TOPLINE:

Benzodiazepine use during pregnancy is associated with a 20% higher risk for preterm birth and a 6% increased risk for small for gestational age, with more pronounced effects observed during the second trimester. The analysis of 454,477 pregnancies revealed that benzodiazepine use was linked to a 58% higher risk for abortion than nonuse.

METHODOLOGY:

• Researchers analyzed data from Taiwan’s National Health Insurance Research Database and National Birth Certificate Application database, covering 454,477 pregnancies between January 1, 2011, and December 31, 2021.
• Analysis included emulation of a sequence of open-label, randomized trials during gestational weeks 0 to 36, with eligibility criteria including pregnancy at gestational weeks 0-36, maternal age between 15 and 55 years, and no benzodiazepine use in the preceding 6 months.
• Primary outcomes measured included abortion (spontaneous and elective), stillbirth, preterm birth, and small for gestational age, with analyses stratified by gestational periods: first trimester (weeks 0-13), second trimester (weeks 14-26), and third trimester (weeks 27-36).
• Researchers implemented propensity score with inverse probability weighting to emulate randomization between treatment strategies, with weights truncated at 0.25th and 99.75th percentile.

TAKEAWAY:

• Benzodiazepine use was associated with increased risk for abortion (relative risk [RR], 1.58; 95% CI, 1.50-1.66), spontaneous abortion (RR, 1.65; 95% CI, 1.55-1.76), and elective abortion (RR, 1.83; 95% CI, 1.70-1.98).
• After accounting for competing events, benzodiazepine exposure showed increased risks for preterm birth (RR, 1.20; 95% CI, 1.18-1.23) and small for gestational age (RR, 1.06; 95% CI, 1.00-1.09).
• Risk analysis by trimester revealed more pronounced effects during the second trimester for both preterm birth and small for gestational age outcomes.
• The mean age of participants was 31.9 years (SD, 5.8) in the benzodiazepine group (59,521 pregnancies) and 31.6 years (SD, 5.3) in the nonuse group (394,956 pregnancies).

IN PRACTICE:

“Our findings may help inform clinicians’ prescribing thresholds for benzodiazepines during pregnancy by balancing the attenuated risks (compared with previous studies) against the potential therapeutic benefits for the underlying condition,” the authors of the study wrote. “Whether risks of adverse pregnancy outcomes differ by type of benzodiazepine, duration, dose, and continuity of treatment remain important unanswered questions. Nonetheless, the population-based risk estimates provided in this study will help to balance the importance of receiving benzodiazepine treatment against the potential increased risks for adverse pregnancy outcomes,” Anna Hung, PharmD, PhD, MS, of the Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, wrote in an accompanying editorial.

SOURCE:

This study was led by Brian Meng-Hsun Li, MClinPharm, School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University in Tainan, Taiwan. It was published online on December 22 in JAMA Internal Medicine.

LIMITATIONS:

According to the authors, while propensity score methods with inverse probability weighting were applied to emulate randomization and achieve balanced characteristics between treatment groups, residual confounding could not be completely ruled out. The study may have been subjected to minimal protopathic bias as some patients might have used benzodiazepines shortly before undergoing elective abortion. Additionally, the Birth Certificate Application database only included pregnancies exceeding 20 weeks, potentially leading to underestimation of abortion risk despite capturing abortion records from the National Health Insurance Research Database.

DISCLOSURES:

This study received support from grants provided by the National Science and Technology Council of Taiwan. Edward Chia-Cheng Lai, PhD, disclosed receiving grants from the National Science and Technology Council of Taiwan outside the submitted work. Hung reported receiving grants from the National Institutes of Health, the US Department of Veterans Affairs, Abbott, and AstraZeneca; personal fees from Genentech; and honoraria from the Academy of Managed Care Pharmacy outside the submitted work.

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