the center for human reproduction chr voice...to go solely by the number of failed ivf cycles, quite...

transferred. Transferring consecutively five great looking embryos of a 23-year-old and failing to achieve a pregnancy has different connotations than transferring five embryos, even all together, in a 45-year-old. How these two parameters at varying ages, however, change has never been determined, and this is the principal reason why, strictly speaking, without proper prior diagnostic definition of this condition, there really cannot even be such a thing as “implantation failure.”

Yet, pretty much every time when they cannot figure out why patients do not conceive on repeated IVF attempts, fertility specialists all over the world use this diagnosis in abundance. Like in association with the so-called “unexplained infertility,” the apparent helplessness of the situation appears to mandate a solution, and one such solution is, of course, the

Whether implantation failure is a real diagnosis remains to be determined. While scientific papers on the subject are published almost daily, nobody really knows what implantation failure really is and/or means. The definitions have varied: Some go by the number of failed IVF cycles, others by the number of good quality embryos transferred. Like with the pseudo-diagnosis of “unexplained infertility," it often seems that everybody has different definitions of what represents implantation failure.

To go solely by the number of failed IVF cycles, quite obviously, makes little sense because three failed cycles at age 23 have very different meaning (and likely different causes) than the same number of failed cycles at age 43. The same applies to number of embryos

Welcome back to the CHR VOICE for the fall semester of 2018. For the first time in a decade, the summer months, July and August, passed without us seeing a reason to break the VOICE’s scheduled hiatus during these two months. Here we now are, well rested and ready with a plethora of interesting information we have prepared for this issue, at least partially in response to requests and questions we received from our readers over the last two months.

Our lead article this month addresses the so-called implantation failure, which has remained a highly controversial issue in fertility practice and will in this issue be dissected by our writers with the usual directness and transparency this newsletter has become known for.

Helping older women conceive with use of own eggs, if still possible, has been a frequent topic in these pages because this is one area of infertility practice where CHR has excelled now for over a decade. We have in these pages also repeatedly addressed the subject of third-party egg donation, when one’s own eggs, simply, no longer can do it. In both instances, pregnancy creates significant stress on all body parts in older women. In this issue of the VOICE we will, therefore, in detail address what this means in clinical practice for older women who still wish to conceive.

Santiago Munné, PhD, one of the leading proponents of preimplantation genetic screening (PGS), now renamed preimplantation genetic testing for aneuploidy (PGT-A), was once before subject of a commentary in these pages, when in his position of Scientific

Continue reading on page 11

CHR VOICE the monthly CHR UPDATE

The Center for Human Reproduction

Clinical Care • Research • Education

1

Condition in Focus:

Is implantation failure a real diagnosis? Î Proper treatment can start only when underlying causes are identified

Risk of pregnnacy in your 40s and 50s ...3

Here goes Santiago Muneė again! ...5

Female age as the most important IVF predictor ...6

What fertility patients can do on their own ...8

Questions from the public ...13

September2018

Why unexplained infertility is a pseudo-diagnosis:http://kaywa.me/vpw01


Previously on PGT-A/PGS:http://kaywa.me/ZCR7a

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for patients who require more individualized medical care. Indeed, such patients in consolidated practice areas often fall between the cracks in routine protocols and standardized treatment protocols. And nothing is, of course, as important in providing fertility services to older women than individualization of care, not only when it comes to fertility treatments but also in preparing patients for a potential pregnancy.

The principal reasons for this statement are obvious: Pregnancy creates functional stress on every organ of a woman’s body. CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, who for many years, and over a number of different editions, was the editor of the principal textbook on medical problems in pregnancy (Principle & Practice of Medical Therapy in Pregnancy), therefore, coined the phrase, “pregnancy is a universal stress test on the female body.” Practically, this means that any bodily function (the skeleton included) is at risk of decompensating during pregnancy if, prior to pregnancy, it already is only marginal in function. Examples abound: Women who are pre-diabetic, very likely will become outright diabetic during pregnancy (so-called gestational diabetes); borderline hypertension often leads to hypertension in pregnancy, including preeclampsia/eclampsia; women with cardiac problems run the risk of seeing their hearts decompensate, leading to congestive heart failure; autoimmune diseases, while usually mostly improving during pregnancy, at very high likelihood flare at end of pregnancy and, especially, in the postpartum period; and, to demonstrate the effects on the skeleton, spinal problems like lower back pain, often, get much worse in pregnancy because pregnancy hormones loosen ligaments, thereby increasing the chances of disc problems.

In addition, maternal medical problems during pregnancy, of course, can, and in most cases will, affect pregnancies: Having to go through surgery uniformly increases the risk of premature labor; practically all significant medical problems, indeed, are associated with increased risks for premature delivery, including hypertensive disease of pregnancy, cardiac diseases and, of course, autoimmune diseases. And the prevalence of all medical problems increases with advancing female age.

3

Just before the summer break, the news media were filled with reports about record low birth rates in the U.S., - especially over the last decade. One of the more remarkable developments receiving much less attention, however, was the fact that birth rates have been plummeting only in younger women; in older women, and especially in women above age 40, they have actually been increasing to quite surprising degrees.

Especially in more prosperous countries, national birth rates have been plummeting for quite some time, often falling significantly below population replacement rates. Among most affected countries are economically developed countries, like Japan, South Korea and Italy. The U.S. population has continued to grow only because of immigration. In absence of new immigrants, the U.S. population would have stagnated for quite some time. Except for Africa, even in the developing world birthrates have been declining. China, indeed, reversed her one-child policy because of a rapidly aging population, fearsome that in the not too distant future a decline in working age adults could cause severe economic difficulties for the country.

In the U.S. women above age 40 have, proportionally, been the most rapidly growing age group having children. Not surprisingly, trends like this are widely considered to predict an economic boom for the fertility industry because they promise continuous growth in treatment cycles over many years to come. Increasingly, non-physician financial interests, therefore, have been entering the industry, and hardly a week passes without a new announcement in the U.S. of an investor group purchasing a fertility center outright or, at least, making investments and assuming management responsibilities. In Australia, where this kind of consolidation is most advanced, 80-90% of IVF centers are controlled by only three major companies. In the U.S., the most recent developments are purchases of centers by Chinese, German and Spanish commercial entities. A rapidly evolving consolidation of fertility centers in the U.S., therefore, increasingly appears unavoidable.

We are raising this subject here because aging patient populations in IVF centers require significantly more attention than younger patients. Above noted consolidation trends in Australia and elsewhere, proved not very promising

Fertility and Pregnancy in Older WomenHow Risky Is Pregnancy for Women in Their 40s and Even 50s?

Î As all risks go up with age, they need to be proactively managed


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4

So here is a little background on this piece: Santiago Munné, PhD, initially came to the attention of the IVF community as a talented geneticist who closely worked with one of the pioneering clinical embryologists in IVF, Jacques Cohen, PhD, in the area of preimplantation genetic diagnosis (PGD) of mostly single gene diseases. His reputation quickly grew, and he succeeded in developing one of only three leading genetic laboratories that offered these services to most U.S. IVF centers.

As preimplantation genetic screening (PGS), now renamed preimplantation genetic testing for aneuploidy (PGT-A), entered clinical practice in its first incarnation without prior clinical validation studies, he, much more quickly than other leading PGD laboratories, recognized the commercial opportunity and became the dominant proponent of this new screening test. In parallel, his laboratory also became dominant in performing this test in the U.S. (and soon thereafter in other regions of the world).

As the screening test in its initial form (PGS 1.0) started to receive increasing criticism (including from CHR investigators), Munné became the test’s main defender. As the American Society for Reproductive Medicine (ASRM) declared PGS 1.0 ineffective in improving IVF outcomes and reducing miscarriages ca. 10 years ago, he became one of the principal proponents of PGS 2.0, once again advocating unsupported claims of effectiveness in improving IVF outcomes and in reducing miscarriage rates for a completely unvalidated test prior to its marketing to IVF centers and the public.

In this context it is important to understand that exactly 5

a decade after issuing the above-noted opinion on PGS 1.0, ASRM, this time in conjunction with the Society for Assisted Reproduction (SART), very recently again issued a formal opinion on PGS/PGT-A, reemphasizing that, till today, no IVF outcome improvements by PGS/PGT-A have been confirmed and, indeed, have been mostly refuted.

Munné, himself, has in multiple oral and written statements in recent months acknowledged that PGS/PGT-A “cannot improve pregnancy and live births rates.” His retreat from original claims of improvements in IVF outcomes is further demonstrated by his “new” claim that PGS/PGT-A should be performed because it “speeds up time to pregnancy.” He also still maintains that it reduces miscarriages, though, as repeatedly discussed in these pages, considerable evidence, indeed, suggests that this is not the case.

Repeatedly moving the goal posts in describing PGS/PGT-A benefits for IVF has, therefore, been a constant feature of how Munné, and the PGS industry in general, have been marketing the successive versions of this, till today completely unvalidated, diagnostic screening test in versions PGS 1.0 through PGS 3.0, forming the basis for discarding so-called “abnormal” embryos.

PGS 3.0 was initiated by the industry in July of 2016, when the Preimplantation Genetic Diagnosis International Society (PGDIS), unexpectedly, completely revamped how the test was to be performed in the laboratory and reported to IVF centers (and patients), how reports were to be acted upon and, incidentally, in order to reflect the radical break with the past, also gave the test a brand-


Accepting a Challenge

Here Goes Santiago Munné Again!

Image by Markus Spiske via Unsplash

Î PGS/PGT-A debate degenerates as it drifts away from science

Previously on PGT-A/PGS:http://kaywa.me/ZCR7a

The honest truth is that nobody fully understands why age is by far the most important predictor of pregnancy success, whether women attempt pregnancies with or without medical help. But there can be no doubt that female age plays a very essential role that goes far beyond the fact that women are born with, likely all of their eggs, and constantly lose some when they are recruited from their resting stage (in primordial follicles) into a maturation process called folliculogenesis that lasts up to three to four months. As women age, their ovaries, therefore, contain fewer and fewer eggs. As a consequence, the number of eggs recruited into maturation declines and the number of eggs retrieved in IVF cycles diminishes. Declining egg numbers, therefore, unquestionably, are one factor that contributes to declining fertility.

That, however, is not the only and, likely, not even the principal, reason. In parallel with declining numbers, quality of eggs also declines. We know that because egg quality makes up roughly 95% of embryo quality, and the chance for an embryo to implant is radically age-dependent: An embryo produced from a 25-year old egg will, therefore, have a much higher implantation and pregnancy potential than an embryo made from a 35- or even 45-year-old egg. Though there are exceptions, the general rule, therefore, is that egg numbers and egg quality run in parallel.

6

Importance of Age:

Why female age is the most important predictor of spontaneous and treatment-induced pregnancies

Î Advancing age usually means declining chances of pregnancy, but too many women are pushed into egg donation prematurely

CHR investigators, however, added some subtlety to this formula, when establishing what since has been called “CHR’s theory of ovarian aging," which states that the ovarian aging process is not only the consequence of aging eggs while sitting in ovaries at resting stage, but also is caused by aging of the ovarian stroma, in which recruited follicles (and their eggs) mature after recruitment. The theory further argues that, in contrast to often genetic damage that over time affects eggs at resting stages, significant additional damage is encountered following recruitment during follicle maturation because of aging stroma that represents the microenvironment in which follicles mature. In contrast to the mostly genetic damages at resting stages, this “environmental” damage imposed by the ovarian microenvironment can, however, be remedied at least partially, by supplementing factors to the microenvironment that have gone lost with aging.

The classical example CHR investigators have been quoting in supporting this point, is supplementation of ovaries with androgens (mostly dehydroepiandrosterone, DHEA) in women with low testosterone values, which has been proven highly effective (please note the conflict statement at the end of this article). Another example is the recently growing utilization of human growth hormone (HGH) in IVF practice. Like androgen supplementation, HGH supplementation (via IGF-1) acts on small growing follicles, which is the initial maturation stage of follicles after recruitment. Both supplementations, indeed, synergistically support the impact of FSH on follicle growth, resulting in more and better-quality eggs. To achieve this benefit, so-treated follicles in small growing stages must, however, be allowed to continue maturing for at least another 6-8 weeks before they reach the so-called gonadotropin-sensitive phase of folliculogenesis, when these follicles become responsive to fertility drugs. To supplement DHEA and/or HGH only during cycle stimulation, therefore, makes little sense.

Though so far no other components of the ovarian

CHR's theory of ovarian aging:http://kaywa.me/T9kCG

Eggs in ovaries are almost completely depleted by the time women reach their mid-40s and early 50s.

Age-related decline in ovarian reserve/egg count


Previously on DHEA use in IVF:http://kaywa.me/ZO9Ex

7

microenvironment have been identified that may benefit from supplementation at advanced female ages (or in younger women with premature ovarian aging or POA, also called occult primary ovarian insufficiency or oPOI), logic suggests that there must be a significant number of other biological factors that change in concentrations within ovaries over time and, therefore, if properly supplemented, might be helpful in improving follicle maturation. CHR investigators also in recent years discovered (and reported in the medical literature) that biological processes within follicles, which are fully dependent on the surrounding stroma for nutritional support, accelerate. At CHR, this discovery led to routine utilization of Highly Individualized Egg Retrieval (HIER) in older women and younger patients with POA/oPOI, a treatment change which has radically advanced IVF practice over the last three years.

Advancing female age is, thus, such an important predictor of pregnancy and live birth chances in a quantitative as well as qualitative way, since egg and, therefore, embryo numbers and, in parallel egg and embryo quality, in IVF cycles decline. As science so far cannot, yet, produce “new” eggs, the only therapeutic interventions that can be pursued is making ovaries perform at what currently can be defined as their maximal potential. And that, as noted above, requires that older ovaries, whether “older” because of female age or POA/oPOI, be adequately “prepared” prior to every IVF cycle and that the ovarian stimulation during the IVF cycle be specifically adjusted to patients’ ages through the HIER process and to other specific requirements patients’ histories mandate. Such radical individualization of IVF cycle management is, therefore, currently the only tool that allows for improvements in IVF outcomes in complex IVF patients, whether younger or older.

Unfortunately, this message is only starting to resonate among IVF centers; most, indeed, still find it easier to simply advance complex patients into egg donation. These pages have repeatedly addressed CHR’s opinion that far too many, especially younger, women are ending up prematurely in donor egg cycles. We, therefore, here do not want to be repetitive; but this problem appears to be growing exponentially with the increased use of chromosomal testing of embryos prior to transfer (now called preimplantation genetic testing for aneuploidy, PGT-A), which results in the unnecessary discarding of large numbers of entirely normal embryos (also a frequently discussed subject in these pages, addressed in this issue again under the title “Accepting a Challenge” on page 5).

CHR’s physicians over the last two to three years have been struck by the increasing number of younger women, often in their 30s, who, at many IVF centers, after at times only one or two IVF cycles, were advised that “their only chance of pregnancy was egg donation” because none of their embryos was reported as “euploid” (i.e., chromosomally normal). It is, of course, one thing to issue a premature recommendation for donor egg use to a woman in her mid-40s. However, to make such a recommendation to a young woman who, likely, is still in a very fertile time period of her reproductive life is really inexcusable.

Conflict StatementCHR and some of the center’s physicians are co-owners of a number of U.S. user patents that claim therapeutic benefits from androgen (including DHEA) supplementation in certain women with infertility. CHR and some CHR physicians also receive royalties from these patents from Fertility Nutraceuticals LLC, of which Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist, is also a shareholder.

Read about HIER's success:http://kaywa.me/xT6yL

Importance of age: Continued from Page 6

CHR on premature push for egg donation:http://kaywa.me/CXMi1

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8

Fertility Self-Help

Î Live your normal life and relax, says CHR expert


Likely the most frequently asked question from our patients is this: “What can I do to improve my chances of being successful in my fertility treatments?” The honest answer usually is that “there is really not much to be done.”

Going through fertility treatments is, of course, a very stressful process. Not surprisingly, patients want to do whatever is possible to improve their chances. CHR welcomes this attitude because it demonstrates motivation, which in turn promises discipline in executing the required treatments and, if there is one thing every patient can do to help her chances, it is correct execution and timing of treatment schedules. The desire to maximize chances, however, also sometimes leads to self-prescribing, i.e., the habit of reading something on the Internet (or elsewhere) and deciding to add it to treatments recommended by physicians. While most over-the-counter products, likely, are relatively harmless, some are not. Those that are not, are often not dangerous per se, but may either interfere with diagnostics (i.e., lab test results) or may interact with other supplements and/or prescription drugs that are important for a treatment cycle. Therefore, CHR strongly recommends to patient under fertility treatments to stay away from self-prescribing!

For women who concomitantly are under the care of physicians in other medical specialties, it is also important to remember that those physicians must be informed about intent to conceive, whether spontaneously or via fertility treatments. Some medical problems require changes in therapy for women who are on the verge of conceiving, with chronic hypertension being a good example, where women often must change their medication regimen quite radically.

What Fertility Patients Can Do on Their Own

Here are answers to some frequently asked questions:

Should I change my diet? The answer is no if your regular diet is well tolerated and does not give you gastro-intestinal distress symptoms, like heartburn, gas or cramps. If, on the other hand, bread makes you run to the bathroom or gives you excessive gas and cramps every time you touch it, you may be gluten-sensitive, maybe even have celiac disease. In such a case, trying a gluten-free diet as a withdrawal test may not be a bad idea. If you notice immediate improvements, you may, indeed, be gluten-sensitive (or have celiac disease) and staying off gluten-containing foods may help, because every time your body is exposed to gluten, inflammation flares up in your body.

We do not like inflammation in women who are trying to conceive because the immune system of women with active inflammation does not reprogram itself as well toward the new pregnancy as it should. That, in turn, can increase difficulties for embryos to implant and, if they do implant, can increase miscarriage risks. (See also the article on implantation failure, on page 1.)

Should I stop smoking? Definitely yes! Smoking decreases fertility in women and men but much more so in women. Smoking also affects the pregnancy and results in lower birth weights for offspring. The time when a woman is trying to conceive and/or is pregnant is very clearly not a time to smoke.

How about marijuana use? CHR recommends against recreational use of marijuana during fertility treatments and during pregnancy. There is increasing evidence that offspring of mothers who use marijuana during pregnancy may be adversely affected.

Using fertiliy supplements effectively:http://kaywa.me/ya3ID

Image by Bady QB via Unsplash

more, caffeine than a cup of coffee and countries with strong tea cultures, like Russia and the UK, also have not reported any associated adverse effects on their populations’ fertility from drinking tea. In summary, coffee in moderation is perfectly fine while going through fertility treatments.

Can I continue exercising? Definitely yes! Here, too, the principle applies that women who go through fertility treatments should stick to their regular habits. Those who regularly exercise should continue doing so. Once pregnant, and if the pregnancy progresses normally, recommendations are to decrease length and intensity of exercises by ca. 20% in each trimester of pregnancy.

In following the recommendations not to change behavioral patterns while trying to conceive, this is also not necessarily the best time to start exercising. A much better strategy appears to be to wait until after the delivery to start paying for a new gym membership.

Should I stop working? This is actually a surprisingly frequent question from patients in all socioeconomic groups. Unless there is a clear medical reason for stopping work, we usually strongly recommend against stopping working simply because of infertility treatments. The reason is, again, that radical changes in daily routine often increase, rather than decrease, stress levels.

Does reducing stress help? How much stress a patient is exposed to and how well or poorly a patient deals with stress is, of course, very difficult

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How about other recreational drugs? If we count alcohol as a recreational drug, then CHR does not object to a glass of wine here and there, while trying to conceive. As we noted before in these pages, if such social alcohol consumption adversely affected pregnancy potential and/or offspring, many countries where drinking wine is a national habit, would demonstrate obvious consequences. That countries like France, Italy, Spain and others do not demonstrate such effects, contrary to many proponents with rather scary messages, suggests that mild social consumption of alcohol during periods of fertility treatments is safe. Once pregnancy is established, CHR, however, supports absolute abstinence in view of reports in the medical literature that even minimal amounts of alcohol have been associated with the so-called fetal alcohol syndrome. CHR, of course, also objects to use of other recreational drugs during infertility treatments and in pregnancy.

Should I lose weight? When trying to get pregnant is, in principle, not the right time to change your life’s routine. Fertility treatments create enough stress on their own; changing one’s daily routine only adds to that, and the potential weight loss over a few short weeks to months is not worth the effort.

Weight loss can be helpful in truly obese patients but, when such a strategy is pursued, CHR usually recommends interrupting fertility treatments, so that patients can concentrate on weight loss and exercise during that time period. Once a couple returns to treatment, they should be able to concentrate on their fertility treatments.

Use of such a strategy is, of course, also dependent on the female’s age. As long as they don’t suffer from premature ovarian aging (POA), in younger patients, treatment delays of six months or even of a full year, may be worth the effort. However, if patients are older, the loss in fertility chances from waiting may outweigh the benefits of the weight loss, and in such cases CHR usually proceeds with treatments without attempting prior weight loss.

How about coffee consumption? That coffee consumption is harmful to infertility treatments is, once again, one of those widely distributed messages for which there is really no credible evidence in the scientific literature. Countries with strong coffee cultures, like Italy, Spain, Austria and the Latin American countries are, again, “natural experiments” that strongly contradict this widely claimed association. What also often goes unmentioned is that a cup of tea frequently contains just as much, and in some cases even

Fertility self-help: Continued from Page 8


CHR is currently recruiting patients for a clinical trial of ovarian rejuvenation for patients with premature ovarian failure (POF), utilizing platelet rich plasma (PRP). The PRP procedure itself will be free of charge to study participants.

Normal costs associated with ovarian stimulation and subsequent IVF cycles if follicles develop, including cancellation fees, will be the participants' responsibility.

Please call us at 212-994-4400 if you are interested in participating in the study.

Ovarian rejuvenation study: http://kaywa.me/kZej4

Ovarian Rejuvenation Study

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to assess. Studies on the effects of stress on fertility treatment outcomes are, therefore, sparse. A very recently published study concluded that there was no obvious evidence that stress impacted fertility treatments, but the authors assessed stress by levels of stress hormones in their patients’ bloods, and that is not necessarily a great tool to assess all psychological stress.

That stress, per se, does not cause infertility, is throughout history quite well established because even the most stressful situations, like wars, famines and even rape, result in pregnancies. At the same time, stressful situations are associated with lower birth rates, and war as well as famines are again good examples for significant declines in birth rates. Indeed, even economic recessions affect birth rates to significant degrees, as declining birth rates in the U.S. and elsewhere after the 2008 recession again demonstrated. Whether declining birth rates in such circumstances reflect only conscious choices or may to a degree also reflect declining fecundity (ability to conceive spontaneously) is unclear. But what can be stated with considerable certainty is that, while stress, of course, should be avoided, there is no good evidence that it affects fertility treatments to significant degrees.

Does acupuncture help? CHR is neutral when it comes to use of acupuncture. Whether the procedure affects pregnancy chances with fertility treatments like IVF has remained controversial and a large recently published study, indeed, suggested that there was no outcome benefit observable with IVF. Acupuncture is, however, also alleged to reduce stress, and that, of course, cannot hurt. A good number of CHR patients, indeed, use acupuncture for various reasons and CHR is grateful to acupuncturists who are serving those patients.

Only one word of caution: As already noted above, CHR is concerned with utilization of Chinese herbs, while patients are in infertility treatments, and usually recommends to patients to discontinue their use.

Fertility self-help: Continued from Page 9Director of the CooperGenomics corporation, he published a truly astonishing diatribe against an excellent and highly objective article in NEW YORK magazine by Stephen Hall (September-October 2017) that pointed out many of the weaknesses of PGS/PGT-A. Suffice it to say, related or not, Munné shortly after our detailed response in these pages, no longer was the Scientific Director at CooperGenocmics, but that does not prevent him from continuing to misrepresent facts. In his most recent diatribe, he not only spread again outright false information about PGS/PGT-A but, directly and personally, maligned CHR investigators who had disagreed with his representations. In this issue of the VOICE, you will read their response.

In addition, we will address why female age is the most important predictor of spontaneous as well as treatment-induced pregnancy chances, what you may (and may not) be able to do on your own in order to improve your fertility (so much information you daily are exposed to in the media is simply hogwash) and many more newsworthy items that have come up over the last two months.

Finally, we want to draw the attention of all of our readers to this year’s annual 2018 Translational Reproductive Biology and Clinical Reproductive Endocrinology Conference (FRMC) on November 15 to 18 at the New York Marriott East Side hotel on Lexington Avenue and 49th Street, sponsored by the Foundation for Reproductive Medicine (FRM) and IVF Worldwide, and proudly co-sponsored by CHR. This Conference in a few short years has achieved almost mythical recognition for presenting information and speakers well ahead of other major conferences around the world. As in preceding years, the program is exceptional and unique, bringing to NYC a worldwide faculty of speakers who are driving progress in the field. This year’s Conference, however, for the first time, also makes additional use of such a unique faculty by offering on Sunday afternoon, November 18, a Clinical Fertility Day for the Public. In four hours, leading experts from all over the world will address the most important causes of infertility in concise and up-to-date presentations for the lay public. The afternoon then concludes with an expert panel answering questions from the audience. For registrations for the general Conference and the preceding four workshops, please visit http://frm2018.cme-congresses.com. To register for Clinical Fertility Day for the Public, please visit http://frm2018.cme-congresses.com/cfd/.

Welcome back: Continued from Page 1

For program information:http://kaywa.me/Ny49fFoundation for Reproductive MedicineRegistration, Sponsorship & Exhibition Inquiries:[email protected]

invention of a hypothetical, yet undefinable, diagnosis, like implantation failure or unexplained infertility.

But giving the unknown a name does not solve the problem and, certainly, does not lead to appropriate treatments. Only clear definitions of a clinical conditions in their so-called clinical phenotype (i.e. clinical presentation) may do that. Indeed, the more diffuse the phenotype of a diagnosis, the more difficult will it be to learn what causes the problem.

This does not mean that implantation failure may not really exist. The implantation failure we are referring to, however, cannot be diffuse but must be highly specific: When an embryo enters the endometrial cavity, it does not immediately implant. Indeed, it spends ca. 48 hours within the biological microenvironment of the endometrial cavity, made up of thick mucus produced by endometrial glands. There must be a biological purpose for this 48-hour waystation on the highway to implantation. The embryo during those two days very likely does a lot of different and important things we have absolutely no idea about. One can imagine that, once the embryo enters the uterus, it, for example, sends a message out that says to the mother’s uterus and her immune system, “hi, I’m here.” One can further assume that this message may be followed by a message that politely asks to be let in.

These are reasonable assumptions because the female uterus is in principle radically hostile to potential invaders. Were that not the case, women by that route would constantly be infected by bacteria, viruses and even parasites. And, since

we are already talking about parasites, this blastocyst-stage embryo that is now asking to be allowed to enter through a usually hermetically locked door, very obviously, must have a clue how to unlock this door without at the same time harming the wellbeing of the host. The reason is very clear: Like every other parasite (and as the name says), once the embryo is allowed to enter the mother’s organism, it becomes almost completely dependent on the hosts wellbeing. For example, were the embryo dependent on weakening the maternal immune system in order to implant, implantation would endanger the mother’s life and, therefore, also that little parasite’s future as a parasite within the mother. Embryos, therefore, must have a way to unlock the gate without harming the effectiveness of the mother’s ability to continue refusing entry through the uterus to infectious agents and other parasites.

Implantation failure: Continued from Page 1

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Increasing evidence, on a number of occasions discussed in these pages, now suggests that embryos do all of this in very similar ways to biological parasites (for example, helminths) by inducing the so-called tolerance pathways in the maternal immune system. Interestingly, this is also what many cancers are doing when they metastasize. Like parasites, in all kinds of tricky ways, they succeed in circumventing the mother’s immune system and, thereby, protect themselves from being attacked, as a normally functioning immune system usually does.

The reason why we are mentioning all of these seemingly unrelated facts in discussing implantation failure, is to demonstrate how complex the implantation process really is. And, by the way, we so far have addressed only one of the relevant players, the embryo. Then there is, of course, also the endometrium that, as recently has been suggested, “senses” the quality of embryos that are trying to implant and, literally, reaches out to normal good quality embryos and encases them in preparation for implantation, though does not do so for poor quality embryos. And, finally, as maybe the most important player, there is, of course, the previously mentioned maternal immune system, which must be viewed as the conductor of the orchestra because the immune system is in charge of determining which potential invaders into our bodies must be fought and rejected.

To achieve successful implantation, all three of these players must interact in harmony. Considering the very obvious complexities involved in this process, it seems almost surprising that all goes well so frequently, and embryos are allowed to implant. One, however, also must consider the likelihood that failure may, actually, be more frequent than is generally appreciated. After all, even young couples at peak fertility, who likely produce an embryo every month, on average require between three and four months to conceive. From this observation alone, one can conclude that a large number of human embryos, likely even a majority, do not pass muster, and are not welcomed to implant.

Most of those are likely poor-quality embryos and we should be grateful they are not permitted to implant because this feature of the implantation process protects mankind from many abnormal pregnancies and potential births. But it appears also reasonable to assume that not all failures to implant are caused by abnormal embryos. Clearly, there also must be

Implantation and immune system:http://kaywa.me/yA3DB

The embryo, during those two days, does a lot of important things we have absolutely no idea about..."

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malfunctions in the above-outlined normal implantation processes: The embryo may send no or the wrong signals upon entering the uterus; the endometrium and/or the maternal immune system may not properly register the embryo’s signals and/or respond in improper ways. For example, it has been demonstrated that hyperactive immune systems (i.e., immune systems affected by autoimmunity, inflammation, allergies) lose capacity to induce tolerance pathways.

If in response to signals from the embryo the maternal immune system cannot induce tolerance pathways, the immune system will still perceive the implanting embryo as “foreign” (which it is because it is 50% genetically paternal) and will, therefore, as it is expected to do, attack in order to protect the woman from dangerous invaders. The consequence will be more resistance to implantation, early pregnancy loss (i.e., chemical pregnancies) and increased numbers of miscarriages in women with hyperactive immune systems.

What does all of this mean clinically for women who suffer from difficulties with implantation, early pregnancy loss and repeat miscarriages? Unfortunately, not very much because, though we believe to understand many of the basic principles of the implantation process, the crux, as always, lies in the details, and most details affecting the implantation process of human embryos are still a big black box. For example, we still cannot differentiate between causes why embryos do not implant (and/or miscarry). In other words, we never know for certain, why an IVF cycle failed: was it because embryos were abnormal, because the endometrium did not behave appropriately in welcoming the embryo or was it because the immune system sent out missiles that killed off implanting embryos or the early pregnancies?

Consequently, when colleagues publish studies of women with alleged implantation failure, what does this really mean but a basket of possible conditions which, each, on their own or in combination, can prevent the establishment of successful pregnancy? Even laypeople will, however, understand that appropriate treatments will depend on the underlying problem. Indeed, if the reason why an IVF cycle fails are poor quality embryos, who would even want these embryos to implant? The solution, in such cases, therefore, is improved ability to identify “bad” embryo prior to embryo transfer. That has been attempted but has, largely failed so far, with preimplantation genetic testing for aneuploidy (PGT-A) and embryoscope with time-lapse imaging

Implantation failure: Continued from Page 11

being only the latest examples.

What reflects proper responses of endometrium to an implanting embryos is also still unknown. Laboratories at Cambridge University, in the UK, and here in NYC at Rockefeller University (the Brivanlou Laboratory, with which CHR closely collaborates) have in recent years been successful in establishing in vitro human embryo implantation models. They are, however, limited by current international restrictions that allow human embryos to be cultured only for up to a limited number of days post-fertilization. Remarkably, these studies, however, demonstrated that embryos apparently can develop perfectly normal up to approximately day 14 without any maternal contributions.

This observation, alone, demonstrates the amazingly preprogramed, completely independent developmental abilities of human embryos. To some degrees, this should not come as a surprise since ectopically implanting human embryos, quite obviously, can implant even in absence of endometrium (as in vitro they have been shown able to implant on basically a plastic membrane). In vivo, ectopic pregnancies, however, still have to deal with the maternal immune system, which so-far has not been added to reported in vitro implantation studies of human embryos.

These finding call into question the long-held concept of a hormonal implantation window, which assumes that the endometrium produces under hormonal influences a very narrowly restricted time window for implantation. If there, indeed, exists such a hormonal time window, it does not appear dependent on endometrial tissue! One can also argue that a hypothetical in vitro implantation model that also includes components of the maternal immune system, capable of producing an allogeneic immune response, might demonstrate significantly more restricted implantation potential than currently established in vitro systems that lack immune responses.

Successful implantation in humans, thus, in many ways almost appears to be an accident, more often destined to fail than to succeed. How can one, therefore, be surprised by the fact that IVF much more often fails than succeeds (except, maybe, in young donor egg cycles). That implantation chances are so strongly associated with female age (i.e., the age of the eggs in a woman’s ovaries), speaks to the overwhelming importance of oocytes for successful implantation and pregnancy, and the relative unimportance of everything else. But being relatively unimportant does not mean not


What is the meaning of abnormal NK counts in infertility?Natural killer (NK) cells are an important

subgroup of lymphocytes (a subgroup of white blood cells) which have a large variety of functions, from killing cancer cells to, potentially, also killing the “invading” (i.e., implanting) embryo if the immune system sees the embryo as “foreign.”

Because half of the embryo is paternal, it is not surprising that a maternal immune system would see an implanting embryo as “foreign” – as it would see an organ transplant from the partner – and attack it. Yet, if a woman has a normally functioning immune system, such an attack does not happen because her immune system, in response to messages from the embryo, reprograms itself from rejection to tolerance of the embryo. Women who have hyper-active immune systems due to autoimmunity, inflammation or even from being very hyper-allergenic, do not reprogram their immune systems appropriately. As a consequence, their immune systems still view embryos as “foreign,” attack them, thereby causing implantation failure and/or pregnancy loss.

Research suggests that NK cells play a very important role in developing this tolerance, but further details are still quite iffy because local endometrial NK cells are functionally very different from peripheral NK cells that are measured when a blood test is performed. To conclude from peripheral NK cell counts that a patient may have an implantation

problem, therefore, appears quite far-fetched.

Consequently, CHR does not use NK cell counts as a diagnostic test for either implantation failure or increased miscarriage risk. Instead, CHR is searching for evidence of a hyper-active maternal immune system by testing patients’ bloods for autoimmune markers, inflammatory markers and evidence for a hyper-allergenic state. If such evidence is discovered (and the literature suggests that the prevalence of hyperactive immune systems is much higher in infertile women than in the general population), an assumption is reached that such a patient is likely at risk to develop inadequate maternal tolerance and, therefore, to experience an allogeneic maternal immune response against the fetus, potentially leading to implantation failure and/or miscarriages. Maternal treatment then must be directed at calming down this allogeneic immune response.

Does mechanical injury of the endometrium (endometrial scratching) work to prevent implantation failure?Endometrial scratching was first described

in 2003 as treatment for suspected implantation failure by Israeli investigators (Barash et al., Fertil Steril 2203;79:1317-1322). The procedure has remained controversial ever since, though its utilization has increased worldwide. Dekel et al in 2010 offered evidence that endometrial injury in the preceding luteal phase may induce inflammatory processes in endometrium which in the subsequent cycle may improve implantation chances [Dekel et al., Am J Reprod Immunol 2010;63(1):17-21].

Because, as noted in the implantation failure article starting on page 1, the diagnosis of implantation failure is always highly uncertain, one cannot be surprised that studies of endometrial scratching have offered inconsistent results. The honest truth is that, still, nobody knows whether endometrial scratching indeed improves implantation chances. CHR uses this procedure, therefore, sparingly, and only as a last resort.

CHR's Experts Respond

Four Fertility Questions from the Public

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Either from CHR’s patients or via CHR’s website and YouTube channel from the general public, we received, as usual, many questions over the summer. Here we have chosen a small number among those because they were asked repeatedly.

1

2


Human Natural Killer (NK) Cell

Image by NIAID under Creative Commons 2.0

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What is the value of the Endometrial Receptivity Testing (ERT)?Sometimes there are advantages to practicing in a highly overregulated state like New York.

The advantage in this case is that New York State, in contrast to a good number of other states, has so far not licensed the sale of the Endometrial Receptivity Testing (ERT). Consequently, New York-based patients must go out of state if they want to have this test done, which means not only costs for the test but also travel costs.

For CHR, this offers a convenient explanation why the test is not available at the center. The honest truth, however, is that, even if the test were licensed in New York State, CHR, likely, would not recommend it. The reason is simple: It just appears to be yet another industry-driven test, introduced to the commercial market without appropriate prior validation studies. In addition, the improving understanding of implantation also suggests that the test, likely, makes little biological sense.

Should birth control pills be used in IVF?Almost since the very inception of IVF, oral contraceptive pills (OCPs) have been routinely used to prepare patient for IVF

cycles. They, indeed, are perfect tools to control the timing of cycle starts. But they are "perfect" tools really only in women with normal ovarian reserve. In women with low ovarian reserve, i.e. in women at older ages and in younger women with premature ovarian aging (POA), OCPs, because their function is to suppress ovaries, are counterproductive. They, therefore, should not be used in such women. Like other treatments that suppress ovarian reserve, such as gonadotropin-releasing hormone antagonists and long agonists, they can counteract other treatments give to such patients to improve their ovarian performance, like androgen supplementation and human growth hormone.

having any relevance. Unquestionably, endometrium and the maternal immune system actively participate in the implantation process but how they exactly do that, has remained largely unknown.

We, therefore, have to acknowledge that when the talk turns to an alleged implantation problem or so-called “implantation failure,” nobody really knows what it is all about. Consequently, treatments proposed and applied must be viewed with caution and be acknowledged by patients as well as physicians as largely experimental. Like all physiological processes, implantation, unquestionably, can malfunction, and likely in many different ways. But we currently do not even know what percentage of failed IVF cycles is caused by malfunction of the implantation process rather than by poor embryo quality. Common wisdom in the field holds that true implantation failure is a rare occurrence; whether that means one percent or 15 percent, nobody really knows. And in absence of specific diagnostic tests for implantation failure, to find successful treatments will be exceedingly difficult since effectiveness of treatments can only be assessed in “clean” patient populations, uncontaminated by other conditions.

Implantation failure: Continued from Page 124 Questions: Continued from Page 13

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OPEN POSITION

Board-eligible/certified reproductive endocrinologistCHR is seeking a qualified physician with proven

research interest to join the center’s team of clinicians and biologists. Commensurate with qualifications, appointment are available at

junior, assistant, associate andsenior scientist levels.

CHR offers competitive salaries and benefits, coupled with strong incentives linked to

research efforts and publication success. In combination with the freedom of a private

practice set-up, this position offers a unique opportunity for individuals interested in

exploration of the unknown and in pursuit of discoveries suitable to quick translation into

clinical practice.

The position is available immediately.

Please submit CV to Ms. Jolanta Tapper at [email protected] for consideration.

OPEN POSITIONSBoth require professional and pleasant demeanor, good

interpersonal and communication skills and ability to multitask. Please submit resume to Ms. Jolanta Tapper

at [email protected] for consideration.

Clinical Coordinator/Nurse: RN/NPL or equivalent to join our excellent team of IVF coordinators. Prior IVF experience and knowledge of a foreign language preferred, but we will train the right individual. This position involves a large amount of close and independent interaction with patients. We offer a highly collaborative work environment between physicians, clinical coordinators and embryology staff, competitive salaries and benefits as well as opportunity to participate in research.

Medical Assistant: Must have at least one year of clinical experience and be able to draw bloods, assist physicians during ultrasound and pelvic exams. This is a full-time position. Must be available to work on a rotating basis late afternoons and weekends.

3

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All of this, however, does not mean that older women should not get pregnant. It also does not mean that all women with known medical problems should be refused fertility treatments. To the contrary! Referring to almost all medical problems, studies have clearly demonstrated that most women can safely go through pregnancy if they are properly prepared and properly monitored during pregnancy and into the postpartum period (there, of course, are exceptions, and there are a limited number of medical conditions where pregnancy is clearly contraindicated). But this also means that such a patient must receive individualized diagnostic work ups before conception that do not only relate to their fertility problems. In other words, in CHR’s opinion, the fertility center’s responsibility is not only to help older patients to conceive but, also, to ensure that their pregnancy will be as uncomplicated as possible.

This, of course, applies whether an older woman conceives with her own or with third party donor eggs. The “stress” on the mother’s body remains, in principle, the same, though immunological problems in pregnancy, for example, preeclampsia, and premature deliveries, may, indeed, be further enhanced in donor egg cycles since the maternal immune system now must deal not only with a 50% semi-allograft but a 100% complete allograft.

Pregnancy in older women in their late 40 and early 50s, in summary, is clearly riskier than at younger ages and risks, indeed, gradually increase with maternal age. Most older women, can, however, be still safely managed through pregnancy. In summary:

1. If at all possible, potential medical problems should be identified in advance, so that patients can be proactively placed under appropriate medical co-management by specialists. Proactive management is always preferable!

Risks of pregnancy: Continued from Page 32. Patients must also be informed that neonatal

complications increase in parallel with advancing age, though those in a large majority can also be satisfactorily addressed with proper proactive pregnancy management.

3. Older patients should automatically be advised that their pregnancy will, therefore, be considered relative high-risk and should be delivered in a tertiary-care hospital, with appropriate maternal and neonatal services available to manage complicated pregnancies and their offspring.

4. More so than younger patients, older women also must be more carefully monitored into the postpartum period, with some pregnancy-associated complications manifesting themselves up to 4-5 months postpartum.

5. There are women who should no longer go through pregnancy, and such women, indeed, should be strongly discouraged from attempting pregnancy. These cases are rare and, mostly, include women with cardiac problems, like decompensating valvular heart disease, pulmonary hypertension, Eisenmenger syndrome and prior myocardial infarction (as recently reported, an increasing cause of the rising U.S. maternal mortality rate).

6. At the same time, management of medical problems in pregnancy is constantly improving. A good example is HIV, which at one time was considered an absolute contraindication for pregnancy but today, in most instances, is no longer a barrier to normal and healthy delivery. An even more remarkable example is diabetes, which before insulin became available for treatment, was characterized by extremely high pregnancy loss rates. Diabetic women, indeed, rarely ever delivered. Nowadays pregnancy outcomes of diabetic women are hardly different from those of non-diabetic patients.

Image by Alexander Dummer via Unsplash

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new name: PGT-A. Announcement of PGS 3.0 by the industry, was, however, no coincidence: By that point, quickly increasing reported numbers of healthy euploid births from transfers of, by PGS laboratories declared “aneuploid” or “mosaic” embryos, made the prior positions and practices of the PGS laboratory industry no longer tenable. CHR, indeed, has been the first IVF center in the world to announce transfers of so-called “abnormal” embryos and healthy euploid births from such transfers. By now, hundreds of healthy offspring have been delivered worldwide following such transfers.

Since we have discussed PGS 3.0 in these pages extensively and repeatedly, we do not wish to be repetitive. Moreover, this communication is not meant to again discuss the very obvious shortcomings of PGS/PGT-A, and damages its utilization inflicts on patients. CHR investigators have continued to speak out in peer-reviewed journals: For example, CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, was recently one of the con-voices in a debate, published by Fertility & Sterility (Rosenwaks et al., Fertil Steril 2018;110(3):353-361), the official organ of ASRM.

He and co-workers recently also published a critique in the form of a very detailed letter to the editor in Reproductive Biomedicine Online of a PGS-related article [Grati FR et al., Reprod Biomed Online 2018; 36:442-449], for which Munné provided an accompanying, and very laudatory editorial [Munné S. Reprod Biomed Online 2018;36:369-370]. CHR investigators lauded the authors for the intent of their study but criticized their manuscript and Munné’s accompanying editorial for failing to point out how controversial the use of PGS/PGT-A had become in recent months and years [Gleicher et al., Reprod Biomed Online 2018; 37(2):242-245].

After accepting CHR's correspondence for publication following peer review, it is common practice to let the authors who were criticized in the correspondence to respond in print. This is also what happened in this case, and authors of the original paper as well as Munné, author of the accompanying editorial, were given the opportunity. The authors responded with a succinct and polite letter [Grati et al., Reprod Biomed Online; 2018; 37(2):246], while Munné's response was similar to the written temper tantrum he circulated by e-mail after NEW YORK magazine published an article on PGS in the fall of 2017 that he did not like. Once again, he became inappropriately personal in his response when accusing CHR investigators to be principally motivated by financial gains [Reprod Biomed Online 2018;

Santiago Munné: Continued from Page 537(2):247-249] and made blatantly incorrect scientific representations.

In an attack on CHR’s investigators, already “weakened” at editors' request (we had been privy to the earlier version), CHR investigators were accused in the introductory sentence of Munnés response of attacking the utilization of PGS/PGT-A only in an attempt “of defending their business model, by denouncing PGS as their marketing differentiator from other centers.”

Munné, in other words, implied that CHR’s investigators in their almost 20 years of opposition to the concept of PGS/PGT-A, and their multifaceted research, documented in a large number of publications, were only motivated to express their negative opinions about PGS/PGT-A in pursuing financial gains through a business model that differentiated CHR from other IVF centers.

This is, of course, a very serious, indeed defamatory claim. Though even significantly weakened from an earlier version, such a statement of alleged motivation is still highly unusual within a scientific discourse in a peer-reviewed journal. It, therefore, requires some further comments.

Since its establishment in Chicago in 1981, CHR, has, indeed, pursued a rather unique business model in that it functions more like an academic research center than a typical private IVF facility. CHR’s important research contributions to the infertility field have been many and have significantly affected worldwide infertility practice. Practice improvements introduced by CHR include transvaginal tubal catheterization in replacement of major tubal surgeries to recanalize clogged fallopian tubes; the world’s first vaginal egg retrieval for IVF, when routine practice was operative laparoscopy; dehydroepiandrosterone (DHEA) to improve functional ovarian reserve in infertile women; and many others.

In introducing all of these and other innovations, CHR investigators, uniformly, have been proven correct, even if the always expected (and for the process of introducing innovations, healthy) nay-sayers were never lacking.

Contrast that to Munné’s track record on PGS (his many publications on this subject can be viewed under his name at www.pubmed.com). The repeated and constantly changing promises (i.e., moving of goal posts) will become immediately obvious. We cannot even find one that was proven to be correct.


Our announcement of healthy births:http://kaywa.me/ZrFk2

Read the New York Magazine article:http://kaywa.me/Z4w62

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Even beyond initial and most fundamental claims that PGS would improve pregnancy and live birth chances with IVF (Munné, of course, was not alone among PGS/PGT-A proponents in making those claims), he was more outspoken than others in making secondary claims, later established as false: For example, when trying to convince the IVF community that PGS 2.0 was much better than the PGS 1.0, just dismissed by ASRM, he claimed in a publication that the switch from day-3 to day-5 embryo biopsies would greatly reduce the mosaicism problem. We, of course, now know that the opposite is the case since mitotic mosaicism significantly increases between cleavage and blastocyst stages, as increasing numbers of cell divisions take place in an embryo.

His frequent incorrect representations do not allow a judgement on whether they are primarily based on biological ignorance about early human embryo development or, simply, aberrations of aggressive marketing. Especially remarkable is his apparent ignorance about what represents functional mosaicism in a preimplantation-stage human embryo. His explanation for cut-off values that under the new PGDIS guidelines of 2016 define “normal-euploid,” “mosaic” and “aneuploid-abnormal” embryos, is truly amazing. Yet, these cut offs, are now used worldwide by laboratories to determine which embryos can be transferred or must be disposed of.

As his most recent above cited communication again confirms, he still insists that 80% aneuploid DNA load in a single trophectoderm biopsy represents an adequate cut-off to differentiate between “mosaic” and “aneuploid” embryos, which also means differentiation between potential of transferring or discarding embryos. Incredibly, he also repeats in his written response what, up to this point, he had offered only in an oral presentation as explanation for the 80% cut-off at a 2017 medical congress in Vienna, Austria, namely that “...80% aneuploid DNA load represents 4/5 aneuploid cells in an on average 5-cell biopsy.”

But what if the biopsy contained 6 or 7 cells or, alternatively, lost DNA content from some of the cells, as cells frequently do during embryo biopsies? Under this ridiculous threshold concept, in the first case, the aneuploid DNA load would be artificially diluted, and a supposedly “aneuploid” embryo would, suddenly, be “mosaic.” In the second scenario, the opposite would happen, and a “mosaic” embryo would automatically be upgraded to “aneuploid” and, therefore disposed of.

Using next generation Sequencing (NGS) on such a flimsy mathematical (and biological) basis is not

only irresponsible but, simply, shameless!

This communication is, however, not meant to rehash the many controversies surrounding PGS/PGT-A. We here, instead, want to address the absurdity of Munné’s allegation that the motivation behind CHR’s opposition to the use of PGS/PGT-A has economic/financial connotations.

CHR’s almost 20-year-long involvement with PGS (actually preceding Munné’s own involvement), of course, has absolutely nothing to do with economics (though CHR is concerned about patients, for no good reasons, spending an additional $4,000-5,000 on average for adding PGS/PGT-A to their IVF cycles). CHR has a strict “wall” between research and financial interests, closely controlled by an independent Institutional Review Board (IRB), chaired by an independent, non-CHR physician, even located in a different state. Even more importantly, such an accusation economically (and logically) makes absolutely no sense, since which commercial IVF enterprise would base a marketing approach on, a-priori, foregoing highly significant additional IVF cycle revenue?

The average additional cost of PGS/PGT-A in the U.S. is between $4,000 and $5,000, which (under federal and certain state laws in somewhat questionable fashion) is usually evenly split between IVF centers (for performing the embryo biopsy) and commercial laboratories (for performing the PGS/PGT-A screening test and reporting results). For most IVF centers, performing an IVF cycle with PGS, therefore, adds between $2,000 and $2,500 to cycle revenue. This represents especially in cycles of patients with IVF insurance coverage (which usually are highly discounted) a very significant revenue boost, as insurances do not pay for PGS/PGT-A (correctly considering it an unproven experimental procedure), and patients, therefore, must pay for this test out of pocket. In such cycles these cash payments can often represent 30-40% of additional cycle revenue for IVF centers, creating significant financial incentives for IVF centers to perform PGS/PGT-A.

$2,000-2,500 in laboratory revenue for a simple NGS analysis, of course, also represents a highly profitable business proposition for commercial laboratories, especially since a very small number of these laboratories really perform the large majority of PGS/PGT-A testing.

Though financial incentives unquestionably exist for laboratories and IVF centers (with the latter, likely, on purpose created by the PGS/PGT-A industry), CHR’s

Santiago Munné: Continued from Page 16


18

investigators never believed or implied that incentives for IVF centers were a driving force behind the utilization of PGS/PGT-A. That PGS/PGT-A utilization over the last year appears to have stagnated and even fallen (some major national genetics laboratories that in the past had offered PGS/PGT-A announced their withdrawal from this market segment) is supportive of this assessment of motivations. A reason is likely that the IVF community, finally, had the opportunity over the last year to read opposing opinions on PGS/PGT-A in the medical literature, after proponents of the test for almost a decade had controlled the peer review process on the subject and had made it almost impossible for opponents to publish their manuscripts in leading journals of the profession.

Since CHR never believed the marketing slogans of the PGS/PGT-A industry, this center never recommended PGS/PGT-A to patients, thus literally foregoing millions of dollars in additional cycle revenues in all of these years. Economic and/or financial incentives, therefore, very obviously, were not a motivating factor for CHR. Though CHR’s investigators never even gave thought to call into question Munné’s integrity in advocating his side of the argument in favor of PGS/PGT-A, this is, of course, exactly what he did in accusing CHR of being opposed to PGS/PGT-A for only economic reasons. One, therefore, has to wonder where such a far-fetched allegation may come from in his mind?

And the answer appears very obvious: In clinical psychology theory there, of course, is the concept of “projection.” Wikipedia defines it as “the human ego defending itself against unconscious impulses or qualities by denying their existence in themselves, while attributing them to others.”

Munné’s behavior, especially over the last few years, appears to represent a fairly typical and obvious example of such projective behavior since it is, of course, the PGS/PGT-A laboratory industry that has the financial incentives to sell the PGS/PGT-A test to the IVF community and public at basically all costs. Nobody has, indeed, been economically more successful in doing so than Santiago Munné, who, according to public records, in 2016 sold his U.S. and U.K. laboratory operations to the CooperSurgical corporation for in excess of $60

million and is again already hard at work (this time in Spain) on building another company in the field.

Only a person who is excessively motivated by financial considerations can, indeed, reach an outlandish and economically non-sensical opinion, as expressed by Munné in the introductory sentence of his response to the letter-to-the-editors by Gleicher et al, accusing the authors of opposing utilization of PGS/PGT-A for financial/economic purposes only. One will rarely see a better example of psychological projection in the medical literature, and the editors of the journal are to be congratulated for making this point so obviously transparent by publishing this exchange. A very well-balanced commentary in the same issue of the journal by Peter Braude, MD, from Kings College in London, UK, (Reprod Biomed Online 2018;37(2): 133-135) further added to this exchange of opinion. We strongly recommend that readers of these pages seek out the original source materials here referenced. It will provide important additional insights into PGS/PGT-A.

One important additional point must be made, however: Munné’s above referenced response ended on an even more worrisome note than his disparaging introductory sentence, when he concluded: “While Gleicher and colleagues are still shaking their fist at PGSv1 (likely meaning PGS 1.0-PGS 3.0), the field is moving forward (to) non-invasive PGS.”

Munné, therefore, is obviously again moving the goal posts. We, therefore, better brace for even more “snake oil” from him (and other continued proponents of PGS/PGT-A), to be sold to IVF community and public. One at this point must really wonder what drives one to continue testing embryos for alleged aneuploidy if, even if this alleged aneuploid is factual (and it often is not), a very high percentage of embryos self-corrects downstream. It is like tasting a soup before it is cooked. No method of preimplantation-stage embryo testing can be accurate enough for clinical use, if such testing is performed before embryos have completed self-correction.

Santiago Munné: Continued from Page 17

-The CHRFighting for every egg and embryo!

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Annual 2018 Conference of the Foundation for Reproductive Medicine

TRANSLATIONAL REPRODUCTIVE BIOLOGY ANDCLINICAL REPRODUCTIVE ENDOCRINOLOGY“Paradigm changes you may not hear about elsewhere!” and “Think differently!”

NOVEMBER 15-18, 2018 • NEW YORK, USAClinical Fertility Day for the Public on Sunday, November 18, 2018

For program information, visit the conference website: http://kaywa.me/1Apl1Foundation for Reproductive Medicine21 E 69th Street, New York, NY 10021 | www.FoundationForReprodMed.comAttendee, Sponsorship & Exhibition Inquiries: [email protected]

The 3rd annual meeting of the FRM to stimulate paradigm changes and translational collaborations among basic scientists and clinicians in reproductive medicine4 Pre-Conference Workshops

Î Egg donation is only a second-best choice: What can be done to offer patients best outcomes with their first choice, their own eggs?

Î Avoiding unproven add-ons, and getting back to the basics in IVF

Î Is it “fresh” or is it “frozen,” and is it “slow-freezing” or “vitrification?”

Î From the Brivanlou Laboratory at Rockefeller University, seeing human embryos like never before

Main Conference Sessions Î Breaking News Lecture: Understanding the fragile

X mental retardation 1 (FMR1) gene better further enhances its importance | Ethan J. Greenblatt

Based on most recent publications, the conference presents in a single room the year’s Who’s Who in reproductive biology and clinical reproductive medicine for an authoritative annual update on newly evolving paradigms in basic sciences and clinical medicine. A conference like the FRMC, simply, does not exist anywhere else in the world, which is why we have been welcoming hundreds of attendees from over 40 countries to NYC every year. FRMC offers both clinicians and scientists a unique and intimate framework for interactions and exchanges of ideas.

Î Where our journey is leading to: Parts I-V Î Paradigm Change I: Clarifying the significance of

chromosomal abnormalities in human embryos Î Paradigm Change II: Changing the thinking about

PCOS Î Debate: When is the right time to refer a patient

into egg donation? Î Paradigm Change III: Individualizing IVF practice for

best outcome by age and functional ovarian reserve Î Hidden treasures discovered Î Most interesting ESHRE and ASRM Presentations Î Yet Unpublished Data Î FRMC Closing Lecture: Will human embryos fly? |

Ali H. Brivanlou

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Primary Care Network (PCN) and the Foundation for Reproductive Medicine. Primary Care Network is accredited by the ACCME to provide continuing medical education for physicians. Primary Care Network designates this live activity for a maximum of 22.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

the center for human reproduction chr voice...to go solely by the number of failed ivf cycles, quite...

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