Preimplantation genetic testing for aneuploidy mosaicism reporting lacks clinical predictive value for live birth in...

Preimplantation genetic testing for aneuploidy is used to improve in vitro fertilization outcomes by identifying embryos with lethal chromosomal abnormalities that impair development or lead to pregnancy loss. The adoption of next-generation sequencing has enabled detection of intermediate copy number deviations, often interpreted as putative mosaicism, whose clinical significance remains uncertain.

To determine whether reporting putative mosaicism based on intermediate copy number improves the prediction of reproductive outcomes and should influence embryo selection in clinical practice.

We conducted a large, multisite, double-blinded, nonselection study across US fertility clinics (February 2020-October 2022), including 9828 single-embryo transfers from 7564 in vitro fertilization cycles. Findings were independently validated using 5487 euploid single-embryo transfers from European clinics (May 2022-March 2024). Intermediate copy number status was unblinded only after embryo transfer, allowing unbiased comparison between embryos that would have been classified as euploid or mosaic with our platform. The primary outcome for investigation in the study was live birth rate, defined as delivery after 24 weeks (gestational age).

After unblinding the intermediate copy number status post-transfer, 84.7% (n=8328) of embryos were negative for intermediate copy number (euploid), while 8.8% (n=864) exhibited segmental intermediate copy number and 5.6% (n=562) showed whole-chromosome intermediate copy number within the current clinical and laboratory setting. A modest but statistically significant difference in live birth rate was observed between euploid embryos and those with intermediate copy number (60.0% vs 53.2%; adjusted odds ratio, 0.79; 95% confidence interval, 0.70-0.89), primarily driven by the small subset of embryos with high-level intermediate copy number (P<.001; odds ratio, 0.61; 95% confidence interval, 0.49-0.75). However, intermediate copy number did not enhance predictive models incorporating established clinical and embryological factors (area under the curve=0.552 vs 0.555; all P>.05). Miscarriage, obstetric, and neonatal outcomes were comparable across groups.

Although the presence of high-level intermediate copy number in the trophectoderm biopsy was associated with a modest reduction in live birth rate, because of its low incidence and limited effect size, mosaic reporting did not contribute to a meaningful improvement in clinical outcomes. In our clinical and laboratory setting, reporting putative mosaicism provides no clinical benefit and should not guide embryo selection in routine in vitro fertilization practice.