O-003 Non-invasive metabolic profile of embryo culture media for preimplantation genetic diagnosis of aneuploidy

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Abstract Study question Is it possible to determine the human embryo ploidy by analyzing embryonic culture media using proton nuclear magnetic resonance (1H-NMR)-based metabolomics? Summary answer Preliminary results demonstrated that 1H-NMR-based metabolomics could identify metabolic markers indicative of embryo ploidy. What is known already The current screening methods of early embryo aneuploidy diagnostics struggle with several limitations such as invasiveness, being very time-consuming and costly, requiring highly specialized technicians, and several embryo manipulation steps. To address these limitations, there are currently three trending research areas: associate time-lapse microscopy with AI-based models; analysis of cell-free DNA released by the embryo into the medium; and the correlation metabolomic/proteomic biomarkers present in the spent embryo culture media (SECM) to assess embryo viability. In this study, we propose to develop a method for detecting specific aneuploidy biomarkers in SECM using 1H-NMR Study design, size, duration We conducted a single-center prospective sibling case-control pilot study, assigning paired-sibling embryo culture media (one aneuploid, one euploid) to minimize confounding variables. A total of 76 SECM samples were collected from 38 pairs on days 3 and 5/6. Here we report the outcomes of the first 7-paired embryos (1 aneuploid and 1 euploid per couple) analyzed via 1H-NMR spectroscopy to develop a predictive model, along with 12 unpaired embryos used to test the model. Participants/materials, setting, methods This study included patients who underwent PGT-A. Embryos were cultured in a time-lapse incubator, and SECM were collected from two sequential periods of embryo incubation (day 3 and 5 or 6 after fertilization) and subsequently analyzed by 1H-NMR. Metabolite concentration of SECM from aneuploid and euploid embryos and embryo-free media groups were used for univariate and multivariate statistical analysis, and used to create a prediction model. Main results and the role of chance Seven paired SECM samples from euploid and aneuploid embryos were analyzed using 1H-NMR, allowing for the quantification of 18 metabolites on day 3 and 23 metabolites on day 5 of embryo development. Multivariate statistical analysis produced partial-least square discriminative analysis (PLS-DA) model capable of distinguishing between euploid and aneuploid embryos at both time points. On day 3, euploid embryos demonstrated lower metabolic activity, particularly in amino acid turnover pathways, which increased by day 5. These findings indicate that euploid embryos preferentially absorb metabolites associated with osmoregulation, ammonia removal, and antioxidant functions—critical factors for embryo health. Predictive models developed using discriminant metabolites (5 on day 3 and 11 on day 5) achieved ploidy prediction accuracies of 92% and 83%, respectively. This study highlights that ploidy directly impacts an embryo’s metabolic activity and that a classification model can effectively differentiate between euploid and aneuploid embryos at both stages. Furthermore, the altered SECM profiles observed in aneuploid embryos compared to euploid ones underscore the potential of this approach. Limitations, reasons for caution These are preliminary results of a prospective sibling case-control pilot study, therefore, results should be interpreted with caution taking into account the small sample size. Wider implications of the findings This research study aims to validate SECM analysis by NMR spectroscopy as a faster cost-effective alternative to PGT-A. By offering a non-invasive and accurate predictive model, this workflow could be a valuable addition to clinical practice, potentially reducing time-to-pregnancy, costs, and the risks associated with invasive methods of aneuploidy diagnosis. Trial registration number No

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