Maternal opioid prescriptions and subsequent risk of hospital admission in offspring in South Korea: A nationwide birth cohort study

BACKGROUND: Prenatal opioid exposure may disrupt infant development and immune system function, potentially increasing long-term susceptibility to hospital admissions. Thus, we aimed to investigate the association between prenatal opioid exposure and the risk of hospital admission in children. METHODS AND FINDINGS: We established a population-based birth cohort in South Korea by linking mothers and children using National Health Insurance Service data and followed from January 1, 2009, to December 31, 2023. We constructed propensity score (PS)-matched and sibling comparison cohorts and performed a multi-pronged approach, including dose-dependent and time-attenuation analyses. All 5,249,429 individuals with eligible children born between January 1, 2010, and December 31, 2017, were included (2,236,167 mothers and 3,013,262 children). Infants were followed up for up to 14 years, depending on birth year. Prenatal exposure to opioids was defined as maternal receipt of two or more prescriptions within any given trimester. Adjusted incidence rate ratio (aIRR) of hospital admission among children with prenatal opioid exposure was estimated for causes including infections, non-infectious respiratory conditions, non-infectious gastrointestinal conditions, oral cavity diseases, injuries/external causes, and non-infectious genitourinary conditions. Analyses were adjusted for maternal age at delivery, infant sex, region of residence, household income level, birth season, parity, severe maternal morbidity score, number of outpatient visits and hospital admissions in the year before pregnancy, preterm birth, low birth weight, delivery type, year of delivery, maternal history of substance use and neuropsychiatric disorders, and plurality. Of the 2,928,186 children, we identified 2,809,515 (51.4% male) and 118,671 (51.3% male) infants without and with prenatal opioid exposure, respectively. The rate of hospital admissions in children with prenatal opioid exposure was 28% higher in the PS-matched cohort (aIRR 1.28 [95% CI 1.28, 1.29]; p < 0.001). The association was attenuated in the sibling comparison cohort, indicating the potential influence of shared familial factors, but remained statistically significant (aIRR 1.08 [95% CI 1.07, 1.10]; p < 0.001). Hospital admission rates in children increased in a dose-dependent manner with maternal opioid dose and duration of opioid prescriptions (low-dose exposure: aIRR 1.19 [95% CI 1.19, 1.20]; p < 0.001; high-dose exposure: aIRR 1.40 [95% CI 1.39, 1.41]; p < 0.001). Prenatal opioid exposure was significantly associated with increased rates of hospital admission across several causes of morbidities, including infections, respiratory non-infections, oral cavity, gastrointestinal non-infections, genitourinary non-infections, and injury/external conditions. These associations between prenatal opioid exposure and hospital admission rates in children diminished with age but remained evident up to five years of age. The main limitations of this study's methodology include the use of prescription records, which may not fully capture actual medication intake, and residual confounding that cannot be entirely excluded. CONCLUSIONS: In this nationwide birth cohort study, maternal opioid prescription during pregnancy was associated with a substantial increase in the risk of hospital admissions in the offspring across various causes of morbidities. Although the attenuated estimates in the sibling comparison analysis suggest that familial factors may partly explain this association, these findings may inform postnatal monitoring and management strategies for children born to mothers who received opioid prescriptions during pregnancy.