Study protocol for a randomised trial for atosiban versus placebo in threatened preterm birth: the APOSTEL 8 study

Job Klumper, Wouter Breebaart, Carolien Roos, Christiana A Naaktgeboren, Joris van der Post, Judith Bosmans, Anton van Kaam, Ewoud Schuit, Ben W Mol, Jelle Baalman, Fionnuala McAuliffe, Jim Thornton, Marjolein Kok, Martijn A Oudijk, Job Klumper, Wouter Breebaart, Carolien Roos, Christiana A Naaktgeboren, Joris van der Post, Judith Bosmans, Anton van Kaam, Ewoud Schuit, Ben W Mol, Jelle Baalman, Fionnuala McAuliffe, Jim Thornton, Marjolein Kok, Martijn A Oudijk

Abstract

Introduction: Preterm birth complicates >15 million pregnancies annually worldwide. In many countries, women who present with signs of preterm labour are treated with tocolytics for 48 hours. Although this delays birth, it has never been shown to improve neonatal outcome. In 2015, the WHO stated that the use of tocolytics should be reconsidered and that large placebo-controlled studies to evaluate the effectiveness of tocolytics are urgently needed.

Methods and analysis: We designed an international, multicentre, randomised, double-blinded, placebo-controlled clinical trial. Women with threatened preterm birth (gestational age 30-34 weeks), defined as uterine contractions with (1) a cervical length of < 15 mm or (2) a cervical length of 15-30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) or (4) ruptured membranes, will be randomly allocated to treatment with atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Analysis will be by intention to treat. A sample size of 1514 participants (757 per group) will detect a reduction in adverse neonatal outcome from 10% to 6% (alpha 0.05, beta 0.2). A cost-effectiveness analysis will be performed from a societal perspective.

Ethics and dissemination: This study has been approved by the Research Ethics Committee (REC) of the Amsterdam University Medical Centres, location AMC, as well as the REC's in Dublin and the UK. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results.

Trial registration number: Nederlands Trial Register (Trial NL6469).

Keywords: atosiban; perinatal outcome; preterm birth; preterm labour; tocolysis.

Conflict of interest statement

Competing interests: JT received a number of lectures and medical advisory fees from Ferring pharmaceuticals between 2000 and 2016.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

References

    1. Howson CP, Kinney MV, Lawn JE, eds. Born Too Soon: The Global Action Report on Preterm Birth. Geneva: World Health Organization, 2012.
    1. Liu L, Johnson HL, Cousens S, et al. . Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. The Lancet 2012;379:2151–61. 10.1016/S0140-6736(12)60560-1
    1. Matthews TJ, Macdorman MF, Thoma ME. Infant mortality statistics from the 2013 period linked Birth/Infant death data set. Natl Vital Stat Rep 2015;64:1–30.
    1. Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990's. Early Hum Dev 1999;53:193–218. 10.1016/S0378-3782(98)00052-8
    1. Moore T, Hennessy EM, Myles J, et al. . Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies. BMJ 2012;345:e7961. 10.1136/bmj.e7961
    1. Lozano R, Naghavi M, Foreman K, et al. . Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. The Lancet 2012;380:2095–128. 10.1016/S0140-6736(12)61728-0
    1. Roberts D, Brown J, Medley N, et al. . Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;180. 10.1002/14651858.CD004454.pub3
    1. Haas DM, Imperiale TF, Kirkpatrick PR, et al. . Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009;113:585–94.
    1. Haas DM, Caldwell DM, Kirkpatrick P, et al. . Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ 2012;345:e6226. 10.1136/bmj.e6226
    1. van Vliet EOG, Nijman TAJ, Schuit E, et al. . Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. The Lancet 2016;387:2117–24. 10.1016/S0140-6736(16)00548-1
    1. de Heus R, Mol BW, Erwich J-JHM, et al. . Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study. BMJ 2009;338:b744. 10.1136/bmj.b744
    1. Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour . The worldwide atosiban versus beta-agonists Study Group. BJOG 2001;108:133–42.
    1. Flenady V, Reinebrant HE, Liley HG, et al. . Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database of Systematic Reviews 2014;30:CD004452. 10.1002/14651858.CD004452.pub3
    1. Lyndrup J, Lamont RF. The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban. Expert Opin Investig Drugs 2007;16:843–53. 10.1517/13543784.16.6.843
    1. Tita ATN, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol 2010;37:339–54. 10.1016/j.clp.2010.02.003
    1. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014;345:760–5. 10.1126/science.1251816
    1. Soll R, Özek E, Cochrane Neonatal Group . Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2010;117. 10.1002/14651858.CD001079.pub2
    1. WHO . Who recommendation on the use of tocolytic treatment for inhibiting preterm labour, 2015. Available:
    1. Walker KF, Thornton JG. Tocolysis and preterm labour. The Lancet 2016;387:2068–70. 10.1016/S0140-6736(16)00590-0
    1. van Baaren G-J, Vis JY, Wilms FF, et al. . Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor. Obstet Gynecol 2014;123:1185–92. 10.1097/AOG.0000000000000229
    1. Castor: Amsterdam, Ciwit BV the N . Castor electronic data capture 2017.
    1. van ʼt Hooft J, Duffy JMN, Daly M, et al. . A core outcome set for evaluation of interventions to prevent preterm birth. Obstet Gynecol 2016;127:49–58. 10.1097/AOG.0000000000001195
    1. Jobe AH. Bancalari E: bronchopulmonary dysplasia. Am J Respir Crit Care. Med 2001;163:1723–9.
    1. de Vries LS, Eken P, Dubowitz LMS. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992;49:1–6. 10.1016/S0166-4328(05)80189-5
    1. Ment LR, Bada HS, Barnes P, et al. . Slovis Tl: practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the practice Committee of the child Neurology Society. Neurology 2002;58:1726–38.
    1. Bell MJ, Ternberg JL, Feigin RD, et al. . Neonatal necrotizing enterocolitis. Ann Surg 1978;187:1–7. 10.1097/00000658-197801000-00001
    1. Lorthe E, Goffinet F, Marret S, et al. . Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis. Am J Obstet Gynecol 2017;217:212.e1–212.e12. 10.1016/j.ajog.2017.04.015
    1. van Winden TMS, Roos C, Nijman TAJ, et al. . Tocolysis compared with no tocolysis in women with threatened preterm birth and ruptured membranes: a propensity score analysis. Eur J Obstet Gynecol Reprod Biol 2020;255:67–73. 10.1016/j.ejogrb.2020.10.015
    1. Kahan BC. Accounting for centre-effects in multicentre trials with a binary outcome – when, why, and how? BMC Med Res Methodol 2014;14:20. 10.1186/1471-2288-14-20
    1. Gates S, Brocklehurst P. How should randomised trials including multiple pregnancies be analysed? BJOG 2004;111:213–9. 10.1111/j.1471-0528.2004.00059.x
    1. Buuren Svan, Groothuis-Oudshoorn K. Mice: multivariate imputation by Chained equations in R. J Stat Softw 2011;45:1–68.

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