Study eases concerns over benzodiazepine exposure in early pregnancy

Clinical takeaway: A large U.S. analysis found no substantial increase in major congenital malformations after first-trimester benzodiazepine exposure. These findings can help inform counseling, although prescribing decisions should still account for other maternal and neonatal risks.

Conflicting evidence has complicated counseling about benzodiazepine use during pregnancy. These medications may help selected patients with severe anxiety, but concerns include dependence, withdrawal, and neonatal sedation.

A US cohort study, published in Annals of Internal Medicine, analyzed 4.2 million pregnancies resulting in live births using Medicaid claims from 2000–2018 and commercial insurance claims from 2003–2020. About 79,000 pregnancies had at least one benzodiazepine prescription filled during the first trimester. Researchers compared birth defect risk in these pregnancies with that in pregnancies without benzodiazepine exposure.

After adjustment for patient characteristics, major congenital malformation risks were nearly identical between exposed and unexposed pregnancies. In the Medicaid cohort, risks were 4.0% and 4.1%, respectively; in the commercially insured cohort, they were 4.9% and 4.8%. Results were generally consistent across commonly prescribed benzodiazepines, with no evidence of a dose-response relationship.

The primary analysis, which defined exposure as a single prescription fill, found a 10% increase in gastrointestinal malformations among exposed pregnancies. However, when exposure was restricted to women with at least two first-trimester prescription fills, the estimated increase fell to 2% and was no longer statistically significant.

Analyses of concurrent use of other psychoactive medications suggested possible increases in certain specific defects, but the findings were inconsistent and should be interpreted cautiously pending further study.

As an observational study, the analysis could not confirm whether dispensed medications were actually taken, and residual confounding remains possible. In addition, because the study included only live births, it could not capture malformations in pregnancies ending in miscarriage, stillbirth, or termination.

“We did not observe substantial increases in the risk for congenital malformations associated with first-trimester benzodiazepine use, in contrast to other studies,” the authors wrote. “However, these drugs have other significant risks, regardless of pregnancy, such as dependence, misuse, cognitive adverse effects, and withdrawal.”

Source: Fung K, et al. (2026 Oct 13) Ann Intern Med. Benzodiazepine Use Early in Pregnancy and Risk for Congenital Malformations