The Deferred Embryo Transfer Strategy Seems Not to be a Good Option After Repeated IVF/ICSI Cycle Failures

Abstract

Objective:

The aim of this study was to assess whether a deferred frozen–thawed embryo transfer (Def-ET) offers any benefits compared to a fresh ET strategy in women who have had 2 or more consecutive in vitro fertilization (IVF)/intracytoplasmic injection (ICSI) cycle failures.

Design:

An observational cohort study in a tertiary referral care center including 416 cycles from women with a previous history of 2 or more consecutive IVF/ICSI failures cycles. Both Def-ET and fresh ET strategies were compared using univariate and multivariate logistic regression models. The main outcome measured was the cumulative live birth rate (CLBR).

Results:

A total of 416 cycles were included in the analysis: 197 in the fresh ET group and 219 in the Def-ET group. The CLBR was not significantly different between the fresh and Def-ET groups (58/197 [29.4%] and 57/219 [26.0%], respectively, P = .437). In addition, after the first ET, there was no significant difference in the live birth rate between the fresh ET and Def-ET groups (50/197 [25.4%] vs 44/219 [20.1%], respectively). Multivariate logistic regression analysis indicated that compared to the fresh strategy, the Def-ET strategy was not associated with a higher probability of live birth.

Conclusions:

In cases with 2 or more consecutive prior IVF/ICSI cycle failures, a Def-ET strategy did not result in better ART outcomes than a fresh ET strategy.

Keywords

fresh embryo transfer frozen-thawed embryo transfer IVF/ICSI ART repeated IVF/ICSI cycle failures

Introduction

Implantation is one of the key steps for success with assisted reproduction technology (ART). The ART requires a viable embryo that is synchronous with a receptive endometrium.¹ The implantation window refers to this self-limited period in which the endometrium has acquired an adequate morphological and functional state for embryo attachment.² Endometrial receptivity is essential for conception in natural and infertility treatment cycles. However, implantation failure is a common occurrence in cycles of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Indeed, reports from the European Society of Human Reproduction and Embryology have shown that more than a half of all embryo transfers (ETs) fail to result in a pregnancy. In 2011, the pregnancy rate per transfer in Europe was 33.1%.³ Thus, for a large number of women undergoing an ET, the procedure fails. In addition, pregnancy rates decrease as the number of attempts increase⁴: Pregnancy rates per cycle tend to fall after the third unsuccessful IVF/ICSI attempt.⁵

Although controlled ovarian stimulation (COS) is essential for obtaining a multifollicular development and a successful cycle of ART, numerous studies in the literature have highlighted that endometrial changes can occur after COS that potentially impair endometrial receptivity in fresh autologous IVF/ICSI cycles.^6

–9 Indeed, COS induces histological, genetic, and immunological changes at the level of the endometrium.^6,8,10
–12 It appears that, in specific cases, COS can result in advanced maturation of the endometrium, thereby leading to embryo implantation failure.⁸ “Supraphysiological” concentrations of estradiol (E2) and progesterone (P4) induced by exogenous gonadotrophins could account for an asynchrony between the endometrium and the transferred embryo, leading to a detrimental endometrial environment that is potentially responsible for implantation failure.^13,14 To address these concerns, the “freeze-all” approach has been proposed.^15
–17 This involves cryopreservation of all of the viable embryos after COS, with a deferred ET (Def-ET) of a frozen–thawed embryo in a subsequent cycle. The hypothesis is that introduction of a cryopreserved embryo into a nonstimulated intrauterine environment could avoid possible adverse effects of COS on endometrial receptivity.

A previous study has indicated that women with a history of prior fresh autologous implantation failure may have an increased risk of endometrial impairment from COS.¹⁵ The authors concluded that women with at least 1 failed fresh blastocyst transfer have a significantly greater probability of a live birth with the “freeze-all” and subsequent thaw approach than with another fresh cycle.¹⁵ These preliminary results highlight the potential relevance of a Def-ET strategy for women who have previously experienced an implantation failure.

In order to assess whether Def-ET offers a potential benefit in women with multiple consecutive IVF/ICSI cycle failures, we compared ART outcomes for patients who underwent a fresh ET versus patients who underwent Def-ET after 2 or more consecutive IVF/ICSI cycle failures.

Materials and Methods

Study Design

We conducted a retrospective cohort study that included oocyte retrievals that led to at least 1 ET and that were performed between October 01, 2012, and December 31, 2014, in a single ART unit at the university-based reproductive medicine center of our institution. This study was approved by the National Data Protection Authority (Commission Nationale de l’Informatique et des Libertés, CNIL n° 1988293 v 0).

Patient Cohort

For both groups, the inclusion criteria for this cohort study were as follows: women with a history of at least 2 or more consecutive IVF/ICSI cycle failures in which at least 1 embryo was transferred in every cycle, requirement of ART (IVF or ICSI), age ≤43 years, and having one or more embryo(s) available for transfer after the COS. Exclusion criteria were as follows: vitrified oocyte procedures, no embryo obtained or transferred, and patients who had already been included in another ART research protocol.

Two groups were compared: (1) a study group comprised of “exposed” women who received a Def-ET for the first transfer attempt—this Def-ET strategy consisted of cryopreservation of all of the viable embryos after COS, followed by a frozen–thawed ET in a subsequent cycle—and (2) an “unexposed” control group comprised of women who received a fresh ET for the first transfer attempt. For both of these groups, supernumerary embryos were frozen and transferred when pregnancy was not achieved after the first transfer.

The decision whether to defer the ET or to perform a fresh ET for the first attempt was based on a mutual decision by the patient and the doctor. The information process was conducted according to specific elements required for completeness of informed decision-making outlined by Braddock et al.¹⁸ Therefore, the selected therapeutic measure was not by random allocation. Rather, it was in accordance with the patient’s and the doctor’s preferences.

Ovarian Stimulation

The women were monitored and managed according to our institutional clinical protocols.¹⁹ Thus, all of the patients were synchronized using timed administration of an oral contraceptive containing 0.03 mg of ethinyl E2 and 0.15 mg of levonorgestrel (Minidri; Pfizer Holding, Paris, France), as described previously.²⁰ Various COS protocols were used according to our institutional clinical protocols, with 150 to 450 IU/d of recombinant follicle-stimulating hormone (FSH; Puregon; MSD, France) and urinary FSH (human menopausal gonadotropin; Menopur; Ferring Pharmaceuticals, France): (1) a gonadotropin-releasing hormone (GnRH) antagonist protocol, (2) a long agonist protocol, and (3) a short agonist protocol.²¹ The gonadotropin doses and the type of COS protocol were determined according to the individual patient characteristics. Final oocyte maturation was triggered when ≥3 ovarian follicles of ≥17 mm were visible by ultrasound and when E2 levels were ≥1000 pg/mL. (2) For the Def-ET group, final oocyte maturation was achieved using either a single injection of 0.2 mg of GnRH agonist (Triptorelin, Decapeptyl; Ipsen, France) or by 250 μg of recombinant human chorionic gonadotrophin (rhCG; Ovitrelle; Serono, France), according to the COS protocol. (3) For the fresh ET group, final oocyte maturation was achieved by triggering with rhCG, irrespective of the stimulation protocol. Oocyte retrieval was performed 35 to 36 hours later by transvaginal aspiration under ultrasound guidance.

Oocyte Insemination

Semen samples were collected by masturbation after a sexual abstinence period ranging from 2 to 5 days. Conventional IVF or ICSI was performed according to the sperm parameters.²² Fertilization was assessed by the presence of 2 pronuclei (2PN) and 2 polar bodies at 17 to 18 hours following oocyte insemination or injection.

Embryo Culture, Cryopreservation, and Thawing

For prolonged cultures, embryos were transferred into a 50-μL droplet of 1-step Global culture medium (LifeGlobal, Guilford, Connecticut) and cultured until day 5 or 6 at 37°C in an atmosphere of 5% CO₂, 5% O₂, and 90% N₂. The culture medium was changed on day 3. Embryo morphology was evaluated on the morning of days 5 and 6. Blastocysts were scored according to the grading system of Gardner and Schoolcraft²³ and considered eligible for cryopreservation on day 5 or day 6 if they qualified as full (B3) or expanded (B4-5) blastocysts with a type A-C inner cell mass (ICM) and/or a type A-C trophectoderm. Blastocysts that did not meet these criteria on day 5 were kept in culture and reexamined on day 6. Blastocysts with a type “C” ICM and a type “C” trophectoderm were not cryopreserved, irrespective of their degree of expansion and the day of observation (day 5 to day 6).

The vitrification and thawing protocol was as detailed previously.¹⁹ Briefly, embryo vitrification was performed using closed Cryo-Bio-System vitrification High Security straws in combination with DMSO-EG-S as the cryoprotectants (Irvine Scientific Freeze Kit; Irvine Scientific, Santa Ana, California). For thawing, the Irvine Scientific Thaw Kit was used. Zygotes were warmed the day prior to the ET and kept in culture for 24 hours in the same culture medium (a 50-μL droplet of 1-step Global culture medium [LifeGlobal] at 37°C in an atmosphere of 5% CO₂, 5% O₂, and 90% N₂). On day 2, the embryos were morphologically assessed according to the criteria published in the Istanbul Consensus workshop on embryo assessment guide.²⁴ One or 2 best quality embryos were chosen for transfer. Supernumerary embryos, if there were any, were maintained in extended culture and vitrified when they reached the blastocyst stage. The blastocysts were warmed on the day of the transfer. When the warmed blastocyst had <50% intact cells, an additional blastocyst was warmed if available. If the blastocyst was >50% intact, expansion and reexpansion were assessed 2 to 3 hours later.

Endometrial Preparation Before ET

In the fresh ET group, all of the women began progesterone treatment (a 200 mg vaginal capsule 3 times per day; Utrogestan; Besins International, Montrouge, France) on the day of the oocyte retrieval, and E2 was delivered transdermally (2 mg/d, through 2 Vivelle-Dot 100 systems; Novartis Pharma SA, Rueil-Malmaison, France, simultaneously) or orally (8 mg/d; Provames, Sanofi Aventis, Paris, France) 48 hours after the ET. Day 2 embryos were morphologically assessed, and the 1 or 2 embryos deemed to be the most suitable were selected for transfer. In the Def-ET group, all of the women received progesterone (one 200 mg vaginal capsule, daily) for 10 days in order to ensure proper occurrence of menses. Embryo transfers were scheduled approximately 4 to 5 weeks later. For this, the women received an E2-priming regimen that was delivered transdermally (0.2 mg/d) or orally (8 mg/d). The patients were examined after menses in order to assess the endometrial thickness and to determine their progesterone levels. When conditions were appropriate (eg, an endometrium thickness ≥7 mm and a progesterone level <1.5 ng/mL), vaginal progesterone treatment was initiated at a dose of 200 mg 3 times per day. Day 2 cleavage-stage embryos were transferred on the fourth day of progesterone exposure. Blastocysts were transferred immediately on the fifth day of progesterone exposure. Best quality embryos were chosen for the transfer. The women who became pregnant by these procedures continued to receive progesterone and E2 at the same dose until 12 weeks of gestation.

Data Analysis and Statistics

The general characteristics of the patients in both the groups were recorded prospectively during face-to-face interviews prior to the COS. The following data were collected: age at retrieval (in years), height (in meters), weight (in kg), body mass index (BMI, calculated as weight in kg/height in m²), the number of previous ART cycles, the length of the infertility, smoking habits, the ovarian reserve (day 3 FSH and the antral follicle count), anti-Müllerian hormone (AMH) levels, and the nature of the infertility (ie, ovulation disorder, male factor, tubal factor, endometriosis, idiopathic, diminished ovarian reserve, or more than 1 etiology).

The clinical pregnancy rate (cPR) was determined by ultrasonographic documentation of at least 1 fetus with a heartbeat at 6 to 7 weeks of gestation.²⁵ The live birth rate (LBR) was defined as the delivery of any viable infant at 22 weeks or more of gestation.²⁵

The cumulative cPR and the LBR were the proportion of retrievals that had at least 1 clinical pregnancy and LBR, respectively, whether from the first transfer attempt or subsequent transfers of frozen–thawed supernumerary embryos.¹⁵ Once a woman obtained a live birth from IVF/ICSI, she no longer contributed to the cumulative rates.²⁶

The main ART outcome measure was the cumulative live birth rate (CLBR). All of the data were compiled into a digital database and analyzed using IBM SPSS Statistics version 23.0 software (SPSS Inc Headquarters, Chicago, Illinois). A P value <.05 was considered to be statistically significant. For univariate statistical analyses, we used the following tests: the Pearson χ² test or the Fisher exact test for the qualitative variables and the Student t test or the Mann-Whitney test for the quantitative variables as appropriate.

To identify potential confounding variables that could be independently associated with cumulative live births, we performed a logistic regression analysis. Confounding factors were tested by univariate analysis and added in a multiple logistic regression model. Interactions between explanatory variables were tested 2 × 2: No significant interaction was found. Included variables in the multiple model were those with a significance on univariate analysis of P < .10 or more and those that could potentially impact on the live birth outcome (eg, the type of ET: fresh or Def-ET). Correlation between variables was tested, and if 2 variables were highly correlated, only one of them was introduced in the model, as for the type of stimulation protocol and the total dose of injected gonadotrophins (Pearson correlation coefficient: −0.37; P < .001) and the length of the stimulation and the total dose of the injected gonadotropins (Pearson correlation coefficient: −0.48; P < .001), the latter having been suppressed.

Backward stepwise selection was used to retain variables with a P value of <.05 in each final model. The parameter values for each of the final models were estimated by the maximum likelihood method. In case of significant differences, odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated from the model’s coefficients and their standard deviations.

A 2-stage, 2-sided parallel group procedure with an overall type I error of 0.05 was used to test the primary hypothesis of a difference in the probabilities of CLBRs for the 2 arms in this study, with a sample size of 390 patients (195 patients in each group) needed to achieve 80% power for detecting a difference of 10% in the CLBRs between deferred and fresh ET cycles.

Results

Study Population

The process for our cohort selection is detailed in Figure 1. Overall, 219 cycles were included in the Def-ET group and 197 in the fresh ET group.

Patients and COS Characteristics

The baseline characteristics were comparable with respect to age, BMI, the mean number of previous IVF/ICSI cycles, the length of infertility, the nature of the infertility, smoking habits, and ovarian reserve parameters (Table 1). The COS characteristics are presented in Table 2.

Table 1.

Baseline Characteristics and Potential Confounders in Fresh and Deferred Frozen–Thawed Embryo Transfer Groups.^a

	Fresh ET, n = 197	Def-ET, n = 219	P Value
Patient’s age at IVF/ICSI, years	35.94 ± 4.19	36.26 ± 3.94	.552^b
Age at IVF/ICSI > 35 years old	111 (56.3)	132 (60.3)	.417^c
IVF/ICSI rank			.480^c
Third IVF/ICSI attempt	119 (60.4)	142 (64.8)
Fourth IVF/ICSI attempt	47 (23.9)	51 (23.3)
>Fourth IVF/ICSI attempt	31 (15.7)	26 (11.9)
Length of infertility, years	5.55 ± 3.11	5.77 ± 3.14	.575^b
BMI, kg/m²	24.18 ± 4.13	23.79 ± 4.09	.305^b
BMI >25 kg/m²	67 (34.0)	61 (27.9)	.174^c
Smoker	18 (9.1)	14 (6.4)	.294^c
Cause of infertility			.650^c
Ovulation disorder	14 (7.1)	17 (7.8)
Male factor	61 (31.0)	72 (32.9)
Tubal factor	22 (11.2)	30 (13.7)
Endometriosis	18 (9.1)	27 (12.3)
Idiopathic	40 (20.3)	34 (15.5)
Diminished ovarian reserve	7 (3.6)	9 (4.1)
More than 1 etiology	35 (17.8)	30 (13.7)
Patient’s ovarian reserve
Day 3 FSH >10 IU/L	18 (9.1)	16 (7.3)	.496^c
AFC <10	53 (26.9)	52 (23.7)	.459^c
AMH <1.5 ng/mL	42 (21.3)	37 (16.9)	.251^c

Abbreviations: AFC, antral follicle count; AMH, anti-Müllerian hormone; BMI, body mass index; FSH, follicle-stimulating hormone; IVF/ICSI, in vitro fertilization /intracytoplasmic sperm injection; LH, luteinizing hormone.

^a Data are the mean± standard error or n (%), unless specified otherwise.

^b Mann-Whitney test.

^c Pearson’s χ² test.

Table 2.

ART Characteristics and Outcomes in Fresh and Deferred Frozen Embryo Transfers.^a

	Fresh ET, n = 197	Def-ET, n = 219	P Value
Stimulation protocol			<.001^b
Long protocol	49 (24.9)	8 (3.7)
GnRH antagonist	98 (49.7)	196 (89.5)
Short protocol	50 (25.4)	15 (6.8)
Total dose of injected gonadotropin, IU	2896.70 ± 1079.83	2541.30 ± 779.31	.002^b
Duration of stimulation, days	9.58 ± 1.31	10.41 ± 1.49	<.001^b
Peak estradiol levels, pg/mL^c	1772.88 ± 779.42	1796.93 ± 884.17	.753^b
Peak progesterone levels, ng/mL^c	0.78 ± 0.36	0.77 ± 0.37	.794^b
Mean total number of oocytes retrieved	8.46 ± 4.64	9.47 ± 5.20	.064^b
MII oocytes/total number of oocytes retrieved	83.77 ±19.17	83.53 ±16.82	.306^b
Number of 2PN embryos	4.47 ± 2.65	5.17 ± 3.26	.056^b
Clinical pregnancy rate^d	71/197 (36.0)	75/219 (34.6)	.698^e
Early pregnancy loss rate^d	17/71 (23.9)	27/75 (36.0)	.112^e
Live birth rate^d	50/197 (25.4)	44/219 (20.1)	.197^e
Mean number of ET per patient	1.23 ± 0.58	1.32 ± 0.66	.130^b
Cumulative clinical pregnancy rate	83/197 (42.1)	88/219 (40.2)	.687^e
Cumulative early pregnancy loss rate	22/83 (26.5)	32/88 (36.4)	.166^e
Multiple pregnancy	12/83 (14.46)	1/88 (1.14)	.001^e
Cumulative live birth rate	58/197 (29.4)	57/219 (26.0)	.437^e

Abbreviations: ART, assisted reproduction technology; ET, embryo transfer; 2PN, 2 pronuclei.

^a Data are the mean ± standard error or n (%), unless specified otherwise.

^b Mann-Whitney test.

^c At triggering day.

^d After the first embryo transfer.

^e Pearson χ² test.

Outcomes of ART

The number of 2PN embryos and the fertilization rates were not significantly different between the fresh ET group and the Def-ET group (Table 2). After the first ET, the LBR was not significantly different between the fresh ET group and the Def-ET group (50/197 [25.4%] vs 44/219 [20.1%], respectively). There were similarly no significant differences in terms of the cPR or the early pregnancy loss rate (Table 2).

There was an equal mean number of ET for both the groups (1.23 ± 0.58 for the fresh group vs 1.32 ± 0.66 for the Def-ET group, P = .130). The cumulative outcomes are listed in Table 2. The CLBR were not significantly different between the fresh ET group (58/197 [29.4%]) and the Def-ET (57/219 [26.0%]) group (P = .437). The cumulative cPR (83/197 [42.1%] vs 88/219 [40.2%], P = .687) and the cumulative early pregnancy loss rate (22/83 [26.5%] vs 32/88 [36.4%], respectively, P = .166) were not significantly different between the fresh ET group and the Def-ET group (Table 2). The characteristics of the transferred embryos are provided in Supplemental Table 1.

Variables Independently Associated With Cumulative Live Birth: Multivariate Analysis

A multivariate analysis was performed to identify variables independently associated with a cumulative live birth, and the results are presented in Table 3. The model included the women’s age (>35 years old vs ≤35 years old), BMI (>25 vs ≤25), serum AMH levels (<1.5 ng/mL vs ≥1.5 ng/mL), the length of infertility, the type of protocol (GnRH antagonist vs long and short protocol), the duration of the stimulation, and the type of ET (fresh ET or Def-ET). The variables with a significant impact on the CLBR were maternal age over 35 years old (OR = 0.348, 95% CI: 0.195-0.622) and a BMI over 25 kg/m² (OR = 0.436, 95% CI: 0.211-0.901).

Table 3.

Logistic Regression Analysis for the Prediction of the Cumulative Live Birth Rate.

Variables Included in the Multivariate Model	Odds Ratio	95% CI	P Value
Patient’s age at IVF (years) >35 years old	0.348	0.195-0.622	<.001
BMI, kg/m², >25	0.436	0.211-0.901	.025
AMH level <1.5 ng/mL	0.607	0.249-1.481	.273
Length of infertility	0.908	0.810-1.017	.095
Protocol of stimulation			.303
GnRH-antagonist	1
Long protocol	1.030	0.443-2.391	.946
Short protocol	0.376	0.125-1.135	.083
Duration of stimulation, days	0.820	0.665-1.011	.063
Def-ET versus fresh ET	1.254	0.599-2.627	.548

Abbreviations: AMH, anti-Müllerian hormone; CI, confidence interval; BMI, body mass index; Def-ET, deferred embryo transfer; IVF, in vitro fertilization.

Discussion

Main Finding

This large controlled study showed that, for women with repeated IVF/ICSI cycle failures, the Def-ET strategy did not result in a higher CLBR than the fresh ET strategy.

Strength and Limitations

The strength of this study is based on the following aspects: (1) First, this study addressed the still insufficiently explored topic of fresh versus deferred cryopreserved ET and ART outcomes. To the best of our knowledge, this is the largest study (N = 416) to assess the Def-ET strategy following previous consecutive IVF/ICSI cycle failures. (2) While numerous studies have focused on the LBR after the first transfer to compare the fresh ET versus the Def-ET strategy, in this study, we used the CLBR per oocyte retrieval, as published previously.^26
–28 By providing an all-inclusive success rate, this analysis is of considerable relevance for clinicians, as cryopreservation has become an integral part of ART. Additionally, in our study, the stage of the ET differed between the 2 groups (see Supplemental Table 1). Studying the CLBR therefore provides a better comparison of the 2 analyzed strategies, given that the evidence to date does not indicate that blastocyst transfer is better than cleavage-stage transfer in terms of cumulative pregnancy rates.²⁹ (3) Finally, numerous epidemiological variables were collected prospectively through face-to-face interviews prior to the ART (eg, in regard to surgical history, infertility data, and ovarian stimulation characteristics).

Despite the precautions taken, our study may nonetheless be subject to certain shortcomings and/or biases. (1) Our study suffers from weaknesses inherent to its design, namely, a retrospective analysis of a prospective cohort. The women were not allocated to the fresh or the Def-ET group by randomization, but rather based on a mutual decision by the patient and the doctor. In light of this, great care was taken to minimize sources of bias, particularly through the use of a multivariate model and a large study sample size. In addition, the general patient characteristics such as age, BMI, the causes of infertility, ovarian parameters, and the number of previous IVF/ICSI failures were comparable between the 2 groups. Although retrospective, this study appears original and relevant, as there is no randomized studies on this topic to date.²⁸ Further randomized control studies are needed to confirm our results. (2) Furthermore, some differences persisted between the groups in regard to COS characteristics. These are linked to the ET strategy: In the Def-ET group, there was a higher proportion of antagonist protocol use compared to the fresh ET group (89.5% vs 49.7%, respectively). In our ART center, this protocol is prioritized when the Def-ET strategy is used, since it allows for triggering by GnRH agonist, which can prevent some of the COS-associated risks.³⁰ To evaluate the possible impact of the type of protocol on the LBR, we included this variable in a logistic regression analysis. After multivariate analysis, neither the type of ET strategy nor the type of protocol used was found to be independent factors associated with the LBR. Furthermore, the ovarian stimulation response was similar for the 2 groups, and there were no significant differences in terms of the E2 levels on the trigger day, the number of oocytes retrieved, and the number of 2PN embryos.

Interpretation

There is only a single retrospective study in the literature that focused on women with one prior fresh blastocyst implantation failure. Unlike our results, the authors found that there was an increase in the LBR after the “freeze-all” strategy.¹⁵ The population in the study by Shapiro et al was different from ours: It comprised patients with only 1 prior implantation failure after a fresh transfer, while we focused on women with at least 2 or more consecutive IVF/ICSI failures cycles.

Based on our study, it can be assumed that multiple consecutive IVF/ICSI cycle failures do not depend solely on the endometrial changes secondary to COS that are potential factors impairing endometrial receptivity in fresh autologous IVF/ICSI cycles. Indeed, Def-ET in a subsequent cycle into a nonstimulated intrauterine environment does not improve ART outcomes in women with repeated IVF/ICSI cycle failures. It is likely that more complex and interlinked mechanisms are involved. Although many different approaches seeking to overcome repeated IVF/ICSI failures based on various hypothesis have been published, the pathophysiology remains unknown.^31

–35 For example, endometrial blood flow anomalies, differential gene expression, and immunological changes have been identified in these women.^31

–35 However, none of them was able to fully solve the repeated IVF/ICSI failures in some of these women. Further investigations are therefore required to determine the optimal ART strategy for women with repeated IVF/ICSI cycle failures.

Conclusion

In conclusion, after 2 or more consecutive IVF/ICSI cycle failures, the Def-ET strategy did not improve ART outcomes compared to a fresh ET strategy, as the CLBRs were the same. If there is impairment of endometrial receptivity by ovarian stimulation in this specific population, it does not appear to play a major role in the causes of ART failure, as the Def-ET strategy did not significantly improve the CLBR. Further investigation of women with a history of previous ART failures with well-designed randomized control trials reporting in regard to CLBRs may be warranted.

Supplemental Material

Suppl_Table_1 - The Deferred Embryo Transfer Strategy Seems Not to be a Good Option After Repeated IVF/ICSI Cycle Failures

Suppl_Table_1 for The Deferred Embryo Transfer Strategy Seems Not to be a Good Option After Repeated IVF/ICSI Cycle Failures by Mathilde Bourdon, Pietro Santulli, Yulian Chen, Catherine Patrat, Khaled Pocate-Cheriet, Chloé Maignien, Louis Marcellin and Charles Chapron in Reproductive Sciences

Footnotes

Authors’ Note

M.B. and P.S. are considered as joint first authors. P.S., M.B., and C.C. conceived and designed the study. All of the authors analyzed and interpreted the data. M.B., P.S., and C.P. supervised and reviewed the statistical analysis. M.B., P.S., Y.C. contributed to the data collection. M.B., P.S., and C.C. authored the manuscript. All of the authors read and approved the final version of the manuscript.

Acknowledgments

The authors wish to thank staff members of our department’s operating room for their expert assistance with data collection, especially Sandra Cheniere, Arane Kim, Ronan Calec, and Paul Pirtea. The authors also gratefully acknowledge Valerie Blanchet and Julia Gonnot for unabatedly managing the patient database.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was partially supported by a Finox Forward Research Grant .

Supplemental Material

Supplemental material for this article is available online.

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