Preterm Birth

Preterm birth (PTB) is a global obstetrical challenge. About 13 million preterm deliveries occur per year (Villar et.al.). Preterm birth (PTB) complicates 12% of pregnancies in the United States and accounts for more than 70% of the neonatal and infantile morbidity and mortality (Lockwood et.al.). The frequency of PTB varies from 5-10% in developed regions of the world and can be as high as 40% in certain very poor areas. ( Creasy 1991, Sawitz et al 1991, Lockwood et.al. 2001). In a global study including about 42.000 women the frequency of PTB was 8.6%. Fifty-six percent had spontaneous pre-term delivery, 17% PPROM without any complications, whereas 4% with complications (Vilar et.al.).
Thus PTB is a great problem related to high perinatal mortality and to considerable expense account. Traditional methods of predicting women at risk for PTB i.e. obstetric history, tocodynamometry, biochemical markers, and ultrasonography of the cervix have not lowered the number of PTB (Lockwood et al 1993, Copper et al 1990,). Current methods to predict PTB including sonographic registration of the cervical length or biomarkers i.e. human chorionic gonadotropin (hCG), foetal fibronectin (fFN), estrogens and cytokines do not achieve enough reliability to be recommended as screening methods. The available therapeutic drugs inhibiting preterm contractions have failed to decrease the incidence of PTB (Creasy et al 1980, Mercer et.al. 1996, The Worldwide Atosiban Study BJOG 2001).
The decline in neonatal morbidity and mortality during the last two decades can be referred mostly to improved neonatal intensive care. However the unchanged high frequency of PTB reflects an insufficient knowledge about the pathophysology of PTB. The research has been focused upon the myometrial contractility and the inhibition thereof. The signalling pathway for the myometrial contractility is complicated and has been investigated in vivo an in vitro (Poston). The regulation and the role of oxytocin for term labor have been extensively studied (Thornton). Recently published studies support also the involvement of the uterine ECM surrounding the smooth muscle bundles. The uterine ECM is remodelled in late pregnancy and mostly at established labor (Hjelm et al). Normal term labor is related to an increased genetic expression of the heparan sulphates (HSPG’s), whereas this up regulation fails in women with dystocia (Hjelm). Tocolytic regimens are the dominating therapy at threatening preterm labor. Due to fewer maternal and foetal side effects oxytocin analogues have replaced betamimetica as therapeutic treatment. Calcium channel blockers are also effective in inhibiting myometrial contractions, but their maternal side effects reduce their clinical application. Nevertheless tocolytic therapy has not lowered PTB. The PTB is also related to a preterm cervical ripening. Danforth found 1947 that the human cervix was dominated by extracellular matrix (ECM). This finding focused the interest on the cervix in 70th. The normal and prostaglandin induced cervical ripening process correspond to a pronounced remodelling of the cervical ECM (Ekman et al x flera, Westergren Thorsson et al Calder et al). This remodelling can be looked upon as an inflammatory process with an up regulation of several genes of Cytokines/Chemokines and a significant increase of their protein concentrations. For all clinicians it is well known that a favourable cervical state before onset of labor is crucial for a normal obstetric outcome. On the other hand a preterm cervical ripening increases the risk for a PTB and a delayed ripening results in a post-term pregnancy (Abelin 2004, Almström 1995, Ekman Collagen as a). Several theories exist regarding the initiation and control of pre-term labor (PTL). The hormonal control with a progesterone block has been found well established in sheep but not in humans ( REF. However, there is evidence for a local progesterone/estrogen shift in the cervix at term labor (Stjernholm et.al.) The activation of the maternal or foetal hypothalamic-pituitary-adrenal axis has since 25 years been investigated in different species (Challis et al Endocrine rev 2000). Increased serum levels of CRH at labor support this second theory (Korebrits et al 1998). A third theory suggests oxytocin to play an important role in PTL. No doubt oxytocin is important to support a PTL but it is not established that it initiates PTL. A decidual activation mediated by paracrine acting hormones is a fourth theory (Lockwood et al 2001). Local intrauterine bleeding and /or genital infections are probably involved in the following decidual activation. Pathological uterine distension has been raised as another cause of PTB. (Lye) The dominating hypothesis is that an exogen infection is involved in the pathogenesis of PTB and that some women are more sensitive to exogenous infections than others (Mehmet) A special group constitutes women with preterm premature rupture of the foetal membranes (PPROM). Many investigations point out the connection between PPROM and chorioamnionitis and the activation of the inflammatory cascade of cytokines and MMPs (ref).
The tendency to repeat PTB raises the question for a genetic predisposition (Bakketeig). Porter et al showed an increased risk of PTB across generations (Porter et al). Ethnic differences of PTB have been reported (Goldenberg 1996, Nguyen 2004, Fortunato 2004). Functional genomic on pregnant myometrium from different species has been studied with suppression subtractive hybridisation (SSH) and micro array techniques, showing up regulation of many genes i.e.oxytocin receptor, MMP-9, foetal fibronectin, interleukin-8, EGF, IGF-BP, SOD2, ACE (Romero 2002). Other investigations find polymorphisms in the genes of interleukins-1, -6 and TNF alpha in women with PTB (Genc 2002, Macones 2004, Simhan 2003 and Genc 2004). A parturition defect has been registered in steroid 5 alfa-reductase type 1-knockout mice indicating the role of steroid hormones in the parturition process (Mahendroo 1999). PTB is still an enigma. Our diagnostic and therapeutic tools have failed to reduce the number of PTB. To evaluate a genetic predisposition seems therefore attractive. The aim of this article is to present the signalling pathways involved in the PTB and which genes seem to be relevant to investigate.