The article by Kucherov et al. [1] in this issue of JARG is a good summary of the state of our ART in the years 2014 to 2016. Through careful analysis of audited national data comprising 133,494 autologous IVF cycles, the authors found that among patients who had blastocysts available for transfer, or for preimplantation genetic testing for aneuploidies (PGT-A), those who opted for PGT-A experienced a significantly decreased clinical live birth rate for all age groups except for those women who were older than 40 years. Moreover, even among the oldest patients, there was no evidence of a significant increase in clinical live birth rate among those who used PGT-A. As a benefit, those who used PGT-A experienced lower rates of multiple gestations, preterm births, early pregnancy losses, and low birth weight infants. However, these benefits were achieved at the cost of a lower rate of successful live births.
Not surprisingly, analysis of those who had PGT-A and a subsequent embryo transfer did find consistently high clinical live birth rates in this subgroup. This is in line with what many have believed are the advantages of PGT-A for years. However, we note that even when limiting the analysis to those with PGT-A normal embryos, an age-related decline in clinical live birth rate persisted, despite PGT-A. The observed age-related decline in clinical live-birth rate could possibly be because of mosaic aneuploidy, undiagnosed by the 5–10-cell PGT-A biopsy, which could miss the presence of aneuploid cells outside of the biopsy.
The observed difference between per-cycle and per-transfer live birth rates requires the reader to accept the premise that most patients who underwent PGT-A, and had embryos with a genetically normal trophectoderm biopsy report, will have undergone embryo transfer within the 4-year period after their initial oocyte retrieval and that those who did not have a transfer in this time period were informed that they had no genetically normal embryos for transfer. This is a fair assumption.
Technology moves quickly in our field. Using NGS technology, labs can now detect two aneuploid cell contributions in a 5-cell biopsy. Whereas earlier techniques might have labeled such a biopsy as euploid, it may now be labeled as either euploid, mosaic, or aneuploid depending on the reporting conventions of the laboratory for an embryo with 40% aneuploid DNA. If reported as mosaic, some clinicians and patients may choose to not transfer such embryos and may thereby further diminish the clinical live birth rate for those patients choosing to have PGT-A. Transfer of embryos with intermediate copy number will most often result in normal live birth [2]; why are such embryos often refused transfer?
As we learn increasingly more about early embryo development, we find that the blastocyst stage embryo is still in an unresolved dynamic genetic state and that mosaicism is much more common than can be discerned by a 5–10-cell biopsy. What if we were all knowing and all wise and could see those hidden islands of aneuploidy, how would we respond? What if we learned, as some believe, that all early embryos have at least some degree of aneuploid mosaicism? Would we eliminate all embryos from transfer? No, we would have to admit that the clinical implications of the presence of aneuploidy in these early embryos are a matter of degree. The presence of a few aneuploid cells in a euploid/aneuploid mosaic embryo has little relationship to the embryo’s potential for a clinical live birth. Thus, it follows that the random inclusion of a few aneuploid cells in a trophectoderm biopsy may just reflect random over-sampling of a small clone of aneuploid cells. A test that deselects every embryo will certainly reduce a patient’s risk of miscarriage but will prevent any pregnancy; such testing is indeed absurd [3].
As we work to provide our patients with PGT-A “perfect” embryos, we risk eliminating many “good” embryos with reasonable chances of achieving their goal. Which leads us to the question, “Why do our patients seek our care?” They come to us because they wish to achieve what nature has not provided them on their own; they come to us to achieve the live birth of a normal child.
A careful reading of the article by Kucherov et al. makes us realize that, as part of patient counseling, we should inform patients of this trade-off. If they choose to use PGT-A, and are lucky enough to have a PGT-A “perfect” embryo, they will benefit from a high pregnancy rate per transfer and may further benefit with decreased risks of having a multiple gestation, preterm birth, early pregnancy loss, or a low birth weight infant, but if there is no PGT-A perfect embryo, by choosing to have PGT-A, they will have decreased, or at best not improved, their overall chance of transfer of a “good” embryo and thus lessened their overall chance of having a healthy child.
Declarations
Conflict of interest
The author declares no competing interests.
Footnotes
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References
- 1.Kucherov A, Fazzari M, Lieman H, Ball GD, Doody K, Jindal S. PGT‑A is associated with reduced cumulative live birth rate in first reported IVF stimulation cycles age ≤ 40: an analysis of 133,494 autologous cycles reported to SART CORS. J Assist Reprod Genet 2023. 10.1007/s10815-022-02667-x [DOI] [PMC free article] [PubMed]
- 2.Barad DH, Albertini DF, Molinari E, Gleicher N. IVF outcomes of embryos with abnormal PGT-A biopsy previously refused transfer: a prospective cohort study. Human Reprod. 2022;37:1194. doi: 10.1093/humrep/deac063. [DOI] [PubMed] [Google Scholar]
- 3.Scriven PN. Elucidating the PGT-A paradox: marginalising the detriment relegates the benefit. J Assist Reprod Genet. 2022;39:2475–2481. doi: 10.1007/s10815-022-02640-8. [DOI] [PMC free article] [PubMed] [Google Scholar]