Prenatal exposure to benzodiazepines, z-hypnotics may not increase ADHD risk

Children exposed to benzodiazepines and/or nonbenzodiazepines, also known as z-hypnotics, prenatally may not have increased risk for ADHD, according to data published in JAMA Network Open.

However, because the study had low power and included few cases of exposure, the findings should be interpreted cautiously, according to researchers.

“Between 1% and 4% of individuals are prescribed benzodiazepines and/or z-hypnotics during pregnancy for a variety of indications,” such as anxiety and mild insomnia, according to Lene Maria Sundbakk, MSc, a doctoral research fellow at the University of Oslo in Norway, and colleagues.

“To our knowledge, no previous study has examined the association of prenatal exposure to benzodiazepine and/or z-hypnotics with childhood ADHD,” Sundbakk and colleagues wrote. “Findings from previous studies on childhood behavioral disorders after prenatal exposure to benzodiazepines and/or z-hypnotics are reassuring.”

Methods

Sundbakk and colleagues used data from the population-based Norwegian Mother, Father and Child Cohort Study (MoBa) to prospectively study 82,201 pregnancies from 1999 to 2008. For MoBa, mothers self-reported benzodiazepine and/or z-hypnotic use in the 6 months prior to and during pregnancy.

The researchers linked MoBa data with those from the Medical Birth Registry of Norway, the Norwegian Patient Registry and the Norwegian Prescription Database to assess the main outcome of children’s diagnosis of ADHD or filled ADHD prescription by Dec. 31, 2016.

The researchers conducted a subgroup analysis of 19,585 pregnancies to evaluate this outcome in mother-offspring dyads where the mother indicated she was prescribed benzodiazepines and/or z-hypnotics for anxiety, depression or sleeping problems. The subgroup was termed the mental health sample.

The timing of exposure was divided into an early window (gestational age, 0-16 weeks) and a middle and/or late window (gestational age, 17-28 weeks and/or 29 weeks to delivery). The researchers also noted how many 4-week intervals offspring were exposed to benzodiazepines and/or z-hypnotics.

Findings

In total, 681 (0.8%) offspring in the full cohort and 468 (2.4%) offspring in the mental health sample had prenatal exposure to benzodiazepine and/or z-hypnotics. Overall, benzodiazepine-anxiolytics (n = 332; 0.4%) and z-hypnotics (n= 255; 0.3%) were most common. There were 25 mothers who used both.

More exposures occurred in early (n = 435) vs. middle and/or late pregnancy (n = 374; both 0.5%), and more exposures occurred during a single 4-week period than during multiple periods (n = 436; 0.5% vs. n = 245; 0.3%).

Crude analyses of the full cohort suggested the risk for ADHD was potentially greater with exposure during pregnancy, specifically early in pregnancy. However, the HRs included the null. In weighted analyses, exposure during pregnancy and exposure in early or middle and/or late pregnancy were not associated with increased risk for ADHD.

Similarly, crude calculations for the mental health sample suggested that the risk for ADHD was potentially greater with exposure during pregnancy and early pregnancy specifically. Weighted analyses revealed no association between exposure during pregnancy or at any point in pregnancy and ADHD.

“We observed a slightly increased risk of childhood ADHD after exposure in multiple four-week intervals during pregnancy compared with exposure in a single four-week interval,” Sundbakk and colleagues wrote. However, HRs for this analysis included the null.

Moving forward, the researchers said, studies should investigate the impact of benzodiazepines and z-hypnotics on domains of neurodevelopment other than ADHD, as well as learning outcomes.