No Clinically Relevant ADHD Risk With Prenatal Benzodiazepine, Z-Hypnotic Exposure

Investigators found no substantial increased risk for greater fine motor deficits or ADHD traits in offspring exposed to benzodiazepines or hypnotics at different gestational time points or for a longer duration.

There is no substantial detrimental risk on child fine motor and attention-deficit/hyperactivity disorder (ADHD) symptoms after prenatal benzodiazepine/z-hypnotic exposure alone or in combination with opioids or antidepressants, according to study results published in JAMA Network Open.1

Approximately 15% of pregnant women have an anxiety disorder, and up to 4% are prescribed either benzodiazepines or z-hypnotics. Angela Lupattelli, PhD, PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, University of Oslo, Norway, and colleagues sought to determine the long-term outcomes of gestational benzodiazepine and/or z-hypnotic exposure by timing and duration and coexposure to opioids or antidepressants on motor, communication, and ADHD symptoms in offspring.  

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The study included participants from the nationwide, population-based Norwegian Mother and Child Cohort Study, which recruited pregnant women from 1999 to 2008. Of the eligible pregnancy-child dyads, the study population comprised 36,086 children (51% male) of 32,799 mothers. The study included mothers with depressive/anxiety (n=4195), sleeping problems (n=5260), or pain-related (n=26,631) disorders before and/or during pregnancy.

Maternal depressive and anxiety symptom severity was measured using short versions of the Hopkins Symptom Checklist 25 at gestational weeks 17 and 30. Child follow-up occurred at ages 6, 18, and 36 months, and then ages 5, 7, and 8 years, while the follow-up of teenagers is ongoing. Motor and communication skills were assessed by parents completing Ages and Stages Questionnaires, while the Conners’ Parent Rating Scale–Revised was used to determine ADHD symptoms at child median age of 5.1

Timing analyses targeted children exposed to benzodiazepines/z-hypnotics in midpregnancy (weeks 17-28) or late pregnancy (week 29 or later) vs those born to nonmedicated women. Duration and coexposure analyses compared benzodiazepine/z-hypnotic treatment for multiple 4-week intervals, 1 interval and co-use of benzodiazepine/z-hypnotic with opioids, and antidepressants vs benzodiazepine/z-hypnotic use.

Of 36,086 children, 283 (0.8%) were prenatally exposed to benzodiazepines/z-hypnotics—134 of mothers with depression/anxiety, 89 whose mothers took the medications for pain, and 60 whose mothers had a sleeping disorder. Investigators found 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 and communication deficits than unexposed children (weighted β, 0.67; 95% CI, 0.21-1.13 vs weighted β, 0.35; 95% CI, 0.04-0.65, respectively). This association was only observed in boys (weighted β, 0.91; 95% CI, 0.47-1.35) and for benzodiazepine and z-hypnotic monotherapy exposure. No substantial duration or coexposure associations were noted.

The study was limited by the self-reported nature of symptoms, a lack of dosage information, and a sample comprised solely of Norwegian women.

“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,” investigators concluded. The moderate association of gross motor and communication deficits with late-pregnancy benzodiazepine/z-hypnotic use in women with anxiety/depression, while not clinically relevant, could warrant future dose-effect studies.

In an invited commentary, Simone Vigod, MD, and Cindy-Lee Dennis, PhD, wrote that while the study findings are reassuring with regard to the neurodevelopmental effects of benzodiazepines and/hypnotics on offspring, the use of such medications should be carefully considered.2

“It is important to acknowledge that the use of these medications is not completely benign (in pregnancy or otherwise). The frequent use of these medications in pregnancy and for longer than the recommended 2-week period suggests that strategies to optimize the quality of care for women with symptoms of depression or anxiety, insomnia, and pain during pregnancy are critical,” the commenters wrote. They added that nonpharmacologic treatments and follow-up protocols could also address the needs of pregnant women and support optimal outcomes for their children.

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  1. Lupattelli A, Chambers CD, Bandoli G, Handal M, Skurtveit S, Nordeng H. Association of maternal use of benzodiazepines and z-hypnotics during pregnancy with motor and communication skills and attention-deficit/hyperactivity disorder symptoms in preschoolers. JAMA Netw Open. 2019;2(4):e191435
  2. Vigod SN, Dennis C-L. Benzodiazepines and the z-drugs in pregnancy—reasonably reassuring for neurodevelopment but should we really be using them? JAMA Netw Open. 2019;2(4):e191430.