XFNR D 21 00054 - R1

F&S Reviews
The impact of endometrial receptivity array on personalizing the embryo transfer for
infertile patients: A meta-analysis
--Manuscript Draft--
Manuscript Number: XFNR-D-21-00054R1
Full Title: The impact of endometrial receptivity array on personalizing the embryo transfer for
Short Title: ERA meta-analysis
Article Type: Systematic Review
Keywords: endometrial receptivity array, personalized embryo transfer, window of implantation,

IVF outcomes, ERA test
Corresponding Author: Loc Thai Ly, MD

Hungvuong Hospital
VIET NAM
Corresponding Author Secondary

Information:
Corresponding Author's Institution: Hungvuong Hospital
Corresponding Author's Secondary

Institution:
First Author: Loc Thai Ly, MD
First Author Secondary Information:
Order of Authors: Loc Thai Ly, MD
Huy Phuong Tran, MSc
Thuy Thi-Thanh Tran
Ly Thi Le
Bao The Pham
Sang Ngoc-Thanh Vu
Tuyet Thi-Diem Hoang
Order of Authors Secondary Information:
Abstract: Objective : To investigate the effectiveness of the endometrial receptivity array (ERA)
test on in vitro fertilization (IVF) outcomes.
Design : Meta-analysis.
Setting : Not applicable.
Patients : Infertile women undergoing standard embryo transfer (SET) or personalized

embryo transfer (PET) guided by ERA result.
Interventions : Searches were carried out in the databases: Pubmed/Medline,

ScienceDirect and Scopus. We included studies investigating IVF outcomes between
patients underwent SET and PET.
Main outcome measures : Implantation rate, clinical pregnancy rate, ongoing
pregnancy rate, miscarriage rate and live birth rate.
Results : Seventeen studies that fulfilled the criteria were included in this meta-
analysis. PET based on ERA showed no evidence to optimize the gestational
outcomes including implantation rate (RR = 1, 95%CI: 0.83 - 1.2), clinical pregnancy
rate (RR = 0.99, 95%CI: 0.85 - 1.15), ongoing pregnancy rate (RR = 0.99, 95%CI: 0.89
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- 1.11) and miscarriage rate (RR = 1.12, 95%CI: 0.81 - 1.54). Only patients who
underwent PET following the ERA test on their first IVF cycle significantly increased the
live birth rate (RR = 1.24, 95%CI = 1.03 - 1.49)
Conclusion : ERA does not show any significant improvement of IVF outcomes
except the live birth rate of patients undergoing first IVF cycle. How- ever, due to the
costly and time-consuming procedure of ERA, these patients should follow a standard
IVF to avoid the economical burden and stressful emotion when delaying pregnancy.
Additional research is required to ascertain the efficacy of ERA before achieving a
wider usage.
PROSPERO number : This study has been registered on the International Prospective
Register of Systematic Reviews Platform (PROSPERO). The registration number is
CRD42021255124.
Suggested Reviewers:
Opposed Reviewers:
Additional Information:
Question Response
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Detailed Response to Reviewers
RESPONSE TO EDITOR AND REVIEWERS
Editor note:
[General comment]- The topic is of interest and the analysis well done. However, the
reviewers point out major issues with the paper.
Response: Thank you so much for your precious time and constructive comments for
reviewing our manuscript.
[Minor comment 1]- Issues with the English language and clarity.
Response: Thank you so much for your comment. We went through the manuscript to
eliminate the English language problems and to revise the structure of our work. We hope
this improved version will qualify for the high standard of Fertility and Sterility Reviews.
[Minor comment 2]- Incorrect terminology.
Response: Thank you so much for your kind reminder. The revision was made accordingly.
(Page 3, line 53 to 55)
[Minor comment 3]- Weak introduction and discussion.
Response: Thank you so much for your comments. The revision was made accordingly.
(Page 2 to 5 for the introduction and page 25 to 27 for the discussion)
[Minor comment 4]- Poorly constructed table.
Response: Thank you so much for your kind reminder. The included studies were
rearranged into study design and the table was reconstructed accordingly. (Page 10)
Reviewer 1:
[Comment 1]- The abstract does not seem to summarize all of the cogent results. Although
clearly not everything can fit in the abstract, summarizing the live birth data would seem
important. Gaining a better understanding of the number of RCTs and retrospective studies
may also be important.
Response: Thank you for your comment. We agreed with your opinion and made revisions
accordingly. (Page 1 and 2, the results part in the abstract)
[Comment 2]- The information provided in the introduction is rather basic and takes some
time to arrive at the discussion of the window of implantation and the ERA test, which is the
focus of the manuscript. The readers are likely aware of natural conception, IVF, and FET.
accordingly. (Page 2 and 3)
[Comment 3]- The authors have an odd syntax when referencing specific studies (i.e. Study
[reference]). It would be more commendable to simply state the type of study (i.e. a
retrospective cohort) or state the author's name (i.e. Author et. al. found...).
Response: Thank you for your kind reminder. We agreed with your opinion and made
revisions accordingly.
[Comment 4]- The section on outcome metrics is helpful, but needs to be made more clear
and lay out the purpose of the section at the outset.
accordingly. (Page 3, line 52 to 55)
[Comment 5]- Were there studies which required voting and discussion amongst the three
independent reviewers?
Response: Thank you so much for your comment. We revised the sentence. As described
in the method, voting and discussion will be carried out if there is any disagreement. This is
the initial setting of our method to solve the problem with any discrepancies. However, all the
agreements were achieved by discussion between team members. The conflicts were not
too serious to vote on. (Page 5, line 122 and 123)
[Comment 6]- What studies contained irrelevant content (n=24)? What was irrelevant about
this content? This can certainly impact the outcomes in a meta-analysis.
Response: Thank you so much for your kind reminder. We added an explanation for
excluding 24 full-text studies in the revised version. The irrelevant content means the studies
carried out the ERA test but did not provide the data of gestational outcomes of infertile
patients. For example, case-report studies, studies focused on the bio-markers or
transcriptomic approach of ERA, studies use a different test (Win test) to identify the WOI,
studies focused on the cycle parameter of ERA (estrogen and progesterone level), etc…
(Page 7, line 178 to 180)
[Comment 7]- In the discussion, the authors state "contrary to popular belief". I am not
certain there is a uniform popular belief for this test at present.
accordingly. (Page 25, line 349)
[Comment 8]- The authors state in the discussion that, although the meta-analysis showed
improvement in this population, that patients undergoing their first embryo transfer should
follow a standard IVF procedure. Expounding on this point would be useful.
[Comment 9]- In the limitations section, the limitations of this specific meta-analysis should
be discussed and not limitations from meta-analyses in general.
[Comment 10]- In the conclusion, the authors discuss psychological and economic burdens.
However, this was not the focus of the manuscript and not really discussed until the
conclusion. I would think it best to focus this section on the data presented in the manuscript.
accordingly. (Page 27, line 431 and 432)
Reviewer 2:
[Comment 1]- Citation in tables chaotic
Response: Thank you for your comment. We agree about the chaos of the Table. However,
since the citation is the secondary information, we arranged our table by the study design as
shown in page 10.
[Comment 2]- Peculiar term definitions (short-term outcomes, long-term , instant outcome..)
instead of consensus : The International Glossary on Infertility - Fertility and Sterility.
https://www.fertstert.org › article › pdf by F Zegers-Hochschild · 2017 · Cited by 1070 —
Main Results and the Role of Chance: A consensus-based and ... the American Society for
Reproductive Medicine (ASRM)
[Comment 3]- Inappropriate reference citation, poor English and poor narrative
Response: Thank you very much for your comments. We went through the entire
manuscript to eliminate grammatical mistakes. The structure and references of the
manuscript were also revised. We hope the manuscript has been improved accordingly.
Conflict of Interest
Dear Editor in Chief,
On behalf of team members, I would like to submit the manuscript entitled: “The
impact of endometrial receptivity array on personalizing the embryo transfer for
infertile patients: A meta-analysis” to be considered for publication as an original
article in the Fertility and Sterility journal.
The endometrial receptivity array (ERA) test represents the personalized medicine
trend in the IVF field. It is indicated for patients to discover the displaced window of
implantation. Although many scientists supported the impact of ERA, others still
disagreed with its effectiveness. Our work found that ERA had a significant effect on a
specific group of patients. Therefore, we also encouraged further high-quality
research should be carried out and proposed integration of gestational outcome
metrics in IVF. We believe these findings will be of interest to the readers of your
journal.
We declare that this manuscript is original and has not been published before.
Additionally, the outcomes of our work are not influenced by any financial support. As
the corresponding author, I confirmed the manuscript had been read and approved
for submission by the named authors.
If you have any questions, do not hesitate to contact me via email.
We appreciate your consideration.
Sincerely,
Loc Ly
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Manuscript Click here to view linked References
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9 The impact of endometrial receptivity array on
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11 personalizing the embryo transfer for infertile patients:
12
13 A meta-analysis
14
15
16 Huy Phuong Trana , Thuy Thi-Thanh Trana , Ly Thi Leb , Bao The Phamc ,
17 Sang Ngoc-Thanh Vuc , Loc Thai Lya,∗, Tuyet Thi-Diem Hoanga,∗
18
19 a
Infertility Department, Hung Vuong Hospital, Ho Chi Minh City, Vietnam
20 b
School of Biotechnology, International University—Vietnam National University,
21 Ho Chi Minh City, Vietnam
22 c
Information Science Faculty, Sai Gon University,Ho Chi Minh City, Vietnam
23
24
25
26
27
28
Abstract
29 Objective: To investigate the effectiveness of the endometrial receptivity
30
31 array (ERA) test on in-vitro fertilization (IVF) outcomes.
32 Design: Meta-analysis.
33 Setting: Not applicable.
34 Patients: Infertile women underwent standard embryo transfer (SET) or
35
36 personalized embryo transfer (PET) guided by the ERA result.
37 Interventions: Searches were carried out in the databases: Pubmed/Medline,
38 ScienceDirect and Scopus. We included studies investigating the data of IVF
39
40
outcomes between patients underwent SET and PET.
41 Main outcome measures: Implantation rate, clinical pregnancy rate, on-
42 going pregnancy rate, miscarriage rate and live birth rate.
43 Results: Seventeen studies (4 RCTs and 13 cohort studies) that fulfilled the
44
45 criteria were included in this meta-analysis. PET based on ERA showed no
46 evidence to optimize the gestational outcomes including implantation rate
47 (RR = 1, 95%CI: 0.83 - 1.2), clinical pregnancy rate (RR = 0.99, 95%CI:
48 0.85 - 1.15), ongoing pregnancy rate (RR = 0.99, 95%CI: 0.89 - 1.11) and
49
50 miscarriage rate (RR = 1.12, 95%CI: 0.81 - 1.54). Only the live birth rate
51 significantly improved (RR = 1.17, 95%CI: 1 - 1.37) in the PET arm. Further
52 subgroup analysis indicated patients who underwent PET following the ERA
53
54
55 ∗
Corresponding Author
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59 Preprint submitted to Fertility and Sterility December 4, 2021
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9 test in their first IVF cycle remarkably increased the live birth rate (RR =
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1.24, 95%CI = 1.03 - 1.49). Conversely, PET in patients with a recurrent
12 implantation failure history showed no enhancement in the live birth rate
13 (RR = 0.86, 95%CI = 0.64 - 1.36).
14 Conclusion: ERA does not show any significant improvement of IVF out-
15
16 comes except the live birth rate of patients undergoing first IVF cycle. Addi-
17 tional research is required to ascertain the efficacy of ERA before achieving
18 a wider usage.
19 PROSPERO number: This study has been registered on the International
20
21 Prospective Register of Systematic Reviews Platform (PROSPERO). The
22 registration number is CRD42021255124.
23
24 Keywords: endometrial receptivity array, personalized embryo transfer,
25 window of implantation, , IVF outcomes
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29
1 1. Introduction
30
31 2 1.1. Background
32 3 Infertility is defined when a couple cannot conceive after one year of un-
33 4 protected intercourse [1]. IVF is a method used for assisting infertile couples
34
35 5 which involves the fertilization between eggs and sperm in a laboratory en-
36 6 vironment. With significant improvements in vitrification technology, frozen
37 7 embryo transfer (FET) is gaining popularity because of its safety and preg-
38
39
8 nancy success rate of approximately 45-50 % [2].
40 9 The implantation occurs when an embryo communicates with the uterine
41 10 lining successfully. This stage is called the window of implantation (WOI),
42 11 which starts on day 19 or 20 of the 28-day period and lasts 4 to 5 days [3].
43
44 12 However, it is essential to mention that FET is considered a blind transfer
45 13 since the knowledge of the optimal implantation time is unclear [4]. Re-
46 14 searchers have observed that the endometrial factor has been the primary
47 15 cause of implantation failure [5]. Arguably, several infertile women have dis-
48
49 16 placed WOI leading to failure in IVF [6]. A systematic review and meta
50 17 analysis study have summarized both the conventional and modern markers
51 18 to assess the endometrial receptivity [7].
52
53
19 The personalized embryo transfer (PET) guided by ERA was introduced
54 20 as an alternative to the conventional FET. Briefly, ERA is a commercially
55 21 available test based on the analysis of 238 genes in a endometrial tissue
56 22 sample obtained by biopsy during a specific interval in the menstrual cycle
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9 23 [8]. The endometrium is prepared for the mock cycle to carry out the ERA
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24 test. Noticeably, some patients may undergo one or two endometrial biopsies.
12 25 Embryo transfer is performed in the subsequent cycle after the precise timing
13 26 of WOI is confirmed by ERA. The ERA suggestion has been used to provide
14 27 personalized consideration of each patient’s WOI. The result of ERA has
15
16 28 two possible outcomes: receptive and non-receptive. Receptive endometrium
17 29 suggests that is a suitable time for embryo transfer. Conversely, non-receptive
18 30 endometrium indicates pre-receptive or post-receptive moment, and it is not
19 31 ideal for embryo transfer.
20
21 32 Numerous studies concurred with the effectiveness of ERA [9, 10]. More-
22 33 over, a 5-year randomized controlled trial research suggested performing an
23 34 ERA test for IVF patients in their first appointment may improve the chance
24
25
35 of pregnancy [11]. Despite the advantages of the PET guided by ERA, it still
26 36 remains a contentious topic. For example, R.Bassil et al. demonstrated the
27 37 ineffectiveness of ERA regardless of the good prognosis of IVF patients [12].
28 38 Besides, some case-report publications also described the controversial reli-
29
30 39 ability of ERA. Cho et al. reported the variability of ERA in one patient
31 40 [13]. Particularly, a 44-year-old healthy woman with a history of RIF had
32 41 four different ERA results, including post-receptive, pre-receptive and even
33
42 receptive. Another case-report study also illustrated a 41-year-old woman
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35 43 with ten years of unexplained RIF successfully achieved pregnancy without
36 44 following the assumed WOI guided by ERA [14].
37 45 Under these circumstances, this article performed a meta-analysis to sys-
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39 46 temize the up-to-date evidence of the ERA test on the successful IVF out-
40 47 comes. The measured outcomes were implantation rate (IR), clinical preg-
41 48 nancy rate (CPR), ongoing pregnancy rate (OPR), miscarriage rate (MR)
42 49 and live birth rate (LBR). Further subgroup analysis was also conducted
43
44 50 based on research approaches and characteristics of the patient population.
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46 51 1.2. Outcome metrics
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48
52 Result of a meta analysis is strongly influenced by the data of each com-
49 53 ponent study. Although an international glossary in fertility and sterility has
50 54 been published in 2017 [15], inconsistent calculation between selected studies
51 55 was observed. This section described the data handling of our meta analysis.
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53 56 In the related works, the outcome rate is calculated based on the current
54 57 stage as Eq. 1 or the overall process as Eq. 2. The selection depends on the
55 58 research objectives and the data availability.
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10 Total current success cases
11 Outcomestage = (1)
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Total previous success cases
13 Total current success cases
14 Outcomeoverall = (2)
15 Total embryo transfer cycles
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59 In the first stage, implantation rate (IR) is the number of successful im-
18 60 plantation divided by the number of embryos transferred. Various works
19 61 used this metric to evaluate their methods [11]. The succeeding stages are
20 62 the clinical and ongoing pregnancies. Typically, the studies have considered
21
22 63 the process from implantation to either clinical or ongoing pregnancies [16]
23 64 [9] [17] [18]. Comprehensively, many studies reported the entire pregnancy
24 65 cycle from implantation to delivery [10] [19] [11].
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66 Generally, the clinical pregnancy rate (CPR) has been calculated using
26
27 67 Eq. 2 as the number of patients reaching clinical pregnancy per the num-
28 68 ber of embryo transfer cycles. Similarly, the ongoing pregnancy rate (OPR)
29 69 is the ratio between the number of ongoing pregnancy and the number of
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70 embryo transfer cycles. Finally, the live birth rate (LBR) is determined by
32 71 dividing the number of deliveries by the total cycle attempts. Equally impor-
33 72 tant, the clinical miscarriage rate (MR) is defined as the loss of pregnancy
34 73 after a positive confirmation, either biochemical or clinical at any stage. It
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36 74 should be noticed that the definition of the gestational outcomes in IVF may
37 75 still depend on studies and the perspective of ART (assisted reproduction
38 76 technology) centers. Additionally, the roles of those factors in infertility re-
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77 search are still controversial. For example, IR is usually reported in many
41 78 works to address the chance of successful communication between embryo
42 79 and endometrium. However, a published study did not recommend the use
43 80 of IR due to its interpretational difficulties in both methodological issues and
44
45 81 patient-care perspective [20]. Besides, the cumulative live birth rate was also
46 82 described in related works with an effort to integrate a worldwide standard
47 83 of calculation [21].
48 84 The change in the denominator as in the Eq. 1 is based on the notion
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50 85 that all patients who failed pregnancy should be excluded from the further
51 86 calculation. For instance, the OPR was calculated as the number of ongoing
52 87 pregnancies divided by the total number of successful clinical pregnancies
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88 instead of the number of embryo transfer cycles [9, 18]. Besides, some studies
55 89 reported LBR by the ratio between successful deliveries and either clinical
56 90 or ongoing pregnancy [22, 23]. Noticeably, the decrease of the denominator
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9 91 in the former case leads to a higher value of outcome rate as in the Eq. 1,
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92 which undoubtedly confused patients.
12 93 Under these circumstances, this meta-analysis converted the denominator
13 94 into the total number of embryo transfer cycles as described in Eq. 2 and
14 95 addressed the impact of PET following the ERA suggestion.
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17 96 2. Materials and Methods
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19 97 2.1. Search strategy and study selection
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21 98 A comprehensive search of published English papers was conducted on
22 99 Pubmed/Medline, ScienceDirect and Scopus. Studies in which patients un-
23 100 dergoing the ERA test with gestational outcomes were compared to a matched
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25 101 control group are considered for the meta-analysis. The search procedure
26 102 complied with Preferred Reporting Items for Systematic Reviews and Meta-
27 103 Analysis (PRISMA) guidelines. The selected studies must provide gesta-
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104 tional outcomes, including IR, CPR, OPR, MR and LBR. We accepted ex-
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30 105 perimental and non-experimental studies, including randomized controlled
31 106 trials and cohort studies. The target papers were searched from January 2015
32 107 to December 2020. The suggested keywords were ”assisted reproduction”
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108 or ”in vitro fertilization”, ”endometrial receptivity array” or ”ERA test”,
35 109 ”personalized embryo transfer” or ”customized embryo transfer”, ”implanta-
36 110 tion rate”, ”clinical pregnancy rate”, ”ongoing pregnancy rate”, ”miscarriage
37 111 rate”, and ”live birth rate”. Case report, editorials or expert opinion, review
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39 112 or nonhuman papers were excluded from the search result.
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41 113 2.2. Data extraction
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114 The search and data extraction were performed independently by three
44 115 authors to avoid bias. Data were retrieved from papers and then system-
45 116 atically rearranged into tables. Additional data were achieved through ref-
46 117 erences or other sources, including published conference posters and pro-
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48 118 ceedings. Studies were classified based on experimental or non-experimental
49 119 research design. Other essential criteria were sample size and characteristics
50 120 of participants (age, prognosis, history of recurrent implantation failure, pa-
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121 tients who underwent first IVF cycle, donor cycle). The final results were
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53 122 then compared between team members. Voting and discussion will be carried
54 123 out if there is any disagreement.
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9 124 2.3. Quality assessment of the selected studies
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11 125 We performed the quality evaluation of cohort studies using the STROBE
12 126 guidelines [24]. The method was based on the quality of six criteria: title and
13 127 abstract, introduction, methods, results, discussion and other information.
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15 128 This assessment mainly concentrated on the overall quality of the selected
16 129 cohort studies. It is important to note that low-quality studies were not ex-
17 130 cluded from this analysis. Four answers were provided: ”yes”, ”no”, unclear”,
18 131 and ”N/A”. STROBE score of each study was reported as the percentages
19
20 132 of the total number of ”yes” over the total number of items. The total items
21 133 for each article did not include N/A answers.
22 134 For the bias assessment of RCT studies, we applied the Cochrane Col-
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135 laboration’s tool [25]. Briefly, we evaluated the quality of the RCTs through
25 136 seven domains: random sequence generation, allocation concealment, selec-
26 137 tive reporting, blinding of participants, blinding of the outcome, incomplete
27 138 outcome data and other sources of bias. The risk of bias judgements was
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29 139 classified into ”low”, ”unclear”, and ”high”. The traffic light diagram was
30 140 plotted to visualize the overall quality. There was no exclusion of the low-
31 141 quality studies.
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142 Three team members determined the risk of bias independently. All dis-
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34 143 crepancies related to the author’s judgments were resolved by discussion and
35 144 consensus. Funnel plots were used to assess the publication bias with Egger’s
36 145 test.
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39 146 2.4. Statistical analysis
40 147 Mantel–Haenszel random-effect model was applied to pool data. Compar-
41 148 ative statistics were carried out between the experimental and control groups.
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43 149 The risk ratio with 95% CI was calculated, and forest plots were used to vi-
44 150 sualize the studies effect and the average weight. The I 2 statistical test was
45 151 employed to assess heterogeneity. According to the Cochrane Handbook for
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152 Systematic Reviews of Interventions, the level of heterogeneity may change
48 153 depending on the I 2 level. An I 2 value of 0% indicates no observed hetero-
49 154 geneity, I 2 values from 50% to 75% may represent moderate heterogeneity,
50 155 and I 2 values from 75% or higher may indicate high heterogeneity.
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52 156 Further moderate analysis was performed to address the between-study
53 157 heterogeneity. We divided the subgroup based on the characteristics of the
54 158 population, including patients with RIF history (RIF population), general in-
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159 fertile patients who underwent IVF cycle (IVF population), donor cycle (DC
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9 160 population) and patients who underwent the pre-genetic test (PGT-A pop-
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161 ulation). Moreover, RCT and cohort studies were also analyzed separately
12 162 due to the methodological diversity between experimental and observational
13 163 research.
14 164 According to the Cochrane Handbook for Systematic Reviews of Inter-
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16 165 ventions, when ten or more studies were included in one meta-analysis, we
17 166 assessed the risk of publication bias and the small-study effect using funnel
18 167 plot and Egger’s test. Sensitivity analysis was also carried out using the
19 168 leave-one-out method to address whether the conclusion was robust or influ-
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21 169 enced by any studies. Data were analyzed using R software version 1.4.1106.
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24 170 3. Results
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26 171 3.1. Study selection
27 172 We identified 850 articles from the target databases and 9 records from
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173 other sources through the comprehensive combined search. Then, the dupli-
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30 174 cate removal process excluded 453 studies. The remaining 406 papers were
31 175 then reviewed and resulted in 64 eligible studies for full-text evaluation. After
32 176 that, we excluded the review studies (n=4), book chapters (n=5), trial pro-
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177 tocol (n=2), studies with abstract only (n=8) and conference abstract (n=4).
35 178 Additionally, 24 full-text studies were classified into irrelevant content due
36 179 to the analysis did not concentrate on the data of gestational outcomes of
37 180 infertile patients. Finally, 17 studies satisfied all the pre-determined criteria
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39 181 and qualified for qualitative and quantitative analysis.
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11 Records identified through Additional records identified
Identification
12 database searching (N = 850) through other sources (N = 9)

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Records after removing
18 Duplicate removed (N = 453)
19 duplicates (N = 406)
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Screening
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Records remaining after
24 Records excluded
screening title and abstract
25 (N = 274)
(N = 132)
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Eligibility
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30 Full-text articles assessed for
31 eligibility (N = 64) 1. Full-text articles excluded
32 (N = 24)
33 2. Abstract only (N = 8)
34 3. Conference abstract (N = 4)
35 4, Review (N = 4)
Included
36 Studies included in qualitative 5. Book chapter (N = 5)

37 and quantitative synthesis 6. Trial protocol (N = 2)
38 (N =17)
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42 Figure 1: PRISMA flowchart of the study screening and selection for meta analysis
43
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45 182 3.2. Description of the selected studies
46 183 Detailed characteristics including study design, country, year, patient
47 184 characteristics, sample size, mean age and the primary outcomes of the 17
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49 185 eligible papers were illustrated in Table 1. In general, 17 studies (4 RCTs
50 186 and 13 cohort studies) included the data of 7052 patients who underwent
51 187 PET and SET. Interestingly, data from those papers partly covered the di-
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188 versity of ethnic groups except patients from Africa. The majority of studies
54 189 were published from America (n=9) and Asia (n=7), whereas the remained
55 190 records were contributed from Europe (n=5) and Australia (n=1). The age
56 191 range of female patients was between 18 and 46 years old across the studies.
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9 192 Additionally, almost all studies focused on applying the ERA test on patients
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193 with a history of recurrent implantation failure (n = 12). In contrast, only 5
12 194 studies investigated the impact of ERA on good prognosis patients or general
13 195 patients who underwent IVF. The gestational outcomes of 17 studies were
14 196 IR, CPR, OPR, MR and LBR.
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16 197 The initial number of participants was not the same as the end of the
17 198 experiment for some studies. The nature of long gestation in human caused
18 199 this difference, where patients withdrew at the middle of the studies. There-
19 200 fore, when calculating the effect size from the raw count data, instead of
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21 201 using the total number of enrolled participants, we excluded missing data if
22 202 possible to ensure a more precise and conservative pooled effect estimation.
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24 203 3.3. Quality assessment of the selected studies
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26 204 The summary of quality assessment of 4 RCTs according to the Cochrane
27 205 collaboration tool was illustrated in Figure 2 and 3 which based on the
28 206 methodology quality items and the percentages across all selected studies,
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30 207 respectively. No study described the blinding of participants and outcomes,
31 208 leading to a high risk of bias in all 4 RCTs. Nevertheless, when considering
32 209 the setting of embryo transfer and ERA test, doctors and patients have to
33
34
210 prepare the endometrium for both the mock and transferring cycle. This
35 211 process took long time for dosage adjustment and follow-up examination.
36 212 Additionally, ERA indication must be discussed with patients before the
37 213 process due to high cost and its controversial result. Hence, we suggested
38
39 214 blinding of participants in this circumstance was not applicable. When ex-
40 215 cluding the blinding criteria as in Figure 4 and 5, the two studies of Carlos
41 216 et al. achieved moderate level of quality [33] [11]. However, the remaining
42 217 two RCTs were still at high risk of bias due to the incomplete data outcome
43
44 218 and lack of selective reporting [32] [16].
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 9
60
61
62
63
64
65
65
64
63
62
61
60
59
58
57
56
55
54
53
52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Table 1: Characteristics of the selected studies
Study Study design Country Duration Patients Female age Measured

Characteristics # Experimental Control outcome(s)
IR, CPR,
[19] Cohort review Canada N/A RIF patients 97 36.1 ± 4.0 35.9 ± 3.8
MR, LBR
IR, OPR,
[22] Cohort review Canada 2014 - 2017 RIF patients 88 37.5 ± 4.8
LBR
CPR, OPR,
[26] Cohort review USA N/A IVF patients 347 N/A
MR
IR, CPR,
[9] Cohort study India 2013 - 2017 RIF patients 248 34.11 ± 4.49 33.67 ± 5.12
OPR
IR, CPR,
[10] Cohort study Japan 2015 - 2016 RIF patients 50 40.08 ± 5.16 38.82 ± 3.90 MR, OPR,
LBR
[12] Cohort study Canada 2016 - 2017 IVF patients 53 36.3 ± 0.4 35.6 ± 4 OPR
10
[17] Cohort study Europe 2012 - 2018 RIF patients 501 39.25 ± 3.99 39.18 ± 3.80 IR, CPR
IR, CPR,
[23] Cohort study India 2014 - 2019 RIF patients 722 32.29 ± 5.57 30.93 ± 5.66
MR, LBR
[27] Cohort study Europe 2013 - 2018 RIF patients 2110 18 - 45 OPR
[28] Cohort study USA 2017 - 2019 IVF patients 296 N/A LBR, MR
[29] Cohort study India 2013- 2016 RIF patients 374 34.9 33.7 CPR,MR
IR, CPR,
[30] Cohort study USA 2013 - 2016 RIF patients 27 36.9 ± 3.6 40.7 ± 6.4
LBR
[31] Cohort study USA N/A RIF patients 42 37.6 ± 4.3 36.0 ± 5.7 LBR
Europe, USA IR, CPR,
[11] Randomized controlled trial 2013 - 2017 IVF patients 458 ≤ 37
and Asia MR, LBR
IR, CPR,
[16] Randomized controlled trial Spain 2013 - 2016 IVF patients 356 ≤ 38
OPR, MR
[32] Randomized controlled trial Japan 2016 - 2018 RIF patients 506 36.6 IR
Europe, Asia,
[33] Randomized controlled trial N/A IVF patients 548 ≤ 37 LBR
Australia
1
2
3
4
5
6
7
8
9 Risk of bias domains
10 D1 D2 D3 D4 D5 D6 D7 Overall
11
12
Carlos (2020) ++ -- xx xx ++ ++ ++ xx
13
14 Seshadri (2018) ++ -- xx xx xx xx -- xx
Study
15
16 Simon (2016) ++ -- xx xx xx xx -- xx
17
18 Carlos (2019) ++ -- xx xx ++ ++ ++ xx
19
20 Judgement
D1: Random sequence generation
21 D2: Allocation concealment + Low
D3: Blinding of participants and personnel - Unclear
22 D4: Blinding of outcome assessment
D5: Incomplete outcome data x High
23 D6: Selective reporting
24 D7: Other sources of bias
25
26 Figure 2: Bias assessment diagram of the included RCT studies based on methodological
27 quality items
28
29
30
31 Random sequence generation
32 Allocation concealment
33 Blinding of participants and personnel
34 Blinding of outcome assessment
35 Incomplete outcome data
36 Selective reporting
37 Other sources of bias
38 Overall
39 0% 25% 50% 75% 100%
40
41 High risk of bias Some concerns Low risk of bias
42
43 Figure 3: Bias assessment diagram of the included RCT studies based on percentage
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 11
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9 Risk of bias domains
10 D1 D2 D5 D6 D7 Overall
11
12 Carlos (2020) ++ -- ++ ++ ++ -x
13
14 Seshadri (2018) ++ -- xx xx -- xx
Study
15
16 Simon (2016) ++ -- xx xx -- xx
17
18
19 Carlos (2019) ++ -- ++ ++ ++ -x
20 Judgement
21 D1: Random sequence generation
D2: Allocation concealment + Low
22 D5: Incomplete outcome data - Unclear
D6: Selective reporting
23 D7: Other sources of bias x High
24
25 Figure 4: Bias assessment diagram of the included RCT studies based on methodological
26 quality items after excluding blinding criteria
27
28
29
30 Random sequence generation
31 Allocation concealment
32
Incomplete outcome data
33
Selective reporting
34
Other sources of bias
35
36 Overall
37 0% 25% 50% 75% 100%
38 High risk of bias Some concerns Low risk of bias

39
40
41 Figure 5: Bias assessment diagram of the selected RCT studies based on percentage after
42 excluding blinding criteria
43
44
45 219 Figure 6 showed the bias assessment score in percentages of the 13 cohort
46 220 studies. Generally, no study reached the maximum score. Only one study
47
48
221 of Rosen et al. was rated below 50% (45%) as the lowest quality study
49 222 [26]. However, we did not exclude low-quality papers in this analysis. The
50 223 highest quality (85%) study was achieved by Tan et al. [22]. Furthermore,
51 224 the remaining research showed that the overall scores varied from moderate-
52
53 225 to high-quality levels (50% to 85%).
54 226 When addressing the quality based on sections as in Figure 7, the majority
55 227 of the selected studies had issues in reporting the study size and addressing
56 228 potential bias. The cohort study as mentioned had problems in providing
57
58
59 12
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9 229 variables, data source, bias, study size, which led to the lowest quality at
10
11
230 45% [26]. Additionally, 5 studies did not provide sufficient discussion for
12 231 interpreting their findings [31, 28, 26, 30, 29]. Moreover, the limitation were
13 232 not fully investigated in 7 studies [9, 23, 31, 28, 26, 30, 29]. No information
14 233 of funding and was observed in all studies.
15
16
17 Churchill (2017a)
18
Churchill (2017b)
19
20 Tomoko (2017)
21 Rawad (2018)
22 Tan (2018)
23
24 Nalini (2018)
25 Aaron (2019) Low

26 High
Ana (2019)
27 Unclear
Arianne (2020)
28
29 Mauro (2020)
30 Priya (2020)
31
Hombalegowda (2020)
32
33 Jayesh (2021)
34 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
35
36
37 Figure 6: Bias assessment diagram of the included cohort studies based on percentage
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 13
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9
Hombalegowda
10
11
Churchill
Churchill
Tomoko
(2017a)
(2017b)
Arianne
Jayesh
Rawad
(2018)
12
(2017)
(2018)
(2018)
(2019)
(2019)
(2020)
(2020)
(2020)
(2020)
(2021)
Mauro
Aaron
Nalini
Priya
Ana
Tan
13 Section
14 Title and abstract
Introduction
15 Background
16 Objective
17 Methods
18 Study design
Setting
19 Participants
20 Variables
21 Data sources/Measurements
22 Bias
Study size
23
Quantitative variables
24 Statistical methods
25 Results
26 Participants
Descriptive data
27
Outcome data
28 Main results
29 Other analysis
30 Discussion
31 Key results
Limitations
32 Interpretation
33 Generalizability
34 Other information
35 Funnding
36 Low High Unclear

37
38
39 Figure 7: Bias assessment diagram of the selected cohort studies based on section quality
40
41 234 3.4. Subgroup Analysis
42
43 235 3.4.1. Meta-analysis of Implantation rate
44 236 There were total ten studies which offered the data of IR between patients
45
46 237 underwent SET and PET following ERA suggestion [9, 10, 11, 22, 19, 23, 32,
47 238 16, 30, 17]. Generally, the overall result of ERA did not show any evidences
48 239 to improve the IR (RR = 1, 95%CI: 0.83 - 1.2). The result was not significant
49 240 and the moderate heterogeneity was observed within studies (I 2 = 59%, p
50
51 241 < 0.01). Although many studies supported the conclusion that performing
52 242 PET guided by ERA test may enhance IR, this research found that there
53 243 was no significant difference between two methods.
54
55
244 Figure 8 illustrated the subgroup analysis based on study design. Data
56 245 from 3 RCTs witnessed that ERA improved the IR of the PET arm in com-
57
58
59 14
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9 246 parison to the SET arm (RR = 1.37, 95%CI: 1 - 1.88) with substantial
10
11
247 heterogeneity (I 2 = 66%, p = 0.05). Conversely, pooled data from cohort
12 248 studies did not show any improvement in IR between two group of patients
13 249 (RR = 0.88, 95%CI: 0.73 - 1.05, I 2 = 30%, p = 0.18).
14 250 Regarding subgroup analysis based on characteristics of patient popula-
15
16 251 tion as in Figure 9, IR was improved in the IVF population when applying
17 252 PET (RR = 1.18, 95%CI: 0.98 - 1.42). However, the result was insignifi-
18 253 cant. Regarding PGT-A population, ERA test had no positive impact on
19 254 this group (RR = 0.84, 95%CI: 0.57 - 1.24). Interestingly, the DC patients
20
21 255 who underwent a SET cycle had a significantly higher IR than PET following
22 256 the ERA suggestion (RR = 0.57, 95%CI: 0.36 - 0.92).
23
24 ERA sFET
25 Study Events Total Events Total Risk Ratio RR 95%−CI Weight
26 Approach = Cohort
Tan (2018) 20 31 25 40 1.03 [0.72; 1.47] 10.0%
27 Tomoko (2017)
Arianne (2020)
6
11
19
31
20
9
61
36
0.96
1.42
[0.45;
[0.68;
2.05]
2.97]
4.3%
4.4%
28 Priya (2020)
Churchill (2017a)
109
8
440
26
104
14
432
27
1.03
0.59
[0.81;
[0.30;
1.30]
1.17]
12.7%
4.9%
29 Jayesh (2021)
Jayesh (2021)
21
13
58
42
125
85
320
193
0.93
0.70
[0.64;
[0.44;
1.34]
1.13]
9.7%
7.6%
30 Ana (2019)
Ana (2019)
13
8
24
32
77
91
119
158
0.84
0.43
[0.57;
[0.23;
1.24]
0.80]
9.2%
5.7%
31 Random effects model 703
Heterogeneity: I 2 = 30%, τ2 = 0.0208, p = 0.18
1386 0.88 [0.73; 1.05] 68.5%
32 Approach = RCT
33 Carlos (2020)
Taguchi (2018)
88
48
201
253
80
22
220
253
1.20
2.18
[0.95;
[1.36;
1.52]
3.50]
12.7%
7.7%
34 Simon (2016) 43 90 53 128 1.15 [0.86; 1.56] 11.2%
Random effects model 544 601 1.37 [1.00; 1.88] 31.5%
35 Heterogeneity: I 2 = 66%, τ2 = 0.0504, p = 0.05
36 Random effects model 1247 1987 1.00 [0.83; 1.20] 100.0%

Heterogeneity: I 2 = 59%, τ2 = 0.0540, p < 0.01
37 0.5 1 2
38
39 Figure 8: Forest plot of PET versus SET for the implantation rate outcome based on
40 study design
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 15
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9 ERA sFET
Study Events Total Events Total Risk Ratio RR 95%−CI Weight
10
Population = RIF
11 Tan (2018) 20 31 25 40 1.03 [0.72; 1.47] 10.0%
Tomoko (2017) 6 19 20 61 0.96 [0.45; 2.05] 4.3%
12 Arianne (2020) 11 31 9 36 1.42 [0.68; 2.97] 4.4%
Priya (2020) 109 440 104 432 1.03 [0.81; 1.30] 12.7%
13 Taguchi (2018) 48 253 22 253 2.18 [1.36; 3.50] 7.7%
Churchill (2017a) 8 26 14 27 0.59 [0.30; 1.17] 4.9%
14 Jayesh (2021) 21 58 125 320 0.93 [0.64; 1.34] 9.7%
16 Population = IVF
Carlos (2020) 88 201 80 220 1.20 [0.95; 1.52] 12.7%
17 Simon (2016) 43 90 53 128 1.15 [0.86; 1.56] 11.2%
18 Heterogeneity: I 2 = 0%, τ2 = 0, p = 0.83
19 Population = DC
20 Jayesh (2021)
Ana (2019)
13
8
42
32
85
91
193
158
0.70 [0.44; 1.13]
0.43 [0.23; 0.80]
7.6%
5.7%
351 0.57 [0.36; 0.92] 13.3%
22 Population = PGTA
23 Ana (2019)
Random effects model
13 24
24
77 119
119
0.84 [0.57; 1.24]
0.84 [0.57; 1.24]
9.2%
9.2%
24 Heterogeneity: not applicable

1987 1.00 [0.83; 1.20] 100.0%
26 0.5 1 2
27
28 Figure 9: Forest plot of PET versus SET for the implantation rate outcome based on
29 patient characteristics
30
31
257 3.4.2. Meta-analysis of Clinical pregnancy rate
32
33 258 We included 10 studies to analyze the CPR outcome [9, 10, 11, 19, 23, 16,
34 259 26, 30, 17, 29]. Figure 10 showed the subgroup analysis based on study design
35 260 while Figure 11 described data based on patient characteristics. The overall
36
37 261 pooled data indicated no significant difference in the CPR between two com-
38 262 parators (RR = 0.99, 95%CI: 0.85 - 1.15). The meta-data also suggested a
39 263 moderate heterogeneity among 10 studies (I 2 = 57%, p < 0.01). The results
40
41
264 of CPR were inconsistent between RCT and cohort studies. Meta-data of
42 265 RCT studies revealed that ERA significantly enhanced the CPR (RR = 1.30,
43 266 95%CI: 1.09 - 1.54) while result from cohort studies indicated no significant
44 267 impact (RR = 0.91, 95%CI: 0.79 - 1.06). Low heterogeneity was observed
45
46 268 among these data set, (I 2 = 20%, p = 0.26) and (I 2 = 34%, p = 0.14),
47 269 respectively.
48 270 There was only one study investigating the CPR of the PGT-A popula-
49 271 tion. Subgroup analysis of RIF and PGT-A population revealed that ERA
50
51 272 had no significant effect on this group of patients, (RR = 1.03, 95%CI: 0.87
52 273 - 1.22) and (RR = 0.83, 95%CI: 0.68 - 1.18) respectively. Additionally, no
53 274 heterogeneity (I 2 = 0%) was found in the RIF subgroups. In the IVF popula-
54
55
275 tion, the result demonstrated an increase of CPR in the PET group. However,
56 276 this optimization was not significant and the heterogeneity was substantial
57
58
59 16
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9 277 (RR = 1.17, 95%CI: 0.95 - 1.44), (I 2 = 74%, p = 0.02). Regarding further
10
11
278 subgroup analysis based on the DC population, pooled results witnessed a
12 279 significantly higher CPR in the SET group than that of the PET group (RR
13 280 = 0.59, 95%CI: 0.41 - 0.85). The heterogeneity was not detected in this DC
14 281 population (I 2 = 0%, p = 0.51).
15
16
17 Study
ERA sFET
Events Total Events Total Risk Ratio RR 95%−CI Weight
19 Tomoko (2017)
Arianne (2020)
5
9
10
40
12
12
34
45
1.42
0.84
[0.66; 3.06]
[0.40; 1.79]
3.1%
3.2%
20 Priya (2020)
Aaron (2019)
87
109
179
147
78
148
181
200
1.13
1.00
[0.90; 1.41]
[0.88; 1.14]
13.0%
16.3%
Jayesh (2021)
5
16
11
35
12
87
16
175
0.61
0.92
[0.30; 1.23]
[0.62; 1.36]
3.6%
8.1%
22 Jayesh (2021)
Ana (2019)
9
14
24
24
56
84
101
119
0.68
0.83
[0.39; 1.17]
[0.58; 1.18]
5.3%
8.9%
23 Ana (2019)
Nalini (2018)
11
10
32
16
103
12
158
19
0.53
0.99
[0.32; 0.86]
[0.59; 1.65]
6.1%
5.8%
1048 0.91 [0.79; 1.06] 73.4%
25 Approach = RCT
26 Carlos (2020)
Simon (2016)
83
42
141
49
73
45
148
74
1.19 [0.96; 1.48]
1.41 [1.14; 1.75]
13.4%
13.3%
222 1.30 [1.09; 1.54] 26.6%

29 Heterogeneity: I 2 = 57%, τ2 = 0.0311, p < 0.01
0.5 1 2
30
31 Figure 10: Forest plot of PET versus SET for the clinical pregnancy rate based on study
32
design
33
34
35
36 ERA sFET
37
38 Population = RIF
Tomoko (2017) 5 10 12 34 1.42 [0.66; 3.06] 3.1%
39 Arianne (2020)
Priya (2020)
9
87
40
179
12
78
45
181
0.84
1.13
[0.40;
[0.90;
1.79]
1.41]
3.2%
13.0%
Jayesh (2021)
5
16
11
35
12
87
16
175
0.61
0.92
[0.30;
[0.62;
1.23]
1.36]
3.6%
8.1%
41 Nalini (2018)
10 16
291
12 19
470
0.99
1.03
[0.59;
[0.87;
1.65]
1.22]
5.8%
36.7%
43 Population = IVF
Carlos (2020) 83 141 73 148 1.19 [0.96; 1.48] 13.4%
44 Simon (2016)
Aaron (2019)
42
109
49
147
45
148
74
200
1.41
1.00
[1.14;
[0.88;
1.75]
1.14]
13.3%
16.3%
422 1.17 [0.95; 1.44] 42.9%
46 Population = DC
47 Jayesh (2021)
Ana (2019)
9
11
24
32
56
103
101
158
0.68 [0.39; 1.17]
0.53 [0.32; 0.86]
5.3%
6.1%
48 Random effects model
2 2
Heterogeneity: I = 0%, τ = 0, p = 0.51
56 259 0.59 [0.41; 0.85] 11.4%
49
Population = PGTA
50 Ana (2019) 14 24 84 119 0.83 [0.58; 1.18] 8.9%

53 0.5 1 2
54
55 Figure 11: Forest plot of PET versus SET for the clinical pregnancy rate based on patient
56 characteristics
57
58
59 17
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9 282 3.4.3. Meta-analysis of Ongoing pregnancy rate
10
11 283 The data of 7 studies that evaluated the OPR outcome based on study
12 284 design and patient characteristics was illustrated in Figure 12 and Figure
13 285 13, respectively [9, 10, 12, 22, 27, 26, 16]. The overall risk ratio of OPR
14 286 was 0.99 (95%CI: 0.89 - 1.11), indicating no optimization when applying
15
16 287 PET following ERA suggestion. There was no heterogeneity observed among
17 288 studies. Only one RCT provided OPR data and no significant difference
18 289 was noted between the two comparators (RR = 1.27, 95%CI: 0.86 - 1.77).
19
20
290 Similarly, pooled data from cohort studies yielded consistent results with the
21 291 RCT study (RR = 0.97, 95%CI: 0.87 - 1.09). No heterogeneity was found
22 292 among these groups.
23 293 According to Figure 13, in the good prognosis (GP) group, patients un-
24
25 294 derwent PET following ERA did not show any significant enhancement in
26 295 the OPR outcome (RR = 0.95, 95%CI: 0.55 - 1.64). Similarly, patients who
27 296 underwent DC cycles did not have advantages in the OPR outcome when
28
297 performing the ERA test (RR = 0.69, 95%CI: 0.38 - 1.25). In addition, a
29
30 298 subgroup analysis of RIF and IVF population demonstrated no significant
31 299 enhancement of OPR, (RR = 1.01, 95%CI: 0.87 - 1.17) and (RR = 1.04,
32 300 95%CI: 0.82 - 1.32), respectively. Low heterogeneity was noted among these
33
34
301 subgroups.
35
36 Study
ERA sFET
38 Rawad (2018)
Tan (2018)
9
16
27
31
177 503
20 40
0.95
1.03
[0.55; 1.64]
[0.65; 1.64]
4.0%
5.7%
39 Tomoko (2017)
Mauro (2020)
2
72
18
153
8 59
1147 2445
0.82
1.00
[0.19; 3.52]
[0.84; 1.19]
0.6%
39.9%
40 Aaron (2019)
Jayesh (2021)
77
15
147
35
110 200
73 175
0.95
1.03
[0.78; 1.16]
[0.67; 1.56]
30.4%
6.8%
41 Jayesh (2021)
8 24
435
49 101
3523
0.69
0.97
[0.38; 1.25]
[0.87; 1.09]
3.3%
90.7%
43 Approach = RCT
Simon (2016) 27 49 33 74 1.24 [0.86; 1.77] 9.3%
Heterogeneity: not applicable
45
0.2 0.5 1 2 5
47
48 Figure 12: Forest plot of PET versus SET for the ongoing pregnancy rate based on study
49
design
50
51
52
53
54
55
56
57
58
59 18
60
61
62
63
64
65
1
2
3
4
5
6
7
8
9
ERA sFET
10 Study Events Total Events Total Risk Ratio RR 95%−CI Weight
11 Population = GP
Rawad (2018) 9 27 177 503 0.95 [0.55; 1.64] 4.0%
Heterogeneity: not applicable
13
Population = RIF
14 Tan (2018) 16 31 20 40 1.03 [0.65; 1.64] 5.7%
Tomoko (2017) 2 18 8 59 0.82 [0.19; 3.52] 0.6%
15 Mauro (2020) 72 153 1147 2445 1.00 [0.84; 1.19] 39.9%
Jayesh (2021) 15 35 73 175 1.03 [0.67; 1.56] 6.8%
Heterogeneity: I 2 = 0%, τ2 = 0, p = 0.99
17
Population = IVF
18 Simon (2016) 27 49 33 74 1.24 [0.86; 1.77] 9.3%
Aaron (2019) 77 147 110 200 0.95 [0.78; 1.16] 30.4%
20
Population = DC
21 Jayesh (2021) 8 24 49 101 0.69 [0.38; 1.25] 3.3%

24 0.2 0.5 1 2 5
25
26 Figure 13: Forest plot of PET versus SET for the ongoing pregnancy rate based on patient
27 characteristics
28
29
30 302 3.4.4. Meta-analysis of Miscarriage rate
31
32
303 Seven studies were investigated based on the MR outcome [11, 10, 19,
33 304 23, 16, 26, 29]. Overall, no heterogeneity was noted between these studies
34 305 (I 2 = 0%, p = 0.68). From Figure 15, selected data indicated no significant
35 306 difference (RR = 1.12, 95%CI: 0.81 - 1.54) in the MR between two methods
36
37 307 of embryo transfer no matter patients belonged to RIF or IVF group, (RR =
38 308 0.92, 95%CI: 0.56 : 1.53) and (RR = 1.27, 95%CI: 0.84 - 1.93) respectively.
39 309 Further subgroup analysis based on study design (Figure 14) also witnessed
40
41
310 the consistent result between RCTs (RR = 1.32, 95%CI: 0.76 - 2.28) and
42 311 cohort studies (RR = 1.02, 95%CI: 0.69 - 1.52).
43
44 ERA sFET
45
Approach = Cohort
46 Tomoko (2017) 2 5 6 20 1.33 [0.38; 4.72] 6.4%
Arianne (2020) 4 34 2 40 2.35 [0.46; 12.07] 3.9%
47 Priya (2020) 13 179 19 181 0.69 [0.35; 1.36] 22.7%
Aaron (2019) 16 147 18 200 1.21 [0.64; 2.29] 25.3%
48 Nalini (2018) 4 16 4 16 1.00 [0.30; 3.32] 7.2%
50 Approach = RCT
Carlos (2020) 17 141 11 148 1.62 [0.79; 3.34] 19.8%
51 Simon (2016) 9 49 9 49 1.00 [0.43; 2.30] 14.8%

54 0.1 0.5 1 2 10
55
56 Figure 14: Forest plot of PET versus SET for the miscarriage rate based on study design
57
58
59 19
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65
1
2
3
4
5
6
7
8
9 Study
ERA sFET
10
Population = RIF
11 Tomoko (2017) 2 5 6 20 1.33 [0.38; 4.72] 6.4%
Arianne (2020) 4 34 2 40 2.35 [0.46; 12.07] 3.9%
12 Priya (2020) 13 179 19 181 0.69 [0.35; 1.36] 22.7%
Nalini (2018) 4 16 4 16 1.00 [0.30; 3.32] 7.2%
14
Population = IVF
15 Carlos (2020) 17 141 11 148 1.62 [0.79; 3.34] 19.8%
Simon (2016) 9 49 9 49 1.00 [0.43; 2.30] 14.8%
16 Aaron (2019) 16 147 18 200 1.21 [0.64; 2.29] 25.3%

19 0.1 0.5 1 2 10
20
21 Figure 15: Forest plot of PET versus SET for the miscarriage rate based on patient
22 characteristics
23
24
25 312 3.4.5. Meta-analysis of Live birth rate
26 313 Nine studies reported the LBR outcome based on study design as pre-
27
28 314 sented in Figure 16 [10, 11, 22, 19, 23, 31, 28, 33, 30]. Generally, the selected
29 315 data demonstrated a significant increase in LBR of patients underwent PET
30 316 following ERA result in comparison to that of SET (RR = 1.17, 95%CI: 1
31
317 - 1.37). Moreover, the heterogeneity was low (I 2 = 7%, p = 0.38) among
32
33 318 these studies. The analysis of two RCTs revealed a significant improvement
34 319 of those who underwent PET in comparison to that of SET. No heterogeneity
35 320 was observed among the RCTs (RR = 1.25, 95%CI: 1.01 - 1.54, I 2 = 0%,
36
37 321 p = 0.57). Conversely, selected data based on cohort studies suggested no
38 322 significant difference between two groups (RR = 1.04, 95%CI: 0.79 - 1.38)
39 323 and the heterogeneity was low (I 2 = 24%, p = 0.25).
40 324 We also performed the subgroup analysis to address the LBR in RIF
41
42 325 and IVF patients as described in Figure 17. Interestingly, data form RIF
43 326 population showed that ERA did not enhance the LBR and the heterogeneity
44 327 was low (RR = 0.85, 95%CI: 0.54 - 1.35, I 2 = 34%, p = 0.18). In contrast,
45
46
328 patients in the IVF group had a significant increase on the LBR outcome
47 329 when applying PET following the ERA test (RR = 1.24, 95%CI = 1.03 -
48 330 1.49). No heterogeneity was observed in these studies (I 2 = 0%, p = 0.85).
49
50
51
52
53
54
55
56
57
58
59 20
60
61
62
63
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1
2
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6
7
8
9 ERA sFET
10
Approach = Cohort
11 Tan (2018) 5 31 8 40 0.81 [0.29; 2.22] 2.4%
Tomoko (2017) 1 18 6 59 0.55 [0.07; 4.24] 0.6%
12 Arianne (2020) 0 23 3 30 0.19 [0.01; 3.42] 0.3%
Priya (2020) 74 179 59 181 1.27 [0.97; 1.67] 27.3%
13 Churchill (2017b) 4 10 15 32 0.85 [0.37; 1.98] 3.4%
Hombalegowda (2020) 20 41 102 255 1.22 [0.86; 1.73] 18.0%
14 Churchill (2017a) 3 11 11 16 0.40 [0.14; 1.10] 2.3%
16 Approach = RCT
Carlos (2020) 57 141 51 148 1.17 [0.87; 1.58] 23.4%
17 Carlos (2019) 45 80 39 92 1.33 [0.98; 1.80] 22.4%

20 0.1 0.5 1 2 10
21
22 Figure 16: Forest plot of PET versus SET for the live birth rate based on study design
23
24
25
26 Study
ERA sFET
27 Population = RIF
28 Tan (2018) 5 31 8 40 0.81 [0.29; 2.22] 2.4%
Tomoko (2017) 1 18 6 59 0.55 [0.07; 4.24] 0.6%
29 Arianne (2020) 0 23 3 30 0.19 [0.01; 3.42] 0.3%
Priya (2020) 74 179 59 181 1.27 [0.97; 1.67] 27.3%
30 Churchill (2017b) 4 10 15 32 0.85 [0.37; 1.98] 3.4%
Churchill (2017a) 3 11 11 16 0.40 [0.14; 1.10] 2.3%
32
Population = IVF
33 Carlos (2020) 57 141 51 148 1.17 [0.87; 1.58] 23.4%
Hombalegowda (2020) 20 41 102 255 1.22 [0.86; 1.73] 18.0%
34 Carlos (2019) 45 80 39 92 1.33 [0.98; 1.80] 22.4%

37 0.1 0.5 1 2 10
38
39 Figure 17: Forest plot of PET versus SET for the live birth rate based on patient charac-
40 teristics
41
42
43 331 3.5. Assessment of publication bias
44
45 332 In our meta-analysis, two gestational outcomes including IR and CPR
46 333 with ten studies for each outcome were eligible for publication bias assess-
47 334 ment with Egger’s test. The funnel plot was symmetrically distributed for
48
335 both two outcomes. Further Egger’s test of IR and CPR indicated the inter-
49
50 336 cepts of models were (t = -1.273, p = 0.3141) and (t = -1.402, p = 0.1773),
51 337 respectively. These results were consistent with the funnel plot indicating
52 338 there was a low risk of publication bias.
53
54
55
56
57
58
59 21
60
61
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64
65
1
2
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11
0.0
0.1 > p > 0.05
12 0.05 > p > 0.01
13 < 0.01
14
0.1
15
16
Standard Error
17
0.2
18
19
20
21
0.3
22
23
24
25 0.5 1.0 1.5 2.0
26 Risk Ratio
27
28
29 Figure 18: Funnel plot for the implantation rate
30
31
32
33
34
35
0.0
0.1 > p > 0.05

36 0.05 > p > 0.01
< 0.01
37
38
0.1
39
Standard Error
40
41
0.2
42
43
44
0.3
45
46
47
0.4
48
0.5 1.0 1.5 2.0
49
50 Risk Ratio
51
52 Figure 19: Funnel plot for the clinical pregnancy rate
53
54
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59 22
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1
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9 339 3.6. Sensitivity analysis
10
11 340 A sensitivity test plays a crucial role in demonstrating the trustworthiness
12 341 of the pooled point estimation. Interestingly, serial exclusion of any study
13 342 did not result in a considerable variant in IR, CPR, OPR and MR. Concisely,
14
15
343 the meta-analysis of those factors was robust. However, the outcome of LBR
16 344 could lead to confusion. Particularly, serially omitting one of four studies
17 345 including 2 RCT studies [33] [11] and 2 cohort studies [28] [23] could lead to
18 346 non-significant difference in the live birth rate between groups.
19
20
21 Sorted by Effect Size
22 Omitting Taguchi (2018) − RIF θ^* = 0.95 [0.82−1.11]; I 2 = 40%
23 Omitting Carlos (2020) − IVF θ^* = 0.97 [0.79−1.19]; I 2 = 59%
24 Omitting Simon (2016) − IVF θ^* = 0.97 [0.79−1.20]; I 2 = 62%
25 Omitting Arianne (2020) − RIF θ^* = 0.98 [0.81−1.18]; I 2 = 61%
26 Omitting Priya (2020) − RIF θ^* = 0.99 [0.80−1.22]; I 2 = 62%
27 Omitting Tan (2018) − RIF θ^* = 0.99 [0.81−1.21]; I 2 = 62%
Omitting Tomoko (2017) − RIF θ^* = 1.00 [0.82−1.21]; I 2 = 62%
28 Omitting Jayesh (2021) − RIF θ^* = 1.00 [0.82−1.22]; I 2 = 62%
29 Omitting Ana (2019) − PGTA θ^* = 1.01 [0.83−1.23]; I 2 = 61%
30 Omitting Churchill (2017a) − RIF θ^* = 1.02 [0.85−1.23]; I 2 = 58%
31 Omitting Jayesh (2021) − DC θ^* = 1.03 [0.85−1.24]; I 2 = 58%
32 Omitting Ana (2019) − DC θ^* = 1.05 [0.89−1.24]; I 2 = 47%
33
0.5 1.0 2.0 4.0
34 RR (Random−Effects Model)
35
36
37 Figure 20: Sensitivity test of the implantation rate
38
39
41
Omitting Carlos (2020) − IVF θ^* = 0.95 [0.81−1.13]; I 2 = 59%
44 Omitting Aaron (2019) − IVF θ^* = 0.97 [0.80−1.17]; I 2 = 61%
45 Omitting Tomoko (2017) − RIF θ^* = 0.98 [0.84−1.14]; I 2 = 60%
46 Omitting Nalini (2018) − RIF θ^* = 0.98 [0.84−1.15]; I 2 = 61%
47 Omitting Jayesh (2021) − RIF θ^* = 0.99 [0.84−1.16]; I 2 = 60%
49 Omitting Ana (2019) − PGTA θ^* = 1.01 [0.86−1.18]; I 2 = 58%
Omitting Jayesh (2021) − DC θ^* = 1.01 [0.87−1.17]; I 2 = 56%
51
Omitting Ana (2019) − DC θ^ = 1.05 [0.92−1.19]; I 2 = 43%
*
52
53 0.5 1.0 2.0 4.0
55
56 Figure 21: Sensitivity test of the clinical pregnancy rate
57
58
59 23
60
61
62
63
64
65
1
2
3
4
5
6
7
8
10
12 Omitting Mauro (2020) − RIF θ^* = 0.99 [0.86−1.14]; I 2 = 0%
13
Omitting Jayesh (2021) − RIF θ^* = 0.99 [0.89−1.11]; I 2 = 0%
14
15 Omitting Tan (2018) − RIF θ^* = 0.99 [0.89−1.11]; I 2 = 0%
17 Omitting Rawad (2018) − GP θ^* = 1.00 [0.89−1.11]; I 2 = 0%
18
19 Omitting Jayesh (2021) − DC θ^* = 1.01 [0.90−1.13]; I 2 = 0%
21
22 0.5 1.0 2.0 4.0
24
25 Figure 22: Sensitivity test of the ongoing pregnancy rate
26
27
28
30
31 Omitting Carlos (2020) − IVF θ^* = 1.02 [0.71−1.46]; I 2 = 0%
33
36
37 Omitting Nalini (2018) − RIF θ^* = 1.13 [0.81−1.57]; I 2 = 0%

39
Omitting Priya (2020) − RIF θ^* = 1.29 [0.89−1.85]; I 2 = 0%
40
41
0.5 1.0 2.0 4.0 8.0
42
44
45 Figure 23: Sensitivity test of the miscarriage rate
46
47
48
49
50
51
52
53
54
55
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57
58
59 24
60
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1
2
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5
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8
10
12 Omitting Carlos (2019) − IVF θ^ = 1.12 [0.93−1.36]; I 2 = 11%
*
13 Omitting Hombalegowda (2020) − IVF θ^* = 1.14 [0.93−1.39]; I 2 = 18%

14 Omitting Carlos (2020) − IVF θ^ = 1.14 [0.93−1.41]; I 2 = 19%
*
15
Omitting Tomoko (2017) − RIF θ^* = 1.17 [1.00−1.38]; I 2 = 12%
16
17 Omitting Tan (2018) − RIF θ^ = 1.18 [1.00−1.39]; I 2 = 12%
*
18 Omitting Churchill (2017b) − RIF θ^* = 1.18 [1.00−1.40]; I 2 = 12%

19 Omitting Arianne (2020) − RIF θ^ = 1.19 [1.03−1.38]; I 2 = 0%
*
21
22 0.5 1.0 2.0 4.0
24
25 Figure 24: Sensitivity test of the live birth rate
26
27
28 347 4. Discussion
29
30 348 Our meta-analysis found that the ERA test did not significantly enhance
31
32 349 the IVF outcomes, including IR (RR = 1, 95%CI: 0.83 - 1.2) , CPR (RR =
33 350 0.99, 95%CI: 0.85 - 1.15), OPR (RR = 0.99, 95%CI: 0.89 - 1.11) and MR
34 351 (RR = 1.12, 95%CI: 0.81 - 1.54). This finding was also consistent with a
35 352 previous publication about the limitations of ERA [34]. Nonetheless, only
36
37 353 selected data of LBR had a significant increase (RR = 1.17, 95%CI: 1 - 1.37)
38 354 in the PET group compared to the SET group. Interestingly, further sub-
39 355 group analysis indicated the LBR data from the IVF patients who underwent
40
41
356 the ERA test in their first appointment or the first embryo transfer cycle con-
42 357 tributed to that significant improvement (RR = 1.24, 95%CI: 1.03 - 1.49).
43 358 These patients, who have a good prognosis, should follow a standard IVF
44 359 procedure rather than extra intervention like ERA. Indeed, a recent prospec-
45
46 360 tive study with large sample size also did not support the routine use of ERA
47 361 on the general population [35]. Furthermore, this conclusion was also con-
48 362 curred by RT Scott [36]. Originally, ERA was studied in the setting of RIF
49 363 patients. Nonetheless, ERA raised several inquiries remaining unclear. For
50
51 364 example, ERA is still applying the array method while the next generation
52 365 sequencing technology is more precise. In addition, the commercial ERA test
53 366 introduced 238 genes expression whereas there were a numerous arguments
54
55
367 about the number of genes should be included in the test [34].
56 368 Another finding of this meta-analysis suggested patients who were indi-
57
58
59 25
60
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64
65
1
2
3
4
5
6
7
8
9 369 cated for a donor cycle should follow basic IVF with SET rather than extra
10
11
370 intervention like PET guided by ERA. Indeed, the pooled data of IR (RR
12 371 = 0.57, 95%CI: 0.36 - 0.92) and CPR (RR = 0.59, 95%CI: 0.41 -0.85) of
13 372 patients with DC cycle supported that conclusion. However, there were only
14 373 two papers that investigated the effectiveness of ERA in the DC population.
15
16 374 Further research should be carried out to support this argument.
17 375 The subgroup analysis between RCTs and cohort studies yielded incon-
18 376 sistent results. Selected data from cohort studies suggested ERA did not con-
19 377 tribute to any enhancement in the gestational outcomes. Conversely, pooled
20
21 378 results from RCTs indicated a significant improvement in the IVF outcomes,
22 379 including IR (RR = 1.37, 95%CI: 1 - 1.88), CPR (RR = 1.3, 95%CI: 1.09
23 380 - 1.54) and LBR (RR = 1.17, 95%CI: 1 - 1.37) of patients who underwent
24
25
381 PET following ERA suggestion. However, the number of RCT papers (n=4)
26 382 were small compare to the cohort ones (n=13), it is still premature to recom-
27 383 mend the widespread use of ERA. Consequently, more RCTs are required,
28 384 especially those focus on good prognosis patients and the ERA was set even
29
30 385 in their first IVF cycle. Accumulating high-quality evidence is proposed for
31 386 gradually shifting from the conventional to the personalized embryo transfer
32 387 with each patient’s WOI [37].
33
388 To the best of our knowledge, this paper is the first one that addressed
34
35 389 the meta-data of ERA effectiveness. The up-to-date evidence was not strong
36 390 enough to encourage the widely use of ERA, especially with RIF patients.
37 391 Moreover, defining RIF is still debating and strongly varied by the perspective
38
39 392 of each ART center [38, 39, 40]. Although the demand for a reliable method
40 393 to access the receptivity of endometrium is undeniable, ERA itself needs more
41 394 evidence of efficacy before achieving wider usage. For example, it is debated
42 395 that an ERA test is sampled at the menstrual cycle, which is unreliable to
43
44 396 predict an event of endometrial receptivity [41]. The cases that patients are
45 397 receptive but still not pregnant after embryo transfer causes the increase
46 398 of the specificity and false-positive rate of ERA. Additionally, assessing the
47
48
399 ERA test is time-consuming and may cost patient around 1800 US dollars
49 400 per cycle [11]. Hence, physicians should carefully discuss with patient to
50 401 consider the economic burdens as well as stressful emotions when delaying
51 402 pregnancy. In a certain case when there is no explanation for RIF or the
52
53 403 embryo supply is lessen, assessing the endometrium to maximize the success
54 404 chance may outweigh its cost [6].
55 405 By focusing on personalizing the time for transfer, we may ignore a much
56 406 larger issue. For example, ERA represents the endometrium perspective
57
58
59 26
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1
2
3
4
5
6
7
8
9 407 while laboratory and other clinical factors also significantly contribute to
10
11
408 the ultimate aim of pregnancy. Indeed, although the list of factors that
12 409 can affect the outcomes has been discovered, the remaining precarious ones
13 410 are still increasing but not fully understand [42]. Furthermore, techniques
14 411 performing embryo transfer also remarkable impact the successful rate toward
15
16 412 PET [43]. Therefore, awareness of other issues besides WOI is also crucial
17 413 to enhance the successful rate and patient compliance.
18 414 Our meta-analysis also consists of several limitations. Firstly, the poor
19 415 quality of four selected RCTs due to the blinding method may yield invalid
20
21 416 results. However, it is difficult to conduct a blinded experiment for the ERA
22 417 test because of its transparent procedure. Secondly, three out of four RCTs
23 418 were contributed by the team of Simon et al. However, the weak methodol-
24
25
419 ogy of those studies was also questioned leading to invalid conclusions [44].
26 420 Thirdly, bias may have been introduced as the inconsistent calculation of the
27 421 gestational outcomes although an international glossary has been published.
28 422 Finally, another limitation of this meta analysis was the different study de-
29
30 423 sign of the included studies. The pooled result of RCTs was inconsistent
31 424 with the cohort ones which has been previously discussed. More well-design
32 425 RCT studies are needed to investigate the effectiveness of ERA.
33
34
35 426 5. Conclusion
36
37 427 In conclusion, PET guided by the ERA test is supposed a promising in-
38 428 tervention in IVF. However, our analysis suggested ERA did not result in
39 429 significantly better gestational outcomes, except patients who underwent the
40
41 430 first IVF cycle may benefit from ERA. Additionally, the lack of available evi-
42 431 dence limits the routine use of this test on general population. Finally, more
43 432 well-designed RCTs should be conducted to confirm the ERA effectiveness
44
45
433 before being widely implemented across IVF centers.
46
47 434 6. Funding
48
49 435 No funding was received for this study.
50
51
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The impact of endometrial receptivity array on personalizing the embryo transfer for
Huy Phuong Trana, Thuy Thi-Thanh Trana, Ly Thi Leb, Bao The Phamc, Sang Ngoc-Thanh Vuc, Loc
Thai Lya,∗, Tuyet Thi-Diem Hoanga,∗
aInfertility Department, Hung Vuong Hospital, Ho Chi Minh City, Vietnam bSchool of
Biotechnology, International University—Vietnam National University, Ho Chi Minh City, Vietnam
cInformation Science Faculty, Sai Gon University,Ho Chi Minh City, Vietnam
Highlights
 The study investigates the effectiveness of the endometrial receptivity array (ERA) test on
in vitro fertilization (IVF) outcomes.
 ERA provides insignificant improvement of IVF outcomes except for the live birth rate of
patients undergoing the first IVF cycle.
 Further research is encouraged to determine the effectiveness of ERA before mass
implementation.
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Manuscript Number: XFNR-D-21-00054R1

Short Title: ERA meta-analysis

Article Type: Systematic Review

Keywords: endometrial receptivity array, personalized embryo transfer, window of implantation,

Corresponding Author: Loc Thai Ly, MD

Corresponding Author Secondary

Corresponding Author's Institution: Hungvuong Hospital

Corresponding Author's Secondary

First Author: Loc Thai Ly, MD

First Author Secondary Information:

Order of Authors: Loc Thai Ly, MD

Huy Phuong Tran, MSc

Thuy Thi-Thanh Tran

Bao The Pham

Tuyet Thi-Diem Hoang

Order of Authors Secondary Information:

Setting : Not applicable.

Patients : Infertile women undergoing standard embryo transfer (SET) or personalized

Interventions : Searches were carried out in the databases: Pubmed/Medline,

RESPONSE TO EDITOR AND REVIEWERS

[Minor comment 2]- Incorrect terminology.

[Minor comment 3]- Weak introduction and discussion.

[Minor comment 4]- Poorly constructed table.

[Comment 1]- Citation in tables chaotic

Dear Editor in Chief,

If you have any questions, do not hesitate to contact me via email.

We appreciate your consideration.

12 database searching (N = 850) through other sources (N = 9)

36 Studies included in qualitative 5. Book chapter (N = 5)

Table 1: Characteristics of the selected studies

Study Study design Country Duration Patients Female age Measured

37 0% 25% 50% 75% 100%

38 High risk of bias Some concerns Low risk of bias

25 Aaron (2019) Low

36 Low High Unclear

36 Random effects model 1247 1987 1.00 [0.83; 1.20] 100.0%

25 Random effects model 1247

28 Random effects model 708 1270 0.99 [0.85; 1.15] 100.0%

52 Random effects model 708 1270 0.99 [0.85; 1.15] 100.0%

23 Random effects model 484 3597 0.99 [0.89; 1.11] 100.0%

53 Random effects model 571 654 1.12 [0.81; 1.54] 100.0%

18 Random effects model 571 654 1.12 [0.81; 1.54] 100.0%

19 Random effects model 534 853 1.17 [1.00; 1.37] 100.0%

36 Random effects model 534 853 1.17 [1.00; 1.37] 100.0%

0.1 > p > 0.05

38 Omitting Simon (2016) − IVF θ^* = 1.14 [0.81−1.61]; I 2 = 0%

13 Omitting Hombalegowda (2020) − IVF θ^* = 1.14 [0.93−1.39]; I 2 = 18%

18 Omitting Churchill (2017b) − RIF θ^* = 1.18 [1.00−1.40]; I 2 = 12%

19 446 trial receptivity. In: Seminars in Reproductive Medicine, 2014; vol.32

25 578 sisted reproduction and genetics 2007; 24(7); 284–287

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