More News on PGS that Should Give Patients and Colleagues Second Thoughts

As previously reported in these pages, one of the most discussed oral presentation at last October’s Annual Meeting of the American Society for Reproductive Medicine (ASRM) in Baltimore was Norbert Gleicher, MD’s. CHR’s Medical Director and Chief Scientist, Dr. Gleicher reported on the establishment of 5 normal pregnancies (3 already delivered) in 8 attempts, after transfer of embryos diagnosed to be chromosomally abnormal (aneuploid) at prominent national preimplantation genetic screening (PGS) laboratories, representing a 62.5% likely live birth rate.

The presentation attracted so much attention because, at that time, it represented the first published report in the world of transfers of allegedly chromosomally abnormal embryos into uteri of infertile women [Gleicher et al., Further evidence against use of PGS in poor prognosis patients: report of normal births after transfer of embryos reported as aneuploidy. Fertil Steril 2015;104 (Sup.3):e59]. Moreover, these patients were mostly poor prognosis patients who produced only small numbers of embryos.

When CHR started offering the option of transferring allegedly chromosomally abnormal embryos in 2014, after developing significant doubts about the ability and/or accuracy of PGS to reliably establish whether an embryo is chromosomally normal or not, two other fertility centers in New York City (headed by Andrea Vidali, MD and Jeffrey Braverman, MD) joined CHR in a research consortium, adopting CHR’s transfer policy, and combining their cases. Above-noted 8 embryo transfers, thus, represented the combined experience of all three centers.
At the ASRM meeting we also learned through personal communications that Israeli investigators at Tel-Aviv University’s Sheba Medical Center had dissected a group of embryos, which could not be used for embryo transfers because they carried single gene diseases. In doing so, they found significant incongruities in chromosomal analyses between multiple biopsies of the same embryos, including between trophectoderm, where embryos are now mostly biopsied with more advanced PGS procedures, and the so-called inner cell mass, from which the fetus arises.

voice_1511_blastocystTheir study, now published (Orvieto et al., Should preimplantation genetic screening be implemented in routine clinical practice? Gynecol Endocrinol 2016 DOI: 10.3109/09513590. 2016.1142962), suggested that biopsies taken from trophectoderm, very much as CHR suspected, did not well reflect the chromosomal makeup of the embryo. The finding was suggested by Canadian colleagues in Toronto earlier, who had noticed significant discrepancies in trophectoderm biopsies sent to different PGS laboratories (Esfandiari et al. Trophectoderm biopsy for aneuploidy screening using different platforms and conflicting test results. Abstract O-034 Annual Meeting of ESHRE, Munich, June 27-July 2, 2014). This Canadian report had, indeed, been instrumental in CHR developing its above-noted transfer policy.

But this is not where the story ends: A few weeks after CHR’s presentation at ASRM, Italian colleagues, who apparently had pursued similar ideas, published a research letter in the New England Journal of Medicine, in which they reported 6 healthy births (out of 18 embryo transfers for a 33.3% live birth rate). While not as high as in our report, the Italian live birth rate is still remarkably high, considering that, here too, only patients with small embryo numbers were included in the study (Greco et al., Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. N Engl J Med 2015;373:2089-90).

In other words, between our Italian colleagues and CHR’s Consortium data, 26 transfers of allegedly aneuploid embryos have so far resulted in 14 healthy pregnancies/births for a combined birth rate of 42.3%. Perhaps even more remarkably, neither group experienced even a single miscarriage although the CHR Consortium did experience one chemical pregnancy in addition.

BaradEven that is not the last word yet: David H. Barad, MD, MS, CHR’s Director of Clinical ART (left), had the opportunity to orally present to considerable attention a still unpublished CHR study at the Late Breaking Abstract Session of the Annual Scientific Meeting of the Society for Reproductive Investigations (SRI) on March 19, 2016. In the study, CHR investigators dissected 11 embryos that had been donated to CHR for research purposes after they were found to have aneuploidy in PGS. Donated embryos were divided into 1-4 specimens and were sent individually to another prominent PGS laboratory for reanalysis [Gleicher et al., Mosaicism in human embryos compromises accuracy of preimplantation genetic screening (PGS), Reprod Sciences 2016;23(Suppl) O-162].

Amazingly, only 18% of embryos received identical chromosomal assessments from the two PGS laboratories, and only 50% of embryos were found to demonstrate identical chromosomal profiles in multiple biopsies. In other words, ca. 50% of embryos were found to be mosaic; i.e., they demonstrated different chromosomal findings in different biopsies of the same embryos.

This is, of course, an absolutely astonishing finding, further expanding on previously noted reports by Esfandiari et al and Orvieto et al, and suggesting that mosaicism (the presence of multiple chromosomal, both normal and abnormal, cell lines in a single embryo) of blastocyst-stage embryos is much more frequent than has been previously suggested. These findings, however, also suggest that the concept of PGS, which is based on accurately differentiating between chromosomally normal and abnormal embryos via a single trophectoderm biopsy, is biologically unachievable.

PGS, therefore, does not appear more reliable than a coin flip, and establishment of a high percentage of healthy pregnancies from transfer of supposedly chromosomally abnormal embryos by our Consortium and Italian colleagues should not surprise. Indeed, one has to conclude that, using PGS, IVF centers all over the world currently are daily discarding a large number of perfectly health embryos, fully capable of leading to entirely normal pregnancies.

CHR’s recommendation to patients who have undergone PGS, therefore, is think twice before allowing your allegedly aneuploidy embryos to be discarded. At least call us at CHR, and speak to one of our physicians before doing so! (See also the Monthly Case Report in this month’s VOICE.)

This is a part of the April 2016 issue of the CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.