Single embryo transfer by Day 3 time-lapse selection versus Day 5 conventional morphological selection: a randomized, open-label, non-inferiority trial.

Yang L ，Cai S ，Zhang S ，Kong X ，Gu Y ，Lu C ，Dai J ，Gong F ，Lu G ，Lin G ... -  《-》

A pilot randomized controlled trial of Day 3 single embryo transfer with adjunctive time-lapse selection versus Day 5 single embryo transfer with or without adjunctive time-lapse selection.

Compared to D5 selection with conventional morphology (CM), does adjunctive use of the Eeva™ test on D3 or D5 improve the clinical pregnancy rate (CPR) per transfer? The evidence is insufficient to conclude that adjunctive use of the Eeva™ test on D3 or D5 improves CPR per transfer as compared to D5 selection with CM. Time-lapse imaging is increasingly used for embryo selection, despite there being no class I data to support its clinical application. Pilot randomized controlled trial included 163 patients from August 2014 to February 2016. Patients up to age 41 years with a planned fresh autologous single embryo transfer (SET), less than four prior oocyte retrievals, and four or more zygotes were blocked according to age (<35, 35-37, 38-40 years) and randomized to one of three study arms: (1) D3 SET + EevaTM, (2) D5 SET + Eeva™ or (3) D5 SET with CM alone. All embryos were cultured in the same time-lapse system under identical conditions. Intention-to-treat (ITT) and as-treated analyses of the primary endpoint (CPR at 7 weeks) and secondary endpoint (ongoing pregnancy rate at 12 weeks) were performed. Multivariate regression analyses adjusted for patient age and ICSI. Of 478 eligible patients, 217 consented and 163 were randomized. Demographic characteristics were similar among the three study arms. There were no statistically significant differences in the clinical pregnancy rate or the ongoing pregnancy rate between the study arms for either the ITT or as-treated analyses (CPR ITT: D3 + Eeva™: 41.1% vs. D5 + Eeva™: 38.9% vs. D5 CM: 49.1%). This study was designed as a pilot randomized controlled trial and was not powered to detect a statistically significant difference at α < 0.05. Importantly, the study was terminated prematurely by the sponsor due to a change in funding priorities, so the sample size is limited and the results should be interpreted with caution due to the role of chance. Furthermore, these findings may not be generalizable to other time-lapse systems. Our findings do not support the clinical application of these time-lapse markers. This study was funded by Progyny, Inc. There are no competing interests. clinicaltrials.gov: NCT02218255. 14 August 2014. 3 September 2014.

Kaser DJ ，Bormann CL ，Missmer SA ，Farland LV ，Ginsburg ES ，Racowsky C ... -  《-》

A double-blind randomized controlled trial investigating a time-lapse algorithm for selecting Day 5 blastocysts for transfer.

Can use of a commercially available time-lapse algorithm for Day 5 blastocyst selection improve pregnancy rates compared with morphology alone? The use of a time-lapse selection model to choose blastocysts for fresh single embryo transfer on Day 5 did not improve ongoing pregnancy rate compared to morphology alone. Evidence from time-lapse monitoring suggests correlations between timing of key developmental events and embryo viability. No good quality evidence exists to support improved pregnancy rates following time-lapse selection. A prospective multicenter randomized controlled trial including 776 randomized patients was performed between 2018 and 2021. Patients with at least two good quality blastocysts on Day 5 were allocated by a computer randomization program in a proportion of 1:1 into either the control group, whereby single blastocysts were selected for transfer by morphology alone, or the intervention group whereby final selection was decided by a commercially available time-lapse model. The embryologists at the time of blastocyst morphological scoring were blinded to which study group the patients would be randomized, and the physician and patients were blind to which group they were allocated until after the primary outcome was known. The primary outcome was number of ongoing pregnancies in the two groups. From 10 Nordic IVF clinics, 776 patients with a minimum of two good quality blastocysts on Day 5 (D5) were randomized into one of the two study groups. A commercial time-lapse model decided the final selection of blastocysts for 387 patients in the intervention (time-lapse) group, and blastocysts with the highest morphological score were transferred for 389 patients in the control group. Only single embryo transfers in fresh cycles were performed. In the full analysis set, the ongoing pregnancy rate for the time-lapse group was 47.4% (175/369) and 48.1% (181/376) in the control group. No statistically significant difference was found between the two groups: mean difference -0.7% (95% CI -8.2, 6.7, P = 0.90). Pregnancy rate (60.2% versus 59.0%, mean difference 1.1%, 95% CI -6.2, 8.4, P = 0.81) and early pregnancy loss (21.2% versus 18.5%, mean difference 2.7%, 95% CI -5.2, 10.6, P = 0.55) were the same for the time-lapse and the control group. Subgroup analyses showed that patient and treatment characteristics did not significantly affect the commercial time-lapse model D5 performance. In the time-lapse group, the choice of best blastocyst changed on 42% of occasions (154/369, 95% CI 36.9, 47.2) after the algorithm was applied, and this rate was similar for most treatment clinics. During 2020, the patient recruitment rate slowed down at participating clinics owing to coronavirus disease-19 restrictions, so the target sample size was not achieved as planned and it was decided to stop the trial prematurely. The study only investigated embryo selection at the blastocyst stage on D5 in fresh IVF transfer cycles. In addition, only blastocysts of good morphological quality were considered for transfer, limiting the number of embryos for selection in both groups: also, it could be argued that this manual preselection of blastocysts limits the theoretical selection power of time-lapse, as well as restricting the results mainly to a good prognosis patient group. Most patients were aimed for blastocyst stage transfer when a minimum of five zygotes were available for extended culture. Finally, the primary clinical outcome evaluated was pregnancy to only 6-8 weeks. The study suggests that time-lapse selection with a commercially available time-lapse model does not increase chance of ongoing pregnancy after single blastocyst transfer on Day 5 compared to morphology alone. The study was financed by a grant from the Swedish state under the ALF-agreement between the Swedish government and the county councils (ALFGBG-723141). Vitrolife supported the study with embryo culture dishes and culture media. During the study period, T.H. changed his employment from Livio AB to Vitrolife AB. All other authors have no conflicts of interests to disclose. ClinicalTrials.gov registration number NCT03445923. 26 February 2018. 11 June 2018.

Ahlström A ，Lundin K ，Lind AK ，Gunnarsson K ，Westlander G ，Park H ，Thurin-Kjellberg A ，Thorsteinsdottir SA ，Einarsson S ，Åström M ，Löfdahl K ，Menezes J ，Callender S ，Nyberg C ，Winerdal J ，Stenfelt C ，Jonassen BR ，Oldereid N ，Nolte L ，Sundler M ，Hardarson T ... -  《-》

Clinical pregnancy rates after blastocyst culture at a stable temperature of 36.6°C versus 37.1°C: a prospective randomized controlled trial.

Is there a difference in clinical pregnancy rates (CPRs) in good prognosis patients after single embryo transfer (SET) on Day 5, in case of stable culture at 36.6°C or 37.1°C? CPR (with heartbeat at 7 weeks) after blastocyst transfer do not differ after culturing at 36.6°C or 37.1°C. Since the beginning of IVF, embryo culture has been performed at 37.0°C; however, the optimal culture temperature remains unknown. Changes in incubator types have led to significant improvements in temperature control. Stable temperature control, i.e. with temperature differences of max. 0.1°C between chambers, is possible in some incubators. A previous prospective pilot study showed that embryo development on Day 5/6 was not affected when embryos were cultured at a stable temperature of 36.6°C or 37.1°C, but culture at 37.1°C resulted in an increased CPR when compared to culture at 36.6°C (74.2% vs 46.4%). A prospective randomized controlled trial was performed in a tertiary fertility centre between February 2017 and November 26, 2022. A sample size of 89/89 patients with fresh single embryo transfer (SET) was required to achieve 80% power to detect a difference of 0.22 between group proportions (0.43-0.65) at a significance level of 0.05 using a two-sided z-test with continuity correction. Patients were recruited on the day of oocyte retrieval based on inclusion criteria with final randomization after denudation once six mature oocytes were present. The primary endpoint was CPR (heartbeat at 7 weeks); secondary endpoints were fertilization rate, blastocyst development, biochemical pregnancy rate, live birth rate (LBR), and cumulative live birth rate (CLBR). A total of 304 patients were eligible for the study; of these 268 signed the consent, 234 (intention-to-treat) were randomized and 181 (per-protocol) received a SET on Day 5: 90 received culture at 36.6°C and 91 at 37.1°C. Patients were on average 32.4 ± 3.5 versus 32.5 ± 4.2 years old, respectively. No differences were observed in embryological outcomes per cycle between culture at 36.6°C versus 37.1°C: 12.0 ± 3.8 vs 12.1 ± 3.8 COCs retrieved (P = 0.88), 10.0 ± 3.1 versus 9.9 ± 2.9 mature oocytes inseminated (P = 0.68), with a maturation rate of 84.2% (901/1083) versus 83.5% (898/1104) (P = 0.87); and 8.0 ± 3.1 versus 7.9 ± 2.7 normally fertilized oocytes with a fertilization rate of 79.7% (720/901) vs 80.5% (718/898) (P = 0.96), respectively. On average 1.5 ± 1.7 versus 1.4 ± 1.9 (P = 0.25) and 1.1 ± 1.1 versus 0.9 ± 1.0 (P = 0.45) supernumerary blastocysts were vitrified on Day 5 and Day 6, respectively. The utilization rate per fertilized oocyte was 46.1% vs 41.5% (P = 0.14). A SET was performed for 181 patients, leading to a biochemical pregnancy rate of 72.2% (65/90) versus 62.7% (57/91) (P = 0.17), respectively. The CPR per fresh transfer cycle was 51.1% (46/90) versus 48.4% (44/91) [OR (95% CI) 1.11 (0.59-2.08), P = 0.710]. To date, a CLBR of 73.3% (66/90) versus 67.0% (61/91) (P = 0.354) has been observed, respectively. In each group, seven patients without live birth have remaining blastocysts frozen. The CPR for the intention-to-treat groups were 38.3% vs 38.6% [OR (95% CI) 0.98 (0.56-1.73), P = 0.967], respectively, for culture at 36.6°C versus 37.1°C. Only selected patients with expected good prognosis were eligible for the study. Embryos tend to tolerate small changes in temperature deviations during culture to the blastocyst stage, as demonstrated by their similar implantation potential at two slightly different temperatures. There is no funding or conflicts of interest to declare. NCT03548532. 23 October 2017. 10 November 2017.

Wouters K ，Mateizel I ，Segers I ，Van de Velde H ，Van Landuyt L ，De Vos A ，Schoemans C ，Jankovic D ，Blockeel C ，Drakopoulos P ，Tournaye H ，De Munck N ... -  《-》

Perinatal outcomes in singleton live births after fresh blastocyst-stage embryo transfer: a retrospective analysis of 67 147 IVF/ICSI cycles.

Are perinatal outcomes different between singleton live births conceived from fresh blastocyst transfer and those following the transfer of fresh cleavage-stage embryos? Fresh blastocyst transfer does not increase risks of preterm birth (PTB), low/high birth weight or congenital anomaly and does not alter the sex ratio at birth or prejudice the chance of having a healthy baby. Extended embryo culture is currently considered the best option for embryo selection, but concerns have been raised about increased risks of preterm delivery and large-for-gestational-age (LGA) babies. We conducted a retrospective cohort study based on data from the Human Fertilisation and Embryology Authority (HFEA) anonymised and cycle-based dataset in the UK between 1999 and 2011. Baseline characteristics were compared between in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) blastocyst-stage and cleavage-stage embryo transfer cycles using the χ2 test for categorical/dichotomised covariates and the Mann-Whitney test for continuous covariates. Statistical significance was set at <0.005. Poisson regression and multinomial logistic regression were used to establish relationships between perinatal outcomes and blastocyst-stage embryo transfer or cleavage-stage embryo transfer. Risk ratios (RRs), adjusted risk ratios (aRRs) and their 99.5% confidence intervals (CIs) were calculated as a measure of strength of associations. Results were adjusted for clinically relevant covariates. A sub-group analysis included women undergoing their first IVF/ICSI treatment. The level of significance was set at <0.05, and 95% CIs were calculated in the sub-group analysis. Of a total of 67 147 IVF/ICSI cycles, 11 152 involved blastocyst-stage embryo(s) and 55 995 involved cleavage-stage embryo(s). The two groups were comparable with regards to the risk of PTB (aRR, 1.00; 99.5% CI, 0.79-1.25), very-preterm birth (VPTB) (aRR, 1.00; 99.5% CI, 0.63-1.54), very-low birth weight (VLBW) (aRR, 0.84; 99.5% CI, 0.53-1.34), low birth weight (LBW) (aRR, 0.92; 99.5% CI, 0.73-1.16), high birth weight (HBW) (aRR, 0.94; 99.5% CI, 0.75-1.18) and very-high birth weight (VHBW) (aRR, 1.05; 99.5% CI, 0.66-1.65). The risk of congenital anomaly was 16% higher in the blastocyst-stage group than in the cleavage-stage group, but this was not statistically significant (aRR, 1.16; 99.5% CI, 0.90-1.49). The chance of having a healthy baby (born at term, with a normal birth weight and no congenital anomalies) was not altered by extended culture (aRR, 1.00; 99.5% CI, 0.93-1.07). Extended culture was associated with a marginal increase in the chance having a male baby in the main cycle-based analysis (aRR, 1.04; 99.5% CI, 1.01-1.09) but not in the sub-group analysis of women undergoing their first cycle of treatment (aRR, 1.04; 95% CI, 1.00-1.08). In the sub-group analysis, the risk of congenital anomalies was significantly higher after blastocyst-stage embryo transfer (aRR, 1.42; 95% CI, 1.12-1.81). This study is limited by the use of observational data and inability to adjust for key confounders, such as maternal smoking status and body mass index (BMI), which were not recorded in the HFEA dataset. As the main analysis was cycle-based and we were unable to link cycles within women undergoing more than one IVF/ICSI cycle, we undertook a sub-group analysis on women undergoing their first treatment cycle. Our findings should reassure women undergoing blastocyst-stage embryo transfer. For the first time, we have shown that babies born after blastocyst transfer have a similar chance of being healthy as those born after cleavage-stage embryos transfer. The research activity of Dr Nicola Marconi was funded by the scholarship 'A. Griffini-J. Miglierina', Fondazione Comunitaria del Varesotto, Provincia di Varese, Italy. The authors do not have any competing interests to disclose. N/A.

Marconi N ，Raja EA ，Bhattacharya S ，Maheshwari A ... -  《-》