Analysis of Prenatal Exposure to Opioid Analgesics and Scholastic Skills in Children in Fifth Grade in Norway.

Importance: Few studies have examined the neurodevelopmental consequences of prenatal exposure to opioid analgesics. Therefore, it is necessary to gain knowledge to inform clinical decisions for pregnant women with moderate to severe pain. Objective: To investigate fifth-grade scholastic skills in children with prenatal exposure to opioid analgesics. Design, Setting, and Participants: A cohort study was conducted based on data from the Norwegian Mother, Father, and Child Cohort (1999-2008). These data were linked to the Medical Birth Registry of Norway, and data from Statistics Norway included 64 256 live-born singletons, born to 54 568 mothers who reported pain during pregnancy, were analyzed. The study was conducted from July 1 to December 15, 2021. Exposures: Self-reported exposure to opioid analgesics during pregnancy, characterized in terms of any exposure, the exposure timing, and the exposure duration. Main Outcomes and Measures: Scores from 3 national tests for children in fifth grade. The tests measured scholastic skills in literacy, numeracy, and the English language. Test scores were standardized to z scores. Differences in z scores were compared between children of mothers exposed to opioid analgesics during pregnancy and children of mothers with only prepregnancy opioid exposure. Results: Of the 64 256 children included, 32 521 were boys (50.6%), and 1483 children (2.3%) were exposed to an opioid analgesic at least once during gestation. All test scores were similar between children with any exposure to opioid analgesics in utero and children with only prepregnancy exposure. Children exposed in the first trimester and those exposed in two or three 4-week intervals during pregnancy scored lower than children of mothers with only prepregnancy exposures on tests in literacy (weighted ß [wß], -0.13; 95% CI, -0.25 to -0.01 and wß, -0.19; 95% CI, -0.35 to -0.04) and numeracy (wß, -0.14; 95% CI, -0.25 to -0.04 and wß, -0.19; 95% CI, -0.34 to -0.05). These differences were small and may not be clinically relevant. Conclusions and Relevance: In this large birth cohort, prenatal exposure to opioid analgesics had no substantial negative association with fifth-grade scholastic skills. However, adequate pain management in pregnancy may be addressed on an individual patient level, bearing in mind the benefits and risks of different analgesic therapies.

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.