A PIECE OF MY MIND: WHAT THE HELL IS GOING ON WITH PGT-A?
By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He can be contacted through the VOICE or directly at ngleicher@thechr.com.
Today starts the issue with an article by the CHR’s founder, Medical Director, and Chief Scientist Norbert Gleicher, MD, which—as will quickly become apparent—was not only a piece of his mind, but also a product of his heart. Being blessed with several different areas of interest, which he explored in his over 500 peer-reviewed publications in many of the leading medical and science journals in the world in a career that by now has spanned over 40 years, the issue of preimplantation genetic testing (PGT) of embryos has clearly been a main subject of his interest over the last two decades. After attending ASRM 2025 in San Antonio, he came back with the distinct feeling that, for the first time in many years, something good may be happening in the IVF field regarding PGT for aneuploidy (PGT-A). Considering his track record, we have stopped second-guessing his “suspicions.” He clearly has proven to be much more often right than wrong, and, therefore, we predict that, while readers may not agree with all of his opinions on PGT-A, they—with considerable certainty—will find food for thought in this article on PGT-A.
Some background
If you attended ASRM-2025 in San Antonio, you with great likelihood visited the exhibition hall; and, if you did, you must have noticed the change from last year (and several years before that) in the number of exhibitors trying to sell laboratory services for preimplantation genetic testing for aneuploidy (PGT-A). Until last year, they were everywhere and had some of the biggest booths in the hall; this year, they were almost nowhere to be seen, mostly replaced by companies peddling artificial intelligence (AI) products. And, if still exhibiting, their booth sizes had significantly shrunk.
And a similar disappearance act was also noticeable among oral presentations and posters on PGT-A, and among the relatively small number of abstracts in comparison to prior years, there was clearly little remaining enthusiasm for the test/procedure. Even if you did not attend the conference, you may already have browsed through accepted abstracts.1 The decline in submissions seemed substantial and, after years of mostly glowing reports claiming all kinds of imaginary outcome benefits for PGT-A on IVF, the mood appears to have changed toward a much more skeptical assessment of PGT-A effects, a message we, here at the CHR, have been communicating for almost 20 years: It simply is no longer deniable, PGT-A, indeed, does not improve IVF cycle outcomes in many—if not most—patient populations and under almost all clinical circumstances. It, therefore, is also increasingly difficult to find excused for proponents of PGT-A who, despite constantly increasing evidence to the contrary, continue to claim to claim such benefits in support of continuous routine utilization of PGT-A. Evidence has, indeed, also become overwhelming that, in several distinct patient populations, PGT-A, indeed reduces pregnancy and live birth chances in IVF cycles.
We, therefore, are asking our readers for forgiveness for the somewhat provocative heading of this Opinion article, which, as of this point, we feel is warranted, considering the accelerated pace of changes we have been witnessing regarding PGT-A, especially over the last year. Remarkably, they are happening so quietly that we are asking ourselves whether anybody but us here at the CHR is really noticing, but, maybe, it is more appropriately to ask, does anybody really want to notice?
So, what has been changing?
No worry, we do not want to rehash here the 20-plus-year-long history of PGT-A (under different names), using steadily improving technologies and changing the timing of embryo biopsy from the cleavage stage to the blastocyst stage. Nor do we want to waste space and time on outlining the CHR’s very well-known opposition to the routine utilization of chromosomal embryo testing since approximately 2006, after a Belgian colleague had published two small—and by many fiercely criticized—prospectively randomized studies of what then was called preimplantation genetic diagnosis (PGD) which failed to demonstrate widely expected outcome benefits in IVF cycles. Like almost everybody else in the field, the CHR, indeed, at that time also questioned the validity of the Belgian studies. In an effort to confirm our opinion, we, indeed, decided to double-check our Belgian colleagues’ reported number in the two papers and, to our chagrin at the time, not only confirmed their analyses, but also had to conclude that PGD, likely, even adversely affected IVF cycle outcomes in older women.2
Because this conclusion so much contradicted what, laterally, everybody in IVF at the time believed, we, for over a year, were unable to get a paper published in which we reported the reanalysis of the Belgian data and our new conclusion that PGD, indeed, in older women may actually reduce pregnancy and live birth chances. Several of the leading fertility and general medical journals often outright rejected the submission even without review. Others rejected the submission after review since reviewers simply refused to believe our report.
Only after Mastenbroek et al. published their milestone paper in The New England Journal of Medicine (it previously was one of the journals that had rejected the CHR’s submission without review) which conclusively demonstrated that PGD, indeed, negatively affected IVF pregnancy rates in older women,2 did the editor-in-chief of Fertility and Sterility recall our paper it had previously rejected and ended up publishing it.3
So, without too much further detail, let us here only summarize positive as well as negative milestones in the clinical evolution of PGD/PGT-A, which—in the CHR’s opinion, many years too late—finally have led to a point in time when the utility of this test/procedure for the first time is seriously questioned (BOX 1 below).
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BOX 1. HISTORICAL KEY-MOMENTS IN THE EVOLUTION OF PGD/PGT-A
Late 1990s - When first proposed, the PGD hypothesis was that deselection of “aneuploid” (chromosomal-abnormal) embryos from an IVF cycle’s embryo cohort would improve pregnancy and live birth rates for the remaining “euploid” (chromosomal-normal) embryos, reduce miscarriage risk (because a majority of miscarriages are chromosomal-abnormal pregnancies), and would speed up the time to pregnancy and delivery.
Early 2000s – Two small prospectively randomized studies by Belgian investigators suggested that none of these expected IVF outcome improvements, indeed, were being achieved.
2007 Mastenbroek et al. confirmed the lack of improvement in IVF cycle outcomes and reported actual declines in pregnancy and live birth rates in older IVF patients.
ALL THREE ABOVE NOTED PUBLICATIONS WERE VICIOUSLY ATTACKED BY PGD PROPONENTS AND FAILURE TO DEMONSTRATE OUTCOME BENEFITS IN THESE THREE STUDIES WAS EXCLUSIVELY AND INCORRECTLY ATTRIBUTED ONLY TO POOR TECHNOLOGY, as at that time embryo biopsies were performed at cleavage-stage (day-3), at which time 1-2 blastomeres were removed from a 6-8-cell embryo and ploidy were only determined in the 6-8 chromosomes, most often found to be abnormal in miscarriages.
Late 2000s - Switch from day-3 to day-5 (blastocyst-stage), which accelerated after 2010, with diagnostic accuracy for aneuploidy testing from on average 5-6 trophectoderm cells improved, because of more DNA availability, for more accurate DNA diagnoses of all 46 chromosomes.
PROPONENTS ARGUED THAT THIS “IMPROVED” METHOD OF CHROMOSOMAL EVALUATION OF EMBRYOS WOULD, FINALLY, DEMONSTRATE OUTCOME BENEFITS IN IVF CYCLES THAT USED PGD/PGT-A. BUT THAT DID NOT HAPPEN. THOUGH THE UTILIZATION OF PGD IN THE U.S. AND ELSEWHERE STEADILY INCREASED, LIVE BIRTH RATES AFTER IVF BETWEEN 2004 AND 2016 ACTUALLY WORLDWIDE CONTINUED DECLINING.4
2015 – First, the CHR5 and shortly after that, Italian colleagues6 reported healthy euploid births after transfer of by PGD as “aneuploid-abnormal” reported embryos.
AS OLDER CLAIMS OF PGD-PROPONENTS IN VIEW OF THESE TWO REPORTS WERE NO LONGER SUSTAINABLE, PROPONENTS OF THE TEST/PROCEDURE UNDERTOOK ANOTHER MAJOR RESTRUCTURING, WHICH THIS TIME ALSO INCLUDED A NAME CHANGE FOR THE TEST/PROCEDURE FROM PGD TO PGT-A.
2016 – Aside from the renaming, an additional important change was made: binary reporting of embryo ploidy as “euploid” and “aneuploid” was replaced by adding a third diagnostic category,
“MOSAICISM.”
AS IT TURNED OUT, THIS CHANGE COMPLICATED THE REPORTING OF PGT-A DIAGNOSES FOR TWO REASONS TO SIGNIFICANT DEGREES: (i) Laboratories chose different percentages of the second DNA lineage amounts for the definition of “mosaicism” (initially a range from 21% to 80%; but different laboratories later used different ranges, some a range as narrow as 40-60%). (ii) To this day, PGT-A laboratories uniformly define “mosaicism” incorrectly. The correct and universal biological definition of “mosaicism” has for decades been the PRESENCE OF MORE THAN ONE CELL LINEAGE IN A COMPLETE ORGANISM DERIVED FROM A SINGLE CELL. This is, however, NOT the definition of “mosaicism” adopted by the PGT-A testing industry. Basically, inventing its own definition, PGT-A laboratories to this day deviate from the worldwide definition in a crucially important point: Instead of defining “mosaicism” as the percentage of DNA from a second cell lineage in a total organism (i.e., in this case blastocyst-stage embryo), the PGT-A industry defines “mosaicism” as THE PERCENTAGE OF DNA FROM A SECOND CELL LINEAGE IN A TROPHECTODERM BIOPSY OF ONLY 5-6 CELLS. In other words, in place of a percentage among over 150 cells, the definition of “mosaicism” now depends on whether a second cell lineage exists in only 5-6 cells of an embryo. It does not take special math or statistics knowledge to understand the difference: the generally accepted definition of “mosaicism” makes biological sense, the PGT-A industry definition—in contrast—is a crapshoot (depending on where a biopsy is taken) and, therefore, biologically, makes absolutely no sense. Because of the increasing confusion surrounding “mosaicism” diagnoses, many IVF clinics have asked laboratories to return to only binary “euploid” vs. “aneuploid” reporting. Moreover, some clinics have started transferring so-called “low mosaic” embryos (with the definition of “low” once again varying between laboratories and clinics), though a majority still do not. EXCEPT FOR THE CHR (SELECTIVELY), ALMOST NO OTHER IVF CLINIC IN THE U.S. CURRENTLY TRANSFERS SO-CALLED “HIGH MOSAIC” OR EVEN AS OUTRIGHT “ANEUPLOID” REPORTED EMBRYOS BY PGT-A.
After 2015 – Over the following 10 years, significant additional evidentiary data that PGT-A does not improve IVF outcomes have been accumulating, in September of 2024, finally leading ASRM (and its daughter society, SART) toward issuing the formal guidance that PGT-A in all these years of ever-increasing clinical utilization has completely failed to establish any clinical utility.7
CONSIDERING, HOWEVER, THAT PGD/PGT-A IN OVER 20 YEARS OF INCREASING UTILIZATION HAS BEEN UNABLE TO OFFER ANY OF THE PROMISED IVF OUTCOME BENEFITS, IT IS DIFFICULT TO UNDERSTAND WHY THIS GUIDELINE DID NOT ALSO REACH THE ONLY ETHICALLY AND CLINICALLY ACCEPTABLE CONCLUSION THAT PGT-A, THEREFORE, NO LONGER SHOULD BE OFFERED AS A ROUTINE CLINICAL TEST/PROCEDURE.
This conclusion is, indeed, further supported by considerable evidence in the literature in recent years suggesting that PGT-A in selected subpopulations not only fails to improve IVF cycle outcomes, but actually reduces pregnancy and live birth chances. This fact is probably best born out by PGT-A mandating blastocyst-stage culture (rather than cleavage-stage transfers) as well as cryopreservation of all embryos and then subsequent thaw-cycles. With cryopreservation, loss of at least some embryos is practically unavoidable. This fact alone, therefore, irrefutably demonstrates that cumulative pregnancy and live birth chances for any IVF cycle’s embryo cohort will, at least to a minor degree, adversely affect this cohort’s cumulative outcome chances.
2023 – Class Action Suit against IVF clinic chain regarding PGT-A settled in Australia.
2025 – Several Class Action Suits underway against selected U.S. PGT-A laboratories, in principle claiming incorrect outcome claims and/or informed consents by PGT-A laboratories.
How then is PGT-A best summarized up to this point in time, when most recently available data still suggest that—at least until very recently—the clinical utilization of PGT-A has continued to increase, and over half of all U.S. IVF cycles (including donor egg cycles, using carefully selected and young egg donors) currently utilize PGT-A. In several IVF clinics and clinic networks, utilization of PGT-A, indeed, is a condition for starting an IVF cycle. BOX 2 attempts to offer answers.
BOX 2. THE CHR’S CURRENT CONCLUSIONS ABOUT PGD/PGT-A
PGT-A—in contrast to years-long representations by its proponents—does not improve routine IVF cycle outcomes7 and, indeed, in several subpopulations of infertile women, adversely affects pregnancy and live birth chances in IVF.
The hypothesis of PGT-A—and yes, PGD/PGT-A was never more than an unproven hypothesis—was based on a poor understanding of genetics and an even poorer understanding of embryology and reproductive biology in general.
That an unproven test/procedure like PGD/PGT-A, which determines daily decisions about the fate of thousands of human embryos, has not only been allowed in practice for over 20 years, but is still allowed to be actively promoted and clinically utilized, is, in its ethical and clinical relevance, unprecedented in medicine, and must be further studied in causality to prevent similar clinical missteps in infertility practice.
Current analysis suggests the following contributing causes to the current PGT-A fiasco:
(i) PGD/PGT-A has seen increasing clinical utilization over more than 20 years, even though its basic hypothesis was never confirmed, it never fulfilled promised outcome improvements in IVF, and it added significant cost to already very costly IVF practice.
(ii) Different from traditional best clinical and ethical medical practice, the onus of proof was never put on proponents of PGD/PGT-A to confirm their hypothesis, but was demanded from opponents who were asked to disprove the hypothesis.
(iii) Lack of adequate communication between the research bench and clinical practice in reproductive medicine has, unquestionably, greatly contributed.
(iv) Instead of turning to reproductive biologists and embryologists for “expertise,” the field mistakenly identified the required “expertise” among geneticists who, indeed, had genetic expertise, but lacked understanding of reproductive biology.
(v) Consequently—as noted in BOX 1—whenever opponents of PGD/PGT-A reported findings that contradicted beneficial outcome claims of proponents of PGD/PGT-A, (genetic) “experts” attributed these findings to technical shortcomings of assays in the detection of embryo aneuploidy, rather than considering potential errors in their understanding of basic biology of preimplantation-stage embryos. This excuse of the genetics community permeates PGT-A advocacy to this day (i.e., “your laboratory is just not good enough”), simply not understanding that the biology of preimplantation-stage embryos is the real explanation of PGT-A’s failures. Aneuploid cells at blastocyst stage must be considered as “normal”, with many embryos self-correcting downstream in the embryonic lineage, though not in the extra-embryonic lineage (the trophectoderm) from where PGT-A biopsies are taken.8
(vi) Yet the infertility field ceded to unqualified geneticists significant control over the IVF process, as, for example, demonstrated by ASRM guideline documents repeatedly referring to (and relying on) professionally truly incompetent guidelines from a small and highly conflicted genetics society, the Preimplantation Genetic Diagnosis International Society (PGDIS).9,10
(vii) Important secondary consequences of routine PGT-A utilization in IVF have so far, moreover, not been addressed, yet can be expected to be highly significant: PGT-A, for example, is, of course, closely linked to routine blastocyst-stage transfer, which has become standard of care in IVF as well as to routine single embryo transfers.
(viii) PGT-A, moreover, with considerable likelihood (in association with routine blastocyst-stage culture and too broadly used single embryo transfer), has since 2010 been the principal culprit in steadily declining pregnancy and live birth rates in U.S. autologous IVF cycles (as well as in other regions of the world), first reported in 2019.11
Current conclusions, therefore, mandate the following:
(i) Having now, with considerable unnecessary delay, finally concluded that in over 20 years of clinical utilization, PGD/PGT-A has not established any clinical utility,7 it is difficult to understand why ASRM has not reached the only logical conclusion that can be derived from this opinion, that the routine utilization of PGT-A practice must be discontinued. It simply makes no sense to spend money and effort on something that, as everybody now finally agrees, doesn’t do anything good in an IVF cycle. The same obligation, of course, also applied to ESHRE and other fertility societies.
(ii) That such an opinion will, for economic reasons, be strenuously opposed by the genetic testing industry and—it must be acknowledged—by some (maybe even many) IVF providers who basically split the income from PGT-A with PGT-A laboratories by charging for the embryo biopsy, can be expected. Still, fertility practice must finally “come clean” on this issue.
(iii) If fertility practice will not lead this effort, fertility clinics will, ultimately, be dragged into the currently already ongoing class action litigation against PGT-A laboratories.
(iv) With large numbers of post-PGD/PGT-A embryos currently still cryopreserved in the U.S. and around the world, it must be openly communicated to the public that many embryos currently refused transfer by IVF clinics may, with only minimal risk, still have varying degrees of likelihood of pregnancy and live birth chances.
(v) Finally, as repeatedly noted by the CHR in its publications (CHRVOICE and The Reproductive Times), the genetic testing industry, promoted by many of the same genetic “experts” who have been responsible for many of the false representations regarding PGD/PGT-A, has initiated a marketing drive for a new and once again completely unvalidated test also requiring embryo biopsy, so-called polygenic risk scoring (PGRS also called PGT-P). It behooves the infertility field not to fall once again for what can only be described as an even more absurd marketing drive than PGD/PGT-A ever was.
A word about responsibility
Considering the fact that that many thousands of human embryos are daily produced in IVF cycles in the U.S (and many more, of course, around the world), are tested and judged with PGT-A regarding their alleged chromosomal complement, and then are—based on this judgment—transferred, cryopreserved, or even discarded, one must ask where is the special consideration and moral status basic science and medicine has always claimed to be giving human embryos and, more recently, even so-called ”embryo-like-structures”12 when it comes to the daily practice of IVF. Let us, therefore, address here the responsible parties for the mess PGT-A currently finds itself in:
We physicians
It, of course, all starts with the ethical obligation of us physicians to serve our patients to the best of our abilities when infertility patients seek out our help with, in principle, only one desire, to conceive and deliver a healthy offspring!
If it is, indeed, our duty as health care providers to advise and help our patients to the best of our abilities, where else in medicine have physicians been not only passively providing, but actively, and at times aggressively promoting, an unproven medical service at quite significant costs (and outside of insurance coverage) that in over 20 years of clinical utilization has been unable to offer any outcome advantages?7 One, indeed, has to wonder how colleagues who to this day routinely recommend PGT-A to their IVF patients explain this not only to their patients, but to themselves?
Having likely been the longest, but certainly the loudest and most outspoken, provider of IVF services in the U.S. opposing the routine utilization of PGT-A in IVF, the CHR (and all of its staff) do not revel in sentiments of “victory” in the decades-long, at times quite uncomfortable, conflict with proponents of PGT-A, but we have to acknowledge that we find ourselves at times questioning the reality of the situation when meeting some of the most aggressive proponents of PGT-A in the past, who always dismissed every single criticism of the test/procedure out of hand, but now, suddenly, claim to have always questioned “how PGD/PGT-A was performed.”
Where were they when patients were refused access to IVF unless they agreed to PGT-A? Where were they when huge numbers of false-positive embryos after PGT-A were either not used or even discarded? Have they ever wondered how many of their patients ended up with third-party donor eggs and embryos because good eggs and embryos were not used because of their PGT-A results? Or have they ever asked themselves how many of their patients, based on their recommendations, gave prematurely up on having children at all?
From not even one of those vehement proponents of PGT-A, and they know who they are, have we ever heard a mea culpa! And neither have, of course, their patients. Yet, based on a very reliable source, one of the most outspoken and most prominent proponents of PGD/PGT-A was the first to contact the plaintiff lawyers who filed the U.S. class action suits against PGT-A laboratories in 2024, offering, of course, not out of goodwill or remorse alone, his services as an expert witness.
Considering all the damage caused by PGD/PGT-A to so many of our IVF patients worldwide, the responsibility, of course, starts with us physician providers of IVF services because, without our recommendations, in many cases strong encouragement, and in some IVF clinics even mandates, only very few patients would voluntarily choose to add the significant costs of PGT-A to the already often almost unaffordable costs of IVF. And there is no excuse for us physicians because we should have known better, and over 20 years of PGD/PGT-A utilization is simply too long for any kind of excuse.
Government authorities
But we providers of fertility services are by no means alone: Patients harmed by the use of PGD/PGT-A have also to thank our government: It is interesting to read in the lay press, whenever the subject of infertility comes up, how “unregulated” IVF is in the US in comparison to, for example, the UK and many other developed countries. But that is incorrect! In many ways, the US is, when it comes to IVF practice, indeed the most over-regulated country in the Western world. The problem is not under-regulation, but extremely poorly over-regulation!
Here is a quintessential example: Under Congressional mandate, all IVF clinics in the U.S. must report to the CDC all started IVF cycle and their outcomes. At the CDC, it takes a group of government bureaucrats ca. three years to publish a report (data from the most recently available year at the time of this writing are from 2022). One, of course, cannot be too surprised by this ridiculous delay because it, of course, also takes our federal government several months to get final election results, when even some third-world countries can do this on the day of the election. In short, with this group of government bureaucrats under the protest of some of our professional societies allegedly laid off by the Trump administration’s Department of Health and Human Services amid recent job cuts at the department, it is currently unclear where, when, and how the CDC will continue publication of these annual clinic-specific outcome data.13
And why has this been done in the first place? First of all, we assume because Congress mandated these reports (and who knows why, considering the fact that, over decades, Congress has demonstrated absolutely no interest in these results). And secondly, one cliché, of course, being as good or bad as any other one, likely, with the intent to inform the public.
At least on first impression, both of these motives seem like reasonable motivations, but neither, in fact, is. And here is a good example of why these reports are, indeed, a major problem: For example, the 2022 median age for all US IVF clinics reporting to the CDC was 36.2 years, when at the CHR the median age at that point was 43 years (it, in 2024, reached 45). And older patients, of course, also means lower pregnancy and live birth chances. Clinic outcomes at a clinic with a median age of 36 will, therefore, always be better than outcomes with a patient population with a median age of 43 or even 45.
But here is the absurdity: Every annual report published by the CDC is preceded by the absolutely correct statement that the report (for the above outlined reasons) should not be used to compare IVF clinics. And if neither Congress nor the public can judge individual IVF clinics based on these reports, what is then their purpose? These reports, indeed, invite cheating in which clinics treat because the goal is no longer providing patients with the best treatments, but how to make the clinic’s cycle outcomes look the best, because the only reason for patients to look at these reports is to compare clinics.
And what are the consequences? Difficult cases are often discouraged from pursuing IVF, are discouraged from using their own eggs, and are prematurely advised that their only “realistic chance” is with the use of third-party egg donations. Consequently, the number of autologous IVF cycles after the ages 42-43 in the U.S. has remained minuscule (of course, except at the CHR, where they represent more than half of all patients).
Consider, however, what opportunity for true quality assessment this CDC registry could offer if the CDC just wanted to make the effort. In view of current computing and AI abilities, the amount of valuable quality of care information that could be extracted from these data with appropriate analyses is, of course, remarkable, and those data are currently completely wasted because nobody, neither Congress nor the bureaucrats at the CDC, really gives a damn about the data. To statistically appropriately adjust these data is not that difficult. But why do that, when doing nothing is so much easier? After all, isn’t the Congressional mandate already warranted by just knowing how many IVF cycles every IVF clinic performs?
Lack of quality control at individual IVF clinics is, however, not the only missed opportunity stemming from the enormous data set the CDC receives from most US clinics (despite Congressional mandate, a small number of US clinics do not report to the CDC but, to demonstrate the poor quality of this government’s supervision effort, Congress passed the mandate without outlining an enforcement effort.
The CDC, therefore, does not even have an instrument to enforce the mandate. Such a huge data set could, of course, also become an extremely valuable data source for outcome research in IVF. And while CDC bureaucrats on some rare occasions have published studies, none were ever of major significance, and some were outright ridiculous due to a lack of even the most basic clinical understanding.
But Congress did not pass the reporting mandate because it really cared about IVF outcomes or how well or poorly IVF clinics were performing. Congress passed the law as a purely demonstrable political act to show that Congress was “watching” the IVF field. To the best of our knowledge, IVF is the only clinical medical practice in all of medicine for which Congress has passed such a reporting mandate.
And then there is, of course, also the Food and Drug Administration (FDA) with regulatory function over the IVF field. But, once again, this aspect of government supervision addresses only a small portion of what IVF clinics do, in this case, supervision over third-party gamete donations (I.e., semen and oocyte donations). Approximately every two years, therefore, one morning an unannounced FDA officer in uniform suddenly shows up at all IVF clinics and, depending on the size of the clinic, usually spends one to two days inspecting medical charts and clinic policies regarding all third-party donor activities.
The administrative costs for IVF clinics to support these government mandates are not insubstantial and are not the only efforts and costs because most states, through their respective health departments, also have an IVF-related review process. In New York State, this process, too, involves usually an inspection visit every two years but in clinics like the CHR, which in a majority serves patients from out of state, often also involves one-on-one consultation with senior staff at The New York State Department of Health, usually involving permission to move gametes (eggs or sperm) or embryos into and out of New York state.
The technical review of PGT-A - The FDA is the agency that approved diagnostic tests
The process of PGT-A, whether viewed as a test or as a procedure, has never undergone review by the FDA or any other authoritative body of government and, therefore, was never approved by the FDA or any other regulatory authority. None of the existing PGT-A laboratories has, indeed, undergone any kind of inspection by the FDA or any other government organization. Who, therefore, can be surprised about the clinical mess PGT-A finds itself in, attacked from several sides, of course, including in these pages, by the CHR.
And how unbelievable does it sound that a test/procedure responsible for the fate of hundreds of thousands of human embryos generated every year in IVF cycles, now, for over 20 years of steadily increasing utilization in the U.S., has never undergone any government scrutiny, either conceptionally or technically. In other words, while the American College of Pathology checks whether the thermometers in our IVF laboratory are regularly and correctly controlled, no government agency and/or—for that matter—professional body has ever more than 20 years ever asked whether PGD/PGT-A can differentiate accurately enough between euploid and aneuploid embryos.
Had this been done, it is reasonable to assume that, at a minimum, it would not have taken 20 plus years to discover that PGD/PGT-A never was, indeed, able to make this distinction accurately enough to positively affect IVF cycle outcomes. At maximum, however, large numbers of human embryos which were wrongly excluded from transfers and/or even discarded, would have led to autologous pregnancies, large numbers of women who gave up on their own eggs in favor of third-party donor eggs would still have had children with autologous eggs, and many women who threw in the towel on maternity would be mothers, often already looking forward to becoming grandmothers.
What in many ways can be viewed as one of the biggest tragedies in modern health care could, in other words, have been largely avoided, had the government, in this case the FDA, as the primarily responsible agency to approve diagnostic tests, done its job!
One then may ask, how was it possible that PGT-A was allowed to conquer the IVF process without any FDA approval The answer is simple: PGT-A is sold to the public by the genetic testing industry as a so-called laboratory-developed test (LDT) and the FDA just—one day several decades ago—simply decided that LDTs did not have to be certified by the FDA like most other diagnostic tests and/or procedures. BOX 3 (below) explains the difference between routine in vitro diagnostic tests (IVDTs) and LDTs.
BOX 3. THE DIFFERENCE BETWEEN IVDTs AND LDTs
In vitro diagnostic tests (IVDTs)
REQUIRES FDA APPROVAL
For sale to diagnostic laboratories, health clinics, and consumers
Requires standardized instrument qualification procedures and commensurate training
Test must be pre-validated with data analyses and bio-informatic report
Must also be CLINICALLY VALIDATED
Laboratory-developed tests (LDTs)
DOES NOT REQUIRE FDA APPROVAL*
Developed by a laboratory for only its own use
Only the laboratory has to establish instrument qualifications and staff training requirements
Often, no standard assay is available
Must be CLINICALLY VERIFIED
Can be implemented quickly for emergency use
*Until recently, the FDA chose NOT to review LDTs, even though the agency always claimed to have the right. The FDA in 2024 announced a change of policy in that it would start selectively reviewing certain LDTs, but was stemmed by a court decision 14
The concept of LDTs arose from the offices of country doctors and was never really meant to be applied to corporate laboratories serving a nationwide (and often international) patient population. Moreover, the FDA always claimed to have the legal right to approve LDTs in a similar way to how IVDTs are being reviewed, but chose not to do so. Unsurprisingly, a large laboratory corporation jumped at the opportunity to circumvent FDA approval by simply listing a test (like PGT-A) as an LDT.
Considering the multidirectional importance PGT-A carries in the IVF process, we cannot think of a test that is more deserving of FDA review than PGT-A. Yet, interestingly, PGT-A was not among the LDTs that the FDA in 2024 announced as candidates for initial review. Obviously not happy with the decision of the FDA to—at least selectively—start reviewing LDTs, the laboratory industry went to war and sued. And the US District Court for the Eastern District of Texas, indeed, vacated the newly published FDA rule with the argument that the FDA lacked authority to do so.14
Though this very likely will not be the last word regarding the FDA’s ability to regulate LDTs, it appears reasonable to assume that PGT-A will not become a target of the FDA in the foreseeable future, even if the courts in the end may decide in this matter in favor of the FDA. In practical terms, this means that, from a regulatory standpoint, not much can be expected regarding PGT-A from the U.S. government.
More on professional societies
And then there are ASRM and its sister society SART, with SART managing a voluntary parallel registry of slightly fewer U.S. IVF cycle outcomes than the CDC, if one can call something “voluntary” on which membership in ASRM is dependent. For the same reasons as the CDC registry, the ASRM/SART registry also cannot be used for comparisons between individual IVF clinics.
In a much too complex and long application process, the ASRM, however, at times grants researchers access to this data bank for research projects that allow at least selected adjustments for co-variables, and the CHR’s researchers have on occasion applied and received access to this data bank for certain study purposes.
ASRM and SART also review outcomes of individual clinics and initiate inquiries and sometimes even inspections (for which the clinic has to pay) if certain IVF outcomes of a clinic for several years in a row fall outside of national statistics.
And finally, most IVF clinics undergo a bi-annual in-house inspection of the American College of Pathology for all aspects of embryology laboratory management, which, usually over two days, is the most intense and detailed of all visiting inspections; and these inspections occur in addition to regular mailed trial samples for laboratory tests performed in-house.
In short, the claim that IVF practice in the U.S. is un- or under-regulated is obviously simply incorrect. How poorly and illogically IVF, however, is currently regulated in the U.S., is not only demonstrated by the here presented description of the various review processes IVF clinics have to deal with independently, but is probably best demonstrated by the simple fact that PGT-A, whether viewed as a test or as a procedure, has never undergone review by FDA or any other authoritative body and, therefore, was never approved by the FDA or any other regulatory authority. None of the existing PGT-A laboratories, therefore, has undergone any kind of inspection by the DA or any other federal agency. Who, therefore, can be surprised that, a the CHR and others reported years ago, different PGT-A laboratories often will report different PGT-A results in blinded studies involving the same embryos.
In short, a test/procedure responsible for the fate of hundreds of thousands of human embryos generated every year in IVF cycles, now, for over 20 years of steadily increasing U.S. utilization, has never even been looked at by any government agency! In other words, while the American College of Pathology checks whether the thermometers in our IVF laboratory are regularly and correctly inspected, no government agency and/or professional body has ever asked over more than 20 years ever asked whether PGD/PGT-A can differentiate accurately enough between euploid and aneuploid embryos. If such a question had ever arisen, the answer would have been obvious: PGT-A, after all of those years of use and very obvious technical improvements, still, cannot reliably distinguish between a truly euploid or truly aneuploid embryo. One, therefore, is left wondering, why do IVF clinics still use this test, often routinely, and why is this test still on the market?
Had a formal review by either a qualified professional society and/or federal agency taken place, it is reasonable to assume that, at a minimum, it would not have taken 20 plus years to discover that PGD/PGT-A never was able to make this distinction accurately enough to positively affect IVF cycle outcomes.7 At maximum, however, large numbers of human embryos which were wrongly excluded from transfers and/or even discarded, would have led to autologous pregnancies, large numbers of women who gave up on their own eggs in favor of third-party donor eggs would still have had children with autologous eggs, and many women who threw in the towel on maternity would be mothers, often already looking forward to becoming grandmothers. What in many ways can be viewed as one of the biggest tragedies in modern health care could, in other words, have been largely avoided, had the government, in this case the FDA, as the primarily responsible agency to approve diagnostic tests, done its job, and/or had, frankly, our professional organizations done their job.
References
1. ASRM. Abstracts of the Annual Meeting. Scientific Oral & Poster Sessions Program Supplement. Fertility and Sterility 2025. https://www.fertstert.org/pb-assets/Health%20Advance/journals/fns/FNS_122_4_S_FULLSET-1729883551470.pdf
2. Mastenbroek et al., N Engl J Med 2007;357:9-17
3. Gleicher et al., Fertil Steril 2008;89:780-788
4. Gleicher et al., Hum Reprod Open 2019;3:hoz017
5. Gleicher et al., Fertil Steril 2015;104:e59 (e1-e387, September 2015)
6. Greco et al., N Engl J Med 2015;373:2089-2090 (November 19, 2015)
7. Practice Committees of the ASRM and SART. Fertil Steril 2024;122(3):421-434
8. Yang et al., Nat Cell Biol 2021; 23:314-321
9. Gleicher et al., Reprod Biol Endocrinol 2020;18(1):57
10. Gleicher et al., J Assist Reprod Genet 2023;40(4):817-826
11. Gleicher et al., Hum Reprod Open 2019(3):hoz017
12. Writing Group of the ESHRE Ethics Committee. Hum Reprod 2024;39(11):2387-2391
13. CDC National ART Summary 2022. https://www.cdc.gov/art/php/national-summary/index.html
14. CONGRESS,GOV. https://www.congress.gov/crs-product/LSB11312. Library of Congress. LSB11312