REPRODUCTIVE GENETICS

RCT finds that previously unobserved factors contribute to oocyte aneuploidy in women aged over 35

Chromosomes DNA

Published 30 November 2023

New evaluation of the ESHRE Study into the Evaluation of oocyte Euploidy by Microarray analysis (ESTEEM) has shown that mechanisms other than abnormal chromosome segregation can cause errors during meiosis.

The older a woman is, the greater the risk that her embryos will be affected by multiple chromosome abnormalities. And the widely held view is that these errors are caused solely by chromosome mis-segregation during both stages of cell division in meiosis.

However, that belief has now been challenged by the authors of a multicentre RCT who say other factors should also be considered. Through thorough chromosomal analyses of a high number of polar bodies (PBs), their study provides evidence of frequent unexpected chromosomal segregation during oogenesis. It also allows better understanding of the effects of chromosomal abnormalities present in the oocyte on embryo development.

The findings (1) based on data sourced from the ESTEEM trial (2) represent one of the largest analyses of its kind, and add to the understanding of low pregnancy rates, pregnancy loss and birth defects among advanced maternal age (AMA) women.

In their recently published paper, the authors write that their results indicate that knowledge of the mechanisms causing aneuploidy in oocytes is ‘incomplete’. They go on to say that their finding around copy numbers ‘challenges the dogmas that aneuploidy in oocytes is exclusively caused by mis-segregation of chromosomes during MI (meiosis I) and MII (meiosis II).’

To date, there has been little research into the underlying mechanisms which give rise to an abnormal number of chromosomes during female meiosis. The studies that have explored this issue have only included a small number of PB pairs for analysis.

The original ESTEEM trial was performed in seven European centres to assess if genetic testing for aneuploidy (PGT-A), by screening both PBs using array comparative genomic hybridization, increased the chance of live birth in ICSI patients aged 36 to 40 years compared with ICSI without PGT-A.

The present study re-evaluated the ESTEEM data based on 693 PB pairs from 396 advanced maternal age women (AMA) (n=205 PGT-A intervention group; n=191 control). This was to characterise the types of chromosomal abnormalities and the chromosomes most frequently affected.

In addition, the aim was to determine what processes take place in the oocytes of AMA patients to cause aneuploidy, and to evaluate any correlation with embryo quality.

The morphology from 1,034 embryos generated from fertilized oocytes (two pronuclei) in the PB biopsy group and 1,082 in the control group were used for statistical analysis.

Results showed that more than two-thirds (n=461/693) of PB pairs showed abnormal segregation in 1,162 out of 10,810 chromosomes.

Of these abnormal segregations, the majority (n=1,050/1,162; 90%) were known segregation errors. Almost half were compatible with precocious separation of sister chromatids in MI (n=568/1,162; 48.9%), over a third with non-disjunction (ND) of chromatids in MII or reverse segregation (n=417/1,162; 35.9%), and less frequently ND in MI (n=65/1,162; 5.6%).

However, the authors say unknown errors were identified in 10% of chromosomes (n=112/1,162) with abnormal PB segregation. In these cases, they say they observed a (chromosome) copy number in the first PB and second PB that could not be explained ‘by any of the known mechanisms causing aneuploidy in oocytes’.
The authors suggest that premeiotic aneuploidy could explain their findings; or alternatively anaphase lagging may have occurred.

Embryos in the PGT-A arm of the RCT did not have a significantly different morphology between 2- and 6-days post-insemination compared to the control group. As such, this indicates that PB biopsy did not affect embryo quality.

Age-adjusted analysis was performed for each embryo evaluation day. Results showed aneuploidy was associated with a decrease in embryo quality on Day 3 (adjusted odds ratio (aOR) 0.62, 95% CI 0.43–0.90), Day 4 (aOR 0.15, 95% CI 0.06–0.39), and Day 5 (aOR 0.28, 95% CI 0.14–0.58). This novel finding that shows embryo development and oocyte chromosome status are interlinked; and is without biased unlike the selection of embryos for biopsy, say the authors.

Limitations of the study included the fact that it was performed in several laboratories and IVF units. The consequence is that the interpretation of results may have varied between centres.

Analysis of oocyte aneuploidy could only be carried out indirectly by PB testing because the oocyte/embryo was unavailable for confirming the expected segregations.

The authors say that the ‘significant number’ of PBs analysed allowed them not only to detect unexpected types of chromosomal segregation, but also to understand better the effects of abnormal meiosis on embryo development.

This enhanced understanding, they add, could lead to intervention strategies in future that could ‘mitigate these detrimental effects’ and reduce the risk of their occurrence.


References:
1 Verdyck P, Altarescu G, Santos-Ribeiro S, Vrettou C, Koehler U, Griesinger G, Goossens V, Magli C, Albanese C, Parriego M, Coll L, Ron-El R, Sermon K, Traeger-Synodinos J. Aneuploidy in oocytes from women of advanced maternal age: analysis of the causal meiotic errors and impact on embryo development. Hum Reprod 2023; dead201, https://doi.org/10.1093/humrep/dead201

2 Verpoest W, Staessen C, Bossuyt PM, Goossens V, Altarescu G, Bonduelle M, Devesa M, Eldar-Geva T, Gianaroli L, Griesinger G, Kakourou G, Kokkali G, Liebenthron J, Magli MC, Parriego M, Schmutzler AG, Tobler M, van der Ven K, Geraedts J, Sermon K. Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial. Hum Reprod. 2018 Sep 1;33(9):1767-1776. doi.org/10.1093/humrep/dey262. PMID: 30085138

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