How much government intervention in reproductive biology and reproductive medicine is too much?

IVF live birth rates by country (2012)In contrast to natural conception, where egg and sperm meet in the body of the female (in vivo) in vitro fertilization (IVF) involves the creation of human embryos from eggs and sperm outside of the female body in the laboratory (in vitro). The concept that a human being could be created in such a fashion even among many reproductive scientists and clinicians as recently as in the mid-1970s was still considered blasphemous. An alleged first in vitro fertilization in a laboratory at Columbia University in the mid 1970s was, indeed, destroyed by the Chairman of the Department of Obstetrics and Gynecology, himself a reproductive endocrinologist.

By July 1978, the first IVF baby was born in the UK, a feat that only 32 years later in 2010 was awarded with a Nobel Prize in Medicine and Physiology. While at the birth of the Brown baby media reports were still full with fears about Frankenstein-like monsters that would be born as the consequence of IVF, the procedure proved itself to be extremely safe, and by the time the Nobel was awarded almost 5 million children were born worldwide following IVF. Today in developed countries ca. 1-2% of annual births are IVF babies. In the U.S. ca. 61,000 (1.5%) of 3.9 million births were IVF babies in 2012. In Israel, the country with the by far largest utilization of IVF in the world, over 4% of children are born every year following IVF.

Absent Government Support

The U.S. till today has by far the best clinical pregnancy and live birth rates of any country in the world, as the figure demonstrates. What is most remarkable about the success of IVF in the U.S., however, is the fact that this medical procedure evolved and succeeded without government support. From early IVF days on, Congress, under Democratic and Republican administrations alike, kept a moratorium which strictly prohibited federal funds from being used for any research in support of IVF. In recent years, this moratorium slightly weakened as selected non-human experimentation and very selected, mostly epidemiological, human IVF-related research was funded but, in principle, the remarkable evolution of IVF in this country was achieved without federal funding support, and was primarily financed by the private clinical IVF market.

Until very recently the government also refused to consider IVF a covered clinical benefit under any government program. Only very recently, in the last few weeks of the Obama administration, did the federal government agree to cover IVF costs for wounded veterans whose infertility was a consequence of an injury. All other government programs, still, exclude IVF as a covered benefit.

Paradoxically, IVF as an example should be of great interest to the Trump administration and the Republican party, currently struggling with repeal and replacement of Obamacare, since over its almost 40 year history, this procedure demonstrated how well the free market can support a useful medical procedure, how competition will constantly improve outcomes and, yet, will achieve all of these improvements while costs, after inflation, actually declined, as IVF cycle fees today are on average lower than they were in the early days of IVF, when live birth rates were a fraction of what can be achieved today.

In addition, a multibillion dollar support industry has grown up around the IVF procedure, with thousands of companies offering supplies, medications, instrumentations and logistical support and, finally, well-paying employment to large numbers of people.

Learning from IVF Experience

Here at CHR, we believe that IVF in many aspects can serve as a model for market-driven medicine. Like most other “industries,” competition led to survival of the “fittest” centers, whether based on outcomes, costs or other qualities, patients valued. Therefore, the IVF industry today involves a large variety of offerings, from small to big programs, from “bread and butter” IVF centers that serve the average fertility patient to highly specialized centers, like CHR, which patients, unfortunately, often choose too late in the process, after having failed repeatedly, and missing valuable time.

But in contrast to what has been happening with Obamacare, patients have a large variety of choices, geographically, based on acceptance of third party insurers, cost of services or any other parameter that may affect a patient’s choice of provider. And with choice usually comes satisfaction about service quality because the patient, of course, at any point also can exercise the choice of changing her provider.

Patients, in principle, face either non-emergent or emergent medical care. The clear majority of medical encounters, including fertility services, involve non-emergent care. In such circumstances, patients can easily exercise choices since non-emergent care allows for careful selection of providers, based on all above noted preferences (and many more). Though quality of medical care is very difficult to judge for lay people, due to information on the Internet it is nowadays much easier to judge the quality of an individual provider or an IVF center than in the past. In emergency situations, choice is, of course, limited because in most instances the quicker a patient gets into the closest emergency room the better. The urgency of the situation here, quite obviously outweighs the benefits of choice. The dynamic of emergent and non-emergent medical services, thus, differ significantly. The economic evolution of IVF, however, can serve well as an example how non-emergent medical care could be structured in the post-Obamacare era.

Supporting Medical Progress

As another piece of evidence that the political establishment in this country has been discriminating against IVF, it is the only medical procedure, which under Congressional mandate must be reported to the Centers for Disease Control and Prevention (CDC). For that reason, almost all IVF centers in the U.S., CHR included) report every IVF cycle electronically to the CDC, and many centers (CHR included) also report voluntarily to the Society for Assisted Reproductive Technology (SART).

We, however, do not complain about this reporting mandate because it, in a way, allows for the monitoring of progress (or lack thereof) in the national IVF arena. Through this reporting we, for example know that until ca. 10 years ago, live birth rates after IVF increased year by year. Over the last decade that progress, however, slowed considerably, especially among older women. Through this reporting we also have learned that the IVF population in the U.S. is aging very rapidly, a theme we have repeatedly addressed in these pages before.

Older and older women are trying to conceive, as women above age 40 have over the last decade been the most rapidly growing age group having children, while younger age groups have been shrinking. So far, most IVF centers have addressed these facts almost exclusively only by strongly advancing the utilization of donor eggs. Donor egg cycles, therefore, have become the most rapidly growing IVF cycle category in the U.S.

We, here at CHR, have been quite frustrated about these developments. While we consider egg donation a wonderful last resort for women who have no other way to conceive (with use of their own eggs), to a degree, we perceive every donor egg cycle as a failure of our treatment efforts. After all, we have never met a woman who did not want to conceive with use of her own eggs rather than donor eggs. CHR, therefore, over the last 15 years developed unique expertise in treating older women and/or younger women with prematurely aging ovaries.

We now, however, are getting increasingly frustrated because new technologies are becoming available, which have the potential of helping older women conceive, while permitting transmission of all of their nuclear genome (nDNA) to their offspring; yet, because of restrictions by the federal government (specifically by the FDA), we are not permitted to pursue these treatments even in investigational protocols with full informed consent from participating patients, who, we know, would line up for such studies.

Nuclear Transfer for Older Women

Based on work with animal models, CHR’s laboratory does have the manual expertise to perfume so-called nuclear and/or spindle transfers. These techniques with great likelihood will offer the next major advance in the IVF field, promising especially in older women additional pregnancy potential.

The principle is the same in both techniques: Animal data suggest that what ages in an egg with advancing female age is mostly the cytoplasm, and not the nucleus, which contains almost all the mother’s nDNA. This observation gave rise to the concept that combining an older woman’s nucleus with a younger woman’s cytoplasm should “rejuvenate” an egg and, therefore, improve pregnancy chances.

Nuclear and or spindle cell transfers do exactly that by removing the nDNA from a young woman’s donor egg and replacing it with the older patient’s nucleus (i.e., the patient’s nDNA). We have extensively reported on these techniques before, when we discussed the treatment of so-called mitochondrial genetic diseases, caused by abnormal genetic mutations in mitochondrial DNA (mDNA). In contrast to the FDA in the U.S., regulatory authorities in the UK issued permissions to British colleagues to use these techniques under experimental informed consents in attempts to prevent inheritance of such diseases into the next generation.

mDNA represents only approximately 1% of an egg’s total DNA and is located, as the name suggests, in small cytoplasmic tubules, called mitochondria. Mutations in mDNA, even though fortunately rare, can cause several severe, mostly fatal inherited diseases. Since mDNA is in mitochondria, and mitochondria are in the cytoplasm, replacing the cytoplasm in eggs of mothers who carry such a mutation is believed to have the potential of interrupting the transmission of these diseases from mothers to offspring (mitochondrial diseases are only transmitted by mothers). The price, however, is that the resulting offspring, besides DNA from mother and father, will also have ca.1% of mDNA from the egg donor. The child will, therefore, have three genetic parents!

We just recently reported in these pages that a New York colleague performed spindle cell transfers on the eggs of a mother carrier for such a mitochondrial disease in Mexico because in the U.S. the FDA has refused to even consider giving permission for such treatment. The birth of a hopefully unaffected child in New York City made headlines all around the world (see also related article on “setting the record straight.”

The January 26, 2017 issue of NATURE now reported that a first baby girl was born via pronuclear transfer (here, nDNA is obtained from a maternal pronucleus and inserted into the enucleated oocyte of a young donor) out of all places in Ukraine, where the indication for the procedure was not a maternal carrier state for a mitochondrial disease but, simply, to treat female infertility. Rumor has it that several additional pregnancies are underway.

Sadly, we, here in the U.S., under current FDA policy, are not permitted to use these techniques for either indication. As noted before, our British colleagues are permitted to use the techniques but only in attempts to prevent mitochondrial diseases. Even though female infertility due to advanced female age is a much more prevalent medical problem than inheritance of mitochondrial diseases, even the British authorities approved the technique only for the much rarer medical problem, once again demonstrating that medical and ethical research communities, still, discriminate against everything and everybody attempting to advance fertility treatments.

The principal argument for all of this caution is that all of these forms of nDNA transfer result in so-called “three parent” babies because resulting offspring have nDNA from both parents but, in addition, ca. 1% mDNA from the young donor who provided the cytoplasm. Assuming absence of complications from such triple genetic parent contributions (as studies with non-human primates and other experiments have suggested), it is difficult to understand why older infertile women should be deprived of the chance to contribute (with their partner) ca. 99% of the child’s genome when the only clinical alternative treatment often is egg donation, which deprives the mother of any genetic motherhood.

What We Hope Will Happen

So, let’s be optimistic for a moment, and assume that President Trump is, indeed, the logical business man, who in all aspects wants “to make America great again.” If that were to be the case, then how can he and his administration accept the fact that older infertile U.S. women may have to travel to Mexico, the Ukraine and, maybe, the UK, to get treatments U.S. scientists and physicians are not allowed to offer.

We, of course, do not argue in favor of unregulated introduction of experimental treatments into IVF, for which, with current knowledge and experience, significant negative consequences cannot yet be ruled out. We, however do propose that the U.S. should not be prevented from maintaining its leadership in the field by prohibiting responsible research in attempts to advance the field.

Over almost 40 years, the field of IVF has through self-control responsibly advanced scientific knowledge as well as clinical care for millions of women who could not conceive and experience motherhood. This historical experience should be enough to demonstrate that this field is responsible and capable of exerting appropriate self-control in advancing science. Reproductive medicine does not need the government to determine what we can or cannot do in advancing our patients chances of safely conceiving. Imagine where IVF would be today, had IVF centers in the early days of IVF been dependent on FDA approvals before being allowed to start operating. Deregulation of government agencies is a major point in the Trump administration’s political program. President Trump, himself, has gone on record promising the radical reorganization of the FDA.

We seriously hope that this reorganization will not only be restricted to benefiting Big Pharma and medical device companies by simplifying the drug and device approval processes but will also help smaller players, like fertility centers, which are anxious to safely drive the practice of IVF forward. It is years now that, at instruction of Congress and without opposition by the prior Obama administration, the FDA has made it impossible for the IVF community to responsibly investigate promising new advances that especially may benefit older women. It is time for government to once again set free the ingenuity of the IVF field in this country. Nobody will benefit more from that than the public.

Here is a real opportunity for President Trump to “make America great again” in an area of not only great medical significance but, as we repeatedly before noted in these pages, also in an area of great societal importance, as having children at older ages is becoming of increasing societal importance in most countries of the developed world, suffering from dwindling birth rates.

This is  a part of the February 2017 VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, 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.