Abstract
The reproductive safety of benzodiazepine/z-hypnotic exposure on child longer-term developmental risks remains unresolved. 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. 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. 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. 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. 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. 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.
Highlights
Up to 15% of pregnant women have an anxiety disorder, often comorbid with depression,[1,2] and benzodiazepines are at times required given their anxiolytic and sedative effects.[3]
Children born to women with depressive/anxiety disorders who took benzodiazepines/z-hypnotics in late pregnancy had greater gross motor and communication deficits than unexposed children
Among 41 146 pregnancychild dyads in this cohort study, a moderate association between benzodiazepine/z-hypnotic exposure in late pregnancy and greater gross motor and communication deficits in children born to women with depressive/anxiety disorders were observed, but not to the extent that the impairment was of clinical relevance
Summary
Up to 15% of pregnant women have an anxiety disorder, often comorbid with depression,[1,2] and benzodiazepines are at times required given their anxiolytic and sedative effects.[3]. Associations between prenatal benzodiazepine exposure and gross motor and fine motor impairment have been observed in toddlers, the gross motor delay resolved as children grew older.[10,11] Confounding by indication, along with small sample size and short follow-up, constitutes a major drawback of this prior research.[10,11,12] Three more recent, methodologically sound studies[13,14,15] found no greater risk for lower language competence or externalizing or aggressive behaviors in offspring at ages 3 and 6 years, a small risk (β, 0.26; 95% CI, 0.00-0.52) of internalizing behaviors was noted after in utero benzodiazepine exposure.[13]
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