The Opioid in Pregnancy: Imaging of Oxygenation, Inflammation, and Development in Brain & Placenta Project (OPIOID BPP)

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Abstract Maternal opioid use disorder (OUD) is rapidly increasing in prevalence, and is associated with severe morbidities in offspring, such as neonatal opioid withdrawal syndrome (NOWS), brain dysmaturation, and impaired neurodevelopment (ND). However, little is known regarding the mechanisms by which maternal OUD causes these outcomes, so our ability to mitigate the impact of prenatal opioid exposure (POE) on outcomes is poor. Here, we propose to test the central hypothesis that POE causes abnormal neurodevelopment through direct actions on the fetal brain. Additionally, we propose that POE causes abnormal neurodevelopment via moderation effects from the placenta through mechanisms of hypoxia and inflammation. Strikingly, our preliminary results from the placental pathology of 17 POE pregnancies confirm hypoxic lesions in every patient. Furthermore, our preliminary work using placental immune imaging (PII), an advanced diffusion magnetic resonance imaging (dMRI) technology, confirmed elevated placental inflammation and decreased oxygenation, both near the chorionic plate in a POE 36-week pregnancy compared to unexposed controls. Placental hypoxia and inflammation are two known etiologies that cause fetal WM injury and brain dysmaturation, and our own data show that fetuses with impaired cerebral oxygenation have the greatest reductions in brain volume and WM alterations. Importantly, we have demonstrated that fetal brain volume most consistently predicted 2-year ND (n=78, r=0.32-0.47; all p<0.05) across all domains. To test our hypothesis, we leverage the Clinic for Acceptance, Recovery, and Empowerment, one of the few wrap-around OUD prenatal clinics in the country, and our ongoing work on the Human Placenta Project (R01HD094381-04) with longitudinal imaging of placental inflammation from unexposed patients, as a respose to the HEAL Initiative: Opioid Exposure and Effects on Placenta Function, Brain Development, and Neurodevelopmental Outcomes (RFA-HD-23-030). We propose this R01 to define the longitudinal effects of POE on placental inflammation and oxygenation (Aim 1), fetal brain development and oxygenation (Aim 2), and the relationship between placental and fetal brain development markers with NOWS and early ND outcomes in infants with POE (Aim 3). Completion of these aims will explore and refine an innovative fetal pathway by which POE leads to adverse outcomes, and identify markers of immune response and oxygenation status in placenta and fetal brain that predict NOWS and ND. In the long term, this work will allow us to identify therapeutic targets to mitigate the adverse effects of maternal OUD on offspring.