Non-Invasive Preimplantation Genetic Testing for Aneuploidy (PGT-A 4.0): Hard to believe, but IVF centers really use it!
Yes, believe it or not, but several IVF centers, including at least two in NYC we know about, have initiated in association with routine IVF cycles so-called non-invasive preimplantation genetic testing for aneuploid (PGT-A). Since we in these pages have repeatedly addressed PGT-A, until 2016 called preimplantation genetic screening (PGS), we assume that a large majority of our readers are familiar with the history of PGT-A and/or require only key points to recall more detail. We, therefore, will be short in our introduction.
A brief history of PGS/PGT-A
The concept of deselecting chromosomally abnormal embryos prior to embryo transfer to improve IVF outcomes for the remaining embryos in a cycle cohort has existed since the mid-1990s. Because chromosomal abnormalities were believed to represent the major cause of failed embryo implantations in IVF and most miscarriages were believed to be caused by chromosomal abnormalities in embryos, this concept appears to make eminent sense. The initial idea was to test 1st and 2nd polar bodies, extruded by embryos after fertilization. This proved, however, technically difficult for most IVF laboratories and the procedure, then referred to as PGS, started gaining traction only once it was based on biopsying a preimplantation-stage embryo at cleavage-stage (day-3 after fertilization), in what now is widely called PGS 1.0.
When, however, several smaller clinical trials did not demonstrate expected outcome advantages and, ultimately a large prospectively randomized study by Dutch investigators demonstrated that PGS 1.0 in older women reduced pregnancy chances, the procedure faced a first major crisis since, in addition, the _American Society for Reproductive Medicine (ASRM) _at roughly the same time (2008) concluded that PGS 1.0 had _not _demonstrated any outcome advantages.
The rapidly growing genetic embryo testing industry, however, had a solution and announced PGS 2.0, claiming the same IVF outcome improvements all over again that PGS 1.0, disappointingly, had failed to meet. The reason why the testing industry got away with the same charade for a second time was that PGS 2.0, technically, indeed, offered significant improvements: By moving embryo biopsy form cleavage- to blastocyst-stage and by biopsying instead of only 1 or 2 blastomeres at cleavage stage, 5-6 trophectoderm cells at blastocyst-stage, more genetic material became available for testing. Moreover, advanced diagnostic platforms allowed testing of all chromosomes at once, when PGS 1.0 allowed only maximal testing of 7-8 most frequently abnormal chromosomes. The industry, therefore, could claim that these improvements would, indeed, finally demonstrate the outcome improvements that PGS 1.0 had failed to produce.
Again introduced without prior validation studies, PGS 2.0, however, like PGS 1.0 before, failed to establish better pregnancy and lower miscarriage rates. A second major crisis hit the genetic embryo testing industry therefore, by 2015 when CHR investigators in collaboration with 2 other NYC-based IVF centers, first reported 5 chromosomally healthy births following by PGS 2.0 as chromosomal-abnormal diagnosed embryos and, a few weeks later, Italian investigators reported 6 healthy births following such transfers. These two reports attracted considerable worldwide attention in the IVF community because what better evidence was there for lack of utility and even harm to outcome than births of healthy offspring after transfers of embryos, based on PGS 2.0, destined for disposal.
The credibility of PGS 2.0 as of this point had reached a, likely, even lower point than in 2008 with PGS 1.0. The response of the genetic testing industry was, however, again the same as on prior occasions: Once again PGS was radically revamped, this time in parallel also including a name change from PGS to PGT-A in order to drive home the conceptual magnitude of those newly introduced changes to the procedure (now here called PGT-A 3.0). PGT-A, however, was again introduced without prior validation studies. Indeed, those changes were published by a small and obscure “society,” principally composed of individuals who made their living from PGS/PGT-A, called the Preimplantation Genetic Diagnosis International Society (PGDIS). Moreover, they were published unsigned and unreferenced on the website of the society, without ever undergoing peer review and without any information concerning who made the rules and under what assumptions and/or data they were based on
Yet remarkably, this publication became the basis for how, to this date, chromosomal testing of human preimplantation-stage embryos has been practiced all over the world.
The testing industry again argued that nothing was wrong with the basic concept of PGS/PGT-A and insisted that PGT-A 3.0 would still fulfill promised improvements of better pregnancy and live birth rates and lower miscarriage risk. According to industry “experts,” the culprit for earlier failures was again not the basic hypothesis behind the procedure but technical difficulties in how PGT-A was performed during PGS 2.0. Suffice it to say, the genetic embryo testing industry, once more, sold IVF centers and the public snake oil. By 2018, the ASRM (and other professional organizations) concluded after a 10-year hiatus for a second time that the procedure had established absolutely no outcome utility for IVF. The testing industry and many IVF centers, nevertheless, have been increasing utilization of PGT-A in association with IVF at unprecedented speed. Increasing numbers of IVF centers, indeed, have made PGT 3.0 mandatory in most, or all, of their IVF cycles. One can only speculate about their motives!
We have discussed the failures of PGT-A 3.0 in these pages on numerous occasions. Within this context, we also predicted as a response from the testing industry to yet another crisis in credibility of PGT-A the usual response: i.e., yet another unvalidated introduction of a 4th generation of useless and, likely, often harmful tests, non-invasive PGT-A (nPGT-A 4.0). We predicted the invention of PGT-A 4.0 because not only has PGT-A 3.0 once more failed to show any clinical utility in conjunction with IVF, but the harmful effect on patients is becoming increasingly obvious, even to those who have been brainwashed by the genetic embryo-testing industry. With hundreds, if not thousands, of chromosomal-normal pregnancies delivered, by now worldwide, after the transfers of allegedly chromosomal-abnormal embryos, without even one chromosomal-abnormal birth from such transfers, even strong supporters of PGT-A have been starting to question the procedure.
For readers interested in the underlying reasons why the various generations of PGS/PGT-A for biological, mathematical and technical reasons, simply cannot work, we suggest a paper destined to momentarily appear electronically in a prestigious science journal, Trends in Molecular Medicine Reviews (a journal in the CELL family of journals), with authors Norbert Gleicher, MD, Medical Director and Chief Scientist at CHR, Pasquale Patrizio, MD, MSc, Head of the IVF Program at Yale University and Prof. Ali Brivanlou, PhD from Rockefeller University (please write to us at email@example.com if you are interested in receiving a free reprint. The paper will appear under “open-access” rules).
Non-invasive PGT-A (nPGT-A 4.0)
We noted above that PGS/PGT-A from the beginning relied on an embryo biopsy and that between PGS 1.0 and PGS 2.0 this biopsy moved from cleavage- to blastocyst-stage. We also noted that none of the various iterations of the procedure so far has demonstrated any of the utilities promised by proponents in the testing industry. Finally, we referred in the preceding paragraph to an impending paper that in detail explains why for various reasons PGS/PGT-A simply cannot work in delivering the promised outcome benefits for IVF.
Richard Paulson, MD, a prominent fertility expert and past president of the ASRM, several years ago started claiming that PGS/PGT-A was losing promised outcome advantages because of the need for an embryo biopsy. Based on mathematical modelling, he claimed that damages from embryo biopsies were the principal cause why PGS/PGT-A has been unable to demonstrate outcome benefits. CHR does not subscribe to this hypothesis. Though embryo biopsy is not as harmless as claimed by the genetic testing industry (they claim there is absolutely zero damage), it by itself does not cause substantial enough damage to negate potential outcome benefits from PGS/PGT-A.
Paulson’s argument, however, gave significant impetus to the investigation of so-called cell-free DNA in spent media in which embryos were cultured. Cell-free DNA has revolutionized several areas in medicine, none more so, however, than early prenatal genetic diagnosis. It was an an Ob/Gyn colleague in Hong Kong who discovered that cell free DNA from the fetus can be found in blood of pregnant women, and very early in pregnancy can be used to detect chromosomal abnormalities in offspring in maternal blood during the 1st trimester of pregnancy.
Pursuing the same approach with spent media has been the goal of investigators now for a good number of years. Several published studies, with one exception, all reported that current technologies were still inadequate and resulted in clearly inferior results to biopsy-driven PGS/PGT-A. Moreover, to our best knowledge, not a single published study, not even the one exception that reported relatively favorable results in comparison to invasive PGS/PGT-A, suggested that nPGT-A was ready for clinical application. All, indeed, pointed out that current abilities to differentiate between fetal and maternal DNA in those small amounts of DNA found in spent media was inadequate to reach clinically reliable conclusions. Yet, we are aware of at least two large IVF centers/chains that have started offering in-house developed nPGT-A in place of invasive PGT-A and even advertise those services publicly on their respective websites.
To say that we are surprised is an understatement because, even though CHR, in principle, has for almost two decades been opposed to utilization of PGS/PGT-A in most women and has vigorously criticized the unvalidated introduction into clinical IVF practice of PGS 1.0 through PGS/PGT-A 3.0, we never would have expected IVF centers to start utilizing nPGT-A, when practically every published study so-far has demonstrated poorer outcome correlations with nPGT-A than with invasive PGT-A. In other words, knowing that PGT 3.0 has failed to demonstrate outcome advantages for IVF, these IVF centers now utilize an even inferior test to diagnose allegedly chromosomal-abnormal embryos.
CHR fails to see the logic in this practice and, as of this point, considering that this test is meant to determine which embryos can be transferred or must be disposed of, does not consider this practice to be in the best interest of patients with infertility.
One concluding remark: We above pointed out the soon to be published paper that in detail explains biological, mathematical and technical reasons why promises made by the genetic testing industry for PGS/PGT-A simply cannot be fulfilled. Among the two major biological reasons is an important observation, first made several years ago in mice. It now recently, in a collaborative paper between Rockefeller University and CHR investigators that won this year’s basic science research award at the annual ASRM conference, was also demonstrated in human embryos and human gastruloids: Embryos possess an innate ability to self-correct by destroying selectively aneuploid cells and having them undergo apoptosis. Even assuming a PGT-A diagnosis of aneuploidy, whether invasive or non-invasive, to be technically correct and clinically accurate, what would then be the purpose of such a procedure if such an embryo still has a high probability of self-correcting downstream? In short, CHR strongly advises against all forms of PGS/PGT-A as a routine add-on to IVF.
This is part of the December 2020 VOICE!
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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