WHAT INITIATES LABOUR?

In a number of mammalian species, the onset of labour is timed primarily by the fetus via secretions of the adrenal cortex which increase oestrogen levels and subsequently PGF_2α in the uterus. PGF_2α activates

Clinical point

Prostaglandin E₂ (PGE₂), administered vaginally, may be used to ripen the cervix or for induction of labour. It is associated with lower rates of failed induction and higher rates of delivery within a reasonable interval than amniotomy and/or oxytocin. There are a wide range of doses and formulations of vaginal PGE₂, with various gels, tablets, pessaries and slow-release inserts, and currently there is no evidence for the superiority of one PGE₂ preparation over another (Keirse 2006).

Critical thinking exercise

Why is it necessary for activation of myometrial cells and ripening/softening of the cervix to occur prior to labour?

myometrial contractions and cervical ripening (Johnson 2007). In humans, it is likely that maternal as well as fetal mechanisms are involved, although the final pathway appears to involve activation of the fetal hypothalamic–pituitary–adrenal axis (Norwitz et al 1999).

Mechanisms leading to labour are mediated by changes in hormone levels. It is important to realise that hormone effectiveness is changed not only through increased synthesis and release of hormones, but also by reduction in the concentration of hormone-binding proteins or, alternatively, by increased number of receptors on target tissues. Thus the plasma concentration of a hormone may not reflect the degree of hormone binding at the local site.

It is known that increases in placental uterotonic hormones are linked to maturation of the fetal adrenal glands and the mechanical stretching of the uterus due to the growing fetus. Maternal adrenal glands and other endocrine or neural mechanisms may also play a role (Johnson 2007).

A growing number of placental hormones have been identified although their exact function in labour is not yet clear (Reis et al 2001). The roles of some of the key hormones and chemical mediators that contribute to labour, such as corticotrophin-releasing hormone (CRH), prostaglandins (PGs), oxytocin, oestrogen, progesterone, relaxin and nitric oxide (NO), are outlined below.

Research activity

Present reasons why it may or may not be appropriate to extrapolate findings from animal research about the initiation of labour to explain the process in humans.

Corticotrophin-releasing hormone

It is suggested that placental CRH plays an important role in the onset of labour (Challis 2001; Grammatopoulos 2008; Grammatopoulos & Hillhouse 1999; Torricelli et al 2007), along with maturation of the fetal hypothalamic–pituitary–adrenal system. CRH is a neuropeptide produced by the hypothalamus, placenta, decidua, chorion and amnion. CRH receptors are found in the decidua and fetal membranes and in the myometrium. The complexity of control is highlighted by the fact that CRH appears to have a dual role: during pregnancy it promotes uterine quiescence; during labour, under the influence of oxytocin, it binds to different receptor types and promotes uterine contraction (Grammatopoulos 2008).

There is strong evidence for the role of CRH in the initiation of labour. For example, placental CRH levels increase markedly after 35 weeks gestation, partly due to a 60% decrease in protein binding of the hormone, and then CRH levels decrease by 50% within 20–30 minutes of birth. Longer duration of labour has been associated with lower levels of CRH (Chrousos, cited in Blackburn 2007). Additionally, CRH levels are increased in preterm labour (Torricelli et al 2007) and in pregnancies complicated by pregnancy-induced hypertension and intrauterine growth restriction (Petraglia, cited in Grammatopoulos & Hillhouse 1999) which may lead to preterm labour.

Grammatopoulos and Hillhouse (1999) proposed that placental CRH initiates labour via mechanisms that increase production of placental oestriol (active form of oestrogen) and fetal cortisol. The pathways for this are shown in Figure 23.1. CRH stimulates the fetal adrenal gland to produce cortisol and the oestrogen precursor dehydroepiandrosterone sulfate (DHEAS). Fetal cortisol exerts positive feedback to increase placental CRH levels, and increases prostaglandin and oxytocin synthesis. DHEAS is an essential precursor to placental oestrogen synthesis, particularly oestriol, which drives other mechanisms associated with the initiation of labour. The specialised fetal adrenal cells responsible for DHEAS production atrophy after birth.

Figure 23.1 Proposed mechanism of labour induction at term

(based on Blackburn 2003)

Although cortisol appears to have a role in the initiation of labour, some evidence suggests that labour may still progress when levels of fetal cortisol are low. For example, neither fetal anencephaly, where there is an absence of adrenocorticotrophic hormone (ACTH), nor adrenal hypoplasia, where cortisol production is reduced, necessarily result in prolonged labour (Johnson 2007). Other clinical evidence indicates that although maternal corticosteroid administration results in a decrease of fetoplacental oestrogen production, it does not delay the onset of labour (Johnson 20007) as would be expected.

In summary, placental CRH behaves differently to hypothalamic CRH. Placental CRH may promote uterine quiescence during pregnancy and then enhance contractility during labour. It is suggested that, via the production of fetal cortisol and DHEAS, CRH leads to increased oestrogen production in the placenta, which drives the other mechanisms of labour such as an increase in numbers of oxytocin receptors and gap junctions and levels of prostaglandins.

Prostaglandins

Prostaglandins are lipids that are synthesised in tissues throughout the body. They are local hormones (paracrine hormones), which act at or near the place where they are synthesised. Prostaglandins are uterotonins directly responsible for uterine contraction. Two prostaglandins are particularly important in labour: PGE₂ and PGF_2α. These prostaglandins stimulate smooth muscle fibres to contract, stimulate the formation of gap junctions in myometrial tissue, and increase calcium levels in myometrial cells. As mentioned previously, prostaglandins also have a role in softening the cervix, enabling effacement and dilation (Johnson 2007; Khan et al 2008).

Levels of PGE₂ and PGF_2α in the amniotic fluid are known to increase before and during labour; however, evidence for an increase of these hormones in maternal plasma before labour begins is not conclusive (Johnson 2007).

Prostaglandin synthesis has a complex pathway, outlined in Figure 23.2. During labour, prostaglandins are synthesised by the decidua, cervix, placenta and fetal membranes. Arachidonic acid is the common precursor of both PGE₂ and PGF_2α. Arachidonic acid is produced by the action of phospholipase A2 on phospholipids in the fetal membranes and the decidua. Phospholipase A2 is stored within lysosomes, which release the enzyme in the presence of oestrogen, and retain the enzyme in the presence of progesterone. Consequently, a rise in the oestrogen-to-progesterone ratio results in increased phospholipase A2, leading to increased production of arachidonic acid and prostaglandin synthesis. Oxytocin also promotes prostaglandin release.

Figure 23.2 Biosynthesis of prostaglandins

(based on Johnson & Everitt 1988)

Other evidence that prostaglandins contribute to the initiation of labour comes from the finding that inhibitors of prostaglandin synthesis, such as the anti-inflammatory drug indomethacin, are effective at reducing preterm labour (Enkin et al 2000; Khan et al 2008).

Oxytocin

Another hormone essential for labour is oxytocin. Oxytocin is released into the systemic circulation from the posterior pituitary in response to tactile stimulation of the reproductive tract, particularly the cervix. This is known as the Ferguson reflex and is outlined in Figure 23.3. There is also a local (paracrine) release of oxytocin from the fetal membranes, decidua and placenta (Reis et al 2001). There is little evidence that oxytocin initiates or is the primary uterotonin of labour, and it can only be used clinically to induce labour if the cervix is ripe (Tenore 2003). Plasma oxytocin levels do not increase physiologically until the second stage of labour, although local concentrations may increase before this. The importance of oxytocin for labour is demonstrated by the increase of oxytocin receptors in the decidua during pregnancy, reaching a 300-fold increase by term (Zeeman, cited in Blackburn 2007; Takemura, cited in Reis et al 2001). Oxytocin binds to these decidual receptors, stimulates the release of prostaglandins from the decidua and stimulates uterine pacemakers.

Figure 23.3 The neuroendocrine reflex (Ferguson reflex), underlying oxytocin synthesis and secretion

(based on Johnson & Everitt 1988)

Oestrogen

Oestrogen has a primary role in initiating many changes that are essential for labour, and levels begin to rise at about 34 weeks gestation. Oestrogen increases the sensitivity of the myometrial oxytocin receptors during pregnancy (Blackburn 2007) and thus facilitates myometrial contractility. Oestrogen promotes the formation of CAPs and prostaglandin synthesis via increases in phospholipase A2 release from lysosomes (Johnson 2007). The synthesis of oestriol (the active oestrogen in pregnancy) relies on the fetal adrenal precursor DHEAS as outlined earlier (see Fig 23.1). Therefore, maternal serum oestriol levels are an indicator of fetal hypothalamic–pituitary–adrenal maturity and elevated levels of oestriol are associated with the onset of labour (Norwitz et al 1999).

Progesterone

Progesterone is also a pregnancy hormone and, like oestrogen, is produced in the placenta. However, in contrast to oestrogen, it is not reliant on fetal precursors for synthesis and its role is in suppressing uterine excitement. Progesterone does this by promoting the uptake of intracellular calcium into the sarcoplasmic reticulum of the myometrium, and works with nitric oxide to inhibit the production of CAPs (Challis 2001). Progesterone also has a role in decreasing oxytocin binding during pregnancy, and it is understood that removal of this effect at the onset of labour could facilitate myometrial contractions (Thornton et al 1999). Maternal plasma progesterone does not decrease at parturition, as it does in some animals (Norwitz et al 1999), but there may be local decreases in progesterone activity through increased progesterone-binding protein. The decreased availability of progesterone and increased synthesis of oestrogen produce an increased oestrogen-to-progesterone ratio, allowing the uterotonic effects of oestrogen to dominate, enabling contraction of uterine muscle.

Relaxin

Relaxin, like progesterone, supports quiescence of the uterus. Relaxin is produced by the myometrium, decidua and placenta. Its levels are highest in the first trimester, but are measurable throughout pregnancy. Relaxin has a role in enhancing cervical ripening; although exogenous application of relaxin promotes cervical ripening, the implications of clinical use of the hormone are not clear (Kelly et al 2001).

Nitric oxide

Nitric oxide (NO) is important in maintaining myometrial quiescence (Longo et al 2003). It is produced by the decidua, fetal membranes, and fetal and placental vascular epithelium. Nitric oxide is believed to interact with progesterone to inhibit the production of CAPs (Challis 2001). Levels of NO in the myometrium decrease near term but increase in the cervix. Nitric oxide production is dependent on the enzyme nitric oxide synthetase (NOS), which has three forms. There is an increase in the expression of one form, iNOS, in the cervix prior to the onset of labour, suggesting that NO contributes to cervical ripening (Ledingham et al 2000).

Critical thinking exercise

Explain why plasma levels of hormones are not necessarily representative of local changes which may initiate and maintain labour.

Research activity

Sometimes evidence from abnormal function leads us to a better understanding of the mechanisms behind normal function. Identify two examples where evidence from impaired function of fetal or maternal hormonal control at the initiation of labour has added to our knowledge of mechanisms that may contribute to the normal initiation of labour.