Scholarly article on topic 'Cumulative live birth rate after GnRH agonist trigger and elective cryopreservation of all embryos in high responders'

Cumulative live birth rate after GnRH agonist trigger and elective cryopreservation of all embryos in high responders Academic research paper on "Animal and dairy science"

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{"Elective embryo cryopreservation" / Freeze-all / "Ovarian hyperstimulation syndrome" / "Vitrified-warmed blastocyst transfer"}

Abstract of research paper on Animal and dairy science, author of scientific article — Veljko Vlaisavljević, Borut Kovačič, Jure Knez

Abstract Elective embryo cryopreservation after using gonadotrophin-releasing hormone (GnRH) antagonist protocols and GnRH agonist triggering is becoming an increasingly important part of medically assisted reproduction. We designed a single-centre retrospective study to assess the cumulative probability of achieving a live birth through consecutive transfers of vitrified-warmed blastocysts after elective embryo cryopreservation in high-responding patients. Hence, 123 women identified to be at high risk for developing ovarian hyperstimulation syndrome were included. They were stimulated using GnRH antagonist protocol, and GnRH agonist was used to trigger final oocyte maturation. All embryos were vitrified at the blastocyst stage and transferred in the subsequent menstrual cycles. Using the Kaplan–Meier survival analysis, a total of 65.9% (95% CI 57.5 to 74.3) women achieved a live birth after a maximum of six embryo transfer cycles using the ‘conservative’ approach. Applying the ‘optimistic’ approach, presuming that women who still had cryopreserved embryos and did not return for embryo transfer had the same chance of achieving a live birth as those returning for transfer, the cumulative live birth rate estimated in six embryo transfer cycles was 76.6% (95% CI 69.1 to 84.1). No cases of severe ovarian hyperstimulation syndrome were recorded.

Academic research paper on topic "Cumulative live birth rate after GnRH agonist trigger and elective cryopreservation of all embryos in high responders"

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Article

Cumulative live birth rate after GnRH agonist trigger and elective cryopreservation of all embryos in high responders

Veljko VlaisavljeviCab, Borut KovaciCa, Jure Knez

a Department of Reproduct ive Med i c i ne and Gynaecolog i c Endocri nology, Un i vers i ty Med i cal Centre Mari bor, 2000 Mari bor, Sloven ia

b B i omed i cal Research Ins i tute (BRIS), 1000 Ljubljana, Sloven ia

Veljko Vlaisavljevic is Professor of Obstetrics and Gynaecology at University of Ljubljana. He founded the Department of Reproductive Medicine at University Medical Centre Maribor. He was a member of the ESHRE executive committee and is the current president of the Slovene Society for Reproductive Medicine. His bibliography comprises over 450 articles.

KEY MESSAGE

Use of gonadotrophin-releasing hormone (GnRH) antagonist cycles and GnRH agonist triggering is effective in reducing the risk of developing ovarian hyperstimulation syndrome in high-responding patients. Patients can be reassured that high cumulative live birth rates can be expected when all embryos are cryopreserved and transferred in the subsequent menstrual cycles.

ABSTRACT

Elective embryo cryopreservation after using gonadotrophin-releasing hormone (GnRH) antagonist protocols and GnRH agonist triggering is becoming an increasingly important part of medically assisted reproduction. We designed a single-centre retrospective study to assess the cumulative probability of achieving a live birth through consecutive transfers of vitrified-warmed blastocysts after elective embryo cryopreservation in high-responding patients. Hence, 123 women identified to be at high risk for developing ovarian hyperstimulation syndrome were included. They were stimulated using GnRH antagonist protocol, and GnRH agonist was used to trigger final oocyte maturation. All embryos were vitrified at the blastocyst stage and transferred in the subsequent menstrual cycles. Using the Kaplan-Meier survival analysis, a total of 65.9% (95% CI 57.5 to 74.3) women achieved a live birth after a maximum of six embryo transfer cycles using the 'conservative' approach. Applying the 'optimistic' approach, presuming that women who still had cryopreserved embryos and did not return for embryo transfer had the same chance of achieving a live birth as those returning for transfer, the cumulative live birth rate estimated in six embryo transfer cycles was 76.6% (95% CI 69.1 to 84.1). No cases of severe ovarian hyperstimulation syndrome were recorded.

© 2017 The Authors. Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author. E-mail address: knez.jure@gmail.com (J Knez). http://dx.doi.org/10.1016/j.rbmo.2017.03.017

1472-6483/© 2017 The Authors. Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Introduction

The efforts to minimize complications of medically assisted reproduction have become an increasingly important part of reproductive medicine in the past decade. Today, ovarian hyperstimulation syndrome (OHSS) is the main potentially life-threatening complication of ovarian stimulation. In recent years, gonadotrophin-releasing hormone (GnRH) antagonist protocols have replaced GnRH agonist protocols as the most commonly used approach to ovarian stimulation. This is especially important when dealing with patients likely to have a high response to ovarian stimulation, as this approach has been associated with significant reduction in OHSS occurrence (Al-Inany et al., 2011; Papanikolaou et al., 2006; Youssef et al., 2011). However, GnRH antagonist protocols also allow for implementation of additional measures, most notably the replacement of HCG with GnRH agonist to induce final oocyte maturation. This approach practically eliminates the risk of developing OHSS (Griesinger et al., 2006; Kolibianakis et al., 2005; Youssef et al., 2010) and the success of oocyte retrieval is comparable in oocyte number and maturation rate to using HCG (Galindo et al., 2009; Hernandez et al., 2009). The drawback is hindered endometrial receptivity caused by rapid luteolysis and the associated luteal phase defect. This is probably caused by excessive negative steroid feedback mechanism that causes suppression at the pituitary level (Casper, 2015; Kol et al., 2015). Hence, early studies have shown significantly reduced pregnancy and live birth rates (Babayof et al., 2006; Griesinger et al., 2006; Humaidan et al., 2005). Intensified luteal support was considered, which can improve the success rate of the following embryo transfer in the same cycle (Humaidan etal., 2010; Iliodromitietal., 2013) but this may come at a cost of increasing the incidence of OHSS development (Seyhan et al., 2013).

Elective cryopreservation of all embryos and transfer in subsequent menstrual cycles, therefore, presents as a rational and logical approach to the treatment of these women. This method was enabled by dramatic improvements in vitrification techniques and embryo survival rates in the past decade (Abdel Hafez et al., 2010). Today, the indications for elective cryopreservation of all embryos are broadening, and many more women, including those with abnormal late follicular progesterone levels and patients in oocyte donation programmes, are candidates for elective embryo cryopreservation. Indeed, frozen-thawed embryo transfer has numerous potential benefits compared with embryo transfer in a fresh cycle, most notably improved embryo-endometrial synchrony and the possibility of better workload organization in the clinic. Moreover, improved obstetrical and neonatal outcomes have also been suggested (Ishihara et al., 2014; Pelkonen et al., 2010; Wennerholm et al., 2013). Wider acceptance of elective cryopreservation of all embryos and transfer in a frozen-thawed cycle could dramatically change the way we will approach IVF in the future (Blockeel et al., 2016). In light of these facts, it is crucial to study the chances of the cycle outcome success after administering GnRH agonist and electively cryopreserving all embryos. We aimed to investigate the cumulative probability of achieving a live birth through consecutive transfers of vitrified-warmed blastocysts after applying the freeze-all strategy in high-responding patients.

Materials and methods Study design

Women undergoing elective cryopreservation of all embryos in consecutive IVF and intracytoplasmic sperm injection (ICSI) cycles from January 2012 to July 2014 were included in the retrospectively designed study. All women were treated with GnRH antagonist protocol. Specifically, according to our clinical practice, only women identified as high risk for developing OHSS during ovarian stimulation were counselled about the possibility of using GnRH agonist to trigger the final oocyte maturation and electively cryopreserving all embryos.

Protocols

All cycles were synchronized using combined oral contraception. Ovarian stimulation was initiated on day 5 of the pill-free interval by administering a starting dose of 150 IU of recombinant FSH (Gonal-F, Merck Serono, Switzerland) or highly purified HMG (Menopur, Ferring, Switzerland) (Vlaisavljevic et al., 2003). On day 6 of the stimulation, 0.25 mg of cetrorelix (Cetrotide; Merck Serono, Switzerland) was started in a fixed protocol. The gonadotrophin dose could be adjusted on day 6 of the stimulation according to the level of the ovarian response as demonstrated by the ultrasound. Cycle monitoring was carried out using the combination of transvaginal ultrasound and serum oestradiol. Women with 19 or more developing follicles were counselled about the possibility of replacing HCG with GnRH agonist. All follicles measuring a mean diameter of 11 mm or wider were considered to be developing follicles. Ultrasound criteria have been shown to be more reliable than endocrinologic characteristics in predicting the possibility of OHSS and, hence, this was used as inclusion criterion (Griesinger et al., 2016; Papanikolaou et al., 2006; Reljic et al., 1999). Nonetheless, we routinely measure oes-tradiol levels before triggering final oocyte maturation in all patients according to our clinical practice. This means that some women with a high number of follicles and low oestradiol levels may not have decided on a freeze-all approach and still opted for routine triggering with HCG. If women decided to take this approach, the final oocyte maturation was achieved by administering 0.2 mg of triptorelin (Diphereline; Ipsen, France). The oocyte retrieval was planned 35 h after the GnRH agonist administration. An IVF or ICSI procedure was performed and successful fertilization of the oocytes was defined as the presence of two pronuclei 17-19 h after the procedure. All fertilized oocytes and embryos were cultured in the BlastAssist System sequential embryo culture media (Origio, Knardrupvej, Denmark) for 5 days. The blastocysts were graded according to our established grading system, previously described (Kovacic et al., 2004). In brief, a blastocyst was considered optimal if it was fully expanded, contained cohesive trophectoderm, compact inner cell mass and the blastocoel completely filled the embryo (Kovacic et al., 2004). The criteria for blastocysts available for cryopreservation were not very rigorous. Only expanded blastocysts were cryopreserved on day 5 or day 6. Also, blastocysts containing cytoplasmic fragments within trophectoderm or excluded blasto-meres in their periviteline space were vitrified if at least a few of the inner-cell-mass cells were observed.

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For vitrification and warming, commercially available cryoprotectant solutions (Vit Kit® - Freeze and Vit Kit® - Thaw, Irvine Scientific, USA) and High Security Vitrification straws (HSV, CryoBio System, France) were used according to the manufacturer's instructions. At least four straws were loaded with single blastocysts of higher quality scores for each patient. Remaining straws contained maximally two blastocysts.

After warming, blastocysts were cultured for 3-4 h in recovery culture medium (BlastAssist, Origio, Knardrupvej, Denmark) supplemented with higher concentration of human serum albumin (12 mg/ ml). Survival was confirmed when at least 50% of embryonic cells were intact and formed a cohesive layer of trophectoderm cells, which enabled blastocyst re-expansion (Kovacic and Vlaisavljevic, 2012).

The blastocysts were transferred in medically prepared cycles with oestradiol (Estrofem, Novo Nordisk, Novo Alle, Belgium) and progesterone (Utrogestan, Besins, Brussels, Belgium) without the use of GnRH agonist for pituitary downregulation. The endometrium was first primed with oestradiol for 10 days and progesterone was added in case the ultrasound examination showed proliferative endometrium of appropriate thickness. After 6 days of progesterone supplementation, the embryo transfer was planned. Either one or maximum of two warmed blastocysts were transferred in each cycle as according to our national regulations and the doctor-patient agreement (Vlaisavljevic et al., 2008). According to our regulations, there is no limit to the number of cryopreserved embryo transfers per fresh cycle from which the cryopreserved embryos derived. All cryopreserved embryos must be used before a new fresh cycle can be started. All embryo transfers were carried out using clinical touch technique by physicians with extensive experience.

The patients were followed up and the results of the subsequent embryo transfers were recorded until the delivery of a live infant, the transfer of all cryopreserved blastocysts or the discontinuation of the treatment. We considered women that had cryopreserved blastocysts, did not deliver a live infant and did not return for embryo transfer in 12 months after oocyte aspiration or the last embryo transfer, to have discontinued the treatment. Afterwards, they were contacted about the reasons for treatment discontinuation. The primary outcome of the study was the delivery of one or more live infants. As the technique used was standard clinical practice and the study involved retrospective analysis of anonymous patient data held in the clinical database Institutional Review Board approval was not obtained.

Statistical analysis

Descriptive statistics were used to analyse the basic demographic characteristics of the patients. We used the Kaplan-Meier method, which censors data, for patients that did not return for embryo transfer, although they had embryos cryopreserved, to estimate the cumulative live birth rates. This method assumes that women who did not return for treatment had the same chance of achieving a live birth as those who did return for treatment. As it is optimistic to presume that every woman would return for treatment, this method may overestimate the cumulative live birth rates. We, therefore, constructed a conservative model presuming that women who had embryos cryopreserved but did not return for embryo transfer for any reason, had no chance of achieving a live birth. The population's realistic predicted cumulative live birth rate probably lies between these two estimates.

Table 1 - Patients' clinical characteristics.

Characteristic Value

Age (mean, SD) 32.2 [3.8]

Body mass index (median, range) 21 [16-46]

Number of retrieved oocytes (mean, SD) 24.9 [9.4]

Number of fertilized oocytes (mean, SD) 16.4 [6.5]

Number of blastocysts (mean, SD) 10.2 [5.1]

Number of optimal blastocysts (mean, SD) 4.2 [3.2]

Number of vitrified blastocysts (mean, SD) 8.8 [4.6]

Number of previous cycles (median, range) 0 [0-4]

Endocrine characteristics

FSH (IU/L) (mean, SD) 5.0 [1.1]

LH (IU/L) (mean, SD) 4.6 [1.6]

Anti-Mullerian hormone (ng/ml) (mean, SD) 6.2 [3.1]

Oestradiol gonadotrophin-releasing hormone 11.7 [1.3 > 18.4]

agonist administration (nmol/L) (median, range)

Results

A total of 123 women underwent elective cryopreservation of all embryos in the study period, and all were included in the retrospective analysis. The women were aged 32 years on average, were undergoing their first IVF attempt, and had on average almost 25 oocytes retrieved at follicle aspiration. The highest number of retrieved oocytes at a single aspiration was 76. The median oestradiol level before final oocyte maturation was 11.7 nmol/L. A total of 13 women had oestradiol levels higher than 18.4 nmol/l. On average, almost nine blastocysts were vitrified per oocyte retrieval cycle. The patients' baseline clinical characteristics are presented in Table 1.

The outcome of the embryo transfer cycles is presented in Table 2. A total of 65.9% (95% CI 57.5 to 74.3) women achieved a live birth after a maximum of six embryo transfer cycles using the conservative approach to live-birth rate estimation. Nineteen twins were born (23.4%, 95% CI 14.2 to 32.6) and no higher order multiples. No cases of severe OHSS was recordeod in our group of women.

Using the Kaplan-Meier survival analysis (Figure 1) and the 'optimistic' approach, presuming that women who still had cryopreserved embryos and did not return for embryo transfer had the same chance of achieving a live birth as those returning for transfer, the cumulative live-birth rate estimate in six embryo transfer cycles would be 76.6% (95% CI 69.1 to 84.1).

Of the 42 women who failed to achieve a live birth, 26 (61.9%) still had surplus embryos cryopreserved. Only one woman had spare embryos after six embryo transfers. She returned for the seventh and eighth attempt of embryo transfer but failed to achieve a pregnancy. The patient flow is presented in Figure 2.

Discussion

We aimed to evaluate a meaningful cumulative live-birth rate after elective cryopreservation of all embryos in the group of high-responding women to ovarian stimulation. To avoid OHSS, the approach of using GnRH antagonist protocols, and triggering the final oocyte maturation with GnRH agonist, is one of the most effective measures known today. It has previously been reported that the threshold of over 18 follicles or oestradiol concentration greater than 5000 pg/ ml (equivalent to 18.36 nmol/l) can predict the occurrence of severe

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Table 2 - Vitrified-warmed blastocyst transfer cycle outcome.

Embryo transfer attempt 1 2 3

Number of embryo transfers Number of warmed blastocysts (mean, SD) Number of blastocysts transferred (mean, SD) Blastocyst survival rate |%, 95% CI] Clinical pregnancy/embryo transfer (%, 95% CI) Live birth/embryo transfer |%, 95% CI) Twin birth rate/embryo transfer (%, 95% CI) Cumulative live birth rate |%, 95% CI) 116 1.35 (0.56) 1.34 (0.47) 98.0% (95.7 to 100) 52 (44.8, 35.8 to 53.9) 49 (42.2, 33.2 to 51.2) 11 (22.4, 10.7 to 34.1) 49 (39.8, 31.2 to 48.5) 58 1.50 (0.59) 1.45 (0.50) 99.2% (97.7 to 100) 24 (41.4, 28.7 to 54.1) 20(34.5, 22.3 to 46.7) 5 (25, 6.0 to 44.0) 69 (56.1, 47.3 to 64.9) 25 1.40 (0.50) 1.40 (0.50) 100 7 (28.0, 10.4 to 45.6) 6 (24.0, 7.3 to 40.7) 0 (0%) 75 (60.9, 51.5 to 68.8

1.60 10.51] 1.60 10.51] 100

5 (35.7, 10.6 to 60.1] 4 (28.6, 4.9 to 52.3] 2 (50, 1.0 to 99.0] I 79 (64.2, 55.7 to 72.7]

1.86 (0.38) 1.86 (0.38) 100

1 (16.7, 0 to 46.5) 1 (16.7, 0 to 46.5) 0(0]

80 (65.0, 56.8 to 73.4)

1.80 (0.45) 1.80 (0.45) 100

1 (50.0, 0 to 100] 1 (50.0, 0 to 100) 1 (1001

81 (65.9, 57.5 to 74.3)

1.43 (0.54) 1.42 (0.49) 98.9% (98.0 to 99.8) 90(40.7, 34.2 to 47.2) 81 (36.7, 30.4 to 43.1) 19(23.5, 14.2 to 32.6) /

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OHSS, with sensitivity of 83% and specificity of 84% in women undergoing ovarian stimulation using GnRH antagonist protocol (Papanikolaou et al., 2006). In our population of patients, 25 oocytes were retrieved at oocyte retrieval on average, and hence these patients represent a true high-risk population for developing severe OHSS. For the first time, we have shown that, in this group of patients, GnRH agonist triggering combined with elective embryo cryopreservation allows for high success rates within only one cycle of ovarian stimulation. By using this approach, up to three-quarters of couples can expect a delivery of a live infant.

Specifically, the estimated cumulative live-birth rate ranged between 65.9% and 76.6%. The higher, optimistic estimation assumes that women who did not return for embryo transfer, but still had cryopreserved embryos, had the same chance of achieving a live birth as those who returned for treatment. Although this is likely an over-estimation, the number of women predicted to achieve a live birth using the 'optimistic' approach is only 10% higher compared with using the 'conservative' approach. It is probable that the true predicted success rate lies somewhere in between these conservative and optimistic estimates. Several studies have pointed out that women who do not return for treatment after an unsuccessful IVF may in fact have poorer prognosis than those continuing treatment (Land et al., 1997; Stolwijk et al., 2000; Witsenburg et al., 2005). On the other hand, our population is specific in their characteristics as they are all high responders to ovarian stimulation and the calculated success rate is based on only one cycle of ovarian stimulation.

Another meaningful aspect that can be deduced from our results is that roughly 60% of women in our group achieved a delivery of a live infant in the first three consecutive embryo transfers. Afterwards, the cumulative success increases slower, which can be seen by the progressively gradual Kaplan-Meier curve (Figure 1). Although the number of women undergoing more than three transfer attempts is relatively small, the effectiveness of these attempts is questionable. It could be that these couples could decrease their time to pregnancy by starting a new ovarian stimulation cycle instead of continuing with further cryopreserved embryo transfer attempts. It is a fact that embryos assessed to be of the highest quality by conventional morphological criteria were transferred in the first cycles. It would be valuable to study whether there is a potential for additional embryo selection techniques when performing subsequent transfers. One potential possibility could be the use of preimplanta-tion genetic screening techniques at blastocyst stage, as studies have been published supporting this approach as a useful tool of improving success rates (Forman et al., 2013; Yang et al., 2013). Although this approach is unlikely to further improve cumulative success rates in this setting, it may have the potential to reduce the time to pregnancy by avoiding the transfer of genetically unviable embryos (Cedars, 2016).

A total of 26 out of 42 women (65%), however, did not return for treatment, although they still had cryopreserved embryos. After data collection, we inquired about the reasons for discontinuing treatment. Interestingly, five out of 26 women (19.2%, 95% CI 4.1 to 34.3%) achieved a spontaneous pregnancy before returning for embryo transfer, which actually means that 70% (95% CI 61.9 to 78.1%) of all women commencing treatment achieved the desired goal, a birth of a live infant. Most women that decided to discontinue treatment owing to other reasons have done so for personal or medical reasons. Furthermore, two women who decided to take a longer break before returning for embryo transfer and, therefore, we could not include them in the analysis.

Elective cryopreservation of all embryos and segmentation of IVF is becoming an increasingly important aspect of assisted reproduction. Although this approach was first used as a result of the observed dramatic decrement in the risk for developing OHSS, there are other benefits, but also some drawbacks to this approach. First, no cases of severe OHSS were recorded in our population of patients, but other reports have shown that the replacement of HCG by GnRH agonist does not completely eradicate the chance of developing OHSS, and some cases of its occurrence have been reported. It can occur even when no luteal support is administered and embryo transfer is deferred (Fatemi et al., 2014; Gurbuz et al., 2014). Furthermore, if embryo transfer is deferred, the drawback of this approach is also lower patient satisfaction, as most patients would like to achieve a pregnancy as soon as possible, preferably in the first fresh cycle.

The essential prerequisite to achieve good results after elective cryopreservation of embryos is the high laboratory quality and a good vitrification programme. This has allowed for higher post-warming embryo survival rate compared with the slow freezing method (Abdel Hafez et al., 2010). It is likely that laboratory developments in the past decade have enabled wider acceptance of the freeze-all strategy. Prolonged culture of embryos to day 5 or 6 and vitrification of all developed blastocysts is an optimal option in this approach. The risk for total blastocyst development failure in prolonged embryo culture is reduced to minimum in this group of patients because they usually have high number of available embryos. We did not record any cases that would result in total developmental arrest of all embryos and complete failure of the cycle. Pregnancy can be achieved earlier with blastocyst than with early stage embryo transfer. This can be a compensation for the time lost owing to postponed embryo transfer. Transfers of warmed blastocysts were usually performed 3 months after the ovarian hyperstimulation, but this time could also be shortened as similar results have been reported when cryopreserved embryos were transferred in the first next menstrual cycle (Blockeel et al., 2016). In our experience, between 99.2 and 100% of all vitrified blastocysts have survived the warming process. The results of the first meta-analysis comparing fresh and frozen embryo transfer cycles suggested significantly higher implantation and clinical pregnancy rates in frozen embryo transfer cycles compared with fresh embryo transfer (Roque et al., 2013). This can be explained by means of improved embryo-endometrium synchrony; however, the findings are based on a small number of studies, and high-quality randomized controlled trials to confirm these findings are needed. This meta-analysis included heterogeneous studies and, in two of the included studies, the embryos were cryopreserved in the pronuclear stage (Aflatoonian et al., 2010; Shapiro et al., 2011). The ongoing pregnancy rates per transfer in these studies ranged from 39.0% to 63.3% in high-responding patients (Aflatoonian et al., 2010; Shapiro et al., 2011). Our calculated cumulative live birth rate is relatively high compared with these reports; additionally, we observed comparably lower incidence of multiple births. In our clinical practice, we generally advised patients to decide for single blastocyst transfer and more than two blastocysts were never transferred. Although the rates of twin pregnancies in the before-mentioned studies ranged from 21.6-59.0%, we have recorded 23.5% (95% CI, 14.3 to 32.7%) of twin births.

As cryopreservation is becoming a growingly important aspect of medically assisted reproduction, it is vital to counsel the patients about the expected outcome. As elective cryopreservation of embryos is applied more broadly in the context of assisted reproduction, however,

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our results may not be generalized to women with other indications. This includes women with abnormal late follicular progesterone levels, oocyte donation programme patients and others. The high-responding patients are specific in their characteristics as they are likely to produce more embryos for cryopreservation and can expect higher cumulative live-birth rates. For a broader application of elective vitrification of all embryos, we need sufficiently powered studies in women with different subfertility indications, and we also need a consensus on the optimal vitrification-warming system. Nonetheless, the results of our study are encouraging, and we can conclude that high-responding patients can be reassured that a high proportion will achieve a live birth after only one cycle of ovarian stimulation. Further studies are needed to support these findings in patients with other indications.

ARTICLE INFO

Article history:

Received 26 October 2016

Received in revised form 21 March 2017

Accepted 22 March 2017

Declaration: The authors report no

financial or commercial conflicts of

interest.

Keywords:

Elective embryo cryopreservation Freeze-all

Ovarian hyperstimulation syndrome Vitrified-warmed blastocyst transfer

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