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

怀孕期间的营养和炎症：对人类早期大脑发育的影响

• 批准号: 10656258
• 负责人: Anne Shee CC Lee
• 金额: $ 63.84万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656258
• 关键词: Accounting; Address; Adherence; Affect; Africa; Africa South of the Sahara; Age; Age Months; Animals; Anthelmintics; Behavior; Behavioral; Biological; Biological Availability; Biological Markers; Birth; Blood specimen; Brain; C-reactive protein; Cephalic; Child; Childhood; Cognitive; Complex; Counseling; Data; Development; Dose; Effectiveness of Interventions; Electroencephalography; Enrollment; Ethiopia; Ferritin; Folic Acid; Funding; Future; Head circumference; Hemorrhage; Homeostasis; Human; Individual; Infant; Infection; Infectious Pregnancy Complications; Inflammation; Inflammatory; Intake; Intention; Interleukin 6 Receptor; Interleukin-6; Intervention; Iron; Iron deficiency anemia; Life; Malnutrition; Measures; Mediating; Metabolic; Molecular; Myelin; National Institute of Child Health and Human Development; Neurocognitive; Neurologic; Newborn Infant; Nutrient; Nutritional; Nutritional Requirements; Nutritional Support; Observational Study; Orosomucoid; Outcome; Parents; Pathway interactions; Performance; Predisposition; Pregnancy; Pregnant Women; Prenatal Nutrition; Prenatal care; Proteins; Randomized; Randomized, Controlled Trials; Research; Resource-limited setting; Rest; Risk Factors; Role; Rural; Serum; Structure; Subgroup; Supplementation; TFRC gene; Testing; Third Pregnancy Trimester; Umbilical Cord Blood; Underweight; Upper arm; Urinary tract infection; Variant; Ventricular; Visual evoked cortical potential; Vulnerable Populations; Woman; Work; antenatal; arm; burden of illness; critical period; early pregnancy; effective intervention; energy balance; fetal; follow-up; fortification; group intervention; helminth infection; hepcidin; high risk population; human fetal brain; improved; in utero; infection management; intervention effect; iodized salt; iron deficiency; memory recognition; modifiable risk; multimodality; neural; neural network; neurobehavior; neurodevelopment; neurotropic; nutrition; offspring; prenatal; prenatal intervention; primary outcome; processing speed; psychologic; receptor; reproductive; secondary analysis; treatment arm; ultrasound; visual tracking; white matter

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.

项目概要 在资源匮乏的环境中，出生后 1000 天内营养不良和感染很普遍，但可以改变 可能对儿童认知和心理发展产生终生影响的风险因素。迅速 发育中的胎儿大脑增加了营养和代谢需求，并且非常容易受到影响 炎症。蛋白质、能量和铁是早期大脑发育所需的关键营养素；然而，其中 撒哈拉以南非洲地区的育龄妇女中，10% 体重不足，20% 缺铁 贫血。妊娠期感染在非洲也很常见，三分之一的妇女患有地蠕虫病 感染，导致缺铁和炎症。铁调素 (Hepcidin) 是铁稳态的调节剂 受炎症刺激，但对妊娠期铁调素以及如何优化胎儿的研究有限 炎症背景下铁的生物利用度。了解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 产前大脑发育的机制主要来自动物和观察研究。 在这里，我们提供了一个前所未有的机会来利用正在进行的、独立资助的随机研究 对照试验（RCT）来检查随意关系并严格研究生物途径 产前营养和炎症会影响营养不良和高营养环境下的人类胎儿大脑发育 埃塞俄比亚农村地区的危险人群。在母试验中，怀孕早期的女性被随机接受：1) 标准产前护理，2) 一套强化营养支持（叶酸铁、碘盐、强化营养） 平衡能量蛋白（BEP）补充剂），3）一揽子感染管理（驱虫、治疗 尿路感染），或 4）两个套餐。拟议项目将支持先进、多模式、婴儿 6 年级神经发育评估（EEG/VEP、颅脑超声、神经系统检查、引发模仿任务） 和 24 个月大时，对孕产妇和新生儿脐带血进行炎症生物标志物分析（C- 反应蛋白、α-1酸性糖蛋白、白细胞介素（IL）-6）、营养神经因子（IL-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）和铁调素。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）研究 对母婴铁和炎症生物标志物的干预措施，以及（3）检查母婴铁和炎症生物标志物的作用 新生儿铁状态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随机对照试验，我们 将确定铁、BEP 和炎症对儿童神经行为高级测量的影响 和功能，并将加深对生物途径和干预目标的理解。我们将 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 改善全球高疾病负担和弱势群体的早期人类大脑发育。