Despite reports of successful outcomes and new guidelines, doubts continue to prevail over the acceptability of transferring mosaic embryos.
Two years ago an editorial in Fertility and Sterility asked if next generation sequencing was a ‘friend or foe’ in preimplantation genetic testing for aneuploidy.(1) The greater screening sensitivity of NGS, the editorial argued, offered enhanced ability to detect chromosomal abnormalities – and thereby ‘in theory’ improve ongoing pregnancy rates – but also to identify a greater number of mosaic embryos. ‘Such findings have made both clinicians and patients hesitant about considering the transfer of an embryo characterized as mosaic after NGS,’ the editorial warned. Now, a new report suggests that clinics – at least in the USA – still have no clear policy of when or if to transfer embryos identified as mosaic.(2)
The case for transferring mosaic embryos had emerged in 2015 with a letter to the New England Journal of Medicine from the group of Francisco Fiorentino in Rome which described six healthy deliveries in a small series of 18 women for whom embryo screening had found no chromosomally normal (euploid) embryos.(3) Two years later, in a preliminary report to ESHRE’s annual meeting in Geneva, Fiorentino argued that success or failure following the transfer of a mosaic embryo in ART depends on the extent of the mosaicism and aneuploidy in the embryo.(4) Results when published showed that mosaic embryos with high aneuploidy percentage (≥50%) had a significantly lower live birth rate than euploid blastocysts (15.2% vs 46.6%), while mosaic embryos with a lower aneuploidy percentage (<50%) had a clinical outcome similar to that of euploid embryos. Up to the publication of this and earlier studies, such mosaic embryos would have been considered non-viable; now, in women for whom no euploid embryos could be detected, these same mosaic embryos may well develop into healthy pregnancies. Thus, a recent report on the outcome of transferring NGS-screened embryos found that mosaics with <40% abnormal cells in the trophectoderm sample had an ongoing implantation rate of 50% compared to 27% for mosaics with 40–80% abnormal cells, and 9% for complex mosaic embryos.(5)
The latest report on everyday policies for transferring aneuploid embryos in IVF was based on a modestly supported survey to all SART-member lab directors in the USA. The survey revealed a patchwork of answers and policies, with most ‘either unsure about or unwilling to transfer embryos with mosaicism’ – although around one half agreed that a trisomy-21 embryo should be available for transfer. The survey’s conclusion was that ‘there is a clear need for specific professional guidelines to address this issue’. And a ‘reflection’ on the report in F&S agreed that ‘IVF practitioners generally hesitate to consider such [mosaic] embryos for transfer’.(6) Instead, the comment added, some clinics advise their patients to freeze mosaic embryos until more data on their viability become available.
Mosaic embryos are commonly found in PGT-A, although a recent review in the era of NGS described calculating the true prevalence of mosaicism as ‘challenging’.(7) So far, the prevalence of mosaicism in trophectoderm biopsies has been reported over a wide range - especially with NGS - and with high variation between centres. However, even those variable calculations have now been thrown into some disarray by a new study proposing that the prevalence of abnormal chromosomes in the genetic profile of early-stage embryos may be far more common – but potentially less threatening – during normal human development than is currently estimated.(8) Thus, while PGT-A analysis on a ‘snapshot’ cluster of trophectoderm cells has so far indicated a widely variable prevalence, this study’s novel technique of analysing single-cell RNA sequencing data was able to quantify ‘parameters of chromosomal mosaicism that have proven elusive to biopsy-based studies’. The result was that 80% of the 74 embryos studied contained at least one aneuploid cell across all cell types and developmental stages – prompting one of the authors to confirm that low-level mosaicism is indeed common in preimplantation embryos, and ‘may even be a normal phenotype’.
Meanwhile, the Preimplantation Genetic Diagnosis International Society (PGDIS) has updated its guidance on the transfer of mosaic embryos and, having first noted that ‘mosaic embryos represent between 5-10% of those tested’, goes on to recommend that ‘the transfer of blastocysts with a normal euploid result should generally be prioritized over those with mosaic results’, but, in considering the transfer of a mosaic blastocyst, the following options should be discussed with the patient: the initiation of a further PGT-A cycle to increase the chance of identifying a euploid blastocyst for transfer; and/or the transfer of a blastocyst with lower level mosaicism, after appropriate counselling.(9) The findings from the F&S study, however, suggest that even with guideline consensus clinics still need the reassurance of more data before routinely transferring mosaic embryos, even in patients with no euploid embryos available. And as the F&S commentary concluded, transferring mosaic (and aneuploid) embryos still remains a ‘conundrum’.
1. Fragouli E. Next generation sequencing for preimplantation genetic testing for aneuploidy: friend or foe? Fertil Steril 2018; 109: 606-607.
2. McGowan R, Pilipenko V, Smolareka TA, et al. Aneuploid embryo transfer: clinical policies and provider opinions at US fertility clinics. Fertil Steril 2020; 114: 110–7.
3. Greco E, Minasi MG, Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. N Engl J Med 2015; 373: 2089-2090.
4. Spinella F, Fiorentino F, Biricik A, et al. Extent of chromosomal mosaicism influences the clinical outcome of in vitro fertilization treatments. Fertil Steril 2018; 109: 77-83. doi.org/10.1016/j.fertnstert.2017.09.025
5. Munne S, Spinella F, Grifo J, et al. Clinical outcomes after the transfer of blastocysts characterized as mosaic by high resolution Next Generation Sequencing - further insights. Eur J Med Genet 2020; 63: doi.org/10.1016/j.ejmg.2019.103741
6. Fragouli E. Preimplantation genetic testing for aneuploidy: the conundrum with aneuploid embryo transfers. Fertil Steril 2020; doi.org/10.1016/j.fertnstert.2020.04.008
7. Popovic M, Dhaenens L, Boel A, et al. Chromosomal mosaicism in human blastocysts: the ultimate diagnostic dilemma. Hum Reprod Update 2020; doi:10.1093/humupd/dmz050
8. Starostik MR, Sosina MR, McCoy R. Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism. Genome Res 2020; doi/10.1101/gr.262774.120.
9. Cram DS, Leigh D, Handyside A, et al. PGDIS Position Statement on the Transfer of Mosaic Embryos 2019. Reprod Biomed Online 2019; doi: 10.1016/j.rbmo.2019.06.012