Yet another “innovation” cannot overcome fundamental fallacy of PGS/PGT-A
It is hard to believe but, as Ellie Kincaid, an Assistant Editor at Forbes, in the last issue of the magazine reported, what we here at CHR have only been joking about, has in fact happened: The 4th consecutive version of PGS/PGT-A (PGS/PGT-A 4.0) has been introduced to the market place. Following a by now well-rehearsed pattern of bringing to market a new version of PGS/PGT-A whenever the pressure against further utilization of the procedure mounts, the Colorado Center for Reproductive Medicine (CCRM), which in recent years has branched out all over the country with satellite centers, including in New York City, announced that the center now offers “non-invasive” PGS/PGT-A (4.0) for clinical use that does not require embryo biopsy because, whether an embryo is chromosomally normal or not, will now be determined from testing spent media in which embryos have been cultured.
This idea has been around for a few years and the VOICE, really jokingly, predicted that this new “hypothesis” would likely become the next version of PGS/PGT-A. As a number of laboratories, however, started reporting very disappointing correlations between chromosomal assessments of media and embryo biopsies, we started believing that our suspicion would not be realized after all. But here we go again, because the PGS/PGT-A industry, simply, never disappoints: Obviously increasingly desperate as the opposition to routine utilization PGS/PGT-A in association with IVF is, finally, rapidly growing, and after the American Society for Reproductive Medicine (ASRM) in association with the Society for Assisted Reproduction (SART), 10 years after a first negative judgment on PGS/PGT-A, once again emphasized that the procedure has not established any clinical utility yet.
The “hypothesis” that CCRM apparently wants to sell the public was probably, at least in part, initiated by a paper the immediate past President of ASRM, Richard Paulson, MD, published in the society’s official journal, Fertility & Sterility. As previously discussed in these pages, he concluded that the false-positive rate of PGS/PGT-A must lie around 40% (an obviously huge number of unnecessarily discarded embryos are, of course, the consequence) but also argued that the embryo biopsy required for PGS/PGT-A, to significant degrees, damages an embryo’s implantation potential. PGS proponents, of course, have been claiming that embryo biopsy does not damage embryos (as they did claim with PGS 1.0 until they started pushing for PGS 2.0 and PGS 3.0 and, suddenly, discovered that embryo biopsy in PGS 1.0 had, indeed, caused damage).
Paulson is, of course, correct because it has been known for decades that how many times an incubator door is opened relates to an embryo’s chances of implantation (the more openings the lower the implantation chances). How anybody with any understanding of embryo culture can then claim that biopsying an embryo’s trophectoderm and removing a whole bunch of cells (5-7 on average) while letting the embryo breath room air, does not affect implantation, is quite mind-blowing. But, then again, who can be surprised by yet another completely baseless and unsupported claim from the PGS/PGT-A industry? The whole evolution of this test/procedure has been built on illusive claims, never validated promises and, of course, in clinical practice in over 20 years never proven efficacy, as ASRM and SART recently again restated.
So, now, according to Forbes, CCRM announces through their spokesperson Mandy Katz-Jaffe, PhD, that their center “developed a protocol in-house that is ready for prime-time release clinically.” She is also quoted as saying that “the largest risk factor for an aneuploid embryo is the mother being older than 35,” and claiming that “other randomized trials and meta-analyses have absolutely shown higher pregnancy and live birth rates with preimplantation genetic testing of embryos.” The latter two statements are obviously absolutely incorrect because the studies Katz-Jaffe is referring to were performed in highly selected women with very good prognosis and excluded poorer prognosis patients from consideration, a reporting technique CCRM is well known for, and which artificially inflates to significant degrees a center’s outcome reporting, as CHR investigators last year reported in detail [Kushnir et al., Reprod Biomed Online 2017;35(2):161-164].
Which leaves Katz-Jaffe’s new claim of having a new non-invasive clinically PGS/PGT-A system ready for clinical use and “ready for prime-time.” Her words were not accidentally chosen because the first major paper CHR investigators in 2008 published, speaking up against utilization of PGS 1.0 in association with IVF had the title, “Preimplantation genetic screening: ‘established’ and ready for prime time?” [Gleicher et al., Fertil Steril 2008;89(4):780-788]. Here at CHR, we consider this word-play as a compliment toward our decades-long efforts to educate colleagues and the public about the harm PGS/PGT-A brings to IVF.
And what is CCRM’s “ready for prime time” new test based on? Fourteen (14) patients, presented in an abstract that claimed that 88% of embryos had enough DNA in their spent media to do the testing and, among those, only in 80% did results in media correlate with embryo biopsy results. In practical terms this means that among 100 women undergoing this test, 88 will demonstrate enough DNA and that ~30/100 (30%) will have paid for the test without getting a result. To claim a “ready for prime-time” test based on such a small number of investigations, on such a small number of patients and with a 30% embryo loss rate before even knowing how well those results correlate – not with a trophectoderm biopsy but the true ploidy of the embryo – is simply outrageous.
As we have stated before in these pages, and as also at least one critic of the CCRM announcement noted in the Forbes article, it appears high time for the Food and Drug Administration (FDA) to intervene by prohibiting the routine clinical use of PGS/PGT-A (on a side note, Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist, was also quoted in the Forbes article, reflecting CHR’s negative opinion about utilization of PGS/PGT-A).
CCRM in the Forbes piece also announces an apparently upcoming clinical trial of their new test but, interestingly, patients will, still, have to pay for it. This is, however, exactly one of the principal issues CHR has decried for so many years: Not only has PGS/PGT-A in 20 years of practice never demonstrated clinical benefits (and at least in some women with small embryo numbers actually shown negative effects on pregnancy and live birth rates) but patients have, in addition, spent significant additional money on a useless and potentially detrimental procedure, when IVF is already too costly for many.
And now the saga continues with PGS/PGT-A 4.0 all over again, even though it is now almost universally accepted (some additional evidence will be presented at this month’s FRM Conference, discussed elsewhere in this issue of the VOICE) that trophectoderm aneuploidy at blastocyst stage is an almost universal phenomenon in human embryos and that many, if not most of these aneuploidies, being mitotic rather than meiotic, self-correct after implantation. Hundreds of healthy newborns following transfers of allegedly chromosomally “abnormal” embryos bear witness to this fact better than any prospectively conducted study of PGS/PGT-A at blastocyst stage can ever demonstrate.
If embryos self-correct in a high percentage of cases downstream from blastocyst stage, what then is the purpose of testing embryos at blastocyst stage, even if such testing were accurate and non-invasive? It is high time to recognize that the PGS/PGT-A failures of 20 years have never really been the consequence of inadequate laboratory techniques and technologies but are the consequence of most basic biological realities of the human embryo. CHR investigators have been making this argument since their above cited paper in 2008. Even the most perfect techniques and technologies, therefore will never be able to predict at blastocyst stage which embryo will be euploid or aneuploid further downstream after self-correction mechanisms have done their job.
The PGS hypothesis, therefore, simply does not work! After all, we do not select our future employees in grammar school, even though the best students will statistically, likely, make somewhat better employees than the worst. Some really bad ones may, however, become the next super-star, while some early starts often fade. By testing embryos at blastocyst-stage, selecting best employees in grammar school is, however, exactly, what PGS/PGT-A does. Time to stop!
This is a part of the November 2018 CHR VOICE.