INTRODUCTION — Term labor is a physiologic process involving a sequential, integrated set of changes within the myometrium, decidua, and cervix that occur gradually over a period of days to weeks, culminating in rapid changes over hours that end with expulsion of the products of conception (fetus and placenta). Biochemical connective tissue changes in the cervix appear to precede uterine contractions and cervical dilation, and all of these events usually occur before rupture of the fetal membranes. After delivery, the uterus gradually reverts to its prepregnant state, except for the external cervical os, which remains patulous.
Term labor may be regarded physiologically as a release from the inhibitory effects of pregnancy on the myometrium, rather than as an active process mediated by uterine stimulants. As an example, strips of myometrium obtained from a quiescent uterus at term and placed in an isotonic water bath will contract vigorously and spontaneously without added stimuli [1,2]. Nevertheless, both inhibitory and stimulatory mechanisms likely play a role in uterine activity. By comparison, many cases of preterm labor appear to be the consequence of activation of labor due to infection, inflammation, or other pathologic disorders, which short circuit or overwhelm the normal parturition cascade at term.
This topic will review the physiology of normal term parturition. The pathogenesis of spontaneous preterm labor and birth is discussed separately. (See "Spontaneous preterm birth: Pathogenesis".)
THE FOUR PHASES OF UTERINE ACTIVITY — Uterine activity during pregnancy can be divided into four distinct physiologic phases: inhibition, activation, stimulation, and involution [3,4].
●Phase 0: Inhibition – Throughout most of pregnancy, the myometrium is in a state of functional quiescence as a result of the action of various putative inhibitors including, but not limited to, the following:
•Prostacyclin (prostaglandin I2)
•Relaxin
•Parathyroid hormone-related peptide
•Nitric oxide
•Calcitonin gene-related peptide
•Adrenomedullin
•Vasoactive intestinal peptide
●Phase 1: Myometrial activation (priming) – As term approaches, there is a functional withdrawal of progesterone action at the level of the uterus, and an increase in the levels of uterotropins, such as estrogen, leads to myometrial activation by increasing expression of a series of contraction-associated proteins (CAPs; including myometrial receptors for prostaglandins and oxytocin), activating specific ion channels, and increasing connexin-43 (a key component of gap junctions). This results in an increase in gap junction formation between adjacent myometrial cells, which leads to electrical synchrony within the myometrium and allows for more effective coordination of contractions.
●Phase 2: Stimulation – Following myometrial activation, endogenous and exogenous uterotonic agonists, such as the stimulatory prostaglandins E2 and F2 alpha and oxytocin, stimulate the primed uterus to contract, leading to delivery.
●Phase 3: Involution – The uterus involutes following delivery. This process is mediated primarily by oxytocin.
PARTURITION CASCADE — It is likely that a "parturition cascade" exists at term which removes the mechanisms maintaining uterine quiescence and recruits factors promoting uterine activity [5-7]. Given its teleological importance, such a cascade would likely have multiple redundant loops to ensure a fail-safe system of securing pregnancy success (and thus preserving the species). In such a model, each element is connected to the next in a sequential fashion, and many of the elements demonstrate positive feed-forward characteristics typical of a cascade mechanism.
The sequential recruitment of signals that serve to augment the labor process suggest that it may not be possible to single out any one signaling mechanism as being responsible for the initiation of labor. Therefore, it is prudent to describe such mechanisms as being responsible for "promoting," rather than "initiating," the process of labor [8].
FETAL ROLE IN LABOR ONSET — Considerable evidence suggests that, in most viviparous animals (animals in whom offspring develop inside the body of the parent and are born alive), the fetus controls the timing of onset of labor [9-11]. During the Hippocratic period, the fetus was thought to be positioned head down at term so it could kick its legs up against the fundus, thereby propelling itself through the birth canal. Although we have moved away from this simple and mechanical view of labor, the factors responsible for the initiation and maintenance of labor at term are still not well defined. Initial investigations focused on endocrine events, such as changes in the profile of hormone levels in the maternal and fetal circulations, but this provides little information about the endocrine milieu at the maternal-fetal interface, which is where parturition is promoted. Subsequent studies have concentrated on the dynamic biochemical dialogue between the fetus and mother (paracrine/autocrine events) in an attempt to understand the molecular mechanisms that regulate such interactions at the level of the uterus. The genetic regulation of the molecular events that occur during parturition is also being investigated [12].
The hypothesis that the fetus is in control of the timing of labor has been elegantly demonstrated in domestic ruminants [13-17]. As an example, parturition in sheep is initiated by a sharp rise in fetal adrenal cortisol secretion related to increased fetal concentrations of and responsiveness to corticotropin [15]. Cortisol acts on placental enzymes active in the biosynthesis of estrogens from progesterone and thereby augments secretion of estrogen and decreases progesterone production. The resulting increase in the ratio of estrogen to progesterone stimulates placental release of prostaglandin F2 alpha, which enhances the myometrial response to oxytocin and stimulates contractions. However, the human placenta lacks the glucocorticoid-inducible 17-alpha-hydroxylase/17,20-lyase enzyme that is essential to this process [11,18,19]. Therefore, activation of the hypothalamic-pituitary-adrenal axis in humans likely results in a different mechanism for initiation of labor. (See 'Estrogen' below.)
A role for the fetal genotype in the initiation of labor was suggested by horse-donkey crossbreeding experiments that resulted in a gestational length intermediate between that of horses (340 days) and that of donkeys (365 days) [11,18]. This concept holds true whether pregnancy is maintained by the fetoplacental unit (as in the sheep and human) or by extrauterine tissues (as in the mouse and goat) [14].
The slow progress in our understanding of the biochemical mechanisms involved in the process of labor in humans reflects, in large part, the difficulty in extrapolating from the endocrine-control mechanisms in various animals to the paracrine/autocrine mechanisms of human parturition, processes that preclude direct investigation.
PHYSIOLOGY
Changes in maternal hormonal activity related to parturition at term — Comprehensive analyses of each of the individual paracrine/autocrine pathways involved in the process of labor have been reviewed in detail elsewhere [3-8,14,18]. A few of the hormones implicated in this process are discussed below.
Prostaglandins — Prostaglandins are predominantly paracrine/autocrine hormones (ie, they act locally at their site of production on contiguous cells). An increase in uterine prostaglandin biosynthesis is a consistent element in the transition into labor [20], and is probably common to all viviparous species [21]. It seems likely that hormonal factors controlling the final pathway for the onset of labor in humans, both at term and preterm, is an increased synthesis of prostaglandins of the E and F series within the uterine compartment, predominantly from the decidua and fetal membranes. The evidence can be summarized as follows:
●Human uterine tissues are selectively enriched with arachidonic acid, the obligate precursor of prostaglandin biosynthesis.
●Concentrations of prostaglandins in amniotic fluid and in maternal plasma and urine are increased during parturition [20,22,23]. Moreover, prostaglandin levels appear to rise prior to the onset of myometrial contractions suggesting that they are a cause, rather than a consequence, of labor [24].
●The intraamniotic, intravenous, or vaginal administration of exogenous prostaglandins can initiate labor at any stage of gestation and in all species [25].
●Prostaglandins have been implicated in the three events most temporally related to the onset of labor [2,26]: the onset of synchronous uterine contractions, cervical ripening, and the increase in myometrial sensitivity to oxytocin related to an increase in myometrial gap junction formation and/or oxytocin receptor concentrations.
●Inhibitors of prostaglandin synthesis (including cyclooxygenase inhibitors such as indomethacin) are capable of suppressing myometrial contractility both in vitro and in vivo, and of prolonging the length of gestation [2,27,28].
Taken together, these data affirm the critical role of prostaglandins in the process of labor. It appears that withdrawal of fetal-paracrine support of the quiescent uterus leads to decidual activation, followed by PGF2 alpha release and subsequent spontaneous labor [23]. Prostaglandin E2 (PGE2) appears to play a more important role in cervical ripening (a remodeling process in which collagen is degraded leading to softening of the cervix) and rupture of the fetal membranes than in uterine contractility [20].
Progesterone — Administration of a progesterone receptor antagonist [29,30] or removal of the corpus luteum [31] readily induces abortion in early pregnancy (before seven postmenstrual weeks of gestation), suggesting that progesterone is necessary for early pregnancy maintenance. Administration of exogenous progesterone after early lutectomy prevents abortion, further supporting the hypothesis that ovarian progesterone production is essential in maintenance of early pregnancy. Placental progesterone production increases between five and seven postmenstrual weeks, and the placenta is the dominant source of progesterone thereafter.
However, the role of progesterone in late pregnancy is not as well defined [32]. Progesterone withdrawal does not occur in all women before labor, and mean circulating progesterone levels during labor are similar to those measured one week prior [33]. Moreover, the administration of progesterone late in pregnancy does not delay the onset of labor in primates [34], and progesterone receptor antagonists are not an effective way of inducing labor at term (although they may promote cervical ripening) [35,36]. Finally, pregnancies complicated by maternal hypobetalipoproteinemia (LDL deficiency with very low levels of progesterone) culminate in spontaneous labor at term without incident [37].
These data suggest that systemic progesterone withdrawal is not a prerequisite for labor in humans. This is in contrast to most mammalian species in which systemic progesterone withdrawal is an essential component of parturition [38]. However, circulating hormone concentrations do not necessarily reflect activity at the tissue level. The onset of labor in women does appear to be preceded by a physiologic withdrawal of progesterone activity ("functional progesterone withdrawal") at the level of the uterus [38].
On the other hand, there is some evidence that supplemental progesterone administration reduces the rate of preterm birth in women at high risk for spontaneous preterm birth, although these data remain controversial. Further investigation is needed to confirm the effectiveness of progesterone supplementation and to understand its mechanism of action.
Estrogen — The placenta is the primary source of estrogen biosynthesis during pregnancy. Estrogens do not themselves cause myometrial contractions, and maternal administration of estradiol to rhesus macaques from 130 days of gestation has no effect on length of pregnancy [39]. Instead, estrogens act by upregulating myometrial gap junctions [40] and uterotonic receptors (including L-type calcium channels and oxytocin receptors) [41], thereby enhancing the capacity of the myometrium to generate contractions.
Longitudinal measurements of circulating estrogen concentrations prior to the onset of labor show an increase in all primate species [42]. Because the human placenta is an incomplete steroidogenic organ, placental estrogen synthesis has an obligate need for C19 steroid precursors (it cannot synthesize estrogen from progesterone) [5,6]. The fetal adrenal provides an abundant C19 estrogen precursor (dehydroepiandrosterone) directly from its intermediate (fetal) zone. In the rhesus monkey, continuous infusion of C19 precursor (androstenedione) leads to preterm delivery [43-45]. This effect is blocked by concurrent infusion of an aromatase inhibitor [45], demonstrating that localized conversion of progesterone to estrogen is important in promoting contractions in this species. A similar effect has been shown using a continuous intraamniotic infusion of estrogen [39]. However, systemic infusion of estrogen failed to induce delivery [39], suggesting that the action of estrogen is likely paracrine/autocrine.
Oxytocin — Oxytocin is a peptide hormone synthesized in the hypothalamus and released from the posterior pituitary in a pulsatile fashion. It is also produced by the placenta. Its biologic half-life in the maternal circulation is approximately three to four minutes, but appears to be shorter when higher doses are infused. Oxytocin is inactivated in the liver and kidney, although during pregnancy it is primarily degraded by placental oxytocinase.
It is unlikely that oxytocin provides the trigger for the initiation of labor, but the release of oxytocin during labor results in more forceful uterine contractions and undoubtedly facilitates delivery of the fetus and placenta. The existence of the so-called Ferguson reflex (release of maternal oxytocin from the posterior pituitary in response to distention of the cervix and/or vagina) remains controversial. Originally described in feline species, it almost certainly does not exist in humans [46].
The evidence in support of a role for oxytocin in parturition can be summarized briefly as follows:
●Oxytocin is the most potent endogenous uterotonic agent, and is capable of stimulating uterine contractions at intravenous infusion rates of 1 to 2 mU/min at term [47,48].
●The frequency and amplitude of oxytocin-induced uterine contractions are identical to those occurring during spontaneous labor.
●More than 100 mU/min oxytocin is needed to elicit uterine contractions in nonpregnant women, while 16 mU/ min is sufficient to elicit contractions at 20 weeks of gestation, 2 to 3 mU/min at 32 weeks, and 1 mU/min at term [47].
●Uterine contractions can be induced by electrical stimulation of the posterior pituitary gland or by nipple stimulation, presumably by increasing oxytocin concentrations in the blood.
●Oxytocin analogues that act as competitive antagonists of endogenous oxytocin are capable of inhibiting uterine contractions [49].
Circulating levels of oxytocin do not change significantly during pregnancy or prior to the onset of labor [47,48]. However, myometrial oxytocin receptor concentrations increase approximately 100- to 200-fold during pregnancy, reaching a maximum during early labor [47,48,50,51]. This rise in receptor concentration accounts for the increased sensitivity of the myometrium to circulating levels of oxytocin during the second half of pregnancy.
In addition to the myometrium, high-affinity oxytocin receptors have also been isolated in the amnion, chorion, and decidua [41,47]. Neither amnion nor decidual cells are contractile, and the action of oxytocin on these tissues is uncertain. Oxytocin may play a dual role in the mechanism of parturition [47,50]: It acts directly through oxytocin receptor-mediated and nonreceptor, voltage-mediated calcium channels to affect intracellular biochemical pathways and promote uterine contractions, and it acts indirectly through stimulation of amniotic and decidual prostaglandin production. Indeed, induction of labor at term is successful only when the oxytocin infusion is associated with an increase in PGF2 alpha production, in spite of apparently adequate uterine contractions [41].
Studies examining fetal pituitary oxytocin production, the umbilical arteriovenous difference in plasma oxytocin concentration, amniotic fluid oxytocin levels, and fetal urinary oxytocin output demonstrate conclusively that the fetus secretes oxytocin into the maternal circulation [47,52]. Furthermore, the calculated oxytocin secretion rates from the fetus suggest an increase from a baseline of 1 mU/min prior to labor to approximately 3 mU/min after spontaneous labor [52]. The latter is similar to the dose of oxytocin normally administered to women to induce labor at term (2 to 8 mU/min). Although maternal serum oxytocin levels are not increased prior to the onset of labor or during the first stage of labor, oxytocin derived from the fetus and possibly from decidua and other uterine sources could act on myometrial oxytocin receptors in a paracrine/autocrine fashion to initiate and maintain effective uterine contractions. (See "Induction of labor with oxytocin".)
Other hormones and peptides — Various neuropeptides and hormones can affect myometrial contractility. The concentration of some of these agents changes in maternal serum during pregnancy suggesting that they might act in an endocrine fashion, while others are produced locally within myometrial smooth muscle cells and act in an autocrine/paracrine manner. However, their role in the initiation and maintenance of labor at term remains controversial. Some of these factors are illustrated below:
●Parathyroid hormone-related peptide – Parathyroid hormone-related peptide is a potent smooth muscle relaxant capable of inhibiting oxytocin-induced contractions in baboons [53]. It is unclear whether it has a physiologically important role in maintaining uterine quiescence prior to the onset of labor.
●Luteinizing hormone/human chorionic gonadotropin – Luteinizing hormone/human chorionic gonadotropin may be important for maintaining uterine quiescence, especially in the first half of pregnancy. Human chorionic gonadotropin decreases gap junction formation in strips of myometrium in vitro, leading to a decrease in contraction frequency and intensity [54]. This effect is likely mediated through the adenyl cyclase signal transduction system resulting in an increase in intracellular cAMP, which favors uterine relaxation.
●Relaxin – Relaxin is a member of the insulin-like growth factor family of proteins. Plasma levels are highest at 8 to 12 weeks of gestation and thereafter decline to low levels, which persist until term [55]. The primary source of relaxin is thought to be the corpus luteum.
Relaxin appears to act indirectly to promote myometrial relaxation by stimulating myometrial prostacyclin production. This effect can be negated by inhibitors of prostaglandin synthesis. Relaxin also has been implicated in cervical ripening and/or rupture of the fetal membranes, but this remains controversial [56].
●Cytokines – Cytokines have long been implicated in the pathophysiology of preterm labor associated with intraamniotic infection [57]. These agents may also be a component of the process of normal term labor [58-61]. Macrophages exert anti-inflammatory functions to promote uterine quiescence until term and then acquire a pro-inflammatory phenotype to promote labor [62]. Proinflammatory mediator levels (interleukin [IL] 1, IL-6, TNF-alpha) appear to increase in the maternal peripheral circulation before the onset of spontaneous term labor [63]. The fetus may produce physical and hormonal signals that stimulate macrophage migration to the uterus, with release of cytokines and activation of inflammatory transcription factors.
Concentrations of IL-8 (but not IL-2 or tumor necrosis factor alpha) in human myometrium, decidua, and fetal membranes are increased during labor [58]. IL-8 is a potent chemotactic cytokine acting primarily on neutrophils. It may cause an increase in collagenase enzyme activity leading to cervical ripening and/or spontaneous rupture of membranes. Moreover, cytokines and eicosanoids appear to interact and to accelerate each other's production in a cascade-like fashion, resulting in further increases in prostaglandin production [64]. It has also been proposed that the increased inflammatory response promotes uterine contractility via direct activation of contractile genes (eg, COX-2, oxytocin receptor, connexin) and/or impairment of the capacity of progesterone to mediate uterine quiescence [65].
Role of membrane rupture — The strength and integrity of fetal membranes derive from extracellular membrane proteins including collagens, fibronectin, and laminins. Matrix metalloproteases (MMPs) are a family of enzymes with varied substrate specificities that decrease membrane strength by increasing collagen degradation [66]. Tissue inhibitors of MMPs (TIMPs) bind to MMPs and shut down proteolysis, thereby helping to maintain membrane integrity [66,67].
The fetal membranes normally remain intact until term due to low MMP activity and high levels of TIMPs [67-71]. Periparturitional activation of MMPs at term may trigger a cascade of events that reduce fetal membrane integrity and promote rupture [72]. Stretch and shear forces from uterine contractions during labor probably contribute to membrane rupture as well.
Although the precise etiology of periparturitional MMP activation is not known, several factors may play a role in this process:
●Compounds such as tumor necrosis factor-alpha, IL-1, prostaglandins E2 and F2 alpha appear to increase collagenase activity and activate inflammatory pathways in fetal membranes at parturition [73-76]. (See "Spontaneous preterm birth: Pathogenesis".)
●Relaxin may induce MMP-9 and MMP-3 activity in fetal membranes by antagonizing the suppressive actions of progesterone and estradiol [77].
●Distension of the fetal membranes may initiate cellular events leading to periparturitional destabilization. Mechanical stretching of fetal membranes activates MMP-1 and MMP-3 and induces IL-8 expression in amnion and chorion cells [78,79].
●The neuro- and placental peptides corticotropin-releasing hormone (CRH) and urocortin (a member of the CRH family of peptides) may induce local MMP-9 activity in fetal membranes [80].
Genetic or epigenetic factors that predispose women to membrane rupture and preterm delivery may be superimposed on these biochemical pathways.
Activation of the fetal hypothalamic-pituitary-adrenal axis — The final common pathway for initiation of labor appears to be activation of the fetal hypothalamic-pituitary-adrenal axis, which is probably a common pathway for all viviparous species.
Activation of the fetal hypothalamic-pituitary-adrenal axis during the latter part of pregnancy results in release of large amounts of fetal cortisol [81,82]. Glucocorticoids (including cortisol) are potent stimulants of placental CRH production, in contrast to their negative effect on hypothalamic CRH production [83]. Inflammatory cytokines, catecholamines, acetylcholine, and oxytocin also increase placental CRH secretion [4], while progesterone and nitric oxide (NO) decrease placental CRH release. Circulating maternal plasma CRH levels increase progressively throughout the latter half of pregnancy, with a dramatic increase in the final six to eight weeks before delivery [81,82].
During pregnancy, CRH bioactivity (as measured by its ability to promote adrenocorticotropic hormone (ACTH) release from the pituitary and to stimulate decidual PGE2 production) is decreased due to an increase in high-affinity CRH-binding protein (CRH-BP). However, in the last three to five weeks of gestation, CRH-BP concentrations fall, resulting in a rapid rise in circulating free CRH [84,85].
Women with an early rapid rise in plasma CRH tend to deliver earlier and those with a slow rise tend to deliver later, suggesting that production of CRH is an important factor in the timing of delivery. This hypothesis has been termed the "placental clock" [86].
CRH has no direct inotropic action on human myometrium, but the increase in placental CRH at term is thought to have multiple actions on the uterus [87]:
●It is secreted back into the fetal compartment where it can act to drive pituitary ACTH release, thereby providing a positive feed-forward loop for labor.
●It may act locally within the placenta to promote fetoplacental vasodilation [88].
●It can directly and preferentially stimulate dehydroepiandrosterone sulfate (DHEA-S) secretion in fetal adrenal cortical cells via a protein kinase system [89,90].
●It exerts effects on the uterus and cervix by upregulation of the NO pathway and by augmenting estrogen effects on these tissues [91].
●It enhances prostaglandin production in the amnion, chorion, and decidua.
●It primes the myometrium and potentiates the effects of oxytocin [92].
Glucocorticoids have several actions that can also help prepare the uterus for labor.
●Glucocorticoids act directly to upregulate prostaglandin production in fetal membranes at term [4,93].
●Cortisol appears to stimulate expression of placental (but not hypothalamic) CRH in vitro [83]. Studies demonstrating an increase in circulating CRH concentrations (as well as a decrease in ACTH and cortisol levels) in women receiving antepartum glucocorticoids to promote fetal lung maturation suggest that this mechanism may also be operative in vivo [94,95]. In addition, measurement of elevated maternal plasma CRH levels between 28 and 30 weeks of gestation may predict women at increased risk of preterm delivery [96].
●In addition, cortisol enhances amnionic cyclooxygenase to enhance prostaglandin synthesis and inhibits chorionic prostaglandin dehydrogenase activity, thereby preventing prostaglandin metabolism [4,87].
Taken together, these data suggest the gradual increase in fetal pituitary-adrenal activity over the last few weeks of gestation may have a role in the initiation of labor at term. (See "Spontaneous preterm birth: Pathogenesis".)
Increased myometrial contractility — Regardless of whether the trigger originates within or outside the fetus, the final common pathway for labor ends in the maternal tissues of the uterus and is characterized by the development of regular phasic uterine contractions. As in other smooth muscles, myometrial contractions are mediated through ATP-dependent binding of myosin to actin. This interaction depends on the phosphorylation of myosin light chain by a calcium/calmodulin-dependent enzyme, myosin light chain kinase. The availability of free intracellular calcium is thus a key modulator of myometrial contractility.
GTP-binding proteins (G-proteins) play a pivotal role in myometrial contractility by coupling cell membrane receptors to effector enzymes and ion channels. As an example, activation of beta-adrenergic and/or PGE2 receptors promote myometrial relaxation via the G-alpha-s/adenyl cyclase/cAMP signal transduction pathway [1,97]. Oxytocin receptors, on the other hand, couple to G-alpha-q/G-alpha-i/phospholipase C pathways leading to an increase in inositol-1,4,5-trisphosphate (which releases calcium from the sarcoplasmic reticulum) and 1,2-diacylglycerol (which activates protein kinase C) [98]. The end result is an increase in intracellular calcium and myometrial contractions [98,99].
Pregnancy affects not only cell surface receptor concentrations, but also the concentrations and coupling of the various G-proteins. G-alpha-q and G-alpha-i are expressed at similar levels in nonpregnant and pregnant myometrium, both before and after the onset of labor. By comparison, G-alpha-s levels are higher in pregnant as compared with nonpregnant myometrium [100], and levels have been shown to decrease before labor, both at term and preterm [101]. It has been suggested, therefore, that labor results from a downregulation of pathways that favor uterine quiescence leading to a relative dominance of stimulatory pathways that increase intracellular calcium bioavailability and promote myometrial contractility [1]. Other myometrial factors (eg, mechanotransduction via stretching or shortening), which could affect initiation, frequency, or strength of contractions, are under investigation [102,103].
In contrast to vascular smooth muscle, myometrial cells have sparse innervation, which is further reduced during pregnancy [104]. The regulation of the contractile mechanism of the uterus is, therefore, largely humoral and/or dependent on intrinsic factors within myometrial cells. A number of hormones have been implicated in this regard.
SUMMARY AND RECOMMENDATIONS
●Overview – Human labor at term is a multifactorial physiologic event involving an integrated set of changes within the maternal tissues of the uterus (myometrium, decidua, and uterine cervix) that occur gradually over a period of days to weeks prior to labor onset. (See 'Introduction' above.)
Such changes include, but are not limited to, an increase in prostaglandin synthesis and release within the uterus, an increase in myometrial gap junction formation, and upregulation of myometrial oxytocin receptors (uterine activation). (See 'The four phases of uterine activity' above.)
●Fetoplacental factors
•Myometrial activity – Once the myometrium and cervix are prepared, endocrine and/or paracrine/autocrine factors from the fetoplacental unit bring about a switch in the pattern of myometrial activity from irregular contractures to regular contractions (uterine stimulation). (See 'Changes in maternal hormonal activity related to parturition at term' above.)
The fetus appears to control the initiation of labor at term by coordinating the switch in myometrial activity via placental steroid hormone production, mechanical distension of the uterus, and by secretion of neurohypophyseal hormones and other stimulators of prostaglandin synthesis. (See 'Fetal role in labor onset' above.)
•Membranes – The strength and integrity of fetal membranes derive from extracellular membrane proteins including collagens, fibronectin, and laminins. The fetal membranes normally remain intact until term due to low matrix metalloprotease (MMP) activity and high levels of tissue inhibitors of MMPs. Periparturitional activation of MMPs at term may trigger a cascade of events that reduce fetal membrane integrity and promote rupture. Stretch and shear forces also play a role. (See 'Role of membrane rupture' above.)
