Antipsychotic drug use during pregnancy and neonatal outcomes: a systematic review and meta-analysis

Abstract Purpose The use of antipsychotics during pregnancy has increased over the past two decades, primarily driven by an increase in the use of second-generation antipsychotic drugs. However, knowledge regarding the reproductive safety of antipsychotic drugs remains limited. This systematic review and meta-analysis investigated the associations between in utero antipsychotic drug exposure and congenital malformations and other neonatal outcomes. Methods A systematic search of MEDLINE, Embase, and PsycInfo was conducted from database inception to February 2024 for cohort and case-control (English language) studies that examined maternal antipsychotic exposure and reported risk estimates for one or more of the following outcomes: congenital malformation, preterm birth, low birth weight, stillbirth, or neonatal intensive care unit admission. Study quality was assessed using the Newcastle-Ottawa Scale, and reporting was guided by the PRISMA statement and MOOSE guidelines. Pooled estimates were calculated using a random-effects model. Results Twelve studies (comprising over 10 million pregnancies across 12 countries) met the inclusion criteria. A pooled meta-analysis of eight studies indicated borderline evidence of an association between the risk of congenital malformations and in utero antipsychotic drug exposure, with moderate heterogeneity (odds ratio [OR] 1.27; 95% confidence interval [CI] 0.996–1.624, p = 0.0535; I 2 = 53%). No association was observed when limited to second-generation antipsychotics (OR 1.16; 95% CI 0.78–1.72, p = 0.47). Regarding the outcome of preterm birth, antipsychotic exposure was associated with an increase in risk (OR 1.35; 95% CI 1.13–1.62, p < 0.01), though there was moderate to high heterogeneity (I 2 = 70%). There was insufficient data to perform a meta-analysis for the other outcomes. Conclusion Meta-analyses did not indicate strong evidence that in utero antipsychotic exposure is a major teratogen; and although an association was observed between maternal antipsychotic use and preterm birth, there was significant heterogeneity across studies. The decision to continue antipsychotic use during pregnancy involves a complex balancing of risks and benefits for women and their healthcare professionals. Any potential risks to the developing foetus must be weighed against the risks of discontinuing treatment, including the possibility of relapse in women with severe mental illness, which can have serious consequences for a woman and her infant. Finally, there is a need for further robustly designed studies.