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Prenatal Opioid Exposure and Subsequent Risk of Fractures in Children: An Emulated Target Trial Using a Nationwide
Hyohyeon Lee1, Kyeongeun Kim2,3, Yeona Jo2,3
1School of Health and Environmental Science, College of Health Science, Korea University, Seoul, South Korea.
Insights
Prenatal opioid exposure did not significantly increase childhood fracture risk overall. However, high-dose or prolonged exposure may warrant caution regarding bone health.
Area of Science:
- Pediatric Health
- Pharmacology
- Epidemiology
Background:
- Prenatal opioid exposure is a growing concern for child development.
- Its impact on childhood musculoskeletal health, specifically fracture risk, remains understudied.
Purpose of the Study:
- To investigate the association between prenatal opioid exposure and the risk of fractures in children.
- To analyze site-specific fracture risks and dose-response relationships.
Main Methods:
- Utilized Korean National Health Insurance Service claims data (2009-2023) to emulate a target trial.
- Defined prenatal opioid exposure as ≥2 maternal opioid prescriptions per trimester.
- Employed propensity score matching and sibling comparison designs with Cox proportional hazards models.
Main Results:
- Identified over 700,000 children, with ~117,000 exposed prenatally to opioids.
- Prenatal opioid exposure showed a slight increase in fracture risk (aHR 1.07), but this was not significant in sibling analyses.
- Fracture risk increased in a dose-dependent manner with higher opioid exposure levels.
Conclusions:
- Overall prenatal opioid exposure was not linked to a substantial increase in childhood fracture risk.
- High-dose, prolonged, or frequent prenatal opioid exposure may necessitate continued monitoring and caution.
- Further research is needed to fully elucidate the long-term musculoskeletal effects.
Objective:
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.
Methods:
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.
Results:
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)].
Conclusion:
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.
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