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

摘要 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。 这些在关键时间点的修改可能会对妊娠结局和后续婴儿产生持久的影响 神经发育。阿片类药物改变胎盘和胎儿大脑的机制，关键时间点 这些修改，以及是否有有用的生物标记物可以在整个怀孕期间进行跟踪是 未知。两种假说驱动机制是：1)基因表达变化；2)宫内 炎症，都是在接触阿片类药物后发生的。这些可以使用生物标记物从 母体血浆和胎盘组织，特别是microRNAs和母婴炎性细胞因子谱。 我们提出了一项前瞻性队列研究，比较了100名接触阿片类药物的孕妇和50名未接触阿片类药物的对照孕妇。 来填补这些知识上的空白。 这项建议的具体目标是：1)比较阿片类药物暴露和对照中的序列miRNA特征 怀孕。在100名阿片类药物受试者和50名对照组受试者中，我们将在第二天收集连续的母体血浆样本 三个月、第三个月和分娩，以及分娩时的胎盘组织。母体外体miRNA 将比较不同组之间的表达水平，重点是胎盘来源的miRNA。顶端miRNA 将确定与产前阿片类药物暴露的关系。2)比较阿片类药物中的系列炎性细胞因子- 暴露并控制怀孕。在100名阿片类药物和50名对照组参与者中，我们将收集连续的母体 血浆样本、胎盘组织和脐带血，用于多重炎症细胞因子分析。 细胞因子水平将在每个时间点在不同组之间进行比较，并确定最大的关联。3) 神经发育：顶端miRNAs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局。通过AIMS 1鉴定的顶级miRNAs和细胞因子 2例将在阿片类药物队列中分析与婴儿神经发育的关系。3A)胎盘健康： 我们将评估顶级生物标记物与胎盘健康措施(IUGR、先兆子痫、早产)的相关性 分娩、胎盘效率评分)。3b)神经成像：超声成像将在妊娠中期进行， 妊娠3个月和1个月的校正孕周，以及评估顶级生物标志物的相关性。(3C) 神经发育：婴儿将接受为期12个月的贝利发育检查。在我们最终的回归中 模型中，我们将检查顶级miRNAs和细胞因子与神经发育之间的关系 考虑胎盘健康(3A)和大脑测量(3B)作为该途径的中介。本研究 将帮助我们深入了解产前阿片类药物暴露的机制和发育时机 胎盘和胎儿的大脑发育，以及最终的婴儿神经发育结果。

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.