Fertility and Sterility On Air - TOC: September 2026

Take a sneak peek at this month's Fertility and Sterility! Articles discussed this month are: 

(02:58) Optimal counseling and treatment of patients undergoing therapeutic donor insemination        
(04:20) Do we still have a Scientific Mission?      
(05:31) Propensity score matching is too good to be true            
(06:30) ASRM Position Statement on Rho(d) Immune Globulin Administration in the First Trimester       
(08:16) Artificial intelligence in the in vitro fertilization laboratory: a committee opinion; 
Clinical Embryology in the United States: Current Landscape and Considerations for Professional Development and Standardization         
(10:07) Segmental aneuploidy in human embryos is frequently mosaic with evidence of meiotic origin: insights from trophectoderm and inner cell mass analyses  
(21:51) Preimplantation Genetic Testing for Aneuploidy in Donor Egg Recipients Does Not Decrease Number of Embryo Transfers Needed to Achieve Live Birth 
(35:40) Reproductive Outcomes in Programmed Ovulatory versus Modified Natural Cycle FET: A Propensity Score–Matched Analysis of Prospective and Retrospective Cohorts 
(43:05) The efficacy of frozen-thawed oocytes compared to fresh oocytes: real-world evidence      
(50:03) Intergenerational fecundity and infertility: a cohort study  
 

View September 2026 Volume 126 Issue 3 of Fertility and Sterility at https://www.fertstert.org/issue/S0015-0282(26)X2008-8

View Fertility and Sterility at https://www.fertstert.org/

Welcome to Fertility and Sterility On Air, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussions with authors and other special features. FNS On Air is brought to you by the Fertility and Sterility family of journals, in conjunction with the American Society for Reproductive Medicine, and is hosted by Dr. Kurt Barnhart, Editor-in-Chief, Dr. Eve Feinberg, Editorial Editor, Dr. Micah Hill, Media Editor, Dr. Pietro Bortoletto, Interactive Associate-in-Chief, and Associate Editor, Dr. Kate Devine.

Hello and welcome to another episode of FNS On Air. I'm your co-host Pietro Bortoletto, and we're here to talk about the September 2026, Volume 126, Issue Number 3, edition of Fertility and Sterility. I'm joined by old faces and new faces, Kurt, Eve, how are you guys? Very good, good morning.

Good morning, I'm sorry you all are not seeing our actual faces, but just our voices. We're smiling, we're present, we're counted for. So those are the old faces, I do have a new face, this is Dr. Blake Evans's, I believe, first formal time joining the FNS On Air podcast, as he's since made the transition from Media Editor for FNS Reviews to Mile Job, Interactive Associate-in-Chief for Fertility and Sterility.

Welcome, Blake. Thank you, long time listener, and as you said, first time FNS On Air podcaster, excited to be here. Yeah, the average height of the podcast has just increased by about three to four inches, we're really excited to have you here.

Yeah, happy to help in any way. It's probably also worth mentioning that we've had a couple of leadership transitions since the last time we all got together. Eve is now stepping into the role of Media Editor for Fertility and Sterility, congratulations Eve.

Thank you, very excited to be in this role. Big shoes to fill, big beer to fill as well, Mike has got a pretty gnarly beard going. Yeah, I won't be filling that one.

And our beloved Blake is stepping into the inaugural role of Deputy Editor for Fertility and Sterility, which is a new role for FNS, but don't worry, his deep baritone voice will still be joining us on the podcast, he's just sitting out this month. Just letting you know, I'll still be the Editor-in-Chief, by the way. Even if you tried to not be, I think everyone would convince you otherwise.

And I'm stepping into the Video Editor role with Dr. John Protrozza and Dr. Rebecca Flyckt. I'm excited for all of these new transitions, but you'll still continue to hear all of our voices across the FNS media empire. We have a bunch of killer articles today.

Eve, why don't you start by telling us a little bit about the views and reviews, this section. Great, thank you, Pietro. This views and reviews is titled Optimal Counseling and Treatment of Patients Undergoing Therapeutic Donor Insemination.

And I feel like it's one of those topics that we all know how to manage, but looking back into the data surrounding all aspects of this, I think was really enjoyable and enlightening. It was put together by Editorial Editor Liz Ginsberg, and the authors talk through the logistics of therapeutic donor insemination, things like whether or not OPKs versus ultrasound monitoring with HCG trigger should be used. And they take into consideration things like cost, ease of LH detection, and access to care for those who live remote from clinics.

They review the data on the use of ovulation induction agents in the population of patients who have regular cycles, but who otherwise are not sperm exposed. And then one of the manuscripts in this series discusses that transition to IVF needs to be individualized for all patients, and things like patient preference, time to pregnancy, and treatment fatigue need to be considered. So I think it's a really great series, and I highly recommend that you read it.

Also in the front matter was an inklings this month that was called Do We Have a Scientific Mission? And this was written by Allison Eubanks and Eric Widra, another Editorial Editor. And this inklings is a call to action for innovative research questions. They discuss how duplicative research questions are being asked and answered again and again.

They distinguish between legitimate replication, which they see as warranted when findings are contested, methodologically limited, tested in a new population, or are assessing a new outcome, from what they call wasteful duplication, which is the same question, same population, and same design. And I think that we can all relate to that. They cite the publish or perish mentality, as well as these pay-to-play journals that are driving this.

They close with a challenge and a call to investigators and journals, especially as we are starting to think about heading into ASRM's annual Congress, let's focus on answering new questions rather than re-answering settled ones. So I thought that was a really good food for thought, just nicely written and concise and to the point. And then in the special contributions, there was a really excellent piece titled Propensity Score Matching is Too Good to be True.

And I think this is a must read for a really good explanation and also a really nice visual diagram of what propensity score matching is, how it works, and how it's actually not superior to traditional regression model for causal inference. And so the practical takeaway point from this contribution, if you're reading the literature and a study labeled propensity score matching analysis shouldn't automatically be treated as more rigorous than a regression adjusted one. So again, a really good piece, and I think especially for fellows and for our trainees, take a special look at the figure that they draw that shows the difference in the comparison groups between regression and PSM.

And I think it'll just solidify what this is and how to think about it. So I think that this next practice guidance is actually life changing for many people. And basically, the ASRM position statement highlighted that they fully endorsed the ACOG position statement on RH immune globulin administration in the first trimester.

And I just really want to read what ACOG says because ASRM affirms what ACOG says. And for patients less than 12 and 0 weeks of gestation who are undergoing abortion and that's managed with uterine aspiration or medication or experiencing pregnancy loss, spontaneous or managed with uterine aspiration or medication, ACOG suggests foregoing routine RH testing and RHOGAM administration, RHIG prophylaxis. So that's a substantive change in the way that I think many of us have practiced.

And they do give a little caveat that they say, although not routinely indicated, RH testing and RHIG administration can be considered on an individual basis in the context of shared decision making and discussion about the potential risks and benefits. But I think it's very different from how we practice at Northwestern. And I just want to highlight that this is a little bit at odds with SMFM statements that still recommend RHOGAM administration and RH testing.

And so admittedly, in our hospital system, our maternal fetal medicine group makes the clinical protocols for management of early pregnancy across the system. And we are still giving RHOGAM. But I wonder if that may be something that changes in the future.

The last part of the front matter, and I'm not really going to dive in too deep into these two. I want to encourage everybody to start reading. But there's a very good committee opinion on artificial intelligence in the IVF laboratory.

And there's also another good piece on clinical embryology in the United States, current landscapes, and considerations for professional development and standardization. So two really, really excellent pieces that I'm just going to send you off all to go read them. Thank you for introducing that.

I'm really proud of the front matter in the journal this year for a couple of reasons. It's a conscious effort. The first, views and reviews, is an old topic that needs a refresher so we don't start going off on our own tangents based on logistics of practice or what we think we knew.

So it's a purposeful review of a bread and butter topic. So I think that's a value to the readership. And bookended by two pieces that, again, show you that we don't want to just be studying the same thing again and again with a new fad of a statistical trend.

Propensity score matching has become a title, which is not at all what I think should be in the title of a paper. Your paper should be titled what the topic is. Propensity score matching is a method.

And again, just because somebody says something you're not familiar with, it doesn't sound shiny and new and therefore better. And that's the purpose of bringing this all out in the journal. We're trying very hard to educate you not only in how to practice best on a day-to-day basis, but look for new and look for what's not new at the same time.

So I thank you for putting that all together. Thanks, Eve. That was a really nice rundown of our front matter and things that are generally not dug into too much depth in the podcast, but worth highlighting and pointing people towards.

This month, I have the honor of discussing our seminal contribution, which if you're ready for a nice genetics lesson, buckle up. This is it. This paper is entitled segmental aneuploid in human embryos is frequently mosaic with evidence of meiotic origin insights from trophectoderm and inner cell mass analysis.

This paper comes to us from across the pond by first author Al Hashimi, as well as some friends of the pod, Nick Macklin and Tony Gordon and Darren Griffin coming to us from London Women's Clinic Institute for Women's Health at University College London, as well with contributions by Cooper Surgical. So let's talk about segmental aneuploidy for a second. Segmental aneuploidy appears in about 7 to 15% of biopsy blastocysts and is functionally the more confusing line of the PGTA report.

The prevailing model is that most segmentals are mitotic arising after fertilization, therefore likely confined to just the trophectoderm, therefore possibly a biopsy artifact that you can safely either retest or set aside and just go ahead and transfer. But this model has always been a bit of a barred one. Whole chromosome aneuploidy is driven by nondisfunction in the oocyte, prolonged mitotic arrest, cohesin deterioration, strongly maternal age dependent, whereas segmental aneuploidy is driven by double-stranded breaks, failed or incorrect repair, recombination area.

It's not obviously age driven. And here we can also have paternal contributions like sperm DNA fragmentation and structural instability during spermatogenesis as plausible contributors. Two different mechanisms producing two superficially similar report lines, but confounded a little bit by some older data.

Almost everything we know about interpreting a PGTA result was worked out on whole chromosome aneuploidy and then applied to segmentals by analogy. This includes the reassurance that we lean on the most, that trophectoderm and inner cell mass concordance for whole chromosome aneuploidy is high. So we treat a single biopsy as a fair proxy for the whole embryo.

Nobody's really gone back and asked whether the analogy holds. This study does that and comes down to four important questions that they hope to answer. One is, how often is a non-mosaic segmental actually mosaic once you sample more of the embryo? Two, where does it come from? Is it maternal, paternal, meiotic or mitotic? And how does that compare with whole chromosome aneuploidy, which we have a heck of a lot more data on.

Three, can early segmental errors be rescued and do they beget further damage on the same chromosome? And finally, four, how faithfully does a single trophectoderm biopsy represent the whole embryo for this specific class of abnormality? So how do they design the study? They had retrospective cohort of research donated embryos, 105 embryos from 86 couples. These were blastocysts with at least one non-mosaic segmental aneuploidy on the initial clinical trophectoderm biopsy. They excluded whole chromosome only aneuploidy, exclusively mosaic segmental findings and known parental structural rearrangements contributing to these embryos.

Where this study really shined and was able to answer lots of questions, the core innovation of this paper is this three-sample design. They had the initial clinical biopsy taken at the time of the actual embryo creation. Then they thawed these embryos, collected a second trophectoderm biopsy, and then they also had the entire inner cell mass that was available, micro-dissected and able to be analyzed.

Analysis was performed on the PGT-Complete platform, which is a Cooper Surgical product. They did the low-pass whole genome sequencing, but they also had integrated SNP analysis along with parental buccal swabs that allowed to assess the origin of some of these abnormalities in embryos. So let's get to the results.

In total, there were 228 segmental events across 135 distinct chromosomes. One chromosome was affected 77% of the time, two chromosomes in 17% of the time, and three chromosomes in 5% of the time. Now, to our four key questions, number one was how often is a non-mosaic segmental actually mosaic? So complete concordance across all three samples with no mosaicism anywhere was only 14%.

Any evidence of mosaicism was 85.8%. That means that nearly 9 out of 10 of these embryos, the rest of the embryo did not match that initial biopsy, which leads us to believe that the word non-mosaic on the report was describing the sample, not the actual embryo, now that we had a second trophectoderm and an inner cell mass available for biopsy. Question two is where does segmental aneuploidy come from and when did it happen? Well, with the benefit of the SNP and the parental genome analysis, they were able to tell us that paternal origin in segmental aneuploidies occurred in 49.5%, maternally derived segmental aneuploidies occurred in 38%. This was a non-statistically significant finding, but I think kind of changed our perception that most of these were coming from maternally derived origin, just like whole chromosome aneuploidy, not necessarily the case here.

Finally, from a time perspective, for most of the embryos, the error did not start after fertilization and arrived with the egg and the sperm and slightly more often with the sperm based on that initial piece of finding I just shared with you. That's the reverse of whole chromosome errors, which come overwhelmingly from the egg and rise with maternal age. So it also means that the abnormality was there from the very beginning and in every cell rather than appearing later in just one branch or lineage of those cells later in the embryo.

Now, question three and four, I think are also super interesting. Question three is, is rescue possible or is further damage to be expected? This gets back to the whole concept that we believe that there's some amount of self correction that happens in embryos. So with regard to rescue, the abnormality present in one sample, but absent in another occurred 37.1% of the time.

That's incredible. Two things can happen after the initial damage. Sometimes the embryo appears to repair itself and the abnormality is present in one part and gone in another, the other times the same chromosome breaks again.

And roughly a third of the embryos showed the first and roughly half of the embryos showed the second. Wow. What about number four? I think number four is probably the question that makes the most sense to me.

When I read it was, does a single biopsy represent the whole embryo in a quarter of the cases, the abnormality turned up only in the original biopsy and nowhere else. So if you saw the embryo, you biopsied a second time, about a third of the embryos that had been set aside would look usable again, but roughly one in 13 would get a clean second result while still carrying that abnormality in the part that becomes the inner cell mass or the fetus. And in nearly all of those, the warning sign was sitting right there.

Fascinating. Now, let me leave you with a couple of key learning points that summarizes this complex paper from a perspective that would matter, I think, to a clinic or a clinician. So number one, a single trophectoderm biopsy is a poor proxy for the embryo when finding is only segmental.

So only 19% of embryos were concordant across all three samples. Number two, non-mosaic segmental describes a biopsy, not an embryo. 85% of the time there was mosaicism somewhere else in one of the other three regions biopsied.

Number three, segmental aneuploidy is not predominantly maternal. 49.5% were paternal in origin. And number four, segmentals are mitotic.

This consensus is under real pressure. I think this data here tells us that the segmental aneuploidies from a technical perspective are actually probably coming much earlier and happening in the meiotic stage, not the mitotic stage. And lastly, I think the part that we should all think about as we interpret this data is that the practice of how we read PGT results and counsel PGT results needs to be a bit distinct when we're counseling on segmental aneuploidies versus whole chromosome aneuploidies.

Timing is different, origin is different, and implications for what the rest of the embryo looks like is also a little bit different. I love this paper. I thought what a great innovation to be able to biopsy other sections of the embryo, have the whole genome sequencing plus the SNP-based parental linkage happening.

They answered something that I think wasn't top of my mind. But now that I have read this paper and I see the next segmental result on a PGT report, I'm going to probably dive into it a little bit more with the patient and be a little bit more nuanced in my counseling. So I really appreciate this kind of data for the counseling that will happen off those PGT reports.

Eve, you were nodding your head a lot during this paper. Did this one spark the same kind of like, huh, in you that it did in me? Yeah, for sure. I think the paternal finding was surprising, but I think it just calls into question a few things.

And I think probably the most worrisome, and we've been talking about this for a long time, but is a biopsy segment representative of what we're seeing in the whole embryo? And what does that mean? And how predictive is it? I think it's why, and we've got some other PGT papers later this morning. But I think it really calls into question our methodology as a whole and why PGT improves outcomes in some people but not all people. And I think the worrisome question really is, are our current methodologies valid? And should we be rethinking how we perform PGT? So I think it's a little bit frightening to me to see how unrepresentative one biopsy sample can be.

I know we talk about it as a screening tool and not a diagnostic tool. And I think this just really highlights that it screens a part of the embryo. It doesn't test the whole embryo.

And we need to be really directed in how we use that language when we talk to patients. I would like to emphasize also that there's a whole special issue on PGTA as a diagnostic or prognostic test for human embryos. And this paper is yet a very well done paper.

But this paper is yet another example of the earliest stages of a test where we're not even sure the test result we're getting in the laboratory is yielding the test result we're looking for, let alone what the clinical significance of this test is. So I want to reiterate in our field, we are adopting clinical practice based on the preliminary aspects of changing technology for the most basic aspects of a test. We don't even know if the test actually helps our patients at this point.

We're just adopting it as such. And I think we're just way out in front of what we know about PGTA and what we know about human embryo biology. I will say at our practice at University of Oklahoma, we're not a PGTA heavy practice, especially in the younger patient population.

But this study particularly gives me pause on those who come in and they're, say, 30 years of age and they're wanting to do PGTA and they come back and they have these PGTA results and possibly limiting the embryos that they could have transferred. So just it certainly gives me pause even more so on these patients that insist on doing it. That's foreshadowing for the next paper that I'm going to talk about.

Boy, was that nicely done. And Eve, why don't we go ahead and jump to yours, just sticking on the theme of PGT and donor egg recipients. Yeah, thanks.

So the title of this paper was Preimplantation Genetic Testing for Aneuploidy in Donor Egg Recipients Does Not Decrease the Number of Embryo Transfers Needed to Achieve a Live Birth with Michelle Bajewski as the first author. And it was out of RMA New York. So I think, you know, as we all know, PGTA use is rising in the U.S. as well as globally.

And patients want this information prior to embryo transfer. And I think, as we all know, in patients who are older, there are some data that have shown higher live birth rates per transfer and lower rates of miscarriage. But the cumulative likelihood of live birth is unchanged as it just is a selection tool.

But to date, we have not seen a published study that has shown significant benefit of PGT in patients under 35 or in donor egg recipients. And while authors have not demonstrated an improvement in cumulative outcomes with PGTA among donor egg recipients, the question these authors wanted to answer was whether PGTA in donor oocytes improves the time to live birth, which I often hear cited as one of the arguments. So the objective of this study was to determine whether PGTA use in donor egg recipients is associated with the number of embryo transfers required to achieve a live birth and with the time to live birth.

And the authors actually hypothesized that PGTA in the donor population would not improve either of these two metrics. So it was a retrospective cohort study at a large urban academic affiliated fertility practice. Patients were included if they underwent a single embryo transfer and they achieved a live birth from January 2016 to December 2024.

Donor egg recipients who did and did not use PGTA were compared and then all embryo transfers of donor derived embryos were performed up until a first live birth were included. Participants who used fresh or frozen donor oocytes and underwent fresh or frozen embryo transfers were included and they only included cases where ICSI was used for insemination. And then patients were excluded if PGTA was only performed on a subset of embryos or if more than one embryo was transferred if a GC was used or a patient had known uterine factors.

And the primary outcome was the number of embryo transfers needed to achieve the first live birth. Secondary outcomes were days from embryo transfer to live birth, days from fertilization to live birth, live birth on first transfer, rate of miscarriage, and they calculated all of these both per patient and per transfer. And then in addition, they did two subgroup analyses that were conducted to assess whether outcomes were driven by oocyte source, whether there was a difference in fresh versus frozen donor egg, and embryo transfer type, program versus a modified natural cycle.

So over the course of the study, there were 1017 donor oocyte recipients, 933 fertilized eggs with ICSI or fertilized cycles with ICSI. And after exclusions, no live birth, double transfers, partial testing, GC use, they had 629 patients who met inclusion criteria, and those 629 patients contributed 927 embryo transfers. So they had 312 patients who used PGTA undergoing 448 transfers and 317 patients without PGT who underwent 479 transfers.

So the primary outcome, the number of transfers needed to achieve a live birth, the key finding in this study was that in both groups, the median number of transfers to first live birth was one, and the interquartile range was one to six, and that was true in both groups. When they looked on Cox proportional hazard model for the number of ETs until first live birth, really there were no differences that were found in the number of embryo transfers between the patients who used PGT versus those that did not. They also used Kaplan-Meier estimates, and they also found no difference in the number of transfers leading to first live birth.

So then they did some group analyses. They looked at patients who used fresh donor oocytes only, and there were no association between PGTA use and number of embryo transfers required to achieve a live birth. And in fact, PGTA was not associated with needing fewer transfers in any of the analyses they did.

So then they turned to their secondary analysis where they looked at time, and they looked to see whether or not there were differences in days from first transfer to live birth. So median was 257 days with PGTA and 255 days without. So not surprisingly, when you look at that metric from time of fertilization, there was a faster time from fertilization to live birth in cycles without PGTA, and that makes sense.

Because you transfer five days post ICSI. So that was 321 days versus 266 days. So 266 in the non-PGTA group.

And that was a 55-day difference between the two, but it wasn't significant after adjustment. And this reflects the extra time for PGTA biopsy, testing, freeze, and not a difference in reproductive potential, just the time that it takes to do the additional interventions. So I do want to highlight the study was done in a top quality IVF program.

Their live birth rates were excellent. Live birth rate on first transfer was 70.5% in the PGTA group and 69.1% in the no PGTA group. So to summarize, across every outcome examined, when they looked at number of transfers, time from transfer to live birth, time from fertilization to live birth, live birth rate on first embryo transfer, and miscarriage rate, PGTA use in donor egg recipients showed no meaningful association once they adjusted for confounders.

So I think, again, it just doesn't help. The one unadjusted signal, 55 extra days from fertilization to birth in the PGTA group is best explained by the added time of PGTA itself, not a worse prognosis. And again, when we talk about what are the benefits and what are the risks, I think for many of our patients who want to be pregnant yesterday, 55 days is not insignificant.

So I think we should all be counseling patients to forego PGTA on donor oocytes. And I strongly counsel my patients as such. Skipping PGTA will not cost them extra transfers.

It will not cost them added time to a live birth. And I think given the added expense of testing, there's actually some benefit in not doing PGTA. So overall, I think this adds meaningful data to the already existing studies showing zero benefit for PGTA in the setting for donor egg.

And I think just to be sort of mindful, and I always play devil's advocate, they only examine time to live birth for the first live birth. So I think the question that I still have is whether this would also hold true for second or third live births, given that there may be more variability in embryo quality from the supernumerary embryos in the cohort. And so especially when you have donors who produce a high number of eggs, you're doing a fresh cycle, you're not splitting, would we potentially see some benefit down the road for second or third live births? So that's sort of one thought.

And my other thought on this before we open it up for discussion is there were patients in this study who were planning on doing PGT, but they actually never had an embryo that made it to biopsy. And so could that plan for PGT in this population have actually harmed these patients more than it helped them in that they didn't even have a chance to attempt pregnancy because they never made it to embryo transfer? So I think that that's definitely one of the considerations, especially when we're talking about a small cohort of frozen eggs from a frozen egg bank. And I know these banks have guarantees, but I just wonder about that.

And are we holding these eggs to a standard that we shouldn't be? And in doing so, are we potentially decreasing reproductive potential? So I think, you know, and again, going back to that initial inkling from Eric Widra and Allison Eubanks, I think this is a study that has been asked and answered several times. But I think that the way that they did this study was exceptionally well done. And I would argue that this is one of those topics where, yes, the question's been asked and answered, but people are still doing this.

So it's like, at what point do we say we're going to pay attention to the data and we're really going to meaningfully change practice patterns? So I'm going to open it up for discussion. Pietro, I am going to give you first comment as I think you look like you are jumping out of your seat there. I had a question for you about what would you tell the listener who is listening to this and thinking, but I have a patient who's using donor egg and is planning on using a GC for that embryo or is coming into this with a history of recurrent pregnancy loss largely based on age-related aneuploidy, but now is using donor egg to kind of mitigate some of that.

How do you counsel that provider who is listening to this conversation and saying, no, no, no, this data still holds true? Yeah, so one thing, we're physicians, not providers. That's a whole separate, maybe that's the next step. Thank you, wonderful correction.

Thank you, Eve. But I counsel my patients not to do PGT on donor egg, full stop. Even with the natural tension of the agencies wanting euploid embryos regardless if they're donor egg or autologous eggs? Yeah, I counsel my patients not to do it and my patients largely don't do it.

There's no benefit. And I have had patients who have done PGT. I'm not going to prevent them from doing PGT.

I believe that there's still an element of reproductive choice, but I view it as my role as a physician to be their advocate and to counsel them on what is going to give them the best outcome in the shortest period of time with the lowest cost. And I think these data are incredibly compelling. And again, kudos to Michelle Bajewski, whose project this was.

But I think that these data are incredibly reassuring that we do not and we should not be doing PGT on donor egg, period. Completely agree with you. I am glad that you called that out because I think we see so much of it on the SART reporting side of how many donor egg cycles are still undergoing PGTA, how many GC cycles with donor eggs are still undergoing PGTA.

It all doesn't make sense to me, but I'm hoping the people listening are hearing this data and taking it to heart. I just wanted to add, too, and I know that Oklahoma is not the only state that does not have mandated coverage for IVF, but we are in a specialty where our patients so commonly say, I want to do everything that I can to improve my chances. And of course, we want that, too.

In the back of our minds, it's like, well, now that you said that, I'm going to add this to increase your chances. Of course, that's not the case. We always want the best interest for our patients.

So going back to what you said, Pietro, about a GC versus someone who's just, you know, they're going to carry the pregnancy themselves, you're going to have the best interest in both patients regardless. I know the stakes are a bit higher if you have a GC that's also using a donor egg just because there's so much more cost involved and time and coordinating. But we still are going to do what we think is best for the patient based off the literature.

So I just wanted to mention that. I'll chime in with something, and I don't mean to be a broken record about this, but PGTA is not an absolutely proven safe test for an embryo. I mean, the only answer to why it's not helping donor eggs or helping young women is that it's harmful to the normal embryo that's biopsied.

And the test which shows that there is no damage to the embryo is a flawed paper that we can talk about at another date where they call it equivalence when it's not equivalence. The biopsy is not necessarily a good thing for an embryo. Think about that.

So therefore, overusing a test that has harm is not a helpful thing, especially in situations like donor eggs or young individuals where it's not really going to improve things. We get away with it because there's a lot of good embryos and people get pregnant anyway. But the point is to explain this is that the process of PGTA is not helpful for a healthy embryo.

I think that's a wonderful spot to transition from the group of PGTA articles to now talking about frozen embryo transfer. And Blake, you have a pair of articles that I guess we'll do back to back, one entitled Reproductive Outcomes in Programmed Ovulatory versus Modified Natural FET, and then a research letter on the efficacy of frozen-thawed oocytes compared to fresh oocytes. Why don't we start with the main article, Blake? Thanks, Pietro.

So this first one, as you'd mentioned, Programmed Ovulatory or as they reference POFET versus Modified Natural Cycle Frozen Embryo Transfer or MNFET. And they look at the reproductive outcomes. This was by first author Filippos Ademiris and senior author Alexander Byfield out of Germany.

So for the fellows out there listening unfamiliar with the NatPro study, this is these natural cycle frozen embryo transfers are becoming very common. And the NatPro study is highly anticipated and soon to be out. And we can see the results of those.

And I was happy to be participating side of that study. But basically, the elevator pitch on this is that the corpus luteum being present is possibly protective in hypertensive disorders and pregnancy after frozen embryo transfer. So although this study doesn't look at natural versus programmed, these are both different variations.

And so the study design was a single center. They did a comparison of two natural cycle FET protocols. So the first, the POFET or Programmed Ovulatory.

The name is a bit confusing because it was really just following the patients and their natural cycle. They didn't program or induce ovulation in any way. Anyway, they just followed their ovulation.

But essentially, they did no HCG trigger. So they followed them for spontaneous ovulation. And they did supplement with an oral dihydrogesterone.

And this was started in the late follicular phase to assist with transfer timing and support the luteal phase. And also they had the modified natural cycle in which they did use an HCG trigger. They had 492 pre-match and then 170 post-match patients.

And they did use 6,500 of HCG. And they did use a variable luteal support, which we'll get back to here in a little bit. But they used a few different types of progesterone in these patients.

Of note, and we'll also get back to this too in terms of statistical analysis. But the POFET, they'd prospectively enrolled these patients, whereas the modified natural, they were retrospective chart data. Their primary outcome was live birth rate.

Secondary outcomes included clinical pregnancy, biochemical pregnancy, and miscarriage rates. They used logistic regression models adjusting from maternal age, BMI, embryo quality, and assessed as the association between treatment protocols. So we're going to jump to the results.

Basically, when they looked at live birth rate, clinical pregnancy rate, biochemical miscarriage rate, none of which were statistically significant in difference. So all of the confidence intervals crossed one and were not significantly different. They did adjusted logistic regression in which they also found that there was not a significantly difference or different in live birth rates.

The main clinical takeaways framed by the authors was that, as I just mentioned, no significant difference detected in any of their variables or their outcomes. And so the injection-free or HCG trigger is something that may not necessarily be needed. Of course, I mentioned earlier as a participant of the NAPRO study, that does add some nuances as well.

Pietra, I know you did quite a few natural cycles in which you followed their ovulation. And so I keep bringing this up for cost as well, but that is something that now the NAPRO study is no longer enrolling. And we do have a lot of patients coming back who were pregnant previously.

And they're like, well, I want to do the modified natural because that's how I got pregnant and had my baby last time. So totally makes sense that they want to do that again. So we're using basically that protocol, but we do the trigger.

So when you have a dominant follicle present, make sure that the LH is low, then you trigger. Or if it is surging, then you shift and do the transfer six days rather than seven days. But what I was initially saying is if you are following just their natural spontaneous ovulation, that is going to add more visits to the clinic, more blood draws, more ultrasounds, more costs.

So that is just something that the study did not mention that is always at the forefront of my mind where I practice. And so a couple of things I wanted to mention was that the luteal support was heterogeneous in these patients. So take that for what you will.

But does that have any bearing on the outcomes as well? There is about four different progesterone administrations or different types of progesterones that were given. I did want to ask, Kurt, as the statistical experts on the pod, so should we have any pause or concern about how there was a prospective enrollment and also a retrospective chart review? Does that raise any concern at all for this? I think it is something you just have to keep an eye on. You cannot treat the data all as prospective.

So, I mean, it is one of those things where you just do not let it oversell the value. Right. So basically, the bottom line for this study is that it is a non-randomizing comparison.

Basically, the HCG trigger is not entirely necessary. There are some nuances in the course of counseling patients on frequency to the clinic and blood draws and ultrasounds and costs as well. But something else we can offer our patients who are considering a natural cycle FET.

You guys have any other thoughts about this? I think the HCG is patient friendly. And for the clinics that have some concern about the unpredictability, irregularity of the natural cycle, it is a way to add some predictability and without sacrificing the clinical outcome. So I am a big believer in it.

I have used it both at my current clinic, my previous clinic, and learned all about its utility at Cornell where I was a fellow. So I encourage people who are a natural frozen embryo transfer cycle concerned that this is a way to take a step in that direction. Yeah, and I would even argue it probably improves outcomes if you're making the embryology lab flow a little bit better and reducing fatigue of the embryologist if there are too many warmings to happen on one day.

So I think the trigger is a really nice way to address all of those issues without compromising and even possibly improving outcomes. I'm always skeptical that artificial intervention and menstrual cycle is better than the natural way. But I mean, I think we should start skeptical that a natural cycle has been around for a long time.

We don't necessarily do better with our medicines. However, having said that, I'm more and more convinced with papers like this that we should study this and it's reassuring. So I always get a little nervous when I say we want our practice logistics to be the primary motivator where I'd like to think we want to do it the right way.

But hopefully they align and this kind of literature is making me more comfortable. Blake, why don't you tell us a little bit about your research letter looking at the efficacy of frozen thawed oocytes compared with fresh oocytes. I feel like it's another topic that we've gone back and forth on and forth on and then back on.

And we continue to ask kind of similar questions. Why is this one a little bit different than the previous questions? Yeah, thanks, Pietro. This is a nice segue from the paper that Eva discussed a bit ago.

But this looks at frozen thawed versus fresh oocytes and looks at real-world outcomes by first author Fitzgerald out of Australia. The study design was retrospective cohort using the Australia and New Zealand Assisted Reproduction Database or ANZARD. The protocols were between 2009 and 2023.

There were a little over 2,000 patients who had used frozen thawed oocytes and then just under 100,000 patients who had used fresh oocytes, all donor oocytes. Both cohorts were restricted to their first, as the authors call it, OPU or oocyte pickup or egg retrieval. And these were in non-surrogacy patients, ICSI fertilized only.

They excluded slow freezing cycles as well. How they looked at this was they did observed versus expected framework and they used covariate adjusted models built on the fresh oocyte cohort and then used to predict the, quote unquote, expected outcomes for frozen thaw patients had they behaved like the fresh patients or fresh oocyte patients. And the gap between the observed and the expected is what is called the effect estimate.

So, this is reported as the absolute risk difference or the OE and also the relative risk. They adjusted for female age, infertility diagnosis, parity, sperm source, male infertility, number of embryos transferred, the stage of the embryo, whether or not PGT was used, and the embryo cryopreservation status. So, the key findings are they looked at the number of oocytes reaching ICSI from the egg retrieval, the thaw survival rate, fertilization rate, and fertilized oocytes that are going on to be an embryo that's transferred.

And they found that basically once you get to embryo transfer stage, the difference is not so much. So, they found that the clinical pregnancy rate per embryo transfer as well as the live birth rate per embryo transfer was lower for the frozen patients, meaning that the fresh patients did it slightly better. We're talking by a very small number, so the confidence interval was minus 0.5 to minus 1.8. It was less than 2% for both of those, the clinical pregnancy rate as well as the live birth rate.

And so, the authors discussed that statistically significant here, or one thing I wanted to point out, doesn't necessarily mean that it's a clinically significant findings. And so, although Micah is not joining us here today, I'm confident that he would want me to point out the number needed to treat to bring my point home. So, for the fellows that are listening, basically you can take the absolute difference and then divide that by 100 or 100 over that number.

And so, for the clinical pregnancy rate embryo transfer, even though it says that the frozen was less than 1.2%, you would need 83 embryo transfers using fresh oocytes instead of frozen thawed oocytes to result in one additional live birth. So, that's how you look at number needed to treat for that. And then for live birth per embryo transfer, you would need 53 embryo transfers using fresh oocytes instead of frozen thawed oocytes to result in one additional live birth rate.

So, again, when it says it's statistically significant, you have to look at it in that way to see, is this really something that's clinically significant? Does it make that big of a difference to where I'm going to have this patient do fresh versus frozen? So, frozen oocytes didn't do as well at each laboratory step. They were lower in each step for the oocytes reaching ICSI, thaw survival rate. Of course, if you're freezing eggs and thawing them, there's going to be some that do not survive the thaw hours.

If you have fresh oocytes, they're not going to have that step to go through. The fertilization rate was slightly lower and the number of embryos that reached embryo stage were slightly lower. But this is mainly on the lab side of things.

So, the main takeaway is that the main clinical outcome, the live birth rate overall was very similar, just slightly lower in the frozens. So, additional findings I wanted to mention. The meaningful variation in outcomes by egg freezing indication, so fertility preservation versus non-fertility versus cancer diagnosis.

They did look at this as a subgroup, and while the small cancer subgroup actually did better overall, the authors flagged this as too small to interpret in terms of, can you take away anything from this? So, bottom line, it's a reassuring finding in that a frozen thawed oocyte, once it gets to the embryo stage, overall has similar outcomes in terms of live birth rate and nearly equivalent to a fresh oocyte donor egg. So, interesting study, very highly impactful. What do you guys think about this study? I think it does not change any of what I do.

I think we've always had this natural tension between fresh versus frozen, and I think the reality is most people go with frozen for many reasons. Speed, cost, availability of a wide variety of donors. There's a very narrow use case for fresh donors, and for me, it's the couples that are looking for multiple kids from the same egg donor needing to do PGTM for autosomal dominant disorders.

It's really, really narrow, and to me, this provides reassurance that we're still making a good decision for the vast majority of our patients who are going the frozen donor egg route. Yeah, agreed. I think the vast majority of our patients do frozen donor eggs, and although this doesn't happen very commonly, but you get, say, a known donor or just any type of anonymous fresh donor, and they just do not respond or stem as well as you would have expected, and then they get far fewer eggs, or they don't fertilize very well, and an unfortunate outcome.

Doesn't happen very often, but it is certainly something that we see when patients use a fresh donor. Thanks, Blake, and then I think a nice call-out for this type of article. Research letters are a wonderful place for people to publish narrow, discreet findings that don't need a full paper to expand on the background, the thorough discussion section, but something that's worth kind of highlighting and bringing to the forefront of our reader's minds.

So we'd love research letters in fertility and sterility. Kurt, I want to end with you. You have a paper that is talking about intergenerational fecundity and infertility.

Tell us about the difference between intergenerational and intragenerational and why they're important. I'm glad we saved this for last. We've had a very dense podcast with you on how to practice specifically and what to do with your patients.

So this one you can let flow over you and enjoy. This one is a more conceptual epidemiologic piece, and the idea is does fertility in one generation affect fertility in the next generation? And this is a nice paper, Intergenerational Fecundity and Infertility, a Cohort Study by Drs. Stockholm is the primary author and Dr. Ramlu Henson out of the Public Health Department in Aarhus University in Denmark.

I like the title because it's provocative, but it doesn't explain everything. But the objective of the study was to investigate whether paternal time to pregnancy and maternal history of infertility was associated with a higher risk of infertility in their sons or daughters, so intergenerational. So this is a traditional cohort study.

It's got more than 11,000 adults, sons and daughters, now adults, sons and daughters participating in a Danish birth cohort study when they were pregnant, and the pregnancy goes back to 1984 to 1987. So the exposure in this cohort study is time to pregnancy, and it was reported by the mothers approximately at age gestational 36 weeks and categorized by how long it took you to get pregnant. At that typical time, the pregnancy is one to six months or seven to 12 months or greater than 12 months.

And then to be more specific, a maternal history of infertility was also defined as self-report examination, underwent fertility examination or underwent fertility treatments as well. And then again, they had a national registry to link all of these things. So the outcome was defined as infertility in the sons and daughters having received the diagnosis of infertility or been treated as assisted reproductive treatments themselves.

So associations were done properly with Cox regression modeling, and I'll go through the results, and then I'll go through a little bit more specific of the paper. So the take-home message was that, first of all, sons and daughters are not the same. I know that, and we all know that.

But sons were born to parents with a long time to pregnancy, had a higher risk of infertility at a hazard ratio of about 1.25, but this was not statistically significant. And you saw a modest trend from very short time to pregnancy to moderate time to pregnancy to infertility, and that was also not significant. However, daughters born with a long time to pregnancy had a relative risk of about 40% higher infertility, and there was a very strong dose response from zero to six to six to 12 to greater than 12, with a positive trend looking at all those things that was a 20% increase.

So maternal history of infertility was associated with a higher risk of infertility for both sons and daughters. I changed the definition there a little bit. That was just definition of infertility, not the time to pregnancy.

So the conclusion was longer paternal time to pregnancy and maternal history of infertility was associated with a higher risk of infertility in adult sons and daughters. So that's the take-home message. Let's play around a little bit with it, because I find this a fascinating story.

So why did they do the study in the first place? So the study was based on the hypothesis that reduced fecundity may be transmitted across generations through either genetic factors or shared environmental factors or both. A lot of previous studies have looked at the intermediate aspects, and there's been papers in FNS about this, about the semen quality in offspring or the reproductive hormones or the antral follicle count, but there was actually very little known about actually the fertility of the offspring. So that's the purpose of this study.

Again, a wonderful opportunity I wish we had in the States. They have a population exposure that they can look at an entire country in 11,000 Danish adults and sons born in this age group. They can very prospectively can assess time to pregnancy and fertility, history and fertility in the sons and daughters.

And the outcome is a clinically important one. It's like studying live birth as opposed to clinical pregnancy rate. They actually got to fertility rates.

So the strengths of the study is that it's two generational. It looks at both time to pregnancy and fertility as an outcome. There's like a near complete follow-up through high-quality national registries.

It looks at, again, infertility outcomes, not just guessing it, and it's adjusted for several important confounders and multiple sensitivity analysis that I won't bore you with the details, but it's really done well. So let me again briefly remind you of the findings. Longer time to pregnancy was associated with increased fertility in daughters, statistically significant with a trend based on how long it took the mother to get pregnant.

And whether you looked at a maternal history of infertility, it was associated with both daughters and sons. Now, the trends in the sons was positive, but it just wasn't statistically significant. They also did adjustment for a lot of potential confounders.

There was modest residual confounding, which would probably not explain the results, which is an important epidemiologic term I just stated. And it was even slightly stronger when you took into account for socioeconomic findings. Again, the availability of treatment for fertility is strongly linked with socioeconomic.

So the results are generally similar when follow-up began as a couple, as well as follow-up started when you wanted to get pregnant. So that's also a quirky thing, but I'm glad they thought of it. So in other words, the finding wasn't just to people that tried to get pregnant, it was all married couples that this came to.

And again, the registries were terrific. So what's the limitations of an epidemiologic study like this? Why should you be discounting it? Well, it's true the cohort necessarily excludes couples who ultimately were not able to conceive because they couldn't have gotten into this cohort. The time to pregnancy is a couple-level measurement, and we really can't identify whether it was a maternal or paternal contribution.

The maternal history was pretty nonspecific, so we really can't delve into what type of infertility might have been the issue. And of course, there might be some residual confounding. But the discussion puts it into perspective, and the reason I liked it.

So prior studies of reproductive characteristics have been very inconsistent, but this study shows evidence on clinically recognized infertility rather than the intermediate markers, as we mentioned, like semen analysis and hormones and ovarian reserve markers and things like that. The findings were weaker in sons than daughters, but it's hard to determine whether that is just something about the data or something about data collection. But it does raise the question about whether there's a sex difference, which is also, again, interesting to let it flow over you.

So then it brings the question, isn't this kind of paradoxical? Because I've thought about this before, that if you really have genetic infertility, how can you pass on genetic infertility to your offspring? Like, wouldn't that just self-select or, in evolutionary terms, take you out of the pool? So, but it's true that it's not absolute infertility. It's sub-fertility. Therefore, affected individuals can still conceive, and sometimes without assistance, even though it might take longer.

So it really is a kind of sub-fertility. And it could be that what we're finding is not an intergenerational infertility, but intergenerational sub-fertility. It might be that assisted reproduction is increasing because of that sub-fertility, which is interesting for our field to know.

And then you think of seeing why. Is it sex-specific, really? Is there really a difference between boys and girls in terms of fertility treatments? That's wonderful. Is it really just kind of a polygenic inheritance that you can get, you know, a lot of variants that contribute to a small amount of risk, and then the child may or may not have that risk in the future? That's also an interesting theory.

Or is it really the shared familiar environment that, you know, an apparent intergenerational association might reflect environmental or behavioral or socioeconomic factors rather than genetic passing on genes alone? So my take on this is this study doesn't demonstrate that infertility is inherited. You know, you can tell your patients, a lot of my patients ask, did I get it from my mother or did I get it from my father? But it does show that the ability to get pregnant or fecundity may cluster across generations, potentially because of gene susceptibility, maybe not a single gene, but it also might be shared environment with a combination of the two. So while this is a well-conducted hypothesis-generating study, it does show credible intergenerational association, but insufficient to say that it's a specific genetic transmission, or I'm not sure it changes my counseling right now.

So this one really was a let it flow over you phenomenon. You know, is fertility decreasing in the world? And I've heard lots of stories about declining sperm counts. We've had views and reviews about it.

Is it harder to get pregnant now? Or is it just that people have more access of infertility treatments and they're using it more frequently? Is this really a genetic basis where we're focusing genes in it? Or is it really behavioral, socioeconomic, and environmental? So this is why I kind of liked reproduction. When I was in medical school, this is why I really went into reproductive endocrinology, because it was more of a big, not just how do I treat somebody, but it was a big study on like, where are we going as a species in reproduction? So I hope this one had a little bit of thought provoking to you and you enjoyed hearing about it. I love when studies are done with this really big data and really well done.

Yes, it's not very granular. Epidemiology never is, but it does make you think. What'd you guys think? Why can't we have nice things like the Scandinavians, Kurt? Why can't we have large data sets at scale? I mean, I don't know that Americans want to be tracked to the degree that tracking occurs in some of these countries.

But I think intellectually, it makes a lot of sense. If you think about things like PMOS, metabolic disease, obesity, as huge contributors, no fertility. You know that women who have obesity in pregnancy or overweight in pregnancy tend to have children that also may have some metabolic defects and that is a contributor of infertility.

We know that endometriosis has a heritability component to it. I wouldn't be surprised if male factors also have somewhat of a heritable component to it. Intellectually, I thought this makes a lot of sense and it affirms how I've always thought about it, that I do think that there is this gray category of some fertility that probably clusters.

I always ask on my initial history when I meet a new couple, I always ask if their parents had difficulty getting pregnant. How many siblings? What is the age gap between siblings? I think anecdotally, it's very much in line with what I've observationally seen in my own practice. I thought it was a beautiful study.

I'm glad it's in fertility and sterility. Yes, the downside of epidemiologic data is you can't get so granular to understand the individual differences. But on a population level, I think that this is important and should be part of our thought process and part of our counseling.

Yeah, there's a great other side to it here, if I may tell a different story. There's a great demographer I worked with here at Penn on occasion that's convinced that there might be polygenic reasons for decline in fertility over time, but he's also convinced that you do what your parents did. It's going to be like two generations.

The increased chance of using ART is going to go up because your mother did, whether you need it or not. So we are going to be seeing, well, I may or may not have carried genes forward for my life, but my mother conceived with ART, therefore I have to have children with ART, therefore my children have to have children with ART. It might also be a divide in socioeconomic of who can do it and who can't.

It's just a fascinating subject, both in terms of treatment and looking at people's behavior and looking at the world. You can see I get excited by thinking not just whether I should use a fresh or frozen egg, there's more to think about in this field than just on a day-to-day basis. Well said.

This is one of those papers that I knew you would be happy with, and I'm glad Micah assigned it to you. In terms of other podcast content, we have a bunch of new episodes coming out. We have the Eshra live from Eshra podcast episodes that are now live.

Hoping people are listening and enjoying them and a shout out to the team that flew to London and recorded live from there, including Eve and the rest of the media team. FNS Unplugged and FNS Roundtable, also live episodes each month. That's all the time we have for today.

Until we meet next time, goodbye from Blake, Pietro, Eve, and Kurt. This concludes our episode of Fertility and Sterility On Air, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield, Dr. Adriana Wong, Dr. Elena HogenEsch, Dr. Selena Park, Dr. Carissa Pekny, and Dr. Nicholas Raja.