The comparative effects of prenatal exposure to methadone versus buprenorphine for opioid use disorder on neonatal outcomes: a systematic review and meta-analysis

BACKGROUND: Both methadone and buprenorphine are considered safe for use for the treatment of opioid use disorder, but the comparative effectiveness of these regimens during pregnancy has not been well-established. The objective of this systematic review and meta-analysis was to identify and synthesize published evidence from randomized controlled trials and observational studies to evaluate the impacts of methadone and buprenorphine on neonatal health outcomes. METHODS: We searched Medline, Embase, PsycINFO, and CINAHL databases for published randomized controlled trials (RCTs) or observational studies that compared outcomes among individuals who received methadone during pregnancy to individuals who received buprenorphine (with or without naloxone) during pregnancy. Outcomes of interest were preterm birth, low birthweight, small for gestational age, stillbirth, neonatal opioid withdrawal syndrome (NOWS) diagnosis, and NOWS treatment. We conducted separate pooled analyses for the RCTs and observational studies to generate pooled unadjusted risk ratios (RR), 95% confidence intervals (CI), and 95% prediction intervals. Risk of bias was evaluated using the Newcastle Ottawa Scale and the Cochrane Risk-of-Bias-2 tool. FINDINGS: A total of 27 studies (22 observational, 4 RCTs, and one study that included an observational arm and an RCT arm) were included for data extraction and synthesis. The studies included a combined total of 14,978 individuals exposed to buprenorphine and 8,358 individuals exposed to methadone. In the pooled unadjusted analyses of the observational studies, compared with methadone, buprenorphine was associated with lower risk of preterm birth (unadjusted RR 0.63; 95% CI: 0.57-0.70); low birthweight (unadjusted RR 0.48; 95% CI: 0.36-0.64), small for gestational age (unadjusted RR: 0.82; 95% CI 0.77-0.89), and NOWS treatment (unadjusted RR: 0.69; 95% CI: 0.61-0.78). Our findings suggested no difference between groups in terms of NOWS diagnosis or stillbirth, although stillbirth was rare. CONCLUSIONS: In this meta-analysis, exposure to buprenorphine during pregnancy was associated with lower unadjusted risk of several adverse birth outcomes. The quality of the available evidence was limited by a lack of adjustment for key covariates, heterogeneity in the included analyses, and small sample sizes.