Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: A systematic review

Neurosci Biobehav Rev. 2022 Jun:137:104647. doi: 10.1016/j.neubiorev.2022.104647. Epub 2022 Apr 1.


When used during pregnancy, benzodiazepines (BZDs) and related z-drugs could pass readily through the placenta and the foetal blood-brain barrier, where they can bind to γ-amino butyric acid (GABA) receptors in the developing foetal brain. Yet, data on long-term safety of prenatal BZD and z-drug use and its impact on offspring neurodevelopment are inconclusive. In this systematic review, we qualitatively synthetize the existing evidence on maternal exposure to various BZDs and z-drugs during pregnancy and offspring cognitive, emotional, behavioural, and motor skills developmental outcomes. Nineteen studies were included. We used harvest plots to visualize the directions of reported associations. Despite several associations between distinct types of BZDs and z-drugs and an increased risk of outcomes within different neurodevelopmental domains were observed, a remarkable scarcity of overall research on the topic and considerable discrepancies in methodology, particularly towards controlling for confounding by indication, precluded drawing conclusions with a reasonable degree of certainty. We outline various research strategies to mitigate methodological limitations and provide directions for future empirical studies on the topic.

Keywords: Antiepileptics; Anxiolytics; Benzodiazepines; Child neurodevelopmental outcomes; Hypnotics; Pregnancy; Prenatal exposure; Z-drugs.

Publication types

  • Review
  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzodiazepines* / adverse effects
  • Female
  • Humans
  • Hypnotics and Sedatives
  • Pregnancy
  • Prenatal Exposure Delayed Effects* / chemically induced
  • Prenatal Exposure Delayed Effects* / psychology


  • Hypnotics and Sedatives
  • Benzodiazepines