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The secret of age—maternal age and embryo aneuploidy


The chromosomal abnormality (aneuploidy) rate increases with maternal age.


By analyzing with next-generation sequencing, more precise information can be obtained.

Preimplantation genetic screening (PGS) is an examination to screen the embryos with abnormal dosage of chromosomes (aneuploid) in the IVF realm, and it is strongly recommended to the women with advanced maternal age or undergoing recurrent miscarriage. By excluding the aneuploid embryo transfer, the success rate of IVF can be significantly improved.


The newly released platform of comprehensive chromosome screening (CCS) in 2014 is next-generation sequencing (NGS). The PGS/NGS have better resolution to detect the low-rate aneuploiy in the embryo biopsy, and the low-rate aneuploidy is known as the pure mosaicism (diploid and aneuploid mixture). By using high-resolution Next-generation sequencing (NGS) to analyze the relationship between maternal age and blastocysts as different ploidies in preimplantation genetic screening (PGS) in 1736 embryos, the result was shown as below,



(The involved embryos were from women aged 21 to 46 years and biopsied on Day 5 and 6: 363 embryos from egg donors (20.9%), and 1373 from non-donors (80.1%). The PGS/NGS includes whole-genome amplification and following sequencing (Miseq®). The copy number variation was analyzed by BlueFuse Multi® software. Absolutely aneuploid was defined as over 50% of aneuploidy, and low-rate aneuploid as between 20% to 50%, and absolutely euploid as under 20%.)

Every woman can always keep one secret—the secret of her age. However, the women can choose not to speak out her age, but can't choose to hide her age. The human body can release one's age by many ways, including the ovarian reserve, hormone levels, and the aneuploid rate of her embryos. The aneuploid rate of each age was shown as below,


Of absolutely aneuploid rate, the percentage continuously increased with the maternal age. The embryo aneuploidy showed lowest in women aged 26 to 29 years and dramatically increased in women over 34 years by non-linear (R2=0.815) and linear regression analyses (R2=0.849), respectively.

The aneuploid rate of embryo increases with maternal age. It is because that the incidence of meiotic errors during the oogenesis is significantly higher in older women, and the main causes to the anomalies are nondisjunction and anaphase lagging. Intriguingly, the mosaicism rate (combining the abnormal mosaic and pure mosaic) remains constant among each age span (around 25%).


 The actual mechanism of mosaicism has not been validated, and it is believed to relate with the mitotic errors during the first three cell divisions. The main causes of these errors might be the culture condition (varied dramatically in the different labs) or male factors (post-zygotic errors).




Conclusively, the aneuploid rate significantly increases with the maternal age in women over 34 years and is lowest at age spanning 26 to 29 years; the mosaicism rate stays constant at each age span (around 25%). The results reflects that the embryo aneuploidy are mainly due to meiotic errors affecting by maternal age, but the embryo mosaicism are mostly caused by mitotic errors, which occur during the post-zygotic stage and do not relate to the maternal age.

References:
Munné S, Grifo J, Wells D. Mosaicism: "survival of the fittest" versus "no embryo left behind". Fertil Steril. 2016;105:1146-1149.
Data were analyzed from the Stork Fertility Center and released in the annual meeting of 2016 Taiwan Society of Reproductive Medicine.
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