Follicular-phase endometrial scratching: a truncated randomized controlled trial

Abstract

STUDY QUESTION Does intentional endometrial injury (scratching) during the follicular phase of ovarian stimulation (OS) increase the clinical pregnancy rate (CPR) in ART? SUMMARY ANSWER CPR did not vary between the endometrial injury and the control group, but the trial was underpowered due to early termination because of a higher clinical miscarriage rate observed in the endometrial injury arm after a prespecified interim analysis. WHAT IS KNOWN ALREADY Intentional endometrial injury has been put forward as an inexpensive clinical tool capable of enhancing endometrial receptivity. However, despite its widespread use, the benefit of endometrial scratching remains controversial, with several recent randomized controlled trials (RCTs) being unable to confirm its added value. So far, most research has focused on endometrial scratching during the luteal phase of the cycle preceding the one with embryo transfer (ET), while only a few studies investigated in-cycle injury during the follicular phase of OS. Also, the persistence of a scratch effect in subsequent treatment cycles remains unclear and possible harms have been insufficiently studied. STUDY DESIGN, SIZE, DURATION This RCT was performed in a tertiary hospital setting between 3 April 2014 and 8 October 2017. A total of 200 women (100 per study arm) undergoing IVF/ICSI in a GnRH antagonist suppressed cycle followed by fresh ET were included. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were randomized with a 1:1 allocation ratio to either undergo a pipelle endometrial biopsy between Days 6 and 8 of OS or to be in the control group. The primary outcome was CPR. Secondary outcomes included biochemical pregnancy rate, live birth rate (LBR), early pregnancy loss (biochemical pregnancy losses and clinical miscarriages), excessive procedure pain/bleeding and cumulative reproductive outcomes within 6 months of the study cycle. MAIN RESULTS AND THE ROLE OF CHANCE The RCT was stopped prematurely by the trial team after the second prespecified interim analysis raised safety concerns, namely a higher clinical miscarriage rate in the intervention group. The intention-to-treat CPR was similar between the biopsy and the control arm (respectively, 44 versus 40%, P = 0.61, risk difference = 3.6 with 95% confidence interval = −10.1;17.3), as was the LBR (respectively, 32 versus 36%, P = 0.52). The incidence of a biochemical pregnancy loss was comparable between both groups (10% in the intervention group versus 15% in the control, P = 0.49), but clinical miscarriages occurred significantly more frequent in the biopsy group (25% versus 8%, P = 0.032). In the intervention group, 3% of the patients experienced excessive procedure pain and 5% bleeding. The cumulative LBR taking into account all conceptions (spontaneous or following ART) within 6 months of randomization was not significantly different between the biopsy and the control group (54% versus 60%, respectively, P = 0.43). LIMITATIONS, REASONS FOR CAUTION The trial was stopped prematurely due to safety concerns after the inclusion of 200 of the required 360 patients. Not reaching the predefined sample size implies that definite conclusions on the outcome parameters cannot be drawn. Furthermore, the pragmatic design of the study may have limited the detection of specific subgroups of women who may benefit from endometrial scratching. WIDER IMPLICATIONS OF THE FINDINGS Intentional endometrial injury during the follicular phase of OS warrants further attention in future research, as it may be harmful. These findings should be taken in consideration together with the growing evidence from other RCTs that scratching may not be beneficial. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by ‘Fonds Wetenschappelijk Onderzoek’ (FWO, Flanders, Belgium, 11M9415N, 1524417N). None of the authors have a conflict of interest to declare with regard to this study.

Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis

“…www.nature.com/scientificreports/ A recent RCT showed a potentially harmful effect of the endometrial biopsy performed in the follicular phase. In fact, authors reported a higher incidence of clinical miscarriages in the context of in-cycle scratching, which led to the study premature halt 174 . This considered, we conducted a sub-analysis on the basis of endometrial injury timing without however observing the superiority of one strategy over the others.…”

Approaches to Improve Endometrial Receptivity in Case of Repeated Implantation Failures

“…The evidence produced from this study (Lensen et al, 2019a), has initiated a long series of debates in terms of the endometrial injury application, along with the ethical dilemma of offering a procedure proven as useless or even possibly harmful (Yeung et al, 2014;Frantz et al, 2019;Lensen et al, 2019b;Mackens et al, 2020). This is especially important in case of selected groups receiving assisted reproduction treatments like women with RIF.…”

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

“…Several controlled trials have identified contradictory evidence, with a 2019 systematic review by Vitagliano et al ( 2019 ) identifying insufficient evidence to support the benefits of ES, concluding that an effect could not be ruled out. Many of these previous studies included heterogeneous patients, including both women undergoing their first IVF cycle, and women undergoing subsequent cycles, and were therefore not powered to detect clinically worthwhile effects in those undergoing their first IVF cycle ( Nastri et al , 2013 ; Yeung et al , 2014 ; Lensen et al , 2019 ; Mackens et al , 2020 ). The two largest trials to focus specifically on women undergoing their first cycle of IVF included 418 and 300 participants and found significant increases in IVF success in women that received ES ( Mahran et al , 2016 ; Maged et al , 2018 ) but, according to the Vitagliano et al review, the risk of bias was deemed to be high in one study ( Mahran et al , 2016 ), and the other did not follow-up participants until delivery ( Maged et al , 2018 ; Vitagliano et al , 2019 ).…”