The definition and impact of preterm birth
Preterm birth, defined as birth at less than 37 completed weeks of gestation1 occurs in 5–10% of all pregnancies, leading to an estimated 13 million preterm births worldwide.2 Preterm birth contributes significantly to perinatal death and long-term handicap, which can require lifelong care at considerable expense. Infants delivered preterm are susceptible to life-threatening complications, such as respiratory distress syndrome, intracranial haemorrhage, necrotising enterocolitis, infection, jaundice, hypothermia and hypoglycaemia.3
Treatment of preterm labour
The goals of managing spontaneous preterm labour are to minimise perinatal morbidity and mortality while preserving maternal health.4 Tocolysis has not been convincingly shown to improve neonatal outcome or survival. Administration of a full course of corticosteroids to aid fetal pulmonary maturation and in utero transfer to a specialist unit where the neonate can receive optimal care, are associated with improved outcome.5,6 The current main aim of tocolysis is to delay delivery long enough to achieve this, which means usually at least 48 hours.
A number of drugs have been used to treat spontaneous preterm labour, including beta-agonists. While these can prolong pregnancy for 48 hours,7 their nonspecific mode of action results in an unfavourable adverse-effect profile, particularly with respect to maternal cardiovascular events. A recent guideline published by the Royal College of Obstetricians and Gynaecologists has stated that the most commonly used beta-agonist, ritodrine, ‘no longer seems to be the best choice’, and has suggested the oxytocin receptor antagonist atosiban or calcium channel blockers (such as nifedipine) as alternatives, based on comparable efficacy and superior maternal and fetal adverse-effect profiles.8
Nifedipine, however, is unlicensed as a tocolytic and contraindicated in pregnancy. Although tested by randomised trials, most of the available data collated in meta-analyses and systematic reviews9,10 comprise smaller and often poor quality trials, which may make their conclusions invalid.11 There are no placebo-controlled trials of nifedipine and large follow-up studies on safety are lacking. A number of anecdotal reports have highlighted the occurrence of serious pulmonary and cardiovascular events following the use of nifedipine or other calcium channel blockers as tocolytics.12–17
In contrast, atosiban has been compared with placebo and beta-agonists in randomised controlled trials. Compared with placebo, significantly more women receiving atosiban remained undelivered after 48 hours without the need for additional tocolytic therapy. The levels of cardiovascular adverse events were similar between the two groups.18 Atosiban has been compared with the beta-agonists ritodrine,19 salbutamol20 and terbutaline21 in three separate double-blind studies. All three studies were of a similar design to allow the preplanned analysis of the pooled data for beta-agonists.22 These trials showed the comparable efficacy and superior safety profiles of atosiban compared with beta-agonists.19–22 In 2005, in a study of 80 women randomised to receive either atosiban or nifedipine,23 the rate of delivery at 48 hours or 7 days was not significantly different between the two treatments. Atosiban was associated with significantly fewer maternal adverse events, particularly cardiovascular adverse events.
Our results from a large, randomised, multicentre European trial to evaluate the efficacy of atosiban compared with usual care in women admitted with threatened spontaneous preterm labour and eligible to receive atosiban have been presented previously.24,25 Significantly, more women receiving atosiban remained undelivered at 48 hours with no alternative tocolytic compared with usual care (77.6 versus 56.6%; P < 0.001). The findings of this study clearly support the use of atosiban for delaying preterm birth and are consistent with previously conducted randomised controlled trials. Atosiban was associated with fewer maternal and fetal adverse events compared with other tocolytics and presented no safety concerns for either the mother or the unborn baby.24
While the indications for administration of atosiban in threatened spontaneous preterm labour can be extrapolated from clinical trials, they may not always be appropriate for guiding clinical management, since trials are designed to facilitate treatment comparison rather than to identify women who would benefit from a delay in delivery. Such difficulties reflect, at least in part, the problems in distinguishing progressive from threatened spontaneous preterm labour. In clinical practice, some women may receive atosiban, or could benefit from atosiban, prior to fulfilling the standard administration criteria. The aim of the current study was to evaluate early versus standard treatment with atosiban, i.e. according to the criteria specified in the summary of product characteristics in terms of duration/frequency of uterine contraction or status of cervical dilation/effacement. This article will present the results of this study and discuss them in light of the recent findings of the large atosiban versus usual care study.24,25