Antipsychotic agents not linked to birth defects
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Exposure to antipsychotics during pregnancy may not increase risk for birth defects, according to a study published in JAMA Psychiatry.
“We conducted this study because psychiatric disorders are common among women of reproductive age and while antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps,” Krista F. Huybrechts, MS, PhD, associate professor of medicine and epidemiology at Harvard Medical School and Harvard T.H. Chan School of Public Health, told Healio.
Exposure to drugs that cross the placenta, such as antipsychotics, can be a major concern during pregnancy due to potential teratogenicity, Huybrechts and colleagues wrote.
To assess the risk of first-trimester exposure to antipsychotic drugs on congenital malformations, the researchers evaluated cohort study data from nationwide health registers from five Nordic countries and the United States collected from 1996 to 2018. The Nordic cohort included all singleton live-born infants and the U.S. cohort included publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract.
The study included a total of 6,455,324 unexposed pregnancies (mean maternal age, 24-31 years), 21,751 pregnancies with exposure to atypical antipsychotics (mean maternal age, 26-31 years) and 6,371 with exposure to typical antipsychotics (mean maternal age, 27-32 years). The most common atypical antipsychotics were quetiapine, aripiprazole and olanzapine and the most common typical antipsychotics were chlorpromazine, dixyrazine (in Nordic countries only) and perphenazine.
Results showed that the prevalence of any major malformation was 2.7% (95% CI, 2.7-2.8) among unexposed infants, 4.3% (95% CI, 4.1-4.6) among infants exposed to atypical antipsychotic drugs and 3.1% (95% CI, 2.7-3.5) among infants exposed to typical antipsychotic drugs in utero.
Adjusted relative risks were generally close to null among the most prevalent exposure-outcome combinations, except for olanzapine exposure and oral cleft, for which the aRR was 2.1 (95% CI, 1.1-4.3).
However, estimates varied across sensitivity analyses, according to the data. Among moderately prevalent combinations, the researchers found increased risks for gastroschisis (aRR, 1.5; 95% CI, 0.8-2.6) and specific brain anomalies (aRR, 1.9; 95% CI, 1.1-3) after exposure to atypical antipsychotics. They also noted an increased risk for cardiac malformations after chlorprothixene exposure (aRR, 1.6; 95% CI, 1-2.7).
Despite an association direction that was consistent across sensitivity analyses, the confidence intervals were wide, Huybrechts and colleagues noted.
“To be most clinically useful, information on the safety of antipsychotic medications during pregnancy must focus on individual drugs and specific teratogenic effects,” Huybrechts said. “We were able to do so by pooling information from six countries. This study clearly illustrates that one, antipsychotics are not major teratogens; and two, spurious associations can — and will — occur, especially in the context of sparse data and a large number of comparisons.”
Huybrechts said in order to meaningfully inform clinical practices, it is “crucial” to present results in a way that conveys the confidence in the findings.
“Our study presented one possible way of doing so,” she said. “We found no consistent safety signals for the causal contrasts supported by a substantial amount of information, suggesting that antipsychotics are not major teratogens.”
Huybrechts noted that some of the findings warrant further study.
“In the context of multiple comparisons, we identified ‘signals’ of increased risks of oral cleft associated with olanzapine, gastroschisis and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene,” she said. “These signals require confirmation as evidence continues to accumulate.”