O-004 Self-correction in human preimplantation development: What do we know?
Authors: Campbell A 
Published: August 2021

Abstract text

Recent advances in preimplantation genetic testing for aneuploidy (PGT-A) and time-lapse imaging have improved our understanding of the early human embryo confirming the variable patterns of development and chromosomal status. Aneuploidy is common and increased sensitivity in PGT-A allows the non-binary reporting of euploid-aneuploid mosaicism. The PGT-A result is the inference of the biopsied embryo’s ploidy status at a point in time, by assessment of a small percentage of cells, and, whilst concordance with the rest of the embryo is high; it is not absolute.

Many reports have demonstrated that, with the transfer of embryos with increasing severity and complexity of mosaicism, comes compromised implantation, reduced ongoing pregnancy rates and increased miscarriage rates. Segmental mosaic embryos have been reported to have slightly reduced implantation potential compared with euploid counterparts. However, complex mosaic embryos are widely reported to result in severely reduced implantation success, if transferred.

Outside of PGT-A treatment cycles, undoubtedly fertility clinics are unwittingly transferring mosaic and aneuploid embryos daily, with variable success. The transfer of embryos in which mosaicism has been detected, although associated with lower implantation and higher miscarriage rates than euploid embryos, can lead to normal pregnancies and healthy births. We know that the placenta can harbour chromosomal aberrations which are absent from the fetus, and there are few reports of births with demonstrably high levels of mosaicism through fetal development. This raises the question as to whether correction mechanisms exist. In other words, do conceptuses become chromosomally more normal as development progresses, and what are the mechanisms, if so?

PGT-A, time lapse, novel live cell imaging and in vitro model techniques have enabled a more detailed study of early embryo development and consideration of the phenomenon of self-correction. This has provided insights and hypotheses surrounding the mechanisms of development and of self-correction.

The relatively lower levels of chromosome abnormality in the blastocyst, compared with cleavage stage, are well documented and indicative of some form of correction. A recent investigation reported that a large proportion of embryos initially diagnosed as mosaic were later diagnosed as euploid when assessed at day 12 of development; providing evidence of the depletion of abnormal cells throughout the early post-implantation stages.

There are many time-lapse reports of anomalous ‘direct’ or multichotomous blastomere divisions being associated with aneuploidy, and leading to developmental arrest or reduced implantation potential and of temporal delays in aneuploid embryos compared with their euploid counterparts. It is possible, therefore, that errors and even attempts to repair them, in individual cells in the rapidly developing embryo; which involve complex biochemical systems, could delay karyo- and cytokinesis, resulting in these detectable delays. The embryonic mortality model suggests that there is selection against embryos based on their degree of aneuploidy, such that aneuploid cell lines are lost during implantation.

We know that irregularities in blastomere cleavage can generate chromosome segregation errors but these may sporadically be confined to cells excluded, or extruded, from the morula or from the blastocyst; a possible exhibition of the clonal depletion or embryo mortality model.

The trisomic/monosomic rescue model suggests that aneuploid cells can give rise to diploid cells (and possibly uniparental disomy) through mitotic chromosome losses or gains. We know that an abnormal number of pronuclei does not always produce an aneuploid blastocyst and that early embryos exhibiting multinucleation can result in healthy live births. Finally, the preferential allocation of aneuploid cells to the trophectoderm model is based on the hypothesis that euploid cells are preferentially retained in the ICM in order to achieve viability.

This presentation aims to consider what we know, and discuss the theories and available evidence for self-correction.