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 TOG
The Obstetrician & Gynaecologist
The journal for continuing professional development
from the RCOG
The CPD journal from the RCOG ISSN 1467-2561/1744-4667 (online)
http://onlinetog.org http://onlinetog.org

Volume 23 Issue 3 2021

Contents

Editorial CPD
167 Editorial 220 CPD questions for volume 23 issue 3
Kate Harding

224 TOG ratings

Commentary
168 How doctors in South-East Asia can benefit from the new RCOG Letters and emails
CPD programme 226 Re: Safe use of electrosurgery in gynaecological laparoscopic
Sambit Mukhopadhyay, Mala Arora surgery
Dhanuson Dharmasena, Abha Govind

Reviews 228 Authors’ reply

Mohsen El-Sayed, Sahar Mohamed, Ertan Saridogan
170 Fertility on ice: an overview of fertility preservation for children
SBA
and adolescents with cancer 229 Re: Management of ovarian cysts in children and adolescents
Lucia Hartigan, Louise E Glover, Mary Wingfield Elizabeth Ande, Sayantana Patra-Das, Abha Govind
177 Nonepithelial ovarian cancers
SBA
Holly Baker-Rand, Katharine Edey
UKOSS update
187 Intrauterine contraception 231 UKOSS update
SBA
Joanne Ritchie, Nicholas Phelan, Paula Briggs Marian Knight
196 Identification and management of fetal anaemia: a practical guide
SBA
James Castleman, Leo Gurney, Mark Kilby, R Katie Morris
And finally…
206 Antenatal venous thromboembolism
SBA
David A Crosby, Ann McHugh, Kevin Ryan, Bridgette Byrne 232 Golden jubilee
James Drife

Education
213 Non-mesh surgery for stress urinary incontinence
Priyanka H Krishnaswamy, Veenu Tyagi, Karen Lesley Guerrero
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 DOI: 10.1111/tog.12753 2021;23:170–6
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Fertility on ice: an overview of fertility preservation for

children and adolescents with cancer
MBBchBAO MRCPI MRCOG, *
a b,c,d e,f,g,h
Lucia Hartigan Louise E Glover BSc PhD, Mary Wingfield MD FRCOG
a
Clinical Research Fellow, National Maternity Hospital and Merrion Fertility Clinic, Dublin 2, Ireland and University College Dublin, School of
Medicine, Dublin 4, Ireland
b
Clinical Research Officer, Merrion Fertility Clinic, Dublin 2, Ireland
c
Adjunct Assistant Clinical Professor/Clinical Lecturer, University College Dublin, School of Medicine, Dublin 4, Ireland
d
Adjunct Assistant Professor, Trinity College Dublin, School of Medicine (Immunology), Dublin 2, Ireland
e
Consultant Obstetrician Gynaecologist, National Maternity Hospital, Dublin 2, Ireland
f
Clinical Director, Merrion Fertility Clinic, Dublin 2, Ireland
g
Associate Clinical Professor/Clinical Lecturer, University College Dublin, School of Medicine, Dublin 4, Ireland
h
Adjunct Professor, Trinity College Dublin, School of Medicine, Dublin 2, Ireland
*Correspondence: Lucia Hartigan. Email: luciahartigan@hotmail.com

Accepted on 20 August 2020. Published online 15 June 2021.

Key content  To raise awareness of the importance of early discussions about FP

 Continued advances in oncology treatments have led to better
survival rates for children and young adults with cancer.
 An important ‘late effect’ of cancer treatment is the loss of fertility.
 Although many survivors of childhood cancers go on to conceive
without difficulty, the potential loss of fertility is a concern for
children and young adults with cancer, their parents and caregivers.
 We review current options for fertility preservation (FP) for
prepubertal and postpubertal girls and boys, including oocyte
cryopreservation, ovarian tissue cryopreservation, sperm
cryopreservation and testicular tissue cryopreservation.
Learning objectives
 To understand the different FP methods available for children and
adolescents, the barriers to FP and ethical and
psychological considerations
with patients who are at risk of infertility from their
cancer treatment.
Ethical Issues
 Autotransplantation of ovarian tissue in survivors of
haematological malignancies, particularly leukaemia, carries a
strong risk of re-introducing the malignancy and should
be avoided.
 Clinicians must consider suitability of the patient for FP, taking
into account emotional maturity, patient and parent desire for FP
and the physical fitness of the patient, including their
immunosuppressive state.
Keywords: child and young adult cancer / fertility preservation /
oocyte cryopreservation / ovarian tissue cryopreservation

Please cite this paper as: Hartigan L, Glover LE, Wingfield M. Fertility on ice: an overview of fertility preservation for children and adolescents with cancer. The
Obstetrician & Gynaecologist 2021;23:170–6. https://doi.org/10.1111/tog.12753

Fertility preservation (FP) is the preservation of an

Introduction
Continued advances in oncology treatments have led to
better survival rates for children (0–14 years), adolescent (15–
19 years) and young adult (20–24 years) cancer patients.1
Overall survival is now greater than 80%. Because of this,
there is increasing emphasis on improving the long-term
quality of life of cancer survivors. Efforts to reduce the
downstream sequelae of treatment are increasingly a priority.
When a patient who has not yet reached their reproductive
goals is given a cancer diagnosis, it is best practice to discuss
their future fertility because chemotherapy, radiotherapy and
some surgical treatments may lead to a reduction or loss of
gonadal function. Thus, one of the most important ‘late
effects’ of cancer treatment is the loss of fertility.2
individual’s oocytes, sperm or gonadal tissue so that the
individual may use them to have their own biological
children in future. Consideration of FP is indicated if there is
a risk of future gonadal failure for any aetiology;3 however,
this review article focuses on FP options for children and
young adults with cancer.
Effects of oncology treatment on
subsequent fertility and reproductive
function
Childhood cancers are treated using various regimens, such as
chemotherapy, surgery, haematopoietic stem cell transplant
and radiotherapy including proton therapy. More recently,

170 ª 2021 Royal College of Obstetricians and Gynaecologists


immune-based therapies have also been adopted.
Conventional treatment modalities can negatively affect
reproductive potential through inadvertent injury to the
hypothalamic–pituitary axis and to the reproductive organs
themselves; for example, the ovary, testes, uterus and vagina.4
The effects of radiotherapy depend on the dose received,
the fractionation schedule and the targeted field of radiation.
The effects of chemotherapy are related to the type of agent
used, as well as the cumulative dose received.5
Total body irradiation, radiotherapy to a field that includes
the ovaries or testes, and the use of alkylating agents including
cyclophosphamide, busulfan and chlorambucil, pose the
greatest risk of gonadotoxicity.6 Higher accumulated doses of
alkylating agents lower anti-m€ ullerian hormone (AMH) levels
and decrease the chance of pregnancy.7 Radiation therapy
damages granulosa cells, with subsequent damage to ovarian
follicles. Irradiation of the ovaries of 10 Gy and above is
associated with premature ovarian insufficiency.7
Methods of fertility preservation
Sperm cryopreservation
Thirty percent of male survivors of childhood cancer suffer
from azoospermia (no sperm) and 18% suffer from
oligospermia (reduced sperm).8 Where appropriate,
postpubertal boys who are given a cancer diagnosis should
be given the option of sperm cryopreservation before
commencing treatment. This method of FP is well
established, relatively noninvasive and, usually, does not
delay oncology treatment to any significant degree.
However, sperm cryopreservation has its limitations. It is
only suitable for postpubertal boys, some boys may suffer
anxiety and be unable to produce a sperm sample by
masturbation, or there may be religious or cultural concerns.9
Limitations may also be imposed by the nature of the disease
itself (for example, patients with cord compression display
impairment of the normal neurological pathways required
for ejaculation) and by medication side effects (such as
analgesic narcotics required for pain control). Nevertheless,
several studies have demonstrated that most adolescent
cancer patients can produce a semen sample, including
boys as young as 12 years of age.10,11
Sperm quantity and quality may also be adversely affected by
the primary tumour, most notably in cases of malignant
testicular neoplasms.8 A UK study published in 200211 looked
at 238 adolescent patients referred for sperm cryopreservation
before cancer treatment. Diagnoses included testicular cancer,
leukaemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma,
osteosarcoma, Ewing’s sarcoma, acute lymphoblastic
leukaemia (ALL) and acute myeloid leukaemia (AML). Of
these 238 patients, 33 (13.9%) were unable to produce a
sample, while 205 (86.1%) successfully provided a sample
suitable for cryopreservation. No cases of azoospermia were
ª 2021 Royal College of Obstetricians and Gynaecologists
Hartigan et al.
reported pre-treatment. Sperm parameters were broadly
uniform across all cancer types, with sperm counts increasing
in an age-dependent manner.11
Oocyte cryopreservation
For postpubertal females, the established options for FP are
embryo or oocyte cryopreservation.12 However, given the
young age of child and young adult patients, oocyte
cryopreservation is usually most appropriate.
Cryopreservation refers to the cooling of cells and tissues
to sub-zero temperatures, thus halting all biological activity
so that they can be preserved for future use.13 The human
metaphase II oocyte is a particularly fragile cell, owing to its
large size, large cytosolic water content and chromosomal
rearrangement.14 Initial oocyte freezing efforts using a ‘slow
freezing’ technique were hampered by cellular damage, ice
crystal formation or excessive dehydration, so this technique
has now been replaced by vitrification. Vitrification is a
process of cryopreservation using high concentrations of
cryoprotectants and rapid cooling to avoid the formation of
ice crystals. This has markedly improved the viability of
cryopreserved cells.13 The first human birth from a frozen
oocyte was reported in 1986.15
Embryo and oocyte vitrification require at least one cycle
of ovarian stimulation with subsequent oocyte retrieval, thus
are not appropriate for prepubertal girls.
Ovarian stimulation usually takes 2 weeks and involves self-
administration of follicle-stimulating hormone injections.
Development of ovarian follicles, each containing an oocyte,
is tracked using ultrasound scans and serum hormone levels.
Ideally, the ovarian stimulation regime begins at the start of the
menstrual cycle. However, random-start protocols are
also used, with obvious benefits for oncology patients who
need to commence cancer treatment as soon as possible.
Recently, the idea of ‘back-to-back’ stimulation protocols has
been introduced. This involves a double ovarian stimulation
during both the follicular and luteal phases, with the intention
of achieving a greater oocyte yield in less time.16 Oocyte retrieval
is typically performed by ultrasound-guided transvaginal
needle aspiration under sedation. Increasing evidence for the
safety of the procedure led oocyte vitrification to be reclassified
from experimental to nonexperimental in 2013 by both the
American Society of Reproductive Medicine (ASRM) and the
European Society for Human Reproduction and Embryology
(ESHRE).17 The procedure is now in routine use in clinical
assisted reproduction.
Risks associated with ovarian stimulation for oocyte
cryopreservation in postpubertal females are 1) delayed
initiation of cancer treatment, 2) ovarian hyperstimulation
syndrome (OHSS) in girls with high ovarian reserve and 3)
the effect of stimulation protocols that increase estrogen
levels on hormone-dependent malignancies. For estrogen-
dependent breast and gynaecologic cancers (rare in under 25-
171
 Fertility on ice
year-olds), current recommendations indicate use of
aromatase inhibitor-based protocols for ovarian
stimulation, because these may mitigate the risk of cancer
recurrence.18 Furthermore, it is important to take into
account that the process of ovarian stimulation and oocyte
retrieval requires ultrasound scans; these are usually
performed transvaginally, so require a certain level of
physical and psychological maturity.
Notably, a recent large multicentre study of oocyte
vitrification and in vitro fertilisation (IVF) outcomes
revealed markedly lower success rates in young women
(≤35 years) who used this fertility preservation method after
cancer diagnosis compared with age-matched women seeking
elective fertility preservation for non-oncological reasons.19
This included significantly lower oocyte survival (81.2%
versus 91.4%), and reduced cumulative live birth rates (40%
versus 70%). This important study suggests that primary
malignancy may affect reproductive potential and should be
taken into consideration when counselling patients.
Ovarian tissue cryopreservation
Ovarian tissue cryopreservation (OTC) involves laparoscopic
surgery to remove all or part of the ovary, followed by
cryopreservation of the excised tissue with a view to
autotransplantation in the future. The tissue may be
transplanted back to the patient’s pelvic cavity
(orthotopically), or to a site outside of the pelvic cavity; for
example, to the forearm or rectus muscle (heterotopically).20
Typically, strips of ovarian cortex are laparoscopically grafted
back to the exposed ovarian medulla or an adjacent site, thus
making spontaneous pregnancy or use of assisted
reproduction techniques possible. Oocyte retrieval and
embryo development have been demonstrated following
heterotopic transplantation of ovarian tissue; however, live
birth rates are very low and natural conception is not possible
with this technique.20
A key benefit of OTC is that ovarian stimulation is not
necessary, so treatment for cancer patients is not delayed.
Additionally, retrieval of tissue for OTC does not require
sexual maturity, so it is suitable for prepubertal girls. A
further advantage is that autotransplantation of ovarian
tissue after puberty can restore general ovarian endocrine
function in addition to preserving fertility.20
The first successful pregnancy after replacement of
cryopreserved human ovarian tissue in an adult female was
reported in 2004.21 Since then, there have been more than
130 live births recorded using this procedure.
Ovarian activity has been reported to resume in over 90%
of women after replacement of their ovarian tissue; this
occurs a median of 4 months after transplantation. Ovarian
activity is sustained for a variable duration of time, but has
been reported to last several years in some cases.22 A recent
publication reported on 95 orthotopic cryopreserved ovarian
172
tissue transplantations in 74 adult women treated for cancer
in in the European FertiProtekt Network.23 Mean age at
cryopreservation and transplantation was 30 years and
34 years, respectively, with the two most common
diagnoses being breast cancer and Hodgkin’s lymphoma.
Of women with premature ovarian insufficiency (POI) at the
time of first transplantation, 62.5% showed evidence of
ovarian activity 1 year post-transplantation, 27.5% achieved
a pregnancy, and 22.5% had a live birth. Importantly, most of
these pregnancies resulted from natural conception. The
potential for natural conception is a primary advantage of
OTC over oocyte or embryo cryopreservation. True success
rates were, however, confounded by several factors, including
residual ovarian activity and transplantations for endocrine
function rather than fertility restoration.22
To date, there have been just two case reports of a successful
live birth following autotransplantation of ovarian tissue that
was cryopreserved pre-menarche.24,25 The first case involved a
woman, originally from the Republic of Congo, who was
diagnosed with sickle-cell anaemia at the age of five. Her right
ovary was laparoscopically removed and cryopreserved at the
age of 13 years and 11 months, before having curative therapy
with haematopoetic stem cell transplant (HSCT). As expected,
following the treatment, the patient developed primary ovarian
failure, with elevated gonadotrophins. Menarche was induced
at the age of 15.5 years.
Ten years later, the patient wished to become pregnant.
The patient underwent ovarian tissue transplantation.
Menstruation occurred 5 months later and was followed by
regular menstrual cycles thereafter.24 Two years post-
transplantation, the patient became pregnant and delivered
a healthy boy in November 2014.24
The youngest worldwide reported case of ovarian tissue
cryopreservation before puberty with subsequent
transplantation of the tissue was a 9-year-old girl suffering
from b-thalassaemia. Her ovarian tissue was cryopreserved
for 14 years before being transplanted back at the age of 23.
Subsequently, she conceived following IVF treatment with an
oocyte derived from the transplanted tissue and delivered a
healthy baby.25
One significant potential disadvantage of OTC is that
ovarian tissue stored prior to cancer treatment may harbour
malignant cells.17 Numerous methods can be used to
determine the extent of malignant cell contamination,
including immunohistochemistry and molecular analysis.
However, these tests are all destructive to tissue, so cannot be
applied to the ovarian tissue intended for transplantation. It
is generally accepted that, where there is no evidence of
metastatic disease of solid cancers, there is low risk of ovarian
malignant contamination.22 However, in the case of
leukaemia, several studies have indicated that the risk that
of malignant cells in the ovary is high.20,21 The use of OTC in
cases of leukaemia is therefore controversial.
ª 2021 Royal College of Obstetricians and Gynaecologists

OTC is now considered non-experimental in some
countries (for example, Denmark and Israel). A 2018 FP
guideline published by the American Society of Clinical
Oncology (ASCO) indicated that the experimental status of
OTC is under evaluation in the USA, based on accumulating
evidence of successful pregnancy outcomes.18
In vitro maturation
In vitro maturation (IVM) of oocytes is another technique
that avoids ovarian stimulation, but is classified as
experimental. This concept was first introduced to reduce
risk by avoiding ovarian stimulation in patients who had
severe OHSS in their previous IVF treatments.26 IVM oocyte
cryopreservation involves the retrieval of immature oocytes
from ovaries after minimal or no gonadotrophin stimulation
and their subsequent maturation in the laboratory. IVM may
be done at the time of oocyte collection, or immature oocytes
may be cryopreserved for use in IVM at a later stage.27
Very few live births have been reported after IVM oocyte
cryopreservation. The first live birth was reported following
cryopreservation using the slow-cooling method of oocytes
retrieved at the immature germinal vesicle (GV) stage in
conventional IVF cycles.28 Subsequently, five live births were
reported following vitrification at metaphase-II (MII) stage
after human chorionic gonadotrophin (hCG)-primed IVM
cycles.29 Live births have also been achieved using the IVM of
immature oocytes obtained from resected ovarian cortex.30 A
retrospective study of 267 patients, which compared fresh
and vitrified IVM-oocytes, showed that vitrification resulted
in lower clinical pregnancy (36.1% versus 10.7%) and live
birth rates (25.9% versus 8.9%).26
IVM is particularly advantageous for oncology patients.
As IVM does not require ovarian stimulation, it does not
delay cancer treatment, and it does not carry the risk of
malignant contamination, as is the case in OTC (described
above). The first live birth following IVM for a cancer
patient was recently reported by Professor Grynberg’s group
in France. In brief, seven immature follicles were retrieved
from a 29-year-old patient and matured in vitro for
48 hours, resulting in six MII oocytes suitable for
vitrification. After 5 years, all six oocytes were thawed and
fertilised (by intracytoplasmic sperm injection, ICSI), and a
single cleavage stage embryo transfer resulted in pregnancy
and healthy live birth.31
Testicular tissue cryopreservation
For prepubertal boys, the only potential option for fertility
preservation is testicular tissue cryopreservation (TTC),
which is still considered to be an experimental technique.
In males, puberty heralds the maturation of germinal
epithelium towards spermatids and mature sperm.
Therefore, retrieval options before puberty are unlikely to
produce cells that can currently be used for assisted
ª 2021 Royal College of Obstetricians and Gynaecologists
Hartigan et al.
reproductive techniques. Thus, the efficacy of TTC has yet
to be proven; no live births from frozen tissue have been
reported in humans to date. In a recent milestone study,
Fayomi et al.32 reported a successful pregnancy in rhesus
macaques using transplanted prepubertal cryopreserved
testicular tissue in conjunction with IVF. Importantly,
complete spermatogenesis was confirmed in all transplanted
testicular tissue grafts.32
Despite the experimental nature of the technique, research
indicates that parents and survivors are undeterred and
remain interested in pursuing this option.9 The procedure of
testicular tissue retrieval is straightforward and can be
coordinated with other procedures requiring general
anaesthetic. For most cases, a 3–5-mm incision of the
tunica albuginea permits collection of three to four small (1–
2 mm3) biopsies, which are placed in media and
immediately transferred to the tissue bank for processing
and storage.9 To generate sperm cells, suggested strategies are
IVM or tissue transplantation, by either grafting onto an
existing testicle or injecting germ cell preparations into the
rete testes.33
Ovarian transposition and the use of gonadotrophin-
releasing hormone agonists
Efforts to reduce the risk of gonadotoxicity include ovarian
transposition or oophoropexy, which is an effective method
of FP for both prepubertal and postpubertal girls requiring
pelvic radiation for non-ovarian tumours. In this technique,
one or both ovaries and fallopian tubes are separated from
the uterus and attached to the wall of the abdomen, away
from the radiation target area.34 Barriers to success with this
method include scattered radiation and alterations in ovarian
blood supply. Overall efficacy is thought to be around 50%.35
In terms of preserving ovarian function in paediatric patients,
success rates are difficult to establish given the limited study
number and follow-up but are estimated to be between 60%
and 83%.36 Large-scale follow-up studies of clinical
pregnancy and livebirth outcomes following ovarian
transposition in child and young adult cancer have yet to
be completed.
Administration of gonadotrophin-releasing hormone
(GnRH) agonists during chemotherapy to suppress ovarian
activity is another example of a strategy to reduce the
negative impact of chemotherapy on ovarian reserve. Meta-
analyses have demonstrated that GnRH agonist use during
chemotherapy in an adult population with breast cancer
improves return of ovarian function and pregnancy rates.37
However, in malignancies other than breast cancer, there is
limited evidence to suggest their role in the prevention of
gonadotoxicity.38,39 GnRH agonists are not useful in a
prepubertal cohort owing to inherent hypogonadotropic
function.7 They could be considered for those who are
postpubertal, although the efficacy of this option remains
173
 Fertility on ice
uncertain. In fact, the recently published draft of ESHRE
guidance on female FP40 advises that, in malignancies other
than breast cancer, GnRH agonists should not be offered as
an option for ovarian function protection and
fertility preservation.
Patient selection for fertility preservation
Appropriate patient selection for FP is essential. It is not
always appropriate for patients to take steps to preserve their
fertility. Many patients will be too unwell to consider FP
methods, or will decide that retaining fertility is not a priority
for them.
For all FP methods, the patient must have a realistic
chance of survival from their disease. If a patient’s
condition is considered palliative, there is potential harm
and no benefit to preserving their fertility. Clinicians must
consider if the patient is medically fit enough to undergo
the FP procedure involved. Consent must be obtained – and
this can be a challenging ethical consideration in the case
of minors.
Another key factor to consider before invasive procedures
such as OTC, oocyte retrieval or testicular tissue freezing, is
the nature of the required oncology treatment; that is,
whether or not the proposed treatment is of sufficiently high
risk to a patient’s fertility to justify the FP procedure. Whole
body, pelvic (or abdominopelvic in children) radiotherapy
and high-dose alkylating agents carry the greatest risk
of gondadotoxicity.
Wallace et al.41 developed the Edinburgh selection criteria
for suitability for OTC as outlined in Box 1. These criteria
have been shown to accurately predict which girls and young
women will or will not develop premature ovarian
insufficiency. They therefore aid appropriate patient
selection for OTC before the start of cancer treatment.41
Reproductive outcomes for survivors
Research has found that most adult survivors of childhood
cancer express the wish to have children.42,43 Many cancer
survivors will go on to conceive spontaneously. However, if
they have trouble conceiving and wish to proceed with use of
their stored sperm, oocytes, embryos or cryopreserved
ovarian tissue, further treatment will be necessary to
achieve a pregnancy.
Anderson and colleagues44 used linkable databases of
cancer registrations and pregnancy-related outcome records
in Scotland (1981–2014) to investigate whether women who
have had a cancer diagnosis are as likely to achieve pregnancy
as their age-comparable counterparts who have not had
cancer.44 Over 23 000 women aged 39 or younger at
diagnosis (including those treated as children) were
included in their assessment. The authors found that
174
Box 1. The Edinburgh selection criteria41
 Age younger than 35 years
 No previous chemotherapy or radiotherapy if aged 15 years or older
at diagnosis, but mild, nongonadotoxic chemotherapy acceptable if
younger than 15 years
 A realistic chance of surviving for 5 years
 A high risk of premature ovarian insufficiency (>50%)
 Informed consent (from parents and, where possible, the patient)
 Negative serology results for HIV, syphilis and hepatitis B
 Not pregnant and no existing children
overall, cancer survivors had a lower than expected number
of pregnancies compared with the general population: 6627
observed compared to 10 736 expected pregnancies. Thus,
survivors of cancer were approximately 38% less likely to
become pregnant, highlighting that at-risk patients should
ideally be provided timely access to fertility counselling and
fertility preservation treatments.44
Fertility preservation counselling and
discussions
It is essential to provide patients with information about FP
in a timely fashion, as soon as possible after a cancer
diagnosis. A systematic review by Taylor et al.45 summarised
that children and young adults with a new cancer diagnosis,
and their parents, value the opportunity to discuss fertility
concerns and preservation options.45 Unfortunately, research
indicates that discussions about fertility and fertility
preservation are not taking place.46–48 children and young
adults with cancer and their parents often report that they
have no recollection of conversations about fertility options
with their clinician.49
A mixed methods systematic review by Vindrola-Padros
and colleagues50 studied healthcare professionals’ (HCPs)
views on discussing FP with children, adolescents and young
cancer patients (aged 0–24). Sixteen papers reporting 14
studies were reviewed, most of which took place in North
America and Western Europe. These authors found that
HCPs had a general awareness of the risks to fertility
associated with oncology treatments, but that they lacked
knowledge of the various FP options. This, naturally, affected
the discussion about FP with children and young adults.
Further reported barriers to adequate discussions about FP
included sense of comfort, patient factors (for example, those
patients who had a poor prognosis or were considered too
young), parent factors, and the lack of availability of
written information.
In Europe, efforts to improve knowledge of oncofertility
preservation options have included the establishment of a
pan-European Consortium (PanCareLIFE) that aims to
develop FP guidelines for children and adolescents
diagnosed with cancer.51 Funding of FP represents an
ª 2021 Royal College of Obstetricians and Gynaecologists

additional barrier in many healthcare systems. A recent study
of 27 European countries revealed that just over 50% (14/27)
cover the cost of oocyte cryopreservation for medical reasons,
either through funding by the state or a compulsory
insurance system.52
Conclusion
The impact of loss of fertility and unintended childlessness
on young men and women who have been previously treated
for cancer cannot be underestimated. Recent technological
advances, such as oocyte vitrification and OTC offer
increasing hope to this group.
In this era of improving survival rates of childhood cancer,
as well as major scientific developments to circumvent
reproductive aging, medical disciplines must carefully ensure
that those who would benefit most have the necessary
information and access to fertility preservation methods.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
LH researched and wrote the article. LEG and MW reviewed
and edited the article. All authors approved the final version.
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ª 2021 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12755 2021;23:177–86
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Nonepithelial ovarian cancers

BMBS BSc (Hons), *
a b
Holly Baker-Rand Katharine Edey MBChB MRCOG PGDip
a
Specialist Registrar, Department of Obstetrics and Gynaecology, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon EX2 5DW, UK
b
Consultant Gynaecological Oncologist, Clinical Leadership Mentor and Gynaecology Governance Lead, Royal Devon and Exeter NHS Foundation
Trust, Exeter, Devon EX2 5DW, UK
*Correspondence: Holly Baker-Rand. Email: hbaker-rand@nhs.net

Accepted on 24 September 2020. Published online 24 June 2021.

Key content regimen of bleomycin, etoposide and cisplatin being most

 Nonepithelial ovarian cancers (NEOCs) are rare forms of ovarian
cancer, including malignant ovarian germ cell tumours
(MOGCTs), sex cord-stromal tumours (SCSTs) and
ovarian sarcoma.
 Tumour markers including alpha-fetoprotein, human chorionic
gonadotrophin, lactate dehydrogenase and inhibin can be useful in
aiding preoperative diagnosis of malignant ovarian masses.
 NEOCs are staged using a similar classification to epithelial ovarian
tumours; however, the staging system for male germ cell tumours
is considered a more useful prognostic tool.
 These tumours can occur at any age; however, many present in the
reproductive years, and fertility-sparing treatments are
often required.
 Advanced-stage MOGCTs and SCSTs are managed with debulking
surgery and platinum-based adjuvant chemotherapy, with the
widely used.
Learning objectives
 To understand the classification and pathology of NEOCs.

To describe the role of tumour markers in diagnostic criteria and
to be aware of the FIGO staging classifications and their
prognostic use.
 To understand management protocols and follow-up regimens.
Ethical issues
 Patients of reproductive age risk infertility if preoperative diagnosis
is incorrect and more extensive surgery involving bilateral
salpingo-oophorectomy is performed.
Keywords: nonepithelial / ovarian cancer / pathology

Please cite this paper as: Baker-Rand H, Edey K. Nonepithelial ovarian cancers. The Obstetrician & Gynaecologist 2021;23:177–86. https://doi.org/10.1111/tog.
12755

dense capsule, the tunica albuginea, and the surface is covered

Introduction
In the UK, ovarian cancer is the sixth commonest cancer in
women and is responsible for over 4000 deaths annually.1
Nonepithelial ovarian cancers (NEOCs) are uncommon forms
of ovarian tumour, accounting for approximately 10% of all
ovarian malignancies.2 The classification includes malignant
ovarian germ cell tumours (MOGCTs), sex cord-stromal
tumours (SCSTs) and very rare primary cancers, such as
ovarian sarcoma and small cell carcinoma of the ovary.3,4
NEOCs can present at any age, including in women of
reproductive age. This Review aims to provide an
understanding of the classification, diagnosis and
management of all NEOCs, focusing on MOGCTs and SCSTs.
Pathophysiology
The ovaries originate from intermediate mesoderm and
develop within the mesonephric ridge, descending through
the pelvis to lie in the ovarian fossae.5 The ovary is divided into
the cortex and medulla.6 The cortex is composed of ovarian
follicles, interstitial gland cells and stroma. It is surrounded by a
with surface epithelium of coelomic origin.7 Epithelial ovarian
tumours, which account for most ovarian malignancies, are
attributed to neometaplasia of surface epithelial cells.8 The
medulla of the ovary is formed from embryonic mesenchyme
and contains the lymphovasculature of the ovary.6 SCSTs arise
from various cell types from the primitive sex cords and
stromal cells.9 Stromal cells include theca cells, fibroblasts and
Leydig cells.9 Granulosa cells and Sertoli cells are present in
gonadal primitive sex cords.3 Germ cells arise in the
endodermal layer of the yolk sac. They migrate via the
hindgut epithelium through the dorsal mesentery and are
incorporated into the developing gonads.3 Most nonepithelial
ovarian tumours arise from these specific cells: germ cells,
granulosa cells, theca cells, stromal fibroblasts and steroid cells.
Less common tumours can arise from nonspecific ovarian cells;
for example, mesenchymal cells.
Clinical presentation
The commonest presenting symptoms include persistent
abdominal distension, pelvic or abdominal pain, urinary

ª 2021 Royal College of Obstetricians and Gynaecologists 177

 Nonepithelial ovarian cancers

urgency or frequency and menstrual irregularities. However, perimenopausal and postmenopausal women, while Sertoli–
as with other ovarian masses, many women are Leydig cell tumours occur in young women.11 The incidence
asymptomatic and tumours are incidental findings.10 An of SCSTs is 2.1 per 1 000 000 women. For small cell
NEOC is an important differential diagnosis to consider in carcinoma of the ovary, hypercalcaemic type (SCCOHT),
premenopausal and postmenopausal women, as well as in the mean age at diagnosis is approximately 24 years.12
adolescent girls, who present with a complex ovarian mass.
Malignant germ cell tumours
Dysgerminomas microscopically exhibit nests of polygonal
Classification of nonepithelial ovarian
cells with prominent nucleoli and clear glycogen-filled
cancers
cytoplasm.4,12 Most show isochromosome 12p and, as with
Box 1 lists the main classifications and subdivisions of all MOGCTs, they express the transcription factor Sal-like
NEOCs.2,4 MOGCTs usually occur in premenopausal women protein 4 (SALL4).12,13 Immature teratomas demonstrate
and represent 80% of preadolescent ovarian malignancies.2 elements from all three germ cells, with the addition of
The yearly adjusted incidence rate of MOGCTs is 3.7 per immature embryonal tissues – usually neuroepithelial or
1 000 000 women. SCSTs can present at any age, with adult- glandular.8 These MOGCTs also express SALL4.
type granulosa cell tumours mainly occurring in Macroscopically, yolk sac tumours are large, with extensive
areas of necrosis and haemorrhage. They resemble the
endoderm and primitive yolk sac mesenchyme, with
Box 1. Adapted World Health Organization (WHO) 2014 intestinal and hepatic embryonal tissue. The presence of
classification of nonepithelial ovarian neoplasms Schiller–Duval bodies is pathognomonic.12
1. Sex cord-stromal tumour
a. Pure sex cord tumours Sex cord-stromal tumours
i. Granulosa cell tumour Granulosa cell tumours are large tumours, with focally cystic
1. Adult-type and solid areas.8 Granulosa cell tumours are associated with
2. Juvenile type
mutations in the Forkhead box L2 (FOXL2) gene.8,12 Sertoli–
ii. Sertoli cell tumour
iii. Sex cord tumour with annular tubules Leydig tumours resemble embryonic testis and cause
b. Pure stromal tumours virilisation.8 Of these, 22% have heterologous elements in
i. Fibroma the form of mucinous glands and – occasionally – skeletal
ii. Thecoma
iii. Fibrosarcoma
muscle or cartilage.2,12 Of all Sertoli–Leydig tumours, 60%
iv. Leydig cell tumour exhibit a DICER1 mutation.8
v. Sclerosing stromal tumour
vi. Signet ring tumour
vii. Steroid (lipid) cell tumour Diagnosis and tumour markers
viii. Leydig cell tumour
c. Mixed sex cord-stromal tumours (Sertoli–Leydig tumours) The Royal College of Obstetricians and Gynaecologists’
2. Germ cell tumour (RCOG) Green-top Guidelines have made clear
a. Teratoma
recommendations for the investigation of ovarian
i. Immature
ii. Mature masses.10,14 Computerised tomography (CT) and magnetic
b. Embryonal carcinoma resonance imaging (MRI) are no more sensitive or specific than
c. Nongestational choriocarcinoma transvaginal ultrasound in detecting malignancy. However, CT
d. Dysgerminoma
is used in the staging of disease and MRI can be useful for
e. Yolk sac tumour (endodermal sinus tumour)
f. Mixed germ cell tumour characterising cysts when ultrasound is inconclusive (see
3. Monodermal teratoma and somatic-type tumours arising Figure 1).14 CT should not be the first-line investigation in girls
from a dermoid cyst – including malignant struma ovarii, and adolescents because of the risk of radiation exposure, as
malignant neuroectodermal tumours and sebaceous well as the good sensitivity and specificity of ultrasound.10
carcinomas Serum CA125, lactic dehydrogenase (LDH),
4. Miscellaneous tumours – including small cell carcinoma,
alphafetoprotein (a-FP) and human chorionic
hypercalcaemic type and small cell carcinoma, pulmonary gonadotrophin (hCG) levels should be measured in all
type women under 40 years of age, with complex ovarian
5. Soft tissue tumours
a. Myoxma masses.10 Serum CA125 should be measured in
b. Others (including angiosarcoma, leiomyosarcoma, liposarcoma, postmenopausal women; carcinoembryonic antigen (CEA)
osteosarcoma) and CA19-9 levels can aid diagnosis and indicate the
Note: Full classification available in WHO Classification of Tumour of
Female Reproductive Organs4
likelihood of mucinous or endometrioid epithelial ovarian
tumours or Krukenberg tumours (e.g. lower or upper

178 ª 2021 Royal College of Obstetricians and Gynaecologists

 Baker-Rand and Edey

gastrointestinal tract).14 This recommendation is to aid the
diagnosis of NEOCs because these proteins and hormones are
secreted by some types of germ cell tumours. Although they
Figure 1. Magnetic resonanance image of an ovarian yolk sac
tumour. Yolk sac tumours are complex ovarian masses with solid
and cystic components.
are nonspecific markers, their levels correlate with staging
and survival statistics.2 Table 1 demonstrates the secreted
proteins of pure malignant germ cells. Serum CA125 levels
(units per millilitre) are usually raised in epithelial ovarian
cancers; however, it is only raised in 50% of early disease and
can be raised secondary to endometriosis, fibroids and pelvic
infections.10 The RCOG does not recommend taking serum
CA125 levels for premenopausal women with simple ovarian
cysts. Where a level has been taken, premenopausal women
with assays greater than 200 U/mL should be discussed with
a gynaecological oncologist. In postmenopausal women, a
risk of malignancy index should be calculated and, for any
score ≥200, a CT scan of the abdomen and pelvis should be
arranged. Referral to the gynaecological oncology
multidisciplinary team (MDT) should also be made.
SCSTs can present with hormone-mediated syndromes
based on whether they are formed from hyperestrogenic
ovarian cells (granulosa and theca cells) or hyperandrogenic
testicular cell types (Sertoli and Leydig cells).
Hyperestrogenic SCSTs may present with precocious
puberty in children, abnormal uterine bleeding or
endometrial hyperplasia.11 Hyperandrogenic SCSTs may
present with defeminisation (loss of hip fat and breast
atrophy), hirsutism, irregular menstruation, hoarse voice or
male-pattern baldness.8,9,15 Inhibin B is secreted by granulosa
cell tumours. It is not routinely measured to aid with
diagnosis because it is an expensive assay to perform;

Table 1. Secreted tumour markers and associated nonepithelial ovarian cancers (modified from Gershenson, UpToDate)36

Tumour type a-FP hCG LDH Inhibin T A4 DHEA AMH

Germ cell tumours

Dysgerminoma – + – – – – –

Embryonal +/ + +/ – – – – –

Immature teratoma +/ – +/ – – – +/ –

Choriocarcinoma – + +/ – – – – –

Yolk sac tumour (endodermal sinus tumour) + – + – – – – –

Sex cord-stromal tumours

Thecoma – – – +/ – – – –

Granulosa cell – – – + +/ – – +

Sex cord tumour with annular tubules – – – – – – – –

Sertoli–Leydig +/ – – +/ +/ +/ +/ –

Abbreviations: a-FP = alphafetoprotein; A4 = androstenedione; AMH = anti-m€ ullerian hormone; DHEA = dehydroepiandrostenedione; E2 =
estradiol; hCG = human chorionic gonadotrophin; LDH = lactic dehydrogenase; T = testosterone.

ª 2021 Royal College of Obstetricians and Gynaecologists 179

 Nonepithelial ovarian cancers

Table 2. FIGO staging classification for cancer of the ovary, fallopian tube and peritoneum16

Stage I: Tumour confined to ovaries or fallopian tube(s)

IA: Tumour limited to one ovary (capsule intact) or fallopian tube; no tumour on ovarian or fallopian tube surface; no malignant cells
in the ascites or peritoneal washings

IB: Tumour limited to both ovaries (capsule intact) or fallopian tubes; no tumour on ovarian or fallopian tube surface; no malignant
cells in the ascites or peritoneal washings

IC: Tumour limited to one or both ovaries or fallopian tubes, with any of the following:

IC1: Surgical spill

IC2: Capsule ruptured before surgery or tumour on ovarian or fallopian tube surface

IC3: Malignant cells in the ascites or peritoneal washings

Stage II: Tumour involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or peritoneal
cancer

IIA: Extension and/or implants on uterus and/or fallopian tubes and/or ovaries

IIB: Extension to other pelvic intraperitoneal tissues

Stage III: Tumour involves one or both ovaries or fallopian tubes, or peritoneal cancer, with cytologically or histologically
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes

IIIA1: Positive retroperitoneal lymph nodes only (cytologically or histologically proven):

IIIA1(i): Metastasis up to 10 mm in greatest dimension

IIIA1(II): Metastasis more than 10 mm in greatest dimension

IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes

IIIB: Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the
retroperitoneal lymph nodes

IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the
retroperitoneal lymph nodes (includes extension of tumour to capsule of liver and spleen without parenchymal involvement of
either organ)

Stage IV: Distant metastasis excluding peritoneal metastases

IVA: Pleural effusion with positive cytology

IVB: Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of
the abdominal cavity)

however, it is commonly used as part of follow-
up protocols.2,8
Staging and prognosis
The International Federation of Gynaecology and Obstetrics
(FIGO) staging classification for cancers of the ovary,
fallopian tube and peritoneum is used to stage all NEOCs
(see Table 2). FIGO recognises that the classification used
for male germ cell tumours may provide better prognostic
information than its own classification; this is because the
FIGO classification focuses predominantly on epithelial
ovarian cancers, in which prognosis is poorer for distant
disease.16 Full staging is achieved through a surgical
approach and includes omentectomy, biopsies of the
peritoneum and pelvic/para-aortic lymph nodes along
with pelvic washings.2,13 However, with a suspected
NEOC, fertility-conserving surgery should be the initial
approach in girls, adolescents and women wishing to retain
fertility. Before surgical staging, preoperative investigations

180 ª 2021 Royal College of Obstetricians and Gynaecologists

 Baker-Rand and Edey

Table 3. IGCCCG stratified risk model for germ cell tumours, adapted by Meisel et al.

Type of cancer Good Intermediate Poor

Dysgerminoma No metastases other than lung, Metastases beyond lung, lymph N/A
lymph nodes or peritoneum nodes and peritoneum

All other subtypes of malignant No metastases other than lung, No metastases other than lung, Metastases beyond lung, lymph
ovarian germ cell tumour lymph nodes, or peritoneum lymph nodes, or peritoneum nodes and peritoneum
AND AND ≥1 of the following OR

 a-FP <1000 ng/L  a-FP 1000–10 000 ng/mL  a-FP >10 000 ng/mL
 hCG <5000 mIU/mL  hCG 5000–50 000 mIU/mL  hCG >50 000 mIU/mL
 LDH <1.59N  LDH 1.5–109N  LDH >109N

5-year overall survival (%) 91 80 50

Abbreviations: a-FP = alphafetoprotein; hCG = human chorionic gonadotrophin; IGCCCG = international germ cell cancer collaborative group; LDH =
lactic dehydrogenase; N = upper limit of normal.

should include a transvaginal pelvic ultrasound scan; a CT
of the thorax, abdomen and pelvis;, a chest x-ray and blood
tests, including appropriate tumour markers.2,16 Fluoro-
deoxyglucose positron emission tomography (PET) is highly
sensitive and is used in selected cases with germ cell
tumours, either after inadequate surgical staging or for
restaging following adjuvant chemotherapy.17 In women
with granulosa cell tumours, endometrial curettage should
be performed owing to the risk of endometrial
abnormalities from the hyperestrogenic effects of
granulosa cell tumours.2
Because MOGCTs and SCSTs are highly sensitive to
chemotherapy,2,8 even advanced disease can be successfully
treated. Five-year overall survival rates are in excess of 80%,
despite metastases to the lungs or lymph nodes.18,19 The
International Germ Cell Cancer Collaborative Group
(IGCCCG) created a stratified risk model for germ cell
tumours based on the spread of disease and the levels of
serum tumour markers. This model was initially created for
testicular tumours and provides information about the risk
of recurrence.20 The information has been extrapolated and
used for female germ cell tumours to provide prognostic
information (see Table 3).18
The American Cancer Society uses information from the
Surveillance, Epidemiology, End Results (SEER) database to
calculate survival statistics for different types of ovarian
cancer. The SEER database organises cancers into the
following groups: localised, regional and distant, instead of
grouping by FIGO stage.19 The 5-year survival rates are
shown in Table 4.

Table 4. SEER survival statistics

5-year relative survival rates for ovarian

cancer

Type of ovarian cancer

SEER stage Invasive epithelial Stromal Germ cell

Localised – no sign that the cancer has spread outside of the ovaries (%) 92 98 98

Regional – the cancer has spread outside the ovaries to nearby structures or lymph nodes (%) 76 89 94

Distant – the cancer has spread to distant parts of the body such as liver or lungs (%) 30 54 74

All SEER stages combined (%) 47 88 93

Abbreviation: SEER = surveillance, epidemiology, and end results.

ª 2021 Royal College of Obstetricians and Gynaecologists 181

 Nonepithelial ovarian cancers

Management Table 5. Management of malignant ovarian germ cell tumours

(adapted from ESMO Clinical Practice Guidelines 2018)2
Surgery and chemotherapy form the pillars of treatment for
NEOCs.2,16 The aim of any surgical intervention is to achieve Type of
cancer
macroscopic cytoreduction of the tumour, as removal of all (Stage) Management
visible deposits is associated with improved survival.2

Fertility-conserving surgery Dysgerminoma

Given the high incidence of NEOCs in young women of or
IA
before reproductive age, fertility-sparing surgery in the form
of unilateral salpingo-oophorectomy has become common
practice.21 Full surgical staging is considered the gold IB-IC
standard of management13 and this has previously been
described. The surgical approach is often carried out through IIA-IV
an open route, usually via a midline laparotomy, which
allows for adequate access and the ability to carefully examine
the abdominal cavity. A laparoscopic approach to NEOCs
Immature teratoma
may be appropriate in some cases; however, the use of
laparoscopy in ovarian cancers remains controversial. IAG1
Concerns about the use of a laparoscopic approach are
related to the possibility of tumour spillage and therefore IAG2-3
upstaging of tumours, the possibility of inadequate staging
and the risk of metastasis at port sites.22 A 2016 Cochrane
review23 comparing laparoscopy and laparotomy for early-
stage ovarian cancer found no high-quality evidence to help
quantify the risks and benefits of a minimally invasive
approach. However, a 2018 literature review by Tantitamit IB-IC
and Lee22 concluded that a laparoscopic approach for the
Fertility-sparing surgery or full surgical staging with
active surveillance
Fertility-sparing surgery or full surgical staging
If fully staged: active surveillance
Full staging/debulking surgery with adjuvant
chemotherapy (fertility sparing surgery may be
indicated)
Fertility-sparing surgery or full surgical staging with
active surveillance
Fertility-sparing surgery or full surgical staging
 If fully staged and negative postoperative tumour
markers: active surveillance
 If not fully staged or positive postoperative tumour
markers: adjuvant chemotherapy
Fertility-sparing surgery or full surgical staging and
adjuvant chemotherapy

treatment of early-stage ovarian cancers is feasible, safe IIA-IV
and effective.
Concerns about reduced fertility and premature
menopause following unilateral salpingo-oophorectomy
have been investigated. There is good evidence to state that
although the quantity of the ovarian reserve is affected, the
rate of successful pregnancies, from both spontaneous Yolk sac tumour
conception and assisted reproduction following unilateral
IA-IB
oophorectomy, are comparable with women who have both
ovaries intact.24,25 For women concerned with early
menopause following unilateral oophorectomy, the HUNT2
population study demonstrated that women who had
undergone unilateral oophorectomy entered menopause
1 year earlier than women with two ovaries; this effect is IC-IV
similar to that of smoking.26
Full staging/debulking surgery with adjuvant
chemotherapy (fertility-sparing surgery may be
indicated)
 Further cytoreductive surgery for residual disease may
be appropriate
Fertility-sparing surgery or full surgical staging
 If fully staged and negative postoperative tumour
markers: active surveillance
 If not fully staged or positive postoperative tumour
markers: adjuvant chemotherapy
Full staging/debulking surgery with adjuvant
chemotherapy (fertility sparing surgery may be
indicated)

Management of malignant germ cell tumours

Malignant germ cell tumours account for 1.5% of ovarian
cancers in Europe, with approximately 100 diagnosed each
year in the UK.27 Of all MOGCTs, 60–70% are diagnosed in
the early stage and are treated with surgery followed by active and testicular germ cell tumours. As most patients presenting
surveillance or adjuvant chemotherapy.2,21 MOGCTs are with MOGCTs are adolescents or young women, the focus of
more sensitive to chemotherapy than SCSTs; this is management is chemotherapy, alongside fertility-conserving
supported by data from the management of both ovarian surgery. Although full surgical staging is the gold standard of

182 ª 2021 Royal College of Obstetricians and Gynaecologists


management, it can be associated with higher morbidity if
full lymphadenectomy is performed. Therefore, more recent
focus has been on the lesser degree of surgical staging
described by Billmire et al.28 This suggests that full pelvic and
para-aortic lymphadenectomy can no longer be justified.28 In
women who have completed their family or who are beyond
childbearing age, more radical surgery, including total
hysterectomy and bilateral salpingo-oophorectomy, is the
most appropriate management. Management of MOGCTs is
detailed in Table 5.
The common adjuvant chemotherapy regimens for the
treatment of NEOCs are etoposide and cisplatin (EP), or
bleomycin, etoposide and cisplatin (BEP). Three to four
cycles of adjuvant chemotherapy with EP or BEP is the
standard treatment regimen for MOGCTs.2,3,13 BEP is used
in patients under the age of 40 years and for those over 40
years old, the EP regimen is used. There are considerable
short and long-term complications from the BEP
chemotherapy regimen, including ototoxicity and hearing
loss, nephrotoxicity, pulmonary dysfunction, Raynaud’s
phenomenon, avascular necrosis and secondary
malignancies – in particular, acute myeloid leukaemia.2,29
There is a risk of gonadal dysfunction leading to iatrogenic
menopause and sterility; therefore, women have the option of
oocyte cryopreservation before chemotherapy. However, the
rate of premature ovarian failure after chemotherapy is low at
3%.27 Successful pregnancies have been reported following
treatment with these chemotherapeutic agents.30
Adequately staged stage 1 cancers can potentially be
managed without chemotherapy to avoid toxicity. Indeed,
this is now the standard of care in stage 1 testicular cancers.
An oncologist with expertise in management of these rare
cancers should discuss the advantages and disadvantages of
chemotherapy with women. Relapse in stage 1a
dysgerminoma is around 20% and most women will be
cured with salvage chemotherapy.
National centres (Charing Cross London, Sheffield and
Dundee) exist for the management of trophoblastic ovarian
tumours. Women with these tumours, although often
managed locally, should be referred to the nearest national
centre for surveillance. The registration and treatment
programme offered by these specialist centres achieves cure
rates >98% and low chemotherapy rates (5–8%).31
Management of sex cord-stromal tumours
Of all SCSTs, 60–95% are diagnosed in the early stage and the
focus of treatment is surgery with adjuvant chemotherapy.2,21
This is the same for advanced SCSTs, which are managed
with more extensive surgery and adjuvant chemotherapy.2,13
Most women presenting with SCSTs are perimenopausal or
postmenopausal and this, combined with SCSTs being
less chemosensitive than MOGCTS, means full staging
surgery, including hysterectomy and bilateral salpingo-
ª 2021 Royal College of Obstetricians and Gynaecologists
Baker-Rand and Edey
oophorectomy, is recommended. Fertility-sparing surgery
may be indicated and is usually considered on an individual
case basis. Chemotherapy regimens for SCSTs are like those
used for MOGCTs and consist of three to four cycles of
adjuvant chemotherapy with EP or BEP, with the same age-
related divisions. However, SCSTs can also be treated with
carboplatin and paclitaxel combination chemotherapy.2,3
Management of SCSTs is detailed in Table 6.
Small cell carcinoma of the ovary,
hypercalcaemic type
SCCOHTs are aggressive ovarian tumours, characterised as
malignant rhabdoid tumours. They are associated with
deleterious mutations of the SMARCA4 (SWI/SNF-related,
matrix associated, actin dependent regulator of chromatin
subfamily A, member 4) remodelling gene.12,13 The median
age at presentation is 24 years old.3 Serum calcium levels are
elevated in approximately two-thirds of patients.32 Most
Table 6. Management of sex cord-stromal tumours
Type of
cancer
(Stage) Management
Granulosa cell tumour
IA Fertility-sparing surgery or full surgical staging with
standard follow-up
IC1 Full staging/debulking surgery including TAH and BSO
(fertility-sparing surgery may be indicated)
IC2-3 Full staging/debulking surgery including TAH and BSO
and adjuvant chemotherapy (fertility-sparing surgery
may be indicated)
IIA-IV Full staging/debulking surgery including TAH and BSO
and adjuvant chemotherapy
Sertoli–Leydig tumour
IA In young patients: fertility-sparing surgery or full
surgical staging
In older patients: full staging surgery including TAH
and BSO
If the tumour is poorly differentiated or has
heterologous elements then adjuvant chemotherapy
is required
>IA Full staging/debulking surgery including TAH and BSO
and adjuvant chemotherapy (fertility sparing surgery
may be indicated)
Abbreviations: TAH = total abdominal hysterectomy; BSO = bilateral
salpingo-oophorectomy
183
 Nonepithelial ovarian cancers
tumours are unilateral and 50% of tumours demonstrate
extraovarian spread at diagnosis.3,32 SCCOHTs are
chemosensitive at the outset, but there is a high risk of
relapse.2,12 There is a lack of evidence to provide clear
recommendations for management. The consensus is for
complete surgical staging followed by adjuvant chemotherapy
and/or pelvic radiotherapy.2 Cisplatin and etoposide are the
chemotherapeutic agents of choice. Recently, autologous
stem cell transplants have been performed as an adjuvant
treatment and these are associated with better survival.2 Five-
year survival is 10%, with most patients dying within 2 years
of diagnosis.3,13
Ovarian sarcoma
Sarcomas of the ovary are exceedingly rare. Adenosarcoma
and carcinosarcoma are mixed epithelial and mesenchymal
tumours, which are managed as epithelial ovarian cancers.
Carcinosarcoma (also known as malignant mixed
mesodermal tumour) is the most common subtype.33
Nonepithelial types of ovarian sarcoma include
angiosarcoma, leiomyosarcoma, liposarcoma and
osteosarcoma.4,13 Of all nonepithelial ovarian sarcomas,
80% occur in postmenopausal women, with the mean age
at diagnosis being 63 years old.3,33 Ovarian sarcomas are
aggressive tumours and most present with distant disease.13
They commonly spread to the liver, lungs and retroperitoneal
lymph nodes. Guidance published by the National Institute
of Health and Care Excellence (NICE)34 recommends that
patients with sarcoma are managed in specialist sarcoma
units, as this has been shown to improve outcomes. The
guidance recognises the limitations of these centres in the
management of gynaecological sarcoma. It also recognises
that, although nonepithelial ovarian sarcomas should be
referred to sarcoma units, management is shared with – and
Table 7. Active surveillance programme for management of malignant ovarian germ cell tumours (modified from ESMO Clinical Practice Guidelines
2018)
Time period Examination Pelvis US
1st year Monthly 2-monthly
2nd year 2-monthly 4-monthly
3rd year 3-monthly 6-monthly
4th year 4-monthly
5th to 10th year 6-monthly
Abbreviations: CTAP = computed tomography abdomen and pelvis; CXR = chest X-ray; US = ultrasound
184
guided by – the gynaecological oncology MDT. The rare
prevalence of these tumours means there is a lack of data and
no clear consensus on treatment regimens. Localised disease
is usually managed with aggressive surgery. Metastatic disease
is managed with chemotherapy, often palliative.
Chemotherapeutic agents that have been used in the
management of ovarian sarcoma include cisplatin,
doxorubicin and ifosfamide.3,33 Secondary cytoreductive
surgery has not been found to be feasible or effective.33
Prognosis is poor and long-term survival is uncommon.3,13,33
Active surveillance and follow-up
Germ cell tumours
Recurrence of MOGCTs usually occurs early, with the highest
risk of relapse being in the first 2 years after treatment.
Therefore, women undergoing fertility-sparing surgery in
early-stage disease are recommended to follow an active
surveillance plan post-treatment according to the RCOG and
European guidelines. This active surveillance programme,
described by Vasquez and Rustin,2 has a demanding visiting
schedule designed to detect recurrence over a 10-year period
(see Table 7). Women wishing to conceive are usually advised
to avoid doing so within the first 2 years post-treatment,
when risk of relapse is greatest.
Sex cord-stromal tumours
After treatment with surgery and adjuvant chemotherapy,
SCSTs follow standard follow-up regimens (see Box 2), which
combine history, examination and evaluation of serum
tumour markers to assess possible recurrence. Physical
examination should include pelvic examination. As SCST
relapse tends to occur late, regular follow-up commences in
the third year and continues indefinitely.3 Serum tumour
marker levels (hCG, a-FP, LDH, CA125 and inhibin B,
Tumour markers CXR CTAP
Every 2 weeks (first 2-monthly 1 month
6 months) and then monthly 3 months
12 months
2-monthly 4-monthly
3-monthly 6-monthly
4-monthly 8-monthly
6-monthly Annually
ª 2021 Royal College of Obstetricians and Gynaecologists

Box 2. ESMO follow-up recommendations for ovarian sex cord-
stromal tumours
History, examination and tumour markers:
 From third year and continued indefinitely, 6-monthly
 Plus 6-monthly pelvic ultrasound for women treated with fertility-
sparing surgery
measured depending on the type of NEOC) are used to assess
response to chemotherapy and subsequently to assess
relapse.2,3 Clinicians should be aware of hyperestrogenic
symptoms, particularly in the absence of ovaries. In such
cases, women may present with an absence of menopausal
symptoms, which may suggest recurrence of granulosa cell
tumours. Virilisation may suggest recurrence of androgenic
Sertoli–Leydig tumours. If lung metastases are suspected in
NEOC recurrence, then a CT of the chest, abdomen and
pelvis should be obtained. The use of PET scan for this
purpose has not been recommended. For any patient who has
undergone fertility-sparing surgery, six-monthly pelvis
ultrasound scan should be performed.2
Hormone replacement
Women made menopausal through radical surgery or
because of adjuvant chemotherapy may request hormone
replacement therapy (HRT). It is recognised that iatrogenic
menopause causes greater prevalence and greater severity of
menopausal symptoms.35 These symptoms, which can
considerably reduce quality of life for women affected,
include low mood; vasomotor symptoms, including
flushing; and sexual dysfunction, including loss of libido.
There are no robust data to evaluate the safety of HRT for
NEOCs. However, given the hormone-dependent nature of
SCSTs, HRT is not recommended and should be avoided in
these patients. In the case of MOGCTs, HRT is usually
considered to be safe and hormonal contraceptives are
not contraindicated.2
Psychological support
The importance of a holistic approach to care and early
psychological support should not be underestimated for young
women who are diagnosed with cancer. Early involvement of
Teenage and Young Adult (TYA) services and specialist nurses,
and joint pathways with paediatric and gynaecological
surgeons, can offer the best care for young patients.
Conclusion
NEOCs are a broad group of malignancies. It is important to
consider them as differential diagnoses, particularly in girls and
young women with a complex ovarian mass. Involvement of
the multidisciplinary gynaecological oncology team is
ª 2021 Royal College of Obstetricians and Gynaecologists
Baker-Rand and Edey
essential. This team should include surgeons, oncologists,
cancer nurse specialists, histopathologists, radiologists and
psychologists. Pathways for involvement of paediatric
surgeons and fertility specialists should be clear.
In girls, adolescents and women of reproductive age,
surgery should be fertility conserving whenever possible. For
premenopausal women receiving chemotherapy, the risk of
premature ovarian failure should be discussed. Referral to
fertility specialists for oocyte preservation should be
considered and discussed with the patient or parents at an
early stage.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
HBR researched and wrote the article. KE provided clinical
expertise and edited the article. All authors approved the
final version.
Acknowledgements
Thank you to Dr Surabhi Agrawal, Consultant
Histopathologist, Musgrove Park Hospital, Taunton, for
providing advice on cellular pathology and classification of
nonepithelial ovarian tumours.
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ª 2021 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12743
The Obstetrician & Gynaecologist
http://onlinetog.org
Intrauterine contraception
Joanne Ritchie MRCOG DFSRH,
a
* Nicholas Phelan
a
Consultant Obstetrician and Gynaecologist, Shrewsbury and Telford NHS Trust, Telford TF1 6TF, UK
b
ST7 Obstetrics and Gynaecology Trainee, St Helens and Knowsley Teaching Hospitals NHS Trust, Prescot L35 5DR, UK
c
Consultant in Sexual and Reproductive Health, Liverpool Womens NHS Foundation Trust, Liverpool L8 7SS, UK
*Correspondence: Joanne Ritchie. Email: joritchie@doctors.org.uk
Accepted on 29 September 2020.
Key content
 An intrauterine device (IUD), also known as intrauterine
contraceptive device (IUCD) or intrauterine contraception (IUC)
offers reliable long-acting reversible contraception; however, some
patients can be hesitant to choose this option because of
misconceptions about side effects and perceived complications. A
comprehensive knowledge of IUC is required to allow adequate
counselling and to dispel myths.
 There are many different methods of IUC, including four different
levonorgestrel-containing intrauterine systems (LNG-IUS) and
multiple different copper intrauterine devices, with different
insertion techniques.
 Considering contraception is important at several life stages,
including post-delivery, post-termination of pregnancy and
around the menopause; these will require different counselling.
Please cite this paper as: Ritchie J, Phelan N, Briggs P. Intrauterine contraception. The Obstetrician & Gynaecologist 2021;23:187–95. https://doi.org/10.1111/tog.
12743
Introduction
Almost 100 years since the first birth control clinics were
established in the UK, the slogan, “children by choice, not
chance” remains as important today as it was then. Although
all hormonal contraception is highly effective, the user has a
considerable effect on typical failure rates.1 In the UK, all
method choices are freely available for women regardless of
circumstances, but very few women choose long-acting
reversible contraception (LARC). The ‘pill’ remains the
most popular hormonal method of contraception,
accounting for over 60% of prescriptions,2 but typical user
failure rates are high (see Table 1).
In contrast, LARC methods remove dependence on the
user and are associated with reduced risk of unplanned
pregnancy. The Choice Study3 demonstrated that, following
counselling, most women (75%) chose a LARC method as
their preferred contraceptive. Of these, 46% chose an
intrauterine system (IUS), 12% a copper intrauterine device
(Cu-IUD) and 17% a subdermal implant.
This article focuses on intrauterine contraception (IUC).
Those looking for a comprehensive review of IUC are
signposted to the Faculty of Sexual and Reproductive
ª 2021 Royal College of Obstetricians and Gynaecologists
2021;23:187–95
Review
MRCOG,
b
Paula Briggs FFSRH FRCGP
c
 The use of IUC can have noncontraceptive benefits, including
relief of heavy menstrual bleeding, management of menopause
and premenstrual syndrome and reducing gynaecological
cancer risk.
Learning objectives
 To learn the different types of IUC, including the different
indications and possible complications.
 To understand the noncontraceptive benefits of IUC.
 To understand the challenges faced when a patient is hesitant to
consider IUC.
Keywords: contraception / counselling / intrauterine
Healthcare (FSRH) guideline on intrauterine
contraception.4 This is a ‘quick look’ reference summary
for the general gynaecologist.
A steady and statistically significant decrease in teenage
pregnancy has been observed in England since 1998,5,6
mirrored by increased use of LARC. However, acceptance of
certain LARCs, particularly IUC, remains a problem. This
might relate to myths and misconceptions, which can be
dispelled with focused counselling, promoting benefits and
discussing risks in a balanced manner.7 Information
concerning insertion of IUC must be realistic, ensuring
women understand that the procedure may be
uncomfortable, while not causing undue anxiety. Parity and
age do not contraindicate use of IUC, and there is no reason
to restrict IUC use to parous women. Almost 60% of women
taking part in a US-based study8 were nulliparous.
An Australian publication demonstrated the following
key messages.9
 Infection rates following IUC insertion are generally low.
 There appears to be little difference in the proportion of
nulliparous or parous women experiencing IUC expulsion.
 Past use of IUC does not appear to impair fertility in
nulliparous or younger women.
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 Intrauterine contraception

Table 1. Percentage of women with an unintended pregnancy within Intrauterine systems

the first year of contraception use (modified from Trussell et al.19)
Levonorgestrel-containing intrauterine systems
Perfect use (%) Typical use (%) There are four branded products.
(theoretical (‘real-world’
Method effectiveness) effectiveness)
 Mirena (Bayer PLC, Newbury, Berkshire, UK). A 52-mg
levonorgestrel-containing intrauterine system (LNG-IUS)
– licensed for 5 years for contraception and HMB, 4 years
Vasectomy 0.10 0.10 for endometrial protection as part of menopausal
hormone therapy.
Tubal sterilisation 0.50 0.50
 Jaydess (Bayer PLC, Newbury, Berkshire, UK). A 13.5-mg
Progestogen subdermal 0.05 0.05 LNG-IUS – licensed for contraception only for 3 years.
implant  Kyleena (Bayer PLC, Newbury, Berkshire, UK). A 19.5-
mg LNG-IUS – licensed for contraception only for 5 years.
(LNG-IUS) 0.20 0.20
 Levosert (Gedeon Richter, Budapest, Hungary). A 52-mg
Cu-IUD 0.60 0.80 LNG-IUS – licensed for 6 years for contraception and 5
years for HMB.
DMPA injection 0.20 6.00
Owing to the different licensed indications of the four
Progestogen-only pill 0.30 9.00 devices, the MHRA has recommended prescription by
brand name.
Combined hormonal 0.30 9.00 All these devices have a T-shaped frame with an elastomere
contraception pill/ring/patch
sleeve containing levonorgestrel (LNG) in varying doses.
Condom 2.00 18.00 Both of the 52-mg LNG-IUSs release approximately
20 micrograms LNG daily, which gradually reduces over
Diaphragm 6.00 12.00 time.4 The 13.5-mg and 19.5-mg LNG-IUSs release lower
Fertility awareness 0.40–5.00 24.00
doses of LNG.4 The mode of action of IUSs is to thicken the
cervical mucus, prevent sperm penetration and thin the
No contraception 85.00 85.00 endometrium. There is also, possibly, a foreign body effect.
Ovulation is not usually inhibited and estrogen levels remain
Abbreviations: Cu-IUD = copper intrauterine device; DMPA = in the normal physiological range.
depot-medroxyprogesterone acetate; LNG-IUS = levonorgestrel- Insertion by trained clinicians can be provided in a clinic
containing intrauterine system.
or outpatient setting for most women. Removal is usually
straightforward, if the threads are visible at the external
 Insertion failure appears to be more common in cervical os. National accreditation by the FSRH is
nulliparous women but can be overcome by referral recommended for all clinicians fitting IUC, including
to a more experienced fitter, use of dilators or an Os gynaecologists. The Letter of Competence in Intrauterine
FinderTM (CooperSurgical, Inc., Trumbull, CT, USA) Techniques (LoC IUT) is subject to 5-yearly recertification.
and use of local anaesthetic. The Os Finder naturally
seeks and gently opens the cervical os. Made of an
Levosert
extremely smooth and malleable Teflon-like material,
Levosert (a 52-mg LNG-IUS) was initially licensed for 3 years
this instrument is ideal for use in intracervical
for contraception and to treat HMB. In January 2019, the
dilatation or uterine sounding, or for
licence was extended to 5 years, bringing it in line with
intrauterine procedures.
Mirena, and in 2021 the licence for contraception only was
 Pain relief should be discussed with all women considering
increased to 6 years. Levosert is currently the least expensive
insertion of IUC, but particularly with younger and
LNG-IUS (£66 + VAT compared with £88 + VAT for
nulliparous women who appear to have higher rates of
Mirena)4 at the point of acquisition. Although both Mirena
discomfort during insertion.
and Levosert contain 52 mg LNG, their licensed indications
Data from community contraceptive services show
differ. Levosert does not have a licence for endometrial
approximately 9% of women in the UK use IUC.10
protection in association with estrogen replacement therapy,
Improving access to and uptake of IUC has the potential to
so Mirena is a better option for women over the age of 45
reduce unplanned pregnancies and to support management
who may also require menopause management. The thread
of several common gynaecological problems, including heavy
for Levosert is blue to aid identification and visibility at post-
menstrual bleeding (HMB), endometriosis, premenstrual
placement checks.
syndrome (PMS) and menopause.

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Jaydess
Jaydess (a 13.5-mg LNG-IUS) is licensed for contraception
only for 3 years. The frame is smaller and the inserter tube is
narrower (3.8 mm), compared with Mirena (4.4 mm) and
Levosert (4.8 mm). Women may experience less pain
on insertion.11
Kyleena
Kyleena (a 19.5-mg LNG) is licensed for contraception only
for 5 years. It has the same smaller sized frame and insertion
tube as Jaydess.
A significant reduction in menstrual bleeding, including
amenorrhoea, is more likely in women using IUSs containing
the higher dose of 52 mg LNG, compared with the lower
dose devices (amenorrhoea rate 8.6% at 1 year for 52-mg
devices versus 6.2% for 13.5-mg devices).12
Common issues with the levonorgestrel-containing
intrauterine systems
Problematic bleeding is a common problem associated with
use of IUSs in the weeks following insertion. This is caused by
shedding of the endometrium and, rather than being
considered a side effect, should be seen as a process, which
usually settles within the first 3–6 months.13 After 1 year of
use, lighter periods are common, with up to 20% of women
experiencing amenorrhoea.13 Return to fertility is not delayed
following removal of an IUS because the LNG in the core of
the device exerts an ‘end organ’ effect, rather than causing
disruption to the hypothalamo–pituitary–ovarian axis. A
small amount of LNG is absorbed systemically, with the
potential to cause hormonal side effects, including headache,
bloating, acne and breast tenderness, but these usually settle
with time. A small number of women are unable to tolerate
the effect of systemic absorption of progestogen, even with
the lower levels associated with intrauterine delivery. Weight
gain has been observed with IUC, although there is no
significant difference between LNG-IUS and Cu-IUD and no
causal link has been found.4 There is no known effect on
libido, although loss of libido can be a problem for
some women.
Table 2. UK Medical Eligibility Criteria ratings for intrauterine systems
and progestogen-only implants and breast cancer14
Intrauterine Progestogen-only
Breast cancer system implant
Current breast 4 4
cancer
Past breast cancer 3 3
ª 2021 Royal College of Obstetricians and Gynaecologists
Ritchie et al.
Table 3. UK Medical Eligibility Criteria (UKMEC) 2016.14
Gynaecologists may not be familiar with this Faculty of Sexual and
Reproductive Health resource
UKMEC
category Definition of category
1 A condition for which there is no restriction for the use
of the method
2 A condition where the advantages of using the
method generally outweigh the theoretical or proven
risks
3 A condition where the theoretical or proven risks
usually outweigh the advantages of using the
method. The provision of a method requires expert
clinical judgement and/or referral to a specialist
contraceptive provider, since use of the method is not
usually recommended unless other more appropriate
methods are not available or not acceptable
4 A condition which represents an unacceptable health
risk if the method is used
Use of IUSs in women who have had breast cancer is
controversial. In women with a history of breast cancer (less
than 5 years since diagnosis), potential risks associated with
use of an IUS can outweigh benefits. For women who have
breast cancer, use of an IUS is absolutely contraindicated
(UK Medical Eligibility Criteria for Contraceptive Use
[UKMEC] Category 4).14
Table 2 and Table 3 are taken from the UKMEC 2016.14
Familiarity with UKMEC for IUC methods is essential to
ensure patient safety.
Copper intrauterine devices
The gold-standard copper intrauterine device (Cu-IUD)
contains 380 mm copper, on the stem and arms of the
device. Copper affects sperm motility and causes a white cell
infiltrate in the endometrium, rendering an environment
hostile to implantation. Complications at insertion are the
same as for IUSs and use is not contraindicated because of
parity or age.
The most commonly used Cu-IUDs have a T-
shaped frame.
There are many different types of Cu-IUDs which fall into
different categories:
 Banded copper arms: Copper T380A (RF Medical
Supplies, Merseyside, UK), TT380 Slimline (Durbin
PLC, Middlesex, UK) T-safe 380A QL (Williams Medical
Supplies Ltd, Gwent, UK).
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 Copper stem: Nova T 380 (RF Medical Supplies, cancer or other medical conditions contraindicating
Merseyside, UK). hormones (Table 4).
 Frameless: GynaeFix (Williams Medical Supplies Ltd,
Gwent, UK).
Counselling for intrauterine contraception
The intrauterine ball (IUBTM; ODCON Medical Ltd,
Modiin, Israel) recently became available in the UK.15 This One barrier preventing women from accepting IUC is the
device contains 300 mm2 copper (shape memory nitinol core ‘advice’ they may have received from friends and family, or
with copper pearls). It is smaller than the T-framed copper that they may have read on the internet. This makes
IUD and conforms to the shape of the intrauterine cavity. dispelling myths an imperative part of the consultation.
Once the IUB is released from the 3.2-mm diameter insertion Once a woman has been given an honest account of what to
tube into the uterus, it coils into a spherical shape measuring expect during the insertion process, and information
15 mm in diameter. regarding safety, efficacy and potential benefits of different
Cu-IUDs contain no hormones, so there are no beneficial IUC choices, she may be more likely to consider an
effects on menstrual bleeding; however, they are an excellent intrauterine method. Availability of pain relief should be
option for women with a history of hormone-dependent highlighted, with options including 10% lidocaine spray
applied to the cervix; an anaesthetic gel (for example,
Instillagel; FARCO-PHARMA, Cologne, Germany); or a
local anaesthetic block, usually with mepivacaine 3%,
Table 4. Summary of intrauterine contraceptives in current UK clinical injected at 12, 4 and 8 o’clock. Adolescents are more likely
practice4
to report pain on insertion of IUC, and to recall the
Diameter of experience as painful and share this with their friends.16 Use
Duration insertion of nitrous oxide (Entonox BOC Healthcare, Manchester,
Type of use Use tube (mm) UK) can be helpful, particularly in a secondary care setting.17
There is no current evidence from clinical trials to support
Mirena 5 years Contraception, HMB 4.40
the use of topical lidocaine, misoprostol or nonsteroidal anti-
4 years Endometrial protection inflammatory drugs (NSAIDs) to improve ease of insertion
(acceptable to use it for or to reduce pain during insertion of intrauterine methods.
5 years, out of product The FSRH e-learning module 18 on intrauterine techniques
license in women
experiencing no bleeding) provides a useful summary of options for pain relief in
association with IUC insertion and removal.
Levosert 6 years Contraception 4.80 A woman’s past contraceptive experience will greatly
5 years HMB
influence her attitude to future method choice.18 Some
Jaydess 3 years Contraception 3.80 women do not like the idea of having ‘something in there’
and it is worth exploring this further. She may be fearful that

Kyleena 5 years Contraception 3.80 her partner might feel the threads during sex (she can be
reassured that the threads will soften and are unlikely to be
Banded copper arms
felt), or she may be concerned about an increased risk of
Copper 10 years Contraception 4.75 sexually transmitted infections (STIs). Women can be
T380 reassured that the risk of pelvic inflammatory disease is
TT 380 10 years Contraception 4.75
low, around 1%.13
Slimline

T Safe 10 years Contraception Efficacy

380A
All longer acting LARCs are highly efficacious, both
Copper stem theoretically (perfect use) and in the real world (typical
use). Any potential discrepancy between perfect and typical
Nova T 5 years Contraception 3.60 user failure rates is avoided by removing dependence on the
380
user in association with ‘fit-and-forget’ delivery.
Frameless The different LNG-IUS systems are associated with a 0.2%
unintended pregnancy rate at 12 months.1
Gynae Fix 5 years Contraception 4.00
The etonogestrel 68 mg radiopaque subdermal implant
(Nexplanon) is the most effective contraceptive method,
Abbreviation: HMB = heavy menstrual bleeding

190 ª 2021 Royal College of Obstetricians and Gynaecologists


with an unintended pregnancy rate of 0.05% at 12 months.1
(See Table 1.)
Efficacy of the copper intrauterine device
The most effective copper IUDs are those with a T-shaped
frame containing 380 mm2 of copper.4 Different Cu-IUDs
vary in shape and diameter. T-shaped devices have a lower
expulsion rate and higher efficacy (compared with frameless
copper-bearing devices).4
Pregnancy rates of between 0.1 and 1% have been reported
for the first year of use, with the largest study to date
demonstrating an expected first year pregnancy rate of
0.8%.19 There is a slight decline in efficacy with prolonged
use, with unintended pregnancy rates of up to 2.2% at
12 years. This should be balanced against a decline in
unplanned pregnancy as women get older. Women can be
reassured that there is no interaction with any medication,
including drugs that induce liver enzymes.
Safety
As with any medical intervention, patients should be
counselled regarding the possible risks of IUC insertion.
The main risks are summarised below.
Uterine perforation
Both Cu-IUDs and LNG-IUSs are associated with very low
rates of perforation (2 per 1000) when inserted by
appropriately trained healthcare professionals.4 Perforation
at the time of insertion may be increased in postpartum
women, with a 6-fold increase in risk associated with
breastfeeding.4 There is no evidence of increased
perforation rates between removal of placenta and 48 hours
postpartum.20 This includes postvaginal delivery or insertion
immediately post caesarean insertion.
Expulsion
The risk of expulsion is around 1 in 20 and is most common
in the first 3 months after insertion.4
Cervical shock
A small number of women experience bradycardia (1.8%)
and hypotension (2.1%)21 when their cervix is stimulated at
the time of IUD insertion. This should be acknowledged as a
rare complication and should not preclude the procedure. In
most cases, lowering the head of the bed and administering
oxygen is sufficient to support recovery. If a bradycardia less
than 40 bpm is sustained, the drug of choice is 500–600
micrograms of atropine delivered (ideally) intravenously. If
intravenous access is not possible, intramuscular delivery is
acceptable.22 Staff involved with IUC insertion should be
trained and updated in resuscitation.
ª 2021 Royal College of Obstetricians and Gynaecologists
Ritchie et al.
Pelvic inflammatory disease
There is a risk of ascending infection when an IUC is inserted
in a woman with a bacterial sexually transmitted infection,
but the risk of pelvic inflammatory disease (PID) developing
is low (1.6 per 1000).23 IUC removal is not routinely required
in women with PID, but should be considered if there is no
response to treatment with antibiotics after 72 hours.
Ectopic pregnancy
The overall risk of ectopic pregnancy is reduced in
association with IUC use versus using no contraception.4
However, if pregnancy does occur in a woman with IUC,
then the risk of the pregnancy being ectopic is increased. This
must be excluded as a matter of priority.
Importance of excluding underlying
pathology before initiating intrauterine
contraception
Sexually transmitted infections
A sexual history should be taken prior to IUC insertion to
help identify those women at greater risk of STIs. If a woman
is identified as being high risk, she should be encouraged to
accept an STI screen.4
In asymptomatic women presenting for IUC insertion,
there is no need to wait for the results of STI screening or to
provide antibiotic cover as long as the woman can be
contacted and promptly treated in the event of a positive
result.10 In symptomatic women, IUC insertion should be
delayed until test results are available, if possible. If a woman
requires emergency contraception and is symptomatic or
high risk, she can be given antibiotic prophylaxis for
common STIs following current guidance from the British
Association for Sexual Health and HIV (BASHH).4
Uterine abnormalities
The UKMEC states that an anatomical abnormality that
distorts the uterine cavity is usually seen as a reason not to
offer IUC. However, it may be appropriate to attempt
insertion of IUC, ideally under ultrasound guidance. A
history of HMB, breech presentation, preterm labour or
recurrent miscarriage may highlight the possibility of a
uterine abnormality. Any distortion of the uterine cavity is
associated with a higher risk of expulsion.4
Pregnancy
Sexual health clinics and some GP surgeries routinely fit IUC
and implants in a clinic setting following verbal consent and
standard record keeping. Patients may be seen twice, with the
first consultation focusing on counselling. The mode of
action of IUC should be explained; as well as discussion of
the insertion procedure and potential complications
associated with insertion, including the risk of infection,
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expulsion and perforation. It is important to ensure that a
reliable method of contraception is used prior to provision of
any LARC, to prevent unplanned pregnancy. Patient
information leaflets are helpful to support verbal advice.
Even though a pregnancy test will be done at the time of
IUC insertion, it remains imperative to ask about
unprotected sex since the last menstrual period because this
could have led to conception before a pregnancy test is able
to show a positive result.
When inserting IUC, regardless of the setting, remember
the following points.
 Establish whether a reliable method of contraception was
used before insertion and whether pregnancy can be
excluded (see Box 1).
 Obtain consent (written or verbal), including a description
of the insertion procedure and the risks associated with it
(failure rate, infection, expulsion and perforation).
 Keep written documentation, including findings of
bimanual and speculum examination.
 Provide post-insertion information, including what to
expect in terms of pain and bleeding and which symptoms
should prompt urgent medical advice.
The FSRH has guidance on Service Standards for
Record Keeping.24
Insertion techniques for different
intrauterine contraceptive devices
Mirena, Jaydess and Kyleena share the same insertion
technique (evoinserter). Once loaded, these devices cannot
be reloaded if the initial insertion attempt fails. Levosert has a
two-handed insertion technique and can be reloaded, on a
sterile field, and reintroduced if the first attempt is
unsuccessful. Although the diameter of the Levosert
introducer (4.8 mm) is slightly wider than the Mirena
introducer (4.4 mm), a study has shown that this makes
little difference to ease of insertion.25
Local anaesthetic and use of a sound dilator or os finder
can help facilitate insertion for more difficult cases (see
Figure 1 and Figure 2).
Intrauterine contraception in
noncontraceptive settings
Emergency contraception
There are three options for emergency contraception (EC):
Cu-IUD, ulipristal acetate and levonorgestrel. A Cu-IUD is
the most effective method because it is the only one that is
effective after ovulation has taken place. All eligible women
requesting EC should be offered the option of a Cu-IUD.
A Cu-IUD can be fitted for EC up to 5 days after multiple
acts of unprotected sexual intercourse (UPSI), or up to day
19 of a regular 28-day cycle and provides ongoing
reliable contraception.26
Contraception postpregnancy
The antenatal period is an optimal time to discuss
contraception following delivery. LARC is associated with
high continuation rates at 12 months postpregnancy.27

Box 1 1. Faculty of Sexual and Reproductive Healthcare criteria for

reasonably excluding pregnancy1

Healthcare practitioners can be reasonably certain that a woman is not

currently pregnant if any one of the following criteria are met and there
are no symptoms or signs of pregnancy: Figure 1. A sound dilatator is used to find the cervical os, and to
 She has not had sexual intercourse since the start of her last normal sound the uterus for the depth and direction.
menstrual period, or is within the first 5 days since childbirth,
abortion, miscarriage, ectopic pregnancy or uterine evacuation for
gestational trophoblastic disease.
 She has been correctly and consistently using a reliable method of
contraception. (For the purposes of being reasonably certain that a
woman is not currently pregnant, barrier methods of contraception
can be considered reliable providing that they have been used
consistently and correctly for all sexual activity.)
 She is within the first 5 days of the onset of a normal menstrual
period.
 She is less than 21 days postpartum (non-breastfeeding women).
 She is fully breastfeeding, amenorrhoeic AND less than 6 months
postpartum.
 She has not had sexual intercourse for >21 days AND has a negative
high-sensitivity urine pregnancy test (able to detect human Figure 2. An os finder is used to find the cervical os and to gently
chorionic gonadotrophin [hCG] levels around 20 mIU/ml).
dilate a stenosed cervix.

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An IUC can be inserted up to 48 hours postdelivery,
including at the time of lower segment caesarean section
with no increase in risk of perforation. However, there
is an increased risk of expulsion because the uterus
involutes. Women should be encouraged to attend a
thread check 6 weeks after insertion.20 If the threads are
not visible, a transvaginal ultrasound should be undertaken
to confirm the presence of the IUC within the
endometrial cavity.
Contraception in women aged over 40
If a Cu-IUD is inserted after the age of 40, it can be used as an
effective method of contraception until menopause28 (2 years
after the last menstrual period in women below age 50, and
1 year after in women above age 50).
If Mirena is inserted at the age of 45 or above, it can be
used for contraception and management of HMB for 7 years,
or longer in women who remain amenorrhoeic.28
Once a woman reaches the age of 55, contraception all can
be stopped.28
Levosert can be fitted for women requiring contraception
and management of HMB, but does not have a licence for
endometrial protection in association with use of estrogen
replacement therapy.
Contraception for adolescents
IUC is an effective option for young women, particularly as
there is no ongoing dependence on the user once the device
is in place. Healthcare professionals sometimes take a
paternalistic approach to counselling adolescents about
contraception; they may not offer IUC as first line owing
to the belief that insertion may be more difficult, or because
of concerns that a teenager using IUC may not use
additional precautions to prevent STIs.29 When
counselling adolescents, it is important to discuss pain
relief options available and the importance of using
condoms for safer sex.
Use of contraception for noncontraceptive
benefits
Heavy menstrual bleeding
Since the introduction of Mirena in the early 1990s, HMB has
been successfully reduced for most women, with
hysterectomy rates dramatically reduced.30
A 52-mg LNG-IUS is the first-line treatment option for
women who have HMB with no significant pathology. This
includes women with adenomyosis and fibroids that are less
than 3 cm in diameter and not distorting the
endometrial cavity.14
Women using Mirena for HMB only can retain it for as
long as it continues to control symptoms.28
ª 2021 Royal College of Obstetricians and Gynaecologists
Ritchie et al.
Menopause management
Many women will experience increasingly heavy and irregular
periods in the menopause transition and some may consider
hormonal treatment for the first time. Mirena is a good
option for HMB, especially in the perimenopausal period.
This is because there is the additional option to use it as the
progestogenic arm of menopausal hormone therapy (MHT),
enabling estrogen-only treatment, with different delivery
route options: oral (pill), transdermal (patch, gel or spray)
or, less commonly, subdermal (estradiol implant).
Women with an intact uterus require progestogen to prevent
hyperplasia of the endometrium – a risk factor for endometrial
cancer. Mirena provides endometrial protection with optimal
bleeding control and many women will have the additional
benefit of amenorrhoea. LNG, an androgenic progestogen, is
absorbed into the systemic circulation, although levels are
lower than those associated with oral delivery.
Mirena 52-mg LNG-IUS can be used to provide endometrial
protection in conjunction with estrogen replacement therapy
for up to 5 years (outside product licence).28
Premenstrual syndrome
Premenstrual syndrome (PMS) can be a debilitating
condition. Some women have such severe symptoms that
their relationships and work lives suffer. At the more extreme
end of the spectrum (premenstrual dysphoric disorder;
PMDD), some women feel suicidal during the luteal phase
of the menstrual cycle. Symptoms of PMS are linked to
ovulation and production of progesterone and its
metabolite, allopregnanolone.
There is no evidence to support Mirena alone to treat PMS
because it is unlikely to inhibit ovulation.31
Mirena can, however, be used in women with PMS to
manage the condition by adding sufficient exogenous estrogen
to supress ovulation. Commonly used treatment options
include use of either an estradiol patch (100 micrograms/
24 hours or more) or estradiol gel (3 mg or more daily).
Increasing the estrogen dose to achieve symptom control is
simplified by transdermal delivery. Mirena, or an alternative
progestogen, is essential to prevent endometrial hyperplasia in
association with use of estradiol.
The Royal College of Obstetricians and Gynaecologists
(RCOG) PMS guideline states that, “women should be
informed that low levels of levonorgestrel released by the
LNG-IUS 52 mg can initially produce PMS-type
adverse effects.”31
Reduction in endometrial hyperplasia and other
gynaecological cancers
Irregular proliferation of the endometrial glands, known as
endometrial hyperplasia, is a precursor for endometrial
cancer. Increased exposure to unopposed estrogen is one of
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 Intrauterine contraception
Figure 3. Hartmann alligator forceps.
the commonest risk factors for both hyperplasia and cancer
and is related to several potential risk factors, including
obesity, anovulatory cycles (polycystic ovary syndrome),
nulliparity, diabetes, hypertension and MHT (unopposed
estrogen). Use of a progestogen in combined MHT reduces
the overall risk of cancer and women with bleeding in the
first 3–6 months of use should be reassured that this is within
normal limits. It would be reasonable to assess the
endometrium using transvaginal ultrasound, but
management in a rapid access service is not required.32
Endometrial hyperplasia can be separated in to two
groups: those with atypia and those without. Atypical
hyperplasia has the highest risk of progressing to
endometrial cancer and hysterectomy is the treatment of
choice. The risk of progressing to endometrial cancer for
women without atypia is less than 5% over 20 years32 and
this condition may regress spontaneously. The use of
progestogens increases the regression rate.
A 52-mg LNG-IUS should be the first-line medical
treatment because, compared with oral progestogens, it has
a higher disease regression rate with a more favourable
bleeding profile and it is associated with fewer
adverse effects.33
Use of this treatment for endometrial hyperplasia without
atypia (out of product licence) should be for a minimum of
6 months to induce histological regression.33 Women with
no adverse effects should be encouraged to keep the device
for 5 years, unless they are planning a pregnancy.
The use of Cu-IUD may be associated with a reduced risk
of endometrial and cervical cancer.34,35
Troubleshooting situations where there is
difficulty in removing intrauterine
contraception
If IUC threads are not visible at the external cervical os, the
healthcare professional first needs to exclude pregnancy. They
should also advise the patient on alternative contraception
194
and, if necessary, provide emergency hormonal
contraception. The first-line investigation is transvaginal
ultrasound to confirm the presence and position of the
device. If the IUC is not seen on ultrasound scan, expulsion
should not be assumed; an X-ray of the abdomen and pelvis
should be done to exclude perforation. The addition of a
negative contrast, such as Instillagel, can be used to enhance
imaging. Identification of the device in the correct position
may be sufficient to reassure the user, avoiding early removal.
If perforation is confirmed, then laparoscopy must
be arranged.
If the device is identified and removal is requested, Spencer
Wells forceps can be used to explore the cervical canal; this is
often more effective than using thread retrievers. If
unsuccessful, Hartmann’s alligator forceps can be used to
retrieve the device from the endometrial cavity (following
administration of a cervical block, if necessary). If this fails,
the patient should be referred for outpatient hysteroscopy to
remove the device, or for removal under general anaesthesia,
depending on patient choice and previous experience.
Threads may be difficult to see in women for whom
insertion was associated with suboptimal placement,
followed by migration to the fundus, taking the threads up
with the device. FSRH guidance is that IUCs located 1–2 cm
from the fundus can remain in situ, rather than being
removed and replaced (Figure 3).
Conclusion
IUC provides reliable ‘fit-and-forget’ user-independent
contraception. Counselling is key to engaging with women.
IUC offers highly effective contraception, with added
noncontraceptive benefits for management of many
common gynaecological problems.
Disclosure of interests
PB has received honoraria from Bayer, Gedeon Richter,
Besins, Mylan, MSD, GSK, Consilient, Shionogi and Astellas.
ª 2021 Royal College of Obstetricians and Gynaecologists

PB has been supported to attend meetings by Bayer, Gedeon
Richter, MSD, GSK and Mylan. JR and NP have no conflicts
of interest.
Contribution to authorship
PB instigated, wrote and edited the article. JR and NP both
wrote and edited the article. All authors approved the
final version.
Supporting Information
Additional supporting information may be found in the
online version of this article at http://wileyonlinelibrary.
com/journal/tog
Infographic S1. Intrauterine contraception
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195
 DOI: 10.1111/tog.12740 2021;23:196–205
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Identification and management of fetal anaemia:

a practical guide
James Castleman MA MD MRCOG,a Leo Gurney MD MRCOG,
a
Mark Kilby MD DSc FRCOG FRCPI,
b,c

R Katie Morris PhD MRCOGb,d*

a
Subspecialty Trainee in Maternal and Fetal Medicine, West Midlands Fetal Medicine Centre, Birmingham Women’s and Children’s NHS
Foundation Trust, Birmingham B15 2TG, UK
b
Honorary Consultant in Maternal and Fetal Medicine, West Midlands Fetal Medicine Centre, Birmingham Women’s and Children’s NHS
Foundation Trust, Birmingham B15 2TG, UK
c
Professor of Fetal Medicine, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK
d
Professor of Obstetrics and Maternal Fetal Medicine, Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, UK
*Correspondence: Katie Morris. Email: r.k.morris@bham.ac.uk

Accepted on 4 August 2020. Published online 9 June 2021.

Key content Learning objectives

 Fetal anaemia can be caused by alloimmune or infectious red cell
destruction, disorders of fetal red cell production, fetal
haemorrhage and as a complication of monochorionic
multifetal pregnancy.
 A fetus at risk from maternal alloimmunisation can be detected by
maternal serum screening for red cell antibodies and by
fetal ultrasonography.
 Undiagnosed cases may present in routine obstetric practice, so
awareness of the identification and initial management of fetal
anaemia is important.
 Pregnancies must be triaged depending on clinical urgency, with
input from fetal medicine specialists required.
 Developments in fetal ultrasound assessment and in fetal therapy
have improved outcomes and contemporary research will focus on
improving long term outcomes for neonatal survivors.
 To understand the varied aetiologies and pathophysiology of fetal
anaemia and to adopt a system for reaching a diagnosis.
 To appreciate the different diagnostic tools available, comprising
ultrasonography, microbiological testing, noninvasive and invasive
tests in fetal medicine units and electronic fetal monitoring in the
acute setting.
Ethical issues
 Management involves balancing maternal and fetal risks.
 Research ethics should be considered in relation to experimental
treatments and trials in fetal therapy.
Keywords: alloimmunisation / fetal anaemia / fetomaternal
haemorrhage / in utero transfusion / middle cerebral artery Doppler

Please cite this paper as: Castleman J, Gurney L, Kilby M, Morris RK. Identification and management of fetal anaemia: a practical guide. The Obstetrician &
Gynaecologist 2021;23:196–205. https://doi.org/10.1111/tog.12740

below the mean for gestation, or less than 0.55 multiples of

Introduction
Fetal anaemia is an uncommon but potentially dangerous
complication of pregnancy that can lead to considerable fetal
or neonatal morbidity and mortality if unrecognised and
untreated. Among the multiple causes of fetal anaemia, the
commonest is antibody-mediated destruction of red blood
cells via maternal alloimmunisation. Infection (most
frequently with parvovirus B19) is the major nonimmune
aetiology of fetal anaemia. Rarer causes include fetal
haemorrhage (occult or revealed), fetal tumours (for
example, placental chorioangioma) and complications of
monochorionicity in multiple pregnancies. Fetal
haemoglobin (fHb) values should increase with advancing
gestation to a mean of 150 g/L at 40 weeks.1 Well-defined
fHb nomograms define severe anaemia as greater than 70 g/L
the median.1,2 Reduced tissue perfusion and oxygenation in
severe anaemia leads to end organ dysfunction, including
brain injury, high-output cardiac failure and, ultimately,
intrauterine fetal death. The ‘hydrops zone’ on the
nomogram is gestation dependent, ranging from fHb
<40 g/L at 18 weeks of gestation to fHb <80 g/L at term.3
This article provides an overview of the prospective
identification and management of fetal anaemia, along with
a tabulated reference guide to key aspects of screening,
diagnosis and management of the main underlying
aetiologies encountered in obstetric practice. Failure to
recognise and appropriately manage suspected fetal
anaemia can be devastating, thus we present a diagnostic
approach to fetal anaemia encompassing core principles of
general obstetric and fetal medicine care, involving

196 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited and is not used for commercial purposes.

ultrasonography, invasive and noninvasive testing and
multidisciplinary counselling.
Red cell alloimmunisation
Haemolytic disease of the fetus and newborn (HDFN) can
develop after a woman is exposed to a mismatch of paternally
derived red blood cell (RBC) antigens from the fetus via, usually,
a sensitising event during pregnancy. This results in maternal
generation of antibodies capable of placental transfer, which
target fetal RBCs containing such antigens for destruction.
There are over 50 RBC alloantibodies, present in about 1 in 80
pregnant women, which cause HDFN in 1 in 300–600 live
births.4 Sensitising events occurring during pregnancy are the
leading cause of female alloimmunisation, followed by blood
transfusion, so obstetricians have a crucial role in risk reduction
(see Box 1). The Rhesus (Rh) group of antigens on RBCs are the
most clinically important in obstetrics; paternally inherited
(autosomal dominant) antigens can trigger alloimmunisation.
Alloimmunisation caused by incompatibility with Rh ‘D’, ‘c’
and ‘E’ antigens can cause severe HDFN. Historically, HDFN
was most frequently caused by anti-D antibody. Anti-D
immunoprophylaxis was discovered in the 1960s.6 Now,
widespread use of anti-D immunoglobulin prenatally and
immediately postnatally has dropped rates of D-
alloimmunisation to 2%.7 Anti-E is now the most prevalent
HDFN-causing alloantibody.4 The rarer ‘K’ and ‘k’ antigens of
the Kell group can cause severe, early-onset anaemia at lower
levels because they suppress erythropoiesis, as well as causing
red cell destruction.8 Other antibody groups capable of causing
HDFN (more commonly neonatal jaundice) include the Fy, Jk
and MNS systems.9 The most clinically important red cell
antigens are listed in Table 1.
About 15% of white European and 5% of African and
Indian ancestral groups lack the D antigen (Rh-negative) on
their RBCs. East Asian women are almost always Rh-
Box 1. Sensitising events for Rh D-negative women in pregnancy
 Ectopic pregnancy
 Early miscarriage complicated by pain and/or excessive bleeding
 Uterine evacuation (miscarriage, molar pregnancy, termination of
pregnancy)
 Any pregnancy loss after 12 weeks (miscarriage and intrauterine
death/stillbirth)
 Invasive fetal tests (amniocentesis, chorionic villus sampling,
cordocentesis)
 Fetal therapy (transfusion, surgery, shunt insertion, laser, fetal
reduction)
 External cephalic version
 Abdominal trauma
 Delivery, regardless of mode
 Intraoperative cell salvage
Adapted with permission from John Wiley and Sons.5
ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Castleman et al.
Table 1. Clinically significant red cell antibodies
Antigen
System Antigen Haemolytic Disease
Rhesus D Frequently severe in fetus and neonate
c Frequently severe in fetus and neonate
c+E Severe in combination, in fetus and neonate
E Infrequently severe, usually in neonate
C Infrequently severe, usually in neonate
e Infrequently severe, usually in neonate
Ce Infrequently severe, usually in neonate
Kell K (K1) Frequently severe in fetus and neonate
(compounded by suppression of
erythropoiesis)
k (K2) Infrequently severe, usually in neonate
Duffy Fya Infrequently severe, usually in neonate
Fyb Infrequently severe, usually in neonate
MNS S Infrequently severe, usually in neonate
s Infrequently severe, usually in neonate
U Infrequently severe, usually in neonate
M Infrequently severe, usually in neonate
Kidd Jka Infrequently severe, usually in neonate
Jkb Usually mild, in neonate
Adapted from Moise, 200881 and RCOG, 201412
positive.10 The first IgM alloantibody response cannot cross
the placenta. However, on re-exposure to the antigen, the
‘secondary’ IgG response is more pronounced so the
antibodies can cross the placenta, potentially causing fetal
anaemia. Given that IgG responses are characteristically
mounted over several months, clinically significant
alloimmune effects that may pose a risk to the fetus are
more likely in a subsequent, rather than index, pregnancy.
IgG transport across the placenta is mediated by the neonatal
Fc receptor (FcRn).11 In the fetal circulation, IgG
alloantibodies target RBCs, or their progenitors, for
destruction. Fetal anaemia results from suppression of
erythropoiesis or by haemolysis.
The Royal College of Obstetricians and Gynaecologists
(RCOG) Green-top guideline on the management of women
with red cell antibodies during pregnancy’12 provides clinicians
with evidence-based recommendations for antenatal screening,
diagnosis and management of alloimmunised pregnancies.
Maternal ABO and D blood group and alloantibody status
should be ascertained at booking and checked again at 28 weeks
of gestation. Pregnancies with a high chance of HDFN include
those in women with a previous history of a fetus or newborn
affected with haemolytic disease, or who have a critical level of
high-risk alloantibody (Table 2). Such women should receive
preconceptual counselling and be referred to a fetal
medicine specialist.
The advent of cell-free fetal DNA (cffDNA) testing from
maternal blood allows noninvasive identification of fetal RBC
antigens, including D, c, C, e, E and Kell.13 The sensitivity
197
 Fetal anaemia

Table 2. Identifying pregnancies with increased chance of fetal anaemia and instituting appropriate management

Condition Specific management guidance

Red cell alloimmunisation Ask:

 Previous baby requiring transfusion or known HDFN
Test:
 Maternal blood group and antibody status
 Fetal and paternal genotyping
Refer to fetal medicine specialist:
 Prior HDFN
 Ultrasound evidence of fetal anaemia (MCA-PSV or hydrops)
 Rapid rise in alloantibody or specific thresholds reached:
Anti-D> 4 IU/ml (>15 likely severe)
Anti-c >7.5 IU/ml (>20 likely severe, lower threshold if co-existent anti-E)
Anti-K as soon as detected
Any other alloantibody titre ≥32
Specifics:
 If maternal transfusion likely, need regular crossmatch sample

Fetal infection Ask:

 Current rash or febrile illness, onset
 Unwell contacts and time of exposure (face-to-face or 15 minutes in same room is significant)
Test:
 No routine screening
 Booking sera for IgG to determine seroconversion since
 Current blood sample (for symptomatic or asymptomatic women with contact); retest one month after contact if no
IgG or IgM at initial test
 Consider amniocentesis or fetal blood sample to detect viral DNA
Specifics:
 Serial ultrasound scanning from 4 weeks after symptom onset
 Parvovirus B19: IgM present in maternal blood from first day after rash onset; no IgM means no infection in last
4 weeks; test saved booking blood for viral DNA load or IgG seroconversion or repeat sample for change in IgM
reactivity; scan fetus weekly from 4–10 weeks after confirmed maternal infection; maternal infection after 24 weeks
usually harmless
 CMV: If maternal CMV IgG and IgM are positive, and IgG avidity low, infection is highly likely to have been within 3
months; antiviral drugs may be beneficial in congenital CMV
 Termination of pregnancy may be considered

Genetic and metabolic Ask:

conditions  Family origin questionnaire (screening for haemoglobinopathy)
Test:
 Haemoglobin electrophoresis
 Parental DNA
 Red cell enzyme assays (pyruvate kinase, G6PD)
 Invasive test for genetic diagnosis

Vascular tumours Specifics:

 Regular Doppler assessment to screen for signs of high output state associated with fetal exsanguination
 MRI
 Laser coagulation or radiofrequency ablation of tumour vessels
 Open maternal fetal surgery for resection of SCT in selected, very preterm cases
 Amniodrainage if severe polyhydramnios
 Neonatal team to prepare for microangiopathic haemolytic anaemia and thrombocytopenia

Vasa praevia Specifics:

 Transvaginal colour Doppler ultrasound and rescan to confirm at 32 weeks
 Palpate for pulsating fetal vessels in the membranes on vaginal examination
 Consider inpatient management if preterm labour likely or antenatal bleeding
 Delivery 34–36 weeks after steroids

198 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
 Castleman et al.

Table 2. (Continued)

Condition Specific management guidance

Complications of
monochorionicity
 Fortnightly scans in local unit from 16 weeks of gestation for all multifetal pregnancies with shared placenta
 Refer monochorionic multifetal pregnancies to a tertiary Fetal medicine centre if:
- Hydrops
- Cardiac dysfunction
- Unexplained polyhydramnios
- Abnormal umbilical artery Doppler velocimetry
- Single twin death
(These fetuses need Doppler assessment of MCA-PSV to detect TAPS)

 Weekly ultrasound surveillance using MCA-PSV after fetoscopic laser ablation for fetofetal transfusion syndrome and in
selective fetal growth restriction (estimated fetal weight discordance ≥25% and an EFW <10th centile)
 Assess neuroanatomy of co-twin survivor(s) with ultrasound and later with MRI
 Fetoscopic laser ablation before 26 weeks, and after 26 weeks IUT for anaemia and exchange transfusion to dilute the
polycythaemic circulation with Hartmann’s solution can be considered32

Abbreviations: CMV = cytomegalovirus; EFW = estimated fetal weight; G6PD = glucose-6-phosphate dehydrogenase; HDFN = haemolytic disease of
the fetus and newborn; IgG = immunoglobulin G; IgM = immunoglobulin M; IU = international unit; IUT = intrauterine transfusion; MCA-PSV =
middle cerebral artery peak systolic velocity; MRI = magnetic resonance imaging; SCT = sacrococcygeal teratoma; TAPS = twin anaemia
polycythaemia sequence

and specificity of cffDNA RhD genotyping is almost 100%, so
it can be considered a diagnostic test when used in this
context.14 Rhesus D, c, C and e are detectable from 16 weeks
of gestation and Kell from 20 weeks. Routine cffDNA-based
testing reduces unnecessary anti-D administration and can be
cost effective.15 Clinicians should be aware of the small risk of
false negative ‘diagnosis’ and, if high-risk alloantibody level
increases, then serial ultrasound surveillance should be
considered, as for a sensitised pregnancy.16 Determination
of paternal RBC antigen status and zygosity may be
considered and, very rarely, invasive testing (chorionic
villus sampling or amniocentesis) remains necessary for
diagnostic certainty (if the father is heterozygous).
Alloimmunised women require blood tests every 4 weeks up
to 28 weeks of gestation and fortnightly thereafter. Absolute
levels of alloantibody (see Table 2), or a rapid rise in level
(doubling over a 14-day period), are important.17 Levels and
titres are less informative in a second at-risk pregnancy, when
earlier referral is required. With Kell alloimmunisation, there is
a lower threshold for specialist input because these
alloantibodies can cause severe and unpredictable fetal
anaemia (caused by suppressed erythropoiesis) irrespective
of antibody levels and previous pregnancy outcome. Follow-up
testing for lower risk alloantibodies is individualised.
Where available, routine use of RhD immune globulin has
reduced the rate of red cell alloimmunisation, with developed
countries following established protocols for
immunoprophylaxis with anti-D IgG.7 An additional dose of
anti-D is required within 72 hours of a recognised sensitising
event where there is possible fetomaternal haemorrhage
(Box 1). Adequate dosing (500 IU injection of anti-D is
sufficient to cover 4 ml of fetal RBCs) is confirmed with the
Kleihauer–Betke test, or with flow cytometry if the sensitising
event occurs after 20 weeks of gestation.7
Fetal infection
Anaemia can be the result of fetal viral infection following
vertical transmission from a symptomatic or asymptomatic
woman. The gestational age of infection and previous
infections or exposure should be considered when assessing
fetal risk. Human parvovirus B19 is probably the most
common cause for viral-related fetal anaemia in the UK. It is
a single-stranded DNA virus usually transmitted via
respiratory droplets. In children, viraemia is usually
heralded by flu-like illness, then manifests as a rash
spreading from the face (‘slapped cheek syndrome’) to
affect the trunk and limbs – possibly with arthralgia.
Infections occurring in adulthood tend to be asymptomatic,
although more severe disease, including aplastic crises, can
occur in people who are immunocompromised. More than
half of pregnant women will be immune because of infection
before pregnancy, but in those without such immunity, an
infection in the first half of pregnancy can cause fetal anaemia
and hydrops secondary to viral destruction of fetal erythroid
progenitor cells.18 The risk of fetal loss is estimated to be 13%
with parvovirus B19 infection before 20 weeks of gestation
and 0.5% with infection occurring later in pregnancy.19
There is no preventive strategy or licensed vaccine available
for parvovirus. Most women infected give a clear history of
exposure to a child with the acute viral illness. Useful
guidance is available from Public Health England,20 with

ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 199
 Fetal anaemia
pregnant women advised to notify a clinician promptly of
any contact with, or development of, rash and to avoid
exposing other pregnant women.20
Cytomegalovirus (CMV) is another important maternal
infection that can cause fetal anaemia. Avidity is an
important property in testing, with the strength of the IgG
and antigen complex gradually increasing with time after
primary infection, thus indicating the latency of infection.
Low avidity is suggestive of recent infection.21
Approximately 2% of cases are associated with reactivation
after a previous primary infection. This is helpful to identify
the timing of the primary infection and to stratify risk to the
fetus. Rarer infective causes of fetal anaemia include
toxoplasmosis, syphilis, malaria, rubella and herpes. Apart
from fetal hydrops, there may be other ultrasound signs of
congenital infection, including echogenic bowel, hepatic
calcifications, organomegaly, a suspicion of dysplastic
kidneys (often with accompanying oligohydramnios),
ventriculomegaly and fetal growth restriction. Myocarditis
and hepatitis may be important sequelae of vertical
transmission of viral infection.
Detailed descriptions of the investigations and
management of viral conditions in pregnancy are outside
the scope of this article, but Table 2 outlines a basic
approach. Further information can be found in the National
Institute for Health and Care Excellence (NICE) Clinical
Knowledge Summary (for parvovirus)22 and the RCOG
Scientific Impact Paper (for CMV).23
Disorders of erythropoiesis
Fetal anaemia can result from problems at any stage of red
cell production in the bone marrow. It can be secondary to
inherited anaemias, metabolic syndromes or bone marrow
failure. Aplastic anaemia can result from toxicity of drugs or
radiation, or an underlying genetic problem. Alpha-
thalassaemia, predominantly in couples of Mediterranean
and Asian origin, is the commonest type of inherited
anaemia, in which the alpha-globin chains in haemoglobin
are reduced or absent. Less normal haemoglobin results in
less oxygen delivery to fetal tissues. A fetus born to two
parents with alpha-thalassaemia trait has a one in four chance
of having alpha-thalassaemia major. In this condition, the
complete lack of normal haemoglobin leads to the so-called
Barts hydrops fetalis, which can be ‘mirrored’ by maternal
pre-eclampsia and is associated with antepartum
haemorrhage.24 A markedly thickened placenta is a classic
sonographic sign.
Genetic disorders of red cell production include congenital
erythropoeitic porphyria, Fanconi anaemia and Diamond–
Blackfan anaemia. Transient abnormal myelopoiesis (TAM)
has a particular association with trisomy 21.25 Glucose-6-
phosphate dehydrogenase (G6PD) deficiency is an X-linked,
200 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
haemolytic anaemia, which is commonest in African
ancestral groups. In G6PD deficiency, red cells are less
tolerant to oxidative stress, which becomes apparent in the
context of infection, maternal fava bean ingestion or drug
toxicity.26 Pyruvate kinase and glucose phosphate isomerase
deficiencies also cause fetal anaemia.
Vascular tumours
Any tumour of the fetus or placenta that sequesters red blood
cells can cause fetal anaemia. Sacrococcygeal teratoma (SCT)
is the commonest fetal tumour, in which red cells can be
consumed or damaged as they pass through, or there can be
bleeding within the tumour leading to fetal anaemia. A large
cohort study27 found that 9.1% of fetuses with SCT
developed hydrops, although such ultrasound findings with
tumours may be attributed to high output cardiac failure
rather than to anaemia. A ‘giant’ placental chorioangioma,
seen on ultrasound with colour Doppler as a ‘mass’
protruding into the amniotic cavity from the placenta with
high vascularity, may cause a hyperdynamic circulation with
associated polyhydramnios. Fetal anaemia results from
sequestration and destruction of fetal RBCs within the
thrombosed vascular mass of the tumour.28 Other tumours,
including haemangiomata (for example, in the fetal liver) and
arteriovenous malformations can similarly cause
fetal anaemia.
Fetomaternal haemorrhage (transplacental
haemorrhage)
Any antepartum haemorrhage can cause loss of fetal red
blood cells into the maternal circulation. A woman may
present without overt clinical signs of bleeding, and reduced
fetal movements may be the only clue. Fetomaternal
haemorrhage (FMH) can be detected by the Kleihauer–
Betke test, or by flow cytometry.7 The effect on the fetus
depends on gestation (because considerable volume
expansion occurs in the fetus and placenta throughout
pregnancy) and timescale, with a gradually evolving chronic
anaemia being better tolerated. In pregnancies with recurrent
FMH remote from term, without acute maternal or fetal
compromise, supportive care with ultrasound surveillance
can be offered; however, the outlook is unpredictable and
these cases require caution.
A sudden large bleed, as in a massive placental abruption
or ruptured vasa praevia, will cause fetal hypotension,
acidaemia and eventually death. Placental abruption is an
obstetric emergency, usually occurring without warning and
mostly in low-risk pregnancies without modifiable risk
factors.29 Other causes of FMH are listed in Box 1.
Guidance for the management of antepartum haemorrhage
is provided by the RCOG.29

Vasa praevia
A diagnosis of vasa praevia may be made following painless
vaginal bleeding coinciding with membrane rupture and
fetal compromise. In such cases, there is no time for
diagnostic testing because of associated ‘fetal distress’
requiring urgent delivery to prevent fetal demise.30
Routine antenatal screening does not currently occur in
the UK for this condition, but if discovered in an
asymptomatic woman, then RCOG guidelines support
delivery by caesarean section at 34–36 weeks of gestation,
after ultrasound confirmation of persistence and
administration of steroids for fetal lung maturity.30 In
situations of anterior placenta praevia, the placenta may
need to be transected during a caesarean section to facilitate
delivery, in which case immediate cord clamping is required
to minimise fetal blood loss.31 In any case of major
antepartum haemorrhage, neonatal support should be
available at delivery. A longer length of cord should be
left attached to the newborn to facilitate umbilical artery
catheterisation in case transfusion is required.29
Complications of monochorionicity in
multifetal pregnancies
Fetal anaemia can be a consequence of vascular anastomoses
connecting the fetal circulations in multiple pregnancies with a
shared placenta. Specific complications of monochorionicity
are subacute/chronic fetal anaemia associated with twin
anaemia polycythaemia sequence (TAPS) and acute anaemia
in the surviving fetus following co-twin demise. TAPS is
defined by a significant discordance in haemoglobin levels
between twins, without substantial differences in amniotic
fluid volume. Prenatal prediction relies on ultrasound Doppler
imaging of the middle cerebral artery peak systolic velocity
(MCA-PSV, described in the next section).32 TAPS arises from
a chronic transfusion of blood from a donor to recipient fetus
via miniscule (<1 mm) artery–vein anastomoses. It
spontaneously affects up to 5% of all monochorionic
diamniotic pregnancies.33,34 After fetoscopic laser ablation
for fetofetal transfusion syndrome, TAPS has been reported in
up to 16% of monochorionic twins. It is associated with
incomplete ablation of placental anastomoses, although the
Solomon technique can reduce the incidence of this
complication to 3%.35
Single intrauterine fetal death complicates 1–2% of
monochorionic twin pregnancies. Following this event, an
acute transfusion from the surviving co-twin to the
demised twin can occur, leading to anaemia,36 with the
surviving co-twin being at significant risk of subsequent
brain injury and death.37 Complexities surrounding the
management of such cases mean that input from a tertiary
fetal medicine centre is recommended; however, in the UK,
ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Castleman et al.
this is not routinely screened for in uncomplicated
monochorionic twins.38
Principles of management of fetal anaemia
Identifying an anaemic fetus
Pregnancies at high risk of fetal anaemia can be identified
antenatally from the booking history, routine screening to
detect maternal serum antibodies at 12 and 28 weeks of
gestation, ultrasonographic evidence of hydrops fetalis, or a
high-risk fetal condition. Parous women should be asked at
booking about prior transfusion history and previous fetal or
neonatal transfusion. A history of neonatal jaundice should
be sought. Maternal reporting of relevant infectious exposure
or possible fetomaternal haemorrhage is more variable, but
should also alert a clinician to evaluate for risk of fetal
anaemia. High-risk cases should then be evaluated early by a
fetal medicine specialist.
Direct fetal blood sampling is the ‘gold standard’ for the
diagnosis of fetal anaemia, but carries a procedure-related
risk of miscarriage or preterm birth of up to 2%.39 Increased
cardiac output and reduced blood viscosity means that
arterial blood flow in the brain of an anaemic fetus is
increased.40 Doppler ultrasound assessment of the fetal
MCA-PSV is used to screen for fetal anaemia (Figure 1).2,41
The ‘action line’ and consideration of fetal blood sampling is
required at 1.5 multiples of the median MCA-PSV for
gestational age. Extramedullary haematopoiesis in a severely
anaemic fetus causes hepatosplenomegaly, with subsequent
liver congestion and impaired synthetic function, leading to
extracellular fluid accumulation.42 Effusions, ascites, oedema
and polyhydramnios can be detected by ultrasound in
hydrops fetalis, defined as abnormal fetal fluid collections
in two or more compartments. Outcomes are worse if
hydrops is present, which makes early detection important.
Ultrasound evidence of cardiac decompensation may include
cardiomegaly and tricuspid regurgitation. When nonimmune
hydrops is detected on ultrasound scan, maternal wellbeing
should be assured, including assessment of blood pressure
and dipstick urinalysis to exclude the maternal pre-
eclampsia-like ‘mirror syndrome’.43
Recently, magnetic resonance imaging (MRI) estimation of
fetal haematocrit has been proposed as a more specific
imaging technique to identify fetal anaemia (93% versus 88%
for ultrasound MCA-PSV). However, this is a more expensive
imaging resource, has not been shown to be cost effective and
is not readily delivered by the bedside.2,44 While MRI is a less
available resource, it may avoid unnecessary intervention at
later gestations, or after fetal therapy where MCA-PSV is less
specific.45 MRI can also provide additional information
about the effect of severe anaemia on the fetal brain.46,47
An anaemic fetus may present with an unusual fetal heart
rate pattern on cardiotocography.48 A sinusoidal trace may be
201
 Fetal anaemia
Figure 1. Middle cerebral artery Doppler assessment. This ultrasound image shows an axial section of the fetal head, with Doppler insonation of
the fetal middle cerebral artery, close to its origin from the internal carotid artery in the Circle of Willis. The peak systolic velocity is measured, using
angle correction and in the absence of fetal breathing movements.
the first objective sign of anaemia or sudden fetomaternal
haemorrhage and should trigger urgent senior review for
consideration of imminent delivery.
Intrauterine transfusion
The first intrauterine transfusion (IUT) occurred in 1963 and is
now performed as an ultrasound-guided percutaneous needle
(usually 20–22G) procedure.49,50 Vascular access is commonly
via the umbilical vein (at the placental cord root or intrahepatic
vein, the latter with lower complication rates).51,52 Umbilical
cord ‘free loops’ may be used. In obese women, or at earlier
gestations (usually <20 weeks) when intravascular transfusion
is technically challenging, intracardiac transfusion may be
performed.53 In modern fetal medicine, intraperitoneal fetal
transfusion is used to manage fetal anaemia (in a nonhydropic
baby) usually prior to 20 weeks of gestation, often used in
combination with maternal intravenous immunoglobulin
(IVIg) therapy in severely alloimmunised women.54 The
evidence base most strongly supports in utero transfusion for
alloimmune anaemia and parvovirus B19 infection, but it can
also be used in selected cases of inherited anaemias.52 In a case
series from the Dutch fetal therapy centre in Leiden,55
alloimmunisation accounted for 86% of IUTs, with the next
commonest indications being parvovirus B19 (9%), TAPS
(3.6%) and FMH (1.3%).
More than one in five women (with red cell
alloimmunisation) undergoing IUT form additional
alloantibodies, which may complicate future pregnancies.56
Precautions to decrease this complication include extended
phenotype matching (Rhesus, K, Duffy, Kidd and S), use of a
single, well-matched donor, or serial maternal blood donations
for IUT.56,57 The presence of adult haemoglobin (from
transfused packed cells) in the fetal circulation affects blood
viscosity and MCA-PSV becomes a less specific screening test
202 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
for fetal anaemia after IUT. Therefore, the timing of second and
subsequent IUTs relies on use of MCA-PSV and the calculated
fall of fetal Hb with time.58 The use of measured reticulocyte
count in pre-transfusion fetal blood samples may give useful
information and aid timing of further IUTs. In anaemia caused
by RBC antibodies, the fetal reticulocyte count falls with
subsequent transfusions and is an indirect marker of
suppression of the endogenous erythropoiesis by the
presence of a high proportion of donor-packed cells.59 This
suppression is evidence that the proportion of circulating fetal
RBCs are predominantly transfused cells and may aid the
decision to space out the transfusions. In fetuses infected with
human parvovirus B19, the fetal reticulocyte count at initial
fetal blood sample provides an indication as to whether the
endogenous erythropoiesis is recovering after infection. A
reticulocyte count of greater than 10% can suggest recovering
endogenous red cell production, thus allowing a more
conservative approach to management. Parvovirus B19 is
usually associated with pancytopenia and, if significant
thrombocytopenia is observed, then a platelet transfusion is
also required. If the fetal haemoglobin is <4 g/L, clinicians
must take caution not to over-transfuse the fetus because
increases in circulating volume and haematocrit can adversely
affect fetal haemodynamics, and a significant number of fetuses
have associated parvovirus myocarditis.60 Fetal and neonatal
top-up transfusions are made more likely by additional
antibody formation after transfusion and the suppression of
fetal erythropoiesis, with a recent study showing that 88% of
neonates required further intervention.61
The risk of harm to the fetus from IUT is 1–3%; intervention
at earlier gestations (<20 weeks) is more hazardous because fetal
vessels are smaller.62 Intrauterine infection (0.1% per
transfusion)52 and ruptured membranes (1.4%)51 may
complicate transfusions and lead to iatrogenic preterm birth63,

but procedure-related preterm birth has been reduced to as low
as 0.1% per procedure in a high volume centre.52 In the largest
series of 1678 IUTs in 589 fetuses, the procedure-related
complication rate was 3.3% and the perinatal mortality rate
1.8%.52 An overall 84% survival rate following IUT has been
reported, with greater than 90% survival in the absence
of hydrops.64,65
Timing of delivery depends on local protocols and the
cause of anaemia. Fetal therapy is unlikely to be offered after
34 weeks of gestation. Term vaginal birth is possible in the
absence of fetal compromise, with induction of labour likely
to be recommended at 37 weeks of gestation if the pregnancy
continues.12,66 Iatrogenic prematurity and the need for
neonatal transfusion or prolonged phototherapy must be
borne in mind.
Medical treatments
Intravenous immunoglobulins (IVIg) given at high doses may
block the transport of alloantibodies across the placenta by
competitive inhibition.12 IVIg can reduce maternal
alloantibody production and delay clinically significant
anaemia until IUT is more feasible.54,67 The Postponing
Early intrauterine Transfusion with Intravenous
immunoglobulin Treatment (PETIT) study68 investigated the
outcomes of pregnancies in women with prior alloimmunised
pregnancy complicated by severe fetal anaemia. IVIg therapy
(24 women) delayed the onset of clinically significant anaemia
compared with the index pregnancy (by 15 days) and
compared with the group not treated with IVIg (28 women,
by 9 days). This prolongation is insufficient to make a
clinically useful reduction in the risk of invasive fetal
therapy. Maternal IVIg therapy was associated with
reduction in hydrops and neonatal exchange transfusion,
especially when initiated early. Overall survival was 88%, with
no difference between groups.
Maternal plasma exchange can clear alloantibodies from the
maternal circulation. It can be beneficial when a previous
pregnancy has been severely affected by fetal anaemia, or if large
quantities of Rh-positive red blood cells need to be cleared from
a Rh-negative patient acutely. Potential adverse effects relate to
maternal morbidity (for example, infection, haematoma
formation) and altered maternal and fetal haemodynamics, as
well as the loss of systemically important proteins.69
Immunomodulatory therapies may prevent
alloimmunisation in high-risk women prior to RBC antigen
exposure, but current evidence is limited to case series, with
azathioprine, promethazine and prednisolone amongst the
candidate drugs.70 A clinical study of M281 (nipocalimab,
Momenta Pharmaceuticals), a monoclonal antibody that
blocks transplacental IgG transfer, is investigating whether it
can attenuate the risks of alloimmune fetal anaemia and
prolong the gestation when IUT may be required.71
ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Castleman et al.
Outcomes of fetal anaemia
Red cell alloimmunisation causes over 50 000 stillbirths per
year worldwide.72 Countries with comprehensive antenatal
care have reduced the prevalence of HDFN to 2.5/100 000
live births.72 Many units now prolong affected pregnancies
until 37 weeks of gestation (if safe) to reduce iatrogenic
preterm birth and caesarean section rates, with their
associated morbidity.73 For babies with antenatally
diagnosed anaemia, deferred cord clamping at the time of
delivery has been shown to reduce the need for neonatal
exchange or top-up transfusion.74 Cord blood of at-risk
babies is screened for HDFN by performing a direct
agglutinin test, with haemoglobin and bilirubin checked
after a positive screen to make the diagnosis.
Maternal antibodies remain in a baby’s circulation for up
to 6 months. Continuing red cell destruction can lead to
chronic unconjugated hyperbilirubinaemia and brain injury
(kernicterus). Neonatal jaundice is treated with phototherapy
or exchange transfusion.75 Cholestatic jaundice (conjugated
hyperbilirubinaemia) complicates the postnatal course of
13% of HDFN cases and is associated with IUT and
RhD alloimmunisation.76
Early neonatal anaemia in HDFN (within 7 days) is
determined by in utero events and late anaemia is divided
into hyporegenerative and haemolytic aetiologies.77 Top-up
transfusions occur in up to four out of five neonates with
HDFN until late postpartum anaemia resolves.75 Multiply
transfused babies are potentially at risk of iron overload. In
a systematic review of nine single-centre studies of
outcomes in children born after IUT, the pooled rate of
cerebral palsy was 2.4% (13/549).78 The LOTUS study
followed up 291 children at a median age of 8.2 years
following IUT for alloimmune fetal anaemia and found
neurodevelopmental impairment in 4.8%.79 After TAPS, the
donor twin is at increased risk of neurodevelopmental
impairment (four-fold higher than the recipient) and the
incidence of cognitive delay and deafness is increased,
warranting long term follow-up.80 ABO incompatibility is a
neonatal, rather than fetal, problem; parents can be
reassured that this mild haemolytic anaemia does not get
worse in successive pregnancies.
Conclusion
Fetal anaemia is an important condition, of which clinicians
of all levels should be aware. Appropriate antenatal screening
and identification of pregnancies at high risk of fetal anaemia
will aid prompt diagnosis. Use of ultrasound and Doppler
investigation of MCA-PSV and referral to fetal medicine
specialists for assessment and therapy has been shown to
improve outcomes.
203
 Fetal anaemia
Disclosure of interests
There are no conflicts of interests.
Contribution to authorship
JC and LG researched and wrote the article. MK reviewed and
edited the article. RKM instigated and edited the article. All
authors approved the final version.
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49 Liley AW. Intrauterine transfusion of foetus in haemolytic disease. BMJ.
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50 Rodeck CH, Kemp JR, Holman CA, Whitmore DN, Karnicki J, Austin MA.
Direct intravascular fetal blood transfusion by fetoscopy in severe Rhesus
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51 Somerset DA, Moore A, Whittle MJ, Martin W, Kilby MD. An audit of
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52 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
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53 Mackie FL, Pretlove SJ, Martin WL, Donovan V, Kilby MD. Fetal intracardiac
transfusions in hydropic fetuses with severe anemia. Fetal Diagn Ther
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54 Fox C, Martin W, Somerset DA, Thompson PJ, Kilby MD. Early intraperitoneal
transfusion and adjuvant maternal immunoglobulin therapy in the
treatment of severe red cell alloimmunization prior to fetal intravascular
transfusion. Fetal Diagn Ther 2008;23:159–63.
55 Lindenburg IT, van Klink JM, Smits-Wintjens VE, van Kamp IL, Oepkes D,
Lopriore E. Long-term neurodevelopmental and cardiovascular outcome
after intrauterine transfusions for fetal anaemia: a review. Prenat Diagn
2013;33:815–22.
56 Doyle B, Quigley J, Lambert M, Crumlish J, Walsh C, Adshead S, et al. Red
cell alloimmunisation following intrauterine transfusion and the feasibility of
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2014;24:311–5.
57 Schonewille H, Prinsen-Zander KJ, Reijnart M, van de Watering L, Zwaginga
JJ, Meerman RH, et al. Extended matched intrauterine transfusions reduce
maternal Duffy, Kidd, and S antibody formation. Transfusion
2015;55:2912–9; quiz 2911.
58 Dodd JM, Andersen C, Dickinson JE, Louise J, Deussen A, Grivell RM, et al.
Fetal middle cerebral artery Doppler to time intrauterine transfusion in red-
cell alloimmunization: a randomized trial. Ultrasound Obstet Gynecol
2018;51:306–12.
59 Ree IMC, Lopriore E, Zwiers C, Bohringer S, Janssen MWM, Oepkes D, et al.
Suppression of compensatory erythropoiesis in hemolytic disease of the
fetus and newborn due to intrauterine transfusions. Am J Obstet Gynecol
2020;223:119.e1–119.e10.
60 Kilby MD, Szwarc RS, Benson LN, Morrow RJ. Left ventricular hemodynamic
effects of rapid, in utero intravascular transfusion in anemic fetal lambs. J
Matern Fetal Med 1998;7:51–8.
61 Ree IMC, de Haas M, Middelburg RA, Zwiers C, Oepkes D, van der Bom JG,
et al. Predicting anaemia and transfusion dependency in severe alloimmune
haemolytic disease of the fetus and newborn in the first 3 months after
birth. Br J Haematol 2019;186:565–73.
62 Lindenburg IT, van Kamp IL, van Zwet EW, Middeldorp JM, Klumper FJ,
Oepkes D. Increased perinatal loss after intrauterine transfusion for
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alloimmune anaemia before 20 weeks of gestation. BJOG
2013;120:847–52.
63 Deka D, Dadhwal V, Sharma AK, Shende U, Agarwal S, Agarwal R, et al.
Perinatal survival and procedure-related complications after intrauterine
transfusion for red cell alloimmunization. Arch Gynecol Obstet
2016;293:967–73.
64 Schumacher B, Moise KJ, Jr. Fetal transfusion for red blood cell
alloimmunization in pregnancy. Obstet Gynecol 1996;88:137–50.
65 van Kamp IL, Klumper FJ, Bakkum RS, Oepkes D, Meerman RH, Scherjon
SA, et al. The severity of immune fetal hydrops is predictive of fetal
outcome after intrauterine treatment. Am J Obstet Gynecol
2001;185:668–73.
66 Lindenburg IT, van Kamp IL, Oepkes D. Intrauterine blood transfusion:
current indications and associated risks. Fetal Diagn Ther
2014;36:263–71.
67 Deka D, Buckshee K, Kinra G. Intravenous immunoglobulin as primary
therapy or adjuvant therapy to intrauterine fetal blood transfusion: a new
approach in the management of severe Rh-immunization. J Obstet
Gynaecol Res 1996;22:561–7.
68 Zwiers C, van der Bom JG, van Kamp IL, van Geloven N, Lopriore E,
Smoleniec J, et al. Postponing Early intrauterine Transfusion with
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hemolytic disease of the fetus and newborn. Am J Obstet Gynecol
2018;219:291.e1–291.e9.
69 Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L,
Delaney M, et al. Guidelines on the use of therapeutic apheresis in clinical
practice – evidence-based approach from the Writing Committee of the
American Society for Apheresis: the seventh special issue. J Clin Apher
2016;31:149–62.
70 Wong KS, Connan K, Rowlands S, Kornman LH, Savoia HF. Antenatal
immunoglobulin for fetal red blood cell alloimmunization. Cochrane
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71 Roy S, Nanovskaya T, Patrikeeva S, Cochran E, Parge V, Guess J, et al.
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72 Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F, et al.
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73 Pasman SA, Claes L, Lewi L, Van Schoubroeck D, Debeer A, Emonds M, et al.
Intrauterine transfusion for fetal anemia due to red blood cell
alloimmunization: 14 years experience in Leuven. Facts Views Vis ObGyn.
2015;7:129–36.
74 Garabedian C, Rakza T, Drumez E, Poleszczuk M, Ghesquiere L, Wibaut B,
et al. Benefits of delayed cord clamping in red blood cell alloimmunization.
Pediatrics. 2016;137:e20153236.
75 Ree IMC, Smits-Wintjens V, van der Bom JG, van Klink JMM, Oepkes D,
Lopriore E. Neonatal management and outcome in alloimmune hemolytic
disease. Exp Rev Hematol 2017;10:607–16.
76 Smits-Wintjens VE, Rath ME, Lindenburg IT, Oepkes D, van Zwet EW,
Walther FJ, et al. Cholestasis in neonates with red cell alloimmune hemolytic
disease: incidence, risk factors and outcome. Neonatology
2012;101:306–10.
77 Rath ME, Smits-Wintjens VE, Walther FJ, Lopriore E. Hematological
morbidity and management in neonates with hemolytic disease due to red
cell alloimmunization. Early Hum Dev 2011;87:583–8.
78 van Klink JM, Koopman HM, Oepkes D, Walther FJ, Lopriore E. Long-term
neurodevelopmental outcome after intrauterine transfusion for fetal
anemia. Early Hum Dev 2011;87:589–93.
79 Lindenburg IT, Smits-Wintjens VE, van Klink JM, Verduin E, van Kamp IL,
Walther FJ, et al. Long-term neurodevelopmental outcome after intrauterine
transfusion for hemolytic disease of the fetus/newborn: the LOTUS study.
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80 Tollenaar LSA, Lopriore E, Slaghekke F, Oepkes D, Middeldorp JM, Haak MC,
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205
 DOI: 10.1111/tog.12744 2021;23:206–12
The Obstetrician & Gynaecologist
http://onlinetog.org
Antenatal venous thromboembolism
David A Crosby MD MSc MBA MRCPI MRCOG,*a Ann McHugh
Bridgette Byrne MD FRCPI FRCOGd
a
Specialist Registrar, Department of Obstetrics and Gynaecology, Coombe Women and Infants University Hospital, Dublin 8, Ireland
b
Maternal-Fetal Medicine Fellow, Maternal Medicine Service, Coombe Women and Infants University Hospital, Dublin 8, Ireland
c
Consultant Haematologist, National Coagulation Centre, St James’s Hospital, Dublin and Coombe Women and Infant’s University Hospital,
Dublin 8, Ireland
d
Senior Lecturer and Consultant Obstetrician and Gynaecologist, Coombe Women and Infants University Hospital, Dublin 8, Ireland
*Correspondence: David A Crosby. Email: crosbyd@tcd.ie
Accepted on 24 September 2020. Published online 20 June 2021.
Key content
 Venous thromboembolism (VTE) remains one of the leading
causes of maternal mortality and morbidity in the
developed world.
 Clinical diagnosis of antenatal VTE is difficult and scoring systems
have historically been of limited benefit in the pregnant
population. However, evidence is emerging to suggest that
pregnant women can be risk stratified for pulmonary embolism
without the need for imaging in all cases.
 Optimal treatment is with weight adjusted therapeutic dose low-
molecular-weight heparin (LMWH) subcutaneously.
 In rare cases, there may be a role for retrievable inferior vena cava
(IVC) filters.
Please cite this paper as: Crosby DA, McHugh A, Ryan K, Byrne B. Antenatal venous thromboembolism. The Obstetrician & Gynaecologist 2021;23:206–12. https://
doi.org/10.1111/tog.12744
Introduction
Venous thromboembolism (VTE) remains one of the leading
causes of maternal mortality in the developed world.1 VTE
usually presents as deep vein thrombosis (DVT) and
pulmonary embolus (PE). More rarely, it can manifest as
cerebral venous sinus thrombosis and cavernous sinus
thrombosis. Overall, there is a five-fold higher risk in
pregnancy and between a 20 and 60-fold increased risk in
the first 3 months postpartum compared with age-matched
nonpregnant women.2,3 This is associated with increased
coagulation factors VIII, IX, X and fibrinogen; a concomitant
decrease in fibrinolytic activity and a reduction in anti-
thrombin (AT) and protein S levels;4 venous stasis and
vascular damage.5 The absolute rate is approximately 1 in
1000 pregnancies6 and, while maternal mortality caused by
lethal PE in the UK declined from 1.56 per 100,000
maternities in 2003–2005 to 0.7 in 2006–2008, subsequent
reports note an increase to 1.39 per 100,000 maternities in
2014–2016. Estimates suggest that up to 90% of women who
206
Review
PhD MRCPI MRCOG,
b
Kevin Ryan MB FRCPI FRCPath,
c
 The obstetrician has a key role in the multidisciplinary team
discussion with the aim of minimising maternal risk of
haemorrhage or thrombosis.
Learning Objectives
 To understand the optimal approach to diagnosing VTE in
pregnancy and the antenatal management of acute VTE.
 To understand the rare indications, risks and benefits of IVC filters
in pregnancy.
 To understand the complexity of decision making around the time
of delivery to minimise the risk of bleeding and
recurrent thrombosis.
Keywords: IVC filter / medical disorders in pregnancy / venous
thromboembolism
develop PE in pregnancy have identifiable risk factors.7
Therefore, screening for these risk factors is of paramount
importance in the prevention of VTE in pregnancy and the
puerperium (for further reading, see the Royal College of
Obstetricians and Gynaecologists’ [RCOG] Green-top
guideline no. 37a).8 However, up to 50% of pregnant
women have at least one identifiable risk factor for VTE,9
which can present a diagnostic challenge. DVT is the most
common manifestation of VTE in pregnancy, with a three-
fold incidence of DVT compared with PE.7 Almost one-
quarter of women with an untreated or undiagnosed DVT
will develop a PE. Of these, up to 15% can be fatal and two-
thirds of deaths occur within 30 minutes of the embolic
event.10,11 The prevalence of confirmed PE in women with
suspected PE can range between 2.0 and 7.1%.12-14
Diagnosis of venous thromboembolism
Individual hospitals should have an agreed protocol for use in
the diagnosis of suspected VTE during pregnancy. Diagnosis
ª 2021 Royal College of Obstetricians and Gynaecologists

should involve a multidisciplinary team (MDT) to include
obstetricians, radiologists, physicians and haematologists, with
diagnostic testing performed for women presenting with
symptoms or signs suggestive of VTE.1
Most women who present with VTE in pregnancy are
symptomatic.15 However, most symptomatic women do not
have VTE. This is because the clinical symptoms and signs
of VTE are common, pregnancy-related physiological
symptoms, such as oedema, dyspnoea and tachycardia.13 In
the nonpregnant population, scoring systems, such as the Wells
score, are designed to assess the pre-test probability of a positive
result to reduce the incidence of unnecessary investigation.
These scores must be modified and validated for pregnancy.12
Some recent, encouraging, results are outlined below.
Deep vein thrombosis
Common presenting symptoms of DVT include unilateral leg
swelling, pain and erythema.16 When there is a clinical
suspicion of a DVT in pregnancy, treatment dose low-
molecular-weight heparin (LMWH) should be commenced
immediately. A diagnostic compression duplex ultrasound of
the deep veins of the symptomatic leg is recommended.17 If the
test confirms a DVT, treatment is continued. If the test is
negative, treatment can be discontinued. However, if there is a
persistent clinical suspicion, RCOG guidance recommends that
treatment should be continued and ultrasound repeated 3 and
7 days later. If this is negative and the clinical suspicion is low,
no further treatment is required, unless clinically indicated.1,18
If an iliac vein thrombosis is suspected, magnetic resonance
venography or contrast venography can be considered if duplex
ultrasonography does not yield a diagnosis.19
Pulmonary embolism
The classical symptoms and signs of PE are dyspnoea,
pleuritic chest pain and haemoptysis; however, patients may
present with vague symptoms in pregnancy. Initial
investigation for pregnant women with these symptoms
and signs should include electrocardiogram (ECG) and chest
X-ray. In pregnancy, normal ECG changes may include sinus
tachycardia, left axis deviation, ectopic beats or T wave
inversion.20 ECG changes such as T wave inversion, S1Q3T3
pattern and right bundle branch block can be observed in
almost 40% of women with acute PE.21 Other common
pathological conditions that can cause S1Q3T3
electrocardiographic abnormality are pneumothorax, cor
pulmonale, acute lung disease and left posterior fascicular
block.22 Chest X-ray is associated with a low dose of radiation
to the fetus and may aid the diagnosis of other respiratory
conditions.23 Arterial blood gas (ABG) testing is of limited
diagnostic value in pregnancy. This is because only 10% of
women subsequently diagnosed with PE in pregnancy have
arterial PO2 levels less than 60 mmHg and 2.9% have oxygen
saturation levels less than 90%.21
ª 2021 Royal College of Obstetricians and Gynaecologists
Crosby et al.
If a woman presents with suspected PE and has symptoms
and signs of DVT, lower limb compression duplex should be
performed. If DVT is confirmed, the diagnosis of PE can be
assumed and no further radiological investigation is
necessary.24 Absence of DVT in the lower limbs cannot rule
out PE in this situation.16 Pregnant women with suspected
PE without symptoms and signs of DVT (and those with
suspected PE and DVT but with negative ultrasound of the
peripheral veins) should have a ventilation/perfusion (V/Q)
scan or a computerised tomography pulmonary angiogram
(CTPA) to confirm or refute the diagnosis.
The role of V/Q and CTPA scanning
Individual hospitals should have an agreed protocol for the
objective diagnosis of suspected PE during pregnancy based
on local availability.1 CTPA is usually more readily available
than V/Q scans25 and can detect other cardiorespiratory
pathology.26 However, some research suggests that V/Q
scanning may have a higher diagnostic yield than CTPA.27
When a chest X-ray is abnormal and there is a clinical
suspicion of PE, CTPA should be performed in preference to
a V/Q scan.
Risks of CTPA and V/Q scanning
Where feasible, women should be involved in the decision-
making process to undergo CTPA or V/Q scanning.1
Compared with CTPA, V/Q scanning may carry a slightly
increased risk of childhood cancer in the baby.28 However,
with both modalities, the doses are well below the accepted
thresholds for teratogenicity (first trimester only) and fetal
growth restriction. CTPA, on the other hand, is associated
with a higher risk of maternal breast cancer owing to
radiation dose exposure 20–100 times greater than that used
for V/Q scanning.29 The greater risk of early onset breast
cancer with CTPA than V/Q scanning has been refuted in a
recent publication.30
The role of D-dimer testing in acute venous
thromboembolism in pregnancy
D-dimer is a fibrin degradation product that can be detected
in elevated levels in blood when acute thrombosis occurs. It is
used as a diagnostic tool, particularly in pre-test probability
scores, such as the Wells score.31 The diagnostic value of this
test has been limited; fibrinolytic activity in the placenta,
which increases with advancing gestation, normally raises D-
dimer levels in pregnancy.32 Trimester-adjusted D-dimer
thresholds have been recommended, but are not yet
validated.33 Additionally, there is evidence to suggest that a
negative D-dimer does not exclude VTE in pregnancy.34
Therefore, D-dimer should not be ordered indiscriminately
in pregnant patients, but may be of use as part of a diagnostic
algorithm. This approach requires further validation
(see below).
207
 Antenatal venous thromboembolism
Scoring systems in pregnancy
Clinical diagnosis of antenatal VTE is difficult and scoring
systems have historically been of limited benefit in the
pregnant population. Therefore, to date, guidance has not
supported the use of pre-test probability assessment in the
management of acute VTE in pregnancy.1 Evidence is
emerging to suggest that pregnant women could be risk-
stratified for PE without the need for imaging in all cases.
However, these findings require further validation before
they are introduced into routine clinical practice.
The modified Wells score (MWS) is a scoring system that
can be applied to patients with clinical suspicion of VTE to
stratify risk. Use of the MWS in pregnancy has been assessed
retrospectively. No women in this study with a MWS of less
than 6 had a PE, giving a negative predictive value of 100%.35
Further work is required on the MWS to validate
these findings.1
Righini et al.36 evaluated an algorithm comprising the
revised Geneva score (RGS), lower limb duplex ultrasound,
CTPA and/or V/Q scan and D-dimer. None of the 367
patients in whom PE was excluded had symptomatic VTE
during the 3-month follow-up period. PE was diagnosed in
7.1% of the study cohort, but despite the algorithm, 84% of
women still required CTPA. Duplex ultrasound of the lower
limbs was performed in all patients, with a diagnosis of DVT
in only 1.7%.12
In the YEARS study, in which pregnant women were
excluded, three clinical criteria were used to predict PE:
clinical signs of DVT, haemoptysis and whether PE is
considered the most likely diagnosis. The YEARS criteria
were then applied to a risk-adjusted D-dimer algorithm,
which uses a threshold of 1000 ng/mL in nonpregnant
patients who have no signs of DVT, no haemoptysis and in
whom PE is not the most likely diagnosis. The authors
showed that the algorithm had a low incidence of VTE at
3 months of 0.61% and that the use of CTPA was 14% lower
when the YEARS algorithm was applied compared with
conventional algorithms. These findings were observed in all
age groups and across several relevant subgroups, but did not
include any pregnant women.37
Performance of the YEARS algorithm was subsequently
assessed in pregnant patients.13 The pregnancy-adapted
YEARS algorithm (Figure 1) was able to safely rule out PE
in pregnant women with suspected PE. In this study of 498
patients, only one patient in whom PE was excluded was
diagnosed with DVT at 3-month follow-up and no patients
were diagnosed with PE during this period. The YEARS
algorithm was more efficient than the combination of the
RGS, ultrasound and the standard D-dimer threshold. This is
because CTPA or V/Q imaging was avoided in 39% of
patients and duplex ultrasound of the lower limbs was
conducted in 15.9% of women. The ability of the algorithm
to rule out PE without CTPA decreased with advancing
208
gestation. CTPA or V/Q scanning was avoided in 65% of
patients enrolled in the first trimester, 46% in the second
trimester and 32% in the third trimester. This probably
reflects the need to incorporate gestation-specific D-dimer
level thresholds.13 While these data suggest that use of the D-
dimer in conjunction with a pre-test probability score may
safely identify pregnant women who do not require further
radiological assessment, further clinical validation would be
welcome before its wider adoption in clinical practice. It is
important to stress that these algorithms have only been
tested when there is a clear clinical suspicion of PE; they
should not be applied when there are nonspecific
chest symptoms.
Management of venous thromboembolism
Owing to adverse effects on the fetus, such as miscarriage,
prematurity and risk of fetal and neonatal haemorrhage,
vitamin K antagonists, such as warfarin, should not be
used for VTE treatment antenatally.1 Direct oral
anticoagulants are also contraindicated in pregnancy
because of potential teratogenicity.38
The treatment of choice in suspected VTE is subcutaneous
LMWH, commenced immediately unless contraindicated.39
LMWHs are more effective than unfractionated heparin
(UFH), and are associated with less haemorrhagic
complications and a lower mortality rate than UFH in the
management of PE.40 Heparin-induced thrombocytopenia
(HIT) has rarely been reported in pregnancy, with an
incidence of less than 0.1%.41 Side effects of LMWH
therapy include osteoporotic fractures (0.04%) and allergic
skin reactions (1.8%).7,42
Before starting LMWH therapy, it is recommended to
carry out a full blood count, serum biochemistry, liver
function tests and coagulation screen. A thrombophilia
screen is not recommended at time of diagnosis owing to
the pathophysiological effects of a thrombus in pregnancy on
the interpretation of the result.1
Dose and timing of low-molecular-weight heparin
There should be clear local guidelines for the dose of LMWH
used. Furthermore, the dose used should be based on the
woman’s booking weight, if available, and if not, against an
early pregnancy weight. Changes in renal glomerular
filtration rate and the volume of distribution in pregnancy
results in pharmacokinetic changes of LMWHs in
pregnancy.43 There is insufficient evidence to recommend
whether the dose of LMWH should be given daily or twice
daily in divided doses.1 Owing to the risk of VTE recurrence,
treatment with therapeutic doses of LMWH should be
continued until delivery, for a minimum of 6 weeks
postnatally and until at least 3 months of treatment has
been completed.1 An intermediate dose of LMWH may be
ª 2021 Royal College of Obstetricians and Gynaecologists
 Crosby et al.

Suspected acute pulmonary embolism

in a pregnant patient

Clinical signs of
Order D-dimer test and asses presence deep vein thrombosis
of the three YEARS criteria:
1. Clinical signs of deep vein thrombosis
2. Haemoptysis
Compression ultrasonography Abnormal
3. Pulmonary embolism as the most likely
of symptomatic leg compression
diagnosis
ultrasonography

Normal compression
ultrasonography Initiate
anticoagulant
treatment

No YEARS criteria and No YEARS criteria and One to three YEARS criteria and One to three YEARS criteria and
D-dimer <1000 ng/ml D-dimer ≥1000 ng/ml D-dimer <500 ng/ml D-dimer ≥500 ng/ml

Pulmonary embolism ruled out
Withhold anticoagulant
treatment
Perform CT pulmonary
angiography
Initiate anticoagulant treatment
if CT pulmonary angioography
indicates pulmonary embolism
Pulmonary embolism ruled out
Withhold anticoagulant
treatment
Perform CT pulmonary
angiography
Initiate anticoagulant treatment
if CT pulmonary angioography
indicates pulmonary embolism

Figure 1. Pregnancy-adapted YEARS algorithm for the management of suspected acute pulmonary embolism in pregnant patients.13
CT = computed tomography.

used antenatally after 3 months of treatment for women
considered at increased risk of haemorrhage,1 but there is a
paucity of data to support this.
Intrapartum care
The decision to anticoagulate a pregnant woman is of great
importance because of the association between pregnancy
and haemorrhage. Prophylactic LMWH is associated with a
0.5% risk of antepartum haemorrhage (APH) and a 1% risk
of postpartum haemorrhage (PPH) that is not different from
clinical trial controls. With treatment dosing, there is a 1.5%
risk of APH and a 2% risk of PPH.44 The challenge for the
obstetrician, anaesthetist and haematologist is to conduct
delivery as safely as possible while minimising the risk of
thrombosis and haemorrhage. This challenge can be more
complex if the pregnant woman has additional obstetric risk
factors or bleeding risks, such as multifetal pregnancy or
placenta praevia.45
LMWH therapy should be discontinued 24 hours prior to
planned delivery. This strategy minimises the risk of bleeding
and is the recommended interval for safety of neuroaxial
anaesthesia.46 If a delivery is unplanned and symptoms and
signs of labour develop, the woman is advised to omit her
heparin dose and seek medical review.1 Postnatally, LMWH
should be avoided for at least 4 hours following spinal
anaesthesia or after the epidural catheter has been removed.46
If there is a high risk of haemorrhage and if heparin
treatment is considered essential, intravenous UFH should be
considered until the risk of haemorrhage has reduced. This is
because UFH has a shorter half-life and potential for reversal
with protamine sulfate.46 A multidisciplinary approach with
an obstetrician, anaesthetist and haematologist is required in
the care planning process.
VTE diagnosis at term leads to a challenging set of
circumstances to balance. Clinicians who are experienced in
the management of birth and VTE should provide their
input. When DVT or PE is diagnosed after 37 weeks of
gestation, full anticoagulation is indicated. Delivery is
optimally delayed to allow organisation of the clot, but
there is a risk that spontaneous onset of labour may occur.

ª 2021 Royal College of Obstetricians and Gynaecologists 209

 Antenatal venous thromboembolism
Reversal of anticoagulation is more difficult with LMWH,
so intravenous UFH can be used because it is more easily
manipulated.1 It is, however, more cumbersome to
administer, the pharmacokinetics are variable and staff
are less familiar with its use.47 It can be useful when
imminent delivery is planned, however, because the
anticoagulant effect is reversed within 4 hours of stopping
the infusion.
The role of inferior vena cava filters in venous
thromboembolism in pregnancy
Inferior vena cava (IVC) filters have a role in the prevention
of lethal PE when anticoagulation is contraindicated or has
been unsuccessful. Pregnant women with an acute thrombus
around the time of birth can be considered for an IVC filter if
delivery is anticipated before clot organisation. The process
of clot organisation takes place within several days.48 The
evidence for IVC filters in the general population has been
well reported,49 but there is a paucity of data on efficacy and
complications in pregnancy. The internal jugular vein (IJV) is
the preferred route of placement to minimise radiation
exposure to the fetus.50 Owing to compression of the
infrarenal IVC in pregnancy, suprarenal positioning may be
required. However, there is a reported risk of renal vein
thrombosis with this route.51 In the second stage of labour,
IVC pressure may be altered. These factors may result in
complications of filter placement, including tilting, fracture,
migration and thrombosis. Failure to retrieve an IVC filter
inserted during pregnancy is more common compared with
filters inserted outside of pregnancy, with nearly one-quarter
of devices not retrieved in the pregnant population.52 If the
filter is not retrieved, there is a risk of subsequent DVT.53 As
there is insufficient evidence to accurately determine the risk–
benefit profile of IVC filters in pregnancy, the role of the
multidisciplinary team in the decision making process
surrounding IVC filter placement is of paramount
importance. Woman should be fully counselled about the
possible risks, benefits and long-term implications of
IVC placement.52
The role of the obstetrician in multidisciplinary
discussion of risk–benefit to the pregnant woman
Management of women diagnosed with VTE in pregnancy
should be reviewed in an MDT setting involving specialist
nurses, midwives, pharmacists and doctors.54 In the MDT
setting, the obstetrician should ensure a clear diagnosis of
VTE and that anticoagulation is clearly indicated. They
should establish the woman’s risk of bleeding during
pregnancy and delivery and clearly communicate this to the
MDT. A clear, written care plan incorporating the woman’s
wishes should be agreed with the MDT,55 focusing
particularly on the timing and mode of delivery to
minimise the risk of both thrombosis and haemorrhage.
210
Follow up after the acute event
Women diagnosed with VTE in pregnancy require specialist
management in high-risk antenatal care settings by experts in
haemostasis and pregnancy. Owing to the risk of VTE
recurrence, it is recommended that treatment with
therapeutic doses of LMWH are continued for the
remainder of the pregnancy, for a minimum of 6 weeks
postnatally and until at least 3 months of treatment has been
given.1 The ongoing risk of thrombosis should be assessed
before discontinuing therapy. There is no universal
recommendation on enhanced surveillance of fetal
wellbeing following a diagnosis of VTE in pregnancy.
A discussion regarding continuation of LMWH or
changing to an oral anticoagulant agent should be
undertaken postnatally and prior to discharge from hospital
for women who develop VTE during pregnancy or in the
puerperium. The risks, benefits and alternatives of each
method should be clearly outlined.1 Women must be
informed that LMWH and warfarin are not contraindicated
while breastfeeding; however, warfarin should not be
commenced until day five postpartum.1 Direct oral
anticoagulants (DOACs), such as rivaroxaban and
apixaban, should be avoided in pregnancy and in women
who are breastfeeding owing to a lack of evidence in these
groups.56 Furthermore, women who are changed to an oral
anticoagulant agent, such as warfarin or a DOAC, should be
advised not to conceive and should be counselled regarding
appropriate robust methods of contraception.57 Estrogen-
containing contraception is contraindicated in women with a
previous personal history of VTE.58 A further postnatal
follow-up review with an obstetrician and haematologist
should be organised.59
Women with a previous diagnosis of VTE in pregnancy are
at higher risk of recurrence in a subsequent pregnancy.
Women should be offered prepregnancy counselling prior to
a subsequent pregnancy, by a doctor with appropriate
experience, to formulate a detailed management plan for
antenatal thromboprophylaxis.8
Conclusion
VTE remains one of the leading causes of maternal mortality
in the developed world. There is a five-fold higher risk in
pregnancy and between a 20 and 60-fold increase in the first
3 months postpartum compared with age-matched
nonpregnant women. Individual hospitals should have an
agreed protocol for use in the diagnosis of suspected VTE
during pregnancy, with MDT involvement to include
obstetricians, radiologists, physicians and haematologists.
Clinical diagnosis of antenatal VTE is difficult and
biomarkers and scoring systems have historically been of
limited benefit in the pregnant population. The treatment of
choice in suspected VTE is subcutaneous LMWH. The
ª 2021 Royal College of Obstetricians and Gynaecologists

challenge for the obstetrician, anaesthetist and haematologist
is to conduct delivery in as safe a manner as possible, while
minimising the risk of thrombosis and haemorrhage. A clear,
written care plan incorporating the woman’s wishes should
be agreed with the MDT, focusing particularly on the timing
and mode of delivery to minimise the risk of both thrombosis
and haemorrhage. This challenge can be more complex if the
pregnant woman has additional obstetric risk factors or
bleeding risks. Pregnant women with an acute thrombus
around the time of birth may be considered for an IVC filter
if delivery is anticipated before clot organisation. A
discussion regarding continuation of LMWH or changing
to an oral anticoagulant agent should be undertaken
postnatally and prior to discharge from hospital for women
who develop VTE during pregnancy or in the puerperium.
Women should be offered prepregnancy counselling prior to
a subsequent pregnancy, by a doctor experienced in this, so
that she knows how to gain early access to appropriate care.
Such care would usually include an early obstetric scan and
subsequent initiation of prophylactic LMWH.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
BB instigated and edited the article. DAC researched and
wrote the article. AM and KR wrote and edited the article. All
authors approved the final version.
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