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Evidence summaries

Oxytocin Receptor Antagonists for Inhibiting Preterm Labour

Oxytocin receptor antagonists (atosiban) are effective for inhibiting preterm labour compared with placebo or no treatment. They appear to be as effective as calcium channel blockers (nifedipine) but with higher costs. Level of evidence: "A"

A Cochrane review [Abstract] 1 included 14 studies with a total of 2 485 women.

Compared with placebo, atosiban (oxytocin receptor antagonist) did not reduce incidence of preterm birth (birth less than 48 hours after trial entry: average RR 1.05, 95% CI 0.15 to 7.43; random-effects, 2 studies, n=152) or improve neonatal outcome. However, the confidence intervals were wide. In one trial (583 infants), atosiban was associated with an increase in infant deaths at 12 months of age compared with placebo (relative risk (RR) 6.15; 95% confidence intervals (CI) 1.39 to 27.22). However, this trial randomised significantly more women to atosiban before 26 weeks' gestation. Use of atosiban resulted in lower infant birthweight (weighted mean difference -138.31 gm; 95% CI -248.76 to -27.86) and more maternal adverse drug reactions (RR 4.02; 95% CI 2.05 to 7.85, 2 trials, 613 women).

Comparing atosiban with nifedipine, no difference was shown in birth less than 48 hours after trial entry (average RR 1.09, 95% CI 0.44 to 2.73, random-effects; 2 studies, n=225). Atosiban resulted in less maternal adverse effects requiring cessation of treatment (RR 0.38, 95% CI 0.21 to 0.68; NNTB 6, 95% CI 5 to 12; 2 studies, n=225).

Comparing atosiban with betamimetics, no statistically significant difference was shown in birth less than 48 hours after trial entry (RR 0.89, 95% CI 0.66 to 1.22; 8 studies, n=1389) or perinatal mortality (RR 0.55, 95% CI 0.21 to 1.48; 3 studies, 816 infants), or major neonatal morbidity. Atosiban resulted in less maternal adverse effects requiring cessation of treatment (RR 0.05, 95% CI 0.02 to 0.11; NNTB 6, 95% CI 6 to 6; 5 studies, n=1161).

A meta-analysis 2 included 7 studies with 992 patients comparing atosiban witt nifedipine. There was no significant difference between atosiban and nifedipine for pregnancy prolongation of 48 hours or more regarding efficacy (RR 1.06, 95% CI 0.92 to 1.22; P=0.440) or effectiveness (0.93, 0.84 to 1.03; P=0.177). Pregnancy prolongation for 7 days or more also did not differ between groups for efficacy (RR 1.04, 95% CI 0.89 to1.21; P=0.656) or effectiveness (0.91, 0.79 to 1.05; P=0.177). Atosiban was associated with fewer maternal side-effects than nifedipine.

A multicentre, randomised controlled trial 4 (the APOSTEL III study) included 500 women with threatened preterm birth (gestational age 25-34 weeks). The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. There was no difference in primary outcome (RR 0.91, 95% CI 0.61 to 1.37). 16 (5%) babies died in the nifedipine group and 7 (2%) died in the atosiban group (RR 2.20, 95% CI 0.91 to 5.33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups.

An economic analysis 3 alongside the APOSTEL III study showed the mean costs per patients were significantly lower in the nifedipine vs atosiban group: singleton pregnancies: €34,897 vs €43,376, mean difference (MD) -€8479, 95% CI -€14,327 to -€2016); multiple pregnancies: €90,248 vs €102,292, MD -€12,044, 95% CI -€21,607 to € -1671. There was a non-significantly higher death rate in the nifedipine group. The difference in costs was mainly driven by a lower neonatal intensive care unit admission (NICU) rate in the nifedipine group.

A Cochrane network meta-analysis [Abstract]5assessing different tocolytic drugs included 122 trials with a total of 13 697 women (table T1). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics.

Delay in birth by 48 hours with different tocolytics compared with placebo or no treatment

OutcomeNetwork evidenceAnticipated absolute effects for network estimate
RR (95% CI) CertaintyRisk with placebo or no treatmentRisk with tocolytic agentRisk difference with tocolytic agent
Betamimetics1.12(1.05 to 1.20) Low645 per 1000722 per 100077 more per 1000(from 32 to 129 more)
Calcium channel blockers1.16(1.07 to 1.24)Low645 per 1000748 per 1000103 per 1000(from 45 to 155 more)
Magnesium sulphate1.12(1.02 to 1.23) Moderate645 per 1000722 per 100077 more per 1000(from 13 to 148 more)
Oxytocin receptor antagonists1.13(1.05 to 1.22) Moderate645 per 1000729 per 100084 more per 1000(from 32 to 142 more)
Nitric oxide donors1.17(1.05 to 1.31) Moderate645 per 1000755 per 1000110 per 1000(from 32 to 200 more)

The following decision support rules contain links to this evidence summary:

    References

    • :Flenady V, Reinebrant HE, Liley HG et al. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2014;(6):CD004452. [PubMed]
    • Ali AA, Sayed AK, El Sherif L et al. Systematic review and meta-analysis of randomized controlled trials of atosiban versus nifedipine for inhibition of preterm labor. Int J Gynaecol Obstet 2019;145(2):139-148. [PubMed]
    • Nijman T, van Baaren GJ, van Vliet E et al. Cost effectiveness of nifedipine compared with atosiban in the treatment of threatened preterm birth (APOSTEL III trial). BJOG 2019;126(7):875-883. [PubMed]
    • 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;387(10033):2117-2124. [PubMed]
    • Wilson A, Hodgetts-Morton VA, Marson EJ et al. Tocolytics for delaying preterm birth: a network meta-analysis (0924). Cochrane Database Syst Rev 2022;(8):CD014978.[PubMed]

Primary/Secondary Keywords