O-020 Aneuploidy and mosaicism in human embryos: How correct detection may improve IVF clinical outcomes
Authors: Munne S , Fragouli E 
Published: August 2021

Abstract text

Study question
Can new next-generation sequencing (NGS) based strategies for preimplantation genetic testing of aneuploidy (PGT-A) improve clinical outcomes after assisted reproductive technology (ART)?

Summary answer
Recent randomised controlled trials (RCTs) suggest that NGS-based PGT-A strategies can improve clinical outcomes for older women. The clinical management of mosaic embryos remains controversial.

What is known already
There are two types of chromosome abnormalities present in embryos, meiotic arising mostly during oogenesis, and mitotic arising after fertilisation. Meiotic aneuploidies are present in all of the embryonic cells and in their vast majority are lethal. Conversely, mitotic abnormalities are present in only part of the embryonic cells with the remaining cells having a different cytogenetic constitution. This phenomenon is known as mosaicism. The sensitivity of NGS meant that mosaic aneuploidy became readily detectable in trophectoderm (TE) samples during PGT-A. The viability and clinical management of mosaic embryos has led to debates and controversies in the reproductive medicine field.

Study design, size, duration
The study involved an assessment of the impact of mosaic chromosome abnormalities to embryonic viability and clinical outcomes after ART cycles using PGT-A via NGS. A large number of embryos generated in IVF clinics in Europe and the USA was examined.

Participants/materials, setting, methods
Embryos were generated by couples referred for PGT-A due to various indications. All embryos were cultured to the blastocyst stage, and underwent a TE biopsy, followed by vitrification. TE samples were shipped to 6 reference PGT laboratories and analysed via the use of the same NGS platform. Mosaic chromosome abnormalities were scored according to validated thresholds set by the reference laboratories. The clinical management of mosaic embryos took place according to published guidelines.

Main results and the role of chance
Comparison of clinical outcomes seen after the transfer of mosaic embryos with those seen after the transfer of euploid embryos led to the following findings:
Mosaic embryos with &lt;40% abnormal cells in the TE sample had an OIR of 50% compared to 27% for mosaics with 40–80% abnormal cells in the TE, and 9% for complex mosaic embryos. Karyotyping of ongoing pregnancies resulting after the transfer of mosaic embryos demonstrated a normal chromosome constitution of the resulting foetuses.

Limitations, reasons for caution
- Cytogenetic classification was based on TE samples removed from blastocysts during PGT-A analysis. As only a fraction of the cells from each embryo are tested, inevitably some mosaic embryos will be incorrectly classified fully euploid or aneuploid. However, this misclassification is expected to have little impact on the results.

Wider implications of the findings
- The transfer of NGS-classified mosaic embryos was associated with poorer clinical outcomes compared to euploid embryos. However, the ongoing pregnancies resulting from mosaic transfers were euploid. NGS’s ability to identify embryos of reduced viability has the potential to improve IVF clinical outcomes.