TOPLINE:

Reporting putative mosaicism based on intermediate copy number in preimplantation genetic testing for aneuploidy (PGT-A) provides no clinical benefit for predicting live birth in in vitro fertilization (IVF) cycles, according to a large multisite, double-blinded study. Among 9828 single-embryo transfers in the primary cohort, live birth rates were 60.0% vs 53.2% for euploid embryos vs those with intermediate copy number, but mosaicism status did not enhance predictive models when evaluated alongside established clinical and embryological factors.

METHODOLOGY:

• Researchers conducted a multisite, double-blinded, prospective nonselection cohort study between February 2020 and October 2022 across five fertility clinics in the US, with independent validation in 17 clinics in Spain from May 2022 to March 2024.
• A total of 9828 single-embryo transfers from 7564 IVF cycles were included in the primary US cohort, with 5487 single-embryo transfers from 4555 IVF cycles in the European validation cohort.
• All embryos underwent trophectoderm biopsy and PGT-A using the PGTSeq-A assay, a targeted next-generation sequencing platform; intermediate copy number status remained blinded to clinicians and patients until after embryo transfer and outcome data collection.
• Participants included women aged 18-45 years at oocyte collection, with embryos transferred to women with BMI < 45; embryos from patients undergoing PGT for monogenic disorders or structural chromosome rearrangements were excluded.
• The primary outcome was live birth rate, defined as delivery after 24 weeks of gestational age; secondary outcomes included clinical pregnancy rate, miscarriage rate, and maternal and neonatal adverse outcomes.

TAKEAWAY:

• After unblinding, 84.7% of embryos were negative for intermediate copy number (euploid), while 8.8% exhibited segmental intermediate copy number and 5.6% showed whole-chromosome intermediate copy number; 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 [OR], 0.79; 95% CI, 0.70-0.89).
• The association was primarily driven by embryos with high-level intermediate copy number (≥ 50% deviation), which showed reduced live birth potential (P < .001; OR, 0.61; 95% CI, 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; P > .05).
• Miscarriage rates were comparable between euploid embryos and those with intermediate copy number (7.6% vs 7.9%; P = .4893; OR, 1.08; 95% CI, 0.87-1.34), with no significant differences observed in obstetrical and neonatal outcomes across groups.
• According to the authors of the study, receiver operating characteristic curve analyses and decision tree modeling confirmed that mosaicism status did not contribute additional predictive value for live birth when evaluated alongside day of biopsy, morphology score, female age, BMI, and prior embryo transfer failures.

IN PRACTICE:

“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, mosaicism reporting does not lead to a meaningful improvement in the prediction of reproductive outcomes and should not guide embryo selection in routine in vitro fertilization practice,” wrote the authors of the study.

SOURCE:

The study was led by Pavan Gill, MD, IVIRMA, Clinical Research, Basking Ridge; Xin Tao, PhD, Juno Genetics, Basking Ridge, New Jersey; and Antonio Capalbo, PhD, Juno Genetics, Rome, Italy. It was published online in the American Journal of Obstetrics & Gynecology.

LIMITATIONS:

According to the authors of the study, the findings may be specific to the PGTSeq platform used across all clinical practices in both cohorts and may not be generalizable to other PGT-A methodologies, underscoring the need for prospective, blinded studies to assess the predictive value of mosaicism findings across different platforms. Information on prior embryo transfer failures was limited to records from referring clinics and did not include reproductive treatments performed elsewhere, and obstetrical and neonatal outcomes were self-reported, introducing potential reporting bias. The study lacks sufficient power to explore chromosome-specific associations between intermediate copy numbers and clinical outcomes because larger studies are needed to determine whether specific combinations of chromosomes and intermediate copy number types have distinct impacts on clinical outcomes. The availability and completeness of patient clinical data were limited, and not all pregnancy and neonatal outcomes recorded in the US cohort were available for assessment in the European validation setting.

DISCLOSURES:

No conflicts of interest statements or disclosures are provided in the study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.