Labor is the process by which the fetus and its supporting placenta and membranes pass from the uterus to the outside world. It is defined as regular uterine contractions that result in thinning and dilatation of the cervix so that the products of conception can pass out of the uterus. Labor involves three key processes: (i) a switch in myometrial activity, from a longer lasting, low-frequency irregular contraction pattern called “contractures” to the frequent, high-intensity, regular pattern known as “contractions”; (ii) softening and dilatation of the cervix; and (iii) rupture of the fetal membranes. Although labor may first become apparent with the isolated appearance of any of these three elements, the physiologic events that produce them typically occur simultaneously.
Phases of labor
It is useful to consider labor as a series of four physiologic phases, characterized by the release of the myometrium from the inhibitory effects of pregnancy and the activation of stimulants of myometrial contractility (Fig. 22.1). Phase 0 comprises the majority of pregnancy. During this phase, the uterus is maintained in a state of quiescence by one or more inhibitors of contractility. Candidate inhibitors include progesterone, prostacyclin, nitric oxide, parathyroid hormone-related peptide (PTHrP), calcitonin gene-related peptide, relaxin, adrenomedullin and vasoactive intestinal peptide (VIP). Near the end of a normal pregnancy, the uterus undergoes the process of activation (Phase 1). During activation, a number of contraction-associated proteins increase under the influence of estrogen. These proteins include myometrial receptors for prostaglandins and oxytocin, membranous ion channels and connexin-43, a key component of gap junctions. The increase in myometrial gap junctions during activation will electrically couple adjacent myometrial cells and maximize the coordination of contraction waves that move from the uterine fundus to the cervix. Phase 2 of labor is called stimulation. During stimulation, oxytocin and stimulatory prostaglandins (PGs) such as PGE2 and PGF2α can induce contractions in the previously primed uterus. The cervix dilates. The fetus, membranes and placenta are expelled from the uterus in a process called parturition. Phase 3 of labor follows parturition and is called involution. During involution, sustained contraction of the uterus promotes necessary hemostasis and eventually reduces the massively enlarged postpartum uterus to a size only slightly larger than its prepregnant state.
Initiation of labor
The average human gestation lasts 280 days (40 weeks) from the beginning of the last menstrual period. Exactly what triggers human labor is unknown. Still, like other species that bear live young, the fetoplacental unit appears to control at what point in gestation labor will occur while maternal signals determine the time of day that it will start. The mechanisms used by the fetoplacental unit to initiate labor vary from species to species. Humans mimic the mechanisms used by other primates much more closely than those used by more distantly related mammals.
Sheep and rodents rely on progesterone withdrawal for labor initiation. In stark contrast, the initiation of labor in primates involves increases in placental estrogen synthesis (Fig. 22.2). Seemingly, this estrogen must be produced by the placenta, because systemic infusion of estrogen does not induce labor at term. Rather, infused androstenedione will induce contractions and this effect can be blocked by inhibiting aromatase activity. Placental aromatase activity (Chapters 2 and 19) increases at term. This is accompanied by an increase in production of adrenal androgen precursors (e.g., androstenedione) by the fetus. Both support increased placental estrogen production.
The stimulus for the increase in fetal adrenal androgen production near term is not known. It does not appear to arise from the fetal hypothalamus (corticotropin-releasing factor, CRH) or fetal pituitary adrenocorticotropic hormone (ACTH) because absence of appropriate brain formation in anencephalic fetuses does not prolong pregnancy. Rather, the stimulus is likely to be placental. Placental CRH is an excellent candidate. Placental CRH is biochemically identical to maternal and fetal hypothalamic CRH but differs in its regulation. Glucocorticoids exert negative feedback on the synthesis and release of hypothalamic CRH, but stimulate placental CRH. Placental CRH appears to stimulate fetal ACTH production and fetal adrenal steroid synthesis (e.g., androstenedione production). It may also have local effects within the uterus, fostering placental vasodilatation, prostaglandin production and myometrial contractility.
In all species, an increase in prostaglandin synthesis by the decidua and the fetal membranes constitutes the final common pathway in labor. Human uterine tissues are selectively enriched with arachidonic acid, an essential fatty acid that is the obligate precursor of those prostaglandins most important in labor: PGE and PGF2α. Both cyclooxygenase enzymes, COX-1 and COX-2, are expressed in the uterus. COX-2, the inducible form of the enzyme, appears to be sensitive to glucocorticoid induction. Evidence for the role of prostaglandins in labor includes observations that: (i) the concentrations of PGs in amniotic fluid, maternal plasma and maternal urine are increased before the onset of labor; (ii) administration of PGs at any stage of pregnancy can initiate labor; (iii) PGs can induce cervical ripening and uterine contractions; (iv) PGs increase myometrial sensitivity to oxytocin; and (v) inhibitors of PG synthesis can suppress contractions and prolong pregnancy (e.g., the COX inhibitor, indomethacin).
Like other smooth muscle cells, myometrial cells are triggered to contract by a rise in intracellular calcium (Ca2+). Prostaglandins raise intracellular Ca2+ by increasing Ca2+ influx across the cell membranes, by stimulating calcium release from intracellular stores and by enhancing myometrial gap junction formation.
Oxytocin, a posterior pituitary hormone, has an important role in labor. Oxytocin acts through its membrane receptor on myometrial cells to activate members of the G protein subfamily. These, in turn, activate phospholipase C and inositol triphosphate, causing a release of intracellular Ca2+. Oxytocin seems to have a role in the maternal control of the time of day that labor will start. Several days to weeks before the onset of recognizable labor, myometrial activity switches away from contractures to contractions. This switch invariably occurs when the lights go off in the animal’s environment and ensures that delivery will occur when the mother is safely at rest away from predators. Nocturnally active animals will thus deliver during the day and vice versa. This circadian rhythm of uterine activity is accompanied by an increase in circulating oxytocin and in myometrial oxytocin receptors.
Oxytocin also has an important role in promoting expulsion of the fetus from the uterus after the cervix is fully dilated. In fact, the oxytocin concentrations in the maternal circulation do not begin to rise until the expulsive stage of labor begins. Still, the gradual increase in the concentrations of oxytocin receptor in the myometrium during the second half of pregnancy may allow for lower concentrations of oxytocin to effect myometrial contractions prior to the onset of expulsion. Oxytocin can induce prostaglandin production and gap junction formation within the uterus, suggesting that it may act in synergy with other factors to initiate labor. To this point, oxytocin can be used clinically to induce and to stimulate labor. The fetus, placenta and fetal membranes all make oxytocin that is selectively secreted toward the maternal compartment.