Review Article
Antidepressants, Antipsychotics, and Mood Stabilizers in
Pregnancy: What Do We Know and How Should We Treat
Pregnant Women with Depression
Asher Ornoy *, Liza Weinstein-Fudim, and Zivanit Ergaz
Depression is generally treated with antidepressants, but may often need
antipsychotics and mood stabilizers. We discuss the updated data regarding
the safety in pregnancy of antidepressants and antipsychotics, except
selective serotonin reuptake inhibitors, and their possible impact on the long-
term development of the offspring. Several earlier studies demonstrated a
slight increase in the rate of major anomalies following maternal tricyclic
antidepressant treatment, but most current literature shows their relative
safety in pregnancy. Data on the development of the offspring are also
reassuring. The antipsychotic drugs are also safe for the developing fetus and
do not seem to induce developmental delay. Both groups of drugs may cause
perinatal withdrawal symptoms and difficulties in neonatal adaptation. The
mood stabilizers, lithium, and several anti-epileptic drugs, may adversely
affect the developing embryo and fetus. While valproic acid, carbamazepine,
and topiramate are teratogenic and may also affect postnatal development,
the newer antiepileptic and mood stabilizers, lamotrigine and levetiracetam,
seem to be safe in pregnancy and apparently have no long-term
Introduction
Psychotropic drugs are a large group of medications that
affect the nervous system through different mechanisms.
When taken during pregnancy, they are able to cross the
placenta and reach the fetal central nervous system (CNS).
Hence, because they easily cross the fetal blood brain bar-
rier, they might not only modify the in utero function of the
fetal brain, but may also have long-term effects on brain
functions. The measurable levels of most psychoactive
drugs found in the amniotic fluid as a measure of trans-
placental passage raise concerns regarding their possible
teratogenic effects, and their possible impact on neonatal
adaptation and on long-term neurodevelopmental outcome
(Schenker et al., 1999; Rahi et al., 2007; Ewing et al., 2015).
In addition, they might affect non-CNS tissues and
organs, causing a variety of congenital anomalies. A typical
example of such a drug is the anticonvulsant and mood sta-
bilizer, valproic acid (VPA), which is a well-known teratogen
Laboratory of Teratology, Department of Medical Neurobiology, Hebrew
University Hadassah Medical School, Jerusalem, Israel
*Correspondence to: Asher Ornoy, Laboratory of Teratology, Department of
Medical Neurobiology, Hebrew University Hadassah Medical School, PO Box
12272, Jerusalem 91120. E-mail: ornoy@cc.huji.ac.il
Published online in Wiley Online Library (wileyonlinelibrary.com). Doi: 10.
1002/bdr2.1079
C 2017 Wiley Periodicals, Inc.
V
neurodevelopmental damage. Lithium may increase the rate of cardiac
anomalies, especially of Ebstein’s anomaly, and may warrant a mid-trimester
fetal echocardiography. Although data on the development of the offspring are
reassuring, we should remember that most studies were carried out during
early childhood, at a time when inattention, learning difficulties, behavioral
and psychiatric problems are not yet identifiable. When considering medical
treatment for depression in women at child-bearing age, we have to weigh the
severity of the symptoms and their impact on the developing fetus and child.
Birth Defects Research 109:933–956, 2017.
C 2017 Wiley Periodicals, Inc.
V
Key words: tricyclic antidepressant; antipsychotics; mood stabilizers; preg-
nancy; anomalies; development
and also has neuro-teratogenic effects (Ornoy, 2009). Most
neurotropic drugs might also cause neonatal withdrawal
(adaptation) symptoms in the first few days after birth.
Women with depression and bipolar disorder (BD) are
treated with a variety of psychopharmaceuticals, depend-
ing on the severity of the symptoms and their clinical pre-
sentation. Among them are antidepressants, such as
selective serotonin reuptake inhibitors (SSRIs), serotonin
norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-
depressants (TCAs); mood stabilizers, such as VPA, lithium
carbonate, carbamazepine, and lamotrigine; and a variety
of antipsychotic drugs that are generally prescribed as
adjunct medical treatment. With the introduction of SSRIs,
there is a constant rise in their use for depression and a
drop in the use of other antidepressants and antipsy-
chotics (Ban et al., 2014). Depressed women use antipsy-
chotics mainly with SSRI failure, or when there is a need
for combined therapy, and rarely as an exclusive drug
(Bulletins–Obstetrics, 2008).
It is difficult to isolate the net effect of each psycho-
tropic drug, because women with psychiatric diseases tend
to take a combination of medications, both psychiatric and
others (Mehta et al., 2014). Additionally, women with psy-
chiatric illness also tend to consume alcohol and tobacco
(Bulletins–Obstetrics, 2008).
Evaluation of the impact of the psychotropic medica-
tions includes single drug data from animal studies, case
934 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY
reports, case series, and cohort studies evaluating specific
drugs used solely or in combination with other medica-
tions, as well as population registries and case–control
studies. Much of the data regarding maternal psychotropic
medications is from studies evaluating medical prescrip-
tions, which might not represent the exact situation, as
adherence to psychotropic medications may be low. In a
multinational study performed in 18 countries in Europe,
North America, and Australia, 78/160 women showed low
adherence to psychiatric medications, regardless of the tri-
mester of pregnancy. Low adherence was significantly
associated with smoking during pregnancy, psychotropic
monotherapy, elevated risk perception of antidepressants,
and depressive symptoms (Lupattelli et al., 2015). Cohort
studies, many of them using prospective data from Terato-
gen Information Services, seem to be more accurate
regarding treatment adherence.
The psychotropic medications are classified according
to their main activity, with some medications being used
for more than one indication.
The generic names of the main drugs used and their
general mode of action are listed in the different sections
of this review. At the end of each section we draw final
conclusions, based on the existing scientific data.
In this review, we discuss the possible effects of TCAs,
antipsychotic drugs, and mood stabilizers on the develop-
ing embryo and fetus, including neonatal adaptation prob-
lems and possible effects on development. SSRIs and
SNRIs are not discussed, as three reviews on these drugs
are published in this issue of the journal (see reviews in
this issue by Gingrich et al., Ornoy and Koren, and Rotem-
Kohavi and Oberlander). Data on each one of the different
TCAs, antipsychotic medications, and mood stabilizers are
also given in the tables according to the year of publica-
tion. Only studies with a sample size of more than 10
pregnancies are cited in the tables. If a study reported on
more than one drug of the same group, the study is cited
in the table for each drug separately. In the tables, we gen-
erally concentrated on congenital anomalies or neurodeve-
lopmental outcome. Data were identified by searching
PubMed for studies related to the effects of these drugs in
pregnancy. We mainly evaluated larger studies that also
contain control groups, as well as meta-analyses, and our
review includes only studies and meta-analyses published
in English language.
Tricyclic and Tetracyclic Antidepressants
TCAs were developed in the mid-1950s and have been
used in clinical practice since then. Tetracylic antidepres-
sants (TeCAs) were developed later and introduced in the
1970. They are used for similar clinical purposes and have
the same mechanisms of action. Before the introduction of
SSRIs, TCAs and TeCAs were widely used by women dur-
ing child-bearing age, pregnancy, and lactation. They are
used for the treatment of depression, anxiety, and several
other psychiatric disorders. TCAs affect the serotonergic
and noradrenergic systems by blocking the serotonin and
norepinephrine transporters, and thus increasing the syn-
aptic concentrations of these neurotransmitters (Green
and Maayani, 1977; Tatsumi et al., 1997). They also have
some antagonistic action by binding to several serotonin
receptors and act as agonists to the r serotonin receptor.
TCAs and TeCAs also act as antihistamines and anticholi-
nergic agents (Green and Maayani, 1977). The TCA group
includes: amitriptyline, amoxapine, clomipramine, desipr-
amine, doxepin, imipramine, nortriptyline, and protripty-
line. Tetracyclic antidepressants include mirtazapine,
maprotiline, and mianserin. Other atypical antidepressants
used in clinical practice are: bupropion, duloxetine, and
nefazodone.
While initial studies suggested that TCA exposure,
mainly imipramine, might be associated with congenital
anomalies, such as cleft palate, diaphragmatic hernia
(Barson, 1972), and limb anomalies (McBride, 1972), later
and larger studies were generally negative. Hence, it is
generally quite clear that prenatal exposure to TCAs or
TeCAs does not increase the rate of major congenital
anomalies (Table 1), nor does it increase the rate of neuro-
developmental problems.
CONGENITAL MALFORMATIONS (TABLE 1)
McElhatton et al. (1996) collected data from the European
Network of the Teratology Information Services and eval-
uated 746 exposures to antidepressants in 689 pregnan-
cies. Of them, 109 used TCA monotherapy and 174 used
TCA plus other, non-antidepressant drugs. Two-thirds of
the mothers exposed to TCA were on multidrug therapy.
Of those on multidrug therapy, over 40% took a benzodia-
zepine; 20% took neuroleptic drugs, and 40% took a wide
range of other drugs. Most women (74%) had short-term
exposure in the first trimester or early second trimester of
pregnancy. Seven of the infants born to women on multi-
drug therapy suffered from withdrawal symptoms and
only one from the group of TCA monotherapy. The inci-
dence of spontaneous abortions (11.5%) and late fetal
deaths (2%) were within the expected range in European
countries. Ninety-seven percent of the live-born babies
had no congenital malformations (McElhatton et al., 1996).
A collaboration of representatives from the American
Psychiatric Association, the American College of Obstetri-
cians and Gynecologists, and a consulting developmental
pediatrician reviewed the English literature on fetal and
neonatal outcomes associated with depression and antide-
pressant treatment during child-bearing. They concluded
that they did not identify studies that linked maternal
depression to congenital anomalies in their infants, and
that most studies have not shown an association between
TCAs use in pregnancy and structural malformations
(Yonkers et al., 2009).
BIRTH DEFECTS RESEARCH 109:933–956 (2017) 935

TABLE 1. Summary of Studies on Fetal Effects of Tricyclic Antidepressants and Tetracyclic Antidepressants in Pregnancy

Drug Author No. of cases and study design Fetal outcome

AMITRIPTYLINE McElhatton 118 amitriptyiline/330 TCA cases, of them 32 as Monotherapy-1- ventricular septal defect

et al., 1996 monotherapy, prospective study

Reis and Kallen, 2010 537/2,446 TCA cases/14,821 on antidepressants, Increases rate of cardiac anomalies on TCA

retrospective cohort study evaluated as a group; OR, 1.33

Berard et al., 318/ 382 TCA cases, retrospective cohort study Slightly increased rate of anomalies, aOR, 1.16;

2017 95% CI, 0.86–1.56

CLOMIPRAMINE McElhatton 134 /330 TCA cases, of them 39 as monotherapy, No increase in congenital anomalies after exposure

et al., 1996 prospective study to mono or combined therapy; 4 exposed to

monotherapy had withdrawal symptoms

Reis and Kallen, 2010 1,800 clomipramine/ 2,446 TCA cases/ 14,821 on Increased rate of cardiac anomalies on TCA,

other antidepressants, retrospective cohort study evaluated as a group, OR, 1.33, as a drug only

clomipramine significant

DOXEPIN McElhatton 14/330 TCA cases, prospective study 4-elective terminations, 1-spontanous abortion,

et al., 1996 1-fetal death, 8-normal babies

IMIPRAMINE McElhatton et al., 30/330 TCA cases, prospective study 1-omphalocelle, 1-polydactily

1996

Reis and Kallen, 2010 13/2,446 TCA cases/14821 on antidepressants, Slightly increased rate of cardiac anomalies on

retrospective cohort study TCA, evaluated as a group, OR, 1.33

MAPROTILINE McElhatton et al., 107/330 TCA cases, prospective study 1-facial dysmorphology, 1-combined with

1996 mianserin- bilateral talipes & hypotonia,

1-hypoglycemia and macrosomia

MIRTAZAPINE Lennestat and Kallen, 145 infants, 9 cases Mirtazapine 1 venlafaxine, No increase in congenital anomalies rate compared

2007 retrospective cohort study to normal controls, 2-ventricular septal defects

type 2, 1-atrial septal defect, 1-cleft palate,

1-hypospadias

Winterfeld et al., 357 pregnancies, including multiple medications, No difference between mirtazapine-exposed,

2015 prospective cohort study SSRI-exposed, and general control pregnancies,

14 (18%) of 76 infants who exposed until

delivery had withdrawal symptoms

Smit et al., Meta-analysis of 31 studies, 390 cases including No increase in the rate of major anomalies – 9

2016 those reported by Lennestat et al., 2007 malformed infants

Data from the Swedish Medical Birth Register (MBR;
National Board of Health and Welfare, 2003), which eval-
uated 1686 early and 784 late TCA exposures (mainly clo-
mipramine), found a slight increase in the risk for
cardiovascular defects (odds ratio [OR], 1.63; 95% confi-
dence interval [CI], 1.12–2.36), slightly higher for ventricu-
lar and atrial septal defects (OR, 1.84; 95% CI, 1.13–2.97)
(Reis and Kallen, 2010).
In a study by Vasilakis-Scaramozza et al. (2013), the
prevalence of congenital anomalies in the offspring of
1608 women exposed to TCAs and 1875 women exposed
to SSRIs during early pregnancy was compared with the
prevalence in the offspring of 6617 women with no expo-
sure to any antidepressants during pregnancy (Vasilakis-
Scaramozza et al., 2013). TCAs and SSRIs were not associ-
ated with increased risk of any specific type of congenital
anomalies. The crude relative risks (RRs) for any anomaly
were 0.9 (95% CI, 0.6–1.2) for TCAs and 0.9 (95% CI, 0.7–
1.2) for SSRIs. Adjustment for confounders did not alter
the crude results.
936 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY
In a U.K. population study, among a total of 349,127
singletons live born between 1990 and 2009 with over
2400 women prescribed TCA, 7600 prescribed SSRI and
over 13,000 mothers with diagnosed unmedicated depres-
sion, the overall major congenital anomalies risk did not
increase with maternal depression or with antidepressant
prescriptions. There was no increased risk for major con-
genital anomalies overall, associated with most SSRIs,
TCAs, or combined exposures (Ban et al., 2014).
In a study reporting 5954 pregnancies exposed to
TCAs in the United States compared with unexposed con-
trols, there was no increase in the incidence of cardiac
anomalies. Drugs included: amitriptyline, amoxapine, clo-
mipramine, desipramine, doxepin, imipramine, maprotiline,
nortriptyline, protriptyline, and trimipramine. However,
there were no data regarding the number of pregnancies
exposed to each drug. The unadjusted RR for cardiac
anomalies was 0.98 (95% CI, 0.72–1.32) and adjusted,
0.77 (95% CI, 0.52–1.14) (Huybrechts et al., 2016).
The Quebec study (Berard et al., 2017) evaluated the
association between first-trimester exposure to antidepres-
sants and the risk of major congenital malformations
among 382 women that were exposed to TCAs: of them,
the 318 women treated with amitriptyline were at higher
risk of having a child with eye, ear, face, neck (adjusted
OR [aOR], 2.45; 95% CI, 1.05–5.72), and digestive system
(adjusted OR, 2.55; 95% CI, 1.40–4.66) anomalies. The
strength of this study is the fact that women were exposed
in the first trimester of pregnancy only to one type of anti-
depressants, while pregnancies with multiple different
antidepressant exposures during organogenesis were
excluded. The exposed women were compared with those
with no exposure to antidepressants.
It is important to add that although several studies
showed a slight increase in the rate of congenital anoma-
lies, the majority of studies did not show any increase.
PREMATURITY
Preterm birth, but not intrauterine growth retardation,
was reported following TCA exposure. A significant
decrease in pregnancy duration was reported in three
studies, including 266 cases among women exposed to
mirtazapine (Smit et al., 2016). However, another previous
study on 746 exposures failed to demonstrate shorter
pregnancy following TCAs exposure (McElhatton et al.,
1996).
NEONATAL ADAPTATION DIFFICULTIES
TCAs were reported to be associated with neonatal symp-
toms, such as tachypnea, tachycardia, cyanosis, irritability,
hypertonia, clonus, spasm, and transient withdrawal symp-
toms (Misri and Sivertz, 1991). Withdrawal symptoms
were described in cases exposed to desipramine (Webster,
1973), imipramine (Eggermont, 1973), and nortriptyline
(Shearer et al., 1972).
A meta-analysis of the data on neonatal complication
following exposure to antidepressants during late gesta-
tion, which evaluated studies from 1966 to 2010, found
that TCAs, mostly clomipramine, but also imipramine and
amitriptyline, were associated with poor neonatal adapta-
tion, including an increased rate of respiratory distress,
temperature instability, hypoglycemia, and convulsions
(Gentile, 2010b).
LONG-TERM EFFECTS ON GUT MOTILITY
The use of TCAs, mostly clomipramine and amitriptyline in
pregnancy, increased laxative use among 76 children from
72 pregnancies, compared with nonexposed children.
Combined exposure to TCAs and SSRIs in pregnancy was
associated with a 10-fold increase in laxative use. Addi-
tionally, anti-diarrheal medication use was significantly
higher in the TCAs-exposed children. The authors hypothe-
sized that TCA exposure during the first trimester led to
increased laxative use, probably through inhibition of the
norepinephrine transporter. Exposure of TCAs anytime in
pregnancy led to increased anti-diarrheal use, possibly
through down-regulation of a2-adrenoceptors or up-
regulation of the pore forming a1c subunit (Nijenhuis et al.,
2012a, 2012b).
NEURODEVELOPMENTAL OUTCOME (TABLE 2)
No difference in global IQ, language development, mood,
arousability, activity level, distractibility, or behavioral
problems was found among 80 children exposed to TCAs
during pregnancy and compared with 55 children whose
mothers had received fluoxetine during pregnancy, and 84
children whose mothers had not been exposed during
pregnancy to any agent known to adversely affect the
fetus (Nulman et al., 1997). Forty of these women took
TCAs during the first trimester and 36 throughout preg-
nancy. Twenty-nine women took amitriptyline, 20 imipr-
amine, 10 clomipramine, 9 desipramine, 8 nortriptyline,
and 4 other TCAs. The TCA group did not differ from the
fluoxetine and control group in perinatal complications
and congenital malformations. The younger children were
tested with the Bayley Scales of Infant Development and
the older ones with the McCarthy Scales of Children’s Abil-
ities (Nulman et al., 1997).
Similar results were found by the same group evaluat-
ing 46 children exposed to TCAs (36 of them were
included in the previous study) at 15 to 71 months. There
were no differences in the children’s global IQ measured
by either the Bayley or McCarthy test, compared with chil-
dren with intrauterine fluoxetine exposure and controls
(Nulman et al., 2002).
Intrauterine exposure to TCAs was associated with
increased rates of autism spectrum disorder (ASD) among
a Swedish cohort of children. In this study, 1679 offspring
(743 with intellectual disability and 936 without) were
compared with 16,845 nonexposed controls. Maternal
BIRTH DEFECTS RESEARCH 109:933–956 (2017) 937

TABLE 2. Summary of Studies Evaluating Neurodevelopmental Outcome of Offspring Exposed to Antidepressants and Antipsychotics during Pregnancy

Author Study design and number of cases Neurodevelopmental outcome

Nulman et al., 1997 Prospective study, TCA-80, fluoxetine-55, unexposed-84. Similar normal global IQ score and language and behavioral

Assessment at 16-86 months development in all groups

Slone et al., 1997 Prospective cohort study, phenothiazines-1990, controls Adjusted IQ scores were similar in the exposed children com-

26,217 evaluated at 4 years pared to controls

Nulman et al., 2002 Prospective study, TCA-46, fluoxetine-40, unexposed-36. Normal global IQ score and language and behavioral develop-

Assessment at 15-71 months ment. Longer duration of maternal depression was associ-

ated with decreased global IQ,

Wichman et al., 2009 Retrospective antidepressants-16 out of 30,092 deliveries Two had behavioral problems initiated after 3 years
Johnson et al., 2012 Prospective controlled study, antipsychotics-22 typical-9, Lower scores on INFANIB composite score (RR 5 3.67; p

atypical-12, both-antidepressants-202, of them hypnotics-40, <0.03) for infants exposed to antipsychotics compared to

anxiolytics-18 and others, controls-85 of whom 28 with his- antidepressants and controls. No significant effect on num-

tory of psychiatric illness, evaluated at 6 months. ber of trials to habituate (p 5 0.19) or average looking

time during the habituation task (p 5 0.66)

Rai et al., 2013 Population based nested case–control study, antidepressants Maternal depression increased ASD risk (aOR, 1.49; 95% CI,

including SSRIs and TCAs: ASD found in 1,679, no ASD in 1.08–2.08), any antidepressants use (aOR, 3.34; 95% CI,

16,845 in a cohort of 589,114; age of 0-17 years. 1.50 to 7.47), evaluated for SSRIs and TCAs Significant for

ASD without intellectual disability - aOR, 2.93 (95% Cl,

0.98–8.82)

Shao et al., 2015 Prospective study, clonazapine-33, risperidone, olanzapine or Evaluated by BSID-III including cognitive, language, motor,

quetiapine-30, antipsychotics; evaluated at 2, 6, and 12 social-emotional and adaptive behavior. Adaptive scores

months were lower in the clozapine exposed infants at 2 and 6

months. No difference in other subscales.

Gentile et al., 2016 Review of published data, 29 articles on antipsychotics; infants Three of 35 healthy infants exposed in utero to antipsychotics

evaluated when older than 4 months, including 35 cases had motor developmental delay and one had delayed

speech acquisition

Boukhris et al., 2016 Registry-based study of an ongoing population based cohort, Any antidepressant use increase ASD risk (aHR, SSRIs (aHR,
1054 ASD from a cohort of 145, 456 singleton full terms. 2.17; 95% CI, 1.20–3.93); the use of more than one class

Evaluated for maternal consumption of SSRIs, TCAs, MAOIs, of drugs (aHR, 4.39; 95% CI,1.44–13.32); TCAs (aOR,

SNRIs and other antidepressants 1.03; 95% CI, 0.23–4.61).

Grzeskowiak et al., 2016 Computer-assisted telephone interviews; antidepressants- 210 No association between maternal treatment and behavioral

including SSRIs-173, TCAs-12, others-19, combination problems including hyperactivity, inattention and peer

therapy-6; depression, no treatment-231, controls-48,737); problems. Untreated maternal depression increased risks

Danish parent-report version of the Strengths and Difficulties of behavioral outcomes

questionnaires at 7 years.

Peterson et al., 2016 Retrospective cohort study, antipsychotics-416, psychiatric ill- No difference in neurodevelopmental disorders (OR, 1.22;

ness who discontinues psychotherapy-670, no history of 95% CI, 0.80–1.84)

antipsychotics-318,434; infants evaluated for behavioral

records within the first 5 years.

BSID-III - Bayley Scales of Infant Development third edition; IMAOIs, monoamine oxidase inhibitors.
938 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY
depression was also associated with ASD, adjusted odds
ratio 1.40 (95% CI, 0.91–2.17). The association with pre-
natal TCA exposure remained significant even after adjust-
ment for confounders, including maternal depression. For
all cases, adjusted odds ratio was 2.69 (95% CI, 1.04–
6.96); for those with intellectual disability, it was 1.72
(95% CI, 0.20–15.03), and for those without intellectual
disability, it was 2.93 (95% CI, 0.98–8.82). Similar results
were found among a group following prenatal SSRI expo-
sure (Rai et al., 2013).
However, Boukhris et al. (2016) did not find any asso-
ciation between intrauterine TCA exposure and ASD
among a Canadian cohort of 1023 ASD cases, compared
with 142,924 controls. The adjusted odd ratio was 1.03
(95% CI, 0.23–4.61) (Boukhris et al., 2016). There was no
association between prenatal antidepressant exposure and
scores for overall behavioral problems among offspring of
210 mothers who were exposed to antidepressants, most
of them to SSRIs, but 12 were exposed to TCA and 6 were
on combination therapy, including TCA. Adjusted RR from
the data of the Strengths and Difficulties Questionnaire
was as follows: for overall problem behavior 1.00 (95%
CI, 0.49–2.05), for hyperactivity/inattention 0.99 (95% CI,
0.56–1.75), and for peer behavioral problems 1.04 (95%
CI, 0.57–1.91), (Grzeskowiak et al., 2016).
IN SUMMARY
The use of TCAs during pregnancy does not seem to be
associated with significant negative effects on the embryo
and fetus. There is no increase in major congenital anoma-
lies nor significant long-term neurodevelopmental prob-
lems. There might be difficulties in neonatal adaptation,
which warrants close follow-up of the neonate by the
medical team during the first postnatal days. The possible
long-term effects on gut motility need further
investigation.
Antipsychotic (Neuroleptic) Drugs
Antipsychotic drugs (first generation, typical) were first
introduced in the 1950s to manage psychosis. The second
generation (atypical) antipsychotics that were developed
more recently are used for similar purposes, but have
fewer side effects. These antipsychotic drugs are currently
used for the treatment of psychosis and as adjunct treat-
ment for depression (mainly BD, often in conjunction with
mood stabilizers) and anxiety. Their mechanism of action
is generally on the dopaminergic system of the brain,
blocking D2 dopamine receptor, and thus reducing the
effects of dopamine mainly in the mesolimbic system and
prefrontal cortex (Stahl, 2003; Liemburg et al., 2012).
The atypical antipsychotics have replaced the typical
agents as first-line medications for psychotic disorders.
They are also used increasingly for the treatment of BD,
obsessive–compulsive disorder, and treatment-resistant
depression (Stahl, 2003). Placental transfer varies between
the antipsychotics. Newport et al. (2007) found umbilical
cord to maternal plasma ratio to be between 23.8% for
quetiapine and 72.1% for olanzapine.
Typical anti psychotics include: chlorpromazine, fluphe-
nazine, haloperidol, loxapine, perphenazine, pimozide, thio-
ridazine, thiothixene, trifluoperazine, and triflupromazine.
The atypical antipsychotics include: aripiprazole, clozapine,
olanzapine, quetiapine, and ziprasidone.
We summarized all larger cohort and case–control
studies on old and newer antipsychotics. Because typical
antipsychotics have been widely used for approximately
50 years, there are cumulative available data that suggest
that the risks of using these agents during pregnancy are
minimal, with respect to teratogenic or toxic effects on the
fetus. In particular, the use of piperazine phenothiazines
(e.g., trifluoperazine and perphenazine) was proven safe
(Bulletins–Obstetrics, 2008). However, for some of the
newer antipsychotic drugs, there seems to be very little
data. Generally, no increase in the rate of major anomalies
or of neurodevelopmental problems was reported.
CONGENITAL MALFORMATIONS (TABLES 3 AND 4)
A prospective cohort study of 1309 pregnancies exposed
to phenothiazines found no increase in the rate of congeni-
tal malformations, intrauterine fetal death, and neonatal
death, compared with 50,282 nonexposed control pregnan-
cies (Slone et al., 1977).
In a study from the Massachusetts pregnancy registry
evaluating reproductive safety of second generation anti
psychotics, 3 of 214 children of the treatment group and 1
of 89 control children had congenital malformations. Medi-
cations included aripiprazole, asenapine, clozapine, iloperi-
done, lurasidone, olanzapine, paliperidone, quetiapine,
risperidone, and ziprasidone. The OR was 1.25, 95% CI,
0.15–12.19. The difference was not statistically significant
(Cohen et al., 2016).
From a cohort of 1,360,101 pregnant women enrolled
in Medicaid during 2000 to 2010, a total of 9258 (0.69%)
filled at least one prescription for an atypical antipsychotic
and 733 (0.05%) filled at least one prescription for a typi-
cal antipsychotic during the first trimester. Mothers suf-
fered from schizophrenia, BD, psychosis, depression,
anxiety, attention deficit hyperactivity disorder, and other
psychiatric disorders. There was no increase in the risk
for congenital malformations following prenatal exposure
to typical or atypical antipsychotics, with a possible excep-
tion for risperidone. After adjustment for possible consid-
ered confounders, the RR was 1.05 (95% CI, 0.96–1.16)
for atypical anti psychotics and 0.90 (95% CI, 0.62–1.31)
for typical anti psychotics.
The findings for cardiac malformations were similar. In
the evaluation of individual agents, a small increased risk
in overall malformations (RR, 1.26; 95% CI, 1.02–1.56)
and cardiac malformations (RR, 1.26; 95% CI, 0.88–1.81)
was found for risperidone that was independent of
BIRTH DEFECTS RESEARCH 109:933–956 (2017) 939

TABLE 3. Summary of Studies on Fetal Effects of Typical Antipsychotic Drugs in Pregnancy

Drug Author No. of patients, study design Fetal outcome

CHLORPROMAZINE Rumeau-Rouquette 57 clorpromazine/304 other phenothiazines; Rate of congenital malformations increased

et al., 1977 prospective cohort study from 1.6% to 3.5% syndactyly-1, multiple

anomalies-1, endocardial fibroelastosis-1,

microcephaly-1

FLUPHENAZINE Reis and Kallen, 2010 17/582 antipsychotics exposure, retrospective study 1 ventricular septal defects

HALOPERIDOL Van Waes and 100, retrospective and prospective data collection 4 miscarriages, no increase in congenital

Van de Velde, 1969 compared to 1,732 controls anomalies

Diav-Citrin et al., 2005 188/631 (ENTIS controls), multicenter prospective No increase in congenital anomalies; 1 lung
study hypoplasia, 1 hand malformation, 1 cystic

hygroma, 1 congenital heart defect, 1

ventricular septal defect. 3/4 had also

exposure to other psychotropic drugs

PERPHENAZINE Reis and Kallena, 2010 90/582 antipsychotics exposure, retrospective study 1 spina bifida, 1 ventricular septal defect

THIORIDAZIDE Reis and Kallena, 2010 35/582 antipsychotics exposure, retrospective study Teratology of Fallot

TRIFLUOPERAZINE Moriarity and Nance, 480 cases, retrospective cohort No increase in congenital malformations 1.%

1963 vs. 1.5% in non-exposed controls

Schrire, 1963, from Smith 478, retrospective cohort, report from 20 investigators 2 miscarriages, all normal babies

Kline & French

Laboratories Ltd.

ENTIS, European Network of Teratology Information Services.

confounders (Huybrechts et al., 2016). A similar slight
increase in the rate of congenital anomalies following pre-
natal risperidone was also observed in other much smaller
studies, with a total of 79 pregnancies (Habermann et al.,
2013; Kulkarni et al., 2015).
In a cohort of pregnant women enrolled in the United King-
dom from 1995 to 2012, a total of 416 Women that were pre-
scribed antipsychotic medication in pregnancy were not at
higher risk of giving birth to a child with major congenital mal-
formations, compared with women without prescribed anti-
psychotics, including 670 women with psychotropic treatment
before pregnancy and 318,434 controls. Of 290 women pre-
scribed antipsychotics up to day 105 of pregnancy, 10 (3.4%)
gave birth to a child with a major congenital malformation in
comparison to 11 of 492 (2.2%) in the cohort of women who
discontinued treatment before pregnancy, and 4162 of
210,966 (2.0%) in the controls. The differences were nonsigni-
ficant after adjustments for concomitant medications, health,
and lifestyle characteristics (Petersen et al., 2016).
NEONATAL ADAPTATION DIFFICULTIES
In a literature review on the impact of exposure to antipsy-
chotics in pregnancy there was increased rate of fetal distress,
low Apgar score, and hypoglycemia among infants born to
women with schizophrenia, regardless of antipsychotic
medications treatment. Symptoms, including agitation, hypoto-
nicity, hypertonicity, somnolence, respiratory distress, and
feeding difficulties, were reported; however, concomitant use
of other drugs was also reported (Gentile, 2010a).
The Australian national register of antipsychotic drugs
in pregnancy reported respiratory distress among 37% of
142 neonates exposed to antipsychotics. However, respira-
tory symptoms were six times more common than in con-
trols following concomitant exposure to mood stabilizers
(Kulkarni et al., 2015). Poor birth outcomes were found in
31 of 290 (10.7%) pregnancies in a U.K. cohort, which
was double the rate (24/492 [4.9%]) in women with anti-
psychotic therapy only before pregnancy and nearly triple
the rate (9244/210,966 [4.4%]) of controls, with no his-
tory of antipsychotic therapy. After adjustment for con-
comitant medication, health, and lifestyle factors, the RRs
were elevated in comparison with controls (RR, 2.62; 95%
CI, 1.52–4.52). Obesity, smoking, alcohol consumption, and
illicit drug use, as well as concomitant medications, all
remained independently associated with poor birth out-
comes (Petersen et al., 2016).
LONG-TERM NEURODEVELOPMENTAL OUTCOME (TABLE 2)
Data regarding outcome of offspring exposed to antipsy-
chotics generally come from case reports, case series, or
940 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY

TABLE 4. Summary of Studies on Fetal Effects of Atypical Antipsychotic Drugs in Pregnancy

Drug Author No. of cases and study design Fetal outcome

ARIPIPRAZOLE Habermann et al., 2013 60/561/1,122 aripripazole/561 atypicals/ 1,122 3 malformations; rate increased compared to

controls, prospective study controls (OR, 2.13; 95% CI, 1.19–3.83); 23%

withdrawal syndrome.

Kulkarni et al., 2015 19/147 exposed to atypicals, prospective study No congenital anomalies.

Huybrechts et al., 2016 1756/9,258 exposed to atypical, retrospective study After adjustment, no increased risk of congenital

anomalies

CLOZAPINE Habermann et al., 2013 73 clozapine/561 atypicals/1122 controls prospective Increased risk compared to controls (aOR, 2.13;

study 95% CI, 1.19–3.83)

Kulkarni et al., 2015 11/147 exposed to atypicals, prospective study 2 congenital anomalies: 1 craniosynosthosis, 1

gastroschisis

OLANZAPINE McKenna et al., 2005 60/151 exposed to atypicals, prospective study 1 cleft lip, encephalocelle and aqueductal stenosis.

Habermann et al., 2013 284/561 exposed typical/atypical/1,122 controls; Rate of congenital malformations was increased

prospective study compared to controls (aOR, 2.13; 95% CI,

1.19–3.83); 15% withdrawal symptoms

Kulkarni et al., 2015 24/147 exposed to atypicals, prospective study 1 DDH

Huybrechts et al., 2016 1,394/9,258 exposed to atypicals, retrospective study After adjustment, no increased risk of congenital

anomalies

QUETIAPINE McKenna et al., 2005 36/151 exposed to atypicals, prospective study No congenital anomalies.

Habermann et al., 2013 185/561 exposed to atypicals, prospective study Increased compared to controls (OR, 2.13; 95% CI,

1.19–3.83). 25% withdrawal syndrome

Kulkarni et al., 2015 74/147 exposed to atypicals, prospective study 3 congenital anomalies: 1 atrial septal defect,

1-cleft lip and palate and hydrocephalus,

1-pulmonic atresia

Huybrechts et al., 2016 4,221/9,258 exposed to atypicals, retrospective study After adjustment, no increased risk of congenital

anomalies

RISPERIDONE McKenna et al., 2005 49/151 exposed to atypicals, prospective study No congenital anomalies.
Habermann et al., 2013 64/561/1122 exposed to atypicals/controls, Rate of anomalies increased compared to controls

prospective study (OR, 2.13; 95% CI, 1.19–3.83)

Kulkarni et al., 2015 15/147 exposed to atypicals, prospective study 2 congenital anomalies: 1-abnormal renal collecting

tubules and bilateral talipes, 1 CHARGE

association

Huybrechts et al., 2016 1,566/9,258 exposed to atypicals, retrospective study After adjustment, increased risk of congenital

anomalies (RR, 1.26; 95% CI, 1.02–1.56) and of

cardiac anomalies (RR, 1.26; 95% CI,

0.88–1.81)

ZIPRASIDONE Habermann et al., 2013 37/561/1122 exposed to atypicals, prospective study Increased risk compared to controls (OR, 2.13;

95% CI, 1.1–3.83)

Huybrechts et al., 2016 697/9,258 exposed to atypicals, prospective study After adjustment no increased risk of congenital

malformations or cardiac anomalies

DDH, developmental dysplasia of the hip joint; CHARGE, coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities,
and ear abnormalities.
BIRTH DEFECTS RESEARCH 109:933–956 (2017)
small cohort studies. In case reports and case series, there
is no possibility to evaluate the impact of the maternal ill-
ness and of the postnatal environment.
Slone et al. (1977) found similar adjusted mean IQ
score at 4 years in a cohort of 1990 children exposed to
phenothiazines, compared with 26217 nonexposed con-
trols (Slone et al., 1977). From 16 infants born to mothers
using antipsychotic drugs enrolled in the Mayo clinic, two
infants (12.5%) were suspected to have behavioral prob-
lems that initiated after the age of 3 years (Wichman,
2009).
Offspring of women enrolled from December 1999
through June 2008 in Atlanta, Georgia, were evaluated at 6
months by The Infant Neurological International Battery
(INFANIB) for Habituation by measuring response
intensity after repeated administration of a stimulus.
Twenty-two offspring of mothers that were treated by anti-
psychotics were included: first generation: haloperidol (n 5
9); second-generation antipsychotic (n 5 12), exposed to
aripiprazole, olanzapine, quetiapine fumarate, risperidone,
and ziprasidone hydrochloride; 12 were exposed to antipsy-
chotic medication during the first trimester, 14 during the
second, and 16 during the third. Concomitant treatment
included antidepressants, n 5 17; anxiolytics, n 5 9; and
hypnotics, n 5 6. Infants were compared with a group of
children exposed to other antidepressants (202) and con-
trols (85). Antipsychotic-exposed infants had lower INFA-
NIB scores, compared with antidepressant-exposed and
nonexposed infants after controlling for relevant covariates
(RR 5 3.67; p < 0.03). Analyses of the habituation task
revealed no significant effect of prenatal medication expo-
sure group on number of trials to habituate (p 5 0.19) or
average looking time during the habituation task (p 5
0.66) (Johnson et al., 2012).
The developmental progress of 76 infants prenatally
exposed to atypical antipsychotics in China was compared
with that of 76 matched control infants who had no pre-
natal exposure to antipsychotics by Bayley Scales of Infant
and Toddler Development, third edition. Mothers had the
diagnosis of schizophrenia and were taking antipsychotic
agents, including clozapine (n 5 33), risperidone (n 5
16), olanzapine (n 5 8), sulpiride (n 5 13), and quetia-
pine (n 5 6). Controls were born to mothers with no men-
tal illness without psychotropic drugs. At 2 and 6 months,
more antipsychotic-exposed infants met the criteria for
delayed development (score was <85) at 2 months in the
cognitive, motor, social-emotional, and adaptive behavior,
and at 6 months for the mean social-emotional behavior.
At 12 months, there was no significant difference between
the two groups in the mean composite scores of all sub-
measures. The percentage of infants with delayed develop-
ment in any of these domains in all groups was similar
(Peng et al., 2013). When the children exposed to cloza-
pine were compared with those exposed to risperidone,
olanzapine, and quetiapine, more clozapine-exposed
941
infants had early delayed development (defined as the
subscale score of <85) for adaptive behavior at 2 and 6
months of age. There was no difference between the two
groups for cognitive, language, motor, social, and emotional
at 2, 6, and 12 months of age (Shao et al., 2015).
Gentile and Fusco (2017) searched the English litera-
ture for neurodevelopmental studies in children exposed
in utero to second generation antipsychotic drugs
between1954 and 2016, and found mainly case reports
and small case series. They performed a meta-analysis, on
long-term outcomes of 35 healthy infants exposed in utero
to antipsychotics. Of these cases, three had motor develop-
mental delays and one had delayed speech acquisition
(Gentile and Fusco, 2017).
In a cohort of women treated for psychiatric illness in
the United Kingdom, children were identified with neuro-
developmental and/or behavioral disorders by searching
for relevant data in the medical records of the exposed
children up to 5 years of age. There was an increased pat-
tern for neurodevelopmental and behavioral disorders that
was significant in the unadjusted analysis (RR, 1.58 (95%
CI, 1.04–2.40), but after adjustment, the RR estimates
attenuated and were no longer statistically significant
(RR 5 1.22; 95% CI, 0.80–1.84) (Petersen et al., 2016).
In summary, it seems obvious that prenatal exposure
to antipsychotic drugs does not seem to increase the rate
of major congenital anomalies or other fetal problems.
However, additional studies are needed for individual anti-
psychotics, especially risperidone. There seems to be a sig-
nificant increased rate of poor neonatal adaptation. Data
evaluating the long-term developmental outcome of the
exposed children are insufficient. Most studies demon-
strated that, apart from some short-term developmental
delay, there is no evidence of long-term problems. How-
ever, most of these studies did not fully consider the possi-
ble effects of maternal mental illness.
Mood Stabilizers
Mood stabilizers are a group of drugs with different phar-
macological actions. Many of them are used primarily as
antiepileptic drugs. They generally reduce the spread of
action potentials by either affecting the voltage-gated
sodium channels influencing brain glutamate, or by
increasing the function of the GABAergic system. Several
of these drugs seem to affect the arachidonic acid system
in the brain (Rao et al., 2008). For some drugs (i.e.,
lithium), the mechanism of action is yet unknown. Most of
these drugs (i.e., VPA, carbamazepine, oxcarbazepine,
lamotrigine) are also weak folic acid antagonists and
women at child-bearing age taking these drugs should,
therefore, receive folic acid supplementation. Moreover,
folic acid deficiency might aggravate the depressive symp-
toms (Mula and Sander, 2007).
942
The more commonly used drugs in this group are: lith-
ium, VPA, carbamazepine, oxcarbazepine, lamotrigine, top-
iramate, and levetiracetam. Each of these drugs will be
discussed separately.
It appears that approximately half of antiepileptic
drugs (AEDs) are used for pain management and for psy-
chiatric indications. Hence, AEDs are among the most com-
mon teratogens prescribed to women of child-bearing age.
Exposure to AEDs during pregnancy is associated with an
increased risk of major congenital malformations, from a
background risk of 2 to 3% to between 4% and 9%
(Kaneko et al., 1999; Morrow et al., 2006). In addition to
congenital anomalies, cognitive developmental delays have
been described in the offspring exposed to some of the
AEDs, in a dose dependent manner (Meador et al., 2007;
Tomson et al., 2011). Older AEDs which are also mood sta-
bilizers, such as valproate and carbamazepine, are associ-
ated with a higher risk of congenital malformations and
developmental delay than newer AEDs, such as lamotri-
gine and levetiracetam. These issues should be properly
considered if there is a need to use a mood stabilizer in
women of child-bearing age.
LITHIUM
Lithium salts, mainly lithium carbonate and lithium citrate,
are used as effective mood stabilizers, especially in the
treatment of BD. Lithium ions equilibrate across the pla-
centa and, therefore, the concentrations in maternal and
fetal blood are almost equal. This might lead to fetal toxic-
ity, including low Apgar score, hypotonicity, heart failure,
and nephrogenic diabetes insipidus (Simard et al., 1989;
Zegers and Andriessen, 2003; Yacobi and Ornoy, 2008).
In this review, we summarized most published studies
in English on the effects of lithium in pregnancy. Several
studies, both retrospective and prospective, have demon-
strated lithium teratogenicity, especially affecting the heart.
In general, there appears to be an increase in the rate of
cardiac anomalies, but not of other major congenital
anomalies. Of special concern is Ebstein’s anomaly
(defined as downward displacement and malformation of
the tricuspid valve, often together with atrial septal defect
[ASD] and right ventricular hypoplasia), and the second,
patent ductus arteriosus (Park et al., 1980). The few stud-
ies on neurodevelopmental outcome showed that lithium
does not cause neurodevelopmental problems in the pre-
natally exposed children.
In the voluntary registry of
Congenital malformations (Table 5).
retrospective cases established in Denmark in 1968, there
were 8% (25 infants) with cardiovascular anomalies
among 225 lithium treated women (Weinstein, 1976). Not
only was this rate almost 10 times higher compared with
the general population, but there were 6 children (2.7%)
with Ebstein’s anomaly, which is regularly found in only
one of 20,000 children. The registry was criticized because
of data collection. A higher rate of cardiac anomalies was
ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY
also observed in prospective cohort studies, but not in all
studies. Kallen and Tandberg (1983) found 4 cases of car-
diac anomalies (7%) in a prospective cohort of 59 children
exposed to lithium in utero. However, other studies have
demonstrated a much lower risk for cardiac anomalies
(Kallen and Tandberg, 1983).
In an uncontrolled prospective study, Cunniff et al.
(1988) identified 72 lithium-treated women with 50 live-
born infants; only 2 of them were malformed (Cunniff
et al., 1988).
Czeizel and Racz (1990) studied 10,698 children with
congenital anomalies between the years 1980 and 1987.
Their case–control study included all malformed still-born
and live-born cases diagnosed from birth until the age of
1 year, as well as prenatally diagnosed and electively ter-
minated malformed fetuses. They observed no association
with maternal lithium use during pregnancy, as only six
infants were exposed to lithium (Czeizel and Racz, 1990).
Similarly, several studies on children with Ebstein’s anom-
aly showed that none of these were exposed in utero to
lithium (Kallen and Tandberg, 1983; Sipek, 1989;
Edmonds and Oakley, 1990).
Jacobson et al. (1992) found, in a controlled prospec-
tive study among 138 lithium treated women, that the rate
of major congenital anomalies among the offspring was
not different from controls (2.8% vs. 2.4%, respectively),
and there was one case of Ebstein’s anomaly. The newborn
infants were significantly heavier in the lithium-exposed
group (Jacobson et al., 1992). In a record linkage study of
Michigan Medicaid recipients (Rosa, 2005), only 2 (3.2%)
of 62 infants of women treated with lithium during the
first trimester of pregnancy were reported to have major
congenital anomalies, and none of them was cardiac.
The results of an American Expert Scientific Committee
on lithium in pregnancy were published by Moore in
1995. They concluded that there is sufficient evidence that
lithium in therapeutic doses may increase the rate of car-
diac anomalies in human, but apparently not in animals
(Moore, 1995).
In the controlled prospective study from our Israeli
Teratogen Information Service, (Diav-Citrin et al., 2014),
we observed among 183 pregnant women exposed in
pregnancy to lithium (90% were exposed from the first
trimester), a higher rate of spontaneous abortions, but the
rate of congenital anomalies (6.5%) was not significantly
different from that in 711 controls (2.7%) or from 72
women with BD without lithium treatment (3.3%). Cardio-
vascular anomalies occurred more frequently in the
lithium-exposed group when compared with the controls
(5/123 [4.1%], compared with 4/711 [0.6%]). Ebstein’s
anomaly was diagnosed in one lithium-exposed fetus and
in two additional retrospective lithium cases that were not
included, because contact with the teratogen information
service was made after the prenatal diagnosis by
ultrasound.
BIRTH DEFECTS RESEARCH 109:933–956 (2017) 943

TABLE 5. Summary of Studies on Fetal Effects of Lithium in Pregnancy

Author & year No. of cases and study design Fetal outcome

Schou, 1976 60 non-malformed lithium babies; prospective neurode- No increased the of developmental disorders

velopmental study follow-up study compared to

siblings

Weinstein, 1976 225 lithium treated women; retrospective study 25 infants (8%) had cardiovascular anomalies,

6 children (2.7%) had Ebstein’s anomaly

Kallen & Tandberg, 1983 59 cases; prospective cohort study 4 cases of cardiac anomalies (7%)

Cunniff et al., 1988 72 lithium-treated women with 50 liveborn infants; 2 malformed infants

prospective cohort study

Czeizel & Racz., 1990 case control study of 10,698 children with congenital Only six of the infants were exposed to lithium, no

anomalies association with maternal lithium use during

pregnancy

Jacobson et al., 1992 105 lithium/148 controls; prospective study One case of Ebstein’s anomaly. No differences in major

congenital anomalies. Birth weight was higher in the

lithium group

Rosa 2005 62 cases; record linkage study 2 (3.2%) cases of major congenital anomalies, none of

them was cardiac

van der Lugt et al., 2012 15 cases; retrospective neurodevelopmental cohort study Cognitive tests within normal limits. Growth, behavior

and general development within the normal range

Diav-Citrin et al., 2014 183 cases, 711 controls; prospective study Higher rate of spontaneous abortions, the rate of

congenital anomalies (6.5%) was not significantly

different from controls (2.7%). High rate of

cardiovascular anomalies in the lithium exposed

when compared to controls (5/123 [4.1%] versus

4/711 [0.6%]). One case of Ebstein’s anomaly

In summary, despite several negative studies of in
utero lithium exposure and congenital malformations, the
overall risk for Ebstein’s anomaly apparently mounts to
1:1500 births in infants exposed in utero to lithium, being
approximately 10 times higher than in the general popula-
tion. Other cardiac anomalies, although more prevalent,
are probably mild. There is no increase in other major
anomalies.
Neurodevelopmental studies. Several human case reports have
demonstrated transient neurodevelopmental deficits in
infants born to lithium-exposed mothers. However, long-
term developmental studies on lithium-exposed children
are generally lacking. In a single prospective follow-up
study, Schou (1976) compared the motor and mental
development of 60 nonmalformed lithium babies to their
own 57 siblings, who were not exposed to lithium in utero
by using questionnaires and letters sent to doctors (psy-
chiatrists/general practitioners) who primarily reported
the children. Out of 60 lithium-exposed children, 10 were
abnormally developed, in 6 developmental delay was tran-
sitory, and in 4 it was permanent. In this group, three chil-
dren were exposed to lithium only in the first trimester,
and the seven others throughout pregnancy. In the 57 con-
trol siblings, 6 children were identified with persistent
abnormal development. These data indicate that in utero
exposure to lithium does not increase the risk of develop-
mental disorders (Schou, 1976). In a more recent study on
15 children exposed to lithium in utero, using the WISC III
and WPPSI-R psychological tests, the researchers did not
find any difference with the normal population. Weight,
height, and head circumference were also normal (van der
Lugt et al., 2012). These studies are reassuring, but more
data are needed for a conclusive statement.
Lithium has the potential for perinatal tox-
Perinatal Toxicity.
icity as reported in a relatively large number of pregnan-
cies, especially among the case reports (Moore, 1995). A
higher rate of prematurity and macrosomia (large for ges-
tational age) were also reported. Most of the toxic effects
944 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY
reported in newborn infants of lithium treated mothers
were transient and self-limited. The complications
included: goiter that was higher in cases of polytherapy,
respiratory distress, apnea, cyanosis and asphyxia, cardio-
megaly, atrioventricular block, atrial flutter, supra-
ventricular tachycardia, poor reflexes, and hypotonicity. In
several cases of toxicity, the lithium concentration in the
newborn infants was higher than that in the maternal
blood (Wilbanks et al., 1970; Nars and Girard, 1977;
Zegers and Andriessen, 2003).
In summary. Evaluation of the studies on lithium in preg-
nancy shows that lithium therapy throughout pregnancy
apparently adds a small risk for cardiovascular defects,
notably Ebstein’s anomaly. There seems to be no other
effects on pregnancy outcome. However, if it is decided to
discontinue lithium in pregnancy, we should remember
that discontinuation might cause a high rate of relapse,
and tapering off should be slow (Cohen et al., 1994; Vig-
uera et al., 2002). We can, therefore, conclude that, when-
ever lithium is the drug of choice, it may be continued in
pregnancy. Monitoring during pregnancy has to include
fetal echocardiography, and studies of serum lithium levels
throughout pregnancy. The risks of lithium exposure in
pregnancy need to be weighed against the risks of
untreated BD. It is, therefore, important to consider the
pros and cons when planning lithium treatment in women
of child-bearing age.
VPA
VPA is a commonly used antiepileptic drug and a popular
mood stabilizer that is also used for the treatment of BDs
and migraine headaches (Duenas-Gonzalez et al., 2008;
Ornoy, 2009). Exposure to VPA during the first trimester
of pregnancy is associated with significantly increased
risks of major and minor congenital malformations, includ-
ing a 20-fold increase in neural tube defects (NTDs),
mainly with lumbosacral meningomyelocele (Robert and
Guibaud, 1982; Weinbaum et al., 1986; Omtzigt et al.,
1992), increased cleft palate (Jackson et al., 2016), cardio-
vascular anomalies, skeletal and limb malformations, geni-
tourinary defects, developmental delay, endocrine
disorders, reduced cognitive functioning including lower
IQ, increased special education needs, and high risk for
ASD (Moore et al., 2000; Williams et al., 2001; Rasalam
et al., 2005; Bromley et al., 2008; Ornoy, 2009). In animals,
VPA causes dose-related teratogenic effects in all species
investigated including rodents, rabbits, and monkeys; these
include skeletal malformations, cardiac and craniofacial
defects (Hendrickx et al., 1988; Narotsky et al., 1994; Mssa
et al., 2005; Ornoy, 2009; Wu et al., 2010).
In a prospective study that
Congenital malformations (Table 6a).
used data from the Australian Pregnancy Registry, Vajda
et al. (2006) presented data on 630 women exposed to
AEDs during pregnancy with 565 fetal outcomes. VPA use
above 1100 mg/day in the first trimester of pregnancy
was associated with a significantly higher incidence of
fetal malformation, when compared with all other AEDs
(carbamazepine, lamotrigine, and phenytoin) (OR, 7.3; p <
0.0001) (Vajda et al., 2006).
In a study published by Diav-Citrin et al. (2008), based
on data from the Israeli Teratogen Information Service, the
outcome of 154 valproate-exposed pregnancies (96.1% at
least in the first trimester) were compared with those of
1315 pregnancies of women exposed to nonteratogenic
drugs. The rate of major anomalies in the valproate group
exposed in the first trimester was 8 of 120 (6.7%), com-
pared with 31 of 1236 (2.5%) in the control group (p 5
0.018; RR, 2.66; 95% CI, 1.25–5.65). Five of the eight
major anomalies in the VPA group were cardiovascular,
two had mental retardation, two of five male infants with
major anomalies had hypospadias, and three of eight were
suspected of having fetal valproate syndrome. A daily dose
of 1000 mg or more was associated with the highest tera-
togenic risk (RR, 8.72; 95% CI, 4.16–18.30) (Diav-Citrin
et al., 2008).
Tomson et al. (2011) assessed the rates of major con-
genital malformations in pregnancies exposed to carbama-
zepine, lamotrigine, VPA, or phenobarbital, based on data
from the EURAP epilepsy and pregnancy registry. They
reported an increase in malformation rates with increasing
dose at the time of conception for all drugs. Doses of VPA
over 1500 mg daily were associated with a congenital mal-
formation rate of 24.2% (OR, 5.8), compared with doses of
700 mg and lower (Tomson et al., 2011).
Werler et al. (2011) used data from the National Birth
Defects Prevention Study, an ongoing, multistate case–con-
trol study in the United States, to assess the use of AEDs
during the first trimester of pregnancy among 172 women,
of which 49 were exposed to VPA monotherapy (compared
with 17,899 controls) and the risk of various major con-
genital malformations. They found an increased risk for a
variety of congenital anomalies: NTDs (aOR, 9.7; 95% CI,
3.4–27.5), oral clefts (aOR, 4.4; 95% CI, 1.6–12.2), heart
defects (aOR, 2.0; 95% CI, 0.78–5.3), and hypospadias
(aOR. 2.4; 95% CI, 0.62–9.0) (Werler et al., 2011).
In a prospective observational study from 1996 until
2012 in the United Kingdom, Campbell et al. (2014) com-
pared between the exposure to VPA, carbamazepine, or
lamotrigine during pregnancy and the risk of congenital
malformation. They reported a significantly higher risk for
malformations with valproate monotherapy 6.7% (95% CI,
5.5% to 8.3%), compared with 2.6% (95% CI, 1.9% to
3.5%) and 2.3% (95% CI, 1.8% to 3.1%) with carbamaze-
pine and lamotrigine, respectively. VPA exposure was asso-
ciated with significantly higher occurrence of NTDs, facial
clefts, hypospadias, and genitourinary anomalies. Skeletal
defects were also more common in VPA-exposed, com-
pared with carbamazepine or lamotrigine, and cardiac
anomalies were significantly more likely to occur with
BIRTH DEFECTS RESEARCH 109:933–956 (2017) 945

TABLE 6a. Summary of Studies on Fetal Effects of VPA in Pregnancy: Congenital Malformations

Author & year Number of cases and study design Fetal outcome

Vajda et al., 2006 113 VPA monotherapy; 56 polytherapy cases; VPA > 1100 mg/day was associated with a high incidence of mal-

prospective and retrospective study formations (in comparison to carbamazepine, lamotrigine and

phenytoin)

Diav-Citrin et al., 2008 154 VPA, 1,236 controls; prospective study High rate of major anomalies (8 of 120 [6.7%] vs 31 of 1,236

[2.5%], p 5 0.018, (RR, 2.66; 95% CI, 1.25–5.65), most were

cardiovascular

Werler et al., 2011 49 VPA, 17,899 controls; case-control study VPA exposure increased the risk for NTDs (aOR, 9.7; 95% CI, 3.4–

27.5), oral clefts (aOR, 4.4; 95% CI, 1.6–12.2), heart defects

(aOR, 2.0; 95% CI, 0.78–5.3), and hypospadias (aOR, 2.4; 95%

CI, 0.62–9.0)

Tomson et al., 2011 1,010 VPA, observational cohort study VPA > 1500mg daily were associated with a congenital malforma-

tion rate of 24.2% (OR, 5.8) compared with doses of 700 mg

and lower

Campbell et al., 2014 1,290 cases, prospective observational study VPA monotherapy; malformation rate of 6.7% (95% CI, 5.5%–8.3%)

compared with 2.6% with carbamazepine (95% CI, 1.9%–3.5%)

and 2.3% with lamotrigine (95% CI, 1.8%–3.1%).

Weston et al., 2016 467 VPA, literature meta-analysis Malformations risk with VPA monotherapy was 6.7% (95% CI,

5.5%–8.3%) compared with 2.6% with carbamazepine (95% CI,

1.9%–3.5%) and 2.3% with lamotrigine (95% CI, 1.8%–3.1%)

TABLE 6b. Summary of Studies Evaluating Neurodevelopmental Outcome of Offspring Exposed to VPA during Pregnancy

Author & year No. of cases and study design Fetal outcome

Bromley et al., 2010 42 VPA, 257 controls (230 born to women without VPA exposed had a significant increased risk of

epilepsy and 27 to women with untreated epi- delayed early development compared to controls.

lepsy); prospective study

Rihtman et al, 2013 30 VPA monotherapy, 42 lamotrigine, 52 controls. Prenatal VPA reduced non-verbal IQ and impaired

Prospective cohort study motor and sensory scores compared to controls.

Meador et al., 2013 97 VPA; prospective cohort study High doses of valproate were negatively associated

with IQ (r 5 -0
56, p < 0
0001), verbal ability

(r 5 -0
40, p 5 0
0045), non-verbal ability

(r 5 -0
42, p 5 0
0028), memory (r 5 -0
30,

p 5 0.0434), and executive function (r 5 -0
42,

p 5 0.0004)

Baker et al., 2015 25 VPA 800 mg, 34 VPA cases  800 mg; con- Adjusted mean IQ was 9.7 points lower (95% CI,

trolled cohort study 4.9–-14.6; p < 0.001) for children exposed to

high-dose (VPA > 800 mg daily) with a similar

effect observed for the verbal, nonverbal, and

spatial subscales.
946 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY

TABLE 7. Summary of Studies on Fetal Effects of Carbamazepine in Pregnancy

Author & year No. of cases and study design Fetal outcome

Jones et al., 1989 48 cases; prospective study including Craniofacial abnormalities (11%), fingernail hypoplasia

neurodevelopment (26%); 7/35 (20%) children exposed to carbamazepine

monotherapy had developmental delay

Ornoy and Cohen, 1996 47 cases, 47 controls; prospective Carbamazepine exposed children had lower average

neurodevelopmental study cognitive scores, 6 of them also had typical facial

features of ‘carbamazepine syndrome’

Diav-Citrin et al, 2001 210 cases, 210 controls, prospective study A twofold increase in the rate of major congenital

malformations in the carbamazepine-exposed group.

Matalon et al, 2002 1,255 cases, 3,756 controls. Prospective and 85 carbamazepine exposed infants (6.7%) had congenital

retrospective literature meta-analysis anomalies compared with 88 (2.34%) controls.

Bromley et al., 2010 48 cases, 257 controls; prospective Carbamazepine exposed children did not differ

neurodevelopmental study significantly in their overall developmental ability

Cummings et al., 2011 49 cases, 44 controls; observational cohort study Carbamazepine monotherapy increased the risk of

impaired neurodevelopment (OR, 7.7; 95% CI,

1.4–43.1; p < 0.01)

Baker et al., 2015 50 cases; 287 controls prospective Exposure to carbamazepine was associated with reduced

neurodevelopmental cohort study verbal abilities (24.2; 95% CI, 0.6–27.8; p 5 0.02)

and increased frequency of IQ < 85

Vajda et al., 2016 Prospective and retrospective study, 528 cases, Carbamazepine monotherapy was associated with a two-

515 controls fold increase of fetal malformations

Weston et al., 2016 1,367 cases, 2,146 controls literature Higher risk of malformations compared to those born to

meta-analysis women without epilepsy (RR, 2.01; 95% CI, 1.20–3.36)

or with untreated epilepsy (3,058; RR, 1.50; 95% CI,

1.03–2.19)

exposure to valproate than lamotrigine, with a significant
dose effect of VPA (P 5 0.0006) (Campbell et al., 2014).
In a recently published meta-analysis that included 50
studies published from the 1970s to 2015, Weston et al.
(2016) reported that children exposed to VPA, carbamaze-
pine, phenobarbital, phenytoin, and topiramate were at a
higher risk for malformations than children born to
women without epilepsy or with untreated epilepsy. Chil-
dren exposed to VPA (467) were at the highest risk of
malformations, compared with children born to women
without epilepsy (N 5 1936; RR, 5.69, 95% CI, 3.33 to
9.73) and to women with untreated epilepsy (N 5 1923;
RR, 3.13, 95% CI, 2.16 to 4.54) (Weston et al., 2016).
Neurodevelopmental effects (Table 6b). There are many studies
demonstrating the neuro-teratogenic effects of VPA in ani-
mal models and in man. The intellectual abilities of hun-
dreds of children born to mothers exposed to VPA during
pregnancy have been studied in the past 20 years. Devel-
opmental delay, learning difficulties, inattention, and
especially speech and language delay have been described
by many investigators (Bromley et al., 2008, 2010; Riht-
man et al., 2013). Most of the children with developmental
delays also had the typical facial dysmorphic features of
“VPA syndrome” and other major congenital anomalies.
An association between prenatal VPA exposure and
ASD has been observed in many neurodevelopmental stud-
ies, the rate of ASD ranging between 4 and 10 times that
in the general population of children. This association, first
described by Christianson et al. in 1994 (Christianson
et al., 1994) then by Moore et al. (2000) and by Williams
et al. (2001), prompted many investigators to assess the
ASD-like inducing effect of VPA in rodents, and prenatal
VPA administration is now one of the most popular mod-
els of ASD in rodents (Ergaz et al., 2016).
The most extensive developmental studies on the
developmental outcome of children exposed prenatally to
VPA were apparently carried out by the group of investiga-
tors in the United Kingdom (Liverpool and Manchester
Neurodevelopment Group). They studied the development
BIRTH DEFECTS RESEARCH 109:933–956 (2017)
of a group of children prenatally exposed to VPA at 2, 3,
and 6 years of age. Their development was compared with
that of control children, as well as to children prenatally
exposed to carbamazepine or lamotrigine (Meador et al.,
2007; Bromley et al., 2010; Baker et al., 2015) The VPA-
exposed children performed worse on all developmental
measures studied in a dose-response manner. The control
group of nonepileptic nonexposed consisted of 230 to 287
pregnant women, while the VPA-exposed group consisted
of 38 to 44 children. Children prenatally exposed to daily
VPA doses of 800 mg or more exhibited at all ages a very
significant delay in many cognitive and language measures.
It is interesting to note that, with higher age of the chil-
dren, the difference compared to the controls was reduced,
but was still significantly different from controls at all
ages.
We studied (2013) the developmental outcome of 30
children at 3 to 7 years of age prenatally exposed to VPA
monotherapy, compared with 42 children exposed to lamo-
trigine and 52 controls. The children prenatally exposed to
VPA had reduced nonverbal IQ on the Stanford Binet
scales and impaired motor and sensory scores, as evi-
denced from various tests (Rihtman et al., 2013).
There are many additional studies demonstrating the
significant neurodevelopmental damage of prenatal VPA
on the developing embryo and fetus, which make VPA the
most teratogenic drug of all mood stabilizers.
In summary, there appears to be no doubt that VPA is
the most teratogenic antiepileptic and mood stabilizer
drug. It is also causing increased neurodevelopmental
problems, as well as increased rates of ASD. If possible,
VPA should not be used in women of child-bearing age, as
long as there are other possibilities for effective drug
treatment.
CARBAMAZEPINE
Carbamazepine is an iminostilbene used in the treatment
of epilepsy, neuropathic pain, BD, and trigeminal neuralgia.
While several studies have failed to find any statistically
increased risk of malformations following carbamazepine
exposure (Morrow et al., 2006; Harden et al., 2009), other
studies and meta-analyses have shown that carbamazepine
had a statistically significant teratogenic capacity (Matalon
et al., 2002; Campbell et al., 2014; Weston et al., 2016).
Despite these findings, it remains more widely used than
other “old” antiepileptic drugs in managing epilepsy in
pregnant women. In this review, we summarize all studies
published in English regarding the effects of carbamaze-
pine in pregnancy. While there seems to be an agreement
regarding the increased rate of congenital anomalies, the
literature differs as to the possible effects of carbamaze-
pine on development.
Congenital malformations (Table 7). Carbamazapine has been asso-
ciated with an increased risk of fetal malformations, which
include NTDs, microcephaly, craniofacial skeletal defects,
947
growth retardation, and cardiac anomalies (Thomas et al.,
2008; Weston et al., 2016). Jones et al. (1989) found an
increase in craniofacial defects (11 percent), fingernail
hypoplasia (26 percent), and typical facial dysmorphic fea-
tures (“carbamazepine syndrome”) in 20%, as observed in
a cohort of 35 children who were exposed prenatally to
carbamazepine monotherapy (25) or polytherapy (10)
(Jones et al., 1989). Diav-Citrin et al. (2001) found in a
cohort of 210 pregnant women treated with carbamaze-
pine during the first trimester, a twofold increase in the
rate of major congenital malformations. The authors
reported a lack of NTDs, apparently due to sample size
limitation (Diav-Citrin et al., 2001).
Matalon et al. (2002) in a meta-analysis of 1255 cases
of all studies published on the effects of carbamazepine in
pregnancy until 2001, in relation to major congenital
anomalies that also had comparative controls, found an
increase in the rate of cardiovascular, renal, and oral cleft
malformations, as well as an increase in NTD. The overall
rate of major anomalies was 6.7%, compared with 2.34%
in controls and 2.75% in untreated epileptic women. The
rate for anomalies following carbamazepine monotherapy
was 5.52% (44/797 children), while the addition of
another anticonvulsant raised it to 8.57% (18/210 chil-
dren). The combination of carbamazepine with VPA and
phenobarbital raised it to 38.4% (10/26 children) (Mata-
lon et al., 2002).
In the meta-analysis by Weston et al. (2016) that
included 50 studies published until 2015, it was found
that children exposed to carbamazepine (1367) were at a
higher risk of malformations than children born to women
without epilepsy (2146, RR, 2.01, 95% CI, 1.20 to 3.36)
and from women with untreated epilepsy (3058, RR, 1.50,
95% CI, 1.03 to 2.19) (Weston et al., 2016).
Vajda et al. (2016) found in a cohort study of 528
pregnancies with carbamazapine monotherapy, a malfor-
mation rate of 6.25% (RR, 2.30 95% CI, 1.25–4.25), twice
the rate in the general population (Vajda et al., 2016).
Neurodevelopmental outcome. Many studies have found no effect
of carbamazepine on cognitive development, compared
with the general population (Scolnik et al., 1994; Wide
et al., 2002; Gaily et al., 2004). Other studies reported
increased rates of developmental delay in children
exposed to carbamazepine in utero. Jones et al. (1989)
found, in a prospective study on 25 children prenatally
exposed to carbamazepine alone, developmental delay
among 5 (20%) of the children, and in 2 of 4 children pre-
natally exposed to carbamazepine, phenobarbital, and VPA
(Jones et al., 1989).
Ornoy and Cohen (1996) assessed the physical and
neurological development of 47 children aged from 6
months to 6 years, born to epileptic mothers on carbama-
zepine monotherapy. They reported general developmental
delays and lower intelligence scores, following exposure to
948 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY
carbamazepine in utero (Ornoy and Cohen, 1996). The fol-
lowing studies reported continuous neurodevelopmental
studies on children exposed prenatally to various AEDs
including carbamazepine. Bromley et al. (2010) assessed
cognitive development of children younger than 2 years
born to women with epilepsy. Children exposed to carba-
mazepine in utero (N 5 48) differed significantly from
control children in their early locomotor abilities, showing
an increased risk of motor delay and hand–eye coordina-
tion problems. These differences from controls tended to
disappear after controlling for confounding factors and the
total developmental score was similar to that of controls.
The authors concluded that the differences seen within
the group comparisons may be due to confounding varia-
bles or that the magnitude of difference is small, requiring
a larger cohort (Bromley et al., 2010). At 3 years of age,
there were only slight, insignificant differences between
the carbamazepine-exposed and controls (IQ of 98 vs. 101
in controls) (Meador et al., 2009). At 6 years, the IQ of the
carbamazepine-exposed children was still insignificantly
lower than that in children exposed prenatally to lamotri-
gine (105 vs. 108), phenytoin (108), or controls (108)
(Meador et al., 2013). However, carbamazepine was associ-
ated with significantly decreased verbal abilities at 6 years
(Baker et al., 2015).
Oxcarbazepine is not discussed, because it is similar to
carbamazepine and in many countries is not approved as
a mood stabilizer.
In summary, carbamazepine has relatively low terato-
genic effects, mainly raising the rate of cardiovascular,
renal, and facial anomalies and of NTDs. As to its possible
neuro-teratogenic effects, it generally seems to cause only
a low rate of neurodevelopmental delay. However, because
there are less teratogenic effective mood stabilizers, it is
advisable not to use this drug as a mood stabilizer during
child-bearing age.
LAMOTRIGINE
Lamotrigine is an anti-epileptic drug also used to treat BD.
Lamotrigine has a good safety profile compared with other
AEDs, therefore, it is the preferred treatment option for
women of child-bearing age. Most data on its effects on
pregnancy outcome are from studies on epileptic women
and most studies showed no increase in the rate of major
congenital anomalies. We summarized most studies in
English, especially those published from the different AED
registries that also have control groups.
The data related to treatment of pregnant women with
BD are relatively limited. Wakil et al. (2009) reported
three cases of women with BD exposed to lamotrigine dur-
ing pregnancy with normal outcome (Wakil et al., 2009). A
recent retrospective study by Prakash et al. (2016) fol-
lowed women who presented to the urban maternal men-
tal health center in New Zealand between 2012 and 2014
and were treated with antipsychotics and/or mood
stabilizers. Six of the women were maintained on lamotri-
gine therapy during pregnancy. They reported that two
babies had low birth weight and required neonatal inten-
sive care unit admissions, and one infant was noted to
have a tracheoesophageal fistula that required surgical
repair in the immediate postpartum period. Other growth
parameters, which included length at birth, head circum-
ference, and Apgar scores were within normal limits in all
infants (Prakash et al., 2016).
Congenital malformations (Table 8). Most of the cohort studies
that examined the association between AEDs exposure
during pregnancy and the risk of congenital malformations
did not find any increase in the malformation risk among
infants born to mothers who used lamotrigine, with over-
all risk between 2% and 4.6% close to the background
expectation (Cunnington et al., 2005; Molgaard-Nielsen
and Hviid, 2011; Hernandez-Diaz et al., 2012; Campbell
et al., 2014; Vajda et al., 2014).
Holmes et al. (2008) found among 684 infants exposed
to lamotrigine that 16 (2.3%) had major malformations;
five of them had isolated cleft palate or cleft lip deformity,
an increase of 10.4-fold (95% CI, 4.3–24.9), when com-
pared with the reference population (Holmes et al., 2008).
In the International Lamotrigine Pregnancy Registry estab-
lished in 1992, among 1558 first trimester lamotrigine
monotherapy exposures, there were 35 malformed infants,
suggesting a rate of 2.2%. Lamotrigine polytherapy with-
out valproate resulted in a similar rate of 2.8% (12/430).
However, lamotrigine polytherapy with valproate, a well-
known human teratogen, has been associated with 10.7%
of major congenital anomalies (16/150). Combining all
these studies, lamotrigine does not seem to be a human
teratogen (Cunnington et al., 2011).
A recently published, large population-based case-mal-
formed study covering 10.1 million births with 226,806
malformed infants, classified according to EUROCAT classi-
fication from 1995 to 2011, reported no significant associ-
ation between lamotrigine use during pregnancy and
congenital malformations (OR, 1.31; 95% CI, 0.73–2.33) or
specifically all cases of isolated cleft palate (OR, 1.69; 95%
CI, 0.70–3.65) (Dolk et al., 2016).
In our Teratogen Information Center, we studied a
cohort of 218 lamotrigine-exposed pregnancies (208 in the
first trimester) compared with 865 controls, and observed
no increase in the rate of congenital anomalies and no
case of oral clefts (Diav-Citrin, 2017).
Neurodevelopmental outcome. The data regarding maternal use
of lamotrigine and neurodevelopmental outcome are lim-
ited. Bromley et al. (2010) reported that children exposed
to lamotrigine in utero did not differ significantly in their
overall developmental ability from children who were not
exposed to AEDs when younger than the age of 2 years
(Bromley et al., 2010). The same children were reex-
amined at 3 and 6 years, and still there were no
BIRTH DEFECTS RESEARCH 109:933–956 (2017)
TABLE 8. Summary of Studies on Fetal Effects of Lamotrigine in Pregnancy
Author & year No. of cases and study design
Holmes et al., 2008 684 cases; prospective study
Bromley et al., 2010 34 cases, 257 controls prospective study
Cunnington et al., 2011 1,558 lamotrigine monotherapy cases; prospective study
Cummings et al., 2011 35 lamotrigine cases; observational cohort study
Rihtman et al., 2013 42 lamotrigine cases, 52 controls; prospective, observa-
tional study
Meador et al., 2013 99 lamotrigine cases; prospective study
Baker et al., 2015 30 cases; controlled cohort study
Dolk et al., 2016 Population-based case-malformed control study of
226,806 birth with congenital anomalies of which 147
malformed on lamotrigine monotherapy
Diav-Citrin et al, 2017 Prospective cohort study on 218 exposed compared to
865 controls
IQ – intelligence quotient
differences from controls in their IQ and other develop-
mental measurements (Meador et al., 2009, 2013).
Cummings et al. (2011) reported that exposure to
lamotrigine in utero did not affect child development, as
studied at the age of 5 years (Cummings et al., 2011).
Baker et al (2015) found no significant effect on IQ among
the children exposed to lamotrigine in utero at 6 years of
age (Baker et al., 2015).
Rihtman et al. (2013) assessed the development of 42
preschool children aged 3 to 7 years after in utero expo-
sure to lamotrigine compared with 52 unexposed children.
Children exposed to lamotrigine were found to be poorer
on motor and sensory integration type tasks, but there
were no differences in the cognitive scores between these
children and unexposed children (Rihtman et al., 2013).
In summary, current evidence suggests that lamotri-
gine seems is a relatively safe drug. Thus, if a mood stabi-
lizer should be used, this belongs to the drugs of choice, if
it is effective. We should, however, remember that the data
regarding neurodevelopmental outcome are rather limited.
949
Fetal outcome
16 (2.3%) lamotrigine exposed infants were malformed.
Five infants had oral clefts.
Lamotrigine exposed infants did not differ significantly in
their overall developmental ability.
35 infants with major congenital malformations: 2.2%
(95% CI, 1.6%–3.1%).
One lamotrigine exposed infant (2/9%)had evidence of
mild or significant developmental delay.
Lamotrigine exposed infants were poorer on motor and
sensory integration. No cognitive differences between
these children and unexposed children.
Lamotrigine exposed infants were not different from
controls in their IQ and other developmental measures
at 6 years of age.
In utero exposure to lamotrigine did not have a significant
effect on IQ.
For all congenital anomalies, aOR was 1.31 (95% CI,
0.73–2.33), isolated oral clefts 1.45 (95% CI,
0.80–2.63), isolated cleft palate 1.69 (95% CI,
0.69–4.15).
No increase in major congenital anomalies in exposed
compared to controls.
TOPIRAMATE
Topiramate is increasingly used as an AED, as a mood sta-
bilizer, for the treatment of several psychiatric conditions,
and for migraine headaches. Topiramate is known to cross
the human placenta (Ohman et al., 2002). It appears that
topiramate is teratogenic and might also cause increased
rate of developmental problems.
Congenital anomalies (Table 9). In a study on the outcome of 52
pregnancies where the mothers used topiramate at least
during the first trimester, there was no increase in the
rate of structural abnormalities (Ornoy et al., 2008). There
was an increased rate of spontaneous abortions, appa-
rently not related to the drug effects, but to the fact that
these women approached for advice earlier than the
controls.
Several studies reported increased risk for major con-
genital malformation among infants exposed to topiramate
in utero: Hernandez-Diaz et al. (2012) reported a risk of
major congenital malformation of 4.2% (15/359) for
950 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY

TABLE 9. Summary of Studies on the Effects of Topiramate in Pregnancy

Author & year No. of cases and study design Fetal outcome

Morrow et al., 2006 35 topiramate cases; prospective study 2 children had major congenital anomalies (7.1%), one

had cleft lip and palate and one had hypospadias.

Ornoy et al., 2008 52 topiramate pregnancies with 41 liveborn infants, prospective Two infants were malformed; no increase in the risk for

study congenital anomalies

Hunt et al., 2008 70 topiramate cases; prospective, observational study Three infants had major congenital malformation (4.8%;

95% CI, 1.7%–13.3%)

Hernandez-Diaz 359 topiramate cases; prospective study 15 (4.2%) topiromate exposed children had major con-

et al., 2012 genital malformation

Rihtman et al., 2012 9 cases, 18 controls; prospective neurodevelopmental study Topiramate exposed children performed significantly worse

than controls for almost all of developmental measures.

Margulis et al., 2012 785 cleft palate cases, 6,986 controls; national registry study ORs for the association between topiramate use and cleft

palate was 10.1 (95% CI, 1.1–129.2) in the Slone Epi-

demiology Center Birth Defects Study

Margulis et al., 2012 2,283 cleft palate cases, 8,494 controls; national registry study The odds ratios for the association between topiramate

use and cleft palate was 3.6 (95% CI, 0.7–20.0) in the

National Birth Defects Prevention Study

Weston et al., 2016 359 topiramate exposed cases, 442 untreated healthy controls; Topiramate exposed infants were at an increased risk of

literature meta-analysis malformations compared with children born to women

without epilepsy (N 5 359 vs 442; RR, 3.69; 95% CI,

1.36–10.07)

Bromley et al., 2016 27 cases, 55 controls; cross-sectional neurodevelopmental Prenatal exposure to topiramate was not associated with

observational study reductions in child cognitive abilities

topiramate exposure during pregnancy, compared with
only 2% for lamotrigine, with a RR of 2.2 (95% CI, 1.2–
4.0) (Hernandez-Diaz et al., 2012).
Weston et al. (2016) found in their meta-analysis that
children exposed prenatally to topiramate were at an
increased risk of malformations compared with children
born to women without epilepsy (N 5 359 vs. 442; RR,
3.69; 95% CI, 1.36–10.07), but not when compared with
children of women with untreated epilepsy (N 5 668). They
were also at a higher risk of malformations in comparison to
children exposed to levetiracetam (N 5 473 vs. 817; RR,
2.00; 95% CI, 1.03–3.85) or lamotrigine (N 5 473 vs. 3975;
RR, 1.79; 95% CI, 1.06–2.94) (Weston et al., 2016).
Several studies reported a
Topiramate and oral clefts (Table 9).
possible association between first trimester intrauterine
exposure to topiramate and oral clefts. The RR ranged
from 2.5 to 6.26.
Morrow et al. (2006) reported that in the United
Kingdom epilepsy and pregnancy register of 35
topiramate-exposed pregnancies prospectively ascertained,
there were 28 livebirths, with 2 major congenital
anomalies (7.1%). One of these infants had cleft lip and
palate and 1 had hypospadias (Morrow et al., 2006).
Hunt et al. (2006) found three major congenital mal-
formations among 70 infants exposed to topiramate mono-
therapy (4.8%; 95% CI, 1.7%–13.3%) and 13 in cases
exposed to topiramate as part of a polytherapy regimen
(11.2%; 95% CI, 6.7%–18.2%). Four of them were oral
clefts (2.2%; 95% CI, 0.9%–5.6%), with three infants hav-
ing both cleft lip and cleft palate (Hunt et al., 2008).
Margulis et al. (2012) used data from two large con-
genital malformations case–control studies in North Amer-
ica: The Slone Epidemiology Center Birth Defects Study,
with 785 cleft palate cases and 6986 controls, and the
National Birth Defects Prevention Study that had 2283
cleft palate cases and 8494 controls. They reported that
following topiramate treatment, the ORs for cleft palate
were 10.1 (95% CI, 1.1–129.2) and 3.6 (0.7–20.0), respec-
tively. In the pooled data, the OR was 5.4 (95% CI, 1.5–
20.1) (Margulis et al., 2012).
Taken together, most studies suggest that first-trimester
topiramate exposure is associated with an elevated risk of
major congenital anomalies, especially of oral clefts.
BIRTH DEFECTS RESEARCH 109:933–956 (2017)
TABLE 10. Summary of Studies on the Effects of Levetiracetam in Pregnancy
Author & year No. of cases and study design
Hunt et al., 2006 39 levetiracetam monotheraphy cases; prospective study
Hernandez-Diaz 450 levetiracetam cases, 442 controls; prospective study
et al., 2012
Mawhinney et al., 2013 304 levetiracetam monotheraphy cases; prospective
study
Shallcross et al., 2014 53 cases, 131 controls; observational prospective neuro-
developmental study
Bromley et al., 2016 42 cases, 55 controls; neurodevelopmental observational
study
NEURODEVELOPMENTAL OUTCOME
Developmental effects of topiramate have been assessed
only in two studies. In a small preliminary study, Rihtman
et al. (2012) compared between the developmental out-
comes of nine children of preschool age (3–6 years, 11
months) exposed in utero to topiramate monotherapy to
18 sex- and age-matched controls. They reported that the
topiramate-exposed children had lower IQ scores across
several domains, as well as poorer motor and visual spa-
tial skills. Over half of the exposed children received
speech, occupational, or physical therapy (Rihtman et al.,
2012). In a recently published study, Bromley et al. (2016)
compared the cognitive functioning of children exposed to
levetiracetam (n 5 42), topiramate (n 5 27), or valproate
(n 5 47), and control children (n 5 55). They reported no
association between the IQ, memory, language, or atten-
tional abilities, and prenatal exposure to levetiracetam or
topiramate, although the children born to VPA-treated
mothers had developmental delays (Bromley et al., 2016).
In summary, topiramate appears to be teratogenic,
especially increasing the rate of oral clefts. The data on
the long-term neurodevelopmental outcome are contradic-
tory and inadequate. Hence, if possible, topiramate should
not be used as a mood stabilizer in women of child-
bearing age.
LEVETIRACETAM
Levetiracetam, marketed under the trade name Keppra, is
licensed as adjunctive therapy in the treatment of partial
onset seizures with or without secondary generalization.
Recently, it is also used in some countries as a mood stabi-
lizer, and this indication might increase its use in women
of child-bearing age. Most studies published in English on
the possible effects of this agent in pregnancy seem to be
reassuring.
Congenital malformations (Table 10). Hunt et al. (2006) collected
outcomes data from the U.K. Epilepsy and Pregnancy
Register through July 31, 2005. They detected no major
951
Fetal outcome
No major congenital malformations
11 levetiracetam exposed infants (2.4%) had major
malformations; no increased rate
2 major congenital malformations (OR, 0.70%;
95% CI, 0.19%–2.51%)
Levetiracetam exposed did not differ from controls
on any behavioral scale at 3 years of age
Prenatal exposure to levetiracetam was not associ-
ated with reductions in cognitive abilities
congenital malformations among 39 pregnancies that had
been exposed to levetiracetam monotherapy, and three
major congenital malformations among 78 pregnancies
exposed to levetiracetam as part of AEDs polytherapy
(2.7%; 95% CI, 0.9% to 7.7%) (Hunt et al., 2006).
In a larger prospective study based on data from the
North American AED Pregnancy Registry between 1997
and 2011, Hernandez-Diaz et al. (2012) found 11 major
congenital malformations among 450 children exposed to
levetiracetam monotherapy during pregnancy; a risk of
2.4% (95% CI, 1.2–4.3) (Hernandez-Diaz et al., 2012).
Mawhinney et al. (2013) examined the safety of first-
trimester exposures to levetiracetam also, using data from
the U.K. and Ireland Epilepsy and Pregnancy Registers.
They detected 2 major congenital malformations among
304 pregnancies that had been exposed to levetiracetam
monotherapy (0.70%; 95% CI, 0.19%–2.51%), and 19
when levetiracetam was taken as part of a polytherapy
regimen (6.47%; 95% CI, 4.31%–9.60%), confirming that
there is no additional risk for malformations with levetira-
cetam monotherapy (Mawhinney et al., 2013).
Taken together, these data suggest that levetiracetam
as monotherapy can be considered a safer alternative to
other AEDs for women with epilepsy of child-bearing age.
Development outcome. Shallcross et al. (2014) compared the
cognitive and language development of children exposed
in utero to levetiracetam (N 5 53) or VPA (N 5 44) and
control children (N 5 131), aged between 36 and 54
months. They found no difference between the develop-
mental scores of levetiracetam prenatally exposed children
and controls, while VPA-exposed children scored, on
average, 15.8 points below that of children exposed to lev-
etiracetam on measures of gross motor skills (95% CI,
24.5–27.1; p < 0.001), 6.4 points below on comprehen-
sion language abilities (95% CI, 11.0–21.8; p 5 0.005),
and 9.5 points below on expressive language abilities
(95% CI, 14.7–24.4; p < 0.001) (Shallcross et al., 2014).
Bromley et al. (2016) also found that 42 children born to
952 ANTIDEPRESSANTS, ANTIPSYCHOTICS, AND MOOD STABILIZERS IN PREGNANCY
levetiracetam treated mothers had similar developmental
scores to 55 control children (Bromley et al., 2016).
In summary, levetiracetam seems to be a relatively safe
drug in pregnancy. It did not increase the rate of major
congenital anomalies in the offspring and did not induce
significant neurodevelopmental problems.
General Conclusions
Managing depression and other comorbidities during pregnancy
is important. The need to balance between maternal well-being
and the risk of adverse fetal outcome due to drug exposure
needs to rely on evidence-based medicine that will show the
risk difference between medications. It seems that TCAs, anti-
psychotics, and atypical antidepressants do not carry increased
risk of congenital anomalies or other significant pregnancy com-
plications. However, the long-term neurodevelopmental and
psychiatric outcome following the treatment with antidepres-
sants and antipsychotics is still not completely known.
Although most studies did not demonstrate neurodeve-
lopmental damage, we should remember that they were
mostly carried out on young children, at a time when the
effects on attention span, learning abilities, and behavior
cannot be assessed fully. We are also lacking sufficient
data on the impact of multiple drugs use and the possible
interaction with genetic and environmental factors. In
addition, it is strongly advisable that whenever the adjunct
use of mood stabilizers is needed during child-bearing age,
one should not use VPA, carbamazepine, or topiramate but
rather use atypical neuroleptics such as quetiapine, lamo-
trigine, or lithium. If lithium is used, a fetal echocardiogra-
phy in the second trimester of pregnancy is recommended.
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