Fertility and Sterility On Air - Live from ESHRE 2024: Part 1

Fertility and Sterility On Air brings you the best of ESHRE 2024! In Part 1, hosts Micah Hill, Paul Pirtea, and Kate Devine bring you: embryo reexpansion and live birth with Ibrahim Elkhatib (01:30), a discussion with the RBMO editor, Nick Macklon, and F&S editor, Kurt Barnhart, about “IVF add-ons” (11:21), rescue in vitro maturation with Danilo Cimadomo (24:43), discussion with F&S On Air listener Elizabeth Glanville (31:38), one side of the debate on dual/double triggers with Raoul Orvieto (35:27), and cross-border reproductive care for same-sex male intended parents with Brent Monseur (48:59). 

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 to a special edition of Fertility and Sterility On Air, the F&S podcast. We are live in these two special editions from ESHRE 2024 in Amsterdam. I'm Micah Hill, the Media Editor for F&S.

I'm joined by my podcast co-host, Kate Devine, and Interactive Associate from Europe, Paul Pirtea. We conduct a series of interviews from leaders, such as our ASRM leaders, from people we meet on-site at the auditorium, but especially from the presenters of basic science and debate topics at ESHRE. And we bring you the best of what we found in this two-episode podcast.

If you weren't able to make it to the meeting, we hope you enjoy listening and learning from this episode. So, hello, everyone. My name is Paul Pirtea.

I'm an Interactive Associate for Fertility and Sterility, and we are finding ourselves in the ESHRE Exhibit Hall A at the Annual Meeting in Human Reproduction. And I'm here with someone very interesting who's going to tell you something about his great research. So, because actually, I think this is very fundamental for our field.

So, please. Thank you. Thank you, Paul, for having me.

So, my name is Ibrahim Elkhatib. I'm the Group Embryology Director at Heart Fertility Clinics. Please, Ibrahim, tell me, what is the topic of your research? And what is the title of your presentation that you have in ESHRE? So, the title of the presentation is, Does Embryo Expansion Postbiopsy Predict Live Birth? Or is it associated with live birth? So, and how did you come across it? Why do you think this is important? Well, the utilization of PGTA is a debatable topic nowadays, and I believe there are many factors that eventually will contribute to the implantation or the live birth.

One of these is maybe the best time of freezing the embryo after biopsy or the way we do the warming and so on. So, in non-PGTA cycle, we learned that maybe it's better to artificially collapse the embryo before we freeze them, because this will result in reduction of the volume of the cavity, and maybe this can improve the survivor or the embryo development. So, if we want to apply the same logic in PGTA cycles, then the best time to freeze the embryos is exactly after the biopsy, because the biopsy itself will result in collapsing the blastocyst.

So, we applied that. So, we used to freeze as soon as possible, but, you know, it depends on the workload, availability of stations, embryologists. Then we found out that as soon as possible was sometimes 15 minutes, sometimes 30 minutes, sometimes one hour, one hour and a half.

So, that was a huge time interval. So, we decided, no, we need to standardize the time of freezing, and we decided that one hour is good enough in order to arrange the workload, and at the same time, it will still respect what we learned from collapsing the blastocyst. So, embryos will not be really expanded a lot.

When we applied this in our lab, we noticed that there are three different patterns of re-expansion for these blastocysts. So, we did the biopsy, we waited one hour, and then we froze the embryos. We saw embryos that they remained completely collapsed.

So, we called them grade zero re-expansion. And we had embryos that they started to re-expand at the end of this one hour. So, you can see a very small cavity.

They are referred to as a grade one in the presentation. And the third grade is grade two, and these embryos, you can clearly see a cavity. It's very important to note that despite these embryos re-expanded, but they are still not fully re-expanded.

So, they are relatively considered collapsed. So, we thought, since there are three different patterns of re-expansion, maybe this information is useful to select the embryos for transfer. So, we performed a study of 1,141 single-euploid embryo transfers.

Where did you do this study? So, this study was done in art clinics in Abu Dhabi. Okay. And this is quite challenging.

So, did you have other centers working with you, or? Yeah. So, we have nine clinics, but in order to reduce the variables, this study, all the patients recruited in this study were from a single lab. So, it's from Abu Dhabi lab.

Okay. So, did you have the same technique in the lab in all the clinics? I mean, this one hour, does it apply to all the clinics? All the clinics, yes. Okay.

So, how did you design your study? How do you control for biases? And what were your findings? So, first of all, we only included PGTA patients. So, we excluded PGTA and PGTSR cases. Patients with non-anatomical abnormalities were also excluded.

We accounted for factors that mainly patient-related and unrelated factors that are most commonly associated with live birth, such as the type of endometrial preparation, BMI, patient age, the quality of inner cell mass, trophectoderm, day of biopsy, and at the end, the grade of re-expansion post-biopsy. Okay. So, when we did the univariate analysis, we saw that, as usual, the endometrial preparation, quality of the inner cell mass, quality of trophectoderm, day of biopsy, and the grade of re-expansion were all significantly associated with live birth.

But interestingly, when we applied the multivariate, accounting for all of these confoundings, only the endometrial preparation, the day of biopsy, and the grade of re-expansion were significantly associated with live birth. It means, in other words, that we can use this information as a very important selection tool to select the best embryos with the highest chances of live birth. Regardless of poor or good morphology or… Exactly.

And we even stratified the analysis based on the quality of trophectoderm, it came the same association. Even if we consider the total embryo quality, factoring for the inner cell mass, trophectoderm, and the day of biopsy, we still found the same association. So, irrespective of the quality of the embryo, grade 2 embryos, which they expanded more, they have significantly higher live birth.

So, in the end, how many patients did you really exclude and how many did you have? So, we ended up, after excluding the PGT-M and PGT-SR cases, double embryo transfer, which was rarely done. We ended up with 1,141 embryo transfers, of which we had 50% live birth rate. Okay.

And what do you think is the impact of your findings? I mean, do you think this will… I mean, first of all, will this change the workflow in your clinic? And do you think that for the readers, they should take into account this in the future, or you still believe it's a very young hypothesis and therefore more research is needed? Well, that's a very good question. So, the conclusion of this study is we are introducing a novel independent marker, not reflected by the inner cell mass, the trophic rhythm of the day of biopsy. It doesn't cost anything.

It's a matter of arranging, standardizing the time of freezing. So, it's easy, applicable in everywhere. Now, there is not a very clear or strong recommendation on the best time to freeze embryos after biopsy.

The PGT consortium and the special interest group of embryology, they only recommend to freeze as soon as possible. But I think we agree, as soon as possible is very vague, right? It's a huge time interval. And it depends on the clinic.

Yeah. So, now we're introduced a suggestion that maybe freeze after one hour and utilize the information that you will get at time of freezing. In the time? Yes, at time of freezing, one hour, then you would respect the idea that we should freeze the embryos while they are collapsed.

At the same time, it will allow yourself to apply this for all the embryos. Number three, it's a very important, easy to get tool to select the embryos at time of embryo transfer. Is the time after thawing also important and correlated with the time before freezing? We were also interested in answering this question because this is not novel.

We know that the more expanded embryos at time of transfer, the higher the chances. But we were interested in investigating if the post-warming re-expansion is associated with the post-biopsy re-expansion. So, what we did, our protocol was to warm the embryos.

We check for re-expansion one hour post-warming, and then at time of embryo transfer, which is three to four hours after we do the warming. When we identify the re-expansion in grade one hour and at time of transfer as a slope, we found that the faster the embryo re-expands, the higher the life-birth, which is not novel. It's expected.

But the interesting part, we found that there is significant association between the post-biopsy re-expansion in grade and post-warming re-expansion in grade. So, again, we have a marker that can predict which embryos will re-expand more after warming if you standardize the time to one hour post-biopsy and you utilize this information. I mean, you do the grading.

That's really interesting. So, tell me, what's next? I mean, where do you go from here? Well, as always, whenever we talk about morphology, standard way of assessing morphology, it's very subjective. So, there must be an intra- and inter-operator variation when it comes to assessing the expansion.

So, ideally, we should have studies designed in the future utilizing more objective tools, such as time-lapse. And maybe instead of measuring only expansion, yes or no, maybe we can even correlate the relative re-expansion. So, what is the size of the cavity now compared to a time of freezing? Of course, these require tools such as time-lapse technology.

And but I think it's feasible. It can be done. And hopefully, we will collaborate with someone.

We will do it ourselves to be able to really demonstrate this in a more objective design. So, you proposed actually calculating data of the time-lapse with the expansion prior to freezing and after thawing to predict liberate. Yes.

So, and actually, you're telling me that you're going to do it anyway. Yes. Okay.

That's great news. So, when is your talk going to happen in Mexico? So, tomorrow, Tuesday at 10.30. Okay. So, thank you very much.

And I wish you good luck for the talk. And thank you for your research. Thank you.

Thank you for having me. Thank you very much. Thank you.

All right. Welcome to our listeners for Fertility and Sterility on Air. This is Micah Hill, the media editor.

And we have a couple of great guests with us right now. We have Nick Macklon, Professor McClung, the editor-in-chief of RBMO. And we have our own editor-in-chief, Kurt Barnhart from Fertility and Sterility.

Welcome, both of you. It's great to be here. Thank you.

Nick, thank you very much for joining us. It's a pleasure. So, we have a couple of things that we wanted to pick Nick's mind and Kurt's mind about.

So, Nick, first, we just did an ESHRE Journal Club Live on add-ons. And I just was curious about some of your thoughts and some of the things you said in that. And I'll just start with this thought, that the term add-on in itself is sort of pejorative.

Because if we say it's an add-on, by definition, it almost doesn't have enough evidence. And so, once it has enough evidence, like exceed for severe male factor, then it's no longer an add-on. So, how do you sort of think about add-ons from the standpoint of our practice overall and how we approach the patient? Well, you know, we've been using, as you say, this pejorative term add-ons forever in medicine.

There's always been aspects of our practice where, for an individual patient, we think they might be helpful, but for which the evidence base in all patients is weak. That's part of clinical medicine, is managing that uncertainty. And I think where the add-ons concept has been helpful, it's helped us define a group of interventions or tests which are widely used and which are often charged for, for which the evidence base is known to be weak as a general use.

And I think this document that's been produced by Escher has been quite helpful in just laying out the evidence base for each of these. And that can be helpful for us in the way in which we communicate with patients when we're giving them advice whether or not to use it. The other important thing, I think, about the document we were discussing this morning, it's not in any way a tutorial.

It's not waving a finger at people. It understands that clinical medicine is sometimes gray. It's not black and white.

And it's the context which we treat people is just as important as the intervention. And we have to take that into account too. Yeah.

One of the most difficult aspects when you're looking at a journal perspective on add-ons is you have to practice something first to show you something works. Yet often the first case reports or the first report you get are overly optimistic. So it's really a challenge to decide when the evidence is turned to where something is positive or when something is ineffective because we're never going to get randomized trials of all of these kinds.

Yeah. No, I think that's true. And I think that that is where groups like SRA and ASRM have an important role to guide clinicians and embryologists in that gray area when it hasn't sort of turned definitely one way or the other.

I think there have been problems with perhaps prematurely writing off certain interventions because in a particular study, it didn't show to be effective. And I think we've got to be cautious about that because we're still not very good at identifying, understanding the causes of reproductive failure. And therefore, if we're using interventions empirically, we might be doing harm in one patient, good in the other.

But if we put them all into one big pile for a study, it's always going to be negative. And I think we're just going to be aware of that. Again, that is a challenge.

We're looking for novelty to publish in our respective journals. But we have to guard against the overly optimistic or bias of only having positive trials. Yeah, sure.

So we encourage people to do this with rigorous study methodologies. And again, it's not always going to be randomized. And then that's what the purpose of a journal is, to sort out what's good evidence and what's not evidence.

And then you can consolidate that information into guidelines. I think you're spot on there. And one of the other values of this discussion about add-ons is it's probably made negative trials more publishable because the narrative is more critical anyway.

And if a good study comes to me at RBMO, which is negative for an add-on, I'm just likely to accept it as if it was positive. In fact, I'm probably more skeptical of the positive study than I am of the negative, to be honest. There's almost a reverse bias risk.

That's what I've been saying. The skepticism of the positive study, it has to be in our minds all the time. Some of these studies are going to be published because we have to disseminate the information.

But that's why the readers are so important, to be able to distinguish when is this the first study that needs to be corroborated or whether there is actually a bank of evidence that's supporting something. Yeah. I mean, we often talk about IVF as an add-on because if you look at the randomized control trials for IVF, they're very thin.

And there are many aspects of our practice which we have just grown into the mainstream, which when you actually look at the data to support them, it's not there for randomized control trials. But it doesn't always need to be there, as we've discussed. There might be a biological rationale that's incredibly compelling, in which case the burden of proof is that it wouldn't work rather than it would.

And I suppose ICSI is the prime example of that. I think the important thing is we come to it open-minded. We don't come to it with a prejudice against add-ons or indeed for them.

And we remember that I think the vast majority of clinicians who will be listening to this and who read our journals, they are driven genuinely to do the right thing for their patients. And I think that sometimes is missing from the discussion. So that brings us to a good segue.

So we mentioned integrity in trials. And yesterday, there was a meeting that you were both at with leading editors from multiple journals that were there. So tell us sort of the state of our field from the journals in reproductive medicine when it comes to the issue of integrity in the trials and in the studies that are being done.

I think you can look at it in two ways. First of all, the issue that some of the research in our literature is not genuine or is biased shouldn't be a shock to us. And I also want to say it doesn't seem to be higher in our literature than in other medical disciplines.

But we are uncovering that a lot more than I would like of the research in our literature in general. In some cases, it's fabricated. In some cases, it's false.

And in some cases, it's just under-emphasized. And we have to be very careful on weeding that out. We've had whistleblowers in our group that have brought the trial to our attention in many journals.

And we're sifting through those. And you probably will notice that some papers are retracted. And some papers are actually issued a letter of concern.

And that will continue. And I hope people are recognizing that. But I don't think that's a bad thing.

But I'm curious. No, I mean, I think it's really important, the work that's been done by whistleblowers to bring this to everyone's attention. Because I agree with everything you said.

But I also believe that that effort by them has made people more wary of playing in a game. Because they know that people are going to be after them. Whereas not so long ago, the chance of you ever being found out was very, very little.

So I think we're in a period of time where, yes, the challenges are very great with all the AI available to help fabricate data. It's being done very professionally. And we are going to be in a bit of what we've called sometimes an AI arms race between the journals and those who would wish to fraud.

But the fact that we're on it, and they know we're on it, I think is hopefully going to be helpful and weigh the advantages back to us in time. To bring it back to the add-ons, I think some of the most susceptible issues are randomized trials by groups that come out very quickly after the topic gets hot. And they end up to be me-too trials.

In my population, I showed the same difference for add-on X to be a benefit. And we find out that trial never happened, or it was really not randomly. So that, again, tells us that we have to be careful with the hot topics, because that's where I think they're most prone to somebody trying to jump into the game, so to speak.

Well, one thing I'd like to ask you, because we have this discussion at RBMO, is how far do we rely on peer review to detect this issue? One of the ways that we decided to do it, and it was actually Bob Edwards who founded the journal that built this in, is after acceptance, provisional acceptance of a paper by peer reviewers, it then goes through a scientific editing, which is not just around about proofreading. It's actually looking more closely at the data and how it's presented. And it's a slight problem, because it means we get a delay sometimes after acceptance before final publication.

But we've decided to keep doing that. And one of the reasons is that our professional scientific editors really have the time to go and look at these papers very closely, not only to improve them, which they do in most cases, but to just pick up the signs, you know, like the table with replicate data or the figure that's upside down on page two. That might be missed by a busy peer reviewer.

And I was just wondering how you do that. I think we use different vocabulary, but we have a similar process. So a paper is certainly first reviewed by a peer, and then any paper that looks like it's going to be accepted in our journal, that's a methodological review.

Yeah. So we have a small group of methodologists, statisticians that look at a paper from a more scientific point of view. Yeah, yeah.

I sometimes get very discrepant answers where the methodologist likes it, but the clinician doesn't, or the clinician likes it, but the methodologist doesn't. And that's what makes my job fun. Yeah.

But it is a higher rigorous process that everyone survives. Yeah, yeah, yeah, yeah. No, that's great.

No, I think, you know, AI, chat GPT we were talking about yesterday together, it does present challenges to us, but I think it's also going to have advantages for publishing. It's going to shorten the time that authors take to write reasonable text. But in the end, they've got to make sure that they take full responsibility for the content.

And we've got to be very strict, and frankly, ruthless when we uncover attempts at fraud. To be clear, I think the consensus for most of our jobs now is that things like, you know, learning language, AI, to help somebody write a paper, if they don't mind that it helps them work with their English, or helps them make concise language, but AI cannot be used to generate data, generate references to generate data. Or interpret data.

No, no. That's great. So to stay with AI for the last question, obviously, there's a lot of research going on in AI.

We're here in the vendor hall at ESHRE. There's dozens of companies using AI to try to improve ART and other aspects of fertility care. How do you as editors look when you're getting dozens of submissions? Oh, this is my AI.

It predicts this better than an embryologist. And how do you evaluate literature and AI critically? Because I hear people that are all the way from skeptics saying it's not any better than our embryologists, to people that this is going to revolutionize our field in five years. How do you interpret that literature? How do you look at papers as it's coming in? Well, I personally think that you bring the same process of scientific rigor to those papers we do to others.

In other words, what is the claim being made? And does the data support the claims being made? Where it runs into problems, I believe, and has done, is that the claims have been far too strong. And what's usually missing, and still missing for most of the papers that we see, at least, is any validation, external validation of this. Because they will use a training set of data to generate an algorithm, which in that data set, of course, works, because it has changed.

And maybe they'll run it on another group that was generated or drawn from the same population. Well, that's great. But that is probably not going to work in any other setting.

So we need to apply that rigor and really be looking for validation. And the second point I think we're probably both concerned about is most of these AI techniques are purely about pattern recognition and not really understanding the biological rationale behind it. And that's a huge limitation and a challenge for us.

I think we agree. And I think this is, again, a slightly different language. If you re-approach the papers the same way with anything else, it has to have a hypothesis.

You have to know what the methods are. It can't be a black box that says they're doing this. And most importantly, while maybe the first time someone sees a paper, it's not valid.

It's no longer a finding that AI can predict. Tell me that the prediction is going to work for everybody or a generalized one without any sequencing. Fantastic.

Well, thank you both for coming on and talking to our audience today. It's great. And what I hope for all our residents and fellows interested in being researchers that you heard from two editors-in-chiefs, negative trials have an important role and are not less likely to be published.

And I think that's very important. Absolutely. Thank you.

Thank you. Great to see you. Yeah, thanks a lot.

So hello, everyone. My name is Paul Pirtea. I'm an Interactive Associate for Fertility and Stability.

And now I am myself here in ESHRE, the International Meeting for Human Reproduction with Danilo Cimadomo from Italy, who actually just finished presenting a very interesting research. And he's here with us to tell us all about it. Danilo, happy to have you here.

Honored, actually. Tell me, what was your idea and how did you come across it? Thanks, Paul, for having us and for choosing this topic and our study for this podcast. So we were considering the possibility of doing rescue IBM clinically in our centers, which is something that is not considered standard practice and we are still not doing.

This is very fashionable. It is, it is, because you know, we're mostly treating patients that are advanced maternal age. They have a limited number of eggs and many of them sometimes can be immature.

So we were considering the opportunity to rescue them for clinical use, but we need to establish some like statistically sound criteria that we can adopt to this end. And the whole study was designed to this end. How did you how did you design this study? Because I mean, I have noticed recently many papers on the same topic, rescue IVF.

It seems that there are many different details that need to be addressed. So how did you design your study to correctly answer this question? Yeah, that's true. I mean, for years people were not doing this, but now ASHRAE and Alpha with the Istanbul consensus revision, they're coming up with the idea that perhaps we can consider it for poor prognosis patients.

But we don't really have any good practice recommendation or guidelines because for years it has not been done. While just some centers were doing it without publishing on it. So little by little, the evidence were piling up that embryos deriving from these rescued oocytes can make blastocysts.

They can be as employed as sibling M2s and they can even implant. So at the end, you can get baby born out of these oocytes. So I think that we need criteria now to understand which patients may benefit from it, which patient might not benefit from it, whether it is cost effective or not, because the workload obviously is increased if you do that.

So the whole idea of the study was to go through retrospectively our data set from 2008 to 2022 and look for, first of all, what was the weighted average immaturity rate across our patients. It is around 20%, which means that every 5X, one is immature. And then we did a super analysis among first oocytes retrieval of patients with at least 5X because you need at least 5 to have one.

And in that data set, we were looking for confounders. So what are the factors associated with immaturity rate? And it came up that the simulation, the length of the simulation, the trigger that you use, the time between trigger and the muting, these are all factors that are associated that you can act on that to reduce or increase, if you do it not properly, the risk of having immature eggs. If you puncture, for instance, follicles that are too small, there's a high risk that you can find immature eggs in that.

So after this whole analysis, at the end, we came up with what we call a warning limit beyond which perhaps might be reasonable to act during rescue. And that was found as the weighted average plus two standard deviations, like two for KPIs. And it turned out that 51% of immature eggs with at least 5, it's a reasonable criteria which maybe you can consider in doing something that is not still clinically validable, such as rescuing.

So now the idea is after piloting this study clinically, we would like to understand whether we can actually have benefits out of it, in which patient we can do it, if we can actually able to increase the cumulative life of rate by doing it. But we needed some statistically sound criteria that we can rely on. Okay.

So in your point of view, these findings, did they change the way you see things forward in your clinics or not? Yeah, for sure. So now we know that, again, by looking at retrospective data, and I'm talking about 16,000 pickups over 8,000 patients, you know, it turned out that 4% of our patients will have at least once 51% immature eggs. And across multiple pickups, 1% of the patients.

In my view, that's reasonable, because you can start applying it clinically. And if you have it multiple times, you can even candidate these patients for all-exome screening testing, for instance, to understand whether they have mutations in genes associated with maturation. And you would advise this for any age, group of age? Yeah, because actually age didn't turn out as a significant confounder on it.

So the immaturity rate doesn't seem to be dependent on age. Okay. And did you already build up on a prospective trial to clinically validate this data, or is it still ongoing? You know, we're part of a network, like a large network of several IVF clinics worldwide, IVRMA.

So the idea now is to come up with this study, hopefully publish this study, and then come up with this idea that we can discuss with our medical affairs department and make it like some sort of guideline. And in this way, in a few years, I think we can collect a lot of data on the real clinical value of applying this clinically. And then together with Juno, Antonio Capaldo, the idea is then that we can candidate these outlier patients, let's say, if you like, of immaturity rate for exome screening, looking for mutation in certain genes.

And he already did some sort of pilot study with Semra Karaman in Istanbul on that same road. And they found some mutations that were common in patients with this kind of frequent or high risk of immaturity rates of genes that are related with the subcortical maternal complex. So, you know, in the future perspective, you can even have come up with a panel of predisposition to infertility across young women.

Are you aware there's a fertility 3D paper like AIDS deliveries after IVF rescue? What's your opinion? Is your would you use the same methods or you think differently? I mean, that's up for discussion. And one of the conclusions of my presentation today was indeed that one. We need to understand how to do it, to which patients to do it, with protocol, which culture media, you know, this kind of thing.

So the fact that there is, again, a lot of international scientific attention on this topic, that means that there is margin for improvement. And I think that as a scientific community worldwide, not only us as a group, but as a scientific community, we need to start talking again about this and come up with papers like the ones you just mentioned. So just report your data if it's something that you're doing or you have been doing across the last years.

OK, well, thank you. Thank you very much for all the research you do for us. And thank you for participating.

Thanks for having me. All right. We are here on day two at ESHRE and we are live on the fertility and sterility on air podcast.

And we just had a physician, Elizabeth Glanville from New Zealand, come by. She's one of our thousands of listeners around the globe. Elizabeth, thank you for being a listener to the FNS on air podcast.

Well, thank you, because you've really helped and supported me through my last few years of my training in New Zealand as an REI specialist, subspecialist. That's wonderful. We're so glad that people actually listen to what we talk about.

And it's great to get to meet people from our international audience. So have you been to ESHRE before? No. It's your first meeting.

It's my first time here as well. Yeah, yeah, yeah. I'm really grateful to be here.

Yeah, my first visit. And not just because it's in Amsterdam, which is an amazing city, but it just sort of fit perfectly with the school holidays in New Zealand. So I can bring my kids and go home and see my family in the UK.

So your kids are here with you as well. They are. Lovely.

Yeah, yeah. So you're making a little holiday out of it. Yeah, absolutely.

Yeah, we've got a few weeks ahead of us. So we're excited. And so we were just talking, you said you just came from a session with Molly Moravec from Michigan, and she was talking about transgender care here at ESHRE.

Yeah, that's right. And that was one of the things I was looking forward to hearing more about. And I guess I was hoping for some big earth shattering conclusions.

But I guess reassuring to know that from her amazing research on mainly on mice at this stage, looking at the testosterone effects on the ovaries, we're still not really sure what the long term outcomes are for ovarian reserve and also IVF stimulation outcomes. But I've found that personally, recently I've seen more and more transgender patients, and it's really hard to inform those patients. But I feel reassured to know that telling them the right thing at this stage, which is that nobody really knows the long term outcomes, but hopefully there'll be more research in the future.

And I think one of her key messages was that there weren't there aren't many publications at this stage. I think she said there were 328 publications in the literature on transgender care and fertility. And so I think one of the one of the key messages is that everyone should contribute towards that.

And that's something that I'm looking to take home. Good. That's outstanding.

So you're doing a fair amount of transgender care then in New Zealand. Yeah, a reasonable amount and definitely more and more over time. So, you know, people come to us and expect us to be the authority on this.

Of course, that's our job. So I really wanted to be informed today. And I feel I feel well informed, but as well as anyone is.

Yeah, well, Molly's obviously an expert on it. She just chaired the ASRM practice committee practice document on transgender care, which doesn't make a recommendation to stop testosterone prior to IVF because we just don't have data on it that it benefits the patients. And obviously, there's dysphoria and a lot of mental health issues that those patients go through.

If you make them withdraw from testosterone for three months just in order to do an egg retrieval. So I think in the absence of data, not having a strong recommendation made a lot of sense. Absolutely.

Absolutely. And she was an amazing speaker. Very, very clear with her recommendations and really interesting research.

So I really enjoyed it a lot. Well, thank you for listening to the podcast. And thank you for coming on and talking to our audience.

It was a pleasure to meet you today. Thanks very much, Micah. We are back live from Fertility and Sterility on air at ESHRE.

And we have Raoul Orvieto from Israel. He had an interesting debate that took place here at ESHRE on double trigger and dual trigger. And so we invited him here because we thought this was an interesting topic.

And so Raoul, tell us about the debate and what you think about it. You obviously took one of the sides in this debate. The pro side, yes.

So actually, we are speaking about dual and double trigger. It means that we are triggering final follicular maturation with both GNRH agonists and the ACG. At the advantage of this combination, and you actually trigger with LH, FSH, and ACG.

Now, if you're looking, let's say, on the LH receptor, while activating the LH receptor, activating a lot of downstream cascades, it's possible to run a humerus expansion, oocyte maturation, encephalogenesis, et cetera. When LH activates the receptor, it activates this downstream cascade differently than ACG. Right.

The group of Emanuela Simoni showed, Casarini showed that when LH, they use the ganulose culture. So when they added LH to the culture or ACG to the culture, so LH activates more intensively the cascade responsible for oocyte maturation and ACG, those responsible for steroidogenesis. Okay.

Repeat the same study design and we add ACG, LH, and FSH, and LH, FSH, and ACG, and we look at genes. Again, genes related to steroidogenesis and oocyte maturation. Right.

The highest expression was when you combined all the three. The lowest when you add ACG. Just ACG alone.

Just ACG. Okay. When you are looking at studies that, let's say RCTs that compared ACG trigger to GNOH trigger, and you look at the biological parameter, the biological parameters are same or better invented using GNOH agonists.

Right, right. Our problem with GNOH agonists is the receptivity. Luteolysis, not luteolysis, I don't know what, but the pregnancy rate is lower if you are doing agonists without ACG, even if we will give this intense support.

In our end, agonist trigger with intense support, no matter what you are doing, no matter what you are giving this patient, if you're not giving ACG, your ongoing pregnancy is 15%. Okay. You're giving ACG, it goes up to 40.

Right. So if these three hormones are doing differently, probably some patient may benefit from one of these triggers than the other. So why not to combine them? Right.

So, and this was actually the first one who published the paper on, and call it dual trigger was Shapiro. Right. Shapiro, in the old days, when they gave agonist trigger to patient to avoid OHSS, they saw that there is suboptimal response to generate agonist.

We'll be talking about this too. So they added a tiny dose of ACG, let's say 1000 units. So the pregnancy rate was actually restored.

Right. The same. And the risk of OHSS was about 1%, and not 20, 25% as you expect if you give a full dose ACG.

So this was the first report on dual trigger. They call it dual trigger. Right.

And then a study of Flynn and many other studies start to appear in the literature combining a full dose of ACG and GNRH agonist to normal responder, not high responder. Right. And actually there is a lot of evidence, papers showing that if you are combining GNOH agonist, meaning LH and FSH, and ACG, and you compare it to ACG alone, so all the biological parameters are improved.

Right. We had this study published in 2020 in a human reproduction update. The study was an Israeli-Canadian study.

My fellow went to Casper group and we checked. 16 and some patient, normal responder, young girl, the 41 years old, up to the third IVF cycle attempt, randomized to ACG plus placebo and ACG plus agonist. All the baseline characteristics and then the ovarian stimulation parameters were the same.

The only difference was the trigger and all the biological parameters were improved. More oocyte, more mature oocyte, more top quality embryo, more blastocyst, more top quality blastocyst, more pregnant live birth rate. So in normal responder, actually nowadays, and not nowadays, but for the last, let's say five, seven years, we are using the dual trigger.

Get full dose of ACG, full dose of 0.2 milligram of tryptophan, and I suppose it's like 0.5 or 0.3, no, one or four, I will treat you with Lupron. With Lupron? Lupron. Yeah, it depends on who's doing it, but we do 2 milligrams.

So 2 milligrams Lupron and the ACG, 5,000, we have the OB-GYN at 6,500. So it's enough. And if you're triggered, the normal responder with this trigger instead of ACG alone, you will see.

Try to do it for one month and ask your embryologist what's happened. They will tell you. They will ask you what's happened.

Yeah. The issue with dual trigger. There is an issue in dual trigger in poor responders.

You know, poor responders have another problem that went unnoticed with the Bologna Criterion. There is high prevalence of premature luteinization ovulation. Right.

So sometimes if you are dual triggering this patient, and later on, I will speak about double trigger or double trigger this patient, some of them will ovulate. Yeah. So in this subgroup of patients, you have to be to actually to tailor the trigger to this patient according to the stage or how do you find her at the end of the stimulation.

Right. From this patient, if I see her with a follicle of 89, then we'll give the dual trigger or the ACG trigger. Sometimes I will get the pickup and there is no follicle.

They ovulate. So in this case, it's usually we are giving the dual trigger, but we ask for 34 hours following the trigger. Yeah.

If she has a follicle of 17, 18, so 36. But if she has a follicle, you approach the end of the stimulation, follicle 13, 14. Yeah.

In this case, we are giving a double trigger and I will speak about it in a minute. Yeah. And the double trigger will yield a mature oocytes from the follicle of 12, 13, 14 millimeter in diameter.

Now let's move to the double trigger. What's the double trigger? So double trigger is actually, we saw this case report from Israel. Patient with a genuine empty follicle syndrome.

Seven cycle, in Israel we are doing a lot of cycle because it's a subset. Seven cycles, excellent hormonal response, excellent ultrasonographic response, different type of protocol, different type of trigger, zero oocytes. In the eighth cycle, antagonist protocol and they trigger her with agonist.

Neutron, two milligram, let's say, but it was like tryptophan. Right. 40 hours before pickup and 8CG full dose, 34 hours before pickup.

Okay. So they actually, by doing this, they have the advantage to combine, to prolong time between the trigger and stimulation, more time for maturation. Right.

More time for cumulus expansion, release of the oocytes. And also the LH, FSH and 8CG trigger. All the three hormones are there for triggering.

Okay. And of course she had a lot of oocytes, embryos and she conceived. Yeah.

So when we looked at this study, we said, okay, this is a nice case report. It's working on a patient with genuine empty follicles. Why not to use it in a patient with less severe form of abnormal final follicle maturation? Right.

Let's say a patient with low recovery rate. Patients that you're aspirating a lot of mature follicles, no oocytes. So you go to the ambulance, look again, look again, and call help.

Right. No, no. That's low recovery rate.

So in this case, we start to offer them the double trigger. We call it double trigger. Right.

This is now the double trigger. So 40 hours before pickup the agonist, 34 hours before pickup the 8CG. And you don't have people ovulate before retrieval at the 40 hours? No, because there are patients that already underwent one cycle with abnormal final follicle maturation.

They are not ovulating. They are not resuming. They are nothing.

So you're using this in a second cycle when the first person... Yes, yes. In patients with abnormal final, let's say lower recovery rate. So in this case, if you give the double trigger, 40, 34, excellent response, excellent bronchial parameter, a lot of mature oocytes from follicle, 12 or 13 millimeter in diameter and up.

Yeah. So you can actually retrieve follicle, mature follicle, a mature oocyte from smaller follicle. And of course, pregnancy.

And the other subgroup of abnormal final follicle maturation, this patient with high prevalence of immature oocyte, a lot of GB and M1. Right. Some of them are also PCOS patients.

So what do you do? Okay, you're using the old time to give more 8CG to extend the time to include the 8CG. The trigger and the... 40 to 34. You will have a lot of mature oocyte.

If it doesn't work, I'm extending it to 42, 36. Right. Even 44, 36.

Wow, okay. They are not ovulating. They have a problem with final follicle.

Right. It succeeds. So we have the double and the dual.

High responder, they're getting agonist trigger and free zone. Yep, yep. Normal responder, dual trigger.

Both of them 36 hours before pickup. With abnormal final follicle maturation, meaning those with low or high percentage of immature oocyte, the double trigger, 40 hours, 34 hours. And the poor responders, again, depends on which stage you meet them at the end of stimulation.

If they have large follicle, give the dual, because the dual is doing better to the follicle. Right. So you give the dual, but you have to do the pickup 34 hours before, otherwise they will ovulate.

This is the problem with those that start to use the dual-double. You know, I did it, but they ovulate. Okay.

Right. If she has a larger follicle, dual, but aspirate 34 hours before, 16, 17, you can give the dual 36 hours before. And if you meet her, you have 13, 14, give the double trigger.

Don't wait another day, because, you know, we know that when we are following this patient, so today she has a follicle of 14, you expect her to have a 16 millimeter the next day, and she's coming with 20. Right. Right.

And you see it a lot. This is the patient, or this is the problem with correspondence. So if you see 14, give the double trigger and schedule the pickup 40 hours before the first injection or 34 hours before the second.

Yeah. The double trigger sounds like a good tool to have in your arsenal. So you talked about LH and how it's really stimulating the genes for oocyte maturation, HCG, the enzymatic steroid pathway genes.

So explain to our listeners the role of the FSH. FSH is actually for more deformation of LH receptor and enhance cumulus expansion and oocyte maturation. So it actually, it aids the LH to do the work.

Right. Exactly. More in the LH.

This is why there is a study now that compared gene-harmonics to dual trigger. The biological parameters are the same. Okay.

But if you are giving agonist trigger, you can transfer it because the receptivity is lower. Right. So they show it in donor cycle that, okay, you can use the gene-harmonic agonist trigger.

The embryology parameter is excellent, but you can transfer it. So I'm actually recommending to add agonist to HCG, not to add HCG yesterday in the debate, but you know, you increase the risk of oocyte. I'm not.

I'm not giving more HCG. So these are inpatients you would give HCG to anyway. Anyway, add agonist to improve the embryology because agonist, agonist, when you are treating agonist with LH and FSH, the embryological parameter are improved.

Yeah. Either the same or better. That's it.

And everything is published. You can find it also in open access journal. That's fantastic.

Thank you, Raoul, for coming by. A lot of what I learned as a fellow about how follicles work and about gonadotropins is from your research. So it's a pleasure to get to talk to you and hear your perspective on it.

Thank you, sir. Thank you. I'm here in Amsterdam with Dr. Mansour from Stanford to discuss his research that was presented at this meeting as an oral presentation.

This oral presentation was entitled Domestic and Cross-Border Reproductive Care Among Same-Sex Male Intended Parents Comparing Live Birth Rates in a National Retrospective Cohort in the United States. Such important work. Thank you so much for being here, Dr. Mansour.

Tell us a little bit about your study. Yeah, thank you so much for having me. This study was actually initially intended to just look at same-sex relationships and their couples in the United States, which SART began collecting data on in 2017.

And we were surprised to find that 50% of the cycles were actually from international patients. So it kind of took a different direction. That's fascinating.

So when you found that those were international patients, tell me a little bit more about the distribution from where are these patients coming to pursue care? Yeah, so we actually found that it was a very diverse amount of countries. One of 23 different European countries were found, as well as countries from really all over the globe. Most commonly, patients were coming from China, France, Israel, Spain, and the UK.

And obviously, SART database can't necessarily answer these questions. But what do you think was the predominant reason that couples were pursuing this cross-border care? Yeah, so I mean, I think when we think about CBRC, we often think about people leaving the United States to get cheaper care. But there's actually a lot of regulatory reasons that people come to the United States, particularly those in the LGBT community where there may be restrictions that are either discriminatory or just they don't permit compensated egg donation or compensated GC cycles.

So a lot of people come to the United States in order to circumvent these local barriers or discriminatory practices. It's fascinating. So it varies so much across the globe where the United States is more or less progressive, but this might be one area where actually we're providing more options for family building.

So in terms of your overall findings, what to you is the main take-home message? What did you want to convey to readers and where do you want to go next in terms of researching this topic? Yeah, I mean, I think what this really highlights is that the health access barriers particularly for same-sex relationships are really intense. I mean, the cost in the United States for care is $100,000 to $200,000 per child, and there's really no guarantee with that fee. And so the alternative of doing cross-border care, even coming into the United States or going away, it's really a diverse flow of actors, many countries involved, couriers, shipment of gametes.

It's just a very convoluted process. And I think we need to do a better job to make the cost more affordable, not only for patients domestically, but for patients that are having to go through a lot of different barriers in order to build their families. Certainly.

So even though from a regulatory perspective, this is an option for many same-sex male couples, unfortunately, it's a rarefied group that actually can afford this care. And that's true for same-sex male couples in the United States and globally. Yeah, absolutely.

And so I think this is just an area that we really need to keep our tabs on. And then I also think there's just so few clinical studies on same-sex male relationships. So what we're really wanting to look into are what are the practices that we're finding in the SART database? How often are they using PGT, which really isn't necessary if we're using the young donor egg? How often are they using ICSI? How often are they doing double embryo transfers? What is the risk of multiple live birth? So these are just all things that really haven't been explored in this population.

And I'm excited for that to be my next steps. I'm excited for those next steps too. It's been a major priority for ASRM and SART to encourage practitioners to transfer embryos one at a time, especially to gestational carriers who are really doing this largely altruistically.

That said, because of what we just discussed with the high costs, there is so much motivation for couples using GCs to want to transfer too and to save money in that way. So it really is a difficult situation for clinicians, for counseling, but such an important one. Yeah.

And I'll kind of do a shameless plug here. Stay tuned at ASRM. We'll be presenting data on that very topic.

And what we're seeing is actually about a 22% double embryo transfer rate in this group. And really, you know, while there is no specific LGBTQ guidelines in a same-sex male relationship, that number should really approach zero. I agree a hundred percent.

And I'll give a shameless plug as well with my SART hat on that, you know, SART's guidelines have become more and more stringent in terms of clinics that do have high rates of multiple embryo transfer to gestational carriers. And so we hope that, you know, by encouraging best practices, we can also protect the health of gestational carriers. Thank you so much for being here with us, Dr. Monseur.

And this is amazing work. And we look forward to hearing more about what you're doing. Thanks so much for having me.

This concludes our episode of Fertility and Sterility On Air, brought to you by the Fertility and Sterility family of journals in conjunction with the American Society for Reproductive Medicine. 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.

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