Successful pregnancy requires carefully coordinated changes in the immune system that facilitate placentation, promote fetal tolerance and growth, and induce labor. Deviations from this tightly regulated “pregnancy immunological clock” can lead to as pre-eclampsia and complications during labor. The rates of obesity amongst women of childbearing age have increased at an alarming rate, making it one of the most common comorbidities during pregnancy. Previously published studies and our preliminary data indicate an enhancement of monocyte response to LPS between 12 and 37 weeks of gestation Importantly, our preliminary analyses indicate that maternal pregravid body mass index (BMI) >30 abrogates this pregnancy-associated monocyte activation. This observation provides a potential explanation for the increased susceptibility to infections and poor wound healing outcomes observed in obese pregnant women. We hypothesize that chronic low grade inflammation induced by pregravid obesity disrupts the gestational age dependent monocyte activation, skewing them to an immunotolerant phenotype. Additionally, given that macrophages in the decidua are recruited from circulating monocytes, we will investigate the burden of obesity on phenotype and function of decidual macrophages. We further hypothesize that pregravid obesity results in a hyper-inflammatory phenotype within decidual macrophages. We will employ a multi-dimensional approach to test these hypotheses. The novelty of this application lies in the systems biology approach that integrates phenotypic, functional, and genomic readouts longitudinally in peripheral blood and at term in the placenta. Completion of the proposed experiments will reveal the molecular mechanisms that explain progressive changes in monocyte activation over the course of healthy pregnancy, and how that is disrupted with obesity.

NARRATIVE Pre-pregnancy obesity is associated with significant adverse health outcomes for the mother including increased risk of gestational diabetes and hypertension, preeclampsia and infection. Recent studies from our laboratory revealed significant changes in immune cell function in blood samples collected from obese women at week 37 of gestation. Since immune cells play a critical role in anti-microbial defense as well as the development of chronic inflammation, this application will carry out an in-depth investigation of maternal pre-pregnancy obesity- driven changes in the functional, transcriptional, and epigenetic landscape of blood immune cells.