Abstract
Objective:
To determine whether endometrial receptivity analysis (ERA) improves live birth for patients with and without a history of unsuccessful frozen embryo transfer(s) (FET)
Design:
Retrospective cohort study
Setting:
Large reproductive center
Patients:
Patients with and without ERA prior to euploid single FET were included in the analysis
Intervention(s):
Subjects in the exposed group underwent ERA and ERA-timed FETs. Subjects in the unexposed group followed a standard protocol FET without ERA. Outcomes were compared between non-receptive and receptive subjects undergoing an ERA-timed FET and between ERA-timed versus standard protocol FETs
Main Outcome Measure(s):
The primary outcome was live birth, secondary objectives were biochemical and clinical pregnancy rates
Results:
307 ERA-timed FETs and 2284 standard protocol FETs were analyzed. 125 patients (40.7%) were ERA-receptive, 182 (59.3%) non-receptive. Adjusting for the number of previously failed FETs there was no difference in the proportion of receptive and non-receptive ERA result. There was no statistically significant difference in live birth for patients with ERA receptive versus ERA non-receptive results (48.8% and 41.7% respectively, P= 0.27; RR 1.17; 95% CI, 0.97–1.40). There was no statistically significant difference in live birth for patients with or without ERA testing prior to FET (44.6.% and 51.3% respectively, P= 0.08; aOR 0.87; 95% CI, 0.73–1.04)
Conclusions:
Patients with an increasing number of prior failed euploid FET cycles are not at an increased risk for a displaced window of implantation. Patients categorized as receptive versus non-receptive and those without ERA testing have comparable FET success rates
Keywords: Endometrial receptivity analysis, ERA, window of implantation, PGT-A
Capsule:.
Higher numbers of previous unsuccessful embryos transfers do not increase the probability of a displaced window of implantation. Endometrial receptivity analysis guided versus standard protocol embryo transfers have comparable outcomes.
INTRODUCTION
The implantation phase of the menstrual cycle is a complex biological process characterized by significant morphologic and functional changes in the endometrium including an increase in capillary permeability and immune cells, as well as changes in the pattern of gene expression. The two most crucial components for successful implantation are a competent embryo and a receptive endometrium. At best, live birth rates of up to 65% can be achieved after transfer of a euploid embryo. While this represents substantial improvement during the short history of assisted reproductive technologies (ART), it also reflects the considerable gaps that remain in our knowledge and control of sustained implantation of the human embryo (1). In natural reproductive physiology, the endometrium is permissive during days 8–10 after ovulation and ART embryo transfer cycles generally attempt to mimic this timing (2).
Much attention has been devoted to selecting the best embryo for transfer. Advances in embryo culture systems have enabled a push from routine day 3 cleavage stage to day 5 blastocyst embryo transfers. Extended culture has provided the embryologist with more morphologic features to identify and select the embryo with a higher implantation potential. Preimplantation genetic testing for aneuploidy assesses the overall chromosomal composition and several studies have demonstrated improved outcomes after transfer of a known euploid embryo (3).
On the other hand, validated diagnostic tools are lacking to determine receptivity of the endometrium. Assessment of adequate endometrial estrogen priming can be performed via serum estradiol levels and ultrasonic measurement of endometrial thickness and morphological pattern (4, 5). The ERA assesses expression of 248 genes in endometrial tissue, focusing predominantly on those associated with progesterone exposure (6). ERA employs a computational predicter model that classifies the endometrium as pre-receptive, receptive or post-receptive based on its transcriptomic profile. The RNA panel employed by ERA was developed via assessment of: (1) natural cycles (optimal fertile group), (2) controlled ovarian hyperstimulation cycles as (subfertile) and (3) intrauterine device-induced refractory endometrium in otherwise fertile patients (negative control) (7). The ERA aims to identify a personalized window of implantation (WOI) and guide the optimal duration of progesterone exposure prior to embryo transfer, for an individual patient. Several, mainly retrospective, studies have been conducted to assess the utility of ERA, however whether ERA-timed embryo transfers result in superior clinical outcomes compared to standard embryo transfers remains controversial. As expected, prior studies have limitations due to design heterogeneity, small sample size, the use of euploid and untested embryos, single and double embryo transfers, fresh and frozen transfer cycles and very few included a control group with standardized timing (8–10).
The goal of the current study was to compare live birth after single euploid FET according to ERA timing versus routine protocol.
MATERIAL AND METHODS:
Ethical statement
Advarra Institutional Review Board approval under protocol 00027148 was obtained for retrospective review of internal practice data.
Study setting
This retrospective cohort study was conducted from 2018 and 2019 at a large reproductive center in the United States.
Study population selection
All FET cycles from January 2018 to April 2019 were reviewed. Only the most recent single euploid FET per patient within this study period was included in the analysis. All patients received either 50 mg/d intramuscular (IM) Progesterone only, or 200 mg twice daily Endometrin plus 50 mg IM Progesterone every third day, for luteal phase support. Standardized FET timing was defined as 123 +/− 3 hrs of progesterone exposure. A normal uterine cavity was documented for all subjects by saline sonogram and/or hysterosalpingogram within 6 months prior to FET. Patients with unmitigated uterine cavity defects, donor egg or donor embryo cycles were excluded. BMI >40 kg/m2 and current breast feeding are considered contraindications to embryo transfer at our center.
Study design
All patients underwent a standard controlled ovarian hyperstimulation cycle with stimulation protocol at the primary physician’s discretion. Intracytoplasmic sperm injection (ICSI) was applied to fertilize mature oocytes and embryos were cultured to the blastocyst stage. Trophectoderm biopsy and vitrification were performed for all embryos meeting criteria (blastocyst with morphologic grade BB or better) by day 5, 6 or 7 of embryonic development (11). Preimplantation genetic testing for aneuploidy (PGT-A) was performed using next generation sequencing (NGS). All embryos biopsied for PGT-A were vitrified; no fresh embryo transfers were performed. All patients in the exposed group underwent ERA as described below followed by an ERA-timed FET. Patients in the unexposed group did not undergo ERA prior to proceeding with a standard protocol FET. All patients returned approximately 14 days after FET for a quantitative serum hCG to confirm pregnancy with repeat measurement for positive results and transvaginal ultrasound at 6–7 weeks of estimated gestational age (EGA) to confirm clinical intrauterine pregnancy (Supplemental Figure 1). The same hormone replacement protocol was continued until negative hCG, confirmation of nonviable pregnancy, or until 10 weeks EGA in the case of a viable intrauterine pregnancy.
Endometrial receptivity analysis
Endometrial priming for ERA testing was achieved with the administration of estradiol for approximately 14 days prior to assessment of endometrial thickness and serum estradiol and progesterone concentration. Exogenous progesterone was initiated once endometrial thickness measured 7 mm or more, with serum estradiol concentration > 150 pg/mL and serum progesterone concentration <1.0 ng/mL, or at the primary physician’s discretion. Either daily intramuscular progesterone or vaginal progesterone with intramuscular progesterone once every 3 days was used, as these two regimens have demonstrated equivalent outcomes in a recent randomized controlled trial (12). An endometrial pipelle biopsy was then performed to obtain endometrial tissue for ERA testing 123 +/− 3 hours after the first progesterone injection. Endometrial tissue sample was sent to Igenomix, where ERA analysis was conducted using a proprietary protocol which involves the assessment of a specific transcriptomic signature to assess the endometrial receptivity status. Any patient whose ERA analysis did not provide sufficient information to recommend timing for FET underwent repeat ERA testing.
Embryo transfer
Endometrial preparation for FET was performed using the same protocol as described for ERA above. A single vitrified-warmed euploid blastocyst was transferred using ultrasound guidance and the afterload technique, following 123 +/− 3 hours of progesterone exposure, or according to ERA recommended progesterone adjustment. (13).
Outcome
The primary outcome was live birth at 23 weeks gestation or beyond following single euploid FET performed according to ERA timing versus standard protocol timing. The secondary objectives were to compare biochemical and clinical pregnancy rates between study groups.The secondary endpoints were defined as follows: biochemical pregnancy (detection of beta hCG ≥ 5 IU/L) and clinical pregnancy (presence of an intrauterine gestational sac on ultrasound).
Statistical analysis
Descriptive statistics were used to demonstrate the mean standard deviation and median (range) for continuous variables, whereas nominal variables were expressed as case number and percentages. To determine the differences in baseline characteristics (i.e., age, bmi and previous history of failed transfers) between the groups, parametric (independent samples t test) and non-parametric analyzes (Mann–Whitney U) were performed as appropriate after normality analyses. Logistic regression was used to adjust for age, body mass index (BMI), and previous embryo transfers. A P-value level of <0.05 was considered as significant.
Proportions were compared with Chi Square test and Fisher’s exact test. Logistic regression was used to adjust for age, body mass index (BMI), and previous embryo transfers. A P-value level of <0.05 was considered as significant.
All data cleaning, analysis and modeling steps were performed using the R statistical computing system (version 3.6.1), and the R base packages, and the add-on R packages ggplot2, tableone, glm2 and tidyverse (14, 15). A post-hoc power calculation for the current sample size of 307 subjects in the study group and 2284 subjects in the control group indicated a 95% power to demonstrate a 10% difference in live birth between groups given an alpha level of p <0.05 and a 55% anticipated live birth in the control study (based on 2018/2019 success rates among single euploid FET at our center).
RESULTS
A total of 307 ERA-timed FETs and 2284 standard FETs were included in the analysis (Supplemental Figure 1). As shown in Table 1, there were no differences between the exposed group and unexposed group in terms of demographic variables. The number of previously unsuccessful FETs (negative hCG) with euploid and untested embryos was comparable between groups.
Table 1:
Baseline and Cycle Characteristics
| Exposed Group (ERA-timed FET) (N=307) | Unexposed Group (Standard FET) (N=2284) | P-value | |
|---|---|---|---|
| Age (years) a | 36.7 (4.1) | 36.7 (4.3) | 1.00 |
| BMI (kg/m2)a | 26.1 (5.3) | 25.7 (5.0) | 0.12 |
| History of prior total failed embryo transfer(s)b | 2.4 (2.2) | 2.5 (2.1) | 0.46 |
Data are expressed as mean ± SD unless indicated otherwise.
Age and BMI were recorded at the time of IVF cycle start.
Failed embryo transfers (negative hcg) with euploid and untested embryos
ERA results
ERA results were considered receptive if no change from the standard 123+/− 3 hrs of progesterone exposure was recommended. Any result recommending an adjustment in progesterone exposure timing outside the standard progesterone exposure was considered non-receptive, this included the early and late receptive results for which a 12 hrs progesterone adjustment is typically recommended. As shown in Table 2, a higher proportion of patients in the exposed group had non-receptive ERA results compared to receptive ERA results (59.3% and 40.7% respectively). Among the non-receptive results, the majority of patients were categorized as pre-receptive (34.2%). A total of 12 patient underwent a repeat ERA cycle due to a non informative result in their first ERA cycle, mostly due to a poor quality endometrial biopsy sample insufficient to determine the gene expression profile.
Table 2:
Endometrial Receptivity Analysis Results
| ERA RESULT | Exposed Group N=307 |
|---|---|
| Receptive | 125 (40.7) |
| Non-Receptive* | 182 (59.3) |
| • Pre-receptive | 105 (34.2) |
| • Early receptive | 60 (19.5) |
| • Late receptive | 9 (2.9) |
| • Post-receptive | 8 (2.6) |
| Second Biopsy Needed for Informative Result | 12 (3.9) |
Data are expressed as N (%);
ERA result recommended change in timing of FET from standard 123 hrs +/− 3 hours of progesterone exposure.
ERA results according to the number of previous unsuccessful FET cycles
When adjusting for the number of previous failed FETs with euploid embryos, there was no statistically significant difference in terms of ERA results between groups. Patients with no prior history of an unsuccessful FET cycle were as likely to receive a non-receptive result compared to patients with prior failed FET cycle(s), regardless of whether they had 1, 2 or 3 previous unsuccessful FETs. Thirty-two (32/48, 66.7%) patients with no prior unsuccessful FET were classified as non-receptive. For patients with one prior unsuccessful FET the number of non-receptive results was 93/163 (57.1%). Similarly, for patients with 2 previous FETs, ERA reported 47/81 (58.1%) as non-receptive versus 34/81 (41.9%) as receptive. The total number of patients with 3 previous unsuccessful FETs prior to ERA was small, but results were comparable, as 10/15 (66.7%) were categorized as non-receptive versus 5/15 (33.3%) receptive patients (Figure 1).
Figure 1:
ERA results according to the number of previous unsuccessful FETs.
NR= ERA non-receptive, R= ERA receptive
ERA-timed FET outcomes
Comparing ERA-timed FET outcomes in the exposed group, there were no statistically significant differences between the ERA receptive and ERA non-receptive group for any of the assessed outcomes. The rate of positive hCG was comparable in both groups (75.2% versus 67.0% respectively, P=0.16; aOR 1.12; 95% CI, 0.92–1.34). Clinical pregnancy rate was 59.2% in the ERA receptive group versus 51.6% in the ERA non-receptive group (P=0.23; aOR 1.15; 95% CI, 0.95–1.38). There was no statistically significant difference in live birth between groups (48.8% and 41.7% respectively, P=0.27; aOR 1.17; 95% CI, 0.97–1.40) (Table 3).
Table 3:
ERA-timed FET outcomes within the exposed group and ERA-timed FET outcomes for the exposed group versus unexposed group
| ERA receptive N (%) | ERA non-receptive N (%) | aOR (95% CI) | P-value | |
|---|---|---|---|---|
| Total Patients | 125 | 182 | ||
| Positive hCG | 94 (75.2) | 122 (67.0) | 1.12 (0.92–1.34) | 0.16 |
| Clinical pregnancy | 74(59.2) | 94 (51.6) | 1.15 (0.95–1.38) | 0.23 |
| Live birth | 61 (48.8) | 76 (41.7) | 1.17 (0.97–1.40) | 0.27 |
| Exposed Group (ERA-timed FET) N (%) | Unexposed Group (Standard FET) N (%) | aOR (95% CI) | P-value | |
| Total Patients | 307 | 2284 | ||
| Positive hCG | 215 (70.0%) | 1585 (69.4%) | 1.01 (0.84–1.16) | 0.74 |
| Clinical pregnancy | 166 (54.1%) | 1346 (58.9%) | 0.92 (0.79–1.2) | 0.25 |
| Live birth | 137 (44.6%) | 1173 (51.3%) | 0.87 (0.73–1.04) | 0.08 |
Clinical pregnancy = presence of GS at 5–7wks EGA; Live birth = live birth at 23 weeks gestation or beyond
ERA-timed FET outcomes stratified by the number of previous failed FET cycles
When stratifying according to the number of previous failed FETs, there was no differences in any of the assessed outcomes when comparing the ERA receptive group to the ERA non-receptive group for patients with 0,1 and 3 previous unsuccessful euploid FETs, although the total numbers for patients with 3 previous unsuccessful FETs was small (Supplemental Table 1). Patients with a history of 2 previous unsuccessful euploid FETs and a receptive ERA had a statistically significantly higher LB rate compared to patients in the ERA non-receptive group (P=0.01; OR 3.37; 95% CI, 1.33–8.53) however, as reflected by the wide CI, the sample size was too small to draw a clinically meaningful conclusion (Supplemental Table 2).
ERA-timed FET outcomes categorizing early and late receptive as receptive ERA results
As stated above, early and late receptive ERA results recommend a 12 hour adjustment of progesterone and were therefore defined as non-receptive results for statistical analysis. However, including early and late receptive results in the receptive group (early receptive, late receptive, receptive), did not statistically significantly change live birth rates in the ERA receptive compared to ERA non-receptive group (44.8% and 44.2% respectively, P=1.00; RR 1.01; 95% CI, 0.72–1.44).
ERA-timed versus standard protocol FET outcomes
There were no statistically significant differences for any outcomes assessed between patients in the exposed group, undergoing an ERA-timed FET versus those in the unexposed group, who did not have ERA testing prior to embryo transfer.
The rate of positive hCG was comparable in the exposed and unexposed group (70% versus 69.4% respectively, P=0.74; aOR 1.01; 95% CI, 0.84–1.16). The clinical pregnancy rate was 54.1% in the ERA-timed FET group versus 58.9 % in the standard FET group (P=0.25; aOR 0.92; 95% CI, 0.79–1.2). There was no difference in live birth between the ERA-timed FET group and the standard FET group (44.6.% and 51.3% respectively, P=0.08; aOR 0.87; 95% CI, 0.73–1.04) (Table 3).
DISCUSSION
The present study demonstrated no statistically significant difference in live birth for patients pursuing ERA testing and subsequent ERA guided FET or a standard protocol FET without prior ERA. Transfer outcomes were comparable between the exposed group (ERA-timed FET) and unexposed group (no ERA and standard FET). Transfer outcomes were also comparable between ERA receptive patients with subsequent standard FET and non-receptive patients with ERA-timed FETs and adjusted progesterone exposure. Furthermore, there was no statistically significant difference between groups in any of the secondary outcomes observed (biochemical pregnancy and clinical pregnancy). For the exposed group, FET outcomes between ERA receptive and ERA non-receptive patients were comparable regardless of the number of previous failed embryo transfers.
In this study, ERA results were defined as receptive if no change from the standard 123 +/− 3 hrs progesterone exposure prior to FET was recommended. Any recommended change in progesterone exposure outside this transfer window (120–126 hours of progesterone) was classified as non-receptive. As such, the majority of ERA results were non-receptive 59.3% (182/307), compared to 40.7% (125/307) receptive results.
A review of the literature reveals a wide range of non-receptive ERA results (24–64%) although many of these studies had challenges with small samples sizes (16). In 2017, a retrospective study of 50 patients with recurrent implantation failure (RIF) and ERA reported 12 (24%) patients who were classified as non-receptive (10). Similarly, 26% of patients with RIF (22/85) were categorized as non-receptive in a 2013 multicenter clinical trial (17). A large dataset analyzing more than 6000 ERA cycles classified approximately 30% as non-receptive (18). More recent data suggests a higher proportion of non-receptive ERA results with 41% (23/56), 37.5% (30/80) and 59.2%% (87/147) for published studies in 2019, 2020 and 2021 respectively (6, 9, 19).
Previous studies have suggested that patients with RIF are at higher risk for a shifted window of implantation (WOI) outside the standard timing for FET cycles and therefore have higher proportions of non-receptive ERA results (10, 17). Our study included patients with no prior failed FET and up to a maximum of three previous unsuccessful FET cycles with euploid embryos. ERA outcomes (receptive versus non-receptive) were comparable for patients with and without a history of previous unsuccessful FET cycles. It appears that the probability for a displaced WOI does not increase with an increasing number of previous failed embryo transfers.
In the present study, there was no statistically significant difference in the primary or secondary outcomes for patients with non-receptive ERA results who underwent a euploid adjusted FET compared to patients with receptive results and subsequent euploid standard FET. It has been argued in the literature, that the comparable FET outcomes for patients with non-receptive ERA results can be attributed to the adjustment in progesterone exposure time prior to embryo transfer rescuing these cycles from an otherwise expected poorer outcome. However, outcome data from patients with non-receptive ERA results and unadjusted progesterone exposures are lacking and therefore an adequate interpretation with regards to the utility of ERA remains challenging.
The question of whether an ERA-timed transfer improves IVF outcomes has been debated in the literature with studies reporting both superior transfer outcomes as well as lack of efficacy for ERA-timed FET cycles. In 2013, Ruiz-Alonso et al. reported no significant difference in pregnancy rates for non-receptive patients undergoing ERA guided transfers compared to receptive patients (17). However, the study included a small number of non-receptive patients for analysis (n=8), both natural and HRT ERA cycles, transfer of both cleavage and blastocyst embryos and an average of 2 transferred embryos. Superior outcomes for 10 patients with a displaced WOI and ERA guided transfers were reported in 2017 with a pregnancy rate of 50% compared to 35% for patients in the receptive group (10). A moderately larger dataset that included a control group was published in 2018 and compared 41 patients with ERA (27 non-receptive, 14 receptive) and subsequent FET to 503 patients without ERA prior to embryo transfer (16). The authors concluded that their data did not support ERA as a diagnostic tool to improve ART outcomes as the ongoing pregnancy rates between groups did not differ significantly. A study controlling for an embryo factor was published in 2019 and included patients with either euploid embryo transfers or transfers with embryos derived from donor oocytes. The study also included a control group of patients with euploid embryo transfers according to standardized protocol. ERA did not result in improved pregnancy rates between groups. The first prospective randomized three arm clinical trial comparing FET in ERA-timed cycles to standardized FET cycles and fresh blastocyst transfers was published in 2020. The authors reported no statistically significant difference for live birth when comparing ERA-timed FET to standardized FET cycles or ERA-timed FET to fresh blastocyst transfers in the intention to treat (ITT) analysis and per protocol (PP) analysis (6). Unfortunately, the study noted a higher than anticipated drop-out rate (ITT = 434 subjects, PP = 266 subjects) which rendered it underpowered for evaluation of the primary outcome (live birth). They also had challenges with study heterogeneity including different protocols for all three trial arms, transfer of both PGT-A tested and untested embryos and varying luteal phase protocols. Recently, in 2021 a prospective cohort study compared live birth between ERA-timed single euploid FET and standardized FET and included 228 subjects undergoing their first autologous FET. They reported no statistically significant difference in live birth in the ERA-timed group versus the standardized FET group (56.6% and 56.5% respectively) and did not support the routine use of ERA in this particular patient population (19).
The goal of this study was to control for variables and confounders that could impact FET outcomes to yield the most accurate analysis of the intervention effect (i.e. ERA-timed euploid FET). Therefore, only patients with vitrified euploid blastocysts, a standardized luteal phase protocol and no uterine factor were included. This current dataset represents the largest samples size of patients with ERA and subsequent euploid FET reported in the literature to date (12). Limitations include the retrospective nature of the study design and the lack of an unexposed group without ERA, matched for the number of previous failed FETs. Furthermore, residual confounding should be acknowledged as a limitation as only three covariates were included. Factors such as endometriosis, history of surgery, day of vitrification of the transferred embryo or endometrial lining thickness at progesterone start were not accounted for.
CONCLUSIONS
In conclusion, an increasing number of prior unsuccessful FETs does not increase the rate of non-receptive ERA results. Furthermore, live birth rates do not differ when ERA agrees with the standard FET protocol (receptive) versus when it disagrees (non-receptive) and an adjustment in progesterone exposure time is suggested. Patients with ERA guided FET cycles have comparable live birth outcomes to patients undergoing standard protocol transfers without prior ERA.
A randomized controlled trial is required to sufficiently assess whether ERA serves as a beneficial diagnostic adjunct in ART cycles.
Supplementary Material
Supplemental Figure 1: Study flow diagram
PGT-A=preimplantation genetic testing for aneuploidy; ERA=endometrial receptivity analysis
Supplemental Table 1: ERA-timed FET outcomes in the exposed group stratified by the number of previous unsuccessful FET cycles.
Clinical pregnancy = presence of GS at 5–7wks EGA; Live birth = live birth at 23 weeks gestation or beyond
Supplemental Table 2: Odds Ratio (95% CI); P-value for FET outcomes comparing the ERA receptive group to the ERA non-receptive group stratified by the number of previous unsuccessful FET cycles.
Clinical pregnancy = presence of GS at 5–7wks EGA; Live birth = live birth at 23 weeks gestation or beyond
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure 1: Study flow diagram
PGT-A=preimplantation genetic testing for aneuploidy; ERA=endometrial receptivity analysis
Supplemental Table 1: ERA-timed FET outcomes in the exposed group stratified by the number of previous unsuccessful FET cycles.
Clinical pregnancy = presence of GS at 5–7wks EGA; Live birth = live birth at 23 weeks gestation or beyond
Supplemental Table 2: Odds Ratio (95% CI); P-value for FET outcomes comparing the ERA receptive group to the ERA non-receptive group stratified by the number of previous unsuccessful FET cycles.
Clinical pregnancy = presence of GS at 5–7wks EGA; Live birth = live birth at 23 weeks gestation or beyond