Association of Timing and Duration of Prenatal Analgesic Opioid Exposure With Attention-Deficit/Hyperactivity Disorder in Children

IMPORTANCE Prior studies have reported that the use of illicit opioids during pregnancy is associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring; however, evidence regarding the association of analgesic opioids is limited. OBJECTIVE To examine the association of timing and duration of prenatal analgesic opioid exposure with ADHD in children. DESIGN, SETTING, AND PARTICIPANTS This cohort study uses data from the Norwegian Mother, Father and Child Cohort study (1999-2008), a nationwide birth cohort study linked to national health registries, with a mean (SD) follow-up of 10.8 (2.2) years. A total of 73 784 live-born singleton children born to 62 013 mothers who reported a pain-related condition before and/or during pregnancy were included, with 2 comparator groups: (1) mothers who did not use any opioids and (2) mothers who used opioids before pregnancy only. Data were analyzed from June to December 2020. EXPOSURES Maternal self-report of analgesic opioid use during pregnancy, by timing (early and middle and/or late) and duration (>= 5 weeks vs <= 4 weeks). MAIN OUTCOMES AND MEASURES Diagnosis of ADHD or filled prescription for ADHD medication in children and symptoms of ADHD at child age 5 years, measured by Conners' Parent Rating Scale-Revised. Inverse probability of treatment weights were used to control for measured confounding. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs. RESULTS The analyses of ADHD diagnosis and ADHD symptoms included 73 480 children (35 996 [49.0%] girls; mean [SD] maternal age, 30.0 [4.6] years) and 31 270 children (15 377 [49.2%] girls; mean [SD] maternal age, 30.5 [4.4] years), respectively. Overall, 1726 children in the ADHD diagnosis sample (2.3%) and 667 children in the ADHD symptom sample (2.1%) were exposed to an analgesic opioid at least once during gestation. No associations between timing of prenatal analgesic opioid exposure and ADHD diagnosis or symptoms was found. Exposure for 5 or more weeks was associated with an increased risk of ADHD diagnosis (HR, 1.60, 95% CI, 1.04-2.47) compared with exposure for 4 weeks or less; however, there was no such association for the risk of ADHD symptoms. CONCLUSIONS AND RELEVANCE In this cohort study, a slightly elevated risk of ADHD diagnosis after prenatal analgesic opioid exposure for 5 or more weeks was found compared with exposure for 4 weeks or less. This result may be driven by longer duration of use; however, the role of residual or unmeasured confounding cannot be excluded. This finding needs to be replicated in other studies.