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Birth defects: Causes

Aut hor: Carlos A Bacino, MD, FACMG
Sect ion Editors: Helen V Firth, DM, FRCP, DCH, Louise Wilkins-Haug, MD, PhD
Deput y Editor: Elizabeth TePas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Lit erat ure review current t hrough: Jun 2020. | T his topic last updat ed: Jun 11, 2019.

INTRODUCTION

A birt h defect is any st ruct ural anomaly present at birt h. These defect s can be caused by genet ic
abnormalit ies and/or environment al exposures, alt hough t he underlying et iology is oft en unknown [1].
Birt h defect s can be isolat ed or present in a charact erist ic combinat ion or pat t ern t hat may affect
one or more organ syst ems. What is, t hen, a genet ic disorder? It is an abnormalit y caused by a change
or mut at ion in t he genome t hat oft en leads t o medical consequences. Even t hough most genet ic
disorders are congenit al, t hey may have a delayed clinical present at ion or adult onset . These disorders
can be inherit ed or t he result of a new mut at ion.

This t opic discusses t he causes of birt h defect s. The epidemiology, t ypes, pat t erns, and evaluat ion
of birt h defect s are discussed in det ail separat ely, as are specific congenit al anomalies. (See "Birt h
defect s: Epidemiology, t ypes, and pat t erns" and "Birt h defect s: Approach t o evaluat ion".)

OVERVIEW

The causes of congenit al anomalies are genet ic and nongenet ic [2].

Genet ic abnormalit ies include:

● Chromosomal disorders (eg, Down syndrome) (see "Down syndrome: Overview of prenat al
screening" and "Down syndrome: Clinical feat ures and diagnosis")

● Single-gene (monogenic) disorders are disorders wit h different modes of inherit ance including
aut osomal recessive, aut osomal dominant , or X-linked disorders. The following are examples of
 single-gene disorders causing limb malformat ions:

• Aut osomal dominant (eg, ect rodact yly, ect odermal dysplasia, cleft lip, and cleft palat e
[EEC]). Dominant pat hogenic variant s in t he p63 gene are associat ed wit h EEC and ot her
relat ed syndromes [3,4]. Ect rodact yly is a major limb malformat ion charact erized by absence
or underdevelopment of cent ral met acarpals and/or met at arsals leading t o a split hand/foot
deformit y.

• Aut osomal recessive (eg, some forms of Adams-Oliver syndrome). This rare disorder is
charact erized by limb reduct ion defect s (limb hypoplasia, absent digit s, absent feet ,
syndact yly) oft en seen in associat ion wit h cut is aplasia of t he scalp. Alt hough aut osomal
dominant forms are more common, t his syndrome is caused by pat hogenic variant s in many
different genes, including dominant and recessive genes. Pat hogenic variant s in t he
dedicat or of cyt okinesis 6 (DOCK6) gene can cause a recessive form [5].

• X linked (eg, focal dermal hypoplasia or Golt z syndrome). This syndrome is caused by
pat hogenic variant s in t he prot ein-serine O-palmit oleoylt ransferase porcupine homolog
(PORCN) gene at Xp11.23, which lead t o severe limb malformat ions (absent digit s,
polydact yly, syndact yly) as well as cut aneous-dermal defect s wit h fat herniat ion [6,7].

Nongenet ic t erat ogenic et iologies include:

● Mat ernal phenylket onuria (PKU) or diabet es (see 'Mat ernal illnesses' below and "Overview of
phenylket onuria", sect ion on 'Phenylalanine embryopat hy (mat ernal PKU)' and "Infant s of women
wit h diabet es")

● Drugs and chemical agent s (eg, alcohol, oral isot ret inoin) (see 'Drug exposure' below and
'Chemical agent s' below)

● Infect ions during t he prenat al period (cyt omegalovirus [CMV], rubella, Zika virus) (see 'Infect ious
agent s' below and "Overview of TORCH infect ions" and "Zika virus infect ion: Evaluat ion and
management of pregnant women")

● Fet al crowding due t o mult iple gest at ions (see "Neonat al complicat ions, out come, and
management of mult iple birt hs", sect ion on 'Congenit al anomalies')

Mult ifact orial disorders are condit ions t hat result from t he int eract ion of mult iple genes and
environment al fact ors. They include:

● Nonsyndromic cleft lip/palat e (see "Et iology, prenat al diagnosis, obst et ric management , and
recurrence of cleft lip and/or palat e" and "Overview of craniofacial cleft s and
holoprosencephaly")
 ● Nonsyndromic congenit al heart disease (see "Fet al cardiac abnormalit ies: Screening, evaluat ion,
and pregnancy management " and "Cardiac causes of cyanosis in t he newborn")

● Neural t ube defect s (see "Open neural t ube defect s: Risk fact ors, prenat al screening and
diagnosis, and pregnancy management ")

GENETIC ABNORMALITIES

Genet ic abnormalit ies can range from a point mut at ion in a single gene disrupt ing development al
pat hways or prot eins, t o t he presence of addit ional or missing chromosomal mat erial t hat can affect
a small segment t o an ent ire chromosome. (See "Overview of genet ics concept s and t he genet ic
basis of disease", sect ion on 'Genet ic variat ion'.)

Chromosomal disorders — Chromosomal aberrat ions are due t o a change in t he normal chromosome

number (aneuploidies) or a change in t he st ruct ure of a chromosome (sizable delet ions,
microdelet ions, duplicat ions, t ranslocat ions, and inversions).

The syndromes caused by congenit al aneuploidies have several common charact erist ics:

● More t han 90 percent of embryos/fet uses wit h congenit al chromosomal abnormalit ies do not
survive t o t erm. In t risomy 21, for example, 40 percent of fet uses are lost aft er 12 weeks of
gest at ion. Even higher embryonic and fet al loss rat es are found wit h monosomy X [8].

● Mult iple organ syst ems t end t o be involved, especially t he cent ral nervous syst em (CNS).
Int ellect ual disabilit y, in part icular, is a common abnormalit y in viable infant s wit h chromosome
disorders.

● The longevit y and fert ilit y of individuals wit h t hese condit ions t end t o be reduced.

Congenit al chromosomal disorders are reviewed in great er det ail separat ely. (See "Congenit al
cyt ogenet ic abnormalit ies" and "Sex chromosome abnormalit ies" and "Chromosomal t ranslocat ions,
delet ions, and inversions" and "Microdelet ion syndromes (chromosomes 1 t o 11)" and "Microdelet ion
syndromes (chromosomes 12 t o 22)" and "Microduplicat ion syndromes".)

Disorders due to single-gene defects — There is a wide range of birt h defect s caused by single-
gene defect s. These defect s encompass point mut at ions as well as small insert ions or delet ions
(indels) t hat disrupt gene t ranscript ion and prot ein synt hesis. The pat t ern of inherit ance may be
aut osomal dominant , aut osomal recessive, or sex linked. A single defect in a gene on an aut osomal
chromosome (not a sex X or Y chromosome) may cause a disorder wit h aut osomal dominant
inherit ance. In t his case, t he pat ient is het erozygous for t he genet ic defect , and one single change is
sufficient t o cause disease, hence t he name "dominant ." In disorders wit h aut osomal recessive
inherit ance, bot h alleles (copies) of a gene on an aut osomal chromosome pair are mut at ed (pat ernal
and mat ernal copies). The mut at ions can be eit her t he same, ident ical mut at ion (homozygous
mut at ion) or t wo dist inct mut at ions (compound het erozygous). Aut osomal recessive condit ions are
more common when t here is parent al consanguinit y (relat ed as second cousins or closer). The last
form of inherit ance is sex linked or linked t o t he sex chromosomes. X-linked recessive inherit ance is
t he most common example. (See 'Overview' above and "Genet ic counseling: Family hist ory
int erpret at ion and risk assessment " and "Inherit ance pat t erns of monogenic disorders (Mendelian and
non-Mendelian)".)

Single-gene disorders and the environment — Genet ic changes can be direct ly connect ed t o

alt erat ions in environment al exposures such as t he diet . A series of pat ient s wit h mult iple congenit al
malformat ions (cardiac and vert ebral defect s) underwent whole-exome or whole-genome sequencing
in an at t empt t o ident ify a genet ic defect [9]. They were found t o have pat hogenic loss-of-funct ion
variant s in t wo genes (HAAO, encoding 3-hydroxyant hranilic acid 3,4-dioxygenase, and KYNU, encoding
kynureninase) t hat are involved in t he kynurenine pat hway. This pat hway result s in t he de novo
synt hesis of nicot inamide adenine dinucleot ide (NAD) t hrough cat abolism of diet ary t rypt ophan. In
vit ro act ivit y of t he t runcat ed enzymes was low t o absent , upst ream met abolit es were elevat ed, and
downst ream met abolit es were reduced. In Haao-null or Kynu-null mice, supplement at ion of diet ary
niacin during gest at ion correct ed t he NAD deficiency, prevent ing int raut erine deat h and abnormal
embryogenesis. (See "Next -generat ion DNA sequencing (NGS): Principles and clinical applicat ions",
sect ion on 'Diagnosis of complex diseases'.)

Genetic disorders with non-Mendelian patterns of inheritance — Ot her genet ic variat ions t hat can
cause disorders include imprint ing (gamet e-specific gene silencing) disorders leading t o different ial
expression of genet ic mat erial depending upon whet her t he gene or gene region is imprint ed (eg,
Beckwit h-Wiedemann syndrome). (See "Beckwit h-Wiedemann syndrome".)

TERATOGENS

A t erat ogen is an agent t hat can cause abnormalit ies in t he form or funct ion of a developing fet us
(t able 1). It act s by producing cell deat h, alt ering normal growt h of t issues, or int erfering wit h normal
cellular different iat ion or ot her morphologic processes. The consequences of t hese act ions can be
fet al loss, fet al growt h rest rict ion, birt h defect s (eg, a limb reduct ion), or impaired neurologic
performance (eg, alt ered neural connect ions in t he cent ral nervous syst em [CNS] in fet al alcohol
syndrome).
Approximat ely 4 t o 6 percent of birt h defect s are caused by exposure t o t erat ogens in t he
environment [10]. These include mat ernal illnesses (eg, diabet es mellit us or phenylket onuria [PKU]),
infect ious agent s (eg, TORCH [Toxoplasmosis, Ot her (syphilis, varicella-zost er, parvovirus B19),
Rubella, Cyt omegalovirus, and Herpes] infect ions), physical agent s (eg, radiat ion or heat exposure), and
drugs (eg, t halidomide, ant iepilept ic drugs) and chemical agent s (eg, mercury).

Response t o t he t erat ogenic agent is highly individualized and is influenced by mult iple fact ors. These
include mat ernal and fet al genot ypes (genet ic suscept ibilit y), t he dose of t he agent , rout e of
exposure, t iming of exposure, and concurrent exposures or illnesses during gest at ion.

Genetic susceptibility — The genet ic makeup of bot h t he fet us and t he mot her det ermines t he
relat ive resist ance or suscept ibilit y t o t erat ogenic agent s. The degree of genet ic suscept ibilit y is
separat e from any specific genet ic condit ions t hat are known direct causes of birt h defect s.

As an example, albeit an oversimplified one, fet uses wit h defect s in folat e met abolism (eg,
met hylenet et rahydrofolat e reduct ase [MTHFR] gene mut at ions) appear t o be at increased risk for
st ruct ural malformat ions such as neural t ube defect s [11], cleft lip and palat e, and cardiac
malformat ions [12]. The risk of t hese malformat ions may be decreased by mat ernal supplement at ion
wit h folic acid in t he preconcept ional period and in early pregnancy [13,14]. Thus, a malformat ion such
as an open neural t ube defect may result from genet ic suscept ibilit y relat ed t o a combinat ion of
fact ors consist ing of t he presence of a fet al MTHFR gene defect and a st at e of inadequat e mat ernal
folat e int ake.

Anot her example is t hat some fet uses have low or deficient epoxide hydrolase act ivit y t hat result s in
increased levels of t erat ogenic oxidat ive met abolit es when t hey are exposed t o ant iepilept ic drugs
[15].

Finally, cert ain birt h defect s may be seen wit h different frequencies across races or sexes. For
example, post axial polydact yly is more common in African Americans (approximat ely 1 percent ) t han
Caucasians (approximat ely 0.1 percent ). Neural t ube defect s are more common in Caucasians t han
African Americans. Pyloric st enosis and cleft lip are more common in males t han females.

The genet ic makeup of t he mot her and her st at e of healt h also play a role in t erat ogenesis. The
product ion of a malformat ion is dependent upon t he abilit y of a woman t o absorb and met abolize a
t erat ogen. In addit ion, mat ernal medical disease st at es can act as t erat ogens. (See 'Mat ernal
illnesses' below.)

Route of exposure — The rout e of exposure can also impact t erat ogenic effect s. For example, t he
absorpt ion and act ion of a drug is usually different if exposure is t hrough t he dermis versus syst emic
delivery. The syst emic rout e may cause abnormalit ies, while t he dermal delivery may not . As an
affect ed by a problem occurring at t hat t ime.

Fert ilizat ion is t he first st ep and occurs wit hin 24 hours of ovulat ion. Of not e, embryonic age is
count ed from fert ilizat ion (concept ion) and st art s t wo weeks aft er gest at ional age, which is count ed
from t he first day of t he last menst rual period. The following are ot her import ant milest ones in
development (figure 1):

● Preimplant at ion and implant at ion on days 5 t o 11

● Different iat ion int o t hree germ layers (ect oderm, mesoderm, and endoderm) by day 16
● Format ion of t he neural plat e by day 19
● Closure of t he neural t ube by day 27
● Appearance of limb buds by day 30
● Format ion of t he branchial arches, cleft s, pouches, and opt ic vesicle bet ween weeks 4 and 5
● Format ion of t he mat ure heart and kidneys by weeks 5 t o 7
● Achievement of mat ure limb archit ect ure by week 8
● Sexual different iat ion of t he int ernal and ext ernal genit alia bet ween weeks 7 t o 10
● Rot at ion of t he int est ines and ret urn int o t he abdominal cavit y in week 10

A significant exposure t hat occurs during t he first 10 t o 14 days aft er fert ilizat ion may result in cell
deat h. If enough cells die, spont aneous abort ion may occur (see "Pregnancy loss (miscarriage): Risk
fact ors, et iology, clinical manifest at ions, and diagnost ic evaluat ion"). If only a few cells are damaged,
t hen t heir roles may be compensat ed by ot her cells. This is known as t he all-or-none t heory. An
example is an early significant exposure t o radiat ion, which usually result s in eit her pregnancy loss or
no abnormalit ies.

The embryo is most vulnerable t o t erat ogenic insult s since organogenesis is occurring during t he
embryonic period of development . The embryonic period in humans can be defined as from
fert ilizat ion unt il t he end of t he 10th week of gest at ion (8th week post concept ion) [22].

During t he fet al period, t erat ogens can cause cell deat h, ret ardat ion of cell growt h, or inhibit ion of
normal different iat ion. This may result in fet al growt h rest rict ion or disorders of t he CNS t hat may not
be apparent at birt h. The eyes, genit alia, CNS, and hemat opoiet ic syst ems cont inue t o develop during
t he fet al period and remain suscept ible t o t erat ogenic insult s.

As an example, t he risks associat ed wit h angiot ensin-convert ing enzyme (ACE) inhibit or exposure are
significant during t he second and t hird t rimest ers (US Food and Drug Administ rat ion [FDA] cat egory D)
due t o blockade of conversion of angiot ensinogen I t o angiot ensin II in t he developing fet al kidney.
This exposure result s in hypot ension, renal t ubular dysplasia, anuria/oligohydramnios, growt h
rest rict ion, and calvaria defect s. However, t hese drugs can cause ot her defect s, such congenit al
heart defect s, during t he first t rimest er (US FDA cat egory C).
Misoprost ol, a prost aglandin E1 analog, can cause severe vascular disrupt ions in t he first t rimest er (ie,
t erminal limb defect s, Moebius syndrome). It has also been widely used t o induce abort ions in t he first
and second t rimest ers. However, t his drug is safe t o use during delivery for ut erine cervix ripening and
t o induce labor [23].

Some t erat ogens act wit hin a narrow window. As an example, t he t erat ogenic effect of t halidomide
for limb defect s is limit ed t o 21 t o 36 days post concept ion, when limb bud development begins.

Mechanisms of teratogenesis — Terat ogenesis is t hought t o occur aft er fert ilizat ion and result s
from many diverse mechanisms. These include cell deat h (eg, radiat ion); blocking of met abolic
processes (eg, t hioureas, iodides); alt erat ions in cellular growt h and proliferat ion, migrat ion, and
apopt osis (eg, fet al alcohol spect rum disorder); and int eract ions bet ween cells or bet ween cells and
t issues.

Exposure prior t o concept ion may t heoret ically cause genet ic mut at ions, a process known as t oxic
mut agenesis, alt hough t his is a cont roversial t opic. The t iming of t his process differs in males and
females. In females, DNA replicat ion occurs during oogenesis in t he fet us, many years before
ovulat ion. In cont rast , cont inuing spermat ogenesis makes males suscept ible t o mut at ions t hroughout
t heir reproduct ive life. Examples include t he pot ent ial effect s of ionizing radiat ion on
spermat ogenesis [24] and pot ent ial effect s of chemot herapy drugs in t he reproduct ive syst em [25].

Specific teratogens — Numerous t erat ogens in t he environment can lead t o birt h defect s. Common
agent s are list ed below and in t he t able (t able 1).

Infectious agents — Exposure t o infect ious agent s can result in a variet y of problems in t he fet us
and neonat e, including malformat ions, congenit al infect ion, short - and long-t erm disabilit y, and deat h.
The pat hogenesis of t he fet al defect s is usually direct invasion of fet al t issues leading t o damage
from inflammat ion and cell deat h. Agent s known t o be t oxic t o t he fet us or embryo are
t oxoplasmosis, rubella, cyt omegalovirus, herpes, and syphilis (t he so-called TORCH infect ions), as well
as varicella, parvovirus B19, Zika virus, and lymphocyt ic choriomeningit is virus (LCMV). (See "Overview
of TORCH infect ions" and "Syphilis in pregnancy" and "Varicella-zost er virus infect ion in pregnancy" and
"Parvovirus B19 infect ion during pregnancy" and "Rubella in pregnancy" and "Prenat al evaluat ion of
women wit h HIV in resource-rich set t ings" and "Viral meningit is: Clinical feat ures and diagnosis in
children", sect ion on 'Ot her viruses' and "Seasonal influenza and pregnancy" and "Zika virus infect ion:
Evaluat ion and management of pregnant women".)

Nonspecific sonographic signs suggest ive of fet al infect ion include:

● Microcephaly
● Cerebral or hepat ic calcificat ions
 ● Int raut erine growt h rest rict ion
● Hepat osplenomegaly
● Cardiac malformat ions, limb hypoplasia, hydrocephalus
● Hydrops

Birt h defect s associat ed wit h disorders of movement and muscle t one, chorioret init is or cat aract s,
hearing impairment , hepat osplenomegaly, skin rash, t hrombocyt openia, jaundice, or low birt h weight are
suggest ive of congenit al infect ion.

Fever associat ed wit h infect ion also can be t erat ogenic. (See 'Physical agent s' below.)

Maternal illnesses — Several mat ernal illnesses are associat ed wit h birt h defect s. The
mechanism is diffusion of a met abolit e or ant ibody across t he placent a t hat is t oxic t o t he fet us.

● Insulin-dependent diabet es mellit us is associat ed wit h a t wo- t o t hreefold increase in risk of

congenit al anomalies, including congenit al heart disease, cleft palat e, colobomas, and spina bifida,
and, less commonly, caudal regression and focal femoral hypoplasia. (See "Infant s of women wit h
diabet es".)

● Mat ernal phenylket onuria (PKU) if not diet cont rolled is associat ed wit h microcephaly,
int ellect ual disabilit y, and congenit al heart disease. (See "Overview of phenylket onuria".)

● Androgen-producing t umors of t he adrenal glands or ovaries can produce virilizat ion of female
fet uses.

● Mat ernal ant ibodies present in aut oimmune disorders can cross t he placent a and cause t oxicit y in
t he fet us. Examples include myast henia gravis leading t o t ransient neonat al myast henia, mat ernal
Grave disease causing fet al and neonat al t hyrot oxicosis, immune t hrombocyt openia (ITP)
result ing in fet al and neonat al t hrombocyt openia, and syst emic lupus eryt hemat osus causing
fet al heart block. (See "Overview of t he t reat ment of myast henia gravis" and "Hypert hyroidism
during pregnancy: Treat ment " and "Thrombocyt openia in pregnancy" and "Pregnancy in women
wit h syst emic lupus eryt hemat osus".)

Mat ernal obesit y and hypert ensive disorders (including preeclampsia and pre-exist ing hypert ension)
[26] are also associat ed wit h an increased risk of cert ain t ypes of birt h defect s. The mechanism is
unknown, but one hypot hesis is t hat t hese disorders lead t o aberrant early implant at ion or impair early
blood supply t o t he fet us. (See "Obesit y in pregnancy: Complicat ions and mat ernal management ",
sect ion on 'Congenit al anomalies'.)

Physical agents — Physical agent s, such as heat and radiat ion, have been implicat ed in t he
pat hogenesis of birt h defect s. Heat exposure may be due t o hot t ub or sauna use or mat ernal fever.
Elevat ion of mat ernal core t emperat ure more t han 1.5°C in t he first t rimest er of pregnancy for at
least 24 hours may be associat ed wit h an increased risk of neural t ube defect s [27-29]. Ot her clinical
findings associat ed wit h high mat ernal t emperat ure include microcephaly, int ellect ual disabilit y,
hypert onia, hypot onia, and seizures. (See "Int rapart um fever", sect ion on 'Consequences'.)

Excessive exposure t o ionizing radiat ion has t he pot ent ial t o produce fet al deat h, growt h
dist urbances, somat ic abnormalit ies, mut at ion, chromosome fragment at ion, and malignancy. In general,
t oxic levels are not achieved wit h diagnost ic imaging. However, knowledge of a pregnancy should, in
most circumst ances, result in a reappraisal of t he necessit y for and mode of imaging. (See "Diagnost ic
imaging in pregnant and nursing women" and "Radiat ion-relat ed risks of imaging".)

Drug exposure — Mat ernal drug ingest ion, including prescript ion and over-t he-count er medicat ions
as well as recreat ional drugs, can also cause adverse fet al and neonat al out comes. However, it can be
ext remely difficult t o det ermine whet her a part icular subst ance is t erat ogenic. In addit ion, t he t iming
of exposure during pregnancy can affect t he t erat ogenicit y of a drug. A part ial list of addit ional known
t erat ogens is provided in t he t able (t able 1).

The US Food and Drug Administ rat ion (FDA) requires t hat all prescript ion drugs be t est ed in animal
models, usually one rodent and one nonrodent model. Test ing est ablishes bot h t he lowest observed
adverse effect level (LOAEL) and t he no observed adverse effect level (NOAEL). If t he human
exposure level is 100 t imes lower t han t he NOAEL, adverse effect s in humans are considered
unlikely. However, result s from animal models may not always apply t o humans. As an example,
t halidomide is st rongly t erat ogenic in humans, but weakly t erat ogenic in animals, while t he opposit e is
t rue for aspirin. A st udy of drugs approved by t he US FDA from 2000 t o 2010 found t hat t he
t erat ogenic risk in human pregnancy was "undet ermined" for 98 percent of t he drugs approved for
human use [30].

Due t o t he limit at ions of drug t est ing, dat a regarding t he associat ion of drugs or chemicals and birt h
defect s come primarily from case report s of exposed pat ient s. However, t hese also do not always
est ablish t erat ogenicit y and oft en need validat ion by epidemiologic st udies. Two promising
approaches t o providing somewhat bet t er informat ion are prospect ively collect ed exposure dat a
from t erat ogen informat ion agencies and large-scale birt h defect s regist ries [31]. Post -market ing
drug regist ries are also used t o monit or for t erat ogenicit y, but t hese rely on act ive part icipat ion of
clinicians and pregnant women and as such are not comprehensive in t heir surveillance. As previously
discussed, some of t he drugs can be pot ent ially t erat ogenic during specific t imes of fet al
development but be innocuous ot herwise. (See 'Timing' above.)

In 2015, t he US FDA swit ched from labeling prescript ion drugs for use during pregnancy wit h one of
five cat egories (A, B, C, D, or X), ranging from drugs posing no risk t o t he fet us t o t hose known t o be
t erat ogenic, t o t he Pregnancy and Lact at ion Labeling Rule (PLLR or final rule) [32]. The PLLR "requires
t hat t he labeling include a summary of t he risks of using a drug during pregnancy and lact at ion, a
discussion of t he dat a support ing t hat summary, and relevant informat ion t o help healt h care providers
make prescribing decisions and counsel women about t he use of drugs during pregnancy and
lact at ion."

Some common t erat ogenic medicat ions include:

● Angiot ensin-convert ing enzyme (ACE) inhibit ors (see "Adverse effect s of angiot ensin convert ing
enzyme inhibit ors and recept or blockers in pregnancy" and 'Timing' above)

● Ant iconvulsant agent s [33] (see "Risks associat ed wit h epilepsy during pregnancy and post part um
period")

● Ant ineoplast ic agent s (see "Gest at ional breast cancer: Epidemiology and diagnosis" and
"Management of classic Hodgkin lymphoma during pregnancy")

● Thalidomide, met hylene blue, misoprost ol, penicillamine, fluconazole, and lit hium

Addit ional known t erat ogens include t he following:

● Folic acid ant agonist s (eg, t rimet hoprim, t riamt erene, carbamazepine, phenyt oin, phenobarbit al,
primidone, met hot rexat e) increase t he risk of neural t ube defect s and possibly cardiovascular
defect s, oral cleft s, and urinary t ract defect s [20,34].

● Oral isot ret inoin, used t o t reat severe acne, is associat ed wit h ear anomalies (microt ia wit h or
wit hout at resia of t he ear canal), CNS malformat ions, hydrocephalus, neuronal brain migrat ion
defect s, cerebellum abnormalit ies, severe int ellect ual disabilit y, seizures, opt ic nerve/ret inal
abnormalit ies, conot runcal heart defect s, t hymic defect s, and dysmorphic feat ures [35,36]. (See
"Treat ment of acne vulgaris", sect ion on 'Pregnancy and acne t herapy'.)

● The widely used cholest erol-lowering agent s, such as st at ins (HMG-CoA reduct ase inhibit ors) are
complet ely cont raindicat ed during pregnancy because t hey may cause severe birt h defect s due
t o disrupt ion of cholest erol biosynt hesis, which is import ant in cell membrane morphogenesis.
Report ed birt h defect s include limb malformat ions, congenit al heart disease, and CNS
abnormalit ies [37,38].

● Infant s of mot hers who consumed subst ant ial quant it ies of alcohol during pregnancy [39] can
have a neurobehavioral disorder associat ed wit h prenat al alcohol exposure (ND-PAE), alcohol-
relat ed birt h defect s (ARBD), fet al alcohol syndrome, or t hey may be normal (t able 2). (See
"Alcohol int ake and pregnancy" and "Subst ance use during pregnancy: Screening" and "Fet al
alcohol spect rum disorder: Clinical feat ures and diagnosis".)
 ● Cigaret t e smoking is associat ed wit h poor fet al growt h most ly due t o effect s on t he placent a
[40,41]. Smoking is also linked t o increased limb deficiencies in epidemiologic st udies [42]. The
failure or disrupt ion in format ion of limbs or digit s may result from vasoact ive effect s of
cigaret t e compounds on blood vessels. Prenat al exposure can also lead t o impaired funct ion of
t he endocrine, reproduct ive, respirat ory, cardiovascular, and neurologic syst ems [43]. (See
"Cigaret t e and t obacco product s in pregnancy: Impact on pregnancy and t he neonat e".)

Chemical agents — Chemical agent s t hat can act as t erat ogens include lead and mercury.

High plasma lead levels are associat ed wit h adverse neurobehavioral effect s in infant s and children.
Int raut erine exposure may have similar consequences [44]. St udies of pot ent ial associat ions bet ween
parent al lead exposure and congenit al malformat ions in offspring have not demonst rat ed a consist ent
increase in risk or pat t ern of defect s, but oft en lack biologic indices of exposure at development ally
significant t imes [45]. (See "Occupat ional and environment al risks t o reproduct ion in females: Specific
exposures and impact ", sect ion on 'Lead'.)

Met hylmercury exposure, primarily t hrough ingest ion of cont aminat ed fish, can cause severe CNS
damage [46], as well as milder int ellect ual, mot or, and psychosocial impairment [47-49]. Some
limit at ions on fish int ake during pregnancy are recommended. (See "Nut rit ion in pregnancy", sect ion on
'Counseling women about nut rit ion in pregnancy' and "Fish consumpt ion and marine omega-3 fat t y acid
supplement at ion in pregnancy".)

Resources — Several resources are available for informat ion on possible t erat ogenic exposure. These
include:

● Reproduct ive Toxicology Cent er

REPROTOX
Columbia Hospit al for Women Medical Cent er
Washingt on, DC
202-293-5137

● Terat ogen Informat ion Syst em

TERIS and Shepard's Cat alog of Terat ogenic Agent s
Seat t le, WA
206-543-2465

● Pregnancy Exposure Regist ries

● Organizat ion of Terat ology Informat ion Specialist s (OTIS)

877-311-8972
 ● The Terat ology Societ y
The Terat ology Societ y publishes a free t erat ology primer

INFORMATION FOR PATIENTS

UpToDat e offers t wo t ypes of pat ient educat ion mat erials, "The Basics" and "Beyond t he Basics." The
Basics pat ient educat ion pieces are writ t en in plain language, at t he 5th t o 6th grade reading level, and
t hey answer t he four or five key quest ions a pat ient might have about a given condit ion. These
art icles are best for pat ient s who want a general overview and who prefer short , easy-t o-read
mat erials. Beyond t he Basics pat ient educat ion pieces are longer, more sophist icat ed, and more
det ailed. These art icles are writ t en at t he 10th t o 12th grade reading level and are best for pat ient s
who want in-dept h informat ion and are comfort able wit h some medical jargon.

Here are t he pat ient educat ion art icles t hat are relevant t o t his t opic. We encourage you t o print or e-
mail t hese t opics t o your pat ient s. (You can also locat e pat ient educat ion art icles on a variet y of
subject s by searching on "pat ient info" and t he keyword(s) of int erest .)

● Basics t opic (see "Pat ient educat ion: Newborn appearance (The Basics)")

SUMMARY

● A birt h defect is any st ruct ural anomaly present at birt h. These defect s can be caused by
genet ic abnormalit ies and/or environment al exposures (t erat ogens), alt hough t he underlying
et iology is oft en unknown. (See 'Int roduct ion' above and 'Overview' above.)

● Specific t erms are used t o describe congenit al anomalies (t able 3). In addit ion, mult iple
malformat ions are oft en grouped in a recognizable pat t ern (t able 4). (See "Birt h defect s:
Epidemiology, t ypes, and pat t erns", sect ion on 'Types and pat t erns of defect s'.)

● Genet ic causes of congenit al anomalies include chromosomal disorders, single-gene disorders,

somat ic mut at ion, and disorders t hat result from t he int eract ion of mult iple genes and
environment al fact ors (mult ifact orial disorders). (See 'Genet ic abnormalit ies' above.)

● Environment al causes of congenit al anomalies include mult iple gest at ion pregnancy and
t erat ogens. A t erat ogen is an agent t hat can cause abnormalit ies in t he form or funct ion of a
developing fet us (t able 1). The pat t ern and t ype of malformat ion depend in part upon t he t ime of
exposure and/or t he sit e of gene act ion. (See 'Terat ogens' above.)

Use of UpToDat e is subject t o t he Subscript ion and License Agreement .

Topic 110900 Version 14.0
GRAPHICS
Selected agents with potential adverse fetal effects

Alleged fet al Timing of Reproduct ive Alleged fet al Timing of

Reproduct ive t oxin
ef fect s exposure t oxin ef fect s exposure

Drugs Drugs (c ont inue d)

Androgens Ma sculiniza tion of First trim ester for Sulfa drugs These drugs ca n Second a nd
the developing la bia l fusion; a nd vita m in K produce hem olysis in third
fem a le fetus ca n second a nd third som e subpopula tions trim esters
occur from trim esters for of fetuses. Sulfa
a ndrogens a nd clitora l hypertrophy drugs ca n cross the
high doses of som e pla centa a nd bind
m a le-derived proteins displa cing
progestins. bilirubin a nd trigger
kernicterus a t low
Angiotensin-converting Feta l hypotension Second a nd third
bilirubin levels.
enzym e inhibitors a nd resulting in feta l trim esters
a ngiotensin receptor kidney Tetra cycline This drug produces Second a nd
blockers hypoperfusion a nd bone a nd teeth third
a nuria , sta ining; it does not trim esters
oligohydra m nios, increa se the risk of
pulm ona ry a ny other
hypopla sia , cra nia l m a lform a tions.
bone hypopla sia ,
Tha lidom ide Multiple defects in the 22 to 36 days
feta l growth
following system s: postconception
restriction a nd
lim bs, other skeleton,
dem ise.
cra niofa cia l, m a jor
Neona ta l oliguria , orga ns (lungs,
a nuria , ca rdiova scula r,
hypotension, a nd ga strointestina l, a nd
rena l tubula r genitourina ry), a nd
dysgenesis. inguina l hernia .
Anticonvulsa nts Trim ethoprim Ha s been linked to a n First trim ester
increa sed incidence
Ca rba m a zepine Increa ses the risk of First trim ester
of neura l tube defects.
fa cia l
The risk is not high,
dysm orphology,
but it is biologica lly
neura l tube defects,
pla usible beca use of
ca rdiova scula r
the drug's effect on
defects, a nd
lowering folic a cid
urina ry tra ct
levels, which ha s
defects.
resulted in neurologic
Phenytoin Increa ses the risk of 18 to 60 days sym ptom s in a dults
feta l hyda ntoin postconception ta king this drug. It is
syndrom e, (orga nogenesis) a lso a ssocia ted with
consisting of fa cia l ca rdiova scula r
dysm orphology, defects a nd possibly
cleft pa la te, ora l clefts.
ventricula r septa l
Vita m in A Although still Possibly
defect, a nd growth
controversia l, the during the first
a nd intellectua l
m a lform a tions trim ester
disa bility.
reported with the
Trim etha dione Increa ses the risk of First trim ester retinoids have been
a nd cha ra cteristic reported with very
pa ra m etha dione fa cia l high doses of vita m in
dysm orphology, A (retinol). Doses to
 intellectua l produce birth defects
disa bility, V-sha ped would have to be in
eyebrows, low-set excess of 25,000 to
ea rs with a nteriorly 50,000 units/day.
folded helix, high- Other gravida exposed
a rched pa la te, to high doses of
irregula r teeth, CNS vita m in have ha d
a nom a lies, a nd norm a l pregna ncies.
severe Wa rfa rin a nd Ea rly exposure during First trim ester
developm enta l wa rfa rin pregna ncy ca n result
delay. deriva tives in na sa l hypopla sia ,
stippling of seconda ry
Va lproic a cid Increa ses the risk of 18 to 60 days
epiphysis, intra uterine
spina bifida , fa cia l postconception
growth restriction.
dysm orphology, (orga nogenesis)
CNS m a lform a tions
a utism , a tria l
ca n occur in la te
septa l defect, cleft
pregna ncy exposure
pa la te,
beca use of bleeding.
hypospa dia s,
polyda ctyly, Ra dia t ion
cra niosynostosis,
Ionizing Ra dia tion exposure First trim ester
a nd lim b
ra dia tion a bove a threshold of
a bnorm a lities.
20 ra d (0.2 Gy) ca n
Antidepressa nts Publica tions have First a nd third increa se the risk for
im plica ted som e of trim esters som e feta l effects
the SSRIs such a s
a dm inistered in the m icrocepha ly or
la st trim ester with growth reta rda tion,
postna ta l but the threshold for
neurobehaviora l intellectua l disa bility
effects tha t a re is higher.
tra nsient a nd
Ra dioa ctive Tissue- a nd orga n- After eighth
whose long-term
isotopes specific da m a ge week
effects have not
depends on the
been determ ined.
ra dioisotope elem ent
First trim ester
a nd distribution (ie,
exposures to som e
high doses of Iodine-
SSRIs have been
131 a dm inistered to a
reported to increa se
pregna nt wom a n ca n
the risk of som e
ca use feta l thyroid
congenita l
hypopla sia a fter the
m a lform a tions,
eighth week of
predom ina ntly
developm ent).
congenita l hea rt
disea se. The results Che mic a ls
have not been
Ca rbon CNS da m a ge ha s  
consistent, but
m onoxide been reported with
wa rnings have
very high exposures
been issued.
(ca rbon m onoxide
However, other
poisoning), but the
developm enta l
risk seem s to be low.*
toxicities have been
a ssocia ted with Lea d Very high exposures Potentia l risk
SSRIs including ca n ca use pregna ncy throughout
sponta neous loss; intra uterine pregna ncy
a bortions, low birth tera togenesis is not
weight, prem a turity, esta blished a t very low
neona ta l serotonin exposures below 20
syndrom e, neona ta l m icrogra m /percent
behaviora l in the serum of
syndrom e pregna nt m others.
 (withdra wa l), a nd Ga soline Fa cia l Throughout
persistent dysm orphology, the pregna ncy
pulm ona ry intellectua l disa bility,
hypertension of the em bryopa thy from
newborn. exposure due to
ga soline a ddiction.
Antituberculous Isonia zid does not First trim ester a nd
thera py a ppea r to ca use possibly second Methyl m ercury Mina m a ta disea se Throughout
birth defects; trim ester consists of cerebra l the pregna ncy
pa ra a m inosa licylic pa lsy, m icrocepha ly,
a cid m ay ca use a n intellectua l disa bility,
increa sed risk of blindness, a nd
ea r a nd lim b cerebellum
defects a nd hypopla sia . Other
hypospa dia s. epidem ics have
occurred from
Cyclophospha m ide Ma ny First trim ester for
a dultera tion of whea t
a nd other chem othera peutic m a lform a tions;
with m ercury-
chem othera peutic a gents used to trea t second a nd third
conta ining
a gents a nd ca ncer have a trim esters possibly
chem ica ls tha t a re
im m unosuppressive theoretica l risk for a ssocia ted with
used to prevent gra in
a gents (eg, producing feta l growth
spoila ge. Present
cyclosporine, m a lform a tions in restriction a nd
environm enta l levels
leflunom ide) the fetus when pa ncytopenia
of m ercury a re
a dm inistered to
unlikely to represent a
pregna nt wom en,
tera togenic risk, but
especia lly beca use
reducing or lim iting
m ost of these drugs
the consum ption of
a re tera togenic in
ca rnivorous fish ha s
a nim a ls, but the
been suggested to
clinica l da ta a re
avoid exceeding the
not consistent.
m a xim um
Ma ny of these
perm issible exposure
drugs have not
recom m ended by the
been shown to be
Environm enta l
tera togenic, but the
Protection Agency, a n
num bers of ca ses
exposure level fa r
in the studies a re
below the level a t
sm a ll. Ca ution is
which the toxic effects
the byword.
of m ercury a re seen.
Cyclophospha m ide
ca uses congenita l Polychlorina ted Poisoning ha s Throughout
defects when used biphenyls occurred from the pregna ncy
during a dultera tion of food
orga nogenesis, a nd products ("Cola -
feta l bone m a rrow colored ba bies," CNS
suppression m ay effects, pigm enta tion
occur when of gum s, na ils, teeth,
exposure occurs a nd groin;
la ter in pregna ncy. hypopla stic deform ed
na ils; intra uterine
Diethylstilbestrol Adm inistra tion First a nd second
growth reta rda tion;
during pregna ncy trim esters
a bnorm a l skull
produces genita l
ca lcifica tion). The
a bnorm a lities,
threshold exposure
a denosis, a nd clea r
ha s not been
cell
determ ined, but it is
a denoca rcinom a of
unlikely to be
va gina in
tera togenic a t the
a dolescents. The
present
la st ha s a risk of
environm enta l
1:1000 to 1:10,000,
exposures.
 but the other effects, Toluene Fa cia l  
such a s a denosis, dysm orphology,
ca n be quite high. intellectua l disa bility,
em bryopa thy from
Dolutegravir  Prelim ina ry results Fetuses with
exposure due to
from a n exposure a t the tim e
toluene a ddiction.
observa tiona l study of conception or
suggest tha t serious ea rly in the first Embr yonic a nd f e t a l inf e c t ions
ca ses of neura l trim ester a ppea r to
Cytom ega lovirus Retinopa thy, CNS First 6 m onths
tube birth defects be a t higher risk for
infection ca lcifica tion, of pregna ncy
involving the bra in, these defects 
m icrocepha ly,
spine, a nd spina l
intellectua l disa bility.
cord m ay occur in
Occurs in 30 to 50%
ba bies of wom en
of prim a ry infections.
with HIV trea ted
with this drug. [1]   Rubella Dea fness, congenita l Up to 16 weeks
hea rt disea se, a lthough
Etha nol Feta l a lcohol First trim ester for
m icrocepha ly, m ore
syndrom e consists feta l a lcohol
ca ta ra cts, intellectua l significa nt in
of m icrocepha ly, syndrom e or feta l
disa bility. Occurs in the first two
intellectua l a lcohol-rela ted birth
up to 80% of fetuses m onths of
disa bility, growth defects; second a nd
with a prim a ry pregna ncy
restriction, typica l third trim esters for
infections.
fa cia l feta l a lcohol
dysm orphogenesis, neurodevelopm enta l Herpes sim plex Feta l infection, liver Throughout
a bnorm a l ea rs, disorders disea se, dea th. the pregna ncy
sm a ll pa lpebra l
HIV Perina ta l HIV Throughout
fissures.
infection. the pregna ncy
Glucocorticoids High exposures First trim ester
Pa rvovirus Stillbirth, hydrops. Up to 20 weeks
a dm inistered
infection, B19 gesta tion
system ica lly have a
low risk for cleft Syphilis Ma culopa pula r ra sh, Throughout
pa la te in som e hepa tosplenom ega ly, the pregna ncy
studies, but the deform ed na ils,
epidem iologic osteochondritis a t
studies a re not joints of extrem ities,
consistent. congenita l
neurosyphilis,
Insulin shock thera py Microcepha ly a nd First trim ester
a bnorm a l epiphyses,
intellectua l
chorioretinitis.
disa bility.
Toxopla sm osis Hydrocepha ly, Throughout
Lithium thera py Chronic usa ge for First trim ester
m icrophtha lm ia , the pregna ncy
the trea tm ent of
chorioretinitis,
bipola r disorder ha s
intellectua l disa bility.
a n increa sed risk
for Ebstein Va ricella zoster Skin a nd m uscle First trim ester
a nom a ly a nd other defects; intra uterine
m a lform a tions, but growth reta rda tion;
the risk seem s to be lim b reduction
very low. defects, CNS da m a ge
(very low increa sed
Minoxidil Prom otion of ha ir First trim ester
risk).
growth in the fetus
a nd hirsutism in Venezuela n Hydra nencepha ly; First trim ester
newborns. equine m icrophtha lm ia ;
encepha litis destructive CNS
Methim a zole Apla sia cutis ha s First trim ester;
lesions; luxa tion of
been reported to be especia lly weeks 6
hip.
increa sed in to 10
m others Zika virus Microcepha ly, Up to 20 weeks
a dm inistered this intra cra nia l gesta tion
drug during
pregna ncy.* Other
 p g y
ca lcifica tions,
a nom a lies have
intellectua l disa bility.
been reported a nd
include Ma t e rna l dise a se st a t e s
tra cheoesopha gea l
Corticosteroid- Mothers who have  
fistula s, pa tent
secreting Cushing's disea se
vitellointestina l
endocrinopa thy ca n have infa nts
duct, choa na l
with
a tresia ,
hypera drenocorticism ,
om pha locele, a nd
but a na tom ic
om pha lom esenteric
m a lform a tions do not
duct a nom a ly.
seem to be increa sed.
Methotrexa te Pregna ncy loss, 18 to 60 days
Iodine Ca n result in  
growth restriction, postconception
deficiency em bryonic goiter a nd
m icrocepha ly, (orga nogenesis)
intellectua l disa bility.
m eningom yelocele,
intellectua l Intra uterine These defects a re  
disa bility, decrea sed problem s of m ore com m on in
ossifica tion of the constra int a nd m ultiple-birth
ca lva rium , va scula r pregna ncies,
hypopla stic disruption pregna ncies with
supra orbita l ridges, a na tom ic defects of
sm a ll low-set ea rs, the uterus, pla centa l
m icrogna thia , a nd em boli, or a m niotic
lim b defects. ba nds. Possible birth
defects include club
Methylene blue intra - Feta l intestina l 18 to 60 days
feet, lim b-reduction
a m niotic instilla tion a tresia , hem olytic postconception
defects, a pla sia cutis,
a nem ia , a nd (orga nogenesis)
cra nia l a sym m etry,
ja undice in the
externa l ea r
neona ta l period.
m a lform a tions,
This procedure is
m idline closure
no longer used to
defects, cleft pa la te
identify one twin.
a nd m uscle a pla sia ,
Misoprostol A low incidence of First a nd second cleft lip, om pha locele,
va scula r disruptive trim esters a nd encepha locele.
phenom enon, such
Ma terna l Ma sculiniza tion of  
a s lim b-reduction
a ndrogen fem a le fetuses.
defects a nd Mobius
endocrinopa thy
syndrom e, ha s been
(a drena l
reported in
tum ors)
pregna ncies in
which this drug Ma terna l Increa ses the risk of a  
wa s used to induce dia betes with wide va riety of
a n a bortion. poor glycem ic congenita l
control a nom a lies; ca rdia c
Mycophenola te m ofetil First trim ester First trim ester
a bnorm a lities a re
exposure a ssocia ted
m ost com m on.
with m isca rria ge,
a bnorm a lities of Ma terna l folic An increa sed  
the bra in, ea rs, eyes, a cid in reduced incidence of neura l
dista l lim bs, hea rt, a m ounts tube defects.
esopha gus, kidney,
Ma terna l Abortion,  
a nd cleft lip/pa la te.
phenylketonuria m icrocepha ly, a nd
Penicilla m ine (D- This drug results in Tim ing a ssocia ted intellectua l disa bility;
penicilla m ine) the physica l effects with the occurrence very high risk in
referred to a s of these a nom a lies untrea ted pa tients.
"la thyrism ," the is not clea r
Ma terna l Intra uterine growth  
results of poisoning
sta rva tion restriction, a bortion,
by the seeds of the
neura l tube defects
genus Lathyrus. It
ca uses colla gen
 ca uses co a ge
(Dutch fa m ine
disruption, cutis
experience).
la xa , a nd
hyperflexibility of Toba cco Feta l growth  
joints. The sm oking restriction a nd
condition seem s to stillbirth. Although
be reversible, a nd the risk of defects is
the risk is low. sm a ll (a pproxim a tely
twofold), they ca n
Progestin thera py Very high doses of Third trim ester
involve the hea rt a nd
a ndrogen horm one-
grea t vessels, lim bs,
derived progestins
skull, genitourina ry
ca n produce
system , feet,
m a sculiniza tion.
a bdom ina l wa ll,
Ma ny drugs with
sm a ll bowel, a nd
progesta tiona l
m uscles.
a ctivity do not have
m a sculinizing Zinc deficiency* Neura l tube defects.*  
potentia l. None of
these drugs have
the potentia l for
producing
nongenita l
m a lform a tions.

Propylthioura cil This drug a nd other Throughout

a ntithyroid gesta tion
m edica tions
a dm inistered
during pregna ncy
ca n result in a n
infa nt born with a
goiter.

Retinoids System ic retinoic First trim ester

a cid, isotretinoin,
a nd etretina te ca n
ca use increa sed
risk of CNS,
ca rdioa ortic, ea r,
a nd clefting defects
such a s m icrotia ,
a notia , thym ic
a pla sia , other
bra nchia l a rch
a nd a ortic a rch
a bnorm a lities, a nd
certa in congenita l
hea rt
m a lform a tions.

Retinoids, topica l Topica l  

a dm inistra tion is
very unlikely to
have tera togenic
potentia l beca use
tera togenic serum
levels ca nnot be
a tta ined by topica l
exposure to
retinoids.

Streptom ycin Streptom ycin a nd a Throughout

group of ototoxic gesta tion
drugs ca n a ffect
 d ugs ca a ect
the eighth nerve
a nd interfere with
hea ring; it is a
rela tively low-risk
phenom enon.
Children a re less
sensitive tha n
a dults to the ototoxic
effects of these
drugs. However,
dea fness in
newborns ca n
occur.

CNS: centra l nervous system ; SSRI: selective serotonin reupta ke inhibitor; HIV: hum a n im m unodeficiency virus.
* Controversia l.

Reference:
1. FDA drug safety communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca,
Tivicay, Triumeq), May 18, 2018. https://www.fda.gov/Drugs/DrugSafety/ucm608112.htm (Accessed on May 30, 2018).
From: Brent, RL. How does a physician avoid prescribing drugs and medical procedures that have reproductive and developmental risks? Clin
Perinatol 2007; 34:233. Copyright © 2007 Elsevier. Original table modified for this publication.

Gra phic 73369 Version 15.0

Embryonic development

The black bars represent the critical period during which development may be disrupted by a teratogen resulting in a
major structural malformation. Cell differentiation occurs over a longer period (hatched bars); exposure during this
period can result in minor structural malformations, growth restriction, or functional deficiency. Note: embryonic age
is counted from fertilization, whereas menstrual age (ie, gestational age) is counted from the first day of the last
menstrual period. Thus, an embryonic age of 6 weeks corresponds to a menstrual age (gestational age) of 8 weeks.

CNS: centra l nervous system .

Gra phic 65456 Version 5.0

Compilation of diagnostic criteria for fetal alcohol spectrum disorders*

FASD Diagnost ic crit eria

Feta l a lcohol syndrom e At lea st 2 cha ra cteristic fa cia l fea tures
Growth reta rda tion
Clea r evidence of bra in involvem ent
Neurobehaviora l im pa irm ent
With or without docum ented prena ta l a lcohol exposure

Pa rtia l feta l a lcohol syndrom e Wit h doc ume nt e d pre na t a l a lc ohol e xposure :

At lea st 2 cha ra cteristic fa cia l fea tures

Neurobehaviora l im pa irm ent

Wit hout doc ume nt e d pre na t a l a lc ohol e xposure :

At lea st 2 cha ra cteristic fa cia l fea tures

Growth reta rda tion or clea r evidence of bra in involvem ent
Neurobehaviora l im pa irm ent

Alcohol-rela ted neurodevelopm enta l disorder Docum ented prena ta l a lcohol exposure
Neurobehaviora l im pa irm ent
(This dia gnosis ca nnot be definitively dia gnosed in children <3
yea rs of a ge)

Alcohol-rela ted birth defects Docum ented prena ta l a lcohol exposure

At lea st 1 specific m a jor m a lform a tion a ssocia ted with prena ta l
a lcohol exposure

Neurobehaviora l disorder a ssocia ted with prena ta l a lcohol
exposure¶
Docum ented prena ta l a lcohol exposure 
Neurobehaviora l im pa irm ent a nd onset in childhood
Fa cia l fea tures, growth reta rda tion, a nd clea r evidence of bra in
involvem ent not necessa ry (but m ay be present)
Not better expla ined by other tera togens, genetic or m edica l
conditions, or environm enta l neglect

Definit ion of clinical feat ures

Cha ra cteristic fa cia l fea tures Short pa lpebra l fissures Δ
Thin verm illion border (University of Wa shington Lip-Philtrum ra nk
4 or 5)
Sm ooth philtrum (University of Wa shington Lip-Philtrum ra nk 4 or
5)

Growth reta rda tion Height a nd/or weight (a djusted for gesta tiona l a ge) ≤10 th percentile
for a ge, sex, ra ce/ethnicity a t a ny point of tim e (eg, prena ta l or
postna ta l)

CNS involvem ent Clea r evidence of bra in involvem ent For FAS a nd pFAS For ND-PAE

Structura l or neurologic involvem ent (1 of NA

the following):
Hea d circum ference ≤10 th
percentile for a ge a nd sex, or, if
weight a nd height a re <10 th
percentile, hea d circum ference ≤3 rd
percentile
Significa nt structura l a bnorm a lities
on neuroim a ging
Ha rd neurologic signs ◊
 Recurrent seizures tha t a re not due
to postna ta l insult or fever

Neurobehaviora l im pa irm ent Functiona l a bnorm a lities (1 of the Functiona l

following): im pa irm ents/deficits
Significa nt globa l cognitive or in ea ch of the
intellectua l deficits following dom a ins:
Significa nt developm enta l delay § Neurocognitive (a t
¥ lea st 1):
Functiona l deficits in a t lea st 3 of the
following dom a ins: Intellectua l
Cognitive or developm enta l deficits disa bility
or discrepa ncies Executive
Executive functioning deficits functioning
Motor functioning delays Lea rning
Problem s with a ttention or Mem ory
hypera ctivity
Visua l-spa tia l
Socia l skills rea soning
Other, such a s sensory problem s, Self-regula tion (a t
pra gm a tic la ngua ge problem s, lea st 1):
m em ory deficits, etc Mood or
Evidence of significa nt im pa irm ent of behaviora l
self-regula tion in a t lea st 1 of the regula tion
following dom a ins: Attention
Mood or behaviora l regula tion Im pulse control
im pa irm ent
Ada ptive function (a t
Attention deficit lea st 2):
Im pulse control
Com m unica tion
Socia l
com m unica tion
a nd intera ction
Da ily living
skills
Motor skills

FASD: feta l a lcohol spectrum disorder; CNS: centra l nervous system ; FAS: feta l a lcohol syndrom e; pFAS: pa rtia l FAS; ND-PAE:
neurobehaviora l disorder a ssocia ted with prena ta l a lcohol exposure; NA: not a pplica ble.
* Dia gnostic criteria m ay va ry geogra phica lly. Refer to UpToDa te content on dia gnosis of feta l a lcohol spectrum disorder for deta ils.
¶ Som etim es ca lled "neurodevelopm enta l disorder a ssocia ted with prena ta l a lcohol exposure." This ca tegory is sim ila r to a lcohol-rela ted
neurodevelopm enta l disorder, but does not overla p com pletely.
Δ The definition of short pa lpebra l fissures va ries a ccording to the dia gnostic schem a .
◊ "Ha rd" neurologic signs include a bnorm a l reflexes, a bnorm a l tone, a nd cra nia l nerve deficits.
§ The definition of significa nt developm enta l delay va ries a ccording to the dia gnostic criteria .
¥ The definition of functiona l deficit va ries a ccording to the dia gnostic criteria .

Data from:
1. American Psychiatric Association. Neurobehavioral disorder associated with prenatal alcohol exposure. In: Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013. p.798.
2. Astley SJ. Diagnosis of Fetal Alcohol Spectrum Disorders (FASD): The 4-Digit Diagnostic Code, 3 rd edition. University of Washington
Publication Services, Seattle, 2004.
3. Bertrand J, Floyd RL, Weber MK, et al. National Task Force on Fetal alcohol syndrome and fetal alcohol effect. Fetal alcohol syndrome:
Guidelines for referral and diagnosis. Center for Disease Control and Prevention; Atlanta, GA, 2004. Available at:
www.cdc.gov/ncbddd/fasd/documents/fas_guidelines_accessible.pdf (Accessed on February 24, 2014).
4. Hoyme HE, May PA, Kalberg WO, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: Clarification of the
1996 institute of medicine criteria. Pediatrics 2005; 115:39.
5. Hoyme HE, Kalberg WO, Elliot AJ, et al. Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics 2016;
138.
. Hagan JF Jr, Balachova T, Bertrand J, et al. Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure. Pediatrics 2016.

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Terms used to describe congenital abnormalities

Term Definit ion

Ma lform a tion Defects of orga ns or body pa rts due to a n intrinsica lly a bnorm a l developm enta l process

Deform a tion Abnorm a lities of the sha pe a nd position of body pa rts due to extrinsic intra uterine m echa nica l forces tha t m odify a
norm a lly form ed structure

Disruption Defects of orga ns or body pa rts tha t result from destruction of or interference with norm a l va scula r developm ent

Dyspla sia Anom a lies tha t result from the a bnorm a l orga niza tion of cells into tissues

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Recognizable patterns of multiple congenital anomalies

Pat t ern Definit ion

Syndrom e Pa ttern of a nom a lies tha t occur together a nd a re a ssocia ted with a set num ber of signs a nd sym ptom s

Sequence Pa ttern of a nom a lies in which a single known defect in developm ent ca uses a ca sca de of subsequent a bnorm a lities

Field defect Pa ttern of a nom a lies ca used by disturba nce of a developm enta l field (a region of the em bryo tha t develops in a
contiguous physica l spa ce)

Associa tion Two or m ore a nom a lies tha t a re not pa thogenetica lly rela ted a nd occur together m ore frequently tha n expected by
cha nce

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