Opioid analgesic and antidepressant use during pregnancy and the risk of spontaneous preterm birth: A nested case-control study.

Background: Given the high prevalence of both mental health and acute pain conditions during pregnancy, use of antidepressants and analgesic opioids in this period is widespread. Whether single and combined use of these medications is associated with spontaneous preterm birth (sPTB) remains unclear.

Objectives: To investigate the association between maternal prescription opioid and antidepressant medication exposures for co-occurring mental health and acute pain management, either alone or in combination, and sPTB.

Methods: We used Tennessee Medicaid data (2007-2019) linked to birth certificates to conduct a nested case-control study among 15- to 44-year-old pregnant patients with singleton live births. Cases were identified as spontaneous live births between 24 and <37 gestational weeks using a validated birth certificate-based algorithm. We selected up to 10 controls per case, matched on estimated pregnancy start date and other factors. We identified analgesic opioid and antidepressant pharmacy fills to define medication exposures in the 60 days before index date (case delivery date) and categorised them as unexposed, opioid-only, antidepressant-only and combined exposure. We estimated odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression, adjusting for confounders. We assessed the additive interaction between opioids and antidepressants by estimating relative excess risk due to interaction.

Results: We identified 25,406 eligible cases of sPTB and 225,771 matched controls. Opioid-only and combined exposures were associated with higher odds of sPTB relative to unexposed (adjusted OR 1.29, 95% CI 1.23, 1.35 and 1.22, 95% CI 1.06, 1.40, respectively), while antidepressant-only exposure was not (1.04, 95% CI 0.96, 1.12). No additive interaction was identified for combined exposure.

Conclusions: Exposure to prescription opioids during pregnancy, but not antidepressants, was associated with increased relative odds of sPTB. Co-exposure to opioids and antidepressants did not elevate the odds of sPTB above what we observed for opioid-only exposure.