Nutrition and Inflammation in Pregnancy: Impacts on Early Human Brain Development

项目总结 在资源匮乏的环境中，营养不良和生命最初1000天内的感染很普遍，是可以改变的。 可能对儿童的认知和心理发展产生终生影响的风险因素。最快的 发育中的胎儿大脑对营养和代谢的需求增加，对这种影响非常敏感 发炎的症状。蛋白质、能量和铁是早期大脑发育所需的关键营养物质；然而，在 在撒哈拉以南非洲，10%的育龄妇女体重不足，20%的妇女缺铁 贫血。妊娠感染在非洲也很常见，那里每三个妇女中就有一个患有寄生虫。 感染，导致缺铁和发炎。海普西丁是一种铁稳态调节剂， 在炎症的刺激下，关于妊娠期间的海普西丁以及如何优化胎儿的研究很有限 炎症背景下铁的生物可利用性。理解营养和营养之间的复杂关系， 炎症和神经发育是一个主要的研究空白。主要的理解方法 出生前大脑发育的机制主要来自动物和观察性研究。 在这里，我们提供了一个前所未有的机会来利用持续的、独立资助的随机 对照试验(RCT)，以检查偶然的关系，并严格调查生物途径，通过 产前营养和炎症在营养不良和高度营养不良的情况下影响人胎脑发育。 埃塞俄比亚农村的危险人群。在父母试验中，早孕妇女被随机接受：1) 标准产前护理，2)一揽子强化营养支持(叶酸铁、加碘盐、强化 平衡能量蛋白(BEP)补充)，3)一揽子感染管理(驱虫、治疗 尿路感染)，或4)两种包装。拟议的项目将支持先进的、多式联运的婴儿 6岁时进行神经发育评估(EEG/VEP、头颅超声、神经学检查、引出模仿任务) 和24个月龄，并分析母亲和新生儿脐带血的炎症生物标记物(C- 反应蛋白、α-1酸性糖蛋白、白介素6、神经营养因子(白介素6可溶性受体)、铁 储存(血清铁蛋白、可溶性转铁蛋白受体、全身铁)和海普西丁。我们的具体目标是：(1) 确定干预措施对后代神经发育的影响，(2)调查干预措施的影响 对母亲-新生儿铁和炎症生物标志物的干预，以及(3)检查母亲-新生儿铁和炎症生物标志物的作用。 新生儿铁状况和炎症对儿童神经发育的影响。利用埃塞俄比亚正在进行的RCT，我们 将确定铁、BEP和炎症对儿童神经行为高级指标的影响 并将加深对生物途径和干预靶点的理解。我们会 阐明怀孕期间铁和炎症的复杂动态及其对神经网络的影响， 儿童时期的大脑结构和行为。我们的工作将有助于优化产前干预策略，以 改善全球高疾病负担和脆弱人群的早期人脑发育。

PROJECT SUMMARY In low-resource settings, undernutrition and infections during the first 1000 days of life are prevalent, modifiable risk factors that may have lifelong effects on a child’s cognitive and psychological development. The rapidly developing fetal brain has increased nutritional and metabolic demands and is highly susceptible to the effects of inflammation. Protein, energy, and iron are key nutrients required for early brain development; yet, among women of reproductive age in Sub-Saharan Africa, 10% are underweight and 20% have iron deficiency anemia. Pregnancy infections are also common in Africa, where one in three women have a geo-helminthic infection, contributing to iron deficiency and inflammation. Hepcidin, a regulator of iron homeostasis, is stimulated by inflammation, yet there is limited research on hepcidin in pregnancy and how to optimize fetal iron bioavailability in the context of inflammation. Understanding the complex relationship between nutrition, inflammation, and neurodevelopment is a major research gap. The predominant approach to understanding mechanisms of prenatal brain development is derived predominantly from animal and observational studies. Here, we present an unprecedented opportunity to leverage an ongoing, independently funded randomized controlled trial (RCT) to examine casual relationships and rigorously investigate biological pathways by which prenatal nutrition and inflammation influence human fetal brain development in an undernourished and high- risk population in rural Ethiopia. In the parent trial, women in early pregnancy are randomized to receive: 1) standard prenatal care, 2) a package of strengthened nutritional support (iron-folate, iodized salt, fortified balanced energy protein (BEP) supplement), 3) a package of infection management (deworming, treatment of urinary tract infections), or 4) both packages. The proposed project will support advanced, multi-modal, infant neurodevelopmental assessments (EEG/VEP, cranial ultrasound, neurologic exam, elicited imitation tasks) at 6 and 24 months of age, and analysis of maternal and newborn cord blood for inflammation biomarkers (C- reactive protein, alpha-1 acid glycoprotein, Interleukin (IL)-6), neurotropic factors (IL-6 soluble receptor), iron stores (serum ferritin, soluble transferrin receptor, total body iron), and hepcidin. Our specific aims are to: (1) determine the effects of interventions on offspring neurodevelopment, (2) investigate the effects of interventions on maternal-newborn iron and inflammation biomarkers, and (3) examine the role of maternal- newborn iron status and inflammation on child neurodevelopment. Leveraging an ongoing RCT in Ethiopia, we will determine the effects of iron, BEP, and inflammation on advanced measures of childhood neurobehavior and function and will deepen the understanding of biological pathways and intervention targets. We will elucidate the complex dynamics of iron and inflammation in pregnancy and their effects on neural networks, brain structure, and behavior in childhood. Our work will help optimize prenatal intervention strategies to improve early human brain development in high disease burden and vulnerable populations globally.