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

项目总结 母亲阿片使用障碍(OUD)和新生儿阿片戒断综合征(NOWS)显著 增加了，每15分钟就有一个美国儿童出生时患有NOWS。呈指数级增长 产前阿片类药物暴露(POE)和持续的阿片类药物流行因新冠肺炎大流行而进一步恶化。 患有卵巢早衰的母亲有不良妊娠结局的风险，患有POE的婴儿有患NOWS和 长期神经行为结果不佳；目前还没有客观的工具来早期预测或缓解 这些风险。我们之前的研究表明，磁共振成像改变了大脑的结构和休息状态 POE婴儿与非阿片类药物暴露的健康婴儿的功能网络连接性比较。具体来说， 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 并受到母体合并症的影响。婴儿大脑结构和功能的发育是依赖的 关于胎盘-胎儿健康。我们在产前接触阿片类药物的胎儿中发现了较小的小脑尺寸 结果显示，吸烟或吸烟的孕妇胎盘大小发生改变。 多物质使用。我们还表明，阿片类药物相关的不良儿童临床结局与阿片类药物有关。 药物遗传变异，以及胎盘表观遗传学与新生儿阿片类药物戒断相关 爱伦坡综合征。我们的试点数据显示，接受NOWS治疗的幼儿在以下认知领域的得分很低 贝利婴幼儿发展量表-III。根据我们的试点工作，我们假设阿片类药物影响 胎儿大脑的纵向发育会导致儿童不良的长期神经行为结果 这些对胎儿大脑的影响被胎盘功能障碍和母体合并症所缓和。有一个关键的问题 和迫切的未得到满足的需求，以积极主动地识别新的全面的胎盘和 胎儿脑发育和功能预测母婴不良结局的研究。我们的长期合作 目的是提高妊娠期OUD治疗的安全性和有效性，并显著降低 现在，儿童神经发育不良和母亲复发。具体目标是：1)确定 阿片类药物对发育中胎儿脑结构和功能的影响 通过胎盘成像，表观遗传学，评价阿片类药物对胎盘形态和功能的影响 蛋白质组学和阿片类药物遗传学，以及3)胎儿大脑发育受损与胎盘的相关性 NOWS与婴儿神经发育结局的关系。预期结果是确定1)关键 母体胎盘功能障碍和胎儿脑发育改变的纵向影像标志物；2) 胎盘功能障碍的新的阿片类药物遗传学、表观遗传学和蛋白质组生物标志物 现在，以及3)全面和先进的胎盘-胎儿成像以及循环蛋白质组和胎盘 NOWS严重程度和婴儿神经发育不良结局的表观遗传生物标记物。

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.