SUMMARY Maternal opioid use, which dramatically increased in recent years, exerts severe adverse consequences for the offspring’s health. Data from animal models and clinical studies demonstrated that prenatal opioid exposure is significantly associated with preterm birth, fetal growth restriction, low birth weights, neonatal opioid withdrawal syndrome, smaller brain sizes, and impaired neurobehavioral outcomes. However, the mechanistic underpinnings of these adverse outcomes remain poorly understood. Available published data and our preliminary studies strongly suggest that maternal opioid use disorder (OUD) perturbs the placenta-brain axis. One potential mechanism is that OUD disrupts placental development and function, impairing nutrient and gas exchange between mother and fetus. Another mechanism is that opioids accumulate in placental tissues, thereby directly disrupting normal fetal development. However, the molecular underpinnings and the contribution of each pathway remain poorly understood. Therefore, this application will test the central hypothesis that maternal OUD driven inflammation and dysregulation of the placental landscape are linked to adverse neurocognitive outcomes in the offspring. The novelty of this application lies in the systems biology approach that integrates phenotypic, functional, and genomic readouts at the maternal-fetal interface, umbilical cord blood at delivery, and neonatal blood with neurobehavioral and motor skill assessments throughout the first year of life. Completion of the proposed experiments will result in novel insights into the dysregulations of the placenta- brain axis elicited by maternal OUD and will pave the way to building a comprehensive construct and inform the development of early interventions during opioid-exposed pregnancies.

NARRATIVE Maternal opioid use is increasing in the United States and is associated with significant adverse health outcomes for the offspring including preterm birth, neonatal opioid withdrawal syndrome, and impaired neurocognitive outcomes, suggestive of a dysregulated placenta-brain axis. This application will carry out an in-depth investigation of maternal opioid use-changes to placental health and neonatal inflammation as well as neurobehavioral and neuromotor outcomes during the first year of life. This research will contribute to the fundamental knowledge of the placenta-brain axis and identify potential interventions to address opioid-induced dysregulations.