Date Published: June 6, 2019
Publisher: Public Library of Science
Author(s): Lene Maria Sundbakk, Mollie Wood, Jon Michael Gran, Hedvig Nordeng, Omid Beiki.
Many women experience anxiety or sleep disorders during pregnancy and require pharmacological treatment with benzodiazepines (BZDs) or z-hypnotics. Limited information is currently available on how prenatal exposure to these medications affects behavioral problems in children over the long term. Therefore, from a public health perspective, this issue is highly important. The present study aimed to determine whether prenatal exposure to BZDs and z-hypnotics affected externalizing and internalizing behavior problems in children at age 5 years. This study was based on The Norwegian Mother and Child Cohort Study and The Medical Birth Registry of Norway. The final study population included data for 36 401 children, from questionnaires completed by the mothers throughout the 5-year follow up. Children’s behaviors were measured at age 5, based on parental responses to The Child Behavior Checklist. Children T-scores of 63 or above were considered to indicate clinically relevant behavior problems. We applied inverse probability of treatment weighting (IPTW) and log-binomial regression models to estimate risk ratios (RRs) and bootstrapped 95% confidence intervals (CIs) with censoring weights to account for loss during follow-up. Several sensitivity analyses were performed to assess the robustness of the main results. The final sample included 273 (0.75%) children that were exposed to BZDs and/or z-hypnotics during pregnancy. The main, IPTW and censoring weighted analyses showed that prenatal exposure to BZD and/or z-hypnotics increased the risks of internalizing behavioral problems (RR: 1.35, 95% CI: 0.73–2.49) and externalizing behavioral problems (RR: 1.51, 95% CI: 0.86–2.64). However, based on sensitivity analyses, we concluded that the risks of displaying externalizing and internalizing problems at 5 years of age did not significantly increase after prenatal exposure to BZDs and/or z-hypnotics. Instead, the sensitivity analyses suggested that residual confounding and selection bias might explain the increased risks observed in the main analyses.
Up to 15% of women experience anxiety during pregnancy , and of these, 10%-26% require pharmacological treatment with benzodiazepines (BZDs) [2–4]. BZDs, like oxazepam and diazepam, are drugs prescribed for treating mental diseases, anxiety disorders, and/or sleep problems, due to their anxiolytic and sedative effects . The z-hypnotics, zolpidem and zopiclone, are BZD-related drugs that are mainly prescribed as mild sedatives . Both BZDs and z-hypnotics modulate the γ-amino butyric acid (GABAA) receptor . When taken during pregnancy, these medications cross readily the placenta and the blood brain barrier. They act by facilitating the opening of GABA-activated chloride channels  present in the cortical anlage from embryonic age  (i.e. before week 9 after conception), and thus increasing the response to GABA. In the mature central nervous system, GABA is a neurotransmitter that acts in an inhibitory manner. At the early developmental stage, however, GABA acts in an excitatory manner and is involved in neurogenesis, including proliferation, migration, differentiation of neurons, as well as the timing of critical periods and potentially primes the earliest neuronal networks . Consequently, it is biological plausible that BZDs and z-hypnotics could affect fetal neurodevelopment [9, 10].
Our primary study population consisted of 36 401 pregnancies. Of these, 273 (0.75%) children were exposed to BZDs and/or z-hypnotics during gestation. S1 Table presents an overview of the number of individuals that used BZDs and/or z-hypnotics, and those that used different compounds, in different time windows. The most common type of medication used during pregnancy was a BZD-anxiolytic (n = 140), specifically oxazepam (n = 73) and diazepam (n = 69); the next most common type was a z-hypnotic (n = 131), specifically zopiclone (n = 113). Most women used BZDs and z-hypnotics for mental health (46.9% (n = 128)) and/or sleeping problems (21.2% (n = 58)) (S2 Table).
In this large prospective follow-up study of 36 401 pregnancies, we observed a modestly increased risk of internalizing and externalizing behavior problems in 5-year-old children born to mothers that used BZDs and/or z-hypnotics during pregnancy. The effect size was somewhat larger for externalizing problems than for internalizing problems. In the IPTW and censoring weighted analyses of both internalizing and externalizing problems, the confidence intervals were wide and included 1. Moreover, the larger portions of the intervals were above 1, which might be of concern; however, our sensitivity analyses suggested that residual confounding and/or selection bias might have explained some of our results.