Fertility and Sterility On Air - TOC: October 2024

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

03:06 Embryos derived from single pronucleus are suitable for preimplantation genetic testing

09:59 Clinical factors impacting microdissection testicular sperm extraction success in hypogonadal men with nonobstructive azoospermia

24:46 Educational gradients in the prevalence of medically assisted reproduction births in a comparative perspective

32:14 Minimum number of mature oocytes needed to obtain at least one euploid blastocyst according to female age in in vitro fertilization treatment cycles

40:02 In vitro fertilization and perinatal outcomes of patients with advanced maternal age after single frozen euploid embryo transfer: a propensity score-matched analysis of autologous and donor cycles

46:57 Imprinting disorders in children conceived with assisted reproductive technology in Sweden

View Fertility and Sterility October 2024, Volume 122, Issue 4:  https://www.fertstert.org/issue/S0015-0282(24)X0010-2

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 discussion with authors and other special features. F&S On Air is brought to you by 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, and Dr. Pietro Bortoletto, Interactive Associate-in-Chief.

Hello and welcome back to another episode of Fertility and Sterility On Air. I'm Micah Hill, one of the co-hosts of our podcast. I'm joined today by Eve Feinberg.

Eve, it's great to see you back again. Great to see you both. And Kate Devine.

Good morning, Kate, how are you? Good morning, Micah and Eve. So happy to be here. It's great to see you both.

You both have had adventurous summers. Let's just update our audience in like 30 seconds. Eve, we'll start with you.

What have you been up to this summer? It's been a little bit since I've seen your face on the podcast. It's been a whirlwind. I think the highlight of my summer was going to Paris and seeing U.S. women's gymnastics and just being in Paris during the Olympics was magical.

That's awesome. The pictures looked amazing. And Kate, you were also just in Europe, but I don't know if yours sounded as much fun as the Olympics.

What did you do? There was fun and there was work. So I just got back yesterday from a trip that included a marathon in Switzerland, and we raised about $80,000 to fund fertility treatment for families who need help affording it. So that was amazing.

And then it was my 15th wedding anniversary. So my husband and I just went to Madeira and Azores following the marathon, and I couldn't recommend it more strongly. All of our listeners should head there right away.

That sounds amazing. I'm glad you guys both had some good adventures this summer. All right, let's dive into the journal.

We're in October 2024. This is volume 122, number four. We've got some interesting front matter.

So the views and reviews is led by editorial editor, Nanette Santoro, and it's looking about ovarian tissue cryopreservation. Can we live up to the promise? There's a series of really nice articles from experts on where we're at, where the research gaps are, even though it's non-experimental, and what future strategies are being researched now to improve outcomes for these tissue transplants in the future. The fertile battle is led by editorial editor, Marcelle Cedars, on DuoStim and some very passionate voices on both sides over the pros and cons of DuoStim.

So I definitely recommend that you read that. And finally, there's an Inklings from editorial editor, Robert Norman, on Seeds of Hope, fertility support and resource-limited settings, where he lays out some strategy for how to increase access to fertility care in low-resource settings. So some very good content from our editorial editors.

Eve, we're going to jump right into the science, though. You have the seminal article this month, which is looking at 1pn embryos. Tell us about that.

Yeah, this is a great article. And I'm excited to dive right in to this. And I think it'll spark some good discussion.

The title of this article is Embryos Derived from Single Pronucleus are Suitable for Preimplantation Genetic Testing. And this was by Oshrit Lebovitz and others from Tel Aviv University in Israel. The objective of this study was to evaluate the treatment cycle outcome of embryos derived from a single pn versus 2pn in PGTM cycles.

For our learners, we assess fertilization 16 to 18 hours post-insemination. Ideally, we want to see two pronuclei and two polar bodies in a fertilized oocyte. In some situations, though, only a single pn is visualized.

And this can be due to things like parthenogenic activation, asynchronous pn formation, early fusion of the male and female pronuclei, or even extrusion of a third polar body-like unit. The question is whether embryos derived from one pn zygote should be transferred. And this has been debated for years.

And I think we discussed an article advocating for transfer of these several months back. And interestingly, ESHRE guidelines specifically do not recommend transfer of embryos derived from one pns. So to help answer this question, these authors did a retrospective cohort study.

It was from January 2018 to December 2022 at a single academic fertility center. There were a total of 244 patients who underwent 351 PGT-M cycles. And interestingly, PGT-A was not simultaneously performed in this cohort.

And I think that's actually one of the limitations of this study. Biopsy for PGT was either performed on day 3 or day 5 or 6, depending on the number of available embryos. If biopsy was performed on day 3, then embryo transfer results returned in 8 to 24 hours.

And a fresh transfer was performed on day 5. And if blastocyst biopsy was performed, then embryos were subsequently vitrified and an FET was done. In this cohort, there were 494 1pn-derived embryos and just over 3,500 2pn-derived embryos. And so a comparison of these outcomes showed lower blastocyst development rates.

And 38% of 2pn embryos made it to blast compared to 24% of 1pns. And when we look at the total numbers, that leaves us with 187 blasts that are derived from 1pns and 2,060 blasts derived from 2pns. When they looked at the number of blasts that were affected with the monogenic disease, twice as many of the embryos derived from 1pns were affected compared to the 2pns.

During the four-year study period, 85 embryos from 2pns were transferred and 24 from 1pns were transferred. I think kind of low numbers considering four years of data. Of the 85, there were 31 live births, so a live birth rate of 36.5%. And of the 24 that are derived from 1pn, there were four live births, so 16.7%. But again, really low numbers considering the starting point and considering the number of years of data.

So overall, not surprisingly, the 2pns outperformed the 1pns. But I do think, although the numbers are small, the data are compelling. And I think they add to that argument, maybe not to immediately discard those 1pn embryos.

Personally, I really would have liked to see PGT-A performed alongside PGT-M. Even if the embryos weren't transferred, we would have had more data looking at the euploid and aneuploidy status of those embryos. And I think as a clinician, personally, I would be much more comfortable transferring a euploid embryo that's derived from a 1pn.

And I think, again, the numbers are small, 24 transfers, four live births. But I have to think that perhaps those are four babies for individuals or couples that would not otherwise have had a chance to have a genetic child. And so I think that we have to be cautious in our interpretation of this paper.

But I'm really glad to see it published, even though the numbers are small. And I think this is an evolving story of what embryos are suitable for transfer. Micah, Kate, what do you think? Yeah, I mean, I think this is a really fascinating area of investigation, in large part, just due to the fact that though there are small numbers of patients and embryos affected by this, as you say, it may be the difference for those patients and embryos of a child that's genetically related to them versus not.

I agree with you as well about the PGT-A aspect being important and an additional helpful parameter. Some of our listeners may recall that we reviewed an abstract that was presented at PCRS with first author Ariel Yeshua, looking specifically at that. So I anxiously anticipate the publication of that manuscript that I think will supplement this and also was quite reassuring in this way.

So short and sweet, I think ESHRE ought to reconsider that guideline. Yeah, I guess the question is, what if we did PGT-A and then it was a mosaic from a 1PN? I mean, devil's in the details. I think it was a low mosaic.

Go for it. Yeah. Would either of you feel comfortable transferring these embryos without PGT-A if it came from a 1PN? I would say not yet.

I agree with that. Yeah, that's where I would lean to. Eve, I didn't catch it when I read the paper, but you said it.

So the 2PNs were more likely, or I guess the 1PNs were more likely to be a carrier of the monogenic disorder for PGT-M? Yeah, I thought that was interesting. And again, the numbers were small, but they saw twice as many embryos that were affected with the disease of interest in the 1PNs compared to the 2PNs. Do you think that's random chance or is there, I'm trying to think of a biologic plausibility of why these embryos with a host of monogenic conditions might present with more 1PN? Yeah, I think it's random chance.

Yeah. All right, great. So definitely check out that article, something that's very timely.

And as Kate said, we're getting more literature on this every year. Kate, we're moving on to the andrology section and predicting the chance of finding success for non-obstructive azoospermia for getting sperm. Tell us about this paper.

Yeah, I found this to be a really fascinating one and certainly hypothesis generating. I have lots more questions after reading it and had lots of great follow-up conversations with my fantastic urology colleagues. So title of this article is Clinical Factors Impacting Microbiology.

Microdissection Testicular Sperm Extraction Success in Hypogonadal Men with Non-Obstructive Azoospermia. And the first author is Esteves and this is a study out of Brazil. So Esteves and co-authors evaluated 652 consecutive hypogonadal patients with non-obstructive azoospermia, 616 of whom met the inclusion and exclusion criteria.

And so their inclusion criteria were to be hypogonadal. There was a little bit of, there is, I should say, a little controversy in the literature as to what is the definition of hypogonadism in terms of the normal range, the normal upper limit for serum testosterone concentration. But at any rate, they defined it as less than 350 as their upper limit for serum nanograms per deciliter as their upper limit for serum concentration of testosterone.

They excluded patients with thyroid disease. They also excluded patients who were, had been treated with exogenous testosterone. They also excluded patients who had been treated hormonally with medications other than gonadotropins.

Honestly, and this was one quibble I had with the study, they don't express a clear hypothesis as to what exactly they're trying to evaluate at the beginning and rather describe this as a study looking to associate clinical factors in this population with the probability of retrieving sperm at microTESE. And so the two factors that, you know, they dive into most deeply were two factors for which they did see a statistically significant association in their analysis. And those were whether or not the patients were pre-treated with gonadotropins and whether or not the patients underwent a varicocele repair or varicocelectomy, as we sometimes probably inappropriately call it, prior to undergoing microTESE.

And so specifically the patients who received hormones got recombinant HCG subcutaneously, 80 milligrams twice weekly, self-administered, and they made adjustments in order to maintain testosterone levels between 350 and 900. If serum FSH levels dropped during this, they also were given recombinant FSH at a fixed 150 unit dose three times a week. Lastly, if their testosterone to estradiol ratio fell to less than 10, they were co-administered an aromatase inhibitor, one milligram daily by mouth.

So quite a complicated protocol that these gentlemen were administered. Now, importantly as well, patients were able to opt in or out of this protocol per their preference based on the author's description. So all patients in the study, regardless of the presumed etiology of their non-obstructive azoospermia, were offered this therapy and the patients were able to choose based on their understanding of the risks, benefits, and costs.

Now we all know, of course, that provider counseling and their understanding and thought process as to who might benefit most probably also played a role here. In terms of varicocele repair, this was done at least three months prior to the microTESE. And so spermatogenesis was then also characterized at the time of the microTESE based on histopathology and they looked also at what the histopathologic diagnosis was and what the predictive capacity of that was relative to the probability of retrieving sperm.

So overall, these patients did extremely well for non-obstructive azoospermic patients with an overall success rate of 56.6% of patients having sperm retrieved. You know, and speaking to my urology colleagues and in my experience, we would quote patients a dramatically lower probability of success than this. So, you know, perhaps these authors are onto something and we'll dive into a little bit more, I think, in the subsequent conversation.

One significant limitation is that what they defined as spermatogenesis is unfortunately quite vague. The authors acknowledge that in this data set and at their center, they're unable to obtain a quantitative or really qualitative analysis of what sperm was extracted. And we're left to understand that a single sperm, modal or non-modal, would be considered a successful sperm retrieval.

They also do not, unfortunately, have the capacity to report on clinical outcomes, including fertilization, blastulation, and anything downstream from that. Interestingly, they did find a statistically significant difference among patients who received the hormonal therapy that was described. So those patients did do markedly better about, you know, highly statistically significant and, you know, leaves us to wonder, is this something that we should be doing in all of our patients? The other thing that was interesting was that patients who had hypospermatogenesis only on histopathology, which I, you know, I'm led to believe is a diagnosis of exclusion, meaning it wasn't certainly cell only.

It wasn't maturation arrest. Those patients had 100% success rate. So, you know, that may lead us to be doing a little bit more in the way of testicular biopsy or tissue analysis, even in advance of a microdissection, if it's going to be such a significant predictive factor.

I know that some centers do this routinely and some really say, well, we might as well just go ahead and try with the microtese and find that out at that point. Age, the etiology, estradiol, testosterone and testosterone estradiol ratios were not predictive in the univariate analysis. However, in the multivariate analysis, what they found was that the presence of a clinical varicocele and history of a previous varicocelectomy were statistically significantly associated with the probability of achieving a successful sperm retrieval.

So basically, if they had the varicocele repaired, they did better than they didn't. So, you know, frankly, all of these findings are really helpful if this is, in fact, a generalizable study conclusion. So at the end of the day, it's a pretty onerous procedure, both to do a varicocele repair and to go through this at least three months of hormone stimulation.

You know, as was noted in the excellent commentary that accompanies this article, you know, this is a little bit surprising as well, because when we are increasing the testicular testosterone concentrations with HCG, we're also knocking down the FSH. So the large increase in the production of sperm or retrieval of sperm is a little bit surprising. Lastly, you know, this is not a protocol that I've seen used.

And in speaking to my urologists, you know, we're much more likely to use something like Clomid in order to optimize the intratesticular environment and the probability of retrieving sperm. And those patients were excluded in this study. So great results, a protocol that I think requires more evaluation.

Of course, it's a retrospective study and patients were able to opt in. That said, I think that this calls for a randomized controlled trial, particularly looking at those patients who are hypergonadotropic and significantly hypergonadotropic heading into a microtese with non-obstructive azoospermia. Those were the patients that seemed to benefit the most in this cohort.

And I think that if we are going to be seeing results like this among those patients, it's certainly something that we should consider for clinical use. So interested to hear your thoughts and what you've seen, especially you, Eve. I'm not sure whether this is a protocol that you've seen more commonly used in your male population.

Yeah, so I did the math on it and it's about $10,000 worth of gonadotropin. So twice weekly HCG, about $400 times 12 weeks, plus 150 units of FSH, three times weekly for 12 weeks. My question, and we use Clomid in our population, and I guess my question is really like how much better, and our urologists will use HCG on occasion, but I think my big question is how much better are injectable FSH over Clomid? And they do talk a little bit about that, that some of these males do have high FSH levels, and therefore they went around pituitary stimulation.

But I don't know, like it seems like a very onerous and cumbersome protocol, not to mention expensive. $10,000 of gonadotropins on top of a TESE procedure, which is often upwards of $10,000 on top of IVF, which is, as we all know, also upwards of $10,000. And so I just question, I mean, I think if you can get sperm, you can argue that it's priceless, but are there more cost-effective approaches and how do gonadotropins compare head-to-head to Clomid? And maybe that's an interesting clinical trial that needs to be done from these data.

Yeah, I couldn't agree more. I think this calls for an RCT. I hope that these findings are true, but I just have a hard time believing such high success rates, and I think that it's a really good prognosis population.

As you saw, the max FSH level in the entire cohort was 21. I mean, we see much, much higher than that in these men with non-obstructive azoospermia, especially the ones that are going to end up having maturation arrests or totally cell, the really challenging cases. So I agree.

Let's do a three-armed RCT. Let's look at the hypergonadotropic patients and randomize them to no treatment. Gonadotropins or Clomid and get a pharmaceutical company to fund the study that they certainly stand to benefit if it were to show the benefit that these authors found.

Yeah, and I think you brought up a good point that it's not just about retrieval of sperm, but what is the function of those sperm? And then, looking that its non-obstructive azoospermia, then you're probably looking at a fresh Tessie as being more successful than a frozen Tessie. And then just the coordination is challenging. But I think the big question is, are the live birth rates from these sperm superior? Obviously, if you don't get sperm, then your live birth rate's zero.

But I think it also begs the question of, are we helping? And I do think with a young, healthy female partner that you just need a couple of sperm and you'll be fine. And so I agree. I think a three-armed RCT is definitely the way to answer this question.

Kate, I liked how you set up the discussion of the article from a study design standpoint, just highlighting that this really was looking for associations. So really everything they're reporting are odds ratios or relative risks. They do get into predictive stuff a little bit as they talk about the AUCs, but the study really wasn't designed to be predictive.

And I don't know that maximizing sensitivity and specificity is helpful information for these guys, for some of these numbers. I think sometimes you could debate what thresholds you would want to set at for bringing people to surgery. But some of these guys, if there's a 5% chance, they're willing to do that.

So maximizing sensitivity and specificity and getting to these thresholds from AUC curves probably isn't really what this paper was designed to do. So I would echo Peter Schlegel's commentary, and let's just be cautious on the implementation of it. I think this is very thought-provoking, and as you're both saying, warrants further research.

Yeah. And I think one thing, and this is probably common knowledge for us, but for our learners, they make this specific point of a sperm biopsy is really not indicated or warranted, go straight to TESE. And I'm still seeing a fair number of biopsies in the community.

And those biopsies, when negative, the men come in talking about donor sperm. And I really want to stress that a single site or even a multi-site biopsy may not be representative of the entire arena or the entire landscape of the testicle. And so you really do need to do a micro-Tessie and look at those tubules to assess for dilation and see whether or not there's even a single area where you may get sperm from.

And I liked how the authors highlighted that point. Yeah, I think that's a good point. I didn't dive in too much to the predictive value piece, Micah, just because it is a pretty meaty article and exactly what you said.

I don't think it's that helpful. And the AUCs they obtained were quite modest at about 0.64, so barely better than random even when combining multiple factors that we may or may not have access to for every single patient. And Ian, I totally agree.

I think that at the end of the day, you're not going to know until you do the micro-Tessie. And so you kind of just got to take the plunge literally and figuratively. But I was very impressed as well by the strong associations with the histopathology.

So I think both things are true, but you don't know until you know. All said. Great article in the andrology section of the journal.

So we're going to move on to assisted reproduction. And I have the next one. This article is titled Educational Gradients and the Prevalence of Medically Assisted Reproduction Births in a Comparative Perspective.

This is from first author Goisis and senior author Cozzani. They are from Italy. So this study was looking at educational gradients and the use of medically assisted reproduction in five countries around the world.

And by educational gradient, really all they mean is do they have a college degree or not a college degree? And based upon that, were they more likely or less likely to have children using medically assisted reproduction? This isn't just ART. This is including IUIs or any treatment cycle that's medically assisted. They use a variety of data, which you could say a weakness is how can you sort of combine these data.

But this is the best they have when you're sort of talking about a global picture. So they're using data from Denmark, from the Danish Population Registry, France from the neonatal perinatal survey, Spain from the Spanish Fertility Survey, the UK from the Millennial Cohort Study, and the US using CDC and national vital statistics data, which is really birth certificates. And the time frame on these really varies.

So the data they're using from the US is 2019 from CDC and vital statistics. The UK data is from 2000 to 2002. And everything's in between for those other countries.

And obviously, the data that's collected in some of these, you know, US birth certificates versus some of these registry studies versus survey studies varies. And so they had to really simplify things, which is why they did their educational gradient is just college degree or no college degree. They ended up adjusting for age and whether someone was partnered and whether it was the first child or not.

And I'll get into a little bit why they adjusted for those things. So as we might expect, there's a wide variation in how much births, how many births in each country came from medically assisted reproduction. Denmark was the highest at 9%, and the US was the lowest at 2%.

And those other three countries were in between. As you might expect, medically assisted reproductive children, or children born through medical assistance were more likely to be conceived to older mothers. They were also more likely to be born to mothers who had a university degree.

And this really varied substantially from country to country. The lowest difference was 10 percentage points. So an absolute difference of 10% in the UK, more likely to have a college degree.

In the US, it was 40%. So 40 percentage points or absolute number higher for children born medical assisted reproduction that their parents or their mother specifically had a college degree. And when they adjusted for the confounders, these gaps did decrease as far as the hazard ratio or odds ratios in all of these countries.

But it didn't absolutely attenuate it. And so basically, their conclusion was that in countries where there is not governmental access to programs for medical assistance, there's a greater disparity in college education, have those parents having access to medically assisted reproduction, which I don't think surprises any of us. But even when they control for that and look at various countries, the gaps still remain, even in countries that have basically universal access and government funded care.

So in and of itself, it doesn't explain the disparities, but it's certainly a major factor. And I think we would say not surprisingly, the disparity was seen the greatest in the US as compared to the four European countries that they looked at. Eve, Kate, thoughts? Yeah, I mean, I think you said it so well, I can't help but wonder how much individual belief plays into this too, that perhaps with a higher level of educational attainment, people are more comfortable accessing ART, just looking at some of the conversations, not to get too political, but looking at some of the conversations about IVF, it does seem that there is a correlation with educational attainment, and understanding of the technology and willingness to pursue the technology rather than this fatalist approach of, it's God's will that I'm not getting pregnant, and I don't want to play God or intervene.

And so I think that the US perhaps suffers more from that divisiveness and political and, you know, let's call it moral and ethical beliefs about IVF than perhaps the European countries do. So I was not surprised by this at all. But I thought it was a really nicely done study and definitely glad to see it published.

100%. I mean, I also was not surprised. This is yet another really important disparity that we are called upon to address.

And we need to look deeper into what are the barriers for patients who do have a lower educational level. There's no reason why we shouldn't be able to make the information more accessible. And it's not just the information as to how does IVF work, what's the science, what's the treatment, but also the logistical information, right? The financial information, all of the insurance problems are sometimes just prohibitive for patients and they absolutely should not be.

I was actually surprised looking at the disparity in number of ART births between the US versus Spain. So right now, 2% of all live births in the US are due to ART. And in Spain, where access is better, it was 8%.

And so it really begs the question of underutilization and why are patients not able to access that treatment and the care that they need and they deserve? One little tidbit that was buried in there that surprised me, I hadn't heard this before and I tried to fact check it and I couldn't confirm it from the citation, but they said that only about 58% of ART cycles were reported through the CDC and SART when they're comparing it in the US to the birth certificate data. So they're saying the birth certificates are saying there's a lot more ART being done. Now, is that true or is that that the birth certificates are just wrong or this National Vital Statistics source is just overestimating the amount of ART? But Kate and I obviously are involved with SART and so that obviously was like a flash that went off in my head, like, is that really accurate? I checked the source that they cited and the cited source didn't actually say that, that I could find it in the paper.

They said something along the lines that certain states aren't required to report ART and certain states are required. And that was actually the first I had heard of it. Yeah, I mean, I had the exact same thought, Micah, and I think it's probably inaccurate and I wonder to what extent it has to do with whether the year of delivery corresponds to the year that the ART procedure was performed.

But, you know, something for us to look into. Yeah. All right, let's move on.

Eve, we're staying in assisted reproduction and we're coming back to you with something that's very clinically relevant. Tell us about estimating how to get to a euploid blast. Yeah, I liked this paper as well.

The title is minimum number of mature oocytes needed to obtain at least one euploid blast according to female age in in vitro fertilization cycles. And authors were Cristina Rodríguez-Varela, a senior author, and Ernesto Bosch from EV Foundation and the University of Valencia in Spain. So the objective of this study was to find a useful tool for estimating the minimum number of M2 oocytes needed to obtain at least one euploid blastocyst according to female age.

This was a retrospective analysis. They used first IVF-PGT-A cycles with trophectoderm biopsy using an NGS platform, performed over five years at EVRMA Valencia from January 2017 to March 2022. They did include donor oocyte cycles, and that accounted for all of the less than 34 age group in this study since PGT in this center is only performed in women ages 35 and older.

The analysis began at age 35 and each year beyond. So a total of 2,660 cycles were analyzed, including 198 in the donor group, and the donors were ages 18 to 34. The minimum number of M2 oocytes needed to obtain at least one biopsy and one euploid embryo is calculated for each group.

In the patient group, the adjusted multivariate binary regression model, and binary being euploid versus aneuploid, was performed. Having a euploid embryo was considered to be the dependent variable, and the number of oocytes obtained was the independent variable. They created the model using 80% of the patient group sample, they called that the training set, and then later validated using the remaining 20%.

And a calculator for the probability of obtaining at least one euploid blast was created from this training set. The validation process consisted of assessing the success of the model, whose response would be binomial, euploid yes, no. The binomial model was right when it predicted that at least one euploid blast was obtained, and then an ROC curve was performed to test the predictive value of the model.

And so here's what they found. Not surprisingly, the mean number of M2 oocytes needed to obtain at least one euploid blast increased with age. Figure one, which I know we can't show on the podcast, but it's where the meat of the data are, with the top graph showing the mean number of M2 oocytes needed to obtain at least one euploid blast, and the bottom is the mean number of M2 oocytes needed to have a blast for biopsy.

Figure two is a really nice graphic representation of the model with the number of oocytes on the x-axis and the probability of at least one euploid blast on the y-axis, and the line for each age is shown in a different color. The model prediction was correct 72% of the time. So I think definitely check out the data.

It's hard to really go through it in a granular level on the podcast without looking at the graphs, but the highlights are right here. So in the donor group, a mean of 4.30 oocytes were needed for a euploid blast. I don't think that's surprising.

For a 37-year-old though, a mean of 5.8 oocytes was needed, a 39-year-old 7.8 oocytes, a 40-year-old a mean of 12.2, and a 43-year-old a mean of 39.7. Overall, I think it's a really nice paper. To me, it feels a little optimistic that only 5 to 7 oocytes are needed for a single euploid blast in someone who's 37, 38, and 39 years old. I think the data at both ends of the spectrum feel realistic.

For donor eggs, this feels consistent with what we're seeing from donor egg banks. 4.30 oocytes needed for a euploid. For a 44-year-old, the mean number of M2s was 22.8, but they had a range of 12 to 154.

And I think 72% predictive value is okay, but not fabulous. I'm a huge fan of predictive models for patient counseling, and I commend the authors for doing this study, but I definitely think this one needs more work and refinement. And there are other predictor calculators that are out there that ask the same question that have markedly different results.

So, Kate, Micah, I'm curious what you guys think about this. Yeah, I was really excited to see this title and abstract because I do think it's a really important question. I think it's really important, especially to our European readership, given the huge uptick in egg freezing that's going on there and wanting to be able to counsel towards an appropriate amount of treatment.

It's sort of longer standing in the U.S., but I agree. But first of all, that one euploid blast is not necessarily what most of our patients are after, and so it may not be the most helpful tool for counseling. And I also found the results surprising as you did.

That was one of my questions is, you know, obviously there are other predictors out there. We're probably familiar with the Doyle one. There's one from Boston, but they're looking at predicting live birth based upon the number of eggs.

I guess if you're using a tool that predicts blast, then you have to translate what a euploid blast means to a patient as far as the actual likelihood of having a live birth. A 50% chance of having a blast that's euploid isn't a 50% chance of having a baby, which is I think really what they want to know. So I wasn't sure if you had thoughts on why there's a couple of predictors out there that have ended it at blast as opposed to going to live birth.

Is it just the data sets they have available so it's easier to look at that as the outcome? I think so, and I think it's also, you know, as we are doing more egg freezing cycles, I think looking at live birth is important, but I also think looking at that intermediate marker of euploid blast can help to counsel somebody on how many egg freezing cycles should they pursue. But I just, I think these data are very different than other calculators that are out there that ask the exact same question of how many, how many eggs do you need to have a euploid blast? And if you think about it, working backwards from, say, you know, frenzy X data that looks at euploidy by age. And then if you look at those data and you say, okay, in a 35-year-old, you're going to have about 60% euploid.

And then you look at SART data that looks at the number of eggs that the average 35-year-old will produce, like, and then you go egg to embryo, you can say that about 25% of everything that you end up with is going to turn into a biopsy blast if 75% are mature, 75% fertilized, and you assume about a 50% blast development rate, the numbers don't really add up. And so I don't know what to say except that I think the model needs more work and we should be aiming for an 80% or 90% accuracy rather than a 72% accuracy. Yeah, that's well said.

And that's probably why there's a reflection from Merck who has a different calculator, a letter to the editor from some different authors from Merck who have the other calculator as well as a reply from these authors. So certainly some scientific discourse going on about the strengths and weaknesses of these various models. And so certainly a good article to read about.

All right, Kate, we have one more, stain and assisted reproduction. So tell us about outcomes in women with advanced maternal age using donor or autologous euploid embryos. Yeah, so this study is a multi-center European retrospective cohort study.

It includes IVRMA, multiple Italian centers, and then some other European centers as well. It's entitled IVF and perinatal outcomes of advanced maternal age women after single frozen euploid embryo transfer, a propensity matched analysis of autologous and donor cycles. So the authors looked at a cohort of women aged 39 to 46 years old.

There were 278 women in each group and all underwent IVF, ICSI, and transfer, frozen embryo transfer of a single PGT euploid blast from 2017 to 2021. The primary outcome was live birth per first transfer. And secondary outcomes included implantation per embryo and ectopic and miscarriage per pregnancy, as well as the mean gestational age and birth weight at delivery.

So the important piece here is that they did propensity score matching, and they state that they did propensity score matching in order to mimic an RCT. So, you know, that was a fairly bold statement. And they propensity score matched specifically to the age of the woman at transfer, as well as the blastocyst quality in terms of its morphology at time of freeze and its day of freeze, so rate of embryo progression.

So they did propensity score matching for those two things. And then they did a univariate analysis of live birth based upon whether the patients received an embryo resulting from her own egg versus an embryo resulting from the donor egg. The findings are reassuring for those patients, older patients undergoing transfer of an autologous blastocyst.

That's chromosomally normal. They found no differences in any of the outcomes assessed. So live birth rate was 41% among donor recipients and 42% among patients receiving an autologous transfer.

And again, none of the secondary outcomes I discussed were different. Importantly, they did not match. And of course, it's hard to match for everything.

It starts to get increasingly complex and convoluted. But they did not match for BMI, male age, age at embryo creation in the autologous group, FBT protocol. They excluded PGTM and PGTSR, lining less than six millimeters, endometrial fluid, non-trilaminar pattern, severe endo or adeno, thyroid and uterine cavity defects that were not mitigated as well as communicating hydros.

So, I mean, these should be a good prognosis population for transfer other than their age, which is what they're trying to assess. And so, you know, at the end of the day, I think these data are reassuring. I think it's very hard to know for sure whether these are actually well-matched groups.

When you look at the baseline characteristics, the group receiving donor eggs had almost a year longer, or even I think a little bit more than a year longer of infertility. So that's a really important differentiator. And then the other piece of it is that they had a higher proportion of adeno and endo, so presumably not severe, since severe ruled out, higher incidence of idiopathic or other infertility diagnosis, all of which I think you could argue are negative prognostic factors.

So maybe that the donor eggs are kind of just compensating for what's actually a worse prognosis group. But at the end of the day, I think that it's good news for patients who are transferring own embryos at later ages, knowing they're chromosomally normal. Of course, we all worry about non-chromosomal defects in these embryos that could potentially be disadvantaging these patients.

The prior data are mixed on this. And so this certainly does add to the literature. You know, one thing that I would have liked to see is, I could not find anywhere whether the donor eggs were fresh or frozen or a mix in this paper.

And, you know, as time goes on, probably doesn't make a huge difference, but I would have liked to see that. And then the other piece of this is that the authors state that the patients who had PGT on their embryos from donor eggs did so entirely electively, and that this was not medically indicated, and it's not medically indicated. So I would really have liked to see as well, although it's, I guess, a subject for a different study, what's the difference between the patients receiving their own euploid versus those who received untested donor embryos.

So I hope that people don't draw conclusions from this study that we should be doing PGT on embryos from donor eggs. What are your thoughts? Were you surprised by these findings, Micah and Eve, or pretty much in keeping with what you would have expected? Pretty much kept in line with what I would expect it. I mean, their conclusion is that aneuploidy is the main driver in declining reproductive outcomes as women age.

I don't think any of us are surprised by that finding. I think overall, you know, the live birth is a little bit lower than what you might expect for euploid embryo transfer, 41%, 42% with autologous and donor, maybe suggesting what we've seen in some studies, that there is some effect of the uterus aging. It's not as big as the effect we see with aneuploidy, but I know they didn't compare that, but at least suggest that with the slightly lower outcomes than what I would have expected.

Yeah, they had really high initial biochemical pregnancy rates, and then they actually had very high miscarriage rates. And that's what accounted for the lower live birth rates. So it was like 65% down to 42 with miscarriage rates of about 18%.

Not for nothing, they used vaginal progesterone. I didn't even notice that, Kate. Of course you did.

That's great. Yeah, they used vaginal progesterone. I do wonder again, like PGT in a donor egg, like, I don't know, is it too much manipulation? Is it the vaginal progesterone? That's a really high loss rate for donor, and it's a really high loss rate for PGT.

So something is a little bit suspicious there. All right, great discussion. Okay, we're going to move on now to epidemiology.

And I guess I'm glad Kurt's not here, so he can't judge what I say wrong. But this is a cool article on imprinting disorders in children conceived with assisted reproductive technology in Sweden. And so what's nice about this study is this is actually a cohort study.

So for fellows out there, most of the data we have on imprinting disorders are all case control studies. And they're mostly out of Scandinavian countries with good access to data like this. But in general, the way they've had to do it, because these disorders are so rare, they have to go to the imprinting disorder clinic that they have for that country and essentially look at the kids that they have there and then look back at how they were conceived.

And by doing that in the past, they've been able to tell us that kids with these imprinting disorders are more likely to have been conceived by ART than the general population is. But in this case, they're actually doing a cohort study. So they're following all these cases from 1997 to 2017.

It's over 2 million singleton births in Sweden that they have registered. And then they're going to this cohort study and looking at Beckwith-Wiedemann, Prader-Willi, Sylva-Russell, and central precocious puberty as their imprinting disorders. The other nice thing about this study that's a little bit different is they did break down those imprinting disorders separately.

And then they also were able to look at fresh versus frozen ART cycles from the embryo standpoint, as well as ICSI versus conventional insemination. So those are the unique things of this study that we haven't really seen in other trials. Other than that, though, the results are pretty similar to what's been published in the prior case control studies from these northern European countries.

Out of those 2 million singletons, 1,000 children were diagnosed with an imprinting disorder. 52 of them were conceived using ART. The hazard ratio for that is 1.84, and it's statistically significant.

Now, when they adjust for confounders, it comes down. It attenuates that effect a little bit to 1.85 on the hazard ratio. And it just crosses the null.

So it's no longer statistically significant. They tried to break it out between the different imprinting disorders. But when they did that, they lost power.

So again, not statistically significant, although the hazard ratios were in the same range. And then interesting, which maybe isn't unexpected, when they looked at the different types of ART that was done, the greatest risk was if you had ICSI and then combined with frozen embryo transfer. And if you think about erasure and reestablishment of the imprints and the things that were doing that manipulate things during that time, ICSI with frozen embryo transfer would be the most manipulative.

And so the hazard ratio on that was 4.6. It was certainly the highest and the greatest effect. And so they conclude that combining ICSI with cryopreserved embryos has a small, and I appreciate that they put in the word small, elevated risk. Now, what I wish they did, and Kate knows this from journal clubs that we've been going to for 15 years together, I always want the authors of these big epi studies to put it into clinically meaningful data.

And a hazard ratio, when you don't know the prevalence of a disease, is meaningless. What does 1.5 mean? Well, if it's something that's common, that could be a pretty significant effect that would really require some clinical counseling. If it's rare, and here we're talking about 1,000 children out of 2 million births, so you actually have to go to the supplemental tables to get the data.

It's 0.08%, so 8 in 10,000 babies with ART had an imprinting disorder versus 5 in 10,000 babies born naturally. That's a difference of 3 in 10,000 babies. So the number needed to harm would be 3,333 children born with ART to have one increased.

And we know not everyone's going to have a baby, so if you double that and say 50% will, you roughly have to treat 7,000 patients to have one increase in printing disorder. So the three of us might go our careers and never have a child with this. And so I do wish that authors and papers like this would just come out and say it.

They said the word small, that's the only place they ever discuss it. So it's clinically meaningful. I think this is probably something that's on most of our consent forms, on start consent forms.

Certainly something we talk to patients about, but I've never had a patient say, I'm not going to do IVF because of this 1 in 3,000 to 1 in 5,000 chance of having a child with an imprinting disorder. I think Curt would be very proud of that analysis. So the other thing that I thought was really remarkable here was the average age at which they diagnosed these imprinting disorders was 15.

Looking at other data, it seems like, so first of all, intuitively, if this is an overgrowth syndrome and we think about large babies, then I can't help but wonder how subtle are these children that the diagnosis was not made until age 15? And if we look at the average age of diagnosis, a lot of these are diagnosed prenatally. I dove into the literature here. 46% are diagnosed prenatally, and the other 46% in this paper that I looked at were diagnosed within the first 26 months of life.

So the fact that there were so few and diagnosed so late makes me really take it one step further to wonder what is the clinical implication of this? Not to diminish the seriousness of disease, but if it's not diagnosed until age 15, it just gave me a little bit of pause. Yeah, you have to wonder if that's an anomaly of the registry or data entry or something like that. It's just a great example, though, of the difference between relative and absolute risk, and Micah, you articulated it so eloquently.

But it is something that it's very easy for patients to understand, and it really should be a part of our counseling whenever we're talking about the risks of IVF because it really rings true. Again, going back to our early paper, to patients of all educational levels, we can very clearly elucidate the risks of something while also quantifying them for patients in a way that they can understand. So it's too bad that many authors don't do the same in their conclusions.

Yeah, and I feel like as reviewers, we should be asking for those data when we see hazard ratios and when we see epidemiologic studies. Like, I actually think it's sort of unacceptable that it's not put out there in terms of what is the clinical implication of this, because you read the paper and at face value, and if you're thinking about media and how science gets into the Wall Street Journal and the New York Times, they're just reading the abstracts and the hazard ratios, and they're not actually diving in as Micah did to look at what that means. And so I feel like we shouldn't be publishing without that context of prevalence and actual increased risk.

Yeah, and it makes me think of a few years back, the JAMA childhood cancer paper that was like set off such a huge cascade. And I mean, I think all of us probably had 10 patients ask us about it on a single day, and it was, I think, an eight case difference or something silly like that. Not that childhood cancer is ever silly, but we need to be concrete.

Yeah, I can think of. That's the first one that came to my mind as well. There are numerous breast cancer studies similarly showing that, and I think it's irresponsible reporting, but I think it comes from lack of transparency and clarity in the scientific literature.

Great discussions today. It's amazing. I read these papers, and every paper I learned something from both of you that I didn't pick up on.

So it's great having these discussions and seeing how our brains work and pick up different things. But still, I think we generally come to the same conclusions. So I really enjoy this.

The next time we see each other, we will be live at ASRM hosting FNS on air podcast. So come by the booth and listen to Kate, Eve, Kurt, Pietro, and I as we interview some of the best science. The ESHRE podcast just dropped.

So if you're listening to this and have missed the meeting at EHSRE, please listen to that. Kate and Eve, as always, it's great seeing you both. And thanks for all the education and great thoughts on these articles.

Thanks, Micah. Thanks, Eve. Great seeing you both.

And congratulations again, Kate, on not only just running the marathon, but raising a ton of money for helping others achieve their dreams of family. Thank you so much. Thanks for your donation.

All right. Bye, everybody. Bye.

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 and Dr. Adriana Wong. This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource in service to its members and other practicing clinicians.

While the podcast reflects the views of the authors and the hosts, it is not intended to be the only approved standard of practice or to direct an exclusive course of treatment. The opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.