Persistent uterine inflammation following murine chorioamnionitis predisposes to poor outcomes in a subsequent pregnancy 2310301

Abstract

Abstract Introduction Chorioamnionitis, an infection and/or inflammation of the placenta and fetal membranes, is a leading cause of preterm birth (PTB) and an independent risk factor for neonatal morbidities. Women with a history of chorioamnionitis are at increased risk for complications (including implantation failure, PTBs, recurrent chorioamnionitis, and adverse neonatal outcomes) in future pregnancies; however, the mechanisms underlying these subsequent poor outcomes remain unclear. Pathological in-utero inflammation is a key driver of the morbidities seen with chorioamnionitis. Thus, we hypothesized that chorioamnionitis-associated inflammation persists postpartum in the uterus, predisposing to adverse outcomes in future pregnancies. Methods Chorioamnionitis was induced in pregnant C57BL/6 mice at embryonic day 14.5 via intravaginal inoculation with 100 CFU E. coli K1 (or PBS control). Four weeks postpartum, mice were either rebred or euthanized for uterine immune profiling by flow cytometry. Vaginal and uterine swabs were collected to assess persistent E. coli K1 infection. Results Postpartum, uteri from chorioamnionitis-exposed dams (CED) exhibited a significant increase in total immune cells, driven primarily by increased T cell numbers. Specifically, CED uteri showed elevated antigen-experienced CD4+ and CD8+ T cell numbers, increased Tregs with reduced Foxp3 expression, higher frequency and absolute number of inflammatory macrophages, and an accumulation of activated dendritic cells. Notably, uterine and vaginal E. coli K1 colonization persisted in only 12% of CED, indicating that sustained inflammation occurred largely in the absence of ongoing infection. These immune alterations correlated with poor outcomes in a second pregnancy, including dystocia, ∼50% perinatal mortality, and growth-restricted pups. Conclusion These findings suggest that chorioamnionitis drives chronic uterine inflammation postpartum, providing a potential immune-mediated mechanism for adverse outcomes in future pregnancies. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)