Persistent uterine inflammation following murine chorioamnionitis predisposes to poor outcomes in subsequent pregnancy 2260652

Abstract

Abstract Introduction Chorioamnionitis, an infection and/or inflammation of the placenta and fetal membranes, is the leading cause of preterm birth, and an independent risk factor for a variety of neonatal morbidities. Women with a history of chorioamnionitis are at increased risk for complications (including implantation failure, recurrent chorioamnionitis, and adverse neonatal outcomes) in subsequent pregnancies; however, the mechanisms underlying these subsequent poor outcomes remain unclear. Pathological in-utero inflammation is a primary driver of the morbidities seen with chorioamnionitis. Thus, we hypothesized that chorioamnionitis-associated inflammation persists postpartum in the uterus, thereby predisposing to adverse outcomes in subsequent pregnancies. Methods To test this, we induced chorioamnionitis in pregnant syngeneic C57BL/6 mice at embryonic day 14.5 via intravaginal inoculation with 100 CFU of E. coli K1 (or sterile PBS as a control). Four weeks postpartum, mice were either rebred or euthanized for uterine immune profiling via flow cytometry. Vaginal and uterine swabs were collected to assess for persistent E. coli K1 infection. Results Chorioamnionitis-exposed dams (CED) had poor outcomes in their second pregnancy, including dystocia, ∼50% perinatal mortality, and growth-restricted pups. Uterine tissues from CED showed increased frequencies and total numbers of T cells, activated (CD44hi) CD4+ T cells, and Ly6Chi pro-inflammatory macrophages, as well as dendritic cells with significantly high MHC II expression. Uterine and vaginal E. coli K1 colonization persisted in only 12% of CED. Conclusion These findings suggest that chorioamnionitis drives chronic uterine inflammation postpartum. This inflammation appears to be associated with chronic T cell activation, thereby providing a potential immune-mediated mechanism for poor outcomes in subsequent pregnancies. Funding Source R01 AI 141673 Topic Categories Mucosal and Regional Immunology (MUC)