This study explores natural direct and joint natural indirect effects (JNIE) of prenatal opioid exposure on neurodevelopmental disorders (NDDs) in children mediated through pregnancy complications, major and minor congenital malformations, and adverse neonatal outcomes, using Medicaid claims linked to vital statistics in Rhode Island, United States, 2008-2018. A Bayesian mediation analysis with elastic net shrinkage prior was developed to estimate mean time to NDD diagnosis ratio using posterior mean and 95% credible intervals (CrIs) from Markov chain Monte Carlo algorithms. Simulation studies showed desirable model performance. Of 11,176 eligible pregnancies, 332 had ≥2 dispensations of prescription opioids anytime during pregnancy, including 200 (1.8%) having ≥1 dispensation in the first trimester (T1), 169 (1.5%) in the second (T2), and 153 (1.4%) in the third (T3). A significant JNIE of opioid exposure was observed in each trimester (T1, JNIE = 0.97, 95% CrI: 0.95, 0.99; T2, JNIE = 0.97, 95% CrI: 0.95, 0.99; T3, JNIE = 0.96, 95% CrI: 0.94, 0.99). The proportion of JNIE in each trimester was 17.9% (T1), 22.4% (T2), and 56.3% (T3). In conclusion, adverse pregnancy and birth outcomes jointly mediated the association between prenatal opioid exposure and accelerated time to NDD diagnosis. The proportion of JNIE increased as the timing of opioid exposure approached delivery.
Keywords: causal inference; elastic net; neurodevelopmental disorder diagnosis; retrospective study.
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