Popa, Teodora; (2024) Investigating the relationship between chromosomal imbalance and human pre-implantation embryo development in vitro, using time-lapse imaging, artificial intelligence, and genomic data. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis investigates the biological mechanisms underlying human pre-implantation embryo development, particularly focusing on embryo aneuploidy, and their role in advancing new technologies within the field of assisted reproduction. By incorporating data on embryo development through time-lapse imaging, embryo genetics through pre-implantation genetic testing for aneuploidy (PGT-A) data, and clinical outcome information, a comprehensive database was created to facilitate a data-driven approach to understanding early embryo development. Overall, the database encompasses over 2 million data points from 8000+ human embryos, facilitating detailed analyses into the complex relationships between early embryo development in vitro, embryo genetics and embryo viability. The results reveal a synergistic correlation between abnormal cleavage during the first embryo division and embryo fate that could potentially be used as a non-invasive tool for embryo viability assessment. The phenomenon of embryo mosaicism was then investigated in embryos clinically classified as ‘mosaic’ by NGS-based PGT-A. Employing SNP genotyping and karyomap analysis to interrogate the origin of aneuploidy (i.e. meiotic versus mitotic aneuploidy) revealed that 30% of embryos classified as mosaic displayed signatures of meiotic origin and might have been misclassified as mosaic by NGS-based PGT-A. Next, the traditional fertilisation check via visual pronuclei (PN) count was assessed in relation to its accuracy for predicting embryo triploidy/haploidy in the case of 3PN and 1PN embryos, respectively. The results revealed that the majority of embryos initially classified as being abnormally fertilised are, in fact, diploid and could have potentially been rescued through the use of a ‘genetic fertilisation check’. Finally, widely used embryo assessment strategies, including both manual and artificial intelligence (AI)- powered approaches, were investigated concerning sex bias. Surprisingly, XY embryos received higher scores compared to XX embryos and were favoured for transfer, potentially having important consequences for population dynamics. Overall, by advancing the understanding of embryo development and aneuploidy, this work paves the way for advancements in reproductive technologies, with the aim of ultimately improving outcomes for IVF patients.

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