© 2019 by Thieme Medical Publishers, Inc. Objective We sought to compare the efficacy and safety of detoxification from opioids compared with opioid replacement therapy (ORT) during pregnancy. Study Design We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to June 2017 for English-language randomized-controlled trials or cohort studies that compared detoxification with ORT. We sought studies with outcomes data on maternal abstinence at the time of delivery, neonatal abstinence syndrome (NAS), stillbirth, and preterm birth (PTB). We calculated pooled relative risks (RRs) with a random-effects model, assessed heterogeneity using the chi-square test for heterogeneity, and quantified heterogeneity using the I 2 test. We assessed publication bias using funnel plots and the Harbord test. Results Three cohort studies met the inclusion criteria; eligible studies included 235 women with opioid use disorder in pregnancy. Maternal detoxification was associated with increased risk of relapse (RR = 1.91; 95% confidence interval [CI] = 1.14-3.21); however, no treatment differences were observed for the rates of NAS (RR = 0.99; 95% CI = 0.38-2.53) or PTB (RR = 0.39; 95% CI = 0.10-1.60). Conclusion Our findings suggest an increased risk of relapse with detoxification treatment compared with ORT; however, detoxification does not alter the risk of PTB or NAS. Further studies should confirm our findings and explore mechanisms to fight the current opioid epidemic.