荷兰阿姆斯特丹大学Larissa I van der Windt团队研究了阿托西班与安慰剂治疗先兆早产的疗效与安全性。相关论文于2025年3月3日发表在《柳叶刀》杂志上。

国际指南建议使用安胎药治疗先兆早产。阿托西班是一种催产素受体拮抗剂，是一种注册的安胎药物，专门用于治疗先兆早产。尽管安胎药已被证明可以延迟分娩，但对新生儿结局的益处尚未得到证实。在APOSTEL 8试验中，研究组旨在评估在妊娠30周零天（30+0周）至33+6周的先兆早产中，与安慰剂相比，阿托西班安胎治疗在改善新生儿发病率和死亡率方面的优越性。

这项国际性、多中心、随机、双盲、优势试验在荷兰、英格兰和爱尔兰的26家医院进行。在获得书面知情同意后，18岁或以上患有单胎或双胎妊娠且在妊娠30+0至33+6周内有早产危险的女性被随机分配（按中心分层，1:1比例）静脉注射阿托西班或安慰剂。主要结局是围产期死亡率（死产和产后28天内死亡）和六种严重新生儿疾病的综合结局。按意向治疗进行分析。治疗效果估计为相对风险（RR），95%置信区间。该试验已在EudraCT（2017-001007-72）和荷兰试验注册中心（NL-OMON54673）前瞻性注册，并已完成。

在2017年12月4日至2023年7月24日期间，共有755名参与者被随机分配，其中752人被纳入意向治疗分析（阿托西班n=375，安慰剂n=377）。阿托西班组449名婴儿中有37名（8%）出现主要结局，安慰剂组435名婴儿中只有40名（9%）（RR 0.90[95%CI 0.58-1.40]）。死亡婴儿分别为3例（0.7%）和4例（0.9%）（RR 0.73[0.16-3.23]）；所有死亡都被认为不太可能与研究药物有关。两组之间的孕产妇不良事件没有差异，也没有孕产妇死亡。

研究组没有证明阿托西班在改善新生儿结局方面优于安慰剂，因为阿托西班可用于治疗妊娠30+0至33+6周的先兆早产。由于安胎治疗的主要目标应该是改善新生儿结局，该结果对在妊娠30+0至33+6周期间将阿托西班作为治疗先兆早产的标准化使用提出了质疑。该研究结果应减少各国之间的实践差异，并将有助于对先兆早产患者进行循证治疗。

附：英文原文

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

Author: Larissa I van der Windt, Job Klumper, Ruben G Duijnhoven, Marjolein Kok, Carrie Ris-Stalpers, Marjon A de Boer, Anton H van Kaam, Eva Pajkrt, Ben W Mol, Kate F Walker, Fionnuala M McAuliffe, Joris A van der Post, Carolien Roos, Martijn A Oudijk, Jelle M Schaaf, Jim van Eyck, H Marieke Knol, Marieke Sueters, Liesbeth H C J Scheepers, David P van der Ham, Judith O E H van Laar, Eline S A van den Akker, Ralph R Scholten, Nicolette van Gemund, Karlijn C Vollebregt, Harrie Visser, Sanne J Gordijn, Mireille N Bekker, Josje Langenveld

Issue&Volume: 2025-03-03

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.

DOI: 10.1016/S0140-6736(25)00295-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00295-8/abstract