Abstract
ObjectiveWe sought to identify plasma biomarkers associated with spontaneous preterm birth (SPTB, delivery within 21 days of sampling) in women with preterm labor (PTL) without intra-amniotic infection/inflammation (IAI) using label-free quantitative proteomic analysis, as well as to elucidate specific protein pathways involved in these cases.MethodsThis was a retrospective cohort study comprising 104 singleton pregnant women with PTL (24–32 weeks) who underwent amniocentesis and demonstrated no evidence of IAI. Analysis of pooled plasma samples collected from SPTB cases and term birth (TB) controls (n = 10 for each group) was performed using label-free quantitative mass spectrometry for proteome profiling in a nested case-control study design. Eight candidate proteins of interest were validated by ELISA-based assay and a clot-based assay in the total cohort.ResultsNinety-one proteins were differentially expressed (P < 0.05) in plasma samples obtained from SPTB cases, of which 53 (58.2%) were upregulated and 38 (41.8%) were downregulated when compared to TD controls. A validation study confirmed that plasma from women who delivered spontaneously within 21 days of sampling contained significantly higher levels of coagulation factor Ⅴ and lower levels of S100 calcium binding protein A9 (S100A9), especially the former which was independent of baseline variables. The top-ranked pathways related to the 91 differentially expressed proteins were liver-X-receptor/retinoid X receptor (RXR) activation, acute phase response signaling, farnesoid X receptor/RXR activation, coagulation system, and complement system.ConclusionsProteomic analyses in this study identified potential novel biomarkers (i.e., coagulation factor V and S100A9) and potential protein pathways in plasma associated with SPTB in the absence of IAI in women with PTL. The present findings provide novel insights into the molecular pathogenesis and therapeutic targets specific for idiopathic SPTB.
Highlights
Preterm labor (PTL) is observed in 2–3% of all pregnancies and accounts for approximately one-third of spontaneous preterm births (SPTB), which is a major cause of perinatal mortality and morbidity [1,2,3]
A validation study confirmed that plasma from women who delivered spontaneously within 21 days of sampling contained significantly higher levels of coagulation factor V and lower levels of S100 calcium binding protein A9 (S100A9), especially the former which was independent of baseline variables
Proteomic analyses in this study identified potential novel biomarkers and potential protein pathways in plasma associated with SPTB in the absence of IAI in women with PTL
Summary
Preterm labor (PTL) is observed in 2–3% of all pregnancies and accounts for approximately one-third of spontaneous preterm births (SPTB), which is a major cause of perinatal mortality and morbidity [1,2,3]. Accumulated evidence shows (i) fetal CD4+ T cell activation, calciprotein particles, and Q-profile based on the presence of 5 SELDI peaks in the amniotic fluid (AF) and (ii) protein Z levels in maternal plasma as effective potential biomarkers to assess the risk of idiopathic PTL and birth [9,10,11,12] These studies were limited by analyses restricted to selected target markers and the fact that the definition of idiopathic PTL and birth is not enough to completely exclude any infection/inflammatory cases as it was determined based on the analysis of either the AF or placenta alone
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