Front. Endocrinol. Frontiers in Endocrinology Front. Endocrinol. 1664-2392 Frontiers Media S.A. 10.3389/fendo.2023.1251699 Endocrinology Mini Review Does endometrial receptivity array improve reproductive outcomes in euploid embryo transfer cycles? a systematic review Mei Youwen † Wang Yacong † Ke Xue Liang Xuefei Lin Yonghong * Wang Fang * Department of Reproduction and Infertility, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

Edited by: Gedis Grudzinskas, Independent Researcher, London, United Kingdom

Reviewed by: Ana Raquel Neves, IVI-RMA (Portugal), Portugal

*Correspondence: Yonghong Lin, linyhcd2011@163.com; Fang Wang, wangfcd2022@163.com

†These authors have contributed equally to this work

 23 10 2023 2023 14 1251699 02 07 2023 22 09 2023 Copyright © 2023 Mei, Wang, Ke, Liang, Lin and Wang 2023 Mei, Wang, Ke, Liang, Lin and Wang

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Besides chromosomal normality, endometrial receptivity is an important factor in determining successful pregnancies. Endometrial receptivity array (ERA), a promising endometrial receptivity test, was speculated to improve the reproductive outcomes. However, its effectiveness is controversial in clinical practice. Therefore, we conducted this review to investigate its role in in vitro fertilization (IVF) treatment. To eliminate the interference of embryo quality, we only analyzed studies that originally reported the reproductive outcomes of patients who underwent ERA-guided euploid embryo transfer (EET). Unexpectedly, it revealed that ERA could not optimize the reproductive outcomes in EET cycles, no matter in general infertile population or in patients with a history of previous failed embryo transfers.

 endometrial receptivity array euploid embryo transfer in vitro fertilization recurrent implantation failure reproductive outcomes section-in-acceptance Reproduction Introduction

The embryo’s quality and endometrial receptivity are two vital factors for successful pregnancy. As the embryo’s quality could be identified by preimplantation genetic test (PGT) (1), endometrial receptivity is believed to be the last “barrier” (2). Endometrial receptivity refers to endometrial status that supports blastocyst acceptance. Endometrial receptivity array (ERA), a diagnostic molecular tool, could divide endometrium into “receptive” or “non-receptive” status by identifying the expression of 248 molecular genes (3). It was reported that 20% of infertile population and 25% of patients with recurrent implantation failure (RIF) suffered from a “non-receptive” endometrium (4). In addition, the accuracy of ERA was superior to endometrial histology and completely reproducible (5). Therefore, ERA was speculated to optimize the reproductive outcomes in patients who underwent in vitro fertilization (IVF) treatment, especially in patients with RIF, as it proposed a personalized optimal transfer time. However, no consensus has been reached yet. This review aims to investigate if ERA was effective in optimizing the reproductive outcomes in a systematic way. As controlling for the embryo’s quality would allow for a more accurate assessment, we only analyzed the effects of ERA in euploid embryo transfer (EET) cycles.

 Methods Study screening

We systematically searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases from inception to June 2023 according to our search strategy ( Supplementary Text 1 ). The inclusion criteria were as follows: published in English language, irrespective of study design, and studies focusing on the effects of ERA in EET cycles. Review articles, case reports, editorials, animal experimental articles, and studies not related with the effects of ERA in EET cycles were excluded ( Figure 1 ).

PRISMA flowchart.

 The risk of bias assessment

Assessment of risk of bias was done by two independent researchers (MYW and WYC) according to the “modified Newcastle–Ottawa scoring items” ( Supplementary Table S1 ). The scale mainly included five factors: sample representativeness, sampling technique, ascertainment of “receptive or non-receptive” diagnosis, quality of description of the population, and data completeness. Total scores ranged from 0 to 5, and studies were judged to be of low risk of bias (≥3 points) or high risk of bias (<3 points) (6).

 Data extraction and analysis

The selected studies were comprehensively examined, and the relevant data were extracted according to our developed spreadsheet (MYW and WYC). The extracted data included author’s name, publication year, study year and country, study aim, study design, sample size, sample characteristics, embryo stage, number of transferred embryos, and outcome measures. The primary outcomes of interest were ongoing pregnancy rate (OPR) and live birth rate (LBR). Secondary outcomes of interest included implantation rate (IR), clinical pregnancy rate (CPR), biochemical pregnancy loss rate (BPLR), and miscarriage rate (MR). This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (7).

 Results Studies selection and characteristics

In total, 1,686 articles were obtained, and 1,525 articles remained after 161 duplicates were removed. Of these, 29 reviews, 50 case reports, 11 editorials, and 13 animal experimental studies were excluded. Subsequently, 1,411 articles were found irrelevant and excluded. Finally, 11 articles were included in this review, which consisted of one double-blind randomized clinical trial, two prospective reports, and eight retrospective studies. These studies were all published between 2018 and 2023, while most studies were from the Occident. The population were mainly divided into two groups: general infertile patients and those with a history of previous failed embryo transfers. The great heterogeneity among these studies precluded the possibility of a meta-analysis. However, we also tried to present a comprehensive review of the implications of ERA in EET cycles. The basic clinical characteristics and reproductive outcomes of these studies are presented in Table 1 .

Reproductive outcomes in ERA group and non-ERA group.

Reference Study year/country Study design Inclusion criteria Cycle Study group No. of cases Age Embryo stage No. of ET OPR or LBR IR CPR BPLR or MR
Leondires, 2018 (8) 2016–2017 Spain Prospective ≥ One failed euploid ET FET (HRT) PGT, ERA 15 34.5 ± 4 – – 73.30% 87.50% – BPLR6.7%, MR20%
Tan, 2018 (9) 2014–2017 Netherlands Retrospective RIF, One prior failure, No prior failures FET (HRT) PGT, ERA 17 36.8 ± 4.1 blastocyst 1.09 ± 0.3 64.70% 76.50% – –
PGT, no ERA 26 37.6 ± 3.9 1 42.30% 53.8% – –
Rosen, 2019 (10) – the USA Retrospective General infertile population FET (HRT) PGT, ERA(receptive) 200 – blastocyst – 55% – 74% MR 9%
PGT, ERA(non-receptive) 147 52.40% – 72.70% MR 10.9%
Neves, 2019 (11) 2012–2018 Portugal Retrospective ≥ 1 failed euploid–ET FET (HRT) PGT, ERA 24 39.25 ± 3.99 blastocyst 1.13 ± 0.34 – 55.60% 58.30% –
PGT, no ERA 119 39.18 ± 3.80 1.18 ± 0.38 – 65.00% 70.60% –
Bergin, 2020 (12) 2014–2019 the USA Retrospective General infertile population – PGT, ERA after PSM 99 36.92 ± 3.64 blastocyst 1 51.52% – – –
PGT, no ERA after PSM 176 36.79 ± 3.81 56.82% – – –
Cozzolino, 2020 (13) 2013–2018 Italy Retrospective RIF Natural or HRT M-RIF 2110 blastocyst Total ET – – – –
No PGT, no ERA 1840 37.9 (37.7–38.1) 2636 35.89% 34.20% – –
PGT, no ERA 144 38.2(38.0–38.5) 183 58,36.25% 38.20% – –
No PGT, ERA 111 38.6(38.3–38.9) 160 84,45.9% 40% – –
ERA, PGT 15 38.5(38.1–39.0) 21 7,33.33% 33.30% – –
S-RIF 488 blastocyst – – – –
No PGT, no ERA 408 38.5(38.2–38.7) 591 201,34.01% 34.80% – –
PGT, no ERA 53 38.3(38.1–38.6) 72 14,40% 39.80% – –
No PGT, ERA 23 38.9(37.8–41.9) 35 26,36.11% 37% – –
ERA, PGT 4 37.9(37.7–38.5) 6 2,33.33% 33.30% – –
Rao, 2021 (14) 2014- 2019 India Retrospective RIF – PGT, ERA 79 – blastocyst 1 53% – –
PGT, no ERA 54 1 – 47% – –
No PGT, no ERA 189 1 – 42% – –
Fodina, 2021 (15) 2017–2020 Latvia Retrospective RIF in ICSI cycles – No PGT, no ERA 72 34.0 (37.0–32.0 blastocyst – – – 44.40% BPLR 5.6%; MR1.4%
No PGT, ERA 22 36.0 (38.0–34.0) – – 36.40% BPLR 4.5%; MR9.1%
PGT, no ERA 87 35.0 (37.0–33.0) – – 49.30% BPLR 17.9%;MR4.5%
PGT, ERA 72 34.0 (38.0–32.5) – – 55.60% BPLR 1.4%;MR1.4%
Riestenberg, 2021 (16) 2018–2019 the USA Prospective General infertile population FET (HRT) PGT, ERA 147 36.9 ± 3.8 blastocyst 1 LBR 56.5% – 67.40% BPLR 15.4%;MR 15.2%
PGT, no ERA 81 34.9 ± 3.8 1 LBR 55.6% – 65.40% BPLR 14.8%;MR 13.2%
Doyle, 2022 (17) –the USA Retrospective General infertile population FET PGT, ERA 307 36.7 ± 4.1 blastocyst 1 44.60% 54.10%
ERA receptive N (%) 125 LBR48.8% 59.20%
ERA non-receptive N (%) 182 LBR41.7% 51.60%
PGT, no ERA 2284 36.7 ± 4.3 1 51.30% 58.90%
Doyle, 2022 (18) – the USA Double-blind, randomized, multicenter clinical trial General infertile population FET PGT, ERA 381 34.7 ± 2.7 blastocyst 1 LBR 58.5% 77.20% 68.80%
PGT, no ERA 386 34.5 ± 2.7 1 LBR 61.9% 79.50% 72.80%

The superscript “–” refers to missing data.

ERA: 1663.

 ERA could not optimize the reproductive outcomes in EET cycles in the general infertile population

In 2019, Rosen (10) conducted a retrospective study to describe the reproductive outcomes of 347 patients who had ERA-guided EET. The patients with non-receptive endometrium (42.3%) had a modified protocol accordingly. As a result, the patients with receptive endometrium and those with non-receptive endometrium had similar ongoing pregnancy rate (55% vs. 52.4%) and miscarriage rate (9% vs. 10.9%). However, this article did not include a control group who did not undergo ERA. Therefore, the effects of ERA may not be well demonstrated.

In 2021, Bergin (12) conducted a retrospective study, which included 110 patients who underwent ERA in EET cycles and 2,550 controls (non-ERA in EET cycles). Following propensity score matching (PSM), 99 patients in the study group were successfully matched to 176 controls. The results revealed that the live birth rate did not differ in the ERA group (n=99) and the non-ERA group (n=176) (51.52% vs. 56.82%). In the same year, Riestenberg conducted a prospective study (16), which included patients who had their first EET cycles with or without ERA. The results showed that the live birth rate was not significantly different between 147 patients with ERA and 81 controls without ERA (56.6% vs. 56.5%). In 2022, Doyle (17) conducted a large retrospective cohort study, which enrolled patients who underwent EET cycles guided by ERA (n=307) or not (n=2,284). The non-receptive rate was 59.1% in the ERA group. However, there was no difference in the live birth rate between ERA group and non-ERA group (44.6% vs. 51.3%). Doyle (18) also conducted a double-blind, multicenter, randomized clinical trial to compare the live birth rate in patients who had ERA (n = 381) or not (n = 386) in their single EET cycle. As a result, there were no significant differences in the live birth rate (58.5% vs. 61.9%), biochemical pregnancy rate (77.2% vs. 79.5%), and clinical pregnancy rate (68.8% vs. 72.8%) in both groups.

 ERA could not optimize the reproductive outcomes in EET cycles in patients with a history of previous failed embryo transfers

At the beginning, some studies reported a favorable trend for the reproductive outcomes in ERA-guided EET cycles in patients with a history of previous failed embryo transfers. In 2018, Leondires (8) conducted a prospective pilot study, which included patients who underwent ERA-guided EET with a history of previous failed EET (n=15). It revealed that the non-receptive rate was up to 86.7%, and the ongoing pregnancy rate could reach 73.3% with a personized embryo transfer (pET) guided by ERA. However, this article did not include a control group without ERA, and the sample size was too small. In the same year, Tan (9) conducted a retrospective study, which included patients with RIF (n=30), or one prior failure (n=13) who underwent EET or not. The results revealed that the patients whose embryo transfer guided by ERA (n=17) had increased implantation (76.5 vs. 53.8%) and ongoing pregnancy rates (64.7 vs. 42.3%) compared with those not (n=26). However, the differences were not statistically significant.

In 2019, Neves (11) conducted a retrospective study to compare the reproductive outcomes of patients with previous failed embryo transfer (≥ 1 previous failed EET) who underwent ERA (n=24) or not (n=119). The results revealed that the implantation rate (55.6% vs. 65.0%) and the pregnancy rate (58.3% vs.70.6%) did not show significant differences in both groups. In 2020, Cozzolino (13) conducted a retrospective multicenter cohort study in which patients classified as moderate RIF (n=2110) and severe RIF (n=488) were enrolled. Moderate RIF was defined as implantation failure after receiving at least three embryos transferred in different single embryo transfers without PGT or ERA, while severe RIF consisted of patients who failed after receiving at least five embryos transferred. The included patients in the moderate/severe RIF group were divided into four groups: group I, no PGT, no ERA (n=946/n=201); group II, PGT, no ERA (n=58/n=14); group III, no PGT, ERA (n=84/n=26); and group IV, ERA, PGT (n=7/n=2). The authors concluded that the reproductive outcomes did not differ between those who underwent ERA and those who did not. In 2021, Rao (14) retrospectively reviewed the reproductive outcomes of patients with RIF (n=322), who were divided into three groups: group I, ERA, PGT (n=79); group II, PGT, no ERA (n=54); and group III, no PGT, no ERA (n=189). Similarly, there was no difference in the implantation rate among the three groups (53% vs. 47% vs. 42%). In the same year, Fodina (15) conducted a retrospective study, which included 253 cycles with a history of RIF. The patients were divided into four groups: group I, no PGT, no ERA (n = 72); group II, PGT, no ERA (n = 87); group III, PGT, ERA (n = 72); and group IV, no PGT, ERA (n = 22). The results also showed that ERA failed to optimize the reproductive outcomes.

 Discussion

Apart from the embryo’s quality, the endometrial receptivity is extremely important, as it is the “soil” for the “seed” (the embryo). To the best of our knowledge, this review may first analyze the effects of ERA, eliminating embryo quality as a confounder. The present review was based on 11 available studies including 7,581 patients of whom 1,663 were evaluated by ERA. It revealed that ERA could not optimize the reproductive outcomes in both general infertile patients and patients with a history of previous failed embryo transfers in EET cycles.

The conclusion of the present review was consistent with previous studies, which stated that ERA was not effective in non-EET cycles. Recently, a retrospective multicenter cohort study with large sample size demonstrated that the LBR and cumulative LBR were even higher in non-ERA group than ERA group in 3,239 autologous transfers, even when considering possible confounders (19). A re-analysis of data from randomized controlled trial also revealed that ERA-guided pET actually reduced rather than increased the LBR in non-EET cycles (20). Another meta-analysis also stated that the LBR and OPR were comparable between the ERA and the non-ERA groups in infertile patients, even in the subgroup of patients with previous embryo transfer failures (21). The underlying mechanisms of ERA’s ineffectiveness may be as follows. First, whether the endometrial status was receptive in the post-ERA cycle was unknown, as endometrial biopsy of a modified cycle was not performed. Furthermore, not all non-receptive endometrium is pathological; an ERA-guided protocol may be not beneficial for successful pregnancy (22). Second, implantation is a multifactorial and complex process; other factors may also affect the endometrial status. One previous study found that only when ERA is used in conjunction with immune profiling that reproductive outcomes can be predicted (11). This indicated that ERA-guided protocol solely is not sufficient for successful implantation.

It should be noted that there remains conflicting data as to the impacts of ERA, especially in patients with RIF. Simon stated that ERA-guided pET group had a higher pregnancy rate per ET and a trend to a higher implantation rate and ongoing pregnancy rate (23). Luo’s (24) and Liu’s (6) meta-analysis both stated that ERA was not beneficial in patients without RIF or good-prognosis patients. However, it may improve the reproductive outcomes of patients with RIF. The underlying mechanism for the conflicting results among different literature may be as follows. First, the patients’ characteristics such as age and body mass index (BMI), IVF cycles protocol, embryo transfer protocol, number of transferred embryos, and the interval of ERA biopsy to pET varied among articles, potentially generating bias in the estimation of the impacts of ERA (25–27). Second, genetic abnormalities, tubal factors, immunological factors, and thrombophilias besides endometrial pathologies were all underlying causes of RIF (28). These would also become confounding factors in evaluating the effects of ERA in RIF. Last but not least, RIF has no clear definition (29). It was reported that when RIF was defined as two or more implantation failures, the live birth rate was significantly lower than when RIF was defined as three or more implantation failures (30). This may be also the reason of the conflicting data about ERA’s impacts.

A significant limitation of the present review is that most of the included studies were retrospective, and only one RCT was available. However, we conducted separate subgroup analyses according to the design of the studies. Another limitation was the heterogeneity of the studies included. Therefore, the results of the present review should be interpreted cautiously, and more randomized controlled trials were required to explore the potential effects of ERA.

 Conclusion

ERA-guided embryo transfers have no beneficial effects in optimizing the reproductive outcomes in general infertile population and patients with a history of previous failed embryo transfers in EET cycles.

 Author contributions

YM and YW drafted the manuscript and participated in data collection and analysis. XK and XL performed the statistical analysis. YL and FW participated in its design and coordination. All authors contributed to the article and approved the submitted version.

 Acknowledgments

We thank Bullet Edits limited for editing and proofreading the article for language proficiency.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1251699/full#supplementary-material

Abbreviations

ERA, endometrial receptivity array; IVF, in vitro fertilization; PGT, preimplantation genetic testing; ET, embryo transfer; RIF, recurrent implantation failure; FET, frozen embryo transfer; HRT, hormone replacement therapy; ICSI, intracytoplasmic sperm injection; IR, implantation rate; CPR, clinical pregnancy rate; LBR, live birth rate; OPR, ongoing pregnancy rate; BPLR, biological pregnancy loss rate; MR, miscarriage rate; PSM, propensity score matching; pET, personized embryo transfer.

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