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This first large-scale report of birth defects in 15,405 offspring conceived by assisted reproductive technologies in China found infants born after IVF alone to have a birth defect frequency comparable to that in the general Chinese population; rates were nonsignificantly higher in infants conceived with use of intracytoplasmic sperm injection compared with those conceived after IVF alone. [Copyright &y& Elsevier]

Fertility societies worldwide responded to the COVID-19 pandemic by recommending that fertility clinics close, or sharply reduce, the clinical operation, leading to a shift in the management of IVF laboratories in three phases: shutdown preparation; maintenance during shutdown; and restart. Each of these phases carries distinct risks that need identification and mitigation, forcing laboratory managers to rethink and adapt their procedures in response to the pandemic. The sudden and unprecedented nature of the pandemic forced laboratory managers from around the world to base decisions on opinion and experience when evidence-based response options were unavailable. These perspectives on pandemic response were presented during a virtual international symposium on COVID-19, held on 3 April 2020, and organized by the London Laboratory Managers' Group. Laboratory managers from seven different countries at different stages of the pandemic (China, Italy, Spain, France, UK, Brazil and Australia) presented their personal experiences to a select audience of experienced laboratory managers from 19 different countries. The intention of this paper is to collect the learnings and considerations from this group of laboratory managers who collaborated to share personal experiences to contribute to the debate surrounding what constitutes good IVF laboratory practice in extraordinary circumstances, such as the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

• Novel variants of ZP1, ZP2 and ZP3 are associated with female infertility. • In-vitro functional studies of ZP protein variants indicate pathogenesis. • The ZP3 variant was overcome with ICSI treatment. • Targeted genetic diagnosis of ZP genes may guide fertilization methods. Which genetic variants might explain the causes of empty follicle syndrome (EFS) and abnormal zona pellucida (ZP) and affect the success of treatment with assisted reproductive technologies (ART)? Whole-exome sequencing was performed in probands with EFS and abnormal ZP. Sanger sequencing was used for variant validation. Using HEK-293T cells, the effects of ZP1 and ZP2 variants on protein expression were explored by western blotting, and the effect of the ZP1 variant on protein location was investigated via immunofluorescence. The protein structure was also analysed to investigate the pathogenicity of variants. A homozygous nonsense variant in ZP1 (c.874C>T, p.Gln292*) was detected in a patient with EFS. A novel homozygous frameshift variant in ZP2 (c.836_837delAG, p.Glu279Valfs*6) and a novel heterozygous missense variant in ZP3 (c.1159G>A, p.Val387Met) were identified in two patients with ZP morphological abnormalities, respectively. Western blotting and immunofluorescence analysis showed that the ZP1 variant results in a premature stop codon, leading to the truncated ZP1 protein. The ZP2 variant, which is situated in the N-terminus, triggers the degradation of a premature termination protein. Additionally, the patient with the ZP3 variant achieved clinical pregnancy following intracytoplasmic sperm injection treatment. These findings expand the mutational spectrum of ZP1, ZP2 and ZP3 , and provide new evidence for genetic diagnosis of female infertility. The targeted genetic diagnosis of ZP genes is recommended to choose appropriate fertilization methods and improve success rates of treatment with ART. [ABSTRACT FROM AUTHOR]

Research question: More than 100 variants have been identified in the TUBB8 gene, which account for approximately 30% of infertile women with oocyte maturation defects. But what is the correlation between the highly phenotypic diversity and genetic variability? Are there other variants in TUBB8 related to female infertility? Design: TUBB8 resequencing was performed in 80 female subjects who were experiencing infertility and were seeking treatment with assisted reproductive technologies (ART), or had ever experienced ART failure due to oocyte maturation defects. All variants were evaluated with pedigree analysis, population frequency, in-silico analysis and molecular modelling. The effects of the variants on oocytes/arrested embryos were assessed by morphological observations, immunostaining, embryo biopsies and chromosome euploidy analysis. Results: Nine missense variants and two frameshift variants from an additional 15 families were identified, including four novel variants and seven previously reported recurrent variants. These TUBB8 variants were related to highly variable phenotypes, including abnormalities in oocyte maturation or morphology, fertilization failure, embryonic development abnormalities and implantation failure. Also further clarified were the incomplete penetrance of heterozygous p.E108K, the likely benign significance of heterozygous p.A313V and the clinical effect of a novel variant of p.R380C. Conclusions: This study significantly expands the variant spectrum of the TUBB8 gene and, together with the available findings on TUBB8 variants and female infertility, will potentially facilitate the genetic counselling of infertile women in future. [ABSTRACT FROM AUTHOR]

[Display omitted] • 17 and 3 intrafollicular fluid metabolites related to ovarian hyperstimulation syndrome risk in non-ovarian etiologic infertility and polycystic ovarian syndrome, respectively. • 9 of the ovarian hyperstimulation syndrome-related metabolites overlapped with the differential metabolites of the polycystic ovarian syndrome, 8 of which are unsaturated fatty acids. • Non-ovarian etiologic infertility and polycystic ovarian syndrome display metabolic heterogeneities in the development of ovarian hyperstimulation syndrome. • Ovarian hyperstimulation syndrome has some shared etiological factors with the polycystic ovarian syndrome. Ovarian hyperstimulation syndrome (OHSS) is the most serious iatrogenic complication of ovulation stimulation during assisted reproductive technology. The main objective of this study was to investigate intrafollicular fluid metabolic change profiles of OHSS in non-ovarian etiologic infertility women (CON) and polycystic ovarian syndrome patients (PCOS). 87 infertile women were divided into four subgroups: CON-Norm (CON with normal ovarian response), CON-OHSS (CON with OHSS), PCOS-Norm (PCOS with normal ovarian response), and PCOS-OHSS (PCOS with OHSS). The intrafollicular fluid metabolic profiles were analyzed with gas chromatography-mass spectrometry. The multivariable-adjusted conditional logistic regression was applied to assess the association of metabolites with OHSS risk. We identified 17 and 3 metabolites that related to OHSS risk in CON and PCOS, respectively. 13 OHSS risk-related metabolites in CON were unsaturated fatty acids, 8 of which were also the significantly altered metabolites between all PCOS and CON-Norm. Our study may shed light on the role of intrafollicular fluid metabolic abnormalities in the pathophysiology of OHSS. The findings suggested that there might be some metabolic heterogeneities underlying the development of OHSS in CON and PCOS women and indicated possible shared etiological factors in the development of PCOS and OHSS. [ABSTRACT FROM AUTHOR]

Is the total duration of spontaneous blastocyst collapse to re-expansion before biopsy related to ploidy and live birth rates after single euploid blastocyst transfer? This was a retrospective cohort study of 600 preimplantation genetic testing cycles for aneuploidy (PGT-A) cycles, involving 2203 biopsied blastocysts, at a large reproductive medicine centre. Features of spontaneous blastocyst collapse from full to expanded stage, before biopsy, were observed using an embryoscope viewer for embryos cultured in a time-lapse incubator. In total, 568 cycles of frozen blastocyst transfers, either single euploid or mosaic, were performed. Correlations between collapse features and PGT-A outcomes were evaluated, as well as live birth rate, following euploid embryo transfer. Blastocysts with lower morphological quality or delayed development had significantly higher rates of collapse, multiple collapses, and a longer duration of collapse to re-expansion. After controlling for confounders, such as oocyte age, morphological quality of blastocyst, and day of biopsy, multivariate logistic regression revealed that the total duration of collapse to re-expansion was an independent predictor of lower euploidy rate; the multivariate OR was 0.85 (95% CI 0.77–0.95; P = 0.00). Furthermore, even with euploid embryo transfer, the probability of a live birth decreased as the total duration of collapse to re-expansion increased; the multivariate OR was 0.79 (95% CI 0.64–0.98; P = 0.033). The total duration of blastocyst collapse to re-expansion could be used as a predictor of lower euploidy and live birth rate. When developing blastocyst algorithms for pregnancy prediction, the duration of spontaneous blastocyst collapse should be included as a significant variable. [ABSTRACT FROM AUTHOR]

The widespread application of nanoparticles (NPs) in various fields has raised health concerns, especially in reproductive health. Our research has shown zinc oxide nanoparticles (ZnONPs) exhibit the most significant toxicity to pre-implantation embryos in mice compared to other common NPs. In patients undergoing assisted reproduction technology (ART), a significant negative correlation was observed between Zn concentration and clinical outcomes. Therefore, this study explores the impact of ZnONPs exposure on pre-implantation embryonic development and its underlying mechanisms. We revealed that both in vivo and in vitro exposure to ZnONPs impairs pre-implantation embryonic development. Moreover, ZnONPs were found to reduce the pluripotency of mouse embryonic stem cells (mESCs), as evidenced by teratoma and diploid chimera assays. Employing multi-omics approaches, including RNA-Seq, CUT&Tag, and ATAC-seq, the embryotoxicity mechanisms of ZnONPs were elucidated. The findings indicate that ZnONPs elevate H3K9me3 levels, leading to increased heterochromatin and consequent inhibition of gene expression related to development and pluripotency. Notably, Chaetocin, a H3K9me3 inhibitor, sucessfully reversed the embryotoxicity effects induced by ZnONPs. Additionally, the direct interaction between ZnONPs and H3K9me3 was verified through pull-down and immunoprecipitation assays. Collectively, these findings offer new insights into the epigenetic mechanisms of ZnONPs toxicity, enhancing our understanding of their impact on human reproductive health. Schematic diagram of the mechanism of the ZnONPs effects on pre-implantation embryos and mESCs. ZnONPs exposure impairs the development of pre-implantation embryos and pluripotency of mESCs (upper), and a model of ZnONPs-triggered H3K9me3-dependent heterochromatin in the suppression of developmental and pluripotency-related genes (below). [Display omitted] [ABSTRACT FROM AUTHOR]

Pronuclei and blastomeres are key structures in early embryonic development, and by localizing these structures simultaneously, the developmental state of the embryo can be assessed more comprehensively. However, there are several unavoidable problems in localization tasks due to the biological characteristics of embryos, including blastomeres overlap, pronuclei overlap, and similarity between pronuclei and background. In this study, we propose a novel localization network for pronuclei and blastomeres, which can solve these localization problems. Firstly, to address the issues related to the overlap of pronuclei and blastomeres, as well as the pronuclei and background similarity problem, we put the vision transformer with bi-level routing attention module (BiFormer) in the backbone. The BiFormer finds attention regions in the embryo image scene to obtain more edge and texture information of both pronuclei and blastomeres, which allows for a better feature realization of the neck region fusion interaction. Subsequently, to enhance model performance and mitigate redundant computation. The localization network uses partial convolution (PConv) in the backbone. The backbone network allows more efficient extraction of features by simultaneously reducing redundancy in computation with the effect of PConv. In addition, to mitigate the impact of low-quality samples in embryo images on localization, as well as to pay more attention to ordinary quality samples, we use wise intersection over union version 3 (WIoUv3) loss function with a dynamic non-monotonic focusing mechanism in the localization network, thus improving the overall performance of the algorithm. The experimental results show our model mAP@0.5 is 92.4% in localizing pronuclei and blastomeres. In practical terms, the ability to accurately localize pronuclei and blastomeres allows for better assessment of embryo quality and selects the best embryos. [Display omitted] • For the first time, we propose a target localization scheme to locate pronuclei and blastomeres in embryo images. • We use BiFormer to help the network better extract edge, and texture features of pronuclei and blastomeres. • We use partial convolution in YOLOv7-PB to reduce the number of network parameters by reducing redundant computations. • Our proposed YOLOv7-PB network incorporates WIoUv3 as part of the bounding box regression loss. [ABSTRACT FROM AUTHOR]

Could the mitochondrial DNA (mtDNA) copy number of cumulus cells be used as a biomarker of the potential of embryo implantation in good prognosis IVF patients? A prospective cohort study on good prognosis IVF patients from a large reproductive medicine centre. A total of 392 embryos from 61 cycles (including 31 implanted and 30 non-implanted cycles) were enrolled in the study. The corresponding cumulus cell mtDNA copy number of embryos was tested by real-time quantitative polymerase chain reaction. The corresponding cumulus cell mtDNA copy numbers were compared between implanted and non-implanted embryos and also compared between high quality and poor quality embryos. Then, a mitochondrial function assay including mitochondrial membrane potentials, concentration of reactive oxygen species (ROS) and ATP content of the corresponding cumulus cells were compared between high quality and poor quality embryos to verify the above experimental findings. For the same population, the mean cumulus cell mtDNA copy numbers for implanted and non-implanted embryos were 255.61 ± 81.02 and 254.50 ± 73.29 (P = 0.47), and those for high quality and poor quality embryos were 266.02 ± 98.56 and 295.71 ± 70.64 (P = 0.99), respectively. There was no significant difference in cumulus cell mtDNA copy number between implanted and non-implanted embryos or between high quality and poor quality embryos. The mitochondrial membrane potential, ROS levels and ATP content of the corresponding cumulus cells did not differ significantly between high quality and poor quality groups. Measurement of cumulus cell mtDNA copy number might not provide any advantage to embryo prioritization in good prognosis IVF patients. Any suggested link between cumulus cell mtDNA copy number and embryo implantation requires further validation. [ABSTRACT FROM AUTHOR]

Could objective embryo assessment using iDAScore Version 2.0 perform as well as conventional morphological assessment? A retrospective cohort study of fresh day 3 embryo transfer cycles was conducted at a large reproductive medicine centre. In total, 7786 embryos from 4328 cycles with known implantation data were cultured in a time-lapse incubator and included in the study. Fetal heartbeat (FHB) rate was analysed retrospectively using iDAScore Version 2.0 and conventional morphological assessment associated with the transferred embryos. The pregnancy-prediction performance of the two assessment methods was compared using area under the curve (AUC) values for predicting FHB. AUC values were significantly higher for iDAScore compared with morphological assessment for all cycles (0.62 versus 0.60; P = 0.005), single-embryo transfer cycles (0.63 versus 0.60; P = 0.043) and double-embryo transfer cycles (0.61 versus 0.59; P = 0.012). For the age subgroups, AUC values were significantly higher for iDAScore compared with morphological assessment in the <35 years subgroup (0.62 versus 0.60; P = 0.009); however, no significant difference was found in the ≥35 years subgroup. In terms of the number of blastomeres, AUC values were significantly higher for iDAScore compared with morphological assessment for both the <8c subgroup (0.67 versus 0.56; P < 0.001) and the ≥8c subgroup (0.58 versus 0.55; P = 0.012). iDAScore Version 2.0 performed as well as, or better than, conventional morphological assessment in fresh day 3 embryo transfer cycles. iDAScore Version 2.0 may therefore constitute a promising tool for selecting embryos with the highest likelihood of implantation. [ABSTRACT FROM AUTHOR]

Maternal aging is associated with a decline in oocyte quality, which leads to the decreased fertility. Therefore, developing approaches to reduce aging-induced deterioration of oocyte quality in older women is important. Near-infrared cell protector-61 (IR-61), a novel heptamethine cyanine dye, has the potential for antioxidant effects. In this study, we found that IR-61 can accumulate in the ovaries and improved ovarian function of naturally aged mice; it also increased the oocyte maturation rate and quality by maintaining the integrity of the spindle/chromosomal structure and reducing the aneuploidy rate. In addition, the embryonic developmental competence of aged oocytes was improved. Finally, RNA-sequencing analysis indicated that IR-61 might perform the beneficial effects on aged oocytes by regulating mitochondrial function, this was confirmed by immunofluorescence analysis of mitochondrial distribution and reactive oxygen species. Taken together, our findings demonstrate that IR-61 supplementation in vivo can increase oocyte quality and protect oocytes from aging-induced mitochondrial dysfunction, and thus could improve the fertility of older women and efficiency of assisted reproductive technology. IR-61 can accumulate in the ovaries and improve the quality of aged oocytes by restoring mitochondrial function, enhancing meiotic competence, reducing the aneuploidy rate, and increasing embryonic development potential. These findings provide a theoretical basis for improving the reproductive outcomes of women of advanced maternal age. [Display omitted] • IR-61 accumulates in the ovaries and increases oocyte quantity in aged mice. • IR-61 supplementation enhances maturation competence and reduces the aneuploidy rate of aged oocytes. • IR-61 supplementation improves the developmental potential of aged oocytes. • IR-61 supplementation restores the mitochondrial function of aged oocytes. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to identify candidates for a morphokinetic embryo selection model for day-3 transfer through the analysis of known implantation data.Study Design: A diagnostic trial study was conducted. Two hundred twelve embryos from 109 patients participating in in-vitro fertilization (IVF) protocols.Results: In this diagnostic trial study, we analyzed cleavage times of transferred embryos with either failed (n=102) or full implantations (n=110). The logistic regression (LR) model of the relationship between the morphokinetic parameters and the implantation rate had a sensitivity of 79.61% and specificity of 47.56%. Results also showed that morphokinetic parameters such as tPNf (the time when pronuclei disappearanced), t2 (t2 for two cells), t4 (t4 for four cells) and t4-t3 were significantly different between embryos in the two groups (p<0.037). Implantation rates of embryos within the time interval of 21.27 h< t2 < 26.725 h were higher than those of embryos outside this period (60.83% vs. 40.21%, p=0.003). Fifty-seven patients with fully implanted embryos included five patients with pregnancy loss and 52 patients with live births. Embryos that met the time interval criteria for t2 and were also within the range of 11hConclusions: Selection and transfer of embryos that reach specific developmental stages within critical time intervals during IVF may improve the outcome of transfers and result in higher implantation rates and live birth rates. [ABSTRACT FROM AUTHOR]

A correction to the article "Efficiency of an Automated Dehydrated Carrier for the Vitrification of Human Embryos Derived from Three Pronuclei Fertilized Zygotes" published in "Reproductive BioMedicine Online 30" is presented.