November/December Voice by thechr

THE CENTER FOR HUMAN REPRODUCTION

V O I C E NOVEMBER/DECEMBER 2023

IN THIS MONTH’S ISSUE THE CHR LETTER

HOW THE CHR HELPED HIVPOSITIVE MALES IN NEW YORK STATE ACHIEVE PARENTHOOD THROUGH IVF

SO, WE ATTENDED ASRM-2023 IN NEW ORLEANS AND HERE IS WHAT WE FOUND

ASRM ANNOUNCES A NEW DEFINITION OF INFERTILITY?

QUESTIONS FROM PATIENTS AND PUBLIC

CASE REPORT OF THE MONTH- THE FREQUENTLY OVERLOOKED PCOS

THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 2023

WILL A.I. TAKE OVER HANDS-ON MANUAL EMBRYOLOGY?

WE ARE CELEBRATING PREMATURITY AWARENESS MONTH

“BARTERING” YOUR EGGS: IS IT ETHICAL? DOES IT MAKE ECONOMIC SENSE?

MENOPAUSE, A PHYSIOLOGICMEDICAL BUT ALSO SOCIAL PHENOMENON

REAFFIRMING A PHYSICIAN’S DUTY DURING WAR: MEDICAL PRACTICE MUST REMAIN APOLITICAL!

A PIECE OF MY MIND: J’ACCUSE! THE SHAME OF AMERICAN ACADEMIA

RECENT LITERATURE RELEVANT TO REPRODUCTIVE MEDICINE

THE IMPORTANCE OF FOOD FOR REPRODUCTION

The CHR is known as a “fertility center of last resort,” primarily serving patients who have previously failed treatments elsewhere. Among CHR’s areas of special expertise are treatments of “older” ovaries, whether due to advanced female age or premature ovarian aging (POA), immunological problems affecting reproduction, repeated pregnancy loss, endometriosis, polycystic ovary syndrome (PCOS), tubal disease, male factor infertility, etc.

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@CHRNewYork

NOVEMBER/DECEMBER 2023 Dear Reader,

The VOICE

We welcome all of you to the November issue of The VOICE which, going forward will offer several changes in content, format, and presentation. This newsletter over the years has undergone quite remarkable changes: Starting as an informal communique-like pamphlet of just a few pages (a rather simple communication format for practically only the CHR’s patients), it has evolved into a formally registered and copyrighted magazine-like journal, meant to inform a much broader audience of over 80,000, no longer only the CHR’s patients, but also including a rapidly growing number of physician-colleagues and scientific investigators, as well as an equally quickly growing media list. For these quite different audiences, The VOICE is meant to become not only a reliable new source of fertility-related information, but also a source of new ideas that deserve wider coverage than they often receive. Since a large majority of our readers receive The VOICE in electronic format, we now have detailed information regarding opening rates (for the September issue at a smashing record of 40%) and time spent reading the various contributions. Consequently, we now are able to better understand the preferences of our readers when it comes to article subjects and article formats (length, graphic content, etc.). Our goal is to mold in this way the continuing evolution of The VOICE into a forceful independent voice in reproductive medicine. Because of the patients we primarily treat, the CHR prides itself on being unique. Now worldwide recognized as a leading last resort provider of fertility services, the CHR likely treats the most unfavorably selected patient population of any outcome-reporting fertility center, characterized by, a-priori, lowest pregnancy- and live birth-chances. In more practical terms this means that over half of the CHR’s new patient consult with the CHR after being advised elsewhere that their only realistic chance of conceiving was through third-party egg donation. Since in excess of 90% of the center’s new patients previously failed treatments elsewhere, often at multiple well-respected clinics, to offer such patients the same treatment approaches they previously already failed elsewhere, simply does not make sense. The CHR already years ago concluded that, for such patients to have even only a reasonable chance with their own eggs, they had to be offered alternative treatments. With the motto, to “think differently,” as the CHR’s guiding light since its inception, it then became quite successful in developing several important new fertility treatments, among many others including the concept of transvaginal tubal catheterizations to recanalized obstructed fallopian tubes (replacing major surgery), inventing vaginal egg retrieval under ultrasound control (up to that point retrievals were performed by laparoscopy in operating rooms), androgen supplementation in hypo-androgenic women (please note the CONFLICT STATEMENT following this paragraph) and, most recently HIER (Highly Individualized Egg Retrieval), which eliminated the longstanding dogma that egg retrievals in all patients should be performed at similar lead follicle sizes. POTENTIAL CONFLICT STATEMENT The CHR and some of its staff members own shares in a company (Fertility Nutraceuticals, LLC, doing business under the name Ovaterra), which produces a DHEA product to supplement androgen levels in hypo-androgenic infertile women. Since this editorial notes that the CHR pioneered androgen supplementation in hypo-androgenic, infertile women, readers are advised that opinions expressed about androgen supplementation in infertile women may be biased by potential financial conflicts. However, introducing new concepts into medicine is not always a smooth process (see also the article on the 2023 Nobel Prize in Physiology or Medicine). Neither is it to stand in opposition to ineffective and/or at times even harmful tests and/or treatments, many of which, unfortunately especially over the last two decades, entered the infertility field in ever larger numbers. In opposing treatments, established dogmas among healthcare providers are often especially difficult to overcome. Even more difficult to overcome has, however, been the increasing influence of equity investors and/or venture capitalists and of companies supplying the infertility field. Their substantial marketing prowess and increasing influence on professional societies since pharma companies mostly left the field, has been almost impossible to overcome. Opposing unvalidated bad infertility tests and treatments can, therefore, be at least as important as discovering new ones. Since bad treatment often not only fails to improve outcomes but, often, can cause harm, opposing unnecessary testing and/or bad treatments may, at times, be even more valuable than discoveries. The CHR, we believe, by following its motto, “think differently,” has excelled on this front, with the CHR’s longstanding opposition (since 2008) to PGT-A (previously called PGS), likely, representing the most obvious example.’ However, there have been many more. Fighting these battles has remained one of the principal motivations for the CHR’s growing financial investments in The VOICE. Though we welcome advertisements, sponsorships, and other forms of support from companies in the fertility field, this publication will not be influenced in its opinions by such contributions and will continue to counter-punch against even powerful economic interests if they sell snake oil. We welcome our readers’ opinions about the changes we have made in this newsletter. Please let us know what you think about the revised format of The VOICE by writing to melias@thechr.com. We also always welcome new suggestions and ideas. The Editorial Staff of The CHR VOICE

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BRIEFING • David H. Barad, MD, The CHR’s Director of Clinical IVF and Head of Research, tells the story of how a chance encounter with two HIV-positive patients at the CHR led New York State to create a new pathway for HIV-positive males to become fathers. • This pathway is applicable to gay as well as heterosexual couples including an HIV-positive male. In April 2021, I conducted an initial consultation with two gay men eager to start a family with the help of an egg donor and a gestational carrier, taking advantage of the recently newly established gestational surrogacy pathway in New York state. Both were HIV-1 positive for seven years but had been medically managed successfully, resulting in an undetectable viral load for the HIV virus. Scientific evidence now suggests that males with undetectable viral HIV load are no longer infectious,1 giving rise to an international campaign under the heading “U=U,” standing for Undetectable = Untransmissible. Aware of Dr. Ann Kiessling’s Special Program of Assisted Reproduction (SPAR) in Massachusetts, operated by the Bedford Research Foundation Clinical Laboratory, which has enabled hundreds of HIV-positive men to safely build their families through surrogacy, our couple collaborated with SPAR to produce semen that underwent so-called Nucleic Acid Amplification Testing (NAT testing) to determine whether even the most minimal amount of nucleic acid from the HIV virus was still detectable in semen of both partners. After meticulous analyses, the specimens of both men were found to be free of virus. Continued on page 6

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However, at that point, New York State tissue bank regulations still dictated that individuals contributing gametes for creating embryos intended for gestational surrogacy must follow the same procedures and protocols as any other gamete donor, strictly prohibiting the use of gamete donors with a “history of behavior or factors that place them at high risk for human immunodeficiency virus (HIV) infection.” This included “men who have engaged in anal intercourse or oral sex with another man within the past five years and individuals with evidence of HIV infection.” Consequently, these guidelines at that point prevented the use of our couple’s semen to create embryos for gestational surrogacy. In August 2022, I corresponded with Matthew Kohn, PhD, Director of the Tissue Resources Program at the New York State Department of Health Wadsworth Center, explaining our patients’ unique circumstances and bringing to his attention the Bedford Research Foundation’s SPAR program. At that time, no previous cases had been approved for the use of a gestational surrogate by a male couple with a history of HIV in New York State. Dr. Kohn responded a month later, stating that they had engaged in discussions with colleagues but needed more time before providing a definitive response. I followed up with Dr. Kohn and shared a note that I received from Dr. Ann Kiessling, who mentioned that the situation was unprecedented in New York due to the novelty of surrogacy in the state. Although tested sperm had been transferred to New York IVF clinics for heterosexual couples in the past, it had not been done for several years. Thus, there was no precedent for a male couple with an HIV history to undergo this procedure in New York. After several months of further extensive discussions, the New York State Department of Health on March 21, 2023, published the following updated policy: “10 NYCRR Part 52 mandates that all semen donors must test negative for HIV-1 and HIV-2, and it prohibits the use of semen from donors who have tested positive for either virus. Since 2017, the Department has adopted the policy that U = U, meaning ‘Undetectable = Untransmittable.’ According to this policy, individuals living with HIV (PLWH) who have achieved and maintained an undetectable viral load do not sexually transmit HIV. Under Part 52-3.8, the Department may grant an exemption to a tissue bank from specific requirements in Part 52 under limited circumstances. Requests for exceptions to allow assisted reproductive procedures using semen from directed (known) donors who are living with HIV may be considered under the following conditions: • The semen donor is consistently taking antiretroviral therapy as prescribed and maintains an undetectable viral load as confirmed by blood testing concurrent with the collection of the semen specimen(s) to be used. • The recipient, including any gestational carrier, receives comprehensive information and counseling about associated risks from the tissue bank’s medical director or attending physician, with documentation of such. • The recipient is offered pre- and post-exposure prophylaxis for HIV, including 20 days preceding the embryo transfer and 28 days following the embryo transfer procedure. • The tissue bank adheres to the CDC’s Universal Precautions in handling reproductive tissues. • To prevent inadvertent mixing with other donor samples, the tissue bank segregates the semen specimens and any resulting embryos. • If a gestational carrier is employed, the tissue bank must be registered as an Assisted Reproductive Technology Service Provider, and the surrogacy agreement must comply with the requirements outlined in the Child-Parent Security Act along with the Gestational Surrogates’ Bill of Rights.” The CHR thanks Dr. Barad for his persistence in this matter, a feeling, we are certain, is shared by many HIV-positive males in the state. This decision by New York State, importantly, also offers significant additional benefits for even a broader public since it, of course, does not only apply to the LGBTQ+ community, but it also reemphasizes U=U as a very important principle for heterosexual couples with an infected male who are desirous of conception. For further information, please contact us by calling The CHR at 212-994-4400 or writing to us at melias@thechr.com. REFERENCES 1. https://www.tht.org.uk/hiv-and-sexual-health/about-hiv/viral-load-and-being-undetectable#:~:text=What%20does%20it%20mean%20to,viral%20load%20 or%20being%20undetectable.

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BRIEFING • We here are offering a brief summary of the annual ASRM 2023 Scientific Congress & Expo, which this year took place on October 1418 at the New Orleans Convention Center in Louisiana. • No attendance numbers were made public as of this point but lecture halls as well as the exhibition area appeared still relatively empty in comparison to pre-COVID-19 conferences. • The only well-attended event seemed to be the Presidential Ball, a major fund-raising event for ASRM (at $500 per person). • Because of an incredible number of small and mostly new exhibitors, the overall number of exhibitors was quite astonishing. • The science offered was disappointing. More on that below. • Overall impression: The primary emphasis of this event is increasingly trending from being an annual scientific congress to becoming a commercial expo and fundraiser for the ASRM.

Yes, we attended ASRM 2023, however many U.S. colleagues did not, even though New Orleans, in contrast to other recent host cities, is a popular convention destination. Even preceding the COVID-19 pandemic, this annual event, which for decades had been the leading scientific congress in reproductive medicine in the world, had lost its position to a now much larger annual ESHRE Congress, organized by our European colleagues. The U.S. meeting, unfortunately, appears to have continued to fade after COVID-19. The evolutionary contrast between ASRM and ESHRE events could not be more obvious, and not only in overall attendance numbers where we suspect ESHRE by now must exceed ASRM by at least a 2:1 ratio (and likely more), but also in who attends: Aside of increasingly obvious declines in U.S. attendance, foreign colleagues are also increasingly staying away. For many colleagues in South America, Asia, and Europe, attendance at the annual ASRM meeting used to be a fixed commitment on their calendars. Nowadays, their numbers are minimal, yet the whole world (except the U.S.) appears to be attending ESHRE in increasing numbers. It appears to us that U.S. colleagues are returning to in-person attendance at medical conferences at a slower pace than the rest of the world. There are several reasons for these developments but, one among them appears central several years ago characterized by the name change for the annual ASRM conference to “Scientific Congress & Expo.” This name change in our opinion clearly signaled a redirection from a primarily scientific meeting to a more commercially directed “expo.” Unsurprisingly, such a newly evolving emphasis has had consequences: On the good side, ASRM, likely, has increased the revenue the organization earns through this event, allegedly covering over half of the ASRM’s annual budget (though declining attendance raises the question of whether this really has been achieved). On the bad side, the consequence has been a clear deterioration in the quality of presented science.

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The 2023 event in that regard appears to have hit a new low: The prize papers speak for themselves. For example, the SART Prize Paper, based on a SART CORS (Clinical Outcome Reporting System) analysis of 45,712 singleton births from frozen blastocyst transfers, absurdly claimed that trophectoderm biopsies are associated with a lower risk of moderate and severe preterm births and low birth weight.1 However, has nobody considered that patients who produced blastocysts (a prerequisite for a trophectoderm biopsy) may, a priori, be better prognosis patients than those who didn’t, not only when it comes to fertility treatment outcomes, but also when considering pregnancy outcomes? It is truly astonishing that the SART’s judges still don’t understand these and similar patient selection biases, which have plagued the IVF field now for over 20 years. Also, doesn’t SART care that at the same meeting, another research group reported absolutely no effects from trophectoderm biopsies on perinatal outcomes?2 Accepting a bad paper for oral presentation is a preventable problem, but selecting a poorly designed study as a price-paper is a reflection on the organization that made the selection. Even if the choice of societal price papers has to be viewed as controversial, expectations regarding the selection of oral and poster presentations instantly and unsurprisingly decline. One paper accepted for oral presentation reported, for example, the “astonishing” (meant facetiously) finding that AMH hormone levels are associated with a chance of natural conception chances (really??), which were found reduced even in younger women if their AMH was below 1.0 ng/mL.3 Other investigators reported that especially BRACA 1 (rather than BRACA 2) mutations are associated with decreased follicle density in ovaries in comparison to control ovaries. Yet, both BRACA 1 and BRCA 2 patients showed increased oocyte damage.4 CHR’s investigators already reported in 2010 that, even at young ages, BRACA-positive women already demonstrated lower functional ovarian reserve than controls.5 Probably one of the most “remarkable” (again meant facetiously) papers at the meeting was presentation # 01 which addresses one of the “hot” topics of the conference: machine learning models and AI.5 Specifically, the reported study attempted to rank blastocysts using a double-blinded randomized comparative reader study (whatever that means!) and concluded – and we quote – “the machine learning model was non-inferior to manual embryo selection overall. When there was group consensus on the top embryo for selection, the machine learning model agreed in nearly all cases.”6 That this was chosen as the conference’s # 01 oral presentation seems to say it all: Obviously completely misunderstanding that the purpose of machine learning and AI in such a circumstance is not the absence of inferiority (which one could argue was also not really properly documented), but obvious clinical superiority over what standard embryology can provide, one again must wonder about the judgments made as to which science was to be presented prominently at the conference. If these decisions were made poorly, one also cannot escape from the conclusion that poor decisions must also have been made at the other extreme, leading to rejections of potentially valuable contributions. All of this raises the question of whether all of this poor decision-making happened because of poorly chosen judges or because decisions are often influenced by commercial interests and machine learning, as well as AI are currently at the very top of commercial interests in medicine, including reproductive medicine, as the exhibition hall so well demonstrated. Interestingly, this was also one of a small number of papers promoted by ASRM to the general media. Unsurprisingly, they missed the boat and failed to look behind the curtain. One report, for example. had the headline, “AI as good as embryologists at selecting embryos for transfer, trial finds near-equal clinical pregnancy rates.”7 The article itself then describes the technology in exuberant tones when, in reality, at least so far, it has failed. But, fortunately, not everything was bad science: Viotti and co-workers continued to offer interesting data on pregnancy outcomes of what under current PGT-A standards are described as “mosaic” embryos 8 (we previously in these pages and the literature repeatedly pointed out that the current definition used by most PGT-A laboratories to define an embryo as “mosaic,” is biologically incorrect and underreports mosaicism while overreporting aneuploidy). We also found a study of considerable interest that reported on pregnancy outcomes in gestational carrier pregnancies (GC) in comparison to controls.9 Again relying on the SART CORS between 2014-2020 GC cycles increased every year between 2014 and 2019, but decreased (likely due to COVID-19) between 2019 and 2020. Even though a larger proportion of GC cycles used egg donors, they still utilized PGT-A over twice as much as control cycles (63.2% vs. 30.7%), which is another example of illogical utilization of PGT-A. Most interestingly, however, even after adjustments for most imaginable co-variables, GC cycles still demonstrated marginally better live birth rates than controls (RR 1.11, 95% CI 1.10, 1.12), and risks of preterm as well as very preterm were lower in GC cycles (RR 0.76, 95%CI 0.70, 0.83 and RR0.76, 95% CI 0.70, 0.80, respectively). The risk of multiples was also increased in GC cycles. Finally, even though not necessarily the material for a deserving oral presentation, we found presentation O-128 of interest, but our interest was primarily motivated because of the CHR’s association with the commercial production of certain nutraceuticals for use in female and male infertile patients [This is noted here as a potential conflict statement]. The researchers in this study reviewed the top 41 selling fertility nutraceuticals on Amazon.10 Unsurprisingly 31 were female and only 10 were male products. In female products, the most common ingredients were myo-inositol, folate, vitamin C, Vitamin B6, and Vitamin B12. In male products, they were vitamin C, folate, zinc, vitamin B3, and vitamin B6.

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“Myo-inositol, as repeatedly discussed in The VOICE, may represent effective treatment in hyper-androgenic PCOS patients but may, actually, be harmful to female infertile women who have normal or even low androgen levels.”

These are quite surprising findings because, except for myo-inositol, none of the listed ingredients have really been demonstrated to have much effect beyond what a multivitamin may already offer. Myo-inositol, as repeatedly discussed in The VOICE, may represent effective treatment in hyper-androgenic PCOS patients but may, actually, be harmful to female infertile women who have normal or even low androgen levels. There were many additional oral and poster presentations of interest and, even though mostly disappointing, often misleading, and at times irrelevant, we still recommend looking through all the presented abstracts. They are available on the Fertility and Sterility website.11 REFERENCES 1. https://www.asrm.org/news-and-events/asrm-scientific-congress--expo/ scientific-congress-abstract-awards2/affiliated-society-prize-papers/?_t_ tags=siteid%3a01216f06-3dc9-4ac9-96da-555740dd020c%2clanguage%3aen&_t_hit. id=ASRM_Models_Pages_ContentPage/_ee365511-26b7-4b12-b7a7f750b45e4205_en&_t_hit.pos=1 2. Bedient et al., Fertil Steril 2023;120(4):Suppl/ E51 3. Nelson et al., Fertil Steril 2023;120(4):Suppl, E35 4. Matevossiian et al., Fertil Steril 2023(4):Suppl. E10 5. Oktay et al., J Clin Oncol 2019;28(2):240-244 6. Oleskii et al., Fertil Steril 2023;120(4). Suppl. E1 7. Robertson R. Medpage, October 17, 2023. https:///www.medpagetoday.com/meetingcoverage/ asrm/106851 8. Viotti et al., Fertil Steril 2023;120(4). Suppl. E20-E21 9. Shandley et al., Fertil Steril 2023;120(4). Suppl. E93-E94 10. Stansbury et al., Fertil Steril 2023;120(4): Suppl. E54 11. https://www.fertstert.org/issue/S0015-0282(23)X0012-0

TRYING TO REACH THE INFERTILITY COMMUNITY? Have you thought about advertising in the VOICE? This newsletter every month goes electronically to ca. 80,000 infertility patients, medical professionals in the field, and members of the media, with over 25% (an unusually high number) also opening the VOICE. For further information, please contact: Ms. Alexandra Rata (212) 994-4400 or e-mail to arata@thechr.com

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BRIEFING • A new definition of infertility by the ASRM clarifies that infertility is not only a condition/disease affecting heterosexual couples, but it can also affect same-sex couples and individual women and men outside of a relationship. Since we already are talking about ASRM 2023, on October 15, on the second day of the conference, the ASRM publicly announced a new, “more inclusive” definition of infertility.1 Here it is: “Infertility” is a disease, condition, or status characterized by any of the following: • • •

The inability to achieve a successful pregnancy based on a patient’s medical, sexual and reproductive history, age, physical findings, diagnostic testing, or any combination of those factors. The need for medical intervention, including, but not limited to, the use of donor gametes or donor embryos to achieve a successful pregnancy either as an individual or with a partner. In patients having regular, unprotected intercourse and without any known etiology for either partner suggestive of impaired reproductive ability, evaluation should be initiated at 12 months when the female partner is under 35 years of age and at six months when the female partner is 35 years of age or older.

Nothing in this definition shall be used to deny or delay treatment to any individual, regardless of relationship status or sexual orientation. REFERENCE 1. https://www.asrm.org/news-and-events/asrm-news/latest-news/oct-15-2023-asrm-publishes-infertility/

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How good/bad are the various home-testing tools and apps that are flooding the market?

That is a very good question because these tests, tools, and apps are flooding the market. Interestingly, without having formally studied the issue, the impression we are getting is that a large majority are directed at women trying to conceive, want to prevent conception, or attempt to address menopause-related issues. There is not one answer to the question that covers all of these now quite aggressively marketed goods: some are better than others, and some can be pretty bad. However, our recommendations regarding all of them are pretty simple. (i) If what you are trying to achieve with any one of them is important to you, don’t engage without first consulting with your physician. (ii) If you just “want to try out” something, do it but do it only for a relatively short time. (iii) Whenever in doubt, stay away from it until you can get reliable information on the product. Remember that, like supplements, most of these products have not undergone any form of regulatory scrutiny by either the FDA or any other regulatory body. If on rare occasions they have, that automatically puts them into a more credible Continued on page 12

category. However, it is important to understand that “FDAregistered” products are not necessarily “FDA-approved” products, with the former basically having little practical meaning regarding the credibility and/or effectiveness of a product. One final word regarding confidentiality: Medical practice under federal law is mandated to maintain strict confidentiality about practically all aspects of medical care. Such confidentiality is not necessarily guaranteed in commercial transactions. The media, for example, just recently reported on a significant data breach at 23andMe.1 REFERENCE 1. https://www.wired.com/ story/23andme-data-leak-gets-worse-security-roundup/

Does diet affect hormones?

This is yet another very good question and, as obviously pertinent as the question is for the infertility field, surprisingly little has been published on the subject. But already in the 1980s it was well established that food can affect hormone levels in a variety of ways: By direct action on the gut, through nervous reflexes, through changes in certain metabolites in blood, and through changes in circulating hormone levels. The explosion of gastric inhibitory polypeptides on

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oval sperm heads). Yet, even some commercial laboratories report semen analyses without assessments of morphology because the determination of morphology mandates the fixation of the specimen. Morphology has been proposed to be the best indicator among all three parameters in predicting a semen sample’s ability to fertilize. Home tests usually do not provide this information. Therefore, home tests are good as screening tests, but if a home test is off in even minute ways, it seems better to get a formal semen analysis in a fertility center. Most clinics have semen donation rooms. Therefore, a sperm sample can be produced fresh and can be immediately processed, which always will give more accurate results than specimens reaching labs only hours after production.

Should an ERA (endometrial receptivity assay) be performed in a natural or in a mock cycle?

the market especially in recent years,2 has brought substantial attention to the slowing of gastric emptying times and declines in absorption of foods (as well as medications) as a consequence of many of these drugs, widely prescribed for adult-onset diabetes and weight loss. Special concern has recently been expressed about the reduced effectiveness of oral contraceptives from the increasing use of GLP-1 receptor agonists, like Ozempic and Wegovy, and in combination drugs like Mounjaro.3 Then, as we have learned in recent years, there is the “newly discovered organ” in the human body, the gut microbiome, made up of 300-500 different bacteria, containing over 2 million genes, and taking part in many bodily functions involving all organs in the body, even the brain.4 In short, there remains little doubt that what we eat can affect our endocrine system. REFERENCES 1. Marks V. Clin Biochem 1985;18(3):149-153 2. Mark V. Pepides 2020;125:170276 3. Miller M. Verywell Health. April 18, 2023. https://www.verywell health.com/ozempic-mounjaro-wegovy-birth-control-7481043 4. Carabotti et al., Ann Gastroenterol 2015;28(2):203-209

Are home-semen analyses as good as those in fertility clinics?

For a change, this is a simple question to answer, and the answer is an unequivocal NO. Here is why: A most basic semen analysis must inform on: (i) The numbers of spermatozoa, (ii) their motility, and (iii) their so-called morphology (normal

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Here as well, the answer is simple: NEITHER! The CHR does not recommend and/or utilize ERAs because they simply don’t work (as repeatedly previously discussed in The VOICE). If patients insist on having the test performed, we gladly comply, but we consider the evidence against using ERAs by now to be compelling in that ERAs not only do not improve IVF outcomes but, as so often when it comes to new “add-ons” to IVF, may actually harm certain subgroups of patients.1 REFERENCE 1. Ben Rafael Z. Hum Reprod Open 2021;1(2):hoab010

BRIEFING • We here present on a monthly basis the case report of a patient seen at the CHR which offers a teachable moment. • This case involves what is described as a Phenotype D Polycystic Ovary Syndrome (PCOS) patient under Rotterdam Criteria, which is one of the most frequently overlooked diagnoses in fertility practice in the CHR’s experience.

Presentation

A 39-year-old female, gravidity 0 (G0), presented to the CHR after two years of failed infertility treatments at two well-regarded IVF clinics. She reported over three years of unsuccessful attempts at conception. Her menses were regular every 28 days, and her BMI was 22. Her past medical history was negative except for multiple environmental allergies and what she perceived to be gluten sensitivity. Therefore, she had mostly excluded gluten from her diet and did not recall having been investigated for celiac disease. Her FSH was 9.8 mIU/mL with normal estradiol. Her AMH was 5.8 ng/mL. Her family history was negative, except that her younger sister as a child was diagnosed with juvenile rheumatoid arthritis, but has been in full remission since age 18. The patient had stopped oral contraceptives at age 36 and consulted a fertility clinic for the first time at age 37 after not conceiving (with her husband) in over a year of spontaneous attempts. An initial infertility work-up at that clinic was negative and the couple was advised that their infertility was “unexplained.” They then underwent three unsuccessful intrauterine insemination cycles, which were followed by two IVF cycles at the same clinic. These two cycles yielded 18 and 22 oocytes, respectively, but only two and three blastocyst-stage embryos which underwent PGT-A. Both embryos in the first cycle were reported as “aneuploid” and discarded. The second cycle yielded two “aneuploid” and one “euploid” embryo which was later unsuccessfully transferred in a frozen-thawed cycle (FET). The two “aneuploid” embryos had been discarded. Continued on page 14

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The couple at that point switched clinics and at the new provider underwent an updated diagnostic work-up, which again was mostly negative, though the male’s repeat semen analysis demonstrated only 3% morphology. The couple was advised that this could have been the cause of their infertility, and they were further advised to continue IVF treatment. In two cycles at this second clinic, the female produced 24 oocytes and after a reduction in stimulation dosage, 14 oocytes and four and one blastocyst, respectively, with all five blasts tested by PGT-A together and yielding only two “euploid” embryos, three “aneuploid” embryos were again discarded. The two “euploid” embryos were unsuccessfully transferred in a single FET, at which point the couple decided to consult with the CHR.

Reaching a correct diagnosis

As the CHR has noted in these pages and in the medical literature1,2 on many occasions over the years, we consider a diagnosis of “unexplained infertility” to be an oxymoron and always assume that patients with such a diagnosis have undergone an only inadequate diagnostic work-up. In this case, we also noted what was felt to be several potential oversights: (i) This woman of mildly advanced age demonstrated obviously high-for-age AMH and at two IVF clinics had also produced large-for-age egg yields. Upon query, the female confirmed that she had raised at both clinics the possibility of a PCOS diagnosis, but was told that she did not have PCOS because she had regular menses and was “skinny.” (ii) This female appeared to have potential evidence for a hyper-active immune system by being hyper-allergic and, likely, gluten sensitive enough to cut gluten mostly out of her diet. (iii) The female also had a family history of autoimmune disease, with her younger sister as a child suffering from juvenile rheumatoid arthritis. This combination of historical findings at the CHR immediately raised the possibility that this patient’s principal diagnosis had been overlooked at her two earlier fertility clinics because her presentation was fairly typical for a woman with PCOS, phenotype D under Rotterdam criteria, above age 35 (see Box A). BOX A: Under Rotterdam criteria, PCOS is made up of four phenotypes (A, also called the “classical” phenotype, B, C, and D, also called “lean” phenotype). Though established decades ago and in recent years repeatedly by several experts held responsible for the lack of progress in PCOS research, Rotterdam criteria have still not formally been replaced and have remained in use. The CHR’s research on the D phenotype has dramatically changed our understanding not only of this phenotype, but of PCOS in general. 3-5 Widely described in the literature as the rarest among the four phenotypes, the CHR’s research of the D phenotype has drastically changed our understanding of this phenotype, and not only in its prevalence which for good reasons appears understated in the literature, but also in its clinical presentation. Widely considered to be the only non-hyper-androgenic phenotype, we discovered this to be incorrect. Like all other Rotterdam phenotypes, the D phenotype is also initially (between menarche and roughly age 25) hyper-androgenic. The female adrenal androgen production, however, then starts declining. For ca. 10 years, androgens remain in “normal” range, only to exit normal range after approximately age 35 into hypo-androgenic range.3-5 However, ovaries need normal androgen levels in order to produce eggs in good quantity and quality. Too low androgen levels will, as in this patient, lead to large egg numbers at retrieval and, because of poor embryo quality, to very few embryos. Assuming our tentative diagnosis of phenotype D PCOS to be correct, this already 39-year-old patient should already demonstrate abnormally low androgen hormones (and often as a consequence, high SHBG), which is the reason why after age 35, we also call this phenotype hyper-/hypo-androgenic PCOS (HHPCOS). This is exactly what she demonstrated. However, there is an additional diagnostic finding in women with HH-PCOS: approximately 85% demonstrate evidence of a hyper-active immune system manifesting by immunological abnormalities suggestive of autoimmunity, inflammation, or even by just being hyper-allergic. This is what this patient as well demonstrated: She had a positive ANA at 1:160 titer and of mixed homogenous and nucleolar pattern, she demonstrated positive anti-phospholipid antibodies (APAs) in IgM isotype (suggestive of an ongoing immune response), and elevated IL-6, of course an inflammatory marker, all not too surprising, considering she had a sister with juvenile rheumatoid arthritis. Her test for celiac disease was negative, but considering she was on a gluten-free diet, this was not necessarily surprising either, even if that was her diagnosis.

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Treatment CONFLICT STATEMENT The CHR and some of its staff members own shares in a company (Fertility Nutraceuticals, LLC, doing business under the name Ovaterra), which produces a DHEA product. Since the following paragraphs address androgen supplementation with DHEA, readers of this paragraph are advised that opinions expressed in this paragraph may, therefore, be biased by financial interests. We reported that in hypo-androgenic HH-PCOS patients, supplementation with DHEA reversed treatment resistance in IVF,5 and this is exactly what happened: After raising the female’s androgen levels, she conceived in her first IVF cycle at the CHR and delivered a healthy offspring. Because of her hyper-active immune system, we also considered her at increased risk for a miscarriage and also placed her on immunosuppressive treatment with low-dose aspirin, lovenox, and oral prednisone, which was tapered off after positive fetal heart, when her APAs remained stable.

Conclusions

•HH-PCOS is a frequently overlooked diagnosis in infertile women, even though it has a fairly typical presentation. •Due to hypo-androgenism after approximately age 35, it is characterized by treatment resistance in IVF, unless the hypo-andro genism of adrenal origin is remedied at least for 6-8 weeks prior to IVF cycle start. •Because so-affected patients in ca. 85% also demonstrate evidence of a hyper-active immune system, they are at increased miscarriage risk and must receive appropriate preventive immune-suppressive treatments. REFERENCES 1. Gleicher N, Barad D., Hum Reprod 2006;21(8):1951-1955 2. Gleicher et al., Lancet 2018;392(10157):1516-1517 3. Gleicher et al., J Steroid Biochem Mol Biol 2017;167:144-152 4. Gleicher et al., Endocrine 2020;18:59:661-676 5. Gleicher et al., Biomedicines 2022;10:1505

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Scan the QR code to watch the FMRC 2023 introduction video!

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ADVERTISEMENT ADVERTISEMENT

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“For their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19.” *Source: The Noble Prize https://www. nobelprize.org/prizes/medicine/2023/ kariko/facts/

Prize share: 1/2

Why does it matter for reproductive medicine?

• Almost every viral respiratory disease in pregnancy demonstrates a more severe clinical phenotype than in the non-pregnant state. Therefore, prevention through vaccination is even more important for women attempting to conceive or are already pregnant. • Maternal vaccination often also protects the fetus and newborn. • This technology will not only benefit vaccine development against infectious diseases but will, likely, also benefit vaccine development in other medical fields, including autoimmunity and cancer.

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RELATED COMMENT

Women winning the Nobel Prize for Physiology or Medicine is a rare occurrence. As of 2023, the prize has been awarded 226 times, with Katalin Karikó, PhD, this year’s co-awardee, only being the 13th (see Table). The first was awarded to Gerty Theresa Cori, an Austrian/ Czech-American biochemist in 1947 for her role in the discovery of the course of the catalytic conversion of glycogen.

Table. Female Nobel Prize Winners in Physiology or Medicine 2023 Katalin Karikó “For discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19” 2015 Tu Youyou “For her discoveries concerning a novel therapy against Malaria” 2014 May-Britt Moser “For discoveries of cells that constitute a positioning system in the brain”

Interestingly, two from among these 13 (15.4%) women received the Nobel Prize after working at the periphery of major teaching and research institutions. Katalin Karikó, PhD, this year’s winner and Rosalyn Yalow, PhD, a physicist, who won the award in 1977 for co-developing the radioimmunoassay (RIA), which changed medicine and nowhere more so than in endocrinology. As the media in detail reported, this year’s female awardee, Karikó, until recently was “disdained” by her employer, the University of Pennsylvania, as well as by its scientists. She was demoted by her employer by shunting her to a lab on the outskirts of the university campus and cutting her salary. Now, the university “is basking in her glow and in that of her co-winner, Drew Weissman, MD, PhD.”1

2009 Elizabeth H. Blackburn “For discovery of how chromosomes are protected by telomeres and the enzyme telomerase” + 2009 Carol W. Greider “For discovery of how chromosomes are protected by telomeres and the enzyme telomerase”

Male Nobel Prize winners at times also had to overcome skepticism regarding their research. For example, who can forget the skepticism Barry J Marshall, MD and J Robin Warren, MD faced when

1977 Rosalyn Yalow “For development of radioimmunoassays of peptide hormones”

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2008 Françoise Barré-Sinoussi “For discovery of the human immunodeficiency virus” 2004 Linda B. Buck “For discoveries of odorant receptors and the organization of the olfactory system” 1995 Christiane Nüsslein-Volhard “For discoveries concerning the genetic control of early embryonic development” 1988 Gertrude B. Elion “For discoveries of important principles for drug treatment” 1986 Rita Levi-Montalcini “For discoveries of growth factors” 1983 Barbara McClintock “For her discovery of mobile genetic elements”

1947 Gerty Theresa Cori, née Radnitz “For discovery of the course of the catalytic conversion of glycogen” Source: The Noble Prize https://www.nobelprize.org/prizes/medicine/2023/kariko/facts/

suggesting that the bacterium Helicobacter pylori caused gastritis and peptic ulcer disease.2 But, we were unable to find any male winners who were shunned and banned by their institutions, and there were not only 13 recipients, but 213.

The laboratory of Rosalyn Sussman Yalow, PhD, was never at a pristine institution, but was located at the Bronx VA Hospital - not ever exactly a hot spot of research. Though never “disdained” by her institution like Karikó, she apparently was also not especially loved by Mount Sinai. After assuming staffing responsibilities for the VA, hospital, she apparently never was offered a formal position and/ or laboratory at Mount Sinai. However, in 1968, she did receive an academic appointment as a research professor in the Department of Medicine). Only after receiving the Nobel Prize, did she become the Solomon Berson Distinguished Professor at Large at Mount Sinai, named after her long collaborator Salomon A. Berson, MD, who died before the Nobel was awarded which he, otherwise, undoubtedly would have shared. Basic research as well as clinical medicine are changing, with females now representing a majority of students and postdocs. One wonders how long it will take before institutions and the Nobel Prize in Physiology or Medicine will reflect this fact? REFERENCES 1. Zuckerman G. The Wall Street Journal, October 5, 2023.pA2; https://www.wsj. com/health/after-shunning-scientist-university-of-pennsylvania-cele brates-her-nobel-prize-96157321 2. https://www.nobelprize.org/prizes/medicine/2005/prize-announcement/

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BRIEFING • Based on the exploding commercial activity in this arena, it appears that machine learning and A.I. is on the verge of taking over the embryology laboratory. • We here argue that at least in the foreseeable future and in currently proposed clinical applications, this will not be the case. • There are two reasons for this skepticism: (i) In current clinical applications, there may be no outcome benefit between embryos for example. (ii) An existing outcome benefit may be so small that economically, the application of A.I. tools may not be worth it. In the preceding report about ASRM 2023 (page 7), we already pointed out how much reproductive medicine seems to have fallen in love with machine learning and A.I. We also noted that this appears to be happening in practically almost all medical specialty field. As before discussed in prior issues of The VOICE, even best machine learning and most sophisticated A.I. programming can not detect differences between circumstances if such differences do not exist. Embryology demonstrates this fact very well when it comes to embryo selection. Embryo selection in closed incubation systems and under constant visual monitoring has failed to improve outcomes in IVF because, in contrast to expectations, initially constant observation by embryologists, and later attempted replacement by machine learning, have (as again presented at ASRM 2023 in New Orleans),1 to this point been unable to demonstrate outcome advantages in IVF that are worthwhile pursuing. We are unaware of even a single commercial product offered on that basis that has been able to demonstrate outcome improvements in IVF and, considering our understanding of early embryo biology, one must wonder whether differences in characteristics between embryos of a single cycle cohort really warrant all of this effort. The voice | nov/dec 2023 | 25 Continued on page 26

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Besides embryo selection from among a single embryo cohort, A.I. is also utilized in all kinds of semen selection efforts and/or semen analyses, as ASRM 2023 especially in the exhibition hall so well demonstrated. But, once again, one must ask whether all of this effort is economically really warranted? Considering that ICSI is taking care of at least 95% of all male infertility, what is then the real purpose of improving semen analyses and or selecting the “best” spermatozoa based on A.I. rather than just using the experience of embryologist. IVF clinics have spent millions of dollars for closed incubation systems with time lapse observation capabilities, without being able to demonstrate outcome benefits on pregnancy and live birth rates but, also, without demonstrating cost saving on staffing in embryology laboratories. To the contrary, data suggest that the introduction of these semi-automated systems, actually, increased the workload for embryologists. Where is the logic? REFERENCE 1. Oleskii et al., Fertil Steril 2023;120(4). Suppl. E1

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BRIEFING • November is prematurity awareness month, meant to reemphasize that premature deliveries represent the biggest risk in pregnancy by far.

Why does it matter for infertile women? • Women who conceive after fertility treatments are statistically at higher risk for premature deliveries than women who spontaneously conceive. • However, this is not likely due to infertility treatments but to the fact that infertile individuals often have un derlying medical problems that predispose to premature deliveries. When an infant is delivered before 37 weeks, such timing is considered a premature delivery. A normal gestational period is considered to exist between 40-42 weeks, while deliveries beyond 42 weeks are considered postmature. Both premature as well as postmature deliveries are associated with increased maternal as well as fetal risks and are generally for that reason avoided if possible. Despite being the largest cause of perinatal complications and deaths by far, much about premature labor is still not well understood. For example, it is to this day still unclear what initiates labor, whether at term, premature or postmature. Increasing evidence points to the fact that onset of labor is likely induced by inflammatory processes – possibly relating to the termination of immunological tolerance of the Continued on page 16

fetal-placental allograft by the maternal immune system , but what exactly initiates the process is still unclear. Without this understanding it becomes obvious that our understanding of premature and postmature deliveries also must be incomplete. There are well-known association, for example, between premature labor and intra-amniotic infections, vaginal microbiome, and smoking during pregnancy. Certain maternal medical diseases are highly associated with premature deliveries, with especially autoimmune diseases being a good example,1 but premature labor can also occur for traumatic reasons, or for mechanical reasons, when, for example, the maternal cervix is not tightly enough closed, a so-called “incompetent cervix.” Women who have one premature delivery often are at risk for it happening again, as for example, with an “incompetent cervix.” At other times, for example, if labor started because of a physical trauma, or because of an infection, it may not repeat itself. REFERENCE 1. Gleicher N. Clin Rev Allergy Immunol 2010;39(3):194=206

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BRIEFING • To barter one’s eggs in practical terms means to trade away (usually ca. half of) one’s eggs produced in a cycle in return for services the egg donor receives herself from the fertility center. • This commentary argues that this practice raises serious ethical issues and economically makes little sense. Because paying egg donors for their eggs beyond symbolic reimbursements in many European countries is forbidden, to trade, i.e., “barter,” eggs for fertility services is a practice much more prevalent in Europe than the U.S. Well-known ethicist at NYU Grossman School of Medicine in NYC, and longstanding friend and, at times, collaborator of the CHR, Arthur L. Caplan, PhD, recently addressed the ethical issues arising from this practice in a short commentary.1 More recently, this practice appears to grow in popularity also in the U.S. Especially in conjunction with social egg-freezing, young women are increasingly pursuing bartering. More specifically, he described the case of a 32-year-old resident who became interested in freezing her eggs. She was considering a deal offered by an infertility clinic, under which she would donate half of her eggs and in return would receive a commensurate discount on her egg-freezing cycle. So, for example, if she agreed to donate half of her eggs, her egg-freezing cycle would be discounted by half. In discussing ethical concerns with the practice, Caplan noted that guaranteed anonymity, in the past routinely offered to egg donors, considering 23andMe and similar companies allowing the tracing of ancestry and genetic relatives, now no longer can be guaranteed. 23andMe recently also was the target of a deeply worrisome data breach targeting Ashkenazi Jews.2 He also correctly reemphasized in his commentary, the uncertainty of the process of egg-freezing (all repeatedly addressed in The VOICE in recent issues) which never guarantees that a woman who later in life wants to make use of her frozen eggs will have a large enough number of eggs. The chance of pregnancy at that point will depend on the number of available eggs for thawing. The most convincing argument against “bartering” eggs is the fact that it is a poor business deal with all the financial advantages going to the IVF clinic, which buys eggs cheaply and goes on to sell them then with significant profit to one of their infertility patients. Why should that profit not go to the egg donor instead? We suggest to young women who are considering freezing their eggs and to “barter” their eggs in partial payment, don’t do it! Instead, consider becoming a real egg donor. You, for a complete donor cycle in NYC will now receive on average between $8,000 to $12,000, usually more than enough to pay at a program of your choice for a complete egg-freezing cycle and – at least at the CHR – enough in most cases for half of a 4-cycle package of egg-freezing cycles, which with great likelihood, will give you an adequate number of frozen eggs (a single cycle rarely does it!). For further information on such an arrangement at the CHR, please call us at (212) 994-4400 or contact us by e-mail at registration@thechr.com REFERENCE 1. Caplan AL., Medscape, October 16, 2023. https://www.medscape.com/viewarticle/996888 2. Collier K., U.S. News. October 7, 2023. https://www.nbcnews.com/news/us-news/23andme-user-data-targeting-ashkenazi-jews-leaked-online-rc na119324

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BRIEFING • Menopause affects women differently, but affects every woman as she runs out of most of the eggs she was born with. • We here offer some unconventional thoughts regarding menopause not only as a medical phenomenon, but also as a socially important societal one.

October was menopause awareness month, but better awareness of menopause as a serious social, as well as medical issue is warranted all year round. Here are some maybe somewhat non-traditional thoughts about menopause: During and after World War II, women in large numbers started entering the workforce, from the ground up changing the social fabric of U.S. society. Women entering the workforce initially were young. Their participation in the workforce quickly required an adjustment of working conditions for women when it came to pregnancy. From this recognition arose concepts of maternity (and more recently paternity) leaves. But, as the female workforce started aging, suddenly another physiological condition increasingly obviously affected the female workforce – menopause. Paradoxically, for the longest time it did not attract much attention and, especially during transition years, left women mostly suffering in silence. Fortunately, recent years have witnessed an awakening of interest regarding this issue, not unexpectedly largely driven by the entry of so many women into the OB/GYN specialty. The importance of menopause as a social as well as medical phenomenon has not only increased because of women increasingly having entered the workforce. This importance has started to already grow decades earlier simply based on the lengthening of female life expectancy. As the Table demonstrates, until roughly 1900, most women succumbed before reaching menopause. Since the year 2000, with average menopause occurring at age 52, life expectancy, however, offers them on average at least 30 years of postmenopausal life, a life extension without the ability to reproduce, which in length matches a woman’s complete life expectancy and reproductive years as recently as in the year 1800. Continued on page 30

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LIFE EXPECTANCY OVER THE AGES Millions of Years Ago 1800 1900 1980 >2000

15 years 30 years 50 years Males 70 years; Females 77.5 years Females ~ 83 years

This dramatic social change was further compounded by the average age of first birth in the developed world steadily increasing, in many countries now exceeding age 30. As a consequence, an increasing number of women also have their first child above age 40 (see Figure 1). Therefore, their postmenopausal lifespan not only equals total female life expectancy around 1,800, but in addition, so-far cannot compensate for the “lost” reproductive time at younger years that has gone unused because of the new career demands on women from modernity. Figure 1.

Society cannot be surprised by the desire of women to extend their reproductive period into what currently is menopause. Society, science, and medicine, therefore, have an obligation to accommodate those desires. However, the reality of reproductive insufficiency for women is even more extreme than so-far outlined because their fertility starts declining long before menopause. Age 38 is widely considered the turning point from normal infertility to declining fertility. Age 43, a full 9 years before full menopause (i.e.., cessation of menses), is widely also described as the beginning of functional menopause, a time period of on average 7-9 years till full menopause, when the ability to conceive rapidly declines. Indeed, after age 45, even with state-of-the-art fertility treatments (third-party egg donation, of course, excluded), pregnancies will be rare and deliveries even rarer. SOCIETY CANNOT BE SURPRISED BY THE Society, as well as the medical and scientific DESIRE OF WOMEN TO EXTEND THEIR community owe women the possibility to REPRODUCTIVE PERIOD INTO WHAT extend their reproductive lifespan at least into functional menopause, - if not even CURRENTLY IS MENOPAUSE. SOCIETY, beyond that into full menopause. Considering SCIENCE, AND MEDICINE, THEREFORE, that women are born with most, if not all of their eggs, and these eggs not only constantly HAVE AN OBLIGATION TO ACCOMMODATE decline in numbers, but, as we get older, in THOSE DESIRES. parallel to other cells in our bodies, also age, this likely means that we either will have to learn how to rejuvenate older eggs or how to make new eggs from other cells in a woman’s body (or both). There really is no time to be lost!

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• We are here reprinting in full-length and unedited, a recent article by Joel Zivot, MD,1 that was published in MedPage Today (where he is a contributing writer) on October 23, 2022, 16 days after Israel was attacked by Hamas. • The writer apparently is Israeli, but is currently an associate professor of anesthesiology/surgery at Emory University and a senior fellow at the Emory Center for Ethics. • We are publishing this article in its full length because it reflects what, likely, represents the most basic essence of being a physician (or any other health care provider).

he Israel-Hamas war is an ongoing mass casualty event and will require a complex medical effort to save as many lives as possible. Physicians are involved in this conflict, some on the front lines. Bioethicist Edmund Pellegrino stated in the practice of medicine, ethics must be the same for civilian and military physicians "except in the most extreme contingencies." In the current moment of hostilities between Israel and Hamas, some might wonder, is this that extreme moment? The answer to this is no. Since the mid-1800s, physicians have been considered non-combatants, so they may provide clinical care based on need alone. A doctor contributes to the mission by affirming the primacy of the patient. That is the doctor's job.

TEL AVIV, ISRAEL - 2023/10/07: Special terrain ambulance brings injured people to the Ichilov hospital in Tel Aviv from the south following a Hamas incursion into Israeli settlements around the Gaza strip. (Photo by Matan Golan/SOPA Images/LightRocket via Getty Images).

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I completed some of my medical training at Rambam Hospital in Haifa, Israel. Rambam Hospital is on the beach, and house staff would sometimes leave their windsurfing boards there in case time opened for a break. I was there first on a medical student rotation and later for part of my critical care fellowship. During my fellowship training, the department head was Belgian, and the assistant director was German. The house staff consisted of an ethnic mix of health professionals, including Italian, American, Canadian, Israeli, and a couple of Arab doctors from the West Bank. The Arab doctors had gone to medical school in Israel. This was no small feat as acceptance to medical school, particularly for Arab applicants, was very competitive. I recall them to be very smart and capable. Rounds were a back-and-forth cacophony of language. We spoke French, German, Italian, English, Hebrew, and Arabic. After rounds, the chief would invite us all into the inner sanctum of his office. There, he would provide delicious pastries and teach us some magical medical topics as he smoked his Gitanes cigarettes. In my time there, I learned many things about critical care medicine, including an outsized knowledge about chemical warfare and Scud missiles. I loved it, and the international flavor of collaboration as we cared for the sick is among the best memories of my life as a physician. I was in Israel during a relatively peaceful time, and when a mass casualty event occurs outside of a war zone, the bioethical reply informing triage is cleaner. However, the intensity of the recent attack by Hamas, the immense Israeli response, and the barrage of social media disinformation present challenges for physicians who must remain clear-headed and impartial in the provision of care. Physicians may find themselves in uniform at the front line. In modern war,

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triage and the role of the medic and medical care run the risk of becoming mired in the conflict. In circumstances where a physician must triage, there is pressure to sort patients for reasons other than medical considerations (e.g. political reasons or beliefs). Such pressure should be resisted. Medical practice has always been an arm of state power, and the use of power to advance a political agenda that departs from bioethics is the end of medical professionalism. In Vom Kriege (On War), Prussian general Carl von Clausewitz saw war as a continuation of politics by other means. Now, more than ever, we must strive to keep the apolitical nature of medical practice at the forefront of our actions. It’s possible to imagine certain battlefield conditions that might lead a military commander to order the suspension of patient-centered medical ethics. Under the international law of armed conflict, medical personnel are deemed non-combatants and therefore afforded some protection. While physicians may defend themselves and their patients, they are not permitted to engage in offensive military action. The motto of the U.S. Army medical corps is to conserve fighting strength and the Israeli Defense Force directs all soldiers to “preserve human dignity...regardless of race, faith, nationality, gender, or status.” Regardless of combatant status, military medical personnel are part of a fighting force and receive combat training. When sorting the wounded, the enemy combatant may also be a patient. Soldiers in uniform enjoy protection according to the Geneva Convention. Such protection is not afforded to the combatant not in uniform. Notably, Hamas is a non-state actor, including its military wing, the Izz al-Din al-Qassam Brigades, meaning they fight in civilian clothing. This can complicate matters. While it is not the job of the physician to punish by withholding medical care, the current emotional state among Israeli and Palestinian medical personnel

is tense. Providing care to the enemy, or simply to people we do not like, might naturally generate feelings of enmity. However, I have long recognized in myself that the patient I like the most is more often the one I like the least as a person. In that circumstance, the work is pure. Physicians are discouraged from caring for close friends and family because the positive emotional connection impedes the necessary cool-headed thinking sometimes needed to make tough treatment decisions. Certainly, the reverse is true, but I do not need a tragic story to do my best. I do not need to be petitioned to try. In this current conflict, one must also consider the safety of physicians providing care - not only physicians, but the hospitals where care occurs. Article 18 of the Geneva Convention stipulates that under no circumstances can a civilian hospital organized to give care to the wounded or sick be the object of attack. A military target, on the other hand, is any location for attack that through its nature, content, or use, makes it an effective component of the military actions of the other side. In this Israel-Hamas war, and in the wider war, a blurred line now exists between civilian and combatant, between the front line and any other place, and between legitimate military targets and safe places. In war, physicians are presented with divided duties and potentially complex loyalties. The Israel-Hamas war has put neighbors against each other, and the fight is not only ideological, but personal. Pellegrino wondered if certain wars would provide the contingency needed to set aside bioethical practice. I repeat that in the Israel-Hamas war, my answer is no. REFERENCES 1. Zivot J. MedPage Today. October 23, 2023. https://www.medpageto day.com/opinion/unchartedterritory/106947

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BRIEFING • On Saturday, October 7, 2023, over 1,300 Jews were murdered in Israel by Hamas and Islamic Jihad. Enjoying the closing hours of a rave-concert for peace, ca. 260 of 3,000 young attendees were brutally slaughtered, and others were abducted as hostages. Only a few miles outside of Gaza in the Israeli desert the terrorists then advanced their killing spree into several small agricultural settlements, where they murdered babies, some by being decapitated, and others by being burned alive. A fetus of advanced gestational age was found still connected to the mother’s uterus through the umbilical cord and cut out of the mother’s abdomen, either before or after her murder. Neither young nor old were spared (including a female holocaust survivor), neither women nor men, neither parents in front of their children nor children in front of their parents, often with hands bound behind their backs and burned alive. An additional approximately 220 infants, children, and adults were abducted and brought as hostages into the confines of Gaza. • This column addresses the shameful behavior of American academia in the follow-up to these events, defined by absurdly non-committal immediate responses from several presidents of leading academic institutions and outrageous statements by senior faculty as well as student organizations, for much too long going unrebutted by the leadership of academic institutions, obfuscating the enormity of the transgressions performed by Hamas. • This behavior of academia mandates reconsideration of the tax-exempt status of colleges and universities, no longer able (or willing) to point out what, undoubtedly, is “immorally evil.” From this, one also must conclude that we no longer can entrust to these institutions that they can educate our children as to what is moral or not. How then, can we entrust them with teaching our children anything? • These institutions no longer deserve to be subsidized by tax-payors because of their not-for-profit status and their tax-exempt status must be removed. • Still too few members by far of the mega-donor class on their boards have, finally, recognized the absurdity of their donations to these institutions and have announced the discontinuation of their financial support. One can only wonder why their numbers have remained so small. If boards at all of these institutions are to fulfill their oversight obligations, they must start by recruiting new leadership and teaching faculties with a commitment to basic human morality ahead of all other concerns. The voice | nov/dec 2023 | 33 Continued on page 34

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On January 1898, the French literary treasure, Émil Zola, published his famous open letter in L’Aurore under the heading J’Accuse!, accusing the French government, because of the Dreyfus affair, of the injustice of antisemitism. In response, Zola was prosecuted for libel by his own government and, after being found guilty, fled the country to England. The expression of J’Accuse! Has since become a universal battle cry in fighting injustice in general, though especially the injustice of antisemitism. Preceding Germany’s Third Reich by decades, Zola’s J’Accuse! reflects the fact that antisemitism did not start in Nazi Germany, but has been an ancient plague over millennia. During the Third Reich, it only reached new heights in brutality and efficiency. Not even 80 years after the defeat of Nazi Germany, the same injustice is now again screaming out to the heavens with at least equal brutality and disturbing efficiency, this time perpetrated in Israel by Palestinian Hamas and Islamic Jihad barbarians. Those modern-day Nazis, in just a few short hours, took over 1,300 Jewish civilian lives, young and old, women and men, including 260 teens and young adults at a peace-rave, as recent media reports suggest were likely the primary intended target for the Hamas attack on that day. Almost impossible to believe the depravity, among the victims were also 40 babies and small children, many beheaded in front of their parents, who then often were also gruesomely murdered.

SOURCE: This is a frame from a video released by Hamas showing a Hamas member holding two abducted Israeli hostage children (https://nypost.com/2023/10/13/ hamas-seen-holding-kidnapped-israeli-children-babies-in-footage)

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Nazi Germany murdered multiple-generational families during the Holocaust in concentration camps in a futile attempt of bringing thousands of years of Jewish history to its final conclusion in what was then called the “final solution.” In a few short hours during Shabbat on October 7, 2023, current-day Palestinian Hamas and Islamic Jihad Nazis acted with exactly the same intent, in the process killing the largest number of Jews since Nazi concentration camps existed. Like Nazi Germany’s attempt at the “final solution” was documented in writing, the intent of “killing all Jews,” is also proudly documented in the Hamas charter. As disturbing as this may seem, this is not the main subject of this column. That is what transpired in the U.S. (and elsewhere in Western democracies) since October 7, 2023, at academic institutions. To issue a J’Accuse! pronouncement against Hamas, Islamic Jihad, their Iranian masters, and whoever else actively supports their inhumane murderous efforts, would be just a wasted effort. A J’Accuse! directed at academic institutions may at least invigorate an intellectual self-examination at those institutions. Naked antisemitism, indisputably, has again reared its ugly head in this country (and elsewhere) in conjunction with what happened on October 7, 2023, in Israel. Likely unmatched in societal implications, and definitely deserving of a J’Accuse! – pronouncement, is almost the universally inexcusable behavior of the country’s institutions of higher learning, including many – if not most - of this country’s leading colleges and universities, whether Harvard, Stanford, UCLA, Northwestern, The University of Pennsylvania, CUNY, Columbia, Yale, or NYU (to name only a few), which, shamefully, have failed to fully condemn the enormity of inhumanity that, in gruesome pictures, often in their glee on camera shots provided by the perpetrators themselves, was witnessed in kibbutzim close to the Gaza border. Under the false pretext of defending free speech, Harvard, for example, allowed over 30 student groups continuous presence on campus, even though they in a signed letter declared full solidarity with the Palestinian murderers, while assigning full blame for the carnage to Israel which, on a day in historical infamy not different from Pearl Harbor and 9/11, lost over 1,300 innocent lives. In analogy to population sizes, this would represent ca. 35,000 victims in the U.S. Other universities and colleges also failed to criticize and/or take actions against their student organizations or often faculty members, who expressed in public similarly immoral opinions in full solidarity with the Hamas henchmen. In a time when so-called “micro-aggressions” can lead to the expulsion of students from colleges and universities, publicly identifying with and, therefore, supporting the mass-murder of Jews and their children, for many academic administrations apparently does not reflect a problem worth pointing out and condemning. If presidents of some academic institutions did offer statements about what happened on October 7, 2023,

A P I EC E O F M Y M I N D they usually tried to appear “balanced,” thereby morally falsely equating criminal perpetrators and innocent victims. But, as these last few days also well demonstrated, the occasion offered ample evidence for increasing antisemitism elsewhere in society: Some media, for example, were apparently impressed when a prominent New York law firm announced the cancellation of an employment contract for a student leader at NYU after she publicly supported Hamas, after the group’s recent atrocities. However, what nobody reported was that this student should have never received her job offer from this law firm in the first place because she had openly supported the philosophy, and policies of Hamas on repeated prior occasions even before being offered employment by the law firm. Her initial job offer quite obviously was, at least influenced by then, “politically correct” considerations. That a strong J’Accuse! is in place when it comes to many of our institutions of higher learning is not only demonstrated by the failure of so many of them in unequivocally pointing out the evil of what transpired in Israel outside of Gaza. More importantly, these colleges and universities must be held responsible for the lack of moral judgment, so obviously seen in these students. It is, after all, these institutions’ responsibility to teach their students moral clarity. However, what they are very often taught instead by these institutions of allegedly higher learning is exactly the opposite: Their messages not only often lack the required clarity, but often are outright immoral. There is no better proof for this conclusion than the first statement of Harvard’s president when she noted that “even 31 Harvard-based student groups don’t speak for Harvard University.” So, who then taught them, if not Harvard? Who do they represent in their immoral opinions, if not Harvard University? It is high time for academic institutions to take responsibility for the consequences of what they teach. With ideology to ever more serious degrees replacing morality in many of our most prominent institutions of higher education, these institutions are becoming an existential threat to society. Time has once again come, to reassess whether their tax-exempt status still is useful to society. We would argue that the opposite is the case: By subsidizing these schools, we are concomitantly subsidizing with our tax dollars the subversions of traditional U.S. societal values and characteristics. Therefore, congress should simply terminate their tax-exempt status. One must also ask why do the alumni of these institutions still support them with their donations? The disappointing response of so many prominent colleges and universities to the tragedy that unfolded on October 7, 2023, in Israel, is evidence of the moral bankruptcy of our supposedly most advanced places of learning. The response

of large parts of U.S. academia in addition also demonstrates the increasing antisemitism that has been engulfing academia in recent years. Jewish students at CUNY and many other universities are hiding their Magen David necklaces, are afraid to wear their yarmulkes, often try to hide their Jewish identity, and are afraid to speak out on political issues affecting Israel because they fear for their safety. Today in 2023, this is happening at campuses in New York City, Boston, New Haven, Philadelphia, Los Angeles, and many other places. Why does all of this feel like Berlin, Germany, in the 1930s and Vienna, Austria, in 1938, the city I grew up in after WWII, a city where in 1938, Jewish professors represented a considerable part of the University’s medical school faculty? After the Anschluss of Austria to Germany, they initially lost the ability to speak out, shortly thereafter, they lost their jobs and, finally, one day arrived with their families, like cattle, packed into trains in Auschwitz. This brief analogy brings us back to what just happened on October 7, 2023, in Israel, the largest one-day murder of Jews since the Third Reich! Academic intellect, as those historical precedents so well demonstrate, does not protect from immoral beliefs and ideologies. On the contrary, as we here again witness, immoral beliefs are often born in academic institutions, where professors then advance them in class to their students. These professors must be exposed whenever and wherever they raise their ugly heads; and what currently is happening in many academic institutions when it comes to blatant, and increasingly violent, antisemitism, masquerading as anti-Zionism, is shameful and deserving of a loud and unequivocal J’Accuse! toward American academia; Never again!

“WITH IDEOLOGY TO EVER MORE SERIOUS DEGREES REPLACING MORALITY IN MANY OF OUR MOST PROMINENT INSTITUTIONS OF HIGHER EDUCATION, THESE INSTITUTIONS ARE BECOMING AN EXISTENTIAL THREAT TO SOCIETY.” The voice | nov/dec 2023 | 35

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The VOICE in this section of the newsletter offers commentaries on a broad survey of recent articles in the English literature, which the CHR found of interest, even if at times not immediately applicable to daily clinical practice. Articles are mostly chosen for their translational value to clinical medicine, often helping in determining where clinical practice will likely go. Translational research is, since its founding in 1981, one of the CHR’s principal goals and has over the years produced some milestone discoveries and several U.S. patents. It has also propelled the CHR into its current status as a worldwide center of last resort for infertile patients who have failed treatments elsewhere. This section of The VOICE demonstrates and makes public the process through which the CHR has been following for decades and interpreting the published literature, a process always at the very core of how research and clinical practice have evolved at the CHR. Though this section is primarily directed at physicians and basic scientists, THE VOICE is striving in its writing style to also make it accessible and understandable to our other readers.

Is medical and scientific publishing in crisis?

It is difficult not to answer this question in the affirmative, considering the many problems we are witnessing these days in the medical and scientific publishing world. It is difficult to decide where to start in listing all the major problems the publishing industry is facing (see table). It is not surprising that several prominent experts on the subject, in announcing the 10th International Congress on Peer Review and Scientific Publication, chose as the title of their editorial in JAMA, “Peer Review and Scientific Publication at a Crossroads”. 1 One always knows that a subject gets “hot,” when it is suddenly addressed in multiple medical and scientific publications at the same time. This is exactly what has been observable recently: Nature Medicine published a commentary on how publishers can fight misinformation in and about science and medicine.2 Richard Horton, Editorin-Chief of The Lancet, titled his offline commentary on the subject “Scientific journals – irrational, perhaps, but necessary.” 3 Continued on page 38

Table. Major problems of the medical publishing industry • Increasingly poor and inadequate peer review processes. • Overwhelming manuscript submission numbers. • Insufficient numbers of competent reviewers. • Conversion from subscription to open-access models. • Ascendence of quotable pre-publication publications. • Fake journals lacking any reasonable level of peer review. • Paper factories (mostly in China). • Increasing popularity of “special subject issues” with often limited peer review. • Seemingly increasing numbers of fraudulent data submissions. • Rapidly increasing numbers of manuscript withdrawals. • increasing difficulties in fraud detection. • How to handle A.I. utilization. • Increasing commercial/economic conflicts of authors as well as editors. • Increasing influence of industry on what is published. • Misinformation in translation of medical/scientific publications by professional and social media. • etc.

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Several authors within this overall context stressed the importance of communicating real evidence to the public and lamenting that this nowadays so often fails, in the process even leading to the implementation of wrong policies by policymakers. 4,5 Who does not remember the COVID-19 pandemic!? JAMA’s Editor-in-Chief, Kirsten Bibbins-Domingo, PhD, MD, MAS, in her new interview section of the journal brought in Google Health’s Chief Clinical Officer, Michael Powel, MD, MPH, to discuss the incorporation of AI into health care.6 Yes, even Fertility & Sterility chimed in with an article by Afshi Azimirad, MD, headlined, “Peer Review Today – Necessary, Yet Inadequate.”7 Unfortunately, at least in the short term, despite the increasingly obvious insights into what is wrong, we do not see any impending changes for the better. On the contrary, many of the observations listed in the table above appear to get worse. What we are left with is a feeling of increasing – we hope healthy - skepticism when consuming the medical literature and this is exactly what this section of The VOICE is meant to contribute to. REFERENCES 1. Ioannidis et al., JAMA 2023;330(13):1232-1234 2. Bergstrom CT, West J., Nat Med 2023;29:2174-2176 3. Horton R., Lancet 2023;402:1219 4. Gravitt PE., Nat Med 2023;29:2166 5. Keating C., Lancet 2023;402:1225-1227 6. Volkers R., JAMA 2023;330(14):13151317 7. Azimirad A., Fertil Steril. August 23, 2023; DOI:10.1016/829f4248-dcab-4278-8d4f-053a48129378

The business of infertility

Our favorite source for what is going on in the business world of infertility is the founder of Fertility Bridge, Griffin Jones, on October 12, 2023, who again sent out one of his famous and infamous e-mails. In it, he reported on significant executive changes at several fertility clinic networks: The Fertility Network, describing itself as “one of Canada’s leading fertility centres,” brought Derek Larkin on board as its new CEO. This company was founded in 2019 and currently has 36 clinic locations in Canada and the U.S., which represents 14 IVF centers (labs). According to this e-mail, the company has 75 physicians and 1,000 employees overall. Derek Larkin is (at least at the CHR) best known because of his earlier employment at EMD Serono, Inc., in those days the dominant pharma company in the fertility arena in the U.S. More recently, he was with Boston IVF for almost 12 years, between 2012 and 2019 as the company’s CEO. Between 2019 and 2020, he was CEO at LaserMD Med Span, and in May of 2020 joined First Fertility as CEO. During this time, First Fertility acquired NewLIFE in Florida, which was co-owned and managed in the position of COO by Brijinder Minhas, PhD, HCLD, MBA. To demonstrate how small the field of IVF still is, Minhas, before moving to Florida, used to work for a period for the CHR in Chicago, where he seems to have returned to as Vice President of Healthcare at MidCap Advisors, LLC in Kenilworth, IL.

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Upon Larkin’s appointment as CEO of The Fertility Partners, Cara Reyman took over as CEO at First Fertility. Before, she had been CEO at Fertilitas between 2022 and 2023, a much smaller chain of fertility clinics in the Chicagoland area. However, the biggest news in Jones’ newsletter was just a brief footnote at its end which, dated October 4, 2023, noted that KKR is acquiring the Eugin Group for US$ 525 million from the German hospital chain Fresenius. Should this be the case, this would be another major earthquake in the fertility industry, considering that KKR only months ago purchased IVIRMA Worldwide at an enterprise value exceeding US$ 4 billion. Because KKR at that time already owed other IVF clinics in Spain, this purchase was greatly delayed due to monopolistic concerns of the EU about the purchase. A purchase of the second-largest IVF network in Spain after IVI (which Eugin is) by KKR would rightly find itself under considerable scrutiny from the EU. Eugin in the U.S. owns, among other smaller centers, Boston IVF. The national IVF wars are getting more and more interesting!

Interesting aspects of general medicine Two general aspects

This section of the literature review in this month’s issue of The VOICE is unusually brief but addresses two very interesting and widely divergent subjects: In one, physicists describe a powerful interface between physics and biology that claims to describe the evolutionary processes leading to natural selection.1 To understand the importance of this paper, we need to reemphasize that we (and all living beings) are the product of physical interactions between fundamental particles described by physics. But, as an accompanying commentary so well explains, since physics does not have a concept of function, it cannot distinguish the emergent functional features central to biology.2 Consequently, physics currently cannot explain how highly complex structures with specific functions, like for example, the vascular tree (see picture below) evolved. The assembly theory in the paper by Sharma et al. may help in finding the explanation. Related, this is also one of several subjects addressed in Patrick Olson’s very interesting new play/monolog/musical/dance performance, “Emergence,” merging art, science, and music Off-Broadway at the Pershing Square Signature Center on 42nd Street, which we wholeheartedly recommend.3 The second publication we want to bring to your attention is an anonymous editorial in The Lancet that addressed the immigration crisis in the U.S., noting that the year 2022 was the deadliest year on record for migrants, with the USA-Mexico border being described as the most dangerous overland migration route in the world.4 Considering The Lancet’s known political stance on the left, it is unsurprising that the editorial advocates for an open border between Mexico and the USA as the only humanitarian solution. However, what is surprising is the contradiction in the editorial’s position which in the title of the piece correctly notes that “health must come first” and then in the body of the article proposes an unrealistic futuristic position that is simply unachievable. While pointing out

General infertility

Two recent studies in JAMA Network Open reported cohort studies of mixed infertility populations, a study design we never liked because to assume, as an example, that women with tubal infertility, even with the best possible statistical adjustments, can in any sensible statistical way be bunched together with women who are in infertility treatments because of male-factor infertility is, of course, totally absurd.

Are pre-cycle diets affecting IVF outcomes?

3D illustration of a tree of blood vessels on a black background

the danger to health (and life) in what currently is happening, basically further advising the turbo-charged continuation of current policies simply makes no sense! As we also know only too well from medical practice, proposing great-sounding ideas is not only easy, but also at several levels very rewarding. It is especially easy if the responsibility for carrying them out can be passed on to others! We fully agree with the editorial that “health must come first.” What is going on at the southern border (and increasingly also on our border with Canada), and by extension now also in our big cities (including NYC), is simply incompatible with the great-sounding headline that “health comes first!” REFERENCES 1. Sharma et al., Nature 2023;622:321-328 2. Ellis GFR. Nature 2023;622:347-349 3. Culwell-Block L. Playbill. September 6, 2023. https://playbill.com/article/ patrick-olson-to-merge-art-science-and-music-in-new-show-emergenceoff-broadway 4. Editorial. Lancet 2023;402:1107

More on the good and the bad of cannabis

Australian investigators in a double-blind crossover trial of patients with severe Tourett’s syndrome produced solid evidence that treatment with THC (tetrahydrocannabinol) and CBD (cannabidiol) leads to a significant and meaningful reduction in motor and vocal tics.1 At the same time, Canadian investigators reported additional evidence for the potential dangers of increased cannabis utilization after legalization in most states (we previously have pointed out in these pages) by demonstrating that the recent commercialization could be linked to more hospitalizations, including cannabis-induced psychoses. REFERENCES 1. Mosley et al., NEJM Evid 2023;2(9): DOI:10.1056 2. Lowry F. Medscape. October 10, 2023; https://www.medscape.com/ viewarticle/997219

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The first study by U.S. and Spanish investigators, conducted in Boston, MA, at a single fertility center, investigated women undergoing intrauterine inseminations (IUIs) and/or in vitro fertilization (IVF) cycles, and was based on collected data between 2007 and 2019.1 Patients’ eight pretreatment diets were evaluated by questionnaire (of course not the most reliable study design, especially considering that the study went 13 years back) and the study attempted to determine, and we are quoting, “whether adherence to dietary patterns promoted the prevention of cardiovascular disease and other chronic conditions associated with the outcome of infertility treatment.” Based on dietary patterns, live birth chances were the primary outcome and clinical pregnancy vs. miscarriage was the secondary outcome using multivariable generalized linear mixed models to account for repeat cycles. Interestingly, the study included only 612 patients, undergoing 804 IUIs and 768 IVF cycles. Considering a study period of 13 years, this means on average a whopping 47.1 patients per study year. Moreover, considering a 13-year-long study period fertility practice and staff at the center where the study was performed must have significantly changed over the years. Unsurprisingly, considering the small number of patients, the large number of varying diets, and the varying underlying causes for fertility treatments, the study demonstrated no outcome differences in primary outcomes (live births) or the secondary outcome of clinical pregnancy. The adjusted probability for pregnancy loss in the lowest and highest quartiles for use of the so-called American Heart Association (AHA) index were 0.41(95%CI, 0.33050) and 0.28(95% CI, 0.21-036), respectively, for a “whopping” alleged P for trend = 0.02. The corresponding adjusted probability of clinical pregnancy loss was 0.30 (95%CI, 0.22-0.39) and 0.15 (95%CI, 0.10-0.23) (P for trend = 0.007). The authors then added to the results that six out of eight other diets demonstrated “similar patterns,” with the only exception being a plant-based diet, though none achieved significance. Most absurdly, they concluded, and we are quoting again, that “the findings of this cohort study suggest that adherence to a preconception AHA diet may be associated with a lower likelihood of pregnancy loss during infertility treatments.” The only thing more bizarre than this paper is the fact that it went through peer review at a major JAMA journal (one wonders who the editor was) and was funded by National Institute of Health grants and the Ministry of Science and Innovation in Spain. This paper is clearly deserving of the WORST PAPER AWARD OF THE MONTH!

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Is there a best gestational age to deliver after fertility treatments?

print. Now, let’s quickly assess how many labs from around the world over the last 18 months reported on human embryo models from stem cells. We have stopped counting, from Ali Brivanlou, PhD’s lab The second study by Ohio-based researchers investigated which gesat Rockefeller University here in NYC to Magdalene Zernicka-Goetz, tational age at delivery is associated with the best perinatal outcomes PhD, in her two labs at Cal Tech in California and at Cambridge in term singleton pregnancies, unfortunately once again associated University in the UK. Then, there was Nicolas Rivron, PhD from the with different fertility treatments.2 In contrast to the prior study with Vienna BioCenter of the Austrian Academy of Sciences, and Jacob H. insufficient case numbers, this study was based on 178,448 singleHanna, MD, PhD from the Weizmann Institute of Science in Israel, ton-term pregnancies (generally defined as 37 to 42 weeks). Their with Goetz and Hanna having successfully breached over from findings were clear and appear indisputable. They also make sense: mouse to human models within one year. Women delivered at 39 weeks demonstrated the lowest neonatal morbidity and infant death in comparison to deliveries in later Why this background? Because, what we currently are witnessing weeks of pregnancy. in this arena in print, had, already roughly two to three years ago, to be pretty obvious to this small group of visionaries who over the last Though it would be of interest to know whether there are differences 18 months are with increasing certainty demonstrating that we are in ideal delivery time depending on underlying infertility etiologies getting closer and closer, not only to producing stem cell models of (and we suspect there are), this study reemphasizes the long-known human embryos for research purposes, but of embryos for potential fact that women with infertility have more underlying medical reproductive use. problems than fertile populations. Those medical problems are often associated with premature placental aging and insufficiency which As Katsuhiko Hayashi, PhD, now in Osaka, Japan, who already may mandate earlier delivery. Infertility patients should always be several years ago produced fertilizable eggs in a mouse model, which suspected of being high-risk obstetrical patients and be managed produced embryos as well as offspring in multiple generations, in a accordingly. recent interview in The Wall Street Journal noted, science should in analogy to what he succeeded doing in mice, within a decade be able REFERENCES to produce human eggs from peripheral skin cells.1 1. Salas-Huetos et al., JAMA Network Open 2023;6(8):e2329982 WORST PAPER AWARD OF THE MONTH 2. Hamilton et al., JAMA 2023;6(8):2328335

Basic research in reproductive biology It seems all about human embryo models these days

Returning to human embryo models from stem cells, a single issue of Nature magazine recently published reports on such models from three different labs: Hanna et al., reported on a complete human day 14 post-implantation embryo model from naïve ES cells.2 This was followed by an article from a relatively new lab in this area of research at Yale University3 which reported on self-patterning of human stem cells into post-implantation lineages.3 Finally, Zernicka-Goetz and colleagues closed the trifecta with another study on a pluripotent stem cell-derived model of post-implantation human embryos.4 All three of these studies are informing on the preimplantation period and not only allow for the study of the development of human model embryos throughout day 14, but it will also allow for important insights into the implantation process, itself, which to a large degree has remained a black box.2

A 3D image of the Hanna lab's human embryo model on Day 14, including the placenta. The image was provided by the Hanna lab and resized by Fierce. (Jacob Hanna, PhD, Weizmann Institute for Science). Hanna will be a speaker at the annual FRMC on December 1-3 in NYC, co-sponsored by the CHR. https://www.fiercebiotech.com/research/ new-human-embryo-models-offer-window-earliest-stages-development

As we previously discussed in The VOICE, Nicolas Rivron and colleagues recently proposed ethical rules for work with these human embryo models because, as they become closer and closer to natural human embryos, restrictions currently in place for natural human embryos may also have to be considered for these model embryos. This is also reemphasized in two separate commentaries by Jannet Rossant, Jianping Fu,5 and Naomi Moris6 in the same issue of Nature magazine.

In eLife, Noor M. Kotab and Prashanth Rangan from the Icahn School of Medicine at Mount Sinai, here in NYC in another comJust think about how much time it takes between developing the idea mentary,7 related to a research article by Peng et al in that journal,8 for a project in human biology, its execution, submission to a leading comment on experiments in fruit flies which revealed more about science journal, going through revisions, etc. A year? 18 months? the molecular mechanisms involved in germline stem cell transition Over 18 months, from first submission to Nature magazine until to become egg cells. They describe the process as “delicate” because publication, a friend and colleague of the CHR working in oncology genes specific to the stem cells must be silenced, and egg-specific only recently disclosed after his milestone paper finally appeared in genes must be activated.

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In summary, we live at the edge of a major revolution in our understanding of early embryology and are advancing at a rapid pace toward the ability of producing autologous human eggs (and therefore, embryos) from peripheral somatic cells. The world will look different when this happens. REFERENCES 1. Dockser-Marcus A. The Wall Street Journal, October 27, 2023, https://www.wsj.com/health/ what-if-anyone-could-make-a-human-egg-22002407 2. Oldak et al., Nature 2023;622(7983):562-573 3. Pedroza et al., Nature et al., 2023;622:574-583 4. Weatherbee et al., Nature 2023;622(7983):584-593. 5. Rossant J, Fu J. nature 2023;622(7983):454-456 6. Moris N. Nature 2023; 622(7983):469-470 7. Kotb NM, Rngan P. eLife 2023;12:e91998 8. Peng et al., eLife 2023;12:RP90509

Understanding what leads to the depletion of primordial follicles in obesity?

Chinese investigators in a mouse model in Fertility and Sterility reported the alleged transcriptome of the molecular regulatory network leading to the premature depletion of primordial follicles,1suggesting that ferroptosis is a key pathway activated within immature ovarian follicles in transition from primordial to primary follicle stages. These data furthermore suggest that this pathway may also be involved in the physiological transition between these two follicle stages. REFERENCE 1. Zhou et al., Fertil Steril 2023;120(4):899-910

How the embryo receives its energy support during periconception

Only available as a reviewed preprint in eLife so far, sponsored in part by the Igenomix and Carlos Simon Foundations, Spanish investigators recently published an interesting study, suggesting that vertical transmission of maternal DNA through extracellular vesicles modulates embryo bioenergetics during the periconception period.1 The paper reports that the human endometrium secretes all three known subtypes of extracellular vesicles, apoptotic bodies, microvesicles, and exosomes into endometrial fluids. Interestingly, mitochondrial (mi) DNA secretion is more active than the secretion of apoptotic bodies or exosomes. During the (alleged) window of implantation, microvesicles apparently demonstrated 11-fold higher levels of miDNA in comparison to “cells-of-origin” in a “receptive” endometrium (whatever that means), which possessed a lower miDNA content and demonstrated an upregulated expression of macrophage-related genes. In a murine model, the study demonstrated the internalization of nuclear-encoded DNA/mtDNA by trophoblast cells- associated with a reduction in mi-respiration and ATP production. In accordance with eLife’s publication model, the journal also published the peer review and an “eLife assessment” that stated the following: “The manuscript offers important findings on the potential influence of maternally derived extracellular vesicles on embryo metabolism. However, while the content is convincing, Continued on page 42

the title appears to overstate the study’s conclusions due to its speculative nature on the DNA transmission and embryo bioenergetics connection. A more measured title would better represent the evidence presented.” We fully agree but, in addition, have further concerns relating to wellknown commercial conflicts of involved individuals (and foundations): This study was based on the definition of an implantation window via a commercial test which in several recent studies has failed to fulfill its advertised purpose of improving IVF cycle outcomes by accurately defining a woman’s implantation window. Since the implantation window represents a central reference point in this study, one must consider the here-presented data with caution and can only hope that these data are not just meant as the basis for yet another commercial “implantation test.” However, the data are interesting enough to warrant follow-up studies. REFERENCE 1. Bolumar et al., Reviewed preprint; eLife. 2023. https://doi.org/10.7554/ eLife.88008.2

Y chromosome proteins in female tissues: another example of unreliable test results

The determination of the correct sex is a central issue in health and disease. A recent opinion paper in Science magazine pointed out how insufficient the currently available diagnostic tools are for the assessment of sex chromosome-encoded proteins.1 As a consequence, the two authors note that “an alarming number of protein-based resources are simply wrong, inaccurate, or at least misleading by, for example, reporting Y-chromosome-encoded protein expression in cells and tissues that completely lack a Y chromosome.” Molecular mechanisms of sexual dimorphism in human health and disease have increasingly come into better focus, creating an urgent need for reliable testing methodologies. As the two authors point out, unfortunately, many protein-based tests are really unable to accurately distinguish between X and Y chromosome-encoded gametologs. Better diagnostic products are needed if our ability to identify molecular mechanisms of sexual dimorphism in human health and disease is to further improve. REFERENCE 1. Gelfand BD, Ambati J. Science 2023;382(6666):39-40

Clinical infertility What’s new in IVF?

Regarding adenomyosis Spanish and Belgian colleagues in a retrospective cohort study attempted to address the long-standing and controversial question of whether uterine adenomyosis affects IVF outcomes. They investigated 140 patients with adenomyosis based on MUSA (Morphological Uterus Sonographic Assessment) criteria undergoing a first frozen-thawed blastocyst-stage embryo transfer. The choice of studying frozen-thawed cycles must be applauded because it removed, at least to large degrees, many possible covariables that one would have to confront in fresh IVF cycles. One, must at the same time acknowledge that many issues relating to retrospective studies in general, remain.

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The figure demonstrates a vaginal ultrasound examination: The uterus demonstrates ADENOMYOSIS. The arrowheads point toward solid adenomyosis, while the black arrow points toward a cystic adenomyosis lesion.

This concern is further aggravated by some of the study’s results themselves: Women with adenomyosis in comparison to controls deferred their frozen transfers more frequently (P =0.002), and were more likely treated with GnRH agonists before transfer (P<0.001), both interventions with the potential to affect IVF cycle outcomes. Somewhat surprisingly, adenomyosis affected clinical pregnancy rates only marginally (P=0.040), while affecting live birth rates more significantly (P=0.003), likely because of a marginally increased miscarriage rate (P=0.045). Multivariant logistic regression adjusting for age, PGT-A, deferred FET, GnRH agonist treatment, and embryo number transferred, demonstrated that the use of GnRH did not affect any of the outcomes. The authors, in our opinion, incorrectly concluded that adenomyosis created a significant negative outcome in patients undergoing frozen-thawed cycles and that GnRH pretreatment before transfer did not reverse this effect. What the study in our opinion demonstrates is that the adverse effects of adenomyosis were, at best marginal, and mostly based on an increased miscarriage risk. In our opinion, this raises the question of why that may be. Since adenomyosis is basically the phenotypical presentation of endometriosis in the uterus, we suspect that this study may offer further evidence for the decades-known association between endometriosis and, likely, immunological pregnancy loss. CHR’s investigators in collaboration with other colleagues years ago demonstrated that GnRH agonists did not affect this association, while good old-fashioned danazol did.2 Maybe adenomyosis patients may benefit in their miscarriage rate from pretreatment with danazol for three months? In contrast to the authors’ conclusions, the really important message of this paper is that at worst, adenomyosis likely has only marginal negative effects on IVF outcomes. Once more, this is a good example of authors overinterpreting their results and editors letting them get away with it! Home-based cycle monitoring? Since we are already talking about studies in frozen-thawed cycles, colleagues from The Netherlands reported in The Lancet a so-called randomized non-inferiority trial of home-based versus traditional office-based cycle monitoring, 3 also accompanied by a commentary.4 Investigators at the CHR so strongly disagreed with the conclusions of this paper, that they decided to submit a critical letter of commentary to The Lancet 5 which, as this commentary is written, is still in limbo at the journal, as to whether it will be accepted for publication or not.

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However, such a submission prohibits any preceding publication and we, beyond just our general opinion that the authors’ conclusions are incorrect, can, as of this moment, not offer further detail regarding the CHR’s criticism of this study. Anomalies in offspring after IVF? We have on several prior occasions noted in The VOICE that the success of modern infertility treatments often overrides evolutionary blockage of reproduction meant to prevent transmission of genetic risks into future generations of offspring. Examples we offered were diabetes and urogenital abnormalities in males, which respectively, in diabetic women prevented fertility and caused miscarriages before insulin, and in men by sterility prevented them from becoming genetic fathers before ICSI (intracytoplasmic sperm injection). As a consequence, diabetic mothers now pass on their genetic predispositions to their offspring, and fathers with urogenital problems produce male offspring with an increased prevalence of such problems. There are many additional examples, and it should not surprise that IVF pregnancies lead to more problems in offspring in such cases. Australian investigators just confirmed this fact once more by reporting that among 851,984 children delivered between 2009 and 2017, the congenital abnormality rate was 459 per 10,000 in singleton and 757 per 10,000 in multiple births pregnancies.6 Based on prior studies, as expected through IVF conceived pregnancies had an elevated risk for major urogenital abnormalities (adjusted risk difference 19.0 cases per 10,000). Interestingly, the risk remained unchanged when compared with control infants (after accounting for parental infertility), suggesting an independent IVF-related risk of 47.8 cases per 10,000 singleton births. Further strengthening the association with IVF itself, there was no increase in congenital anomalies after insemination cycles. The authors suggested that the increased risk noted with IVF may be due to the ICSI procedure and concluded that ICSI should be avoided in the absence of a male infertility factor. What about the vaginal microbiome? There have been several studies in the recent literature suggesting that vaginal and/ or uterine microbiomes may have relevance for IVF outcomes. Others, on the other hand, were unable to find associations. Now come investigators from Bangkok, Thailand, who in Scientific Reports, published a study that tested the effects of vaginal probiotic supplementation with vaginal (Gynoflor, Medinova AG, Zurich, Switzerland) lyophilized Lactobacillus acidophilus (LB) KS400 bacteria [100 million colony-forming units per tablet] on frozen-thawed cycle outcomes in a prospectively randomized study of 340 infertile women.7 The results were quite surprising: Supplementation did not demonstrate significant effects on FET outcomes regarding chemical and clinical pregnancy rates (39.9% vs 41.8% and 34.2% vs. 31.7%). When only blastocyst-stage embryos were compared, the study group did significantly better in live birth rate (35.71% vs. 22.22%, P=0.03). Interestingly, the miscarriage rate in the whole study group (whether cleavage-stage or blastocyst-stage transfer) significantly decreased (9.5% vs 19.1%, P=0.02). As previously noted, conducting studies in FETs rather than fresh cycles eliminates many co-variables and is a positive factor in assessing IVF outcome studies. Unfortunately, the study population,

otherwise, was again very inhomogeneous, best demonstrated by the reported outcome differences between cleavage and blastocyst transfers. Moreover, outcome differences were at times quite substantial without reaching statistical significance, suggesting inadequate population sizes. For example, in women with bacterial vaginosis (where supplementation with LB would potentially be expected to help by its effect on vaginosis, the live birth rate in the study group was 42.3% and in controls only 26.1%; yet this difference was not significant (P=0.23). Yet, among women undergoing blastocyst-stage embryo transfer, a comparison of live birth rates of 35.7% in the study group and 22.2% in controls was significant (P=0.03) and linked to lower miscarriage rate (8.2% vs.24.3%, P=0.002). On first impression, one could suspect that supplementation with LA may help in activation tolerance pathways in the mother’s immune system, thus reducing miscarriage risks. But on second thought, it appears much more likely that the observed difference is based on patient selection, with patients who have blastocysts being better prognosis patients than women who have only cleavage stage embryos for transfer. In other words, yet another paper in Scientific Reports with seemingly very poor peer review and editorial supervision. The continuous pursuit of the hypothesis of embryo selection With a degree of skepticism, this newsletter has in the past repeatedly addressed the hypothesis of embryo selection, which has been a cornerstone of IVF practice for over 40 years. Among several arguments supportive of our skepticism, a very important one has been that even if there is a/are a few best embryo(s), the observed difference may not be of enough clinical significance to warrant the effort, time, and additional costs of embryo selection beyond routine morphological observation during routine embryology? A recent study by British investigators now offered further evidence in support of the argument that detectable differences, likely, do not warrant all the efforts. The study investigated whether a so-called aneuploidy risk score developed from a morpho-kinetic ploidy prediction model (called PREFER) was statistically associated with miscarriage risk and live birth rates in IVF.8 The PREFER model was developed based on 8,147 blastocyst specimens in an attempt to predict ploidy status based on morpho-kinetic and clinical biodata (in discussing our skepticism about embryo selection, we previously have pointed out that in our opinion, only studies combining morpho-kinetic and clinical patient data might be able to produce clinically worthwhile embryo selection models). The study also investigated a second model (P-PREFER-MK) which, in contrast, used only morpho-kinetic predictors. Both models then categorized embryos into three risk categories for aneuploidy: low, medium, and high risk, with primary study outcomes being miscarriage and live birth and secondary outcomes being chemical pregnancy per single embryo transfer (the latter is a very important point, we will return to). Miscarriage rates with PREFER were 12%, 14%, and 22%, respectively, basically attributable to the age of the female. At the same ages, there was no difference between risk categories and P-PREFER-MK also demonstrated no difference. However, the study did suggest a positive association with live birth rates, which were 50%, 49%, and 38%. Comparing only low- to high-risk Continued on page 44

patients, the authors claimed (in our opinion incorrectly) a statistically significant association (OR, 1.95; 95%CI, 1.65-2.25). The reason why the claimed association in our opinion likely does not really exist is the traditional statistical mistake innumerable papers in the fertility field unfortunately make in reporting IVF cycle outcomes by only including patients who reach embryo transfer. This is a highly selected patient population, that does not reflect the population that started the study and results are therefore, not applicable to a general patient population. Moreover, even assuming that the claims of efficacy made by the authors were correct, can an outcome difference between 38% and 50% be reason enough for blastocyst-stage transfer and PGT-A for everybody? We don’t think so! This paper was accompanied by a commentary from two Spanish colleagues, well known as supporters of the hypothesis of embryo selection, whether through morpho-kinetics of embryos or PGT-A.9 Unsurprisingly, they believe, and we quote, “the integration of morpho-kinetics and AI (artificial intelligence) has revolutionized embryo selection in IVF treatments, leading to more accurate and objective assessments.” We seriously wonder what this conclusion is based on. More on rescue in vitro maturation of embryos The CHR has been practicing rescue in vitro maturation since ca. 2014.10 We recently reported in The VOICE on a paper by the Fatemi group in Abu Dhabi which confirmed our long-standing opinion that rescue in vitro fertilization adds pregnancy chance to IVF cycles.11 Now a group of Canadian colleagues came to the same conclusion in a paper in Fertility and Sterility.12 The time, thus, appears to have come for all IVF clinics to integrate in vitro rescue maturation into routine IVF practice. REFERENCES 1. Sachs-Guedj et al., J Clin Med 2023;12(18):6058 2. El-Roeiy et al., Fertil Steril 1988;50(6):864-861 3. Zaat et al., Lancet 2023;402:1347-1355 4. Mackens S, Blockeel C. Lancet 2023;402:1304-1306 5. Gleicher et al., The Lancet 2023; submitted for publication. 6. Venetis et al., Ann Int Med 2023;176(10): 1308-1320 7. Thanaboonyawat et al., Sci Rep 2023;13:11892 8. Bamford et al., Fertil Steril 2023;120(4):834-843 9. Gimenez-Rodrigues C, Meseguer M. Fertil Steril 2023;120(4):811-812 10. Lee et al., Endocrine. 2016;52(1):166-171 11. Elkhabid et al., Hum Reprod 2023;38(8):1473-1483 12. Kuperman et al., Fertil Steril 2023;120:860-869

The future of Reproductive Endocrinology

A large group of prominent professional “expert-politicians” appear

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to have finally recognized that the field of reproductive endocrinology and infertility (REI) “is at a crossroads,” besides other reasons caused “by a mismatch between demand for reproductive endocrinology, infertility, and assisted reproductive technology (ART) services, and availability of care” (i.e., trained physicians and embryologists).1 One can only ask, where have they been for the last 20 years? Where has ACOG been? Where has ASRM been? And where are all of those colleagues who for decades have argued “against training our competition” and now, often struggle to find colleagues willing, and financially able, to take over their clinics upon their retirement? Now, suddenly, everybody seems surprised that there is not enough trained manpower in the field available which has significantly grown over the decades and, in addition, in very recent years has witnessed the retirement of almost all first-generation IVF specialists in this country. Not less than 25 of these experts, many among them for years part of the political “click” that has been running the sub-specialty, now in a “free article” in Fertility & Sterility were telling us what should be done to improve upon the current crisis. Here are almost verbatim their proposals, as summarized in the abstract of their communications: Our field should aggressively explore and implement courses of action to increase the number of qualified, highly trained REI physicians trained annually. We recommend that efforts to increase the number of REI fellowships and the size-complement of existing fellowships be prioritized wherever possible. These courses of action should include: (a) Increases in the number of REI fellowship training programs, (b) Increases in number of fellows trained at current REI fellowship programs, (c) Pros and cons of a two-year focused clinical fellowship track for fellows interested primarily in ART practice were extensively explored. We do not recommend shortening the REI fellowship to two years at this time, because efforts should be focused on increasing the number of fellowship training slots (a and b). It is furthermore recommended that the field aggressively implements courses of action to increase the number of and appropriate usage of non-REI providers to increase clinical efficiency under appropriate board-certified REI physician supervision. Automating processes through technological improvements can free providers at all levels to practice at the top of their license. It is unclear who gathered these 25 authors to issue such an opinion paper, nor does the manuscript disclose how they reached their 3-point opinion, which, frankly, resembles more of an “alibi” than a real “proposal” to solve a by now, indeed, very serious problem. The field not only maintained ridiculous restrictions on the number of fellowship programs and fellowship positions, but at some point, even undertook the absurd step of extending the fellowship from an already too-long two years, to a much too-long three years.

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As is unfortunately only too common in our specialty, leadership made this decision based on an unvalidated hypothesis, namely that a third research year would train more “academic” and “research-oriented” fellows. Unvalidated hypotheses not only in clinical practice often don’t pan out! The third year not only failed to produce more and better investigators; the effect, likely, was the opposite: After four years of OBG/GYN residency and three, rather than two years of poor salaries as fellows, graduating fellows couldn’t wait to get into private practice and start earning real money. Who could blame them, considering the enormous student loans many had to start paying back for seven years of postgraduate education, four years of medical school, and 3-4 years of undergraduate education?

Isn’t it absolute insanity that it now takes 14-15 years to become a fertility specialist? If anybody only tried, this pathway could, likely, be easily achieved in 2-3 years of premed in college, three years of medical school (already being tested in some schools), three years of general OB/GYN residency, and one year of REI fellowship for those who want to be clinicians or, akin to postdocs, by 1-2 years of fellowship for those striving for an academic research-driven career. Time it takes to become an REI YEARS Undergrad/Premed Medical school Ob/Gyn residency REI fellowship

Currently 3-4 4 4 3

Possible 2-3 3 3 1-2

TOTAL

14-15

9-11

Likely because there is none, the purpose of the 10-page-long paper here discussed remains unclear in contrast to a barely one-page-long commentary on the subject by Brolinson and Widra from the NIH who conclude their piece with the following brief paragraph: “Let us not fear change but embrace the needs of our patients and colleagues. We stand to thrive from ‘going back to the future’ with 2-year fellowships.” They at least offer something even if considering the mess the field, finds itself in these days, even their comments appear to be too little and too late.

REFERENCES 1. Hariton et al., Fertil Steril 2023;120(4):755765 2. Brolinson M, Widra EA., Fertil Steril 2023;120(4):745

manuscript, mostly because of two other recent tests with apparently better predictive values, but also because the validation study was apparently not large enough to be fully credible.

We welcome a new medical journal in the field

On a more positive note, a recent meta-analysis suggested that women who experienced preeclampsia may have a reduced risk for breast cancer. Considering the popularity of meta-analyses in China, this paper is of course, of Chinese provenance.3 Fifteen studies included were all cohort studies, reflecting a cumulative patient sample of 7,838,693 women. Women with preeclampsia demonstrated a reduced breast cancer risk of ca. 11% (P < 0.001). Sensitivity analysis did not change results. Somewhat surprisingly, the authors described this difference as “minimal” and maybe not even worth it, considering other limitations of the study. One then must ask, why did they submit and publish it?

IVF-Worldwide.com presents itself as the largest and most comprehensive IVF unit directory as well as an IVF-focused website for doctors, embryologists, nurses, and social workers in the world.1 And, yes, the company now also started the publication of a new journal in REI, the Journal of IVF Worldwide (JIVFww).2 One of the first articles to appear in the journal was a commentary by the CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, 3 in which he explained the importance of a paper published in August by CHR investigators in iScience.4 It takes on average at least 2-3 years to get a new journal going, but considering the worldwide reach of the company that publishes this journal, one can hope for a potentially important contribution to the REI field from this new journal. We already noticed two interesting papers.5,6 REFERENCES 1. https://ivf-worldwide.com/about-us.html 2. https://jivfww.scholasticahq.com/ 3. https://jivfww.scholasticahq.com/article/85177-a-recently-pub lished-study-further-advances-the-drive-toward-precision-medicine-in-ivf 4. Nicholas et al., iScience 2023;26:107308 or https://jivfww.scholas ticahq.com/article/85177-a-recently-published-study-further-advanc es-the-drive-toward-precision-medicine-in-ivf 5. Fischer R. https://jivfww.scholasticahq.com/ article/88456-the-fischer-concept-protocol-its-impact-on-embryo-quality 6. Dozortsey D, Diamond MP. https://jivfww.scholasticahq.com/ar ticle/87947-minimal-stimulation-highly-individualized-egg-retriev al-and-term-stimulation-as-alternative-strategies-for-improving-egg-qual ity-in-older-pati

Pregnancy and Obstetrics

Yet another way to diagnose preeclampsia early and does preeclampsia prevent breast cancer?

We kind of lost count of how many different early preeclampsia tests we reported in these pages over the last year. Here is yet another one from Belgium and this time in the very prestigious medical journal Nature Medicine.1 It also involves a very different methodology of testing because, here, cell-free DNA methylome analysis was performed to predict preeclampsia. The study investigated 1st-trimester cell-free methylomes from 498 pregnant women, with approximately one-third developing early preeclampsia. These numbers were sufficient to detect significant differences in DNA methylation between preeclampsia and non-preeclampsia patients allowing for stratification for risk at the time of diagnosis but also already earlier, prior to symptom development at approximately 12 weeks (range 9-14 weeks). This 1st-trimester risk prediction model was validated with the help of an external patient cohort and integrated with routine risk factors. A combined risk score correctly predicted 72% of patients with early-onset preeclampsia at 80% specificity. The paper and its results were commented on in a new Reviews article.2 For good reasons, this commentary was not too excited about the Continued on page 46

Reflecting here on the rare opportunity in our literature reviews to disagree favorably with authors about the meaning of their work (usually it is exactly the opposite), we feel that these data warrants further follow-up studies. Our opinion is not only based on the fact that an 11% difference in breast cancer incidence in our opinion is not only statistically but also clinically highly significant, but also on the potential biological logic of such a finding, and here is why: The CHR considers preeclampsia with great likelihood to be the reflection of a hyperactive immune system, prematurely ending the tolerance of the paternal semi-allograft. That this happens represents some distinctively different immune system status in these women than in a majority of women who do not develop preeclampsia. It appears entirely logical that the immune system that predisposes to preeclampsia for the same reasons is hyperactive not only against the products of conception during pregnancy but, in the long run, also against breast cancer cells, thereby preventing breast cancer occurrence in some women (see also the later “immunology” section of this literature review). REFERENCE 1. De Borre et al., Nat Med 2023;29:2206-2215 2. Kaitu’u-Lino et al., Nat Med 2022;29:2177-2178 3. Yao et al., Hypertension in Pregnancy 2023;42(1):2265482

The maternal microbiome aids placental growth

As investigators from UCLA recently reported, at least in the mouse, the maternal microbiome to significant degrees promotes placental development.1 Depletion of maternal gut microbiota restricted placental growth significantly and impaired fetoplacental vascularization. In pregnant mice lacking microbiota, short-chain fatty acids stimulated cultured endothelial cell tube formation and prevented abnormalities in placental vascularity. Assuming that the gut microbiome in humans influences pregnancy in similar ways (and that is not a given), these findings have considerable potential translational relevance. As the authors put it, “advancing our understanding of how the maternal gut microbiome affects placental structure and function may inform new approaches to promote maternal and fetal health and to decrease risk for chronic diseases.” REFERENCE 1. Pronovost et al., Sci Adv 2023;9(40):eadk1887

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What does smoking and coffee drinking really do to these two pregnancy hormones remodel parenting circuits in anticipation of future behavioral needs. An accompanying commentary pregnancy? also points out that male adjustments to parenthood are even less This is the question a relatively small study by Australian and British investigators, using very accurate criteria of measurements, indeed attempted to answer. Compared with prior, likely less rigorously obtained data, this study revealed stronger associations between consistent smoking exposure and fetal growth restriction, spontaneous preterm birth, and lower birth weight. Interestingly, the study did not demonstrate a relationship to the occurrence of preeclampsia and caffeine exposure was not independently associated with adverse obstetrical outcomes. Since the CHR never believed reported adverse outcomes in association with coffee intake, the latter finding did not surprise us. After all, were there such an association in reality, the Middle East, Italy, France, and other countries in the world, considering their coffee habits, should demonstrate rather miserable perinatal outcomes, and they never did. REFERENCE 1. Selvaratnam et al., Int J Epidemiol 2023;dyad123

Does climate change increase the risks of adverse pregnancy outcomes?

This is at least what a recent “thematic review” in the Journal of Endocrinology attempted to claim,1- though with, in our opinion, limited success. Claiming that an increasing incidence and increasing severity of heatwaves has globally led to concomitant health complications, including as the paper claims compromised maternal as well as neonatal outcomes, the manuscript, however, lacks much supportive evidence. For example, it cites only one reference that alleges increased congenital abnormalities and acknowledges that there currently does not exist any evidence for increased miscarriage rates. Yet elsewhere, the author states that epidemiological studies and animal models reveal that exposure to heat in pregnancy elicits an array of health problems, including miscarriages, congenital anomalies, low birth weight, stillbirths, and preterm births. So, what is it? REFERENCE 1. Wyrwoll CS. J Endocrinol 2023;259(1):e230030

well understood but that testosterone levels apparently drop significantly in new fathers.2 Certainly an interesting subject with much more to be learned, not only regarding what is considered normal parental behavior but also about abnormal behavior toward one’s children (and maybe others). REFERENCES 1. Ammari et al., Science 2023;382(6666):76-81 2. Mcarthy MM. Science 2023;382(6666):33-34

Did you know fathers also suffer from postpartum depression (PPD)?

It apparently affects between 8-13% of fathers, a very similar prevalence to the 6.5-20.0% quoted in the literature of mothers. Like most behavioral studies, the number of study subjects recruited by the investigators was very small: A total of 29 fathers “were contacted,” of which 24 completed a screening questionnaire (age range 19-48 years; 87% belonged to a racial minority group). Hard to believe, but 30% screened positive for PPD, which would mean an even higher prevalence than reported in women. In other words, as in so many behavioral studies, unfortunately not a very credible result! REFERENCE 1. Wainwright et al., BMC Pregnancy Childbirth 2023;23:675

Genetics in reproductive medicine

Improving the transfer of spindle-chromosomal complexes

A widely reported technical problem with spindle transfers is the carryover of maternal mitochondrial (mi)DNA that occurs in most cases. Chinese investigators now described, based on mouse as well as human (preclinical) studies, how maximal residue removal can be accomplished in metaphase II (MII, i.e., mature) oocytes. They in addition also demonstrated that their novel strategy was fully compatible with normal embryo development.

Pregnancy, however, remodels the brain for being a Spindle cell transfer has found so far only limited application in remother and father productive medicine in principle two areas: prevention of maternal Becoming a parent requires behavioral adaptations. Based on a mouse model, a recent study suggested how pregnancy hormones remodel parenting circuits in the brain. Apparently, estradiol and progesterone act on galanin (Gal)-expressing neurons in the mouse medial preoptic area (MPOA) which is critical for pregnancy-induced parental behavior. While estradiol silenced MPOAGal neurons and paradoxically increased their excitability, progesterone permanently rewired this circuit node by promoting dendritic spine formation and recruitment of excitatory synaptic inputs. MPOAGal-specific neural remodeling sparse population activity in vivo and results in persistently stronger, more selective responses to pup stimuli. The authors conclude that

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transmission of so-called mitochondrial diseases and, to an even lesser extent, in cytoplasmic exchanges of eggs from older women in attempts to improve an oocyte’s chance of leading to pregnancy. Preventing mitochondrial carryover would be especially important in the prevention of mitochondrial diseases in offspring, where mitochondrial drift unfortunately happens quite commonly.2 REFERENCES 1. Liao et al., PLoS Biol 2023; https://doi.org/10.1371/journal.pbio.3002313. Online, ahead of print. 2. Yamada et al., Cell Stem Cell 2016;18(6):749-754

A new Committee Opinion of the ASRM regarding the management of “mosaic” results in PGT-A

if the embryo is mosaic. If the official PGT-A result is “euploid-normal,” the embryo is still most likely mosaic, while a reported result of “abnormal-aneuploid” means that the embryo is most likely aneuploid, but in some cases can also still be mosaic. Most importantly the document also fails to address the most basic of all questions, which is what is the purpose of PGT-A or, in other words, what rate of false-positive results leads to the non-use and/or disposal of embryos and an indisputable reduction in cumulative pregnancy chance from a single embryo cohort in an IVF cycle, is ethically and clinically acceptable? REFERENCE 1. Practice Committees of the ASRM and Genetic Counseling Professional Group. Fertil Steril 2023 120:973-982

And yet we continue in the search for a utility for PGT-A! ASRM finally published a revised document regarding the management of mosaic results from PGT-A testing of blastocyst-stage embryos. Unfortunately, it again lacks context, is missing important information, and is biased in the selection of references, even though it claims “to incorporate a growing number of published studies about mosaic embryo transfer and provides current evidence-based considerations for the clinical management of embryos with mosaic results on PGT-A.“1 Most disturbing is the continuous absence of any acknowledgment that, under the acquiescence and, indeed, the guidance of the ASRM (and other professional societies), IVF practice for over two decades has discarded (or at least left unused) huge numbers of human embryos with considerable pregnancy potential and has adversely affected IVF outcomes and harmed patients. Without such an acknowledgment, any revision in recommendations sounds shallow and misses the opportunity of concomitantly addressing the fact that the IVF field over the last two decades has added many other “add-ons” to IVF that have failed to improve IVF outcomes and, in many instances have been harming IVF cycle outcomes. By failing to acknowledge this fact with an appropriate “mea culpa,” the field is missing the opportunity for a teachable moment regarding how new practice patterns should not be introduced into routine practice.

In the prior section on “What’s new in IVF” on page 41, we already addressed the recent paper by Bamford et al. in Fertility and Sterility within the general context of embryo selection, making the argument that even if there is/are one or several best embryo(s) in a cycle’s embryo cohort, it remains questionable whether the observed difference is of enough clinical significance to warrant effort, time, and additional costs of embryo selection beyond routine morphological observation during routine embryology?1 As we do not want to be repetitive, we refer to the earlier detailed discussion of this paper. REFERENCE 1. Bamford et al., Fertil Steril 2023;120:834-843

Distinct and shared genetic influences between placental and fetal growth

Using placental weight as a proxy for placental growth, a multicenter-study involving 88 authors reported in Nature Genetics a genome-wide association analyses in fetal (n = 65,405), maternal (n = 61,228), and paternal (n = 52,392) genomes, yielding 40 independent association signals. 26 signals were classified as fetal, four as maternal, and three as fetal and maternal. A maternal parent-of-origin effect was detected near KCNQ1.

Genetic correlation and colocalization analyses revealed overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development Though the document notes that on a technical level, mosaicism and morphology, and transport of antibodies and amino acids. is defined “as the presence of more than one chromosomally distinct Mendelian randomization analyses indicated that fetal genetically mecell line in one individual“ (the correct biological definition is the diated higher placental weight is causally associated with preeclampsia presence of more than one cell lineage in one organism derived risk and shorter gestational duration. Moreover, these analyses support from a single cell), the document does not clearly state that an the role of fetal insulin in regulating placental weight, providing a key overage 5-cell trophectoderm biopsy can never accurately represent link between fetal and placental growth. a complete blastocyst-stage embryo with on average of approxiREFERENCE mately 250 cells, made up of two distinct cell lineages (with quite 1. Beaumont et al., Nat Genet 2023; doi: 10.1038/s41588-023-01520-w. Online different characteristics), the embryonic cell lineage producing ahead of print. the fetus, and the extraembryonic cell lineage which produces the trophectoderm and later the placenta. Consequently, what the document describes as a so-called “mosaic result” will only be correct Continued on page 48

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The immune system and reproduction How mothers tolerate their fetal-placental semi-allograft

Microchimerism We have in the pages of The VOICE repeatedly presented the CHR’s view that pregnancy, in principle, is an immune system-driven rather than an endocrine-driven phenomenon, with the main argument being that the establishment of tolerance of the maternal immune system, simply, logically, must be the first step in establishing a successful pregnancy. If that were not the case, the maternal immune system not only would reject every implanting (allogeneic) embryo (preventing entry of “foreign” agents into our body is a principal function of the immune system) but, likely, would even prevent most implantations in the first place. We also repeatedly pointed out that the induction of these tolerance pathways, very likely, occurs sequentially and, in addition, to the tolerance of for example a transplanted solid organ must be adjustable to an in-size logarithmic-growing transplant over an average of a 40-week-long period.

could contribute to the occurrence of preeclampsia3 and autoimmune diseases.4 Moreover, cell traffic does not only go one way. Similarly, maternal cells enter the fetal compartment during pregnancy and may become sessile there as well. Now come Ohio-based investigators who demonstrated in a mouse model that pregnancy confers partner-specific protection against complications in future pregnancies that parallels the number of fetal microchimeric cells after parturition.5 Moreover, microchimeric cells are replaced by new microchimeric cells in subsequent pregnancies and their tonic stimulation is essential for the expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells, so-called Treg cells. Daughters similarly turn over maternal microchimeric as well as Treg cells, suggesting a microchimeric cell niche. As noninherited maternal antigen tolerance is functionally erased by pregnancy, any partner-specific resiliency against pregnancy complications persists in mothers even if paternity changes. All of this allows mothers because of FOXP3 expression plasticity to “remember” their babies, while daughters “forget” their mothers immunologically once they get imprinted with new immunological memories from their children. An accompanying commentary suggests that this newly evolving knowledge may be used to design therapeutics that may be able to manipulate antigen depots to coerce tolerance instead of immune reactions, which could have therapeutic implications for as different areas of medicine as cancer immunology, autoimmunity, and organ transplantation.6 We would add to this infertility and miscarriages.

Figure. A “pregnancy souvenir” for mothers: Cells from your baby. Fetal microchimerism was first discovered after male pregnancies by detecting after delivery, and often for decades, cells with Y chromosomes in various tissues of mothers. Such microchimerism is now understood to be an important contributor to fetal immunologic tolerance during pregnancy but can also have adverse effects on the health of the mother. They, for example, have been associated with an increased risk for autoimmune diseases.

A mechanism coming into play for the first time later in the first trimester is the presence of fetal microchimeric cells within the mother. The importance of donor organ microchimerism for tolerance by the recipient in allogeneic solid organ transplantation was first demonstrated in the early 1990s by Thomas E. Starzl, MD, and co-workers in liver transplants.1 That fetal cell microchimerism in mothers contributed significantly to maternal tolerance of the fetal-placental allograft was proposed shortly thereafter by several scientists and was demonstrated to persist in mothers for over 20 years (see above Figure) .2 Shortly thereafter, it was also demonstrated that such microchimerism in mothers

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Decidualization An earlier stage of tolerance must be induced in the peri-implantation period, a time period where the embryo penetrates maternal defenses by invading the endometrium for up to at least 10 days without any contribution from the mother.7 Regarding this important time period, Chinese investigators just published a paper in Cell in which they offered spatiotemporal insights into early pregnancy governed by immune-featured stromal cells.8 More specifically, they investigated in a mouse model decidualization of the endometrium which is known to be essential for implantation and placentation. A core finding of their study was that immature decidual stromal cells attract immune cells and induce decidual angiogenesis. This appears to happen at what they call the mesenchymal-epithelial transition hub during the initiation of decidualization of the endometrium. A newly discovered dual-featured type of immature immune-featured immune decidual stromal cells enables immune cell recruitment and immune suppression, governs vascularization, and promotes cytolysis at immune cell assembling and vascular hubs. When these cells become dysfunctional and spatially disordered they cause abnormal accumulation of immune cells in the vascular hub, disrupting decidual hub-specification, and leading to pregnancy complications. All of this is reported in a mouse model (DBA/2-mated CBA/J mice) and humans are not mice. However, similar processes in human endometrial decidualization would make sense and, for example, could very well explain at least some immunologically caused miscarriages.

REFERENCES 1. Starzl et al., N Engl J Med 1993;328(11):745-749 2. Bianchi et al., Proc Natl Acad Sci U S A 1996;93(2):705-708 3. Jacobson et al., J Reprod Immunol 2023;159:104124 4. Rak et al., Arthritis Rheum 2009;60(1):73-80 5. Shao et al., Science 2023;381(6664):1324-1330 6. Porret P., Science 2023;381(6664):1286 7. Deglincerti et al., Nature 2016;533(7602):251-254 8. Yanh et al., Cell 2023;186:4271-4288

The dynamics of human macrophages during early development

Another group of Chinese investigators, also in Cell, reported an immune cell atlas that reveals the dynamics of human macrophage specification during early human development.1 The authors in their paper offer a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravel their varying functions during early development across 19 tissues. One of the more surprising findings, and contradicting current dogma, they report that at such early developmental stage cells with microglia phenotype are broadly distributed outside of the central nervous system, considering their distribution pattern, likely playing diverse roles. REFERENCE 1. Wang et al., Cell 2023;186:4454-4471

Effects of hormone supplementation on rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most frequent autoimmune diseases in women and is quite frequently encountered in REI practice. Using data from a British biobank, Swedish investigators from Uppsala University now reported on the effects of oral contraceptives (n = 236,602 study subjects) and menopausal (n = 102,466 study subjects) hormone supplementation on the risks of rheumatoid arthritis.1 What they found was somewhat surprising: Oral contraceptives (as has previously been reported) decreased the risk of developing RA in ever-users as well as current users. In contrast, and somewhat of a surprise, menopausal hormone replacement was associated with a significantly increased risk of late-onset RA in ever-users as well as former users. We recently reported in an earlier monthly issue of The VOICE on a substantial study that associated postmenopausal hormone replacement therapy with an increased risk of developing Alzheimer’s disease and dementia in general.2 This here-discussed study suggests an increased risk for RA following postmenopausal hormonal supplementation. Two obvious questions must now be asked: (i) What other diseases may be enhanced in their occurrence by postmenopausal hormone treatments? (ii) Possibly related, is the patient’s immune system (in both diseases involved in their pathophysiology) in any way involved in producing this excessive risk? REFERENCES 1. Hadizadeh et al., Rheumatology 2023; kead513. doi: 10.1093/rheumatology/ kead513. Online ahead of print. 2. Pourhadi et al., BMJ. 2023;381:e072770