REPRODUCTIVE IMMUNOLOGY: A warning for other subspecialties in reproductive medicine
Norbert Gleicher, MD is the Medical and Laboratory Director and Chief Scientist at the Center for Human Reproduction in New York City. He can be reached through The Reproductive Times or at ngleicher@thechr.com or ngleicher@rockefeller.edu.
This article was modified from an article in the October 2024 issue of the CHR VOICE with permission of the publisher.
Briefing: Reproductive immunology evolved as a distinct subspecialty area within reproductive medicine in the late 1970s and was quickly recognized as an area with the potential for significant contributions to reproductive medicine. The good will toward this new medical specialty, however, quickly abated once some leading reproductive immunology “experts” overpromised in their publications and under-delivered in clinical practice. Becoming commercial vendors of the diagnostic tests they promoted—of course, obvious economic conflicts—also did not help. As a consequence, reproductive immunology to this day is widely dismissed as irrelevant for reproductive medicine. Yet, as immunology in other medical specialties has made substantial progress, reproductive medicine has largely missed out on the opportunity to take part in this progress. Using reproductive immunology as an example, this article reveals the potential long-term consequences the premature and unvalidated introduction of diagnostic tests and treatments into fertility practice can have at a time when the premature introduction and commercial promotion of unvalidated new tests and treatments (often summarized as “add-ons”) in association with IVF has reached unprecedented proportions.
One reason why reproductive immunology to this day has relatively low credibility in the fertility field is a history of false scientific claims, poor-quality studies, and commercial exploitation, especially in the late 1980s and early 1990s. One of the more telling examples was the marketing by some prominent reproductive immunology “experts” of antiphospholipid antibody testing as an almost universal panacea for everything in reproductive medicine. It was also the time when reproductive immunology for the first time was considered a new sub-specialty within reproductive medicine(1) and two journals were founded – the Journal of Immunology in Europe and the American Journal of Reproductive Immunology (JARG) here in the U.S. – which this writer had the honor of editing for almost 20 years.
This author had, indeed, also the honor of being the first head of a formal division of reproductive immunology at a U.S. medical school department, in 1979 formally established within the Obstetrics and Gynecology Department at what then still was called the Mount Sinai Medical Center and now is the Mount Sinai Health System in New York City.
It in retrospect was also the beginning of the recognition that “experts” in a small subspecialty area, otherwise not well understood by many colleagues in the larger field of reproductive medicine, had the opportunity to establish a successful and prosperous clinical practice in their medical field of allegedly special expertise. And establishing practice, among other determinations, meant that they were given the opportunity to define allegedly useful tests in managing clinical practice. These “experts,” however, also quickly discovered that by being the authorities who establishing testing paradigms, they had a unique opportunity to also become the providers of such testing services. And if this sounds familiar, considering developments in other subspecialty areas of reproductive medicine in recent years, this is exactly the purpose of this article.
Several prominent reproductive immunologists, indeed, became the primary purveyors of antiphospholipid antibody testing and of other immunological tests in the U.S., which unsurprisingly created undeniable economic conflicts of interest. In retrospect, this experience can likely be viewed as the dawn of the idea in reproductive medicine that academic research can be expanded into commercial enterprises (more on that below).
This manna from heaven, however, did not last for very long because exaggerations and misrepresentations by the new immunological “testing industry” quite expeditiously became very apparent through the kind of self-control over research all medical fields should exercise. Considering many of the so-called “add-ons” to IVF which in more recent years have been added to routine IVF practice without proper prior validation studies, reproductive medicine appears to have lost this self-control.
Even after exercising proper control, reproductive immunology could not escape a resulting backlash which—unfortunately—to some degree is still ongoing, with one reason likely being that it went to the opposite extreme. Some prominent reproductive endocrinologists (REs)—not necessarily very knowledgeable in immunology of reproduction—simply concluding that practically all reproductive immunology was irrelevant for reproductive medicine (2), thereby almost completely excluding reproductive immunology from the practice of infertility. This experience should be of concern for other specialty areas within reproductive medicine, which—at times for too long—have allowed, and sometimes even promoted, the use of poorly validated tests and treatments.
Regarding immunology, these developments had unfortunate consequences for fertility practice because they happened at the dawn of an incredible surge in immunology knowledge in other medical specialty areas and a greatly improved understanding of the immune system. And this new knowledge has found very valuable clinical applications in many medical fields but—of course—not in fertility practice. Clinicians, it seems, were not really interested and simply never pursued the necessary collaboration with the basic science community other specialty areas have demonstrated.
Reproductive immunology—which really should be an integral part of reproductive endocrinology and infertility (REI), therefore, at best has remained only a peripheral entity within REI. One consequence is too many poor- and too few good-quality papers in the literature, with a recent poor article becoming the “inspiration” for this article. The article referred to is a paper published in Early Human Development (3), generally considered a better journal than its rather low impact factor would suggest.
Its three authors claim as a fact that human pregnancies established with “unrelated” embryos (i.e., egg donation and use of gestational carriers) are “riskier” than normal semi-allogeneic pregnancies, where the birthmother contributes the egg. Evidence for such a claim simply does not exist. Nor do increasing percentages of aneuploidy necessarily support more pregnancy complications on a theoretical level, since at least one hypothesis of allogeneic tolerance argues exactly the opposite, namely that poor allogeneity of the male reduces reproductive fitness of a couple and may lead to increased miscarriage risks (4).
But neither of these argument prevented the authors (all three biologists) from building their own hypothesis around an alleged increased risk of a 100% allogeneic pregnancy in comparison to an only 50% natural allogeneic pregnancy.
It is exactly this kind of unsupported grandiosness in pronouncements that has led reproductive immunology into medical exile. The article, therefore, is here discussed to demonstrate how easy it is these days to plant important-sounding concepts into clinical practice without sufficient evidence. And the ease of the process is, of course, further enhanced if the information comes from recognized “experts.” All three authors are reputable biologists (though not practicing physicians) at very reputable institutions, but really project little understanding of clinical medicine, yet they offer without any hesitation amid the paper’s conclusions “several medical proposals.”
And to be fair, we quote their own words: “First, egg donors and surrogates should be informed of the increased health risks they would face. In consideration of the increased risk” (in our opinion really unproven), “these young, fertile women should not be compared to older, infertile women undergoing IVF; the proper comparison group is other young, fertile women” (an argument difficult to agree to since the age of the egg-donor, of course, defines significant risk). “Second, contrary to some medical advice, perhaps genetically related egg-donors and surrogates should be preferred, all else equal” (the lack of reality in this statement should be obvious). “An immunological matching scheme, like what is used for organ transplants, could improve surrogate pregnancy outcomes” (a rather absurd statement).
One is left wondering who reviewed this paper and how little appreciation for reproductive immunology there really is left in a journal like Early Human Reproduction.
Which brings us back to the important subject of “experts” in medicine, we here recently also addressed when discussing the potential implications of a recently filed class action lawsuit accusing genetic testing companies of defrauding the public in how they promote preimplantation genetic testing for aneuploidy (PGT-A).
As the COVID pandemic well demonstrated, “experts” are one of the weakest points in our national medical enterprise. During the 1970s, as noted earlier, reproductive immunologists were “revealed” in their biases with relative ease and in relatively short time. Contrast this during in vitro fertilization (IVF), for example, with preimplantation genetic testing for aneuploidy (PGT-A), first introduced to IVF practice in the late 1990s and since then steadily growing in popularity. The test is by now utilized worldwide—in the U.S. in over half of all IVF cycles—despite the fact that in over 25 years nobody has been able to demonstrate clinical efficacy for the test, as finally only very recently also for the first time acknowledged in a combined statement by the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) (5).
Or take the concept of endometrial receptivity testing, which, like PGT-A, made all kinds of promises about how it would improve IVF outcomes without fulfilling any of them and, also like PGT-A, gave rise to multimillion-dollar testing companies that offered these tests. The U.K.’s Human Fertilisation & Embryology Authority, or HEFA, rates the test for most patients as red “because the findings from moderate/high quality evidence shows that this “add-on” (to IVF) may (actually) reduce (IVF) treatment effects (6).”
Just as “experts” in reproductive immunology misled the reproductive medicine community and the public about the effectiveness of immunological tests and, in doing so, ruined reproductive immunology’s credibility for decades to come, so must genetics “experts” be held responsible for the huge number of human embryos not used and/or the huge numbers of embryos with excellent pregnancy potential that were simply discarded. Unnecessary prolongation of infertility, considerable additional costs, and unnecessary use of third-party donor eggs were the consequences for large numbers of infertile patients, all because of poorly validated tests introduced into fertility practice at the recommendation of genetics “experts.”
Excessive reliance on “experts” has been for centuries criticized by philosophers, historians, and writers in the humanities with the argument that “experts” are, of course, essential in receiving advice; they, however, should not allowed to be the decision makers and, most certainly, should not be allowed to benefit financially from advice they provide. The incentive to adjust advice according to such financial incentives, otherwise, would be too large.
References
1. Hatasaka et al., J Reprod Immunol 1997;34(2):137-153
2. Hill JA, Scott RT. Fertil Steril 2000;74(3):439-442
3. McCoy et al., Early Hum Development 2024;196:106072
4. Oikonomou et al., Cureus 2023;13(3):e36584
5. Practice Committees of the ASRM and SART 2024; . Fertil Steril 2024; May 18: S0015-0282(24)00241-3. doi: 10.1016/j.fertnstert.2024.04.013. Online ahead of print.
6. HEFA. https://www.hfea.gov.uk/treatments/treatment-add-ons/endometrial-receptivity-testing/#:~:text=Endometrial%20receptivity%20testing%20involves%20taking,receptive%20to%20an%20embryo%20implanting. Next review date: 10/9/25