The newer “atypical” or second-generation antipsychotic agents are now used to treat a spectrum of psychiatric disorders, including schizophrenia, bipolar disorder, major depression, PTSD and other anxiety disorders.  The National Pregnancy Registry for Atypical Antipsychotics and other studies have yielded important information on the reproductive safety of these agents; however, there is less information on long-term neurodevelopmental outcomes in children exposed to this newer class of medication.  In a recent study using data from two large medical databases looks at neurodevelopmental outcomes in a total of 10,772 children with prenatal exposure to an antipsychotic medication.

This birth cohort study harvested data from two large databases: the Medicaid Analytic eXtract (MAX, 2000-2014) and the IBM Health MarketScan Research Database (MarketScan, 2003-2015), generating a nationwide sample of mother-child dyads who are publicly (MAX) and privately (MarketScan) insured.  Antipsychotic exposure was defined as at least one dispensing of an antipsychotic medication (typical or atypical) during the second half of pregnancy. (This window of exposure was selected because synaptogenesis and brain development begin after the first trimester.)  The vast majority of exposures were to atypical antipsychotic drugs (?90% in both cohorts).

The MAX cohort included 9551 children with prenatal exposure to antipsychotic medications and 2,034,883 unexposed children.  The MarketScan cohort included1221 exposed and 1,306,408 unexposed children.  Children were followed up to 14 years of age.  ICD-10 codes were used to identify children with autism spectrum disorder, attention-deficit/hyperactivity disorder, learning disability, speech or language disorders, developmental coordination disorder, intellectual disability, and behavioral disorders.  

The unadjusted analysis suggested an approximately twofold increase in risk for any type of neurodevelopmental disorder.  However, after the researchers controlled for potential confounding factors, they no longer observed an association between prenatal antipsychotic exposure and risk of neurodevelopmental disorder.  (In the unadjusted analysis, the hazard ratio [95% CI] for any neurodevelopmental disorder after any antipsychotic exposure was 1.91 [1.79-2.03] compared to a hazard ratio of 1.08 [1.01-1.17] in the adjusted analysis.)  Looking at specific antipsychotic medications, the only antipsychotic possibly associated with increased risk was aripiprazole (HR 1.36; 95% CI 1.14-1.63). 

Reassuring Findings from the Largest Study To Date

This birth cohort study, including over ten thousand children with prenatal exposure to antipsychotic medications, is the largest to date.  Another strength of the study is that the majority of the children were assessed after 8 years of age, a long enough period of time to allow for the diagnosis of most neurodevelopmental disorders.  Although the study observed a higher incidence of neurodevelopmental disorders among children exposed to antipsychotic drugs during the second half of pregnancy compared to unexposed children, this finding was no longer significant after adjustment for confounding by maternal characteristics and other factors which negatively affect fetal development, with the possible exception of aripiprazole. 

Further studies are necessary to better understand the potential risk of neurodevelopmental disorders associated with aripiprazole exposure; this study does not establish a causal link between aripiprazole exposure and risk of neurodevelopmental disorders. In this study, aripiprazole was one of the newer antipsychotic medications, and the authors hypothesized that women treated with aripiprazole may have more severe illness and that severe illness may be associated with other factors which influence outcomes. However, even if we consider that there may be an increased risk of neurodevelopmental disorders in children exposed to aripiprazole, it is a relatively small increase in risk.  Decisions to maintain or discontinue a given medication must be made on a case-by-case basis, considering the risks related to exposure, as well as  the risks associated with discontinuing a particular medication, specifically recurrence of illness.   

Ruta Nonacs, MD PhD

Straub L, Hernández-Díaz S, Bateman BT, Wisner KL, Gray KJ, Pennell PB, Lester B, McDougle CJ, Suarez EA, Zhu Y, Zakoul H, Mogun H, Huybrechts KF. Association of Antipsychotic Drug Exposure in Pregnancy With Risk of Neurodevelopmental Disorders: A National Birth Cohort Study. JAMA Intern Med. 2022 Mar 28. 


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