Background Elective freezing of all good quality embryos and transfer in subsequent cycles, i.e. elective frozen embryo transfer (eFET), has recently increased significantly with the introduction of the GnRH agonist trigger protocol and improvements in cryo-techniques. The ongoing discussion focuses on whether eFET should be offered to the overall IVF population or only to specific subsets of patients. Until recently, the clinical usage of eFET was supported by only a few randomized controlled trials (RCT) and meta-analyses, suggesting that the eFET not only reduced ovarian hyperstimulation syndrome (OHSS), but also improved reproductive outcomes. However, the evidence is not unequivocal, and recent RCTs challenge the use of eFET for the general IVF population. Objective and rationale This systematic review and meta-analysis aimed at evaluating whether eFET is advantageous for reproductive, obstetric and perinatal outcomes compared with fresh embryo transfer in IVF/ICSI cycles. Additionally, we evaluated the effectiveness of eFET in comparison to fresh embryo transfer in different subgroups of patients undergoing IVF/ICSI cycles. Search methods We conducted a systematic review, using PubMed/Medline and EMBASE to identify all relevant RCTs published until March 2018. The participants included infertile couples undergoing IVF/ICSI with or without preimplantation genetic testing for aneuploidy (PGT-A). The primary outcome was the live birth rate (LBR), whereas secondary outcomes were cumulative LBR, implantation rate, miscarriage, OHSS, ectopic pregnancy, preterm birth, pregnancy-induced hypertension, pre-eclampsia, mean birthweight and congenital anomalies. Subgroup analyses included normal and hyper-responder patients, embryo developmental stage on the day of embryo transfer, freezing method and the route of progesterone administration for luteal phase support in eFET cycles. Outcomes Eleven studies, including 5379 patients, fulfilling the inclusion criteria were subjected to qualitative and quantitative analysis. A significant increase in LBR was noted with eFET compared with fresh embryo transfer in the overall IVF/ICSI population [risk ratio (RR) = 1.12; 95% CI: 1.01-1.24]. Subgroup analyses indicated higher LBRs by eFET than by fresh embryo transfer in hyper-responders (RR = 1.16; 95% CI: 1.05-1.28) and in PGT-A cycles (RR = 1.55; 95% CI: 1.14-2.10). However, no differences were observed for LBR in normo-responders (RR = 1.03; 95% CI: 0.91-1.17); moreover, the cumulative LBR was not significantly different in the overall population (RR = 1.04; 95% CI: 0.97-1.11). Regarding safety, the risk of moderate/severe OHSS was significantly lower with eFET than with fresh embryo transfer (RR = 0.42; 95% CI: 0.19-0.96). In contrast, the risk of pre-eclampsia increased with eFET (RR = 1.79; 95% CI: 1.03-3.09). No statistical differences were noted in the remaining secondary outcomes. Wider implications Although the use of eFET has steadily increased in recent years, a significant increase in LBR with eFET was solely noted in hyper-responders and in patients undergoing PGT-A. Concerning safety, eFET significantly decreases the risk of moderate and severe OHSS, albeit at the expense of an increased risk of pre-eclampsia.

/pdf/fresh-versus-elective-frozen-embryo-transfer-in-ivf-icsi-2jhyh75bje.pdf

Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes.

Purpose
This publication will evaluate the available evidence in the literature comparing fresh embryo transfer (ET) and elective frozen-thawed embryo transfer (FET) regarding the possible interference of controlled ovarian stimulation (COS) in implantation and endometrial receptivity, IVF safety, and obstetric and perinatal outcomes.

/pdf/freeze-all-policy-is-it-time-for-that-ygumtnwyts.pdf

Freeze-all policy: is it time for that?

STUDY QUESTION Is it possible to determine the receptivity status of an endometrium by combined quantitative reverse transcription PCR (RT-qPCR) expression analysis of genes involved in endometrial proliferation and immunity? SUMMARY ANSWER The new ER Map®/ER Grade® test can predict endometrial receptivity status by RT-qPCR using a new panel of genes involved in endometrial proliferation and the maternal immune response associated to embryonic implantation. WHAT IS KNOWN ALREADY The human endometrium reaches a receptive status adequate for embryonic implantation around Days 19-21 of the menstrual cycle. During this period, known as the window of implantation (WOI), the endometrium shows a specific gene expression profile suitable for endometrial function evaluation. The number of molecular diagnostic tools currently available to characterize this process is very limited. In this study, a new system for human endometrial receptivity evaluation was optimized and presented for the first time. STUDY DESIGN, SIZE, DURATION ER Map®/ER Grade® validation was achieved on 312 endometrial samples including fertile women and patients undergoing fertility treatment between July 2014 and March 2016. Expression analyses of 184 genes involved in endometrial receptivity and immune response were performed. Samples were additionally tested with an independent endometrial receptivity test. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 96 fertile women and 120 assisted reproduction treatment (ART) patients participated in the study. Endometrial biopsy samples were obtained at LH + 2 and LH + 7 days in fertile subjects in a natural cycle and at the window of implantation (WOI) in patients in a hormone-replacement therapy (HRT) cycle. Total RNA was purified, quality-checked and reverse-transcribed. Gene expression was quantified by high-throughput RT-qPCR and statistically analyzed. Informative genes were selected and used to classify samples into four different groups of endometrial receptivity status. MAIN RESULTS AND THE ROLE OF CHANCE Significantly different gene expression levels were found in 85 out of 184 selected genes when comparing LH + 2 and LH + 7 samples (paired t-test, P < 0.05). Gene ontology analyses revealed that cell division and proliferation, cell signaling and response, extracellular organization and communication, immunological activity, vascular proliferation, blood pressure regulation and embryo implantation are the most over-represented biological terms in this group of genes. Principal component analysis and discriminant functional analysis showed that 40 of the differentially expressed genes allowed accurate classification of samples according to endometrial status (proliferative, pre-receptive, receptive and post-receptive) in both fertile and infertile groups. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION To evaluate the efficacy of this new tool to improve ART outcomes, further investigations such as non-selection studies and randomized controlled trials will also be required. WIDER IMPLICATIONS OF THE FINDINGS A new comprehensive system for human endometrial receptivity evaluation based on gene expression analysis has been developed. The identification of the optimal time for embryo transfer is essential to maximize the effectiveness of ART. This study is a new step in the field of personalized medicine in human reproduction which may help in the management of endometrial preparation for embryo transfer, increasing the chances of pregnancy for many couples. STUDY FUNDING/COMPETING INTEREST(S) The authors have no potential conflict of interest to declare. No external funding was obtained for this study.

/pdf/development-of-a-new-comprehensive-and-reliable-endometrial-4h8ef0ez08.pdf

Development of a new comprehensive and reliable endometrial receptivity map (ER Map/ER Grade) based on RT-qPCR gene expression analysis.

Background 
Controlled ovarian stimulation in assisted reproduction technology (ART) may alters endometrial receptivity by an advancement of endometrial development. Recently, technical improvements in vitrification make deferred frozen-thawed embryo transfer (Def-ET) a feasible alternative to fresh embryo transfer (ET). In endometriosis-related infertility the eutopic endometrium is abnormal and its functional alterations are seen as likely to alter the quality of endometrial receptivity. One question in the endometriosis ART-management is to know whether Def-ET could restore optimal receptivity in endometriosis-affected women leading to increase in pregnancy rates.


Objective 
To compare cumulative ART-outcomes between fresh versus Def-ET in endometriosis-infertile women.


Materials and methods 
This matched cohort study compared def-ET strategy to fresh ET strategy between 01/10/2012 and 31/12/2014. One hundred and thirty-five endometriosis-affected women with a scheduled def-ET cycle and 424 endometriosis-affected women with a scheduled fresh ET cycle were eligible for matching. Matching criteria were: age, number of prior ART cycles, and endometriosis phenotype. Statistical analyses were conducted using univariable and multivariable logistic regression models.


Results 
135 in the fresh ET group and 135 in the def-ET group were included in the analysis. The cumulative clinical pregnancy rate was significantly increased in the def-ET group compared to the fresh ET group [58 (43%) vs. 40 (29.6%), p = 0.047]. The cumulative ongoing pregnancy rate was 34.8% (n = 47) and 17.8% (n = 24) respectively in the Def-ET and the fresh-ET groups (p = 0.005). After multivariable conditional logistic regression analysis, Def-ET was associated with a significant increase in the cumulative ongoing pregnancy rate as compared to fresh ET (OR = 1.76, CI95% 1.06–2.92, p = 0.028).


Conclusion 
Def-ET in endometriosis-affected women was associated with significantly higher cumulative ongoing pregnancy rates. Our preliminary results suggest that Def-ET for endometriosis-affected women is an attractive option that could increase their ART success rates. Future studies, with a randomized design, should be conducted to further confirm those results.

/pdf/the-deferred-embryo-transfer-strategy-improves-cumulative-2xfugd10an.pdf

The deferred embryo transfer strategy improves cumulative pregnancy rates in endometriosis-related infertility: A retrospective matched cohort study.

STUDY QUESTION How do live birth rates (LBRs), following fresh and vitrified/warmed embryo transfer, compare according to morphological grade, developmental stage and culturing strategy of human blastocysts in vitro? SUMMARY ANSWER Equivalent LBRs were obtained after fresh embryo transfer and after vitrified/warmed embryo transfer of blastocysts of top or non-top quality, while vitrification after prolonged embryo culture of blastocysts with delayed development had a positive impact on LBR. WHAT IS KNOWN ALREADY Blastocyst morphology correlates with clinical outcome; however, few data are available on vitrified/warmed embryo transfer using non-top quality blastocysts. The aim of this study was to determine clinical outcomes of non-top quality blastocysts and blastocysts with delayed development that underwent vitrified/warmed embryo transfer. STUDY DESIGN, SIZE, DURATION This retrospective, single-centre study (conducted January 2009 to June 2013) compared 1010 fresh embryo transfer and 1270 vitrified/warmed embryo transfer of blastocysts originating from the same stimulation cycle. Furthermore, 636 fresh embryo transfers and 304 vitrified/warmed embryo transfer after delayed expansion or blastulation in the same period were also analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS Clinical outcomes after fresh and vitrified/warmed embryo transfer according to blastocyst morphology were compared in both groups. MAIN RESULTS AND THE ROLE OF CHANCE Similar LBRs after fresh embryo transfer or after vitrified/warmed embryo transfer of top or non-top quality blastocysts were observed. A statistically significant improvement in clinical outcomes was obtained after vitrified/warmed embryo transfer of Day 5 embryos with delayed expansion or blastulation when applying prolonged culture. Our study suggests that vitrification of non-top quality blastocysts as well as delayed cavitating and blastulating Day 5 embryos should be considered in autologous IVF cycles. LIMITATIONS AND REASONS FOR CAUTION Given that the present retrospective study used aseptic vitrification of blastocysts, the results, particularly the survival rates, may not be fully applicable to other vitrification protocols. The retrospective nature of the study has to be mentioned. WIDER IMPLICATIONS OF THE FINDINGS Restriction of vitrification to top quality blastocysts may result in discarding potentially viable embryos. STUDY FUNDING AND COMPETING INTERESTS This study was not externally funded. There are no conflicts of interest to declare.

Pregnancy and birth outcomes following fresh or vitrified embryo transfer according to blastocyst morphology and expansion stage, and culturing strategy for delayed development

Implantation failure has various causes, including impaired uterine receptivity following ovarian stimulation. This retrospective cohort study compared outcomes in patients with prior implantation failure who elected to undergo another fresh cycle versus those who opted for embryo cohort cryopreservation (freeze-all) and subsequent thaw. There were 269 patients with implantation failure following fresh autologous blastocyst transfer opting to undergo a subsequent cycle, with 163 choosing another fresh cycle and 106 electing freeze-all and subsequent thaw. Multiple logistic regression analysis indicated that cohort cryopreservation was associated with greater chance of live birth when compared with another fresh cycle (P < 0.0001). The odds ratio for live birth with freeze-all relative to a fresh cycle was 3.8 (95% CI 2.1-7.2). A second analysis was then performed using cumulative live birth rate as the outcome measure. Multiple logistic regression indicated freeze-all was associated with greater cumulative live birth rate than was a fresh cycle (OR 1.9, 95% CI 1.1-3.3, P = 0.0287). These findings suggest that, following implantation failure with fresh blastocysts, patients have a significantly greater chance of live birth with freeze-all and subsequent thaw than with another fresh cycle.

Freeze-all can be a superior therapy to another fresh cycle in patients with prior fresh blastocyst implantation failure

To determine if the change in endometrial thickness following exogenous progesterone (P) initiation correlates with outcome following autologous transfer of a single thawed blastocyst. The study is a retrospective observational cohort study conducted at a private fertility center. Patients scheduled for thawed blastocyst transfer received artificial endometrial preparation (artificial cycle FET) and underwent serial ultrasonography. The main outcomes were the rate of ongoing pregnancy (fetal heart motion at 12 weeks of gestation) and early pregnancy loss. Logistic regression was used to test for correlations between these outcomes and the change in endometrial thickness while adjusting for potential confounders (patient age, embryo quality, and the use of genetic testing). There were 232 qualifying autologous single-blastocyst transfers in the 20-month study period ending 31 December 2019. Mean endometrial thicknesses were 3.8 mm, 10.0 mm, and 11.2 mm at baseline, P initiation, and at transfer, respectively. The change in endometrial thickness after exogenous P exposure ranged from − 5 to + 9 mm and negatively correlated with ongoing pregnancy in logistic regression analyses. Specifically, ongoing pregnancy rates per transfer were 63.2% in 19 cases where endometria compacted by 10% or more, 64.2% in 95 cases where there was unchanged endometrial thickness, and 52.5% in 118 cases where endometria expanded. The change in endometrial thickness after P initiation was associated with the probability of ongoing pregnancy but not with early pregnancy loss. Ongoing pregnancy rates were greater in endometria with negative growth (compaction) when compared to endometria that grew (expanded) after P exposure.

The change in endometrial thickness following progesterone exposure correlates with in vitro fertilization outcome after transfer of vitrified-warmed blastocysts.

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Freeze-all can be a superior therapy to another fresh cycle in patients with prior fresh blastocyst implantation failure

The change in endometrial thickness following progesterone exposure correlates with in vitro fertilization outcome after transfer of vitrified-warmed blastocysts.