Maternal plasma cytokines and the subsequent risk of uterine atony and postpartum hemorrhage

Objectives: To determine whether the maternal plasma concentrations of cytokines are higher in pregnant women with postpartum hemorrhage (PPH) compared to pregnant women without PPH. Methods: A retrospective case-control study included 36 women with PPH and 72 matched controls. Cases and controls were matched for gestational age at delivery, labor status, delivery route, parity, and year of sample collection. Maternal plasma samples were collected up to 3 days prior to delivery. Comparison of the plasma concentrations of 29 cytokines was performed by using linear mixed-effects models and included adjustment for covariates and multiple testing. A false discovery rate adjusted p-value <0.1 was used to infer significance. Random forest models with evaluation by leave-one-out and 9-fold cross-validation were used to assess the combined value of the proteins in predicting PPH. Results: Concentrations of interleukin (IL)-16, IL-6, IL-12/IL-23p40, monocyte chemotactic protein 1 (MCP-1), and IL-1β were significantly higher in PPH than in the control group. This difference remained significant after adjustment for maternal age, clinical chorioamnionitis, and preeclampsia. Multi-protein random forest proteomics models had moderate cross-validated accuracy for prediction of PPH [area under the ROC curve, 0.69 (0.58-0.81) by leave-one-out cross validation and 0.73 (0.65-0.81) by 9-fold cross-validation], and the inclusion of clinical and demographic information did not increase the prediction performance. Conclusions: Pregnant women with severe PPH had higher median maternal plasma concentrations of IL-16, IL-6, IL-12/IL-23p40, MCP-1, and IL-1β than patients without PPH. These cytokines could serve as biomarkers or their pathways may be therapeutic targets.