Plasma IGFBP‐1, Fas, kallistatin, and P‐selectin as predictive biomarkers of histologic chorioamnionitis and associated intra‐amniotic infection in women with preterm labor

Abstract

Problem To determine whether altered levels of 13 plasma biomarkers, alone or in combination, could be independently associated with histologic chorioamnionitis (HCA) and microbial‐associated HCA (defined as the presence of HCA along with microbial invasion) in women with preterm labor (PTL). Methods of Study This was a retrospective cohort study involving 77 singleton pregnant women with PTL (23–34 gestational weeks) who delivered within 96 h of plasma and amniotic fluid (AF) sampling. DKK‐3, E‐selectin, Fas, haptoglobin, IGFBP‐1, kallistatin, MMP‐2, MMP‐8, pentraxin 3, progranulin, P‐selectin, SAA4, and TGFBI levels were assayed in plasma samples by ELISA. AF obtained via amniocentesis was used for microorganism identification. Results Multiple logistic regression analyses revealed significant associations between low plasma IGFBP‐1 levels and acute HCA, and between low plasma Fas and kallistatin levels, and elevated plasma P‐selectin levels and microbial‐associated HCA (all p < .05), after adjusting for gestational age. Using a stepwise regression procedure, a multi‐biomarker panel for microbial‐associated HCA was developed, which included plasma MMP‐2, kallistatin, and P‐selectin levels (area under the curve [AUC], .867). The AUC for this three‐marker panel was significantly or borderline significantly greater than that of any single variable included in the panel. However, a predictive model for acute HCA could not be developed because only one variable (MMP‐2) was selected. Conclusions These findings demonstrate that IGFBP‐1, Fas, kallistatin, and P‐selectin are associated with acute HCA and microbial‐associated HCA in women with PTL. Their combined use can significantly improve the diagnostic ability for the detection of microbial‐associated HCA.

Identification and characterization of plasma proteins associated with intra-amniotic inflammation and/or infection in women with preterm labor

“…In particular, kallistatin acts as a negative acute phase protein that rapidly reduces its expression after lipopolysaccharide-induced inflammation in the liver, contributing to the decreased levels of kallistatin observed in the serum/plasma of patients with inflammation-related conditions, such as obesity, inflammatory bowel disease, and septic syndrome 46 , 48 , 49 . In line with inflammatory disease-related data 46 , 48 , 49 , our previous studies on pregnancies complicated by PTL or PPROM also showed that kallistatin levels are significantly decreased in the plasma of women with acute HCA or microbial-associated HCA 50 , 51 . Overall, the findings from the aforementioned studies 63 , 64 , as well as the inflammatory biological properties and expression profiles of kallistatin, are consistent with and support the herein described association between plasma kallistatin levels and MIAC, IAI, or SPTB risk outcome, given the reported relationships between these endpoints and acute HCA 4 , 52 , 53 .…”

An Early Gestation Plasma Inflammasome in Rural Bangladeshi Women

“…Our analysis identified a strong, negative correlation of AGP with plasma kallistatin, a circulating serine protease inhibitor with pleiotropic antioxidant, anti-inflammatory, and immunoregulatory functions affecting cardiovascular homeostasis [38]. A low plasma kallistatin level has recently been associated with an increased risk of chorioamnionitis in women experiencing preterm labor [39] and the preterm rupture of membranes [40], implicating its potential utility as a biomarker of chorionic inflammation.…”

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

“…The precision and accuracy of the nine ELISAs were validated for plasma samples before use through spike‐and‐recovery and linearity‐of‐dilution experiments, which revealed their good performance. These proteins were selected to be explored in the present study because (i) they were previously suggested to be useful blood biomarkers for the detection of histologic inflammation in the placenta; however, whether their altered expression in the plasma is associated with AF inflammation/infection and adverse neonatal outcomes in the context of PPROM remains unclear [22, 23]; (ii) they could have potential clinical significance in the maternal blood regarding the outcomes of interest herein investigated, considering previous proteomic profiling studies that suggested that they could be potential candidates biomarkers for MIAC, IAI, or preterm birth [18, 24–26, 28, 32]; and because (iii) their related signaling pathways (such as inflammation/immune‐, cell adhesion, and ECM homeostasis [https://www.uniprot.org/]) are known to be involved in the pathogenesis of adverse pregnancy and neonatal outcomes [33–36].…”

“…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][19][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][22][23]. Furthermore, the roles of other inflammatory proteins, including alpha-fetoprotein (AFP), C-X-C motif chemokine 14 (CXCL14), galectin-3-binding protein (Gal-3BP), kallistatin, and vitamin D-binding protein (VDBP),…”