Prenatal Opioid Exposure and Subsequent Risk of Fractures in Children: An Emulated Target Trial Using a Nationwide...

Prenatal opioid exposure has been linked to adverse developmental outcomes, but its effects on childhood musculoskeletal health are unclear. This study examined the association between prenatal opioid exposure and fracture risk in children.

This study emulated a target trial using a nationwide mother-child linked birth cohort from the Korean National Health Insurance Service claims data from January 1, 2009 to December 31, 2023. Prenatal opioid exposure was defined as maternal receipt of ≥ 2 opioid prescriptions during any trimester. The primary outcome was the postnatal diagnosis of any fracture, and secondary outcomes were site-specific fractures, including the head, spine, upper limb, lower limb, or other anatomical sites, as identified by relevant International Classification of Diseases 10th edition codes. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models with propensity score matching and a sibling comparison design.

After propensity score matching, we identified 584,400 children (51.3% boys) without and 117,065 (51.3% boys) children with prenatal opioid exposure. Children with prenatal opioid exposure had an increased risk of fractures [aHR 1.07 (95% CI 1.06-1.08)], whereas no significant association was observed in the sibling comparison cohort analyses [1.02 (0.99-1.04)]. Risk of fractures showed a dose-dependent manner [low-dose exposure: 1.06 (1.05-1.08); high-dose exposure: 1.09 (1.06-1.12)].

Opioid exposure during pregnancy was not associated with a substantial increase in the risk of fractures in the children. However, exposure to high opioid doses, prolonged or frequent prenatal opioid exposure, may still warrant caution.