Emerging tocolytics for maintenance therapy of preterm labour: oxytocin antagonists and calcium channel blockers
Prof A Kim, Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-dong Songpa-gu, Seoul 138-736, Korea. Email firstname.lastname@example.org
The incidence of spontaneous preterm labour and preterm birth has increased, and its management worldwide remains suboptimal. While considerable debate remains as to whether long-term maintenance tocolysis is appropriate after an episode of spontaneous preterm labour, many practitioners support its use. Several drugs have been used for maintenance tocolysis, but they differ in terms of safety and efficacy. Atosiban and nifedipine are preferable for maintenance tocolysis, as they have been shown to be as effective as ritodrine while being associated with fewer adverse effects. Nifedipine is not licensed for use as a tocolytic. An ideal tocolytic should be utero specific, with few fetomaternal and fetal adverse effects, and should significantly improve perinatal outcome. To warrant the use of maintenance therapy, larger trials in women at particular gestational age ranges may be needed, in which the primary endpoints are perinatal outcomes. The inclusion of cost-effectiveness analyses would also be of benefit.
Spontaneous preterm labour and preterm birth remains the most common risk factor for perinatal morbidity and mortality. Its incidence has not decreased, and its management worldwide remains inadequate. The most common method used to manage spontaneous preterm labour has been pharmacological inhibition of preterm uterine contractions. A number of tocolytic agents have been used, including beta-agonists, calcium channel antagonists, magnesium sulphate and oxytocin receptor antagonists, but they are not equally effective or safe.
While acute intravenous tocolytic therapy is effective in reducing birth within 48 hours, most clinical trials have found no evidence of an associated decrease in the likelihood of preterm birth and perinatal morbidity.1,2 Despite their widespread use, there is limited evidence to show that these drugs are safe for the mother and her fetus. In their clinical guideline on spontaneous preterm labour, the Royal College of Obstetricians and Gynaecologists (RCOG) states that it is reasonable not to use tocolytics because there is little clear evidence that they improve perinatal outcome.3 They fail to record that no study of sufficient sample size has ever been conducted to show such an effect. The guideline also states that tocolysis should be considered if a delay of labour for a few days will allow completion of a course of corticosteroids or facilitate in utero transfer. If a tocolytic is used, the RCOG has recommended that ritodrine no longer be considered the drug of first choice. Rather, atosiban and nifedipine should be used since their effectiveness has been shown to be comparable with that of ritodrine, but they have been associated with a lower risk of adverse effects.3
Women who experience episodes of spontaneous preterm labour, but who remain undelivered after acute tocolysis, are at risk of subsequent episodes of spontaneous preterm labour and may require rehospitalisation and preterm delivery. Randomised trials have found that overall recurrence rates after treatment of spontaneous preterm labour were 174 and 21%,5 regardless of tocolytic drugs.
Although there is no consensus as to whether long-term maintenance tocolysis is appropriate after an episode of spontaneous preterm labour, many practitioners support its use. A recent survey by the Society for Maternal–Fetal Medicine6 found that 41% of respondents would use maintenance tocolysis in a woman with arrested preterm labour at 31 + 2 weeks of gestation. A similar survey in Australia and New Zealand7 showed a wide range of opinions and uncertainty over the gestational age at which to start and discontinue tocolytic therapy, the most appropriate drug and the use of maintenance tocolytic therapy.
Well-designed, randomised controlled trials have tested several drugs for maintenance tocolysis, but their benefit is not altogether clear. In a review of the current evidence for the effectiveness of maintenance tocolysis, beta-agonists and magnesium sulphate were found ineffective in prolonging gestation or reducing adverse fetal outcomes.8 In contrast, conclusions could not be drawn about nifedipine and atosiban because of a lack of published data.8
Emerging tocolytics for maintenance therapy
Oxytocin antagonists (atosiban)
Atosiban has been shown to completely inhibit the uterotonic action of oxytocin in a competitive and dose-dependent manner,9 and to downregulate oxytocin receptors.10 In both pregnant and nonpregnant women, the elimination of atosiban is characterised by a rapid initial phase with a short half-life (18 ± 3 minutes).11 Reported adverse effects of atosiban are headache, nausea, vomiting and dizziness. In a trial of atosiban and various beta-agonists in the treatment of spontaneous preterm labour, atosiban was found to be superior with respect to safety and as effective as the beta-agonists.5
In a well-designed trial,12 maintenance therapy with atosiban achieved a significant gestational prolongation. A continuous infusion of atosiban (30 mg/minute) was more effective than placebo for maintenance therapy in women who achieved successful tocolysis initially with atosiban. As with other studies, this trial did not assess the effects on perinatal outcomes.
Atosiban has some limitations for maintenance tocolysis. Maintenance tocolysis with atosiban was effective in women who initially responded to this drug in acute preterm labour, and not to other tocolytic drugs.12 In addition, atosiban is a relatively expensive tocolytic drug, which may preclude its widespread use in developing countries and could restrict its use to haemodynamically high-risk patients. Furthermore, although one trial of atosiban followed up children for 6–12 months,13 there is limited information to date about the safety of atosiban for fetuses and newborns due to a lack of long-term follow up. Finally, atosiban was designed only for parenteral use.
A new generation of oxytocin antagonists is currently being investigated in Europe for use as tocolytic agents.14–16 Among these, barusiban has been found to have a higher selectivity and a higher potency compared with previous oxytocin antagonists, with a faster onset and longer duration of action following parenteral administration. This agent is currently undergoing phase II trials in Europe.
Calcium channel blockers (nifedipine)
To date, nifedipine has been used in the majority of clinical trials, evaluating the use of calcium channel blockers for the management of spontaneous preterm labour. Nifedipine has been shown to act by reducing the intracellular influx of calcium, which inhibits contractile activity in the nonpregnant, pregnant and postpartum myometrium. Maternal adverse effects predominantly result from the vasodilatory effects and include dizziness, hypotension, headache, flushing and oedema. A recent systematic review reported that nifedipine was more effective than beta-agonists in prolonging pregnancy, was much less likely to cause maternal adverse effects, and was associated with reduced neonatal morbidity.17 In this review, a clinical protocol for the administration of nifedipine in maintenance tocolysis was suggested.
We found only two randomised studies of nifedipine maintenance therapy. In one,18 a positive correlation between nifedipine and expectancy was not found, whereas the second19 found significant differences in gestational age, and time gained from initiation of maintenance therapy to delivery when nifedipine was administered at a dose of 20 mg every 6 hours, following acute intravenous tocolysis with ritodrine and verapamil. No decrease was observed in the recurrence of spontaneous preterm labour or improvements in perinatal outcomes.
The benefits of nifedipine over other tocolytics for maintenance therapy include its oral route of administration and relatively low cost. In comparing the long-term psychosocial and motor effects on children exposed to nifedipine or ritodrine in utero for the management of spontaneous preterm labour, the nifedipine group had long-term psychosocial and motor functioning equal to that of normal controls.20
The use of nifedipine for maintenance tocolysis has limitations since it readily crosses the placenta, and its maternal and fetal serum concentrations are comparable.21 There is a risk of adverse effects on fetal or placental circulation following nifedipine exposure. In addition, nifedipine has not been licensed for use in pregnancy or for the treatment of spontaneous preterm labour. It is unlikely that its manufacturers will attempt to have it licensed for these indications, making any adverse effects the responsibility of the prescribing clinicians.22 Finally, since nifedipine may have adverse effects on the cardiovascular system, it should be avoided in women with apparent or possible cardiovascular problems, including those with multiple pregnancies.
An ideal tocolytic should be utero specific, with few fetomaternal adverse effects and should significantly improve perinatal outcomes. In evaluating the efficacy of maintenance tocolysis, several specific aspects must be considered. First, most fetuses may be too advanced in gestational age for maintenance tocolysis to have a significant effect on perinatal outcomes. Consequently, maintenance therapy may only be beneficial for women with fetuses of lower gestational ages. Secondly, clinical trials of tocolytic drugs have not used improved perinatal outcomes as the primary efficacy endpoint. Consequently, the number of women enrolled in these trials was not high enough to detect significant drug-related differences in perinatal outcome.
To warrant the use of maintenance tocolytic therapy, larger trials are needed, using women with fetuses at particular gestational age ranges, and in which the primary endpoints are perinatal outcomes. These trials should also include formal cost-effectiveness analyses.