Is Endometrial Scratching Beneficial for Patients Undergoing a Donor
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diagnostics Article Is Endometrial Scratching Beneficial for Patients Undergoing a Donor-Egg Cycle with or without Previous Implantation Failures? Results of a Post-Hoc Analysis of an RCT Alexandra Izquierdo 1,*, Laura de la Fuente 2, Katharina Spies 3, David Lora 4,5 and Alberto Galindo 6 1 Gynaecology Unit, Médipôle Hôpital Mutualiste Lyon-Villeurbanne, 69100 Villeurbanne, France 2 Human Reproduction Unit, Department of Obstetrics and Gynaecology, University Hospital 12 de Octubre, Avda, Andalucia s/n, 28041 Madrid, Spain; [email protected] 3 ProcreaTec–IVF Spain, Manuel de Falla 6, 28036 Madrid, Spain; [email protected] 4 Clinical Research Unit (imas12-CIBERESP), University Hospital 12 de Octubre, Avda, Andalucia s/n, 28041 Madrid, Spain; [email protected] 5 Facultad de Estudios Estadísticos, Complutense University of Madrid, 28040 Madrid, Spain 6 Fetal Medicine Unit—Maternal and Child Health and Development Network (Red SAMIDRD12/0026/0016), Department of Obstetrics and Gynaecology, 12 de Octubre Research Institute (imas12), University Hospital 12 de Octubre, Complutense University of Madrid, Avda, Andalucia s/n, 28041 Madrid, Spain; [email protected] * Correspondence: [email protected] Abstract: Endometrial scratching (ES) has been proposed as a useful technique to improve outcomes in in vitro fertilization (IVF) cycles, particularly in patients with previous implantation failures. Our objective was to determine if patients undergoing egg-donor IVF cycles had better live birth rates Citation: Izquierdo, A.; de la Fuente, after ES, according to their previous implantation failures. Secondary outcomes were pregnancy L.; Spies, K.; Lora, D.; Galindo, A. Is rate, clinical pregnancy rate, ongoing pregnancy rate, miscarriage rate, and multiple pregnancy rate. Endometrial Scratching Beneficial for We analysed the results of 352 patients included in the Endoscratch Trial (NCT03108157). A total of Patients Undergoing a Donor-Egg 209 were patients with one or no previous implantation failures (105 with an ES done in the previous Cycle with or without Previous cycle, group A1, and 104 without ES, group B1), and 143 were patients with at least two previous Implantation Failures? Results of a failed implantations (71 patients with ES, group A2, and 72 without ES, group B2). We found an Post-Hoc Analysis of an RCT. improvement in pregnancy rates (62.9% in group A1 vs. 55.8% in group B1 vs. 70.4% in group A2 vs. Diagnostics 2021, 11, 1167. https:// doi.org/10.3390/diagnostics11071167 76.4% in group B2, p = 0.028) in patients with at least two previous implantation failures, but this difference was not statistically different when we compared clinical pregnancy rates (59.1% vs. 51.0% Academic Editor: Antonio Maccio vs. 64.8% vs. 68.1% in groups A1, B1, A2 and B2, respectively, p = 0.104) and live birth rates (52.4% vs. 43.3% vs. 57.8% vs. 55.6% in groups A1, B1, A2 and B2, respectively, p = 0.218). According to these Received: 19 March 2021 results, we conclude that there is no evidence to recommend ES in egg-donor IVF cycles, regardless Accepted: 24 June 2021 of the number of previous failed cycles. Published: 26 June 2021 Keywords: endometrial scratching; in vitro fertilization; recurrent implantation failure; egg donor Publisher’s Note: MDPI stays neutral IVF cycle; endometrial receptivity with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction In 2003, Barash et al. published for the first time their results on patients undergoing endometrial scratching (ES) before an in vitro fertilization (IVF) cycle. They aimed to Copyright: © 2021 by the authors. enhance endometrial receptivity, as this had been seen in guinea pigs when an intentional Licensee MDPI, Basel, Switzerland. injury was caused before embryo implantation [1]. They performed four endometrial This article is an open access article injuries during the cycle prior to the embryo transfer and found an improvement in implan- distributed under the terms and tation rate (IR), pregnancy rate (PR), and live birth rate (LBR) in the study group [2]. Several conditions of the Creative Commons studies were conducted after that and some authors reached the same conclusions [3,4], Attribution (CC BY) license (https:// but others did not [5]. When only patients with recurrent implantation failure (RIF) were creativecommons.org/licenses/by/ 4.0/). Diagnostics 2021, 11, 1167. https://doi.org/10.3390/diagnostics11071167 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 1167 2 of 11 considered, ES seemed to have a better impact on the outcomes [6], as the review by Potdar et al. [7] and the Cochrane review by Nastri et al. showed in their results [8]. In 2019, Vitagliano et al. published a meta-analysis on the impact of ES in infertile women undergoing a first embryo transfer, and they could not find a difference between groups in terms of clinical pregnancy rates (CPR), miscarriage rate (MR), ongoing preg- nancy rate (OPR), LBR, multiple pregnancy rate (MulPR), and ectopic pregnancy rate (EPR) in fresh or frozen embryo transfers [9]. They found a negative impact in one study that eval- uated ES performed on the day of the oocyte retrieval [10]. The same authors published a meta-analysis of studies including patients with at least one previous failure, and found an increased LBR and CPR in patients who had two or more previous unsuccessful cycles [11]. In addition, a review conducted of studies that included patients who had at least one previous failed cycle found a significative increase in CPR and LBR after ES, but differences were not significative if studies with a high risk of bias were excluded [12]. Nevertheless, neither of these reviews included the last randomised controlled trial (RCT) published, the largest to date, that could not find, in their subgroup analysis of IVF patients, any difference in the LBR of patients undergoing a first cycle or after previous failed attempts [13]. The underlying mechanism that would lead to benefits of ES remains uncertain. Some authors have suggested that ES would lead to a better synchronization between embryo and endometrium through the endometrial maturation retardation [14], while others have advocated that ES would enhance decidualization through the induction of cytokine and growth factor secretion as well as immune cell invasion [15], or that ES would modify endometrial gene expression of specific factors involved in embryo implantation [16]. It is known that ovarian stimulation may induce an asynchrony between the embryo and the endometrium [17], due to the high oestrogen levels achieved during controlled ovarian stimulation, and this endometrial development is also different from one patient to another as it is determined by each woman’s ovarian reserve and stimulation protocols. In addition, embryo implantation potential may also be very different among patients undergoing IVF cycles as embryo quality and euploidy depend on maternal age [18]. With this background, we designed an RCT in egg donor recipients in order to assess the real effect of ES under similar endometrial conditions and with the highest embryo quality [19], including patients with and without previous implantation failures. Our results showed no differences in PR (65.9% vs. 64.2%, p = 0.823), CPR (61.4 vs. 58.0, p = 0.587) and LBR (54.5% vs. 48.3%, p = 0.286) between intervention and control groups in intention-to-treat (ITT) analysis. The definition of RIF has been subject of debate during the last years as it is difficult to determine if a negative result is due to implantation deficient phenomena or to impaired embryo quality. This has led to many different definitions among authors, who may consider recurrent implantation failure from two to six previous failed embryo transfers, with fresh or frozen embryos [20]. In 2014, a thorough review of implantation failure definition and therapies defined RIF as the implantation failure of four or more good quality embryos, including fresh and frozen embryos, in at least three embryo transfers [21]. Nevertheless, recent meta-analyses and reviews consider RIF patients those who have undergone at least two previous embryo transfers, as they have found that, according to this definition, RIF patients had improved outcomes when an ES was performed [8,9,11]. The reduction in the total number of transferred embryos considered in the RIF definition is related to an increase in embryo selection due to laboratory culture conditions and pre-implantation genetic testing, reducing the impact of implantation failure associated with impaired embryo quality or embryo genetic conditions. Thus, we performed a subgroup analysis of the outcomes of patients included in the Endoscratch Trial (NCT03108157), dividing our patients into RIF patients (with two or more previous failed implantations) and non-RIF patients (with a maximum of one previous failed embryo transfer) to determine the efficacy of ES in improving live birth rates in egg-donor IVF cycles according to previous implantation failures. Diagnostics 2021, 11, 1167 3 of 11 2. Materials and Methods The overall number of patients included in the Endoscratch Trial (NCT03108157) was 352, of whom 176 were allocated to receive an ES in the luteal phase of the cycle preceding the embryo transfer cycle (group A), and another 176 to receive no intervention (group B). Sample size was calculated upon egg-donor IVF average pregnancy rates (60%) in order to detect a difference of 15% between the two groups. We performed an analysis according to the number of previous failed embryo transfers, including own egg and donor egg, and fresh and frozen embryo transfers. This secondary analysis of our RCT was not included in the original design of the trial and thus sample size according to the number of implantation failure patients to be included in each arm was not calculated. Out of the 352 patients, 209 had a maximum of 1 previous failed embryo transfer (non-RIF patients), and 143 had at least two previous failed transfers (RIF patients).