Major Congenital Malformations Associated With Exposure to Second-Generation Antipsychotic Drugs During Pregnancy

Major congenital malformations (MCMs) are gestational outcomes that are seen in about 2%-3% of pregnancies in the general population. In this context, many studies have examined the MCM risk associated with gestational antipsychotic exposure. These articles were summarized in a recent meta-analysis. The present article examines the findings of the meta-analysis as well as the findings of 2 recent observational studies that were not included in the meta-analysis; an outcome of specific interest was the risk of MCMs after first-trimester gestational exposure to second-generation antipsychotic (SGA) drugs. In brief, meta-analysis of data from 6 observational studies found that exposure to antipsychotic drugs during pregnancy was not associated with a significantly increased risk of MCMs; this finding was also true of early pregnancy exposure and of SGA exposure alone. A large, retrospective, population-based cohort study from Finland found that first-trimester gestational exposure to SGAs was not associated with a significantly increased MCM risk relative to either no exposure or exposure to first-generation antipsychotics; however, in exploratory analyses, olanzapine was associated with increased risk relative to unexposed pregnancies, and specifically so for musculoskeletal malformations. Prospective data from a US pregnancy registry also found no increase in risk associated with first trimester gestational exposure to SGAs in a cohort of women with psychiatric disorders. In smaller studies that used data from the same registry, neither quetiapine nor aripiprazole were associated with increased MCM risk after first trimester use. It is possible that where risk was identified, such as in unadjusted or exploratory analyses, the significant findings were false positives arising from multiple hypothesis testing, or findings driven by residual confounding. The substantial benefits associated with use of antipsychotics, when indicated, must therefore be weighed against the unsubstantiated risks of MCMs in a shared decision-making process.