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

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 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.