The in utero environment experienced by a fetus can have significant impacts on an infant's growth trajectory. Although there is epidemiological evidence linking the uterine environment and growth in early infancy, there remains a poor understanding of the impact maternal infection and/or placental inflammation may have on growth, particularly during early childhood. Herein, we aim to evaluate the impact of maternal infection on nutrient transport across the placenta and fetal metabolic hormone production, as two potential mechanistic links between a compromised uterine environment and subsequent growth during early childhood. We hypothesize that these mechanisms contribute to poor linear growth and nutritional status in early childhood both through reduced birth weight and continued influences ex utero. Human schistosomiasis infects 200 million individuals, including 40 million women of childbearing age, and is a significant cause of morbidity and mortality in areas where the parasite is endemic. We have shown that schistosome infection in humans results in a pro-inflammatory response at the maternal-fetal interface, and may have a detrimental impact on birth weight of the affected offspring. This proposal is novel in its ability to link insults experienced in utero, even in the absence of gross infection of the placenta or fetus, to development of metabolic responses and infant growth. This will be achieved by leveraging well characterized samples and outcomes from an NIH funded randomized controlled trial (RCT) of Praziquantel (PZQ) treatment during pregnancy, as well as recruiting a new cohort of pregnant women. The overall research hypothesis is that S. japonicum infection during pregnancy impairs nutrient availability and metabolic profiles in utero, resulting in growth restricted offspring and disadvantaged newborns for subsequent growth. The potential impacts of schistosomiasis during the initial stages of gestation and consequences for fetal growth will be rigorously evaluated through completion of three aims: 1) comparison of transporter expression and amino acid levels in the placenta and cord blood from women PZQ, 2) comparison of the metabolic hormone profiles at 6 and 12 months of age between infants from pregnancies PZQ, and 3) recruitment of a new cohort of mother-infant pairs to examine the impact of maternal schistosomiasis as well as other helminth infections on metabolic profiles and growth in the offspring up to two years of age. Placental biopsies, maternal, infant blood and maternal milk are available from the RCT and a follow-up Thrasher Foundation grant. In addition, the initiation of a new cohort of pregnant women residing in the same endemic region of the Philippines will allow for direct linkage of infection status throughout gestation and growth characteristics through the first two years of life. Innovative techniques including laser capture microscopy (LCM), quantitative PCR, reversed phase high performance liquid chromatography (RP-HPLC), ELISA, and placental perfusion will provide quantifiable answers to these research questions. Completion of all three aims will 1) highlight nutritional deficiencies experienced in utero in the context of schistosomiasis, 2) establish a precedent for altered metabolic hormonal control during initial insult and into the first year of life, and 3) evaluate the impact of maternal helminth infection during gestation on fetal growth in a longitudinal manner with direct comparison to pregnancies not complicated by schistosomiasis at the time of conception. My background in placental biology and molecular biology, coupled with my postdoctoral training in global health has created a solid foundation for this proposal. Under the tutelage of four mentors providing distinct expertise to support my career development, I will apply basic science techniques and questions to field-based global health research in order to make a significant and novel contribution to the area of maternal-fetal health. This will be accomplished by acquiring critical new skills in the following three key areas: 1) conducting complex overseas field projects, 2) epidemiology and applied biostatistics, and 3) parasitology and reproductive biology. Specifically, I will spend significant time in the field under the guidance of mentors, collecting samples and initiating a new population-based study. Additional training will be obtained through a rigorous plan of coursework, seminars, international meetings and one-on-one training sessions with mentors specific to their areas of expertise. The proposed research experiences will prepare me to achieve my longterm career goal of becoming a productive, independent investigator making meaningful contributions to the field of maternal-fetal health. It is expected that the completion f the proposed studies will lead to additional grant submissions, including an R01 application. I benefit from an exceptionally strong research environment in which I will complete the proposed studies. The Center for International Health Research (CIHR) has an excellent track record in training junior faculty for successful independent careers in global health. In addition, the outstanding, established collaboration between CIHR and the Research Institute of Tropical Medicine (RITM) in the Philippines will allow me to experience all aspects of overseas field studies in a productive environment with highly trained staff. The full support of Rhode Island Hospital, as well as mentors at both Women and Infants Hospital and Brown University will round out a research environment in which both global and reproductive health research are institutional priorities and will further strengthen the training experience delineated in this proposal.
Approximately 40 million women of childbearing age suffer from schistosome infection globally. Animal and human studies suggest that schistosome infection results in poor pregnancy outcomes, however the impact of schistosomiasis during pregnancy on the well-being of the offspring has not been investigated. This proposal aims to identify mechanisms by which schistosome infection may lead to decreased nutrient availability for the fetus in utero and the impact this may have on a newborn's ability to use nutrients to grow.
|McDonald, Emily A; Stuart, Ronald; Joshi, Ayush et al. (2018) Endotoxin at the Maternal-Fetal Interface in a Resource-Constrained Setting: Risk Factors and Associated Birth Outcomes. Am J Trop Med Hyg 99:495-501|