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C. Breadon and J. Kulkarni
withdrawal symptoms in 15% of babies, which appeared to be dose-related and
which took up to 6–8weeks to subside. Kulkarni etal. (2014) noted that there was
a trend towards exposure to higher doses of medication at 12weeks’ gestation in
babies who experienced withdrawal symptoms (p=0.162).
Interestingly, Convertino et al. (2016) also drew some distinctions between
reported symptom proles after withdrawal from specic medications: seizures in
one case of a baby exposed to risperidone; heat regulation, hyperbilirubinaemia
and feeding difculties in another. These authors note case reports of thermoregulation difculties, tremor, vomiting, poor feeding and decreased muscle tone in
haloperidol exposure, and respiratory distress, hypotonia, poor feeding in olanzapine exposure; retinopathy and transient neonatal hypoxaemic encephalopathy in
clozapine exposure. They also note a report of delayed neurological and extrapyramidal symptoms in uphenazine exposure, presenting a month after delivery.
Worsley etal. (2013) commented on outcomes for 114 babies in the NRAMP database referred to above. In this analysis, babies who were exclusively breastfed
from delivery (12.2%) were less likely to have withdrawal symptoms than babies
who were exclusively bottle-fed (27.5%), with OR 2.74, CI 1.02–7.32, p=0.04. A
full discussion of this issue is beyond the scope of this chapter, however it remains
an interesting outcome when considering ways to reduce the impact of adverse
events on neonates.
Sadowski etal. (2013) found higher rates of foetal distress at delivery amongst
babies exposed to second-generation antipsychotics, at rates of 22.5% vs. 14.3%
in those unexposed (though this did not reach statistical signicance). This group
also had much higher rates of Neonatal Intensive Care Unit (NICU) admission,
at 25.3% vs. 9.5%, and much greater rates of signs of neonatal abstinence syndrome (which they labelled “PNA”: 16.5% vs. 5.2%). These researchers considered PNA to include central nervous system, respiratory, and gastrointestinal
problems.
The 2007 study by Newport etal. demonstrated APGAR at 5min to be broadly
similar across all treatment groups, with a mean between 8 and 9. Olanzapine and
quetiapine were associated with higher rates of NICU admission (30.8% and 9.5%
respectively), both of which are higher rates than those observed in the general
population. Notably, again, olanzapine seemed to be associated with a higher rate of
cardiovascular and respiratory complications, with 23.1% and 30.8% of babies
experiencing these adverse outcomes at delivery.
Gentile’s 2010 review found high rates of neonatal adverse events in babies of
mothers taking clozapine in pregnancy, including transient oppy infant syndrome,
noting that most of these women were also taking other medications. He found 63
of 419 babies exposed to olanzapine who experienced “perinatal complications”,
not further specied. He found neonatal complications in babies exposed to risperidone, including withdrawals and seizures, but did not further characterise these. He
also found reports of neonatal adverse events relating to late-pregnancy use of
chlorpromazine including extrapyramidal signs, respiratory distress, seizures, and
transient neurodevelopmental delay.
8 Antipsychotics inPregnancy
211
8.13.5 Aripiprazole andAdverse Neonatal Events
Bellet etal. (2015) found 2 babies who experienced neonatal adverse events associated with aripiprazole exposure. The rst had a withdrawal syndrome with pulmonary hypertension and respiratory distress. The second had an aspiration pneumonia
in the context of premature rupture of membranes. More generally, APGAR scores
were lower at both 1 and 5min in babies exposed to aripiprazole.
8.13.6 Clozapine andAdverse Neonatal Events
Isolated case reports of reduced heart rate variability have been noted in foetuses of
women taking clozapine in pregnancy (Yogev et al. 2002; Guyon et al. 2015;
Nguyen etal. 2020). There have been several case reports of oppy infant syndrome
in babies exposed to clozapine in utero (Di Michele etal. 1996; Karakula et al.
2004). The longer-term sequelae of this syndrome can include motor delay and
other developmental difculties (Igarashi 2004). Seizures have been reported in
clozapine-exposed babies (Stoner etal. 1997; Karakula etal. 2004). The authors
speculated that these could result from immature infant hepatic metabolism, or
alternatively from withdrawals from the medication, given that some seizures have
occurred several days after delivery. There have been several reports of shoulder
dystocia, suggesting possible macrosomia at delivery (Waldman and Safferman
1993; Dickson and Hogg 1998).
Reports of agranulocytosis of babies breastfed by mothers taking clozapine (Dev
and Krupp 1995) suggest that this effect could also occur as a consequence of treatment in utero. On this basis, Kulkarni etal. (2015) have suggested that weekly white
cell monitoring should occur up to 6months after delivery for babies exposed to
clozapine in utero.
8.13.7 Lifestyle Factors Elevating Risk ofAdverse
Neonatal Events
Whereas the absolute rates of adverse neonatal events were higher in babies of
women taking antipsychotics throughout pregnancy at 6% in the 2016 study by
Petersen etal., it is notable that 4.7% of babies of women not taking antipsychotics
in pregnancy, but who had previously been prescribed these, also experienced these
outcomes. Rates of adverse neonatal events for babies of women never exposed to
antipsychotics were much lower, at 2.5%. After adjustment for age, obesity, alcohol
problems, smoking, illicit drug use, and antidepressant and anticonvulsant prescribing, the differences between these groups were not signicant. These results raise
the issue, also raised elsewhere, of the contribution of underlying illness or clustering lifestyle factors to adverse outcomes, rather than solely relating to the administration of medication itself.
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C. Breadon and J. Kulkarni
8.13.8 Polypharmacy Escalates Risk ofAdverse Neonatal Events
Coppola etal. (2007), considering only risperidone, noted 1 of 68 pregnancies in
which the baby experienced a possible withdrawal syndrome. The mother of this
child was also taking imipramine, clonazepam and alcohol through pregnancy. The
baby experienced sleepiness, jitteriness, and slow sucking, but did not require transfer to a NICU or special care nursery. These authors also found 21 of 197 retrospectively reported pregnancies exposed to risperidone which reported adverse neonatal
events. These included drug withdrawal in 13 (in 5 of which drug withdrawal was
attributed to other drugs taken by the woman in pregnancy), movement disorder or
tremor in 9, jitteriness or irritability in 8, feeding problems in 8, somnolence and
lethargy in 3 and seizures in 3. 18 of the 21 were complicated by concomitant use
of other drugs, illicit or prescribed, known to be associated with withdrawal syndromes. 3 of these babies were transferred to NICU for further care, 3 required
oxygen, tube feeding or treatment with anticonvulsants, and 15 did not require any
specic treatment.
Consistent with these ndings, Sadowski etal. (2013) found that adverse neonatal events were much more common in those exposed to polypharmacy, with signs
at 21.2% vs. 4% of monotherapy babies, and NICU admission at rates of 28.8% vs.
16%. When those exposed to polypharmacy were excluded, babies exposed to second-generation antipsychotics had similar rates of abstinence symptoms to those in
the unexposed group. Similarly, Diav-Citrin etal. (2005) found that the rate of neonatal adverse outcomes was 5% in a cohort treated with haloperidol. Most of these
babies were born to women treated with multiple psychotropic medications. The
cohort examined by Kulkarni etal. (2014) also demonstrated high rates of polypharmacy, with 11% of women taking an additional antipsychotic medication, and 43%
of women prescribed antipsychotics also taking an antidepressant. This study found
a strikingly high rate of neonatal respiratory distress in babies exposed to these
multiple medications, at 37%. The authors noted that babies also exposed to mood
stabilisers were over six times more likely to experience respiratory distress.
Overall, these babies were also sicker than most other cohorts examined; over 40%
required transfer to a neonatal ICU or special care nursery (SCN), compared with
expected community rates of 14.2%. The authors noted that higher doses of antipsychotics in pregnancy increased the risk of admission to NICU or SCN.
The 2013 study by Habermann etal. adjusted for alcohol consumption, smoking,
and gestational age at birth, all of which were shown to have a signicant effect on
neonatal adverse events. After adjustment, exposure to second-generation antipsychotics was also signicant in this regard (OR=6.24, 95% CI=3.51–11.10) as was
exposure to rst-generation antipsychotics (OR=5.03, 95%CI=2.21–11.44). The
outcomes measured for newborns included jitteriness, somnolence, and seizures.
The authors noted that co-medication with additional psychoactive medications
greatly added to the risk of postnatal disorders for all babies exposed to antipsychotics in utero, raising rates from 10.8% and 10.3% respectively to 29.5% and 36.4%.
Hence polypharmacy appears to dramatically escalate the risk of neonatal morbidity
in these vulnerable babies. The medications most associated with neonatal
8 Antipsychotics inPregnancy
symptoms included quetiapine at 25.8% and aripiprazole at 23.5%, followed by
olanzapine at 15.1%. As a consequence of these very marked results, Habermann
etal. (2013) recommend that babies born to women taking any antipsychotic medication in the nal week of pregnancy should have their delivery planned with access
to a neonatal intensive care unit.
213
8.14 Neurocognitive Development oftheInfant:
Developmental Delay, Autism Spectrum Disorder,
andAttention Deficit-Hyperactivity Disorder: What Is
theEvidence?
The quality and quantity of evidence in relation to conditions such as developmental delay, autism spectrum disorder (ASD), and attention decit-hyperactivity
disorder (ADHD) have improved substantially in the past few years. There is
existing support for a strong genetic component to the development of ADHD and
autism, which also often co-occur. Twin-twin concordance studies have shown a
strong degree of heritability in particular for autism spectrum disorder of up to
90% (Tick etal. 2016), with 70% heritability for ADHD (Sciberras etal. 2017).
Multiple studies have implicated a variety of genes in the later development of
autism, intellectual disability and ADHD (Torrico etal. 2015; Forrest etal. 2018;
Lahbib etal. 2019). In a search for environmental or other inuences which could
accentuate vulnerability to either condition, researchers have posited a number of
factors.
Autism spectrum disorder has been associated with various environmental pollutants, such as trafc fumes (Gong etal. 2017), ame retardants (Lyall etal. 2017),
or plastics (Hamra etal. 2019); in-pregnancy exposures such as use of NSAIDS
(Chowdhury etal. 2023) or low levels of vitamin D in pregnancy (Windham etal.
2020), vitamin supplementation rates (DeVilbiss etal. 2017), maternal melatonin
levels (Braam etal. 2018), or prenatal stress (Hecht etal. 2016), and genetic vulnerability such as intellectual disability or epilepsy (Breuillard etal. 2016), as well as
other factors including birth complications (Modabbernia etal. 2016), autoimmune
(Vinet etal. 2015; Spann etal. 2019; Sjölander etal. 2022) or inammatory conditions (Dale etal. 2017; Brynge etal. 2022; Ramirez-Celis etal. 2022), infections
(Guisso etal. 2018), obesity (Ahlberg etal. 2022), and even sh consumption at
conception (Gao etal. 2016). Others have focused on maternal physical health conditions such as PCOS (Kosidou etal. 2016) or other metabolic disorders (Connolly
etal. 2016; Qin etal. 2017), or family migration (Fairthorne etal. 2017; Abdullahi
etal. 2019; Morinaga etal. 2021).
The diversity of inuences and comorbid conditions (for example, co-occurring
intellectual disability in children with ASD), as well as the identication of multiple
loci of interest in relation to heritable ASD and ID traits, has led to a widespread
view that ASD is an umbrella term which describes a number of individual phenotypes which may have distinct aetiologies, or a number of clustering contributors
which separately add to the risk of ASD as a diagnosable outcome.
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C. Breadon and J. Kulkarni
8.14.1 Evidence Relating totheUse ofAntipsychotic Medication
inPregnancy andRisks ofDevelopmental Delay, ASD
andADHD
Specically in relation to the risks around the use of antipsychotic medications in
pregnancy, several papers have been published in recent years which have made
substantial improvements in study design and analysis on prior research. This was
the case with a large Scandinavian study published in 2021 (Hálfdánarson etal.
2022), covering 2 decades and including 4 million children, of whom 15,466 were
exposed to antipsychotic medication in utero. Responding perhaps to criticism of
earlier studies with less sophisticated design and analysis, this study considered
women with major mental illness whose pregnancies were not exposed to antipsychotic medication as a comparator group to account for confounding by indication,
and then considered unexposed sibling pairs to account for unmeasured confounders such as genetic or shared environmental confounders. Primary outcomes of
interest were childhood diagnoses of ADHD or ASD.Importantly for the clarity of
this research, children diagnosed with a chromosomal abnormality or foetal alcohol
syndrome were excluded from the analysis. The study considered both rst- and
second-generation antipsychotics separately, and did not include lithium or prochlorperazine in the results. Whilst any exposure in pregnancy was considered, the
authors also looked at trimester timing of exposure. Covariates examined included
sociodemographic status, smoking, BMI, maternal age, parity and child’s sex.
Country and birth year were also considered, possibly due to differences in regional
diagnoses for these conditions and the changes in diagnosis of each condition
over time.
Much of the prior research into ADHD and ASD risk has been affected by comparison of large datasets of children with ADHD comparing rates between exposed
and unexposed groups. This of course yields an impressive hazard ratio, as it did in
this case: 2.28 (CI 2.08–2.49). However, it is not a sophisticated reading of the relationship, as demonstrated in Hálfdánarson etal. (2022), who went on to perform a
multivariate regression using the covariates described above, resulting in a less substantial HR of 1.10, CI 1.00–1.21. I would still consider this type of analysis to be
misleading, however, as it does not consider major confounders such as maternal
mental illness and other genetic and epigenetic vulnerabilities; it would be far more
appropriate to compare the cohort of women taking antipsychotics to a more similar
comparator group. Fortunately, this was the next step for Hálfdánarson etal., who
then found HR for ADHD of 0.90 (CI 0.70–1.15) for babies of women with psychotic illnesses or bipolar disorder; 0.96 (0.82–1.12) for babies of women with
other psychiatric disorders, and 1.44 (1.25–1.66) for babies of women with no diagnosed psychiatric condition. This shows, interestingly, that women with psychosis
or bipolar who take medication in pregnancy are actually, if anything, less likely to
have babies with ADHD than their unmedicated comparators who also suffer these
conditions. Even this analysis can be criticised due to confounding by severity,
prompting a further secondary analysis, which considered women who took antipsychotic medication before pregnancy (hence requiring treatment) and then ceased
8 Antipsychotics inPregnancy
215
in pregnancy. These women were found more likely to have babies who developed
ADHD, suggesting that a genetic vulnerability related to underlying mental illhealth is probably a relevant factor.
A similar relationship was found between antipsychotic exposure and ASD, for
which an unadjusted HR was 2.12 (1.86–2.41) but when covariates were considered
this dropped to insignicance, with HR 1.12 (CI 0.97–1.29). Aside from the relationship between antipsychotic exposure in women with no psychiatric condition
recorded (HR 1.27, CI 1.00–1.60), none of the subgroups of women suffering mental illness reached signicance. This group is a highly unusual one: who takes an
antipsychotic in pregnancy with no mental health indication? Considering this was
the only group in whom a signicant result was obtained, it would be interesting to
know more about the reasons for prescribing.
Sibling analysis, considering an even more closely paired comparator group, was
similarly revealing: of 322 children whose siblings were not exposed to antipsychotics there was a non-signicant HR of 1.14 (CI 0.79–1.64) for ADHD and for
127 children whose siblings were unexposed there was also a non-signicant HR of
1.34 (CI 0.75–2.39) for ASD.
It was interesting that trimester timing of exposure did not appear to affect
outcomes for this study. This is consistent with the development of the neurological system in utero, which continues throughout gestation, and also consistent with the effect of sodium valproate on neurological development, which
does not appear to be tethered to a specic trimester. The authors commented on
the robust association between underlying maternal psychotic and bipolar disorder and children’s development of the conditions of interest. A strength of this
study was the relatively long follow-up period of up to 9years, though I note
that longer-term follow-up into adulthood may be an additional benet in future
research.
A slightly earlier British study tracked neurodevelopmental and multiple other
outcomes for babies in a large UK primary care dataset between 1995 and 2012
(Petersen etal. 2016a, b). Exposures of interest were antipsychotic and mood
stabiliser medications, including sodium valproate and lithium taken in pregnancy. Within this cohort, 554 women were prescribed antipsychotic medication
in pregnancy. A large percentage of these were also taking other psychotropics:
387 were also taking an antidepressant; 80 were also taking an antidepressant and
a hypnotic; 35 were taking antidepressant, hypnotic, anxiolytic as well as an antipsychotic, and 34 were taking an anticonvulsant and antidepressant in addition to
an antipsychotic. Thus of the 554 total, only 18 were solely taking an antipsychotic medication in pregnancy. From these pregnancies, 290 children exposed to
antipsychotic medication were followed through to between 2 and 3 years
post-birth.
This study included women taking antipsychotic medication prior to pregnancy
as a comparator group, as well as the larger “healthy women” cohort from the
broader dataset. Notably, even this smaller comparator group had half the incidence
of obesity as the cohort of interest (10.7% vs. 20%) and a lower smoking and alcohol use rate. Women treated in pregnancy were older than either comparator cohort.
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C. Breadon and J. Kulkarni
Relevant outcomes for neonates included a broad “developmental delay” category
as well as behavioural problems within the scope of the study (i.e. prior to 15months
of age).
When compared with the broader cohort, babies exposed to antipsychotic medications in pregnancy were found to be no more likely to be at risk of neurodevelopmental and behavioural disorder, after adjustment for confounders. When compared with
other women who had taken antipsychotic medication prior to pregnancy, these pregnancies were no more likely to result in birth of a child suffering neurodevelopmental
delay or behavioural problems, even prior to adjustment for confounders. Whilst this
study did not differentiate between antipsychotics, the overall lack of a signal for
adverse outcomes meant adjustment was not as important a consideration.
This study noted by contrast the strong signal for sodium valproate in relation to
congenital birth defects and neurodevelopmental abnormalities, consistent with
existing research, and related guidelines emphasising the importance of considering
childbearing potential when prescribing valproate.
Yet another administrative dataset studied similar outcomes, this time for
American women and babies (Straub etal. 2022). These authors noted the expanded
uses to which antipsychotic medications are put in an American context, also noting
the ability of these drugs to cross the placenta. Babies were followed for up to
14years. Interestingly, this research selected for antipsychotic prescribing in the
second half of pregnancy, rather than the rst, due to a view that neural synaptogenesis occurs later in pregnancy. This approach differs somewhat from other studies
(e.g. Halfdanarson) which have emphasised neural tube development in the rst
trimester. Specic diagnoses of ADHD and ASD were evaluated, as well as neurodevelopmental disorder more broadly. 9551+ 1221 pregnancies were exposed to
antipsychotics during the period 2000–2014. Given the larger sample size, this
study could evaluate for specic antipsychotics as well as distinguish between
classes. This study utilised high-dimensional propensity scoring to account for
residual confounding. A potential signal was found for aripiprazole, which then
caused the researchers to focus on this drug in a subsequent analysis.
In this study, the vast majority of prescriptions were for quetiapine, accounting
for about 40% of exposures; slightly less commonly prescribed was aripiprazole
(16–23%). Most women took only 1 antipsychotic in pregnancy. This study noted
the older age of women taking antipsychotics in pregnancy, and that they were more
likely to take illicit drugs, smoke cigarettes, and drink alcohol.
Straub etal. (2022) showed very high rates of diagnosis with neurodevelopmental abnormalities, with 37% of publicly insured children exposed to antipsychotics
in the second half of pregnancy subsequently diagnosed with NDD by age 8, including 24.5% diagnosed with ADHD and 3.5% diagnosed with ASD.Rates were lower
in the privately insured cohort, but still very high by international standards: 24.5%
NDD, 17.5% ADHD, 3.8% ASD.However, in adjusted analysis, there was no statistical difference found between exposed and unexposed groups, aside from aripiprazole in the second half of pregnancy: pooled adjusted HR for NDD 1.35, CI
1.14–1.63; this lost signicance for the two specic outcomes of ADHD (paHR
1.36, CI 0.98–1.89) and ASD (paHR 1.49, CI 0.91–2.47).
8 Antipsychotics inPregnancy
217
Authors considered the possibility that aripiprazole is prescribed for women with
more severe illness, so compared women taking higher doses of aripiprazole in
pregnancy with those taking lower doses; this did not meaningfully affect the outcomes, which remained consistent also when aripiprazole was prescribed in the rst
half of pregnancy. They then compared these women with those taking aripiprazole
prior to pregnancy, which again did not meaningfully affect the results. The authors
pointed out the slightly different mechanism of action for aripiprazole which might
affect prolactin, and considered the risk for an effect on breastfeeding, which might
in turn affect NDD.
A well-designed Danish study (Momen etal. 2022) utilised a populationbased register to examine all births 1998–2015. Of these, authors considered
women taking antipsychotics prior to pregnancy, and compared those who continued taking antipsychotics in pregnancy with those who did not. This neatly
addressed concerns about confounding by indication and about lifestyle,
sociodemographic and residual confounders which arise when those who do not
suffer mental ill-health requiring antipsychotic medications are compared with
those who do. The authors also considered paternal antipsychotic use in the
hope that this may address additional genetic or environmental factors which
could inuence outcomes related to intrauterine exposure to antipsychotics. As
a consequence of this decision, all children for whom paternal information was
missing were also excluded from the dataset. The authors further excluded children with diagnosed chromosomal abnormalities. The eventual target cohort of
children of women continuing to take antipsychotic medications in pregnancy
was 2035, compared with 6976 pregnancies where antipsychotic medication
was discontinued in pregnancy. A new user group of 857 women was included
in this study, of women who had not previously taken antipsychotic medication
in pregnancy who then started this medication de novo in pregnancy. Children
were followed until the end of the study period or until they reached an endpoint
as dened by the outcomes of the study. This study examined children up to the
age of 15years.
Comparisons were adjusted using covariates such as maternal and paternal age,
severity of illness (judged by hospital admissions; women who had inpatient psychiatric admissions in the 2years prior to birth were excluded from the analysis),
socioeconomic status, smoking, and year of delivery, amongst other variables.
Exposure timing in trimesters was specied. Unfortunately this dataset did not provide diagnosis codes for maternal mental health, so the indication for use of antipsychotic was unclear. These patients were subsequently added for sensitivity analysis,
and there was no a signicant difference in their outcomes. Some exclusions from
the data seem counterintuitive, such as excluding all women who had a psychiatric
admission in the 2years prior to delivery, as this would have been a useful indicator
of severity of illness, which is an important consideration and is difcult to adjust
for. Additionally, women who received comorbid diagnosis of substance use disorder were excluded, as were women who took other psychotropic medications in
pregnancy. Again, these are women who are frequently seen in clinical practice, and
the information on their babies’ outcomes is important to ascertain. Often this
218
C. Breadon and J. Kulkarni
information is not available in other studies, and in this case could have been used
as a covariate for analysis. I hope that this may be considered in this group’s future
research.
In comparing babies exposed to antipsychotics in pregnancy with those whose
mothers had ceased taking antipsychotics in pregnancy, exposed babies went on to
have 10% higher rates of psychiatric disorders overall than the comparator group,
though this was not statistically signicant: HR 1.10, CI 0.93–1.30. In relation to
timing, interestingly second and third trimesters appeared to have a greater magnitude of effect (HR 1.42) but the difference was non-signicant (CI 0.86–2.35). The
authors considered duration of use of antipsychotic medication in pregnancy, and
this also did not appear to increase risk: HR 1.00, CI 0.98–1.02. Paternal use of
antipsychotics was overall not signicant: HR 1.05 (CI 0.89–1.24).
In relation to ADHD and ASD diagnoses, point prevalence was lower in the
cohorts exposed to intrauterine antipsychotic: ADHD HR 0.85 (CI 0.62–1.15), ASD
HR 0.83 (CI 0.90–1.26), though the difference was non-signicant. Hence other
behavioural and emotional disorders, neurotic, stress-related and somatoform disorders, and psychiatric disorders more generally, all appear to have been higher in the
treatment group.
This study also looked at antipsychotics differentiated by structure; this was a bit
confusing and might not be immediately useful to clinicians. All antipsychotic
structures, including N05AA Phenothiazines with aliphatic side-chain antipsychotic
(prochlorperazine, chlorpromazine, and promethazine), antipsychotics with piperidine side chains (risperidone), thioxanthenes (upenthixol, zuclopenthixol)
appeared to have lower HRs than the control group, aside from thioxanthene derivatives (upenthixol, zuclopenthixol): HR 1.28, CI 1.01–1.62. The authors noted the
limitations of being unable to consider indication in this study, as well as dosage,
due to low power in the available dataset, and advised future studies to evaluate
these. They also mentioned that the reduced time of follow-up meant that adultonset disorders may not be fully ascertained. Their discussion noted that when comparing sex of the child, there was a higher risk of neurodevelopmental abnormalities
in male babies, which is a well-established nding.
A Taiwanese study (Yeh etal. 2021) utilised nationalised health register data to
enrol 5669 women since 2002 with an ICD-9 diagnosis of Bipolar Disorder, of
whom 426 women took a psychiatric medication prior to and during pregnancy, and
only 45 were taking antipsychotic medication during pregnancy. These women
were matched with women without a diagnosis of major mental illness according to
age and residence. Children of these pregnancies were then followed until 2011 (so
a maximum of 9years post-partum) to elicit a diagnosis of ADHD or ASD. The
authors stratied exposure into trimester, and adjusted for urban environment.
This study again reinforced the inuence of underlying mental illness on ADHD
and ASD outcomes, nding that all women diagnosed with bipolar disorder regardless of medication treatment were more likely to have children with ADHD (OR
1.51, CI 1.28–1.77) and ASD (OR 1.85, CI 1.20–2.85) than those who did not have
a diagnosis of major mental illness. When comparing those with bipolar disorder
who took medication in pregnancy with those who did not, for those taking an
8 Antipsychotics inPregnancy
219
antipsychotic medication at any point during pregnancy the association with ADHD
and ASD was not signicant: OR 1.38, CI 0.56–3.41. The authors highlighted that
for women taking antipsychotic medication specically within the third trimester,
the association with later onset ADHD was signicant, at OR 3.83 (CI 1.12–13.12),
but I would note the absolute number of these women was 35, and the CI correspondingly broad, suggesting this is not a highly reliable result.
Wang etal. (2021a, b) used a clinical data register in Hong Kong to evaluate children born between 2001 and 2015 and exposed to antipsychotic medications in utero
for outcomes of ADHD and ASD.This study used sibling matching to address residual confounding, and a propensity score stratication method to manage measured
confounders. To ascertain the outcome of ADHD, researchers limited their study to
children who were aged at least 6 at the end of the study period, and for ASD, to
children aged at least 3. Babies were excluded if they were also exposed to lithium or
an antidepressant in pregnancy. Comparator groups included women with and without a psychiatric diagnosis who had never taken antipsychotics, and those who had
previously taken antipsychotics but discontinued these in pregnancy. Covariates
were maternal age, year at delivery, sex, parity, maternal comorbidities including
epilepsy, gestational diabetes and pre-existing diabetes, and socioeconomic status. In
relation to ADHD, babies exposed to antipsychotics in utero were slightly less likely
than their unexposed peers to develop ADHD if their mother had previously taken
antipsychotics prior to pregnancy: HR 0.99, CI 0.60–1.61. Babies whose mothers
had previously taken antipsychotics but ceased them in pregnancy were more likely
to develop ADHD than those whose mothers had never taken antipsychotics, as were
babies of women who had never taken antipsychotics but had a mental health diagnosis compared with those whose mothers had never taken an antipsychotic and
didn’t have a mental health diagnosis. These two results highlight what has been
shown in other studies, the risk associated with underlying mental illness, which
seems to be robust in relation to the association between bipolar disorder and ADHD.
Similarly, all outcomes for ASD were non-signicant aside from the association
between those who had never taken antipsychotics but had a diagnosis of mental
disorder, compared with those who had never taken an antipsychotic and did not
have a mental health diagnosis (the broader population).
Propensity score stratied matching for sibling pairs suggested that babies
exposed to antipsychotics in pregnancy were marginally less likely than their siblings to develop ADHD or ASD in childhood, though neither of these results held
signicance. Whilst this study examined the effect of trimester exposure, the authors
did not nd any trimester held a greater risk than another for the outcomes examined.
The overall impression gained from these later studies undertaken between 2016
and 2022 is that maternal mental ill-health seems to play a role in children’s later
development of ASD and ADHD, and treatment with antipsychotic medication in
pregnancy appears not to have a substantial impact on this risk. To quantify this
impression, Wang et al. (2024) undertook a meta-analysis of these studies. This
meta-analysis found a slight increase in risk when pooled results were used to compare exposed cohorts with “never exposed” cohorts; RR of ADHD 1.11, CI
1.03–1.19. However, all studies also considered the impact of maternal