Gestational Exposure to Benzodiazepines and Z-Hypnotics and the Risk of Major Congenital Malformations, Ectopic Pregnancy, and Other Adverse Pregnancy Outcomes.

A small proportion of women with anxiety, insomnia, and other conditions may require benzodiazepines or z-hypnotics intermittently or daily sometime during pregnancy. This article provides an update on pregnancy outcomes associated with pre-gestational or gestational exposure to benzodiazepines and z-hypnotics based on results from 2 meta-analyses, 2 registry-based studies, and 2 large retrospective cohort studies. In summary, the meta-analyses found that exposure was associated with an increased risk of spontaneous abortion, induced abortion, preterm birth, low birth weight, small for gestational age, low Apgar scores at 5 min, and neonatal intensive care unit admission. Whereas meta-analyses and registry studies found that first trimester exposure to benzodiazepines and/or z-hypnotics was not associated with increased risk of congenital malformations, a nationwide observational study with 10 times as many exposed pregnancies as in all the previous studies combined found that first trimester exposure to benzodiazepines was associated with a small but statistically significantly increased risk of overall malformations as well as, specifically, cardiac malformations; in this study, analyses that examined the potential role of confounding by indication suggested that the adverse findings may not have been due to confounding. Finally, a large observational study found that exposure to benzodiazepines in the 90 days before conception was associated with an increased risk of ectopic pregnancy; in this study, as well, the findings were consistent in analyses that examined possible confounding by indication. In no reviewed study could residual confounding be ruled out. The take-home message is that benzodiazepine and z-drug exposure before and during pregnancy is associated with many adverse gestational outcomes, but it is unclear to what extent the findings are due to exposure to drugs vs exposure to the indication for treatment. Therefore, all treatment decisions need to be tailored to context and shared between health care professionals, patients, and their caregivers.