Research Article: Association of prenatal exposure to benzodiazepines and child internalizing problems: A sibling-controlled cohort study

Date Published: July 26, 2017

Publisher: Public Library of Science

Author(s): Ragnhild E. Brandlistuen, Eivind Ystrom, Sonia Hernandez-Diaz, Svetlana Skurtveit, Randi Selmer, Marte Handal, Hedvig Nordeng, Daimei Sasayama.


During pregnancy, many women experience sleep problems and anxiety that require treatment. The long-term safety for the child of maternal benzodiazepine (BZD) and z-hypnotic use during pregnancy remains controversial.

We conducted a cohort and a sibling control study using data from the Norwegian Mother and Child Cohort Study. Data on use of BZD and z-hypnotics, internalizing and externalizing outcomes, and covariates were collected from mothers at gestational weeks 17 and 30 and when children were 0.5, 1.5, and 3 years of age. The total sample consisted of 71,996 children (19,297 siblings) at 1.5 years and 55,081 children (13,779 siblings) at 3 years. Short-term use was defined as use in one pregnancy period only. Long-term use was defined as use in two or more pregnancy periods. Linear full cohort random-effect and sibling-matched fixed-effect regression models were used to compare internalizing and externalizing behavior in children prenatally exposed compared to those unexposed in the full cohort of pregnancies accounting for family clusters, as well as within sibling clusters comparing pregnancies with discordant exposures. Propensity score (PS) adjustment included variables on indication for use (sleep problems, symptoms of anxiety and depression) and other potential confounding factors.

Long-term prenatal exposure to BZD or z-hypnotics was associated with increased internalizing behavior in crude cohort analyses and at age 1.5 years after PS adjustment in sibling-matched fixed-effect models [β 0.60, 95% confidence interval 0.17–0.95]. Analyses on specific drug groups showed that prenatal exposure to BZD-anxiolytics was associated with increased internalizing problems at both 1.5 years [β 0.25, 0.01–0.49] and 3 years [β 0.26, 0.002–0.52] while exposure to z-hypnotics was not associated with any adverse outcomes after adjustment.

The findings suggest a moderate association between BZD-anxiolytic exposure and child internalizing problems that is not likely due to stable familial confounding factors.

Partial Text

Up to 20% of women are estimated to experience sleep problems and symptoms of anxiety during pregnancy [1, 2]. Between 1 and 3% of Norwegian women use benzodiazepine (BZD) or z-hypnotic drugs to treat anxiety disorders or insomnia while pregnant [3]. These medications have sedative, hypnotic, anxiolytic, anticonvulsant, and muscle-relaxing effects depending primarily on how long they act on the gamma-aminobutyric acid (GABAA) receptor [4]. BZDs and z-hypnotics cross the placenta and have the potential to bind to receptors in the developing embryonal/fetal central nervous system [5]. It has been proposed that exposure to medications that mimic GABA at GABAA receptors also trigger apoptotic neurodegeneration in the developing brain [6].

In total, 0.8% of the children were exposed to BZDs and z-hypnotics during pregnancy (N1.5 years = 577 of 71,996; N3 years = 440 of 55,081) (Fig 1).

In this large prospective follow-up study including siblings discordantly exposed to BZDs or z-hypnotic drugs, we found that prenatal long-term exposure to BZDs or z-hypnotics was associated with increased internalizing behavior problems among children aged 1.5 years. Of importance, when studied separately, BZD-anxiolytics exposure was associated with increased internalizing problems at both 1.5 and 3 years of follow-up while z-hypnotic exposure was not associated with any adverse outcomes.




0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments