Atosiban in individuals with previous implantation failure undergoing frozen blastocyst transfer: a randomized controlled trial

Abstract

STUDY QUESTION Does the intravenous administration of Atosiban around the time of frozen blastocyst transfer to reduce uterine contractility increase the likelihood of live birth in individuals undergoing ART treatment? SUMMARY ANSWER In individuals with a history of one previous implantation failure, Atosiban did not significantly increase the live birth rates following frozen blastocyst transfer. WHAT IS KNOWN ALREADY Excessive uterine contraction waves during the embryo transfer procedure have been associated with decreased pregnancy rates. Atosiban, an oxytocin receptor antagonist, could reduce uterine contractions and potentially enhance implantation success in ART. However, data are inconclusive. STUDY DESIGN, SIZE, DURATION This study is a randomized, controlled, single-center, randomized, placebo-controlled clinical trial. Recruitment was from July 2019 to June 2023, with follow-up until May 2024. Participants, treating clinicians and embryologists were blinded to group assignment. Participants were randomized in a 1:1 ratio to receive intravenous Atosiban (37.5 mg) (n = 549) or placebo 30 min (n = 551) before the transfer procedure. PARTICIPANTS/MATERIALS, SETTING, METHODS Eleven hundred individuals scheduled for single frozen blastocyst transfer who had previously experienced one episode of implantation failure during ART. Uterine contractility was assessed via transvaginal ultrasound before administering the assigned intervention. The primary outcome was live birth. A pre-specified subgroup analysis was performed in individuals with and without abnormal uterine contractions. MAIN RESULTS AND THE ROLE OF CHANCE Of the 1100 randomized participants (mean age, 31 years), 1099 (99.9%) were assessed for the primary outcomes, with the exception of one participant in the placebo group who was lost to follow-up after clinical pregnancy. Live birth occurred in 272/549 (49.5%) in the Atosiban group and 246/550 (44.7%) in the placebo group (absolute difference 4.8%, 95% CI −1.1 to 10.7; risk ratio [RR] 1.11, 95% CI 0.98 to 1.26; P = 0.10). Uterine contractility was evaluated in 720 participants (65% of the total cohort). Among them, 163 participants (23%) with abnormal contractions had live birth rates of 51.9% and 39.3% in the Atosiban and placebo groups, respectively (absolute difference 12.6%, 95% CI −2.6 to 27.8; RR 1.32, 95% CI 0.94 to 1.86; P = 0.11). LIMITATIONS, REASONS FOR CAUTION The study’s findings may not be widely applicable due to its single-center design, subjective video assessments, and focus on a specific subset of individuals experiencing failed embryo implantation, potentially introducing biases and confounding factors. Additionally, the limited examination of uterine contractions in only 65% of participants and the absence of re-evaluation due to resource constraints restrict the study’s analytical power and the confirmation of Atosiban’s effectiveness. WIDER IMPLICATIONS OF THE FINDINGS Our study shows do not support the routine use of intravenous Atosiban to improve pregnancy outcomes among individuals undergoing frozen embryo transfers. STUDY FUNDING/COMPETING INTEREST(S) Science and Technology Department of Shaanxi Province, China (2022SF-564); Innovation Team of Shaanxi Provincial Health and Reproductive Medicine Research (2023TD-04); Key Industrial Chain Projects in Shaanxi Province: Research on Assisted Reproductive Technologies and Precision Prevention System for Genetic Diseases Preconception (2023-ZDLSF-48); Northwest Women’s and Children’s Hospital, Xi’an, China and Ferring Pharmaceuticals (Shanghai) Company Limited. Ferring Pharmaceuticals (Shanghai) Company Limited supplied Atosiban free of charge. All funding parties had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decisions to submit the results for publication. B.W.M. reports consultancy, travel support, and research funding from Merck and consultancy for Organon and Norgine; owning stock in ObsEva; and holding an NHMRC Investigator Grant (GNT1176437). W.L. is supported by an NHMRC Investigator grant (GNT2016729). All other authors declare no competing interests. TRIAL REGISTRATION NUMBER The RCT was registered in the Chinese Clinical Trial Registry; Study Number: ChiCTR1900022333. TRIAL REGISTRATION DATE 5 April 2019. DATE OF FIRST PATIENT’S ENROLMENT 1 July 2019.