Atosiban versus placebo for threatened preterm birth (APOSTEL 8): a multicentre, randomised controlled trial

Abstract

Background: Tocolytics are recommended in international guidelines as treatment for threatened preterm birth. Atosiban, an oxytocin receptor antagonist, is a registered tocolytic drug specifically indicated for the treatment of threatened preterm birth. Although tocolytics have been shown to delay birth, benefits on neonatal outcomes have not been demonstrated. In the APOSTEL 8 trial we aimed to assess superiority of tocolysis with atosiban compared with placebo in threatened preterm birth from 30 weeks and 0 days (30⁺⁰ weeks) to 33⁺⁶ weeks of gestation in improving neonatal morbidity and mortality.

Methods: This was an international, multicentre, randomised, double-blind, superiority trial conducted in 26 hospitals in the Netherlands, England, and Ireland. After written informed consent, women aged 18 years or older with a singleton or twin pregnancy with threatened preterm birth from 30⁺⁰ to 33⁺⁶ weeks of gestation were randomly assigned (stratified by centre, 1:1 ratio) to intravenous atosiban or placebo. The primary outcome was a composite of perinatal mortality (stillbirth and death until 28 days postpartum) and six severe neonatal morbidities. Analysis was by intention-to-treat. Treatment effect was estimated as relative risk (RR) with 95% CI. This trial was prospectively registered at EudraCT (2017-001007-72) and the Netherlands Trial Registry (NL-OMON54673), and is complete.

Findings: Between Dec 4, 2017, and July 24, 2023, a total of 755 participants were randomly assigned, of whom 752 were included in the intention-to-treat analysis (atosiban n=375, placebo n=377). The primary outcome occurred in 37 (8%) of 449 infants in the atosiban group and 40 (9%) of 435 in the placebo group (RR 0·90 [95% CI 0·58-1·40]). There were three (0·7%) and four (0·9%) infants who died, respectively (RR 0·73 [0·16-3·23]); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups, and there were no maternal deaths.

Interpretation: We did not demonstrate superiority of atosiban over placebo in improving neonatal outcomes as treatment for threatened preterm birth from 30⁺⁰ to 33⁺⁶ weeks of gestation. As the primary goal of tocolysis should be improvement of neonatal outcomes, our outcomes question the standardised use of atosiban as treatment for threatened preterm birth from 30⁺⁰ to 33⁺⁶ weeks of gestation. Our findings should reduce practice variation across countries and will contribute to evidence-based treatment for patients with threatened preterm birth.

Funding: ZonMw.