Impact of Mediators Present in Amniotic Fluid on Preterm

Preterm birth continues to be one of the most important issues in current obstetric medicine, being the single largest cause of perinatal morbidity and mortality. The signals that initiate preterm and term labour remain a mystery. Intrauterine inflammation with the secretion of cytokines is one of the accepted explanations for the mechanism of initiation of preterm labour. This review discusses the current understanding of the molecular mechanisms for the initiation of preterm labour, focusing chiefly on the role of intraamniotic fluid mediators, whether endogenous or infectioninduced, in the regulation of inflammatory response pathways associated with spontaneous preterm labour. Prostaglandins (PGs) are considered to be one of the key mediators of preterm labour, with the concentration of biologically active PGs in the amniotic fluid, particularly PGE2 and PGF2α, being significantly higher in women with preterm labour. Cytokines, such as interleukins and tumour necrosis factor alpha, additionally play a dominant role in preterm labour, particularly in association with infection. Elevated amniotic fluid concentrations of extracellular matrix mediators, including metalloproteases, are also implicated in the process of foetal membrane rupture in preterm labour. Allelic variations in the main amniotic fluid mediators may be the key to understanding the disparity in the rates of preterm birth between different ethnic populations. We also discuss the role of other potential mediators such as cell-adhesion molecules, nitric oxide and novel biomarkers found in the amniotic fluid. About one in ten live births is a preterm birth. This is an enormous public health issue since many of these preterm infants survive with neurocognitive, behavioural and motor disability. To date, there is no proven accurate method of prediction, prevention or treatment of preterm birth (1-3). Thus, one of the foci of current research is to understand the underlying pathophysiology of the preterm birth process and to use this to develop better diagnostic tests and improve therapeutic strategies. It is now well recognised that labour at term resembles an inflammatory reaction, with changes in progesterone and corticotrophin realising hormone levels (4) and with an up-regulation of inflammatory cytokines and prostaglandins in the myometrium, foetal membranes, amniotic fluid and the cervix. Fluctuation in the cytokine concentrations in amniotic fluid has been shown to be indicative of various inflammatory processes and such changes may be associated with preterm labour or chorioamnionitis. Anti-inflammatory cytokines may be essential for a successful normal pregnancy, while on the other hand, increased concentrations of pro-inflammatory cytokines may be a cause of preterm labour. Although the aetiology of preterm labour is multifactorial, in the majority of cases, a similar inflammatory reaction is seen and is thought to result from the pathologic activation of those inflammatory pathways. Infection is a pathological process for which a causal relationship with preterm labour has been established (5, 6). Studies have demonstrated a racial disparity in spontaneous preterm birth between African-Americans and Caucasians, this probably being related to differences in patterns of 799 Correspondence to: Nikolaos Vrachnis, MD, Second Department of Obstetrics and Gynaecology, University of Athens Medical School, Aretaieio Hospital, 124B Vasilisis Sofias Ave., 11526, Athens, Greece. Tel: +30 6974441144, e-mail: [email protected]