PGT-A Mosaicism Reporting Lacks Clinical Predictive Value: Evidence from a Multisite, Double-Blinded Study with Independent Validation Across 15,315 Single-Embryo Transfers

Abstract

Preimplantation genetic testing for aneuploidy (PGT-A) aims to improve IVF outcomes by identifying embryos with lethal chromosomal abnormalities leading to impaired embryonic development and pregnancy loss, particularly with advancing maternal age. The adoption of next-generation sequencing (NGS) has enabled the detection of subtler chromosomal variations of uncertain clinical significance, such as intermediate copy number (ICN), leading to the classification of putative mosaicism. To assess the clinical utility of mosaicism reporting in PGT, we conducted a large, multi-site, double-blinded, non-selection study across U.S. fertility clinics (Feb 2020-Oct 2022), analyzing 9,828 single embryo transfers (SETs) from 7,564 IVF cycles. The findings were independently validated using a separate dataset of 5,487 euploid SETs from European clinics (May 2022-March 2024), representing a distinct patient population with different clinical characteristics. This design allowed for ICN values to be unblinded post-transfer, enabling unbiased comparisons between embryos that, under a mosaic reporting framework, would have been labeled as mosaic or euploid. In both cohorts, the presence of ICN showed no significant impact on clinical outcomes when mosaicism status was blinded and evaluated alongside established clinical and embryological parameters. AUROC analysis revealed no meaningful difference in predictive performance between models with and without ICN data (AUC = 0.552 vs. 0.555; 0.569 vs. 0.578; all P > 0.05). Miscarriage, obstetric, and neonatal outcomes were also comparable. These findings strongly suggest that reporting putative mosaicism based on ICN lacks clinical utility and should not be used to inform embryo selection policies.