The prevalence of opioid use disorder (OUD) in pregnancy has risen markedly in the United States over the past two decades, reflecting trends observed in the general population. Guidelines recommend that pregnant patients with OUD should receive medications for opioid use disorder (MOUD) during pregnancy to reduce the risk of illicit opioid use and to improve fetal and maternal outcomes. In the context of R01 DA049822, we found that buprenorphine use during pregnancy compared to methadone is associated with a lower risk of neonatal abstinence syndrome, preterm delivery, small-for-gestational age, as and most congenital defects. However, we also found that retention in MOUD treatment during pregnancy and the postpartum period is suboptimal, particularly for buprenorphine, and lack of treatment in the postpartum period is associated with a markedly higher risk of maternal overdose death. Co-exposure to psychotropics is highly prevalent in pregnant patients treated with MOUD, with 54% being co-exposed. Likewise, non-opioid substance use disorders are common in those treated with MOUD: 8% are diagnosed with illicit stimulant use, 8% with cocaine use disorder, 14% with cannabis use disorder, and 7% with alcohol use disorder. Given plausible pharmacodynamic and pharmacokinetic mechanisms by which these co-exposures might affect the comparative safety and effectiveness of MOUD treatments, there is a need to better understand risks associated with co-exposure to psychotropic medications and non-opioid substance use disorders and how they should impact the choice of MOUD. The recent surge of highly potent fentanyl in the drug supply also introduces complexity into treatment decisions regarding type of MOUD and optimal treatment protocols that needs to be evaluated. The suboptimal retention in MOUD treatment points to the need to identify modifiable factors that can improve treatment retention (including provider, medication dosing and dispensing schedule, and care delivery model), and thus maternal and neonatal outcomes. Finally, the use of naltrexone to treat OUD has increased rapidly in recent years in women of reproductive age, leading to a rapid rise in pregnancy exposure. Yet very few data are available regarding the safety of use during pregnancy, creating a critical gap in the evidence needed to guide the growing number of pregnant patients (or those planning pregnancy) who have been successfully treated with naltrexone. In this competing renewal application, we propose to build on the team’s significant experience studying OUD treatments to address these newly emerging critical gaps in evidence. We will use state-of-the-art and innovative epidemiological methods applied to large nationwide cohorts of publicly and commercially insured pregnancies that are continuously updated. The resulting evidence will help steer providers toward the optimal treatment choice for individual patients and will identify factors that can be intervened upon directly to...