PROJECT SUMMARY Maternal Opioid Use Disorder (OUD) and Neonatal Opioid Withdrawal Syndrome (NOWS) have dramatically increased, with an American child born suffering from NOWS every 15 minutes. The exponentially increasing prenatal opioid exposure (POE) and ongoing opioid epidemic are further worsened by the COVID-19 pandemic. Mothers with OUD are at risk of adverse pregnancy outcomes, and infants with POE are at risk for NOWS and poor long-term neurobehavioral outcomes; there are currently no objective tools for early prediction or mitigation of these risks. Our previous studies have shown MR imaging alterations in brain structural and resting state functional network connectivity in infants with POE compared to non-opioid exposed healthy infants. Specifically, we showed that, in infants with POE, thalamo-frontal functional connectivity correlated with severity of NOWS and was modulated by maternal comorbidities. Infant brain structural and functional development is dependent on placenta-fetal health. We identified smaller cerebellar dimensions in fetuses with prenatal opioid exposure and showed alterations in placental size in pregnant women on OUD who had concomitant smoking or polysubstance use. We also showed that opioid related poor childhood clinical outcomes are related to opioid pharmacogenetic variations, and that placental epigenetics is correlated with neonatal opioid withdrawal syndrome in POE. Our pilot data show that toddlers treated for NOWS score poorly on the cognitive domain of the Bayley Scales of Infant Development-III. Based on our pilot work, we hypothesize that opioids affect longitudinal fetal brain development resulting in adverse long-term childhood neurobehavioral outcomes and that these fetal brain effects are moderated by placental dysfunction and maternal comorbidities. There is a critical and urgent unmet need for proactive identification of novel comprehensive multimodal markers of placental and fetal brain growth and function to predict adverse maternal and infant outcomes in maternal OUD. Our long-term goal is to improve safety and efficacy of OUD treatment during pregnancy, and significantly reduce the risks of NOWS, poor childhood neurodevelopment and maternal relapse. The Specific Aims are to 1) determine the effects of opioids on the developing fetal brain through longitudinal structural and functional fetal brain MRI, 2) assess the impact of opioids on placental morphology and function through placental imaging, epigenetics, proteomics and opioid pharmacogenetics, and 3) correlate impaired fetal brain development and placental function with NOWS and infant neurodevelopmental outcomes. The expected outcomes are to identify 1) critical longitudinal imaging markers of placental dysfunction and altered fetal brain development in maternal OUD; 2) novel opioid pharmacogenetic, epigenetic and proteomic biomarkers of placental dysfunction in OUD and NOWS, and 3) comprehensive and advanced placental-fetal imaging, and circulating proteomic and placental epigenetic biomarkers of severity of NOWS and poor infant neurodevelopmental outcome.

Project Narrative Opioid use disorder during pregnancy, neonatal opioid withdrawal syndrome and associated poor infant neurodevelopment are worsening public health crises. Our research will provide a critical understanding of how prenatal opioid use affects fetal brain development and placental function using advanced fetal brain and placental imaging, genetics of opioid uptake, transport and metabolism, and tissue and blood biomarkers of placental health. This research has significant public health relevance because it will provide novel and early multimodal objective biomarkers to predict opioid use disorder related placental dysfunction, neonatal opioid withdrawal syndrome, and poor infant neurodevelopment in millions of Americans.