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

 描述（由申请人提供）：低出生体重，特别是由于胎儿生长受限（FGR），不成比例地影响居住在低收入和中等收入国家（LMIC）的妇女，并使新生儿的发病率和死亡率风险增加。在中低收入国家，胎儿生长迟缓比早产对低出生体重负担的影响更大。尽管如此，我们对FGR病因的理解仍然存在重大缺陷，阻碍了合理干预措施的设计，以解决这一巨大的负担。本申请的总体目标是：1）为LMIC中的酒精和妊娠研究建立基础设施; 2）进一步了解酒精暴露与LMIC环境特有的其他暴露相互作用的机制，以增加在胎儿酒精谱系障碍（特别是FGR）背景下观察到的不良妊娠结局风险。FASD占全球酒精相关死亡的约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资助的妊娠期吡喹酮治疗RCT中，超过75%的受试者报告在妊娠12-16周时持续饮酒。对于当前的应用，我们将招募N=400名妊娠10-16周的女性，以检查LMIC（酒精，蠕虫病，营养不良）中普遍暴露的独立贡献，并正式解决这些暴露是否相互作用，以增加新生儿和婴儿不良结局的风险，特别是FGR（SA 1）。我们假设这些暴露中的每一种都会破坏肠道完整性，正如我们在血吸虫病的背景下所证明的那样，最终导致微生物易位，从而在母体体循环和母体胎儿界面中可检测到内毒素和其他微生物产物。在SA 2中，我们将评估这些暴露导致不良出生结局的胎盘机制，包括向更促炎的胎盘微环境的转变，用组织学和分子技术捕获的胎盘形成的破坏，以及IGF途径的下调。在SA 3中，我们将构建复杂的结构方程模型，以研究普遍暴露如何影响胎盘健康，最终导致FGR、婴儿期生长发育迟缓和12个月龄时神经认知缺陷造成的巨大全球疾病负担。鉴于共同研究者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，这将为产前干预提供信息，以减少这些风险。

 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.