Study Reassures on Benzodiazepines in Early Pregnancy

— Past research on congenital malformations has been mixed

Benzodiazepine exposure in early pregnancy wasn't associated with congenital malformations, a large cohort study showed.

Across more than 4 million pregnancies, children born to women who filled a benzodiazepine prescription during the first trimester did not have elevated risk of congenital malformations compared with children of women with no such fills (pooled adjusted RR 0.99, 95% CI 0.96-1.03), reported Kelly Fung, MS, of Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues.

In Medicaid-insured pregnancies, the adjusted absolute risk for any congenital malformation was 4.0% among those exposed to benzodiazepines and 4.1% for unexposed. For commercially insured patients, these absolute risks were 4.9% and 4.8% for exposed and unexposed, respectively, they wrote in Annals of Internal Medicineopens in a new tab or window.

The pooled analysis also didn't reveal any significant differences in risk of organ-specific malformations, including cardiac (aRR 1.02, 0.96-1.08), oral cleft (aRR 0.89, 0.75-1.07), gastrointestinal (aRR 1.10, 1.01-1.19), central nervous system (aRR 0.97, 0.84-1.12), or eye malformations (aRR 1.07, 0.80-1.44).

Co-author Krista Huybrechts, MS, PhD, also of Brigham and Women's Hospital and Harvard Medical School, told MedPage Today this study "provides the most comprehensive U.S. evidence to date on benzodiazepine use early in pregnancy and major congenital malformations."

"These findings are reassuring with respect to major congenital malformations, but benzodiazepines are not risk-free," she added, noting that they can come with dependence, misuse, cognitive adverse effects, and withdrawal.

About one in five women experience anxiety disorders during pregnancy and postpartum. The American College of Obstetricians and Gynecologists recommendsopens in a new tab or window that mental health treatment in pregnancy is collaboratively determined by both mental health and obstetric providers.

"Yet for benzodiazepines, rigorous and comprehensive safety data to inform such decisions are sparse, evidence is conflicting, and numerous concerns have been raised," Huybrechts said.

Some previous researchopens in a new tab or window has suggested elevated risk for some malformations associated with benzodiazepine use, but those studies have been small and limited. So, the authors conducted this large analysis to address this information gap.

For this population-based cohort study, the team used two large U.S. health insurance databases: Medicaid and Merative MarketScan. They looked at pregnant women between ages 12 and 55 linked to live-born infants. Eligible women were insured from 3 months before their last menstrual period through 1 month after delivery, and their infants were also insured for at least 3 months after birth.

Women who had one filled prescription for a benzodiazepine in the first trimester of pregnancy were identified and compared to women with no fills for 3 months before their last menstrual period. The benzodiazepines included were alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, temazepam, and triazolam.

Of the more than 2.4 million publicly insured pregnancies, 2.1% had benzodiazepine exposure and 1.6% of the 1.7 million commercially insured pregnancies did. In both cohorts, women exposed to benzodiazepines skewed older and had more psychiatric and chronic health conditions than the unexposed group.

The primary outcomes were overall malformations and organ-specific malformations previously associated with benzodiazepine exposure. Other types of organ-specific malformations were secondary outcomes. Congenital malformations were identified via ICD codes.

Several sensitivity analyses largely yielded similar results to the main findings. For instance, there were no major differences among pregnancies with at least two benzodiazepine fills in the first trimester or with different doses.

Results were similar among different benzodiazepines, though there was an increase in eye malformation risk observed among commercially insured women exposed to diazepam. Some organ-specific malformations had increased risk with co-exposure to benzodiazepines and other psychoactive medications, but there was not a consistent pattern.

The authors noted some limitations, including that it's possible patients didn't take their filled prescriptions, that some malformation cases may have been missed, and residual confounding. The analysis was also restricted to live births, which means that severe malformations that resulted in miscarriage, stillbirth, or pregnancy termination would have been missed.

Huybrechts noted that research looking beyond major birth defects to other outcomes like miscarriageopens in a new tab or window, preterm birth, and neonatal effects is still needed.

"Ultimately, the goal is to provide a fuller picture of both the risks of medication and the risks of leaving serious psychiatric conditions untreated," she said.