Previously reported and here added cases demonstrate euploid pregnancies followed by PGT-A as “mosaic” as well as “aneuploid” designated embryos

Though proponents of PGT-A claim that a single trophectoderm biopsy (TEB) can distinguish between “mosaic” and “aneuploid” embryos, a single, on average 5-cell TEB, for biological as well as mathematical reasons, simply cannot discriminate between “mosaic” and “aneuploid” embryos [1, 4, 5]. A biological main reason is that TE and fetus derive from different cell lineages (extraembryonic and embryonic, respectively), which at preimplantation stages do not always correspond in respective ploidy. Both of these lineages downstream from the blastocyst stage, in addition, differ in their respective abilities to exclude aneuploid cells and, thereby, allow for selective self-correction in the embryonic lineage of the epiblast, while failing to do so in the extraembryonic lineage-producing trophectoderm and, ultimately, the placenta [12]. This difference is documented by the observation that chromosomally euploid and perfectly normal newborns still deliver with placentas with, often, considerable confined placental aneuploidy and an amalgam of genomic mutations [13]. Unsurprisingly, mathematical modeling, therefore, demonstrated indisputably that, even under the most favorable statistical assumptions, a 5-cell TEB (this is the number of average TE cells in a single biopsy claimed in the literature) cannot inform on the status of a complete embryo. To do so would require over 20 cells [14].

An even more important biological argument against differentiating between “mosaic” and “aneuploid” embryos when it comes to their transferability lies, however in how the PGT-A industry incorrectly defined “mosaicism” since 2016 [1, 4, 5]. While under uniform biological consensus, this term describes a single organism (in this case an embryo) that contains more than a single normal 46, XX, or 46, XY cell lineage, PGT-A laboratories describe an embryo incorrectly as “mosaic” (and, therefore the use of quotation marks) if only a single TEB of only approximately 5 cells contains more than a single normal 46, XX or 46, XY cell lineage.

The difference between the correct biological definition of mosaicism and the PGT-A definition, therefore, in itself, is disqualifying PGT-A from defining the correct ploidy status of an embryo after a single TEB at blastocyst-stage. It, indeed, does not take special genetics expertise to understand that, for this reason alone, a PGT-A diagnosis of “euploidy” or “aneuploidy” is practically worthless: “Euploidy,” even if all 5 biopsied cells are euploid, does not mean that “aneuploid” cells may not exist elsewhere in the embryo. The correct diagnosis of this embryo then, however, would be mosaicism, and not “euploidy.” Similarly, a diagnosis of “aneuploidy,” based on all 5 cells of a TEB being aneuploid, is worthless because most of the rest of the embryo may be euploid if only an island of aneuploidy was accidentally biopsied. Since a large majority of aneuploidies at blastocyst-stage are of mitotic origin, they are clonal and insular. Here, too, the correct diagnosis of the embryo would be mosaicism, and not “aneuploidy.” Considering how much more frequent mitotic than meiotic aneuploidies are, one is left with the conclusion that most PGT-A diagnoses of “euploidy” and “aneuploidy” are really mosaic embryos, a conclusion also supported by the reported prevalence of aneuploid cells in ca. 80% of embryos at blastocyst-stage [12].

Further indisputable conclusions, therefore, are that current PGT-A practice greatly exaggerates diagnoses of euploidy and aneuploidy and greatly underestimates diagnoses of mosaicism. A large majority of embryos undergoing PGT-A, including “euploid” as well as “aneuploid” embryos will, therefore, contain a mixture of euploid and aneuploid cells, with the ratio between cell lineages being variable. Then such variability, of course, raises the question of whether differences in percentages between euploid and aneuploid lineages matter.

Under the assumption that these differences do matter, some PGT-A laboratories have started to differentiate in their reports between “low” and “high” “mosaicism,” making the argument that embryos with lower percentages have better pregnancy and live birth rates [10, 15]. One of these studies was, however, refuted by a corrected reanalysis of that paper’s own data [16]. More importantly, however, as the previous discussion of the correct definition of mosaicism should already have exposed, considering ratios between euploid and aneuploid cell lineages in a 5-cell biopsy, simply, make no sense and cannot be predictive for the complete embryo. The only information a “mosaic” PGT-A result with absolute certainty provides is the assurance that this embryo really is mosaic. Whether within this relatively small group of mosaic embryos stronger presence of the aneuploid lineage means poorer outcome, is currently undetermined and cannot be completely precluded but, whatever that ratio may be, the correct biological definition of mosaicism establishes beyond reasonable doubt that the ratio found in a 5-cell TEB does not represent the likely ultimately important ratio for the complete embryo.

A purely empirical assessment of what currently is known, therefore, allows for the conclusion that any judgment of current PGT-A practice must conclude that restrictions of transferability of embryos based on current PGT-A definitions of “euploid,” “mosaic,” and “aneuploid,” have no biological, mathematical, or ethical basis and, therefore, should be withdrawn. Our center, therefore, as of this point in time recommends on chromosomal grounds only the withholding from the transfer of embryos with reported aneuploidies known to survive and, even this restriction, may turn out to be excessive.

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