Prenatal Opioid Exposure and Autoimmune‐Related Diseases in Children: A Cohort Study in South Korea and Japan

Background Prenatal opioid exposure has been associated with acute neonatal complications and longer‐term immune‐related outcomes, but its association with autoimmune diseases in children remains unclear. Objectives To investigate the association between prenatal opioid exposure and the risk of autoimmune diseases in children. Methods We used the South Korean National Health Insurance Service (NHIS) birth cohort (discovery cohort; 2,930,720 children, 2,188,898 mothers) and the Japan Medical Data Center (JMDC) cohort (replication cohort; 176,528 children, 147,423 mothers). Children born between January 2010 and December 2017 were followed through December 2023. Prenatal opioid exposure was defined as at least two maternal opioid prescriptions during pregnancy. The primary outcome was any autoimmune‐related disease, with 22 prespecified subcategories. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using propensity score overlap‐weighted Cox models. Sibling‐comparison analyses were conducted in both cohorts. Results In the South Korean cohort, 118,726 children (4.1%) were prenatally exposed to opioids. Exposure was associated with modestly increased risk of autoimmune‐related diseases in overlap‐weighted analyses in both South Korea (HR 1.05, 95% CI 1.02, 1.08) and Japan (HR 1.14, 95% CI 1.09, 1.20), with a pooled HR of 1.10 (95% CI 1.00, 1.20). Risks increased with greater numbers and longer durations of opioid prescriptions. Associations were observed for autoimmune thyroid disease (HR 1.06, 95% CI 1.01, 1.12), autoimmune adrenal and polyglandular diseases (HR 1.07, 95% CI 1.02, 1.12) and reactive arthritis (HR 1.10, 95% CI 1.00, 1.21). However, sibling‐comparison analyses showed no association in South Korea or Japan. Conclusions The absence of associations in sibling‐comparison analyses suggests that shared familial, genetic or environmental factors may explain the observed population‐level associations rather than a clinically meaningful independent effect of prenatal opioid exposure on autoimmune disease risk in offspring.