Mass General Hospital

Harvard Medical School

Prenatal exposure to benzodiazepines and sibling-controlled cohort study

 

Over the last decade, we have seen multiple studies looking at the long term effects of prenatal exposure to antidepressants, particularly the selective serotonin reuptake inhibitors or SSRIs, on children’s behavior.  Although benzodiazepines, such as lorazepam (Ativan) and clonazepam (Klonopin), and sedative-hypnotic medications are used relatively frequently during pregnancy, we have much less information regarding the long-term effects of prenatal exposure to these medications.  Using data from the Norwegian Mother and Child Cohort Study, researchers looked at internalizing and externalizing behaviors in children at 0.5, 1.5, and 3 years of age, comparing children exposed to benzodiazepines (BZDs) and sedative-hypnotics (also called z-hypnotics) during pregnancy to unexposed children.  

This study included 71,996 children (19,297 siblings) at 1.5 years and 55,081 children (13,779 siblings) at 3 years. Short-term use of medication was defined as use during only one trimester of  pregnancy. Long-term use was defined as use during two or more trimesters. The Child Behavior Checklist (CBCL) was used to assess children at 1.5 and 3 years; a shortened version of this instrument was used to identify both externalizing (i.e., aggression, attention problems) and internalizing behavior (i.e., anxiousness, emotional reactivity, somatic complaints).  

Genetic or environmental (familial) factors might result in increased risk for mood and anxiety disorders in the mother and behavioral problems in the child.  In addition, living with a mother with these disorders could affect a child’s behavior. In an effort to distinguish the effects of prenatal exposure from genetic and environmental factors, the researchers analyzed outcomes in siblings discordant for exposure to medication.  In addition, propensity scores were used to adjust for potential confounding variables, including indication for use (sleep problems, symptoms of anxiety and depression).

In this large prospective follow-up study, 0.8% of the children were exposed to BZDs and/or z-hypnotics during pregnancy.  Long-term exposure to BZDs or z-hypnotics was associated with increased internalizing behaviors among children. However, when analyzed separately, exposure to BZDs, but not z-hypnotics, was associated with increased internalizing problems at both 1.5 and 3 years of age.  Exposure to BZDs or z-hypnotic medications was not associated with externalizing problems.These findings could not be explained by shared familial factors, reported indication for medication use, or other measured confounding factors; however,residual unmeasured confounding cannot be ruled out.

This is the largest study to date looking at the effects of prenatal exposure to benzodiazepines and sedative-hypnotics and, unlike previous studies, was able to control for a relatively large number of potential confounding variables.  While this study demonstrated an association between benzodiazepine exposure and internalizing behaviors, it is reassuring that the effect size was relatively small.  Furthermore, we must point out that with all non-randomized studies, we cannot assume that the women who choose to use medications during pregnancy are exactly the same as women who choose not or do not need to use medication.  The sibling-matched analysis helps to address this problem; however, it is possible that there are residual counting factors that have not been captured in this analysis.  

Ruta Nonacs, MD PhD

 

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

Brandlistuen RE, Ystrom E, Hernandez-Diaz S, Skurtveit S, Selmer R, Handal M, Nordeng H.  PLoS One. 2017 Jul 26.   Free Article

 

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