Association of maternal, fetal and placental biomarkers with neonatal neuroimaging and development following in-utero opioid exposure

母体、胎儿和胎盘生物标志物与宫内阿片类药物暴露后新生儿神经影像和发育的关系

• 批准号: 10748626
• 负责人: Elisha Wachman
• 金额: $ 257.33万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748626
• 关键词: Affect; Behavior; Bioinformatics; Biological Markers; Brain; Brain imaging; Cognitive; Control Groups; Development; Diagnosis; Evaluation; Exposure to; Fetal Growth Retardation; Future; Gene Expression; Gestational Age; Growth; Health; Infant; Inflammatory; Intervention; Knowledge; Language; Measurement; Measures; MicroRNAs; Modeling; Modification; Motor; Neonatal; Neurocognitive; Neurodevelopmental Impairment; Opioid; Outcome; Participant; Pathway interactions; Patient Self-Report; Placenta; Plasma; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Prospective, cohort study; Quantitative Reverse Transcriptase PCR; Risk; Sampling; Screening procedure; Second Pregnancy Trimester; Shapes; Substance Use Disorder; Third Pregnancy Trimester; Time; Tissues; Ultrasonography; Umbilical Cord Blood; Untranslated RNA; behavioral outcome; cohort; cytokine; exosome; fetal; fetal opioid exposure; high risk; in utero; insight; intrauterine inflammation; mRNA Expression; microRNA biomarkers; neonatal brain; neonatal brain development; neurobehavioral; neurodevelopment; neuroimaging; novel; novel marker; opioid exposure; perinatal period; skills; ultrasound

ABSTRACT Prenatal opioid exposure can influence the integrity and health of the placenta and the developing fetal brain. These modifications at critical time points can have lasting effects on pregnancy outcomes and subsequent infant neurodevelopment. The mechanisms by which opioids modify the placenta and fetal brain, critical time points for these modifications, and whether there are useful biomarkers that can be tracked throughout the pregnancy are unknown. Two hypothesis driven mechanisms are 1) gene expression changes, and 2) intrauterine inflammation, both known to occur after exposure to opioids. These can be measured using biomarkers from maternal plasma and placental tissue, specifically microRNAs and maternal-infant inflammatory cytokine profiles. We propose a prospective cohort study comparing 100 opioid-exposed to 50 non-exposed control pregnancies to fill these gaps in knowledge. The specific aims of this proposal are: 1) Compare serial miRNA signatures in opioid-exposed and control pregnancies. In 100 opioid and 50 control participants, we will collect serial maternal plasma samples in the 2nd trimester, 3rd trimester, and delivery, as well as placental tissue at delivery. Maternal exosomal miRNA expression levels will be compared between groups with a focus on placenta-derived miRNA. Top miRNA associations with prenatal opioid exposure will be identified. 2) Compare serial inflammatory cytokines in opioid- exposed and control pregnancies. In the 100 opioid and 50 control participants, we will collect serial maternal plasma samples, placental tissue, and cord blood for analysis with a multiplex inflammatory cytokine panel. Cytokine levels will be compared between groups at each time point, and top associations identified. 3) Neurodevelopment: Association of top miRNAs and cytokines with placental health, infant neuroimaging and developmental outcomes in opioid-exposed pregnancies. Top miRNAs and cytokines identified through Aims 1 and 2 will be analyzed for association with infant neurodevelopment in the opioid cohort. 3A) Placental health: We will evaluate associations of top biomarkers with placental health measures (IUGR, pre-eclampsia, preterm birth, placental efficiency scores). 3B) Neuroimaging: Ultrasound imaging will be obtained in the 2nd trimester, 3rd trimester, and 1-month corrected gestational age, and associations evaluated for top biomarkers. 3C) Neurodevelopment: Infants will undergo a 12-month Bayley development examination. In our final regression model, we will examine associations between top miRNAs and cytokines with neurodevelopment with consideration of placental health (3A) and brain measurements (3B) as intermediates in the pathway. This study will help us to gain insight into mechanisms and developmental timing of how prenatal opioid exposure shapes both placental and fetal brain development, and ultimately infant neurodevelopmental outcomes.

抽象的 产前阿片类药物暴露会影响胎盘和发育中的胎儿大脑的完整性和健康。 在关键时间点进行的这些修改可能会对妊娠结局和随后的婴儿产生持久影响 神经发育。阿片类药物修改胎盘和胎儿大脑的机制，关键时间点 这些修饰以及整个怀孕期间是否可以跟踪有用的生物标志物是 未知。两个假设驱动的机制是1）基因表达变化，2）宫内 炎症，都已知在接触阿片类药物后发生。可以使用来自 母体血浆和胎盘组织，特别是microRNA和母体感染的炎症细胞因子谱。 我们提出了一项前瞻性队列研究，将100种阿片类药物与50个不暴露对照妊娠进行比较 在知识中填补这些空白。 该提案的具体目的是：1）比较阿片类药物暴露和控制中的串行miRNA签名 怀孕。在100名阿片类药物和50名对照参与者中，我们将在第二个中收集串行母体血浆样本 三个月，三个月，分娩以及分娩时的胎盘组织。母体外泌体miRNA 将比较以胎盘衍生的miRNA的群体之间的表达水平。顶部mirna 将确定与产前阿片类药物暴露的关联。 2）比较阿片类药物中的连续炎症细胞因子 暴露并控制怀孕。在100名阿片类药物和50名对照参与者中，我们将收集串行母亲 血浆样品，胎盘组织和脐带血，可通过多重炎症细胞因子面板进行分析。 在每个时间点之间，将比较组之间的细胞因子水平，并确定最高关联。 3） 神经发育：顶部miRNA和细胞因子与胎盘健康，婴儿神经成像和 阿片类药物暴露妊娠的发育结果。通过目标1鉴定的顶部miRNA和细胞因子1 和2将分析与阿片类药物队列中婴儿神经发育的关联。 3a）胎盘健康： 我们将评估顶级生物标志物与胎盘健康措施的关联（IUGR，先兆子痫，早产 出生，胎盘效率分数）。 3b）神经影像学：超声成像将在第二个孕期获得 三个月和1个月校正的胎龄，并评估了顶级生物标志物的关联。 3C） 神经发育：婴儿将接受12个月的Bayley发展检查。在我们的最后回归中 模型，我们将检查顶部miRNA和细胞因子与神经发育之间的关联 考虑胎盘健康（3A）和脑测量值（3B）作为途径中的中间体。这项研究 将帮助我们深入了解产前阿片类药物暴露形状的机制和发展时机 胎盘和胎儿脑发育均发育，以及最终是婴儿神经发育结果。