Do chromosomal inversion carriers really need preimplantation genetic testing?

To evaluate whether increasing total gonadotropin (Gn) dose is associated with changes in euploid blastocyst rate in preimplantation genetic testing (PGT) oocytes. This retrospective cohort study was conducted between 2017 and 2022, and 19,246 oocytes were grouped and analyzed based on tri-sectional quantiles of total Gn doses. Single reproductive medical center. All the patients who underwent PGT cycles, including PGT for aneuploidy, monogenic disorders, and structural rearrangements, were included. Next-generation sequencing platforms for chromosomal analysis. Blastocyst formation and euploid blastocyst rates. In total, 19,246 oocytes and 5375 PGT blastocysts were analyzed. There were significant differences in blastocyst formation and euploid blastocyst rates among the groups classified according to tri-sectional quantiles of total Gn doses. Significant differences in age, body mass index (BMI), proportion of primary infertility, anti-Müllerian hormone (AMH) levels, number of oocytes retrieved, controlled ovarian stimulation (COS) regimen, type of Gn, and PGT category were observed among the three groups. After stratifying the analysis by age, BMI, infertility diagnosis, AMH levels, number of oocytes retrieved, PGT category, type of Gn, and COS regimen, significant differences were only seen in a small number of specific subgroups. Furthermore, the results of the multiple logistic regression analysis showed that the blastocyst formation and euploid blastocyst rates did not significantly increase or decrease with the total Gn dose, whether treated as a continuous variable or divided into three Gn groups as categorical variables. Notably, advancing age was a risk factor for blastocyst formation and euploid blastocyst rates. PGT for structural rearrangements was a risk factor for blastocyst formation and euploid blastocyst rates as compared with PGT for aneuploidy. In the total PGT cycles, advancing age, and preimplantation genetic testing for structural rearrangements negatively affected blastocyst formation and euploid blastocyst rates; however, the total Gn dose did not affect blastocyst formation and euploid blastocyst rates.

Blastocyst conversion rate and ploidy in translocation carriers

Preimplantation genetic testing for structural rearrangement based on low-coverage next-generation sequencing accurately discriminates between normal and carrier embryos for patients with translocations

Impact of application of next generation technologies on the outcome of preimplantation genetic testing for structural rearrangements (PGT-SR)

To study reproductive outcomes of transferring embryos with mosaic chromosomal aneuploidies unrelated to target loci in preimplantation genetic testing for structural rearrangement (PGT-SR). A retrospective analysis of 1712 PGT-SR cycles (involving 1373 couples) from a single center was conducted. Comprehensive chromosomal analysis was performed on trophectoderm biopsy samples using whole-genome amplification combined with next-generation sequencing. Clinical outcomes after single embryo transfer, including clinical pregnancy rate, miscarriage rate, live birth rate, and ectopic pregnancy rate, were compared between mosaic embryo transfers and completely euploid embryo transfers. In PGT-SR cycles, euploid embryo transfers (1338 cycles) demonstrated a clinical pregnancy rate of 65.17%, live birth rate of 58.67%, miscarriage rate of 6.05%, and ectopic pregnancy rate of 0.45%, whereas mosaic embryo transfers (165 cycles) exhibited comparable outcomes with 58.18%, 54.55%, 3.64%, and 0%, respectively. The subgroup analysis by mosaic degree which revealed low-level mosaicism (20%-29% and 30%-49%) had outcomes similar to euploid embryos. High-level mosaicism (50%-69%) demonstrated significantly reduced clinical pregnancy (OR = 0.20, 95% CI 0.06-0.54) and live birth rates (OR = 0.20, 95% CI 0.06-0.56), though miscarriage remained comparable. No significant outcome variations were observed across chromosomal types. In PGT-SR cycles, embryos with low-level mosaicism (20%-49%) unrelated to target loci demonstrate equivalent clinical pregnancy and live birth outcomes to completely euploid embryos. Although high-level mosaicism (50%-69%) is likely associated with reduced live birth rates, these embryos still retain potential for healthy live births.

Preimplantation Genetic Testing (PGT) enables the genetic analysis of embryos generated through in vitro fertilization (IVF). Traditional applications of PGT include PGT for aneuploides (PGT-A - to identify whole-chromosome aneuploidies), PGT for structural rearrangements (PGT-SR - to detect chromosomal imbalances resulting from a balanced structural rearrangement, such as chromosomal translocations or inversions, in one of the patients), and PGT for monogenic disorders (PGT-M - to minimize the risk of transmitting a known inherited monogenic disorder). Recent advancements in Next Generation Sequencing (NGS) technologies used in PGT, combined with a substantial reduction in associated costs, have made Whole Genome Sequencing (WGS) a feasible approach at the embryonic level. This methodology provides genome-wide data, albeit typically at low coverage depth.These technological developments have enabled novel applications of PGT, such as screening embryos for monogenic variants (including de novo mutations) and polygenic embryo screening (PES). However, these approaches raise significant limitations and challenges, particularly from ethical and genetic counseling perspectives.This session will offer an overview of the key ethical and counseling dilemmas associated with the use of these emerging technologies, in order to facilitate a broader discussion on the scope and boundaries of PGT.

Initially categorized 46,XY embryo transfer ending with 45,X products of conception—a case report and a review of discordant result management

Effect of carriers' sex on meiotic segregation patterns and chromosome stability of reciprocal translocations

Low serum progesterone concentration on frozen embryo transfer (FET) day in hormone replacement therapy (HRT) cycles results in lower reproductive outcomes. Recent studies showed the efficiency of a "rescue protocol'' to restore reproductive outcomes in these patients. Here, we compared reproductive outcomes in HRT FET cycles in women with low serum progesterone levels who received individualized luteal phase support (iLPS) and in women with adequate serum progesterone levels who underwent in vitro fertilization for pre-implantation genetic testing for structural rearrangements or monogenic disorders. This retrospective cohort study included women (18-43 years of age) undergoing HRT FET cycles with pre-implantation genetic testing at Montpellier University Hospital between June 2020 and May 2022.A standard HRT was used: vaginal micronized estradiol (6mg/day) followed by vaginal micronized progesterone (VMP; 800 mg/day). Serum progesterone was measured after four doses of VMP: if <11ng/ml, 25mg/day subcutaneous progesterone or 30mg/day oral dydrogesterone was introduced. 125 HRT FET cycles were performed in 111 patients. Oral/subcutaneous progesterone supplementation concerned 39 cycles (n=20 with subcutaneous progesterone and n=19 with oral dydrogesterone). Clinical and laboratory parameters of the cycles were comparable between groups. The ongoing pregnancy rate (OPR) was 41.03% in the supplemented group and 18.60% in the non-supplemented group (p= 0.008). The biochemical pregnancy rate and miscarriages rate tended to be higher in the non-supplemented group versus the supplemented group: 13.95% versus 5.13% and 38.46% versus 15.79% (p=0.147 and 0.182 respectively). Multivariate logistic regression analysis found that progesterone supplementation was significantly associated with higher OPR ​​ (adjusted OR = 3.25, 95% CI [1.38 - 7.68], p=0.007). In HRT FET cycles, progesterone supplementation in patients with serum progesterone concentration <11 ng/mL after four doses of VMP significantly increases the OPR.

The interchromosomal effect (ICE) refers to the uncertainty during meiosis where the rearrangement of the chromosomes affects the segregation of the chromosomes that are not involved in the structural chromosomal abnormalities. The aim of this study is to investigate the existence of ICE in the sperm nuclei of the males who have structural chromosomal abnormalities. Nine male individuals who are the carriers of the structural chromosomal abnormalities (patient group) and 14 male individuals who did not have any chromosomal abnormalities (control group) were diagnosed by the classical cytogenetic analysis. The aneuploidy of chromosomes 2, 3, 12, 13, 17, 18, 21, X, and Y in the sperm nuclei was investigated using the fluorescence in situ hybridization (FISH) method in these individuals. The patient group included 5 Robertsonian translocation (ROB) carriers, 3 reciprocal translocation (RCP) carriers, and 1 inversion carrier. A total of 51921 sperm nuclei were analyzed (19484 from the patient group and 32437 from the control group). While ICE was determined in 4 of 5 patients who were the carriers of ROB and an inversion carrier patient, it was not determined in the patient carrier of RCP. Our results suggest that there is ICE in the male carriers with a structural chromosomal abnormality, which appears to be translocation, breakpoint, chromosome, and patient dependent.

The aim of our study was to investigate the effect of maternal and embryo MTHFR C677T and A1298C polymorphisms on embryo aneuploidies and mosaicism and the correlation between these genetic variants in transferred euploid embryos and IVF outcomes. MTHFR genotype was analyzed in 77 women who performed an IVF/ICSI cycle with PGT-A. Moreover, to evaluate the effect of embryo MTHFR polymorphisms on embryo aneuploidies and mosaicism, the MTHFR genotype was analyzed in 191 biopsied embryos from the PGT-A cycles of these patients. Additionally, 218 DNA samples from trophectoderm biopsies belonging to a different group of patients were also genotyped. MTHFR polymorphisms were analyzed in a total amount of 409 trophectoderm samples. The main parameters analyzed were embryo aneuploidy and mosaicism rates. Finally, the IVF outcomes of 241 single euploid embryo transfers were assessed and compared between different MTHFR embryo genotypes. The aneuploidy rates were similar in embryos from homozygous normal women and women with at least one mutated allele (54.7% vs. 30.2% in 677C>T and 37.8% vs. 42.7% in 1298A>C). Furthermore, no differences were observed in the mosaicism rate (24.0% vs. 13.8% in 677C>T and 17.1% vs. 17.3% in 1298A>C). A similar analysis was performed, taking into account the embryo genotype results. No differences in aneuploidy rate were observed between the study groups. The only significant difference was the mosaicism rate among 677C>T genotype (13.5% in 677CC group vs. 5.4% in 677CT/TT; p = 0.019). Implantation rate, biochemical and clinical miscarriage rates, and ongoing pregnancy rate were compared between different embryo genotypes, and no statistically significant differences were found. In conclusion, the maternal MTHFR genotype did not influence embryo chromosomal abnormalities. Moreover, the embryo MTHFR genotype was not associated with embryo aneuploidy or IVF outcomes such as implantation, pregnancy loss, and ongoing pregnancy when euploid embryos were transferred. Abbreviations: MTHFR: methylenetetrahydrofolate reductase; IVF: in vitro fertilization; PGT-A: preimplantation genetic testing for aneuploidies; SAM: S-adenosyl methionine; SNP: single nucleotide polymorphism; SPSS: Statistical Package for Social Sciences; RIF: recurrent implantation failure; RPL: recurrent pregnancy loss; hCG: human chorionic gonadotropin; PBS: phosphate buffered saline; CGH: comparative genomic hybridization; NGS: next generation sequencing

Recent studies have reported that embryos diagnosed as aneuploid by preimplantation genetic testing (PGT) can still result in successful live births after transfer. This suggests that, in addition to mosaic embryos, fully aneuploid embryos may also carry a risk of diagnostic error, potentially reducing the overall accuracy of PGT. Therefore, thoroughly investigating the risk and characteristics of aneuploidy misdiagnosis is crucial for optimizing PGT strategies and improving clinical outcomes in assisted reproductive technology (ART). Relevant studies published from January 2000 to December 2024 were identified through PubMed and Web of Science. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). A diagnostic meta-analysis was conducted using a random-effects model to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs), combining sensitivity and specificity. Results were visualized using forest plots. A total of 22 studies were included to assess the discordance between trophectoderm (TE) biopsy and inner cell mass (ICM) or whole blastocyst (WB) results. The discordance rate for euploid embryo diagnosis was low (2.6%), whereas it was significantly higher for aneuploid embryos (9.2%). Segmental aneuploidies showed the highest discordance rate (17.4%). In the PGT-A population, misdiagnosis of segmental aneuploid embryos was particularly prominent (OR = 10.04, 95% CI: 7.60-13.27, I2 = 0%, P < 0.001). The results indicate that embryos with segmental aneuploidies have a significantly higher risk of misdiagnosis, especially in the PGT-A population. This highlights the need for caution when interpreting trophectoderm (TE) biopsy results involving segmental aneuploidies, to avoid misdiagnosis and the inadvertent discard of potentially viable embryos.

The effect of two embryo culture systems on blastocyst development, euploidy and mosaicism rates

Is there a correlation between paternal age and aneuploidy rate? An analysis of 3,118 embryos derived from young egg donors

Next-Generation Sequencing Is More Efficient at Detecting Mosaic Embryos and Improving Pregnancy Outcomes than Single-Nucleotide Polymorphism Array Analysis