S. Mackens

Impact of late-follicular phase elevated serum progesterone on cumulative live birth rates: is there a deleterious effect on embryo quality?

STUDY QUESTION Is elevated late-follicular phase progesterone (EP) associated with a deleterious impact on embryo quality (EQ) and cumulative live birth rates (LBRs)? SUMMARY ANSWER EP was associated with a decrease in embryo utilization and cumulative LBRs. WHAT IS KNOWN ALREADY Ovarian stimulation promotes the production of progesterone (P) which adversely affects IVF pregnancy outcomes. However, evidence regarding a potential association between EP an EQ is lacking. STUDY DESIGN, SIZE, DURATION A retrospective analysis of all GnRH antagonist down-regulated ICSI cycles followed by a fresh embryo transfer (ET) between 2010 and 2015 was performed. The sample was stratified according to the following P levels on the day of ovulation triggering: ≤0.50, 0.51-1.49 and ≥1.50 ng/ml. The primary outcomes were embryo utilization rates (number of embryos transferred or cryopreserved) and cumulative LBR, defined as the occurrence of the first live-birth after either the fresh or one of the subsequent frozen ET. PARTICIPANTS/MATERIALS, SETTING, METHODS Overall, 3400 cycles were included in the analysis, using multivariable regression to account for potential confounding. MAIN RESULTS AND THE ROLE OF CHANCE Female age and the number of oocytes retrieved increased significantly with increasing serum P values. Utilization rates decreased linearly as P increased for Day 3 embryos (72.3, 63.0 and 45.4%, respectively), while for Day 5 embryos only the EP group was associated with a significant decrease (48.8, 47.8 and 38.8%, respectively). EP was also associated with decreased fresh and cumulative LBRs. LIMITATIONS REASONS FOR CAUTION The main limitations of this study were its retrospective nature and the fact that it was restricted to GnRH antagonist cycles. WIDER IMPLICATIONS OF THE FINDINGS These results raise the question whether EP may also be associated with a decrease in cumulative pregnancy outcomes by increasing embryo wastage. Further studies may evaluate the potential benefit of additional measures besides the freeze-all strategy to avoid this issue, such as lowering the stimulation dose or applying a step-down protocol. STUDY FUNDING/COMPETING INTEREST(S) None.

Frozen embryo transfer: a review on the optimal endometrial preparation and timing

STUDY QUESTION What is the optimal endometrial preparation protocol for a frozen embryo transfer (FET)? SUMMARY ANSWER Although the optimal endometrial preparation protocol for FET needs further research and is yet to be determined, we propose a standardized timing strategy based on the current available evidence which could assist in the harmonization and comparability of clinic practice and future trials. WHAT IS KNOWN ALREADY Amid a continuous increase in the number of FET cycles, determining the optimal endometrial preparation protocol has become paramount to maximize ART success. In current daily practice, different FET preparation methods and timing strategies are used. STUDY DESIGN, SIZE, DURATION This is a review of the current literature on FET preparation methods, with special attention to the timing of the embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS Literature on the topic was retrieved in PubMed and references from relevant articles were investigated until June 2017. MAIN RESULTS AND THE ROLE OF CHANCE The number of high quality randomized controlled trials (RCTs) is scarce and, hence, the evidence for the best protocol for FET is poor. Future research should compare both the pregnancy and neonatal outcomes between HRT and true natural cycle (NC) FET. In terms of embryo transfer timing, we propose to start progesterone intake on the theoretical day of oocyte retrieval in HRT and to perform blastocyst transfer at hCG + 7 or LH + 6 in modified or true NC, respectively. LIMITATIONS REASONS FOR CAUTION As only a few high quality RCTs on the optimal preparation for FET are available in the existing literature, no definitive conclusion for benefit of one protocol over the other can be drawn so far. WIDER IMPLICATIONS OF THE FINDINGS Caution when using HRT for FET is warranted since the rate of early pregnancy loss is alarmingly high in some reports. STUDY FUNDING/COMPETING INTEREST(S) S.M. is funded by the Research Fund of Flanders (FWO). H.T. and C.B. report grants from Merck, Goodlife, Besins and Abbott during the conduct of the study. TRIAL REGISTRATION NUMBER Not applicable.

Vitrified-warmed blastocyst transfer on the 5th or 7th day of progesterone supplementation in an artificial cycle: a randomised controlled trial

Abstract Prospective studies comparing different durations of progesterone supplementation before transfer of vitrified-warmed blastocysts in an artificial cycle are lacking. However, in oocyte donation programmes, the sporadic available evidence demonstrates considerable differences in clinical pregnancy rates according to the duration of progesterone administration. This randomised controlled trial (RCT), included 303 patients undergoing a frozen-thawed embryo transfer (FET) of one or two vitrified-warmed blastocyst(s) in an artificial cycle. Randomisation was performed when the endometrial thickness reached ≥7 mm after oestrogen supplementation. One hundred and fifty two patients in group A received 7 d of vaginal micronised progesterone tablets and 151 patients in group B received 5 d of micronised vaginal progesterone before FET. No differences were seen in clinical pregnancy rate between both groups: 42/152 (27.6%) in group A versus 49/151 (32.5%) in group B. Although no statistically significant difference was observed in clinical pregnancy rates, our study was powered to detect an absolute difference of 16%. In this regard, we cannot exclude that smaller, clinically relevant differences might exist and our study did not have the power to detect this. Patients were also not blinded for the intervention, causing a potential bias.

Optimal Preparation Prior to the Use of Cryopreserved Oocytes

The early 1980s saw the first cases of live births after the transfer of autologous frozen embryos be reported [1, 2]. These preliminary reports were met with reasonable resistance by the scientific community owing to the limited efficacy of earlier cryopreservation methods and concerns regarding the overall safety of embryo cryopreservation. This uncertainty effectively relayed embryo cryopreservation at its genesis to the status of an “adjuvant method” for cycles in which the number of embryos produced was deemed too excessive for simultaneous replacement during the fresh embryo transfer (ET) attempt. However, following the advent of more efficient cryopreservation strategies [3] (i.e. vitrification) and reassuring safety data [4, 5], the use of embryo cryopreservation has progressively increased, currently accounting for up to one third of all children born after assisted reproductive technologies (ART) in the United States [6]. Furthermore, cryopreservation has now become an indispensable tool in everyday clinical practice, providing the necessary means to assure the safe storage of embryos while minimizing the many risks associated to the multiple pregnancies [7]. For this reason, an increasing amount of scientific societies and governments have encouraged [8] or even enforced [9, 10] elective single ET policies to ART clinics, progressively changing the benchmark of ART from pregnancy rates to Birth Emphasizing a Successful Singleton at Term (BESST) [11]. These considerations have set the stage for a new stance on embryo cryopreservation in modern-day medicine, which is no longer viewed as a simple adjuvant of fresh ET [12], a mindset that has transpired across to oocyte donation and/or embryo cryopreservation programs as well. In parallel, an increasing number of women are currently opting to electively cryopreserve oocytes in anticipation of age-related gamete exhaustion. Since the first live birth following the transfer of a cryopreserved oocyte occurred already in 1986 [13], physicians have the possibility to extrapolate from the abundance of data already existent from both fresh/frozen oocyte donation and embryo cryopreservation programs in order to determine the best ET strategy for women thawing electively cryopreserved oocytes. In this chapter, we give a detailed explanation on how the preparation of the uterus for the transfer of embryos deriving from cryopreserved oocytes is generally performed, followed by a brief overview of which methods one may consider to optimize the safety and pregnancy/neonatal outcomes of these treatment cycles.

Endometrial receptivity enhancement through induced injury and repair during ovarian stimulation: the Receptivity Enhancement by Follicular-phase Renewal after Endometrial ScratcHing (REFRESH) trial protocol

Abstract STUDY QUESTION Does intentional endometrial injury (i.e. endometrial scratching) during ART enhance pregnancy rates? SUMMARY ANSWER We propose a randomized controlled clinical trial in women performing ART in which the intervention group will undergo an additional endometrial biopsy during exogenous ovarian stimulation. WHAT IS KNOWN ALREADY Although endometrial receptivity has been extensively studied, the mechanisms behind the implantation of an embryo remain largely a mystery. Intentional endometrial injury has been put forward by many researchers as an inexpensive clinical tool capable of enhancing endometrial receptivity. However, despite its widespread use, the benefit of endometrial scratching is still a contentious and unresolved issue. STUDY DESIGN, SIZE, DURATION Pragmatic two-arm randomized, single-centre, controlled open-label trial in women undergoing exogenous gonadotropin ovarian stimulation for ART followed by a fresh embryo transfer in a gonadotropin-releasing hormone antagonist suppressed cycle. The trial will include 360 women in total with a 1:1 allocation ratio and an expected total duration of up to 45 months. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects in the intervention group will undergo an endometrial biopsy during the follicular phase, on the sixth to eighth day of exogenous stimulation. Furthermore, nested within this clinical trial, we will also evaluate whether the transcriptomic signatures of the material collected during the biopsy may accurately distinguish women who become pregnant from those who do not. These endometrial transcriptomic signatures will be assessed both immediately after the biopsy and following in-vitro decidualization. MAIN RESULTS AND THE ROLE OF CHANCE Our primary objective is to assess the effect of endometrial injury during exogenous gonadotropin ovarian stimulation on clinical pregnancy rates after ART. Secondary efficacy and safety outcomes include: live-birth delivery after 24 weeks, the endometrial transcriptomic profile among women in the intervention group, short-term safety (e.g. procedure intolerance due to pain, post-procedure bleeding) and long-term safety (e.g. cancelled transfers, miscarriage) outcomes. LIMITATIONS, REASONS FOR CAUTION Owing to its pragmatic design, this study may have limited power to determine one or more of our secondary outcomes and whether there are specific subgroups of women who may benefit significantly from performing endometrial scratching and endometrial transcriptomic profiling. WIDER IMPLICATIONS OF THE FINDINGS Despite the weak biological plausibility, heterogeneity in the existing randomized controlled trials and lack of evaluation of any potential risks associated with endometrial scratching, this procedure is still widely applied in current clinical practice. This clinical trial aims to pragmatically assess the potential benefits and harms of the generalized use of this strategy. STUDY FUNDING/COMPETING INTEREST(S) this study has received a grant from the Research Foundation—Flanders (FWO, 1524417N). This organization has no further role in the study, namely with regards to protocol development, study conduction and evaluation of results. TRIAL REGISTRATION NUMBER NCT02061228. TRIAL REGISTRATION DATE 10 February 2014. DATE OF FIRST PATIENT’S ENROLMENT 3 April 2014. PROTOCOL VERSION 2.0.