Broekmans, F. J.M.

van Hoogenhuijze, N. E.

Utrecht University Repository

Reply: Endometrial scratching: the light at the end of the tunnelSir,We would like to thank Dr Vitagliano (Vitagliano and Cicinella, 2024) and his colleagues for taking the time and effort to comment on our individual participant data meta-analysis (IPD) on endometrial scratching, and we encourage exchanging thoughts on both endometrial scratching and the undertaking of IPD’s.We agree that the enormous amount of research papers on endometrial scratching and the shifts in ‘the answer on endome-trial scratching’ have asked for flexibility of mind from the read-ers and practitioners in this field. While we acknowledge that not one study or research undertaking can be flawless and provide The Truth, we indeed think that the current IPD is the best avail-able evidence at this moment, and that it should lead to investi-gating subsequent questions such as the optimal timing and method of scratching, and its biological mechanism of action. We finally acknowledge the statement that science prevails, not only over opinions but also over personal beliefs.Where endometrial scratching once started with the sugges-tion to be effective in women with repeated endometrial failure (RIF) (Gnainsky et al., 2015), it soon shifted to investigating its effective-ness in all women (Nastri et al., 2013; Yeung et al., 2014; Lensen et al., 2018; Mackens et al., 2020). Results of individual studies var-ied widely, and meta-analyses including different selections of studies also reported different results: a meta-analysis on RIF patients presented significant outcomes (Potdar et al., 2012), others reported (a trend of) increasing effectiveness (Nastri et al., 2015; Vitagliano et al., 2018, 2019), and another meta-analysis found no significant effect except for clinical pregnancy rate in women with one failed embryo transfer, but not in those with 0 or �2 failed transfers (van Hoogenhuijze et al., 2019). However, the hypothesis of increasing effectiveness with increasing num-ber of failed transfers has remained vivid in many of us.Our IPD could not identify such a correlation in a one-stage participant-level interaction analysis. The suggestion to dichoto-mize the population and test for different cut-offs of number of previous failed transfers is understandable but is generally ad-vised against by expert IPD statisticians (Fisher et al., 2011; Riley et al., 2020). The reason is that categorization of continuous varia-bles reduces power to detect a true interaction with an effect, be-cause a lot of the information is lost when assembling it in groups. Also, logically speaking, it is hard to explain why some-one with three failed transfers is more comparable to someone with two failed transfers than to someone with four failed trans-fers, in case of an arbitrary cut-off of �3 or >3. We therefore be-lieve that to detect a possible interaction between the number of failed transfers and the effect of scratching, a continuous vari-able and interaction analysis is the best approach.As Dr Vitagliano rightly mentions, we have used a linear model for the interaction analysis, while a potential effect modi-fication could be non-linear. This can indeed be true, but we question whether from a biological perspective it is more likely to be a non-linear interaction than a linear interaction. As the num-ber of previous failed transfers is both influenced by the endome-trial receptivity and the number and quality of embryos a couple ‘generates’, it can also be argued that with an increasing number of failed embryo transfers, the more likely it is that a woman suf-fers from an endometrial factor—and thus that it may be a linear relation. Nevertheless, we did consider performing non-linear analysis but this appeared impossible due to the complexity of the model, resulting in convergence problems. Also, interpreta-tion could have been problematic as the different studies all have different covariate means (mean number of previous failed transfers). We performed the interaction analysis using the cen-tred study means of the covariate (in order to avoid aggregation bias), and therefore the change in treatment effect of a one-step increase from the covariate mean will have a different meaning for each study—making the summary outcome uninterpretable (Riley et al., 2020).In our opinion, the underlying issue of the discussion on women with repeated implantation failure in relation to scratch-ing, is the hypothesis that specifically women with an ‘endometrial factor’ may benefit from endometrial scratching. The problem is, however, that we do not know how to identify these women and that we have used the number of failed em-bryo transfers as a proxy—even though this number is influenced by other, non-endometrial, factors as well. We therefore suppose that further research should focus on unravelling the role of the endometrium in embryo implantation, such that we may be able to identify women with an endometrial factor and then investi-gate if it is indeed this group who benefits endome-trial scratching.All in all, we agree with Dr Vitagliano that at this moment, the IPD provides the best available evidence on the effect of endome-trial scratching. While the long-standing hypothesis of increasing benefit in women with repeated failed embryo transfers intui-tively seems plausible, we have not been able to identify such an effect, with the caveat of not having performed a non-linear re-gression analysis. Nonetheless, in our opinion, further research should focus on whether an ‘endometrial factor’ exists and on how to identify these women, as well as on the biological mecha-nism of action of endometrial scratching and its optimal timing.# The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved.  For permissions, please email: journals.permissions@oup.com Human Reproduction Update, 2024, 30(2), 240–241  https://doi.org/10.1093/humupd/dmad038 Advance Access Publication Date: January 27, 2024 Letter to the Editor   Conflict of interestNone.N.E. van Hoogenhuijze � and F.J.M. BroekmansDepartment of Gynaecology & Reproductive Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands�Correspondence address. Department of Gynaecology & Reproductive Medicine, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands. E-mail: n.e.vanhoogen-huijze-2@umcutrecht.nl https://orcid.org/0000-0001- 9057-1306ReferencesFisher DJ, Copas AJ, Tierney JF, Parmar MKB. A critical review of methods for the assessment of patient-level interactions in indi-vidual participant data meta-analysis of randomized trials, and guidance for practitioners. J Clin Epidemiol 2011;64:949–967.Gnainsky Y, Granot I, Aldo P, Barash A, Or Y, Mor G, Dekel N. Biopsy- induced inflammatory conditions improve endometrial receptiv-ity: the mechanism of action. Reproduction 2015;149:75–85.Lensen S, Osavyluk D, Armstrong S, Napier E, Sadler L, Hennes A, Stadelmann C, Hamoda H, Khalaf Y, Webber L et al. Endometrial scratching by pipelle biopsy in IVF (the PIP study): a pragmatic randomised controlled study. Human Reproduction 2018;33 (Supplement 1):i62.Mackens S, Racca A, Van de Velde H, Drakopoulos P, Tournaye H, Stoop D, Blockeel C, Santos-Ribeiro S. Follicular-phase endome-trial scratching: a truncated randomized controlled trial. 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