Physiology of parturition UpToDate (http://www.uptodate.com/online/content/topic.do?

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Author Errol R Norwitz, MD, PhD

Section Editor Charles J Lockwood, MD

Deputy Editor Vanessa A Barss, MD

Last literature review version 17.1: January 2009 | This topic last updated: November 19, 2008 (More) INTRODUCTION Labor is a physiological event involving a sequential, integrated set of changes within the myometrium, decidua, and uterine cervix that occur gradually over a period of days to weeks. Biochemical connective tissue changes in the uterine cervix appear to precede uterine contractions and cervical dilation, and all of these events usually occur before rupture of the fetal membranes. Labor is characterized by an increase in myometrial activity or, more precisely, a change in the myometrial contractility pattern from "contractures" (long-lasting, low frequency activity) to "contractions" (high intensity, high frequency activity) [1], resulting in effacement and dilatation of the uterine cervix. Labor is a clinical diagnosis, classically defined by the triad of regular painful uterine contractions, progressive cervical effacement and dilatation, and show (bloody discharge). Cervical dilatation in the absence of uterine contractions is seen most commonly in the second trimester and is suggestive of cervical insufficiency. (See "Cervical insufficiency"). Similarly, the presence of uterine contractions in the absence of cervical change does not meet criteria for the diagnosis of labor. Such contractions are often attributed to "false labor" or uterine irritability. Labor and delivery are not passive processes by which uterine contractions push a rigid object through a fixed aperture. The ability of the fetus to successfully negotiate the pelvis during labor and delivery depends upon a complex interaction of three variables: power (uterine contractions), passenger (fetus), and passage (both bony pelvis and pelvic soft tissues). Although conventional wisdom dictates that powerful contractions are more likely to be associated with a successful outcome, there are no data to support this conclusion. Furthermore, precipitous labor probably results from low resistance of the pelvic soft tissues (the cervix in the first stage of labor and the muscles of the pelvic floor in the second stage) rather than from high myometrial activity [2]. LABOR AT TERM The mean duration of human singleton pregnancy is 280 days (40 weeks) from the first day of the last menstrual period. A term pregnancy is defined as the period from 259 to 293 days after the first day of the last menstrual period (37 to 41 and 6/7th weeks).

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 [3,4]. Nevertheless, both inhibitory and stimulatory mechanisms likely play a role in uterine activity. PHYSIOLOGICAL PHASES OF MYOMETRIAL ACTIVITY The regulation of uterine activity during pregnancy can be divided into four distinct physiologic phases [5,6]: Phase 0: inhibitors active During pregnancy the uterus is maintained in a state of functional quiescence through the action of various putative inhibitors including, but not limited to: - Progesterone - Prostacyclin (prostaglandin I-2) - Relaxin - Parathyroid hormone-related peptide - Nitric oxide - Calcitonin gene-related peptide - Adrenomedullin - Vasoactive intestinal peptide. Phase 1: myometrial activation As term approaches the uterus becomes activated in response to uterotropins, such as estrogen. This phase is characterized by increased expression of a series of contraction-associated proteins (CAPs) (including myometrial receptors for prostaglandins and oxytocin), activation of specific ion channels, and an increase in connexin-43 (a key component of gap junctions). An increase in gap junction formation between adjacent myometrial cells leads to electrical synchrony within the myometrium and allows for effective coordination of contractions. Phase 2: stimulatory phase Following activation, the "primed" uterus can be stimulated to contract by the action of uterotonic agonists, such as the stimulatory prostaglandins E2 and F2 alpha and oxytocin. Phase 3: involution Involution of the uterus after delivery occurs during phase 3 and 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 [2,7,8]. 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 [9]. THE ROLE OF THE FETUS Considerable evidence suggests that in most viviparous animals the fetus controls the timing of onset of labor [10-12]. 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 of the uterus, thereby propelling itself through the birth canal. While 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 not well defined. Initial investigations focused on endocrine events, such as changes in the profile of circulating hormone levels in the maternal and fetal circulations. 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. The genetic regulation of the molecular events that occur during parturition are also being investigated [13]. The hypothesis that the fetus is in control of the timing of labor was elegantly demonstrated in domestic ruminants [14-18]. 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 [16]. Cortisol acts on placental enzymes active in the biosynthesis of estrogens from progesterone to augment secretion of estrogen and decrease 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/17,20lyase enzyme that is essential to this process [12,19,20]. 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) [12,19]. 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) [15]. 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 endocrinecontrol mechanisms in various animals to the paracrine/autocrine mechanisms of human parturition, processes that preclude direct investigation. MYOMETRIAL ACTIVATION 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 is dependent upon 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 (show figure 1). 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 Gas/adenyl cyclase/cAMP signal transduction pathway [3,21]. Oxytocin receptors, on the other hand, couple to Gaq/Gai/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) [22]. The end result is an increase in intracellular calcium and myometrial contractions [22,23]. Pregnancy affects not only cell surface receptor concentrations, but also the concentrations and coupling of the various G-proteins. Gaq and Gai are expressed at similar levels in nonpregnant and pregnant myometrium, both before and after the onset of labor. By comparison, Gas levels are higher in pregnant as compared with nonpregnant myometrium [24], and levels have been shown to decrease before labor, both at term and preterm [25]. It has been suggested, therefore, that labor results from a down-regulation of pathways that favor uterine quiescence leading to a relative dominance of stimulatory pathways that increase intracellular calcium bioavailability and promote myometrial contractility [3]. Other myometrial factors (eg, mechanotransduction via stretching or shortening) which could affect initiation, frequency, or strength of contractions are under investigation [26,27]. In contrast to vascular smooth muscle, myometrial cells have sparse innervation, which is further reduced during pregnancy [28]. The regulation of the contractile mechanism of the uterus is therefore largely humoral and/or dependent upon intrinsic factors within myometrial cells. A number of hormones have been implicated in this regard. Some of these are discussed below. HORMONES INVOLVED IN THE PARTURITIONAL CASCADE Comprehensive analyses of each of the individual paracrine/autocrine pathways involved in the process of labor have been reviewed in detailed elsewhere (show figure 2) [2,5-9,15,19]. 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 [29], and is probably common to all species [30]. It seems likely that hormonal factors controlling the final pathway for the onset of labor in women, 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 [29,31,32]. Moreover, prostaglandin levels appear to rise prior to the onset of myometrial concentrations suggesting that they are a cause, rather than a consequence, of labor [33]. The intraamniotic, intravenous, or vaginal administration of exogenous prostaglandins can initiate labor at any stage of gestation and in all species [34]. Prostaglandins have been implicated in the three events most temporally related to the onset of labor [4,35]: the onset of synchronous uterine contractions, cervical ripening, and the increase in myometrial sensitivity to oxytocin due 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 [4,36,37].

Taken together, these data affirm the critical role of prostaglandins, especially PGF2 alpha, in the initiation 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 [32]. 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 [29]. Progesterone Administration of a progesterone receptor antagonist [38,39] or removal of the corpus luteum [40] readily induces abortion in early pregnancy (before 7 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 becomes important between 7 and 9 weeks, and the placenta is the dominant source of progesterone thereafter. However, the role of progesterone in late pregnancy is not as well defined. 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 [41]. Moreover, the administration of progesterone late in pregnancy does not delay the onset of labor in primates [42], and progesterone receptor antagonists are not capable of inducing labor at term (although they may promote cervical ripening) [43,44]. Finally, pregnancies complicated by maternal hypobetalipoproteinemia (LDL deficiency with very low levels of progesterone) culminate in spontaneous labor at term without incident [45]. These data suggest that progesterone withdrawal is not a prerequisite for labor in humans. This is in contrast to most mammalian species in which progesterone withdrawal is an essential component of parturition [46]. However, circulating hormone concentrations do not necessarily reflect activity at the tissue level. The onset of labor in women may be preceded by a physiologic

withdrawal of progesterone activity ("functional progesterone withdrawal") at the level of the uterus [46]. On the other hand, there is increasing evidence that supplemental progesterone administration may reduce the rate of preterm birth in high risk women. A meta-analysis of placebo-controlled trials involving prophylactic administration of 17 alpha-hydroxyprogesterone caproate suggested that it reduced the frequency of preterm birth by 15 to 70 percent, but did not achieve a significant reduction in perinatal mortality and morbidity [47]. Similar findings were reported in two recent studies, one using weekly injections of 17 alpha-hydroxyprogesterone caproate [48] and the other using daily 100 mg progesterone vaginal suppositories as prophylaxis against development of preterm labor [49]. Further investigations are needed to confirm the effectiveness of progesterone supplementation and to understand its mechanism of action. It has not been studied as a tocolytic for active preterm labor. (See "Prevention of spontaneous preterm birth" section on Supplemental progesterone). 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 [50]. Instead, estrogens act by upregulating myometrial gap junctions [51] and uterotonic receptors (including L-type calcium channels and oxytocin receptors) [52], 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 [53]. Because the primate placenta is an incomplete steroidogenic organ, placental estrogen synthesis has an obligate need for C-19 steroid precursors (it cannot synthesize estrogen from progesterone) [2,7]. The fetal adrenal provides an abundant C19 estrogen precursor (dehydroepiandrostenedione) directly from its intermediate (fetal) zone. In the rhesus monkey, continuous infusion of C19 precursor (androstenedione) leads to preterm delivery [54-56]. This effect is blocked by concurrent infusion of an aromatase inhibitor [56], demonstrating that conversion to estrogen is important in promoting contractions. A similar effect has been shown using a continuous intraamniotic infusion of estrogen [50]. However, systemic infusion of estrogen failed to induce delivery [50], 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. Its biologic half-life is approximately three to four minutes, but appears shorter when higher doses are infused. Oxytocin is inactivated in the liver and kidney, although during pregnancy it is primarily degraded by placental oxytocinase. 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 [57,58]. 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 [57]. 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 effectively inhibit labor [59].

Circulating levels of oxytocin do not change significantly during pregnancy or prior to the onset of labor [57,58]. However, myometrial oxytocin receptor concentrations increase approximately 100 to 200-fold during pregnancy, reaching a maximum during early labor [57,58,60,61]. This rise in receptor concentration accounts for the increased sensitivity of the myometrium to circulating levels of oxytocin during the second half of pregnancy. Specific high-affinity oxytocin receptors have also been isolated apart from the myometrium in the human amnion and decidua parietalis, but not decidua vera [52,57]. 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 [57,60]: it may act directly through oxytocin receptor-mediated and nonreceptor, voltage-mediated calcium channels to affect intracellular biochemical pathways and promote uterine contractions or it may act indirectly through stimulation of amniotic and decidual prostaglandin production. 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 [52]. 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 [57,62]. 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 [62]. 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 local decidual 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"). 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 [63].

Hypothalamic-pituitary-adrenal factors 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 species. Corticotropin releasing hormone Activation of the fetal hypothalamic-pituitary-adrenal axis during the latter part of pregnancy results in release of large amounts of fetal cortisol [64,65]. Glucocorticoids (including cortisol) are potent stimulants of placental corticotropin releasing hormone (CRH) production, in contrast to their negative effect on hypothalamic CRH production (show figure 3) [66]. Inflammatory cytokines, catecholamines, acetylcholine, and oxytocin also increase placental CRH secretion [6], 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 [64,65]. During pregnancy, CRH bioactivity (as measured by its ability to promote ACTH release from the pituitary and to stimulate decidual PGE2 production) is decreased due to an increase in highaffinity 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 [67,68]. 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" [69]. 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 [70]:

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 vasodilatation [71] It can directly and preferentially stimulate DHEA-S secretion in fetal adrenal cortical cells via a protein kinase system [72,73] It exerts effects on the uterus and cervix by upregulation of the nitric oxide pathway and by augmenting estrogen effects on these tissues [74] It enhances prostaglandin production in the amnion, chorion and decidua It primes the myometrium and potentiates the effects of oxytocin [75]

Glucocorticoids These hormones have several actions that can also help prepare the uterus for labor.

Glucocorticoids act directly to upregulate prostaglandin production in fetal membranes at term [6,76].

Cortisol appears to stimulate expression of placental (but not hypothalamic) CRH in vitro [66]. 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 [77,78]. 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 [79]. In addition, cortisol enhances amnionic cyclooxygenase to enhance prostaglandin synthesis and inhibits chorionic prostaglandin dehydrogenase activity, thereby preventing prostaglandin metabolism [6,70].

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 "Pathogenesis of preterm birth"). Other 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 [80]. 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 [81]. 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 [82]. 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 [83]. Cytokines Cytokines have long been implicated in the pathophysiology of preterm labor associated with intraamniotic infection [84]. These agents may also be a component of the process of normal term labor [85-87]. As an example, concentrations of interleukin (IL) -8 (but

not IL-2 or tumor necrosis factor alpha) in human myometrium, decidua, and fetal membranes are increased during labor [85]. 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 [88]. There is no good evidence that sexual activity at term hastens the onset of labor [89]. SUMMARY AND RECOMMENDATIONS

Human labor at term is a multifactorial physiological event involving an integrated set of changes within the maternal tissues of the uterus (myometrium, decidua, and uterine cervix) which occur gradually over a period of days to weeks. 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). 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). The fetus appears to control the initiation of labor 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. Labor is a clinical diagnosis based upon regular painful uterine contractions, progressive cervical effacement and dilatation, and a show (bloody discharge). The ability of the fetus to successfully negotiate the pelvis during labor and delivery is dependent on the complex interaction of three variables: the powers, the passenger, and the passage.

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