Fertility and Sterility On Air - Best of ASRM and ESHRE 2025

Fertility & Sterility on Air brings you a panel discussion from Best of ASRM and ESHRE 2025. Join our host, Dr. Eve Feinberg and the following panelists:

1. Aleks Rajkovic - 01:04
2. Henriette Nielsen - 10:09
3. Thomas Ebner/Sangita Jindal - 20:20
4. Angela Lawson - 29:24
5. Antonio Capalbo/Catherine Racowsky - 46:24
6. Herman Tournaye - 01:02:00

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.

Hi listeners, good morning. This is Eve Feinberg, and... Hi everybody, Kurt Barnhart. Hi, Anne Steiner, Editor-in-Chief of F&S Reviews.

And we are here today at the Best of ESHRE and ASRM in Lisbon, Portugal. It's great to have a mixture of both the experts from ASRM and ESHRE at this meeting, and hopefully we're going to have a great podcast for you with lots to learn from. I'm Aleks Rajkovic, I'm from the University of California at San Francisco, and I'm an OBGYN and reproductive geneticist, and my talk at ASRM-ESHRE combined meeting here in Lisbon, Portugal, will be actually about the decoding of mysteries of recurrent pregnancy loss, and specifically looking at genetic factors that contribute to recurrent pregnancy loss.

Excited to hear the talk today. Can you tell me a little bit more about what got you interested in this topic, why you're pursuing this area of research and presenting on this this week? I had a long interest in infertility, and I've been studying a lot the role of ovary in contribution to specifically women's infertility. And to me recurrent pregnancy loss is a continuum from actually the ovary to conception and beyond in terms of losses.

So infertility, a lot of losses are due to factors that cause eggs to be lost or early embryo arrests, and then we have this whole large losses that occur, of course, after conception. Some estimate that over 80% of all conceptions are lost, and the ones that are clinically actually detectable are about 10 to 20% of losses, and recurrent pregnancy loss is something that is devastating to individuals. And so for me, this topic really represents sort of a continuum of infertility to a degree.

And so we, with a group at Stanford actually, got a relatively large award to look into it from the genetic factors. And so we have been in it for the past four years trying to decipher what is actually the genetics behind recurrent pregnancy loss. Well, wonderful.

So unfortunately our readership and listenership can't be here today. So what are the take-home points that you would, if you had maybe three take-home points, what would those be for our listeners? Yes, so I think that what we are finding so far is that the genes that cause these losses are many. What we are finding out is that a large portion of the human genome is associated with losses.

And we call these lethal genes, intolerant, there are various terms out there. And what we are finding out is that genes that have been involved in losses that actually occur later in pregnancy or actually in the newborn period are also involved in pregnancy losses that occur very early in the first trimester and so on. Also we find that diversity of genetic mechanisms that cause these losses is quite extensive.

So sometimes you do have to spend a lot of time trying to figure out what is causing a loss in a particular case. And we do find that in some individuals the causes are due to gonadal mosaicism, meaning that it's not in the parents but it's in their ovary or in the testes where the mutation hides and can lead to, for some reason, preferential transmission in conception. And those are all the things that are still we're trying to figure out.

And I guess my other question is how much of this would you say is environmentally mediated, if any? I think patients always ask about the effect of things like environmental exposures, microplastics. How much of an interaction are you seeing, if any, between environmental factors and changing genetics of the embryo? Yes, it's a very interesting topic and we actually have started to also look into this issue of environmental agents and whether there is a preponderance of certain agents that associate with recurrent pregnancy loss. And what we have done is we have taken, actually, blood from women that are undergoing the loss versus women that are having a continuing pregnancy.

And using mass spectroscopy, we do actually find differences in environmental profiles. And these profiles are still currently under analysis. They are relatively small studies based on approximately 50 patients that we will have to expand in the future.

And so we do think there may be environmental factors that associate with recurrent pregnancy loss, but how they interact with the genetics of the individual is something that is unknown at this time. So areas of controversy. What are some of the controversy and areas we need to maybe do a little more research on to answer those controversies or address this? Well, the controversy, of course, you know, how much of this is, as you mentioned, is actually environmental.

How much is it due to the autoimmune system or immunity? How much is it due to reproductive factors such as uterine anomalies, hormonal imbalances versus genetics? And how all these things interact is still unknown, I would argue, because a lot of losses that we know, already know, almost actually half of losses that occur in the first trimester associated with the chromosome abnormalities, wherever there is a chromosome abnormality, they usually are also single gene disorders. So I would argue that the majority of losses are due to genetics. But figuring out the genetics is difficult because we know very few genes that cause losses, and to discover new genes really requires large numbers of individuals to be sequenced, which is something that we and others are actually doing, but it will require much, much more effort in it.

I also think that there have been reports, some people claim that they can explain the majority of losses through a combination of studies, and I'm skeptical of that. I think that what we attribute is a loss to antiphospholipid syndrome or some other autoimmune syndrome could actually very well be a genetically based loss that we just don't know about. So I think that those are some of the controversies regarding to, you know, currently related to my particular research.

Aleks, this is Kurt Barnhart. Thank you for joining us on this. You didn't say it explicitly, but when you say genetics, our field tends to think genetics is just aneuploidy.

Can you explain that we're going beyond aneuploidy in your opinion, or am I putting words in your mouth? No, thank you Kurt for actually saying that. Aneuploidy unfortunately is just scratching the surface, and unfortunately in our field we haven't been at the cutting edge like pediatricians that are using genomes all the time for any disorder that comes their way. And our study actually has been to use genomes to try to really put much more granularity on this problem, and aneuploidy is just a small, it's not a small portion, it's an important portion of it, but the genomes really are helping us get to the bottom of a resolution that otherwise wouldn't be possible.

And when you talk about that, are you talking about deletions and duplications, or are you talking about things like oncogenes or other genetic factors that could be activated in the developing embryo? Yes, so what I'm talking about is a first karyotype, which is something that we use in our practice all the time, is very gross looking at morphology and anatomy and architecture, but we can't of course look at the individual letters, and the genomes allow us to look at individual letters, also we can look at much subtler rearrangements that otherwise we wouldn't actually do using the karyotypes, and it allows us to really screen for thousands of genes, which we think could be involved in pregnancy losses. So it's, it provides for really an unprecedented resolution. Now of course we only understand the function of 2 percent of the genome, and so we think that there will be significant efforts that will take, honestly, a significant amount of time for us to really understand the 2 percent that contribute to RPL, but then to discover what the other 98 percent do, because we're also finding that very subtle rearrangements are also important in RPL, something that karyotype will not find, but that if you were really looking carefully at it, we wouldn't even find on just looking at the genome sequencing.

Well thank you so much for your time, I appreciate it. I'm Henriette from Copenhagen Recurrent Pregnancy Loss Unit, and happy to be here together with you. Hi everyone, this is Ruth Lathi, I'm at Stanford University, and looking forward to our session on recurrent pregnancy loss and exploring immunology.

Well thank you so much for taking the time to meet with us today. So why do we want to know about the immunology of reproductive recurrent pregnancy loss? I think if we had to answer that question, that has kind of been the go-to when we don't know what to do about recurrent pregnancy loss, and I think that is definitely to question, and I think that's what we will be doing. Ruth and I are both leading big projects where we want to explore the euploid pregnancy losses, and I think this is where we have to find the secrets of these losses, and I believe immunology is some of it, but there's so much more to it, and we need to dig into the biology in order to understand that.

I'd just like to echo that as well. We want to make sure that we're not overusing immunology for all recurrent pregnancy loss because there are so many causes, and patient selection for our studies and our treatments is really important. Give us a little bit, just kind of the background, little bit of tips, I don't want to dive into testing at this time point, but just why do you think immunology might play a role? I spent 10 years on my thesis exploring why we saw that more women with secondary recurrent pregnancy loss had given birth to a boy prior to the series of miscarriages, so we looked at immunology against male fetuses.

So it has been something very close to my heart, but I think there's so much more to the story now. So the big brother is killing you theory is one part, but I think there's so much more to dig into, but we don't know yet how to really identify the patients that need treatments and we don't even know what treatment to give them. Yeah, and I want to just reiterate that last point because I think that it's something that we don't pay a lot of attention to, and I think ever since I interviewed you at ESHRE the other summer, that really wasn't on my radar.

And so the thought is that if you have a male first, that it may activate the immune system and you may have subsequent secondary recurrent pregnancy loss in the setting of having a male fetus first. Is that correct? It's exactly correct, yes. And that's what we saw in the trials that we had been running, so much more having a male.

We also saw if they were getting a child afterwards, it was more likely to be a girl. I went to Stanford actually to study HY antibodies in these women and we saw that the women who had the antibodies were more likely to go forward with a girl compared to a boy. So I think there's something there for a very select group.

What to treat them with, that's still the question. Yeah, so I think it's not safe to say that you could do PGT for sex selection to have a female in the setting of RPL, so I just want to make that really, really clear. Yes.

Learning something this quickly is lovely, but I'm sure there's much more to just sex selection on immunology and recurrent pregnancy loss. Can you give us just a couple bullet points from what you're discussing and debating at this meeting on what else is going into this umbrella of immunological loss? I think there's two things that I will bring into the discussions tomorrow, and one of them is that we are trying to understand immunology by looking at immunology in between the fetus and the endometrial lining, and we use peripheral blood to do that, and I think that's problematic. So I will tell you about a small study we are doing with ultra-low doses PET scans for pregnant women to really get into where we can see immunology.

So that's one thing, so we can monitor differently and actually get a view of the immune system in a different way using new machinery. And the other thing I would like to bring in is that we have this huge Copenhagen Pregnancy Loss Cohort, where the 11th of April we'll reach 3,000 pregnancy loss trios that we have deeply phenotyped, and one of the things there is that we see a signal between having a high CRP and euploid pregnancy loss. Interesting.

Yeah, what I'll be talking about is moving backwards a little bit in terms of what we're doing in the U.S. Controversies that I'll be discussing are the use of thyroid antibodies in the setting of recurrent pregnancy loss, the new data that we have on that, and the changing guidelines there, as well as antiphospholipid syndrome, something that we've been talking about, you know, since my years in training, but our definitions and our diagnoses is evolving. What we're seeing is the antibodies alone without an activation of the immune system may not be as harmful, and how do we sort that out? Who's got the antibodies and who has the syndrome is nuanced, but we are learning more and more as we explore this topic. Yeah, so I think you had said something to me at dinner yesterday that was really interesting, which is your immune system today is different than your immune system yesterday.

Can you expand upon that a little bit? Well, in my disclosures slide, I make sure I mention I am not an immunologist, but our immune system does change based on our hormones, based on our exposures, based on, you know, so many things can activate or suppress the immune system in our environment, and it's constantly changing, so we have so much to learn, and it's hard to do immune testing to predict the future because we know these antibodies and these cell types and these cytokines fluctuate so wildly. If I can add to that controversy, I mean, immunology is, what cliche do I want to use? The Wild West. We don't understand it fully, yet we only have like really high-level tools, like serum assessments of certain antibodies or certain things.

Explain a little bit of why we might be missing the mark by these macro tests as opposed to what might be more micro. I think there is so much ongoing that interacts, and I think that's where the problem comes. We have been looking in microbiome transplantation, so we have been doing randomized controlled trial on vaginal microbiome transplantation.

So taking vaginal secretion from women with really good bacteria and giving them to women that have reduced biosis, and what we see there when we do immune testing transcriptomic analysis of the cervical secretion, when we do the transplantation and we have a successful transplantation, we see a strong shift in the transcriptome. So using new technologies, we can see that the microenvironment is changing. And then you can start asking the question, is it the microbes or is it the environment that they make that is actually adding to this problem? And I think that's where at least immunology and how it's influenced by a lot of other factors needs to be taken into account, and that we can see that shift in the vaginal secretion I think is interesting.

Yeah, I have colleagues also at Penn that are trying to delve into this a little bit, and they keep telling me that the microenvironment of the uterus and implantation is very, very different from the macroenvironment that you might be able to test with serum levels. Exactly, exactly. Yeah, and so I think basically that take-home point really is there may be some immunologic factors at play, but the tests that we're currently using, drawing blood tests, peripheral blood tests, are the wrong tests to do.

Help us better understand. I've heard a little bit more that the limitations on serum testing. I'm going to take it further and say, well, then some people would say, since they're so limited, why don't we just go move forward with treatment and use something like IV IgG to help modulate the immune system? I think I'll go back to my first comment, which is it's all about patient selection.

All about patient selection. We aren't sure who's going to benefit from it. We don't have a good way to select those who benefit, and so giving it to everyone is costly.

It has its risks, and focusing on immunology can take our attention away from other really important causes, such as genetics or hormones or other things that we do know how to treat. So we want to be sure we're not missing other causes as well. How would IV IgG work theoretically to improve? That's a good question, and coming from a unit where IV IgG has been tested in several trials, and I think that the idea is that you give these a lot of different antibodies that would then react to an increased immune system, but the thing is, we have not been able to find any predictors in the peripheral blood, again, as the criteria.

Where we have seen something is women who have secondary recurrent pregnancy loss and five losses. There might seem to be a benefit there for IV IgG, and also in the women with free IVF pregnancy losses. That has been the subgroup.

Now as for guidelines open up after the Japanese study that came out last summer, they are opening up to consider IV IgG use after four unexplained recurrent pregnancy losses. I just want to add a small thing to this, because we had this very high-selected group that I just said, five or more losses after a child or three or more losses after IVF treatment, ICSI-IVF, and in that group we had been giving IV IgG in our clinic. Then when COVID came, we had no supply of IV IgG, so what to do, and then we shifted to use tracolimus.

And what we see now when we do just, this is non-published data, but we see that we get the same results from using tracolimus as we used when we used IV IgG. So hello, my name is Thomas Ebner, I'm Austrian, and I'm a lab director at the University of Linz. And yesterday, we had a wonderful debate on artificial oocyte activation, which is quite a controversially discussed topic right now.

Hello, my name is Sangita Jindal, and I'm an IVF laboratory director at Montefiore Einstein in New York and a number of other clinics across the U.S. And yes, as Thomas said, we debated whether oocyte activation should be used to improve IVF outcomes, and I took the con side, and Thomas took the pro side. Well, this is a method that actually aims for improving or increasing the calcium within the cell to overcome fertilization failure. And so when in the IVF process is it done, and how is it done? Well, as it stands, it's done right after IgG, so you do the injection of the oocytes, and then you use a medium supplied with ionophore for 15 minutes.

After that, you have three washing steps, and then you go back to your culture, and everything else is as usual. We were asked yesterday to hear about other forms of activation that are being used. In other words, we began the discussion with oocyte activation, but then moved into other uses of activation sperm and embryo.

Can you talk to me a little bit more about this movement? Yeah, well, to be honest, this is not recommended by ESHRE or HFEA, so it's only recommended to be used right after IgG to overcome fertilization problems and less than 30 percent fertilization in the previous cycle. But now the indications broaden in a way that we try to also improve the calcium later on in development, meaning that the increase in mitotic rate is the aim. So, we use it and try to overcome developmental problems of the embryo, complete embryo arrest.

But this is, off the record, not accepted now and not recommended, so this is a long way to go. So, Thomas, you took the pro side for the argument, and can you talk a little bit about why you think that oocyte activation should be performed? Well, it should be performed because it saves patient cycles and it makes baby, and the babies seem to be as healthy as the regular IgG. So, the only thing is, it should be only applied with a proper indication, and it needs some control and some regulation.

And, Sangita, you said that you don't think we should be using it. Can you speak a little bit more to that? I think I would be more nuanced. I would say we should not be using it broadly to broadly improve IVF outcomes.

I think that's an over-application. As Thomas said, it should be used for the correct indication, which at this point is oocyte activation failure due to male factor, specifically the deficiency of the PLC zeta protein that is required to implement these calcium oscillations in vivo, and often with tessie sperm or round-headed sperm, Globozoa spermia, or round-spermated heads, they lack PLC zeta. And, absolutely, the next cycle or even the first cycle, one could do the incubation with the calcium ionophore to make sure that there's fertilization, embryo development, maybe even a live birth and a baby.

So, I think that's completely appropriate. But we can't test for the presence or absence of PLC zeta, can we? And so, how do we know who to even think about this technology in? Yeah, I think that's really the area that we could do some work on going forward. I think, to Tomas' point, this is now being applied widely and perhaps without indication.

It would be much better to develop a test diagnostically to determine whether or not there is a deficiency of PLC zeta, and it is from the sperm. Because oocyte activation failure may also be due to oocyte activation failure, not the sperm, and we can't fix that with activation through calcium. Thank you.

My question is, I've received a lot of concerns or expressions of concerns from some embryologists about using this technology, and most of the time they've cited concerns about the offspring and health. Can you talk about why they might have that concern and data that might refute that concern? Well, I think the data that's there, even though it's not high-quality data, but the case reports are real, and encouragingly, the offspring seem to be completely fine. They are the same as with regular ICSI offspring.

So, I think that they should not be nervous that they are creating a problem, that there's nothing that's been noted in the literature. Having said that, there are animal studies that are a little bit concerning, that when there is a very non-physiologic, super-physiologic exposure at fertilization to calcium, that the embryos that result in pups in the mouse model are larger than the control group pups, and that the male pups are impacted, their metabolism is impaired. They have higher levels of insulin, they have higher levels of fat, and less lean content.

So, I think there is some caution that can be advised for broad use of this, and I don't think the fears have been founded in human cases, but the studies, of course, don't exist there. I think, from a physiological point of view, I think a major concern comes from the fact that it's not like in vivo fertilization, like an oscillatory pattern of calcium, but it's just a single peak that you can create. And a single peak may be sufficient to cross a certain threshold, or maybe not.

And this is actually the problem. It's not a physiological calcium pattern. What about multiple injections, though? Could you overcome that physiological pattern by doing more than one injection into the oocyte? This is a very good point, and it has been tried.

So, double application of ionophore is actually also a way to rescue these cycles that did not respond to a single cycle, but always the second stimulus gives you a lower amplitude of calcium peak. So, you can create more calcium peaks, but at the end, the third one, maybe the fourth one, then you won't have any reaction. And so, when we think about introduction of new technology into the IVF laboratory, at what point do you think that this should become standard of care? Well, personally, I think there should be at least one randomness control trial to prove it.

The problem with AOA is artificial oocyte activation, if you do it in a prospective way, a randomness control way, then it's always one group that does not get this compound, for example. And this might be unethical. Yeah, it's a good question.

I think, with indication, this can be implemented as standard. It's certainly, I would not consider it experimental. It's somewhere in a gray area.

And I think once it does have, there's a media that you can purchase. Once it has FDA approval, I think that will smooth the path to acquiring this media routinely. It'll be part of our toolkit for helping our patients in the laboratory and will probably move closer to standard of care.

Having said that, I do worry that it will be over-applied. I do think it's important to stick to the indications, which is activation failure due to sperm factor at the time of ICSI. I would not like to see this applied generally over the course of embryo development in vitro.

I don't know what the calcium is doing at high levels. I don't know that this is helping our oocytes and our embryos. We have no evidence that that works, to my knowledge, and certainly no robust studies to prove that otherwise.

Yeah, I'm absolutely in line with you. So it should only be used with the proper indication and according to the standard operation protocol that has been published. In conclusion, I just want to hear, are there any thoughts that you have that perhaps we didn't bring up during the past 10 minutes or so of discussion that you think is important to share with our listeners? Personally, I think everything was covered, and let's wait for a paper coming up.

Yes, I agree. Thank you, Thomas. This was fun.

Thanks to you both. So excited to be talking, meeting with you all both today. If you don't mind giving us, just introducing yourself, where you're from, and a little introduce your topic that you'll be discussing.

My name is Jacky Boivin. I'm a professor of health psychology at Cardiff University in Wales in the United Kingdom. You'll notice that I'm not Welsh because I'm originally Canadian.

And I'm also director of Women's Health Research Wales, which focuses on inequalities in women's health. And I'm going to be debating the pro side of mental health evaluations should be mandatory in ART. Hi, I'm Angela Lawson.

I'm a former professor at Northwestern University where I worked in the fertility clinic for a little over 15 years. And I currently own a private practice where I conduct both forensic evaluations for the courts and clinical evaluations in the context of reproduction for gestational carriers, egg donors, and the like. And I'm going to be arguing against actually conducting these evaluations in the context of IVF.

Welcome to you both. And Angela, I'm not going to lie. You can see some tears at the former Northwestern part.

So what do you really think about this? Do you think that ART patients should be mandated to have mental health evaluations? I mean, look, we know from the research, and there's a vast amount of research, that at least in the US, the majority of patients and their partners are depressed and anxious at clinical levels. And we see lower but non-zero rates of depression and anxiety among fertility patients in Europe and throughout the world. We know that patients are distressed.

We know that they need help. Do I think that a psychological evaluation is going to get them the help they need? In all likelihood, no. Do we need to do something? Yes.

Because our patients are distressed. They're not getting referrals. They don't know where to go for help.

And when they find somewhere to go for help, there are often barriers in accessing that help. How about you, Jacky? I think that you've described the context well. If we're going to have mandatory evaluations, I think we need to think about what those evaluations are meant to do.

So far, they're primarily about screening for anxiety and depression. But the approaches that are taken towards screening for anxiety and depression are not very good. And most of the approaches don't actually meet the standards that we have right now for having mandatory evaluations.

So we do, as Angela says, we do need to change that. What is the focus of these evaluations? And that should be the question, rather than whether we should have them or not have them. It's what is in a mandatory evaluation.

I also think the word evaluation is a little loaded. So at Northwestern, we had three psychologists embedded in the fertility clinic. And we did require all patients starting IVF to have a psychological consultation.

When patients mistakenly heard that it was going to be an evaluation, they got very angry. Right? Why, just because I'm not able to conceive on my own, do I have to undergo a psychological evaluation? I think exactly in the way that you're talking, Jacky, the way that we frame what we're doing in these sessions is really important. And if we do require, and I actually, I do think that we should consider requiring consultations at the start of IVF, but actually not just at the start of IVF.

I think at the start of any fertility treatment, when patients walk through the clinic's doors, we then normalize the receipt of mental health support. And in these consultations, we can talk to patients about coping with what comes ahead. We can talk about communication strategies, decision-making, and we can provide the referrals that patients might need.

But that's a consultation, not a psychological evaluation. Yeah. And I will say our practice admittedly changed, where we no longer require it.

We do offer it to all patients. But we do interestingly require psychological consultation for all patients utilizing third-party reproduction. Do you think that that's a distinction that clinics should adopt? Do you think that every patient who is using donor egg, donor sperm, gestational carrier should have a mental health evaluation? I think your clinic would not be unique in that.

When you look at the guidelines internationally, the use of third-party reproduction, surrogacy, and so on, they are privileged in that way of having mandatory or highly, highly recommended evaluations, whereas that's not the case when we talk about people doing exactly the same thing but using their own gametes. So the question is really about whether we think that people have enough knowledge to do the implications, understand fully the implications. And in that case, there's two components.

What information do they have? And then, do they have the opportunity to deliberate the decision? And often, you can get a lot of information, but you don't have the opportunity to actually deliberate the decision. So the pros and cons of the different options. And that's what tends to be missing, and that's why I think they're in that privileged position for third-party reproduction.

I actually think that only requiring the consultations for patients who are undergoing third-party reproduction can be seen as a little discriminatory. And at Northwestern, the psychologists in the clinic, because we were doing more than just these required consultations, we were seeing therapy patients, we were doing third-party psyche valves of the donors of gestational carriers, it led to a little bit of a slowdown in starting IVF, which was part of why we backed off requiring the consultations at the start of IVF. I think if we had embedded mental health professionals in clinics, or at least clinics had strong relationships with mental health professionals who were solely focused on these initial consultations, we could go back to required consultations for IVF and for third-party reproduction.

We would have to think about other barriers. Who's going to pay for these consultations? We're very fortunate in Illinois that these are largely covered. That's not going to be the case in other states or other countries, maybe.

But I think everyone should get a consultation. It's just as you get medical counseling and medical consultation when you begin treatment, I think the equivalent of mental health consultation should be provided for all patients. Thank you very much.

I'm hearing that the goal of the initial consultation is for evaluation and to potentially identify anxiety and depression that could be subsequently treated. Is there evidence that that will improve outcomes such that we can see either IVF outcomes or other outcomes? So is there an ultimate benefit that we're going to see to the patient and that this isn't just potentially punitive financially or personally, but actually potential benefit? Is there evidence beyond that? Thank you. So there is.

That's a great question. The evidence with regard to outcomes for fertility, there is actually no rigorous research that shows that going to therapy or relaxing will help get you pregnant. All 39 randomized controlled trials at the time of the 2016 Cochrane Review found that all of those randomized controlled trials were so flawed as to be biased and unreliable.

And of course, it's unethical to create RCTs where we stress out one group of patients and not the others and see who gets pregnant and who doesn't. But the evidence that we have right now does not show a benefit between relaxing via therapy and getting pregnant. The benefit that we do see, and there's quite a bit of research on, for example, embedding mental health professionals into those clinics shows that mental health treatment gets normalized.

Those patients are more likely to engage in therapy. Their distress is seen to go down. And we do have one small study in the area of reproductive medicine that shows that when mental health support is offered, it also improves patient satisfaction in fertility clinics.

So, I agree that there's no evidence that doing these kinds of psychological interventions impact clinical outcomes, whether that's looking at live birth rates or patient continuation in treatment. And that's part of the reason why, what's the point of screening? If you're going to screen, you need to have the next thing, which is an effective treatment. And those aren't available.

But there are other models of care that are associated with these clinical outcomes. And those are the models that are focused on supporting patients' efficacy in being able to sustain their efforts in treatment, i.e., that they don't disengage with treatment or even that they don't engage with treatment because there is an underutilization of fertility care when you look at need versus uptake. And so, those are the way forward, if you will, for these kinds of evaluations is to support people in that particular way because those are the ones that are linked to positive outcomes, whether it's live birth rate because you sustain your efforts in treatment or more rapid decision making and so on.

Yeah. And I would say, I think that's the key and at least how I counsel patients is that the greatest barrier to achieving success is often the mental health component. The stress of treatment leads to dropout and the emotional toll of infertility treatment often leads to couples giving up.

And for the majority of patients, we know that they will ultimately be successful in having a baby if they continue treatment. And so, I think the key for mental health really in my mind is to keep that patient feeling good about themselves, feeling good about their treatment plan, feeling good about their therapeutic relationship, and keeping them going until they have a baby. And so, I think that should it be mandated? No, I don't think anything should be mandated.

But should it be offered? I think universally, yes. I'm so glad we're having this conversation. It's another wonderful reason to have this meeting.

I'm going to go back to where we were talking about the difference between intake to a fertility practice and third party reproduction. I've always looked at it that the intake was, let's see what we can do to help you out and learn from you, whereas the third party is more, there's really information that we want to convey back to them about the differences in third party. I'm wondering if you ever thought of ways to distinguish that to make it less stigmatizing because I really think they're overlapping with different processes.

So, if I understand, you're making a distinction between what would be offered to patients using their own gametes versus patients that are coming in for third party reproduction? It's not much offered, but it's more of a two-way street in the third party. It's more that there's information we want you to know on how it impacts you and how it's different from just on your own. So, it's not just where are you in the state and how can I help you get through it.

It's have you considered this? Are these issues weighing on you? I find it to be a very different conversation. No, absolutely, but this kind of integrated model of co-produced fertility care between patients and healthcare practitioners is the way forward. With the current ART as it stands and with the population of people using ART, this idea of co-production that you're working and there's reciprocal relationships between the patients and the clinics, this is precisely the relationship that needs to become more highly valued as opposed to I'm giving you information or you're giving me information because this responds better to the current needs of people undergoing fertility treatment at this time.

And I would say, in many ways, when I see a patient at the start of fertility treatment using their own gametes or I'm seeing a patient who's using donor gametes, it's actually a very similar two-way conversation. Patients don't know what they don't know and they are often anxious and depressed when they first walk through the clinic's door. They say many times, I'll never do IVF and then, of course, many of them wind up doing IVF.

And you can talk to them early on about what may be coming ahead, decisions that they may face and give them early strategies and tools to begin to think through some of those potential first decisions. Thank you. Understanding that we've mentioned or discussed that mandated may not be the way to go, evaluations or meeting, are there alternative screening mechanisms that a clinic could employ potentially to achieve such goals? So that is actually what I am going to be arguing for in my portion of the debate.

I think we could do screening for all and we could do it in a fairly straightforward way, given that most of us use electronic medical records. These psychology screeners are embedded in the system. So, for example, in Epic, you can automatically have an email sent to every new patient that is then also sent to them after every IUI that is unsuccessful, every retrieval that's unsuccessful, every miscarriage at various time points along the way.

You send them the psychological screener. It automatically generates an email back that tells the patient their score. You can have your Epic teams add to that email messaging below saying, we care about your mental health, even if your score is, you know, you're happier than anyone we've ever seen.

And here are the supports that we have in place. And I do think it needs to be signed, that email, by a real-life mental health professional who's either embedded in the clinic or, again, strongly connected to the clinic, so that if a patient does want to reach out for that support, there's a person at the end of the line that they can contact and get that support. I think there's nothing wrong with that.

I would agree with doing something like that. But the screening is not actually what's going to help the majority of patients that undergo ART. Only less than 1% of people are denied treatment because of mental health disorders.

7% are delayed, i.e., you've got a disorder, we think you should get a bit of help before you start. So that means that actually 90% of people are not going to be detected on the screening. And so what are we going to be offering those people? So we cannot make screening the centerpiece of the offer for mental health evaluations.

Now, you said that you heard that it shouldn't be mandated. But, in fact, I think that mental health evaluations, or consultations if you want, should actually be the status quo. And that's what we need to work towards.

We don't need to use the word mandatory. There are some things that are status quo in clinics, like telling patients that cumulative pregnancy rates are better than if you stick to just one cycle. And so there are other status quo psychological information that we can use to guide patients.

And that should just be part of the routine. And that's what I would advocate. Because the screening is going to miss a lot of people who could benefit from lots of pre-treatment, let's say, information and guidance.

Thank you. I think we'll just conclude there, given the time. Thank you so much for your contributions today.

Thank you. Thank you very much. Antonio Capalbo, and Chief Scientific Officer for Juno Genetics.

And, I mean, my career has been based on trying to develop technologies and clinical application for improving embryo selection, primarily looking at the issue of aneuploidies. And I had the pleasure today to have this great debate with Catherine, who is here next to me. And I will let her introduce herself.

So thank you so much, Antonio. Yes, so I'm Catherine Racowsky. I used to live in the United States, but absconded to France four years ago.

As with Antonio, I spent, gosh, I don't even know how many decades thinking about embryos and trying to understand how they tick and how best to actually assess embryos. So I'm now based at a hospital in Paris, where I do my academic work. And today I had the great pleasure of debating with Antonio whether non-invasive PGTA is actually going to be the next thing in prime time for genetic testing of aneuploidy.

So I thought your talk was amazing. Thank you both for sharing your wealth of knowledge and information with the audience. I think what was most interesting to me, Catherine, was some of the data that you discussed on trophectoderm biopsy and how the biopsy itself may actually damage the embryo.

And so as we think about non-invasive PGT, we're really thinking about how do we select the best embryo and how do we do the least amount of harm. Can you speak a little bit to that here? Of course. It would be my pleasure.

So the data I presented was based on mouse data primarily, although there is some human data as well. As I said during my presentation, I think it's very easy just to say, well, let's just do a trophectoderm biopsy for a patient. Actually, if you're the embryologist sitting at a microscope doing the biopsy, it is not a trivial procedure at all.

I've done multiple trophectoderm biopsy, hundreds, and there's hardly an embryo that I don't think as I'm doing it, oh my goodness, I'm doing something that might damage this embryo. Because trophectoderm cells are very cohesive. They adhere to each other and it's quite difficult to actually extract the embryos.

So with respect to the data that's available, there is human data from Nicholas Plachter's lab at Penn showing quite clearly that there is some damage done to human embryos when doing a trophectoderm biopsy with respect to the increase of this, what he calls site DNA, which is an increase in nuclear budding of the embryo. There's also some mouse data, not just on the placenta, but on actually the fetus during pregnancy, but also on offspring that shows there is some perturbation of epigenetic marks and dysregulation of metabolic function in the offspring. So, albeit that's mouse data, it's not human data, and we need to acknowledge that, I do think that as with all the procedures that we do in the IVF lab, we have to be very cautious that we're not doing harm.

Antonio, this debate was lovely and you both came to a pretty good consensus. The other side of that debate is if we can be non-invasive, the difficulty might be we're farther away from the embryo. And you did a good job, and maybe you could summarize on why you think not being directly at the embryo is going to limit the accuracy of a non-invasive test.

Well, I think that's pretty much very clear in the literature, especially if we have a critical view of the data that have been published so far. We have seen that if you look carefully and critically at the data and you look only at the concordance rate on a full chromosome base, then this is showing a concordance rate of the non-invasive analysis on culture media of about 50 percent, which of course then translates in really poor predicting values in the clinical setting, as we have seen also in other blinded studies that have been recently published. So, all in all, I think the performance that we are seeing and witnessing today with non-invasive PGT are definitely not enough to justify any kind of clinical application.

Can you elaborate a little bit more on just the theory on why you think the non-invasive test is just not going to be as accurate? Yeah, because that's what has been proven so far. What we have seen so far when comparison has been made with non-invasive analysis versus the biopsy or the remaining embryos, and also in studies where embryos were transferred in a blinded way, non-invasive analysis was really poorly predictive of outcomes. I think there's room for improvement in the testing, for sure, but what I struggle a little bit with, and maybe Catherine, you can answer this, is a lot of the studies that have looked at non-invasive PGT have done those studies side by side with PGT as the comparison group, and you're breaching the zona in those blastocysts, or you're breaching the integrity of the blastocysts to get the DNA out, and so how do you envision that we're going to get that data from the blastocyst without actually breaching the integrity of the blastocyst if that's what we think is damaging the embryo? I actually disagree, and actually I think it was Marcelle who asked this question.

Not all the studies have actually involved assisted hatching on day three and then culturing the embryos out to blastocyst stage. Several of the studies have not done so. The DNA does leach out of the embryo regardless of whether there is a breach to the zona or not.

So I just would like to push back what Antonio said because it's not entirely true that all the studies have shown around a 50 percent concordance by any means. I mean, I showed the data, I showed the ranges, and a lot of work is being done to try to improve the concordance with respect to the handling of the embryos, the timing of culture. We have to take into consideration the quality of the embryos, of course, and then, of course, we have to control for maternal DNA contamination.

And I know for sure that there's a nice lot of work done. Actually, it's ongoing in Stanford. You may be familiar with this work at the moment that's really trying to develop technologies for accurately testing or distinguishing between maternal DNA and embryonic DNA in the diagnostic platforms that are actually being used, the algorithms that are being used, I should say.

So I don't think it's not just 50 percent. There are indeed studies that show near 50 percent concordance, but there are other studies that show a much higher concordance rate. As I said in my presentation, I just think we have to be fair to this.

You know, NIPGTA has only been going on for about 10 years, and invasive PGTA has a long history. And when invasive PGTA started, you know, it was a rocky road to begin with, we know. And a lot of work has been done to improve the technology, improve the algorithms to where we are today, and I think we just need to bide our time a little bit and be a little bit more lenient with non-invasive PGTA that maybe in the future it actually will have some real efficacy and really be helpful without the invasiveness of the embryo.

So I learned something today that a lot of the studies on non-invasive PGTA have been done on previously frozen embryos and then thawed. And I'd love to hear a little bit more about that, whether that is true. And if so, could we flip side and see that as a benefit? For those people that have in the past had embryos frozen and not tested, would this potentially be a technology that could be used instead of doing thaw, biopsy, refreeze, but thaw, test non-invasively, and refreeze? I don't know.

But this was a surprise. I didn't realize that a lot of the data had been done on previously frozen. So I'll allow either one.

So if I may, Antonia, I'll just tackle that first, and then, of course, it's your turn. So actually, I think probably the most robust of the randomized control trials that have been done at the moment testing non-invasive PGTA is the Rubio trial. And those embryos were not frozen ahead of time.

These were clinical embryos that were used. So they were fresh. It is true that a lot of the studies have involved frozen and then thawed embryos, which is obviously a limitation.

I mean, this work, as is so often the case with technologies in our field, we have to depend upon donated embryos from patients in order to start developing a technology. So I think that's obviously one of the reasons why a lot of the embryos have been frozen, but certainly not all of them. Thank you, Catherine.

I have a completely different perspective. I wouldn't offer any non-invasive PGTA clinically for any indication or, I mean, situation. I think so far there is no validation, particular clinical validation.

We have seen only one study recently published where the embryos were transferred in a blended non-selection analysis and the outcomes were compared with the culture media results. And basically, this study showed that 25% of the euploid embryo transfer had a sex discordance with the fetus. That means you can only see and assess discordance on the sex level when it goes from male to female.

So you're missing also the other 25% of the cases. So actually, in the best sense today, now we know that 50% of the putative euploid embryos transfer are really contaminated. And on the other side, when they transfer embryos with an unemployed findings into the culture media, 40% result in a live birth.

That means that also positive predicting value is really, to say it's optimal or I would say really bad. So with this information that we have, I wouldn't consider any clinical application for non-invasive PGTA. Also in terms of do not harm, as Catherine was saying before, I think that the harm here is offering a technology that is not validated to patients and it also comes with costs.

That's my viewpoint. Yeah, Antonio, I agree with you that we're not ready to use it clinically. I don't think that's the debate.

But since I have such an expert here, I want to ask you a theoretical question that's always confused me. There's a lot of work in the obstetrics about getting cell-free DNA very early in pregnancy. How is that DNA different from what we're getting from a culture or is it different? Well, that is a completely different context and biological substrates that we can get.

Here in the media, of course, we have a few cells that are growing for a few days in culture and may start releasing or may start getting DNA at the very latest stages of embryo development in vitro. Indeed, one of the significant modifications that has been suggested for non-invasive PGT is to push culture for all embryos to at least day six when you can improve a little bit in formativity and the concordance rate, which is, again, another controversial aspect of non-invasive PGT because we have no experience of pushing an expanded blastocyst on day five down to day six. And then in the context of NIPT, this is a test that went through very extensive clinical validation and confirmation rate and where positive and negative predicting values are very well known and established and can be communicated to inform reproductive decision-making to patients, something that we are really far away in the context of non-invasive PGT now.

If I may, I have these two experts in front of me and I want to say, is there ever, could you envision a future and how would it look with first PGT being performed? We know that gets us to a 60% live birth rate. And then non-invasive testing on the side or culture testing something to get us above that 60%. And what would that testing of that culture media be? Well, myself, I think I would invest more energies going forward to trying to standardize biopsy-based PGT that we have today and to improve technologies for analyzing the cells going forward and to get additional, maybe clinically relevant features of the embryonic genetic that are missing right now and can explain this 40% of implantation failure with diploid embryos rather than investing resources in analyzing something that can be really redundant with what we're doing already.

So, I find that absolutely fascinating, Antonio. I mean, knowing what we know about the embryo and the metabolism of the embryo, as I said, at the podium, there is so much more than just the genetics of the embryo and some very elegant work. Yes, it bombed on metabolomics, for example, two decades ago, Emre Seli's work.

It didn't pan out. But there is a lot of work afoot to try to understand what other approaches we might take to integrate with PGTA if we really want to use PGTA and trophectin and biopsy, which as I said, I think may carry some risks. So, in my view, my humble view, I think the future holds a multi-pronged approach for assessment of embryo viability, whether it be to integrate metabolomics, whether it be to understand better how the cumulus cells themselves impact upon oocyte viability.

You may or may not know that I've been doing a lot of work on fluorescence lifetime imaging with my colleague Dan Needleman at Harvard to try to understand how the FLIM signatures of NADH and FAD actually do inform the viability of the oocyte, which is the key driver of embryo viability. The sperm has some role, obviously, but the oocyte is the key driver. So, I envision for the future that we really have to think much more carefully about adding in these different approaches, time-lapse imaging being another one.

And I presented some data today, which I think is fairly convincing. It's new data and shows that you really can improve the performance characteristics by integrating NIPGTA and time-lapse imaging as compared with each one of them individually. Yeah, I think the future is bright.

I'm just not sure what direction it will go in. One of the previous debates that we heard was on oocyte activation, and to me, it seems a little bit worrisome. I always say, like, don't poke the bear, and we're going to be poking the embryo again and again and again.

And I worry that the cumulative damage to that embryo may be not sustainable in terms of implantation and continued growth and development. So, thank you so much for joining us for this fantastic debate. It was amazing to hear on stage and great to have you on the podcast.

Thank you. Here we are today, and I'd like for you to go ahead and introduce yourself and tell us about what you'll be speaking on today. So, my name is Herman Tournaye, and I'm the chairman of Brussels IVF.

It's the Center of Reproductive Medicine in Brussels, Belgium. And my talk today will be on the pre-pubertal stem cell banking and fertility preservation in general. It's a topic that is quite interesting, I think, because the idea to bank, right, preserve stem cells in young boys, well, it's more than 20 years old, actually.

In 1994, I read, with great interest, a paper by Ralph Brinster from Pennsylvania, so Philadelphia. Ralph Brinster, in fact, introduced a model in the mice where he tried to transfect the stem cells of male mice in order to produce transgenic mice. Okay? So, the idea was he would take stem cells from the mice, in vitro transfect them, and transplant them back.

And of course, as many other reproductive andrologists, I was very interested by that paper because the idea came, why are we not going to do the same with pre-pubertal boys? They don't produce sperm yet, and it will only be from age 13, 14 onwards. But if a boy of nine years old is facing leukemia, for example, needs gonadotoxic treatment, he will be sterile. So, the idea in those days, people started to bank ovarian tissue, and so the idea came, why are we not going to bank stem cells in these boys? And so, eventually, I proposed the protocol to my ethical committee of the hospital, and they accepted it.

So, in 2002, we were the first in the world to start banking testicle tissue. In those days, people said, what is this? This is pure experimental. And even today, it's still experimental, but worldwide, lots of people are doing it.

Also, in the States, a lot of centers are now banking stem cells in young boys that are facing gonadotoxicity. So, how do they do that? Do you remove the whole testes? Do you tell me a little bit more? In the early days, in 2002, indeed, we removed the whole testes, because many of these boys have got a very small, peanut-sized testes. And the surgeons with whom we were working, they said, look, if we take a small biopsy, there will be some bleeding, and eventually, the whole testes will be lost, and there may be complications.

So, rather, we take the full, the whole testes. But after a couple of years, we decided to go for small pieces, smaller pieces. When those boys, now men, are ready to conceive, how do you go about re-implanting the tissue, or how do you get sperm from that stem cell tissue? Well, at the moment, we don't.

But what happened this last year, we started, well, the past few years already, these boys where we were banking more than 20 years ago, well, they start showing up, of course, because they survived, which is good, of course. And eventually, they have a partner, and they're thinking about having children. So, they do the test, a sperm test.

They are azoospermic, so no sperm, as expected in many of them. And then they show up and ask, we banked a long time ago, my parents told us, because sometimes they were very young, what can we do? And because of that, we started to go again to the ethical committee and ask, can we start now a protocol of transplanting, so grafting, the tissue pieces? And that was also a green light for us. So, eventually, last year, the end of last year, we did the first grafting worldwide.

The result, we have to wait, but what we do is we put some grafts of the tissue that was banked almost 20 years before in the testis, but also under the skin, because there is some research in monkeys that shows that even subcutaneous grafting may work. So, the hope is that indeed, well, normally the protocol says over about six months is the early point, and in the meantime, we will follow up with ultrasound, endocrine markers to see what happens with the grafted tissue pieces. Well, this is very exciting.

It sounds like you've decided to pursue an in vivo method for achieving spermatogenesis. Are there in vitro methodologies that could potentially be used with these pieces that have been banked? Yeah, well, about 10 years ago, in Europe, we started a network together with Amsterdam and Brussels, and then eventually other people, well, they joined in. It was called GrowSperm.

We got a lot of, well, support, financial support for the European community, which stopped now, unfortunately. But basically, the whole project at the moment in rodent models, sometimes it works, sometimes it doesn't work. So, it's not that reliable.

So, the step towards doing this with human tissue probably is still far away, I'm afraid. And just to follow up on that, obviously, the goal with the transplant would be to obtain mature spermatozoa that could be used for ICSI. Yeah, yeah.

Because, indeed, yeah. Before, so, Kyle Orwig from Pennsylvania, they did, well, they tried a couple of years ago. It's never been published, so probably it was not successful.

They started to freeze suspensions of cells. So, that means that cell suspension, you cannot graft, but you have to infuse it again in the testis, which was also done in a lot of animal models. But so far, no good news.

So, we opted from the start to bank tissue pieces because, yeah, tissue pieces you can graft, and you can turn them into a suspension, if you like, later on. Since we're talking to an expert here, can you briefly say what would have to happen for us to use in vitro gametes for ICSI? Has that happened in animal models at this point? In some publications, it was successful, yes, but from what I read, what I hear is that it's not always a method that you can, well, it's not reproduced easily. So, I'm afraid that it's still, well, futuristic at the moment.

Why do you transplant the tissue back to the subcutaneous space? Is that for endocrine control to get better? No, not necessarily, because in the rhesus monkey models, it also worked fine. So, you don't have to, eventually, the idea is to get sperm. Do you need to put the grafts into the testis for that? Maybe, yes, because in the testis, testosterone might be higher, but from these animal models, it seems that it's not really needed.

Anyhow, you need to go to take a biopsy again to do ICSI, so it might be much easier, nicer to go just for the subcutaneous grafts, of course. Got it. So, unlike female ovarian tissue transplantation, where the goal is to transplant that tissue back to the ovary, have these women ovulate and conceive without medical assistance, the goal here is really just to get a few sperm.

So, those sperm are not ejaculated then, correct? No, no, no. You see, if you go for the transfusion protocol, the idea is that you can recolonize the seminiferous tubules, but then also the problem would be, if there would be sperm production, does it come from your cryopreserved suspension, or is it maybe just because we know that in many of these boys, eventually, after many years, they still will have some own sperm production. With the grafts, it's definitely, if you have, let's say, production of sperm in the grafts, you're 100% sure it's because of your grafting.

It seems like forearm would be a lot easier if the goal is not to get sperm in the ejaculate, but you would have to go back in and retrieve it. To me, it seems like it would be less traumatic physically and mentally for these males to have the tissue transplanted to a subcutaneous area. Yeah.

Well, you never know, because maybe the suspension infusion may work also very well, and then maybe you never know that eventually spontaneous conception is also possible. It would also be nice, of course. In this patient of yours, are you providing gonadotropin support in addition, or any type of medication? No, not at all, because the gonadotropins are very high, because they go to chemotherapy.

Most of them will have quite high FSH, or at least normal high FSH. And have they been on testosterone, or are most of them not needed testosterone? No, we just put the grafts, and well, the rest should happen spontaneously. Have you all, can I ask, have you looked at levels? Have you looked so far to see if you see any changes in endocrine levels? Are you anticipating not any changes in endocrine levels? It's a whole experimental protocol where every three months we will have a look to all these parameters, but the first grafting worldwide happened in December last year.

Oh, okay, we're really on. We are cutting edge. Our listeners are hearing about this cutting edge.

Well, this has been wonderful. We've learned so much about this, and exciting work that you're doing. Anything else that you'd like to share with our listeners before we wrap things up? Well, I hope that whenever tissue has been banked and people start to graft it again, that all these data are gathered together, because we need to have a certainty for our patients whether this works or not.

And if every center is doing some cases, we need to have a multi-center approach to know whether it really works. So I'm eager to see what other people are doing in this field. Wonderful.

Well, thank you so much for your time. You're welcome. And we look forward to hearing your talk today.

Okay, thank you. Congratulations, and thanks for being on the podcast. It's cutting edge.

Yeah. And that's a wrap. Another meeting in the books.

Yes, this was the best of ESHRE and ASRM in Lisbon, Portugal. And I hope you enjoyed the podcast. It's been a pleasure speaking with you, Kurt.

This was a lot of fun. For those of you who couldn't attend the meeting, it's like you were here to hear all the wonderful science we did. So I hope you enjoyed it.

And you, Anne. It's been such a pleasure having you on the podcast as well. Yes, and we're very hopeful that you will soon be seeing reviews on these topics in F&S Reviews.

Take care, everyone. Until next month. 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.