8.2.2 Parturition

Labour is the physiological process by which the products of conception are passed from the uterus to the outside world. Timely onset is the key determinant of perinatal outcome. Although all viviparous animals share this process, the molecular and cellular mechanisms appear to differ in humans. Most animal models have demonstrated that the fetus is in control of the timing of labour. However, the parturition cascade in humans appears to be autocrine/paracrine in nature, thus precluding direct investigation. This chapter summarizes the current knowledge on the biological mechanisms responsible for the onset of labour at term in the human, as well as reviewing the limited treatment options when these mechanisms falter.

During the time of Hippocrates, it was believed that the fetus presented head first so that it could kick its legs up against the fundus of the uterus and propel itself through the birth canal. Although we have moved away from this mechanical model, the suggestion that the fetus triggers labour is likely true in all viviparous species. Extensive experimental work in a number of animal models suggests that the fetus initiates labour through a mechanism that involves activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis. In sheep, for example, an increase in adrenocortico-trophic hormone (ACTH) stimulates the fetal adrenal gland to produce cortisol, which catalyses the conversion of progesterone to oestrogen in the placenta. This resultant change in the oestrogen/progesterone ratio triggers prostaglandin production, uterine contractions, and labour (1). Additional evidence in support of the concept that the fetus drives the onset of labour comes from horse-donkey cross-breeding experiments. Such cross-breeding results in a gestational length intermediate between that of horses (340 days) and that of donkeys (365 days), suggesting an important role for the fetal genotype in the initiation of labour (2).

While an endocrine-paracrine cascade originating within the fetus had been shown to be responsible for the onset of labour in domestic ruminants, Ligand et al. demonstrated that the human placenta lacked a critical enzyme in this cascade (3). The missing enzyme, glucocorticoid-inducible 17α-hydroxylase/C_17,20-lyase, catalyses the conversion of pregnenolone to 17α-hydroxy-pregnenolone and dehydroepiandrostenedione. As such, the mechanism responsible for the onset of labour in ruminants does not apply in humans. This explains, at least in part, why the decrease in circulating progesterone levels prior to the onset of labour seen in most laboratory animals does not occur in humans (4). The human fetus therefore has to develop a different mechanism to initiate labour.

Pregnancy and labour are associated with morphological changes in all tissues of the reproductive tract, but most especially in the uterus and cervix (Table 8.2.2.1). Early in pregnancy, the uterus grows through cellular hyperplasia. As pregnancy progresses, the cells undergo hypertrophy. Much of this process is mediated by oestrogen (8). Changes also occur in the cervical matrix. Cervical collagenase activity increases with increasing gestational age, likely through the action of hormones (oestrogen, progesterone, and relaxin) causing collagen fibrils to decrease in concentration and organization. Near term, the increase in hyaluronic acid draws in water causing further dispersion of the collagen fibres (9). These changes lead to cervical softening, effacement (shortening), and dilation.

Once the myometrium and cervix are prepared, endocrine and/or paracrine/autocrine factors from the fetal membranes and placenta bring about a transition in the pattern of myometrial activity so that regular uterine contractions occur. As 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 have a sparse innervation, which is further reduced during pregnancy (10). The regulation of the contractile mechanism of the uterus is therefore largely humoral and dependent on intrinsic factors within myometrial cells. During pregnancy, the contractile activity of the uterus is maintained in a state of functional quiescence through the action of various inhibitors. The onset of uterine contractions at term is a consequence of release from the inhibitory effects of pregnancy on the myometrium, as well as recruitment of uterine stimulants such as oxytocin and the stimulatory prostaglandins (PGF_2α and PGE₂) (11).

Current evidence suggests that all of the physiological changes described above occur in an orchestrated and systematic fashion through a tightly regulated autocrine/paracrine mechanism. This ‘parturition cascade’ (Fig. 8.2.2.1) is responsible at term for removal of the mechanisms maintaining uterine quiescence and recruitment of factors acting to promote uterine activity (12). Given its teleological importance, such a cascade has multiple redundant loops to ensure a fail-safe system of securing pregnancy success and, ultimately, the preservation of 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-forwards characteristics typical of a cascade mechanism. The sequential recruitment of signals that serve to augment the labour process suggest that it may not be possible to identify any one signalling mechanism as being uniquely responsible for the initiation of labour. The role of several key hormones involved in the timing of labour are discussed below.

Levels of CRH in the maternal circulation increase from 10–100 pg/ml in nonpregnant women to 500–3000 pg/ml in the third trimester of pregnancy, and then decrease precipitously after delivery (13). The source of this excess CRH is the syncytiotrophoblast cells of the placenta, and—in contrast to the hypothalamus where corticosteroids suppress CRH expression in a classic endocrine feedback inhibition loop—the production of CRH by the placenta is up-regulated by corticosteroids produced primarily by the fetal adrenal glands at the end of pregnancy (14). Under the influence of oestrogen, hepatic-derived CRH-binding protein (CRH-BP) concentrations also increase in pregnancy. CRH-BP binds and maintains CRH in an inactivate form. Importantly, circulating CRH levels increase and CRH-BP levels decrease prior to the onset of both term and preterm labour, resulting in a marked increase in free (biologically active) CRH (15). In addition to stimulating the production of ACTH by the fetal pituitary, CRH may also act directly on the fetal adrenal glands to promote the production of C-19 steroid precursor, dehydroepiandrostenedione sulphate (DHEAS) (16). For these reasons, some authorities have proposed that CRH may control the duration of pregnancy. In support of this hypothesis, circulating levels of CRH have been shown to be increased in pregnant women with anxiety and depression, which may account for the increased incidence of preterm birth in such women (17). However, recent studies have shown that measurements of maternal CRH are not clinically useful because of substantial intra- and inter-patient variability (18), which likely reflects the mixed endocrine and paracrine role of placental, fetal membrane, and decidual CRH in the initiation of parturition.

At a molecular level, CRH acts by binding to specific nuclear receptors and affecting transcription of target genes. A number of CRH receptor isoforms have been described. During pregnancy, high-affinity CRH receptor isoforms dominate, and CRH promotes myometrial quiescence by inhibiting the production and increasing the degradation of prostaglandins, increasing intracellular cAMP, and stimulating nitric oxide synthase activity (19). At term, CRH acts primarily through its low-affinity receptor isoforms, which promotes myometrial contractility by stimulating prostaglandin production from the decidua and fetal membranes (20) and potentiating the contractile effects of oxytocin and prostaglandins on the myometrium (21).

In virtually every animal species studied, there is an increase in the concentration of the major adrenal glucocorticoid product in the fetal circulation in late gestation (cortisol in the sheep and human; corticosterone in the rat and mouse). As with other viviparous species, the final common pathway towards parturition in the human also appears to be maturation and activation of the fetal HPA axis. The end result is a dramatic increase in the production of C-19 steroid (DHEAS) from the intermediate (fetal) zone of the fetal adrenal. DHEAS is transported to the placenta where it is converted to oestriol (Fig. 8.2.2.1). The human placenta is an incomplete steroidogenic organ and cannot synthesize oestrogen in the absence of C-19 steroid precursor (22).

Like many of the hormones involved in the parturition cascade, glucocorticoids have multiple regulatory effects. Cortisol is believed to influence the production of prostaglandins at the maternal-fetal interface by affecting the expression of the enzymes responsible for prostaglandin production and degradation, amnionic prostaglandin H synthase (PGHS) and chorionic 15-hydroxy-prostaglandin dehydrogenase (PGDH), respectively (23). Glucocorticoids up-regulate placental oxytocin expression (24) and interfere with progesterone signalling in the placenta (25). Lastly, they regulate their own levels locally within the placenta and fetal membranes by affecting the expression and activity of the 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme. This enzyme exists in two isoforms. HSD-1 acts principally as a reductase enzyme converting cortisone to cortisol, and is the predominant isoform found in the fetal membranes. HSD-2 predominates in the placental syncytiotrophoblast and serves as a dehydrogenase that oxidizes cortisol to inactive cortisone. It has been proposed that placental 11β-HSD-2 protects the fetus from high levels of maternal glucocorticoids (26).

Progesterone is a steroid hormone that plays a critical role in each step of human pregnancy. It acts through a receptor that is a member of the family of ligand-activated nuclear transcription regulators. Progesterone produced by the corpus luteum is critical to the maintenance of early pregnancy until the placenta takes over this function at 7–9 weeks of gestation, hence its name (pro-gestational steroid hormone). Indeed, surgical removal of the corpus luteum (24) or administration of a progesterone receptor (PR) antagonist, such as RU 486 (28), readily induces abortion before 7 weeks (49 days) of gestation. The role of progesterone in later pregnancy, however, is less clear. It has been proposed that progesterone may be important in maintaining uterine quiescence in the latter half of pregnancy by limiting the production of stimulatory prostaglandins and inhibiting the expression of contraction-associated protein genes (ion channels, oxytocin, and prostaglandin receptors, and gap junctions) within the myometrium (25).

In most laboratory animals (with the noted exception of the guinea pig and armadillo), systemic withdrawal of progesterone is an essential component of parturition (25). In humans, however, circulating progesterone levels during labour are similar to levels measured 1 week prior to labour and levels remain elevated until after delivery of the placenta (4), suggesting that systemic progesterone withdrawal is not a prerequisite for labour at term. However, circulating levels do not necessarily reflect tissue activity. There is increasing evidence to suggest that the onset of labour in humans may be preceded by a physiologic (functional) withdrawal of progesterone activity at the level of the uterus (25). For example, the administration of a PR antagonist (such as RU486) at term leads to increased uterine activity and cervical ripening (29). Moreover, antenatal supplementation with progesterone from 16–20 weeks through 34–36 weeks of gestation has been shown to reduce the rate of preterm birth in approximately one-third of women judged to be at high risk by virtue of a prior spontaneous preterm birth (30, 31) or cervical shortening (32). Although not a panacea, this is the first intervention in the past four decades that has been shown to effectively decrease the rate of preterm birth.

The molecular mechanisms by which progesterone maintains uterine quiescence and prevents preterm birth in some high-risk women is not clear. Six possible mechanisms have been proposed in the literature. These can be summarized briefly as follows:

In the rhesus monkey, infusion of a C-19 steroid precursor (androstenedione) leads to preterm delivery (41). This effect is blocked by concurrent infusion of the aromatase inhibitor, 4-hydroxy-androstenedione (42), demonstrating that conversion of C-19 steroid precursors to oestrogen at the level of the fetoplacental unit is important. However, systemic infusion of oestrogen failed to induce delivery, suggesting that the action of oestrogen is likely paracrine/autocrine (41). Levels of oestrogen in the maternal circulation are significantly elevated throughout gestation and are derived primarily from the placenta. In contrast to many animal species (such as the sheep), the high circulating levels of oestrogens in the human are already at the K_d for the oestrogen receptor, which explains why there is no need for an additional increase in oestrogen production at term.

At a cellular level, oestrogens exert their effect by binding to specific nuclear receptors and affecting the transcription of target genes. Two distinct oestrogen receptors are described: ERα and ERβ. Each is coded by its own gene (ESR1 and ER2, respectively), and requires dimerization before binding to its ligand. At the level of the uterus, ERα appears to be dominant. Expression of ERα increases in concert with the increase in PR-A/PR-B expression ratio with increasing gestational age in nonlabouring myometrium (43). These findings suggest that functional oestrogen activation and functional progesterone withdrawal are linked.

For most of pregnancy, progesterone decreases myometrial oestrogen responsiveness by inhibiting ERα expression. Such an interaction would explain why the human myometrium is refractory to the high levels of circulating oestrogens for most of pregnancy. At term, however, functional progesterone withdrawal removes the suppression of myometrial ERα expression leading to an increase in myometrial oestrogen responsiveness. oestrogen can then act to transform the myometrium into a contractile phenotype. This model may explain why disruption of progesterone action alone can trigger the parturition cascade. The link between functional progesterone withdrawal and functional oestrogen activation may be a critical mechanism for the endocrine/paracrine control of human labour at term.

Endogenous levels of prostaglandins in the decidua are lower in pregnancy than in the endometrium at any stage of the menstrual cycle, due primarily to a decrease in prostaglandin synthesis (44). This is true also of prostaglandin production in other uterine tissues. Additionally, the administration of exogenous prostaglandins (intravenously, intra-amniotically or vaginally) in all species examined and, at any stage of gestation, have the ability to induce abortion (45). These findings together support the hypothesis that pregnancy is maintained by a mechanism that tonically suppresses prostaglandin synthesis, release, and/or activity throughout gestation.

Similarly, overwhelming evidence suggests that labour, both preterm and term, involves prostaglandin stimulation (7, 25). While this is likely common to all viviparous species, exogenous administration of prostaglandin stimulate uterine contractility both in vitro and in vivo in humans at any gestational age (46). Additionally, drugs that block prostaglandin synthesis can inhibit uterine contractility and in some cases prolong gestation (47). Prostaglandin levels increase in maternal plasma, urine, and amniotic fluid prior to the onset of uterine contractions (48, 49), suggesting that it is a cause and not a consequence of labour.

Maternally-derived oxytocin is synthesized in the hypothalamus and released from the posterior pituitary in a pulsatile fashion. It is rapidly inactivated in the liver and kidney, resulting in a biological half-life of 3–4 min in the maternal circulation. During pregnancy, oxytocin is degraded primarily by placental oxytocinase. Concentrations of oxytocin in the maternal circulation do not change significantly during pregnancy or prior to the onset of labour, but do rise late in the second stage of labour (50). Studies on fetal pituitary oxytocin production, the umbilical arteriovenous difference in oxytocin concentration, amniotic fluid oxytocin levels, and fetal urinary oxytocin output demonstrate conclusively that the fetus secretes oxytocin towards the maternal side (51). Furthermore, the calculated rate of oxytocin secretion from the fetus increases from a baseline of 1 mU/min prior to labour to approximately 3 mU/min after spontaneous labour, which is similar to that normally administered to women to induce labour at term.

Specific receptors for oxytocin are present in the myometrium, and there appears to be regional differences in oxytocin receptor distribution with large numbers of receptors in the fundal area and few receptors in the lower uterine segment and cervix. Myometrial oxytocin receptor concentrations increase 50–100-fold in the first trimester of pregnancy compared with the nonpregnant state and increase an additional 200–300-fold during pregnancy, reaching a maximum during early labour (52). This is mediated primarily by the sex steroid hormones, with oestrogen-promoting and progesterone-inhibiting myometrial oxytocin receptor expression. This rise in receptor concentration is paralleled by an increase in myometrial sensitivity to circulating levels of oxytocin (53). Activation of myometrial oxytocin receptors results in interaction with the guanosine triphosphate (GTP) binding proteins of the Gα_q/11 subfamily of G-proteins that stimulate phospholipase C activity resulting in increased production of inositol triphosphate (54) and calcium influx (55).

In addition to the hormones listed above, a number of additional proteins and peptides have been implicated in the onset and maintenance of parturition and are discussed briefly below.

PTHrP is ubiquitously expressed throughout the body and has a number of functions both during development and in adult tissues, including regulation of vascular tone, bone remodelling, placental calcium transport, and myometrial relaxation. Levels of PTHrP mRNA increase in rat myometrium during late gestation and are higher in gravid compared with non-gravid tissues (56). Administration of PTHrP(1–34) to pregnant rats inhibits spontaneous myometrial contractions (57). PTHrP(1–34) has also been shown to exert a significant relaxant effect on human myometrium collected from late gestation tissues obtained before but not after the onset of labour (58). Taken together, these data suggest that the onset of labour is associated with a removal of the ability of PTHrP to exert its myometrial relaxant effect.

Circulating levels of CGRP are increased during pregnancy, and have been implicated in the maintenance of myometrial quiescence throughout gestation in both rats (59) and humans (60). However, this effect disappears after the onset of labour, suggesting that progesterone may be required to mediate GCRP activity (59).

This 21-amino acid peptide has potent vasoconstrictor properties. It binds to specific receptors on vascular endothelial cells to regulate vascular haemostasis. Endothelin receptors have also been isolated in amnion, chorion, endometrium, and myometrium (61, 62), and appear to increase in the myometrium during labour (61). Endothelin promotes uterine contractility directly by increasing intracellular calcium concentrations (62), and indirectly by stimulating prostaglandin production by the decidua and fetal membranes (61).

EGF is a promiscuous growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation throughout the body. It acts by binding to specific cell-surface tyrosine-kinase receptors that have been identified also in decidua and myometrium. It appears to be up-regulated by oestrogen (62) and may promote uterine contractility, directly by increasing intracellular calcium concentrations (63) and indirectly by mobilizing arachidonic acid, and increasing the synthesis and release of prostaglandins by the decidua and fetal membranes (61).

Regardless of the precise mechanisms responsible for the onset of labour, the final common pathway for labour ends in the maternal tissues of the uterus and is characterized by the development of regular phasic uterine contractions. The structural basis for contractions is the relative movement of thick and thin filaments within the myometrial cells allowing them to slide over each other with resultant shortening of the myocyte. Myosin makes up the thick filaments of the contractile apparatus and actin comprises the thin filaments. The actin-myosin interaction is summarized in Fig. 8.2.2.2, and is regulated in large part by intracellular calcium concentration.

Labour is a clinical diagnosis characterized by regular phasic uterine contractions increasing in frequency and intensity, leading to progressive cervical effacement and dilatation, and culminating in delivery of the products of conception. An initial cervical examination of at least 2 cm dilatation or at least 80% effacement in the setting of regular contractions is also accepted as being sufficient for the diagnosis of labour in nulliparous women. A bloody discharge (‘show’) is often included in the description of labour, but is not a prerequisite for the diagnosis. When contractions occur without cervical change, it is commonly referred to as Braxton Hicks contractions. When there is cervical change without contractions, the diagnosis of cervical insufficiency should be entertained, especially if this occurs in the late second trimester.

Although labour is a continuum, it has traditionally been divided into three stages for the purposes of description and to guide clinical management (Fig. 8.2.2.3) (64). Stage I refers to the period from the onset of labour to full cervical dilatation. It can be further divided into two phases: the latent phase (which involves slow cervical change and can last hours to days) and the active phase (which begins when the rate of cervical change begins to increase exponentially). The transition from latent to active phase typically occurs between 2 and 6 cm of cervical dilation. The speed with which labour progresses depends on a number of factors, the most significant of which is parity. In active phase, nulliparous women should exhibit a minimum of 1.2 cm of cervical dilation per hour (2 SD below the mean) and multiparous women should exhibit at least 1.5 cm of cervical dilatation per hour (Table 8.2.2.2). The strength of uterine contractions, which is measured most accurately using an intrauterine pressure catheter, also differs between latent and active phase with a mean peak intensity +25 to +30 mmHg versus +60 to +65 mmHg, respectively (65).

The second stage of labour begins at full cervical dilatation and concludes with delivery of the fetus. The duration of this stage depends on maternal parity, the position of the fetus, and the presence or absence of regional anaesthesia. A prolonged second stage of labour is defined by the American College of Obstetricians and Gynaecologists (ACOG) as longer than 2 h in a nulliparous woman (greater than 3 h with regional anaesthesia) and longer than 1 h in a multiparous woman (more than 2 h with regional anaesthesia). The third stage of labour refers to the time interval from delivery of the fetus to delivery of the placenta. Regardless of parity, the mean duration of the third stage of labour is approximately 10 min, although up to 30 min can be allowed for delivery of the placenta in the absence of excessive bleeding.

Labour is not a passive process in which uterine contractions push a rigid object through a fixed aperture. The ability of the fetus to successfully negotiate the pelvis during delivery is dependent on the complex interaction of three critical variables: the forces generated by the uterine musculature (‘power’), the size and orientation of the fetus (‘passenger’), and the size, shape, and resistance of the bony pelvis and soft tissues of the pelvic floor (‘passage’). When labour does not progress in the appropriate time course, all of these factors must be considered. Further discussion of these factors are beyond the scope of this review, but have been addresses in detail in elsewhere (11).

The appropriate timing of delivery is a critical determinant of pregnancy outcome. The mean duration of human singleton pregnancy is 280 days (40 weeks) from the first day of the last normal menstrual period. ‘Term’ is defined as the period from 37–0/7 to 42–0/7 weeks of gestation. When labour occurs before 37–0/7 weeks, it is referred to as preterm labour. Post-term pregnancy refers to any pregnancy that continues beyond 42–0/7 weeks (294 days) from the first day of the last normal menstrual period. Both pre- birth and post-term pregnancy are associated with increased perinatal morbidity and mortality.

Preterm birth complicates 7–12% of all deliveries, but accounts for over 85% of all perinatal morbidity and mortality. Preterm labour likely represents a syndrome, rather than a diagnosis because the aetiologies are varied. Approximately 20% of preterm deliveries are iatrogenic and are performed for maternal or fetal indications, including intrauterine growth restriction (IUGR), pre-eclampsia, placenta previa, and nonreassuring fetal testing. Of the remaining cases, approximately 30% occur in the setting of preterm premature rupture of the membranes, 20–25% result from intra-amniotic inflammation and/or infection, and the remaining 25–30% are due to spontaneous (unexplained) preterm labour.

Spontaneous preterm labour may reflect a breakdown in the normal mechanisms responsible for maintaining uterine quiescence, or a short-circuiting or overwhelming of the normal parturition cascade (12). An important feature of the proposed parturition cascade would be the ability of the fetoplacental unit to trigger labour prematurely if the intrauterine environment became hostile and threatened the well-being of the fetus. Up to 25% of preterm births occur in the setting of intra-amniotic inflammation/infection (66). In many patients with infection, elevated levels of lipoxygenase and cyclo-oxygenase pathway products can be demonstrated (49). There are also increased concentrations of cytokines in the amniotic fluid of such women. Cytokines and eicosanoids appear to interact and to accelerate each other’s production in a cascade-like fashion, which may act to overwhelm the normal parturition cascade and result in preterm labour. Recently, thrombin has been shown to be a powerful uterotonic agent (67), thereby providing a physiological mechanism for preterm labour secondary to placental abruption.

Numerous risk factors for preterm birth have been identified (Table 8.2.2.3), and several tests have been developed in an attempt to predict women at risk of preterm delivery (Box 8.2.2.1). However, prevention of preterm labour has been largely unsuccessful (Box 8.2.2.2). Improvements in perinatal outcome during this same time period have resulted primarily from antepartum corticosteroid administration and from advances in neonatal care.

Guidelines for the management of preterm labour are summarized in Box 8.2.2.3. In many instances, premature labour represents a necessary escape of the fetus from a hostile intrauterine environment and, as such, aggressive intervention to stop labour may be counterproductive. Every effort should be made to exclude contraindications to expectant management and tocolysis, including, among others, intrauterine infection, unexplained vaginal bleeding, non-reassuring fetal testing, and intrauterine fetal demise. Bed rest and hydration are commonly recommended for the treatment of preterm labour, but without confirmed efficacy (68). Although there is substantial data that broad-spectrum antibiotic therapy can prolong latency in the setting of preterm premature rupture of the membranes remote from term, there is no consistent evidence that such an approach can delay delivery in women with preterm labour and intact membranes (69).

Pharmacological tocolytic therapy remains the cornerstone of management for acute preterm labour. Although a number of alternative agents are now available (Table 8.2.2.4) (12), there are no consistent or reliable data to suggest that any of these agents are able to delay delivery in women presenting with preterm labour for longer than 24–48 h. Because no single agent has a clear therapeutic advantage, the adverse effect profile of each of the drugs will often determine which to use in a given clinical setting. Maintenance tocolytic therapy beyond 24–48 h has not been shown to confer any therapeutic benefit, but does pose a substantial risk of adverse effects. As such, maintenance tocolytic therapy is not generally recommended. Similarly, the concurrent use of two or more tocolytic agents has not been shown to be more effective than a single agent alone, and the cumulative risk of adverse effects generally precludes this course of management. In the setting of preterm premature rupture of the fetal membranes, tocolysis has not been shown to be effective and is best avoided.

There is increasing evidence that progesterone supplementation may reduce the rate of preterm birth in women at high risk by virtue of a prior spontaneous (unexplained) preterm birth (70, 71) or a short cervix (72). However, not all studies have shown a benefit (73, 74) and, even in the most promising of these studies, only approximately one-third of women will benefit. As such, although this is an exciting and active area of research, progesterone supplementation is not a panacea. Further investigations are needed to confirm the effectiveness of progesterone supplementation in various high-risk populations and to understand its mechanism of action.

Post-term (prolonged) pregnancy refers to any pregnancy that has extended to or beyond 42 weeks (294 days) of gestation. Approximately 10% (range, 3–14%) of all singleton pregnancies continue beyond 42 weeks of gestation (75). Accurate pregnancy dating is critical to the diagnosis. The lowest incidence of post-term pregnancy is reported in studies using routine sonography for confirmation of gestational age.

Although the majority of post-term pregnancies have no known cause, an explanation may be found in a minority of cases. Primiparity and prior post-term pregnancy are the most common identifiable risk factors for prolongation of pregnancy. Genetic predisposition may also play a role as concordance for post-term pregnancy is higher in monozygotic twins than dizygotic twins. Women who themselves are a product of a prolonged pregnancy are at 1.3-fold increased risk of having a prolonged pregnancy, and recurrence for prolonged pregnancy is increased two- to threefold in women who previously delivered after 42 weeks (76). Rarely, post-term pregnancy may be associated with placental sulfatase deficiency or fetal anencephaly (in the absence of polyhydramnios) or CAH.

Perinatal mortality after 42 weeks of gestation is twice that at term (4–7 versus 2–3 deaths per 1000 deliveries), and is increased 4-fold at 43 weeks and five- to sevenfold at 44 weeks compared with 40 weeks (75). Uteroplacental insufficiency, asphyxia (with and without meconium), intrauterine infection, and ‘fetal dysmaturity (postmaturity) syndrome’ (which refers to chronic IUGR due to uteroplacental insufficiency) all contribute to the excess perinatal deaths. Post-term infants are larger than term infants, with a higher incidence of macrosomia. Complications associated with fetal macrosomia include prolonged labour, cephalopelvic disproportion, and shoulder dystocia with resultant risks of orthopaedic or neurological injury. Prolonged pregnancy does not appear to be associated with any long-term neurological or behavioural sequelae (77).

Post-term pregnancy is also associated with risks to the mother, including an increase in labour dystocia, an increase in severe perineal injury related to macrosomia, and a doubling in the rate of caesarean delivery (75). The latter is associated with higher risks of complications such as endometritis, haemorrhage, and thromboembolic disease.

The management of post-term pregnancy should include confirmation of gestational age, antepartum fetal surveillance, and induction of labour if spontaneous labour does not occur. Post-term pregnancy is a universally accepted indication for antenatal fetal monitoring, although the efficacy of this approach has not been validated by prospective randomized trials. No single method of antepartum fetal testing has been shown to be superior. ACOG has recommended that antepartum fetal surveillance be initiated between 41 and 42 weeks of gestation, without a specific recommendation regarding type of test or frequency (75). Many investigators would advise twice-weekly testing with some evaluation of amniotic fluid volume.

Delivery is typically recommended when the risks to the fetus by continuing the pregnancy are greater than those faced by the neonate after birth. In high-risk pregnancies, the balance appears to shift in favour of delivery at 38–39 weeks of gestation. Management of low-risk pregnancies is more controversial. Factors that need to be considered include results of antepartum fetal assessment, favourability of the cervix, gestational age, and maternal preference after discussion of the risks, benefits, and alternatives to expectant management with antepartum monitoring versus labour induction. Delivery should be affected immediately if there is evidence of fetal compromise or oligohydramnios (78).

In low-risk post-term gravida, both expectant management and labour induction are associated with low complication rates. However, the risk of unexplained intrauterine fetal demise—which, in one large series, was 1 in 926 at 40 weeks, 1 in 826 at 41 weeks, 1 in 769 at 42 weeks, and 1 in 633 at 43 weeks (79)—disappears after a fetus is delivered. Several large randomized controlled clinical trials have shown that induction of labour in low-risk pregnancy at 41 weeks of gestation is associated with a lower caesarean delivery rate, no difference in perinatal outcome, and increased patient satisfaction compared with parturients randomized to continued expectant management (80, 81). A subsequent meta-analysis of 26 trials of routine versus selective induction of labour in post-term patients found that routine induction after 41 weeks was associated with a lower rate of perinatal mortality (OR 0.20; 95% CI 0.06–0.70) and no increase in the caesarean delivery rate (78). Taken together, these data suggest that there does appear to be an advantage to routine induction of labour at 41 weeks of gestation using cervical ripening agents, when indicated, regardless of parity or method of induction. Options for cervical ripening are summarized in Table 8.2.2.5.

Labour is a physiological process by which the products of conception are passed from the uterus to the outside world. The factors responsible for the onset and maintenance of labour are not completely understood, and continue to be under active investigation. A better understanding of the mechanisms leading to the onset of labour at term will improve our ability to diagnose and manage conditions characterized by abnormal parturition, including preterm labour and birth, and post-term pregnancy.