Looking at the cover of the September 18/October 1 issue of New York Magazine (left), the cute baby photo on first impulse suggested yet another, likely, banal baby story. Superimposed on the, indeed, very cute baby picture, large white letters in the title of the lead story, “Tens of thousands of women thought they couldn’t have babies. But what if they could,” followed by the even more intriguing subtitle “The Abnormal Embryos That Aren’t,” suggested, however, that this issue’s lead article addressed a much more substantial subject.
Even though the cover did not reveal what the article was about, that Stephen S. Hall, one of the country’s most prominent and highly regarded medical science writers, was the author, further enhanced the presumed gravitas of the article. Starting on page 34 of the magazine, Hall then presented not only the first discussion ever in the lay media on preimplantation genetic screening (PGS), recently renamed preimplantation genetic testing for aneuploidy (PGT-A), but a true tour-de-force on the subject. He interviewed literally almost every important figure in the field in the U.S., in Europe, and even in Israel, in order to present a balanced picture of what, likely, has become the single most controversial issue in reproductive medicine.
Here at CHR, we have been aware that this piece was in the works because Hall spent significant time interviewing CHR’s Senior Scientist and Director of Laboratories, David F. Albertini, PhD, who is also the Editor-in-Chief of the Journal for Assisted Reproduction and Genetics (JARG), the official basic science journal of the American Society of Reproductive Medicine (ASRM), and CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD. Especially Dr. Gleicher is extensively quoted in the article.
Upon publication, we were pleasantly surprised by the thoroughness of the investigational effort, the detail of information revealed and, most of all, about the balanced presentation of information, which gave ample opportunity for opposing opinions to be heard.
On behalf of the many patients and colleagues who either already have utilized PGS/PGT-A or are currently struggling with the question whether to utilize this test in conjunction with future IVF cycles, we were also grateful for the positive ways in which Hall addressed this highly complex subject. As title and subtitle of the article so well demonstrate, instead of choosing an accusatory tone, he presented recently evolving opinions on PGS/PGT-A as an additional potential opportunity for women who previously failed IVF when using PGS/PGT-A.
We here do not wish to regurgitate the content of Hall’s article but strongly recommend that every patient undergoing IVF and every physician and embryologist involved with IVF, either utilizing PGS/PGT-a or considering its use, read this piece in New York Magazine in print or online. We were very pleased to learn that at least one very prominent national chain of infertility centers already made this article the subject of their weekly journal club.
CHR’s opinions about the utility of PGS/PGT-A are by now very well known to readers of the VOICE. It, therefore, is also not our intent to regurgitate those opinions. Hall’s piece was, however, especially gratifying to us here at CHR because it, ultimately, confirmed that CHR, for so many years a minority opinion on the subject of PGS/PGT-A, finally, has succeeded in convincing many colleagues that the CHR position on PGS/PGT-A, ultimately, was the correct one from the beginning.
This is probably best documented by an excellent short video the magazine attached to the article on the Web in which Richard Paulson, MD, the current President of ASRM, comments on PGS/PGT-A, reaching the conclusion that the procedure appears “not ready for primetime” (Paulson R. Preimplantation genetic screening: what is the clinical efficiency? Fertile Steril 2017;108(2):228-230). We also have reasons to believe that ASRM soon will publish an updated formal “opinion” on the utilization of PGS, in which it, once again (it did so with an earlier version of the procedure, PGS 1.0), will state that PGS/PGT-A has so-far failed to demonstrate clinical efficacy.
What makes Paulson’s comment especially interesting to us here at CHR is that, over 10 years ago, when CHR investigators for the first time started wondering whether PGS really improved IVF outcomes, and started worrying that the procedure in poor prognosis patients with small embryo numbers may actually reduce pregnancy chances in IVF, a manuscript trying to make both of these points was repeatedly rejected by many medical journals for over two years, until it was “recalled” by the then editor-in-chief at Fertility & Sterility and expedited for publication. Its title was, “Preimplantation genetic screening: ‘established’ and ready for prime time?” and the answer in the article was then the same Paulson now gave, when interviewed by Hall: No, PGS is NOT ready for prime time! [Gleicher N, Weghofer A, Barad D. Fertil Steril 2008;89(4)780-788].
In the U.S., for the longest time, CHR has been a lone voice in warning against inappropriate clinical use of PGS, making the point that the procedure not only had failed to improve IVF outcomes but, likely, especially for women with low ovarian reserve and/or small embryo numbers, did the opposite (in The Netherlands, Mastenbroek and colleagues and in Israel Orvieto et al offered similar opinions). Our efforts to educate colleagues and the public were, however, greatly outperformed by proponents of PGS, many of them geneticists with strong economic interests in PGS, which quickly became a significant income source for reproductive genetics laboratories. PGS, indeed, became the main “product” of laboratories, which up to that point had, almost exclusively only offered preimplantation genetic diagnosis (PGD), the testing of embryos for single gene diseases. All of these laboratories now suddenly turned into PGS laboratories. The Preimplantation Genetic Diagnosis International Society (PGDIS), as the name indicates up to that point supposedly the expert society for PGD, now by issuing practice guidelines, also usurped authority over PGS, for all practical purposes becoming the international “PGS Society.”
In trying to understand what went wrong with PGS, this development, in retrospect, appears to us as a major contributing factor because the PGDIS is mostly a society of geneticists, often excellent basic scientists, but mostly not clinically active physicians. Scientifically, emotionally and even ethically this can make quite a difference because only physicians grow up with the first rule of medicine, “to do no harm!”
When at a very recent scientific meeting a leading non-physician PGD/PGS expert and laboratory director was asked how he feels about the fact that large numbers of mosaic embryos until recently were routinely discarded, which as of July 2016, under new PGDIS guidelines, are now available for potential transfer in the uterus, he offered neither excuses nor apologies but, simply stated, and we are paraphrasing, that “everything in medicine constantly undergoes improvements,” and that the PGS community had always told physicians and public that PGS “was not perfect.” In other words, he viewed the loss of tens of thousands of perfectly fine embryos, often the last chance of infertile women to conceive, as the perfectly normal evolution of a clinical test. The PGS community had fulfilled its ethical obligations by, as he noted (and we are again paraphrasing) openly communicating to patients and IVF centers that “PGS was not perfect.”
It is unlikely that a physician would ever offer such a response since it would be comparable to a surgeon describing a patient’s surgical risk as minimal, when the proposed surgery results in 50% mortality. This is, however, exactly what the PGS laboratory community has been doing for years, not only by constantly reassuring IVF centers and public how low the diagnostic error rates were with PGS but by aggressively opposing and preventing publications of opposing opinions.
In above quoted recent paper by the current ASRM President, Richard Paulson, MD, the risk of false positive embryo diagnoses from PGS was estimated at approximately 40%. We consider the risk at least that high and, likely, even higher. Whether the PGS community for so many years underestimated this risk consciously or subconsciously really does not matter. Basic ethics of medical practice should never have allowed the clinical utilization of a procedure with such a degree of potential mortality without prior validation of safety and clinical efficiency.
Because members of the PGS laboratory community were considered “the experts,” their opinions appeared more credible than those of a handful of opponents, who mostly were clinicians. They also were the reviewers journal editors turned to when CHR investigators and other authors, critical of PGS, submitted manuscripts. Opponents of PGS, therefore, often had great difficulties in getting manuscripts published. Even those that, finally, were accepted, usually were published only with significant delays, thereby causing delays in getting the message out. The so-called “experts,” in contrast, literally at will, were able to put their often highly misleading manuscripts into print because they, of course, reviewed each other’s submissions.
That happened already between 2010 and 2012, when CHR was unable to get above cited manuscript into print for over two years and, even more remarkably, it happened again in more recent years, when CHR (in 2014-2015, as noted in Hall’s manuscript, in collaboration with 2 other New York City-based IVF centers) progressively accumulated normal euploid deliveries after transfer of allegedly “aneuploid” embryos.
Though CHR’s first healthy birth after transfer of allegedly “aneuploid” embryos was recorded after a 2012 embryo transfer, the Consortium only in October of 2015 for the first time succeeded to get into print with the message that such embryos could be safely transferred. This happened when an abstract was accepted at the Annual ASRM Meeting in Baltimore, MD, and published in Fertility & Sterility. Though Dr. Gleicher’s oral presentation of those data at that meeting attracted enormous attention (the Consortium by that point had accumulated 5 normal pregnancies following 8 transfer of allegedly “aneuploid” embryos), a full-length paper was, still, rejected by all leading medical journals in the field for ca. 18 moths following the meeting, including by Fertility & Sterility, demonstrating the persistent and controlling power of the PGS laboratory community in preventing publications of scientific data that contradicted claims of efficacy of PGS.
Mosaic embryos, which until July 2016 would have uniformly been discarded, by now have worldwide resulted in close to 100 healthy ongoing pregnancies and deliveries. We are hopeful that the editors of medical journals in our field, who over many years have failed in their primary responsibility of securing objective scientific exchanges in the pages of their journals, now will recognize the lessons PGS/PGT-A has to teach us all.
Though Hall, likely, knew all of this, he smartly avoided recriminatory comments. Instead of lamenting the tens-of-thousands of unnecessarily discarded embryos over the years, and the many women who erroneously were told that they no longer had any chances of conception with use of their own eggs (and have to use donor eggs), he presented the subject with a more hopeful viewpoint by stressing that tens-of-thousands of women who thought they could no longer have babies with use of their own eggs, now may discover that they still may have a chance.
For public consumption, this, unquestionably, is the appropriate message. For the professional infertility community, the almost 20-year history of PGS, however, should be grounds for a serious revaluation of values and processes. The in 2018 upcoming 40th anniversary of the first IVF birth in 1978, indeed, offers a good opportunity for a careful review of current IVF practices. We in these pages noted that the mostly stellar history of steadily improving IVF pregnancy and live birth rates over the first three decades has come to a halt over the last 10 years and, indeed, over the last few years, has witnessed significant declines. Increasing evidence suggests that these declines are the consequence of what our British colleagues have come to call add-on treatments to IVF. PGS/PGT-A is, likely among the most harmful among those!
If, going forward, PGS/PGT-A can serve one useful function in IVF, then it is as a stellar example for the need of appropriate validation studies for tests and procedures before they are routinely added to IVF. Medical journal editors can perform an important role in securing compliance by not accepting for publication reports that utilize unvalidated tests and/or procedures, unless performed under experimental protocols with appropriate study consents signed by patients.
As editors, they, likely, have no more important function because publication of unvalidated results entices the clinical community into harmful treatments under the (currently often wrong) assumption that published manuscripts in credible medical journals have undergone proper peer review and, therefore, can be believed.
This is a part of the October 2017 VOICE.