Arch Gynecol Obstet (2010) 281:975–982 DOI 10.1007/s00404-010-1365-9 M A T ER N O - F E T A L M E D I C I N E The onset of human parturition Remah Moustafa Kamel Received: 11 December 2009 / Accepted: 7 January 2010 / Published online: 3 February 2010  Springer-Verlag 2010 Abstract Background Despite impressive progress in the science and technology of reproduction, the mechanism by which labour is initiated in humans remains obscure. Objectives As the labour in humans is a distinct event diVers from what happens in animals, this study aims to gather the current theories that could explain when and why the onset of human parturition occurs. Methods In a comprehensive review study done at the School of Medicine and Dentistry, University of Bristol, United Kingdom, MetaLib, the university web-based electronic library, was cross-searched for the factors behind the onset of labour in humans through diVerent medical databases such as; Allied and Complementary Medicine Database (AMED), BIOSIS Previews on Web of Knowledge, PubMed, Cochrane Library, Medline and Web of Science, in-addition to the relevant printed medical journals and periodicals. Results The study revealed that among the potential factors involved in the process of human parturition are the changes in hormonal levels of estrogen and progesterone, increased production of prostaglandins and oxytocin, and the high levels of corticotrophin releasing hormone and cortisol are some among the potential factors involved in the process of human parturition. InXammatory reactions R. M. Kamel Department of Obstetrics and Gynaecology, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia R. M. Kamel (&) 4 Tyndall’s Park Road, Clifton, Bristol BS8 1PG, UK e-mail: remah.kamel.07@bristol.ac.uk; remahmoustafa@hotmail.com with the release of cytokines are among the most accepted theories for term and preterm labours. It is most likely that the interaction between all these factors and others, yet to be discovered, play in harmony to initiate the process of labour in women. Conclusion The result show that birth is a result of complex, partially deWned, events that are tightly regulated by a variety of mechanisms and mediators of endocrine, nervous and immune systems. Unfortunately, none of them is completely elucidated. Keywords Onset of human birth · Labour · Parturition Introduction Scientists have long been puzzled about the factors involved in the initiation of human parturition. Hippocrates and Aristoteles [1] believed that the foetus may decide to born when he becomes big enough and his mother cannot support him anymore with essential foods. Studies on the human parturition are complicated by lacking of direct testing, where endocrine diversities between animal species make it diYcult to extrapolate to the humans. The current most accepted theories recruit steroid hormones, paracrine molecules and inXammatory mediators in the process of labour. The interaction between these factors seems to play an essential role, yet the precise mechanism is still mysterious [2–4]. Current theories: functional progesterone withdrawal and estrogen activation In human parturition, progesterone withdrawal and estrogen activation are not caused by changes in their genuine 123 976 Arch Gynecol Obstet (2010) 281:975–982 Fig. 1 Diagrammatic model for the role of estrogen and progesterone in the regulation of human pregnancy and parturition serum levels. Instead, these events are aided by changes in the sensitivity of the myometrium to the progesterone and estrogen hormones through alteration in the rate of expression of their receptors. During pregnancy, progesterone hormone exerts its relaxation eVect by reducing myometrial estrogen sensitivity through inhibiting the expression of estrogen receptors alpha (ER-). This may explain why the human myometrium is refractory to the circulating high levels of estrogens during gestation. At term, the myometrial sensitivity to progesterone changes, with more expression of progesterone receptors-A (PR-A) relative to progesterone receptors-B (PR-B), and such changed ratio leads to functional progesterone withdrawal [5] (Fig. 1). The functional withdrawal of progesterone leads to elimination of the suppressive eVect of progesterone on ER- expression, leading to functional estrogen activation and increased myometrial sensitivity to estrogen. Thus, the interaction between the PR and ER systems in the myometrium seems essential for the control of human parturition [6]. However, exogenous administration of progestogens could prevent the preterm labour but not the term one [7]. The concept of functional progesterone withdrawal in association with the onset of labour in humans has been accepted by many scientists and a number of mechanisms have been suggested [8, 9]. Among the recent postulated mechanisms are the catabolism of progesterone into inactive metabolites, changes in the cofactor protein levels aVecting PR activation, regulation of PR responsive genes through the nuclear factor kappa-B (NF-rB) promoter sites, and the non-genomic eVects of progesterone and its metabolite 5-dihydroprogesterone (5DHP) [10–12]. This explains why disruption of progesterone alone could trigger the full parturition cascade [13]. 123 Prostaglandins and thromboxane There is a controversy whether prostaglandins (PG) play a vital role in the initiation of human parturition. Several investigators reported that the amniotic Xuid concentrations of PGE2 and PGF2 increase late in the course of labour (after-eVect) and therefore they do not play a role in the initiation of parturition. However, Romero and his colleagues [14] noticed an increase in the prostaglandin bioavailability before the onset of labour. Literature survey yielded many evidences for the role of PG in the human parturition. For examples: a rise in the level of arachidonic acid was noticed in the amniotic Xuid during labour and after cervical manipulation; stripping of foetal membranes augmented uterine contractions through endogenous release of PG; and therapeutic use of PGE2 induced cervical ripening and labour process. Allport and his co-workers [15] demonstrated that human parturition was associated with up-regulation of prostaglandins within the uterus, synthesized by type-2 cyclo-oxygenase enzyme (COX-2). This led to remodelling of foetal membranes and cervix with stimulation of myometrial contraction. Recently, Fischer and his colleagues [16] found that prostaglandins E2, F2 and thromboxane (TX) mediated uterine contractility through targeting prostanoid EP, FP and TP receptors, respectively. In labour, there is a loss of myometrial responsiveness to prostaglandins F2, but not to thromboxane (TX). Furthermore, the concentration of prostanoid in the amniotic Xuid increases [17]. On the other hand, relaxin hormone, which is present in the maternal decidua and chorion laeve at term, might have a paracrine eVect on the foetal membranes and inhibits PGE2 production during pregnancy [18]. Accordingly, anti-prostaglandins (such as Aspirin and Indomethacin) may have a signiWcant eVect in prolongation of pregnancy in women with preterm labour. Arch Gynecol Obstet (2010) 281:975–982 977 Oxytocin and vasopressin Oxytocin and vasopressin secretion is stimulated by estrogen, an eVect which is counteracted by progestagens. During labour, foetus can produce substantial amounts of oxytocin and vasopressin. The myometrium can be activated via speciWc oxytocin receptors (OTR) and vasopressin (V1a) receptors that increased in numbers before labour [19–21]. Binding of the oxytocin to its receptors in the myometrium activates phospholipase C, which increases the intracellular calcium and thus potentiates uterine contractions. Oxytocin has also been found to stimulate prostaglandin synthesis in the chorion, decidua and amnion, thus assisting in cervical ripening process [22, 23]. Consequently, synthetic oxytocin is used in daily practice for augmentation of already started labour [2]. Adrenocorticotrophin and cortisol During pregnancy, there is a progressive increase in the production of corticotrophin releasing hormone (CRH) from the placental and foetal membranes. The precise mechanism that regulates production of CRH is still unknown, although it inhibited by progesterone and stimulated by prostaglandins, oxytocin and stress. The CRH levels in the amniotic Xuid and maternal circulation increase as labour approaches with a corresponding decrease in the CRH-binding proteins. Such increased level of free active CRH near term not only stimulates foetal cortisol production, which promotes foetal lung maturation, but also increases placental estrogen synthesis and prostaglandin release in foetal membranes, decidua and myometrium [7]. The eYciency of CRH action is determined by the expression of its functional receptors (CRH-R) which increased at onset of labour by 2- to 3-folds (Fig. 2). Although the foetal adrenocorticotrophic hormone (ACTH) is important for the onset of cortisol production, late gestational surge in cortisol occurs despite falling in the ACTH level. This could explain why not all anencephalic foetuses are born late. Rehman and his colleagues [24] recorded high cord blood cortisol levels in infants born after spontaneous onset of labour. McLean and Smith [25] proposed that CRH (through interactions with estrogen, adrenal steroids, prostaglandins and oxytocin) established positive-feedback loops that initiate parturition. However, excess oxytocin administration has an inhibitory eVect of on ACTH and cortisol release. Such inhibitory eVect is dose- and time-dependent [26]. On 2007, Markovic and his colleagues [27] found that prolonged treatment of myometrial cells with interleukin-1 beta (IL-1) increased the expression of CRH-R1 by 1.5- to 2-folds. This Wnding suggests that IL-1 is an important Fig. 2 The role of corticotrophin releasing hormone (CRH) in human parturition regulator of CRH-R1 activity, and this interaction may play a role in switching the uterus from a quiescent into an active state. Placental CRH and foetal pituitary ACTH stimulate the foetal adrenal glands to secrete dehydroepiandrosterone sulphate (DHEAS), which the placenta is able to convert it into estrogen necessary for spontaneous delivery. The role of foetal DHEAS in the initiation of human parturition was studied by Marton [28] through direct estimation of its umbilical blood levels in correlation to oxytocin consumption during induced labours. The study found a close relation between the high levels of foetal cord DHEAS and the low amounts of oxytocin required for induction of labour. Activin, inhibin and follistatin In humans, the placenta synthesises and secretes many paracrine and autocrine factors during pregnancy. Among these are activin-A, its antagonist inhibin-A and its binding glycoprotein follistatin [29]. These factors have been isolated from the human placenta, foetal membranes and from the choriodecidual tissue. Their levels rise during pregnancy, particularly near term. Women with spontaneous labours have concentrations higher than those with induced labours or after operative delivery [29, 30]. However, the available data do not support a signiWcant association between their rising levels and preterm labour [29, 31]. InXammatory cytokines, chemokines and immunomodulators The elaboration of cytokines, chemokines and immunomodulators in the placenta and foetal membranes has been 123 978 extensively investigated in the context of normal and abnormal labours. Expression of cytokines in foetal membranes and decidua suggests an inXammatory reaction occurs at term and preterm labours. These inXammatory cytokines regulate the release of uterotonins such as prostaglandins [32]. The levels of prostaglandin-H synthase type-2 (PGHS2), IL-1, IL-6 and IL-8 messenger ribonucleic acid (mRNA) expression are signiWcantly higher in term compared with preterm labours. These changes may occur in response to the release of inXammatory cytokines by labour-associated inXammatory inWltration [33]. Enhanced chemokine expression, chieXy evident in deliveries complicated with chorioamnionitis, is presumably responsible for recruiting inWltrating leukocytes into the foetal membranes. Thus, it ampliWes inXammation and hastens membrane rupture and delivery [34]. Nuclear factor kappa B (NF-rB) is classically linked to inXammation. Accumulating data point to the role of NF-rB in the pathophysiology of labour. Its activity increases with onset of labour, the function of which is expression of Cyclo-oxygenase-2 (COX-2) that contributes to functional progesterone withdrawal and stimulation of prostaglandins [35, 36]. Lappas and Rice [37] proposed that spontaneous onset labour might happen due to withdrawal of peroxisome proliferator-activated receptors (PPAR) and progesterone receptors on the pro-labour pathways of NF-rB (Fig. 3). Synthesis and release of tumour necrosis factor alpha (TNF-) and transforming growth factor-beta 1 (TGF-1) by foetal membranes at term are related to oxytocin, hydrocortisone and progesterone hormones [38]. Their levels in the amniotic Xuid rise during labour [39]. In order to demonstrate the inXammatory reactions within the human placental tissues in association with normal term and preterm labours, the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) was studied by the immuno-histochemical methods in both trophoblastic villi and umbilical cord. The results revealed that ICAM-1 expression in the endothelium of foetal vascular system was associated with labour and reXected sharing of immune-inXammatory reactions [40]. Proteolytic enzymes Human labour is characterized by dramatic physiological alterations in the cervix and foetal membranes leading to myometrial activation and delivery. A number of tightly regulated proteolytic enzyme systems such as plasminogen activation and matrix metalloproteases play integral role in remodelling of extracellular matrix during pregnancy and parturition [41]. 123 Arch Gynecol Obstet (2010) 281:975–982 Fig. 3 Nuclear factor kappa B (NF-rB) and labour pathway A relationship was thought to exist between tissue concentrations of IL-8, matrix metalloproteinase (MMP)-8 and MMP-9 and a number of leukocytes inWltrating the lower uterine segment during parturition. The IL-8 induces inWltration of the cervix by neutrophils with a subsequent release of proteinases that play a key role in parturition [42]. In Di Quinzio study [43], 2D-PAGE proteomic analysis on serial cervicovaginal Xuid obtained from women during labour identiWed nine protein spots that were signiWcantly altered in association with spontaneous term labour. These proteins were involved in the protease inhibition, antiinXammatory cytokine activity and in the oxidative defense. Inositol phosphoglycans Inositol phosphoglycans (IPGs) have been linked to the pathogenesis of some conditions such as diabetes mellitus and pre-eclampsia [44, 45] that complicate pregnancy. Paine and his co-workers [46] noticed a constant rise in the urinary IPG-P levels in women at time of labour whether spontaneous or induced. Amnion apoptosis The mechanism by which foetal membranes rupture at birth is still unknown. As the inXammatory cytokines increase at term, collagen remodelling of foetal membranes may induce weakness and fragility [47]. Studies designed by Arch Gynecol Obstet (2010) 281:975–982 Hsu and his co-workers [48], as well as by Kumagai and his colleagues [49] aimed to detect apoptosis in the foetal amnion at term. It revealed that apoptosis in the amniotic epithelium was evident at term, and it could play a role in the fragility and spontaneous rupture of foetal membranes at labour. Intracellular calcium and myosin light chain kinase The individual myometrial Wbre contracts when the two Wlaments of actin and myosin combine via phosphorylation by enzyme myosin light chain kinase (MLCK) to form actino-myosin. This reaction requires an increased availability of intracellular calcium that released from the cellular stores (sarcoplasmic reticulum), provoked by oxytocin and PGF2 via second messenger inositol triphosphate. Additionally, the extracellular calcium may be transported into the myometrial cells via calcium channels. The increased intracellular calcium concentrations and the number of gap junctions at term initiate uterine contractions. On the other hand, contractility of myometrial cells may be inhibited by progesterone and -adrenergic drugs that are commonly used for preterm labours [6, 23, 50, 51]. 979 Ethnicity Background veriWcation exists concerning the relation between duration of gestation and ethnicity. A Britishbased study [53] compared gestational length amongst a group of white European, black African and Asian women with spontaneous onset of labour. The study found that the duration of pregnancy was shorter among the African and Asian women compared with that of the European women. This Wnding may be related to a possible early in-utero foetal maturation or spontaneous preterm birth among the African and Asian women. Placental insuYciency Women living at high altitude are more liable for preterm birth in comparison with those living at sea level [54]. Foetuses with comparatively light-weight placentae remain in average a shorter time in-utero than those with heavyweight placentae [55]. These Wndings lead to the assumption of a relative state of placental insuYciency as a determining factor for triggering the onset of labour. Genetic alteration Haemostatic system The haemostatic system consists of blood coagulation factors, kinin–kallikrein system, Wbrinolytic activity and platelet function. The most prominent change in the haemostatic system during labour occurs in the kinin–kallikrein portion. At onset of labour, prekallikrein decreases quickly which triggers the changes in blood coagulation factors and Wbrinolytic activity. Platelet aggregation decreases with a slight increase in the Wbrin degeneration products (FDP) [52]. Currently, molecular biology assesses the activity of genes in the uterus and foetal membranes [6]. Many gene-defects result in endocrine alterations that might be relevant to abnormal onset of labour [2]. The timing of birth necessitates coupling of foetal maturation with the onset of parturition. Studies in human preterm births of familial and racial disparities have contributed to the fact that preterm birth is a heritable health problem. A signiWcant portion of this heritability is due to polygenic causes [56]. Fig. 4 SimpliWed scheme of hormonal control of pregnancy and parturition (red arrows indicate stimulatory eVect while blue arrows indicate inhibitory eVect) 123 980 Pulmonary surfactant Pulmonary surfactant is a surface-active lipoprotein complex produced by type II pneumocytes and secreted by fetus into the amniotic Xuid. A study carried out by Tinnakorn Chaiworapongsa and her colleagues [57] aimed to determine whether the amniotic Xuid concentrations of pulmonary surfactant protein (SP)-A and -B change during human parturition. The study found that foetal pulmonary SP-A concentration decreased following spontaneous labour, while there was no signiWcant change in the SP-B concentration. Foetal surfactant stimulates prostaglandins production by the amnion cells. This Wnding was proved by Andres Lopez Bernal and Patrick Phizackerley study [58]. Weather condition and the moon A widely held traditional belief among the public is that human births occur more frequently during times of bad weather as in severe storms or sudden drops in temperature. Climate data were examined by Driscoll and Merker [59] for their relationship with the time at which pregnant women at term Wrst experienced true labour pains. Onset of labour on winter days with low temperature and high wind speeds were 34% above the average. To determine whether there is any correlation between the barometric pressure and onset of labour, a retrospective study was done by Elizabeth King and her colleagues [60] in Houston, USA. The overall number of women went into spontaneous labour, in the study, was high when a signiWcant drop in the barometric pressure occurred. Another study investigated the inXuence of early and full moon on the onset of human parturition and spontaneous rupture of foetal membranes [61]. Its results indicated a relationship between the onset of labour and the full moon state when barometric pressure was not controlled and with spontaneous rupture of foetal membranes when barometric pressure was controlled. Foetal sex Male foetuses are more likely to be born before term. This event was supported by the studies carried out by Jennifer Zeitlin and her assistants [62, 63] which linked foetal sex with the onset of labour. Conclusion The timing of the labour in women is not precisely known and its aetiology is likely to be a multifactorial. The process of human parturition seems to begin before the actual onset of labour. It becomes clear that the endocrine system plays 123 Arch Gynecol Obstet (2010) 281:975–982 an important role in maintenance of uterine quiescence during pregnancy and in initiating uterine activity at labour. Balance between the eVects of estrogen and progesterone is critical (Fig. 4). 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