Maternal inflammatory markers for chorioamnionitis in preterm prelabour rupture of membranes: a systematic review and meta-analysis of diagnostic test accuracy studies

Background: There is no consensus on the role of inflammatory markers in identifying chorioamnionitis in preterm prelabour rupture of membranes (PPROM). We set out to evaluate the accuracy of maternal blood C-reactive protein (CRP), procalcitonin and interleukin 6 (IL6) in diagnosis of histological chorioamnionitis and/or funisitis (HCA/Funisitis) in PPROM. Methods: We searched MEDLINE, EMBASE and The Cochrane Library from inception to January 2020 for studies where maternal blood CRP, procalcitonin or IL6 was assessed against a reference standard of HCA/Funisitis in PPROM. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool was used to assess methodological quality. Hierarchical summary receiver operating characteristic (SROC) models were used to construct summary curves. Bivariate models were used to obtain summary estimates for studies with the same cut-off. Results: We included 23 studies reporting HCA/Funisitis in 902 of 1717 women, median prevalence 50% (inter-quartile range 38-57). Of these studies, 20 were prospective cohort design and 3 were retrospective cohort. Eleven studies reported the index test against a reference standard of HCA and/or funisitis, 10 reported HCA alone and 2 reported funisitis alone. Many studies had high risk of bias scores on the QUADAS-2 assessment but low concerns for applicability. Sensitivity and specificity for CRP >= 20 mg/L (5 studies, 252 participants) was 59% (95% CI 48-69) and 83% (95% CI 74-89) respectively. SROC curves are provided for each index test. At selected specificity of 80%, the sensitivities for CRP (all cut-offs, 17 studies, 1404 participants), PCT ( all cut-offs, 6 studies, 231 participants) and IL6 (all cut-offs, 5 studies, 299 participants) were 59%(95% CI 52-68), 56%(95% CI 50-69) and 52% (95% CI 50-86) respectively. Conclusions: There is insufficient evidence to support use of CRP, procalcitonin or IL6 in maternal blood for diagnosis of HCA/Funisitis in PPROM. This review followed recommended methodology and data analytic methods that made the most of the data regardless of the different cut-offs used. However, the evidence is based on few studies with generally small sample sizes, poor-quality scores and substantial heterogeneity. There is a need for good-quality diagnostic accuracy studies to better assess the role of these biomarkers in PPROM.