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Live Birth After Transfer of A Single Euploid Vitrified-Warmed Blastocyst According To Standard Timing vs. Timing As Recommended by Endometrial Receptivity Analysis
Live Birth After Transfer of A Single Euploid Vitrified-Warmed Blastocyst According To Standard Timing vs. Timing As Recommended by Endometrial Receptivity Analysis
Objective: To determine whether endometrial receptivity analysis (ERA) improves live births in patients with and without a history of
unsuccessful frozen embryo transfers (FETs).
Design: Retrospective cohort study.
Setting: Large reproductive center.
Patient(s): Patients with and without ERA before 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 nonreceptive and receptive subjects undergoing an ERA-
timed FET and between ERA-timed vs. standard protocol FETs.
Main Outcome Measure(s): The primary outcome was a live birth; secondary outcomes were biochemical and clinical pregnancy rates.
Result(s): A total of 307 ERA-timed FETs and 2,284 standard protocol FETs were analyzed. One hundred twenty-five patients (40.7%)
were ERA receptive, and 182 (59.3%) were ERA nonreceptive. After adjusting for the number of the previously failed FETs, there was no
difference in the proportion of receptive and nonreceptive ERA results. There were no statistically significant differences in live births in
patients with ERA-receptive vs. ERA-nonreceptive results (48.8% and 41.7%, respectively; adjusted odds ratio 1.17; 95% CI, 0.97–1.40).
There were no statistically significant differences in live births in patients with or without ERA testing results before FET (44.6% and
51.3%, respectively; adjusted odds ratio 0.87; 95% CI, 0.73–1.04).
Conclusion(s): Patients with an increasing number of previous failed euploid FET cycles are not at an increased risk of a displaced
window of implantation. Patients categorized as receptive vs. nonreceptive and those without ERA testing results have comparable
FET success rates. (Fertil SterilÒ 2022;118:314–21. Ó2022 by American Society for Reproductive Medicine.)
El resumen está disponible en Español al final del artículo.
Key Words: Endometrial receptivity analysis, ERA, window of implantation, PGT-A
DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33520
T
he implantation phase of the and immune cells, as well as changes be achieved after euploid embryo trans-
menstrual cycle is a complex bio- in the pattern of gene expression. The fer. Although this represents substantial
logic process characterized by 2 most crucial components for success- improvement during the short history of
significant morphologic and functional ful implantation are a competent em- assisted reproductive technology (ART),
changes in the endometrium, including bryo and a receptive endometrium. At it also reflects the considerable gaps
an increase in capillary permeability best, live birth rates of up to 65% can that remain in our knowledge and con-
Received July 18, 2021; revised May 5, 2022; accepted May 6, 2022; published online June 13, 2022.
trol of sustained implantation of the hu-
N.D. has nothing to disclose. J.C.C. has nothing to disclose. S.J. has nothing to disclose. V.W. has man embryo (1). In natural reproductive
nothing to disclose. K.D. has nothing to disclose. J.E.O has nothing to disclose. physiology, the endometrium is permis-
Reprint requests: Nicole Doyle, M.D., Shady Grove Fertility Center, 9601 Blackwell Road, 4th Floor,
Rockville, Maryland 20850 (E-mail: nicole.pfaeffl[email protected]). sive to an embryo during days 6–12 af-
ter ovulation, and ART embryo transfer
Fertility and Sterility® Vol. 118, No. 2, August 2022 0015-0282/$36.00 cycles generally attempt to mimic this
Copyright ©2022 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2022.05.013 timing (2).
Much attention has been devoted to selecting the best em- conducted from 2018 to 2019 at a large reproductive center
bryo for transfer. Advances in embryo culture systems have in the United States.
enabled a push from routine day 3 cleavage stage to day 5
blastocyst embryo transfers. Extended culture has provided
the embryologists with more morphologic features to identify Study Population Selection
and select the embryos with a higher implantation potential. All FET cycles from January 2018 to April 2019 were re-
Preimplantation genetic testing for aneuploidy assesses the viewed. Only the most recent single euploid FET per patient
overall chromosomal composition, and several studies have within this study period was included in the analysis. All pa-
demonstrated improved outcomes after the transfer of a tients received either 50 mg/d intramuscular progesterone
known euploid embryo (3, 4). only or 200-mg twice daily progesterone vaginal (Endome-
Validated diagnostic tools to determine the receptivity of trin) plus 50-mg intramuscular progesterone every third day
the endometrium are lacking. The assessment of adequate endo- for luteal phase support. Standardized FET timing was defined
metrial estrogen priming can be performed through serum as 123 3 hours of progesterone exposure. A normal uterine
estradiol levels and ultrasonic measurement of endometrial cavity was documented for all subjects by a saline sonogram
thickness and morphological patterns (5, 6). Endometrial recep- and/or hysterosalpingogram within 6 months before FET. Pa-
tivity analysis (ERA) assesses the expression of 238 genes in the tients with unmitigated uterine cavity defects, donor egg, or
endometrial tissue, focusing predominantly on those associated donor embryo cycles were excluded. At our center, a body
with progesterone exposure (7). It employs a computational pre- mass index of >40 kg/m2 and current breast feeding are
dicter model that classifies the endometrium as prereceptive, considered contraindications to embryo transfer.
receptive, or postreceptive on the basis of its transcriptomic pro-
file. The RNA panel employed by ERA was developed through
an assessment of natural cycles (optimal fertile group); Study Design
controlled ovarian hyperstimulation cycles as (subfertile); and All patients underwent a standard controlled ovarian hyper-
intrauterine device–induced refractory endometrium in other- stimulation cycle with stimulation protocol at the primary
wise fertile patients (negative control) (8). The ERA aims to iden- physician’s discretion. Intracytoplasmic sperm injection was
tify a personalized window of implantation (WOI) and guide the used to fertilize mature oocytes, and embryos were cultured
optimal duration of progesterone exposure before embryo to the blastocyst stage. Trophectoderm biopsy and vitrifica-
transfer, for an individual patient. Several, mainly retrospec- tion were performed for all embryos meeting the criteria (blas-
tive, studies have been conducted to assess the use of ERA; how- tocyst with morphologic grade BB or better) by days 5, 6, or 7
ever, whether ERA-timed embryo transfers result in superior of embryonic development (12). Preimplantation genetic
clinical outcomes compared with standard embryo transfers testing for aneuploidy (PGT-A) was performed using next-
remain controversial (9–11). As expected, previous studies generation sequencing. All embryos biopsied for PGT-A
have limitations because of design heterogeneity; small were vitrified; no fresh embryo transfers were performed.
sample size; the use of euploid and untested embryos; single All patients in the exposed group underwent ERA, followed
and double embryo transfers; and fresh and frozen transfer by an ERA-timed FET. Patients in the unexposed group did
cycles and very few included a control group with not undergo ERA before undergoing a standard protocol
standardized timing (9–11). The goal of the current study was FET. All patients returned approximately 14 days after FET
to compare live birth after single euploid frozen embryo for a quantitative serum human chorionic gonadotropin
transfer (FET) according to ERA timing vs. routine protocol. (hCG) evaluation to confirm pregnancy with repeat measure-
ment for positive results and transvaginal ultrasound between
6 and 7 weeks of estimated gestational age to confirm clinical
MATERIAL AND METHODS intrauterine pregnancy (Supplemental Fig. 1, available on-
Ethical Statement and Study Setting line). The same hormone replacement protocol was continued
The Advarra Institutional Review Board approval under pro- until a negative hCG test report was obtained, confirmation of
tocol 00027148 was obtained for the retrospective review of nonviable pregnancy, or until 10-weeks estimated gestational
internal practice data. This retrospective cohort study was age in the case of a viable intrauterine pregnancy.
TABLE 1
Endometrial Receptivity Analysis All data cleaning, analysis, and modeling steps were per-
Endometrial priming for ERA testing was achieved with the formed using the R statistical computing system (version
administration of estradiol for approximately 14 days before 3.6.1) and the R base packages and the add-on R packages
the assessment of endometrial thickness and serum estradiol ggplot2, tableone, glm2, and tidyverse (15, 16). A post hoc po-
and progesterone concentrations. Exogenous progesterone wer calculation for the current sample size of 307 subjects in
was initiated once endometrial thickness measured R7 mm, the study group and 2,284 subjects in the control group indi-
with serum estradiol concentration of >150 pg/mL and serum cated a 95% power to demonstrate a 10% difference in the live
progesterone concentration of <1.0 ng/mL, or at the primary birth rate between the groups, given an a level of <0.05 and a
physician’s discretion. Either daily intramuscular progester- 55% anticipated live birth rate in the control study (on the ba-
one or vaginal progesterone with intramuscular progesterone sis of 2018 and 2019 success rates among single euploid FET
once every 3 days was used, as these 2 regimens have demon- at our center).
strated equivalent outcomes in a recent randomized
controlled trial (13). An endometrial pipelle biopsy was then RESULTS
performed to obtain endometrial tissue for ERA testing 123 A total of 307 ERA-timed FETs and 2,284 standard FETs were
3 hours after the first progesterone injection. Endometrial included in the analysis (Supplemental Fig. 1). As shown in
tissue sample was sent to Igenomix (Valencia, Spain), where Table 1, there were no differences between the exposed and
ERA analysis was conducted using a proprietary protocol, unexposed groups in terms of demographic variables. The
which involves the assessment of a specific transcriptomic number of previously unsuccessful FETs (negative hCG)
signature to assess the endometrial receptivity status. Any pa- with euploid and untested embryos was comparable between
tient whose ERA analysis did not provide sufficient informa- the groups.
tion to recommend timing for FET underwent repeat ERA The results of ERA were considered ‘‘receptive’’ if no
testing. change from the standard 123 3 hours of progesterone
exposure was recommended. Any result recommending an
Embryo Transfer adjustment in progesterone exposure timing outside the stan-
dard progesterone exposure was considered ‘‘nonreceptive’’;
Endometrial preparation for FET was performed using the this included the early and late receptive results for which a
same protocol as followed for ERA. A single vitrified- 12-hour progesterone adjustment is typically recommended.
warmed euploid blastocyst was transferred using ultrasound As shown in Table 2, a higher proportion of patients in the
guidance and the afterload technique, after 123 3 hours exposed group had nonreceptive ERA results compared with
of progesterone exposure or according to ERA recommended receptive ERA results (59.3% and 40.7%, respectively).
progesterone adjustment (14). Among the nonreceptive results, most patients were catego-
rized as prereceptive (34.2%). A total of 12 patients underwent
Outcome a repeat ERA cycle because of a noninformative result in their
first ERA cycle, mostly because of a poor quality endometrial
The primary outcome was a live birth at 23 weeks gestation or
biopsy sample insufficient to determine the gene expression
beyond after single euploid FET performed according to ERA
profile.
timing vs. standard protocol timing. The secondary objectives
were to compare biochemical and clinical pregnancy rates be-
tween the study groups. The secondary endpoints were ERA Results According to the Number of Previous
defined as follows: biochemical pregnancy (detection of Unsuccessful FET Cycles
b-hCG R 5 IU/L) and clinical pregnancy (presence of an in- When adjusting for the number of previous failed FETs with
trauterine gestational sac on ultrasound). euploid embryos, there was no statistically significant
Statistical Analysis
Descriptive statistics were used to demonstrate the mean stan-
TABLE 2
dard deviation and median (range) for continuous variables,
ERA results.
whereas nominal variables were expressed as case numbers
and percentages. To determine the differences in baseline ERA result Exposed group (N [ 307)
characteristics (age, body mass index, and previous history Receptive 125 (40.7)
of failed) between the groups, parametric (independent sam- Nonreceptive* 182 (59.3)
Prereceptive 105 (34.2)
ples t test) and nonparametric analyses (Mann-Whitney Early receptive 60 (19.5)
U test) were performed as appropriate after normality ana- Late receptive 9 (2.9)
lyses. Logistic regression was used to adjust for age, body Postreceptive 8 (2.6)
mass index, and previous embryo transfers. A P value of Second biopsy required for 12 (3.9)
informative result
< .05 was considered significant. Proportions were compared
Note: Data are expressed as n (%). ERA ¼ endometrial receptivity analysis.
with chi-square test and Fisher’s exact test. Logistic regres- * ERA result recommended change in the timing of FET from standard 123 3 hours of pro-
gesterone exposure.
sion was used to adjust for age, body mass index, and previ-
Doyle. Endometrial receptivity analysis. Fertil Steril 2022.
ous embryo transfers.
difference in terms of ERA results between the groups. group (P¼.23; aOR 1.15; 95% CI, 0.95–1.38). There was no
Patients with no previous history of an unsuccessful FET cycle statistically significant difference in live birth between the
were likely to receive a nonreceptive result compared with pa- groups (48.8% and 41.7%, respectively, P¼.27; aOR 1.17;
tients with previous failed FET cycle(s), regardless of whether 95% CI, 0.97–1.40) (Table 3).
they had 1, 2, or 3 previous unsuccessful FETs. Thirty-two of
48 (66.7%) patients with no previous unsuccessful FET were ERA-Timed FET Outcomes Stratified by the
classified as nonreceptive. For patients with 1 previous unsuc- Number of Previous Failed FET cycles
cessful FET, the number of nonreceptive results was 93 of 163
(57.1%). Similarly, for patients with 2 previous FETs, ERA re- When stratifying according to the number of previous failed
ported 47 of 81 (58.1%) patients as nonreceptive vs. 34 of 81 FETs, there were no differences in any of the assessed out-
(41.9%) patients as receptive. The total number of patients comes when comparing the ERA-receptive group to the
with 3 previous unsuccessful FETs before ERA was small, ERA-nonreceptive group for patients with 0,1, and 3 previous
but results were comparable, as 10 of 15 (66.7%) patients unsuccessful euploid FETs, although the total number of pa-
were categorized as nonreceptive vs. 5 of 15 (33.3%) patients tients with 3 previous unsuccessful FETs was small
categorized as receptive (Fig. 1). (Supplemental Table 1, available online). Patients with a his-
tory of 2 previous unsuccessful euploid FETs and a receptive
ERA had a statistically significantly higher live birth rate
ERA-Timed FET Outcomes compared with patients in the ERA nonreceptive group
(P¼.01; OR 3.37; 95% CI, 1.33–8.53); however, as reflected
Comparing ERA-timed FET outcomes in the exposed group, by the wide CI, the sample size was too small to draw a clin-
there were no statistically significant differences between ically meaningful conclusion (Supplemental Table 2).
the ERA-receptive and ERA-nonreceptive groups for any of
the assessed outcomes. The rate of positive hCG was compa-
rable in both groups (75.2% vs. 67.0%, respectively, P¼.16; ERA-Timed FET Outcomes Categorizing Early and
adjusted odds ratio (aOR) 1.12; 95% confidence interval (CI), Late Receptive as Receptive ERA Results
0.92–1.34). The clinical pregnancy rate was 59.2% in the Early and late receptive ERA results recommend a 12-hour
ERA-receptive group vs. 51.6% in the ERA-nonreceptive adjustment of progesterone and were, therefore, defined as
FIGURE 1
Endometrial receptivity analysis results according to the number of previous unsuccessful FETs. FET ¼ frozen embryo transfer; NR ¼ nonreceptive;
R¼ receptive.
Doyle. Endometrial receptivity analysis. Fertil Steril 2022.
TABLE 3
ERA-timed FET outcomes within the exposed group and ERA-timed FET outcomes for exposed vs. unexposed groups.
ERA receptive n (%) ERA nonreceptive n (%) aOR (95% CI) P value
Total patients 125 182
Positive hCG 94 (75.2) 122 (67.0) 1.12 (0.92-1.34) .16
Clinical pregnancya 74(59.2) 94 (51.6) 1.15 (0.95-1.38) .23
Live birthb 61 (48.8) 76 (41.7) 1.17 (0.97-1.40) .27
Exposed group Unexposed group
(ERA-timed FET) n (%) (Standard FET) n (%) aOR (95% CI) P value
Total patients 307 2,284
Positive hCG 215 (70.0%) 1,585 (69.4%) 1.01 (0.84-1.16) .74
Clinical pregnancya 166 (54.1%) 1,346 (58.9%) 0.92 (0.79-1.2) .25
Live birthb 137 (44.6%) 1,173 (51.3%) 0.87 (0.73-1.04) .08
Note: aOR ¼ adjusted odds ratio; CI ¼ confidence interval; ERA ¼ endometrial receptivity analysis; FET ¼ frozen embryo transfer; hCG ¼ human chorionic gonadotropin.
a
Clinical pregnancy ¼ presence of gestational sac at 5 to 7 weeks of estimated gestational age.
b
Live birth ¼ live birth at 23 weeks gestation or beyond.
Doyle. Endometrial receptivity analysis. Fertil Steril 2022.
nonreceptive results for statistical analysis. However, ERA-nonreceptive patients were comparable regardless of
including early and late receptive results in the receptive the number of previous failed embryo transfers.
group (early receptive, late receptive, receptive), did not sta- In this study, ERA results were defined as receptive if no
tistically significantly change live birth rates in the ERA- change from the standard 123 3 hours progesterone expo-
receptive compared with the ERA-nonreceptive group sure before FET was recommended. Any recommended
(44.8% and 44.2%, respectively, P¼1.00; RR 1.01; 95% CI, change in progesterone exposure outside this transfer window
0.72–1.44). (120–126 hours of progesterone) was classified as nonrecep-
tive. As such, most ERA results were nonreceptive (59.3%;
182/307), compared with receptive results (40.7%; 125/307).
ERA-Timed Versus Standard Protocol FET A review of the literature reveals a wide range of nonre-
Outcomes ceptive ERA results (24%–64%) although many of these
There were no statistically significant differences for any studies had challenges with small sample sizes (17). In 2017,
outcomes assessed between patients in the exposed group, a retrospective study of 50 patients with recurrent implanta-
undergoing an ERA-timed FET vs. those in the unexposed tion failure and ERA reported 12 (24%) patients who were
group, who did not undergo ERA testing before embryo classified as nonreceptive (11). Similarly, 22 of 85 (26%) pa-
transfer. tients with recurrent implantation failure were categorized
The rate of positive hCG was comparable in the exposed as nonreceptive in a 2013 multicenter clinical trial (18). A
and unexposed groups (70% vs. 69.4%, respectively, P¼.74; large data set analyzing >6,000 ERA cycles classified approx-
aOR 1.01; 95% CI, 0.84–1.16). The clinical pregnancy rate imately 30% as nonreceptive (19). More recent data suggest a
was 54.1% in the ERA-timed FET group vs. 58.9% in the stan- high proportion of nonreceptive ERA results—41% (23/56),
dard FET group (P¼.25; aOR 0.92; 95% CI, 0.79–1.2). There 37.5% (30/80), and 59.2% (87/147) in studies published in
was no difference in live birth between the ERA-timed FET 2019, 2020, and 2021, respectively (7, 10, 20).
group and the standard FET group (44.6% and 51.3%, respec- Previous studies have suggested that patients with recur-
tively, P¼.08; aOR 0.87; 95% CI, 0.73–1.04) (Table 3). rent implantation failure are at a high risk for a shifted WOI
outside the standard timing for FET cycles and, therefore,
have higher proportions of nonreceptive ERA results (11,
DISCUSSION 18). Our study included patients with no previous failed FET
The present study demonstrated no statistically significant and up to a maximum of 3 previous unsuccessful FET cycles
differences in live birth for patients opting for ERA testing with euploid embryos. Endometrial receptivity analysis out-
and subsequent ERA-guided FET or a standard protocol FET comes (receptive vs. nonreceptive) were comparable for pa-
without previous ERA. The transfer outcomes were compara- tients with and without a history of previous unsuccessful
ble between the exposed (ERA-timed FET) and unexposed (no FET cycles. It appears that the probability for a displaced
ERA and standard FET) groups. The transfer outcomes were WOI does not increase with an increasing number of previous
also comparable between ERA-receptive patients with subse- failed embryo transfers.
quent standard FET and nonreceptive patients with ERA- In the present study, there were no statistically significant
timed FETs and adjusted progesterone exposure. Furthermore, differences in the primary or secondary outcomes for patients
there were no statistically significant differences between the with nonreceptive ERA results who underwent a euploid
groups in any of the secondary outcomes observed (biochem- adjusted FET compared with patients with receptive results
ical pregnancy and clinical pregnancy). For the exposed and subsequent euploid standard FET. It has been argued in
group, FET outcomes between ERA-receptive and the literature that the comparable FET outcomes for patients
with nonreceptive ERA results can be attributed to the adjust- most accurate analysis of the intervention effect (i.e., ERA-
ment in progesterone exposure time before embryo transfer timed euploid FET). Therefore, only patients with vitrified
rescuing these cycles from an otherwise expected poor euploid blastocysts, a standardized luteal phase protocol,
outcome. However, outcome data from patients with nonre- and no uterine factor were included. This current data set rep-
ceptive ERA results and unadjusted progesterone exposures resents the largest sample size of patients with ERA and sub-
are lacking and, therefore, an adequate interpretation with sequent euploid FET reported in the literature to date (13).
regard to the use of ERA remains challenging. Limitations include the retrospective nature of the study
The question of whether an ERA-timed transfer improves design and the lack of an unexposed group without ERA,
in vitro fertilization outcomes has been debated in the litera- matched for the number of previous failed FETs. Furthermore,
ture with studies reporting both superior transfer outcomes, as residual confounding should be acknowledged as a limitation
well as lack of efficacy for ERA-timed FET cycles. In 2013, as only 3 covariates were included. Factors such as endome-
Ruiz-Alonso et al. (18) reported no significant difference in triosis, history of surgery, the day of vitrification of the trans-
pregnancy rates for nonreceptive patients undergoing ERA- ferred embryo or endometrial lining thickness at initiating
guided transfers compared with receptive patients. However, progesterone therapy were not accounted for.
the study included a small number of nonreceptive patients
for analysis (n ¼ 8), both natural and hormone replacement
therapy ERA cycles, transfer of both cleavage and blastocyst CONCLUSION
embryos and an average of 2 transferred embryos. Superior In conclusion, an increasing number of previous unsuccessful
outcomes for 10 patients with displaced WOI and ERA- FETs does not increase the rate of nonreceptive ERA results.
guided transfers were reported in 2017 with a pregnancy Furthermore, live birth rates do not differ when ERA agrees
rate of 50% compared with 35% for patients in the receptive with the standard FET protocol (receptive) vs. when it dis-
group (11). A moderately larger data set that included a con- agrees (nonreceptive) and an adjustment in progesterone
trol group was published in 2018 and compared 41 patients exposure time is suggested. Patients with ERA-guided FET cy-
with ERA (27 nonreceptive, 14 receptive) and subsequent cles have comparable live birth outcomes to patients under-
FET with 503 patients without ERA before embryo transfer going standard protocol transfers without previous ERA. A
(17). The investigators concluded that their data did not sup- randomized controlled trial is required to sufficiently assess
port ERA as a diagnostic tool to improve ART outcomes as the whether ERA serves as a beneficial diagnostic adjunct in
ongoing pregnancy rates between groups did not differ ART cycles.
significantly. A study controlling for an embryo factor was
published in 2019 and included patients with either euploid DIALOG: You can discuss this article with its authors and
embryo transfers or transfers with embryos derived from other readers at https://www.fertstertdialog.com/posts/
33520
donor oocytes. The study also included a control group of pa-
tients with euploid embryo transfers according to a standard-
ized protocol. Pregnancy rates did not improve between
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