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

Abstract

STUDY QUESTION What 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, METHODS Participants 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 FINDINGS This 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

Endometrial scratch in women undergoing first-time IVF treatment: a systematic review and meta-analysis of randomized controlled trials

“…After screening, 11 RCTs were eligible for inclusion in the review. We also included the results of our recently conducted Endometrial Scratch Trial, published after the searches were undertaken, thus bringing the total to 12 RCTs (Metwally et al, 2021) published between 2010 and 2021. Details of literature search and study selection can be seen in figure 1.…”

“…Recently we have published evidence from a large definitive multicentre RCT in the United Kingdom (the Endometrial Scratch Trial) which focussed only women undergoing first IVF cycle, with or without intracytoplasmic sperm injection (ICSI) (Metwally et al, 2021). In this trial we did not find evidence for any significant benefit from the ES.…”

“…Two trials undertook ES during the IVF cycle, either on the day of egg collection (Karimzade et al, 2010), or during ovarian stimulation (Mackens et al, 2020). Ten trials undertook ES in the menstrual cycle prior to IVF, with seven within the luteal phase (Eskew et al, 2019;Izquierdo Rodriguez et al, 2020;Maged et al, 2018;Mahran et al, 2016;Metwally et al, 2021;Polanski et al, 2014;Yeung et al, 2014), and one during the early or midluteal phase (Nastri et al, 2013). Lensen et al undertook ES at any point between day three of the menstrual cycle prior to ES (Lensen et al, 2019), and day three of the cycle in which IVF was being undertaken.…”

“…Trials used different participant eligibility criteria. Ten trials had age restrictions with an upper limit of between 35 and 49 years (Eskew et al, 2019;Karimzade et al, 2010;Lensen et al, 2019;Liu et al, 2017;Mackens et al, 2020;Maged et al, 2018;Mahran et al, 2016;Metwally et al, 2021;Nastri et al, 2013;Polanski et al, 2014). Three trials restricted the body mass index (BMI) to an upper limit ranging from 30 to 35 kg/m 2 (Karimzade et al, 2010;Maged et al, 2018;Metwally et al, 2021).…”

“…Ten trials had age restrictions with an upper limit of between 35 and 49 years (Eskew et al, 2019;Karimzade et al, 2010;Lensen et al, 2019;Liu et al, 2017;Mackens et al, 2020;Maged et al, 2018;Mahran et al, 2016;Metwally et al, 2021;Nastri et al, 2013;Polanski et al, 2014). Three trials restricted the body mass index (BMI) to an upper limit ranging from 30 to 35 kg/m 2 (Karimzade et al, 2010;Maged et al, 2018;Metwally et al, 2021). Five trials selected women that were deemed to have a good ovarian reserve, by allowing only those with a certain level of follicle stimulating hormone (FSH) to participate, with a maximum level of 10 IU/mL and 12 IU/mL in two (Maged et al, 2018;Metwally et al, 2021), and three studies (Karimzade et al, 2010;Liu et al, 2017;Mahran et al, 2016), respectively.…”