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though did not further stratify these patients into medication class. These authors
found a malformation rate of 3.5% in this group, with p of 0.11; 1 each of talipes
equinovarus, cleft palate, urinary system agenesis, and heart malformation.
A more recent paper (Chan etal. 2024) considered “treated” and “untreated”
women with bipolar disorder and examined a range of adverse outcomes, including
congenital malformations. The outcomes of this otherwise well-conducted paper
were tainted by the unfortunate decision to include all “mood stabilisers”, including
sodium valproate, lithium, and antipsychotic medications, in a single category, possibly due to low numbers of women treated in pregnancy. As all of these medications have diverse modes of action and differing known associations with congenital
malformations, this did not help to clarify the risk related to the use of antipsychotics in pregnancy and congenital malformations.
C. Breadon and J. Kulkarni
8.9.4 Typical Antipsychotic Medication andtheRisk
ofCongenital Malformations
An older large-scale study of typical antipsychotics (Diav-Citrin etal. 2005) was an
international collaboration which followed 188 women prescribed haloperidol at
therapeutic doses for major mental illness (median 5 mg/day) throughout pregnancy, including in the rst trimester in 78.2% of women. Most of these women, as
in other studies, were also taking other medication (75%). These women were also,
as in other studies, more likely to be older and to smoke than the reference group.
This study found no statistical increase in the rate of major malformations in the
group treated with haloperidol.
Munk etal. (2005) found increased rates of congenital abnormalities which did
not reach signicance in a small cohort of 69 babies exposed to rst-generation
antipsychotics when compared with the general population in several Danish
counties.
Huybrechts et al. (2023) found a risk of congenital malformations in babies
exposed to typical antipsychotics in pregnancy of 3.1% (CI 2.7–3.5%), actually
lower than their unexposed comparator groups whose mothers had a history of mental health diagnosis (3.7%).
8.9.5 Typical Versus Atypical Antipsychotic Medication: Is There
aDifference inRisk?
8.9.5.1 Voluntary Reporting Cohorts andCase-Control Studies
ofCongenital Abnormalities inBabies Exposed toAtypical
Antipsychotics inUtero
I note the retrospective study by Wichman (2009) of 16 babies exposed in utero to
atypical antipsychotics, compared with a tertiary hospital peer cohort. The rate of
malformations was 6.25% (one baby) in this (very low powered) study, with 3
babies exhibiting heart murmurs which resolved by the end of the rst year.
8 Antipsychotics inPregnancy
191
Brunner etal. (2013) found a congenital malformation rate of 4.4% in 610 pregnancies using voluntary reporting to Eli Lilly of pregnancy outcomes for women
exposed to olanzapine. The authors suggest that the general population rate of malformations is 3–5%, and hence 4.4% falls within the expected reference range, consistent with most international surveillance authorities (Public Health Agency of
Canada 2013).
McKenna etal. (2005) provide an earlier, but well-conducted study of rates of
congenital malformations amongst babies exposed to atypical antipsychotics in
pregnancy, comparing exposed women with unexposed age-matched peers. They
found that the exposed group was overall more likely to have high rates of factors
known to worsen the outcome of pregnancy, including having an unplanned pregnancy (57% vs. 23%) and not taking folate or multivitamins during pregnancy (15%
vs. 2%). Interestingly, both groups reported relatively high rates of alcohol use in
pregnancy (14% vs. 12%), but there was a substantial difference in smoking rates
(38% vs. 13%). This study, as most others, reported a high rate of polypharmacy in
women taking psychotropics, with 57% also taking an antidepressant, 34% a benzodiazepine and 17% an anticonvulsant (of whom 72% were taking valproate). These
authors found a rate of major malformations in babies exposed to atypical antipsychotics of 0.9% vs. 1.5%, both lower than that found in most general population
samples.
Cohen etal. (2016) reported on results from the National Pregnancy Registry for
Atypical Antipsychotics at Massachusetts General Hospital, similar to the NRAMP
study in Australasia, to track outcomes for women taking second-generation antipsychotic medication in pregnancy. This group published data on 214 babies
exposed in pregnancy, and found there was no signicant increase in risk in the
exposed group (1.4%, CI 0.29–4.04). Unadjusted odds ratio found an increase in
rates of 1.25in exposed babies over those unexposed. However, after performing
sensitivity analysis, these authors used propensity scoring to assess for the relative
contribution of confounders they considered, using the diagnosis of bipolar disorder
as a basis for comparison. Confounders considered included smoking, stimulant,
illicit drug or alcohol use in the rst trimester, concomitant anticonvulsant, lithium,
anxiolytic, sedative, antidepressant, or typical antipsychotic use, a diagnosis of
depression or anxiety, chronicity of illness, the use of prenatal vitamins, ethnicity,
age, BMI, or planned pregnancy. Incorporating these factors reduced the adjusted
odds ratio to close to parity. However, excluding women taking known teratogens
including valproate, lithium, isotretinoin, and illicit drugs, the odds ratio returned
to 1.25.
Outcomes from this register were updated in 2021 (Viguera etal. 2021) with an
increased pool of 640 live births in the exposed group and 704 controls. This study
showed a non-signicant increased OR of 1.48, CI 0.625–3.517. The authors also
noted that there was no organ-specic or other pattern in relation to the congenital
malformations identied, suggesting that there was no particular mechanism that
could be identied which would unify these outcomes.
192
C. Breadon and J. Kulkarni
8.9.5.2 Large-Scale Studies Examining Rates ofCongenital
Abnormalities inWomen Taking Atypical Antipsychotics:
Habermann etal. (2013), Huybrechts etal. (2016),
Montastruc etal. (2016)
Habermann etal. (2013) found a statistical difference between the rates of congenital abnormalities in babies of women taking second-generation antipsychotics and
those unexposed (OR 2.13, 95% CI 1.19–3.80), though not between babies of those
taking rst-generation antipsychotics and those unexposed (OR 1.75, 95% CI
0.80–3.80). This group adjusted carefully for known confounders, including maternal age, alcohol consumption, smoking, BMI, past history of malformations in
pregnancy, and past history of miscarriage. Of these, only alcohol had a signicant
inuence on the outcome and was therefore included in the nal analysis. The difference in incidence remained signicant after this adjustment. No specic secondgeneration antipsychotic was associated with statistically signicant differences in
rates, though these rates did vary; a rate of 3.59% was found with quetiapine (5/139)
and 6.81% (3/44) with aripiprazole. No malformations were observed with amisulpride (though low numbers were examined: 13) or zotepine (2).
Habermann etal. (2013) drew a distinction between major and minor malformations, and though these authors found a slightly higher rate of minor malformations
in the group of women taking rst-generation antipsychotics (5.5%) than those taking second-generation antipsychotics (3.2%), this difference was not signicant.
Huybrechts etal. (2016) published a large-scale dataset examining 1.3 million
pregnancies, of whom 9258 took an atypical antipsychotic in the rst trimester and
733 took a typical antipsychotic during the same period. In common with other
research (Habermann etal. 2013; Kulkarni etal. 2014), the most commonly used
atypical antipsychotic medication was quetiapine (46% of all atypical prescriptions). These authors observed that, as in other studies, women who took antipsychotic medication in pregnancy were generally older, in poorer health, and used
more other medications and illicit drugs known to be associated with congenital
defects than their peers. Therefore, these researchers controlled for indication and
other confounders including smoking, ethnicity, age, obesity, and general physical
and obstetric morbidity. Considering the large number of factors controlled for, this
study used propensity scores as a method of data reduction. Absolute risk of congenital defects for those treated with atypical antipsychotics was higher at 4.5%
(95% CI 40.5–48.9) than for those treated with typical antipsychotics at 3.8% (95%
CI 26.6–54.7) or the baseline risk in the general population in this study of 3.3%.
Overall unadjusted cardiac risks were greater for babies of all women taking
antipsychotic medications, but disappeared for those taking typical antipsychotic
medications when psychiatric illness was accounted for. Huybrechts etal. (2016)
noted that a large component of the increased risk for both overall and cardiovascular anomalies in babies exposed to atypical antipsychotics was accounted for by
risperidone. The updated study published in 2023 (Huybrechts etal. 2023) did not
conrm this preponderance of risperidone in affected babies, but did demonstrate an
increase in rates of babies exposed to olanzapine developing oral cleft
abnormalities.
8 Antipsychotics inPregnancy
193
Consistent with the outcomes for Huybrecht’s group, Monstastruc etal. 2016)
noted in a very large scale study examining all outcomes from the World Health
Organisation Collaborating Centre for International Drug Monitoring over four
decades, that only two second-generation antipsychotic medications showed a signal of increased risk of congenital malformations: risperidone and aripiprazole, specically in relation to gastrointestinal malformations. This is a surprising nding, as
major gastrointestinal abnormalities (oesophageal atresia, anorectal atresia; some
authors include in this list cleft lip and palate) are not commonly noted in the literature to date in relation to novel antipsychotics. This group also found a signal for
phenothiazine medications with a piperazine side chain. However, the widespread
use of these medications for nausea in pregnancy throughout the past 60years might
inuence the utility of this nding in relation to antipsychotic medications specically used for mental illness. By contrast, risperidone and aripiprazole are very
rarely prescribed for nausea in pregnancy. The authors were cautious not to attribute
causality to this nding, but did note the necessity for further research on medication-specic risks of teratogenicity, echoing other authors such as Gentile (2010).
Considering the possibility that specic medications could confer specic risks, it is
worthwhile examining some of these medications in more detail.
8.9.5.3 Retrospective Reviews ofData Reporting
Congenital Abnormalities
Einarsson and Boskovic (2009), of the Motherisk team at the Hospital for Sick
Children in Toronto, performed a retrospective review of all studies relating to typical and atypical antipsychotics at that time. These authors discussed phenothiazines
including promethazine, widely used for nausea in pregnancy, and noted that these
medications do not seem to be associated with any known adverse outcomes for
babies. Prochlorperazine, also widely used for nausea, was used in the rst trimester
in 877 pregnancies, and did not result in an increase in the rate of congenital abnormalities (Slone etal. 1977). Similarly, Briggs etal. (2008) found no increase in risk
above baseline in 704 babies after rst-trimester exposure to prochlorperazine.
These researchers found a study in 1982 which evaluated 264 women taking chlorpromazine in pregnancy for nausea, with no increase in the rate of malformations
amongst their babies (Hannah etal. 1982). Einarsson cites Diav-Citrin etal. (2005)
in relation to haloperidol with no increased risk found, and Slone etal. (1977) in
relation to perphenazine (no increased risk found in relation to perinatal mortality,
birth weight, or intelligence at 4years). Triuoperazine, now rarely used in most
centres, was evaluated in relation to risk of exposure in early pregnancy in a study
of 480 women, for whom the incidence of birth defects was 1.1%; well within the
expected incidence of the general population (Moriarty etal. 1963). For completeness’ sake, Einarsson etal. (Einarsson and Boskovic 2009) include data on loxapine
(3 cases of abnormalities including achondroplasia, unspecied malformations, and
tremors at 15weeks old Heel etal. 1978), and thioridazine (2 major malformations
in 63 exposed newborns Briggs etal. 2008). Einarsson reports extremely limited
data on upenthixol (3 pregnancies reported without abnormalities) and uphenazine (Briggs etal. 2008).
194
C. Breadon and J. Kulkarni
Though these authors did not further discuss the results, they mentioned that
post-marketing data for clozapine included 523 cases of known exposure to clozapine in pregnancy, which resulted in 22 reports of malformations without any pattern
of defects found. Similarly, correspondence with the manufacturers by the authors
resulted in a report of 144 prospective and 98 retrospective pregnancy outcomes for
women taking olanzapine with no increase in rates of malformations, but no further
information regarding these. Discussion with the manufacturer of quetiapine by the
authors resulted in 298 pregnancy exposures, of which there were 14 reports of
congenital anomalies with no pattern of defects found. Discussion with manufacturers of ziprasidone by the authors revealed 57 known pregnancy outcomes, of which
50 showed no malformation, 5 had miscarriages, one twin pair of which one of the
twins had a malformation, and one woman had a stillbirth. The frustrating aspect of
these relatively large data samples is the paucity of further information on women
and their babies in every category, limiting their utility for ascertaining risk.
Gentile (2010) painstakingly collated all available data, including case reports,
on both typical and atypical antipsychotics at the time of writing, and found inadequate human data to guide prescribing on amisulpride, ziprazidone and sertindole.
He found 3 case reports on aripiprazole. Hence he advised avoidance of all these
medications in pregnancy due to limited data. He found 200 babies exposed to clozapine in utero, of whom there were 15 cases of congenital malformation reported,
though these could not be further investigated in most cases. He found 419 cases of
olanzapine-exposed foetuses, of whom 26 had congenital malformations, including
neural tube defects in 4. Further, this study found 227 babies exposed to quetiapine,
of whom 8 had congenital malformations, not further specied, and 321 babies
exposed to risperidone, of whom 15 had congenital malformations. 411 babies were
exposed to haloperidol in utero, of whom 14 cases of foetal abnormalities were
observed, including 3 limb malformations. Gentile notes the risks of late uterine
exposure associated with haloperidol, including body temperature instability. He
also found over 400 cases of exposure to chlorpromazine, of which only 5 cases of
malformations were described. His recommendations based on this review are discussed elsewhere.
8.9.5.4 Meta-Analyses ofData Reporting Congenital Abnormalities
Coughlin etal. (2015) attempted to provide a comprehensive analysis of available
data, given the small sample sizes of most studies. This meta-analysis compiled
results from 3346 babies over a variety of outcomes. Investigators noted a large
degree of heterogeneity amongst trials, but no publication bias. This study found no
signicant difference between the rates of congenital malformations for babies
exposed to either typical or atypical antipsychotics. The most common abnormality
reported was a heart defect. This meta-analysis found that exposure to antipsychotic
medication, typical or atypical, signicantly increased the risk of heart defects with
OR 2.09, CI 1.50–2.91, p<0.001.
A similar approach to aggregating data was undertaken by Terrana etal. (2015),
focusing on outcomes for babies of mothers taking second-generation
8 Antipsychotics inPregnancy
antipsychotics in pregnancy, specically congenital malformations. Examining all
reported case-control studies, this group found an aggregate of 12 studies meeting
at least level 6 on the Newcastle-Ottawa Assessment Scale. A total of 1872 subjects
formed the nal pool of data including 631 women taking olanzapine, 424 taking
quetiapine, 314 taking risperidone, 254 taking aripiprazole, 152 taking clozapine,
37 taking ziprasidone, 17 taking amisulpride, and 7 taking zotepine. Importantly,
when this data was analysed, babies of these women were signicantly more likely
to have congenital malformations, with OR 2.03 (1.41–2.93). A specic pattern of
malformations was not found.
195
8.9.6 Polypharmacy: Does theUse ofMultiple Medications
inPregnancy Escalate theRisk
ofCongenital Malformations?
Examining data from the Motherisk Program in Toronto, Sadowski etal. (2013)
found that rates of major congenital malformations were higher in the cohort
exposed to second-generation antipsychotics than the unexposed group, at 6.2%
compared with 2.6%. However, this difference did not reach signicance. All babies
who had major malformations at birth were exposed to polypharmacy in utero, suggesting that there may be other factors at play in the development of congenital
malformations in this group. These authors suggested that the practice of polypharmacy severely affected outcomes for babies, and advocated for the use of a minimal
number of medications in pregnancy.
8.9.7 Cardiovascular Risk Revisited; theRisk Posed by Specific
Classes ofAntipsychotic
When considering major malformations, the striking example in the study by
Habermann’s group was cardiac malformations. At a rate of 2.8% in the secondgeneration-exposed subgroup in comparison with 1.4% in the rst-generationexposed and 0.6% in the unexposed subgroup, these authors found a signicant
difference between the second-generation-exposed and unexposed cohorts
(OR= 3.21, 95% CI 1.34–7.67). These defects were largely atrial or ventricular
septal defects. This result is complicated by the co-administration of lithium to 3
children in the second-generation-exposed cohort (the total number of children with
a cardiovascular abnormality in this cohort was 12).
In reference to the nding of elevated rates of cardiac malformations in babies of
women taking second-generation antipsychotics in pregnancy, Habermann et al.
(2013) recommend that babies of mothers exposed to these medications in the rst
trimester of pregnancy should be offered a detailed ultrasound to conrm normal
cardiac development.
196
C. Breadon and J. Kulkarni
8.9.8 Special Cases
8.9.8.1 Risperidone
Coppola etal. (2007) found 197 retrospective reports of risperidone in pregnancy,
amongst which there were 12 reports of major congenital abnormality without any
clear pattern of organ system involvement. Ten of these women were also taking
other medications known to increase the risk of congenital abnormality. These
authors concluded that the low rate of malformations reported (6.09%), together
with the absence of specic organ pattern involvement, suggested that risperidone is
not likely to be implicated in specic teratogenic risk.
In their large dataset analysis, Huybrechts etal. (2016) found that within the
group of women taking atypical antipsychotic medication, the overall risk of malformations in those taking risperidone was signicant (RR 1.26, 95% CI 1.02–1.56),
and remained appreciable, though non-signicant when considering cardiac defects
specically (RR 1.26, 95%CI 0.88–1.81). Interestingly, this group also examined
the relationship between the dose of medications and the risk of defects. This did
not appear to be a factor for any medications aside from risperidone, for which
doses above 2mg/day were related to an increased risk for cardiac malformations
(RR 2.08, 95% CI 1.32–3.28). These authors are cautious about interpretation of
their results, referring to the increased risk associated with risperidone use in the
rst trimester as a “safety signal”, though they also point to a prior systematic
review (Ennis and Damkier 2015) which found a similar unadjusted RR of 1.5 for
risperidone and major malformations (though 95% CI was 0.9–2.2). Updated data
from Huybrechts et al. (2023) included an additional 1232 risperidone-exposed
pregnancies, with a propensity-score weighted SMR rate of 0.9/1000 exposed
babies (or non-signicant aRR 0.95 (CI 0.66–1.37).
8.9.8.2 Aripiprazole
Aripiprazole is an unusual antipsychotic with a distinct mode of action, acting as a
partial agonist at D2 and 5-HT1A receptors, and as an antagonist at 5-HT2A receptors (Bellet etal. 2015). Its use merits specic discussion because of its uniqueness
in mode of action (which could lead to unique teratogenic risks) and its reduced
effect on weight gain when compared to other second-generation antipsychotic
medications such as olanzapine or quetiapine. Hence it may be an option considered
if weight gain, gestational diabetes, hypertension or other metabolic risks are a
major concern for a woman considering pregnancy.
A review conducted by Cuomo etal. (2017) suggests that concerns raised by
non-human teratogenesis relating to aripiprazole use have not been replicated in
human subjects. These researchers mention the miscarriage signal in aripiprazole
use in pregnancy reported by Sakai etal. (2017), but also mention other studies
which do not seem to support an increase in the rate of congenital malformations or
of miscarriage (Huybrechts etal. 2016; Habermann etal. 2013).
Bellet etal. (2015) divided congenital malformations into major and minor categories according to EUROCAT, and found that the rate of major malformations
was higher in the group exposed to aripiprazole (2.8%) compared with the unexposed group (1.2%), though this difference was not statistically signicant.
8 Antipsychotics inPregnancy
197
Interestingly, one of the babies suffering a malformation had a gastrointestinal tract
abnormality (oesophageal atresia) consistent with the ndings by Montastruc etal.
(2016) in regard to aripiprazole in pregnancy (see previous section for more detail).
Freeman etal. (2021) found that, comparing 158 babies exposed to aripiprazole
with 690 controls, aOR for major malformations was 1.35, with CI 0.43–4.20, a
non-signicant result.
8.9.8.3 Clozapine
The use of clozapine in pregnancy presents special challenges. Most women take
clozapine for treatment-refractory symptoms of psychosis, hence switching medications or ceasing medications during pregnancy is not always feasible. Cessation
of clozapine in particular can result in severe relapses of psychotic symptoms, as
demonstrated by case reports (Mendhekar etal. 2003). The chaos associated with a
severe relapse of psychosis could have multiple negative effects for both mother and
baby. Therefore, decisions about treatment with clozapine in pregnancy need to be
well informed of all potential risks to both mother and baby.
Mehta and Van Lieshout (2017) note that Novartis Pharmaceuticals has reported
523 cases of clozapine exposure in pregnancy, of whom 22 have reported malformations. At 4.2%, this lies within baseline rates for the general population. Higher rates
of 8.2% have been reported by Dev and Krupp (1995) in a series of 61 babies
exposed to clozapine. Boden etal. (2012a, b) report macrocephaly associated with
clozapine or olanzapine in pregnancy. Kulkarni etal. (2014) report on the relatively
high rate of congenital abnormalities in their group of babies exposed to clozapine
in utero: of 11 babies, 2 were born with major congenital abnormalities: craniosynostosis, hypospadias and hypertelorism in one baby, and gastroschisis and horseshoe kidney in the other. Notably, there does not appear to be a pattern of organs
affected by clozapine in this case series.
Nguyen etal. (2020) report on a case series of 9 women taking clozapine throughout pregnancy, none of whom had mental health relapses during their pregnancy. Of
their babies, notably all those who underwent CTG monitoring (7) all had at least
one non-reactive CTG. 8 required neonatal resuscitation, and 4 were transferred to
the special care nursery. No babies experienced agranulocytosis, and all babies were
formula fed because of concerns about induced agranulocytosis. All babies received
antenatal ultrasound testing, resulting in 2 congenital abnormalities noted: pyloric
stenosis in one baby and pulmonary artery stenosis and atrial septal defect in
another. Both cases were managed conservatively.
8.9.8.4 Olanzapine
An unexpected signal relating to olanzapine and teratogenesis in pregnancy was
found in a Finnish national register, which also included terminations for reasons of
major congenital malformations (Ellfolk etal. 2021). This group found an increased
risk of major congenital malformations in olanzapine-exposed babies of OR 2.12
(CI 1.19–3.76), specically musculoskeletal malformations: OR 3.71 (CI
1.35–10.1). These authors also seemed bemused by their nding, as their overall
assessment of second-generation antipsychotic use in pregnancy did not appear to
support an association with congenital malformations. Authors hypothesised a
198
potential link with genetic vulnerabilities to hyperglycaemia prevalent in the study
population, suggesting that a possible mechanism might be olanzapine promoting
an increase in congenital malformations through hyperglycaemia in early pregnancy.
A signal in relation to olanzapine was also found in a large multinational study
incorporating American and Scandinavian populations (Huybrechts et al. 2023).
This study found babies exposed to olanzapine in pregnancy were more likely to
have oral cleft abnormalities, with aRR 2.14 (1.07–4.27). Again, the authors were
cautious about this nding, suggesting that future studies would be helpful to conrm or disconrm.
C. Breadon and J. Kulkarni
8.10 Elective Terminations, Spontaneous Abortion,
Miscarriage, andStillbirth
Many authors have commented on the high rate of elective terminations found in
women prescribed antipsychotics in pregnancy (Huybrechts etal. 2016; Habermann
etal. 2013; Coughlin etal. 2015; Diav-Citrin 2005; McKenna etal. 2005; Brunner
etal. 2013). Several have speculated on the reasons for this, some citing the high
rates of unplanned pregnancy in this group (McKenna etal. 2005).
A 2015 meta-analysis by Coughlin etal. conrmed this trend, with pooled odds
ratio of 5.98 (CI=2.94–12.14, p<0.001). These authors considered the possibility
that this high rate may be masking a concealed higher rate of congenital malformations, but noted that the indication for termination was not mentioned in the studies
which reported this result. Huybrechts etal. (2016) noted that the relative risk for
any congenital malformation in the context of atypical antipsychotic use increased
from 1.05 to 1.09–1.14 after accounting for the increased rates of termination
amongst treated and untreated women. Somewhat confusingly, a recent study (Fabre
etal. 2021) considered stillbirth and medical abortions in the same category, and
found an increased rate of stillbirth/medical abortion in women with schizophrenia
at aOR 2.17 (1.62–2.90).
Increased termination rates appear to relate to women taking both typical and
atypical medications. Diav-Citrin etal. (2005) found a higher rate of elective terminations in women exposed to haloperidol than in a control group (8.8% vs. 3.8%),
p=0.004. Habermann etal. (2013) found an increased rate of elective terminations
of pregnancy in women taking both second-generation and rst-generation antipsychotics (9.4%, 8.1%) compared with those not taking these medications (5.7%).
McKenna etal. (2005) found a high rate of elective terminations amongst women
exposed to atypical antipsychotics: 9.9% vs. 1.3% in the comparator group.
8.10.1 Stillbirths andNeonatal Deaths inWomen withMajor
Mental Illness
Lee and Lin (2012) cite Howard etal. (2004a, b) in suggesting that women with a
history of psychotic disorders have higher rates of stillbirths and neonatal deaths
8 Antipsychotics inPregnancy
than other women. These authors also cite other earlier studies suggesting that
women with schizophrenia are at increased risk of stillbirth (Nilsson etal. 2002;
Rifkin etal. 1994; Bennedsen etal. 1999; Sacker etal. 1996), and cite Webb etal.
(2007) in suggesting that maternal mood disorders are associated with a higher risk
of fatal congenital defects.
Whereas these earlier studies seemed to link a diagnosis of major mental illness
with an increased risk of stillbirth, this nding is not corroborated by more recent
research. Habermann etal. (2013), Vigod etal. (2015), Reis and Kallen (2008),
Diav-Citrin etal. (2005), Terrana etal. (2015), Coughlin etal. (2015), Brunner etal.
(2013), and Boden etal. (2012a, b) all found rates of stillbirth or neonatal death
which approximated rates found in the general population. Jablensky etal. (2005)
found no signicant differences between women with schizophrenia, affective psychosis, or the general population in terms of stillbirth, neonatal deaths, or deaths
within the rst year of life. Of note, Vigod etal. (2014) did not nd a signicantly
elevated risk of neonatal death in a population-based sample examining obstetric
outcomes for women with schizophrenia. However, in their subsequent review of
research ndings, the authors commented that the observed neonatal mortality rate
of 1% was still twice that of the general population.
199
8.10.2 Miscarriage/Spontaneous Abortion/Ectopic Pregnancy/
Foetal Death inUtero
In a pooled meta-analysis of women diagnosed with schizophrenia, Matevosyan
(2011) found rates of miscarriage of 5.1% (RR=2.04). The authors reported this to
be a higher rate than the reference population, though this difference did not reach
signicance. Sadowski et al. (2013) dened miscarriage as occurring prior to
20weeks, foetal death as occurring after 20weeks, and found that neither occurred
more frequently in women exposed to second-generation antipsychotics. Habermann
et al. (2013) found no signicant increase in risk of spontaneous abortion after
exposure to antipsychotics either second or rst generation, reporting consistency
with outcomes observed by other authors (Goldstein etal. 2000; Garayt and Merieux
2009; Paulus etal. 2005). Diav-Citrin etal. (2005), Terrana etal. (2015), Coppola
etal. (2007), Coughlin etal. (2015), and Brunner etal. (2013) found no signicant
difference between rates of miscarriage in women treated with either typical or
atypical antipsychotic medications, and the general population. Two authors mentioned no difference in rates of ectopic pregnancy between women treated with
antipsychotics and those unexposed (Diav-Citrin etal. 2005; Brunner etal. 2013).
8.10.3 Specific Antipsychotics: Aripiprazole andtheRisk
ofMiscarriage
Sakai etal. (2017) examined the relative risk for miscarriage of aripiprazole specically, in comparison with other second-generation antipsychotics including