Opioid Analgesic Exposure and Mental Health Disorders During Pregnancy: Exploring Their Independent and Joint Association With Adverse Birth Outcomes

BACKGROUND: Opioid use, depression and anxiety during pregnancy are independently associated with adverse perinatal outcomes, but their joint associations are less understood. OBJECTIVE: To examine the independent and joint associations, including interaction, of prenatal opioid analgesic exposure and maternal anxiety and depression with gestational age, preterm birth and birthweight-for-gestational-age percentile. METHODS: We conducted a retrospective cohort study of 230,810 Wisconsin Medicaid singleton live births (2011-2019), linking Medicaid with birth record data. Multivariable regression models adjusted for maternal sociodemographics, comorbidities and year of delivery. Interaction was assessed using cross-product terms and the relative excess risk due to interaction (RERI). Exposure duration was evaluated for dose-response effects. RESULTS: Prenatal anxiety, depression and opioid analgesic exposure were independently associated with modest reductions in gestational age and birthweight-for-gestational-age percentile, and increased risk for preterm birth. There was no evidence of interaction between opioid analgesic exposure and anxiety or depression. Individuals with ≥ 90 days of opioid exposure and anxiety or depression had the largest deficits in gestational age (anxiety: -0.29 weeks, 95% confidence interval [CI] -0.49, -0.10; depression: -0.34 weeks, 95% CI -0.53, -0.15) and birthweight-for-gestational-age percentile (anxiety: -4.14, 95% CI -6.63, -1.64; depression: -3.27, 95% CI -5.90, -0.64). For preterm birth, ≥ 90 days of opioid exposure was associated with increased risk among individuals with depression (RR 1.35, 95% CI 1.12, 1.63), whereas among those with anxiety, the association was strongest at 30-89 days of opioid exposure (RR 1.17, 95% CI 1.05, 1.30) and was not associated at ≥ 90 days (RR 1.18, 95% CI 0.97, 1.44). CONCLUSIONS: Maternal anxiety or depression and prenatal opioid analgesic exposure were each associated with modest but consistent reductions in gestational age and birthweight-for-gestational-age. Individuals with co-occurring mental health conditions and prolonged opioid exposure experienced the greatest reductions, although there was no evidence of statistical interaction.