Benzo teratogenic ?


This article presents a critical appraisal of a recent meta-analysis on the assocation between gestational exposure to benzodiazepines and major congenital malformations in the offspring.





Sept 12, 2019: Vol 19 No 95


In a systematic review and meta-analysis of 8 cohort studies, Grigoriadis et al (2019) found that first trimester exposure to benzodiazepines, anytime gestational exposure to benzodiazepines, and gestational exposure to benzodiazepines in studies that adjust for psychiatric diagnosis show no association with major congenital malformation (MCM) risk. Likewise, gestational exposure to benzodiazepines is not associated with the cardiac malformation risk. However, first trimester exposure to combined benzodiazepines and antidepressants is associated with increased MCM risk.


1. In some of the analyses, such as that of overall MCM risk associated with anytime gestational benzodiazepine exposure, and cardiac malformation risk associated with anytime exposure, the 95% CI suggested that the findings were compatible with a population OR value representing increased risk.

2. The above notwithstanding, all ORs were small to negligibly small. Given that the absolute risk was itself low, a small increase in a low absolute risk would represent a finding of low clinical significance.

3. Finally, a significant association does not imply a causal association because, in observational studies such as cohort studies, inadequately measured, unmeasured, and unknown confounds cannot be adjusted for. Examples of such confounds include illness-related behaviors that are not recorded or are below thresholds for clinical detection; such confounds tend to be associated with greater severity of illness and hence the likelihood of benzodiazepine use (confounding by indication).. At best, it can be concluded that benzodiazepine exposure anytime during pregnancy may be a marginal marker for MCMs and cardiac malformations; a causal association and one that is clinically significant is very far from being established.


Grigoriadis S, Graves L, Peer M, et al. Benzodiazepine use during pregnancy alone or in combination with an antidepressant and congenital malformations: systematic review and meta-analysis. J Clin Psychiatry. 2019;80(4):18r12412.


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