Why CHR is such a different fertility center

Posted on Jan 18, 2019

Fertility center with a unique institutional structure

When looking at what differentiates fertility centers, all starts with ownership and structure. Traditionally, there were only two formats of fertility centers in the market place, either institutional IVF centers located in hospitals and universities, or private centers, owned by physicians. Institutional centers were usually more academic, pursuing research in addition to offering clinical services, while private centers, with very few exceptions (CHR, likely, being the most obvious one), usually only concentrated on providing clinical care.

As we recently discussed in the VOICE, a third ownership model has arisen over the last decade and has made significant inroads: the investor-owned fertility center. In a process we have given the term “industrialization” of IVF practice, equity investors, viewing fertility centers as a potential growth industry, have all over the world started buying up fertility centers at rapid pace. In the U.S., some very well-known private centers, such as the Colorado Center for Reproductive Medicine (CCRM), which also established a satellite center in New York City, have in the process transferred majority ownerships to investment interests. “Industrialization” is, however, not only limited to privately owned centers. Very recently, the NYU Langone Fertility Center, one of New York City’s oldest and most recognized academic centers, also announced its “affiliation” with Prelude Fertility, currently the largest aggregator of fertility centers in the U.S., supported just for that purpose by a $200 million investment fund from Lee Equity Partners, a New York private equity firm.

Such investments are even coming from outside the U.S. For example, one of the largest East Coast centers, Reproductive Medicine Associates of New Jersey (RMA-NJ) was recently swallowed up by the Spanish IVI Group, which, with 65 locations in 11 countries, represents itself as the largest IVF company in the world. Chinese investors have also been increasingly active in the U.S. market. Beijing’s AmCare, an operator of hospitals and IVF clinics in China, acquired an IVF center in Washington DC in 2017. Chengdu-based Jinxin _is planning a public offering in Hong Kong, apparently attempting to raise $500 million to acquire IVF clinics in mainland China and make acquisitions in the U.S. They already acquired HRC Fertility_, one of the oldest providers offering IVF services in the Los Angeles and Orange County areas in California.

Dr. Gleicher explains why patients choose CHR.

Changes in practice patterns of IVF are, therefore, taking place very quickly. As some areas of the world demonstrate where they have most advanced, patients and physician providers are not always very enthusiastic about the results. The latter have to learn to exist in a practice environment where revenue and profit are suddenly more dominant considerations than clinical outcomes. Most advanced in the world in the evolution of fertility services as an “industrialized” medical specialty is Australia, where only three companies control roughly 85 percent of the IVF market. As we have noted in these pages before, in parallel to growing “industrialization,” Australia demonstrated steady declines in live birth rates with IVF, yet increase in costs and, not surprisingly, declines in patient satisfaction.

Like probably most well-known IVF centers in the U.S., CHR has received quite a number of inquiries from interested equity investors over the last two years, but has no interest in going the route so many other IVF centers have taken and/or are contemplating. The overwhelming reason for that is the unique structure and practice philosophy introduced by CHR’s founder, Norbert Gleicher, MD, in 1981 at the inception of CHR as a full-time academic practice in Chicago, Illinois. Structure and philosophy are well summarized by the three characteristics he chose to describe the principal functions of CHR: clinical care, research and education.

Those functions carried over when CHR became a free-standing private fertility center, first in Chicago and later in New York City, and also defined the personnel CHR hired. Contradicting the longstanding myth that physicians are either good clinicians or good researchers but cannot be both, Dr. Gleicher, from the very beginning, insisted on finding physicians who were excellent clinicians and, at the same time also driven investigators and writers. The same applied to the laboratory staff who were not only expected to be superior clinical embryologists, but also had to demonstrate a strong drive to advance the laboratory practice of IVF through original research.

Though patient care always receives primacy at CHR over all other pursuits, every physician as well as biologist/embryologist is expected to find the necessary time to pursue research and to publish in prestigious medical/science journals. Many good people who could not do both well, therefore, were over the years asked to leave CHR’s employment, often with considerable regret because they excelled in one or the other sphere but not in both.

Besides clinical care and research, the third leg CHR has been standing on is postgraduate education. Building on its initial establishment as a full-time academic practice, CHR always considered the postgraduate education of peers an essential responsibility. Consequently, CHR over decades, and in recent years in close collaboration with the Foundation for Reproductive Medicine, has been conducting postgraduate programs for colleagues in clinical practice and/or basic research. These activities have now expanded into a highly successful annual conference every year on the November weekend before Thanksgiving, the Foundation for Reproductive Medicine Conference for Translational Reproductive Biology and Clinical Reproductive Endocrinology, which has been attracting more than 200 clinicians and basic scientists from over 40 countries every year.

Supporting a sizable research effort and local as well as international postgraduate educational programs, of course, does not come cheaply, which is one reason why we know of no other private fertility center in the U.S. (or elsewhere in the world) that has such clearly outlined purposes to serve the public good.

The CHR model

In many ways, the CHR model is actually an “academic” model. In academic practice at medical schools, faculty members traditionally earned their upkeep by generating grant support for their research projects, with institutions that employed the scientists charging the granting institutions significant overhead costs (often almost as high as grants awarded for research) for providing space and other support. Clinicians, in addition, were often given the opportunity of _limited _private practice, with the institution, again, retaining a significant portion of the clinician’s practice income for practice space, staffing and other overhead support. Most academic clinician-scientists in those days, however, considered private practice only a third priority, after teaching (of students and house staff) and conducting research.

This picture, however, changed radically over the last three decades, as the availability of grant moneys dramatically declined. With less funding for research available from government and private sources, academic institutions became increasingly dependent on clinical practice income from their faculties. Administrations, therefore, expanded private practice within teaching institutions and increasingly forced academic faculties to be more productive in private practice. As a consequence, clinicians became less and less competitive with basic scientists in competing for research grants, creating an obvious vicious circle that discouraged clinicians from applying for grant moneys and, instead, encouraged them to concentrate on in-hospital private practice.

In the infertility field, some of the best academicians, therefore, started leaving academic medicine, arguing that, if they already have to spend a majority of their time in clinical private practice, why not do it for their own benefit. IVF, therefore, started moving out of academia by the early 1990s, with most of the leading IVF experts establishing their own private centers.

CHR, in those days exclusively in Chicago, was no exception. Initially founded in 1981 as one of the first IVF centers in the country and the first in the Midwest, in 1990 starting out with only one other colleague, Dr. Gleicher moved CHR into the private sector where, within two years, CHR became the largest IVF center in the city and one of the largest in the country, performing over 2000 IVF cycles per year, considered a huge number in those days.

Though now a private free-standing fertility center, CHR, however, still maintained its prior academic structure, continuing its clinical excellence, while in parallel developing a rapidly growing research program. In 1998 CHR established a satellite center in New York City in collaboration with a local academic institution, the current CHR-NY. When after a year this joint venture did not work out, Dr. Gleicher assumed primary management responsibility for the NYC center in addition to Chicago’s CHR and, between 1999 and 2004, commuted every week between Chicago and New York City, spending half a week in each city. In July of 2001 he moved the New York center from a rented space on Madison Avenue (now occupied by RMA-NY) into the current building on 69th Street (at the corner of Madison Avenue). By 2004, he merged the Chicago center with that of a trusted colleague and, himself, relocated fulltime back to NYC, where he had initially started his career (as a fulltime academician at Mount Sinai Medical Center - New York) before being recruited as Chairman and Professor of Ob/Gyn as well as Microbiology and Immunology at Mount Sinai Hospital of Chicago and Rush Medical College.

Over the last 15 years, CHR-NY developed a growing reputation as an IVF center of last resort. This development was the result of a strategic decision reached approximately 15 years ago, which determined that, going forward, the aging ovary would become CHR’s primary clinical as well as research interest. This decision not only proved prescient in predicting the field’s future needs but, ever since, also allowed CHR to develop the special expertise that has made CHR the center of last resort for patients from all over the world.

CHR’s clinical and research interests in other areas of the fertility field did not diminish, but the aging ovary clearly became the center’s priority. In the past, before that crucial decision, CHR’s investigators had already contributed major milestones to infertility practice. They, for example, were essential in establishing reproductive immunology as a subspecialty area (Dr. Gleicher established the first Division of Reproductive Immunology in the world at Mount Sinai – New York in 1979 and continued the program then at Mount Sinai – Chicago), was founding Vice-President of the American Society for Reproductive Immunology and the founding editor-in-chief of the American Journal of Reproductive Immunology (AJRI), which he edited for 20 years. Through many publications, CHR investigators greatly contributed to the recognition that autoimmunity is associated with increased miscarriage risk and, till today, in innumerable publications have been stressing the fact that the very special immunological status of pregnancy does not get adequate attention.

At a time when all IVF cycles used surgical retrievals in operating rooms, CHR investigators were the first to report (in the prestigious medical journal, The Lancet) that eggs can be safely retrieved trans-vaginally. They, thereby, revolutionized IVF because vaginal egg retrievals, which quickly became the norm, allowed IVF to move out of expensive hospital settings and, therefore, made the procedure available to a broader public.

Also still in Chicago days, at a time when every tubal obstruction was treated with major surgical interventions, CHR investigators were the first to report successful transvaginal tubal catheterizations, which since then have become routine practice but, unfortunately, are now mostly performed only by our radiology colleagues.

CHR’s great breakthrough in treating older ovaries, whether because of advancing female age or in women with premature ovarian aging (POA), also called occult primary ovarian insufficiency (oPOI), occurred in NYC with the recognition that dehydroepiandrosterone (DHEA) supplementation improves treatment outcomes in women with low ovarian reserve. Since that observation was made (at that point completely unexplained), the need for adequate intraovarian testosterone levels has been well established (DHEA is effective because it is converted to testosterone), and knowledge about androgen supplementation has greatly increased. With increasing prominence of the Internet, and the word about androgen supplementation quickly spreading, CHR started attracting an increasingly cosmopolitan patient population, with most women presenting after they had numerous failed IVF cycles, often at quite a number of different IVF centers. CHR investigators in NYC were also the first to bring the FMR1 (fragile X mental retardation 1) gene into the fertility arena, with now, ca. 10 years later, full recognition being given to the importance of this gene in female, and most recently also in male, reproduction.

CHR and its investigators now hold a large number of patents covering these discoveries and, like academic institutions, shares royalties earned from these patents with the investigators who conducted the research that led to those patents. CHR’s practice model, therefore, is very similar to the traditional academic model, except for the fact that each scientist is no longer expected to bring grant money into the institution (though, if that happens, that, of course, is also rewarded) but, instead earns his/her keep through clinical work.

Why CHR’s patient population is so different from other IVF centers

As already noted above, with the word about CHR’s special expertise with older ovaries quickly spreading, the center’s patient population started to change rapidly, as more and more women with this medical problem approached CHR. As a consequence, median ages for newly presenting women increased year by year. By 2017, the median age for CHR’s IVF patients had risen to 43.0 years, making the center’s patient population the by far oldest among all approximately 500 outcome-reporting IVF centers in the U.S. (and likely the world).

But the center’s patient population also changed beyond age: Even younger women presenting to CHR, usually did so only after they had multiple failed IVF cycles elsewhere. They, practically uniformly, demonstrated extremely low ovarian reserve (i.e., high FSH and/or low AMH). Even young patients at CHR, therefore, are not the “usual” young patients most IVF centers treat (i.e., young women with tubal infertility or with the male partner as the principal cause of the couple’s infertility). CHR, therefore, not only serves the oldest patient population among all U.S. IVF centers but, with over 90% of new patients reaching CHR only after multiple prior failed IVF cycles elsewhere, often at a number of different IVF centers, also likely the most adversely selected patient population of any IVF center.

Still achieving surprisingly excellent outcomes for many of these very difficult patients, the word has been spreading, initially in the U.S. and Canada, but more recently all around the world, resulting in more than half of CHR’s patients coming from long distances to NYC, roughly half from the U.S. and Canada and the other half from overseas. In addition, the selection trends toward increasingly difficult patients continues. Analyzing just obtained data, the figure demonstrates how between 2015 and 2018 the distribution of patient ages changed: The biggest difference can be observed by following the two youngest and two oldest age groups over the four years. As the figure clearly demonstrates, they inverted in prominence: the two youngest groups significantly shrank, while the two oldest groups grew dramatically.

CHR's patient age 2015 and 2018 Proportion of women over 45 seeking fertility treatment grew significantly at CHR from 2015 to 2018.

In summary, CHR’s patients are more and more difficult to treat, a development CHR clinicians and investigators, obviously, are increasingly concerned about. One seemingly obvious reason is that most patients seek out CHR only as a last resort choice. We here at CHR, therefore, frequently wonder how much more we could do for our patients, had they only presented to CHR a little earlier.

While obviously concerning, these trends, at the same time, have paradoxically been the ultimate reason why CHR has been able to develop such a unique expertise in treating highly complex infertility cases. Let us explain: The treatment of infertility is best described as a pyramid: At the base, representing the “easy-to-treat” cases, are patients who, whichever fertility center they choose to attend, conceive rapidly with standard treatments. More “difficult” patients who usually require more attention to detail and individualized care, however, will not receive this kind of attention and expertise in every fertility center. If they choose their center inappropriately, they, therefore, may have multiple failed cycles before reaching the conclusion to turn elsewhere. The more complex the patients’ underlying problems, the longer they will linger in unqualified hands, until they choose a qualified provider at the top of the treatment pyramid, like CHR. Those who finally reach the tip of the pyramid, therefore, represent a concentrated patient population with the most difficult-to-treat infertility problems, often going unrecognized in most first-line infertility centers. Often they also are prematurely advised that egg donation is their only realistic option of conceiving.

The high concentration of the most complex fertility problems in these patients, of course, offers unique opportunities for research. Here is one example: When, a few years ago, one of CHR’s clinical investigators got interested in what happens with advancing age to typical clinical characteristics of women with polycystic ovary syndrome (PCOS), he, to everybody’s surprise, noted that CHR basically never saw PCOS patients with the so-called “classical” phenotype of the condition. Instead, virtually all PCOS patients at CHR were of the “lean” phenotype. According to the literature, both of these phenotypes are, however, evenly distributed in the population, each representing ca. 40% of PCOS patients. Here accidentally discovered absence of “classical” and virtual uniformity of “lean” PCOS patients at CHR, therefore, could have only one explanation: “Classical” PCOS patients conceived elsewhere at other fertility centers before reaching CHR; yet, with “lean” PCOS patients, the opposite appeared to be the case. Since they did not conceive elsewhere with standard treatments, they presented in highly concentrated prevalence at CHR.

This was an extremely unexpected finding because the “classical” PCOS phenotype had generally been considered the by far “less desirable” of the two phenotypes, characterized by truncal obesity, excessive hair growth (hirsutism), failure to ovulate and, later in life, so-called metabolic syndrome. In contrast, as the name already pointed out, “lean” PCOS patients were not obese and also did not carry most of the other stigmata of “classical PCOS.” The question, therefore, arose, why did the seemingly more desirable “lean” PCOS phenotype, actually, represent more-difficult to treat infertility patients?

With this important question arising, a major new research project was born at CHR, leading to publication of a number of papers in the medical endocrine literature that described this all-new phenotype and its ontogeny with advancing age, from the early 20s into advanced ages under the name the hypo-androgenic PCOS-like phenotype (H-PCOS). Only the unique opportunity of seeing such an unusual concentration of H-PCOS patients due to above noted concentration effects, allowed CHR investigators to identify this new phenotype and, once identified, to describe its ontogeny and pathophysiology as a likely autoimmune adrenal condition, characterized by adrenal hypo-androgenism.

Another excellent example why the ability to treat patients at the top of the pyramid offers unique research opportunities is the evolution of HIER (Highly Individualized Egg Retrieval) at CHR. This treatment evolved out of a research project that was initiated a number of years ago by CHR investigators who wanted to find out why pregnancy rates were gradually declining up to age 43 but dropped much more precipitously after that age. Investigating the molecular biology of follicles during IVF cycles at different ages, CHR investigators discovered (and published in two manuscripts) that biological processes in follicles sped up with advancing age, leading to premature luteinization of follicles, which represents a toxic environment for maturing eggs. CHR investigators, therefore, concluded that, in older women and women with POA/oPOI, oocytes must be retrieved earlier, before premature luteinization adversely affects egg quality, leading to the development of HIER.

The impetus for these investigations came, however, from the fact that, in contrast to most other IVF centers, CHR routinely treats large numbers of women who are trying to get pregnant after ages 42-43. The routine utilization of HIER at CHR over the last few years is, therefore, another excellent example for how the high prevalence of a seemingly intractable fertility problem in CHR’s patient population led to an important research project. Starting in the laboratory, the results of this research led, in turn, to a clinical research project that investigated a radical change in IVF practice. Once confirmed as clinically effective, it led to a radical change in CHR’s routine treatment of older women and women with POA/oPOI, utilizing HIER. This radially new treatment approach, since, allowed CHR to report pregnancy and delivery of the oldest woman ever reported in the medical literature to have a child with use of her own eggs and an embryo transfer just weeks short of her 48th birthday.

Fertility treatments with significant differences at CHR

One of the most frequently asked questions from new patients we hear at CHR is, what will you do differently in our case from what we experienced at other IVF centers previously? Most patients are then quite surprised by the answer, which in most cases is that practically everything will be different in the IVF cycle they will receive at CHR from what they experienced before.

One of the most frequently asked questions from new patients we hear at CHR is, what will you do differently in our case from what we experienced at other IVF centers previously? Most patients are then quite surprised by the answer, which in most cases is that practically everything will be different in the IVF cycle they will receive at CHR from what they experienced before.

We then go into specifics and explain to the patients that, in contrast to most other IVF centers, we do not just initiate IVF cycles at a whim but, first, prepare ovaries for up to two months, so they function at peak capability, once we do start an IVF cycle. We also explain that we do not follow in IVF “fashions of the moment,” often introduced to the practice of IVF by colleagues, with really absolutely no clinical evidence in support for claims of improved IVF outcomes.

Differences in CHR’s IVF cycles, therefore, are not only things we do differently from other centers but, at times, simply things we do not _do, which other centers have added to their protocols. Especially in women with low ovarian reserve, “fashions of the moment” often, actually, reduce pregnancy chances with IVF. Many of these “fashions of the moment” have been discussed before in the _VOICE, including mild ovarian stimulation, also called “mini-IVF,” natural cycle IVF, all-freeze cycle for embryo banking purposes, and all-freeze cycles under the argument that frozen-thawed cycle in following months offer higher pregnancy and live birth rates than fresh cycles.

As also well known to readers of the VOICE, the currently for CHR most abusive clinical practice in IVF is, however, preimplantation genetic testing for aneuploidy (PGT-A), previously called preimplantation genetic screening (PGS). We do not recommend utilization of PGT-A/PGS, except in rare cases of gender selection. The principal reasons lie in the inaccuracy of diagnosis and exceedingly high false-positive rates, leading to the unnecessary discarding of large numbers of perfectly normal embryos. Especially women who produce only small embryo numbers cannot afford the unnecessary loss of false-positive embryos. In such women, the procedure not only does not improve IVF outcomes but, actually, significantly adversely affects pregnancy and live birth chances.

Differences of treatments, however, also include many in-house developed new therapeutic approaches. They, therefore, enter clinical utility at CHR long before becoming available elsewhere. Recent examples abound, starting with androgen pre-supplementation prior to IVF in hypo-androgenic women, which CHR started 15 years ago (the first paper was published 13 years ago). More recent examples are the in the prior section noted diagnosis and treatment of H-PCOS and HIER, both now at CHR routine treatments for almost 3 years; yet, only starting to be utilized by other IVF centers.

The world’s oldest woman to give birth with use of her own eggs was triggered with hCG at lead follicle size 12mm. As Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist, recently commented in a presentation on HIER at an international conference, “had anybody told me 4-5 years ago that we would trigger IVF cycles at lead follicle sizes of 12mm (and sometimes even smaller) and get mature eggs, healthy embryos, pregnancies and live birth, I would have declared that person insane.”

Equally unlikely would just a few years ago above described H-PCOS findings have been: That “lean” PCOS-like patients may experience more difficulties in conceiving than “classical” PCOS patients would, simply, not have been credible. That the primary reason for these patients’ difficulties to conceive to a large degree is hypo-androgenism, would also have been difficult to accept because PCOS patients are universally considered hyperandrogenic. Finally, that the hypo-androgenism of H-PCOS is adrenal rather than ovarian was also never a consideration.

Besides here cited example, many other additional research findings are constantly integrated into clinical practice at CHR. In contrast to modifications of IVF practices at other centers, CHR makes such changes, however, only very carefully and after internal validation studies. Whether changes involve laboratory or clinical practices, none is introduced without prior careful validation to make sure that, at minimum, that change does not adversely affect outcomes. This internal validation mandate has proven highly effective. It also has proven valuable not only in protecting clinical outcomes (as in CHR’s decision, despite financial incentives, not to jump on the PGT-A/PGS bandwagon) but also in saving CHR from unnecessary expenditures (as, for example, in not converting the center’s IVF laboratory to automated incubation systems).

The literature demonstrates that in almost all medical specialties it on average takes 12-15 years for new research findings to filter through into daily routine clinical practice. Fertility treatments are no exception. To have a very active research program that constantly offers new hypotheses for clinical investigations is, therefore, a monumental advantage CHR has over many, if not most, other IVF centers. In addition, CHR enjoys the advantage of serving a highly selected patient population with very poor prognoses. This combination of circumstances creates a unique research environment that allows for the recognition of effective treatments in relatively small patient populations. CHR’s, thus, in many ways has recreated the research environment that existed in IVF during the early days, when expected pregnancy and live birth rates were exceedingly low. The rapid progress that IVF outcomes achieved in those days was to a large degree the consequence of small studies that demonstrated “obvious” outcome improvements.

As outcomes with IVF improved, progress became more incremental, and studies that established true validity for changes in treatments required increasingly large patient numbers to achieve required statistical power. Because such studies are costly and often difficult to recruit for, many new claims in the field have increasingly been based on inadequate studies and, therefore, over time have been proven false. CHR investigators also believe that the decline in live birth rates observed all over the world is a consequence of such inadequately performed studies. One, however, must note that, in contrast, practically all by CHR reported innovations, have over the years reaffirmed their validity and values. For that, we have to thank not only CHR’s researchers but, especially, our unique patient population.

What is often misunderstood or falsely reported about CHR

Because CHR has such worldwide recognition and visibility, many perceive it to be one of those mega-centers of IVF that are performing thousands of cycles annually. This is not what CHR is; indeed, it would be impossible to run thousands of IVF cycles at CHR, considering the attention and individualization every patient and every cycle requires.

CHR is also not a fertility center that can compete based on cost of IVF and other fertility treatments. Because of individualization of care for practically every patient, increased staff attention patients with repeatedly failed prior IVF cycles rightly insist on, the center’s overhead costs in the most exclusive area of NYC and CHR’s costly research and educational programs, CHR’s cost structure clearly exceeds other centers'. CHR, therefore, can work only with a limited number of insurance companies that in their reimbursement rates consider the center’s overhead costs. CHR, nevertheless, prides itself on very competitive pricing with other leading IVF providers in the city and across the country and, in fulfilling one of its most basic social responsibilities, offers significant IVF discounts to active duty members of the military and income-associated discounts to local patients without insurance coverage.

Though CHR aggressively protects the many patents its scientists have been awarded, CHR follows in publications and promotions of products a strict conflict-of-interest policy, characterized by full disclosure of all, even only theoretical, conflicts. A prominent member of the genetic testing industry recently accused CHR in a publication of opposing PGT-A/PGS “as a marketing tool to differentiate CHR from other IVF centers." Considering the substantial financial gain IVF centers earn from performing PGT-A/PGS, this is, of course, an absurd accusation and more of a projection. It warrants, however, a clear statement about CHR’s complete independence from _all _commercial influences, as not only demonstrated regarding PGT-A/PGS and other practices of the genetic testing industry CHR opposes, but also when commercial influences of other industrial players misrepresent facts, whether in association with automated embryology systems or pharma company interests.

This is a part of the January 2019 CHR VOICE.

Norbert Gleicher, MD, FACOG, FACS

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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