Important IVF news from the literature
Fresh or frozen embryo transfers, - what is better?
Since the earliest papers appeared in the infertility literature suggesting that frozen embryo transfers in delayed cycles improve IVF outcomes over fresh embryo transfers,¹ the Center for Human Reproduction (CHR) has viewed this rapidly growing trend—especially in recent years—as yet another major misdirection in IVF practice. And, as has happened many times before on other subjects, the CHR was proven correct.²
Now, Chinese investigators—uniquely positioned to conduct such large-scale studies based on their national cycle volumes—have published one of their multicenter, prospectively randomized studies. This time, it was designed as a “pragmatic” trial, randomizing patients on the day of egg retrieval in a 1:1 ratio to either delayed frozen embryo transfer or fresh transfer in the same cycle.³ Strangely, the study also claims it was conducted in poor prognosis patients; however, the inclusion criteria (up to 9 retrieved oocytes) suggest otherwise. At the CHR, we would be thrilled to have such “poor prognosis” patients!
The primary outcome of the study was live birth (defined as delivery beyond 28 weeks), with secondary outcomes including clinical pregnancy rates, singleton and twin pregnancy rates, pregnancy loss, ectopic pregnancies, maternal and/or neonatal complications, and—importantly—cumulative live birth rates within one year of randomization.
In an intention-to-treat analysis of 838 women (419 in each group), with median ages of 34 and 33 years and tubal factor infertility present in 55.9% and 56.6%, respectively (again, clearly not poor prognosis patients), live birth rates were significantly lower in the frozen transfer group (32% vs. 40%; P<0.009), as were clinical pregnancy rates (39% vs. 47%) and cumulative live birth rates (44% vs. 51%). None of the other secondary outcomes showed any significant differences.
The authors concluded that fresh transfer “may be a better choice” than a freeze-all strategy with delayed frozen-thawed transfer in poor prognosis patients. We must respectfully disagree: This study actually reconfirms that in a general, average-risk population—as is typical in a pragmatic trial—a freeze-all strategy reduces patients’ chances of achieving a live birth. In true poor prognosis patients, this harm would likely be even more pronounced. It is time to put an end to the routine use of all-freeze cycles!
Readers interested in this topic may also want to read the editorial accompanying the article in The BMJ,⁴ although its very prominent authors also failed to acknowledge that this study did not truly assess poor prognosis patients.
References
1. Shapiro et al., Fertil Steril 2021;96:516-518
2. Zaat et al., Cochrane Database Syst Rev 2021;2:CD011184
3. Wei et al., BMJ 2025;388:e081474
4. Cornelisse S, Mastenboek S. BMJ 2025;388:r49
All you want to know about triggering follicles, - except for timing
CHR friend and colleague from Israel, Raoul Orvieto, MD, one of the most prolific authors in the fertility field with a wide range of research interests, is perhaps best known for his work on ovarian stimulation protocols and as the “father” of the double trigger using chorionic gonadotropin (hCG) and a GnRH agonist (GnRHa). It is therefore noteworthy that he recently published a review on follicle triggering in IVF cycles.¹
In the article, Dr. Orvieto offers a detailed review of the various trigger options and explains which approaches are best suited for different patient populations. His work with women who have low functional ovarian reserve even led the CHR to switch, several years ago, from using a single hCG trigger to a double trigger in this patient population—though, of course, only after first verifying and confirming his findings.
The article does not address the timing of ovulation triggers, which has become a central theme of research and clinical practice at the CHR over the last decade. This work forms the foundation of what the Center has termed Highly Individualized Egg Retrieval (HIER).² In principle, HIER involves progressively earlier triggering as women age. Due to the very advanced age of most CHR patients, this now means that many—if not most—are triggered when the lead follicle reaches just 12 mm or even smaller. As we have repeatedly noted in these pages, this experience has led us to believe that, in many ways, the timing of HIER is likely even more important than the choice of trigger method.
References
1. Orvieto R. Reprod Biol Endocrinol 2025;23:12
2. Gleicher N. J IVF Worldwide 2023;1(1): https://jivfww.scholasticahq.com/article/85177
Be careful what you believe, - especially when the source is a corporate press release
NOT REALLY A BREAKTHROUGH FOR IN VITRO MATURATION - In mid-December, several news outlets, including Inside Precision Medicine¹ reported that a startup named Gameto² announced, via press release, the birth of the “first baby born using technology that matures eggs outside the body.”
Maturing eggs outside the body, of course, refers to in vitro maturation (IVM), which has been a component of IVF—in various forms—for decades. The CHR has, with very good results, been using so-called rescue IVM (rIVM) routinely to mature immature eggs for over a decade.
Immature eggs are retrieved in nearly all IVF cycles. Several colleagues have reported using standard IVM—often with no or only minimal gonadotropin stimulation—particularly in women with polycystic ovary syndrome (PCOS), both to avoid ovarian hyperstimulation and to reduce the high costs of gonadotropin medications. Given this background, the media’s interpretation of Gameto’s press release was, to put it mildly, highly exaggerated, as thousands of women have given birth using oocytes matured through IVM for decades.
Gameto is a relatively new startup that describes itself as a “female-led biotech company developing treatment solutions to improve women’s reproductive health throughout their lives—from egg freezing, infertility, and diseases of the reproductive years to menopause and conditions that occur afterward.” The company boasts an impressive scientific advisory board, including David Albertini, PhD—well known to VOICE readers for his contributions and as a former Laboratory Director at CHR, now a Visiting Scientist—and Harvard University’s George Church, PhD.³ Church is arguably the world’s most entrepreneurial scientist, known for co-founding numerous biotech startups and, famously, for his efforts to “resurrect” the woolly mammoth. One of his ventures recently announced the "resurrection" of the white wolf—though the resulting animal turned out to be a gray wolf with white fur, not a true genetic restoration.
At this time, no peer-reviewed scientific publication has reported the details of the alleged “first baby” birth. According to the press release, the company likely used induced pluripotent stem cells (iPSCs) to produce granulosa- and/or cumulus-like cells, which were then co-cultured with immature oocytes. However, this approach is far from novel. The CHR explored similar co-cultures years ago with rIVM and found no significant improvement in oocyte maturation compared to cultures without added cells.
Moreover, the reported case did not eliminate gonadotropin stimulation, it merely reduced it by approximately 80%. So, aside from the addition of iPSC-derived cells (which, in CHR’s experience, offered little benefit), this process is virtually identical to CHR’s long-standing rIVM protocol. CHR, for instance, has successfully matured oocytes from follicles as small as 6 mm for many years.
Unless a detailed scientific publication describing this case and, ideally, additional cases emerge to demonstrate truly new interventions that outperform current methods in controlled trials, the company's claim remains overstated. As things stand, this case is neither a “milestone” nor a “turning point” in reproductive technology, and whether it has “immense potential” remains, at best, unproven.
George Church, PhD
David Albertini, PhD
We are nevertheless spending too much time on this announcement because it reminds us of many other announcements from the last two decades which were as grandiose as this one. These new companies led to the inclusion of several products into routine IVF care (and rather remarkable valuations of the companies), only to be revealed to useless and sometimes harmful to patient success years later by real scientific studies. We, of course, hope that this will not be the case here!
HOME-BASED IVF MONITORING – Since we're already discussing the premature introduction of new technologies into the IVF field, it's worth revisiting a 2023 paper published by Dutch colleagues in the prestigious medical journal The Lancet. The study described a system purported to enable home-based ovulation monitoring. At the time, the CHR briefly commented on it in VOICE with some skepticism, and also submitted a more detailed critique to the journal. Now, over a year later, we are pleased to report that our Letter to the Editor has been accepted and published.³
It seems the IVF field consistently fails to learn from past experience. The examples are numerous: after hundreds of millions of dollars were spent on closed incubation systems with real-time video monitoring of embryos—promoted as a way to improve IVF outcomes—it is now broadly acknowledged that these systems are interesting research tools, but they do not improve outcomes.⁴
Because the CHR does not adopt major changes to its routine IVF practices without first confirming potential benefits in-house, we never implemented these systems. Our internal studies, conducted as early as 2015,⁵ demonstrated no improvement in IVF outcomes for our patients.
There are far too many other examples of unvalidated tests and procedures being prematurely adopted into standard IVF care. Whether it's a diagnostic test, device, or protocol, the fact that a researcher or company—often acting in concert and with vested interests—claims a benefit does not mean it applies universally to all patients. In fact, in many cases, it may not be applicable or beneficial to any infertility patient.
The IVF field must finally confront this reality and take meaningful steps to prevent the routine adoption of poorly validated new interventions. Once such technologies are widely accepted, it becomes extremely difficult to eliminate them—even when evidence eventually proves them ineffective or even detrimental.
THE IMPACT OF INDUSTRY PAYMENTS ON IVF – On a related note, a recent study published in Fertility and Sterility by investigators from the Albert Einstein/Montefiore and Columbia University programs in New York City sheds more light on the role of industry influence in clinical IVF practice.⁶ The study sought to determine whether industry payments to physicians were associated with variations in IVF practices and clinical outcomes.
While the study’s methodology invites some critique, its conclusions appear credible: Industry payments were not associated with overall IVF success rates at clinics. However, larger clinic setups—presumably including most Private Equity–owned IVF networks—were significantly more likely to utilize costly “add-ons,” such as PGT-A and frozen embryo transfers, largely due to routine all-freeze cycle protocols.
If this finding sounds familiar, that’s because it is. CHR investigators recently reported similar trends, noting that Private Equity–owned IVF clinics utilize PGT-A at significantly higher rates than academic, hospital-based, or physician-owned clinics.⁷
No one should be surprised: Private Equity firms are focused on maximizing short-term returns, often within an investment window of just 5 to 7 years. In such a framework, financial motivations—not clinical benefit—can drive clinical decisions.
References
1. Inside Precision Medicine. December 17,2024. https://www.insideprecisionmedicine.co/topics/patient-care/first-baby-born-using-technology-taht-matures-eggs-outside-the-body/
3. Gleicher et al., Lancet 2025, 405:892-893
4. Bhide et al., The Lancet 2024.404(10449):256-265
5. Wu et al., Reprod Biol Endocrinol 2016;14:49
6. Jain et al., Fertil Steril 2025;123(1):115-119
7. Patrizio et al., J Assist reprod genet 2025;42:81-84
And for a change, some really interesting research news affecting IVF
THE EMBRYOS’ SECRETOME DURING CULTURE – That embryos produce a secretome into the media in which they are cultured has been known for some time. Interestingly, the small country of Austria has become a notable center for investigations into this phenomenon, with active research groups based in Vienna and in Innsbruck/Bregenz working to uncover potential translational applications with clinical relevance.
At the Foundation for Reproductive Medicine Conference (FRMC) in December 2024, Alok Javali, PhD—originally from the remarkable laboratory of Nicolas Rivron, PhD, in the Vienna-based group and now a co-founder of the start-up “dawn-bio”, gave a particularly interesting talk. He discussed bioactive substances identified in the embryonic secretome that may hold clinical potential for improving embryo culture conditions.
This same group had already made headlines in 2022 with a groundbreaking Nature publication describing a human blastoid model formed from stem cells, capable of attaching to hormonally stimulated endometrial cells—thus mimicking implantation.¹ This model provided an excellent platform for studying the human embryo secretome. A year later, the team offered further practical insights into this model.²
More recently, a mostly Innsbruck-based team published a compelling study in Reproductive Biology and Endocrinology, pursuing a similar hypothesis: that the embryonic secretome may contain key substances that influence IVF outcomes.³ The researchers prospectively collected spent media from embryos that either did or did not result in implantation, then analyzed the media using protein arrays or by applying it to monocyte-derived dendritic cells. Their goal was to assess the immunomodulatory effects of the media, potentially shedding light on the immunological aspects of implantation.
Their findings were significant: human blastocyst-stage embryos secrete an abundance of molecules capable of affecting—and even regulating—immune cells in their environment. Remarkably, the impact on dendritic cells varied depending on whether the embryo ultimately implanted successfully or not.
These results suggest that "treasure-hunting" in spent culture media for biologically active substances is a promising strategy—not only for gaining a deeper understanding of early embryonic physiology and implantation, but also for uncovering translational insights. Such discoveries may one day help optimize in vitro embryo culture conditions and potentially improve implantation rates.
References
1. Kagawa et al., Nature 2022;601-605
2. Heidari Khoei, et al., Nat Protocols. 2023;18:1584-1620
3. Kyvelidou, et al., Reprod Biol Endocrinol 2024;22:150