The ultimate evidence from leading proponents of PGS that flipping a coin is as good as PGS 3.0 in determining embryo ploidy

Yes, we know that, over many months now, almost every issue of the VOICE contained an article about PGS. Yet, here we go again, because the audacity of the PGS industry, simply, leaves us no other choice.

The industry’s misrepresentations, simply, cannot be made up, and just continue giving fodder for further commentary. Trying not to be repetitive, we already in last month’s issue outlined why the name change for PGS to PGT-A, recently parenthetically announced in Fertility & Sterility (the official organ of the ASRM), in our opinion just represented yet another marketing tactic, which (hopefully unsuccessfully) attempts to divert attention away from the increasingly obvious failure of PGS 2.0, as practiced over the last half a dozen years.

Readers of the VOICE, of course, know that PGS 2.0 replaced PGS 1.0 once (much too late), the latter finally declared ineffective by ASRM and other professional organizations in improving pregnancy and reducing miscarriage rates in association with IVF. Effectiveness of PGS 2.0 was then touted with even bigger fanfares by the PGS industry, resulting in even wider utilization (and even more rapid growth of PGS laboratories and the industry as a whole).

The loudest proponents of PGS 2.0, with few exceptions, were, of course, the same “experts” who had previously argued in favor of PGS 1.0. None of them, however, appeared bothered in the least about having sold to the IVF community PGS 1.0 without prior clinical validation over many years. As we all finally learned, PGS was not only clinically useless but, at least in poor prognosis patients, actually reduced IVF pregnancy chances [Mastenbroek et al., N Engl J Med 207;357(1):9-17].

Those supposed experts’ certainty that PGS 2.0 would succeed where PGS 1.0 had miserably failed before was so profound that, amazingly, they, again, brought the new PGS to market without proper prior validation studies. A small group of PGS skeptics on both sides of the Atlantic (including CHR) called for caution, and warned that the IVF community may be repeating the mistakes made in association with PGS 1.0, but were “out-marketed” by proponents of PGS, some of whom are undoubtedly honest and true believers in the procedure, but others, unquestionably, primarily driven by more profit-focused commercial interests.

Inexplicably, as noted in the last month’s issue of this newsletter, the PGS industry received a surprising degree of support from a number of medical journals in the specialty, which clearly favored articles in support of PGS over those that attempted to critically examine its use. No team of editors in the field, indeed, acted in a more biased manner than the editors at Fertility & Sterility (F&S), the official journal of the ASRM, where proponents of PGS 2.0 were practically given free reign (the same had happened earlier for PGS 1.0 under a different team of editors), and ended up deciding which PGS papers would be accepted for publication and which would be rejected.

F&S, therefore, has been almost exclusively publishing manuscripts in support of PGS 2.0, while, almost universally, rejecting manuscripts critical of the procedure, including (without sour grapes) a good number of manuscripts from CHR investigators, which, fortunately, had no problems being accepted elsewhere. Some of these rejected manuscripts offered important new information. One, indeed, reported the first group of healthy live births in the world after transfer of allegedly “aneuploid” embryos. These data have since been confirmed by other investigators and, as will be discussed further, created the impetus for the major restructuring of PGS reporting by the PGS laboratory industry. Recitation of this background information is important because this CHR research became a crucial turning point in the recently observed demise of PGS 2.0 with publication of new reporting guidelines for PGS (i.e., creation of PGS 3.0).

It all started with an oral presentation by Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist, at the October 2015 Annual ASRM Meeting in Baltimore, reporting the first three live births after transfer of “aneuploid’ embryos. His presentation, likely, was the most talked about of that meeting. It, unquestionably, became the starting point for changes in PGS practice, which ultimately led to the announcement of new practice guidelines for PGS by the Preimplantation Genetic Diagnosis International Society (PGDIS) barely a year later in 2016 and, therefore, to a switch from PGS 2.0 to PGS 3.0 (now also called PGT-A).

CHR’s initial ASRM report was followed shortly thereafter by a confirmatory report from Italian colleagues in a research letter in the New England Journal of Medicine, which further shook up the PGS establishment and by a report of the Bernabeu group in Alicante, Spain, at the ESHRE meeting in 2016.

Increasing numbers of healthy births from all over the world following transfers of allegedly “aneuploid” embryos are finally leaving the PGS industry with no other choice but to acknowledge that their many-years-long policy of defining embryos via PGS 2.0 as either euploid or aneuploid was no longer sustainable.

When CHR as the first center in the world (in association with some colleagues at other New York centers) in 2014/2015 announced a new program of transferring so-called “aneuploid” embryos in certain situations, the PGS establishment quite viciously attacked the program as unethical. By late 2016, the same PGS “experts” were no longer able to maintain the position of defining any level of aneuploidy as “abnormal,” and recommending the disposal of any embryo with even minute alleged chromosomal abnormalities.

Surprisingly high pregnancy and live birth rates reported by CHR and other centers from transfers of allegedly “aneuploid” embryos only too obviously demonstrated that old PGS testing methods and reporting procedures were no longer sustainable. Like PGS 1.0 before, PGS 2.0 also had failed in improving IVF outcomes. Even more disturbingly, however, these new transfer data of allegedly “aneuploid” embryos offered strong supportive evidence that embryos, declared unsuitable for transfer by PGS 2.0, could lead to healthy live births in surprisingly high rates. Especially for poorer prognosis patients, this meant that they apparently had discarded their last pregnancy chances when their IVF centers disposed of their allegedly “aneuploid” embryos.

History, thus, repeated itself like CHR and a small group of other colleagues had warned about for a good number of years: Like PGS 1.0 before, only after years of clinical use had been exposed as clinically ineffective and even harmful to poor prognosis patients, PGS 2.0 now had met more or less the same fate, and the PGS industry found itself, once again, faced with  immediate need to rescue its testing business.

Many of the same “experts,” who so smoothly had managed their laboratories’ transition from PGS 1.0 to PGS 2.0, now, again, jumped on the bandwagon of the inevitable, suddenly claiming to be leading a perfectly natural switch from PGS 2.0 to PGS 3.0. They are not to be believed and, indeed, are to be held responsible for fooling the IVF community twice before. Shame on us, if we allow them to fool us a third time!

Which, finally, brings us to the main reason for this lengthy introduction. That reason is a paper, so far  published only in electronic format by (of course) F&S, with two of the world’s most prominent PGS proponents as senior authors (Munné and Fragoulis et al., Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high-resolution next-generation sequencing. Fertil Steril). Not surprisingly, some of the strongest proponents over three generations of PGS (and, concomitantly, representatives of some of the largest PGS laboratories in the U.S. and elsewhere), are apparently quite desperate to establish yet another indication for use of PGS 3.0. They, now fully accepting that many mosaic embryos can and should be transferred, in this paper are attempting to claim that, PGS 3.0 may be just the right tool to differentiate which mosaic embryos should receive priority for transfer. Like so many others before from the PGS industry, careful analysis of their manuscript, however, resolutely debunks this claim.

But let’s not get ahead of ourselves, and start from the beginning: Though a good number of authors on this paper were among the most outspoken opponents of transfers of allegedly “aneuploid” embryos when it was first announced by CHR investigators and colleagues, this group of PGS proponents from all over the world now, quite remarkably, reported on cycle outcomes of 143 allegedly “aneuploid” embryos (now under new PGDIS criteria called “mosaic”) that were, nevertheless, transferred, in their paper. Though our colleagues did not give us the professional courtesy of referencing our preceding published work in their manuscript, we do want to congratulate them on this combined effort, which represents the, so far, largest number of reported IVF cycles using aneuploid/mosaic embryos. We are, however, especially grateful for this publication because, contrary to the authors’ obvious intent, the data in their publication allowed us to reach very obvious conclusions, further demonstrating the futility of all PGS as a diagnostic procedure. Like in the two prior PGS marketing rounds for PGS 1.0 and PGS 2.0, claims for PGS 3.0 are, once again, false.

Here is why: In compliance with 2016 PGDIS recommendations, chromosomal analyses were performed with Next Generation Sequencing (NGS) in the study. Also in compliance, normal-euploidy was defined as below 20% aneuploidy (i.e., mosaicism) in a single embryo biopsy, aneuploid-mosaic as 20-80% mosaic, and outright aneuploidy as above 80% mosaic. We refer readers to the June issue of the VOICE for explanation why this classification biologically makes absolutely no sense. Aside from that fact, only normal-euploid and aneuploid-mosaic embryos by this classification were transferred. Embryos with over 80% mosaicism were still disposed of as “aneuploid” – a point we will return to later.

Overall a remarkable 41% of mosaic embryos (i.e., embryos, which, under the old classification of PGS 2.0, would have been discarded) produced an ongoing implantation (pregnancy). Single aneuploid mosaics had as high as 50% implantation rates. Monosomies did equally well as trisomies. Complex chromosomally abnormal embryos did more poorly but still resulted in ongoing pregnancies of ca. 10%.

Though this study does not report on live birth rates, reported IVF outcome numbers are, nevertheless, remarkable, not only because they fully confirm CHR’s earlier reported pregnancy and live birth rates after transfer of allegedly “aneuploid” embryos, but also because they demonstrate once more how many potentially good embryos have been disposed of  over many years by PGS laboratories during the PGS 2.0 period.

Yet, instead of acknowledging that despite quickly expanding utilization, PGS has remained a diagnostic test in search of a clinical purpose, the PGS industry is trying again to develop yet another rationale why PGS should be continued as the new PGS 3.0 (or PGT-A). Why anybody should or would order a test that, as this study by PGS proponents again demonstrates, cannot differentiate between embryos that can safely be transferred or should be discarded, is unclear. Here at CHR, where we are used to “fighting for every egg and embryo,” we assume that patients do not want to discard by mistake even a single healthy embryo that may still have pregnancy potential! Why, then, utilize a test in the first place that cannot reliably differentiate between embryos that do and those that don’t?

Trying to invent yet another reason for continued use of PGS, the authors of above cited manuscript came up with only one conclusion: PGS 3.0 should be performed to determine which embryos should be given priority for transfer. They could not even muscle enough data, however, to make a logical argument in support of that conclusion because the PGS industry, still, has not learned from past failures: The study still generalizes outcomes obtained in favorable prognosis patients, while the utility of PGS, of course, varies at different ages and with different degrees of ovarian reserve.

Even putting this very obvious criticism aside, the authors’ conclusions are nonsensical: Let’s for a moment assume a patient’s embryo does have a single chromosomal abnormality, either a monosomy or trisomy (the most frequent abnormal findings in human embryos on PGS). Such an embryo, according to the study, has a 50/50 chance of implantation. In other words, a coin flip would give us an equal chance of assessing this embryo correctly! And, even assuming an embryo has a slightly higher or lower chance of implantation, would that really affect clinical IVF outcomes to significant degrees, worth an additional $4,000, tacked on to an already exorbitantly expensive IVF cycle?  We do not think so!

What further shames this manuscript is, of course, that the authors, still, recommended discarding all embryos with over 80% of mosaicism. As PGDIS guidelines refer to this cut off without any supportive underlying data, so does the materials and methods section of this manuscript. There really is no published evidence whatsoever in the literature that embryos with over 80% aneuploidy in a single biopsy sample are really abnormal and incapable of developing into normal offspring. As we noted in the last month’s article on PGS in these pages, to presume that an embryo with 79% aneuploidy can be transferred safely but one with 81% cannot, makes absolutely no biological sense. It also demonstrates a lack of statistical knowledge!

Further undermining the validity of this cut off, CHR investigators, collaborating with investigators from Rockefeller University, have demonstrated that a single 6-cell trophectoderm biopsy, mathematically, simply cannot determine whether a trophectoderm is normal, mosaic or aneuploid, even at 100% aneuploidy if all 6 cells are aneuploid [Gleicher et al., Reprod Biol Endocrinol 2017;15(1)33].

By confirming unexpectedly high pregnancy rates from transfer of aneuploid-mosaic embryos in the so far largest published patient cohort, the authors of the above noted paper, despite their very obvious intent, actually bear witness to the clinical futility of PGS. The procedure cannot differentiate reliably enough whether an embryo is normal-euploid, mosaic or aneuploid and, therefore, whether an embryo can be transferred with reasonable expectation of pregnancy or should be discarded. The PGS-test has no clinical purpose!

The authors of the paper are, nevertheless, to be congratulated on this publication, though for obviously different reasons than they, likely, had hoped for. Offering in their manuscript considerable amounts of raw data, allowing detailed reassessments of their statistical evaluations, they provided additional opportunities. As these words are written, CHR investigators and statisticians are, indeed, already hard at work in reanalyzing their raw data in more detail. We are sure results will be interesting and will, of course, be shared in these pages in the future!

This is a part of the July 2017 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.