Given the number of younger women using atypical or second-generation antipsychotic medications, there is an urgent need for more accurate data regarding the reproductive safety of these medications. Thus far, studies have not documented an increased risk of malformations among women using newer antipsychotic medications during pregnancy; however, the information on the reproductive safety of this class of medications is limited.

In a recent population-based cohort study from Denmark of singleton pregnancies, researchers compared the risk of major malformations in pregnancies exposed to antipsychotics in the first trimester and unexposed pregnancies. Rates of major congenital malformations in the antipsychotic medication-exposed group were compared to rates in unexposed pregnancies and in unexposed pregnancies of women who used antipsychotics before but not during pregnancy (discontinuers). 

Of the 503,158 pregnancies ending in miscarriage, termination, stillbirth, and live birth were included in this study, with a total of 1,252 (0.2%) women who filled an antipsychotic prescription in the first trimester. Major malformations were present in 7.3% of antipsychotic-exposed pregnancies, 5.1% of unexposed pregnancies, and 6.0% of discontinuers’ pregnancies. After adjusting for potential confounding variables, the researchers calculated an adjusted prevalence ratio of 1.14 (95% CI , 0.88-1.48) comparing exposed pregnancies with discontinuers.

In a sibling analysis, where they compared siblings born to the same mother (one exposed and one unexposed), the adjusted prevalence ratio was 1.08 (95% CI, 0.47-2.49). In this study, the majority of the women (n=868, with 594 on quetiapine) were taking newer atypical or second-generation antipsychotic medications. While the study was not adequately powered to identify differences between exposures to individual antipsychotics, the researchers observed similar rates of malformations when comparing first vs. second-generation antipsychotics. 

Little or No Risk of Malformations

In this register-based cohort study from Denmark of 503,158 clinically recognized pregnancies, including miscarriages, terminations, and stillbirth, the current study observed little or no risk of teratogenesis associated with first trimester exposure to antipsychotic medications. Given the sample size, it is not possible to rule out a small increase in the overall risk of malformations or increased risk of specific but rare malformations. Nonetheless, the data are reassuring and do not suggest a major teratogenic risk.

While most studies analyzing risk of major malformations rely on the analysis of liveborn children, the current study looks at risk in all identified singleton pregnancies, including miscarriages, terminations, and stillbirth. (This is why the overall rate of malformations is so high in this study: 5.1% in unexposed pregnancies.) It is possible that studies examining only liveborn children may potentially miss more serious malformations that lead either to termination or pregnancy loss; thus, it is reassuring that the findings of the current study are consistent with previous studies assessing the risk for malformations in antipsychotic-exposed liveborn children.

For individual antipsychotic medications, with estimations based on very few cases, further studies with sufficient sample size and power are warranted. Because the data available regarding the use of atypical or second generation antipsychotic medications in pregnancy is sparse, there is a great need to study these medications and their use in pregnancy. The National Pregnancy Registry for Atypical Antipsychotics is currently enrolling pregnant patients taking atypical antipsychotic medications to learn more about reproductive safety of these medications. Those interested in the study may call TOLL-FREE: 1-866-961-2388.

Ruta Nonacs, MD PhD

Liu X, Kolding L, Momen N, Gasse C, Pedersen LH. Maternal antipsychotic use during pregnancy and congenital malformations. Am J Obstet Gynecol MFM. 2023 Jun;5(6):100950.

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