Clinical Value of Mosaicism Diagnosis on the Trophectoderm Biopsies

Aneuploidy, Chromosome Abnormality

Mosaicism, PGT-A, Blastocyst biopsy, Aneuploidy testing, Preimplantation genetics

Mosaicism within an embryo is defined as the presence of two or more cell populations with different genotypes. Blastocysts classified as mosaic by Preimplamtation Genetic Testing for Aneuploidy (PGT-A) have been reported to implant less and miscarry more frequently than embryos classified as euploid. Because of the unknown impact of mosaicism on embryo development, these embryos are given low priority and are discarded for transfer. However, recent papers on the transfer of human embryos classified by PGT-A as mosaic suggest that embryos with a low fraction of abnormal cells resulting in viable, chromosomally normal ongoing pregnancies, and high-level mosaics resulting in fewer viable pregnancies, but so far none producing mosaic babies. The apparent presence of mosaicism in an embryo is used as a selection criteria for embryo transfer (ET), introducing a strong bias in terms of patient prognosis and embryo quality. Additionally, it is also possible that some embryos are incorrectly classified as mosaic due to technical variability derived from the processing of a uniform aneuploid embryo. The aims of this study is to provide evidences about the clinical significance of chromosomal mosaicism in PGT-A cycles by a prospective non-selection based methodology.

One of the most common reasons why in vitro fertilization (IVF) is unsuccessful, or why miscarriages occur, is because of chromosomal abnormalities in the embryo. Embryos with less than 20% aneuploidy are considered as euploid, while those between 20-80% are reported as mosaic, and those over 80% as aneuploid. Embryos with the correct number of chromosomes (euploid) have a higher chance of leading to a successful pregnancy than those with the incorrect number of chromosomes (aneuploid) or mosaics. Mosaicism within an embryo is defined as the presence of two or more cell populations with different genotypes. Preliminary data suggested that embryos identified as mosaic by Preimplamtation Genetic Testing for Aneuploidy (PGT-A) may have a reduced chance of implantation compared with euploid and may play a significant role in pregnancy loss. Because of the unknown impact of mosaicism on embryo development, these embryos are given low priority and are discarded for transfer. They are transferred mostly in poor prognosis patients, explaining the reported lower clinical performances. However, other recent data regarding the transfer of embryos diagnosed as mosaic has shown that embryos with a low fraction of abnormal cells may result in viable, chromosomally normal ongoing pregnancies. The apparent presence of mosaicism in an embryo is used as a selection criteria for embryo transfer (ET), introducing a strong bias in terms of patient prognosis and embryo quality. Additionally, it is also possible that some embryos are incorrectly classified as mosaic due to technical variability derived from the processing of a uniform aneuploid embryo. Thus, there is an urgent need to understand how to appropriately select and counsel patients regarding such embryos. This study aims to provide evidences about the clinical significance of chromosomal mosaicism in PGT-A cycles by a prospective non-selection based methodology. The objectives are to investigate the clinical predictive value for intermediate copy number results consistent with the presence of low mosaicism in TE biopsies, and to validate the thresholds for the classification of embryos in relation with their reproductive potential, providing comprehensive data for clinicians and patients. To demonstrate these objectives, a total of 878 participants are expected to be recruited in 18 months. As the datapoints required for comparison concern embryo transfers rather than participants, this number could be lower depending on the number of embryo transfers received by each participant.

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