Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

A healthy pregnancy is associated with dynamic changes in the maternal immune system that facilitates placentation, fetal growth, fetal tolerance, and labor. Pregravid obesity is associated with severe adverse maternal health outcomes, notably increased risk of infection as well as the incidence of gestational diabetes, preeclampsia, and preterm birth. These vulnerabilities suggest perturbations in the maternal immunological state; however, the mechanisms by which pregravid obesity disrupts the pregnancy immune clock are still unknown. To address this question, we collected blood samples from women during the first and third trimesters of pregnancy to determine the impact of both pregnancy and pregravid obesity on circulating immune mediators, immune cell frequencies, and peripheral immune responses. While regardless of BMI, pregnancy was associated with an elevation in both Th1 and Th2 cytokines, pregravid obesity was associated with a dysregulation in circulating myeloid factors at term. Moreover, pregnancy in lean subjects was associated with enhanced monocyte activation, augmented chromatin accessibility at inflammatory loci, and heightened responses to LPS. Pregravid obesity disrupted this trajectory and was accompanied by a lack of transcriptional and epigenetic changes as well as alterations in metabolic status strongly suggesting a skewing towards immunotolerance. These findings provide novel insight into the increased susceptibility to infections in women with obesity observed during pregnancy and following cesarean delivery.