Rethinking Mosaicism: Why Reporting Putative Mosaic Embryos Fails to Improve IVF Outcomes

Introduction: The Dilemma of the Mosaic Embryo

For decades, preimplantation genetic testing for aneuploidy (PGT-A) has been a cornerstone of advanced reproductive technology, designed to identify chromosomal abnormalities that would otherwise lead to implantation failure or pregnancy loss. However, the transition from older technologies to highly sensitive next-generation sequencing (NGS) has introduced a complex clinical challenge: the detection of intermediate copy number (ICN) deviations, commonly referred to as mosaicism. While the industry has rushed to categorize these embryos, a critical question remains: does reporting these findings actually improve a patient’s chance of having a healthy baby? A landmark multisite study, recently published in the American Journal of Obstetrics and Gynecology, suggests that the answer may be a definitive no.

The Evolution of PGT-A and the Rise of ICN

The primary goal of PGT-A is to distinguish between euploid embryos (those with a normal set of 46 chromosomes) and aneuploid embryos (those with an incorrect number of chromosomes). As sequencing resolution increased, laboratories began identifying biopsies where some cells appeared normal and others appeared abnormal—a state termed mosaicism. In clinical practice, embryos labeled as mosaic are often deprioritized or discarded, causing significant emotional and financial stress for patients who may have few other options. Despite its widespread adoption, the clinical predictive value of reporting ICN has been a subject of intense debate, largely due to a lack of high-quality, blinded data.

Study Design: A Double-Blinded, Non-Selection Approach

To address this evidence gap, researchers conducted a large-scale, multisite, double-blinded, non-selection study. This methodological gold standard ensures that the ICN status of an embryo does not influence the decision to transfer it, thereby eliminating selection bias. The study, conducted between February 2020 and October 2022 across several U.S. fertility clinics, included 9,828 single-embryo transfers (SETs) from 7,564 IVF cycles. The findings were further validated using a European cohort of 5,487 euploid SETs between 2022 and 2024.

The key innovation of this study was the unblinding process. ICN status was revealed only after the embryo transfer had occurred. This allowed the research team to compare outcomes between embryos that would have been classified as euploid and those that would have been labeled as mosaic under current laboratory standards, without the clinicians or patients knowing the classification at the time of transfer. The primary endpoint was the live birth rate (LBR), defined as delivery after 24 weeks of gestation.

Key Findings: Does ICN Predict Success?

Live Birth Rates and Effect Sizes

After unblinding the data, the researchers found that 84.7% of the embryos were negative for ICN (euploid), while 8.8% exhibited segmental ICN and 5.6% showed whole-chromosome ICN. When comparing the groups, a modest but statistically significant difference in live-birth rates was observed. Euploid embryos resulted in a 60.0% live birth rate, compared to 53.2% for those with ICN (adjusted Odds Ratio [OR] 0.79, 95% CI 0.70-0.89). This reduction was primarily driven by a small subset of embryos with high-level ICN, where the OR was 0.61.

Predictive Modeling and AUC Analysis

While the difference in birth rates reached statistical significance, the clinical utility of a marker depends on its predictive power. Researchers used Area Under the Curve (AUC) analysis to determine if adding ICN status to existing clinical models (which include factors like maternal age and embryo morphology) improved the ability to predict a live birth. The results were telling: the AUC only shifted from 0.552 to 0.555. In clinical terms, this change is negligible, indicating that ICN status does not provide meaningful information beyond what is already known from standard clinical and embryological factors.

Safety and Neonatal Outcomes

One of the primary concerns regarding mosaic embryos is the potential for increased miscarriage rates or adverse neonatal outcomes. However, this study provided reassuring data. Miscarriage rates, obstetric complications, and neonatal health markers were comparable between the euploid and ICN groups. This suggests that while an ICN embryo might have a slightly lower chance of resulting in a pregnancy, if it does result in a pregnancy, the safety profile is essentially equivalent to that of a strictly euploid embryo.

Clinical Implications: To Report or Not to Report?

The findings of this study challenge the current practice of reporting mosaicism in routine IVF. The authors conclude that because of its low incidence and limited effect size, reporting putative mosaicism provides no clinical benefit. In fact, reporting these findings may do more harm than good by leading to the deprioritization or disposal of embryos that have a high probability of resulting in a healthy live birth. For clinicians, this means that an embryo’s ICN status should likely not be a primary factor in selection, especially when the alternative is no transfer at all.

Expert Commentary and Methodological Strengths

The strength of this study lies in its double-blinded, non-selection design and its large sample size. Previous studies on mosaicism were often retrospective or influenced by selection bias—where only “low-level” mosaics were transferred, or mosaics were only transferred as a last resort. By transferring all embryos regardless of ICN status and only unblinding the data later, this study provides the most accurate assessment to date of the true reproductive potential of these embryos. Experts in the field note that these results should prompt a re-evaluation of PGT-A reporting standards globally, moving toward a more binary (euploid vs. aneuploid) reporting system to simplify clinical decision-making and maximize patient success.

Conclusion: Moving Beyond the Mosaic Label

The clinical management of mosaic embryos has been one of the most contentious issues in modern reproductive medicine. This study provides much-needed clarity, demonstrating that while ICN is associated with a slight decrease in live birth rates, it lacks the predictive value necessary to justify its use in routine embryo selection. For the thousands of patients undergoing IVF, these results offer hope that more of their embryos may be viable than previously thought, and for the medical community, it serves as a reminder to prioritize data-driven outcomes over technological sensitivity.

References

Gill P, Tao X, Zhan Y, et al. PGT-A Mosaicism Reporting Lacks Clinical Predictive Value For Live Birth in a Multisite, Double-Blinded Study with Independent Validation. Am J Obstet Gynecol. 2025 Dec 16:S0002-9378(25)00930-5. doi: 10.1016/j.ajog.2025.12.033. Epub ahead of print. PMID: 41412422.