Association of Maternal Use of Benzodiazepines and Z-Hypnotics During Pregnancy With Motor and Communication Skills and Attention-Deficit/Hyperactivity Disorder Symptoms in Preschoolers
Authors: Angela Lupattelli, Christina D. Chambers, Gretchen Bandoli, Marte Handal, Svetlana Skurtveit, Hedvig Nordeng
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The reproductive safety of benzodiazepine/z-hypnotic exposure on child longer-term developmental risks remains unresolved. <h3>Objective</h3> To quantify the association of motor, communication, and attention-deficit/hyperactivity disorder (ADHD) symptoms in preschoolers with gestational benzodiazepine/z-hypnotic exposure by timing and duration and coexposure to opioids or antidepressants. <h3>Design, Setting, and Participants</h3> Nationwide, population-based Norwegian Mother and Child Cohort Study, recruiting pregnant women from 1999 to 2008, with child follow-up from ages 6, 18, and 36 months to ages 5, 7, and 8 years. Follow-up of teenagers is ongoing. The study included women with depressive/anxiety (n = 4195), sleeping (n = 5260), or pain-related (n = 26 631) disorders before and/or during pregnancy. <h3>Exposures</h3> For the timing analyses, children exposed to benzodiazepines/z-hypnotics in midpregnancy (weeks 17-28) or late pregnancy (week 29 or later) vs those born to nonmedicated women. For the duration and coexposure analyses, benzodiazepine/z-hypnotic treatment for multiple 4-week intervals vs 1 and co-use of benzodiazepine/z-hypnotic with opioids or antidepressants vs sole benzodiazepine/z-hypnotic use. <h3>Main Outcomes and Measures</h3> Parent-reported motor and communication skills (Ages and Stages Questionnaires) and ADHD symptoms (Conners' Parent Rating Scale–Revised) at child median age of 5.1 years (interquartile range, 5.0-5.3 years) as standardized mean scores. General linear propensity score–adjusted and marginal structural models were fitted. Analyses were stratified by maternal disorder. <h3>Results</h3> Of 41 146 eligible pregnancy-child dyads, 36 086 children (18 330 boys and 17 756 girls) were included, of whom 283 (0.8%) were prenatally exposed to benzodiazepines/z-hypnotics (134 in the depressive/anxiety, 60 in the sleeping, and 89 in the pain-related disorders). There was no increased risk for greater ADHD symptoms or fine motor deficits after intrauterine benzodiazepine/z-hypnotic exposure at different time points. Children born to women with depressive/anxiety disorders who took benzodiazepines/z-hypnotics in late pregnancy had greater gross motor (weighted β, 0.67; 95% CI, 0.21-1.13) and communication (weighted β, 0.35; 95% CI, 0.04-0.65) deficits than unexposed children. There was no evidence for substantial duration or coexposure associations. <h3>Conclusions and Relevance</h3> These findings suggest no substantial detrimental risk on child fine motor and ADHD symptoms after prenatal benzodiazepine/z-hypnotic exposure alone or in combination with opioids or antidepressants. Residual confounding by indication and/or a higher drug dose regimen among women with anxiety/depression may explain the moderate association of gross motor and communication deficits with late-pregnancy benzodiazepine/z-hypnotic use.