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

阿片类药物使用障碍临床结果的多模态胎儿和胎盘成像和生物标志物

• 批准号: 10750306
• 负责人: Rupa Radhakrishnan
• 金额: $ 314.53万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750306
• 关键词: 2 year old; Address; Affect; American; Asphyxia Neonatorum; Biological Markers; Blood; Brain; Brain region; Buprenorphine; CCL17 gene; COVID-19 pandemic; Child; Childhood; Clinical; Cognitive; DNA; Data; Development; Dimensions; Economic Burden; Epigenetic Process; Fetal Development; Fetal health; Fetus; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genetic Variation; Genomics; Goals; Growth; Health; Image; Impairment; Infant; Infant Development; Interleukin-1 beta; Interleukin-2; Knowledge; Length of Stay; Link; Magnetic Resonance Imaging; Mental Depression; Metabolic Pathway; Metabolism; Methadone; Methylation; MicroRNAs; Mothers; Multimodal Imaging; Neonatal Abstinence Syndrome; Opioid; Outcome; Pharmacogenetics; Pilot Projects; Placenta; Pregnancy; Pregnancy Proteins; Pregnant Women; Premature Birth; Proteome; Proteomics; Psychological Factors; Public Health; Relapse; Reporting; Research; Research Personnel; Rest; Risk; Safety; Second Pregnancy Trimester; Severities; Site; Smoking; Structure; Third Pregnancy Trimester; Tissues; Toddler; Variant; Vascular Endothelial Growth Factor D; Work; adverse outcome; adverse pregnancy outcome; behavioral outcome; blood oxygen level dependent; brain magnetic resonance imaging; circulating biomarkers; comparison control; epigenetic marker; fetal; fetal opioid exposure; high risk; imaging biomarker; improved; individualized prevention; infant outcome; innovation; magnetic resonance imaging biomarker; maternal comorbidity; maternal opioid use; maternal outcome; maternal risk; medication for opioid use disorder; morphometry; multidisciplinary; multimodality; neurobehavioral; neurodevelopment; neuroimaging; non-opioid analgesic; novel; opioid epidemic; opioid use disorder; opioid use in pregnancy; personalized predictions; placental morphology; polysubstance use; public health relevance; risk mitigation; serial imaging; socioeconomics; substance use; tissue biomarkers; tool; uptake

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.

项目摘要 产妇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）急剧 增加，一个美国的孩子每15分钟遭受每15分钟的痛苦。指数增加 共同19岁的大流行进一步恶化了产前阿片类药物（POE）和持续的阿片类药物流行。 患有OUD的母亲有妊娠不良后果的风险，而有POE的婴儿有现状的风险 长期神经行为结局不良；当前没有客观的工具用于早期预测或缓解 这些风险。我们先前的研究表明，MR成像改变了大脑结构和静止状态 与非阿片类暴露的健康婴儿相比，POE婴儿的功能网络连通性。具体来说， 我们表明，在带有POE的婴儿中，丘脑额叶功能连通性与现在的严重程度相关 并由孕产妇合并症调节。婴儿大脑结构和功能发展取决于 在胎盘 - 爆发健康上。我们确定了产前阿片类药物暴露的胎儿中较小的小脑尺寸 并显示出与吸烟或伴随吸烟或 使用多物质。我们还表明，与阿片类药物相关的儿童期临床结果与阿片类药物有关 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有关 POE中的综合征。我们的飞行员数据表明​​，现在处理过的幼儿在认知领域得分很差 婴儿发育的Bayley量表。根据我们的试点工作，我们假设阿片类药物会影响 纵向胎儿脑发育，导致长期儿童神经行为的不良后果，并且 这些胎儿大脑的影响通过胎盘功能障碍和孕产妇合并症调节。有关键 紧急未满足的需要积极地识别胎盘和 胎儿脑的生长和功能，以预测母体OUD中的不良母体和婴儿结局。我们的长期 目的是提高怀孕期间OUD治疗的安全性和功效，并显着降低 现在，童年的神经发育和孕产妇复发不良。具体目的是1）确定 阿片类药物通过纵向结构和功能性胎儿脑MRI的影响对发育中的胎儿大脑的影响，2） 通过胎盘成像，表观遗传学，评估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）将受损的胎儿发育和胎盘相关联 与Nows和婴儿神经发育结局一起发挥作用。预期的结果是确定1）关键 胎盘功能障碍和胎儿脑发育的纵向成像标记； 2） OUD和 现在和3）全面，先进的胎盘 - 狂热成像，以及循环蛋白质组学和胎盘 NOW和婴儿神经发育结果的严重程度的表观遗传生物标志物。