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Physiology of parturition at term

Physiology of parturition at term
Literature review current through: Jan 2024.
This topic last updated: Jan 26, 2024.

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 precede uterine contractions and cervical dilation, which in turn usually occur before rupture of the fetal membranes. After delivery, the uterus gradually largely reverts to its prepregnant state.

Term labor may be best regarded as a withdrawal of the inhibitory effects of pregnancy on the tissue of the uterus, rather than as an active process mediated by the release of uterine stimulants. As an example, strips of myometrium obtained from a quiescent, noncontractile uterus at term and placed in an isotonic water bath will contract vigorously and spontaneously without added stimuli [1,2]. However, both inhibitory and stimulatory mechanisms likely play a role. In contrast, many cases of preterm labor appear to be the consequence of activation of labor due to infection, inflammation, hemorrhage, or other pathologic disorders, which bypass or overwhelm the mechanisms maintaining uterine quiescence.

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 PARTURITION CASCADE — It is likely that a "parturition cascade" exists at term that removes the mechanisms maintaining uterine quiescence and recruits factors promoting uterine activity [3-5]. Given its teleological importance, such a cascade would likely have multiple redundant loops to ensure a fail-safe system of securing pregnancy success. 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 individual 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 [6].

THE FOUR PHASES OF UTERINE ACTIVITY — Uterine activity during pregnancy can be divided into four physiologic phases: inhibition, activation, stimulation, and involution [7,8].

Phase 0: Inhibition – The human uterus exits mostly in the nonpregnant state. The normal phenotype of the myometrium is contractile. It is responsible each month for actively expelling the endometrial lining (menstruation) and compressing the uterine radial (penetrating) arteries to minimize menstrual blood loss. During pregnancy, this contractile phenotype must be actively suppressed, and myometrium maintained in a state of functional quiescence [9,10]. This is achieved through the action of various putative inhibitors including, but not limited to, the following:

Progesterone

Prostacyclin (prostaglandin I2)

Relaxin

Parathyroid hormone-related peptide

Nitric oxide

Calcitonin gene-related peptide

Adrenomedullin

Vasoactive intestinal peptide

Phase 1: Myometrial activation (priming) – Although there is no systemic progesterone withdrawal prior to the onset of labor in humans, a functional withdrawal of progesterone activity at the level of the uterus does occur as term approaches. A withdrawal of the inhibitory actions of progesterone on myometrial cells in concert with an increase in circulating levels of uterotropins (eg, estrogen) results in increased expression of the 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, which results in an increase in gap junction formation between adjacent myometrial cells). The resulting improvement in electrical synchrony in the myometrium enables more effective coordination of contractions.

Phase 2: Stimulation – Following myometrial activation, endogenous and exogenous uterotonic agonists, such as oxytocin and the stimulatory prostaglandins E2 and F2 alpha, cause the primed uterus to contract, eventually leading to delivery.

Phase 3: Involution – The uterus involutes in the days and weeks following delivery. This process is mediated primarily by oxytocin.

MATERNAL AND FETOPLACENTAL FACTORS IN LABOR INITIATION

Overview — 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 labor [11-13]. However, the factors responsible for the promotion and maintenance of human labor at term are still not well defined. Initial investigations focused on endocrine events (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 actively investigated [9,14].

The hypothesis that the fetus is in control of the timing of labor has been elegantly demonstrated in domestic ruminants [15-19]. 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 [17]. In this species, fetal adrenal cortisol induces expression of 17-alpha-hydroxylase/17,20-lyase to convert progesterone to estrogens. The resulting increase in estrogens and decrease in progesterone stimulates placental release of PGF2 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 [13,20,21]. As such, activation of the fetal hypothalamic-pituitary-adrenal axis in humans likely results in a different mechanism for initiation of labor. (See 'Role of the fetal hypothalamic-pituitary-adrenal axis' below.)

A role for the fetoplacental genotype in the initiation of labor was first 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) [13,20]. This concept holds true whether pregnancy is maintained by the tissues of the uterus (as in the sheep and human) or by extrauterine tissues (as in the mouse and goat) [16].

The precise genetic factors that affect the duration of pregnancy are not well characterized. It appears that the genetic variants most strongly associated with gestational length are located in the maternal genome, and may act independently or in combination with fetoplacental genetic variants [22]. (See "Spontaneous preterm birth: Overview of risk factors and prognosis", section on 'Genetic variants'.)

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.

Role of maternal hormones, neuropeptides, and neuroproteins — Comprehensive analyses of each of the individual paracrine/autocrine pathways involved in the process of labor have been reviewed in detail elsewhere [3-8,16,20]. A few of the key hormones and neuropeptides 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). Although structurally almost identical, PGE2 and PGF2 alpha signal through distinct receptors and have different and often antagonistic activities. An increase in uterine prostaglandin biosynthesis is a consistent element in the onset of labor [23] common to all viviparous species [24]. The final common pathway for the onset of labor in humans, both at term and preterm, appears to be 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 [23,25,26]. 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 [27].

The intraamniotic, intravenous, or vaginal administration of exogenous prostaglandins can initiate labor at any stage of gestation and in all species [28].

Prostaglandins have been implicated in the three events most temporally related to the onset of labor [2,29]: the onset of synchronous uterine contractions, cervical ripening, and the increase in myometrial sensitivity to oxytocin related to an increase in gap junction formation and 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 [2,30,31].

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" (see 'Role of the fetal hypothalamic-pituitary-adrenal axis' below), followed by PGF2 alpha release and subsequent spontaneous labor [26]. 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 [23].

Progesterone — Administration of a progesterone receptor antagonist [32,33] or removal of the corpus luteum [34] before 7 postmenstrual weeks of gestation readily induces pregnancy loss, demonstrating that ovarian progesterone production is necessary for early pregnancy maintenance. After 5 to 7 postmenstrual weeks, the placenta becomes the dominant source of progesterone production and the corpus luteum regresses.

The role of progesterone in late pregnancy is less well defined [35]. In humans, systemic progesterone withdrawal does not occur before labor, and mean circulating progesterone levels during labor are similar to those measured one week prior [36]. Moreover, the administration of progesterone late in pregnancy does not delay the onset of labor [37], and progesterone receptor antagonists alone are not an effective way of inducing labor at term (although they may promote cervical ripening) [38,39].

These data suggest that systemic progesterone withdrawal is not a prerequisite for labor in humans. This contrasts with most mammalian species in which systemic progesterone withdrawal is an essential component of parturition [40]. However, circulating hormone concentrations do not necessarily reflect activity at the tissue level. The onset of labor in humans does appear to be preceded by a physiologic withdrawal of progesterone activity ("functional progesterone withdrawal") at the level of the uterus [40].

Estrogens — 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 [41]. Instead, estrogens act by upregulating myometrial gap junctions [42] and uterotonic receptors (including L-type calcium channels and oxytocin receptors) [43], 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 [44]. 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) [3,4]. 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 [45-47]. This effect is blocked by concurrent infusion of an aromatase inhibitor [47], 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 [41]. However, systemic infusion of estrogen failed to induce delivery [41], suggesting that the action of estrogen is likely paracrine/autocrine within the tissues of the uterus.

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 promotion of labor, although the release of oxytocin during labor (originating most likely from the placenta) and/or exogenous administration of oxytocin results in more forceful uterine contractions and undoubtedly facilitates delivery. 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 [48].

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 [49,50].

The frequency and amplitude of exogenous 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 females, 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 [49].

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 [51].

Circulating levels of oxytocin do not change significantly during pregnancy or prior to the onset of labor [49,50]. Levels only increase in the maternal circulation during the third stage of labor (ie, after delivery), highlighting the importance of oxytocin in preventing postpartum hemorrhage, facilitating uterine involution, and promoting breastmilk let down. However, myometrial oxytocin receptor concentrations increase approximately 100- to 200-fold during pregnancy, reaching a maximum during early labor [49,50,52,53]. This rise in myometrial oxytocin receptor concentration is what accounts for the increased sensitivity of the myometrium to stable 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 [43,49]. Neither amnion nor decidual cells are contractile, which raises questions about the action of oxytocin on these tissues. It is now clear that oxytocin has a dual role to play in the mechanism of parturition: 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 [49,52]. 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 [43].

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 fetoplacental unit secretes oxytocin into the maternal circulation [49,54]. Furthermore, the calculated oxytocin secretion rates from the fetoplacental unit suggest an increase from a baseline of 1 mU/min prior to labor to approximately 3 mU/min after spontaneous labor [54]. The latter is similar to the dose of oxytocin normally administered 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".)

Cytokines — Cytokines have long been implicated in the pathophysiology of preterm labor associated with intraamniotic infection [55]. These agents may also be a component of the process of normal term labor [9,56-58]. Macrophages exert anti-inflammatory functions to promote uterine quiescence until term and then acquire a pro-inflammatory phenotype to promote labor [59]. 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 [60]. IL-1 beta inhibits decidual cell progesterone receptor expression via ERK1/2 activation [61]. The fetus may also 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 [56]. 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 [62]. 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 [63].

Other hormones and peptides — Various other 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 promotion and maintenance of labor at term remains controversial. Some of these factors include parathyroid hormone-related peptide [64], luteinizing hormone/human chorionic gonadotropin [65], and relaxin [66,67].

Role of the fetal hypothalamic-pituitary-adrenal axis — Activation of the fetal hypothalamic-pituitary-adrenal axis during the latter part of pregnancy results in release of large amounts of cortisol from the intermediate (fetal) zone of the fetal adrenal glands [68,69]. Glucocorticoids (including cortisol) are potent stimulants of fetal membrane, decidual, and placental corticotropin-releasing hormone (CRH) production, in contrast to their negative effect on hypothalamic CRH production [70,71]. Inflammatory cytokines, catecholamines, acetylcholine, and oxytocin also increase placental CRH secretion [8], 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 [68,69].

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 [8,72].

Cortisol appears to stimulate expression of placental (but not hypothalamic) CRH in vitro [70]. Studies demonstrating an increase in circulating CRH concentrations (as well as a decrease in ACTH and cortisol levels) in patients receiving antepartum glucocorticoids to promote fetal lung maturation suggest that this mechanism may also be operative in vivo [73,74]. In addition, measurement of elevated maternal plasma CRH levels between 28 and 30 weeks of gestation may predict individuals at increased risk of preterm birth [75].

Cortisol enhances amnionic cyclooxygenase to enhance prostaglandin synthesis and inhibits chorionic prostaglandin dehydrogenase activity, thereby preventing prostaglandin metabolism [8,76].

Glucocorticoids also enhance expression of the immunophilin FKBP51 in term decidual cells, which blocks progesterone receptor-mediated gene transcription, and both term and idiopathic preterm birth are associated with increased expression of decidual cell FKBP51 [77].

Taken together, these data suggest the gradual increase in maternal and/or fetal pituitary-adrenal activity over the last few weeks of gestation may have a role in the promotion of labor at term. (See "Spontaneous preterm birth: Pathogenesis".)

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 [78]. Tissue inhibitors of MMPs (TIMPs) bind to MMPs and shut down proteolysis, thereby helping to maintain membrane integrity [78,79].

The fetal membranes normally remain intact until term due to low MMP activity and high levels of TIMPs [79-83]. Periparturitional activation of MMPs at term may trigger a cascade of events that reduce fetal membrane integrity and promote rupture [84]. 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-1β, prostaglandins E2 and F2 alpha appear to increase collagenase activity and activate inflammatory pathways in fetal membranes at parturition [85-88]. (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 [89]. The placenta (trophoblast cells), decidua, and fetal membranes express two relaxin genes: H1 and H2. In the decidua, both genes upregulate MMP-9 and MMP-3 expression, but not MMP-1 or TIMP-1. In contrast, the primary effect in fetal membranes (amniochorion) is an increase in MMP-1 and tPA; release of IL-6 and IL-8 may also occur but is not seen as robustly as with infection.

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 [90,91].

The neuro- and placental peptides CRH and urocortin (a member of the CRH family of peptides) may induce local MMP-9 activity in fetal membranes [92].

Certain medications (such as fluoxetine) may induce a sterile inflammation within the membranes, leading to weakening, premature rupture, and preterm birth [93].

Genetic or epigenetic factors that predispose to membrane rupture and preterm birth may be superimposed on these biochemical pathways.

Role of myometrial factors — Regardless of whether the 'trigger' for onset of parturition originates within or outside the fetus, the final result is characterized by the development of regular phasic uterine contractions increasing in frequency and intensity. 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 [1,94]. 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) [95]. The end result is an increase in intracellular calcium and myometrial contractions [95,96].

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 [97], and levels have been shown to decrease before labor, both at term and preterm [98]. 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 [99,100].

In contrast to vascular smooth muscle, myometrial cells have sparse innervation, which is further reduced during pregnancy [101]. The regulation of the contractile mechanism of the uterus is, therefore, largely humoral and/or dependent on intrinsic factors within myometrial cells. Several hormones have been implicated in this regard. (See 'Role of maternal hormones, neuropeptides, and neuroproteins' above and 'Role of the fetal hypothalamic-pituitary-adrenal axis' above.)

WHICH TISSUE IS PRIMARILY RESPONSIBLE FOR PROMOTING LABOR AT TERM: THE PLACENTA OR THE DECIDUA? — Initial studies suggested that the fetoplacental unit is in control of the timing of birth through early detection of stress signals by the placenta mediated through corticotropin-releasing hormone (CRH) signaling (a so-called "placental clock") [102,103]. However, the inner workings of this putative "placental clock" have not been elucidated despite many years of investigation. We posit that this is because the primary role of the placenta is to support, nourish, and protect the fetus, not to promote or drive parturition.

More recent data suggest that it is not a "placental clock" that regulates the timing of birth, but rather a "decidual clock" [9]. The evidence in support of the decidua as the organ primarily responsible for the timing of birth can be summarized briefly as follows:

The decidualized endometrium (decidua) is the maternal tissue (organ) most intimately associated with the fetoplacental unit. It is a specialized stromal tissue with intrinsic and specific immunological and endocrine functions.

The endometrium must be optimally primed during the secretory phase of the menstrual cycle in anticipation of the arrival of the blastocyst. This process, known as decidualization, involves hormonal, biochemical, and immunological factors. Failure to optimally prime the endometrium will lead to pregnancy failure or complications thereof [104].

The endometrium exists mainly in the nonpregnant state, during which time it communicates directly with the outside environment and is exposed constantly to external stimuli (eg, sperm, infectious organisms, commensal bacteria, environmental toxins) which have the ability to induce a robust proinflammatory response. During pregnancy, this proinflammatory phenotype must be actively suppressed and the decidua maintained in a state of functional quiescence to prevent pregnancy loss. By way of example, endogenous levels of prostaglandin in the decidua are 200-fold lower in pregnancy than in the endometrium at any stage of the menstrual cycle [105]. Moreover, failure to suppress prostaglandin production in the endometrium around the time of implantation is associated with spontaneous abortion [106].

The factors responsible for regulating (dampening) the immune response within the decidua are put in place early in pregnancy and appear to have a set time limit.

Advancing gestational age is associated with a slow withdrawal of active suppression and an enhanced ability to induce inflammatory signals within the decidua. This, in turn, promotes the production and release of a variety of biologically active inflammatory mediators (prostaglandins, cytokines, growth factors, chemokines, and reactive oxygen species) at the maternal-fetal interface leading to labor.

If active anti-inflammatory mechanisms are withdrawn too soon or if the decidua is metabolically dysregulated too early in gestation, spontaneous preterm labor will ensue.

There is a genetic predisposition for preterm birth that is carried primarily in the maternal lineage. It is the decidua (and not the placenta) that is maternal in origin.

UTERINE INVOLUTION — After delivery, the uterus undergoes a process of remodeling and repair. Uterine involution refers to the physiological process by which the uterus returns to its normal prepregnant state, both structurally and functionally. It is characterized by a decrease in uterine muscle mass (through apoptosis and autophagy of myometrial smooth muscle cells and a decrease in the amount of connective tissue), reduced uterine blood flow and endometrial vascularity, endometrial regeneration, and a resumption of ovarian function. This process is very rapid during the first week postpartum and mediated primarily by oxytocin; it then continues progressively and is usually complete by the sixth week postpartum. It appears to occur more rapidly in the cervix than in the uterine corpus. The uterine cavity is slightly larger in parous females than in nulligravidas and the external os is slit-like instead of round in those who labored and may have indentations after a vaginal birth [107]. (See "Overview of the postpartum period: Normal physiology and routine maternal care", section on 'Uterine involution'.)

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. (See 'The four phases of uterine activity' above.)

Parturition cascade – It is likely that a "parturition cascade" exists at term that removes the mechanisms maintaining uterine quiescence and recruits factors promoting uterine activity. (See 'The parturition cascade' above.)

Physiological changes in preparation for labor (See 'Maternal and fetoplacental factors in labor initiation' above.) – Once the myometrium and cervix are prepared, endocrine and/or paracrine/autocrine factors from the fetoplacental unit (primarily from the decidua) bring about a switch in the pattern of myometrial activity from irregular contractures to regular, coordinated contractions. The end result is cervical effacement and dilatation, rupture of the fetal membranes, and expulsion of the products of conception (fetus and placenta).

Timing of labor – The fetus appears to control the timing 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.

Uterine involution – In the days and weeks after delivery, the uterus undergoes involution; the process is mediated primarily by oxytocin.

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Topic 6758 Version 25.0

References

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