02. Risk of Major Malformations Following First-Trimester Exposure to Olanzapine

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Hi! David Rosenberg here for the Psychopharmacology Institute. In this Child and Adolescent Psychiatry Smart Take, we’ll take a close look at the risk of major malformations following first trimester exposure to olanzapine. Following FDA approval, olanzapine became one of the most prescribed antipsychotics. Due to significant weight gain and other metabolic side effects, its use as the primary pharmacotherapy for bipolar disorder and schizophrenia has decreased; however, it remains a crucial treatment option. Despite its side effects, it is one of the most effective antipsychotics. Olanzapine, combined with fluoxetine, is FDA approved for bipolar I depression and treatment-resistant depression. Major concerns surround lithium’s use in reproductive-aged women, especially during the first trimester. Lithium’s onset of action may be slower compared with second-generation antipsychotics.

Now, the FDA announced the release of a combination medication: Olanzapine and samidorphan. This combination seems to pose a significantly lower risk of weight gain vs olanzapine alone. Beyond its FDA-approved uses, olanzapine is employed for various off-label indications: Autism spectrum disorder, eating disorders, anxiety, aggression, sleep disturbance, and delirium, among others. Given these factors, a comprehensive assessment of its risk for major malformations in women exposed to olanzapine during the first trimester is imperative—especially considering potential delays in recognizing pregnancy.

The Massachusetts General Hospital National Pregnancy Registry for Psychotropic Medication tracks pregnant women both during pregnancy and postpartum. Initially focusing on atypical antipsychotics, it now encompasses other psychotropic medication classes. The authors analyzed data from over 2,600 women. Of these, 49 infants exposed to olanzapine were compared with 1,156 infants whose mothers had psychiatric disorders but did not use a second-generation antipsychotic.

The findings were encouraging: No major malformations were linked to olanzapine exposure during the first trimester. Although preliminary, these data build on prior reproductive safety data for olanzapine use during pregnancy—particularly the first trimester. It is noteworthy that the analysis could not dismiss smaller effects from olanzapine exposure; however, major malformations were not observed. Both the olanzapine-exposed group and the comparison group had a risk of major malformations that was significantly lower than expected in the broader population. This disparity may reflect healthier behaviors in pregnant women who enroll in registries or might be attributed to random variations.

However, there are limitations. The data might not be applicable to other antipsychotics. Potential dose effects, interactions with other medications, and other factors weren’t clear. Larger samples are required to determine the risk associated with olanzapine and other antipsychotic medications during the first trimester. Most women in this study were White, married, and highly educated, which may not represent the general population. Furthermore, many women in this registry were diagnosed with bipolar disorder, not schizophrenia; thus, schizophrenia was underrepresented. Importantly, many authors of this study had significant ties to the pharmaceutical industry, including companies producing second-generation antipsychotic medications.

In conclusion, this research supports the notion that olanzapine exposure during the first trimester does not correlate with major malformations. Although minor effects cannot be dismissed based on this preliminary sample, the findings are reassuring for practitioners treating women of reproductive age.

Abstract

Purpose/background: Since its US Food and Drug Administration approval in 1996, olanzapine has been one of the most commonly prescribed atypical antipsychotics, making a better understanding of its reproductive safety profile critical. The goal of the current analysis was to determine the risk of major malformations among infants exposed to olanzapine during pregnancy compared with a group of nonexposed infants.

Methods/procedures: The National Pregnancy Registry for Psychiatric Medications is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Labor and delivery and pediatric medical records were screened for evidence of major malformations followed by adjudication by a dysmorphologist blinded to medication exposure. Infants with first-trimester exposure to olanzapine were compared with controls without second-generation antipsychotic exposure.

Findings/results: As of April 18, 2022, 2619 women have enrolled in the study. At the time of data extraction, 49 olanzapine-exposed infants and 1156 infants in the comparison group were eligible for these analyses. There were no major malformations associated with olanzapine exposure in the first trimester. The absolute risk for major malformations in the exposure group was 0.00% (95% confidence interval, 0.00-7.25) for olanzapine compared with 1.64% (95% confidence interval, 0.99-2.55) in the control group.

Implications/conclusions: In this prospective cohort, no major malformations were associated with olanzapine exposure during the first trimester. Although these data are preliminary and cannot rule out more modest effects, they are nonetheless important, adding to the growing reproductive safety data for olanzapine.

Reference

Viguera, A. C., Freeman, M. P., Kobylski, L. A., Rossa, E. T., Gaccione, P., Chitayat, D., et al. (2023). Risk of major malformations following first-trimester exposure to olanzapine: Preliminary data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications. Journal of Clinical Psychopharmacology, 43(2), 106-112.