Duration and Timing of In Utero Opioid Exposure and Incidence of Neonatal Withdrawal Syndrome

OBJECTIVE:To evaluate the association between prenatal prescription opioid analgesic exposure (duration, timing) and neonatal opioid withdrawal syndrome (NOWS).METHODS:We conducted a retrospective cohort study of Wisconsin Medicaid-covered singleton live births from 2011 to 2019. The primary outcome was a NOWS diagnosis in the first 30 days of life. Opioid exposure was identified with any claim for prescription opioid analgesic fills during pregnancy. We measured exposure duration cumulatively in days (1-6, 7-29, 30-89, and 90 or more) and identified timing as early (first two trimesters only) or late (third trimester, regardless of earlier pregnancy use). We used logistic regression modeling to assess NOWS incidence by exposure duration and timing, with and without propensity score matching.RESULTS:Overall, 31,456 (14.3%) of 220,570 neonates were exposed to prescription opioid analgesics prenatally. Among exposed neonates, 19,880 (63.2%) had 1-6 days of exposure, 7,694 (24.5%) had 7-29 days, 2,188 (7.0%) had 30-89 days, and 1,694 (5.4%) had 90 or more days of exposure; 15,032 (47.8%) had late exposure. Absolute NOWS incidence among neonates with 1-6 days of exposure was 7.29 per 1,000 neonates (95% CI 6.11-8.48), and incidence increased with longer exposure: 7-29 days (19.63, 95% CI 16.53-22.73); 30-89 days (58.96, 95% CI 49.08-68.84); and 90 or more days (177.10, 95% CI 158.90-195.29). Absolute NOWS incidence for early and late exposures were 11.26 per 1,000 neonates (95% CI 9.65-12.88) and 35.92 per 1,000 neonates (95% CI 32.95-38.90), respectively. When adjusting for confounders including timing of exposure, neonates exposed for 1-6 days had no increased odds of NOWS compared with unexposed neonates, whereas those exposed for 30 or more days had increased odds of NOWS (30-89 days: adjusted odds ratio [aOR] 2.15, 95% CI 1.22-3.79; 90 or more days: 2.80, 95% CI 1.36-5.76). Late exposure was associated with elevated odds of NOWS (aOR 1.57, 95% CI 1.25-1.96) when compared with unexposed after adjustment for exposure duration.CONCLUSION:More than 30 days of prenatal prescription opioid exposure was associated with NOWS regardless of exposure timing. Third-trimester opioid exposure, irrespective of exposure duration, was associated with NOWS.