The CHR’s Editorial Staff

By Norbert Gleicher, MD, Medical Director and Chief Scientist, at the Center for Human Reproduction in New York City. He is also the Editor-in-Chief of the _CHRVOICE and The Reproductive Times and can be contacted though either the CHR’s editorial office or directly at either of his two e-mails: ngleicher@thechr.com or ngleicher@rockefeller.edu.

In the medical literature, the Center for Human Reproduction (CHR) still holds the record for the oldest woman delivering an offspring with the use of autologous oocytes, who was two weeks short of age 48 when she had her embryo transfer.¹ And even though we have not had older women than that deliver, we have had older women conceive and miscarry. Moreover, autologous pregnancies and deliveries of pregnancies over age 45 – in the infertility literature still treated as “ancient” – can no longer be considered a rarity, at least at the CHR.

Yet even we at the CHR are puzzled by the fact that while no autologous IVF pregnancies over age 48 have been reported in association with IVF, spontaneous pregnancies after that age have been sporadically reported in the medical literature for decades. And nobody has studied this subject with more intensity than old CHR friend and colleague from Israel, Neri Laufer, MD, who made his scientific name in the early IVF days in the U.S. (Yale and Mount Sinai, NY) and later as Chair and professor of OB/GYN at the Hadassah Medical Center and Hebrew University in Jerusalem, Israel.²

And though already retired for several years, his work going back to 2004 is still puzzling us. He then published a by-now classical paper on a substantial group of women who delivered an infant after a spontaneous pregnancy after the age of 45 years.² His collection of Methuselah Moms, indeed, included a then quite astonishing number of 209 women. This is important because this number can be assumed to include a significant number of women who conceived at age 44 and then delivered at age 45 (a difference of one year matters here!).

And his paper reported the following: The mean (±SD) age at last delivery was 45.7 ± 0.9 years (range: 45–49). The mean parity was 9.6 ± 4 children (range: 2–20): 81% of the women were grand-multiparas (≥6 deliveries) and 46% were grand-grand-multiparas (≥11 deliveries). The mean number of spontaneous abortions (SAB) was 1.9 ± 1.9 (range: 0–9). Increased parity did not have a protective effect on abortion rate: 12.9% for parity 2–5, 15.6% for parity 6–10, and 21.3% for parity 11–20. Women in the study group differed significantly in their SAB rate from a general population: 11.3% vs. 17.7% at age 39, 13.2% vs. 33.8% at age 44, and 9.1% vs. 33.8% at age 45 (see Figure below).

Laufer and colleagues, of course, logically concluded then that women who delivered at or after 45 years of age were mostly grand-multiparas. They also correctly hypothesized that this unique group of grand-multiparous women might possess a genetic propensity that delays the normal rate of ovarian and oocyte senescence.

That is, of course, one possible explanation; but it is not the only one, and it is also possible that underlying genetic and non-genetic causes share responsibility. And while the very low miscarriage rate in this population, in comparison with age-specific by parity unselected women, supports a genetic causality, one, of course, can argue that almost everything in medicine is “genetic.”

But one can also ask what came first in these women (egg or chicken?), - a genetic predisposition, a mechanistic explanation that suggests that early (by age) and frequent use of a physiologic function (like spontaneous conception), or both in combination strengthens its performance and, thereby, achieves its repetition. In other words, the question arises whether grand-multiparity is causally related to still-spontaneous conceptions at advanced ages, better quality of pregnancies, and, therefore, fewer miscarriages. Starting early and doing something (in this case, having babies) more frequently may simply get all engines performing at their best. This is what, after all, recently has been increasingly emphasized in male infertility, - where increased ejaculation frequency has in general been associated with improved semen quality.³

One more interesting point is worth noting: The median age at delivery of Laufer’s patient group in 2004 was 45 years, meaning that they conceived at median ages of 44-45 years. This is, however, exactly the median age of the CHR’s patient population over at least the last three years as we reported in the literature, suggesting that Laufer’s group of spontaneously pregnant women who delivered were not really as old as they were made out to be.

They on first impression may appear unusually old because in the U.S. (and likely also elsewhere in the world), the median age of women undergoing autologous IVF – for quite some time – has been fixed at approximately 36 years (likely a consequence of women after ages 42-43 being quite automatically advanced into egg donation).

Defining female patients at ages 44 or 45 as Methuselahs may, therefore, no longer be appropriate, - especially as we have demonstrated in the CHR’s patient population increasing ongoing pregnancy rates from 8% in 2022 to 10% in 2023, and 12% in 2024/2025 if these women produced even only one day-3 embryo for transfer in their IVF cycle.

With the autologous pregnancy and live birth rate in IVF reported up to age 48, the above-noted pregnancy rates clearly appear to exceed spontaneous pregnancies in these age groups. They most certainly, however, don’t underperform them, and Methuselah Moms, therefore, require a new age definition.

We, indeed, would suggest that a real Methuselah Mom is only a woman who, either through spontaneous conception or IVF, establishes an ongoing pregnancy after age 50. One, of course, wonders how many of those really do exist after spontaneous conception (as noted, - after IVF, none of them have been reported so far beyond 48).

We, moreover, would argue that, considering the increasing frequency of ongoing pregnancies up to ages 47-48 years, IVF already appears to be doing better than spontaneous conception. It, therefore, appears time to reject the myths of genetically specially endowed women somewhere on this planet achieving motherhood at especially advanced ages. As is the case in biology in practically all of its functionality – and everywhere – these data strongly suggest that we are dealing here only with the usually progressively poorer statistical probabilities that come with advancing age and – whatever the reason(s) for this decline – ultimately, IVF will beat out spontaneous conception at very advanced ages, - just as it does at younger ages.

REFERENCES

1. Gleicher et al., Reprod Biomed Online 2018;37(2):172-177

2. Laufer et al., Fertil Steril 20004;81(5):1328-1332

3. Clay N. Ejaculatory frequency and male fertility: a literature and evidence-based recommendation. Transl Androl Urolog 2026;15(2):63

The CHR’s Editorial Staff

More News on How the Maternal Immune System Adapts to Pregnancy

We here report on a very interesting recent paper in Nature magazine by investigators who – using a mouse model – reported previously unknown intestinal immune-responses in pregnancy. By way of background, the authors in their paper pointed out that mammalian reproduction requires substantial immune adaptations to safeguard reproductive success and to ultimately shape the evolutionary trajectories of a species.

Practically, this means that systemic and placental immunity shift toward tolerance (also a reason why several autoimmune diseases clinically improve in the mid-phase of pregnancy when tolerance is at its peak). The authors, however, also noted that how maternal immunity adapts in barrier tissues – which are sites of frequent infection and inflammation and, therefore, do need good immune responses – is not yet well understood.

They, therefore, investigate this in the intestines of mice, as intestines in all species are, of course, frequently associated with (food) allergies and all kinds of infections, including parasitic helminth infections. What they found was a previously unrecognized role for eosinophils, a type of granulocyte typically associated with allergies and helminth infections, in remodeling the intestinal barrier during reproduction.

Beginning in pregnancy and peaking during lactation, eosinophils accumulate in the small intestine in the absence of infection or inflammation. The authors further demonstrated that eosinophils promoted goblet cell differentiation in a stem-cell-intrinsic manner that led to increased protective mucus production. This remodeling indeed culminated during lactation and limited the entry and dissemination of pathogens conferring broad innate protection against enteric bacterial infections. In mice, this intestinal remodeling and innate defense, indeed, persisted for weeks beyond cessation of lactation.

The authors concluded that despite a general trend toward systemic immune modulation during reproduction, the maternal intestine undergoes remodeling to strengthen innate defenses, a mechanism that may have evolved to protect mothers and offspring in pathogen-rich environments. They also claimed to have established a framework for studying tissue-specific immune adaptation across the reproductive cycle, - highlighting that tissues can retain changes following physiological reproduction, with lasting implications for host defense and women’s health.

All of this is, of course, incredibly interesting and important for everybody interested in reproductive immunology (which we here at the CHR always are). This paper, however, made an additional impression on us because we – for some time – have been struggling in explaining observations in abnormal peripheral eosinophil counts and IgE antibody levels in an unusual number of our female infertility patients. And allergen-specific IgE and eosinophils, especially in allergic diseases and parasitic infections, are closely connected.

Specifically, IgE is an antibody class involved in allergic responses. Eosinophils, in turn, are white blood cells involved in inflammation, allergies, asthma, and defense against parasites and they interact through the same immune signaling pathways: Allergens (or parasites) stimulate a so-called Th2 Immune response (which is also the immune response stimulated in normal pregnancy). Th2 cells produce cytokines such as IL-4, IL-5, and IL-13, with IL=4 and IL-13 promoting IgE production by B lymphocytes and IL-5 promotes eosinophil growth, activation, and survival (see Figure below). But IgE and eosinophils do not always rise in parallel.

This paper, therefore, potentially directs us toward the gut of female fertility patients with abnormalities in IgE and eosinophil counts. And we like nothing as much as papers that give us new ideas for the CHR’s research.

REFERENCE

1. Huang et al., Nature 2026;654:209218

And More News on Eosinophils

And as further evidence that almost everything in our bodies is connected to everything else, a study just published in Science detailed a neuro-immunological mechanism in which psychological stress exacerbates skin inflammation, defined by a specific sympathetic-eosinophil axis that links mental stress and atopic dermatitis flare-ups.¹

That psychological stress can exacerbate dermatitis has been well established, but the mechanisms involved in this process have remained unclear. The authors of this very interesting study now identified a subset of prodynorphin-positive (Pdyn⁺) noradrenergic sympathetic neurons in mice that specifically innervate hairy skin and mediate stress-induced exacerbation of skin inflammation in eosinophil-dependent manner. Genetic ablation of these sympathetic neurons or of eosinophils-mitigated stress-drive worsening of inflammation in atopic dermatitis-like mice, while optogenetic activation of neurons recruited eosinophils through the CCL11-CCR3 axis, activating them in inflamed skin through the adrenergic receptor beta2(Adrb2), - a finding that will likely lead to more effective treatments of atopic dermatitis should this axis also be active in humans.

REFERENCE

1. Tian et al., Science 2026 391(6791):1269-1277

In New York City this September 9th? Come enjoy the Center for Human Reproduction’s 25th Anniversary Gala at the iconic venue Guastavino’s! The gala boasts world-class entertainment and celebration, including the 400-year cultural dance Awa Odori. Reserve your seat here.

The CHR’s Editorial Staff

Identifying Increased Elevated Cancer Risk in Pediatric Patients Through Germline Variant Identification

Chinese investigators now in an article in Nature Medicine confirmed that cancer risk and tumor characteristics could be identified in children with pathogenic germline variants, - thus providing information for genetic counseling and early preventative measures.¹ The study was performed using 2016-2025 data from a large genomic analysis of 75,602 children, assessing variations across 139 pediatric cancer-predisposition genes in relation to their tumor outcomes, - among those 203 tumors that were already present at the time of initial genetic testing, 97 malignant. Such preexisting tumors included Wilms tumors, retinoblastoma, neuroblastoma, and hepatoblastomas, as well as 106 benign tumors, mostly teratomas, hamartomas, and neurofibromas. In a follow-up cohort of 75,399 children initially tumor-free, P/LP germline variants were detected in 1.9%. Longitudinal follow-up of these children showed that in 85.15% of these children (n=64,187), 208 new tumor diagnoses were made.

These findings support the notion that pathological germline variants found in children are not innocent incidental findings, but can and should be used for subsequent genetic counseling, risk advice, and fitting clinical surveillance for these children. The paper was also accompanied by a Research Briefing that summarized these findings.²

REFERENCES

1. Dong X, Zhang K. Nat Med 2026;32:2238-2244:

2. Wang et al., Nat Med 2026;32:1991

And the Continuing Saga of Preimplantation Genetic Testing for Aneuploidy (PGT-A)

MOSAICISM IN PGT-A -- And in another study by Chinese investigators, the discussion continues, - though, unfortunately, under continuing incorrect ground rules, starting with the use of the term “mosaicism” for the “diagnosis” being made based on the presence of more than one DNA cell lineage being detected in an on-average 5-6-cell trophectoderm biopsy, while the correct definition of the term “mosaicism” is detection of more than one cell lineage in a complete organism derived from a single cell. In the case of PGT-A, this, therefore, should mean detection of a second cell lineage in any of the cells of a blastocyst-stage embryo.

With this basic definition of “mosaicism” not followed, the here-presented retrospective data analysis is already defined as incorrect and, consequently, we are again presented with data defining a medical diagnosis (“mosaicism”) in an incorrectly selected patient population that renders the study basically worthless because the study population is to an unknown degree contaminated by embryos that in reality are not “mosaic.”

The results of the study, described by the authors as “segmental and chromosomal monosomy mosaic embryos having pregnancy outcomes comparable with euploid embryos, whereas chromosomal trisomy mosaic embryos are associated with significantly poorer outcomes,” are, therefore, biased and incorrect.

IMPACT OF NUMBER OF BIOPSIED CELLS -- And a third study from Chinese investigators – this time in Reproductive Medicine Online – in a row investigated the impact of the number of biopsied trophectoderm cells on the “quality” of PGT-A.²

Once again, we see here a paper that made it into the press with authors, reviewers, and editors missing an essential design flaw, - in this case, a power analysis between range in the number of biopsied trophectoderm cells in relationship to total number of cells a biopsied embryo has at the moment of biopsy. And this failure does not even consider the fact that it is technically impossible to know the exact number of cells biopsied. In other words: a study design that biologically and statistically has no chance of offering a valid result. No wonder they were unable to demonstrate an outcome difference based on alleged cell numbers biopsied!

REPORT ON THE PGDIS TASK GROUP ON THE STATUS OF PGT-A -- And one more disappointing paper in Reproductive Biomedicine Online, this time by several prominent PGT-A proponents associated with the Preimplantation Genetic Diagnosis International Society (PGDIS), which for too long has been “poisoning” IVF practice with misleading published guidelines, which IVF practice, unfortunately, has been mostly following.³

The CHR’s investigators and some other members of the International Do No Harm Group in IVF (DNHG-IVF) submitted a detailed rebuttal article to the journal, which is currently under peer review. We, therefore, cannot go into further detail here but strongly encourage our readers to look for this article and consider it critically.

REFERENCES

1. Jin et al., Fertil Steril 2026;125(5):786-795

2. Kung et al., Reprod Biomed Online 2026;52(5):105407.

3. Leigh et al., Reprod Biomed Online 2026; 52(6): 105498

And That Also Applies to Polygenic Risk Screening of Embryos (PGT-P)

If the almost universal utilization of PGT-A in IVF by many IVF clinics is already an unprecedented shame for IVF practice, - the marketing of PGT-P by several genetic testing laboratories and IVF clinics goes even beyond that. Two colleagues from the University of Pennsylvania are, therefore, to be congratulated for an Inkling article in Fertility and Sterility (F&S) – yes, an Inkling article. While we dislike most Inkling articles, some are exceptions, and this is one of those – because the article describes the marketing “hype” surrounding PGT-P well.¹

The authors correctly argue that enthusiasm for PGT-P is moving faster than the scientific evidence supporting it. They caution fertility clinics against offering the technology routinely before its clinical value, accuracy, and ethical implications are properly established. They correctly point out the following concerns: (i) Limited predictive accuracy: Polygenic scores are imperfect and often do not translate reliably from population studies to individual embryos. Small differences between embryos may not be clinically meaningful. (ii) Lack of validated clinical benefit: There is currently insufficient evidence showing that selecting embryos using PGT-P leads to healthier children or better long-term outcomes. (iii) Risk of misleading patients: The marketing may create unrealistic expectations that embryos can be optimized or that disease risk can be substantially eliminated, when in reality genetics is only one contributor to complex disease, and, indeed, contributes only a relative minority of predisposition. (iv) Ethical and social concerns: The authors warn about possible expansion toward non-medical trait selection and broader societal concerns around “designer babies,” inequity, and discrimination. (v) Need for oversight and research: They advocate for cautious use only within research settings until safety, effectiveness, and ethical standards are better established. 

We totally agree with points (i) through (iv), but must disagree with point (v), probably - we assume - just added out of courtesy (which we, of course, don’t possess) because they do point out in their point (iii) that genetics contributes only a minority of every phenotype, with a majority determined by environmental factors in utero and after birth. Biology, therefore, completely contradicts the concept of PGT-P, - even more so than for PGT-A.

Congratulations to the authors, reviewers, and editors of F&S for publishing this Inkling article!

REFERENCE

1. Dokras P, Gracia C. Fertil Steril 2026; 125(5):784-785

The CHR’s Editorial Staff

Does Hyperemesis Gravidarum Adversely Affect Pregnancy Outcomes?

Hyperemesis Gravidarum (HG) is a serious form of nausea and vomiting during pregnancy that goes beyond just typical “morning sickness.” It affects between 1-3% of all pregnancies and is the leading cause of hospitalization during early pregnancy. What causes HG is basically unknown. A hypothesis suggests that maternal undernutrition (whatever that means) leads to abnormal placental development and function, thereby increasing adverse pregnancy outcomes. Interestingly, “morning sickness” is in contrast generally viewed as a reassuring sign in early pregnancy and often viewed as confirmation of an appropriate maternal immune response toward the fetus.

Whether HG adversely affects pregnancy outcomes is basically still unknown. Investigators from Stanford University now evaluated a possible association between HG and adverse pregnancy outcomes in a data set of 2.5 million singleton live births in California between 2007 and 2011 and found that – after adjustments for confounders – HG was associated with higher risk for preeclampsia, gestational hypertension, preterm birth, small for gestational age (SGA) births, placental abruption, and anemia. Risks in most instances were higher if a first hospitalization already occurred in the second trimester of pregnancy.

We actually like this study for what the authors did not address, - namely the fact that all adverse pregnancy outcomes discovered to be associated with HG are basically likely evidence for early termination of immunological tolerance by the maternal immune system (prematurity, preeclampsia, SGA, etc.) also seen with practically all autoimmune diseases in pregnancy or are the secondary consequences of those conditions (i.e., placental abruption in hypertensive diseases, for example).

If one were to assume that this, indeed, does represent the correct interpretation of these rather unique study’s results, then the silly nutrition hypothesis can really be finally buried (maybe except for extreme eating disorders), and research should switch to trying to figure out what happens so differently to the mother’s immune system when she experiences no “morning sickness,” has “morning sickness” in early pregnancy, or experiences HG.

REFERENCE

1. Gardner RM, et al., Am J Epidem 2026; kwag134. https://doi.org/10.1093/aje/kwag134

How Good is Low-Dose Aspirin in Preventing Preeclampsia?

The answer is “very good,” based on an abstract presented at the annual conference of the Society for Maternal-Fetal Medicine 2026 in February in Las Vegas, NV.¹ The study, involving over 18,000 pregnant women who received 162 mg of aspirin (i.e., double the standard “baby-aspirin” dosage of 81mg/day) demonstrated a 29% reduction in severe preeclampsia. The benefit was observed in patients with as well as without a history of chronic hypertension, and the study observed no increase in hemorrhagic complications in pregnancy.

Clearly a wonder drug!

REFERENCE

1. Duryea et al., Society for Maternal-Fetal Medicine 2026; February 8-13, Las Vegas, NV; Abstract LBA02

Promising News Regarding the Treatment of Anhydramnios Due to Fetal Kidney Failure

Lethal pulmonary hypoplasia (PH) is the usual consequence of anhydramnios due to fetal kidney failure. Now, investigators from a consortium of U.S. academic institutions investigated whether serial amnioinfusions instituted before 26 weeks of gestation may prevent occurrence of PH and demonstrated in a nonrandomized clinical trial thatneonatal survival to 14 days or longer with dialysis access was achieved for 19 of 29 live-born neonates (65.5%) with fetal kidney failure not due to bilateral renal agenesis.¹ Longer-term infant survival was lower, with 48% surviving to hospital discharge. The treatment was not associated with significant maternal complications.

Serial amnioinfusions, thus, to a degree, mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Independent of early lung function, significant neonatal morbidity and mortality, however, persisted. Interestingly, Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s² bilateral renal agenesis cohort (this is a multicenter, prospective clinical study evaluating the use of serial in-utero amnioinfusions for fetuses with Early Pregnancy Renal Anhydramnios), suggesting common mechanistic pathways for mitigating pulmonary hypoplasia.

REFERENCES

1. Miller et al., JAMA Online ahead of print. July 1, 2026.

2. NIH, RAFT. https://raft-trial.org/

Effects of a Second Pregnancy on a Woman’s Brain Structure and Function

The same group of Dutch investigators that previously demonstrated that a first pregnancy changes women’s brain structure and resting-state brain activity (which we at the time commented on)¹ now reported how a woman’s brain is transformed when she undergoes another pregnancy in a prospective pre-conception cohort study involving 110 women, including women who became pregnant with their second (PRG2) or first child (PRG1) and compared them to nulliparous women.²

Multimodal MRI data demonstrated differential changes between PRG2 and PRG1 in grey matter volume, white matter tracts, and functional neural network organization, - though similar, were less pronounced in PRG2 in regard to structural and functional changes in default mode and frontoparietal network. These observations suggest a primary adaptation of these networks in first-time mothers, - further fine-tuned across a second pregnancy.

Stronger alterations were found in PRG2 in the dorsal attention and somatomotor network, including the corticospinal tract, pointing to an enhanced plasticity within these externally-oriented networks.

Combining all data, the authors concluded that neurostructural changes in both groups related to mother-infant attachment and peripartum depression. A second pregnancy, however, still uniquely changes a woman’s brain, entailing both convergent and distinct neural transformations.

REFERENCES

1. Hoekzema et al., Nat Commun 2022;6931

2. Straathof et al., Nat Commun 2026;17:1495

In New York City this September 9th? Come celebrate the Center for Human Reproduction’s 25th Anniversary Gala at the iconic venue Guastavino’s! Reserve your seat here.

The CHR’s Editorial Staff

Already Used to the New Name – PMOS – for PCOS?

To be frank, we haven’t completely gotten used to it yet, and, therefore, we still use both terms together for a transition period; but we are trying to get there.

The discussion about the name change has, indeed, heated up: As we have already opined, we are certainly not enamored as much by the name change as many of our more “politically” oriented colleagues apparently are because we would rather have put more emphasis on improvements in study designs and clinical practice. A name change alone will, of course, not do either.

We therefore were pleased to see in a recent Medscape article that we are not the only ones who are skeptical about the name change from Polycystic Ovary Syndrome (PCOS) to Polyendocrine Metabolic Ovarian Syndrome (PMOS).¹ We were especially pleased that Andrea E. Dunaif, MD, Head of the Medical Endocrine program at the Mount Sinai System, for many years worldwide recognized as a leading authority on PCOS/PMOS, was critical. As we repeatedly before noted, the results her genomics laboratory obtained in defining PCOS/PMOS phenotypes largely overlapped with the CHR’s clinical research on PCOS/PMOS phenotypes. Her laboratory was, indeed, the first to report genomic analyses of these distinct biological subtypes of PCOS/PMOS.

Interestingly – and, in our opinion, also correctly – Dunaif et al. not only criticized the absence of any recognition of these now genomically (and by the CHR clinically²) defined biological subtypes of PCOS/PMOS, but also the lack of recognition that this disorder now has also been identified in men and, therefore, represents a metabolic disorder across sexes. And she voiced her discontent, as the Medscape article described, with “Shakespearean flourish,” when introducing her talk to the consortium by announcing her intent “not to praise but to bury the term PMOS.”

Other prominent figures had other reasons to oppose the renaming, among those David A. Ehrmann, MD, professor emeritus and expert on PCOS at the University of Chicago, and Ellen W. Seely, MD, director of clinical research in the division of Endocrinology, Diabetes and Hypertension at Brigham and Women’s Hospital in Boston. Meanwhile, China announced that it will continue using PCOS as the clinical term, while trying to introduce PMOS as a possible academic term (whatever that is supposed to mean).

We frankly don’t understand all the fuss in lay media about the name change – and also felt that supporting articles about the name change in Nature Metabolism, Nature Medicine, The Lancet, The Lancet Child & Adolescent Health, Obstetrics, Gynecology & Women’s Health were just too much marketing and too little science and more of a self-aggrandizement by the “political” leadership that had pushed for the name change (and, of course, also authored the papers). Like in most aspects of life, medical practice too, is usually dictated by medical “politicians” and not the medical “scientists.”

REFERENCES

1. https://www.medscape.com/viewarticle/critics-question-science-and-process-behind-new-term-pcos-2026a1000lr2

2. Gleicher et al., Biomedicines. 2022;10(7):1505

Managing Infertility in Obese PCOS Patients

Two recent papers addressed this issue: In a first, Canadian authors investigated whether lifestyle interventions before and during fertility treatments in obese and overweight women with PCOS/PMOS made any difference.¹ The study’s conclusion was that comparing lifestyle interventions alone for 6 months – and then followed by infertility treatments – in comparison to usual care (without any interventions) within 18 months did not lead to an increase in live births following fertility treatment, but significantly increased spontaneous pregnancy rates, potentially leading them to avoid costly infertility treatments.

This paper is very difficult to evaluate since this randomized study – without question – has considerable shortcomings, starting with the fact that it included obese women as well as simply overweight women with PCOS/PMOS, - and some PCOS/PMOS patients were included with slightly lower BMIs as they allegedly “exhibit metabolic consequences already at lower BMIs.” Moreover, the trial “was planned” in 2011. Study consistency, therefore, of course, is a major issue because IVF practice has radically changed since then. And we could go on and on with study design criticisms.

However, this paper does offer at least one important point for consideration that especially applies in consideration of the above-noted name change from PCOS to PMOS: Why is it that the very important and very basic question whether – and by which methods – lifestyle interventions potentially can positively affect spontaneous conception rates and/or fertility treatment success has not yet been resolved? And then there is, of course, the point we have been making by now for literally decades, - why are PCOS studies almost uniformly of unacceptably poor quality?

A second paper – this time from U.S. investigators – was much simpler in its design and, therefore, also much easier to judge. Here, the goal was to determine whether time-restricted eating (TRE) was a successful strategy in reducing body weight in women with PCOS/PMOS. The efficiency of TRE for weight management in PCOS is not well understood. The authors, therefore, evaluated the effectiveness of TRE compared with standard care [daily calorie restriction (CR)] and a no-intervention control in women with PCOS.

The study involved only 76 participants who randomly were assigned for 6 months to one out of three study subgroups: (i) a 6-hour TRE regimen (all meals consumed between 1 p.m. and 7 p.m., without calorie tracking): (ii) a CR plan (25% daily energy restriction); and (iii) a control group with no dietary changes. Endpoint of the study was the percent change in body weight at 6 months.

And by month 6, body weight had indeed significantly decreased in TRE (-4.32% (95% CI, -6.20, -2.44), P < 0.01) as well as CR groups (-4.66% (95% CI, -7.13, -2.19), P < 0.01), relative to controls and there was, therefore, no difference between the TRE and CR groups (0.34% (95% CI, -2.15, 2.83), P = 0.79). In short, TRE and CR had similar effects, thereby – at least to a degree – rebutting the first here-discussed study.

Though clearly a much better-quality study than the first study, it is important to note that the definition of PCOS/PMOS in this study – like in practically almost all studies of this condition – was all-encompassing and not – as should be the case – broken out ideally by genomic and/or clinical sub-types or at least standard old-fashioned phenotypes under Rotterdam criteria. And since by now it is undeniable that lean and obese PCOS/PMOS patients present with distinct clinical-biological as well as genomic characteristics, including lean patients indiscriminately into the large majority of obese patients risks selection biases dependent on the distribution of these two distinct patient groups within the complete study population. In a study as small in size as the here-discussed paper, even small changes in distribution can make statistically significant changes.

This is, of course, a very significant shortcoming of this paper, and we, therefore, were somewhat surprised by its acceptance by Nature Medicine.

Defining Adolescent Lean PCOS

A very interesting paper for us was recently published by Boston-based investigators in The Journal of Clinical Endocrinology and Metabolism³ because – to the best of our knowledge – the concept of a hyperandrogenic “lean” PCOS phenotype in adolescence has never before been reported, - except for one paper from NIH investigators several years ago, which described a group of such adolescents who exhibited what the authors described as microgranular adrenal hyperplasia.⁴

We have since suspected that this microgranular pattern of adrenal hyperplasia in teens likely is what under Rotterdam criteria was described as the only non-hyper-androgenic and lean PCOS/PMOS phenotype-D and demonstrated that this group of young women, indeed, like all other women in the postmenarchal period, are hyperandrogenic (therefore, the suspected association with micronodular adrenal hyperplasia). They, however, at very young ages, develop increasing insufficiency in adrenal androgen production and by approximately age 25 have become normo-androgenic. Because ca. 90% of PCOS/PMOS diagnoses are made between ages 25-35 years, Rotterdam erroneously considered these women, therefore, as non-hyperandrogenic!⁵

Because of our interest in lean PCOS/PMOS, this new paper about lean adolescent PCOS patients immediately attracted our attention even though the principal issue the paper investigated – metabolic findings (insulin resistance and adipokine profiles) – are not issues we considered particularly relevant for this group of young women. The authors recruited pregnant women at their initial prenatal visit between 1999-2002. In-person study visits occurred during infancy, early and mid-childhood, and early and mid-teen years. Between visits, participants received annual mailed or online questionnaires. Only 51 participants met the study’s criteria for a PCOS/PMOS diagnosis and among those with normally low BMI were only 27.

Somewhat surprisingly, we need to acknowledge, the study demonstrated that even these young women with apparently lean PCOS/PMOS demonstrated altered adipokine profiles suggestive of adipose tissue dysfunction. In other words, - even in the absence of obesity, this dysfunction exists. This is interesting because – after having doubts whether our lean PCOS/PMOS patients who after age 35 usually become hypo-androgenic and who, in contrast to all other PCOS/PMOS patients, usually do not develop metabolic syndrome, - instead demonstrating a very high association with hyperactive immune system activity (and, therefore, miscarriage risk) really should still be viewed as PCOS/PMOS patients, these findings would support keeping them within this designation. It also supports the notion that if PCOS/PMOS really is genomically and biologically made up of in principle only two biological subgroups (or phenotypes), there likely exists a third one that demonstrates overlapping characteristics from both main types at different proportions. Considering the obvious polygenic etiology of PCOS/PMOS, such a conclusion, of course, makes sense.

The Immune System in PCOS/PMOS

And since we are already talking about the immune system, a recent paper from the University of Wisconsin in Madison reported on a single cell analysis of follicular fluid in PCOS/PMOS, suggesting dysregulation of immune function in PCOS/PMOS patients undergoing ovarian stimulation.⁶ As the authors noted in their paper, since PCOS/PMOS has been known for some time to be characterized by an inflammatory cytokine and leukocyte bias, this association has been made for all of PCOS/PMOS. It was, indeed, only the CHR’s research that isolated this association with a hyperactive immune system primarily to the lean PCOS/PMOS phenotype under Rotterdam called the D-phenotype. But assuming again overlapping characteristics in some patients, it should not surprise anyone that these immune abnormalities were attributed to all PCOS/PMOS patients.

How these immune abnormalities, however, affect ovaries is not well understood and was, therefore, the subject of this investigation. And even though this study once again – like most PCOS/PMOS studies – did not define individual sub-groupings of the condition in their study population, the study’s results were interesting, and the authors hypothesize that the ovarian follicular immune environment in these patients is uniquely dysregulated.

Using single-cell RNA and surface protein analysis of peripheral blood and follicular fluid from patients undergoing IVF, they then discovered that follicles in general - both in PCOS/PMOS as well as in controls - were immunologically distinct from what happened in the circulation. At the systemic level, they found that ovulation induction in PCOS/PMOS women may alleviate systemic inflammation, while healthy control ovaries experienced acute immune-directed ovulatory signaling. PCOS/PMOS follicles were deficient in key pro-ovulatory cell to cell communications and displayed instead a chronic low-grade inflammatory state with fibrotic features.

It now, of course, would be more than interesting to determine whether these characteristics are mostly concentrated in lean PCOS/PMOS patients, but that would be, indeed, what we would expect, considering that the lean PCOS/PMOS patient population demonstrates evidence of a hyperactive immune system (autoimmunity, inflammation allergies) in over 85%.⁵

Is Pain a Characteristic of PCOS/PMOS?

This is what a preprint in eLife recently suggested, which in the journal’s editorial assessment “presented valuable findings on the high prevalence of pain in women with PCOS/PMOS.⁷ The journal’s assessment also concluded that “the evidence supporting the conclusions is compelling, utilizing a massive global dataset and rigorous propensity score matching to identify pain as a critical, yet underexplored, clinical marker.”

We acknowledge surprise about this association. Conducted in January 2026, using data from 120 Health Care Organizations within the TriNetX Global Network, the study involved 103,675,738 women from diverse racial backgrounds. The analysis focused on the prevalence of pain among women with PCOS/PMOS, both overall and in those prescribed PCOS-related medications. The study found that 20.67% of women with PCOS/PMOS experienced pain, with the highest prevalence among Black or African American (32.70%) and White (30.78%) populations. Both the PCOS/PMOS and PCOS/PMOS and pain cohorts exhibited increased relative risk for various health conditions, with significant differences noted across racial groups for infertility, ovarian cysts, obesity, and respiratory diseases. Additionally, women with PCOS/PMOS who were treated with PCOS/PMOS-related medications showed a decrease in pain diagnoses following treatment. In conclusion, this study highlights the critical need to address pain in the diagnosis and management of PCOS/PMOS due to its significant impact on patient health outcomes.

After reading this preprint, we must say we are unconvinced and – if anything – even more skeptical, - at least how the paper is presented. The data – we agree – are believable and, of course, gigantic in numbers of patients. But where is the evidence that any of the pain symptoms described in these PCOS/PMOS patients have anything to do with their PCOS/PMOS? Or even more surprising, considering the laudatory editorial assessment of this paper by eLife, where is the evidence that we are really dealing with PCOS/PMOS patients, considering how inaccurate a diagnosis this is (as already noted here) and has been for decades? If this paper had already completed peer review and been published, it definitely would have deserved even stronger criticism from us. But because it still is a preprint, we will withhold final judgment.

REFERENCES

1. Belan et al., J Clin Endocrinol Metab. 2026;111:e1643-e1652.

2. Corapi et al., Nat Med 2026;32:2155-2163

3. Whooten et al., J Clin Endocrinol Metab 2026;111:e1364-1372

4. Gourgari et al., J Clin Endocrinol Metab 2016;101(9):3353-3360

5. Gleicher et al., Biomedicines. 2022;10(7):1505

6. Wgrzynowicz et al., Biol Reprod 2026;114(5):1736-1746

7. Cherlin et al., eLife, Reviewed Preprint. June 9, 2026. https://elifesciences.org/reviewed-preprints/103875

The CHR’s Editorial Staff

The Clitoris – Likely the Most Under-Studied Organ in Humans – is Suddenly in the News

For centuries, medical science treated female sexual anatomy as secondary or mysterious. As Manuela Callari, a medical writer at Medscape, recently noted, mapping the clitoris — especially its full internal structure and nerve network — has fundamentally changed that view and reshaped women’s health in several important ways.¹

First, researchers discovered that the clitoris is not just the small external glans visible at the vulva. Most of the organ is internal, extending deep into the pelvis with erectile tissue, bulbs, and branching nerves surrounding the vaginal canal. Modern imaging and anatomical studies showed it is a complex sensory organ comparable in structural sophistication to the penis.

Older medical models often framed women’s orgasm mainly around vaginal penetration. Clitoral mapping showed that the clitoris is central to female sexual pleasure and orgasm for many women. Researchers now increasingly describe orgasm as involving a broader “clitourethrovaginal complex” rather than a single isolated “G-spot.” This has improved sexual health education, diagnoses of sexual dysfunction, counseling for pain during sex, and treatments in general gynecology. Importantly, precise nerve mapping can have major surgical implications since pelvic surgeries can damage clitoral nerves unintentionally because the anatomy was poorly understood or not even discussed during surgical training.

Recently, precise mapping studies have greatly helped in avoiding such damage during especially vulvar cancer surgeries, reconstructive surgeries, gender-affirming surgeries, and after female genital cutting (in many non-Muslim countries forbidden) or other pelvic trauma. A 2026 report described the first full 3D mapping of the clitoral nerve network, revealing that the nerve branches are more extensive than previously believed. Researchers argued that this could reduce loss of sexual function after surgery.² 

In summary, the clitoris is an intensive internal nerve network, rather than a small external structure. Pelvic surgery can cause long-term sensory loss and impair orgasm, while clitoral mapping may improve episiotomy and vulvar reconstruction in general. Here-noted detailed nerve mapping of the clitoris became possible technically through Synchrotron x-ray imaging by neuroscientist Ju Young Lee, PhD, a research associate at Amsterdam UMC, The Netherlands.

REFERENCES

1. Callari M. Medscape Medical News June 17, 2026. https://www.medscape.com/viewarticle/mapping-clitoris-reshapes-our-understanding-womens-health-2026a1000kgb

2. Sims C. The Guardian. March 29, 2026, https://www.theguardian.com/society/2026/mar/29/full-network-clitoral-nerves-mapped-out-first-time-women-pelvic-surgery?utm_source=chatgpt.com

Using Menstrual Effluent for Diagnostic Purposes

Researchers are increasingly treating menstrual effluent (“period blood,” though it also contains endometrial tissue, immune cells, proteins, RNA, lipids, and microbes) as a kind of noninvasive “liquid biopsy” of the uterus. The field is still in its early days, but there are some genuinely promising findings—especially when it comes to endometriosis. A recent systematic review of the subject analyzed 35 studies and found that menstrual effluent consistently reflects known endometriosis biology, including progesterone dynamics, impaired decidualization, inflammatory signaling, immune dysfunction, abnormal angiogenesis, and altered stem cell behavior.¹

But there are still important caveats: Studies reported are universally still very small and, therefore, statistically not very solid. Moreover, almost no real-world data exist, - as most studies were performed in highly selected patient populations. Some studies hint at the possibility that patients with infertility and/or recurrent implantation failure (if such a diagnosis really exists) may, indeed, demonstrate abnormal cellular and/or molecular patterns in menstrual effluent.

Menstrual effluent as a research subject is, therefore, attracting increasing attention, as also suggested by a recently published paper in the JCEM, which tried to shed some light on the known association of low vitamin D levels with female infertility.² The study investigated in healthy females from ages 19 to 40 years the effects of active vitamin D (Calcitrol) on endometrial stromal cell decidualization as defined by menstrual effluent.

Results suggested that vitamin D enhanced decidualization of endometrial stromal cells to a very significant degree (P< 0.0001), - an effect likely produced through reducing protein kinase B (AKT) signaling and further downstream events, suggesting its potential role in female fertility. Vitamin D biomarkers were moreover clearly measurable in menstrual effluent, reemphasizing menstrual effluent as an increasingly interesting research target.

REFERENCES

1. Watrowski et al., Diagnostics (Basel); 2026;16(5):677. https://doi.org/10.3390/diagnostics16050677

2. Metz et al., J Clin Endocrinol Metab 2026;11(6):e1532-e1543

What’s the Relevance of Thyroid Disorders for Female Infertility?

Thyroid disorders are highly prevalent during reproductive years, including both thyroid dysfunction and thyroid autoimmunity (TAI). Infertility practice is paying careful attention to thyroid function in infertile women, - though not necessarily because abnormal thyroid function affects female fertility (more on that below), but because even mild hypothyroidism has been associated with lower IQ in offspring.¹ Data, however, also suggest that thyroid disease may impair fertility through hormonal and immune-mediated mechanisms.

A recent review article by Belgian colleagues in the JCEM tried to synthesize current evidence regarding effects of thyroid dysfunction, particularly subclinical and overt hypothyroidism, as well as TAI, on female fertility and outcomes of assisted reproductive technology (ART). Especially the role of subclinical hypothyroidism and euthyroid TAI remains controversial.

Interestingly, these investigators in their review article basically ignored the fetal effects of thyroid disease. In concentrating on the effects on female fertility, they concluded that despite limited supporting evidence in the literature, levothyroxine (LT4) is nevertheless widely used in clinical practice, often initiated at thyroid-stimulating hormone (TSH) thresholds of 2.5 mIU/L to define subclinical hypothyroidism and commence treatment.

They then argue that recent data suggest that implementing such thresholds may not be associated with improved fertility outcomes, and that, therefore, higher TSH cutoffs for diagnosis and treatment in the preconception settings may be indicated. They furthermore argued in their paper that ART (i.e., especially IVF) introduces additional considerations, with thyroid status and autoimmunity potentially influencing ovarian response, embryo quality, and pregnancy outcomes and, therefore, concluded that in the light of these uncertainties, treatment decisions increasingly rely on individualized assessment of thyroid function, antibody status, and reproductive context.

Unfortunately – to state it bluntly – even though this review article was accepted in a relatively reputable medical journal, the authors very obviously had no idea what they were talking about. That the JCEM accepted the article and published the paper is moreover clearly a black eye for the mother journal of all Endocrine Society journals. Very obviously, this paper written by medical endocrinologists for a medical endocrinology journal most likely did not see the eyes of a reproductive endocrinologist during the peer review process.

The reasons for this assumption speak for themselves: (i) As already noted above, the threshold of 2.5,IU/L for TSH never had anything to do with a maternal diagnosis of hypothyroidism or with maternal autoimmunity; this cut-off was chosen to not expose offspring to even mild hypothyroidism. This cut-off has absolutely nothing to do with either a diagnosis of hypothyroidism or with consideration of hypothyroidism as a cause of infertility. Indeed, - except for hypothyroidism-associated hyperprolactinemia, - we are unaware of hypothyroidism in any way directly adversely affecting female infertility and/or affecting fertility treatments.

(ii) Similarly, the relationship of autoimmunity is much more complex than the review article reflects. Thyroid disease is, of course, almost always an autoimmune disease. Autoimmune thyroid disease is, indeed, one of the most frequently diagnosed autoimmune diseases during a woman’s reproductive lifespan. But that does not mean that autoimmunity – per se – either through thyroid disease or in other ways – automatically causes infertility.

Though women with thyroid disease trying to conceive are usually, indeed, started on thyroid replacement with thyroxin if the TSH is under 2.5 IU/L, this is done for the benefit of the growing fetus, - and not for the protection of the mother’s well-being. The authors’ argument that there is a growing tendency to - preconceptionally - adopt higher TSH cutoffs for diagnosis and treatment of hypothyroidism by adopting higher TSH, therefore, is non-sensical because the tight control of TSH values is not geared at the mother.

The conceptional mix-up between treating the mother’s potential hypothyroidism to improve her fertility problem – except for correcting potentially her hypothyroid-driven hyperprolactinemia – and preventing a loss of IQ points in the offspring alone, - warrants for this review paper rightful criticism.

REFERENCE

1. Murphy et al., Austr New Zel Obstet Gynecol 2015;55(5):459-463

2. Unuane et al., J Clin Endocrinol Metab 2026;111(5):e1239-e1251

In New York City this September 9th? Come celebrate the Center for Human Reproduction’s 25th Anniversary Gala at Guastavino’s! Reserve your seat here.

The CHR has been investigating this issue for many years and – for what we believe are very good reasons – has disagreed with this consensus in several publications and on many different grounds. Following the CHR’s longstanding practice of at times counter-arguing established dogma in infertility practice by “thinking differently” and, therefore, following several prior precedents, through which the CHR has contributed to worldwide improvements in misguided fertility practices, we have not been willing to accept the dogma of almost universal eSET as a settled subject. We, therefore, hope to once again reopen the discussion of this subject with this article.

The CHR’s Editorial Staff

A PIECE OF MY MIND: Many Twin Pregnancies Have Mistakenly Been Defined as Adverse IVF Outcomes, Leading to Overuse of eSETs — In View of Real Cycle Outcomes and Patient Desires, Time to Reconsider!

By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He is also the Editor-in-Chief of the _CHRVOICE and The Reproductive Times and can be contacted though either the CHR’s editorial office or directly at either of his two e-mails: ngleicher@thechr.com or ngleicher@rockefeller.edu.

Preamble

During the last two decades, professional societies have increasingly characterized twin pregnancies after assisted reproductive technologies (ART) as adverse treatment outcomes. This concept originated largely from Scandinavian investigators and subsequently became incorporated into international IVF guidelines on both sides of the Atlantic, promoting almost universal elective single-embryo transfer (eSET). The obviously declining twin pregnancy rates as a consequence have, moreover, been celebrated as evidence of “success” by ESHRE and ASRM, the two leading professional societies in the fertility field.

Although reducing preventable obstetrical and neonatal complications are, of course, appropriate outcome goals for IVF practice, the universal characterization of twins as treatment failures is based on several very questionable ethical assumptions and methodological approaches that clearly not only deserve but mandate reconsideration. Current dogma, moreover, ignores the likely most basic tenant of proper risk-benefit and cost-benefit considerations: While many are gleefully pointing out the alleged benefits of significant reductions in twin pregnancy rates, the discussion of the subject has completely ignored any discussion of adverse consequences of reducing twinning rates and those, of course, do exist.

This article, therefore, argues that the current eSET doctrine suffers from five major shortcomings: (i) It limits patient autonomy; (ii) It applies a uniform standard to highly heterogeneous infertility patients; (iii) It relies on inappropriate statistical comparisons between one twin pregnancy and one singleton pregnancy instead of comparing equal reproductive outcomes; (iv) It ignores the reality that infertility patients cannot be assured of achieving a second singleton pregnancy; and (v) it has completely ignored what must be considered adverse outcomes from reductions of at least some twin pregnancies.

Some History

Beginning in the late 1990s and early 2000s, investigators from Scandinavian countries and Belgium increasingly promoted the concept that IVF success should no longer be measured simply by establishment of pregnancies or live births, but by the birth of only a single healthy infant. These views eventually resulted in widespread advocacy of eSET,^1-3 and as recently as 2020, in the argument that “one (embryo) at a time should be the normal routine.”⁴ The most recent ESHRE Practice Guideline, published in 2024, noted that “no clinical or embryological factor per se justifies a recommendation of double embryo transfer (2ET) instead of eSET,” - a rather astonishing comment in an even more astonishing Practice Guideline.⁵

Though practically saying the same thing, the ASRM said it more sensibly by noting that “the most direct way to limit the risks of multiple gestation from ART is to transfer a single embryo.” The ASRM, in its last policy statement on the subject in 2022, at least noted the potentially improved pregnancy chances with 2-ETs (or transfer of more than one embryo in general), and, therefore, acknowledged that there is a “price” to pay for an (almost) universal eSET policy, - and that “price” is lowered pregnancy and live birth chances.⁶

And this conclusion then automatically clashes with extensive literature that suggests that successful conception within a desired timeframe clearly represents a frequently top-ranked desire of infertility patients,⁷ - though it, of course, does not universally outweigh everything. The relative weight of “success/quick conception” versus “risk and burden” varies by individual, age, prognosis, and life circumstances; the literature very clearly emphasizes heterogeneity rather than a single hierarchy.⁸

This is, of course, an incredibly important point that must be made, with especially age being likely the best example: The urgency of a 25-year-old to conceive will likely be smaller than the urgency of a 35-year-old or 45-year-old patient, with the latter representing roughly the median age of the CHR’s patient population over the last three years (compared to 36 years for all U.S. IVF clinics).

The Marginalization of Patient Autonomy

Modern medicine increasingly emphasizes shared decision making. Yet, in IVF, one finds a remarkable exception: Professional societies increasingly prioritize the physician – not the patient – in determining what constitutes an acceptable treatment outcome.

Are physicians entitled to demand eSET and refuse 2-ET, - and are medical societies entitled to do so?

Patients may reasonably value completing family building in one pregnancy, - especially if they are older, have already failed multiple IVF cycles, and/or are running out of money. Don’t they have a right to try to avoid repeating IVF cycles, minimizing repeated anesthesia, trying to avoid potential miscarriages, and/or repeated implantation failures (if such a thing really exists)? And shouldn’t they at least try to avoid – as already noted – financial consequences while trying to “beat” advancing maternal age?

For many patients, particularly women over age 40, twins represent success – not failure. So where is patient autonomy, when physicians practically take it away?

Uniform Standards in Highly Heterogenous Patient Populations

When all of medicine is pivoting toward the highly-individualized care of precision medicine, the infertility field is going the opposite way. And this is the case not only when it comes to eSET for (almost) all patients. It’s applied to almost all of infertility practice: We stimulate ovaries with gonadotropins produced in glycolization patterns that mimic gonadotropins extracted from postmenopausal urine of nuns because that had been the original source of gonadotropins. Why is nobody asking why we treat young women with nature’s gonadotropins for older, postmenopausal women?

Or why is one prominent NYC fertility clinic allegedly denying women above age 43 appointments, - if they don’t have a prior agreement to use third-party egg donations? Haven’t they noticed yet that there are women with “young” ovaries over age 43 and women with very old-behaving ovaries at age 33? Or how about all-blastocyst-stage culture for everybody, or all-freeze embryo banking cycles for everybody, or how about refusing patients IVF cycles unless they agree to PGT-A of their embryos?

Medicine increasingly emphasizes individualized care, - while embryo transfer policy has evolved toward exactly the opposite. Important variables in patient populations that are overlooked in the process are, of course, female age (the average 28-year-old woman differs fundamentally from the average 43-year-old), a patient’s prognosis (is it her 1^st or 10^th IVF cycle?), and her cause of infertility (is it tubal disease, male factor, diminished ovarian reserve, endometriosis, immune-mediated implantation failure, or something else?).

And then there are, of course, financial considerations at play. Repeated IVF cycles may be affordable in Scandinavia, where they in Sweden, for example, are usually covered by government insurance until age 40 (there are exceptions, of course). A dogmatic eSET policy under such circumstances may – at least at the margins – appear more logical but – when carefully considered – still remains totally non-sensical.

Moreover, in the United States, many patients still do not have insurance coverage for infertility services, especially IVF. Healthcare economics, therefore, directly affect acceptable risks for patients.

Statistical Outcome Risk Comparisons Between Twin and Singleton Pregnancies Have Been Fundamentally Flawed in Most Cases

This is perhaps the most strident argument against current eSET recommendations because this argument questions the basic hypothesis behind routine eSET practice, which is dependent on the claim that twin pregnancies create excessive maternal as well as neonatal newborn outcome risks, in comparison to singleton pregnancies. Assuming that such a significant risk does not really exist, not only could consideration of 2-ET no longer be attacked as harmful, but – in view of how important timely pregnancy success should be in every IVF treatment – 2-ET, indeed, would for many, if not most patients, have to be considered a very viable option and, indeed, maybe a preferable treatment over eSET.

And – considering the history of how this argument was introduced into the medical literature – there, indeed, are some significant doubts: At least initially, when our Scandinavian colleagues proposed the eSET policy, all studies compared outcome complications between one twin pregnancy with one singleton pregnancy. But these outcomes are biologically unequal, - comparing one twin pregnancy, which produces two infants, to one singleton pregnancy, which, of course, produces only one offspring. A statistically proper comparison should therefore be made with a comparison of one twin pregnancy with two consecutive singleton pregnancies (more on this below), a point we, here at the CHR, have been making since the eSET hypothesis was first introduced into the literature.^9,10

After years of making this argument, Swedish colleagues conducted such a study demonstrating practically no longer any meaningful differences in pregnancy outcomes – maternal and/or neonatal.¹¹ Key findings were: (i) When comparing one twin pregnancy to two singleton pregnancies in the same mothers (or matched cohorts), differences in many serious outcomes were minimal or absent after adjustment. (ii) Neonatal risks were largely limited to minor/short-term issues like respiratory complications and jaundice (higher in twins), with no significant differences in perinatal mortality, Apgar scores <7, first-year mortality, or congenital abnormalities. (iii) Maternal risks (e.g., preeclampsia, gestational diabetes) also showed limited or no differences in key areas. The study emphasized that twin pregnancies carried higher preterm/low birth weight risks, but the overall profile supported nuanced risk assessments.

And this does not even take into account that Luke et al. reported that twin-risks for most adverse outcomes are elevated in sub-fertile and IVF twins, compared to fertile twins.¹² This paper supported discussions on the added risks of multiples in association with IVF, - while highlighting factors like fertility status. It therefore contributed to the broader context of comparing twin vs. singleton (or cumulative singleton) risks in infertility treatment, a finding first already reported in the BMJ by the Dutch investigator F.M. Helmerhorst in 2004.¹³

Then – and to this day – widely ignored by the infertility field, he pointed out that IVF twins demonstrated significantly worse outcomes after assisted conception than after spontaneous conception (e.g., higher risks of very preterm birth [RR 3.27], preterm birth [RR 2.04], very low birth weight [RR 3.00], low birth weight [RR 1.70], as well as higher Cesarean section rates, NICU admissions, and perinatal mortality [RR 1.68]).

In contrast, the risks of twin births were much closer and significantly lower in assisted vs. natural conceptions. Notably,  perinatal mortality was about 40% lower after IVF (RR 0.58 in matched studies). There were minimal or no increases in very preterm birth, very low birth weight, or other major issues; only some outcomes like Cesarean section and NICU admission showed small increases.

While these outcome data on first impression may appear counterintuitive, they actually do make sense if one considers the fact that IVF pregnancies are diagnosed much earlier than spontaneous pregnancies and that, of course, means that IVF twins receive from early on much closer medical attention. His data thus already in 2004 pointed out that the most basic premise of the eSET hypothesis – significantly increased statistical risks from twin pregnancies in comparison to singleton pregnancies – is faulty.

But That Is Not Even All

All of this, moreover, does not even yet take into account the time and effort required to establish a second pregnancy and achieve a second delivery, - nor does it consider related costs for a second round of infertility treatments. But probably most importantly, a comparison between one twin and two singleton pregnancies does not take into account that – especially in an infertile patient population – even the best fertility clinic cannot guarantee a fertility patient a successful second pregnancy. Indeed, with infertile patient populations aging all around the world, the success of a second pregnancy attempt – because of pregnancy length, lactation period, and recovery time for the mother on average at least a two-year period – has a notably reduced chance, as after age 38-40, pregnancy chances quickly decline.

One successful twin pregnancy may, therefore, for many women, represent the only realistic opportunity to achieve a desired family size and, therefore, by itself, fundamentally alter the ethical balance in the discussion of eSET versus 2-ET.

This is also a fundamental reason why the argument by Finnish colleagues that eSET should also be the rule in older patients between ages 40 and 44 was so bizarre when it appeared unchallenged in 2013 in Human Reproduction,¹⁴ – yet receiving much more attention in the infertility field than, for example, Helmerhorst’s above-noted groundbreaking 2004 study.

How the Scandinavian Perspective About eSET Fooled the World

The original Scandinavian recommendations for eSET, defining twin births as basically adverse – and under all circumstances to be avoided - IVF outcomes, emerged from countries characterized by government-funded IVF, excellent neonatal intensive care, strong public health orientation, at that point at least still relatively homogeneous populations, and minimal financial burden for patients. These assumptions do not generalize internationally and, therefore, - even assuming that they, at least to a degree, support an eSET concept – do not apply to big parts of the world, including the U.S.

But aside from the fact that even these explanations do not warrant current eSET policies ethically, they, of course, appear almost bizarre in their undisputed acceptance in the U.S., where patients often pay tens of thousands of dollars out of pocket for IVF treatments. The calculus in the U.S. and in many other countries, therefore, differs substantially from the Scandinavian calculus and we wonder – considering the relative silence of our Scandinavian colleagues regarding this subject in most recent years – whether in view of increasing heterogeneity in their populations from immigration and considering increasing financial pressures on their health care systems – there has not been at least silent recognition of how much damage the current eSET policy they brought to the world really has caused and is still causing. One, therefore, would wish that they spoke out on the subject. As the original initiators of this practice, they, indeed, have a certain responsibility to speak out and, of course, have the standing to do so!

So, What is the Solution?

As in so many other areas in medicine, what we are witnessing regarding the here-discussed issue once more demonstrates that any rule that is applied “to everybody,” - i.e., rigid protocols like “eSET for everybody,” is non-sensical. Unfortunately, the infertility field has been going into this direction for much too long regarding so many different practices, from routine blastocyst culture for everybody, to routine all-freeze cycles, to preimplantation genetic testing (PGT-A) for all.

And all of this is happening in the fertility field at a time when almost everybody else in medicine is trying to implement “precision medicine,”- highly individualized medical practice specifically geared at the circumstances with which a patient presents. And these circumstances, of course, also include risk-benefit and cost-benefit assessments for every medical intervention.

Whether patients undergo eSETs or 2-ETs, therefore, must be individualized.

Rather than universal eSET, embryo transfer policy should incorporate maternal age, patient prognosis, number of previous failed IVF cycles, functional ovarian reserve, patient preferences, financial considerations, medical co-morbidities, desired family size, and obstetrical history, - in other words, an approach consistent with precision medicine.

The goal of infertility treatment is not merely to optimize obstetrical statistics, but to help patients build the families they desire. Accordingly, embryo transfer decisions must be individualized, rather than dictated by a universal preference for singleton gestations.

REFERENCES

1. Bergh C. Hum Reprod 2005;20(2):323-327

2. De Neubourg D, Gerris J. Hum Reprod 2006;21(4)843-846

3. Nygren et al., Acta Obstet Gynecol Scand 2007;86:774-782

4. Bergh et al., Fertil Steril 2020;114:673-679

5. ESHRE Guideline Group on the Number of Embryos to Transfer. Hum Reprod 2024;39(4):647-657

6. ASRM. A Committee Opinion. Fertil Steril 1022;117:498-511

7. Assaysh-Öberg et al., Sex Reprod Health 2023;37:100879

8. Carson SA, Kallen N. JAMA 2021;326(1):65-76

9. Gleicher N, Barad D. Fertil Steril 2009;91(6)”2426-2441

10. Gleicher N. Contemp Ob/Gyn September 1, 2013

11. Sazonova et al., Fertil Steril 2013;99(3):731-737

12. Luke et al., Am J Obstet Gynecol 2017;217(3):330.e1-330.e15

13. Helmerhurst FM. Brit Med J. 2004;328

14. Niinimäki et al., Hum Reprod 2013;28(2):331-335

The CHR’s Editorial Staff

Have You Heard About Sperm Racing as a Competitive “Sport”?

Don’t tell us that we don’t keep our readers abreast of all the most important new developments in reproductive medicine. But when we first heard about the here-reported new development, we thought it was a – not-so-funny – joke; then, the very serious BMJ published a serious article about it,¹ and we decided to check out what really is going on here. And we were quite surprised and here is why:

Yes, “sperm racing” is a real — and a very internet-era — competition where sperm cells are put into a microscopic “race” to compare motility (how effectively they swim). The idea mixes fertility science, biotech, sports-style presentation, and viral marketing. It emerged in 2025. A first highly publicized event was reportedly held – where else but in Los Angeles, CA, at the Hollywood Palladium (UPI reported on it on April 17, 2025²). And – allegedly – representatives from two competing California schools of higher learning – the University of Southern California and the University of California, Los Angeles – provided the microscopic swimmers for the inaugural Sperm Race.

A real start-up called Sperm Racing³ (watch their web site) has been promoting a “Sperm Racing World Cup” for 2026, with contestants from different countries competing for a $100,000 prize. And this is how it is supposed to work: Participants submit semen samples. Labs isolate motile sperm cells using standard fertility-lab techniques. The sperm are placed into tiny microfluidic channels designed to mimic aspects of the reproductive tract. Under a microscope, the sperm “race” toward a finish line. High-speed cameras and software track which sperm reaches the end first. Winners then advance tournament style. 

The organizers frame it like an e-sport or sporting event, with betting on brackets, head-to-head matchups, etc. Competitions are live-streamed, there are leaderboards, and there, of course, is “professional” commentary. Unsurprisingly, considering the crazy world we are living in, the concept went viral. It was likely helped by its biotech aesthetics, meme culture, influencer-style promotion, gambling/spectator elements, “tech bro” startup culture, and shock value.

Some reports and online critics questioned, however, whether parts of those races were genuine live microscopy or heavily simulated/animated. One Spanish-language report even claimed portions were computer-generated visualizations, rather than literal real-time sperm movements.⁴

So, how about the science?: Sperm movements, of course, are not linear and organized, but complex and chaotic. To believe that there is really a fastest sperm that “wins” fertilization – as it has been presented in some of the marketing materials – is a clear biological oversimplification. Moreover, the sperm’s motility alone is not a complete measure of male fertility, but only one of three major criteria (motility, morphology, and count). So while sperm motility is a real medical metric, turning it into a spectator race is more entertainment/media spectacle than established science.

But, maybe, the Center for Human Reproduction should organize a multi-center collaborative prospective study to see whether winners in these races have better fertilization rates and better pregnancy rates than losers. And here is yet another brilliant idea, especially for cash-short fertility clinics: How about a backroom for sperm racing between leftover sperm samples (of course, only with appropriate patient consent)? Sorry, just a stupid joke!

REFERENCES

1. The BMJ. 2026;393. June 8, 2026.376385. doi: https://doi.org/10.1136/bmj-2026-376385

2. UPI. April 17, 2025 . https://www.upi.com/Odd_News/2025/04/17/Sperm-Racing-Los-Angeles-Hollywood-Palladium/1181744921463/?utm_source=chatgpt.com

3. Sperm Racing World Cup 2026. https://www.spermracing.com/worldcup?utm_source=chatgpt.com. Accessed July 4, 2026.

4. Focus. https://www.focus.it/cultura/curiosita/che-cos-e-la-sperm-racing-la-gara-degli-spermatozoi?utm_source=chatgpt.com

Good News About GLP-1s Regarding Male Fertility

There are apparently only three randomized controlled trials in the literature that investigated the impact of long-term GLP-1 use on male reproductive hormones and fertility based on a recent systematic review of the literature that was presented at Endo 2026, and they showed no negative impact from this class of drugs.¹ We would argue that this finding is not surprising, considering what already is known about these medications (see the latest issue of the _CHRVOICE). The study, indeed, suggested that they may offer the usual benefits also seen in women. The one issue not addressed so far is whether the medications should be stopped during times of fertility attempts; but there – at least currently – appears no evidence that this may be required.

REFERENCE

1. Endocrine Society. Press Release. June 13, 2026. https://www.endocrine.org/news-and-advocacy/news-room/2026/natesh-press-release-endo-2026

The Importance of Paternal Nutrition on Fetal and Placental Development

Currently only a preprint in eLife, a study of U.K. investigators recently reported that paternal diet influences do not only affect testicular morphology, but also placental and fetal development¹ and, thereby, supporting a role for paternal contributions in general to the health of offspring. What adds to the interest in this paper is that the study also considered potential links between the male microbiome and male reproductive health, by itself, of course, a “hot” subject in female as well as male infertility.

The editorial evaluation of the manuscript found the study – based on the combination of transcriptomic and histological analyses across multiple tissues – “convincing.” It is, however, still basically before peer-review and, therefore, we are just flagging it.

REFERENCE

1. Morgan et al., eLife. https://doi.org/10.7554/eLife.109392.2

Important News Regarding the Preservation of Fertility in Young Males Before Intensive Chemotherapy

Two recent Medscape articles barely one month apart recently addressed progress made in the use of transplanted frozen testicular tissue from prepubescent male children. Males at such young ages – unlike adolescents and adults – do not yet produce sperm. Consequently, standard sperm freezing methods cannot be used in them. As described in an interview with the principal investigator of a group of researchers at Vrije Universiteit Brussel in Brussels, Belgium, Ellen Goossens, PhD, the breakthrough had been achieved of producing spermatozoa in testicular tissue frozen for more than 17 years.¹ They restored sperm production in the frozen testicular specimen of a 27-year-old man who had frozen his testicular tissue at age 10.²

The second Medscape article had appeared already earlier on May 5, 2026, after Francesca Tondo, an Italian biologist from Milan, Italy, reported this case in an abstract at the 9^th Congress of the Italian Society of Human Reproduction.³

Though this is only a first step, they finally suggest that it may become possible to preserve reproductive capacity also in prepubescent males.

REFERENCES

1. Interview by Stavart C of Goossens E. Medscape. June 10, 20226.

2. The Guardian. May 4, 2026; 11111 https://www.theguardian.com/society/2026/may/04/man-produces-sperm-from-testicular-tissue-frozen-as-a-child-in-breakthrough-trial

3. Valsecchi MC. Medscape. May 5, 2026. https://www.medscape.com/viewarticle/can-cryopreserved-testicular-tissue-enable-fertility-2026a1000eb0Do

The CHR’s Editorial Staff

Questions and Answers: What is Reciprocal IVF?

With Sonia Gayete-Lafuente, MD, who is an Associate Physician-Scientist at the CHR and at The Foundation for Reproductive Medicine (FRM) and a Visiting Researcher at Rockefeller University in NYC. She is also the Director of Medical Education at the CHR and the FRM and an Associate Editor for Collaboration on the Editorial Board of the CHR. She can be reached through the CHR’s editorial office or directly at sgayete@thechr.com.

Q: In summary, what is RECIPROCAL IVF (rIVF)?

A: Reciprocal IVF (rIVF) is a family-building option that an increasing number of female same-sex couples have been choosing. It allows both partners to be part of the pregnancy in a unique way: One partner provides the eggs in an IVF cycle (which are fertilized with donor semen selected by the couple), and one or more resulting embryos are then – after proper preparation of the other partner – transferred into the other partner’s uterus. She – hopefully – conceives and carries the pregnancy to delivery. rIVF has proven to be a wonderful and very rewarding option for couples who in together creating and/or growing their families together want to share technical as well as biological experiences of motherhood.

Q: If neither partner has known fertility problems, do they still need to be medically evaluated?

A: Yes, and the main reason is that there is no test available to determine the fertility status of a woman, except for a history of repeated recent successful/unsuccessful exposure to semen, - a history partners in a female same-sex relationship usually do not have. In rIVF, therefore, it is important to assess the ability of one partner to serve as the source of “good” eggs and to assess the other partner’s ability to go normally through an embryo implantation process. If problems are found on one or both sides, this then allows the CHR’s physicians to individualize protocols to the need of each patient, as it also, of course, is the routine at the CHR in regular IVF cycles.

As rIVF practically involves an “egg-donation” from one partner to the other – and FDA egg-donor requirements in such cases mandate certain very strict - mostly infectious-disease-related – screenings, if the donor and recipient are not intimate sexually, these rules also apply to same-sex couples. They, however, of course, can be waived if the couple confirms sexual intimacy, though the general professional recommendation, even in such a circumstance, is still to undergo the testing, - mostly to protect any potential pregnancy from infections.

Since rIVF also involves the use of donor semen, this also means that the FDA’s very strict rules regarding donor semen (from a donor who is not sexually intimate with the recipient of the embryos) apply. Donor semen obtained from licensed sperm banks has already undergone required testing and quarantine periods. Use of a so-called “open” or “directed” semen donor (usually a sperm donor known to the recipient and not sexually intimate with the embryo recipient), however, requires under FDA guidelines not only the testing of the donor for infectious diseases, but also a six-month quarantine period for every semen sample before use.

Q: Who is “the mother” in rIVF pregnancies?

A: People often ask, - who’s the mom in reciprocal IVF? The answer is both partners! Both, of course, end up having varying biological relationships to the pregnancy, - with one partner - after providing the egg - being the “genetic” mother/parent, while the other partner becomes the “gestational” mother/parent by carrying the pregnancy and giving birth. Both, therefore, have a very valid claim at motherhood, parenting, and raising the child.

The legal definition of parenthood, however, does not always align automatically with these genetic and gestational roles. Depending on where the couple lives and the marital status, the partner who gives birth may be recognized as the legal parent at birth, while the egg-providing partner may sometimes require additional documentation, - such as a consent form, a parentage order, or a second-parent adoption- to secure legal recognition, especially for couples who are not married. Marital status and the use of donor sperm may also affect the requirements. Because parentage laws vary by jurisdiction, couples considering rIVF are strongly advised to review the local legal state requirements early and, when appropriate, consult an attorney specializing in reproductive and family law to ensure all documents are in place, - so all goes smoothly.

Q: Can both partners undergo rIVF and switch roles? Can they share the same sperm donor?

A: Yes. Many couples choose to complete two rIVF cycles, switching roles so that each partner has the opportunity to provide eggs and carry a pregnancy. For example, one partner may carry an embryo created from the other partner’s egg and have a first baby, and then they may reverse roles for a future second offspring.

The same sperm donor can be used to fertilize eggs from both partners, which is very often the preferred option. If each partner has a child using embryos created with that donor, the siblings would have the same genetic father, making them biological half-siblings. Couples interested in this option may wish to reserve enough sperm from the same donor in advance, as donor availability cannot always be guaranteed in the future. Medical suitability, timing, cost, and the desired number of children should all be considered when planning this approach.

Q: What does rIVF teach us about motherhood?

A: One of the beautiful things about rIVF is that it reminds us that motherhood isn’t defined by just one experience. Genetics, pregnancy, birth, caregiving, and the love and commitment you bring to your child are all part of the journey. Every path to loving parenthood deserves to be celebrated.

If you’re considering reciprocal IVF and would like to learn more about your options, our team at the CHR is here to help. Contact us to schedule a consultation and explore the path that’s right for you!

The CHR’s Editorial Staff

Red-Light Therapy and Fertility: Hope, Hype, and What Actually Is Known

By David H. Barad, MD, who at the CHR is Associate Medical Director, Head of Clinical Assisted Reproduction, and Senior Physician Scientist as well as Associate Editor for Statistics and Truth at CHR’s publications, including the _CHRVOICE and The Reproductive Times.

In the digital age, patients trying to build families are surrounded by readily available but often unfiltered information—information that can raise hope, - but may also lead them toward interventions of uncertain value. In recent months, several CHR patients have told me that they have either already started or are considering red-light therapy.

It is easy to understand the appeal of red-light therapy. After all, it is widely advertised as healing almost everything (see figure below), sounds like a gentle treatment, noninvasive, “natural,” and scientifically plausible.

Red-light therapy is now being promoted in some fertility clinics, by providers of acupuncture and wellness treatments, and even in spas and cosmetic studios as a way to improve fertility. Claims include benefits for both female and male infertility, improvement in PCOS—now increasingly referred to as PMOS, or polyendocrine metabolic ovarian syndrome—better egg quality, improved ovarian reserve, enhanced embryo implantation, higher IVF success rates, and even reduced miscarriage risk.

The idea has also reached academic IVF laboratories. Investigators at Columbia University Irving Medical Center here in New York have publicly announced that they are studying near-infrared light exposure for early embryos, based on the hope that brief exposure to red or near-infrared light might improve embryo development and, ultimately, IVF outcomes. To date, however, I am not aware that results from this work have been reported in the peer-reviewed medical literature.

And red-light therapy is not only advertised for female infertility. Males allegedly also can improve their contribution (see below).

But as with many so-called “add-ons” to standard fertility treatments, biological plausibility is not the same as clinical proof.

Because I was not familiar with red-light therapy as a fertility treatment, I was naturally skeptical regarding the claim that simply exposing the body to red light could meaningfully affect ovarian function, endometrial growth and receptivity, or fertility outcomes. To better understand what my patients might be investing their time, money, and hope in, I therefore decided to look more closely into the published literature to understand better the basis for these claims.

Red-light therapy is also called photobiomodulation, or low-level laser/light therapy. It uses red or near-infrared light, usually in the 600–1000 nm range, with the goal of influencing cellular metabolism. In other areas of medicine, photobiomodulation has been studied for pain, inflammation, wound healing, skin changes, and hair growth. Some devices have FDA clearance for selected non-fertility-related uses, but this should not be confused with evidence that red-light therapy improves ovarian reserve or IVF live birth rates. FDA clearance for a device generally relates to safety and a specific intended use; it does not mean the device has been proven to improve fertility.

The proposed fertility mechanism is biologically interesting. Red and near-infrared light may be absorbed by mitochondrial enzymes, especially cytochrome Coxidase, potentially increasing electron transport, mitochondrial membrane potential, and ATP production. Downstream effects may include changes in nitric oxide signaling, oxidative stress pathways, calcium signaling, inflammation, apoptosis, and local blood flow. Since oocytes and early embryos are highly dependent on mitochondrial function, it is understandable that investigators would ask whether carefully delivered light could improve reproductive function.

The important question, however, is not whether the idea is plausible. The question is whether it improves patient-centered fertility outcomes.

Most of the evidence supporting red-light therapy for ovarian function remains preclinical. In animal studies, low-level laser therapy has been reported to affect follicular dynamics, increase some growing follicle populations, reduce apoptosis, and improve markers such as AMH-positive follicles (Oubiña, Pascuali et al. 2019). Some studies in chemotherapy-induced ovarian injury models suggest a possible protective effect (Oubiña, Pascuali et al. 2021). In PCOS-like animal models, photobiomodulation has also been reported to alter follicle number, corpus luteum number, cyst formation, and reproductive hormones (Alves, Bonfá et al. 2019).

An important limitation, however, is that in many of these animal experiments, the ovary was surgically exteriorized and directly exposed to the light source—a very different situation from noninvasive treatment in human patients applied through the skin.

These findings are interesting, but they do not show that red-light therapy regenerates human ovaries. One key point is often lost in typical marketing lingo: Improving the activity or survival of growing follicles is not the same as restoring the resting primordial follicle pool. In at least one animal study, the primordial follicle pool, which represents the fundamental functional ovarian reserve, was not increased. In plain English, - red light did not create new eggs (Oubiña, Pascuali et al. 2019).

Human data are, moreover, far more limited. A small prospective case series reported improved fertility outcomes, including live births, in three women with unexplained age-related infertility after multiwavelength red and near-infrared photobiomodulation (Phypers, Berisha-Muharremi et al. 2024). But a case series of three patients cannot establish efficacy. It cannot separate treatment effect from chance, patient selection, concurrent treatment, or the natural variability we often see in fertility care.

There exist also early laboratory studies suggesting that photobiomodulation may improve mitochondrial activity and maturation of immature human oocytes in vitro. That is scientifically intriguing, but it is not the same as showing that shining light externally on the pelvis improves ovarian reserve, embryo competence, euploidy, pregnancy, or live birth.

Cost is another practical issue. General red-light therapy sessions in wellness settings commonly range from about $25 to $200 per session, depending on whether the treatment is handheld, panel-based, or full-body. Fertility-oriented laser or laser-acupuncture treatments around embryo transfer may cost roughly $200 to $350, and repeated protocols can easily add several hundred to more than a thousand dollars to IVF cycle costs. At-home devices may cost $100 to $1,000 or even more. All of these costs are typically not under insurance coverage and, therefore, out of pocket.

This does not mean red-light therapy is necessarily harmful. When properly used, it appears relatively low risk, though patients should avoid overheating, use eye protection, and be cautious with photosensitizing medications or skin conditions. The larger concern is not physical harm; it is misplaced confidence, the delaying of effective treatments, and - of course - additional expense.

At the CHR, we have long emphasized the distinction between ovarian reserve markers and meaningful reproductive outcomes. AMH, antral follicle count, follicle growth, and even oocyte numbers are useful intermediate measures. But patients ultimately care about embryo competence, pregnancy, miscarriage risk, live birth, time, cost, and emotional burden. A therapy that modestly changes a surrogate marker is not necessarily a therapy that helps patients have babies.

The current bottom line therefore is caution: red-light therapy for ovarian reserve should be considered investigational. The biology is plausible, and the early laboratory and animal data are interesting, - but robust human clinical evidence is lacking. We do not yet have any adequately powered randomized trials showing that red-light therapy improves ovarian reserve, egg quality, cumulative IVF success, or live birth rates.

For patients who wish to try red-light therapy as a relaxation or wellness intervention, and for whom the cost is modest and does not come at the expense of better-established treatments, doing so may be reasonable. The important caveat is that it should not delay proven treatments or replace individualized fertility care.

At the same time, red-light therapy should not be marketed—either inside or outside fertility clinics—as “ovarian rejuvenation.” Patients should be cautious about claims that it can reverse ovarian aging, restore ovarian reserve, or replenish their egg supply.

IVF already suffers from an overabundance of “add-ons” that have failed to demonstrate meaningful clinical benefit; some have even been shown to reduce pregnancy and live-birth chances. Yet these add-ons have contributed, since roughly 2010, to a substantial increase in the average cost of an IVF cycle. Patients do not need more expensive promises unsupported by evidence.

In fertility medicine, hope is essential. But hope serves patients best when it is paired with honesty. Red-light therapy may one day find a defined role in reproductive medicine, perhaps in carefully controlled laboratory applications or in specific patient groups. For now, however, it remains a promising hypothesis—not an established fertility treatment.

REFERENCES – in alphabetic order by author:

1. Alves, E. D., A. L. O. Bonfá, G. R. Pigatto, J. A. Anselmo-Franci, J. A. Achcar, N. A. Parizotto and L. H. Montrezor (2019). “Photobiomodulation can improve ovarian activity in polycystic ovary syndrome-induced rats.” J Photochem Photobiol B 194: 6–13.

2. Phypers, R., V. Berisha-Muharremi and R. Hanna (2024). “The Efficacy of Multiwavelength Red and Near-Infrared Transdermal Photobiomodulation Light Therapy in Enhancing Female Fertility Outcomes and Improving Reproductive Health: A Prospective Case Series with 9-Month Follow-Up.” J Clin Med 13(23).

3. Oubiña, G., N. Pascuali, L. Scotti, S. Bianchi, M. May, J. E. Martínez, C. Marchese Ragona, J. Higuera, D. Abramovich and F. Parborell (2021). “Local application of low level laser therapy in mice ameliorates ovarian damage induced by cyclophosphamide.” Mol Cell Endocrinol 531: 111318.

4. Oubiña, G., N. Pascuali, L. Scotti, M. Di Pietro, F. A. La Spina, M. G. Buffone, J. Higuera, D. Abramovich and F. Parborell (2019). “Low level laser therapy (LLLT) modulates ovarian function in mature female mice.” ProgBiophys Mol Biol 145: 10–18.

The CHR’s Editorial Staff

How Perimenopause Affects Fertility and Pregnancy

By Jaclyn Anglis, MA, who is a Communications Specialist and Editor at the CHR and as such is the Associate Editor for production on the CHR’s Editorial Board. She can be reached through the _CHRVOICE or directly at janglis@thechr.com.

Right now, millions of women around the world are going through perimenopause. However, this important transitional phase before menopause remains widely misunderstood by the public. This paves the way for myths and misconceptions to spread about fertility and pregnancy during perimenopause, sometimes even wrongly leading women in their 40s to believe that they’ve missed out on their chance to have a baby.

Let’s therefore take a close look at what really happens to a woman’s fertility during perimenopause, what she can do to improve her chances of conceiving, and how a pregnancy during perimenopause differs from a pregnancy that happens during earlier reproductive years.

What is Perimenopause?

The American College of Obstetricians and Gynecologists (ACOG) defines perimenopause as the last few years leading up to menopause. During this time, the amount of estrogen produced by a woman’s ovaries starts to fluctuate, often leading to noticeable changes in her menstrual cycle before she eventually reaches menopause and her period stops entirely.¹

“This is usually not an on-and-off switch,” explains Sonia Gayete-Lafuente, MD, PhD, a Fertility Specialist and Director of Medical Education at the Center for Human Reproduction (CHR). “There is usually a certain period of time at the end of our reproductive lifespan where our cycles become a little more irregular, sometimes cycles tend to shorten, sometimes we can skip some ovulation, because basically the ovaries are doing the best they can with the very little ovarian reserve that is left in there.”

Many women begin perimenopause around their late 40s, eventually reaching menopause by their early 50s.² However, this can vary quite a bit. For women who reach early menopause, their perimenopause phase can begin while they’re still in their 30s.

Dr. Gayete-Lafuente says the number one sign of perimenopause is the emergence of constant period irregularities, but some other signs can include hot flashes, night sweats, mood changes, fatigue, insomnia, and low libido. According to ACOG, perimenopausal women may also experience vaginal dryness, leading to possible pain during sex and an increased risk of vaginal infections. As a woman’s ovaries work with a lower and lower number of eggs, her estrogen levels drop, leading to the above-mentioned unpleasant symptoms.

Since some of these symptoms can also occur during menopause, how does a woman know that perimenopause is over and she’s reached menopause? Clinically, doctors consider a woman menopausal if she’s gone one year — a full 12 months — with no menstrual period.

The Truth About Perimenopause and Fertility

Though menopause is well known among the public (who hasn’t seen a t-shirt or coffee mug with the classic joke, “I’m still hot, it just comes in flashes now”?), the same cannot be said for perimenopause. This has led to a widespread lack of understanding about what’s really happening to a woman’s fertility and her chances for pregnancy during this time.

“One of the biggest myths is that if you are perimenopausal, you cannot get pregnant,” says Dr. Gayete-Lafuente. “As long as there is an egg, there is still a chance. Of course, the chance will be lower than it would have been 10 years ago… but if there is an egg, there is always a chance of having an embryo and eventually having a child. A low chance is not no chance.”

Even after a woman has reached menopause and has no more eggs, she can still carry a pregnancy if she undergoes an embryo transfer with the appropriate hormonal support and treatment. This could be an embryo created with the help of an egg donor — or an embryo that was previously created by the aspiring mother herself during her reproductive years.

While a woman is still in perimenopause, she is no longer as fertile as she was in earlier years, but the specifics of her fertility can vary based on her age and any health conditions she has.

For example, a woman who starts perimenopause early in her 30s may have very few eggs, but they — possibly compensating for the low number — likely will be higher-quality eggs than those of a woman in her 40s. On the flip side, an older patient with polyendocrine metabolic ovarian syndrome (PMOS) — formerly known as polycystic ovary syndrome (PCOS) — may have a higher number of eggs than a younger woman. Though many of this patient’s eggs will probably be of low-quality, the larger number also provides more chances for a high-quality egg to emerge.

These differences are exactly why perimenopausal women need treatments specifically tailored to them if they’re interested in conceiving. According to Dr. Gayete-Lafuente, this should begin with a full evaluation of the woman’s age, health conditions that may be affecting her reproductive capabilities, follicle-stimulating hormone (FSH) levels, and the current state of her ovarian reserve. For women who have a diminished ovarian reserve (DOR), fertility doctors will want to do everything they can to maximize the amount and quality of her eggs in a treatment cycle. This often requires pretreatments of her ovaries to get them into the best possible shape and tailored ovarian stimulation before retrieving eggs during in vitro fertilization (IVF).

Under physician supervision, some women may find that androgen pre-supplementation may help in getting their ovaries into the best shape. The CHR prefers to do this through dehydroepiandrosterone (DHEA) supplementation rather than direct testosterone supplementation since the latter can more easily lead to over-supplementation. Normalizing abnormally low androgen levels can help ovaries with their response to the fertility treatments they undergo. Women may also consider limiting refined sugars and trans fats in their diets and adding more antioxidants — the Mediterranean diet is a good potential option here. “Antioxidants promote healthy fertilization, implantation, and embryo development, so that would be a way to improve their chances of success in a low interventional way,” says Dr. Gayete-Lafuente.

According to the European Society of Human Reproduction and Embryology (ESHRE), other potential adjustments to improve female fertility are avoidance of smoking and excessive drinking of alcohol, staying physically active, and maintaining a healthy weight.³

All combined, tailored ovarian stimulation, a carefully planned IVF cycle, and implementing the above-noted positive lifestyle changes can improve even a perimenopausal woman’s chances of still getting pregnant with her own eggs. But there, of course, never can be a guarantee that this will happen. If a patient doesn’t respond to fertility treatments or if she struggles to produce high-quality embryos, egg donation may, ultimately, have to be the way to go.

But what distinguishes the CHR from most other IVF clinics is that the CHR considers third-party egg donation to be – strictly – a last-resort treatment. If a patient reaches the point where she is convinced that only egg donation will make her a mom, then it becomes a wonderful treatment option, and by delivery, the woman will have forgotten where the egg came from because going through pregnancy with a developing fetus is what makes her the mom of this baby. That said, women who enter egg donation too early can sometimes face second thoughts later in life, wondering whether they couldn’t have also done it with their own eggs.

“Lots of patients are a little resistant to egg donation at the beginning,” says Dr. Gayete-Lafuente. “But after many years in the field, I also want to say that when women use egg donation as a last resort and are successful in having their baby, many repeat the experience and no one regrets. We nowadays have women in their 50s (and in full menopause) quite routinely having babies with the help of donor eggs. This can be seen as a testimonial from thousands of women from all over the globe. It’s really -ultimately - a beautiful experience.”

Important Things to Know About Being Pregnant During Perimenopause

As women grow older, there are more risks associated with being pregnant. These risks are usually not linked to perimenopause itself. This is, of course, especially true for women with premature ovarian aging, who, therefore, start perimenopause early, - often only in their 30s. But once perimenopausal women are in their 40s, they should be aware of risks related to their advanced maternal age before and after conception.

An important consideration is that at advanced female ages, the chromosomes in eggs can become imbalanced, leading to an increased risk of carrying a child with a chromosomal disorder, - a so-called aneuploidy. The likely best-known aneuploidy is Down syndrome (trisomy 21), which nowadays – together with other frequently occurring aneuploidies – is routinely screened for early on during pregnancies with a simple maternal blood test recommended for all pregnant patients regardless of age. More aneuploidies are also one reason why older pregnant women have a higher risk of miscarriages.

Older perimenopausal women can also have an increased risk of gestational diabetes, high blood pressure disorders (including so-called preeclampsia), and preterm labor. In principle, almost any medical problem increases in prevalence with age. This is especially the case with thyroid issues and heart problems. This is why it’s so important for perimenopausal women who still want to go through pregnancy to disclose all details of their past medical history to their fertility doctors — and why their doctors need to make sure that the patient and treating physicians can manage their patients appropriately and without surprises before and during a pregnancy.

The older a woman is, the more likely it is that she will require multidisciplinary care from a variety of doctors during her pregnancy — and not only from her obstetrician (her infertility doctor will already likely be out of her medical life). Depending on her specific needs, her care may require an adjustment of the medications she’s taking and/or making significant changes to her lifestyle.

Aside from making regular doctor’s visits and heeding professional advice, Dr. Gayete-Lafuente says there are also some other important, yet simple, ways in which perimenopausal women can prioritize their health during pregnancy. This is, of course, particularly important during the sweltering summer months. After all, the last thing you want to do while you’re pregnant is faint! Therefore, “remember to stay very well hydrated,” she says. “Many times, older women don’t tolerate heat well, or tend to get dehydrated easily, so it’s very important that they keep up with fluids because pregnancy is physically very demanding.”

Another thing to keep in mind is that your Vitamin D levels will decline while you’re pregnant because they are diluted in a ca. 40% larger blood volume. This can lead to other health risks. So make sure you’re either getting enough Vitamin D in your diet (it’s found naturally in cheese, egg yolks, and the flesh of fatty fish)⁴ or simply supplement with oral Vitamin D.

While pregnancy during perimenopause certainly comes with its challenges and vulnerabilities, there are plenty of ways to help improve your experience and protect your health during this important time. You, of course, owe it to your future self, and your new baby.

REFERENCES:

1. American College of Obstetricians and Gynecologists. “The Menopause Years.” Last reviewed: December 2025. https://www.acog.org/womens-health/faqs/the-menopause-years

2. Wegrzynowicz AK, Walls AC, Godfrey M, Beckley A. Insights into Perimenopause: A Survey of Perceptions, Opinions on Treatment, and Potential Approaches. Women (Basel). 2025 Mar;5(1):4. doi: 10.3390/women5010004. Epub2025 Jan 31. PMID: 40264725; PMCID: PMC12014197.

3. European Society of Human Reproduction and Embryology. International Reproductive Health Education Collaboration. “Female fertility and age.” PDF Only.

4. National Institutes of Health: Office of Dietary Supplements. “Vitamin D.” Last updated: June 27, 2025. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

However, the publication very clearly pointed out how poorly understood, poorly discussed, and poorly taught female sexual physiology still is when it comes to women above age 35. To say it bluntly, the issue is not what the body was or was not "designed" for, but rather that sexual relationships, contraceptive use, and reproductive intent are now frequently separated across time as society faces delays in the family-building process. As a result, many women experience most of their adult sexual life during periods when pregnancy is not intended, and only later attempt conception at an age when female fecundity has already declined.

With this timing gap being central to understanding contemporary sexual health and infertility patterns in women over age 35 and 40, understanding this divergence is central to contemporary infertility care, as well as women's sexual health.

The CHR’s Editorial Staff

When Sex and Fertility Disconnect: The Timing Gap in Modern Reproduction

By Sonia Gayete-Lafuente, MD, who is an Associate Physician-Scientist at the CHR and at The Foundation for Reproductive Medicine (FRM) and a Visiting Researcher at Rockefeller University in NYC. She is also the Director of Medical Education at the CHR and the FRM and an Associate Editor for Collaboration on the Editorial Board of the CHR. She can be reached through the CHR’s editorial office or directly at sgayete@thechr.com.

The Biology of Female Sex: From Puberty to Menopause

To understand the timing gap between sex and reproduction, we must first appreciate that the female body undergoes profound biological transformations across the reproductive lifespan. These affect not only fertility, but also sexual desire, arousal, pleasure, and orgasm.

The reproductive axis activates during puberty through the hypothalamic-pituitary-gonadal (HPG) axis. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. These hormones, in turn, drive ovarian development, gametogenesis, and sex-steroid production.

Adrenarche, the maturation of the hypothalamic-pituitary-adrenal axis, typically begins between ages 6 and 8 with a rise in adrenal androgens such as dehydroepiandrosterone sulfate (DHEA-S). Gonadarche follows between approximately ages 8 and 14, marked by rising ovarian estradiol, breast development, and eventually menarche. These hormonal changes do more than prepare the body for reproduction: they also help establish the neurobiological foundations of sexual desire, arousal, and orgasmic capacity.

Androgen levels in women peak in early adulthood and decline through the reproductive years. Estrogen plays a critical role in female sexual physiology by maintaining genital tissue sensitivity and elasticity, vaginal secretions, pH, and the vaginal microbiome. It also modulates central nervous system pathways, including dopamine and nitric oxide signaling, that contribute to the sexual response. The biological substrate supporting fertility and sexual pleasure is therefore not static; it changes continuously across a woman’s life.

The Physiology of Pleasure and Orgasm

Sexual pleasure and orgasm are not incidental features of reproductive biology. They are complex psychophysiological processes with distinct neuroanatomical and neuroendocrine substratas.

The female sexual response is now understood as nonlinear and circular, rather than as the rigid sequence of desire, arousal, orgasm, and resolution proposed in earlier medical models. Basson’s contemporary model recognizes that desire may be responsive rather than spontaneous, that desire and arousal frequently overlap, and that motivations for sex extend beyond reproduction to include emotional intimacy, pair bonding, and pleasure. Among 2,400 multiethnic women in the Study of Women’s Health Across the Nation (SWAN), 40% reported never or infrequently experiencing spontaneous sexual desire, yet most remained capable of arousal and only 13% expressed dissatisfaction with their sexual experiences.

The clitoris is the principal organ of female sexual pleasure. It consists not only of the external glans and hood, but also of extensive internal structures, including the body, roots, crura, and bulbs. During arousal, smooth-muscle relaxation within the clitoral erectile tissue increases blood flow and engorgement through mechanisms mediated by neurotransmitters, vasoactive peptides, and sex-steroid hormones. Vaginal lubrication results from vascular transudation and glandular secretions, while stimulation of the anterior vaginal wall may contribute to orgasm through the clito-urethro-vaginal complex, rather than through a discrete anatomical “G-spot.”

At the cerebral level, orgasm engages cortical, subcortical, and brainstem regions involved in reward, emotion, memory, motivation, and sensory processing. Dopamine has a central role in sexual motivation, arousal, and reward, while reduced activity in regions involved in behavioral inhibition may contribute to the immersive quality of orgasm. Oxytocin rises during pleasurable sexual activity and remains elevated afterward, contributing to smooth-muscle contractions, emotional bonding, and feelings of well-being. Its interaction with dopamine and endogenous opioid pathways within the brain’s reward centers is believed to support not only sexual pleasure, but also pair bonding and selective social attachment.

These neurobiological systems are not merely accessories to reproduction. They support stress reduction, bonding between lovers, emotional regulation, and subjective well-being. Remarkably, many of these functions persist throughout life, independent of reproductive intent.

How Sexual Pleasure Changes with Age and Menopause

Sexual pleasure can continue across the lifespan, but its physical conditions do not remain constant. Aging and the menopausal transition affect multiple dimensions of sexual function, although the trajectory is considerably morenuanced than a simple decline.

The Melbourne Women’s Midlife Health Project, which prospectively assessed women ages 45 to 55 over eight years, documented an increase in sexual complaints from 42% to 88%, correlated with decreasing estradiol levels. The Global Study of Sexual Attitudes and Behaviors, conducted across 29 countries and including nearly 14,000 women ages 53 to 58, found that lack of sexual interest was the most commonly reported sexual difficulty, followed by difficulty reaching orgasm and poor lubrication.

The mechanisms are multifactorial. Declining estrogen can lead to genitourinary changes, including thinning of the vaginal epithelium, altered collagen, reduced lubrication, and increased tissue resistance, all of which may predispose to dyspareunia. Genital perfusion, engorgement, lubrication, touch perception, and vibratory sensation may also decrease. Reduced estrogen can further attenuate central dopaminergic and nitric oxide, signaling pathways that modulate sexual response.

Even so, orgasmic capacity is generally maintained with age. Some women may require more direct or intense clitoral stimulation, or a longer period of arousal, to reach climax. Reduced pelvic floor muscle tension and changes in uterine contractions may diminish the physical intensity of orgasm or shorten its resolution phase; in some women, uterine contractions may become uncomfortable. Yet validated measures such as the Orgasm Rating Scale and the Bodily Sensations of Orgasm Scale show that the subjective dimensions of orgasm, including pleasure, satisfaction, ecstasy, emotional intimacy, and relaxation, remain broadly comparable across premenopausal, perimenopausal, and postmenopausal women, even when physical sensations change.

Critically, relationship satisfaction, emotional support, self-esteem, optimism, health, and context may predict sexual functioning in midlife and older women more strongly than hormone levels alone. Testosterone has been positively associated with orgasmic function in some studies, but endocrine changes do not fully explain sexual experience once psychosocial variables are considered. Sexual pleasure in later life is therefore neither purely hormonal nor purely psychological; it emerges from the interaction of physiology, relationships, health, and context.

Despite those changes, importantly, sexual life does not end at the boundary of reproductive capacity at all! Women continue to experience desire, arousal, and orgasm well beyond the fertile window, while the biological substrate supporting these experiences shifts.

The Female Body was Never Properly Explained

Despite this complexity, female sexuality has long been treated as mysterious, secondary, or relevant only mainly to reproduction. Many women are never taught the full structure of their sexual anatomy or how female sexual response may change over time.

In that absence of knowledge, normal features of female arousal may be interpreted as personal failure: needing more time, more direct stimulation, greater emotional safety, additional lubrication, clearer communication, or not experiencing spontaneous desire in the way male-centered models have historically defined it. When women and their partners do not understand these differences, the conclusion too often becomes, “She has low libido.”Sometimes, the more accurate explanation is that no one adjusted the conditions her body needs in order to respond!

Unfortunately, a woman may enter midlife with decades of sexual experience, yet she may have received little accurate education about the clitoris, responsive desire, perimenopause, lubrication, pelvic floor function, orgasmic variability, or sexual pain. Her partner may know even less. Because sexual pleasure is often relational, this ignorance has consequences, as it shapes what is requested, assumed, rushed, sometimes pathologized, or - worst case scenario - simply left unspoken.

If a partner interprets slower arousal as rejection, lower spontaneous desire as disinterest, lubrication changes as lack of attraction, or the need for direct clitoral stimulation as “difficulty,” the woman’s body becomes mislabeled. A normal physiological or contextual shift can then become a relationship problem, a confidence problem, or an unnecessary diagnosis.

This is where the claim that women were not “designed” for the sex they are having after 35 becomes useful only if it is turned away from blame. The problem is not that women after 35 are having sex outside of reproduction! The problem is that many women - and their lovers - are navigating sex without understanding female physiology.

When Sexuality and Fertility Begin to Follow Different Timelines

One of the most consequential yet under-recognized changes in modern reproductive health is that sexuality and reproduction no longer occur in parallel. For much of human history, sexual activity, partnership formation, and childbearing tended to occur within a relatively narrow age range. Today, sexual relationships often begin in adolescence or early adulthood, while attempts at conception are increasingly postponed until the mid-to-late thirties or beyond.

This shift is not simply the product of isolated individual choices. It reflects structural and social changes, including longer education, delayed partnership formation, economic pressures, housing costs, changing expectations of relationships and careers, and access to reliable contraception. Many women consequently spend one or two decades experiencing the benefits of sexuality - pleasure, intimacy, attachment, and emotional connection - during years when pregnancy is often neither desired nor planned.

Modern contraception has allowed sexual pleasure and reproduction to be separated more completely than at any previous point in human history - one of the most consequential advances in women’s lives. The paradox is that the same technologies that liberated sexuality from reproduction made the biological constraints of reproduction more visible. Estimates covering 1990 to 2021 suggest that approximately 17.5% of adults worldwide experience infertility during their lifetimes, with delayed childbearing and age-related declines in female fertility contributing substantially to infertility patterns in many regions. Pregnancy could be postponed, but ovarian biology did not move with the social timeline, and that’s why the natural step following long-term contraception has to be fertility preservation counseling!

When Fertility Finally Becomes Relevant, Can Assisted Reproductive Technology Overcome the Timing Gap?

Most individuals do not experience fertility as a continuous biological process. Rather, fertility becomes visible only when pregnancy is desired. In clinical practice, patients often present after months or years of unsuccessful attempts at conception, assuming that timing, stress, or chance may be the principal obstacle. In younger women, this may sometimes be true, but beyond age 35-37, the dominant limiting factor is oocyte age.

Assisted reproductive technologies (ART) - including IVF, embryo cryopreservation, and oocyte freezing - have expanded reproductive options and partially compensated for age-related fertility decline. However, they cannot fully reverse the age-dependent deterioration of oocyte quality with advancing age. The good news is that, clinically, age-related infertility does not occur as an abrupt pathological event but instead represents the delayed recognition of a biological process that has been unfolding silently for years. The key, therefore, is female education and counseling, aiming for recognition of a developing problem, - while still actionable.

Conclusions

Society successfully separated sex from reproduction, but biology did not separate fertility from age. The central issue in contemporary reproductive medicine is that sexual relationships, reproductive intent, and attempts at conception are increasingly decoupled from the biological window of peak female fertility, without sufficiently broad counseling of fertility preservation options alongside extended long-term contraception.

At the same time, medicine and culture have failed to teach women how their sexual physiology changes across the same years in which their reproductive potential declines. Women may feel fully alive sexually and relationally at precisely the stage when fertility is becoming more fragile. That is the modern timing gap: Sexuality may remain active, rewarding, and adaptive across adult life, while reproductive capacity follows a much narrower timetable, which too many women learn too late.

The task of reproductive medicine is therefore not solely to treat age-related infertility in older women. It is also to help all women understand the widening gap between social and biological timelines and do so without reducing sexuality to reproduction or treating physiologic fertility decline as a personal failure. Reproductive medicine cannot eliminate this divergence, but it can help patients recognize it early enough to make informed choices about family building, which may be one of the most important fertility interventions we can offer.

READING LIST

• Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics. Hart RJ. Physiological Reviews. 2016;96(3):873-909. doi:10.1152/physrev.00023.2015.

• Partial Progress in Sexual and Reproductive Health and Rights: The Influence of Sociocultural, Behavioural, Structural, and Technological Changes on Epidemiological Trends. Grulich AE, Mercer CH, Sturrock B, et al. Lancet (London, England). 2025;406(10515):2100-2118. doi:10.1016/S0140-6736(25)01188-2.

• Sexual Desire and Arousal Disorders in Women. Basson R. The New England Journal of Medicine. 2006;354(14):1497-1506. doi:10.1056/NEJMcp050154.

• The Neurobiology of Pair Bonding. Young LJ, Wang Z. Nature Neuroscience. 2004;7(10):1048-1054. doi:10.1038/nn1327.

• Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia. Loth MK, Donaldson ZR. Endocrinology. 2021;162(2):bqaa223. doi:10.1210/endocr/bqaa223.

• Brain Activity Unique to Orgasm in Women: An fMRI Analysis. Wise NJ, Frangos E, Komisaruk BR. The Journal of Sexual Medicine. 2017;14(11):1380-1391. doi:10.1016/j.jsxm.2017.08.014.

• Optimizing Natural Fertility: A Committee Opinion. Penzias A, Azziz R, Bendikson K, et al. Fertility and Sterility. 2022;117(1):53-63. doi:10.1016/j.fertnstert.2021.10.007.

• Assisted Conception in Women of Advanced Maternal Age. Seshadri S, Morris G, Serhal P, Saab W. Best Practice & Research Clinical Obstetrics & Gynaecology. 2021;70:10-20. doi:10.1016/j.bpobgyn.2020.06.012.

The “M-Type brain” is a popular term on social media right now, usually referring to women who are ambitious, driven, and passionate about many different topics. While the category isn’t officially recognized by any medical fields, there is a real pattern hiding under the pop-psychology label — and it’s one that fertility specialists at the Center for Human Reproduction know well. Therefore, there’s an interesting conversation to be had about how this social media trend ties back to subjects of fertility and infertility.

The CHR’s Editorial Staff

YOUR BRAIN TYPE AND BIOLOGICAL CLOCK: What the “M-Type Brain” Trend Gets Right (and Wrong) About Fertility

By Lyka Mochizuki, MSc, a past Research Fellow at CHR and now Project Manager at CHR. She can be reached through the editorial offices of the _CHRVOICE and The Reproductive Times.

If you’ve been on Instagram lately, you’ve probably scrolled past a video about the “M-Type brain” — usually describing women who are curious, ambitious, dopamine-driven, and always chasing the next big idea, project, or pivot. The videos often hint, vaguely, that this brain type might affect fertility.

Let’s clear something up first: the “M-Type brain” isn’t a recognized medical or neuroscientific category. It’s a pop-psychology framework that loosely overlaps with established personality research on openness to experience, novelty-seeking, and multi-potentialite tendencies. There’s no brain scan that diagnoses it, and there’s no direct biological mechanism linking it to your ovaries.

But — and this is where things get interesting — there is a real conversation hiding amidst the trend. Internationally recognized as a “center of last resort” for its expertise in treating the most complex infertility cases, particularly in women with severely diminished ovarian reserve, the Center for Human Reproduction (CHR) routinely cares for patients in their late 30s, 40s, and even into their 50s — many of whom describe themselves exactly the way these videos do: driven, multi-passionate, exploratory, late to settle. The “M-Type” label might be made up, but the pattern it describes is one our fertility specialists know well.

Here are four real ways the cognitive and lifestyle patterns behind this trend intersect with reproductive health.

1. The Multipotentialite Fertility Gap

The research is clear: personality genuinely shapes reproductive timelines. A recent study published in Evolutionary Behavioral Sciences found that individuals who possess a strong desire for novelty and intellectual exploration tend to have fewer children over their lifetimes, in part because these individuals often delay parenthood, experience shorter romantic relationships, and report fewer positive motivations for starting a family (PsyPost). Earlier research in the Journal of Population Research similarly found that childfree adults who decided early in life not to have children scored significantly higher in Openness to Experience (Springer).

This isn’t just personality theory — it shows up clearly in national data. According to the CDC’s National Vital Statistics System, the mean age of mothers at first birth in the United States increased from 26.6 in 2016 to 27.5 in 2023, and since 1970, when the average first-time mother was just 21.4 years old, the age has steadily increased, with the most dramatic rises occurring after 2009 (CDC). In large metropolitan areas like New York City, first-time mothers now average 28.5 years, and Asian women average 31.5 years at first birth (ABC News).

The challenge is that ovarian biology hasn’t adapted to these modern timelines. According to the American College of Obstetricians and Gynecologists (ACOG), the number of oocytes decreases to approximately 1–2 million at birth, 300,000–500,000 at puberty, 25,000 at age 37, and 1,000 at age 51 — the average age of menopause in the United States (ACOG). A woman can be at the peak of her career, mental sharpness, and self-knowledge at 38 — and still be working with a meaningfully smaller ovarian reserve than she had at 28.

This is the gap the CHR’s patient base reflects every day. Many of our patients aren’t struggling with fertility because something is “wrong” with them. They’re struggling because life took them through interesting, winding paths first — and biology kept its own clock running in the background.

2. Your Brain Wants Novelty. Your Ovaries Want a Schedule.

There’s a real tension worth naming here. The traits associated with this so-called “M-Type” — curiosity, exploration, dopamine-driven novelty-seeking — are wonderful for building a rich, varied life. They’re less compatible with the linear, time-sensitive nature of reproductive biology.

The numbers tell the story. Ovarian reserve declines gradually between puberty and the mid-thirties, then drops off more steeply, with both egg quantity and quality affected after age 35 (Cleveland Clinic). ACOG now recommends that women older than 40 trying to conceive see a fertility specialist immediately, while women 36 to 40 should seek evaluation after six months of trying (ACOG).

This isn’t a judgment of either system. It’s just an honest observation that one of the most common reasons women come to CHR is that these two timelines didn’t align. Recognizing this tension early, in the late 20s or early 30s, opens the door to options like AMH testing, antral follicle count assessments, and fertility preservation — tools that let you keep exploring without giving up future possibilities.

3. Stress, Burnout, and the HPG Axis

This is where the science gets solid. Women with high-drive, high-novelty personalities are also more prone to chronic stress and burnout, particularly when stuck in environments that don’t match their cognitive style.

The mechanism is well-documented. As research published in Frontiers in Global Women’s Health explains, stress is known to impact women’s health through hypothalamic-pituitary-gonadal (HPG) axis dysfunction and resultant ovulatory dysfunction, which may manifest in menstrual irregularities and/or infertility. More specifically, elevated cortisol levels can suppress GnRH secretion from the hypothalamus, leading to a reduction in LH and FSH production — hormones essential for healthy ovulation and menstrual regularity (Frontiers; CHR).

In plain terms: when the brain perceives sustained stress, it deprioritizes reproduction. The hypothalamus interprets a chronically stressful environment as one that is unsafe for sustaining a pregnancy, and stress hormones directly inhibit the release of GnRH — the master signal for the HPG axis.

So while no personality “causes” infertility, the lifestyle patterns that often come with a high-achieving, always-on mindset absolutely can affect reproductive hormones. The good news: This is one of the more modifiable factors. Stress management, sleep, and lifestyle calibration can meaningfully support reproductive health, even alongside medical treatment.

4. The Patterns We’re Seeing at CHR

CHR has long specialized in helping patients other clinics often turn away. As one of the first IVF centers established in the U.S., CHR has gained national and international recognition as the fertility center of last resort for patients from around the world who have had multiple failed IVF cycles elsewhere — with special knowledge and expertise in treating diminished ovarian reserve, a classic finding in older women or in younger women with prematurely aging ovaries.

Dr. Gleicher and our team routinely see patients over 40, over 45, and even into their early 50s — many of whom were turned away by other clinics. As described in CHR’s Multiple IVF Cycle Program, in most fertility centers around the world, women with severely diminished ovarian reserve are refused IVF treatment with their own eggs because of the extremely poor prognosis. CHR offers options precisely because we’ve built decades of experience and research around this exact patient population.

Over the past several years, our patient demographic has shifted noticeably older — mirroring the national trend. The “M-Type brain” framing may be internet pop-psychology, but it captures something real about a generation of women: educated, ambitious, intellectually restless, and statistically more likely to delay family-building. Many of them eventually arrive at a fertility specialist’s office not because anything is wrong with them, but because the timeline of their interests and the timeline of their biology never quite matched up.

That’s not a personality flaw. It’s a modern reality — and it’s one of the reasons fertility care has had to evolve.

So, Does Your “Brain Type” Affect Your Fertility?

Not directly. There’s no neurological wiring that determines your AMH level or your egg count. But the patterns associated with these personality traits — delayed childbearing, chronic stress, nonlinear life paths — absolutely intersect with reproductive health in meaningful ways.

If the IG videos have you thinking about your own fertility, the most useful thing you can do isn’t to diagnose your brain type. It’s to know your numbers. An AMH test, an antral follicle count, and a conversation with a fertility specialist will tell you far more about your reproductive future than any personality quiz ever could.

And if you’ve been one of those curious, multi-passionate women whose timeline didn’t follow a straight line — you’re in good company. That’s most of our patient population at CHR. Even for women who’ve been told elsewhere that their options are limited, there are often still paths forward.

REFERENCES in links

• ABC News. U.S. women waiting longer to have children, CDC data shows (June 2025). abcnews.go.com

• American College of Obstetricians and Gynecologists (ACOG). Committee Statement No. 22: Anticipatory Counseling Regarding Ovarian-Factor Fertility Decline. Obstetrics & Gynecology 2025;146:e98–e104. DOI: 10.1097/AOG.0000000000006078. acog.org

• Centers for Disease Control and Prevention (CDC), National Center for Health Statistics. Trends in Mean Age of Mothers: United States, 2016–2023. National Vital Statistics Reports, Vol. 74, No. 9 (June 13, 2025). cdc.gov

• Chronic Stress and Ovulatory Dysfunction. Frontiers in Global Women’s Health (2022). frontiersin.org

• Center for Human Reproduction. The Impacts of Stress on Fertility. centerforhumanreprod.com

• Center for Human Reproduction. About Us — The “Center of Last Resort.” centerforhumanreprod.com/about-us

• Center for Human Reproduction. Multiple IVF Cycle Program. centerforhumanreprod.com/multiple-ivf-cycle-program

• Cleveland Clinic. Diminished Ovarian Reserve: Causes, Symptoms & Treatment. my.clevelandclinic.org

• Milić, A., & Međedović, J. Openness to Experience and reproductive outcomes. Evolutionary Behavioral Sciences. Summary via PsyPost

• Personality and voluntary childlessness. Journal of Population Research. Springer

Today’s posting offers an article by David H. Barad, MD, MS, a Director of Clinical ART and Senior Scientist at the Center for Human Reproduction. In a recent lecture he attended at the Lamont-Doherty Earth Observatory of Columbia Climate School in Palisades, New York, he learned about some valuable discoveries and research that may eventually help explain how life started on Earth. Though the article mainly addresses Earth and space-related science, arguably nothing is more relevant to reproductive biology than how life started in the first place. As always, we are welcoming comments and further discussion from our readers.

The CHR’s Editorial Staff

Seeds from the Stars: Important New Insights on How Life May Have Started on Earth

By David H. Barad, MD, MS, one of the CHR’s REI physicians, Associate Editor of CHR Publications, Director Clinical IVF, Director of CHR-Research and a Senior Scientist. He can be reached through the editorial office of the _CHRVOICE and The Reproductive Times.

On a cool evening in late April, I had the pleasure of attending a lecture at the Lamont-Doherty Earth Observatory of Columbia Climate School in Palisades, New York. Founded in 1949 and perched atop the scenic Palisades overlooking the Hudson River, the Observatory has long been a leader in the world of Earth sciences. The talk was part of a free public lecture series hosted on site.

The speaker, Senior Research Scientist Kerstin A. Lehnert, PhD, presented “NASA’s Billion $$$ Samples: Space Rocks, Open Science, and the Era of AI.” Her lecture focused on extraterrestrial materials returned to Earth through NASA missions. Dr. Lehnert and her team have played a central role in cataloging these samples and maintaining a comprehensive, publicly accessible database that integrates both the materials themselves, and the growing body of research derived from them.

Midway through her fascinating lecture, she turned to the OSIRIS-REx mission to the near-Earth asteroid 101955 Bennu. This NASA-led mission was designed to collect and return pristine samples in order to better understand early solar system formation and the origins of life.

Launched in September 2016, the spacecraft arrived at Bennu in December 2018, where it conducted detailed mapping and compositional analysis using advanced imaging and spectroscopic instruments. In October 2020, it executed a brief touch-and-go maneuver, successfully collecting more than 70 grams of material—exceeding its target.

On its return, as the spacecraft approached Earth in September 2023, it released a small sample-return capsule that parachuted into the Utah Test and Training Range, while the spacecraft itself continued onward on an extended mission to another asteroid.

The most striking aspect of the returned 101955 Bennu samples was the richness of their organic chemistry. Early analyses identified carbon-containing compounds, nitrogen-bearing molecules, water-bearing clay minerals, and several classes of compounds considered important to prebiotic chemistry. In space science, the term “prebiotic” refers to “Complex Organic Molecules” (COMs): molecules that are not themselves alive, but that serve as the chemical precursors to life. These compounds represent the raw ingredients—the “recipe”—from which essential biological structures such as DNA, RNA, proteins, and cellular membranes can eventually arise.

Scientists detected amino acids, nucleobase-related compounds, and simple sugars in the Bennu samples, molecules that on Earth play central roles in biology. Importantly, these materials were recovered directly from space and returned under carefully controlled conditions, minimizing terrestrial contamination and making the findings especially compelling.

Researchers emphasized that these discoveries do not represent evidence of life itself, but rather evidence that the chemical building blocks associated with life can arise through entirely abiotic processes. This distinction is important. In chemistry, “organic” simply refers to carbon-based molecules and does not imply a biological origin. The Bennu samples support the growing understanding that complex organic chemistry may be a natural consequence of planetary and interstellar processes, rather than something unique to Earth. Primitive asteroids such as Bennu appear capable of acting as long-term reservoirs, preserving materials formed during the earliest history of the solar system.

These findings are further supported by observations from the James Webb Space Telescope (JWST), which has recently revealed what many scientists describe as a “treasure trove” of prebiotic chemistry throughout the universe. Using its Mid-Infrared Instrument (MIRI), JWST identified multiple complex organic molecules frozen within icy grains surrounding the young star ST6 in the Large Magellanic Cloud. These included ethanol, acetic acid, methanol, acetaldehyde, and methyl format—molecules considered important intermediates in the formation of amino acids and nucleotides.

Remarkably, this represented the first detection of several such “prebiotic seeds” as ices outside the Milky Way. JWST has also identified rich organic chemistry within heavily obscured galactic cores, including the first detection beyond our galaxy of the highly reactive methyl radical (CH3), an important intermediate in organic synthesis pathways.

In addition, JWST has detected polycyclic aromatic hydrocarbons (PAHs)—large, carbon-based molecules composed of fused aromatic rings—in galaxies more than 12 billion light-years away. These observations suggest that the universe was capable of producing chemically sophisticated organic compounds only about 1.5 billion years after the Big Bang. Together, the Bennu samples and JWST observations support a profound shift in perspective: the ingredients associated with life may not be rare or uniquely terrestrial but instead may emerge naturally wherever suitable physical and chemical conditions exist.

Equally important was the evidence of water-related chemistry within Bennu’s parent body. The presence of hydrated minerals suggests that the asteroid, or the larger body from which it originated, once interacted extensively with liquid water. Such environments are thought to facilitate complex chemical reactions, potentially allowing simple compounds to evolve into more sophisticated prebiotic molecules. This has strengthened scientific interest in the possibility that asteroids and comets may have delivered not only water to the early Earth, but also a rich inventory of organic materials that contributed to the emergence of life.

Taken together, these discoveries invite a profound reconsideration of humanity’s oldest question: how life began. The early Earth may not have been an isolated cradle struggling to invent biology from nothing, but rather a chemically fertile world repeatedly enriched by material arriving from space. One can imagine the young planet as a receptive and dynamic environment—oceans, minerals, atmosphere, lightning, and volcanic energy interacting with a continual rain of carbon-rich asteroids and comets carrying the molecular seeds of complexity.

In this view, bodies such as 101955 Bennu were not just inert rocks drifting through space, but cosmic couriers delivering the ingredients from which biology could eventually emerge. Whether life itself is common or exceedingly rare remains unknown, but missions such as the OSIRIS-REx mission and observations from the James Webb Space Telescope suggest that the chemistry leading toward life may be woven deeply into the fabric of the universe itself.

Today’s posting offers a look at recent news related to genetics, including a surprising review on PGT-A from some of its biggest proponents – who acknowledged some “uncertainty”surrounding the test. Also included is an unusual story about a woman in a relationship with identical twins, and how a genetic test failed to determine which identical twin fathered the woman’s baby. As always, we welcome your comments and opinions.

The CHR’s Editorial Staff

An Interesting Assessment of PGT-A From a Group of Very Well-Known Proponents

Papers – like people – sometimes offer messages between the lines, and one such paper is what we are commenting on here. Five well-known colleagues who – as strong proponents of Preimplantation Genetic Testing for Aneuploidy (PGT-A) – all have extensively published on the subject, got together and in Human Reproduction basically wrote an Opinion article in the format of a Mini Review (whatever that may mean) on the current status of PGT-A, under the heading, “Navigating uncertainty in PGT-A: aligning analytical, biological, and clinical evidence.”¹

And you may ask, - so what, - what makes this a worthwhile article to consider?

The answer is, - that there is probably more interesting stuff in this opinion article than may appear on first impression because, even the notion of “uncertainty” is already remarkable progress, considering how “certain” the PGT-A establishment has been about all of its positions in the past.

Who doesn’t remember the days when we were told PGT-A improved IVF outcomes and everybody who didn’t believe it was crucified? Or who doesn’t remember the days when we were told that every PGT-A diagnosis is binary, - either euploid or aneuploid, and whatever is aneuploid must be disposed?

And then, in 2016, a so-called society of experts in PGT-A (in reality, a coalition of mostly economically interested individuals who profited financially from increasing utilization of PGT-A) published truly absurd new guidelines because none of their prior positions were sustainable anymore and added the alleged diagnosis of “mosaicism” to PGT-A. You may have noted the wording of this last sentence with the emphasis being on “diagnosis” rather than “determination” (anybody can reach a diagnosis, but a determination is expected to reflect reality) because – as it turned out – those experts didn’t even understand the physiological definition of “mosaicism” when calling an embryo with more than just one euploid cell lineage in a tiny number of 5-maximally 10 trophectoderm cells “mosaic” (obviously, only a whole organism can be “mosaic”).

And we, of course, could go on and on about all the certainty proponents projected in their pronouncements over more than 20 years of supporting the ever-increasing utilization of PGT-A. But we, instead, want to quote from their abstract (with mild edits) because it – to a degree, surprisingly, after over 20 years of more-or-less hogwash – presented a very reasonably updated viewpoint, - even if unnecessarily complicated when spelled out:

PGT-A is widely used to guide embryo selection, yet its analytical performance, interpretive consistency, and clinical value remain active areas of debate. Advances in sequencing and haplotype-based methods have improved resolution and enabled classification of aneuploidies by their mechanistic origin. They, however, have also revealed substantial variability between platforms, laboratory thresholds, and reporting practices. As a result, the same embryo may receive different classifications depending on the analytical framework, with direct implications for transfer decisions and cumulative live birth potential. Across the available evidence, whole-chromosome meiotic aneuploidies show consistent patterns that support their clinical relevance. In contrast, diagnoses of chromosomal mosaicism and segmental abnormalities remain variable and less consistently predictive. Taken together, these observations underscore the need for validation frameworks that integrate analytical precision, biological plausibility, and outcome-anchored clinical data. Without such measures, increasing technological complexity risks widening…”

Between the lines – even if it hurts – the message is clear and can be formulated in much simpler ways:

(i) The primary purpose of IVF is the achievement of pregnancy.

(ii) The embryo cohort generated in an IVF cycle, through quantity and quality of these embryos, represents a large majority of the cumulative pregnancy and live birth chances of this cycle to achieve this goal.

(iii) Best IVF practice mandates, therefore, to maximize the chances of pregnancy and live birth by safely maximizing embryo quality and quantity.

(iv) Since, as this Mini Review acknowledged, current PGT-A does not yet allow the categorical distinction between definitely “euploid” and definitely “aneuploid” embryo, PGT-A will always result in non-use or disposal of embryos with normal pregnancy potential.

(v) The routine use of PGT-A, therefore, is not only non-sensical, - but unethical.

REFERENCE

1. Popovic et al., Hum Reprod 2026;41(5):665-676

A Case Where Even Genetic Testing Could Not Establish Paternity

So imagine, - a woman has a relationship with two identical twins and she conceives. Everybody now wants to know who the father is, including a court. And if you think that this is a made-up story, you are mistaken; it really happened, and a panel of judges just ruled that it is impossible to determine which of the two identical twins fathered the baby.

REFERENCE

1. Rudy M. FOX News. April 1, 2026. https://www.aol.com/articles/woman-double-twin-relationship-sparks-210521899.html

The Concern about Genetic Discrimination by Insurance Companies

It is interesting that out of all medical and science journals, Science picked up on this issue in a recent article on genetics and the law. And the two authors did a terrific job in explaining a very complex issue.¹ While the U.S. Congress passed in 2008 the so-called Genetic Information Nondiscrimination Act (GINA), - most of the heavy lifting regarding the subject was left to the states. In many – if not most – states, the issues, however, remain unresolved or have been only partially resolved. We clearly are all at risk of being discriminated against by insurance companies based on our supposed private and confidential genetic makeup that, likely, is at least theoretically accessible by all kinds of dark sources. Rumor has it, for example, that China is building genetic information banks not only of its own citizens but also of us, - members of the Western world.

We recommend this brief article. It is eye-opening!

REFERENCE

1. Prince AER, Eckel T. Science 10.1126/science.aee2317

Today’s posting covers topics that should be very familiar to readers: the debated use of Tylenol during pregnancy, COVID-19 vaccinations for pregnant women, and the potential impact of Long COVID on some fertility patients. Though these subjects have all been addressed numerous times in lay media at this point, it’s always worth examining the latest scientific research on these matters, as the newest updates may go underreported in some larger news publications. As always, we welcome your comments and discussion.

The CHR’s Editorial Staff

More on Acetaminophen (Tylenol) During Pregnancy and the Risk of Autism in Offspring

This is, of course, a subject addressed exhaustively in medical journals and the lay press, but the study here presented was a very large Danish nationwide cohort analysis, involving more than 1.5 million children born between 1997 and 2022 that examined whether prenatal exposure to acetaminophen (Tylenol/paracetamol) was associated with autism risk in offspring.

And the main conclusions were that (i) after adjusting for confounding factors, the researchers found no meaningful association between acetaminophen use during pregnancy and autism in children. (ii) Absence of association persisted across different pregnancy trimesters, at low and high exposure levels, and in sibling-comparison analyses designed to reduce genetic and family-environment confounding.

Earlier studies suggesting a link may have been affected by “confounding by indication” — meaning that women taking acetaminophen during pregnancy may differ medically from women who do not, and those underlying differences, rather than the drug itself, may explain prior signals.

Clinically, the article very convincingly supports the current view that acetaminophen remains one of the preferred pain and fever medications during pregnancy, when medically indicated.

REFERENCE

1. Philipsen Prahm, et al., JAMA Pediatrics. 2026, Online ahead of print. Doi: 101001/jamapediatrics. 2026.0646

More on COVID-19 Vaccines in Pregnancy

Yes, we know that everybody is tired of hearing more about COVID-19 vaccinations in pregnancy, but even though COVID is no longer the threat it used to be, it still exists endemically in the U.S., and it still is a more severe disease in pregnancy than in the non-pregnant state. Information about vaccinations, therefore, is still of importance.

This is why we here report on an interesting recent study from Norway, which examined associations between COVID-19 vaccination during pregnancy and the risk of various subsequent infections of offspring in early childhood. And the results were really interesting: COVID-19 vaccination during pregnancy protected the offspring against hospital contact for COVID-19 during the first 6 months of life, but no apparent effects were observed for other infections, demonstrating that the protection is highly specific. This is an important finding because there exists considerable evidence that under different conditions, cross-reactivity can exist with other flu-like viruses (see Figure below).

In summary, maternal vaccination against COVID-19 during pregnancy offers a waning protection to the offspring against hospital contact for COVID-19 in the first 6 months of life.

But here is more exciting news from two papers in JAMA and eClinicalMedicine (a Lancet journal), respectively: The JAMA paper, in a study of 26,584 cases, of which 19,899 were eligible for analysis, reported that vaccination prior to and during pregnancy (before diagnosis of COVID-19) was significantly associated with lower risk of severe maternal disease and preterm birth, regardless of variant time period.² The eClinicalMedicine article, in turn, involving no fewer than 69 authors from 18 countries all over the world, reported a truly astonishing finding: COVID-19 vaccination with a booster reduced the odds of preeclampsia (PE) by 30%, approaching 60% reduction among women with pre-existing morbidities.³

And here is the full story: The authors confirmed the previously suggested independent association between COVID-19 and PE (aOR: 1.45; 95% CI: 1.15–1.84), particularly in unvaccinated women (aOR: 1.78; 95% CI: 1.31–2.42). Overall, after adjusting for confounders, any vaccination offered protection against PE during the index pregnancy (aOR: 0.85; 95% CI: 0.65–1.10), further strengthened with a booster (aOR: 0.67; 95% CI: 0.45–0.99). Among women with pre-existing morbidities who received a booster dose, the odds were reduced by 58% (aOR: 0.42; 95% CI: 0.20–0.87) – mainly observed in women diagnosed with COVID-19. Adjustments did not alter the magnitude of the effect. Vaccination amongst women who received a booster dose was also associated with decreased odds of maternal (aOR: 0.68; 95% CI: 0.55–0.83) and perinatal (aOR: 0.71; 95% CI: 0.54–0.95) morbidity and mortality, and as in the JAMA study – with preterm birth (aOR: 0.67; 95% CI: 0.53–0.85).

These findings are not only remarkable in their very obvious and here-summarized detail, but, potentially, also offer important insights on a completely different level: The fact that these vaccinations demonstrate such an enormous effect on PE, increasingly understood as a condition of dwindling immune tolerance of the mother toward her fetal-placental unit – strongly implies that these vaccines affect the maternal immune system by “replenishing” its capacity for tolerance. If correct, this would suggest that PE may be preventable through timely vaccinations.

REFERENCES

1. Eide HN, et al., Pediatrics. 2026;157(4):e2025073661

2. McCkaymont et al., JAMA 2026;335(2):154-162

3. Cavoretto, et al., eClinicalMedicine 2026; 103785

Long COVID Activates Proinflammatory and Immune Exhaustive Pathways

And since we are already on the subject of COVID, here is some insight on Long COVID, which – fortunately only rarely – we also have started seeing in some infertility patients.

Long COVID (LC) involves a spectrum of chronic symptoms, and current hypotheses for the pathogenesis of LC include persistence of the virus, tissue damage, autoimmunity, endocrine insufficiencies, immune dysfunction, and complement activation. It finally appears that some mysteries of Long COVID are slowly revealing themselves. Within that context, a recent paper in Nature Immunology was a good example when it demonstrated that in so-affected patients, proinflammatory pathways are persistently upregulated. These are potentially important discoveries because they may lead to new therapeutic targets for this condition and may also allow for discovery of new potential biomarkers for the disease.¹

REFERENCE

1. Aid et al., Nat Immunol 2026;27:61-71

Today’s posting focuses on recent news related to Geroscience, alternatively called Longevity Medicine or simply the science of aging. From a potential cause of aging-related memory loss to how much of our lifespan is actually inherited, these topics deserve a much closer look by all our readers, regardless of their current age. With so many lingering questions about aging out there, it’s always encouraging to see some scientists searching for real answers. If the research can help others increase their lifespan — and not just survive, but thrive — all the better. As always, we welcome your comments and discussion.

The CHR’s Editorial Staff

It is difficult to know where we stand in the quick evolution of Longevity Medicine, or, as a recent article in The New York Times called it, Geroscience. Whatever we call it, it in many ways appears like a parallel universe next to A.I. with almost daily announcements about only recently unimaginable breakthroughs. But are they for real? The recent NYT article believed that even though Longevity Medicine is “under scrutiny” and is ripe with opportunity and opportunism, there are good ways to navigate the process.¹ We with this section want to help a little bit in this process.

REFERENCE

1. Smith DG. The New York Times. April 14, 2026. https://www.nytimes.com/2026/04/07/well/longevity-medicine-definition.html

Rockefeller University Scientists Have Mapped How Aging Reshapes Cells Across the Entire Mammalian Body

Though done in mice, this study has to be considered a force majeure, probably very soon repeated in humans. To investigate cellular alterations and epigenomic dynamics during aging, the authors constructed a single-cell chromatin accessibility atlas, spanning 21 mouse tissues across three age groups and both sexes.

What they found was pretty amazing: Approximately one-quarter of 536 organ-specific cell types and 1,828 finer-grained subtypes exhibited considerable age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, suggesting systemic signals that control/coordinate these changes.

Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying in these shifts. Moreover, ~40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.

But the findings went beyond that: While it was generally believed that aging meant declining functions in cells and not fewer cells, that was not confirmed. Approximately a quarter of cells also declined in numbers. Moreover, declines in cell populations appear to happen already quite early and are coordinated across even distant organs, which hints that there exists some kind of central control in this aging process, - a master switch???

Less surprisingly, the study also demonstrated profound differences between the two sexes, with women demonstrating a much broader immune activation than men with aging. And here we go again, because this observation was considered a possible hint why autoimmune diseases were so much more frequent in women than men.

REFERENCE

1. Lu et al., Science 2026;291(6788). DOI: 10.1126/science.adw6273

Is Aging-Related Memory Loss Fueled by Gut Microbes?

A News article in Nature¹ brought our attention to this paper with 49 authors, also appearing in Nature.² Following the authors’ summary in the abstract – like the preceding paper – this was also a mouse study with considerable likely implications for the human experience.

Aging leads to declining memory function, which can manifest in humans in many different ways. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as target interventions, but the underlying mechanisms have remained unclear.

By charting microbiome aging and its functional consequences throughout the lifespan of mice, the authors identified a mechanism by which inhibition of gut-brain signaling during aging resulted in impaired neuronal activation in the hippocampus and loss of memory encoding. Specifically, accumulation of gut bacteria that produce medium-chain fatty acids, such as Parabacteroides goldsteinii, can drive peripheral myeloid cell inflammation through GPR84 signaling.

As a result, the function of vagal afferent neurons is impaired, the interoceptive signal received by the brain is weakened, and hippocampal function declines. The authors then leverage this pathway to define interventions that enhance memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition, and restoration of vagal activity. These findings indicate a key role for interoceptive dysfunction in brain aging and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.

Brilliant and potentially quickly clinically applicable!

REFERENCES

1. Chen E. Nature 2026;651:567568

2. Coc et al., Nature 2026;652(8109):442-450

A Bigger Part of Our Lifespan is Inherited than was Assumed

And here goes another widely held belief out the window, as a new study suggested that ca. 55% of the human lifespan is inherited; i.e., attributable to our genes;¹ and discussed in a new Commentary² in the same issue of Nature. This is not what used to be the common belief; that was only ca. 10-25%.

What now becomes the question is, - what are the involved genes and can we affect them?

In another Commentary regarding the original Nature article, this time two authors comment in Science on the (max.) 55% finding, noting that these percentages vary by disease group. So, for example, cardiovascular disease and dementia show much higher heritability than cancers.

And then, there is another important point to consider: The other roughly half is not genetic. What we eat, how we live, what our weight is, etc., of course also affects lifespan and is to a large degree under our control. So don’t give up, - treat yourself well!

REFERENCES

1. Shenhar, et al., Science 2025;391:504-510

2. Kozlov M. Nature 2026;650:283-284

3. Bakula D, Scheibye-Knudsen M. Science 2026; 10.1126/science.aee3844

Today’s posting offers a close look at timely issues related to in vitro fertilization (IVF) and the infertility field as a whole. From arguments over who gets unused embryos after a couple splits up to debates about whether Jewish law allows for the posthumous use of semen from deceased soldiers, these stories shed light on important questions that don’t always have easy answers. Surprisingly, some of these subjects have been addressed in the media on numerous occasions in the past, showing that even seemingly settled topics can still inspire heated debate or more thorough research. As always, we welcome your comments and your opinions on the best ways to resolve these ongoing issues, especially if they differ from ours.

The CHR’s Editorial Staff

Insights From 8 years of Planned Oocyte Cryopreservation at an “Egg Freezing Clinic”

There are several reasons why a recent paper attracted our attention, with the first being that the clinic that published the paper identified itself – for the first time we ever have seen this – as an “egg-freezing clinic.” We consider this an important definition because clinics that primarily only conduct egg-freezing cycles – only here and there intermingled with a real IVF cycle trying to immediately achieve a pregnancy – must lack ovarian stimulation experience because egg-freezing cycles do not offer immediate cycle outcomes beyond oocyte numbers, maturity, and morphology. For all practical purposes, they often lack experience with the most important IVF cycle outcome parameters, pregnancy and delivery rates.

But, aside from this point, egg-freezing experiences are important to publish. Despite the explosive growth in egg-freezing cycles in the U.S., reported outcome data have remained remarkably sparse and in general have demonstrated surprisingly low efficiency for the concept of egg-freezing to preserve fertility, as later use of frozen eggs in almost all studies was found to be surprisingly low.

The here-discussed study from a NYC-based “egg-freezing clinic,” therefore, added important information over an 8-year span: Between 2016 and 2023, the clinic completed 4,659 cycles for 3,138 patients, with the mean cycle start age actually decreasing from 36.9 ± 2.8 years at the onset to 35.0 ± 3.5 years in the final year of the study.

The mean length of time between freezing and thawing was 3.4 ± 1.9 years. The mean age at first thawing was 39.9 ± 3.5 years, with a median (interquartile range) of 40 (39, 42) years. Among patients who had completed at least one freezing cycle before 2020 (n = 2,163), allowing for a minimum follow-up period of 4 years, only a remarkably low 10.4% (n = 226) returned for warming of their oocytes.

Across 271 such warming cycles, the mean number of MII oocytes warmed was 15, with very good survival and fertilization rates of 90.7% and 77.2%, respectively. Among patients who underwent cryopreservation at ≤40 years of age, warming a higher number of MII oocytes was associated with increased euploid embryo yield. The cumulative ongoing pregnancy/live birth rate for the cohort was 70.3%, ranging from 58.3% for 1–9 MII oocytes warmed to 81.8% for >20 MII oocytes warmed. We here at the CHR would, of course, argue that avoiding the use of PGT-A would likely have resulted in even better pregnancy rates.

So these, then, are the conclusions:

1. We are not certain that the decline in age of patients in this study is typical. At least, at the CHR, the trend has been going strongly the other way. But we – certainly – are also not primarily an “egg-freezing clinic!”

2. The main point is clearly that the usage rates of frozen eggs has – overall and especially in young women – indeed remained incredibly low, raising the question of what can – or maybe what should – be done to screen especially younger women in ways to avoid so many, in retrospect, useless cycles of fertility preservation. And recognizing the obvious difficulties in predicting who will or will not need frozen eggs to achieve motherhood, maybe the field should search for alternative solutions. One such alternative could, for example, at a certain age, be an egg-donation option for unused oocytes, including a partial refund of egg-freezing costs and permission for the “egg-freezing clinic” to use those eggs in anonymous donor egg cycles.

3. Finally, we need more precise outcome data. While the paper-presented cycle outcomes appear quite satisfactory, they – ultimately – cannot be really judged as presented in the paper.

Nevertheless, this was an interesting paper on egg-freezing, especially since it did not come from the NYU group, which so far has been dominating this ongoing discussion.

REFERENCE

1. Klein et al., Fertil Steril 2026;125(4):671-678

Back Again Under Legal Scrutiny: Who Gets Custody of Unused Embryos When a Couple Splits Up?

We thought that courts all over the country had resolved this issue a long time ago, because who does not remember cases where older women pleaded for the use of embryos they had produced while they were still married? They often argued that these embryos represented their last chance of genetic motherhood, while their ex-husbands often refused their consent with the argument that they no longer wanted to become genetic fathers and couldn’t be forced to agree against their will. And the courts usually held that nobody can be forced into genetic parenthood.

But here we go again, as The New York Times recently reported.¹ The case the Times article reported on appears, indeed, still legally surprisingly unsettled since only approximately one-third of states have considered the issue at the appeals court level, where precedent is set.

Moreover, state legislatures are apparently getting interested in the subject: The Michigan Supreme Court in 2025 urged the state’s Legislature to consider the question of such embryo disputes. Arizona already in 2018 became the first state to pass a law requiring that – in case of such a dispute – existing embryos go to whichever party was planning on using them to have children. And in New York, the New York Times article suggested that everybody expects this case to be decisive.

And what is the CHR’s opinion? This is one of those issues where we are happy not to be the judge and happy not to have to make such difficult Solomonian decisions. But if we were forced to make the decision, we, likely, would award the parent who is ready to try to produce a child the right to do so, as long as this would not mean any form of parental responsibility – including financial responsibilities – for the unwilling parent.

But, as we already are making speculative judgment, what would be the decision if both parents want to use a single embryo to have “their own” child? It seems to us that it is only a matter of time until this potential issue will reach the courts. What then?

A modern-day King Solomon would – no doubt – split the embryo. But what could we do?

REFERENCE

1. Kitchener C. The New York Times, May 24, 2026. https://www.nytimes.com/2026/05/24/us/ivf-embryos-custody.html

Also Back Again: Is Undergoing Assisted Reproduction Procedures Like IVF Increasing Cancer Risks?

This is a question as old as IVF itself and, indeed, even older because it was already raised with the use of the first fertility drugs before IVF became a reality. In those days, they were the oral clomiphene citrate and the injectable Pergonal (the first drug derived from postmenopausal urinary gonadotropins of nuns).

But this study is worth mentioning because of its size: A multi-center cohort study of patients all over the world, it involved 417,984 women exposed to assisted reproduction procedures in Australia between 1991 and 2018, and the findings were once again reassuring: The all-cancer incidence was not different from the age-, jurisdiction-, and calendar year-matched general population of women. Incidence for some hormone-sensitive cancers (uterine, ovarian) and cutaneous melanoma were marginally higher, while incidence for cervical cancer and cancer of the trachea, bronchus, and lungs were marginally but notably reduced.

Specifically, in the total of 417, 984 exposed women, with 274 ,676 (65.7%) having used ART (median age, 34 [31-38] years; median follow-up time, 9.42 [5.08-15.42] years), and 175, 510 (42.0%) having ever used clomiphene citrate (median age, 32 [28-36] years; median follow-up time, 9.42 [5.42-13.58] years), - the overall incidence of invasive cancer was comparable with the general population for the ART (IVF) and IUI (SIR, 0.99; 95% CI, 0.97-1.02) cohorts and slightly elevated for the clomiphene citrate cohort (SIR, 1.04; 95% CI, 1.00-1.07).

For all cohorts, incidence of uterine cancer (SIRs, 1.23-1.83) and in situ and invasive melanoma (SIRs, 1.07-1.15) were elevated, and incidence of cervical cancer (SIRs, 0.52-0.61) and cancer of the trachea, bronchus, and lungs (SIRs, 0.62-0.70) were lower. Ovarian cancer incidence was elevated for the ART (SIR, 1.23; 95% CI, 1.10-1.37) and IUI/OS (SIR, 1.18; 95% CI, 1.01-1.37) cohorts. In situ breast cancer incidence was elevated for the ART cohort only (SIR, 1.24; 95% CI, 1.12-1.38). Incidence of invasive breast cancer was not elevated. Rate differences for invasive cancers with elevated incidence were all small (<1 to 6.51 cases per 100 000 person-years).

The conclusion, therefore, was that the overall incidence of cancer was comparable with that of the general population. The incidence of certain cancers appeared elevated; however, the excess numbers of these cancers were small, and there was a reduced incidence of other cancers. Causation can definitely not be inferred from this descriptive evidence.

REFERENCE

1. Vajdic et al., JAMA Network Open 2026;9(3):e261332

And Also Back Again: The Question of Whether Time Lapse is Cost Effective in Improving IVF Outcomes?

When time lapse monitoring was first introduced to embryology laboratories, the CHR – rather than purchasing one or more units of what was then called the “embryoscope” (as many clinics did) – decided to first test this new product reaching the market. Securing one of these instruments from a company for several months as a loan, for testing purposes only, we were looking to confirm claims at the time made by proponents of the product (some among them, as later tuned out, with undisclosed financial interests in the company that offered the product) that it would significantly improve pregnancy rates in IVF, shorten the staff time involvement per patient, and would also greatly enhance research on preimplantation-stage embryos. Our short study only was able to confirm the last claim, and even that in only limited ways. Moreover, we found that this new equipment actually increased the time embryologists spent on each patient.¹

We, therefore, thanked the company, returned the instrument, and have been practicing without even a single time lapse monitor ever since. And as such, the CHR is likely one of only a very small number of IVF clinics without an abundance of time lapse monitors. Indeed, by now, a large majority of embryos in IVF clinics in the U.S. are routinely monitored in the – granted, steady – environment in such units.

And while steadiness of the environment is, of course, a relatively strong argument, especially in favor of time-lapse equipment for IVF clinics with large embryology staffs, which often diverge in cycle outcomes within a program, this, however, became exactly also the principal reason we chose against converting our embryology from manual morphology to time lapse. While we confirmed that it, of course, allowed for close observations of every embryo (if one wants to do this and spend the time), it forces every embryo into the same protocol. One, of course, theoretically can still individualize, but will one really do this? We didn’t think so, and we, to this day, consider this to have been the right decision for the CHR’s highly unusual patient population. The CHR, therefore, still does not use time lapse monitoring of embryos in routine clinical practice.

As ever-increasing numbers of time lapse systems were purchased by IVF clinics and increasing numbers of manufacturers started to offer such equipment, consensus was, however, reached in parallel through several well-designed studies that – like with so many other “add-ons” to IVF practice since 2010 – time lapse monitoring actually failed to fulfill the many promises its proponents had made in convincing the field to spend millions of dollars on this new equipment (with costs, of course, passed on to patients). Many clinics, even to this day, still charge patients extra “time lapse fees” in every cycle.

And now, as A.I. is trying to secure a foothold in the IVF laboratory, the combination of time lapse monitoring with A.I., of course, looked very enticing and underwent heavy promotion by several start-ups with alleged A.I. programs that could basically “guarantee” IVF pregnancies.

We, of course, are kidding!

At least as of the time of this writing, we are unaware of even a single study having demonstrated outcome benefits for embryo selection via A.I. in IVF cycles. We, however, are aware of at least one company making this claim having gone out of business because, - as we were told by the founder and CEO, “the financial benefit for IVF clinics was not big enough for them to warrant the purchase of the A.I. product.”

And, as with several other useless “add-ons” to IVF, the IVF field once again was lucky in that – what we have come to call the “Dutch Cavalry” – recently took up (as it has done in the past for many different “add-ons,” including, for example, PGT-A) the important research question, whether time lapse monitoring represented a cost-effective service?² We coined the term “Dutch Cavalry” based on the fact that our Dutch colleagues succeeded in publishing so many important clinical studies, including large patient numbers in a very small country, and because they succeeded in setting up a unique collaborative multi-center research network involving all medical schools in The Netherlands. The study just published reported on the cost-effectiveness of time lapse monitoring with or without the use of embryo selection software compared to routine incubation and selection.²

And here is what they – for us here at the CHR completely unsurprisingly – found: The chance of having a baby within 12 months was similar for time lapse incubators and standard incubators. Time lapse incubators are, however, more expensive. The use of time lapse monitoring, therefore, - even in association with A.I. is, therefore, only unlikely to be cost-effective, - meaning that the higher costs are not balanced by better outcomes.

And for patients, this means that time lapse technology does not increase their chance of having a baby, but it does increase their costs of IVF treatment. The old-fashioned standard method of growing and selecting embryos, therefore, remains the most cost-effective option.

And why were we not surprised by these results? Because, as we just suggested in a very recent paper in Human Reproduction Open, all the evidence in the world now suggests that the concept of embryo selection – one of the earliest dogmas in IVF – simply no longer makes sense.³ Whatever technology we will throw at embryo selection (and how many investments we will make) - for basic biological and statistical reasons, embryo selection within a cycle cohort of embryos will never outbid basic, solid manual embryology in selecting the “best” embryos.

It would exceed the space we have here for this argument to go into further detail, but the absolutely correct logic behind why embryo selection – by whatever means – beyond routine manual embryology does not make sense is in detail explained in our recent publication.³ Thank you to The Netherlands for another important paper!

REFERENCE

1. Wu et al., Reprod Biol Endocrinol 2016;14(1):49

2. Kieslinger et al., Hum Reprod Open 2026;2:hoag034

3. Gleicher et al., Hum Reprod Open 2025;2:hoaf011

Does Jewish Law Allow Making Babies from the DNA (Semen) of Deceased Soldiers?

For obviously tragic reasons, this subject has occupied the Israeli public and media since October 7, 2023, to very significant degrees and has done so with considerable urgency after more than 940 young IDF soldiers in their peak reproductive years and over 210 members of Israel’s security forces lost their lives since that date. Though, of course, a problem of limited relevance to the U.S. public, it is important to recognize that ethical, religious, and legal issues that arose in Israel in obvious association with October 7, 2023, and what has followed since, also can apply to deaths outside of a war zone (for example, in NYC’s subway system, or on Chicago’s South Side).

We are here, therefore, reprinting selected passages of an article posted on Facebook by Hezy Laing, an independent journalist living in Jerusalem, in which he addressed this issue, - obviously from a religious Jewish viewpoint, which, however, as will quickly become apparent, addresses universal ethical, religious, and legal issues.

Among the most poignant stories addressing the issue of posthumous use of semen is that of Dr. Hadas Levy, a pediatrician whose fiancé, Capt. (res.) Netanel Silberg, was killed in Gaza in December 2023. Levy became the first woman in Israel to give birth to a child conceived from the genetic material of a soldier killed in the war.

Her experience, along with the roughly 250 families who have requested retrieval of genetic material from fallen soldiers, has brought unprecedented halachic questions (questions under Jewish law) to the forefront. The issue is especially pressing because sperm retrieval is extremely time‑sensitive. Success is about 75 percent within 24 hours of death and drops sharply after 72 hours.

This urgency intersects with Israeli law, which has evolved since the Attorney General’s 2013 guidelines, which said the following:

• Widows or partners may request retrieval without court approval, unless a relative objects.

• Parents must normally obtain family court approval, though, due to the narrow time window.

During the early months of the war, the Tel Aviv Family Court temporarily allowed retrieval without prior approval.

• Regardless of who requests retrieval, use of the sperm always requires court authorization.

• Widows are generally approved based on the presumption that the deceased wished to have children with them; parents must demonstrate evidence of the son’s wishes.

Halachically, the matter is, however, far more complex. Three scenarios must be evaluated separately under Jewish law: A married soldier with children, a married soldier without children (raising issues of so-called yibbum and chalitzah), and a single soldier, where the use of an unmarried woman’s womb introduces additional concerns.

These distinctions shape the positions of three major contemporary poskim (religious judges): Rav Mordechai Halperin argued that, although the deceased cannot fulfill the mitzvah of Peru U’revu after death, enabling his wish to leave a legacy may constitute chesed shel emes, similar to saying Kaddish or performing other acts on behalf of the dead. He later refined his view, but maintained that fulfilling the deceased’s will can be permissible, especially when the desire to leave a “name and remnant” is clear.

Rav Asher Weiss strongly opposed this. He maintains that there is no mitzvah after death, that “mitzvah l’kayem divrei ha‑meis” applies only to monetary matters, and that creating a child for a deceased bachelor inevitably leads to single motherhood, which he considered outside of Torah norms. He further warned that permitting such procedures could normalize parenthood outside of marriage and concluded that such requests should not be fulfilled.

Rav Zalman Nechemiah Goldberg offered a middle position: Without explicit consent, the procedure is forbidden; with clear consent or a strong umdana that this was the soldier’s wish, it is permitted. He bases this on the Torah’s valuation of preserving a person’s “name and remnant,” drawing an analogy from the rationale behind yibbum.

He further argued that the human desire for continuity is deeply rooted in Torah values and can justify posthumous reproduction when the deceased’s intent is known.

Together, these halachic, legal, and emotional dimensions have made posthumous reproduction one of the most sensitive and urgent questions facing Israel today.

REFERENCE

1. Laing H.Facebook. May 6, 2026. https://www.facebook.com/gershon.shapiro.9/posts/it-is-a-tough-call-one-that-would-require-in-my-opinion-a-sanhedrin-type-court-m/2182582522542965/

Today’s posting involves an Editorial by the CHR’s Editorial Board and, therefore, represents the opinion of the CHR and clinical as well as ethical practice principles of the CHR. For that reason, we reserve this publication format to only include the most important issues that arise in the fertility field.

The CHR has for many years been on record as a leading opponent of several so-called “add-ons” to IVF. CHR investigators have pointed out in several papers over almost 20 years that these add-ons have not only failed patients in improving IVF outcomes, but also in many instances have actually harmed IVF cycle outcomes in selected patient populations. They, of course, uniformly also significantly increase IVF costs.

Examples abound,- from preimplantation genetic testing for aneuploidy (PGT-A), polygenic risk screening of embryos (PGT-P), routine all-freeze cycles with delayed frozen embryo transfer cycles, - to many more. The CHR in many of these publications has also criticized the frequently observed silence of professional societies in the fertility field in this matter.

Today’s Editorial was spawned by an article by several prominent European colleagues who claimed that the poor IVF outcomes in poor-prognosis patients should be “fought” not with better cycle management (maybe excluding some of the above-noted harmful “add-ons” to IVF in such patients), but by simply manipulating outcome data, - so they looked better by no longer presenting outcomes to patients based on single-cycle outcomes, but based on multiple-cycle outcomes. In other words, - sell IVF to poor-prognosis patients in multiple-cycle packages (which, of course, lock patients into multiple-cycle commitments). One, therefore, wonders who would really benefit from this kind of a change? Certainly not the patient!

The CHR’s Editorial Staff

Making IVF Always More Expensive, But - Unfortunately - Never any Better in Outcomes!

The Editorial Board of the _CHRVOICE and The Reproductive Times

Sometimes it is not enough to speak quietly, and raising one’s voice becomes essential if one wants to be heard at all. In this article, the CHR’s Editorial Board does exactly that when addressing the fact that the IVF field is overrun by a stampede of great-sounding clinical ideas, - including so-called “add-ons”- offered by often prominent “experts” in the field and introduced into routine clinical practice, - simply based on the power of the names of the “experts.” And as is well recognized, expert opinion – yet deservedly - sits at the very bottom of the evidence pyramid because a good idea is, of course, cheap and not at all enough to support introducing new treatments, - even if such treatments – especially if not depending on FDA approval - at times can also become quite profitable.

Colleagues often too generously offer such opinions through the quickly increasing plethora of opinion articles in many medical journals, sometimes with clear intent, - but frequently simply out of ignorance about potential negative consequences.

This Editorial was in reaction to such a recent article in a prominent European infertility journal, which – without any cost and other considerations like time to pregnancy - claimed to introduce a new treatment paradigm with the goal of benefitting clinical patient outcomes. Though patient outcomes, of course, must be at the center of all benefit considerations, they also must not exclude risk assessments and costs. Both of these considerations, however, did not at all enter consideration in this proposal, and that must be viewed by editors as a clear warning signal before publication that other than pure scientific considerations may be - subconsciously or consciously - at the core of a new submission for publication.

We fully recognize the controversial nature of this Editorial, but, considering the uncontrolled proliferation of unvalidated “add-ons” to IVF practice since approximately 2010, the IVF field will not improve IVF cycle outcomes that have stagnated since that date overall, and for certain patient sub-groupings (like autologous IVF cycles), they have actually dramatically declined. Because of the controversial nature of this Editorial, we – more than ever – are looking forward to our readers’ opinions.

Especially our European colleagues always appear on the outlook for new ideas about IVF, - but for some reason, - those ideas never appear to improve IVF outcomes as promised. They most certainly, however, increase IVF costs. And, paradoxically, it almost appears like, – the more expensive, the quicker the new ideas are accepted by the IVF field, - even in absence of significant evidence. There is, of course, reason to wonder why this has been such a recurring theme?

When Austrian/German colleague Georg Griesinger, MD,¹ for the first time in 2007, and Paul Devroey, MD and colleagues in Brussels, Belgium² in 2011, for example, proposed so-called segmentation of IVF, a term created to denote the conceptual separation of ovarian stimulation from embryo transfer, the primary purpose was to prevent the ovarian hyperstimulation syndrome (OHSS) in IVF cycles with excessive follicle numbers. The idea of all-freeze cycles under such circumstances, then, of course, made sense.

But what followed was that the concept then was expanded to practically all IVF cycles under the dubious – and, to this day, unproven – allegations that ovarian stimulation in IVF cycles in some ways adversely affects endometrial receptivity. And, suddenly, all-freeze cycles became the “fashion of the moment” (and, yes, IVF constantly does go through such “fashions of the moment”) for all IVF cycles after they were heavily promoted by Las Vegas-based Bruce S. Shapiro, MD, and co-workers (too much gambling going on in Las Vegas, apparently!).³ But that fashion did not maintain popularity because some “real” studies very quickly demonstrated that this kind of segmentation did not – as claimed by Shapiro et al (and others) – improve IVF outcomes, but actually reduced cumulative pregnancy chances.⁴ But by adding freezing costs and additional costs for a thaw-out frozen embryo cycle, it surely raised overall IVF costs (and, of course, increased IVF clinic income) significantly, while in addition prolonging the time to pregnancy.

But that is only one “fashion of the moment” that has obviously negatively affected IVF practice (and is still going on in too many U.S. and European IVF clinics). Again, especially some European colleagues have apparently convinced themselves that they know what we should spend our money on: A.I., of course, can improve donor oocyte assessment⁵ and basically everything else in embryology, DuoStim is, of course, effective in improving egg numbers (and how about quality?).⁶ It also, of course, prevents all fresh embryo transfers and, therefore, requires an additional thaw cycle; but who cares about that?

And, yes, all embryology, of course, must be automated⁷ (because closed incubation systems really delivered on all the promised improvements the manufacturers touted) and, therefore, let’s just expand automatization to everything in the embryology laboratory (and it, of course, helps if we hold shares in a company that sells the needed equipment).

A group of prominent European colleagues recently published a commentary in Reproductive Biomedicine Online (RBMO), in which they – kind of unexpectedly – proposed to “change the narrative for poor-prognosis patients in IVF by unlocking success through a multi-cycle approach.”⁸

So, why were we interested in this subject? Not only because one of the authors was a senior associate editor of the journal (the topic of editors publishing in their own journals was recently addressed in a prior issue of the _CHRVOICE). No, - what we found, rather shamefully, was that these authors were not trying to suggest that it was time to try to improve the kind of IVF that is offered to poor-prognosis patients all over the world, - but they were suggesting the amazing – almost mind-blowing – allegedly new concept of offering them multiple-cycle packages as the solution for the patients’ poor prognosis.⁸ Not a word, however, on the fact that relatively promising treatments exist for many women above ages 42-43 that - even with autologous oocytes - still offer very decent pregnancy chances.

Most U.S. IVF clinics, however, are no longer even interested in trying to treat patients with their own autologous eggs. U.S. statistics well demonstrate this fact through the quick fall into nothing of U.S. autologous IVF cycles after age 43. This is indeed why we started this commentary with the subject of “all-freeze cycles.”

The authors, then, of course, also had to add to their absolutely “brilliant” idea of multiple-cycle packages in poor-prognosis IVF patients the following, -quoting the authors verbatim: “A multicycle approach, adopting approaches such as oocyte/embryo accumulation from several stimulations or two consecutive stimulations, - i.e., DuoStim (yes, they threw that in as well!), enables the advance planning of multiple attempts (really?). It helps shorten time to pregnancy (evidence?), reduces treatment discontinuation (evidence?), and offers support for patients facing setbacks (how?).

Poor-prognosis patients, of course, have poorer pregnancy chances than average-prognosis and especially good-prognosis patients. And, as usually one of the best-informed patient populations in all of medicine, infertility patients, of course, understand that – in practical terms – this means that they can expect to need more IVF cycles than most other patients. Multiple-cycle packages in such cases then, of course, may make sense for some patients, but, of course, only if significantly discounted.

But to make this the centerpiece of a Commentary article in a major infertility journal with not a word about how poorly poor-prognosis patients are currently treated (if at all!) in most IVF clinics is just further evidence for how much more emphasis is dedicated these days to improving the economics of IVF (for providers) rather than the execution of high-quality infertility care (for patients).

All of this must also be seen against the overall clinical realities of steadily declining pregnancy and live birth rates in autologous IVF cycles versus steeply increasing IVF cycle costs based on U.S. registry data (see figure below). Considering, under these circumstances, multi-cycle programs as the solution , - rather than advocating for better per-cycle outcomes first, appears more than just a misdirection. Since the “add-on” revolution around 2010 started to explode, these kinds of unfortunately only poorly-thought-through commentaries have, however, been fairly typical, - not infrequently driven by false narratives by European colleagues.

And the consequence?

To the best of our knowledge, autologous IVF - at least in the U.S. - has earned the “honor” of being the only widely accepted primary treatment in all of medicine which over the last 15 years has experienced an almost straight line downwards to progressively poorer outcomes (see again figure below, with background information for this figure provided as a footnote).

Three U.S colleagues recently submitted a letter-to-the-editor to Human Reproduction Open in which – describing themselves as “leaders of the Society for Assisted Reproductive Technology (SART),” a sister society of the American Society for Reproductive Medicine (ASRM) – they criticized a recently published paper in this prominent journal by CHR investigators that pointed out “the declining efficiency since approximately 2010 of (autologous) IVF in the U.S.,”⁹ as also described in the above figure. We, of course, are not permitted to reveal the content of their criticism before publication of their letter and the CHR authors’ response. But it appears appropriate to point out here that this Editorial made its points appear even more timely in view of the comments made by SART leadership in this letter and we strongly encourage the readers of this Editorial to seek out this exchange of letters, which should appear within weeks in Human Reproduction Open.

REFERENCES

1. Griesinger et al., Hum Reprod 2007;22(5):1348-1352

2. Devroey, et al., Hum Reprod 2011;26(10):2593-2597

3. Shapiro et al., Fertil Steril 2014;102;3-9

4. Wong et al., Hum Reprod 2021;36(4):998-1006

5. Cimadomo et al., Hum Reprod 2025;40(10):1886-1892

6. Vaiarelli et al., Upsale J Med Sci. 2020;125(2):121-130

7. Racowsky et al., Fertil Steril 2026;125(1):2-12

8. Vaiarelli et al., Reprod Biomed Online 2026;52(5):105465

9. Gleicher et al., Hum Reprod Open 2026(1):,hoag004

Today’s posting offers an article by Lyka Mochizuki, MSc, who, several years ago while a research assistant and research fellow at the CHR, wrote a remarkable article on PGT-A in the JARG and now – here – is revisiting the same theme. But without disclosing too much, it wasn’t then just another opinion article on PGT-A and it is not now either, and you will have to read the article to know why. We think you will find the article to be quite interesting.

And if you wondered why we so far didn’t post this week, Monday was, of course, a holiday and Tuesday we were extremely busy completing the April/May issue of the _CHRVOICE, which is scheduled to drop tomorrow.

The CHR’s Editorial Staff

THE PGT-A CONTROVERSY What Five Years Later A.I. May or May Not Change

By: Lyka Mochizuki, MSc, past Research Fellow and currently Project Manager at the CHR. She can be reached through the editorial office of the _CHRVOICE and The Reproductive Times.

This article follows a highly unusual article on the then still very acutely controversial subject of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF) by the same author in the Journal for Assisted Reproduction and Genetics. The article was so unusual because in addressing the then still much more heated differences of opinion, she for the first time applied the concept of conflict resolution to the dispute (the author holds a MSc in Conflict Resolution from Columbia University in NYC). Now - in a different position - once again a member of the CHR team, she agreed to revisit the subject, though in consideration of the current Zeitgeist in which A.I. is changing the world and, with it, of course, medicine. We are certain you will enjoy this article and, as always, we are welcoming responses.

And as a side note, the April/May _CHRVOICE should be dropping tomorrow! Here, too, we are awaiting your responses.

In 2020, I co-authored a paper in the Journal of Assisted Reproduction and Genetics that approached the controversy surrounding preimplantation genetic testing for aneuploidy (PGT-A) through an unusual lens: a formal conflict resolution analysis.¹ Rather than entering the clinical debate as another voice for or against PGT-A, the paper examined why the debate itself had become so durable — and what it would take to move past it.

The argument was that the persistent disagreement over PGT-A could not be resolved by more data alone. It was a structured conflict between physicians and professional bodies, rooted in competing interpretations of overlapping evidence, competing incentives, and competing definitions of what counts as a successful in vitro fertilization (IVF) cycle.

Five years later, the controversy has evolved, but not resolved, and a new element has entered the conversation, - artificial intelligence (A.I.) applied directly to PGT-A. This article, therefore, asks two questions: Can A.I. resolve the conflict between physicians, or relocate it? And what would real resolution actually require?

Where the Controversy Stands in 2026

The clinical evidence has not been kind to the broadest claims made for PGT-A: A 2021 randomized controlled trial in the New England Journal of Medicine found that, among good-prognosis patients, cumulative live birth rates were lower in the PGT-A group than in the conventional IVF group.² A 2025 review described PGT-A’s clinical value as an open controversy after nearly thirty years of practice.³ A recent analysis of the UK Human Fertilisation and Embryology Authority registry found that, in routine practice, PGT-A was associated with reduced live birth rates compared to standard IVF.⁴ The American Society for Reproductive Medicine’s 2024 committee opinion concluded that PGT-A should not be recommended for routine use.⁵

At the same time, subgroup evidence has somewhat shrouded the picture when some authors suggested that PGT-A improves live birth rates in women over age 35,⁶ though ignoring the growing importance of patient selection bias with advancing female age. Successful blastocyst-stage culture – an obvious prerequisite for PGT-A – of course increasingly biases patient selection toward good-prognosis patients, as poorer-prognosis patients simply will no longer produce blastocysts. Obstetrical safety data after PGT-A use are, however, reassuring.⁷

That ambiguity has become the controversy. Physicians who emphasize per-transfer success and argue that avoidance of miscarriages is a worthwhile goal to pursue read this evidence one way. Physicians who instead emphasize cumulative outcomes and embryo conservation read it in a very different way. Both sides claim not to misread the data and my comments here are not meant to be the judge between these two opinions (even though – as a scientist – I, of course, have an opinion). What I am instead trying to achieve, is to stop both sides from yelling at each other.

What A.I. is Doing Now

A.I. has attempted to move from embryo morphology into the genetic analysis itself. A 2023 study of nearly 25,000 embryos reported that A.I.-augmented PGT-A allegedly produced higher euploidy rates, lower mosaicism rates, and was associated with higher live birth rates in subsequent transfers.⁸ [Please note industry conflict regarding this statement further explained at the end of this manuscript.] Other A.I. models are alleged to detect complex abnormalities, including triploidy, that standard PGT-A can miss.⁹ Interestingly, the MIT Technology Review named A.I.-based embryo scoring one of its breakthrough technologies of 2026.¹⁰

While the technical promise appears to be real, - reliability was, however, never the whole controversy. It was always only one layer of it.

The Layers A.I. Touches, and Doesn’t Touch

It is reasonable to assume that the PGT-A controversy has three layers and that A.I. affects them unevenly. The first is technical and is defined by how accurately can the test classify an embryo’s chromosomal status? This is likely the layer A.I. can most directly improve.

The second layer is clinical: Even when the classification is accurate, does acting on this information really improve outcomes across an entire IVF cycle? This is where most of the disagreement between physicians lives. While A.I. can improve the label, it does not necessarily resolve the question of what to do with the label. This, of course, especially applies to mosaic or intermediate results, where clinical judgment remains shaped by individual values and risk tolerance.

The third layer is structural and addresses the question, - what is PGT-A for, and who benefits from its widespread use? Somewhat surprisingly, adoption has continued to grow, - even as evidence for its routine use has weakened. The financial structure of IVF adds additional complexity: So-called “add-on” tests are often billed outside of insurance coverage. PGT-A is a good example: Considering PGT-A is still experimental, insurance companies even in covered IVF cycles usually do not include PGT-A coverage. Patients, therefore, pay for this service out of pocket and undiscounted, greatly enhancing overall cycle profitability for IVF clinics, otherwise forced to greatly discount cycle fees to insurance companies.

Moreover, while advertising IVF outcomes with reference embryo transfer rather than cycle start, success rates offered to the public are often significantly exaggerated and unrelated to increasingly accepted evidence. A.I. does not touch this layer but – if anything – A.I.-augmented PGT-A may, in itself, become a new add-on with its own opportunity for marketing.

Our 2020 paper argued that more data alone likely could not resolve this conflict and A.I. in effect means more data. It is improving the technical layer while leaving the clinical and structural layers untouched. The conflict has not been resolved, but its terrain has shifted.

Toward Common Ground

If A.I. cannot resolve the disagreement between physicians, then what can? We suggest that three steps, drawn from conflict resolution practice rather than clinical debate may be able to achieve this goal.

1. Agree on the outcome that matters most. Much of the disagreement disappears when physicians specify, in advance, whether they are optimizing for per-transfer success, cumulative live birth per cycle started, time to first pregnancy, or miscarriage reduction. These are different goals, and a test that helps one can hurt another. Naming the goal before recommending the test is the single most useful step.

2. Separate the test from the decision. A.I. improves PGT-A’s classification accuracy, but classification is not the same as a transfer decision. A mosaic or intermediate result is a piece of information, not an instruction. Building decision frameworks that treat ambiguous results as starting points for patient conversation, rather than disposal criteria, would address one of the most persistent sources of physician disagreement — and one of the most painful sources of patient harm.

3. Acknowledge the structural layer openly. The financial and competitive structure of IVF shapes which tests get offered, marketed, and adopted. Pretending those incentives do not exist makes the clinical debate harder than it needs to be. A field that openly discusses how its payment structure influences its practice patterns is better positioned to evaluate new technologies on their merits, — including A.I.

None of these steps requires a new study. They require a different kind of conversation, between physicians who currently talk past each other.

Why This Matters Beyond PGT-A

This behavior pattern is likely not unique to reproductive medicine. Across health care, A.I. is being introduced into long-standing controversies, such as mammography screening, prostate cancer overdiagnosis, and even psychiatric diagnostic categories. In each case, A.I. offers improved classifications, better consistency, and faster analysis. And in each case, the underlying disagreement persists, because tests do not exist in a vacuum. They exist inside workflows, payment structures, and definitions of success that carry their own incentives.

A more accurate test inside a contested system produces more accurate contested results. Resolving a conflict between physicians requires more than better information. It requires a willingness to revisit the goals, the incentives, and the values that shaped the disagreement in the first place.

This work, for now, at least remains in human hands.

A.I. Disclosure Notice:

This article was written with help of several A.I. platforms during the research phase. The final product was fully vetted and edited.

Industry Conflict:

This study⁸ was conducted at NYU Langone Prelude Fertility Center using CooperSurgical’s proprietary PGTai℠ and PGTai 2.0 platforms. CooperSurgical has a direct commercial interest in PGT-A. This article acknowledges that the strongest evidence for A.I.-augmented PGT-A benefits has come from studies on commercial A.I. platforms by groups with industry relationships, an observation that strengthens the article’s central argument that A.I. does not resolve the underlying conflict, but only relocates it.

REFERENCES

1. Mochizuki L, Gleicher N.. J Assist Reprod Genet. 2020;37(3):677-687.

2. Yan J, et al. N Engl J of Medi. 2021; 385(22):2047-2058

3. Coussa et al., J Assist Reprod Genet. 2025;42:179-184

4. Roberts, et al., Reprod Biomed Online. May 2, 2026:105747. S1472648326002889

5. ASRM; A Committee Opinion 2024. Fertil Steril. 2024;122(3):421-434

6. Simopoulou et al. J Assist Reprod Genet. 2021 38(8):1939-1957

7. Hyttel, et al. Hum Reprod. 2026;deag049; on line ahead of print.

8. Buldo-Licciardi et al., J Assist Reprod Genet. 2023;40(2):289-299

9. Xiet et al., Hum Reprod Open. 2025;,hoaf054

10. MIT Technology Review. May 7, 2026. https://www.technologyreview.com/2026/05/07/1136946/whats-next-for-ivf-ai-robot-pgt-gene-editing/