BACKGROUND: The extent to which the documented association between prenatal prescribed opioid analgesic (POA) exposure and neurodevelopmental disorders in children is causal or due to confounding is unknown. The objective of this study was to evaluate associations between dose and duration of POA exposure during pregnancy and autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children while minimizing bias due to confounding and other sources.

METHODS AND FINDINGS: This retrospective study analyzed a population-based cohort of births using national register data from Sweden. The ASD analysis cohort consisted of 1,267,978 children born in Sweden from July 1st, 2007 to December 31st, 2018, with follow-up through 2021. A shorter eligibility period was used to study ADHD given its later age of typical diagnosis, consisting of 918,771 children born through December 31st, 2015. Text-mining algorithms were used to derive cumulative dose and duration of POA exposure during pregnancy from filled POA prescriptions, as well as to identify prescriptions that were to be taken on an "as needed" basis. Outcomes were identified through inpatient or outpatient clinical diagnosis of ASD and ADHD or dispensed ADHD medications. Cox proportional hazards regression models were adjusted for measured covariates from multiple domains. Several designs were used to help address unmeasured confounding: comparisons with children whose birthing parent had a diagnosed painful condition but did not receive POAs, children whose birthing parent received POAs in the year before but not during pregnancy, and siblings who were not exposed to POAs. Of the 1,267,978 children, 48.6% were female and 4.4% were exposed to POAs during pregnancy. At age 10, cumulative incidence of ASD was 2.0% among children unexposed to POAs, 2.9% among children exposed to a low dose across pregnancy, and 3.6% among children exposed to a high dose. In unadjusted models (e.g., hazard ratio [HR]high, 1.74, 95% confidence interval [CI], 1.63, 1.87) and when accounting for measured covariates, cumulative maximum dose was associated with increased risk of ASD (e.g., HRhigh, 1.34, 95% CI, 1.24, 1.44). However, the associations were largely or fully attenuated when using alternative designs (particularly when comparing to children whose birthing parent received POAs before but not during pregnancy: HRhigh, 1.10, 95% CI, 1.00, 1.21). No associations were observed in the sibling comparison (HRhigh, 0.99, 95% CI, 0.81, 1.21). This overall pattern of associations was also observed when considering duration of exposure, and in numerous sensitivity analyses, as well as for analyses of ADHD. A main limitation of this study was that the distribution of dose and duration of POAs prescribed to birthing parents in Sweden limited our ability to explore the effects of extremely high dose and duration on risk for neurodevelopmental disorders.

CONCLUSIONS: While increased risks with high amounts of POA exposure cannot be ruled out, the results suggest that confounding may largely explain the increased risks of ASD and ADHD associated with prenatal POA exposure at the levels observed in this cohort.