O-104 Determining the pre- and post-fertilization origins of aneuploidies: a new paradigm in assisted reproduction to substantially enhance embryo selection

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Abstract Study question To investigate the clinical utility of preimplantation genetic testing for aneuploidy origin (PGT-AO), which determines the meiotic/mitotic origin of aneuploidies and their level of mosaicism. Summary answer PGT-AO together with sequencing-based PGT-M avoids unnecessary transfer of embryos with meiotic trisomies and most monosomies. Determining meiotic/mitotic origin based on mosaicism level is incorrect. What is known already Rising global parental age increases aneuploidy risk in offspring, driving demand for advanced PGT. Preimplantation genetic testing for aneuploidy (PGT-A) is widely used in in vitro fertilization for embryo selection. However, large clinical trials have questioned its efficacy, as current PGT-A may discard viable embryos. PGT-A overlooks the mosaic nature of embryos, causing concern in the field, since it is now evident that mosaic embryos, i.e. embryos that contain both euploid and aneuploid cells, may lead to healthy live births. We evaluated the clinical utility of PGT-AO, which determines the meiotic/mitotic origin of aneuploidies. Study design, size, duration In a nationwide non-selection study, we retrospectively analyzed the genomes of 5,975 embryos sequenced for PGT for monogenic disorders (PGT-M) using either genotyping-by-sequencing (n = 2,493) or whole-genome sequencing (n = 3,482). Genome haplarithmisis determined the meiotic/mitotic origin of aneuploidies and their mosaicism level. The aberrations were correlated with recorded clinical outcomes, such as birth status, heart rate, HCG status, ovarian stimulation protocol and duration, maternal and paternal age, endometrial thickness, and pregnancy complications. Participants/materials, setting, methods Couples were counseled by clinical geneticists at University Medical Centers (UMCs) of the Netherlands, in Maastricht, Amsterdam, Utrecht, and Groningen, and enrolled in the diagnostic PGT procedure after signing an informed consent form. Embryos (n = 946) eligible for transfer based on PGT-M (i.e. chromosomal aneuploidies were not accounted for) are analyzed by haplarithmisis-based PGT-AO including parental information. This information allows for the detection of chromosomal abnormalities and their mosaicism, and parental and segregational origin. Main results and the role of chance Among 946 transferred embryos, 253 (26.7%) resulted in a live birth, while 693 (73.3%) failed, including implantation failure (n = 546, 78.8%), early embryonic arrest (n = 104, 15.0%) and pregnancy loss (n = 43, 6.2%). All embryos with a meiotic trisomy failed, whereas 17.0% of embryos with a mosaic mitotic trisomy resulted in a healthy live birth. Furthermore, only 6.8% of monosomic embryos lead to a healthy live birth. Remarkably, different ovarian stimulation protocols affected transfer outcomes and aneuploidy rates. Maternal age at ovum pickup is positively correlated with meiotic trisomy rate in contrast to mitotic trisomy rate. Our results show embryos with meiotic trisomies and most monosomies should not be selected for embryo transfer. In contrast to embryos with meiotic trisomies, embryos with mitotic trisomies are often mosaic and the abnormality may not be uniformly distributed throughout the blastocyst and could potentially be considered for transfer. Limitations, reasons for caution Haplarithmisis relies on the inclusion of parental DNA to phase the embryonic genome and thus determine the segregational origin of aberrations. Additionally, mitosis and meiosis II trisomies cannot be discerned when there is no crossover event in the chromosome of interest. Wider implications of the findings Embryos with meiotic trisomies and most monosomies should be considered non-viable, while those with mitotic trisomies may result in live births. PGT-AO combined with sequencing-based PGT-M avoids unnecessary embryo transfer. If applied non-invasively, it may increase successful embryo transfers following IVF. We envision PGT-AO making a paradigm-shift in embryo selection. Trial registration number No

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