Why “engineering” the future of Reproductive Medicine will not work: Learning from past mistakes
By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He can be contacted though The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu
Today’s postings is an article by Norbert Gleicher, MD, Medical Director and Chief Scientist of the CHR in NYC, in which he offers his opinion why U.S. and international live birth rates after autologous fresh IVF cycles have been steadily declining since 2010-2011. And the explanations he offers will likely be – at least to a degree - unexpected for many readers.
The concept of embryo selection has been a dogma of IVF practice almost since its inception. What it means is that every oocyte and embryo cohort produced in an IVF cycle should have a (or a few) best embryos with highest pregnancy and live birth chances. The purpose of embryo selection is then to find this/these embryo(s) from among all others in the cohort more efficiently than standard embryology already does.
No subject and no single hypothesis over more than 40 years of IVF practice has been more investigated and more invested in than the concept/hypothesis of embryo selection, which Gleicher now describes as the biggest error and waste in the history of IVF. But there are, of course, also other issues that have and still are adversely contributing to the decline in successful IVF cycle outcomes over the last approximately 15 years. And you should not miss this original article!
- The Editorial Team
BRIEFING: Norbert Gleicher, MD, the Medical Director and Chief Scientist of the Center for Human Reproduction (CHR) in NYC offers here a quite challenging analysis of current IVF practice. Building on the fact that live birth rates in fresh autologous IVF cycle in the U.S. (and in most other parts of the world) have been declining from an all-time peak around approximately the years 2010 – 2011 while IVF cycle costs have been dramatically increasing, he is pointing out the main reasons for these developments. And they are likely not what you expect!
“Developing” not “engineering” should be the goal of infertility practice
For several reasons - intending to present to its readers recent innovations in IVF and reproductive medicine - a relatively new virtual newsletter caught our attention: First, because we had found earlier issues of this newsletter quite interesting and, at least on one occasion had already referred to an article in one of our medical literature reviews in the VOICE. But the principal reason why this article had a special impact (we will later discuss one more important reason) were only a few words in its heading which were supposed to convene its principal purpose, - “engineering the future of reproductive medicine.”1
Title and introductory image of an article by Prof. Zeev Shoham, MD, published in the Worldwide-IVF Newsletter, which provided
the impetus for this article.
What was then so special about these six – obviously very innocent sounding – words?
The answer may surprise because, having especially in most recent years become increasingly convinced that infertility practice over the last 20 years has stagnated and, in many ways even regressed, these six words perfectly crystallized the reason for this stagnation: Instead of “developing” the infertility field further, infertility practice has for much too long been trying to “engineer” the future of the field.
With both of these words on first impression potentially appearing to have very similar meanings, what then could be important enough a difference between “developing” and “engineering” the future of infertility practice? The answer may once again surprise because the difference is not only – as we in medicine are used to strive for – statistical significance; on more careful reconsideration, it is, indeed, much more profound than that.
Let me explain: Anything we engineer is based on a purpose. We are engineering a building to live or work in it, a car to drive us from point A to point B, an elevator to allow us to avoid stairs, a toot brush to clean our teeth. But engineering a device or even a process in support of achieving a goal is always the second or even a third step in the development of an end product. Long before the engineering process can start, there – first of all – usually must be a need. Then, as a second step, a hypothesis is developed how this need theoretically may be remedied.
This may include the building of models, all kinds of calculations based on solidly established rules of physics, economic, etc., (i.e., that a properly engineered car would not drive is basically impossible, that a properly engineered building would collapse is unthinkable). In other words, engineering establishes virtual certainty of being able to accomplish a goal that only a relatively short time earlier may just have been a little speck in the imagination of a smart person (think Elon Musk – by profession an engineer – for the first time thinking about an electric car). By the time Musk had the blueprints ready for the first Tesla model, there was no doubt that this newly conceived car would drive and would drive well, could be produced at a cost that allowed a profit upon sale, etc.
But medicine (and science in general) is different: Here everything, of course, also starts with a need, followed by a hypothesis about how to resolve this need. This hypothesis, however, cannot solely rely on previously confirmed laws of physics, biology, economy, etc. As medicine and science in general never have the same certainty that engineering has in its underlying tools, any medical idea and/or concept, of course, must be scientifically confirmed before formally entering clinical practice.
Yes, we can plan studies to test a new drug, a new treatment algorhythm, a new surgical procedure, or a new test and we can do these studies at highest and most expensive evidence levels (prospectively randomized studies) or lower levels (other study designs). But we will never even come close to the certainty of success of a well-engineered project because even the best prospectively randomized clinical trial will not and cannot apply to every potential patient.2 Yet, even a just decently engineered car will still always drive and even a just decently engineered building will still likely not collapse whoever enters and, while some tooth brushes may last longer than others, all can at least be used for some time.
In other words, if a process is initiated or a product is launched based on solid engineering, the expectation is appropriate that this endeavor will offer an expected outcome. In medicine, even if best tools are used in attempts at confirmation of effectiveness, this same level of certainty can never be achieved. And this is the case even under best of all circumstances. One can imagine how only unlikely expectations will be met if confirmatory tools used to show efficacy of a medical treatment are not even at highest evidence level. Or – as in the last 20 years in fertility practice has happened over and over again, - a large number of treatments, called “add-ons” have been brought into clinical IVF practice with at times highly exaggerated claims, - simply based on a brilliantly sounding hypotheses, though without confirmatory studies.
And the most frequent reason why this has been happening – and not only in reproductive medicine – was, indeed, the incorrect assumption that medicine can “engineer” progress by – like engineers – simply building on irrefutable evidence and experiences from the past. As convincing as this past evidence may appear, it for several reasons may not be applicable: It may have been obtained in a different patient population, under different conditions, and with known or even unknown co-dependencies. Even engineering understands that universality is not limitless: While still applicable to a large number of structures in a given geographic risk area, engineering requirements for buildings in an earthquake zone will, for example, universally be more stringent.
Individualization in medicine is, however, a much more profound need than in engineering (not so, however, with architecture and interior design) because individual patients can, of course, vary from each other to highly significant degrees, - even if they are neighbors.
The false assumption that we can “engineer” clinical practice by, simply, extrapolating from past intellectual experiences has been at the core of practice patterns that not only have been fully integrated into routine IVF but have become dogmatic component of this most important infertility treatment, such as (and more on those below) the general concept of embryo selection, routine culture of embryos to blastocyst-stage, exclusively single embryo transfers, routine preimplantation genetic testing for aneuploidy (PGT-A, in increasing numbers of clinics, indeed, mandated), embryo banking in place fresh embryo transfers, time-lapse imaging, endometrial receptivity testing, etc.
All of these practices (and many others), unfortunately, universally have gained in popularity, even though increasing evidence has been developed demonstrating that their alleged outcome benefits in IVF cycles don’t really exist. As already noted, this evidence - more often than not - moreover suggested that most of these “add-ons” in selected subpopulations of patients, indeed adversely affect IVF cycle outcomes and, moreover, lead to declining live birth rates all over the world in autologous fresh IVF cycles.3 They, moreover, of course also increase costs, - the end result being that IVF cycle costs have steadily increased, while IVF cycle outcomes have been steadily declining.
Unsurprisingly, these two trends have been accelerating in parallel with the growth and development of a financially strongly motivated support industry for the infertility field and especially IVF, which by now has even penetrated clinical IVF through non-professional (i.e., non-MD) ownership of fertility clinics. A recent Lancet editorial noted that in the U.S. already over a third of all IVF cycles are done in clinics owned by private equity firms and that PGT-A is done more frequently in equity-owned clinics,4 an observation recently also reported by the CHR’s investigators.5
leading – as note in the introduction - to stagnation and even regression in IVF cycle outcomes worldwide, including in the U.S.5 “Engineering” the future of reproductive medicine and especially infertility practice, therefore, is exactly what must be stopped, hopefully to be replaced by organic “development” of truly best-evidence-based practice, - fully recognizing that best evidence never can be perfect but – at absolute minimum must be transparent and honest.
The remaining part of this communication will outline how big parts of what has become routine worldwide IVF practice are really useless and wasteful “addons” to IVF, often even damaging to patients’ IVF cycle outcomes. Most of these integral components of the IVF process yet are still increasing in utilization in routine U.S. clinical practice.
Where IVF practice started going wrong: The concept/hypothesis of embryo selection
It all started in the early days of IVF when the concept was born that every oocyte/embryo cohort in an IVF cycle must have a “best” egg/embryo. Who invented the concept and when is unclear; the concept – or should we better call it a hypothesis – however has dominated IVF-related research and clinical practice since the early days of IVF. It, however got supercharged by what has, likely, been the most damaging publication to the IVF field ever, the in the year 2000 published paper by Gardner and Schoolcraft (with 3 more co-authors), in which the authors concluded – and we are quoting: “The ability to transfer one high-scoring blastocyst should lead to pregnancy rates greater than 60%, without the complications of twins.”6 To the detriment of the IVF field, this paper, unfortunately exerted very significant influence on IVF practice worldwide and, indeed, does so to a degree to these days.
Even though a quarter century after this publication it has become indisputably obvious that practically everything about this paper was incorrect, remarkably, neither authors nor the journal where the article was published have found it appropriate to withdraw the paper, - or at least to publish a correcting commentary. This now must be stated loud and clearly because everything about the concept/hypothesis of embryos selections has since been established as biologically, physiologically, clinically and, ultimately, mathematically incorrect and, therefore, has become indefensible. To the applause of a surprisingly large number of colleagues, we here at the CHR, indeed, made this argument in a recently published paper in the medical journal Human Reproduction Open.7
Gardner and Schoolcraft’s paper not only turbocharged the concept of embryo selection but also initiated a worldwide IVF practice change form routine dya-3 cleavage stage transfers to day-5 (and now up to day-7) blastocyst-stage transfers, both practice patterns which by now have been indisputably demonstrated not to improve IVF cycle outcomes, yet are now by a large majority of IVF practitioners still considered practice dogmas. This opinion still prevails, even though nobody but highly selected good-prognosis patients – likely representing only approximately 15% of a general patient population at most, will demonstrate alleged pregnancy rates in the original paper (which had studied only best-prognosis patients) , while a much greater percentage of women will actually loose pregnancy chances to a significant degree because none of their embryos will survive in vitro culture to blastocyst- stage (the still made argument by some proponents of blastocyst-stage culture that this is due to poor embryo laboratory practices has been solidly rebutted!).
But the damages caused by the Gardner and Schoolcraft paper to IVF practice does not end here: Blastocyst stage embryo transfer, as noted in above quotation of their abstract summary, also – favors elective single embryo transfer (eSET) because it minimizes twin pregnancies. And twin pregnancies, of course, are widely (even by ASRM and ESHRE) - because they allegedly “increase pregnancy risks to mothers and babies” - considered a really bad IVF outcome.
This widely held believe has, however, also been solidly rebutted once the singleton to twin pregnancy comparison is conducted statistically correct. Historically that has not been the case in most published papers alleging increased twin pregnancy risks because these papers incorrectly compared apples and oranges - the birth of one child to the birth of two children. If compared correctly (one twin to two consecutive singleton pregnancies), the alleged increased risks to mother and offspring basically disappear.8 Many potential mothers (and their partners) with longstanding infertility, of course, would like twins more than anything else. Twins, therefore, can become a wonderful choice for patients, - of course only if mothers have the physical health to tolerate the increased physical stresses of a twin pregnancy.
And then there is, of course, PGT-A, a procedure, currently likely the most expensive, useless and, often, even harmful addition to IVF practice, now already use in more than half of all IVF cycles in the U.S. Again, basically another disproven hypothesis that was allowed to become a routine part of IVF practice without any evidence that claims made in its favor were supported by serious scientific evidence.
In addition, PGT-A is, of course, yet another embryo selection method alleged for over 20 years to improve IVF outcomes, which has been proven to do nothing like that, as even the ASRM had to finally acknowledge: It does not improve pregnancy rates, not live birth rates, not miscarriage rates, and not even time to pregnancy.9
For unclear reasons the ASRM described blastocyst-stage culture (in place of cleavage-stage culture) as standard of care in IVF. Proponents of PGT-A, therefore, have argued, if we already are culturing embryos to blastocyst-stage, why not at the same time also biopsy them for PGT-A, and freeze them rather than transfer them fresh.
So called all-freeze cycles – in place of fresh embryo transfers have become another “fashion of the moment” in IVF, even-though scientific evidence quite categorically demonstrated that alleged IVF cycle outcome improvements are pure fantasy. And, yes, PGT-A, of course, adds at least $5,000 to the IVF cycle bill, which usually is not covered by insurance, even if the IVF cycle is covered. And all-freeze cycles, while they are alleged to safe the embryo transfer fee, what frequently remains unmentioned is the added embryo freezing fee and, of course, the completely new additional cycle charge for a frozen-thawed cycle. In short, already unreasonably high IVF cycle costs in the U.S. just continue to increase without offering any outcome benefits.
The accumulating damage from the industrialization of infertility practice
We previously alluded to the fact that infertility practice – and especially IVF practice – in the U.S. and elsewhere in the world, is increasingly owned by investors rather than physicians and/or academic institutions. We also noted the service industry that has arisen around infertility practice and IVF. It in its early days was mostly restricted to pharma companies producing fertility medications. But while their influence on the fertility field has radically declined, the field has witnessed significantly increasing influence especially from genetic testing companies and private equity companies which are buying up fertility clinics in efforts to establish national networks, and from conglomerates that own provider networks in conjunction with other support services, such as genetic testing companies, financing companies for fertility services, and even insurance companies covering fertility services.
Their influence on ASRM in the U.S., ESHRE in Europe, and other professional societies in other parts of the world is steadily growing and the unsurprising consequences are, of course, not always the best for fertility practice because the loyalty of these companies – understandably - is first and foremost to their investors, which in practical terms means to maximal sales of their products rather than to the overall improvement of fertility services and – for example – improvements in IVF cycle outcomes.
Within this context, one kind of company deserves special mention, and that is the single product company. Here is one historical example to make a point: It was one at the time Scandinavian company that brought the first so-called embryoscope to the market and, by doing so, in a sense revolutionized how most embryology laboratories work. The company at the time presented the concept of a closed incubation system that did not require much intervention between fertilization and blastocyst stage and time-lapse imaging of embryos as the new panacea for IVF that would make everything conjunction with IVF better: better embryology overall, better blastocyst rates, all – of course - resulting in better pregnancy and live birth rates, savings in embryology time per patient, other cost-savings, etc.
None, of course, was ever confirmed. Indeed, to the contrary, what was confirmed is that these systems did nothing of what had been promised, though they, of course allowed for interesting observations in human embryo development and, therefore, turned out to be an at times valuable research instrument.10
But by the time all of that had become obvious, most embryology laboratories had spent already hundreds of thousands of dollar on these systems and, indeed, a whole bunch of companies had started manufacturing them. In other words, the marketing effort of one single company (and, of course, the investment of its owners) not only had created a new industry, but at the same time had dramatically affected the cost of worldwide IVF practice (new equipment costs, of course, had to be amortized) without any of the promised positive effects on IVF outcomes.
And this is only one among many examples of companies which – by their foundation – changed the field of IVF with questionable effects of the IVF field. Igenomix is, of course another such company. Founded based on the so-called Endometrial Receptivity Analysis (ERA, and since then expanded into several other tests, including PGT-A), this test has also achieved dogmatic adulation from a large number of fertility clinics even though its effectiveness has been challenged in several studies and the British Human fertilization & Embryology Authority (HFEA) rated the test red, which means that findings from moderate/high quality evidence shows that this add-on may actually reduce treatment effectiveness in IVF.11
Which brings us back to the introduction of this article and our comment that it was inspired by the IVF-Worldwide Newsletter and its use of the word “engineering” in describing the future of reproductive medicine. We then, however, also noted that there would be an additional issue that attracted us to this article and this issue relates to single product companies because the newsletter featured as an innovator in IVF and reproductive medicine an Austin, Texas -based company with offices in NYC, called Gameto, which has started promoting its first product called Fertilo which – and we are quoting – “is an engineered line of ovarian support cells that aid egg maturation, developed by reprogramming stem cells (iPSCs).”12
And further quoting from the company website: “Maturing eggs outside the body could reduce the need for hormonal injections, improving the patient experience and safety while maintaining efficacy.” The following figure illustrates the hypothesis of this new “engineered” product.
And the company then with carefully chosen wording notes that, “by making these processes easier and less expensive, Fertilo could lower barriers to adoption of IVF and egg freezing, unlocking more of the market and helping more families reach their reproductive goals.”
We were impressed and pleasantly surprised by the conditional tone of this statement ( … could lower barriers ….) at the company’s website because the article in the IVF-Worldwide Newsletter is much less restrained stating that “Fertilo represents a significant advancement in reproductive medicine, offering a less invasive and potentially more cost-effective alternative to traditional IVF methods.”
But then things get even more exiting because in explaining that the FDA approved Fertilo for a Phase 3 clinical trial, the article described this iPSC-based therapy as a “revolutionary breakthrough” and as the “Gameto Fertilo breakthrough.”
But is it really a breakthrough? The CHR has been triggering older women after 1, 2, or 3 days of stimulation already for years. And at least in this older population, it works also without stem cells. And, frankly the Phase 1/2 results don’t really look that good: Fertilo achieved a 70% maturation rate in 40 patients compared with 52% using standard in vitro maturation (IVM). Is that really a statistically and clinically significant difference? And euploid blastocysts were achieved in 10% per egg with Fertilo and in only 2% with standard IVM; - we would argue almost identically poor rates. And how did they get IRB approval for fertilization? That 8/10 Fertilo vs. only 3/10 standard IVM patients had at least one euploid transferrable embryo is, moreover, really presented as groundbreaking, when every serious scientist obviously knows that it is not.
And this is, unfortunately, how so much garbage science has over the last two decades contributed treatments to IVF which in a large majority have not improved IVF outcomes and for many patients have actually reduced pregnancy and live birth chances, while having to pay ever more for every try. We sincerely hope that Fertilo will, indeed, be a successful product that does all those wonderful things it promises to deliver (see below).
More natural
Safer
Faster
More Comfortable
Effective
More Accessible
But we also hope that this does not become yet another add-on to IVF practice that does nothing but increases costs. It would be so much better if marketing campaigns started after publications of real data. That, indeed, should be the law or, at least, the ethical way how innovations are introduced to clinical practice. We must develop IVF through evidence, - not engineer it based on the hunch of the moment!
REFERENCES
Shoham Z. IVF-Worldwide Newsletter. https://ivf.cme-congresses.com/innovation-in-ivf-and-reproductive-medicine-engineering-the-future-of-reproductive-medicine/
Kostis JB, Dobrzynski JM. Am J Cardiol 2020;:109-115
Gleicher et al., Hum Reprod Open 2019(3):hoz017
Editorial. Lancet 2024;404:215
Patrizio et al., J Assist Reprod Genet 2025;42:81-84
Gardner et al., Fertil Steril 2000;7396):1155-1158
Gleicher et al., Hum Reprod Open 2025(2):hoaf011
Gleicher N, barad D. Fertil Steril 2009;91(6):2426-2431
ASRM/SART Practice Committees. Fertil Steril 2024; 122(3):421-434
Bhide et al., Lancet 2024;404(10449):P256-P265
Gameto. https://www.gametogen.com/fertilo/