Multimodal Fetal and Placental Imaging and Biomarkers of Clinical Outcomes in Opioid Use Disorder

项目摘要 母体阿片类药物使用障碍（OUD）和新生儿阿片类药物戒断综合征（NOWS） 每15分钟就有一名美国儿童患有NOWS。呈指数级增长的 产前阿片类药物暴露（POE）和持续的阿片类药物流行因COVID-19大流行而进一步恶化。 患有OUD的母亲有不良妊娠结局的风险，患有POE的婴儿有NOWS和 长期神经行为结果不佳;目前没有早期预测或缓解的客观工具 这些风险。我们以前的研究表明，磁共振成像改变脑结构和静息状态 与非阿片类药物暴露的健康婴儿相比，POE婴儿的功能网络连接。具体地说， 我们发现，在POE婴儿中，丘脑-额叶功能连接与NOWS的严重程度相关 并受母体合并症的影响。婴儿大脑结构和功能的发展依赖于 关于胎盘胎儿健康我们发现，胎儿出生前暴露于阿片类药物的小脑尺寸较小 并显示伴随吸烟的OUD孕妇的胎盘大小发生变化， 多物质使用。我们还表明，阿片类药物相关的儿童临床结局不良与阿片类药物有关。 药物遗传学变异，胎盘表观遗传学与新生儿阿片类药物戒断相关 综合征。我们的试验数据显示，接受NOWS治疗的幼儿在认知领域得分很低， 贝利婴儿发展量表III基于我们的试点工作，我们假设阿片类药物影响 纵向胎儿大脑发育导致不良的长期儿童神经行为结果， 这些胎儿脑效应由胎盘功能障碍和母体合并症缓和。存在一个临界 以及对主动鉴定胎盘和哺乳动物的新的综合多模式标志物的迫切未满足的需求。 胎儿脑生长和功能预测母亲OUD的不良母婴结局。我们的长期 目的是提高妊娠期间OUD治疗的安全性和有效性，并显著降低 NOWS，儿童神经发育不良和母亲复发。具体目标是：1）确定 通过纵向结构和功能性胎脑MRI观察阿片类药物对发育中胎脑的影响，2） 通过胎盘成像，表观遗传学， 蛋白质组学和阿片类药物遗传学，以及3）将受损的胎儿脑发育和胎盘 NOWS功能和婴儿神经发育结果。预期结果是确定1）关键 母体OUD中胎盘功能障碍和胎儿脑发育改变的纵向成像标志物; 2） OUD中胎盘功能障碍的新型阿片类药物遗传学、表观遗传学和蛋白质组学生物标志物， NOWS和3）全面和先进的胎盘-胎儿成像，以及循环蛋白质组学和胎盘 NOWS严重程度和婴儿神经发育不良结果的表观遗传生物标志物。

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.