Undernutrition-helminth-alcohol interactions, placental mechanisms, and FASD risk

 描述(申请人提供)：低出生体重，特别是由于胎儿生长受限(FGR)，对居住在低收入和中等收入国家(LMIC)的妇女影响不成比例，并使新生儿面临更高的发病率和死亡率风险。在LMIC中，FGR对LBW负担的贡献比早产更大。尽管如此，在我们对FGR病因的理解方面仍然存在重大空白，阻碍了为解决这一巨大负担而设计的合理干预措施。本应用程序的总体目标是：1)建立酒精与LMICs妊娠研究的基础设施；2)加深我们对酒精暴露与LMIC环境中其他暴露的相互作用机制的理解，以增加在胎儿酒精谱系障碍，特别是FGR背景下出现的不良妊娠结局的风险。在全球因酒精导致的死亡中，FASD约占12.5%，全球疾病负担的很大一部分与发病率有关。在我们最近完成的NIH资助的孕期吡喹酮随机对照试验中，超过75%的受试者报告在怀孕12-16周时继续饮酒。对于目前的应用，我们将招募怀孕10-16周的N=400名妇女来检查LMIC中普遍暴露(酒精、蠕虫病、营养不良)的独立贡献，并正式解决这些暴露是否相互作用增加新生儿和婴儿不良结局的风险，特别是FGR(SA1)。我们假设，每一次暴露都会破坏肠道完整性，就像我们在血吸虫病背景下所展示的那样，最终导致微生物易位，从而在母体体循环和母胎界面可检测到内毒素和其他微生物产物。在SA2中，我们将评估这些暴露最终导致不良分娩结局的胎盘机制，包括转向更有利于炎症的胎盘微环境，用组织学和分子技术捕获胎盘破坏，以及IGF途径的下调。在SA3中，我们将构建复杂的结构方程模型，以调查普遍的暴露如何影响胎盘健康，最终导致FGR、婴儿生长发育迟缓和12个月大的神经认知缺陷造成的巨大全球疾病负担。鉴于合作调查员的跨学科专业知识和我们在莱特的实地工作人员的丰富经验，我们准备迅速启动这些创新研究，为产前干预提供信息，以降低这些风险。

 DESCRIPTION (provided by applicant): Low birth weight, particularly as a result of fetal growth restriction (FGR), disproportionately affects women residing in low and middle income countries (LMICs) and places newborns at increased risk of morbidity and mortality. In LMICs, FGR contributes more significantly to the burden of LBW than does prematurity. Despite this, significant lacunae remain with respect to our understanding of the etiology of FGR, hampering the design of rationale interventions to address this enormous burden. The overarching goals of this application are to 1) build an infrastructure for studies of alcohol and pregnancy in LMICs and 2) further our understanding of the mechanisms through which alcohol exposure interacts with other exposures unique to the LMIC setting to increase risk for adverse pregnancy outcomes seen in the context of fetal alcohol spectrum disorders, in particular FGR. FASDs are responsible for approximately 12.5% of alcohol-attributable deaths globally, with a significant portion of the global burden of disease is related to morbidity. In our recently completed NIH funded RCT of Praziquantel treatment during pregnancy, over 75% of subjects reported continued alcohol consumption at 12-16 weeks gestation. For the current application we will recruit N=400 women at 10-16 weeks gestation to examine the independent contribution of prevalent exposures in LMICs (alcohol, helminthiasis, undernutrition) and formally address whether these exposures interact to increase risk for adverse newborn and infant outcomes, in particular FGR (SA1). We hypothesize that each of these exposures will disrupt gut integrity, as we have demonstrated in the context of schistosomiasis, culminating in microbial translocation whereby endotoxin and other microbial products are detectable in the maternal systemic circulation and at the maternal fetal interface. In SA2, we will assess the placental mechanisms through which these exposures culminate in adverse birth outcomes, including a shift to a more pro-inflammatory placental micro-environment, disruptions in placentation captured with histologic and molecular techniques, and downmodulation of IGF pathways. In SA3, we will construct sophisticated Structural Equation Models to investigate how prevalent exposures impact placental health to ultimately contribute to the enormous global burden of disease due to FGR, growth stunting in infancy, and neurocognitive deficits at 12 months of age. Given the interdisciplinary expertise of co-investigators and the extensive experience of our field staff in Leyte, we are poised to rapidly initiate these innovative studies, which will inform pre-natal interventions to reduce these risks.