Expression of inflammatory, angiogenic, and extracellular matrix‐related mediators in the cervicovaginal fluid of women with preterm premature rupture of membranes: Relationship with acute histological chorioamnionitis

Abstract

Problem: To investigate whether altered expression of various inflammation-, angiogenesis-, and extracellular matrix-related mediators in cervicovaginal fluid (CVF) could be independently associated with acute histological chorioamnionitis (HCA), microbial-associated HCA, and funisitis in women with preterm premature rupture of membranes (PPROM). Method of Study:Clinical data of 102 consecutive singleton pregnant women with PPROM at 23+0 to 34+0 weeks were retrospectively analyzed. CVF samples were collected upon admission. Levels of APRIL, DKK-3, IGFBP-1/2, IL-6/8, lipocalin-2, M-CSF, MIP-1α, MMP-8/9, S100A8A9, TGFBI, TIMP-1, TNFR2, uPA, and VDBP were determined by ELISA. Placentas were histologically examined after birth.Results: Multivariate logistic regression analyses showed that: (1) elevated CVF levels of IL-8 and TNFR2 were independently associated with acute HCA; (2) elevated CVF levels of IL-6, IL-8, M-CSF, MMP-8, and TNFR2 were independently associated with microbial-associated HCA; and (3) elevated CVF IL-8 and MMP-8 levels were independently associated with funisitis when adjusted for gestational age. Areas under the curves of the aforementioned CVF biomarkers ranged within 0.61-0.77, thereby demonstrating poor to fair diagnostic capacity for these clinical endpoints. HCA risk significantly increased as the CVF levels of each inflammatory mediator increased (P for trend < 0.05).Conclusions: Herein, we identified several inflammatory biomarkers (IL-6/8, M-CSF, MMP-8, and TNFR2) in the CVF that are independently associated with acute HCA, microbial-associated HCA, and funisitis in women with PPROM. Furthermore, the degree of inflammatory response in the CVF, based on the levels of these proteins, demonstrated a direct relationship with HCA risk (especially risk severity).

Plasma Kallistatin and Progranulin as Predictive Biomarkers of Intraamniotic Inflammation, Microbial Invasion of the Amniotic Cavity, and Composite Neonatal Morbidity/Mortality in Women With Preterm Premature Rupture of Membranes

“…Despite the aforementioned significant associations of kallistatin and progranulin, these plasma proteins as single markers for IAI/MIAC and CNMM exhibited a fair‐to‐moderate predictive accuracy (0.60 and 0.79, respectively) [48], which is of limited clinical utility. Similar results were reported for other inflammation‐ and angiogenesis‐associated biomarkers identified in the serum and plasma of patients with PPROM, such as IL‐6, LBP, FCGR3A, haptoglobin, and endostatin [5, 18–20]. In fact, it is difficult and challenging to discover blood‐based biomarkers that can be clinically useful for the identification of PPROM‐related complications, mainly because of the large dynamic range of proteins, interference from highly abundant proteins, and inherent biological variability in serum/plasma samples [49, 50].…”

“…All participants provided written informed consent for amniocentesis, and for the collection and use of biological specimens and clinical data for research purposes. Several demographic and clinical data described herein, except data on the proteins assayed in plasma samples, were also described in previous reports (published in Am J Reprod Immunol [ n = 76 and 81, respectively] and Sci Rep [ n = 76]), which describe their association with SPTB, MIAC, IAI, CNMM, and acute histologic chorioamnionitis (HCA) [18, 20, 22].…”

“…MIAC was defined as a positive AF culture result for microorganisms detected using conventional culture techniques. IAI was defined as AF IL‐6 levels ≥2.6 ng/mL, based on previous reports [20, 37, 38]. IAI/MIAC was characterized by the presence of IAI and/or MIAC.…”

“…All the aforementioned observations suggest that changes in AF inflammatory biomarkers associated with in utero inflammation/infection and SPTB may be detected also in the maternal circulation. Several inflammatory proteins, such as interleukin (IL)‐6, low‐affinity immunoglobulin gamma Fc region receptor III‐A (FCGR3A), haptoglobin, lipopolysaccharide binding protein (LBP), matrix metalloproteinase (MMP)‐9, and S100A8/A9, were previously reported as predictors of intraamniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) in the plasma of women with PPROM [5, 18–20]. However, in contrast to inflammatory plasma/serum markers, the role of adhesion‐ and extracellular matrix (ECM)‐related biomarkers in the maternal plasma remains unclear with respect to IAI/MIAC and CNMM, despite the reported associations between their AF levels and in utero inflammation/infection, and between their plasma levels and placental inflammation [21–23].…”

Immunomodulatory role of decidual prolactin on the human fetal membranes and placenta

“…These collagen fibers are the major components of the basal lamina that supports the amniotic epithelium. The increased secretion and activity of these MMPs due to the inflammatory response leads to an irreversible change in the structure of the membranes and impairs their function as a physical and immunological barrier (112)(113)(114). At the histological level, PRL prevents the structural changes induced by LPS in the inner layers of the amnion and preserves the structural integrity of the tissue (82).…”