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Benzodiazepine Use Early in Pregnancy and Risk for Congenital Malformations
Kelly Fung1, Ayesha C Sujan2, Brian T Bateman2
1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (K.F., L.S., G.B., Y.Z.).
Background:
Existing data on malformations associated with benzodiazepine use in pregnancy are conflicting.
Objective:
To assess the risk for major congenital malformations from first-trimester exposure to benzodiazepines.
Design:
Population-based U.S. cohort study.
Setting:
Medicaid (2000-2018) and Merative MarketScan (2003-2020) databases.
Participants:
Pregnant persons enrolled from 90 days before pregnancy to 30 days after delivery, and their live-born infants enrolled for 90 days after birth.
Measurements:
Exposure was defined as at least 1 fill of a benzodiazepine in the first trimester. Primary outcomes were any major congenital malformation and organ-specific malformations previously associated with benzodiazepine exposure. The investigators estimated relative risks (RRs) comparing exposed versus unexposed pregnancies with propensity score fine stratification weights to control for confounders. An RR of 1.3 or higher was prespecified as clinically significant.
Results:
In total, 51 339 of 2 478 434 (2.1%) publicly insured and 27 779 of 1 750 721 (1.6%) commercially insured pregnancies had benzodiazepine exposure. The adjusted absolute risks for any malformation in exposed versus unexposed pregnancies were 4.0% versus 4.1% for Medicaid and 4.9% versus 4.8% for MarketScan. The pooled adjusted RR was 0.99 (95% CI, 0.96 to 1.03). Associations with organ-specific malformations were not consistently observed in sensitivity analyses, nor was a dose-response relationship observed. Analyses of different benzodiazepines yielded similar results. The risk for selected organ-specific malformations was increased in some analyses of coexposure to benzodiazepines and other psychoactive medications, but a consistent pattern did not emerge.
Limitations:
Potential nondifferential exposure and outcome misclassification; analyses restricted to malformations prevalent at birth.
Conclusion:
No substantial increase in the risk for malformations was consistently identified across data sources. Findings from coexposure analyses were inconsistent and warrant further study.
Primary Funding Source:
National Institute of Child Health and Human Development.