Antenatal corticosteroids reduce the burden of prematurity

Twenty‐one studies including data on over 4200 babies were included in the recently updated Cochrane systematic review assessing antenatal administration of corticosteroids (Roberts 2006): 24 mg of betamethasone or dexamethasone administered to women expected to give birth preterm was associated with a significant reduction in mortality (relative risk (RR) 0.69, 95% confidence interval (CI) 0.58 to 0.81), respiratory distress syndrome (RR 0.66, 95% CI 0.59 to 0.73) and cerebroventricular haemorrhage (RR 0.54, 95% CI 0.43 to 0.69) and other relevant neonatal outcomes. Data derived from the randomised trials of postnatal surfactant therapy indicate that the benefits of postnatal surfactant are enhanced by antenatal corticosteroid administration (Jobe 1994). Furthermore, treatment with antenatal corticosteroids was associated with less developmental delay in childhood (RR 0.49, 95% CI 0.24 to 1.00) and a trend towards a decrease in cerebral palsy at two to six years of age (RR 0.60; 95% CI 0.34 to 1.03) (Roberts 2006). The cost and duration of neonatal care was also reduced in the corticosteroids groups (RCOG 2004). The international data continue to support unequivocally the use and efficacy of a single course of antenatal corticosteroids using the dosage and interval of administration specified in the NIH 1994 Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes report (NICHHD 1994).

A Cochrane systematic review that assesses the effectiveness and safety of a repeat dose(s) of prenatal corticosteroids, given to women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids (Crowther 2000), showed that fewer infants in the repeat dose(s) of corticosteroids group had severe lung disease compared with infants in the placebo group (RR 0.64, 95% CI 0.44 to 0.93; one trial, 500 infants). This evidence is supported by a recently published randomised controlled trial including 982 women (Crowther 2006), which shows that fewer babies exposed to repeat corticosteroids had respiratory distress syndrome (RR 0.82, 95% CI 0.71 to 0.95), severe lung disease (RR 0.60, 95% CI 0.46 to 0.79), needed less oxygen therapy, and had shorter duration of mechanical ventilation than those in the placebo group. However, the current data on long‐term outcomes are insufficient to assert whether this intervention is related to benefits and risks that continue into childhood and beyond and, therefore, further assessment should be considered to incorporate routine use of repeat course(s) of antenatal corticosteroids in clinical practice (Crowther 2000; Crowther 2006; NIH 2000).

Tocolytic therapy

Tocolytic agents include a wide range of drugs that can inhibit labour, slow down or suppress the contractions of the uterus. In situations where clinical considerations make it desirable to install tocolytic treatment to prolong pregnancy, the primary outcome considered is time gained allowing (a) the fetus to mature more before being born; (b) enhance lung maturation by antenatal corticosteroid administration; and (c) time for in‐uterus transfer to a tertiary care centre with neonatal intensive care facilities (Anotayanonth 2004; NHMRC 2000). The overall goal is to either avoid preterm birth where appropriate or to minimise its effects and ensure that babies are born in the best conditions possible with reduced morbidity and mortality of the neonate, reduced morbidity in the mother and improved long‐term family outcomes (ONS 2005). A variety of tocolytic treatments have been used to inhibit uterine activity in women in preterm labour. Agents used include beta‐adrenergic receptor agonists (betamimetics), prostaglandin inhibitors, calcium channel blockers, oxytocin receptor antagonists and magnesium sulphate (Anotayanonth 2004; Crowther 1998; Crowther 2002; Duckitt 2002; Gaunekar 2004; King 2003; King 2005; Papatsonis 2005). The ideal tocolytic agent should be easy to administer, inexpensive, without significant maternal, fetal or neonatal side‐effects, and effective at delaying preterm birth, at least long enough to permit the use of prenatal corticosteroids (Crowther 2002). There is considerable variation in the type of tocolytic agent used in different parts of the world.

Although there is evidence that some of these groups of tocolytic agents could decrease the number of women in preterm labour giving birth within 48 hours when compared to placebo and, therefore, increase the chances of receiving a full course of antenatal corticosteroids with a safe margin of at least 24 hours before birth, the percentage of side‐effects and withdrawals from treatment, and the lack of benefits observed for other long‐term outcomes and more robust short‐term neonatal outcomes, leads to the decision to use tocolytic therapy for inhibiting preterm birth to be based on an imprecise balance between risks and benefits. Some factors relevant in determining the likelihood of adverse effects with commonly used tocolytics are (i) mechanism of drug action; (ii) target tissues; (iii) dosage and route of administration; (iv) pharmacokinetics and pharmacodynamics.

Tocolytic agents that affect contractile proteins

The tocolytics currently in use affect myometrial contractility by one of two major pathways: they affect either the contractile proteins (usually the phosphorylation of myosin) by generation or alteration of an intracellular messenger or they inhibit the synthesis of, or block the action of, a known myometrial stimulant. The first group is represented by the betamimetics, nitric oxide donors, magnesium sulphate and the calcium channel blockers. The betamimetics (ritodrine, isoxsuprine, terbutaline, salbutamol, hexoprenaline and orciprenaline), by binding with cell membrane beta‐adrenergic receptors, lead to an increase in intracellular cyclic adenosine monophosphate that inhibits the ability of myosin light chain kinase to phosphorylate myosin. Nitric oxide donors produce a similar response through cyclic guanosine monophosphate. Magnesium sulphate and calcium channel blockers (nifedipine, nicardipine, verapamil, diltiazem) lower intracellular calcium by preventing an influx of calcium ions, thereby reducing the activity of myosin light chain kinase and inhibiting the phosphorylation of myosin (Caritis 2005).

Tocolytic agents that block the action of myometrial stimulants

Oxytocin and prostaglandins are the major endogenous myometrial stimulants. Atosiban is an oxytocin receptor antagonist. It binds to the receptor in the myometrium and other gestational tissues, thus, preventing the oxytocin‐induced increase in inositol triphosphate, the messenger that increases intracellular calcium and causes myometrial contractions and up‐regulates prostaglandin production. Prostaglandins are produced in the myometrium and other gestational tissues. Agents such as indomethacin inhibit the cyclo‐oxygenase (COX) enzymes, which are key to the production of these prostaglandins. General inhibitors of both the COX‐1 (constitutive) and COX‐2 (inducible) enzymes include indomethacin and sulindac. Selective COX‐2 inhibitors include agents such as nimesulide and rofecoxib (Caritis 2005).

In vitro studies have demonstrated that simultaneous blockage of these different pathways could result in an additive or even synergistic effect capable of potentiating the uterine relaxation induced by each single drug and, most importantly, allow a reduction of the therapeutic concentration needed for each single drug (Doret 2003). However, it is unlikely that additional effects or synergy of effects could take place in other tissues if, for instance, a specific oxytocin receptor antagonist, only active on breast myoepithelial cells outside the uterus, is combined with any other group of tocolytic agents (Goodwin 1996; Goodwin 1998). Based on these assumptions, a combination of agents of two of these different groups could be used to improve myometrial effects without an increment in maternal or neonatal side‐effects, or both, or to reduce the dosage and time of administration of one or more of them, thereby leading to a decrease in maternal and fetal side‐effects without decreasing the tocolytic effect magnitude. Pathological effects, though, might also occur as a result of non‐physiological effects in various tissues. Examples of non‐specific effects include the nausea associated with atosiban or perhaps magnesium sulphate, and the oedema noted with calcium channel blocker usage. Pulmonary oedema associated with tocolytic therapy has been reported with beta‐agonists, magnesium sulphate and the calcium channel blockers.