
assessment of both mother and fetus rather than a cutoff
number. Dobutamine has little effect on resting uterine
tone even at high doses, but decreases uterine blood flow
in gravid ewes [153]. Human data are lacking. It is unlikely
that fetal concerns would be paramount in a situation in
which the maternal condition was sufficiently dire to con-
sider adding dobutamine to vasopressor therapy.
Maternal-Fetal Evidence Based Guidelines
4. IV hydrocortisone should not be used to treat septic
shock patients if adequate fluid resuscitation and vaso-
pressor therapy are able to restore hemodynamic stabil-
ity. If this is not achievable, IV hydrocortisone at a dose
of 200 mg per day may be considered [141]. There are no
specific data in pregnancy. Note that dexamethasone (6 mg
daily × 10 days) has been shown to reduce mortality in
COVID-19 patients receiving mechanical ventilation [154].
In this trial, however, the researchers modified the protocol
for pregnant patients, substituting either oral prednisolone
(40 mg once daily) or intravenous hydrocortisone (80 mg
twice daily), specifically because neither drug crosses the
placenta [155]. The rationale for changing the protocol for
pregnant patients related to concerns about the effect of
a long course of high-dose dexamethasone on fetal health
[personal communication], despite the ubiquitous use of
a shorter course of dexamethasone or betamethasone for
maturation of fetal lungs.
SSC also makes recommendations for blood product admin-
istration, thromboprophylaxis, stress ulcer prophylaxis, feed-
ing, and glucose control in the setting of sepsis and septic shock;
see Box 42.4.
BOX 42.4: ADDITIONAL SSC
RECOMMENDATIONS FOR MANAGEMENT OF
SEPSIS IN ADULTS (SEE FURTHER REF. [142])
1. Defer RBC transfusion until hemoglobin con-
centration is less than 7.0 g/dL.
2. Platelets should be given when the platelet
count is <10,000/mm3 or <20,000/mm3 if the
patient is at high risk of bleeding.
3. Pharmacologic venous thromboembolism (VTE)
prophylaxis is recommended with either
unfractionated heparin or low molecular
weight heparin when not contraindicated.
Mechanical VTE prophylaxis should be used
when pharmacologic is contraindicated.
4. Stress ulcer prophylaxis with either proton
pump inhibitors or histamine-2 receptor
antagonists is recommended in patients con-
sidered at risk for gastrointestinal bleeding.
5. Oral or enteral feeding is preferred over paren-
teral nutrition or fasting.
6. A former recommendation for tight glucose
control (<110 mg/dL), using insulin infusion as
necessary, has been updated to maintain blood
glucose <180 mg/dL in adult patients with
sepsis. (Note: Obstetricians are already accus-
tomed to targeting glucose control in diabetic
pregnancy, and frequently use insulin infusions
in labor. It must be cautioned, however, that the
ideal range for glucose in critically ill pregnant
patients has not been studied; obstetricians may
be tempted to aim for the usual range recom-
mended in diabetes of 80–120 mg/dL, in an effort
to minimize fetal hyperinsulinemia and neonatal
hypoglycemia, but this may or may not be correct
in the management of sepsis.)
Critical Care
The final recommendations in the SSC guidelines are univer-
sally applicable, and underappreciated. These state that the prog-
nosis and goals of care should be discussed with the patient
and family, as soon as feasible, and that the goals of care should
be incorporated into treatment, including end-of-life plan-
ning [141]. Goals for a pregnant or postpartum patient in ICU
may be challenging to set or may be painful for the patient, her
family members, or the healthcare professionals involved, but
cannot be shunted aside. Some women may prioritize the out-
come for the fetus/neonate above their own health; in other cases,
the family may need to make unwelcome choices between the
critically ill woman and the potential new baby. It may be helpful
to bring in multiple perspectives, including, in some cases, a pal-
liative care team or an ethicist.
What is missing from this discussion are the voices of women
themselves who have survived a stay in the intensive care unit.
Post-intensive care syndrome encompasses ICU-acquired weak-
ness, neuromuscular dysfunction, cognitive impairment, and
psychological distress; most survivors will have one or more of
these complications, and in some cases, it can persist for years
[156]. The long-term outcome of women who have survived
maternal critical care remains underreported in the medical
literature, though physical and psychiatric sequelae are com-
mon among ICU survivors in general. A few qualitative surveys
of women’s experiences in maternal critical care elucidate several
themes; the distance between their expectations about childbirth
and the reality they experienced, the pain of being separated from
their newborn regardless of how sick they were, and the difficulty
of being transferred out of ICU to a maternity ward [157, 158].
Many women were shocked or frightened to wake up in the ICU,
slow in understanding why, disturbed or powerless being in the
ICU, and unsupported in their specific needs once out of ICU.
The aftercare needed for these ICU survivors is another area in
desperate need of research.
I didn’t expect that it would be this snowball, that the
ground would open up under me, that I would be in a
hole…because anyone who goes through this knows that
life is short [158].
References
1. Panchal S, Arria AM, Labhsetwar SA. Maternal mortality during hospital
admission for delivery: a retrospective analysis using a state-maintained
database. Anesth Anal 2001; 93:134–411. [II-2; case-control; n = 135]
2. Keizer JL, Zwart JJ, Meerman RH, et al. Obstetric intensive care admissions:
a 12-year review in a tertiary care centre. Eur J Obstet Gynecol Reprod Biol
2006; 128:152–156. [II-3; case series; n = 142]
3. Umo-Etuk J, Lumley J, Holdcroft A. Critically ill parturient women and
admission to intensive care: a 5-year review. Int J Obstet Anesth 1996;
5:79–84. [II-3; case series, n = 39]
4. Hazelgrove JF, Price C, Pappachan VJ, et al. Multicenter study of obstetric
admissions to 14 intensive care units in southern England. Crit Care Med
2001; 29:770–775. [II-3; case series, n = 210]
5. Lapinsky SE, Kruczynski K, Seaward GR, et al. Critical care management of
the obstetric patient. Can J Anaesth 1997; 44:325–329. [II-3; case series, n =
65]
6. Selo-Ojeme DO, Omosaiye M, Battacharjee P, et al. Risk factors for
obstetric admissions to the intensive care unit in a tertiary hospital: a
case-control study. Arch Gynecol Obstet 2005; 272:207–210. [II-2; case-
control, 33 cases]
7. Munnur U, Karnad DR, Bandi VD, et al. Critically ill obstetric patients
in an American and an Indian public hospital: comparison of case-mix,
organ dysfunction, intensive care requirements, and outcomes. Intensive
Care Med 2005; 31(8):1087–1094. [II-3; case series, 174 in Houston, 754 in
Mumbai]
429
8. Brace V, Penney G, Hall M. Quantifying severe maternal morbidity: a
Scottish population study. BJOG 2004; 111:481–484. [II-2; audit, n = 196]
9. Heinonen S, Tyrvainen E, Saarikoski S, et al. Need for maternal critical
care in obstetrics: a population-based analysis. Int J Obstet Anesth 2002;
11:260–264. [II-3; case series, n = 22]
10. Baskett TF, O’Connell CM. Maternal critical care in obstetrics. J Obstet
Gynaecol Can 2009; 31:218–221. [II-3; case series, n = 117]
11. Pollock W, Rose L, Dennis CL. Pregnant and postpartum admissions to
the intensive care unit: a systematic review. Intensive Care Med 2010; 36:
1465–1474. [Review, 40 studies, n = 7887 patients]
12. Leung NYW, Lau ACW, Chan KKC, Yan WW. Clinical characteristics and
outcomes of obstetric patients admitted to the Intensive Care Unit: a 10-year
retrospective review. Hong Kong Med J 2010; 16: 18–25. [case series, n = 50]
13. Chantry AA, Deneux-Tharaux C, Bonnet M-P, Bouvier-Colle M-H.
Pregnancy-related ICU admissions in France: trends in rate and sever-
ity, 2006–2009. Crit Care Med 2015; 43: 78–86. [administrative data, n =
11,824]
14. Wanderer JP, Leffert LR, Mhyre JM, et al. Epidemiology of obstetric-
related ICU admissions in Maryland: 1999-2008. Crit Care Med 2013; 41:
1844–1852. [administrative data, n = 2927]
15. Zhao A, Han S, Yao G, et al. Pregnancy-related ICU admissions from
2008–2016 in China: a first multicenter report. Crit Care Med 2018;
46:e1002–e1009. [case series, n = 491]
16. Zwart JJ, Dupuis JRO, Richters M, Ory F, van Roosmalen J. Obstetric inten-
sive care unit admission: a 2-year nation-wide population-based cohort
study. Intens Care Med 2010; 36: 256–263. [prospective cohort study, n =
847]
17. Ryan M, Hamilton V, Bowen M, et al. The role of a high-dependency unit
in a regional obstetric hospital. Anaesthesia 2000; 55:1155–1158. [II-3; case
series, n = 123]
18. Zeeman GG, Wendel GD, Cunningham FG. A blueprint for obstetric criti-
cal care. Am J Obstet Gynecol 2003; 188:532–536. [II-3; case series, n = 483]
19. Saravanakumar K, Davies L, Lewis M, et al. High dependency care in an
obstetric setting in the UK. Anaesthesia 2008; 63:1081–1086. [II-3; case
series, 3551]
20. Wen SW, Liston R, Heaman M, et al. For the Maternal Health Study Group,
Canadian Perinatal Surveillance System. Severe maternal morbidity in
Canada, 1991–2001. CMAJ 2005; 173:759–764. [II-2; population database,
n = 11,066]
21. Joseph KS, Liu S, Rouleau J, et al. Severe maternal morbidity in Canada,
2003–2007: surveillance including routine hospitalization data and ICD-9
codes. J Obstet Gynaecol Can 2010; 32:837–846. [II-2; administrative data-
base of 1.3 million]
22. Liu S, Joseph KS, Bartholomew S, et al. Temporal trends and regional
variations in severe maternal morbidity in Canada, 2003 to 2007. J Obstet
Gynaecol Can 2010; 32:847–855. [II-2; administrative database]
23. Fingar KR, Hambrick MM, Heslin KC, Moore JE. Trends and disparities in
delivery hospitalizations involving severe maternal morbidity, 2006–2015.
Statistical brief #243. September 2018. Agency for Healthcare Research and
Quality. Healthcare Cost and Utilization Project. https://www.hcup-us.
ahrq.gov/reports/statbriefs/sb243-Severe-Maternal-Morbidity-Delivery-
Trends-Disparities.jsp. Accessed 11/21/2020. [II-2]
24. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK. Births: Final Data
for 2018. National Vital Statistics Reports; vol. 68, no 13. Hyattsville, MD:
National Center for Health Statistics. 2019. [II-2; administrative data]
25. Roberts CL, Ford JB, Algert CS, et al. Trends in adverse maternal outcomes
during childbirth: a population-based study of severe maternal morbidity.
BMC Pregnancy Childbirth 2009; 9:7. [II; administrative dataset, n = 6242]
26. Knight M, Callaghan WS, Berg C, et al. Trends in postpartum hemor-
rhage in high resource countries: a review and recommendations from
the International Postpartum Hemorrhage Collaborative Group. BMC
Pregnancy Childbirth 2009; 9:55. [II-2; multiple datasets]
27. Callagan WM, Creanga AA, Kuklina EV. Severe maternal morbidity among
delivery and postpartum hospitalizations in the United States. Obstet
Gynecol 2012; 120: 1029–1036. [II-2; administrative database; 50 million
records, 597,000 qualifying cases]
28. Plante LA. Public health consequences of cesarean on demand. Obstet
Gynecol Surv 2006; 61:807–815. [III; decision analysis]
29. Galyean AM, Lagrew DC, Bush MC, et al. Previous cesarean section and
the risk of postpartum maternal complications and adverse neonatal out-
comes in future pregnancies. J Perinatol 2009; 29:726–730. [II-3; database,
n = 17,406]
30. Petersen EE, Davis NL, Goodman D, et al. Vital Signs: pregnancy-related
deaths, United States, 2011-2015, and strategies for prevention, 13 states,
2013–2017. MMWR 2019; 68(18):423–429. [II-2]
430
31. Marshall JC, Bosco L, Adhikari NK, et al. What is an intensive care unit
(ICU): a report of the task force of the World Federation of Societies of
Intensive and Critical Care Medicine. J Crit Care 2017; 37:270–276. [III;
expert committee]
32. Nasrawat SA, Cohen IL, Dennis RC, et al. Guidelines on admission and dis-
charge for adult intermediate care units. Crit Care Med 1998; 26:607–610.
[III; expert opinion]
33. Zimmerman JE, Wagner DP, Sun X, et al. Planning patient services for
intermediate care units: insights based on care for intensive care unit low-
risk monitor admissions. Crit Care Med 1996; 24:1626–1632. [II-2; cohort
study, n = 8040]
34. Seppelt I, for ANZIC writing committee. Critical illness due to 2009A/
H1N1 influenza in pregnant and postpartum women: population based
cohort study. BMJ 2010; 340:c1279. [II-2; cohort study, n = 64]
35. Louie JK, Acosta M, Jamieson DJ, et al. For the California Pandemic (H1N1)
Working Group. Severe 2009 H1N1 influenza in pregnant and postpartum
women in California. N Engl J Med 2010; 362:27–35. [II-2; cohort, n = 102]
36. Siston AM, Rasmussen SA, Honein MA, et al. for the Pandemic H1N1
Influenza in Pregnancy Working Group. Pandemic 2009 influenza A
(H1N1) virus illness among pregnant women in the United States. JAMA
2010; 303:1517–1525. [II; public health surveillance dataset, n = 788]
37. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symp-
tomatic women of reproductive age with laboratory-confirmed SARS-
CoV-2 infection by pregnancy status—United States, January 22–October
3, 2020. Morbid Mortal Weekly Rep 2020; November 6; 44: 1641–1647. [II-2,
cohort, n = 23,434]
38. Intensive Care Society. Levels of Adult Critical Care, 2nd Ed. 2009. https://
ics.ac.uk/ICS/ICS/Guidelines/PDFs/Levels_of_Care_25_ 3_21.aspx.
Accessed 4/28/21 [III; guideline]
39. Maternal Critical Care Working Group. The Royal College of Obstetricians
and Gynaecologists, the Royal College of Anaesthetists, the Royal College
of Midwives, the Intensive Care Society, the Faculty of Intensive Care
Medicine, and the Obstetric Anaesthetists’ Association. Care of the criti-
cally ill woman in childbirth; enhanced maternal care. August 2018. Online
at https://www.rcoa.ac.uk/sites/default/files/documents/2019-09/EMC-
Guidelines2018.pdf Accessed 4/28/21 [III; expert committee guideline]
40. American College of Obstetricians and Gynecologists and Society for
Maternal-Fetal Medicine. Obstetric Care Consensus No. 9. Levels of mater-
nal care. Obstet Gynecol 2019; 134:e41–e55. [III; guideline]
41. Martin SR, Foley MR. Intensive care in obstetrics: an evidence-based
review. Am J Obstet Gynecol 2006; 195:673–689. [III; opinion]
42. Critical care in pregnancy. ACOG Practice Bulletin No. 211. American
College of Obstetricians and Gynecologists Committee on Practice
Bulletins. Obstet Gynecol 2019; 133:e303–e319. [III; expert opinion]
43. Bouvier-Colle M-H, Salanave B, Ancel P-Y, et al. Obstetric patients treated
in intensive care units and maternal mortality. Eur J Obstet Gynecol Reprod
Biol 1996; 65:121–125. [III; population-based survey, n = 435]
44. Collop NA, Sahn SA. Critical illness in pregnancy: an analysis of 20 patients
admitted to a medical intensive care unit. Chest 1993; 103:1548–1552. [II-3;
case series, n = 20]
45. Gilbert TT, Smulian JC, Martin AA, et al. Obstetric admissions to the
intensive care unit: outcomes and severity of illness. Obstet Gynecol 2003;
102:897–903. [II-3; case series, n = 233]
46. Graham SG, Luxton MC. The requirement for intensive care support for the
pregnant population. Anaesthesia 1989; 44:581–584. [II-3; case series, n = 23]
47. Karnad D, Guntupalli KK. Critical illness and pregnancy: review of a global
problem. Crit Care Clin 2004; 20:555–576. [III; review]
48. Kilpatrick SJ, Matthay MA. Obstetric patients requiring critical care: a five-
year review. Chest 1992; 101:1407–1412. [II-3; case series, n = 32]
49. Kwee A, Bots ML, Visser GHA, et al. Emergency peripartum hysterectomy:
a prospective study in the Netherlands. Eur J Obstet Gynecol Reprod Biol
2006; 124:187–192. [III; survey: 48 reports]
50. Mabie WC, Sibai BM. Treatment in an obstetric intensive care unit. Am J
Obstet Gynecol 1990; 162:1–4. [II-3; case series]
51. Mahutte NG, Murphy-Kaulbeck L, Le Q, et al. Obstetric admissions to
the intensive care unit. Obstet Gynecol 1999; 94:263–266. [II-3; case
series, n = 131]
52. Monaco TK, Spielman FJ, Katz VL. Pregnant patients in the intensive care
unit: a descriptive analysis. South Med J 1993; 86:414–417. [II-3; case series,
n = 38]
53. Say L, Pattinson RC, Gülmezoglu AM. WHO systematic review of maternal
morbidity and mortality: the prevalence of severe acute maternal morbidity
(near miss). Reprod Health 2004; 1:3.. [Systematic review, 30 studies]
54. Soubra SH, Guntupalli KK. Critical illness in pregnancy: an overview. Crit
Care Med 2005; 33:S248–S55. [III; review]
Maternal-Fetal Evidence Based Guidelines
55. Sriram S, Robertson MS. Critically ill obstetrics patients in Australia: a ret-
rospective audit of 8 years’ experience in a tertiary intensive care unit. Crit
Care Resusc 2008; 10:120–124. [II-3; case series, n = 56]
56. Zhang W-H, Alexander S, Bouvier-Colle M-H, et al. Incidence of severe
pre-eclampsia, postpartum haemorrhage and sepsis as a surrogate marker
for severe maternal morbidity in a European population-based study: the
MOMS-B survey. BJOG 2005; 112:89–96. [III; survey, 1734 responses]
57. Crozier TM, Wallace EM. Obstetric admissions to an integrated general
intensive care unit in a quaternary maternity facility. Aust NZ J Obstet
Gynaecol 2011; 51:233–238. [case series, n = 60]
58. Paxton JL, Presneill J, Aitken L. Characteristics of obstetric patients
referred to intensive care in an Australian tertiary hospital. Aust NZ J
Obstet Gynaecol 2014; 54:445–339. [case series, n = 249]
59. Brilli RJ, Spevetz A, Branson RD, et al. Members of the American College
of Critical Care Medicine Task Force on Models of Critical Care Delivery,
American College of Critical Care Medicine Guidelines for the Definition
of an Intensivist, and Practice of Critical Care Medicine. Critical care deliv-
ery in the intensive care unit: defining clinical roles and the best practice
model. Crit Care Med 2001; 29:2001–2019. [III; task force, expert report]
60. D’Alton ME, Bonanno CA, Berkowitz RL, et al. Putting the “M” back in
maternal-fetal medicine. Am J Obstet Gyn 2013; 208:442–448. [III]
61. Edwards Z, Lucas DN, Gauntlett R. Is training in obstetric critical care ade-
quate? An international comparison. Int J Obstet Anesth 2017; 37:96–105. [III]
62. Dorman T, Angood P, Angus DC, et al. Guidelines for critical care medi-
cine training and continuing medical education. Crit Care Med 2004; 32:
263–272. [III; task force, expert opinion]
63. Soylemez Weiner R, Welch HG. Trends in the use of the pulmonary artery
catheter in the United States, 1993 to 2004. JAMA 2007; 298:423–429. [II-3;
administrative database]
64. The Critical Care Anesthesiology Milestone Project. A joint initiative of the
Accreditation Council for Graduate Medical Education and the American
Board of Anesthesiology. October, 2014. https://www.acgme.org/acg-
meweb/Portals/0/PDFs/Milestones/CriticalCareMedicine.pdf Accessed
10/4/15. [III; guideline]
65. The Surgical Critical Care Milestone Project. A joint initiative of the
Accreditation Council for Graduate Medical Education and the American
Board of Surgery. July 2015. https://www.acgme.org/globalassets/PDFs/
Milestones/SurgicalCriticalCareMilestones.pdf Accessed 10/4/15.
[III; guideline]
66. Catanzarite V, Willms D, Wong D, et al. Acute respiratory distress syn-
drome in pregnancy and the puerperium: causes, courses, and outcomes.
Obstet Gynecol 2001; 97:760–764. [III; case series, n = 28]
67. Tomlinson MW, Caruthers TJ, Whitty JE. Does delivery improve maternal
condition in the respiratory-compromised gravida? Obstet Gynecol 1998;
91:92–96. [III; case series, n = 10]
68. Romagnano MP, Guerrero K, Spillane N, et al. Perinatal outcomes in
critically ill pregnant women with coronavirus disease 2019. Am J Obstet
Gynecol MFM 2020; 2(3):100151[case series, n = 8]
69. McLaren RA, London V, Atallah F, et al. Delivery for respiratory compro-
mise among pregnant women with coronavirus disease 2019. Am J Obstet
Gynecol 2020; 222:451. [case series, n = 9]
70. Kayem G, Alessandrini V, Azria E, et al. A snapshot of the Covid-19 pan-
demic among pregnant women in France. J Gynecol Obstet Human Reprod
2020; 49(7):101826. [case series, n = 128]
71. Pierce-Williams RAM, Burd J, Felder L, et al. Clinical course of severe and
critical COVID-19 in hospitalized pregnancies: a US cohort study. Am J
Obstet Gynecol MFM 2020; 2(3):100134. [cohort, n = 64]
72. Cartin-Ceba R, Gajic O, Iyer V, et al. Fetal outcomes of critically ill preg-
nant women admitted to the intensive care unit for nonobstetric causes.
Crit Care Med 2008; 36:2746–2751. [II-2; cohort study, n = 153]
73. Warren J, Fromm RE, Orr RA, et al. Guidelines for the inter- and intrahos-
pital transport of critically ill patients. Crit Care Med 2004; 32:256–262.
[III; expert opinion]
74. American Hospital Association. AHA Hospital Statistics 2008. Chicago, IL:
Health Forum LLC, 2008. [Epidemiologic data]
75. Mhyre JM. D’Oria R, Hameed AB, et al. The maternal early warning crite-
ria: a proposal from the National Partnership for Maternal Safety. Obstet
Gynecol 2014; 124:782–786. [III]
76. Shields LE, Wiesner S, Klein C, Pelletreau B, Hedriana HL. Use of mater-
nal early warning trigger tool reduces maternal morbidity. Am J Obstet
Gynecol 2016; 214:527.e1–6. [II-3, n = 183,191]
77. Nates JL, Nunnally M, Kleinpell R, et al. ICU admission, discharge, and tri-
age guidelines: a framework to enhance clinical operations, development
of institutional policies, and further research. Crit Care Med 2016; 44:
1553–1602. [III]
Critical Care
78. Covino M, Sandroni C, Santor M, et al. Predicting intensive care unit
admission and death for COVID-19 patients in the emergency department
using early warning scores. Resuscitation 2020; 156:84–91. [II-2, n = 334]
79. Zeeman GG. Obstetric critical care: a blueprint for improved outcomes.
Crit Care Med 2006; 34(suppl):S208–S214. [III; review]
80. Pronovost PJ, Angus DC, Dorman T, et al. Physician staffing patterns and
clinical outcomes in critically ill patients: a systematic review. JAMA 2002;
288:2151–2162. [Systematic review, 26 observational studies]
81. Jenkins TM, Troiano NH, Graves CR, et al. Mechanical ventilation in
an obstetric population: characteristics and delivery rates. Am J Obstet
Gynecol 2003; 188:549–552. [III; case series, n = 43]
82. Plante LA. Mechanical ventilation in an obstetric population [letter]. Am J
Obstet Gynecol 2003; 189:1516. [III]
83. Soares FM, Pacagnella RC, Tuncalp A, et al. Provision of intensive care to
severely ill pregnant women is associated with reduced mortality: results
from the WHO Multicountry Survey on Maternal and Newborn Health. Int
J Gynecol Obstet 2020; 150:346–353. [cross-sectional study; n = 16,981]
84. Chang SY, Multz AS, Hall JB. Critical care organization. Crit Care Clin
2005; 21:43–53. [III; review]
85. Barba CA. The intensive care unit as an operating room. Surg Clin N Am
2000; 80:957–973. [III; review]
86. Kelly JJ, Puyana JC, Callery MP, et al. The feasibility and accuracy of diag-
nostic laparoscopy in the septic ICU patient. Surg Endosc 2000; 14:617–621.
[II-3; case series, n = 16]
87. Pecoraro AP, Cacchione RN, Sayad P, et al. The routine use of laparoscopy in the
intensive care unit. Surg Endosc 2001; 15:638–641. [II-3; case series, n = 11]
88. Jaramillo EJ, Trevino JM, Berghoff KR, et al. Bedside diagnostic laparoscopy
in the intensive care unit: a 13-year experience. JSLS 2006; 10:155–159. [III;
case series, n = 13]
89. Charalambous C, Zipitis CS, Keenan DJ. Chest reexploration in the intensive
care unit after cardiac surgery: a safe alternative to returning to the operating
theater. Ann Thorac Surg 2006; 81:191–194. [II-2; cohort study, n = 240]
90. Schreiber J, Nierhaus A, Vettorazzi E, et al. Rescue bedside laparotomy in
the intensive care unit in patients too unstable for transport to the operat-
ing room. Crit Care 2014; 18(3):R123. [II-3; case series, n = 41]
91. Piper GL, Maerz LL, Schuster KM, et al. When the ICU is the operating
room. J Trauma Acute Care Surg 2013; 74: 871–875. [ III]
92. Weber DJ, Sickbert-Bennett EE, Brown V, et al. Comparison on hospitalwide
surveillance and targeted intensive care unit surveillance of healthcare-
associated infections. Infect Control Hosp Epidemiol 2007; 28:1361–1366.
[III; surveillance data]
93. Edwards JR, Peterson KD, Andrus ML, et al. National Healthcare Safety
Network (NHSN) Report, data summary for 2006. Am J Infect Control
2007; 35:290–301. [III; surveillance data]
94. Sperling D. Do pregnant women have (living) will? J Health Care Law Policy
2005; 8(2):331–342. [III; review]
95. American College of Obstetricians and Gynecologists Committee on
Professional Liability. Committee Opinion No. 551. Coping with the
stress of medical professional liability litigation. January 2013. American
College of Obstetricians and Gynecologists, Washington DC. https://www.
acog.org/-/media/project/acog/acogorg/clinical/files/committee-opinion/
articles/2013/01/coping-with-the-stress-of-medical-professional-liability-
litigation.pdf Accessed 11/22/2020
96. Raheja R, Brahmavar M, Joshi D, Raman D. Application of lung ultrasound
in critical care setting: a review. Cureus 2019; 11(7): e5233. [III]
97. Vetrugno L, Bove T, Guadagnin GM, Orso D, Brussa A, Volpicelli G.
Advances in lung ultrasound in critically ill patients. J Emerg Crit Care Med
2019; 3:32. [III]
98. Ambrozic J, Brzan Simenc G, Prokselj K, Tul N, Cvijic M, Lucovnik M.
Lung and cardiac ultrasound for hemodynamic monitoring of patients with
severe pre-eclampsia. Ultrasound Obstet Gynecol 2017; 49: 104–109. [II-3,
case series, n = 21]
99. Inchingolo R, Smargiassi A, Moro F, et al. The diagnosis of pneumonia in a
pregnant woman with coronavirus disease 2019 using maternal lung ultra-
sound. Am J Obstet Gynecol 2020; 223(1): 9–11. [case report, n = 1]
100. Buonsenso D, Raffaelli F, Tamburrini E, et al. Clinical role of lung ultra-
sound for the diagnosis and monitoring of COVID-19 pneumonia in preg-
nant women. Ultrasound Obstet Gynecol 2020; 56(1):106–109. [II-3, case
series, n = 4]
101. Moro F, Buonsenso D, Moruzzi MC, et al. How to perform lung ultrasound
in pregnant women with suspected COVID-19. Ultrasound Obstet Gynecol
2020; 55: 593–598. [III, expert opinion]
102. Dennis AT. Transthoracic echocardiography in obstetric anaesthesia and
obstetric critical illness. Int J Obstet Anesthesia 2011; 20:16–18. [III, expert
opinion]
431
103. Bernard GR, Artigas A, Brigham KL, et al. Report of the American-
European consensus conference on ARDS: definitions, mechanisms, rel-
evant outcomes and clinical trial coordination. Intensive Care Med 1994;
20:225–232. [III; expert opinion, consensus]
104. Pierrakos C, Karanikolas M, Scolletta S, Karamouzos V, Velissaeis D. Acute
respiratory distress syndrome: pathophysiology and therapeutic options. J
Clin Med Res 2012; 4(1):7–16.
105. The ARDS Definition Task Force. Acute respiratory distress syndrome: the
Berlin definition. JAMA 2012; 307:2526–2533. [III; consensus guideline]
106. Mabie WC, Barton JR, Sibai BM. Adult respiratory distress syndrome in
pregnancy. Am J Obstet Gynecol 1992; 167:950–957. [III; case series, n = 16]
107. Callaghan WM, Creanga AA, Kuklina EV. Severe maternal morbidity
among delivery and postpartum hospitalizations in the United States.
Obstet Gynecol 2012; 120:1029–1036. [II-2, administrative dataset, n =
597,920 records]
108. Joseph KS, Liu S, Rouleau J, et al. For the Maternal Health Study Group of
the Canadian Perinatal Surveillance System. Severe maternal morbidity in
Canada, 2003 to 2007: surveillance using routing hospitalization data and
ICD-10CA codes. J Obstet Gynaecol Can 2010; 32:837–846. [II-2, adminis-
trative dataset, 1.3 million records]
109. Rush B, Martinka P, Kilb B, McDermid RC, Boyd JH, Celi LA. Acute
Respiratory Distress Syndrome in Pregnant Women. Obstet Gynecol 2017;
129(3):530–535. [II-2, n = 2808]
110. Creanga AA, Johnson TF, Graitcer SB, et al. Severity of 2009 pandemic
influenza A (H1N1) virus infection in pregnant women. Obstet Gynecol
2010; 115:717–726. [II-3; case series, n = 62]
111. Davies AR, Jones D, Bailey M, et al. for the Australia and New Zealand
Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza
Investigators. Extracorporeal membrane oxygenation for 2009 influenza A
(H1N1) acute respiratory distress syndrome. JAMA 2009; 302:1888–1895.
[II-3; case series, n = 68]
112. Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy:
A systematic review and meta-analysis of clinical features and pregnancy
outcomes. E Clinical Medicine 2020; 25:100446. [III, review]
113. Smith JL, Thomas F, Orne JF, et al. Adult respiratory distress syndrome
during pregnancy and the puerperium. West Med J 1990; 153: 508–510.
[II-3; case series, n = 14]
114. Perry KG, Martin RW, Blake PG, et al. Maternal mortality associated with
adult respiratory distress syndrome. South Med J 1998; 91:441–445. [II-3;
case series, n = 41]
115. Vasquez DN, Estenssoro E, Canales HS, et al. Clinical characteristics and
outcomes of obstetric patients requiring ICU admission. Chest 2007; 131:
718–724. [II-3; cohort study, n = 161]
116. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of
acute lung injury. N Engl J Med 2005; 353:1685–1693. [II-2; cohort study,
n = 1113]
117. Nicolaides KH, Economides DL, Soothill PW. Blood gases, pH, and lactate
in appropriate- and small-for-gestational-age fetuses. Am J Obstet Gynecol
1989; 161:996–1001. [II-3; cross-sectional study, n = 404]
118. Polvi HJ, Pirhonen JP, Erkkola RU. The hemodynamic effects of maternal
hypo- and hyperoxygenation in healthy term pregnancies. Obstet Gynecol
1995; 86: 795–799. [II-1, n = 10]
119. Lapinsky SE, Rojas-Suarez JA, Crozier TM, et al. Mechanical ventilation in
critically-ill pregnant women: a case series. Int J Obstet Anesthesia 2015;
24: 323–328. [II-3, n = 29]
120. The Acute Respiratory Distress Syndrome Network (ARDSNet). Ventilation
with lower tidal volumes as compared with traditional tidal volumes for
acute lung injury and the acute respiratory distress syndrome. N Engl J Med
2000; 342:1301–1308. [I; RCT, n = 861]
121. Fraser D, Jensen D, Wolfe LA, et al. Fetal heart rate response to maternal
hypocapnia and hypercapnia in late gestation. J Obstet Gynaecol Can 2008;
30(4):312–316. [II-3; n = 35]
122. Siddiqi AK, Gouda H, Multz AS, et al. Ventilator strategy for status asth-
maticus in pregnancy: a case-based review. J Asthma 2005; 42:159–162. [II-
3; case series, n = 2]
123. Elsayegh D, Shapiro JM. Management of the obstetric patient with status
asthmaticus. J Intensive Care Med 2008; 23(6):396–402. [II-3; case series,
n = 5]
124. Hirani A, Marik PE, Plante LA. Airway pressure release ventilation in preg-
nant patients with acute respiratory distress syndrome: a novel strategy.
Respir Care 2009; 54:1405–1409. [II-3; case series, n = 2]
125. Grisaru-Granovsky S, Ioscovich A, Hersch M, et al. Temporizing treatment
for the respiratory-compromised gravida: an observational study of mater-
nal and neonatal outcome. Int J Obstet Anesthesia 2007; 16:261–264. [II-3;
case series, n = 3]
432
126. Ramanathan K, Tan CS, Rycus P, et al. Extracorporeal membrane oxy-
genation in pregnancy: an analysis of the Extracorporeal Life Support
Organization Registry. Crit Care Med 2020; 48: 696–703. [II-3, n = 280]
127. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO
systematic analysis. Lancet Global Health 2014; 2: e323–333. [III, review]
128. Singer M, Deutschman CS, Seymour CW, et al. The Third International
Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;
315: 801–810. [III]
129. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new defini-
tion and assessing new clinical criteria for septic shock. JAMA 2016; 315:
775–787. [III]
130. Bowyer L, Robinson HL, Barrett H, et al. SOMANZ guidelines for the inves-
tigation and management of sepsis in pregnancy. Aust NZ Obstet Gynaecol
2017; 57:540–551. [III, expert opinion]
131. Bauer ME, Bateman BT, Bauer ST, Shanks AM, Mhyre JM. Maternal sep-
sis mortality and morbidity during hospitalization for delivery: temporal
trends and independent associations for severe sepsis. Anesth Analg 2013;
117:944–950. [II-3, case series, n = 22]
132. Oud L, Watkins P. Evolving trends in the epidemiology, resource utiliza-
tion, and outcomes of pregnancy-associated severe sepsis: a population-
based cohort study. J Clin Med Res 2015; 7:400–416. [II-2, n = 1007]
133. Al-Ostad G, Kezouh A, Spence AR, Abenhaim HA. Incidence and risk fac-
tors of sepsis mortality in labor, delivery and after birth: population-based
study in the USA. J Obstet Gynaecol Res 2015; 41: 1201–1206. [II-2, cohort
study, n = 5 million]
134. Bonet M, Souza JP, Gulmezoglu AM, et al. For the WHO Global Maternal
Sepsis Study (GLOSS) Research Group. Lancet Global Health 2020; 8:
e661–671 [cross-sectional study, n = 2850]
135. Acosta CD, Kurinczuk JJ, Lucas DN, Tuffnell DJ, Sellers S, Knight M, on
behalf of the United Kingdom Obstetric Surveillance System. Severe mater-
nal sepsis in the UK, 2011–2012: a national case-control study. PLOS Med
2014; 11(7): e1001672. [II-3, case control, n = 365]
136. Kelso A, Wills A, and Knight M, on behalf of the MBRRACE-UK.
Maternal Mortality in the UK 2012-2014: Surveillance and Epidemiology.
In: Knight M, Nair M, Tuffnell D, Shakespeare J, et al. (Eds.) on behalf of
MBRRACE-UK. Saving Lives, Improving Mothers’ Care—Lessons learned
to inform maternity care from the UK and Ireland Confidential Enquiries
into Maternal Deaths an Morbidity 2013–15. Oxford: National Perinatal
Epidemiology Unit, University of Oxford, 2017: 6–14.
137 Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on
survival in patients with severe sepsis or septic shock in whom early goal-
directed therapy was initiated in the emergency department. Crit Care Med
2010; 38: 1045–1053. [II-2, cohort, n = 261]
138. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment
reduces mortality in severe sepsis and septic shock from the first hour:
results from a guideline-based performance improvement program. Crit
Care Med 2014; 42:17491755. [II-2, cohort, n = 17,990]
139. Churchill D, Rodger A, Clift J, Tuffnell D, on behalf of the MBRRACE-UK
sepsis chapter writing group. Think sepsis. In: Knight M, Kenyon S,
Brocklehurst P, Neilson J, Shakespeare J, Kurinczuk JJ (Eds.) on behalf of
MBRRACE-UK. Saving Lives, Improving Mothers’ Care – Lessons Learned
to Inform Future Maternity Care from the UK and Ireland Confidential
Enquiries into Maternal Deaths and Morbidity 2009–2012. Oxford:
National Perinatal Epidemiology Unit, University of Oxford, 2014: 27–43.
[II-3, case series; and III, expert opinion]
140. Ryan HM, Jones MA, Payne BA, et al. Validating the performance of the
Modified Early Obstetric Warning System multivariable model to predict
maternal intensive care unit admission. J Obstet Gynaecol Can 2017; 39(9):
728–733. [II-2, case-control, n = 184]
Maternal-Fetal Evidence Based Guidelines
141. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign:
International Guidelines for Management of Sepsis and Septic Shock: 2016.
Crit Care Med 2017; 45(3):486–552. [III, guideline]
142. Lefrant JY, Muller L, Raillard A, et al. Reduction of the severe sepsis or sep-
tic shock associated mortality by reinforcement of the recommendations
bundle: a multicenter study. Ann Fr Anesth Reanim 2010; 29:621–628. [II-3;
time series, n = 445]
143. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign:
guidelines on the management of critically ill adults with Coronavirus
Disease 2019 (COVID-19). Intens Care Med 2020; 45: 854–887. [III]
144. Plante LA, Pacheco LR, Louis JM. SMFM Consult Series #47: Sepsis during
pregnancy and the puerperium. Am J Obstet Gynecol 2019; 220(4): B2–B10.
[III, expert opinion]
145. Kankuri E, Kurki T, Hiilesma V. Incidence, treatment and outcome of peri-
partum sepsis. Acta Obstet Gynecol Scand 2003; 82:730–735. [II-2; cohort,
n = 798]
146. Zhou P, Qian Y, Xu J, et al. Occurrence of congenital syphilis after mater-
nal treatment with azithromycin during pregnancy. Sex Transm Dis 2007;
34:472–474. [II-3; case series, n =5]
147. Acosta CD, Knight M, Lee HC, Kurinczuk JJ, Gould JB, Lyndon A. The con-
tinuum of maternal sepsis severity: incidence and risk factors in a popula-
tion-based cohort study. PLOS ONE 2013; 8(7): e67175. [II-2, cohort, n = 1.6
million]
148. Kramer HMC, Schutte JM, Zwart JJ, Schuitemaker NEW, Steegers EAP, van
Roosmalen J. Maternal mortality and severe morbidity from sepsis in the
Netherlands. Acta Obstet Gynecol 2009; 88: 647–653. [II-2, cohort, n = 78]
149. Miyazaki K, Furuhashi M, Matsuo K, et al. Impact of subclinical chorioam-
nionitis on maternal and neonatal outcomes. Acta Obstet Gynecol Scand
2007; 86:191–197. [II-2; cohort study, n = 100]
150. Ngan Kee WD, Lee SWY, Ng FF, Tan PE, Khaw KS. Randomized double-
blinded comparison of norepinephrine and phenylephrine for mainte-
nance of blood pressure during spinal anesthesia for cesarean delivery.
Anesthesiology 2015; 122: 736–745. [I, RCT, n = 104]
151. Mintzer BH, Johnson RF, Paschall RL, et al. The diverse effects of vaso-
pressors on the fetoplacental circulation of the perfused human placenta.
Anesth Analg 2010; 110:857–862. [II-1]
152. Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment of
normal term pregnancy. Am J Obstet Gynecol 1989; 161:1439–1442. [II-3;
cross-sectional study, n = 10]
153. Fishburne JI, Meis PJ, Urban RB, et al. Vascular and uterine responses to
dobutamine and dopamine in the gravid ewe. Am J Obstet Gynecol 1980;
137:944–952. [II-1; n = 6]
154. Horby P, Lim WS, Emberson JR, et al. For the RECOVERY Collaborative
Group. Dexamethasone in hospitalized patients with Covid-19—prelimi-
nary report. New Engl J Med 2020: NEJMoa2021436. [I, RCT, n = 6405]
155. Randomised evaluation of COVID-19 therapy: the RECOVERY trial.
Collaborators’ meeting, 14–15 September 2020. https://www.recovery-
trial.net/files/professional-downloads/recovery-collaborators-meeting-
2020-09-14.pdf. Accessed 11/21/2020
156. Harvey MA, Davidson JE. Postintensive care syndrome: right care, right
now…and later. Crit Care Med 2016; 44: 381–385. [III]
157. Hinton L, Locock L, Knight M. Maternal critical care: what can we learn
from patient experience? A qualitative study. BMJ Open 2015; 5:e006676.
[III, qualitative; n = 46]
158. Souza JP, Cecatti JG, Parpinelli MA, Krupa F, Osis MJD. An emerging
“maternal near-miss syndrome”: narratives of women who almost died dur-
ing pregnancy and childbirth. Birth 2009; 36(2):149–158. [III, qualitative]
43
AMNIOTIC FLUID EMBOLISM
Zaid Diken, Antonio F. Saad, and Luis D. Pacheco
Key points
• Amniotic fluid embolism (AFE) classically presents as a
triad of sudden hypoxia, hypotension, and coagulopathy.
• Management of AFE is mainly supportive.
• In the case of a viable pregnancy, immediate delivery is
advised.
• Early high-quality cardiopulmonary resuscitation and
adherence to advanced cardiac life support guidelines are
recommended.
• The initial phase is defined by right ventricular failure
physiology. Bedside transthoracic echocardiography is a
valuable tool in identifying this phase early.
• Later phase is predominated by left ventricular failure and
treatment should be tailored accordingly.
• Early management of AFE-related coagulopathy should be
initiated as soon as possible with the use of massive trans-
fusion protocols if indicated.
• A multidisciplinary team of maternal fetal medicine physi-
cians, intensivists, and anesthesiologist should be involved
in the management of these patients.
Background
Amniotic fluid embolism (AFE) is a rare, often lethal disease that
occurs in pregnancy or in the immediate puerperium period.
In the developed world, it is one of the most common etiologies
of maternal mortality. It is estimated that up to 10% of mater-
nal deaths are caused by AFE [1]. According to a recent United
States national registry review of around 1.5 million deliveries,
AFE, second only to pre-eclampsia, was the most common dis-
ease leading to maternal death [2]. Historically, AFE patients have
a poor prognosis. Based on a 1995 national registry, mortality
rate after an AFE event was reported to be 61% and neurological
intact maternal survival rate to be only 15% [3]. Recent data has
reported better outcomes with maternal mortality rates as low as
26% and neurological intact survival rates up to 93% [4, 5]. Other
investigators have shown that the risk of death and/or perma-
nent neurological injury can range between 30–41% depending
on the case definition utilized [6]. Perinatal mortality has been
described to be as high as 25%.
Incidence
The incidence of AFE ranges from 0.8–1.8/100,000 [6]. Absence of
a validated case definition that excludes false positives can lead to
overestimation and even doubling of its incidence [7]. For research
purposes, the case definition of AFE usually includes the sudden
onset of a triad of hypoxemia, systemic hypotension/hemody-
namic collapse, and coagulopathy [8]. By accounting for false posi-
tive cases, the true incidence of AFE can be better elucidated [7, 9].
Pathophysiology
The pathophysiology of AFE remains unclear. Historically, it was
thought to occur secondary to traveling of acellular fragments
DOI: 10.1201/9781003099062-43
and squamous cells from the amniotic fluid to the pulmonary
system with vessel obstruction leading to acute right ventricular
failure, and eventually to death. Examples of inciting factors that
promote the travelling of amniotic fluid into the maternal side
include pelvic lacerations, placental abruption and cesarean sec-
tion. The embolism hypothesis has been recently discredited
by studies that failed to reproduce the syndrome after direct
injection of amniotic fluid into the pulmonary vascular space
[3, 10, 11] in animal models. Moreover, despite fetal or amniotic-
derived tissue being found in the pulmonary vascular system
of pregnant women, patients did not develop AFE [12]. Since
the presence of these histologic landmarks are neither sensitive
nor specific and are not necessary for the development of AFE,
genetic predisposition may explain why some women develop the
syndrome of AFE and others don’t.
Recently AFE has been linked to a massive inflammatory
response secondary to activation of maternal immunity by
fetal antigens/epitopes. Amniotic fluid consists of a milieu rich
in potent mediators that can explain the different clinical mani-
festations of AFE. Examples include platelet activator factor,
cytokines, bradykinin, histamine, arachidonic acid, leukotrienes,
prostaglandins, tissue factor, and endothelin [13, 14].
Endothelin has been suggested as a major mediator in the
pathogenesis of AFE. It is a potent constrictor that can cause
prominent pulmonary vasoconstriction and acute elevation of
the pulmonary vascular resistances. Within the first minutes of
AFE (first phase), the resulting surge in pulmonary afterload
leads to acute core pulmonale even in the absence of anatomi-
cal occlusion of the pulmonary vasculature [15]. Two major det-
rimental events result from acute right ventricular failure and
chamber dilation: Massive ventricular ischemia from compres-
sive occlusion of the feeding right coronary vessels within the
myocardium leading to a right ventricular infarction, and
displacement of the inter-ventricular septum towards the left
ventricle, decreasing left ventricular preload and cardiac out-
put secondary to acute diastolic dysfunction.
Left ventricular failure, cardiogenic pulmonary edema, and
hypotension define the second phase of the disease. During
this time, the mainstream of management includes the use of
vasopressors and inotropes [16]. The observed left ventricular
dysfunction is due to an amalgamation of cardiac stunning from
hypoxia that occurred in the first phase of the disease and to
cytokine induced myocardial depression from inflammatory pro-
teins such as tumor necrosis factor α, nitric oxide, platelet acti-
vating factor, and interleukin-1 [17]. The physiologic consequence
of decreased left heart function is cardiogenic pulmonary edema.
Disseminated intravascular coagulation (DIC) is another
feature of AFE, occurring in up to 83% of reported cases [3].
Amniotic fluid tissue factor binds to maternal serum factor VII
activating the extrinsic pathway of the clotting cascade. Amniotic
fluid alone has also been reported to directly activate factor X
and platelets. Other important stimulators of the clotting cascade
include major inflammatory proteins from tissue factor released
433
434
from activated monocytes and neutrophils. DIC in AFE is mainly
a consumptive coagulopathy manifested as hemorrhage.
For those that survive the first two phases, a third phase of AFE
is ensued. It is characterized by slow and delay improvement in
left ventricular function secondary to prolonged severe inflam-
mation coupled with the need for prolonged critical care (risk
factor for nosocomial infections like ventilator associated pneu-
monia, line bacteremia, urinary tract infections, sinusitis), and by
distributive shock with inflammation induced non-cardiogenic
pulmonary edema [16].
Some have suggested a common link between AFE and ana-
phylaxis [3]. In addition, up to 41% of patients with AFE have
reported a previous history of atopy [3]. The proposed similarity
is justified since all three conditions – AFE, anaphylaxis, and sep-
sis – involve significant inflammatory responses. This relation-
ship has been challenged as severe biventricular heart failure and
profound coagulopathy, the defining pillars of AFE, are not found
in anaphylaxis.
Risk factors for amniotic fluid embolus
There are modifiable and non-modifiable risk factors for AFE [15].
Modifiable risk factors include medical induction of labor, instru-
mental vaginal delivery (forceps and vacuum assisted deliveries),
cervical lacerations, uterine rupture, and cesarean section. Non-
modifiable risk factors include advanced maternal age (more than
30 years old), African American race, eclampsia, polyhydram-
nios, male fetus, placenta previa, placental abruption, and mul-
tiple pregnancies [7, 9, 18–20].
The association between AFE and oxytocin administration or
prolonged protracted labor has been inconsistent [3]. The com-
mon use of oxytocin in contrast to the paucity of AFE, makes
this causative link extremely unlikely [21]. Others have ques-
tioned the relationship between oxytocin use and AFE while
suggesting an association with the use of prostaglandins [6].
Another misconception is that uterine tone anomalies (hypo-
or hypertonous) may play a role in AFE development, instead,
it appears that uterine hypoperfusion due to maternal hypoxia
and shock with massive adrenergic surge is responsible for the
tone anomalies [3].
Currently, evidence is lacking to determine if cesarean or
operative vaginal deliveries are associated with AFE. Most pub-
lications lack information on the temporal relationship between
operative delivery and AFE. It is unclear if the interventions
indeed preceded AFE events or they were performed after the
AFE to improve fetal outcomes [7].
Despite identifiable risk factors, AFE remains unpredict-
able and unpreventable. The inability for the described risk
factors to predict AFE may be secondary to their non-specificity
along with the rarity of the disease. Modifying obstetrical prac-
tice for the sole purpose to prevent AFE is not recommended.
Diagnosis
Clinical presentation of amniotic fluid embolism
Based on the national registry data, AFE cases have occurred 70%
during labor, 11% after a vaginal delivery, and 19% during a cesar-
ean delivery [3].
AFE classically presents as a triad of sudden hypoxia, hypo-
tension, and coagulopathy. It seldom happens in the second or
third trimester, at the time of amniocentesis or pregnancy ter-
mination [22]. It may be preceded by a period of anxiety, altered
mental status, agitation, and sensation of “doom” [23]. AFE
Maternal-Fetal Evidence Based Guidelines
should be considered in the differential workup in any woman
that is pregnant or recently delivered with acute cardiovascular
collapse, seizures, severe respiratory difficulty/arrest, or coagu-
lopathy unexplained by other etiologies.
Localized arterial pulmonary vasoconstriction (induced by
both mechanical obstruction and constriction secondary to local
constrictors such as endothelin) with diversion of flow to adjacent
areas results in ventilation/perfusion mismatch and shunting
with subsequent hypoxemia. Decreased arterial pressure results
from right ventricular dilation and impingement of the interven-
tricular septum into the left ventricular chamber, decreasing cav-
ity size and end-diastolic volume, ultimately diminishing cardiac
output. The subsequent hypoxemia increases the hazard of sei-
zures, left heart failure, and uterine atony [16].
Cardiac arrest may occur suddenly, with asystole, ventricular
fibrillation, pulseless electrical activity (PEA), or pulseless ven-
tricular tachycardia. If arrest occurs while pregnant, common
fetal heart tracings include fetal tachycardia, decelerations, loss
of variability, bradycardia, and terminal decelerations.
DIC is a common finding in up to 83% of AFE cases [3]. It is
secondary to consumptive activation of the clotting cascade by
either amniotic fluid constituents (e.g. tissue factor) or by the
systemic inflammatory response that is triggered during the
event. During inflammation, monocytes and neutrophils will
express tissue factor in their surface. The latter binds to Factor
VII, activating the extrinsic pathway of the clotting cascade.
Rarely, coagulopathy can be the only manifestation in AFE
[24–26]. AFE patients with DIC are at risk for the following seri-
ous hemorrhagic complications: Venipuncture bleeding, gastro-
intestinal hemorrhage, hematuria, pelvic lacerations bleeding,
and uterine bleeding.
Differential diagnosis of AFE
Despite being long, one should narrow the differential diagnosis
to clinical relevant diseases that have specific treatment strate-
gies. More importantly, one should initiate treatment for sus-
pected AFE even before an exact diagnosis is determined. This is
especially true, since management mainly involves life-supporting
interventions (i.e. cardiorespiratory resuscitation). Common
medical conditions that need to be considered when ruling out
AFE include myocardial infarction, thromboembolism, high
spinal anesthesia, air embolism, eclampsia, and anaphylactic
shock.
Bedside echocardiography with evidence of right ventricular
dysfunction favors the diagnosis of AFE over anaphylaxis and
most of the other conditions that mimic AFE.
Patients with the following risks factors, such as, diabetes,
smoking, obesity, advanced maternal age, chronic hypertension,
dyslipidemia, and previous history of coronary artery disease
should be ruled out for acute myocardial infarction. Workup
should include cardiac troponins and a 12-lead electrocardio-
graph as soon as possible. A bedside echocardiography is a useful
tool in assisting in the diagnosis of cardiogenic shock secondary
to myocardial ischemia or to rare causes such as a peri-partum
dilated cardiomyopathy [27].
Pulmonary embolism from a pelvic clot needs to be considered
high in the differential list. Findings of acute right ventricular
dilation and hypo-contractility in a bedside transthoracic echo-
cardiography during the acute event may be helpful. Once the
patient is stabilized, confirmatory testing such as a computed
tomography angiography or ventilation perfusion scan should
be considered. The possibility of thromboembolism is unlikely in
Amniotic Fluid Embolism
cases with profuse bleeding (the combination of right ventricular
failure with coagulopathy strongly suggests AFE).
In the absence of cardiac decompensation and hemorrhage,
high spinal anesthesia leading to apnea should be considered in
the differential diagnosis. Local anesthetic toxicity secondary to
inadvertent intravascular injection can manifest by seizures and
cardiovascular collapse [28]. Timing between injection and onset
of symptoms is of utmost importance. If suspicion is high cardio-
pulmonary resuscitation should be initiated as soon as possible
and administration of intravenous lipids (20% Intralipid) should
be started [29].
Acute cardiorespiratory compromise can also be seen with
air embolism. The initial management of this condition is
identical to that of AFE. In addition, normobaric 100% oxygen
should be administered if highly suspected. Patient should also
be placed in left lateral decubitus position to avoid air from
traveling to the pulmonary vasculature. If a central venous
catheter is in place, blood aspiration of air bubbles can be
attempted. Hyperbaric oxygen therapy may be used in cases of
arterial air embolism.
In the absence of profound coagulopathy and cardiopulmonary
decompensation, eclampsia should be high in the differential
diagnosis of patients presenting with new onset of seizures.
Anaphylactic shock is a known imitator of AFE and it should
be considered when AFE is suspected. Important clues that
favor anaphylaxis versus AFE include development of urticarial
rash, laryngospasm, and bronchospasm. The latter is only pres-
ent in 15% of cases of AFE. Coagulopathy and cardiac dysfunc-
tion are seldom seen in anaphylaxis. The observed hypotension
is secondary to vasodilation and increased vascular permeability
rather than ventricular failure. Treatment of anaphylactic shock
involves prompt administration of epinephrine, steroids, and
inhaled bronchodilators.
Diagnostic laboratory testing
AFE is not diagnosed based on a specific laboratory test, but
rather based on exclusion. Historically, the presence of acellu-
lar fetal debris or fetal squamous cells in the maternal circula-
tion was believed to be pathognomonic of the disease. This has
been challenged, since the same pathologic findings have been
described in normal asymptomatic pregnant women and are not
always present in women with AFE [12, 30].
Recent data has proposed a novel serum biomarker for AFE:
Insulin like growth factor binding protein 1 (IGFBP-1) [31].
Further evidence is needed, before it reaches the confirmatory
stage.
Investigators have proposed renaming AFE to “anaphylac-
toid reaction of pregnancy” due to similarities in inflamma-
tory biomarkers between anaphylaxis and AFE [3]. Of note, these
biomarkers are not exclusive to either disease and are found in
other nonspecific inflammatory responses. While in anaphylaxis
serum tryptase is commonly elevated, this is not found in cases
with AFE [32–34]. Moreover, this evidence refutes the hypoth-
esis that AFE and anaphylaxis have similar pathogenesis [35]. We
believe AFE and anaphylaxis have little in common.
Activation of the complement pathway has also been shown in
AFE [35]. Confirmation of the disease is not advised based on low
serum complement levels, due to poor sensitivity and specificity.
In summary, diagnosis of AFE is mainly based in clinical
presentation, and there is no specific confirmatory labora-
tory testing. Importantly, a clear diagnosis is not required ini-
tially as the first step in most cases is to provide high quality
435
cardiopulmonary resuscitation; the latter does not require a spe-
cific diagnosis.
Management of cardiac arrest
The main basis of initial management of cardiac arrest is support-
ive care with standard resuscitative efforts; immediate cardiopul-
monary resuscitation (CPR) should be initiated as soon as possible.
Since most events occur inpatient and are witnessed, blood oxygen
content is initially normal; hence, high quality chest compressions
are recommended before administration of rescue breathing [36].
Chest compressions should be performed using a firm black
board, with the patient in supine position, hands in center of
chest at the lower half of the sternum (as in non-pregnant patient)
and achieving a depth of at least 2 inches (5 cm). It is important
to allow full chest recoil between compressions to favor preload.
Initially, if no advanced airway is in place, the compression rate
is 30 compressions followed by 2 ventilations. Once an advanced
airway in in place, compressions are provided at 100–120/minute
while delivering a breath every 6 seconds (10 per minute) [37]. If
the patient is undelivered and at least 20 weeks pregnant, con-
tinuous manual left uterine displacement to prevent aorto-caval
compression [37]. The use of vasopressors, anti-arrhythmics, and
defibrillating doses should be no different than those utilized in
non-pregnant individuals. There is no evidence that fetal moni-
tors will result in electrical arcing, defibrillation may be per-
formed with the monitors in place.
If the patient has a viable pregnancy at the time of the arrest,
expeditious operative assisted vaginal delivery (forceps or vacuum)
is recommended when the cervix is dilated and fetal head is at
low station. Immediate preparation for perimortem cesarean sec-
tion should be undertaken. If vaginal delivery is not possible and
return of spontaneous circulation (ROSC) has not been achieved
within four minutes despite initial resuscitative interventions, a
perimortem cesarean section (PMCD) should be performed in
patients with known gestational age of more than 23 weeks or the
appearance of a gravid uterus above the umbilicus [38].
Delivery will not only benefit the fetus (if viable) but also will
increase the chances of return of spontaneous circulation by
relieving aortocaval compression [39].
Waiting for full 4 minutes to initiate PMCD is not an abso-
lute rule; earlier delivery may be indicated depending on the
gestational age (e.g. after 2 minutes of unsuccessful CPR with a
38-week fetus, it is reasonable to start a PMCD instead of waiting
2 more minutes of CPR).
Post cardiac arrest management is of paramount importance
[40]. After ROSC, patients are often hemodynamic unstable,
and management is mainly based on administration of fluids,
vasopressors, and inotropes. Mean arterial blood pressure of
65–70 mmHg should be maintained [40]. To decrease ischemia-
reperfusion injury, fever should be avoided and aggressively
treated. Hyperoxia should be avoided for the same reason and
administration of 100% oxygen to patients after survival of car-
diac arrest is not recommended. This is achieved by weaning the
inspired fraction of oxygen to sustain pulse oximetry values of
94–98% [41]. As standard of care in any critically ill patient, serum
glucose levels should be maintained between 140 and 180 mg/dL
with implementation of an insulin drip if needed.
Mild therapeutic hypothermia (TH) has been shown to benefit
comatose adult non-pregnant survivors after outpatient cardiac
arrest. It consists of bringing down the patient’ s body tempera-
ture to 32–34°C (89.6°F–93.2°F) for 12–24 hours. The American
Heart Association has recommended temperature management
436 Maternal-Fetal Evidence Based Guidelines

and it has become standard of care in this patient population [40,
42]. A recent clinical trial has shown no difference in outcomes
when comparing targeted temperatures of 33°C versus 36°C in
patients that achieved ROSC after cardiac arrest [43]. Current
guidelines recommend maintaining temperature between 32°C
and 36°C after cardiac arrest [44].
A recent trial found that in non-shockable rhythms (asystole
and pulseless electrical activity), targeting a temperature of 33°C
results in better neurologic outcomes compared to 36°C [45].
Evidence on TH during pregnancy is scant, and based on case
reports and its application should be considered on an individual
basis [46, 47]. Most survivors of AFE will not be pregnant anymore
after successful resuscitation. One of the major adverse effects or
complications of TH is the risk of hemorrhage. TH should be con-
sidered in patients whose bleeding risk is low. We suggest a target
temperature of 36°C (rather than lower temperatures) to decrease
the risk of bleeding for AFE related cardiac arrest survivors at
high risk of hemorrhage.
After return of spontaneous circulation, where available, a
transthoracic and/or transesophageal echocardiography should
be performed without delay. Pertinent findings include a severely
dilated hypokinetic right ventricle with left sided deviation of the
inter-ventricular septum. During the initial phase of right ventricu-
lar failure, acidosis, hypercapnia and hypoxia should be avoided as
they worsen the condition by increasing pulmonary vascular resis-
tances [15]. Dobutamine and milrinone are the drugs of choice for
right ventricular heart failure since along with being inotropes, they
also are pulmonary vasodilators. Other specific agents that decrease
the pulmonary vascular resistances include sildenafil, inhaled or
intravenous prostacyclin, and inhaled nitric oxide. Common vaso-
pressors used to treat hypotension include norepinephrine or vaso-
pressin [48]. Of paramount importance is that hypotension in the
setting of a severely dilated right ventricle should not be treated with
fluids as the latter will dilate the right ventricle even more leading
to worse compression of the septum with subsequent obliteration
of the left ventricle. Similarly, over distention of the right ventricle
with aggressive fluid therapy will compress the right ventricular
free wall against the pericardium with coronary compression and
right ventricular ischemia [49]. Table 43.1 contains commonly used
dosages of the described agents.

TABLE 43.1: Common Drugs Used in Cases of Acute Right Ventricular Failure
Agent Mechanism of Action Contraindication/Adverse Effects Dose
Sildenafil Selective inhibitor of cGMP-PDE5; vasodilator by Hypotension risk in patients with severe 20 mg tid PO or through
relaxing the vascular smooth muscle. Selective aortic stenosis, left ventricular outflow nasogastric/orogastric
pulmonary vasodilator in patients with pulmonary tract obstruction, concomitant nitrates, tube
hypertension or hypovolemia
Dobutamine Direct beta-2-receptors agonist with chronotropic, Avoid in idiopathic hypertrophic sub 2.5–5.0 μg/kg/minute
arrhythmogenic, and vasodilative effects aortic stenosis
Hypersensitivity
Higher doses may compromise right
ventricular filling time due to
tachycardia
Milrinone Selective inhibitor of peak III cAMP phosphodiesterase Hypersensitivity 0.25–0.75 μg/kg/minute
isozyme in cardiac and vascular smooth muscle Systemic hypotension
Inhaled nitric Stimulates guanylate cyclase leading to increase in Methemoglobinemia 5–40 ppm. Follow
oxide cGMP and protein phosphorylation leading to methemoglobin levels
selective pulmonary vasodilator of those areas of the every 6 hours and avoid
lung being ventilated abrupt discontinuation
Inhaled Inhibits platelet activation Hypersensitivity 10–50 ng/kg/minute
prostacyclin Selective pulmonary vasodilator of those areas of the
lung being ventilated
Anti-inflammatory properties
Intravenous Inhibits platelet activation Avoid in severe left ventricular systolic Start at 1–2 ng/kg/minute
prostacyclin Non-selective pulmonary vasodilator dysfunction through a central line and
Hypersensitivity titrate to desired effect
Systemic hypotension
Nausea/vomiting
Headache
Jaw pain
Diarrhea
Norepinephrine Peripheral vasoconstrictor (alpha-adrenergic action) None 0.05–3.3 μg/kg/minute
and inotropic stimulator of the heart and dilator of
coronary arteries (beta-adrenergic action). Alpha
action is greater than beta action
Vasopressin Potent analogue of the posterior pituitary hormone Hypersensitivity 0.03–0.04 units/minute
anti-diuretic hormone Hyponatremia and water retention
Effects are through the V1 vascular receptors
Abbreviations: PDE5, phosphodiesterase type 5; ppm, parts per million; tid, three times per day; po, orally.
Amniotic Fluid Embolism 437

In patients with refractory shock despite the use of inotro-
pic and vasopressor support, venoarterial extracorporeal mem-
brane oxygenation (ECMO) can be considered [49]. ECMO
cannulation is usually performed at bedside accessing the femo-
ral artery and vein which provides both respiratory and hemo-
dynamic support until cardiac function recovery. Once ECMO
is initiated, the physician should be aware of common compli-
cations like hemolysis, bleeding, infection, circuit thrombosis,
and intracranial hemorrhage. Blood from the ECMO circuit
enters the femoral artery and travels retrogradely in the sys-
temic circulation competing with the native cardiac output
resulting in mixing points. Compromised lung function in such
a scenario increases the risk of perfusing the brain and part of
the upper extremities with poorly oxygenated blood causing
brain ischemia or what is known as North-South syndrome.
This can be best monitored and managed by measurement of
partial pressure of oxygen in the right radial artery [50]. The use
of anticoagulation in ECMO can worsen bleeding in a patient
with underlying coagulopathy and DIC. This should be balanced
against the risk of circuit thrombosis without the use of sys-
temic heparin. In patients with active bleeding (e.g. post AFE
after an emergent cesarean section and coagulopathy), ECMO
can be started without anticoagulation and once the bleeding
risk decreases anticoagulation can be gradually started; usu-
ally after a few hours. The use of higher flow rates or heparin-
bonded circuits can allow maintenance of flow in the ECMO
circuit without systemic anticoagulation.
Within hours of initial presentation, right ventricular dysfunc-
tion starts to recover. A phase of predominantly left ventricular
failure ensues (likely form ischemia-reperfusion injury) with car-
diogenic pulmonary edema [23]. Non-invasive mechanical ven-
tilation or endotracheal intubation should be considered early
in patients who are not intubated. The mainstay of therapy at
this point consists of fluid restriction, diuretics (in normoten-
sive patients), vasopressors (mainly norepinephrine) in cases of
hypotension, and inotropes (dobutamine or milrinone) with the
aim of maintaining coronary perfusion and optimizing left ven-
tricular contractility. Persistent pulmonary congestion despite
diuretic therapy may necessitate renal replacement therapy for
fluid removal.
The role of steroids in the management of AFE remains contro-
versial and is not indicated.
Prolonged care in the intensive care unit and persistent
severe inflammation predispose survivors to develop nosoco-
mial infections and distributive shock with non-cardiogenic
pulmonary edema secondary to endothelial injury from severe
sepsis [16]. Figure 43.1 summarizes the main points in the man-
agement of AFE.
Management of coagulopathy associated
with amniotic fluid embolism
DIC is often present in AFE cases, its onset is variable, and it can
occur in early or late phases of the syndrome. Therapy involves
medical and surgical approaches.
Medical management includes administration of blood prod-
ucts to maintain a platelet count above 50,000/mm3, an activated
partial thromboplastin time (aPTT) less than 1.5 the upper limit
of normal, international normalized ratio (INR) less than 2, and

AFE Event Call for help

Alert Multidiscplinary Team:

Initiate High quality neonatology, maternal fetal
CPR-ACLS medicine, anesthesiology,
intensivist

Viable Pregnancy:
Right Ventricular Failure Left Ventricular Failure Obstetrical Hemorrhage
Immediate delivery
(Early Phase) Cardiogenic Pulmonary (Immediate or Delay
(operative vaginal delivery
Consider bedside TTE Edema (Second Phase) Onset DIC)
or emergent cesarean)

Restrictive Fluid Rescucitation Massive transfusion protocol

Norepinephrine for Activation
Restrictive Fluid Rescucitation Agressive Management
MAP> 65 mmHg
Norepinephrine for of Uterine
Inotropes : dobutamine
MAP> 65 mmHg Atony
or milrinone
Inotropes : dobutamine Rule out anatomic etiologies
Inhaled Nitric Oxide or
or milrinone of bleeding such as
Inhaled or IV
Prostacyclin pelvic lacerations

FIGURE 43.1 Pearls in the management of suspected cases of amniotic fluid embolism. Abbreviations: AFE, amniotic fluid
embolism; CPR, cardio-pulmonary resuscitation; ACLS, advanced cardiovascular life support; TTE, transthoracic echocardiogram;
DIC, disseminated intravascular coagulopathy; map, mean arterial pressure.
438
a serum fibrinogen level above 150–200 mg/dL [51]. In cases of
massive hemorrhage, massive transfusion protocols should be
activated with no delay regardless of laboratory coagulation tests.
Early aggressive hemostatic resuscitation with a 1:1:1 ratio of
packed red blood cells, fresh-frozen plasma, and platelets is likely
to result in improved outcomes [52]. Although administration of
recombinant activated factor VII has been described in cases of
AFE [53–55], some authors believe that excessive diffuse throm-
bosis and multi organ failure can occur secondary to the combi-
nation of recombinant activated factor VII and elevated levels of
tissue factor present in AFE. Hence, it is recommended to con-
sider using this agent only as a last resort in cases of intractable
hemorrhage despite massive blood component replacement and
surgical interventions [54].
Amniotic fluid has been shown to contain both plasmino-
gen activators and plasminogen activator inhibitors [56].
Hyperfibrinolysis has been described in AFE related coagulopa-
thy and is believed to happen early before the rapid consumption
of coagulation factors [57, 58]. Early administration of anti-fibri-
nolytics like tranexamic acid or epsilon aminocaproic acid along
with bedside thromboelastography should be considered in the
management of AFE [59].
In the United States, most of the fibrinogen replacement is done
in the form of cryoprecipitates (150–350 mg of fibrinogen per
unit of cryoprecipitate). Each unit of cryoprecipitate will increase
the serum fibrinogen by 10 mg/dL. Just like fresh frozen plasma,
cryoprecipitate needs to be thawed before its use and carries the
risk for virus transmission. Although not widely available in the
United States, fibrinogen concentrates have emerged as another
alternative to replenish serum fibrinogen levels without the risk
of viral transmission or transfusion reactions like TRALI (trans-
fusion related acute lung injury). It is stored at room temperature
and available for immediate use. Fibrinogen concentrates contain
high concentrations of fibrinogen (100 ml contains 2 g of fibrin-
ogen). In any case, either cryoprecipitate or fibrinogen concen-
trates should be administered in bleeding patients to maintain a
serum fibrinogen above 150–200 mg/dL.
Prolonged aPTT and PT should trigger the administration of
fresh frozen plasma in patients with active bleeding.
Uterine atony, when present, should be managed aggressively
with the use of uterotonics such as oxytocin, ergot derivatives,
and prostaglandins [60]. If medical therapy fails, uterine tam-
ponade with the use of packing or commercially available intra-
uterine balloons should be considered. Surgical approaches such
as bilateral uterine artery ligation, B-Lynch stitch, or even a hys-
terectomy may be needed in extreme cases of uterine atony and
bleeding.
After vaginal delivery, thorough assessment of vaginal canal
lacerations as potential sources of bleeding is strongly recom-
mended. For patients undergoing a cesarean section with diffuse
bleeding not amenable to surgical control, damage control sur-
gery should be considered with packing the pelvis and transfer to
the intensive care unit for further medical therapy with delayed
closure/abdominal [61].
Prognosis of patients who
survive an AFE event
Survival of in-hospital cardiac arrest is 15–20% [62]. Due to
improvement in the health care system, better outcomes have
been reported after AFE with maternal mortality rates of
Maternal-Fetal Evidence Based Guidelines
26% and up to 93% of survivors been neurologically intact
[4, 5]. Perinatal mortality has been reported to be as high
as 25%. Of note, when discussing outcomes of cases with sus-
pected AFE, one should account for patients’ characteristics,
since these can skew the data to either better or worse survival/
mortality rates. For example, in patients with the full blown
syndrome of coagulopathy and cardiorespiratory arrest mor-
tality rates would be invariable higher than those with isolated
coagulopathy alone [21].
Postpartum counseling about
recurrence rates of AFE
AFE is so rare that recurrence rates are difficult, if not impos-
sible, to describe. In the literature, multiple cases of unevent-
ful pregnancies after an episode of AFE have been reported
[63, 64]. No recurrent cases have been published and no
data exists to counsel AFE survivors about the possibility of
recurrence.
Summary
AFE is a rare and often lethal condition. In the past decade, better
maternal and perinatal outcomes have been observed secondary
to improvements in the management of the critical ill patient. Its
pathophysiology remains largely unknown. Diagnosis is mainly
clinical and one of exclusion since specific diagnostic tests are
currently absent. Management consists mainly of supportive
care. Core treatment principles include delivery of fetus when
indicated, respiratory support (usually in the form of endotra-
cheal intubation and mechanical ventilation), and hemodynamic
support. Judicious use of fluids, vasopressors, inotropes, and pul-
monary vasodilators are crucial in the therapy of the underlying
cardiovascular dysfunction. High index of suspicion with prompt
initiation of treatment is crucial to improve outcomes of this seri-
ous and lethal disease.
References
1. Conde-Agudelo A, Romero R. Amniotic fluid embolism: an evidence-based
review. Am J Obstet Gynecol 2009;201(5):445.e441–413. [Review, 2 popula-
tion-based cohort studies and 6 case-control studies]
2. Clark SL, Belfort MA, Dildy GA, Herbst MA, Meyers JA, Hankins GD.
Maternal death in the 21st century: causes, prevention, and relationship
to cesarean delivery. Am J Obstet Gynecol 2008;199(1):36.e31–35. [II-2;
Retrospective chart review, n = 95]
3. Clark SL, Hankins GD, Dudley DA, Dildy GA, Porter TF. Amniotic fluid
embolism: analysis of the national registry. Am J Obstet Gynecol 1995;172(4
Pt 1):1158–1167. [II-2; Retrospective chart review, n = 46]
4. Gilbert WM, Danielsen B. Amniotic fluid embolism: decreased mortal-
ity in a population-based study. Obstet Gynecol 1999;93(6):973–977. [II-2;
Retrospective chart review, n = 53]
5. Tuffnell DJ. United kingdom amniotic fluid embolism register. BJOG
2005;112(12):1625–1629. [II-2; Retrospective chart review, n = 44]
6. Fitzpatrick KE, van den Akker T, Bloemenkamp KWM, et al. Risk factors,
management, and outcomes of amniotic fluid embolism: a multicoun-
try, population-based cohort and nested case-control study. PLOS Med
2019;16(11):e1002962.
7. Knight M, Berg C, Brocklehurst P, et al. Amniotic fluid embolism incidence,
risk factors and outcomes: a review and recommendations. BMC Preg
Childbirth 2012;12:7. [II-2; Retrospective chart review, n = 2341]
8. Clark SL, Romero R, Dildy GA, et al. Proposed diagnostic criteria for the
case definition of amniotic fluid embolism in research studies. Am J Obstet
Gynecol 2016;215(4):408–412.
9. Kramer MS, Rouleau J, Liu S, Bartholomew S, Joseph KS. Amniotic fluid
embolism: incidence, risk factors, and impact on perinatal outcome. BJOG
2012;119(7):874–879. [Review]
Amniotic Fluid Embolism
10. Petroianu GA, Altmannsberger SH, Maleck WH, et al. Meconium and
amniotic fluid embolism: effects on coagulation in pregnant mini-pigs. Crit
Care Med 1999;27(2):348–355. [Animal Study]
11. Hankins GD, Snyder RR, Clark SL, Schwartz L, Patterson WR, Butzin CA.
Acute hemodynamic and respiratory effects of amniotic fluid embolism
in the pregnant goat model. Am J Obstet Gynecol 1993;168(4):1113–1129.
[Animal study]
12. Lee W, Ginsburg KA, Cotton DB, Kaufman RH. Squamous and trophoblas-
tic cells in the maternal pulmonary circulation identified by invasive hemo-
dynamic monitoring during the peripartum period. Am J Obstet Gynecol
1986;155(5):999–1001. [II-2; Cohort n = 14]
13. Tuffnell DJ. Amniotic fluid embolism. Curr Opin Obstet 2003;15(2):
119–122. [III; Review]
14. Margarit L, Griffiths AN, Tsapanos V, Tsakas S, Decavalas G. Amniotic
fluid endothelin levels and the incidence of premature rupture of mem-
branes. Int J Gynecol Obstet 2006;93(1):18–21. [II-2; Case-control; n = 125]
15. Dean LS, Rogers RP, 3rd, Harley RA, Hood DD. Case scenario: amniotic
fluid embolism. Anesthesiology 2012;116(1):186–192. [II-2; Population-
based cohort study, n = 292]
16. Moore J, Baldisseri MR. Amniotic fluid embolism. Crit Care Med
2005;33(Suppl 10):S279–285. [III; Review]
17. Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth 2010;104(1):3–11.
[III; Review]
18. Knight M, Tuffnell D, Brocklehurst P, Spark P, Kurinczuk JJ. Incidence
and risk factors for amniotic-fluid embolism. Obstet Gynecol 2010;115(5):
910–917. [II-2; Case control; n = 60]
19. Stein PD, Matta F, Yaekoub AY. Incidence of amniotic fluid embolism: rela-
tion to cesarean section and to age. J Women’s Health 2009;18(3):327–329.
[II-2; Retrospective chart review, n = 1200]
20. Kramer MS, Rouleau J, Baskett TF, Joseph KS. Amniotic-fluid embolism
and medical induction of labour: a retrospective, population-based cohort
study. Lancet (London) 2006;368(9545):1444–1448. [II-2; Retrospective
chart review, n = 180]
21. Clark SL. Amniotic fluid embolism. Obstet Gynecol 2014;123(2 Pt 1):
337–348. [III; Review]
22. Cromey MG, Taylor PJ, Cumming DC. Probable amniotic fluid embolism
after first-trimester pregnancy termination. A case report. J Reprod Med
1983;28(3):209–211. [III; Case Report]
23. Ecker JL, Solt K, Fitzsimons MG, MacGillivray TE. Case records of the
Massachusetts General Hospital. Case 40-2012. A 43-year-old woman
with cardiorespiratory arrest after a cesarean section. New Engl J Med
2012;367(26):2528–2536. [III; Case Report]
24. Awad IT, Shorten GD. Amniotic fluid embolism and isolated coagulopa-
thy: atypical presentation of amniotic fluid embolism. Eur J Anesthes
2001;18(6):410–413. [III; Case Report]
25. Yang JI, Kim HS, Chang KH, Ryu HS, Joo HJ. Amniotic fluid embolism with
isolated coagulopathy: a case report. J Reprod Med 2006;51(1):64–66. [III;
Case Report]
26. Laforga JB. Amniotic fluid embolism. Report of two cases with coagulation
disorder. Acta Obstet Gynecol Scand 1997;76(8):805–806. [III; Case Report]
27. Stafford I, Sheffield J. Amniotic fluid embolism. Obstet Gynecol Clin North
Am 2007;34(3):545–553, xii. [III; Review]
28. Marwick PC, Levin AI, Coetzee AR. Recurrence of cardiotoxicity after
lipid rescue from bupivacaine-induced cardiac arrest. Anesth Analg
2009;108(4):1344–1346. [III; Case Report]
29. Mazoit JX, Le Guen R, Beloeil H, Benhamou D. Binding of long-lasting local
anesthetics to lipid emulsions. Anesthesiology 2009;110(2):380–386. [Non-
clinical; Basic science]
30. Hankins GD, Snyder R, Dinh T, Van Hook J, Clark S, Vandelan A.
Documentation of amniotic fluid embolism via lung histopathology. Fact or
fiction? J Reprod Med 2002;47(12):1021–1024. [Animal study]
31. Legrand M, Rossignol M, Dreux S, et al. Diagnostic accuracy of insulin-
like growth factor binding protein-1 for amniotic fluid embolism*. Crit Care
Med 2012;40(7):2059–2063. [II-3, Case control, n =119]
32. Benson MD, Kobayashi H, Silver RK, Oi H, Greenberger PA, Terao T.
Immunologic studies in presumed amniotic fluid embolism. Obstet
Gynecol 2001;97(4):510–514. [II-3; Case series, n = 31]
33. Farrar SC, Gherman RB. Serum tryptase analysis in a woman with amni-
otic fluid embolism. A case report. J Reprod Med 2001;46(10):926–928. [III;
Case Report]
34. Marcus BJ, Collins KA, Harley RA. Ancillary studies in amniotic fluid
embolism: a case report and review of the literature. Am J Forensic Med
Pathol 2005;26(1):92–95. [III; Review]
35. Benson MD. Current concepts of immunology and diagnosis in amniotic
fluid embolism. Clin Develop Immun 2012;2012:946576. [III; Review]
439
36. Field JM, Hazinski MF, Sayre MR, et al. Part 1: executive summary: 2010
American Heart Association guidelines for cardiopulmonary resuscita-
tion and emergency cardiovascular care. Circulation 2010;122(18 Suppl
3):S640–656. [Guidelines]
37. Jeejeebhoy FM, Zelop CM, Lipman S, et al. Cardiac arrest in pregnancy:
a scientific statement from the American Heart Association. Circulation
2015;132(18):1747–1773. [Guidelines]
38. Pacheco LD, Saade G, Hankins GD, Clark SL. Amniotic fluid embolism:
diagnosis and management. Am J Obstet Gynecol 2016;215(2):B16–24.
39. Katz VL. Perimortem cesarean delivery: its role in maternal mortality.
Semin Perinatol 2012;36(1):68–72. [III; Review]
40. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest
care: 2010 American Heart Association Guidelines for Cardiopulmonary
Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122(18
Suppl 3):S768–786. [Guidelines]
41. Nolan JP. Optimizing outcome after cardiac arrest. Curr Opin Crit Care
2011;17(5):520–526. [III; Review]
42. Weng Y, Sun S. Therapeutic hypothermia after cardiac arrest in adults:
mechanism of neuroprotection, phases of hypothermia, and methods of
cooling. Crit Care Clin 2012;28(2):231–243. [III; Review]
43. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature man-
agement at 33°C versus 36°C after cardiac arrest. New Engl J Med
2013;369(23):2197–2206. [I; Randomized Control Trial n = 939]
44. Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post-cardiac arrest care:
2015 American Heart Association guidelines update for cardiopulmonary
resuscitation and emergency cardiovascular care. Circulation 2015;132(18
Suppl 2):S465–482.
45. Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted temperature man-
agement for cardiac arrest with Nonshockable rhythm. New Engl J Med
2019;381(24):2327–2337.
46. Chauhan A, Musunuru H, Donnino M, McCurdy MT, Chauhan V,
Walsh M. The use of therapeutic hypothermia after cardiac arrest in
a pregnant patient. Annal Emerg Med 2012;60(6):786–789. [III; Case
Report]
47. Wible EF, Kass JS, Lopez GA. A report of fetal demise during therapeutic
hypothermia after cardiac arrest. Neurocrit Care 2010;13(2):239–242. [III;
Case Report]
48. Duarte AG, Thomas S, Safdar Z, et al. Management of pulmonary arte-
rial hypertension during pregnancy: a retrospective, multicenter expe-
rience. Chest 2013;143(5):1330–1336. [II-2; Multicenter retrospective
cohort n = 18]
49. Pacheco LD, Clark SL, Klassen M, Hankins GDV. Amniotic fluid embo-
lism: principles of early clinical management. Am J Obstet Gynecol
2020;222(1):48–52.
50. Pacheco LD, Saade GR, Hankins GDV. Extracorporeal membrane oxygen-
ation (ECMO) during pregnancy and postpartum. Seminars in Perinatology
2018;42(1):21–25.
51. Pacheco LD, Saade GR, Hankins GDV. Medical management of postpartum
hemorrhage: An update. Semin. Perinatol 2019;43(1):22–26.
52. Pacheco LD, Saade GR, Gei AF, Hankins GD. Cutting-edge advances in
the medical management of obstetrical hemorrhage. Am J Obstet Gynecol
2011;205(6):526–532. [III; Review]
53. Franchini M, Manzato F, Salvagno GL, Lippi G. Potential role of recom-
binant activated factor VII for the treatment of severe bleeding associ-
ated with disseminated intravascular coagulation: a systematic review.
Blood Coagul Fibrinolysis 2007;18(7):589–593. [II-3; Systemic review,
n = 99]
54. Leighton BL, Wall MH, Lockhart EM, Phillips LE, Zatta AJ. Use of recom-
binant factor VIIa in patients with amniotic fluid embolism: a system-
atic review of case reports. Anesthesiology 2011;115(6):1201–1208. [II-3;
Systemic review n = 13]
55. Lim Y, Loo CC, Chia V, Fun W. Recombinant factor VIIa after amniotic
fluid embolism and disseminated intravascular coagulopathy. Inter J
Gynaecol Obstet 2004;87(2):178–179. [III; Case Report]
56. Uszyński M, Uszyński W. Coagulation and fibrinolysis in amniotic fluid:
physiology and observations on amniotic fluid embolism, preterm fetal
membrane rupture, and pre-eclampsia. Seminars in Thrombosis and
Hemostasis 2011;37(2):165–174. [III; Review]
57. Collins NF, Bloor M, McDonnell NJ. Hyperfibrinolysis diagnosed by rota-
tional thromboelastometry in a case of suspected amniotic fluid embolism.
Int J Obstet Anesth 2013;22(1):71–76. [III; Case Report]
58. Fudaba M, Tachibana D, Misugi T, Nakano A, Koyama M. Excessive fibri-
nolysis detected with thromboelastography in a case of amniotic fluid
embolism: fibrinolysis may precede coagulopathy. J Thromb Thrombolys
2020.
440
59. Schröder L, Hellmund A, Gembruch U, Merz WM. Amniotic fluid embo-
lism-associated coagulopathy: a single-center observational study. Arch
Gynecol Obstet 2020;301(4):923–929.
60. Matsuda Y, Kamitomo M. Amniotic fluid embolism: a comparison between
patients who survived and those who died. J Inter Med Res 2009;37(5):
1515–1521. [II-3; Case series, n = 9]
61. Pacheco LD, Lozada MJ, Saade GR, Hankins GDV. Damage-control surgery
for obstetric hemorrhage. Obstet Gynecol 2018;132(2):423–427.
Maternal-Fetal Evidence Based Guidelines
62. Sandroni C, Nolan J, Cavallaro F, Antonelli M. In-hospital cardiac arrest:
incidence, prognosis and possible measures to improve survival. Intensive
Care Me 2007;33(2):237–245. [III; Review]
63. Clark SL. Successful pregnancy outcomes after amniotic fluid embolism.
Am J Obstet Gynecol 1992;167(2):511–512. [III; Case Report]
64. Stiller RJ, Siddiqui D, Laifer SA, Tiakowski RL, Whetham JC. Successful preg-
nancy after suspected anaphylactoid syndrome of pregnancy (amniotic fluid
embolus). A case report. J Reprod Med 2000;45(12):1007–1009. [III; Case Report]
44
CANCER
Elyce Cardonick, Charlotte Maggen, and Puja Patel
Key points
Cancer diagnosed in pregnancy
• Avoid delay in diagnosis, by performing necessary diag-
nostic studies in a timely and adequate fashion as in non-
pregnant adults, with rare exceptions.
• Postpone radiologic studies which will not alter cancer
treatment or patient decisions during pregnancy.
• Avoid iatrogenic preterm deliveries.
• Whole body diffusion-weighted MRI (WB-DWI/MRI)
could be used for staging and detection of distant metasta-
sis in solid tumors and lymphomas and to evaluate tumor
response in pregnant women with cancer.
• When choosing a chemotherapeutic regimen for a particu-
lar cancer, choose the one with the most experience of use
and proven safety during pregnancy, as long as it will offer
a similar chance of cure for the patient.
• Administer the same doses of chemotherapy as given to
non-pregnant women, based on the actual height and
weight of the patient during pregnancy. Pre-pregnancy
weight or ideal body weight should not be used to calculate
chemotherapy dosage during pregnancy.
• At least 3 weeks between a cycle of chemotherapy during
pregnancy and delivery is recommended. Interrupt/or aim
to complete chemotherapy regimens by 34/35 weeks’ gestation
• Send placental pathology for all cancers, especially in
cases of melanoma.
• Prenatal diagnosis based on cell free DNA (Non-invasive
prenatal testing, NIPT) should not be offered to pregnant
women with known malignancy.
• Close multidisciplinary management, with an oncologist
and maternal-fetal specialist knowledgeable regarding the
unique considerations of cancer during pregnancy, is vital
to optimize outcomes.
Cancer diagnosed before pregnancy
• Women who have been treated for childhood cancer
with chemotherapy, radiation therapy, or both are not
at increased risk of having children with congenital or
chromosomal anomalies.
• The available data do not support an adverse effect of prior
chemotherapy on the risk of miscarriage or fetal demise.
Depending on cancer type, some cancer survivors may have a
higher risk for preterm birth or small for gestational age infants.
• Women who have received prior irradiation deliver infants
with a statistically lower birth-weight compared to survivors
only treated with chemotherapy, while those with a history
of pelvic irradiation specifically can have perinatal com-
plications such as miscarriage, preterm labor and delivery,
low birth weight, and placenta accreta. Patients with prior
abdominal radiation were found in one study to have higher
gestational diabetes and pregnancy induced hypertension
due to irradiation of the pancreas and kidney respectively.
DOI: 10.1201/9781003099062-44
• Unless the cancer suffered by the patient was part of an
inherited syndrome, such as retinoblastoma, the offspring
of cancer survivors are not at increased risk for cancer.
• With the possible exception of gestational trophoblastic
disease, pregnancy does not affect the risk of recurrence of
any type of cancer.
• Women with a history of left-sided chest radiation therapy
or anthracycline-based chemotherapy (daunorubicin,
doxorubicin, idarubicin, epirubicin, and mitoxantrone) can
have delayed cardiac toxicity and should undergo cardiac
evaluation prior to pregnancy. A baseline echocardiogram
is recommended for a history of these exposures as well as
a history of trastuzumab (Herceptin) prior to pregnancy.
Cancer diagnosed in pregnancy
Incidence/Epidemiology
Cancer complicates approximately 1/1000 pregnancies, and 1 out
of every 118 malignancies is associated with pregnancy [1]. There
is no increased incidence of malignancy in pregnant women. The
biggest risk for cancer during pregnancy is advanced maternal
age, as the incidence of cancer in women increases with age. The
most common cancers that occur during pregnancy are breast,
cervical, leukemia, lymphoma, thyroid, and melanoma. The dis-
tribution of cancer types diagnosed during pregnancy is compa-
rable to the expected rates in young, premenopausal women [2].
General considerations
Delays in diagnosis should be avoided. The necessary diagnos-
tic studies to work up a concerning sign or symptom in a pregnant
patient should proceed in the same timely and efficient matter as
if the patient were not pregnant [3]. The safest diagnostic studies
should be employed, for example, an MRI in place of CT, if simi-
lar diagnostic information can be obtained. Staging procedures
and radiologic studies should be limited during pregnancy to
those that will determine the treatment course during preg-
nancy or affect patient decisions about continuing the preg-
nancy. For radiographic imaging, abdomen lead shielding will
reassure and support the emotional being of the patients, but will
not significantly alter the fetal exposure dose from internal scat-
ter radiation [4]. Chemotherapy regimens should be compara-
ble to those used in non-pregnant patients; however, using the
newest agents is not recommended in absence of safety data,
even if favored for non-pregnant patients. Different drugs in
the same class of chemotherapy agents may have different proper-
ties (molecular weight, lipophilicity, ionization) that allow more
placental transfer, such as the more lipophilic idarubicin which
has been associated with transient cardiomyopathy in infants
exposed in utero [5, 6]. Once the regimen is chosen, the preg-
nant woman should be given the same doses of chemother-
apy as given to non-pregnant women with the same cancer
type and stage. The woman’s changing weight during preg-
nancy should be used, not pre-pregnancy or ideal body weight,
441
442
to determine the dose of chemotherapy [7]. This recommenda-
tion may change if pharmacokinetic studies are performed in the
future on pregnant women receiving chemotherapy, as free drug
levels may not be the same as in non-pregnant women due to the
many physiologic changes during pregnancy which affect drug
metabolism. Neonatal neutropenia and lymphopenia have been
reported for infants delivered within 3–4 weeks of chemotherapy,
therefore it is not recommended to continue chemotherapy
beyond 34/35 weeks [8, 9]. An overall rate of leukopenia of 3.0%
(defined as white blood cell count <5000 cells/μL) and of neutro-
penia of 7.4% (defined as neutrophils <1000 cells/μL was reported
in 135 children exposed to chemotherapy in utero [8].
For most cancers, termination of pregnancy does not
improve or affect outcome. If the patient wishes to continue the
pregnancy, cancer treatment is discussed if treatment cannot be
delayed until postpartum without compromising the woman’s
disease-free or overall survival. This concept brings into conflict
what is best for maternal survival yet not harmful to the develop-
ing fetus. Close multidisciplinary management, especially with
oncologists and maternal-fetal specialists knowledgeable in can-
cer and pregnancy, and the neonatal team is vital to optimize
outcomes. Obstetrical management and mode of delivery (aside
from cervical or vulvar cancers) rarely need to be altered, and evi-
dence-based interventions proven beneficial in pregnancy should
be available to all pregnant women with cancer. The presence
of tumor derived cfDNA can induce an aberrant NIPT result
masking the fetal chromosomal makeup and is discouraged in
pregnant women with known malignancy. Prenatal diagnosis
options in this population include combined screening (includ-
ing nuchal translucency), structural echography or amniocente-
sis prior to initiation of cancer treatment, if desired.
Iatrogenic preterm deliveries prior to 34/35 weeks should be
avoided. Placental pathology should be sent for all cancers, espe-
cially in cases of melanoma.
General chemotherapy considerations
Chemotherapy given during the first trimester has the highest
chance of causing malformations, as the majority of organogen-
esis occurs between 2 and 8 weeks post-conception. The literature
supports the relative safety of fetal exposure to chemotherapy
during the second and third trimesters [10–12].
The ability of a drug to cross the placenta is defined by the
physicochemical properties of drugs such as lipid solubility
and ionization constant, molecular weight, and protein bind-
ing. Due to the relatively low molecular weight, most cytotoxic
drugs can cross the placenta [13]. Placental transfer of various
chemotherapeutic agents can be modified by placenta proteins
such as P-glycoprotein which act as efflux proteins to decrease
fetal exposure [14]. Fluorouracil-epirubicin-cyclophosphamide
(FEC) and doxorubicin-bleomycin-vinblastine-dacarbazine
(ABVD) were administered to pregnant baboons. At predefined
time points over the first 25 hours after drug administration,
fetal and maternal blood samples, amniotic fluid (AF), urine,
fetal, and maternal tissues, and cerebrospinal fluid (CSF) were
collected. High-performance liquid chromatography (HPLC)
and liquid chromatography-mass spectrometry (LC-MS) were
used for bioanalysis of doxorubicin, epirubicin, vinblastine, and
cyclophosphamide. Limited fetal exposure after maternal admin-
istration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-­
cyclophosphamide was seen [15]. Taxanes have a low potential
to cross the placenta, however, they can accumulate in the fetal
Maternal-Fetal Evidence Based Guidelines
tissues, hereby bypassing placental metabolization, as showed in
both animal studies as human data [16, 17]. Umbilical blood sam-
pling 2 and 5 weeks post multiagent chemotherapy for maternal
leukemia showed that fetal hematopoiesis was normal [18].
By crossing the placenta, chemotherapy has the potential to
impact the intra-uterine fetal growth. In the pregnant cancer
population, other risk factors for impaired fetal growth such as
maternal age, cancer, poor general health, malnutrition, treat-
ment-related stress, are common. Available large case series
reveal that neonates prenatally exposed to chemotherapy are at
risk of being born SGA (small for gestational age), defined as a
birth-weight percentile below 10 [19, 20]. Because of practical rea-
sons (prospective study is complex on this rare topic) the current
literature focuses on SGA, however this definition also incorpo-
rates fetuses that are ‘constitutional’, normal small. Of note, the
pathological small neonates that do not reach their growth poten-
tial (IUGR or intra-uterine growth restriction) are ideally identi-
fied prenatally by obstetric scans.
In general, 4–8% of all infants born in developed countries are
classified as growth-restricted newborns [21]. The largest cohort
study on pregnant cancer patients revealed an SGA incidence
of 21% and the highest rate of SGA are reported in hematologi-
cal cancers [19, 20, 22]. The highest odds ratio (OR) for SGA are
reported for platinum agents (OR 3.12, 95% CI 1.45–6.70) and
taxanes (OR 2.07, 95% CI 1.11–3.86) [19]. In order to detect FGR,
two-weekly prenatal ultrasound to monitor fetal growth and
amniotic fluid during the course of antenatal chemotherapy is
recommended [23]. A direct damaging effect of chemotherapy to
the placenta has not been identified yet, but is strongly suspected,
as placental weight is significantly lower after maternal chemo-
therapy treatment [24, 25]. A cohort study on 25 placentas from
patients that received chemotherapy during pregnancy and 66
control patients revealed an increase of oxidative DNA damage in
the exposed placentas [25].
Chemotherapy during pregnancy is associated with preterm
contractions and delivery, explained by stress-related activa-
tion of the maternal hypothalamic-pituitary-adrenal axis or
chemotherapy-induced apoptosis in fetal membranes [19]. When
a patient presents with preterm contractions following chemo-
therapy, the threshold to admit for observation and administra-
tion of tocolytics should be low, in order to avoid delivery around
the nadir with the risk of maternal and neonatal hematological
toxicities.
Breast cancer
Breast cancer is the most common cancer complicating pregnancy.
Currently 15% of breast cancers are seen in women of child bearing
age, and the current trend in many populations to delay pregnancy
until a later age may increase this proportion [26]. The histology of
breast cancer diagnosed during pregnancy is no different from the
non-pregnant patient population, with invasive ductal carcinoma
being the most common subtype [27]. Patients with a breast can-
cer diagnosis within one year after delivery tend to have a worse
prognosis [2, 28]. Women diagnosed with and treated for breast
cancer during pregnancy have comparable survival to age and stage-
matched non-pregnant women [29–32]. For patients diagnosed with
breast cancer during pregnancy, any treatment intervention dur-
ing pregnancy provided a trend toward improved overall survival
compared to delaying evaluation and treatment until after delivery,
78.8% versus 44.6%, P = 0.68 [29]. Loibl, too, found that delaying treat-
ment until after delivery did not afford a survival advantage [32].
Cancer 443

Pregnant women may be more likely to be diagnosed at stage II
compared to non-pregnant women (74% vs. 37%), and less likely to
be diagnosed with early-stage disease (21% vs. 54%) [33]. Pregnant
and non-pregnant women younger than 40 are more likely to be
diagnosed with stage-II disease compared to women older than 40.
When matched for stage, women younger than 40 have a statisti-
cally worse 5-year survival compared to women older than 40 years
of age at diagnosis (55% vs. 75%). Accordingly, it may be the age of
reproductive age women which has a stronger influence on survival
than pregnancy [33].
Delay in diagnosis
Breast cancer during pregnancy often presents at advanced
stages compared to non-pregnant women due to delayed diag-
nosis. A delay in diagnosis worsens prognosis, and depend-
ing on the doubling time of the tumor, will increase risk for
lymphatic metastases [34]. Suspicious masses in the breast and
axilla should be investigated identically to non-pregnant women
During routine prenatal care, the examination of the breasts
should be performed, including all the way into the axillae as
this can be the sole area of a breast cancer presentation dur-
ing pregnancy.
Diagnostic tests and safety in pregnancy
The fetal exposure to mammography is not the deterrent to per-
forming this as the first line for the work up of a mass in preg-
nancy as the exposure is only 0.4 rads [4]. Mammography has
less sensitivity for screening in pregnancy, due to the increased
overall density, vascularity, cellularity, and water content, which
leads to less contrast during pregnancy. During pregnancy, breast
ultrasound has a better accuracy than mammography and should
be performed for palpable masses (Figure 44.1). The sensitivity

Breast or axillary lump in pregnancy

Imaging: - sonography (core biopsy if solid mass on sonogram)

-bilateral mammography (to exclude multifocal or bilateral cancer)

Diagnosis of breast cancer in pregnancy

Near term (37 weeks)* Before term (before 37 weeks)

Staging**: US liver, Xray chest

Delivery at ≥ 37 weeks
MRI bone or bone scan if symptomatic

Staging and treatment -Surgery:

-Breast conserving surgery or mastectomy
-Sentinel procedure or axillary dissection
-(Neo-) Adjuvant chemotherapy
-After the first trimester
-Currently used cytotoxic drugs are allowed

No chemotherapy after 35 weeks

Schedule delivery ≥ 37 weeks
Chemo-delivery interval of 3 weeks

Completion of treatment

FIGURE 44.1 Breast lump workup. (From Amant F et al., Breast cancer in pregnancy: recommendations of an international consen-
sus meeting, Eur J Cancer 2010; 46(18): 3158–3168, with permission.) Abbreviation: US, ultrasound.
444
and specificity of ultrasound to detect solid versus cystic breast
masses is not altered by pregnancy. MRI is not recommended
due to the requirement for gadolinium, which should be avoided
during pregnancy [30]. The biopsy of a solitary mass should be
offered as in non-pregnant women, with core needle biopsy
preferred over fine needle aspiration during pregnancy. False
positive cytological findings can occur in pregnancy due to the
highly proliferative state of the breast and the pathologist should
be aware that the patient is pregnant [35]. As in premenopausal
non-pregnant women, most tumors in pregnant women are
estrogen receptor negative [36]. HER2neu expression is compa-
rable to non-pregnant pre-menopausal women [36]. Maternal
age, rather than pregnancy, determines the biologic features of
breast cancer.
Effects on the pregnancy
There is no indication that breast cancer itself (excluding therapy)
directly affects perinatal outcome.
Termination of pregnancy and breast cancer
Routine termination of pregnancy does not appear to offer a sur-
vival advantage for pregnant women diagnosed with breast can-
cer [31, 32, 37]. Termination may be advised in cases of recurrent
or advanced disease diagnosed early in the first trimester.
Staging during pregnancy
Bilateral mammography (at least one medio-lateral view) is
indicated once breast cancer is diagnosed during pregnancy,
to exclude multifocal disease in the affected breast or cancer
in the contralateral breast. To detect metastases to lungs, liver,
or bone, the most common sites of metastases in breast can-
cer, a chest x-ray (with abdominal shielding) is recommended
and can be safely performed with fetal exposure of 0.06 mrad.
Abdominal ultrasound can be performed to detect liver metas-
tases, while liver function tests are not reliable for management
decisions as alkaline phosphatase is physiologically increased in
pregnancy. The risk of bony metastasis with stage-I or -II breast
cancer is 3–7%. A bone scan can be safely deferred until after
pregnancy for asymptomatic patients with early-stage disease.
If a patient is symptomatic, or has advanced-stage disease, a
bone scan can be performed with a Foley catheter in place and
intravenous hydration to promote washout of the excreted
radiopharmaceutical from patient’s bladder. An exposure of 10
mCi rather than 20 mCi of Technitium-99m (Tc-99m) methy-
lene diphosphonate (MDP) and doubling the imaging time can
reduce fetal radiation exposure [38]. Alternatively an MRI of the
skeleton can detect 80% of metastatic deposits. Brain scan is of
little yield unless patient has neurologic symptoms and physi-
cal findings. Alternatively, a whole-body diffusion-weighted
MRI has shown to be equally effective in the detection of nodal
and distant metastasis in women diagnosed with cancer dur-
ing pregnancy [39]. Positron emission tomography (PET) scans
are performed postpartum. Detecting spread to regional lymph
nodes is discussed later.
Surgery during pregnancy
Either modified radical mastectomy or breast conservation sur-
gery with axillary or sentinel lymph node dissection can be safely
performed at any gestational age, with attention paid to avoid
the supine position after 20 weeks’ gestation. Intraoperative
fetal monitoring is performed during a procedure at or after 24
weeks’ gestation, otherwise fetal viability is documented before
Maternal-Fetal Evidence Based Guidelines
and after surgery. Pregnant patients should have the same discus-
sion as non-pregnant women with breast cancer about the pros
and cons of breast conservation surgery. There does not appear
to be survival advantage of mastectomy over breast conservation
[40]. Patients choosing breast conservation and patients requir-
ing radiation despite mastectomy will need to defer radiotherapy
until postpartum. Chemotherapy can be given during the time
between surgery during pregnancy and radiation postpartum.
Autologous breast reconstruction is delayed for the best cosmetic
results to match the unaffected postpartum breast, but expand-
ers/spacers can be placed without a significant increase in opera-
tive time. Surgeons should be advised of the safe use of narcotics
in pregnancy for postoperative pain management.
Sentinel node biopsy
Sentinel node mapping and biopsy (SLNB) is commonly used for
non-pregnant women to avoid the complications of lymphedema
after complete axillary lymphadenectomy. Accuracy of SLNB
does not appear affected by the physiologic modification of lym-
phatic drainage during pregnancy [41]. Sentinel node biopsy can
be safely performed in pregnancy with Tc-99m sulfur colloid,
which identifies the first draining node(s) relative to the site
of the primary invasive tumor [42]. For sentinel node imaging,
only a minimal dose (500–600 mCi) of double-filtered Tc-99m
sulfur colloid is injected at the site of the breast tumor. The entire
radioisotope stays trapped at the sight of injection or within the
lymphatics until decay occurs (half-life = 6 hours), not traveling
throughout the body to expose the fetus [42]. Use of blue dyes
such as lymphazurin for sentinel node mapping in pregnancy is
discouraged as this carries a risk of anaphylaxis in 0.5% of proce-
dures, while indocyanine green has been safely used in pregnant
patients [43]. The current recommendation is to use Tc-99 as a
same day procedure.
Treatment during pregnancy (Figure 44.1)
Radiation therapy is usually postponed until postpartum.
As the pregnancy advances, the fetus has increased proxim-
ity to the breast and radiation field increasing exposure risk.
Neoadjuvant chemotherapy with large tumors at presentation
allows pathologic evidence of response to therapy which can be
prognostic. The regimen used should adhere to the standard
recommended chemotherapy regimens in the non-pregnant
population [30]. The majority of pregnant women reported in the
literature are treated with cyclophosphamide (C), doxorubicin
(A) or epirubicin (E), with or without 5-fluouracil (5FU). AC or EC
alone are preferable as recent evidence reveals no survival ben-
efit of 5FU in breast cancer patients. A single study reported dose
dense AC (every 2 weeks) but majority of case reports and small
series administer AC every 3 weeks [44]. Currently doxorubicin is
the preferred anthracycline to use during pregnancy and is com-
monly included in the regimens to treat various types of cancer
during pregnancy. Data regarding the use of epirubicin in preg-
nancy is accumulating in Europe as it has lower myelotoxic and
cardiotoxic properties and is better tolerated in non-pregnant
patients. Transient neonatal cardiomyopathy has been reported
after idarubicin exposure and the use of this anthracycline is not
recommended during pregnancy [5, 6].
Taxanes, widely used as standard first-line treatment for high-
risk early-stage and advanced/metastatic breast cancer in non-
pregnant women, result in a better response rate and longer
time to progression than standard anthracycline-based regimens
alone and should be offered to pregnant women if anthracycline
Cancer
based chemotherapy is completed prior to 32 weeks’ gestation.
Taxanes and can be given weekly to biweekly, with paclitaxel
preferred over docetaxel [44–49]. Placental transfer rate in pri-
mate studies was very low, however accumulation in fetal tissues
is demonstrated [16]. Herceptin (trastuzumab) use is contraindi-
cated in pregnancy as its use has been found to be associated with
oligohydramnios and pulmonary hypoplasia [50–55]. Hormonal
agents such as tamoxifen are also postponed until postpartum.
Hodgkin’s disease
Lymphoma during pregnancy is a potentially curable disease with
good outcomes for the mother and the fetus. Pregnant women
with Hodgkin’s disease (HD) are not more likely to be diagnosed
at a higher stage compared to non-pregnant women and survival
is comparable [56–58]. The majority of patients present with
nodular sclerosing HD, which is also the most common histology
seen in women younger than 40 years of age.
Presentation, diagnostic tests and safety in pregnancy
The clinical behavior of HD during pregnancy does not appear to
differ from non-pregnant women. Pregnant women can present
with a cough, night sweats, and weight loss. A patient with such
complaints should have a complete physical exam and clavicu-
lar adenopathy can be safely biopsied during pregnancy. Pruritis
unrelated to cholestasis of pregnancy, nor relieved with delivery
should raise suspicion. A chest x-ray can be performed safely with
minimal fetal exposure. A bone marrow biopsy can also be safely
performed with appropriate analgesia.
Staging of disease in pregnancy
The staging of lymphoma is based on history and physical exami-
nation, hematologic and biochemical testing, bone marrow
biopsy, and radiologic imaging. Currently, women with stages
I and II receive combination modality treatment, so full stag-
ing during pregnancy is unlikely to change the recommended
treatment during the course of pregnancy and can be delayed to
the postpartum period. Image staging in non-pregnant patients
includes a chest x-ray and CT. In the pregnant woman, a two-
view chest x-ray is suggested. A chest MRI can assess lymph-
adenopathy, and the information gained is comparable to a CT
[59]. MRI can also evaluate the bone marrow and detect splenic
involvement that may be undetectable with CT. Abdominal ultra-
sound can evaluate the spleen depending on size of gravid uterus.
Diffusion weighted whole body MRI is a safer alternative during
pregnancy [39]. After delivery a PET scan can be performed. Pet
scan is avoided in pregnancy as fludeoxyglucose crosses the pla-
centa and involves radiation as well.
Effects on pregnancy
Infants born to women with HD do not have a higher risk for pre-
maturity, although women treated with chemotherapy did expe-
rience increased preterm contractions and premature rupture of
membranes without a significant difference in gestational age at
delivery [59]. The incidence of small for gestational age neonates
in pregnant HD patients was 21% in a series of 123 patients, which
is higher compared to the general population. The administra-
tion of chemotherapy (ABVD) during pregnancy was associated
with lower birth-weight percentiles compared to non-exposed
neonates [59].
Termination of pregnancy
Therapeutic termination of a pregnancy does not improve the
course of disease [38, 39].
445
Surgery during pregnancy
At times, histologic examination of a clavicular lymph node is
inconclusive. In such cases, if mediastinal adenopathy is evident
on x-ray or CT of the chest, a guided thorascopic biopsy may be
indicated to confirm a diagnosis.
Treatment of HD during pregnancy
In selected patients, who present with asymptomatic, early
stage-IA/B or -IIA non-mediastinal HD, treatment may be
deferred until after delivery, especially if diagnosis is made dur-
ing the third trimester. Evens et al. found that standard chemo-
therapy regimens for NHL and HL (without antimetabolites)
administered during the second and third trimester, including
as early as 13 weeks’ gestation in some cases, was associated
with minimal maternal complications or fetal detriment. In
addition, patients with low-risk clinical scenarios (e.g. indolent
NHL, low tumor burden, and/or late gestational diagnosis)
had therapy safely deferred to postpartum. The most common
perinatal events were induction of labor, PROM, and cesarean
delivery in a series of patients diagnosed with Hodgkin’s and
non-Hodgkin’s lymphoma in pregnancy. There were no differ-
ences in events among patients who received antenatal versus
postpartum therapy. The safety of the doxorubicin bleomycin/
vincristine/dacarbazine (ABVD) during pregnancy has been
documented [11, 57, 60]. Similar doses should be given to the
pregnant patient with adjustment for weight gain during preg-
nancy. Chemotherapy during organogenesis in the first trimes-
ter will increase the risk for malformations. If patients require
treatment during the first trimester, consider single-agent treat-
ment with vinblastine or corticosteroids followed by a complete
regimen during second and third trimesters [61]. BEACOPP, a
more intense regimen is not recommended in pregnancy. An
echocardiogram should replace the routinely performed multi-
gated acquisition scan (MUGA) to evaluate cardiac health prior
to giving anthracyclines.
Radiotherapy during pregnancy
Current treatment for HD incorporates chemotherapy, whether
or not followed by radiation therapy on indication [62]. In clini-
cal practice usually radiation therapy will be given after delivery,
hereby avoiding potential harmful fetal effects. Hence, radio-
therapy for HD during pregnancy has been reported to be tol-
erable for the fetus at certain gestational ages [63]. Exposure of
the fetus to radiation is determined by the internal scatter, leak-
age from the tube head, and scatter from the collimator. Internal
scatter depends on the source of radiation, the distance of the
fetus from the source, and the size of treatment fields. Blocks are
not recommended in pregnancy because of the additional scatter
they create. Exposure of the fetus can be estimated with simu-
lated measurements, which have shown that treatment with a
6 MV linear accelerator exposes the fetus to less radiation than
treatment with Cobalt 60 [63]. The highest risk of brain dam-
age and mental retardation is between 8 and 15 weeks’ gestation
[64]. Radiation for HD is usually reserved for cases progressing
despite chemotherapy, masses causing respiratory distress, lym-
phocyte predominant type that requires immediate treatment, or
if chemotherapy is not an option. Radiation can also be consid-
ered in patients diagnosed with isolated and symptomatic supra-
diaphragmatic disease in the first trimester [58].
Treatments for recurrent HL outside pregnancy include plati-
num-based chemotherapy followed by high-dose therapy (HDT)
and an autologous stem cell transplantation.
446
HDT is contraindicated during pregnancy due to significant
risks of fetal toxicity. For relapsed HL in pregnancy, the gesta-
tional age, the status of the disease, and the first-line treatments
previously given should all be taken into account. If the relapse
occurs in early pregnancy, termination of the pregnancy might
become unavoidable. During the second trimester, platinum and/
or gemcitabine-based regimens may be considered. For recurrent
disease presenting in the third trimester, administering a short
course of ABVD awaiting delivery or late preterm delivery should
be considered [65].
Non-Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma (NHL) is rarely reported during preg-
nancy as this generally occurs in an older age group (mean age at
diagnosis is 42 years). NHL refers to a group of lymphoprolifera-
tive diseases (ranging from indolent to aggressive) among which,
diffuse large B cell lymphoma is the most commonly reported,
and often diagnosed at advanced stages [66]. Pregnant women
present with an aggressive histology, but the response to treat-
ment, failure, and progression rates are reported to be similar to
non-pregnant patients [66–68]. Women with NHL in one study
was shown to be at an increased risk for pre-eclampsia, cesarean-
section, preterm births, and postpartum blood transfusions [69].
Symptoms can vary widely, with many complaints and presenta-
tions such as ovarian masses can be similar to symptoms in nor-
mal pregnancy, which can lead to a delay in diagnosis of NHL
in pregnancy. Superior vena cava syndrome can occur in which
the patient will complain of swelling in upper extremity and face
after a long duration of elevation of the arms.
Avoid delay in diagnosis
Pregnant women with NHL can present with breast or ovarian
masses, misleading the initial diagnosis to a gynecologic malig-
nancy. When masses are bilateral and massive in size, one should
suspect NHL, see later in this chapter.
Effects of cancer on the pregnancy and vice versa
NHL does not directly affect pregnancy. However, pregnancy can
affect the presentation of NHL, and some authors report a pro-
gression of NHL postpartum [67, 68]. In some cases, such as lym-
phoproliferative T-cell lymphoma, a component of Epstein–Barr
virus in the etiology of NHL may explain, given the immunosup-
pression of pregnancy, why some cases of NHL seem to progress
more rapidly in pregnant women. The number of cases, how-
ever, is too small to determine if termination of the pregnancy
would improve prognosis. In addition to the typical presentation
of lymphadenopathy, pregnant patients can have involvement of
the breasts, ovaries, and uterus. A hormonal influence of preg-
nancy on the progression of NHL is suggested by the frequent and
massive involvement of such organs during pregnancy, which are
otherwise unusually involved with NHL in non-pregnant patients
[66, 67].
Treatment of NHL during pregnancy
Breast or ovarian masses should not be surgically removed
after biopsy confirms non-Hodgkin’s lymphoma. The masses
will respond to systemic chemotherapy. If a patient presents with
symptomatic disease presents late in the first trimester, a short
course of steroids, with or without cyclophosphamide could be
given as a bridging to full anthracycline regimen after organo-
genesis [70]. In the case of a low disease burden, asymptom-
atic disease, diagnosed during late first trimester, it is possible
to watch and wait until after the first trimester. Standard dose
Maternal-Fetal Evidence Based Guidelines
CHOP (cyclophosphamide, doxorubicin, vincristine, and pred-
nisone) chemotherapy with or without rituximab is the most
common regimen used to treat NHL during pregnancy. EPOCH
(rituximab, etoposide, prednisolone, vincristine, cyclophos-
phamide, doxorubicin) is an alternative. A cohort on 80 NHL
pregnant women, of who 54 (68%) received chemotherapy dur-
ing pregnancy revealed a high incidence of small for gestational
age (SGA) neonates (39%), preterm delivery (52%), obstetric (41%)
and neonatal complications (12.5%), that could not exclusively be
explained by the receipt of antenatal chemotherapy. Rituximab is
often used in non-pregnant patients in addition to chemotherapy
for diffuse large B cell lymphoma in pregnancy. It is a chimeric
IgG 1 antibody, which can cross the placenta (increasing with
gestational age) and interact with fetal B cells. It is unlikely that
rituximab has any mutagenic potential and no infectious conse-
quences have been reported in over 200 exposures in pregnancies
[71]. Infants exposed to rituximab in pregnancy initially had a
period of low IgG and absent B cells, but B-cell counts normal-
ized by 4 months after birth and the period with low IgG might
not have been longer than average [72]. The newborn’s immune
reaction to vaccinations was uninterrupted [73]. It should be
used during pregnancy with caution, balancing maternal survival
benefits and fetal risks. Asymptomatic indolent NHL such as fol-
licular or mucosa-associated lymphatic tissue (MALT) are closely
observed and not treated during pregnancy. If symptoms occur,
single agent rituximab has been used.
Leukemia
Acute leukemia
Acute leukemia is rarely diagnosed during pregnancy as affected
women usually have amenorrhea.
Avoid delay in diagnosis
Pregnant women with leukemia can present with severe anemia,
fatigue, thrombocytopenia, neutropenia, infection or sepsis,
fever, bone pain, or bleeding. Physical exam can be significant for
ecchymoses and petechiae, lymphadenopathy, or splenomegaly.
Diagnostic tests and safety in pregnancy
Bone marrow biopsy can be safely performed during pregnancy.
Termination of pregnancy issues
Termination of pregnancy has not been shown to improve prog-
nosis but may be a clinically relevant option for pregnant women
diagnosed during the first trimester as chemotherapy cannot be
delayed until after 12 weeks’ gestation. Patients newly diagnosed
with acute leukemia are too ill to safely undergo a dilatation
and curettage procedure even when termination is elected
without first undergoing induction chemotherapy. It is sug-
gested to start therapy before termination to induce remission so
that the procedure can be safely performed. The patient is other-
wise at too high a risk for the complications such as infection and
sepsis, uterine perforation and hemorrhage, and disseminated
intravascular coagulation (DIC).
Effects of cancer on the pregnancy
Acute leukemia is one of the cancers which can affect perinatal
outcome. The earlier the diagnosis is made in pregnancy, the
higher the perinatal mortality. Pregnancies complicated by acute
leukemia are at higher risk for miscarriage, intrauterine fetal
demise, preterm labor, and fetal growth restriction, unrelated to
cancer treatment [9, 74]. Suspected etiologies include maternal
anemia, DIC, or leukemic cells affecting blood flow and nutrient
Cancer
exchange in the intervillous spaces of the placenta, and decreased
oxygen transport to the fetus [74]. When intensive chemotherapy
is given in pregnancy, complete remission is achieved in 75% of
patients and survival is comparable to matched non-pregnant
women [74].
Treatment of cancer during pregnancy:
Chemotherapy, radiation therapy
Aggressive hematologic and obstetric management is advocated
when acute leukemia is diagnosed.
Lymphoblastic leukemia
All lymphoblastic leukemias are treated with multi agent che-
motherapy including anthracyclines, vinca alkaloids, steroids,
cyclosphosphamide, L-asparagenase and intrathecal methotrex-
ate for CNS prophylaxis. Intrathecal methotrexate use in preg-
nancy is not recommended before 20 weeks due to reports of
mental and physical disabilities when administered at early gesta-
tional stages of development [75]. The prognosis for both mother
and fetus is poor when acute leukemia is not treated during
pregnancy. Without therapy, maternal death may occur within
2 months [74]. Chemotherapy treatment during pregnancy is
associated with higher maternal and fetal/neonatal survival com-
pared to postponing chemotherapy until postpartum [74]. All
cases with anomalies occurred with first-trimester exposure to
cytarabine or 6-thioguanine, alone or in combination with an
anthracycline. Cytarabine and 6-thioguanine should be avoided
in the first trimester if possible. Combinations including vincris-
tine, 6-mercaptopurine (6-MP), doxorubicin or daunorubicin,
cyclophosphamide, prednisone, and methotrexate were used in
all trimesters without anomalies. Transient myelosuppression
can occur in neonates, especially if delivered within 3–4 weeks of
chemotherapy [8, 76]. More rarely, transient neonatal cardiomy-
opathy has been reported. Cardiomyopathy occurred mostly after
use of idarubicin [5, 6]. Iatrogenic preterm deliveries or elective
inductions should be avoided before induction of chemotherapy
is attempted, as the patient with acute leukemia is at risk for hem-
orrhage, DIC, and sepsis during labor and delivery if lacerations,
uterine atony or endometritis occurs.
AML acute myeloid leukemia
Leukemic blasts can accumulate in peripheral blood causing sig-
nificant leukocytosis which occludes the vasculature and can lead
to respiratory or neurologic disease. This can be further aggra-
vated by pregnancy. Treatment may require urgent leukapheresis
at any gestational age [77]. Chemotherapy after the first trimes-
ter would be similar to regimens used for non-pregnant women
including cytarabine and an anthracycline. For concerns with
idarubicin mentioned previously, daunorubicin is recommended
instead of idarubicin in pregnancy.
APL acute promyelocytic leukemia
Patients can present with DIC. All trans-retinoic acid, ATRA, is
an important component of therapy to control DIC in APL and
has been safely used during pregnancy [78–80]. ATRA is given
with daunorubicin. The response seen with ATRA alone versus
with daunorubicin is not significant, however, it may impact
relapse rate. Being similar to retinoid, ATRA is contraindicated
during the first trimester. A serious side effect of ATRA is differ-
entiation syndrome (unexplained fever, respiratory distress due
to capillary leak) and is treated with steroids. Arsenic trioxide,
also used with ATRA in non-pregnant women, is also teratogenic
447
during first trimester. There are limited case reports of safe use of
arsenic in the second and third trimesters [81–83].
Chronic leukemia
Pregnancy does not alter the natural course of chronic leuke-
mia, but there are potentially perinatal risks of placental insuf-
ficiency secondary to leukostasis, as well as maternal risks if left
untreated. Diagnosis usually occurs in the fifth decade of life, so
is rarely diagnosed during pregnancy. Patients with CML who
conceive while taking imatinib are advised to discontinue use
during pregnancy, with the majority of patients able to regain
remission status postpartum [84].
Treatment of chronic leukemia in pregnancy
Treatment of severe leukocytosis is necessary to reduce maternal
risk of stroke hypoxia, deep venous thrombosis (DVT). There are
case reports of observation alone during pregnancy in patients
without splenomegaly. Leukophoresis can be a temporizing mea-
sure to reduce WBC and spleen size if necessary [85]. Tyrosine
kinase inhibitors such as imatinib, the newest advance in the
treatment of chronic leukemia in non-pregnant adults, has been
shown to cause teratogenic effects in rats, including exencephaly
or encephalocele and absent or reduced frontal and absent pari-
etal bones. If a pregnant patient newly diagnosed with CML is
symptomatic with splenomegaly, with no clinical response to leu-
kapheresis or other medications and is beyond the first trimester,
imatinib would be preferred over second generation tyro-
sine kinase inhibitors such as dasatinib or nilotinib. Reports
show imatinib is 95% bound to plasma proteins with a molecular
weight of 590 which suggests low placental transfer. Case reports
of tyrosine kinase inhibitor imatinib during pregnancy beyond
the first trimester have been reassuring with prompt responses in
pregnancy [86–89].
Melanoma
One-third of women diagnosed with malignant melanoma are
of childbearing age. Slingluff reported that pregnancy at diag-
nosis was significantly associated with metastatic disease when
controlling for tumor site, thickness, and Clark level, still with
survival not significantly decreased for pregnant patients [90].
When pregnant patients are matched to non-pregnant controls
for prognostic factors such as tumor thickness, there is no signifi-
cant difference in survival rates for pregnant women with stage-I
melanoma [91, 92].
Avoid delay in diagnosis
Pregnant women are diagnosed with thicker tumors compared to
non-pregnant women. This (as well as the increase in metastatic
disease) has been ascribed to a delay in biopsy leading to delayed
diagnosis when changes in moles’ appearances are ascribed to
pregnancy or the surgeon is hesitant to perform a biopsy dur-
ing pregnancy. Hyperpigmentation can occur secondary to an
increased secretion of melanocyte-stimulating hormone (MSH);
however, the color of the mole should still be uniform, and benign
moles should not cause itching. Maximum increases/decreases in
the size of melanocytic nevi in pregnancy is 1 mm [93]. During
pregnancy, one must still look for signs of melanoma, which
should not be ascribed to normal changes in pregnancy. These
signs include the ABCD signs: A for asymmetry; B for notched,
irregular, or indistinct borders; C for an uneven color; D for diam-
eter greater than 6 mm. Again, itching of a mole can be an early
sign of malignant melanoma.
448
Effects of cancer on the pregnancy
Melanoma is one of the rare cancers that can metastasize to the
placenta. Approximately 100 cases of placenta/fetal metastasis
have been reported in the literature (all tumor types) [94, 95]. The
largest percentage (31%) was in cases of maternal melanoma [96].
Women presenting with placental metastases usually have wide-
spread disease and poor prognosis [97]. The placenta should be
sent for pathologic evaluation in all cases of melanoma diagnosed
during pregnancy. If melanoma is found in the placenta, the
neonate should be followed closely for 1 year with frequent skin
evaluations.
Termination of pregnancy issues
No advantage in prognosis or survival has been demonstrated
with elective pregnancy termination in patients with stage-I
melanoma.
Surgery during pregnancy
Wide local excision can be safely performed during pregnancy
at any gestational age. Patients should be positioned with uterine
displacement after 20 weeks’ gestation. See sentinel node biopsy
next.
Staging and sentinel node biopsy
Sentinel node mapping can be safely performed during pregnancy
with Tc-99 sulfur colloid. Intradermal injection of technetium-
labeled sulfur colloid exposes the fetus to negligible ionizing
radiation. The majority of the dose stays localized to the injection
site or within the lymphatics until decay occurs. For stage-I or -II
melanoma, a chest x-ray is indicated for staging if the melanoma
is greater than 1.0-mm thick. For stage-III disease, an MRI of the
chest, abdomen with or without the pelvis is additionally recom-
mended for evaluation of lymphadenopathy or evidence of liver
metastases. MRI of the brain and skeleton is also recommended.
Treatment of melanoma during pregnancy
After wide local excision and evaluation of regional lymph nodes,
dacarbazine chemotherapy has not been shown to significantly
prolong survival. Recent research of targeted and immune thera-
pies for patients with advanced melanoma has improved progres-
sion free and overall survival. Young patients with melanoma
are more likely to have BRAF oncogene mutations which can be
targeted by vemurafenib and dabrafenib. Experience with these
agents during pregnancy is limited to few case reports. In one
patient, vemurafenib was started at 25 weeks for metastatic
melanoma with shrinkage of the tumor and normalization of
transaminases. Fetal growth restriction was diagnosed prior to
starting medication which didn’t improve with tumor response.
An iatrogenic preterm delivery occurred at 30 weeks without
complications for the newborn. Less than 50% of maternal serum
concentration was detected in cord and neonatal blood [98].
Unfortunately, another patient treated with vemurafenib during
pregnancy developed a serious drug-related anaphylactic reac-
tion. Vemurafenib was started at 22 weeks for widespread recur-
rent metastatic melanoma. The patient developed mild skin rash
in 12 days and continued the medication, this then progressed in
the next 9 days to toxic epidermal necrolysis (TEN). The twins,
spontaneously delivered at 26 weeks, were appropriately grown
and were developmentally normal at 15 months of age [99].
Tragically, the patient died of intracranial hemorrhage due to
metastases a few days after giving birth. Of note, vemurafenib
contains a sulfonamide group; cross-reactivity to sulfonamide
Maternal-Fetal Evidence Based Guidelines
compounds has been reported in allergic patients. Vemurafenib
may cause TEN alone or in relation to concomitantly/previously
used checkpoint inhibitor drugs [100].
Burotto reported normal development of an infant at 11 months
of age whose mother was treated with check point inhibitors ipi-
limumab (anti CTLA4) and nivolumab (anti PD-1) starting at 9
weeks x4 cycles for recurrent metastatic melanoma stage IV [101].
Masses decreased in size during pregnancy however autoimmune
hepatitis developed. An iatrogenic PTB occurred at 32 weeks.
Monoclonal antibodies are known to cross at higher rates late in
the third trimester, how much a preterm delivery contributed to
this reassuring outcome for the neonate is unknown. Mehta also
reported normal development at 32 months after exposure to ipi-
limumab including during the first trimester [102].
Ovarian cancer
Ovarian cancer in pregnancy is often diagnosed at early stages
due to detection of masses during routine prenatal ultrasounds.
Surgery, staging and treatment
Masses should be removed for the same indications as in non-
pregnant women-solid areas, suspicious borders or excrescences,
septations, i.e. a complex appearance (see also Chapter 33 in
Obstetric Evidence Based Guidelines). Laparoscopy is preferred
to laparotomy for ovarian cysts in pregnancy and unilateral sal-
pingo-ophorectomy is preferred to cystectomy to avoid cyst rup-
ture in case of suspicious mass. If bilateral salpino-ophorectomy
is required before the 14th week of gestation, progesterone should
be administered since placental function is not yet well developed.
Staging procedures during pregnancy may include infracolic
omentectomy, appendectomy, pelvic-peritoneal biopsies and
lymph nodes. A general recommendation is that, if the pelvic
peritoneum and the pouch of Douglas cannot be reliably exam-
ined during surgery because of the enlarged dimension of the
uterus and the limited possibility to manipulate it, restaging sur-
gery should be planned postpartum [103].
Chemotherapy during second and third trimester is deter-
mined based on histologic type of ovarian cancer. Cisplatin
carries a risk of presumed dose-dependent ototoxicity in children
that were exposed during pregnancy [104]. Carboplatin is pre-
ferred for gynecological malignancies except for germ cell can-
cers, in which a cisplatin-based schedule is standard of care.
Invasive cervical cancer
Invasive carcinoma of the cervix occurs in approximately 1 out of
2200 pregnancies. Tumor characteristics and maternal survival are
not adversely affected by pregnancy, in fact pregnant women are
more likely to be diagnosed with earlier-stage disease as cervical
screening is routine during prenatal care. Post-coital bleeding is
also reported as a presenting symptom in pregnant patients. The
predominant histologic type is squamous cell. Prognosis is compa-
rable to non-pregnant patients [105, 106]. (For non-invasive cervi-
cal cancer, see Chap. 34 in Obstetric Evidence Based Guidelines).
Avoid delay in diagnosis
When pregnant patients complain of vaginal bleeding, the cervix
should be visualized for lesions.
Diagnostic tests and safety in pregnancy
The cytobrush can be safely used during pregnancy to obtain an
adequate Papanicolaou screen during prenatal care. Pregnant
patients should be warned of the possibility of bleeding afterwards.
Cancer 449

Effects of cancer on the pregnancy
Cervical cancer does not adversely affect pregnancy directly;
however, cancer treatment affects future fertility if hysterectomy
is indicated.
Termination of pregnancy issues
A spontaneous loss of the pregnancy may occur when treatment
for cervical cancer is initiated for patients diagnosed prior to 18
weeks’ gestation.
Considerations regarding therapy during
pregnancy for cervical cancer
When opting not to preserve pregnancy: The gestational age
at diagnosis determines the management choices for the preg-
nant patient. For operable disease (IA2-IB2) a radical hyster-
ectomy with fetus in utero, or after hysterotomy (late second
trimester), can be performed [21]. For stages IB3 and higher
diagnosed before 18 weeks, immediate chemoradiotherapy
treatment is recommended with the fetus in situ. Often a
spontaneous miscarriage will occur within a short time after
radiotherapy. With advanced pregnancy, a pregnancy termi-
nation by hysterotomy is preferred, as it reduces the risk of
obstetrical complications (bleeding, rupture of the cervix,
DIC) and the psychological impact on the patient [21]. Prior to
treatment, a feticide can be considered for ethical and psycho-
logical reasons.
Staging of cervical cancer during pregnancy
Tumor size and evaluation of regional lymph nodes are impor-
tant prognostic factors in patients with cervical cancer. MRI can
identify enlarged lymph nodes. MRI can also detect depth
of stromal invasion, involvement of the parametria, and a
dilated collecting system, but should not be relied upon to
predict nodal metastases.
pregnancy this procedure is discouraged. A cone biopsy may be
used to treat IA1 tumors without lymphovascular space invasion.
For stage IA1 with lymphovascular space invasion, IA2 and IB1,
staging lymphadenectomy should be performed as a first step.
Standardized pelvic lymphadenectomy (P-LND) in patients with
cervical cancer during the first and second trimester under 22
weeks of pregnancy, is a safe procedure with good oncological
and obstetrical outcomes [107]. The survival outcomes for preg-
nant women and their children when hysterectomy for cervical
cancer is intentionally delayed for 6–17 weeks is very good, with
fetal outcomes markedly improved by avoiding preterm births
while maternal survival is not adversely affected by delayed sur-
gery [108].
Treatment for invasive cervical cancer involves either sur-
gery, radiation or both, depending on the stage at diagnosis
(Figure 44.2). Neoadjuvant chemotherapy for invasive cervical
disease may be given during the second and third trimesters of
pregnancy for patients with positive nodes [109, 110]. See also
Chapter 34 in Obstetrics Evidence Based Guidelines.
Delivery for patients with invasive
cervical cancer during pregnancy
In the majority of cases, a cesarean section is advised with radi-
cal hysterectomy performed simultaneously. A classical cesar-
ean delivery is recommended to avoid extension into the lower
uterine segment [111]. At the time of cesarean section pelvic and
para-aortic nodes should be sampled, and an oophoropexy can
be performed to move the ovaries out of the planned radiation
field. Presurgical consultation with a radiation oncologist is sug-
gested prior to delivery. Episiotomy site recurrences of cervical
cancer have been reported for women diagnosed with invasive
cervical cancer during pregnancy who delivered vaginally [112].
Microinvasion of the cervix is not a contraindication to vaginal
delivery.

Surgery for cervical cancer Thyroid cancer

diagnosed during pregnancy The mean age of diagnosis for thyroid cancer is between
Radical trachelectomy during pregnancy carries too high a 30 and 34 years of age, with most cases in pregnancy pre-
risk for maternal and or fetal complications therefore during senting as a solitary nodule [113]. There is no evidence that

IA2, IB1 <2 cm IB1 >2 cm IB2 and higher

<22 weeks >22 weeks <22 weeks >22 weeks <22 weeks >22 weeks

PLND NAC NAC NAC NAC

or PLND NAC or or or
DTAD DTAD TER DTAD
Positive Negative
Positive Negative
TER ST
or or TER NAC
NAC DTAD or
NAC

FIGURE 44.2 Guidelines for cervical cancer diagnosed during pregnancy. (From Halaska MJ, Rob L, Robova H, Cerny M.
Treatment of gynecological cancers diagnosed during pregnancy. Future Oncol 2016;12(19):2265–2275. Ref. [111], with permission.)
Abbreviations: DTAD, delayed treatment after delivery; PLND, pelvic lymph node dissection; NAC, neoadjuvant chemotherapy; TER,
termination of pregnancy; ST, simple trachelectomy
450
pregnancy changes the clinical course of the disease, and no
evidence that thyroid cancer adversely affects pregnancy out-
come. The prognosis of differentiated thyroid cancer is the
same in pregnant and non-pregnant women [114]. No endo-
crine association between maternal hormonal changes and
thyroid cancer has been found. Treatment depends on histo-
logic subtype, degree of differentiation, stage, and gestational
age at diagnosis.
Avoid delay in diagnosis
The thyroid can enlarge during normal pregnancy, but solitary
nodules should be evaluated.
Diagnostic tests and safety in pregnancy
Ultrasound is used to screen abnormal physical findings of the
thyroid during pregnancy. If microcalcifications, irregular mar-
gins, hypoechoic masses or other radiologic malignant signs are
seen, a biopsy of any suspicious nodule can be safely performed
during pregnancy at any gestational age.
Termination of pregnancy issues
Elective termination of pregnancy for thyroid cancer is not asso-
ciated with any survival advantage.
Surgery during pregnancy
The histologic type of thyroid cancer and the gestational age at
diagnosis determine if thyroidectomy is necessary during preg-
nancy or can be safely postponed until postpartum. Papillary is
the most common type. See next section.
Treatment of thyroid cancer during pregnancy
Differentiated types of thyroid cancer such as papillary, follicu-
lar, or mixed types are slow growing, and surgery can be post-
poned until postpartum for patients diagnosed after 12 weeks’
gestation. Total thyroidectomy is reserved for large tumors and
lymph node dissection depends on tumor size and involvement
of lymph nodes. Prior to 12 weeks, a subtotal thyroidectomy
is recommended [115]. If a nodule is noted to enlarge during
pregnancy, if the surrounding tissues are fixed, or lymphatic
invasion is seen on the original biopsy, surgery should not be
delayed to postpartum, regardless of the gestational age at diag-
nosis. Patients who delay treatment due to pregnancy should be
advised to undergo surgery within 1 year of diagnosis [116]. If
differentiated thyroid cancer is detected and surgery is to be
postponed to postpartum, it is advised to start levothyroxine
(LT4) therapy. This aims to keep TSH levels below 0.1–1 mU/l.
If surgery is done during pregnancy, then LT4 must be started
immediately after [97].
Medullary or anaplastic types of thyroid cancer are more
aggressive, and surgery should not be postponed. The risk of
spread to regional lymph nodes is higher than with well dif-
ferentiated thyroid cancers. A total thyroidectomy with lymph
node dissection is necessary. Ultrasound or MRI can detect
disease in the lateral neck. If the lesion is compromising the
airway, radiotherapy may be necessary during pregnancy. After
total thyroidectomy, levothyroxine should be started [117,
118]. During total thyroidectomy, parathyroid tissue is often
inadvertently removed as well. For the remainder of the preg-
nancy and during delivery, calcium balance should be watched
carefully. When magnesium is given for preterm labor or pre-
eclampsia calcium levels should be followed as should symp-
toms of hypocalcemia.
Maternal-Fetal Evidence Based Guidelines
For all cancer types diagnosed
during pregnancy
Complications of cancer therapy
During chemotherapy, side effects such as nausea and vomiting
can occur, and can compound the nausea related to the preg-
nancy. Ondansetron, metoclopramide, Kytril, and Benadryl can
be safely given for nausea. Corticosteroids can also be given
to enhance the effectiveness of antiemetics (see section Fetal
Surveillance and Timing of Delivery). The use of hydrocorti-
sone and prednisolone is preferred over dexa- or betametha-
sone as these are extensively metabolized in the placenta.
Repeated administrations of betamethasone are associated
with attention problems and cerebral palsy [119]. A common
complaint during or immediately after chemotherapy sessions
is uterine contractions. Patients should be well hydrated before,
during, and after chemotherapy sessions. Given the relative
immunosuppression of pregnancy, combined with the bone
marrow suppression with chemotherapy, pregnant women are
at risk for infection, and therefore the fetuses are at risk for
exposure as well. Several authors reported normal newborn
outcomes at birth after late trimester exposure to Neupogen/
Neulasta for various maternal indications [120–124]. In a ret-
rospective review of cancer cases treated during pregnancy, the
perinatal well-being of 34 newborns exposed to chemotherapy
with Neupogen (filgrastim) or Neulasta (pegfilgrastim) was
compared to 142 newborns exposed to chemotherapy alone,
no significant differences were seen in gestational age at birth,
congenital anomalies, or birth-weight, mean WBC, or neutro-
penia at birth or incidence of long-term medical issues between
groups [125].
Given that many pregnant women maintain white blood cell
counts despite chemotherapy, one can consider using Neupogen
(filgrastim) or Neulasta (pegfilgrastim) during pregnancy once
neutropenia is demonstrated, rather than prophylactically as in
the non-pregnant setting.
Another complication can be poor maternal weight gain due to
either nausea and vomiting, or chemotherapy-induced stomatitis.
Patients should increase caloric and protein intake in the weeks
preceding and following chemotherapy. Nutritional supplemen-
tation is sometimes necessary. Theoretically additional antioxi-
dants should not be supplemented with the prenatal vitamin as
free radicals are supposed to be created by the chemotherapy and
this may impede its therapeutic effect.
Maternal surveillance
An echocardiogram is preferred over a MUGA scan to evaluate
baseline cardiac function prior to anthracycline therapy. This
can provide the necessary information regarding cardiac func-
tion and valvular disease. Patients who experience fever during
chemotherapy require comprehensive evaluations for presence of
infection, especially during the nadir period. Monitor weight gain
throughout pregnancy.
Fetal surveillance and timing of delivery
If the patient requires tocolysis for preterm labor, steroids such
as dexamethasone/betamethasone can considered to stimu-
late fetal maturity. However, if dexamethasone/betamethasone
was already administered with chemotherapy to enhance the
effectiveness of antiemetics, this drug should not be repeated.
The fetal/neonatal safety of repeated doses of steroids has not
been demonstrated and repeated courses of steroids are not
Cancer
currently recommended (see Chap. 19 in Obstetrics Evidence
Based Guidelines).
The preterm infant cannot metabolize the chemotherapy agents
as well as the term infant, therefore, iatrogenic preterm deliveries
should be avoided in patients receiving chemotherapy, and pre-
term labor should be treated with a low threshold. Chemotherapy
may need to be temporarily withheld/delayed if the patient has
preterm labor. Growth ultrasounds in the late second and third
trimesters are suggested for women receiving chemotherapy dur-
ing pregnancy, especially for patients diagnosed with acute leuke-
mia, given the increased risk of intrauterine growth restriction.
Transient bone marrow suppression of the neonate can occur
if delivery is within 3–4 weeks of treatment [8]. Chemotherapy
should not be given after 34 weeks as the patient could potentially
go into spontaneous labor during the nadir period. If additional
treatment is still required, one can consider a late preterm induc-
tion so that the interval between the last treatment in pregnancy
and the postpartum treatment is not greater than 6 weeks (e.g.
if treatment is 33 weeks, consider induction at 38 weeks so that
1 week afterward the patient can resume chemo with a 6-week
interval between last treatment during pregnancy and postpar-
tum treatment).
Fetal/Neonatal evaluation after
chemotherapy during pregnancy
Long-term follow-up of children exposed to chemotherapy is lim-
ited but ongoing. A case series of neurodevelopmental follow-up
for a mean of 18 years on 84 children exposed in utero to vari-
ous types of chemotherapy for maternal hematologic malignancy
shows that their clinical health status is comparable to their
unexposed siblings [11]. All displayed normal growth, develop-
ment, neurologic function, and school performance. Cytogenetic
studies were normal. Neurological, intellectual and visual-motor
assessments were no different for exposed children compared to
their siblings and unrelated controls. No cancer has been diag-
nosed in any of the children, and 12 children exposed in utero
have now had their own children. All second-generation chil-
dren were normal in appearance but did not undergo the same
rigorous testing as their parents [11]. Drs. Amant, Calsteren and
Halaska et al. reported a prospective study on the developmen-
tal outcomes of 70 children exposed to cancer treatment in utero
[126]. Children were assessed for cognitive performance and
compared to population norms. The children showing delays in
development were concentrated in the group delivered preterm,
the majority of which were iatrogenically delivered prematurely
[126]. In another prospective follow-up study of children exposed
to chemotherapy in utero, no significant differences were noted
in cognitive ability, school performance, or behavioral compe-
tence for children exposed to chemotherapy in utero compared
with non-exposed controls (also born to women diagnosed with
cancer during pregnancy). Ninety-five percent scored within
normal limits on cognitive assessments; 71% and 79% of chil-
dren demonstrated at or above age equivalency in mathematics
and reading scores, respectively [127]. Amant at al. evaluated 96
children exposed to chemotherapy (alone or in combination with
other treatments), 11 to radiotherapy (alone or in combination),
13 to surgery alone, 2 to other drug treatments for cancer, and 14
untreated in pregnancy and compared the outcomes with age-
and sex-matched children born from uncomplicated pregnancies.
There was no significant between-group difference in cognitive
development on the Bayley scores. The gestational age at birth
was correlated with the cognitive outcome in the two study
451
groups. Cardiologic evaluation among 47 children at 36 months
of age showed normal cardiac findings [128]. An updated analy-
sis of the INCIP cohort (n = 132) at the age of 6 years confirmed
overall reassuring cognitive and cardiac outcomes compared
to the control group [129]. Although within normal ranges, a
statistical significant lower verbal IQ and lower visuospatial
long-term memory scores, as well as higher diastolic blood
pressure was observed in the exposed group. Interestingly, in
a post-hoc analysis, the difference of verbal intelligence was
more distinct in the group of children who lost their mother
to cancer. Hence, detection of verbal development delays and
early psychosocial stimulation to prevent underdevelopment
could be considered. In a group of 21 newborns exposed to
anthracycline/cyclophosphamide-based chemotherapy in utero,
no differences in fetal brain growth were found compared to a
group of healthy controls [130]. A cohort study on 20 children
prenatally exposed to chemotherapy and 20 healthy controls
revealed an effect of prenatal exposure to chemotherapy on the
development of executive functioning [131]. Hence, long-term
follow-up until adulthood is recommended.
The placenta should be sent for pathology examination in
all cases of women diagnosed with cancer during pregnancy,
regardless of cancer type or treatment. Placental metastasis are
very rare and are most often seen in malignancies with particular
invasive properties, such as melanoma. A complete blood count
with differential is recommended on either the cord blood or the
neonate when chemotherapy has been given during pregnancy.
Additional long-term follow-up on the children exposed to can-
cer and its treatment in utero is ongoing. Two cancer and preg-
nancy registries are established to follow all mother/child pairs
after a diagnosis of cancer during pregnancy. Information about
cancer diagnosis, treatment, pregnancy outcomes, and long-term
neonatal health and maternal survival is collected and kept confi-
dential. Contacting the Cancer and Pregnancy Registry: 1-877-
635-4499 or Cancerinpregnancy.com (and the International
Network on Cancer, Infertility, and Pregnancy [INCIP] at
www.cancerinpregnancy.org).
Cancer diagnosed before pregnancy
General principles
Pregnancy after chemotherapy
The Childhood Cancer Survivor Study compared pregnancy out-
come in 5-year female cancer survivors who were less than 21 years
old at diagnosis, with pregnancy outcomes in their sibling con-
trols [132]. The most frequently used agents were cyclophospha-
mide, doxorubicin, vincristine, dactinomycin, and daunorubicin.
Over 1900 females reported 4029 pregnancies. There were no sig-
nificant differences in pregnancy outcome between patients who
had received chemotherapy and controls. Additional case control
series did not show any adverse effect of prior chemotherapy on
the risk of miscarriage, fetal growth, congenital malformations
and development, fetal demise, or uterine function [132–138].
Hartnett et al. found that cancer type may influence perinatal
complications. Authors looked at diagnoses from cancer regis-
tries and linked cancer types to pregnancy outcomes from birth
certificates in three U.S. states, limiting analyses to the first, live
singleton birth conceived after diagnosis. Births to women with-
out a previous cancer diagnosis in the registry were matched to
cancer survivors for age at delivery, parity, race/ethnicity and
education. Risk ratios were estimated using log-binomial regres-
sion. Survivors of cervical cancer had higher risks of preterm
452
birth (Risk ratio [RR] 2.8, 95% CI 2.1-3.7), as did survivors of inva-
sive breast cancer (RR 1.3, 95% CI 1.1-1.7) and leukemia (RR 2.1,
95% CI 1.3-3.5). A higher risk of small for gestational age (SGA)
infants (<10% of weight for age based on a national distribution)
was found in survivors of brain cancer (RR 1.7, 95% CI 1.1-2.8) and
extranodal non-Hodgkin lymphoma (RR 2.3, 95% CI 1.5-3.6).This
may indirectly be related to radiation exposure which has been
shown in other studies to influence neonatal weight at birth [139].
An increased risk of infants born preterm, low birth-weight, or
SGA was not seen in pregnancies conceived after thyroid cancer,
melanoma, or Hodgkin lymphoma.
Chemotherapy-induced cardiac toxicity
We suggest that women who received anthracyclines (dauno-
rubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone)
undergo cardiac evaluation prior to pregnancy [140].
Pregnancy after radiation
Pregnancy in women who have received prior pelvic irradiation
appears to be associated with complications such as miscar-
riage, preterm labor and delivery, low birth weight, impaired
fetal growth, placenta accreta, and stillbirth [132, 141–145].
Hypotheses for these complications include changes in the uter-
ine vasculature and its response to cytotrophoblast invasion, or
decreased uterine elasticity and volume from radiation-induced
myometrial fibrosis. These responses to radiation, especially
if before puberty, can affect fetoplacental blood flow or result
in a small uterine size leading to preterm labor and delivery. In
addition, radiotherapy may injure the endometrium and pre-
vent normal decidualization, resulting in disorders of placental
attachment, such as placenta accreta or percreta [143, 144].
In the Childhood Cancer Survivor Study, compared with the
children of survivors who did not receive any radiotherapy, the
children of survivors treated with high-dose radiotherapy to
the uterus (>500 cGy) were at significantly increased risk of pre-
term birth (50.0% vs. 19.6%), low birth weight (36.2% vs. 7.6%),
and small for gestational age (18.2% vs. 7.8%). These risks were
also noted at lower uterine radiotherapy doses (starting at 50 cGy
for preterm birth and at 250 cGy for low birth weight) [132]. In
a cohort study comparing female survivors of childhood cancer
who received abdominal radiation with survivors who did not,
treatment with abdominal radiation therapy was associated with
a threefold increased risk of gestational diabetes and twofold
increased risk of anemia complicating pregnancy [134]. In addi-
tion, women who received radiation therapy for Wilms tumor had
a threefold increased risk of hypertension in pregnancy. Possible
mechanisms include interstitial renal disease and pancreatic islet
cell injury as result of the radiation fields.
Radiation-induced cardiac toxicity due to fibrosis
The clinical spectrum of cardiac injury resulting from radia-
tion includes delayed pericarditis that can present abruptly or as
chronic pericardial effusion or constriction; pancarditis, which
includes pericardial and myocardial fibrosis with or without endo-
cardial fibroelastosis; cardiomyopathy; coronary artery disease,
and functional valve injury and conduction defects [146]. Women
with a history of prior thoracic radiation therapy (including
left-sided breast cancer) should undergo a baseline echocardio-
gram and electrocardiogram prior to pregnancy to detect sub-
clinical radiation-induced cardiac sequelae. Consultation with a
cardiologist is advised if the echocardiogram is abnormal or an
arrhythmia is noted.
Maternal-Fetal Evidence Based Guidelines
Patients who have undergone mediastinal/mantle radiation
such as after Hodgkin’s disease may be at risk for hypothy-
roidism and should have thyroid function studies performed
at initial prenatal visit.
Children of cancer survivors: No
increased risk for cancer
The offspring of cancer survivors are not at increased risk for can-
cer unless the tumor suffered by the parent was a component of
an inherited syndrome, such as retinoblastoma [147–149].
Pregnancy after cancer: Risk of recurrence?
With the possible exception of gestational trophoblastic disease,
pregnancy does not affect the risk of recurrence of any type of
cancer, although the diagnosis may be delayed because of the
pregnancy. In particular, recurrence of melanoma [150, 151] and
breast cancer [152–154] appear to be unaffected by a subsequent
pregnancy.
Pregnancy after specific cancers
Aside from a history of choriocarcinoma, a pregnancy subse-
quent to cancer treatment should not increase a woman’s risk for
cancer recurrence or death.
Pregnancy after breast cancer
Breast cancer being hormonally driven, is the most common
cancer for which women hesitate to have subsequent pregnan-
cies. Reports suggest that a subsequent pregnancy after treatment
of early-stage breast cancer has a favorable impact on survival
[155–158]. Prognosis is determined by nodal status and stage,
not subsequent pregnancy [159]. In one series, 94 women with
early-stage disease who became pregnant after breast cancer
were compared to 188 breast cancer survivors without subse-
quent pregnancies matched for nodal status, tumor size, age, and
year of diagnosis [158]. The risk ratio for death was significantly
lower (0.44) for women who became pregnant subsequent to the
diagnosis of breast cancer compared to women with breast can-
cer who did not have a subsequent pregnancy. Sankila (RR 0.2
95% CI [0.1–0.5]) and Mueller (RR 0.54 95% CI [0.41–0.71]) also
showed a decreased risk of death for women with subsequent
pregnancy after breast cancer compared to controls matched
for age, stage, and year of diagnosis [149, 160]. Even for women
with a history of estrogen receptor positive breast cancer, a sub-
sequent pregnancy was not deleterious for survival status. In a
multicenter retrospective cohort study, 333 pregnant patients
and 874 matched non-pregnant patients were analyzed, of whom
686 patients had ER-positive disease. No difference in disease
free survival was observed between pregnant and non-pregnant
patients in the ER-positive (HR 0.91; 95% CI 0.67–1.24, p 0.55)
or the ER-negative (HR 0.75; 95% CI 0.51–1.08, p 0.12) cohorts
(median follow-up 4.7 years) [161]. Updated survival analysis of
the same cohort, with a median follow-up of 7.2 years, confirmed
these reassuring outcomes [162]. This cohort did not demonstrate
a protective effect from pregnancy subsequent to the diagnosis of
breast cancer [161]. Breast cancer survivors on endocrine therapy
such as tamoxifen may not wish to delay pregnancy for 5 years
to complete the suggested course. Ongoing trials are attempting
to answer the safe time interval for elective interruption of hor-
monal therapy to pursue pregnancy (e.g. POSITIVE trial).
Birth control should be strongly advised while survivors
are taking tamoxifen and trastuzumab. There have been case
reports of ambiguous genitalia and Goldenhar syndrome in chil-
dren exposed to tamoxifen in utero [163, 164]. Animal studies
Cancer
show rib abnormalities, metaplastic and dysplastic changes in
the epithelium of the uterus and reproductive tract similar to
DES, growth restriction, and death [164–166]. A recent litera-
ture review reported an increased incidence of fetal abnormali-
ties following prenatal exposure to tamoxifen (12.6% vs. 3.9% in
the general population), however no causal relationship could be
established [167]. As a consequence, the authors suggest that the
use of tamoxifen during pregnancy should not be absolutely con-
traindicated and patients should be counseled on disadvantages
of both discontinuing or postponing treatment. Pregnancies
exposed to trastuzumab have been complicated by reversible
oligohydramnios and fetal renal insufficiency [50–55, 168, 169].
Trastuzumab is able to cross the placenta by active transport
from the second trimester of pregnancy onwards. For women
who become accidentally pregnant while taking trastuzumab and
wish to continue pregnancy, trastuzumab should be stopped and
pregnancy could be allowed to continue.
Aside from issues pertaining to estrogen receptor status and
the role of 5–10 years of tamoxifen use for ER+ tumors (see previ-
ous section), the issue is how long should breast cancer survivors
wait before pursuing a subsequent pregnancy. One study linked
data from three cancer registries to birth certificate data to evalu-
ate survival of breast cancer patients who had pregnancies subse-
quent to cancer treatment [160]. Women with a history of breast
cancer should plan to delay subsequent pregnancy at least 10
months after completing cancer treatment (not after diagnosis),
realizing that the first 2 years after diagnosis carries the highest
risk for recurrence. A total of 438 women with invasive breast
cancer were matched to 2775 controls for age at diagnosis, race,
year of diagnosis, and stage. Among women who were lymph-
node negative at diagnosis, younger than 35 years of age, or with
only localized disease, pregnancy did not affect cancer mortal-
ity, even if conception occurred within 10 months of diagnosis.
Among women with positive lymph nodes at diagnosis, older
than 35 years of age, or diagnosed with regional recurrence prior
to pregnancy, there was a significant increase in cancer mortal-
ity if they conceived within 10 months of diagnosis. Women who
conceived at least 10 months after diagnosis had lower mortal-
ity than women without births after breast cancer (RR 0.54, 95%
CI 0.41–0.71). Decreased mortality was noted regardless of local/
metastatic disease, maternal age, tumor size, or lymph-node sta-
tus. For each year delay in conception after breast cancer, the
relative risk of death was further decreased: 2–3 years after diag-
nosis, RR 0.49 (95% CI 0.27–0.86); 3–4 years after diagnosis,
RR 0.30 (95% CI 0.12–0.71); and 4–5 years after diagnosis,
RR 0.19 (95% CI 0.05–0.81).
The half-life of methotrexate (a commonly used agent in the
CMF [cyclophosphamide, methotrexate, fluorouracil] regimen) is
approximately 8–15 hours and it is retained for several weeks to
months in the kidney and liver, respectively, leading this author to
recommend delaying conception for at least 12 weeks after stop-
ping methotrexate [170].
Breast feeding after treatment for breast cancer: Most women
who have undergone irradiation for breast cancer are able to pro-
duce milk on the affected side, but the amount of milk produced
may be less than that in a nonirradiated breast, particularly if the
lumpectomy site was close to the areolar complex or transected
many ducts [171]. Even when breast milk is produced, breast-­
feeding from the irradiated breast is not advised because masti-
tis will be difficult to treat if it occurs [172, 173]. As chemotherapy
has the ability to cross over to breast milk, breastfeeding is con-
traindicated. Patients that received chemotherapy demonstrate
453
reduced lactational ability [174]. Breastfeeding can only be
resumed following a safety period (of at least 3 weeks, depending
on the cytotoxic drug), when potential harmful metabolites are
cleared from the maternal circulation [175]. Aromatase inhibitors
are indicated during lactation because of the impact on the estro-
gen metabolism of the infant, whereas the lactational safety of
tamoxifen is unknown [176]. The ongoing POSITIVE trial, a pro-
spective randomized trial, is designed to obtain a better insight
on the safety of interrupting endocrine therapy for up to 2 years
for childbearing and breastfeeding [177].
Pregnancy after Hodgkin’s lymphoma
After mantle/mediastinal radiation, patients may have undi-
agnosed hypothyroidism and should be screened with thyroid
function studies at the beginning of pregnancy. Also, they have a
lifetime risk for secondary cancers so during prenatal care breast
and skin examination is important.
Pregnancy after chronic leukemia
Patients with CML who conceive while taking imatinib (Gleevec)
are advised to discontinue use during pregnancy, with the major-
ity of patients able to regain remission status postpartum [79].
Pregnancy after melanoma
The highest risk for recurrence after an adequately excised mela-
noma is during the first 2 years so women are often advised to
avoid pregnancy during this time period, but having a preg-
nancy during this time period does not increase one’s risk for
recurrence. Preconception counselling will be largely driven by
prognostic factors such as invasion depth and ulceration of the
primary tumor [178]. Placental pathology should be sent after
delivery in women with a history of melanoma, and prenatal skin
examination should be performed at the first prenatal visit and
vigilantly by the patient. Moles may darken and even increase in
size during pregnancy but should not become irregular or itch.
Pregnancy after thyroid carcinoma
After a total thyroidectomy, calcium balance may become an
issue during the exertion of labor or if magnesium therapy is
given for preterm labor or pre-eclampsia, as parathyroid glands
may have been inadvertently removed during thyroidectomy.
Check calcium levels during magnesium treatment, and labor.
References
1. Weisz B, Meirow D, Schiff E, Lishner M. Impact and treatment of cancer
during pregnancy. Expert Rev Anticancer Ther 2004;4(5):889–902. [II-2]
2. Stensheim H, Moller B, van Dijk T, Fossa SD. Cause-specific survival for
women diagnosed with cancer during pregnancy or lactation: a registry-
based cohort study. J Clin Oncol 2009;27(1):45–51. [II-2]
3. Barnavon Y, Wallack MK. Management of the pregnant patient with carci-
noma of the breast. Surg Gynecol Obstet 1990;171(4):347–352. [II-3]
4. The American College of Radiology. ACR–SPR practice parameter for
imaging pregnant or potentially pregnant adolescents and women with
ionizing radiation 2018; https://www.acr.org/-/media/ACR/Files/Practice-
Parameters/Pregnant-Pts.pdf.[III]
5. Achtari C, Hohlfeld P. Cardiotoxic transplacental effect of idarubicin
administered during the second trimester of pregnancy. Am J Obstet
Gynecol 2000;183(2):511–512. [II-3]
6. Siu BL, Alonzo MR, Vargo TA, Fenrich AL. Transient dilated cardiomy-
opathy in a newborn exposed to idarubicin and all-trans-retinoic acid
(ATRA) early in the second trimester of pregnancy. Int J Gynecol Cancer
2002;12(4):399–402. [II-3]
7. van Hasselt JG, van Calsteren K, Heyns L, et al. Optimizing anticancer drug
treatment in pregnant cancer patients: pharmacokinetic analysis of gesta-
tion-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel.
Ann Oncol 2014;25(10):2059–2065.[II-2]
454
8. La Nasa M, Gaughan J, Cardonick E. Incidence of neonatal neutropenia and
leukopenia after in utero exposure to chemotherapy for maternal cancer.
Am J Clin Oncol 2019;42(4):351–354. [II-3]
9. Reynoso EE, Shepherd FA, Messner HA, Farquharson HA, Garvey MB,
Baker MA. Acute leukemia during pregnancy: the Toronto Leukemia Study
Group experience with long-term follow-up of children exposed in utero to
chemotherapeutic agents. J Clin Oncol 1987;5(7):1098–1106. [II-2]
10. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy.
Lancet Oncol 2004;5(5):283–291. [II-3]
11. Aviles A, Neri N. Hematological malignancies and pregnancy: a final
report of 84 children who received chemotherapy in utero. Clin Lymphoma
2001;2(3):173–177. [II-2]
12. Hahn KM, Johnson PH, Gordon N, et al. Treatment of pregnant breast can-
cer patients and outcomes of children exposed to chemotherapy in utero.
Cancer 2006;107(6):1219–1226. [II-2]
13. Berveiller P, Marty O, Vialard F, Mir O. Use of anticancer agents in gyneco-
logical oncology during pregnancy: a systematic review of maternal phar-
macokinetics and transplacental transfer. Expert Opin Drug Metab Toxicol
2016;12(5):523–531. [II-2]
14. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the
human placenta. Clin Pharmacokinet 2004;43(8):487–514. [II-3]
15. Van Calsteren K, Verbesselt R, Beijnen J, et al. Transplacental transfer of
anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon
model. Gynecol Oncol 2010;119(3):594–600. [III]
16. Calsteren KV, Verbesselt R, Devlieger R, et al. Transplacental transfer of
paclitaxel, docetaxel, carboplatin, and trastuzumab in a baboon model. Int
J Gynecol Cancer 2010;20(9):1456–1464. [III]
17. Cardonick E, Broadrup R, Xu P, Doan MT, Jiang H, Snyder NW. Preliminary
results of identification and quantification of paclitaxel and its metabolites
in human meconium from newborns with gestational chemotherapeutic
exposure. PLOS ONE 2019;14(2):e0211821. [II-2]
18. Morishita S, Imai A, Kawabata I, Tamaya T. Acute myelogenous leukemia
in pregnancy: fetal blood sampling and early effects of chemotherapy. Int J
Gynaecol Obstet 1994;44(3):273–277. [II-2]
19. de Haan J, Verheecke M, Van Calsteren K, et al. Oncological management
and obstetric and neonatal outcomes for women diagnosed with cancer
during pregnancy: a 20-year international cohort study of 1170 patients.
Lancet Oncol 2018. [II-2]
20. Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an
analysis of 215 patients emphasizing the obstetrical and the neonatal out-
comes. J Clin Oncol 2010;28(4):683–689. [II-2]
21. Resnik R, Creasy RK. Intrauterine growth restriction. In Creasy and Resnik’s
Maternal-Fetal Medicine: Principles and Practice Elsevier, 2009;635–650. [III]
22. Lu D, Ludvigsson JF, Smedby KE, et al. Maternal cancer during preg-
nancy and risks of stillbirth and infant mortality. J Clin Oncol 2017;35(14):
1522–1529. [II-2]
23. Amant F, Berveiller P, Boere IA, et al. Gynecologic cancers in pregnancy:
guidelines based on a third international consensus meeting. Ann Oncol
2019;30(10):1601–1612. [III]
24. Kantarovich D, Archer S, Khoshnam N, et al. Increased incidence of villitis
in placentas exposed to chemotherapy during pregnancy: is there a correla-
tion? Pediatr Dev Pathol 2019;22(6):540–545. [II-3]
25. Verheecke M, Cortès Calabuig A, Finalet Ferreiro J, et al. Genetic and
microscopic assessment of the human chemotherapy-exposed placenta
reveals possible pathways contributive to fetal growth restriction. Placenta
2018;64:61–70.[II-2]
26. Saunders CM, Baum M. Breast cancer and pregnancy: a review. J R Soc Med
1993;86(3):162–165.9.[II-3]
27. Loibl S, Han SN, von Minckwitz G, et al. Treatment of breast cancer during
pregnancy: an observational study. Lancet Oncol 2012;13(9):887–896.[III]
28. Goddard ET, Bassale S, Schedin T, et al. Association between postpartum
breast cancer diagnosis and metastasis and the clinical features underlying
risk. JAMA Netw Open 2019;2(1):e186997.[II-2]
29. Beadle BM, Woodward WA, Middleton LP, et al. The impact of pregnancy
on breast cancer outcomes in women<or=35 years. Cancer 2009;115(6):
1174–1184. [II-1]
30. Loibl S, Schmidt A, Gentilini O, et al. Breast cancer diagnosed during preg-
nancy: adapting recent advances in breast cancer care for pregnant patients.
JAMA Oncol 2015;1(8):1145–1153.[III]
31. Amant F, von Minckwitz G, Han SN, et al. Prognosis of women with pri-
mary breast cancer diagnosed during pregnancy: results from an interna-
tional collaborative study. J Clin Oncol 2013;31(20):2532–2539. [II-3]
32. Loibl S, von Minckwitz G, Gwyn K, et al. Breast carcinoma during preg-
nancy. International recommendations from an expert meeting. Cancer
2006;106(2):237–246. [III]
Maternal-Fetal Evidence Based Guidelines
33. Nugent P, O’Connell TX. Breast cancer and pregnancy. Arch Surg
1985;120(11):1221–1224. [II-3]
34. Nettleton J, Long J, Kuban D, Wu R, Shaefffer J, El-Mahdi A. Breast cancer
during pregnancy: quantifying the risk of treatment delay. Obstet Gynecol
1996;87(3):414–418.[III]
35. Finley JL, Silverman JF, Lannin DR. Fine-needle aspiration cytology
of breast masses in pregnant and lactating women. Diagn Cytopathol
1989;5(3):255–259. [II-3]
36. Middleton LP, Amin M, Gwyn K, Theriault R, Sahin A. Breast carcinoma in
pregnant women: assessment of clinicopathologic and immunohistochemi-
cal features. Cancer 2003;98(5):1055–1060. [II-2]
37. Jacobs IA, Chang CK, Salti GI. Coexistence of pregnancy and cancer. Am
Surg 2004;70(11):1025–1029. [II-2]
38. Baker J, Ali A, Groch MW, Fordham E, Economou SG. Bone scanning
in pregnant patients with breast carcinoma. Clin Nucl Med 1987;12(7):
519–524. [II-3]
39. Han SN, Amant F, Michielsen K, et al. Feasibility of whole-body diffusion-
weighted MRI for detection of primary tumour, nodal and distant metas-
tases in women with cancer during pregnancy: a pilot study. Eur Radiol
2018;28(5):1862–1874.[II-2]
40. Kuerer HM, Gwyn K, Ames FC, Theriault RL. Conservative surgery
and chemotherapy for breast carcinoma during pregnancy. Surgery
2002;131(1):108–110.[II-3]
41. Han SN, Amant F, Cardonick EH, et al. Axillary staging for breast cancer
during pregnancy: feasibility and safety of sentinel lymph node biopsy.
Breast Cancer Res Treat 2017. [II-2]
42. Keleher A, Wendt R, 3rd, Delpassand E, Stachowiak AM, Kuerer HM.
The safety of lymphatic mapping in pregnant breast cancer patients using
Tc-99m sulfur colloid. Breast J 2004;10(6):492–495. [II-3]
43. Rubinchik-Stern M, Shmuel M, Bar J, Eyal S, Kovo M. Maternal-fetal trans-
fer of indocyanine green across the perfused human placenta. Reprod
Toxicol 2016;62:100–105.[II-2]
44. Cardonick E, Gilmandyar D, Somer RA. Maternal and neonatal outcomes of
dose-dense chemotherapy for breast cancer in pregnancy. Obstet Gynecol
2012;120(6):1267–1272.[II-2]
45. Mir O, Berveiller P, Ropert S, et al. Emerging therapeutic options for breast can-
cer chemotherapy during pregnancy. Ann Oncol 2008;19(4):607–613. [II-3]
46. Potluri V, Lewis D, Burton GV. Chemotherapy with taxanes in breast can-
cer during pregnancy: case report and review of the literature. Clin Breast
Cancer 2006;7(2):167–170. [II-3]
47. Gadducci A, Cosio S, Fanucchi A, et al. Chemotherapy with epirubicin and
paclitaxel for breast cancer during pregnancy: case report and review of the
literature. Anticancer Res 2003;23(6D):5225–5229. [II-3]
48. Gonzalez-Angulo AM, Walters RS, Carpenter RJ, Jr., et al. Paclitaxel che-
motherapy in a pregnant patient with bilateral breast cancer. Clin Breast
Cancer 2004;5(4):317–319. [II-3]
49. Gainford MC, Clemons M. Breast cancer in pregnancy: are taxanes safe?
Clin Oncol (R Coll Radiol) 2006;18(2):159. [II-3]
50. Sekar R, Stone PR. Trastuzumab use for metastatic breast cancer in preg-
nancy. Obstet Gynecol 2007;110(2 Pt 2):507–510. [II-3]
51. Fanale MA, Uyei AR, Theriault RL, Adam K, Thompson RA. Treatment of
metastatic breast cancer with trastuzumab and vinorelbine during preg-
nancy. Clin Breast Cancer 2005;6(4):354–356. [II-3]
52. Watson WJ. Herceptin (trastuzumab) therapy during pregnancy: association
with reversible anhydramnios. Obstet Gynecol 2005;105(3):642–643. [II-3]
53. Bader AA, Schlembach D, Tamussino KF, Pristauz G, Petru E. Anhydramnios
associated with administration of trastuzumab and paclitaxel for meta-
static breast cancer during pregnancy. Lancet Oncol 2007;8(1):79–81. [II-3]
54. Shrim A, Garcia-Bournissen F, Maxwell C, Farine D, Koren G. Favorable
pregnancy outcome following Trastuzumab (Herceptin) use during
pregnancy – Case report and updated literature review. Reprod Toxicol
2007;23(4):611–613. [II-3]
55. Waterston AM, Graham J. Effect of adjuvant trastuzumab on pregnancy. J
Clin Oncol 2006;24(2):321–322. [II-3]
56. Lishner M, Zemlickis D, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G.
Maternal and foetal outcome following Hodgkin’s disease in pregnancy. Br
J Cancer 1992;65(1):114–117. [III]
57. Maggen C, Dierickx D, Lugtenburg P, et al. Obstetric and maternal out-
comes in patients diagnosed with Hodgkin lymphoma during pregnancy: a
multicentre, retrospective, cohort study. Lancet Haematol 2019. [III]
58. Pereg D, Koren G, Lishner M. The treatment of Hodgkin’s and non-Hodg-
kin’s lymphoma in pregnancy. Haematologica 2007;92(9):1230–1237. [II-3]
59. Vermoolen MA, Kwee TC, Nievelstein RA. Whole-body MRI for stag-
ing Hodgkin lymphoma in a pregnant patient. Am J Hematol 2010;85(6):
443. [III]
Cancer
60. Evens AM, Advani R, Press OW, et al. Lymphoma occurring during preg-
nancy: antenatal therapy, complications, and maternal survival in a multi-
center analysis. J Clin Oncol 2013;31(32):4132–4139. [II-2]
61. Gurevich-Shapiro A, Avivi I. Current treatment of lymphoma in pregnancy.
Expert Rev Hematol 2019;12(6):449–459. [III]
62. Hoppe RT, Advani RH, Ai WZ, et al. NCCN Guidelines Insights:
Hodgkin lymphoma, Version 1.2018. J Natl Compr Canc Netw 2018;16(3):
245–254. [III]
63. Woo SY, Fuller LM, Cundiff JH, et al. Radiotherapy during pregnancy
for clinical stages IA-IIA Hodgkin’s disease. Int J Radiat Oncol Biol Phys
1992;23(2):407–412. [II-3]
64. Dekaban AS. Abnormalities in children exposed to x-radiation during vari-
ous stages of gestation: tentative timetable of radiation injury to the human
fetus. I. J Nucl Med 1968;9(9):471–477. [II-3]
65. George-Carey R, Parisaei M, Koniman W, Pluckinski M, Lambert J.
Relapsed Hodgkin’s lymphoma in pregnancy: a case review. Obstet Med
2017;10(4):183–185.[III]
66. Horowitz NA, Benyamini N, Wohlfart K, Brenner B, Avivi I. Reproductive
organ involvement in non-Hodgkin lymphoma during pregnancy: a system-
atic review. Lancet Oncol 2013;14(7):e275–282. [II-3]
67. Ioachim HL. Non-Hodgkin’s lymphoma in pregnancy. Three cases and
review of the literature. Arch Pathol Lab Med 1985;109(9):803–809. [II-3]
68. Mavrommatis CG, Daskalakis GJ, Papageorgiou IS, Antsaklis AJ, Michalas
SK. Non-Hodgkin’s lymphoma during pregnancy–case report. Eur J Obstet
Gynecol Reprod Biol 1998;79(1):95–97. [II-3]
69. El-Messidi A, Patenaude V, Abenhaim HA. Incidence and outcomes of
women with non-Hodgkin’s lymphoma in pregnancy: a population-based
study on 7.9 million births. J Obstet Gynaecol Res 2015;41(4):582–589. [II-2]
70. Avivi I, Farbstein D, Brenner B, Horowitz NA. Non-Hodgkin lymphomas
in pregnancy: tackling therapeutic quandaries. Blood Rev 2014;28(5):
213–220. [III]
71. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes
after maternal exposure to rituximab. Blood 2011;117(5):1499–1506. [II-2]
72. Klink DT, van Elburg RM, Schreurs MW, van Well GT. Rituximab adminis-
tration in third trimester of pregnancy suppresses neonatal B-cell develop-
ment. Clin Dev Immunol 2008;2008:271363. [II-2]
73. Decker M, Rothermundt C, Hollander G, Tichelli A, Rochlitz C. Rituximab
plus CHOP for treatment of diffuse large B-cell lymphoma during second
trimester of pregnancy. Lancet Oncol 2006;7(8):693–694. [III]
74. Catanzarite VA, Ferguson JE, 2nd. Acute leukemia and pregnancy: a
review of management and outcome, 1972-1982. Obstet Gynecol Surv
1984;39(11):663–678. [II-2]
75. Del Campo M, Kosaki K, Bennett FC, Jones KL. Developmental delay
in fetal aminopterin/methotrexate syndrome. Teratology 1999;60(1):
10–12. [III]
76. Okun DB, Groncy PK, Sieger L, Tanaka KR. Acute leukemia in pregnancy:
transient n6onatal myelosuppression after combination chemotherapy in
the mother. Med Pediatr Oncol 1979;7(4):315–319. [II-3]
77. Thomas X. Acute myeloid leukemia in the pregnant patient. Eur J Haematol
2015. [III]
78. Giagounidis AA, Beckmann MW, Giagounidis AS, et al. Acute promyelo-
cytic leukemia and pregnancy. Eur J Haematol 2000;64(4):267–271. [III]
79. Valappil S, Kurkar M, Howell R. Outcome of pregnancy in women
treated with all-trans retinoic acid; a case report and review of literature.
Hematology 2007;12(5):415–418. [III]
80. Agarwal K, Patel M, Agarwal V. A Complicated case of acute promyelocytic
leukemia in the second trimester of pregnancy successfully treated with all-
trans-retinoic acid. Case Rep Hematol 2015;2015:634252. [III]
81. Cochet C, Simonet M, Cattin J, et al. Arsenic trioxide treatment during
pregnancy for acute promyelocytic leukemia in a 22-year-old woman. Case
Rep Hematol 2020;2020:3686584. [III]
82. Khosla H, Jain A, Tatawadiya S, et al. First report of successful management
of acute promyelocytic leukemia in a pregnant female with all-trans-reti-
noic acid and arsenic trioxide-based induction regimen. Blood Cells Mol
Dis 2020;85:102476. [III]
83. Ammatuna E, Cavaliere A, Divona M, Amadori S, Scambia G, Lo-Coco F.
Successful pregnancy after arsenic trioxide therapy for relapsed acute pro-
myelocytic leukaemia. Br J Haematol 2009;146(3):341. [III]
84. Ali R, Ozkalemkas F, Ozcelik T, et al. Pregnancy under treatment of ima-
tinib and successful labor in a patient with chronic myelogenous leukemia
(CML). Outcome of discontinuation of imatinib therapy after achieving a
molecular remission. Leuk Res 2005;29(8):971–973. [II-2]
85. Fitzgerald D, Rowe JM, Heal J. Leukapheresis for control of chronic
myelogenous leukemia during pregnancy. Am J Hematol 1986;22(2):
213–218. [II-3]
455
86. AlKindi S, Dennison D, Pathare A. Imatinib in pregnancy. Eur J Haematol
2005;74(6):535–537. [II-2]
87. Yadav U, Solanki SL, Yadav R. Chronic myeloid leukemia with preg-
nancy: successful management of pregnancy and delivery with hydroxy-
urea and imatinib continued till delivery. J Cancer Res Ther 2013;9(3):
484–486. [II-2]
88. Russell MA, Carpenter MW, Akhtar MS, Lagattuta TF, Egorin MJ. Imatinib
mesylate and metabolite concentrations in maternal blood, umbilical cord
blood, placenta and breast milk. J Perinatol 2007;27(4):241–243. [II-2]
89. Eskander RN, Tarsa M, Herbst KD, Kelly TF. Chronic myelocytic leukemia
in pregnancy: a case report describing successful treatment using multi-
modal therapy. J Obstet Gynaecol Res 2011;37(11):1731–1733. [II-2]
90. Slingluff CL, Jr., Reintgen D. Malignant melanoma and the prognostic
implications of pregnancy, oral contraceptives, and exogenous hormones.
Semin Surg Oncol 1993;9(3):228–231. [II-2]
91. Colbourn DS, Nathanson L, Belilos E. Pregnancy and malignant melanoma.
Semin Oncol 1989;16(5):377–387. [II-3]
92. Lens MB, Rosdahl I, Ahlbom A, et al. Effect of pregnancy on sur-
vival in women with cutaneous malignant melanoma. J Clin Oncol
2004;22(21):4369–4375. [II-2]
93. Pennoyer JW, Grin CM, Driscoll MS, et al. Changes in size of melanocytic
nevi during pregnancy. J Am Acad Dermatol 1997;36(3 Pt 1):378–382. [II-3]
94. Jackisch C, Louwen F, Schwenkhagen A, et al. Lung cancer during preg-
nancy involving the products of conception and a review of the literature.
Arch Gynecol Obstet 2003;268(2):69–77. [II-3]
95. Alexander A, Samlowski WE, Grossman D, et al. Metastatic melanoma
in pregnancy: risk of transplacental metastases in the infant. J Clin Oncol
2003;21(11):2179–2186. [II-3]
96. Baergen RN, Johnson D, Moore T, Benirschke K. Maternal melanoma meta-
static to the placenta: a case report and review of the literature. Arch Pathol
Lab Med 1997;121(5):508–511. [II-3]
97. Wei P, Jin M, Jiang L, et al. The clinical and pathological features of mater-
nal gastric adenocarcinoma metastatic to placenta. Fetal Pediatr Pathol
2017;36(6):465–471. [II-3]
98. Maleka A, Enblad G, Sjors G, Lindqvist A, Ullenhag GJ. Treatment of meta-
static malignant melanoma with vemurafenib during pregnancy. J Clin
Oncol 2013;31(11):e192–193. [II-3]
99. de Haan J, van Thienen JV, Casaer M, et al. Severe adverse reaction to vemu-
rafenib in a pregnant woman with metastatic melanoma. Case Rep Oncol
2018;11(1):119–124. [II-3]
100. Bellon T, Lerma V, Gonzalez-Valle O, Gonzalez Herrada C, de Abajo FJ.
Vemurafenib-induced toxic epidermal necrolysis: possible cross-reac-
tivity with other sulfonamide compounds. Br J Dermatol 2016;174(3):
621–624. [III]
101. Burotto M, Gormaz JG, Samtani S, et al. Viable pregnancy in a patient with
metastatic melanoma treated with double checkpoint immunotherapy.
Semin Oncol 2018;45(3):164–169. [II-3]
102. Mehta A, Kim KB, Minor DR. Case report of a pregnancy during ipilim-
umab therapy. J Glob Oncol 2018;4:1–3.[II-3]
103. Amant F, Berveiller P, Boere I, et al. Gynecologic cancers in pregnancy:
guidelines based on a third international consensus meeting. Annals of
Oncology 2019; in press. [III]
104. Geijteman EC, Wensveen CW, Duvekot JJ, van Zuylen L. A child with severe
hearing loss associated with maternal cisplatin treatment during preg-
nancy. Obstet Gynecol 2014;124(2 Pt 2 Suppl 1):454–456. [II-3]
105. Van Calsteren K, Vergote I, Amant F. Cervical neoplasia during pregnancy:
diagnosis, management and prognosis. Best Pract Res Clin Obstet Gynaecol
2005;19(4):611–630. [II-3]
106. Halaska MJ, Uzan C, Han SN, et al. Characteristics of patients with cervical
cancer during pregnancy: a multicenter matched cohort study. An initiative
from the International Network on Cancer, Infertility and Pregnancy. Int J
Gynecol Cancer 2019. [II-2]
107. Vercellino GF, Koehler C, Erdemoglu E, et al. Laparoscopic pelvic lymphad-
enectomy in 32 pregnant patients with cervical cancer: rationale, descrip-
tion of the technique, and outcome. Int J Gynecol Cancer 2014;24(2)
:364–371. [II-2]
108. Duggan B, Muderspach LI, Roman LD, Curtin JP, d’Ablaing G, 3rd, Morrow
CP. Cervical cancer in pregnancy: reporting on planned delay in therapy.
Obstet Gynecol 1993;82(4 Pt 1):598–602. [II-3]
109. Fruscio R, Villa A, Chiari S, et al. Delivery delay with neoadjuvant chemo-
therapy for cervical cancer patients during pregnancy: a series of nine cases
and literature review. Gynecol Oncol 2012;126(2):192–197. [II-3]
110. Marana HR, de Andrade JM, da Silva Mathes AC, Duarte G, da Cunha SP,
Bighetti S. Chemotherapy in the treatment of locally advanced cervical can-
cer and pregnancy. Gynecol Oncol 2001;80(2):272–274. [II-2]
456
111. Halaska MJ, Rob L, Robova H, Cerny M. Treatment of gynecologi-
cal cancers diagnosed during pregnancy. Future Oncol 2016;12(19):
2265–2275. [III]
112. Cliby WA, Dodson MK, Podratz KC. Cervical cancer complicated by
pregnancy: episiotomy site recurrences following vaginal delivery. Obstet
Gynecol 1994;84(2):179–182. [II-3]
113. Morris PC. Thyroid cancer complicating pregnancy. Obstet Gynecol Clin
North Am 1998;25(2):401–405. [III]
114. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer
diagnosed in pregnant women. J Clin Endocrinol Metab 1997;82(9):
2862–2866. [II-2]
115. Vini L, Hyer S, Pratt B, Harmer C. Management of differentiated thy-
roid cancer diagnosed during pregnancy. Eur J Endocrinol 1999;140(5):
404–406. [II-3]
116. Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and
interpretation of assays for monitoring autophagy (3rd edition). Autophagy
2016;12(1):1–222. [III]
117. Khaled H, Al Lahloubi N, Rashad N. A review on thyroid cancer during
pregnancy: Multitasking is required. J Adv Res 2016;7(4):565–570. [III]
118. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American
Thyroid Association for the diagnosis and management of thyroid disease
during pregnancy and the postpartum. Thyroid 2017;27(3):315–389. [III]
119. Wapner RJ, Sorokin Y, Mele L, et al. Long-term outcomes after repeat doses
of antenatal corticosteroids. N Engl J Med 2007;357(12):1190–1198. [I]
120. Fujiwaki R, Hata T, Hata K, Kitao M, Furuya H, Katoh Y. Effective treat-
ment of drug-induced agranulocytosis using recombinant human granu-
locyte colony stimulating factor in pregnancy. Gynecol Obstet Inves
1995;40(4):276–277. [II-3]
121. Arango HA, Kalter CS, Decesare SL, Fiorica JV, Lyman GH, Spellacy WN.
Management of chemotherapy in a pregnancy complicated by a large neu-
roblastoma. Obstet Gynecol 1994;84(4 Pt 2):665–668. [II-3]
122. Kaufmann SJ, Sharif K, Sharma V, McVerry BA. Term delivery in a woman
with severe congenital neutropenia, treated with growth colony stimulating
factor. Hum Reprod 1998;13(2):498–499. [II-3]
123. Sangalli MR, Peek M, McDonald A. Prophylactic granulocyte colony-stim-
ulating factor treatment for acquired chronic severe neutropenia in preg-
nancy. Aust N Z J Obstet Gynaecol 2001;41(4):470–471. [II-3]
124. Kikkawa M, Matsubara S, Takatoku M, et al. Granulocyte-colony stimu-
lating factor for the treatment of ritodrine-induced neutropenia. J Obstet
Gynaecol Res 2008;34(2):286–290. [II-3]
125. Cardonick E, Irfan F, Torres N. The use of neupogen (filgrastim) or neu-
lasta (pegfilgrastim) during pregnancy when chemotherapy is indicated for
maternal cancer treatment. J Cancer Ther 2012;3:157–161. [II-2]
126. Amant F, Van Calsteren K, Halaska MJ, et al. Long-term cognitive and
cardiac outcomes after prenatal exposure to chemotherapy in children
aged 18 months or older: an observational study. Lancet Oncol 2012;13(3):
256–264. [III]
127. Cardonick EH, Gringlas MB, Hunter K, Greenspan J. Development of chil-
dren born to mothers with cancer during pregnancy: comparing in utero
chemotherapy-exposed children with nonexposed controls. Am J Obstet
Gynecol 2015;212(5):658 e651–658. [III]
128. Amant F, Vandenbroucke T, Verheecke M, et al. Pediatric Outcome
after Maternal Cancer Diagnosed during Pregnancy. N Engl J Med
2015;373(19):1824–1834. [II-2]
129. Vandenbroucke T, Verheecke M, van Gerwen M, et al. Child development
at 6 years after maternal cancer diagnosis and treatment during pregnancy.
Eur J Cancer 2020;138:57–67. [II-2]
130. Passera S, Contarino V, Scarfone G, et al. Effects of in-utero exposure to
chemotherapy on fetal brain growth. Int J Gynecol Cancer. 2019;29(7):
1195–1202. [II-2]
131. Blommaert J, Zink R, Deprez S, et al. Long-term impact of prenatal
exposure to chemotherapy on executive functioning: an ERP study. Clin
Neurophysiol 2019;130(9):1655–1664. [II-2]
132. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome of female sur-
vivors of childhood cancer: a report from the Childhood Cancer Survivor
Study. Am J Obstet Gynecol 2002;187(4):1070–1080. [II-1]
133. Chiarelli AM, Marrett LD, Darlington GA. Pregnancy outcomes
in females after treatment for childhood cancer. Epidemiology
2000;11(2):161–166. [II-3]
134. Reulen RC, Zeegers MP, Wallace WH, et al. Pregnancy outcomes among
adult survivors of childhood cancer in the British Childhood Cancer Survivor
Study. Cancer Epidemiol Biomarkers Prev. 2009;18(8):2239–2247 [II-1]
135. Dodds L, Marrett LD, Tomkins DJ, Green B, Sherman G. Case-control
study of congenital anomalies in children of cancer patients. BMJ
1993;307(6897):164–168. [II-2]
Maternal-Fetal Evidence Based Guidelines
136. Blatt J, Mulvihill JJ, Ziegler JL, Young RC, Poplack DG. Pregnancy outcome
following cancer chemotherapy. Am J Med 1980;69(6):828–832. [II-3]
137. Byrne J, Rasmussen SA, Steinhorn SC, et al. Genetic disease in offspring of
long-term survivors of childhood and adolescent cancer. Am J Hum Genet
1998;62(1):45–52. [II-3]
138. Li FP, Fine W, Jaffe N, Holmes GE, Holmes FF. Offspring of patients treated
for cancer in childhood. J Natl Cancer Inst 1979;62(5):1193–1197. [II-3]
139. Hartnett KP, Ward KC, Kramer MR, et al. The risk of preterm birth and
growth restriction in pregnancy after cancer. Int J Cancer 2017;141(11):
2187–2196. [II-3]
140. Bar J, Davidi O, Goshen Y, Hod M, Yaniv I, Hirsch R. Pregnancy outcome
in women treated with doxorubicin for childhood cancer. Am J Obstet
Gynecol 2003;189(3):853–857. [II-3]
141. Hawkins MM, Smith RA. Pregnancy outcomes in childhood cancer sur-
vivors: probable effects of abdominal irradiation. Int J Cancer 1989;43(3):
399–402. [II-3]
142. Holm K, Nysom K, Brocks V, Hertz H, Jacobsen N, Muller J. Ultrasound
B-mode changes in the uterus and ovaries and Doppler changes in the
uterus after total body irradiation and allogeneic bone marrow transplanta-
tion in childhood. Bone Marrow Transplant 1999;23(3):259–263. [II-3]
143. Pridjian G, Rich NE, Montag AG. Pregnancy hemoperitoneum and placenta
percreta in a patient with previous pelvic irradiation and ovarian failure.
Am J Obstet Gynecol 1990;162(5):1205–1206. [II-3]
144. Norwitz ER, Stern HM, Grier H, Lee-Parritz A. Placenta percreta and uter-
ine rupture associated with prior whole body radiation therapy. Obstet
Gynecol 2001;98(5 Pt 2):929–931. [II-3]
145. Signorello LB, Cohen SS, Bosetti C, et al. Female survivors of childhood
cancer: preterm birth and low birth weight among their children. J Natl
Cancer Inst 2006;98(20):1453–1461. [II-3]
146. Stewart JR, Fajardo LF, Gillette SM, Constine LS. Radiation injury to the
heart. Int J Radiat Oncol Biol Phys 1995;31(5):1205–1211. [II-3]
147. Sankila R, Heinavaara S, Hakulinen T. Survival of breast cancer patients
after subsequent term pregnancy: “healthy mother effect.” Am J Obstet
Gynecol 1994;170(3):818–823. [III]
148. Mulvihill JJ, Myers MH, Connelly RR, et al. Cancer in offspring of long-
term survivors of childhood and adolescent cancer. Lancet 1987;2(8563):
813–817. [III]
149. Sankila R, Olsen JH, Anderson H, et al. Risk of cancer among offspring of
childhood-cancer survivors. Association of the Nordic Cancer Registries
and the Nordic Society of Paediatric Haematology and Oncology. N Engl J
Med 1998;338(19):1339–1344. [III]
150. Reintgen DS, McCarty KS, Jr., Vollmer R, Cox E, Seigler HF. Malignant
melanoma and pregnancy. Cancer 1985;55(6):1340–1344. [II-3]
151. Grin CM, Driscoll MS, Grant-Kels JM. The relationship of pregnancy, hor-
mones, and melanoma. Semin Cutan Med Surg 1998;17(3):167–171. [II-3]
152. Azim HA, Jr., Santoro L, Pavlidis N, et al. Safety of pregnancy follow-
ing breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer
2011;47(1):74–83. [II-2]
153. Velentgas P, Daling JR, Malone KE, et al. Pregnancy after breast carcinoma:
outcomes and influence on mortality. Cancer 1999;85(11):2424–2432. [II-2]
154. Danforth DN, Jr. How subsequent pregnancy affects outcome in women
with a prior breast cancer. Oncology (Williston Park) 1991;5(11):23–30;
discussion 30-21, 35. [II-3]
155. Cooper DR, Butterfield J. Pregnancy subsequent to mastectomy for cancer
of the breast. Ann Surg 1970;171(3):429–433. [II-3]
156. von Schoultz E, Johansson H, Wilking N, Rutqvist LE. Influence of prior
and subsequent pregnancy on breast cancer prognosis. J Clin Oncol
1995;13(2):430–434. [II-2]
157. Kroman N, Jensen MB, Melbye M, Wohlfahrt J, Mouridsen HT. Should
women be advised against pregnancy after breast-cancer treatment? Lancet
1997;350(9074):319–322. [II-2]
158. Gelber S, Coates AS, Goldhirsch A, et al. Effect of pregnancy on over-
all survival after the diagnosis of early-stage breast cancer. J Clin Oncol
2001;19(6):1671–1675. [II-2]
159. Ariel IM, Kempner R. The prognosis of patients who become pregnant after
mastectomy for breast cancer. Int Surg 1989;74(3):185–187. [II-3]
160. Mueller BA, Simon MS, Deapen D, Kamineni A, Malone KE, Daling JR.
Childbearing and survival after breast carcinoma in young women. Cancer
2003;98(6):1131–1140. [II-1]
161. Azim HA, Jr., Kroman N, Paesmans M, et al. Prognostic impact of preg-
nancy after breast cancer according to estrogen receptor status: a multi-
center retrospective study. J Clin Oncol 2013;31(1):73–79. [II-2]
162. Lambertini M, Kroman N, Ameye L, et al. Long-term safety of pregnancy
following breast cancer according to estrogen receptor status. J Natl Cancer
Inst 2017. [II-3]
Cancer
163. Tewari K, Bonebrake RG, Asrat T, Shanberg AM. Ambiguous genitalia in
infant exposed to tamoxifen in utero. Lancet 1997;350(9072):183. [II-3]
164. Cullins SL, Pridjian G, Sutherland CM. Goldenhar’s syndrome asso-
ciated with tamoxifen given to the mother during gestation. JAMA
1994;271(24):1905–1906. [II-3]
165. Wisel MS, Datta JK, Saxena RN. Effects of anti-estrogens on early preg-
nancy in guinea pigs. Int J Fertil Menopausal Stud 1994;39(3):156–163.
[II-3]
166. Diwan BA, Anderson LM, Ward JM. Proliferative lesions of oviduct and
uterus in CD-1 mice exposed prenatally to tamoxifen. Carcinogenesis
1997;18(10):2009–2014. [II-3]
167. Schuurman TN, Witteveen PO, van der Wall E, et al. Tamoxifen and
pregnancy: an absolute contraindication? Breast Cancer Res Treat
2019;175(1):17–25. [II-3]
168. Gottschalk I, Berg C, Harbeck N, Stressig R, Kozlowski P. Fetal renal
insufficiency following trastuzumab treatment for breast cancer in preg-
nancy: case report und review of the current literature. Breast Care (Basel).
2011;6(6):475–478. [II-3]
169. Witzel ID, Muller V, Harps E, Janicke F, Dewit M. Trastuzumab in preg-
nancy associated with poor fetal outcome. Ann Oncol 2008;19(1):191–192.
[II-3]
170. Donnenfeld AE, Pastuszak A, Noah JS, Schick B, Rose NC, Koren G.
Methotrexate exposure prior to and during pregnancy. Teratology
1994;49(2):79–81. [III]
457
171. Wobbes T. Effect of a breast saving procedure on lactation. Eur J Surg
1996;162(5):419–420. [II-3]
172. Findlay PA, Gorrell CR, d’Angelo T, Glatstein E. Lactation after breast radi-
ation. Int J Radiat Oncol Biol Phys 1988;15(2):511–512. [III]
173. Higgins S, Haffty BG. Pregnancy and lactation after breast-conserving
therapy for early stage breast cancer. Cancer 1994;73(8):2175–2180. [III]
174. Stopenski S, Aslam A, Zhang X, Cardonick E. After chemotherapy treat-
ment for maternal cancer during pregnancy, is breastfeeding possible?
Breastfeed Med 2017;12:91–97. [II-2]
175. Johnson HM, Mitchell KB, Academy of Breastfeeding M. ABM Clinical
Protocol #34: Breast Cancer and Breastfeeding. Breastfeed Med
2020;15(7):429–434. [III]
176. Johnson HM, Mitchell KB. Breastfeeding and breast cancer: managing
lactation in survivors and women with a new diagnosis. Ann Surg Oncol
2019;26(10):3032–3039. [III]
177. Pagani O, Ruggeri M, Manunta S, et al. Pregnancy after breast can-
cer: are young patients willing to participate in clinical studies? Breast
2015;24(3):201–207. [II-2]
178. Byrom L, Olsen CM, Knight L, Khosrotehrani K, Green AC. Does preg-
nancy after a diagnosis of melanoma affect prognosis? Systematic review
and meta-analysis. Dermatol Surg 2015;41(8):875–882. [II-2]
45
DERMATOSES OF PREGNANCY
Hannah J. Anderson, Dana Correale, and Jason B. Lee
Background
Polymorphic eruption of pregnancy (PEP) comprises the only
pregnancy-specific dermatosis. All other dermatoses mentioned
herein may be encountered outside of pregnancy, but they have
been traditionally grouped and discussed as dermatoses of preg-
nancy as they represent common and uncommon dermatoses
encountered during pregnancy.
Stretch marks are the only dermatologic condition for which
there are trials for interventions. Dermatoses of pregnancy as well
as melanoma in pregnancy are not well studied, with no specific
trials regarding treatment. Most evidence regarding pathogenesis
and etiology, as well as typical disease presentation is based on
case reports and case series. Dermatoses of pregnancy have been
plagued by disagreements about their nomenclature and classifi-
cation. Though likely to be reworked and reclassified in the future,
the current widely accepted classification, based on the largest
series to date, consists of four major categories: (1) polymorphic
eruption of pregnancy (PEP), (2) atopic eruption of pregnancy
(AEP), (3) pemphigoid gestationis (PG), and (4) intrahepatic
cholestasis of pregnancy (ICP). Under this classification, AEP
has subsumed atopic dermatitis (eczema) of pregnancy, prurigo
of pregnancy (PP), and pruritic folliculitis of pregnancy (PFP).
Intrahepatic cholestasis of pregnancy, while not associated with
any primary skin lesions, is currently accepted as one of the
dermatoses of pregnancy. The most common skin disorder in
pregnancy is atopic eruption of pregnancy. Pruritus represents
a significant symptom in all four dermatoses. Differentiating
among these entities, especially in their early stages, may pose a
significant diagnostic challenge, requiring excluding each of the
dermatoses methodically. Though not included in the current
classification, impetigo herpetiformis (IH), a variant of pustular
psoriasis, is frequently discussed together with dermatoses of
pregnancy, considered by some as the fifth dermatosis of preg-
nancy. Table 45.1 provides a summary and classification of the
dermatoses of pregnancy. Multidisciplinary management involv-
ing a dermatologist expert in dermatologic conditions in preg-
nancy is of paramount importance.
Striae gravidarum
Key points
• The exact cause of striae gravidarum (SG) is unknown,
but the strongest associated risk factors for their develop-
ment are presence of preexisting breast and thigh striae,
and a family history.
• There is no widely available product that has been
shown to prevent the formation of SG.
• Topical tretinoin and various types of laser therapy
have been shown to be helpful in the treatment of SG.
458
Diagnosis/Definition
Striae distensae (SD), or stretch marks, do not represent a dis-
ease, but rather are a cosmetic problem for many people. They
often occur for the first time during pregnancy and are referred
to as SG. SD initially appear as linear patches that are red to
purple in color and lack noticeable surface change (striae rubra).
With time, their color fades to lighter than normal skin tone.
They become atrophic or depressed with a fine, wrinkled surface
(striae alba).
Symptoms
SD are largely asymptomatic. They may be slightly pruritic in
their early stages.
Epidemiology/Incidence
The prevalence of SG ranges from 50% to 90% [1]. The mean ges-
tational age for the onset of SG is 25 weeks [1].
Genetics
There is no known clear genetic cause of SG; however, there may
be a familial tendency to develop them [1].
Etiology/Basic pathology
As opposed to the tightly packed bundles of collagen that are seen
in normal skin, collagen bundles in SG are separated and inter-
mixed with loosely packed, disorganized collagen fibrils, changes
that persist postpartum [2]. It is also known that elastin and
fibrillin fibers, components of the dermal extracellular matrix,
are reduced in SD [3].
Risk factors/Associations
Factors strongly associated with the development of SG are the
presence of breast or thigh striae, having a mother with SG,
having additional family members with SG, and belonging
to a non-white race. While past studies showed no association
between SG and pre-pregnancy body mass index (BMI), mean
weight gain during pregnancy, mean percent weight gain, and
mean change in BMI [1], a recent study of 800 primiparas found
that higher pre-pregnancy weight and BMI, weight at delivery and
gestational weight gain were significantly associated with pres-
ence of SG postpartum (p < 0.001) [4]. A recent cross-­sectional
study found that primigravid patients with normal vitamin D3
levels (>30 ng/mL) were significantly less likely to have SG com-
pared to primigravid patients with scarce vitamin D3 levels
(<20 ng/mL), suggesting that vitamin D deficiency may be a risk
factor for SG development [5].
DOI: 10.1201/9781003099062-45
Dermatoses of Pregnancy 459

TABLE 45.1: Summary and Classification of the Dermatoses of Pregnancy

Dermatosis Course
PEP Third trimester.
Resolution postpartum
AEP First to third trimesters.
Can persist postpartum
ICP See Chapter 10
PG Second or third trimester.
Resolution postpartum
after weeks to months
IH Third trimester. Persists
after delivery if untreated
Abbreviations: PEP, polymorphic eruption of pregnancy; AEP, atopic eruption of pregnancy; ICP, intrahepatic cholestasis of pregnancy; PG, pemphigoid gestationis; IH, impe-
tigo herpetiformis.
Skin Findings Fetal Risks Treatment
Urticarial lesions on the abdomen, often within None Low- to mid-potency topical
striae with sparing of the periumbilical area. steroids
Extension to upper thighs and buttocks
Hyperpigmented lichenified, excoriated patches None Low- to mid-potency topical
and plaques on flexural surfaces in 80% and steroids, emollients, and oral
papules and/or prurigo nodules in 20% antihistamines
Ranges from annular and polycyclic urticarial Prematurity Topical steroid for mild cases
papules and plaques to grouped blisters on the and small-for- and systemic steroid for more
abdomen and extremities involving the gestational- severe cases
periumbilical and umbilical skin age at birth
Symmetric, erythematous patches with peripheral Placental Systemic corticosteroids
superficial sterile pustules on flexural skin insufficiency
and fetal loss

Management In addition to tretinoin therapy, improvement in the appear-

Prevention
A 2012 Cochrane Review found no high-quality evidence to sup-
port the use of any topical preparation for the prevention of SG
during pregnancy [6]. Cocoa butter lotion has not been found to
be associated with reduction in the likelihood of developing SG
in two randomized controlled trials [7, 8]. The efficacy of olive
oil in preventing SG has been evaluated in three randomized
controlled clinical trials with no significant reduction found in
the frequency or severity of SG [9–11]. A double-blind random-
ized trial found that aloe vera and sweet almond oil creams were
more effective than vehicle in reducing itching and erythema of
SG but did not reduce the diameter or number of striae [12]. A
cream containing hydroxyprolisilane C, rosehip oil, Centella asi-
atica triterpenes, and vitamin E did not decrease incidence of SG
overall compared to vehicle, but was found to be associated with
a decreased severity of SG that developed during pregnancy and
decreased incidence of SG in women who had no history of SD
prior to pregnancy [13].
Therapy
Once SG have formed, there are treatment options. Topical treti-
noin 0.1% cream has been shown to reduce the appearance of SG/
SD when used on early lesions (striae rubra) [14]. It is important
to note that once striae have become white and atrophic, topi-
cal tretinoin was shown to have no benefit in a double-blind, pla-
cebo-controlled study [15]. Topical tretinoin (Retin-A) works by
binding to cytoplasmic proteins and nuclear receptors of kera-
tinocytes and altering downstream gene transcription. The end
biologic effect is to regulate the growth and differentiation of
keratinocytes [16]. In addition to regulating keratinocyte prolif-
eration, topical retinoids have been shown to decrease fine wrin-
kling, increase dermal collagen, and repair elastin fiber formation
[17]. Improvement in the appearance of SD/SG is most likely the
result of this particular biologic effect. Tretinoin is pregnancy
category C, so use during pregnancy is not recommended. Its use
is contraindicated during breastfeeding, which makes it difficult
to use during the early stages of SG. The side effects of tretinoin
therapy are erythema, desquamation, and photosensitivity lim-
ited to the application site.
ance of SD/SG can be achieved with laser therapy. Laser therapy
is a rapidly evolving field with new lasers and applications emerg-
ing on a regular basis. Two large, blinded studies using an objec-
tive grading system evaluating the treatment of SD with a 585-nm
pulsed dye laser have shown improvement in their appearance [18].
Both increases and decreases in collagen production have been
shown posttreatment depending on the wavelength and energy
density of laser used. An increase in dermal elastin content has
also been shown in biopsies obtained after laser therapy [18].
Again, newer, more erythematous striae respond more favorably
to pulsed dye laser treatment. This may be a more reasonable
treatment option during the postpartum period as laser therapy is
believed to be safe in breastfeeding women. A more recent study
evaluating the effects of a XeCl excimer ultraviolet B (UVB) laser
and a UVB light device showed re-pigmentation of striae alba [19].
Re-pigmentation was associated with an increase in melanin con-
tent, hypertrophy of melanocytes, and an increase in number
of melanocytes 6 months after treatment. Treatment with frac-
tional CO2 laser was found to increase number of collagen fibers
and decrease SG width in one non-randomized study [20]. Non-
ablative fractionated laser has been shown to improve SD both
clinically and histologically [21]. A recent randomized controlled
trial found that the combination of topical tretinoin and frac-
tional radiofrequency therapy was more effective in improving SG
clinical appearance and skin thickness than either intervention
alone [22]. A limitation to these studies is their small sample size.
Polymorphic eruption of pregnancy (pruritic
urticarial papules and plaques of pregnancy)
Key points
• Polymorphic eruption of pregnancy (pruritic urticarial
papules and plaques of pregnancy ([UPPP]) is an extremely
pruritic urticarial eruption occurring during the third tri-
mester of pregnancy.
• There is no associated fetal morbidity or mortality.
• The mainstay of treatment is topical steroids.
460
FIGURE 45.1 Polymorphous eruption of pregnancy (PEP). A 28-year-old primigravida with abrupt onset of extremely pruritic urti-
carial papules on the abdomen (a) and thighs (b) during her 39th week of pregnancy. Note the predilection for the abdominal striae
with periumbilical sparing.
Historic notes
This entity was originally described by Lawley and colleagues in
1979 in a series of seven patients [23].
Diagnosis/Definition
PEP is characterized by urticarial lesions that begin on the
abdomen, often within abdominal striae, and spare the peri-
umbilical area (Figure 45.1). Lesions frequently spread to the
upper thighs and buttocks and occasionally may affect the
arms. The face, palms, and soles are usually spared. Despite the
severe pruritus, there is notable lack of excoriation. As its name
implies, PEP is polymorphous. Clinical lesions may appear
vesicular, targetoid, or purpuric. This eruption is seen mostly
in primigravidas with onset in the third trimester of pregnancy.
It resolves shortly after delivery, but there have been a few cases
reported in which onset of the disease has occurred in the
postpartum period [24–26]. The diagnosis is primarily clinical.
Histopathologic examination of affected skin most often yields
nonspecific findings.
Symptoms
The eruption is accompanied by extreme pruritus. The itching is
often so severe that it may interfere with sleep.
Epidemiology/Incidence
PEP is one of the most common dermatoses of pregnancy. It
occurs in approximately 0.5% of pregnancies [27].
Genetics
There are no known genetic factors in PEP. In fact, some studies
have looked for, but failed to document, a human leukocyte anti-
gen (HLA) association [28, 29].
Maternal-Fetal Evidence Based Guidelines
Etiology/Basic pathology
To date, there are no widely accepted theories to explain the
etiology of this disease. Associated factors include increased
abdominal distension secondary to excessive maternal weight
gain and fetal birth weight [25, 29, 30], increased incidence of
multiple pregnancies [24, 27, 29, 31], decreased serum cortisol
levels [32, 33], and fetal DNA migration in PEP skin lesions [34].
Autoimmune mechanisms have not been found to play a role [35].
Complications
There have been no consistent maternal or fetal complications
associated with PEP, with newborns not affected with any related
skin disease [26, 29, 32].
Management
Workup
The most important disease to exclude when diagnosing PEP is
PG, which can present with urticarial lesions in the absence of
more prototypical blisters. PG is usually a widespread eruption
which begins on the abdomen but does not show a predilection
for striae nor spares the periumbilical area. PG is rare, but it is
associated with significant maternal and fetal morbidity and
mortality [23, 36]. Exclusion of PG relies on the clinical presenta-
tion, but direct immunofluorescence (DIF) of affected skin may
be required in equivocal cases. There are no consistent DIF find-
ings in PEP [25, 26, 29, 32, 37]. When positive DIF findings have
been reported in PEP, they have been considered non-diagnostic
for any particular disease [26, 37]. In contrast, PG is associated
with very consistent and reliable DIF findings [36].
Preconception counseling
The vast majority of cases of PEP do not recur with subsequent
pregnancies [23, 29, 32] or oral contraceptive use [29]. A few women
affected by PEP have been reported to have episodes of transient
hives while breastfeeding after the initial eruption resolved [23].
Dermatoses of Pregnancy 461

Therapy
Low- to mid-potency topical steroids are preferred for management
of PEP. A 2012 Cochrane Review found a probable causal associa-
tion between use of potent to very potent topical steroids during
pregnancy and low birthweight, but no association between use
of low- to mid-potency topical steroids and birthweight [38]. The
same review found no association between topical corticosteroids
of any potency and congenital abnormalities such as orofacial cleft,
premature birth, type of delivery, or low Apgar scores [38]. Because
of the relationship between fetal growth restriction and use of
potent to very potent topical corticosteroids, low- to mid-potency
topical steroids are recommended as first-line therapy, and when
potent or very potent topical steroids are required, they should be
used for the shortest duration possible [39]. However, it should be
noted that the risks of high-potency topical steroids are lower than
that of systemic corticosteroids [39]. The decision to use oral corti-
costeroids during pregnancy must weigh the benefits to the patient FIGURE 45.2 Atopic eruption of pregnancy. A 42-year-old
with the risks to the fetus. A recent meta-analysis demonstrated an G1P0 with multiple, lichenified, hyperpigmented patches and
increased risk of orofacial clefts from maternal corticosteroid use plaques on the abdomen and extremities.
during the first trimester of pregnancy [40]. Studies have also dem-
onstrated associations between systemic corticosteroid use during
pregnancy and low birthweight and premature birth, but many of
these studies did not adjust for maternal disease or disease severity,
confounding the association [41]. In severe and widespread cases of
PEP, short courses of oral corticosteroids have been used effectively
[23, 29, 32]. There is one reported case of severe PEP that required
delivery by cesarean section at 35 weeks’ gestation for intractable
pruritus uncontrolled by topical and oral corticosteroids [42].
In this case, the patient’s symptoms were significantly improved
within 12 hours of delivery.

Atopic eruption of pregnancy

Key points
• Atopic eruption of pregnancy (AEP) is an intensely pruritic
eruption characterized by eczematous plaques or papular FIGURE 45.3 Atopic eruption of pregnancy. A 28-year-old
lesions involving the trunk and extremities. woman with erythematous, follicular papules on the abdomen.
• The mainstay of therapy is topical steroids and emollients.
• There is no associated maternal or fetal morbidity or
mortality.

Diagnosis/Definition
The former diagnoses atopic dermatitis (eczema) of pregnancy,
prurigo of pregnancy, and pruritic folliculitis of pregnancy (an
eruption of pruritic, sterile papules and pustules) have been sub-
sumed into one all-encompassing category, atopic eruption of preg-
nancy [43–45]. AEP is characterized by intense itch accompanied
by lichenified plaques or papular lesions in patients with a personal
or family history of atopy and/or elevated IgE levels. The eruption
most commonly presents before the third trimester of pregnancy
in 75% of patients, with onset occurring in all three trimesters, and
is a diagnosis of exclusion [43]. Recurrence in subsequent preg-
nancies is expected due to the background of atopy. The eruption
consists of atopic dermatitis-like plaques and/or prurigo-like nod-
ules accompanied by excoriations and secondary skin infections
(Figures 45.2–45.4). AEP classically involves the trunk and extrem- FIGURE 45.4 Atopic eruption of pregnancy. Grouped excori-
ities in typical atopic sites such as the neck, décolletage, or flexural ated papules on the thigh of a 24-year-old primigravida with a
surfaces of extremities. Characteristic atopic clinical findings are prior history of asthma and seasonal allergies.
462
key for diagnosis, as histopathologic findings are nonspecific and
DIF reveals no immunoreactive deposition [46].
Symptoms
AEP is accompanied by intense pruritus which can lead to exco-
riations and secondary skin infections.
Epidemiology/Incidence
AEP is the most frequent dermatosis in pregnancy [33, 43, 47].
Etiology/Basic pathology
Although causally linked to a personal or family history of atopy,
there is no definitive evidence currently. One theory reflects a
deterioration of existing atopic dermatitis or an exacerbation of
a quiescent atopic state due to a Th2 shift in cytokine expression
during pregnancy [33, 47].
Pregnancy considerations
There are no reports of adverse maternal or fetal outcomes in
AEP. There is inadequate evidence to prescribe specific dietary
intake for pregnant women to prevent atopic dermatitis in the
newborn [48, 49].
Management
Workup
The diagnosis of AEP is made clinically due to the characteristic
clinical atopic presentation. Other specific dermatoses of pregnancy
must first be ruled out. Sparing of striae and time of onset differ-
entiate from PEP. Elevated IgE levels may be present in 20–70% of
cases but are not diagnostic [43]. Total serum bile acid levels must
be in the normal range. The relatively non-specific histopathologic
changes of AEP do not discriminate among other pruritic dermato-
ses of pregnancy [50]. If PG is a diagnostic consideration, histopath-
ologic exam and DIF testing may be performed in equivocal cases.
Therapy
Treatment strategies vary depending on the severity of the patient’s
clinical findings and symptoms. The mainstay of therapy for AEP is
low- to mid-potency topical steroids accompanied by liberal use
of emollients, with or without antihistamines [46]. If necessary, the
first-generation antihistamines diphenhydramine and chlorpheni-
ramine are pregnancy class B and are considered the first-line anti-
histamines in pregnancy [16]. In severe cases, a tapered course of
systemic corticosteroids (CS) may be required, in addition to treat-
ment with phototherapy (UVB) [46]. In recalcitrant cases, systemic
immunosuppressants such as cyclosporine may be considered while
avoiding methotrexate and mycophenolate mofetil [51].
Pemphigoid gestationis (herpes gestationis)
Key points
• Pemphigoid gestationis (PG) is a very rare autoimmune
blistering disease in which patients develop autoantibodies
against collagen XVII (BP180), a transmembrane protein
found in the basement membrane zone of the skin
Maternal-Fetal Evidence Based Guidelines
• Patients develop extremely pruritic urticarial and blister-
ing lesions, involving the periumbilical and umbilical skin,
typically in the second and third trimester that usually
resolve several weeks or months after parturition
• Circulating autoantibodies are detectable in over 92% of
the cases using a commercially available ELISA test
Historic notes
This entity was originally described in 1872 by English dermatolo-
gist John Laws Milton, the founder of London’s St John’s Hospital
for Diseases of the Skin [52]. The designation pemphigoid gestatio-
nis has gained favor over herpes gestationis recently to highlight its
close resemblance to bullous pemphigoid with respect to its clini-
cal, histologic, serologic, and immunofluorescent findings.
Diagnosis/Definition
Skin lesions range from urticarial and edematous papules and
plaques that may be annular or polycyclic to grouped (i.e. her-
petiform), tense sub-epidermal blisters (Figure 45.5). Typically,
lesions begin on the abdomen involving the periumbilical and
umbilical skin in contrast to PEP, spreading centrifugally to the
extremities including the palms and soles. As a rule, face and
mucosae are spared. PG usually appears in the second and third
trimester with a mean gestational age of onset that ranges from
21 to 28 weeks [53]. Although clinical course varies, there is a
trend for exacerbation at the time of delivery, corresponding to
the hormonal fluctuation during this period [52]. The disease
usually remits within weeks to months after parturition, but a
small percentage of patients have an unremitting chronic course.
The disease usually recurs during subsequent pregnancies, typi-
cally earlier in onset with increased severity, and may recur with
subsequent menses or oral contraceptive use [52]. The diagnosis
is based on clinical, histologic, serologic, and/or immunofluores-
cent studies. As circulating autoantibodies are detectable in over
FIGURE 45.5 Pemphigoid gestationis. Urticarial annular
plaques on the abdomen of a 31-year-old primigravida with no
prior history of blistering disease. Note the involvement of the
periumbilical skin with grouped tense blisters. (Courtesy of Sylvia
Hsu, MD, Lewis Katz School of Medicine at Temple University.)
Dermatoses of Pregnancy 463

92% of cases, a commercially available ELISA test is becoming the

confirmatory test of choice [54].
Impetigo herpetiformis (pustular
psoriasis of pregnancy)
Symptoms
Similar to other dermatoses of pregnancy and classic bullous Key points
pemphigoid, severe pruritus is a significant symptom for patients
• Impetigo herpetiformis (IH) represents pustular psoriasis
with PG. The sub-epidermal blisters may also cause pain.
that occurs during pregnancy.
• Most patients have no prior history of psoriasis.
Epidemiology/Incidence • There is an increased risk of placental insufficiency and
fetal loss.
PG is a very rare autoimmune blistering disease with an approxi-
• Patients are at risk for recurrence of disease with subse-
mate incidence of 1 in 50,000 births. There is no racial predilec-
quent pregnancies.
tion of the disease.
• The mainstay of therapy is oral corticosteroids.

Genetics
Historic notes
While there is no known genetic basis of the disease, expres-
This disease was first described in 1872 by Von Hebra in a series
sion of major histocompatibility complex (MHC) II HLA-DR3
of five pregnant women, 40 years before the first description of
or HLA-DR4 are highly associated with developing PG as most
generalized pustular psoriasis [56].
patients express one or both of these HLAs [53].

Etiology/Basic pathology Diagnosis/Definition

In contrast to other dermatoses of pregnancy, the pathomecha- IH is characterized by symmetric, erythematous patches with
nism of PG has been well-delineated. Patients with PG develop peripheral superficial sterile pustules (Figure 45.6). There is no
autoantibodies against the transmembrane protein collagen XVII,
also known as BP180, in the basement membrane zone of the
skin [52]. Once the autoantibodies bind to this antigen, a comple-
ment cascade is triggered that recruits additional inflammatory
mediators resulting in local tissue injury and subsequent blisters.
Characteristic histopathologic findings consist of a sub-epidermal
blister accompanied by numerous eosinophils. On perilesional
skin, linear deposition of C3 is uniformly detected, while linear
deposition of IgG is detected in about half of the cases [53, 54].

Complications
PG is associated with prematurity in about 20% of the cases and
small-for-gestational-age weight at birth. Passive transfer of anti-
bodies to the infant occurs in about 5–10% of the cases, resulting
in transient neonatal skin involvement with no long-term adverse
sequelae [53, 54].

Management
Workup
A patient suspected of having PG should undergo lesional and
perilesional skin biopsies for routine histologic examination and
direct immunofluorescence study, respectively. Alternatively,
because the sensitivity of serologic testing is relatively high,
ELISA can be ordered as an additional confirmatory test or in
lieu of the immunofluorescent studies.

Therapy
In mild cases, topical steroid may suffice to control the symp-
toms and skin lesions. In most cases, however, systemic steroid
is required to sufficiently control the disease (e.g. prednisolone
20–40 mg daily or 1–2 mg/kg/day). In recalcitrant unremitting FIGURE 45.6 Impetigo herpetiformis. A 30-year-old pregnant
cases, other systemic agents used in autoimmune diseases may be woman with erythematous plaques studded by numerous pus-
considered such as rituximab, intravenous immunoglobulin, and tules on the trunk and extremities. There was no prior history of
plasmapheresis [55]. psoriasis.
464
underlying infectious etiology despite the name this disor-
der was given. The eruption begins over the intertriginous and
flexural skin and expands outward. Older lesions may become
crusted or secondarily infected.
Symptoms
Patients may report very mild pruritus or burning at the sites
of the lesions; however, most are asymptomatic. There may be
accompanying fever, malaise, diarrhea, and vomiting.
Epidemiology/Incidence
There are no formal epidemiological data. IH is very rare, with
only about 100 cases being reported in the literature. The erup-
tion most often occurs in the third trimester, but can occur as
early as the first trimester. Most women do not have a prior his-
tory of psoriasis.
Genetics
Generalized pustular psoriasis is associated with HLA types B17
and Cw6 [57].
Etiology/Basic pathology
IH is considered a variant of pustular psoriasis that occurs
during pregnancy [36, 57, 58]. The basic underlying etiology is
unknown. Many theories exist including hormonal dysregula-
tion and electrolyte imbalance, but these are based on a few case
reports. Histopathology of the skin shows a characteristic sterile
pustule containing neutrophils in the epidermis referred to as
a spongiform pustule of Kogoj, which is indistinguishable from
findings that are seen in pustular psoriasis. There may also be
elongation of the rete ridges and overlying parakeratosis.
Risk factors/Associations
Patients usually do not have a prior history of psoriasis and there
is no evidence that having such a history increases the risk of IH
in pregnancy [36].
Complications
The most important complication is placental insufficiency and
fetal death, the etiology of which is unknown [36, 57]. There
may be hypocalcemia or decreased vitamin D levels as a result of
hypoparathyroidism or hypoalbuminemia [36, 57, 59]. If severe,
these changes may lead to tetany or seizure.
Management
Principles
Pregnancy is speculated to be a trigger for IH [36]. The effect of
the disease on the pregnancy is discussed earlier.
Workup
Workup includes skin biopsy for routine histopathology as well
as a second specimen for DIF in order to rule out other pregnancy-
specific dermatoses such as PG. When the presentation is accom-
panied by systemic symptoms, systemic infection must be ruled
out with blood cultures as well as bacterial and viral cultures of
Maternal-Fetal Evidence Based Guidelines
one or more pustules. Serum calcium, vitamin D, and parathyroid
hormone levels should be monitored. The patient should be ques-
tioned regarding the history of skin eruptions during any previ-
ous pregnancies.
Prevention
None.
Preconception counseling
Any patient with a history of IH should be counseled that it may
recur with subsequent pregnancies.
Therapy
The mainstay of therapy of IH is corticosteroids, usually in the
form of prednisone at a dose of 15–30 mg/day. Doses as high as
60–80 mg/day may be required [36]. Evidence for corticosteroids
is based on case reports [56–58, 60]. Once the disease is under
control, steroids may be tapered very slowly. Disease rebound is
common with rapid tapering.
When IH is insufficiently controlled with CS alone, the next
therapeutic option is cyclosporine A (CsA). Doses of 3–10 mg/kg/
day have been reported in the treatment of IH [60–62]. Again,
medication should be tapered to the lowest possible dose that
results in control of the disease. The mechanism of action is
inhibition of calcineurin with resultant decrease in interleu-
kin-2 production by CD4+ T cells. CsA also inhibits interferon-γ
production by T cells. CsA is pregnancy category C. The most
serious adverse effects are renal dysfunction and hypertension
[16]. Renal function and blood pressure should be monitored
during therapy. In a study of transplant recipients treated with
CsA during pregnancy there was no evidence of teratogenicity
[63]. However, 44.5% of infants were born at less than 37 weeks’
gestation and 44.3% weighed less than 2500 g at birth [63]. CsA
is excreted in human breast milk and breastfeeding should be
avoided during therapy. Biologic therapies may be considered
as an alternative to cyclosporine or next-in-line therapy. Tumor
necrosis factor (TNF) α inhibitors and ustekinumab are preg-
nancy category B drugs. As no significant pregnancy adverse
outcomes have been observed, TNFα inhibitors such as inflix-
imab may be considered, even as the first-line therapy [64]. No
human safety data during pregnancy are available for newer
biologic agents such as brodalumab, ixekizumab, guselkumab,
secukinumab, and tildrakizumab, but animal studies showed no
adverse effects [16].
Antepartum testing
Patients must be monitored closely with fetal ultrasound and
fetal testing because of the risk of placental insufficiency [56].
Cutaneous melanoma
See Chapter 44, “Cancer.”
Key points
• Pregnancy at the time of diagnosis or subsequent to the
diagnosis of melanoma has no impact on overall survival,
tumor thickness, or disease-free survival.
• Pregnant women who are diagnosed with melanoma
should not be counseled or managed any differently
than a nonpregnant woman with a similar stage of
disease.
Dermatoses of Pregnancy
FIGURE 45.7 Melanoma. A 25-year-old G2P1 with a new,
irregularly pigmented, asymmetric lesion on her back that had
been gradually expanding over the past several months. Note the
irregular borders.
Diagnosis/Definition
Cutaneous melanoma is a malignant neoplasm of melanocytes
that arises in the skin. Melanomas often display irregularities
in color, border, and symmetry, although these observations are
neither sensitive nor specific (Figure 45.7). Even the most experi-
enced dermatologist may have difficulty differentiating a benign
pigmented lesion from a malignant one. The gold standard for
the diagnosis of melanoma is excisional biopsy of the entire
lesion for tissue pathology. Most commonly, a deep shave/sau-
cerization biopsy is performed [65]. Biopsy specimens of all clini-
cally pigmented lesions should be evaluated by an experienced
dermatopathologist.
Symptoms
Melanomas are usually asymptomatic. They may rarely itch or
bleed spontaneously.
Epidemiology/Incidence
In the United States, the lifetime risk of developing melanoma is
about 2.6% (1 in 38) for Caucasians, 0.6% (1 in 167) for Hispanics,
and 0.1% (1 in 1000) for African Americans [66]. While the over-
all incidence is low for all cancers during pregnancy, melanoma
is the most common cancer observed during pregnancy fol-
lowed by cervical and breast carcinoma [67, 68]. The estimated
incidence of melanoma during pregnancy is between 2.8 and 5
in 100,000 [69].
Genetics
A rare group of patients with a family history of melanoma and
many moles may carry germline mutations in CDKN2A and
CDK4. An individual who carries one of these mutations has a
60–90% lifetime risk of melanoma [70]. BRAF and c-KIT repre-
sent known somatic mutations for which systemic therapies have
been developed, interfering with the signaling pathway these
mutations turn on.
465
Classification
There are four main clinical types of melanoma. They are super-
ficial spreading, acral lentiginous, lentigo maligna, and nodular
melanoma. The clinical type bears no significance on the progno-
sis in melanoma. Melanoma is staged based on prognostic factors
such as the Breslow depth, a measure of tumor thickness; ulcer-
ation; non-nodal locoregional metastasis; regional lymph node
spread; and distant metastasis [71].
Risk factors
The major risk factors are fair skin, blue or green eyes, blond
or red hair, inability to tan, intense intermittent sun exposure
(especially during childhood), use of tanning beds, and inherited
mutations in CDKN2A or CDK4 [70].
Complications
Melanoma is a malignant neoplasm that can metastasize to
regional lymph nodes as well as viscera. In general, the thicker
the primary cutaneous melanoma, the higher the likelihood for
metastasis at the time of diagnosis.
Pregnancy considerations
For many years it was believed that pregnancy had an adverse
impact on survival in patients diagnosed with malignant melanoma
(MM). This belief was based on case reports and uncontrolled series
in which confounding variables were not accounted for, namely,
tumor thickness at the time of diagnosis [69, 72]. Several large, ret-
rospective, controlled cohort studies of women who were diagnosed
with melanoma during their pregnancy have confirmed that this
is not the case [69, 73–76]. In fact, these recent large cohort stud-
ies have shown that there is no difference in overall survival or
tumor thickness between pregnant and non-pregnant age- and
disease stage-matched patients [69, 73–76]. The disease-free sur-
vival rate is the same in pregnant and non-pregnant women [74,
75]. Pregnancy in women who have been previously diagnosed
with melanoma does not affect overall survival [75]. An impor-
tant point related to pregnancy and melanoma is the concept that
benign nevi may darken and change during pregnancy. There has
been debate in recent years regarding this belief. The clinical lesions
that are reported by patients to darken or change during pregnancy
are often nonpigmented lesions, such as dermatofibromas or skin
tags [77]. Two studies have shown that nevi on the breast and abdo-
men do increase in size during pregnancy, largely as a consequence
of skin stretching; nevi elsewhere, such as the back and legs, gener-
ally do not expand during pregnancy [65, 78]. Studies do not support
the commonly held belief that nevi darken during pregnancy [78].
Therefore, changing or darkening nevi should be evaluated by a
dermatologist and biopsied if felt to be suspicious clinically or
dermoscopically [65, 78]. The belief that nevi may normally darken
and change during pregnancy may lead to a false sense of security
and a delay in the diagnosis of melanoma [72, 77, 79].
Management
Pregnancy management
There is no difference in pregnancy outcomes including cesarean
delivery, length of stay, risk of low birthweight, prematurity, or
neonatal death [72]. Pregnant women who are diagnosed with
466
melanoma should not be counseled any differently than non-
pregnant women with a similar stage of disease with respect to
both pregnancy outcomes and their overall prognosis [72, 75].
There are approximately 22 cases of placental metastases of mela-
noma reported in the literature. Indeed, of all malignancies that
tend to metastasize to the placenta, melanoma is the most com-
mon [72]. However, metastasis to the fetus and/or placenta is an
extremely rare event and has occurred exclusively in the setting of
hematogenous dissemination of metastatic disease in the mother
[80–82]. Placental involvement implies a fatal prognosis for the
mother and approximately 22% risk of metastasis to the fetus [82].
Workup
The extensiveness of the workup of primary cutaneous melanoma
is primarily based on tumor thickness at the time of diagnosis.
Initial diagnosis is made by tissue pathology. It is strongly rec-
ommended that all suspicious lesions be removed by excisional
biopsy with narrow margins for diagnostic purposes [65]. Once
the diagnosis of melanoma is made, all patients should have a
thorough review of systems and physical exam, with special
attention given to the lymph nodes. There is no evidence that rou-
tine laboratory tests and imaging studies detect occult metasta-
ses in asymptomatic patients with tumors less than 4.0 mm in
thickness [70, 72]. Therefore, chest radiography is reserved for
patients who are symptomatic or with stage IIB or higher mela-
noma, and serum lactate dehydrogenase evaluation is reserved
for patients with stage IV disease [65]. Patients should be taught
to give themselves monthly self-exams and should be seen one
to four times per year for the first 2 years after the initial diag-
nosis and then 1–2 times yearly thereafter, depending on stage at
diagnosis [65]. The goal of follow-up is to detect recurrence or a
new primary lesion. Screening tests should be ordered based on
history and physical examination findings during follow-up care.
Sentinel lymph node biopsy in melanoma is used as a staging
procedure. It is used to detect occult nodal metastases at the time
of diagnosis and is generally reserved for patients with tumors
that are 1.0 mm or greater in thickness and for lesions that are
less than 1.0 mm but are associated with presence of an ulcer [83].
Sentinel lymph node biopsy is typically performed at the time of
definitive excision. This procedure is considered safe to perform
during pregnancy [72]. For patients with microscopic or clinically
apparent nodal disease, a full metastatic work up is indicated [72],
including bloodwork and CT or MRI of the chest, abdomen, and
pelvis. MRI is preferable in pregnant patients because it is the
safer alternative [72].
Prevention
General preventative measures include the use of sun protection
via sunscreens and protective clothing, especially during child-
hood and adolescence. Regular skin examination by a physician
is recommended. Melanomas that are detected by a physician
are diagnosed at an earlier stage than those detected by patients;
however, evidence for a direct reduction in mortality is low [84].
Preconception counseling
Since melanomas tend to recur within the first 2–3 years after
diagnosis, women diagnosed with higher risk melanomas (stage II
or higher) should be counseled to wait this length of time before
conceiving [65]. Again, there is no evidence that pregnancy results
in a higher rate of recurrence, but it seems unwise to conceive
if there is any risk for recurrence of a potentially fatal disease.
Additionally, in patients diagnosed with melanoma, future use
Maternal-Fetal Evidence Based Guidelines
of oral contraceptives and hormone replacement therapy has not
been shown to enhance the risk for developing melanoma [75].
Therapy
The treatment of melanoma is primarily surgical. After the ini-
tial diagnostic biopsy, excision of the primary lesion with
0.5–2 cm margins, depending on tumor thickness, is recom-
mended [65]. Patients with metastatic melanoma had limited
therapeutic options historically, but significant advances in tar-
geted molecular therapy have resulted in several FDA-approved
systemic agents. Combined BRAF and MEK inhibitors, such as
dabrafenib/trametinib and vemurafenib/cobimetinib, have been
approved for patients with metastatic melanoma associated with
a BRAF V600_ mutation [85]. Immune checkpoint inhibitors such
as ipilimumab, targeting CTLA-4, and nivolumab and pembroli-
zumab, targeting PD-1, have also been approved for the treatment
of metastatic melanoma [86]. Human data on safety of these new
targeted therapies during pregnancy is not available. One case of
successful delivery of a premature healthy baby exposed to vemu-
rafenib has been reported [87].
References
1. Chang ALS, Agredano YZ, Kimball AB. Risk factors associated with striae
gravidarum. J Am Acad Dermatol 2004;51:881–85. [III]
2. Wang F, Calderone K, Do TT, Smith NR, et al. Severe disruption and dis-
organization of dermal collagen fibrils in early striae gravidarum. Br J
Dermatol. 2018;178(3):749–60. [II-2]
3. Watson REB, Parry EJ, Humphries JD, et al. Fibrillin microfibrils are
reduced in skin exhibiting striae distensae. Br J Dermatol 1998;138:931–37.
[II-3]
4. Picard D, Sellier S, Houivet E, et al. Incidence and risk factors for striae
gravidarum. J Am Acad Dermatol 2015;73(4):699–700. [II-2]
5. Hocaoglu E, Hocaoglu M, Akdeniz E. Association between serum
25-hydroxyvitamin D levels and the presence and severity of striae gravi-
darum in primigravid women. J Cosmet Dermatol. 2020;19(11):3107–14.
[II-3]
6. Brennan M, Young G, Devane D. Topical preparations for preventing stretch
marks in pregnancy. Cochrane Database Syst Rev. 2012;11:CD000066.
[Meta-analysis; I; 6 RCTs, n = 800]
7. Osman H, Usta IM, Rubeiz N, et al. Cocoa butter lotion for prevention of
striae gravidarum: a double-blind, randomized and placebo-controlled
trial. Br J Obstet Gynecol 2008;115:1138–42. [RCT, n = 175]
8. Buchanan K, Fletcher HM, Reid M. Prevention of striae gravidarum with
cocoa butter cream. Int J Gynaecol Obstet 2010;108(1):65–8. [I]
9. Soltanipoor F, Delaram M, Taavoni S, Haghani H. The effect of olive oil
on prevention of striae gravidarum: a randomized controlled clinical trial.
Complement Ther Med 2012;20(5):263–6. [I]
10. Soltanipour F, Delaram M, Taavoni S, Haghani H. The effect of olive oil and
the Saj® cream in prevention of striae gravidarum: A randomized controlled
clinical trial. Complement Ther Med 2014;22(2):220–5. [I]
11. Taavoni S, Soltanipour F, Haghani H, Ansarian H, Kheirkhah M. Effects
of olive oil on striae gravidarum in the second trimester of pregnancy.
Complement Ther Clin Pract 2011;17(3):167–9. [I]
12. Hajhashemi M, Rafieian M, Rouhi Boroujeni HA, et al. The effect of Aloe
vera gel and sweet almond oil on striae gravidarum in nulliparous women. J
Matern Fetal Neonatal Med 2018;31(13):1703–8. [I]
13. García Hernández JÁ, Madera González D, Padilla Castillo M, Figueras
Falcón T. Use of a specific anti-stretch mark cream for preventing or reduc-
ing the severity of striae gravidarum. Randomized, double-blind, controlled
trial. Int J Cosmet Sci 2013;35(3):233–7. [I]
14. Kang S, Kim KJ, Griffiths CEM, et al. Topical tretinoin (retinoic acid)
improves early stretch marks. Arch Dermatol 1996;132:519–26. [I]
15. Pribanich S, Simpson FG, Held B, et al. Low-dose tretinoin does not
improve striae distensae: a double-blind, placebo-controlled study. Cutis
1994;54:121–4. [I]
16. Wolverton SE. Comprehensive Dermatologic Drug Therapy. Philadelphia:
Elsevier, 2021:529–532, 355, 187–197, 714–724. [III]
17. Kligman AM, Grove GL, Hirose R, et al. Topical tretinoin for photodam-
aged skin. J Am Acad Dermatol 1986;15:836–59. [II-1]
Dermatoses of Pregnancy
18. McDaniel DH. Laser therapy of stretch marks. Dermatol Clin 2002;20:67–
76. [III]
19. Goldberg DJ, Marmur ES, Schmults C, et al. Histologic and ultrastructural
analysis of ultraviolet B laser and light source treatment of leukoderma in
striae distensae. Dermatol Surg 2005;31:385–87. [II-3]
20. Crocco EI, Muzy G, Schowe NM, Albuquerque MS, Barros MD, Buck HS.
Fractional ablative carbon-dioxide laser treatment improves histologic and
clinical aspects of striae gravidarum: A prospective open label paired study.
J Am Acad Dermatol 2018;79(2):363–4. [II-1]
21. Wang K, Ross N, Osley K, Sahu J, Saedi N. Evaluation of a 1540-nm and
a 1410-nm Nonablative Fractionated Laser for the Treatment of Striae.
Dermatol Surg 2016;42(2):225–31. [II-1]
22. Tian T, Luo Y-J, Wang H, Chen H-D, Li Y-H. Efficacy and Safety of a
Sublative Bipolar Fractional Radiofrequency System Combined With
Topical Tretinoin in Treating Striae Gravidarum: A Randomized Pilot
Study. Dermatol Surg 2019;45(10):1245–52. [I]
23. Lawley TJ, Hertz KC, Wade TR, et al. Pruritic urticarial papules and plaques
of pregnancy. J Am Med Assoc 1979;241:1696–9. [III]
24. Roger D, Vaillant L, Lorette G. Pruritic urticarial papules and plaques of
pregnancy are not related to maternal or fetal weight gain. Arch Dermatol
1990;126:1517. [III]
25. Cohen LM, Capeless EL, Krusinski PA, et al. Pruritic urticarial papules and
plaques of pregnancy and its relationship to maternal-fetal weight gain and
twin pregnancy. Arch Dermatol 1989;125:1534–6. [III]
26. Aronson IK, Bond S, Fiedler VC, et al. Pruritic urticarial papules and
plaques of pregnancy: clinical and immunopathologic observations in 57
patients. J Am Acad Dermatol 1998;39:933–9. [II-3]
27. Powell FC. Pruritic urticarial papules and plaques of pregnancy and mul-
tiple pregnancies. J Am Acad Dermatol 2000;43:730–1. [II-3]
28. Weiss R, Hull P. Familial occurrence of pruritic urticarial papules and
plaques of pregnancy. J Am Acad Dermatol 1992;26:715–7. [III]
29. Yancey KB, Hall RP, Lawley TJ. Pruritic urticarial papules and plaques of
pregnancy: clinical experience in twenty-five patients. J Am Acad Dermatol
1984;10:473–80. [II-3]
30. Beckett MA, Goldberg NS. Pruritic urticarial papules and plaques of preg-
nancy and skin distension. Arch Dermatol 1991;127: 125–6. [III]
31. Kroumpouzos G, Cohen LM. Specific dermatoses of pregnancy: an evi-
dence-based systematic review. Am J Obstet Gynecol 2003;188:1083–92.
[Meta-analysis; I; n = 282]
32. Callen JP, Hanno R. Pruritic urticarial papules and plaques of pregnancy
(PEP). J Am Acad Dermatol 1981;5:401–5. [II-3]
33. Vaughan Jones SA, Hern S, Nelson-Piercy C, et al. A prospective study of
200 women with dermatoses of pregnancy correlating clinical findings with
hormonal and immunopathological profiles. Br J Dermatol 1999;141:71–81.
[II-2; n = 44]
34. Aractingi S, Berkane P, LeGoue’ C, et al. Fetal DNA in skin of polymorphic
eruptions of pregnancy. Lancet 1998;352:1898–901. [II-2]
35. Alcalay J, Ingber A, Kafri B, et al. Hormonal evaluation and autoimmune
background in pruritic urticarial papules and plaques of pregnancy. Am J
Obstet Gynecol 1988;158:417–20. [II-3]
36. Kroumpouzos GK, Cohen LM. Dermatoses of pregnancy. J Am Acad
Dermatol 2001;45:1–19. [III]
37. Alcalay J, Ingber A, David M, et al. Pruritic urticarial papules and plaques of
pregnancy. J Reprod Med 1987;32:315–6. [II-3]
38. Chi C-C, Wang S-H, Wojnarowska F, Kirtschig G, Davies E, Bennett C.
Safety of topical corticosteroids in pregnancy. Cochrane Database Syst
Rev. 2015;(10):CD007346. [Meta-analysis; I; 5 cohort studies, 9 case-control
studies, n = 1,601,515]
39. Chi C-C, Kirtschig G, Aberer W, et al. Updated evidence-based (S2e)
European Dermatology Forum guideline on topical corticosteroids in preg-
nancy. J Eur Acad Dermatol Venereol. 2017;31(5):761–73. [Review; III]
40. Xiao W-L, Liu X-Y, Liu Y-S, Zhang D-Z, Xue L-F. The relationship between
maternal corticosteroid use and orofacial clefts-a meta-analysis. Reprod
Toxicol. 2017;69:99–105. [Meta-analysis; I; 7 case-control studies, 5 cohort
studies, n = 1,023,361]
41. Bandoli G, Palmsten K, Forbess Smith CJ, Chambers CD. A review of systemic
corticosteroid use in pregnancy and the risk of select pregnancy and birth out-
comes. Rheum Dis Clin North Am. 2017;43(3):489–502. [Review; III]
42. Beltrani VP, Beltrani VS. Pruritic Urticarial papules and plaques of preg-
nancy: a severe case requiring early delivery for relief of symptoms. J Am
Acad Dermatol 1991;26:266–7. [III]
43. Ambros-Rudolph CM, Müllegger RR, Vaughan-Jones S, et al. The specific
dermatoses of pregnancy revisited and reclassified: results of a retrospec-
tive two-center study on 505 pregnant patients. J Am Acad Dermatol
2006;54:395–404. [II-2]
467
44. Cohen LM, Kroumpouzos G. Pruritic dermatoses of pregnancy: to lump or
to split? J Am Acad Dermatol 2007;56:708–9. [II-2]
45. Ambros-Rudolph CM, Jones SV, Black MM. Best serving the pregnant
patient with pruritus. J Am Acad Dermatol 2008;59:530–1. [II-2]
46. Roth MM. Pregnancy dermatoses: diagnosis, management, and controver-
sies. Am J Clin Dermatol 2011;1:25–41. [Review]
47. Ambros-Rudolph CM. Dermatoses of pregnancy. J Dtsch Dermatol Ges
2006;9:748–59. [Review]
48. Kramer MS, Kakuma R. Maternal dietary antigen avoidance during preg-
nancy or lactation, or both, for preventing or treating atopic disease in the
child. Evid Based Child Health 2014;9:447–8. [Review; I]
49. Netting MJ, Middleton PF, Makrides M. Does maternal diet during preg-
nancy and lactation affect outcomes in offspring? A systematic review of
food-based approaches. Nutrition 2014;30: 1225–41. [Review; I]
50. Massone C, Cerroni L, Heidrun N, et al. Histopathological diagnosis of
atopic eruption of pregnancy and polymorphic eruption of pregnancy: a
study on 41 cases. Am J Dermatopathol 2014;36:812–21. [Review; II-3]
51. Babalola O, Strober BE. Treatment of atopic dermatitis in pregnancy.
Dermatol Ther 2013;26: 293–301. [III]
52. Al-Fouzan AS, Galadari I, Oumeish I, et al. Herpes gestationis (Pemphigoid
gestationis). Clinics in Dermatology 2006;24, 109–12. [Review; II-3]
53. Semkova K, Black M. Pemphigoid gestationis: Current insights into patho-
genesis and treatment. Eur J Obstet Gynecol Reprod Biol 2009;145:138–44.
[Review; II-3]
54. Tani N, Kimura Y, Kawakami KT, et al. Clinical and immunological profiles
of 25 patients with pemphigoid gestationis. Br J Dermatol 2015;172:120–9.
[II-3]
55. Lehrhoff S, Pomeranz M. Specific dermatoses of pregnancy and their treat-
ment. Dermatol Ther 2013;26: 274–84. [Review; III]
56. Lotem M, Katzenelson V, Rotem A, et al. Impetigo herpetiformis: a vari-
ant of pustular psoriasis or a separate entity? J Am Acad Dermatol 1989;20:
338–41. [III]
57. Breier-Maly J, Ortel B, Breier F, et al. Generalized pustular psoriasis of preg-
nancy (impetigo herpetiformis). Dermatology 1999;198:61–4. [III]
58. Chang SE. Impetigo herpetiformis followed by generalized pustular
psoriasis: more evidence of the same disease entity. Int J Soc Dermatol
2003;42:754–5. [III]
59. Ott F, Krakowski A, Tur E, et al. Impetigo herpetiformis with lowered serum
level of vitamin D and its diminished intestinal absorption. Dermatologica
1982;164:360–5. [III]
60. Imai N, Watanabe R, Fujiwara H, et al. Successful treatment of impetigo
herpetiformis with oral cyclosporine during pregnancy. Arch Dermatol
2002;138:128–9. [III]
61. Raddadi AA, Damanhoury ZB. Cyclosporin and pregnancy. Br J Dermatol
1999;140:1197–8. [III]
62. Finch TM, Tan CY. Pustular psoriasis exacerbated by pregnancy and con-
trolled by cyclosporine A. Br J Dermatol 2000;142: 582–4. [III]
63. Lamarque V, Leleu MF, Monka C, et al. Analysis of 629 pregnancy out-
comes in transplant recipients treated with sandimmun. Transpl Proc
1997;29:2480. [II-3; n = 629]
64. Bae YC, Van Voorhees AS, Hsu S, et al. Review of treatment options for
psoriasis in pregnant or lactating women: From the Medical Board of the
National Psoriasis Foundation. J Amer Acad Dermatol 2012;67: 459–77.
[Review; III]
65. Swetter SM, Tsao H, Bichakjian CK, et al. Guidelines of care for the
management of primary cutaneous melanoma. J Am Acad Dermatol
2019;80(1):208–50. [III]
66. American Cancer Society. About Melanoma Skin Cancer. Revised August
14, 2019. https://www.cancer.org/content/dam/CRC/PDF/Public/8823.00.
pdf (Accessed on September 14, 2020). [III]
67. Andersson TM, Johansson AL, Fredriksson I, et al. Cancer during preg-
nancy and the postpartum period: a population-based study. Cancer
2015;121:2072–77. [II-2]
68. Eibye S, Kjær SK, Mellemkjær L. Incidence of pregnancy-associated cancer
in Denmark, 1977–2006 Obstet Gynecol 2013;122:608–17. [II-2]
69. Lens MB, Rosdahl I, Ahlbom A, et al. Effect of pregnancy on survival in
women with cutaneous malignant melanoma. J Clin Oncol 2004;22:
4369–75. [II-2]
70. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl
J Med 2004;351:998–1012. [III]
71. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-
based changes in the American Joint Committee on Cancer eighth edition
cancer staging manual. CA Cancer J Clin. 2017;67(6):472–92. [III]
72. Katz VL, Farmer RM, Dotters D. From nevus to neoplasm: myths of mela-
noma in pregnancy. Obstet Gynecol Surv 2002;57:112–9. [III]
468
73. O’Meara AT, Cress R, Xing G, et al. Malignant melanoma in pregnancy. A
population-based evaluation. Cancer 2005;103:1217–26. [II-2]
74. Daryanani D, Plukker JT, De Hullu JA, et al. Pregnancy and early-stage
melanoma. Cancer 2003;97:2248–53. [II-2]
75. Gupta A, Driscoll MS. Do hormones influence melanoma? Facts and con-
troversies. Clin Dermatol 2010;28:287–92. [III]
76. Johansson AL, Andersson TML, Plym A, et al. Mortality in women
with pregnancy-associated malignant melanoma. J Am Acad Dermatol
2014;71:1093–101. [III]
77. Foucar E, Bentley TJ, Laube DW, et al. A histopathologic evaluation of nevo-
cellular nevi in pregnancy. Arch Dermatol 1985;121:350–4. [II-2]
78. Bieber AK, Martires KJ, Driscoll MS, Grant-Kels JM, Pomeranz MK, Stein
JA. Nevi and pregnancy. J Am Acad Dermatol. 2016;75(4):661–6. [I]
79. Pennoyer JW, Grin CM, Driscoll MS, et al. Changes in size of melanocytic
nevi during pregnancy. J Am Acad Dermatol 1997;36:378–82. [II-2]
80. Borden EC. Melanoma and pregnancy. Semin Oncol 2000;27:654–6. [III]
81. Altman JF, Lowe L, Redman B, et al. Placental metastasis of maternal mela-
noma. J Am Acad Dermatol 2003;49:1150–54. [III]
82. Alexander A, Harris RM, Grossman D, et al. Vulvar melanoma: diffuse melanosis
and metastasis to the placenta. J Am Acad Dermatol 2004;50:293–8. [III]
Maternal-Fetal Evidence Based Guidelines
83. Wong SL, Faries MB, Kennedy EB, et al. Sentinel lymph node biopsy and
management of regional lymph nodes in melanoma: American Society
of Clinical Oncology and Society of Surgical Oncology Clinical Practice
Guideline Update. J Clin Oncol. 2018;36(4):399–413. [III]
84. Brunssen A, Waldmann A, Eisemann N, Katalinic A. Impact of skin cancer
screening and secondary prevention campaigns on skin cancer incidence
and mortality: A systematic review. J Am Acad Dermatol. 2017;76(1):129–
139.e10. [Systematic review; 11 ecological studies, 1 stimulation study, 1
survey, 1 case-control study, 1 cohort study]
85. Kakadia S, Yarlagadda N, Awad R, et al. Mechanisms of resistance to
BRAF and MEK inhibitors and clinical update of US Food and Drug
Administration-approved targeted therapy in advanced melanoma.
OncoTargets and Therapy. 2018;11:7095–107. [Review; III]
86. Queirolo P, Boutros A, Tanda E, Spagnolo F, Quaglino P. Immune-
checkpoint inhibitors for the treatment of metastatic melanoma: a
model of cancer immunotherapy. Semin Cancer Biol. 2019;59:290–7.
[Review; III]
87. Maleka A, Enblad G, Sjörs G, Lindqvist A, Ullenhag GJ. Treatment of meta-
static malignant melanoma with vemurafenib during pregnancy. J Clin
Oncol 2013;21:e192–e193. [III]
46
MULTIPLE GESTATIONS
Edward J. Hayes and Michelle R. Hayes
Key points
• Determination of chorionicity by early (preferably first
trimester) ultrasound is of paramount importance for
appropriate management of multiple gestations.
• Preterm birth (PTB) is the main reason for the increased
morbidity and mortality associated with multiples.
• Multifetal pregnancy reduction should be offered in
higher-order gestations (triplets or higher) to decrease the
likelihood of PTB.
• Transvaginal ultrasound (TVU) cervical length (CL)
screening at 18–23 weeks in twin gestations can be consid-
ered, as vaginal progesterone is associated in a decrease
in PTB in twins with a TVU CL ≤25 mm before 24 weeks.
• Physical exam-indicated cerclage in diamniotic twins
with cervical dilation about 1–4 cm before 24 weeks
should be recommended, as it is associated with significant
decreases in PTB and perinatal mortality.
• For noninvasive aneuploidy screening, nuchal translu-
cency (NT) testing can be used in any multifetal gestation.
Sequential screening (NT and serum analytes) can be used
in twin gestations. Cell-free DNA has been shown to be an
effective screening modality for trisomy 21 in twins, how-
ever the predictive performance for trisomies 18 and 13 has
yet to be determined.
• Multiples have higher rates of pre-eclampsia. To decrease
the likelihood of developing pre-eclampsia, patients with
multiple gestations should start low-dose aspirin, 81 mg
per day, between 12 weeks and 28 weeks (optimally before
16 weeks) and continue it daily until delivery.
• Ultrasounds for estimated fetal weight (EFW) and amni-
otic fluid assessment should be performed after 20 weeks
about every 4 weeks in all multiple gestations.
• Discordant growth (e.g. >20%) between multiples may be
a marker for genetic or structural anomalies, infection,
twin-to-twin transfusion, or placental issues; however,
evidence of FGR (EFW <10% or abdominal circumference
<10%), not discordance, best predicts adverse neonatal
outcome.
• A single fetal death in multiple gestations should not
mandate immediate delivery; the risk of disseminated
intravascular coagulation (DIC) is extremely small, and
if they are monochorionic, adverse effects on the remain-
ing fetus have already occurred at the time of the co-twin
death.
• Routine antepartum testing has not been proven to be
advantageous in multiple gestations without coexisting
morbidity.
• Chorionicity and amnionicity of otherwise uncom-
plicated twin gestations determine timing of delivery.
Monoamniotic twins (MA/MC) should be delivered
at around 32°–346 weeks. Monochorionic diamniotic
DOI: 10.1201/9781003099062-46
(MC/DA) should be delivered at around 34°–366 weeks.
Dichorionic/diamniotic (DC/DA) should be delivered
around 37°–376 weeks.
• Twin-to-twin transfusion syndrome has significant
perinatal mortality (>70%) if left untreated, particularly
if diagnosed in the second trimester. Laser coagulation is
the treatment of choice for stages II-IV between 16 and 24
weeks gestation.
Definition
Multiple gestation is a gestation carrying >1 fetus. The over-
whelming majority are twins. There are two types of twins:
• Monozygotic (MZ) twins are formed when a single fer-
tilized ovum splits into two individuals who are almost
always genetically identical, unless after their division a
there is a spontaneous mutation.
• Dizygotic (DZ) twins are formed when two separate ova
are fertilized by two different sperm resulting in geneti-
cally different individuals.
Epidemiology/Incidence
It is important to differentiate the natural from the actual inci-
dence of multiple gestations. Natural incidence of multiple gesta-
tions (Figure 46.1):
• MZ twining occurs at a constant rate of about 4 per 1000
(1/250)
• DZ twining rates vary with the individual’s characteristics,
such as race (low in Asians, high in blacks), age (increases
with advanced maternal age), parity (increases with parity),
and family history (especially on maternal side). The “natu-
ral” incidence of twins and triplets in the United States as
reported in 1973 was 1 in 80 and 1 in 800 respectively [1].
Actual incidence of multiple gestations has been heavily influ-
enced by use of assisted reproductive technologies (ART) since
the 1980s. Currently >50% of multiple gestations in developed
countries are from ART. The proportion of live births that are
multiple gestations in the United States has increased signifi-
cantly over the last three decades in association with the increase
use of ART treatments, with a 65% increase in twins and a 500%
increase in triplets and higher-order births which peaked in 1998
[2]. Understanding the significant morbidity and mortality asso-
ciated with higher order multiples, there has been a 70% reduction
in the transfer of three or more embryos during an IVF cycle. This
has resulted in a 52% decrease in the proportion of triplets and
higher-order births attributable from 193.5 per 100,000 births in
1998 to 93.5 in 2018 [3]. This trend is also reflected in twins fol-
lowing more than three decades of increases, the twin birth rate
469
470 Maternal-Fetal Evidence Based Guidelines

Twins

Cleavage
Monozygotic (20–33%) Dyzygotic (67–80%)

Days 1–3

DC/DA MC/MA Conjoined DC/DA

(15–25%) (1–2%) (rare) (100%) Morula
Dichorionic/Diamniotic
MC/DA
(75%)
(~3/1,000 pregnancies)
Cleavage
FIGURE 46.1 Natural incidence of twin gestations.
Days 4–8

declined 4% during 2014–2018, to the lowest rate in more than a

Blastocyst
decade, 32.6 twins per 1000 total births in 2018 [4] Although the
vast majority of these pregnancies are DZ, MZ twin rates increase Monochorionic/Diamniotic
with ART to 3–5% [5], stressing the importance of determining
chorionicity even when multiples were conceived via ART.
Cleavage
Etiology
Days 8–13
DZ twins are formed by two distinct fertilized ova and always
have separate chorion and amnion (Dichorionic/Diamniotic, DC/
DA). Implanted
Blastocyst
MZ twin are formed from the division of one fertilized egg. The Monochorionic/Monoamniotic
type is determined by the timing of the fertilized ovum division
(Figure 46.2).

Diagnosis Cleavage

The clinical signs for suspecting multiple gestations are a uterus
larger than dates, and pregnancy that has resulted from ART.
The accuracy of diagnosing twins on clinical criteria is poor, as
37% of women who do not undergo routine ultrasound screen-
ing will not have their twins diagnosed by 26 weeks, and 13%
of multiples will only be diagnosed at the time of admission for
delivery [6].
Ultrasound is 100% accurate in diagnosing multiple gesta-
tions [6]. The best time for accurate diagnosis is the first trimester,
as this is the optimum time to determine not only fetal number,
but especially chorionicity and amnionicity. Determination of
chorionicity and zygocity is paramount for correct risk assess-
ment, counseling, and management of complications (e.g. TTTS,
FGR, single fetal death). In addition, this determination will help
future medical care of the babies for genetic component of dis-
eases and organ transplantation compatibility.
Determination of chorionicity and amnionicity in the first
trimester is shown in Figure 46.3. Determination of chorion-
icity and amnionicity status after first trimester is shown in
Figures 46.4 and 46.5. In the 30–40% of cases in which there are
clearly two placentas, or differing fetal sex, the pregnancy is DC/
DA, and dizygotic. In the majority of cases, the best ultrasound
characteristic to distinguish chorio- and amnionicity is the twin
peak sign. Twin peak sign (also called lambda or delta sign) is a
triangular projection of tissue with the same echogenicity as the
placenta extending beyond the chorionic surface of the placenta
(Figure 46.5) [7]. DNA fingerprinting through polymorphisms or
other means can also determine zygocity, but it is invasive and
therefore associated with complications.
Days 13–15
Formed
Embryonic Disc Conjoined Twins
FIGURE 46.2 Timing of zygote division and types of
twins. (With permission from Dufendach, K. [Artist], 2008.
Placentation. Retrieved from http://commons.wikimedia.org/
wiki/File:Placentation.svg.)
Complications
The incidence and severity of complications is related to chorion-
icity and amnionicity. ART multiple pregnancies are associated
with a higher incidence of fetal/neonatal and maternal complica-
tions. Complications more common in all types of multiple gesta-
tions compared to singleton gestations follow.
Fetal
Spontaneous pregnancy loss
A significant number of multiple gestations diagnosed in the
first trimester undergo spontaneous reduction of one sac in the
first trimester, referred to as the “vanishing twin.” The rates of
wastage of at least one gestation is increased compared to sin-
gletons both in the first and even the second trimester, and is
directly correlated with the initial number of gestational sacs, i.e.
about 20–50% of twins, 53% of triplets, and 65% of quadruplet
[8]. If vanishing twin, fetal demise, or anomaly is identified in
Multiple Gestations 471

Count the number of sacs

and the number of fetuses
to determine chorionicity

Each sac has only one fetus Sac has two or more fetuses

The number of Monochorionic:

amnion and Wait till at least 8
chorions are equal weeks (best 9 to 10)
(dischorionic when the amnion is
diamniotic twins) seen separate from the
embryo to determine
amnionicity

One amnion containing at least two embryos

One amniotic sac per embryo

Monoamniotic gestation Multiple amniotic sacs within a

ie. Monoamniotic twins single chorion
ie. Diamniotic Monochorionic Twins

FIGURE 46.3 Determination of chorionicity and amnionicity in the first trimester.

one fetus, there is significant risk of an inaccurate test result if pregnancy, especially in the first but also in the second trimester,
serum based aneuploid screening or cell free DNA is used [9], and is increased.
therefore should be avoided. The risk of miscarriage of the whole
Higher rates of chromosomal and
congenital anomalies
Number of Due to the increased number of fetuses, particularly dizygotic,
placentas the risk of having one fetus affected by a trisomy is increased
above the baseline risk of a singleton [10]. Therefore the Downs
Two syndrome risk of a 35-year-old singleton mother is obtained in
twins at about age 31–33 [11], and for triplets this risk is obtained
One or unknown
at about age 28 [12]. Structural defects occur two to three times
more commonly in live-born MZ twins than in DZ twins or sin-
Dichorionic
gletons [13]. However, in only 5–20% are both MZ twins affected
Fetal Sex Diamniotic
Different with the same structural defect.

Fetal growth restriction and discordant growth

Same or unknown Twin Peak sign Discordant growth of multiples is usually defined as a 20–25%
Thick membrane > 2mm reduction in EFW of the smaller compared to the larger fetus
Three or four layers (difference of larger minus smaller EFW, divided by larger EFW).
Approximately 14% of DCDA twins have 20% discordance [14].
Discordance may be a marker for structural or genetic anomalies,
Dividing membrane
characteristics infection, twin to twin transfusion syndrome, or placental issues.
However, it is not the discordance per se, but evidence of FGR of
one fetus that predicts adverse neonatal outcome [15]. The risk of
Absent mortality or neonatal morbidity is higher among neonates in SGA-
No twin peak sign
Thin membrane discordant twins than in AGA-discordant twins (20% vs. 6%) [16].
Two layers
Single fetal demise in multiple gestations
Up to 5% of twins and 17% of triplets in the second or third tri-
Monochorionic Monochorionic mester undergo spontaneous loss of one or more fetuses [17].
monoamniotic diamniotic Preterm birth is the most common consequence, but the survivor
is at increased risk for perinatal demise and long-term neurode-
velopmental comorbidity [18]. This magnitude of this risk is asso-
FIGURE 46.4 Determination of chorionicity and amnionicity
ciated with chorionicity (Table 46.1).
after the first trimester.
472 Maternal-Fetal Evidence Based Guidelines

FIGURE 46.5 T-sign and twin-peak sign. On the left: T-sign (MC/DA gestation); always monozygotic. On the right: twin-peak sign
(DC/DA gestation).

Complications specific to monochorionic gestations multiples, for twins may have a higher rate of RDS when matched
Twin-twin transfusion syndrome (TTTS), acardiac twins, mono- with gestational- age-matched singletons (Table 46.2) [22].
amniotic twins, and conjoined twins are all complications associ-
ated with monochorionicity. They are described later. Maternal
In addition to above: Heartburn, hemorrhoids, tiredness, anxi-
Preterm birth ety, hyperemesis gravidarum, anemia, postpartum hemor-
Preterm birth (PTB) is the main reason for the increased rhage, postpartum depression, death, as well as the following.
morbidity and mortality associated with multiples. Increasing
numbers of fetuses are inversely associated with gestational age Pre-eclampsia
at birth, so that 20.5% of twins in the United States deliver at Multiples have a higher rate of pre-eclampsia, whose incidence
less than 34 weeks, while 82.6% of quadruplets deliver prior to is inversely proportional to the total fetal number. Increasing
34 weeks [3]. Also the way the multiples were conceived plays a incidence of pre-eclampsia with twins (8%), triplets (10%), and
role in determining the gestational age of delivery, for twins con-
ceived after in vitro fertilization are more likely deliver prior to 32 TABLE 46.2: Delivery and Infant Outcomes per Number of
weeks than spontaneously conceived twins (OR 1.52 [1.18–1.97]) Fetuses
[19]. Earlier delivery explains why multiples are 10 times as likely
to be very low birth weight than singletons (11.6% vs. 1.1%) [20]. Characteristic Singleton Twins Triplets Quadruplets
However the earlier gestational age at delivery does not solely Mean birth weight (grams) a 3296 2336 1660 1291
explain the higher rates of morbidity [21] and mortality [21] in Mean gestational age at 38.7 35.3 31.9 29.5
delivery (weeks)a
Delivery <34 weeksb 2.1% 19.5% 63.1% 82.6%
TABLE 46.1: Consequences of Single Fetal Death in Twin Very low birth weight 1.09% 9.07% 33.60% 50.44%
Pregnancies, According to Chorionicity (<1500 grams)b
Rate of cerebral palsy per 1.6 7 28 N/A
Odds Ratio Comparing
1000 live birthsc
MC DC MC vs. DC
Infant mortality rate 5.36 23.62 52.49 96.29e
Co-twin death 41% 22.4% 2.06 [95% CI 1.14–3.71] per 1,000d
Preterm birth 58.5% 53.7% 1.42 [95% CI 0.67–2.99] a Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Kirmeyer S, Mathews TJ, Wilson
Abnormal postnatal 43% 21.2% 5.41 [95% CI 1.03–28.58] EC. Births: final data for 2009 Natl. Vital Stat. Rep., 2011, 60, 1, 1–70, United States.
cranial imaging b Martin JA, Hamilton BE, Osterman MJK, Driscoll AK. Births: final data for 2018.
Neonatal death 27.9% 21.2% 1.95 [95% CI 1.00–3.79] Natl. Vital Stat. Rep. 68, 13. Hyattsville, MD: National Center for Health Statistics.
Neuro-developmental 28.5% 10% 3.06 [95% CI 0.88–10.61] 2019.
c Petterson B, Nelson KB, Watson L, Stanley F. Twins, triplets and cerebral palsy in
comorbidity
births in Western Australia. BMJ 1993;307:1239–43.
Source: Adapted from Mackie FL, Rigby A, Morris RK, Kilby MD. Prognosis of the d Luke B, Brown M. The changing risk of infant mortality by gestation, plurality, and
co-twin following spontaneous single intrauterine death in twin pregnancies: race: 1989–1991 versus 1999–2001. Pediatrics 2006;118: 2488–97.
a systematic review and meta-analysis. BJOG 2019;126:569–578. [II-1]. e Quadruplets and quintuplets combined.
Multiple Gestations
quadruplets (12%) has been reported [23]. Multiples, besides having
a higher rate of pre-eclampsia, are more likely manifest this disease
in an atypical fashion [24]. Multiple gestations that are a result of
ART are at greater risk of developing hypertensive complications
than spontaneous multiple gestations (relative risk, 2.1) [25].
Abruptio placentae
It is more common in multiples and exhibit a correlation to the
number of fetuses (1.2% of twins; 1.6% of triplets) [3].
Thrombocytopenia
Up to one third of triplets gestations can be complicated by
thrombocytopenia, and unlike singletons where the number one
cause of thrombocytopenia is gestational, severe pre-eclampsia is
the most common cause in triplets [26].
Acute fatty liver
In contrast to singleton gestations where the rate of fatty liver is 1
in 10,000, the rate in triplets is up to 7% [27].
Gestational diabetes
There is a mild correlation between twins and gestational diabe-
tes when compared to singletons, although insulin requirements
between these two groups are not significantly different [28]. A
significant association is demonstrated with triplets with a gesta-
tional diabetes rate of 22% [29].
Peripartum hysterectomy
It is significantly increased risk of emergent peripartum hysterec-
tomy compared to singletons [30]
Pregnancy considerations
Compared to singleton gestations, physiologic changes in twins
include a 50–60% increase in maternal blood volume (40–50% in
singletons) leading to higher incidence of anemia, higher increase
in cardiac output, slightly lower diastolic blood pressure, and
more discomfort such as pressure, difficulty in ambulation, etc.
Pregnancy management
Nutrition
For twin pregnancies, the Institute of Medicine (IOM) recom-
mends a gestational weight gain of 16.8–24.5 kg (37–54 lb) for
women of normal weight, 14.1–22.7 kg (31–50 lb) for overweight
women, and 11.3–19.1 kg (25–42 lb) for obese women [31]. Diet
should include an increase in caloric intake by 300 kcal above
singletons (600 kcal above non-pregnant state), or caloric intake
for twins is 40–45 kcal/kg each day. Extra supplementation above
that supplied by a prenatal vitamin has been suggested for folic
acid (1 mg/day); iron (60 mg/day); as well as possibly magnesium,
and zinc. Less data for a recommendation is available for omega-3
fatty acids and vitamin D [32].
Low-dose aspirin
ACOG and SMFM recommend low-dose aspirin (81 mg/day) in
women with multiple gestations to prevent or delay the onset of
pre-eclampsia. Low-dose aspirin should be initiated between 12
and 28 weeks gestation (optimally before 16 weeks) and continued
daily until delivery [33].
Prenatal diagnosis
First trimester: Nuchal translucency and maternal age iden-
tify about 75–85% of trisomy 21 and 66.7% of trisomy 18 preg-
nancies with a 5% false-positive rate in twin gestations [34–36].
473
However, only nuchal translucency alone has been validated for
the detection of these disorders in higher order gestations [37]. In
a recent meta-analysis, first trimester combined test in twins had
a pooled sensitivity of 0.893 (95% confidence interval [CI] 0.797–
0.947) and a pooled specificity of 0.946 (95% CI 0.933–0.957). The
performance of the test was good (summary receiver operating
characteristic area under the curve: 0.817). In dichorionic twins,
sensitivity and specificity were 0.862 (95% CI 0.728–0.936) and
0.952 (95% CI 0.942–0.96), respectively. In monochorionic twins,
the sensitivity and specificity were 0.874% (95% CI 0.526–0.977)
and 0.954% (95% CI 0.943–0.963), respectively [38]. Cell free
DNA has been shown to have a pooled weighted detection rate
for T21 of 98.2% (95% CI 83.2–99.8%) and false positive rate 0.05%
(95 CI, 0.01–0.26%) in twins, however predictive value for T13
and T18 has yet to be determined [39].ACOG and SMFM recently
endorsed cell-free DNA for the detection of T21 in twin gesta-
tions [40]. Chorionic villus sampling can be performed between
10 to 12 weeks. It has the same risks as amniocentesis in multiples
[41], and has a 1.1 rate of twin-twin contamination [42].
Second trimester: Serum screening for neural tube defects with
MSAFP using a cutoff of 4.5 MoM has a detection rate is 50–85%
with a 5% false positive rate. Maternal serum marker screen-
ing for Trisomy 21 is 63% sensitive in twin gestations (71% when
both twins were affected and 60% when one was affected), with a
false-positive rates of 10.8% [43]. Genetic amniocentesis has been
reported to have a loss rate with multiples similar to singletons
[44]. At sampling of the first sac, indigo carmine (not available in
U.S.) or Evan’s blue can be injected; a clear sample obtained from
the second sac insures that two different sacs have been sampled.
Methylene blue dye should not be used because of the risks of fetal
hemolytic anemia, small intestinal atresia, and fetal demise. If ges-
tation is MC, sampling of one sac is suggested for karyotype.
Prediction of PTB
Transvaginal ultrasound (TVU) cervical length (CL) performed
between 18–23 [6] weeks gestation is a strong predictor of pre-
term delivery in asymptomatic women with twin gestations. A CL
≤20 mm increases the pretest probability of preterm birth prior
to 32 weeks from 6.8–42.4%, whereas a CL >20 mm decreased the
risk to 4.5% [45]. Given that vaginal progesterone (please see sec-
tion Progesterone) appears to be of benefit in twins with a short
cervix in the mid-trimester, one may consider performing TVU
CL at the time of the anatomical survey in the second trimester.
Several other tests for prediction of PTB have been investigated
in twin gestations and none have been so far been shown to be
helpful in preventing preterm delivery [46].
Prevention and management
of complications
Selective termination of an anomalous fetus
Selective termination of an anomalous fetus is usually performed in
second trimester due to the time of diagnosis of the fetal anomaly.
In DC pregnancies, the procedure consists of injection of
potassium chloride into the fetal heart transabdominally. The
loss rate of the entire pregnancy is about 4% of those performed
prior to 24 weeks, with a difference if twins were reduced versus
higher order multiples (2.4% vs. 11.1%) and if more than 1 fetus is
terminated (2.6% loss if one fetus vs. 42.9% if two) [47]. In a recent
review of twin dichorionic pregnancies discordant for fetal anen-
cephaly there was no difference in survival of the non-affected
twin between those who elected selective termination versus
474
expectant management however there was a statistically signifi-
cant difference between both groups in mean gestational age at
delivery (38.0 weeks vs. 34.9 weeks) [48].
In MC pregnancies, potassium chloride should not be used, as
it crosses to the other fetus through the placental anastomoses
and causes fetal death therefore of both fetuses. Cord ligation, or
occlusion with clips, diathermy or other means have been used,
with insufficient data for effective comparison.
Preterm birth (see also Chapter 18 in Obstetric Evidence
Based Guidelines).
Prevention of multiple gestations
The incidence of multiple gestation is increased with both ovula-
tion induction, which represent the majority of ART multiples,
and IVF. Excessive stimulation, and insemination in the presence
of excessive number of ripe follicles, should be avoided. Transfer
of one embryo almost guarantees avoidance of multiple gesta-
tion, and is associated with rates of successful pregnancy similar
to transfer of >1 embryos with modern techniques. Many devel-
oped countries have laws which allow the transfer of only one, or
maximum of two embryos. No more than three embryos should
ever be transferred, even in the woman with poor prognosis (i.e.
>40 years old). The successful outcome of ART should be based
on the rate of healthy term singleton per cycle.
Weight gain
There have been several observational studies that suggest
improved perinatal outcomes, decreased preterm birth rates and
larger birthweights, in women with twin pregnancies who meet
the IOM weight gain guidelines, see earlier in this chapter [49, 50].
Multifetal pregnancy reduction
The goal of first trimester fetal reduction is to decrease the
number of fetuses in higher order gestations thereby lessening
the likelihood of a premature delivery and the associated mor-
bidity and mortality. A review of nonrandomized trials in the
Cochrane database concluded that pregnancy reduction from
triplets to twins versus expectant management appears to
be associated with reduction in pregnancy loss, birth before
36 weeks, cesarean birth, low birth weight infants, and neo-
natal deaths, similar to spontaneously conceived twins [51].
Maternal morbidity has also been shown to be decreased: 14% of
twin pregnancies remaining after multifetal reduction developed
pre-eclampsia compared with 30% of unreduced triplet pregnan-
cies [52]. As reduction involves termination of one triplet fetus,
overall perinatal survival is not different, and might actually be
slightly decreased, but improvements in morbidity and mortality
are seen in “remaining” twin fetuses compared to non-reduced
triplets yield a higher rate of “intact” normal babies in the
reduced-to-twins compared to the non-reduced triplets. In light
of both improvement in maternal morbidity and fetal and neona-
tal morbidity and mortality, it is reasonable to offer reduction
to all patients with higher order (triplets or higher) multiples.
Over 90% of women who underwent pregnancy reduction would
opt for the procedure again.
Triplets with a MC twin pair present a unique situation.
Reduction of the MC twin pair is associated with significantly
decreased early preterm birth and its associated long-term mor-
bidity. On the other hand, miscarriage rate is lowest with expect-
ant management, and affords the parents the highest chance of a
liveborn infant [53]. Again, parents should be informed of their
options and allowed to decide regarding reduction according to
their own personal wishes and priorities.
Maternal-Fetal Evidence Based Guidelines
Bed rest
Either prophylactic (before symptoms) or therapeutic (with symp-
toms of PTL) bed rest does not prevent PTB in multiple gestations
[54]. Compared to normal activity, prophylactic bed rest in the
hospital increases the rate of PTB <34 weeks by 84% [43, 55] in
uncomplicated twin pregnancies. There is no reduction in low
birth weight or perinatal mortality.
Progesterone
In a meta-analysis of the randomized trials, neither 17–hydroxy-
progesterone caproate nor vaginally administered natu-
ral progesterone reduced the incidence of adverse perinatal
outcome in unselected uncomplicated asymptomatic twin
pregnancies [56]. However, the use of vaginal progesterone to
asymptomatic women with a twin gestation and a sonographic
short cervix (<25 mm) in the mid trimester has been shown to
reduce the risk of PTB occurring at <30 to <35 weeks, neona-
tal mortality and some neonatal morbidity [57]. In higher order
multiples, progesterone use was associated with a significant
increased rate of midtrimester fetal loss [58].
Cerclage
Cerclage, either history-indicated [59] or ultrasound-indicated for
short TVU CL [60] does not prevent PTB in twins and triplet [61]
gestations. However, in patients with asymptomatic cervical are dila-
tion from 1–5 cm with twins between 16 0/7 weeks and 23 6/7 weeks,
placement of a physical exam-indicated cerclage has been shown in
a small randomized controlled trial to decrease the incidence of very
early PTB by 50% and to decrease perinatal mortality by 78% [62].
Pessary
The placement of a pessary in unselected twins [63] or those with
a short cervix [64] does not prevent PTB or improve neonatal
outcomes.
Home uterine activity monitoring
Home uterine activity monitoring has not been proven to
decrease the incidence of preterm birth in multiple gestations
[65] and, therefore, this costly screening intervention should not
be undertaken.
Prophylactic tocolysis
Prophylactic tocolysis has no proven effect on the incidence
of preterm birth, low birth weight, or neonatal mortality (all
similar incidences with placebo) in twin gestations, and therefore
this practice should be avoided [66].
Preterm labor
Women with multiple gestations and preterm labor (PTL) should
be delivered if any of the following are present: ≥34 week gesta-
tion, PPROM, chorioamnionitis, or non-reassuring testing. If
<34 weeks and none of the aforementioned criteria are present,
management of multiples presenting <34 weeks in threatened
PTL should be based on TVU CL, for this directly correlates with
delivery within 7 days in woman with regular painful contrac-
tions at 24–36 weeks [67]:
1. > 25 mm: 0%
2. 21–25 mm: 7%
3. 16–20 mm: 21%
4. 11–15 mm: 29%
5. 6–10 mm: 46%
6. 1–5 mm: 80%
Multiple Gestations
Administration of one course of antenatal corticosteroids to
woman with singleton gestations at risk for delivering between
24 and 34 weeks gestation has been shown to decrease the inci-
dence of neonatal death, respiratory distress syndrome, intra-
ventricular hemorrhage, and necrotizing enterocolitis [68]. In
preterm twins antenatal corticosteroids has been associated
with significantly associated with a reduced rate of periven-
tricular leukomalacia or intraventricular hemorrhage grade III/
IV (adjusted odds ratio [aOR] 0.2; CI 95% 0.1–0.5), in-hospital
mortality (aOR 0.3; CI 0.1–0.6) [69]. ACOG recommends one
course of betamethasone (12 mg q24h × 2 doses) or dexametha-
sone (6 mg q12h × 4 doses) be administered to all women who are
between 24 and 33 6/7 weeks and at high risk (e.g. CL ≤20 mm) of
delivery within 7 days [70].
In light of recent meta-analysis of randomized trials show-
ing that prenatal administration of magnesium sulfate reduced
the occurrence of cerebral palsy [71–73] it is reasonable to offer
magnesium for neuroprotection for those multiples at risk to
deliver at 23 0/7–31 6/7 weeks within the next 30 minutes to
24 hours in an ACOG endorsed protocol [74].
Tocolytics have not been sufficiently studied in multiple gesta-
tions (no specific trials) with PTL to assess their efficacy in PTB
prevention. They should be used judiciously due to higher inci-
dence of side effects in multiple, i.e. pulmonary edema, compared
to singleton gestations.
Preterm premature rupture of membranes
Women with multiple gestations and Preterm premature rupture
of membranes (PPROM) should be delivered if any of the follow-
ing are present: ≥34 weeks’ gestation, PTL, chorioamnionitis,
or non-reassuring testing. If less than 34 weeks and none of the
aforementioned criteria are present, then expectant management
with antibiotics, usually ampicillin and a macrolide, together with
corticosteroids and magnesium sulfate for neuroprotection as
discussed earlier. There is insufficient evidence to support toco-
lytic therapy for women with PPROM, as there was an increase
in maternal chorioamnionitis without significant benefits to the
infant in the meta-analysis of randomized trials [75].
Subsequent pregnancy outcomes
after preterm delivery of twins
Prior spontaneous PTB of twins is a risk factor for PTB if the
woman is now carrying a singleton only if the prior birth of twins
occurred before 34 weeks [76].
FGR/discordant twins
If neither fetus of a DC/DA pregnancy is growth restricted (EFW
<10% for GA), no significant change in management needs to
be done, as there is no increased risk in adverse perinatal out-
comes [77]. If one fetus is growth restricted, then: Review of all
prenatal exposures; perform specialized ultrasound examina-
tion for anomalies; consider amniocentesis for karyotype [42];
and consider twice weekly NSTs or BPPs and weekly umbilical
artery Doppler velocimetry. See also Chapter 58. Delivery timing
of growth restricted twins should be based on chorionicity and
Doppler studies (Table 46.3).
Single fetal death
Single fetal death is associated with significant complications
for the remaining twins, in DC and even more MC pregnancies
(Table 46.1) [78]. Management therefore depends on chorionicity
and gestational age.
475
TABLE 46.3: Delivery Timing for Twins
Suggested Timing of
Type of Twin Pregnancy Planned Delivery
DC/DA twins uncomplicated 37 0/7–37 6/7 weeksa
DC/DA with one growth restricted twin with 36 0/7–36 6/7 weeksc
normal UA Doppler
DC/DA twins with one growth restricted twin 34 0/7–34 6/7 weeks
with abnormal UA Doppler (but some
forward diastolic flow)
DC/DA twins with one growth restricted twin 32 0/7–33 6/7 weeks
with absent UA Doppler
DC/DA twins with one growth restricted twin 30 0/7–31 6/7 weeks
with reversed UA Doppler
DC/DA twins complicated by maternal 32 0/7–34 6/7 weeksc
co-morbidity such as pre-eclampsia
MC/DA twins uncomplicated 35 0/7–36 6/7 weeksc
MC/DA with one growth restricted twin 32 0/7–35 6/7 weeksc
MC/MA twin gestation 32 0 days–34 6/7 weeksb
a Saccone G, Berghella V. Planned delivery at 37 weeks in twins: a systematic review
and meta-analysis of randomized trials. J Matern Fetal Neonatal Med. 2015 Jul
26:1–5. [Meta-analysis; 2 RCTs, n=271]).
b Van Mieghem T, De Heus R, Lewi L, Karitsch P, Kollmann M, Baud D, et al.
Prenatal management of monoamniotic twin pregnancies. Obstet Gynecol
2014;124:498–506.
c Medically indicated later-preterm and early-term deliveries. Committee Opinion
No 560. American College of Obstetricians and Gynecologists. Obstet Gynecol
201;121:908–10.
Dichorionic gestation:
<12 weeks: Usually no consequences, so no intervention needed.
>12 weeks: Immediate delivery has no benefit for the remaining
fetus and the often-quoted maternal risk of disseminated
intravascular coagulation has not been demonstrated.
Monochorionic gestation:
<12 weeks: Associated with high risk of loss of other twin, with
no intervention studied.
>12 weeks: Associated with about 41% risk of intrauterine
death and additional 28% risk of neurologic complications
in other twin. These risks seem to occur from hypotension
due to transfusion of blood from other to already demised
twin. At the time the demise is discovered, the greatest
harm has most likely already occurred in the remaining
fetus, and there seems to be no benefit in immediate deliv-
ery, especially if the surviving fetus(es) are very preterm
and otherwise healthy. In such cases, allowing the preg-
nancy to continue may provide the most benefit. The coag-
ulopathy risk for the mother is minimal, probably <2%.
Twin-to-twin transfusion syndrome
Incidence
Twin-to-twin transfusion syndrome (TTTS) occurs in about 10%
of MC/DA pregnancies, and therefore in about 1/2500 pregnan-
cies. Rare cases have been reported in MA/MC pregnancies.
Etiology
All monochorionic pregnancies have one placenta only, all with
anastomoses of artery-to-artery (AA), vein-to-vein (VV), and
artery-to-vein (AV) of the two twins. TTTS may not occur in
476 Maternal-Fetal Evidence Based Guidelines

MC/MA gestations because of more AA, and less AV anastomoses Screening

than in MC/DA gestations. An imbalance of arterial circulation
of one twin (donor) to the venous circulation of another (recipi-
ent) probably through an AV anastomosis can lead to TTTS. Over
50% of TTTS placentas have ≥1 velamentous cord insertion,
possibly associated with this imbalance. The donor twin develops
anemia and resultant effects (e.g. IUGR, oligohydramnios), while
the recipient twin has polyhydramnios, becomes polycythemic,
and can develop heart failure.
All MC/DA twin gestations should have serial sonographic
evaluation of MVP every 2 weeks from 16 weeks until delivery
to monitor for development of TTTS (Figure 46.6) [79]. Screening
for congenital heart disease is warranted in all monochorionic
twins, in particular those complicated by TTTS.
Staging
Staging is described in Table 46.4 [80].

Diagnosis Prognosis and counseling

The antepartum diagnosis requires ultrasound. The criteria are
MC/DA gestation (see earlier) with oligohydramnios (maxi-
mum vertical pocket [MVP] <2 cm) in one sac, and polyhydram-
nios (MVP >8 cm) in the other. Supporting (but NOT diagnostic)
criteria can be the presence of same sex twins with a single pla-
centa, and significant discordance in fetal growth. It is important
to rule out other etiologies for similar findings, such as FGR of
just one twin with normal other twin, chromosomal or structural
abnormalities, infection, etc.
The natural history of TTTS is associated with poor prognosis,
and depends mostly on gestational age at diagnosis and stage of
disease. About 5% of TTTS, especially in early stages, can regress.
Survival with diagnosis at less than 26 weeks without treat-
ment is 30% [81]. Survival can often be with severe morbidity,
including neurologic, cardiac, ischemia/necrosis of extremities,
renal cortical necrosis, etc. Extensive counseling is necessary in
cases of TTS, given the gravity of the condition and the paucity of
level 1 data on best management.

MCDA Pregnancy

First Trimester:
- Confirm monochorionic,
diamniotic placentation
- NT screening

~16 Weeks
Start ultrasound surveillance with MVP in each sac, and fetal bladder, every
2 weeks, until delivery

MVP >2cm and <8cm in each sac

Yes No

Continue ultrasound surveillance every 2 weeks MVP <2cm in one sac and MVP >8cm
in other sac: Diagnosis = TTTS

See Figure 46.7

FIGURE 46.6 Algorithm for: screening for TTTS. (Adapted from Simpson L, for the Society for Maternal-Fetal Medicine. Twin-
Twin transfusion syndrome. Am J Obstet and Gynecol 2013: 3–17.) Abbreviations: MVP, maximum vertical pocket; TTTS, twin-twin
transfusion syndrome.
Multiple Gestations 477

TABLE 46.4: Staging for TTTS
Stage 1 MC/DA gestation with oligo (MVP < 2 cm)
and polyhydramnios (MVP > 8 cm)
Stage 2 Absent (empty) bladder (in donor)
Stage 3 Abnormal Dopplera
Stage 4 Hydrops
Stage 5 Death of one twin
Source: Adapted from Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson
PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol
1999;19:550–5. [II-2].
a Defined as either umbilical artery absent or reversed diastolic flow; ductus veno-
sus absent or reversed diastolic flow; or umbilical vein pulsatile flow.
Therapy
Therapy for TTTS depends on the stage (Figure 46.7).
Stage I
The natural history of stage 1 TTTS is that more than 75% cases
regress or remain stable without intervention with a perinatal
survival rate of 86%. Therefore expectant management with
close follow-up at least weekly is the treatment of choice [82].
Stages II, III, and IV
Most experts consider fetoscopic laser coagulation to be the
best approach to treating advanced disease in continuing preg-
nancies less than 26 weeks. Laser therapy involves coagulation
of the placental vessels transferring blood from the donor to the
recipient twin. This can be done selectively treating only those
vessels visualized on the placental surface or by laser coagulation
of the entire vascular equator. However a meta-analysis of the
two RCTs showed no significant survival benefit, and the long
term neurologic outcomes in the Eurofetus trial were not dif-
ferent than in nonlaser treated (amnioreduction) group [82].
Of note, there were 12 voluntary terminations in the laser group
of the largest trial, which if eliminated would result in no benefit
from laser compared to amnioreduction [83]. It is important to
counsel the patient that laser treated TTTS has a 30–50% chance
of perinatal death and a 5–20% risk of long-term neurologic
handicap [82] This procedure should be undertaken for Quintero
Stage II-IV disease between 16 0/7 weeks and 24 weeks in the
United States (the upper threshold for gestational age has been
set by the FDA), and 25 6/7 elsewhere based on data [84]. Laser
coagulation of the entire vascular equator has been shown
to be superior to selective vessel coagulation when examining
the outcomes of overall survival rate and recurrent TTTS [85].
Steroids for fetal maturation should be considered at 22 0/7 to
33 6/7 weeks, particularly in pregnancies complicated by stage
≥III TTTS, and those undergoing invasive interventions.
Stage V
The woman should be counselled regarding co-twin 10% risk of
death and 10–30% risk of neurologic complications. Expectant
management is usually considered, unless gestational age is near-
term or term.
Other possible interventions have been studied for women
with TTTS. Amnio-reduction involves removing with a 20–22
gauge needle excess fluid from the polyhydramniotic sac, so to
restore MVP <8. While in 20% of cases one amnioreduction
is sufficient to resolve TTTS, in the other cases it might need
to be performed serially, as often fluid quickly reaccumulates.
The theory behind it efficacy is that it prevents preterm delivery
due to polyhydramnios and also helps to stabilize the flow in
arterial-venous connections and thereby slow the rate of blood

MCDA pregnancy with MVP <2 cm in one sac

and MVP <8 cm in other sac: Diagnosis =
TTTS

Do staging (Figure 46.2): Check fetal bladder,

UA Doppler

Stage I Stage II, III, IV Stage V

Counseling. Consider Counseling. Consider Counsel regarding co-

expectant management, referral to Fetal Center for twin 10% risk of death
with fetal bladder, UA laser treatment at 16–25 6/7 and 10–30% risk of
Doppler, and hydrops weeks; if unable neurologic
ultrasonographic checks or outside eligibility complications.
at least once per week criteria, consider Consider expectant
amnioreduction management.

FIGURE 46.7 Algorithm for management of TTTS. (Adapted from Ref. Simpson L, for the Society for Maternal-Fetal Medicine.
Twin-Twin transfusion syndrome. Am J Obstet and Gynecol 2013: 3–17.) Abbreviations: MCDA, monochorionic diamniotic; MVP,
maximum vertical pocket; TTTS, twin-twin transfusion syndrome; UA, umbilical artery.
478
transfer and fluid re-accumulation [86]. The meta-analysis of
the RCTs which compared amnioreduction to laser showed
similar results [82], as shown earlier, so amnioreduction can
be considered, especially in cases where laser therapy is not
available.
Septostomy involves purposefully perforating the intertwine
membrane under ultrasound guidance with a 22-gauge needle,
thus allowing equalization of pressure in the two sacs. One RCT
did not find it superior to amnioreduction [87].
Selective fetocide via bipolar diathermy can allow the survival
of one twin without neurologic complications [88]. Most common
indication for selective fetocide in twin to twin is one of the twins
has an anomaly or hydrops with impending fetal death. There are
no trials available. The rate of loss or PPROM within 2–3 weeks of
the procedure of the remaining twin is about 20%.
There is insufficient evidence to evaluate the efficacy of other
interventions reported for TTTS, such as transfusion therapy,
indomethacin, digoxin, etc. Cerclage placement for short cervix
at the time of laser therapy has not been shown to be beneficial in
limited data [89].
Monoamniotic twins
The incidence of MA twins is 1 in 10,000 pregnancies, but it is
more common with IVF using zona manipulation affecting up
to 17% of multiples using this technique [90]. Diagnosis is by
ultrasound: Prior to 8 weeks, 1 yolk sac and two fetal poles is
diagnostic [91]; If after 8 weeks, then same sex, single placenta,
and single amniotic sac with no dividing amniotic membrane
allow diagnosis. Fetuses must be of the same sex. Demonstration
of umbilical cord entanglement is also diagnostic of monoam-
niotic twins.
The overall incidence of fetal loss in MCMA pregnancies is
approximately 6%, with 4.3% occurring at 24–30 weeks, 1.0% at
31–32 weeks, and 2.2% at 33–34 weeks [92].
Due to rarity of the condition, there are no randomized tri-
als available. Several non-randomized but controlled series have
suggested: Offer first trimester screening with NT measurement;
serial assessment of amniotic fluid, fetal urinary bladders and
Dopplers studies to rule out signs of TTTS; Fetal echocardiog-
raphy at 22–24 weeks; ultrasound every 3 weeks to assess fetal
biometry and cord entanglement. Admission at 24–26 weeks
with very frequent fetal monitoring should be offered since the
incidence of fetal loss in MCMA twins of pregnancies managed
mainly inpatient was 3% as compared with 7% in those followed
up as outpatients [92].
It is difficult to give management recommendation in the
rare cases in which only one twin of a MA pair dies. If ges-
tational age is less than 30 weeks, expectant management can
continue with close monitoring. This can be considered even
up to 32 weeks.
Cesarean delivery at around 32 0/7–34 6/7 weeks is the pre-
ferred mode of delivery due to the risk of fetal interlocking and
cord entanglement and to avoid the risk of inadvertently clamp-
ing and dividing the cord of the second twin during the delivery
of the first twin, premature placental separation and cord pro-
lapse [93].
Acardiac twin
Acardiac twin (also called Twin Reversal Arterial Perfusion –
TRAP – syndrome) is a MZ, MC pregnancy characterized by a
fetus lacking a normal developed heart and usually a head
(“acardiac twin”). It occurs in 1% of MC twins, or about 1/35,000
Maternal-Fetal Evidence Based Guidelines
pregnancies. This acardiac fetus survives in utero due to pla-
cental anastomoses shunting blood flow from the “pump twin.”
Diagnosis needs ultrasound Doppler confirmation of blood being
pumped in from “pump” twin. The “pump twin” can develop
a high cardiac output state and subsequent failure, resulting
in intrauterine or neonatal death of this normal twin in about
35–50% of cases [94].
Due to rarity of the condition, there are no trials available. As
cardiac failure is more common when the EFW of the acardiac
twin is >70% of EFW of pump twin, interventions to “terminate”
in utero the acardiac twin have been proposed for EFW of acar-
diac >70% together with “pump” twin compromise. Of all the
proposed techniques, ultrasound-guided laser coagulation or
radiofrequency ablation of intrafetal vessels seems to be the
first line of treatment in centers experienced with these tech-
niques. Cord ligation and occlusion have also been reported with
some success [95].
Conjoined twins
Conjoined twins are an anomaly linked to MZ twining with
incidence of 1 in 50,000 to 1 in 10,000 births [96]. Classification
is based on the site of connection with the suffix pagus added.
Of those diagnosed in utero, 28% will die prior to delivery, 54%
die immediately after birth, with only an 18% survival rate [97].
Diagnosis of shared anatomy is imperative to management and
prognosis [30]. Due to rarity of the condition, there are no trials
available. Voluntary termination would be considered if cardiac
(thoracopagus) or cerebral (craniopagus) fusion due to poor out-
come [31], or if the pregnancy outcome due to the level of defor-
mity is unacceptable to the parents. If pregnancy is continued,
planned cesarean at term is recommended.
Antepartum testing
Ultrasounds
An ultrasound should be performed in the first trimester assess-
ing viability, gestational age, and chorionicity. An ultrasound
should be performed between 18 and 20 weeks assessing ges-
tational age, chorionicity (if not done previously), placental cord
insertion sites, fetal anatomic surveys, fetal genders, and TVU
CL. Twins grow at the same rate as singletons up to 28–32 weeks,
and then the growth of twins slows, so that fetal twin charts
are best used for management. No uniform frequency of fetal
growth scans. Sonographic assessment for twin growth can
performed every 4 weeks from 18–20 weeks until delivery.
If discordance or FGR is diagnosed then frequency is increased
to every 3 weeks. Multiple methods to access amniotic fluid by
ultrasound in multiples has been described, including subjective
assessment, total AFI, individual AFI, maximum vertical pocket
(MVP), two-diameter pocket, and others. The MVP technique,
using <2 cm for polyhydramnios and >8 cm for polyhydramnios,
is accurate in assessing amniotic fluid volume.
Fetal surveillance
Routine antepartum testing has not been proven valuable in the
management of multiple gestations; therefore, antepartum fetal
surveillance in multiple gestations is recommended in all situ-
ations in which surveillance would ordinarily be performed in
a singleton pregnancy (e.g. FGR, maternal disease, decreased
fetal movement, etc.) [42]. Some start NSTs in all twin gesta-
tions at around 32–34 weeks, but there is no firm evidence
for or against this intervention. Doppler flow studies are not
Multiple Gestations
routinely beneficial [98], but probably have the same benefit in
fetal morbidity and mortality in cases of twin FGR as in cases of
singleton FGR.
Delivery
Timing of delivery
Timing of delivery is about 37 0/7–37 6/7 weeks for uncompli-
cated DCDA twin pregnancies, as it is associated with similar
maternal outcomes and lower incidence of serious adverse infant
outcomes compared to expectant management until 38 weeks
[99]. While there are no RCTs to suggest the best timing of deliv-
ery for other twins or higher order multiple gestations, Table 46.3
offers some guidance based on non-RCT data [99–101]. Timing of
delivery should not be based on fetal lung maturity testing. If this
is done nonetheless, as disparity in lung maturity occurs usually
in only 5% of twins, just one gestational sac may be sampled for
assessment of lung maturity. In certain circumstances, such as
diabetes or growth discordance, a bigger difference in maturity
discordance may necessitate sampling both sacs.
Route of delivery
Twins
There are no trials for twins presenting vertex/vertex (40% of
twin pregnancies), with trial of labor usually suggested as this
has been shown to be safe.
In twin pregnancy at 32 0/7 weeks and beyond with the first
twin in cephalic presentation, there is no benefit to planned
cesarean section over trial at vaginal delivery in perinatal out-
comes [102]. Attempt at vaginal twin delivery has been supported
especially for twins with EFW of >1500 grams, and can only be
performed with adequate experience of obstetrician, and continu-
ous availability of expert anesthesia, usually in or very close to an
operating room. Interval between first and second twin deliveries
is not critical, as long as the second twin is monitored continu-
ously and accurately. Oxytocin may need to be (re)started as con-
tractions often diminish, and amniotomy should be performed
only when presenting part is engaged. Total breech extraction is
associated with shorter maternal stay and lower neonatal pulmo-
nary disease, infection, and ICN stay compared to podalic version
in retrospective studies [103, 104].
There are no trials for twins presenting with first twin non-
vertex (about 26%), with recommendation for CD made based
mostly on data from singleton gestations. Successful external
cephalic version (ECV) of non-vertex twin A has been reported
in 57% (13/23) of women and 48% (11/23) had a successful vaginal
delivery [105].
Triplets and higher order multiples
Planned cesarean delivery is recommended for triplets given
the low success rate with attempted vaginal delivery (16.7%) and
higher rate of maternal transfusion (20.8% vs. 3.6%), neonatal
mechanical ventilation (26.4% vs. 7.7%) when compared to cesar-
ean delivery [106].
Delayed interval delivery
Preterm labor or PPROM can result in the delivery of only one
twin or other multiple gestation fetus. Delaying the delivery
of the remaining fetus(es) may result in decreased morbidity
and mortality of these remaining fetuses, with no trials to fully
assess the effect of this intervention. Delayed delivery should
not be attempted if MC gestation, abruption, pre-eclampsia,
479
chorioamnionitis, need of CD or other indications for deliv-
ery are present, making only about 25% of multiple deliveries
in the second trimester candidates for this attempt. Delayed
delivery is not very successful and does not result in significant
improvements at >28 weeks (delay <2 weeks even with success).
While tocolytics, antibiotics and cerclage are often used, there
is no firm evidence of their benefit. Delayed delivery is asso-
ciated with decreases in perinatal and infant mortality, with
averages gain of about 2–5 weeks if successful. The interval
between delivery is inversely correlated with gestational age of
first delivery [107].
Neonatal
There is probably no significant difference between multiples and
singletons in odds of mortality and major neonatal morbidities
(severe neurologic injury, retinopathy of prematurity, etc.) at a
given gestational age in those unaffected by FGR [108, 109].
References
1. Benirschke K, Kim CK. Multiple pregnancy. N Engl J Med 1973;288(24):
1276–84.[II-3]
2. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2002. Natl
Vital Stat Rep 2003;52(10):1–102. [II-3]
3. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK. Births: final data
for 2018. National Vital Statistics Reports 68(13). Hyattsville, MD: National
Center for Health Statistics. 2019.
4. Martin JA, Osterman MJK. Is twin childbearing on the decline? Twin births
in the United States, 2014–2018. NCHS Data Brief 351. Hyattsville, MD:
National Center for Health Statistics. 2019.
5. Wenstrom KD, Syrop CH, Hammitt DG, van Voorhis BJ. Increased risk
of monochorionic twinning associated with assisted reproduction. Fertil
Steril 1993;60:510–4. [III]
6. LeFevre ML, Bain RP, Ewigman BG et al. A randomized trial of prenatal
ultrasonographic screening: impact on maternal management and out-
come. RADIUS (Routine Antenatal Diagnostic Imaging with Ultrasound)
Study Group. Am J Obstet Gynecology 1993;169(3):483–9.[I, RCT]
7. Finberg HJ. The “twin peak” sign: Reliable evidence of dichorionic twin-
ning. J Ultrasound Med 1992;11(11):571–7. [II-3]
8. Dickey RP, Taylor SN, Lu PY, et al. Spontaneous reduction of multiple
pregnancy: Incidence and effect on outcome. Am J Obstet and Gynecol
2002;186(1):77–83. [II-2]
9. American College of Obstetricians and Gynecologists’ Committee on
Practice Bulletins—Obstetrics; Committee on Genetics; Society for
Maternal-Fetal Medicine. Screening for fetal chromosomal abnor-
malities: ACOG Practice Bulletin, Number 226. Obstet Gynecol 2020
Oct;136(4):e48–e69.
10. Meyers C, Adam R, Dungan J, Prenger V. Aneuploidy in twin gestations:
when is maternal age advanced? Obstet Gynecol 1997;89:248–51. [II-2]
11. Rodis JF, Egan JFX, Craffey A, et al. Calculated risks of chromosomal abnor-
malities in twin gestations. Obstet Gynecol 1990;76(6):1037–41. [II-2]
12. Malone FD, D’Alton ME. Multiple gestation clinical characteristics and
management. Maternal-Fetal Medicine Principles and Practice, 5th ed.
Philadelphia, PA: Saunders, 2004. [III]
13. Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th ed,
Philadelphia, PA: WB Saunders, 1997:654. [III]
14. Miller J, Chauhan SP, Abuhamad AZ. Discordant twins: diagnosis, evalua-
tion, and management. Am J Obstet Gynecology. 206:10–20. [II-2]
15. Harper LM, Weis Ma, Odibo AO, et al. Significance of growth discordance
in appropriately grown twins. AJOG 2013;208(393):e1–5. [II-1]
16. Yinon Y, Mazkereth R, Rosentzweig N, et al. Growth restriction as a
determinant of outcome in preterm discordant twins. Obstet Gynecol.
2005;105:80–84. [II-3]
17. D’Alton ME, Simpson LL. Syndromes in twins. Semin Perinatol.
1995;19(5):375–86. [Level II-3]
18. Mackie FL, Rigby A, Morris RK, Kilby MD. Prognosis of the co-twin follow-
ing spontaneous single intrauterine death in twin pregnancies: a systematic
review and meta-analysis. BJOG 2019;126:569–78.
19. Kallen B, Finnstrom O, Lindam A, et al. Selected neonatal outcomes in
dizygotic twins after IVF versus non-IVF pregnancies. BJOG 2010;117:
676–82. [II-2]
480
20. Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Kirmeyer S, Mathews
TJ, Wilson EC. Births: final data for 2009. Natl Vital Stat Rep 2011;60(1):
1–70. United States [II-2]
21. Luke B, Brown M. The changing risk of infant mortality by gestation, plural-
ity, and race: 1989-1991 versus 1999–2001. Pediatrics 2006;118: 2488–97.
[II-2]
22. Chasen ST, Madden A, Chervenak FA. Cesarean delivery of twins and neo-
natal respiratory disorders. Am J Obstet Gynecol. 1999;181 (5 Pt 1):1052–6.
[II-2]
23. Wen SW, Demissie K, Yang Q, Walker MC. Maternal morbidity and obstet-
ric complications in triplet pregnancies and quadruplet and higher-order
multiple pregnancies. Am J Obstet Gynecol 2004;191:254–8. [II-2]
24. Sibai BM, Hauth J, Caritis S, et al. Hypertensive disorders in twin ver-
sus singleton gestations. National Institute of Child Health and Human
Development Network of Maternal-Fetal Medicine Units. Am J Obstet
Gynecol 2000;182:938–42. [I]
25. Lynch A, McDuffie R, Jr, Murphy J, Faber K, Orleans M. Preeclampsia in
multiple gestation: the role of assisted reproductive technologies. Obstet
Gynecol 2002;99(3):445–51. [II-2]
26. Al-Kouatly HB, Chasen ST, Kalish RB, Chervenak, FA. Causes of throm-
bocytopenia in triplet gestations. Am J Obstet Gynecol. 2003;189(1):
177–80. [II-2]
27. Malone FD, Kaufman GE, Chelmow D, et al. Maternal morbidity associated
with triplet pregnancy. Am J Perinatol 1998;15:73–77. [II-3]
28. Schwartz DB, Daoud Y, Zazula P, et al. Gestational diabetes mellitus: meta-
bolic and blood glucose parameters in singleton versus twin pregnancies.
Am J Obstet Gynecol. 1999;181(4):912–4. [II-2]
29. Silvan E, Maman E, Homko CJ, et al. Impact of fetal reduction on the inci-
dence of gestational diabetes. Obstet Gynecol 2002;99:91–4. [II-3]
30. Francois K, Ortiz J, Harris C, et al. Is peripartum hysterectomy more com-
mon in multiple gestations? Obstet Gynecol. 2005;105(6);1369–72. [II-3]
31. Institute of Medicine. Weight Gain during Pregnancy Reexaming the
Guidelines. Washington, DC: National Academies Press; 2009.
32. Goodnight W, Newman R, SMFM. Optimal Nutrition for improved twin
pregnancy outcome. Obstet Gynecol 2009;114:1121–34. [II-2]
33. ACOG Committee Opinion no. 743: low-dose aspirin use during preg-
nancy. Obstet Gynecol 2018;132:e44–52.
34. Chasen ST, Perni SC, Kalish RB, Chervenak FA. First-trimester risk assess-
ment for trisomies 21 and 18 in twin pregnancy. Am J Obstet Gynecol
2007;197(4):374.e1–374.e3. [II-2]
35. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W, Nicolaides KH. Screening
for trisomy 21 in twin pregnancies by maternal age and fetal nuchal
translucency thickness at 10–14 weeks of gestation. Br J Obstet Gynaecol
1996;103(10):999–1003. [II-2]
36. Bush MC, Malone FD. Down syndrome screening in twins. Clin Perinatol
2005;32(2):373–86, vi. [Review]
37. Sepulveda W, Wong AE, Casasbuenas A. Nuchal translucency and nasal
bone in first-trimester ultrasound screening for aneuploidy in multiple
pregnancies. Ultrasound Obstet Gynecol 2009;33(2):152–6. [II-2]
38. Prats P, Rodríguez I, Comas C, Puerto B. Systematic review of screening
for trisomy 21 in twin pregnancies in first trimester combining nuchal
translucency and biochemical markers: a meta-analysis. Prenat Diagn
2014;34(11):1077. [Meta-analysis 12,974 with 69 Trisomy 21]
39. Gil MM, Galeva S, Jani J, et al. Screening for trisomies by cfDNA test-
ing of maternal bloody in twin pregnancy: update of The Fetal Medicine
Foundation results and meta-analysis. Ultrasound Obstet Gynecol
2019;53:737–42.
40. ACOG Practice Bulletin No 226. Screening for fetal chromosomal abnor-
malities. Obstet Gynecol 2020;136.
41. Wapner RJ, Johnson A, Davis G: Prenatal diagnosis in twin gestations: a
comparison between second trimester amniocentesis and first trimester
chorionic villus sampling. Obstet Gynecol 1993;82(1):49–56. [I-2]
42. Eddleman KA, Stone JL, Lynch L, Berkowitz RL. Chorionic villus sam-
pling before multifetal pregnancy reduction. Am J Obstet Gynecol
2000;183(5):1078–1081. [II-3]
43. Garchet-Beaudron A, Dreux S, Leporrier N, et al. Second-trimester Down
syndrome maternal serum marker screening: a prospective study of 11 040
twin pregnancies. Prenat Diagn 2008;28(12):1105–09. [II-2]
44. Ghidini A, Lynch, L, Hicks, C, et al. The risk of second-trimester amnio-
centesis in twin gestations: a case-control study. Am J Obstet Gynecol.
1993;169(4):1013–6. [II-2]
45. Conde-Agudelo A, Romero R, Hassan SS, et al. Transvaginal sonographic
cervical length for the prediction of spontaneous preterm birth in twin
pregnancies: a systematic review and metaanalysis. Am J Obstet Gynecol
2010;203:128.e1–12. [Meta-analysis]
Maternal-Fetal Evidence Based Guidelines
46. Conde-Agudelo A, Romero R. Prediction of preterm birth in twin ges-
tations using biophysical and biochemical tests. Am J Obstet Gynecol
2014;211(6)583–95. [Review]
47. Eddleman KA, Stone JL, Lynch L, Berkowitz RL. Selective termination of
anomalous fetuses in multifetal pregnancies: two hundred cases at a single
center. Am J Obstet Gynecol 2002;187:1168–72. [II-3]
48. Lust A, De Catt L, Lewi L, et al. Monochorionic and dichorionic twin preg-
nancies discordant for fetal anencephaly: a systematic review of manage-
ment options. Prenat Diagn 2008;28:275–79. [II-2]
49. Gonzalez-Quintero VH, Kathiresan AS, Tudela FJ, Rhea D, Desch C, Istwan
N. The association of gestational weight gain per institute of medicine
guidelines and prepregnancy body mass index on outcomes of twin preg-
nancies. Am J Perinatol 2012;29(6):435–40. [II-2]
50. Goodnight W, Newman R, Society of Maternal-Fetal Medicine. Optimal
nutrition for improved twin pregnancy outcome. Obstet Gynecol
2009;114(5):1121–34. [Review]
51. Dodd JM, Crowther CA. Reduction of the number of fetuses for women
with triplet and higher order multiple pregnancies. Cochrane Database
Syst Rev 2003;(2):CD003932. doi: 10.1002/14651858.CD003932. Update
in: Cochrane Database Syst Rev 2012;10:CD003932. PMID: 12804495.
[Review/Meta-analysis]
52. Smith-Levitin M, Kowalik A, Birnholz J, et al. Selective reduction of multi-
fetal pregnancies to twins improves outcome over nonreduced triplet gesta-
tions. Am J Obstet Gynecol 1996;175(4 Pt 1):878–82. [I-3]
53. Morlando M, Ferrara L, Lawin-O’Brien A, et al. Dichorionic triplet preg-
nancies: risk of miscarriage and severe preterm delivery with fetal reduction
versus expectant management. Outcomes of a cohort study and systematic
review. BJOG 2015;122:1053–60. [II-2, systematic review]
54. Crowther CA. Hospitalization and bed rest for multiple pregnancies.
Cochrane 1, 2005. [meta-analysis; 4 RCTs, >1000 women. Mostly in Harare,
Zimbabwe]
55. Crowther CA, Neilson JP, Verkuyl DAA, Bannerman C, Ashurst HM.
Preterm labour in twin pregnancies: can it be prevented by hospital admis-
sion? BJOG 1989;96:850–3. [RCT, n = 139]
56. Schuit E, Stock S, Rode L, et al. A Global Obstetrics Network collabora-
tion. Effectiveness of progestogens to improve perinatal outcome in twin
pregnancies: an individual participant data meta-analysis. BJOG 2015;122:
27–37. [Meta-analysis; 13 RCTs, n = 3768 women, 7536 babies]
57. Romero R, Conde-Agudelo A, El-Refaie W, et al. Vaginal progesterone
decreases preterm birth and neonatal morbidity and mortality in women
with a twin gestation and a short cervix; an updated meta-analysis of indi-
vidual patient data. Ultrasound Obstet Gynecol 2017;49(3):303.
58. Combs CA, Garite T, Maurel K, Das A, Porto M, Obstetrix Collaborative
Research Network. Failure of 17-hydroxyprogesterone to reduce neonatal
morbidity or prolong triplet pregnancy: a double-blind, randomized clinical
trial. Obstet Gynecol 2010;203(3):248.e1–248.e9. [RCT]
59. Dor J, Shalev J, Mashiach S, et al. Elective cervical suture of twins pregnan-
cies diagnosed ultrasonically in the first trimester following induced ovula-
tion. Gynecol Obstet Invest 1982;13(1):55–60. [RCT, n = 50]
60. Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short
cervix on ultrasonography: meta-analysis of trials using individual patient-
level data. Obstet Gynecol 2005;106(1):181–9. [Meta-analysis; 4 RCTs, n =
49 twin gestations]
61. Rebarber A, Roman AS, Istwan N, Rhea D, Stanziano G. Prophylactic
cerclage in the management of triplet gestations. Am J Obstet Gynecol
2005;193:1193–6. [II-2]
62. Roman A, Zork N, Haeri S, et al. Physical exam indicated cerclage in twin
pregnancy; a randomized controlled trial, Am J Obstet Gynecol 2020
December;223(6):902–e1.
63. Nicolaides KH, Syngelaki A, Poon LC et al. Cervical pessary placement for
prevention of preterm birth in unselected twin pregnancies: a randomized
controlled trial. Am J Obstet Gynecol. 2016;214(1):3.e1–9.
64. Saccone G, Ciardulli A, Xodo S, et al. Cervical pessary for preventing preterm
birth in twin pregnancies with short cervical length: a systematic review
and meta-analysis. J Matern Fetal Neonatal Med. 2017;30(24):2918–25.
65. Reichmann J. Home uterine activity monitoring; an evidence review of
its utility in multiple gestations. J Reprod Med 2009;54:559–62. [Review/
meta-analysis]
66. Yamasmit W, Chaithongwongwatthana S, Tolosa JE, Limpongsanurak S,
Pereira L, Lumbiganon P. Prophylactic oral betamimetics for reducing pre-
term birth in women with a twin pregnancy. Cochrane Database Syst Rev 4,
2005. [meta-analysis; 5 RCTs, n = 344]
67. Fuchs I, Tsoi E, Henrich W, et al. Sonographic measurement of cervical
length in twin pregnancies in threatened preterm labor. Ultrasound Obstet
Gynecol 2004;23:42–45. [Level II-3]
Multiple Gestations
68. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung
maturation for women at risk of preterm birth. Cochrane Database Syst Rev
2006;3:004454. [Review/meta-analysis]
69. Palas D, Ehlinger V, Alberge CI, et al. Efficach of antenatal corticosteroids in
preterm twins: the EPIPAGE-2 cohort study. BJOPG 2018;125:1164–70.
70. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH
Consens Statement 1994;12:1–24. [III]
71. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium
sulphate for women at risk of preterm birth for neuroprotection of
the fetus. Cochrane Database Syst Rev 2009 Jan 21;(1):CD004661.
doi: 10.1002/14651858.CD004661.pub3. PMID: 19160238. [Review/
meta-analysis]
72. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the preven-
tion of cerebral palsy in preterm infants less than 34 weeks’ gestation: a
systematic review and metaanalysis. Am J Obstet Gynecol 2009;200(6):595–
609. [Review/meta-analysis]
73. Costantine MM, Weiner SJ, Eunice Kennedy Shriver National Institute of
Child Health and Human Development Maternal-Fetal Medicine Units
Network. Effects of antenatal exposure to magnesium sulfate on neuropro-
tection and mortality in preterm infants: a meta-analysis. Obstet Gynecol
2009;114(2 Pt 1):354–364 [Meta-analysis]
74. Patient safety checklist no. 7: magnesium sulfate before anticipated pre-
term birth for neuroprotection. Obstet Gynecol 2012;120(2 Pt 1):432–433.
[Guideline]
75. Mackeen AD, Seibel-Seamon J, Muhammad J, Baxter JK, Berghella V.
Tocolytics for preterm premature rupture of membranes. Cochrane
Database System Rev 2014, (2). Art. No.: CD007062.
76. Rafael TJ, Hoffman MK, Leiby BE, Berghella V. Gestational age of previous
twin preterm birth as a predictor for subsequent singleton preterm birth.
AJOG 2012;206:156.e1–6. [II-1]
77. Harper LM, Weis Ma, Odibo AO, et al. Significance of growth discordance
in appropriately grown twins. AJOG 2013;208(393):e1–5 [II-1].
78. Hillman SC, Morris RK, Kilby MD. Co-twin prognosis after single
fetal death. A systematic review and meta-analysis. Obstet Gynecol
2011;1118:928–40. [II-1]
79. Simpson LL, Society for Maternal-Fetal Medicine, Twin-twin transfusion
syndrome. Am J Obstet Gynecol. 2013;208(1):3–18. [Review]
80. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M.
Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550–5 [II-2]
81. Berghella V, Kaufmann M. Natural history of twin-twin transfusion syn-
drome. J Reprod Med;46(5):480–4. [II-3]
82. Society for Maternal-Fetal Medicine, Simpson LL. Twin-twin transfusion
syndrome. Am J Obstet Gynecol 2013 Jan;208(1):3–18. [Review]
83. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic
laser surgery versus serial amnioreduction for severe twin-to-twin transfu-
sion syndrome. N Engl J Med. 2004;351(2):136–44. [RCT]
84. Emery SP, Bahtiyar MO, Moise KJ. The north American fetal therapy net-
work consensus statement. Management of complicated monochorionic
gestations. Obstet Gynecol 2015;126:575–84. [Review]
85. Slaghekke F, Lopriore E, Lewi L, et al. Fetoscopic laser coagulation of the
vascular equator versus selective coagulation for twin-to-twin transfu-
sion syndrome: an open- labeled randomized controlled trial. Lancet
2014;383:2144–51 [RCT, n = 274]
86. Bower SJ, Flack NJ, Sepulveda W, et al. Uterine artery blood flow response
to correction of amniotic fluid volume. Am J Obstet Gynecol 1995;173:
502–7. [II-3]
87. Moise KJ Jr, Dorman K, Lamvu G, et al. A randomized trial of amniore-
duction versus septostomy in the treatment of twin-twin transfusion syn-
drome. Am J Obstet Gynecol 2005;193:701–7.[RCT, n = 71])
88. Taylor MJ, Shalev E, Tanawattanacharoen S, et al. Ultrasound guided
umbilical chord occlusion using bipolar diathery for stage III/IV twin-twin
transfusion syndrome. Prenat Diagn 2002;22:70–6. [Level II-3]
481
89. Papanna R, Habli M, Baschat AA, et al. Cerclage for cervical shortening
at fetoscopic laser photocoagulation in twin-twin transfusion syndrome.
AJOG 2012;206:425.e1–7. [II-2]
90. Slotnick RN, Ortega JE. Monoamniotic twining and zona manipulation: a
survey of U.S. IVF centers correlating zona manipulation procedures and
high-risk twinning frequency. J Assist Reprod Genet 1996;13:381–5. [II-3]
91. Bromley B, Benacerraf B. Using the number of yolk sacs to determine
amniocity in early first trimester monochorionic twins. J Ultrasound Med
1995;14:415–9. [II-2]
92. D’Antonio Odibo A, Berghella V, et al. Perinatal mortality, timing
of delivery and prenatal management of monoamniotic twin preg-
nancy: systemic review and meta-analysis. Ultrasound Obstet Gynecol
2019;53:166–74.
93. Lee YM. Delivery of twins. Semin Perinatol. 2012;36(3):195–200. [Review]
94. Van Gemert MJ, Umur A, van den Wijngaard JP, et al. Increasing cardiac
output and decreasing oxygenation sequence in pump twins of acardiac
twin pregnancies. Phys Med Biol. 2005;50(3):N33–42. [II-3]
95. Wong AE, Sepulveda W. Acardiac anomaly: current issues in prenatal
assessment and treatment. Prenat Diagn 2005;25:796–806. [II-3]
96. Spitz L, Kiely EM. Conjoined twins. JAMA. March 12, 2003;289(10):
1307–10. [Level II-3]
97. Mackenzie TC, Crombleholme TM, Johnson MP, et al. The natural history
of prenatally diagnosed conjoined twins. J Pediatr Surg. 2002;37(3):303–9.
[II-3]
98. Giles, W, Bisits, A, O’Callaghan, S, Gill, A. The Doppler assessment in mul-
tiple pregnancy randomized controlled trial of ultrasound biometry ver-
sus umbilical artery Doppler ultrasound and biometry in twin pregnancy.
BJOG 2003;110(6):593–7. [I]
99. Saccone G, Berghella V. Planned delivery at 37 weeks in twins: a systematic
review and meta-analysis of randomized trials. JMFNM 2015;xx:xx. [Meta-
analysis; 2 RCTs, n = 271].
100. American College of Obstetricians and Gynecologists. Committee Opinion
No 560. Medically indicated late-preterm and early-term deliveries. Obstet
Gynecol 2013;121:908–10. [III]
101. Van Mieghem T, De Heus R, Lewi L, et al. Prenatal management of mono-
amniotic twin pregnancies. Obstet Gynecol 2014;124:498–506. [II-3]
102. Barrett JF, Hannah ME, Hutton EK, et al. A randomized trial of
planned cesarean or vaginal delivery for twin pregnancy. N Engl J Med
2013;369:1295–305. [RCT, n = 2795]
103. Hogle KL, Hutton EK, McBrien KA, Barrett JFR, Hannah ME. Cesarean deliv-
ery for twins: a systematic review and meta-analysis. Am J Obstet Gynecol
2003;188:220–7. [Meta-analysis; 4 studies – only 1 RCT, [RCT, n = 1932]
104. Maudin JG, Newman RB, Mauldin PD. Cost-effective delivery manage-
ment of the vertex and non-vertex twin gestation. Am J Obstet Gynecol
1998;179:864–9. [II-2]
105. Felder AL, McCurdy R, Berghella V. External cephalic version of the non-
cephalic presenting twin: a systematic review. J Matern Fetal Neonatal Med
2020;1–7.
106. Lappen JR, Hackney DN, Bailit JL. Maternal and neonatal outcomes of
attempted vaginal compared with planned cesarean delivery in triplet ges-
tations. AM J Obstet Gynecol 2016: 215:493.e1–6.
107. Oyelese, Y, Ananth, CV, Smulian, JC, Vintzileos, AM. Delayed interval
delivery in twin pregnancies in the United States: Impact on perinatal mor-
tality and morbidity. Am J Obstet Gynecol 2005;192:439–44. [II-3]
108. Garite TJ, Clark RH, Elliot JP, and Thorp, JA. Twins and triplets: The effect
of plurality and growth on neonatal outcome compared with singleton
infants. Am J Obstet Gynecology 2004;191:700–7. [II-2]
109. Shah PS, Kusuda S, Håkansson S, et al. Neonatal outcomes of very preterm
or very low birth weight triplets. Pediatrics 2018 Dec;142(6):e20181938.
47
FETAL GROWTH RESTRICTION
Juliana Gevaerd Martins and Alfred Abuhamad
Key points
• Fetal growth restriction (FGR) is diagnosed with a sono-
graphic estimated fetal weight (EFW) or abdominal cir-
cumference (AC) < 10th percentile for gestational age.
Small for Gestational Age (SGA) should be used to describe
a newborn whose birth-weight is below the 10th percentile.
• Severe growth restriction is defined as EFW below the
3rd percentile for gestational age or EFW/AC below
the 10th percentile with abnormal umbilical artery
Doppler.
• FGR is classified into two different phenotypes accord-
ing to gestational age at diagnosis: Early-onset (diagnosed
< 32 weeks) and late-onset (diagnosed ≥ 32 weeks).
• Population-based fetal growth references (such as Hadlock)
should be used to determine fetal weight percentiles.
Screening and diagnosis of FGR are based on ultrasound
biometry that is dependent on accurate dating by an early
ultrasound (preferably first trimester).
• Placental insufficiency is the most common cause of FGR
(30–40% of all cases) followed by chromosomal disorders
and congenital malformations (20% of all cases).
• Risk factors associated with FGR are numerous, and
include maternal, fetal, and placental factors (Table 47.1).
• Complications of FGR occur in utero and in later life
• Fetus: Oligohydramnios, non-reassuring fetal heart
testing (NRFHR), and stillbirth.
• Neonate: Preterm birth and its consequences (respi-
ratory distress syndrome (RDS), intraventricular
hemorrhage (IVH), necrotizing enterocolitis [NEC]),
hypoglycemia, hyperbilirubinemia, hypothermia, sei-
zures, sepsis, neurodevelopmental delay and neonatal
death.
• Infant and child (as well as later in life): Impaired gross
motor development, cerebral palsy, lower intelligence
quotient, mental retardation, speech/reading disabili-
ties, learning deficits, poor academic achievement, and
suicide.
• Adult: Hypertension, coronary artery disease, diabe-
tes, obesity.
• Maternal complications:
• Hypertension in 50% of cases at the time of diagnosis
and 70% at the time of delivery (in pregnancies compli-
cated by early-onset FGR).
• Increased risk of cesarean delivery.
• Initial assessment upon diagnosis should include the
following:
• Identification and treatment of modifiable risk fac-
tors (e.g., smoking, medical disorders).
• Detailed obstetric ultrasound examination, includ-
ing umbilical artery Doppler, especially with early-
onset FGR since up to 20% of cases are associated with
fetal or chromosomal abnormalities.
482
• Prenatal diagnostic testing with CMA in the setting of:
– FGR detected in association with fetal malforma-
tion or polyhydramnios, regardless of the gesta-
tional age.
– Unexplained isolated FGR diagnosed at less than
32 weeks of gestation.
• Routine serologies for TORCH infections may not be
warranted in the absence of risk factors or sonographic
markers.
• Surveillance should include the following:
• Growth ultrasound every 3 to 4 weeks. Three-week
(or even two-week) intervals should be done in par-
ticular the setting of severe FGR or with abnormal
umbilical artery Doppler.
• Umbilical artery Doppler assessment should be per-
formed initially usually every 1 week to assess for
deterioration. If the umbilical artery Doppler remains
normal following this initial assessment, a less fre-
quent interval of umbilical artery Doppler testing (e.g.,
every 2–4 weeks) can be considered.
– With decreased end-diastolic velocity (DEDV),
i.e., flow ratios greater than the 95th percen-
tile, or in pregnancies with severe FGR (EFW
less than the 3rd percentile), weekly umbilical
artery Doppler evaluation should be performed.
– With absent end diastolic flow (AEDV), umbili-
cal artery Doppler assessment up to 2 to 3 times
per week is recommended due to the potential
for deterioration and development of reversed
end diastolic flow (REDV).
– With REDV, consideration should be given for
hospitalization, administration of antenatal cor-
ticosteroids, heightened surveillance with car-
diotocography (CTG) at least 1 to 2 times per day.
• Middle cerebral artery, ductus venosus, and uterine
artery Doppler are not recommended for routine
clinical management of FGR. Maternal fetal-medi-
cine practices that wish to incorporate DV in clinical
management of FGR may consider restricting its appli-
cation to fetuses with A/REDV of the UA between 28
and 32 weeks of gestational age.
• CTG at least weekly should be performed in preg-
nancies complicated by FGR. Frequency should
be increased in the presence of A/REDV or other
comorbidities and risk factors.
• BPP alone (without CTG component) is not recom-
mended for fetal well-being in high-risk pregnancies.
• Preparation for delivery:
• Antenatal corticosteroids are indicated if delivery
is anticipated before 33 6/7 weeks of gestation or
for pregnancies between 34 0/7 and 36 6/7 weeks of
gestation in women without contraindications who
are at risk of preterm delivery within 7 days and
DOI: 10.1201/9781003099062-47
Fetal Growth Restriction
who have not received a prior course of antenatal
corticosteroids.
• Magnesium sulfate for fetal and neonatal neuro-
protection is indicated for women with pregnancies
that are less than 32 0/7 weeks of gestation in whom
delivery is likely.
• Timing for delivery include the following:
• 38 0/7 to 39 0/7 weeks of gestation in pregnancies
complicated by FGR with an EFW between the
3rd and the 10th percentile and normal umbilical
artery Doppler.
• 37 0/7 weeks of gestation in pregnancies complicated
by FGR with an umbilical artery Doppler waveform
with decreased diastolic flow (S/D, RI or PI above than
the 95th percentile) but without A/REDV or in the set-
ting of severe FGR (EFW less than the 3rd percentile).
• 33 0/7 to 34 0/7 weeks in pregnancies complicated
by FGR in the presence of AEDV.
• 30 0/7 to 32 0/7 weeks in pregnancies complicated
by FGR in the presence of REDV.
• 34 0/7 to 37 6/7 weeks of gestation for FGR associ-
ated with oligohydramnios.
• Irrespective of Doppler findings, and in viable preg-
nancies with FGR, delivery is always indicated in
the presence of non-reassuring fetal heart testing,
or maternal indications.
• Delivery before 26 weeks of gestation or 500 grams
should include coordination of care between maternal-
fetal medicine and neonatology services, along with
comprehensive patient counseling.
• Mode of delivery:
• Cesarean delivery should be considered in pregnan-
cies with FGR complicated by A/REDV, based on the
entire clinical scenario.
TABLE 47.1: Variables/Etiologies Associated with FGR
Maternal
Pregnancy-related hypertensive diseases
Pregestational diabetes
Autoimmune diseases (e.g. systemic lupus erythematosus)
Antiphospholipid syndrome
Cyanotic cardiac disease
Pulmonary disease
Renal disease
Environmental (smoking, alcohol, drugs, malnutrition)
Teratogen exposure (e.g. antineoplastic medications such as
cyclophosphamide, antiepileptic medications such as valproic acid,
antithrombotic medications such as warfarin)
Living at high altitudes
Fetal
Genetic and structural disorders
Infections
Multiple gestation
Placental
Placental disorders and umbilical cord disorders
Mosaicism
Implantation abnormalities with abnormal analytes on serum screening
Source: See further Refs. [3, 8].
483
• Induction of labor with mechanical methods appear
to have a lower association with adverse outcomes
when compared to induction with prostaglandins.
• Recurrence rate of SGA neonate at birth appears to be
increased. Low-dose aspirin is not recommended for the
sole indication of FGR prevention. In the subsequent preg-
nancy, screening for FGR with ultrasound surveillance of
fetal growth should be considered in the third trimester.
Definitions/Diagnosis
Fetal growth restriction (FGR) is defined as the inability of the
fetus to achieve its growth potential. FGR is a complex and mul-
tifactorial disorder resulting from maternal, fetal and placental
conditions (Table 47.1) [1]. Placental insufficiency is the most com-
mon cause of FGR (30–40% of all cases) followed by chromosomal
disorders and congenital malformations (20% of all cases) [2, 3].
It is widely accepted among several national guidelines that
FGR is diagnosed when sonographic estimation of the fetal weight
is below the 10th percentile [4, 5]. Abdominal circumference (AC)
has been assessed as a predictor of SGA at birth and studies have
shown (including a meta-analysis with 5119 pregnancies) that an
AC alone <10th percentile predicted SGA as well as sonographic
EFW <10th percentile, with comparable sensitivity and specific-
ity [6, 7]. According to recent guidelines, FGR is defined as a
sonographic EFW or AC below the 10th percentile for gesta-
tional age [5].
One of the main challenges in clinical practice is to distinguish
between growth-restricted fetuses from those that are constitu-
tionally small [5, 8]. The categorization of FGR as <10th percen-
tile has often been criticized secondary to the inclusion of many
fetuses that are constitutionally small and not at risk for poor peri-
natal outcome [9, 10]. In fact, the majority of fetuses (up to 70%)
with an EFW of <10th percentile is not at risk for adverse perinatal
outcome, while the remaining 30% truly have pathologic FGR, and
these fetuses (and neonates) are most at risk [10–13].
Some studies have shown that the use of customized growth
standards (adjusted to factors that are known to affect birth-
weight such as maternal height, weight in early pregnancy, parity
and ethnic group), improve the ability to distinguish growth-
restricted fetuses from those that are constitutionally small when
compared to population-based references [14–22]. Evidence to
date indicates that these new formulas in clinical practice do not
improve the detection and outcome of FGR [23–25]. Some authors
advocate that growth deceleration is more reflective of the fetal
nutritional status rather than an estimation of the fetal weight
at a single point in pregnancy and has a better association with
perinatal morbidity [26]. Reduced growth velocity (fall between
consecutive ultrasound scans of >50 percentiles for EFW or AC)
in the third trimester has been associated with increased risk
of adverse outcomes [27]. An individualized growth assessment
program (iGAP) has been developed to determine the early fetal
growth trajectory, which allows the estimation of growth and it
is considered another method of evaluating fetal growth velocity
[26]. Further research is warranted to assess their reproducibility
and clinical utility. Current national guidelines recommend
the use of population-based fetal growth references (such as
Hadlock) in determining fetal weight [5].
FGR and small for gestational age (SGA) are terms currently
used interchangeably in clinical practice to describe small fetuses
with considerable overlap [8]. The majority of fetuses with an
EFW of <10th percentile is not SGA at birth and will not be at
484 Maternal-Fetal Evidence Based Guidelines

risk for adverse perinatal outcome [10–12]. SGA neonates have TABLE 47.2: Recurrence Risks of Etiologies of FGR
often not been diagnosed as growth-restricted on prenatal ultra-
Risk of Recurrence Risk of FGR in the
sound [4, 8]. To avoid confusions with terminology, the American
Previous Pregnancy According to Presence of Risk
College of Obstetricians and Gynecologists (ACOG) and the
Condition Etiology Factors
Society for Maternal-Fetal Medicine (SMFM) suggests the use
of FGR to describe a fetus with a sonographic estimated fetal Maternal
weight (EFW) below the 10th percentile and SGA to describe • Vascular disease Generally persistent Up to 50%
a newborn whose birth-weight is below the 10th percentile for (HTN, PGDM, renal,
gestational [5, 8]. autoimmune)
• Inherited or acquired Generally persistent 30–80%
thrombophilia
Epidemiology/Incidence • Substance abuse Situation dependent Substance-specific
FGR occurs > 10% of pregnancies and is second to premature • Malnutrition Situation dependent Minimal if treated
birth as cause of infant morbidity and mortality [1, 28, 29].
Fetal
Prenatal identification of FGR is associated with lower rates of
• Autosomal trisomy 1% or maternal Abnormality-specific
stillbirth, highlighting the importance of ultrasound diagnosis
age-related risk
and surveillance [30].
• Sex chromosome <1% Abnormality-specific
There is an increased risk of stillbirth at fetal weights below
abnormality
the 10th percentile for gestational age (approximately 1.5%, twice
the rate of fetuses with normal growth) [8]. Infants with birth • Triploidy <1% 100%
weights below the 10th percentile are more likely to have severe • Unbalanced <1% Abnormality-specific
acidosis at birth, low 5-minute Apgar scores and to be admitted translocation (de
to the neonatal intensive care unit [31, 32]. Perinatal outcomes novo)
are largely dependent on the severity of FGR, with the worst out- • Unbalanced Variable Abnormality-specific
comes noted in fetuses with estimated fetal weights at less than translocation
the 3rd percentile or in association with fetal Doppler abnormal- (inherited)
ities [12, 28]. • Autosomal recessive 25% Abnormality-specific
• Structural 3–5% if multifactorial Abnormality-specific
malformation
Genetics/Inheritance/Recurrence (isolated)
Determining the underlying cause of FGR can be difficult as it • Congenital <1% Infection-specific
results from a variety of maternal, fetal, and placental factors. infections Variable, 3% of live Up to 25%
Recurrence risks greatly depend on these underlying conditions • Multifetal gestation births
(Table 47.2) [33].
Placental
Almost 20% of early-onset FGR cases are associated with
• Single umbilical 0.4% Up to 7%
fetal or chromosomal abnormalities which are more frequent in
artery
pregnancies with structural anomalies [2, 3, 34, 35]. Early-onset,
presence of polyhydramnios and the presence of structural mal- • Velamentous cord 1–2% 15–20%
formations increase the likelihood of a chromosomal abnormal- insertion
ity [31]. The recurrence risk for an aneuploidy is approximately • Placental abruption 22% Approximately 18%
1%; however, in the setting of a genetic syndrome, the recurrence Source: From Ref. [33], with permission.
risk is dependent on the specific associated condition [31].
In fetuses with no structural malformations, the mean rate of
chromosomal anomalies has been reported as 6.4% [33]. Studies only for gestational age at onset, but also for clinical manifesta-
that have evaluated the role of chromosomal microarray (CMA) tions, patters of deterioration, association with hypertension and
in fetuses with early-onset FGR and no structural malformations severity of placental dysfunction (Table 47.3) [41].
have identified a 4–10% incremental yield of CMA over karyotype Early-onset FGR (diagnosed < 32 weeks) represents 20–30%
[36–38]. of all FGR, is typically more severe, tends to follow an established
The risk of recurrence of SGA in a subsequent pregnancy Doppler pattern of fetal deterioration (from abnormalities in the
appears to be increased. In a large prospective cohort study of umbilical artery and ductus venosus to abnormal biophysical
women with non-anomalous singleton pregnancy, the risk of parameters), is more commonly associated with maternal hyper-
SGA in the second pregnancy was 23% in women with previ- tensive disorders of pregnancy (in up to 70% of cases) and shows
ous SGA neonate versus 3.4% in women without a previous SGA more significant placental dysfunction [5, 41].
neonate (adjusted OR 8.1; 95% CI 7.8–8.5) [39]. Late-onset FGR (diagnosed ≥ 32 weeks) is more common
(70–80% of the cases), shows a weaker association with hyperten-
Classification sion (approximately 10%) and do not present the same sequence
of Doppler deterioration described for early-onset FGR [5, 41].
Timing of diagnosis Doppler of the umbilical arteries are usually normal and the pat-
FGR is classified into two different phenotypes according to ges- tern of fetal adaptation is typically limited to the cerebral circu-
tational age at onset, with an arbitrary cutoff set at 32 weeks to lation [42]. Placental histopathologic findings of underperfusion
maximize its differences [40]. Early- and late-onset FGR differ not are typically less significant [42].
Fetal Growth Restriction 485

TABLE 47.3: Features between Clinical Phenotypes of FGR depends on the capacity of the villous trophoblast and fetoplacen-
tal circulation to transport these nutrients [52]. Remodeling of
Early-Onset FGR Late-Onset FGR
maternal arteries is considered key to accommodate the demands
Prevalence 0.5–1% 5–10% for increased blood flow to the uteroplacental circulation [53].
Challenge Management (gestational Detection and diagnosis The placenta vasculature needs to undergo major remodeling
age at delivery) to become fully hemochorial and this process takes place towards
Evidence of High Low the end of the first trimester and extends into the second trimes-
placental disease 70% abnormal UA Doppler < 10% abnormal UA ter [52, 53]. The terminal branches of the uterine arteries: the
60% association with Doppler spiral arteries, will undergo significant remodeling, losing the
pre-eclampsia 15% association with smooth muscle cells and elastin from arterial walls. Interactions
Severe angiogenic imbalance pre-eclampsia between the trophoblast and the immune system, in particular
Mild angiogenic imbalance the natural killer cells, is necessary to assure an adequate remod-
Pathophysiology Hypoxia +/+ eling as they are part of differentiation and loss of the smooth
and oxygen Systemic cardiovascular Hypoxia +/- muscle cells within the arterial walls [52, 53].
delivery to the adaptation Central cardiovascular As a result of vascular remodeling, a low-impedance circula-
brain adaptation tion, associated with a 10-fold increase in blood supply to the
Clinical impact High mortality and Low mortality/morbidity fetal-­placental unit will be generated [52, 53]. The increased villous
morbidity BUT high prevalence = surface area increases the efficiency of active transport mecha-
large etiological fraction nisms of three major nutrient classes – glucose, amino acids and
of adverse outcomes free fatty acids. Glucose is the predominant oxidative fuel and
amino acids are major contributors to protein synthesis [54].
Source: From Ref. [42], with permission.
Fetal circulation allows preferential distribution of nutrients in
the fetus – nutrient- and oxygen-rich blood enters the circulation
Severity of FGR via the umbilical vein. The ductus venosus (DV) is the vascular
An abnormal umbilical artery (UA) Doppler ultrasound is effec- shunt that modulates the proportion of umbilical venous blood
tive in differentiating between pathologic FGR and a constitu- that is distributed to the liver and heart. The direction and veloc-
tionally small fetus [10, 43]. ity of the blood coming from the DV to the right atrium, ensures
When considering weight alone as a predictor of adverse out- preferential streaming of nutrient-rich blood to the left ventricle,
comes, studies have shown that an EFW < 3rd percentile is asso- myocardium and brain [54].
ciated with an increased risk of adverse perinatal outcomes, Normal placental and fetal growth is characterized by sequen-
including a risk of stillbirth threefold over the 3rd to 5th percentile tial cellular hyperplasia, hyperplasia plus hypertrophy and lastly
at all gestational ages, an increased risk of fourfold to sevenfold hypertrophy alone [53]. Placental growth plateaus in midgesta-
over the 5th to 10th percentile group [44–46]. These findings are tion before the exponential fetal growth that occurs in the third
in agreement with neonatal data [47]. Severe growth restriction trimester. In singleton pregnancies, fetal growth rates accelerate
is defined as EFW below the 3rd percentile for gestational age, from 5 g per day at 14–15 weeks’ gestation to 10 g per day at 20
or EFW/AC below the 10th percentile with abnormal umbilical weeks, peaking at 30–35 g per day at 32–34 weeks, after which
artery Doppler; the majority of these cases are associated with growth rate decreases [2].
pathologic reasons for FGR [5]. The etiology of FGR can be broadly categorized into maternal,
Symmetric and asymmetric FGR fetal and placental (Table 47.1) [8].
FGR has been classified as asymmetric or symmetric based on the
ratio between head circumference and the abdominal circumfer- Maternal factors
ence (HC/AC), with an HC/AC ratio > 95th percentile is used as Maternal hypertensive disease is common in early-onset FGR and
a cutoff for asymmetric [10]. Asymmetric FGR refers to a reduc- plays an important role in pregnancy outcomes [5, 55]. In a large,
tion in abdominal circumference (AC) relative to other measures, randomized trial of delivery timing in early-onset FGR (TRUFFLE
such as head circumference (HC). Often, symmetric FGR is char- study), the rate of maternal hypertensive disease was 50% dur-
acterized by a similar reduction in all biometric measurements. ing the study and 70% at the time of delivery [55]. Chronic dis-
Usually, the etiology is present from the beginning of the preg- eases (especially associated with vascular disease) may result in
nancy, and it can include aneuploid or euploid genetic diseases, FGR such as diabetes, renal insufficiency and cardiac disease [8].
viral infection, drug/toxic exposure, and/or placental causes [48]. Diabetes is complicated by FGR in 10–20% of the cases irrespec-
This classification has been traditionally used as a tool to dis- tive of glycemic control [3]. Antiphospholipid syndrome has been
tinguish between etiologies, with asymmetry pointing to a pla- associated with FGR. In contrast, hereditary thrombophilias have
cental cause; however, early onset of placental disease may also not been found consistently to be associated with FGR [8].
lead to symmetric FGR, making the classification less helpful. Substance use in pregnancy may result in FGR such as alcohol,
Recent studies have shown that HC/AC was not found to be an cocaine and narcotics [8]. Tobacco use is associated with 3.5-fold
independent predictor of adverse outcomes and therefore, should increased risk of SGA [8]. Exposure to certain maternal medica-
not be considered a classification of FGR [49–51]. tions has also been associated with FGR and the effect on the fetal
growth is dependent on the inherent teratogenicity, timing and
Etiology/Basic pathophysiology duration of exposure [8].

Fetal growth depends on an adequate balance between nutrient Fetal factors

availability and delivery. The first is related to maternal diet, utero- Chromosomal abnormalities are present in almost 20% of early-
placental blood supply and placenta villous development; the latter onset growth restricted fetuses [5]. At least 50% of fetuses with
486
trisomy 13 or trisomy 18 are growth restricted [8]. Structural mal-
formation without chromosomal or genetic abnormalities such as
congenital heart disease and gastroschisis also have an increased
risk of fetal growth restriction [8]. Previous studies have reported
an incidence of 5–10% of congenital infections in pregnancies
complicated by FGR [8, 33], however recent studies have shown
lower incidences [56–59]. In a study that included 319 pregnancies
with FGR, congenital CMV was found in 1.8% of cases (0.6% of the
fetuses had no sonographic findings) and no cases of maternal or
congenital toxoplasmosis, rubella or herpes were found [56].
Multiple gestations have a high incidence of FGR – 20% to 30%
of dichorionic twin pregnancies and 40% of monochorionic twin
pregnancies will suffer from FGR (see Chap. 46) [3].
Placental factors
Suboptimal placental perfusion is the most common pathology
associated with FGR (30–40% of all cases) [5]. Placental disor-
ders (abruption, hemangioma, chorioangioma and circumvallate
shape) and umbilical cord abnormalities (velamentous or mar-
ginal cord insertion, single umbilical artery) have also been asso-
ciated with FGR [8]. In over 20% of fetuses with idiopathic FGR,
confined placental mosaicism was detected in the placenta [3].
Complications
FGR is associated with morbidity and mortality to the fetus and
infant [10]. FGR is the largest category associated with still-
birth accounting for up to 43% of stillbirths and has also been
found in the majority of stillbirths considered unexplained [60].
Pregnancies complicated by SGA have a 5-fold increased risk of
stillbirth beyond 37 weeks [10]. Furthermore, using cumulative
risk analyses, there is a significant risk of stillbirth for each week of
gestation > 37 weeks [61]. Perinatal death may be increased up to
100-times compared to normally grown babies [10]. Additionally,
intrapartum asphyxia has been reported to complicate 50% of
pregnancies with FGR [62]. In addition to stillbirth, FGR increases
the risk of preterm birth, NEC, and RDS [26, 63]. Preterm infants
with birth weight < 3rd percentile carries the highest perinatal
morbidity and mortality risk. When matched for gestational age
at both term and preterm gestations, the smallest infants are at the
highest risk for low Apgar score, acidosis, intubation, seizures,
and death in the first 28 days of life [47].
The impact of FGR goes beyond the neonatal period [64–73].
Children who were born with growth restriction have a higher
risk of cerebral palsy, short stature, and cognitive delay [32]. In
later life, adults who had FGR have a higher incidence of hyper-
tension, coronary artery disease, stroke, type II diabetes mel-
litus, and obesity [74].
The primary risk to the mother is cesarean section with a
reported cesarean section rate of 43% if induction is performed
in fetuses that have an EFW < 5th percentile [75]. Rates as high
as 90% were reported in the GRIT study [76]. Maternal hyper-
tensive disease complicates up to 70% of early severe FGR (< 32
weeks) with pre-eclampsia complicating 50% of all FGR cases [55].
Management
Prevention
Gestational age determination
Since gestational age is the primary component dictating
whether a fetus is measuring small, accurate determination
of an estimated date of confinement (EDC) is paramount.
Maternal-Fetal Evidence Based Guidelines
First-trimester ultrasound < 13 weeks and 6 days is the most
precise method to determine the EDC. For precise estimation of
gestational age by ultrasound, see Table 2 in Chapter 4, Obstetric
Evidence Based Guidelines [10].
Interpregnancy interval
Interpregnancy intervals less than 6 months are associated with
FGR (OR 1.3; 95% CI 1.1–1.5) [77]. In a large retrospective study of
173,205 birth certificates, infants conceived 18–23 months after
a previous live birth had the lowest risks of adverse perinatal out-
comes including SGA at birth [78].
Smoking cessation
In a Cochrane analysis that evaluated 72 trials including 56 ran-
domized controlled trials (over 20,000 pregnant women) and 9
cluster-randomized trials (over 5000 women), smoking cessa-
tion interventions in pregnancy reduced the rate of low birth-
weight (RR 0.83, 95% CI 0.73–0.95) (see Chap. 22) [10, 79].
Bed rest and nutrition
There is no consistent evidence that nutritional and dietary sup-
plements or bed rest prevents FGR or reduces the incidence of
SGA births [8].
In low-risk women, significant dietary management does not
prevent FGR [10]. In this population, ineffective methods include
individualized nutritional advice; increased fish, low-fat meats,
grain, fruits, and vegetables; low-salt diet; iron supplementation;
and calcium supplementation. Dietary supplements that may be
beneficial include magnesium and vitamin D [10]. Vitamin D lev-
els have recently been reported to be low in patients with SGA in
early onset severe pre-eclampsia, but supplement trials showing
benefit are lacking. In general, evidence is still limited for the use
of dietary supplements to specifically reduce the risk of FGR, and
they cannot be recommended for clinical use at this time [10].
In high-risk women with nutritional deficiencies, increas-
ing caloric intake with low-protein supplementation reduces
the risk of FGR by 32%. In the absence of nutritional defi-
ciency, high protein supplementation may lead to higher rates
of FGR and should be avoided [10, 80].
Control of maternal medical disorders
Modification of maternal risk factors for FGR can be performed
as a primary preventative factor. Hypertension has been associ-
ated with an increased risk of FGR but placing women on anti-
hypertensive medication when the blood pressure is between
140–169/90–109 has not been shown to improve the rate of
pre-eclampsia, FGR, preterm birth, or stillbirth [81]. However,
it does decrease the rates of severe hypertension. The Control
of Hypertension in Pregnancy Study (CHIPS trial) was a RCT
trial to test if less-tight control (target diastolic blood pressure,
100 mm Hg) or tight control (target diastolic blood pressure,
85 mm Hg) of chronic hypertension in pregnancy demonstrated
differences in maternal and fetal outcomes. No differences were
seen between groups for birth-weight < 10th or < 3rd percen-
tiles, or any other maternal or fetal outcomes, although less-tight
control was associated with a significantly higher frequency of
severe maternal hypertension [82]. Current ACOG recommenda-
tions are to continue with existing guidelines for management of
women with mild-moderate hypertension (defined as systolic BP
≥ 140 mm Hg but < 160 mm Hg or diastolic BP ≥ 90 mm Hg but <
110 mm Hg) [83], i.e., no need to lower BP further if SBP < 160 and
DBP < 105; and this is endorsed by the Society of Maternal-Fetal
Medicine [84]. For women with persistent chronic hypertension
Fetal Growth Restriction
with systolic BP ≥ 160 mm Hg or diastolic BP >105 mm Hg, anti-
hypertensive therapy is recommended. Controlling diabetes,
autoimmune disorders, and other medical illnesses is important
for both maternal and fetal health.
Aspirin
The use of prophylactic low-dose aspirin (LDA) was shown to
provide a modest risk reduction in FGR and SGA in two meta-
analyses [85, 86]. However, this finding was not confirmed
in the Aspirin for Evidence-Based Pre-eclampsia Prevention
Trial (ASPRE), which was primarily designed for preterm
pre-eclampsia prevention [87, 88]. Due to conflicting evidence
on the role of LDA in the prevention of recurrent FGR in low-risk
women, ACOG recommends against the use of LDA for the sole
indication of FGR prevention [89].
Low-molecular-weight heparin
A meta-analysis of multicenter trial data does not demonstrate
any positive preventative effect of low-molecular-weight heparin
on a primary composite outcome of placenta-mediated complica-
tions including fetal growth restriction (18% versus 18%; absolute
risk difference, 0.6%; 95% CI 10.4–9.2) [87].
The use of low-molecular-weight heparin has not shown to
reduce the risk of recurrent placenta-mediated pregnancy com-
plications in at-risk women [87].
Screening
Maternal serum analytes
PAPP-A levels below the 5th percentile have been associated
with abnormal pregnancy outcomes including abnormal fetal
growth [90, 91] with a sensitivity, positive predictive value and
negative predictive value of 10.4%, 18.7% and 91.3% respectively for
birth weight < 10th percentile [92, 93]. Abnormal second-trimester
analytes such as AFP > 2.0 multiple of the median (MoM), uE3
< 0.5 MoM and an inhibin A > 2.0 MoM have also been associ-
ated with FGR and birth weight < 10th percentile [93, 94].
Fundal height
Serial abdominal palpation has been evaluated for the screening
of FGR in a large cohort of 6318 low-risk pregnancies, demon-
strating a low detection rate (21%) with a FPR of 4% [95]. A ran-
domized controlled trial (RCT) of 1639 patients evaluated serial
fundal height (SFH) versus abdominal palpation for the screening
of SGA – detection rate was 28% for SFH and 48% for abdominal
palpation with FPR ranging from 3–36% [96]. A recent Cochrane
Review concluded that there is insufficient evidence to determine
if fundal height is effective in detecting FGR [97].
Selective versus universal third trimester ultrasound
A prospective cohort compared the detection rates between
selective third trimester ultrasound in 1666 women with clini-
cal indications versus universal third trimester ultrasound at 28
and 36 weeks in 2322 nulliparous low risk women [98]. Screening
with universal ultrasonographic estimation detected 57% of SGA
neonates (versus 20% with selective screening) and 77% of severe
SGA neonates (versus 32% with selective screening), with a very
low positive predictive value (PPV of 35% for SGA and 12% for
severe SGA). Only 14% of SGA babies were at increased risk of
neonatal morbidity [98].
A RCT compared universal third-trimester ultrasound at 36
weeks in 1314 low-risk patients versus at 32 weeks in 1272 low-
risk patients with a primary outcome to detect SGA (custom-
ized BW < 10th percentile) and severe SGA (customized BW
487
< 3rd percentile) [99]. There were no differences in perinatal out-
comes between those who underwent a scan at 32 weeks versus
36 weeks. Severe SGA was associated with increased risks of neo-
natal adverse outcomes. At a similar FPR (6.4% versus 8.2%), SGA
detection rates were superior at 36 versus 32 weeks (sensitivity
38.8% versus 22.5%, p = 0.006), with positive and negative likeli-
hood ratios (LHR) of 6.1 versus 2.7 and 0.65 versus 0.84, respec-
tively. In cases of severe SGA, at a similar FPR (8.5% versus 8.7%),
detection rates were superior at 36 versus 32 weeks (61.4% versus
32.5%, p = 0.008), with positive and negative LR of 7.2 versus 3.7
and 0.4 versus 0.74, respectively [99].
A recent systematic review and meta-analysis evaluated
whether routine third-trimester ultrasound in low-risk pregnan-
cies decrease the rate of perinatal death compared with regular
antenatal care with serial fundal height measurements [100]. A
total of seven randomized control trials with 23,643 patients
were included. The rate of fetal growth restriction was higher in
the ultrasound group (763 of 10,388 [7%] versus 337 of 9021 [4%];
RR 2.11; 95% CI 1.86–2.39); however, the total rate of perinatal
death was similar among groups (41 of 11,322 [0.4%] versus 34 of
10,285 [0.3%]; RR, 1.14; 95% CI 0.68–1.89). Despite sample size
limitations and the need for an adequately powered trial to assess
perinatal mortality outcome, current evidence does not sup-
port the use of routine third-trimester ultrasound, as it would
increase the detection of SGA babies at the cost of a substan-
tial increase in the number of false positive results with a net
effect of unnecessary interventions on healthy babies [98–101].
Doppler
Uterine artery Doppler
Uterine artery (UtA) Doppler assesses the maternal component
of placental blood flow and is a marker of remodeling of the spiral
arteries by trophoblastic cellular invasion [5]. Failure of tropho-
blastic invasion results in reduced uteroplacental perfusion and
has been associated with pre-eclampsia and FGR [5].
A number of studies have evaluated uterine artery Doppler in
the first and second trimester of low and high-risk pregnancies
to stratify the risk for the development of FGR. The presence of
diastolic notching or an elevated index of resistance (systolic/dia-
stolic [S/D] ratio, pulsatility index [PI], or resistance index [RI])
has been used to predict the onset of FGR [102].
A systematic review and meta-analysis of 61 studies (41,131
patients) of uterine artery Doppler prediction of FGR in low-risk
patients determined that UtA Doppler provided a more accurate
prediction when performed in the second trimester than in the
first trimester, however most Doppler indices had poor predictive
characteristics, varying with patient risk and outcome severity.
An increased PI with notching was the best predictor of overall
(positive LHR 9.1) and severe (positive LHR 14.6) FGR among low
risk patients [103].
A large prospective in 8024 women evaluated the utility of early
second-trimester UtA Doppler as a predictor of SGA neonates.
Nulliparous low- and high-risk patients were seen longitudinally
at 3 visits from 16 0/7 to 22 6/7 weeks and PI, RI and diastolic
notching were measured. Abnormal UtA Doppler indices were
associated with BW < 5th percentile (p < 0.0001) but the positive
predictive value for these values were all < 15% and under receiver
operating characteristic curves ranged from 0.56–0.62 [102, 103].
Uterine artery Doppler has limited diagnostic accuracy and
clinical utility in predicting FGR, SGA at birth and perinatal
mortality and is not recommended for routine screening of
FGR [5].
488
Umbilical artery Doppler
A systemic review of five trials (14,185 women were analyzed)
found no evidence of maternal and neonatal benefit from the
routine use of umbilical artery Doppler in low-risk or unselected
population [104].
Combined models
First-, second- and third-trimester screening algorithms includ-
ing maternal characteristics, biochemical markers (such as
pregnancy-associated plasma protein-A [PAPP-A], serum pla-
cental growth factor and free β-human chorionic gonadotrophin
[βhCG]) and biophysical parameters (multivessel Doppler) have
been evaluated for the prediction of FGR [105–109]. In a screen-
ing study in 1536 FGR and 31,314 normal pregnancies, a first tri-
mester screening model detected 73% of SGA requiring delivery
before 37 weeks and 46% for those delivering at term, at a false
positive rate (FPR) of 10% [105]. The SPREE trial (Screening pro-
gram for pre-eclampsia), a prospective multicenter cohort study
that evaluated over 17,000 women for the performance of a com-
bined first-trimester screening algorithm for pre-eclampsia and
FGR, identified a high-risk group that contained about 46% of
FGR < 10th percentile born at < 37 weeks and 56% of those born
at < 32 weeks with an overall screen-positive rate of 12.2% [106].
A model combining first- and second-trimester screening
parameters predicted 78.6% of the prenatally detected and 59.6%
of the overall late-onset FGR for a 10% FPR (area under the curve
0.901 [95% CI 0.856–0.947] and 0.855 [95% CI 0.818–0.891]) [107].
The performance of third-trimester screening based on EFW
alone versus combined model in 1590 singleton pregnancies from
32 0/7 to 36 6/7 weeks showed that EFW alone predicted 52% of
SGA (AUC 0.82 [95% CI 0.77–0.85]) and 64% of FGR (AUC 0.86
[95% CI 0.81–0.91]) while a combined model predicted 61% of
SGA (AUC 0.86 [95% CI 0.83–0.89], p < 0.001) and 77% of FGR
(AUC 0.92 [95% CI 0.88–0.95], p = 0.002) [108].
Overall, the prediction of FGR using combined models is asso-
ciated with low positive predictive values and there is limited evi-
dence to recommend their use for FGR screening.
Workup: Initial assessment upon diagnosis
FGR is defined as a sonographic EFW or AC below the 10th
percentile for gestational age using population-based fetal
growth references (such as Hadlock) to determine fetal weight
percentiles. Accurate pregnancy dating must be confirmed as
it is an important prerequisite to diagnosing FGR [5].
Upon diagnosis, FGR should be classified into early-onset and
late-onset, with early-onset FGR first diagnosed before 32 weeks
of gestation, and late-onset FGR diagnosed at or after 32 weeks of
gestation [5]. Severe FGR is suspected with sonographic estimation
of the fetal weight is below the 3rd percentile for gestational age [5].
Identification of risk factors, especially modifiable risk
factors, can be obtained by review of the medical history
(Table 47.1). Maternal blood pressure can be obtained, and if
abnormal, exclusion of pre-eclampsia is warranted. Any sub-
stance abuse should be discussed, and cessation of these sub-
stances should be encouraged. The identification of maternal
diseases that increase the risk for FGR is helpful since optimal
management of those disorders may improve growth in the
fetus for the remainder of the pregnancy [10].
A detailed obstetric ultrasound examination with umbili-
cal artery Doppler should be performed with early-onset FGR
since up to 20% of cases are associated with fetal or chromosomal
abnormalities [2, 3, 5, 35].
Maternal-Fetal Evidence Based Guidelines
Fetal diagnostic testing, including chromosomal microarray
(CMA), should be offered when FGR is associated with a con-
genital malformation, polyhydramnios, or both, regardless of
the gestational age [5]. In isolated early-onset FGR with no struc-
tural malformations, CMA has shown a diagnostic increment of
4–10% over karyotype and should be offered for unexplained iso-
lated FGR at less than 32 weeks of gestations [5, 34, 36–38, 110].
Previous studies estimated that congenital infections
(TORCH) were responsible for approximately 5–10% of FGR
cases [35, 111] however this association was recently evaluated
in over 300 pregnancies and no cases of maternal or congeni-
tal infection with toxoplasmosis, rubella and herpes were found
[53]. CMV was diagnosed in six fetuses (1.8%) and only two
(0.6%) had no sonographic findings other than FGR [53]. Given
the low incidence of TORCH infections in cases of FGR [56, 57],
the lack of antenatal intervention [112] and the limited utility of
serologic testing for CMV in the third trimester [57, 58], routine
infectious serologies may not be warranted in the absence of
risk factors or sonographic markers [5]. If diagnostic testing
for CMV is elected, amniocentesis with PCR evaluation should
be considered [5].
Treatment
There are no proven treatments of FGR that will improve fetal
growth or outcome once it is diagnosed [8, 87].
Avoidance of toxins
Discontinuation of toxins known to be associated with FGR
should be stressed. When the toxins are the result of substance
abuse, such as in smoking, strong counseling should be per-
formed to encourage cessation of the substance associated with
FGR (Table 47.1). Very rarely, if the toxin is a pharmacotherapy,
weighing the potential risks of cessation of the medication with
continued exposure to the fetus should be performed. Discussion
of alternative therapies should be considered. However, once the
fetus is identified as FGR, data is lacking on whether cessation of
the offending agent will improve growth during the remainder of
pregnancy, but biological plausibility exists, and cessation should
still be encouraged [10].
Therapy for medical conditions
Proper treatment of chronic hypertension, pre-eclampsia, dia-
betes, or other medical condition is important, but there are no
trials to prove a beneficial effect on FGR [10].
Bed rest
Bed rest has long been used by obstetricians as a tool for improv-
ing pregnancy outcome, even though data is lacking to support
its use. The only RCT showed no difference in birth-weight
(RR 0.43, 95% CI 0.15–1.27) or neonatal outcomes when bed
rest was compared to ambulation in patients with FGR [113]. A
recent summary of Cochrane reviews of bed rest in which 6 RCTs
were identified, there was no support found for “therapeutic” bed
rest for threatened abortion, hypertension, pre-eclampsia, pre-
term birth, multiple gestations, or impaired fetal growth [114].
Therefore, there is insufficient evidence to support the use of bed
rest to treat patients with FGR. Hospitalization for bed rest is
possibly dangerous (e.g., associated with venous thromboembo-
lism), expensive, and inconvenient for the pregnant woman.
Nutrient therapy
Improving nutrient delivery to the fetus by increasing maternal
intake of these nutrients has been widely studied. Some nutrient
Fetal Growth Restriction
supplementations may be beneficial in preventing FGR, while
others are not. Docosahexaenoic acid has been shown in a large
RCT to result in larger birth weights if patients continue with
the supplementation in pregnancy [115]. Maternal micronutri-
ent therapy with the UNICEF/WHO/UNO international mul-
tiple micronutrient preparation has been shown to increase birth
weight in regions where nutritional supplementation is rare [116].
Long-chain polyunsaturated fatty acid supplementation has not
been shown to improve birth weight [117]. Although supplemen-
tation may improve birth weight prior to the development of FGR,
once there is FGR, there is insufficient evidence that supple-
menting the mother with amino acids, minerals, vitamins, glu-
cose, or energy supplements improves birth weight [118].
Betamimetics
The theoretical basis for using betamimetic therapy for impaired
fetal growth is promoting fetal growth by increasing the avail-
ability of nutrients and by decreasing vascular resistance. In
fetuses diagnosed with FGR, the administration of betamimetics
is not associated with improvement in birth weight or neonatal
morbidity and mortality [119]. Betamimetics are associated with
several complications, and therefore should not be used for this
indication.
Calcium channel blockers
There is currently insufficient evidence to promote the use of
calcium channel blockers for FGR. Calcium channel blockers may
theoretically increase uteroplacental perfusion, and, therefore,
improve nutrient and oxygen delivery to a fetus that is at risk or
currently growth restricted. Only one study has been published
which randomized 100 smoking women to either flunarizine or
placebo. The treatment group had a higher mean birth weight, but
no other significant differences were seen [120].
Aspirin
In high-risk populations, such as in women with a first-tri-
mester uterine artery Doppler PI that is abnormal, low-dose
aspirin has been shown to decrease the incidence of FGR when
initiated prior to 16 weeks [85–87, 121, 122]. After this gesta-
tional age, and once FGR is established, aspirin has no proven
benefit.
Heparin
There is insufficient evidence to assess the effect of heparin ther-
apy in FGR pregnancies. In an RCT, with heterogeneous inclusion
criteria for FGR including fundal height < 10%, heparin was asso-
ciated with better growth and almost a week-later gestational age
at delivery compared to a Chinese root called Dan-shen [87, 123].
Oxygen
There is insufficient evidence to evaluate the benefits and risks
of maternal oxygen therapy for suspected impaired fetal growth.
A Cochrane analysis showed that oxygen administration to preg-
nancies with suspected FGR decreased the rates of perinatal
mortality (33% versus 65%; a 50% reduction) compared to no
oxygenation [124]. In all studies birth weights were higher in the
oxygen group, despite similar (average range: 10–20 days) inter-
vals to delivery. No significant side-effects or adverse outcomes
have been reported. Higher gestational age in the oxygenation
groups may have accounted for the difference in mortality rates.
Also, two of the studies did not use placebos, there was no blind-
ing, and the small number of patients does not allow a thorough
assessment of effect [124].
489
Plasma volume expansion
There is insufficient evidence to assess the effect of increase in
maternal fluid intake (either IV or orally) on FGR. In pregnancies
complicated by FGR, maternal volume expansion is lower than
in pregnancies with normally grown fetuses [125]. Expanding
maternal plasma volume once FGR has been identified was
evaluated in only one very small trial in patients with AEDV of
the UA. Compared to no volume expansion, volume expansion
in women with FGR fetuses with AEDV of UA was associated
with a decrease (2/7 versus 6/7) in perinatal mortality. There was
no difference in the gestational age at delivery and mean birth
weight [126].
Abdominal decompression
There is insufficient evidence to assess the effect of this interven-
tion, as all trials are old, and they contain serious bias. Abdominal
decompression consists of a rigid dome placed about the abdo-
men and covered with an airtight suit, with the space around the
abdomen decompressed to −50 to −100 mm Hg for 15–30 sec-
onds out of each minute for 30 minutes once to thrice daily, or
with uterine contractions during labor. This is thought to “pump”
blood through the intervillous space. Therapeutic abdominal
decompression is associated with reductions in persistent pre-
eclampsia; “fetal distress” in labor; low birth weight; Apgar scores
less than six at one minute; and perinatal mortality (7% versus
40%) [127].
Nitric oxide donors
There is insufficient evidence to recommend the use of nitric
oxide donors to fetuses with FGR. L-Arginine is a precursor to
nitric oxide and may play a role in placental blood flow. In one
randomized study evaluating pregnancies with FGR, admin-
istration of this compound did not increase mean birth weight
or duration of pregnancy [128]. Alternatively, two other non-
randomized studies showed improvement in fetal growth when
L-arginine was given, either orally or intravenously, to pregnan-
cies with suspected FGR [129, 130].
Sildenafil
There is no evidence that sildenafil improves placental perfu-
sion and outcome in pregnancies with FGR [131]. A multicenter
randomized controlled trial of sildenafil therapy in early-onset
FGR (STRIDER NZAus) evaluated the use of oral administra-
tion of 25 mg sildenafil citrate versus placebo in pregnancies
complicated by early-onset FGR and found that sildenafil did
not affect the proportion of pregnancies with an increase in fetal
growth velocity (52.5%) sildenafil-treated, 68.4% placebo-treated
(adjusted odds ratio [OR] 0.49, 95% CI 0.23–1.05) and had no
effect on abdominal circumference Z-scores (p = 0.61) [131].
Other interventions
Several potential new therapies are under investigation, such as
maternal VEGF gene therapy, nanoparticles, microRNAs, statins,
nitric oxide donors, hydrogen sulfide, proton pump inhibitors,
melatonin, creatine and N-acetylcysteine, however many are
being investigated for pre-eclampsia treatment with FGR as a
secondary outcome [87].
Antepartum testing
There is currently no treatment for FGR, and the management
is based on early diagnosis, optimal fetal surveillance and timely
delivery (Figure 47.1). See Chap. 58.
490 Maternal-Fetal Evidence Based Guidelines

Diagnosis
EFW < 10%
and / or
AC < 10%

Classification
Early FGR: < 32 weeks at initial diagnosis
Late FGR: ≥ 32 weeks at initial diagnosis
Severe FGR: EFW < 3rd %ile or abnormal UA Doppler

Workup
• Detailed obstetric ultrasound
• Diagnostic genetic testing (CMA) for:
• Early FGR
• Sonographic markers
• Fluid abnormalities
• Consider CMV serologies

Fetal Surveillance
• UA Doppler
• CTG

Deliver for repetitive late

decelerations post fetal viability

Normal UA: UA Decreased EDV: UA Absent EDV: UA Reversed EDV:

S/D, PI, Rl ≤ 95% S/D, PI, Rl > 95%
Consider inpatient admission Inpatient admission
UA Doppler weekly UA Doppler 2–3x per week Steroids for fetal maturity
CTG 2x per week Steroids for fetal maturity CTG 1–2x per day
EFW Q 2 weeks CTG daily EFW Q 2 weeks
EFW Q 2 weeks

Deliver at 37 weeks Deliver at 33–34 weeks Deliver at 30–32 weeks

EFW ≥ 3rd – 9th %ile EFW < 3rd %ile

UA Doppler Q 2–4 weeks UA Doppler weekly
CTG 1–2x per week CTG 2x per week
EFW Q 3–4 weeks EFW Q 2 weeks

Deliver at 38–39 weeks Deliver at 37 weeks

FIGURE 47.1 Management of FGR. (From Martins JG, Abuhamad AZ, Biggio JR. Society for maternal-fetal medicine (SMFM) consult series
#52: diagnosis and management of fetal growth restriction. Am J Obstet Gynecol 2020;223(4):B2–B17. [III]. Ref. [5], with permission.)
Fetal Growth Restriction
Intervals of growth assessment
Once FGR is diagnosed, assessment of fetal growth and weight
should be performed at least every 3 to 4 weeks; consideration
can be given for a 2-week interval in cases of severe FGR or with
abnormal umbilical artery Doppler [5].
Doppler in the management of FGR
Umbilical artery Doppler
Doppler velocimetry of the umbilical artery (UA) reflects the pla-
cental function by assessing the resistance to blood flow [5, 27].
Abnormal UA Doppler result from spiral artery maladaptation
and reflects the presence of placental insufficiency, differentiating
fetuses that are constitutionally small from those that are patho-
logically growth restricted [5, 27].
Doppler waveforms can be obtained from any segment along
the umbilical cord as the variation is minimal and does not
impact clinical decision-making [5]. Doppler measurements of
both umbilical arteries also do not improve predictive value for
adverse perinatal outcomes since the two umbilical arteries show
good agreement in terms of their PI values [132].
The pulsatility index (PI), resistance index (RI), or systolic/dia-
stolic (S/D) ratio can be used for quantification of the Doppler
waveform in the umbilical artery and are considered abnormal
when PI, RI or S/D ration are greater than the 95th percentile
for gestational age or in the presence of an absent or reversed
end-diastolic velocity (AEDV or REDV) [5]. Absent or reduced
end-diastolic velocity (A/REDV) reflects significant placental
deterioration and is associated with high perinatal mortality [5].
UA Doppler is an essential component of fetal surveillance in
pregnancies complicated by FGR. Incorporation of UA Doppler
in the management has been shown to significantly reduce the
risk of perinatal death (29% decrease) [133]. In a large study on
FGR, the mean time-to-delivery interval for umbilical artery PI
greater than the 95th percentile, AEDV, and REDV was 26, 12,
and 4 days, respectively [134].
Evidence suggests that umbilical artery Doppler does not reli-
ably predict adverse pregnancy outcome in late-onset FGR [135–
137]. This result is probably related to the lower frequency of
placental pathologic findings in late-onset FGR when compared
with early-onset FGR [138–140].
There are currently no randomized trials with adequate sam-
ple size to inform recommendations regarding the optimal fre-
quency of umbilical artery Doppler for FGR surveillance [141].
A prospective observational study of the progression of Doppler
abnormalities in FGR suggests that rapid progression, if it is
going to occur, is typically noted within the first 2 weeks after
diagnosis [142].
Once FGR is diagnosed, umbilical artery Doppler assess-
ment should be performed every 1–2 weeks to assess for
deterioration [5]. If the umbilical artery Doppler remains nor-
mal following this initial assessment, a less frequent interval of
umbilical artery Doppler testing, e.g., every 2 to 4 weeks, may be
considered [5, 143].
With decreased end-diastolic velocity (DEDV), i.e., flow
ratios greater than the 95th percentile, or in pregnancies with
severe FGR (EFW less than the 3rd percentile), weekly umbili-
cal artery Doppler evaluation should be performed [5].
With AEDV, umbilical artery Doppler assessment up to 2–3
times per week is recommended due to the potential for dete-
rioration and development of REDV. In the setting of REDV,
consideration should be given for hospitalization, administra-
tion of antenatal corticosteroids, heightened surveillance
491
with cardiotocography (CTG) at least 1–2 times per day, and
consideration of delivery depending on the entire clinical pic-
ture and results of additional evaluation of fetal well-being [5].
Middle cerebral artery Doppler
Fetal hypoxemia associated with growth restriction results
in cerebral vasodilation, an early hemodynamic phenomenon
called “brain-sparing” [5, 27]. Measurement of flow through the
middle cerebral artery using Doppler can identify cerebral vaso-
dilation, which can be qualified using the pulsatility index (PI) or
the cerebroplacental ratio (CPR). The CPR is calculated by divid-
ing the middle cerebral artery PI by the umbilical artery PI and
values below 1.08 or the 5th percentile are considered abnormal
[144, 145].
The role of middle cerebral artery Doppler in the manage-
ment of early-onset FGR has been evaluated in several studies
[146–148], showing that middle cerebral artery Doppler did
not add useful information beyond umbilical artery and ductus
venosus Doppler assessments for optimizing the timing of deliv-
ery [149] due to a low likelihood ratio for prediction of perinatal
mortality [LR 1.36 (1.10–1.67)] and adverse perinatal outcome
[LR 2.77(1.93–3.96)] [150].
In late-onset FGR, studies have demonstrated that 15–20% of
fetuses with normal umbilical blood flow have middle cerebral
artery Doppler findings of cerebral vasodilation, and CPR has
also been studied for its utility in predicting adverse outcomes
and guiding the timing of delivery in late-onset cases [151–159].
The role of CPR in the prediction of adverse perinatal outcome
was evaluated in 881 fetuses with FGR at 24 0/7–36 6/7 weeks of
gestation in a large trial. Abnormal CPR evaluation had a sensitiv-
ity of 87% and specificity of 61% for the prediction of adverse out-
comes, conferring an 11-fold increased risk when compared with
cases with normal CPR [159]. The neurodevelopment outcome of
these children (n = 373) was assessed at 3 years and children from
fetal growth-restricted pregnancies with an abnormal CPR had
significantly poorer neurologic outcome compared to children
from growth-restricted pregnancies with both normal Doppler
and abnormal UA Doppler alone [160].
Cerebral redistribution is associated with short and long-
term perinatal outcomes however there is no evidence to guide
its use in the management and delivery timing in the setting of
late-onset FGR. Four out of six main national guidelines recom-
mend undertaking cerebral Doppler and using the information
to determine delivery timing at 37 weeks [4]. In the recently
published Practice Guidelines by The International Society of
Ultrasound in Obstetrics and Gynecology (ISUOG), in pregnan-
cies with late FGR and signs of cerebral blood-flow redistribution,
delivery should be considered at 38 0/7 and not later than 38 6/7
weeks [27].
Despite its promising role in the management of late-onset
FGR, available evidence does not demonstrate improved accuracy
of CPR over UA Doppler [160, 161] and larger studies are needed
to evaluate the effectiveness on CPR in the management of preg-
nancies complicated by late-onset FGR [162]. Based on the avail-
able evidence, Doppler assessment of the cerebral circulation
is not recommended for routine clinical management of early-
and late-onset FGR [5].
Ductus venosus Doppler
Increased placental blood flow resistance such as absent or
reversed umbilical artery end-diastolic flow places the growth-
restricted fetus for late cardiovascular changes that are associated
492
with fetal deterioration and decompensation [41, 150, 163–171].
Doppler abnormalities of the ductus venosus (DV) in FGR reflect
the massive increase in placental afterload leading to a decreased
myocardial performance and compliance due to myocardial
hypoxia [172, 173], representing an advanced stage of fetal com-
promise, associated with increased perinatal morbidity and mor-
tality [163–171].
The DV Doppler is the strongest single Doppler parameter to
predict the short-term risk of fetal death in early-onset FGR [174],
with odds ratios for stillbirth of 11.16 (95% CI 6.31–19.73) for
absent or reversed A-wave of the ductus venosus and a frequency
of stillbirth of 20%; the risk of stillbirth with a reversed A-wave
was 46% in pregnancies below 34 weeks [175].
In early-onset FGR, DV abnormalities precedes the loss of
short-term variability in the fetal heart rate and in 90% of the
cases it becomes abnormal only 48–72 hours before the biophysi-
cal profile, providing a good window to perform steroids for lung
maturation followed by delivery [3, 163, 164]. After 32 weeks, DV
changes are not useful in the surveillance of growth restricted
fetuses since abnormal cardiotocography findings will almost
invariably precede DV abnormalities [176].
The Trial of Umbilical Fetal Flow in Europe (TRUFFLE) is the
only RCT to assess the effect of using venous Doppler for clini-
cal management in FGR [55]. Severe and early FGR pregnancies
enrolled at < 32 weeks were randomized to one of three groups
for timing of delivery: (1) Reduced computerized cardiotoco-
graphic short-term variation (cSTV), (2) Early DV changes (DV
PI > 95th percentile but with forward atrial-wave flow), (3) Late
DV changes (a-wave at [absent] or below [reversed] baseline). The
primary endpoint of the study was survival without cerebral palsy
or neurosensory impairment or a Bayley III developmental score
< 85 at 2 years of age. After correction for prematurity, survival
without neurological impairment was found to be significantly
higher in the group delivered according to late ductus venosus
changes (95%) compared with cSTV (85%) [55].
Findings of the TRUFFLE trial should not be extrapolated to
practice in the United States [5]. There were several limitations
of the TRUFFLE study including: (1) the survival and outcomes
were much better than anticipated and, thus, the sample size for
detecting differences may have been underestimated; (2) moni-
toring frequency among centers varied. The frequency of moni-
toring (UA Doppler and CTG) was set at a minimum of once per
week, but left to local protocols; (3) delivery criteria after 32 weeks
varied among centers. After 32 weeks, delivery was based on local
policy and could be based on CTG STV, elevated PI or A/REDF in
UA or DV changes. Perhaps the group delivered < 32 weeks should
have been assessed separately rather than including outcomes of
those delivering after 32 weeks; and 4) all study groups had UA
Doppler performed; however, it was specifically stated that the
CTG STV group did not have DV Doppler performed [10, 55]. This
is a major limitation because it results in a blending of study groups
rather than a true comparison of different delivery criteria. For
example, an abnormality in the DV has been shown to occur in
50–70% of cases prior to an abnormal CTG or biophysical profile
(BPP) and these should have been eliminated from the TRUFFLE
CTG STV group in order to allow for a true comparison of CTG
versus DV [10]. 5) Finally, there is limitation of generalizability of
this study to the U.S. population where computerized CTG and
assessment of STV is not nearly universally performed [10]. Based
on the available evidence [177], Doppler assessment of the duc-
tus venosus is not recommended for routine clinical manage-
ment of early- and late-onset FGR [5]. Maternal fetal medicine
Maternal-Fetal Evidence Based Guidelines
practices that wish to incorporate DV in clinical management
of FGR may consider restricting its application to fetuses with
A/REDV of the UA between 28 and 32 weeks of gestational age.
Uterine artery Doppler
Abnormal uterine artery (UtA) Doppler has been associated with
adverse pregnancy outcomes, including pre-eclampsia, FGR, and
perinatal mortality [178–181] however, studies have shown lim-
ited diagnostic accuracy and clinical utility in predicting FGR,
SGA birth, and perinatal mortality, suggesting that UtA Doppler
does not add clinically valuable information for the diagnosis and
management of FGR [102, 182].
In suspected late-onset FGR, since most of events of adverse
outcomes occur with normal umbilical artery Doppler, uterine
artery Doppler has been proposed as a tool, along with CPR,
UA Doppler, and EFW for the selection of cases with a higher
risk of adverse perinatal outcomes due to placental insufficiency
[136, 183]. Studies that looked into longitudinal changes of UtA
Doppler in pregnancies complicated by FGR have reported that
indices remain unchanged from diagnosis to delivery, supporting
the notion that uteroplacental Doppler is of little clinical value
in pregnancies complicated by late-onset FGR [136]. The role of
uteroplacental Doppler for the management of established FGR
and in the third trimester is limited [3].
Based on the available evidence, Doppler assessment of the
uterine artery is not recommended for routine clinical man-
agement of early- and late-onset FGR [5].
Fetal kick counts
While there are no RCTs to assess the efficacy of fetal kick
counts specifically in FGR pregnancies, they are still com-
monly recommended in guidelines [8, 10, 110]. While several
methods have been described for maternal assessment of fetal
activity, a simple technique is for the mother to lay on her side and
record any distinct fetal movements once or twice daily. While
most fetuses will achieve this degree of movement within the first
5–10 minutes, failure to achieve 10 movements within a 2-hour
period warrants further evaluation of the fetus with non-stress
testing [10]. See Chap. 58.
Biophysical parameters in the management of FGR
Cardiotocography
Cardiotocography (CTG) as a surveillance tool in pregnancies
complicated by FGR has not been well-evaluated with high-­
quality studies[10]. When comparing CTG with no CTG, there is
no difference in the prediction of perinatal mortality, preventable
deaths, or cesarean sections [10, 184]. There is limited evidence
from randomized controlled trials to inform best practice for fetal
surveillance regimens and even their frequency when caring for
women with pregnancies affected by FGR [10, 185]. Computerized
CTG may improve perinatal mortality when compared to tradi-
tional CTG [10, 184], however, this analysis was not limited to
FGR fetuses, and the benefit of antenatal CTG has yet to be fully
investigated in this population. In many management schemas,
CTG has been cited as a standard monitoring tool, despite the
lack of rigorous studies proving its efficacy [8, 10]. Nonreactive
and abnormal CTG has been associated with acidosis and hypox-
emia [10, 186, 187] and this justifies its use as a screening tool for
fetal well-being.
While there is limited evidence to support the frequency of
CTG in pregnancies with FGR, it is reasonable to initiate test-
ing at diagnosis if after viability, or at viability or a gestational
Fetal Growth Restriction
age at which an abnormal finding would trigger intervention [5].
Weekly CTG testing (after viability) should be performed
in pregnancies complicated by FGR. Frequency should be
increased in the presence of A/REDV or other comorbidities
and risk factors [5].
Biophysical profile
Evidence from RCTs does not support the use of BPP as a test
of fetal well-being in high-risk pregnancies [10, 188]. In high-risk
pregnancies (including FGR, post-term pregnancies, hyperten-
sive disorders, or other conditions), when comparing a BPP to
other tests of fetal well-being, there is no difference in perinatal
deaths or low Apgar scores [10, 188]. Although the overall inci-
dence of adverse outcomes was low, there is no significant dif-
ference between the groups in perinatal deaths (RR 1.33, 95% CI
0.60–2.98) or in Apgar score < 7 at 5 minutes (RR 1.27, 95% CI
0.85–1.92). Combined data from the two high-quality RCTs sug-
gest an increased risk of cesarean section in the BPP group (RR
1.60, 95% CI 1.05–2.44) [10, 188].
More recent studies have questioned the value of BPP in fetal
surveillance of pregnancies complicated by early-onset severe
FGR, due to a high prevalence of false-positive and false-negative
results [5, 189, 190]. Based on the available evidence, the use of
BPP alone (without CTG) is not recommended in the manage-
ment of pregnancies complicated by FGR [5].
Amniotic fluid volume
The PORTO study, which included over 1100 pregnancies with
FGR, noted that amniotic fluid volume abnormalities did not
independently increase the risk for adverse outcomes in FGR [44].
There is currently a paucity of data on the role of amniotic fluid
volume measurement in FGR management and delivery [5].
Estriol levels
Compared to concealed levels, knowledge of plasma estriol levels
does not affect perinatal mortality (3% in each group) in women
with FGR, hypertension, or adverse obstetric history [191].
Delivery
The decision for delivery is a delicate balance between the risk
of prematurity and perinatal death and it depends on both fetal
and maternal factors [5]. Gestational age is the most important
prognostic factor as intact survival increases 1–2% for every addi-
tional day spent in utero until 32 weeks of gestation [135, 174].
Near the limit of viability, the decision for delivery is complex
and challenging. Data on morbidity and mortality of early-onset
FGR, delivered before 26 weeks of gestation is available from a
handful of studies [192–197]. Previous research has shown that
in early-onset FGR associated with abnormal Doppler studies,
neonatal survival increased from 13% at 24 weeks to 43% at 25
weeks and 58–76% at 26 weeks of gestation. Intact survival was
0% at 24 weeks, 13% at 25 weeks, and 6–31% at 26 weeks of gesta-
tion [41, 192]. These findings suggest that the outcome of growth-
restricted fetuses delivered before 26 weeks of gestation appear to
be considerably poorer than that of appropriately grown fetuses
[192–197]. For this reason, thresholds of 26 weeks of gestation or
500 grams have been suggested for the delivery of severe early-
onset FGR [5].
Preparation: Steroids and magnesium sulfate
When fetal testing in the FGR fetus suggests need for delivery at
24–34 weeks, several strategies should be considered. If delivery
493
is anticipated within seven days, steroids for fetal maturity
should be administered to the mother. Either betamethasone
or dexamethasone can be used. Betamethasone 12 mg IM q24h
× 2 doses (one course) is associated with decrease in RDS, IVH,
NEC, and perinatal mortality [198]. A single “rescue” course can
be considered > 14 days from the first course, if pregnancy is
still < 32 weeks [199, 200]. Steroids can temporarily affect NST,
BPS, and Doppler testing (see also Chapter 17, Obstetric Evidence
Based Guidelines). The evidence for safety and effectiveness of
steroids specifically in FGR pregnancies is limited [201]. One
recent, relatively small, retrospective study comparing steroids to
no steroids in severe and early FGR pregnancies (delivered < 32
weeks’ gestation) failed to show any immediate neonatal benefit
of steroids (except for improved cord pH and 5-minute Apgar
score) or long-term infant benefit (no improvement in Griffith’s
score at 2 years of age) [202]. Thus, further investigation of steroid
benefit in FGR is needed in this early severe FGR group. However,
in contrast to this study, an older and larger (n = 19,759 VLBW
cases) study from the Vermont Oxford Database of FGR fetuses
between 501–1500 gm, antenatal steroids were associated with
significant reductions in RDS, IVH and severe IVH, but not in
necrotizing enterocolitis [203].
Although no study has addressed the benefit of magnesium
sulfate and neuroprotection in FGR pregnancies alone, this
medication should be administered for neuroprotection based
on published protocols [204–206]. Lastly, delivery should be
accomplished at a facility that has neonatal intensive care unit
capabilities [8].
In accordance with other guidelines, antenatal corticoste-
roids are indicated if delivery is anticipated before 33 6/7
weeks of gestation or for pregnancies between 34 0/7 and 36
6/7 weeks of gestation in women without contraindications
who are at risk of preterm delivery within 7 days and who
have not received a prior course of antenatal corticosteroids
[207, 208].
Magnesium sulfate for fetal and neonatal neuroprotection
is indicated for women with pregnancies that are less than 32
weeks of gestation in whom delivery is likely [209].
Timing of delivery
If active management of FGR is contemplated before 26 0/7
weeks of gestation or 500 grams, coordination of care between
maternal-fetal medicine and neonatology services, along with
comprehensive patient counseling on neonatal morbidity and
mortality and shared decision-making regarding pregnancy
management [5] (Figure 47.1).
A meta-analysis on the risk of fetal death in FGR before 34
weeks of gestation reported that, in the setting of AEDV in the
umbilical artery Doppler, the risks of stillbirth are 6.8% and
these risks are higher than the risks of prematurity at 33–34
weeks [odds ratio (OR) for fetal death of 3.59 (95% CI 2.3–5.6)]
[175]. In the setting of REDV in the umbilical artery Doppler,
the risks of stillbirth are 19% and these risks are higher than the
risks of prematurity at 30–32 weeks [odds ratio (OR) for fetal
death of 7.27 (95% CI 4.6–11.4)] [175]. Therefore, in the presence
of AEDV, delivery is recommended at 33 0/7 to 34 0/7 weeks
of gestation for pregnancies with FGR [5]. In the presence of
REDV, delivery is recommended at 30 0/7–32 0/7 weeks of
gestation [5].
The evidence supporting the timing of delivery in pregnancies
with FGR and DEDV in the UA Doppler is limited. Delivery at 37
weeks of gestation results in a decrease in the stillbirth rate in
494
the presence of risk factors, such as FGR [210]. In pregnancies
complicated by FGR with an umbilical artery Doppler wave-
form with decreased diastolic flow (S/D, RI or PI above than
the 95th percentile) but without A/REDV or in the setting of
severe FGR (EFW alone less than the 3rd percentile), delivery
is recommended at 37 weeks of gestation [5].
Delivery is recommended at 38–39 weeks of gestation in
pregnancies complicated by FGR with an EFW between the
3rd and the 10th percentile and normal umbilical artery
Doppler [5].
Current guidelines on medically indicated late-preterm and
early-term deliveries suggest delivery at 34 0/7–37 6/7 weeks of
gestation for FGR associated with oligohydramnios [211].
Irrespective of Doppler findings, and in viable pregnancies
with FGR, delivery is always indicated in the presence of spon-
taneous repetitive fetal heart rate decelerations, or maternal
indications [5].
Multiple gestation and FGR
There are no trials of timing delivery in either monochorionic/
diamniotic or dichorionic/diamniotic twin gestations affected by
one or two FGR co-twins. Assuming that fetal surveillance has
continued to be reassuring, recommendations based on expert
opinion are provided by a committee opinion document from
the ACOG [211]. In DC/DA twin gestations with isolated FGR,
delivery in the late preterm (36 0/7–36 6/7 weeks) is suggested.
If DC/DA twins have concurrent conditions, such as abnormal
Doppler studies or maternal co-morbidities (e.g., pre-eclampsia
or chronic hypertension), delivery in the later preterm period is
suggested (32 0/7–34 6/7 weeks). Because of the higher rate of
fetal demise in the third trimester, even without FGR, in mono-
chorionic/diamniotic twins, delivery in the later preterm period
is recommended (32 0/7–34 6/7 weeks). Consider delivery of
twins if one twin has REDF of UA at 30–31 weeks, AEDF of UA at
32–33 weeks, or abnormal (but not REDF or AEDF) UA Doppler
at 35–36 weeks. For more details, see Chap. 46.
Mode of delivery
FGR complicated by A/REDV is associated with an increased
risk of intrapartum complications [212, 213], with reported rates
of fetal heart rate decelerations during labor requiring cesarean
delivery as high as 75–95% of the cases [214, 215]. National guide-
lines from four countries recommend cesarean delivery when
FGR is complicated by A/REDV of the umbilical artery [4]. Studies
that have assessed the outcomes of pregnancies complicated by
FGR with A/REDV, the mode of delivery was primarily by cesar-
ean, thus rendering it impossible to determine the likelihood of
adverse outcomes associated with spontaneous or induced vaginal
delivery [110]. Given these data and outcomes, cesarean delivery
should be considered in pregnancies with FGR complicated by
A/REDV, based on the entire clinical scenario [5].
There is still controversy regarding the relationship between
labor induction and increased risks of cesarean section and other
adverse outcomes in pregnancies complicated by FGR [216].
Previous studies have compared mechanical methods (Foley
balloon) versus prostaglandins (dinoprostone and misoprostol)
for cervical ripening in pregnancies complicated by late-onset
FGR [216–218]. A recent systematic review and meta-analysis
of 12 studies (1711 pregnancies) reported a lower rate of over-
all composite adverse intrapartum outcome, cesarean section
for non-reassuring fetal heart tracing, uterine tachysystole and
Maternal-Fetal Evidence Based Guidelines
composite adverse perinatal outcomes in pregnancies induced
with Foley balloon compared to dinoprostone and misoprostol
[218]. Mechanical methods appear to be associated with a lower
occurrence of adverse intrapartum outcome; however, the quality
of the studies was low with considerable clinical and statistical
heterogeneity [218].
Neonatology management
FGR neonates frequently require assistance with ventilation and
feeding, especially if born preterm. FGR neonates < 32 weeks
or < 1500 g requires special care, usually in a tertiary care cen-
ter [10]. Workup of the etiology of FGR should be completed if
not already done prenatally [10]. Hypoglycemia, polycythemia,
and coagulopathies are common, and may need treatment.
Involvement of the neonatology team on counseling the patient
prior to delivery on expectations in the intensive care unit may
be helpful for families [10].
Future pregnancy preconception counseling
Recurrence risks are dependent upon the etiology, but when the
etiology is uncertain, the rate of recurrence is increased to as high
as 23% [39, 219]. Despite the increased risk in recurrence rates,
there are currently no preventative strategies or treatments for
FGR that have been proven to be effective [4].
In the subsequent pregnancy, screening for FGR with ultra-
sound surveillance of fetal growth should be considered in the
third trimester.
References
1. Swanson AM, David AL. Animal models of fetal growth restriction: consid-
erations for translational medicine. Placenta 2015;36(6):623–30. [II-2]
2. Resnik R. Intrauterine growth restriction. Obstet Gynecol 2002;99(3):
490–6. [III]
3. Bamfo JE, Odibo AO. Diagnosis and management of fetal growth restric-
tion. J Pregnancy 2011;2011:640715. [III]
4. McCowan LM, Figueras F, Anderson NH. Evidence-based national guide-
lines for the management of suspected fetal growth restriction: compari-
son, consensus, and controversy. Am J Obstet Gynecol 2018;218:S855–S68.
[III]
5. Martins JG, Abuhamad AZ, Biggio JR. Society for maternal-fetal medicine
(SMFM) consult series #52: diagnosis and management of fetal growth
restriction. Am J Obstet Gynecol 2020;223(4):B2–B17. [III]
6. Blue NR, Yordan JMP, Holbrook BD, Nirgudkar PA, Mozurkewich EL.
Abdominal circumference alone versus estimated fetal weight after 24
weeks to predict small or large for gestational age at birth: a meta-analysis.
Am J Perinatol 2017;34:1115–24. [I]
7. Caradeux J, Martinez-Portilla RJ, Peguero A, Sotiriadis A, Figueras F.
Diagnostic performance of third-trimester ultrasound for the prediction of
late-onset fetal growth restriction: a systematic review and meta-analysis.
Am J Obstet Gynecol 2019;220:449–59.e19. [I]
8. American College of Obstetricians and Gynecologists’ Committee
on Practice Bulletins—Obstetrics and the Society for Maternal-Fetal
Medicine. ACOG Practice Bulletin No. 204: fetal growth restriction. Obstet
Gynecol 2019;133:e97–e109. [III]
9. Favre R, Nisand G, Bettahar K, et al. Measurement of limb circumferences
with three-dimensional ultrasound for fetal weight estimation. Ultrasound
Obstet Gynecol 1993;3:176–79. [III]
10. Berghella V. Fetal growth restriction. In: Berghella V. ed. Maternal-
Fetal Evidence Based Guidelines. 3rd ed. Boca Raton: CRC Press, 2017.
387–406. [III]
11. Ott WJ. The diagnosis of altered fetal growth. Obstet Gynecol Clin North
Am 1988;15:237. [II-2]
12. Unterscheider J, Daly S, Geary MP, et al. Optimizing the definition of intra-
uterine growth restriction: the multicenter prospective PORTO Study. Am
J Obstet Gynecol 2013;208:290.e1–6. [II-2]
Fetal Growth Restriction
13. Monier I, Ancel PY, Ego A, et al. Fetal and neonatal outcomes of preterm
infants born before 32 weeks of gestation according to antenatal vs post-
natal assessments of restricted growth. Am J Obstet Gynecol 2017;216:516.
e1–.e1. [II-2]
14. Papageorghiou AT, Kennedy SH, Salomon LJ, et al. The INTERGROWTH-
21(st) fetal growth standards: toward the global integration of pregnancy
and pediatric care. Am J Obstet Gynecol 2018;218:S630–s40. [II-2]
15. Papageorghiou AT, Ohuma EO, Altman DG, et al. International stan-
dards for fetal growth based on serial ultrasound measurements: the Fetal
Growth Longitudinal Study of the INTERGROWTH-21st Project. Lancet
2014;384:869–79. [II-2]
16. Villar J, Cheikh Ismail L, Staines Urias E, et al. The satisfactory growth and
development at 2 years of age of the INTERGROWTH-21(st) Fetal Growth
Standards cohort support its appropriateness for constructing interna-
tional standards. Am J Obstet Gynecol 2018;218:S841–S54.e2. [II-2]
17. Hanley GE, Janssen PA. Ethnicity-specific birthweight distributions
improve identification of term newborns at risk for short-term morbidity.
Am J Obstet Gynecol 2013;209:428.e1–6. [II-2]
18. Anderson NH, Sadler LC, McKinlay CJD, McCowan LME.
INTERGROWTH-21st vs customized birthweight standards for iden-
tification of perinatal mortality and morbidity. Am J Obstet Gynecol
2016;214:509.e1–.e7. [II-2]
19. Buck Louis GM, Grewal J, Albert PS, et al. Racial/ethnic standards for
fetal growth: the NICHD Fetal Growth Studies. Am J Obstet Gynecol
2015;213:449.e1–.e41. [II-2]
20. Kiserud T, Piaggio G, Carroli G, et al. The World Health Organization fetal
growth charts: a multinational longitudinal study of ultrasound biometric
measurements and estimated fetal weight. PLOS Med 2017;14:e1002220. [II-2]
21. Kiserud T, Benachi A, Hecher K, et al. The World Health Organization fetal
growth charts: concept, findings, interpretation, and application. Am J
Obstet Gynecol 2018;218:S619–s29. [II-2]
22. Gardosi J, Francis A, Turner S, Williams M. Customized growth
charts: rationale, validation and clinical benefits. Am J Obstet Gynecol
2018;218:S609–s18. [II-2]
23. Blue NR, Beddow ME, Savabi M, Katukuri VR, Chao CR. Comparing the
Hadlock fetal growth standard to the Eunice Kennedy Shriver National
Institute of Child Health and Human Development racial/ethnic standard
for the prediction of neonatal morbidity and small for gestational age. Am J
Obstet Gynecol 2018;219:474.e1–.e12. [II-2]
24. Blue NR, Savabi M, Beddow ME, et al. The Hadlock method is supe-
rior to newer methods for the prediction of the birth weight percentile. J
Ultrasound Med 2019;38:587–96. [II-2]
25. Monier I, Ego A, Benachi A, Ancel PY, Goffinet F, Zeitlin J. Comparison
of the Hadlock and INTERGROWTH formulas for calculating estimated
fetal weight in a preterm population in France. Am J Obstet Gynecol
2018;219:476.e1–.e12. [II-2]
26. Deter RL, Lee W, Yeo L, Erez O, Ramamurthy U, Naik M, Romero R.
Individualized growth assessment: conceptual framework and practical
implementation for the evaluation of fetal growth and neonatal growth out-
come. Am J Obstet Gynecol 2018;218(2S): S656–78. [II-2]
27. Lees CC, Stampalija T, Baschat A, et al. ISUOG Practice Guidelines: diag-
nosis and management of small-for-gestational-age fetus and fetal growth
restriction. Ultrasound Obstet Gynecol 2020;56(2):298–312. [III]
28. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity
and mortality among very-low-birth-weight neonates with intrauterine
growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol
2000;182:198–206. [II-2]
29. Unterscheider J, Daly S, Geary MP, et al. Predictable progressive
Doppler deterioration in IUGR: does it really exist? Am J Obstet Gynecol
2013;209:539.e1–7. [II-2]
30. Nohuz E, Riviere O, Coste K, Vendittelli F. Prenatal identification of small-
for-gestational age and risk of neonatal morbidity and stillbirth. Ultrasound
Obstet Gynecol 2020;55(5):621–8. [II-2]
31. Madden JV, Flatley CJ, Kumar S. Term small-for-gestational-age infants
from low-risk women are at significantly greater risk of adverse neonatal
outcomes. Am J Obstet Gynecol 2018;218:525.e1–.e9. [II-2]
32. Pallotto EK, Kilbride HW. Perinatal outcome and later implications of
intrauterine growth restriction. Clin Obstet Gynecol 2006;49:257–69. [II-2]
33. Kinzler W, Kaminsky L. Fetal growth restriction and subsequent pregnancy
risks. Semin Perinatol 2007;31(3):126–34. [III]
34. Sagi-Dain L, Peleg A, Sagi S. Risk for chromosomal aberrations in appar-
ently isolated intrauterine growth restriction: A systematic review. Prenat
Diagn 2017;37:1061–6. [II-2]
35. Hendrix N, Berghella V. Non-placental causes of intrauterine growth
restriction. Semin Perinatol 2008;32:161–5. [III]
495
36. Borrell A, Grande M, Pauta M, Rodriguez-Revenga L, Figueras F.
Chromosomal microarray analysis in fetuses with growth restriction and
normal karyotype: a systematic review and meta-analysis. Fetal Diagn Ther
2018;44:1–9. [II-1]
37. Borrell A, Grande M, Meler E, et al. Genomic microarray in fetuses with
early growth restriction: a multicenter study. Fetal Diagn Ther 2017;42:
174–80. [II-2]
38. An G, Lin Y, Xu LP, et al. Application of chromosomal microarray to inves-
tigate genetic causes of isolated fetal growth restriction. Mol Cytogenet
2018;11:33. [II-2]
39. Voskamp BJ, Kazemier BM, Ravelli ACJ et al. Recurrence of small-for gesta-
tional- age pregnancy: analysis of first and subsequent singleton pregnan-
cies in The Netherlands. Am J Obstet Gynecol 2013;208:374.e1–e6. [II-2]
40. Savchev S, Figueras F, Sanz-Cortes M, et al. Evaluation of an optimal ges-
tational age cut-off for the definition of early- and late-onset fetal growth
restriction. Fetal Diagn Ther 2014;36:99–105. [II-1]
41. Dall’Asta A, Brunelli V, Prefumo F, Frusca T, Lees CC. Early onset fetal
growth restriction. Matern Health Neonatol Perinatol 2017;3:2. [III]
42. Figueras F, Caradeux J, Crispi F, Eixarch E, Peguero A, Gratacos E. Diagnosis
and surveillance of late-onset fetal growth restriction. Am J Obstet Gynecol
2018;218:S790–S802.e1. [III]
43. Morris RK, Malin G, Robson SC, et al. Fetal umbilical artery Doppler to
predict compromise of fetal/neonatal wellbeing in a high-risk population:
systematic review and bivariate meta-analysis. Ultrasound Obstet Gynecol
2011;37:135–42. [II-1]
44. Unterscheider J, O’Donoghue K, Daly S, et al. Fetal growth restriction and
the risk of perinatal mortality-case studies from the multicentre PORTO
study. BMC Pregnancy Childbirth 2014;14:63. [II-1]
45. Savchev S, Figueras F, Cruz-Martinez R, Illa M, Botet F, Gratacos E.
Estimated weight centile as a predictor of perinatal outcome in small-for-
gestational-age pregnancies with normal fetal and maternal Doppler indi-
ces. Ultrasound Obstet Gynecol 2012;39:299–303. [II-1]
46. Pilliod RA, Cheng YW, Snowden JM, Doss AE, Caughey AB. The risk of
intrauterine fetal death in the small-for-gestational-age fetus. Am J Obstet
Gynecol 2012;207:318.e1–6. [II-2]
47. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in rela-
tion to morbidity and mortality among newborn infants. N Engl J Med
1999;340:1234–8. [II-2]
48. Dashe J, McIntire D, Lucas M, et al. Effects of symmetric and asymmetric fetal
growth on pregnancy outcomes. Obstet Gynecol 2000;1996(3):321–7. [II-2]
49. David C, Gabriellie S, Pilu G, et al. The head-to-abdomen circumference
ratio: a reappraisal. Ultrasound Obstet Gynecol 1995;5(4):256–9. [II-2]
50. Hiersch L, Melamed N. Fetal growth velocity and body proportion in the
assessment of growth. Am J Obstet Gynecol 2018;218:S700–S11.e1. [III]
51. Bocca-Tjeertes I, Bos A, Kerstjens J, de Winter A, Reijneveld S. Symmetrical
and asymmetrical growth restriction in preterm-born children. Pediatrics
2014;133:e650–6.
52. Burton GJ, Janiaux E. Pathophysiology of placental-derived fetal growth
restriction. Am J Obstet Gynecol 2018;218(S):S745–S761. [II-3]
53. Labarrere CA, DiCarlo HL, Bammerlin E, et al. Failure of physiologic trans-
formation of spiral arteries, endothelial and throphoblast cell activation,
and acute atherosis in the basal plate of the placenta. Am J Obstet Gynecol
2017;261(3):287.e1–287.e16. [II-3]
54. Landon MB, Galan HL, Janiaux E, et al. Fetal growth restriction. In: Gabbe’s
Obstetrics: Normal and Problem Pregnancies. 8th ed. Philadelphia: Elsevier,
2021:555–85.e1. [III]
55. Lees CC, Marlow N, van Wassenaer-Leemhuis A, et al. Two-year neuro-
developmental and intermediate perinatal outcomes in infants with very
preterm fetal growth restriction (TRUFFLE): a randomised trial. Lancet
2015;385:2162–72. [II-2]
56. Yamamoto R, Ishii K, Shimada M, et al. Significance of maternal screen-
ing for toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus
infection in cases of fetal growth restriction. J Obstet Gynaecol Res 2013;39:
653–7. [II-2]
57. Tsuge M, Hida AI, Minematsu T, et al. Prospective cohort study of congeni-
tal cytomegalovirus infection during pregnancy with fetal growth restric-
tion: serologic analysis and placental pathology. J Pediatr 2019;206:42–8.e2.
[II-2]
58. Chung MH, Shin CO, Lee J. TORCH (toxoplasmosis, rubella, cytomegalo-
virus, and herpes simplex virus) screening of small for gestational age and
intrauterine growth restricted neonates: efficacy study in a single institute
in Korea. Korean J Pediatr 2018;61:114–20. [II-2]
59. Sukenik-Halevy R, Katz A, Regev RH, et al. The yield of the prenatal work-
up in intrauterine growth restriction and the spectrum of fetal abnormali-
ties detected postnatally. J Matern Fetal Neonatal Med 2019;32:753–9. [II-2]
496
60. Reddy UM. Prediction and prevention of Recurrent stillbirth. Obstet
Gynecol 2007;110:1151–64. [III]
61. Trudell AS, Cahill AG, Tuuli et al. Risk of stillbirth after 37 weeks in preg-
nancies complicated by small-for-gestational-age fetuses. Am J Obstet
Gynecol 2013;208(5):376.e1–7. [II-2]
62. Hepburn M, Rosenburg K. An audit of the detection and management of
small-for-gestational age babies. Br J Obstet Gynaecol 1986;93:212–6. [II-2]
63. Lackman F, Capewell V, Richardson B, et al. The risks of spontaneous pre-
term delivery and perinatal mortality in relation to size at birth accord-
ing to fetal versus neonatal growth standards. Am J Obstet Gynecol
2001;184:946–53. [II-2]
64. Crispi F, Miranda J, Gratacos E. Long-term cardiovascular consequences of
fetal growth restriction: biology, clinical implications, and opportunities for
prevention of adult disease. Am J Obstet Gynecol 2018;218:S869–S79. [III]
65. Crispi F, Figueras F, Cruz-Lemini M, Bartrons J, Bijnens B, Gratacos E.
Cardiovascular programming in children born small for gestational age
and relationship with prenatal signs of severity. Am J Obstet Gynecol
2012;207:121.e1–9. [II-2]
66. Cruz-Lemini M, Crispi F, Valenzuela-Alcaraz B, et al. Fetal cardiovascular
remodeling persists at 6 months in infants with intrauterine growth restric-
tion. Ultrasound Obstet Gynecol 2016;48:349–56. [II-2]
67. Crispi F, Bijnens B, Figueras F, et al. Fetal growth restriction results in
remodeled and less efficient hearts in children. Circulation 2010;121:
2427–36. [II-2]
68. Tolsa CB, Zimine S, Warfield SK, et al. Early alteration of structural and
functional brain development in premature infants born with intrauterine
growth restriction. Pediatr Res 2004;56:132–8. [II-2]
69. Egana-Ugrinovic G, Sanz-Cortes M, Figueras F, Bargallo N, Gratacos E.
Differences in cortical development assessed by fetal MRI in late-onset
intrauterine growth restriction. Am J Obstet Gynecol 2013;209:126.e1–8.
[II-2]
70. Egana-Ugrinovic G, Sanz-Cortes M, Couve-Perez C, Figueras F, Gratacos E.
Corpus callosum differences assessed by fetal MRI in late-onset intrauter-
ine growth restriction and its association with neurobehavior. Prenat Diagn
2014;34:843–9. [II-2]
71. Sanz-Cortes M, Figueras F, Bargallo N, Padilla N, Amat-Roldan I, Gratacos
E. Abnormal brain microstructure and metabolism in small-for-­gestational-
age term fetuses with normal umbilical artery Doppler. Ultrasound Obstet
Gynecol 2010;36:159–65. [II-2]
72. Sanz-Cortes M, Egana-Ugrinovic G, Zupan R, Figueras F, Gratacos E.
Brainstem and cerebellar differences and their association with neurobe-
havior in term small-for-gestational-age fetuses assessed by fetal MRI. Am
J Obstet Gynecol 2014;210:452.e1–8. [II-2]
73. Story L, Damodaram MS, Allsop JM, et al. Brain metabolism in fetal intra-
uterine growth restriction: a proton magnetic resonance spectroscopy
study. Am J Obstet Gynecol 2011;205:483.e1–8. [II-2]
74. Barker D. Adult consequences of fetal growth restriction. Clin Obstet
Gynecol 2006;49(2):270–83. [III]
75. Maslovitz S, Shenhav M, Levin I, et al. Outcome of induced deliveries in
growth-restricted fetuses: second thoughts about the vaginal option. Arch
Gynecol Obstet 2009;279:139–43. [II-3]
76. The GRIT study group. A randomized trial of timed delivery for the com-
promised preterm fetus: short term outcomes and Bayesian interpretation.
Br J Obstet Gynecol 2003;110:27–32. [I]
77. Smith G, Pell J, Dobbie R. Interpregnancy interval and risk of preterm birth
and neonatal death: retrospective cohort study. Br Med J 2003;327:313–9.
[II-2]
78. Zhu B, Rolfs R, Nangle B, et al. Effect of the interval between pregnancies on
perinatal outcomes. N Engl J Med 1999;340:589–94. [II-2]
79. Lumley J, Chamberlain C, Dowswell T, et al. Interventions for promot-
ing smoking cessation during pregnancy. Cochrane Database Syst Rev
2009;3:CD001055. [I]
80. Kramer MS, Kakuma R. Energy and protein intake in pregnancy. Cochrane
Database Syst Rev 2003;4:CD000032. [I]
81. Abalos E, Duley L, Steyn D, et al. Antihypertensive drug therapy for mild
to moderate hypertension during pregnancy. Cochrane Database Syst Rev
2007;1:CD002252. [I]
82. Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of
hypertension in pregnancy. N Eng J Med 2015;372:407–17. [I]
83. The American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 203: Chronic hypertension in pregnancy. Obstet Gynecol
2019;133: e26–e50. [III]
84. SMFM Publications Committee. SMFM Statement: benefit of antihyper-
tensive therapy for mild-to-moderate chronic hypertension during preg-
nancy remains uncertain. Am J Obstet Gynecol 2015;213(1):3–4. [III]
Maternal-Fetal Evidence Based Guidelines
85. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role
of aspirin dose on the prevention of pre-eclampsia and fetal growth restric-
tion: systematic review and meta-analysis. Am J Obstet Gynecol 2017;216:
110–20.e6. [I]
86. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after
16 weeks’ gestation for preventing pre-eclampsia: an individual participant
data meta-analysis. Am J Obstet Gynecol 2017;216:121–8.e2. [I]
87. Groom KM, David AL. The role of aspirin, heparin, and other interventions
in the prevention and treatment of fetal growth restriction. Am J Obstet
Gynecol 2018;218:S829–s40. [III]
88. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies
at high risk for preterm pre-eclampsia. N Engl J Med 2017;377:613–22. [I]
89. ACOG Committee Opinion No. 743: low-dose aspirin use during preg-
nancy. Obstet Gynecol 2018;132:e44–52. [III]
90. Dugoff L, Hobbins JC, Malone FD, et al. First-trimester maternal serum
PAPP-A and free beta subunit human chorionic gonadotropin concentra-
tions and nuchal translucency are associated with obstetric complications:
a population-based screening study (The FASTER Trial). Am J Obstet
Gynecol 2004;191:1446–51. [II-2]
91. Spencer K, Cowans NJ, Avgidou K, et al. First-trimester biochemical mark-
ers of aneuploidy and the prediction of small-for-gestational age fetuses.
Ultrasound Obstet Gynecol 2008;31:15–19. [II-2]
92. Krantz D, Goetzl L, Simpson JL, et al. Association of extreme first-
trimester free human chorionic gonadotropin-beta, pregnancy-associated
plasma protein A, and nuchal translucency with intrauterine growth
restriction and other adverse pregnancy outcomes. Am J Obstet Gynecol
2004;191:1452–58. [II-2]
93. Dugoff L. First-and second-trimester maternal serum markers for aneuploidy
and adverse obstetric outcomes. Obstet Gynecol 2010;115:1052–61. [III]
94. Dugoff L, Hobbins J, Malone F, et al. Quad screen as a predictor of adverse
pregnancy outcome. Obstet Gynecol 2005;106(2):260–7. [II-2]
95. Bais JM, Eskes M, Pel M, Bonsel GJ, Bleker OP. Effectiveness of detection
of intrauterine growth restriction by abdominal palpation as a screening
test in a low risk population: an observational study. Eur J Obstet Gynecol
Reprod Biol 2004;116(2):164–9. [II-2]
96. Lidhard A, Nielsen PV, Mouritsen LA, Zachariassen A, Sorensen HU,
Roseno H. The implications of introducing the symphyseal-fundal height
measurement: a prospective randomized controlled trial. Br J Obstet
Gynaecol 1990;97:675–80. [I]
97. Robert PJ, Ho JJ, Villiapan J, Sivasangari S. Symphysial fundal height (SFH)
measurement in pregnancy for detecting abnormal fetal growth. Cochrane
Database Syst Rev 2012;7:CD008136. [II]
98. Sovio U, White IR, Dacey A, Pasupathy D, Smith GC. Screening for fetal
growth restriction with universal third trimester ultrasonography in nul-
liparous women in the Pregnancy Outcome Prediction (POP) study: a pro-
spective cohort study. Lancet 2015;386:2089–97. [II-1]
99. Roma E, Arnau A, Berdala R, Bergos C, Montesinos J, Figueras F. Ultrasound
screening for fetal growth restriction at 36 vs 32 weeks’ gestation: a ran-
domized trial (ROUTE). Ultrasound Obstet Gynecol 2015;46(4):391–7. [I]
100. Al-Hafez L, Chauhan S, Riegel M, Balogun O, Hammad I, Berghella V.
Routine third-trimester ultrasound in low-risk pregnancies and perinatal
death: a systematic review and meta-analysis. Am J Obstet Gynecol MFM
2020;2(4):100242. [II-2]
101. Henrichs J, Verfaille V, Jellema P, et al. Effectiveness of routine third tri-
mester ultrasonography to reduce adverse perinatal outcomes in low-risk
pregnancy (the IRIS study): nationwide, pragmatic, multicentre, stepped
wedge cluster randomized trial. BMJ 2019;367:15517. [I]
102. Cnossen JS, Morris RK, Riet G, et al. Use of uterine artery Doppler ultrasonogra-
phy to predict pre-eclampsia and intrauterine growth restriction: a systematic
review and bivariable meta-analysis. CMAJ 2008;178(6):701–11. [II-2]
103. Parry S, Sciscione A, Haas DM, et al. Role of early second-trimester uterine
artery Doppler screening to predict small-for-gestational-age babies in nul-
liparous women. Am J Obstet Gynecol 2017;217:594.e1–.e10. [II-2]
104. Alfirevic A, Stampalija T, Medley N. Fetal and umbilical Doppler ultrasound
in normal pregnancy. Cochrane Database Syst Rev 2015 (4):CD001450. [I]
105. Karagiannis G, Akolekar R, Sarquis R, Wright D, Nicolaides KH. Prediction
of small-for-gestation neonates from biophysical and biochemical markers
at 11–13 weeks. Fetal Diagn Ther 2011;29(2):148–54. [II-2]
106. Tan MY, Poon LC, Rolnik DL, et al. Prediction and prevention of small-
for-gestational age neonates: evidence from SPREE and ASPRE. Ultrasound
Obstet Gynecol 2018;52(1):52–59. [II-2]
107. Poon LC, Lesmes C, Gallo DM, Akolekar R, Nicolaides KH. Prediction
of small-for-gestational age neonates: screening by biophysical and bio-
chemical markers at 19–24 weeks. Ultrasound Obstet Gynecol 2015;46(4):
437–45. [II-2]
Fetal Growth Restriction
108. Miranda J, Triunfo S, Figueras F, Crispi F, Gratacos E. Performance of fetal
growth restriction using estimated fetal weight vs a combined screen-
ing model in the third trimester. Ultrasound Obstet Gynecol 2017;50(5):
603–11. [II-2]
109. Sotiriadis A, Figueras F, Eleftheriades M, Papaioannou GK, Chorozoglou
G, Dinas K, Papantoniou N. First-trimester and combined first- and second
trimester prediction of small-for-gestational age and late onset fetal growth
restriction. Ultrasound Obstet Gynecol 2019;53(1):55–61. [II-2]
110. The investigation and management of the small-for-gestational age fetus.
RCOG Green-top Guideline No. 31. 2014. Accessed September 12, 2020, at
https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_31.pdf [III]
111. Maulik D. Fetal growth restriction: the etiology. Clin Obstet Gynecol
2006;49(2):228–35. [III]
112. Society for Maternal-Fetal Medicine (SMFM), Hughes BL, Gyamfi-
Bannerman C. Diagnosis and antenatal management of congenital cyto-
megalovirus infection. Am J Obstet Gynecol 2016;214(6):B5–B11. [III]
113. Laurin J, Persson P-H. The effect of bedrest in hospital on fetal outcome in
pregnancies complicated by intra-uterine growth retardation. Acta Obstet
Gynecol Scand 1987;66:407–11. [I]
114. McCall CA, Grimes DA, Lyerly AD. “Therapeutic” bed rest in pregnancy.
Unethical and unsupported by data. Obstet Gynecol 2013;121:1305–8. [III]
115. Ramakrishnan U, Stein A, Parra-Cabrera S, et al. Effects of docosahexae-
noic acid supplementation during pregnancy on gestational age and size at
birth: randomized, double-blind, placebo-controlled trial in Mexico. Food
Nutr Bull 2010;31 (Suppl 2):S108–S116. [I]
116. Roberfroid D, Huybregts L, Lanou H, et al. MISAME Study Group. Effects
of maternal multiple micronutrient supplementation on fetal growth: a
double-blind randomized controlled trial in rural Burkina Faso. Am J Clin
Nutr 2008;88(5):1220–40. [I]
117. Horvath A, Koletzko B, Szajewska H. Effect of supplementation of women in
high-risk pregnancies with long-chain polyunsaturated fatty acids on preg-
nancy outcomes and growth measures at birth: a meta-analysis of random-
ized controlled trials. Br J Nutr 2007;98(2):253–59. [I]
118. Say L, Gulmezoglu AM, Hofmeyr GJ. Maternal nutrient supplementation
for suspected impaired fetal growth. Cochrane Database Syst Rev 2010;
(7):1–19. [I]
119. Say L, Gulmezoglu AM, Hofmeyr JG. Betamimetics for suspected impaired
fetal growth. Cochrane Database Syst Rev 2009; (4):1–13. [I]
120. Janssens D. Prevention of low birth weight by flunarizine given to smoking
mothers. Arch Gynecol 1985;237(Suppl 1):397. [I]
121. Bujold E, Roberge S, Lacasse Y, et al. Prevention of pre-eclampsia and intra-
uterine growth restriction with aspirin started in early pregnancy: a meta-
analysis. Obstet Gynecol 2010;116(2):402–14. [I]
122. Knight M, Duley L, Henderson-Smart DJ, et al. Antiplatelet agents for pre-
venting and treating pre-eclampsia. Cochrane Database Syst Rev 4, 2005. [I]
123. Yu Y-H, Shen L-Y, Zou H, et al. Heparin for patients with growth restricted
fetus: a prospective randomized controlled trial. J Matern Fetal Neonatal
Med 2010;23(9):980–7. [I]
124. Say L, Gulmezoglu AM, Hofmeyr GJ. Maternal oxygen administration for
suspected impaired fetal growth. Cochrane Database Syst Rev 4, 2005:1–11.
[I]
125. Salas SP, Rosso P, Espinoza R, et al. Maternal plasma volume expansion
and hormonal changes in women with idiopathic fetal growth retardation.
Obstet Gynecol 1993;81(6):1029–30. [II-2]
126. Karsdorp VHM, van Vugt JMG, Dekker GA, et al. Reappearance of end-­
diastolic velocities in the umbilical artery following maternal volume
expansion: a preliminary study. Obstet Gynecol 1992;80:679–83. [I]
127. Hofmeyr GJ. Abdominal decompression for suspected fetal compromise/
pre-eclampsia. Cochrane Database Syst Rev 4, 2005:1–13. [I]
128. Winer N, Branger B, Azria E, et al. L-Arginine treatment for severe vascu-
lar fetal intrauterine growth restricition: a randomized double-blind con-
trolled trial. Clin Nutr 2009;28(3):243–48. [I]
129. Sieroszewski P, Suzin J, Karowicz-Bilinska A. Ultrasound evalua-
tion of intrauterine growth restriction therapy by a nitric oxide donors
(L-arginine). J Matern Fetal Neonatal Med 2003;13:115–8. [II-1]
130. Xiao XM, Li LP. L-Arginine treatment for asymmetric fetal growth restric-
tion. Int J Gynaecol Obstet 2005;88:15–8. [II-1]
131. Groom KM, McCowan LM, Mackay LK, et al. STRIDER NZAus: a multi-
centre randomised controlled trial of sildenafil therapy in early-onset fetal
growth restriction. BJOG 2019;126:997–1006. [I]
132. Vollgraff Heidweiller-Schreurs CA, van Maasakker NE, van de Ven PM, de
Groot CJM, Bax CJ, de Boer MA. Doppler measurements of both umbili-
cal arteries do not improve predictive value for adverse perinatal outcomes
in small-for-gestational age fetuses. Eur J Obstet Gynecol Reprod Biol
2018;231:169–73. [II-2]
497
133. Alfirevic Z, Stampalija T, Dowswell T. Fetal and umbilical Doppler
ultrasound in high-risk pregnancies. Cochrane Database Syst Rev
2017;6:CD007529. [I]
134. Unterscheider J, Daly S, Geary MP, et al. Optimizing the definition of intra-
uterine growth restriction: the multicenter prospective PORTO Study. Am
J Obstet Gynecol 2013;208:290.e1–6. [II]
135. Vergani P, Andreotti C, Roncaglia N, et al. Doppler predictors of adverse
neonatal outcome in the growth restricted fetus at 34 weeks’ gestation or
beyond. Am J Obstet Gynecol 2003;189:1007–11. [II]
136. Oros D, Figueras F, Cruz-Martinez R, Meler E, Munmany M, Gratacos
E. Longitudinal changes in uterine, umbilical and fetal cerebral Doppler
indices in late-onset small-for-gestational age fetuses. Ultrasound Obstet
Gynecol 2011;37:191–5. [II-1]
137. Gordijn SJ, Beune IM, Thilaganathan B, et al. Consensus definition of
fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol
2016;48:333–9. [III]
138. Apel-Sarid L, Levy A, Holcberg G, Sheiner E. Term and preterm (<34 and
<37 weeks gestation) placental pathologies associated with fetal growth
restriction. Arch Gynecol Obstet 2010;282:487–92. [III]
139. Salafia CM, Vintzileos AM, Silberman L, Bantham KF, Vogel CA. Placental
pathology of idiopathic intrauterine growth retardation at term. Am J
Perinatol 1992;9:179–84. [III]
140. Stanek J. Comparison of placental pathology in preterm, late-preterm, near-
term, and term births. Am J Obstet Gynecol 2014;210:234.e1–6. [II-2]
141. Grivell RM, Wong L, Bhatia V. Regimens of fetal surveillance for impaired
fetal growth. Cochrane Database Syst Rev 2012:CD007113. [I]
142. Baschat AA, Gembruch U. The cerebroplacental Doppler ratio revisited.
Ultrasound Obstet Gynecol 2003;21:124–7. [II-2]
143. Turan OM, Turan S, Gungor S, et al. Progression of Doppler abnor-
malities in intrauterine growth restriction. Ultrasound Obstet Gynecol
2008;32:160–7. [II-2]
144. Odibo AO, Riddick C, Pare E, Stamilio DM, Macones GA. Cerebroplacental
Doppler ratio and adverse perinatal outcomes in intrauterine growth
restriction: evaluating the impact of using gestational age-specific reference
values. J Ultrasound Med 2005;24:1223–8. [II-2]
145. DeVore GR. The importance of the cerebroplacental ratio in the evalu-
ation of fetal well-being in SGA and AGA fetuses. Am J Obstet Gynecol
2015;213:5–15. [III]
146. Meher S, Hernandez-Andrade E, Basheer SN, Lees C. Impact of cerebral
redistribution on neurodevelopmental outcome in small-for-gestational-
age or growth-restricted babies: a systematic review. Ultrasound Obstet
Gynecol 2015;46:398–404. [II-2]
147. Hernandez-Andrade E, Stampalija T, Figueras F. Cerebral blood flow stud-
ies in the diagnosis and management of intrauterine growth restriction.
Curr Opin Obstet Gynecol 2013;25:138–44. [II-2]
148. Morris RK, Say R, Robson SC, Kleijnen J, Khan KS. Systematic review and
meta-analysis of middle cerebral artery Doppler to predict perinatal well-
being. Eur J Obstet Gynecol Reprod Biol 2012;165:141–55. [I]
149. Stampalija T, Arabin B, Wolf H, Bilardo CM, Lees C. Is middle cerebral
artery Doppler related to neonatal and 2-year infant outcome in early fetal
growth restriction? Am J Obstet Gynecol 2017;216:521.e1–.e13. [II-1]
150. Severi FM, Bocchi C, Visentin A, et al. Uterine and fetal cerebral Doppler
predict the outcome of third-trimester small-for-gestational age fetuses
with normal umbilical artery Doppler. Ultrasound Obstet Gynecol
2002;19:225–8. [II-2]
151. Ganzevoort W, Mensing Van Charante N, Thilaganathan B, et al. How to
monitor pregnancies complicated by fetal growth restriction and delivery
before 32 weeks: post-hoc analysis of TRUFFLE study. Ultrasound Obstet
Gynecol 2017;49:769–77. [II-1]
152. Hershkovitz R, Kingdom JC, Geary M, Rodeck CH. Fetal cerebral blood
flow redistribution in late gestation: identification of compromise in small
fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol
2000;15:209–12. [II-2]
153. Eixarch E, Batalle D, Illa M, et al. Neonatal neurobehavior and diffusion
MRI changes in brain reorganization due to intrauterine growth restriction
in a rabbit model. PLOS ONE 2012;7:e31497. [II-1]
154. Cruz-Martinez R, Figueras F, Oros D, et al. Cerebral blood perfusion
and neurobehavioral performance in full-term small-for-gestational-age
fetuses. Am J Obstet Gynecol 2009;201:474.e1–7. [II-2]
155. Healy P, Gordjin S, Ganzevoort W, Beune I, Baschat A, Khalil A,
Papageorghiou A. A core outcome set for the prevention and treatment of
fetal growth restriction: developing endpoints: the COSGROVE study. Am
J Obstet Gynecol 2019;221:339.e1–10. [III]
156. Hernandez-Andrade E, Figueroa-Diesel H, Jansson T, Rangel-Nava H,
Gratacos E. Changes in regional fetal cerebral blood flow perfusion in
498
relation to hemodynamic deterioration in severely growth-restricted
fetuses. Ultrasound Obstet Gynecol 2008;32:71–6. [II-2]
157. Cruz-Martinez R, Figueras F, Hernandez-Andrade E, Puerto B, Gratacos E.
Longitudinal brain perfusion changes in near-term small-for-gestational-
age fetuses as measured by spectral Doppler indices or by fractional moving
blood volume. Am J Obstet Gynecol 2010;203:42.e1–6. [II]
158. Cruz-Martinez R, Figueras F, Hernandez-Andrade E, Oros D, Gratacos E.
Fetal brain Doppler to predict cesarean delivery for nonreassuring fetal
status in term small-for-gestational-age fetuses. Obstet Gynecol 2011;117:
618–26. [II]
159. Flood K, Unterscheider J, Daly S, et al. The role of brain sparing in the prediction
of adverse outcomes in intrauterine growth restriction: results of the multi-
center PORTO Study. Am J Obstet Gynecol 2014;211:288.e1–5 [II-1]
160. Monteith C, Flood K, Pinnamaneni R, et al. An abnormal cerebroplacental
ratio (CPR) is predictive of early childhood delayed neurodevelopment in
the setting of fetal growth restriction. Am J Obstet Gynecol 2019;221(3):273.
e1–273.e9. [II-1]
161. Stampalija T, Thornton J, Marlow N, et al. Fetal cerebral Doppler changes
and outcomes in late preterm fetal growth restriction: prospective cohort
study. Ultrasound Obstet Gynecol 2020;56:173–81. [II-2]
162. Vollgraff Heidweiller-Schreurs CA, De Boer MA, Heymans MW, et al.
Prognostic accuracy of cerebroplacental ratio and middle cerebral artery
Doppler for adverse perinatal outcome: systematic review and meta-analy-
sis. Ultrasound Obstet Gynecol 2018;51:313–22. [I]
163. Figueras F, Gratacos E. Stage-based approach to the management of fetal
growth restriction. Prenat Diagn 2014;34:655–9. [III]
164. Baschat AA. Arterial and venous Doppler in the diagnosis and management
of early onset fetal growth restriction. Early Hum Dev 2005;81:877–87. [III]
165. Bellotti M, Pennati G, De Gasperi C, Bozzo M, Battaglia FC, Ferrazzi E.
Simultaneous measurements of umbilical venous, fetal hepatic, and duc-
tus venosus blood flow in growth-restricted human fetuses. Am J Obstet
Gynecol 2004;190:1347–58. [II-2]
166. Hecher K, Bilardo CM, Stigter RH, et al. Monitoring of fetuses with
intrauterine growth restriction: a longitudinal study. Ultrasound Obstet
Gynecol 2001;18:564–70. [II]
167. Ferrazzi E, Bozzo M, Rigano S, et al. Temporal sequence of abnormal
Doppler changes in the peripheral and central circulatory systems of the
severely growth-restricted fetus. Ultrasound Obstet Gynecol 2002;19:
140–6. [II]
168. Ferrazzi E, Rigano S, Bozzo M, et al. Umbilical vein blood flow in growth-
restricted fetuses. Ultrasound Obstet Gynecol 2000;16:432–8. [II-2]
169. Frauenschuh I, Frambach T, Karl S, Dietl J, Muller T. Ductus venosus blood
flow prior to intrauterine foetal death in severe placental insufficiency can
be unaffected as shown by Doppler sonography. Z Geburtshilfe Neonatol
2014;218:218–22. [II-3]
170. Schwarze A, Gembruch U, Krapp M, Katalinic A, Germer U, Axt-Fliedner R.
Qualitative venous Doppler flow waveform analysis in preterm intrauterine
growth-restricted fetuses with ARED flow in the umbilical artery–correlation
with short-term outcome. Ultrasound Obstet Gynecol 2005;25:573–9. [II-2]
171. Baschat AA, Gembruch U, Weiner CP, Harman CR. Qualitative venous
Doppler waveform analysis improves prediction of critical perinatal out-
comes in premature growth-restricted fetuses. Ultrasound Obstet Gynecol
2003;22:240–5. [II-2]
172. Seravalli V, Miller J, Block-Abraham D, Baschat AA. Ductus venosus
Doppler in the assessment of fetal cardiovascular health: an updated practi-
cal approach. Acta Obstet Gynecol Scand 2016;95(6):635–44. [III]
173. Abuhamad A, Chaoui R. A Practical Guide to Fetal Echocardiography:
Normal and Abnormal Hearts. 3rd ed. Philadelphia: Wolters Kluwer;
2016. [III]
174. Baschat AA, Cosmi E, Bilardo CM, et al. Predictors of neonatal outcome in
early-onset placental dysfunction. Obstet Gynecol 2007;109:253–61. [II-2]
175. Caradeux J, Martinez-Portilla RJ, Basuki TR, Kiserud T, Figueras F. Risk
of fetal death in growth-restricted fetuses with umbilical and/or ductus
venosus absent or reversed end-diastolic velocities before 34 weeks of
gestation: a systematic review and meta-analysis. Am J Obstet Gynecol
2018;218:S774–S82.e21. [I]
176. Baschat AA. Neurodevelopment following fetal growth restriction and
its relationship with antepartum parameters of placental dysfunction.
Ultrasound Obstet Gynecol 2011;37:501–14. [II-2]
177. Bilardo CM, Hecher K, Visser GHA, et al. Severe fetal growth restriction at
26–32 weeks: key messages from the TRUFFLE study. Ultrasound Obstet
Gynecol 2017;50:285–90. [III]
178. Conde-Agudelo A, Bird S, Kennedy SH, Villar J, Papageorghiou AT. First-
and second-trimester tests to predict stillbirth in unselected pregnant
women: a systematic review and meta-analysis. Bjog 2015;122:41–55. [II]
Maternal-Fetal Evidence Based Guidelines
179. Papageorghiou AT, Roberts N. Uterine artery Doppler screening for adverse
pregnancy outcome. Curr Opin Obstet Gynecol 2005;17:584–90. [III]
180. Roberts LA, Ling HZ, Poon LC, Nicolaides KH, Kametas NA. Maternal
hemodynamics, fetal biometry and Doppler indices in pregnancies fol-
lowed up for suspected fetal growth restriction. Ultrasound Obstet Gynecol
2018;52:507–14. [II-2]
181. Khalil A, Morales-Rosello J, Townsend R, et al. Value of third-trimester
cerebroplacental ratio and uterine artery Doppler indices as predictors of
stillbirth and perinatal loss. Ultrasound Obstet Gynecol 2016;47:74–80.
[II-2]
182. Chien PF, Arnott N, Gordon A, Owen P, Khan KS. How useful is uter-
ine artery Doppler flow velocimetry in the prediction of pre-eclampsia,
intrauterine growth retardation and perinatal death? An overview. BJOG
2000;107:196–208. [III]
183. Cruz-Martinez R, Savchev S, Cruz-Lemini M, Mendez A, Gratacos E,
Figueras F. Clinical utility of third-trimester uterine artery Doppler in
the prediction of brain hemodynamic deterioration and adverse perinatal
outcome in small-for-gestational-age fetuses. Ultrasound Obstet Gynecol
2015;45:273–8. [II-2]
184. Grivell RM, Alfirevic Z, Gyte GML, Devane D. Antenatal cardiotocography for
fetal assessment. Cochrane Database Syst Rev 2015;2015:CD007863-CD. [I]
185. Grivell RM, Wong L, Bhatia V. Regimens of fetal surveillance for impaired
fetal growth. Cochrane Database Syst Rev 2012;2012: CD007113. [I]
186. Visser G, Sandovsky G, Nicolaides K. Antepartum fetal heart rate patterns
in small-for-gestational-age third-trimester fetuses: correlations with blood
gas values obtained at cordocentesis. Am J Obstet Gynecol 1990;162:698–
703. [II-2]
187. Donner C, Vermeylen D, Kirkpatrick C, et al. Management of the growth-
restricted fetus: the role of noninvasive tests and fetal blood sampling.
Obstet Gynecol 1995;85:965–70. [II-3]
188. Lalor JG, Fawole B, Alfirevic Z, Devane D. Biophysical profile for fetal
assessment in high risk pregnancies. Cochrane Database Syst Rev
2008:CD000038. [I]
189. Kaur S, Picconi JL, Chadha R, Kruger M, Mari G. Biophysical profile in the
treatment of intrauterine growth-restricted fetuses who weigh <1000 g. Am
J Obstet Gynecol 2008;199:264.e1–4. [II-2]
190. Figueras F, Gardosi J. Intrauterine growth restriction: new concepts in
antenatal surveillance, diagnosis, and management. Am J Obstet Gynecol
2011;204:288–300. [III]
191. Duenhoelter JH, Whalley PJ, MacDonald PC. An analysis of the utility of
plasma immunoreactive estrogen measurements in determining delivery
time of gravidas with a fetus considered at high risk. Am J Obstet Gynecol
1976;125:889–98. [I]
192. Visser GH, Bilardo CM, Lees C. Fetal growth restriction at the limits of
viability. Fetal Diagn Ther 2014;36:162–5. [III]
193. Raju TN, Mercer BM, Burchfield DJ, Joseph GF, Jr. Periviable birth: execu-
tive summary of a joint workshop by the Eunice Kennedy Shriver National
Institute of Child Health and Human Development, Society for Maternal-
Fetal Medicine, American Academy of Pediatrics, and American College
of Obstetricians and Gynecologists. Obstet Gynecol. United States
2014:1083–96. [III]
194. The American College of Obstetricians and Gynecologists and the Society
for Maternal-Fetal Medicine. Obstetric Care consensus No. 6: periviable
birth. Obstet Gynecol 2017;130:e187–e99. [III]
195. Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S, Reichman B. Excess
mortality and morbidity among small-for-gestational-age premature
infants: a population-based study. J Pediatr 2003;143:186–91. [II-2]
196. Westby Wold SH, Sommerfelt K, Reigstad H, et al. Neonatal mortality and
morbidity in extremely preterm small for gestational age infants: a popula-
tion based study. Arch Dis Child Fetal Neonatal Ed 2009;94:F363–7. [II-2]
197. De Jesus LC, Pappas A, Shankaran S, et al. Outcomes of small for gesta-
tional age infants born at <27 weeks’ gestation. J Pediatr 2013;163:55–60.
e1-3. [II-2]
198. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung
maturation for woman at risk for preterm birth. Cochrane Database Syst
Rev 2006;3:CD004454. [I]
199. Garite T, Kurtzman J, Maurel K, et al. Impact of a ‘rescue course’ of antena-
tal corticosteroids: a multicenter randomized placebo-controlled trial. Am
J Obstet Gynecol 2009;200:248.e1–e9. [I]
200. McLaughlin K, Crowther C, Walker N, et al. Effects of a single course of
corticosteroids given more than 7 days before birth: a systematic review.
Aust N Z J Obstet Gynecol 2003;43:101–6. [II-1]
201. Vidaeff AC, Blackwell SC. Potential risks and benefits of antenatal cortico-
steroid therapy prior to preterm birth in pregnancies complicated by severe
fetal growth restriction. Obstet Gynecol Clin N Am 2011;38(2):205–14. [III]
Fetal Growth Restriction
202. Mitsiakos G, Kovacs L, Papageorgiou A. Are antenatal steroids benefi-
cial to severely growth restricted fetuses. J. Matern Fetal neonatal Med
2013;26(15):1496–9. [II]
203. Bernstein IM, Horbar JD, Badger GJ, et al. Morbidity and mortality among
very-low-birth-weight neonates with intrauterine growth restriction. The
Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198–206. [II]
204. ACOG Committee Opinion No. 455. Magnesium sulfate before anticipated
preterm birth for neuroprotection. Obstet Gynecol 2010;115:669–71. [III]
205. Marret S, Marpeau L, Zupan-Simunetk V, et al. Magnesium sulphate given
before very-preterm birth to protect infant brain: the randomized con-
trolled PREMAG trial. PREMAG Trial Group. BJOG 2007;114:310–8. [I]
206. Rouse DJ, Hirtz DG, Thorn E, et al. A randomized controlled trial of
magnesium sulfate for the prevention of cerebral palsy. Eunice Kennedy
Shriver NICHD Maternal-Fetal Medicine Units network. N Engl J Med
2008;359:895–905. [I]
207. American College of Obstetricians and Gynecologists. Committee Opinion
No. 713: Antenatal corticosteroid therapy for fetal maturation. Obstet
Gynecol 2017;130:e102–e9. [III]
208. Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal beta-
methasone for women at risk for late preterm delivery. N Engl J Med
2016;374:1311–20. [I]
209. ACOG Committee Opinion No. 455: Magnesium sulfate before anticipated
preterm birth for neuroprotection. Obstet Gynecol 2010;115(3):669–71. [III]
210. Kahn B, Lumey LH, Zybert PA, et al. Prospective risk of fetal death in single-
ton, twin, and triplet gestations: implications for practice. Obstet Gynecol
2003;102:685–92. [II-1]
211. ACOG Committee Opinion No. 764: Medically indicated late-preterm and
early-term deliveries. Obstet Gynecol 2019;133:e151–e5. [III]
499
212. Baschat AA, Weiner CP. Umbilical artery Doppler screening for detection
of the small fetus in need of antepartum surveillance. Am J Obstet Gynecol
2000;182:154–8. [II-2]
213. Lin CC, Moawad AH, Rosenow PJ, River P. Acid-base characteristics of
fetuses with intrauterine growth retardation during labor and delivery. Am
J Obstet Gynecol 1980;137:553–9. [II-3]
214. Forouzan I. Absence of end-diastolic flow velocity in the umbilical artery: a
review. Obstet Gynecol Surv 1995;50:219–27. [III]
215. Karsdorp VH, van Vugt JM, van Geijn HP, et al. Clinical significance of
absent or reversed end diastolic velocity waveforms in umbilical artery.
Lancet 1994;344:1664–8. [II-2]
216. Villalain C, Herraiz I, Quezada MS, Gomez Arriaga P, Simon E, Gomez-
Montes E, Galindo A. Labor Induction in late-onset fetal growth restric-
tion: Folley Balloon versus vaginal dinoprostone. Fetal Diagn Ther
2019;46(1):67–74. [II-2]
217. Villalain C, Quezada MS, Gómez-Arriaga P, Simón E, Gómez-Montes E,
Galindo A, Herraiz I. Prognostic factors of successful cervical ripening and
labor induction on late-onset fetal growth restriction. Fetal Diagn Ther
2020;47(7):536–44. [II-2]
218. Familiari A, Khalil A, Rizzo G, et al. Adverse intrapartum outcome in preg-
nancies complicated by small for gestational age and late onset fetal growth
restriction undergoing induction of labor with dinoprostone, misopros-
tol or mechanical methods: a systematic review and meta-analysis. Eur J
Obstet Gynecol Reprod Biol 2020;252:455–67. [I]
219. Berghella V. Prevention of recurrent fetal growth restriction. Obstet
Gynecol 2007;110(4):904–12. [III]
48
FETAL MACROSOMIA
Sipika Tyagi
Key points
• Though clinical and sonographic estimated fetal weight
(EFW) can identify newborns with weight ≥4000 g (defi-
nition of fetal macrosomia), both methods are poor at
detecting neonates who will weigh ≥4500 g.
• Prevention of macrosomia is obtained, in women with
gestational diabetes (GDM), with the following:
• Diet and glucose monitoring with insulin if needed,
compared to no treatment or diet only.
• Postprandial blood glucose monitoring, compared
to pre-prandial, in GDM requiring insulin therapy.
• Strict glucose control, with fasting blood sugar <95
and 2 hours postprandial <120.
• Bariatric surgery prior to pregnancy is associated with
decreased odds of macrosomia in obese women (body mass
index > 30 kg/m2)
• Prenatal exercise reduces the odds of delivering a macro-
somic newborn
• Among uncomplicated pregnancies, induction for sus-
pected macrosomia at around 38 weeks 0 days–38 weeks
6 days (EFW >4000 grams, or >95% for gestational age)
as compared to expectant management is found to be
associated with lower incidences of fetal fractures with-
out increasing the likelihood of cesarean delivery.
• There is insufficient evidence to recommend best management
of suspected macrosomia among pregnancies complicated by
diabetes mellitus, prior cesarean delivery, or shoulder dys-
tocia, because of the lack of randomized trials and the inac-
curacy of predicting birth weight. The American College of
Obstetricians and Gynecologists (ACOG) suggests a planned
cesarean for women with no diabetes and an EFW of
>5000 g, and for those with diabetes and an EFW of 4500 g,
but these suggestions are not based on Level 1 evidence.
Definition
A fetus with EFW ≥4000 g can be presumed to be macroso-
mic and macrosomia can be classified as grades I (birthweight
4000–4499 g), II (4500–4999 g), and III (≥5000 g) [1]. This clas-
sification is clinically relevant because the grades are associated
with different types of complications. Newborn morbidity is
higher in grade I as compared to general obstetrics population.
Newborn morbidity increases further in grade II and newborn
mortality increases significantly in grade III [2]. Large for gesta-
tional age is defined as EFW>90th percentile for gestational age
and this is not the same as macrosomia.
Epidemiology/Incidence
The prevalence of macrosomia in high-income countries is
about 2% to 10% of all pregnancies [3]. In low and middle income
countries, the prevalence of macrosomia is typically 1–5%, but
500
ranges from 0.5 to 14.9% [4]. Between 5% and 10% of macrosomic
fetuses are associated with clinically detected maternal diabetes.
According to National Vital Statistics report 2018, in the United
States approximately 8% of all live-born infants weigh >4000 g
and approximately 1% weigh >4500 g [5]. The rate of neonates
in the United States weighing ≥4000 g was 10.2% in 1996, 9.2% in
2002, and 8.0% in 2013 [6]. For newborns weighing ≥5000 g, the
decrease in the prevalence has been notable as well (from 0.16% in
1996, to 0.13% in 2002, and 0.10% in 2008) [6, 7]. The incidence of
macrosomia varies with ethnicity, and is lower in Chinese popu-
lation, reported to be only 3.4% [8].
Risk factors
Risk factors commonly associated with fetal macrosomia are shown
in Table 48.1. A large study done in United States identifying the risk
factors for excess fetal growth concluded that GDM, pre-­pregnancy
adiposity, pregnancy weight gain were independently associated
with higher risk of macrosomia/LGA across all races (except GDM
among non-Hispanic Whites). Among non-Hispanic Whites, non-
Hispanic Black and Hispanic women, the joint effect of all three
factors substantially increased the risks of LGA [9].
Complications
Maternal and perinatal complications commonly associated with
fetal macrosomia are shown in Table 48.2. Birth weight >4500 g
has a significant association with shoulder dystocia and obstetrics
anal sphincter injury (OASIS) [2]. Perinatal complications include
also clavicular fracture, obstetric brachial plexus injuries (OBPI).
Shoulder dystocia occurs in 0.2–3.0% of all vaginal deliveries and
risk is higher for EFW>4500 g [2]. Shoulder dystocia usually can-
not be accurately predicted and most cases occur in nondiabetic
women with normal sized infants (in Obstetric Evidence Based
Guidelines, Chapter 27) [10]. Other neonatal complications asso-
ciated with macrosomia are low Apgar scores, hypoglycemia,
respiratory problems, meconium aspiration and increased rates
of admission and prolong neonatal ICU stay [2]. According to
a systematic review, in pregnancies with birthweight >4000 g,
there is an increased risk of emergency CD, postpartum hemor-
rhage, and OASIS, which increase even more with higher classes
of macrosomia. Similarly, for birthweight >4000 g there is an
increased risk of neonatal shoulder dystocia, OBPI and birth frac-
tures, which increase even further for birthweight >4500 g [11].
Management
Prevention
In diabetic women a significant decrease in the rate of macroso-
mia can be obtained with the following:
• Diet and glucose monitoring with insulin if needed
compared to no treatment or diet only [12].
DOI: 10.1201/9781003099062-48
Fetal Macrosomia
TABLE 48.1: Common Risks Factors Associated with Fetal
Macrosomia
• Maternal diabetes (pre or gestational diabetes)
• Gestational age ≥ 40 weeks
• Advanced maternal age
• Male fetal sex
• Excessive weight gain during pregnancy
• Maternal prepregnancy obesity
• Race, ethnicity (e.g. Black; Hispanic)
• Maternal birthweight >8 lbs
• Grand multiparity
• Prior macrosomic fetus
• Abnormal glucose screening (e.g. even one abnormal value on 3-hour
glucose screen)
• Postprandial versus pre-prandial blood glucose moni-
toring in DM requiring insulin therapy [13].
• In some studies, continuous glucose monitoring compared to
standard antenatal care with intermittent self-monitoring [14].
• Management of DM with fasting blood sugar <95 mg/dL
and 2 hour postprandial <120 mg/dL reduces the risk of
macrosomia [15].
• Treatment, including nutrition instruction, diet, glu-
cose testing, and insulin if necessary, of mild or bor-
derline GDM, defined by abnormal one-hour glucose
challenge test but normal three-hour glucose tolerance
test [16, 17]. In fact, screening for GDM should be done
with the One step, 2-hour, test (Chapter 5).
In non-diabetic women, rates of macrosomia are decreased
with the following:
• Bariatric surgery in eligible obese women, i.e. BMI ≥40
m2/kg or BMI ≥35 m2/kg and co-morbidities [18, 19].
Compared to obese women who had not undergone bariat-
ric surgery, those receiving the procedure had lower odds
of macrosomia (OR 0.46; 95% CI 0.34–0.62) [18].
• Prenatal exercise reduced the odds of having a macroso-
mic newborn by 31% (OR 0.69, 95% CI 0.55–0.86) [20].
In limited data, the rate of macrosomia was not signifi-
cantly decreased with: administering insulin twice daily
versus four times daily in women with pre- and gestational
diabetes [21]; use of glyburide or metformin as alternatives to
insulin therapy [22].
TABLE 48.2: Selected Complications Associated with Fetal
Macrosomia
Maternal Complications Fetal/Neonatal Complications
Protracted labor, arrest of labor Shoulder dystocia
Operative vaginal delivery Clavicular fracture
Cesarean delivery Obstetric brachial plexus injury (OBPI)
Postpartum hemorrhage Low Apgar scores
Intra-amniotic infections Meconium aspiration
Vaginal and perineal lacerations Increased NICU admission rates
Hypoglycemia
Abbreviation: NICU, neonatal intensive care admission.
501
Screening and diagnosis
Ultrasonography is most commonly used tool for screening
and diagnosis of fetal macrosomia. According to a meta-analysis,
ultrasound biometry is 56% sensitive and 92% specific in predict-
ing fetal macrosomia. There is insufficient evidence to say if MRI
EFW is more sensitive than ultrasound abdominal circumfer-
ence, which is itself more sensitive than ultrasound EFW [23].
During labor, the detection of neonates weighing at least 4000 g is
similar with clinical or sonographic EFWs, though the likelihood
ratio with clinicians’ estimate was 15, while with measurements
of biometric parameters it was 42 (i.e. better) [24]. Neither clini-
cal nor sonographic EFW can accurately identify neonates that
weigh 4500 g or more [25, 26], systematically overestimating the
actual birth weight.
Management of suspected macrosomia
Whenever macrosomia is suspected, the pregnancy should be
classified into one of the following groups: (1) uncomplicated
(without diabetes or prior cesarean delivery or prior shoulder
dystocia), (2) pre-gestational or gestational diabetes, (3) prior
cesarean delivery, or (4) history of shoulder dystocia (Figure 48.1).
Without diabetes or prior cesarean
delivery or prior shoulder dystocia
A systematic review and meta-analysis of RCTs of suspected
fetal macrosomia comparing labor induction versus expectant
management in term pregnancy showed that induction of labor
≥38 weeks for suspected fetal macrosomia is associated with
significant decrease in fetal fractures, and therefore can be
considered as a reasonable option. Pooled data from these 4
RCTs including 1190 non-diabetic women with suspected fetal
macrosomia at term did not show a significant difference in
incidence of cesarean delivery (RR 0.91), operative and spon-
taneous vaginal delivery, shoulder dystocia, intracranial hem-
orrhage, brachial plexus injury, Apgar scores <7 at 5 minutes,
cord blood pH<7, and mean birthweight comparing women who
were induced at term versus who were managed expectantly.
The induction group had a significant lower time to delivery,
lower rate of birthweight ≥4000 g, and lower incidence of fetal
fractures (RR 0.17) as compared to the expectant management
group [27].
According to a multi-centric randomized control trial pub-
lished in 2015, induction of labor done between 37 0/7 and 38
6/7 weeks for suspected fetal macrosomia (EFW ≥4000 g) in
nondiabetic women has been associated with a reduced risk
for shoulder dystocia (RR 0.32, 95% CI 0.12–0.85) and asso-
ciated morbidities (RR 0.32, 95% CI 0.15–0.71) when com-
pared to expectant management, without increasing the risk for
cesarean [28]. However, ACOG latest practice bulletin on fetal
macrosomia recommends against delivery before 39 weeks for
uncomplicated suspected macrosomia stating more evidence
is needed to support early delivery for suspected fetal macro-
somia. ACOG suggests that planned cesarean delivery should
be considered for a non-diabetic patient if the EFW is at least
5000 g, though there is insufficient evidence to assess this inter-
vention [2].
Diabetes
In insulin requiring diabetic pregnancies, induction at about 38
weeks, compared to expectant management is associated with a
significant decrease in the rate of macrosomic fetuses, but the lim-
ited sample size does not permit drawing firm conclusions [29, 30].
502 Maternal-Fetal Evidence Based Guidelines

Sonographic EFW ≥ 4000 g

or > 95% for gestational age

Uncomplicated Maternal Diabetes Prior Cesarean Delivery Prior Shoulder Dystocia

Consider IOL between 38
0/7 – 38 6/7 weeks
Consider IOL between 38
0/7 – 38 6/7 weeks
* Individualization and
Patient Counseling
* Consider planned
repeat cesarean delivery
if VBAC success rate < 60%
Consider offering planned
primary cesarean delivery
between 39 0/7 – 39 6/7
weeks

FIGURE 48.1 An algorithm for the management of suspected macrosomia. *Based on results from the Maternal-Fetal Medicine
Network Units (MFMU) online calculator. Abbreviations: EFW, estimated fetal weight, IOL = induction of labor, VBAC = vaginal birth
after cesarean.

There have not been enough studies done on uncomplicated diabetic
women with suspected macrosomia to provide delivery recom-
mendations. As per ACOG, in women with well controlled diabetes
with suspected macrosomia, delivery before 39 weeks needs more
research before this practice can be routinely adopted [31]. While
the ACOG practice bulletin on fetal macrosomia [2, 32] suggests that
cesarean delivery among diabetics is indicated if the EFW is ≥4500 g,
others have set the threshold at ≥4000 g [29, 33] or at ≥4250 g
(see also Chapters 4 and 5) [29].
Prior cesarean delivery
The majority of patients attempting vaginal birth after cesarean
delivery (VBAC) can successfully deliver a fetus estimated to be
macrosomic [34, 35]. The rate of uterine rupture may be higher
(3.6%) for a macrosomic trial of labor with prior cesarean delivery,
if the patient has not delivered vaginally before [36]. Thus, obstet-
ric factors (prior deliveries, need for induction, etc.) should be
considered when attempting VBAC with suspected macrosomia
(see Obstetric Evidence Based Guidelines, Chapter 15).
Prior shoulder dystocia
Women with prior shoulder dystocia are at much higher risk
(about up to15%) of recurrence (see Obstetric Evidence Based
Guidelines, Chapter 27) [37, 38]. In the general obstetric popula-
tion, the likelihood of brachial plexus injury is 1.4/1000 births,
but among women who had prior shoulder dystocia and deliver
vaginally, it is 13/1000 if there is no recurrent dystocia. If there
is recurrent shoulder dystocia, the likelihood of brachial plexus
injury is 45/1000 [38].
There are no randomized trials [4] on how to manage these
pregnancies, but it is reasonable to discuss cesarean delivery
at term when managing a patient with a prior shoulder dys-
tocia, especially with fetal macrosomia because of the high
risks of recurrent shoulder dystocia and of neurologic injury (see
Obstetric Evidence Based Guidelines, Chapter 27).
References
1. Boulet SL, Alexander GR, Salihu HM, Pass M. Macrosomic births in the
United States: determinants, outcomes, and proposed grades of risk. Am J
Obstet Gynecol. 2003;188(5):1372–8. [Level II-1]
2. ACOG Practice Bulletin No. 216. Macrosomia. Obstet Gynecol
2020;135(1):e18–e35. [Level I–III]
3. Campbell S. Fetal macrosomia: a problem in need of a policy. Ultrasound
Obstet Gynecol 2014;43(1):3–10. [Level III]
4. Koyanagi A, Zhang J, Dagvadorj A, et al. Macrosomia in 23 developing
countries: an analysis of a multicountry, facility-based, cross-sectional sur-
vey. Lancet Lond Engl 2013;381(9865):476–83. [Level II-2]
5. Martin JA, Hamilton, BE, Osterman, MJK, et al. Births: final data for 2018.
National Vital Stat Rep 2019;68(13)1–47. [Epidemiological data]
6. Hamilton BE, Martin JA, Osterman MH. et al. Births: preliminary data for
2014. National Vital Stat Rep 2015;64(6):1–19. [Epidemiologic data]
7. Chauhan SP, Grobman WA, Gherman RA, et al. Suspicion and treatment of
the macrosomic fetus: a review. Am J Obstet Gynecol 2005;193(2):332–46.
[Level III]
8. Cheng YK, Lao T. Fetal and maternal complications in macrosomic preg-
nancies. Res Report Neonat 2014;4:65–70. [Level II-3]
9. Bowers K, Laughon SK, Kiely M, Brite J, Chen Z, Zhang C. Gestational dia-
betes, pre-pregnancy obesity and pregnancy weight gain in relation to excess
fetal growth: variations by race/ethnicity. Diabetologia 2013;56:1263–71.
[Level II-3]
10. ACOG Practice Bulletin No. 178. Shoulder dystocia. Obstet Gynecol 2017
May;129(5):e123–e133. [Level II-3]
11. Beta J, Khan N, Khalil A, Fiolna M, Ramadan G, Akolekar R. Maternal and
neonatal complications of fetal macrosomia: systematic review and meta-
analysis. Ultrasound Obstet Gynecol 2019; PMID: 30938004. [Level II-3]
12. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational
diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–86.
[RCT, n = 1000. Impaired glucose tolerance (defined following 75 g OGTT
as fasting <7.0 mmol/L, 2 hour between 7.8 mmol/L and 11.0 mmol/L). Diet,
glucose monitoring, and insulin as needed vs. routine care]
13. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus prepran-
dial blood glucose monitoring in women with gestational diabetes mellitus
requiring insulin therapy. N Engl J Med 1995;333:1237–41. [Level I, RCT, n
= 66]
14. Murphy H, Rayman G, Lewis K, et al. Effectiveness of continuous glucose
monitoring in pregnant women with diabetes: randomised clinical trial. Br
Med J 2008;337:a1680. [Level I, RCT, n = 71]
Fetal Macrosomia
15. American Diabetes Association. Diabetes Care 2020 Jan;43(Suppl
1):S183–S92. [Level III]
16. Bonomo M, Corica D, Mion E, et al. Evaluating the therapeutic approach in
pregnancies complicated by borderline glucose intolerance: a randomized
clinical trial. Diabet Med 2005;1536–41. [Level I, RCT, n = 300]
17. Landon M, Sponge C, Thom E, et al. A multicenter, randomized trial of
treatment for mild gestational diabetes. N Engl J Med 2009;361:1339–48.
[Level I, RCT, n = 958]
18. Galazis N, Docheva N, Smillis C, Nicolaides K. Maternal and neonatal
outcomes in women undergoing bariatric surgery: a systematic review and
meta-analysis. Eur J Obstet Gynecol Reprod Biol 2014;181:45–53. [Meta-
analysis, 17 studies, n = 166,134]
19. Johanson K, Cnattingius, Näslund I, et.al. Outcomes of pregnancy after
bariatric surgery. NEJM 2015;372:814–24. [Level II-1]
20. Wiebe H, Boulé N, Chari R. The effect of supervised prenatal exercise on
fetal growth. Obstet Gynecol 2015;125:1185–94. [Meta-analysis, 36 studies,
of which 28 were RCTs; n = 5322]
21. Nachum Z, Ben-Shlomo I, Weiner E, et al. Twice daily versus four times
daily insulin dose regimens for diabetes in pregnancy: randomised con-
trolled trial. Br Med J 1999;319:1223–27. [RCT, n = 392]
22. Nicholson W, Bolen S, Witkop CT, et al. Benefits and risks of oral diabetes
agents compared with insulin in women with gestational diabetes: a sys-
tematic review. Obstet Gynecol 2009;113:193–205. [Meta-analysis; 9 stud-
ies of which 4 RCTs, n = 1229]
23. Malin GL, Bugg GJ, Takwoingi Y, Thornton JG, Jones NW. Antenatal mag-
netic resonance imaging versus ultrasound for predicting neonatal macro-
somia: a systematic review and meta-analysis. BJOG. 2016;123(1):77–88.
[Systematic review and meta-analysis]
24. Hendrix NW, Grady CS, Chauhan SP. Clinical vs sonographic estimate of
birth weight in term parturients: a randomized clinical trial. J Reprod Med
2000;45:317–22. [RCT, n = 758]
25. Gonen R, Spiegel D, Abend M. Is macrosomia predictable, and are shoulder
dystocia and birth trauma preventable? Obstet Gynecol 1996;88:526–29.
[Level II-1]
26. Gonen R, Bader D, Ajami M. Effects of a policy of elective cesarean deliv-
ery in cases of suspected fetal macrosomia on the incidence of brachial
503
plexus injury and the rate of cesarean delivery. Am J Obstet Gynecol
2000;183:1296–300. [Level II-1]
27. Magro-Malosso ER, Saccone G, Chen M, Navathe R, Di Tommaso M,
Berghella V. Induction of labour for suspected macrosomia at term in
non-diabetic women: a systematic review and meta-analysis of random-
ized controlled trials. BJOG. 2017;124(3):414–21. [Systematic review and
meta-analysis]
28. Boulvain M, Senat M, Perrotin F, et al. Induction of labour versus expect-
ant management for large-for-date fetuses: a randomized controlled trial.
Lancet 2015;385:2600–05. [RCT, n = 818]
29. Boulvain M, Stan C, Irion O. Elective delivery in diabetic pregnant women.
Cochrane Database Syst Rev 2001;(2):CD001997. [Meta-analysis, n = 200]
30. Witkop C, Neale D, Wilson LM, et al. Active compared with expectant
delivery management in women with gestational diabetes: a systematic
review. Obstet Gynecol 2009;113(1):206–17. [Meta-analysis; 5 studies of
which 1 RCT, n = 200]
31. ACOG Practice Bulletin No. 201 Pregestational diabetes mellitus. Obstet
Gynecol 2018 December;132(6):e228–e48. [Level III]
32. ACOG Practice Bulletin No. 22 Fetal macrosomia. Obstet Gynecol
2000;96(5). (reaffirmed 2015). [Level III]
33. Conway DL, Langer O. Elective delivery of infants with macrosomia in dia-
betic women: reduced shoulder dystocia versus increased cesarean deliver-
ies. Am J Obstet Gynecol 1998;178:922–25. [Level II-1]
34. Phelan JP, Eglinton GS, Horenstein JM, et al. Previous cesarean birth. Trial
of labor in women with macrosomic infants. J Reprod Med 1984;29:36–40.
[Level II-1]
35. Zelop CM, Shipp TD, Repke JT, et al. Outcomes of trial of labor following
previous cesarean delivery among women with fetuses weighing > 4000 g.
Am J Obstet Gynecol 2001;185:903–5. [Level II-1]
36. Elkousy MA, Sammel M, Stevens E, et al. The effect of birth weight on
vaginal birth after cesarean delivery success rates. Am J Obstet Gynecol
2003;188:824–30. [Level II-1]
37. Lewis DF, Raymond RC, Perkins MB, et al. Recurrence rate of shoulder dys-
tocia. Am J Obstet Gynecol 1995;172:1369–71. [Level II-2]
38. Bingham J, Chauhan SP, Hayes E, et al. Recurrent shoulder dystocia: a
review. Obstet Gynecol Surv 2010;65:183–8. [Level II-2]
49
CYTOMEGALOVIRUS
Timothy J. Rafael
Key points
• Cytomegalovirus (CMV) is the most common cause of viral
intrauterine infection, affecting 0.5–1.5% of all neonates.
• In most of the cases, pregnant women acquire CMV by
exposure to children in their home or from occupational
exposure to children.
• Approximately 1–4% of immunoglobulin G (IgG)-
negative women acquire CMV infection during preg-
nancy. Approximately 1/3 (range 30–65%) of pregnant
women with a primary infection transmit CMV infec-
tion to their fetus. The rate of transmission increases
with an increase in gestational age (highest in the third
trimester), but the severity of disease is instead inversely
proportional to gestational age (the infant is most affected
when maternal infection is in first trimester). Overall,
about 15–20% of infected infants develop sequelae
(so about 5–8% of infected mothers have infants with
sequelae).
• Complications of affected infants with congenital CMV
infection include jaundice, petechiae (“blueberry muffin
baby”), thrombocytopenia, hepatosplenomegaly, growth
restriction, microcephaly, intracranial calcifications, non-
immune hydrops, and preterm birth, as well as late com-
plications such as hearing loss, mental retardation, delay in
psychomotor development, chorioretinitis, optic atrophy,
seizures, expressive language delays, and learning disabili-
ties. Long-term mortality for severely affected infants is
about 5%.
• Compared with no prevention, preventative measures are
acceptable to pregnant women (including avoiding inti-
mate contact with children, frequent handwashing, and
glove use), can impact behavior, and have the potential
to reduce CMV in pregnancy.
• CMV screening in pregnancy is not routinely recom-
mended in most countries, until an appropriate fetal inter-
vention is proven to decrease neonatal disease in cases of
maternal CMV infection.
• Maternal diagnosis of primary CMV infection is by
serum IgM+.
• Fetal diagnosis of CMV infection is by detection of virus
in amniotic fluid (AF) by polymerase chain reaction
(PCR) testing.
• Presence or absence of fetal abnormalities on ultra-
sound can help counseling (Table 49.2), but ultrasound is
not sensitive and poorly predictive of an affected (symp-
tomatic) child, especially when information regarding
maternal serology is not known.
• There is no in utero therapy for CMV supported by
robust level 1 data. Hyperimmune globulin has not been
found to be effective at preventing vertical transmission of
CMV in randomized controlled trials. Gancyclovir has not
504
been evaluated in an RCT. Valacyclovir has been shown
to decrease the risk of vertical transmission in a small ran-
domized controlled trial, and was shown to mitigate some
of the effects of congenital disease among infected fetuses
in a multicenter open label study.
Pathogen
CMV is a double-stranded DNA virus of the herpes family [1].
Incidence/Epidemiology
CMV is the most common cause of viral intrauterine infec-
tion, affecting 0.5–1.5% of all neonates in different parts of the
world [2, 3]. The birth prevalence of neonatal infection correlates
with maternal seroprevalence, ranging from 0.4 to 1% in coun-
tries with lower and higher seroprevalence, respectively [4]. The
prevalence of CMV infection varies according to socioeconomic
background, with Black infants having a higher congenital
CMV prevalence compared with Hispanic and non-Hispanic
White infants [5]. The CMV seropositivity, by background, is
40–50% for women of middle and high, and 60% to more than
80% for women of lower socioeconomic background. The overall
age-adjusted seroprevalence of CMV did not change significantly
from 1988–1994 to 1999–2004 [6]. Globally, the seroprevalence
among women of reproductive age is estimated to be approxi-
mately 86%, with the highest seroprevalence seen in the WHO
Eastern Mediterranean region (92%), and the Americas having a
seroprevalence of 79%; the lowest seroprevalence is noted in the
WHO European region (70%) [7].
Transmission/Risk factors/Associations
Transmission usually occurs from close contact, with contamina-
tion from urine, saliva, blood, semen, and cervical secretions [8],
with the virus being acquired at mucosal sites or by blood-borne
transmission [4]. Risk factors are low socioeconomic status, expo-
sure to infective individuals, multiple partners, extremes of age,
multiparity, and blood transfusion. Only cellular blood products
that contain leukocytes are capable of transmitting. Using leuko-
reduced blood products, the risk of transmission from a transfu-
sion is approximately 0.2-3% in immunocompetent recipients [9].
The incidence of cases with congenital disease following maternal
recurrent infection has been shown to be increased with immuno-
deficiency, hormonal exposure, nutritional deficiency, and genital
tract infections [10]. Although sexual transmission of CMV can
occur, in most cases pregnant women acquire CMV by exposure
to children in their home or from occupational exposure to
children. Data extrapolated to the U.S. population estimate that
every two years between 31,000 and 168,000 susceptible pregnant
women will be exposed to CMV by an infected child [11].
DOI: 10.1201/9781003099062-49
Cytomegalovirus
Symptoms
CMV is usually asymptomatic or with symptoms so mild
that it goes undiagnosed. The symptoms might include a
mononucleosis-like or flu-like syndrome, malaise, fatigue,
lymphadenopathy, or persistent fever, and abnormal labora-
tory values (lymphocytosis, or increased aminotransferase
levels). Rarely, hepatosplenomegaly, cough, headache, rash,
and gastrointestinal symptoms can occur [12]. The presence of
symptoms or laboratory abnormalities is highly suggestive of
primary infection [13].
Pathophysiology/Classification
General
The CMV virus leads to infected large cells with intranuclear
inclusions. It has a 4- to 8-week period of incubation, and 3- to
12-month-long viremia (infants can shed virus for up to 6 years).
Serious disease occurs only in immunocompromised adults or
fetuses. The transmission of the virus to the fetus can follow
either a primary or recurrent infection. Approximately 1–4%
of immunoglobulin G (IgG)-negative women acquire CMV
infection during pregnancy [14]. Approximately 1/3 (range
30–65%) of pregnant women with a primary infection trans-
mit CMV infection to their fetus (Figure 49.1) [2, 3]. Even peri-
conception infection a week before or up to 5 weeks after the last
menstrual period (LMP) is associated with this rate of trans-
mission, although these rates may not be as high as previously
thought [15]. The rate of transmission increases with increase
in gestational age (highest in third trimester) but the sever-
ity of disease is instead inversely proportional to gestational
Natural history of CMV perinatal infection
Primary* maternal infection (CMV IgM + or PCR +)
30%–40% Fetal infection (CMV PCR + in AF)
90% 10%
Asymptomatic at birth Symptomatic at birth
10–15% 40–60%
develop develop
permanent sequelae permanent sequelae
FIGURE 49.1 Natural history of CMV perinatal infection.
(From Refs. [2, 3].) * Vertical transmission after recurrent infec-
tion is 0.5–2%. Abbreviations: CMV, cytomegalovirus; PCR,
polymerase chain reaction; IgM, immunoglobulin M; AF, amni-
otic fluid.
505
TABLE 49.1: Pooled Likelihood of Congenital Infection by
Timing of Maternal Infection
Probability of Congenital
Maternal Infection Infection (%)
Preconceptiona 5.2
Periconceptiona 16.4
First trimester 36.5
Second trimester 40.1
Third trimester 65
Source: Based on data from Ref. [16].
a In their cohort, Picone et al (Ref. [16]) define the “preconception” time period as 2
months to 3 weeks before the date of conception, and “periconception” as 3 weeks
before to 3 weeks after the date of conception. Please note that this table repre-
sents their data combined with other existing literature, where the definitions of
pre- and periconception vary slightly.
age (infant is most affected when maternal infection is in the
first trimester) (Table 49.1) [16]. One series reported no affected
neonates if fetuses were infected after 26 weeks, if the ultrasound
examination was normal [17]. These findings were confirmed by
a larger cohort of patients who seroconverted in the third tri-
mester [18]. A more recent study examining data from 2011 to
2017 found no increased risk of neonatal sensorineural hearing
loss and/or neurologic sequelae following maternal infection in
the second or third trimesters [19]. The risk of congenital CMV
disease at birth is mainly associated with maternal primary infec-
tion, but the presence of maternal antibodies before conception
does not prevent transmission in all cases, even if it is protective
in most cases. In fact, depending on the CMV prevalence of the
particular region, up to 50–90% of congenital CMV may be due
to a nonprimary maternal infection [4].
Primary infection
Vertical transmission with fetal infection, along with the poten-
tial for neonatal sequelae generally occurs following a maternal
primary infection, but can also occur following recurrent CMV
infection (Figure 49.1). Of the women who are not immune (IgG–,
IgM–) for CMV at the beginning of pregnancy, about 2% acquire
maternal infection. Transplacental transmission may occur
weeks or months after primary maternal CMV infection, and
can be isolated from the AF by a PCR DNA technique to posi-
tively identify intrauterine transmission of CMV. Overall, about
15–20% of infected infants develop sequelae (so about 5–8%
of infected mothers have infants with sequelae).
Recurrent infection
Nonprimary or recurrent infections can occur with immuno-
suppression and during pregnancy. Recurrent infections during
pregnancy are most often asymptomatic and primarily caused by
the reactivation of the endogenous virus, but can also be caused
by a low-grade chronic infection or reinfection by a different
strain of CMV [20]. The risk of vertical transmission with recur-
rent infection is about 1.4% (range 0.5–2%) [3], but due to the
high seroprevalence of CMV worldwide, 50–90% of congenital
CMV is a result of recurrent infection [4]. While it was pre-
viously believed that neonates infected from recurrent maternal
infection had no symptoms at birth [12], it appears that the rate
of hearing loss is similar after primary and nonprimary infection
at 10% and 11%, respectively [4].
506 Maternal-Fetal Evidence Based Guidelines

Clinical neonatal findings and complications TABLE 49.2: Chance of Affected (i.e., Symptomatic) Neonate
Clinical findings of symptomatic congenital CMV infection Depending on Clinical Scenario of CMV Infection
include jaundice, petechiae (blueberry muffin baby), throm- Affected Infant
bocytopenia, hepatosplenomegaly, growth restriction, micro- Maternal Fetal Ultrasound [Reference]
cephaly, intracranial calcifications, nonimmune hydrops, and
preterm birth [1, 21]. Primary and recurrent CMV has also been Confirmed infection Unknown Normal 5–7% [8]
suggested as causes of isolated idiopathic IUGR [22]. CMV disease (e.g., seroconversion,
has late complications such as hearing loss, neurodevelopmen- with positive IgM)
tal delay, delay in psychomotor development, chorioretinitis, Unknown Abnormal 35% [26]
optic atrophy, seizures, expressive language delays, and learn- Confirmed Normal 3–7% [42]
ing disabilities [23]. CMV is the most common cause of congeni- infection (e.g.,
tal sensorineural hearing loss [24]. It appears that moderate or positive AF PCR)
severe outcomes, when present, are identified by 1 year of age. Confirmed Abnormal 78% [26]
Most impairment detected for the first time after 1 year of age infection (e.g.,
appears to be milder in nature [25]. Long-term mortality for positive AF PCR)
severely affected infants is about 5%.
Abbreviations: AF, amniotic fluid; PCR, polymerase chain reaction.

Pregnancy management
Counseling/Prognosis
Counseling should include at least the natural history of the
disease, the chances of vertical transmission, prognosis, and
complications (Figure 49.1 and Table 49.2) [8, 26]. A quanti-
tative PCR count of ≥103 genome equivalents/mL in amni-
otic fluid is a certain sign of congenital infection, and ≥10 5
genome equivalents/mL can predict symptomatic infection
(Figure 49.2) [27]. In cases of severely injured fetuses on ultra-
sound, there is a high likelihood of sequelae, and pregnancy
termination can be offered as a management option [28]. When
no ultrasonographic abnormalities are detected, the incidence
of postnatal neurologic abnormalities may be as high as 15–20%
[29, 30], with newer data suggesting lower rates of sequelae (see
Ultrasound Fetal Findings).

Assessment of chance of fetal infection and long-term

complications by quantitative PCR in AF (4, 27, 47)
92% probably
PCR on amniotic fluid Negative of absence of
21–22 Weeks result infection in the
fetus/newborn;
0% risk of long-
term sequelae

Positive
result

qPCR

Cutoff point Cutoff point

<10(3) ≥10(3) < 10(5) ≥10(5)

81% probability of 100% probability of 92% probability of 100% probability of
absence of infection presence of infection absence of clinical presence of clinical
symptomatology symptomatology

FIGURE 49.2 Assessment of chance of fetal infection and long-term complications by quantitative PCR in AF. Abbreviations: PCR,
polymerase chain reaction; AF, amniotic fluid.
Cytomegalovirus
Prevention
Hygiene
Despite a higher prevalence of CMV-related childhood morbid-
ity and mortality when compared with other infections, a survey
study demonstrated only 13% of women being aware of congenital
CMV. Most women practice behaviors that may place them at risk
when interacting with children (e.g., kissing on lips, sharing uten-
sils, sharing food, changing diapers, wiping child’s nose, handling
child’s toys) [31]. Compared with no prevention, preventative
measures are acceptable to pregnant women (including avoid-
ing intimate contact with children, frequent handwashing,
and glove use), can impact behavior, and have the potential to
reduce CMV in pregnancy [32]. Compared with no prevention,
prevention is associated with an 84% decrease in CMV sero-
conversion during pregnancy, especially in women in contact
with children in day care facilities [33]. Following the administra-
tion of oral and written hygienic information to susceptible preg-
nant women, seroconversion rates during pregnancy have been
reported to be as low as 0.26% [34]. There is currently a phase 1
trial entitled “Reducing Acquisition of CMV Through Antenatal
Education (RACEFIT)” underway in the United Kingdom (https://
clinicaltrials.gov/ct2/show/NCT03511274).
Vaccine
A live-attenuated CMV vaccine is available, but may be reac-
tivated, and safety issues have not been resolved. In a trial
including CMV-seronegative women of childbearing age, a glyco-
protein B vaccine demonstrated a 50% efficacy in preventing
CMV infection. One congenital infection occurred in the vac-
cine group, and three infections occurred in the placebo group,
although the sample size was not large enough to test the efficacy
in reducing congenital infection [35]. While this vaccine, along
with multiple additional novel vaccine candidates are being stud-
ied, all aimed at prevention of maternal and congenital CMV
infection, it is unlikely that a CMV vaccine will be available
clinically for several years [4].
Screening
Serum
CMV screening in pregnancy is not routinely recommended in
many countries, even in women who are seronegative, mainly given
the lack of proven intervention if seroconversion is detected [1],
along with screening failing to detect nonprimary infections [36].
If an appropriate fetal intervention is proven to decrease neo-
natal disease in cases of CMV, screening with IgM and IgG levels
should be performed on all pregnant women between 8 and 12
weeks. IgM is 75% sensitive, and persists for four to eight months.
Seronegative women should be provided with basic information
on how to avoid infection [34]. A second and possibly a third anti-
body control at 18–20 weeks and at 30–32 weeks could be rec-
ommended. IgG-positive and IgM-negative women with high IgG
avidity index (e.g., >65%) could be assured of no risk of primary
infection, which causes the majority of sequelae in the fetus [37].
Currently though, there is no in utero therapy for CMV pre-
vention or treatment supported by robust Level 1 data, and
therefore routine CMV screening in pregnancy cannot as of
yet be recommended [1, 14]. Nevertheless, in an effort to pro-
vide reassurance to patients at the first prenatal visit, providers
are often wont to confirm negative serology or serology indica-
tive of past infection, but instead are faced with a positive IgM
for CMV; in these situations, checking a CMV IgG avidity and
possibly CMV PCR in maternal serum has clinical value. In a
507
cohort of consecutive women screened in the first trimester, all
of whom were IgM-positive, among those with low or interme-
diate IgG avidity, vertical fetal transmission was later found to
be 23.6% [38]. For this cohort of patients, careful ultrasound fol-
low up and confirmatory diagnostic testing with amniocentesis
should be offered.
Ultrasound fetal findings
These findings are growth restriction, ventriculomegaly, oli-
gohydramnios, echogenic bowel, choroid plexus cyst (uni-
lateral), pleural effusion, brain and liver calcification, and
hydrops fetalis [29]. Microcephaly, hydrocephaly, and intracra-
nial calcifications are signs of high risk for neonatal sequelae [23].
A fetal cerebral periventricular “halo” seen on ultrasound exami-
nation is also suggestive of fetal infection, and may be associated
with white-matter lesions [39]. Fetal abnormalities may become
evident late, change or disappear during pregnancy, and women
should be informed that ultrasound abnormalities can appear 12
weeks or more after maternal infection, so detailed ultrasound
follow up (every 2–4 weeks) is indicated [40]. Ultrasound detects
fetal abnormalities in only 8.5% of women with primary CMV
infection, and in 15% of congenitally CMV-infected fetuses. That
said, among cohorts where the diagnosis is known antenatally,
and targeted ultrasounds can be performed, the ability of pre-
natal imaging to predict any and severe sequelae increases dra-
matically, with the sensitivity for predicting long-term sequelae
and severe long-term sequelae being 91% and 100%, respectively,
in one cohort [41]. If fetal ultrasound abnormalities are detected,
symptomatic CMV infection is present in 35% of neonates of
primary-infected mothers, and 78% of congenitally infected neo-
nates (Table 49.2) [26]. There are varying data regarding outcomes
among fetuses with known infection and normal ultrasound find-
ings: older data suggested that the risk of a symptomatic neonate
was as high as 14–20% [8], while a recent systematic review found
that among infected fetuses/neonates who had normal prena-
tal ultrasound(s), the risk of symptomatic infection was 1.5%,
the rate of neurodevelopmental anomalies was 3.1%, and the
occurrence of hearing problems was 6.5% [42]. These results
may be attributable to ever-improving ultrasound technology and
knowledge of sonographic findings associated with CMV, as over
half of the studies in this systematic review were published within
the last 10 years. Nevertheless, it must be stressed to patients that
not all features of congenital inclusion disease are detect-
able by ultrasound, and normal antepartum ultrasounds and/
or MRI examinations do not completely rule out neonatal
sequelae, especially hearing outcomes [40].
Investigations/Diagnosis/Workup
Maternal primary CMV infection is diagnosed by IgM+
serum, which persists for 4–8 months, and the degree of IgG
avidity. Although seroconversion is a reliable method for diag-
nosing primary CMV infection, the diagnosis can be problematic.
The rise in CMV-specific antibodies may be delayed for up to 4
weeks, and the presence of CMV-specific IgM can be found in up
to 10% of women with recurrent disease. Of newly found IgM+
women, approximately 50% will be found on follow up immu-
noblot testing to be IgM negative, with high CMV IgG avidity,
and can be provided some reassurance [43]. In first trimester
patients who are IgM-positive, and have a low or intermedi-
ate IgG avidity, vertical fetal transmission can be as high as
24% [38]. For this cohort of patients, along with those suspected
of having recurrent infection, careful ultrasound follow up and
508
confirmatory diagnostic testing with amniocentesis should
be offered.
At present, detection of virus in AF by PCR testing is the
most accurate means of diagnosis for CMV infection in
the fetus, with sensitivities ranging from 80% to 100% [30].
Amniocentesis provides a direct method of diagnosing intrauter-
ine CMV infection because the infected fetus excretes the virus
via urine into AF. The sensitivity of detecting a true infec-
tion by sampling the AF increases after 21 weeks’ gestation
and after a minimum of 6 weeks following maternal primary
infection, so that if an amniocentesis is performed before this
interval, it should be repeated later [10, 30]. Recent data suggest
that as long as 8 weeks have passed between seroconversion and
amniocentesis, there are no significant differences when amnio-
centesis is performed ≥17 0/7 versus ≥20 0/7 weeks [44, 45]. It
does not appear that amniocentesis, in and of itself, is implicated
in iatrogenic CMV infection of the fetus [46].
CMV DNA detected in AF reveals a history of viremia but it
does not directly demonstrate the current fetal condition [24].
Quantitative PCR in amniotic fluid can help predict infection
and later sequelae (Figure 49.2). Infected fetuses may also have
abnormal ultrasound findings. Normal fetal ultrasound does not
rule out severe neurological damage or the possibility of child-
hood sensorineural hearing loss. Percutaneous umbilical blood
sampling (PUBS) should be avoided, and has been used in the past
to diagnose the fetus with a high suspicion for CMV and nega-
tive PCR. The use of viral culture has decreased, also because it
takes 2–6 weeks to obtain final results. Even in cases of a negative
amniocentesis via PCR in cases of primary maternal infections,
it must be discussed with patients that there have been reported
instances of neonatal congenital CMV infection. Fortunately,
it does not appear that any of these cases result in neurological
sequelae, and the risk of hearing impairment at birth is less than
3%. These children have excellent long-term outcomes [47].
Neonatal diagnosis is based on detection of PCR in body flu-
ids, in particular in urine.
Therapy
CMV-specific hyperimmune globulin
There is insufficient evidence to recommend CMV-specific
hyperimmune globulin for prevention or treatment of CMV
congenital infection. In a nonrandomized study, CMV hyper-
immune globulin IV 100 U/kg every month until delivery to the
mother for prevention of vertical transmission in primary mater-
nal CMV infection was associated with a decrease in the incidence
of infected neonates from 40% in controls to 16% [48]. Maternal
CMV hyperimmune globulin 200 U/kg IV to the mother (with
additional amniotic fluid or umbilical cord infusions for per-
sistent ultrasound findings) for therapy of known CMV DNA +
fetuses was associated with a decrease in the incidence of symp-
tomatic CMV disease at birth from 50% in controls to 3% [48].
Follow-up to this study demonstrated a resolution of abnormal
ultrasound findings in three treated fetuses, who subsequently
had normal sensory, mental, and motor development at 4–7 years
of age [49]. In the original study, almost all these women were
infected in the first or second trimester. A case of resolution of
hydrops secondary to CMV fetal infection with CMV-specific
hyperimmune globulin has been reported [50]. These findings
were not validated in a randomized, placebo-controlled, dou-
ble-blind study conducted in Italy [51]. This study randomized
124 pregnant women with primary CMV infection at 5–26 weeks
Maternal-Fetal Evidence Based Guidelines
to monthly hyperimmune globulin (100 U/kg) or placebo until
36 weeks’ gestation, or until detection of CMV in amniotic
fluid. The rate of congenital infection was 30% in the hyperim-
mune globulin group and 44% in the placebo group (p = 0.13).
There was no significant difference between the two groups in
viral DNA load in the amniotic fluid of infected fetuses, or with
respect to viral DNA in the urine or blood in infected newborns.
Obstetrical complications (preterm birth, pre-eclampsia, and
fetal growth restriction) occurred in 13% of the women in the
hyperimmune globulin group compared with 2% in the placebo
group (p = 0.06). A subsequent randomized, placebo-controlled
trial performed in the United States was stopped for futility at
the interim analysis of the first 399 cases, after vertical transmis-
sion rates for the hyperimmune globulin and placebo arms were
found to be similar (22.7% versus 19.4%, respectively) [52]. As the
half-life of hyperimmune globulin may be shorter than previously
suspected, a recent non-randomized phase I study evaluated 200
IU/kg of hyperimmune globulin given every 2 weeks, in an effort
to prevent vertical transmission. Compared to a matched histori-
cal cohort having a 35.2% vertical transmission rate, the hyper-
immune globulin arm had a decreased vertical transmission rate
of 7.5% (p < 0.0001) [53]. While these results are encouraging, at
this time the use of hyperimmune globulin for the prevention
of vertical transmission of CMV is not recommended [14].
Ganciclovir and valacyclovir
Ganciclovir inhibits viral DNA polymerase, and has been used
successfully in adults, especially immunocompromised (AIDS,
transplant, etc.) patients. There are no randomized controlled
trials evaluating fetal therapy with ganciclovir. Ganciclovir
administration into the umbilical vein and anti-CMV IgG injec-
tions into the fetal abdominal cavity have been reported in case
reports [24], as has ganciclovir given orally to a pregnant woman
with CMV DNA in the AF, but the evaluation of the prognosis is
not well established; case reports have shown no teratogenicity
of ganciclovir given in the early stages of pregnancy [54]. A small
pediatric trial demonstrated reduction of hearing loss in neonates
with proven congenital CMV infection with CNS involvement
when treatment was begun within one month of birth [55].
Valacyclovir (8 g/day orally for a median of 7 weeks) given
to women with congenitally CMV-infected fetuses at about 30
weeks of gestations was associated with about a 50% normal child
outcome at 1–5 years of age in one non-randomized study [56].
A pediatric trial examining 6-week versus 6-month regimens of
valganciclovir for the treatment of symptomatic congenital CMV
infants found that the 6-month regimen did not improve hearing
in the short term, but appeared to modestly improve hearing and
developmental outcomes in the longer term, when compared to
the 6-week regimen [57]. There have been two recent prospective
analyses of valacyclovir use during pregnancy, one to prevent ver-
tical transmission of CMV, and the other to potentially mitigate
the effects of CMV among already infected fetuses:
• A randomized, double-blind, placebo-controlled trial
examined the effects of valacyclovir among pregnant
patients with serological evidence of a primary CMV infec-
tion acquired either periconceptionally or during the first
trimester of pregnancy, were randomly assigned to oral
valacyclovir (8 g total daily, divided into 4 g twice daily)
or placebo, from enrollment until amniocentesis at 21–22
weeks’ gestation. Five amniocenteses (11.1%) were posi-
tive for CMV in the valacyclovir group, compared with 14
Cytomegalovirus
(29.8%) in the placebo group, which was statistically sig-
nificant (p = 0.027; Odds ratio 0.29, 95% CI 0.09–0.90 for
vertical CMV transmission), signifying a 71% decrease in
fetal infection [58].
• A phase II multicenter non-randomized open label study for
women carrying a confirmed infected fetus in the second
trimester (confirmed by a positive CMV-PCR by amniocen-
tesis >21 weeks, together with the presence of ≥1 extrace-
rebral ultrasound features compatible with CMV infection
and/or one isolated cerebral abnormality). High-dose vala-
cyclovir (8 g total daily, divided into 2 g four times daily)
begun at a median of 25 weeks’ gestation was associated
with a higher proportion of asymptomatic neonates (82%)
than that in an untreated historical cohort (43%). No mater-
nal, fetal, or neonatal adverse effects were reported [59].
While both of these trials demonstrate promising results,
until more Level 1 evidence is obtained in preventing verti-
cal transmission, and a higher level of evidence is obtained in
mitigating the effects of congenital CMV, the use of valacyclo-
vir for prevention of CMV fetal infection and related adverse
consequences cannot yet be routinely recommended, and is
indeed promising.
References
1. ACOG Practice Bulletin No 151. Cytomegalovirus, Parvovirus B19, Varicella
Zoster, and Toxoplasmosis in Pregnancy, June 2015 (Reaffirmed 2017). [III]
2. Dollard SC, Grosse SD, Ross, DS. New estimates of the prevalence of neu-
rological and sensory sequelae and mortality associated with congenital
cytomegalovirus infection. Rev Med Virol 2007;17(5):355–363. [III]
3. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology
of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007;
17:253–276. [III]
4. Leruez-Ville M, Foulon I, Pass R, Ville Y. Cytomegalovirus infection dur-
ing pregnancy: state of the science. Am J Obstet Gynecol 2020;223(3):
330–349. [III]
5. Fowler KB, Ross SA, Shimamura M, et al. Racial and ethnic differences
in the prevalence of congenital cytomegalovirus infection. J Pediatr
2018;200:196–201. [II-3]
6. Lewis Bate S, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in
the United States: the national health and nutrition examination surveys,
1988–2004. Clin Infect Dis 2010;50(11):1439–1447. [III]
7. Zuhair M, Smit GSA, Wallis G, et al. Estimation of the worldwide serop-
revalence of cytomegalovirus: a systematic review and meta-analysis. Rev
Med Virol 2019;29:e2034. [Systematic review, 250 published datasets]
8. Bhide A, Papageoghiou AT. Managing primary CMV infection in preg-
nancy. BJOG 2008;115:805–807. [III]
9. Wu Y, Zou S, Cable R, et al. Direct assessment of cytomegalovirus trans-
fusion-transmitted risks after universal leukoreduction. Transfusion
2010;50:776–786.[II-3]
10. Henrich W, Meckies J, Dudenhausen JW, et al. Recurrent CMV infec-
tion during pregnancy: ultrasonographic diagnosis and fetal outcome.
Ultrasound Obstet Gynecol 2002;19:608–611. [II-3]
11. Marshall BC, Adler SP. The frequency of pregnancy and exposure to cyto-
megalovirus infections among women with a young child in day care. Am J
Obstet Gynecol 2009;200:163.e1–163.e5. [III]
12. Nigro G. Maternal-fetal cytomegalovirus infection: from diagnosis to ther-
apy. J Matern Fetal Neonatal Med 2009;22(2):169–174. [III]
13. Nigro G, Anceschi MM, Cosmi EV. Clinical manifestations and abnormal
laboratory findings in pregnant women with primary cytomegalovirus
infection. BJOG 2003;110:572–577. [II-3]
14. Society for Maternal-Fetal Medicine (SMFM), Hughes BL, Gyamfi-
Bannerman C. Diagnosis and antenatal management of congenital cyto-
megalovirus (CMV) infection. Am J Obstet Gynecol 2016;214(6):B5–B11.
[III; Guideline]
15. Hadar E, Yogev Y, Melamed N, et al. Periconceptional cytomegalovirus
infection: pregnancy outcome and rate of vertical transmission. Prenat
Diagn 2010;30:1213–1216. [II-3]
509
16. Picone O, Vauloup-Fellous C, Cordier AG, et al. A series of 238 cytomega-
lovirus primary infections during pregnancy: description and outcome.
Prenatal Diagn 2013;33:751–758. [II-3]
17. Gindes L, Teperberg-Oikawa M, Sherman D, et al. Congenital cytomegalo-
virus infection following primary maternal infection in the third trimester.
BJOG 2008;115:830–835. [II-2]
18. Enders G, Daiminger A, Bäder U, et al. Intrauterine transmission and clini-
cal outcome of 248 pregnancies with primary cytomegalovirus infection in
relation to gestational age. J Clin Virol 2011;52(3):244–246. [II-2]
19. Faure-Bardon V, Magny JF, Parodi M, et al. Sequelae of congenital cyto-
megalovirus following maternal primary infections are limited to those
acquired in the first trimester of pregnancy. Clin Infect Dis 2019;69(9):
1526–1532. [II-2]
20. Boppana SH, Rivera L, Fowler KB, et al. Intrauterine transmission of
CMV to infants of women with preconceptional immunity. N Engl J Med
2001;344:1366–1371. [II-3]
21. Kylat RI, Kelly EN, Ford-Jones EL. Clinical findings and adverse outcome in
neonates with symptomatic congenital cytomegalovirus (SCCMV) infec-
tion. Eur J Pediatr 2006;165:773–778. [II-3]
22. Pereira L, Petitt M, Fong A, et al. Intrauterine growth restriction caused
by underlying congenital cytomegalovirus infection. J Infect Dis 2014;209:
1573–1584. [II-3]
23. Azam A-Z, Vial Y, Fawer CL, et al. Prenatal diagnosis of congenital CMV
infection. Obstet Gynecol 2001;97:443–448. [II-2]
24. Matsuda H, Kawakami Y, Furaya K, et al. Intrauterine therapy for a CMV
infected symptomatic fetus. BJOG 2004;111:756–757. [II-3]
25. Townsend CL, Forsgren M, Ahlfors K, et al. Long-term outcomes of con-
genital cytomegalovirus infection in Sweden and the United Kingdom. Clin
Infect Dis 2013;56(9): 1232–1239. [II-2]
26. Guerra B, Simonazzi G, Puccetti C, et al. Ultrasound prediction of symp-
tomatic congenital cytomegalovirus infection. Am J Obstet Gynecol
2008;198:380.e1–380.e7. [II-3]
27. Guerra B, Lazzarotto T, Quarta S, et al. Prenatal diagnosis of symptomatic
congenital CMV infection. Am J Ostet Gynecol 2000;183:476–482. [II-2]
28. Liesnard C, Donner C, Brancart F, et al. Prenatal diagnosis of congeni-
tal CMV infection: prospective study of 237 pregnancies at risk. Obstet
Gynecol 2000;95:881–888. [II-2]
29. Lipitz S, Achiron R, Zalen Y, et al. Outcome of pregnancies with verti-
cal transmission of primary CMV infection. ACOG. Obstet Gynecol
2002;100:428–433. [II-3]
30. Oshiro BR. CMV infection in pregnancy. Contemp Obstet Gynecol
1999;11:16–24. [Review]
31. Cannon MJ, Westbrook K, Levis D, et al. Awareness of and behavior related
to child-to-mother transmission of cytomegalovirus. Prevent Med 2012;54:
351–357. [II-3]
32. Barber V, Calvert A, Vandrevala T, et al. Prevention of acquisition of cyto-
megalovirus infection in pregnancy through hygiene-based behavioral
interventions: a systematic review and gap analysis. Pediatr Infect Dis J
2020;39:949–954. [Systematic review, 7 studies, n = 7042]
33. Adler SP, Finney JW, Manganello AM, et al. Prevention of child-to-mother
transmission of cytomegalovirus among pregnant women. J Pediatr
2004;145:485–491. [I, RCT, n = 166]
34. Picone O, Vauloup-Fellous C, Cordier AG, et al. A 2-year study on cyto-
megalovirus infection during pregnancy in a French hospital. BJOG
2009;116:818–823. [II-3]
35. Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomega-
lovirus infection. N Engl J Med 2009;360:1191–1199. [I, RCT, n = 464]
36. Tanimura K, Tairaku S, Morioka I, et al. Universal screening with use of
immunoglobulin G avidity for congenital cytomegalovirus infection. Clin
Infect Dis 2017;65(10):1652–1658. [II-3]
37. Kanengisser-Pines B, Hazan Y, Pines G, et al. High cytomegalovirus IgG
avidity is a reliable indicator of past infection in patients with positive IgM
detected during the first trimester of pregnancy. J Perinat Med 2009;37:15–
18. [II-3]
38. Leruez-Ville M, Sellier Y, Salomon LJ, et al. Prediction of fetal infection in cases
with cytomegalovirus immunoglobulin M in the first trimester of pregnancy:
a retrospective cohort. Clin Infect Dis 2013;56(10):1428–1435. [II-2]
39. Simonazzi G, Guerra B, Bonasoni P, et al. Fetal cerebral periventricular halo
at midgestation: an ultrasound finding suggestive of fetal cytomegalovirus
infection. Am J Obstet Gynecol.2010;202:599.e1–599.e5. [II-3]
40. Khalil A, Sotiriadis A, Chaoui R, et al. ISUOG Practice Guidelines:
role of ultrasound in congenital infection. Ultrasound Obstet Gynecol
2020;56:128–151. [III]
41. Leruez-Ville M, Ren S, Magny JF, et al. Accuracy of prenatal ultrasound
screening to identify fetuses infected by cytomegalovirus who will
510
develop severe long-term sequelae. Ultrasound Obstet Gynecol 2021;57(1):
97-104. [II-2]
42. Buca D, Di Mascio D, Rizzo G, et al. Outcome of fetuses with congeni-
tal cytomegalovirus infection: A systematic review and meta-analysis.
Ultrasound Obstet Gynecol 2020. doi: 10.1002/uog.23143. Online ahead of
print. [Systematic review, 26 studies, n = 2603]
43. Lazzarotto T, Guerra B, Lanari M, et al. New advances in the diagnosis
of congenital cytomegalovirus infection. J Clin Virol 2008;41(3):192–197.
[Review]
44. Enders M, Daiminger A, Exler S, et al. Prenatal diagnosis of congenital
cytomegalovirus infection in 115 cases: a 5 years’ single center experience.
Prenat Diagn 2017;37:389–398. [II-2]
45. Enders M, Daiminger A, Exler S, et al. Amniocentesis for prenatal diagnosis
of cytomegalovirus infection: challenging the 21 weeks’ threshold. Prenat
Diagn 2017;37(9):940–942. [II-2]
46. Revello MG, Furione M, Zavattoni M, et al. Human cytomegalovirus
(HCMV) DNAemia in the mother at amniocentesis as a risk factor for iatro-
genic HCMV infection of the fetus. J Infect Dis 2008;197:593–596. [II-3]
47. Bilavsky E, Pardo J, Attias J, et al. Clinical implications for children born
with a congenital cytomegalovirus infection following a negative amnio-
centesis. Clin Infect Dis 2016;63(1):33–38. [II-2]
48. Nigro G, Adler SP, La Torre R, et al. Passive immunization during pregnancy
for Congenital CMV infection. N Engl J Med 2005;353:1350–1362. [II-1]
49. Nigro G, La Torre R, Pentimalli H, et al. Regression of fetal cerebral abnor-
malities by primary cytomegalovirus infection following hyperimmuno-
globulin therapy. Prenat Diagn 2008;28:512–517. [II-3]
50. Moxley K, Knudson EJ. Resolution of hydrops secondary to cytomegalovi-
rus after maternal and fetal treatment with human cytomegalovirus hyper-
immune globulin. Obstet Gynecol 2008;111:524–526. [Case report; III]
Maternal-Fetal Evidence Based Guidelines
51. Revello MG, Lazzarotto T, Guerra B, et al. A randomized trial of hyper-
immune globulin to prevent congenital cytomegalovirus. N Engl J Med
2014;370: 1316–1326. [I, RCT, n = 124]
52. Hughes BL. A randomized trial to prevent congenital CMV. ID Week;2020,
October 21–25, 2019, Philadelphia, PA.
53. Kagan KO, Enders M, Schampera MS, et al. Prevention of maternal-fetal
transmission of cytomegalovirus after primary maternal infection in
the first trimester by biweekly hyperimmunoglobulin administration.
Ultrasound Obstet Gynecol 2019;53:383–389. [II-1, n = 40]
54. Adler SP, Nigro G, Pereira L. Recent advances in the prevention and
treatment of congenital cytomegalovirus infections. Semin Perinatol
2007;31(1):10–18. [Review]
55. Kimberlin DW, Lin C-Y, Sanchez PJ, et al. Effect of ganciclovir therapy
on hearing in symptomatic congenital cytomegalovirus disease involv-
ing the central nervous system: a randomized, controlled trial. J Pediatr
2003;143:16–25. [I, RCT, n = 42]
56. Jacquemard F, Yamamoto M, Costa J-M, et al. Maternal administration of
valacyclovir in symptomatic intrauterine cytomegalovirus infection. BJOG
2007;114:1113–1121. [II-2]
57. Kimberlin DW, Jester PM, Sanchez PJ, et al. Valganciclovir for symptomatic
congenital cytomegalovirus disease. N Engl J Med 2015;372: 933–943. [I,
RCT, n = 96]
58. Shahar-Nissan K, Pardo J, Peled O, et al. Valacyclovir to prevent vertical
transmission of cytomegalovirus after maternal primary infection during
pregnancy: a randomized, double-blind, placebo-controlled trial. Lancet
2020;396:779–785. [I, RCT, n = 100]
59. Leruez-Ville M, Ghout I, Bussières L, et al. In utero treatment of congenital
cytomegalovirus infection with valacyclovir in a multicenter, open-label,
phase II study. Am J Obstet Gynecol 2016;215:462.e1–10. [II-1; n = 41]
50
TOXOPLASMOSIS
Corina N. Schoen and Elizabeth A. Morgan

Key points The incidence of congenital infection is approximately 1.5 cases

per 1000 live births worldwide, 0.5–1.5 per 1000 live births in
• Maternal infection starts with ingestion of cysts from France/Europe [5, 6], and 0.7 per 1000 live births in the United
uncooked/undercooked meat of infected animals States [6, 7].
or contact with oocysts from infected cats or feces-
contaminated soil, vegetables, fruit and water.
• Fetal/neonatal disease is more severe if maternal infec-
Symptoms
tion occurs in the first trimester; the incidence of Maternal symptoms are infrequent (10–30%), and most com-
maternal-fetal transmission is directly proportional to monly consist of head and neck lymphadenopathy, mild flu-like
gestational age (lower in the first trimester, higher in the illness, and rash. Rarely, pregnant women will present with visual
third trimester). changes due to chorioretinitis from recently acquired infection or
• Prevention through maternal education to avoid expo- reactivation of chronic infection [8, 9].
sures has been shown to decrease the incidence of the
disease and remains the most important intervention.
• Prenatal and/or neonatal screening is controversial and Pathophysiology
is not adopted in most countries because of low incidence,
Cats and other felines are the natural reservoirs of T. gondii
concerns with poor/difficult diagnosis, availability of diag-
(supporting both sexual and asexual reproduction), though any
nostic and therapeutic services, population compliance,
mammal can serve as an intermediate host. The parasite can
and risk of terminating pregnancies based on false-positive
exist as a(n):
results.
• The principle method used to diagnose and evaluate tim-
1. Trophozoite (invasive form)
ing of congenital infection is based on detection of spe-
2. Cyst (latent form)
cific antibodies and by monitoring the immune response.
3. Oocyst (fecal contaminant)
Definitive diagnosis of maternal infection through
serologic testing should be performed by a reference
Sexual reproduction occurs in the small intestine of felines that
laboratory. Fetal congenital infection is diagnosed by
have eaten tissue cysts containing T. gondii. Cats are only infec-
amniotic fluid (AF) polymerase chain reaction (PCR).
tious during this first exposure, as these oocysts are produced
• Correct interpretation of serologic testing carried out
for two weeks and contain infectious sporozoites. Oocysts can
in a reference laboratory decreases unnecessary anxiety
remain infectious for years in soil.
and even terminations.
Human infection starts with ingestion of cysts from
• Historically, if maternal infection was confirmed by a ref-
uncooked/undercooked meat of infected animals (e.g., pork,
erence laboratory, spiramycin prophylaxis 3–4 g/day was
lamb and mutton) or contact with oocysts from infected cats
started, and if fetal infection was diagnosed through posi-
or feces-contaminated soil, unwashed vegetables and fruit,
tive AF PCR, therapeutic sulfadiazine, pyrimethamine, and
and water. The average incubation period is 7 days [4–18]. Very
folinic acid was initiated. Newer data now favors treatment
few cases of congenital toxoplasmosis transmitted by moth-
with pyrimethamine + sulfadiazine for all cases, after
ers who were infected prior to conception have been reported;
the first trimester, to prevent transmission and congenital
they can be attributed to either reinfection with a different strain
infection.
or to reactivation of chronic disease. This reactivation is rare
but can occur especially in an immunocompromised woman.
Pathogen Immunocompetent women with prior toxoplasmosis can be reas-
sured that the risks to the subsequent fetus/neonate are exceed-
Toxoplasma gondii (T. gondii) is an obligate intracellular proto- ingly rare, especially >9 months after infection [4].
zoan (parasite).
Maternal-fetal transmission
Incidence/Epidemiology
The vertical transmission rate after primary maternal T. gondii
The incidence of primary acute maternal infection is 0.01% to infection ranges from approximately 20–50%, and is highly
0.1% in the United States and United Kingdom. The prevalence dependent on gestational age, with transmission rates up to 65%
of past infection is approximately 22% in the United States [1, 2], in the third trimester (Table 50.1 and Figure 50.1) [4, 10, 11]. One
as high as 44% in France/Europe [3], 50–70% in Latin American meta-analysis based on 20 cohorts worldwide reported trans-
countries, and 5–35% in Asia, China, and Korea. Primary infec- mission rates of approximately 20% [11]. However, this analy-
tion induces lifelong immunity [4]. sis did not include the many European cohorts which had been

DOI: 10.1201/9781003099062-50 511

512
TABLE 50.1: Likelihood of Congenital Infection by Timing
of Maternal Infection
Probability of Congenital
Maternal Infection Infection (%)
Preconceptiona 1
First trimester 10–25
Second trimester 30–54
Third trimester 60–65
Source: From Ref. [4], with permission.
a Usually within nine months of conception.
included in another individual patient data meta-analysis by the
SYROCOT study group. That analysis reported much higher
transmission rates ranging from 16–52% [10].
Of congenitally infected fetuses who are PCR positive by
amniocentesis, 74–81% manifest only subclinical infection, while
up to 19–26% develop fetal/childhood illness even if treated [10,
12]. However, newer data from a large Austrian Register show
rates <10% depending on treatment protocol [13]. Overall, con-
genital toxoplasmosis affects about 7% of the offspring of women
who develop primary infection during pregnancy. Fetal/neona-
tal transmission is inversely proportional to time of primary
infection. Disease is less common but more severe if mater-
nal infection occurs in the first trimester, and more common
but less severe if maternal infection occurs in the third trimester.
Congenital infection is rare if primary maternal infection occurs
at less than 4 weeks’ gestational age (less than 1/1000 risk) [4].
Complications
Fetal/neonatal complications are present in 36% of cases in one
series, and include ventriculomegaly, increased placental thick-
ness, hepatomegaly, ascites, intracranial calcifications, hydro-
cephalus, microcephaly, and hepatosplenomegaly [14]. Neonatal
congenital toxoplasmosis infection is associated with neonatal
chorioretinitis (the most prevalent consequence of T. gondii)
[12], occasional subsequent blindness, deafness, decreased IQ,
seizure disorders, and delay in neuropsychomotor development
[4]. Neurological outcomes are variable and not necessarily
Primary Maternal Infection
Amniotic fluid PCR
after 18 weeks
Negative fetal infection Positive fetal infection
(20–50%)
74–81%
No sequelae
FIGURE 50.1 Natural history of toxoplasmosis in pregnancy.
Maternal-Fetal Evidence Based Guidelines
TABLE 50.2: Prevention of Congenital Toxoplasmosis
• Avoid raw or undercooked meat or eggs or any origin
• Use gloves when in contact with soil
• Wash fruits and vegetables before eating
• Avoid changing cat litter. Wash hands after handling cats/litter
• Keep pet cats indoors and use commercial pet food
proportional to intracranial findings. One small retrospective
study reported that neurologic prognosis may be more favorable,
even in the presence of intracranial lesions, if ventriculomegaly
was not present [15].
Congenital infection may also be associated with an increased
risk of adverse pregnancy outcomes including preterm birth
(PTB) (OR 3.49, 95% CI 1.91–6.37), abortion (OR 6.63, 95% CI
4.56–9.65), stillbirth (OR 4.63, 95% CI 2.72–7.90), and fetal
growth restriction (FGR) (OR 4.49, 95% CI 2.10–9.57) compared
to uninfected controls. Neonatal death is rare [11].
Pregnancy management
Principles
Counseling regarding basic pathophysiology, maternal-fetal
transmission, complications, and preventive/therapeutic man-
agement should be done. Termination can be offered, especially if
the fetus is definitively positive (PCR-positive AF) and the infec-
tion occurred in the first trimester (carrying a worse prognosis).
Prevention
Prevention has been shown to decrease the incidence of
the disease and remains the most important intervention
(Table 50.2). While many U.S. obstetricians adequately counsel
patients on avoidance of cat litter, less information is provided
on avoidance of raw or undercooked meat, gardening, and wash-
ing fruits and vegetables [16]. Prenatal education can effectively
change pregnant women’s behavior as it increases pet, personal,
and food hygiene [17]. Observational studies suggest prenatal
education may have a positive effect on the congenital toxoplas-
mosis rate, but there is limited evidence from RCTs supporting
this [18].
Start spiramycin
(can consider sulfadiazine and
pyrimethamine based on RCT data)
Stop spiramycin
Start:
• Sulfadiazine
• Pyrimethamine
• Folinic acid
19–26%
Neonatal and long-term
complications
Toxoplasmosis
Screening
Serum
Routine toxoplasmosis screening programs for pregnant women
have been established in some European countries with a high
disease prevalence, such as France and Austria. In the United
Kingdom and the United States prenatal or neonatal screen-
ing for T. gondii is not formally recommended, though this
remains controversial [9, 19]. Prenatal maternal screening has
not been recommended in the United States because of low inci-
dence, concerns with poor/difficult diagnosis, availability of diag-
nostic and therapeutic services, population compliance, and high
risk of false positive results. In places where prenatal screening is
recommended, it is started preconception or in the first trimester,
and is repeated every month, bimonthly, or each trimester in all
IgG-negative mothers (Figure 50.2) [13, 20].
Neonatal screening in the United States would detect about one
positive neonate for every 12,000 screened mothers. The infected
woman could receive treatment that may prevent severe sequelae,
but this would probably not be cost-effective. In a decision anal-
ysis applying the French prenatal screening protocol to a U.S.
population, monthly maternal screening was predicted to have a
cost-savings of $620 per child screened. Although accounting for
low prevalence of maternal toxoplasmosis in the United States,
the study did not account for a high false-positive antibody screen
likely to be encountered in this population [21]. Further study
should be performed before clinical guidelines on screening are
changed from the current recommendations against screening, at
least in the United States.
Ultrasound
Screening based on ultrasound findings associated with congeni-
tal toxoplasmosis is currently performed. Findings can include
intracranial calcifications, microcephaly, ventricular dilatation
and hydrocephalus, ascites, hepatosplenomegaly, and increased
placental thickness [22]. While T. gondii has been associated with
Check for previous test results
Positive prior to Never tests or
pregnancy known negative
No further screening Initial screen
Positive Negative
Serology to reference Store serum
center for confirmation (at least until delivery)
and evaluation of primary
infection
Repeat screening every
trimester
FIGURE 50.2 Laboratory diagnosis of congenital toxoplasmo-
sis. (From Ref. [4], with permission.)
513
FGR, the Society for Maternal-Fetal Medicine currently recom-
mends against serologic screening when there are no other risk
factors or findings [23].
Workup/Diagnosis
The principle method used to diagnose and evaluate the tim-
ing of congenital infection is based on detection of specific
antibodies and monitoring the immune response (Figure
50.2). IgG antibodies usually appear within 2 weeks of infection
and persist in the body indefinitely. IgM antibodies are consid-
ered a sign of recent infection and can be detected by enzyme
immunoassays (EIAs) or an immunosorbent agglutination assay
test (IAAT) within 2 weeks of infection. They often remain posi-
tive for 1–2 years. A positive IgM antibody test result at any
time does not necessarily mean the infection was acquired
recently; this needs to be confirmed at a reference laboratory.
Only 22–40% of positive IgM results obtained at non-reference
laboratories in the United States are deemed to have had a recent
acute infection [8, 24]. IgA antibodies may also persist for more
than one year and their detection is informative mainly for the
diagnosis of congenital toxoplasmosis. IgE antibodies increase
rapidly and remain detectable for less than 4 months after infec-
tion, which is a very short time to use them for a diagnostic test.
The Sabin–Feldman dye test (SFDT) is still considered the
“gold standard” for maternal infection [4]. It detects the pres-
ence of anti-Toxoplasma-specific antibodies (total Ig). The abso-
lute antibody titer is also important: values over 250 IU/mL
are considered highly suggestive of recent infection. IgG avid-
ity testing is based on the increase in functional affinity (avid-
ity) between Toxoplasma-specific IgG and antigen over time, as
the host immune response evolves. Pregnant women with high
avidity antibodies are those who have been infected at least 3–5
months earlier [25]. In a prospective cohort of 139 women, an
avidity index above 30% was not associated with any positive AF
testing or congenital infection [26]. Current testing cannot define
which specific strain of T. gondii caused the antibody response,
so that reinfection with the same or different strains cannot be
determined.
Maternal infection is diagnosed by sending maternal
serology to a reference laboratory (in the United States: Jack
Remington, Palo Alto: 650-853-4828; FAX 650-614-3292; http://
www.pamf.org/serology/clinicianguide.html). It is best to make
the diagnosis based on two different serum specimens collected
at least 4 weeks apart. Usually, the reference laboratory reports
many serologic results, with a high possibility of infection if
there is:
• Seroconversion during pregnancy;
• Increase in both specific IgG titer (>3-fold) and dye test
titer (>3-fold); or
• Presence of specific IgM and dye test ≥300 IU/mL.
Correct interpretation of serologic testing done in a refer-
ence laboratory decreases unnecessary anxiety and even ter-
minations [27].
Fetal congenital infection is diagnosed by AF PCR. The spec-
ificity and positive predictive value on AF samples are close to
100%. Sensitivity is around 70–80%, but is best when maternal
infection occurs between 17 and 21 weeks of pregnancy. Real-
time PCR appears to have a sensitivity of 92%, negative predic-
tive value of 98%, and may not be as gestational-age dependent
as conventional PCR [28]. Due to varying sensitivity and time
514
for transplacental passage, it is recommended amniocentesis
for fetal diagnosis be performed after 18 weeks, and no sooner
than 4 weeks after primary maternal infection [20]. A negative
AF PCR does not always completely rule out congenital infection.
Ultrasound can also aid in diagnosis of fetal infection (see section
Complications), but it has very poor sensitivity and specificity.
Therapy
If maternal infection is detected, patients should be counseled
regarding the risk of transmission, treatment, and the possibility
of termination (especially in the first trimester).
If maternal infection is confirmed by a reference laboratory,
spiramycin can be initiated at a dose of 3–4 g/day (1 g every
8 hours). This is available in the United States only through the
Food and Drug Administration (FDA) when Palo Alto serology
is positive. Spiramycin concentrates in the placenta, which may
help protect against vertical transmission, but may not be reliable
for treatment of congenital infection itself [8, 20].
If AF PCR is positive, representing congenital infection,
treatment should include sulfadiazine (initial dose of 75 mg/kg,
followed by 50 mg/kg every 12 hours with a maximum of 4 g/day)
and pyrimethamine (50 mg every 12 hours for 2 days followed
by 50 mg daily). Folinic acid or leucovorin (10–20 mg with each
dose of pyrimethamine) is given 1 week after completion of pyri-
methamine therapy to reduce bone marrow toxicity [8]. Length
of therapy is controversial and has varied from a minimum of 28
days (with ½ dose until term) to continuing therapy at full dose
until term. Treatment with pyrimethamine and sulfadiazine to
prevent fetal infection is contraindicated during the first trimes-
ter (pyrimethamine is teratogenic), but at this time sulfadiazine
can be used alone [29, 30]. Some experts recommend blood cell
count every 1–2 weeks during treatment to monitor for neutro-
penia (neutrophil count <1500/mm3) [20]. This treatment should
be stopped in the last few weeks of pregnancy. This is the basic
treatment protocol recommended by the WHO and CDC [4].
Other drugs such as spiramycin (3–4 g/day × 3–4 weeks) are rec-
ommended in certain circumstances. Until recently, treatment
with sulfadiazine-pyrimethamine was not shown to be superior
to spiramycin alone for treatment of congenital T. gondii. More
contemporary data from a recent RCT now favors treatment
with pyrimethamine + sulfadiazine, especially when started
expeditiously; however, larger studies are still needed [31]. Mode
of delivery should not be influenced by maternal infection, as
cesarean delivery does not reduce the risk of congenital infec-
tion [32].
Treatment decreases complications of T. gondii, but possibly
not fetal infection. In a meta-analysis of 7055 women with toxo-
plasmosis acquired during pregnancy, the pooled rate of con-
genital T. gondii who received treatment was 16%. The rate of
vertical transmission was similar for both spiramycin-only and
spiramycin + sulfadiazine regimens (13%) [11]. It is estimated
that for every three congenitally infected fetuses that are treated,
one case of serious neurological sequela is prevented [33]. In one
study, fetuses/neonates treated and subsequently followed for
12–250 months had a 17% rate of congenital Toxoplasma, with
74% of the children asymptomatic, 26% developing chorioretinitis
(72% peripheral and unilateral), and all except one child having
age-appropriate neurological and intellectual development [12].
In another prospective trial following treated children for a
median of 10.5 years, while 30% had at least one ocular lesion,
most lesions caused little or no visual impairment [34]. Other
long-term follow up of ante- and post-natally treated individuals
Maternal-Fetal Evidence Based Guidelines
suggests that in most cases congenital Toxoplasma may actu-
ally have little effect on overall quality of life and visual func-
tion [35]. Recently, a large Austrian cohort looked retrospectively
over a 17-year time period at the impact of maternal treatment
on vertical transmission and congenital infection. They found a
6-fold decrease in transmission rate when using their treatment
protocol even with a treatment delay of up to 4 weeks. The num-
ber needed to treat (NNT) to prevent one infected infant was only
two in their cohort [13].
Despite these encouraging findings, well-designed randomized
controlled trials are still needed to elucidate the best treatment
regimen and duration in affected pregnancies, optimally consid-
ering gestational age at seroconversion.
References
1. Jones JL, Kruszon-Moran D, Sanders-Lewis K, Wilson M. Toxoplasma gon-
dii infection in the United States, 1999 2004, decline from the prior decade.
Am J Trop Med Hyg 2007;77(3):405–10. [III]
2. Center for Disease Control and Prevention. Parasites – Toxoplasmosis.
Cited 2021. Available from: http://www.cdc.gov/parasites/toxoplasmosis.
[Epidemiological data, III]
3. Berger F, Goulet V, Le Strat Y, Desenclos JC. Toxoplasmosis among preg-
nant women in France: risk factors and change of prevalence between 1995
and 2003. Rev Epidemiol Sante Publique 2009;57(4):241–8. [III]
4. Rorman E, Zamir CS, Rilkis I, Ben-David H. Congenital toxoplasmo-
sis–prenatal aspects of Toxoplasma gondii infection. Reprod Toxicol
2006;21(4):458–72. Review, III]
5. Villena I, Ancelle T, Delmas C, Garcia P, Brezin AP, Thulliez P, et al.
Congenital toxoplasmosis in France in 2007: first results from a national
surveillance system. Euro Surveill 2010;15(25). [III]
6. Torgerson PR, Mastroiacovo P. The global burden of congenital toxoplas-
mosis: a systematic review. Bull World Health Organ 2013;91(7):501–8.
[Epidemiological report, III]
7. Feldman DM, Keller R, Borgida AF. Toxoplasmosis, parvovirus, and cyto-
megalovirus in pregnancy. Clin Lab Med 2016;36(2):407–19. [Review, III]
8. Montoya JG, Remington JS. Management of Toxoplasma gondii infection
during pregnancy. Clin Infect Dis 2008;47(4):554–66. [Review, III]
9. Practice Bulletin No. 151: Cytomegalovirus, parvovirus B19, varicella zos-
ter, and toxoplasmosis in pregnancy. Obstet Gynecol 2015;125(6):1510–25.
[Review, III]
10. Thiébaut R, Leproust S, Chêne G, Gilbert R, group SSRoCTs. Effectiveness
of prenatal treatment for congenital toxoplasmosis: a meta-analysis of indi-
vidual patients’ data. Lancet 2007;369(9556):115–22. [Meta-analysis: no
RCTs, 26 cohorts, n = 691 infected liveborn infants]
11. Li XL, Wei HX, Zhang H, Peng HJ, Lindsay DS. A meta-analysis on risks of adverse
pregnancy outcomes in Toxoplasma gondii infection. PLOS ONE 2014;9(5):e97775.
[Meta-analysis, no RCT, 53 case-control and cohort studies, II-2]
12. Berrébi A, Assouline C, Bessières MH, Lathière M, Cassaing S, Minville V,
et al. Long-term outcome of children with congenital toxoplasmosis. Am J
Obstet Gynecol 2010;203(6):552.e1–6. [II-2]
13. Prusa AR, Kasper DC, Pollak A, Gleiss A, Waldhoer T, Hayde M.
The Austrian Toxoplasmosis Register, 1992–2008. Clin Infect Dis
2015;60(2):e4–e10. [II-2]
14. Hohlfeld P, MacAleese J, Capella-Pavlovski M, Giovangrandi Y, Thulliez P,
Forestier F, et al. Fetal toxoplasmosis: ultrasonographic signs. Ultrasound
Obstet Gynecol 1991;1(4):241–4. [III]
15. Dhombres F, Friszer S, Maurice P, Gonzales M, Kieffer F, Garel C, et al.
Prognosis of fetal parenchymal cerebral lesions without ventriculomegaly
in congenital toxoplasmosis infection. Fetal Diagn Ther 2017;41(1):8–14.
[III]
16. Jones JL, Krueger A, Schulkin J, Schantz PM. Toxoplasmosis prevention
and testing in pregnancy, survey of obstetrician-gynaecologists. Zoonoses
Public Health 2010;57(1):27–33. [III]
17. Carter AO, Gelmon SB, Wells GA, Toepell AP. The effectiveness of a prena-
tal education programme for the prevention of congenital toxoplasmosis.
Epidemiol Infect 1989;103(3):539–45. [Cluster RCT, n = 432]
18. Di Mario S, Basevi V, Gagliotti C, Spettoli D, Gori G, D’Amico R, et al.
Prenatal education for congenital toxoplasmosis. Cochrane Database Syst
Rev 2015(10):CD006171. [Meta-analysis, two cluster RCTs, n = 5455]
19. Neto EC, Rubin R, Schulte J, Giugliani R. Newborn screening for congenital
infectious diseases. Emerg Infect Dis 2004;10(6):1068–73. [II-3]
Toxoplasmosis
20. Peyron F, L’ollivier C, Mandelbrot L, Wallon M, Piarroux R, Kieffer F,
et al. Maternal and congenital toxoplasmosis: diagnosis and treatment
recommendations of a French multidisciplinary working group. Pathogens
2019;8(1). [III]
21. Stillwaggon E, Carrier CS, Sautter M, McLeod R. Maternal serologic
screening to prevent congenital toxoplasmosis: a decision-analytic eco-
nomic model. PLoS Negl Trop Dis 2011;5(9):e1333. [Decision-analysis, III]
22. El Ayoubi M, de Bethmann O, Monset-Couchard M. Lenticulostriate echo-
genic vessels: clinical and sonographic study of 70 neonatal cases. Pediatr
Radiol 2003;33(10):697–703. [II-3]
23. Society for Maternal-Fetal Medicine (SMFM), Martins JG, Biggio JR,
Abuhamad A. Society for Maternal-Fetal Medicine Consult Series #52:
diagnosis and management of fetal growth restriction: (Replaces Clinical
Guideline Number 3, April 2012). Am J Obstet Gynecol 2020;223(4):
B2–B17. [Review, III]
24. Dhakal R, Gajurel K, Pomares C, Talucod J, Press CJ, Montoya JG.
Significance of a positive toxoplasma immunoglobulin M test result in the
United States. J Clin Microbiol 2015;53(11):3601–5. [III]
25. Montoya JG, Liesenfeld O, Kinney S, Press C, Remington JS. VIDAS test for
avidity of Toxoplasma-specific immunoglobulin G for confirmatory testing
of pregnant women. J Clin Microbiol 2002;40(7):2504–8. [II-3]
26. Tanimura K, Nishikawa A, Tairaku S, Shinozaki N, Deguchi M, Morizane
M, et al. The IgG avidity value for the prediction of Toxoplasma gondii
infection in the amniotic fluid. J Infect Chemother 2015;21(9):668–71. [III]
27. Liesenfeld O, Montoya JG, Tathineni NJ, Davis M, Brown BW, Cobb KL,
et al. Confirmatory serologic testing for acute toxoplasmosis and rate of
induced abortions among women reported to have positive Toxoplasma
515
immunoglobulin M antibody titers. Am J Obstet Gynecol 2001;184(2):
140–5. [II-2]
28. Wallon M, Franck J, Thulliez P, Huissoud C, Peyron F, Garcia-Meric P, et al.
Accuracy of real-time polymerase chain reaction for Toxoplasma gondii in
amniotic fluid. Obstet Gynecol 2010;115(4):727–33. [III]
29. WHO Model Prescribing Information. Drugs Used in Parasitic Diseases.
2nd ed. Geneva: World Health Organization; 1995. [Review, III]
30. Chin J. Toxoplasmosis. In: Control of Communicable Disease Manual. 17th
ed. Washington, DC: American Public Health Association. 500–3. [Review,
III]
31. Mandelbrot L, Kieffer F, Sitta R, Laurichesse-Delmas H, Winer N, Mesnard
L, et al. Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin
to reduce placental transmission of toxoplasmosis: a multicenter, random-
ized trial. Am J Obstet Gynecol 2018;219(4):386.e1–.e9. [I]
32. Wallon M, Kieffer F, Huissoud C, Peyron F. Cesarean delivery or induction
of labor does not prevent vertical transmission of toxoplasmosis in late
pregnancy. Int J Gynaecol Obstet 2015;129(2):176–7. [III]
33. Cortina-Borja M, Tan HK, Wallon M, Paul M, Prusa A, Buffolano W, et al.
Prenatal treatment for serious neurological sequelae of congenital toxoplas-
mosis: an observational prospective cohort study. PLOS Med 2010;7(10). [II-3]
34. Wallon M, Garweg JG, Abrahamowicz M, Cornu C, Vinault S, Quantin C,
et al. Ophthalmic outcomes of congenital toxoplasmosis followed until ado-
lescence. Pediatrics 2014;133(3):e601–8. [II-3]
35. Peyron F, Garweg JG, Wallon M, Descloux E, Rolland M, Barth J. Long-term
impact of treated congenital toxoplasmosis on quality of life and visual per-
formance. Pediatr Infect Dis J 2011;30(7):597–600. [III]
51
PARVOVIRUS
Timothy J. Rafael
Key points
• The incidence of acute primary maternal parvovirus
B19 infection during pregnancy is about 1–2%.
• The major means of infection is by contact with young
infected children. The infection is usually asymptomatic
in the adult (and pregnant woman).
• About 25–30% of fetuses of mothers with primary par-
vovirus B19 infection become infected themselves by
vertical transmission.
• Perinatal complications of fetal infection occur in about
10% of fetuses, and include fetal anemia and myocarditis,
leading to hydrops (2–6%), and occasionally fetal death if
infection occurs <20 weeks.
• Screening is not recommended, since 1/5000 screened
women would be at risk for fetal hydrops from parvovirus
B19.
• Maternal infection is usually diagnosed by IgM+ or by
IgG seroconversion.
• Fetal ultrasound can screen for development of ane-
mia and/or hydropic changes in the infected mother by
increased peak systolic velocity (PSV) of the middle cere-
bral artery (MCA) using a threshold of ≥1.50 multiples of
the median (MoM). If MCA PSV values are <1.50 MoM,
it is suggested to continue weekly ultrasound scans for
10–12 weeks after the exposure.
• If MCA PSV is ≥1.50 or fetal hydrops is seen on ultra-
sound, fetal transfusion is indicated, since the incidence
of spontaneous resolution of hydrops is only about 5%, and
survival with transfusion is 70–75%.
• In cases of fetuses transfused in utero for parvovirus B19-
induced hydrops, there are differing data regarding long-
term outcomes among survivors. There does not appear to
be an increased risk of infant or childhood morbidity and
mortality following parvovirus infection during pregnancy
in general. In cases of fetal anemia or hydrops undergoing
transfusion, however, there may be an increased risk of severe
neurodevelopmental delay. Patients need to be counseled
regarding the overall uncertainty regarding long-term
neurodevelopmental outcomes among survivors.
Pathogen
Human parvovirus B19 is a single-stranded DNA virus.
Parvovirus B19 is the only known parvovirus which is a human
pathogen.
Incidence/Epidemiology
The incidence of acute primary maternal parvovirus B19
infection during pregnancy in susceptible women is about 1–2%
[1, 2]. The parvovirus B19-specific immunoglobulin G (IgG)
516
seroconversion incidence in susceptible pregnant women (primary
infection) goes from 1% to 1.5% during an endemic, to 13% to
13.5% during epidemic periods [2]. Approximately 50–75% of
women of reproductive age are IgG+ (immune) for parvovirus
B19, with approximately 25–50% of women being susceptible to
parvovirus B19 infection during pregnancy [1].
Risk factors/Associations
The infection is more common in the winter and spring. The
risk of infection is associated with the level of contact with
young infected children. The highest infection rates occur in
schoolteachers, daycare workers, and women with nursery or
school-aged children in the home. Around 50–80% of suscep-
tible household members and 20–30% of individuals exposed
in a classroom acquire acute infection from an infected child.
Daycare workers also have a higher seroconversion rate com-
pared to the general population (RR 2.63) [3]. Adverse prognostic
factors are older maternal age, maternal immunity and serocon-
version, raised maternal serum alpha-fetoprotein (MSAFP), and
ultrasound findings.
Symptoms
In adults, at least half of the infections are asymptomatic [2].
About 30% may have flu-like symptoms, arthralgias, and adenop-
athy. Parvovirus B19 causes a common exanthematous disease in
children 5–14 years old, called fifth disease or erythema infec-
tiosum. Children have symptoms such as low-grade fever and a
“slapped-cheeks” rash, and are usually diagnosed just based on
these symptoms.
Pathophysiology
Parvovirus B19 is mainly transmitted by respiratory droplets. The
incubation period for erythema infectiosum is 13–18 days, and
infectivity is greatest 7–10 days before the onset of symptoms.
The major target cells for parvovirus B19 are erythroid progeni-
tors bearing the main cellular parvovirus B19 receptor P blood
group antigen globoside on their surface (Figure 51.1). The virus
is believed to cause arrest of maturation of red blood cell (RBC)
precursors at the late normoblast stage and causes a decrease in
the number of platelets. The virus causes infection and lysis of
erythroid progenitor cells by apoptosis, leading to hemolysis and
transient aplastic crisis. Subsequent fetal anemia is thought
to be responsible for the development of skin edema and effu-
sions. Hepatitis, placentitis, and myocarditis leading to heart
failure may contribute to the development of fetal hydrops
[2, 4, 5]. Parvovirus B19 has been demonstrated to carry an
apoptosis-inducing factor and to induce cell-cycle arrest. Cells in
the S-phase of DNA mitosis are particularly vulnerable to parvo-
virus B19, and the fetus is at risk because of the vast number of
DOI: 10.1201/9781003099062-51
Parvovirus
Transplacental transfer B19 virus
Infection of red cell precursors
Arrested red cell production
Severe anemia
Acute myocarditis in fetuses
Edema/Hydrops
FIGURE 51.1 Pathophysiology of parvovirus B19 fetal infection.
cells in active mitosis, shorter half-life of RBCs, and an immature
immune system.
Maternal-fetal transmission
About 25–30% of fetuses of mothers with primary parvovirus
B19 infection become infected themselves by vertical trans-
mission (Figure 51.2). The majority of infected fetuses have no
sequelae from this intrauterine infection [2]. Although it is not
easy to determine the exact timing of transmission of parvovirus
Maternal Primary Parvovirus Infection
(Incidence 1–2% if susceptible)
25–30%
Fetal Infection
~ 80–95% ~ 5–20%
No Sequelae Fetal Anemia
2–6% of all fetuses infected
1–4% of all mothers infected
Fetal Hydrops
1–6% of all fetuses/mothers infected
Fetal/Neonatal Death
(if infection < 20 weeks)
FIGURE 51.2 Natural history of parvovirus infection in
pregnancy.
517
B19 infection to the fetus, it is likely that parvovirus B19 infects
the fetus during or immediately after maternal viremia, even in
the early stages of gestation. Parvovirus B19 can persist until term
or after birth, even when infection occurs early in gestation.
Complications
Of the infected fetuses, about 5–20% can develop anemia, of
which 30–50% develop hydrops fetalis (about 2–6% of all infected
fetuses), with some series showing hydrops rates as high as 66% of
anemic fetuses (Figure 51.2) [6]. Overall the data suggest a rate of
1–4% for fetal hydrops in infected mothers [4], with rates as high as
8–10% with infections occurring between 9 and 20 weeks [7]. The
risk of fetal death is 1–6% of all infected fetuses [8]. Fetal death
occurs almost exclusively in hydropic cases diagnosed at <20 weeks
[9], especially if cases >20 weeks are treated with timely transfusion
(90% survival) [8]. Early embryonic/fetal death may manifest as mis-
carriage. A recent case-control study demonstrated an increased
association of first trimester miscarriage with positive parvovirus
IgM women (OR 1.71, 95% CI 1.02–2.86) [10]. Overall, for infected
mothers <20 weeks without therapy there is an approximate 10%
risk for fetal loss. Although acute parvovirus infection may occur
relatively commonly during pregnancy, an adverse fetal outcome is
an uncommon complication [5, 11, 12]. Various case reports have
reported congenital anomalies in confirmed cases of parvovirus
(e.g. hydrocephalus, microphthalmia, myocarditis, ventricular
septal defects, echogenic bowel, meconium peritonitis, cleft lip/
palate), but it is unclear if these malformations seen with parvovi-
rus are just coincidental, and not related to the viral infection [13].
Parvovirus B19 may be an important cause of fetal death, although
possibly not as prevalent as once thought when considering all
cases of stillbirth. A recent review of 66 infection-related stillbirths
identified parvovirus as a causative factor in two (3%) cases, both of
which involved non-immune hydrops [14]. Nevertheless, in cases
of fetal death, especially those associated with hydrops, there
should be consideration for testing for parvovirus B19 by poly-
merase chain reaction (PCR). Maternal serology might be a less
sensitive determinant for parvovirus B19-associated fetal death,
since immunoglobulin M (IgM) response generally lasts for 2–4
months, and parvovirus B19 infection can already be persistent in
fetuses during the early stages of pregnancy, eventually leading to
fetal death months later (see also Chapter 57). The more mature
immune response in older fetuses could delay any pathogenic con-
sequences of parvovirus B19 infection, resulting in a lower rate of
hydrops than in younger fetuses [15, 16].
Ultrasound fetal findings
Sonographically detectable markers of fetal compromise include
pericardial or pleural effusion, ascites, abdominal wall/skin
edema, bilateral hydroceles, oligohydramnios or hydramnios,
increased (>95th percentile) cardiac biventricular outer diameter,
and, rarely, hydrocephalus, microcephaly, and intracranial and
hepatic calcifications [4, 5].
Pregnancy management
Counseling/Prognosis
Counseling should include the natural history of the disease,
including vertical transmission, chances of fetal disease (anemia
and hydrops), prognosis, and possible interventions. The long-
term outcome of fetuses affected after 20 weeks is very good.
518
Prevention
Avoidance of contact with infected children—or, if possible, chil-
dren in general—is the best prevention. This is not always feasible.
No specific antiviral therapy or vaccine is available for parvovirus
B19 infection. Frequent hand washing is effective in preventing
disease transmission [2]. Intravenous immunoglobulin (IVIG)
prophylaxis is reasonable to consider for documented exposures
in immunocompromised patients, although it is not currently
recommended for prophylaxis in pregnancy.
Screening
Universal screening is not recommended, as the risk of fetal
hydrops from parvovirus infection is about 1/5000 screened
pregnancies, making screening not warranted. Screening may
be warranted in pregnant women who teach and/or take care of
young children, especially during epidemics [4].
Workup/Diagnosis
Workup includes determination of serum IgG and IgM. Maternal
infection is usually diagnosed by IgM+ or by IgG seroconver-
sion. IgM appears by 3 days of an acute infection, peaks at 25–30
days, and disappears by 4 months. Serum IgG appears a few days
after IgM, and coincides with resolution of maternal symptoms.
The detection of viral DNA by PCR is another means of diagnosis,
as there may be up to a 15% risk of false negative serologies [17]. In
cases where there remains a high suspicion of infection following
an exposure, there should be consideration to repeating negative
serologies, or performing PCR on amniotic fluid for viral DNA.
Electron microscopy (EM) is also possible, whereas virus culture
usually fails. Increased MSAFP has also been used as a prognostic
factor for poor outcome [18], although this has been questioned
in recent studies [6].
Once maternal infection has been diagnosed, fetal ultrasound
can screen for development of anemia and/or hydropic changes.
Anemia can be detected by increased PSV of the MCA prior to
the appearance of sonographically detectable markers of hydrops
[19]. This is based on the observation (first in rhesus immuniza-
tion, where the mechanism leading to anemia is different) that
with fetal anemia there is an increase of fetal cardiac output to
maintain adequate oxygen delivery to tissues, leading to increased
blood flow velocities also in anemic fetuses with hydrops from
parvovirus B19. MCA PSV using a threshold of ≥1.50 MoM has
a high sensitivity (100%) and specificity (100%) for detecting fetal
anemia [19]. If MCA PSV values are <1.50 MoM, it is suggested to
continue weekly ultrasound scans for 10–12 weeks after the
exposure [20] to follow those fetuses that potentially are at high
risk for anemia and hydrops (Figure 51.3). The peak incidence of
hydrops is at about 4–6 weeks after maternal infection. Fetal sur-
veillance should be initiated no later than 4 weeks after the onset
of illness or estimate of seroconversion [2]. In cases of elevated
MCA PSV but no hydrops, if umbilical cord sampling is not per-
formed, surveillance should be increased with ultrasound evalua-
tions 2–3 times per week to detect any sign of hydrops.
Fetal diagnosis is by amniotic fluid (AF) PCR+. There is
at present no need for percutaneous umbilical blood sampling
(PUBS) for diagnosis.
Therapy
There are no trials evaluating therapeutic interventions. No
antiviral therapy is available.
Treatment should be directed at fetuses with abnormal
MCA PSV and/or hydropic changes. In these fetuses, anemia
Maternal-Fetal Evidence Based Guidelines
Workup: Maternal IgG, IgM
IgM +
U/S MCA PSV q 1 week
≥1.50 MOM <1.50 MOM
PUBS ± transfusion Continue MCA PSV q 1 week x
10–12 weeks after exposure
FIGURE 51.3 Management of parvovirus infection in preg-
nancy. Abbreviations: MCA, middle cerebral artery; IgG, immu-
noglobulin G; IgM, immunoglobulin M; PSV, peak systolic
velocity; MoM, multiples of the median; PUBS, percutaneous
umbilical blood sampling.
and even hydrops can resolve spontaneously over 4–6 weeks,
with recent data suggesting spontaneous resolution of anemia
and hydrops of 49.6% and 5.2%, respectively [21]. Resolution is
more common in older (>20 weeks) fetuses because of a more
mature immune system. Intervention for anemic and/or hydropic
fetuses is gestational-age dependent:
• Between 24 and 33 6/7 weeks, steroids for fetal lung matu-
rity should be given. Fetal cordocentesis to document
anemia and transfusion as necessary improve outcome in
anemic and/or hydropic fetuses. Frequently, one transfu-
sion is sufficient [2, 6, 21]; among hydropic fetuses, up to
37% may require two or more transfusions [21].
• Before 24 weeks, with severe hydrops, termination may be
offered, but transfusion can be beneficial, with apparently
minimal to no significant sequelae if successful.
• After 34 weeks, delivery should be considered.
If cordocentesis is performed, anemia could be detected before
a critical decrease of hemoglobin of <6 g/dL and before the devel-
opment of severe hydrops. Blood sampling can allow testing for
fetal hemoglobin/hematocrit and leukocyte and platelet counts.
Once sonographic signs of hydrops are present, transfusion
is indicated using erythrocytes. Platelets should also be ready
at the time of PUBS, as multiple series have demonstrated a
concomitantly high incidence of fetal thrombocytopenia at
the time of transfusion [22–24]. An example of a step-by-step
guide for both the set up and performance of fetal blood trans-
fusion is described in Chapter 55 [20]. Several nonrandomized
but controlled studies suggest a significant benefit of transfusion
of fetuses with anemia and/or hydrops from parvovirus infec-
tion compared with conservative treatment [5, 8, 25]. In cases of
hydrops, while approximately 5% can resolve without treatment,
death may occur in a large proportion of untreated fetuses, com-
pared with a 70–75% survival rate with one or more transfusions
[21]. Intracardiac transfusion is a last resort alternative to intra-
umbilical cord transfusion, particularly when intraumbilical cord
Parvovirus
transfusion is not possible, because of risks of bradycardia and
cardiac arrest of this procedure [26, 27].
Neonate and long-term follow-up
Infants born to IgM+ mothers are born IgG+ (mostly mater-
nal), and 25% stay IgG+ at 1 year, as they were infected and
have become immune. Regarding overall long-term outcomes of
children born to women infected with parvovirus during preg-
nancy (measured by serum IgM), a large registry did not find an
increased risk of infant or childhood morbidity and mortality
[28]. While the general health status of survivors is no different
compared with the general population, there is conflicting evi-
dence regarding incidences of developmental delay. Some trials
illustrate an incidence of developmental delay similar to the gen-
eral population even in cases of fetuses transfused in utero for
parvovirus B19-induced hydrops [29, 30]. Updated data of trans-
fused survivors, aged 6 months to 8 years, demonstrated a 32%
incidence of psychomotor developmental delay, independent
of pretransfusion hemoglobin, platelet, or blood pH values [31].
In a recent systematic review, fetal hydrops was associated with
a 9.5% risk of abnormal neurodevelopmental outcome, compared
to a 0% risk among those not affected by hydrops [21]. Patients
need to be counseled regarding the overall uncertainty
regarding long-term neurodevelopmental outcome among
survivors, especially when the pregnancy is complicated by
hydrops. Two phases of the infantile infection are described:
A first phase of viremia of 2–3 days, accompanied by fever and
myalgia; a second phase that can last several weeks, with derma-
tological signs such as erythema infectiosum, vasculitis, arthral-
gias, or arthritis.
References
1. Mossong J, Hens N, Friederichs V, et al. Parvovirus B19 infection in five
European countries: seroepidemiology, force of infection and maternal risk
of infection. Epidemiol Infect 2008;136:1059–1068. [II-3]
2. Lamont RF, Sobel JD, Vaisbuch E, et al. Parvovirus B19 infection in human
pregnancy. BJOG 2011;118:175–186. [III]
3. Romero Starke K, Kofahl M, Freiberg A, et al. Are daycare workers at a
higher risk of parvovirus B19 infection? A systematic review and meta-
analysis. Int J Environ Res Public Health 2019;16:1392. [Systematic Review,
n = 2276]
4. Van Gessel PH, Gayvant MA, Vossen ACTM, et al. Incidence of parvovi-
rus B19 infection among an unselected population of pregnant women in
the Netherlands: a prospective study. Eur J Obstet Gynecol Reprod Biol
2006;128:46–49. [II-3]
5. Von Kaisenberg CS, Jonat W. Fetal parvovirus B19. Ultrasound Obstet
Gynecol 2001;18:280–288. [II-3]
6. Simms RA, Liebling RE, Patel RR, et al. Management and outcome of preg-
nancies with parvovirus B19 infection over seven years in a tertiary fetal
medicine unit. Fetal Diagn Ther 2009;25:373–378. [II-3]
7. Enders M, Klingel K, Weidner A, et al. Risk of fetal hydrops and non-
hydropic late intrauterine fetal death after gestational parvovirus B19 infec-
tion. J Clin Virol 2010;49:163-168. [II-3]
8. Enders M, Weidner A, Zoellner I, et al. Fetal morbidity and mortality after
acute human parvovirus B19 infection in pregnancy: prospective evalua-
tion of 108 cases. Prenatal Diagn 2004;24:513–518. [II-2]
519
9. Puccetti C, Contoli M, Bonvicini F, et al. Parvovirus B19 in pregnancy:
possible consequences of vertical transmission. Prenatal Diagn 2012;32:
897–902. [II-3]
10. Lassen J, Jensen AKV, Bager P, et al. Parvovirus B19 infection in the first tri-
mester of pregnancy and risk of fetal loss: a population-based case-control
study. Am J Epidemiol 2012;176(9):803–807. [II-2]
11. Sarfraz AA, Samuelsen SO, Bruu AL, et al. Maternal human parvovirus
B19 infection and the risk of fetal death and low birthweight: a case-control
study within 35,940 pregnant women. BJOG 2009;116:1492–1498. [II-2]
12. Riipinen A, Väisänen E, Nuutila M, et al. Parvovirus B19 infection in fetal
deaths. Clin Infect Dis 2008;47:1519–1525. [II-2]
13. Ornoy A, Ergaz Z. Parvovirus B19 infection during pregnancy and risks to
the fetus. Birth Defects Research 2017;109:311–323. [III]
14. Page JM, Bardsley T, Thorsten V, et al. Stillbirth associated with infection in
a diverse U.S. cohort. Obstet Gynecol 2019;134(6):1187–1196. [II-3]
15. Tolfvenstam T, Papadogiannakis N, Norbeck O, et al. Frequency of human
parvovirus B19 infection in intrauterine fetal death. Lancet 2001;357:
1494–1497. [II-2]
16. Skjöldebrand-Sparre L, Tolfvenstam T, Papadogiannakis N. Association
with the third trimester intrauterine fetal death. BJOG 2000;107:476–480.
[II-2]
17. Enders M, Weidner A, Rosenthal T, et al. Improved diagnosis of gestational
parvovirus B19 infection at the time of nonimmune fetal hydrops. J Infect
Dis 2008;197:58–62. [II-3]
18. Bernstein IM, Capeless IL. Elevated maternal serum alphafetoprotein and
hydrops fetalis in association with fetal parvovirus B19 infection in the
human fetus. BJOG 1989;74:456–457. [II-2]
19. Cosmi E, Mari G, Delle Chiaie L, et al. Noninvasive diagnosis by Doppler
ultrasonography of fetal anemia resulting from parvovirus infection. Am J
Obstet Gynecol 2002;187:1290–1293. [II-2]
20. Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: the
fetus at risk for anemia – diagnosis and management. Am J Obstet Gynecol
2015;212(6):697–710. [III]
21. Bascietto F, Liberati M, Murgano D, et al. Outcome of fetuses with
congenital parvovirus B19 infection: systematic review and meta-anal-
ysis. Ultrasound Obstet Gynecol 2018;52:569–576. [Systematic Review,
n = 611]
22. Segata M, Chaoui R, Khalek N, et al. Fetal thrombocytopenia second-
ary to parvovirus infection. Am J Obstet Gynecol 2007;196:61.e1–61.e4.
[II-3]
23. de Haan TR, van den Akker ESA, Porcelijn L, et al. Thrombocytopenia in
hydropic fetuses with parvovirus B19 infection: incidence, treatment and
correlation with fetal B19 viral load. BJOG 2008;115:76–81. [II-3]
24. Melamed N, Whittle W, Kelly EN, et al. Fetal thrombocytopenia in preg-
nancies with fetal human parvovirus-B19 infection. Am J Obstet Gynecol
2015;212:793.e1–8. [II-3]
25. Schild RL, Bald R, Plath H, et al. Intrauterine management of fetal parvovi-
rus B19 infection. Ultrasound Obstet Gynecol 1999;13:161–166. [II-2]
26. Galligan BR, Cairns R, Schifano JV, et al. Preparation of packed red cells
suitable for intravascular transfusion in utero. Transfusion 1989;29(2):
179–181. [II-3]
27. Allaf MB, Matha S, Chavez MR, Vintzileos AM. Intracardiac fetal trans-
fusion for Parvovirus-induced hydrops fetalis: A salvage procedure. J
Ultrasound Med 2015;34:2107–2109. [III]
28. Lassen J, Bager P, Wohlfahrt J, Böttiger B, Melbye M. Parvovirus B19 infec-
tion in pregnancy and subsequent morbidity and mortality in offspring. Int
J Epidemiol 2013;42:1070–1076. [II-2]
29. Dembinski J, Haverkamp F, Maara H, et al. Neurodevelopmental outcome
after intrauterine red cell transfusion for Parvovirus B19-induced fetal
hydrops. BJOG 2002;109:1232–1234. [II-2]
30. Rodis JF, Rodner C, Hansen AA, et al. Long-term outcome of children
following maternal human parvovirus B19 infection. Obstet Gynecol
1998;91:125–128. [II-2]
31. Nagel HT, de Haan TR, Vandenbussche FP, et al. Long-term outcome after
fetal transfusion for hydrops associated with parvovirus B19 infection.
Obstet Gynecol 2007;109:42–47. [II-3]
52
HERPES
Timothy J. Rafael
Key points
• Around 20–25% of pregnant women have immunoglobu-
lin G (IgG) for herpes simplex virus (HSV)-2 (prior infec-
tion) and are therefore infected with it, with intermittent
shedding from the vaginal mucosa. About 2–4% of IgG-
negative women seroconvert (acquire HSV and convert
to IgM+) during pregnancy, and 90% of these women are
undiagnosed because they are asymptomatic.
• Most neonatal infections result from contact with infected
maternal genital secretions during delivery. Transplacental
HSV vertical transmission is rare. Primary first-episode
infection, defined as HSV confirmed in a person without
prior HSV-1 or HSV-2 antibodies, can lead to a 25–50%
vertical transmission rate if delivery occurs vaginally
during this episode and, therefore, represents the most
important clinical scenario to avoid. Vaginal delivery dur-
ing recurrent infection is associated with a <1% incidence
of neonatal HSV infection.
• Prevention of maternal infection is the most important
management strategy.
• Universal maternal screening with HSV-1 and HSV-2
specific serology has not been tested in a trial, and is
not currently recommended.
• If the woman is seronegative, the partner should be
tested. If he is seropositive, avoidance of direct orogen-
ital contact, use of condoms, the possibility of absti-
nence, and medical suppression of the partner should
be discussed.
• If the woman is seropositive, or has a history of
HSV, education, suppression with acyclovir or
valacyclovir from 36 weeks until delivery, exami-
nation for lesions in labor with cesarean delivery
(CD) if they are present, and avoidance (if possible)
of artificial rupture of membranes (AROM), scalp
electrodes, vacuum extractors, and forceps should be
recommended.
• Diagnosis of genital herpes is most sensitive with poly-
merase chain reaction (PCR) assay of genital lesions (typed
to determine whether HSV-1 or HSV-2 is the cause of the
infection). Type-specific (HSV-1 and HSV-2) glycoprotein
G-based serologic testing should also be sent.
• Women with primary or first-episode genital HSV in
pregnancy should receive acyclovir 400 mg po tid × 7–10
days, or valacyclovir (Valtrex) 1 g po bid × 7–10 days
(treatment can be extended in case of incomplete heal-
ing), and receive suppression with acyclovir 400 mg po tid
or valacyclovir 500 mg po bid at 36 weeks until delivery.
• Women with reactivation (recurrent) symptomatic HSV
should receive either acyclovir 400 mg po tid × 5 days, or
valacyclovir (Valtrex) 500 mg po bid × 3 days, and receive
suppression with acyclovir or valacyclovir at 36 weeks until
delivery.
520
• Women with a history of genital HSV, but without a recur-
rence during pregnancy, should also be offered suppression
therapy from 36 weeks until delivery.
• Regarding mode of delivery:
• If any genital lesion suspicious for HSV is seen at
the time of labor, a CD should be performed.
• For women with a primary or non-primary first-episode
genital HSV infection during the third trimester of preg-
nancy, cesarean delivery may be offered due to the pos-
sibility of prolonged viral shedding, particularly those
developing symptoms within 6 weeks of expected delivery.
• An indicated CD for active genital HSV should be per-
formed before membrane rupture, or as soon as possible
(ideally within 4–6 hours) following rupture of mem-
branes. A CD may be of benefit regardless of duration of
membrane rupture.
• Neonatal HSV causes disseminated or CNS disease
(seizures, lethargy, irritability, tremors, poor feeding,
temperature instability, and bulging fontanelles) in
approximately 55% of cases. Up to 30% of infants will
die and more than 50% can have neurologic damage
despite antiviral therapy.
Pathogens
HSV-1 and HSV-2 are both DNA viruses.
Incidence/Epidemiology
Genital herpes is an infection (HSV-1 or HSV-2) causing ulceration
in the genital area. The actual incidence of genital HSV infection is
not known, as it is not a reportable disease. In the United States,
HSV-1 and HSV-2 seroprevalence among pregnant women
remained stable between 1999 and 2014. Approximately 21.1%
of pregnant women have IgG for HSV-2, and 59.3% are HSV-1
seropositive (prior infection), and are therefore infected with it;
30.6% are HSV seronegative [1]. Approximately 12–20% of couples
in early pregnancy are discordant for HSV status, with the woman
at risk to get a primary infection from her partner [2]. About 2–4%
of IgG-negative women seroconvert (acquire HSV) during
pregnancy [3], and 75–90% of HSV-2 infected people are not
aware of having the infection [2]. Approximately 0.1–1% of preg-
nant women carry HSV in their genitalia. The incidence of neona-
tal herpes is 1/60,000 live births annually in the United Kingdom
and 12–60/100,000 live births annually in United States [2].
Risk factors/Associations
Risk factors for maternal HSV infection are immunocompro-
mise, other sexually transmitted diseases (STDs), and risk factors
for STDs. Risk factors for neonatal HSV infection are HSV in the
genital tract at the time of delivery, primary HSV infection, and
invasive obstetrical procedures [2].
DOI: 10.1201/9781003099062-52
Herpes
Symptoms
About 70% of newly acquired HSV infections among pregnant
women are asymptomatic, and 30% of women have clinical pre-
sentations that range from minimal lesions to widespread genital
lesions associated with severe local pain, dysuria, sacral paresthe-
sia, tender regional lymph node enlargement, fever, malaise, and
headache (rarely meningitis).
Classification/Pathophysiology
HSV infection causes intranuclear inclusion bodies and mul-
tinucleated giant cells. Overall, HSV-1 causes about 90% of oral
infections, and 10% of genital infections, while HSV-2 causes 10%
of oral and 90% of genital infections, although among college-
age populations, the majority of new cases of genital HSV
are caused by HSV-1 [2]. The following are types of infections
included.
Primary first episode
Primary first-episode infection is defined as herpes simplex
virus confirmed in a person without prior HSV-1 or HSV-2
antibodies. About 2–4% of these seronegative women serocon-
vert to HSV-1 or HSV-2 during pregnancy (only 30% have symp-
toms—if symptoms are present, they are severe—and 50% have
recurrence within 6 months), with no fetal consequences unless
they convert shortly before labor and deliver vaginally; viral shed-
ding is very high with primary infection, with 50–80% of cases of
neonatal HSV infection resulting from women who acquire geni-
tal HSV-1 or HSV-2 infection near term [4].
Nonprimary first episode
Nonprimary first-episode infection is HSV-2 confirmed in a person
with prior findings of HSV-1 antibodies, or vice versa. About 1.5–2%
of HSV-1 IgG+ women seroconvert to HSV-2+, whereas the risk of
conversion from HSV-2 IgG to HSV-1+ is <1%. If symptoms are pres-
ent, they are usually milder than first-episode primary infection.
Reactivation (recurrent) genital herpes
Reactivation (recurrent) genital herpes is caused by reactivation
of latent HSV, usually HSV-2. If symptoms are present, they last
7–10 days, are mild, with low viral load shedding for 3–5 days. Some
clinicians distinguish another category within this one, called first-
recognized recurrence, which is HSV-1 (or HSV-2) confirmed in a
person with prior findings of HSV-1 (or HSV-2) antibodies, but this
is not clinically different from reactivation disease.
Over 90% of HSV episodes in pregnancy are either recurrent
or nonprimary first-episode HSV. Intimate contact between a
susceptible person (without antibodies against the virus) and an
individual who is actively shedding the virus, or with body flu-
ids containing the virus is required for HSV infection to occur.
Contact must involve mucous membranes or open or abraded skin.
HSV invades and replicates in neurons as well as in epidermal and
dermal cells. Virions travel from the initial site of infection on the
skin or mucosa to the sensory dorsal root ganglion, where latency
is established. Viral replication in the sensory ganglia leads to
recurrent clinical outbreaks. These outbreaks can be induced by
various stimuli, such as trauma, ultraviolet radiation, extremes
in temperature, stress, immunosuppression, or hormonal fluc-
tuations. Viral shedding, leading to possible transmission, occurs
during primary infection, during subsequent recurrences, and
during periods of asymptomatic viral shedding.
521
Maternal-fetal transmission
Maternal-fetal transmission of HSV usually occurs at deliv-
ery from contact with infected genital secretions. The global
incidence of neonatal herpes is estimated to be approximately 10
cases per 100,000 live births, equivalent to be ~14,000 cases per
year [5]. Women with a history of HSV can have viral shedding
at the time of delivery. HSV-2 is detected in genital secretions
at term by PCR assay in 8–15% of HSV-2 seropositive women,
most of whom have no clinically detectable lesions at the time
[4]. Vaginal delivery during primary infection or nonprimary
first-episode genital infection is associated with a 25–50% inci-
dence of neonatal HSV infection. Vaginal delivery during recur-
rent infection is associated with a <1% incidence of neonatal
HSV infection [2]. The infant of the mother with primary HSV
in the third trimester lacks the protection of transplacental type-
specific antibodies (which take 6–12 weeks to fully protect the
infant), and is at risk of exposure during delivery when viral shed-
ding could be of greatest load. The major sites of intrapartum
viral entry are the neonatal eyes, nasopharynx, or a break in skin.
Transplacental (congenital) infection is very rare, and
limited to case reports. First-episode primary infection dur-
ing pregnancy can rarely lead to fetal growth restriction, micro-
cephaly, microphthalmia, ventriculomegaly, spasticity, echogenic
bowel, and hepatosplenomegaly [6].
Complications
In the mother, primary infection can lead to severe symptoms,
and occasionally to disseminated disease and encephalitis.
HSV hepatitis is another rare sequela, with a mean gestational age
at diagnosis of 30 weeks; it should remain on the differential when
a pregnant patient presents with fever, abdominal tenderness, and
transaminitis, as it carries a high maternal and perinatal mortal-
ity rate if untreated [7].
Factors that influence the risk of fetal infection include primary
maternal infection, gestational age, delivery mode, status of mem-
branes, and maternal antibodies. Primary, rather than recurrent
genital HSV, is the main risk factor for neonatal HSV. In the first
episode, if genital herpes lesions are present at the time of delivery
and the baby is delivered vaginally, the risk of neonatal herpes is
25–50%, calculated in different studies. The risk of neonatal infec-
tion in women with established infection and recurrence at term is
<1% [4]. The risk of neonatal infection from postnatal transmission
without prevention is 15% [8]. Neonatal HSV causes disseminated
or CNS disease (seizures, lethargy, irritability, tremors, poor
feeding, temperature instability, and bulging fontanelles) in
approximately 55% of cases. Up to 30% of infants will die and
more than 50% can have neurologic damage despite antiviral
therapy [4]. Prenatal ultrasonography can detect microcephaly,
hydrocephaly, intracranial calcification, and placental calcifi-
cations that result from a chronic fetal infection [6].
Pregnancy management
Pregnancy considerations
The course of HSV infection in pregnancy is similar to that in
non-pregnant women.
Counseling/Prognosis
Prevention, natural history, incidence of vertical transmission
and sequelae, prognosis, and therapeutic options should all be
522 Maternal-Fetal Evidence Based Guidelines

reviewed with the pregnant woman with maternal HSV infection,
especially if primary.
Prevention
Prevention of maternal infection includes avoidance of sexual
contact with infected individuals. A preventive strategy for
maternal infection involving universal screening has been pro-
posed (Figure 52.1) [9]. Condoms can usually prevent infection
from infected male partners, if the condom covers the lesion(s),
however, there should be consideration for abstinence during
the third trimester, as condoms do not always protect again
sexual transmission. For prevention of fetal/neonatal infection,
avoidance of vaginal delivery at times of primary infection
is most important. If any genital lesion suspicious for HSV
is seen at time of labor, a CD should be performed. About
46% of these lesions test positive by PCR. Clinical diagnosis by
visual exam fails to identify all women with HSV in their genital
secretions [10]. No scalp electrode, forceps, or vacuum should
be used if viral shedding is possible. Prevention of neonatal
infection is critical, as neonatal treatment is poorly effective
at avoiding long-term CNS complications (see also section
Therapy).
Screening
Universal screening is not generally offered to pregnant women,
but it has been proposed (Figure 52.1). The U.S. Preventive Task
Force as well as ACOG currently recommend against routine
serologic screening in asymptomatic adolescents and adults,
including those who are pregnant [11, 12]. There has been no
evidence that screening women to identify pregnancies at risk
of new infections will effectively decrease incidence of infection
at term, as such a study would require thousands of women.
Screening to identify pregnant women with asymptomatic herpes
infections may have no value at present without any known safe
and effective interventions to prevent an already unlikely neona-
tal transmission. All pregnant women should be asked about
their own and their partner’s histories of genital (and oral)
herpes and examined for evidence of active herpes at delivery.
Asymptomatic pregnant women with positive partners, as well
as HIV-positive pregnant women, should be offered type-specific
serologic testing.
Workup/Diagnosis
Diagnosis of genital herpes relies on laboratory confirmation
with HSV culture or PCR assay of genital lesions (typed to
determine whether HSV-1 or HSV-2 is the cause of the infec-
tion). Type-specific (HSV-1 and HSV-2) glycoprotein G–based
serologic testing should also be sent. PCR assays are more
sensitive, and are now preferred, but lack of HSV detection
by PCR does not indicate lack of HSV infection, because viral
shedding is intermittent. HSV culture should be done within
48–72 hours of appearance of the lesion. If the serology type-
specific result is discrepant from the culture or PCR result, a
new infection is diagnosed [2]. If a new infection is suspected,
but the virus is not isolated from the lesion via PCR or culture,
serologic testing should be repeated in 3–4 weeks. HSV anti-
bodies appear during the first weeks after infection, and persist
for life [9]. Tzanck smear (Wright’s stain with material from the
vesicle) is diagnostic with multinucleated giant cells and viral
inclusions. An option exists for rapid HSV PCR at the time of
delivery [13], but until this has been validated by prospective
trials, is not currently recommended.

HSV -1 IgG and IgM, and HSV -2 IgG and IgM (preferably
at <18 wks)

HSV seronegative HSV 1 seropositive HSV 2 seropositive

Partner HSV 1 Partner HSV 2

positive seropositive

- Examination for lesions in

- Avoid oro-genital contact
- Condoms
- Abstinence
- Suppression (partner)
- Avoid oro-genital contact
- Condoms
- Abstinence
- Suppression (partner)
labor
- Education
- Suppression (patient)
- Avoid if possible: AROM,
Scalp electrodes, vacuum
extractors, forceps

FIGURE 52.1 Testing and counseling women regarding HSV. (Adapted from Ref. [9].) Abbreviations. HSV, herpes simplex virus;
IgG, immunoglobulin G; IgM, immunoglobulin M; AROM, artificial rupture of membranes.
Herpes 523

TABLE 52.1: Recommended Doses of Antiviral Medications These women should receive suppression with acyclovir
for Herpes in Pregnancy 400 mg po tid or valacyclovir 500 mg po bid at 36 weeks until
delivery. Suppression decreases the incidence of recurrent geni-
Indication Acyclovir Valacyclovir
tal lesions at term, viral shedding, and therefore the need for CD.
Primary or 400 mg orally, three times 1 g orally, twice daily, for There is insufficient evidence to justify suppression based on
first-episode daily, for 7–10 days 7–10 days neonatal HSV, since this outcome is so rare. It is worth noting
infection that suppression does not always eliminate all viral shedding, as
Symptomatic 400 mg orally, three times 500 mg orally, twice illustrated by a case series of eight neonates infected with HSV,
recurrent daily, for 5 days or 800 mg daily, for 3 days, or 1 g where five of the mothers were on suppressive therapy at the time
episode orally, twice daily, for 5 days orally, daily, for 5 days of delivery [16].
Daily 400 mg orally, three times 500 mg orally, twice
suppression daily, from 36 weeks daily, from 36 week Complicated HSV infection
estimated gestational age estimated gestational Women with disseminated genital HSV, pneumonitis, hepati-
until delivery age until delivery tis, or CNS complications should receive the following:
Severe or 5–10 mg/kg, intravenously, • IV acyclovir 5–10 mg/kg body weight q8h until clinical
disseminated every 8 hours for 2–7 days, improvement, followed by oral antiviral therapy for
disease then oral therapy for primary 10 days of total therapy
infection to complete 10 days
History of HSV
Source: Adapted from Ref. [12]. Data from Centers for Disease Control and
Women with a history of HSV with reactivation (recurrent)
Prevention. Genital HSV infections. In: 2015 sexually transmitted diseases
treatment guidelines. Atlanta, GA: CDC; 2015. Available at: https://cdc.
symptomatic HSV during pregnancy should be treated with the
gov/std/tg2015/herpes.htm. Accessed on October 1, 2020. following:

• Analgesia (topical and systemic) as needed

Therapy (Table 52.1)
Antiviral drugs
Acyclovir and the other HSV antivirals have, as mechanism
of action, the specific inhibition of viral thymidine kinase.
They cross the placenta but do not accumulate in the fetus.
All these antivirals appear to be safe for the fetus, as expo-
sure to acyclovir and valacyclovir do not appear to increase
the overall risk of birth defects [14], although some data raise
the possibility of an association with first trimester exposure
and gastroschisis [15].
Valacyclovir (Valtrex) is the prodrug of acyclovir and requires
hepatic metabolism to become active. As for famciclovir, valacy-
clovir has better absorption, longer half-life, and decreased dura-
tion of pain and shedding compared to acyclovir.
Famciclovir is the prodrug of penciclovir and also requires
hepatic metabolism to become active. As there are very limited
studies in pregnant women taking famciclovir, acyclovir and
valacyclovir are preferred.
Trials in non-pregnant adults show no differences in outcomes
with any of these drugs for primary HSV.
Primary or first-episode HSV
Women with primary or first-episode genital HSV in preg-
nancy should be treated with the following:
• Hygienic support to avoid secondary yeast and bacterial
infection as needed
• Antiviral therapy (hastens lesion healing, and decreases
viral shedding) with either:
• Acyclovir 400 mg po tid × 5 days or
• Valacyclovir (Valtrex) 500 mg po bid × three days, or
1 g po qd for 5 days
These women should receive suppression (see dosages ear-
lier) with acyclovir or valacyclovir at 36 weeks until delivery, or
starting even earlier if there are frequent recurrent episodes. In
women with recurrent genital herpes, antiviral suppressive
medication initiated from 36 weeks until delivery reduces
viral shedding and recurrences at delivery, and reduces the
need for CD. There is insufficient evidence, given the rarity of
this outcome, to assess if antiviral prophylaxis reduces the inci-
dence of neonatal HSV [17].
There is insufficient evidence to assess suppression in
women with a history of genital HSV and no recurrence
during pregnancy, but suppression at 36 weeks is a reason-
able option after counseling [9]. Four out of 7 RCTs evaluating
suppression included women with a history of genital HSV but
not necessarily a recurrence during the index pregnancy [17].
The ACOG recommends these women be offered suppres-
sive therapy [12].

• Analgesia (topical and systemic) Mode of delivery

• Hygienic support to avoid secondary yeast and bacterial
infection
• Antiviral therapy (hastens lesion healing and decreases
viral shedding) with either:
• Acyclovir 400 mg po tid × 7–10 days, or
• Valacyclovir (Valtrex) 1 g po bid × 7–10 days
Either regimen duration may be extended if healing is incom-
plete after 10 days. For primary outbreaks that occur in the third
trimester, continuing antiviral therapy until delivery may be con-
sidered [12].
• With active genital lesions, or prodromal symptoms
of HSV (either primary or reactivation), especially in
women presenting with first-episode genital herpes
lesions at the time of delivery, cesarean section is rec-
ommended. The Royal College of Obstetricians recom-
mends CD for ALL women developing first-episode genital
herpes in the third trimester, particularly those develop-
ing symptoms within 6 weeks of expected delivery, as the
risk of neonatal transmission of HSV is very high [18].
The ACOG states “…for women with a primary or non-­
primary first-episode genital HSV infection during the third
524
trimester of pregnancy, cesarean delivery may be offered
due to the possibility of prolonged viral shedding;” Level C
Recommendation [12].
• For an indicated CD, it should be performed before mem-
brane rupture, or as soon as possible (ideally within 4–6
hours) following rupture of membranes. A CD may be of
benefit regardless of duration of membrane rupture.
• A reactivation/recurrent episode of genital herpes
occurring during pregnancy is not an indication for
delivery by cesarean section. In women with a history
of genital HSV but without active genital lesions or
prodromal symptoms at the time of labor, CD is not
indicated.
• CD is not recommended for women with nongenital lesions
(e.g. lesions on back, thigh, buttock), as these lesions can
be covered with an occlusive dressing, and the patient can
give birth vaginally [12].
Postpartum/Neonate
Seventy percent of mothers of HSV-infected neonates are asymp-
tomatic. Neonates with infection manifest symptoms at the end
of the first week of life with skin lesions, cough, tachypnea, cya-
nosis, jaundice, seizures, and disseminated intravascular coagu-
lation (DIC). The classic triad is skin lesions, chorioretinitis, and
CNS abnormalities. Severe HSV neonatal infection can lead to a
30% incidence of death and more than 50% incidence of mental
problems/neurologic damage in survivors despite antiviral ther-
apy [4].
A neonate born to a mother with active HSV lesions will
require contact precautions if the mother delivered vaginally
OR if the mother delivered by C-section and had ruptured
membranes greater than 4 hours prior to delivery. Contact pre-
cautions are to be maintained until all cultures are finalized.
This information must be communicated with all members of
the healthcare team, including obstetricians, pediatricians, and
nurses. Mothers with HSV at the time of delivery should wash
their hands and cover any lesions, but can handle their neonate.
No additional precautions (except standard precautions) are
necessary for neonates born to mothers who have active lesions
and are delivered by cesarean section without ruptured mem-
branes prior to delivery OR had rupture of membranes less than
4 hours prior to delivery by cesarean section. Acyclovir is com-
patible with breastfeeding.
Maternal-Fetal Evidence Based Guidelines
References
1. Patton ME, Bernstein K, Liu G, et al. Seroprevalence of herpes simplex virus
types 1 and 2 among pregnant women and sexually active, nonpregnant
women in the United States. Clin Infect Dis 2018; 67(10):1535–1542. [II-3]
2. Gardella C, Brown Z. Prevention of neonatal herpes. BJOG 2011; 118:
187–192. [III]
3. Brown ZA, Selke SA, Zeh J, et al. Acquisition of herpes simplex virus during
pregnancy. N Engl J Med 1997; 337:509–515. [II-2]
4. Corey L, Wald A. Maternal and neonatal herpes simplex virus infections.
N Engl J Med 2009; 361:1376–1385. [III]
5. Looker KJ, Magaret AS, May MT, et al. First estimates of the global and
regional incidence of neonatal herpes infection. Lancet Glob Heal 2017;
5:e300–309. [II-3]
6. Fa F, Laup L, Mandelbrot L, et al. Fetal and neonatal abnormalities due
to congenital herpes simplex virus infection: a literature review. Prenatal
Diagn 2020; 40:408–414. [III]
7. McCormack AL, Rabie N, Whittemore B, et al. HSV hepatitis in pregnancy:
a review of the literature. Obstet Gynecol Surv 2019; 74(2):93–98. [III]
8. Jungmann E. Genital herpes. Clinical evidence. Br Med J 2004; 11:
2073–2088. [II-2]
9. Brown ZA, Gardella C, Wald A, et al. Genital herpes complicating preg-
nancy. Obstet Gynecol 2005; 106:845–856. [III]
10. Gardella C, Brown ZA, Wald A, et al. Poor correlation between genital
lesions and detection of herpes simplex virus in women in labor. Obstet
Gynecol 2005; 106:268–274. [II-2]
11. U.S. Preventive Services Task Force, Bibbins-Domingo K, Grossman DC,
et al. Serologic screening for genital herpes infection: US preventive services
task force recommendation statement. JAMA 2016; 316(23):2525–2530.
12. ACOG Practice Bulletin No. 220. Management of genital herpes in preg-
nancy. Clinical management guidelines for obstetrician gynecologists.
Obstet Gynecol 2020; 135(5):e193–e202. [III]
13. Gardella C, Huang ML, Wald A, et al. Rapid polymerase chain reaction
assay to detect herpes simplex virus in the genital tract of women in labor.
Obstet Gynecol 2010; 115:1209–1216. [II-3]
14. Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the
first trimester of pregnancy and the risk of birth defects. J Am Med Assoc
2010; 304(8):859–866. [II-2]
15. Ahrens KA, Anderka MT, Feldkamp ML, et al. Antiherpetic medication
use and the risk of gastroschisis: findings from the National Birth Defects
Prevention Study, 1997–2007. Paediatr Perinat Epidemiol 2013; 27(4):
340–345. [II-2]
16. Pinninti SG, Angara R, Feja KN, et al. Neonatal herpes disease following
maternal antenatal antiviral suppressive therapy: a multicenter case series.
J Pediatr 2012; 161:134–138. [II-3]
17. Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for prevent-
ing maternal genital herpes simplex virus (HSV) recurrences and neonatal
infection. Cochrane Database Syst Rev 2008; (1):CD004946. [Meta-analysis:
7 RCTs, n = 1249]
18. Royal College of Obstetricians and Gynaecologists. Management of geni-
tal herpes in pregnancy, October 2014. https://www.rcog.org.uk/globalas-
sets/documents/guidelines/management-genital-herpes.pdf (Accessed on
October 1, 2020).
53
VARICELLA
Timothy J. Rafael
Key points
• As about 95% of pregnant women are immune (VZV
IgG+) to varicella, primary maternal varicella zoster
virus (VZV) infection (chickenpox) occurs in about 0.5–
3/1000 pregnancies.
• Pneumonia can occur in up to 5–10% of pregnant women
with chickenpox.
• Congenital varicella syndrome (CVS) occurs in 0.4–2%
of all maternal infections, usually if maternal VZV
infection occurs at <20 weeks of gestation.
• CVS includes congenital limb hypoplasia, dermatomal skin
scarring, rudimentary digits, intrauterine growth restriction
(IUGR), and occasionally damage to the eyes (chorioretinitis,
cataracts) and central nervous system (microcephaly, cortical
atrophy, leading to neurodevelopmental delay).
• All pregnant (and reproductive-age) women should be
asked at their first prenatal visit if they have had a chicken-
pox infection. All women who did not have chickenpox
in the past, are unsure about their history, or had only
one dose of the varicella vaccine, should have VZV IgG
serology. VZV IgG-negative women should receive the
vaccine postpartum.
• Diagnosis of maternal chickenpox is usually made based
on clinical findings alone, and confirmed by VZV IgM.
• Ultrasound can help in the diagnosis and estimation of the
probability of CVS. At least 5 weeks should be allowed
between the onset of maternal symptoms and fetal
ultrasound. Fetal infection can be diagnosed by VZV DNA
in amniotic fluid, but this does not predict risk of CVS.
• VZV-seronegative pregnant women exposed to VZV
should receive VZV IgG (also known as VariZIG™) as soon
as possible, and within 96 hours (4 days) of exposure, up to
a period of 10 days post exposure.
• Pregnant women who develop chickenpox should receive
oral (or intravenous [IV] if severe) acyclovir within
24 hours of rash, and should avoid contact with susceptible
individuals such as other pregnant women or children.
Varicella zoster immune globulin (VariZIG™) has no thera-
peutic effect once chickenpox has developed.
• Delivery should be delayed until 5 days after the onset of
maternal illness, to allow for passive transfer of maternal
IgG. Neonates born to women who develop chickenpox
between 5 days before and 2 days after delivery should
receive VZV IgG. If neonatal infection occurs, the neonate
should receive acyclovir.
• Pregnant women who develop varicella pneumonia
should be immediately hospitalized in isolation, and
receive IV acyclovir.
• Maternal shingles (herpes zoster) is not a risk for the
infant who is protected from passively acquired maternal
antibodies.
DOI: 10.1201/9781003099062-53
• Nonimmune women should be offered postpartum vari-
cella vaccination. The vaccine is considered safe in breast-
feeding women. Conception should be delayed until one
month after the VZV vaccine was given (live attenuated
vaccine).
Pathogen
VZV is a DNA virus of the herpes family.
Incidence/Epidemiology
The incidence of varicella is not precisely known, as it is not a
reportable disease. As about 95% of pregnant women are immune
(VZV IgG+) to varicella, primary maternal VZV infection
(commonly called chickenpox, or VZD) is uncommon, and esti-
mated to complicate about 0.5–3/1000 pregnancies. Women
from tropical areas are more susceptible (50% immunity only)
to the development of chickenpox. VZV vaccine was licensed in
1995 and decreased the incidence of disease by 85–90% in the
decade following licensure [1].
Risk factors/Associations
Maternal varicella infection is associated with contact with
infected individuals, which usually are children, if not immu-
nized. Risk factors for varicella pneumonia during pregnancy are
cigarette smoking, >100 skin lesions, and advanced gestational
age at the time of infection [2].
Symptoms
Symptoms consist of a pruritic rash with maculopapular skin
lesions in crops, which become vesicles and pustules, and later
crust over, along with fever and malaise.
Pathophysiology
VZV is highly contagious and transmitted by respiratory drop-
lets and direct personal contact with vesicle fluid, or indirectly
via fomites. The incubation period is about 15 (10–21) days. The
disease is infectious 48 hours before the rash appears, and con-
tinues to be infectious until the vesicles crust over (Figure 53.1).
The rash lasts 7–10 days. Chickenpox (or primary VZV infection)
is a common childhood disease that usually causes a mild infec-
tion, leading to the 90% seropositivity among pregnant women.
After the primary infection, the virus remains dormant in sen-
sory nerve root ganglia, and can be reactivated to cause a vesicu-
lar erythematous skin rash known as herpes zoster (commonly
called shingles).
525
526
Exposure
Incubation period 10–21 days
Viremia
2 days
Rash
5 days
lgM/IgG appear in blood
Vesicles crust over
FIGURE 53.1 VZV infectious sequence. Abbreviation: VZV,
varicella zoster virus.
Maternal-fetal transmission
Primary maternal infection leads to an approximate 8% vertical
transmission, causing primary fetal infection. Of these, about
10% develop CVS (0.4–2% of all maternal infections) usually if
maternal VZV occurs <20 weeks of gestation [3].
Complications
Maternal
Although varicella infection is much less common in adults than
in children, in adults it is more often associated with pneumonia,
hepatitis, and encephalitis. Historically pneumonia can occur in
up to 5–10% of pregnant women with chickenpox, and the sever-
ity seems increased in later gestation. More recent data points to
a lower incidence of 2.5% for varicella pneumonia during preg-
nancy [4]. Pulmonary symptoms start 2–6 days after the rash,
with a mild cough leading to hemoptysis, chest pain, dyspnea,
and cyanosis. The mortality rate with treatment for varicella
pneumonia is now <1%.
Fetal
Sequelae are dependent on fetal age at the time of infection.
In up to 98% of cases of maternal infection, the fetus remains
healthy without clinical signs of illness, but when infection
occurs, it can result in CVS, neonatal varicella, or asymptomatic
seroconversion.
The overall rate for CVS when maternal infection occurs
in the first 20 weeks of gestation has been demonstrated to
be about 0.4–2% [1, 3, 5–8]. Worldwide, there have only been
130 reported cases of CVS from 1947 to 2013 [9]. CVS is char-
acterized by congenital limb hypoplasia, dermatomal skin
scarring, rudimentary digits, IUGR, and occasionally dam-
age to the eyes (microphthalmia, chorioretinitis, cataracts)
and central nervous system (microcephaly, cortical atrophy,
leading to neurodevelopmental delay). It is hypothesized
Maternal-Fetal Evidence Based Guidelines
that CVS may reflect disseminated infection in utero or con-
sequences of failure of virus-host interaction to result in
establishment of latency, as normally occurs in postnatal VZV
infection [1]. Prenatal ultrasound findings can include limb
deformity, microcephaly, hydrocephalus, soft tissue calcifica-
tion, and IUGR [10].
CVS with maternal infection >20 weeks is very rare, as it
has only been reported in 10 case reports (<1/1000 risk) [5, 9].
Maternal infection after 20 weeks and up to 36 weeks may present
as shingles in the first few years of infant life, as a reactivation of
the virus after a primary infection in utero.
If maternal infection occurs 1–4 weeks before delivery, up to
50% of babies are infected and up to 23% of these develop clini-
cal varicella. Severe chickenpox occurs more often if the infant
is born within 7 days of the onset of the mother’s rash, when
cord blood VZV IgG is low. Both intrauterine and peripartum
VZV infection predispose to development of childhood zoster.
Historically, neonates born to mothers who contract chickenpox
between 5 days before delivery and 2 days after delivery have a
17–30% chance of developing neonatal varicella [11]. Before
VZV immunoglobulin was available, the risk of death among
these neonates was as high as 31%, with current rates decreasing
to 7% when the use of varicella immunoglobulin was introduced
and neonatal intensive care improved [1]. Since the advent of rou-
tine varicella vaccination, the overall incidences of both CVS and
neonatal varicella appear to be further decreasing [12]. There are
no fetal consequences for herpes zoster, since the viral load is very
low, and the mother has already VZV IgGs that cross the placenta
and protect the fetus.
Pregnancy management
Pregnancy considerations
Chickenpox is a more severe disease in the adult than in the child.
In pregnant women, frequency of VZV, frequency of pneumonia,
and mortality are not increased compared to non-pregnant adults.
Pneumonia may be more severe in pregnant women, with up to
an overall 5% risk of maternal death even with therapy, although
a more recent study reported no maternal deaths among 23 cases
of VZV pneumonia diagnosed during pregnancy [4].
Counseling
Natural history, incidence of vertical transmission and sequelae
(mostly occurring if maternal infection occurs <20 weeks),
prognosis, and therapeutic options should all be reviewed with
the pregnant woman with primary maternal VZV infection
(Table 53.1).
Prevention
VZV-seronegative pregnant women should avoid exposure to
individuals with chickenpox. A live attenuated varicella vaccine
(Varivax®, Merck, NJ, U.S.) has been demonstrated to be safe in
preventing chickenpox in adults. In the United States, seronega-
tive women presenting for preconception counseling or women
undergoing infertility treatment should be offered vaccination.
The vaccine is not available in the United Kingdom for these
indications. Varicella vaccine is contraindicated in pregnant
women. If a woman accidentally receives VZV vaccine within
one month of conception or in pregnancy, the incidence of fetal
infection and complications does not appear to be increased
from baseline, and termination should not be recommended. In
one registry, among 131 live births to VZV-seronegative women,
Varicella
TABLE 53.1: Counseling Advice for Pregnant Women at Risk
Risk for
Maternal Varicella
Rash Appears Embryopathy Counseling Advice
First 20 weeks 0.5–2% above VZV IgG ASAP, or at most within 10 days
the baseline after contact if the woman is seronegative
risk
Ultrasound 5 weeks after maternal rash
appears to detect defects
21–28 weeks Rare VZV IgG ASAP, or at most within 10 days
after contact if the woman is seronegative
Ultrasound 5 weeks after maternal rash
appears to detect defects
After 28 None VZV IgG ASAP, or at most within 10 days
weeks after contact if the woman is seronegative
to prevent varicella complications
Explain baseline risk
Five days None If possible, delay the delivery until 5–7
before or two days after the onset of maternal rash
days after
Administer VZV IgG to neonate if exposed
IV Acyclovir is warranted for severe cases
Maternal IV Acyclovir 10–15 mg/kg every 8 hour for
varicella 5–10 days and antibiotics as needed
pneumonia Blood gas, mechanical ventilation, and
supportive therapy as needed
Source: Compiled from Ref. [19].
Abbreviations: VZV, varicella zoster virus; ASAP, as soon as possible.
there was no evidence of CVS, and the major birth defect rate
was not statistically increased [13]. Nonimmune health workers
exposed to VZV should minimize patient contact from days 8 to
21 post-contact.
Screening
Routine serologic screening of all pregnant women is currently not
recommended. All pregnant (and preconception reproductive-
age) women should be asked at the first prenatal visit if they
have had a prior chickenpox infection. Over 97% of women who
report a prior varicella infection with a typical presentation have
VZV IgG and are therefore immune. All women who did not
have chickenpox in the past, are unsure about their history,
or had only one dose of the varicella vaccine, should have VZV
IgG serology. In the United States, of women who are uncertain
or give negative histories, approximately 80–90% have VZV IgG
[14]. If testing is done in the preconception period, women can be
offered two doses of the varicella vaccine at least 1 month apart.
Pregnancy should be delayed 1 month after vaccination. Based
on a decision model, the above prenatal screening (selective sero-
testing) with postpartum vaccination of susceptibles would seem
cost-effective [15].
Workup/Diagnosis
Diagnosis of maternal chickenpox is usually made based on
clinical findings alone. Diagnosis can be confirmed by VZV IgM
newly positive by ELISA (enzyme-linked immunosorbent assay),
or by VZV antigen (Ag) in skin/vesicular lesions by immunofluo-
rescence antibody (Ab) to membrane Ag. Fetal infection can be
diagnosed by VZV DNA detected by polymerase chain reaction
527
(PCR) in amniotic fluid, but its presence has a poor positive
predictive value for both fetal disease and disease severity [1].
The presence of fetal varicella-specific IgM, which remains in the
blood for 4–5 weeks, is diagnostic [16]. Ultrasound can help in
diagnosis and estimation of probability of CVS. At least 5 weeks
should be allowed between the onset of maternal symptoms
and fetal ultrasound, to avoid false negative results. Initial PCR
testing of amniotic fluid at 17–21 weeks may be negative with nor-
mal ultrasound findings, suggesting a low risk of CVS. Positive
PCR at 17–21 weeks with normal ultrasound should lead to a
repeat ultrasound at 22–26 weeks. A normal ultrasound at that
stage makes CVS very unlikely. In contrast, an abnormal ultra-
sound suggests a high likelihood of CVS [17, 18].
Therapy
Exposure
• VZV-seronegative pregnant women exposed to VZV
should receive VZV IgG (VariZIG™) ideally as soon as
possible (Table 53.1), and within 96 hours (4 days) of expo-
sure, up to a period of 10 days post exposure. In 2012, the
Food and Drug Administration approved VariZIG™, a
varicella zoster immune globulin preparation for use in
the United States for postexposure prophylaxis for indi-
viduals at high risk for severe disease, and subsequently
extended the period for administration from 4 days to 10
days [19]. VariZIG can be obtained 24 hours a day from
the sole authorized U.S. distributor (FFF Enterprises,
Temecula, CA, U.S., tel. 1-800-843-7477 or online at
http://www.fffenterprises.com). The recommended dose
is 125 units/10 kg of body weight, up to a maximum of
625 units IM (five vials) [20]. VariZIG is well tolerated
and appears to be effective, as its use is associated with
a low risk of varicella among exposed pregnant patients,
regardless of when it is administered within 10 days post-
exposure [21]. However, it probably does not affect fetal
infection, and it is expensive.
Chickenpox
• Pregnant women who develop chickenpox should
receive oral acyclovir within 24 hours of rash. Acyclovir
is a synthetic nucleoside analogue of guanine, highly spe-
cific for cells infected by VZV or HSV; it inhibits viral
DNA polymerase which stops the replication of human
herpes viruses [22]. Oral acyclovir (800 mg, 5 times daily
for 7 days) reduces the duration of fever and symptoms of
varicella infection in immunocompetent adults if com-
menced within 24 hours of developing the onset of rash
[23]. Alternatively, valacyclovir, 1 gram, 3 times daily for
7 days, may be used [22]. Administration of acyclovir does
not appear to be teratogenic, as the observed rates of birth
defects for pregnancies exposed to oral or IV acyclovir do
not differ significantly from those in the general population
[24]. Acyclovir is prescribed to treat extensive varicella at
the high dose of 15 mg/kg of body weight or 500 mg/m2
IV every 8 hours. Major side effects often include local tis-
sue irritation, transient elevation of hepatic transaminases,
CNS toxicity, and renal dysfunction. Transplacental pas-
sage of acyclovir is prompt and therapeutic levels reach
the placenta and fetal blood [16]. There is no information
about whether giving acyclovir or valacyclovir to preg-
nant women with varicella reduces the already low risk
for CVS [1].
528
• Pregnant women who develop chickenpox should avoid
contact with susceptible individuals such as other preg-
nant women or children.
• Pregnant women who develop chickenpox should
undergo symptomatic treatment and maintain hygiene to
avoid bacterial superinfection.
• VZV IgG has no therapeutic effect once chickenpox has
developed.
• If maternal infection occurs at term there is a signifi-
cant risk of varicella in the newborn. Delivery should
be delayed until 5 days after the onset of maternal ill-
ness, to allow for passive transfer of maternal IgG. Infants
delivered when maternal symptoms develop 5 days prior to
2 days after delivery are at 17–30% risk of getting neonatal
varicella, and of these, about 7% can die. Neonates born to
women who develop chickenpox between 5 days before
and 2 days after delivery should receive VZV IgG. If neo-
natal infection occurs, the neonate should receive acyclovir.
• If there is neonatal exposure in the first 7 days of life
(e.g., from an infected sibling), no intervention is required
if the mother is immune; however, the neonate should be
given VZV IgG if the mother is not immune to varicella.
Neonates who develop chickenpox in the first 14 days of life
should receive IV acyclovir.
• Pregnant women who develop varicella pneumonia should
be immediately hospitalized in isolation. They should receive
IV acyclovir 10–15 mg/kg every 8 hours × 7 days within
72 hours of symptoms (decreases severity and mortality).
Maternal shingles (herpes zoster)
Despite maternal varicella being associated with the aforemen-
tioned fetal/neonatal risks, no cases of CVS have been reported
following maternal herpes zoster. There was, however, one case
report of a child born with findings consistent with CVS follow-
ing maternal disseminated herpes zoster at 12 weeks [22]. Should
treatment be deemed necessary for zoster during pregnancy (e.g.,
moderate to severe rash, acute neuritis), oral acyclovir (800 mg 5
times daily for 7–10 days) or valacyclovir (1000 mg 3 times daily
for 7 days) can be used [25]. Maternal shingles is not a risk for
the infant who is protected from passively acquired maternal
antibodies [6].
Nonimmune women
Nonimmune women should be offered postpartum varicella
vaccination (2 doses, one month apart). The vaccine is consid-
ered safe in breastfeeding women. Conception should be delayed
until one month after the VZV vaccine was given (live attenuated
vaccine).
Clinical neonatal findings of CVS [18]
• Skin scarring in a dermatomal distribution: 73%
• Neurological abnormalities (microcephaly, cortical atro-
phy, neurodevelopmental delay): 62%
• Eye defects (microphthalmia, chorioretinitis), 52%
• Hypoplasia of the limbs: 46%
• Muscle hypoplasia: 20%
• Gastrointestinal abnormalities: 19%
• Genitourinary abnormalities: 12%
• Internal organs effects: 13%
• Developmental delay: 12%
Maternal-Fetal Evidence Based Guidelines
References
1. Smith CK, Arvin AM. Varicella in the fetus and newborn. Semin Fetal
Neonatal Med 2009; 14:209–217. [III]
2. Harger JH, Ernest JM, Thurnau GR, et al. Risk factors and outcome of
varicella-zoster virus pneumonia in pregnant women. J Infect Dis 2002;
185:422–427. [II-2]
3. Harger JH, Ernest JM, Thurnau GR, et al. Frequency of congenital varicella
syndrome in a prospective cohort of 347 pregnant women. Obstet Gynecol
2002; 100:260–265. [II-3]
4. Zhang HJ, Patenaude V, Abenhaim HA. Maternal outcomes in pregnancies
affected by varicella zoster virus infections: population-based study on 7.7
million pregnancy admissions. J Obstet Gynaecol Res 2015; 41:62–68. [II-2]
5. Tan MP, Koren G. Chickenpox in pregnancy: revisited. Reprod Toxicol
2006; 21(4):410–420. [III]
6. Royal College of Obstet and Gynecol. Clinical green top guideline: chicken-
pox in pregnancy. January 17, 2005. [Guideline]
7. Sanchez MA, Bello-Munoz JC, Cebrecos I, et al. The prevalence of congeni-
tal varicella syndrome after a maternal infection, but before 20 weeks of
pregnancy: a prospective cohort study. J Matern Fetal Neonatal Med 2011;
24(2):341–347. [II-3]
8. Enders G, Miller E, Cradock-Watson J, et al. Consequences of varicella and
herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 1994;
343:1548–1551. [II-3]
9. Ahn KH, Park YJ, Hong SC, et al. Congenital varicella syndrome: a system-
atic review. J Obstet Gynaecol 2016; 36(5):563–566. [II-3, 13 cohort studies,
38 case reports, n = 130]
10. Pretorius DH, Hayward I, Jones KL, et al. Sonographic evaluation of preg-
nancies with maternal varicella infection. J Ultrasound Med 1992; 11:
459–463. [II-3]
11. National Advisory Committee on Immunization update on varicella. Can
Common Dis Rep 2004; 30:1–26. [III]
12. Khandaker G, Marshall H, Peadon E, et al. Congenital and neonatal vari-
cella: impact of the national varicella vaccination programme in Australia.
Arch Dis Child 2011; 96:453–456. [II-3]
13. Wilson E, Goss MA, Marin M, et al. Varicella vaccine exposure during
pregnancy: data from 10 years of the pregnancy registry. J Infect Dis 2008;
197:S178–S184. [II-3]
14. Watson B, Civen R, Reynolds M, et al. Validity of self-reported varicella dis-
ease history in pregnant women attending prenatal clinics. Public Health
Rep 2007; 122:499–506. [III]
15. De Moira AP, Edmunds WJ, Breuer J. The cost-effectiveness of antenatal
varicella screening with post-partum vaccination of susceptibles. Vaccine
2006; 24:1298–1307. [III]
16. Mc Gregor JA. Varicella zoster infection in pregnancy. Contemp Obstet
Gynecol 2002; 47–55. [III]
17. Enders G, Miller E. Varicella and Herpes Zoster in Pregnancy and in
Newborn Cambridge: Cambridge University Press, 2000:317–347. [III]
18. Koren G. Congenital varicella syndrome in the third trimester. Lancet
2005; 366:1591–1592. [III]
19. Centers for Disease Control and Prevention (CDC). Updated
Recommendations for use of VariZIG-United States, 2013. MMWR Morb
Mortal Wkly Rep July 19, 2013, 62(28);574–576.
20. Centers for Disease Control and Prevention (CDC). A new product
(VariZIG) for postexposure prophylaxis of varicella available under an
investigational new drug application expanded access protocol. MMWR
Morb Mortal Wkly Rep 2006; 55:209–210. [III]
21. Levin MJ, Duchon JM, Swamy GK, et al. Varicella zoster immune globulin
(VARIZIG) administration up to 10 days after varicella exposure in preg-
nant women, immunocompromised participants, and infants: Varicella
outcomes and safety results from a large, open-label, expanded-access pro-
gram. PLOS ONE 2019; 14(7):e0217749. [II-3, 137 pregnant women]
22. Lamont RF, Sobel JD, Carrington D, et al. Varicella-zoster virus (chicken-
pox) infection in pregnancy. BJOG 2011; 118:1155–1162. [III]
23. Wallace MR, Bawler WA, Murray NB, et al. Treatment of adult varicella
with oral acyclovir. A randomized placebo-controlled trial. Ann Intern
Med 1992; 117:358–363. [I, non-pregnant adults, n = 148]
24. Stone KM, Reiff-Eldridge R, White AD, et al. pregnancy outcomes following
systemic prenatal acyclovir exposure: conclusions from the International
Acyclovir Pregnancy Registry, 1984–1999. Birth Defects Res A Clin Mol
Teratol 2004; 70:201. [II-3]
25. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the man-
agement of herpes zoster. Clin Infect Dis 2007; 44:S1–S26. [III]
54
FETAL AND NEONATAL ALLOIMMUNE THROMBOCYTOPENIA
Leen Al-Hafez
Key points
• Fetal and neonatal alloimmune thrombocytopenia (FNAIT)
is a disorder resulting in fetal platelet destruction (throm-
bocytopenia) from maternal antibodies against fetal
human platelet antigens (HPA) inherited from the father.
• Diagnosis is usually made retrospectively after a first
affected infant.
• The most serious complication is the 10–30% risk of intra-
cranial hemorrhage. Approximately 75% occur antenatally,
with more than half developing prior to 28 weeks. The neo-
natal mortality from intracranial hemorrhage (ICH) is 5–13%.
• Only HPA-1a antigen and past history of ICH predict a
more severe thrombocytopenia.
• Goal of management is to prevent ICH in the fetus and neo-
nate. Keeping fetal/neonatal platelets >20,000/μL achieves
this goal.
• Routine universal maternal screening is not cost-effective
and is not recommended.
• Intravenous immunoglobulin (IVIG) is associated with
a 75% response rate, and a very rare risk of ICH, with
half of the non-responders showing improvement with the
addition of a high dose of prednisone.
• Fetal blood sampling (FBS) with or without platelet
transfusion is associated with a 2.8% risk of perinatal loss
per procedure, with a cumulative complication rate of 11%
(the most common reason being emergent cesarean deliv-
ery for non-reassuring fetal status).
• Management is usually based on IVIG therapy, with or
without steroids as determined by prior history of ICH and
associated risks (Figure. 54.1). FBS is reserved only to deter-
mine mode of delivery in women desiring a trial of labor.
Definition
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is
fetal/neonatal thrombocytopenia due to platelet destruction from
maternal antibodies against fetal human platelet antigens (HPA)
inherited from the father. It is also called neonatal Alloimmune
thrombocytopenia (NAIT), alloimmune thrombocytopenia (AIT),
or fetal maternal alloimmune thrombocytopenia (FMAIT).
Epidemiology/Incidence
1/1000 to 1/1500 births [1]. FNAIT is the most common reason
for severe thrombocytopenia and/or ICH in term newborns.
Etiology/Basic pathophysiology
The fetus inherits paternal human platelet antigens (HPA) that are
not present on maternal platelets. Maternally produced anti-HPA
IgG antibodies can cross the placenta resulting in destruction of
DOI: 10.1201/9781003099062-54
fetal platelets and thrombocytopenia. Maternal platelet count
and function is normal (although 10% of women with NAIT may
have gestational thrombocytopenia). Although around 1 in 42
pregnancies is incompatible for HPA antigens, FNAIT devel-
ops in only 1 of 10 of these cases [2, 3].
FNAIT is similar to RBC Rh disease:
• Like red blood cells, platelets have specific surface proteins
called antigens.
• Fetus inherits paternal antigens that the mother lacks
(platelet antigen incompatibility).
• Mother develops antibodies (becomes sensitized) to fetal
platelet antigens during pregnancy.
• Maternal IgG anti-platelet antibodies cross the placenta
and coat fetal platelets resulting in sequestration and
destruction of platelets in the fetal reticuloendothelial
system.
FNAIT differs from Rh disease:
• Antiplatelet IgG production can occur in first pregnancy.
• Firstborn children are often affected since anti-platelet
IgG production can occur in a first pregnancy; nulliparous
women account for 20–60% of cases.
• Maternal antibody titers do not predict pregnancy
outcome.
Genetics/Inheritance
The most common cause of FNAIT, and responsible for the most
severe cases, is sensitization against HPA-1a. HPA-1a and HPA-1b
are the two allelic variants located on the glycoprotein GpIIIa
(integrin β3). A single amino acid substitution (proline to leucine)
determines the difference between having HPA-1a or HPA-1b
(i.e. HPA-1a negative women) [4, 5]. Platelet antigens are inher-
ited in the fetus in an autosomal co-dominant fashion.
Classification
Alloantigens are antigens present in the majority of individuals
in a population but absent in some individuals. There are 24 rec-
ognized platelet-specific alloantigens numbered in the order in
which they were discovered.
• Twelve of the platelet alloantigens are grouped into biallelic
systems (HPA 1, 2, 3, 4, 5, 15), which are further divided
into subcategories “a” for high frequency and “b” for low
frequency. The old and new nomenclature is described in
Table 54.1.
• Of Caucasian women, 97–98% express HPA-1a: 68% are
homozygotes (HPA-1a1a), and 29% are heterozygotes
(HPA-1a/HPA-1b).
529
530 Maternal-Fetal Evidence Based Guidelines

TABLE 54.1: Nomenclature for FNAIT • Mostly intraparenchymal, leading to encephalo­

malacia.
New Nomenclature (in
• May result in porencephalic cysts (which may be seen
Old Nomenclature Order of Discovery)
by ultrasound).
PlA1, PLA-1, ZWA HPA-1a Most common (>75%) • Sometimes intraventricular hemorrhage (IVH), lead-
(2% Whites, 0.4% Blacks, ing to arachnoiditis +/– hydrocephalus.
<0.1% Asians are negative) • Neonatal mortality is 5–13%.
PlA2, PLA-2 HPA-1b Worse severity • First case in family usually detected shortly after birth (due
Kob HPA-2a to petechiae, bleeding, or incidentally).
Koa HPA-2b
Baka, Leka HPA-3a Second most common (15% Factors affecting severity of disease
whites are negative)
Bakb, Lekb, PLA-3 HPA-3b
• Pregnancy order: Previous retrospective studies sug-
gested that subsequent pregnancies were always more
Pena, Yukb HPA-4a
severely affected than the index pregnancy complicated
Penb, Yuka HPA-4b More common in Asians
with FNAIT. However, a prospective study assessing
Brb HPA-5a
45 HPA-1a immunized women who had two or more
Br3, PLA-5 HPA-5b Third most common (<1% pregnancies, showed that the neonatal platelet count
whites are negative) Most in the subsequent pregnancies was the same or higher
common in Japan than the index pregnancy in 70% of cases. None of these
a High-frequency antigen. women received antenatal treatment for FNAIT [10].
b Low-frequency antigen. • HPA-1a antibody level: Increasing levels of maternal
Abbreviation: FNAIT, neonatal alloimmune thrombocytopenia. anti-HPA-1a antibody in subsequent pregnancies have
been associated with lower fetal/neonatal platelet lev-
• Only 2% of Caucasian women are HPA-1a negative (HPA- els compared with index pregnancies [10]. However,
1b/1b) [6]. in a systematic review examining the association with
• Only 10% of HPA-1a negative pregnant women develop maternal HPA-1a titers with severity of FNAIT, a single
anti-HPA-1a IgG antibodies [6]. antibody level was found to not be highly predictive of
• Rarely alloantibodies may also be made against human outcomes (positive predictive value of 54–97%) [11].
leukocyte antigens (HLA). • ICH in previous pregnancies: Fetal ICH related to FNAIT
• Human leukocyte antigens (HLA) are proteins located increases the recurrence risk of fetal ICH in subsequent
on white blood cells and other tissues including pregnancies, to approximately 80% without in utero treat-
platelets. ment [12, 13].
• There are 3 HLA groups (HLA-A, HLA-B and • Type of platelet antigen: HPA-1a alloimmunization causes
HLA-DR), each with many different proteins desig- severe disease; HPA-5b alloimmunization is less severe.
nated numerically (e.g. HLA-A1, HLA-A2, etc.). • Human leukocyte antigens (HLA): Human leukocyte
• HLA is inherited as a “set” of the three HLA groups – antigens (HLA) are proteins located on white blood cells
A, B, DR. and other tissues including platelets, and alloantibod-
• Each HLA set is a haplotype, and a haplotype is inher- ies can also be made against them. There is a known
ited from each parent. association between HPA-1a immunization and HLA-
• Of HPA-1a negative pregnant women who develop anti- DRB3*01:01. Based on recent systematic reviews and
HPA-1a IgG antibodies, ~1/3 are positive for the HLA-DR meta-analyses:
antigen B3*0101 (which is linked to HPA-1a). These women • The risk of becoming HPA-1a immunized is 25 times
are at high risk to become immunized against HPA-1a when more likely for women who are HLA-DRB3*01:01 posi-
they carry an HPA-1a positive fetus [6]. tive, compared to HPA-1a negative women expressing
this HLA allele [4].
The frequency of HPAs varies worldwide. In the Asian popu- • The level of anti-HPA-1a antibody is lower in HLA-
lations, HPA-4 incompatibility is the most common cause of DRB3*01:01 negative women compared to women who
FNAIT. have this allele [14].
• Neonatal platelet count is higher in children born to
Natural history/Complications HLA-DRB3*01:01 negative mothers [4, 14].
• The odds of severe fetal/neonatal outcomes are low for
The natural history of FNAIT ranges from mild asymptomatic HPA-1a-immunized women who are HLA-DRB3*01:01
fetal/neonatal thrombocytopenia to severe thrombocytopenia negative (OR 0.08, 95% CI 0.02–0.37) [4].
leading to intracranial hemorrhage with potentially severe peri-
natal morbidity and mortality. Diagnosis
• Ninety percent affected neonates having diffuse petechiae. The diagnosis is most often made retrospectively after delivery
• Ten percent to 30% ICH [7, 8]. of an infant with thrombocytopenia or fetal/neonatal ICH.
• Approximately 75% occur antenatally, as early as 20 Occasionally FNAIT may be diagnosed via family history if the
weeks. Based on a multicenter registry, approximately mother’s sister had an affected child or if prenatal screening was
54% occur prior to 28 weeks [9]. performed.
Fetal and Neonatal Alloimmune Thrombocytopenia
Indications for testing
• Neonate with petechiae and ecchymosis, unexplained
thrombocytopenia.
• Fetus with unexplained ICH, hydrocephalus, or porence-
phalic cyst.
• Woman incidentally found to be HPA-1a negative.
• Family history of NAIT.
Diagnostic criteria: Fetal or neonatal thrombocytopenia
(< 150,000 platelets/μL) plus identification of a paternal, fetal,
or neonatal platelet antigen with identification of maternal anti-
bodies to that specific antigen.
• Serologic testing
• Test parents in reference laboratory (e.g., Blood Center
of Southeastern Wisconsin).
• Initial testing: Maternal platelet antibody.
– If maternal antibody positive, perform mater-
nal and paternal human platelet antigen testing
simultaneously.
– Reference laboratories vary in the number of plate-
let alloantigens screened. They typically test for
HPA-1a and b, 3a and b, 4a and b, and 5a and b, but
cannot test for every platelet antigen.
Therefore, diagnosis is made if mother is antibody positive
(specific to father and fetal platelet antigen) and antigen negative.
The father’s antigen zygosity determines the risk of recur-
rence in subsequent pregnancies: 100% if father is homozygous,
50% if heterozygous. If the father is heterozygous for the incom-
patible antigen, fetal genotyping should be performed by CVS or
amniocentesis. Amniocentesis is the preferred testing modality
as there is theoretical concerns that CVS is more likely to lead to
exacerbation of maternal immune response.
This documentation of maternal, paternal, and neonatal
serologic diagnosis should be always reviewed to guide man-
agement in the next pregnancy.
Prevention and screening
Some have advocated routine universal maternal serologic
screening for platelet antigens to identify pregnancies at risk for
FNAIT before it happens in the first pregnancy without warning [15].
However, screening for HPA-1a alloimmunization detects about
two cases in every 1000 pregnancies. Severe NAIT occurs in
about 31% of these immunized pregnancies, and perinatal ICH
in about 10% of pregnancies with severe NAIT. Therefore, nearly
15,000 pregnancies would need to be screened to identify one
case of ICH for possible prevention [16].
Rationale against routine maternal
serologic screening
• Twenty-five percent of FNAIT is NOT caused by the most
common antigen.
• Maternal immune response is influenced by other factors
(e.g., HLA type).
• Only a minority of infants of mothers negative for platelet
antigen will develop significant thrombocytopenia.
• There are many false-negatives and false-positives.
• No major organizations consider maternal HPA-1a typing
an appropriate routine prenatal screening test.
• Screening by fetal ultrasound is not useful since fetal
thrombocytopenia cannot be detected by ultrasound, and
531
when it is so severe as to cause fetal ICH, it is too late for
effective intervention.
• Screening is not cost effective, given the low prevalence of
NAIT (1/1000 births) and the inability to predict the risk
of fetal ICH in pregnancies at risk but with no history of a
previously affected neonate.
• A prospective epidemiologic study estimated that it would
cost approximately $100,000 to detect one severe case of
NAIT and approximately $2,000,000 to prevent a case of
intracranial hemorrhage, assuming that early detection
allowed successful intervention [17].
Since there is no consensus regarding utility of screening unaf-
fected women for alloimmune antiplatelet antibodies, active
management of the disease is usually confined to women who
have had a previously affected fetus.
• Clinical history of affected sibling is the best indicator of
risk in current/future pregnancy.
• There is no correlation between platelet count at cordo-
centesis and degree of thrombocytopenia in previously
affected infant. How severe NAIT was in the last preg-
nancy is not as predictive.
• Only HPA-1a alloimmunization and past history of ICH
predict a more severe thrombocytopenia.
• Prior ICH: Greatest risk, only true predictor of severity.
• Fetal platelets in first-monitored pregnancy: 70%
<50,000/μL at first percutaneous umbilical blood sam-
pling (PUBS); 50% <20,000/μL, 50% <24 weeks. If the count
is >50,000/μL on first PUBS, it is still possible that it will
decrease later (in HPA-1a, fetal platelets decrease as much
as about 23,000/μL/week) [5].
• The father’s antigen zygosity and neonatal antigen
determines the risk of recurrence in subsequent pregnan-
cies: 100% if father is homozygous, 50% if heterozygous.
Management
Optimal management of FNAIT has not been determined, and
no one therapy is proven to be 100% effective [8, 18]. Studies are
which to base treatment are largely observational or small RCTs
due to the low incidence of FNAIT. There are some RCTs and
several case series that can help guide management. The current
preferred approach recommends risk-stratified management
with IVIG and prednisone without FBS [8]. This is an empiric
approach, which tries to avoid FBS, which is associated with sig-
nificant complications and pregnancy loss.
Principles
• Goal: Prevent hemorrhage, specifically ICH, in fetus
and neonate.
• ICH is rare with platelets >20,000/μL, therefore, the goal is
to keep platelets >20,000/μL. The normal platelet count
of a fetus ≥18 weeks is ≥150,000/μL, as in an adult.
• FBS with direct measurement of fetal platelet count is the
only method to assess disease severity.
There are two antenatal treatment options:
1. Intravenous immunoglobulin with or without corticoste-
roids (preferred option).
• >$1,000/dose.
532
• Most common initial therapy in North America.
• Pooled blood product, but risks of hepatitis and HIV
transmission are minuscule (donor screening and viral
inactivation procedures decrease risk).
• Usually given as weekly infusion over 6–12 hours.
• IVIG has unclear mechanism of action, but is theo-
rized to work via:
– Fc-receptor saturation in the placenta with a
reduction of antibody transfer across the placenta
(most probable main mechanism).
– Fc-receptor blockade on macrophages leading to
inhibition of uptake of the antibody-coated plate-
lets by fetal macrophages. Endothelial stabilization
prevents damage by maternal platelet antibodies
(low platelets not a cause of ICH).
– Suppression of maternal IgG antibody production.
• IVIG cannot only prevent/improve thrombocytopenia in
the majority of cases, it also prevents ICH. There are only
very rare reports of IVIG failures to prevent ICH [19].
• Side effects: Headaches and febrile reactions (pretreat
with Benadryl and acetaminophen).
• Only way to monitor efficacy of IVIG treatment is via FBS.
• 75% respond to weekly IVIG, with a 98.7% success
rate for preventing ICH [13]. For those that do not
response, half improve with the addition of high-dose
prednisone (1 mg/kg = 60 mg/day) [20]. Dexamethasone
has not been shown to be beneficial and has been associ-
ated with oligohydramnios and FGR [20].
• IVIG is administered with or without steroid adminis-
tration. Side effects of maternal steroid administration
include osteoporosis, hypertension, impaired glucose
tolerance and gestational diabetes, depressed immu-
nity, mood swings, and gastrointestinal irritation
2. Repeated intrauterine transfusion (IUT) of antigen-­
compatible platelets via FBS (abandoned).
• FBS as the main treatment option has largely been
abandoned due to significant procedure-related
risk.
• In the past, weekly in utero transfusion of platelets via
FBS was often required after 20 weeks.
• Goal was to prevent under-treatment which can result
in risk of ICH in utero and to avoid overtreatment
which is expensive and can cause adverse maternal
side effects.
• Empiric therapy has not been compared with fetal
blood sampling-indicated treatment in a randomized
trial.
• Risk of increasing sensitization due to feto-maternal
hemorrhage.
• Overall risk of complications associated with FBS
is 11%, with the most common reason being emer-
gency cesarean delivery for non-reassuring fetal
monitoring. Risk of perinatal death is 2.8% per
procedure [13]. Procedure-related fetal loss rates
are higher when the first IUT occurs <20 weeks (5%)
[21, 22].
• Platelet transfusions are best reserved for severe
cases refractory to other therapies such as IVIG and
steroids.
• FBS is now used primarily to assess response to IVIG
therapy, or to determine eligibility for vaginal deliv-
ery (performed at or after 32 weeks) [8].
Maternal-Fetal Evidence Based Guidelines
• If FBS is used to guide eligibility for vaginal deliv-
ery, goal platelet count is >100,000/μL [5].
• If FBS is performed to guide IVIG (and/or steroid)
therapy (usually between 20 and 35 weeks), the follow-
ing principles are generally followed:
– If adequate (platelet count ≥50,000/μL), continue
current regimen to term.
– If the first fetal platelet count is >20,000/μL while
on IVIG, the chance of platelet count >20,000/μL
at a later sampling is 89%, while if the first count
is ≤20,000/μL, this chance is only 51% [23].
Therefore, if the response is adequate (>50,000
μL), continue current regimen [23].
– If inadequate platelet count <50,000/μL,
increase therapy depending on current treat-
ment (up to maximum of IVIG 2 g/kg/week +
prednisone 1 mg/kg/d).
• FBS technique:
– Have platelets ready at any FBS, with slow transfu-
sion started after sampling even before platelet count
(PC) is available to minimize risk fetal hemorrhage.
– Transfuse maternal platelets (antigen negative),
packed, washed, and irradiated. Transfusion volume:
Aim for 200,000 to 400,000 platelets to avoid volume
overload, by using the equation in Table 54.2.
– Typical volume of platelet concentrate transfused
is 5–15 mL.
– Goal: Platelets >50,000/μL, and usually 200,000 to
400,000/μL.
– Because of risk of emergent delivery, corticoste-
roids for fetal lung maturity before FBS are sug-
gested at ≥24 weeks.
– In fetuses with platelets >80,000/μL at first FBS
and not treated, follow-up FBS showed decreases
of at least 10,000/μL/wk.
There is no evidence that prednisone alone is an effective
approach for empiric treatment of FNAIT [8, 13]
TABLE 54.2: Calculations for Fetal Platelet
Transfusion for FNAIT
Volume (in mL) to Raise Platelet Count by 50,000
(fetal weight in grams)(0.14)(50,000)(2)
=
Platelet count from labexpressed as per uLa
Platelet Goal Volume to Infuse
100,000
150,000
200,000
250,000
300,000
350,000
400,000
a If volume is given in milliliters, just divide by mL volume ×
1000; that is, if given total platelets is 6 million in 55 mL, then
(6,000,000/55,000) = platelet count from lab.
The factor of “2” is used in the numerator of the equation to allow
for possible platelet sequestration in the fetal spleen or liver
Then one can use the following chart to fill in, according to initial
fetal platelet count obtained at PUBS.
Abbreviation: FNAIT, neonatal alloimmune thrombocytopenia.
Fetal and Neonatal Alloimmune Thrombocytopenia 533

Risk-based fetal therapy for
pregnancies at risk for FNAIT
There is insufficient data to assess different types of interventions
for the pregnancy with NAIT. Current preferred management is
based upon the risk of ICH. Fetuses at highest risk are those with a
sibling affected by ICH [8, 12]. The earlier the ICH occurred in the
sibling, the greater the risk for intracranial hemorrhage in the cur-
rently affected fetus. The approach stated below is also consistent
with a 2017 systematic review assessing all available evidence for
treatment and concluded that a non-invasive approach consisting of
weekly IVIG with or without steroids is the preferred approach [13].
Risk is based on history of ICH in past pregnancy as defined
below [8]:
1. Standard risk: Previous child had thrombocytopenia
without intracranial hemorrhage
2. High risk: Previous child had an intracranial hemorrhage
in the third trimester or neonatal period
3. Extremely high risk: Previous child had an intracranial
hemorrhage in the second trimester
STANDARD RISK = Criteria for NAIT is met; previous sib-
lings with thrombocytopenia but NO in utero ICH (Figure 54.1).
A. At 20 weeks’ gestation, begin IVIG at 1 g/kg/week with
prednisone 0.5mg/kg/day
• Alternative regimen: IVIG at 2 g/kg/week; this option
was shown to be comparable in a RCT [24].
• Consider starting at the higher dose (2 g/kg/week) if
the initial platelet count of the affected neonate was
<20,000/μL at birth [23, 24].
• Some advocate using IVIG only as initial therapy due
to the side effects of prednisone [24].

History of:
Neonate with thrombocytopenia of unknown etiology
Neonate with thrombocytopenia with platelets <50,000, regardless of suspected etiology
Fetus or neonate with intracranial hemorrhage of uncertain etiology

Evaluate for maternal anti-platelet antibodies

OR history of immune thrombocytopenia Maternal Thrombocytopenia
Yes
No
Maternal platelet antigen typing
Paternal platelet antigen typing
Maternal platelet HPA antibody testing using sensitive assays*
*Perform in reference platelet laboratory

No incompatibility at HPA loci (1–5, 6, 9, 15) Maternal-paternal incompatibility at HPA loci Maternal-paternal incompatibility at HPA loci
Non-specific or No maternal anti-HPA (1–5, 6, 9, 15) AND specific maternal anti-HPA (1–5,6,9,15) Specific maternal anti-HPA antibody to any
antibodies present antibodies present of the above NOT present

Maternal anti-HPA antibody screening FNAIT DIAGNOSIS Maternal anti-HPA antibody screening and cross-
against paternal platelets at 30 weeks If positive If positive match with paternal platelets at 12, 20, 32 weeks

Father Homozygous Father Heterozygous PCR testing via amniocentesis (NOT

CVS) for fetal platelet genotype

Antigen Positive Fetus

Antigen-Negative Fetus

STANDARD RISK HIGH RISK VERY HIGH RISK

Prior Infant with Thrombocytopenia withOUT ICH Prior Fetus or infant with ICH < 28 weeks Prior Fetus or infant with ICH < 28 weeks
No further Evaluation Needed

EGA 20 weeks: EGA 12 weeks: EGA 12 weeks:

IVIG 1g/kg/week + prednisone 0.5mg/kg/day IVIG 1 to 2 g/kg/week IVIG 2g/kg/week
Alternative: IVIG 2g/kg/week

EGA 20 weeks:
EGA 20 weeks:
EGA 32 weeks: Increase IVIG to 2g/kg/week
Add prednisone 1mg/kg/day
IIVIG 2g/kg/week + prednisone OR add prednisone 0.5mg/kg/day
0.5mg/kg/day

EGA 28 weeks: Cesarean Delivery at 35–36 weeks

Cesarean Delivery at 37–38 weeks IVIG 2g/kg/week * Vaginal delivery only if FBS ≥ 33–34
* Vaginal delivery only if FBS ≥ 35–36 AND prednisone 0.5mg/kg/day weeks reveals >100,000 platelets
weeks reveals >100,000 platelets.

FIGURE 54.1 Suggested antenatal management for FNAIT. (Adapted from Pacheco LD, Berkowitz RL, Moise KJ. Fetal and neo-
natal alloimmune thrombocytopenia: a management algorithm based on risk stratification. Obstet Gynecol, 2011;118: 1157–1163.)
Abbreviations: FNAIT, fetal and neonatal alloimmune thrombocytopenia; ICH, intracranial hemorrhage; IVIG, intravenous immuno-
globulin therapy; FBS, fetal blood sampling; EGA, estimated gestational age.
534
• Treatment can be tailored to the patient after discus-
sion of adverse effects of both arms.
B. At 32 weeks, escalate therapy to IVIG at 2 g/kg/week
with prednisone 0.5mg/kg/day.
• Previous data recommended FBS to assess therapy at
32 weeks, but therapy prevented ICH in all 73 patients
[24]. Expanded data from those authors showed only
three cases of mild grade I ICH out of 100 cases,
which is similar to a group of normal term neonates
[8, 24]. Additionally, a 2016 RCT of 99 women showed
that omission of FBS with empiric escalation had
similar birth platelet counts as those undergoing FBS
and receiving escalated treatment due to counts <
50,000/μL at 32 weeks. Furthermore, this RCT showed
that compared to those neonates who did not receive
escalated therapy at 32 weeks, the higher dose of IVIG
with prednisone resulted in higher neonatal platelet
counts, demonstrating that the escalated therapy was
effective [25].
• Thus, current recommendation is escalate therapy
without FBS [8, 25].
C. Delivery at 37–38 weeks by cesarean section [8].
• For those desiring vaginal delivery, perform FBS at
35–36 weeks (see FBS technique earlier). Vaginal deliv-
ery at 37–38 weeks only recommended if FBS reveals
>100K platelets.
HIGH RISK = Previous sibling had in utero ICH in the third
trimester or neonatal period (Figure 52.1) [8, 12].
A. At 12 weeks’ gestation, begin IVIG at 1 to 2 g/kg/week
(Figure 54.1)
B. At 20 weeks’ gestation, either add prednisone 0.5 mg/kg/
day OR increase the dose of IVIG to 2 g/kg/week.
C. At 28 weeks’ gestation, give IVIG 2 g/kg/week AND
prednisone 0.5 mg/kg/day.
D. Deliver at 35–36 weeks by cesarean section.
• For those desiring vaginal delivery, perform FBS at 35–36
weeks (see FBS technique earlier). Vaginal delivery only
recommended if FBS weeks reveals >100K platelets.
VERY HIGH RISK = Previous sibling had in utero ICH <28
weeks (Figure 52.1) [8, 12].
A. At 12 weeks’ gestation, begin IVIG at 2 g/kg/week
(Figure 54.1).
B. At 20 weeks’ gestation, add prednisone 1 mg/kg/day.
C. Deliver at 35–36 weeks by cesarean section.
• For those desiring vaginal delivery, perform FBS at
35–36 weeks (See FBS technique earlier). Vaginal delivery
only recommended if FBS weeks reveals >100K platelets.
Other clinical concerns/issues regarding therapy
• Patients should avoid activities (i.e., sports) that could
result in potential trauma.
• External cephalic versions and NSAIDs are contraindicated.
• There are reported cases of ICH while receiving IVIG treat-
ment [19], so that IVIG should be considered a highly effective,
but not perfect therapy to prevent ICH (and in some situations
FBS and possible transfusions may still be indicated).
• Women with prior IVIG administration should have their
serum checked for HTLV I+II and Hep C antibodies.
Maternal-Fetal Evidence Based Guidelines
Other clinical scenarios
1. Personal history of fetal intracranial hemorrhage/neonatal
thrombocytopenia and HPA incompatibility but no anti-
bodies —> does NOT meet criteria for NAIT, but is at risk
of developing it as the pregnancy progresses [8].
• Perform serially testing of maternal serum for anti-
HPA antibodies at 12, 24, and 32 weeks of gestation
by both a panel of platelets expressing common HPA
antigens and cross-matching against paternal platelets
to detect alloimmunization to a rare antigen carried by
the father [8]. If antibodies are detected, treatment is
initiated as per standard risk.
2. Personal history of fetal intracranial hemorrhage/neona-
tal thrombocytopenia, but no HPA incompatibility and no
antibodies — > does NOT meet criteria for NAIT [8].
• Consider maternal serum for anti-HPA antibodies at
30 weeks of gestation, which includes cross matching
of maternal and paternal platelets, to check for devel-
opment of previously undetected antibodies. If nega-
tive, no further workup/treatment necessary.
3. No personal history of fetal intracranial hemorrhage or neo-
natal thrombocytopenia, but HPA incompatibility [8].
• Routine screening for HPA incompatibility is not rec-
ommended. However, if detected, perform serial test-
ing of maternal serum for anti-HPA antibodies for the
specific antigen associated with the incompatibility
at 12, 24, and 32 weeks of gestation. If antibodies are
detected, treatment is initiated as per standard risk.
4. Patient’s sister whose child may have or had FNAIT.
• Women who have a sister complicated by a pregnancy
confirmed or suggestive of FNAIT are at increased risk
of not having the same platelet antigen, and thus are
at risk for platelet incompatibility. These pregnancies
should be tested for platelet incompatibility, and if
positive, test for the presence of anti-HPA antibodies
as described in Scenario 1 [8].
Counseling
Prognosis, natural history and complications, and management
criteria should all be reviewed with the family. All patients
should be advised that the optimal management of NAIT has
not been determined and that no one therapy has proven to be
100% effective.
Investigations and consultations
With heterozygous father, consider amniocentesis to deter-
mine fetal antigen status by PCR (CVS only if mother would
terminate affected fetus). Multidisciplinary management should
involve a hematologist and the blood bank.
Fetal monitoring/testing
Serial ultrasounds may be performed every 4–6 weeks to evaluate
for ICH, but, if ICH is detected, it is too late for intervention to
prevent severe sequelae.
Anesthesia
No special precautions, since maternal platelets are usu-
ally normal, but 10% of women with FNAIT have gestational
thrombocytopenia.
Fetal and Neonatal Alloimmune Thrombocytopenia
Delivery
• Avoid fetal trauma: Avoid maternal abdominal trauma,
external cephalic version, fetal scalp lead, vacuum, or
forceps.
• There is no evidence to prove that cesarean delivery pre-
vents ICH.
• If platelet count >100,000/μL at the 35–36 weeks FBS, and
patient is compliant with the effective therapy, vaginal
delivery can be allowed. Therefore, in cases with platelets
>100,000/μL, trial of labor and attempt at vaginal delivery
can be considered [12].
Neonatology management
• Maternal platelets (Ag negative, obtained by plasmapher-
esis, plasma depleted, washed, irradiated, and packed)
should always be available for transfusion after delivery.
• Neonatal treatment is with IVIG, IV steroids, and antigen-
compatible platelets until platelet count recovers, usually
by 7–10 days of age.
• The volume of platelets transfused can be calculated as blood
volume × (desired platelet count – actual platelet count/
platelet concentration). For a term neonate, this equates to
1 cc platelet = increase platelet count by 5000/μL (10 cc =
50,000; 20 cc = 100,000). Often neonatologists choose to
transfuse 10 cc of platelets per kg of neonatal weight.
Future pregnancy preconception counseling
Management, events, and outcome of the pregnancy should be
reviewed with the family postpartum (after discharge of the neo-
nate). As stated above, the natural history of NAIT is that, if it
recurs (depending on father’s zygocity), it is more severe than in
the previous pregnancy.
• Recurrence risk is close to 100% of antigen (+) fetuses/
neonates [8].
• For women with high-risk and extremely high-risk prior
pregnancies, options include sperm donation using an
HPA-1b/1b donor or in vitro fertilization (IVF) with pre-
implantation genetic diagnosis (PGD) if the partner is a
HPA heterozygote (HPA-1a/1b).
References
1. Davoren A, McParland P, Crowley J, et al. Antenatal screening for human
platelet antigen 1a: results of a prospective study at a large maternity hospi-
tal in Ireland. Br J Obstet Gynecol 2003; 110:492–496. [II-2]
2. Kelton JG, Inwood MJ, Barr RM, et al. The prenatal prediction of thrombo-
cytopenia in infants of mothers with clinically diagnosed immune throm-
bocytopenia. Am J Obstet Gynecol 1992; 144:449–454. [II-2]
3. Taaning E, Skibsted L. The frequency of platelet alloantibodies in preg-
nant women and the occurrence and management of neonatal alloimmune
thrombocytopenic purpura. Obstet Gynecol Surv 1990; 45:521–525. [II-2]
4. Kjeldsen-Kragh J, Fergusson D, Kjaer M, et al. Fetal/Neonatal alloimmune
thrombocytopenia: a systematic review of impact of HLA-DRB3*01:01 on
fetal/neonatal outcome. Blood Adv 2020; 4(14):3368–3377. [Systematic
review]
535
5. Bussel JB, Zabusky MR, Berkowitz RL, et al. Fetal alloimmune thrombocy-
topenia. N Engl J Med 1997; 337:22–26. [II-3]
6. Peterson JA, McFarland JG, Curtis BR, et al. Neonatal alloimmune throm-
bocytopenia: pathogenesis, diagnosis and management. Br J Haematol
2013; 161:3–14. [Literature review]
7. Spencer JA, Burrows RF. Feto-maternal alloimmune thrombocytopenia: a
literature review and statistical analysis. Aust N Z J Obstet Gynaecol 2002;
41:45–55. [Literature review]
8. Pacheco LD, Berkowitz RL, Moise KJ. Fetal and neonatal alloimmune
thrombocytopenia: a management algorithm based on risk stratification.
Obstet Gynecol 2011; 118:1157–1163. [Literature review]
9. Tiller H, Kamphuis MM, Flodmark O, et al. Fetal intracranial haemor-
rhages caused by fetal and neonatal alloimmune thrombocytopenia: an
observational cohort study of 43 cases from an international multicentre
registry. BMJ Open 2013; 3(3):e002490. [II-2]
10. Tiller H, Husebekk A, Skiogen B, et al. True risk of fetal/neonatal alloim-
mune thrombocytopenia in subsequent pregnancies: a prospective obser-
vational follow-up study. Br J Obstet Gynecol 2016; 123(5):738744 [II-2]
11. Kjaer M, Bertrand G, Bakchoul T, et al. International collaboration for trans-
fusion medicine guidelines. Maternal HPA-1a antibody level and its role in
predicting the severity of fetal/neonatal alloimmune thrombocytopenia: a
systematic review. Vox Sang 2019; 114(1):79–94. [Systematic review]
12. Bussel JB, Berkowitz RL, Hung C. Intracranial hemorrhage in alloimmune
thrombocytopenia: stratified management to prevent recurrence in the
subsequent affected fetus. Am J Obstet Gynecol 2010; 203:135.e1. [I, based
on 2 RCTs, n = 37 pregnancies]
13. Winkelhorst D, Murphy MF, Greinacher A, et al. Antenatal management
in fetal and neonatal alloimmune thrombocytopenia: a systematic review.
Blood 2017; 129(11):1538–1547. [Systematic review]
14. Kjeldsen-Kragh J, Titze TL, Lie BA, et al. HLA-DRB3*01:01 exhibits a
dose-dependent impact on HPA-1a antibody levels in HPA-1a-immunized
women. Blood Adv 2019; 3(7):945–951. [II-2]
15. Tiller H, Killie MK, Skogen B, et al. Neonatal alloimmune thrombocyto-
penia in Norway: poor detection rate with non-screening versus a general
screening programme. Br J Obstet Gynecol 2009; 116:594–598. [II-3]
16. Kamphuis MM, Paridaans N, Porcelijn L, et al. Screening in pregnancy for
fetal or neonatal alloimmune thrombocytopenia: systematic review. Br J
Obstet Gynecol 2010; 117:1335–1343. [Systematic review]
17. Turner ML, Bessos H, Fagge T, et al. Prospective epidemiologic study of
the outcome and cost-effectiveness of antenatal screening to detect neona-
tal alloimmune thrombocytopenia due to anti-HPA-1a. Transfusion 2005;
45:1945. [II-2]
18. Rayment R, Brunskill SJ, Soothill PW, et al. Antenatal interventions for
feto-maternal alloimmune thrombocytopenia. Cochrane Database Syst Rev
2011; (5):CD004226. [Systematic review]
19. Kroll H, Kiefel V, Giers G, et al. Maternal intravenous immunoglobulin
treatment does not prevent intracranial haemorrhage in fetal alloimmune
thrombocytopenia. Transfus Med 1994; 4(4):293–296. [II-2]
20. Bussel JB, Berkowitz RL, Lynch L, et al. Antenatal management of alloim-
mune thrombocytopenia with intravenous gamma-globulin: a randomized
trial of the addition of low dose steroid to intravenous gamma-globulin. Am
J Obstet Gynecol 1996; 174(5):1414–1423. [RCT, n = 54]
21. Lindenburg ITM, van Kamp IL, van Zwet EW, et al. Increased perinatal loss
after intrauterine transfusion for alloimmune anaemia before 20 weeks’
gestation. Br J Obstet Gynecol 2013:847–852. [II-2]
22. Paidas MJ, Berkowitz RL, Lynch L, et al. Alloimmune thrombocytopenia:
fetal and neonatal losses related to cordocentesis. Am J Obstet Gynecol
1995; 172:475–479. [II-3]
23. Gaddipatti S, Berkowitz RL, Lembert AA, et al. Initial fetal platelet counts
predict the response to intravenous gammaglobulin therapy in fetuses
that are affected by PLA1 incompatibility. Am J Obstet Gynecol 2001; 185:
976–980. [II-2]
24. Berkowitz RL, Lesser ML, McFarland JG, et al. Antepartum treatment with-
out early cordocentesis for standard-risk alloimmune thrombocytopenia.
Obstet Gynecol 2007; 110:249–255. [RCT, n = 73]
25. Lakkaraja M, Berkowitz RL, Vinograd CA, et al. Omission of fetal sam-
pling in treatment of subsequent pregnancies in fetal-neonatal alloim-
mune thrombocytopenia. Am J Obstet Gynecol 2016; 215(4):471.e1–9.
[RCT, n = 99]
55
HEMOLYTIC DISEASE OF THE FETUS AND NEWBORN
Pedro Argoti, Ana M. Angarita, and Giancarlo Mari
Key points
• The formation of maternal antibodies to fetal red blood cell
(RBC) antigens is called RBC alloimmunization and can
lead to hemolytic disease and anemia of the fetus and new-
born (HDFN).
• The most common antigens causing alloimmunization in
the United States today are Rh(D) and Kell. IgG alloanti-
bodies cross the placenta, bind to the antigens on the fetal
RBCs, and can lead to hemolysis. Kell alloimmunization is
mainly caused by previous blood transfusions but may also
occur by maternal-fetal hemorrhage during pregnancy.
• Anti-D immune globulin prophylaxis reduces the rate
of Anti-D alloimmunization to less than 0.2% if given
both antepartum and postpartum. ACOG recommends
anti-D immunoglobulin to unsensitized Rh(D) negative
women at 28 weeks of gestation, and a second dose, if the
newborn is Rh(D) positive, within 72 hours after birth.
Routine antibody screening before antenatal prophylaxis is
advised. Anti-D immune globulin can be given as late as
28 days postpartum if previously not given but indicated
(the longer prophylaxis is delayed after delivery, the less
likely to be effective). The routine anti-D immunoglobu-
lin prophylaxis dose used in the United States consist of a
300 μg (1 μg = 5 IU) (single dose) at 28 weeks’ gestation, as
well as an additional and similar dose after delivery, if the
neonate is Rh(D) positive (for exposures up to 30 mL of Rh
D-positive fetal whole blood). Other antenatal dosing regi-
mens exist, e.g. 100 μg at 28 and 34 weeks. Screening for
excessive fetal-maternal hemorrhage is recommended
for all Rh-D negative women giving birth to an Rh-D
positive infant. The appropriate dose of anti-D immune
globulin should be given accordingly.
• Mothers with a weak or partial D phenotype (formerly
called Du) should receive anti-D prophylaxis.
• Currently, there are no prophylactic immune globulins
to prevent alloimmunization from antigens other than
Rh(D). Antigen testing for K antigens is not routinely per-
formed on blood donors in the United States.
• Management of the alloimmunized pregnancy is shown in
Figure 55.1. Paternal and/or fetal genotyping for antigen
status determination, should be undertaken when feasible.
• Fetal genotype is typically determined invasively by
polymerase chain reaction (PCR) analysis of amnio-
cytes or non-invasively with cell free DNA testing of
maternal serum or plasma.
• Most laboratories consider 16 as the critical antibody
titer for Rh(D) and non-Rh(D) alloimmunized pregnan-
cies, except for Kell-immunized pregnancies in which
case 4 is considered the critical titer.
• The middle cerebral artery peak systolic velocity (MCA-
PSV) performs well as a screening tool for severe fetal
536
anemia of any etiology and it is associated with a reduc-
tion in the number of invasive tests. Screening with MCA-
PSV can be started as early as 15 weeks. If the MCA-PSV
is ≥1.5 multiples of the median (MoM), fetal blood sam-
pling (FBS) is indicated. Blood transfusions should be ini-
tiated for fetal hemoglobin <5th percentile, 2SD below the
mean for gestational age or HTC <30%.
Definition
Red blood cells (RBC) alloimmunization, formerly known as
isoimmunization, or erythroblastosis fetalis, is the formation
of maternal antibodies to fetal RBC antigens [1]. This immu-
nologic response can cause hemolytic disease of the fetus and
newborn (HDFN) which is associated with serious morbidity and
mortality.
Epidemiology/Incidence
More than 50 RBC antigens have been reported to be associated
with HDFN some of the antibodies include anti Rh e/E (Rhesus
group), Fy(a)/Fy(b) (Duffy group), Kidd, anti-M (MNS system),
etc. [2]. However, only few antigens are commonly implicated
in HDFN including the Rh(D), Kell, Rh(c) and Rh(E) antigens
[3, 4]. The incidence of alloimmunization has been reported to be
between 0.4 and 1.2% [5, 6]. A recent large retrospective study
estimated an incidence of HDFN of 0.6 per 1000. Of the pregnan-
cies at risks (cognate positive newborn), about a third developed
HDFN [4]. Non anti Rh D antibodies have become more impor-
tant causes of fetal hemolytic anemia. The introduction of Rh
(D) immunoglobulin in 1968 has greatly decreased the incidence
of HDFN [7, 8]. In a large prospective series in the Netherlands,
screen positive pregnancies were noted in 1232 per 100.000 preg-
nancies. Anti (D) antibodies in 7% of screen-positive samples and
HDFN relevant antibodies other than anti (D) in 26% of screen-
positive samples. Severe HDFN, requiring intrauterine or post-
natal (exchange) transfusions, occurred in 3.7% of fetuses at
risk [2]. Kell sensitized pregnancies account for 10% of cases of
HDFN that undergo intrauterine transfusion [9]. In developing
nations, stillbirth occurs in 14% of Rh(D) alloimmunized preg-
nancies and 50% of the survivors will either die if untreated or
will develop brain damage [10].
Genetics
Rh(D) negative genotype, implies that the Rh (D) gene (cytogenetic
location: 1p36.11) is either absent or altered resulting in gene inac-
tivation [11]. More than 170 distinct D alleles capable of expressing
D variant antigens have been described [11]. A clinically relevant
variant is the “partial D” or “weak D”, also known as Rh mod, D(u),
D(el). Either decreased expression of intact D antigens or miss-
ing “epitopes” of the same antigens, explain this phenotype [12].
DOI: 10.1201/9781003099062-55
Hemolytic Disease of the Fetus and Newborn 537

Alloimmunization

Previously
First affected
affected
pregnancy
pregnancy

Titers surveillance

Critical antibody titer

Paternal
antigen status

Negative Not available Positive

Paternal
zygosity

Heterozygous Homozygous

Routine Not at risk of Fetal

prenatal care fetal anemia genotyping
(Amniocentesis
or cfDNA)

Negative Positive

At risk of fetal
anemia

MCA PSV

≥ ≥ MCA PSV
≤
Cordocentesis 1.5 MoM 1.5 MoM Surveillance
1.5 MoM
(<35 weeks) (>35 weeks)

Delivery

FIGURE 55.1 Algorithm for clinical management of alloimmunization. Abbreviations: MCA, middle cerebral artery; PSV, peak
systolic velocity; MoM, multiple of the median.

Women with these variants may become alloimmunized, as thus
the American Association of Blood Banks (AABB) recommends
that transfusion recipients be characterized as Rh(D) [13]. By the
same rationale, ACOG recommends to administer Rh (D) immu-
noglobulin to women with this variant [14].
Etiology/Basic pathophysiology
Maternal RBC alloimmunization occurs when the immune sys-
tem is sensitized to foreign erythrocyte antigens, stimulating the
production immunoglobulin G (IgG) antibodies.
538 Maternal-Fetal Evidence Based Guidelines

Two conditions are necessary for the development of HDFN: stillbirth), fetal death [22], trauma, spontaneous or induced abor-
tion (including pregnancy-related uterine curettage) [8], threat-
1. Transplacental transfer of antibodies (Ig M does not cross ened abortion [23], ectopic pregnancy [24], molar pregnancy [25],
the placenta, therefore it is not associated with HDFN e.g. antepartum vaginal bleeding (e.g. placenta previa or abruptio
Lewis, I and P). placentae) [26], invasive obstetric procedures (CVS, amniocen-
2. Presence of the cognate antigen in the fetal RBC (If the fetus tesis, cordocentesis, fetoscopy, multifetal reduction) [27], exter-
is negative for the antigen or the antigen is not expressed in nal cephalic version (ECV) [28]. In 80% of cases, no recognizable
fetal life, then there is not risk of HDFN e.g. Lu(b) and Yta). fetomaternal bleeding event is identified [14]. Fetomaternal
bleeding can also occur spontaneously, and its incidence and vol-
IgG antibodies cross the placenta, bind to the antigens present ume increases with gestational age (GA) (3%, 12%, and 46%, per
on the fetal RBCs, and can cause hemolysis. trimester respectively) and is highest at delivery (64%) [29]. The
Hemolysis leads to extramedullary erythropoiesis, reticuloen- larger the volume of allogenic blood exposed to, the higher the
dothelial clearance of RBC, fetal anemia, hydrops and eventually likelihood of alloimmunization.
fetal death [15]. The Kell antigen is present in fetal cells early in A volume of fetal RBCs of 0.1 mL or less can result in allo-
development and it is also expressed on bone marrow erythroid immunization [29]. Blood transfusion is likely the most common
progenitor cells. Anti-Kell alloimmunization leads to hemoly- mechanism of anti-Kell alloimmunization as antigen testing for
sis of RBC as well as suppression of normal erythropoiesis [16, Kell antigen is not routinely performed in blood donors in the
17]. The presence of multiple antibodies seems to predict a more United States [30]. Exposure to other people’s blood via contami-
rapid decline in fetal hemoglobin [18]. nated needles is also considered a potential source of alloimmu-
HDFN results from exposure to a foreign RBC antigen. nization [31].
Sensitization results most frequently from fetomaternal bleeding Following sensitization, future exposure to the same antigen in
or previous blood transfusion to the mother [19]. It is believed subsequent pregnancies will elicit a humoral response of unpre-
that hydrops fetalis (fluid accumulation in at least two compart- dictable intensity and timing. Each subsequent pregnancy fol-
ments such as skin, pleura, peritoneum, etc.) is the consequence lowing the first HDFN-affected pregnancy has a higher risk
of hepatic extramedullary erythropoiesis, and it is more likely of more severe disease at an earlier gestational age. Besides
when the fetal hemoglobin deficit is at least 7 g/dL below the volume, among other factors that influence the immunologic
mean for gestational age (hemoglobin <5 g/dL) [20]. response are the frequency of FMH and ABO compatibility [32].
Fetal hyperbilirubinemia in utero is not a problem as fetal bil- ABO incompatibility decreases the risk of Rh alloimmunization
irubin crosses the placenta and it is conjugated by the mother. likely through prompt elimination of ABO incompatible fetal
During the neonatal period, hyperbilirubinemia and kernicterus RBCs with decreased exposure of D-positive RBC to the maternal
are significant contributors of morbidity and mortality and man- immune system [33].
agement revolves around it. Management consists intensive pho-
totherapy and exchange transfusions [21].
Potential situations that can result in fetomaternal hemor- Screening
rhage (FMH) are many (Table 55.1) [14]: Delivery (live birth or
ABO and Rh type and antibody screen should be ordered in all
pregnant women at the initial prenatal visit [34]. Rh Type, iden-
TABLE 55.1: Risk of Red Blood Cell Alloimmunization in tifies Rh negative women at risk of developing Rh disease who
Different Clinical Situations are candidates for Rh immunoglobulin [34]. Antibody screening
Risk of Red Blood Cell identifies pregnancies at risk of HDFN and affords the opportu-
Clinical Situation Alloimmunization (%) nity to stratify the risk (antibody titer) and to guide management
[34]. Antibody screen should be repeated between 24–28 weeks
D&C 4–5 before the routine antenatal dose of Rh immunoglobulin [14].
Spontaneous miscarriage 1–2 The rationale behind this recommendation is the identification
Chorionic villus sampling 14 of women who had become alloimmunized and manage them
Amniocentesis 7–152-7 accordingly [14].
External cephalic version 2–6
Threatened abortion 3–11↑ (controversial)
Antepartum hemorrhage ↑↑
Prevention (Anti-D immune globulin)
Placenta previa with bleeding ↑ Unfortunately, there is no immune globulin available for pre-
Suspected abruption ↑ vention of RBC alloimmunization for antigens other than
Blunt trauma to abdomen ↑ Rh(D).
(including motor vehicle accidents)
Fetal death ↑ • Source: Most anti-D immune globulin is extracted by cold
Fetal blood sampling ↑ alcohol fractionation or ion exchange chromatography
Fetal surgery ↑
from pooled plasma of individuals with high-titer anti (D)
IgG antibodies (typically from alloimmunized Rh (D) nega-
Ectopic pregnancy ↑
tive male volunteers).
Partial molar pregnancy ↑
• In order to minimize the potential risk of infection trans-
Manual removal of the placenta ↑ mission and allergic reactions and to enhancing avail-
Source: Adapted from data in Refs. [6, 14]. ability; synthetic anti-D immunoglobulins have been
Hemolytic Disease of the Fetus and Newborn
investigated [35, 36]. No synthetic preparations are cur-
rently available for clinical use.
• Mechanism of action: The mechanism of action remains
elusive. Macrophage mediated clearance of antibody
labeled RBC as well as down regulation of antigen specific
B cells are possible [32].
• Dosage: 300 µg (standard dose) of anti-D immunoglob-
ulin can prevent Rh (D) alloimmunization, following
exposure of up to 30 mL of Rh (D) positive fetal whole
blood or 15 mL of Rh (D) positive fetal RBC [37]. In the
first trimester, 50 µg (microdose) of Anti-D immunoglobu-
lin is an option as it prevents alloimmunization for expo-
sures up to 2.5 mL of fetal RBC. The mean fetal RBC volume
at 12 weeks of gestation is below this 1.5 mL. However, the
standard dose (300 µg) may be more readily available, and
it is also appropriate.
• Pharmacology: The median half-life of Rh immunoglob-
ulin is 21 days regardless of the route of administration
(IM or IV). Peak serum levels (C max) are higher with IV
versus IM administration (71 versus 22 ng/mL). Mean time
taken to reach maximum concentration (T max) IV ver-
sus IM administration (1 versus 5.5 days) [38, 39]. A low
maternal anti Rh (D) titer (typically <4) can be detected
for several weeks after the administration of Rh immu-
noglobulin [38].
• Efficacy: Before the implementation of Rh(D) immuno-
globulin prophylaxis, 16% of Rh (D) negative women
would become alloimmunized after delivering two Rh (D)
positive/ABO compatible infants [40]. With routine post-
partum administration of a single dose of Rh (D) immuno-
globulin the rate of alloimmunization dropped to 1–2% [41].
With routine postpartum administration plus a third
trimester dose of Rh (D) immunoglobulin the rate of allo-
immunization, further dropped to 01–0.2% [42]. These
benefits are seen regardless of the ABO status of the mother
and neonate. HDFN continues to be the leading cause of fetal
anemia despite the introduction of Rh D immunoglobu-
lin prophylaxis. Possible contributors to the persistence of
this condition are unrecognized fetomaternal hemorrhage
events, less than optimal Rh D immunoglobulin use when
indicated, no universal pre-transfusion Kell typing protocols,
and lack of prophylaxis for other RBC antigen [43].
• Side effects: Theoretical concerns include: 1) Enhanced pri-
mary immune response to Rh (D) positive RBC (not shown
in trials) [44, 45]. 2) Allergic reactions: The majority of stud-
ies have reported no serious reactions. Manufacturers’ data
have revealed sporadic serious reactions (out of million
doses administered) possibly related to Rh immunoglobu-
lin administration [44]. 3) Fetal anemia due to the passive
transfer of antibodies: The dose seems to be too small to
cause anemia and no reports of fetal anemia related to Rh
immunoglobulin administration exist. 4) Less effective
postpartum rubella immunization: There is no published
evidence to substantiate this concern. 5) Immunologic dys-
regulation in the offspring of antenatal exposure to Rh (D)
immunoglobulin: There is no published evidence to sup-
port this concern. 6) Bloodborne infection transmission:
As the source of immunoglobulin is human plasma, viral
transmission is possible. Although hepatitis C transmis-
sion has been reported in the past [46], newer methods of
immunoglobulin extraction (e.g. cold alcohol fractionation
539
and ion exchange chromatography isolation) and strict pro-
tocols for infectious screening of donor’s plasma make viral
transmission unlikely [47] 7) Transmission of prions asso-
ciated with Creutzfeldt-Jakob disease: The risk estimation
is unquantifiable, and no evidence of transmission exists,
however, as a precaution the immunoglobulin used in the
United Kingdom is manufactured in the United States.
• Indications
1. ACOG recommend routine antenatal and postpar-
tum prophylaxis in Rh (D) negative, non alloim-
munized pregnancies, unless paternity is certain,
and the father is known to be Rh negative [14]. A
concern with this strategy is the mean rate of non-
paternity, that has been estimated to be 3% [48]. A
cost analysis revealed that in the United States., this
strategy, universal prophylaxis with paternity consid-
eration, compared to prophylaxis without paternity
consideration, results in lower charges but, it leads to
more cases of alloimmunization [49]. Routine single
dose of prophylactic Rh Immunoglobulin (300 µg) at
28 weeks’ gestation: In the United States, if a woman
is Rh (D) negative and the antibody screen is nega-
tive for anti–D antibodies, the patient is given anti-D
immune globulin [14]. Repeat antibody screening
(in addition to the first prenatal visit antibody
screen), previous to Rh immunoglobulin adminis-
tration at 28 weeks of gestation, is recommended
[14]. Alternative dose regimens are available in other
countries.
2. Following delivery: If the newborn is Rh (D) posi-
tive (cord blood typing), and the mother is not
sensitized, the patient is given a second dose of Rh
immune globulin, as soon as possible within the ini-
tial 72 hours after delivery [14]. Rh immunoglobulin
can be given up to 13 days post exposure (e.g. delivery),
however, based on experimental data, some experts
recommend immunoglobulin administration as late
as 28 days port exposure, with the understanding that
the longer prophylaxis is delayed, the less likely it is
to be effective [8]. 300 µg suffice in the majority of
cases (exposure of up to 30 mL of Rh (D) positive
fetal whole blood). Larger volumes of fetomaternal
bleeding (>30 mL) occurs rarely at a rate of about
2–3 cases per 1000 deliveries [50]. Larger bleeding
(>30 mL) is only identified in 50% of cases based on
risk factors such as placental abruption, Caesarean
delivery, etc. [51]. Therefore, assessing the volume of
fetomaternal bleeding in all non-sensitized pregnan-
cies who deliver Rh D positive newborns, is recom-
mended [14].
A suggested stepwise approach to testing consists of:
a. The rosette test (qualitative test): Suggested as the
initial test. It consists on the visualization under
light microscopy of “rosettes” or small agglutinates
of fetal cells, following incubation of maternal blood
with Rh (D) immunoglobulin and addition of an
enzyme-treated indicator. The Rosette test is sensi-
tive, and it is reported as negative, with volumes of
<2 mL or 0.04% of fetal RBC in maternal circula-
tion [52]. If the rosette test is negative, no additional
doses of immunoglobulin are needed. If the rosette
540
test is positive, either the Kleihauer–Betke test or
flow cytometry test are ordered.
b. The Kleihauer–Betke (KB) test (quantitative test):
Suggested as an alternative follow up test in case
of a positive Rosette test. It consists of the expo-
sure of a maternal blood smear to an acid solution.
HbF is resistant to acid, while HbA is removed.
The smear is then stained via Shepard’s method,
coloring fetal cells “pink-rose,” while the maternal
cells to not uptake the stain and have a “ghost-like”
appearance. The percentage of fetal to maternal
RBC is calculated. Although the KB test lacks pre-
cision and standardization, it does not require spe-
cial equipment [53].
c. Flow cytometry (FC) (quantitative test): Suggested
as an alternative follow up test in case of a positive
Rosette test, and preferred to KB test if available.
FC consist on the use monoclonal antibodies tar-
geted to HbF or Rh D antigens with quantification
of fluorescence. The test is sensitive and accurate
but may not be readily available [53].
The MFH volume is calculated by multiplying the
percentage of red blood cells by 50. Fifty is the factor
representing the average maternal blood volume (5 L).
If additional doses of immunoglobulin are indicated,
the transfusion medicine service should be consulted
if available. The number of vials needed is calculated
as follows: Fetomaternal bleeding volume divided by 30
(one vial or 300 µg prevent alloimmunization of expo-
sure up to 30 ml of fetal blood) [13]. One vial (standard
dose) = 300 µg of Rh D immunoglobulin. In order to
avoid underdosing, the AABB recommends rounding
up a fractional unit >0.5% and adding an additional
vial [13, 54]. In case of large fetomaternal bleeding, do
not exceed five (300 µg) doses, intramuscularly, over a
24-hour period. An alternative is the administration of
an intravenous preparation of no more than 600 µg every
8 hours, until the total calculated dose is completed
3. In the United States, Rh (D) immunoglobulin admin-
istration is recommended for Rh(D) negative women
whose antibody screen is negative for anti (D) antibod-
ies (non alloimmunized), carries a known Rh (D) posi-
tive or likely positive fetus and has an event potentially
associated with disruption of the fetomaternal inter-
phase and lead to fetomaternal bleeding [14]. These
events were discussed before in the pathophysiology
section (Situations That Can Result in Fetomaternal
Hemorrhage).
While ACOG [14] and the Society of Family Planning
among other societies, continue to recommend the
administration of Rh immunoglobulin to all Rh nega-
tive women with spontaneous or induced abortion; the
National Abortion Federation released a statement
in 2019 [55], recommended that it is reasonable to
forego Rh typing and immunoglobulin administra-
tion for any type of induced abortion under 8 weeks
of gestation and medication abortion under 10 weeks
of gestation as estimated by last menstrual period.
Currently, there is no strong evidence against or in
favor of either policy.
Maternal-Fetal Evidence Based Guidelines
Alternative strategies for selective administration of pro-
phylactic Rh (D) immunoglobulin (e.g. based on paternal and/or
fetal (D) typing), including the use of cell-free DNA have been
explored and are currently the standard of care in several coun-
tries [56–58].
1. Cell-free DNA for Rh genotyping and selective admin-
istration of prophylactic Rh (D) immunoglobulin is a
promising strategy. The test has excellent performance.
A metanalysis of the accuracy of cell free DNA testing for
fetal Rh genotyping that included 30 studies and 10,290
tests (first and second trimesters) reported a summary
sensitivity of 0.993 (95% CI 0.982–0.977), specificity of
0.84 (95% CI 0.964–0.993), positive likelihood of 61 (95%
CI 22–167), and negative likelihood ratio of 0.007 (95% CI
0.003–0.186) [59]. Support to the cost effectiveness of this
strategy in Australia [60], and in the United Kingdom (if
the overall cost of testing is < £24) has been reported [56].
A cost analysis in the United States, that modeled the costs
related to the care of subsequent alloimmunized pregnan-
cies and used historical data from a large database failed to
support cost effectiveness of this strategy, in comparison
to universal prophylaxis [49]. ACOG currently, does not
endorse the routine use of fetal Rh D genotyping for guid-
ing immunoprophylaxis [14].
2. Immunologic determination of paternal Rh type and
selective administration of prophylactic Rh (D) immu-
noglobulin. A cost-effectiveness analysis in Canada sug-
gests that the routine use of Rh immunoglobulin at 28
weeks of gestation compared with an strategy of immu-
nologic determination of paternal Rh type is equally cost
effective, however, routine prophylaxis is the preferred
option as paternal typing would most likely not be carried
out by the majority of clinicians [61].
Management of RBC
alloimmunized pregnancies
Counseling
Pregnancies at risk are identified on the basis of the obstetric his-
tory (HDFN) or when a maternal antibody screening test reveals
an alloantibody associated with HDFN.
Estimation of the risk of fetal anemia, is paramount for guid-
ing management [15, 47]. With the advent of non-invasive meth-
ods for fetal surveillance such as the use of the MCA Doppler
and the decline of invasive procedures such as amniocentesis and
intrauterine transfusion procedures, the outcomes have greatly
improved and the perinatal mortality has decreased [62, 63]. A
recent retrospective single center study at a tertiary care center
in Canada over a 6-year period reported a rate of alloimmuniza-
tion (clinically significant alloantibodies) of 0.4% (128/32,750).
Sixty-two percent of alloimmunized patients had a titer over 32
(considered critical). Overall, 53% of the neonates had a positive
phenotype status (CoAg+) for the cognate antigen of the mater-
nal antibody (at risk of HDFN). Seventy-eight percent of anti-Kell
alloimmunized pregnancies delivered CoAg- neonates (not at
risk), conversely, only 5% of anti Rh D alloimmunized pregnancies
delivered CoAg- neonates. HDFN was diagnosed in 28% of CoAg+
newborns. The majority of cases of HDFN (57%) involved the
anti-D antibody. Three percent of fetuses underwent intrauterine
Hemolytic Disease of the Fetus and Newborn
transfusions. Among the cases of HDFN, 58% required observa-
tion alone, 23% intensive phototherapy, 9% top up transfusion, 3%
exchange transfusion, no neonatal or fetal deaths occurred [4].
Due to the immune anamnestic response (memory), subsequent
alloimmunized pregnancies (second, third or fourth gestations)
tend to result in more severe HDFN (fetal anemia is usually more
severe and develops earlier in gestation). Repeated exposure to the
same antigen leads to a more “efficient” response [64].
Outcomes
Fetal outcomes
Perinatal survival has been consistently reported as higher
than 90% [65]; when fetal hydrops is present, the survival
rate is >80% [66]. There is no trial that has assessed the best
management for RBC alloimmunized pregnancies; however,
fetal transfusion is probably the most beneficial of all the avail-
able therapies. Although it is reported that the risk of fetal
demise is between 1% and 2% for each FBS, there are situa-
tions in which the risk is much higher, such as when cordocen-
tesis and transfusions are performed at (GAs) as early as 15–18
weeks [67]. Severe fetal anemia in utero may lead to an increased
risk of fetal brain damage with some intracranial structures at a
particularly higher risk of injury due to increased susceptibility
to insults [68].
Long-term neurologic outcomes after common fetal inter-
ventions have been reported [69]. They reported the outcomes
of 564 patients (4 studies) that underwent intrauterine transfu-
sion (IUT) due to alloimmunization. Studies with follow up to
24 months after delivery were included. In this study, perina-
tal mortality rates were 12% in cases of alloimmunization.
Neurologic outcomes were classified as normal, mild impairment
and severe impairment. In cases of alloimmunization, normal
outcomes were reported in 82% of cases, mild impairment in
13% of cases, and severe impairment in 5% of cases.
The outcomes of a large cohort of children that underwent IUT
(291 children) have been reported [70]. This study had a follow up
median of 8.2 years. The reported perinatal survival rate was
91%. Cerebral palsy was noted in 2.1%, severe developmental
delay in 3.1%, bilateral deafness in 1%. The overall incidence
of neurodevelopmental impairment was 4.8%. Hydrops was
independently associated with neurodevelopmental impairment
(OR 11.2 (95% CI 1.7–92.7).
Only few small studies have addressed the long-term effects of
fetal anemia and IUT in the cardiovascular system. Myocardial
hypertrophy in neonates with hemolytic disease has been
described [71]. In a follow-up study in children affected by HDFN
and received IUT, echocardiogram evaluation suggested signifi-
cant smaller left ventricular mass in these children [72].
Maternal outcomes
Intrauterine transfusion is associated with a high risk of addi-
tional RBC antibody production, and the risk exceeds that of any
poly-transfused group. Up to 25% of women who undergo intra-
uterine transfusions develop new antibodies, and after delivery
up to 72% of patients have multiple RBC antibodies. [73, 74]. The
mechanism of this phenomenon is unclear.
Workup/Investigations required
Management of the alloimmunized pregnancy is shown in
Figure 55.1. In patients at risk for fetal anemia because of red cell
alloimmunization, it is important to perform a first-trimester
541
ultrasound to establish the GA. Assessment for risk of fetal ane-
mia depends on (1) history of HDFN in previous pregnancies, (2)
RBC antibody titers, and (3) MCA-PSV values.
In the first affected pregnancy, severe fetal anemia may
not develop or develops late in gestation, conversely, fetal ane-
mia is usually more severe and develops earlier in gestation in
subsequently affected pregnancies. In the first alloimmunized
pregnancy, serial indirect Coombs testing (antibody titers) is
followed. The goal is to determine if a substantial “risk threshold”
for development of severe fetal anemia or hydrops fetalis has been
reached. This threshold is also known as a “critical titer” [75].
The critical titer is set by each laboratory and it may be different
for each antibody. Titers are also subject to laboratory variations;
therefore consistency in lab follow-up is recommended whenever
possible; two or three dilutions difference among samples may
not be due to a real titer rise [13, 76]. As the rate of affected ges-
tations continues to drop, many institutions may not be able to
establish their own critical value, hence, titers of 16 and 32 have
been suggested as generalizable critical values. In the United
States, most labs follow the AABB (American Association of
Blood Banks) publication recommendations that consider 16 to
32 as a critical titer [13, 77]. Optimal critical thresholds for Rh D
antibodies have been less studied. Fifteen units/mL has been sug-
gested as the critical value in Europe based on comparison with
an international standard [78]. Although the ideal threshold has
been challenged [79], until more evidence of a more ideal cutoff
becomes available, it is recommended to continue to use 16 and
32 as the “critical titer.” A recent analysis suggest that for anti-
Kell alloimmunization, a titer of 4, is an optimal threshold for
the diagnosis of severe fetal anemia [80].
There is no standard follow up interval for repeating anti-
body titers before a critical titer is reached. However serial titers
(except for anti-Kell antibody) in gestations under 15 weeks is
usually not undertaken due to the low risk of anemia. In a series
of 590 alloimmunized pregnancies (anti Rh D alloimmunization),
70% developed a critical titer and the mean gestational at the time
of development was 26 weeks and 3 days of gestation [18]. Most
practitioners repeat antibody titers every four weeks. There are
many atypical (irregular) blood group antibodies that are capa-
ble of producing hemolytic disease. Given their rarity, and the
absence of large studies or any trial, the management of antibod-
ies known to cause hemolytic disease other than Rh(D) is based
on poor evidence. Many aspects of management are unknown
or similar to Rh(D) alloimmunization, except for the details pre-
sented later.
Once a critical titer has been reached, the likelihood of the
fetus with a positive phenotype status (CoAg +) for the cog-
nate antigen of the maternal antibody (at risk of HDFN) should
be determined when possible. If the fetus is determined to be
likely negative for the cognate antigen, then no further surveil-
lance is necessary as the pregnancy is considered to be at no
risk of fetal anemia. Confirmation of paternity is important.
Document the discussion of paternity in the medical record.
There is always a concern for nonpaternity rates in men with
high paternity confidence (estimated to be about 1.9–3%)
[81]. Once paternity is confirmed, the paternal antigen status
should be investigated. If the father’s antigen status is negative,
the fetus is assumed to be negative too and the pregnancy is at
no risk of fetal anemia.
If the father is antigen positive, then a test of zygosity
should be undertaken. For Rh D zygosity determination usually
542 Maternal-Fetal Evidence Based Guidelines

PCR is employed, however, for other antibodies DNA methods TABLE 55.2: Expected Peak Velocity of Systolic Blood Flow in
are unnecessary as non-dominant alleles of these gene systems the Middle Cerebral Artery as a Function of
are always expressed, therefore serology often suffice [75]. If Gestational Age
the father is homozygous for the antigen, the fetus has a 100%
Multiples of the Median
chance of having a positive phenotype status (CoAg +) for the
cognate antigen of the maternal antibody (at risk of HDFN). If the Gestational Age 1.00 1.29 1.50 1.55
father is heterozygous for the antigen, the fetus has a 50% chance 18 23.2 a 29.9 34.8 36.0
of being positive. If the father is heterozygous or paternity cannot
20 25.5 32.8 38.2 39.5
be confirmed, few options are available: Including amniocentesis
for fetal genotyping, or fetal genotyping by the use of circulating 22 27.9 36.0 41.9 43.3
cell free fetal DNA from maternal serum. 24 30.7 39.5 46.0 47.5
Fetal genotyping is determined by PCR from amniocytes 26 33.6 43.3 50.4 52.1
after 15 weeks of gestation with >95% accuracy (sensitivity and 28 36.9 47.9 55.4 57.2
specificity) [82]. Chorionic villus sampling (CVS) and transpla- 30 40.5 52.2 60.7 62.8
cental amniocentesis are not advised, as they can worsen alloim-
32 44.4 57.3 66.6 68.9
munization from fetomaternal hemorrhage [83]. Determination
of some fetal antigen status such as Rh(D) and Kell can also be 34 48.7 62.9 73.1 75.6
done non-invasively, with fetal DNA analysis from maternal 36 53.5 69.0 80.2 82.9
blood [84, 85]. 38 58.7 75.7 88.0 91.0
Circulating cell free DNA for Rh genotyping is a relatively 40 64.4 83.0 96.6 99.8
new test. In a large cohort of patients (25,789 participants) the
Source: From Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise
reported sensitivity and specificity of this test is 99.94% (95%
KJ, Jr., et al. Noninvasive diagnosis by Doppler ultrasonography of fetal
CI 97.43–98.02) and 97.74% (95% CI 97.43–98.02) respectively.
anemia due to maternal red-cell alloimmunization. Collaborative Group
The false negative rate was 0.03% (95% CI 0.01%–0.06%) [58]. for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J
Although the false negative rate appears to be low, the possibil- Med 2000;342(1):9–14. Ref. [63], with permission.
ity of false negative results and its clinical consequences should Mild anemia: MCA-PSV between 1.29 and 1.49 MoM; Moderate anemia: MCA-PSV
be considered. Currently, assays for other severe fetal anemia- between 1.50 and 1.54; MoM; severe anemia: MCA-PSV ≥1.55 MoM.
associated antigens exist (e.g. E, Kell, and c antigens) [85, 86]. a Data shown are in cm/sec (median).

Although initial studies suggest good performance, robust, test

performance information for these antigens is unavailable.
Once a critical titer has been reached and the fetus determined
to have a high likelihood of having an antigen positive genotype,
the next the step, in management involves MCA-PSV surveillance TABLE 55.3: Reference Ranges for Fetal Hemoglobin
[87]. In cases where paternity information is not available or fetal Concentrations as a Function of Gestational Age
antigen status cannot be determined and a critical titer has been
reached, MCA-PSV surveillance should be initiated. Multiples of the Median
If the patient has had a prior affected pregnancy, and the Gestational Age 1.16 1.00 0.84 0.65 0.55
fetus is known to be antigen positive, titers are not necessary
(as they are not informative and do not correlate with the severity 18 12.3 a 10.6 8.9 6.9 5.8
of anemia). These fetuses should be followed with MCA-PSV to 20 12.9 11.1 9.3 7.2 6.1
evaluate for anemia. The presence of additional antibodies with 22 13.4 11.6 9.7 7.5 6.4
anti-D increases the need for intrauterine fetal transfusions [18]. 24 13.9 12.0 10.1 7.8 6.6
26 14.3 12.3 10.3 8.0 6.8
MCA-PSV surveillance 28 14.6 12.6 10.6 8.2 6.9
Ultrasound is the screening method of choice for fetal anemia.
30 14.8 12.8 10.8 8.3 7.1
With fetal anemia there is decreased blood viscosity which leads
to increased venous return and subsequent increase in cardiac 32 15.2 13.1 10.9 8.5 7.2
output and blood flow velocity in all vessels [88]. Although several 34 15.4 13.3 11.2 8.6 7.3
vessels [89] and even different aspects of the MCA Doppler wave- 36 15.6 13.5 11.3 8.7 7.4
form has been explored in an effort to predict fetal anemia [90, 91] 38 15.8 13.6 11.4 8.9 7.5
the PSV consistently offers the best reported test performance.
40 16.0 13.8 11.6 9.0 7.6
The MCA-PSV value in the diagnosis of fetal anemia was initially
suggested in 1990 [92]; confirmed in 1995 [93] and introduced Source: From Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise
in the seminal work of Mari et al. [63]. Doppler assessment is KJ, Jr., et al. Noninvasive diagnosis by Doppler ultrasonography of fetal
anemia due to maternal red-cell alloimmunization. Collaborative Group
used to measure the peak systolic velocity in the fetal middle
for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J
cerebral artery. Degrees of blood velocity (Table 55.2) correlate
Med 2000;342(1):9–14. Ref. [63], with permission.
with anemia (Table 55.3) [63]. The main advantage of the MCA is The values at 1.16 and 0.84 multiples of the median correspond to the 95th and 5th
that it is easy to measure at a 0° angle. In the biparietal diameter percentiles, respectively (normal range).
view, the MCA can be visualized with color Doppler. The MCA- Mild anemia: Hemoglobin concentration between 0.84 and 0.66 MoM; moderate
PSV should be measured at its proximal point, after the origin anemia: Hemoglobin concentration between 0.65 and 0.55 MoM; severe anemia:
from the internal carotid artery, at a 0° angle. Avoid angle cor- Hemoglobin concentration <0.65 MoM.
rection if possible, although angle correction (up to 30°) may not a Data shown are in g/dL (median).
Hemolytic Disease of the Fetus and Newborn
affect the estimation [94]. Measurement at this point allows the
lowest intra- and interobserver variability as well as standardiza-
tion of the measurement [95]. Multiples of the median (MoM)
for the hemoglobin concentration and MCA-PSV correct for the
effect of GA on the measurement. The MCA-PSV had a sensitivity
of close to 100% (95% CI 0.86–1.0) for detection of moderate to
severe fetal anemia with a false-positive rate of 12% at 1.50 MoM
in one study [63]. A meta-analysis estimated that MCA-PSV ≥1.5
MoM had a sensitivity of 86% and a specificity of 71% for the
diagnosis of severe anemia in untransfused fetuses [96]. Other
studies have reported lower sensitivity, but in general above
85%–90% [97]. The false positive rate increases after 35 weeks
of gestation. This rate can be reduced by evaluating the MCA-
PSV trend [98, 99]. Compared with amniocentesis for ΔOD450, the
MCA-PSV assessment is associated with a 70% to 80% reduction
in the number of invasive tests [63]. The MCA-PSV is more accu-
rate than amniocentesis in detecting fetal anemia [97, 99, 100].
Intrauterine blood transfusion for fetal anemia significantly
decreases and normalizes the value of fetal MCA-PSV [101, 102]
because of an increased blood viscosity and an increased oxy-
gen concentration in fetal blood. The MCA-PSV can be used
in fetuses previously transfused; however, the accuracy of the
Doppler assessment decreases with more intrauterine transfu-
sions [96, 103].
Accuracy with the MCA-PSV can only be achieved with
appropriate training and quality assurance. Screening with
MCA-PSV should be started at a gestational age when fetal blood
sampling and intrauterine transfusion are feasible, around 18–20
weeks [87]. In first affected pregnancies severe anemia is unlike
at earlier gestational ages. In subsequent pregnancies (after the
first affected one), surveillance should start earlier, around 16–18
weeks, the same is true for fetuses affected by anti-Kell alloim-
munization or patients with a history of HDFN in previous ges-
tations. The MCA-PSV can also be used for other causes of
anemia, including parvovirus infection, nonimmune hydrops
and fetal-maternal hemorrhage [104–107].
(a) (b)
(c) (d)
(e)
FIGURE 55.2 The MCA-PSV assessment technique as described by Mari et al. (From Mari G, Abuhamad AZ, Cosmi E, Segata M,
Altaye M, Akiyama M. Middle cerebral artery peak systolic velocity: technique and variability. J Ultrasound Med 2005;24(4):425–30.
Ref. [95], with permission.)
543
The MCA-PSV assessment technique [95] is represented in
Figure 55.2.
1. Aim to obtain an axial section of the fetal head at the level
of the sphenoid bones. Displacing the transducer caudally
from the trans-thalamic intracranial plane may be helpful.
2. Obtain an image of the Circle of Willis with the Doppler.
3. Identify the middle cerebral arteries (MCA) and visualize
its entire trajectory.
4. Zoom in the area of the MCA to be sampled, ideally the
middle cerebral artery closer to the transducer although
the contralateral MCA is still valid [95, 108].
5. Place the sample (2–3 mm gate wide) soon after the ori-
gin of the MCA from the internal carotid artery as it has
been noted to have the lowest intra and interobserver vari-
ability [95, 108]. The sample should be parallel (0 angle
degree) to the trajectory of the entire artery. Avoid angle
correction if possible as intra and interobserver variability
increases [95].
6. Acquire the MCA waveforms. A total of 50–100 wave-
forms, in at least 3 sets per study (5–10 minutes) is sug-
gested, in an effort to reduce the false positive rate [109].
7. Measure the highest point of the waveform.
8. When the velocity is approximately the same in each set,
the highest measurement is considered reliable enough for
clinical decision making [95, 110].
When estimating the MCA-PSV avoid fetal movements and/or
breathing as this may affect the fetal heart rate, other factors that
may affect the MCA-PSV waveform include uterine contractions
and fetal hear rate decelerations [111]. When performing Doppler
studies of the MCA, be aware that normal “variants” of the MCA
may exist, e.g. double MCA artery, familiarity with the waveforms
of its collaterals such as the lenticulostriate arteries may be ben-
eficial [62]. The Doppler studies of the MCA are reproducible and
with proper technique low intra and inter-observer variability is
It is easy to sample the
MCA with an angle of
zero degrees, which
allows for the real
velocity of the blood flow
to be determined.
These are the steps for
the correct sampling of
the middle cerebral
artery peak systolic
velocity.
The use of an angle
(f ) corrector increases the
intra- and inter-observer
variablility; therefore, its
use is not recommended.
544
expected [95, 108]; in despite of this, an error of 5–10% is possible.
The false positive rate may be decreased by using the trend of the
MCA PSV. Severe intrauterine growth restriction also shows an
increased MCA-PSV [112]52. Therefore, this should be taken into
account when the MCA-PSV is used to diagnose fetal anemia.
Moderate to severe anemia may also be suggested by hydropic
signs (at least two of pericardial or pleural effusion, ascites, or
skin edema), an increase in the size of fetal liver or placental
thickness, polyhydramnios or tricuspid regurgitation.
Surveillance intervals depend on gestational age, prior obstet-
ric history, the estimated MCA-PSV and the MCA-PSV trend.
Pregnancies affected by alloimmunization to more than one anti-
gen, seem to have more severe clinical courses as additional anti-
bodies seem to have synergistic effects [18]. In these cases, closer
surveillance, seems appropriate. A regression curve of the MCA-
PSV as a function of gestational age has been reported in normal,
mild and severely anemic fetuses (Figure 55.3) [113]. Samson et al.
[110] proposed a method for estimation of MCA-PSV follow-up
intervals based on linear regression analysis of the MCA-PSV.
This method employs the last 3 MCA-PSV measurements in
order to plot a curve. If the obtained curve remains to the right of
the mild anemia curve and the MCA-PSV is under 1.5 MoM, then
MCA-PSV is repeated in 2–3-week intervals until 34–35 weeks of
gestation, conversely if the obtained curve remains to the left of
the mild anemia curve and the MCA-PSV is under 1.5 MoM, then
MCA-PSV is repeated in 2–3 days.
When the fetus is at risk of severe fetal anemia, based on
the MCA-PSV (above 1.5 MoM), fetal blood sampling (FBS) is
typically offered to the parents after appropriate counseling.
Historically, serial amniocentesis procedures with spectropho-
tometric assessment of the amniotic fluid for bilirubin concen-
trations and delta optical density 450 or DO 450, was used for
the screening of fetal anemia [114]. These methods, originally
introduced by Liley in 1961 [115] have been replaced in clinical
practice by a noninvasive and better performing test: The middle
100
90
80 Severe and Moderate
Anemia
70
MCA-PVS (cm/sec)
60
50
40 Mild or Non Anemia
30
20
10
0
10 15 20 25 30 35
Gestational Age (weeks)
FIGURE 55.3 Regression curve of the MCA-PSV as a function
of gestational age in normal, mild, and severely anemic fetuses.
(From Detti L, Oz U, Guney I, Ferguson JE, Bahado-Singh RO,
Mari G, et al. Doppler ultrasound velocimetry for timing the sec-
ond intrauterine transfusion in fetuses with anemia from red cell
alloimmunization. Am J Obstet Gynecol 2001;185(5):1048–51.
Ref. [103], with permission.)
Maternal-Fetal Evidence Based Guidelines
cerebral artery Doppler estimation of the peak systolic velocity
(MCA-PSV) [87].
Fetal blood sampling and intrauterine transfusion
Fetal blood sampling (FBS) is indicated when the MCA-PSV is
consistently elevated to ≥1.5 MOM, suggesting and increased
risk of severe fetal anemia. (Table 55.2). Hydrops may also
suggest fetal anemia. Table 55.4 shows an example of FBS and
TABLE 55.4: Sample Guide for Preparing for Fetal Blood
Transfusion
• Obtain O negative, CMV-negative, irradiated packed red blood cells
from the blood bank. O positive blood may be needed when
antibodies to the c antigen are present because the rate of O negative
and c negative blood is very rare (0.0001%).
• Under sterile conditions open:
• Four drapes or single sterile drape.
• Towel clips as needed.
• Twenty- or 22-gauge spinal needle (22 gauge for transfusions
<24–28 weeks of gestation or if thrombocytopenia is suspected)
prepared with heparin to prevent clot formation.
• Length of needle is determined ahead by measuring distance on
ultrasound from maternal abdominal wall to cord insertion site.
• Sterile ultrasound probe cover.
• Sterile ultrasound gel.
• A skin preparation solution (chlorhexidine-alcohol solution).
• Eight to 10 1 mL syringes flushed with heparin to avoid clot
formation.
• One 1 mL syringe for paralytic agent (atracurium or vecuronium).
• Five to 10 20 mL syringes (for storing blood).
• Four 12 mL syringes.
• One 3 mL syringe.
• Three needles 18 or 20 gauge for drawing blood from blood bank
into 20 mL syringes.
• A 5.5 inch small bore extension set with t-connector and luer
adaptor).
• Three-way stopcock.
• Fill two 5 mL syringes with physiological saline solution.
• Flush 1 mL syringes with heparin, save one unflushed 1 mL syringe
for vecuronium (or atracurium).
• Draw up normal saline to make three saline flushes, remove air
bubbles by holding syringes upright and tapping to release bubbles to
top, attach small bore connection tubing, and flush air through.
• Reconstitute vecuronium with 10 mL of normal saline.
• Draw up 1 mL of vecuronium and 9 mL of normal saline in a
12 mL syringe.
• Transfer 1 mL of vecuronium mixture to a unheparinized 1 mL
syringe.
• Mark both the 12 mL and 1 mL syringes with vecuronium to avoid
confusion.
40 45
• Usual dose of vecuronium is 0.1 mg/kg and atracurium is
0.4 mg/kg.
• Draw up 1–2% lidocaine in 3 mL syringe, attached to 22- or 25-gauge
needle for injection at puncture site for maternal local anesthesia.
• Care should be taken to maintain sterility when drawing up
solutions: Either have an assistant holding saline, vecuronium,
lidocaine, and blood from blood bank or use single operator
technique keeping one hand sterile and one hand unsterile.
• Attach intravenous connection tubing to unit of packed red blood
cells.
Hemolytic Disease of the Fetus and Newborn 545

TABLE 55.4 (Continued): Sample Guide for Preparing for transfusion setup. Intrauterine transfusion (IUT) is considered
Fetal Blood Transfusion nowadays a safe procedure and the “most successful invasive
treatment in fetal medicine” [116], however IUT could lead to
• Attach stopcock, taking care to maintain sterility on one end of the
serious complications. Zwiers et al. [67]. compared the rate of
stopcock.
complications among procedures performed in two different
• Fill 20 mL syringes with blood by opening stopcock.
time periods 1988–2001 and 2001–2015 respectively. Overtime
• Remove any air bubbles that may be present by holding syringes
an overall increase in survival and decreased rate of complica-
upright and tapping side of syringe to release air bubbles.
tions was observed. In the most recent cohort of patients, they
• Have tubes available to send for laboratory studies.
reported an overall rate of complications of 3.3% per fetus and
• Remember to include not only initial, midway, and final blood
1.2% per procedure. Specific reported rates of complications of
counts plus any additional tubes for genetic studies, liver function
intravascular transfusion include [67]: Fetal demise (1.8% per
studies, or other tests.
fetus and 0.6% per procedure); emergency cesarean delivery
• Obtain maternal sample of blood.
(1.2% per fetus and 0.4% per procedure), preterm premature
• Pre-calculate amount of fetal transfusion needed based on different
rupture of membranes (0.3% per fetus and 0.1% per procedures),
possible fetal hematocrit values (see text)
infection (0.3% per fetus and 0.1% per procedures) and fetal
• Perform ultrasound to select site.
demise (1.8% per fetus and 0.6% per procedures). A fetal loss
• Placental cord insertion, free loop, umbilical cord insertion or
rate of 17% when the fetal blood sampling is performed at
intrahepatic vein.
<20 weeks [67]. It has been suggested that intravascular trans-
• Obtain measurement from maternal abdomen to umbilical vein
fusion may lead to immediate fetal hemodynamic changes, and
site of puncture to ensure correct needle length.
in severely anemic fetuses the hematocrit should be gradually
• Document fetal heart rate.
increased [117]. It is possible that these hemodynamic changes
• Have sonographer and assistant ready in addition to main operator.
impose additional strain in an already compromised fetus play a
• Intravenous access and use of antibiotics is not always necessary and
role in some of the complications described following IUT. The
is at the preference of the operator.
rate of intrauterine transfusion complications also seem to be
• Under aseptic conditions prepare patient with antibacterial solute
related to the expertise of the operator, with less complications
and place drapes leaving abdomen exposed.
in high volume centers [67], complications also seems to be cor-
• Cover ultrasound transducer with sterile cover.
related with procedural techniques that may minimize the risk of
• Identify site of puncture.
complications (e.g. avoidance of free loop and arterial puncture,
• Give local anesthesia to patient (mother).
routine use of fetal paralysis) [67].
• Inject fetus with intramuscular paralytic agent if necessary
FBS and IUT are feasible after 15 weeks of gestation and surveil-
(vecuronium or atracurium).
lance with serial MCA-PSV should be started after this gestational
• Use 20- or 22-gauge needle to enter umbilical vein.
age if deemed necessary. Feasibility of IUT is determined not only by
• Remove stylet.
the gestational age, size and thickness of the umbilical cord, but also
• If flow is immediate, obtain sample in 1 mL syringe and send to
by the placental location, maternal body habitus, amount of amni-
laboratory.
otic fluid, among other factors. FBS, is usually not performed after
• If flow is not immediate and you think you are in Wharton’s jelly,
35 weeks of gestation as the risks seems to outweigh the benefits of
slowly and carefully reposition the needle to enter into the vein.
this procedure after this gestational age (Figure 55.1). In case of sus-
• Some operators document flow by injecting saline: If that is done
pected severe fetal anemia, delivery is the typical recommendation.
prior to obtain fetal blood sample, discard first 1 mL fetal blood
Occasionally hydrops fetalis develops at very early gestational
because it may be diluted with saline.
ages, and in these cases, practitioners oftentimes offer intraperi-
• Document fetal blood sample by comparing maternal (previously
toneal fetal transfusion followed by intravascular transfusion
drawn and analyzed) and fetal hematocrit and MCV. This may not be
later on gestation when technically feasible [118]; there is sugges-
necessary if sampling a free loop or the intrahepatic vein or if
tion that this may be a safer approach under 22 weeks of gesta-
document flow with saline.
tion, although the effectiveness of this procedure, especially in
• Attach tubing to transfuse slowly: Assistant can push blood slowly;
the setting of hydrops, is questionable as the ability to absorb
watch segment of umbilical cord to see if blood is flowing through
blood from the peritoneal cavity into the intravascular compart-
umbilical vein. A small slow transfusion of blood may be performed
ment may be impaired in cases of hydrops fetalis.
prior to obtaining confirmatory results of fetal blood from the
Zwiers et al. described a retrospective cohort of patients
laboratory to prevent clot from forming.
(PETIT study) [119] from 12 fetal therapy centers, in which early
• When the fetal hematocrit returns and a transfusion is needed,
onset, (<13 weeks of gestation) intrauterine immunoglobulin
calculate the amount of blood needed to transfuse based on
treatment, of pregnancies previously affected by severe hemo-
pre-calculations.
lytic disease of the fetus and newborn (HDFN) was employed.
• Intermittently obtain fetal heart rate.
The results suggested that this therapy may delay the onset of
• When transfusion is complete, obtain final hematocrit, and draw any
severe anemia and may decrease the incidence of hydrops and the
other blood needed for workup.
need of newborn exchange transfusion.
• After the transfusion is complete and the needle is removed, watch
When preparing for FBS, the practitioner should always be
the puncture site for streaming and check fetal heart rate for
ready for intrauterine transfusion in case that severe fetal anemia
bradycardia.
is confirmed. Referral of patients to a specialized center with
• Monitor the patient and fetus after transfusion for at least 1–2 hours.
expertise in management of alloimmunization and intra-
Source: Adapted from Ref. [87]. uterine transfusion is suggested, as this may lead to improved
Abbreviations: GA, gestational age; MCV, mean corpuscular volume. outcomes [67]. The availability of a blood bank with expertise in
intrauterine transfusion is also of paramount importance.
546
Exchange transfusion rather than the simple or “top off” trans-
fusion is an alternative for intrauterine correction of fetal ane-
mia and experience with this alternative therapeutic modality
has been reported [120]. The hypothesized advantages include
lower risk of hypervolemia and improvement of the efficacy of
the transfusion by removal of incompatible fetal red blood cells.
However retrospective studies have failed to support these antici-
pated benefits and/or increased risks [120]. Combination of IUT
and partial exchange transfusion has been reported in the man-
agement of twin anemia polycythemia sequence (TAPS) [121].
Intrauterine transfusion procedure
Donor blood requirements (as per the guidelines of the American
Association of Blood Banks) [13]:
1. Rh D negative donor blood
2. CMV antibody negative
3. Irradiation (25 Gy of gamma radiation to the central part
of the donor bag)
4. Negative hemoglobin S screening
5. Leukoreduction
6. Donor units should be fresh (<7 days old)
7. Units should be washed and packed to a final hematocrit
of 75–85%
8. Some centers undergo extended cross-matching e.g. S,
Duffy, and Kidd antigens
Sources of donor red blood cells for IUT include maternal red
blood cells, maternal siblings or random donor. Advantages of
maternal donor red cells include lower likelihood of sensitization
to additional antigens and possibly a lower risk of blood-borne
viral infections. Potential disadvantages include the need of extra
washings, and an increased likelihood of graft versus host disease.
When planning an IUT, one of the critical preparation steps
is to estimate the blood volume to be transfused. Red blood
cells are usually packed at higher concentrations, than the con-
centrations used for adult transfusions. This “extra packing” is
done with the aim to minimize fetal volume overload. The typical
donor hematocrit concentration is 75–85%.
Several formulas to calculate the blood volume to be trans-
fused have been described, and most of them incorporate into
their equation the fetal estimated weight (in grams), the donor
unit hematocrit and the target fetal hematocrit. Gestational age,
pre-transfusion fetal hematocrit, severity of the fetal condition
and several other factors may also be considerations for the
operator when determining the volume to transfuse. No specific
method seems to be superior to the other ones, and the choice of
method comes down to practitioner preference and familiarity
[122]. For fetuses over 24 weeks of gestation, a simple method
consists of subtracting the desired hematocrit from the sample’s
pretransfusion hematocrit, divided by the donor hematocrit
minus the desired hematocrit, this multiplied by the fetoplacen-
tal volume [123]. A common formula to estimate the volume
of blood to be transfused is: Desired hematocrit-fetal hema-
tocrit/donor hematocrit-desired hematocrit) x Fetoplacental
volume.
In early gestations (18–24 weeks), the suggested target hema-
tocrit should not exceed 25% or a fourfold increase from the pre-
transfusion hematocrit, due to the potential increased risk of
complications [124, 125]. A second transfusion 48 hours after the
initial one could be attempted in order to raise the hematocrit to
a target concentration of about 45% (40–50%).
Maternal-Fetal Evidence Based Guidelines
For pregnancies after 24 weeks of gestation, the target hemato-
crit is typically 45% (40–50%).
If the fetus is not anemic (e.g. hematocrit <35%), no transfusion
is recommended in order to avoid complications, higher target
hematocrits (above 45–50%) may lead to complications related to
hyper-viscosity [123].
Some practitioners undertake a “dual transfusion approach”,
consisting of an intravascular and an intraperitoneal trans-
fusion during the same procedure. The rationale behind this
approach is prolongation of the interval in between IUT proce-
dures [126], minimizing the risks as less procedures are needed.
Intraperitoneal absorption of red blood cells is gradual over the
span of 7 to 10 days. In early gestations (typically under 22 weeks
of gestation), intra-peritoneal transfusion may be the safest
approach especially when other technical conditions are less than
ideal [127] Intraperitoneal transfusion enables transfusion when
direct access to the fetal vasculature is technically challenging
or hazardous [123]. A method to calculate the blood volume to
be transfused intraperitoneally consists of subtracting 20 from
gestational age in weeks and multiplying this number by 10 [123].
So volume to transfuse intraperitoneally: (GA in weeks – 20) ×
10. The volume transfused intraperitoneally should not interfere
with the umbilical vein blood flow, which is potentially affected
by increased intraperitoneal pressure. Decreased venous return
may lead to fetal bradycardia.
Tubing and syringes should be heparinized. For maternal local
anesthesia use 1% lidocaine at the point of needle entry should
be used. A 20- (usually after 28 weeks) or 22-gauge (usually <28
weeks) needle typically is used for the procedure. After enter-
ing the umbilical vein, a sample of fetal blood is withdrawn, and
the hemoglobin immediately (within one or two minutes) deter-
mined. Fetal blood is confirmed by a mean corpuscular volume
(MCV) >110 μm3. Then the fetus is given a paralytic agent (e.g.
pancuronium 0.1 mg/kg) to stop fetal movements. Routine use of
fetal paralysis may prevent procedure-related fetal loss in 80% of
the cases and thus improve the safety of the procedure [116].
Fetal thrombocytopenia (<100,000/mm3), which is associ-
ated with fetal hydrops and perinatal mortality, can be found
in about 9% of Rh(D) alloimmunized fetuses at times of fetal
sampling [128]. A meta-analysis showed a prevalence of throm-
bocytopenia of 18%, with severe thrombocytopenia (<50,000/
mm3) in 6% of cases [129]. The mechanism of thrombocytope-
nia in alloimmunized pregnancies is unknown. Even tough is not
clear if transfusion of platelets in addition to RBC improve out-
comes, it seems prudent to have platelets readily available when
performing IUT when feasible.
Following an initial IUT procedure and if the process leading
to anemia persist (e.g. alloimmunization), a second or more IUT
procedures are typically needed. Detti et al. demonstrated the
accuracy of the MCA-PSV for prediction of severe fetal anemia,
after a first transfusion procedure [103], however the suggested
threshold for the diagnosis of severe fetal anemia after an
initial transfusion procedure is higher (>1.69 MoM) probably
due to the effect of the transfused adult red blood cells in viscos-
ity and also due to the inherent oxygen carrying profile of adult
hemoglobin.
After an initial intravascular fetal transfusion procedure, the
decline in hemoglobin is approximately 0.4 g/dL per day or
a decline in hematocrit of 1% per day [126]. The decline rate
is more constant after the second transfusion procedure, once
the transfused adult RBC become the predominant type of RBC
in the fetal circulation. At this point the decline mechanism is
Hemolytic Disease of the Fetus and Newborn
not related to hemolysis anymore but rather to fetal growth and
volume expansion. Estimations of the optimal interval for the
second and subsequent IUT procedures can be made based on
the combination of MCA-PSV, anticipated hemoglobin decline
rate, and final hematocrit at the end of the prior IUT procedure.
Although it has been suggested that the accuracy of the MCA-
PSV declines with subsequent transfusions (e.g. third or fourth
transfusion procedures) [130], the MCA-PSV hold its negative
predictive value and may be factored when planning subse-
quent IUT intervals. A randomized trial, that compared timing
of subsequent transfusions with the use of the MCA-PSV (serial
upward trend of values >1.5 MoM) versus expected decrease in
fetal hematocrit found no differences in mean hemoglobin lev-
els at birth, number of IUT procedures or in the rates of adverse
infant outcomes [131].
IUT intervals should be individualized and determined by a
combination of factors including gestational age, post-transfu-
sion fetal hematocrit, severity of the anemia, and etiology of the
fetal anemia.
Fetal blood sampling preparation
1. Consider administration of a steroid course if viability has
been reached. If this is the case also consider planning the
procedure in the OR in case that an emergency cesarean
delivery may be needed.
2. Prepare blood products for transfusion and transfusion
equipment.
3. The procedure is performed under continuous ultrasound
guidance.
4. Although some providers elect to use prophylactic antibi-
otics, no trial has evaluated optimal class, timing, or dos-
ing of antibiotics to prove the efficacy of this practice [132].
Therefore, there is no recommendation of prophylactic
antibiotic use in these procedures.
5. After 24 weeks of gestation, the procedure should be ideally
performed in a location close to the operating room and the
anesthesiologist consulted should an emergency occur.
6. Select fetal access.
IUT could be aimed at the umbilical vein, umbilical artery, fetal
heart or fetal peritoneal cavity. Intravascular transfusion is pre-
ferred over an intraperitoneal approach as survival is increased
particularly in hydropic fetuses [133]. Intracardiac access has
been associated with the highest mortality, however, a more
recent report suggest acceptable survival rates [134] and it
appears to be an option for severe early-onset anemia and lack of
a different IUT access. The most frequently used access for IUT
is the umbilical vein. The umbilical vein can be accessed either
at the placental cord insertion segment or at the intrahepatic seg-
ment. The choice between these two targets is up to the discre-
tion and expertise of the operator and also accessibility (placental
location, fetal position, etc.).
When the placental cord insertion segment is selected, the
potential for pain and fetal distress is minimized, as well as the
risk for intraabdominal injury. On the other hand bradycardia
may be more likely due to the possible inadvertent puncture of
the umbilical artery with subsequent vasospasm. With the intra-
hepatic umbilical vein is selected, extravasation of blood is less
of a concern as blood is readily reabsorbed from the intraperito-
neal space. Trevett et al. [135] described the use of phenobarbital
(30 mg, three times a day after the last IUT until delivery) in an
effort to enhance fetal hepatic maturity and to reduce the need
547
of neonatal exchange transfusion. The relative risk of exchange
transfusion in pregnancies that were treated with phenobarbital
was 0.23 (95% CI 0.06–0.76).
Fetal monitoring/Testing
The American Congress of Obstetrics and Gynecology (ACOG)
guidelines recommend antenatal testing for pregnancies at risk
of fetal anemia [136], however no specific guidelines, for the type
of screening test or frequency is suggested. Although MCA-PSV
surveillance is the mainstay in the management of pregnancies
at risk of fetal anemia additional methods of antenatal testing e.g.
biophysical profile and non-stress test are available. Presence of
decelerations in the non-stress test seem to have correlation with
the degree of anemia [137].
When planning antenatal testing, it seems prudent to individu-
alize care, considering factors such as the severity of the anemia,
the MCA-PSV, gestational age and presence of additional mater-
nal or fetal complications. Antenatal testing is typically started
once “viability” has been reached, and it is usually continued
until delivery. No evidence suggesting improved outcomes with
the routine use of adjunctive antenatal testing methods is avail-
able. Fetuses undergoing intrauterine transfusions due to severe
anemia (hemoglobin ≤2 g/dL) have had brain imaging notable for
intracerebellar hemorrhage among other intracranial injuries.
Therefore, some studies have advocated fetal neuro-imaging by
ultrasound and/or MRI.
Delivery
Delivery recommendations are based mainly on expert opinion,
as high-quality data to support definitive recommendations is
lacking [115]. Timing of delivery should balance the risk of still-
birth, the morbidity of fetal anemia and the risks of prematurity.
The Society for Maternal Fetal Medicine (SMFM) clinical guide-
lines suggest proceeding with delivery at 37–38 weeks’ gesta-
tion [115]. These recommendations are nonspecific for either
pregnancies at risk of anemia or for pregnancies that underwent
IUT. In cases of alloimmunization with no concern for severe
fetal anemia and when antibody titers have not reached the criti-
cal value, delivery at 39 weeks should be considered [75]. Delivery
and neonatal care teams should anticipate and prepare for the
delivery of an affected pregnancy. Readiness for possible neonatal
transfusion should be an important condition. See Figure 55.1 for
management including delivery. The mode of delivery depends on
routine obstetrical indications.
Anesthesia
There are no specific anesthesia precautions.
Neonatology management
Anemic neonates are usually treated with transfusions or
exchange transfusions as necessary. They often need photother-
apy for hyperbilirubinemia. Breastfeeding is not contraindicated.
A hearing screening test is indicated during the neonatal period
and at 2 years of age given that hyperbilirubinemia can cause sen-
sorineural hearing loss.
Other “atypical” antibodies
There are many atypical (irregular) blood group antibodies that
are capable of producing hemolytic disease. Given their rarity,
and the absence of large studies or any trial, the management of
antibodies known to cause hemolytic disease other than Rh(D)
is based on poor evidence. Many aspects of management are
548
unknown or similar to Rh(D) alloimmunization, except for the
details presented later. Once again, it should be acknowledged
that the critical titer for antibodies other than Rh(D) has not been
well-established.
Kell alloimmunization
The Kell antigen system is complex, consisting of over two dozen
antigens. Kell 1 (Kell, or K1) and its allelic partner Kell 2 (Cellano,
or K2) are strong immunogens [138]. The K antigen is found on
9% of Caucasians and 2% of individuals of African descent
[139] Over 90% of partners of Kell-immunized women are Kell
negative. Anti-K is related to severe hemolytic disease of the new-
born in 11.6% of the K-sensitized pregnancies according to a large
population study [139]. In a large retrospective cohort study in
the Netherlands, 52% of anti-Kell pregnancies with a Kell positive
fetus required intrauterine of postnatal transfusion therapy. They
evaluated the optimal critical titer cutoff value, suggesting a titer
of 4 provided as the optimal thresholds with 100% sensitivity [140].
The Kell glycoprotein is expressed early in erythroid progenitor
cells. Antibody to Kell appears to inhibit erythropoiesis, suggest-
ing another functional role for Kell in addition to its endopeptidase
activity [17]. The most common mechanism of Kell sensitization in
reproductive age women is a prior blood transfusion [30].
Genotyping of the father of the baby (FOB) is extremely
important. Most will be Kell negative, and, if paternity is cer-
tain, no further testing is necessary. The vast majority (>90%) of
Kell positive FOBs are heterozygote, as thus, fetal status needs to
be determined by amniocentesis PCR (cfDNA is available in
Europe). Maternal titers and ΔOD450 levels do not correlate well
with fetal anemia [9]. Anti-Kell anemic fetuses have lower retic-
ulocyte counts and bilirubin levels compared to anti-D anemic
fetuses [17]. MCA-PSV screening is predictive and accurate
for the diagnosis of fetal anemia from Kell alloimmunization
[141]. MCA-PSV monitoring should start at 15 weeks and be per-
formed as suggested in Figure 55.2.
Other CDE system antigens
Antibodies against these antigens are usually find at low titer and
in conjunction with anti Rh(D) [142]. c (small): This antigen car-
ries a 10% risk of severe hemolytic disease [2]. A large popula-
tions study showed that severe hemolytic disease of the newborn
occurred in 8.5% of the fetuses with anti-C and in 1.1% of the
fetuses with anti-E [2]. C (big) and E (big) are associated with
mild to severe hemolytic disease of the newborn [87].
MNS antigen system
Contains M, N, S, s, U antigens among many others. Anti-Mur,
S, anti s and anti-U can cause mild to severe hemolytic disease of
the newborn. Anti-M rarely causes fetal anemia since it is mainly
immunoglobulin M. No cases of hemolytic disease were seen in
175 pregnancies [143]. However, Asians can develop moderate
hemolytic disease as described in a case report [144].
Others
Other rare, but potentially lethal, antigens are Duffy (Fya, Fyb,
Fy3, etc.), and Kidd, as well as others.
References
1. Levine P, Katzin EM, Burnham L. Isoimmunization in pregnancy: its pos-
sible bearing on the etiology of erythroblastosis foetalis. J Am Med Assoc
1941;116(9):825–7. [II-3]
Maternal-Fetal Evidence Based Guidelines
2. Koelewijn JM, Vrijkotte TG, van der Schoot CE, Bonsel GJ, de Haas M. Effect
of screening for red cell antibodies, other than anti-D, to detect hemolytic
disease of the fetus and newborn: a population study in the Netherlands.
Transfusion 2008;48(5):941–52. [II-2]
3. Geifman-Holtzman O, Wojtowycz M, Kosmas E, Artal R. Female alloim-
munization with antibodies known to cause hemolytic disease. Obstet
Gynecol 1997;89(2):272–5. [II-3]
4. Lieberman L, Callum J, Cohen R, Cserti-Gazdewich C, Ladhani NNN,
Buckstein J, et al. Impact of red blood cell alloimmunization on fetal
and neonatal outcomes: a single center cohort study. Transfusion
2020;60(11):2537–46. [II-2]
5. Zwingerman R, Jain V, Hannon J, Zwingerman N, Clarke G. Alloimmune
red blood cell antibodies: prevalence and pathogenicity in a Canadian pre-
natal population. J Obstet Gynaecol Can 2015;37(9):784–90. [II-2]
6. Koelewijn JM, Vrijkotte TG, de Haas M, van der Schoot CE, Bonsel GJ. Risk
factors for the presence of non-rhesus D red blood cell antibodies in preg-
nancy. BJOG 2009;116(5):655–64. [II-2]
7. de Haas M, Finning K, Massey E, Roberts DJ. Anti-D prophylaxis: past,
present and future. Transfus Med 2014;24(1):1–7. [Review; III]
8. Bowman J. Thirty-five years of Rh prophylaxis. Transfusion 2003;43(12):
1661–6. [Review; III]
9. McKenna DS, Nagaraja HN, O’Shaughnessy R. Management of pregnan-
cies complicated by anti-Kell isoimmunization. Obstet Gynecol 1999;93(5
Pt 1):667–73. [II-3]
10. Zipursky A, Paul VK. The global burden of Rh disease. Arch Dis Child Fetal
Neonatal Ed 2011;96(2):F84–5. [III]
11. Flegel WA. The genetics of the Rhesus blood group system. Blood Transfus
2007;5(2):50–7. [III]
12. Rizzo C, Castiglia L, Arena E, Gangi S, Mazzola G, Caruso C, et al.
Weak D and partial D: our experience in daily activity. Blood Transfus
2012;10(2):235–6. [III]
13. Fung MK GB, Hillyer CD, Westhoff CM. Technical Manual of the American
Association of Blood Banks, 18th ed. Bethesda, MD: AABB, 2014. [III]
14. Practice Bulletin No. 181. Summary: prevention of Rh D alloimmunization.
Obstet Gynecol 2017;130(2):481–3. [III]
15. Argoti PS, Mari G. Fetal anemia. Minerva Ginecol 2019;71(2):97–112. [III]
16. Vaughan JI, Warwick R, Letsky E, Nicolini U, Rodeck CH, Fisk NM.
Erythropoietic suppression in fetal anemia because of Kell alloimmuniza-
tion. Am J Obstet Gynecol 1994;171(1):247–52. [II-2]
17. Vaughan JI, Manning M, Warwick RM, Letsky EA, Murray NA, Roberts
IA. Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal
alloimmune anemia. N Engl J Med 1998;338(12):798–803. [II-2]
18. Markham KB, Rossi KQ, Nagaraja HN, O’Shaughnessy RW. Hemolytic dis-
ease of the fetus and newborn due to multiple maternal antibodies. Am J
Obstet Gynecol 2015;213(1):68 e1–e5. [II-2]
19. Bowman J. The management of hemolytic disease in the fetus and newborn.
Semin Perinatol 1997;21(1):39–44. [III]
20. Nicolaides KH, Thilaganathan B, Rodeck CH, Mibashan RS. Erythroblastosis
and reticulocytosis in anemic fetuses. Am J Obstet Gynecol 1988;159(5):
1063–5. [II-3]
21. Ree IMC, Smits-Wintjens V, van der Bom JG, van Klink JMM, Oepkes D,
Lopriore E. Neonatal management and outcome in alloimmune hemolytic
disease. Expert Rev Hematol 2017;10(7):607–16. [III]
22. Laube DW, Schauberger CW. Fetomaternal bleeding as a cause for “unex-
plained” fetal death. Obstet Gynecol 1982;60(5):649–51. [II-3]
23. Von Stein GA, Munsick RA, Stiver K, Ryder K. Fetomaternal hemorrhage in
threatened abortion. Obstet Gynecol 1992;79(3):383–6. [II-2]
24. Krause HG, Goh JT. Positive Kleihauer result following an ectopic preg-
nancy. Aust N Z J Obstet Gynaecol 1996;36(3):324–5. [III]
25. Matsuhashi M, Tsuno NH, Kawabata M, Yokoyama T, Tazaki Y, Takashima
T, et al. The first case of alloantibody against human platelet antigen-15b
in Japan: possible alloimmunization by a hydatidiform mole. Transfusion
2010;50(5):1126–30. [II-3]
26. Fisher M. Acute Rh isoimmunization following abdominal trauma
associated with late abruption placenta. Acta Obstet Gynecol Scand
1989;68(7):657–9. [III]
27. Kristensen SS, Norgaard LN, Tabor A, Sundberg K, Dziegiel MH,
Hedegaard M, et al. Do chorionic villus samplings (CVS) or amniocenteses
(AC) induce RhD immunisation? An evaluation of a large Danish cohort
with no routine administration of anti-D after invasive prenatal testing.
BJOG 2019;126(12):1476–80. [II-2]
28. Pollock A. Transplacental haemorrhage after external cephalic version.
Lancet 1968;1(7543):612. [III]
29. Bowman JM, Pollock JM, Penston LE. Fetomaternal transplacental hemorrhage
during pregnancy and after delivery. Vox Sang 1986;51(2):117–21. [II-3]
Hemolytic Disease of the Fetus and Newborn
30. Moise KJ. Fetal anemia due to non-Rhesus-D red-cell alloimmunization.
Semin Fetal Neonatal Med 2008;13(4):207–14. [III]
31. Lappen JR, Stark S, Gibson KS, Prasad M, Bailit JL. Intravenous drug use
is associated with alloimmunization in pregnancy. Am J Obstet Gynecol
2016;215(3):344 e1–6. [II-3]
32. Kumpel BM. On the immunologic basis of Rh immune globulin (anti-D)
prophylaxis. Transfusion 2006;46(8):1271–5. [iii]
33. Bowman JM. The management of Rh-Isoimmunization. Obstet Gynecol
1978;52(1):1–16. [III]
34. Kilpatrick. SJ, Papile LA, Macone GA. Eds. Guidelines for Perinatal Care,
8th ed. Itasca, IL: American Academy of Pediatrics. 2017. [III]
35. Stasi R. Rozrolimupab, symphobodies against rhesus D, for the poten-
tial prevention of hemolytic disease of the newborn and the treatment of
idiopathic thrombocytopenic purpura. Curr Opin Mol Ther 2010;12(6):
734–40. [III]
36. Chauhan AR, Nandanwar YS, Ramaiah A, Yelikar KA, Rashmi MD,
Sachan R, et al. A multicenter, randomized, open-label trial comparing
the efficacy and safety of monoclonal anti-Rh (D) immunoglobulin with
polyclonal anti-Rh (D) immunoglobulin for the prevention of maternal
Rh-isoimmunization. J Obstet Gynaecol India 2019;69(5):420–5. [RCT; I]
37. Pollack W, Ascari WQ, Kochesky RJ, O’Connor RR, Ho TY, Tripodi D.
Studies on Rh prophylaxis. 1. Relationship between doses of anti-Rh and
size of antigenic stimulus. Transfusion 1971;11(6):333–9. [II-1]
38. Bichler J, Schondorfer G, Pabst G, Andresen I. Pharmacokinetics of
anti-D IgG in pregnant RhD-negative women. BJOG 2003;110(1):39–45.
[RCT; I]
39. Tiblad E, Wikman A, Rane A, Jansson Y, Westgren M. Pharmacokinetics of
250 mug anti-D IgG in the third trimester of pregnancy: an observational
study. Acta Obstet Gynecol Scand 2012;91(5):587–92. [II-3]
40. Bowman JM. Controversies in Rh prophylaxis. Who needs Rh immune
globulin and when should it be given? Am J Obstet Gynecol 1985;151(3):
289–94. [iii]
41. Huchet J, Dallemagne S, Huchet C, Brossard Y, Larsen M, Parnet-Mathieu
F. Ante-partum administration of preventive treatment of Rh-D immu-
nization in rhesus-negative women. Parallel evaluation of transplacental
passage of fetal blood cells. Results of a multicenter study carried out in
the Paris region. J Gynecol Obstet Biol Reprod (Paris) 1987;16(1):101–11.
[RCT;I]
42. Crowther C, Middleton P. Anti-D administration after childbirth for pre-
venting Rhesus alloimmunisation. Cochrane Database Syst Rev 2000;(2):
CD000021. [Meta-analysis]
43. Fyfe TM, Ritchey MJ, Taruc C, Crompton D, Galliford B, Perrin R.
Appropriate provision of anti-D prophylaxis to RhD negative pregnant
women: a scoping review. BMC Pregnancy Childbirth 2014;14:411. [III]
44. Jones ML, Wray J, Wight J, Chilcott J, Forman K, Tappenden P, et al. A
review of the clinical effectiveness of routine antenatal anti-D prophylaxis
for rhesus-negative women who are pregnant. BJOG 2004;111(9):892–902.
[Meta-analysis]
45. Urbaniak SJ. The scientific basis of antenatal prophylaxis. Br J Obstet
Gynaecol 1998;105 (Suppl 18):11–8.[III]
46. Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contam-
inated anti-D immune globulin. Irish Hepatology Research Group. N Engl J
Med 1999;340(16):1228–33. [II-2]
47. Moise KJ, Jr. Management of rhesus alloimmunization in pregnancy. Obstet
Gynecol 2008;112(1):164–76. [III]
48. Voracek M, Haubner T, Fisher ML. Recent decline in nonpaternity rates:
a cross-temporal meta-analysis. Psychol Rep 2008;103(3):799–811.
[Meta-analysis]
49. Moise KJ, Jr., Hashmi SS, Markham K, Argoti PS, Bebbington M. Cell free
fetal DNA to triage antenatal rhesus immune globulin: Is it really cost-
effective in the United States? Prenat Diagn 2019;39(3):238–47. [II-3]
50. Sebring ES, Polesky HF. Fetomaternal hemorrhage: incidence, risk fac-
tors, time of occurrence, and clinical effects. Transfusion 1990;30(4):
344–57. [III]
51. Ness PM, Baldwin ML, Niebyl JR. Clinical high-risk designation does
not predict excess fetal-maternal hemorrhage. Am J Obstet Gynecol
1987;156(1):154–8. [II-2]
52. Stedman CM, Baudin JC, White CA, Cooper ES. Use of the erythrocyte
rosette test to screen for excessive fetomaternal hemorrhage in Rh-negative
women. Am J Obstet Gynecol 1986;154(6):1363–9. [II-3]
53. Kim YA, Makar RS. Detection of fetomaternal hemorrhage. Am J Hematol
2012;87(4):417–23. [III]
54. Yu A, Morris E, Adams R, Fung MK. Obstetrics and gynecology phy-
sician knowledge of Rh immune globulin prophylaxis. Transfusion
2017;57(6):1385–90. [III]
549
55. Mark A, Foster AM, Grossman D, et al. Foregoing Rh testing and anti-D
immunoglobulin for women presenting for early abortion: a recommenda-
tion from the national abortion federation’s clinical policies committee.
Contraception 2019;99(5):265–6.[III]
56. National Institute for Health and Care Excellence. High-throughput non-
invasive prenatal testing for fetal RHD genotype 1: Recommendations.
Accessed on August 09, 2017. Available from: https://www.nice.org.uk/
guidance/dg25/chapter/1-Recommendations. [III]
57. Clausen FB, Christiansen M, Steffensen R, Jorgensen S, Nielsen C, Jakobsen
MA, et al. Report of the first nationally implemented clinical routine
screening for fetal RHD in D-pregnant women to ascertain the requirement
for antenatal RhD prophylaxis. Transfusion 2012;52(4):752–8. [II-2]
58. de Haas M, Thurik FF, van der Ploeg CP, Veldhuisen B, Hirschberg H,
Soussan AA, et al. Sensitivity of fetal RHD screening for safe guidance of
targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a
nationwide programme in the Netherlands. BMJ 2016;355:i5789. [II-2]
59. Mackie FL, Hemming K, Allen S, Morris RK, Kilby MD. The accuracy
of cell-free fetal DNA-based non-invasive prenatal testing in single-
ton pregnancies: a systematic review and bivariate meta-analysis. BJOG
2017;124(1):32–46. [Meta analysis]
60. Gordon LG, Hyland CA, Hyett JA, O’Brien H, Millard G, Flower RL, et al.
Noninvasive fetal RHD genotyping of RhD negative pregnant women for
targeted anti-D therapy in Australia: A cost-effectiveness analysis. Prenat
Diagn 2017;37(12):1245–53. [Cost-effectiveness analysis]
61. Duplantie J, Gonzales OM, Bois A, Nshimyumukiza L, Gekas J, Bujold
E, et al. Cost-effectiveness of the management of Rh-negative pregnant
women. J Obstet Gynaecol Can 2013;35(8):730–40. [Cost-effectiveness
analysis]
62. Mari G. Middle cerebral artery peak systolic velocity for the diagnosis
of fetal anemia: the untold story. Ultrasound Obstet Gynecol 2005;25(4):
323–30. [II-2]
63. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ,
Jr., et al. Noninvasive diagnosis by Doppler ultrasonography of fetal ane-
mia due to maternal red-cell alloimmunization. Collaborative Group for
Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med
2000;342(1):9–14. [II-2]
64. Brinc D, Lazarus AH. Mechanisms of anti-D action in the prevention of
hemolytic disease of the fetus and newborn. Hematology Am Soc Hematol
Educ Program 2009:185–91. [III]
65. Schumacher B, Moise KJ, Jr. Fetal transfusion for red blood cell alloimmu-
nization in pregnancy. Obstet Gynecol 1996;88(1):137–50. [III]
66. Snelgrove JW, D’Souza R, Seaward PGR, Windrim R, Kelly EN, Ryan G.
Predicting intrauterine transfusion interval and perinatal outcomes in allo-
immunized pregnancies: time-to-event survival analysis. Fetal Diagn Ther
2019;46(6):425–32. [II-3]
67. Zwiers C, Lindenburg ITM, Klumper FJ, de Haas M, Oepkes D, Van Kamp
IL. Complications of intrauterine intravascular blood transfusion: lessons
learned after 1678 procedures. Ultrasound Obstet Gynecol 2017;50(2):
180–6. [II-2]
68. Simonazzi G, Bernabini D, Curti A, Bisulli M, Pilu G, Brill CB, et al. Fetal
cerebellar damage in fetuses with severe anemia undergoing intrauterine
transfusions. J Matern Fetal Neonatal Med 2016;29(3):389–92. [III]
69. Gebb J, Dar P, Rosner M, Evans MI. Long-term neurologic outcomes after
common fetal interventions. Am J Obstet Gynecol 2015;212(4):527 e1–9.
[Systematic review]
70. Lindenburg IT, Smits-Wintjens VE, van Klink JM, Verduin E, van Kamp
IL, Walther FJ, et al. Long-term neurodevelopmental outcome after intra-
uterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS
study. Am J Obstet Gynecol 2012;206(2):141 e1–8. [II-2]
71. Carter BS, DiGiacomo JE, Balderston SM, Wiggins JW, Merenstein GB.
Disproportionate septal hypertrophy associated with erythroblastosis feta-
lis. Am J Dis Child 1990;144(11):1225–8. [III]
72. Dickinson JE, Sharpe J, Warner TM, Nathan EA, D’Orsogna L. Childhood
cardiac function after severe maternal red cell isoimmunization. Obstet
Gynecol 2010;116(4):851–7. [II-2]
73. Schonewille H, Klumper FJ, van de Watering LM, Kanhai HH, Brand A.
High additional maternal red cell alloimmunization after Rhesus- and
K-matched intrauterine intravascular transfusions for hemolytic disease of
the fetus. Am J Obstet Gynecol 2007;196(2):143 e1–6. [II-3]
74. Vietor HE, Kanhai HH, Brand A. Induction of additional red cell alloan-
tibodies after intrauterine transfusions. Transfusion 1994;34(11):970–4.
[II-2]
75. Moise KJ, Jr., Argoti PS. Management and prevention of red cell allo-
immunization in pregnancy: a systematic review. Obstet Gynecol
2012;120(5):1132–9. [Systematic review]
550
76. Finck R, Lui-Deguzman C, Teng SM, Davis R, Yuan S. Comparison of a gel
microcolumn assay with the conventional tube test for red blood cell allo-
antibody titration. Transfusion 2013;53(4):811–5. [II-3]
77. Bachegowda LS, Cheng YH, Long T, Shaz BH. Impact of uniform methods
on interlaboratory antibody titration variability: antibody titration and uni-
form methods. Arch Pathol Lab Med 2017;141(1):131–8. [II-3]
78. Nicolaides KH, Rodeck CH. Maternal serum anti-D antibody concentra-
tion and assessment of rhesus isoimmunisation. BMJ 1992;304(6835):
1155–6. [II-3]
79. Walsh CA, Doyle B, Quigley J, McAuliffe FM, Fitzgerald J, Mahony R,
et al. Reassessing critical maternal antibody threshold in RhD alloimmu-
nization: a 16-year retrospective cohort study. Ultrasound Obstet Gynecol
2014;44(6):669–73. [II-2]
80. Slootweg YM, Lindenburg IT, Koelewijn JM, van Kamp IL, Oepkes D, de
Haas M. Predicting anti-Kell mediated hemolytic disease of the fetus and
newborn, diagnostic accuracy of laboratory management. Am J Obstet
Gynecol 2018;219(4):393–e1. [III]
81. Anderson, K. How well does paternity confidence match actual pater-
nity? Evidence from worldwide nonpaternity rates. Curr Anthropol
2006;47(3):513–20. [III]
82. Van den Veyver IB, Moise KJ, Jr. Fetal RhD typing by polymerase chain
reaction in pregnancies complicated by rhesus alloimmunization. Obstet
Gynecol 1996;88(6):1061–7. [Systematic review]
83. Peddle LJ. Increase of antibody titer following amniocentesis. Am J Obstet
Gynecol 1968;100(4):567–9. [II-3]
84. Moise KJ, Jr., Boring NH, O’Shaughnessy R, Simpson LL, Wolfe HM, Baxter
JK, et al. Circulating cell-free fetal DNA for the detection of RHD status and
sex using reflex fetal identifiers. Prenat Diagn 2013;33(1):95–101. [II-2]
85. Rieneck K, Bak M, Jonson L, Clausen FB, Krog GR, Tommerup N, et al.
Next-generation sequencing: proof of concept for antenatal prediction of
the fetal Kell blood group phenotype from cell-free fetal DNA in maternal
plasma. Transfusion 2013;53(11 Suppl 2):2892–8. [II-3]
86. Rieneck K, Clausen FB, Dziegiel MH. Noninvasive antenatal determination
of fetal blood group using next-generation sequencing. Cold Spring Harb
Perspect Med 2015;6(1):a023093. [III]
87. Mari G, Norton M, Stone J, Berghella V, Sciscione AC, Tate D, Schenone
MH. Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline
#8: the fetus at risk for anemia–diagnosis and management. Am J Obstet
Gynecol 2015;212(6):697–710. [III]
88. Rightmire DA, Nicolaides KH, Rodeck CH, Campbell S. Fetal blood veloci-
ties in Rh isoimmunization: relationship to gestational age and to fetal
hematocrit. Obstet Gynecol 1986;68(2):233–6. [II-3]
89. Bahado-Singh R, Oz U, Deren O, Kovanchi E, Hsu CD, Copel J, et al. Splenic
artery Doppler peak systolic velocity predicts severe fetal anemia in rhesus
disease. Am J Obstet Gynecol 2000;182(5):1222–6. [II-2]
90. Bahado-Singh RO, Oz AU, Hsu C, Kovanci E, Deren O, Onderoglu L, et al.
Middle cerebral artery Doppler velocimetric deceleration angle as a pre-
dictor of fetal anemia in Rh-alloimmunized fetuses without hydrops. Am J
Obstet Gynecol 2000;183(3):746–51. [II-3]
91. Vyas S, Nicolaides KH, Campbell S. Doppler examination of the middle
cerebral artery in anemic fetuses. Am J Obstet Gynecol 1990;162(4):
1066–8. [II-3]
92. Mari G, Moise KJ, Jr., Deter RL, Kirshon B, Carpenter RJ, Jr., Huhta JC.
Doppler assessment of the pulsatility index in the cerebral circulation of
the human fetus. Am J Obstet Gynecol 1989;160(3):698–703. [II-3]
93. Mari G, Adrignolo A, Abuhamad AZ, Pirhonen J, Jones DC, Ludomirsky A,
et al. Diagnosis of fetal anemia with Doppler ultrasound in the pregnancy
complicated by maternal blood group immunization. Ultrasound Obstet
Gynecol 1995;5(6):400–5. [II-2]
94. Ruma MS, Swartz AE, Kim E, Herring AH, Menard MK, Moise KJ, Jr. Angle
correction can be used to measure peak systolic velocity in the fetal middle
cerebral artery. Am J Obstet Gynecol 2009;200(4):397 e1–3. [II-3]
95. Mari G, Abuhamad AZ, Cosmi E, Segata M, Altaye M, Akiyama M.
Middle cerebral artery peak systolic velocity: technique and variability. J
Ultrasound Med 2005;24(4):425–30. [II-2]
96. Martinez-Portilla RJ, Lopez-Felix J, Hawkins-Villareal A, Villafan-Bernal
JR, Paz YMF, Figueras F, et al. Performance of fetal middle cerebral artery
peak systolic velocity for prediction of anemia in untransfused and trans-
fused fetuses: systematic review and meta-analysis. Ultrasound Obstet
Gynecol 2019;54(6):722–31. [Meta-analysis]
97. Oepkes D, Seaward PG, Vandenbussche FP, Windrim R, Kingdom J, Beyene
J, et al. Doppler ultrasonography versus amniocentesis to predict fetal ane-
mia. N Engl J Med 2006;355(2):156–64. [II-1]
98. Zimmerman R, Carpenter RJ, Jr., Durig P, Mari G. Longitudinal mea-
surement of peak systolic velocity in the fetal middle cerebral artery for
Maternal-Fetal Evidence Based Guidelines
monitoring pregnancies complicated by red cell alloimmunisation: a
prospective multicentre trial with intention-to-treat. BJOG 2002;109(7):
746–52. [II-2]
99. Pereira L, Jenkins TM, Berghella V. Conventional management of maternal
red cell alloimmunization compared with management by Doppler assess-
ment of middle cerebral artery peak systolic velocity. Am J Obstet Gynecol
2003;189(4):1002–6. [II-3]
100. Nishie EN, Brizot ML, Liao AW, Carvalho MH, Toma O, Zugaib M. A com-
parison between middle cerebral artery peak systolic velocity and amni-
otic fluid optical density at 450 nm in the prediction of fetal anemia. Am J
Obstet Gynecol 2003;188(1):214–9. [II-2]
101. Mari G, Rahman F, Olofsson P, Ozcan T, Copel JA. Increase of fetal hema-
tocrit decreases the middle cerebral artery peak systolic velocity in preg-
nancies complicated by rhesus alloimmunization. J Matern Fetal Med
1997;6(4):206–8. [II-3]
102. Stefos T, Cosmi E, Detti L, Mari G. Correction of fetal anemia on the
middle cerebral artery peak systolic velocity. Obstet Gynecol 2002;99(2):
211–5. [II-2]
103. Detti L, Oz U, Guney I, Ferguson JE, Bahado-Singh RO, Mari G, et al.
Doppler ultrasound velocimetry for timing the second intrauterine trans-
fusion in fetuses with anemia from red cell alloimmunization. Am J Obstet
Gynecol 2001;185(5):1048–51. [II-3]
104. Cosmi E, Mari G, Delle Chiaie L, Detti L, Akiyama M, Murphy J,
et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia
resulting from parvovirus infection. Am J Obstet Gynecol 2002;187(5):
1290–3. [II-3]
105. Senat MV, Loizeau S, Couderc S, Bernard JP, Ville Y. The value of middle
cerebral artery peak systolic velocity in the diagnosis of fetal anemia after
intrauterine death of one monochorionic twin. Am J Obstet Gynecol
2003;189(5):1320–4. [II-3]
106. Sueters M, Arabin B, Oepkes D. Doppler sonography for predicting fetal
anemia caused by massive fetomaternal hemorrhage. Ultrasound Obstet
Gynecol 2003;22(2):186–9. [III]
107. Hernandez-Andrade E, Scheier M, Dezerega V, Carmo A, Nicolaides
KH. Fetal middle cerebral artery peak systolic velocity in the investiga-
tion of non-immune hydrops. Ultrasound Obstet Gynecol 2004;23(5):
442–5. [II-3]
108. Abel DE, Grambow SC, Brancazio LR, Hertzberg BS. Ultrasound assess-
ment of the fetal middle cerebral artery peak systolic velocity: A com-
parison of the near-field versus far-field vessel. Am J Obstet Gynecol
2003;189(4):986–9. [II-3]
109. Schenone MH, Mari G. The MCA Doppler and its role in the evaluation of fetal
anemia and fetal growth restriction. Clin Perinatol 2011;38(1):83–102, vi. [III]
110. Samson J, Block D, Mari G. Middle cerebral artery Doppler for managing
fetal anemia. Clin Obstet Gynecol 2010;53(4):851–7. [III]
111. Mari G. Doppler ultrasonography in obstetrics: from the diagnosis of fetal
anemia to the treatment of intrauterine growth-restricted fetuses. Am J
Obstet Gynecol 2009;200(6):613 e1–9. [III]
112. Mari G, Hanif F, Kruger M, Cosmi E, Santolaya-Forgas J, Treadwell MC.
Middle cerebral artery peak systolic velocity: a new Doppler parameter in
the assessment of growth-restricted fetuses. Ultrasound Obstet Gynecol
2007;29(3):310–6. [II-3]
113. Detti L, Mari G, Akiyama M, Cosmi E, Moise KJ, Jr., Stefor T, et al.
Longitudinal assessment of the middle cerebral artery peak systolic veloc-
ity in healthy fetuses and in fetuses at risk for anemia. Am J Obstet Gynecol
2002;187(4):937–9. [II-2]
114. Bevis DC. The composition of liquor amnii in haemolytic disease of the
newborn. J Obstet Gynaecol Br Emp 1953;60(2):244–51. [II-3]
115. Liley AW. Liquor amnil analysis in the management of the pregnancy com-
plicated by resus sensitization. Am J Obstet Gynecol 1961;82:1359–70. [II-2]
116. Lindenburg IT, van Kamp IL, Oepkes D. Intrauterine blood transfusion:
current indications and associated risks. Fetal Diagn Ther 2014;36(4):
263–71. [III]
117. Mari G, Moise KJ, Jr., Deter RL, Carpenter RJ, Jr. Flow velocity waveforms of
the umbilical and cerebral arteries before and after intravascular transfu-
sion. Obstet Gynecol 1990;75(4):584–9. [II-3]
118. Fox C, Martin W, Somerset DA, Thompson PJ, Kilby MD. Early intraperi-
toneal transfusion and adjuvant maternal immunoglobulin therapy in the
treatment of severe red cell alloimmunization prior to fetal intravascular
transfusion. Fetal Diagn Ther 2008;23(2):159–63. [III]
119. Zwiers C, van der Bom JG, van Kamp IL, van Geloven N, Lopriore E,
Smoleniec J, et al. Postponing Early intrauterine Transfusion with
Intravenous immunoglobulin Treatment; the PETIT study on severe hemo-
lytic disease of the fetus and newborn. Am J Obstet Gynecol 2018;219(3):291
e1–e9. [II-2]
Hemolytic Disease of the Fetus and Newborn
120. Guilbaud L, Garabedian C, Cortey A, Rakza T, Carbonne B, Houfflin-
Debarge V. In utero treatment of severe fetal anemia resulting from fetoma-
ternal red blood cell incompatibility: a comparison of simple transfusion
and exchange transfusion. Eur J Obstet Gynecol Reprod Biol 2016;201:
85–8. [III]
121. Bahtiyar MO, Ekmekci E, Demirel E, Irani RA, Copel JA. In utero partial
exchange transfusion combined with in utero blood transfusion for prena-
tal management of twin anemia-polycythemia sequence. Fetal Diagn Ther
2018. [III]
122. Giannina G, Moise KJ, Jr., Dorman K. A simple method to estimate volume
for fetal intravascular transfusions. Fetal Diagn Ther 1998;13(2):94–7. [III]
123. Charles Rodeck MW. Fetal Medicine. 2nd ed. London: Churchill
Livingstone, 2008. [III]
124. Radunovic N, Lockwood CJ, Alvarez M, Plecas D, Chitkara U, Berkowitz RL. The
severely anemic and hydropic isoimmune fetus: changes in fetal hematocrit
associated with intrauterine death. Obstet Gynecol 1992;79(3):390–3. [II-3]
125. Mari G, Moise KJ, Jr., Deter RL, Kirshon B, Stefos T, Carpenter RJ, Jr. Flow
velocity waveforms of the vascular system in the anemic fetus before and
after intravascular transfusion for severe red blood cell alloimmunization.
Am J Obstet Gynecol 1990;162(4):1060–4. [II-3]
126. Nicolini U, Kochenour NK, Greco P, Letsky E, Rodeck CH. When to per-
form the next intra-uterine transfusion in patients with Rh allo-immuniza-
tion: combined intravascular and intraperitoneal transfusion allows longer
intervals. Fetal Ther 1989;4(1):14–20. [II-3]
127. Howe DT, Michailidis GD. Intraperitoneal transfusion in severe, early-
onset Rh isoimmunization. Obstet Gynecol 2007;110(4):880–4. [III]
128. van den Akker ES, de Haan TR, Lopriore E, Brand A, Kanhai HH, Oepkes
D. Severe fetal thrombocytopenia in Rhesus D alloimmunized pregnancies.
Am J Obstet Gynecol 2008;199(4):387 e1–4. [II-3]
129. Rosenbloom JI, Bruno AM, Conner SN, Tuuli MG, Simon LE, Macones
GA, et al. Fetal thrombocytopenia in pregnancies complicated by fetal ane-
mia due to red-cell alloimmunization: cohort study and meta-analysis. J
Perinatol 2019;39(7):920–6. [Meta-analysis]
130. Scheier M, Hernandez-Andrade E, Fonseca EB, Nicolaides KH. Prediction
of severe fetal anemia in red blood cell alloimmunization after previous
intrauterine transfusions. Am J Obstet Gynecol 2006;195(6):1550–6. [II-3]
131. Dodd JM, Andersen C, Dickinson JE, Louise J, Deussen A, Grivell RM, et al.
Fetal middle cerebral artery Doppler to time intrauterine transfusion in
551
red-cell alloimmunization: a randomized trial. Ultrasound Obstet Gynecol
2018;51(3):306–12. [RCT; I]
132. Society for Maternal-Fetal M, Berry SM, Stone J, Norton ME, Johnson
D, Berghella V. Fetal blood sampling. Am J Obstet Gynecol 2013;209(3):
170–80. [III]
133. Harman CR, Bowman JM, Manning FA, Menticoglou SM. Intrauterine
transfusion–intraperitoneal versus intravascular approach: a case-control
comparison. Am J Obstet Gynecol 1990;162(4):1053–9. [II-2]
134. Mackie FL, Pretlove SJ, Martin WL, Donovan V, Kilby MD. Fetal intracar-
diac transfusions in hydropic fetuses with severe anemia. Fetal Diagn Ther
2015;38(1):61–4. [III]
135. Trevett TN, Jr., Moise KJ, Jr. Twin pregnancy complicated by severe hemo-
lytic disease of the fetus and newborn due to anti-g and anti-C. Obstet
Gynecol 2005;106(5 Pt 2):1178–80. [III]
136. Practice bulletin no. 145: antepartum fetal surveillance. Obstet Gynecol
2014;124(1):182–92. [III]
137. Olofsson P, Stangenberg M, Selbing A, Rahman F, Westgren M. Fetal
heart rate responses to anemia in Rh isoimmunization. J Perinat Med
1990;18(3):187–94. [II-3]
138. Weinstein L. Irregular antibodies causing hemolytic disease of the new-
born: a continuing problem. Clin Obstet Gynecol 1982;25(2):321–32. [III]
139. Reid M, Lomas-Francis, C, Olsson, M. The Blood Group Antigen Facts Book.
2nd ed. New York: Elsevier Academic Press. 2004. [III]
140. Slootweg YM, Lindenburg IT, Koelewijn JM, Van Kamp IL, Oepkes D, De
Haas M. Predicting anti-Kell-mediated hemolytic disease of the fetus and
newborn: diagnostic accuracy of laboratory management. Am J Obstet
Gynecol 2018;219(4):393 e1–e8. [III]
141. van Dongen H, Klumper FJ, Sikkel E, Vandenbussche FP, Oepkes D. Non-
invasive tests to predict fetal anemia in Kell-alloimmunized pregnancies.
Ultrasound Obstet Gynecol 2005;25(4):341–5. [II-3]
142. Spong CY, Porter AE, Queenan JT. Management of isoimmunization
in the presence of multiple maternal antibodies. Am J Obstet Gynecol
2001;185(2):481–4. [II-2]
143. Stetson B, Scrape S, Markham KB. Anti-M alloimmunization: management
and outcome at a single institution. AJP Rep 2017;7(4):e205–e10. [III]
144. Li S, Mo C, Huang L, Shi X, Luo G, Ji Y, et al. Hemolytic disease of the fetus
and newborn due to alloanti-M: three Chinese case reports and a review of
the literature. Transfusion 2019;59(1):385–95. [III]
56
NONIMMUNE HYDROPS FETALIS
Chelsea DeBolt, Katherine Connolly, Mary E. Norton, and Joanne Stone
Key points
• Fetal hydrops is defined as the accumulation of fluid in
two or more fetal extravascular compartments, includ-
ing ascites, pleural effusion, pericardial effusion, and skin
edema. These findings are commonly accompanied by
polyhydramnios and placentomegaly.
• Nonimmune hydrops fetalis (NIH) is defined by the
absence of maternal antibodies against fetal cells (nega-
tive indirect Coombs test in maternal serum).
• Because of the wide use of anti-Rh prophylaxis, currently most
cases (90%) of fetal hydrops are nonimmune in origin. The
incidence of NIH has been estimated between 1/1700 to 3000
pregnancies and reported to be 1/4000 live births.
• The prognosis for NIH is often dismal, with an overall
perinatal mortality of 50–100%, which is related to the
etiology, gestational age at presentation, the presence of
early and significant pleural effusions and the availability
of treatment for certain conditions (e.g., parvovirus B19-
induced NIH). Current data indicate that, among those
who survive the neonatal period, 50% are free of long-term
sequelae at one year of age.
• NIH is a condition associated with a large number of causes.
In general, the etiology is suspected or confirmed pre-
natally in 50–80% of cases. Chromosomal abnormalities
account for a significant fraction of cases of NIH before 24
weeks, while structural abnormalities of the heart and infec-
tious conditions are more frequently found after 24 weeks’
gestation. After delivery, 5% of newborns remain classified as
idiopathic. Following is a simplified etiologic summary:
• Cardiovascular anomalies: 20%
• Non-cardiovascular anomalies: 15–25%
• Chromosomal abnormalities: 15–20%
• Infection: 10–15%
• Hematologic disorders: 5–15%
• Complications of monochorionic twins: 5%
• Genetic syndromes: 1%
• Metabolic syndromes: 1–5%
– Overlapping of these conditions is frequent (e.g.,
a fetus with trisomy 21 and cardiac structural
malformations)
• No identifiable primary cause: 20%
• Evaluation of cases with NIH should be exercised accord-
ing to local resources, and when required, cases should be
transferred to a tertiary center where advanced diagnostic
tests/procedures and potential treatments are available.
• Always make sure that antibody screening (indirect
Coombs) is negative (even in Rh-positive patients).
• Because of the broad spectrum of the disease, efforts
should be made to establish whether a treatable con-
dition is present. Likewise, identification of recurrent
causes of the disease is mandatory to provide appropri-
ate counseling.
552
• Suggested evaluation may include the following:
– Detailed history (recent flu-like symptoms, ethnic
background, family history).
– Ultrasound to evaluate fetal anatomy, amniotic
fluid volume, placenta, umbilical cord, echocar-
diogram and middle cerebral artery peak systolic
velocity to search for cardiac and extracardiac
malformations, arrhythmias and fetal anemia.
– Maternal laboratory tests:
– blood type and antibody screening to rule out
immune-mediated anemia.
– CBC with red blood cell indices and hemo-
globin electrophoresis to assess for alpha
thalassemia.
– serology for parvovirus, CMV, rubella.
– nontreponemal tests for syphilis (RPR).
– Kleihauer–Betke to exclude fetal anemia from
fetomaternal hemorrhage.
– Other tests if there is a suggestive history (e.g.,
HSV, Listeria monocytogenes) or the etiology
of the condition remains elusive. On the other
hand, the workup may be concise or stopped if
the etiology arises soon after initial evaluation
of the patient.
– Amniocentesis to perform fetal karyotype with
microarray, PCR for parvovirus B19, toxoplasmosis,
and CMV as needed. It is a good practice to freeze
and store amniotic fluid with the aim to test for
genetic conditions if additional phenotypic data sug-
gests a RASopathy or lysosomal storage disorder.
– In cases still idiopathic after the workup above
has been completed, consideration should be
given to testing for genetic disorders such as
RASopathies or lysosomal storage disorders
(LSD), as approximately 29% of otherwise unex-
plained NIH may be due to a genetic disorder.
• Management of NIH is based on the etiology and may
include the following:
• Treatment of conditions that benefit from maternal
interventions (e.g., penicillin for syphilis-induced
NIH) or fetal interventions (e.g., intrauterine blood
transfusion for parvovirus B19–induced fetal anemia/
thrombocytopenia).
• Rarely, the mother may develop generalized edema,
which could be life threatening (mirror syndrome).
• Termination of pregnancy depending on patient
preference.
• Fetal monitoring: Nonstress test, biophysical profile,
Doppler studies of umbilical artery and middle cere-
bral artery, as well as heart and venous system as fea-
sible and indicated.
• Antenatal steroids to reduce the likelihood of neonatal
complications associated with preterm delivery.
DOI: 10.1201/9781003099062-56
Nonimmune Hydrops Fetalis 553

• Delivery if there is evidence of fetal or maternal deteriora- (a) (b)

tion (e.g., mirror syndrome). Delivery may be preceded by
interventions aimed to improve the immediate neonatal
status, and to reduce the frequency of dystocia and fetal
trauma (e.g., aspiration of excessive pericardial, pleural or
peritoneal fluid). NIH increases the risk of postpartum
hemorrhage and retained placenta.
Skin edema Pleural effusion

Diagnosis/Definition (c) (d)

Hydrops fetalis is the end stage of many different disorders, charac-

terized by the pathologic accumulation of fluid in body cavities or
tissues. The diagnosis of NIH (non-immune hydrops) is established
if at least two of the following conditions are present: Hydrothorax,
ascites, pericardial effusion, and skin edema (>5 mm measured at
Ascites Pericardial effusion
the level of skull or chest wall) (Figure 56.1). These diagnostic find-
ings can be associated with polyhydramnios (in 40–75% of cases) and
placentomegaly (placental thickness ≥4 cm in the second trimester FIGURE 56.1 Diagnostic criteria for hydrops: need ≥2 of these
or ≥6 cm in the third trimester) [1]. Immune hydrops is associated four: (a) Skin edema; (b) pleural effusion, (c) ascites, and (d) peri-
with alloimmunization to an RBC antigen (e.g., Rh disease) (see cardial effusion.
Chapter 55), while NIH includes all other etiologies.
significantly decreased. Thus, NIH now represents 90% of
Epidemiology/Incidence all hydrops cases [1].

The incidence of NIH ranges between 1/1700 and 1/3000
pregnancies and 1/4000 live births [1, 2], and as high as 0.5%
in tertiary referral centers. The incidence may be as high as
1/150 on ultrasound, as the lower incidence in live-born infants
is secondary to intrauterine death and elective termination of
pregnancy. NIH may account for up to 3% of perinatal mor-
tality. When Potter described for the first time NIH in 1943,
its incidence was very low compared to fetal hydrops for iso-
immunization. After the introduction of anti-D prophylaxis,
however, the incidence of Rh(D) alloimmunization has
Etiology/Basic pathophysiology
NIH is the final phenotype of hundreds of different disorders.
The exact pathogenesis depends on the underlying disorder, but the
common disorder is an imbalance in the regulation of fluid move-
ment between the vascular and interstitial spaces [1]. There are four
main mechanisms proposed to explain the distribution of fluid in
NIH: (1) increase in hydrostatic capillary pressure, (2) reduction in
plasma oncotic pressure, (3) obstruction of lymphatic flow, and
(4) damage to peripheral capillary integrity (Figure 56.2) [3].

Physiopathology
of Hydrops Hydrostatic pressure Oncotic pressure

Impaired lymphatic flow

OBSTRUCTION CARDIAC EXTRAVASATION

FAILURE

venous Iymphatic Primary Secondary hypoproteinemia

ä permeability
CHD Anemia
Congenital anomalies Hypervolemia Infections
CHD (recipient twin) Metabolic diseases
Chylothorax A-V Shunt

FIGURE 56.2 Possible pathophysiologic mechanisms for hydrops fetalis. Abbreviations: CHD, congenital heart disease; A–V,
arterio–venous.
554 Maternal-Fetal Evidence Based Guidelines

These various etiologic factors and complex mechanisms lead
to extra-accumulation of fluid in the fetal interstitial space, with
10–20% of hydrops causes still undetermined after workup [4].
The complex physiopathology of hydrops makes it a challenge for
the obstetrician to investigate its etiology and decide upon the
management.
Associations/Possible etiologies/
Differential diagnosis (Table 56.1) [4–6]
Cardiovascular disorders (20%)
The main causal association of NIH is with fetal cardiovascular
disease [7]. The most common disorders involved are tachyar-
rhythmias (40%), cardiac structural malformations (20%),
high-output cardiac failure (15%), and bradyarrhythmias (6%)
resulting from congenital heart malformation or maternal con-
nective disorders (antibody mediated).
Fetal arrhythmias are the leading cause of cardiac disorders
associated with NIH (40%) [8]. Most of them are secondary to
tachyarrhythmias and another fraction is the result of heart block.
The most frequent tachyarrhythmia is supraventricular tachycar-
dia, followed by atrial flutter and atrial fibrillation. Etiopathogenic
disturbances induced by arrhythmias include reduction of the
stroke volume, end-diastolic overload, and systemic venous con-
gestion. Sustained fetal tachycardia results in elevated ventricu-
lar end-diastolic pressure, which may lead to increased central
venous pressure and decreased cardiac output, resulting in NIH,
which occurs in about half of these cases, leading to fetal demise
in 9% of untreated cases [9]. These conditions are susceptible to in

TABLE 56.1: Conditions Associated with Nonimmune Fetal Hydrops and Suggested Workup

Conditions Associated with NIH Suggested Workup

Cardiovascular (20%)
Fetal arrhythmias Fetal echocardiogram for morphological and functional study,
Supraventricular tachycardia, atrial flutter, heart block with bradyarrhythmia, with 2D, M-mode, pulsed Doppler, color Doppler, including
Wolff-Parkinson-White, non-conducted premature atrial contractions, others functional assessment of output tracts, ductus arteriosus and
the fetal venous system (ductus venosus)
Structural Detailed fetal anatomical ultrasound, including the umbilical
Atrioventricular septal defects, hypoplastic left ventricle, hypoplastic right cord and placenta
ventricle, large ventricular septal defects, atrial septal defects, Ebstein
anomaly, premature closure of the ductus arteriosus, closure of the foramen
ovale, tetralogy of Fallot and its variants, truncus, transposition of the great
vessels, severe atrioventricular or arterial valve insufficiency, others
Mass Color and pulsed Doppler of peripheral vessels including
Cardiac rhabdomyoma, pericardial/intrapericardial/intracardiac teratoma umbilical cord, placenta, cranial venous system (especially the
base of the skull, under the hemispheres), and middle cerebral
artery peak systolic velocity
High cardiac output failure
Chorioangioma (>5 cm), aneurysmal malformation of the vein of Galen, large
sacrococcygeal teratoma, umbilical cord aneurysms, neuroblastoma, vena
cava obstruction
Vascular disorders
Cardiomyopathy, peripheral artery thrombosis
Extracardiac anomalies (15–25%) Detailed fetal anatomical ultrasound
Thorax Consider thoracocentesis, or paracentesis, with biochemical,
Congenital pulmonary airway malformation (e.g., CCAM, pulmonary cytological, and microbiological analysis
sequestration), congenital diaphragmatic hernia, pulmonary
lymphangiectasia, chylothorax, bronchogenic cyst, any thoracic tumors
Urinary
Posterior urethral valves, urethral stenosis/atresia, prune-belly syndrome,
congenital nephrosis
Gastrointestinal
Volvulus-atresia, malrotation, duplication, meconium, peritonitis, hepatic
fibrosis, cholestasis, billiary atresia, cloacal dysgenesis, hemochromatosis
Skeletal dysplasias
Thanatophoric dysplasia, short rib-polydactyly, osteogenesis imperfecta,
achondrogenesis, hypophosphatasia
Chromosomal abnormalities (15–20%) Amniocentesis
45x (or mosaic 45X/46XX), trisomy 21, trisomy 18, trisomy 13, triploidy, others
Infections (10–15%) RPR, serology for parvovirus B19, CMV, toxoplasmosis,
Parvovirus B19, CMV, syphilis, toxoplasmosis, rubella, lysteria, adenovirus, rubella, and others if suspected
coxsackie B, others Amniocentesis: PCR (or culture) of fluid
Nonimmune Hydrops Fetalis
TABLE 56.1 (Continued): Conditions Associated with Nonimmune Fetal Hydrops and Suggested Workup
Conditions Associated with NIH
Hematologic (5–15%)
Excessive red cells loss
α-Thalassemia, G6PD-deficit, fetomaternal transfusion, Twin-to-twin
transfusion syndrome (TTTS), fetal hemorrhage, red cell enzyme deficiencies,
congenital leukemia, others
Underproduction
Fetal liver and bone marrow replacement syndromes
Congenital leukemia
Parvovirus B19
Red cell aplasia
Monochorionic twin pregnancy (5%)
Twin-to-twin transfusion syndrome (TTTS) TRAP sequence
Genetic syndromes (1%)
Myotonic dystrophy, arthrogryposis, multiple pterygium, Noonan syndrome
(congenital lymphedema), skeletal (see earlier)
Metabolic (1–5%)
Lysosomal storage disorders, Gaucher’s disease, Niemann-Pick disease (types C
and A), mucopolysaccharidosis (especially type VII), mucolipidosis, sialidosis,
galactosialidosis, GM1-gangliosidosis, infantile sialic acid storage disease, othersa
a For complete detailed list, see Ref. [39].
Abbreviations: NIH, nonimmune hydrops fetalis; CCAM, congenital cystic adenomatoid malformation; AF, amniotic fluid; CMV, cytomegalovirus; RPR, rapid plasma
reagin; MCA, middle cerebral artery; PUBS, percutaneous umbilical blood sampling
utero treatment with antiarrhythmic drugs administered to the
mother or the fetus, improving survival. Historically, the first-
line drug has been digoxin. Alternatives are flecainide, sotalol,
amiodarone, verapamil, and adenosine. Maternal administration
of these drugs is frequently hampered by difficulties associated
with an enlarged placenta [10]. Therefore, direct administration
to the fetus has been suggested as an alternative, particularly in
cases where there is no fetal response to maternal oral adminis-
tration of medications.
Bradyarrhythmias are most commonly the result of congeni-
tal heart block, either from an autoimmune cause or structural
abnormalities affecting cardiac conduction. Transplacental pas-
sage of maternal antibodies associated with autoimmune diseases
is seen in 30–50% of these cases. They can be present in asso-
ciation with anti-Sjogren’s- syndrome-related antigen A (anti-Ro)
or the combination or anti-Ro/SSA and anti-La/SSB antibodies
(see Chapter 27) [1]. Structural abnormalities such as endocar-
dial cushion defects in the setting of heterotaxy syndrome can
also interfere with cardiac conduction and lead to heart block.
Complete fetal heart block can lead to hydrops when the fetal
heart rate is below 60 beats per minute. There have been sev-
eral case reports showing successful prevention of hydrops after
maternal administration of beta-sympathomimetics, such as ter-
butaline, though data are very limited [11, 12]. Corticosteroids
have also been studied as possible treatment for fetal heart block
555
Suggested Workup
Maternal testing
• Indirect Coombs testing
• Mean corpuscular volume
• Hemoglobin electrophoresis
• Maternal blood chemistry
• Kleihauer–Betke
Ultrasound: MCA peak systolic velocity, PUBS (if indicated by
other workup)
• Fetal complete blood cell count
• Hemoglobin electrophoresis
• Fetal albumin
Accurate fetal ultrasound with hemodynamic studies
Accurate fetal ultrasound, genetic and tissue studies from AF
If indicated, amniocentesis: enzymatic analysis of supernatant
and cultivated amniocytes (freeze AF if needed)
Maternal testing
and shown not to be effective in reversing third-degree block or
preventing progression from second- to third-degree block [13].
At this time, in utero treatment of fetal hydrops as a result of fetal
bradyarrhythmia is not recommended [1].
Structural abnormalities leading to NIH are most commonly
right heart defects, but can also include atrioventricular septal
defects (AV canal), hypoplastic left ventricle, large ventricular
septal defects, atrial septal defects, Ebstein anomaly, and prema-
ture closure of the ductus arteriosus [4, 14]. The pathophysiology
underlying the NIH associated with these conditions is diverse
and complex, but is mainly attributable to an increase in the sys-
temic venous pressure resulting from obstruction of right heart
output as well as the transmission of systemic arterial pressure to
the right heart by means of several pathologic shunts, including
the primary or secondary closure of the foramen ovale. The pres-
ence of heart failure in the setting of structural heart abnormali-
ties is poor, with a combined fetal and neonatal mortality rate of
92% [15].
Genetics/Chromosomal abnormalities
(15–20%) [7, 16, 17]
The incidence of chromosome abnormalities is inversely propor-
tional to GA at diagnosis of NIH, with 50–75% incidence when
NIH is diagnosed <20 weeks [16]. Turner and Down syndromes
account for 90% of all aneuploidies associated with hydrops,
556
although many other chromosomal abnormalities such as tri-
somy 18 and 13, 45X/46XX mosaicism, triploidy, and tetraploidy
have been reported. The main features of Turner syndrome are
cystic hygroma and tubular coarctation of the aorta, suggesting
both lymphatic and cardiac etiology of hydrops [18]. The mere
finding of a cystic hygroma in the first trimester strongly suggests
aneuploidy (60% of risk) [18]. Due to the high incidence of aneu-
ploidy in cases of NIH, prenatal diagnostic testing with karyotype
or microarray, fluorescence in situ hybridization is recommended
even in the setting of severe anemia [1].
Extracardiac anomalies (15–25%)
Thoracic (5–10%) [19, 20]
Congenital pulmonary airway malformation (CPAM) (previously
also called congenital cystic adenomatoid malformation, CCAM),
pulmonary sequestration, and congenital diaphragmatic hernia
(CDH) are the most common causes of NIH in this category.
Other less common causes in this category are lymphangiectasia,
bronchogenic cyst, and other thoracic tumors. Congenital high
airway obstruction sequence (CHAOS) has also been linked to the
development of NIH, as a result of aplasia or intrinsic obstruction
of the larynx and/or trachea that occurs during development [21].
Proposed pathophysiological mechanisms for these cases are
the compression or deviation of the mediastinum due to the pres-
ence of a large lesion or effusion, with resultant obstruction of
lymphatic or venous return. This obstruction leads to cardiac fail-
ure. Compression of the esophagus may also lead to associated
polyhydramnios. CDH produces compression of venous return
especially when liver is herniated in the chest and worse progno-
sis is expected when it is associated with hydrops. Not only are
these fetuses at risk for NIH due to obstruction of cardiac out-
put, but those cases with substantial lung compression before 24
weeks are at risk for pulmonary hypoplasia.
Primary hydrothorax is the accumulation of lymphatic fluid
in the pleural cavity without any other demonstrated anomaly
(mass or chromosomal abnormality) and usually arises from a
lymphatic malformation. The most common cause of primary
hydrothorax in neonates is chylothorax, characterized by a milky
pleural fluid with a high concentration of lymphocytes. This fluid
may be sampled and the diagnosis made by the presence of >80%
lymphocytes in the absence of infection. With thoraco-amniotic
shunt placement, survival exceeds 50% in this setting [22].
Similar management has been proposed for fetuses with
pulmonary sequestration and CPAM since the development
of hydrops in this setting is associated with poor prognosis if
untreated. Macrocystic lesions in fetuses with hydrops may be
treated expectantly, or with needle drainage or thoraco-amniotic
shunt placement. For microcystic lesions in fetuses with hydrops,
management options include expectant management, steroid
administration, or open fetal surgery. In a non-randomized
study comparing steroid treatment with fetal surgery, there was
a statistically significant increase in resolution of hydrops in the
steroid group, though no difference in survival was seen. [23].
Intrapleural injection of OK-432, a sclerosant product obtained
from group A Streptococcus pyogenes, has been shown to have
promising results in three studies reported [20]. The practice of
serial thoracocentesis (e.g., every 48 hours) is discouraged.
Genitourinary (3%)
Urinary tract anomalies may be associated with ascites, but
rarely lead to generalized hydrops. Lower tract obstruction pro-
duces bladder overdistention that can leak into the abdominal
Maternal-Fetal Evidence Based Guidelines
cavity. More rare causes of ascites are the rupture of a dilated
renal pelvis or renal thrombosis. Congenital nephrotic syndrome
of Finnish type, a rare fatal autosomal recessive disease, can be
associated with fetal hydrops due to hypoproteinemia; this disor-
der can be detected by markedly elevated serum or amniotic fluid
α-fetoprotein.
Gastrointestinal (1%)
The primary gastrointestinal abnormalities that have been asso-
ciated with NIH are diaphragmatic hernia, midgut volvulus,
obstruction, jejunal atresia, malrotation of the intestines, and
meconium peritonitis [4, 15]. Gastrointestinal obstruction may
lead to NIH due to decreased colloid osmotic pressure from pro-
tein loss [15]. Intestinal perforation produces variable degrees of
ascites (meconium peritonitis) not easy to differentiate from other
forms of intra-abdominal serum effusion. The presence of meco-
nium seen as bright plaques or echo-poor cystic areas should lead
to the diagnosis even in absence of dilated bowel. When meco-
nium peritonitis is not associated with generalized hydrops,
the prognosis is good. Meconium peritonitis may be associated
with cystic fibrosis and a workup for this disorder is suggested.
Prenatal causes of bowel obstruction are atresia (“apple-peel”
syndrome) and volvulus. Intraabdominal masses may cause NIH
due to obstruction of venous return. Hemangioma of the liver
has also been associated with NIH, likely due to arterio-venous
shunting leading to high output cardiac failure [1]. Other hepatic
disorders, such as cirrhosis, biliary atresia, hepatic hamartomas,
and polycystic disease have also been associated with NIH, likely
as a result of hypoproteinemia [1].
Skeletal dysplasia (1%)
Many different skeletal dysplasias can be associated with hydrops,
with severe thoracic hypoplasia impairing venous return lead-
ing to hydrops and polyhydramnios. It has also been proposed
that this is compounded by hepatic enlargement that occurs
secondary to intrahepatic proliferation of blood cell precursors
to compensate for small bone marrow volume. It is thought that
this hepatic enlargement causes a decrease in venous return
and resultant anasarca [1]. Conditions for which NIH has been
described include, but are not limited to, campomelic dyspla-
sia, thanatophoric dysplasia, short rib-polydactyly, osteogenesis
imperfecta, achondrogenesis, and hypophosphatasia. The out-
come is uniformly poor.
Vascular (<1%)
Vascular tumors or arterio-venous malformations can cause NIH
due to high output cardiac failure. Placental chorioangiomas
occur in 1% of pregnancies and are usually clinically insignificant,
however lesions >5 cm can act as high volume arterio-venous
shunts. Similarly, hemangiomas can lead to NIH due to severe
anemia, hypoproteinemia, or extramedullary erythropoiesis [1].
Aneurysm of the great vein of Galen is a large cerebral arteriove-
nous malformation that can cause right-to-left shunting, leading
to congestive heart failure and hydrops.
Congenital infections (10–15%) [17, 24]
Parvovirus B19 is the most common infective agent leading
to severe anemia and NIH, and representing about 5% of all
cases of NIH. When congenital defects are excluded, parvovi-
rus B19 infection accounts for about 25–50% of fetal hydrops.
Approximately 30–50% of pregnant women are nonimmune and
the incidence of acute parvovirus infection during pregnancy is
1–2%, though may be as high as 13% during epidemic periods.
Nonimmune Hydrops Fetalis
The risk of vertical transmission is 30%, though in the majority
of these cases the fetus is unaffected [17]. The risk of developing
NIH after maternal infection with parvovirus is dependent on the
gestational age at time of infection. In one study, the overall rate
of development of NIH was 4.2%, with a significantly higher rate
seen in those patients infected 9–20 weeks’ gestation (10.6%) [25].
Parvovirus is cytotoxic to bone marrow erythroid progeni-
tor cells and the destruction of these cells by the virus leads to
transient aplastic crises in the fetus [26]. Fetal infection may lead
to severe anemia, congestive heart failure, myocarditis, NIH or
death. Cardiac failure may either be the result of severe anemia
or arrhythmias in the setting of myocarditis [17]. Among women
infected with parvovirus, evidence of hydrops on ultrasound is
associated with an increased risk of intrauterine death and peri-
natal death (OR 3.60, 95% CI 1.3–10.5; p = 0.014 and OR 4.16,
95% CI 1.6–11.0; p = 0.004, respectively) compared to those cases
without evidence of hydrops [27]. The sonographic landmark of
the disease is a hydropic fetus with a significant increase in the
middle cerebral artery peak systolic velocity (MCS PSV). The
process is often self-limited, but the degree of anemia frequently
requires intrauterine fetal transfusions until the pathologic pro-
cess remits. Fetuses affected by parvovirus B19 with evidence
of NIH are more likely to require intrauterine transfusion than
those without evidence of hydrops (OR 159, 95% CI 41.5–611;
p <0.001) [27]. Numerous studies have shown improved out-
comes after fetal intrauterine transfusion [17, 28]. In one
study, the rate of intrauterine death was significantly lower
with transfusion than without treatment (6% versus 30%)
[17, 24, 29]. Due to improved outcomes, transfusion is recom-
mended in this setting, unless the pregnancy is at a gestational
age at which risks of delivery are lower than continued pregnancy
with transfusion (see Chapter 51) [1].
Syphilis is a rare cause of fetal hydrops, which is the conse-
quence of anemia and hepatic dysfunction resulting in hypo-
proteinemia and portal hypertension. Other infections such as
toxoplasmosis, coxsackie virus, herpes simplex virus, rubella,
and CMV have been shown to be occasionally associated with
NIH. The pathophysiologic mechanisms involved in fetal hydrops
because of infection are multiple and involve anemia (e.g., parvo-
virus B19, toxoplasmosis, and CMV), hepatitis with hypoprotein-
emia (e.g., CMV), and myocarditis (e.g., toxoplasmosis, rubella,
and CMV). The diagnosis of these infections may be performed
by demonstrating maternal seroconversion or through various
specialized tests (mainly polymerase chain reaction, PCR). The
treatment will vary according to the infectious agent involved.
Infections with CMV or toxoplasmosis have little response to
intrauterine treatment and the prognosis is poor (see Chapters 49
and 50). Sonographic landmarks of poor prognosis for NIH due
to infection include fetal growth restriction (frequently early and
severe), microcephaly, cerebral ventriculomegaly, and calcifica-
tion of various organs including the brain and the liver.
Hematological disorders (5–15%)
Anemia is the most frequent hematologic cause of NIH. Fetuses
with anemia develop hydrops because of the combination of
high-output heart failure and endothelial damage secondary to
hypoxia, leakage of proteins, and reduction in the oncotic pres-
sure. The diagnosis of fetal anemia can be made noninvasively
through Doppler evaluation of the cerebral circulation, which has
proven to be valuable in identifying anemia of both immune and
nonimmune origins. The mechanisms leading to fetal anemia can
be classified as follows.
557
Reduced red blood cell/Hemoglobin production
α-Thalassemia is a common cause of fetal hydrops in southeast
Asia and European Mediterranean countries, where it accounts
for 28–55% of all cases of NIH [30, 31]. This disease is character-
ized by a fetus that is unable to produce globin chains to form
hemoglobin F in utero, leading to hypoxia and endothelial dam-
age (see Chapter 14). A complete blood count can be used for car-
rier screening, as the mean cell volume will be <80 fL in carriers.
Hemoglobin electrophoresis is normal in α-thalassemia carriers
and the diagnosis requires DNA testing. Other causes include:
The aplastic crisis seen in parvovirus B19 infection, as well as
transient myeloproliferative disorder and congenital leukemia,
both associated with trisomy 21, which cause profound anemia
secondary to bone marrow infiltration [32].
Hemolysis
Excessive erythrocyte loss by hemolysis may be caused by intrin-
sic erythrocyte defects or, more rarely, extrinsic causes. This has
been observed in some cases of glucose 6 phosphate dehydroge-
nase deficiency and infection (CMV and toxoplasmosis).
Hemorrhage
Fetomaternal hemorrhage may be significant enough to induce
NIH and should be suspected after trauma or placental abrup-
tion. Even without a bleeding history, in one review NIH was
the presenting sign of fetomaternal hemorrhage greater than
50 mL in 7.5% of cases [33]. A Kleihauer–Betke test or flow cytom-
etry may be used to aid in diagnosis and to assess the magnitude
of the transfusion. Management with delivery or intrauterine
transfusion should be considered, depending on gestational age
and results of fetal testing. If left untreated, fetuses subjected to
severe anemia may develop cardiac failure, hydrops, hypovolemic
shock, fetal or neonatal death, neurologic damage, cerebral palsy,
or persistent pulmonary hypertension [33].
Twin-to-twin transfusion syndrome (1–5%)
This complication of monochorionic twins leads to an imbalance
in blood flow between the two fetuses, as the placenta acts as a
site of arteriovenous communication between the two fetal circu-
lations. The pathophysiology is not clearly understood, though it
appears to be linked to disturbances in volume with a subsequent
increase in central venous pressure [7]. This leads to hypoxia in
the donor twin and vascular overload in the recipient twin. In
some cases of twin-to-twin transfusion syndrome (TTTS) and
TRAP sequence, invasive therapy with fetoscopy and laser coag-
ulation or umbilical cord ligation have been associated in some
studies with improved fetal survival (see Chapter 46).
Fetal tumors (1–5%)
Fetal tumors, such as lymphangiomas; hemangiomas; sacrococcy-
geal, mediastinal, and pharyngeal teratomas; and neuroblastomas
have been associated with NIH [15, 32, 34]. The likely mechanism
in these cases is the development of high output cardiac failure
due to their vascular nature. In utero treatment has been offered
in cases of sacrococcygeal teratoma and open surgery resulted in
survival in 6/11 cases and minimally invasive approaches resulted
in survival in 6/20 cases [35]. Rhabdomyomas, cardiac tumors
often associated with tuberous sclerosis, can obstruct outflow or
filling and result in NIH. The associated liver fibrosis can lead to
hepatic failure and NIH. Intrapericardial teratomas are usually
benign but rapidly growing fetal tumors and are almost always
associated with pericardial effusions. Subsequent development
558
of NIH is attributed to the mass effect of the tumor itself, tam-
ponade physiology secondary to the pericardial effusion or a
result of a combination of these factors [36].
Inborn errors of metabolism (1–5%) [37, 38]
Metabolic diseases have historically been reported to account
for only 1–2% of NIH. However, some studies have reported that
as many as 15–30% of NIH cases may be associated with inborn
errors of metabolism (IEM), particularly lysosomal storage dis-
eases (LSD). There have been 14 specific LSDs identified that
cause NIH. The likely mechanisms include: Hypoproteinemia as
a result of liver failure, obstruction of venous return due to vis-
ceromegaly or decreased erythropoiesis leading to anemia [1]. In
a review of 678 cases of NIH, the overall incidence of LSD was
5.2%. A diagnosis of LSD was made in 17.4% of the idiopathic
cases overall and in 29.6% of those idiopathic NIH cases in which
a more comprehensive LSD workup was done in a specialized
laboratory [39].
Congenital disorders of glycosylation (CDG) are another
category of IEM that have been shown to cause NIH. CDG are
a large family of rare genetic diseases resulting from defects in
the glycosylation of proteins or lipids. Glycosylation defects may
show a highly diverse clinical presentation, as there are more
than 130 identified genetic disorders across several glycosylation
pathways. In a recent review, patients with CDG and NIH, had
poor outcomes, among live births, 71% of infants died and among
those who survived beyond the neonatal period, 80% reported
developmental delay [40].
Although diagnosis is expensive, investigation for metabolic
diseases is justified after the initial workup has been completed
and the most frequent causes have been ruled out [41, 42].
Evaluation for prenatal LSD in the setting of NIH can be done by
specialized gene panels. Although uncommon, the identification
of these disorders is important also due to their recurrence risk.
Further, identification of the exact mutation in the proband or in
the heterozygous parent can be used to aid in preimplantation
and prenatal diagnosis in future pregnancies.
Other genetic disorders
NIH can be the presenting feature of a number of genetic dis-
orders. Noonan syndrome and other RASopathies, a group of
disorders affecting the RAS–MAPK cell-signaling pathway, have
been associated with NIH. Exome sequencing in cases of NIH
has been found to identify a genetic cause in 29% of cases, with
RASopathies composing the largest proportion. Other causative
genetic disorders include inborn errors of metabolism, and mus-
culoskeletal lymphatic, neurodevelopmental, cardiovascular,
hematologic, immunologic and renal disorders, as well as ciliopa-
thies and overgrowth syndromes [43].
Maternal complications
“Mirror syndrome,” also known as “Ballantyne’s syndrome,”
is a rare complication of NIH in which edema develops in the
mother that mirrors the hydropic fetus. The exact underlying
pathogenesis is unknown, but this condition is characterized by
edema and pre-eclampsia-like symptoms, such as weight gain and
edema (84% of cases), hypertension (60.1%), anemia/hemodilu-
tion (51.3%), dyspnea or pulmonary edema (30%), transaminitis
(19.4%), and oliguria (15%) [44]. The incidence of mirror syn-
drome is so low that the distinction between mirror syndrome
and pre-eclampsia has been difficult to assess. In a review of 113
Maternal-Fetal Evidence Based Guidelines
cases from 1956–2016 [44], the average age of diagnosis was 27
± 4.3 weeks. The median time needed for maternal symptoms to
resolve was 5.5 days after delivery or successful treatment of the
fetal hydrops. A total of eight cases exhibited complete reversal of
maternal symptoms prior to delivery, following supportive treat-
ment or blood transfusion. The average rate of intrauterine fetal
demise was 57.9%. No cases of maternal mortality were reported.
There are currently no management studies on expectant man-
agement in cases of mirror syndrome. In some cases of NIH with
a potentially treatable etiology, resolution of maternal symptoms
has been seen after fetal treatment. Caution is advised in these
situations and delivery should not be delayed in the case of wors-
ening maternal status. In most cases of mirror syndrome, deliv-
ery is recommended [1].
There are other obstetric complications associated with NIH.
Polyhydramnios is seen in 33.6% of cases [44], which can lead
to maternal respiratory symptoms, preterm delivery, placental
abruption, or postpartum hemorrhage. The increased rates of
postpartum hemorrhage seen in cases of NIH are likely occur due
to a combination of uterine atony secondary to polyhydramnios
and the presence of large edematous placentas (62.8% of cases)
[44], which may have greater uterine adherence [45].
Management
Counseling/Prognosis
NIH is the end stage of many severe diseases and the outcome
is related to the etiology, the severity, and the time of onset. In
general, perinatal mortality in pregnancies complicated by
NIH ranges between 50% and 100%, depending on the etiol-
ogy [46]. Outcomes are best in cases with potentially treatable
etiology, such as parvovirus or fetal cardiac arrhythmias. Infants
with chromosomal abnormalities have the highest mortality
(99%), followed by infants with genetic syndromes and inborn
errors of metabolism. Infections and placental causes result in
the lowest rates of mortality [15]. In those cases of live birth,
there is a 64% survival. In those infants born alive, 40% will have
associated morbidity [46]. Overall mortality of infants with NIH
is influenced by gestational age at delivery, birthweight, presence
of polyhydramnios, aneuploidy, complex congenital heart disease
and other major structural birth defects [2]. The most significant
factors associated with neonatal death are the underlying cause
of NIH, gestational age at delivery, and lower serum albumin level
at birth [47]. There are limited data regarding long-term follow-
up in these children. However, in two studies with follow-up at
1 year, 16% of children had severe psychomotor developmental
delay and 16% had mild intellectual disability.
The worst prognosis is expected in cases diagnosed before 24
weeks gestation, cases in which a cystic hygroma is present, or
cases with chromosomal abnormalities. Half of cases diagnosed
prior to 24 weeks are associated with aneuploidy and have very
poor survival. Even in those cases diagnosed prior to 24 weeks
without aneuploidy, survival is less than 50% [48]. Counseling
should include the option of termination depending on patient
preferences. After 24 weeks of gestation, the survival rate in
euploid fetuses is nearly 50% when effective treatments are per-
formed. Fetal anemia and fetal arrhythmia are two of the etiolo-
gies of NIH associated with >70–90% survival rate, if appropriate
treatment is instituted (1). Consideration should also be given to
transferring the patient to a tertiary care center for management
and delivery where possible.
Nonimmune Hydrops Fetalis 559

Workup/Diagnosis (Figures 56.3
and 56.4, and Table 56.1)
After the finding of hydrops by ultrasound, a systematic workup
is mandatory. A thorough evaluation of cases with fetal hydrops
allows determination of the cause in up to 80% of cases. This is
important to determine the therapeutic strategies that should be
considered as well as to provide appropriate genetic counseling
for future pregnancies.
Basic workup
Demographic and clinical history: Ethnicity and race, consanguin-
ity, work exposure to infections, drug exposure, family history of
genetic/metabolic diseases, congenital anomalies, autoimmune
diseases, and events of the pregnancy, including previous infec-
tion screening and ultrasound findings, should all be reviewed.
Laboratory: Rule out Rh disease or any other cause of immune
fetal anemia. Identifications of infectious diseases such as
syphilis, parvovirus B19, toxoplasmosis, cytomegalovirus,
rubella, coxsackie, HSV-1 and HSV-2, and Listeria. Perform the
Kleihauer–Betke test and SSA and SSB antibody tests if patient
has lupus and bradycardia is present.
Ultrasound: Include assessment of the following:
• Abdomen for ascites, thorax for pleural/pericardial effu-
sion, and skin for edema
• Complete anatomy survey to look for anomalies of the
fetus, placenta and umbilical cord
• Assessment of amniotic fluid volume
• Fetal heart: Arrhythmias (M-mode), structural anomalies,
function (Doppler)
• Doppler analysis of umbilical artery, MCA PSV, ductus
venosus, and possibly other arteries and veins
• Liver length, spleen size
• Placental thickness, malformations
Hydrothorax is an easily observable collection of fluid in the
pleural space. It can be unilateral or bilateral, and when severe
and presenting early in pregnancy, can lead to pulmonary hypo-
plasia. In the presence of severe-moderate ascites, liquid is evi-
dent throughout the abdominal circumference. With mild
ascites, careful attention is necessary to differentiate true ascites
from the hypoechogenic rim produced by dorsal and abdominal
musculature just beneath the abdominal wall. Pericardial effu-
sion distends the pericardium without any motion during car-
diac activity. Placental edema is diagnosed when its thickness
is >6 cm, and polyhydramnios is conventionally defined as an
amniotic fluid index ≥25 cm, or a maximum pocket of amni-
otic fluid ≥8 cm.
A detailed sonographic examination is important to identify
anatomical defects associated with fetal hydrops. A system-
atic analysis should be performed to evaluate cardiac anatomy,
fetal heart rate and rhythm, and signs of heart failure that can
be secondary to extracardiac anomalies such as placental or fetal
tumors (e.g., chorioangioma and teratoma), as well as arteriove-
nous shunts such as those of vein of Galen aneurysm and hepatic
hemangioendothelioma. Also, signs of intrauterine infection
should be evaluated, including the presence of brain or hepatic
calcifications, ventriculomegaly or hydrocephalus, hyperecho-
genic bowel, and fetal growth restriction. Magnetic resonance
imaging can be employed to aid in diagnosis of anomalies.

Etiology

Infections
10-15%
Cardiac Other structural
30–40% anomalies Chromosomal
Unexplained

15–20% Metabolic
abnormalities 1%
15–20%
Twins abnormalities Anemia
5–10% 5–10% Genetic
1%

Amniocentesis Maternal
Fetal ultrasound and Kariotype Lab
echocardiography PCR tests
Metabololic
MCA PSV

50–70% 15–20% 10–15% 10%

FIGURE 56.3 Etiology of hydrops. Abbreviations. MCA PSV, middle cerebral artery peak systolic velocity; PCR, polymerase chain
reaction.
560 Maternal-Fetal Evidence Based Guidelines

Detailed maternal history and

maternal bloodwork including
CBC, CMV/Toxo/Parvovirus
serologies, Kleihaure-Betke,
VDRL

Fetal anatomic survey

including fetal echocardiogram

Structurally Normal: Structurally abnormal:

MCA PSV Doppler Invasive prenatal testing

If elevated: fetal blood sampling with

If normal: Amnio for
possible intrauterine transfusion;
karyotype +/- Karyotype/CMA;
PCR CMA, parvo, toxo; MCV of possible CMV/Toxo PCR
CMA, PCR cmv/toxo.
parents, DNA testing for α thalassemia
If no etiology found, if MCV <80fL. If no etiology found, test
test for lysosomal for G6PD, pyruvate kinase deficiency,
storage diseases and lysosomal storage diseases

FIGURE 56.4 Workup of nonimmune hydrops.

Fetal echocardiography aims first to examine position, size,
function, and rhythm of the heart. The systematic observation
of a four chamber view, outflow tracts, great arteries, and arches
can rule out the majority of CHD associated with hydrops. The
addition of color and pulse wave Doppler allows a more complete
evaluation of heart function and flow across atrioventricular
valves and arterial valves, while M-mode allows a more accurate
study of cardiac contractility, wall thickness, and rhythm. Color
Doppler investigation can demonstrate atrioventricular valve
regurgitation, and insonation of peripheral vessels can show
abnormal venous pulsatility in the ductus venosus or hepatic
veins as signs of cardiac failure or provide information on right
atrium pressure and heart function.
Fetal Doppler velocimetry, M-mode, and color mapping can
be useful to diagnose and evaluate cases of fetal arrhythmia, as
well as fetal anemia by evaluating the MCA PSV. MCA PSV is
>90% sensitive and specific for fetal anemia at a cutoff of >1.5
MoM [49, 50]. The most likely explanation for the observed
increase in MCA PSV is the reduction of blood viscosity, lead-
ing to enhanced venous return and preload with consequent
increase in cardiac output. Fetal Doppler studies are useful for
the evaluation of the venous circulation (ductus venosus and
inferior vena cava), to determine the prognosis of fetal hydrops
of cardiovascular origin, and to evaluate fetal response to treat-
ment. Along with other modalities to monitor fetal well-being, it
plays an important role in defining the appropriate moment for
a timely delivery.
Amniocentesis: Different analyses of amniotic fluid permit
the investigation of fetal karyotype, congenital infections, and
metabolic diseases. FISH (fluorescence in situ hybridization)
and QF-PCR (quantitative fluorescent polymerase chain reac-
tion) can provide a rapid assessment of chromosome 13, 18,
21, X and Y, assessing about 70% of chromosomal anomalies.
A full karyotype from culture of amniocytes rules out chro-
mosome anomalies larger than 5–10 Mb. While chromosomal
microarray is useful in the evaluation of fetal structural
anomalies, the yield for NIH is limited [51]. Exome sequenc-
ing has yielded promising results, identifying a causative
genomic variant in 29% or more of otherwise unexplained NIH
cases [43].
For the investigation of infectious etiology, PCR in the
amniotic fluid is the most sensitive test, although a negative
result does not exclude the presence of infection. Parvovirus B19,
CMV, and toxoplasmosis are the most common infectious eti-
ologies of NIH. Exome sequencing or gene panel testing allows
the investigation of inborn errors of metabolism or other genetic
Nonimmune Hydrops Fetalis
disorders, such as RASopathies. Consider freezing amniotic
fluid/extra fetal serum for future tests to study additional condi-
tions when etiology remains unclear.
Cordocentesis and other invasive procedures: Cordocentesis
should not be considered a routine procedure in the workup of
NIH but is strongly recommended when fetal anemia is suspected
(i.e., MCA PSV >1.5 MOM). The fragile hemodynamic condi-
tion of the fetus with NIH suggests caution when the procedure
is performed, especially in severely compromised fetuses with
functional cardiac involvement. When performed, fetal blood
tests should include full blood count, blood group and Coombs
test, and serum biochemistry. In some cases, thalassemia testing
(e.g., hemoglobin electrophoresis), total IgM, and G6PD in male
fetuses can be investigated. PCR for infectious etiologies and test-
ing for other genetic disorders can also be done with fetal blood
sampling. Peritoneal fluid, pleural fluid, and urine can be obtained
with diagnostic and sometimes therapeutic purposes. Cytological
and biochemical analysis of these fluids may help determine the
etiology of NIH. Likewise, karyotype and microorganisms can be
searched from these fluids.
Therapeutic approach
Management, including fetal monitoring, treatment, and deliv-
ery, should follow the appropriate guidelines for the specific
etiology of the NIH.
Fetal monitoring/Testing
There are no studies on the utility of antenatal fetal testing
in the setting of NIH [52]. Testing is reasonable if the etiol-
ogy of the NIH is non-lethal, the fetus is at a potentially via-
ble gestational age, and if the findings of fetal testing would
aid in guiding delivery timing [1]. Doppler studies (especially
umbilical artery and MCA Doppler interrogation), NSTs, and
BPPs (at ≥28 weeks) can be performed at weekly intervals in the
hydropic fetus to assess fetal status and determine the appro-
priate time for delivery.
Treatment
Therapeutic approach depends on the differential diagnosis of
the etiology of NIH. Careful assessment of the risks, benefits,
and alternatives to each therapy should be considered and dis-
cussed with parents. These cases should be referred to tertiary
care centers with physicians experienced with providing the
appropriate treatment.
For parvovirus B19 and arrhythmias, treatment is feasible
and effective. Intrauterine transfusion of fetuses with severe
hydrops because of parvovirus B19 infection reduces the risk of
fetal death. When heart failure and hydrops are associated with
supraventricular tachycardia, historically, the first-line drug has
been digoxin. Alternatives are flecainide, sotalol, amiodarone,
verapamil, and adenosine. However, in fetuses with NIH, the
bioavailability of digoxin is decreased compared to non-hydropic
fetuses, while flecainide has increased bioavailability in hydropic
fetuses. In fetuses with NIH and SVT, digoxin had lower rates of
tachycardia resolution compared with flecainide (OR 0.412, 95%
CI 0.268–0.632; I2 0%) [9]. In patients with any type of fetal tachy-
cardia, flecainide remained superior to digoxin for conversion
to sinus rhythm in hydropic fetuses (OR 5.0, 95% CI 2.5–10, I2
0%, p <0.001) [53]. Maternal side effects and rate of fetal demise
were not increased in those that were treated with flecainide [9,
53]. Difficulties derived from placental enlargement may render
561
maternal administration unpredictable and direct administra-
tion to the umbilical cord is an alternative.
With severe pleural effusions, pulmonary compression may
lead to lung hypoplasia and polyhydramnios because of mediasti-
nal compression and obstruction of fetal swallowing, increasing
the risk of preterm labor. These conditions as well as low output
cardiac failure may explain the poor prognosis of severe hydro-
thorax. In these cases, thoracoamniotic shunting may be helpful.
In one series, the overall survival has been reported to range from
48–68% after thoracoamniotic shunting with hydrops resolution
occurring in 46–89% of cases [54]. Several series over the past
20 years suggest that this procedure may improve fetal and neo-
natal outcome.
In cases of macrocystic CPAM, drainage and maternal corti-
costeroid administration is recommended. Cases of twin-to-twin
transfusion syndrome (TTTS) should be referred to specialized
centers for possible fetoscopic laser photocoagulation <26 weeks
[1]. In some specialized centers in specific cases, open fetal surgi-
cal resection of masses, such as lung lesions and sacrococcygeal
teratomas have been offered [35, 55]
Amniodrainage may be considered in cases of severe polyhy-
dramnios to reduce maternal respiratory dysfunction.
Obstetric management
There are no studies assessing the benefit of corticosteroids prior
to delivery in the setting of NIH. In two retrospective studies,
there was no improvement in neonatal survival after steroids
[56, 57]. Based on expert opinion, it is reasonable to administer a
course of corticosteroids if an intervention or delivery is planned
between 24–36 weeks.
Tocolysis for preterm labor may not be advisable in all cases.
Pre-eclampsia may develop in up to 50% of cases, adding another
factor to consider when defining the time of delivery. Again,
delivery at a tertiary care center is recommended.
Delivery timing
There are no trials assessing the ideal timing of delivery in the
setting of NIH. It has been suggested that prognosis is worse in
cases of delivery <34 weeks [47]. Each case needs to be considered
individually, given the spectrum of etiologies and severity. Based
on expert opinion, delivery is reasonable after 34 weeks with
evidence of worsening fetal status and by 37 weeks if status
has remained stable and delivery was not otherwise indicated
earlier [1].
Delivery/anesthesia
The delivery route will depend on the obstetrical conditions.
However, the unique cardiovascular derangements usually pres-
ent in hydropic fetuses, leading to non-reassuring fetal testing,
may necessitate cesarean delivery. Hemodynamically stable
fetuses may be offered a vaginal delivery. Aspiration of excessive
fluid from the pericardium, pleural, and peritoneal cavities may
be beneficial to facilitate delivery, minimize trauma, and improve
neonatal resuscitative efforts. At all times, the patient should be
informed about the diagnosis, prognosis, and management of
NIH in general and the specific characteristics of the case. Fetal
monitoring results, size of effusions, and need for procedures
before delivery should all be taken into consideration. Written
consent is mandatory, emphasizing the paucity of information
about NIH. In cases where the decision has been made by the
mother not to intervene for fetal indications, vaginal delivery is
preferred, unless contraindicated [1].
562
Neonatology management
In cases where fetal survival may potentially be improved with
neonatal intervention, delivery should occur at a center with a
Level III neonatal intensive care unit [1]. These neonates require
expert, intensive, and multidisciplinary management. Often
prompt intubation is necessary. Prior to delivery, the neonatal
team should be prepared to perform thoracentesis, paracente-
sis, and even pericardiocentesis if necessary. Intervention after
delivery is targeted toward adequate physiologic support, contin-
ued diagnostic evaluation and potential therapeutic treatments
to reverse NIH. In cases of fetal or neonatal death, an autopsy
should be performed to determine the cause of NIH and death.
Long-term follow-up shows that the majority of hydropic neo-
nates who are born and discharged alive have intact long-term
survival [58].
Maternal postpartum
A separate outpatient visit should be set up to discuss a postpar-
tum review of the possible etiology of the NIH, including recur-
rence risks. Recurrent NIH is uncommon but can occur in the
setting of genetic causes.
References
1. Society for Maternal-Fetal Medicine (SMFM), Norton ME, Chauhan SP,
Dashe JS Society for maternal-fetal medicine (SMFM) Clinical Guideline
#7: nonimmune hydrops fetalis. Am J Obstet Gynecol 2015;212(2): 127–39.
[Review]
2. Steurer M, et al. Epidemiology of live born infants with nonimmune hydrops
fetalis – insights from a population-based dataset. J Pediatr 2017;187:
182–8. [II-2]
3. Bellini C, Hennekam R Non-immune hydrops fetalis: a short review of
etiology and pathophysiology. Am J Med Genet A 2012;158A(3): 597–605.
[Review]
4. Machin GA, Hydrops revisited: literature review of 1,414 cases published in
the 1980s. Am J Med Genet 1989;34(3): 366–90. [Review]
5. Heinonen S, Ryynanen M, Kirkinen P. Etiology and outcome of second
trimester non-immunologic fetal hydrops. Acta Obstet Gynecol Scand
2000;79(1): 15–8. [II-2]
6. Sohan K, et al. Analysis of outcome in hydrops fetalis in relation to gesta-
tional age at diagnosis, cause and treatment. Acta Obstet Gynecol Scand
2001;80(8): 726–30. [II-3]
7. Bellini C, et al. Etiology of nonimmune hydrops fetalis: a systematic review.
Am J Med Genet A 2009;149A(5): 844–51. [I]
8. Fukushima K, et al. Short-term and long-term outcomes of 214 cases of non-
immune hydrops fetalis. Early Hum Dev 2011;87(8): 571–5. [II-3]
9. Alsaied T, et al. First-line antiarrhythmic transplacental treatment for fetal
tachyarrhythmia: a systematic review and meta-analysis. J Am Heart Assoc
2017;8(12): e007164. [Review]
10. Hahurij ND, et al. Perinatal management and long-term cardiac outcome in
fetal arrhythmia. Early Hum Dev 2011;87(2): 83–7. [II-3]
11. Cuneo, BF, et al. Atrial and ventricular rate response and patterns of heart
rate acceleration during maternal-fetal terbutaline treatment of fetal com-
plete heart block. Am J Cardiol 2007;100(4): 661–5. [II-1]
12. Yoshida H, et al. Treatment of fetal congenital complete heart block with
maternal administration of beta-sympathomimetics (terbutaline): a case
report. Gynecol Obstet Invest 2001;52(2): 142–4. [III]
13. Friedman DM, et al. Prospective evaluation of fetuses with autoim-
mune-associated congenital heart block followed in the PR Interval and
Dexamethasone Evaluation (PRIDE) Study. Am J Cardiol 2009;103(8):
1102–6. [II-1]
14. Abrams ME, et al. Hydrops fetalis: a retrospective review of cases reported
to a large national database and identification of risk factors associated with
death. Pediatrics 2007;120(1): 84–9. [II-2]
15. Randenberg AL Nonimmune hydrops fetalis part II: does etiology influence
mortality? Neonatal Netw 2010;29(6): 367–80. [III]
Maternal-Fetal Evidence Based Guidelines
16. Iskaros, J, Jauniaux E, Rodeck C. Outcome of nonimmune hydrops fetalis diag-
nosed during the first half of pregnancy. Obstet Gynecol 1997;90(3): 321–5. [II-3]
17. Lamont RF, et al. Parvovirus B19 infection in human pregnancy. BJOG
2011;118(2): 175–86. [Review]
18. Ganapathy R, et al. Natural history and outcome of prenatally diagnosed
cystic hygroma. Prenat Diagn 2004;24(12): 965–8. [II-2]
19. Aubard Y, et al. Primary fetal hydrothorax: a literature review and proposed
antenatal clinical strategy. Fetal Diagn Ther 1998;13(6): 325–33. [Review]
20. Yinon Y, Kelly E, Ryan G. Fetal pleural effusions. Best Pract Res Clin Obstet
Gynaecol 2008;22(1): 77–96. [Review]
21. Sanford E, et al. Congenital high airway obstruction sequence (CHAOS):
a new case and a review of phenotypic features. Am J Med Genet A
2012;158A(12): 3126–36. [III]
22. Yinon Y, et al. Perinatal outcome following fetal chest shunt insertion for
pleural effusion. Ultrasound Obstet Gynecol 2010;36(1): 58–64. [II-2]
23. Loh, KC, et al. Microcystic congenital pulmonary airway malforma-
tion with hydrops fetalis: steroids vs open fetal resection. J Pediatr Surg
2012;47(1): 36–9. [II-2]
24. Tolfvenstam T, Broliden K. Parvovirus B19 infection. Semin Fetal Neonatal
Med 2009;14(4): 218–21. [Review]
25. Enders M, et al. Risk of fetal hydrops and non-hydropic late intrauter-
ine fetal death after gestational parvovirus B19 infection. J Clin Virol
2010;49(3): 163–8. [II-2]
26. Young N, et al. Direct demonstration of the human parvovirus in erythroid
progenitor cells infected in vitro. J Clin Invest 1984;74(6): 2024–32. [III]
27. Bascietto F, et al. Outcome of fetuses with congenital parvovirus B19 infec-
tion: systematic review and meta-analysis. Ultrasound Obstet Gynecol
2018;52(5): 569–76. [Review].
28. Enders M, et al. Fetal morbidity and mortality after acute human parvovi-
rus B19 infection in pregnancy: prospective evaluation of 1018 cases. Prenat
Diagn 2004;24(7): 513–8. [II-2]
29. Rodis JF, et al. Management of parvovirus infection in pregnancy and
outcomes of hydrops: a survey of members of the Society of Perinatal
Obstetricians. Am J Obstet Gynecol 1998;179(4): 985–8. [III]
30. Liao C, et al. Nonimmune hydrops fetalis diagnosed during the second half
of pregnancy in Southern China. Fetal Diagn Ther 2007;22(4): 302–5. [II-2]
31. Suwanrath-Kengpol C, et al. Etiology and outcome of non-immune hydrops
fetalis in southern Thailand. Gynecol Obstet Invest 2005;59(3): 134–7. [II-2]
32. Isaacs H, Jr., Fetal hydrops associated with tumors. Am J Perinatol
2008;25(1): 43–68. [III]
33. Wylie BJ, D’Alton ME. Fetomaternal hemorrhage. Obstet Gynecol
2010;115(5): 1039–51. [III]
34. Noreen S, Heller DS, Faye-Petersen O. Mediastinal teratoma as a rare cause
of hydrops fetalis and death: report of 3 cases. J Reprod Med 2008;53(9):
708–10. [III]
35. Van Mieghem T, et al. Minimally invasive therapy for fetal sacrococcygeal
teratoma: case series and systematic review of the literature. Ultrasound
Obstet Gynecol 2014;43(6): 611–9. [III]
36. Nassr A, et al. Prenatal management of fetal intrapericardial teratoma: a
systematic review. Prenat Diagn 2017;37(9): 849–63. [Review]
37. Stone, DL, Sidransky E. Hydrops fetalis: lysosomal storage disorders in
extremis. Adv Pediatr 1999;46: 409–40. [II-3]
38. Burin, MG, et al. Investigation of lysosomal storage diseases in nonimmune
hydrops fetalis. Prenat Diagn 2004;24(8): 653–7. [II-3]
39. Gimovsky, AC, Luzi P, Berghella V. Lysosomal storage disease as an etiology
of nonimmune hydrops. Am J Obstet Gynecol 2015;212(3): 281–90. [I]
40. Makhamreh M, et al. Nonimmune hydrops fetalis and congenital disor-
ders of glycosylation: A systematic literature review. J Inherit Metab Dis
2020;43(2): 223–33. [Review]
41. Laneri GG, Claassen DL, Scher MS. Brain lesions of fetal onset in
encephalopathic infants with nonimmune hydrops fetalis. Pediatr Neurol
1994;11(1):18–22. [III]
42. Larroche JC, Aubry MC, Narcy F, Intrauterine brain damage in nonimmune
hydrops fetalis. Biol Neonate 1992;61(5): 273–80. [III]
43. Sparks T, et al. Exome sequencing for prenatal diagnosis in nonimmune
hydrops fetalis. N Engl J Med 2020;383(18): 1746–56. [III]
44. Allarakia S, Khayat H, Karami M, et al. Characteristics and manage-
ment of mirror syndrome: a systematic review (1956-2016). J Perinat Med
2017;45(9): 1013–21. [Review]
45. Hutchison AA, et al. Nonimmunologic hydrops fetalis: a review of 61 cases.
Obstet Gynecol 1982;59(3): 347–52. [III]
46. Santo S, et al. Prenatal diagnosis of non-immune hydrops fetalis: what do we
tell the parents? Prenat Diagn 2011;31(2): 186–95. [Review]
47. Huang HR, et al. Prognostic factors and clinical features in liveborn neo-
nates with hydrops fetalis. Am J Perinatol 2007;24(1): 33–8. [II-2]
Nonimmune Hydrops Fetalis
48. Santolaya J, et al. Antenatal classification of hydrops fetalis. Obstet Gynecol
1992;79(2): 256–9. [III]
49. Hernandez-Andrade E, et al. Fetal middle cerebral artery peak systolic
velocity in the investigation of non-immune hydrops. Ultrasound Obstet
Gynecol 2004;23(5): 442–5. [II-3]
50. Cosmi E, et al. Middle cerebral artery peak systolic and ductus venosus
velocity waveforms in the hydropic fetus. J Ultrasound Med 2005;24(2):
209–13. [II-3]
51. Mardy A, et al. A system-based approach to the genetic etiologies of non-
immune hydrops fetalis. Prenat Diagn 2019;39(9): 732–50. [III]
52. ACOG Practice bulletin no. 145: antepartum fetal surveillance. Obstet
Gynecol 2014;124(1): 182–92. [III]
53. Hill G, et al. Transplacental treatment of fetal tachycardia: a systematic
review and meta-analysis. Prenat Diagn 2017;37(11): 1076–83. [Review].
563
54. Abbasi N, Ryan G. Fetal primary pleural effusions: prenatal diagnosis and
management. Best Pract Res Clin Obstet Gynaecol 2019;58: 66–77. [III]
55. Grethel E, et al. Fetal intervention for mass lesions and hydrops improves
outcome: a 15-year experience. J Pediatr Surg 2007;42(1): 117–23. [II-3]
56. Wy CA, et al. Outcome of infants with a diagnosis of hydrops fetalis in the
1990s. Am J Perinatol 1999;16(10): 561–7. [III]
57. Simpson JH, et al. Severity of non-immune hydrops fetalis at birth contin-
ues to predict survival despite advances in perinatal care. Fetal Diagn Ther
2006;21(4): 380–2. [III]
58. Haverkamp F, et al. Good prognosis for psychomotor development in survi-
vors with nonimmune hydrops fetalis. BJOG 2000;107(2): 282–4. [II-3]
57
FETAL DEATH
Emily A. Oliver and Uma M. Reddy
Key points
• Unfortunately, there is no uniformly accepted defini-
tion of fetal death. Stillbirth is the term preferred by
parent groups, and therefore has been increasingly used
for fetal deaths ≥20 weeks of gestation or weight >350 g.
• Ultrasound examination should be performed for con-
firmation of fetal death.
• Most informative exams to find the etiology of fetal death
are autopsy; examination of the placenta, cord, and
membranes; and genetic evaluation.
• Induction of labor in patients with fetal death is recom-
mended unless patient is already in labor.
• For fetal death at about 14–28 weeks, misoprostol
(200–400 µg vaginally every 4 hours, 400 µg orally every
4 hours, 200 µg buccal or 600 µg vaginally every 12 hours)
is the most cost-effective method of delivery, with
acceptable side effects. After 28 weeks of gestation, drugs
such as balloon, misoprostol, and oxytocin administered
for induction of labor can be given according to standard
obstetric protocols (see Chapter 23, Obstetric Evidence
Based Guidelines).
Definitions
Fetal death is defined by the U.S. National Center for Health
Statistics (NCHS), a division of the Centers for Disease Control
and Prevention, as death prior to the complete expulsion or
extraction from the mother of a product of human concep-
tion, irrespective of the duration of pregnancy and which is not
an induced termination of pregnancy. The death is indicated by
the fact that after such expulsion or extraction, the fetus does not
breathe or show any other evidence of life such as beating of the
heart, pulsation of the umbilical cord, or definite movements of
voluntary muscles. Heartbeats are to be distinguished from tran-
sient cardiac contractions; respirations are to be distinguished
from fleeting respiratory efforts or gasps [1].
The WHO defines stillbirth as a neonate with no signs of life born
at or after 28 weeks’ gestation. There is not complete uniformity
among U.S. states regarding the birthweight and gestational age cri-
teria for reporting fetal deaths. However, NCHS defines stillbirth as
fetal deaths at ≥20 weeks of gestation with known gestational age or
weight ≥350 g if the gestational age is unknown [2]. 350 g is the 50th
percentile for weight at 20 weeks of gestation. Fetal losses because of
terminations of pregnancy and inductions of labor for previable pre-
mature rupture of membranes are excluded from these statistics and
are classified separately as terminations of pregnancy. Embryonic
death can be defined as death occurring at ≤12 weeks. Early fetal
death can be defined as death occurring at 13–19 6/7 weeks of gesta-
tion. Intermediate fetal death can be defined as death occurring at
20–27 weeks of gestation. Late fetal death can be defined as death
occurring at greater than 28 weeks of gestation.
564
Stillbirth is the term preferred by parent groups, and therefore
has been increasingly used by the research community and by
ACOG for fetal deaths ≥20 weeks of gestation or weight >350 g [3]
and can be used as a synonym for fetal death. Fetal demise (often
abbreviated IUFD, or intrauterine fetal demise) is often also used
interchangeably with fetal death. Unexplained fetal death is
defined as death before delivery with no identifiable cause after
complete evaluation is performed.
Diagnosis
The diagnosis of fetal death should be confirmed by ultrasound,
with absence of fetal cardiac activity.
Epidemiology/Incidence
An estimated 2.6 million stillbirths occur annually worldwide;
98% of all stillbirths occur in low- and middle-income countries,
with two-thirds of stillbirths occurring in Southeast Asia and
Sub-Saharan Africa [3–5]. This disparity suggests that large num-
bers of stillbirths are preventable. In the United States, there are
about 23,000 stillbirths annually. Between 2007 and 2018, still-
births declined slightly from 5.7 to 5.6 per 1000 [6].
Associations/Risk factors/Possible etiologies
There are many maternal and fetal factors that have been associ-
ated with fetal death (Table 57.1). Many classification schemes for
assigning cause of stillbirth are currently used throughout the
world. Over 80 classification systems have been published in the
literature [7, 8]. The Stillbirth Collaborative Research Network
(SCRN) Initial Causes of Fetal Death was devised to provide a
structured system so that the definitions used to assign the most
likely cause of stillbirth are uniform and those reviewing the
potential causes of stillbirth can communicate using a common
language. An important goal of this system was to use the best
available evidence and rigorous definitions determined before a
case review when assigning a cause of death [9]. Stillbirth rate
is an important marker of quality of health care. Other factors
associated with stillbirth are advanced maternal age, non-Hispanic
Black race, nulliparity or multiparity (>5), maternal medical dis-
ease including chronic hypertension and diabetes, unmarried sta-
tus, low socioeconomic status, low education, multiple gestation,
assisted reproductive technology, and past obstetric history (previ-
ous stillbirth, preterm delivery, postdates, or fetal growth restric-
tion) [10–19]. Racial disparity among stillbirths is significant, with
a 2.2-fold increased risk of stillbirth in Black women compared to
White women [20]. Obesity, smoking, substance use, and alco-
hol abuse are common modifiable risk factors for fetal death.
Pesticides, radiation, and fertility drugs have also been associated
with fetal death [21]. In developing countries, the most common
causes of stillbirths are complications of labor and infection.
DOI: 10.1201/9781003099062-57
Fetal Death 565

TABLE 57.1: Associations/Risk Factors/Possible Etiologies of • Detection and management of diabetes in pregnancy
Fetal Death • Smoking cessation
• Detection and management of fetal growth restriction (FGR)
Maternal Risk Factors Fetal Risk Factors
• Induction at 39 weeks
Chronic hypertension Congenital malformations (15–20%) • Skilled care at birth
Pre-eclampsia Chromosomal/genetic • Basic and comprehensive emergency obstetric care
Diabetes mellitus, thyroid abnormalities (8–13%): Monosomy
disorders X, trisomy 21, trisomy 18, and The following interventions have been studied, but do not yet
Renal disease trisomy 13 appear to significantly and definitively decrease stillbirth as stud-
Systemic lupus erythematosus Single gene disorders: ied so far. They deserve mention and further assessment:
Autoimmune disease Hemoglobinopathies (e.g., alpha-
Antiphospholipid syndrome thalassemia); metabolic diseases • For women with a diagnosis of intrahepatic cholestasis
Cholestasis of pregnancy (e.g., Smith–Lemli–Opitz syndrome) of pregnancy, ursodiol does not decrease the incidence of
Alloimmunization Missense mutations leading to long stillbirth compared to placebo [25].
Obesity QT syndrome • Although many women report decreased fetal movement
Substance abuse (especially Glycogen storage diseases prior to the diagnosis of stillbirth, awareness of fetal move-
cocaine, alcohol) Peroxisomal disorders amino acid ment and performing fetal kick counts does not appear
Smoking disorders to significantly decrease stillbirth – 20% non-significant
Viral infections: Confined placental mosaicism reduction in stillbirths associated with fetal kick counts
Parvovirus B19 (aneuploidy in placenta with a [26, 27]. See Chapter 58.
Cytomegalovirus euploid fetus) • Sleeping in the non-left lateral position does not increase
Enteroviruses (e.g., coxsackie Placental abruption, placenta and vasa the risk of stillbirth [28].
virus) previa • Routine induction of labor at 39 weeks in low risk pregnan-
Echoviruses Placental pathology cies could potentially decrease the risk of stillbirth, though
HSV-1, HSV-2 Chronic villitis the number needed to treat is high (NNT 1675) [29].
HIV Massive chorionic intervillositis
Bacterial infections: Complications of multifetal gestation
Listeria monocytogenes (e.g., twin-twin transfusion, twin
Pregnancy management
Escherichia coli reversed arterial perfusion Counseling
Group B streptococci syndrome, and discordant growth) After confirmation of stillbirth, initial counseling should include
Ureaplasma urealyticum Umbilical cord complications, the communication of fetal death to the parents using clear and
Treponema pallidum fetomaternal hemorrhage unambiguous language, preferably by an experienced provider.
Parasitic infections: Fetal growth restriction After the initial counseling, the management options should be
Toxoplasma gondii Uteroplacental insufficiency discussed, including recommended workup (Table 57.1 and 57.2),
Uterine malformations Intrauterine asphyxia delivery options, as well as possible complications. Grief coun-
Abdominal trauma Preterm labor or rupture of seling should be included, referral to grieving help groups should
membranes be encouraged. Staff interacting with the family should refer to
Post-term the stillborn baby by name, if one was given. Understanding the
Note: In bold, most common associations. cause of stillbirth is important to parents and has implications in
the management of future pregnancies. Obtaining consent for
autopsies, surgical investigations, imaging, and other investi-
Prevention gations is difficult for both parents and healthcare providers, and
must often be done over several conversations. Investigating the
Some of the risk factors listed in Table 57.1, in particular obesity, best possible way to support parental decision making is impor-
smoking, and substance use and alcohol abuse, are modifiable, tant [30]. Review of risk of recurrence, prevention of recurrence,
and should be avoided. Basic emergency obstetric care, births and best management for a future pregnancy (Table 57.3) should
in adequate facilities with option for safe cesarean delivery be done postpartum.
(CD), improvement in nutrition, and prevention and treat-
ment of syphilis, tuberculosis, and malaria are the most fea- Workup
sible and cost-effective interventions in developing countries Evaluation of the etiology of fetal death is essential to coun-
to decrease the incidence of stillbirth [22]. sel regarding recurrence risks, facilitate the grieving process,
As the vast majority of fetal deaths occur in developing coun- and improve understanding to facilitate therapeutic measures
tries, interventions should be focused on prevention in these set- (Table 57.2) [31–41]. The evaluation can be emotionally difficult
tings, and include [23] the following: and should be multidisciplinary (obstetrician, maternal-fetal
specialist, pathologist, geneticist, radiologist, and neonatolo-
• Improving maternal nutritional status such as micronu- gist). Communication between all these members is important.
trient supplementation Parents should be informed about the potential result yield for
• Periconception folate fortification [24] each part of the workup as well as potential cost. Parents should
• Insecticide-treated bed nets or intermittent preventa- be informed that even an extensive workup may not yield a cause
tive treatment for malaria of fetal death. The highest yield components of the evalua-
• Syphilis detection and treatment tion of a stillbirth are: Examination of the placenta, cord, and
• Detection and treatment of hypertensive disorders membranes; fetal autopsy; genetic evaluation; and evaluation
566 Maternal-Fetal Evidence Based Guidelines

TABLE 57.2: Maternal and Fetal Investigation for Fetal Death for antiphospholipid syndrome [42]. A complete evaluation
[31] identifies a probable or possible cause in >75% of fetal
Predelivery
deaths [43], and should include the following:
• Amniotic fluid for cytogenetics
• Screen for coagulopathy (only if fetal death >4 weeks from delivery)
1. Review all relevant maternal, perinatal, family history,
• CBC, antibody screen
and risk factors to help identify possible etiologies (Table
• Kleihauer-Betke testing or flow cytometry
57.1). See specific guideline if a specific risk factor is identi-
• Lupus anticoagulant, anticardiolipin antibodies (IgM, IgG) and
fied as probable cause. In family history particular attention
anti-β2-glycoprotein antibodies (IgM, IgG)
should be paid to pregnancy losses, consanguinity, devel-
• Syphilis testing (RPR or VDRL)
opmental delay, diabetes, and congenital anomalies with a
• Glucose screening (oral glucose tolerance test, hemoglobin A1c) (if
three-generation pedigree. Family history of arrhythmia
glucose screening not done in pregnancy)
or sudden cardiac death should also be included [44]. All
• Urine drug screen if drug use is suspected or in cases of abruption
records should be reviewed for any possible association.
Postdelivery 2. Before delivery, a detailed fetal ultrasound should be
• Autopsy and placental examination done, in particular if an anatomy ultrasound has not been
• Fetal and placental tissue for cytogenetics performed during the pregnancy.
3. Parents should be counseled on the utility of genetic evalu-
Note: Consider workup for parvovirus especially in cases with fetal hydrops or
other signs of this viral infection.
ation. Karyotypic analysis is not possible in 50% of still-
born neonates after birth because of cell culture failure. To
increase the yield of cell culture, an amniocentesis (and/or
TABLE 57.3: Management of Subsequent Pregnancy after CVS) should be offered for microarray [36] and fetal infec-
Stillbirth tion workup. Even if 5–10% of cells from amniotic fluid of
fetal deaths fail to grow, this yield is much higher than that
Preconception or initial prenatal visit
obtained from postnatal study of karyotype [37]. See also
• Detailed medical and obstetrical history
below for genetic postnatal workup.
• Evaluation/workup of previous stillbirth
4. Consent for fetal autopsy should be obtained by a
• Determination of recurrence risk
trained provider. It does not need to be obtained prior to
• Discussion of increased risk of other obstetrical complications
delivery, but the idea should be introduced.
• Smoking cessation
5. At delivery, examine the fetus, placenta, and cord care-
• Achieve normal body mass index
fully. General exam immediately after delivery should
• Genetic counseling if family genetic condition exists
• Support and reassurance
include noting any dysmorphology/congenital abnormali-
ties as well as obtaining weight, length, and head circum-
First trimester ference. The degree of skin sloughing as well as signs of
• Dating ultrasound by crown-rump length (first trimester) maceration should be noted, to determine timing of demise
• First trimester screen-PAPP-A, hCG, and nuchal translucency or in relation to delivery. Photographs should be obtained;
cell free fetal DNA testing of the whole body, frontal and profile views of the face,
• Diabetes screen extremities, palms; and close-up photographs of specific
• Antiphospholipid antibodies abnormalities [31]. The placenta should be examined, and
• Support and reassurance sent to pathology for histologic evaluation. Any umbilical
cord abnormalities such as knots, should be noted. Clinical
Second trimester
geneticist evaluation if available is often helpful.
• Fetal anatomic survey at 18–20 weeks
6. Genetic evaluation via karyotype or preferably micro-
• Quadruple screen-MSAFP, hCG, estriol, and inhibin-A at 15–18
array if available should be performed on all stillbirths
weeks (no later than 22 weeks) if aneuploidy screening not possible
after parental consent is obtained, unless an amniocente-
• Support and reassurance
sis or CVS had previously been performed in pregnancy.
Third trimester Ideally, an amniocentesis should be performed prior to
• Serial ultrasounds about every 4 weeks to rule out fetal growth delivery. If this is not possible, or the patient declines, a
restriction, starting at 28 weeks placental block taken from below the cord insertion site
• Fetal movement counting starting at 28 weeks on the unfixed placenta or umbilical cord closest to the
• Antepartum fetal surveillance (e.g., nonstress tests or biophysical placenta, followed by fetal cartilage obtained from the
profiles) starting at 32 weeks or 1 to 2 weeks earlier prior to costochondral junction or patella. Skin surface should
gestational age of previous stillbirth be cleansed with Betadine or Hibiclens prior to obtain-
• Support and reassurance ing specimen. Tissue should be placed in Hanks solution,
or normal saline if Hanks solution is not available, not in
Delivery formalin. Attempts at cell culture, however, fail in half of
• Planned induction at 39 weeks, or as indicated by maternal or fetal cases. Ideally, genetic counseling should be performed to
conditions. In cases of severe patient anxiety, early term delivery discuss option for genetic testing. Aside from karyotype,
(37 0/7–38 6/7 weeks) may be undertaken as long as decision microarray should be offered as it is more likely to pro-
incorporates understanding increased risks of neonatal vide a genetic diagnosis due to the fact that it is more
complications with early term delivery. likely to yield a result in non-viable tissue. Microarray
Source: Adapted from Ref. [31]. provides an even higher yield when congenital anoma-
a Provides risk modification but does not alter management. lies are present [45]. Whole exome sequencing (WES)
Fetal Death
can also be offered if microarray is normal; additional
diagnostic genetic variants are found in approximately
8–10% of fetuses when WES is used in fetuses with a struc-
tural anomaly [46, 47]. Testing for rarer causes of stillbirth
such as single gene disorders or mutations in Long QT
genes should be guided by clinical suspicion or family his-
tory [48].
7. Autopsy is the one of the most useful tests in identifying
the cause of fetal death. Not only are gross birth defects
and morphologic abnormalities identified, but subtle
findings of the autopsy may confirm infection, anemia,
hypoxia, and metabolic abnormalities as the cause of death.
Autopsy reduces the number of unexplained fetal deaths by
at least 10% [38]. Autopsy findings altered counseling and
recurrence risks autopsy in 26% of all cases at one insti-
tution [49]. The addition of autopsy to clinical and labo-
ratory data, placental examination resulted in improved
identification of probable cause of death to 74% in a cohort
study at a tertiary care center [50]. The SCRN has pro-
vided guidelines on the components of fetal autopsy
which were established with a multidisciplinary team
including pathologists, clinicians and epidemiologists [51].
Recommendations include fetal measurements including
weight, toe-heel length, fetal imaging including whole-
body X-ray with anterior-posterior and lateral views,
as well as external and internal macroscopic examina-
tion. Estimation of the interval between intrauterine death
and delivery should be performed by assessing the grade
of maceration. Clinical information, all records including
ultrasound reports, and any specific requests, should be
made available to the pathologist. It is suggested for the
obstetrician to call the pathology resident/attending
assigned to autopsy for discussion. A perinatal patholo-
gist with experience in fetal death cases should perform
the autopsy if available. Examination by a physician expe-
rienced in genetics and dysmorphology may increase the
yield of autopsy. If autopsy is declined, it is important to
consider a head- sparing autopsy, or at least MRI of the
stillborn child [52]. If a complete autopsy is not feasible,
minimal invasive autopsy which includes postnatal MRI,
blood sampling from the dead fetus at autopsy, clinical
history review, and external evaluation can be performed
[53, 54]. Ultrasound of the brain may also be considered
for confirmation or refining the diagnosis of genetic syn-
dromes and chromosomal abnormalities in addition to
autopsy [55].
8. Send placenta, membranes, and umbilical cord for gross
and microscopic pathologic examination. Conditions
causing or contributing to stillbirth may be diagnosed such
as abruption, placental infarcts, umbilical cord thrombo-
sis, velamentous cord insertion, and vasa previa. Placental
evaluation can also yield important information regarding
infection, genetic abnormalities, anemia, and thrombo-
philia. Umbilical cord knots and tangling should be noted
but interpreted carefully as cord entanglement occurs in
around 25% of normal pregnancies [56]. Umbilical cord
abnormalities were the cause of stillbirth in 19% in one
study [57]. Examination of the placenta vasculature and
membranes is particularly useful in multifetal gestations
by establishing chorionicity and vascular anastomoses.
9. If autopsy, placental pathology, or history is suggestive
of an infectious etiology, maternal or neonatal serology,
567
special tissue stains, and/or testing for bacterial or viral
nucleic acids may be undertaken. If clinical or histologic
evidence is lacking, then routine testing for infection is
of questionable benefit. An example is parvovirus test-
ing, which should be considered if the fetus/neonatal is
found to hydropic and/or anemic.
10. Maternal labs (Table 57.2) [31]
a. Flow cytometry (preferred) or Kleihauer–Betke testing
are sent to evaluate for fetal-maternal hemorrhage (as
soon as possible after stillbirth and prior to delivery).
b. Lupus anticoagulant, anticardiolipin antibodies (IgM,
IgG) and anti-β2-glycoprotein antibodies (IgM, IgG)
should be sent to test for antiphospholipid syndrome.
Presence of lupus anticoagulant or anticardiolipin
antibodies of moderate to high titer (>40 immuno-
globulin M [IgM] binding/immunoglobulin G [IgG]
binding or >99th percentile) or anti-β 2-glycoprotein
antibody titer (>99th percentile) are all considered
positive but should be confirmed with repeat testing
12 weeks later (see also Chapter 28) [58].
c. Syphilis testing should be sent.
d. Glucose screening (oral glucose tolerance test,
hemoglobin A1c) (if glucose screening not done in
pregnancy).
e. Routine testing for inherited thrombophilias is not
recommended [31, 59].
f. Toxicology screening should be sent in select cases.
11. Consider any other workup, depending on risk factor
identified in Table 57.1. For fetal death before 20 weeks,
consider individualized workup and refer to chapter on
pregnancy loss (Chapter 16).
Delivery/Anesthesia
Once diagnosis is confirmed, and counseling and workup initi-
ated, options for delivery should be discussed. Options include
expectant management, induction, or dilation and evacuation
(D&E). Induction or D&E are the most common management
options chosen by the patient with stillbirth.
Expectant management
Between 80% and 90% of women with fetal death will spon-
taneously go into labor within 2 weeks of fetal demise [60].
Duration of labor is shorter in patients with spontaneous labor [61].
However, endomyometritis rate is higher in the spontaneous
labor group (6% versus 1%) compared to induction. There is no
difference in the frequency of postpartum hemorrhage, retained
placenta, or need for blood transfusion. Retention of a dead fetus
can cause chronic consumptive coagulopathy because of gradual
release of thromboplastin from the placenta into the maternal
circulation [37]. This usually occurs after four weeks, but may
occur earlier. Coagulation abnormalities occur in about 3%
to 4% of patients with uncomplicated fetal deaths over the next
4–8 weeks, and this number rises in the presence of abruption
or uterine perforation [37]. Another disadvantage of expectant
management is a long interval between fetal death and spon-
taneous labor, limiting the amount of information that can be
obtained about the cause of death from a postmortem examina-
tion or autopsy of the baby. Moreover, women with fetal death
find it difficult psychologically to continue a pregnancy with a
known fetal death [62]. In patients opting for spontaneous labor
(especially with greater than a 4-week interval between fetal
568
death and time of delivery), a screen for coagulopathy (fibrin-
ogen level, platelet count, prothrombin time and activated par-
tial thromboplastin measurement) should be obtained prior to
administration of neuraxial anesthesia, as well as other invasive
procedures [37].
Dilation and evacuation
Comparing complication rates of patients who undergo D&E or
medical induction between 14 and 24 weeks of gestation, D&E
is a safe method in this time frame, especially if done by experi-
enced operators, under continuous ultrasound guidance [63, 64].
Surgical termination of pregnancy between 14 and 24 weeks of
gestation has a lower overall rate of complications (4%), as com-
pared to 29% in women undergoing labor induction [63]. Patients
undergoing D&E are less likely to have failure of the initial method
for delivery and retained products of conception. However, both
groups are similar in the need for blood transfusion, infection,
cervical laceration, maternal organ damage, or hospital readmis-
sion. Placement of laminaria is associated with a lower risk of
complications from D&E, while misoprostol is associated with a
lower complication rate in women undergoing medical termina-
tion [63]. A cost-effectiveness analysis concluded that D&E is less
expensive and more effective than misoprostol induction of labor
for second-trimester pregnancy termination [65]. Studies do not
show an increased rate of complications in subsequent pregnan-
cies after D&E, although data are limited [66, 67]. Both methods
for delivery are considered reasonably safe. Thus, mode of deliv-
ery should usually be based on the patient’s wishes. However,
patients should be counseled that efficacy of autopsy is very lim-
ited with D&E [31, 68]. In addition, the availability of D&E may
be limited by provider experience or gestational age.
Induction
Induction of labor in women with fetal death is usually recom-
mended, unless the patient is already in labor, given the prob-
lems mentioned with expectant management. Induction of labor
is typically initiated soon after diagnosis of fetal death. Most of
the data for management of fetal death is from randomized trials
of second-trimester pregnancy termination.
Up to 28 weeks
Options for induction of labor for fetal death at about 16–28
weeks include misoprostol (prostaglandin E1, PGE1); prostaglan-
dins E2 (PGE2); high-dose oxytocin.
Available evidence from randomized trials do support the use of
vaginal misoprostol as a medical treatment to terminate nonviable
pregnancies before 24 weeks of gestation [69, 70]. Therefore, for
gestations less than 28 weeks, misoprostol is the most efficient
method of induction, regardless of Bishop score, although high-
dose oxytocin infusion is an acceptable alternative [31]. Typical dos-
ages for misoprostol use are 200–400 µg vaginally, orally, or 200 µg
buccal every 4–12 hours [31]. Examples of regimens for misoprostol
dosing are 200 µg vaginally every 4 hours, 400 µg vaginally every
3–4 hours, or 600 µg vaginally every 12 hours. Buccal route can
also be used. These result in successful expulsion (mostly within
24 hours) in 80–100% of cases [31, 71–77]. A Cochrane system-
atic review evaluated prostaglandins for termination of pregnancy
in the second or third trimester, and found that vaginal misopro-
stol is as effective as other prostaglandin preparations, as well as
being more effective than oral misoprostol [78]. Misoprostol 600 µg
administered vaginally at 12-hour intervals is associated with fewer
adverse effects and is as effective as dosing at 6-hour interval [76].
Maternal-Fetal Evidence Based Guidelines
Rarely, high-dose oxytocin (200 units in 500 mL saline at
50 mL/hour) also may be used for induction of labor remote from
term, if misoprostol is not available or contraindicated [79]. The
mother should be observed for signs of water intoxication and
maternal electrolyte concentrations should be monitored at least
every 24 hours. Nausea and malaise are the earliest findings of
hyponatremia, and may be seen when the plasma sodium con-
centration falls below 125–130 mEq/L. This may be followed by
headache, lethargy, obtundation and eventually seizures, coma,
and respiratory arrest.
Historically, PGE2 suppositories, with a dose of 20 mg inserted
vaginally every 4 hours, were also utilized for labor induction
before 28 weeks. High-dose PGE2 suppositories are contraindi-
cated >28 weeks gestation [80]. Misoprostol is more efficacious,
and at least as safe, and cheaper, than PGE2, and so the use of
PGE2 for induction of fetal death before 28 weeks is not recom-
mended, and of mostly historic importance only.
The efficacy and tolerance of mifepristone (RU 486), a
progesterone antagonist, was investigated in a double-blind
controlled multicenter study involving 94 patients with an
intrauterine fetal death [81]. Success of treatment was defined
as the occurrence of fetal expulsion within 72 hours after the
first drug intake. Mifepristone treatment (600 mg/day for 2
days) was considered to be effective in 29 of 46 patients (63%).
There were only eight successes in 48 patients (17.4%) in the pla-
cebo group (p = 0.001). Tolerance was good in the mifepristone
group. In the placebo group, disseminated intravascular coagu-
lation occurred in one woman for whom the investigator waited
several weeks for spontaneous expulsion. Another randomized
controlled trial (RCT) compared high-concentration oxytocin
to misoprostol given 36 hours after initial mifepristone 200 mg
in second trimester abortion for either IUFD or voluntary ter-
mination. The mifepristone-oxytocin regimen had longer time
until expulsion but fewer side effects [82]. An RCT comparing
200 mg of mifepristone compared to placebo 24–36 hours
before misoprostol found a higher rate of vaginal delivery
and a shortened induction to delivery time [83]. Mifepristone
should be considered prior to induction of labor with miso-
prostol, if available.
To date, there are no studies evaluating laminaria for ripen-
ing of cervix in conjunction with other methods of induction for
cases of fetal death.
After 28 weeks
After 28 weeks of gestation, interventions such as bal-
loon catheter and misoprostol in combination, oxytocin,
administered for induction of labor can be given according
to standard obstetric protocols (see Chapter 23, Obstetric
Evidence Based Guidelines) [31]. Cesarean delivery for stillbirth
is reserved for unusual circumstances (maternal indications)
because it is associated with maternal morbidity without fetal
benefit [31].
Women with prior uterine scar
Women with a prior uterine scar represent a special group and
treatment should be individualized. For women with a previ-
ous low transverse incision and a uterus less than 28 weeks
in size, the usual protocols for misoprostol induction at less
than 28 weeks may be used [31, 69]. Several studies have evalu-
ated the use of misoprostol at a dosage of 400 µg every 6 hours in
women with a stillbirth up to 28 weeks of gestation and a prior
uterine scar [84, 85]. There does not appear to be an increase
Fetal Death
in complications in those women. The risk of uterine rupture
is about 0.4% with one prior low transverse CD, up to 9% with
≥2 prior CD, and up to 50% with prior vertical CD [86]. Further
research is required to assess effectiveness and safety, optimal
route of administration, and dose [71].
For women with a previous low transverse incision, after
28 weeks of gestation, oxytocin protocols may be utilized and
cervical ripening with Foley bulb may be considered [31, 69].
Given the absence of fetal benefit, cesarean section should in gen-
eral be avoided. Therefore, on the basis of limited data in patients
with a prior low transverse CD, trial of labor remains the pref-
erable option [31, 69]. There are limited data for patients with a
prior classical uterine incision or prior myomectomy, therefore
the delivery plan should be individualized [31, 69].
Postpartum
Prior to discharge, the family needs to be counseled that results
of all investigations may take two or three months for comple-
tion and that despite extensive evaluation a cause of death may
not be found. Patients should be offered the opportunity to see
and hold their infant and be offered keepsake items such as
photos, hand/footprints, or special blankets or clothing. Grief
counseling should be initiated prior to discharge from hospital.
Referral to a bereavement counselor, religious leader, peer sup-
port group, or mental health professional is advisable for manage-
ment of grief and depression.
Fetal death causes grief also in the majority of obstetricians,
who can experience self-doubt, depression, and self-blame, in
relation to their patient’s loss [87]. Counseling service should be
available to staff.
Prevention of recurrence and
management in a future pregnancy
A special outpatient visit should be set up to review the results
of the complete workup, and discuss possible etiology and
future management (Table 57.3). If a particular medical prob-
lem is identified in the mother, it should be addressed prior to
next conception (see specific guidelines). For example, optimiz-
ing diabetic control, or chronic hypertension, prior to concep-
tion. Preconception counseling is helpful if congenital anomalies
or genetic abnormalities are found. In some cases, such as cord
occlusion, the patient can be assured that recurrence is unlikely
[56, 57, 88]. Overall, there is an increased incidence of pregnancy
complications, such as stillbirth (2.5- to 10-fold increase depend-
ing on the study) [18, 89], preterm birth (OR 2.8, 95% CI 1.9–4.2),
pre-eclampsia (OR 3.1, 95% CI 1.7–5.7) and placental abruption
(OR 9.4, 95% CI 4.5–19.7) in subsequent pregnancies [90].
In an international retrospective cohort study on interpreg-
nancy interval after stillbirth, conception within 12 months after
stillbirth was not associated with an increased risk of adverse
outcomes compared to 24–59 months [91]. Most patients find
increased fetal surveillance with the next pregnancy reassur-
ing. Fetal growth ultrasounds and kick counts starting at 28
weeks and antepartum surveillance starting at 32 weeks may
be implemented [31]. In a woman with a prior stillbirth, planned
induction at 39 0/7 weeks can be offered unless earlier deliv-
ery is indicated by maternal or fetal conditions [31]. Occasionally
due to severe patient anxiety, patient may request an early term
delivery (37 0/7–38 6/7 weeks) to prevent recurrent stillbirth.
569
A decision to undertake an early term delivery must incorporate
an understanding of the increased risk of neonatal complications
compared to delivery at 39 0/7 weeks [31].
References
1. MacDorman MF, Kirmeyer S. Fetal and perinatal mortality, United States,
2005. Natl Vital Stat Rep 2009; 57:1–19. [II-2]
2. Centers for Disease Control and Prevention, National Center for Health
Statistics. Model State Vital Statistics Act and Regulations. 1992 revision.
Hyattsville MD: NCHS; 1994. Available at http://www.cdc.gov/nchs/data/
misc/mvsact92b.pdf. Retrieved January 16, 2011. [Review; III]
3. de Bernis L, Kinney MV, Stones W, et al. Stillbirths: ending preventable
deaths by 2030. Lancet 2016; 387(10019):703–716. [Review; III]
4. Cousens S, Blencowe H, Stanton C, et al. National, regional, and worldwide
estimates of stillbirth rates in 2009 with trends since 1995: a systematic
analysis. Lancet 2011; 377(9774):1319–1330. [II-2]
5. Lawn JE, Blencowe H, Pattison R, et al. Stillbirths: where? when? why? how
to make the data count? Lancet 2011; 377(9775):1448–1463. [II-2]
6. Ananth CV, Goldenberg RL, Friedman AM, et al. Association of Temporal
Changes in Gestational Age With Perinatal Mortality in the United States,
2007–2015. JAMA Pediatr 2018; 172(7):627–634. [II-2]
7. International Stillbirth Alliance Collaborative for Improving Classification
of Perinatal Deaths, Flenady V, Wojcieszek AM, et al. Classification of
causes and associated conditions for stillbirths and neonatal deaths. Semin
Fetal Neonatal Med 2017; 22(3):176–185. [Review; III]
8. Reddy UM, Goldenberg R, Silver R, et al. Stillbirth classification— devel-
oping an international consensus for research: executive summary of a
National Institute of Child Health and Human Development workshop.
Obstet Gynecol 2009; 114(4):901–914. [III]
9. Dudley DJ, Goldenberg R, Conway D, et al. Stillbirth Research Collaborative
Network. A new system for determining the causes of stillbirth. Obstet
Gynecol 2010; 116(2 pt 1):254–260. [III]
10. Reddy UM, Ko CW, Willinger M. Maternal age and the risk of stillbirth
throughout pregnancy in the United States. Am J Obstet Gynecol 2006;
195:764–770. [II-2]
11. Sharma PP, Salihu HM, Oyelese Y, et al. Is race a determinant of stillbirth
recurrence? Obstet Gynecol 2006; 107:391–397. [II-2]
12. Vintzileos AM, Ananth CV, Smulian, et al. Prenatal care black- white fetal
death disparity in the United States: heterogeneity by high-risk conditions.
Obstet Gynecol 2002; 99(3):483–489. [II-3]
13. Froen JF, Arnestad M, Frey K, et al. Risk factors for sudden intrauterine
unexplained death: epidemiologic characteristics of singleton cases in Oslo,
Norway, 1986–1995. Am J Obstet Gynecol 2001; 184:694–702. [II-2]
14. Oron T, Sheiner E, Shoham-Vardi I, et al. Risk factors for antepartum fetal
death. J Reprod Med 2001; 46(9):825–830. [II-2]
15. Nohr EA, Bech BH, Davies MJ, et al. Prepregnancy obesity and fetal death:
a study within the Danish National Birth Cohort. Obstet Gynecol 2005;
106:250–259. [II-2]
16. Raymond EG, Cnattingius S, Kiely JL. Effects of maternal age, parity, and
smoking on the risk of stillbirth. BJOG 1994; 101:301–306. [II-2]
17. Wisborg K, Ingerslev HJ, Henriksen TB. IVF and stillbirth: a prospective
follow-up study. Hum Reprod 2010; 25:1312–1316. [II-2]
18. Surkan PJ, Stephansson O, Dickman PW, et al. Previous preterm and small-
for-gestational-age births and the subsequent risk of stillbirth. N Engl J
Med 2004; 350:777–785. [II-2]
19. Gardosi J, Kady SM, McGeown P, et al. Classification of stillbirth by rel-
evant condition at death (ReCoDe): population based cohort study. BMJ
2005; 331:1113–1117. [II-2]
20. Willinger M, Ko CW, Reddy UM. Racial disparities in stillbirth risk across
gestation in the United States. Am J Obstet Gynecol 2009; 201(5):469.e1–8.
[II-2]
21. Signorello LB, Mulvihill JJ, Green DM, et al. Stillbirth and neonatal death
in relation to radiation exposure before conception: a retrospective cohort
study. Lancet 2010; 376(9741):624–630. [II-2]
22. Lawn JE, Blencowe H, Waiswa P, et al, Lancet Ending Preventable Stillbirths
Series study group; Lancet Stillbirth Epidemiology investigator group.
Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 2016;
387(10018):587–603. [III]
23. Bhutta ZA, Yakoob MY, Lawn JE, et al. Stillbirths: what difference can we
make and at what cost? Lancet 2011; 377:1523–1538. [II-2]
24. Gaskins AJ, Rich-Edwards JW, Hauser R, et al. maternal Prepregnancy
folate intake and risk of spontaneous abortion and stillbirth. Obstet
Gynecol 2014; 124:23–31. [II-2]
570
25. Chappell LC, Bell JL, Smith A, et al. Ursodeoxycholic acid versus placebo
in women with intrahepatic cholestasis of pregnancy (PITCHES): a ran-
domised controlled trial. Lancet 2019; 394(10201):849–860. [I]
26. Bellussi F, Po’ G, Livi A, Saccone G, De Vivo V, Oliver EA, Berghella V. Fetal
Movement Counting and Perinatal Mortality: A Systematic Review and
Meta-analysis. Obstet Gynecol 2020; 135(2):453–462. [I]
27. Norman JE, Heazell AEP, Rodriguez A, et al.; AFFIRM investigators.
Awareness of fetal movements and care package to reduce fetal mortal-
ity (AFFIRM): a stepped wedge, cluster-randomised trial. Lancet 2018;
392(10158):1629–1638. [I]
28. Silver RM, Hunter S, Reddy UM, et al. Nulliparous Pregnancy Outcomes
Study: Monitoring Mothers-to-Be (NuMoM2b) Study. Prospective
Evaluation of Maternal Sleep Position Through 30 Weeks of Gestation and
Adverse Pregnancy Outcomes. Obstet Gynecol 2019; 134(4):667–676. [II-2]
29. Po’ G, Oliver EA, Reddy UM, et al. The impact of induction of labor at
39 weeks in low-risk women on the incidence of stillbirth. Am J Obstet
Gynecol 2020; 222(1):88–90. [II-2]
30. Horey D, Flenady V, Haezell AEP, et al. Interventions for supporting parents’
decision about autopsy after stillbirth (Review). Cochrane Data System Rev
2013; (2):CD009932. [Review]
31. Society for Maternal-Fetal Medicine. Management of Stillbirth: Obstetric
Care Consensus No. 10. Obstet Gynecol 2020; 135(3):e110–e132. [III]
32. Reddy UM. Prediction and prevention of recurrent stillbirth. Obstet
Gynecol 2007; 110:1151–1164. [Review]
33. Brady K, Duff P, Harlass FE, et al. The role of amniotic fluid cytogenetic
analysis in the evaluation of recent fetal death. Am J Perinatol 1991;
8:68–70. [II-2]
34. Lockwood CJ, Rand JH. The immunobiology and obstetrical consequences
of antiphospholipid antibodies. Obstet Gynecol Surv 1994; 49:432–441.
[II-3]
35. Laube DW, Schauberger CW. Fetomaternal bleeding as a cause for “unex-
plained” fetal death. Obstet Gynecol 1982; 60:649–651. [II-3]
36. Owen J, Stedman CM, Tucker TL. Comparison of predelivery versus
postdelivery Kleihauer–Betke stains in cases of fetal death. Am J Obstet
Gynecol 1989; 161:663–666. [II-2]
37. Maslow AD, Breen TW, Sarna MC, et al. Prevalence of coagulation abnor-
malities associated with intrauterine fetal death. Can J Anaesth 1996;
43(12):1237–1243. [II-3]
38. Incerpi MH, Miller DA, Samandi R, et al. Stillbirth evaluation: what tests
are needed? Am J Obstet Gynecol 1998; 178:1121–1125. [II-3]
39. Ahlenius I, Floberg J, Thomassen P. Sixty-six cases of intrauterine fetal
death. A prospective study with an extensive test protocol. Acta Obstet
Gynecol Scand 1995; 74(2):109–117. [II-2]
40. Langston C, Kaplan C, Macpherson T, et al. Practice guideline for exami-
nation of the placenta: developed by the Placental Pathology Practice
Guideline Development Task Force of the College of American Pathologists.
Arch Pathol Lab Med 1997; 121:449–476. [Review]
41. Silver RM, Varner MW, Reddy U, et al. Work-up of stillbirth: a review of the
evidence. Am J Obstet Gynecol 2007; 196(5):433–444. [Review]
42. Page JM, Christiansen-Lindquist L, Thorsten V, et al. Diagnostic tests for
evaluation of stillbirth: results from the Stillbirth Collaborative Research
Network. Obstet Gynecol 2017; 129(4):699–706. [II-2]
43. The Stillbirth Collaborative Research Network Writing Group. Causes of
death among stillbirths. JAMA 2011; 306;2459–2468. [II-1]
44. Cuneo BF, Kaizer AM, Clur SA, et al. Mothers with long QT syndrome are
at increased risk for fetal death: findings from a multicenter international
study. Am J Obstet Gynecol 2020; 222(3):263.e1–263.e11. [II-2]
45. Reddy UM, Page GP, Saade GR, et al; NICHD Stillbirth Collaborative
Research Network. Karyotype versus microarray testing for genetic abnor-
malities after stillbirth. N Engl J Med 2012; 367(23):2185–2193. [II-2]
46. Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in
the evaluation of fetal structural anomalies: a prospective cohort study.
Lancet 2019; 393(10173):758–767. [II-2]
47. Stanley KE, Giordano J, Thorsten V, et al. Causal genetic variants in still-
birth. N Engl J Med 2020; 383(12):1107–1116. [II-2]
48. Crotti L, Tester DJ, White WM, et al. Long QT syndrome-associated muta-
tions in intrauterine fetal death. JAMA 2013; 309(14). [II-3]
49. Faye-Petersen OM, Guinn DA, Wenstrom KD. Value of perinatal autopsy.
Obstet Gynecol 1999; 94(6):915–920. [II-3]
50. Miller ES, Minturn L, Linn R, Weese-Mayer DE, Ernst LM, stillbirth evalu-
ation: a stepwise assessment of placental pathology and autopsy. Am J
Obstet Gynecol 2016 January; 214(1):115-e1. [II-3]
51. Pinar H, Koch MA, Hawkins H, et al. The stillbirth collaborative research
network postmortem examination protocol. Am J Perinatol 2012; 29(3):
187–202. [III]
Maternal-Fetal Evidence Based Guidelines
52. Thayyil S, Cleary JO, Sebire NJ, et al. Post-mortem examination of human
fetuses: a comparison of whole body high-field MRI at 9.4 T with conven-
tional MRI and invasive autopsy. Lancet 2009; 374:467–475. [II-2]
53. Thayyil S, Sebire NJ, Chitty LS, et al. Post-mortem MRI versus conventional
autopsy in fetuses and children: a prospective validation study. Lancet 2013;
382:223–233. [II-2]
54. Kang X, Carlin A, Cannie MM, et al. Fetal postmortem imaging: an over-
view of current techniques and future perspectives. Am J Obstet Gynecol
2020;223(4):493–515. [III]
55. Cain MA, Guidi CB, Steffensen T, et al. Postmortem ultrasonography of
the macerated fetus complements Autopsy following in utero fetal demise.
Pediatr Dev Pathol 2014; 17:217–220. [II-3]
56. Carey JC, Rayburn WF. Nuchal cord encirclements and risk of stillbirth. Int
J Gynaecol Obstet 2000; 69(2):173–174. [II-2]
57. Hammad IA, Blue NR, Allshouse AA, et al. Umbilical cord abnormalities
and stillbirth. Obstet Gynecol 2020; 135(3):644–652. [II-2]
58. Committee on Practice Bulletins—Obstetrics, American College
of Obstetricians and Gynecologists. Practice Bulletin No. 132:
Antiphospholipid syndrome. Obstet Gynecol 2012;120(6):1514–1521. [III]
59. Silver RM, Saade GR, Thorsten V, et al. Factor V Leiden, prothrombin
G20210A, and methylene tetrahydrofolate reductase mutations and still-
birth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol
2016; 215(4):468.e1–468.e17. [II-2]
60. Goldstein DP, Reid DE. Circulating fibrinolytic activity—a precursor of
hypofibrinogenemia following fetal death in utero. Obstet Gynecol 1963;
22:174–180. [III]
61. Salamat SM, Landy HJ, O’Sullivan MJ. Labor induction after fetal death. A
retrospective analysis. J Reprod Med 2002; 47(1):23–26. [II-2]
62. Erlandsson K, Lindgren H, Malm MC, et al. Mother’s experiences of the
time after the diagnosis of an intrauterine death until the induction of the
delivery: A qualitative Internet-based study. J Obstet Gynacol Res 2011;
37(11):1677–1684. [II-3]
63. Autry AM, Hayes EC, Jacobson GF, et al. A comparison of medical induc-
tion and dilation and evacuation for second-trimester abortion. Am J
Obstet Gynecol 2002; 187(2):393–397. [RCT; n = 297]
64. Lohr PA, Hayes JL, Gemzell-Danielsson K. Surgical versus medical meth-
ods for second trimester induced abortion. Cochrane Database Syst Rev
2008; 1:CD006714. [Meta-analysis]
65. Cowett AA, Golub RM, Grobman WA. Cost-effectiveness of dilation and
evacuation versus the induction of labor for second trimester pregnancy
termination. Am J Obstet Gynecol 2006; 194:768–773. [II-3]
66. Jackson JE, Grobman WA, Haney E, et al. Mid-trimester dilation and evacu-
ation with laminaria does not increase the risk for severe subsequent preg-
nancy complications. Int J Gynaecol Obstet 2007; 96:12–15. [II-2]
67. Schneider D, Halperin R, Langer R, et al. Abortion at 18–22 weeks by lami-
naria dilation and evacuation. Obstet Gynecol 1996; 88:412–414. [II-2]
68. Lal AK, Kominiarek MA, Sprawka NM. Induction of labor compared
to dilation and evacuation for postmortem analysis. Prenat Diagn 2014;
34(6):547–551. [II-2]
69. ACOG. Induction of labor. ACOG Practice Bulletin No. 107. Obstet Gynecol
2009; 114(2 pt 1):386–397. [Review, III]
70. Neilson JP, Hickey M, Vazquez J. Medical treatment for early fetal death
(less than 24 weeks). Cochrane Database Syst Rev 2006; 3:CD002253.
[Review, III]
71. Bugalho A, Bique C, Machungo F, et al. Vaginal misoprostol as an alterna-
tive to oxytocin for induction of labor in women with late fetal death. Acta
Obstet Gynecol Scand 1995; 74:194. [II-2]
72. Bugalho A, Bique C, Machungo F, et al. Induction of labor with intravagi-
nal misoprostol in intrauterine fetal death. Am J Obstet Gynecol 1994;
171(2):538–541. [II-2]
73. Merrell DA, Koch MA. Induction of labour with intravaginal misoprostol
in the second and third trimesters of pregnancy. S Afr Med J 1995; 85(Suppl
10):1088–1090. [II-2]
74. Eng NS, Guan AC. Comparative study of intravaginal misoprostol with
gemeprost as an abortifacient in second trimester missed abortion. Aust N
Z J Obstet Gynaecol 1997; 37(3):331–334. [II-1]
75. Chittacharoen A, Herabutya Y, Punyavachira P. A randomized trial of oral
and vaginal misoprostol to manage delivery in cases of fetal death. Obstet
Gynecol 2003; 101(1):70–73. [RCT, n = 80]
76. Herabutya Y, Chanrachakul B, Punyavachira P. A randomized controlled trial
of 6 and 12 hourly administration of vaginal misoprostol for second trimester
pregnancy termination. BJOG 2005; 112(9):1297–1301. [RCT, n = 279, I]
77. Bracken H, Ngoc NTN, Banks E, et al. Buccal misoprostol for treatment of
fetal death at 14-28 weeks of pregnancy: a double-blind randomized con-
trolled trial. Contraception 2014; 89:187–192. [1, RCT, n = 153]
Fetal Death
78. Dodd JM, Crowther CA. Misoprostol for induction of labour to terminate
pregnancy in the second or third trimester for women with a fetal anom-
aly or after intrauterine fetal death. Cochrane Database Syst Rev 2010;
2010(4):CD004901. [I]
79. Toaff R, Ayalon D, Gogol G. Clinical use of high concentration drip. Obstet
Gynecol 1971; 37:112. [II-3]
80. PROSTIN E2® Vaginal Suppository package insert. [III]
81. Cabrol D, Dubois C, Cronje H, et al. Induction of labor with mifepristone
(RU 486) in intrauterine fetal death. Am J Obstet Gynecol 1990; 163(2):
540–542. [II-2]
82. Elami-Suzin M, freeman MD, Porat N, et al. Mifepristone followed by
misoprostol or oxytocin for second trimester abortion. A randomized trial.
Obstet Gynecol 2013; 122:815–820. [RCT, n = 145]
83. Chaudhuri P, Datta S. Mifepristone and misoprostol compared with miso-
prostol alone for induction of labor in intrauterine fetal death: A random-
ized trial. J Obstet Gynaecol Res 2015; 41(12):1884–1890. [I]
84. Dickinson JE. Misoprostol for second-trimester pregnancy termination in
women with a prior cesarean delivery. Obstet Gynecol 2005; 105:352–356.
[Level II-2]
571
85. Daskalakis GJ, Mesogitis SA, Papantoniou NE, et al. Misoprostol for second
trimester pregnancy termination in women with prior caesarean section.
BJOG 2005; 112:97–99. [II-2]
86. Berghella V, Airoldi J, O’Neill AM, et al. Misoprostol for second trimester
pregnancy termination in women with prior caesarean: a systematic review.
BJOG 2009; 116(9):1151–1157. [II-2]
87. Farrow VA, Goldenberg RL, Fretts R, et al. psychological impact of still-
births on obstetricians. JMFNM 2013; 26:748–52 [II-2]
88. Verdel MJ, Exalto N. Tight nuchal coiling of the umbilical cord causing fetal
death. J Clin Ultrasound 1994; 22(1):64–66. [II-2]
89. Samueloff A, Xenakis EM, Berkus MD, et al. Recurrent stillbirth.
Significance and characteristics. J Reprod Med 1993; 38(11):883–886.
[II-3]
90. Black M, Shetty A, Bhattacharya S. Obstetric outcomes subsequent to
intrauterine death in the first pregnancy. BJOG 2008; 115(2):269–274. [II-2]
91. Regan AK, Gissler M, Magnus MC, et al. Association between interpreg-
nancy interval and adverse birth outcomes in women with a previous still-
birth: an international cohort study. Lancet 2019; 393(10180):1527–1535.
[II-2]
58
ANTEPARTUM TESTING
Nora Graham
Key points
• There are no randomized trial data proving that ante-
partum testing reduces long-term neurologic deficits.
Although entrenched in high-risk pregnancy management,
most antenatal testing schemes are not supported by high-
level evidence.
• Formal maternal counting of fetal movement has been
associated with a non-significant 20% decrease in perinatal
mortality.
• Multiple parameter testing schemes have better correla-
tion with fetal condition than do single-parameter tests.
• Antenatal non-stress test (NST) results appear to have no
significant effect on perinatal mortality (PNM) or poten-
tially preventable deaths. The NST alone is not adequate to
exclude several important sources of perinatal injury.
• Biophysical profile score (BPS) surveillance may be beneficial
in reducing cerebral palsy, with insufficient trial evidence.
Compared to other fetal testing (usually NST), biophysical
profile increases the incidence of induction and cesarean
delivery, but not admission to intensive care nurseries or
perinatal mortality. Individual components have been com-
pared in some trials, but the value of that evidence is limited.
• Umbilical artery (UA) Doppler decreases perinatal mor-
tality in antenatal management of fetal growth restriction
(FGR) fetuses, and should be routinely used in these pregnan-
cies, but not in normal pregnancies. Compared to no Doppler
ultrasound, UA Doppler ultrasound in high-risk pregnancy
(especially those complicated by hypertension or presumed
FGR) is associated with a reduction in perinatal deaths, with
fewer inductions of labor and fewer hospital admissions.
• There are few studies and no management trials comparing
Doppler versus BPS. BPS may correlate better with perina-
tal results, but this has not been shown to improve long-
term neurologic outcomes. The combination of Doppler
and BPS may improve perinatal mortality in severe IUGR,
with limited evidence.
• Ancillary tests such as contraction stress test and vibro-
acoustic stimulation, may have specific uses, but limited
applicability.
• Testing frequency and complexity should be adjusted to
reflect the stability of the clinical situation.
• Delivery decisions should carefully take into account ges-
tational age and risks of prematurity even in the setting of
abnormal testing results.
Background
The main motive underlying antepartum fetal assessment is to
prevent stillbirth. Prevention of neurologic handicap, such as
cerebral palsy, is another aim. Preventing these outcomes by
prompt intervention for proven fetal compromise is balanced
by avoiding impacts of unnecessary intervention, for both
572
fetus (iatrogenic prematurity) and mother (surgical compli-
cations). Extending the pregnancy to reduce prematurity may
increase the risk of unexpected stillbirth, but has measurable
benefits in reduced long-term neurologic outcomes. Optimizing
testing regimens means choosing methods, frequency, and dis-
ease-specific components, while accounting for gestational-age
influences, drug interactions, test variability, and even the inter-
action of test components. If we want to choose the test that is
best at reducing stillbirth, there is limited high-level evidence
to inform us.
Principles of fetal monitoring
The ideal antenatal fetal testing regime should do the following:
• Identify impending fetal injury with near-perfect sensi-
tivity, with warning advanced enough to allow effective
intervention.
• Distinguish normal variation, benign abnormality, and
degrees of significant abnormality, facilitating graded
response.
• Identify normal fetal condition with near-perfect predic-
tive value, reliably excluding stillbirth or injury for a clini-
cally relevant interval.
• Exclude grievous fetal abnormality as the source of abnor-
mal testing.
• Be applicable to a variety of common sources of fetal com-
promise, practicable in common prenatal settings, and
reproducible between situations.
• Produce measurable benefits in reduction of perinatal
death and long-term neurologic handicap.
Fetal-monitoring methods
Fetal movement counting in low-risk pregnancy
There is no standard definition of reduced fetal movements (RFM).
The “count to ten” method (count to ten movements, then
resume normal activity) versus counting for a specified length
of time (e.g., 30 minutes of counting every 6–8 hours) was associ-
ated with better patient compliance [1]. There are, however, no
standard guidelines as to the subsequent evaluation for reduced
fetal movement. A large randomized trial of maternal monitoring
of fetal movement [2] failed to show any benefit over “informal
inquiry about movement during standard antenatal care.” More
recently, another large randomized trial, the AFFIRM trial, failed
to show a significant decrease in stillbirth from increased mater-
nal awareness of fetal movements and a recommended manage-
ment plan for RFM [3]. There was an increase in induction and
cesarean deliveries, as well as neonatal intensive care unit admis-
sion lengths of stay [3]. The Mindfetalness study, also aimed at
increasing awareness, did not improve Apgar scores at birth, but
did decrease small gestational age births and, in contrast to the
AFFIRM trial, cesarean section births [4]. A systematic review and
DOI: 10.1201/9781003099062-58
Antepartum Testing 573

meta-analysis assessing the association of fetal movement count-
ing and perinatal mortality found no statistical differences in peri-
natal outcomes including stillbirths (perinatal mortality was 20%
non-significantly lower, but this could be a clinically significant
finding), and there was an increase in preterm deliveries, induc-
tion of labor, and cesarean deliveries [5]. “My Baby’s Movements
Trial” is a large Australian cluster trial in progress to further
investigate this issue Overall, data are still limited to support
routine fetal movement counting in low-risk pregnancies, or
between episodes of formal fetal assessment in high-risk preg-
nancies [1, 6]. The 20% decrease in perinatal mortality seen in
the latest meta-analysis [5] was statistically non-significant,
but could be interpreted as clinically significant.
Fetal heart rate testing (non-stress
test or cardiotocography)
In this chapter, we use non-stress test (NST, more used in US)
and cardiotocography (CTG, more used everywhere else in the
world) interchangeably. The NST (or CTG) is defined as “reac-
tive” when there are two or more accelerations of at least 15
beats per minute (bpm) above the baseline, that last for at least
15 seconds, in a 20-minute period of combined fetal heart rate
(FHR) and uterine activity monitoring (Figure 58.1). A CTG (or
NST) without these characteristics is called “nonreactive.” These
criteria should only be used for fetuses ≥32 weeks.
Up to 50% of NSTs from 24–28 weeks and 15% of NSTs 28–32
weeks are nonreactive. Criteria, therefore, were adapted to pre-
mature fetuses <32 weeks, assigning reactivity to accelerations of
at least 10 bpm for at least 10 seconds [7–10]. These criteria based
on accelerations have not been associated with any change in out-
comes [11, 12], so a fetus <32 weeks should not be delivered for a
non-reactive NST, but only for bradycardia or other similar non-
reassuring fetal heart tracings. These criteria for interpretation
<32 weeks have been endorsed in national guidelines [7, 13–15].
In fetuses ≥32 weeks, the concordance between fetal movement
and accelerations in FHR is good evidence of fetal well-being,
with a negative predictive value against fetal demise within
7 days of 99.5–99.8% [16]. However, in specific circumstances,
such as FGR with abnormal placental resistance, the NST may
give a false-positive reassurance against acidosis, as high as 15%
[17]. Missed anomalies and missed oligohydramnios are major
contributors to fetal complications in patients with reactive trac-
ings, when NST is used in isolation. Strong evidence, includ-
ing randomized trial data, suggests that the NST should not
be used as a solitary method of monitoring high-risk fetuses
and NST has not clearly been shown to improve perinatal
outcomes [18–21]. In a meta-analysis of randomized trials, com-
pared to no NST or concealment of information, knowledge of
antenatal NST results appears to have no significant effect on
perinatal mortality (PNM) or potentially preventable deaths,

FIGURE 58.1 FHR monitoring. (a) A reactive NST, demonstrates multiple FHR accelerations associated with fetal movements. This
external tracing, obtained at 37 weeks’ gestation, is highly reassuring of fetal health, the absence of hypoxemia and the presence of a
normal umbilical arterial pH. (b) Cyclic fetal behavior demonstrated by FHR tracing. For the first 9 minutes the fetus was virtually
inactive, with a nonreactive segment. When fetal movements resumed, an increase in variability and repetitive accelerations, demon-
strates conversion to active sleep (a “state change” from the left to the right). Abbreviations: FHR, fetal heart rate; NST, nonstress test.
574
with a worrying trend toward harm (RR 2.46, 95% CI 0.96–6.30).
There is no significant impact on cesarean section rate or on the
occurrence of various secondary outcomes [20].
In practical monitoring terms, the false-alarming non-reac-
tive NST is more problematic, occurring in up to 10% of tests at
term [9], and up to 50% of the time at 24–28 weeks gestational
age. Variable decelerations that are less than 30 seconds and non-
repetitive denote an “equivocal” NST, and are not associated with
fetal compromise [22]. Repetitive variable decelerations are asso-
ciated with increased cesarean delivery [23], while decelerations
lasting longer than 1 minute are associated with increased risk of
cesarean delivery, but also fetal demise [24–26]. When the subse-
quent confirmatory test [BPS, contraction stress test, vibroacous-
tic stimulation, as examples] is performed after a nonreactive NST,
up to 85% will be normal. If performed, the NST should be done
in the semi-Fowler (“sitting”) position as this decreases the need
for prolonged monitoring compared to the supine position [27, 28].
Computerized interpretation of FHR monitoring has evolved
as a more specific, objective means of maximizing the information
obtained from the NST [29]. Computerized CTG (CCTG) analyzes
digitized epochs of FHR for numerical criteria, out-putting objec-
tive data on short-term variability (mean of 4–8 milliseconds) and
overall variability, recorded as mean minute variation. Values for
short-term variability below three milliseconds show strong corre-
lation with fetal acidosis. The CCTG is not as limited by gestational
age, and does not require vigorous fetal activity to document a nor-
mal result, so it might be adopted as a better version of FHR analysis
for a broader range of fetal indications. CCTG is superior to simple
CTG in performance time, positive and negative predictive accura-
cies, and fewer equivocal test results [30]. Computerized assess-
ment is associated with lower PNM compared to traditional
CTG interpretation (9/1000 vs. 4.2/1000, RR 0.20, 95% CI 0.04–
0.88), but the clinical significance of this difference is elusive, as
there was no difference in potentially preventable deaths [20]. A
randomized controlled trial found that CCTG use during labor did
not improve outcomes [31]. Antenatal assessment using CCTG for
high-risk premature fetuses may produce more accurate correla-
tion with fetal condition (as compared to traditional NST) but has
limited value as a standalone test [32].
Modifications to CTG
Modified CTG recording methods utilize fetal stimulation to
shorten the time to reach reactivity, to convert nonreactive
FHR tracings to reactivity, as a confirmatory test for nonreactive
NST, and in highest-risk populations, as a more precise test of
fetal well-being.
A type of stimulation is vibroacoustic stimulation (VAS) [33].
The fetus is stimulated by external high-amplitude white noise
applied to the maternal abdomen. This is capable of causing state
change in most fetuses at term [34]. Occasional side effects include
conversion to fixed fetal arrhythmia, and serious concerns about
delivery of high-pressure sound (up to 130 decibels) and effects
on fetal hearing [34]. Since premature fetuses typically require
more sound pressure to elicit responses, and are more suscepti-
ble to hearing injury, use of VAS before 32 weeks should be very
cautious. Compared to no such stimulation, fetal VAS has been
associated with a reduction in the incidence of nonreactive
antenatal CTG test (RR 0.62, 95% CI 0.48–0.81) and reduced
the overall mean CTG testing time by about 7 minutes [35].
Applied to modified BPS testing, VAS is associated with a 67%
false-alarm rate requiring performance of full BPS [36]. More crit-
ical, however, is the false-negative rate – 55% of fetuses with sub-
sequent FHR abnormalities had reassuring VAS-NST [37]. Sound
Maternal-Fetal Evidence Based Guidelines
responsiveness is reduced in many high-risk groups (less than 32
weeks, hypertension, depression, severe IUGR, cocaine exposure,
treatment with magnesium sulfate or antenatal steroids) [34].
Specific trials have demonstrated superiority of multivariable test-
ing including Doppler, NST, and biophysical variables over either
contraction stress test (CST) or VAS in prolonged pregnancy and
IUGR. Both trials concluded CST and VAS could be eliminated
from fetal testing regimes [38, 39]. The proven effect of VAS to
provoke fetal neurologic state change seems outweighed by
its ability to generate false reassurance. Routine application in
high-risk fetal populations is not recommended.
Compared to no administration, antenatal maternal glucose
administration (20–50 mg orally, e.g., as orange juice) does not
decrease the incidence of nonreactive antenatal CTG tests,
regardless of prior fasting or non-fasting [40]. Compared to con-
trols, neither orange juice nor chocolate decrease the incidence of
nonreactive antenatal CTG tests [41].
Compared to no manipulation, or to VAS, manual fetal
manipulation does not decrease the incidence of nonreactive
antenatal CTG test [42].
Ambien light exposure does not shorten the time to complete BPS
or change score [43]. Shining a bright halogen light on the mother’s
abdomen shortens the time to first acceleration on NST [44].
Response to abnormal CTG test results
Management depends heavily on gestational age. Due to the
high false positive rate of NST, at ≥32 weeks, a non-reactive
NST should be followed immediately by full BPS. In specific
circumstances, intervention may be based on FHR testing alone.
At term, in a fetus previously documented as having reactive
NST with normal variability, delivery should be considered if
the tracing shows minimal or absent variability and/or repeti-
tive late decelerations. In uncommon cases, an NST may detect
a fetal arrhythmia, requiring prompt referral for fetal echocar-
diography and ultrasound examination. In other circumstances,
(e.g., fetal growth restriction), umbilical artery Doppler testing is
the main criteria which guides management, together with the
CTG. Before 32 weeks, a non-reactive CTG is often normal, as
stated earlier, and may only require outpatient follow-up.
Contraction stress test
The contraction stress test (CST or oxytocin challenge test) is
a fetal test in which spontaneous or induced contractions stress
the fetoplacental unit. At least three contractions must be present
in a 10-minute period and if decelerations are present with 50%
or more of the contractions, then the test is abnormal or posi-
tive. These tests have a higher negative predictive value than NST
alone, similar to biophysical and Doppler methods (3–4 per 10,000
tests), but have high rates of equivocal and false-alarming results.
For example, when BPS is used as the backup test for positive
(abnormal) CST, at least 50% of pregnancies can safely continue
for at least a week [45]. High cost, requirement of hospital facilities,
disagreement on fundamental interpretation of the test, and occa-
sional complications resulting from the test methods have margin-
alized these techniques. The OCT may have a role in determining
the route of delivery when the need for intervention has already
been determined (e.g., a positive OCT means proceed to cesarean
section), but the data available do not justify any firm conclusion.
Biophysical profile scoring
This ultrasound-based modality uses five parameters of fetal
behavior in a protocol-driven format (Table 58.1) to manage high-
risk pregnancies [46]. The parameters have different sensitivities
Antepartum Testing 575

TABLE 58.1: Interpretation of BPS Variables 100

Normal Behavior Abnormal Behavior
Fetal Variable (score = 2) (score = 0)
90
Fetal breathingIntermittent, multiple episodes Continuous breathing
movements of more than 30-second without cessation.
duration, within 30-minute Completely absent 80
BPS time frame. Hiccups breathing or no
count. Continuous FBM for sustained episodes 70
30 minute = R/O fetal acidosis
Body or limb At least four discrete body Three or fewer body/
movements movements in 30 minute limb movements in a 60

≤7
Includes fine motor 30-minute observation

Percent

AR
PG
movements, rolling period
50

nA
movements, and so on, but not

5m
REM or mouthing movements
Fetal tone/ Demonstration of active Low-velocity movement 40
.20
posture extension with rapid return only. Incomplete ≤7
pH

FD
to flexion of fetal limbs and flexion, flaccid

-FD
30

CS
brisk repositioning/ trunk extremity positions,

LS
rotation. Opening and abnormal fetal posture.
closing of hand, mouth, Must score = 0 when 20
kicking, and so on FM completely absent
Cardiotocogram At least two episodes of fetal Fetal movement and
10
acceleration of >15 bpm and of accelerations not
>15 second duration. Normal coupled. Insufficient
mean variation (computerized accelerations, absent 0
10 6 4 2 0
FHR interpretation), accelerations, or
accelerations associated with decelerations. Mean Normal Equivocal Abnormal Very abnormal
maternal palpation FM variation <20 on Last BPS before delivery
(accelerations graded for numerical analysis of
gestation), 20-minute CTG CTG
FIGURE 58.2 BPS has an exponential relationship to neonatal
Amniotic fluid At least one pocket >2 cm No cord-free pocket >2 outcome. Declining scores strongly predict increasing frequency
evaluation with no umbilical cord. Also cm or multiple of FD, cesarean section for fetal distress (LSCS-FD), low 5-minute
consider criteria for elements of Apgar score, and acidotic umbilical vein pH [65]. Abbreviation:
subjectively reduced fluid subjectively reduced BPS, Biophysical profile score; FD, fetal distress.
amniotic fluid volume
Abbreviations: BPS, biophysical profile score; CTG, cardiotocogram; FBM, fetal
breathing movements; FHR, fetal heart rate; FM, fetal movement; REM, rapid eye comparing Doppler methods to BPS have been very small, and
movement; R/O, rule-out. unable to evaluate such infrequent outcomes [53–57]. Compared
to other fetal testing (usually NST), BPS may increase the inci-
for different fetal outcomes, but combining the variables gives a dence of cesarean section, but does not affect incidences of low
more accurate prediction of fetal status (Figure 58.2) [34, 47, 48]. Apgar scores, admission to intensive care nurseries, or PNM (2
Application of BPS has been shown to reduce PNM (historical trials) [58]. Further trials are needed to assess the utility of BPS in
controls, Table 58.2) [49–51], and long-term neurologic handicap, high-risk pregnancies.
however, randomized trials of BPS versus no monitoring have
not been done. The only attempt at a randomized trial compar- Fetal breathing movements
ing BPP versus NST is a quasi-randomized (odds vs even numbers) These are rhythmic contractions of the fetal diaphragms that
non-blinded trial, done over 35 years ago. It concludes that BPS has demonstrate a maturational pattern. They are unrelated to fetal
a similar sensitivity of overall abnormal fetal outcomes, includ- CO2 levels, but related to diurnal rhythms and fetal cortisol lev-
ing perinatal mortality, compared to NST [52]. Randomized trials els. Human fetuses are stimulated to breathe by maternal glucose
levels; therefore, outpatient BPS can be done most efficiently fol-
TABLE 58.2: Perinatal Mortality Changes with BPS lowing mealtimes. Fetal breathing movements are very sensi-
Application tive to hypoxemia, first illustrating longer periods of fetal apnea
between bursts, then being lost altogether [59]. In BPS, fetal hic-
Number PNM PNM cups are treated equivalently.
Program Tested with BPS without BPS
Ireland [49] 3200 4.1 10.7 Fetal body movements
Nova Scotia [50] 5000 3.1 6.6 Total fetal activity declines when hypoxemia begins [60]. The
frequency of fetal movements is a maturational variable – many
Manitoba [16] 56,000 1.9 7.7
term fetuses will move during only 10–15 minutes in an hour of
California [51] 15,000 1.3 8.8
observation, while a 28-week fetus who only did that would fre-
Abbreviations: BPS, biophysical profile score; PNM, perinatal mortality/1000. quently prove abnormal.
576
TABLE 58.3: Systematic Application of Biophysical Profile Scoring
BPS Interpretation
10/10 No evidence of fetal asphyxia
8/8 present
8/10 (AFV-normal)
8/10-OLIGO Chronic fetal compromise likely
6/10 (AFV-normal) Equivocal test, fetal asphyxia is
not excluded
4/10 Acute fetal asphyxia likely. If
AFV-OLIGO, acute on
chronic asphyxia very likely
2/10 Acute fetal asphyxia, most likely
with chronic decompensation
0/10 Severe, acute asphyxia virtually
certain
a Per 1000 live births, within one week of test result shown, without intervention. For scores of 0, 2, or 4, intervention should begin virtually immediately, provided the fetus
is viable.
Abbreviations: AVF, amniotic fluid volume; PNM, perinatal mortality; OLIGO, oligohydramnios.
Fetal tone
The fetus must move to demonstrate tone – it is not simply a
flexed posture. The spasm of fetal activity during startle motions
provoked by acoustic stimulation does not constitute normal
muscle tone and may give a misleading impression of well-being.
Amniotic fluid volume
This is discussed in detail in a separate guideline (see Chapter 59).
In BPS, the maximum vertical pocket (MVP) is the standard [61, 62].
MVP ≥ 2 cm meets criteria for BPS score of 2 (34). Reduced amni-
otic fluid volume is thought to represent reduced fetal urine pro-
duction assuming normal fetal swallowing. Hemodynamically
mediated redistribution of fetal blood flow, not hypoxemic renal
ischemia as once suggested, is the probable mechanism.
CTG
The FHR is a sensitive indicator of fetal compromise with serial
loss of CTG reactivity, reduced variability, no variability, and
appearance of late decelerations. However, fetuses show the first
two of these during normal cyclic behavior, so a BPS of 8/8 is just
as indicative of normal well-being as a score of 10/10, NST, there-
fore, should only be used in fetuses not demonstrating normal
behavior in the ultrasound parameters done first [63]. When
done in this order, only 2.7% require an NST. As noted earlier,
BPS applies prematurity criteria to NST interpretation.
BPS management
If biophysical profile testing is performed, the manag-
ing physician should be willing to act on the test results.
Management by BPS follows a protocol that relates fetal condi-
tion, assumed perinatal risks, gestational age, and recommended
action (Table 58.3). When BPS is persistently 8/10 on serial test-
ing with the same variable missing, specific inquiry should be
made about cause. In some cases, that is obvious from the clini-
cal context (e.g., oligohydramnios in preterm premature rup-
ture of membranes with normal fetal status). In other cases, it
is not so clear. As suggested by Table 58.4, equivocal results in
Maternal-Fetal Evidence Based Guidelines
Predicted
PNM/ 1000a Recommended Management
Less than 1/1000 No acute intervention on fetal basis. Serial testing indicated by
disorder-specific protocols
89/1000 For absolute oligohydramnios, prove normal urinary tract, and
disprove asymptomatic rupture of membranes
Depends on Repeat testing in about 6 hours, before assigning final value. If score
progression is 6/10, then 10/10, in two continuous 30-min periods, manage as
(61/1000 on average) 10/10. For persistent 6/10, deliver the term fetus, repeat within
24 hour in the preterm fetus, then deliver if less than 6/10
91/1000 Deliver by obstetrically appropriate method, with continuous
monitoring
125/1000 Deliver for fetal indications (usually needs cesarean section for
intolerance to labor)
600/1000 Deliver for fetal indications (usually needs cesarean section for
intolerance to labor)
the preterm fetus call for repeated testing, transfer to appropriate
neonatal resources, antenatal steroid administration, and so on,
before moving to delivery. In high-risk fetuses, delivery can wait
for valuable maturation time with normal BPS of 8/8 or 10/10 as
proof that the fetus is not acidotic [64]. On the other hand, a BPS
of 0–2/10 or 4/10 repeatedly, should justify delivery at local
thresholds of viability in absence of a transient cause [65]. If
very premature gestational age (e.g., <26 weeks) means deliv-
ery is not mandated by BPS no matter how low the score, then
we advise not to utilize BPS for fetal monitoring.
Modified biophysical profile score
Many modifications have been proposed. The most popular com-
bination suggested has been the AFV (amniotic fluid volume)-NST
combination [66], including optional use of VAS [67, 68], to shorten
observation time. This combination uses AFV to reflect long-term
uteroplacental function while the NST serves as an indicator of
short-term function. MVP is used for AFV assessment. When stud-
ied, full BPS (all five variables) as the backup test was required in
15–30% of cases. The simplified test reduced the time and com-
plexity of BPS, without altering the false-­negative rate, which is
TABLE 58.4: Risks of Stillbirth vs. Neonatal Death Due to
Prematurity
Equivalent Neonatal
BPS Stillbirth Ratea Death Rate (week)
0 560 25.4
2 153 28.3
4 91 29.1
6 61 30.0
8 0.5 Full term
10 0.5 Full term
a Death (per 1000 births) within one week if the fetus remains undelivered. These
figures change with time and differ between centers, including differences between
inborn and transported babies.
Antepartum Testing 577

about 3–8 per 10,000 tests [67, 69]. However, in assessing differences
in the false-positive rate, either the data are too few or the full BPS
was superior to the restricted tests in avoiding unnecessary inter-
vention. Shortening the BPS is not validated for high-risk fetuses
with abnormal Doppler indices, preterm fetuses, postdate preg-
nancy, fetal anomalies, multiple gestation, or fetuses with arrhyth-
mia, infection, anemia, or diabetic macrosomia. The exceptions
are trials of FGR management in which the modified BPS included
Doppler information (umbilical artery). In those cases, addition of
Doppler assessment both improved classification of fetal acidosis
and reduced interference for false-alarm BPS [66, 67].
Doppler of fetal vessels
The umbilical artery (UA) is the vessel most useful to screen by
Doppler in clinical care, in particular for FGR fetuses or preg-
nancies complicated by hypertensive disorders. High-velocity
diastolic flow is normal through this artery, but flow slows,
is absent or reverses with progressively worse conditions. UA
resistance progressively rises from tertiary stem villous defi-
ciency and decreasing placental perfusion area, and therefore
is used as an indicator of placental function (Figure 58.3). UA
Doppler assessment requires careful attention to technical detail,
and is usually done in the mid-portion of the free umbilical cord

FIGURE 58.3 Abnormalities in Doppler velocity wave forms of the umbilical artery depict increasing placental resistance. These
Doppler examinations are from the same patient as pregnancy progresses. (a) The umbilical artery resistance is modestly elevated at 18
weeks (PI 1.47). By 24 weeks (b), end-diastolic velocities are absent in most cardiac cycles. Abbreviation: PI, pulsatility index.
(Continued)
578 Maternal-Fetal Evidence Based Guidelines

FIGURE 58.3 (Continued) By 28 weeks (c), reversal of end-diastolic flow occupies nearly one quarter of the cardiac cycle. Cesarean
section was carried out on the basis of oligohydramnios at 29+ weeks, with umbilical venous pH 7.18.

[70]. Although each mathematical expression of the Doppler arte-
rial flow velocity waveform has some advantages, the pulsatility
index (PI) has the advantage of infinite expression (remaining
valid even when end-diastolic flow is reversed), and autocorrela-
tion with the volume of the waveform itself. When UA PI reaches
an individualized threshold, higher blood pressure leads to car-
diac and systemic effects, including a shift toward more cerebral
perfusion which can be measured using the Doppler waveform
of the middle cerebral artery (MCA, Figure 58.4). Initially the
subtle change in the cerebroplacental ratio (CPR) is called cen-
tralization and thought to be from resistance-mediated diversion
of flow away from an ailing placenta. Further deterioration in pla-
cental function may lead to a significant decline in the MCA PI
as diastolic blood flow rises, which has been called brain sparing
and may be mediated by hypoxemia-induced cerebral vasorelax-
ation [71]. As hemodynamic and respiratory declines continue to
interact, oxygen-sensitive interfaces between nutrient rich and
non-rich streams begin to dictate flow [72]. Diversion through an

FIGURE 58.4 (a) Serial MCA Dopplers demonstrate an increase in diastolic blood flow, termed centralization. Normally, the mid-
dle cerebral artery shows high resistance with low diastolic velocity (high PI 1.83). Abbreviations: PI, pulsatility index; MCA, middle
cerebral artery.
Antepartum Testing 579

FIGURE 58.4 (Continued) (b) Diversion of blood flow toward the brain correlates with worsening umbilical artery depiction of
increased placental resistance, with falling cerebrovascular resistance, increased end-diastolic velocities, and PI falling to 1.09.

opening ductus venosus (DV) is readily depicted as progressive Doppler application

changes in waveform pattern (Figure 58.5). Deep reversal of the
atrial contraction wave, a-wave, indicates both cardiac impair-
ment (forward volume flow insufficiency forcing the waveform
more retrograde) and hypoxemia (dilating the DV itself). DV
contains the highest venous velocities in the fetal abdomen, but
when the waveform is abnormal, it must be carefully differenti-
ated from adjacent hepatic venous structures.
Routine application of UA and/or uterine artery Doppler in
normal pregnancy is of no proven benefit [73, 74]. UA Doppler
is instead beneficial and recommended in some high-risk
pregnancies, specifically those complicated by FGR where
it has been shown to improve outcomes [75]. Worsening UA
Doppler correlates well with declining placental function and
the emergence of hypoxemia and acidosis [71]. The UA Doppler

FIGURE 58.5 Progressive changes in venous return to the heart as depicted in the ductus venosus. (a) There are normally four
phases in the waveform, consisting of (1) atrial contraction, (2) ventricular contraction, (3) restitution of the annulus, and (4) diastole.
Typically, the a-wave (1) shows the only significant downward deflection, a modest reduction in forward flow.
(Continued)
580 Maternal-Fetal Evidence Based Guidelines

FIGURE 58.5 (Continued) (b) Increase afterload from placental resistance causes abnormal forward cardiac output, with the a-wave
nearly retrograde. (c) Further progression in placental insufficiency is associated with cardiac malfunction, with severe retrograde a-waves,
as well as distorted cardiac function, producing midwave depression as the annulus rises against an overfilled circulation.

will start to increase when the placenta is 60–70% compromised
[76]. Absent end-diastolic velocities denote an increasing risk of
stillbirth, preterm delivery, birthweight below 10th percentile,
and many neonatal complications (Table 58.5) [77]. UA Doppler
is useful in directing care – small fetuses with normal Dopplers
probably do not need the same level of surveillance as do those
with abnormal umbilical flow [78]. Perinatal outcome is superior
when UA Doppler is utilized in decision-making, although inter-
ventions based on umbilical Doppler alone have a substantial
risk of causing unnecessary prematurity [79, 80]. A Cochrane
Review assessing use of Doppler ultrasound in high risk pregnan-
cies included over 10,000 pregnancies and found that, compared
with no Doppler ultrasound, Doppler (mostly UA) ultrasound is
associated with a reduction in perinatal death (1.2% vs. 1.7%,
Antepartum Testing 581

TABLE 58.5: Abnormal Umbilical Artery Doppler Correlates Evaluation of venous Doppler waveforms may be useful in
with Neonatal Compromise prediction of morbidity and mortality in FGR. Ductus venosus
(DV) abnormality is a strong predictor of adverse perinatal out-
Cesarean Section for Fetal Nonreassuring Testing
come, surpassing all other predictors [71, 92]. However, the best
Acidosis outcomes occurred when BPS was used to maximize the safe
Hypoxemia prolongation of pregnancy [93]. Even in the most compromised
Low Apgar-5 pregnancy, gestational age was the most influential factor in
Ventilator required determining outcome. These principles have been amplified fur-
Long-term oxygen ther in nontrial observations. First, the most severe DV abnormal-
Bronchopulmonary dysplasia ity, absence or reversal of the a-wave (Figure 58.5), is an accurate
Anemia predictor of stillbirth when it exists >7 days (in fetuses with the
Increased NRBC most severe UA patterns) [94]. Second, however, when severe DV
Thrombocytopenia abnormality is found without abnormal UA Doppler, outcome
Prolonged NRBC release may well be normal. A large randomized trial, the TRUFFLE
Neutropenia trial, suggests that there is no difference in neuroimpairment of
Transfusions required surviving infants even at 2 years if they are delivered based on
IVH CCTG short term variation, early DV changes (>95th percentile
NEC PI), or late DV changes (A wave reversal) [95]. There is no Level 1
Perinatal mortality
evidence that DV Doppler improves perinatal or infant out-
comes, and therefore it should not be used routinely for clini-
For all of these outcomes, their frequency rises exponentially from abnormal indices cal management in unselected patients. Again, the principle is
to absent end-diastolic velocities to reversed end-diastolic velocities.
emphasized: Solitary DV Doppler abnormality, even reverse
Abbreviations: BPD, bronchopulmonary dysplasia; NRBC, nucleated red blood cells;
a-wave in the DV, is not sufficient for intervention [96].
IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis.
A high-level of evidence is now available, showing that wait-
ing until the need for delivery is certain maximizes intrauter-
RR 0.71,95% CI 0.52–0.98) with a number needed to treat of 203 ine time, optimizes reduction of prematurity, and at the same
(81) The use of Doppler ultrasound is also associated with fewer time, does not add morbidity or mortality by “delaying” inter-
inductions of labor (RR 0.89) and fewer cesarean sections (RR vention [71, 92–94, 97–102]. In virtually all Doppler-outcome
0.90) without reports of adverse effects. No difference is found for trials, the single most critical influence on outcome has been
FHR abnormalities in labor or low Apgar scores (see Chapter 47). gestational age at delivery and its determination of adverse
In cases of FGR, fetuses with absent end-diastolic UA impacts of prematurity. In general, no Doppler abnormality
Doppler flow should be delivered around 34 weeks, and those by itself warrants iatrogenic delivery before 32 weeks, even in
with reversed end-diastolic UA Doppler flow should be deliv- a growth restricted fetus. At present, Level 1 data suggests that
ered around 32 weeks [82]. Despite the strong correlations with the only Doppler useful for timing of delivery and improv-
fetal status, basing delivery decisions on UA Doppler alone, espe- ing outcomes is the UA Doppler. Other Doppler studies remain
cially before 32–34 weeks and without the presence of absent or of limited clinical utility for fetal testing and timing of delivery
reversed diastolic flow, may lead to unnecessary mortality and (with the exception of MCA for fetal anemia). For management of
morbidity due to extreme prematurity [83–85]. This was shown FGR, see also Chapter 47.
also by the GRIT trial (Table 58.6) [86, 87]. An approach to sequential testing with Doppler establishing
Use of the CPR or MCA PI in monitoring FGR fetuses has estab- the appropriate level of intense surveillance and BPS indicating
lished relation to neurodevelopmental outcome [88] and could help the timing of delivery has been proposed by several independent
predict the need for Cesarean delivery for intrapartum fetal compro- teams. An example is shown in Table 58.7.
mise [89], but CPR performs poorly as a screening test for adverse
outcomes [90]. As with all Doppler studies, the cerebroplacental
TABLE 58.7: Umbilical Artery Doppler Index Abnormality
ratio should not be used in isolation, if used at all. There is no man-
Suggests NST/MVP or BPS Surveillance
agement trial data to support use for the CPR to direct care [91].
NST/MVP or
Abnormalitya BPS Frequencyb Decision to Deliver (Fetal)c
TABLE 58.6: GRIT Trial
Decreased but present Weekly Abnormal BPSd or ≥36–37
Immediate Delayed
diastolic flow weeks
Endpoint Delivery Delivery Odds Ratio
AEDV Twice weekly Abnormal BPSd or ≥34 weeks
C/S rate 91% 79% 2.7 (CI 1.6–4.5) REDV Daily Abnormal BPSd or ≥32 weeks
Early PNM 10% 9% 1.1 (CI 0.61–1.8) a Umbilical artery (UA) and precordial venous Doppler. MCA abnormalities con-
Late PNM 2% 2% 1.0 firm the elevated placental resistance, but do not directly alter management
Cerebral palsy 5% 1% Not calculated according to this scheme.
b Minimum frequency, increased on the basis of severity—maternal condition(s),
All disabilities 8% 4% Not calculated
Death or disability 55/290 44/283 1.1 (CI 0.7–1.8) degree of IUGR, gestational age.
c Neonatology consultation, maternal clinical factors, fetal blood sampling param-
at 2 years 19% 15.5%
eters, all will impact this collaborative decision.
Source: Modified from Refs. [87, 88]. d Any BPS ≤4/10.

Abbreviations: C/S, cesarean section; PNM, perinatal mortality; CI, 95% confidence Abbreviations: NST, nonstress test; MVP, maximum vertical pocket; BPS, biophysical
interval. profile scoring.
582 Maternal-Fetal Evidence Based Guidelines

FIGURE 58.6 Percentage of abnormal testing findings in the week prior to delivery. Virtually all fetuses were delivered for abnor-
mal BPS (*), but progressive changes in multivessel Doppler occur in sequence days before the BPS deteriorates in many fetuses.
Most of these IUGR fetuses had reached the end of their Doppler progression before delivery. Abbreviations: A/REDV, absent or
reversed ­diastolic velocity; MCA, middle cerebral artery; DV, ductus venosus; BPS, biophysical profile score; UA, umbilical artery; UV,
­umbilical vein.

Doppler surveillance and BPS:
Integrated fetal testing
Fetuses at risk for placental insufficiency are best assessed with
UA Doppler. Elevated UA resistance, however, may persist for
months, absent end-diastolic velocity for weeks, and a-wave
reversal for days without fetal deterioration [97]. Especially in the
critical gestational ages before 32 weeks, such an interval may
be crucial in reducing prematurity impacts. A non-randomized
study of 113 pregnancies managed by combined UA and DV
Doppler, with delivery triggered by BPS, concluded that gesta-
tional age and birthweight were “the predominant factors for
poor neurodevelopment” assessed at age 2 [103]. The rationale
underlying the multivessel Doppler and BPS approach is the rela-
tionship of deterioration in vascular indices to the (later) decline
in BPS (Figure 58.6) [98]. Integrated fetal testing has not been
studied in randomized trials, and so its real safety and effec-
tiveness are unknown.
Condition-specific testing
Many conditions have increased risks of fetal compromise, but
may not have identical patterns of fetal deterioration; it may be
necessary/beneficial to modify testing to fit the disorder. FGR,
late-term pregnancy, and PPROM are the only conditions in
which there is evidence from RCTs regarding antenatal fetal
testing. Many other conditions have been proposed as necessitat-
ing antenatal fetal testing (Table 58.8) [104]. Table 58.9 summa-
rizes our suggested management for antenatal fetal testing based
on different conditions.

TABLE 58.8: Examples of Possible Indications for Antenatal Surveillancea

Primarily Maternal Conditions
Hyperthyroidism
Symptomatic hemoglobinopathy
Cyanotic heart disease
Chronic renal disease
Type I diabetes
Marked uterine anomalies
Advanced maternal age
Obesity
Organ transplant
Source: Modified from Ref. [105].
a Not a complete list.
Primarily Placental Conditions
Antiphospholipid syndrome
Systemic lupus erythematosus
Hypertensive disorders
Marked placental anomalies
Umbilical artery
Doppler abnormalities
Gestational diabetes
Primarily Fetal Conditions Miscellaneous Conditions
Decreased fetal movement IVF pregnancy
Oligohydramnios Previous stillbirth
Polyhydramnios Previous recurrent abruption
Intrauterine growth restriction Teratogen exposure
Postdates pregnancy
Alloimmunization
Macrosomia
Anomalies/aneuploidy
Multiple gestation
Preterm premature rupture of membranes
Fetal arrhythmia
Antepartum Testing 583

TABLE 58.9: Suggested Antenatal Surveillance for Specific Conditions

Initiation of Growth
Condition Initiation of Testing Ultrasoundsf Delivery (weeks)
Chronic HTN 32 weeks Weekly NST a 24 weeks (if Q4 weeks No meds 38 0/7–39 6/7
on meds) Controlled on meds 37 0/7–39 6/7
Poorly controlled 36 0/7–37 6/7
Gestational HTN 32 weeks Weekly NST At diagnosis Q4 weeks 37 0/7–37 6/7
Pre-eclampsia At diagnosis Twice-weekly NST At diagnosis Q4 weeks Without severe features 37 0/7–37 6/7
With severe features 34 0/7–34 6/7
GDMA1 None None 30–32 weeks once Early delivery <39 weeks usually not indicated
GDMA2 32 weeks Weekly NST/MVP At diagnosis Q4 weeks Late preterm or early term delivery might be
36 weeks Twice-weekly NST/MVP indicated if poorly controlled
Pregestational 32 weeks Weekly NST 24 weeks (if Q4 weeks Well controlled: 39 0/7–39 6/7 weeks
DM 36 weeks Twice-weekly NSTc on meds) Poorly controlled/complications: 36 0/7–38 6/7
Fetal growth restriction At diagnosis Twice-weekly NST/MVP At diagnosis Q3 weeks No other abnormalities 38 0/7–39 6/7
and Dopplers Reversed UA end diastolic flow 34 0/7–34 6/7
Absent UA end diastolic flow 32 0/7–32 6/7
Two vessel cord 32 weeks Weekly NST 32 weeks Q4 weeks Early delivery <39 weeks usually not indicated
Maternal age at delivery 36 weeks Weekly NST 30–32 weeks once Early delivery <39 weeks usually not indicated
≥35 years
Obesity Weekly NST — — Early delivery <39 weeks usually not indicated
Preterm premature ruptured At diagnosis In patient management At diagnosis Q3 weeks 34 0/7 (or laterg)
membranes
Post Dates 40 weeks Weekly NST — — 41 0/7–41 6/7 weeks
41 weeks Twice-weekly NST
Di/di twins None Noneb 24 weeks Q4 weeks 38 0/7–38 6/7
Mono/di twins 32 weeks Weekly NST, Q2 week 18–20 weeks Q2 weeks 34 0/7–37 6/7
Dopplers
Mono/mono twins 24–28 weeks Consider hospitalization, 24 weeks Q3 weeks 32 0/7–34 0/7
if not twice-weekly NST,
Q2 week Dopplers
Prior unexplained IUFD 1 week prior to Weekly NST 28 weeks Q4 weeks 39 0/7–39 6/7
IUFD, but not
before 28 weeks
SLE or renal disease 32 weeks Weekly NST 24 weeks Q4 weeks 39 0/7–39 6/7
Organ transplant 32 weeks Weekly NST 28 weeks Q4 weeks Early delivery <39 weeks usually not indicated
Hypothyroidism or 32 weeksd Weekly NSTd 30–32 weeks once Early delivery <39 weeks usually not indicated
Hyperthyroidism
Cholestasis 32 week Weekly NST — — Total bile acids <100 μmol/L 36 0/7–39 0/7
Total bile acids >100 μmol/L 36 0/7–36 6/7
Maternal Cardiac disease Individualize 28 weeks Q4 weeks Early delivery <39 weeks usually not indicated
Oligohydramnios (MVP<2 cm) 32 weeke Weekly NST/MVP At diagnosis Q3–4 weeks 36 0/7–37 6/7 weeks
Polyhydramnios (MVP>8 cm) 28 weeke Weekly NST/MVP At diagnosis Q3–4 weeks Early delivery <39 weeks usually not indicated
Sickle Cell Disease 32 week Weekly NST 24 weeks Q4 weeks Early delivery <39 weeks usually not indicated
Fetal arrhythmia At diagnosis Weekly NST At diagnosis Q4 weeks Early delivery <39 weeks usually not indicated
a Instead of NSTs, some practitioners use biophysical profile score (BPS), or modified BPS (NST and MVP). There is no level 1 evidence to compare NST to BPS (or modified
BPS) fetal testing.
b Some practitioners starts NSTs (or BPS) fetal testing in multiple gestations at 32–36 weeks, with very limited evidence.

c If poorly controlled consider starting at 28 weeks twice weekly.

d For hypothyroidism, only if poorly controlled.

e Or at diagnosis if diagnosed later.

f cHTN off meds, abnormal placentation, substance abuse in pregnancy, uterine fibroids >5 cm all indications for one growth scan at 30 week.
g See Chapter 20 in Obstetric Evidence Based Guidelines for more details.

Abbreviations: HTN, hypertension; q, every; meds, mediations; GDMA, gestational diabetes mellitus; NST, non stress test; MVP, maximum vertical pocket; DM, diabetes
mellitus; IUGR, intrauterine growth restriction; di/di, chorionic diamniotic; mono/di, monochorionic diamniotic; mono/mono, monochorionic monoamniotic; IUFD, intra-
uterine fetal demise; SLE, systemic lupus erythematosus; MVP, maximum vertical pocket; Late preterm, 34 0/8–36 6/7 weeks; early term, 37 6/7–38 6/7 weeks; MVP, maxi-
mum vertical pocket of amniotic fluid.
584
Pre-eclampsia
There are no randomized trials to determine type or frequency
of fetal monitoring for pre-eclampsia. We recommend a fetal
growth scan and MVP and UA Doppler at the time of diagnosis
and twice weekly NSTs to evaluate for placental insufficiency, if
initial assessments are normal.
Diabetes
The critical issue is glycemic control – when this is good, antenatal
testing is less critical. When diabetic control is poor, identification
and monitoring of the macrosomic fetus requires individualized
care [105, 106]. Poor glycemic control as judged by maternal blood
sugars, or as denoted by fetal macrosomia (estimated fetal weight
>90th percentile) and polyhydramnios, or both, requires increased
surveillance. Diabetic women with hypertension, cardiac, renal,
and other vascular diabetopathy, and fetuses with FGR have preg-
nancies with the highest risk of adverse outcome from elevated
placental resistance. UA Doppler can detect this and is thought
to correctly stratify the adverse outcomes better than BPS [107],
although prospective randomized evaluation of management has
not been reported. In the absence of Doppler abnormalities, man-
agement by BPS protocol using twice-weekly testing achieves the
same or better outcome (cord vein pH, mortality, neonatal mor-
bidity) than euglycemic controls [108]. Expert opinion generally
recommends weekly NSTs starting at 32 weeks and then twice-
weekly NSTs starting around 36 weeks and serial growth ultra-
sounds for all women requiring medications to achieve glycemic
control. There is no standard for testing women whom achieve
glycemic control without medications [109].
Fetal growth restriction
This issue is covered in more details in Chapter 47. UA Doppler
monitoring of the FGR fetus is associated with improved
perinatal outcomes, including less perinatal death [110].
Therefore, weekly UA Dopplers should be performed after
FGR is diagnosed. A FGR fetus should be delivered around 34
weeks for absent UA end-diastolic flow, or around 32 weeks if
reversed UA end-diastolic flow (Table 58.7) [82]. Doppler stud-
ies of other vessels have not been shown to be associated with
perinatal benefits, and therefore remain investigational [95]. In
addition to UA Dopplers, CTG, and amniotic fluid assessment
should be performed regularly.
Advanced maternal age
The number of women delivering over the age of 35 years is rising.
The risk of stillbirth increases with age with women over 40 years
old at 39 weeks’ gestation having similar stillbirth rates to women
25–29 years old at 41 weeks [111]. Many experts, therefore, rec-
ommend delivery at 39 weeks. A randomized controlled trial
comparing induction of labor at 39 weeks’ gestation compared to
expectant management in women age 35 years or older found no
significant difference in cesarean delivery rate or adverse mater-
nal or neonatal outcomes [112]. We recommend weekly NST/
MVP starting at 36 weeks, as well as one growth ultrasound
around 30 weeks.
Obesity
The exponential rise in obesity and morbid obesity in pregnancy
is alarming in many respects, including accelerated fetal risks
[113]. These associations include the effects of associated medi-
cal disorders such as hypertension and diabetes, but obesity itself
has an independent impact on fetal macrosomia, stillbirth, and
Maternal-Fetal Evidence Based Guidelines
intrapartum complications that mandates heightened monitor-
ing [114]. Many experts now recommend at least weekly NSTs
or BPS for women with BMI ≥30 (or ≥35), starting at either
32 or 36 weeks, based on the fact that the incidence of fetal
death is increased in this population [115]. Early delivery is not
recommended.
Preterm premature ruptured membranes
NST or BPS management may be helpful in managing preterm
premature ruptured membranes (PPROM), but the evidence for
effectiveness is very limited. When the NST was nonreactive and
fetal breathing was absent, delivery produced superior neonatal
and maternal infectious outcomes in one [116]. This finding has
not been replicated in other studies. Randomized comparison
of BPS and NST alone in this setting showed that neither
test has good sensitivity (25.0% and 39.1%, respectively) in
predicting infectious morbidity, but both had good predic-
tive accuracy when abnormal (66.7% and 52.9%, respectively)
[117]. Neither amniocentesis [118] nor endovaginal ultrasounds
[119] decrease neonatal death. A Cochrane review reports that
there is insufficient evidence to draw clear conclusions for ante-
natal testing in PPROM from the existing evidence [120]. Expert
opinion varies greatly between countries; in the United States
inpatient antenatal fetal monitoring of women with PPROM
between 23 and 33 6/7 weeks is recommended, including
CTG 2–3 times daily. Delivery is indicated usually once 34
weeks is reached, but newest evidence may allow expectant
management up to 37 weeks (see Chapter 20, Obstetric Evidence
Based Guidelines).
Pregnancy at 39 weeks
Compelling data has emerged indicating that prolonging preg-
nancy past 39 weeks’ gestation is not beneficial. The ARRIVE trial
compared induction of labor (in low risk pregnancies) at 39 weeks
with expectant management and showed a 20% non-significant
difference in perinatal death or severe neonatal complications
(RR 0.8, 95% CI 0.64–1.00) with an absolute decrease in cesar-
ean delivery of approximately 4% (RR 0.84, 95% CI 0.76–0.93)
[121]. Meta-analyses have come to similar conclusions [122, 123].
Delivery, therefore, can be considered at 39 weeks. If patients
chose to continue their pregnancies, additional testing should be
considered starting at least by 41 0/7 with weekly CTG/MVP and
twice weekly at 42 0/7 [124]. Fetal monitoring may need to start
at 40 weeks as admission and delivery outcomes for pregnancies
being monitored at 40 and 41 weeks’ gestation were the same [125]
(see Chapters 22 and 23, Obstetric Evidence Based Guidelines).
Fetal anemia
MCA Doppler velocimetry is effective in determining the need
for fetal transfusion, the timing between transfusions, and in dif-
ferentiating degrees of fetal anemia [126]. However, since there
is a 1–10% failure rate in detecting severe anemia, and a higher
rate of missing mild anemia (which may progress rapidly) [127],
MCA should form the core of a comprehensive approach that also
includes fetal blood sampling by cordocentesis, and an experienced
team familiar with fetal hematology (see Chapter 55) [128, 129].
Non-obstetric procedure monitoring
Before the locally accepted viable gestational age (currently
about 23 weeks in the United States), fetal heart tones should be
obtained before and after the procedure. When the fetus is consid-
ered viable, the decision to monitor fetal heart tones continuously
Antepartum Testing
throughout the case should be made on a case-by-case basis. If
continuous intraoperative CTG is to be performed, there should
at least be a skilled obstetrical provider available to perform an
emergent cesarean section, and the non-obstetrical procedure
taking place should be able to be stopped in order for delivery to
be performed. Postoperative CTG should be considered in proce-
dures that might increase the risk of preterm labor [130].
Practical antenatal testing: Who,
when, how, and why?
Table 58.9 summarizes our recommendations. No trial has
conclusively proven that antenatal testing lowers long-term
adverse neurologic outcomes, so recommendations might be
rated as Level B or even C (i.e., consensus, expert opinion, but
no clear evidence). The standard of care, accordingly, can only
be a suggestion, and probably varies considerably from region to
region [131].
Thresholds for viability, knowledge of the disease process,
severity of individual cases, and past history all may indicate
starting monitoring earlier than recommended by general guide-
lines (32–34 weeks for most at-risk fetuses, according to ACOG).
Routine application of testing methods such as NST or UA
Doppler alone, pose substantial risk of iatrogenic prematurity
in fetuses with abnormal testing—a blanket proposal of “testing
early and testing often” is potentially more dangerous than help-
ful. Testing should be timed in recognition of the characteristics
of the test and the fetus.
The choice of test is determined not only by specific condition-
related advantages above, but also by available personnel and
equipment, cost, availability of effective treatment for abnormal
results, and evidence of outcome impact of the management pro-
tocol (Table 56.9). Testing interval will depend on severity (e.g.,
up to 3 times daily or even continuous in FGR fetuses with the
worst UA Doppler pattern).
Last, one should remember that the goal of antenatal fetal test-
ing is to decrease perinatal morbidity and mortality. Many other
interventions (e.g. smoking cessation for smokers, euglycemia
for diabetics) can help achieve the same goal of better perinatal
health, and should be implemented aggressively to complement
antenatal fetal testing.
References
1. Olesen AG, Svare JA. Decreased fetal movements: background, assessment,
and clinical management. Acta Obstet Gynecol Scand 2004;83(9):818–826.
[III; Review]
2. Grant A, Chalmers I. Randomized trial of fetal movement counting. Lancet
1982;2(8296):501. [I; RCT, n = 68,000]
3. Norman JE, Heazell AEP, Rodriquez A, et al. Awareness of fetal movements
and care package to reduce fetal mortality (AFFIRM): a stepped wedge,
cluster-randomised trial. Lancet 2018;392(10158):1629–1638. [I; RCT, n =
409,175]
4. Akselsson A, Lindgren H, Georgsson S, et al. Mindfetalness to increase
women’s awareness of fetal movements and pregnancy outcomes: a
cluster-randomised controlled trial including 39,865 women. BJOG
2020;127(7)829–837. [I]
5. Bellussi F, Po’ G, Livi A, et al. Fetal movement counting and perina-
tal mortality: a systematic review and meta-analysis. Obstet-Gynecol
2020;135(2):452–462. [I; 5 RCT, n = 468,601]
6. Mangesi L, Hofmeyr GJ, Smith V, Smyth RMD. Fetal movement counting
for assessment of fetal wellbeing. Cochrane Database Syst Rev 2015;10:
CD004909. [I; Meta-analysis; 5 RCTs, n = 71,458]
7. Liston R, Sawchuck D, Young D. Fetal health surveillance: antepartum and
intrapartum consensus guideline. J Obstet Gynaecol Can 2007;29(Suppl
4):S3–S56. [III]
585
8. Bishop EH. Fetal acceleration test. Am J Obstet Gynecol 1981;141:905–909.
[II]
9. Lavin JP Jr., Miodovnik M, Barden TP. Relationship of nonstress test reac-
tivity and gestational age. Obstet Gynecol 1984;63: 338–344. [II-3]
10. Druzin ML, Fox A, Kogut E, Carlson C. The relationship of the nonstress
test to gestational age. Am J Obstet Gynecol 1985;153:386–389. [III]
11. Cousins LM, Poeltler DM, Faron S, et al. Nonstress testing at ≤ 32.0 weeks’
gestation: a randomized trial comparing different assessment criteria. Am J
Obstet Gynecol 2012;207:311. [I]
12. Glantz JC, Bertoia N. Preterm nonstress testing: 10-beat compared with
15-beat criteria. Obstet Gynecol 2011;118:87–93. [II-3]
13. Macones GA, Hankins GD, Spong CY, et al. The 2008 national institute of
child health and human development worksheet on electronic fetal moni-
toring: update on definitions, interpretation, and research guidelines. J
Obstet Neonatal Nurs 2008;37(5): 510–515. [III]
14. Snijders RJ, McLaren R, Nicolaides KH. Computer-assisted analysis of fetal
heart rate patterns at 20-41 week’s gestation. Fetal Diagn Ther 1990;5(2):
79–83. [II-2]
15. Park MI, Hwang JH, Cha KJ, et al. Computerized analysis of fetal heart rate
parameters by gestational age. Int J Gynaecol Obstet 2001;74(2):157–164.
[II-2]
16. Manning FA. The fetal heart rate. In: Fetal Medicine: Principles and
Practice. Norwalk, CT: Appleton & Lange, 1995:13–111. [III; Review]
17. Visser GH, Sadovsky G, Nicolaides KH. Antepartum heart rate patterns in
small-for-gestational-age third-trimester fetuses: correlations with blood
gas values obtained at cordocentesis. Am J Obstet Gynecol 1990;162(3):
698–702. [II-2; Case control study of fetal heart rate patterns correlated
with cordocentesis-derived blood gas values]
18. Manning FA, Lange IR, Morrison I, et al. Fetal biophysical profile score and
the nonstress test: a comparative trial. Obstet Gynecol 1984;326–331. [I;
RCT]
19. Keane MW, Horger EO III, Vice L. Comparative study of stressed and non-
stressed antepartum fetal heart rate testing. Obstet Gynecol 1981;57(3):
320–324. [II-1; Sequential testing used each high-risk fetus (n = 566) as its
own control. Only 24.8% of nonreactive NST had positive CST]
20. Grivell RM, Alfirevic Z, Gyte GM, et al. Antenatal cardiotocography for
fetal assessment. Cochrane Database Syst Rev 2015;9:CD007863. [I; Meta-
analysis; 6 RCTs, n = 2105]
21. Morrison I, Menticoglou S, Manning FA, et al. Comparison of antepartum
results to perinatal outcome. J Matern Fetal Med 1994;3:75–83. [II-2; All
FGR fetuses underwent all tests: NST, BPS, umbilical artery Doppler and
OCT. The best prediction of poor outcome used all tests. NST alone pre-
dicted only 32% of compromised fetuses]
22. Meis PH, Ureda JR, Swain M, et al. Variable decelerations during nonstress
tests are not a sign of fetal compromise. Am J Obstet Gynecol 1986;154:
586–590. [II-3]
23. Anyaegbunam A, Brustman L, Divon M, Langer O. The significance of
antepartum variable decelerations. Am J Obstet Gynecol 1986;155:707–710.
[II-3]
24. Bourgeois FJ, Thiagarajah S, Harbert GM Jr. The significance of fetal
heart rate decelerations during nonstress testing. AM J Obstet Gynecol
1984;150:213–216. [III]
25. Druzin ML, Gratacos J, Keegan KA, Paul RH. Antepartum fetal heart rate
testing. VII. The significance of fetal bradycardia. Am J Obstet Gynecol
1981;139:194–198. [III]
26. Pazos R, Vuolo K, Aladjem S, et al. Association of spontaneous fetal heart
rate decelerations during antepartum nonstress testing and intrauterine
growth retardation. Am J Obstet Gynecol 1982;144:574–577. [III]
27. Nathan EB, Haberman S, Burgess T, et al. The relationship of maternal posi-
tion to the results of brief nonstress tests: a randomized trial. Am J Obstet
Gynecol 2000;182:1070–1072. [I; RCT, n = 108]
28. Alus M, Okumus H, Mete S, et al. The effects of different maternal positions
on non-stress test: an experimental study. J Clin Nurs 2007;16(3):562–568.
[II-3]
29. Visser GH, Dawes GS, Redman CW. Numerical analysis of the normal
human antenatal fetal heart rate. Br J Obstet Gynaecol 1981;88(8):792–802.
[III; Original development of the system, 196 fetal heart records]
30. Bracero LA, Morgan S, Byrne DW. Comparison of visual and computerized
interpretation of nonstress test results in a randomized controlled trial.
Am J Obstet Gynecol 1999;181(5 pt 1):1254–1258. [I; RCT, n = 410; com-
puterized evaluation of fetal heart rate testing is superior to standard visual
interpretation]
31. INFANT Collaborative Group. Computerised interpretation of fetal heart
rate during labour (INFANT); a randomised controlled trial. Lancet
2017;389(10080):1719–1729. [I; RCT, n = 47,062]
586
32. Turan S, Turan OM, Berg C, et al. Computerized fetal heart rate analy-
sis, Doppler ultrasound and biophysical profile score in the prediction of
acid-base status of growth-restricted fetuses. Ultrasound Obstet Gynecol
2007;30(5):750–756. [II-2]
33. Gagnon R, Patrick J, Foreman J, et al. Stimulation of human fetuses with
sound and vibration. Am J Obstet Gynecol 1986;155 (4):451–484. [II-3;
Development of VAS]
34. Harman CR. Antenatal assessment of fetal status. In: Creasy R, Iams J,
Resnik R, eds. Maternal-Fetal Medicine. 6th ed. Toronto: WB Saunders,
2010. [III; Review]
35. Tan KH, Smyth R, Wei X. Fetal vibroacoustic stimulation for facilitation
of tests of fetal wellbeing. Cochrane Database Syst Rev 2010;1. [I; Meta-
analysis; 12 RCTs, n = 6822]
36. Kamel HS, Makhlouf AM, Youssef AA. Simplified biophysical profile: an
antepartum fetal screening test. Gynecol Obstet Invest 1999;47(4):223–228.
[II-2; Although vibroacoustic stimulation shortened the testing time for
normal results, 67% of the abnormal results were false-alarms]
37. Serafini P, Lindsay MP, Nagey DA, et al. Antepartum fetal heart rate response
to sound stimulation: the acoustic stimulation test. Am J Obstet Gynecol
1984;148(1):41–44. [II-2; Comparative study showed testing efficiency of
VAS, but included 55% false-negative results for prediction of fetal distress]
38. Arabin B, Becker R, Mohnhaupt A, et al. Prediction of fetal distress and
poor outcome in prolonged pregnancy using Doppler ultrasound and fetal
heart rate monitoring combined with stress tests (II). Fetal Diagn Ther
1994;9(1):1–6. [II-2; CTG was the only reliable prediction of acidemia in
post-term pregnancy. Doppler, CST, and OCT were all irrelevant to predict-
ing acidemia, while none were effective in predicting low Apgar scores]
39. Arabin B, Becker R, Mohnhaupt A, et al. Prediction of fetal distress and
poor outcome in intrauterine-growth retardation—a comparison of fetal
heart rate monitoring combined with stress tests and Doppler ultrasound.
Fetal Diagn Ther 1993;8(4):234–240. [II-2; IUGR fetuses (n = 103) were
studied with NST/CST, VAS, and Doppler. The passive tests—Doppler
and NST—were better predictors of adverse outcome. The authors recom-
mended abolishing the stress test]
40. Tan KH, Sabapathy A. Maternal glucose administration for facilitating tests
of fetal wellbeing. Cochrane Database Syst Rev 2012;9:CD003397. [I; Meta-
analysis; 2 RCTs, n = 708]
41. Esin S, Baser E, Cakir C, et al. Chocolate or orange juice for non-reactive
non-stress test (NST) patterns: a randomized prospective controlled study.
JMFNM 2013;26(9):915–919. [I; RCT, n = 180]
42. Tan KH, Sabapathy A, Wei X. Fetal manipulation for facilitating tests of
fetal wellbeing. Cochrane Database Syst Rev 2013;12;CD003396. [I; Meta-
analysis; 4 RCTs, n = 1280]
43. Said H, Gupta S, Vricella L, et al. Effect of ambient light on the time needed
to complete a fetal biophysical profile: A randomized controlled trial. Eur J
Obstet Gynecol Repro Biol 2017;217:59–65. [I; RCT, n = 357, No change in
behavior]
44. Caridi BJ, Bolnick JM, Fletcher BG, et al. Effect of halogen light stimulation
on nonstress testing. Am J Obstet Gynecol 2004;190 (5):1470–1472. [I; RCT
fetal light perception shortens NST time]
45. Nageotte MP, Towers CV, Asrat T, et al. The value of a negative antepar-
tum test: contraction stress test and modified biophysical profile. Obstet
Gynecol 1994;84(2):231–234. [II-1; Controlled study, not randomized. New
surveillance method, modified BPS was compared in a high risk population
to CST. The authors agreed that CST was no longer first line]
46. Manning FA, Platt LD, Sipos L. Antepartum fetal evaluation: development
of a fetal biophysical profile. Am J Obstet Gynecol 1980;136(6):787–795. [II-
1; Blinded study of first clinical BPS application, n = 216]
47. Manning FA, Morrison I, Lange IR, et al. Fetal assessment based on fetal
biophysical profile scoring: experience in 12,620 referred high-risk preg-
nancies. I. Perinatal mortality by frequency and etiology. Am J Obstet
Gynecol 1985;151(3):343–350. [III-3; Combined variables provided best
indication of perinatal mortality]
48. Manning FA, Morrison I, Harman CR, et al. The abnormal fetal biophysical
profile score. V. Predictive accuracy according to score composition. Am J
Obstet Gynecol 1990;162(4):918–924. [III-3; Different adverse outcomes are
predicted better by different combinations of variables. This study included
only fetuses with abnormal scores 131–6/10, 258–4/10, 113–2/10]
49. Chamberlain PF. Later fetal death—has ultrasound a role to play in its pre-
vention? Irish J Med Science 1991;160:251–254. [II-3; Application of bio-
physical profile score in an Irish healthcare region dropped PNM by more
than 60%. Historical/concurrent nonrandomized controls]
50. Baskett TG, Allen AC, Gray JH, et al. Fetal biophysical profile and perina-
tal death. Obstet Gynecol 1987;70:357–360. [II-2; Concurrent controls had
PNM more than double those managed by BPS]
Maternal-Fetal Evidence Based Guidelines
51. Miller DA, Rabello YA, Paul RH. The modified biophysical profile: ante-
partum testing in the 1990s. Am J Obstet Gynecol 1996;174:812–817. [II-2;
Large comparative trial of biophysical methodology demonstrated signifi-
cant difference in outcome of cases managed or not managed by BPS]
52. Platt LD, Walla CA, Paul RH, et al. A prospective trial of the fetal biophysi-
cal profile versus the nonstress tests in the management of high-risk preg-
nancies. Am J Obstet Gynecol 1985;153(6):624–633. [I; RCT; n = 652]
53. Vintzileos AM, Campbell WA, Rodis JF, et al. The relationship between
fetal biophysical assessment, umbilical artery velocimetry and fetal acido-
sis. Obstet Gynecol 1991;77:622–626. [II-3; Clinical study showed BPS was
superior and Doppler added nothing, in detection of fetal acidosis, n = 62]
54. Soothill PW, Ajayi RA, Campbell S, et al. Prediction of morbidity in small
and normally grown fetuses by fetal heart rate variability, biophysical
profile score and umbilical artery Doppler studies. Br J Obstet Gynaecol
1993;100:742–745. [II-3; Prospective longitudinal study of 191 women stud-
ied with all three methods. Doppler discriminated small “sick” fetuses from
small normal fetuses, while the other tests did not]
55. Shalev E, Zalel Y, Weiner E. A comparison of the nonstress test, oxytocin
challenge test, Doppler velocimetry and biophysical profile in predict-
ing umbilical vein pH in growth-retarded fetuses. Int J Gynaecol Obstet
1993;43:15–19. [II-3; Clinical series of 23 IUGR fetuses studied by all meth-
ods. NST, OCT, and BPS all had positive predictive values of 57%, while
Doppler was only 14%]
56. Yoon BH, Romero R, Roh CR, et al. Relationship between the fetal bio-
physical profile score, umbilical artery Doppler velocimetry and fetal
blood acid-base status determined by cordocentesis. Am J Obstet Gynecol
1993;169:1586–1594. [II-2; Interventional cohort study. Doppler and BPS
both had statistically significant association with acidemia and hypercarbia
at cordocentesis, but Doppler scored higher in logistic regression, n = 24]
57. Bardakci M, Balci O, Acar A, et al. Comparison of modified biophysical pro-
file and Doppler ultrasound in predicting the perinatal outcome at or over
36 weeks of gestation. Gynecol Obstet Invest 2010;69(4):245–250. [II]
58. Lalor JG, Fawole B, Alfirevic Z, Devane, D. Biophysical profile for fetal
assessment in high risk pregnancies. Cochrane Database Syst Rev
2008;23(1):CD000038. [I; Meta-analysis]
59. Bocking AD, Harding R. Effects of reduced uterine blood flow in electro-
cortical activity, breathing and skeletal muscle activity in fetal sheep. Am J
Obstet Gynecol 1986;154(3):655–662. [II-1; Controlled study of fetal sheep
model showed increased sensitivity to hypoxia in abolishing FBM as gesta-
tion progresses]
60. Ribbert LS, Nicolaides KH, Visser GH. Prediction of fetal acidaemia in
intrauterine growth retardation: comparison of quantified fetal activity
with biophysical profile score. Br J Obstet Gynecol 1993;100(7):653–656.
[II-2; Comparative trial of multi-variable testing methods]
61. Magann EF, Doherty D, Field K, et al. Biophysical profile with amniotic fluid
volume assessments. Obstet Gynecol 2004;104 (1):5–10. [I; RCT demon-
strates lower false-positive cases, fewer iatrogenic interventions, more accu-
rate depiction of fetal status with single pocket method compared to AFI]
62. Naghan AF, Abdelmoula YA. Amniotic fluid index versus single deep-
est vertical pocket: a meta-analysis of randomized controlled trials. Int J
Gynaecol Obstet 2009;104(3):184–188. [I; Meta-analysis]
63. Manning FA, Morrison I, Lange IR, et al. Fetal biophysical profile scoring:
selective use of the nonstress test. Am J Obstet Gynecol 1987;156(3):709–
712. [II-3]
64. Manning FA, Snijders R, Harman CR, et al. Fetal biophysical profile score.
VI. Correlation with antepartum umbilical venous fetal pH. Am J Obstet
Gynecol 1993;169(4):755–763. [II-2; Multicenter clinical trial demonstrates
close relationship of multi-variable testing to fetal pH determined by ante-
natal cordocentesis, n = 493]
65. Manning FA, Harman CR, Morrison I, et al. Fetal assessment based on
fetal biophysical profile scoring. III. Positive predictive accuracy of the
very abnormal test (biophysical profile score = 0). Am J Obstet Gynecol
1990;162(2):398–402. [II-2; A score of 0/10 is rare (9.2/10,000 tests), but has
100% positive predictive value for death or severe permanent handicap, jus-
tifying immediate delivery]
66. Nageotte MP, Towers CV, Asrat T, et al. Perinatal outcome with the modi-
fied biophysical profile. Am J Obstet Gynecol 1994;170(6):1672–1676. [I;
RCT; clinical trial valuating BPS (NST plus AFI) with randomized back-up
testing (full BPS or CST) for abnormal values. MBPS discrimination well
between adverse outcome (RR 2.0) and IUGR (RR 2.2) and those without
these outcomes. CST was without benefit and led to iatrogenic morbidity
compared to BPS]
67. Phattanachindakun B, Boonyagulsrirung T, Chanprapaph P. The correla-
tion in antepartum fetal test between full fetal biophysical profile (FBP) and
rapid biophysical profile (rBPP). J Med Assoc 2010;93(7):759–764. [II-2]
Antepartum Testing
68. Papadopoulos VG, Decavalas GO, Kondakis XG, et al. Vibroacoustic stimu-
lation in abnormal biophysical profile: verification of facilitation of fetal
well-being. Early Hum Dev 2007;83(3):191–197. [II-3]
69. Manning FA, Morrison I, Harman CR, et al. Fetal assessment based on fetal
biophysical profile scoring: experience in 19,221 referred high-risk preg-
nancies. II. An analysis of false-negative fetal deaths. Am J Obstet Gynecol
1987;157:880. [II-2]
70. Harman CR, Baschat AA. Arterial and venous Dopplers in IUGR. Clin
Obstet Gynecol 2003;46(4):931–946. [III; Review]
71. Baschat AA, Gembruch R, Reiss I, et al. Relationship between arterial
and venous Doppler and perinatal outcome in fetal growth restriction.
Ultrasound Obstet Gynecol 2000;16:407–413. [II-2; Multicenter cohort
study using multivessel Doppler to evaluate severe IUGR. Abnormal venous
patterns denoted the worst outcomes, while prematurity retains a critical
role]
72. Bellotti M, Pennati G, De Gasperi C, et al. Simultaneous measurements of
umbilical venous, fetal hepatic and ductus venosus blood flow in growth-
restricted human fetuses. Am J Obstet Gynecol 2004;190(5):1347–1358.
[II-2; Case-control study depicting the progression of ductal opening and
increased flow as condition deteriorated in 56 IUGR fetuses]
73. Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound
in normal pregnancy. Cochrane Database Syst Rev 2015;4:CD001450.
[I; Meta-analysis; 5 RCTs, n = 14,185]
74. Stampalija T, Gyte GM, Alfirevic Z. Utero-placental Doppler ultra-
sound for improving pregnancy outcome. Cochrane Database Syst Rev
2010;8(9):CD008363. [I; Meta-analysis; 2 RCTs, n = 4993]
75. American College of Obstetricians and Gynecologists’ Committee on
Practice Bulletins-Obstetrics and the Society for Maternal-Fetal Medicine.
ACOG Practice Bulletin No. 204: Fetal Growth Restriction. Obstet Gynecol
2019;133(2):e97–e109. [III; Review]
76. Thompson RS, Trudinger BJ. Doppler waveform pulsatility index and resis-
tance, pressure and flow in the umbilical placental circulation: an investiga-
tion using a mathematical model. Ultrasound Med Biol 1990;16(5):449. [III]
77. Maulik D, Mundy D, Heitmann E, et al. Evidence-based approach to umbili-
cal artery Doppler fetal surveillance in high-risk pregnancies: an update.
Clin Obstet Gynecol 2010;53(4):869–878. [III]
78. Baschat AA, Weiner CP. Umbilical artery Doppler screening for the small
for gestational age fetus in need of antenatal surveillance. Am J Obstet
Gynecol 2000;182:154–158. [II-2; Case-control trial. Umbilical artery
Doppler differentiates small fetuses who do not need intensive surveillance,
from those with serious IUGR]
79. Alfirevic Z, Neilson JP. Doppler ultrasonography in high-risk pregnan-
cies: systemic review with meta-analysis. Am J Obstet Gynecol 1995;
172(5):1379–1387. [I; Meta-analysis; umbilical artery Doppler application
reduces perinatal mortality and critical neonatal impacts in IUGR and
pre-eclampsia]
80. Divon MY. Randomized control trials of umbilical artery Doppler velocim-
etry: how many are too many? Ultrasound Obstet Gynecol 1995;6:377–379.
[III; Review]
81. Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound
in high-risk pregnancies. Cochrane Database Syst Rev 2017;6:CD007529.
[I; Meta-analysis; 19 RCTs, n = 10,667]
82. SMFM, Berkley, E, et al. Doppler assessment of the fetus with intrauter-
ine growth restriction. Am J Obstet Gynecol 2012;206(4):300–308. [III;
Review]
83. Nelson KB. The epidemiology of cerebral palsy in term infants. Ment Retard
Dev Disabil Res Rev 2002;8(3):146–150. [III; Review]
84. Goffinet F, Paril-Llado J, Nisand I, et al. Umbilical artery Doppler velocim-
etry in unselected and low risk pregnancies: a review of randomized con-
trolled trials. Br J Obstet Gynaecol 1997;104:425–430. [III; Review]
85. Divon MY, Girz BA, Lieblich R, et al. Clinical management of the fetus
with markedly diminished umbilical artery end-diastolic flow. Am J Obstet
Gynecol 1989;161(6 pt 1):1523–1527. [II-2; Case control study of 51 fetuses
with severe elevation of umbilical artery resistance. Immediate delivery may
not be necessary. Combined surveillance can safely prolong the pregnancy]
86. Thorton JG, Hornbuckle J, Vail A, et al. Infant wellbeing at 2 years of age in
the Growth Restriction Invervention Trial (GRIT): multicentered random-
ized controlled trial. Lancet 2004;364(9433):513–520. [I]
87. GRIT study group. A randomized trial of timed delivery for the compro-
mised preterm fetus: short term outcomes and Bayesian interpretation. Br J
Obstet Gynecol 2003;110(1):27–32. [I; Multicenter RCT]
88. Meher S, Hernandez-Andrade E, Basheer SN, Lees C. Impact of cerebral
redistribution on neurodevelopmental outcomes in small-for-gestational-
age or growth-restricted babies: a systematic review. Ultrasound Obstet
Gynecol 2015;46(4): 398–404. [III; Review]
587
89. Bligh LN, Alsolai AA, Greer RM, Kumar S. Cerebroplacental ratio thresh-
olds measured within 2 weeks before birth and risk of cesarean section for
intrapartum fetal compromise and adverse neonatal outcome. Ultrasound
Obstet Gynecol 2018;52(3):340–346. [II-2; n = 483, CPR 10 th percentile
threshold could be used for risk assessment for Cesarean section]
90. Bakalis S, Akolekar R, Gallo DM, et al. Umbilical and fetal middle cerebral
artery Doppler at 30-34 weeks’ gestation in the prediction of adverse peri-
natal outcome. Ultrasound Obstet Gynecol 2015;45(4);409–420. [II-3]
91. DeVore GR. The importance of the cerebroplacental ratio in the evalu-
ation of fetal well-being in SGA and AGA fetuses. Am J Obsete Gynecol
2015;213(1):5–15. [III]
92. Baschat AA, Gembruch U, Weiner CP, et al. Qualitative venous Doppler
waveform analysis improves prediction of critical perinatal outcomes
in premature growth-restricted fetuses. Ultrasound Obstet Gynecol
2003;22(3):240–245. [II-2; Cohort study demonstrates combined arterial
and venous Doppler maximized prediction of critical outcomes, n = 224]
93. Baschat AA, Cosmi E, Bilardo CM, et al. Predictors of neonatal outcome
in early-onset placental dysfunction. Obstet Gynecol 2007;109(2 pt 1):253–
261. [II-2]
94. Turan OM, Turan S, Berg C, et al. The duration of persistent abnormal
ductus venosus flow and its impact on perinatal outcome in fetal growth
restriction. Ultrasound Obstet Gynecol 2011;38:295–302. [II-2 Multicenter
Study of FGR. Secondary analysis of 175 FGR fetuses with DV abnormality
demonstrates that the duration of a-wave reversal is the factor predictive of
stillbirth.]
95. Lees CC, Marlow N, van Wassenaer-Leemhuis, et al. 2 year neurodevel-
opmental and intermediate perinatal outcomes in infants with very pre-
term fetal growth restriction (TRUFFLE): a randomised trial. Lancet
2015;385(9983):2162–2172. [I]
96. Baschat AA, Harman CR. Discordance of arterial and venous flow velocity
waveforms in severe placenta-based fetal growth restriction. Ultrasound
Obstet Gynecol 2011;37(3):369–370. [II-3]
97. Baschat AA, Galan HL, Bhide A, et al. Doppler and biophysical assessment
in growth restricted fetuses: distribution of test results. Ultrasound Obstet
Gynecol 2006;27(1):41–47. [II-1; Multicenter study of combined Doppler
and biophysical profile in IUGR suggests both should be used to maximize
gestational age, n = 38]
98. Baschat AA, Gembruch U, Harman CR. The sequence of changes in Doppler
and biophysical parameters as severe fetal growth restriction worsens.
Ultrasound Obstet Gynecol 2001;18:571–577. [II-2]
99. Cosmi E, Ambrosini G, D’Antona D, et al. Doppler, cardiotocography, and
biophysical profile changes in growth-restricted fetuses. Obstet Gynecol
2005;106(6):1240–1245. [II-2]
100. Tyrrel SN, Lilford RJ, MacDonald HN, et al. Randomized comparison of
routine vs. highly selective use of Doppler ultrasound and biophysical
profile scoring to investigate high risk pregnancies. Br J Obstet Gynaecol
1990;97(10):909–916. [I; RCT demonstrating combined Doppler and BPS
reduced neonatal morbidity by directing intervention, but did not increase
iatrogenic prematurity, n = 500]
101. Habek D, Hodek B, Herman R, et al. Fetal biophysical profile and cerebro-
umbilical ratio in assessment of perinatal outcome in growth-restricted
fetuses. Fetal Diagn Ther 2003;18(1):12–16. [II-2; Clinical trial demon-
strated the complimentary positive predictive values of biophysical profile
and Doppler, n = 87 FGR fetuses]
102. Williams KP, Farwuharson DF, Bebbington M, et al. Screening for fetal well-
being in a high-risk pregnant population comparing the nonstress test with
umbilical artery Doppler velocimetry: a randomized controlled clinical trial.
Am J Obstet Gynecol 2003;188(5):1366–1371. [I; RCT; Randomized “high-
risk” patients, beyond 32 weeks, to umbilical artery Doppler or nonstress
testing as primary monitoring, amniotic fluid volume as secondary test]
103. Baschat AA, Viscardi RM, Hussey-Gardner B, et al. Infant neurodevelop-
ment following fetal growth restriction: relationship with antepartum sur-
veillance parameters. Ultrasound Obstet Gynecol 2009;33(1):44–50. [II-3]
104. Practice bulletin no. 145: antepartum fetal surveillance. Reaffirmed 2019.
Obstet Gynecol 2014;124(1):182–192. [III; Review]
105. Graves CR. Antepartum fetal surveillance and timing of delivery in
the pregnancy complicated by diabetes mellitus. Clin Obstet Gynecol
2007;50(4):1007–1013. [II-2]
106. Zisser HC, Biersmith MA, Jovanovic LB, et al. Fetal risk assessment in
pregnancies complicated by diabetes mellitus. J Diabetes Sci Technol
2010;4(6):1368–1373. [II-3]
107. Maulik D, Lysikiewicz A, Sicuranaza G. Umbilical arterial Doppler sonog-
raphy for fetal surveillance in pregnancies complicated by pregestational
diabetes mellitus. J Matern Fetal Neonatal Med 2002;12(6):417–422. [III;
Review]
588
108. Harman CR, Menticoglou SM. Fetal surveillance in diabetic pregnancy.
Curr Opin Obstet Gynecol 1997;9(2):83–90. [III; Review]
109. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet
Gynecol 2018;131(2):e49–e64. [III; Review]
110. Alfirevic Z, Stampalija T, Dowswell, T. Fetal and umbilical Doppler ultra-
sound in high-risk pregnancies. Cochrane Database Syst 2017;6:CD007529.
[I; Meta-analysis; 19 studies, n = 10,667]
111. Rath W, Wolff F. Increased risk of stillbirth in older mothers—a ratio-
nale for induction of labour before term? Z Geburtshife Neonatol
2014;218(5):190–194. [III]
112. Walker KF, Bugg GJ, Macpherson M, et al. Randomized Trial of
Labor Induction in Women 35 Years of Age or Older. N Engl J Med
2016;374(9):813–822. [I; n = 619, Cesarean section RR 0.99, CI 0.81–1.14]
113. Davies GA, Maxwell C, McLeod L, et al. Obesity in pregnancy. J Obstet
Gynaecol Can 2010;32(2):165–173. [II-3]
114. Ehrenberg HM, Mercer BM, Catalano PM. The influence of obesity
and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol
2004;191(3):964–968. [II-2]
115. Chu SY, Kim SY, Lau J, et al. Maternal obesity and risk of stillbirth: a meta-
analysis. Am J Obstet Gynecol 2007;197(3):223–228. [I; Meta-analysis]
116. Vintzileos AM, Bors-Koefoed R, Pelegano JF, et al. The use of fetal biophysi-
cal profile improves pregnancy outcome in premature rupture of the mem-
branes. Am J Obstet Gynecol 1987;157(2):236–240. [II-2]
117. Lewis DF, Adair CD, Weeks JW, et al. A randomized clinical trial of
daily nonstress testing versus biophysical profile in the management
of preterm premature rupture of membranes. Am J Obstet Gynecol
1999;181(6):1495–1499. [I; RCT of two schemes of monitoring patients after
PPROM. Both NST and BPS had good specificity, but detected less than half
the babies who developed infectious complications]
118. Cotton DB, Gonik B, Bottoms SF. Conservative vs aggressive management
of preterm rupture of membranes. A randomized trial of amniocentesis.
Am J Perinatol 1984;1:322–324. [I]
119. Carlan SJ, Richmond LB, O’Brien WF. Randomized trial of endovaginal
ultrasound in preterm premature rupture of membranes. Obstet Gynecol
1997;89(3):458–461. [I]
120. Sharp GC, Stock SJ, Norman JE. Fetal assessment methods for improv-
ing neonatal and maternal outcomes in preterm prelabour rupture
Maternal-Fetal Evidence Based Guidelines
of membranes. Cochrane Database Syst Rev 2014;3:10:CD010209. [I;
Meta-analysis]
121. Grobman WA, Rice MM, Reddy UM, et al. Labor induction versus
expectant management in low-risk nulliparous women. N Engl J Med
2018;379(6):513–523. [I, n=3062]
122. Grobman WA, Caughey AB. Elective induction of labor at 39 weeks com-
pared with expectant management: a meta-analysis of cohort studies. Am J
Obstet Gynecol 2019;221(4):304–310. [I, 6 studies, n = 66,019]
123. Sotiriadis, A, Petousis S, Thilaganathan B, et al. Maternal and perina-
tal outcomes after elective induction of labor at 39 weeks in uncompli-
cated singleton pregnancy: a meta-analysis. Ultrasound Obstet Gynecol
2019;53(1):26–35. [I, 5 studies, n = 7261]
124. Clinical Practice Obsetrics Committee; Maternal Fetal Medicine
Committee, Delaney M, Roggensack A, Leduc DC, et al. Guidelines for the
management of pregnancy at 41+0 to 42+0 weeks. J Obstet Gynaecol Can
2008;30(9):800–823. [III]
125. Mackeen AD, Edelson PK, Wisch S, et al. Antenatal testing in uncom-
plicated pregnancies: should testing be initiated after 40 or 41 weeks? J.
Perinat Med 2015;43(2): 233–237. [II-2]
126. Mari G. Middle cerebral artery peak systemic velocity: is it the standard of
care for the diagnosis of fetal anemia? J Ultrasound Med 2005;24(5):697–
702. [III; Review]
127. Divakaran TG, Waugh J, Clark TJ, et al. Noninvasive techniques to detect
fetal anemia due to red blood cell alloimmunization: a systemic review.
Obstet Gynecol 2001;98(3):509–517. [I; Meta-analysis suggests MCA
Doppler lacks precision and the studies are incomplete]
128. Illanes S, Soothill P. Management of red cell alloimmunisation in
pregnancy: the non-invasive monitoring of the disease. Prenat Diagn
2010;30(7):668–673. [III; Review]
129. Mari G, Norton ME, Stone J, et al. Society for Maternal-Fetal Medicine
(SMFM) Clinical Guideline #8: the fetus at risk of anemia—diagnosis and
management. Am J Obstet Gynecol 2015;212(6):697–701. [III; Review]
130. ACOG Committee Opinion No. 775: Nonobstetric surgery during preg-
nancy. Obstet Gynecol 2019;133(4):844–845. [III; Review]
131. Unterscheider J, Daly S, Geary MP, Kennelly MM, et al. Definition and man-
agement of fetal growth restriction: a survey of contemporary attitudes. Eur
J Obstet Gynecol Reprod Biol 2014;174:41–5. [III]
59
SONOGRAPHIC ASSESSMENT OF AMNIOTIC FLUID
Oligohydramnios and Polyhydramnios
Ariel T. Levy
Amniotic fluid assessment in
singleton pregnancies
Key points
• Ultrasound estimates of amniotic fluid volume (AFV) cor-
relate poorly with reference standards (dye-determined or
directly measured) when AFV is abnormal (oligohydram-
nios and polyhydramnios).
• The maximum vertical pocket (MVP), also called at
times single deepest pocket (SDP), is the best ultrasound
technique to diagnose oligohydramnios (MVP < 2 cm)
in both singleton and twin gestations since the amniotic
fluid index (AFI) leads to overdiagnosis, resulting in more
unnecessary inductions and cesarean deliveries without
concomitant neonatal benefit.
• AFI (preferred) or MVP are both acceptable methods
to diagnose polyhydramnios. However, MVP may lead to
overdiagnosis of polyhydramnios when compared to AFI
measurement, without specific benefits. Therefore, AFI is
currently preferred for the diagnosis of polyhydramnios.
Background
• The primary component of amniotic fluid (AF) in the sec-
ond half of pregnancy is fetal urine. Key embryologic time
points relating to urine production include:
• 8–9 weeks: Urethra patent.
• 18 weeks: About 50–100 cc of urine produced per day.
• At term: 800 cc of urine produced per day, or 5 cc/kg/hour
• After 40 weeks: AFV declines by 8% each week [1].
• Fetuses swallow half of their AF per day (about 0.5 L/day
at term).
• Lungs also produce and absorb AF. Other systems involved
include skin, saliva/nasal, membranes/placenta/cord.
• The fetus with in utero placental insufficiency will shunt
blood flow to the brain, heart, and adrenal glands at the
expense of the rest of the organ systems, including the kid-
neys. Inadequate renal perfusion will result in decreased
urinary output and oligohydramnios.
Indications
Measurement of AFV is a standard component of all second- and
third-trimester ultrasounds. In addition, AFV can be particularly
helpful in the assessment of the following:
• Evidence of fetal anomalies (e.g., urinary obstruction or
dysfunction).
DOI: 10.1201/9781003099062-59
• Severe fetal growth restriction (FGR), which is commonly
associated with fetal aneuploidy.
• Assist in the confirmation of preterm premature rupture of
fetal membranes (PPROM).
• Assessment of fetal well-being when used along with
the non-stress test (NST) or with the other components
of the biophysical profile (BPP) in pregnancies in the late
second and third trimester that are at-risk for adverse
outcomes.
Techniques
AFV can be precisely measured antenatally by a dye-dilution
technique (the dye marker is placed into the uterine cavity by
amniocentesis) and directly at the time of cesarean delivery.
However, these measurement techniques are invasive, time
consuming, require laboratory support, and if measured at time
of cesarean, can only be done at the time of delivery. Because
of these limitations, the AFV is estimated antenatally via
ultrasound.
The following are three ultrasound methods of estimating
AFV and identifying abnormalities of fluid:
• The subjective assessment evaluates the AFV without
measurements and labels the observed volume as low, nor-
mal, or high. It is usually done at the time of the second
trimester ultrasound, between 16 and 24 weeks [2].
• The AFI divides the abdomen into four quadrants and
measures the deepest pockets of fluid without fetal small
parts or cord in each and sums the measurements [3]. AFI
≤ 5.0 cm is labeled as oligohydramnios, 5.1 cm to 24.9 cm
as normal, and ≥ 25 cm as polyhydramnios [4]. The AFI can
also be evaluated by gestational age (GA)-specific charts
that label AFV as oligohydramnios (< 5th percentile), nor-
mal (5th–95th percentile), and polyhydramnios (> 95th
percentile) [5, 6].
• The maximum vertical pocket (MVP), also called single
deepest pocket (SDP), identifies the deepest vertical pocket
of fluid that has a horizontal measurement of at least 1 cm
and is without cord or fetal small parts [7]. MVP ≤ 2 cm is
consistent with oligohydramnios, 2.1 cm to 7.9 cm is nor-
mal, and ≥ 8 cm is considered polyhydramnios.
Originally, the pocket of fluid was measured if it did not have
an aggregate of cord or small parts [4]. There is a significantly
greater number of low dye-determined AFVs identified using
the “to the cord” measurement technique rather than “through
the cord” without any difference for normal and high dye-deter-
mined volumes [8]. Therefore, the “to the cord” measurement is
recommended.
589
590
Use of color Doppler to estimate AFV
Color Doppler has been suggested to increase the detection of
oligohydramnios by identifying pockets of fluid containing the
umbilical cord that would otherwise not be detected by gray-scale.
Both the measurements of the AFI and the MVP are decreased
by approximately 20% with the use of color Doppler compared
with gray-scale [9–11]. In a study comparing color Doppler versus
gray-scale to determine if the color Doppler identified more dye-­
determined oligohydramnios than gray-scale, color Doppler not
only did not identify any more dye-determined oligohydramnios,
but also labeled 21% of normal pregnancies as having oligohy-
dramnios [10]. Because of the overdiagnosis of oligohydramnios
and because its use has not been shown to correlate with improved
peripartum outcomes, the routine use of color Doppler cannot
be recommended in ultrasound estimates of AFV.
Accuracy of ultrasound in assessing AFV
When compared to direct measurements at the time of cesarean
delivery or dye-determined fluid volumes, all three of the ultra-
sound techniques used to estimate AFV (subjective evalua-
tion, AFI, and MVP) can accurately identify normal volumes
but poorly identify oligohydramnios and polyhydramnios
[12]. Although the subjective estimation of AFV is as accurate
as the AFI and MVP in the identification of dye-determined low,
normal, and high AFVs [2], nearly all ultrasound evaluation and
studies use either the AFI or the MVP technique.
The cumulative world’s literature shows that the association
between ultrasound measurements and actual volume is good
when normal (sensitivity of 70–98%), but in the clinically con-
cerning area of oligohydramnios and polyhydramnios, the asso-
ciation between an ultrasound-estimated AFV and the actual
volume is poor with sensitivities of 6–18% [2, 12–20] and 23–83%
[12, 19, 21, 22], respectively. A comparison of the third and fifth
percentiles of the AFI and MVP adjusted for GA and the fixed
cutoffs of an AFI of ≤ 5 cm and the MVP of ≤ 2 cm, all com-
pared to actual AFVs, showed that the percentiles were no bet-
ter predictors of actual oligohydramnios or polyhydramnios [21].
Additionally, the normal values and percentiles for one specific
patient population aren’t generalizable to other patient popula-
tions; therefore, if percentiles are used, then population-specific
normative values should be established [5, 6].
Accuracy of the ultrasound estimates of
AFV to predict pregnancy outcomes
The role of the AFI in classifying a pregnancy as high risk on
antenatal testing remains uncertain. Prior research has suggested
that an AFI of ≤ 5 cm is associated with an increased risk of non-
reassuring fetal heart tracing (NRFHT) in labor, meconium-
stained AF, cesarean delivery for NRFHT, and low Apgar scores at
1 and 5 minutes [4, 23]. However, some investigators have found
no association with an AFI ≤ 5 cm and adverse pregnancy out-
comes [24, 25]. Among diabetic patients specifically, low AFV is
not associated with cesarean delivery for NRFHT [26].
In postdate pregnancies and other high-risk pregnancies, when
comparing MVP with AFI, use of AFI labels more pregnan-
cies as having oligohydramnios (relative risk – RR 2.39, 95% CI
1.73–3.28), resulting in more labor inductions (RR 1.92; 95%
CI 1.50–2.46) and subsequent cesarean deliveries for NRFHT
(RR 1.46; 95% CI 1.08–1.96), without a concomitant decrease
Maternal-Fetal Evidence Based Guidelines
in the likelihood of admission to neonatal intensive care unit
(RR 1.04; 95% CI 0.85, 1.26) or in umbilical arterial pH < 7.10
(RR 1.10; 95% CI 0.74, 1.65) [27]. Similar results were also found
in low-risk pregnancies in the SAFE Trial, a multicenter random-
ized controlled study that assessed differences in perinatal out-
comes when using AFI versus MVP [28].
Cesarean deliveries for NRFHT and Apgar scores of < 7 at
5 minutes occurs in a significantly greater number of women
if the AFI is ≤ 5 cm compared to controls [29]. Both the Apgar
score < 7 at 5 minutes and cesarean delivery for NRFHT are sub-
jective evaluations and can be influenced by a number of factors.
The most objective assessment, umbilical arterial pH, has not
been linked with an AFI ≤ 5.0 cm [28–29]. The above findings
were confirmed in a meta-analysis that included 43 studies and
over 244,490 fetuses [30]. Additionally, as intrapartum screening
tests, neither AFI nor MVP are found to be good predictors of
adverse intrapartum outcomes [31].
Do we estimate AFV with
the MVP or the AFI?
The AFI has been compared with the MVP as a component of the
BPP (fetal movement, fetal tone, fetal breathing movement, NST,
and AFV estimation) and the modified BPP (NST + AFV estima-
tion) in the antepartum evaluation of at-risk pregnancies, as well as
a fetal admission test. In low AFV, both fluid estimations have been
linked with fetal intolerance of labor, cesarean deliveries for NRFHT,
and low Apgar scores; however, only the MVP as a component of
the BPP has been correlated with the umbilical cord pH [32]. As
a stand-alone test, the MVP has also been linked with perina-
tal morbidity and mortality [33], while AFI alone has never been
evaluated for this outcome. Additionally, MVP, as a component of the
BPP, has been linked to cerebral palsy [34], but no investigations have
evaluated this relationship with AFI alone or AFI with NST. A low
BPP is associated with antenatal asphyxial events, and may be of use
in selected pregnancies to prevent poor pregnancy outcomes [35–36].
In high-risk pregnancies monitored using the BPP [37], AFI
and MVP are similar in their ability to predict adverse ante-
partum or intrapartum outcomes; however, AFI diagnoses
twice as many women with low fluid compared to the MVP,
resulting in more interventions without any improvement
in outcome [27]. Similarly, in high-risk pregnancies undergo-
ing modified BPP, more women are labeled as having low fluid
with use of the AFI, leading to more interventions without any
improvement in outcome compared to the MVP [38]. In contrast,
a recent study has suggested that in the setting of high AFV, use
of MVP resulted in a higher rate of misdiagnosis of polyhydram-
nios when compared to AFI (OR 5.5; 95% CI 2.04–14.97) [22].
For these reasons the MVP is the preferred method to esti-
mate low AFV in use with the NST, as part of the BPP, or as a
stand-alone test. However, in the setting of high AFV, MVP may
overcall the diagnosis of polyhydramnios and could therefore
lead to increased intervention when compared to AFI [11, 22].
Future research is needed to explore this association and deter-
mine the implications of increased polyhydramnios diagnoses
when MVP is used as an assessment of AFV.
Management
In pregnancies at-risk for an adverse pregnancy outcome, ante-
natal surveillance can be undertaken with either the NST and
MVP technique or MVP as part of the BPP. If an estimation of
Sonographic Assessment of Amniotic Fluid
the AFV is undertaken on admission to labor and delivery to iden-
tify those pregnancies that will have a greater risk of intrapartum
complications, then the MVP techniques should also be used.
A Cochrane Review (5 trials with 3226 pregnancies), compar-
ing AFI to MVP, showed that there was no improvement in peri-
partum outcomes, such as operative vaginal or cesarean delivery,
Apgar score <7 at 5 minutes, admission to NICU, and umbili-
cal artery pH less than 7.1. The diagnosis of oligohydramnios
is more frequent (RR 2.39; 95% CI 1.73, 3.28) when AFI rather
than MVP is used as well as induction of labor and rate of
cesarean deliveries for fetal distress (RR 1.46; 95% CI 1.08, 1.96)
[27]. Conversely, polyhydramnios is more likely to be inaccu-
rately diagnosed (OR 5.5; 95% CI 2.04–14.97) when MVP rather
than AFI is used [22].
Oligohydramnios
Key points
• Oligohydramnios should be defined as a MVP ≤ 2 cm.
This definition correlates with abnormal neonatal out-
come, with the lowest false-positive rate. Using the AFI
(e.g., < 5th percentile for gestational age or ≤ 5.0 cm) is not
recommended to define oligohydramnios.
• Question the woman regarding possible (P)PROM.
• Document by ultrasound normal fetal kidneys, bladder,
and fetal weight.
• If diagnosed in the second trimester or with severe oli-
gohydramnios (MVP < 1 cm) at any gestational age, and
PPROM is ruled out, consider amniocentesis to assess fetal
karyotype if not previously done.
• Suggest increased maternal oral hydration with 2 L of
water daily.
Approach to management based on gestational age at diagnosis:
• At 16–24 weeks: Consider amniocentesis, if feasible.
• At 28 to < 36 weeks: Perform modified BPP (NST +
MVP) or BPP to assure fetal well-being. If reassuring,
continue weekly or biweekly testing depending on fetal
status.
• At ≥ 36 weeks: Consider induction/delivery with idio-
pathic oligohydramnios and persistent MVP ≤ 2 cm
despite hydration.
• At ≥ 39 weeks: Proceed with induction/delivery.
Diagnosis/Definition
Oligohydramnios should be defined because low AFV is linked
with adverse pregnancy outcomes. Therefore, oligohydramnios
can be defined as an MVP of ≤ 2 cm measured vertically. Severe
oligohydramnios is defined as MVP of < 1 cm. The measured
pocket of fluid should not include umbilical cord or fetal parts
and should measure at least 1 cm horizontally.
Epidemiology/Incidence
The true incidence of oligohydramnios appears to be approxi-
mately 0.2% in the second trimester and 3–5% in the third tri-
mester. The incidence depends on definition, being lower when
defined as MVP ≤ 2 cm.
591
Etiology
Spontaneous rupture of membranes, fetal renal hypofunction or
urinary obstruction, and placental insufficiency with or without
FGR are the most common etiologies. Concomitant fetal anoma-
lies are found in up to 50% of severe oligohydramnios that is diag-
nosed in the second trimester [39].
Complications
Persistent oligohydramnios can lead to structural (i.e., skeletal)
abnormalities and pulmonary hypoplasia [40]. The risk of pul-
monary hypoplasia depends largely on gestational age at diag-
nosis and severity of oligohydramnios. When diagnosed after 26
weeks, the risk of pulmonary hypoplasia is less than 2%; however,
if diagnosed before 24 weeks, the risk increases to 30% [41, 42].
Additionally, in patients with prolonged, severe oligohydramnios,
risk of pulmonary hypoplasia is estimated to be as high as 43%
[43]. The risk of skeletal deformities is over 50% with severe oli-
gohydramnios [43]. Gestational age at diagnosis does not appear
to affect risk of skeletal deformities [41, 43]. Fetal anomalies have
been reported in up to 30% with oligohydramnios in the second
trimester, up to 50% if severe oligohydramnios.
Oligohydramnios, in particular when defined as MVP ≤ 2 cm,
has been associated with FGR, NRFHT, CD for NRFHT, endome-
tritis, etc., but the true natural history is not well-known since
many intervene for oligohydramnios.
There is a significant association between oligohydramnios,
small for gestational age, cord compression, perinatal mortality,
and neonatal death [30, 44]. Isolated oligohydramnios at term
is associated with increased rate of emergency CD for NRFHT,
NICU admission, and meconium aspiration syndrome [44].
Management
Question woman regarding possible (P)PROM, and perform
clinical exam if (P)PROM suspected.
The ultrasound should document normal fetal kidneys, blad-
der, stomach bubble, and fetal weight.
For any oligohydramnios, encourage maternal hydration
with 2 L of water per day.
Transcervical amnioinfusion can be discussed and offered to
women at or near term with oligohydramnios, but data are lim-
ited regarding safety and efficacy.
Approach to management based on gestational age at diagnosis
(Figure 59.1):
• At 16–24 weeks: Consider amniocentesis, if feasible.
Also consider transabdominal amnioinfusion for bet-
ter diagnostic visualization. The role of amnioinfusion as
therapy for pregnancy prolongation and prevention of pul-
monary hypoplasia in women with oligohydramnios but
not ROM has not been tested in a trial.
• At 24–38 weeks: Consider interventions as with oligohy-
dramnios diagnosed at 16 to 24 weeks, if severe oligohy-
dramnios is present and fetal karyotype and anatomy have
not been checked before.
• At 28 to < 36 weeks: Perform modified BPP (NST +
MVP) or BPP to assure fetal well-being. If reassuring, con-
tinue weekly or biweekly testing depending on fetal status.
a. If MVP is > 2 cm on repeat ultrasound, follow with
weekly NST + MVP or BPP.
592 Maternal-Fetal Evidence Based Guidelines

Diagnosis of oligohydramnios (MVP ≤2 cm)a

Gestational ageb

<24 weeks 24 to <36 weeks ≥36 weeks ≥39 weeks

Consider NST+MVP Consider induction Induction and

amniocentesis or BPP and deliveryc deliveryc

Consider
amnioinfusion
for better MVP > 2cm on
visualization repeat U/S

Yes No

Weekly 2x/week
NST+MVP NST + MVP
orBPP or BPP

Abnormal NST,
BPP, or UA
MVP > 2cm MVP ≤ 2cm Dopplers
on U/S x2 on repeat
U/S

Consider induction
Routine and deliveryc
care

FIGURE 59.1 Management of oligohydramnios. Abbreviations: MVP, maximum vertical pocket; U/S, ultrasound; NST, non-stress
test; BPP, biophysical profile; UA, umbilical artery.
a When amniotic membrane is intact and preterm premature rupture of membranes has been ruled out.
b For severe oligohydramnios at any gestational age, should consider amniocentesis if karyotype has not previously been checked.
c Cesarean delivery for obstetrical indications.

b. If MVP ≤ 2 cm, we suggest at least twice weekly NST/ Maternal hydration

AFIs.
c. If MVP is > 2 cm on two consecutive ultrasounds,
return to routine care.
d. Consider delivery only if there are substantial signs of
fetal compromise such as abnormal BPP, UA Doppler
flow, NST, etc.
• At ≥ 36 weeks: Consider induction/delivery with idio-
pathic oligohydramnios and persistent MVP ≤ 2 cm
despite hydration [45].
• At ≥ 39 weeks: Proceed with induction/delivery.
The effects of maternal hydration on the AFV, as estimated by an
increase in the AFI or an increase in fetal urine production, have
been assessed in many randomized trials [46–53]. A 2003 meta-
analysis of four trials with 122 women concluded that hydration
(oral or intravenous) increases AF, as assessed by pre- and
post-hydration AFI [54]. For oral hydration, the women were
asked to drink 2 L of water before having a repeat ultrasound
examination. Maternal hydration in women with and without
oligohydramnios was associated with an increase in amniotic
Sonographic Assessment of Amniotic Fluid
volume (mean difference [MD] for women with oligohydramnios
2.01, 95% CI 1.43–2.60; MD for women with normal AFV 4.50,
95% CI 2.92–6.08). Another randomized trial in pregnancies
complicated by third trimester idiopathic oligohydramnios
found that long-term hydration (6 days) of intravenous iso-
tonic infusion (1500 mL/day) increased the mean AFI from
39.7 to 77.7 mm. Patients were then randomized to home oral
hydration therapy of 1500 or 2500 mL/day and the higher vol-
ume group demonstrated significantly increased amniotic fluid
at delivery compared to the lower volume group (112.45 ± 14.92
versus 86.21 ± 16.89 mm, p < 0.001) [55].
A 2015 meta-analysis confirmed that maternal hydration
(intravenous isotonic, intravenous hypotonic, or oral hypo-
tonic) in patients with isolated oligohydramnios resulted in
a statistically significant increase in AFV [56]. Additionally,
in three of the included studies where hydration resulted in
improvement in AFV, there was an associated reduction in rate
of CD [55–57]. However, due to study heterogeneity, the authors
were unable to determine a definitive effect of maternal hydra-
tion on perinatal outcomes. Thus, oral or intravenous hydration
seems safe and efficacious in increasing AFV, and can be rec-
ommended in women with oligohydramnios; additional stud-
ies are warranted to further assess clinical benefit [54].
Amnioinfusion
If oligohydramnios is diagnosed in the second trimester:
• Transabdominal amnioinfusion can be used for diag-
nostic purposes. Infusion of lactated Ringer’s solution can
increase rate of adequate visualization of fetal structures
from 51% to 77% [58].
If oligohydramnios (without PROM) is detected just before or
in labor when woman is near or at term:
• Transabdominal amnioinfusion reduces NRFHT (from
42% to 5%) and CD for NRFHT (from 25% to 5%) [59].
• Transcervical amnioinfusion of about 500 cc of normal
saline or more as needed in term women with oligohy-
dramnios (usually AFI < 5 cm) decreases CD for NRFHT
by 77%, overall CD by 48%, umbilical artery pH < 7.20
by 60%, NRFHT by 76%, and low Apgar scores < 7 at
5 minutes by 48% [60–62]. The rate of endometritis tended
to be lower with amnioinfusion [60–62]. There is no differ-
ence in outcomes in one RCT between prophylactic versus
therapeutic amnioinfusion [63].
• Given better results and amount of data with this latter
technique, prophylactic transcervical amnioinfusion
can be considered and offered to women at or near term
with oligohydramnios.
Sildenafil citrate
A pilot study from 2017 on the use of oral sildenafil citrate in
patients with isolated oligohydramnios found that there was a
significant increase in AFI in patients receiving sildenafil citrate
plus IV hydration compared to IV hydration alone [64]. However,
in a follow-up placebo-controlled study on the use of sildenafil
in the treatment of patients with early-onset FGR, a dispropor-
tion number of fetal deaths were noted in the intervention group
593
and the study was terminated prior to completion [65]. Therefore,
until future research can ensure the safety of this medication,
the use of sildenafil citrate for treatment of oligohydramnios
should be considered experimental, and not for clinical use.
Polyhydramnios (AKA hydramnios)
Key points
• Polyhydramnios is defined as a AFI ≥ 25 cm (≥ 97.5th
percentile for GA). Another accepted definition of poly-
hydramnios is MVP ≥ 8 cm. Severe polyhydramnios is
defined as a AFI of ≥ 35 cm or MVP ≥ 16 cm.
• Most common etiologies are diabetes and fetal mal-
formation, but 50–60% of polyhydramnios, especially
when mild, is idiopathic.
• Polyhydramnios is associated with higher rates of macro-
somia, malpresentation, cord prolapse, abruption, pri-
mary cesarean delivery, and uterine atony.
• Workup should include (at least) a glucose screening test,
antibody screen, RPR, and detailed fetal anatomy ultra-
sound. Parvovirus, toxoplasmosis, and CMV IgM/IgG can
be included. Amniocentesis should be strongly considered
if there is severe polyhydramnios, polyhydramnios with
fetal anomaly on ultrasound, or polyhydramnios associ-
ated with FGR or detected < 24 weeks.
• Increased antenatal surveillance with NST, BPP,
or serial US and early delivery are not indicated for
patients with idiopathic mild polyhydramnios.
Diagnosis/Definition
AFI ≥ 25 cm, or MVP ≥ 8 cm. Different AFI thresholds, depend-
ing on gestational age, have been proposed. In the third trimester,
an AFI of ≥ 24 cm corresponds to ≥ 95th percentile and an AFI
of ≥ 25 cm corresponds to ≥ 97.5 percentile [66]. Any of these
ultrasound measurements are preferred over subjective measure-
ment. The degree of polyhydramnios can be further classified as
follows [67, 68]:
• Mild polyhydramnios: AFI of 25–29.9 cm or MVP of
8–11 cm
• Moderate polyhydramnios: AFI of 30–34.9 cm or MVP of
12–15 cm
• Severe polyhydramnios: AFI ≥ 35 cm or MVP ≥16 cm
Incidence/Epidemiology
One percent to 5% of singleton pregnancies depending on defini-
tion, but < 1% are complicated by severe polyhydramnios.
Etiology
The cause of polyhydramnios is either excess fetal urine pro-
duction or decreased clearance. The most common etiologies
of polyhydramnios are maternal diabetes or fetal anomalies
that result in defective swallowing (e.g., anencephaly, Dandy
Walker malformation, cleft palate, micrognathia, neurologic
disorders, obstruction of the trachea or gastrointestinal tract,
594 Maternal-Fetal Evidence Based Guidelines

CDH, CCAM). Other fetal causes are: Conditions that causes TABLE 59.1: Fetal Conditions That Are Associated with
high-output cardiac state (e.g., tetralogy of Fallot, aortic coarc- Polyhydramnios
tation, supraventricular tachycardia, complete heart block, thy-
Organ System Ultrasound Findings
rotoxicosis), uteropelvic junction obstruction, Bartter syndrome,
and multifetal gestation (e.g., twin-to-twin transfusion syndrome CNS/Neuro Anencephaly
[TTTS]). Less common etiologies include Rh or other isoim- Holoprosencephaly
munization, congenital infections (e.g., parvovirus, cytomega- Dandy Walker malformation
lovirus, syphilis), and maternal Ballantynes syndrome. In about Lissencephaly
50–60% of cases of polyhydramnios, especially when mild, the Agenesis of corpus callosum
cause is unknown [69, 70]. Severe polyhydramnios is usually Neural tube defects
pathologic. Neuromuscular Arthogryposis
Cardiac Septal defects
Complications Truncus arteriosus
Aortic coarctation
The risk of major anomaly on prenatal ultrasound is 8% with AFI Arch interruption
< 30, 12% with AFI 30–34.9, and 31% with AFI ≥ 35. Risk of major Arrhythmias
anomaly at birth after normal ultrasound is 1% with AFI < 30, Thoracic Congenital diaphragmatic hernia
2% with AFI 30–34.9, 11% with AFI ≥ 35. Additionally, the Congenital cystic adenomatoid malformation
fetus may have a chromosomal abnormality. The risk of aneu- Chylothorax
ploidy is ≤ 1% if normal ultrasound, but approximately 10% if Tracheal atresia
major anomaly is present. Aneuploidies are more common in the Gastrointestinal Cleft lip/palate
setting of fetuses with IUGR than normal or macrosomic fetuses TE fistula
[71]. Detailed ultrasound should detect about 60–80% of major Esophageal or intestinal atresia
anomalies associated with polyhydramnios. Perinatal mortality Imperforate anus
for fetuses with normal anatomy is < 5%. For anomalous fetuses, Abdominal wall defects
the mortality rate is 10–80% depending on the anomaly [72]. Annular pancreas
There is an association between the rate of adverse pregnancy Skeletal Achondroplasia
outcomes and the severity of polyhydramnios, as reflected by the Thanatophoric dysplasia
maximal AFI [69]. Preterm birth (PTB) after preterm labor (PTL) Campomelic dysplasia
or PPROM is increased, especially with severe polyhydramnios. Osteogenesis imperfect
Polyhydramnios is associated with higher rates of macrosomia, Hypophosphatasia
malpresentation, cord prolapse, abruption, primary cesarean Other Multifetal gestation (i.e., TTTS)
delivery and uterine atony. Idiopathic polyhydramnios is linked Cystic hygroma
with fetal macrosomia, fetal labor intolerance, low 5 minute Neck masses
Apgar scores, greater risk for newborn intensive care unit admis- Goiter
sion, and a two to fivefold increase in perinatal mortality [70, Sickle cell trait
73]. In the Cochrane meta-analysis, there was no evidence of an
association between polyhydramnios and birth-weight < 10th Abbreviation: TTTS, twin-to-twin transfusion syndrome.
percentile or < 2500 grams, 1 minute Apgar score < 7, fetal dis-
tress, or neonatal death. However, there was a strong association ultrasound, polyhydramnios associated with IUGR, or
between polyhydramnios and birth-weight > 90th percentile [30]. detected < 24 weeks. Some advocate offering amniocen-
tesis to all women with polyhydramnios given the 0.5–1%
Workup incidence of aneuploidy. If amniocentesis is done, the fol-
lowing should be included:
Evaluation should include: 1. Karyotype and/or microarray. Trisomy 21, trisomy 18,
trisomy 13, and 45, X are the most common aneuploi-
• Fetal ultrasound evaluation for structural anomalies, esti- dies associated with polyhydramnios.
mated growth, presence of hydrops, and TTTS in the set- 2. PCR for parvovirus, CMV, toxoplasmosis, syphilis.
ting of multifetal gestations (Table 59.1). 3. Myotonic dystrophy study if positive family history or
• Umbilical and middle cerebral artery (PI and PSV) Doppler. ultrasound evidence of hypotonia (e.g., clubbed feet or
• Diabetes mellitus screening, if not already done. Can also positional abnormalities of the extremities) [75].
consider repeating testing if more than 4 weeks between 4. Inborn errors of metabolism (e.g., Gaucher, gangliosi-
original screening and diagnosis of polyhydramnios [74]. dosis, mucopolysaccharidoses) testing if positive fam-
• Detailed personal history (e.g., Rh isoimmunization) and ily history or above workup negative in the setting of
family history (e.g., myotonic dystrophy or inborn errors severe polyhydramnios.
of metabolism).
• Laboratory tests should include antibody screen and RPR Labor precautions
(to rule out syphilis).
• Parvovirus IgM and IgG; toxoplasmosis IgM and IgG; For appropriate management to decrease complications from
CMV IgM and IgG. polyhydramnios such as macrosomia, malpresentation, cord pro-
• Strongly consider amniocentesis if severe polyhydram- lapse, abruption, primary cesarean delivery, and uterine atony,
nios, detection of major or minor fetal anomaly on see appropriate chapters. Consider delaying or avoiding artificial
Sonographic Assessment of Amniotic Fluid
rupture of membranes to avoid cord prolapse, or at least “needl­
ing” the membranes.
Management
• Appropriate workup and counseling regarding compli-
cations as above.
• Manage anomaly, aneuploidy, maternal disease, or fetal
condition if detected during workup.
• There is no evidence showing decreased perinatal mortal-
ity with increased antenatal surveillance in patients with
idiopathic mild polyhydramnios. Therefore, use of NST,
BPP, or serial ultrasounds are not required for this indi-
cation [74].
• Tocolysis using indomethacin has been associated
with decreased urine production in the fetus and has
therefore been suggested as a therapeutic approach
to treatment of polyhydramnios [76]. However, due to
the increased risk for neonatal complications with use
of this medication, such as necrotizing enterocolitis
and intraventricular hemorrhage, current guidelines
advise against the use of indomethacin as a treat-
ment for polyhydramnios [74].
Approach based on gestational age diagnosis:
• GA < 24 weeks: Strongly consider amniocentesis.
• GA 24–38 6/7 weeks:
a. Consider amniocentesis, especially if severe polyhy-
dramnios, associated with FGR, or if fetal anomaly is
detected.
b. With moderate polyhydramnios, perform weekly
AFI/MVP with or without NST/BPP and growth ultra-
sound every 3–4 weeks.
c. In patients with severe polyhydramnios manage as
per moderate polyhydramnios. In addition, in patients
reporting symptoms of discomfort or shortness of
breath, can consider amnioreduction. Goal is to nor-
malize AFV. The complication rate is 1.5% and includes
risk of PTL, PPROM, chorioamnionitis, abruption, and
membrane detachment. Risk is increased if > 2 L taken
out at one time.
• GA ≥ 39 weeks: Induction/delivery should be offered to all
patients, but especially in the setting of maternal discom-
fort with moderate or severe polyhydramnios. However,
there is no medical indication for earlier (< 39 weeks)
induction of labor in the setting of mild polyhydram-
nios. Cesarean delivery should be for obstetrical indica-
tions only.
Amniotic fluid assessment
in twin pregnancies
Background
In twin pregnancies, the AFV of each sac is about the same or
slightly exceeds that for normal singleton pregnancies of similar
third trimester GA [77].
Technique
The most consistent method of estimating AFV in twin pregnan-
cies is the MVP technique. The dividing membrane is identified
and the MVP in each amniotic sac is measured. Since the AFVs of
595
twin pregnancies are similar to single pregnancies, the same cat-
egories of oligohydramnios (MVP ≤ 2 cm) and polyhydram-
nios (MVP ≥ 8 cm) can be used.
The summated AFI technique [78, 79], which measures the
sums of the four MVPs without regard to membrane placement
or fetal position, is inaccurate. When compared to the dye dilu-
tion technique in twin pregnancies, AFI has low sensitivity for
inter-twin differences in AFV and does not accurately identify
twin pairs with either oligohydramnios or polyhydramnios [80].
Both subjective and quantitative estimations of AFV in twin
pregnancies tends to falsely diagnose abnormalities when the
AFV is normal [81].
Management of oligohydramnios
and/or polyhydramnios
In dichorionic diamniotic twin pregnancies, workup and man-
agement of either oligohydramnios or polyhydramnios is simi-
lar to singleton gestations. If MVP ≤ 2 cm in one sac and MVP
≥ 8 cm in the other sac are found in a monochorionic gestation,
the diagnosis of TTTS should be considered, with workup and
management covered in Chapter 46.
References
1. Moore TR. The role of amniotic fluid assessment in evaluating fetal well-
being. Clin Perinatol 2011; 38(1):33–46. [Review; III]
2. Magann EF, Perry KG, Chauhan SP, et al. The accuracy of ultrasound evalu-
ation of amniotic fluid volume in singleton pregnancies. The effect of opera-
tor experience and ultrasound interpretive technique. J Clin Ultrasound
1997; 25:249–253. [II-2]
3. Phelan JP, Ahn MO, Smith CV. Amniotic fluid index measurements during
pregnancy. J Reprod Med 1987; 32:601–604. [II-3]
4. Rutherford SE, Smith CV, Phelan JP, et al. The four quadrant assessment of
amniotic fluid volume; an adjunct to antepartum fetal heart rate testing.
Obstet Gynecol 1987; 87:353–356. [II-3]
5. Moore TR, Cayle TE. The amniotic fluid index in normal human pregnancy.
Am J Obstet Gynecol 1990; 162:1168–1173. [II-2]
6. Magann EF, Sanderson M, Martin JN Jr., et al. The amniotic fluid index, sin-
gle deepest pocket, and two-diameter pocket in normal human pregnancy.
Am J Obstet Gynecol 2000; 182:1581–1588. [II-2]
7. Manning FA, Platt LD, Sipos L. Antepartum fetal evaluation: development
of a fetal biophysical profile. Am J Obstet Gynecol 1980; 136:787–795. [II-3]
8. Magann EF, Chauhan SP, Washington W, et al. Ultrasound estimation of
amniotic fluid volume using the largest vertical pocket containing umbili-
cal cord: measure to or through the cord? Ultrasound Obstet Gynecol 2002;
20:464–467. [II-2]
9. Bianco A, Rosen T, Kuczynski E, et al. Measurement of the amniotic fluid
index with and without color Doppler. J Perinat Med 1999; 27:245–249.
[II-2]
10. Magann EF, Chauhan SP, Barrilleaux S, et al. Ultrasound estimate of amni-
otic fluid volume: color Doppler overdiagnosis of oligohydramnios. Obstet
Gynecol 2001; 98:71–74. [II-2]
11. Odibo IN, Whittemore BS, Hughes DS, et al. Addition of color Doppler
sonography for detection of amniotic fluid disturbances and its implica-
tions on perinatal outcomes. J Ultrasound Med 2017; 36:1875–1881. [II-1]
12. Magann EF, Nolan TE, Hess LW. Measurement of amniotic fluid volume:
accuracy of ultrasonography techniques. Am J Obstet Gynecol 1992;
167:1533. [II-2]
13. Croom CS, Banias BB, Ramos-Santos E. Do semiquantitative amniotic fluid
indexes reflect actual volume. Am J Obstet Gynecol 1992; 167:995. [II-2]
14. Dildy GA, Lira N, Moise KJ. Amniotic fluid volume assessment: comparison
of ultrasonographic estimates versus direct measurement with a dye-dilu-
tion technique in human pregnancy. Am J Obstet Gynecol 1992; 167:986.
[II-2]
15. Horsager R, Nathan L, Leveno KJ. Correlation of measured amniotic fluid
volume and sonographic predictions of oligohydramnios. Am J Obstet
Gynecol 1994; 83:955. [II-3]
16. Sepulveda W, Flack NJ, Fisk NM. Direct volume measurement at midtri-
mester amnioinfusion in relation to ultrasonographic indexes of amniotic
fluid volume. Am J Obstet Gynecol 1994; 170:1160–1163. [II-3]
596
17. Magann EF, Morton ML, Nolan TE, et al. Comparative efficacy of two sono-
graphic measurements for the detection of aberrations in the amniotic fluid
volume and the effect of amniotic fluid volume on pregnancy outcome.
Obstet Gynecol 1994; 83:959–962. [II-2]
18. Magann EF, Nevils BD, Chauhan SP, et al. Low amniotic fluid volume is
poorly identified in singleton and twin pregnancies using the 2 × 2 pocket
technique of the biophysical profile. South Med J 1999; 92:802–805. [II-2]
19. Chauhan SP, Magann EF, Morrison JC, et al. Ultrasonographic assess-
ment of amniotic fluid volume does not reflect actual volume. Am J Obstet
Gynecol 1997; 177:291–297. [II-2]
20. Magann EF, Chauhan SP, Martin JN Jr. Oligohydramnios at term and preg-
nancy outcome. Fetal Matern Med Rev 2001; 12:209–227. [II-3]
21. Magann EF, Doherty DA, Chauhan SP, et al. How well do the amniotic fluid
index and single deepest pocket indices (below the 3rd and the 5th and
above the 95th and 97th percentiles) predict oligohydramnios and hydram-
nios? Am J Obstet Gynecol 2004; 190:164–169. [II-2]
22. Hughes DS, Magann EF, Whittington JR, et al. Accuracy of the ultrasound
estimate of the amniotic fluid volume (amniotic fluid index and single deep-
est pocket) to identify actual low, normal, and high amniotic fluid volumes
as determined by quantile regression. J Ultrasound Med 2020; 39:373–378.
[II-3]
23. Miller DA, Rabello YA, Paul RH. The modified biophysical profile: antepar-
tum testing in the 1990s. Am J Obstet Gynecol 1996; 174:812–817. [II-3]
24. Magann EF, Chauhan SP, Kinsella MJ, et al. Antenatal testing among 1001
high risk women: the role of the ultrasonographic estimate of amniotic fluid
volume. Am J Obstet Gynecol 1999; 180:1330–1336. [II-3]
25. Garmel SH, Chelmow D, Sha SJ, et al. Oligohydramnios and the appropri-
ately grown fetus. Am J Perinat 1997; 14:359–363. [II-3]
26. Kjos SL, Leung A, Henry OA, et al. Antepartum surveillance in diabetic
pregnancies: predictors of fetal distress in labor. Am J Obstet Gynecol 1995;
173:1532–1539. [II-2]
27. Nabhan AF, Abdelmoula YA. Amniotic fluid index versus single deepest
vertical pocket as a screening test for preventing adverse pregnancy out-
come. Cochrane Database Syst Rev 2008; (3): CD006593. [Meta-analysis;
5 RCT; n = 3326]
28. Kehl S, Schelkle A, Thomas A, et al. Single deepest vertical pocket or amni-
otic fluid index as evaluation test for predicting adverse pregnancy out-
come (SAFE trial): a multicenter, open-label, randomized controlled trial.
Ultrasound Obstet Gynecol 2016; 47:674–679. [RCT, n = 1002; I]
29. Chauhan SP, Sanderson M, Hendrix NW, et al. Perinatal outcome and
amniotic fluid index in the antepartum and intrapartum periods: a meta-
analysis. Am J Obstet Gynecol 1999; 181:1473–1478. [Meta-analysis; 18
studies, n = 10,551]
30. Morris RK, Meller CH, Tamblyn J, Malin GM, Riley RD, Kilby MD, Robson
SC, Khan KS. Association and prediction of amniotic fluid measurements
for adverse pregnancy outcome: systematic review and meta-analysis.
BJOG 2014; 121(6):686–699. [Meta-analysis; 43 studies, n = 244,493]
31. Moses J, Doherty DA, Magann EF, et al. A randomized clinical trial of the
intrapartum assessment of amniotic fluid volume: amniotic fluid index ver-
sus the single deepest pocket. Am J Obstet Gynecol 2004; 190:1564–1569.
[RCT, n = 1000; I]
32. Manning FA, Harman CR, Morrison I, et al. Fetal assessment based on fetal
biophysical profile scoring IV. An analysis of perinatal morbidity and mor-
tality. Am J Obstet Gynecol 1990; 162:703–709. [II-2]
33. Chamberlain PR, Manning FA, Morrison I, et al. Ultrasound evaluation of
amniotic fluid. I The relationship of marginal and decreased amniotic fluid
volumes to perinatal outcomes. Am J Obstet Gynecol 1984; 150:245–249.
[II-3]
34. Magann EF, Chauhan SP, Bofill JA, et al. Comparability of the amniotic fluid
index and single deepest pocket measurements in clinical practice. Aust N
Z J Obstet Gynaecol 2003; 43:75–77. [II-2]
35. Manning FA, Bondaji N, Harman CR, et al. Fetal assessment based on the
fetal biophysical profile score: relationship of the last BPS result to subse-
quent cerebral palsy. J Gynecol Obstet Biol Reprod 1997; 26:720–729. [II-3]
36. Manning FA, Bondaji N, Harman CR, et al. Fetal assessment based on
fetal biophysical scoring VIII. The incidence of cerebral palsy in tested and
untested perinates. Am J Obstet Gynecol 1998; 178:696–706. [II-2]
37. Magann EF, Doherty DA, Field K, et al. Biophysical profile with amniotic
fluid volume assessments. Obstet Gynecol 2004; 104:5–10. [II-3]
38. Chauhan SP, Doherty DA, Magann EF, et al. Amniotic fluid index vs. single
deepest pocket technique during modified biophysical profile: a randomized
clinical trial. Am J Obstet Gynecol 2004; 191:661–667. [RCT, n = 1080; I]
39. Shipp TD, Bromley B, Pauker S, et al. Outcome of singleton pregnancies
with severe oligohydramnios in the second and third trimesters. Ultrasound
Obstet Gynecol 1996; 7:108–113. [II-2]
Maternal-Fetal Evidence Based Guidelines
40. Scott RJ, Goodburn SF. Potter’s syndrome in the second trimester-­prenatal
screening and pathological findings in 60 cases of oligohydramnios
sequence. Prenat Diagn 1995; 15:519–525. [II-3]
41. Rotschild A, Ling EW, Puterman ML, Farquharson D. Neonatal outcome
after prolonged preterm rupture of membranes. Am J Obstet Gynecol 1990;
162:46–52. [II-2]
42. Kiver V, Boos V, Thomas A, et al. Perinatal outcomes after previable pre-
term premature rupture of membranes before 24 weeks of gestation. J
Perinat Med 2018; 46:555–556. [II-2]
43. Kilbride HW, Yeast J, Thibeault DW. Defining limits of survival: lethal pul-
monary hypoplasia after midtrimester premature rupture of membranes.
Am J Obstet Gynecol 1996; 175:675–681. [II-2]
44. Rabie N, Magann E, Steelman S, Ounpraseuth S. Oligohydramnios in
complicated and uncomplicated pregnancy: a systematic review and meta-
analysis. Ultrasound Obstet Gynecol 2017; 49:442–49. [Meta-analysis; 15
studies, n = 35,593]
45. Spong CY, Mercer BM, D’Alton M, et al. Timing of indicated late-preterm
and early-term birth. Obstet Gynecol 2012; 118:323–333. [III]
46. Kilpatrick SJ, Safford SL. Maternal hydration increases the amniotic fluid
index in women with normal amniotic fluid volume. Obstet Gynecol 1993;
81:49–52. [RCT, n = 40; I]
47. Kilpatrick SJ, Safford SL, Pomeroy T, et al. Maternal hydration increases the
amniotic fluid index. Obstet Gynecol 1991; 78:1098–1102. [RCT, n = 36; I]
48. Doi S, Osada H, Seki K, et al. Effect of maternal hydration on oligohydram-
nios. A comparison of three volume expansion methods. Obstet Gynecol
1998; 92:525–529. [RCT, n = 84; I]
49. Yan-Rosenberg L, Burt B, Bombard AT, et al. A randomized clinical trial
comparing the effect of maternal intravenous hydration and placebo on
the amniotic fluid index in oligohydramnios. J Matern Fetal Neonatal Med
2007; 20(10):715–718. [RCT, n = 44; I]
50. Deka D, Malhotra B. Role of maternal oral hydration in increasing amni-
otic fluid volume in pregnant women with oligohydramnios. Int J Gynaecol
Obstet 2001; 73(2):155–156. [II-2]
51. Lorzadeh N, Kazemirad S, Lorzadeh M, Najafi S. Comparison of the effect
of oral and intravenous fluid therapy on women with oligohydramnios. Res
J Obstet Gynecol 2008; 1:25–29. [RCT, n = 40; I]
52. Ghafarnejad M, Tehrani MB, Anaraki FB, et al. Oral hydration therapy in
oligohydramnios. J Obstet Gynaecol Res 2009; 35(5):895–900. [RCT, n =
44; I]
53. Akter MD, Kabir N, Shah MS, et al. Effect of maternal oral hydration ther-
apy in oligohydramnios. Mymensingh Med J 2012; 21(4): 723–728. [RCT; I]
54. Hofmeyr GJ, Gülmezoglu AM, Novikova N. Maternal hydration for
increasing amniotic fluid volume in oligohydramnios and normal amni-
otic fluid volume. Cochrane Database Syst Rev 2002; (1):CD000134.
DOI:10.1002/14651858.CD000134. [Meta-analysis]
55. Patrelli TS, Gizzo S, Cosmi E, et al. Maternal hydration therapy improves
the quantity of amniotic fluid and the pregnancy outcome in third-trimes-
ter isolated oligohydramnios: a controlled randomized institutional trial. J
Ultrasound Med 2012; 31(2):239–244.[RCT, n = 137; I]
56. Gizzo S, Noventa M, Vitagliano A, et al. An update on maternal hydration
strategies for amniotic fluid improvement in isolated oligohydramnios and
normohydramnios: evidence from a systematic review of literature and
meta-analysis. PLOS ONE 2015; 10(12):e0144334. [Meta-analysis; 16 stud-
ies, n = 1121]
57. Shahnazi M, Manizheh Sayyah M, Hamoony F, et al. The effects of intra-
venous hydration on amniotic fluid volume and pregnancy outcomes in
women with term pregnancy and oligohydramnios: a randomized clinical
trial. J Caring Sci 2012; 1(3):123–128. [RCT, n = 20; I]
58. Pryde PG, Hallak M, Lauria MR, et al. Severe oligohydramnios with intact
membranes: an indication for diagnostic amnioinfusion. Fetal Diagn Ther
2000; 15:46–49. [II-2]
59. Vergani P, Ceruti P, Strobelt N, et al. Transabdominal amnioinfusion in oli-
gohydramnios at term before induction of labor with intact membranes: a
randomized clinical trial. Am J Obstet Gynecol 1996; 175:465–470. [RCT;
n = 79; I]
60. Pitt C, Sanchez-Ramos L, Kaunitz AM, et al. Prophylactic amnioinfusion
for intrapartum oligohydramnios: a meta-analysis of randomized con-
trolled trials. Obstet Gynecol 2000; 96:861–866. [Meta-analysis; 14 RCTs;
n = 793/740]
61. Amin AF, Mohammed MS, Sayed GH, et al. Prophylactic transcervical
amnioinfusion in laboring women with oligohydramnios. Int J Gynecol
Obstet 2003; 81:183–189. [RCT; n = 160; I]
62. Hofmeyr GJ, Justus G. Amnioinfusion for potential or suspected umbilical
cord compression in labour. (Cochrane Review). Cochrane Database Syst
Rev 2010; 8. [Meta-analysis; 14 RCTs, most with <200 women each]
Sonographic Assessment of Amniotic Fluid
63. Novikova N, Hofmeyr GJ, Essilfie-Appiah G. Prophylactic versus therapeu-
tic amnioinfusion for oligohydramnios in labour. Cochrane Database Syst
Rev 2012; (9):CD000176. [Meta-analysis; 1 RCT, n = 116]
64. Maher AM, Sayyed TM, Elkhouly N. Sildenafil citrate therapy for oligohy-
dramnios. Obstet Gynecol 2017; 129(4):615–620. [RCT, n = 166; I]
65. Hawkes N. Trial of Viagra for fetal growth restriction is halted after baby
deaths. BMJ 2018; 362:k3247. [III]
66. Alley MH, Hadjiev A, Mazneikova V, Dimitrov A. Four-quadrant assess-
ment of gestational age-specific values of amniotic fluid volume in uncom-
plicated pregnancies. Acta Obstet Gynecol Scand 1998; 77:290–294. [II-2]
67. Lazebnik N, Many A. The severity of polyhydramnios, estimated fetal
weight, and preterm delivery are independent risk factors for the presence
of congenital anomalies. Gynecol Obstet Invest 1999; 48:28–32. [II-2]
68. Reddy UM, Abuhamad AZ, Levine D, et al. Fetal imaging: executive sum-
mary of a joint Eunice Kennedy Shriver National Institute of Child Health
and Human Development, Society for Maternal-Fetal Medicine, American
Institute of Ultrasound in Medicine, American College of Obstetricians
and Gynecologists, American College of Radiology, Society for Pediatric
Radiology, and Society of Radiologists in Ultrasound Fetal Imaging work-
shop. Obstet Gynecol 2014; 123(5):1070. [II-2]
69. Pri-Paz S, Khalek N, Fuchs KM, et al. Maximal amniotic fluid index
as a prognostic factor in pregnancies complicated by polyhydramnios.
Ultrasound Obstet Gynecol 2012;39(6):648–653. [II-2]
70. Magann EF, Chauhan SP, Doherty DA, et al. A review of idiopathic hydram-
nios and pregnancy outcomes. Obstet Gynecol Surv 2007; 62:795–802. [II-2]
71. Sickler GK, Nyberg DA, Sohaey R, Luthy DA. Polyhydramnios and fetal
intrauterine growth restriction: ominous combination. J Ultrasound Med
1997; 16:609–614. [III]
597
72. Dashe JS, McIntire DD, Ramus RM, et al. Hydramnios: anomaly prevalence
and sonographic detection. Obstet Gynecol 2002; 100:134–139. [II-3, n =
672, largest series of hydramnios] [II-2]
73. Magann EF, Doherty DA, Lutgendorf MA, et al. Peripartum outcomes of
high risk pregnancies complicated by oligo-and polyhydramnios. A longi-
tudinal prospective study. J Obstet Gynaecol Res 2010; 36:268–277. [II-2]
74. Dashe JS, Pressman EK, Hibbard JU. SMFM consult series #46: evalua-
tion and management of polyhydramnios. Am J Obstet Gynecol 2018;
219(4):B2–8. [III]
75. Esplin MS, Hallam S, Farrington PF, et al. Myotonic dystrophy is a sig-
nificant cause of idiopathic polyhydramnios. Am J Obstet Gynecol 1998;
179:974–977. [II-3]
76. Kirshon B, Mari G, Moise KJ. Indomethacin therapy in the treatment of
symptomatic polyhydramnios. Obstet Gynecol 1990; 75(2):202–205. [II-3]
77. Magann EF, Whitworth NS, Bass JD, et al. Amniotic fluid volume of third-
trimester diamniotic twins. Obstet Gynecol 1995; 85:857–860. [II-2]
78. Porter TF, Dildy GA, Blanchard JR, et al. Normal values for amniotic
fluid index during uncomplicated twin pregnancy. Obstet Gynecol 1996;
87:699–702. [II-2]
79. Chau AC, Kjos SC, Kovacs BW. Ultrasonographic measurement of amniotic
fluid volume in normal diamniotic twin pregnancies. Am J Obstet Gynecol
1996; 174:1003–1007. [II-2]
80. Magann EF, Chauhan SP, Whitworth NS, et al. Accuracy of the summated
AFI in evaluating amniotic fluid volume in diamniotic twin pregnancies.
Am J Obstet Gynecol 1997; 177:1041–1045. [II-2]
81. Ippolito DL, Bergstrom JE, Lutgendorf MA, et al. A systematic review of
amniotic fluid assessment in twin pregnancies. J Ultrasound Med 2014;
33:1353–1364. [Meta-analysis; 19 studies, n = 3775]
 INDEX

Note: Locators in italics represent figures and bold indicate tables in the text.

A Adipokines, 38 incarcerated hernias, 135

Adiponectin, 38
Abatacept, 301, 302 Advanced maternal age, 584
Abdominal decompression, 489 Adverse consequences of prophylaxis, 390
Abnormal blood chemistry and liver function AFE, see Amniotic fluid embolism
tests, 139 Air bags, 403
Abnormalities in vestibulo-ocular reflex Airway pressure release ventilation
pathway, 99 (ARPV), 424
Abruption, 3, 6, 8, 13, 21, 59, 79, 318, 402, 594 AKI, see Acute kidney injury
Abruptio placentae, 8, 11, 18, 195, 473, 538 Alanine aminotransferase (ALT), 8, 354
Acardiac twin, 478 Alcoholic liver disease, 137
ACE inhibitor, 5 Alimentary tract diseases, 129
Acquired thrombophilia, 316 acute cholecystitis, 130
Activated charcoal, 115 classification, 130
Activated partial thromboplastin time complications, 131
(aPTT), 437 epidemiology/incidence, 131
Activated protein C (APC), 317 etiology/pathogenesis, 131
Acupressure wrist bands, 104 labor and delivery
Acupuncture, 104, 228 considerations, 132
Acustimulation wrist bands, 104 management, 131
Acute cellular rejection, 139 pregnancy considerations, 131
Acute chest syndrome, 155, 158–159 risk factors/associations, 131
Acute cholecystitis, 129–130 symptoms, 130–131
classification, 130 appendicitis
complications, 131 complications, 134
epidemiology/incidence, 131 diagnosis/definition, 134
etiology/pathogenesis, 131 differential diagnosis, 134
labor and delivery considerations, 132 epidemiology/incidence, 134
management, 131 etiology/pathophysiology, 134
pregnancy considerations, 131 labor and delivery issues, 134
risk factors/associations, 131 management, 134
symptoms, 130–131 risk factors/associations, 134
Acute fatty liver, 473 symptoms, 134
Acute glomerulonephritis, 168 biliary pancreatitis
Acute hepatitis B in pregnancy, 348 classification, 133
Acute interstitial nephritis (AIN), 168 complications, 133
Acute kidney injury (AKI), 166 diagnosis/definition, 133
classification and clinical approach, 167 differential diagnosis, 133
definition, 166–167, 167 etiology/pathophysiology, 133
epidemiology, 167 labor and delivery issues, 134
postrenal, 168 management, 133–134
pre-eclampsia, 168–169 risk factors/associations, 133
pregnancy considerations and symptoms, 133
outcomes, 170 bowel obstructions, 135
prerenal, 167 choledocholithiasis
renal, 167–168 complications, 132
renal biopsy, 169 diagnosis/definition, 132
treatment, 169–170 differential diagnosis, 132
urine and laboratory values, 167 epidemiology/incidence, 132
Acute lung injury (ALI), 422 etiology/pathophysiology, 132
Acute pancreatitis severity, 133 labor and delivery issues, 132
Acute pulmonary embolism, Pregnancy- management, 132
adapted algorithm for the risk factors/associations, 132
management of, 328 symptoms, 132
Acute respiratory distress syndrome cholelithiasis
(ARDS), 422 complications, 129
Acute right ventricular failure, 436 diagnosis/definition, 129
Acute severe ulcerative colitis (ASUC), 123 differential diagnosis, 129
Acute tubular necrosis (ATN), 168 epidemiology/incidence, 129
Acute vaso-occlusive episodes, 155 etiology/pathophysiology, 129
Acyclovir, 523–524 management, 129–130
Adalimumab, 122, 301 risk factors/associations, 129
Addiction, 233 symptoms, 129
inflammatory bowel disease (IBD), 135
All-cause mortality, 48
Allogenic hematopoietic stem cell
transplantation, 156
Allogenic organ transplantation, 137
Alloimmune thrombocytopenia (AIT), 529
Alloimmunization, 158
clinical management, 537
Alpha- and beta-blocker (Labetalol), 5
Alpha tumor necrosis, 38
Ambulatory blood pressure monitoring, 4
American Academy of Neurology (AAN), 188
Aminotransferase (AST), 354
Amniocentesis, 552
Amniotic fluid (AF), 504
Amniotic fluid embolism (AFE), 433
diagnosis
clinical presentation, 434
diagnostic laboratory testing, 435
differential diagnosis, 434–435
management of cardiac arrest, 435–437
management of coagulopathy
associated with amniotic fluid
embolism, 437–438
incidence, 433
management, 437
pathophysiology, 433–434
postpartum counseling, 438
prognosis of patients who survive, 438
risk factors for amniotic fluid embolus, 434
Amniotic fluid volume (AFV), 493
in singleton pregnancies, 589
color Doppler, 590
estimation, 590
indications, 589
management, 590–591
techniques, 589
Amoxicillin, 178, 374
Amoxicillin-clavulanate, 178
Amphetamines, 232, 245
anesthesia, 247
antepartum testing, 247
complications, 246–247
diagnosis/definition, 245
epidemiology/incidence, 246
etiology/basic pathophysiology, 246
postpartum/breastfeeding, 247
risk factors/associations, 246
symptoms, signs and organ toxicity,
245–246
therapy, 247
Ampicillin, 178
Anakira, 301
Anaphylactoid reaction of pregnancy, 435
Anemia, 139, 157, 194, 517; see also
Maternal anemia
characterized by mechanism, 147
hematological studies, 149
iron deficiency, 146
macrocytic, 149
normocytic, 146
in pregnancy, 144, 145

599
600
Anesthesia, 46, 72, 158
chronic hypertension, 7
pre-eclampsia, 16
pregestational diabetes, 63
Aneurysms, 199–200
Angiotensin-converting enzyme (ACE)
inhibitors, 1, 6
Angiotensin receptor blockers, 6
Annual influenza vaccination, 282
Antenatal late preterm steroids (ALPS), 46
Antenatal prophylaxis, 333
Antenatal surveillance, 582–583
Antenatal testing, 16, 158
Antepartum, 39
Antepartum fetal testing, 45
Antepartum stillbirth, 38
Antepartum testing, 7, 62–63, 63, 88–89, 125,
150, 572
ductus venosus Doppler, 491–492
fetal kick counts, 492
fetal monitoring, 572
biophysical profile scoring, 574–576
cardiotocography (CTG), 573–574
condition-specific testing, 582–585
contraction stress test, 574
Doppler of fetal vessels, 577–582
Doppler surveillance and BPS, 582
fetal heart rate testing, 573–574
fetal movement counting in low-risk
pregnancy, 572–573
modified biophysical profile score,
576–577
fetal surveillance, 478–479
growth assessment, 491
middle cerebral artery Doppler, 491
ultrasound, 478
umbilical artery Doppler, 491
uterine artery Doppler, 492
Anthrax vaccine, 396
Anti-beta-2 glycoprotein-I (B2GP-I), 309
Antibiotics, 121, 153, 157
Anticardiolipin antibodies (ACAs), 309
Anti-chlamydia IgM, 374
Anticholinergics, 277
Anticoagulation regimen, 330
Antidepressants, 207, 215
Antidepressants in pregnancy and lactation,
208–209
Anti-D immune globulin, 536
Antidiuretic hormone, 164
Antiemetic therapy, 105
Antiepileptic drugs (AEDs), 187
pharmacokinetic profile, 189
Antigen/antibody immunoassay, 359
Antigen zygosity, 531
Anti-hepatitis A virus (anti-HAV)
immunoglobulin M, 340
Antihistamines (histamine-1 receptor
antagonists), 102, 105
Antihypertensive drugs, 5, 9
Antihypertensive medications, 6
Antihypertensive therapy, 16, 196
Anti-integrin agents, 122
Anti-Kell alloimmunization, 541
Antimetabolite, 302
Antioxidants, 14
Antioxidant therapy, 8, 14
Antiphospholipid antibodies (APAs), 309
Antiphospholipid syndrome (APS), 309,
324–325
anesthesia, 313
antepartum testing, 313
antiphospholipid antibody testing, 309
classification, 309
clinical criteria for diagnosis, 310
complications, 309–310
delivery, 313
diagnosis, 309
epidemiology/incidence, 309
etiology/basic pathophysiology, 309
historic notes, 309
laboratory criteria for the diagnosis, 310
management, 310–313
postpartum/breastfeeding, 313
pregnancy considerations, 310
preparations for delivery, 313
symptoms, 309
Antiplatelet agents, 16
Antiretroviral (ARV) regimens, 360
Antiretroviral therapy (ART), 359
Antithrombin deficiency, 315
Antithrombin III (ATIII) deficiency, 315
Antithyroid antibodies, 78
Anti-tumor necrosis factors, 121
Anxiety, 119
Aorta, coarctation of, 4
Aortic stenosis, 31
Aplastic crisis, 155
Apoptosis hypothesis, 303
Appendicitis
complications, 134
diagnosis/definition, 134
differential diagnosis, 134
epidemiology/incidence, 134
etiology/pathophysiology, 134
labor and delivery issues, 134
management, 134
risk factors/associations, 134
symptoms, 134
Arrhythmia, 28
Arterial catheters, 421
Arterial pulmonary vasoconstriction, 434
5 As for Patients Who Are Willing to Quit
Smoking, 224, 226
Aspartate aminotransferase (AST), 8
Aspirin, 8, 13, 45, 166, 301, 332, 487, 489
Assisted reproductive technologies (ART), 469
Asthma, 286–287
acute treatment, 277
anesthesia, 277
antepartum testing, 277
classification, 269, 270
delivery, 277
diagnosis, 269
epidemiology, 269
etiology/basic pathophysiology, 269
exacerbations during pregnancy, 275
management, 272–273, 274
medication for exacerbations during
pregnancy, 271
postpartum/breastfeeding, 277
pregnancy complications, 271–272
pregnancy considerations, 272
status asthmaticus, 277
symptoms, 269
therapy, 273–277
Index
Atherosclerotic coronary artery disease, 26
Atopic eruption of pregnancy, 461
diagnosis/definition, 461–462
epidemiology/incidence, 462
etiology/basic pathology, 462
management, 462
pregnancy considerations, 462
symptoms, 462
Attention-deficit hyperactivity disorder
(ADHD), 211, 245
Atypical (irregular) blood group
antibodies, 547
Auras, 188
Auricular acupressure, 104
Autism spectrum disorder (ASD), 211
Autoimmune hepatitis, 138, 345
Autoimmune thrombocytopenia, 310
Autonomic dysreflexia (ADR), 194, 196
Auto-transfus, 30
Azathioprine, 6, 140, 140, 176, 301, 301
Azithromycin, 374
Aztreonam, 178
B
Bariatric surgery, 35, 42, 43, 501
Bed rest, 474, 488
Bed rest and nutrition, 486
Belimumab, 301
Benzodiazepines, 107, 232, 247
antepartum testing, 249
complications, 248
diagnosis/definition, 248
epidemiology/incidence, 248
etiology/basic pathophysiology, 248
historic notes, 247
postpartum/breastfeeding, 249
risk factors/associations, 248
symptoms, 248
therapy, 249
Beta-blockers, 5, 7, 30, 88
Beta-human chorionic gonadotropin
(β-hCG), 10
Betamethasone, 301
Betamimetics, 489
β-agonists, 274–275
Bile acids, 114
Biliary pancreatitis
classification, 133
complications, 133
diagnosis/definition, 133
differential diagnosis, 133
etiology/pathophysiology, 133
labor and delivery issues, 134
management, 133–134
risk factors/associations, 133
symptoms, 133
Biophysical profile, 493
scoring, 574, 575, 575
Biopsy, 38
Bipolar disorder in pregnancy and postpartum
definitions and epidemiology, 205
risk factors, 205
timing of symptoms, 205
Birth defects, 140
Bleeding, 329
Blood culture, 279
Blood pressure, 21
Index
Body mass index (BMI), 35, 60
Bowel inflammation, 119
Bowel obstructions, 135
BP in adults, 3
Bradycardia, 195
Brain-sparing, 491
Breast cancer, 442–443
delay in diagnosis, 443
diagnostic tests and safety in,
443–444
effects on, 444
pregnancy, treatment during, 444–445
pregnancy after, 452–453
sentinel node biopsy, 444
staging during pregnancy, 444
surgery during pregnancy, 444
termination of pregnancy, 444
Breastfeeding, 47, 66, 97, 194, 336
Brexanolone, 209, 211
Bromocriptine (parlodel), 92, 94, 94–95
B19-specific immunoglobulin G (IgG), 516
Buprenorphine, 241–242
Bupropion, 209
Bupropion HCl (Zyban®, Wellbutrin®), 228
C risk factor, 28
Cabergoline (dostinex), 92, 94, 95
Calcium, 14
Calcium channel
blockers, 5, 7, 489
hypothesis, 303
Campylobacter jejuni, 198
Cancer
diagnosed before pregnancy, 441, 451
after chemotherapy, 451–452
chemotherapy-induced cardiac
toxicity, 452
children of cancer survivors, 452
pregnancy after cancer, 452–453
after radiation, 452
radiation-induced cardiac toxicity due
to fibrosis, 452
diagnosed during pregnancy
complications, 450
fetal/neonatal evaluation after
chemotherapy during
pregnancy, 451
fetal surveillance and timing of
delivery, 450–451
maternal surveillance, 450
diagnosed in pregnancy
breast cancer, 442–445
chemotherapy, 442
general considerations, 441–442
Hodgkin’s disease, 445–446
incidence/epidemiology, 441
invasive cervical cancer, 448–449
leukemia, 446–447
melanoma, 447–448
non-Hodgkin’s lymphoma, 446
ovarian cancer, 448
thyroid cancer, 449–450
treatment, 447
Cannabis, 122
Carbamazepine, 212–213
Carbon monoxide, 224
Carcinogens, 224; see also Cancer
Cardiac arrest, 30, 434
Cardiac disease, 26
classification, 28
complications, 28–29
epidemiology/incidence, 26–27
etiology/basic pathophysiology/pregnancy
considerations, 27–28
genetics, 27
management
aortic stenosis, 31
coarctation of aorta, 31
coronary artery disease, 33
dilated cardiomyopathy, 32–33
general management, 29–30
hypertrophic cardiomyopathy, 32
Marfan syndrome, 32
mechanical heart valves, 31–32
mitral valve stenosis, 31
peripartum cardiomyopathy, 32
pre-conception counseling, 29
pregnancy management, 30
prenatal care/antepartum testing, 29
pulmonary hypertension, 30–31
pulmonic stenosis, 31
tetralogy of fallot, 31
symptoms/signs, 26
Cardiac failure, 8
Cardiac screening algorithm, 41
Cardiomyopathy, 28
Cardiopulmonary resuscitation (CPR), 408, 435
Cardiotocography, 492
Cardiovascular diseases, 26
Cardiovascular morbidity, 48
Cardiovascular syphilis, 379
Carpenter–Coustan criteria, 67
Cefazolin, 178
Cefepime, 178
Cefpodoxime, 178
Ceftriaxon, 178
Central venous catheters, 421
Cephalexin, 178
Cerclage, 474
Cerebral hemorrhage, 8
Cerebrospinal fluid (CSF), 379
Certolizumab, 122, 301
Cervicitis/urethritis, 373
Cesarean delivery (CD), 38–39, 46–47, 63, 119,
483, 565; see also Pregnancy
Chantix®, 228
Chickenpox, 525
Child Abuse Prevention and Treatment Act
(CAPTA), 234
Childhood trauma, 233
Chlamydia, 372
clinical categories, 372
complications/risks, 373
epidemiology/incidence, 372
management, 373–374
pathophysiology/etiology, 373
symptoms, 372
cervicitis/urethritis, 373
chlamydial conjunctivitis, 373
LGV, 373
maternal genital infection, 372–373
proctitis/proctocolitis, 373
transmission, 373
treatment, 374–375
601
Chlamydial conjunctivitis, 373
Chlamydia trachomatis, 372–373
Cholecystectomy, 129, 132
Choledocholithiasis, 131
complications, 132
diagnosis/definition, 132
differential diagnosis, 132
epidemiology/incidence, 132
etiology/pathophysiology, 132
labor and delivery issues, 132
management, 132
risk factors/associations, 132
symptoms, 132
Cholelithiasis
complications, 129
diagnosis/definition, 129
differential diagnosis, 129
epidemiology/incidence, 129
etiology/pathophysiology, 129
management, 129–130
risk factors/associations, 129, 130
symptoms, 129
2018 Tokyo Guidelines, 130
Cholesterol metabolism, 113
Cholestyramine, 115, 302
Chorioretinitis, 512
Chronic hemolytic anemia, 154
Chronic hepatitis C virus infection, 137
Chronic hypertension (CHTN), 1, 57
anesthesia, 7
antepartum testing, 7
antihypertensive medications in
pregnancy, 1
classification, 3
complications, 3
delivery, 7
diagnosis/definition, 1–3, 2
epidemiology/incidence, 3
etiology/basic pathophysiology, 3
fetal complications, 1
high-risk, 1
management, 3–7
maternal complications, 1
postpartum/breastfeeding, 7
preconception counseling, 4
in pregnancy, 1, 2
risk factors/associations, 3
Chronic kidney disease, 166
complications, 171
definition, 170, 170
effects of pregnancy, 171
epidemiology, 171
lupus nephritis, 174
nephrotic syndrome, 173–174
stages, 170
symptoms, 171
vasculopathies, 174
Chronic restrict lung disease, 155
Chronic thromboembolic pulmonary
hypertension (CTPH), 327
CHTN, see Chronic hypertension
Cimetidine (tagamet), 102
Citalopram, 208
Clindamycin, 375
Clinical hypothyroidism
antepartum management, 82
complications, 79
definitions, 78
602 Index

incidence, 78 Coxsackie B virus, 345 pathophysiology/classification, 505

management, 79 Crack lung, 243 clinical neonatal findings and
neonatal, 82 Cranberry juice, 177 complications, 505
pathophysiology, 78 Craniosynostosis, 89 primary infection, 505
postpartum, 82 Critical care, 412 recurrent infection, 505
pregnancy considerations, 79–80 admission to intensive care, 418–419 perinatal infection, 505
screening/diagnosis, 80–81 considerations in transfer, 418 pregnancy management
signs/symptoms, 78 incidence, 412 counseling/prognosis, 506
treatment, 81 levels of, 412–414 investigations/diagnosis/workup,
type, 81 primary ICU, 412–414 507–508
Clinical opioid withdrawal scale, 239 secondary ICU, 414 prevention, 507
Clonidine, 107, 228 tertiary ICU, 414 screening, 507
Clostridium difficile, 119, 123 logistics, 419–420 therapy, 508–509
Coagulation abnormalities, 567 organization of obstetric critical care symptoms, 505
Coagulations cascade and some pregnancy services, 414–417 transmission/risk factors/associations, 504
changes, 325 role of OB-GYN, 420–421 vaccine, 507
Coarctation of aorta, 31 sepsis, 424–429
Cocaine (benzoylmethylecognine) specific conditions, 422 D
anesthesia, 245 acute respiratory distress syndrome,
antepartum testing, 245 422–424 Dactylitis, 155
diagnosis/definition, 243 mechanical ventilation, 422–424 D-chiro-inositol, 69
epidemiology/incidence, 243 tools and techniques, 421 D-Dimer, 327
etiology/basic pathophysiology, 243–244 hemodynamic monitoring, 421 Deep vein thrombosis, 327
historic notes, 243 mechanical ventilation, 421 Delivery, 158
maternal and perinatal complications, 244 point of care ultrasound, 421 timing for twins, 475
postpartum/breastfeeding, 245 transthoracic echocardiography, Depot medroxyprogesterone acetate
risk factors/associations, 244 421–422 (DMPA), 158
symptoms, signs and cardiopulmonary Crohn’s disease Depression, 45, 119, 204
complications, 243 aminosalicylates, 121 Dermatoses of pregnancy, 458
therapy, 244–245 antepartum testing, 122 atopic eruption of pregnancy, 461–462
Colectomy, 125 antibiotics, 121 cutaneous melanoma, 464–466
Common bile duct (CBD), 132 anti-integrin agents, 122 impetigo herpetiformis (pustular psoriasis
Comorbidity and risk factors, 138–139 anti-tumor necrosis factors, 121–122 of pregnancy), 463–464
Complete blood count (CBC), 144 azathioprine/6-mercaptopurine, 121 pemphigoid gestationis (herpes
Complex partial seizures (CPS), 188 complications, 118–119 gestationis), 462–463
Complications, 155 corticosteroids, 121 polymorphic eruption of pregnancy,
Comprehensive Addiction and Recovery Act cyclosporin, 121 459–461
(CARA), 234 definition, 117, 118 striae gravidarum (SG), 458–459
Computed tomography (CT), 421 delivery, 122 Dexamethasone, 9, 89, 90, 115, 291, 301, 304
Computed tomography pulmonary diagnosis, 118 Diabetes, 139, 501–502, 584
angiography (CTPA), 324 epidemiology/incidence, 118 intrapartum management of, 60
Condoms, 368, 373, 384–385 etiology/basic pathophysiology, 118 workup in pregnancy, 58
Congenital anomalies, 237 management, 119–120 Diabetes mellitus (DM), 57
Congenital cystic adenomatoid malformation methotrexate, 121 in non-pregnant state, 58
(CCAM), 556 oral janus kinase inhibiting agents, 122 Diabetic ketoacidosis, 57
Congenital heart defects (CHD), 38 postpartum/breastfeeding, 123 in pregnancy, 62
Congenital infection, 511 pregnancy considerations, 119 Diabetic nephropathy, 58
Congenital pulmonary airway malformation signs/symptoms, 118 Diabetic neuropathy, 58
(CPAM), 556 Cromolyn, 275 Diabetic retinopathy, 58
Congenital syphilis, 377 Cushing’s syndrome, 4 Diabetic screening, 45
Conjoined twins, 478 Cutaneous melanoma, 464–465 Dialysis in ESRD, 174–175
Contraception, 47–48, 158, 194 classification, 465 antepartum testing, 175
Contraction stress test (CST), 574 complications, 465 labor and delivery, 175
Coronary artery disease (CAD), 26, 28, 33 diagnosis/definition, 465 neonatology, 175
Corticosteroids, 19, 106–107, 121, 301, 301–302 genetics, 465 postpartum, 175
Counseling/coaching, 45 management, 465–466 Diet, 44, 60, 69, 106, 122, 214
COVID-19, 421 pregnancy considerations, 465 Dietary Approaches to Stop Hypertension
delivery, 292 risk factors, 465 (DASH), 68
diagnosis, 288–289 symptoms, 465 Dietary counseling, 69
epidemiology, 288 Cyclophosphamide, 301, 302 Dilated cardiomyopathy (DCM), 32–33
etiology/basic pathophysiology, 288 Cyclosporine, 121, 139–140, 140, 301 Dimenhydrinate (dramamine), 102
management, 289–292 Cyclosporine A, 176 Diphenhydramine (benadryl), 102
pharmacologic treatment of, 291 CYP1A1, 223 Dipstick urinalysis, 177
pregnancy considerations, 289 CYP2A6, 223 Direct oral anticoagulants (DOACs), 329
risk factors/associations, 288 Cytomegalovirus acute infection, 139 Disseminated intravascular coagulation
severity classification, 290 Cytomegalovirus (CMV), 345, 504 (DIC), 8, 433
symptoms, 288 incidence/epidemiology, 504 Diuretics, 5, 14
vaccination, 397–398 pathogen, 504 Dizygotic (DZ) twins, 469
Index
Dobutamine, 436
Domestic violence against pregnant
patients, 400
Dopamine agonist, 95
Dopamine2—antagonists, 102
Doppler velocimetry, 491
Doxorubicin-bleomycin-vinblastine-
dacarbazine (ABVD), 442
Doxycycline, 375
Doxylamine, 102, 104–106
Droperidol (inapsine), 102
Ductus arteriosus, 131
Ductus venosus Doppler, 491–492
Ductus venosus (DV), 579
Duloxetine, 209
Dysfibrinogenemia, 315
Dysreflexia, 194
E Fetal blood transfusion, 544–545
Early fetal death, 564
Echocardiography, 29, 31
Eclampsia, 2, 8–9
Eclampsia prophylaxis, 21
Electroconvulsive therapy, 214
Electronic cigarettes (e-cigarettes) in
pregnancy, 225
Embolectomy, 333
Embryonic death, 564
Embryopathy, 334
Endocarditis, 28
Endometritis, 155
Endoscopic retrograde
cholangiopancreatography
(ERCP), 129
End-stage liver disease (ESLD), 137
Enteral nutrition, 107
Enteric-coated mycopheno-late sodium
(EC-MPS), 140
Epidural analgesia, 16
Epidural anesthesia, 197
Epilepsy, 187–189
Epstein–Barr virus (EBV), 345
Erythromycin, 374
Escitalopram, 208
Esomeprazole (nexium), 102
Etanercept, 301
Euglycemic with diet only (A1GDM), 71
Exercise, 44, 60, 69, 214
Expedited partner treatment (EPT), 374
Extend Hurt/Insult/Threaten/Scream
(E-HITS), 258
Extracorporeal membrane oxygenation
(ECMO), 424, 437
F placental factors, 486
Factor V Leiden (FVL), 315–316
Famciclovir, 523
Famotidine (pepcid), 102
Fecal calprotectin, 123
Fecal microbiotia transplantation, 122
Fetal and neonatal alloimmune
thrombocytopenia (FNAIT), 529
anesthesia, 534
antenatal management for, 533
classification, 529–530
counseling, 534
603
defined, 529 selective versus universal third
delivery, 535 trimester ultrasound, 487
diagnosis, 530–531 smoking cessation, 486
epidemiology/incidence, 529 umbilical artery Doppler, 488
etiology/basic pathophysiology, 529 uterine artery Doppler, 487
factors affecting severity of disease, 530 neonatology management, 494
fetal monitoring/testing, 534 treatment, 488
future pregnancy preconception abdominal decompression, 489
counseling, 535 aspirin, 489
genetics/inheritance, 529 avoidance of toxins, 488
investigations and consultations, 534 bed rest, 488
management, 531–532 betamimetics, 489
natural history/complications, 530 calcium channel blockers, 489
neonatology management, 535 heparin, 489
prevention and screening, 531 nitric oxide donors, 489
risk-based fetal therapy, 533–534 nutrient therapy, 488–489
Fetal anemia, 584 oxygen, 489
Fetal blood sampling (FBS), 529 plasma volume expansion, 489
sildenafil, 489
Fetal congenital infection, 511 therapy for medical conditions, 488
Fetal death, 79, 402, 564 Fetal hemoglobin concentrations, 542
associations/risk factors/possible etiologies, Fetal hypothyroidism, 88
564–565 Fetal injury, 402
defined, 564 Fetal kick counts, 492
delivery/anesthesia, 567–569 Fetal lung maturity, 72
diagnosis, 564 Fetal macrosomia, 500
epidemiology/incidence, 564 complications, 500
pregnancy management, 565–567 definition, 500
prevention, 565 epidemiology/incidence, 500
Fetal growth restriction (FGR), 10, 482–483, 584 management, 500–501
amniotic fluid volume, 493 diabetes, 501–502
antepartum testing, 489 prevention, 500–501
ductus venosus Doppler, 491–492 prior cesarean delivery, 502
fetal kick counts, 492 prior shoulder dystocia, 502
growth assessment, 491 screening and diagnosis, 501
middle cerebral artery Doppler, 491 suspected macrosomia, 501
umbilical artery Doppler, 491 risk factors, 500
uterine artery Doppler, 492 Fetal maternal alloimmune thrombocytopenia
biophysical profile, 493 (FMAIT), 529
cardiotocography, 492–493 Fetal monitoring, 419
classification Fetal/neonatal morphometrics, 237
symmetric and asymmetric, 485 Fetal thrombocytopenia, 546–547
timing of diagnosis, 484–485 FGR/discordant twins, 475
complications, 486 Fish oil, 14
definitions/diagnosis, 483–484 Flow cytometry (FC), 540
delivery, 493 Fluorouracil-epirubicin-cyclophosphamide
mode, 494 (FEC), 442
multiple gestation, 494 Fluoxetine, 208
preparation, 493 Fluticasone, 275
timing of delivery, 493 Fluvoxamine, 208
epidemiology/incidence, 484 Folate supplementation, 149
estriol levels, 493 Folic acid, 187, 190
etiology/basic pathophysiology, 485 Fundal height, 487
fetal factors, 485–486 Furosemide, 21
maternal factors, 485
G
genetics/inheritance/recurrence, 484
management, 490 Gadolinium-enhanced MRI, 97
aspirin, 487 Gallbladder cancer, 131
bed rest and nutrition, 486 Gallstones, 129
combined models, 488 Ganciclovir, 508–509
control of maternal medical disorders, Garlic, 14
486–487 Gastrointestinal (GI) motility, 99
fundal height, 487 Gastrointestinal obstruction, 556
gestational age determination, 486 GBS, see Group B streptococcus
interpregnancy interval, 486 Genetic counseling, 156
low-molecular-weight heparin, 487 Genital chlamydial infection, 372
maternal serum analytes, 487 Gestational age determination, 486
604 Index

Gestational age (LGA) infants, 66 GSTT1, 223 outcomes, 541

Gestational diabetes mellitus (GDM), 66, 473 Guar gum, 115 workup/investigations required,
complications, 68 Guillain–Barré syndrome, 194, 198, 198 541–542
incidence, 68 anesthesia, 199 MNS antigen system, 548
pathophysiology, 68 delivery, 199 prevention (anti-D immune globulin),
pharmacologic management, 70–73 diagnosis/definition, 198 538–540
antepartum testing and ultrasound epidemiology/incidence, 198 screening, 538
assessment, 71 pregnancy management, 198–199 Hemorrhage, 416, 557
delivery, 71–72 Gummas, 379 Hepadinaviridae, 343
glyburide, 70 Heparin, 14, 489
insulin, 70–71 H Heparin-induced osteoporosis, 330
intrapartum glucose management, 72 Heparin-induced thrombocytopenia (HIT),
metformin, 70 Hallucinogens 312–313, 329–330
nutritional supplementation, 71 antepartum testing, 251 Hepatitis A virus (HAV), 340, 345
oral hypoglycemic agents, 70 complications, 251 complications, 341
postpartum screening, 72 diagnosis/definition, 250 pregnancy considerations, 341
prevention, 68–69 epidemiology/incidence, 250 pregnancy management, 341
risk factors/associations, 68 etiology/basic pathophysiology, 250 prenatal care, 342
screening/diagnosis, 66–68, 67 historic notes, 250 prevention/preconception counseling,
treatment, 69–70 postpartum/breastfeeding, 251 341–342
diet, 69 symptoms, 250 diagnosis, 340
exercise, 69 therapy, 251 epidemiology/incidence, 340
glucose monitoring, 69–70 HARK (Humiliation, Afraid, Rape, Kick) etiology/basic pathophysiology, 340
Gestational hypertension, 2, 7, 11 instrument, 258, 259 genetics, 340
Gestational thyrotoxicosis, 86 Harris–Benedict equation, 107 prophylaxis vaccination, 342
Ghrelin, 38 Hashimoto’s thyroiditis, 78 risk factors/associations, 340–341
Ginger, 104 HBIg, 347 symptoms, 340
extract, 102 HbSC disease, 159 vaccine, 395
Glucagon, 61 HbS-/βTHAL, 159 Hepatitis B virus (HBV), 139, 343
Glucocorticoids, 103 Headache, 182 anesthesia, 348
Glucose control, 58 background/epidemiology, 182 classification, 345
Glucose monitoring, 61, 69–70 diagnosis, 182–183 complications, 345
Glyburide, 70 epidemiology/pathophysiology, 182–183 delivery, 348
Glycemic control, 67 genetics, 183 diagnosis/definition, 344–345
Glycosylated hemoglobin, 61 management, 184–185 epidemiology/incidence, 343
Golimumab, 301 pregnancy considerations, 183–184 etiology/basic pathophysiology, 345
Gonadotropin-releasing hormone, 137 Heart failure symptoms, 28; see also genetics, 343–344
Gonococcal Isolate Surveillance Program Cardiac disease interpretation, 344
(GISP), 367 Helicobacter pylori, 99 management, 347–348
Gonorrhea, 367 HELLP syndrome, 9, 11, 18–21, 19, 111, 129 markers, 346
complications, 368 complications of, 19 postpartum/breastfeeding, 348
epidemiology/incidence, 367 differential diagnosis, 18 pregnancy considerations, 345
etiology, 368 management of, 19 risk factors/associations, 345
management, 368–370 signs and symptoms, 18 symptoms, 345
pathophysiology/transmission, 368 syndrome, 19 vaccination, 396–397
recommendations for treatment, 370 Hematological disorders, 557 vaccine, 347
screening and diagnostic tests, 369 hemolysis, 557 Hepatitis C virus (HCV), 345, 350–351
symptoms, 368 hemorrhage, 557 antepartum testing, 355
G-protein-coupled thyrotropin receptor, 87 reduced red blood cell/hemoglobin diagnosis, 351
Graves’ disease, 86–87 production, 557 epidemiology, 352–353
Grief counseling, 565 twin-to-twin transfusion syndrome, 557 extrahepatic conditions, 352
GRIT trial, 581, 581 Hematological studies and clinical severity of genetics, 353
Group B streptococcus (GBS), 387 thalassemias, 147 intrapartum management, 355–356
bacteriuria, 391 Hemoglobin E, 159 management, 353–354
complications, 387 Hemoglobin electrophoresis, 144, 147 mother-to-child transmission (MTCT),
epidemiology/incidence, 387 Hemolysis, 9, 557 351, 353
management, 388–391 Hemolytic disease of fetus and newborn, 536 natural history, 351–352
intrapartum prophylaxis, 389–390 atypical antibodies, 547–548 pathogenesis and risk factors, 353
intrapartum treatment, 388 CDE system antigens, 548 postpartum management, 356
neonatal (screening and) treatment, 388 definition, 536 pregnancy, effects on, 354
prenatal screening and intrapartum epidemiology/incidence, 536 recommended workup and management
treatment, 388 etiology/basic pathophysiology, 537–538 for pregnant women, 351–352
screening, 389 genetics, 536–537 risk factors, 351
universal maternal treatment, 388 Kell alloimmunization, 548 symptoms, 351
neonatal management, 391 management of RBC alloimmunized treatment, 354–355
prophylaxis, 390 pregnancies Hepatitis D virus (HDV), 348
risk factors/associations, 387 counseling, 540–541 Hepatitis virus reactivation, 138–139
symptoms, 387 MCA-PSV surveillance, 542–547 Hepatocellular carcinoma (HCC), 137
Index 605

Herbal supplements, probiotics, risk factors, 360 Hyperthyroidism, 86

acupuncture, 122 statistics and features, 360 antepartum testing, 88–89
Heritable thrombophilia, 333 Human leukocyte antigen (HLA), 530 basic physiology/pathophysiology, 87
Herpes simplex virus (HSV), 345, 520 Human parvovirus B19, 516 complications, 87
classification/pathophysiology, 521 Human platelet antigens (HPA), 529 definitions, 86
maternal-fetal transmission, 521 Human pregnancies, 38 etiology, 86–87
nonprimary first episode, 521 Hurt/Insult/Threaten/Scream (HITS), 258 incidence, 86
primary first episode, 521 Hydralazine, 6, 16 neonate, 89
reactivation (recurrent) genital Hydrocephaly, 38 postpartum, 89
herpes, 521 Hydrocortisone, 103 screening/diagnosis, 87
complications, 521 Hydromorphone, 157 signs/symptoms, 86
history, 523 Hydropic signs, 544 thyroid nodule, 89
incidence/epidemiology, 520 Hydrops fetalis, 538, 545, 552, 559; see also thyroid storm, 89–90
pathogens, 520 Nonimmune hydrops (NIH) fetalis treatment, 87–88
pregnancy management Hydrothorax, 556 beta-blocker, 88
counseling/prognosis, 521–522 Hydroxychloroquine, 301, 304 iodine, 88
pregnancy considerations, 521 Hydroxychloroquine sulfate (Plaquenil), 300 methimazole, 88
prevention, 522 Hydroxyurea, 153 propylthiouracil, 88
screening, 522 Hydroxyzine (atarax, vistaril), 102, 115 radioiodine, 88
workup/diagnosis, 522 Hyperaldosteronism, 4 surgery, 88
risk factors/associations, 520 Hyperbilirubinemia, 66 thionamides, 88
symptoms, 521 Hypercoagulability, 27–28 Hypertrophic cardiomyopathy (HCM), 32
therapy Hypercoagulable blood, 326 Hypnosis, 228
antiviral drugs, 522 Hyperemesis gravidarum (HG), 86–87, Hypoglycemia, 62
complicated HSV infection, 522 99; see also Nausea/vomiting of Hypomania, 206
primary or first-episode HSV, 522 pregnancy (NVP) and hyperemesis Hypotension, 195
High-dependency unit (HDU), 414; see also gravidarum (HG) Hypothalamic-pituitary-adrenal (HPA), 174
Intensive care unit Hyperglycemia, 66 dysregulation, 204
Histamine-2 receptor antagonists, 105 Hyperglycemia and Adverse Pregnancy Hypothalamic-pituitary-gonadal
HIV, see Human immunodeficiency virus Outcome (HAPO), 66 dysfunction, 137
Hemoglobins, 146 Hyperglycemic or medication-assisted Hypothermia, 195
Hodgkin’s disease, 445 (A2GDM), 71 Hypothyroidism, 78, 88
effects on pregnancy, 445 Hyperhomocysteinemia, 319, 321 clinical hypothyroidism
presentation, diagnostic tests and Hyperimmune globulin, 508 antepartum management, 82
safety, 445 Hyperprolactinemia complications, 79
radiotherapy during pregnancy, 445–446 etiology, 93 definitions, 78
staging of disease during pregnancy, 445 treatment, 93 incidence, 78
surgery during pregnancy, 445 Hypertension, 171–172, 243, 416 management, 79
termination of pregnancy, 445 Hypertension and renal insufficiency, 139 neonatal, 82
treatment during pregnancy, 445 Hypertensive disorders, 266 pathophysiology, 78
Home blood pressure monitoring, 1 antihypertensive medications, 6 postpartum, 82
Home uterine activity monitoring, 474 chronic hypertension, 1 pregnancy considerations, 79–80
H2 receptor antagonists, 102 anesthesia, 7 screening/diagnosis, 80–81
5-HT3 (Seratonin) receptor antagonist, 103 antepartum testing, 7 signs/symptoms, 78
Human immunodeficiency virus (HIV), 283, classification, 3 treatment, 81
353, 359 complications, 3 type, 81
aneuploidy screening, 364 delivery, 7 hypothyroxinemia, 78, 82
antepartum testing, 364 diagnosis/definition, 1–3 postpartum thyroiditis, 83
breastfeeding, 364 epidemiology/incidence, 3 primary vs. secondary, 80
classification, 360 etiology/basic pathophysiology, 3 subclinical hypothyroidism, 82
complications, 360–361 management, 3–7 thyroid nodule, 83
delivery, 364 postpartum/breastfeeding, 7 TPO-antibodies only, 82–83
diagnosis, 359 risk factors/associations, 3 Hypothyroxinemia, 78, 82
diagnosis of HIV infection in the gestational hypertension, 7 Hypoxia, 158
infant, 365 pre-eclampsia, 8–9
epidemiology, 359–360 anesthesia, 16 I
follow-up of infants, 365 classification, 10
historical notes, 359 complications, 11, 17–18 Ideal body weight (IBW), 60
immunizations, 363–364 delivery, 16–17 Ileal pouch–anal anastomosis (IPAA), 123, 125
intrapartum care, 364 diagnoses/definitions, 9 Immunochromatographic strip (ICS), 381
maternal postpartum care, 364–365 epidemiology/incidence, 10 Immunomodulators/immunosuppressants, 121
pathophysiology, 360 etiology/basic pathophysiology, 10 Impaired psychomotor function, 79
pregnancy considerations, 361 HELLP syndrome, 18–21 Impairment of carbohydrate tolerance, 39
pregnancy management, 361–363 long-term counseling, 21 Impetigo herpetiformis (pustular psoriasis of
preterm premature rupture of management, 11–16 pregnancy), 463
membranes, 364 prediction, 10 complications, 464
prophylaxis for opportunistic risk factors/associations, 10 diagnosis/definition, 463–464
infections, 363 symptoms, 9 epidemiology/incidence, 464
606
etiology/basic pathology, 464
genetics, 464
historic notes, 463
management, 464
risk factors/associations, 464
symptoms, 464
Incarcerated hernias, 135
Individualized growth assessment program
(iGAP), 483
Infections, 139
Inferior vena cava (IVC) filters, 333
Infertility, 79, 92, 171
Inflammatory bowel disease (IBD), 117, 135
Crohn’s disease, 117–123
extraintestinal manifestations, 118
medications, 120, 120–121
ulcerative colitis, 123–125
Inflammatory processes, 204
Infliximab, 121–122, 301
Influenza, 280
complications, 281
diagnosis, 280–281
epidemiology, 280
etiology/basic pathophysiology, 280
management, 282
pregnancy considerations, 281–282
symptoms, 280
therapy, 282–283
vaccination, 394–396
virus testing methods, 281
Infra-renal aortic graft, 139
Inhaled nitric oxide, 436
Inhaled prostacyclin, 436
Inherited thrombophilia, 315
and adverse pregnancy outcomes, 318
classification, 317
complications, 317–318
defined, 315
dose dependency, 319
epidemiology/incidence, 315–316
etiology/basic pathophysiology, 316
fetal thrombophilias, 319
genetics/classification
antithrombin III, 316
factor V Leiden, 316
MTHFR/homocysteinemia, 317
protein C, 316
protein S, 316–317
prothrombin G20210A, 316
management, 319–321
risk factors/associations, 317
Instrumental delivery, 38
Insulin, 61–62, 66, 70–71
Insulin glargine/detemir, 70
Insulin pump therapy, 62
Intensive care unit (ICU), 412; see also
Critical care
defined, 412
equipment and support, 414
Interleukin-1, 38
Interleukin-6, 38
Intermediate care unit (IMCU), 414; see also
Intensive care unit
Intermediate fetal death, 564
Internalized racism, 265
International classification of adult
underweight, overweight, and
obesity according to BMI, 36
Index
Interpersonal therapy (ITP), 213 J
Interpregnancy interval, 486
Intersectionality of discrimination, 265 Japanese encephalitis vaccine, 396
Intervention services, 257 Jarisch–Herxheimer reaction, 382
Intestinal complication, 119
Intestinal transplantation, 142 K
Intimate partner violence (IPV), 257, 258, 403
anesthesia, 260 Kell alloimmunization, 548
antepartum testing, 260 Ketamine, 213
definitions, 257 mood stabilizers, 212–213
delivery, 260 Kidney disease, 4
epidemiology/incidence, 257 Kleihauer–Betke (KB) test, 407, 540
management, 259–260
postpartum/breastfeeding, 260 L
screening, 257–259
symptoms and signs, 257 Labetalol, 6, 7, 16
Intracellular pathology, 27 Lactation, 214–215
Intracranial aneurysm, 199 Laminaria, 568
anesthesia, 200 Lamotrigine, 213
classification and rupture risk, 199 Lansoprazole (prevacid), 102
delivery, 200 Laparoscopic cholecystectomy, 129
epidemiology/incidence, 199 LARCs (long-acting reversible
pregnancy management contraceptives), 48
acute rupture, 199 L-Arginine therapy, 21
preconception counseling, 200 Late fetal death, 564
prenatal care, 200 Latent tuberculosis infection, 283
Intracranial hemorrhage (ICH), 529 Leflunomide, 301, 302
Intrahepatic cholestasis of pregnancy Leptin, 38
(ICP), 111 Leukemia
antepartum testing, 115 acute leukemia, 446–447
classification, 113 chronic leukemia, 447
complications (without treatment), 113 lymphoblastic leukemia, 447
delivery, 115–116 Leukotriene receptor antagonists, 275
diagnosis/definition, 111 Levothyroxine, 81
etiology/basic pathophysiology, 113 Levothyroxine replacement therapy, 81
genetics, 113 Lifestyle changes and bed rest, 4
historic notes, 111 Lifestyle/dietary changes, 104
incidence/epidemiology, 111–113 Lipoprotein receptor-related protein 4
management, 114–115 (LRP4), 200
pregnancy considerations, 113 Lithium, 212
pregnancy management/evaluation, 114 Liver biopsy, 141
risk factors/associations, 113 Liver disease, 111; see also Intrahepatic
symptoms, 111 cholestasis of pregnancy
treatment algorithm, 114 Liver hemorrhage, 8
Intrapartum antibiotic prophylaxis, 389 Liver transplantation (LTx), 137
Intrapartum management of diabetes, 59, 60 Long-term counseling, 21
Intraperitoneal fetal transfusion, 545 Low birth weight, 79, 119
Intrauterine device (IUD), 47 Low birthweight, 171
Intrauterine growth restriction (IUGR), Lower urinary tract infection
8, 139 complications, 177
Intrauterine immunoglobulin treatment, 545 definitions, 177
Intrauterine transfusion (IUT), 532, 546 diagnosis, 177
Intravenous drug use (IVDU), 345 follow-up, 178
Intravenous fluid hydration, 106 microbiologic etiology, 177
Intravenous fluids, 157 screening, 177
Intravenous immunoglobulin (IVIG), symptoms, 177
518, 529 treatment, 178
Intravenous iron (IV), 150 Low-molecular-weight heparin (LMWH),
Intravenous (IV) routes, 150 324, 487
Intravenous prostacyclin, 436 Lung ultrasound (LUS), 421
Invasive cervical cancer, 448–449 Lupus anticoagulant (LA), 309
Iodine, 88 Lysergic acid diethylamide, 250–251
Iodine supplementation, 78, 81
IPV, see Intimate partner violence
M
Iron deficiency, 144
anemia, 146, 148 Macroadenomas, 92–93, 95
Iron supplementation, 149 Macrocytic anemia, 146, 149
Ischemia-reperfusion injury, 437 Macrosomia, 39, 501
Index
Magic mushrooms, 250–251
Magnesium, 14, 21
prophylaxis, 15
sulfate, 493
Marfan syndrome, 32
Marijuana (cannabis), 232, 236
anesthesia, 238
antepartum testing, 238
complications, 237
diagnosis/definition, 236
epidemiology/incidence, 236
etiology/basic pathophysiology, 236
postpartum/breastfeeding, 238
risk factors/associations, 236–237
symptoms, 236
therapy, 237
Maternal anemia, 144
antepartum testing, 150
complications, 147–148
defined, 144
delivery and anesthesia, 150
diagnosis, 148–149
etiology/pathophysiology, 144–146
genetics, 144
iron deficiency anemia, 146
postpartum/breastfeeding, 150
prevalence, 144
prevention, 149
risk factors, 146–147
symptoms, 144
therapy, 149–150
Maternal care, 415–416
Maternal death, 8
Maternal-fetal medicine (MFM), 354
Maternal infection, 516
Maternal mortality, 412, 413
Maternal serum analytes, 487
MCA-PSV surveillance, 542
Mean pulmonary artery pressure (mPAP), 30
Mechanical heart valves, 31–32
Meclizine (bonine, antivert), 102
Meconium aspiration, 38
Medication, 44–45
Mediterranean diets, 68
Melanoma, 447
avoid delay in diagnosis, 447
effects of cancer on pregnancy, 448
staging and sentinel node biopsy, 448
surgery during pregnancy, 448
termination of pregnancy issues, 448
treatment during pregnancy, 448
Meningococcal vaccine, 395
Menstrual abnormalities, 137
6-Mercaptopurine, 121, 447
Mescaline, 250–251
Metabolic abnormality, 57
Metformin (glucophage), 70
Methadone, 241
Methicillin-resistant S. aureus (MRSA), 279
Methimazole, 88–89
Methotrexate, 121, 301, 302
Methyldopa (Aldomet), 5, 6, 7
Methylenetetrahydrofolate reductase
(MTHFR), 317
Methylprednisolone, 103
Metoclopramide (dopamine-2 antagonist),
102, 105–106
Microadenomas, 92, 95, 97
607
Microcytic anemia, 148 m-Tor inhibitors, 176
Microscopic hematuria in pregnancy Mucosal inflammation, 122
definition, 180 Multi-drug resistant organisms, 367
differential diagnosis, 180 Multifetal pregnancy reduction, 474
incidence, 180 Multiple-dose insulin (MDI) injection
management, 180 therapy, 61
risk factors for significant disease, 180 Multiple gestations, 469, 474
Middle cerebral artery doppler, 491 antepartum testing, 478–479
Mild-to-moderate HTN, 5–6 complications, 469–473
Milrinone, 436 abruptio placentae, 473
Mirtazapine, 209 acute fatty liver, 473
Miscarriage, 79 fetal growth restriction and discordant
Misoprostol, 568 growth, 471
Mitral stenosis, 30 gestational diabetes, 473
Mitral valve stenosis, 31 higher rates of chromosomal and
MNS antigen system, 548 congenital anomalies, 471
Moclobemide, 228 monochorionic gestations, 472
Mofetil, 301 peripartum hysterectomy, 473
Monoamniotic twins, 478 pre-eclampsia, 472–473
Monotherapy, 286 preterm birth, 472
Monozygotic (MZ) twins, 469 single fetal demise in multiple
Mood disorders, 203 gestations, 471
bipolar disorder in pregnancy and postpartum spontaneous pregnancy loss, 470–471
definitions and epidemiology, 205 thrombocytopenia, 473
risk factors, 205 definition, 469
timing of symptoms, 205 delivery, 479
brexanolone, 211 diagnosis, 469
depression in pregnancy and postpartum epidemiology/incidence, 469
complications of, 204 etiology, 469
definitions and epidemiology, 203–204 pregnancy considerations, 473
risk factors, 204 prevention and management of
management of mood disorders complications, 473–478
antidepressants, 207 Muscle-specific tyrosine-kinase (MuSK), 200
autism spectrum disorders, 211 Myasthenia gravis, 200
general considerations, 207 anesthesia, 201
persistent pulmonary hypertension of classification, 200
newborn, 210 delivery, 200–201
poor neonatal adaptation syndrome, diagnosis/definition, 200
210–211 epidemiology/incidence, 200
postpartum hemorrhage, 211 postpartum care and breastfeeding, 201
pre-eclampsia, 211 pregnancy management, 200
psychopharmacology, 207 Mycophenolate, 301
spontaneous abortion, 210 Mycophenolate mofetil (MMF), 140, 140, 176,
teratogenicity, 207–210 302
non-pharmacologic management Mycophenolic acid (MPA) products, 140
antidepressants, 215 Myo-inositol, 68
diet, 214
electroconvulsive therapy, 214 N
exercise, 214
lactation considerations, 214–215 Naltrexone, 122
mood stabilizers, 215–217 Narcotics, 157
psychotherapy, 213 Natalizumab, 122
transcranial magnetic stimulation, 214 National Transplantation Pregnancy Registry
screening, recommendations, 205–207 (NTPR), 137
Mood Disorders Questionnaire (MDQ), 207 Nausea/vomiting of pregnancy (NVP) and
Mood stabilizers hyperemesis gravidarum (HG), 99
carbamazepine and oxcarbazepine, 215 classification, 99
ketamine, 211–213 complications, 100
lamotrigine, 215 diagnosis/definition, 99, 100
lithium, 215 epidemiology/incidence, 99
in pregnancy and lactation, 216 etiology, 99
second-generation antipsychotics, 215–217 genetics, 99
valproic acid, 215 management of, 101
Morphine, 157 postpartum, 108
Morphine or hydromorphone, 157 pregnancy management, 100–101
Motor vehicle collision (MVC), 400 risk factors/associations, 99–100
M-RNA vaccines, 393 treatment, 101–107, 102–103
MTHFR/homocysteinemia, 317 Near-miss mortality, 412
608 Index

Neisseria gonorrhoeae, 368 NOTES (Natural Orifice Transluminal etiology, 591

Neonatal alloimmune thrombocytopenia Endoscopic Surgery), 131 management, 591–592, 592
(NAIT), 529 NSAIDs (nonsteroidal anti-inflammatory maternal hydration, 592–593
Neonatal congenital syphilis, 382 drugs), 300–301 sildenafil citrate, 593
Neonatal death, 576 Nucleic acid amplification test (NAAT) Omeprazole (prilosec), 102
Neonatal Graves’ disease, 89 positive, 340 Ondansetron (5-HT3 receptor antagonist),
Neonatal hypoglycemia, 70 Nucleoside analogue drugs, 363 105–106
Neonatal infection, 372 Nucleoside/nucleotide analogs, 347 Opioids, 228, 232
Neonatal toxicity, 216, 244 Nucleoside reverse transcriptase inhibitor anesthesia, 242
Neonatal withdrawal, 237 (NRTI), 362 antepartum testing, 242
Nephritic syndrome (NS), 168 Nucleotide mutation, 153 complications, 240–241
Nephrostomy tube placement, 179 Nulliparity, 10 delivery, 242
Neural tube defects (NTD), 38 Nutrient therapy, 488–489 diagnosis/definition, 238
Neuraxial anesthesia, 196, 335 Nutritional supplementation, 43, 107 epidemiology/incidence, 238–239
Neurodevelopmental effects, 211 Nutrition (Harris–Benedict equation), 107 historic notes, 238
Neurologic disease in pregnancy postpartum/breastfeeding, 243
anesthesia, 193–194 O risk factors/associations, 239
delivery and delivery planning, 193 symptoms, 238
postpartum care and breastfeeding, 194 OARS, 41 therapy, 241–242
pregnancy management, 193 Obese gravida, 41–42 Opioid use disorder, 238
Neutral protamine Hagedorn (NPH), 61, 70 Obesity, 35, 584 Oral contraceptives, 137
New onset diabetes mellitus (NODM), 138 definition and classification, 35–36 Oral corticosteroids, 277
Ngenital diaphragmatic hernia (CDH), 556 epidemiology/incidence, 36–38 Oral hormonal contraception, 47
Nicotine replacement therapy, 227, 227–228 etiology/basic pathophysiology, 38 Oral hypoglycemic agents, 61
Nicotinic acetylcholine receptor genetics, 38 Oral janus kinase inhibiting agents, 122
(AchR Ab), 200 health risks, 38 Orofacial clefts, 38
Nifedipine, 6, 21 intrapartum care, 46 Osteomyelitis, 155
Nitric oxide, 14 anesthesia, 46 Osteoporosis, 329
donors, 489 cesarean delivery, 46–47 Ovarian cancer, 448
Nitrofurantoin, 178 long-term maternal and offspring risks, 48 Oxcarbazepine, 212
N-methyl D-aspartate (NMDA), 249 postpartum, 47 Oxygen, 489
Non-alcoholic steatohepatitis, 137 breastfeeding, 47
Non-Hodgkin’s lymphoma, 446 contraception, 47–48 P
avoid delay in diagnosis, 446 psychological implications, 47
effects on pregnancy, 446 venous thromboembolism, 47 Painless labor, 196
treatment during pregnancy, 446 preconception care/prevention, 39–43 Palpitations, 30
Nonimmune hydrops (NIH) fetalis, 552–553 bariatric surgery, 42–43 Pantoprazole (protonix), 102
associations/possible etiologies/differential behavior therapy, 42 Papillary necrosis, 155
diagnosis, 554–555 pharmacotherapy, 42 Parenteral nutrition, 107
congenital infections, 556–557 physical activity, 42 Paroxetine, 209, 210
extracardiac anomalies, 556 preconception evaluation, 39–40 Partner Violence Screen (PVS), 258
fetal tumors, 557–558 prepregnancy weight reduction, 40–42 Parvovirus, 516
genetics/chromosomal abnormalities, preconception management, 40 complications, 517
555–556 pregnancy complications, 38–39 incidence/epidemiology, 516
hematological disorders, 557 prenatal care, 43 maternal-fetal transmission, 517
conditions associated, 554–555 antepartum fetal testing, 45 natural history of, 517
diagnosis/definition, 553 aspirin, 45 neonate and long-term follow-up, 519
epidemiology/incidence, 553 baseline screening, 45 pathogen, 516
etiology/basic pathophysiology, 553–554 fetal ultrasound, 45 pathophysiology, 516–517
management ideal weight gain, 43–45 pregnancy management
counseling/prognosis, 558 mental health and related issues, 45 counseling/prognosis, 517
therapeutic approach, 561 office accommodations, 45 prevention, 518
workup/diagnosis, 559–561 preterm steroids, 46 screening, 518
maternal complications, 558 prevention of preterm birth, 46 therapy, 518–519
maternal postpartum, 562 risk factors, 35, 38 workup/diagnosis, 518
neonatology management, 562 OB-GYN, 418 risk factors/associations, 516
pathophysiologic mechanisms, 553 Obstetrical complications, 237 symptoms, 516
workup, 560 Obstetric Care Consensus, 417 ultrasound fetal findings, 517
Noninvasive methods of ventilation, 417 Obstetric racism, 262–263 Parvovirus B19, 516, 517
Non-NAAT testing, 369 Obstetrics anal sphincter injury (OASIS), 500 Pathophysiology, 153
Non-obstetric procedure monitoring, 584 Obstructive sleep apnea (OSA), 39 Patient-delivered partner therapy (PDPT), 375
Non-pharmacologic management Odansetron (zofran), 103 Patient Health Questionnaire 9 (PHQ-9), 206
psychotherapy, 213–214 Office accommodations, 45 Pegylated interferon (PEG-IFN), 350, 355
transcranial magnetic stimulation, 214 Oligohydramnios, 131, 591 Pelvic fracture, 402
Nonproteinuric hypertension, 4 amnioinfusion, 593 Pemphigoid gestationis (herpes
Norepinephrine, 436 complications, 591 gestationis), 462
Normocytic anemia, 146, 148 diagnosis/definition, 591 complications, 463
Nortriptyline, 228 epidemiology/incidence, 591 diagnosis/definition, 462–463
Index
epidemiology/incidence, 463
etiology/basic pathology, 463
genetics, 463
historic notes, 462
management, 463
symptoms, 463
Penicillin allergy, 377, 390
People living with HIV (PLHIV), 286
Perimortem cesarean delivery (PMCD), 408, 435
Perinatal mortality, 171
Peripartum cardiomyopathy, 32
Peripartum depression, 203
Peripartum hysterectomy, 473
Persistent pulmonary hypertension of
newborn (PPHN), 210
Pessary, 474
Peyote (mescaline), 250–251
PGE2 suppositories, 568
Pharmacologic thromboprophylaxis in
pregnancy and the postpartum
period, 331
Pharmacotherapies, 42, 227–228
Phencyclidine (PCP), 233, 249
antepartum testing, 250
epidemiology/incidence, 249
etiology/basic pathophysiology, 249
historic notes, 249
postpartum/breastfeeding, 250
pregnancy complications, 249–250
risk factors/associations, 249
symptoms, 249
therapy, 250
Phenothiazines (D2-receptor antagonists), 103
Phenytoin, 15
Pheochromocytoma, 4
Phospholipids, 309
Physical dependence, 233
Physiologic renal changes in pregnancy, 164
Placental abruption, 402
Placental growth factor (PlGF), 10
Placental insufficiency, 483
Placental protein-13, 10
Plasma volume expansion, 17, 489
Pneumococcal and influenza vaccines, 153
Pneumococcal vaccination, 354, 395
Pneumonia, 21, 155, 277–278
classification, 278
diagnosis, 278
epidemiology, 278
etiology/basic pathophysiology, 278
management, 279
pregnancy considerations, 278–279
risk factor, 278
symptoms, 278
treatment, 279–280
Point of care ultrasound (POCUS), 421
Polio vaccine, 395
Polyhydramnios (hydramnios), 593
amniotic fluid assessment in twin
pregnancies, 595
complications, 594
diagnosis/definition, 593
etiology, 593–594
fetal conditions, 594
incidence/epidemiology, 593
labor precautions, 594–595
management, 595
workup, 594
Polymerase chain reaction (PCR), 345, 517
Polymorphic eruption of pregnancy, 459–461
complications, 460
diagnosis/definition, 460
epidemiology/incidence, 460
etiology/basic pathology, 460
genetics, 460
historic notes, 460
management, 460
symptoms, 460
Poor neonatal adaptation syndrome, 210–211
Postpartum/breastfeeding, 7, 72
Postpartum contraceptive management, 30
Postpartum hemorrhage, 211
Postpartum management of
anticoagulation, 336
Postpartum psychosis, 204
Postpartum thyroiditis, 83
Postpartum urinary retention
definition, 179
incidence, 179
management, 179–180
risk factors, 179
Post-thrombotic syndrome (PTS), 326
Pre-conception counseling, 29, 57
Prednisolone, 103
Prednisone, 140, 301
Pre-eclampsia, 8–9, 12, 38, 79, 139, 171–172,
211, 310, 584
anesthesia, 16
classification, 10
complications, 11, 17–18
delivery, 16–17
diagnoses/definitions, 8–9
epidemiology/incidence, 10
etiology/basic pathophysiology, 10
HELLP syndrome, 18–21
long-term counseling, 21
management, 11–16
prediction, 10
risk factors/associations, 4, 10
with severe features, 2, 8
symptoms, 9
without severe features, 2
Pregestational diabetes, 57
anesthesia, 63
antepartum testing, 62–63
basic pathophysiology, 57
classification, 57–58
complications, 58
delivery
intrapartum glucose management, 63
mode, 63
timing, 63
diabetic ketoacidosis, 62
diagnosis/definition, 57
epidemiology/incidence, 57
management, 59, 59
pathophysiology, 57
postpartum/breastfeeding, 63
preconception counseling, 59
pregnancy considerations, 58
prenatal care, 59–60
diet, 60
exercise, 60
glucose monitoring, 61
insulin, 61–62
oral hypoglycemic agents, 61
609
risk factors/associations, 58
symptoms, 57
very tight versus tight control, 62
Pregestational DM, 70
Pregnancy, 26; see also specific entries
antiretroviral therapy in, 361
after breast cancer, 452–453
after cancer, 452
and cardiac disease, 27
after chronic leukemia, 453
complications of obesity, 36–37
delivery timing, 63
diabetes workup in, 58
diabetic ketoacidosis in, 62
after Hodgkin’s lymphoma, 453
hypertrophic cardiomyopathy, 32
after intestinal transplantation, 142
intrapartum, 42
after melanoma, 453
2nd/3rd trimester, 42
postpartum, 42
preconception, 41–42
pruritus during, 112
with pulmonary hypertension, 30
1st trimester, 42
after thyroid carcinoma, 453
after uterine transplantation, 142
and vaccine-preventable diseases, 393
Pregnancy after liver transplantation, 137
antepartum testing, 141
breastfeeding, 141
comorbidity and risk factors, 138–139
acute cellular rejection, 139
anemia, 139
cytomegalovirus acute infection, 139
diabetes, 139
hepatitis virus reactivation, 138–139
hypertension and renal
insufficiency, 139
infections, 139
infra-renal aortic graft, 139
complications, 139
abnormal blood chemistry and liver
function tests, 139
intrauterine growth restriction, 139
pre-eclampsia, 139
preterm birth and low birth weight, 139
definition/symptoms and signs of end stage
of liver disease, 137
epidemiology, 137
historic notes, 137
immunosuppression therapy, 139–140
indications, 137
labor and delivery issues, 141
pathophysiology, 137–138
workup and management, 140–141
Pregnancy-associated plasma protein-A
(PAPP-A), 10
Pregnancy Mortality Surveillance System
(PMSS), 264
Pregnancy-related mortality ratio
(PRMR), 262
Pregnancy-unique quantification of emesis/
nausea (PUQE), 99
Prenatal care, 59, 59–60
diet, 60
exercise, 60
glucose monitoring, 61
610 Index

insulin, 61–62 Pulmonary sequestration, 556 epidemiology, 288

oral hypoglycemic agents, 61 Pulmonic stenosis, 31 etiology/basic pathophysiology, 288
Prenatal care/antepartum testing, 29 Pulsatility index (PI), 491 management, 289–292
Prenatal exercise, 501 Purified protein derivative (PPD), 284 pregnancy considerations, 289
Prepregnancy obesity, 39 Pyelonephritis, 177–178 risk factors/associations, 288
Preterm birth, 39, 79, 119, 210; see also Pyridoxine, 106, 286 symptoms, 288
Cesarean delivery; Pregnancy; influenza, 280
specific entries R complications, 281
and low birth weight, 139 diagnosis, 280–281
prevention, 46 Rabies vaccine, 395 epidemiology, 280
Preterm labor, 171, 474 Race, 263 etiology/basic pathophysiology, 280
Preterm premature ruptured membranes, 584 Racial disparities in obstetrics, 264 management, 282
Prevention of urinary incontinence, 179 Racism and racial disparity in obstetrics, pregnancy considerations, 281–282
incidence, 179 262–263 symptoms, 280
prevention, 179 anesthesia and analgesia, 267 therapy, 282–283
Primary acute maternal infection, 511 hypertensive disorders, 266–267 pneumonia, 277–278
Prochlorperazine maleate (compazine; interpersonal discrimination influencing classification, 278
bukatel), 103 quality of care, 264–266 diagnosis, 278
Proctitis/proctocolitis, 373 maternal mortality, 264 epidemiology, 278
Progesterone, 14, 474 epidemiology, 264 etiology/basic pathophysiology, 278
Prolactinoma, 92 interventions, 265 management, 279
anesthesia, 96 mechanisms, 264–265 pregnancy considerations, 278–279
antepartum testing, 96 prenatal care, 266–267 risk factors, 278
classification, 92 preterm birth, 265 symptoms, 278
complications Radiation dose, 407 treatment, 279–280
fetus, 93 Radioiodine, 88 tuberculosis, 283
mother, 92–93 Randomized controlled trials (RCTs), 241 diagnosis, 285
delivery, 96 Ranitidine (zantac), 102 epidemiology, 283
diagnosis/definition, 92 Rapid testing, 359 etiology/basic pathophysiology, 283
epidemiology/incidence, 92 RBC alloimmunization, 536 management, 285–286
etiology/basic pathophysiology, 92 RECOVERY trial, 416 pregnancy considerations, 285
postpartum, 96 Red blood cell alloimmunization, 538 pregnancy management, 285
pregnancy considerations, 93 Red blood cells (RBC), 144, 536 risk factors/associations, 283–284
pregnancy-related management, 93–96 Reduced red blood cell/hemoglobin screening, 284
prenatal care, 96 production, 557 symptoms (of active disease), 284
symptoms, 92 Renal artery stenosis, 4 therapy, 286–287
Promethazine (phenothiazines), 103, 106 Renal failure, 8 Rest/exercise, 14
Prophylactic antibiotics, 47 Renal transplantations, 141, 175 Resuscitative hysterotomy (RH), 408
Prophylactic blood transfusions, 153 complications, 175 Ribavirin, 350, 355
Prophylactic tocolysis, 474 effects of pregnancy on KT, 176–177 Rituximab, 301
Prophylaxis after cesarean delivery, 336 labor and delivery, 177 5 Rs for Smokers, 224
Prophylaxis for APS during pregnancy and preconception counseling, 175–176 Rubella, 345
postpartum, 312 principles, 175
Prophylaxis for opportunistic infections, 363 Renovascular hypertension, 4 S
Propranolol, 88 Repetitive transcranial magnetic stimulation
Propylthiouracil (PTU), 88–89 (rTMS), 214 S-adenosylmethionine (SAMe), 115
Prostaglandin F2α (Carboprost), 277 Resistance index (RI), 491 Salmeterol (advair), 275
Protease inhibitor (PI), 355, 361, 363 Resistin, 38 Salt intake, 14
Protein C, 315–316 Respiratory diseases, 269 Seat belts, 403
Protein S, 315–317 asthma Second generation antipsychotics, 213
Proteinuria, 171–172 acute treatment, 277 Secukinumab, 301
Prothrombin 20210A gene mutation (PGM), 315 anesthesia, 277 Seizures, 8, 187
Prothrombin G20210A, 316 antepartum testing, 277 classification, 188
Proton pump inhibitors (PPIs), 102, 105 classification, 269 complications, 188–189
Pruritus, 113 delivery, 277 delivery, 191
during pregnancy, 112 diagnosis, 269 diagnoses/definitions, 187–188
Pseudomonas aeruginosa, 279 epidemiology, 269 epidemiology/incidence, 188
Psilocybin (magic mushrooms), 250–251 etiology/basic pathophysiology, 269 management, 189–191
Psychological dependence, 233 management, 272–273 postpartum/breastfeeding, 191
Psychopharmacology, 207 postpartum/breastfeeding, 277 risk factors/associations, 188
Psychotherapy, 213–214 pregnancy complications, 271–272 symptoms, 188
Ptyalism, 100 pregnancy considerations, 272 therapy, 191
Pulmonary angiography, 328 status asthmaticus, 277 Selenium, 79
Pulmonary edema, 8 symptoms, 269 Sepsis, 424–429
Pulmonary embolism (PE), 324, 328, 434 therapy, 273–277 Serial echocardiography, 33
Pulmonary embolus, workup for, 329 COVID-19 Serotonin and norepinephrine reuptake
Pulmonary hypertension, 28, 30–31 delivery, 292 inhibitors (SNRIs), 207
classification, 30 diagnosis, 288–289 Serotonin reuptake inhibitors, 228
Index 611

Sertraline, 208 therapy, 226–228 cocaine (benzoylmethylecognine)

Serum, 507 assessment for intervention, 226 anesthesia, 245
Serum ferritin, 144 bupropion HCl (Zyban®, antepartum testing, 245
Serum fibrinogen, 438 Wellbutrin®), 228 diagnosis/definition, 243
Severe HTN, 6 combination therapies, 228 epidemiology/incidence, 243
Severe maternal morbidity, 412, 413 counseling, 226–227 etiology/basic pathophysiology, 243
Severe obesity, 35 nicotine replacement therapy, historic notes, 243
Severe pulmonary hypertension, 26 227–228 maternal and perinatal
Sexual intercourse, 377 pharmacotherapies, 227–228 complications, 244
Sexually transmitted diseases (STDs), 345 varenicline (Chantix®), 228 postpartum/breastfeeding, 245
Short-acting β-agonists (SABA), 271 Societal-level barriers, 262 risk factors/associations, 244
Shoulder dystocia, 38, 500 Sodium nitroprusside, 16 symptoms, signs and cardiopulmonary
Sickle cell disease, 153 Soluble Flt-1, 10 complications, 243
acute chest syndrome, 158–159 Spinal cord injury and autonomic therapy, 244–245
alloimmunization, 158 dysreflexia, 194 defined, 233
anesthesia, 158 anesthesia, 197 hallucinogens
antenatal testing, 158 classification, 194 antepartum testing, 251
complications, 155 complications, 194 complications, 251
contraception, 158 delivery, 196–197 diagnosis/definition, 250
delivery, 158 diagnosis/definition, 194 epidemiology/incidence, 250
diagnosis, 154 epidemiology/incidence, 194 etiology/basic pathophysiology, 250
epidemiology/incidence, 154 postpartum care and breastfeeding, historic notes, 250
genetics/inheritance, 154 197–198 postpartum/breastfeeding, 251
HbSC disease, 159 pregnancy management, 194–196 symptoms, 250
HbS-/βTHAL, 159 Splenic infarctions, 155 therapy, 251
hemoglobin E, 159 Spontaneous abortion, 210 incidence, 233
historic notes, 153 Stage 1 hypertension, 3 management, 235
pathophysiology, 153 Steroids, 176, 547 marijuana (cannabis), 232, 236
postpartum, 158 and magnesium sulfate, 493 anesthesia, 238
pregnancy management, 156–157 Stillbirth, 119, 124, 225, 564, 576 antepartum testing, 238
sickle cell trait, 159 Streptococcus pneumoniae vaccination, 397 complications, 237
symptoms, 154, 154–155 Stress, 204 diagnosis/definition, 236
therapy, 157 Striae gravidarum (SG) epidemiology/incidence, 236
Sickle cell trait, 159 diagnosis/definition, 458 etiology/basic pathophysiology, 236
Sildenafil, 436, 489 epidemiology/incidence, 458 postpartum/breastfeeding, 238
Single fetal death, 475 etiology/basic pathology, 458 risk factors/associations,
Sirolimus, 140 genetics, 458 236–237
Skin reactions, 329 management, 459 symptoms, 236
Smokeless tobacco, 225 risk factors/associations, 458 therapy, 237
Smoking, 223 Subclinical hyperthyroidism, 86 opioids, 232
5 As for Patients Who Are Willing to Subclinical hypothyroidism, 78, 82 anesthesia, 242
Quit Smoking, 224 Substance abuse, 233 antepartum testing, 242
bans, 226 signs and symptoms, 234 complications, 240–241
breastfeeding, 229 Substance use, 233 delivery, 242
cessation, 226, 486 Substance use disorders (SUD), 232–233 diagnosis/definition, 238
cessation counseling, 224 amphetamines, 232, 245 epidemiology/incidence, 238–239
complications, 225 anesthesia, 247 historic notes, 238
diagnosis/definition, 223 antepartum testing, 247 postpartum/breastfeeding, 243
epidemiology/incidence, 223 complications, 246–247 risk factors/associations, 239
etiology/basic pathology, 223–224 diagnosis/definition, 245 symptoms, 238
carbon monoxide, 224 epidemiology/incidence, 246 therapy, 241–242
carcinogens, 224 etiology/basic pathophysiology, 246 phencyclidine (PCP), 233, 249
nicotine, 223–224 postpartum/breastfeeding, 247 antepartum testing, 250
genetics, 223 risk factors/associations, 246 epidemiology/incidence, 249
historic notes, 223 symptoms, signs and organ etiology/basic pathophysiology, 249
management, 226 toxicity, 245–246 historic notes, 249
postpartum, 229 therapy, 247 postpartum/breastfeeding, 250
pregnancy considerations, 226 benzodiazepines, 232, 247 pregnancy complications, 249–250
prevention, 229 antepartum testing, 249 risk factors/associations, 249
reduce consequences of smoking in complications, 248 symptoms, 249
newborn, 229 diagnosis/definition, 247–248 therapy, 250
reduce initiation, 229 epidemiology/incidence, 248 preconception counseling,
reduce pregnancy etiology/basic pathophysiology, 248 235–236
complications, 229 historic notes, 247 prenatal care, 236
relapse prevention, 229 postpartum/breastfeeding, 249 prevention, 235
principles, 226 risk factors/associations, 248 4Ps, 234
risk factors, 224–225 symptoms, 248 risk factors, 233–234
taxation, 226 therapy, 249 workup, 234–235
612 Index

Superimposed pre-eclampsia, 2, 17 Thyroid-stimulating hormone-binding stabilization, 405

Syphilis, 377
complications, 379
defined, 377
incidence/epidemiology, 377
management, 379–383
oral desensitization protocol, 382
pathophysiology and transmission,
377–378
risk factors, 379
screening, 380, 380
serologic testing, 380
symptoms and classification, 378–379
treatment, 381
Systemic hypertension, 194
Systemic lupus erythematosus (SLE),
297, 309
antepartum testing, 303
cardiac neonatal lupus/congenital heart
block, 303–305
complications
fetal/neonatal, 299
maternal, 299
contraception, 305
delivery, 303
diagnosis, 297
epidemiology/incidence, 297
etiology/basic pathophysiology, 297
management, 299–300, 299–303
neonatal lupus, 303
postpartum/breastfeeding, 303
pregnancy considerations, 299
symptoms, 297
Systemic vascular resistance (SVR), 27
Systolic/diastolic (S/D) ratio, 491
T cardiopulmonary resuscitation, 408
Tachycardia, 31, 243
Tacrolimus, 140, 176, 301
Td/Tdap vaccination, 396
Tenofovir, 347
Tenofovir disoproxil fumarate (TDF), 347
Teratogenicity, 207–210
Tetralogy of fallot, 31
α-Thalassemia, 147
β-Thalassemia, 147
Theophylline, 275
Therapeutic anticoagulation, 324
Thiazide diuretics, 6
Thionamides, 88
Thrombophrophylaxis, 48, 122
for pregnancies, 320
Thrombosis, 194
Thrombotic microangiopathies
(TMA), 169
Thrombotic thrombocytopenic purpura
(TTP), 168
Thromboxane, 10
Thyroid-binding globulin (TBG), 79
Thyroid cancer, 449–450
Thyroid disease, 78
Thyroid dysfunction in pregnancy, 80, 81
Thyroidectomy, 88
Thyroid function tests, 207
Thyroid nodule, 83, 89
Thyroid physiology, 79
inhibitory immunoglobulins workup and management, 404
(TBIIs), 86 prognostic factors, 401
Thyroid-stimulating hormone Trauma-informed approach, 258
percentiles, 80 Trazadone, 209
Thyroid-stimulating immunoglobulins Treponema carateum, 380
(TSIs), 86 Treponema pallidum, 377, 379
Thyroid storm, 86, 89–90 Trichomonas, 384
Thyrothoxicosis, 86, 88 complications/risks, 384–385
Thyroxine replacement, 81 epidemiology/incidence, 384
Tobacco dependence, 223; see also Smoking management, 385–386
Tocilizumab, 301 pathophysiology/etiology, 384
Tofacitinib, 122 symptoms/signs, 384
Tolerance, 233 transmission, 384
Toxins, avoidance of, 488 Trichomonas vaginalis, 384–385
Toxoplasma gondii (T. gondii), 511 screening/diagnostic tests, 385
Toxoplasmosis, 511 Trimethobenzamide (tigan), 102
complications, 512 Trimetoprim-sulfamethoxazole, 178
maternal-fetal transmission, 511–512 TSH receptor antibodies, 86
pathogen, 511 TTTS, see Twin-to-twin transfusion
pathophysiology, 511 syndrome
pregnancy management Tuberculin skin test (TST), 283
prevention, 512 reaction, 284
principles, 512 Tuberculosis, 283
screening, 513 diagnosis, 285
therapy, 514 epidemiology, 283
workup/diagnosis, 513–514 etiology/basic pathophysiology, 283
symptoms, 511 management, 285–286
TPO-antibodies only, 82–83 pregnancy considerations, 285
Transaminases, 111, 114 pregnancy management, 285
Transcranial magnetic stimulation, 214 risk factors/associations, 283–284
Transient ischemic attacks, 155 screening, 284
Transthoracic echocardiography (TTE), symptoms (of active disease), 284
421–422 therapy, 286–287
Transverse myelitis, 194 Tuberculosis screening algorithm, 285
Trauma, 400 Tumor necrosis factors inhibitors (TNF
inhibitors), 302
complications, 401 Twin gestations, 470, 470
fetal death, 402 Twin-to-twin transfusion syndrome (TTTS),
fetal injury, 402 472, 557
fetal/neonatal outcomes, 401 diagnosis, 476
hospitalization, 401 etiology, 475–476
hysterectomy, 401 incidence, 475
maternal death, 401 management of, 477
pelvic fracture, 402 prognosis and counseling, 476
placental abruption, 402 screening for, 476
transfusion, 401 staging for, 476, 477
uterine rupture, 402 Typhoid vaccine, 396
complications from assault, 402
defined, 400 U
delivery, 408–409
etiology/basic pathophysiology, 400–401 Ulcerative colitis
incidence, 400 classification, 123
management algorithm for trauma in complications, 123–124
pregnancy, 404 definition, 123
maternal stabilization, 405 diagnosis, 123
pregnancy considerations, 402–403 epidemiology/incidence, 123
pregnancy management, 403–408 etiology/basic pathophysiology, 123
care of pregnant trauma patient, 403 management, 124–125
evaluation and diagnostic studies, Montreal classification, 123
405–408 pregnancy considerations, 124
mass transfusion protocol, 407 signs/symptoms, 123
pre hospital decision making, Ultrasound, 89
403–404 Umbilical artery Doppler, 488, 491
prevention of injury, 403 Umbilical artery doppler index
radiation in the pregnant trauma abnormality, 581
patient, 407–408 Unfractionated heparin (UFH), 311, 324
Index 613

Upper urinary tract infection (pyelonephritis) postpartum urinary retention Valacyclovir, 508–509, 523
complications, 178 definition, 179 Valproic acid, 212
definition, 178 incidence, 179 Varenicline (Chantix®), 228
diagnosis, 178 management, 179–180 Varicella vaccination, 364
incidence, 178 risk factors, 179 Varicella zoster virus (VZV), 345, 525
management, 178 prevention of urinary incontinence, 179 complications, 526
symptoms, 178 incidence, 179 incidence/epidemiology, 525
Urinary nephrolithiasis prevention, 179 infectious sequence, 526
complications, 179 renal transplantation, 175 maternal-fetal transmission, 525–526
diagnosis, 179 complications, 175 pathogen, 525
incidence, 178–179 effects of pregnancy on KT, 176–177 pathophysiology, 525–526
management, 179 labor and delivery, 177 pregnancy management
risk factors, 179 preconception counseling, 175–176 chickenpox, 527–528
Urinary tract disease, 164 principles, 175 counseling, 526
acute kidney injury upper urinary tract infection exposed to VZV, 527
classification and clinical (pyelonephritis) maternal shingles (herpes zoster), 528
approach, 167 complications, 178 nonimmune women, 528
definition, 166–167 definition, 178 pregnancy considerations, 526
epidemiology, 167 diagnosis, 178 prevention, 526
postrenal, 168 incidence, 178 screening, 527
pre-eclampsia, 168–169 management, 178 therapy, 527–528
pregnancy considerations and symptoms, 178 workup/diagnosis, 527
outcomes, 170 urinary nephrolithiasis risk factors/associations, 525
prerenal, 167 complications, 179 symptoms, 525
renal, 167–168 diagnosis, 179 Vascular damage, 326
renal biopsy, 169 incidence, 178–179 Vascular endothelial growth factor
treatment, 169–170 management, 179 (VEGF), 10
chronic kidney disease risk factors, 179 Vascular injury, 163
complications, 171 Urinary tract infections, 155, 158 Vasopressin, 436
definition, 170 Urine cotinine testing, 226 Vedolizumab, 122
effects of pregnancy, 171 Urine culture sensitivity, 178 Venlafaxine, 209
epidemiology, 171 Urine drug screen (UDS), 234 Venous plasma glucose levels, 61
lupus nephritis, 174 Urine protein-creatinine ratio (P/Cr), 166 Venous stasis, 326
nephrotic syndrome, 173–174 Ursodeoxycholic acid (Ursodiol), 114–115 Venous thromboembolism (VTE), 47, 315
symptoms, 171 Ustekinumab, 122, 301 antepartum testing, 335
vasculopathies, 174 Uterine and anticoagulation, 324
dialysis in ESRD, 174–175 artery Doppler, 10, 487, 492 complications, 326–327
antepartum testing, 175 atony, 438 contraception, 336
labor and delivery, 175 hypoperfusion, 434 defined, 324
neonatology, 175 palpation techniques, 196 delivery and anesthesia, 335–336
postpartum, 175 rupture, 402 epidemiology and incidence, 325
lower urinary tract infection transplantation, 142 etiology/basic pathophysiology,
complications, 177 325–326
definitions, 177 V genetics, 325
diagnosis, 177 management, 327–328
follow-up, 178 Vaccination, 393 clinical scenarios, and anticoagulation,
microbiologic etiology, 177 clinical guide summary, 397 329–332
screening, 177 contraindications to, 398 onset DVT and PE in pregnancy, treatment
symptoms, 177 general guidelines, 393–394 of, 332–333
treatment, 178 historical notes, 393 postpartum management of
management, 171 not recommended in pregnancy, 397 anticoagulation, 336
antepartum testing, 173 pregnancy and vaccine-preventable prevention, 333–334
delivery, 173 diseases, 393 prophylaxis, 157
long-term renal prognosis, 173 recommended for all women of prophylaxis after cesarean delivery, 336
postpartum/breastfeeding, 173 childbearing age, 394 prophylaxis in women with mechanical
preconception, 172 recommended for pregnant women, heart valves, 334–335
prenatal care, 172–173 395–396 radiation exposures of diagnostic
workup, 171–172 specific vaccines, 394 tests, 327
microscopic hematuria in pregnancy COVID-19, 397–398 risk factors/associations, 326
definition, 180 hepatitis B, 396–397 symptoms, 324–325
differential diagnosis, 180 influenza, 394–396 Ventricular septal defects (VSD), 30
incidence, 180 streptococcus pneumoniae, 397 Vibroacoustic stimulation (VAS), 574
management, 180 Td/Tdap, 396 Viral load (VL), 360
risk factors for significant Vaginal birth after cesarean (VBAC) Vitamin B6 (pyridoxine), 102, 104–105
disease, 180 section, 46 Vitamin C, 229
physiologic renal changes in Vaginal delivery, 16, 33, 197, 200, 438 Vitamin E 400 IU supplementation, 229
pregnancy, 164 Vaginal intercourse, 384 Vitamin K, 115
614
Vitamin K–dependent polypeptide, 316
Von Willebrand disease, 161
classification, 161–162
complications, 162
diagnosis/definition, 161
epidemiology/incidence, 161
etiology/basic pathophysiology, 161
genetics, 161
historic notes, 161
peripartum management, 164
pregnancy considerations, 162
pregnancy management, 162–165
symptoms, 161
Index
W Wet mount, 385
Woman abuse screening tool (WAST), 258
Warfarin (coumadin), 324, 331–332
Warfarin therapy, 334
Weight gain, 44–45, 474 Y
counseling/coaching, 45 Yellow fever vaccine, 396
diet, 44
exercise, 44
medication, 44–45 Z
Weight loss, assess readiness for, 40 Zidovudine, 362
Weight loss with diet, 35 Zinc supplements, 71
Wellbutrin®, 228 Zyban®, 228
Wernicke’s encephalopathy, 100