A randomised controlled trial to assess the clinical effectiveness and safety of the endometrial scratch procedure prior to first-time IVF, with or without ICSI.

study questionWhat is the clinical-effectiveness and safety of the endometrial scratch (ES) procedure compared to no ES, prior to usual first time in vitro fertilisation (IVF) treatment? SUMMARY ANSWER: ES was safe but did not improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF cycle, with or without intracytoplasmic sperm injection (ICSI). WHAT IS KNOWN ALREADY: ES is an 'add-on' treatment that is available to women undergoing a first cycle of IVF, with or without ICSI, despite a lack of evidence to support its use. STUDY DESIGN, SIZE, DURATION: This pragmatic, superiority, open-label, multi-centre, parallel-group randomised controlled trial involving 1048 women assessed the clinical effectiveness and safety of the ES procedure prior to first time IVF, with or without ICSI, between July 2016 and October 2019. PARTICIPANTS/MATERIALS, SETTING,

methodsParticipants aged 18-37 years undergoing their first cycle of IVF, with or without ICSI, were recruited from 16 UK fertility clinics and randomised (1:1) by a web-based system with restricted access rights that concealed allocation. Stratified block randomisation was used to allocate participants to TAU or ES in the mid-luteal phase followed by usual IVF with or without ICSI treatment. The primary outcome was live birth after completing 24 weeks gestation within 10.5 months of egg collection. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1048 women randomised to TAU (n = 525) and ES (n = 523) were available for intention to treat analysis. In the ES group, 453 (86.6%) received the ES procedure. IVF, with or without ICSI, was received in 494 (94.1%) and 497 (95.0%) of ES and TAU participants respectively. Live birth rate was 37.1% (195/525) in the TAU and 38.6% (202/523) in the ES: an unadjusted absolute difference of 1.5% (95% CI -4.4% to 7.4%, P = 0.621). There were no statistical differences in secondary outcomes. Adverse events were comparable across groups. LIMITATIONS, REASONS FOR CAUTION: A sham ES procedure was not undertaken in the control group, however, we do not believe this would have influenced the results as objective fertility outcomes were used. WIDER IMPLICATIONS OF THE

findingsThis is the largest trial that is adequately powered to assess the impact of ES on women undergoing their first cycle of IVF. ES was safe, but did not significantly improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF or ICSI cycle. We recommend that ES is not undertaken in this population. STUDY FUNDING/COMPETING INTEREST(S): Funded by the National Institute of Health Research. Stephen Walters is an National Institute for Health Research (NIHR) Senior Investigator (2018 to present) and was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2011-2017), NIHR HTA Commissioning Strategy Group (2012 to 2017); NIHR Programme Grants for Applied Research Committee (2020 to present); NIHR Pre doctoral Fellowship Committee (2019 to present). Dr. Martins da Silva reports grants from AstraZeneca, during the conduct of the study; and is Associate editor of Human Reproduction and Editorial Board member of Reproduction and Fertility. Dr. Bhide reports grants from Bart's Charity and grants and non-financial support from Pharmasure Pharmaceuticals outside the submitted work. TRIAL REGISTRATION NUMBER: ISRCTN number: ISRCTN23800982. TRIAL REGISTRATION DATE: 31 May 2016. DATE OF FIRST PATIENT’S ENROLMENT: 04 July 2016.