Miscarriages are a frequent and often unpreventable complication of pregnancy. On average ca. 15% of all pregnancies get miscarried but the rate is lower in younger and higher in older women. By age 45, the miscarriage rate, indeed, can reach ca. 50%. It is generally believed that chromosomal abnormalities are the by far most frequent cause of miscarriages. Though this statement is, likely still correct, the prevalence of chromosomal causes has been exaggerated. The principal reason is similar to why chromosomal testing of embryos, now called preimplantation genetic testing for aneuploidy (PGT-A), is so inaccurate: Placenta and fetus do not always present with the same chromosomal findings. Indeed, placenta and its embryonic precursor, the trophectoderm, demonstrate much more aneuploid cell clones. In other words, just because the placenta contains aneuploid cells, does not yet mean the fetus (and newborn) are chromosomally abnormal.

Since cells from the fetus proper did not culture as well, for the longest time products of conception from abortuses where chromosomally investigated through cell cultures, usually taken from the placenta (just as PGT-A is performed by taking a biopsy from the trophectoderm). The prevalence of aneuploidy, as to this day still expressed in textbooks, therefore, unquestionably must be exaggerated. Chromosomal abnormalities at all ages and at all gestational ages, though, still cause a majority of spontaneous pregnancy losses.

CHR Explains

Causes and Prevention of Early Miscarriages at 6-8 Weeks

Î Early miscarriages tend to have different causes than miscarriages later in pregnancy, and that means preventive measures should be targeted

How quickly time passes, especially during the summer months! It seems only like yesterday that we wished all of our readers a wonderful vacation season and announced our usual summer break in publishing this newsletter for the months of July and August. As we are writing this introduction to our September VOICE, the end of summer is upon us and, before we know it, we will be speeding toward the year-end holiday season. One reason why here at CHR the summer months passed so quickly this year was that they were unusually busy clinically. We, therefore, also expect a busier fall season than usual. With summer vacations over, we are back to full manpower, and are looking forward to the challenges.

When it comes to medically relevant news, the summer months this year were surprisingly quiet. Only one subject that made headlines over the summer got our writers’ fingers a bit itchy but, ultimately, was not considered worth interrupting the VOICE’s summer hiatus; and that was the disturbing story that some fertility centers, through direct-to-public genetic testing, were found to have used their own physicians’ semen in place of semen from sperm donor agencies, as had been represented to patients. We are addressing this subject in this newsletter, together with another development that caught the attention of the media: colleagues down the street at Weill-Cornell starting to experiment with genetic editing of sperm that carries abnormal mutations using CRISPR/Cas-9. As always, we also address issues our readers raised, such a causes and prevention of early miscarriages (our lead article), the so-called lymphocyte immunization to prevent miscarriages and a new treatment developed at CHR, which we've termed "rebound."

CHR VOICE the monthly CHR UPDATE

The Center for Human Reproduction

Clinical Care • Research • Education

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REIs as sperm donors ...3

Lymphocyte immunization therapy ...6

Gene editing for sperm...7

Rebound effect in IVF...8

CHR in the media ...8

Letter from a patient ...8

September2019

Annual 2019 Conference of the Foundation for Reproductive Medicine

TRANSLATIONAL REPRODUCTIVE BIOLOGY ANDCLINICAL REPRODUCTIVE ENDOCRINOLOGY“Think differently!” and “Paradigm changes you will hear here first”

NOVEMBER 21-24, 2019 • NEW YORK, USANew York Marriott East Side

Advance registration rates extended till November 1, 2019 for Foundation for Reproductive Medicine members, with a tax-deductible donation of $250 and up!For membership, attendee, sponsorship and exhibition inquiries, contact us at info@FoundationForReprodMed.comhttp://kaywa.me/ZO9ExVisit the conference website for the full scientific program, workshop details, CME information and more.

The 4th conference of the FRM offers to clinicians, basic scientists and trainees in a single lecture hall over two-and-a-half days a comprehensive and very contemporary update on reproductive biology and reproductive clinical endocrinology/infertility. It also presents unique opportunities for interaction between basic scientists and clinicians, with the ultimate goal of the conference being to enhance the quick translation of new developments in reproductive biology to clinical practice in reproductive endocrinology/infertility.

Confirmed FacultyEli Y. Adashi, MD, MS, MA (USA)David H. Barad, MD, MS, FACOG (USA)Juan Carlos Izpisua Belmonte, PhD (USA)Boback Berookhim, MD, MBA (USA)Shalender Bhasin, MD (USA)Zeev Blumenfeld, MD (Israel)Mats Brannstrom, MD (Denmark)Ali H. Brivanlou, PhD (USA)Jan J. Brosens, MD, PhD (UK)

David F. Albertini, PhD, USAEditor-in-Chief, Journal of Assisted Reproduction and Genetics (JARG), Senior Visiting Scientist,

The Center for Human Reproduction-NY

Norbert Gleicher, MD, USAMedical Director and Chief-Scientist, The Center for Human Reproduction-NY; Visiting Researcher, Stem Cell Biology and Molecular Embryology Laboratory; Visiting Researcher, The Rockefeller

University; Professor (Adj.), Department of Obstetrics & Gynecology, University of Vienna Medical School; President, The Foundation for Reproductive Medicine

Zeev Shoham, MD, IsraelDirector Reproductive Endocrinology Unit, Kaplan Medical Center; Professor of Obstetrics

and Gynecology, Hadassah Medical School of Hebrew University

Conference Chairs

Foundation for Reproductive Medicine21 E 69th Street, New York, NY 10021 | www.FoundationForReprodMed.com

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Human M. Fatemi, MD, PhD (Dubai)Demián Glujovsky, MD (Argentina)Anna-Katerina Hadjantonakis, PhD (USA)Brian P. Hermann, PhD (USA)Peter Husslein, MD (Austria)T. Rajendra Kumar, PhD (USA)John McCarrey, PhD (USA)Rajiv C. McCoy, PhD (USA)Shoukhrat Mitalipov, PhD (USA)Hazel B. Nichols, PhD (USA)

Sonja Nowotschin, PhD (USA)Nicole Noyes, MD, FACOG (USA)Raoul Orvieto, MD (Israel)Pasquale Patrizio, MD, MS, FACOG (USA)Oliver J. Rando, MD, PhD (USA)Peter N. Schlegel, MD (USA)Sherman J. Silber, MD (USA)Evelyn Telfer, PhD (UK)Andrea Weghofer, MD, PhD, MBA (Austria)Miles F. Wilkinson, PhD (USA)

all of these allegations, he was convicted in court of 52 counts of mail fraud, wire fraud and perjury and was sentenced to five years in prison. In addition, he, of course, also lost his medical license and, fortunately, no longer practices medicine.

On August 30, 2018, Mihir Zaveri, a New York Times writer published an article under the heading, “A Fertility Doctor Used His Sperm on Unwitting Women. Their Children Want Answers.” In this report a fertility doctor in Indianapolis, Indiana, by the name Donald Cline, MD, acknowledged deceptively using his own semen, and is now believed to have fathered 61 children according to an article by Hannah Smothers in COSMOPOLITAN on August 22, 2019.

On Wednesday, August 21, 2019, the writer Jacqueline Mroz penned

an article in The New York Times under the title, “Their Mothers Chose Donor Sperm. The Doctors Used Their Own,” subtitled, “Scores of people born through artificial insemination have learned from DNA tests that their biological fathers were the doctors who performed the procedure.”

Dictionaries define “scores” as “large numbers.” Mroz in her article describes approximately 20 cases worldwide, where physicians have been accused of fraudulently using their own semen in place of third-part-donor semen. Twenty such cases, of course, are 20 too many; but 20 cases worldwide do not represent “scores” and, most certainly, also do not reflect “a generalized practice of deception,” as a prominent law professor and ethicist from the San Diego University School of Law in California by the name of Dov Fox claimed, as quoted in the recent New York Times and COSMOPOLITAN articles.

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It was this time The New York Times that, within a few days, in two articles featured the subject of fertility providers, secretly, using their own semen, rather that third-party-donor semen, in treating their infertility patients. This is, of course, not the first time that this subject has attracted media attention. The case that comes immediately to mind is that of Cecile Byran Jacobson, MD, a general obstetrician/gynecologist who in the 1980s operated a reproductive genetics and infertility center in Virginia. In the late 1980s he was accused of having fathered over 70 children by using his own semen in place of donor semen and, at least in one case, also in place of husband semen.

Studying his professional life, Jacobson must, however, be viewed as a sociopathic personality and serial criminal. While head of a reproductive genetic program at George Washington University School of Medicine in Washington, DC, he made the bizarre claim of having impregnated a male baboon by placing a female baboon’s eggs into the male’s abdominal cavity. Without offering any evidence, he further claimed to have terminated the pregnancy at four months.

In later years, when offering private fertility services, he claimed to “support” early pregnancies with injections of the pregnancy hormone, human chorionic gonadotropin (hCG), but then turned around and tested these patients for pregnancy by evaluating their hCG levels. They, of course, had positive pregnancy tests because of the injections they received, and Dr. Jacobson further misled them by claiming to see those non-existing pregnancies on ultrasound examinations. Use of his own semen was accidentally discovered during investigations of his other fraudulent activities. Though he maintained his innocence regarding

Infertility doctors as their (unknowing) patients' sperm donors?

Î The shocking news highlights uncomfortable, if less obvious, developments surrounding third-party gamete donations

2nd New York Times article:https://kaywa.me/SPYe8

COSMOPOLITAN article:https://kaywa.me/WBH95

1st New York Times article:https://kaywa.me/HEte1

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Effects of excessive inflammation on female fertilityExcessive inflammation can make the immune systems hyperactive, negatively affecting women’s fertility. Infertile women also demonstrate a higher prevalence of excessive inflammation, which can reduce pregnancy rates and increase miscarriage risks. Physicians and patients are often unaware of immune system hyperactivity, because it can be completely asymptomatic.

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Crazy and/or dishonest, people exist in every profession. Medicine and the infertility field are, obviously, no exception. At the same time, the attention apparently given to this subject by the media seemingly primarily during the month of August, may suggest that it is more the doldrums of summer that bring this subject to the forefront than real concern about an “epidemic” of dishonest fertility specialists.

Both recent articles did, however, serve one very important purpose: They very clearly pointed out that confidential and anonymous third-party gamete donations, whether of semen or eggs, no longer exist. While fertility centers like CHR remain absolutely committed to anonymous third-party donations, the reality of direct to consumer genetic testing through such companies as 23andMe, makes it not only possible to trace criminals through family connections but also gamete donors.

The real story The New York Times and COSMOPOLITAN magazine, therefore, brought us over the summer, was not, as claimed by Professor Fox, “a generalized practice of deception,” but an end to anonymous gamete donation with potentially very important consequences for fertility practice. CHR, therefore, has amended all consent forms regarding gamete and/or embryo donations, to point out to donors and recipients, alike, the possibility, even likelihood, that the days of donor and recipient anonymity have passed. While CHR remains fully committed to confidentiality of the medical record and anonymity of all patients, CHR can only be responsible for sequestration of medical records at CHR. CHR and other IVF centers are, however, powerless in preventing, especially gamete donors, from losing their anonymity simply through genetic associations of close relatives, which now often can be freely accessed on the Internet through companies that sell direct-to-consumer genetic testing.

Recipients of donor gametes, therefore, likely no longer have free choice of telling or not telling their offspring where the gametes came from that created them. It appears increasingly obvious that parents must tell their children before they discover the truth accidentally on their own. Donors of gametes, therefore, should not be surprised if, one day a genetic offspring suddenly contacts them, just as offspring should not be surprised if a genetic father or mother unexpectedly enters their lives. Donor and/or recipient anonymity no longer exists!

Both above quoted recent articles on the subject of fertility docs being their own semen donors emphasized this point and correctly predicted that there, likely, will be, indeed, a few more cases discovered around the world; but to expect “scores” of cases, as suggested by The New York Times in above cited article, is an obvious exaggeration. Even “The Gray Lady,” apparently, these days must foster sensationalism to sell newspaper. How else can responsible editors allow a

headline that equates 20 cases worldwide with “scores.”

And when it comes to law professors and ethicists: Dov Fox is the Herzog Endowed Scholar, Professor of Law; Director, Center for Health Law Policy & Bioethics at University of San Diego School of Law, where he directs the Center for Health Law Policy & Bioethics. A Rhodes scholar, he graduated from Harvard College, Yale Law School, and the University of Oxford, where he received a doctorate in political philosophy. More evidence that even very smart people at times can say stupid things and that behind every opinion there is self-interest. What the two writers that quoted him as an “expert” did not disclose to readers, is that in his book, Reproductive Negligence, Professor Fox strongly promoted a “newly recognized tort of reproductive negligence,” which, of course, is great new candy for plaintiff attorneys and will make Professor Fox a very valuable expert witness in court cases.

The public is also not told in these articles that, in the U.S., any third-party donation (eggs, semen, embryos) is strictly regulated by the Food and Drug Administration (FDA) under rules that follow organ-donation requirements. Fertility centers accredited by the FDA to use donor gametes and embryos are subject to unannounced inspections by FDA inspectors, who in detail review every such donation that has taken place since the last inspection. In addition, most states, New York included, have strict third-party state donation laws. New York State, for example, mandates that every frozen sperm and egg bank that offers samples to fertility clinics in the state, be licensed by the New York State Department of Health, wherever the bank may be located. Fertility centers in New York State, in addition, must have individual written contracts with all sperm and egg banks they are doing business with, and all of this is subject to regular inspections by investigators from the New York State Department of Health on both sides of the transaction.

Laws and regulations, of course, per-se do not prevent individuals from breaching them; but with the establishment of commercial frozen sperm banks and of frozen commercial egg banks over the last decade, third-party gamete and embryo donations have become part of a rather well-designed regulatory review framework that, under law, basically must include every such donation. Existence of such a system, of course, does not preclude breaches; but if such breaches were to occur in the U.S., it appears inconceivable that this would happen in reputable fertility centers, usually licensed and inspected by the FDA, often also by the College of American Pathologists (CAP) and local state departments of health. CHR, of course, is licensed and regularly inspected by all three of these certifying agencies.

Sperm donor: Continued from Page 3

Donor-recipient anonymity can no longer be expected in 3rd-party gamete donations.

“

The term “lymphocyte immunization” is rarely heard since 2002, when the Food and Drug Administration (FDA) prohibited this treatment in the U.S. outside of clinical trials. Up to that point, immunomodulation of the maternal immune response to paternal antigens on the trophoblast via active immunization with partner-lymphocytes was common practice.

The hypothesis behind this treatment was that stimulation of a hypo-reactive maternal immune system by paternal antigens on lymphocytes will, in a subsequent pregnancy, lead to improved immune-recognition of the implanting embryo and, therefore, in the maternal immune system to better induction of what now is recognized as tolerance pathways. The expectation was that such treatment would improve implantation and reduce the risk of miscarriages.

Because of the FDA edict, lymphocyte immunization is since 2002 no longer available as clinical treatment in the U.S.A. However, a considerable number of U.S. patients still travel to receive such treatments, with Mexico being the primary destination. Lymphocyte immunizations are, however, also available in many other countries, including in Europe. A first serious formal claim for the treatment’s efficacy was, indeed, made by British investigators.

The treatment was originally primarily only given to patients with repeated pregnancy losses. When first proposed, these treatments were only reserved for women with confirmed hypo-reactivity toward

Question from the Public

Is lymphocyte immunization a clinically valuable treatment?

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the male partners’ antigens, usually diagnosed in vitro with specific lymphocyte mixing tests. Over time, criteria for utilization were expanded and lymphocyte immunization became almost a standard treatment for all patients with repeat pregnancy loss and, increasingly, was also considered treatment for the so-called implantation failure. The latter is, of course, a rather problematic diagnosis because nobody knows how to define implantation failure and, therefore, how to reach such a diagnosis in reproducible fashion. No wonder reported outcomes after lymphocyte immunizations were all over the scale and the procedure remained highly controversial.

CHR never utilized lymphocyte immunization as a treatment for either repeated pregnancy loss or implantation failure. Even before the FDA’s edict, CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, urged caution in using paternal lymphocyte immunization for fear of inducing autoimmune reactions in mothers. He proved prescient in that concern. Even among the treatment’s proponents, evidence of autoimmunity is currently considered an absolute contraindication for the treatment. The problem with this approach, as Gleicher pointed out 30 years ago, lies in the fact that so many women with infertility and/or repeated pregnancy loss suffer from subclinical autoimmunity, which will be detected only through appropriate investigations (and even then, not always). To simply rely on a history of autoimmunity does not appear adequate.

Induction of autoimmunity will, of course, have exactly the opposite effects on miscarriage risk as one expects from lymphocyte immunization. Frequently discussed in these pages before, autoimmunity is an almost certain way to create a hyper-active immune system, which does not appropriately induce required tolerance pathways for the products of conception by the maternal immune system. In such cases, lymphocyte immunization can, therefore, actually further increase miscarriage risks. Unsurprisingly, CHR has remained skeptical of the concept and still does not recommend lymphocyte immunization as a treatment.

An electron microscopic photo of a human lymphocyte. Image source: Public domain image by National Cancer Institute via Wikimedia Commons

Human lymphocyte

CRISPR/Cas-9 for genetic sperm editing?

CHR received a good number of calls and messages following a report on NPR’s Health News on August 22, 2019 by Rob Stein that investigators at Weill-Cornell Medicine are attempting to use CRISPR/Cas-9 to alter genes in human sperm. The report was something of a surprise, considering how sensitive an issue genetic germline editing in humans has become. Obviously, one can safely assume that our colleagues at Weill-Cornell have no intention of using so-modified sperm in creating human embryos and that they have received all the necessary ethical approvals for their research.

The purpose of this research makes sense: genetic mutations are not only passed on through the egg but also through a fertilizing spermatozoon. Eliminating for example mutations that increase cancer risks may, therefore, also in semen make sense.

The laboratory that is conducting this research is run by Gianpiero Palermo, MD, Professor of embryology in obstetrics and gynecology at Weill-Cornell and a leading authority in male infertility. He almost single-handedly revolutionized the treatment of male infertility, when in those days working in Brussels, Belgium, he performed the first successful cases of

intracytoplasmic sperm injections (ICSI) in the world.

The success of ICSI has changed the world of male infertility and has allowed millions of men to become genetic fathers who before ICSI would have had no or only minimal chances. We are looking forward to reports of this group’s success in the medical literature. Considering some of the technical difficulties surrounding this research, but even more so the many ethical and legal issues that will have to be resolved as part of this kind of research, it is reasonable to assume that it will take some time before potential clinical applications may be approached.

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Read about sperm gene editing on NPR:https://kaywa.me/l72Pe

OPEN POSITIONBoard-eligible/certified

reproductive endocrinologistCHR seeks a qualified physician with proven

research interest to join the team of clinicians and biologists. Based on qualifications, appointment are available at junior, assistant, associate and senior

scientist levels.

CHR offers competitive salaries and benefits, coupled with strong incentives linked to research efforts and publication success. 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 jtapper@thechr.com.

OPEN POSITIONSBoth require professional and pleasant demeanor, good interpersonal and communication skills and ability to multitask. Please submit resume to Ms.

Jolanta Tapperat jtapper@thechr.com for consideration.

Clinical Coordinator/NurseRN/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 AssistantMust 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.

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Discoveries at CHR

What is the "Rebound Effect" in IVF?Since a paper has been submitted reporting on here described so-called rebound effect, we cannot go too much into detail in describing this phenomenon. However, because we feel that this discovery again offers one of those incremental additions to CHR’s armamentarium in battling the challenges of “older” ovaries, we want to make sure our patients know about it.

What we have come to call the rebound effect was initially an accidental finding. Because it, on rare instances, appeared to help some patients to respond to ovarian stimulation, CHR’s physicians over a few years started integrating it into daily routine practice: When gonadotropin stimulation was interrupted for a few days, some women, who completely failed to respond to even maximal ovarian stimulation with exogenous gonadotropins, suddenly, responded with at least some follicle growth.

Though this recognition was integrated into CHR’s treatment of such unfavorable patients, the impression was that this kind of "rebound" was rare, maybe affecting 15-20% of patients who

did not respond at all to ovarian stimulation. When Assoc. Prof. Andrea Weghofer, MD, PhD, MS, MBA, a senior visiting scientist from the Medical University of Vienna in Vienna, Austria, came to CHR in April of 2018, she decided to investigate this observation in more detail.

Utilizing CHR's electronic research data bank, she made the discovery that successful rebound effects in patients otherwise resistant to ovarian stimulation were, actually, much more frequent than CHR’s impression had been. This observation then led to a study, encompassing an even larger number of patients, which confirmed her initial results and, as noted above, was just submitted for publication.

Though an important observation, the rebound effect is, of course, not a revolutionary finding. It, is, however, yet another small step in what CHR sees its main obligation as a research, as well as a clinical, infertility center: to incrementally enhance pregnancy chances for the worst-prognosis patients who, are not even given a chance with use of their own eggs in most fertility centers and automatically referred into third-party egg donation.

Heard on the Internet

"CHR was our last chance to conceive"I'm from Australia and had extensive dealings with CHR. Trust me when I tell you that Dr. Barad and Dr. Gleicher are the best in the business. I have had around 20 IVF cycles both in Australia and the US combined, so I know what I'm talking about. They know their stuff about IVF and how to get older women pregnant. I'm proof of that!

They were our last chance to conceive biological children with IVF. To anyone out there who have had failures at other clinics and really want to get pregnant, try CHR! Dr. Barad is a lovely, lovely man and I had countless conversations with him by phone and in the flesh. Maria and Dorota I love! They're extremely professional and don't muck around. Keep up the good work!

- B.W. from Australia, on Yelp.com

In late July, Well+Good writer Kara Brown interviewed Dr. Gleicher for an article on menstrual periods. He urged women to see an OB/GYN when they notice irregularities in their periods, as these can be a sign of fertility-impacting issues like perimenopause or PCOS.

Dr. Gleicher was also quoted extensively in an August 5 article on Harper's Bazaar, by Didi Gluck, titled "The Pill for Better Sex." The article explains that there are two FDA-approved medications to help women with low sexual satisfaction--Addyi and Vyleesi--but they are not very effective and cause unpleasant and sometimes life-threatening side effects (nausea for up to two hours after a Vyleesi injection or fainting with Addyi). Dr. Gleicher presented the results of CHR's recent study on DHEA's positive effects on women's sexual wellbeing and contrasted DHEA's ease of use, lack of serious side effects and statistically significant improvements to the drawbacks of the two drugs.

CHR in the media

Chromosomal abnormalities, however, have a tendency to lead to relative early pregnancy losses, mostly before a fetal heart is heard or seen on ultrasound. The later a pregnancy loss occurs, the less likely is it, therefore, chromosomal in nature and other causes must be looked for. Though quite a number of reasons can exist for a spontaneous miscarriage, after chromosomal abnormalities, the most frequent culprit is the maternal immune system.

The reason has been repeatedly discussed in these pages, and is the implanting embryo being genetically in 50% “foreign” to the maternal immune system (a “semi-allograft”). Immunologically speaking, a pregnancy, therefore, is nothing but a 50% “organ transplant” from the male partner. Yet, assuming a normally functioning immune system, this transplant will be allowed entry into the maternal organism and will not be rejected by the maternal immune system, as would happen in case of any organ transplant from male to female partner. The reason why no rejection takes place if the mother’s immune system works normally, is that the immune system reprograms itself from rejection to tolerance by developing (or “inducing”) certain so-called tolerance pathways.

Women with hyper-active immune systems due to, for example autoimmunity, lose the ability to induce these tolerance pathways appropriately. Consequently, the immune system sees implanting embryos still as “foreign,” and starts attacking them. The results are greater difficulties with implantation and early (chemical-) as well as later clinical miscarriages.

After chromosomal and immunologic causes of early pregnancy losses, there are, of course, others as well. For example, chromosomal abnormalities can not only play roles in embryos but also in parents. If one of the parents carries a so-called balanced translocation between two chromosomes, this balanced translocation can become unbalances when half of that parents’

Early miscarriages: Continued from Page 1

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genome merges with that of the other partner. An unbalanced translocation then can become cause for even repeated miscarriages. Miscarriages can also be caused by anatomical abnormalities of the uterus, such as uterine septa or fibroid tumors (myomas) or even small endometrial polyps.

The principal reasons of miscarriages are, however, either chromosomal abnormalities in the pregnancy or immunologic abnormalities in the mother. One, therefore, can almost assume that if it is not one, then it must be the other. For that reason, investigating products of conception after miscarriages is so important: If the products of conception demonstrate a normal female (45,XX) or normal male (46,XY) karyotype, one can practically automatically assume that the mother must have an immune-problem. Things are, however, a little more complicated with the opposite assumption: For decades it has been assumed that, once products of conception are diagnosed as chromosomal abnormal, that must be the reason for the miscarriage. This can, however, be a wrong assumption.

For two reasons, such a conclusion is not always appropriate: A placental biopsy, as noted before, does not always reflect the fetal cell lineage; a placental biopsy demonstrating aneuploid cells, therefore, does not necessarily automatically denote that the fetus, arising from the embryonic cell lineage, is also chromosomal abnormal. In addition, however, data in the immunology literature suggest that maternal autoimmunity, in itself, may increase aneuploidy risks in her offspring. One, therefore, in those circumstances can never be certain what came first, the egg or the chicken; i.e., aneuploidy or autoimmunity, and clinical responses must be made being aware of this uncertainty.

Correct differentiation between chromosomal and immunologic causes of miscarriages is, of course, of great clinical importance: Unless passed down from a parent, true chromosomal abnormalities in a pregnancy are random events and, therefore (unless a patient experiences repeat miscarriages) not predictive of future miscarriage risk. Immunological miscarriages, however, do denote automatic repeat miscarriage risk. Moreover, true chromosomal abnormalities, in a large majority of cases cannot be prevented from miscarrying (since miscarriages are a protective mechanism of nature to prevent abnormal births) and must not be prevented.

Continued on page 10Watch Dr. Gleicher explain immune issues in IVF:http://kaywa.me/xT6yL

Videos on immune infertility CHR's YouTube channel (and the video gallery on our website) has a number of videos explaining the effects of maternal immune system on reproduction, from implantation failures to miscarriages to immunological infertility.

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How to diagnose women at risk for miscarriages

Like in practically all medical diagnoses, nothing is as important as a detailed medical history. Obtaining a very detailed medical history is, therefore, at CHR always a crucially important first step. It is almost incredulous how often we hear from new patients that their autoimmune diseases at other centers were dismissed as irrelevant to their infertility and/or miscarriages. Autoimmunity is, of course, highly relevant to both. The importance of a reliable medical history goes, however, far beyond that: For example, whether miscarriages in repeat aborters happen earlier and earlier or later and later, can give us important hints about underlying causes; With immunological causes, miscarriages often start after a first, often successful pregnancy, and then tend to happen earlier and earlier in pregnancy. With congenital uterine abnormalities, the opposite is the case: Miscarriages happen later and later. The importance of medical history-taking can, therefore, not be overemphasized.

With ca. 15% of all pregnancies ending in miscarriages, it is also important to understand that in many instances, miscarriages are a normal part of a woman’s reproductive life. Just because a woman experiences a miscarriage does not mean the event suggests that she has a medical problem. Once a woman, however, experiences repeat miscarriages, this assessment must change. Medical text books still describe the diagnosis of being a repeat (or “habitual”) aborter as having experienced three consecutive 1st trimester or two consecutive 1st and 2nd trimester miscarriages. We, here at CHR, consider this a too stringent definition, especially in a patient population already in fertility treatments.

Based on criteria we find more logical, CHR, therefore, starts to search for causes of miscarriages much earlier: So, for example, we consider so-called chemical pregnancies in this context as very early miscarriages and, therefore, count them as such. This conclusion was reached after, a number of years ago, colleagues published a study demonstrating similar predictive values for chemical and early 1st trimester pregnancy losses. These results make sense since chemical pregnancies denote implantations of at least one embryo. Though we do not consider them as “clinical” pregnancies and, therefore, do not count them in pregnancy statistics, to consider them within a miscarriage-context makes sense.CHR, in addition, pays special attention to whether an early 1st trimester miscarriage occurred before or after

Early miscarriages: Continued from Page 9

a fetal heart was detected. Once again, this timing does not categorically differentiate between chromosomal and immunological miscarriages, but miscarriages after fetal heart have a much greater likelihood of being immunological in etiology than earlier losses. As noted earlier, the later a pregnancy loss occurs in pregnancy, the more likely is it immune rather than chromosomal.

Summarizing our diagnostic approach toward causes of miscarriages, CHR will initiate a so-called miscarriage work up in every woman with 2 or more pregnancy losses (chemical pregnancies included) but even after only 1 loss if that loss occurred after a fetal heart was confirmed. In women with autoimmunity, evidence of inflammation and/or with evidence of severe and broadly-based allergies (i.e., in women with a hyper-active immune system) an increased miscarriage risk is assumed even without a history of prior miscarriage (we never understood why one should wait for miscarriages to occur before initiating treatments). The table describes CHR’s general miscarriage work-up. It may be amended if a patient’s medical history calls for additional testing.

How to prevent preventable miscarriages

As already stated, one does not have to wait for miscarriages, to try to prevent them from occurring. Having reason to believe that conditions exist that favor miscarriages, preventive steps must, of course, be taken as soon as possible. At CHR this means that treatment is “case-specific.” Once a patient is suspected of having a hyper-active immune system that may interfere with development of appropriate tolerance pathways, she becomes a candidate for treatment. What that may entail, will depend on her laboratory findings. For example, if she demonstrates inflammatory markers,

Continued on page 11

CHR's miscarriage work-up

Î Karyotype (chromosomes) for both partners Î Hysterosonogram/hysterosalpingogram Î Female: Autoimmune panel Î Female: Inflammatory panel Î Female: immunoglobulin panel Î Ovarian reserve assessment Î Class II HLA typing

*This work up is performed on every couple considered at increased risk for miscarriages

11

she may require longer-term anti-inflammatory treatments that may be started weeks to months before IVF cycle start. Acute allergic responses will be treated in more contemporary fashion with antihistamines and boosts of prednisone. The most complex treatment is reserved for patients with evidence of autoimmunity and is individualized not only in medications used but also in dosages of those medications.

The general principle of preventing a potentially preventable miscarriage is to eliminate any causes. If an endometrial polyp is present, it should be removed. If a submucous myoma is present, it may have to be shaved off. If a uterine septum is detected it may have to be excised. If a hyper-active immune system is suspected, it must be suppressed and, thereby, hopefully prevented from attacking an implanting embryo or an already existing pregnancy.

Because here involved areas of study are experimentally difficult to access, they, rightly, have remained controversial. It, therefore, is important to understand that, currently, there is in principle no right or wrong treatment of pregnancy loss. No treatment, indeed, can claim to have established itself as sufficiently effective. CHR investigators fully recognize this fact when making treatment suggestions, as in this case.

In its various treatment approaches, CHR, however, attempts to extract treatment principles form similar biological circumstances which, in the case of pregnancy and pregnancy loss, must be the allogeneic organ transplant since the fetus is basically just a semi-allogeneic organ transplant from male to female partner.

Because the treatment of immunologic pregnancy loss has changed very little over the last 30 or more years, significant progress in the treatment of allogeneic organ rejection must, sooner or later, sharpen our understanding and, ultimately treatment of miscarriages. So far, many of recently successfully introduced anti-rejection drugs in organ transplantation have found only limited utilization in the treatment of immunological pregnancy complications, like miscarriages. The principal reason is that drug companies not only never express desire to investigate their drugs in pregnancy but, because of liability concerns, often actively oppose use of their drugs in pregnancy. Fortunately, however, post-marketing surveys of women who unknowingly conceived while on some of these drugs, increasingly demonstrate their relative safety in pregnancy. One, therefore, can assume that, in addition to such medications as intravenous gamma globulin (IV-Ig), intralipid, and granulocyte-colony stimulating factor (G-CSF), soon other medications, like for example Tacrolimus (an immunosuppressive anti-rejection drug), will find increasing utilization in the prevention of certain miscarriages. CHR has for decades been on the forefront of research in this area of reproductive medicine and will remain a pioneer in utilization of any of these new treatment options.

Early miscarriages: Continued from Page 10

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