Author:

Keywords:

preterm birth, inflammation, maternal serum

Abstract:

Preterm birth (PTB), defined as a delivery at less than 37 weeks of gestation, is the leading cause of perinatal morbidity and mortality worldwide. The serious effects of PTB on parents, infant and society make PTB an important issue to public health. Despite significant advances in perinatal care and advancing knowledge of risk factors and mechanisms associated with PTB, there has been little progress in reducing the PTB rate. Diagnosis of preterm labour as well as accurate prediction of PTB is notoriously difficult, because of the heterogeneity of the condition. PTB is a syndrome initiated by multiple mechanisms including infection or inflammation which is the only pathological process for which both a firm causal link with PTB has been established and a molecular pathophysiology defined. Intrauterine infection evokes an immune response that involves the release of cytokines and chemokines, prostaglandins and matrix-degrading enzymes. These substances trigger uterine contractions, membrane rupture and cervical ripening. Most intra-uterine infections are chronic and subclinical in nature and consequently hard to diagnose before labour or rupture of the membranes. A tremendous amount of efforts has been expended to identify markers to predict PTB and to improve our understanding of the mechanisms and pathways leading to PTB. The best studied site of infection is amniotic fluid, but obtaining this sample requires an invasive and sometimes risky procedure (e.g. amniocentesis). A non-invasive approach seems to be more relevant to clinical practice because of the feasibility and accessibility. However, few studies have investigated the maternal inflammatory response during preterm labour. Therefore, the overall objective of this study was to determine several inflammatory markers in maternal serum from pregnant women in labour (either term or preterm) vs. non-labouring controls. We completed a nested case control study in which singleton pregnancies were recruited at the obstetric department of Ghent University Hospital and divided into groups according to gestational age and labour status. Multiple proteins were evaluated in maternal serum using enzyme-linked or multiplex bead immunoassays including soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), matrix metalloproteinases (MMP)-9 and MMP-3, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4 and a panel of 30 cytokines, chemokines and growth factors. Our study showed that serum levels of sTREM-1 were elevated during spontaneous term and preterm labour vs. non-labouring women. sTREM-1 concentrations were significantly higher in preterm vs. term labour. In line with previous studies, MMP-9 concentrations were elevated during preterm labour. TIMP-1 and TIMP-2 were lower in preterm gestation, irrespective of labour, while TIMP-4 concentrations were raised in labour. One of the most intriguing findings of our study is that MMP-9:TIMP-1 and MMP-9:TIMP-2 balances in maternal serum were tilting in favour of matrix degradation (gelatinolysis) in women with preterm labour. This observation suggests that aberrant serum expression of MMP:TIMP ratios may provide a far less invasive method to determine enzymes essential in the degradation of extracellular matrix (ECM) during pregnancy and parturition. Among the 30 inflammatory serum markers, only hepatocyte growth factor (HGF) was increased in women with PTB, while interleukin (IL)-12 serum levels were lower in labouring women and interferon gamma induced protein (IP)-10 serum levels were higher in women at term gestation. This may indicate that the inflammatory response in serum of women with term and preterm labour is rather weak. Until present, few biomarkers have shown clinical usefulness, because they are nonspecific or become positive too late. Among the biomarkers evaluated to date, the most powerful and consistent predictors of PTB are the presence of foetal fibronectin in cervicovaginal fluid and a short cervix on transvaginal ultrasound examination. The clinical value of both tests primarily lies in their negative predictive value thereby guiding clinicians in decision-making and avoiding unnecessary interventions. During the last decades, it has become clear that single or universal biomarkers will not be capable to predict PTB accurately in all populations. Future research should focus on multiple biomarkers in different PTB subtypes to allow differentiation depending on the underlying causes. The future development of an accurate, minimally invasive multiple marker test is necessary to permit incorporation into clinical practice. The availability of new technologies capable of probing the genome offers exciting possibilities to gain new insights into the mechanisms leading to PTB and to develop targeted therapies.