Taiwan: Study on Benzodiazepine Use and Miscarriage Risk

A nationwide case-time-control study showed an increased miscarriage risk associated with benzodiazepine use during pregnancy after accounting for measurable confounders, and findings were unlikely to be due to unmeasured confounding.

The findings published in JAMA Psychiatry indicate that healthcare professionals should meticulously balance the risk-benefit ratio when considering benzodiazepine use for treating sleep and psychiatric disorders during pregnancy.

"The study of more than 3 million pregnancies found that benzodiazepine use was linked with a 69% increased risk of miscarriage," the researchers reported. "The increased risk was present for both long-acting (OR 1.67) and short-acting (OR 1.66) benzodiazepines."

Owing to the potential adverse effects of benzodiazepine on neonates, the use of this drug class during pregnancy has raised significant concerns. There are limited studies on the association between benzodiazepine use and the risk of miscarriage. To fill this knowledge gap, Lin-Chieh Meng, National Taiwan University, Taipei, Taiwan, and colleagues aimed to quantify the risk of miscarriage linked with benzodiazepine use during pregnancy after controlling for unmeasured confounders and exposure time trends.

The nationwide, population-based case-time-control study was conducted using Taiwan’s National Birth Certificate Application database and the National Health Insurance database. The pregnancies that resulted in miscarriage between 2004 and 2018 were included in the case group. They were 1:1 matched with exposure time-trend control individuals using disease risk score, considering prepregnancy comorbidities and demographic characteristics.

Discordant exposures to benzodiazepines during the risk period (1-28 days before miscarriage) and two reference periods (31-58 days and 181-208 days prior to the last menstrual period) were compared for each pregnancy.

Miscarriage was defined as any pregnancy loss that occurred between the first prenatal care visit (usually 8 weeks) and the 19th completed pregnancy week.

Findings

• This study included 3,067,122 pregnancies among 1,957,601 women, 4.4% of which resulted in miscarriage. The mean age of the study population was 30.61 years.
• Benzodiazepine use during pregnancy was associated with an increased risk of miscarriage (odds ratio [OR], 1.69), and consistent findings were observed across multiple sensitivity analyses considering different time windows and accounting for misclassification.
• In subgroup analyses, an increased risk of miscarriage was associated with each commonly used individual benzodiazepine, ranging from case-time-control ORs of 1.39 for alprazolam to 2.52 for fludiazepam.

"The observation of an increased miscarriage risk associated with the use of benzodiazepines suggests that benzodiazepines should only be used after a thorough evaluation of the potential benefits and risks for both the mother and child," the researchers concluded.

Reference

Meng L, Lin C, Chuang H, Chen L, Hsiao F. Benzodiazepine Use During Pregnancy and Risk of Miscarriage. JAMA Psychiatry. Published online December 27, 2023. doi:10.1001/jamapsychiatry.2023.4912