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C. Breadon and J. Kulkarni
characteristics, comparing prior exposure with current exposure: RR of ADHD 0.78
(0.63–0.96), or sibling characteristics: RR of ADHD 1.11, CI 0.78–1.60. When
these more similar cohorts were compared, the relationship did not reach signicance. Results were similar for ASD.All cohorts, exposed or previously exposed to
antipsychotics, were far more likely to develop ADHD or ASD, suggesting that the
relationship may not be mediated by the direct effect of antipsychotic medication on
the baby’s developing brain, but related instead to the indication for treatment in the
mother. This is consistent with earlier research suggesting an association between
ADHD and ASD in children of women with mental health disorders (Fairthorne
etal. 2016; Vizzini etal. 2019; Nidey etal. 2021). The authors noted that, despite
their use of tools which assess for bias, their analysis was limited by the limitations
inherent in the studies examined:
1. The heterogeneity of diagnoses for which antipsychotics are utilised, which
made it more difcult to ascertain whether there was a specic underlying diagnosis, or severity of illness, more closely associated with the development of
ADHD or ASD.
2. Whether there is a dose effect, or if specic antipsychotics are more closely
associated with development of ADHD/ASD.
3. Whether a longer-term follow-up may ascertain a larger number of cases.
These issues remain open for subsequent research.
8.15 Conclusion
Table 8.1 shows expert recommendations based on scientic evidence and clinical
experience on this topic.
A woman with a diagnosis of major mental illness facing pregnancy also faces a
host of related challenges which include the direct effect of her illness on her mental
and physical health and that of her baby, and also the social and economic disadvantage that this illness confers.
There is a broad consensus on important contributing factors to adverse outcomes for women in this population: poorer general health in women suffering
major mental illness including high rates of obesity and diabetes, increased rates of
smoking, alcohol and illicit drug use. For pregnant women in particular, factors
contributing to adverse outcomes include reduced attendance at antenatal appointments, reduced use of prenatal vitamins, folate and thyroid hormone, increased rates
of unplanned and unwanted pregnancy, limited social support and increased rates of
domestic abuse, poverty and disadvantage.
The study of the impact of antipsychotic medications in pregnancy is complicated
by the imperative for many women to remain well in pregnancy and the postpartum.
Multiple potential error sources in data derived from studies observing these women
include confounding by indication; such confounders already identied include
severity of illness, socioeconomic, historical or lifestyle factors, and detection bias.
8 Antipsychotics inPregnancy
Table 8.1 Expert recommendations based on scientic evidence and clinical experience
Pre-conception planning for women with major mental illness includes contraception and
fertility advice and management in addition to medication safety advice in pregnancy
Women with major mental illness require both physical and mental health monitoring
throughout pregnancy
Physical health issues to address with women presenting with major mental illness in
pregnancy include
Support around smoking, drug and alcohol use cessation
Prenatal vitamin supplementation
Evidence-based advice around medication safety
Avoid or minimise polypharmacy and switching medications
Mental health monitoring and support includes additional support for social safety, including
detecting and addressing issues of homelessness, domestic abuse, and social disadvantage or
poverty
Assess for and address obesity in all women of childbearing age who present with a major
mental illness
Monitor and manage obesity in pregnancy for women taking antipsychotic medications
Assess for and manage diabetes in pregnancy for women taking antipsychotic medications,
including liaison with expert medical teams
Antipsychotic medication and congenital abnormalities
Whereas the data does not at this stage suggest signicantly increased risk of structural
abnormalities for babies exposed to antipsychotic medications in utero, the evidence base is
small
Antipsychotic medication can increase the risk for premature birth, low birth weight or small
for gestational age infants, or high birth weight infants
Consider intrauterine ultrasound for structural and growth abnormalities in all babies exposed
to antipsychotic medication in utero. In particular, consider high-resolution ultrasound for
cardiac defects at 20weeks and at 36weeks
A baby exposed to antipsychotic medications in utero is at increased risk of neonatal
withdrawal symptoms and distress; ensure that tertiary neonatal support is available at delivery
There is at present no strong evidence supporting developmental delay or disadvantage for
babies exposed to antipsychotic medication in utero
221
What is striking about recent research is that more sophisticated methods of
analysis suggest that problems relating to the experience of disadvantage for women
with a major mental illness may actually form a signicant aspect of the negative
outcomes measured for these women (Vigod et al. 2015). There are two further
conclusions that can be drawn from this: rstly, that harms previously attributed
either to the illness itself or to antipsychotic medication treatment may relate more
closely to socioeconomic factors.
Secondly, if a more holistic approach to support of these women in pregnancy
included efforts to avert homelessness, identify and protect against physical or
emotional abuse, support the use of prenatal vitamins, and reduce incidence of
smoking, alcohol and illicit drug use, a large proportion of the harms to the foetus
and baby could be minimised. Hence care in pregnancy for women with a major
mental illness needs to encompass far more than just careful prescribing of appropriate medications; this is only the rst step in averting harm. As psychiatrists, we
must advocate for best practice in using evidence-based prescribing as part of an
overall care package which incorporates these other elements as well.
222
C. Breadon and J. Kulkarni
Emerging evidence does suggest that iatrogenic harms can accrue to the mother
and her baby from psychotropic medication treatment. In the case of antipsychotic
medication, the harms seem to be becoming more clearly dened. In the rst
instance, the risk of harms to women appears to be shifting slightly over time.
Whereas the risk of reduced fertility from hyperprolactinaemia was previously
highly prevalent and associated with rst-generation antipsychotic medication
(Ajmal et al. 2014), reproductive risks in the era of widespread use of secondgeneration antipsychotic medication relate more to the risks associated with obesity
and diabetes in pregnancy (Newham etal. 2008).
A common thread in several recent research papers is the risk of pre-pregnancy
weight gain for subsequent development of gestational diabetes. This suggests that
this risk should be considered for every woman with reproductive potential suffering a major mental illness from the age of 15–50. This is especially important given
the increased rates of unplanned pregnancy in this group. The cascading risks relating to obesity and gestational diabetes for both mother and baby in pregnancy
include increased rates of congenital malformations and macrosomia, increased
rates of instrumental delivery and emergency caesarean section, and increased rates
of transfer to neonatal intensive care.
Despite these associated risks, the risk and rate of major congenital abnormalities relating directly to exposure to antipsychotic medications in pregnancy does not
seem to be signicantly elevated (Huybrechts etal. 2016). However, rates of neonatal distress and withdrawal symptoms are high in these babies, and seem to be higher
for some antipsychotic medications than others. There is some very limited research
to suggest that there is also a dose-related increase in these symptoms.
Notably, in addition to all the socioeconomic harms previously mentioned, these
babies are very rarely exposed to just one medication, or just one class of medications. The dramatically elevated risk of neonatal adverse events severe enough to
prompt transfer to a NICU occurs in the context of polypharmacy (Sadowski etal.
2013). This is a harm that can be greatly curtailed by sensible, sparing prescribing
of only those medications (such as antipsychotics) which are required to maintain a
stable mental state. The high rates of transient adverse outcomes at delivery for
these babies also suggest that babies of women prescribed psychotropics in pregnancy should birth in a centre with access to neonatal resuscitation and intensive
care support (Habermann etal. 2013).
There is a positive note in this discussion; that neurodevelopmental studies, limited though they are at this stage, suggest that developmental delay noted in babies
exposed to antipsychotics in pregnancy is unlikely to persist to 1year postpartum,
despite high rates of psychiatric symptoms in women in the rst year after delivery
(Kulkarni etal. 2014). In recent years, focus has been placed on specic conditions
such as autism spectrum disorders and attention decit hyperactivity disorder.
Several well-conducted studies using appropriate analytic techniques to manage the
risks inherent in observational data have found, reassuringly, that treatment with
antipsychotic medication in pregnancy does not appear to be associated with an
increased risk of these specic conditions. However, women who have diagnoses of
schizophrenia and bipolar disorder, amongst other mental health diagnoses, may
8 Antipsychotics inPregnancy
223
have a genetic vulnerability to these conditions which they may then pass on to their
children. This is clearly an avenue of ongoing future research as our understanding
of these conditions matures.
In concert with a more sophisticated approach to modelling and analysis, borrowing approaches from other research elds such as health economics (high
dimensional propensity scoring, for example, or machine learning techniques), several authors have called for a more sophisticated approach to research in psychotropics (Gentile 2010; Convertino etal. 2016; Habermann etal. 2013; Uguz 2019). It
is probably not good enough to lump antipsychotic medications into two baskets
and analyse harms associated with each; individual drugs within both novel and
older antipsychotic groups have specic modes of action and associated risks which
may be distinct, and whose specic harms may be masked by considering them all
together. Whereas in the past few years aripiprazole was a focus of concern, now
olanzapine appears to be associated with slightly more adverse outcomes for mothers and babies than previously appreciated.
The future of best practice care for women living with a major mental illness in
pregnancy and the postpartum incorporates careful analysis of both large population-based data sets and granular review of symptoms and side effects in long-term
follow-up studies of mother and baby pairs to inform prescribing practice.
Consideration of a woman’s reproductive health should be integrated into her care
throughout her life, and the care of mothers and babies in the context of maternal
mental illness should be a trigger to provide enhanced social, emotional, economic
and psychiatric support to avert harm and improve outcomes.
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