The use of the newer “atypical” or second-generation antipsychotic agents continues to increase.  These medications are used to treat a spectrum of psychiatric disorders, including schizophrenia, bipolar disorder, major depression, PTSD and anxiety disorders.  Although most of the women taking atypical antipsychotics are of childbearing age, our information on the reproductive safety of these newer atypical agents lags behind.

When evaluating the reproductive safety of the atypical antipsychotics, the richest data regarding the potential risks of exposure come from prospective studies, where pregnant women taking a particular medication are enrolled during the early stages of pregnancy (before outcomes are known). One example of such a study analyzed data collected through the National Pregnancy Registry for Atypical Antipsychotics.  This study included a total of 489 women taking atypical antipsychotics; rates of congenital malformations did not differ significantly between exposed and unexposed groups.

This type of study is the gold standard and gives us the most detailed information on pregnancy exposures to antipsychotics, potentially allowing us to control for potential confounding factors — for example, exposure to other medications, medical illness, and use of tobacco, alcohol and recreational drugs.  However, the numbers of women included in prospective studies are typically small.  Larger numbers of exposed infants are required in order to accurately and quantify the risks associated with exposure to specific antipsychotic medications.  

In order to retrieve data from larger numbers of pregnancy exposures, analyses can be conducted using large healthcare delivery databases.  While this approach dramatically increases the number of exposures, one downside is that these databases usually include less detailed information regarding other variables which may affect pregnancy outcomes.  In a study published last week in JAMA Psychiatry, Huybrechts and colleagues examined the risk of congenital malformations associated with first-trimester exposure to antipsychotic medications.  This analysis collected data from a nationwide sample of 1?360?101 pregnant women enrolled in Medicaid who gave birth to a live infant between January 1, 2000 and December 31, 2010.   

During the first trimester, 9258 women (0.69%) filled at least one prescription for an atypical antipsychotic and 733 women (0.05%) filled at least one prescription for a typical antipsychotic.  In the group of women taking atypicals, the most commonly used medications were quetiapine (n = 4221), aripiprazole (n = 1756), risperidone (n = 1566), olanzapine (n = 1394), and ziprasidone (n = 697).

The presence of congenital malformations was defined on the basis of inpatient or outpatient diagnoses and procedure codes.  In women with no exposure to antipsychotic medication, 32.7 (95% CI, 32.4-33.0) per 1000 infants were diagnosed with congenital malformations compared to 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical antipsychotics.

In an unadjusted analysis, the researchers calculated a small but statistically significant increase in risk for malformations for atypical antipsychotics (RR=1.36; 95% CI, 1.24-1.50) but not for typical antipsychotics (RR=1.17; 95% CI, 0.81-1.68).  However, after controlling for potential confounding variables, the relative risk was reduced to 1.05 (95% CI, 0.96-1.16) for atypical antipsychotics and 0.90 (95% CI, 0.62-1.31) for typical antipsychotics.

The researchers also specifically examined risk for cardiac malformations.  The overall risk for cardiac malformations was not increased when comparing exposed versus unexposed infants.  However, when individual agents were evaluated, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was observed for risperidone.

The Take-Home Message

These findings, taken together with other studies,  suggest that prenatal exposure to atypical antipsychotics does not meaningfully increase the risk for congenital malformation or cardiac malformations, with the possible exception of risperidone. In addition, this study did not include adequate numbers of exposures to some of the newest atypicals, such as lurasidone (Latuda), iloperidone (Fanapt), and brexpiprazole (Rexulti).

It is unclear how to interpret the data regarding risperidone.  In another study, Ennis and Damkier  reported an unadjusted relative risk for major congenital malformations of 1.5 (95% CI, 0.9-2.2) for risperidone (432 exposed pregnancies).  The authors note that the small increase in absolute risk and relative risk for malformations observed with risperidone “should be interpreted with caution because no apparent biological mechanism can readily explain this outcome, and the possibility of a chance finding cannot be ruled out.”  Further studies are required to better understand the risks associated with risperidone.  That said, even if we assume that there is an increased risk associated with the use of risperidone, the risk appears to be relatively small.

The findings of this study increases our comfort with using the atypical antipsychotics in women who are pregnant or planning to conceive.  We will continue to gather information on the reproductive safety of this class of medications through the National Pregnancy Registry for Atypical Antipsychotics.  Those interested in the study may call  TOLL-FREE to learn more 1-866-961-2388 or may fill out this Patient Interest Form to be contacted by our research coordinator. All information is kept strictly confidential.  

Ruta Nonacs, MD PhD

Huybrechts KF, Hernández-Díaz S, Patorno E, Desai RJ, Mogun H, Dejene SZ, Cohen JM, Panchaud A, Cohen L, Bateman BT.  Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations.  JAMA Psychiatry. 2016 Aug 17. [Epub ahead of print]


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