January/February Voice

IN THIS ISSUE THE CHR LETTER

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FEUILLETON

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THINK DIFFERENTLY - A CHR OPINION LIKE IN OTHER HUMAN ENDEVOURS, “FASHIONS” ALSO DETERMINE CLINICAL MEDICAL PRACTICE

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MONTHLY LEAD - THE RAPIDLY CHANGING WORLD OF 13 INFERTILITY PRACTICE: WHERE WILL IT LEAD TO? A SUMMARY OF THE 2023 FOUNDATION FOR REPRODUCTIVE MEDICINE CONFERENCE (FRMC)

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QUESTIONS FROM PATIENTS AND PUBLIC

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CASE REPORT OF THE MONTH: THE CHR’S UNIQUE HIGHLY INDIVIDUALIZED EGG RETRIEVAL (HIER) PROTOCOL

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SOME VERY PERSONAL THOUGHTS ABOUT THE YEAR WE JUST LEFT BEHIND: HOW MUCH MORE CHAOTIC CAN IT GET? THE IMPORTANCE OF GOOD NUTRITION FOR REPRODUCTION RECENT LITERATURE RELEVANT TO REPRODUCTIVE MEDICINE

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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

@CHRNewYork

@CHRNewYork

Dear Reader,

JA N UA RY 2 0 2 4

VOICE

As the world reached the New Year—some would say barely— the CHR is pleased to welcome you, our readers, back with this January-February 2024 issue of The Voice. With seemingly ever-growing numbers of countries in the world at war and our own country facing an election year, it has certainly been a chaotic time. That we here at the CHR have transitioned into 2024 without any major upheaval (except for a major waterpipe break between Chanukah and Christmas that fortunately did not affect our laboratories, but did require a major clean-up and the replacement of several computers), is therefore worth celebrating.

The CHR ended the year 2023 with several positive experiences, so there is good cause for optimism. As the principal co-sponsor of the annual Foundation for Reproductive Medicine Conference (FRMC) in December, the CHR was able to bask with the FRM in the shared acclaim the event received from faculty and audience members. The FRMC, following a years-long hiatus caused by the pandemic, convened in New York City from December 1-3, boasting the longstanding leitmotiv of the CHR and the FRM to “think differently.” The goal of the event remained the same—to bring leading researchers and clinicians in reproductive medicine from all over the world together in one room to discuss recent discoveries as well as initiatives to further advance clinical infertility practice.

Because such a conference does not exist anywhere else, the FRMC quickly achieved worldwide acclaim and notoriety far beyond its size after its establishment in 2018. We now can proudly state, based on practically unanimous comments from attendees, that the December event even outperformed the pre-pandemic ones. Even the last sessions of the conference, which usually feature a diminished attendance as people trickle out at the end of the day, were still packed.

A summary of this conference will be published in JARG 1 and can also be found on page 21 of this newsletter in a shorter format.

Full transparency requires that we here briefly describe the relationship between the CHR and the FRM. While the CHR is a for-profit medical corporation, the FRM is a not-for-profit tax-exempt organization, where earned or donated funds must be used exclusively for pursuing the organization’s objectives (in this case, research and education in reproductive medicine) and paying for its running costs. Nonprofit funds never go to the group’s members, directors, or officers.2 The FRMC routinely supports research at the CHR (and elsewhere); but, at the same time, the CHR is annually usually among the biggest donors to the FRM. The FRMC is the foundation’s biggest annual venture and its biggest expense.

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Within this context, we are also pleased to report that the CHR added its first FRM Research Fellow to the staff. Sónia Gayete, MD, PhD joined the CHR in January to assume responsibility for CHR’s multiple research collaborations with academic institutions.

Sonja is a well-published subspecialty trained-and-certified reproductive endocrinologist (RE) and PhD- trained basic scientist from Spain, who completed two years in a postdoc position at Yale University.

Content-wise this issue presents the usual sections. Considering that the November and December issues were combined, the number of interesting articles we want to point out for our readers that appeared in the literature over the last two months is larger than usual, so the back part of the newsletter with our review runs somewhat long.

We very much hope you will enjoy this issue of the VOICE and, as always, want to reemphasize that we welcome your uninvited contributions. Please send them with a short covering note to jbeebe@thechr.com References 1. Gleicher N, Albertini DF. A brief report on the Annual Foundation for Reproductive Medicine Conference (FRMC) in Reproductive Biology and Reproductive Clinical Endocrinology in NYC – December 1-3, 2023. J Assist Reprod Genet; In press.

2. Kenton W. https://www.investopedia.com/terms/n/not-for-profit.asp. December 7, 2023.

The Editorial Team of the VOICE We love eggs!

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In the series Friends, the character Phoebe undergoes an embryo transfer to help her brother and his wife conceive a baby. (Image credit: Friends/HBO Max)

Infertility’s Portrayal in Pop Culture Over the last several years, infertility treatment has become an increasingly popular subject explored in mainstream media.

Dealing with fertility problems, desiring to be older before becoming a parent, or wanting a child in a same-sex relationship are just a few of the many reasons that people might turn to in vitro fertilization (IVF) for help in creating their families. The IVF process has occasionally made appearances in various media like television series and movies, becoming an increasingly mainstream topic in more recent years. Myriad characters on the screen have coped with the emotional and physical consequences of their fertility struggles or have turned to IVF treatment to get pregnant. While some of the portrayals of infertility difficulties on TV are clearly fictionalized and can unfortunately lead to wrong assumptions about the process, most of them are genuine attempts at sharing people’s stories and widening the reach of the infertility conversation.

Infertility as Seen on TV

Infertility had its small television moments in the past, with the title character of Murphy Brown considering IVF in season one, and with Ally McBeal’s title character discovering in the show’s last season that eggs she had donated in the past were actually fertilized without her knowledge, leading to her genetic daughter Continued on page 6 Continued on page 6

(shockingly) showing up on her doorstep. As time went on, the references to infertility became more nuanced as the term “IVF” grew more mainstream and more of the general public gained an understanding of the treatment.

In 1998, in the 12th episode of season 4 of Friends titled “The One with the Embryos,” the character Phoebe has a procedure at a doctor’s office, undergoing an embryo transfer to help her brother and his wife conceive a child by being their surrogate. When Phoebe finds out that there’s a low chance she will become pregnant after having five embryos transferred, she feels a lot of pressure—her brother and his wife put all their money into this, what if it doesn’t work? But seemingly hours later, Phoebe sits upside-down to “let gravity do its job,” and minutes later she is declaring that her pregnancy test is positive. Of course, this portrayal of an embryo transfer is highly fictionalized for television; in reality, it would take multiple weeks to become pregnant.

Later in the series Friends, the issue of infertility comes up again when the characters Monica and Chandler struggle to get pregnant in season 9, episode 21’s “The One With the Fertility Test.”

They go to a fertility center to assess their reproductive health; later, Monica is told she has an “inhospitable environment” for a fetus, while Chandler has “low-motility sperm.” Eventually the characters move on to adopt a child, but the episode nevertheless succeeds in bringing viewers’ attention to the fact that many couple struggle to conceive, and several turn to fertility clinics for assistance.

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The Mindy Project is another show that brings awareness to fertility treatment. The title character eventually runs the clinic “Lahiri Fertility Center” as her job; in the episode “Fertility Bites” she scrambles to find patients, selling a “spring break” trip for college girls who want to freeze their eggs. Mindy means for the initiative to have young women spend eight days out of town, ending with a procedure to freeze their eggs. While this series was oft-praised for inserting fertility-related language into the popular lexicon, it was also criticized for its lack of accurate medical and clinical portrayals; not including an initial consultation, the egg-freezing process takes approximately two weeks to complete, and can’t just be done anywhere or haphazardly (plus its timing depends on the patient’s ovulation cycle). The show does get right, though, the fact that it is OK if young people do not want to have babies during their fertile years—because an option exists for them to wait. “You’re freezing your eggs, which is going to give you time to find the right guy,” Mindy tells them.

The show Friends from College also steers into IVF territory; from the first episode, characters Ethan and Lisa are a married couple going through a round of IVF. The show’s fourth episode, “Mission Impossible,” features a montage of Ethan administering hormone shots into Lisa’s abdomen day after day, demonstrating the exhaustion and the emotion behind the process as her bruises darken, and encapsulating the frustration of the treatment when Ethan accidentally breaks a vail of hCG. This realistic portrayal garnered praise from critics, and as it turns out, the story is based on the real-life experience of series creators Francesca Delbanco and Nick Stoller. “It was very

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In the show The Mindy Project, the title character runs a fertility clinic. (Image credit: The Mindy Project/Fox)

cathartic and therapeutic,” Delbanco said in a 2017 interview with Refinery29, to take their difficult experience and “turn it into something that could be a piece of entertainment for people.”

Delbanco continued: “… Everyone knows what IVF is, but if you haven’t experienced it, you have no idea what it entails. You just know it’s IVF, and people do it when they have infertility, and they come out with a baby—but you don’t know what it means. It’s knowledge that you acquire if it happens to you, and otherwise you don’t really think about it. [We thought] it would be kind of amazing to show what an ordeal it is for people, because a lot of people go through it.”

While Miranda and Charlotte’s stories in Sex and the City touched on fertility issues (with Charlotte eventually choosing the adoption route), the show’s reboot And Just Like That does a better job of tackling the sensitive topic. In its sixth episode, the show portrays Miranda’s law professor Dr. Nya Wallace, who has undergone IVF attempts in the past, becoming frustrated that her friend has conceived a baby by natural means so easily. Her partner suggests a third IVF round, but she resists, saying that the treatment is tough on her body and makes it difficult to save money to buy an apartment. These are some realistic thoughts behind the infertility journey that often go unspoken.

In terms of drama shows, the series This Is Us features the character Kate undergoing IVF treatment in its third season; in episode three, she and her husband begin the process, with Kate clearly emotional as she wonders anxiously how many eggs were found during her retrieval. The series was praised by those

who have personal experience in infertility for how it handled the character’s reactions to motions of IVF. Master of None also joined the infertility conversation on the screen in its most recent third season, which shifts the focus toward the character Denise and her wife Alicia, who are trying to conceive a child via IVF as a lesbian couple (“I’m 34 years old—my ovaries are starting to get stale,” Alicia says). The show demonstrates Alicia’s infertility journey in detail, from her fear of her first hormone injection to her discovery that many American insurance plans do not account for LGBTQ+ people who wish to become pregnant. The episode “Moments in Love, Chapter 4” shows Alicia receiving the news that her first round of IVF failed, and her grief-filled reaction to the news. Jess Venable-Novak, family engagement manager on the show, told The Washington Post in 2021 that it was validating to see this story depicted on the screen, especially because of “how powerful it is for young people who are queer…who might one day want to form families.”

The Big Screen and Infertility Treatment

When it comes to movies, there are several from recent years that have explored the topic of infertility, some more gracefully than others. The 2018 drama Private Life is a notable example, featuring Kathryn Hahn and Paul Giamatti as a married, middle-aged couple desperate to finally have a baby after spending years focused on their careers. The movie delves into the gritty details of a couple’s infertility journey, down to the specifics around egg donation and testicular extraction. The couple’s attempt at a $10,000-IVF cycle,

though, fails due to insufficient eggs and blocked sperm. They keep trying, largely in an effort to save their marriage. The scenes of hormone shot injections and arguments about the treatment extremely accurately demonstrate the emotional toll IVF can take on a relationship.

Another example of a film that focuses on infertility is 2021’s horror fare False Positive, in which the main character Lucy (Ilana Glazer) has a seemingly perfect life—other than the fact that she can’t seem to get pregnant. “As a woman, this is the one thing I’m supposed to be able to do, and yet I can’t do it,” she says to her husband. While the movie goes on to explore horror themes and scares, viewers who have struggled with their own shame around fertility can certainly relate to that sentiment.

Ultimately, any media that (even only somewhat) accurately portrays a character going through the IVF process is a welcome addition to pop culture, as it helps in the broader mission of spreading awareness about infertility and the fact that it is not easy for everyone to have a family. While in some cases infertility has been dealt with insensitively on the screen—as it is joked about in The Switch, or treated with a negative stigma on reality shows—this is happening less and less as society and technology advance and as people break from traditional pathways concerning their reproductive lives.

In the movie Private Life, a husband and wife undergo the difficult process of trying to conceive a child via IVF. (Image credit: Past Lives/Netflix)

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BRIEFING: This article is based on a lecture on the introduction of “Precision Medicine” into infertility practice, which the CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, was invited to give on December 18, 2023, at the Ovarian Club (Asia) in Hong Kong, China.

Like almost all industries, medicine is subject to fashion trends (and, yes, medicine is, indeed, an important industry; the U.S. in 2021 spent 18.8% of GDP- on medical care—by far the most of any nation in the world). That idea might seem surprising, but just like mankind falls in (and out) of love with what we wear, what style cars we drive, and what music we are listening to, so do physicians with fashions relating to the practice of medicine.

Like in other frameworks of human existence, the underlying idea does not have to be new; after all, fashion designers have long resurrected trends from years past. In medicine, sometimes something as simple as a change in name will spark Continued on page 10

inspiration. In the 1980s, for instance, a small group of medical academicians in Canada and the U.S. felt that the way in which treatment decisions in medicine were reached was inadequate and unfairly influenced by the personal opinions of senior physicians rather than objective findings (and, too often, by the pharma industry…does that sound familiar?). This led, in 1990, to McMaster University’s (Canada) Gordon Guyatt, MD creating the term “evidence-based medicine” (EBM), popularizing the concept that medical practice should be based on the latest and best scientific knowledge available. This term stuck and, for his achievements regarding the development of EBM, Guyatt was entered into the Canadian Medical Hall of Fame.1

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Prospectively randomized clinical trials (RCTs) were, since the 1960s, already recognized as the “gold- standard” for all therapeutic investigations in medicine (though primarily only related to pharma products). But EBM proposed that the latest and best scientific knowledge could only be uncovered through a new, clearly defined process that relied upon the structured analysis of recently published RCTs (and possibly lower evidence-level studies), which had to include a detailed quality assessment of each included study so that the weight of evidence of each study could be properly judged, leading to a combined overall assessment. Practically, this process came to involve five steps: Definition of a clinical question ¯ Research of literature for best evidence ¯ Critical assessment of this evidence ¯ Determination of whether evidence is applicable ¯ Evaluation of performance of process

after systematic reviews at the top, the medical field perceived that medical practice was no longer primarily driven by the biases of experts and drug manufacturers (at least not to the same degree).

Moreover, it quickly became apparent that this new research method (instead of planning and executing RCTs and then analyzing and interpreting those data) allowed for much simpler gathering of data, analysis, and interpretation of the already existing published data of others, yet offered similar academic recognition and opportunity for enhanced career development. Unsurprisingly, the new fashion of performing MAs through systematic reviews of RCTs (or even, at times, observational studies) bloomed nowhere more than in China, where MA-factories were created, spewing out enormous numbers of MAs with minimal, if any, clinical value. A new academic research specialty evolved around the world, building careers on the conduct of MAs and systematic reviews.

As these MAs and reviews are performed at the desk and not in the clinic, many of these new “experts” were often far removed from the clinical practice they were investigating and reporting on. What was “best practice,” therefore, was no longer decided by clinicians relying on their (biased) experiences, but by this new slew of “experts” in study design with mostly little practical experience. Shockingly, it took decades to understand how deeply flawed this system was.

Considering that the numbers of systematic reviews is still peaking, moreover, suggests that many physicians—and they are not alone— have failed to recognize that that the EBM-fashion is losing luster.

The statistical combination of results from at least two separate studies is called a “meta-analysis” (MA).2 It represents the basic building block for the concept of EBM. Starting in the 1990s, worldwide medicine became increasingly enamored with this concept of EBM. But how truly “new” this concept was is rather questionable, considering that best medical diagnosis (and treatment) has strived for “best evidence” and “best treatment success” since the earliest days of medical The same unfortunately also still applies to many medical societies, practice. which continue to put out ever-increasing numbers of new “guidelines,” “opinions,” or other formats of guidance documents based As the concept of EBM started to spread, the number of RCTs in all on EBM. This often created self-fulfilling and allegedly evidentiary medical specialty areas increased rapidly, in combination with parallel prophecy loops, completely removed from clinical reality. An excelincreasing numbers in MAs, taking up steadily more printed pages in lent recent example is a publication from the ESHRE Add-ons Working medical journals.

Group, which in 42 printed pages in Human Reproduction makes the audacious claim of having formulated 42 good-practice recommenAs desired by the creators of EBM, with expert opinion relegated to dations on the use of so-called 42 add-ons to IVF.3 As we previously the bottom of the evidentiary pyramid (see Figure below) and MA commented in an earlier issue of the VOICE, this means an average of

FIGURE: The evidentiary pyramid, demonstrating expert opinion at the very bottom and the building stones of EBM, RCTs and systematic reviews of RCTs at the very top. From Validity of Meta-analysis in Diabetes: Meta-analysis Is an Indispensable Tool in Evidence Synthesis by E.Bass, 2013, Research Gate (https://www.researchgate.net/figure/ Evidence-based-medicine-pyramid-Thelevels-of-evidence-are-appropriatelyrepresented-by_fig1_257072438). CC BY-NC-ND 3.0

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one page per add-on, supposedly (and conveniently) fulfilling the aim of “developing clinically relevant and evidence-based recommendations focusing on the safety and efficacy of add-ons currently used in fertility procedure in order to improve the quality of care for patients with infertility.”

Here is how this practice recommendation was developed, and we are again quoting: “ESHRE appointed a European multidisciplinary working group consisting of individuals who have demonstrated leadership and expertise in the care and research of infertility … In the absence of any clear scientific evidence, recommendations were based on the professional experience and consensus of the working group.” And it gets even more interesting: “Among 42 recommendations, none could be based on high-quality evidence and only four could be based on moderate-quality evidence.” So, what kind of lousy evidence were those 42 recommendations based on? And why did they waste 42 pages in Human Reproduction?

Oh, yes, we almost forgot: “Prior to publication, the guidelines were reviewed by 46 independent international reviewers … A total of 272 comments were received and incorporated where relevant.”

across RCTs and systematic reviews: “To answer the stated question, more (and hopefully better) RCTs will be required to answer the stated question.”

As with the many other rather absurd decisions made regarding this lengthy document, one is left wondering what motivated the split between European experts who developed the recommendations and international experts who were allowed to comment. But probably the most relevant question left to be asked is—why all the effort when it is so obvious that most add-ons introduced to IVF practice over the last 20 years have no evidence-based support whatsoever?

That fact could be stated by any real expert following the literature over the last two decades. Our point is that expert opinion—the lowest level of evidence—now more than ever rules medicine (including reproductive medicine). Who, then, can be surprised that MA “experts,” for over 30 years, remained basically clueless about how non-sensical and removed from clinical reality their approach of determining best clinical practice in most cases really had become?

Another obvious reason that shortcomings in the fashion of MAs should have been recognized much earlier was the old IBM company dictum, “garbage in, garbage out,” which, of course, is self-explanatory when it comes to MAs. If a study, even if in RCT format, is of poor quality, why include it in an MA in the first place? To include poor-quality studies in MAs, when the primary purpose of EBM was claimed to be the discovery of current “best” evidence, simply never made sense. Yet, as the above-cited ESHRE study demonstrates, most MAs include a majority of low-quality studies. Why not instead simply state in the first place that a careful review of the literature did not reveal enough high-quality studies to reach a conclusion?

After the fashion of EBM started, most MAs were unable to offer clear answers about whether investigated treatments were effective or not. The likely most frequently abused cliché in medical writing, therefore, was encountering the following closing sentence

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Such a logical thought would, of course, have deprived the new “MA expert” class of considerable publication potential and, therefore, of academic promotions and professional power to regulate.

Fortunately, all fashions at some point fall out of favor,—after all, even “disco” did! Over the last two years especially, we have been witnessing the accelerating demise of the EBM-fashion, only for it to be replaced by a competing fashion called “real world data” (RWD).

This allegedly new concept states the indisputable fact that RCTs, still widely accepted as the gold standard in study design for clinical outcome studies, is basically severely biased. The core issue of contention here is that the study design for a well-designed RCT requires a strict definition of the characteristics of patient populations as well as control groups. But in daily clinical practice, such “clean” patient populations do not exist.

Another ground rule of study design is that results only apply to the kind of patient population in which they were investigated. Practically this, of course, means that not even the best RCT (or, maybe especially not the best RCT) can be seen as representative of what can be expected in the “real world” of daily practice. The Food and Drug Administration (FDA) recognized this fact years ago, leading to the introduction of post-marketing observational studies (Phase IV

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studies) for continuous data collection for many approved drugs.4 Medical practice, however, only recognized the importance of “real world data” recently, with the term appearing in increasing numbers of study titles of even very prominent medical journals (which, until recently, would have been insulted if anybody had dared to submit an unrandomized observational study of any kind).

But let us be honest; as much as the CHR welcomes the increasing recognition of the importance of RWD, the way medicine in general (including the infertility field) approaches RWD must be viewed as a “fashion of the moment.” What has been—and still is—missing is the recognition that fancy names, like EBM or RWD, are just that, and cannot replace plain logical thinking. To believe that the biases of experienced clinicians are inferior to the biases of clinically incompetent MA experts, is not only illogical, but truly absurd. That, of course, does not mean that one bias is better than the next—because all biases interfere with objective data analyses—but that practically all data analyses are, to a degree, biased. Even analyses driven by Artificial Intelligence (AI) are biased, based on what underlying materials were utilized to “educate” the AI system. The utilization of human logic in minimizing these biases and, when appropriate, adjusting analyses, therefore, appears irreplaceable—at least until AI becomes competent to perform on its own.

The CHR, in these pages and in its publications and presentations over the last two years, has been picking up on another recently fashionable term gaining popularity across medicine: so -called “precision medicine” (PM). We are fully aware of our usage of this trending term of the moment which, in principle, only reemphasizes

an age-old basic principle of medical care—the individualization of medical practice to the special needs of an individual patient. But because EBM has, over the decades, now been associated with the concept of uniform, protocol-driven, equal medical care to all (aren’t most IVF clinics using rather uniform protocols on patients of all ages?), it is important to note that the RWD trend perfectly matches with PM. So, for the next few years, let us be clear and transparent about what we are talking about when we use these acronyms. For as long as we understand that they represent only fashions of the moment in an ongoing and persistent struggle to improve medical practice, their usage appears appropriate. However, they cannot be allowed to replace logical thinking and the “art” of medicine, which comes from collecting experiences in daily clinical practice. Everything we know about medicine we have learned from our patients. And here at the CHR, we are still learning daily from our patients to “think differently!”

REFERENCES 1. https://www.cdnmedhall.ca/laureates/gordonguyatt 2. https://training.cochrane.org/handbook/current/chapter-10#:~: text=Meta%2Danalysis%20is%20the%20statistical,controversies%20 arising%20from%20conflicting%20claims 3. ESHRE Add-ons working group et al. Hum Reprod 2023;38(11):2062-2104.

4. https://www.sciencedirect.com/topics/pharmacology-toxicolo gy-and-pharmaceutical-science/phase-iv#:~:text=Phase%20IV%20

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BRIEFING: This article describes the radical changes in business models driving infertility care since the inception of IVF, which created the impetus for establishment of a separate sub-specialty of Reproductive Endocrinology and Infertility (REI). We here describe how this small new sub-specialty area of gynecology grew, over 45 years, into a highly influential subspecialty and, ultimately, into a true “industry” supported by ever-growing numbers of provider clinics and, in parallel, an equally quickly growing full-service support industry. Especially over the last decade, as the finance-world has discovered fertility as a growth industry, the world has witnessed an acceleration in the pace of change, the largest being that only a minority of individual IVF clinic sites in the U.S. are still physician-owned.

Throughout the country, but especially in larger cities, it appears that Wall Street has taken over; large national chains of IVF clinics are mostly owned by private equity firms that buy up physician-owned clinics at record pace to compete among themselves for market share.

How these developments have already affected the provision of Continued on page 14

fertility services, and what they will lead to, is the topic of this article, with particular attention paid to the New York tri-state area.

Modern infertility practice is only 45 years old. It started with the birth of Louise Brown on July 25, 1978, in Oldham, a town in northwestern England. Brown was known as the world’s first “test-tube baby,” as in vitro fertilization (IVF) births were referred to in those days.1 Up to that point, the treatment of infertility was still widely in the hands of general obstetrician-gynecologists, because the handful of gynecologists presenting themselves to the public as “fertility experts” did not have many treatments options to offer; female infertility was treated either with surgery, ovulation induction, and/or intrauterine inseminations (IUIs), and male infertility with IUIs and/or third-party donor sperm inseminations.

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The possibility of IVF was rumored at the time, but not really taken seriously by fertility specialists. Partially because of fear that IVF might produce Frankenstein-like human “monsters,” 2 and partially because of religious consideration,3 IVF was still widely perceived as unethical in those days. A good example of this comes from the story of what happened to Landrum Shettles, a well-known scientist at Columbia University in New York City at the time. On September 12, 1973, about five years before the birth of Brown, Shettles—at the request of a couple that had failed multiple tubal surgeries and IUIs—attempted IVF, using the wife’s egg and the husband’s sperm. Raymond Vande Wiele, chair of the Obstetrics & Gynecology department at Columbia (and himself a widely respected fertility specialists) was reported to have learned of Shettles’ ongoings and stormed into his laboratory, singlehandedly destroying the experiment.4 When the couple later sued Vande Wiele and Columbia University, Vande Wiele allegedly defended his action based on the fear that the experiment might have produced a monster.

controlled a large part of the IVF market. In selected European countries, quickly growing physician-owned clinic chains, like IVI in Spain, evolved and became the example for the development of similar chains in the U.S.

The announcement of the first IVF birth, therefore, was initially received with considerable skepticism. But with other IVF pregnancies following rather quickly in Australia and elsewhere around the globe, the treatment became more mainstream and it dawned on the gynecology field that a new gynecological subspecialty was evolving, requiring knowledge, practical expertise, and other qualifications that were distinct from what current gynecologists (and even the small group of already existing fertility experts) could offer. The development of IVF was quick, mostly driven by American IVF clinics and spearheaded by the Norfolk Clinic at Eastern Virginia Medical School in Norfolk, Virginia; Howard Wilbur Jones Jr. and his wife Georgeanna Jones, after retiring from illustrious careers at John Hopkins University, led the way.

The New York City (NYC) Tristate market

Most of the pioneering first-generation IVF clinics in the country were hospital-based—the CHR (in those days, located at Mount Sinai Hospital in Chicago, Illinois and the first IVF clinic in the whole Midwest) included. This, however, changed in 1983, when the CHR’s investigators reported in The Lancet (as a research letter, the same format used several years earlier when Steptoe and Edwards reported the first IVF baby) that eggs could be retrieved for IVF transvaginal under ultrasound control.5 This meant that retrievals could be performed outside of operating rooms, where all retrievals had taken place up to that point, mostly under full anesthesia.

Vaginal egg retrievals very quickly became the world’s standard retrieval method in IVF and, with it, IVF was no longer limited to the availability of operating rooms and, therefore, no longer dependent on being in hospitals. This led to the first explosive growth period for IVF in the U.S., as ambulatory IVF clinics were established all over the country, almost exclusively in private practice frameworks. This remained thereafter the dominant practice pattern in IVF for approximately 20 years. Then, private equity firms started to express interest in the fertility field, initially in Australia and New Zealand, where within a few relatively short years three companies

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In parallel, academic IVF centers like Norfolk, Yale, and John Hopkins, among others which, in early years of IVF practice, were the principal drivers of progress in the field in the U.S., progressively lost luster and leadership, often replaced in this role by rapidly growing privately-owned regional clinic networks, which were mostly supported in their expansion by insurance mandates for IVF coverage that a handful of states already passed in the late 1980s and early 1990s. Such mandates were state-wide and, therefore, encouraged the expansion from single-center operations to regional clinic networks and led to the first multi-thousand IVF cycle operations, like Boston IVF in Boston, Shady Grove in the Washington, D.C. area and Virginia, and the CHR in Chicago (later replaced by the Fertility Centers of Illinois (FCI).

Interestingly, while most larger cities very quickly developed dominant IVF centers (some, indeed, multiple), New York City lagged. Boston, Maryland, and Chicago had already established the above-noted local provider networks, but

New York only offered IVF services at a few small clinics; most New York patients who needed IVF traveled to the Yale program in New Haven, CT. None of the major academic institutions in the city in these early days offered IVF services worth mentioning.

This changed when (what then was called) Cornell hired Zev Rosenwaks away from Norfolk, (at that point, still the nation’s leading IVF center). Rosenwaks, at that time, was the Jones’s “young Turk” at the Norfolk program, just a few years out of fellowship training, brought there as one of the program’s first clinical hires. What turned the new Cornell program into the undisputed IVF leader in the city—and replaced the Norfolk program in its national leadership—was the fact that Rosenwaks also succeeded in bringing Norfolk’s founding IVF laboratory director, Lucinda Veeks, who at that point was clearly the nation’s top-embryologist, with him. Thus, Cornell, in one masterful strategic move, went from zero to becoming the country’s most prominent IVF program, easily able to recruit other leading young voices in the field, like the clinician Jamie A. Grifo out of Yale and the prominent European embryologist Jacques Cohen.

Observing Rosenwaks’ enormous success at Cornell from afar, other major institutions also decided to enter the IVF market.

Considering the still very small pool of IVF- qualified experts at that time, this was not a simple task. The best solution was to copy Cornell’s strategy of hiring professionals from other programs with offers they could not refuse. As noted above, because of its prominence, Cornell had been able to accumulate many such individuals on the clinical as well as laboratory side of operations. New York University (NYU) and St. Barnabas in New Jersey, instantly succeeded in establishing prominent IVF programs by, basically, partially dismantling Rosenwaks’ program. Under the leadership of Grifo, a significant portion of Cornell’s clinical program moved a few blocks south to NYU, while the mostly embryology staff from Cornell, under the leadership of Cohen, moved across the Hudson River to New Jersey. Rosenwaks must be given enormous credit for maintaining Cornell’s position as a leading IVF center despite all of this upheaval.

Other institutions made similar efforts in recruiting from other already successful academic programs like the Yale program.

Mount Sinai, for instance, hired Yale’s Neri Laufer, a temporary visitor from Israel (later to become professor and chair of the Obstetrics & Gynecology department at the famous Hadassah Hospital in Jerusalem) who ran Yale’s program under the auspices of Alan H. DeCherney, then the head of the REI division and more of a surgical than IVF expert at the time. Once Laufer returned to Israel, another Yale individual of Israeli background, Daniel Navot, who took over his position at the Mount Sinai program. Columbia University, in turn, hired Mark Sauer from the successful Los Angeles program at the University of Southern California USC. By the mid- to late-1980s, all major medical schools in the tri-state area had established IVF programs—some more successful

than others—and, at the same time, smaller, physician-owned, private IVF centers had also started to flourish.

As we previously detailed, the CHR at that point was headquartered in Chicago and was one of the largest IVF centers in the country, with multiple clinical locations and two IVF laboratories in the larger Chicagoland area, as well as a handful of clinics in other states. CHR entered the New York City market in 1988 in an initial contractual relationship with the Columbia and Mount Sinai programs to establish a combined program. Mount Sinai later withdrew from this contractual agreement, leaving the CHR only in a relationship with the Columbia program. After CHR-New York opened (in the space that now houses the RMA-NY program), this relationship (under the stewardship of Sauer) lasted for about a year, at which point CHR’s current Medical Director and Chief Scientist, Norbert Gleicher, took over the reign (moving the CHR into its current quarters by 2001).

Though private IVF programs continued to proliferate, the tri-state marketplace otherwise remained more or less stable through ca. 2010, with Cornell and NYU remaining the two largest IVF programs in the city and St. Barnabas in New Jersey featuring a highly successful program after Richard T. Scott Jr. joined Jacques Cohen on the clinical side of the program’s operations. The program, however, did not last after Scott decided to break off into his own private set-up, called RMA-NJ (after an initial short hook-up, unrelated to RMA-NY). RMA-NJ became a successful multi-center chain of

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TABLE: Tristate area’s fertility centers and their ownership format (in alphabetic order) _______________________________________________________________________________ Name Ownership Format _______________________________________________________________________________ Advanced Fertility Services Private Braverman IVF & Reproductive Immunology Private Center for Advanced Reproductive Medicine & Fertility Private CCRM Fertility -NY Equity – national chain CCRM - Institute for Reproductive Medicine Equity – national chain CCRM - Institute for Reproductive Medicine and Science Equity – national chain Chelsea Fertility NYC Private CHR Private Columbia University Fertility Center Academic Diamond Institute for Infertility & Menopause Private Extend Fertility* Private Fertility Institute of NJ & NY Private Generation Next Fertility Private Genesis Fertility & Reproductive Medicine Private Greenwich Fertility Private Island Reproductive Services Private IVI-RMA-NJ Worldwide Equity – worldwide chain Kindbody Equity – national chain Kofinas Fertility Group Private Legacy IVF Private Morgan Fertility and Reproductive Medicine Private New Hope Fertility Center Private Neway Fertility Private Northwell Health Fertility Academic NYU Langone Fertility Center Equity – national chain Offices for Fertility and Reproductive Medicine Private Rejuvenating Fertility Center Private RMA-NY Equity – national chain Sher Fertility Solutions Equity – national chain Spring Fertility* Equity – national chain Stony Brook Medicine – Island Fertility Academic The New York Fertility Center Private Weill Cornell Medicine – Center for Reproductive Medicine Academic _______________________________________________________________________________ *Primarily provider of egg-freezing services

clinics (more about its interesting history later), while the St. Barnabas program significantly declined in size and especially scientific importance.

What happened in the tri-state market since around 2010 can only be characterized as revolutionary—yet it has remained mostly under the radar and is the principal motivation for this article.

The most recent years Changes in the fertility field since 2010 have been dramatic, both in how medicine is practiced and how it is structurally organized. The clinical aspects have been dominated by the introduction of many so-called “add-ons” to IVF and are constantly discussed in the pages of the VOICE. This article has the purpose of pointing out the structural changes which, nationwide, have led to most IVF clinics in the nation (and

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in many other regions of the world) now being owned by investors rather than physicians. That this is also the case in the New York tri-state area, therefore, should not surprise.

But what may surprise is the fact that this also includes some well-known IVF centers still operating under the name of their former (not-for-profit) academic institutions. Moreover, even among privately owned IVF clinics, many have sold to equity-owned companies building still growing national networks of IVF clinics (see Table).

For example, NYU Langone Health in New York City describes itself as “one of the nation’s premier academic medical centers devoted to patient care, education, and research” and nobody can argue with that description, considering the many recent accomplishments of the institution, which clearly outcompeted other medical schools in the city. The NYU Langone Fertility Center, as its website suggests, is part of NYU Langone

recent years expanded into several other states in the process becoming one of the largest clinic networks in the country.

It was acquired in 2019 by NMH Health PLC, an Emiratesowned London Stock Exchange listed healthcare company that also owned Spain’s second-biggest IVF clinic network, the Eugin Group, into which Boston IVF was integrated.

By December 2020, NMH sold Eugin (with Boston IVF) to the German hospital network company Fresenius Helios for $525.7 million.12 But this saga does not end here; in November of 2023, KKR & Co., which just the year before had acquired IVI-RMA Worldwide, announced the acquisition of U.S. and Canadian operations of the Eugin Group (likely because of anti-trust concerns already expressed by the EU during the prior purchase, this acquisition did not include Eugin’s Spanish and other European assets) for a rumored $600 million.

Health; but as its website suggests it is also part of a network of IVF clinics managed by a company with the name Prelude Fertility Inc.,6 an equity-owned national network of IVF clinics (and other IVF-related businesses) claiming to be the largest in the U.S. Above noted James A Grifo is, indeed, director of the NYU Langone Fertility Center in the city and, at the same time, Prelude’s Chief Medical Officer.7 Or take, for example, the Reproductive Medical Associates of New York (RMA-NY), which, as mentioned earlier, has its Manhattan main offices in the space originally built out for the CHR, On its website, the RMA-NY proudly announces itself as “the Department of Reproductive Endocrinology and Infertility for the Mount Sinai Health System.”8 In 2023, it proudly announced to have joined with all of its locations another national network of IVF clinics called U.S. Fertility,9 claiming to be the nation’s largest physician-led fertility network.10 This company rose out of the local East Coast network Shady Grove, mentioned earlier, which (with help of equity investments) has since expanded far beyond its original practice area. As the VOICE reported last October, its Manhattan location had lost its Medical Director, Tomer Singer, to Northwell’s fertility program and, with the addition of RMA-NY, is scheduled to close.

Another example of the upheaval in the IVF field is RMA-NJ (again, except for a very brief initial connection, unrelated to RMA-NY). As noted, after separation from St. Barnabas, a very successful and academically productive regional IVF clinic network, RMA-NJ was in 2017 acquired by the Valencia Fertility Institute (IVI), at the time one of the largest international chains of fertility centers (and originally started in Spain, in the process creating IVI-RMA Global).11 As also previously reported in these pages, IVI-RMA Global, in 2022 in a record-breaking blockbuster deal, was acquired by KKR & Co. at an approximate enterprise value of $4 billion. But that is not the end of the story: Boston IVF was one of the pioneering IVF clinic networks in the U.S., and in more

And then there is the Colorado Center for Reproductive Medicine (CCRM), founded by William Schoolcraft as a private infertility center, which rose to significant academic prominence—not the least for promoting blastocyst-stage embryo transfer during Australia’s David K. Gardner’s tenure as the lead embryologist at the center 14 (and, as readers of the VOICE know, not an equally favored routine practice at the CHR). After establishing one of the earliest national networks of IVF clinics, with growing presence in New York City, in 2021 CCRM sold after several earlier investment trunks, to private equity under the name United Women’s Healthcare (Unified).14 New York, like much of the rest of the country is no longer just a competitive marketplace among private and academic fertility centers, as the field started out, but is increasingly dominated by large investor-owned and managed IVF clinic networks in a quite frantic competitive clash for market share. That these developments have major consequences on how fertility treatments are dispensed, therefore, cannot surprise, and is the subject of the next section.

The consequences of these developments As the Table demonstrates, the New York tri-state area is currently served by approximately 33 separately identified fertility provider organizations, many with more than one office location. Among those, only four boast exclusively academic ownership; nine are equity (investor)-owned and are parts of national or worldwide clinic IVF chains; and the remaining 20 are still privately owned by their physicians.

What will be obvious is that the latter are clearly smaller centers and, except for the CHR, have no significant national and/or international visibility (and/or patient following) and have little or no academic connection and/or scientific production. Though still a majority, these private centers, even combined, likely represent only a minority of IVF cycles performed in the region.

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The current direction the field of infertility in the tri-state area follows national and international trends toward fewer IVF cycles performed in academic and private IVF clinics, increasingly conducted by rapidly growing national and international clinic networks (mostly funded by outside equity investments). That such a trend has significant consequences when it comes to how clinical care is provided, the quality of care, and the costs will be obvious, and has already been studied in other areas of medicine that have undergone similar consolidations financed by outside investments. Here are some areas of hope and concern:

Areas of hope Professional management: That professional management improves efficiencies, capital utilization, and informatics is unquestionable. One of the original founders of IVI always notes that the company did not really become “successful” until they brought professional management on board (personal communication).

Availability of capital: Similarly, there can be no doubt that deep-pocketed equity-supported companies have significant growth as well as development advantages over companies who only can self-finance through bank loans and/or profits.

Cost effectiveness of size: Rapid growth and increase in size also bolsters the purchasing power of a company, lowering costs of purchases and, of course, improving the competitiveness of the company versus companies with higher purchasing costs.

Hiring advantages: Larger and better-funded companies also have clear hiring advantages—not only over privately owned clinics, but also academically and hospital-owned enterprises:15 Not only can they afford to pay higher salaries and offer better benefits (as recent history has well demonstrated), but they offer what candidates for employment perceive to be better job security. In addition, through purchases of academic IVF clinics, these companies have also “purchased” fellowship training programs, and are thus often given first choice in hiring graduating REI fellows.

Improved access to fertility treatments: Finally, it is frequently claimed by proponents of the industrialization of medical practice away from physician-ownership that access to medical care is improved. We, however, have so-far not seen any evidence for such a claim, and as further addressed below, current evidence that entry of equity investments into medical practice actually increases costs would argue against such a conclusion.

Areas of concern While for the longest time only theoretical, these areas of concern, based on several recent publications (repeatedly addressed in the VOICE), have come into better focus.

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The profit motive: Equity investments, in principle, have one overwhelming motive: to make money! And this does not only mean to be profitable, but to be as profitable as possible as quickly as possible, because equity investments’ profits generally are expected to be realized within a time frame of five to seven years. In practical terms, this means that an equity investor in a company expects within ca. five to seven years (there, of course, are exceptions on both ends) to improve the profitability of the company by so much that they will be able to sell the company with significant profit. In other words, equity investors have absolutely no interest in remaining long-term owners of a company; their interests are exclusively short-term and this will be reflected in their business plan. As acknowledged by the finance industry itself, “concerns over how private equity affects healthcare access, quality, and cost in the U.S. has exploded in the past few years, reflecting the growing activity of private investors in health care markets.”16 Pressure for revenue and profit generation: Since any future sale of the company will depend on the degree of the company’s improved profitability, this, in practical terms, always means that professional management’s principal goal will be the quick achievement of improving profitability which, in turn, means increasing revenue and reducing overhead costs. Consequences, therefore, should not surprise. A recent article in the Harvard Business Review suggests concerns about surprise billings of patients after purchases of hospitals by private equity, scaling back of support staff (including nurses), avoidance of low-margin services (primarily used by vulnerable populations), and promotion of high-margin services.17 It seems reasonable to assume that, if such concerns are warranted after hospital acquisitions by private equity, the same should apply after clinic acquisition and/or if private equity manages clinic networks. A recent study in JAMA Health Forum (and previously discussed in the VOICE) indeed confirmed this suspicion.18 Studying 578 private equity acquisitions of dermatology, gastroenterology, and ophthalmology physician practices, the study revealed that equity-owned practices increased costs (amount of allowed charges per claim) and utilization of services (volume of encounters, and volume of new patients seen).

The study also suggested that further research was required

regarding quality of care, patient satisfaction, and—not to be forgotten— physician, nursing, and other staff satisfaction in such a framework. Preliminary data from Germany suggested significant concerns, with arguments being that such frameworks restrict physician autonomy in treating their patients and therefore have an adverse impact on quality of care, as well as work-life balance considerations. Significant concern was also expressed about the lack of medical understanding by professional management.19 A most recent systematic review of the subject in the BMJ concluded that in the U.S., equity ownership across almost all healthcare setting (including medical practices) were often associated with harmful impacts on costs to patients or payers and with mixed to harmful impacts on quality of care.20 Probably most disturbing, a recent U.S. study published in JAMA revealed rather devastating evidence about the adverse effect of hospital inpatient outcomes after hospitals were acquired by private equity, Quoting the paper, “private equity acquisition was associated with increased hospital-acquired adverse events, including falls and central line–associated bloodstream infections, along with a larger but less statistically precise increase in surgical site infections. Shifts in patient mix toward younger and fewer dually eligible beneficiaries admitted and increased transfers to other hospitals may explain the small decrease in in-hospital mortality at private equity hospitals relative to the control hospitals, which was no longer evident 30 days after discharge. These findings heighten concerns about the implications of private equity on health care delivery.”21 Specific studies on the subject in the practice area of REI are lacking. We, however, recently presented at the 2023 ASRM Congress in New Orleans, Louisiana, in abstract format, a study (currently submitted for publication and under peer review) which, based on U.S. national reporting data by IVF centers, unequivocally demonstrated that equity and venture capital-owned IVF clinics utilized preimplantation genetic testing for aneuploidy (PGT-A) significantly more frequently than academic-owned, hospital-owned, and physician-owned clinics, even though the chance of live birth significantly declined with increasing utilization of PGT-A.22 As one would expect, the REI field, therefore, appears to demonstrate similar behavior patterns as other medical specialty areas in medicine when taken over by private equity.

De-individualization of medical care: We on page 9 in this issue of the VOICE address the need for improved individualization of patient care in fertility treatments, utilizing the recently increasingly popular term “precision medicine” to make this point. Within such a context it is, however, also important to point out that one of the main arguments of proponents of clinic networks in IVF is their ability to establish “best practices,” thereby allegedly improving fertility treatments overall. Aside from the fact that the PGT-A utilization findings contradict this argument rather vehemently, it also appears obvious that clinic networks must standardize Continued on page 20

care if they want to achieve consistency, predictability, and cost efficiency. So, we must conclude that they, by definition, simply in their existence, already contradict the concept of “precision medicine.” Accepting this conclusion then allows for considerations of certain solutions for at least some of the above outlined shortcomings of large clinic networks, discussed in the final section of this article.

Are there solutions?

At the current time, regional, countrywide, and even international IVF clinic networks appear unstoppable. Encouraged by the incredible price KKR & Co. was willing to pay for IVI-RMA Global, and the American and Canadian assets of Eugin (including Boston IVF), the speed of clinic purchases and establishment of new clinics by network companies even appears to be accelerating. In addition, some smaller clinic networks are already being swallowed-up by larger ones to become even larger.

Will it work?

That remains to be seen, and we acknowledge a degree of skepticism in the ability of management to wring enough profit out of those clinics over the next few years to warrant even more exorbitant purchase prices for the clinic networks that then will have to find new owners.

That our skepticism may be warranted is supported by the observation that, based on the behavior of management at several clinic chains, the initial “good times” appear to have ended; investments are curtailed, costs are trimmed, and if staff is not laid off yet, their production quotas are raised. Concerns at these companies are further aggravated because national IVF cycle numbers have not increased at the rate that had been forecast. As we previously discussed in these pages, we also do not consider the decision of Morgan Stanley Capital Partners to divest of all its IVF assets,23and of German Fresenius Helios12 to do basically almost the same, to have been accidental. Both owned their fertility-related assets just long enough to better understand their earnings potentials and decided to sell without the usually expected profits.

We foresee the industry entering a period of significant belt-tightening that will inevitably be followed by increasing staff dissatisfaction and, consequently, declining quality of care.

This will in turn lead to increasing patient dissatisfaction and a vicious cycle of even more disappointing growth in IVF cycle numbers. We, however, also see a possible solution for how such a period of belt tightening can be successfully managed for a large majority of infertility patients without causing above pointed out self-fulfilling prophecy. Such a solution would require that the management of clinic chains learns to understand that not all IVF patients are the same.

As the CHR demonstrated even in overall poor-prognosis patients, every patient population undergoing IVF can be stratified into good-prognosis patients (ca. 15-20%), average-prognosis patients (60-70%), and poor-prognosis patients (15-20%).24

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Good- and average-prognosis patients, representing ca. 8085% of every patient population, with current IVF practice will achieve excellent pregnancy rates with relatively minimal diagnostic workups and basic standard IVF. Their IVF cycle, therefore, can be protocol-driven—utilizing simple protocols (no PGT-A, for example), increasingly automated embryology laboratories, and, in many instances, physician extenders. Such IVF cycles can be offered relatively inexpensively yet will still achieve satisfactory pregnancy and live birth rates.

What to a significant degree raises IVF costs in the U.S. to, at times, almost absurd levels, are in principle mostly only two so-far unaddressed causes: (i) Unnecessary treatments (like PGT-A); and (ii) poor-prognosis patients, representing only ca. 15-20% of all patients. A big part of this patient population is older women. Because IVF patient populations in the economically more developed world are increasingly getting older, poor-prognosis patients are rising in numbers and need much more specialized treatments (i.e. precision medicine). Currently, they are part of the general population of IVF clinics, greatly contributing to overtreatment of good-prognosis patients (because of their large majority this is a costly proposition) and to undertreatment of poor prognosis patients (even though only a minority, there is still a great expense because their undertreatment leads to treatment failures and the need for additional unnecessary repeat IVF cycles).

During the very early days of IVF, good clinics could be easily differentiated from poorer ones based on their clinical pregnancy rates. People would turn to these clinics because they heard they had achieved pregnancies in older women or helped with other difficult cases. Today, practically every reporting IVF center in the U.S. has the knowledge and technical skills to achieve pregnancy in most good- and average- prognosis patients. Most, however, do not have the required skills (or, frankly, time) to properly treat the socalled poor-prognosis population with the required “precision medicine.”

Our proposal, therefore, is that clinic chains, in principle, concentrate on mostly only good- and average-prognosis patients, while referring poor-prognosis patients to specialized clinics within their networks. If they do not exist, such clinics can be set-up regionally or, if that is not possible, clinic networks could subcontract for such services in local markets in which qualified providers exist. Such a discriminatory system based on prognostic status of patients would reduce average costs for IVF, yet at the same time improve overall IVF outcomes, which in the U.S. steadily increased until 2010, but has since been declining. 25

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REFERENCES 1. Dow K. Med Hist 2019;63(2):189-208 2. Mulkay M. Sci Tech & Hum values 1996;21(2):157-176 3. Haas JM. https://www.usccb.org/issues-and-action/ human-life-and-dignity/reproductive-technology/ begotten-not-made-a-catholic-view-of-reproductive-technology 4. https://www.pbs.org/wgbh/americanexperience/features/ babies-bio-shettles/ 5. Gleicher et al., Lancet 1983;2(8348):508-509 6. https://nyulangone.org/locations/fertility-center?cid=sem_ google&googadcamp=Master_Brand_Performance_ Max&googadgroup=Performance_ Max&googkeyword=&googmatchtype=&insitesid=1370&gad_ source=5&gclid=EAIaIQobChMI877WssymgwMV7lxHAR2IqgK iEAAYAiAAEgJRb_D_BwE 7. https://www.bloomberg.com/profile/person/20813491 8. https://www.rmany.com/?utm_source=google&utm_medium=cp c&utm_campaign=Branded+Campaign&gclid=EAIaIQobChMIxf bLi9amgwMVyVFBAh04Sgr7EAAYASAAEgJjdvD_BwE 9. https://www.prnewswire.com/news-releases/rma-of-new-yorkjoins-us-fertility-301890287.html 10. https://www.usfertility.com/about-us-fertility/ 11. https://www.thefreelibrary.com/ Fertility+Networks+RMANJ%2C+IVI+to+Merge-a0481424027 12. https://www.fresenius.com/node/5159 13. https://finance.yahoo.com/news/ivirma-acquire-north-american-074600576. html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2x lLmNvbS8&guce_referrer_sig=AQAAAN25RHM6G4b-xseH7Vx vwT0ohcwOW-CakDXTZGcUciEXnAp8CgFafqrlbAhQlwcJtbF NtvEkexUaJuu7IXS8IL7WPbGFo2SbFOiSEJMAyMDOZuWpT4Su48SssFzyo9EI5fvYAA9oYLedyUPjQkSYqKOs QI-lpUjGZuRZo2SezYO 14. https://www.businesswire.com/news/home/20210618005302/ en/Unified-Women%E2%80%99s-Healthcare-and-CCRMFertility-Establish-Strategic-Partnership 15. Patrizio et al., J Assist Repod Genet 2022;39(2):305-313 16. Blumenthal D. The Commonwealth Fund. https://www.com monwealthfund.org/publications/explainer/2023/nov/private-eq uity-role-health-care#:~:text=Given%20its%20short%2Dterm%20 financial,reduce%20costs%2C%20thus%20improving%20value.

17. Cerullo et al., Harvard Business Revue, March 20, 2023; https://hbr.org/2023/03/ research-what-happens-when-private-equity-firms-buy-hospitals 18. Singh et al., JAMA Health Forum 2022;3(9):e222886 19. Nolte et al., Int J Eviron Res Public Health 2022;19(23):15480 20. Borsa et al., BMJ 2023;382:e075244 21. Kannan et al., JAMA 2023;330(24):2365-2375 22. Patrizio et al., Fertil Steril 2023;120(4 Suppl):E124-E125 (abstract) 23. Morgan Stanley, Press Release. https://www.morganstanley.com/ im/en-us/individual-investor/about-us/newsroom/press-release/ capital-partners-enters-agreement-to-sell-ovation-fertility-to-us-fer tility.html#:~:text=Investment%20funds%20managed%20by%20 Morgan,the%20transaction%20were%20not%20disclosed.

24. Gleicher et al., J Transl Med 2016;14(1):172 25. Gleicher et al., Hum Reprod Open 2019(3):hoz017

BRIEFING: We here summarize the annual FRMC which, after a hiatus due to the pandemic, successfully resumed its annual schedule between December 1-3, 2023.

The Foundation for Reproductive Medicine Conference (FRMC), as the name indicates, is sponsored by the notfor-profit Foundation for Reproductive Medicine (FRM) and co-sponsored by the CHR. Held annually in New York City since 2018, prior to the onset of COVID-19, the FRMC earned a well-deserved worldwide reputation for its unique content, driven by the motto “Think Differently” and by the intent of bringing leading basic reproductive scientists and clinicians together over three days in one single room. The clinicians learn from the scientists about newest discoveries, while the scientists learn from the clinicians about translational practical needs in the infertility field.

lectures by some of the leading voices in this currently highly competitive research area. Expectations are considerable that these models will, finally, allow the discovery of some long overdue answers, such as what allows implantation (or prevents it from happening), and what causes non-chromosomal miscarriages and/or repeated pregnancy loss.

Maybe somewhat surprising, another theme that came up throughout the conference was aging. As a very unusual and seemingly premature aging process in comparison to other organs, it appears that ovarian aging may have

The FRMC began on the first of December, just two days after the city’s traditional Christmas tree lighting ceremony only a few blocks aways from the event’s venue. The conference’s grand return was met with renewed energy from its participants. In contrast to other scientific conferences in reproductive medicine, the FRMC presented a carefully selected speaker faculty, with professionals selected from all over the world. These speakers covered a broad spectrum of subjects, ranging from state-of-the-art science in some of the leading reproductive biology laboratories in the world, to the most important clinical reproductive medicine issues, to the almost revolutionary changes the infertility field is undergoing on a structural and organizational level. As during previous years, several main themes emerged, organically, summarized below.

Research

From stem cell produced embryo models, so-called “synthetic embryos” were one prominent subject of several Continued on page 22

Limor Man giving a presentation on “The importance of insulin-like growth factor 1 (IGF-1) in follicular physiology – an important consideration in using human growth hormone (HGH) in IVF” at the 2023 FRMC

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something to teach us about aging in general. Juan Carlos Izpisua Belmonte, a repeat lecturer at earlier FRMCs when still at the Salk Institute in La Jolla, CA, and now head of the San Diego Division of the Altos Institute of Science, a private company now at the center of worldwide aging research after being backed by unprecedented sums of start-up funds, addressed this subject in detail. Further demonstrating how interrelated biological processes are in different organs, the conference also presented fascinating data pointing toward common denominators between how cancers avoid rejection by the host’s immune system and how the implanting fetus may do the same. Ashley Laughney from Weil Cornell Medicine in New York City, demonstrated in a study just published with her husband, Samuel F. Bakhoum from Sloan Kettering Memorial Hospital in the city, amazing novel computational tools for single cell transcriptomics applied to the study the mechanistic basis for cancer progression,1 which could also be applied to study embryo-endometrial crosstalk during and following implantation. Further expanding on this theme, Bakhoum, in his lecture, reemphasized chromosomal instability and its consequences in establishing immunological tolerance in cancer patients toward their cancers. Presenting only the second time at the FRMC, he not only has recently published several groundbreaking papers in Nature within weeks of each other,1-3 but also has in recent years won almost every important young investigator awards in biological sciences.4 His talk was clearly one of the highlights of the conference when demonstrating how chromosome instability (CIN) in cancer and pregnancy may play similar roles. Failure to fully segregate chromosomes during mitosis fragments the genome into pieces which then are incorporated into “micronuclei,” Bakhoum explained, leading to genetic and epigenetic aberrations that either compromise embryo development (pregnancy failure) or enhance a progenitor cancer cells capacity to survive. Raoul Orvieto, from Tel Aviv University in Israel, within this context reminded everybody about his lab’s previously published observation that embryos often extrude fragments or even complete cells, which his group identifies as chromosomal-abnormal.5

Clinical practice

The topic of aging also came up within discussions of another important genetic issue in reproductive medicine—the clinical utilization of preimplantation genetic testing for aneuploidy (PGT-A) (as readers of the VOICE know, a recurring topic in these pages). There indeed was considerable discussion on this subject during past FRMCs, including a luncheon symposium involving a divergence of opinions.

This year’s conference, however, demonstrated how much opinions have changed since the last FRMC before the COVID-19 pandemic. There exists now almost a consensus that many embryos with non-euploid PGT-A diagnoses can

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safely be transferred and achieve basically normal pregnancy rates. This includes segmental abnormalities and so-called “low-mosaic” embryos (by many labs now defined as up to 50% abnormal DNA in a single trophectoderm biopsy).

At the other end of the past divide, we and others fully recognize that the amount of chromosomal “abnormal” DNA in a single trophectoderm biopsy does matter (CHR, of course, always did). This seems obvious because the more aneuploid DNA will be found in a random trophectoderm biopsy, the more can be on average expected in the complete embryo (and, of course, vice versa).

A divide, however, still exists. The CHR believes that even a 100% aneuploid embryo biopsy in a small percentage of cases can still represent a mosaic embryo, allowing for a normal euploid pregnancy and delivery. Our former opponents, who until recently objected to transfers of any chromosomal abnormality, still object to transfers of embryos reported as “aneuploid,” while the CHR still offers transfer of selected such embryos if patients understand the relatively low chance of ongoing pregnancy with such transfers. Though differences have significantly narrowed toward the CHR’s longstanding positions regarding PGT-A, many IVF clinics, unfortunately, still often refuse to transfer even low-mosaic embryos. Orvieto also pointed out that the shortcomings of PGT-A also apply to so-called noninvasive PGT-A and made the point that his lab’s above noted study was consistent with embryos being able to eliminate abnormal genetic material during self-correction.5 “Add-ons” to IVF fell, in general, under criticism. In contrast, though, individualized care of patients apparently has found new proponents, and highly individualized protocols—now for many years proposed by the CHR—appear to gain support. Within such a context, the CHR’s investigators, in several lectures, presented on the CHR’s drive toward “precision medicine.” (As we have detailed these changes in clinical practice of IVF at the CHR in these pages before, we will here not be repetitive). The changes, of course, primarily involve Highly Individualized Egg Retrieval (HIER) 6 and the distinct approach to diagnosis and treatment of phenotype D (under Rotterdam criteria) PCOS.7

Where the field is moving to

What lies ahead for reproductive medicine is, likely, mostly dependent on what we can further learn about human embryo development. This is demonstrated by several examples. Previously noted likely common denominators between tumor and fetal tolerance by a priori, hostile host immune system. This issue, of course, reemphasizes a point repeatedly made in these pages over many years—namely that reproductive medicine must start taking the maternal immune system more seriously. The CHR’s Norbert Gleicher

presented a lecture in which he argued that pregnancy is not, as widely perceived, an endocrine but an immunological condition. In vitro gametogenesis is a widely pursued concept since, several years ago, Japanese investigators demonstrated a completed cycle of gametogenesis, including multiple generations of healthy pubs in a mouse model. Well described by Eli Y. Adashi (Brown University, Providence, RI), this subject attracted attention not only for its biological intricacies but also regarding profound ethical concerns.

As already noted, the same author also addressed biological as well as ethical aspects regarding the future of germline editing and genetic disease correction in reproductive medicine. Serious ethical and biological concerns were also expressed by several speakers regarding the introduction in the U.S. of clinical IVF of PGT-P (polygenic), the testing of embryos for polygenic conditions (from blue eyes to heart disease to diabetes and other polygenic diseases). Though in Europe it is formally defined as clinically inappropriate and unethical by a major society of geneticists as well as ESHRE and U.S. counterparts, have interestingly remained quiet on the subject. Unsurprisingly, several PGT-laboratories and IVF clinics in the U.S. have started to offer PGT-P as a routine addition to IVF cycles.

David Albertini (Bedford Research Foundation, Bedford, MA and, the CHR, NYC) raised the important question of whether the concept of embryo selection in IVF was still sustainable.

Noting that human embryos at preimplantation stages now are almost universally considered to contain aneuploid cell lineages, such aneuploidy appears to be the norm rather than exception. Whether selection strategies based on genetic or genomic outputs are any longer sustainable, given what we have learned about human embryo biology, therefore, appears questionable. Paolo Rinaudo (University of California, San Francisco, CA) was a principal voice in raising the importance of changes in the methylome of newborns in association with IVF, an issue that in recent months and years has been attracting increasing attention.

Addressing more general concerns, Howard Bauchner, former editor-in-chief of JAMA journals, addressed obvious problems in current medical and scientific publishing. Jared C Robbins, CEO of the ASRM, presented an interesting talk on the status of infertility care in the U.S. and where he (sic., the ASRM) saw things going, considering the rapid changes the field is undergoing in ownership of fertility clinics, and in open physician, embryology, and nursing positions in the fertility field. The latter was also addressed by Pasquale Patrizio (University of Miami School of Medicine, Miami, FL) also pointing out the increasing difficulties academic institutions have when it comes to competing for employees with equity-owned clinic networks.

Continued on page 24

Artificial Intelligence (A.I.), of course, cannot be avoided these days. Marcello O. Magnasco (Rockefeller University, NYC) offered a brilliant description of what A.I. currently can and cannot contribute to the field. Robert Kiltz (CNY Fertility, Buffalo, NY), who built his clinic network on the concept “If you keep it affordable, they will come,” pointed out that in the U.S., fertility services remain largely unaffordable.

The Closing Lecture was given by Antonio Pellicer (dean-emeritus, Medical School of the University of Valencia, Valencia, Spain, now residing in Rome, Italy), one of the two founders of IVI-RMA International, a worldwide IVF clinic network company since 2022 owned by private equity (KKR) after a record sale for at an enterprise value of ca. US $4 billion. In describing how IVI-RMA was built, he, better than anybody else, demonstrated the structural economic future of the infertility field worldwide.

The FRMC of 2023, in summary, brought about the topics of contradictory trends: a strong push towards automation, the utilization of A.I., the standardization of protocols, as well as, in contrast, a strong desire for “precision medicine” and the individualization of care, especially for older patients and other poorer prognosis patients.

Does this mean a split in the possible format of provider clinics into first- and second-tier providers, with mostly younger good- and average-prognosis patients going through a highly automated and protocol-driven, lower-cost first-tier set-up and poorer prognosis patients being assigned to second-tier clinics, where highly individualized “precision medicine” is practiced? Perhaps, because the detail required

Antonio Pellicer giving the Closing Lecture of the FRMC 2023

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for individualized adjustments in IVF cycles for poorer prognosis patients is, simply, not affordable for everybody. For further detail, please also read the article on page 9.

References 1. Li J, Huiscz MJ, Earlie EM, Duran MA, Hong C, et al. Non-cellautonomous cancer progression from chromosomal instability.

Nature 2023;620(7976):1080-1088 2. Ahustinus AS, Al-Rawi D, Dameracharla B, Raviram R, Jones BSCL, et al. Epigenetic dysregulation from chromosomal transit in micro nuclei. Nature 2023;619(7968):176-183 3. Lin YF, Hu Q, Mazzagatti A, Valle-Incián JE, Maurais EG, et al. Miotic clustering of pulverized chromosomes from micronuclei. Nature 2023;618(7967):1041-1048

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4. Bakhoum SF. Targeting the undruggable. Science 2023;380(6640):47 5. Aizer A, Harel-Inbar N, Shani H, Orvieto R. Can expelled cell/ debris from a developing embryo be used for PGT-A? J Ovarian Res 2021;14(1):104 6. Nicholas C, Darmon S, Patrizio P, Albertini DF, Barad DH, Gleicher N. Changing clinical significance of oocyte maturity grades with advancing female age advanced precision medi cine. iScience 2023;26:107308 7. Gleicher N, Darmon S, Patrizion P, Barad DH. Reconsidering the Polycystic Ovary Syndrome. Biomedicines 2022;10:1505

My husband and I like to smoke a joint once in a while. I have told him we have to stop if we want a baby, but he says that is not true. What is true?

Though we do not like to get involved in disagreements among couples, this is a fair question that demands a fair answer. As we have repeatedly pointed out in recent issues of the VOICE, substantial evidence has been accumulating in recent years—especially since cannabis has been legalized in so many states—that today’s cannabis is much more potent than that of your parents’ generation. Consequently, you are likely consuming much more of the psychoactive component of cannabis (called delta9-THC). Indeed, THC does not only affect you and your husband, but also on the baby that you might eventually carry.

THC is one of two so-called Phyto-cannabinoids in cannabis (also called marijuana). The other one is cannabidiol (CBD).

From animal experiments, it has been known for quite some time that brain cells in embryos in utero already have the receptor for THC. Whether this substance, however, affects brain development at such early stages was unknown—until just recently, in an experiment involving a mouse model, where clear evidence was obtained that this is indeed the Continued on page 26

case.1 Ultimately, cannabis use by a pregnant person has been reported to lead to a newborn baby with low birth weight, preterm birth, and an increased chance of admission to the NICU.2 Researchers were also able to determine that many of these negative effects on the baby were due to changes in placental function of mothers who were using cannabis during pregnancy.3 Regarding fertility, cannabis has been shown to cause adverse effects on males in reducing sperm quality as well a quantity.4 In female adolescent mice, cannabis depletes the ovarian reserve (i.e. follicle numbers).5 In short, you should definitely stop using cannabis as far ahead of planning a pregnancy as is possible. Your husband’s smoking is less dangerous to the baby, as long as he stays away from you while he smokes, so you don’t get exposed to second-hand smoke. But you can tell him that if he does continue smoking (especially if he consumes a lot), it may take him longer than usual to get you pregnant.

REFERENCES 1. Verdikt et al., eLife 2023;12:RP88795 2. Avalos et al., Am J Obstet Gynecol 2023; 27:S0002-9378(23)02034-3. doi: 10.1016/j.ajog.2023.11.1232.Online ahead of print.

3. Metz et al., N Engl J Med 2023;330(22):2191-2199 4. Hamed et al., Reprod Biol Endocrinol 2023;21:69 5. Lim et al., Toxicol Sci. 2023;193(1):31-47

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I was told by my gynecologist that it is now possible to test embryos to determine whether they are at risk for diseases like diabetes or heart disease. Is this correct?

Your gynecologist is a little bit right—but a lot more wrong.

They are right in that some laboratories and IVF clinics have started offering what is called polygenic risk scoring (PRS).

This is a technique developed for risk scoring of adults to predict whether they are at increased risk for such diseases as diabetes and heart disease, which are both caused by a constellation of multiple genes. Such risk scores can only be calculated by a full genomic analysis of an individual. Even in adults, this testing is still considered “experimental,” and in embryos, as of this point, it has been declared inappropriate and even unethical (by a European genetics society and ESHRE, as we have previously discussed in these pages).

One U.S. center apparently offers this test to select embryos with blue eyes. The Wall Street Journal, on December 14, 2023, reported that a new startup company in San Francisco, California, called Orchid Biosciences, recently also started offering the test. This means that at least three to four genetic testing labs in in the U.S. are offering PRS. Since this test, like PGT-A, requires an embryo biopsy at blastocyst-stage, it requires IVF treatment. The CHR, for

several reasons that we gladly will explain to couples, currently strongly recommends against using this test, unless you have a strong family history of a life-threatening polygenic disease at relatively young ages. Otherwise, the test is unnecessary and you will spend considerably more on an IVF cycle than you would otherwise, without ever even knowing whether the testing was right or not. What you, however, will have done, especially if you are no longer in your 20s, is reduce your chances of conceiving during your IVF cycle. So, not a good idea, in our opinion!

REFERENCE 1. Gormley B. The Wall Street Journal, December 23, 2023. https://www. wsj.com/articles/startup-orchid-rolls-out-genetic-testing-service-forivf-raises-12-million-8c0753ad

Our family is complete, but we have four embryos left and don’t know what to do with them. Can you help?

This is not an infrequent question we receive from patients who have extra embryos left from IVF after achieving their desired number of children. We can indeed help you decide what you want to do with your extra embryos, but this is a very personal choice only you and your partner can make.

Everybody who goes through IVF is usually asked to sign a written consent which, among many other important issues, addresses what patients want to happen to all embryos the cycle generates. In principle, there always are six potential options: (i) have the embryos transferred into your own uterus; (ii) have the embryos transferred into somebody else’s uterus, usually a so-called gestational carrier; (iii) have the embryos cryopreserved for future use, either by yourself or for other purposes; (iv) donate the embryos anonymously or openly (called a “directed” donation) to another infertile patient; (v) donate the embryos to research (not all IVF clinics can offer this option because they may not have research programs and/ or the necessary ethical supervision required for such a process); and (vi) instruct the clinic to ethically dispose of your embryos.

Faced with these options, most patients will first use their embryos to build their own families. Most infertile patients will not have too many embryos left over; the more likely problem is not having enough. To have “leftover” embryos is, therefore, in many ways a lucky problem to have, even though it can certainly lead to a difficult decision-making process (as is carefully detailed in a recent Wall Street Journal article1).

As a very active research center that also collaborates with several prominent research laboratories at universities in the U.S. and elsewhere, we at the CHR are always interested in receiving “leftover” embryos for research purposes. Because many IVF clinics do not have research programs and, therefore, do not have the administrative ability to dispense such embryos

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birth, they would be given the opportunity to meet the child.

The CHR does not accept embryos for anonymous donation to other patients with such conditions attached; the reason is not a lack of understanding the desire of donors to have contact, but the CHR’s inability to guarantee such access at later points. The CHR, therefore, accepts donation of embryos only if they are unconditional for the designated purpose.

As noted before, we welcome inquiries about embryo donations whatever the purpose. Please call the CHR at 1 (212) 994 4400 and tell our staff that you would like a free consultation with a CHR physician to discuss a possible embryo donation, either for clinical use in other infertile patients or for research purposes.

REFERENCE 1. Dockser Marcus A. Wall Street Journal, December 26, 2023; https://www.wsj.com/lifestyle/relationships/ adoption-invitro-foster-care-surrogacy-17400499.

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An 8-cell human embryo

according to accepted ethical and research requirements to IRB-approved research studies, the CHR quite frequently receives inquiries from patients at other IVF centers who are considering donating their embryos, which we very much welcome. The CHR, indeed, offers a free consultation with one of our physicians whenever there is a patient who might wish to donate their leftover embryos—either to research or, anonymously, to another infertile patient.

For three very distinct reasons, such consultations with physicians are very important. First, the gravity of this decision warrants a detailed reappraisal of available options with patients, reemphasizing all available choices to them all over again, even though they likely heard those before. Second, we feel ethically obliged to discuss the chance of later regrets.

Third, not all embryos are suited for donation and, therefore, not all embryos can be accepted for such a purpose, though any such deselection is not necessarily indicative of poor embryo quality.

Finally, the most sensitive personal as well as ethical decision is, likely, the anonymous donation of embryos to another infertile couple. The decision that such a donation may lead to delivery of a child, of course, means that the couple has another genetic child who will be raised by other parents.

Such a circumstance can be difficult to imagine for many potential donors and, as the Journal article demonstrated, in selected cases some couples might insist that should there be

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For further information, please contact: Ms. Alexandra Rata (212) 994-4400 or e-mail to arata@thechr.com

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BRIEFING • Attempting to offer a teachable moment, we on a monthly basis present in this section of the VOICE an anonymized case report from the files of the CHR. •

The here presented case involves a 44-year-old woman who presented to the CHR after she had failed 6 IVF cycles at three different IVF centers with a principal diagnosis of advanced age and secondary “unexplained” infertility of over 3 years.

•

This case is presented to point out how differently the CHR approaches IVF in older women, as compared to most other IVF centers.

•

We, moreover, offer special emphasis on the CHR-developed early retrieval method, given the acronym HIER. __________________________________________________________________

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 this case report, among other subjects, addresses androgen supplementation with DHEA, readers are advised that expressed opinions in this paragraph, therefore, may be accordingly biased. __________________________________________________________________

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Case-presentation A 44-, almost 45-year-old G3P1 presented to the CHR with the desire to have a second child. She reported an uneventful pregnancy and vaginal delivery of a normal female (now five years old) following spontaneous conception. Expecting once again an uncomplicated conception, the couple at female age 41 reinitiated attempts to conceive.

After an unsuccessful six months, they consulted with their gynecologist, who recommended that they continue with their attempts for up to another six months. With the female at age 42, six months later they consulted locally for the first time with a fertility center.

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There they underwent a basic infertility evaluation, which was reported to them as negative in its findings, and they were advised that their difficulty in conceiving was likely due to the female’s advanced age. Her FSH at that point was 9.2 mIU/mL and her AMH was 0.6ng/mL. They were presented with three treatment options: (i) oral fertility drugs and intrauterine inseminations (IUIs), (ii) in vitro fertilization (IVF) under gonadotropin stimulation, and (iii) third party egg-donation. They chose IUIs and were started in a letrozole/IUI cycle, which yielded only one follicle and did not result in pregnancy. Because of the resistance to stimulation the female demonstrated in that cycle, the clinic’s treatment recommendation at that point changed to egg donation, a recommendation the couple did not wish to pursue. Consequently, the clinic and patients agreed to pursue IVF with use of autologous oocytes.

The couple thus pursued two consecutive IVF cycles at the same clinic, utilizing a routine antagonist protocol with 300 and 450 IU, respectively, of pure FSH stimulation daily, which yielded two and three oocytes, respectively. In both cycles, two oocytes fertilized but embryos arrested after days 2 and 3 with the intent having been culture to blastocyst and PGT-A of embryos. The couple decided to switch to an IVF clinic in another city, which in an initial consultation agreed with the original center’s diagnoses but recommended mild ovarian stimulation (“mini-IVF”). The couple again underwent two consecutive cycles with such stimulation, resulting in one cycle that yielded zero eggs at retrieval and a second cycle that yielded two oocytes. One of these oocytes fertilized but arrested on the way to blastocyst-stage and PGT-A, leaving the couple, once again, short of an embryo transfer. At that point, once again, they changed IVF clinics. The third clinic also recommended egg-donation but the coupe again rejected the idea and, instead, pursued two more autologous IVF cycles, this time utilizing a short micro-agonist protocol. This time four and three oocytes, respectively, were retrieved and one embryo reached day-6 blastocyst-stage and was cryopreserved. Because the couple objected, the embryo was not sent for PGT-A as had been intended. Why the embryo was not transferred fresh under those circumstances was unclear when the couple presented to the CHR for a second opinion consultation.

CHR’s diagnoses, conclusions, and offered options Reviewing the couple’s past treatment history and laboratory results, the CHR’s diagnostic assessment of this couple differed from their prior assessments, starting with the assessment by their general gynecologist, who, in the CHR’s opinion, gave the couple an incorrect recommendation when advising them to continue trying to conceive on their own for another six months, when the female by that point was already over age 41. She already at that point should have been referred into fertility treatment. The CHR also disagreed with the opinion that the couple’s infertility was basically “unexplained,” except for the obviously advanced age of the female.

Though the female’s advanced age was, of course, relevant, based on her age-specific functional ovarian reserve (FSH 9.2 mIU/mL and AMH 0.6ng/mL), her correct diagnoses should have included a diagnosis of premature ovarian aging (POA). Looking at her FSH and AMH values age-appropriate, one must conclude that her FSH was abnormally high and her AMH abnormally low for age, unquestionably supporting a diagnosis of POA. This is important because a POA diagnosis is in virtually 100% of cases is also linked to hypoandrogenism, which is closely linked to infertility and requires androgen pre-supplementation for at least 6-8 weeks before the IVF cycle starts, if patients are to have a good pregnancy chance with IVF.1 None of the three fertility centers this couple attended before presenting to the CHR, however, even investigated her androgen levels. Unsurprisingly, she did demonstrate low testosterone (both free and total) and high sex hormone binding globulin (SHBG), once tested at the CHR. Her FSH value by that point was 10.4mIU/mL and her AMH was 0.3ng/mL. Making or not making such a diagnosis in a timely fashion has additional consequences beyond just androgen supplementation, in that it also affects the CHR’s choice of ovarian stimulation protocol, the timing of the patient’s ovulation trigger (see further discussion of HIER below),2,3 the decision of whether embryos should be transferred at cleavage-stage (usually day 3) or grown to blastocyst-stage (days 5-7) and, finally, also how oocytes and embryos are assessed and treated in the embryology laboratory.4,5 Upon completion of a thorough diagnostic workup, the CHR’s assessment of this couple at presentation, therefore, was quite different from the assessments of their prior three IVF clinics. This was communicated to the couple by explaining that, though their chances would have been significantly better had they presented to the CHR already at female age 41 (rather than 44), they still appeared to have a reasonable chance of pregnancy and live birth with autologous oocytes once the female’s

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ovaries were properly pretreated prior to and during an IVF cycle, she received a different ovarian stimulation protocol with early retrieval (HIER), and fresh day-3 embryo transfer with no use of PGT-A. They also had the option of transferring in a next step their single, by PGT-A untested, blastocyst in a frozen-thawed cycle. Though the CHR was aware that they were uninterested in third-party egg donation (that was, indeed, the principal reason why they had contacted the CHR from out of town for a second opinion consultation), they were also once more advised that egg donation would offer much higher pregnancy and live birth chances. The couple decided to proceed with another fresh IVF cycle—their seventh overall.

Treatment and outcome Women at age 44 practically uniformly receive two treatments at the CHR. (i) Because such women, as already noted above, virtually always are hypo-androgenic, they receive androgen supplementation with a usual starting dose of 25mg TID DHEA for at least six weeks prior to IVF cycle start. (ii) They have early egg retrievals (HIER), with lead follicle sizes for double-trigger timing in a first IVF cycle, in principle, being determined by patient age [see Box A]. Based on a detailed prior cycle review, if a patient does not conceive in her first cycle, trigger timing is frequently adjusted; in 9/10 cases, adjustments are made toward earlier retrievals. Patients are also pre-supplemented with CoQ10 (preferably a ubiquinol product), 600 mg/day.

BOX A: Lead follicle size at early timing of double ovulation trigger based on female age (HIER)* AGE (years) <40 40 – 43 43 – 45 >45

LEAD FOLLICLE SIZE (mm) 18-23 15-16 12-14 9-11

*Those age-based baseline recommendation are often adjusted down in lead follicle size depending on the patient’s functional ovarian reserve and prior cycle experience.

Much more rarely, older women and younger POA patients are also pre-supplemented with human growth hormone (HGH), but this treatment is given at CHR only if the patient demonstrates low levels of insulin-like growth factor I (IGF-I), and that was not the case with this patient.

Her first IVF cycle was stimulated with 300IU of pure FSH and 150IU of AMH, and hMG product daily. Because, based on HIER, there was no concern of premature spontaneous ovulation, she required neither agonist nor antagonist treatment to prevent ovulation. Stimulation was, therefore, started on cycle day 2 without either. Based on her age, her trigger was set at 12-14mm lead follicle size. Eight oocytes were retrieved, 4 MIIs, 3 MIs, and 1 GV. MIIs demonstrated wide perivitelline spaces (PVSs, a sign of over-maturity). MIs and GVs underwent overnight in vitro maturation, with two M1s advancing to MIIs and being fertilized. Three embryos made it to cleavage-stage (d-3) and were transferred fresh. The patient did not conceive.

She restarted, back-to-back, a second cycle under exactly the same protocol, except for a one-day earlier egg retrieval. This conclusion was reached based on several observations during the analysis of her failed cycle: (i) That cycle had been triggered, with her two largest follicles being 16 and 15mm, respectively. Her planned trigger timing, therefore, was overshot by at least 2mm.

This had happened because her follicles demonstrated an unusual jump in sized over the last 24 hours before trigger, going from lead follicle sizes 11mm and 12mm to 15mm and 16mm. Unusually large jumps in follicle size are a sign of metabolic insufficiency of follicles and often accompanied by significant progesterone rises. (ii) Such a rise in progesterone was, indeed, also observed on day of trigger, with both of these observations post-factum being obvious, but unpredictable on the day before trigger. (iii) As previously noted, the patient’s oocytes’ wide PVSs also suggested post-maturity. The patient’s trigger for her second cycle, therefore, was set for no larger follicle size than 12mm, where her follicles had been on the day before she received her trigger shots.

Her second cycle yielded nine oocytes, again 4 MIIs, 2 MIs and 3 GVs. The MIIs looked much better than in her first cycle, both MIs matured overnight and were successfully fertilized, as was 1 GV oocyte. She again had a day-3 transfer of three embryos, while two embryos were cryopreserved. She conceived and delivered a healthy female child by Cesarean section.

Conclusions This case report in many ways represents the “typical” CHR patient: she was older (age 44), suffered from mild to moderate (undiagnosed and untreated) POA, had undergone multiple failed IVF cycles at multiple IVF centers (in six cycles produced only one transferrable embryo), and was advised by several IVF clinics that her only realistic chance of pregnancy was through third-party egg donation.

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The case also demonstrates the logic and clinical application of HIER, which at times requires adjustments after failed cycles based on a detailed post-factum “autopsy” of those failed cycles.

The CHR, through this case presentation, in no way wishes to imply that every patient with such (or a similar) history, under the CHR-developed protocols, will conceive and deliver. Very much to the contrary: pregnancies and deliveries in such highly adversely selected patients, even with proper diagnoses, preparation of ovaries, and HIER, will be relatively rare (and the CHR, therefore, is working hard on improving current protocols further). But this case demonstrates well that, for patients for whom egg donation is not an acceptable option, alternative options exist.

Finally, this case also demonstrates how important accurate diagnosis is. Had this patient sought out care at the CHR when she first approached a fertility clinic at age 41, treatment would have been much less complicated, and it is reasonable to assume she would have conceived and delivered much earlier. But let us not forget, this couple still has two embryos cryopreserved!

REFERENCES 1. Gleicher et al., Hum Reprod 2013;28(4):1084-1091 2. Wu et al., J Endocrinol 2015;226(3):167-180 3. Wu et al., J ovarian Res 2018;11(1):23 4. Lazzaroni-Tealdi et al., PLoS One 2015;10(12):e0143632 5. Nicholas et al., iScience 2023; PMID: 37539038

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The opinions expressed in this column belong solely to Dr. Norbert Gleicher, MD, and do not necessarily reflect the values of the Center for Human Reproduction. As always, the VOICE welcomes comments, even from those who don’t share the author’s opinions.

Some years are easier than others to leave behind. Only few among us will, therefore, likely miss the year 2023, and most hope for a much better 2024. What a horrible year has it been, leaving us almost without positive memories. But positive moments usually exist even in worst of times—even if only because something worse has been successfully avoided.

We have come close many times: On the medical side COVID— now an endemic seasonally expected wave of infection like influenza, could have become endemic not only as a highly infectious but also as a continuously morbid strain of the SARS-CoV-2 virus.

Though some hospitals have reinstituted mask mandates because of this year’s triple threat during “flu-season” from COVID, influenza, and the respiratory syncytial virus (RSV), nobody is talking about general mandates of any kind, nor will indoor gatherings be restricted and we, therefore, will not have to freeze in temporary makeshift outdoor contraptions at restaurants. Which raises the question, why are there still so many of these around in NYC? Mr. Mayor, please take down at least the ugliest ones!

Good news is also that there are no more vaccination mandates (though older and immune-compromised citizens should be re-vaccinated against COVID, the flu, and RSV). Hopefully that also means that nobody will lose their job simply for not being vaccinated. Even our military is apparently offering to take back soldiers who were previously discharged because they had refused anti-COVID vaccines. Our government finally recognized that sacrificing one’s life for the country is more important than whether soldiers get anti-COVID vaccines or not.

How the nation’s youth currently feel about this country—or about defending the country—is, however, not great news, as recruiting soldiers into the military has become a tough challenge.1 Why that is has remained controversial but an explanation one increasingly hears is that since World War II the U.S. military has not won even a single war (and there were plenty of those!).

And then, of course, came the horrific withdrawal of U.S. troops from Afghanistan, the pictures of which on TV even the most Continued on page 34

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“creative” explanations by our government could not erase.

Combined with the loss of life the U.S. military suffered during the chaotic withdrawal, one can hardly think about a more persuasive scenario for dissuading our youth from signing up as new recruits.

Maybe a little more creativity could help. The French, for example, never have had a problem in recruiting internationally to fill the jobs in their elite French Foreign Legion. With millions of military-age males welcomed into our country over the last three years, how difficult can it be to recruit among them a few hundred thousand good potential fighters? Media reports, indeed, suggest that some may already have received military training before being sent by their security services to cross our “well-secured” Southern border to take residency in the U.S. Harvard’s (and other universities’) student organizations have for months now tried to make us aware what wonderful people Hamas fighters are. Many U.S. universities and colleges undoubtedly would welcome them warmly from the river (maybe the Mississippi) to both seas (Atlantic and Pacific Oceans). Their talent in building deep under- ground tunnel systems could also be put to work: Imagine if pro-Hamas demonstrators could, at Christmas tree lightings or New Year celebrations in Time Square, just pop up from such systems without any warning for New York’s Finest.

Considering how well The University of Pennsylvania helped to organize the Palestine Writes Literature Festival last September, just a few days before October 7, by not allowing prior accusations of outrageous antisemitism to derail this important event,

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the university would, likely, be equally successful in organizing a similar academic conference for Hamas and Hezbollah recruits. Though obviously part of Palestine literature, their specific contribution may, indeed, be even more fascinating in its radicalism than the literature presented by the university in its “festival.”

Russia could also possibly teach the Pentagon how to do better in recruiting new soldiers. Like approximately two years ago so astutely suggested by President Biden to Russia’s President Putin, the latter should have initiated only a “small invasion” into Ukraine.3 But, no, he insisted on knowing better than our president and went all-in with his army. When things didn’t go as expected and large numbers of Russian soldiers were killed and wounded, the army had an urgent need for new recruits. As not many volunteers came forward, the army started recruiting the country’s prisoners, in the process, as a side-benefit, emptying their prisons.

This seems like a more cost-effective way to empty prisons than what our country is currently pursuing. Just in December, the outgoing governor of Louisiana, John Bell Edwards, announced the pardon of not less than 40 murderers.4 Convincing them to join the army in return for getting out of jail, might have been a much more cost-effective solution. And on a side note, if we let even murderers go free, what is really the purpose of putting anybody else into jail? We may as well, consider closing-down all jails in the country.

Moving on, consider how bad the economy has been, with everybody predicting a recession after the Federal Reserve had

A P I EC E O F M Y M I N D to raise interest rates to fight inflation. And now the stock market is booming, and everybody is, suddenly, convinced that there will be a “soft landing.” The question is—for whom? Certainly not for our children and grandchildren after the nation in 2023 added over 10% to our national debt that now exceeds $33 trillion and by 2026 is expected to reach $41 trillion.4 And the really bizarre thing is that pretty much the same crowd that got us into these horrendous budget troubles by overspending our children’s’ and grandchildren’s’ money is now running this year again for reelection.

For those who have not yet noticed, 2023 was characterized by truly unprecedented decision making. Who could, indeed, have imagined that our country as of this point would be led by a cognitively and physically impaired president? But, if that isn’t already strange enough, it is beyond credulity that he is running for another four-year term, practically unopposed in his party. At the same time, his likely opponent in the general election is the president who preceded him and lost his bid for reelection to the current president, who’s cognitive and physical limitations at the time were already obvious (though not as obvious as they have become since).

And yet, a majority of the country went for the new guy and did so for only one reason: Even though most U.S. citizens probably liked many of his policies, they simply did not like the personality of the sitting president!

And, amazingly, this has not changed. Based on a January 9, 2024, poll, according to The Wall Street Journal, he is rated unfavorably by a majority of Americans.5 As things stand right now, it looks like the country in November will face the same choice as four years earlier between a by age cognitively and physically impaired and a widely disliked candidate. And how extreme would that be for any country in the world, and we are not just any country—we are the U.S.!

As the at times tongue-and-cheek tone of this commentary attempts to reflect, the year 2023—in many different circumstances, and at many different levels—crossed previously unimaginable borders of behavior by individuals as well as governments. The practical consequences were breakdowns in what was considered normative behavior at local as well as international levels. It, therefore, is not surprising that a surprising number of this country’s youths no longer only hold opposing protests but consider themselves entitled to rob stores, to protest in support of Hamas murderers and depraved rapists, and consider this country no longer worth defending. It should not surprise that the presidents of three leading universities in unison did not unequivocally consider antisemitism among their student bodies and faculties to be breaches of university policies, and that in Ukraine and, especially in Israel, we have seen atrocities which the world, for many decades, has no longer considered possible.

It all to a large degree comes down to education at international and local levels: What the United Nations Relief and Continued on page 36

Works Agency for Palestine Refugees in the Near East (UNWRA) for decades has been teaching in Gaza (and elsewhere in the Middle East), can be directly linked to the unprecedented inhumanity of Hamas on October 7, 2023 and is now, finally, subject of a congressional investigation.7 And what America’s premier institutions of higher learning now, for decades, have been teaching students, has led them in many instances to openly support those atrocities to astonishing degrees.

Harvard and UNWRA, of course, are very different organizations, but the consequences of their teachings are basically the same and create self-fulfilling consequences. In academia, they lead to the selection of unqualified students, appointments of unqualified faculty and, ultimately, to unqualified leadership, as Harvard, MIT, and the University of Pennsylvania, all three among the world’s most accomplished universities, in the recent congressional hearing unfortunately made obvious, - for the whole world to see.

At the time this communication is written, it was just announced that Harvard’s president, Claudine Gay, PhD, had resigned. I, in a way, feel pity for what she had to go through, though not for the victimhood she clad herself in for an Op-ed in The New York Times.8 Her real victimhood does not lie in the accusation that her scholarly oeuvre of a dozen publications of minor importance likely never warranted even an academic appointment as a full professor nor in the fact that even this minimal oeuvre was heavily plagiarized. Nor lies her victimhood in being accused of antisemitism because of her non-response to obviously recent antisemitic transgressions of students and faculty at Harvard.

Her real victimhood lies in her own Ivy League education which taught her to ignore meritocracy and, instead, to concentrate on equity of outcome.

“HARVARD AND UNWRA, OF COURSE, ARE VERY DIFFERENT ORGANIZATIONS, BUT THE CONSEQUENCES OF THEIR TEACHINGS ARE BASICALLY THE SAME AND CREATE SELF-FULFILLING CONSEQUENCES.” The voice | 35

Continued from page 35

A P I EC E O F M Y M I N D Since mankind is biologically blessed by extreme heterogeneity, to believe in societal equity of outcome is as illogical as the long-held believe in medicine (which I was taught in medical school) that every gene in every human body has one and the same function—or that every medication will have the same benefits and side effects in everybody. Fortunately, nothing in nature is the same in every organism, so equity of outcome is not only unfair but is also rejected by evolution and, therefore, the universe’s likely most basic law of nature.

Harvard University’s immediate past President, Claudine Gay, PhD Equity of outcome, of course, significantly differs from equality of opportunity, with the former as a societal goal not only being unachievable but appearing to be outright unfair. Why shouldn’t, for example, harder work be rewarded? Equality of opportunity, in contrast—though on a practical level, also hardly achievable—not only appears to be a much fairer proposition but at least mandates a similar starting point in life, which returns the discussion to the two principal points this communication attempted to make: (i) Our nation needs better education opportunities for everybody and (ii) our society cannot prosper without meritocracy.

REFERENCES 1. Serbu J. Federal News Network. October 4, 2023. https://federalnewsnetwork.com/army/2023/10/ army-plans-major-changes-to-recruiting-after-falling-short-of-2023goals/ 2. Fortinsky S. November 8, 2023; https://thehill.com/homenews/ campaign/4301065-scott-sleeper-terrorist-cells-america/ 3. Liptak K. CNN.. January 19, 2022. https://www.cnn.com/2022/01/19/pol itics/russia-ukraine-joe-biden-news-conference/index.html 4. Severi M. Washington Examiner, December 23, 2023. https://gazette. com/news/wex/outgoing-louisiana-governor-pardons-40-murder ers-in-attempt-to-reduce-prison-population/article_230a15f3-8c495d3f-8c94-adef27331516.html#:~:text=Gov.,out%20of%20office%20 next%20month.

5. The Wall Street Journal. January 9, 2024; https://projects.fivethirtye ight.com/polls/favorability/donald-trump/ 6. US Debt Clock. https://www.usdebtclock.org/ 7. Sabes A. Fox News. December 23, 2023. https://www.foxnews.com/ politics/house-committee-launch-investigation-un-agency-al leged-troubling-connection-hamas 8. Gay C. The New York Times. January 3, 2024; https://www.nytimes. com/2024/01/03/opinion/claudine-gay-harvard-president.html

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T

THE IMPORTANCE OF FOOD FOR

BRIEFING: Nutrition is of crucial importance for both our physical and mental wellbeing. In this monthly food section, we discuss everything related to food and food supplements that we consider of interest (don’t worry—there will be no recipes!), from recommended and not recommended foods, to restaurants we recommend to our patients who visit New York and, yes, sometimes also very brief restaurant reviews. Over 60% of our patients travel to the CHR from outside the larger tri-state area and, often, from outside the U.S., so we feel they may benefit from this information. As in other sections of the VOICE, we welcome comments and suggestions, which are to be sent to jbeebe@thechr.com.

Should you and your partner change your diet when planning on conceiving?

“Should we change our diet, now that we are trying to conceive?” is, likely, one of the most frequently asked questions heard in fertility centers. And while there is no one right answer to this question, here are a few possible answers under several different conditions.

Nutrition is, of course, beyond important for our existence—it is essential! But there is relatively little evidence that nutrition makes much of a difference in conceiving spontaneously or conceiving through infertility treatments. The conversation on this subject, nevertheless, never ends. Here is a brief summary of how the CHR usually answers the question.

We emphasize the importance of balanced diets, with some recent literature pointing toward the Mediterranean diet as potentially beneficial for couple trying to conceive.1 While a very recent systematic review found very little evidence for a benefit of such a diet on female fertility, the study suggested that it may improve Continued on page 38

sperm (i.e., male fertility).2 Other fertility experts recommend to their patient almost the opposite—a high-fat and meat and low-carbohydrate diet.

The truth is that good studies on this topic do not exist. We suspect that whatever effects nutrition has on fertility may be indirect. What we mean by this is the following: As often noted in the VOICE, fertility providers do not like it when their patients demonstrate so-called inflammatory markers. In other words, we do not like inflammation, whatever the cause, whether it means autoimmunity, outright inflammation, or even simple allergies. (It is also important to remember that endometriosis and adenomyosis are inflammatory conditions).

Whenever we detect evidence of inflammation in laboratory findings, or whenever a patient arrives at the CHR with a fitting medical history, we do recommend an anti-inflammatory diet, meaning abstinence from all gluten, dairy, and sugar. We have seen quite astonishing improvements in levels of inflammation in women with endometriosis who have pursued such a diet. But without laboratory findings, and/or appropriate symptoms, we do

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Continued from page 37

not recommend diet changes beyond a balanced diet. There is one exception: if patients experience repeatedly gastrointestinal or other symptoms after specific food, we recommend patients abstain from these foods while attempting pregnancy.

The reason is that such symptoms (like bloating, excessive flatus, abdominal cramps, diarrhea, and brain fog) often suggest that the relevant food item may be inflammatory to the patient.

REFERENCES 1. https://www.unisa.edu.au/media-centre/ Releases/2022/amediterranean-diet-not-only-boosts-health--but-al so-improves-fertility/ 2. Muffone et al., Nut Rev 2023;81(7):775-789

The CHR’s current favorite restaurants in NYC

All listed restaurants are in Manhattan, unless otherwise noted. Like all opinions about restaurants, ours are subjective and are to be understood as such. If you visit one of them, let us know whether you agree with our ratings. We value your feedback.

HOW WE RATE PRICES $ Inexpensive or Not worth a trip $$ Moderately expensive $$$ Expensive $$$$ Very expensive SPECIAL COMMENTS + ………. Overall favorite restaurant in NYC v ……….. Special vibe M ………. Michelin-starred FOOD QUALITY • Good •• Very good ••• Excellent •••• Uniquely delicious

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TABLE: The CHR’s favorite NYC restaurants AUSTRIAN Koloman +/•••/$$/v Wallsé +/•••/$$/v/*

16 W 29th Street 344 W 11th St

(212) 790-8970 (212) 352-2300

42 East Broadway

(212) 966-6002

121 Hudson St., Tribeca 324E 57th Street

(212) 965 9500 (212) 751 9030

FRENCH Le Gratin ••/$$ Le Charlot +/•• /SS Le B •••/$$$ Le Bernadine +/••••/$$$$/ MMM

5 Beekman St. 19 E 69th St. 283 W 12th St 155 W 51st St

(212) 597-9020 (212) 794-6419 (212) 675-2808 (212) 554-1119

GREEC Elias Corner (Queens) ••/$

24-02 31st St.

(718) 932-1510

HAMBURGER Jackson Hole Burgers (the “original”) +/••/$

232 E 64th St.

(212) 371-7187

Elio’s +/•••/$$/v Principe ••/$$/v Avena •••/$$$$ Sistina •••/$$$

376 West Broadway 781 5th Avenue 1621 2nd Ave. 50 West Broadway 22 E 69th St. 24 E 81st St.

(212) 343 0999 (212) 753-5566 (212) 772-2242 (212) 335-0509 (646) 596-8447 (212) 861-7660

JAPANESE SUSHI Sushi Ann +/••• /$$$$

8 E 51st St.

(212) 755-1780

JAPANESE GENERAL Sakagura +/•••/$$ Yakitori Torishin +/+++/$$$

211 E 43rd St. 362 West 53rd Street

(212) 953-7253 (212) 757 0108

KOREAN Jungsik •••/$$$$/ MM Oiji Mi +/•••/$$/v / M

2 Harrison St. 17 W. 19th St.

(212) 219-0900 (212) 256-1259

MIDDLE EASTERN/ISRAELI Dagon ••/$$

2454 Broadway

(212) 873 2466

NEW YORK JEWISH DELI P. J. Bernstein’s Deli •/$

1215 3rd Avenue

(212) 879-0914

PERUVIAN Mission Ceviche •••/$$

1400 2nd Avenue

(212) 650-0014

PIZZA San Matteo Pizzeria e Cuccina ••/$

1559 2nd Avenue

(212) 861-2434

POLISH Karczma (Brooklyn) +/•/$

136 Greenpoint Avenue

(718) 349-1744

UKRAINIAN/RUSSIAN Caviar Russe +/••••/$$$$/ M Russian Samovar •/$/v

538 Madison Avenue 256 West 56th St.

(212) 980-5908 (212) 757 0168

CHINESE Hwa Yuan Szechuan +/•••/$$/v Mr. Chow Downtown/Uptown +/••/$$$/v

ITALIAN Cipriani Downtown/Uptown +/••/$$/v

The voice | 39

The VOICE, in this section of the newsletter, offers commentary on a broad survey of recent articles in the English literature that 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 a good number of U.S. patents. Such research has also propelled the CHR to its current status as a worldwide center of last resort for infertile patients who have failed with treatments elsewhere. This section of the VOICE demonstrates and makes public the way the CHR has been following and interpreting the published literature, a process always at the very core of how research and clinical practice have evolved at the center.

Primarily directed at physicians and basic scientists, this section of the VOICE has, to our surprise, also attracted many of the CHR’s patients. The VOICE, therefore, strives through its writing style to make this section also accessible and understandable for a general audience.

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resolute condemnations, hold perpetrators accountable, and implement decisive actions to release all hostages and eradicate GBV.

From THE LANCET: ”Victims of gender-based violence (GBV) on October 7 must be given a voice.”

We could not agree more and, therefore, are calling especially upon all our professional societies to speak up. Better late than never!

Humanity

Under the above noted headline, Mathew Ari Fox and Tamara Kolitz—both physicians in Israel—published a brief correspondence article on December 16, 2023, in The Lancet. As the headline well represents the core message, we here concentrate on one paragraph of the letter that we consider highly pertinent, considering the deafening silence of professional societies and medical journals in our main specialty of obstetrics and gynecology (and all its sub-specialties, including reproductive endocrinology and infertility) regarding the occurrences of October 7. After all, our professional societies always claim to represent and support women.

The two authors wrote:1 “We call upon medical societies, journals, and governing bodies to take a clear moral stance by vocally condemning the GBV atrocities perpetrated by Hamas on Oct 7, 2023.

We must vehemently reject repetition of the legacy of silent bystanders complicit in the Holocaust. The global medical community must issue

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REFERENCE 1. Fox MA, Kolitz T. Lancet. 2023;402(10419),2290-2291

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General medicine

Interesting new information about our brain A recent review in the JCEM reminded us how pulsatile secretion of GnRH is essential for activating and maintaining the hypothalamic-pituitary-gonadal axis and, therefore, puberty and fertility.

The review also informed on recent studies demonstrating that the neurons in brain that produce GnRH also control postnatal brain maturation, odor discrimination, and, most importantly, adult cognition. Pulsatile GnRH may, therefore, have therapeutic potential in cognitive disorders in the elderly.1

News has also been announced regarding the science behind short naps. An article in Scientific America by contributing editor Lydia Denworth pointed out that short naps can really help our minds. As she noted, naps as short as 10 minutes, around midday, can improve memory and various types of thinking.2 So sleep well, even if just for 10 minutes!

In his often very interesting weekly “Impact Factor” article on Medscape, F. Perry Wilson, MD of the Yale School of Medicine recently commented on a brain study of a small number of comatose dying patients with minimal brain activity—who demonstrated a short and surprising spike of brain activity moments before death.3 Their brains, in these short moments, acted as if they had a conscious experience, not too dissimilar from brain activity seen during dreaming. Well-structured power spikes were seen in the somatosensory cortex and the dorsolateral prefrontal cortex, both areas associated with conscious experiences, about five minutes before death. What immediately comes to mind when absorbing all of this are, of course, the widely reported near-death experiences so much has been written about.

REFERENCES 1. Prévot et al., JCEM 2023:108:2747-2758 2. Denworth L. Scientific America 2023; December 2023; p77 3. Wilson F., Medscape 2023; https://www.medscape.com/ viewarticle/991370?form=fpf#vp_2

More on Vitamin D Among experts as well as lay people, opinions on vitamin supplementation in healthy individuals vary greatly, from those who opine that vitamins are useless to those who swallow supplements by the fistful. Christie Aschwanden recently published an excellent article in Scientific America under the title “The Rise and Fall of Vitamin D,” reaching the conclusion that “worries about widespread vitamin D deficiencies and claims of several health benefits are overblown.”

We agree in principle, though with the caveat that individuals with profound vitamin D deficiency do exist and probably should be supplemented. We studied vitamin D in 2017 in women with low functional ovarian reserve at the CHR and found no association between ovarian reserve and the vitamin’s blood levels.2 This, of course, does not mean that low vitamin D levels may not influence female and/or male fertility in other ways—but, in principle, we feel that Aschwanden is correct and the need for vitamin D supplementation is overblown.

That vitamin D supplementation may be necessary in some patients, though, was an idea recently demonstrated in a reviewed and revised preprint after peer review in eLIfe.3 One group of individuals whose vitamin D levels may be of importance, for instance, are patients with inflammation. This recent paper now reported that the vitamin constrains inflammation by modulating the expression of key genes on chromosome 17 at q-21.1. Since inflammation is a common finding in infertile women, and many REIs (at the CHR included) do not like inflammation in women who are trying to conceive, one can conclude that infertile women with low vitamin D levels should be supplemented.

Continued on page 42

REFERENCES 1. Aschwanded C. Scientific America, January 2024pp26-35 2. Shapiro et al., Fertil Steril 2018;110(4):761-766 3. Kiliç et al., eLife 2023; https:/doi.org/10.7554/eLife.89270.2

General infertility

Does infertility increase the risk of autism in offspring?

That advanced paternal age increases the autism risk in offspring has been known for quite some time.1 But whether infertility or infertility treatments are associated has long been unclear. Now, Canadian investigators (in an article in JAMA Network Open) attempted to answer these questions. They assessed 1,370,152 children, among those 51.35% males, 86.5% with unassisted conception, 10.3% with parental subfertility, 1.5% following ovulation induction (OI) and/or intrauterine inseminations (IUI), and 1.7% following IVF with or without ICSI. Autism spectrum disorder was 1.93/1000 person years after unassisted conception, (adjusted HR 1.20); it was 1.21 after OI/IUI; and was 1.16 after IVF/ICSI. Obstetrical and neonatal factors appeared to mediate most of those associations, for IVF/ICSI 29% were mediated by Cesarean section, 78% by multiple pregnancies, 50% by preterm birth, and 25% by severe neonatal morbidity. In other words, the risk of autism is barely related to an infertility diagnosis and mostly mediated by certain obstetrical and neonatal factors.2 We, however, were surprised that the study did not adjust for male age and this paper, therefore, is a runner up to the ‘WORST PAPER OF THE MONTH.” “Add-ons” in IVF The first-place prize winner for “WORST PAPER OF THE MONTH” ended up going to ESHRE’s Good Practice Recommendations regarding “add-ons” to IVF.3 We discussed this publication by the ESHRE Add-ons Working Group briefly before in the VOICE, after its electronic publication, and in this issue on page 9 in our THINK DIFFERENTLY – CHR OPINION section.

Though obviously a lot of work went into this publication, it reflects everything that is bad in the fertility field in how alleged “best evidence” is presented. This paper is shameful in its superficiality, description of evidence appropriation, and reference biases, but most of all, for coming from a society which constantly preaches the importance of evidence-based medicine. Presenting “best evidence” correctly does not only mean presenting with accuracy what

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Continued from page 41

works, but also with equal accuracy what does not work. If that is not possible, the best thing is to simply say nothing.

Unexplained infertility And since we are already at it, here is another runner-up for WORST PAPER OF THE MONTH—yet another ESHRE document, this time called an “evidence-based guideline” on so-called “unexplained infertility,” published by The Guideline Group on Unexplained Infertility of ESHRE 4. Here, the absurdity lies in the fact that ESHRE issues a formal guideline on a diagnosis that really does not even exist. As the document noted, “unexplained infertility” is defined by “absence of any abnormalities of the female and male reproductive systems after ‘standard’ investigations.” This definition, as we already in 2006 noted in the same journal where ESHRE now published the guideline5 is, however, hogwash and an oxymoron at the same time, because a ‘standard’ investigation means nothing. The deeper one digs, the more frequently one will find a diagnosis, and vice versa. How one can establish formal guidelines on something that does not exist—and offer no less than 52 recommendations—is puzzling. What makes this a problem for all of us is that they call it “best available evidence.”

Endometrial receptivity As we on repeated occasions have discussed in the VOICE, one test which has lost all credibility is endometrial receptivity testing.

Several well-performed studies have not only demonstrated that the test does not improve pregnancy chances in IVF; one study even suggested that the test may achieve opposite effects. Now Chinese investigators published a systematic review with meta-analysis which basically confirmed all over again that testing for alleged endometrial receptivity does not improve IVF outcomes.6 To exclude embryo quality as a contributing factor, the authors concentrated only on studies that euploid embryo transfers after PGT-A. Time to stop using this test!

How long should we wait after miscarriage to start all over again?

Getting pregnant is hard enough for many infertile women, and losing a pregnancy can be devastating, especially if patients are

older and time is not on their side. How long a person should wait after a miscarriage before attempting pregnancy again is, therefore, often a difficult subject to discuss. Recommendations patients usually receive is between 3-6 months, but the literature is surprisingly sparse on the subject—and quite conflicted. A U.S study several years ago, for example, suggested that an interpregnancy interval of less than three months was associated with the lowest repeat miscarriage risk.7 In contrast, a very recent Chinese study suggested that delaying a next frozen embryo transfer (FET) for at least six months was associated with lower subsequent pregnancy loss.8 So, what should be done? The honest answer is that we don’t really know for sure, but a few basic logical considerations should be considered. First, the older the gestational age was at time of miscarriage, the longer one should probably wait, because it will take the uterus longer to remodel itself (there, indeed, is some evidence that suggests that after chemical pregnancies one, for example, does not have to wait at all). Second, patient age should play an important role, because six months in a 25-year-old means nothing, but in a 45 year old it means a lot more. The obvious answer, therefore, is individualization. And, on a side note, we also do not know how long to wait for after extrauterine pregnancies.

Improving semen in vitro We noted in the November-December issue of the VOICE that the large number of new exhibitors at the last annual ASRM meeting in New Orleans were mostly either genetic testing companies or andrology offerings. Regarding the second group, we have been asking ourselves for quite some time what makes andrology so economically attractive, considering that ICSI in association has solved male infertility in almost all cases.

According to a paper that was recently published in Cells, that exposure of sperm during swim-up to a secretome of cumulus cells improved sperm function.9 We are not certain that looking up this paper is really worthwhile, but should you do this, you will see in Figure 1 that the swim-up improved motility (as one would expect), but further improvement from adding the secretome was, at best, minimal (P<0.05) and, clinically, very likely irrelevant. And the alleged reduction in DNA damage in sperm was also minimal (P<0.05). We are still puzzled by why so much investment goes into male infertility.

REFERENCES 1. Nybo Andersen A-M, Kjaer Urhoi S. Fertil Steril;107(2):312-318 2. Velez, et al., JAMA Network Open 2023;6(1):e2343954 [runner up to WORST PAPER OF THE MONTH] 3. ESHRE Add-ons working group, et al., Hum Reprod 2023;38(11):2062-2104 4. ESHRE The Guideline Group on Unexplained Infertility, et al., Hum Reprod 2023;38(10):1881-1890 5. Gleicher N, Barad D. Hum Reprod 2006;21(8):1951-1955 6. Mei et al., Front Endocrinol (Lausanne) 2023;14:1102777 7. Sundermann et al., Obstet Gynecol 2017; 130 8. Wang et al., JAMA Network Open 2023;6(10):e2340709

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In vitro fertilization (IVF)

Legal considerations when embryos are “mixed up” There exists no worse nightmare scenario in IVF practice than an embryo “mix-up” during an embryo transfer. Every IVF clinic follows detailed rules and practices to, under all circumstances, prevent such occurrences. Among other steps, there is a strict chain of custody for gametes and embryos and a four-eye rule (two independent individuals identifying the origin of gametes and embryos during handovers). Yet, unfortunately, almost every year there are still cases reported all over the world concerning embryo mix-ups.

The VOICE, over the last two years, reported on one such case in New York City that led to the permanent closure of an IVF clinic in the city, and on another case in Israel’s largest IVF laboratory that attracted considerable attention worldwide. There is strong suspicion that additional cases must exist, either not recognized or not disclosed to the public.

A recent paper by two lawyers from Stanford and Harvard Universities and Vardit Ravitsky, PhD—a prominent reproductive ethicist just recently appointed as the new President of the Hastings Institute north of New York City (and, coincidentally, the CHR’s GrandRounds speaker on January 16, 2024)—addressed the legal and ethical issues regarding such occurrences.1 The discovery of such a circumstance creates highly complex ethical as well as legal issues, with an almost unlimited number of possible consequences, further complicated when such a “mix-up” is recognized. The early recognition of a “mix-up,” of course, offers different circumstances and options than recognition of a “mix-up” after birth. The authors in the article explore several possibilities concerning how legal parentage can be established: either through pregnancy and the marital presumption, by following the legal principle of the best interest of the child, or by recognizing multiple individuals as legal parents. The authors were also very clear in their recommendation that the resolution of embryo “mix-ups” should be done proactively through legislation and guidelines, rather than post-factum and via individual court decisions. We agree!

infertility diagnosis, use of donor oocytes, use of ICSI, use of assisted hatching, fresh vs. frozen cycles, use of PGT-A, day of transfer, and embryo number transferred, almost all outcome differences almost completely disappeared, suggested, however, a different interpretation of this study.

Though in raw numbers pregnancy and live birth rates were, indeed, roughly 10% better in GC cycles, the significance of reported differences quickly declined after the above noted adjustments.

So, for example, the RR (95%CI) for all forms of pregnancy was 1.12 (1.14-1.16) but declined to 1.06 (1,06-1.07) after adjustments.

Clinical pregnancy went from 1.20 (1.19-1.21) to 1.09 (1.08-1.10), and live birth went from 1.25 (1.23-1.26) to only 1.11(1.0-1.12).

Miscarriage rates went the other way, with GC cycle demonstrating lower rates than self-carrying women (14.3% vs. 17.1%0 but the RR (95%CI) remained almost identical by going from 0.84 (0.81-0.86) to 0.89 (0.86-0.92. Moreover, multiple pregnancies the authors were so concerned about were higher in GC cycles (14.8% vs. 12.6%), but after adjustments RR (95%CI) barely changed from 1.17 (1.14-1.21) to 1.15 (1.11-1.18).

In other words, adjustments eliminated, to a large degree, most observed differences pointed out by the investigators, with remaining differences easily caused by other co-variables not considered by appropriate adjustments. Only small differences in miscarriage rates and twin pregnancies were not affected by adjustments, suggesting that these two observations may be real. The question then is—why do GC cycles have lower miscarriage and higher twinning rates? If we had to guess, we would argue the following: These data support that in self-carrying women, adjustments simply do not appear to catch factors that predispose to more miscarriages and fewer twin pregnancies. We, for example, only very recently reported that recipient age alone can increase miscarriage risk in donor-egg cycles.3

There is still no good answer as to why minority populations have lower pregnancy rates in IVF That minorities, especially women of African descent, have lower pregnancy and live birth rates in comparison to Caucasian women is a fact that has long been known. Why that is, however, has not yet Incorrect conclusions from gestational carrier (GC) IVF cycles? become clear, though it is obvious that socio-economic factors may Using data from the SART National Clinical Outcome Reporting play a role. One example is that there are disparities in the quality System between 2014 and 2020, U.S. investigators from Atlanta, GA, of health care offered to Caucasian women versus Black women and in a research letter in JAMA, reported seemingly interesting findings other women of color. Studies that adjusted accordingly, however, which, on closer examination, disappointed:2 Comparing GC to still demonstrated lower pregnancy and live birth rates in Black non-GC IVF cycle, based on the authors’ interpretation of results, women. A study in Fertility and Sterility recently investigated the using a GC improved the likelihood of live births. According to the hypothesis that the reason may be lower responsiveness to gonadoauthors, even after appropriate adjustments, GC cycles still produced tropins.4 As it, however, turns out, women of African descent demonmore twin pregnancies. Whenever better pregnancy and live birth strated better responses than Caucasian women, while continuing to rates are reported in association with larger multiple pregnancy show poorer IVF outcomes. rates, the correct conclusion is, usually, that a tested intervention— in this case the choice of using a GC rather than the patient carrying This may be an opportune time to point out the CHR’s past work herself—produced improved IVF outcomes. regarding the so-called FMR1 gene, which resulted in a good number of published papers suggesting important effects of this gene on The authors’ interpretation of their own results was, however, unsatovarian function. In one of these papers, the CHR’s investigators reisfactory. Offering poorly supported opinions, they suggested that ported highly significant differences in CGG-repeat patterns between “increased use of PGT-A and multiple embryo transfers (the latter African American, Asian (Han-Chinese), and Caucasian women, against ASRM recommendation) contributed to improved outcomes which ran in parallel with reported IVF outcomes, where Caucasian in GC cycles. That with appropriate adjustments for oocyte age, women appear to have best chances, followed by Chinese women and then African American women.5 Continued on page 44

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The never-ending saga of endometrial scratching.

In a recent issues of the VOICE, we reviewed a well-performed systematic literature search and meta-analysis regarding the use of endometrial scratching in the luteal phase of preceding cycles which to everybody’s surprise (the investigators included) offered strong support for the procedure.6 Now comes another European group publishing yet another systematic review and meta-analysis on the same subject, with very similar results,7 reporting significantly higher probability of live birth after endometrial scratching (RR 1.12, 95%CI 1.05-1.20). Subgroup analyses offered additional information: Scratching during the menses before embryo transfer improved live birth chances significantly further (RR 1.18, 95%CI 1.06-1.27). If scratching was performed during transfer, no improvement was seen.

Combined, both studies suggest that endometrial scratching is probably underused in IVF. Whether it should be used in all IVF cycles remains to be determined; but the procedure should definitely be considered after prior IVF failures.

The biological efficiency of oocytes to produce life births In 2009, Pasquale Patrizio MD and Deny Sakkas, PhD, both at that time at Yale University, published an important paper in which they proposed a new metric in determining the ability of oocytes to lead to a live birth. They reported only a 5.5% live birth rate per retrieved oocyte.8 Now, more than a decade later, they revisited basically the same question, anticipating improvements, considering that oocyte freezing has greatly improved and, possibly, considering the increasing utilization of PGT-A. Investigating in a single center 12,717 patients, with 20,677 retrieval cycles between 2014-2020, results were overall disappointing: In women who had used up all their oocytes/embryos the overall live birth rate per oocyte was only 2.8% (11.3% under age 35 and 1.2% over age 42). With and without PGT-A, results were similar: 2.88% and 2.79%, respectively. Projections in patients with remaining embryos were higher (8.34%) and, in accordance with several recent studies, the efficacy of PGT-A changed with female age; an age threshold of 38.5 defined lowered live birth rates with PGT-A than with no PGT-A. Despite the addition of many “add-ons” to IVF, live births per embryo have not improved over the last decade, and neither did increased utilization of PGT-A improve IVF outcomes per oocyte.

Considering our feelings about most recent “add-ons,” and especially PGT-A, we cannot say that we are surprised!

REFERENCES 1. Simana et al., J Med Ehics 2023;jme-2023-109401 2. Shandley et al., JAMA 2023;330(17): 1691-1694 3. Gleicher et al., J Ovarian Res 2023;16:190 4. Lee et al., Fertil Steril 2023;120:1023-1032 5. Gleicher et al., Reprod Biomed Online 2010;20(4):485-491 van Hoogenhuijze et al., Hum Reprod Update 2023;29(6):721-740 6. Iakovidou et al., Reprod Biol Endocrinol 2023:21:89 7. Patrizio P, Sakkas D. fertile Steril 2009;91:1061-1066

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Obesity as a general medical manifestation

As the use of weight-loss drugs like semaglutide (Ozempic and Wegovy) and tirzepatide (Mounjaro) is revolutionizing medicine, it is becoming increasingly clear that the substantial weight loss achieved by these drugs in most obese patients also offers significant secondary health benefits beyond just weight loss. So far, these drugs have assisted people with cardio-vascular diseases including hypertension and, more recently, people with renal diseases, with skeletal benefits from weight loss proving obvious. Because of the association of PCOS with obesity and metabolic syndrome, one can also anticipate benefits from these medications in reproductive medicine. We, therefore, are pleased to announce that, starting with this issue, we have in this issue of the VOICE for the first time added a section on “obesity” to our literature review.

Effects of anti-obesity drugs on oral contraceptives and other drugs One way that this new family of weight loss drugs leads to weight loss is by slowing gastric emptying time. This can affect absorption of oral medications. A good example is oral contraceptives, which reportedly may decrease their effectiveness. Mounjaro appears to be a culprit, supposedly having been a cause for several surprise pregnancies.1 Hypogonadism in women due to obesity Obesity-associated hypogonadism is well defined in males, but less so in women. In women, obesity is associated with PCOS, which is not associated with low gonadotropins as male obesity-related secondary hypogonadism (MOSH) is. In a recent paper in Endocrine Reviews, British investigators propose a female counterpart to MOSH, which they give the name “female-obesity-related secondary hypogonadism” (FOSH), which differs from MOSH in men and non-obese PCOS in women (under Rotterdam criteria, the D-phenotype).2 This paper is only hypothesis-generating, but nevertheless worth a read.

REFERENCES 1. Scherer L, Medscape. https://www.medscape.com/s/ viewarticle/997498?src=FYE 2. Eng et al Endocrine Reviews 2023; bnad027

Menopause

Do mammals have menopause?

Suddenly everybody is interested whether all mammals have menopause. Cell published a lengthy commentary on the subject, summarizing what little is known.1 The two authors incorrectly concluded that, using only mostly demographic data on wild populations, menopause is rare in mammals. Considering, however, additional data from captive species, the picture changes, and what is called “oopause” (the end of ovulation) is actually quite common.

Attention around this subject is growing as a consequence of the booming interest in human menopause research—not only as an endocrine phenomenon in women, but also as a relevant model for premature organ aging in humans. Then, of course, there is the growing desire of women to extend their ability to conceive at older ages. As this article notes, looking at human menopause (and mammal oopause) from an evolutionary perspective, its purpose is still not understood. Indeed, there is not even consensus on whether the trait was positively selected.

The so-called grandmother hypothesis, assuming positive selection, suggests menopause is meant to make the female available to help her descendants at later life. Alternatively, menopause could just be a byproduct of longer lifespans, with no direct benefit for survival.

Shortly after that article, Science magazine printed its own report on menopause in chimpanzees. Once again, the writer stressed the importance of this information for gaining better insights into human evolution.2 This commentary relates to an article in the same issue which reported that chimpanzees in Uganda exhibit signs of menopause and, akin to humans, survive long after experiencing menopause.3 The grandmother hypothesis may, therefore, be correct after all. Women in a relatively isolated tribe in Africa, for example, experience menopause at age 41 (ca. 10 years before women in the more developed world) yet then maintain an average life expectancy of 60 (in other words, their non-fertile life span is relatively similar to that of women in the developed world). In wildlife, as similar post-reproductive lifespan has so-far only been shown in several species of whales.

REFERENCES 1. Winkler I, Goncalves A. Cell 2023;186:47294733 2. Cant M. Science 2023;382(6669):368-369 3. Wood et al., Science 382;eadd5473

Aging and life expectancy

Continuing the discussion around evolutionary influences, we are now turning to aging. As a recent paper in Science Advances demonstrates, selection for alleles advantageous for reproductive success at the same time advances human aging. Once again, we are dealing here with a still unconfirmed hypothesis; the so-called antagonistic pleiotropy hypothesis suggests that natural selection for pleiotropic mutations which support earlier and/or more reproduction but impair post-reproductive life enhances aging. Using the genotypes, reproductive phenotypes, and the death registry of 276,406 participants in the UK Biobank, the authors tested the hypothesis.1 They found a strong negative genetic correlation between reproductive traits and life spans of individuals with high polygenic scores favoring reproduction resulting in lower rates of survival to age 76.

Another recent study examined the correlation between time to pregnancy and life expectancy.2 Here, the results were the opposite: Prolonged time to pregnancy (i.e., a degree of infertility), dose-dependently, was associated with increasing maternal as well as paternal mortality, thus suggesting that decreased fertility was associated with shortened life expectancy.

Our understanding of human aging is still limited. For those interested in this field of research we do strongly recommend a terrific recent review article in Cell which offers a very comprehensive summary and great insight into biomarkers of aging that may be useful in identifying and evaluating longevity interventions.3 Yet another new feature article in Nature Medicine is further evidence for how “hot” the subject of human aging has become. The article points out that while billions of dollars are poured into longevity biotechs, little remains known about the biology of aging and success has thus remained challenging.4

Finally, a recent paper in Nature magazine deserves mention because it informs on the fact that our organs do not age in synchrony, but that—at least according to animal models—aging varies between individuals, and organs of individuals also vary in their respective aging curves.6 There is probably no better example for this than the ovary, which ages far ahead of the rest of a woman’s body. At the other extreme is the nearby uterus, which apparently only minimally ages, as recently was again demonstrated by a 70-year-old African woman delivering twins (of, course from third party donor eggs).

70-year-old Ugandan woman who gave birth to twins [BBC] Based on individual patients’ plasma proteomes from different organs, the researchers measured aging differences in living individuals to determine whether the observed differences in aging between organs in animal models were also apparent in humans.

They discovered that almost 20% of people demonstrate strongly advanced age in one organ, and 1.7% in multiple organs. Also, such accelerated aging confers 20-50% higher risk of mortality, while accelerated heart aging increases the risk of congestive heart failure by 250% and accelerated brain and vascular aging are predictive of Alzheimer’s. The significance of these findings cannot be overstated, for their impact on diagnostic as well as potential therapeutic advances in medicine. We strongly recommend this paper for more detailed review.

REFERENCES 1. Long E, Zhang J. Science Advances 2023;9(49):eadh4990 2. Lindahl-Jacobsen et al., Hum Reprod 2023; dead260. doi: 10.1093/humrep/ dead260. Online ahead of print.

3. Moqri et al., Cell 2023;186(18):3758-3775 4. May M. Nat Med 2023;29:2673-2676 5. Kupemba DN. BBC News, December 1, 2023; https://www.bbc.com/news/ world-africa-67577038 6. Oh HS-H et al., Nature 2023;624:164172

Pregnancy & Obstetrics

Medical problems in pregnancy and postpartum A recent study in JAMA investigated whether early initiation of metformin treatment in gestational diabetes reduces insulin initiation or improves fasting hyperglycemia by 32-38 weeks gestational age.1 The answer was that early treatment with metformin was not superior to placebo.

A study in the American Journal of Obstetrics & Gynecology reported on the risk of stillbirth in women with intrahepatic cholestasis of pregnancy,2 which in the literature—absent of intervention—has Continued on page 46

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been reported to demonstrate a 4-10-fold increase. Based on 2025-2020 national date from the National Readmission Database, cholestasis-patients delivered earlier than women without the condition (30.19% vs. 9.3%; P<0.001) but, surprisingly, stillbirths were reduced (160 fewer/100,000 deliveries (95%CI 127-194).

Though not pursued by the authors, these rather surprising findings call for an explanation. A first likely conclusion is that the treatment of the condition may have improved. Considering the earlier deliveries observed in the study group, this may suggest that these patients are induced earlier than in the past, thereby preventing stillbirth. Like late pregnancy and peripartum onset of disease, early delivery is also a typical clinical phenotype for all autoimmune diseases.2 This observation may, therefore, also inform on a possible immune etiology of the condition, which is generally attributed to hormonal influences in late pregnancy that affect hepatocytes in secretion of bile.

Amyotrophic lateral sclerosis (ALS), an ultimately fatal disease, is fortunately a rare occurrence in pregnancy. A review of 38 published cases is likely the so-far largest experience reported.3 The study demonstrated uneventful deliveries in all but two pregnancies, which ended in stillbirths. However, 67% of pregnancies delivered prematurely. Moreover, pregnancies in ALS patient may be associated with severe flairs of the disease. Combined, all these observations may here, too, speak to a possible immune system contribution in the etiology of ALS (in ca. 10% considered a genetic disease; but in a large majority of cases is still considered of unknown etiology), as flairs in association with pregnancy are a typical finding in autoimmune diseases.

For several reasons, postpartum depression (PPD) has recently been appearing in the news quite frequently, the main reason likely being the first market release of a rapidly-acting anti-depressant for treatment of PPD.4 Concomitantly, new screening recommendations were published by ACOG.5 A recent review article on the subject noted that the term PPD should be referred to more accurately, with the name “perinatal depression (PND),” because the condition presents in roughly a third of cases during pregnancy and in ca. only 40% of cases postpartum.6 This distribution of presentation is, once again, fairly typical for an autoimmune disease, as pointed out by the CHR’s Norbert Gleicher, MD, already in 2007.7 The review also pointed out that until the newly approved drug reached the market, selective serotonin reuptake inhibitors (SSRIs) were the standard of care (but could take up to four-six weeks until symptom improvement).

A study in Obstetrics & Gynecology investigated perinatal outcomes associated with treated stage I hypertension in pregnancy (BP < 130/80 mm/Hg).8 These women with mild chronic hypertension actually demonstrated improved pregnancy outcomes, in comparison to controls and no increase in small for gestational age infants.

Amazing what a little closer watching of patients during pregnancy can accomplish!

Finally, another study published in Obstetrics & Gynecology attempted to quantify what happened during the active stages of the COVID-19 pandemic in terms of obstetric interventions and perinatal outcomes.9 Interestingly, the pre-pandemic period was

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already characterized by temporal increases in preterm birth, preterm labor induction, and cesarean section (CS) rates, and with temporary reductions in macrosomia, post-term birth, and perinatal mortality. The apparent onset of the pandemic was associated with significant decreases in preterm births (0.322/100 live births, 95CI 0.506-0.139) and preterm labor induction or CS (decrease of 0.190/100 live births, 95% CI 0.334-0.047) and absolute increase in macrosomia (0.046/100 live births, 95% CI 0.046), and post-term births (0.015/100 live births).

That even the pre-pandemic period already demonstrated changes, of course, raises the question of why. That changes quickly returned to normal levels suggests that during early stages—maybe even still unrecognized stages of the pandemic—treatments obviously were not yet “adjusted.” But once they were, obstetrical outcomes normalized quickly.

Opinions apparently differ among experts regarding whether the development of congenital atrio-ventricular fetal heart block (CFHB) in presence of anti-Ro/SSA antibodies can be mitigated or not. Consensus Statement #64 of the Society for Maternal Fetal Medicine suggested that surveillance of fetal heart by echocardiography is unwarranted and unnecessary because treatment is futile, as treatment does not prevent progression from incomplete from incomplete to complete block. Now a group of 46 authors published a contradictory opinion, making the point that recent literature on the subject warrants a more subtle approach.10 We fully agree with this dissenting opinion!

Hyperemesis gravidarum (HG) is, to this day, only a poorly understood phenomenon of many pregnancies. Now a hormone called GDF15, acting on the brainstem, has been implicated in nausea and vomiting during pregnancy,11 supporting a putative causal role.

This finding may open brand-new approaches to prevention and treatment of HG. REFERENCES 1. Dunne et al., JAMA 2023;330(16):1547-1556 2. Gleicher N. Clin Rev Allergy Immunol 2010;39(3):194-206 3. Hamad et al., Neurol Sci 2023;44(12):4219-4231 4. https://www.zurzuvaehcp.com/?cid=PPC-GOOGLE-Health care+Industry_Treatment_Exact~S~PH~BR~NER~HCP~TREdrug+for+postpartum+depression-NA-p78930214599-ZU RZUVAE+Overview_Treatment&gclid=EAIaIQobChMI_

LmatZS6gwMVjGBHAR3eAQYtEAAYAiAAEgKi6vD_BwE&gclsrc=aw.ds 5. ACOG Clinical Practice Guideline No.4. Obstet Gynecol 2023l141(16):1232-1261 6. Moore Simas et al., JAMA 2023;330(23):2295-2296 7. Gleicher N. Autoimmunity 2007;6(8):572-576 8. Bailey et al., Obstet Gynecol 2023;142(6):13951404 9. Simon et al., Obstet Gynecol 2023;142(6):14051415 10. Cueno et al., Am J Obstet Gynecol 2023;229(4):P361-P363 11. Fejzo et al., Nature 2023; doi: 10.1038/s41586-023-06921-9. Online ahead of print.

Medications in pregnancy The use of low-dose aspirin in the prevention of preeclampsia appears to now be well established. As a recent opinion article, however, pointed out in the American Journal of Obstetrics & Gynecology, the dosage of aspirin and the timing may need further evaluation to find a point of greatest effectiveness. As the article suggested, based on published studies, doses above 100mg of aspirin daily, initiated before 16 weeks of gestation, appear most effective, though this conclusion requires confirmation through a randomized trial of 81mg vs. 162 mg daily.1 Such studies are apparently already underway. A recent narrative review of aspirin usage in the prevention of preeclampsia in Obstetrics & Gynecology concurred that the daily aspirin dosage should be over 100mg daily and should be initiated between 12-16 weeks.2 A recent study in JAMA Psychiatry confirmed that benzodiazepine use (diazepam, lorazepam, etc.) during pregnancy was associated with increased miscarriage risk.3 This risk was maintained after adjustments for confounders, including confounders related to genetics and family environment (OR, 1.69; 95% CI, 1.52-1.87). Findings were consistent across multiple sensitivity analyses and suggest that benzodiazepines should be used with considerable caution during early pregnancy and, possibly also in women attempting pregnancy.

The same group in a separate paper in Lancet Psychiatry found no adverse effects of this group of medications often prescribed during pregnancy for anxiety and insomnia in association with stillbirth and/or preterm birth.

REFERENCES 1. Horgan et al., Am J Obstet Gynecol 2023; 229(4):410-418 2. Jones Pullins et al., Obstet Gynecol 2023;142:1333-1340 3. Meng L-C, JAMA Psychiatry 2023; doi:10.1001/jamapsychiatry.2023.4912

Drugs in pregnancy Fentanyl has become the nation’s primary drug problem, killing, according to various media reports, over 100,000 mostly young people over the last two years. Either knowingly or, through lacing of other drugs, unknowingly, prenatal and in pregnancy—exposure to this deadly drug is becoming more common. U.S. investigators from several universities published a new syndrome in newborns associated with maternal prenatal fentanyl exposure.1 The syndrome appears characterized by short stature, microcephaly, distinctive facial features, and congenital anomalies including cleft palate, rocker bottom feet, and chordee or hypospadias, among others. Biochemical studies after delivery demonstrated abnormalities in the cholesterol metabolism pathway which subsequently resolved. Based on self-reported past medical history of mothers, the authors concluded that fentanyl was teratogenic by possibly interfering with cholesterol metabolism Continued on page 48

in the fetus, producing a new syndrome similar to the Smith-LemliOpitz syndrome. Considering that this conclusion was reached based on only 10 cases, the effects of fentanyl on fetuses must be further explored.

REFERENCE 1. Wadman et al., Genetics in Med Open 2023;1:100834,

Further evidence that risk factors in singleton and twin pregnancies vary It has now been more than 20 years that the CHR has argued that the risks present in singleton and twin pregnancies cannot be considered in the same ways, and that risks can only be compared for similar outcomes. The outcome of twins is two offspring, while a singleton pregnancy produces only one. Simply comparing pregnancy outcomes between singleton and twin pregnancies without controlling for one vs. two children-outcomes, therefore, is statistically incorrect but, to this day, is one of the basic building stones for the widely held (incorrect) opinion that twin pregnancies should always be considered adverse outcomes of fertility treatments and, therefore, must always be avoided.

Now British investigators produced even further evidence in support of the CHR’s longstanding arguments that those policies are mistaken.1 For example, advanced maternal age predisposes twin pregnancies to higher risks of mortality, admissions to the NICU, and preterm birth than singleton pregnancies—an obvious argument against twin pregnancies with advanced female age, but why at younger ages? Moreover, the impact of BMI, socioeconomic inequality, smoking, Assisted Reproductive Technologies (ART)—another point stressed for many years by CHR investigators—and hypertension are less for twin pregnancies than singleton ones, even without adjustments for birth of two offspring rather than one. Indeed, ART use and gestational diabetes appear outright protective for twins against perinatal mortality.1 In short, here is excellent additional new evidence that the rigid no-twins policy propagated by ASRM, ESHRE, and our perinatology colleagues makes no sense. For infertility patients, the adverse consequences from this policy go even further, because the policy has also driven the widely recommended and followed elective single embryo transfer policy, which clearly reduces pregnancy and live birth chances. In other words, a double whammy for infertile women!

REFERENCE 1. Whittacker et al., J Mat Fet Neonat Med 2023;36(2):2240467

Genetics

Preimplantation genetic testing for aneuploidy (PGT-A) The paper we are here discussing investigated chromosomal copy numbers (i.e. chromosomal abnormalities) in human reconstituted embryos after spindle transfer.1 The study investigated the basic question of how well trophectoderm and inner cell mass correlate in their chromosomal make-up and whether this correlation changes between spontaneously produced embryos and embryos that are the product of spindle cell transfer. The answers provided by the authors are interesting, but not always fully representative of their data.

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They interpreted their data to demonstrate “good chromosomal concordance” between trophectoderm and inner cell MAs with a kappa of only 0.659 (P<0.05), which we would not necessarily consider a good concordance if one considers that PGT-A relies on a trophectoderm biopsy (a product of the extraembryonic cell lineage forming the placenta) to judge the chromosomal make-up of the inner cell mass (a product of the embryonic cell lineage, producing the fetus). Obviously, one would want the correlation to be as close as possible to 100%, so that judgments about transferability of embryos can be made with accuracy. That the two cell lineages are far from identical (or even close to that) has by now been well established and is one main reason why PGT-A utilization is so controversial.

The second finding is much more interesting; as the researchers observed, embryos produced through spindle transfer had additional chromosomal abnormalities to what was found in spontaneously produced embryos. As there has been talk about using spindle cell transfer in preventing inheritance of mitochondrial diseases from mother to offspring—and, possibly, also in cytoplasm-exchanges of oocytes from older women—this finding may find relevance in the future. Currently, the FDA in the U.S. does not permit spindle cell transfers.

Manuel Viotti, PhD, who contributed several important papers to the PGT-A literature, recently published a new paper—with no less than 24 co-authors from IVF clinics worldwide2—in which he wanted to determine chromosomal, gestational, and neonatal outcomes of embryos classified by PGT-A as “mosaic.” As always, we put the word mosaic within quotation marks because what PGT-A describes as “mosaic” is not compatible with the correct biological definition of mosaicism. Since we discussed this fact repeatedly before in the VOICE and in the medical literature, we here will not be repetitive. The authors, moreover, defined “mosaic” in this study as 20-80% intermediate copy numbers (i.e., 20-80% aneuploid DNA) in an on average 5-6-cell trophectoderm biopsy and reported the following results in comparing “euploid” to “mosaic” embryo transfer outcomes: “Euploid” embryos produced fewer miscarriages (8.9% vs. 22.2%).

Highest risk for spontaneous miscarriages was produced by whole chromosome abnormalities (27.6%). Birthweights and length of gestation did not differ. Out 250 pregnancies established from “mosaic” embryos, 3 carried the same abnormality as detected in the original PGT-A. Among those, one demonstrated multiple anatomical abnormalities on ultrasound and was aborted; the other two delivered apparently normal offspring.

The authors concluded that embryos by current PGT-A defined as “mosaic” have higher, mostly very early miscarriage rates but the same live birth rates as observed in by PGT-A as “euploid” signed out embryos. The results not only confirm what simple logic would dictate if the basic physiology of preimplantation-stage embryos is correctly understood, but confirms what the CHR has been saying for almost 10 years about PGT-A and the possibility to safely transfer a majority of embryos with chromosomal abnormalities. Viotti and colleagues are to be congratulated on

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another important paper. We also want to complement the writer of the accompanying “Reflections” article in the journal, which raised several additional pertinent points.

Interestingly, publication of this article coincided with publication of a new guidance article on the “clinical management of mosaic results from preimplantation genetic testing for aneuploidy of blastocysts,” published by the Practice Committee of the ASRM and the Genetic Counseling Professional Group,3 which we for several reasons, unfortunately, cannot equally laude. First, we do not understand why the Practice Committee, which is supposed to be free of commercial interests, would now repeatedly (on this one and only subject) conjoin with the Genetic Counseling Professional Group, which, based on how its members make a big part of their living through PGT-A, must have at least some biases. Second, and clearly more importantly, the ASRM, once again fails in its prime responsibility of guiding infertility practice in the U.S. The primary responsibility of the ASRM’s is not to offer comprehensive review articles of the literature. That, almost anybody can. What others, however, cannot do equally objectively (if done correctly) is take available data and interpret those to reach morally and ethically driven decisions that allow the issuance of guidelines as to how U.S. fertility practitioners should best manage patients in certain clinical situations. With that in mind, it is difficult to understand that after more than 20 years of PGT-A practice (under various names), the ASRM has not yet come out with a clear statement regarding PGT-A that acknowledges significant past mis-directions and, in the process, setting the record straight by making points like the following: The profession has been largely mistaken in the way how it introduced PGT-A to routine practice without proper prior validation.

Contrary to initial understanding, it by now is clear that PGT-A cannot improve cumulative pregnancy and live birth chances of an IVF cycle. In selected patient populations, it can only achieve the opposite.

Because of not having spoken out earlier, hundreds of thousands of embryos with pregnancy potential have been discarded, are still being discarded daily, and/or are still sitting unused in cryo-tanks.

As another consequence, large numbers of patients have prematurely left autologous IVF and switched to third-party egg donation, and many others have completely dropped out of trying to conceive.

And, most importantly, we the ASRM, as the “mother ship” of fertility care in this country have learned our lesson, and herby commit to speaking out in the future when we see inappropriate clinical practices enter the mainstream of infertility practice.

Relating to the above addressed ASRM document3 and the excellent paper by Viotti et al,2 another recently published paper deserves mention because it comes from New York City’s NYU IVF program (as noted on page 13, now part of the Prelude IVF clinic chain), which over many years has been among the most outspoken in criticizing the CHR for arguing in favor of transferring chromosomal abnormal selected embryos. It, therefore, is very pleasing for us at the CHR to now be able to report that even our colleagues at NYU have finally (at least partially) seen the light and acknowledged that whole chromosome “mosaicism,” segmental aneuploidies, and segmental mosaicism “may be suitable for transfer.”4

One final word on PGT-A for this issue of the VOICE: In the November-December 2023 issue of the VOICE, we noted (in our review of the annual ASRM Conference in New Orleans) how quickly the genetic testing industry has become dominant among exhibitors, to a large degree represented by relatively new start-ups. One subject that the industry appears to pursue with extra vigor is the hypothesis that machine learning will allow the non-invasive detection of embryo aneuploidy through computer vision (i.e. optical imaging).5 As above discussed comments in this section should have made abundantly clear, determining whether a blastocyst contains chromosomal-abnormal cells is not the question that needs to be addressed.

The question that must be answered is whether an embryo is inappropriately excluded from transfer. If the answer is yes, whether that is because of invasive or non-invasive means, makes little difference. In both instances a falsely excluded embryo reduces a patient’s pregnancy chances, whether through machine learning applied to computer vision5 or testing of spent media.6

In a mosquito model, investigators reported the discovery of a key regulator for dosage compensation.1 They initially observed only two genes that were expressed more in males than females at 3.5 hours after egg laying, with the male X at 3.5 hours only producing half of the output of female X chromosomes. By nine hours, they, however, had already equalized. One was already well-known and the other was previously uncharacterized and was named sex chromosome activation (SOA). The shortened SOA protein in females binds in vitro non-specifically to DNA but a full-length version, as produced in males, localizes to active genes on the X chromosome.

Because an IVF cycle’s pregnancy and live birth chances—once eggs have been retrieved—are in-the-positive predetermined, we are skeptical about start-ups which promise “best” embryo selection with the purpose of improving pregnancy and live birth chances. For everybody who understands basic embryo physiology, it should be clear that they are chasing the impossible.

REFERENCES 1. Kalita et al., Nature 2023;623:175-182 2. Lauria Sneidman PP, Meller VH/ Nature 2021;623:34=35

REFERENCES 1. Søderhamn Bülow, et al., Hum Reprod 2023;38(1):2154-2165 2. Viotti et al., Fertil Steril 120(5):957-966 3. Practice Committee of the ASRM and the Genetic Counseling Professional Group. Fertil Steril 2023;120(5)973-981 4. Druckenmiller Cascante et al., Fertil Steril 2023;120:1161-1169 5. Gilboa D, et al., Fertil Steril 2023; 120(4)Suppl): E218l Abstract 6. Orvieto et al., Hum Reprod 2021;36(5):1186-1190.

An equalizer for gene expression of the X chromosome in males In organisms with X as well as Y chromosomes, gene expression between the two must be equalized in a process called dosage compensation. In this process in males (with one X and one Y chromosome), both chromosomes must achieve similar expression levels for hundreds of genes on the (female) X chromosome. How this happens varies greatly between species and, for most, is not well understood yet.

As noted in an accompanying commentary, these findings are not only important as a new model for the study of sex determination and dosage compensation but may also play a major role in current attempts to combat by mosquitos transferred severe infectious diseases by releasing, for example, only sterile males into a region where diseases are being transmitted via mosquitos.2

Sex bias in gene expression So called sexual dimorphism leads to differences in gene expression between females and males, which can have varying consequences, from the sexes looking different to distinctions in morphology, physiology, or behavior. How sexual dimorphisms arise, has largely remained unknown, but it is assumed to have originated in early human embryos.

Though the process appears to vary between species, a new study in Science magazine suggests that dimorphism arises much later than was assumed until now, namely at time of sexual maturity.1 As an accompanying commentary notes, the apparently low expression of sex-biased genes during embryogenesis and the sharp increase around sexual maturity has two potential explanations:2 Either organs reach sexual identity through hormones at time of puberty or the process builds slowly from embryogenesis. Future large scale human studies will be required to find the answer.

REFERENCES 1. Rodigues-Montes, et al., Science 2023; 382:eadf1046 2. Sémon M. Science 382(6670):515-516

Meiotic DNA breaks are an important cause of mutations in the human germ line An additional recent article in Science also corrected another misperception in that the investigators demonstrated that certain error-prone repair mechanisms which, to this point, were believed not to be used or to be suppressed during meiosis, indeed cause havoc during meiosis, leading to the pathogenic disruption of gene functions. Mutation rates, moreover, are higher in males. The authors conclude that the evolutionary benefit of increased genetic diversity from meiotic recombinations comes with a substantial price in mutational and disease burden.

REFERENCE 1. Hinch et al., Science 2023;382:eadh2531

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Interesting new data on young female BRCA carriers after breast cancer diagnosis A worldwide collaborative cohort study involving 58 institutions in young female BRCA carriers after breast cancer offered interesting new data.1 As the paper notes, breast cancer survivors among carriers of pathogenic variants of BRCA1 and BRC2 face significant challenges regarding their future fertility, with prior studies having demonstrated the feasibility and safety of pregnancy in breast cancer survivors in general, but at best only limited data is available regarding surviving BRCA carriers. Moreover, for the first time at the CHR,2 BRCA carriers have also been reported to demonstrate diminished ovarian reserve for age, as more recently confirmed by Italian colleagues.3 Reporting on 4,732 BRCA carriers, of which 659 had at least one pregnancy after breast cancer (median age 35, range, 31-38), the population demonstrated a cumulative pregnancy rate over 10 years of 22% (95%CI, 21-24%). Median time from conception was 3.5 years. Induced pregnancy terminations occurred in 6.9% of pregnancies; a miscarriage in 9.7%. Among deliveries, 91% occurred at term, 10.4% had twins, 0.9% of offspring demonstrated congenital anomalies. Most importantly, there was no difference in disease-free survival in women with or without pregnancy.

Indeed, remarkably, women who experienced a pregnancy had significantly better breast-cancer-specific survival and overall survival.

The latter finding is, of course, astonishing, and would appear to have to be considered with caution until further confirmed. If confirmed, it would be one more piece of evidence for a breast cancer-protective effect of pregnancy, which has been claimed for decades.4 REFERENCES 1. Lambertini et al., JAMA 2023; e2325463, doi: 10.1001/ jama.2023.25463. Online ahead of print.

2. Oktay et al., Clin Oncol 2010;28:4664 3. Porcu et al., J Assist reprod Genet 2020;37(3):709-715 4. Husby et al., Nat Commun 2018;9(1):4255

Shared genetic risk between low functional ovarian reserve (LFOR) for age and miscarriage For the CHR, LFOR and miscarriages have been etiologically linked for decades, as both are highly associated with autoimmunity.1 It was therefore pleasing to see a recent paper by Chinese investigators in Human Reproduction that confirmed the association based on 17,786 IVF cycles and epidemiological data from the UK Biobank including 35,316 Caucasian women.2 Women undergoing IVF with low AMH (<1.1ng/mL) were 1.57-times more likely to have a miscarriage, with low antral follicle count (<5) 1.62-times, and with high FSH (>10.0mIU/ mL) 1.39-times. In the UK data base, women with three or more miscarriages had a one-third higher risk of early menopause. The study, moreover, identified 158 shared genetic risk loci affecting miscarriage and time of menopause, which enrichment analyses demonstrated involved with antigen processing/presentation and autoimmune disease pathways.

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This is the second time within one year that an association made some time ago at the CHR through observational studies has been now independently confirmed by other investigators on a genomic level. The other such association was the CHR’s recognition that the under Rotterdam criteria defined PCOS phenotype D has been for decades misinterpreted and, likely, is genotypically distinct form the A, B, and C phenotypes,3 which genomic was confirmed by Dapas et al.4 REFERENCES 1. Gleicher et al., Reprod Biol Endocrinol 20097:108 2. Yi et al., Hum Reprod 2023;38(11):2247-2258 3. Gleicher et al., Biomedicines 2022;10:1505 4. Dapas et al., PLoS Med 2020;17:e1003132

General immunology and autoimmunity

Autoimmune diseases in pregnancy Are chlamydial infections responsible for rheumatoid arthritis? A recent study supported such a possibility when 17.9% of patients with rheumatoid arthritis (RA) self-reported a history of chlamydia and only 9.8% of controls (P<0.001). After adjustments, the association remained intact and stronger effect size was obtained in later stages of the disease.1 Also, we may be getting a new blood test for RA that allegedly can correctly identify 96% of people without RA, and over 90% with RA. The test is based on capturing gene expressions from synovium-specific signatures in blood of patients with RA. A machine learning model identified 3,424 epigenetic features with statistically significant discrimination mapped to 929 genes.2 Also, based on a new study by Swedish researchers (using again the UK Biobank), oral contraceptives appear to protect from regular RA, while postmenopausal hormone replacement may increase the risk of late-onset RA.3 Rather unsurprisingly, a recent article in the American Journal of Obstetrics & Gynecology MFM reported that mothers with dermatologic autoimmune skin diseases carried increased risks of fetal as well as maternal adverse pregnancy outcomes. For us here at the CHR that does not come as a surprise, since practically all autoimmune conditions are associated with increased likelihood of adverse maternal and neonatal pregnancy outcomes—from miscarriages and

intrauterine deaths too small for gestational age infants, placental insufficiency, premature labor and delivery, preeclampsia risk, and, of course, autoimmune disease exacerbation peripartum, carrying up to five months into the postpartum period. The authors seemed especially surprised by the risk for miscarriages. 4 All autoimmunity is based on an identical underlying immune system defect: the inability to properly self-tolerate through induction of proper tolerance pathways. The same thing also in principle happens when a maternal immune system fails to induce proper tolerance pathways against the paternal histocompatibility loci of the fetus.

A paper in Digestive Diseases and Sciences reported on autoimmune hepatitis in pregnancy.5 Using a national U.S data set, the authors confirmed the association with preterm delivery but found no increased risk for hypertensive complications, Frankly, it is not a very convincing paper and is somewhat contradictive to earlier papers on the subject.5 A Chinses paper in Rheumatology reported on the reproductive health of 342 women with scleroderma (systemic sclerosis).6 The authors reported that 31.8% presented with reproductive health problems: Earlier menopause (45.2 vs. 48 years, P<0.001), fertility was unaffected but miscarriage rates were increased (12.2% vs 4,3%, P<0.001), deliveries were more frequently premature (21.8% vs, 6.4%, P=0.003), low birth rate was more frequent (27,3% vs 5.5%, P<0.001), and Cesarean section deliveries were more frequent (49.1% vs. 19.1%, P<0.001).

Another Chinese paper reported a Mendelian randomized study of circulating inflammatory cytokines in female reproductive diseases.

They identified four correlated pairs implying to be potential drug targets: Macrophage colony stimulating factor (M-CSF), growth stimulating oncogene-alpha, and soluble intercellular adhesion molecule-1 were associated with increased risk of endometriosis, infertility, and preeclampsia, respectively, while high platelet-derived growth factor-BB apparently reduced risk of ovarian aging.7 Finally, we also want to mention an interesting case report affecting a pregnant cancer patient with melanoma (stage IIIB), treated with immune checkpoint blockade (ICPB) with pembrolizumab.8 ICPB has become standard therapy in many cancers. It involves the targeting of the pathway consisting of programmed cell death protein 1 (PD-1) and its ligand (PF-1L). Anti-PF-1 monoclonal antibodies often enhance T-cell mediated anti-tumor responses by the host immune system. Side effects of such treatments can, however, be once again loss of peripheral tolerance, giving rise to an autoimmune-like phenotype.

During pregnancy, ICPB can also lead to problems in establishing and maintaining normal fetal tolerance by the maternal immune system.9 Above noted monoclonal antibodies, after week 14, pass the placenta, causing sever adverse fetal effects and even death. The paper noted that, to this point, 14 such cases have been reported in the literature often leading to termination of pregnancy or premature delivery. Absence of IgG-transporting neonatal Fc receptor on the placenta before 14 weeks, therefore, should reduce fetal effects from ICPB dramatically, while in the third trimester of pregnancy transfer Continued on page 52

of the antibody is the highest, with fetal levels often exceeding maternal levels.

In the here presented case report, the antibody was administered during the second and third trimesters of pregnancy, leading to severe immune-related gastroenterocolitis. The infant was at 37 weeks—three weeks after the last pembrolizumab administration— delivered because of maternal cholestasis (please note our earlier discussion of pregnancy induced maternal cholestasis of pregnancy on page 45, in which we discussed a possible autoimmune etiology). A healthy male was uneventfully born vaginally (3300gm) with APGARs of 10/10. The newborn was fine until the age of four months, when he was first seen in a local hospital for watery diarrhea. No diagnosis was reached until age 4.5 months, when the infant was transferred to a tertiary medical center for further evaluation.

There, after a prolonged work-up, a gastroduodenal and subtotal colonoscopy was performed, which revealed duodenal changes resembling an anti-PD-1 associated immune-related gastrointestinal toxicity in adult patients.

The diagnosis was further confirmed through peripheral immunological tests on the infant but, mostly, based on successful treatment as is given to adults who develop this toxicity. The authors of this remarkable case report point out that this case once again stresses how carefully ICPB must be given in pregnancy and that adverse sequalae of such treatments in offspring apparently can arise months after delivery (not dissimilar to the observation that postpartum autoimmune flairs in women with autoimmune diseases can occur up to five months postpartum).

REFERENCES 1. Lamacchia et al., Rheumatology )Oxford) 2023;:kead682. doi: 10.1093/rheu matology/kead682.Online ahead of print.

2. MDedge.com/Medscape Professional Network. https://www.medscape.com/s/ viewarticle/998668 3. Hadizadeh et al., Rheumatology (Oxford) 2023; kead513. Doi: 10.1093/rheu matology/kead513. Online ahead of print 4. Keum et al., Am J Obstet Gynecol MFM 2023;6(1):101226 5. Kilani et al., Digest Dis Sci 2023;68:4389-4397 6. Dai et al., Rheumatology (Oxford) 2023; kead497. Doi 10.1093/rheumatology/ kead497 7. Lin et al., HCEM 2023;108:3154-3164 8. Baarslag et al., N Engl J Med 2023;389(19):17901797 9. Zhang Y-H, et a., Am J Reprod Immunol 2015;74(3):201-208

CAR T-cell therapy in autoimmune diseases Recent reports suggested that CAR T-cell therapy - T cells engineered tumor cells via chimeric antigen receptors (CARs)—initially developed for cancer treatments—may also be effective in autoimmune diseases. In this case, autologous CAR-T cells of patients are engineered directed against CD19 antigen. This induces a rapid and sustained depletion of circulating B lymphocytes which, in turn, has resulted in complete clinical and serological remission of systemic lupus erythematosus (SLE), dermatomyositis, and other autoimmune disease. A recent review offers an excellent update.1 REFERENCE 1. Schett et al., Lancet 2023;402:20342044

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New classification criteria for the antiphospholipid syndrome (APS) For over three decades the APS (at some point also called anti-phospholipid antibody syndrome, APAS) has created within rheumatology a whole “sub-specialty”—in the CHR’s opinion, completely out of proportion to its prevalence and importance, and with constantly changing diagnostic criteria. And here, it seems, we go again with new 2023 ACR/EULAR criteria.1 They now include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within three years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thrombus, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains [upus anticoagulant (LA), assay IgM/IgG anticardiolipin and/or IgG/IgM anti-beta 2-glycoprotein antibodies]. At least three accumulated points each from clinical and laboratory domains are classified as having APS. No more talk about miscarriages, which in combination with a single thrombotic event and a positive LA, initially defined the APAS. With miscarriage finally removed from the definition of this ever-changing syndrome, reproductive medicine appears equally removed from the subject. We must acknowledge—it is almost a relief!

REFERENCE 2. Barbhaiya et al., Ann Rheum Dis 2023;82:1258-1270

Basic science investigations

Definition of a new cell sub-type in the inner cell mass (ICM) A group of German and British investigators, through single cell analysis on multiple independent datasets, identifies a cell type in the ICM which lacks commitment markers that segregate after gene activation of the embryo and then quickly undergoes apoptosis.

Defining “sister cells” which do not undergo apoptosis and remain viable, they describe the embryo as a “selection arena” in which one group of cells selectively dies, while others persist. 1 This is, however, a somewhat unprecise characterization of their findings because the process the authors described in their paper did not occur in the whole embryo. It was only observed in the ICM, a product of the embryonic cell lineage. This does not mean that it also occurs in the extraembryonic cell lineage, producing trophectoderm and, ultimately, the placenta. Indeed, as repeatedly noted in prior issues of the VOICE, it is now well established that these two cell lineages have quite different abilities to self-correct from aneuploidies, involving the active elimination of aneuploid cells in the ICM, while the trophectoderm of early-stage embryos lack this ability (or possess it only to much smaller degree). What the authors of this paper, therefore, are describing may very well just be a feature of embryos’ ability at early embryonic stages to self-correct in the ICM from clinically relevant mosaicism. It is interesting that, despite quoting 99 references, the authors did not mention this possibility in their paper.

REFERENCE 1. Singh et al., PLOS Biol 2023;21(6):e3002162

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The importance of mitochondria transfers between cells When we in reproductive medicine address mitochondria transfer, what is usually meant is mitochondria transfer through cytoplasmic exchange between oocytes using either spindle or nuclear transfers with the goal of replacing existing mitochondria in an oocyte either in attempts to prevent transmission of mitochondrial diseases from mothers to their offspring or in the hope of “rejuvenating” older eggs in the IVF process to improve pregnancy and live birth chances. What, however, so far has not attracted sufficient attention in reproductive medicine, is that mitochondria transfer between cells is very common phenomenon and can happen through several distinct mechanisms, extremely well described in a recent publication in a Perspectivearticle in Nature magazine.1 The authors point out that cells transfer mitochondria through transient cellular connections between cells, such as tunneling nanotubes and are exported from cells via multivesicular bodies.

Mitochondria-derived vesicles and whole mitochondria are packaged in vesicles and released as extracellular vesicles for capture by other cells. Recipient cells then degrade captured vesicles via the lysosome. Finally, mitochondria can also be released from cells as free mitochondria for capture by recipient cells.

Functional roles for mitochondria transfer have, according to the article, so far been described as limiting strokes, lessening pain, cancer metabolism and growth, wound healing, hematopoiesis, dampening inflammation, reducing obesity, improving ischemic reperfusion injury, and bone health and bone remodeling. We, however, as of this moment are unaware of any studies regarding reproductive processes and/or in human embryos and therefore strongly recommend this paper as an introduction for future considerations in reproductive medicine.

REFERENCE 1. Borcherding N, Brestoff JR. Nature 2023;632:283-291

Live birth of a highly chimeric monkey We have often in these pages noted that we all are chimeras, carrying cells from our mothers and maybe even our grandparents. We are also chimeras because many of our organs, at least temporarily, contain aneuploid and even cancerous cells. The CHR’s investigators were, likely, the first to demonstrate that transplantation of sex-diverging cells into embryos at preimplantation stages produces normally developing embryos.1 Chimeras have since, indeed, become excellent models for studying development.2 Now Chinese investigators went a step further by producing a live highly chimeric monkey with very high donor cell contribution. Donor cell contribution in various organs went as high as 90%.3 That this is possible in monkeys, of course, also suggests similar possibilities in the human experience, offering moreover the opportunity for the study of naïve pluripotency and genetic engineering. In a commentary on this paper, Clarissa Wong in

Nature points out that this hybrid monkey, made from cells from two distinct embryos, pays furthermore the way for scientists to use chimeric primates to study human disease.4 REFERENCES 1. Gleicher N, Tang XY. Fertil Steril 2004;81(4):977-981 2. Martyn et al, Methods Mol Biol 2019:2005:77-89 3. Cao et al., Cell 2023;186:4996-5014 4. Wong C. Nature 2023;623:468-469

Artificial intelligence (A.I.)

That A.I. has here been assigned its own subsection, bears witness not only to the expectations the whole field of medicine has for its expected contributions to progress, but also is reflective of the many concerns expressed by the public concerning where A.I. usage may be leading us to. That the process may not always be smooth is reflected in a recent Commentary in Nature Medicine, which pointed out that A.I.-powered chatbots used in patient care are regulated by the FDA as medical devices, yet their current unreliability precludes their approval as such.1 In another Perspectives article in JAMA, these authors (in an interview session with the journal’s editor-in-chief) ask the question of whether A.I. will succeed, considering that electronic health care records bitterly failed in improving the physicians’ professional lives.2 The answer to this question is obviously still pending but, at least for the foreseeable future, we have our doubts.

In an interesting paper on “how to modernize medical evidence for the misinformation era,” Clare Watson in Nature Medicine proposes the utilization of A.I. to find and screen studies and extract data as one of the approaches that may improve systematic reviews and meta-analyses.3 Considering how dependent current A.I. still is on possible selection biases in data used to “feed” it, this is one good example for what we feel, as of this point, is exaggerated hope in the science community that A.I. is close to offering breakthrough advances in how medicine is studied, taught, and practiced.

REFERENCES 1. Gilbert et al., Nat Med 2023;29:2396-2398 2. Hswen Y, Voelker R. JAMA 2023;330(16):1509 3. Watson C. Nat Med 2023;29:2383-2386

The business of infertility

It is interesting, though considering basic economics not surprising, that at a time of general inflation, the percentage of Gross Domestic Product (GDP) that is ascribed to medical services actually shrunk in the U.S. from 19.7% in 2020, to 18.3% in 2021, and 17.3% in 2022, the latter just recently published.1 It thus is a hugely important part of the U.S. economy and, indeed, more important in the U.S. than in other developed countries because no one else spends such a large percentage of GDP on medical care. According to the OECD, Germany, for example, spent 12.7% and France 12.1% of their respective GDPs on health care in 2022. Israel, which has the by far highest IVF utilization of any country in the world because the government pays for almost unlimited cycle attempts until a family has three children, spends according to the OECD only 7.4% of GDP on general health care.

Suffice it to say that medicine in the U.S. is not two-to-three times better than in these other countries; according to many parameters, it. Indeed, is not better at all. But since the percentage of GDP is so much higher, the health care industry in this country is also that more powerful as an active or passive influencer of government policy. And this, of course, creates a vicious cycle, steadily expanding the difference between the U.S. and other countries with no real benefit for the U.S. population in return.

We are offering this general information as a preamble for this sub-section of our literature review by no means as an argument toward one or the other medical systems that other countries employ. It is, however, also interesting to note that most of these other countries employ a basic government-run system but in recent years have increasingly morphed into public-private systems, often with much higher satisfaction levels than the U.S. system receives from the public. Also indisputable is the fact that wherever one looks, the U.S. health care system is driven by economic interest groups, and some not-for profits are among the biggest abusers.

Establishing final FDA oversight over Laboratory-Developed Tests (LDTs) Readers of the VOICE, know that the CHR has been advocating for years that the FDA finally assumes responsibility for oversight over LDTs, which have been ignored decades. Originally on a voluntary basis excluded by the FDA from oversight, these tests were meant to be of minor significance, mostly only in physician-offices performed tests. The laboratory testing industry saw this exclusion, however, as an opportunity to introduce to the marketplace as alleged LDTs highly influential tests nationally without FDA review. This included many tests in oncology and in reproductive medicine, including such important tests as PGT-A and NIPT in early pregnancy.

We previously noted that the FDA now decided to reverse its policy of tolerance regarding LTDs, but it seems important to note that, so far, this has been only an announcement of intent. The laboratory testing industry is obviously not very happy about the decision and can be expected to let their lobbyists loose on Congress. In this context, The New England Journal of Medicine found the subject important enough to publish an article suggesting that FDA oversight

Continued on page 54

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over LDTs should lead to better safety, validity, and utility of those tests.2 The article stresses that the FDA must find a logical middle ground in who they review; there are, of course, tests which do not warrant reviews, while others in often controversial utilizations are screaming for such reviews.

REFERENCES 1. Center for Medicare & Medicaid Services. https://www.cms.gov/data-re search/statistics-trends-and-reports/national-health-expenditure-data/ historical#:~:text=The%20data%20are%20presented%20by,spending%20 accounted%20for%2017.3%20percent.

2. Singhal et al., N ENl J Med 2023;389(19):1735-1337

The medical publishing business Having found a way to live with open-access publishing (and, indeed, making more money than ever before), the medical publishing industry has reasons for concerns: The same group of people who initiated open-access publishing have now started advocating a “community-based” and “scholar-led” open research communication system in which publishers are no longer the gatekeepers.

Instead, authors would decide when and where to publish the initial account of their research. The only remaining function of publishers would be as service providers, paid for specific services, like handling submissions and printing.

An article in Nature offered a well formulated summary of the desires of (some) authors and the fears of publishers.1 Somewhere in this discussion we are, however, missing the point when it comes to the proposed changes by members of the author-community and even find reasons to be concerned. Having scientists “manage” the business of medical journal publishing does not appear to be a very good idea, and assuming current medical publishers would be satisfied to contract for copy editing and printing services, appears rather unrealistic. Moreover, we feel that the main problem of medical publishing does not lie in who owns the journals and what the owners’ profits are, but in who runs the journals (i.e., editors) and in whether they have adequate resources at their disposition.

The medical publishing industry’s principal concerns today are too many paper submissions, too few good reviewers, and overworked editors who, simply, do not have the time that is required to assess manuscripts for quality, choose appropriate reviewers, and recognize undisclosed conflicts. Moreover, with a new record of over 10,000 research papers retracted in roughly 20 years before 2023,2 we have also created a “fake” publishing industry that must be shut down. An unpublished analysis shared with Nature magazine suggested that over the last two decades over 400,000 research articles were published by paper mills with strong textual similarities to known studies, 70,000 only over the last two years. Among biology and medical publications, ca 3% of papers are likely paper mill products.3 Leading the list of journals publishing large numbers of “fake” articles has been Hindawi, a publisher of open access journals, originally founded in Egypt but then purchased and to this day owned by John Wiley & Sons. In December, likely concerned to have Wiley’s

54 | The Voice

brand adversely affected, the publisher announced the closing of Hindawi as a brand. Four journals under that company imprint were folded back into Wiley.2 We don’t want to be repetitive about what we have covered, but we must note that at the core of medical and all scientific publishing stands the peer review process. Considering the exploding number of submitted manuscripts to research journals, no editor can ever find enough qualified reviewers agreeing to review. There is only one way to resolve this problem: reviewers must be paid for the time they are spending on a review. Like any consultation in any other profession, peer review must be paid for!

REFERENCES 1. Liverpool L. Nature 2023;623:238-240 2. Van Noorden R. Nature 2023; 624(7992):479-481 3. Van Noorden R. Nature 2023;623(7987):466-467

Ethics

And the saga of fertility doctors using their own sperm continues It is difficult to understand why so many OB/GYNs, in the days before establishments of sperm banks, apparently felt a need to use their own semen samples in place of, as they usually represented, samples from medical students and residents. It couldn’t be the money because not only did a semen donation in those days not pay much, but the involved physicians usually were well-off and did not need the money.

A good example is the last one publicly accused of this misdeed in 1980: Merle Berger, MD, a founder of Boston IVF, one of the largest and most prestigious IVF clinic networks in the country.

He certainly didn’t need the money. A daughter was born in 1981 who is now 43 years old. Based on media reports, she allegedly discovered her real biological paternity—as it these days usually happens—when she tested her own genetic make-up through Ancestry and 23andMe in 2023 and learned that she was related to Berger’s granddaughter and his second cousin. Speaking to them, it became clear who her biological father was.

We here at the CHR have known Merle Berger since the founding of Boston IVF and, knowing him for so long, it makes this whole story even harder to believe. His lawyers released a statement that reads: “Dr. Merle Berger was a pioneer in the medical fertility field who in 50 years of practice helped thousands of families fulfill their dreams of having a child. He is widely known for his sensitivity to the emotional anguish of the women who came to him for help conceiving. The allegations concern events from over 40 years ago, in the early days of artificial insemination. At a time before sperm banks and IVF, it was dramatically different from modern-day fertility treatment. The allegations, which have changed repeatedly in the six months since the plaintiff ’s attorney first contacted Dr. Berger, have no legal or factual merit, and will

be disproven in court.” We agree with how his lawyers described him, but genetics are difficult to disprove and, if reaffirmed, the question remains—why?

REFERENCE 1. Rex K. CBS New Boston. December 14, 2023. https://www.cbsnews.com/ boston/news/dr-merle-berger-boston-ivf-impregnating-patient/

The CHR

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NEWSLETTER INFORMATION The CHR VOICE is the newsletter of The Center for Human Reproduction (CHR), an independent, academically affiliated infertility and research center located at 21 East 69th Street in Manhattan, New York, N.Y 10021. www.centerforhumanreprod.com. Telephone +212 994 4400.

The CHR VOICE attempts to inform and engage a global community of infertility patients, infertility service providers, and researchers in reproductive medicine, physiology, and biology. The mission of The CHR is clinical care, research, and education, all at highest standards, with empathy, honesty, integrity, and equity.The newsletter is published 10 times a year (except July and August). Copyright © 2023 by The CHR. All rights reserved. Print ISSN 2836-3086. Online ISSN 2836-3094. Copyright © 2023 by The CHR. All rights reserved.

For letters to the editor, comments, and suggestions, please contact jbeebe@thechr.com.

For all advertisements or sponsorships in The VOICE , please contact arata@thechr.com.

Advertisements appearing in The CHR VOICE do not necessarily reflect the opinions of The CHR.

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