Increased miscarriage risk linked to benzodiazepine use in pregnancy

Key takeaways:

• Both long- and short-acting benzodiazepine use in pregnancy was associated with increased risk for miscarriage.
• Miscarriage risks were associated with each commonly used individual benzodiazepine type.

Benzodiazepine use during early pregnancy was associated with almost 70% increased risk for miscarriage after accounting for measurable confounders, according to study results published in JAMA Psychiatry.

“When used during pregnancy, benzodiazepines can readily cross the placental barrier and accumulate substantially in embryo and fetal tissues,” Lin-Chieh Meng, MS, from the Graduate Institute of Clinical Pharmacy at the College of Medicine at National Taiwan University, Taipei, and colleagues wrote. “Given their potential role in cell proliferation and differentiation processes, it is plausible that benzodiazepines may cause fetal developmental abnormalities, ultimately leading to miscarriage.”

Meng and colleagues conducted a nationwide, population-based case-time-control study with data from 3,067,122 pregnancies from 1,957,601 women (mean age, 30.61 years) occurring from 2004 to 2018. Data were obtained from Taiwan’s National Birth Certificate Application database and the National Health Insurance database. Of these pregnancies, 4.4% resulted in miscarriage, defined as any pregnancy loss between the first prenatal care visit and the 19th completed week of pregnancy. These were matched with exposure time-trend control individuals. Researchers assessed discordant benzodiazepine exposures during the risk period — 1 to 28 days before miscarriage — and during two reference periods — 31 to 58 days and 181 to 208 days before last menstruation.

Overall, 1,502 pregnancies were exposed to benzodiazepines during the risk period and 2,806 were exposed during the reference periods.

Benzodiazepine use in pregnancy was linked to increased miscarriage risk (OR = 1.69; 95% CI, 1.52-1.87) with both long-acting (OR = 1.67; 95% CI, 1.44-1.93) and short-acting (OR = 1.66; 95% CI, 1.47-1.87) benzodiazepines. Findings were consistent across multiple sensitivity analyses that considered different time windows and misclassification.

In subgroup analyses, researchers noted that miscarriage risk increases were associated with each commonly used individual benzodiazepine type ranging from an OR of 1.39 for alprazolam to 2.52 for fludiazepam.

“These findings suggest that caution is warranted when using benzodiazepines during early pregnancy,” the researchers wrote. “The findings of this study also provide evidence to guide clinicians in making informed decisions regarding the treatment of psychiatric and sleep disorders in pregnant women.”