Chromosome Abnormality and Female Age 染色体异常和年龄之间的关系

The most relevant and recent evidences suggest that failed implantation due to embryo aneuploidy rather than failed conception is the primary cause of low human fertility. Some of the earlier studies underestimate chromosome abnormalities in spontaneous miscarriage because conventional karyotyping requires tissue culture, which is prone to maternal contamination.

最新相关的证据表明，人类生育能力低下的主要原因是胚胎非整倍体，而不是移植失败。早期的一些研究低估了自然流产案例中染色体异常的概率，因为传统的核型分析需要组织培养，而组织容易受到母体污染。

The most significant variable related to the production of aneuploid embryos is the age of the female partner. It is well known that the female age is associated with an increase in aneuploidy rate, correlated with a reduced implantation and a higher abortion rates. Direct cytogenetic analysis of human oocytes demonstrates that oocyte aneuploidy rates could reach even 50 percent for women over 40 years of age and that almost all chromosomes are involved in meiotic errors albeit with different frequencies. (1-2)

与胚胎非整倍体相关的最重要变量是女性的年龄。众所周知，女性年龄与非整倍体率的增加有关，与着床率降低和流产率升高有关。对人类卵母细胞的直接细胞遗传学分析表明，对于40岁以上的女性，卵母细胞非整倍体率甚至可以达到50%，几乎所有染色体都存在减数分裂错误的情况，尽管频率不同。(1-2)

Oocyte derived factors play a critical role in maintaining chromosome stability and euploidy in early-cleavage embryogenesis. An age-related defective cytoplasmic maturation during the antral follicle growth in older women could probably induce an alteration in spindle assembly, chromosome alignment and spindle assembly checkpoint (SAC) in a transcriptionally quiescence state of embryonic genome and in the absence of strong cell cycle control mechanisms. Since standard FISH probes combination can detect 72-83 percent of the chromosomally abnormal fetuses routinely detected by karyotyping in women of advanced maternal age it was proposed that PGD-AS should eliminate close to 80 percent of all chromosomally abnormal embryos at risk of causing a miscarriage. These data are supported by oocyte donation programs showing that older women failing to conceive with their own oocytes may conceive by using donor oocytes from younger women. Therefore,advanced-female reproductive age (ARA) (cut off varies between 35 and 40 years of age,depending on the center) was the primary indication proposed for PGD-AS in order to improve IVF outcomes and reduce chromosomal syndromes as an alternative to PND. (3-4)

卵母细胞衍生因子在早期卵裂胚胎形成中对维持染色体稳定性和整倍性起着关键作用。高龄女性窦状卵泡生长期间，与年龄相关的细胞质成熟缺陷可能导致胚胎基因组转录静止状态中纺锤体组装、染色体排列和纺锤体组装检查点的改变，并且缺乏强有力的细胞周期控制机制。由于标准FISH探针组合可以检测到72-83%的染色体异常胎儿，这些异常胎儿常规情况下是通过对高龄产妇进行染色体核型检查检测出的。预计植入前遗传学诊断-非整倍体筛查可以淘汰将近80%的可导致流产的染色体异常胚胎。这些数据有卵子捐赠项目作为支撑论点，该项目证明，不能用自己的卵母细胞受孕的高龄女性可以使用年轻女性捐赠的卵母细胞受孕。因此，为了改善体外受精结局和减少染色体综合征，作为孕期诊断的替代方案，高龄女性生殖年龄是进行植入前遗传学诊断-非整倍体筛查的主要指征(不同中心对高龄的界定不同，在35至40岁之间变化)。(3-4)

Reference数据参考

1. Gutiérrez-Mateo C, Benet J, Wells D, et al. Aneuploidy study ofhuman oocytes first polar body comparative genomic hybrid.ization and metaphase Il fluorescence in situ hybridizationanalysis. Hum Reprod 2004; 19: 2859-68.

2. Fragouli E, Wells D, Thornhill A, Serhal P, Faed MJ, Harper JC,Delhanty ID. Comparative genomic hybridization analysis ofhuman oocytes and polar bodies. Hum Reprod 2006;21:2319-28.

3. Munne S, Alikani M, Tomkin G, et al. Embryo morphology,developmental rates, and maternal age are correlated withchromosome abnormalities. Fertil Steril 1995; 64: 382-91.

4. Zheng P, Dean J. Role of Filia, a maternal effect gene, in main-taining euploidy during cleavage-stage mouse embryogenesis.PNAS 2009; 18: 7473-8.