Safety of Prenatal Exposure to Benzodiazepines, Z-Drugs Inconclusive

Currently, the long-term safety of prenatal exposure to benzodiazepines (BZPs) and z-drugs is inconclusive, according to study findings published in the journal Neuroscience and Biobehavioral Reviews.

BZPs and z-drugs might pass readily through the placenta and the fetal blood-brain barrier when used during pregnancy. These drugs have the potential to bind to γ-amino butyric acid receptors in the developing fetal brain. This prompted the researchers to evaluate the impact of these agents on neurodevelopmental outcomes in offspring. In a systematic review, they examined the effects of BZP and z-drug use during pregnancy and cognitive, behavioral, emotional, and motor skills developmental outcomes.

After conducting an extensive search of possible relevant studies, a total of 19 studies were ultimately found to be eligible for inclusion in the analysis. All of the 19 studies selected had a cohort design, had been conducted between 1958 and 2016, and had been published from 1975 to 2020. Overall, 12 of the studies originated from Western Europe, whereas the remaining 7 studies were conducted in North America.

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Harvest plots were used to visualize the directions of the reported associations. Exposures were grouped by type of drugs, based on the exposure definitions and the ATC codes provided in the original studies: (1) any BZDs and z-drugs; (2) BZDs only; (3) z drugs only; (4) BZD anxiolytics only; (5) BZD antiepileptics only; (6) BZD-anxiolytics/sedatives/hypnotics and z-drugs (if BZD-anxiolytics were not included); and (7) BZDs unspecified (if the exact agents were not specified).

Outcomes were categorized according to 4 developmental domains: (1) cognitive development; (2) emotional development; (3) behavior development; and (4) motor skills development. For each of the developmental domains, a separate harvest plot with multiple panels was created (ie, one panel for each type of drug exposure).

The researchers noted that despite finding several associations between specific types of BZPs and z-drugs, and the increased risk for neurodevelopmental outcomes, like lower communication skills, research on the topic was extremely limited. They highlighted inconsistencies in the methodology previous studies used, in particular, the controlling for confounding by indication. Hence, they agreed they would not be able to draw any reasonable conclusions with certainty regarding the long-term safety of maternal exposure to these drugs on neurodevelopmental outcomes in infants.

Study limitations the overall scarcity of data on prenatal exposure to BZPs and/or z-drugs and neurodevelopmental conditions in offspring — particularly the limited data on exposure to distinct types of agents.

The investigators concluded that “High-quality empirical research on the safety of BZD and z-drug use during different stages on fetal brain development is urgently needed.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Wang X, Zhang T, Ekheden I, et al. Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: a systematic review. Neurosci Biobehav Rev. Published online April 1, 2022. doi:10.1016/j.neubiorev.2022.104647

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