ABSTRACT The frequency of opioid use disorders (OUD) during pregnancy has increased substantially during the past two decades, reflecting the risk observed in the general population. The current recommendation from guideline groups is that pregnant women with OUD be treated with opioid agonist therapy (OAT). OAT has been shown to improve pregnancy outcomes in women with OUD because it prevents opioid withdrawal symptoms that can be disruptive to fetal well-being and to reduce illicit opioid and other substance use. Methadone has historically been the mainstay of OUD treatment during pregnancy. However, in recent years, buprenorphine use has increased and is now used in approximately equal measure with methadone. Methadone and buprenorphine have different pharmacologic effects. The way in which these treatments are administered is also different. Methadone is dispensed under observation via a federally- regulated opioid treatment program. In contrast, buprenorphine is generally dispensed by prescription in a routine office-based setting. Buprenorphine also comes in two formulations, as a monoproduct and in combination with naloxone, an opioid antagonist, which is intended to deter misuse via injection. Comparative safety and effectiveness data for pharmacologic approaches to the treatment of OUD in pregnancy are very limited. The MOTHER trial demonstrated that buprenorphine is associated with less severe neonatal abstinence syndrome compared to methadone. Data regarding the comparative safety of buprenorphine and methadone with respect to other adverse pregnancy outcomes and the impact on long-term neurodevelopment are few and subject to a number of potential biases and limitations. The comparative effectiveness of buprenorphine and methadone with respect to retention in treatment and impact on adequacy of prenatal care has also not been fully defined. For those prescribed buprenorphine in pregnancy, the use of the monoproduct is generally recommended, despite the higher risk for misuse, because there are few data regarding the safety of the combination product which includes naloxone. The overall goal of this study is to utilize state of the art design and analytic epidemiological methods applied to a large cohort of women defined using nationwide Medicaid data to generate the best possible evidence regarding the comparative safety and effectiveness of medications used to treat OUD in pregnancy. Specific methods that we intend to employ include propensity score fine stratification, high-dimensional propensity score adjustment, alternative referents (discontinuer comparisons), and bias analyses to account for potential misclassification of exposure and outcome and residual confounding. The results of the studies are expected to have an important and direct clinical impact guiding clinicians’ and patients’ selection of the best treatment for OUD in order to ensure a good outcome for mothers and their children.