Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH)

Abstract

Study question: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle?

Summary answer: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%.

What is known already: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes.

Study design, size, duration: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate.

Participants/materials, setting, methods: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%).

Main results and the role of chance: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI).

Limitations, reasons for caution: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%.

Wider implications of the findings: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials.

Study funding/competing interest(s): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work.

Trial registration number: Registered in the Netherlands Trial Register (NL5193/NTR 5342).

Trial registration date: 31 July 2015.

Date of first patient’s enrolment: 26 January 2016.

Keywords: ICSI; IVF; cumulative live birth; embryo implantation; endometrial biopsy catheter; endometrial injury; endometrial scratch; endometrium; live birth; pregnancy.

Figure 1.

Flow chart of study inclusion. IC, informed consent; ITT, intention to treat. ^aTwo participants provided IC but were accidentally registered as refuser due to misinterpretation of one of the items on the randomisation form. After discovering the unintended mistake, the randomisation was still performed. Cases were considered as protocol violations if the outcome was contrary to the misinterpreted allocation, and were analysed according to the ITT and the as-treated principle. ^bHardcopy IC was mandatory by the Institutional Review Board. Participants who were randomised based on a digital copy of the IC and failed to hand over the hardcopy IC (despite repeated attempts to retrieve this) had to be excluded from analysis.

Figure 2.

Flow chart of follow-up period. SET, single embryo transfer; DET, double embryo transfer; OPU, ovum pick-up; ET, embryo transfer. Only treatments are included of which the transfer could have resulted in an ongoing pregnancy (gestational age 10 weeks) at 12 months after randomisation. ^aScratch group: one participant was withdrawn by the local investigator because of serious intercurrent disease. Control group: four participants withdrew consent immediately after randomisation. The other participants were true lost to follow-up. ^bOther reasons for cancel OPU: Scratch group: one used wrong stimulation dose, one personal circumstances. Control group: one ovarian cyst, one intercurrent disease, one premature ovulation, two no spermatozoa, one intracavitary remnants of previous miscarriage, two patient preference. ^cData on SET or DET are missing for one participant, but it is known that she had an embryo transfer. ^dSupplementary Table SII provides cumulative information about the subsequent IVF/ICSI treatments.

Figure 3.

Time to biochemical pregnancy leading to live birth. Intention-to-treat analysis. Kaplan–Meier curve showing the time to biochemical pregnancy for the scratch (n = 467) and control (n = 466) groups. Participants who were lost to follow-up (scratch group n = 22; control group n = 22) were regarded as ‘not pregnant/no live birth’.