Early Benzodiazepine Use: No Major Rise in Birth Defect Risk

TOPLINE Exposure to benzodiazepines during the first trimester was not linked to a substantially higher risk for major congenital malformations. METHODOLOGY Researchers conducted a population-based cohort study using data from Medicaid (from 2000 to 2018) and Merative MarketScan (from 2003 to 2020) databases to assess the link between exposure to benzodiazepines during early pregnancy and the risk for congenital malformations.

Among nearly 2.5 million publicly insured and about 1.75 million commercially insured pregnancies in the US, 2.1% and 1.6%, respectively, had at least one filled prescription for a benzodiazepine during the first trimester. The benzodiazepine category included alprazolam (the most commonly prescribed), clobazam, clonazepam, chlordiazepoxide, clorazepate, diazepam, and others.

Those without any filled prescriptions for benzodiazepines in the 3 months preceding the last menstrual period and during the first trimester served as the comparison group. The main outcomes were any major congenital defects and organ-specific anomalies that were reported earlier to be linked to exposure to benzodiazepines (ie, cardiac, oral cleft, central nervous system, gastrointestinal, and eye malformations).

Propensity score fine stratification weights were estimated to adjust for confounding factors. A pooled adjusted relative risk (aRR) of at least 1.3 was prespecified as a possible signal of malformations and was considered when an increased risk was noted in both cohorts. TAKEAWAY Among enrollees of Medicaid, the absolute risk for any malformation with vs without exposure to benzodiazepines was 4.00% vs 3.25% in the unadjusted analysis.

Among commercially insured individuals, the absolute risks were 4.90% vs 3.74%, respectively. The pooled risk for any major congenital malformation was not increased with benzodiazepines (pooled aRR, 0.99; 95% CI, 0.96-1.03). A small increase was noted in the risk for malformations in the gastrointestinal system (pooled aRR, 1.10; 95% CI, 1.01-1.19).

RRs for malformations in other organ systems remained under the threshold of 1.3, with similar findings observed for exposures to alprazolam, clonazepam, or lorazepam. Coexposure analyses showed higher risks for malformations in the gastrointestinal or central nervous system with exposure to benzodiazepines combined with antiepileptic drugs and mood stabilizers than with exposure to neither medication, but estimates approached the null value when compared with exposure to the psychoactive medication alone.

IN PRACTICE "We did not observe substantial increases in the risk for congenital malformations associated with first-trimester benzodiazepine use, in contrast to other studies," the researchers wrote. "The safety profile of benzodiazepine use during pregnancy requires further research to examine these risks and other adverse pregnancy outcomes, including preterm birth and nonlive birth," they added.

SOURCE The study was led by Kelly Fung, MS, of the Department of Medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, and Ayesha C. Sujan, PhD, of the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University School of Medicine in Stanford, California.

It was published online on October 12 in Annals of Internal Medicine . LIMITATIONS Exposure was determined by whether a prescription for a benzodiazepine was filled during the first 3 months of pregnancy; however, the medication may not have actually been taken, which could weaken the associations.

Outcomes were based on medical diagnoses and procedure codes within 90 days after delivery, so some cases might have been overlooked. The study only included live births. DISCLOSURES The study was funded by the National Institute of Child Health and Human Development.

Additional disclosures are noted with the article online. This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.