Tocolysis and preterm labour 

With 15 million premature babies born worldwide every year, premature birth is the biggest problem in obstetrics.1 It is not only the most common reason that newborn babies die,1 but is also an important cause of long-term brain, bowel, lung, and eye damage. Antenatal steroids reduce the risk of lung disease, intracranial bleeding, and death2 and magnesium sulphate reduces cerebral palsy.3 Obstetricians often also prescribe uterine relaxant, or tocolytic, drugs to delay birth, albeit without much evidence to support this practice. Current policy4,5 is generally to limit tocolysis to 48 h to gain the maximum benefit from steroids and allow in-utero transfer to a suitable intensive-care facility. But which tocolytic should be used?

Five drug groups have been tried. β adrenoceptor agonists and cyclooxygenase inhibitors have been all but abandoned due to side-effects and magnesium sulphate, although neuroprotective, is an ineffective tocolytic.6 Only calcium-channel blockers, of which nifedipine is the most widely studied, and the oxytocin antagonist atosiban remain in widespread use. Three direct comparison trials have been done but were small7–9 and two were unregistered.7,8 Efforts to compare the two drugs by indirect10 or network meta-analyses11 have been unconvincing because of the variable methodological quality of the component trials. Nevertheless, most international guidelines (apart from those in the USA where atosiban is unavailable) currently recommend one of these drugs as first-line tocolytic drugs.4,5

In The Lancet, Elvira van Vliet and colleagues12 present findings from APOSTEL III, a large, multicentre, randomised trial to compare perinatal outcomes after 48 h of tocolysis with nifedipine versus atosiban in 510 women with threatened preterm birth (25–34 weeks of gestation). 254 women were randomly assigned to oral nifedipine and 256 women to intravenous atosiban, with the primary outcome a composite endpoint of in-hospital perinatal mortality and bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. This outcome occurred in 42 (14%) of 297 neonates born in the nifedipine group and in 45 (15%) of 294 neonates born in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61–1·37). No individual components of the primary outcome differed by treatment group. 16 (5%) neonates died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91–5·33). The only possibly significant interaction between prespecified subgroups was one between membrane rupture and prolongation of pregnancy, with time to delivery longer with nifedipine than atosiban in women without ruptured membranes (median time to delivery 24 days [IQR 4·0–54·8] in nifedipine group vs 14 days [2·0–51·5] in atosiban group; p_interaction=0·0412).

Despite the findings of APOSTEL III, there are drug differences. Atosiban is licensed in the European Union for threatened preterm birth, administered intravenously, and costs £70 for 48 h treatment. Oral nifedipine is licensed only as an antihypertensive drug and therefore used off-label and costs £1·30. In the USA whereatosibanremainsunlicensedforpretermbirthand any other indication and therefore unavailable even off- label,andincountrieswheremoneyistight,nifedipine is likely to be the drug of choice. In other countries, doctors might be nervous to use an unlicensed agent and therefore prefer to use atosiban. However, cost and licensing status are not the most important issue.

Although the primary composite outcome reported by van Vliet was prespecified, and the overall result unbiased, some components matter more than others. Perinatal mortality is worse than, say, culture-proven sepsis. More importantly, some components go in opposite directions—for example, the 16 deaths in the 

nifedipine group versus seven in the atosiban group, and the 11 cases of bronchopulmonary dysplasia in the nifedipine group versus 21 in the atosiban group.12 All deaths were judged by a panel of experts to be unlikely to be related to the study drug. But, as the authors note, other studies have reported fetal death after nifedipine13 and a large cohort study in the Netherlands observed more maternal adverse events (mainly hypotension and tachycardia) with nifedipine than with atosiban.14 The differences reported could be chance, so for now van Vliet and colleagues’ conclusion that both drugs are reasonable treatment options is correct. But much larger comparative trials will be needed to establish whether perhaps atosiban reduces mortality at the expense of increasing lung disease. Or will they?

The elephant in the room is that that no trial has ever convincingly shown a tocolytic drug to reduce any important adverse outcomes as compared with placebo or no treatment. Randomised trial evidence is vital, not least because there is no completely accurate diagnostic test for preterm birth, and so many patients in suspected preterm labour will not deliver early, irrespective of treatment. Older trials of tocolysis might have had negative results because they were too small or because they failed to exclude participants with underlying fetal compromise such that prolonging pregnancy did more harm than good. Future trials need to recruit only women with healthy fetuses, and if they are also to rule out the possibility that tocolysis results only in the births of severely ill babies who would otherwise have died, need to be much larger even than the one by van Vliet and colleagues—large enough to measure the effect on perinatal death and on clinically significant morbidity, separately.

With the differing licensing status of the drugs in the two continents, perhaps North American obstetricians should run a large nifedipine versus placebo trial and European obstetricians run an atosiban versus placebo one. Given the global burden of preterm birth, both are long overdue.

Kate F Walker, *Jim G Thornton

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK (KFW, JGT); and Department of Obstetrics and Gynaecology, Chesterfield Royal Hospital NHS Foundation Trust, Chesterfield, UK (KFW)

KFW declares no competing interests. JGT reports lecture fees and travel expenses from Ferring Pharmaceuticals. 

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11. Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ.
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12. van Vliet EOG, Nijman TAJ, Schuit E, et al. Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. Lancet 2016; published online March 1. http://dx.doi. org/10.1016/S0140-6736(16)00548-1.

13. van Veen AJ, Pelinck MJ, van Pampus MG, Erwich JJ. Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG 2005; 112: 509–10.
    

14. de Heus R, Mulder EJ, Derks JB, Visser GH. The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow. J Matern Fetal Neonatal Med 2009; 22: 485–90.