Labor is the physiologic process by which a fetus is expelled from the uterus to the outside world. Labor is defined as an increase in myometrial activity or, more precisely, a switch in the pattern of myometrial contractility from irregular contractures (long-lasting, low-frequency activity) to regular contractions (high-intensity, high-frequency activity), resulting in effacement and dilatation of the uterine cervix. In normal labor, there appears to be a time-dependent relation between the biochemical changes in the connective tissue in the cervix that usually precede uterine contractions and cervical dilatation. All these events usually occur before the spontaneous rupture of the fetal membranes.2 Labor remains a clinical diagnosis.

Labor at Term

Labor at term may best 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. Strips of quiescent myometrial tissue obtained from a uterus at term and placed in an isotonic water bath, for example, will contract vigorously and spontaneously without added stimuli. In vivo, however, it is likely that both mechanisms are important.

The regulation of uterine activity during pregnancy and labor can be divided into four distinct physiologic phases. During pregnancy, the uterus is maintained in a state of functional quiescence (phase 0) through the action of various putative inhibitors, including progesterone, prostacyclin, relaxin, nitric oxide, parathyroid hormone–related peptide, corticotropin-releasing hormone, human placental lactogen, calcitonin gene–related peptide, adrenomedullin, and vasoactive intestinal peptide. Before term, the uterus undergoes activation (phase 1) and stimulation (phase 2). Activation occurs in response to uterotropins, including estrogen, and is characterized by increased expression of a series of contraction-associated proteins (including myometrial receptors for prostaglandins and oxytocin), activation of certain ion channels, and an increase in connexin 43 (a key component of gap junctions). An increase in gap junctions between adjacent myometrial cells leads to electrical synchrony within the myometrium and allows effective coordination of contractions.7 Once activated, the “primed” uterus can be stimulated to contract by the actions of uterotonins such as oxytocin and the stimulatory prostaglandins E2 and F2{alpha}. Involution of the uterus after delivery occurs during phase 3 and is mediated primarily by oxytocin.

The Endocrine Control of Labor at Term

Considerable evidence suggests that in most viviparous animals, the fetus is in control of the timing of labor. In sheep and cows, the mechanism by which the fetus triggers labor at term has been elegantly elucidated. However, the placenta of humans lacks the glucocorticoid-inducible enzyme 17α-hydroxylase–17,20-lyase, which is critical to this pathway, and thus this mechanism does not apply to humans. The slow progress in our understanding of the biochemical mechanisms involved in the process of labor in humans in large part reflects the difficulty of extrapolating from the endocrine-control mechanisms in various animals to the paracrine and autocrine mechanisms of parturition in humans — processes that cannot be investigated directly.

Regardless of whether labor is triggered by the fetus or outside the fetus, the final pathway for labor ends in the uterus and is characterized by the development of regular phasic uterine contractions. As is the case in other smooth muscles, myometrial contractions are mediated through the ATP-dependent binding of myosin to actin. In contrast to vascular smooth muscle, however, myometrial cells are sparsely innervated and become even less so during pregnancy. The regulation of the contractile mechanism of the uterus is therefore largely humoral, dependent on intrinsic factors within myometrial cells, or both.

It is likely that there is a parturition cascade at term that removes the mechanisms maintaining uterine quiescence and recruits factors promoting uterine activity. In such a model, each element is connected to the next, and many of the elements are part of multiple positive-feedback loops.

The paracrine and autocrine pathways involved in labor have been reviewed in detail elsewhere. In brief, human labor at term is a physiologic event involving an integrated series of changes within the tissues of the uterus (the myometrium, decidua, and uterine cervix) that occur over a period of days or weeks. Such changes include an increase in the synthesis and release of prostaglandins within the uterus, an increase in the formation of myometrial gap junctions, and the activation of myometrial oxytocin receptors (uterine activation).

Once the myometrium and cervix are prepared, endocrine, paracrine, and 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 may coordinate this switch in myometrial activity through its influence on the production of placental steroid hormones, through mechanical distention of the uterus, and through secretion of neurohypophysial hormones and other stimulators of prostaglandin synthesis. The final common pathway for labor in all species appears to be the activation of the fetal hypothalamic–pituitary–adrenal axis.

Figure 2.  Proposed Mechanism of Labor Induction at Term.

The major hormones and paracrine and autocrine factors responsible for promoting uterine contractions at term in an integrated parturition cascade are shown. CRH denotes corticotropin-releasing hormone, DHEAS dehydroepiandrosterone sulfate, and SROM spontaneous rupture of the fetal membranes. Adapted from Norwitz et al. Plus signs indicate activation or up-regulation.

Preterm Labor

Preterm labor, defined as labor before 37 weeks’ gestation, occurs in 7 to 10 percent of all births but accounts for more than 85 percent of all perinatal complications and death. Preterm labor probably represents a syndrome rather than a specific diagnosis, since the causes are varied. It may reflect a breakdown in the mechanisms responsible for maintaining uterine quiescence. For example, the choriodecidua is selectively enriched with 15-hydroxyprostaglandin dehydrogenase, the enzyme responsible for degrading the primary prostaglandins. A deficiency in chorio-decidual 15-hydroxyprostaglandin dehydrogenase activity may impair the ability of the fetal membranes to metabolize the primary prostaglandins, thereby allowing prostaglandin E2 to reach the myometrium and initiate contractions. Such a deficiency may account for up to 15 percent of cases of idiopathic preterm labor.

Alternatively, premature labor may represent a short-circuiting or overwhelming of the normal parturition cascade. Indeed, in this cascade, the fetoplacental unit could trigger labor prematurely if the intrauterine environment became hostile and threatened the well-being of the fetus. For example, up to 30 percent of preterm labors are thought to result from intraamniotic infection. In many patients with infection, levels of the products of the lipoxygenase and cyclooxygenase pathways are elevated. There are also increased levels of cytokines (including interleukin-1β, interleukin-6, and tumor necrosis factor {alpha}) in the amniotic fluid of women with infection. Cytokines and eicosanoids appear to be synergistic, and the net effect may be to overwhelm the normal parturition cascade, resulting in preterm labor. Recently, thrombin has been shown to be a powerful uterotonic agent, and it may be the physiologic mechanism for preterm labor due to placental abruption.

Predictive Factors

The risk factors for preterm labor include previous preterm delivery, multiple gestation, uterine anomalies, hydramnios, infection, smoking, and demographic variables, such as very young or older maternal age, black race, low weight before pregnancy, and low socioeconomic status. Reliance on these risk factors alone, however, will fail to identify over 50 percent of the women who will have preterm delivery. Similarly, although an increase in uterine activity is a prerequisite for preterm labor, home monitoring of uterine activity in women at high risk for preterm labor does not reduce the incidence of preterm delivery. Serial digital evaluation of the cervix is useful if the results of the examination are normal. However, an abnormal cervical finding (shortening or dilatation of the cervix or both) is associated with preterm delivery in only 4 percent of women at low risk and 12 to 20 percent of those at high risk. Real-time sonographic evaluation of the cervix, on the other hand, shows a strong inverse correlation between cervical length and the risk of preterm delivery. Women with a cervical length below the 10th percentile for gestational age are six times as likely to give birth before 35 weeks’ gestation as women with longer cervixes. Less than 2 percent of women at low risk have a cervical length of 15 mm or less at 23 weeks’ gestation, but 60 percent of such women will give birth before 28 weeks’ gestation and 90 percent will give birth before 32 weeks’ gestation.

Vaginal infections, such as bacterial vaginosis and those due to Neisseria gonorrhoeae, Chlamydia trachomatis, group B streptococcus, Ureaplasma urealyticum, and Trichomonas vaginalis, have been associated with preterm delivery. Screening for and treatment of such infections may be warranted, although it is unclear whether treatment is necessary for ureaplasma or group B streptococcus infection. Definitive diagnosis requires a positive amniotic-fluid culture, but markers of infection in amniotic fluid (such as the presence of interleukin-6 and glucose, and a high white-cell count) may suggest the diagnosis.

Several biochemical markers have been associated with preterm delivery, including activin, inhibin, follistatin, fibronectin, collagenase, and tissue inhibitors of metalloproteinases. To date, only fibronectin has been used in a screening test for preterm delivery. Elevated levels of fetal fibronectin in cervicovaginal secretions, which may reflect separation of the fetal membranes from the maternal decidua, are associated with premature delivery. However, in a low-risk population, a positive fibronectin test at 22 to 24 weeks’ gestation had a predictive value of 13 percent for spontaneous preterm delivery before 28 weeks and 36 percent for delivery before 37 weeks. The usefulness of this test may lie in its negative predictive value (99 percent of patients with a negative fibronectin test will not deliver within seven days), which may reduce the risk of unnecessary hospitalization.

Despite initial disappointments, there has been a recent resurgence of interest in the development of endocrine assays to assess the risk of preterm labor. A decrease in maternal serum progesterone levels is not a prerequisite for labor in humans, and serum progesterone levels or ratios of serum progesterone to estradiol-17β cannot be used to identify women at risk for preterm labor. On the other hand, maternal serum estriol levels accurately reflect activation of the fetal hypothalamic–pituitary–adrenal axis, which occurs before the onset of labor, both at term and preterm. Salivary estriol levels mirror the level of biologically active (unconjugated) estriol in the circulation. The detection of elevated levels of estriol in maternal saliva (≥ 2.1 ng per milliliter [7.7 nmol per liter]) is predictive of delivery before 37 weeks’ gestation in high-risk women, with a sensitivity of 68 percent to 87 percent, a specificity of 77 percent, and a false positive rate of 23 percent. Serial (weekly) measurements are more accurate than a single measurement. Other endocrine markers of preterm delivery under investigation include relaxin and corticotropin-releasing hormone.

Management

In many instances, premature labor represents the need of the fetus to escape from a hostile intrauterine environment, so aggressive intervention to stop labor may be counterproductive. Contraindications to tocolysis include intrauterine infection, unexplained vaginal bleeding, and fetal distress. Bed rest and hydration are commonly recommended but have not been proved to be efficacious in halting preterm labor. Drug therapy remains the cornerstone of modern management. Ethanol (which inhibits the release of oxytocin from the posterior pituitary) was the first effective tocolytic agent, but adverse maternal side effects have limited its use. Although a number of alternative agents are now available, there are no reliable data to suggest that any of them delay delivery for more than 48 hours. Since no single drug has a clear therapeutic advantage, the side effects of the drugs will often determine which ones to use in a given woman.

Magnesium sulfate suppresses the transmission of nervous impulses to uterine smooth muscle and lowers the levels of intracellular calcium in myometrial cells, the presence of which is necessary for the activation of the myosin–actin contractile unit. Magnesium sulfate is safe and has become the first-line treatment for preterm labor in North America. β-Adrenergic agonists are also commonly used. These drugs reduce intracellular calcium levels and decrease the sensitivity of the myosin–actin contractile unit to calcium through a mechanism that is dependent on cyclic AMP. Ritodrine hydrochloride is the only drug that has received approval from the Food and Drug Administration for the treatment of preterm labor. However, this drug has a higher incidence of serious adverse effects than magnesium sulfate. Nifedipine, a type II dipyridamole calcium-entry blocker, is as effective as magnesium sulfate and β-adrenergic agonists in delaying preterm delivery and is associated with fewer maternal side effects. The main concern limiting the use of calcium-channel–blocking drugs, however, is the reported adverse effect on uteroplacental blood flow. Inhibitors of prostaglandin synthesis, such as indomethacin, although capable of delaying premature birth, have been associated with serious neonatal complications, especially if given shortly before delivery. Promising newer drugs include potassium-channel openers and oxytocin-receptor antagonists, although recent studies suggest that the oxytocin-receptor antagonist atosiban is no more effective than other tocolytic drugs.

Maintenance therapy for more than 48 hours does not confer any benefit and poses a considerable risk of adverse effects. Similarly, the concurrent use of two or more tocolytic drugs is not more effective than the use of a single drug, and the cumulative risk of side effects generally precludes this method of management. The use of sequential therapy, however, may be beneficial. In women with preterm premature rupture of the fetal membranes, tocolysis has not been shown to be effective and is best avoided.

Conclusions

Labor at term is a complex physiologic process involving fetal and placental, as well as maternal, signals. Considerable evidence suggests that the fetus controls the timing of labor and thus its birth, but exactly how is still unknown. A better understanding of the mechanisms responsible for the process of labor at term will further our knowledge of disorders of parturition, such as preterm labor, and improve our ability to ensure a successful outcome of pregnancy.

Supported in part by a grant (5K12 HD00849) from the National Institutes of Health and by the Medical Research Council of Canada (Group in Fetal and Neonatal Health). Dr. Norwitz is a Scholar of the Reproductive Scientist Development Program of the National Institute of Child Health and Human Development–Association of Professors of Obstetrics and Gynecology.

Source Information

From the Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital and Harvard Medical School, Boston (E.R.N., J.N.R.); and the Department of Physiology, University of Toronto, Toronto (J.R.G.C.).

Address reprint requests to Dr. Norwitz at the Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, or at .(JavaScript must be enabled to view this email address).

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Errol R. Norwitz, M.D., Ph.D., Julian N. Robinson, M.D., and John R.G. Challis, Ph.D., F.R.S.C.
The New England Journal of Medicine
Volume 341:660-666 August 26, 1999 Number 9