Personalized embryo transfer reduces success rates because endometrial receptivity analysis fails to accurately identify the window of implantation.

After more than a decade of increasingly widespread clinical use, personalized embryo transfer guided by endometrial receptivity analysis (ERA) remains controversial and unproven. One key element missing from the historical literature is the recognition that potential benefits from personalized embryo transfer are entirely dependent on the accuracy and predictive value of the ERA test. Results from the first comprehensive clinical trial, designed in a way that allowed independent evaluation of both potential benefits of personalized embryo transfer and the predictive value of the ERA test upon which it is based, were recently published. However, the authors failed to conduct an appropriate analysis or recognize the significance of their results. Here, we present a simple reanalysis of data from this otherwise excellent randomized controlled trial, demonstrating for the first time that the ERA was unable to identify the window of implantation as purported and that, as a result, personalized embryo transfer based on the ERA actually reduced rather than increased the birth rates. Based on these results and the lack of any contradictory evidence, it is our opinion that all clinical use of ERA-guided personalized embryo transfer should be discontinued immediately, outside of a controlled experimental setting with appropriate informed consent of all participating patients.

Personalized embryo transfer guided by endometrial receptivity analysis: a systematic review with meta-analysis.

STUDY QUESTION: Does a personalized embryo transfer (pET) guided by tests for endometrial receptivity (TER) increase the effectiveness of ART procedures? SUMMARY ANSWER: The use of TER-guided pET is not supported by current published evidence in women without repeated implantation failure (RIF), while in women with RIF more research is needed to assess a potential benefit. WHAT IS KNOWN ALREADY: Implantation rates are still far from ideal, especially in some patients that have RIF with good-quality embryos. As a potential solution, a wide range of diverse TER use different sets of genes to identify displacements of the window of implantation to adjust the individual length of progesterone exposure in a pET. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was performed. Search terms included endometrial receptivity analysis, ERA, personalized embryo transfer. CENTRAL, PubMed, Embase, reference lists, clinical trials registers, and conference proceedings (search date October 2022) were searched, with no language restrictions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Randomized controlled trials (RCTs) and cohort studies comparing a pET guided by TER vs standard embryo transfer (sET) in different subgroups that undergo ART were identified. We also investigated pET in non-receptive-TER vs sET in receptive-TER, and pET in a specific population vs sET in a general population. Risk of bias (RoB) was assessed with the Cochrane tool and ROBINS-I. Only those with low/moderate RoB underwent meta-analysis. The GRADE approach was used to evaluate the certainty of evidence (CoE). MAIN RESULTS AND THE ROLE OF CHANCE: We screened 2136 studies and included 35 (85% used ERA and 15% used other TER). Two studies were RCTs comparing endometrial receptivity analysis (ERA)-guided pET vs sET in women with no history of RIF. In women without RIF, no important differences (moderate-CoE) were found in live birth rates and clinical pregnancy rates (CPR). We also performed a meta-analysis of four cohort studies that were adjusted for confounding. In agreement with the RCTs, no benefits were found in women without RIF. However, in women with RIF, low CoE suggests that pET might improve the CPR (OR 2.50, 95% CI 1.42-4.40). LIMITATIONS, REASONS FOR CAUTION: We found few studies with low RoB. Only two RCTs in women without RIF were published, and none in women with RIF. Furthermore, the heterogeneity observed in populations, interventions, co-interventions, outcomes, comparisons, and procedures limited the pooling of many of the included studies. WIDER IMPLICATIONS OF THE FINDINGS: In the population of women without RIF, in agreement with previously published reviews, pET did not prove to be more effective than sET and, therefore, it precludes the routine use of this strategy in this population until more evidence is available. However, more research is advisable in women with RIF as low-certainty evidence from observational studies adjusted for confounders suggests that the CPR might be higher with pET guided by TER in this population. Although this review presents the best available evidence, it is still insufficient to change current policies. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. There are no conflicts of interest to declare. REGISTRATION NUMBER: PROSPERO CRD42022299827.

Personalized embryo transfer based on RNA sequencing endometrial receptivity test in repeated implantation failure patients: artificial cycle versus natural cycle.

INTRODUCTION: Embryo implantation provides an efficient way for patients with repeated implantation failure (RIF) to achieve pregnancy. The aim of this study is to compare the implantation outcomes of RIF patients in artificial cycle to those in natural cycle, both were treated with RNA sequencing endometrial receptivity test (rsERT) based personalized embryo implantation. METHODS: The endometrial receptivity (ER) analysis was performed using rsERT followed by personalized embryo transfer at optimal window of implantation (WOI). The implantation rate (IR), clinical pregnancy rate (CPR) and live birth rate (LBR) were calculated. The expression levels of biomarkers involved in pregnancy process in the patients detected as in receptivity status were also analyzed. RESULTS: The rsERT shown that 44.8% (natural cycle) and 47.8% (artificial cycle) patients were in non-receptive status, which indicated a WOI displacement. After personalized embryo transfer, the IR of patients in artificial cycle was higher than those in natural cycle (52.2% vs 27.6%). The expressions of FKBP52, MUC1 and LPAR3 were significantly lower in artificial cycle than in natural cycle. CONCLUSION: Using artificial cycle for personalized embryo transfer based on rsERT may yield better pregnancy outcomes for RIF patients. A gene expression analysis of FKBP52, MUC1 and LPAR3 provided a potential way to increase implantation outcomes for RIF patients.

Do clinical outcomes differ for day-5 versus day-6 single embryo transfers controlled for endometrial factor?

RESEARCH QUESTION: Is there is a difference in clinical outcomes between day-5 versus day-6 blastocysts when transferred in a personalized embryo transfer (PET) cycle guided by Endometrial Receptivity Analysis (ERA)? DESIGN: Multicentre, retrospective study; 260 patients who underwent a single embryo transfer with either a day-5 or day-6 blastocyst in a PET cycle guided by ERA between January 2017 and December 2019. RESULTS: A total of 260 blastocysts were transferred in a single embryo PET cycle guided by ERA. Of those, 183 (70.4%) were day-5 blastocysts and 77 (29.6%) were day-6 blastocysts. Clinical outcomes were similar when transferring day-5 blastocysts versus day-6 blastocysts: pregnancy rate was 75.4% (138/183) and 70.1% (54/77) (P = 0.465); implantation rate was 67.8% (124/183) and 63.6% (49/77) (P = 0.476); and ongoing pregnancy rate was 57.9% (106/183) and 58.4% (45/77) (P = 0.728), respectively. CONCLUSIONS: The data suggest that the clinical potential of day-5 and day-6 blastocysts are similar, as no difference in clinical outcomes are observed when transferring at the time of optimal endometrial receptivity as determined by ERA.

Clinical relevance of a newly developed endometrial receptivity test for patients with recurrent implantation failure in Japan.

Purpose: To assess the clinical efficacy of personalized embryo transfer (pET) guided by a new endometrial receptivity test, ERPeakSM, in patients with recurrent implantation failure (RIF). Methods: Recurrent implantation failure patients of all ages at two private Japanese clinics from April 2019 to June 2020 were retrospectively analyzed. The intervention group (n = 244) received pET in accordance with endometrial receptivity testing results and was compared to control group (n = 306) receiving standardized timing, non-personalized embryo transfer (npET). In propensity score matching analysis, the clinical pregnancy rate (CPR) and live birth rate (LBR) were compared between groups, and a subanalysis of advanced maternal age (AMA) (≥38 years old) versus non-AMA (<38 years old) patients was also conducted. Results: The CPR and LBR of the pET group were significantly higher than those of the npET group (37.7% vs. 20.0%, adjusted OR: 2.64; 95%CI, 1.70-4.11, p < 0.001 and 29.9% vs. 9.7%, adjusted OR: 4.13; 95%CI, 2.40-7.13, p < 0.001, respectively). Furthermore, in the subanalyses, the CPR and LBR of the pET group were significantly higher than those of the npET group in both the AMA non-AMA patients. Conclusions: The new ERPeakSM endometrial receptivity test is a useful alternative diagnostic tool for poor-prognosis patients, regardless of age.

The role of transcriptomic biomarkers of endometrial receptivity in personalized embryo transfer for patients with repeated implantation failure.

BACKGROUND: Window of implantation (WOI) displacement is one of the endometrial origins of embryo implantation failure, especially repeated implantation failure (RIF). An accurate prediction tool for endometrial receptivity (ER) is extraordinarily needed to precisely guide successful embryo implantation. We aimed to establish an RNA-Seq-based endometrial receptivity test (rsERT) tool using transcriptomic biomarkers and to evaluate the benefit of personalized embryo transfer (pET) guided by this tool in patients with RIF. METHODS: This was a two-phase strategy comprising tool establishment with retrospective data and benefit evaluation with a prospective, nonrandomized controlled trial. In the first phase, rsERT was established by sequencing and analyzing the RNA of endometrial tissues from 50 IVF patients with normal WOI timing. In the second phase, 142 patients with RIF were recruited and grouped by patient self-selection (experimental group, n = 56; control group, n = 86). pET guided by rsERT was performed in the experimental group and conventional ET in the control group. RESULTS: The rsERT, comprising 175 biomarker genes, showed an average accuracy of 98.4% by using tenfold cross-validation. The intrauterine pregnancy rate (IPR) of the experimental group (50.0%) was significantly improved compared to that (23.7%) of the control group (RR, 2.107; 95% CI 1.159 to 3.830; P = 0.017) when transferring day-3 embryos. Although not significantly different, the IPR of the experimental group (63.6%) was still 20 percentage points higher than that (40.7%) of the control group (RR, 1.562; 95% CI 0.898 to 2.718; P = 0.111) when transferring blastocysts. CONCLUSIONS: The rsERT was developed to accurately predict the WOI period and significantly improve the pregnancy outcomes of patients with RIF, indicating the clinical potential of rsERT-guided pET. Trial registration Chinese Clinical Trial Registry: ChiCTR-DDD-17013375. Registered 14 November 2017, http://www.chictr.org.cn/index.aspx.

A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF.

RESEARCH QUESTION: Does clinical performance of personalized embryo transfer (PET) guided by endometrial receptivity analysis (ERA) differ from frozen embryo transfer (FET) or fresh embryo transfer in infertile patients undergoing IVF? DESIGN: Multicentre, open-label randomized controlled trial; 458 patients aged 37 years or younger undergoing IVF with blastocyst transfer at first appointment were randomized to PET guided by ERA, FET or fresh embryo transfer in 16 reproductive clinics. RESULTS: Clinical outcomes by intention-to-treat analysis were comparable, but cumulative pregnancy rate was significantly higher in the PET (93.6%) compared with FET (79.7%) (P = 0.0005) and fresh embryo transfer groups (80.7%) (P = 0.0013). Analysis per protocol demonstrates that live birth rates at first embryo transfer were 56.2% in PET versus 42.4% in FET (P = 0.09), and 45.7% in fresh embryo transfer groups (P = 0.17). Cumulative live birth rates after 12 months were 71.2% in PET versus 55.4% in FET (P = 0.04), and 48.9% in fresh embryo transfer (P = 0.003). Pregnancy rates at the first embryo transfer in PET, FET and fresh embryo transfer arms were 72.5% versus 54.3% (P = 0.01) and 58.5% (P = 0.05), respectively. Implantation rates at first embryo transfer were 57.3% versus 43.2% (P = 0.03), and 38.6% (P = 0.004), respectively. Obstetrical outcomes, type of delivery and neonatal outcomes were similar in all groups. CONCLUSIONS: Despite 50% of patients dropping out compared with 30% initially planned, per protocol analysis demonstrates statistically significant improvement in pregnancy, implantation and cumulative live birth rates in PET compared with FET and fresh embryo transfer arms, indicating the potential utility of PET guided by the ERA test at the first appointment.

Development of a new comprehensive and reliable endometrial receptivity map (ER Map/ER Grade) based on RT-qPCR gene expression analysis.

STUDY QUESTION: Is it possible to determine the receptivity status of an endometrium by combined quantitative reverse transcription PCR (RT-qPCR) expression analysis of genes involved in endometrial proliferation and immunity? SUMMARY ANSWER: The new ER Map®/ER Grade® test can predict endometrial receptivity status by RT-qPCR using a new panel of genes involved in endometrial proliferation and the maternal immune response associated to embryonic implantation. WHAT IS KNOWN ALREADY: The human endometrium reaches a receptive status adequate for embryonic implantation around Days 19-21 of the menstrual cycle. During this period, known as the window of implantation (WOI), the endometrium shows a specific gene expression profile suitable for endometrial function evaluation. The number of molecular diagnostic tools currently available to characterize this process is very limited. In this study, a new system for human endometrial receptivity evaluation was optimized and presented for the first time. STUDY DESIGN, SIZE, DURATION: ER Map®/ER Grade® validation was achieved on 312 endometrial samples including fertile women and patients undergoing fertility treatment between July 2014 and March 2016. Expression analyses of 184 genes involved in endometrial receptivity and immune response were performed. Samples were additionally tested with an independent endometrial receptivity test. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 96 fertile women and 120 assisted reproduction treatment (ART) patients participated in the study. Endometrial biopsy samples were obtained at LH + 2 and LH + 7 days in fertile subjects in a natural cycle and at the window of implantation (WOI) in patients in a hormone-replacement therapy (HRT) cycle. Total RNA was purified, quality-checked and reverse-transcribed. Gene expression was quantified by high-throughput RT-qPCR and statistically analyzed. Informative genes were selected and used to classify samples into four different groups of endometrial receptivity status. MAIN RESULTS AND THE ROLE OF CHANCE: Significantly different gene expression levels were found in 85 out of 184 selected genes when comparing LH + 2 and LH + 7 samples (paired t-test, P < 0.05). Gene ontology analyses revealed that cell division and proliferation, cell signaling and response, extracellular organization and communication, immunological activity, vascular proliferation, blood pressure regulation and embryo implantation are the most over-represented biological terms in this group of genes. Principal component analysis and discriminant functional analysis showed that 40 of the differentially expressed genes allowed accurate classification of samples according to endometrial status (proliferative, pre-receptive, receptive and post-receptive) in both fertile and infertile groups. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: To evaluate the efficacy of this new tool to improve ART outcomes, further investigations such as non-selection studies and randomized controlled trials will also be required. WIDER IMPLICATIONS OF THE FINDINGS: A new comprehensive system for human endometrial receptivity evaluation based on gene expression analysis has been developed. The identification of the optimal time for embryo transfer is essential to maximize the effectiveness of ART. This study is a new step in the field of personalized medicine in human reproduction which may help in the management of endometrial preparation for embryo transfer, increasing the chances of pregnancy for many couples. STUDY FUNDING/COMPETING INTEREST(S): The authors have no potential conflict of interest to declare. No external funding was obtained for this study.

Efficacy of the endometrial receptivity array for repeated implantation failure in Japan: A retrospective, two-centers study.

Aim: This study aimed to assess the efficacy of the endometrial receptivity array (ERA) as a diagnostic tool and the impact of personalized embryo transfer (pET) for the treatment of patients with recurrent implantation failure (RIF) in Japan. Methods: Fifty patients with a history of RIF with frozen-thawed blastocyst transfers were recruited from July, 2015 to April, 2016. Endometrial sampling for the ERA and histological dating and a pET according to the ERA were performed. The receptive (R) or non-receptive (NR) status of the endometrium as a result of the first ERA, endometrial dating, and pregnancy rates after the pET were analyzed. Results: Of the patients with RIF, 12 (24%) were NR. Among them, eight (66.7%) were prereceptive. A clinical follow-up was possible in 44 patients who underwent the pET. The pregnancy rates were 58.8% per patient and 35.3% per first pET in the R patients and 50.0% per patient and 50.0% per first pET in the NR patients. Discrepancies between the ERA results and histological dating were seen more in the NR patients than in the R patients. Conclusions: For patients with unexplained RIF, there is a significance in searching for their personal window of implantation (WOI) using the ERA, considering the percentage of those who were NR and the pregnancy rates that resulted from the pET. By transferring euploid embryos in a personal WOI, much better pregnancy rates are expected.

What a difference two days make: "personalized" embryo transfer (pET) paradigm: a case report and pilot study.

Embryo implantation requires that the blastocyst will attach during the receptive stage of the endometrium, known as window of implantation (WOI). Historically, it has been assumed that the WOI is always constant in all women. However, molecular analyses of endometrial receptivity demonstrates a personalized WOI (pWOI) that is displaced in one out of four patients suffering from recurrent implantation failure (RIF) of endometrial origin and illustrates the utility of a personalized endometrial diagnostic approach. Here, we report a clinical case of successful personalized embryo transfer (pET) after four IVF and three oocyte donation failed attempts in which different embryo transfer strategies were attempted. This case report is complemented by a pilot study of 17 patients undergoing oocyte donation and who suffered failed implantations with routine embryo transfer (ET) but were then treated with pET after the personalized diagnosis of their WOI.

Precise hourly personalized embryo transfer significantly improves clinical outcomes in patients with repeated implantation failure.

Purpose: This study investigated whether RNA-Seq-based endometrial receptivity test (rsERT)-which provides precision for the optimal hour of the window of implantation (WOI)-can improve clinical outcomes of frozen embryo transfer (FET) cycles in patients with a history of repeated implantation failure (RIF). Methods: Patients with a history of RIF who received at least one autologous high-quality blastocyst during the subsequent FET cycle were retrospectively enrolled and divided into two groups: rsERT and FET, comprising patients who underwent rsERT-guided pET (n=115) and standard FET without rsERT (n=272), respectively. Results: In the rsERT group, 39.1% (45/115) of patients were receptive. rsERT patients showed a higher probability of achieving both positive human chorionic gonadotropin (63.5% vs. 51.5%, P=0.03) and clinical pregnancy (54.8% vs. 38.6%, P=0.003) rates. In subgroup analysis, rsERT patients with non-receptive results had higher clinical pregnancy rates than patients undergoing FET (58.6% vs. 38.6%, P=0.003). rsERT patients with receptive results guided by rsERT with a precise WOI time had higher, although non-significant, clinical pregnancy rates (48.9% vs. 38.6%, P=0.192) than patients who underwent standard-time FET. Conclusion: Hourly precise rsERT can significantly improve the probability of achieving clinical pregnancy in patients with RIF, especially in those with non-receptive rsERT results.

Efficacy of endometrial receptivity testing for recurrent implantation failure in patients with euploid embryo transfers: study protocol for a randomized controlled trial.

BACKGROUND: Embryo implantation remains a critical barrier in assisted reproductive technologies. One of the main causes of unsuccessful embryo implantation is window of implantation (WOI) displacement, particularly in patients with recurrent implantation failure (RIF). Therefore, a reliable diagnostic tool for identifying the optimal WOI is essential. Previous data has suggested that a novel RNA-Seq-based endometrial receptivity testing (ERT) can diagnose WOI, guide personalized embryo transfer (pET), and improve pregnancy outcomes in patients with RIF compared to standard embryo transfer (sET). However, there is still a lack of evidence from randomized controlled trials (RCT) with sufficient power to determine whether pET based on ERT can increase the rate of live births as the primary outcome. METHODS: This trial is a prospective, single-blind, parallel-group RCT (1:1 ratio of pET versus sET). Infertile women with RIF who intend to undergo frozen-thawed embryo transfer (FET) after preimplantation genetic testing for aneuploidy (PGT-A) with the availability of at least one euploid blastocyst for transfer will be enrolled and assigned into two parallel groups randomly. Participants in the intervention group will undergo ERT and then pET based on the results of ERT, while those in the control group will undergo sET. The primary outcome is live birth rate. DISCUSSION: The findings of this study will provide evidence for the effect of pET guided by ERT on pregnancy outcomes in patients with RIF. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100049041. Registered on 20 July 2021.

Unlocking Infertility: Enhancing Pregnancy Rates With Personalized Embryo Transfers Using Optimal Time for Endometrial Receptivity Analysis in Recurrent Implantation Failure Patients Undergoing In Vitro Fertilization.

Background Infertility remains a significant global challenge, and recurrent implantation failure (RIF) poses a considerable concern in assisted reproductive technology. Understanding the factors contributing to implantation failure is essential for developing accurate diagnostic tools and treatment strategies. Endometrial receptivity (ER) during the window of implantation is crucial for successful embryo implantation in in vitro fertilization (IVF) procedures. Molecular-based endometrial receptivity analysis and next-generation sequencing provide insights into ER, but there is a lack of research on these in the Indian population, particularly in patients with RIF. This retrospective cohort study evaluates the effectiveness of Optimal Timing for Endometrial Receptivity Analysis (OpERA)-guided personalized embryo transfer (pET) in Indian patients with a history of RIF. Methodology The study includes 158 female patients with a history of failed embryo transfers who underwent OpERA testing before frozen embryo transfer. Patients were categorized based on the number of previous failed transfers. OpERA outcomes were assessed, and clinical outcomes were compared between groups undergoing preimplantation genetic testing for aneuploidy (PGT-A) with and without OpERA. Endometrial preparation involved hormone replacement therapy, and OpERA testing was performed at the Neuberg Centre for Genomic Medicine using RNA extraction, cDNA conversion, and sequencing. Results OpERA outcomes showed no significant differences in receptive rates among patient groups. Group 3, with three or more failed transfers, exhibited significantly higher biochemical pregnancy rates (BPRs), clinical pregnancy rates (CPRs), and abortion rates (ARs) compared to Groups 1 and 2. OpERA with PGT-A showed significantly higher BPR, implantation rate, CPR, and lower AR compared to OpERA without PGT-A. Conclusions OpERA-guided pET, especially with PGT-A, demonstrated improved pregnancy outcomes, particularly in patients with a history of RIF. The study emphasizes the importance of OpERA in determining optimal transfer timing, moving beyond the traditional reliance on embryo quality alone. OpERA presents promise in predicting pregnancy outcomes for Indian patients with previous IVF failures. The integration of OpERA and PGT-A represents a significant advancement in personalized reproductive medicine, offering new hope for individuals grappling with infertility complexities.

Personalized embryo transfer guided by rsERT improves pregnancy outcomes in patients with repeated implantation failure.

Introduction: Embryo implantation requires synchronous communication between the embryo and maternal endometrium. Inadequate maternal endometrial receptivity is one of the principal causes for embryo implantation failure [especially repeated implantation failure (RIF)] when biopsied good-quality euploid embryos are transferred. An RNA-seq-based endometrial receptivity test (rsERT) was previously established to precisely guide successful embryo implantation. In this study, we aimed to evaluate the effect of personalized embryo transfer (pET) via rsERT on the clinical outcomes in patients with RIF. Methods: A total of 155 patients with RIF were included in the present retrospective study and were divided into two groups: 60 patients who underwent rsERT and pET (Group rsERT) and 95 patients who underwent standard frozen embryo transfer (FET) without rsERT (Group FET). Reproductive outcomes were compared for patients who underwent rsERT-guided pET and standard FET. Results: Forty percent (24/60) of the patients who underwent rsERT were receptive, and the remaining 60% (36/60) were non-receptive. The positive human chorionic gonadotropin (ß-hCG) rate (56.3% vs. 30.5%, P = 0.003) and clinical pregnancy rate (43.8% vs. 24.2%, P = 0.017) were significantly higher in Group rsERT patients than in FET group patients. Additionally, Group rsERT patients also showed a higher implantation rate (32.1% vs. 22.1%, P = 0.104) and live birth rate (35.4% vs. 21.1%, P = 0.064) when compared with FET patients, although without significance. For subpopulation analysis, the positive ß-hCG rate, clinical pregnancy rate, implantation rate, and live birth rate of receptive patients were not statistically significant different from those of non-receptive patients. Conclusions: The rsERT can significantly improve the pregnancy outcomes of RIF patients, indicating the clinical potential of rsERT-guided pET.

A Comprehensive Review of the Endometrial Receptivity Array in Euploid Embryo Transfer Cycles.

The Endometrial Receptivity Array (ERA) is a revolutionary molecular diagnostic tool that determines the optimal timing for embryo transfer by analyzing the gene expression profile of endometrial tissue. This comprehensive review examines the significance and application of ERA in euploid embryo transfer cycles, where the implantation of embryos with the correct number of chromosomes is critical for achieving successful pregnancy outcomes. This review underscores its role in enhancing implantation rates and reducing pregnancy loss by assessing the evolution, methodology, clinical applications, efficacy, and challenges associated with ERA. Key findings highlight ERA's superior accuracy in identifying the window of implantation compared to traditional methods, resulting in improved clinical outcomes in assisted reproductive technology (ART) cycles. Despite its benefits, the review acknowledges challenges such as cost, accessibility, and the need for standardization. Recommendations for clinical practice emphasize the integration of ERA into routine ART protocols, comprehensive patient counseling, and the importance of multidisciplinary collaboration. The review outlines promising prospects, including technological advancements to make ERA more cost-effective, the development of refined gene expression profiles, and the potential integration with other emerging ART technologies. Further research directions include long-term studies on the outcomes of ERA-guided pregnancies and exploring its application in cases of recurrent implantation failure and unexplained infertility. Overall, ERA represents a significant advancement in reproductive medicine, offering a personalized approach to embryo transfer timing that can significantly improve the success rates of euploid embryo transfers.

Integrated treatment guided by RNA-seq-based endometrial receptivity assessment for infertility complicated by MEN1.

Background: Preimplantation genetic testing (PGT) serves as a tool to avoid genetic disorders in patients with known genetic conditions. However, once a selected embryo is transferred, implantation success is attained independent of embryo quality. Using PGT alone is unable to tackle implantation failure caused by endometrial receptivity (ER) abnormalities in these patients. Methods: We validated our newly developed RNA-seq-based ER test (rsERT) in a retrospective cohort study including 511 PGT cycles and reported experience in treating an infertile female patient complicated by multiple endocrine neoplasia type 1 (MEN1). Results: Significant improvement in the clinical pregnancy rate was found in the performed personalized embryo transfer (pET) group (CR, 69.7%; P = 0.035). In the rare MEN1 case, pET was done according to the prediction of the optimal time of window of implantation after unaffected blastocysts were obtained by PGT-M, which ultimately led to a healthy live birth. However, none of the mRNA variants identified in the patient showed a strong association with the MEN1 gene. Conclusions: Applying the new rsERT along with PGT improved ART outcomes and brought awareness of the importance of the ER examination in MEN1 infertile female patients. MEN1-induced endocrine disorder rather than MEN1 mutation contributes to the ER abnormality. Trial Registration: Reproductive Medicine Ethics Committee of Xiangya Hospital Registry No.: 2022010.

The Clinical Efficacy of Personalized Embryo Transfer Guided by the Endometrial Receptivity Array/Analysis on IVF/ICSI Outcomes: A Systematic Review and Meta-Analysis.

Objective: To assess the prevalence of displaced window of implantation (WOI) in infertile women, and the clinical utility of personalized embryo transfer (pET) guided by the endometrial receptivity array/analysis (ERA) on IVF/ICSI outcomes. Methods: The protocol was registered at Prospero: CRD42020204237. We systematically searched all published English literature related to the prevalence of WOI displacement and ongoing pregnancy rate/live birth rate in the overall good-prognosis infertile patients (GPP) and/or repeated implantation failure (RIF) patients undergoing IVF/ICSI-ET cycles after ERA test until August 2021. Result(s): 11 published studies were enrolled in the final analysis. The estimate of the incidence of WOI displacement based on ERA was 38% (95%CI 19-57%) in GPP and 34% (95%CI 24-43%) in RIF, respectively. There was no difference in OPR/LBR between patients undergoing routine ET without ERA test and those who following pET with ERA (39.5 vs. 53.7%, OR 1.28, p = 0.49, 95%CI 0.92-1.77, I 2 = 0%) in relative GPP. Notably, the meta-analysis revealed that OPR/LBR of patients with RIF undergoing pET who had non-receptive ERA increased to the level of to those undergoing sET with receptive ERA (40.7 vs.49.6%, OR 0.94, p = 0.85, 95%CI 0.70-1.26, I 2 = 0%). Conclusion: Considering the approximately one third of infertile women could suffered from displaced WOI, the ERA test emerged as a promising tool. Although the present meta-analysis demonstrates that patients with general good-prognosis may not benefit from ERA, pET guided by ERA significantly increases the chances of pregnancy for non-receptive patients with RIF of endometrial origin.

Personalized Embryo Transfer Outcomes in Recurrent Implantation Failure Patients Following Endometrial Receptivity Array With Pre-Implantation Genetic Testing.

Introduction Implantation failure is a trending problem for pregnancy outcomes. Women's reproduction rates can increase by in-vitro fertilization, which comes with frequent implantation failures. These failures can be mitigated by the personalization of embryo transfer depending on the patient's implantation window. The study aimed to assess the importance of using an endometrial receptivity array (ERA) combined with pre-implantation genetic testing in patients with recurrent implantation failure (RIF) and the significant role of personalized embryo transfer (PET) after ERA in patients with a displaced window of implantation. The study also determined the efficacy of this approach in improving clinical outcomes. Methods We conducted this observational retrospective study following approval by the Ethics Committee of Wings In-Vitro Fertilization (IVF) Women's Hospital, a unit of Reveba Infertility Clinics Pvt. Ltd., Ahmadabad (Approval No. 2019/002/31B). Two hundred ninety-one RIF patients were recruited and categorized into Group I (patients without ERA group) and Group II (ERA study group). Patients in the ERA study group were screened for ERA and subclassified into receptive and nonreceptive ERA groups. PET was performed for all subjects in the ERA study group according to their receptivity as assessed by ERA. We also screened some of the patients for ploidy (genetic) status of embryos by pre-implantation genetic testing for aneuploidy (PGT-A) before embryo transfer. The study had a power of 95% and an alpha of 0.05; therefore, 80 ± 2 subjects were required to conduct the study.  Results The primary outcome was the clinical pregnancy rate followed by the implantation rate. We found an improved clinical pregnancy rate and implantation rate (73.5% and 78.6%) in the nonreceptive endometrial group after adjusting their embryo transfer schedule to their endometrial receptivity. The clinical pregnancy rate (64% and 65%) and implantation rate (65% and 74%) in receptive and nonreceptive ERA (respectively) were high in subjects with donor oocytes for IVF/intracytoplasmic sperm injection. In addition, patients who opted for PGT-A to eliminate the risk of transferring aneuploidy embryos had significantly better implantation (88% and 95% receptive and nonreceptive, respectively) and clinical pregnancy rates (100% in both groups) compared to non-PGT-A screened patients (p<0.05; 34% and 37% clinical pregnancy rate, 96% and 57% implantation rate in receptive and nonreceptive groups, respectively). Conclusion Endometrial receptivity assessment is a highly beneficial method to assess the genetic expression of the endometrium and embryo transfer timing. In our study, in patients with recurrent implantation failure, this technology found receptivity issues and provided a chance to plan embryo transfer according to the window of implantation. The combination of PGT-A with ERA rules out the genetic issues related to embryos. In RIF patients, ERA results-guided PET improved the implantation rate and reproductive outcomes.

The RNA-seq based endometrial receptivity test (rsERT) compared to pinopode: A better diagnostic tool for endometrial receptivity for patients with recurrent implantation failure in Chinese population.

Displaced window of implantation (WOI) is one of the endometrial origins that accounts for implantation failure, especially for patients with recurrent implantation failure (RIF), yet no standard diagnostic tool has been recognized. The study consists of two parts, aiming to compare the concordance and efficacy of the diagnostic tools, the newly developed RNA-seq based endometrial receptivity test (rsERT) to the conventional pinopode, in diagnosing WOI and guiding personalized embryo transfer (pET). With the same group of RIF patients, the rsERT diagnosed 32 patients (65.31%) with normal WOIs, and most of the displacements were advancements (30.61%). While according to pinopode, only 14 patients (28.57%) were found with normal WOIs, and most patients (63.27%) presented delayed growth patterns. After conducting pET, patients in the rsERT group had higher successful pregnancy rates while requiring fewer ET cycles (50.00% vs. 16.67%, p=0.001). The study proved poor consistency between the diagnostic tools of endometrial receptivity based on cellular structure and gene profiling, and it supported rsERT as a reliable tool with potential clinical value.

Use of the endometrial receptivity array to guide personalized embryo transfer after a failed transfer attempt was associated with a lower cumulative and per transfer live birth rate during donor and autologous cycles.

OBJECTIVE: To determine whether personalized embryo transfer (pET) guided by endometrial receptivity array (ERA) test improves reproductive outcomes for fresh embryo transfers (fsETs) or frozen embryo transfers (FETs) during autologous and donor cycles. DESIGN: A retrospective, observational, multicenter cohort study. SETTING: University-affiliated in vitro fertilization center. PATIENT(S): The study included patients with a single previous failed transfer and yielded 3,239 autologous transfers and 2,133 donor transfers. Among autologous transfers, 255 were pET guided by ERA; among unguided autologous transfers, 1,122 and 1,862 transfers involved fresh or previously frozen embryos, respectively. Among donor transfers, 319 were ERA-guided; among unguided donor transfers, 1,175 and 639 involved fsETs or FETs, respectively. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcomes were live birth rate per embryo transfer and cumulative live birth rate on consecutive transfers until live birth or cessation of pregnancy. Secondary outcomes were implantation, pregnancy rate, clinical pregnancy rates per embryo transfer, and miscarriage rate per pregnancy. RESULT(S): During both autologous or donor transfers, live birth rate and cumulative live birth rate were higher in FET and fsET than in pET groups, even with euploid transfers. Logistic regression analysis, considering possible confounders, indicated patients receiving pET had poorer outcomes than those undergoing FET and fsET in autologous and donor cycles. Implantation, pregnancy, and clinical pregnancy rates were lower in patients undergoing pET. CONCLUSION(S): Using ERA to guide pET during either autologous or donor cycles after a failed transfer attempt did not improve reproductive outcomes. Conversely, worse outcomes were detected when ERA was used.