Reproductive Immunology as a Warning to Other Subspecialty Areas in Reproductive Medicine
Norbert Gleicher, MD, is the Medical and Laboratory Director as well as Chief Scientist of the Center for Human Reproduction in New York City. He can be reached through The Reproductive Times or at either ngleicher@thechr.com or ngleicher@rockefeller.edu.
This article was modified from an article in the October issue of the CHR VOICE with permission of author and publisher.
Briefing: Reproductive immunology evolved as a distinct subspecialty area within reproductive medicine in the late 20th century and quickly was recognized as an area of special expertise with potential of significantly contributing to improvements in various aspects of reproductive medicine. The good will toward this new medical specialty, however, quickly ended when some leading reproductive immunology “experts” overpromised and under-delivered and, by becoming vendors of diagnostic tests – in addition, often over-aggressively promoted them. As a consequence, reproductive immunology to this day i– in our opinion erroneously – is by many reproductive endocrinologists widely dismissed as practically irrelevant. These circumstances surrounding reproductive immunology are here presented in detail to make the point that the in recent years increasingly frequent introduction of often only improperly validated diagnostic tests into fertility practice – and their promotion by alleged “experts”- raises the specter of similar backslashes in other highly subspecialty areas of reproductive medicine with which most practicing reproductive endocrinologists are not especially familiar with. Risks of that happening appear especially likely in genetic – including chromosomal - and genomic testing.
One reason why reproductive immunology to this day has 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 a panacea for almost 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 Reproductive Immunology in Europe and the American Journal of Reproductive Immunology (AJRI) here in the U.S. – for which this writer for almost 20 years had the honor of being the editor-in-chief.
Having had in those early days of reproductive immunology in 1979 also the honor of being the first head of a formal division of reproductive immunology of a U.S. 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, this author, thus, had a variety of vintage points from which to observe this new subspecialty area in reproductive medicine.
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. The “birth” of reproductive immunology – after all – preceded the “birth” of IVF by only a few year. And establishing practice, among other determinations, meant that they were given the opportunity to define allegedly useful tests in managing clinical practice. Moreover, “experts” 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, considering developments in other subspecialty areas of reproductive medicine in recent years, this sounds familiar, - then this article achieved its first desired goal.
Several prominent reproductive immunologists then, indeed, became the primary purveyors of antiphospholipid antibody testing and of other immunological tests in the U.S. which, unsurprisingly, of course 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, - but more on that below.
This mana from heaven, however, did not last for very long because exaggerations and misrepresentations by the new immunological “testing industry” within a relatively short time period became very obvious. A resulting backlash became unavoidable but, unfortunately, went to the opposite extreme, with some prominent reproductive endocrinologists - not necessarily very knowledgeable in immunology of reproduction - simply concluding that practically all of reproductive immunology was irrelevant for reproductive medicine (2), thereby almost completely excluding reproductive immunology from the practice of infertility.
These developments had unfortunate consequences for fertility practice because they happened at the dawn of an incredible surge in immunology research in other medical specialty areas and a greatly improved understanding of the immune system. And this new knowledge has found clinically very valuable applications in many medical specialty fields but – of course not – in fertility practice. Clinicians and serious basic investigators basically never did really get together, as so successfully has happened in, for example, oncology and rheumatology.
Reproductive immunology – which really should be an integral part of reproductive endocrinology and infertility (REI), therefore, at best has remained on the periphery within REI – and considering the lack of good research, at least partially deservingly so. A very recent such paper in Early Human Development (3), actually became the “inspiration” for this article.
Somehow this paper made it through the journal’s peer review process (despite a quite low impact factor, the journal has overall a good reputation) even though it, likely, shouldn’t have. Its three authors – all biologists without clinical training - claimed 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. What their claim was based on remains unclear because evidence for significantly increased maternal and/or fetal risks in 100% allogeneic vs. 50% allogeneic pregnancies really does not exist (which does not mean that some minor outcome differences have, indeed, been reported). Nor do, as the authors also claimed, increasing percentages of aneuploidy necessarily support more pregnancy complications on a theoretical level, since at least one hypothesis of allogeneic pregnancy tolerance argues exactly the opposite, - namely that genetic similarity between partners reduces reproductive fitness of a couple and may lead to poorer implantation chances and increased miscarriage risks (4).
The authors, yet, still claimed that a 100% allogeneic pregnancy (oocyte donor + father or gestational carrier pregnant with an allogeneic couple’s embryo) in comparison to an only 50% allogeneic pregnancy (carrying mother provided the egg) and, based on this obviously very flimsy hypothesis, then even called for changes in informed consent (especially for gestational carriers) and made treatment and informed consent recommendations that equated pregnancy with solid organ transplantation.
It is exactly this kind of grandiosness in pronouncements that has led reproductive immunology into the medical exile it now still finds itself in. All three authors are reputable biologists (not physicians) at highly reputable academic institutions; but, as their paper demonstrates – and of course not unexpectedly considering their lack of clinical training – they lack any understanding of clinical medicine; yet, without hesitation, their paper, still, offers “several medical proposals.”
And we quote: “First, egg donors and surrogates should be informed of the increased health risks they would face. In consideration of this alleged (and in our opinion really unproven increased risk), these young, fertile women should not be compared to older, infertile women undergoing IVF (as if anybody would do that); the proper comparison group is other young, fertile women. Second, contrary to some medical advice, perhaps genetically related egg-donors and surrogates should be preferred, all else equal (the lack of any clinical reality in this sentence should be obvious to everybody). An immunological matching scheme, like what is used for organ transplants, could improve surrogate pregnancy outcomes (undoubtedly an absurd statements that never should have made it through peer-review). Third, more research is needed on microchimerism, sperm exposure, and long-term impact of allogeneic pregnancies on maternal and child health.”
This manuscript, therefore, offers an excellent example for what happens when research bench and clinical practice fail to get together and each side goes off on its own tangent. And in only very few areas of medicine have basic science and clinical medicine failed to collaborate to the degree seen in reproductive medicine. And this does not only apply to reproductive immunology, where here presented example showcases basic scientists off on their own tangent, But, similarly, so have and, often still are, clinicians going of on theirs’s.
Lack of collaboration then not only results in lagging progress (as seen in reproductive medicine not only in immunology) but can also be outright damaging because it can – and routinely does - lead to integration of poorly validated practice patterns into routine clinical care. Immunology is not alone within reproductive medicine in failing to overcome this schism between bench and clinic. Take, for example genetics, - another subspecialty area within reproductive medicine: Here, in so-called preimplantation genetic testing for aneuploidy (PGT-A) of embryos, a small number of so-called genetics “experts” drove clinical practice over 20 years and, as recent history suggests, did not do too well (5).
Which brings us to the enormously (and we are not exaggerating) important subject of “experts” in a small niche of a much larger field of medicine. As the COVID pandemic demonstrated, “experts” in our current national medical enterprise often represent one of its weakest points. Reproductive immunology most certainly does not stand there on its own and/or alone. To the contrary, as noted above, reproductive immunology was “revealed” for what it really was with relative ease and in relatively short time. This, however, stands in stark contrast to, for example, PGT-A of embryos in association with in vitro fertilization (IVF), first introduced to IVF practice in the late 1990s and since then steadily growing in popularity. It 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 was ever 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 let’s look into genomic testing taking for example the concept of endometrial receptivity testing, which, like PGT-A, made all kinds of promises about how it would improve IVF outcomes without ever fulfilling them and - also like PGT-A - gave rise to multimillion dollar testing companies owned by “experts” who promoted these tests. HEFA, the U.K.’s Human Fertilization & Embryology Authority 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).
Like “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 after utilization of PGT-A. 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 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 the advice they provide. The incentive to adjust advice according to such financial incentives, otherwise, would be too profound.
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.