Association of prenatal exposure to benzodiazepines and child internalizing problems: A sibling-controlled cohort study

Abstract

BackgroundDuring pregnancy, many women experience sleep problems and anxiety that require treatment. The long-term safety for the child of maternal benzodiazepine (BZD) and z-hypnotic use during pregnancy remains controversial.MethodWe conducted a cohort and a sibling control study using data from the Norwegian Mother and Child Cohort Study. Data on use of BZD and z-hypnotics, internalizing and externalizing outcomes, and covariates were collected from mothers at gestational weeks 17 and 30 and when children were 0.5, 1.5, and 3 years of age. The total sample consisted of 71,996 children (19,297 siblings) at 1.5 years and 55,081 children (13,779 siblings) at 3 years. Short-term use was defined as use in one pregnancy period only. Long-term use was defined as use in two or more pregnancy periods. Linear full cohort random-effect and sibling-matched fixed-effect regression models were used to compare internalizing and externalizing behavior in children prenatally exposed compared to those unexposed in the full cohort of pregnancies accounting for family clusters, as well as within sibling clusters comparing pregnancies with discordant exposures. Propensity score (PS) adjustment included variables on indication for use (sleep problems, symptoms of anxiety and depression) and other potential confounding factors.ResultsLong-term prenatal exposure to BZD or z-hypnotics was associated with increased internalizing behavior in crude cohort analyses and at age 1.5 years after PS adjustment in sibling-matched fixed-effect models [β 0.60, 95% confidence interval 0.17–0.95]. Analyses on specific drug groups showed that prenatal exposure to BZD-anxiolytics was associated with increased internalizing problems at both 1.5 years [β 0.25, 0.01–0.49] and 3 years [β 0.26, 0.002–0.52] while exposure to z-hypnotics was not associated with any adverse outcomes after adjustment.ConclusionThe findings suggest a moderate association between BZD-anxiolytic exposure and child internalizing problems that is not likely due to stable familial confounding factors.

Impact of prenatal exposure to benzodiazepines and z-hypnotics on behavioral problems at 5 years of age: A study from the Norwegian Mother and Child Cohort Study

“…To the best of our knowledge, only three previous studies have addressed long-term behavioral outcomes in children after prenatal exposure to BZDs and/or z-hypnotics. Our findings should be interpreted in light of findings from a previous study that showed an increased risk of internalizing problems at 3 years of age [19]. Moreover, that study revealed a small increased risk of internalizing problems at both 1.5 years and 3 years of age associated with prenatal BZD-anxiolytics exposure.…”

“…They evaluated internalizing and externalizing problems at 1.5 years (19 297 siblings) and 3 years (13 779 siblings). That study suggested that internalizing behaviors were slightly increased at both 1.5 years (standardized β: 0.25, 95% CI: 0.01–0.49) and 3 years (standardized β: 0.26, 95% CI: 0.002–0.5) after prenatal exposure to anxiolytics [19]. Consequently, uncertainty remains about the long-term neurodevelopmental safety of BZDs and z-hypnotics during pregnancy.…”

“…As a follow up to the Norwegian sibling-comparison study [19], we aimed to determine whether prenatal exposure to BZDs and z-hypnotics affected externalizing and internalizing behavior problems in 5-year-old children in the MoBa. Specifically, we aimed to apply appropriate statistical methods, including propensity score (PS) methods, to control for important measured confounders and to explore the role of unmeasured confounding factors.…”

Association of Maternal Use of Benzodiazepines and Z-Hypnotics During Pregnancy With Motor and Communication Skills and Attention-Deficit/Hyperactivity Disorder Symptoms in Preschoolers

“…However, such risk could not be substantiated by recent research, including the present study. 13 , 14 Our null association between prenatal benzodiazepine/z-hypnotic use and greater ADHD traits in offspring was consistently observed across the various maternal disorder strata. On the individual drug class level, the negligible association that emerged specifically for benzodiazepine exposure was likely a chance finding or an overestimation of the true drug association due to a failure to correct for exposure misclassification and unmeasured confounding by maternal personality traits and/or familial genetic risk.…”

“… 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, although a small risk (β, 0.26; 95% CI, 0.00-0.52) of internalizing behaviors was noted after in utero benzodiazepine exposure. 13 …”