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First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study

Ban, Lu; West, Joe; Gibson, Jack E.; Fiaschi, Linda; Sokal, Rachel; Doyle, Pat; Hubbard, Richard; Smeeth, Liam; Tata, Laila J.


Lu Ban

Professor of Epidemiology

Assistant Professor in Epidemiology

Senior Research Fellow in Health

Rachel Sokal

Pat Doyle

Blf/Gsk Professor of Epidemiological Resp Research

Liam Smeeth


BACKGROUND: Despite their widespread use the effects of taking benzodiazepines and non-benzodiazepine hypnotics during pregnancy on the risk of major congenital anomaly (MCA) are uncertain. The objectives were to estimate absolute and relative risks of MCAs in children exposed to specific anxiolytic and hypnotic drugs taken in the first trimester of pregnancy, compared with children of mothers with depression and/or anxiety but not treated with medication and children of mothers without diagnosed mental illness during pregnancy.

METHODS: We identified singleton children born to women aged 15–45 years between 1990 and 2010 from a large United Kingdom primary care database. We calculated absolute risks of MCAs for children with first trimester exposures of different anxiolytic and hypnotic drugs and used logistic regression with a generalised estimating equation to compare risks adjusted for year of childbirth, maternal age, smoking, body mass index, and socioeconomic status.

RESULTS: Overall MCA prevalence was 2.7% in 1,159 children of mothers prescribed diazepam, 2.9% in 379 children with temazepam, 2.5% in 406 children with zopiclone, and 2.7% in 19,193 children whose mothers had diagnosed depression and/or anxiety but no first trimester drug exposures. When compared with 2.7% in 351,785 children with no diagnosed depression/anxiety nor medication use, the adjusted odds ratios were 1.02 (99% confidence interval 0.63–1.64) for diazepam, 1.07 (0.49–2.37) for temazepam, 0.96 (0.42–2.20) for zopiclone and 1.27 (0.43–3.75) for other anxiolytic/hypnotic drugs and 1.01 (0.90–1.14) for un-medicated depression/anxiety. Risks of system-specific MCAs were generally similar in children exposed and not exposed to such medications.

CONCLUSIONS: We found no evidence for an increase in MCAs in children exposed to benzodiazepines and non-benzodiazepine hypnotics in the first trimester of pregnancy. These findings suggest that prescription of these drugs during early pregnancy may be safe in terms of MCA risk, but findings from other studies are required before safety can be confirmed.


Ban, L., West, J., Gibson, J. E., Fiaschi, L., Sokal, R., Doyle, P., …Tata, L. J. (2014). First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study. PLoS ONE, 9(6),

Journal Article Type Article
Acceptance Date May 31, 2014
Publication Date Jun 25, 2014
Deposit Date Apr 11, 2016
Publicly Available Date Apr 11, 2016
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 6
Article Number e100996
Public URL
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Copyright Statement Copyright information regarding this work can be found at the following address:


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