br Materials and methods br Author contributions
Materials and methods
Acknowledgements Supported by grants from the Zhejiang Provincial Natural Science Foundation (LY16H030016, LY17H030012), and the Zhejiang Science and Technology Public Welfare Project (2015C33279), Anesthesiology Center in North of Zhejiang Province, Jiaxing key laboratory of neurology and pain medicine, Centers for Disease Control OF Jiaxing, Center for gastroenterology and hepatology connecting with Shanghai.
Introduction Preterm birth is the major cause of neonatal death worldwide, with approximately 15 million babies born preterm each year , , and it is a heterogeneous phenotype with many biological pathways. Most preterm births are because of the spontaneous onset of labor without a known cause or effective prevention. The identification of risk factors is important for the prediction of spontaneous preterm birth (sPTB); however, the low sensitivities of the current methods, based on the demographic and behavioral risk factors, make it non-effective for the identification of the pregnant women who are at increased risk of sPTB. The use of biomarkers for the prediction of sPTB has been widely investigated. The previous history of sPTB is the single strongest predictor of subsequent sPTB , . However, it is not applicable for primipara. Several studies have shown that biomarkers such as fetal fibronectin and cervical length are effective for the prediction of sPTB in symptomatic women . These biomarkers have limited accuracy in predicting sPTB in pregnant women without the clinical manifestations of premature delivery. For asymptomatic women, a reliable evaluation of the risk factors of sPTB using biomarkers is beneficial in deciding whether further screening and clinical intervention are required. Although there are multiple causes underlying sPTB, inflammation is the major risk factor for preterm birth , . Pregnancy has been considered as a state of special maternal–fetal immune tolerance, and cytokines play an important role in the maintenance of immune sodium fluoride . An early study of circulating cytokines is promising for the identification of simple blood-based biomarkers for possible clinical use. Several studies have reported the relationship between maternal serum levels of cytokines, including IL-6, IL-8, IL-10, IL-16, IL-17A, TNF-α, MCP-3, IFN-γ, and MMP-9 and sPTB risk , , , . Although the previous studies have identified several different biomarkers, no single biomarker can accurately predict the risk of sPTB in asymptomatic women .
Discussion In terms of single cytokine, the findings of top predictors (TNF-α and TRAIL) derived from the elastic model were consistent with the findings from conditional logistic regression model. According to the findings from conditional logistic regression models, TNF-α and TRAIL might play a causal role in sPTB, as evident from the observed dose-response reaction across the quartiles (Table 3). TNF-α, being a cell signaling protein, is involved in systemic inflammation and is one of the cytokines that constitute the acute phase response. Inflammation at the maternal–fetal interface is well defined because of sPTB , . Systemic or local infection can trigger a cascade of events resulting in preterm labor , . Previous studies have suggested that a severe inflammation is incompatible with a normal pregnancy , , . Abnormal increases in pro-inflammatory cytokines increase the risk of preterm labor , , . Excessive cytokines can accelerate preterm delivery by triggering uterine contractions and activating cervical ripening , . Brou et al. found that higher concentration of TNF-α in African-American women contributed to the higher incidence of sPTB compared to the Caucasian women who were presented with a low concentration of TNF-α . Mbongo et al.  reported that the women who delivered preterm had significantly higher levels of TNF-α compared with the women who delivered at term. Moreover, a murine model of lipopolysaccharide -induced preterm birth has shown that anti-TNF-α therapy might decrease fetal deaths and preterm labor . TRAIL is a member of the TNF family. It can trigger apoptotic cell death by binding to certain death receptors. In our study, the elevated level of TRAIL was associated with sPTB risk. But the exact mechanism is unclear. Apoptosis plays an important role in the normal development of placenta, and an imbalance between proliferation and apoptosis of villous trophoblast is associated with abnormal pregnancy , . Studies suggested that elevated expression of inflammatory cytokines such as TNF-α, increased activity of proteases, dissolution of extracellular matrix components, and apoptosis are involved in the abnormal pregnancy process , . As a tumor necrosis factor-related apoptosis-inducing ligand, the potential pro-apoptotic effects support the hypothesis that TRAIL may increase the risk of sPTB.