The Changing Practice of Assisted Reproduction

Mostly unnoticed and/or unmentioned by media, because of what has been happening in many countries to national health care systems (the U.S. included), brought on by the COVID-19 pandemic, the practice of medicine is undergoing likely the most dramatic changes in decades. A few trends relate to practically all areas of medicine; others are more specific to individual practice areas.

The coronavirus that our readers must be quite familiar with at this point.

How medicine in general is affected

Among general trends, visits to emergency rooms have drastically declined. This is not necessarily a bad development because large swaths of the population historically, especially in the U.S., utilized emergency rooms for very expensive non-emergent medical care. In compensation, urgent care centers have seen increases in patient flow but, most importantly, electronic medical consultations, practically overnight, have become routine and an integral part of health care.

Before COVID-19 such long-distance consultations were frowned upon by most of the medical establishment, state governments, medical insurance companies, federal governments (who uniformly refused to cover the costs of such consultations), as well as medical malpractice insurance companies (who refused to offer malpractice coverage for such consultations). Similarly, most states have greatly simplified licensing processes for physicians and other medical personnel across state lines, now often offering reciprocity in licensure between states. We consider most of these changes to be positive developments which, hopefully, will be maintained, even once the COVID-19 pandemic is over. But, like with practically all medical interventions, one cannot only look at positive consequences. As the COVID-19 pandemic so well demonstrated, often, indeed, even more important is the timely consideration of unintended negative consequences brought on by medical interventions.

For example, not every patient-physician encounter can be properly managed through virtual contact over the Internet. Often, patients must be examined in order to reach a correct diagnosis. Virtual consultations, therefore, must be carefully restricted to only such encounters that can be managed adequately via any of the now available electronic means, such as Skype (least secure), Zoom or Microsoft Teams. Because for quite some time a majority of CHR’s patients have been long-distance patients, many, indeed, from outside the U.S., our center has already been employing virtual consultations for many years (and, yes, we had to purchase additional malpractice insurance for this purpose because our center’s general medical malpractice insurance did not cover such consultations until very recently).

Unintended consequences of interventions in how health care has been provided during the COVID-19 pandemic have been, to this day, only inadequately explored. Moreover, attempts, almost uniformly, get caught up in the “fog of war” between the country’s two main political parties in preparation for the November 3 presidential election. The attitude of the population toward health care has, however, unquestionably radically changed, not the least because one can no longer deny that considerable trust in the national health care system has been lost. That loss of trust involves health care provider organizations (mostly hospitals and nursing homes), state governments and state agencies as well as the federal government, including federal health agencies, like the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). Likely the best evidence is that, according to opinion polls, currently, only ca. half of the population would be willing to get immunized against the SARS-CoV-2 virus, even if a vaccine becomes available, is approved by the FDA for human use and offered for free.

Potential consequences of such loss of trust can be highly significant: Hospitals, for example, are largely empty because the public does not trust in their ability to protect patients from the virus. A recent CHR patient with proven antibody immunity to COVID-19, for example, was, nevertheless, required by her employer to temporarily quarantine at home and undergo fresh COVID-19 testing, just because she accompanied a friend during an emergency room visit. Rightly or wrongly, much of the public feels that visiting a hospital, currently, increases the risk of being infected with COVID-19.

Unsurprisingly, the general population over the last six months has been delaying routine medical maintenance care. This has been well demonstrated by reported declines in cancer diagnoses, immunizations of children (both, of course, troubling findings); yet, interestingly, also by declines in acute cardiac events (of course, a potentially positive finding). Other potentially positive consequences of COVID-19 have also been pointed out by epidemiologists: Since social distancing  and other mitigation measures against COVID-19 are equally effective against the flu, reported experiences in the Southern hemisphere with this year’s influenza season actually predict an unusually mild influenza season in the coming fall in the U.S. in contrast to political fear mongering by media and politicians about an awful  combined influenza-COVID-19 fall epidemic. If confirmed, declining deaths from influenza, as observed in the Southern hemisphere, could compensate for the, unfortunate, still rapidly increasing COVID-19 deaths in the U.S., which in September crossed 200,000.

Pointing to significant decreases in the so-called elective and semi-elective surgeries (and other invasive treatments like cardiac catheterizations) without (at least so-far) recorded increases in secondary mortality, some public health experts consider this to represent an “experiment of nature” that confirmed a widely held belief among many health care experts that a considerable portion of national health care costs are currently expended on unnecessary medical care.

In this context it is also important to remind our readers that, as was in more detail discussed in the September issue of the CHR VOICENew York City over almost two months has been demonstrating only minimal testing-positivity for COVID-19 (below 1%), minimal hospital admission (a major hospital system reported on September 18 only 1 patient with COVID-19 in their main NYC hospital), and minimal death rates, reaffirming the hypothesis that NYC has reached a minimally adequate level of immunity against the SARS-CoV-2 virus and, hopefully will not face a significant fall wave of the pandemic (unless a new pathogenic mutation of the virus is unleashed).

The effects on industry

The medical-industrial complex is, unquestionably, among the most affected industries from COVID-19. It is also a very significant reason why this country was so completely unprepared for the pandemic. With most of medical-related manufacturing moved out of the U.S. over the last 10-15 years (mostly to China), the country found itself completely dependent on supplies from other countries, often at significantly inflated prices. Since even some of the most basic medications no longer are produced on U.S. territory after U.S. politicians of both parties allowed the decimation of what used to be a highly productive and successful pharma manufacturing industry in Puerto Rico, a rebalancing of at least basic medical supplies for the country is overdue. In practical terms this, hopefully, will mean that significant manufacturing capabilities will be returned to the U.S. relating to the medical field (though similar considerations are also appropriate in other economic areas).

Industry has quickly picked up on the rapid increase in utilization of virtual medicine and has started developing devices and applications that allow physicians to even perform physical examinations by virtual means. Devices that have already reached the market are electronic stethoscopes, EKGs and, yes, obstetrical ultrasounds. In a recent electronic world conference, attended by over 13,000 fertility doctors, a European group reported on a still experimental device for vaginal ultrasound self-monitoring of follicle size by patients. Pictures of ovarian follicles are then transmitted to the IVF center for analysis, thus potentially eliminating the need for frequent patient visits to IVF centers during cycle monitoring.

This device also represents an excellent pivot toward the discussion what all of these changes will mean for the infertility field, assisted reproduction and especially IVF.

How assisted reproductive services are affected

We here will in principle concentrate on developments in the U.S. Most observations made in the U.S., , also to significant degrees, however, apply to other countries. Moreover, every discussion of assisted reproduction in the year 2020 must be initiated with one all-determining fact: Utilization of assisted reproduction is highly dependent on political and economic circumstances. With almost the whole world due to COVID-19 now characterized by political instability and deep economic recession, a highly significant impact on the infertility field is unavoidable. Political uncertainty and recessions have historically been closely associated with declining national birth rates and, as CHR investigators following the 2008 recession demonstrated, IVF cycle starts usually significantly decline in parallel. Considering the severity of the 2020 recession and the fact that most IVF centers, indeed, shut their doors between March and May, one, therefore, must assume that 2020 IVF cycle numbers are significantly lagging in comparison to recent years.

This fact alone will have significant consequences on the IVF community which predicted that the U.S. “infertility market” would more than double from $7 billion in 2017 to 15.4 billion by 2023.1 We considered these predictions to be grossly exaggerated when they were first made; by now they appear far beyond exaggeration. Based on these unrealistic predictions, $646 million was invested in 2018 from outside financial sources into fertility-related research and development, not including hundreds of millions of dollars spent on acquiring and/or establishing new IVF centers. More centers for fewer patients and IVF cycles, of course, does not represent a healthy business model, either.

Exaggerated expectations are nothing new for investments in the medical field, including the infertility field. During the late 1990s, when Wall Street first attempted to establish national chains of medical practices in different specialties (later referred to as the “physician practice management bubble”), the infertility field was not spared. After a relatively quiet decade, the idea has, however, witnessed an even more aggressive resurgence, with most recent data suggesting that national IVF chains, as of today, may be employing up to 40% of all fertility specialists in the U.S. In Australia, three companies control over 90% of the IVF market.

Exaggerated expectations, however, do not only extend to physician practice management but also involve–often difficult to understand–huge investments in biotech companies. A good example in the infertility arena was a company called OvaScience, a publicly traded biotechnology company founded in 2011 that at some point reached a market valuation in excess of $600million based on pursuit of a scientific goal that most experts in the field at the time, simply, considered ridiculous. Outside investments, nevertheless, reached hundreds of millions of dollars2 before the company was basically liquidated in late 2018 in a so-called reverse merger with a Michigan-based company with practically no value left in the company. Considering such experiences, we would have expected the investment community to be more cautious about oversold expectations in the field; but that does not appear the case, as some investments continue to pursue business concepts which, often appear to be beyond speculative.

Considering COVID-19, investors who counted on significant growth in the field must be disappointed, especially since we do not foresee a quick recovery. Indeed, we do not expect a full recovery in the IVF field until year-end 2021 at the earliest (possibly, even later). Since IVF centers in the U.S. have in recent years greatly increased, even reaching pre-COVID-19 IVF cycle numbers in the U.S. will, therefore, likely not mean for individual IVF centers a return to pre-COVID-19 cycle numbers. If one then further considers that most investors work with a ca. 5-year investment horizon, one must assume that many investments in the fertility arena are currently under water and are undergoing reevaluation as we speak.

Cash flow of IVF centers may be affected by additional storm clouds gathering around IVF and related industrial interests. In recent years, IVF centers have in their cash flow become increasingly dependent on the so-called “add-ons to IVF.” The most important has been the chromosomal testing of embryos prior to transfer, frequently before discussed in these pages. This procedure, now called preimplantation genetic testing for aneuploidy (or PGT-A), for many IVF centers nowadays can represent as much as 25% of average cycle revenue. Considering that PGT-A is responsible for non-use and/or disposal of large numbers of embryos with entirely normal pregnancy and live birth potential for healthy offspring, the procedure not only does not improve IVF outcomes (which is the main argument for its use) but actually for many infertile couples reduces pregnancy and live birth chances.

CHR, therefore, expects that it is only a matter of time until a professional organization and/or a regulatory government authority declares PGT-A contraindicated in routine IVF practice. Should that happen, a significant number of IVF centers, especially those that use PGT-A in most of their IVF cycles, will encounter serious uncertainties in their economic survival. A recent study of PGT-A in the U.S. not only confirmed significant increases in utilization of PGT-A by IVF centers but also that some individual centers and practice chains have, indeed, started mandating PGT-A in all their IVF cycles. Those centers and chains, of course, can expect to be most impacted, should PGT-A be formally restricted.

Commercial entities that offer the laboratory component of PGT-A and receive roughly half the revenue from PGT-A (the other half is charged by the IVF center), would, of course, also be significantly affected. Within this context it is also important to point out that PGT-A is not recognized as a covered benefit by all medical insurances since the procedure’s clinical benefits have never been established. Consequently, patients must pay for PGT-A “out of pocket,” even if their IVF cycle is covered by insurance.

In the wake of COVID-19, several IVF centers have already permanently closed their doors. Others have changed ownership, including some that were sold back to their original physician owners by practice chains. Other centers have merged to take advantage of larger scale. We fully expect changes to continue as we consider the IVF field to be significantly above required capacity.

IntegraMed America, the first-ever publicly held company in the fertility space, after even surviving the “physician practice management bubble” on Wall Street in the late 1990s, recently succumbed to increasing competition in the IVF field and filed for Chapter 7 bankruptcy, dissolving after being in the business of practice management and/or practice ownership for almost 30 years.

Private equity investments have been driving attempts at consolidation in national practice chains under the hypothesis that such consolidated networks would benefit from outcome improvements due to “best practice” protocols.1 The literature, however, suggests otherwise, with CHR investigators having been at the forefront of investigations and having pointed out that outside equity investments into such consolidations, indeed, achieved exactly the opposite effects. Outcomes of fresh IVF cycles deteriorated in parallel with patient satisfaction, while cycle costs increased.2 CHR investigators further suggested that increasing PGT-A utilization played a significant role in declining IVF pregnancy rates all over the world which, if confirmed, would further suggest a major shakeup regarding this clinical practice, with considerable consequences for the economic stability of many individual centers and consolidated center chains which appear especially vulnerable.

In a March 2020 artice,4  “How fertility care went from an evolutionary need to a luxury” (which also quoted CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD) the science writer Katherine Ellen Foley noted that in the 1990s the fields of embryology and genetics “merged.” The truth, however, is far more serious: Genetics has “taken over” IVF, mostly driven by the additional economic benefits genetic testing of embryos brings to fertility centers. How IVF is practiced today is no longer determined by physicians who are fertility experts but by geneticists, mostly without MD degrees and with no clinical knowledge about infertility and, often, also with no understanding of basic human embryology. They then misrepresent clinical benefits of genetic testing to a largely uninformed clientele of clinicians in IVF who, unfortunately, do not know better.

How far this takeover has gone is best demonstrated by the fact that the global PGT-A guidance (and, therefore, IVF practice) since 2016 has not been provided by professional organizations in the fertility field, like ASRM/SART in the U.S. or ESHRE in Europe, but by a small society, called the Preimplantation genetic Diagnosis International Society (PGDIS) with barely 200 worldwide members, mostly composed of individuals with strong economic interests in performance of PGT-A.

Economic interests, therefore, have conquered the fertility field from all directions, by not only acquiring fertility centers all over the world and industrial companies that serve them but, also, by assuming guidance as to how fertility services should be provided to patients. That this does not represent a healthy development and does not offer a good prognosis for the future of the field should be obvious even to the uneducated observer. Hopefully, the above-noted consequences of COVID-19 will reverse this trend or at least slow it down. Under such circumstances, COVID-19 will, at least, have produced some positive consequences.

REFERENCES

  1. Harito E. Sabel D. SUMIT: IVF – discussing the future of assisted reproduction. F&S Reports S2666-3341(20)30001-5 https://doi.org/10.1016/j.xfre.2020.03.001; XFRE 1
  2. https://en.wikipedia.org/wiki/OvaScience
  3. Gleicher N, Kushnir VA, Barad DH. Worldwide decline of IVF birth rates and its probable causes. Hum Reprod Open 2019;2019(3); hoz017.doi: 10.1093/hropen/hoz017. eCollection 2019.
  4. https://qz.com/1817726/how-fertility-treatment-became-a-multibillion-dollar-industry/

This is a part of the October 2020 CHR VOICE.

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.