Prophylactic treatment of bipolar disorder in
pregnancy and breastfeeding: focus on
emerging mood stabilizers
There are some specific features of bipolar disor-
ders in women that set them apart from other
patient populations. The course of recurrences is
often severe, showing a high incidence of rapid-
cycling forms, mixed mania, and antidepressant-
induced mania (1, 2); comorbidities for other
psychiatric disorders and medical diseases such as
obesity, migraine, and thyroid dysfunctions are
also common (1, 3). Moreover, it is well-known
that prophylactic treatment with lithium is less
effective in these specific situations (4).
Women with bipolar disorders are typically in
their teens and early 20s at onset of the illness,
which places them at risk for episodes during the
childbearing age (5). The female reproductive cycle
also introduces multi-factorial complexities in the
treatment of the disease (6). In addition, because
Gentile S. Prophylactic treatment of bipolar disorder in pregnancy and
breastfeeding: focus on emerging mood stabilizers.
Bipolar Disord 2006: 8: 207–220. ª Blackwell Munksgaard, 2006
Objectives: Bipolar disorders are reported to have a high incidence
during childbearing years and the need may arise to start or continue a
pharmacological treatment during pregnancy and the postpartum
period. In the last few years several investigations have evaluated the
efficacy of emerging mood-stabilizing agents in the treatment of bipolar
disorders, such as lamotrigine, olanzapine, risperidone, quetiapine,
aripiprazole and ziprasidone. A number of studies, which examined the
use of oxcarbazepine, point to its potential usefulness in prophylactic
treatment. The aim of this review is to compare information from the
literature on the safety of lamotrigine, oxcarbazepine, risperidone,
olanzapine, and quetiapine to the safety data on classic mood stabilizers
during pregnancy and the postpartum period.
Methods: A computerized search carried out from 1980 to April 5,
2006 led to the summarization of the results. (References were updated
after acceptance and prior to publication.)
Results: Emerging mood stabilizers show uncertain safety parameters
in pregnancy and lactation. Limited information on lamotrigine and
oxcarbazepine does not suggest a clear increase in teratogenicity, while
olanzapine appears to be associated with a higher risk of metabolic
complications in pregnant women. Data about risperidone and
quetiapine are still inconclusive. Finally, the literature on the safety of
these compounds in breastfeeding is anecdotal.
Conclusions: Untreated pregnant bipolar women are at an increased
risk of poor obstetrical outcomes and relapse of affective symptoms. On
the other hand, classic antiepileptic drugs are well-known human
teratogens, whereas data on lithium are partially ambiguous. The safety
of emerging mood stabilizers in pregnancy and breastfeeding has not
been examined extensively. Therefore, when approaching bipolar
disorder, if possible, each episode must be considered separately.
Department of Mental Health ASL Salerno 1,
Operative Unit District n 4, Salerno, Italy
Key words: antiepileptic drugs – atypical
antipsychotics – bipolar disorder – breastfeeding
– mood stabilizers – pregnancy
for publication 9 December 2005
Corresponding author: Dr Salvatore Gentile,
Department of Mental Health ASL Salerno 1, Head
of Mental Health Center, Operative Unit District n. 4,
Piazza Galdi 84013 Cava de’ Tirreni (SA) Italy.
Fax: +39 089 4455440;
The author of this paper does not have any commercial associations
that might pose a conflict of interest in connection with this manu-
Bipolar Disorders 2006: 8: 207–220
Copyright ª Blackwell Munksgaard 2006
mood episodes have consequences that exceed their
own duration, the prevention of episodes is a
primary target of treatment (7). These factors
necessitate advancement in treatment opportuni-
ties for this group of women.
In the last few years, several investigations have
evaluated the safety and efficacy of different drugs
used for prophylactic treatment of bipolar disorder.
Lamotrigine and olanzapine have been approved
by the Food and Drug Administration for the
prophylactic treatment of bipolar disorder. Prelim-
inary data also suggests that lamotrigine may be
effective in rapid-cycling bipolar II disorder (8).
Quetiapine, risperidone, aripiprazole and ziprasi-
done have been approved for the acute mania phase
(9). A number of studies have also examined
oxcarbazepine, suggesting the potential efficacy of
the compound in preventing the recurrence of
episodes in bipolar patients (10–14).
pharmacological approach to the disease still poses
both clinical and ethical problems. Risks associated
use of new compounds are still limited.
The postpartum period is considered a relatively
high risk period for affective episodes in all women,
especially if affected by pre-existing psychiatric
illness (15). A total of 40–70% of untreated bipolar
women may experience postpartum mania or de-
pression (16), and postpartum mania is considered
to be the most common cause of postpartum
psychosis (17). The risk of postpartum relapse of
the disease is particularly high for those women
who elect to discontinue prophylactic treatment
(18). Nevertheless, at least 50% of postpartum
affective disorders start during pregnancy (19), and
mood changes in pregnancy represent one of the
most relevant risk factors for serious postpartum
problems (20). Despite the high prevalence of
affective disorders during pregnancy (between 6%
and 16%), few women are properly diagnosed (20).
In addition, pregnant women are often undertreat-
ed for fear of fetal malformations, although partial
and ineffective treatment presents a specific risk of
adverse outcomes of pregnancy (21–23).
Teratogenic risks associated with classic mood
Lithium in pregnancy. The incidence of major mal-
fetal life ranges from 4% to 12%, while the rate in
unexposed infants ranges from 2% to 4% (23). The
risk of Ebstein’s anomaly (20 times more common
with lithium) exists especially if the drug is taken
the anomaly. In a recent report, Kozma concludes
that the use of lithium during pregnancy was associ-
alies (25). Other types of lithium-related fetal and
floppy infant syndrome, transient neurodevelop-
mental deficits, nephrogenic diabetes insipidus,
thyroid dysfunctions, and rarely, polyhydramnios.
However, the frequency of these events remains
unknown (25–27). Recently, one case of lithium-
associated anencephaly was described (28). In
addition, higher lithium concentrations in maternal
serum at delivary have recently been associated
with increased risk of perinatal complications (29).
Lithium safety in breastfeeding. Not many reports
have described detrimental effects in newborns
whose mothers continued to take the compound
during the postpartum period; such effects include
lethargy, hypothermia, hypotonia, and T-wave
modifications on ECG (30–32). High concentra-
tions of the drug were reported in infant serum,
breast milk, and maternal serum, with ranges of
5–200% both in infant serum and breast milk, and
of 24–72% in maternal serum (24, 32–34).
Carbamazepine in pregnancy. Theoverall incidence
of CBZ-related fetal malformations is 5.7%. Fetal
malformations include microcephaly, other cranio-
facial skeletal defects, growth retardation, and
cardiac defects. An increased risk of coagulopathies
in infants was also reported (34). In addition, an
increased risk of spina bifida, ranging from 0.5% to
ofmajormalformations and developmental delay in
cases of prenatal exposure to CBZ (craniofacial
anomalies: 11%; fingernail hypoplasia: 26%; devel-
opmental retardation: 20%) (36). The association
between neural tube defects, cardiovascular and
urinary tract anomalies, and cleft palate in neonates
exposed to the compound through the placenta is
in a recent observational study the rate of fetal
malformations in infants exposed in utero to the
compound has been estimated at 2.2% (38).
Carbamazepine safety in breastfeeding. CBZ con-
centrations range from 7% to 95% in breast milk
and from 6% to 65% in infant serum (33).
Nonetheless, there is only one case report describ-
ing minor adverse effects (poor suckling) in
newborns exposed to CBZ via breast milk (39).
Carbamazepine is metabolized rapidly in new-
borns, which may explain a relatively low risk of
adverse effects (40).
Valproate in pregnancy. VPA utilization in preg-
nant women confers an approximately fivefold
increased risk of major malformations and other
serious pregnancy complications, especially if the
compound is administered in the first trimester of
pregnancy (41, 42). The overall incidence of major
malformations is 11% (34). Sometimes associated
risks include spina bifida (1–2%, which is 50 times
the spontaneous rate) and developmental retarda-
tion (up to 71%) (43–45), although cumulative
environmental factors may partly explain the
increased prevalence in determining neurocognitive
symptoms which cannot be excluded (46). Other
risks are represented by skeletal malformations and
cardiovascular abnormalities (47, 48). Coagulopa-
thies, neonatal hypoglycemia, and hepatotoxicity
have also been reported (49, 50).
A specific malformation pattern has been pro-
posed (51, 52), ?fetal valproate syndrome?, consist-
ing of heart defects and withdrawal syndrome
(irritability, jitteriness, hypotonia, and difficulty
eating) (53). Vajda & Eadie and Morrow et al.
found that the rate of major malformations in
fetuses exposed to valproate alone or in combina-
tion with other epileptic drugs ranges between
15.2% and 17.1%, and between 6.2% and 9.0%,
respectively. In addition, the authors also found
that valproate doses higher than 1000–1400 mg/
day were associated with an even greater increase
in malformation rate and a peculiar pattern of
anomalies (38, 54).
Valproate safety in breastfeeding. VPA concentra-
tions range from less than 1% to 10% in breast
milk and infant serum, and from undetectable
levels to 40% in maternal serum (33, 53). Throm-
bocytopenic purpura and anemia were attributed
to valproate exposure through placenta and breast
Aim of the study
The aim of this review was to analyze and
summarize the available literature regarding the
safety of mood stabilizers in pregnancy and
breastfeeding, especially the newer agents that
have been recently approved or are currently being
considered for the treatment of bipolar disorder.
The drugs were analyzed along the following
4 parameters: major/minor malformations, rate of
spontaneous abortion, neonatal complications,
and impact on later neurodevelopmental outcome.
A computerized search was carried out on
Medline/PubMed/TOXNET covering the period
between 1980 and April 5, 2006. The following key
words were used: pregnancy, lactation, breastfeed-
ing, psychotropic drugs, mood stabilizers, antiep-
ileptic drugs (AEDs), anticonvulsants, atypical
antipsychotics, lamotrigine, oxcarbazepine, olanza-
pine, quetiapine, risperidone, aripiprazole and
ziprasidone. Resulting articles were cross-refer-
enced for other relevant articles not identified in
the initial search. Comprehensive reviews about the
safety of valproate, carbamazepine, and lithium
during pregnancy and lactation were also analyzed.
Lamotrigine (LTG). Lamotrigine in pregnancy: It
is well-known that infants born to epileptic women
not exposed to AEDs present an increased risk of
Lamotrigine Pregnancy Registry, mainly focusing
on epileptic women, was initiated in 1992 toidentify
any additional risks of drug-related birth defects
(57, 58). Data from the registry show that major
birth defects can be observed in 2.9% of pregnant
women exposed toLTG
Morrow estimated this percentage at 2.1–3.2%
(38, 60), while Vajda reported it to be 7.7% (61).
However, the percentage substantially decreased
(to 0–2.4%) in the most recent updates of the
Australian Registry of Antiepileptic Drugs (see
Table 1) (54, 62). In contrast, the percentage
reaches values in the range of 10–15.2% in cases
of polytherapy involving VPA. The observed pro-
portion of major defects after LTG polytherapy
without VPA during the first trimester varies from
2.4% to 4.3% (54, 60, 61, 63). In any case, no
specific patterns of abnormalities in any subgroups
or within the registry as a whole were observed
(Table 1). The Swedish Medical Birth Registry
showed analogous results (Table 1) (64). However,
LTG was associated with increased risks of poor
neonatal adaptation and thrombocytopenia (60).
In the same study, one case of major malformation
was reported (Table 1).
Mood stabilizers in pregnancy
Sabers et al. prospectively identified 51 epileptic
women exposed to LTG monotherapy during the
first trimester of pregnancy (Table 1) (65). No
major malformations were recorded in the infants;
one minor malformation (a small defect of the left
auricle) was observed but it was not regarded as
significant. However, a correlation between LTG-
dose greater than 200 mg/day and increased risk of
major malformations has been recently suggested
(38). Only one report analyzed the safety of
lamotrigine for bipolar pregnant women; of the
two pregnancies examined, one resulted in the birth
of a healthy infant and the other was electively
terminated (66, 67).
Three recent studies reported decrease in LTG
levels (from 60% to 65%) between preconception
and the second and third trimester of pregnancy in
35 epileptic women; 11 pregnancies required a
higher dose of LTG to maintain a therapeutic
effect (68–70). An increase in LTG levels was
observed in the last two trimesters; in the postpar-
tum period, LTG levels returned to the precon-
Table 1. Major malformations following prenatal exposure to lamotrigine
other AEDs Presence and type of major malformations
Tennis et al. (57) 168No One case of esophageal malformation, surgically repaired
One case of cleft soft palate
One case of club foot
One case of one extra digit on hand
One case of bilateral talipes, one of atrial septal defect,
one of pulmonary stenosis, one of multiple congenital anomaliesa
One case of heart murmur plus patent foramen ovale
One case of skin tags on ear and absence of auditory canal
One case of lumbar neural tube defect
One case of patent ductus arteriosis plus atrial septal defect
One case of muscle aplasia of the lower lip and asymmetrical abduction of the hips
One case of spina bifida plus hydrocephalus, one of ventricular septal defect
plus plagiocephaly, bronchial narrowing and hypospadias, one of facial
bone anomalies plus hypospadias
PHT-Diazepam One case of plagiocephaly
NoCardiac, neural tube defects, genitourinary and gastrointestinal tract anomalies.
Incidence not specified
OXC One case of ventricular septal defect
No Five cases of malformations (four severe and one not severe), no further
No One case of hydronephrosis with megaureter
No One case of anencephaly
No One case of anus atresia
No One case of ventricular septal defect
No One case of hydronephrosis with oligohydramnios
NoOne case of subpulmunal muscular ventricular septal defect and persistent
No One case of bilateral club feet
No One case of absent right kidney
NoOne case of great vessels-transposition and ventricular septal defect
NoOne case of myelomeningocele and patent foramen ovale and ductus arteriosus
VPAOne case of: pulmonary stenosis; pylorostenosis; ventricular septum defect;
cleft hard palate; meningomyelocele plus limbs deformities; microcephaly plus
abnormal posterior fossa, bony abnormality, encephalocele, Chiari II malformation,
hindbrain herniation, and retrognatia; great vessels-transposition
N/A Cumulative monotherapy malformation-rate: 2.4%
No One case of neural tube defect, one of facial cleft, four cases of cardiac defects,
six cases of hypospadias/genitourinary tract defects, three cases of
gastrointestinal tract defects, two cases of skeletal defects, four cases of
unspecified major malformations
Tennis et al. (57)166CBZ
PHE plus PRI
Cissoko et al. (63)
Vajda et al. (61)
Sabers et al. (65)
Wide et al. (64)
Cunnington et al. (59) 684b
Vajda & Eadie (54)
Morrow et al. (38)
AEDs ¼ antiepileptic drugs; CBZ ¼ carbamazepine; VPA ¼ valproate; PHE ¼ phenytoin; PRI ¼ primidone; GBP ¼ gabapentin;
OXC ¼ oxcarbazepine; PHT ¼ phenobarbital.
aCleft palate, hypertelorism, broad nasal bridge, transverse palmar creases, short proximal thumbs, and supraumbilical hernia.
bThis sample size includes the 334 patients previously enrolled by Tennis et al. (2002).
N/A: data not available.
ception values and LTG dose needed to be
reduced. Some women also showed toxic effects
after delivery (69).
Lamotrigine safety during breastfeeding: Six stud-
ies evaluated the neonatal consequences of LTG
exposure throughout breastfeeding (71–76). The
mean milk/plasma ratio was 0.6 (range: 0.35–0.65).
A considerable amount of LTG (2–5 mg/day) is
excreted in breast milk; the drug-levels in infant
serum actually range from 23% to 33% of mater-
nal levels. Nonetheless, no unusual events were
observed in the newborns, although in some cases
LTG concentration in breastfed children reaches
?therapeutic ranges? (75).
Oxcarbazepine (OXC). Oxcarbazepine in preg-
nancy: Oxcarbazepine produces no epoxide me-
tabolites and thus, it may be less teratogenic than
carbamazepine. However, no studies have been
performed to confirm this hypothesis (5). OXC
crosses the placenta in significant amounts; the
placenta is also to some extent capable of metabo-
lizing the medication into its major metabolite,
10-OH-carbazepine (77). Concentrations of OXC
have been found to be similar in placental tissue
and in maternal and cord serum. However, the
compound was associated with no significant
accumulation in the placental tissue in vivo. In
pregnant epileptic women, available teratogenic
information (summarized in Table 2) is reassuring
(64, 69, 78–87). Nevertheless, the following peri-
natal complications were reported after exposure
to OXC monotherapy (88, 89):
1. three spontaneous abortions;
2. one neonate with amniotic bands (no more
specific details available);
3. one case of urogenital anomalies.
epileptic mother took 300 mg three times a day
of OXC monotherapy throughout the pregnancy
showed mild facial dysmorphism, with a dis-
crete epicanthus and a somewhat broad bridge of
the nose, but no typical signs of embriopathy
Oxcarbazepine safety during breastfeeding: In the
same study, the milk/plasma ratio of OXC and
10-OH-carbazepine was 0.5 (90). From day 3 after
delivery, the child was also exposed to OXC
throughout breastfeeding. No adverse effects were
noted in a short-term follow-up; the baby’s re-
examination at age 13 months showed normal
development, with no sign of mental retardation
or neurological deficit. A second infant whose
epileptic mother was on 600 mg two times a day of
OXC during pregnancy and breastfeeding showed
Table 2. Major malformations following prenatal exposure to oxcarbazepine
to other AEDs Presence and type of major malformations
Retrospective Study, 1993
Lindhout & Omtzigt (79)
12 Data not availableNo
11Data not available
Yes, not specified
Yes, unspecified (not VPA)
Yes, (spina bifida)a
One case of congenital hydronephrosis
One positive outcome and one case of heart malformation
One case of minor oro-facial cleft malformationb
One case of ventricular septal defect
One case of cardiac defect
Nine cases of malformations (no more details available)
One case of urogenital anomalies
One case of unspecified major malformation
One case of unspecified major malformation
6 Fonager et al. (87)
Epilepsy Pregnancy Register,
Buenos Aires, 2002
Je ˛drejczac & Greese-Lyko (86)
Peltola et al. (82)
Isojarvi et al. (81)16
Sabers et al. (65)
Meischenguiser et al. (89)
Novartis Safety Database, 2004
Wide et al. (64)
Artama et al. (89)
AEDs ¼ antiepileptic drugs; VPA ¼ valproate
aDaily dose of oxcarbazepine: 3000 mg.
bThe mother had mild mental retardation, which is associated with an increased risk of developmental anomalies.
cThis sample size may overlap with the cohort of a previous study (Kaaja, 2003).
Mood stabilizers in pregnancy
a normal evolution during the first 12 months of
life (91, 92).
Aripiprazole and Ziprasidone. There was no data
on humans available for ziprasidone, however,
there was one case report recently published which
indicated no adverse events in a woman exposed to
aripiprazole in the pregnancy.1
Risperidone. Risperidone in pregnancy: Approxi-
mately 300 cases of pregnancies exposed to risperi-
done have been reported; in most the outcomes
remain unknown. Eight cases of major malforma-
tions (with no recurrent patterns of anomalies) have
been described (93). Two other fetuses exposed
in utero to maternal daily doses of 4 and 6 mg/day,
respectively, showed normal neurodevelopment
during the first year of life (94). Johnson & Johnson
is currently preparing a manuscript summarizing
their postmarketing surveillance data on the use of
risperidone during pregnancy (Manuela Colombi,
Pharmacovigilance Information Service, Janssen–
Cilag SpA, Italy, written communication).
Risperidone safety during breastfeeding: Hill et al.
(95) calculated risperidone and its active metabolite
milk/plasma ratios, and the estimated infant dose
exposure during breastfeeding (Table 2); however,
this value was well below the attention critical level
of many medications during lactation. To determine
the amount of risperidone and its active metabolite
transferred into breast milk (Table 2), Ilett et al. re-
cation. Two patients breastfed their babies, whereas
the third mother experienced risperidone-induced
galactorrhea. The drug and its metabolite were not
detected in the plasma of the two breastfed infants,
and no adverse effects were noted (96). By contrast,
risperidone and 9-OH-risperidone were detected in
another infant whose mother took the compound
while breastfeeding and drug-levels in breast milk
were 10-fold lower than maternal serum levels (97).
Olanzapine (OLA). Olanzapine in pregnancy: Sev-
eral descriptions of healthy infants born without
complications despite intrauterine exposure to olan-
zapine are available (98–102). The Lilly Worldwide
Pharmacovigilance Safety Database and its more
recent expansions (41, 103, 104) included a total of
144 prospectively and 98 retrospectively identified
pregnant women treated with olanzapine (range of
maternal daily dosage: 5–25 mg). The rates of
spontaneous abortions (8.3%), stillbirths (2.1%),
pre- and postnatal complications (9.0%), and pre-
maturity (4.2%) were within the range of normal
recorded control rates (104–107). Data are also
available regarding the outcome of 60 additional
pregnancies exposed to the medication (93). This
study supports the hypothesis that OLA, as well as
other atypical antipsychotics, is not associated with
increased rates of major structural malformations
may interfere with human embryonic development.2
However, OLA appears to be associated with higher
risk of lower birth weight and perinatal and gesta-
tional metabolic complications, as Table 3 shows
(41, 93, 101, 108–110).
Olanzapine safety during breastfeeding: Thirty
infants subjected to OLA have been evaluated,
the majority of whom were exposed in utero to the
compound (37, 104, 108, 111–113). Five (16.7%)
showed adverse effects, which included cardiac
problems, jaundice, lethargy, poor suckling, shak-
ing, sleep disturbances, rash, gastrointestinal and
extrapyramidal symptoms, and transient neurode-
velopmental delay. OLA appears to be excreted
into breast-milk in relatively small amounts (112);
the milk/plasma ratio ranges from 0.1 to 0.84 and
the relative infant dose from 0.22% to 2.5% (based
on the weight-adjusted maternal daily dosage), at
maternal day dosages of 5–25 mg (114, 115).
Quetiapine (QUE). Quetiapine in pregnancy: To
date, 487 reports have examined prenatal exposure
to QUE at maternal daily doses ranging from 50 to
600 mg; eight cases of congenital anomalies have
been described (93, 116–120).
Quetiapine safety in breastfeeding: Recently, the
amount of QUE ingested by an exclusively breast-
fed infant whose mother took 200 mg/day of the
compound was estimated to be between 0.09% and
0.43% of the weight-adjusted maternal dose. This
study also concludes that the level of infant
exposure to QUE in breast milk appears to be low
for significant drug-related effects (121). In addi-
tion, a 24-year-old woman with bipolar disorder
who had been treated with 25–50 mg/day of QUE
throughout pregnancy had a normal delivery. She
breastfed her infant while continuing to take the
drug, and the baby showed no anomalies during
1Mendehekar DN, Sharma JB, Srilakshmi P. Use of
aripiprazole during late pregnancy in a woman with psy-
chotic illness. Ann Pharmacother 2006; 40:575.
2Arora M, Praharaj SK. Meningocele and ankyloblepharon
following in utero exposure to olanzapine. Eur Psychiatry
2006, in press.
the first 6 weeks of life (116). A recent report also
suggested the safety of paroxetine-quetiapine asso-
ciation (20 and 200 mg/day, respectively) for the
nursing infant. The mother was diagnosed with
bipolar disorder type I at post partum onset,
moderate severity-mixed mood state (122). Another
woman treated with quetiapine–fluvoxamine com-
pound while pregnant and also while breastfeeding
experienced neither gestational complications nor
was her baby adversely effected (123).
Women with epilepsy have been reported to have a
generic risk of birth defects ranging from 2.5% to
9%, (54, 56) but it is not known whether (as in
schizophrenic patients) the risk of fetal anomalies is
higher in bipolar women than in the normal popu-
lation (124). There is still controversy over the
finding that the rates of both neonatal mortality
and delivery complications are higher in mentally ill
mothers (125–128). Jablensky et al. recently report-
to experience placental anomalies and antepartum
hemorrhages (129). Nonetheless, these results
should be evaluated with great caution, since infor-
mation about exposure during pregnancy to both
the duration of the exposure, was not available.
However, a growing body of evidence suggests that
women’s mental health in pregnancy significantly
influences both fetal development and infant birth
outcomes (22). In any case, the risk of fetal and
neonatal injury could be more frequent in women
illness presentations, such as comorbid alcohol
abuse (130), pose frequent obstacles to a correct
pregnancy management and careful infant care.
Lithium. Lithium-related teratogenecity may have
been overestimated in the past (5, 25). There are
diverse opinions on lithium utilization in preg-
nancy. Cohen et al. suggested the maintenance of
lithium treatment for bipolar women with severe
forms of the disease, since the potential lithium-
related teratogenecity in these cases is outweighed
by the risks deriving from drug discontinuation
and disease relapse (23). Williams & Oke recom-
mended the following treatment plan: (a) stop
lithium prior to conception, (b) restart the com-
pound during trimester 2 or 3, (c) discontinue
lithium prenatally, and (d) restore the treatment
postnatally (131). In any case, fetal cardiac
ultrasonography is recommended at weeks 18 and
Table 3. Fetal anomalies, perinatal complications, and gestational detrimental events following maternal olanzapine and quetiapine treatment
Number of cases
Goldstein et al. (103) ⁄ OLA
One case of unilateral dysplastic kidney, one case of
One case of sudden infant death at 2 months
Two cases of gestational diabetes
Kirchheiner et al. (108) ⁄ OLA
One case of gestational diabetes
Littrel et al. (109) ⁄ OLA
One case of gestational diabetes
Ernst & Goldberg (41) ⁄ OLA
One case of major fetal malformation (not further specified)
Friedman & Rosenthal (110) ⁄OLA
One case of Erb’s palsy (infant large for
McKenna et al. (93) ⁄OLA
One case of multiple anomalies, including cleft lip, encephalocele,
and aqueductal stenosis
No statistical difference with comparison group
in the rates of perinatal complications
Eli Lilly, data on file
One case of bilateral talipes
One case of spontaneous abortion of a fetus severely deformeda
One case of pretragus fibrochondromab
One case of additional thumb digitc
One case of clubfootOne case of right dilated kidney pelvisd
McKenna et al. (93) ⁄QUE
No statistical difference with comparison
group in the rates of perinatal complications
Arora & Praharaj ⁄OLAf
One case of meningocele plus ankyloblepharon
a–dThe mothers also used cannabis, alcohol, nicotine, and ecstasy in case a, clorazepate in case b, paroxetine plus temazepam in case c, and valproate in case d.
eDespite a formal request, the documentation received by AstraZeneca Italia SpA did not specify the kind of the recorded malformations.
fEur Psychiatry 2006, in press.
OLA ¼ olanzapine; QUE ¼ quetiapine.
Mood stabilizers in pregnancy
20 of gestation when the maternal clinical condi-
tions require lithium therapy (132). The increase of
renal lithium excretion during pregnancy may
require an increase of the lithium dosage, whereas
it has been suggested that the drug-dosage should
be decreased at the beginning of labor, in order to
reduce the risk of toxicity related to the abrupt
reduction of vascular volume after parturition
(133). In case of prolonged labor, adequate hydra-
tion of the mother should also be maintained (5). A
comprehensive summary of the concerns regarding
the clinical utilization of lithium in pregnancy is
available in a recent review by Yonkers et al. (5).
Classic anticonvulsants. Classic AEDs are well-
known human teratogenic
Valproic acid and carbamazepine are associated
with an increased risk of neural tube defects
because of their folate antagonist property, and
should be avoided by women with a family history
of spina bifida. There is probably a greater increase
of risk associated with valproate than carbamaze-
pine (136). Polytherapy also increases the risk of
teratogenicity, especially when valproate is admin-
istered in combination with carbamazepine (137).
Very recently, it has been suggested that the
mechanism by which valproate induces birth
defects is related to its process of histone deacetyl-
ase inhibition (138). Thus, if valproate or carba-
patients during their childbearing years, folate
supplementation (4–5 mg/day) before conception
andduring the firstmonths ofpregnancyis required
(24). Nonetheless, definitive evidence that folate
supplements administered to women taking AEDs
during pregnancy reduces the risks for neural tube
defects is still lacking (139). Moreover, it has been
demonstrated that intrauterine exposure to valpro-
ate is associated with potential risks for develop-
mental delay (such as lower verbal IQ) and
cognitive impairment later in life (45, 140).
Enzyme-inducing AEDs are also associated with
a greater risk of neonatal bleeding: carbamazepine
shows the highest degree of hepatic enzyme-
inducing activity (141). The mechanism by which
enzyme-inducing AEDs may cause bleeding in
newborns involves alterations in vitamin K metab-
olism (142). A number of studies actually advise
the use of maternal vitamin K supplementation
(10 mg/day orally) during the last month of
pregnancy (143), and that the newborn receive
1 mg of vitamin K intravenously or intramuscu-
larly on day 1 after delivery, regardless of maternal
AED exposure (137). However, in a large prospec-
tive study of 662 pregnancies in women with
epilepsy who used enzyme-inducing AEDs, Kaaja
et al. concluded that the risk of neonatal bleeding is
essentially associated with other conditions known
to increase this risk, such as prematurity, traumatic
delivery, sepsis, fetal alcohol syndrome, and intra-
uterine asphyxia (143).
Emerging mood stabilizers in pregnancy
There are many relevant issues surrounding the
treatment of bipolar disorder during pregnancy.
While there are several clinical observations in the
literature, information concerning the safety of
specific treatments for bipolar disorder in pregnant
women is still lacking.
Antiepileptic drugs. The vast majority of the exist-
ing data comes from the neurology literature
regarding epileptic patients (144, 145). To date,
antiepileptic drugs have proved to have uncertain
safety parameters, as limited studies have indicated
extensive transplacental transfer of the newer
AEDs (146). Nonetheless, neither lamotrigine nor
oxcarbazepine seem to pose a greater generic
teratogenic risk in epileptic pregnant women (56,
147), but this information is partial, especially with
regard to OXC. Oxcarbazepine also shows a degree
of hepatic enzyme-inducing activity (137); thus, its
use during pregnancy may require maternal vita-
min K supplementation, in order to reduce the risk
of neonatal bleeding. Moreover, clinicians must be
aware that the maternal daily LTG dose should be
kept under the threshold of 200 mg in order to
reduce an increase of teratogenic risks. In any case,
studies are urgently needed to investigate the
effects of AEDs on postnatal intellectual develop-
Atypical antipsychotics. The case-registry for OLA
is larger than that of other atypical antipsychotics
(149). However, olanzapine has been associated
with a higher risk of metabolic complications in
pregnant women, including weight gain and glucose
intolerance. Maternal diabetes during pregnancy
places the developing infant at a higher risk of
perinatal mortality, prematurity, congenital abnor-
malities, macrosomia, as well as of developing
diabetes in the future (111). Recently, gestational
glucose intolerance also has been associated with
long-term increased risk of maternal malignant
neoplasm, and particularly malignant neoplasm of
the breast (150). Data regarding risperidone and
quetiapine are inconclusive. In addition, women
taking atypical antipsychotics may present addi-
tional risks of lower birth weight and neural tube
defects in their babies because of associated low
intake of folate and obesity (107, 151).
Lithium and classic anticonvulsants. The American
Academy of Pediatrics (AAP) has stated that
?lithium has been associated with significant effects
on some nursing infants and should be given to
nursing mothers with caution? (152). The manage-
ment of mothers who need lithium-treatment
continuation in the puerperium and who wish to
continue breastfeeding, as well as the effects on the
infant, have been comprehensively summarized by
is made to breastfeed, vigilance against unwanted
hematological events in infants is required (153).
However, six infants born to bipolar mothers, for
whom exposure to the compound occurred exclu-
sively during breastfeeding, showed low valproate
serum levels (0.7–1.5 mcg/mL), thus presenting a
relatively low risk compared to the risk of maternal
disease relapse (154). Valproate is considered com-
patible with breastfeeding by the AAP (152).
Caution is also advised when mothers take CBZ
and breastfeed their babies, since there is little
information on carbamazepine-related toxicity for
suckling infants (151). Maternal CBZ intake is
considered compatible with breastfeeding by the
AAP (152). The milk/plasma ratio of most of the
reviewed drugs is well below the critical attention
levels of many medications taken during lactation.
It is recommended that for safe breastfeeding the
ratio of infant dose exposure to maternal dose not
be greater than 10% (155).
Emerging mood stabilizers. Owing to the scant
information found in the literature, breastfeeding is
not recommended for women taking new mood
stabilizing agents, in particular because of the
safety evaluation of these drugs for suckling infants
is derived from only a few anecdotal reports. If
women who take LTG continue to breastfeed, then
their infants should be closely monitored for
possible adverse effects, such as sedation, poor
suckling, and life-threatening rashes (33, 156).
Severe mental and cognitive impairment due to
maternal psychiatric disease increases the risks of
infanticide and suicide (157); therefore, the discon-
tinuation of pharmacological treatment may not
always be the best option for pregnant and
breastfeeding women (158).
evidence-based conclusions for selecting specific
classic or emerging AEDs for women with child-
clinical utilization of mood stabilizers in the context
of these conditions a balanced judgment should be
made by taking into account: (a) the risk of terato-
genesis and deprivation of maternal milk for the
infants and (b) the necessity of an adequate treat-
There is growing evidence ofgender differences in
several clinical features of bipolar disorder that is
relevant to pharmacological management (160).
Prophylactic treatment of women with bipolar
disorders may be indicated when the benefits of
mood stabilization outweigh the risks of unwanted
however, some major precautions should be taken
such as strictly avoiding polypharmacotherapy
(161), utilizing the lowest possible dose, and care-
fully monitoring the progression of pregnancy and
history suggests the option of using a mood stabi-
lizer during pregnancy then the first choice should
be LTG since the teratogenic safety of LTG-
monotherapy derives from more than 2000 reports.
Conversely, the combination of valproate sodium
and lamotrigine is particularly teratogenic (162).
One must also consider the lithium-related terato-
events, such as significantly low Apgar scores,
longer hospital stays and higher rates of CNS and
neuromuscular complications (29). By contrast,
when the global evaluation of a woman suggests
that the management of disease in pregnancy and
breastfeeding can lie in treating each episode sepa-
rately, a drug should be selected in accordance with
careful consideration of its safety/efficacy profile.
• Manic episodes: Manic episodes may be treated
with typical antipsychotics (136, 163), although
these compounds have been associated with the
onset of extrapyramidal signs in babies at birth
(164). Chlorpromazine and haloperidol have
been studied during pregnancy, but only in
relation to treating hyperemesis gravidarum
in schizophrenia, but not in bipolar disorder.
Information emerging from a number of the
studies seems to indicate that the underlying
illness, rather than the conventional neurolep-
tics, may slightly increase the rate of anomalies
seen during exposure to these medications (165–
168). In fact, a recent study suggests that the
exposure in utero to haloperidol does not present
a major teratogenic risk (169). At present,
risperidone, olanzapine, and quetiapine are not
proven to offer evident advantages during preg-
nancy and the postpartum period when com-
pared with typical neuroleptic agents (170).
Mood stabilizers in pregnancy
• Moderate depressive episodes: Moderate depres-
sive episodes may be managed with cognitive–
behavioral therapy or interpersonal psychother-
apy (171, 172).
• Severe depressive episodes: In the general psy-
chiatric population the APA guidelines favor
beginning maintenance-treatment for bipolar
depression with lithium monotherapy, and
lamotrigine is considered to be an alternative
first-line agent (173). While less evidence-based,
the APA also acknowledges that combination
therapy (with lithium plus an antidepressant) is
appropriate in some circumstances. If possible,
combination therapy should be avoided in
pregnant or breastfeeding women. In cases
of severe depressive episodes where specific
antidepressant-effect is deemed appropriate,
SSRI-monotherapy should be preferred. More-
over, most of these agents seem to be devoid of
structural teratogenic risk (174, 175). By con-
trast, the use of paroxetine during pregnancy
has recently been associated with increased risk
of fetal cardiovascular malformations, espe-
cially ventricular septal defects (176). Although
SSRIs induce significantly fewer cases of mania
or hypomania than tricyclic antidepressants do
(177), SSRI-utilization in pregnancy has also
been associated with increased risk of sponta-
neous abortion. In addition, an increased risk
for perinatal adverse effects has been reported,
especially in cases of exposure during the third
gestational trimester (178–182). Electroconvul-
sive therapy (ECT) should be reserved for
hospitalized patients with severe delusional
depression or severe neurovegetative symptoms
of depression showing little or no response
Although devoid of teratogenic effects, there is
actually much less data on ECT than on
conventional antipsychotics and antidepressant
agents in pregnant or breastfeeding women.
No more than 300 cases of ECT-utilization
in pregnancy have been described and the
incidence of minor obstetrical complications,
such as the onset of uterine contractions (usually
not followed by premature labor) was about
The author states that, to the best of his knowl-
edge, a study on lithium levels in breast-milk and
infant’s serum is in press. Thus, waiting for the
publication of that article, the results and the
conclusions of the review on this topic must be
The author wishes to acknowledge Raffaella Santero, Pharm.
D., Information Specialist, Medical Information Service,
Novartis SpA, Italy for her support in the electronic search
and for providing the full-text versions of the reviewed articles.
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