Interleukin 6 for the Prediction of Chorioamnionitis: A Systematic Review and Meta-Analysis

Background: Chorioamnionitis is the inflammation of the placenta, amniotic fluid, and fetal membranes and its histological confirmation, histologic chorioamnionitis (HCA) is defined as the diffuse infiltration of neutrophils into the chorioamniotic membranes. Several biomarkers have been evaluated for its early prediction, including interleukin-6 (IL-6), which can be measured in plasma, amniotic fluid, and cervicovaginal fluid (CVF). Aims and Scope: We aimed to systematically review and meta-analyze the role of IL-6 in the prediction of HCA, in several body fluids and among distinct subgroups. Methods: A literature search was conducted in PubMed, Embase, Cochrane Library, and CT.gov between March 2024 and July 2024. Studies that measured IL-6 in AF, CVF, or plasma and conducted a placental examination were included. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess methodological quality. Bivariate analysis combined with a linear mixed model was used for quantitative synthesis, and summary estimates were calculated. Summary Receiver Operating Characteristic (SROC) curves were constructed to evaluate diagnostic accuracy. The z-test was used for subgroup comparisons. Results: In total, 43 studies were included in this meta-analysis, 23 for amniotic fluid (AF), 9 for plasma, and 11 for CVF. AF IL-6 in the overall population had a very good diagnostic performance with an AUC = 0.82 (95% CI: 0.78-0.85) for HCA prediction, with a sensitivity of 65% (95% CI: 0.55-0.74) and a specificity of 84% (95% CI: 0.76-0.89), performing superiorly for the preterm labor (PTL) group (Area Under Curve (AUC) = 0.88, 95% confidence interval (CI): 0.85-0.91) compared with the Preterm premature rupture of membranes (PPROM) subgroup (AUC = 0.76, 95% CI: 0.72-0.80). Plasma IL-6 in the overall population had a good diagnostic performance with an AUC = 0.79 (95% CI: 0.76-0.83), similar to that for the PTL and PPROM subgroups, with a sensitivity of 72% (95% CI: 0.58-0.83) and a specificity of 79% (95% CI: 0.72-0.84). CVF IL-6 in the PPROM group had an excellent diagnostic accuracy, the highest observed in our research (AUC = 0.91, 95% CI: 0.88-0.93), higher than CVF in the overall population, where diagnostic accuracy remained very good. The QUADAS-2 tool revealed a high risk of bias overall. Conclusions: CVF IL-6 could serve as a valid, non-invasive screening test for pregnant women to stratify risk for HCA, while a combination of AF, CVF, and plasma IL-6 could be a tractable diagnostic tool for clinicians, but large-scale Randomized Control Trials are needed to validate this hypothesis.