Association between prenatal opioid exposure and long-term neurodevelopmental disorders among children: a nationwide cohort study

Existing evidence on the long-term effects of prenatal opioid exposure on child development remains inconsistent, often limited by short follow-up and insufficient control for maternal clinical indications. We investigated whether maternal opioid use during pregnancy is associated with an increased hazard of long-term neurodevelopmental disorders (LNDD) in children, utilizing an extended 13-year follow-up. This retrospective, population-based cohort study used the National Health Insurance Service database in South Korea, including all live births between 2011 and 2014 (n = 1,553,505). Children were followed until December 31, 2023. Maternal opioid prescriptions were categorized by trimester and duration (1–6 days vs. ≥ 7 days). To address confounding by indication, propensity score (PS) matching (1:10 ratio) and multivariable Cox proportional hazards models were employed, adjusting for maternal psychiatric history and pain-related clinical indications. In the matched cohort (n = 133,147), the incidence of LNDD was 10.53 per 1,000 person-years (PY) in the opioid-exposed group and 9.26 per 1,000 PY in the non-exposed group. Prenatal opioid exposure was associated with a 14% increased hazard of total LNDD (hazard ratio [HR] 1.14; 95% CI 1.08–1.20; P < 0.001). Subtype analysis showed the strongest association for intellectual disabilities (HR 1.33; 95% CI 1.16–1.53; P < 0.001). The hazard was more pronounced with first-trimester exposure (HR 1.17; 95% CI 1.06–1.28; P = 0.001) and longer durations of use (≥ 7 days: HR 1.17; 95% CI 1.09–1.24; P < 0.001). Prenatal opioid exposure is associated with a significantly increased hazard of LNDD, particularly intellectual disabilities, independently of maternal psychiatric and pain conditions. This hazard was particularly pronounced following first-trimester exposure and longer durations of use, with intellectual disabilities showing the strongest association. These findings, based on long-term follow-up into early adolescence, emphasize the need for cautious opioid prescribing during pregnancy and developmental surveillance for exposed offspring.