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Accepting a challenge: Here goes Santiago Munné again!

Posted on Sep 14, 2018

Right Arrow PGS/PGT-A debate degenerates as its proponent drifts away from science

So here is a little background on this piece: Santiago Munné, PhD, initially came to the attention of the IVF community as a talented geneticist who closely worked with one of the pioneering clinical embryologists in IVF, Jacques Cohen, PhD, in the area of preimplantation genetic diagnosis (PGD) of mostly single gene diseases. His reputation quickly grew, and he succeeded in developing one of only three leading genetic laboratories that offered these services to most U.S. IVF centers.

As preimplantation genetic screening (PGS), now renamed preimplantation genetic testing for aneuploidy (PGT-A), entered clinical practice in its first incarnation without prior clinical validation studies, he, much more quickly than other leading PGD laboratories, recognized the commercial opportunity and became the dominant proponent of this new screening test. In parallel, his laboratory also became dominant in performing this test in the U.S. (and soon thereafter in other regions of the world).

As the screening test in its initial form (PGS 1.0) started to receive increasing criticism (including from CHR investigators), Munné became the test’s main defender. As the American Society for Reproductive Medicine (ASRM) declared PGS 1.0 ineffective in improving IVF outcomes and reducing miscarriages ca. 10 years ago, he became one of the principal proponents of PGS 2.0, once again advocating unsupported claims of effectiveness in improving IVF outcomes and in reducing miscarriage rates for a completely unvalidated test prior to its marketing to IVF centers and the public.

In this context it is important to understand that exactly a decade after issuing the above-noted opinion on PGS 1.0, ASRM, this time in conjunction with the Society for Assisted Reproduction (SART), very recently again issued a formal opinion on PGS/PGT-A, reemphasizing that, till today, no IVF outcome improvements by PGS/PGT-A have been confirmed and, indeed, have been mostly refuted.

Munné, himself, has in multiple oral and written statements in recent months acknowledged that PGS/PGT-A “cannot improve pregnancy and live births rates.” His retreat from original claims of improvements in IVF outcomes is further demonstrated by his “new” claim that PGS/PGT-A should be performed because it “speeds up time to pregnancy.” He also still maintains that it reduces miscarriages, though, as repeatedly discussed in these pages, considerable evidence, indeed, suggests that this is not the case.

Repeatedly moving the goal posts in describing PGS/PGT-A benefits for IVF has, therefore, been a constant feature of how Munné, and the PGS industry in general, have been marketing the successive versions of this, till today completely unvalidated, diagnostic screening test in versions PGS 1.0 through PGS 3.0, forming the basis for discarding so-called “abnormal” embryos.

PGS 3.0 was initiated by the industry in July of 2016, when the Preimplantation Genetic Diagnosis International Society (PGDIS), unexpectedly, completely revamped how the test was to be performed in the laboratory and reported to IVF centers (and patients), how reports were to be acted upon and, incidentally, in order to reflect the radical break with the past, also gave the test a brand-new name: PGT-A. Announcement of PGS 3.0 by the industry, was, however, no coincidence: By that point, quickly increasing reported numbers of healthy euploid births from transfers of, by PGS laboratories declared “aneuploid” or “mosaic” embryos, made the prior positions and practices of the PGS laboratory industry no longer tenable. CHR, indeed, has been the first IVF center in the world to announce transfers of so-called “abnormal” embryos and healthy euploid births from such transfers. By now, hundreds of healthy offspring have been delivered worldwide following such transfers.

Since we have discussed PGS 3.0 in these pages extensively and repeatedly, we do not wish to be repetitive. Moreover, this communication is not meant to again discuss the very obvious shortcomings of PGS/PGT-A, and damages its utilization inflicts on patients. CHR investigators have continued to speak out in peer-reviewed journals: For example, CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, was recently one of the con-voices in a debate, published by Fertility & Sterility (Rosenwaks et al., Fertil Steril 2018;110(3):353-361), the official organ of ASRM.

He and co-workers recently also published a critique in the form of a very detailed letter to the editor in Reproductive Biomedicine Online of a PGS-related article [Grati FR et al., Reprod Biomed Online 2018; 36:442-449], for which Munné provided an accompanying, and very laudatory editorial [Munné S. Reprod Biomed Online 2018;36:369-370]. CHR investigators lauded the authors for the intent of their study but criticized their manuscript and Munné’s accompanying editorial for failing to point out how controversial the use of PGS/PGT-A had become in recent months and years [Gleicher et al., Reprod Biomed Online 2018; 37(2):242-245].

After accepting CHR's correspondence for publication following peer review, it is common practice to let the authors who were criticized in the correspondence to respond in print. This is also what happened in this case, and authors of the original paper as well as Munné, author of the accompanying editorial, were given the opportunity. The authors responded with a succinct and polite letter [Grati et al., Reprod Biomed Online; 2018; 37(2):246], while Munné's response was similar to the written temper tantrum he circulated by e-mail after NEW YORK Magazine published an article on PGS in the fall of 2017 that he did not like. Once again, he became inappropriately personal in his response when accusing CHR investigators to be principally motivated by financial gains [Reprod Biomed Online 2018; 37(2):247-249] and made blatantly incorrect scientific representations. In an attack on CHR’s investigators, already “weakened” at editors' request (we had been privy to the earlier version), CHR investigators were accused in the introductory sentence of Munnés response of attacking the utilization of PGS/PGT-A only in an attempt “of defending their business model, by denouncing PGS as their marketing differentiator from other centers.”

Munné, in other words, implied that CHR’s investigators in their almost 20 years of opposition to the concept of PGS/PGT-A, and their multifaceted research, documented in a large number of publications, were only motivated to express their negative opinions about PGS/PGT-A in pursuing financial gains through a business model that differentiated CHR from other IVF centers.

This is, of course, a very serious, indeed defamatory claim. Though even significantly weakened from an earlier version, such a statement of alleged motivation is still highly unusual within a scientific discourse in a peer-reviewed journal. It, therefore, requires some further comments.

Since its establishment in Chicago in 1981, CHR, has, indeed, pursued a rather unique business model in that it functions more like an academic research center than a typical private IVF facility. CHR’s important research contributions to the infertility field have been many and have significantly affected worldwide infertility practice. Practice improvements introduced by CHR include transvaginal tubal catheterization in replacement of major tubal surgeries to recanalize clogged fallopian tubes; the world’s first vaginal egg retrieval for IVF, when routine practice was operative laparoscopy; dehydroepiandrosterone (DHEA) to improve functional ovarian reserve in infertile women; and many others.

In introducing all of these and other innovations, CHR investigators, uniformly, have been proven correct, even if the always expected (and for the process of introducing innovations, healthy) nay-sayers were never lacking.

Contrast that to Munné’s track record on PGS (his many publications on this subject can be viewed under his name at www.pubmed.com). The repeated and constantly changing promises (i.e., moving of goal posts) will become immediately obvious. We cannot even find one that was proven to be correct.

Even beyond initial and most fundamental claims that PGS would improve pregnancy and live birth chances with IVF (Munné, of course, was not alone among PGS/PGT-A proponents in making those claims), he was more outspoken than others in making secondary claims, later established as false: For example, when trying to convince the IVF community that PGS 2.0 was much better than the PGS 1.0, just dismissed by ASRM, he claimed in a publication that the switch from day-3 to day-5 embryo biopsies would greatly reduce the mosaicism problem. We, of course, now know that the opposite is the case since mitotic mosaicism significantly increases between cleavage and blastocyst stages, as increasing numbers of cell divisions take place in an embryo.

His frequent incorrect representations do not allow a judgement on whether they are primarily based on biological ignorance about early human embryo development or, simply, aberrations of aggressive marketing. Especially remarkable is his apparent ignorance about what represents functional mosaicism in a preimplantation-stage human embryo. His explanation for cut-off values that under the new PGDIS guidelines of 2016 define “normal-euploid,” “mosaic” and “aneuploid-abnormal” embryos, is truly amazing. Yet, these cut offs, are now used worldwide by laboratories to determine which embryos can be transferred or must be disposed of.

As his most recent above cited communication again confirms, he still insists that 80% aneuploid DNA load in a single trophectoderm biopsy represents an adequate cut-off to differentiate between “mosaic” and “aneuploid” embryos, which also means differentiation between potential of transferring or discarding embryos. Incredibly, he also repeats in his written response what, up to this point, he had offered only in an oral presentation as explanation for the 80% cut-off at a 2017 medical congress in Vienna, Austria, namely that “...80% aneuploid DNA load represents 4/5 aneuploid cells in an on average 5-cell biopsy.”

But what if the biopsy contained 6 or 7 cells or, alternatively, lost DNA content from some of the cells, as cells frequently do during embryo biopsies? Under this ridiculous threshold concept, in the first case, the aneuploid DNA load would be artificially diluted, and a supposedly “aneuploid” embryo would, suddenly, be “mosaic.” In the second scenario, the opposite would happen, and a “mosaic” embryo would automatically be upgraded to “aneuploid” and, therefore disposed of.

Using next generation Sequencing (NGS) on such a flimsy mathematical (and biological) basis is not only irresponsible but, simply, shameless!

This communication is, however, not meant to rehash the many controversies surrounding PGS/PGT-A. We here, instead, want to address the absurdity of Munné’s allegation that the motivation behind CHR’s opposition to the use of PGS/PGT-A has economic/financial connotations.

CHR’s almost 20-year-long involvement with PGS (actually preceding Munné’s own involvement), of course, has absolutely nothing to do with economics (though CHR is concerned about patients, for no good reasons, spending an additional $4,000-5,000 on average for adding PGS/PGT-A to their IVF cycles). CHR has a strict “wall” between research and financial interests, closely controlled by an independent Institutional Review Board (IRB), chaired by an independent, non-CHR physician, even located in a different state. Even more importantly, such an accusation economically (and logically) makes absolutely no sense, since which commercial IVF enterprise would base a marketing approach on, a-priori, foregoing highly significant additional IVF cycle revenue?

The average additional cost of PGS/PGT-A in the U.S. is between $4,000 and $5,000, which (under federal and certain state laws in somewhat questionable fashion) is usually evenly split between IVF centers (for performing the embryo biopsy) and commercial laboratories (for performing the PGS/PGT-A screening test and reporting results). For most IVF centers, performing an IVF cycle with PGS, therefore, adds between $2,000 and $2,500 to cycle revenue. This represents especially in cycles of patients with IVF insurance coverage (which usually are highly discounted) a very significant revenue boost, as insurances do not pay for PGS/PGT-A (correctly considering it an unproven experimental procedure), and patients, therefore, must pay for this test out of pocket. In such cycles these cash payments can often represent 30-40% of additional cycle revenue for IVF centers, creating significant financial incentives for IVF centers to perform PGS/PGT-A.

$2,000-2,500 in laboratory revenue for a simple NGS analysis, of course, also represents a highly profitable business proposition for commercial laboratories, especially since a very small number of these laboratories really perform the large majority of PGS/PGT-A testing.

Though financial incentives unquestionably exist for laboratories and IVF centers (with the latter, likely, on purpose created by the PGS/PGT-A industry), CHR’s investigators never believed or implied that incentives for IVF centers were a driving force behind the utilization of PGS/PGT-A. That PGS/PGT-A utilization over the last year appears to have stagnated and even fallen (some major national genetics laboratories that in the past had offered PGS/PGT-A announced their withdrawal from this market segment) is supportive of this assessment of motivations. A reason is likely that the IVF community, finally, had the opportunity over the last year to read opposing opinions on PGS/PGT-A in the medical literature, after proponents of the test for almost a decade had controlled the peer review process on the subject and had made it almost impossible for opponents to publish their manuscripts in leading journals of the profession.

Since CHR never believed the marketing slogans of the PGS/PGT-A industry, this center never recommended PGS/PGT-A to patients, thus literally foregoing millions of dollars in additional cycle revenues in all of these years. Economic and/or financial incentives, therefore, very obviously, were not a motivating factor for CHR. Though CHR’s investigators never even gave thought to call into question Munné’s integrity in advocating his side of the argument in favor of PGS/PGT-A, this is, of course, exactly what he did in accusing CHR of being opposed to PGS/PGT-A for only economic reasons. One, therefore, has to wonder where such a far-fetched allegation may come from in his mind?

And the answer appears very obvious: In clinical psychology theory there, of course, is the concept of “projection.” Wikipedia defines it as “the human ego defending itself against unconscious impulses or qualities by denying their existence in themselves, while attributing them to others.”

Munné’s behavior, especially over the last few years, appears to represent a fairly typical and obvious example of such projective behavior since it is, of course, the PGS/PGT-A laboratory industry that has the financial incentives to sell the PGS/PGT-A test to the IVF community and public at basically all costs. Nobody has, indeed, been economically more successful in doing so than Santiago Munné, who, according to public records, in 2016 sold his U.S. and U.K. laboratory operations to the CooperSurgical corporation for in excess of $60 million and is again already hard at work (this time in Spain) on building another company in the field.

Only a person who is excessively motivated by financial considerations can, indeed, reach an outlandish and economically non-sensical opinion, as expressed by Munné in the introductory sentence of his response to the letter-to-the-editors by Gleicher et al, accusing the authors of opposing utilization of PGS/PGT-A for financial/economic purposes only. One will rarely see a better example of psychological projection in the medical literature, and the editors of the journal are to be congratulated for making this point so obviously transparent by publishing this exchange. A very well-balanced commentary in the same issue of the journal by Peter Braude, MD, from Kings College in London, UK, (Reprod Biomed Online 2018;37(2): 133-135) further added to this exchange of opinion. We strongly recommend that readers of these pages seek out the original source materials here referenced. It will provide important additional insights into PGS/PGT-A.

One important additional point must be made, however: Munné’s above referenced response ended on an even more worrisome note than his disparaging introductory sentence, when he concluded: “While Gleicher and colleagues are still shaking their fist at PGSv1 (likely meaning PGS 1.0-PGS 3.0), the field is moving forward (to) non-invasive PGS.”

Munné, therefore, is obviously again moving the goal posts. We, therefore, better brace for even more “snake oil” from him (and other continued proponents of PGS/PGT-A), to be sold to IVF community and public. One at this point must really wonder what drives one to continue testing embryos for alleged aneuploidy if, even if this alleged aneuploid is factual (and it often is not), a very high percentage of embryos self-corrects downstream. It is like tasting a soup before it is cooked. No method of preimplantation-stage embryo testing can be accurate enough for clinical use, if such testing is performed before embryos have completed self-correction.

This is a part of the September 2018 CHR VOICE.

Norbert Gleicher, MD, FACOG, FACS

Norbert Gleicher, MD, FACOG, FACS

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, 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.

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