Developmental kinetics distinguish meiotic from mitotic chromosomal defects: Day-5 blastocyst achievement as...

While maternal age is established as a dominant reproductive risk factor, the mechanistic distinction between age-dependent meiotic errors and age-independent mitotic errors remains uncharacterized. These divergent pathways have profound implications for patient counseling and treatment stratification but are rarely differentiated clinically.

To establish distinct etiological pathways underlying chromosomal abnormalities by quantifying the differential age-sensitivity of whole-chromosome aneuploidies (meiotic origin) versus mosaic abnormalities (mitotic origin), determining whether developmental timing serves as an age-independent biomarker of genomic competence, and enabling practitioners to provide pathway-specific counseling and treatment recommendations.

PubMed, Embase, and ClinicalTrials.gov were searched for relevant studies.

Retrospective cohort of 490 IVF patients (2,472 embryos) stratified by maternal age (≤35, 35-40, ≥40 years) with complete extended culture and next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy.

Age-stratified analysis of developmental kinetics and comprehensive chromosomal classification. Multivariate logistic regression identified independent predictors of aneuploidy, adjusting for maternal age and day-5 blastocyst count.

Whole-chromosome aneuploidies demonstrated striking age-sensitivity (14.0 % to 36.5 %, 2.6-fold increase, p < 0.001), reflecting progressive cohesin complex degradation, spindle checkpoint decline, and mitochondrial bioenergetic insufficiency. Mosaicism remained age-independent (∼41 %, p = 0.383), arising from post-meiotic mitotic errors. Day-5 blastocyst formation declined 30 % with age (p = 0.0154), yet day-6 formation remained age-independent (p = 0.106), indicating developmental delay rather than failure. Day-5 blastocyst count independently protected against aneuploidy (OR 0.965, 95 % CI: 0.944-0.987, p = 0.002), persisting after multivariate adjustment.

Mechanistic differentiation between age-dependent meiotic and age-independent mitotic chromosomal abnormalities reveals fundamentally distinct etiological pathways with profound implications for clinical decision-making. In particular, day-5 blastocyst achievement emerges as an independent biomarker of oocyte quality, enabling precise within-age-group risk stratification regardless of chronological age. These findings translate developmental kinetics into quantitative clinical algorithms that substantially improve reproductive counseling accuracy and patient-specific prognostication beyond traditional age-based approaches.