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The effectiveness of PIEZO-ICSI (P-ICSI) compared to conventional ICSI (C-ICSI) is still controversial. The only confirmed effectiveness of P-ICSI compared to C-ICSI is that it can reduce the number of degenerated oocytes after ICSI. This study included 100 patients undergoing their first IVF cycle. The patients were randomly assigned to C-ICSI group and P-ICSI group, 50 patients per each group. A total of 2,434 oocytes were retrieved from 100 patients. Among them, 1,527 oocytes with visible meiotic spindle were inseminated by C-ICSI or P-ICSI (778 by C-ICSI, 749 by P-ICSI). Fertilization, degeneration after ICSI and blastocyst development were compared between the C-ICSI group and P-ICSI group. Among the embryos developed to blastocysts, good quality blastocysts were vitrified. The frozen-thawed embryo transfer (FET) cycles were carried out in 42 patients of C-ICSI group and in 45 patients of P-ICSI group. Clinical pregnancy outcomes were analyzed. The differences between C-ICSI group and P-ICSI group were statistically analyzed using Mann-Whitney U test or chi-Square test. Patient age was not different between C-ICSI group and P-ICSI group (33.5 ± 2.7 vs. 32.9 ± 2.4, P = 0.12114). Normal fertilization rate of P-ICSI group (584/749, 78.0%) was significantly higher than that of C-ICSI group (565/778, 72.6%, P = 0.0176). The oocyte degeneration rate after ICSI was significantly higher in C-ICSI group (49/778, 6.3%) than in P-ICSI group (24/749, 3.2%, P = 0.0055). Among the fertilized oocytes, 21 did not cleave; 14 were from C-ICSI group (2.48%) and 7 from P-ICSI group (1.20%, P = 0.1250). Blastocyst formation rate (65.5% vs. 67.8%, P = 0.4485) and the rates of blastocyst that were available for vitrification (59.3% vs. 62.6%, P = 0.2724) were not different between C-ICSI group and P-ICSI group. Blastocyst formation rate on day 5 was significantly higher in P-ICSI group (50.3%) than in C-ICSI group (43.9%, P = 0.0367). In FET cycles, average age of patients was 33.6 ± 2.6 years old in C-ICSI group and that was 32.9 ± 2.3 years old in P-ICSI group. The average number of transferred embryos was 1.5 ± 0.5 in C-ICSI group and 1.2 ± 0.4 in P-ICSI group. The clinical pregnancy rate and the abortion rate of C-ICSI group were 64.3% and 18.5%, respectively. Those of P-ICSI group were 66.7% and 23.3%, respectively. This study showed that normal fertilization rate, the survival of oocytes after ICSI and blastocyst formation rate on day 5 were significantly higher in P-ICSI group than in C-ICSI group. Developmental arrest of zygotes was lower in P-ICSI group than in C-ICSI group. The number of embryos available for vitrification can be increased by implementing P-ICSI. P-ICSI has the potential to improve the development of zygotes into blastocysts.

PurposeThis paper aims to investigate the efficacy of IVF with preimplantation genetic testing for aneuploidy (PGT-A), using only best-scoring blastocysts from young (≤ 35 years) infertile patients undergoing single blastocyst frozen embryo transfers (FET).MethodIn this randomized controlled trial (RCT) registered 29 March 2017, 302 infertile patient-couples eligible to participate underwent autologous ICSI blastocyst freeze-all cycles. Two-hundred and twenty patient-couples satisfied the inclusion criteria (i.e., female age ≤ 35 years, two-day 5 ≥ 2BB blastocysts) and were randomized to either the PGT-A (PGT-A group, n = 109) selection arm or morphology score (morphology group, n = 111) selection arm. In both arms, the highest ranking (by morphological score) blastocysts were selected for FET.ResultsOf the 109 best-scoring blastocysts that underwent PGT-A, 80 were predicted to be euploid (73.4%) and were transferred in FET (euploid subgroup). There was no statistical difference in LB rate between the euploid subgroup and morphology group (56.3% vs 58.6%, odds ratio 0.91 (95% CI 0.51–1.63), p = 0.750). In a multiple logistic regression, the transfer of euploid blastocysts was not found to be a significant predictor of LB when adjusting for female age, infertility duration, antral follicle count, and blastocyst quality, with the independent odds expressed as 0.91 (95% CI 0.50–1.66, p = 0.760).ConclusionIn young (≤ 35 years) infertile patients with at least two ≥ 2BB blastocysts, PGT-A blastocyst selection does not result in an enhanced LB rate, with the evidence suggesting that the effectivity of PGT-A may be limited by the effectivity of TE biopsy.Trial registration: ClinicalTrials.gov ID: NCT03095053.

PurposeIs there a difference in implantation and pregnancy rates between embryos transferred electively at cleavage or blastocyst stage in infertile women ≤ 38 years with at least four zygotes on day 1 post retrieval?MethodsA randomized clinical trial was conducted in a single tertiary care hospital with a sample size of 194 patients in each arm for a total population of 388 women. Patients less than 39 years of age with more than three fertilized oocytes and less than four previous assisted reproductive technology (ART) attempts were inclusion criteria.ResultsThe two groups were similar for age, years of infertility, indication to treatment, basal antimüllerian hormone and FSH, number of previous ART cycles, primary or secondary infertility, type of induction protocol, days of stimulation, total gonadotrophin dose, and estradiol (E2) and progesterone (P) levels at trigger. No statistically significant differences were found in terms of number of retrieved oocytes, inseminated oocytes, fertilization rate, canceled transfers (7.73% in blastocyst and 3.61% in cleavage stage group), and cycles with frozen embryos and/or oocytes. Although a higher number of fertilized oocytes were in the blastocyst stage group (6.18 ± 1.46 vs 5.89 ± 1.54, p = 0.052), a statistically greater number of embryos/randomized cycle were transferred at cleavage stage (1.93 ± 0.371) compared with the number of transferred blastocysts (1.80 ± 0.56), probably due to the number of embryos not reaching blastocyst stage (3.09%). The implantation rate (28.37 vs 25.67%), pregnancy rate per cycle (36.06 vs38.66%), transfer (39.66 vs 40.11%), spontaneous abortions (19.72% vs 12.00%), delivery rate per cycle (27.84 vs 32.99%), and transfer (30.17 vs 34.22%) were not significantly different between the blastocyst and cleavage stage groups. The twin delivery rate was higher in the blastocyst stage group, although not significant (42.59 vs 28.12%). The mean numbers of frozen blastocyst (2.30 ± 1.40 vs 2.02 ± 1.00) and frozen oocytes (7.09 ± 3.55vs 6.79 ± 3.26) were not significantly different between the two groups.ConclusionsFresh blastocyst-stage transfer versus cleavage-stage transfer did not show any significant difference in terms of implantation and pregnancy rate in this selected group of patients. A high twin delivery rate in both groups (35.59%) was registered, and although not significant, they were higher in the blastocyst transfer group (42.59 vs 28.12%). Our conclusion supports considering single embryo transfer (SET) policy, even in cleavage stage in patients younger than 39 years with at least four zygotes.Trial registrationClinicalTrials.gov registration number NCT02639000

PurposeTo describe the pregnancy and neonatal outcomes using fresh and vitrified/warmed blastocysts obtained from ovarian stimulation with follitropin delta in controlled trials versus follitropin alfa.MethodsThis investigation evaluated the outcome from 2719 fresh and frozen cycles performed in 1326 IVF/ICSI patients who could start up to three ovarian stimulations in the ESTHER-1 (NCT01956110) and ESTHER-2 (NCT01956123) trials, covering 1012 fresh cycles and 341 frozen cycles with follitropin delta and 1015 fresh cycles and 351 frozen cycles with follitropin alfa. Of the 1326 first cycle patients, 513 continued to cycle 2 and 188 to cycle 3, and 441 patients started frozen cycles after the fresh cycles. Pregnancy follow-up was continued until 4 weeks after birth.ResultsThe overall cumulative take-home baby rate after up to three stimulation cycles was 60.3% with follitropin delta and 60.7% with follitropin alfa (−0.2% [95% CI: −5.4%; 5.0%]), of which the relative contribution was 72.8% from fresh cycles and 27.2% from frozen cycles in each treatment group. Across the fresh cycles, the ongoing implantation rate was 32.1% for follitropin delta and 32.1% for follitropin alfa, while it was 27.6% and 27.8%, respectively, for the frozen cycles. Major congenital anomalies among the live-born neonates up until 4 weeks were reported at an incidence of 1.6% with follitropin delta and 1.8% with follitropin alfa (−0.2% [95% CI: −1.9%; 1.5%]).ConclusionsBased on comparative trials, the pregnancy and neonatal outcomes from fresh and frozen cycles provide reassuring data on the efficacy and safety of follitropin delta.Trial registrationClinicalTrials.gov Identifier: NCT01956110 registered on 8 October 2013; NCT01956123 registered on 8 October 2013.

IntroductionThe quality of the blastocyst (day 5/6 embryo) selected for transfer is critical for the success of in vitro fertilisation (IVF) treatment. Embryologists perform blastocyst evaluation by observing the morphology of each blastocyst. Human assessment is subjective and inconsistent in predicting which blastocyst can result in a successful pregnancy or birth. Several artificial intelligence (AI) methods have been proposed to predict IVF outcomes from blastocyst images. However, the reasoning processes of these AI methods are uninterpretable, causing epistemic and ethical concerns that prevent their implementation in clinical practice. To address this issue, the authors developed a novel interpretable AI method for blastocyst selection. The method is clinically applicable because it is transparent to embryologists and allows them to understand its reasoning processes. This randomised controlled trial (RCT) aims to test the effectiveness of this blastocyst selection method with the aim of improving IVF outcomes.Methods and analysisIn this single-centre, single-blind RCT, we will enrol 1100 women aged 20–35 years undergoing their first cycle of IVF, with or without intracytoplasmic sperm injection. The study will be conducted at Nanjing Drum Tower Hospital, a public class A tertiary hospital in China. On the fifth day of embryo culture, participants with two or more usable blastocysts will be randomised in a 1:1 ratio to either the conventional morphology group or the AI group. The primary outcome is ongoing pregnancy, defined as a viable intrauterine pregnancy of 12 weeks gestation or more.Ethics and disseminationThe research ethics committee of the Nanjing Drum Tower Hospital approved this study (approval number: 2023-259-02). All participants will provide written informed consent prior to enrolment. The findings will be presented at international conferences and published in peer-reviewed journals.Trial registration numberChiCTR2300076851.

Background Recent advances in time-lapse monitoring in IVF treatment have provided new morphokinetic markers for embryonic competence. However, there is still very limited information about the relationship between morphokinetic parameters, chromosomal compositions and implantation potential. Accordingly, this study aimed at investigating the effects of selecting competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing on pregnancy and implantation outcomes for patients undergoing preimplantation genetic screening (PGS). Methods A total of 1163 metaphase II (MII) oocytes were retrieved from 138 PGS patients at a mean age of 36.6 ± 2.4 years. These sibling MII oocytes were then randomized into two groups after ICSI: 1) Group A, oocytes (n = 582) were cultured in the time-lapse system and 2) Group B, oocytes (n = 581) were cultured in the conventional incubator. For both groups, whole genomic amplification and array CGH testing were performed after trophectoderm biopsy on day 5. One to two euploid blastocysts within the most predictive morphokinetic parameters (Group A) or with the best morphological grade available (Group B) were selected for transfer to individual patients on day 6. Ongoing pregnancy and implantation rates were compared between the two groups. Results There were significant differences in clinical pregnancy rates between Group A and Group B (71.1% vs. 45.9%, respectively, p = 0.037). The observed implantation rate per embryo transfer significantly increased in Group A compared to Group B (66.2% vs. 42.4%, respectively, p = 0.011). Moreover, a significant increase in ongoing pregnancy rates was also observed in Group A compared to Group B (68.9% vs. 40.5%. respectively, p = 0.019). However, there was no significant difference in miscarriage rate between the time-lapse system and the conventional incubator (3.1% vs. 11.8%, respectively, p = 0.273). Conclusions This is the first prospective investigation using sibling oocytes to evaluate the efficiency of selecting competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing for PGS patients. Our data clearly demonstrate that the combination of these two advanced technologies to select competent blastocysts for transfer results in improved implantation and ongoing pregnancy rates for PGS patients.

PurposeThe aim of our study was to evaluate the influence of different ejaculatory abstinence time frames (several days versus 1 h) on semen parameters, blastocysts ploidy rate, and clinical results in assisted reproduction cycles on sibling oocytes.MethodsThis is a prospective study including 22 preimplantation genetic testing for aneuploidy (PGT-A) cycles performed between November 2015 and December 2018. Male partners with oligoastenoteratozoospermia produced two semen samples on the day of oocyte retrieval: the first one after several days of abstinence and the second, 1 h after the first one. Oocytes from each patient were divided into two groups: those in group 1 were injected with spermatozoa from the first ejaculate (N = 121) and oocytes in group 2 with spermatozoa from the second one (N = 144). Outcomes of aniline blue test, fertilization, blastocyst formation, ploidy rates, and clinical results were compared between the two groups.ResultsSemen volume resulted lower in the second sperm retrieval. Sperm concentration, motility, and morphology were similar in the two groups. A total of 106 blasotcysts were biospied. Higher blastocyst euploidy rates resulted in group 2 (43.6%) than in group 1 (27.5%). A higher percentage of mature chromatine was observed in group 2.ConclusionUsing spermatozoa from samples with a shorter abstinence could be a simple method to select higher quality spermatozoa, reducing aneuploidy rate in blastocysts. Prospective randomized controlled trials should be performed to confirm the potential advantage of using semen samples with short abstinence period to improve the outcome of assisted reproduction cycles.

The molecular mechanism regulating embryo development under reduced oxygen tension remains elusive. This study aimed to identify the molecular mechanism impacting embryo development under low oxygen conditions. Buffalo embryos were cultured under 5% or 20% oxygen and were evaluated according to their morphological parameters related to embryo development. The protein profiles of these embryos were compared using iTRAQ-based quantitative proteomics. Physiological O2 (5%) significantly promoted blastocyst yield, hatching rate, embryo quality and cell count as compared to atmospheric O2 (20%). The embryos in the 5% O2 group had an improved hatching rate of cryopreserved blastocysts post-warming (p < 0.05). Comparative proteome profiles of hatched blastocysts cultured under 5% vs. 20% O2 levels identified 43 differentially expressed proteins (DEPs). Functional analysis indicated that DEPs were mainly associated with glycolysis, fatty acid degradation, inositol phosphate metabolism and terpenoid backbone synthesis. Our results suggest that embryos under physiological oxygen had greater developmental potential due to the pronounced Warburg Effect (aerobic glycolysis). Moreover, our proteomic data suggested that higher lipid degradation, an elevated cholesterol level and a higher unsaturated to saturated fatty acid ratio might be involved in the better cryo-survival ability reported in embryos cultured under low oxygen. These data provide new information on the early embryo protein repertoire and general molecular mechanisms of embryo development under varying oxygen levels.

Here, a combination of biophysical measurement, modelling, and genetic and experimental manipulation of cell contractile components is used to analyse the formation of the inner cell mass in the early mouse embryo. Early sorting events in the mouse embryo How cells in mouse blastocyst sort themselves out to generate the inner cell mass, and how the embryos respond to manipulation during early development remain unexplained. Previous studies have indicated the importance of differential cell adhesion or oriented cell division along an apical–basal axis in the sorting phenomenon. Jean-Léon Maître et al . use a combination of biophysical measurement, modelling and both genetic and experimental manipulation of contractile components to analyse inner cell mass formation in the early mouse embryo. They suggest that cell polarization generates cells of different contractilities, which trigger their sorting to inner and outer position. The contractile forces are shown to modulate the sub-cellular localization of Yap, a transcriptional regulator known to influence cell fate. During pre-implantation development, the mammalian embryo self-organizes into the blastocyst, which consists of an epithelial layer encapsulating the inner-cell mass (ICM) giving rise to all embryonic tissues 1 . In mice, oriented cell division, apicobasal polarity and actomyosin contractility are thought to contribute to the formation of the ICM 2 , 3 , 4 , 5 . However, how these processes work together remains unclear. Here we show that asymmetric segregation of the apical domain generates blastomeres with different contractilities, which triggers their sorting into inner and outer positions. Three-dimensional physical modelling of embryo morphogenesis reveals that cells internalize only when differences in surface contractility exceed a predictable threshold. We validate this prediction using biophysical measurements, and successfully redirect cell sorting within the developing blastocyst using maternal myosin ( Myh9 )-knockout chimaeric embryos. Finally, we find that loss of contractility causes blastomeres to show ICM-like markers, regardless of their position. In particular, contractility controls Yap subcellular localization 6 , raising the possibility that mechanosensing occurs during blastocyst lineage specification. We conclude that contractility couples the positioning and fate specification of blastomeres. We propose that this ensures the robust self-organization of blastomeres into the blastocyst, which confers remarkable regulative capacities to mammalian embryos.

Pluripotent epiblast (EPI) cells, present in the inner cell mass (ICM) of the mouse blastocyst, are progenitors of both embryonic stem (ES) cells and the fetus. Discovering how pluripotency genes regulate cell fate decisions in the blastocyst provides a valuable way to understand how pluripotency is normally established. EPI cells are specified by two consecutive cell fate decisions. The first decision segregates ICM from trophectoderm (TE), an extraembryonic cell type. The second decision subdivides ICM into EPI and primitive endoderm (PE), another extraembryonic cell type. Here, we investigate the roles and regulation of the pluripotency gene Sox2 during blastocyst formation. First, we investigate the regulation of Sox2 patterning and show that SOX2 is restricted to ICM progenitors prior to blastocyst formation by members of the HIPPO pathway, independent of CDX2, the TE transcription factor that restricts Oct4 and Nanog to the ICM. Second, we investigate the requirement for Sox2 in cell fate specification during blastocyst formation. We show that neither maternal (M) nor zygotic (Z) Sox2 is required for blastocyst formation, nor for initial expression of the pluripotency genes Oct4 or Nanog in the ICM. Rather, Z Sox2 initially promotes development of the primitive endoderm (PE) non cell-autonomously via FGF4, and then later maintains expression of pluripotency genes in the ICM. The significance of these observations is that 1) ICM and TE genes are spatially patterned in parallel prior to blastocyst formation and 2) both the roles and regulation of Sox2 in the blastocyst are unique compared to other pluripotency factors such as Oct4 or Nanog.