Hello world, we are live in Chicago at the Midwest Reproductive Symposium International 2023 and today we are very excited to have a distinguished faculty panel that will be discussing an amazing hot topic in the world of fertility. I would like to introduce Dr. Pietro Bortoletto who is a reproductive endocrinologist, director of reproductive surgery and co-director of oncofertility at Boston IVF and as you all know he helps lead these live fertility and sterility journal clubs and without further ado. Thank you Dr. Baltzos and thanks to all of you for being here and our live audience live from the 2023 Midwestern Reproductive Symposium meeting and welcome to everyone joining globally to this live event.
I'm Pietro Bortoletto, I'm the interactive associate in chief for fertility, sterility and the media editor for FNS reports. I'm so delighted to be here with a group of friends and experts on the topic of in vitro maturation. The title of today's talk is is IVM ready for prime time? There's a great trio of articles that fertility and sterility published earlier this year under the views and review section that if you haven't read I highly suggest you check out but it really marched through the idea of what are the outcomes with IVM? What is IVM? Who stands to benefit from IVM? Something that I think a lot of us in the live audience and a lot of us international audience have heard about but maybe don't have a ton of experience with so we're hoping to really dig into that but as many of you know IVM is not new.
It was done in rabbits in the 30s, it was done in humans in the 40s and the great Bob Edwards actually did it in the 60s but it really wasn't until 2021 that the ASRM removed the experimental label from it and it's now a whole three years later and we're here to talk a little bit about how does this fit into modern ART practice? I want to start by introducing our panel. On my left on the con side of today's argument I have Dr. Victoria Jiang who's now a rising third year fellow at the Massachusetts General REI Fellowship Program. I have Dr. Jared Robbins CEO of the ASRM and on the pro side I have Dr. Luis Hoyos who's a REI in private practice at IVF Florida and then Dr. Scott Nelson who has my old job the chair of OBGYN at the University of Glasgow.
Panelists welcome so to today's event. The format for today is going to be opening remarks. We're going to have 30 to 60 seconds each of people on both sides of the argument introducing their general thesis for why they're for or against and then we're hoping to have a lively debate.
There will be an opportunity for questions from the audience and from our live audience on the internet but let's go ahead and get started. I'm going to give the con side the first opportunity to share a little bit about why they are against IVM. Con side, have at it.
Okay a lot of pressure really starting off this heated debate today. Thank you to MRSI as well as FNS for allowing me to participate in this debate. I think that the major cons that we have to be aware of and why we haven't been using IVM is because it's just an imperfect technique right now and with the efficiencies of IVF that we have currently we've been incrementally increasing our success rates having really kind of reproducible pregnancy rates among clinics and having really efficient culture systems within our labs.
Do we really want to introduce another area where we can introduce errors not allow for streamlined of our processes, increase the workload among our embryologists for an imperfect and what still will be an expensive process for our patients. So many times we think about in non-mandated states like my home state of Georgia when we're thinking about do we really want to go through several cycles of IUI before we proceed to IVF or should we save six thousand ten thousand dollars so that we can ultimately achieve that pregnancy for you through our most efficient process that we have studied very intensely. And I think that ultimately we have to really decide what are we going to have our patients go through before we can ultimately you know prioritize that pregnancy.
The other thing that I think is really challenging with IVM is is that IVM it can be defined in a lot of different ways. So how are you exactly defining IVM? Is it from the germinal vesicle that you are getting from those small antral follicles and then maturing throughout the actual culture system? Is it going to be you know M1s that you're trying to get to M2s like through the after retrieval? And so there's a lot of non-standardization that we have present and we need to make sure that we do this responsibly and I just do not believe that we are in that prime time now. All right Proside we heard a lot of cons there.
Luis tell us why you're for IVM. So I think that first of all like Dr. Yang was saying we need to be talking the same language right. So what is in vitro maturation? Plus or minus FSH plus or minus ACG with the idea of retrieving oocytes from smaller follicles right.
Why are we talking about rescue in vitro maturation which is in a traditional IVF cycle retrieving the oocytes and those that are immature basically culturing you know after a couple hours or overnight to see they become mature right. So both these techniques have different utilizations and I would say that most of us are actually using some type of rescue IVM at least right. So and rescue IVM in and of itself we know that it can increase pregnancy rates by around five percent so any percentage is good and in addition to that there's a recent published article well this is going to be published probably in the next couple months or if it is that has shown that it can increase the number of blastocysts by around 0.5 right.
Any number of blastocysts that we can use is getting our patients one step closer to getting pregnant okay. So for me the rescue IVM is a no-brainer right. Now if we're talking about the other type of IVM it has several advantages that we can exploit.
All this conference we've been talking about increasing access to care. I mean yesterday they were giving examples of couples driving six hours and then staying at an RV for around two weeks just for the process. How much simpler can it be if we for specific for certain types of patients if we can just tell them show up on this date we'll do your retrieval without any type of medications or anything and then we just do IVM we'll let you know when you need to come back for the transfer okay.
So there is some potential here that we need to explode right. Now having said that I think that we need to do IVM for some but not for all. Jared I'm hearing that 0.5 extra blastocysts may be the goal of IVM.
Your arguments. All right so I was involved in the early clinical IVM development back in the early 2000s to mid 2000s and we practiced in a very different time. You know we didn't have antagonist trigger.
We would stimulate PCOS patients and then we would coast them for three days and then we would stimulate them again. Severe hypersimulation syndrome was something that our fellows learned how to take care of. The fellows don't have never seen severe hypersimulation syndrome anymore and so there was a clear need to improve safety of IVF particularly in those high responder patients and that just doesn't exist anymore.
I think that there's you know there's potential of increasing a blastocyst with rescue IVM. I'm not saying I don't want to make the argument the con argument that there's no utility utilization for IVM but I think is it ready for primetime. I just don't think the data is there.
Earlier and during the MRSI conference we heard Dr. Arredondo present a formula for value which is value equals quality over cost and one can make an argument that you are preventing value with IVM by reducing cost but I think during this debate we're going to argue that you actually don't reduce cost. You reduce value. You reduce quality without significantly reducing cost.
In terms of access to care and again I think this is something that will an argument that we'll make during this debate. I don't think you're significantly improving access to care and particularly as was mentioned earlier in today's era where we're struggling to staff our labs to you're actually significantly going to decrease access to care by introducing a procedure that are already over task labs can't handle. It's probably worth mentioning that I've asked this panel to be randomly assigned to sides of the argument that they may not necessarily agree with.
So some people are doing mental gymnastics here but I want to give the last opening segment here to Dr. Scott Nelson to then go into a back and forth debate about some of the arguments raised in these opening remarks. Yeah there's no question about how many how much of the mental gymnastics I'm having to do here. So I guess the question is what's prime time yeah and what does that actually mean in terms of the context of this debate.
What we realized was that this was a technique that was described back in 1935 and in 2021 ASRM 86 years later decided that this was no longer an experimental technique. So ASRM already decided that you know it's not experimental and it is ready for prime time and then that's what I think what we're really going to spend the next you know few minutes discussing is who should we be doing it from and what are the potential advantages because there's going to be a super select group I think for the reasons that Gerda just said when this was developed it was in the context of you know agonists and OHSS the kind of you know iatrogenic risks and complications from IVF. The reality is that now in the era of antagonists and agonist triggers we can do say IVF infinitely safer and I think that's kind of where we you know we think where's the role for IVM and who can we benefit from I think we probably should spend some time diving into that.
I think it's important to clarify and I may be wrong about this but I but the I don't think the ASRM actually I don't think it's a it's a it's proper to to classify that the ASRM says it's not experimental. I think what the ASRM did I think that the current practice opinion didn't say it was experimental but I don't think the absence of saying it's it didn't it didn't that practice committee doesn't say IVM is no longer experimental. All it did was leave out the previous line that says it was experimental.
It did in that practice committee which wasn't among the papers that we were asked to read but it did in that practice committee mention a number of things including the fact that we still don't even that we don't understand the potential and epigenetic impacts of IVM on the embryo and that this continues to need to be studied. So I don't think the lack of stating that it's experimental is the same as stating it's no longer experimental. You know I read that committee opinion today and it did say it's no longer experimental and I respect ASRM a lot.
So whatever my society whatever my society whatever I don't know about you Dr. Robbins but whatever ASRM tells me I will follow. I hope you've got some respect for its chief executive as well. Well one of the things that both sides talked about is there's probably some patients that stand to benefit from IVM.
Some stand to benefit a bit more. I hope the pro side will tell me a little bit who do you think is the perfect IVM candidate? Everyone? Patients with PCOS, the oncofertility patient, who is the IVM the prototypical IVM patient? So I think it's going to be these new fields that are essentially kind of where IVM is going to be taking off because the OHSS you can look at in terms of if they've got PCOS for example with now with antagonists and agonist triggers you can get really high success rates with really safe you know outcomes and there's no question that that's achievable and looking at you know you can look at the first transfer from the Lancet trial you had kind of in those high responders you've got you know live birth from that first transfer at 50 odd percent. So whenever we look and we can come on to the systematic review we're substantially less than that for sure.
So I think that population can be served in other ways. There is a group of women who were the treatment burden to them was so high that they experienced OHSS in the past and they will no longer consider giving gonadotrophins to themselves. They're a fundamental fear and perhaps there's a role for those people because we will not be able to convince them even with psychiatric colleagues and input and so on because they'll be so concerned about that.
So I think it's then thinking about you know fertility preservation and the population where we've got ovaries or parts of ovaries stored I think that's a big population for going forward where there's a really limited amount of you know primordial follicles with that you think of menopausal women I probably still got about a thousand you know follicles left within them and can we harness them or can we take young girls where they've had it from pubertal you know oophorectomy tissues and that thinking again about their long term fertility preservation can we do something with them. I think that's the biggest populations where IVM will absolutely have a role to play going forward. I do a bit of oncofertility in my practice.
Those patients have one shot sometimes at prior preserving tissues for the future. Is IVM the best option that they have when they're thinking about their one shot? You know what I would say is I think that IVM can also create a lot of false hope in these patients and so there are clinics that are offering freeze all stages of eggs with the hope that we'd be able to have technology in the future to be able to mature these eggs and give them additional eggs and so I think optimizing maximizing the number of cryopreserved eggs in these kinds of situations always the goal but if you're stripping the cumulus complex from these GVs and these M1s how can we even guarantee that there's going to be any chance that these eggs will be able to be able to be you know matured in the future and I think the other concept is that when you're thinking about storage fees and the ethics of being able to store and keep these eggs for patients when they come back and they come in you know thaw these eggs to be able to be fertilized how are you going to be ethically continuing to charge them fees when you have M1s and these GVs that are sitting there that we do not currently have that technology quite yet. I think it can create a lot of false hope for patients in a way that we do not have a good standardized form of being able to mature these eggs reliably and if you have it in 10, 15, 20 years who knows when it's going to come.
So I think that again Dr. Yang is referring to rescue in vitro maturation in a sense and you know I do not see this advantage if the patient already has so many tools it's not like they're being charged for that extra M1 that it was frozen so I don't think from an economic perspective there's any damage to that. Now I would like to go back to Dr. Bortoletto's question in terms of oncofertility is this something that we can actually use? I would say that in certain situations it is. I mean we know that for our breast cancer patients a traditional cycle a delay of around two weeks doesn't really impact survival but even though that's the type of cancer that we see the most it is not the only type of cancer we see.
Lymphomas, leukemias those women are really sick you know and sometimes we do not have two weeks so in vitro maturation will be perfect for them. Brain tumors what if the patient has a greater vein reserve and I cannot use a lupron trigger? Am I going to make her sicker? In vitro maturation also perfect for this type of women. There's some other categories of people that have been suggested that may stand to benefit from IVM.
Poor responding patients. Do you think that there's a role for using IVM in patients who you know up front that you're going to get a small amount of eggs and why put them through 300 units of Gonal F and 300 units of Menopur for 14 days to get one or two eggs? I do not think there's a role in diminishing vein reserve patients. No I think that's absolutely correct.
So I think if we just go back to on comfortility for a minute so we realize that you can do superovulation you can do air site freezing that's a classic pathway that all of us do but what we're talking about is can you do additive therapies for those people I think is really what I was suggesting whereby can we do that two weeks and then we realize that we can also do kind of store some ovarian tissue because although there's a linear association between number of eggs in the freezer and the future chances of live birth can we then once that's done perhaps they're not going to have opportunities in the future so it's can we add to that so we can can we add to the probability that they will have the family in the future and I think that's where we see this be the case because IVM if you're thinking it's just kind of from small pre-antral follicles which we might be able to see in ultrasound but we may not be able to see in ultrasound that's where it's really going to have a role I think it's there's the classic examples that Luisa just said are in acutely unwell and we don't have you know even 48 hours we've got to go that day and the options are we either do a laparoscopy and try and preserve some tissue but they might not be well enough to be able to you know cope with that and so that's where as you say a transvaginal egg retrieval into some small follicles might be gives them at least some hope for the future because you don't have that but really what I think what there's going to be an explosion of is actually the synergistic approaches of it and you think of Denmark there's a huge number of women who've been you know freezing their ovaries in terms of that and are they keeping them just for to prevent HRT in the future or are they thinking about you know family planning and I think there's going to be a combination of both of those you know kind of going forward and that's why I think it's synergistic so yeah so I think you're um you're making an argument for us um because the question is is it ready for prime time and I do think that um when we look at data from patients again I think the leukemia patients is a perfect example because you need to do um you know induction therapy within 24 hours of diagnosis they are very sick patients um they're typically um have uh the thrombocytopenic you know where you know I think that um we want to do we want to do something very definitive in that patient population and um there's a lot more data on ovarian tissue cryopreservation than there is on um on IVM in this patient population um and so so yeah maybe IVM is an option for these patients but that but is that prime time like is I think that that's the argument that um while we want to have as many um tools in our tool shed for this patient population that is um that that is a clear potential but not a prime time potential. What is the name of that thing that you do after you do ovarian tissue cryopreservation and you're ready to use them? But is that prime time? IVM right? No no I think it's actually um um ovarian tissue graft with re-implantation it's actually where the babies have been born so IVM is definitely something we would we will hope to be able to do without re-implanting that tissue but that's but prime time is actually ovarian tissue re-implantation. Let's talk a minute about the actual nuts and bolts of doing IVM.
We've been talking a little bit about who the patients are that stand to benefit. Retrieving eggs. It's hard to retrieve big eggs or big follicles it's hard to retrieve medium-sized follicles.
Procyte how hard is it to retrieve follicles that are six seven eight nine millimeters in size? So I think it's infinitely easier from a stimulated ovary you know because reality is we put a needle into every follicle you can see and you drain it and you let the lab worry about whether or not that's mature. I think of this you know the panel actually we accept that if you're going to put it into an unstimulated ovary that's infinitely harder to do and you know Jared's done a lot of these in the past so perhaps Jared will be able to comment on his experience of doing these. We'll allow you to put on your pro hat for a second.
How hard is it to retrieve eggs from an unstimulated ovary? I think it's a skill set like anything else. I think that once you learn that we're using smaller needles you know it's definitely more difficult there's no question it's more difficult than doing it on a stimulated ovary but it's a skill set that you know we can learn and it's not once you once you develop that skill set it's really not that difficult. And the fact that it's not easier that doesn't mean that we shouldn't be doing it.
I mean we're sub-specialists right we're not general OBGYN we do a fellowship we're fellowship trained for a reason we provide that extra skill set. But if you have an entire like group of you know fellows being trained in programs without these skills at what point will you actually be able to have people comfortable in doing these procedures safely while avoiding the bowel while avoiding blood vessels? How much risk are you increasing in these procedures when you're trying to chase after these very small antral follicles within an unstimulated ovary? I think one of the best parts of being doing thousands of retrievals and being able to do these ultrasounds is that as they get bigger they're much easier to retrieve they pop to the top. The distance between the vagina and the ovary is much smaller and so that is a skill set that you can obtain but who is going to teach that? We've seen that time and time again with abdominal retrieval where people do not feel comfortable doing those procedures because they just do not do them frequently enough and so in what generation of doctors are that we going to be starting to do these procedures and what how do we counsel our patients on those risks? Tell us Dr. Hoyos.
I feel like we start now you know you're a third year fellow right so you are the future so I think that you should start developing those skill sets and we as you know young attendings should also work on developing those skills so we can offer the patients. How can we counsel them? I mean the same way that we will counsel with any other procedure. I mean I don't think it should be that should be an excuse not to do it.
Well I look forward to coming to your institution to do a weight rotation to be able to be trained in this wonderful procedure then. I will welcome you with open arms. Tell me for a second how not only how you counsel the patient about the actual technical aspect of the procedure how do you counsel the patient towards IVM? You have the PCOS patient in front of you they have kind of the menu of options three to six rounds of Clomid IUI.
If that doesn't work then we can do IVF with Blueprint Trigger. Do you think the the IVM is a stepping stone between oral medication to injectable medication? Is it a first-line option for patients with PCOS? How does it fit into your counseling? So I think you know the reality is that we're not going to be doing that so what I was intrigued by was you saying well yeah so it's Comafine when actually that's your kind of hierarchy in Boston when actually the rest of the world is using Letrozole because of the efficacy issues. Just suggesting that might be your first step to get you to move forward and then when you know you're going after that.
So the reality would be that I think for those patients we've said you know looking at PCOS patients an antagonist cycle with agonist triggers is very safe. You can use, you can even make it safer by actually dying down your gonadotropin dose. You know Megaset HR is a really good trial with high responders.
AMH is about five nanograms per mil consistent with you know the new definition of PCOM is 2.3 nanograms per mil. So well within that range and you can see that you know you get like 50 new sites on average you know within you know depending on your choice of gonadotropin. So you can do it really safely in terms of being able to do it.
So I think it is very difficult to then say oh let's you know think about doing IVM in those patients when you can have this very safe effective procedure for someone with PCOS. I think that probably brings us on to these systematic reviews in terms of kind of really nicely kind of segwaying into you know because the other two papers are really kind of a basic science reviews you know by Rob Gilchrist which is fantastic if you haven't read that I would definitely recommend that. And then the colleagues in Vietnam and Michelle DeVos so Dr. Vong and you know Michelle from Belgium really trying to do a systematic review of the trials looking at whether or not using IVM versus that for high responders.
And I think it's one of the things that when you look at these papers and you look at the kind of overall conclusion that they come up with I don't want to flip sides or to the other because it's purpose of a debate but it's worthwhile looking at some of the detail because essentially they say there's no difference between these arms. And I think you probably should look at those papers in a wee bit more detail and look at just kind of how you do do those. So just to dive into the trial that really drives that systematic review is one from Vietnam from Vong and colleagues published into Human Reproduction in 2020.
And you know the odds ratio for you know live birth was 0.71 with a 0.50 to 1.1 being the confidence intervals of that. When you go back to look at that paper actually it was designed as a non-inferiority trial with a 10 percent margin associated with that. For most trials now for you know you either need for European registrations you kind of need an eight percent margin.
Some for FDA it's even five percent you know they're kind of making it shifter. And so if you were trying to achieve a trial size based on that control arm you'd need to have a population for if it's 43.6 in the control arm eight percent it'd be 1,350 people that you need to have that. If it was 55 percent in control arm you know and you have a eight percent margin you need 7 to 7.2 but five percent you're back up over a thousand.
So in terms of them saying it's equivalent for PCOS it's because it goes to 1.01 so I don't think we can actually say it's equivalent for PCOS. I think in terms of the going back to your question about the counseling I would think that we should be doing lectures all because it's really good evidence for that even in the New England Journal of Medicine trial. And then we kind of move on to kind of IVF because it is super effective in terms of being able to achieve them a family.
Well you've counseled the patient about the technical aspect of the procedure you've counseled them on the success rate of this technique. How do you counsel your lab to actually bring this in house and do it? We talked a little bit about how to standardize protocols make things easier increase throughput. What does this do to a lab if you're trying to bring in IVM into a busy program? I think that Dr. Robbins kind of mentioned one of the biggest concerns in streamlining these kinds of procedures is is that we already have a very hard-pressed lab staff and we are having a shortage of embryologists at this stage.
So adding an entire new process within that lab it adds additional checks that you have to do changes in media potentially even if you do sequential culturing of these of these GVs to be able to get them to that M2 stage it adds an extra layer of complexity because then they have to go through you know entire embryo culture after fertilization. And so I think that without having really successful procedures that are very standardized and very well known even among United States studies within our own populations of people it can be hard-pressed to really try to introduce and get the buy-in from already very overworked staff that are potentially per diem they're complying in you're trying to address these increasing volumes and if you increase that complexity I think it also increases your likelihood of error. And so I think it could be really challenging to be able to implement really responsibly within these kinds of laboratory environments when you just don't have those pregnancy outcomes to be able to really fall back on.
Jared is the only person on the panel who's actually done some IVM himself. Can you tell us a little bit about the actual practicality of doing it? Is this the kind of thing where you're taking up a whole embryologist for a whole morning or can you do it at the bench side just down the hall and do it in parallel? So the process is definitely more laborious. A little bit depends on the way in which you go about doing IVM.
So you know currently most practitioners using IVM are stimulating for three days. That does make some of that will make finding the eggs a little bit easier. But the IVM, the immature egg doesn't have that expanded cumulus that most of the embryologists are looking for that really makes it easy to identify.
Because you're if you're particularly if you're using a really unstimulated ovary there's definitely there's you have more cellular material within there. There's often blood and so we're filtering through a four micron filter and that you know so there's that process. So the laboratory process of finding these immature eggs is definitely much more intense.
You know then you have the day one check right. And so whereas you know you know we then have to determine whether or not the eggs are mature or not. And so at 24 hours we're then going to go in and and the protocol that we developed when I was at Women and Infants in Rhode Island is that we did a partial stripping.
So we did a 20% stripping of the eggs to find out whether or not they've extruded their polar body. So again that's a another process of going if you got you know on average we would get about 15 eggs in the process. And so you then have to look at all of these 15 eggs partially strip them determine whether that they have a whether or not they've they've divided.
And and then not really divided whether or not they've matured. And and then those that didn't we would then culture for another 24 hours. So that's again you do that again on the next day.
Then again your Fert checks and all the rest is. So this is essentially two days of work on top of the already you know your typical work in the lab. So there's no question that it significantly increases the amount of work that you're that you're imposing on your embryologist.
So that is a big con for implementing an IBM program. I have to point out that one of the main arguments for IBM is the cost effective nature of it. You avoid exposure to expensive gonadotropin.
Scott and I were talking about this before the panel actually started. He said that what's the price for 75 units of gonalef in the UK? You can get it for less than seven pounds. So in terms of dollars that's probably about nine dollars at present in terms of exchange rates.
And the time for one hour's an hour worth of an embryologist is probably significantly more than that. So we're hearing kind of the pro side being con and the con side being pro here a little bit about the cost effective nature of IBM. I want to end up by talking a little bit about IBM as a way to democratize access to care.
Is this a tool that we can be using to like I think Louis said in the beginning give a patient an appointment for a single day to come in have their retrieval and avoid a patient having to have that personal expense the time away from work doing two weeks worth of stimulation. Con side pro side I'll let you start. Do you think this IBM is a tool to increase access? So there's no doubt that in reality when you look at the access to in the U.S. that is driven by the high price.
In reality an American today is probably cheaper getting on a plane and flying and having two week holiday in Greece and having an IVF and a really good high quality center with you know time lapse PGT and everything. Have an embryo transfer you know and fly back and she's still going to be cheaper than having an IVF cycle in the U.S. So the access to the U.S. is being driven because of the high price points. We just talked about the difference in gonadotropin costs between you know the U.S. versus you know the U.K. for example.
When you look across Europe so the reality is access is the price point driven and if you you know facilitated the price coming down actually they'll be widening access. You can then start to think about you know the mandates. I think it's kind of ridiculous that you've only got IVF mandates in like 13 of the of the U.S. states.
It doesn't really make sense to me as to why that would be the case. So it's thinking about that but the reality of I don't think IBM is going to facilitate access because actually all the fundamental costs you've got is the only cost that you're really saving on is on that gonadotropin costs. And although I appreciate that's huge in the U.S. in terms of the overall price of an IVF cycle it is that's the only part and as Jared has said that's going to be offset by you know having to have a more intense laboratory process.
So I don't think Louise would probably correct me here in terms of thinking about you know access. I don't think IBM is a way of facilitating access in the U.S. It may be a way of facilitating access in other jurisdictions but not for the U.S. Should we switch seats? What we said before that Jared should have been on this side and I could have been on that side but the reality was I think as a panel we wanted to give a balanced opinion. It doesn't you know you can play the games for debate for being able to say that but in reality I think as an audience you benefit from actually having a more nuanced discussion across it rather than actually as being forced to kind of be on sides.
And I do think and so that's why I'm so I'm going to speak on the pro side since you spoke on the con side for a minute. I think there is an ability to improve access because what Louis mentioned earlier is that again in a very busy patient population particularly those that may live more than 40 miles from an IVF center which is not an insignificant number of those that live in the Midwest it is a you know there is a huge amount of time necessary in order to do IVF. We expect you we I expect to see you at 7 a.m. in the morning every day and you're a school teacher in Wyoming like that's just not you know there's a impracticality there.
So yeah so maybe maybe they do need to take the week off and go to Greece. I don't know where you've stayed in Greece but I can't do that for an IVF cycle unless I stay with Angie's family. We're all invited I think.
But but I think that the truth is that because of the fact that IVM is so inefficient there are to come back to my seat now there are a lot of new technologies out there that are simplifying that home ultrasound. You know I think there's you know where I think that in terms of that prime time while back in 2000 when we were developing IVM technology access to care was huge for us because again those PCOS patients had to come in every day. Right.
You know nowadays I think that they don't have to come in quite as frequently and with home monitoring which is right on the cusp of the technologies that are being introduced I think that we'll be able to eliminate we'll be able to improve those access points without having to use an inferior technology. So there's a classic kind of phrase I think Kevin Doody popularized it you know kind of show me your monitoring schedule and I'll show you your billing. And the reality of that is that if you go elsewhere in the world you can say you know you don't need to bring people in for all of that.
You see you can use your biomarkers like AMH antral follicle count. You can predict their anticipated response. You give them an appropriate dose.
You know that the duration of stimulation is going to be nine days. You're doing it in an antagonist cycle with a fixed start. You don't need to have the monitoring of the lead follicles.
We know that that is inferior. There's a fantastic human reproduction update summary showing that that's the case. So if you've got the right dose from the start and you've got the right you know fixed start for your antagonists and you haven't predicted you know well it's going to be on nine days of stimulation on average.
Actually how many monitoring visits do you need. Yeah. And you know perhaps one.
And you know with COVID there was laboratories around the world or units around the world that essentially said actually because we don't want face to face interaction we're going to do one visit. Yeah. And you can do it later on.
You know day eight whatever. And then you can do here's the triggering because we all know that follicular growth pattern. So actually do you need all that intensive monitoring.
You know patients love it. I understand that. But actually does improve outcomes in any meaningful way.
I think probably not. And so again just other ways of being able to improve the access so you don't need to have these teachers from Wyoming coming in in the morning. Actually why are you doing that.
You know why are you making them inconvenient for them and improve their experience of the IVF journey. I think that's another way of doing it. Make a small plug for a live audience.
If you have a question go ahead and raise your hand. We're coming towards the tail end of the debate here and I want to make sure that we have an opportunity to ask some questions. While we wait for a question I want to ask a point that I think neither group has addressed which is safety.
We've talked about the patient safety with IVM versus IVF and OHSS risk. But I really want to hear a little bit about the safety of the offspring. What's the safety data tell us about developmental potential epigenetic changes from IVF conceived children.
So you know trying to prepare for this talk you always want to make sure that you're looking at live birth outcomes and then subsequent you know offspring health. And I think that's always been our kind of gold standard as fertility doctors and being able to prioritize our future generation of ART children. And you know the data is just still being decided.
It's just not out there. We do not understand the epigenetic changes that are occurring from prolonged culture in these kinds of environments. We are still trying to figure out even in vivo oocyte maturation processes and we're continuing to do a lot of basic science studies to be able to better understand the complex interactions between all the proteins and the follicular fluid that could be contributing to the likelihood of just getting a mature egg from our traditional IVF procedures and retrievals.
And so I think the data is just not out there to be able to give us really solid you know multiple studies that give us longitudinal outcomes among these children born from these processes that you can even counsel patients reliably. Whereas our IVF populations through traditional controlled ovarian hyperstimulation we do have longer studies. We do have follow up like two year four year ten year you know outcomes looking at the children of these patients and likelihood of birth defects that can be really powerful counseling tools that can allow us to feel the safe being able to offer these procedures.
And we don't have the data because we're not doing it right. So we need to do it. I mean you know I was part of the task force for the oocyte preservation guideline and I was in charge of the part about safety long-term outcomes.
And even that there wasn't really much out there just a couple studies and yet we're doing oocyte cryo every day a lot. So you know that's not an argument. I think a question from the audience.
Oh sure by the way I think it's a tie between the fellow and the young REI. You guys are great. And I do have a question and then I have a comment.
But first the question and I had to write it down is. Oh no where is it? Sorry. Oh okay.
If it's here I can't find where I wrote it down. Is a minimally stimulated ovaries egg is likely to fully mature in the lab is an unstimulated ovaries egg. And what would be the success differential if there is one.
Jared I'll give you this one since you're the only one with some real experience. So I think I think the minimal. So when we do minimal stimulation where we're still retrieving at maturity.
Right. And so we're just not we're just not pushing the ovary as hard. And so but the majority of the eggs that are being retrieved during a minimal stim IVF cycle are still mature eggs.
And so the minimum stim is still is going to be more likely to give you a stimulated egg than an IVM cycle. But we did see again in our trial of looking at doing IVM from the unstimulated egg we did still get maturity in about 50 percent of the of the mature of the eggs that we retrieved. 50.
That seems high. Okay. And then my comment regarding would it be a way to democratize what did you say democratize access to care the performance of IVM.
I think it would be a way to democratize human exploitation. And this is why because you can't separate donor anonymity globally from the equation. One there are countries that harvest babies.
I have proof I have photographic. We're not talking about IVM and donors. I'm just going to pause for a second there.
I'm just it's a very this is a very important value of a human ovary at birth ovaries is one point. We're going to separate the conversation a little bit about donor versus autologous IVM because I think they're very different scenarios with a lot of nuance that I don't think we have time for for today's debate. I want to talk finally about pose a question for both sides.
I want to ask both sides. There are groups internationally outside of the U.S. Vietnam Belgium Australians that are doing this at scale and have been doing this at scale now for a few years with their data being published. What are the things that are missing in North America for us to be able to bring this into primetime if we're not ready for primetime now.
So I think the most important thing that we need to use to contrast ourselves versus those others is universal coverage of IVF. Right. So if I'm going to if I'm going to ask someone to shell out 15 7000 to 15 to twenty five thousand dollars I want to I'm going to make sure I'm giving them the thing that's going to be the most value for their dollar.
I think it's much more reasonable to start thinking about. Can we can we can we think about that value scale that Dr. Arundel proposed. We can look at that value scale when when we can really reduce that cost that did not that the denominator in that equation.
And and that's where in the U.S. we have to really we have to be continue to push for mandated coverage for IVF for fertility care in general coverage and stuff and stuff. So I I'm you know thinking about access to care also is I'm not entirely convinced that this would make a particularly cheaper process. You will be saving money from a Gnatich open standpoint but it doesn't necessarily address the increases in add ons the increases in the lab fees that we would be charging to be able to have these IVM procedures performed even if you do have just three days of stimulation you still have to have the ultrasound you have the same evaluation you're going to come and you do the retrieval that's a fixed anesthesia cost you have two additional days potentially of culture before you start the entire process of IVF in and of itself.
And so I think you know thinking about bringing more patients into the clinic I think is great because that obviously will democratize it in a lot of ways by limiting the number of visits that you have to have but that doesn't address the amount of REIs that we need to be able to be training every year to be able to account for that increased volume it doesn't account for the number of embryologists that we would need to hire and train to be able to provide that additional staff. And so I feel like at this moment if you were trying to introduce IVM as the prime time treatment plan in the United States I think cost is going to be a huge limitation. What about rescue IVM? You know I thought we were just talking about specific types of IVM but you know rescue IVM is definitely being introduced in a lot of clinics pretty reliably and I think that if you're already going through the process but you have to recognize that it still doesn't necessarily address the like the high cost of treatment that patients are battling to be able to afford it.
You know coming from Georgia our patients in Atlanta are mortgaging their houses to be able to go through one cycle and so if you're thinking about equating it to the oncofertility population where they may only have one cycle to be able to go through I think rescue IVM is great in that scenario if you can get one more blastocyst that could give them that chance to be there. But I think if you're thinking about IVM truly from that you know small antral follicle retrieval I just don't think that we're there yet. And I may agree with you but I think the rescue IVM is probably ready for prime time right.
Just those patients the one that you know got a mortgage whatever a reverse mortgage you know they're already going through the process right and we know that increasing the number of blasts is going to increase the chances of getting pregnant. So if you already have those immature eggs and we know that we can get blast from them I think we should use them. Well we're nearing the end here of our time together.
I want to give both sides an opportunity for their closing remarks and summarize for me kind of the general takeaway point for why you are pro IVM being ready for prime time and why you're against IVF being ready for prime time. I'll let the pro side go first. Yeah I mean I think that that was kind of a closing remark already.
You tapped out. So I think what we recognize is that for pro coin in terms of prime time it's prime time for a very specific subpopulation. I think that's what I would suggest is that there are we've heard for the rescue IVM so what we mean by that is whether someone's going through a conventional IVF cycle but they have got a low number of M2s with that.
So they have a high egg yield but a low proportion of M2s. Actually by increasing that that is advantageous for them. So that's a rescue IVM cycle and that makes sense and that's probably what you're actually your labs are already doing or if they're not they should be doing that because as you've said you've spent an inordinate amount of money to get to that through that first stage and it's not going to be an incremental cost is not going to be that excessive for that.
So that's rescue IVM where there's a subgroup of population fantastic response but low M2 yield right. So that's slightly different. Then there's the question about who we're going to do standard IVM in and then you can have that into the context of biphasic.
So they might be as Jair's talked about having a small dose of gonadotropins with that small dose for a couple of days in terms of that and we think there's potentially really limited subgroups of populations that benefit from that. And then I think the last group is really those who have got oncofertility where they can do conventional you know oocyte or embryo banking and then they're going to have cryotissue preservation and then in addition to that can they also be thinking about IVM to thinking about the number of follicles because even if you do classic transplantation back into them auto transplantation that's a relatively small number and can we also perhaps take other bits that can we do IVM and increase the number of oocytes from that. So in reality it's potentially it's prime time but it's for these super select populations it's not for the hundreds of thousands of IVF cycles that are undertaken in the U.S. you know every year it's for very specific populations and that's where we think there's benefit for it and you can be doing that routinely just like.
Okay so dig deep Jair. So I do think that there is obviously I think that there is there's value for IVM in the world. The question is how much and is should IVM be a mainstream treatment strategy.
I would say very much no. Are there subpopulations where you know we've been talking about personalized medicine are there subpopulations where IVM is appropriate. Yes but they're pretty small subpopulations and and perhaps should be focused on specialty centers that could do that that would do IVM routinely.
I'm not a fan of rescue IVM by the way. Dr. Rakowski has I've had pregnancies from rescue IVM so I know that it does work but Dr. Rakowski actually has a paper demonstrating that in the over that you know we all know that blastocyst does not equal pregnancy and that the overwhelming majority of blastocysts that are formed by rescue IVM are incompetent and I can go over the data this biology as to why that is but we don't have time to do that. So you know I don't I don't know that I think rescue IVM should also be reserved for those extreme cases.
I wouldn't be doing rescue IVM routinely in a laboratory and so I do I think that IVM is something we should is a is a tool we should have in our tool shed but is not something we should be using routinely at this point in time. And and I do think that that idea of creating false hope you know is concerning to me particularly in creating embryos that that may ultimately not have significant potential to become children. The concept of therapeutic misconception.
Take us home Dr. Jiang. Well you know I think we've heard a lot of pros and cons on both sides and I think it's undoubtable that IVM will have a place in the future of reproductive medicine but I would just say that but but is it ready now? Thank you. Is it ready for prime time now? I would say it would have to be overwhelmingly answer no.
I think once we have larger institutions that do more studies I think is it responsible for us to be charging for this now? I say no. I think that if we have the data if we have you know institutions that are going to be interested in developing these protocols through research IRBs and being able to actually demonstrate reliable reproducible pregnancy rates and be able to offer it as a middle ground between IUI to IVF it could be an option but in select populations too but I think right now the jury's still out and we still need to figure out how we're going to be able to do this responsibly. Well I look forward to hosting this exact same event in Vietnam, Belgium, or in Australia and ask the exact same question and see if we come up with a different answer.
I'll ask for a round of applause from our live audience for our panelists here on both pros and the con side. I also want to make a mention of our next live event. We're doing a unique event this year.
We're actually going to Acapulco, Mexico and we're doing a live event from the annual reproductive medicine meeting from the Mexican Fertility Society. That's going to be on July 20th. The editor for Fertility Institute, Dr. Kurt Barnhart, is going to be there chairing that panel discussion.
That's going to be in Spanish which is also a nice change of pace for fertility and sterility. Si se habla espanol. I want to thank you our live audience and thank our online audience for joining.
If you found something on this topic that you want to expand upon I want to make the offer. Fertility and Sterility has this new and revamped section called Consider This which is a online only original content section of Fertility and Sterility where we're inviting all of you to write a little bit more about things that don't fit classically into the journal. So if you have an opinion, if you have an idea, if you have a commentary, this is the perfect place to submit it.
This does not live behind a paywall, imminently shareable on social media. So if you have something to say about IVM, I encourage everyone to check that out. You can submit it on Fertstert.com. Again, thank you so much for being here live with us in person and live with us at home and that's all we have for today.
Thank you.
