Fertility and Sterility On Air - TOC: November 2024

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

04:20 LGBTQ+ family building: progress but lots more to do/Therapeutic donor insemination for LGBTQ+ families: a systematic review

09:52 Confirmation and pathogenicity of small copy number variations incidentally detected via a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy platform

23:40 Trends and outcomes of fresh and frozen donor oocyte cycles in the United States

34:11 A survey study evaluating donor gamete utilization rates, patient satisfaction, and fertility treatment outcomes according to desired race and ethnicity

39:29 Racial and ethnic disparities in wait times for donor oocytes

41:16 Return rates and pregnancy outcomes after oocyte preservation for planned fertility delay: a systematic review and meta-analysis

49:23 Longer duration to optimal endometrial thickness in women with premature ovarian insufficiency is associated with clinical pregnancy rate in donor egg cycles

56:30 Feasibility and efficacy of a subcutaneous catheter for controlled ovarian stimulation

01:00:23 International Committee for Monitoring Assisted Reproductive Technology world report: assisted reproductive technology, 2015 and 2016

View Fertility and Sterility October 2024, Volume 122, Issue 5:  https://www.fertstert.org/issue/S0015-0282(24)X0012-6

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

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

Welcome to another episode of Fertility and Sterility On Air. I'm Micah Hill, the Media Editor. We are in the November edition of the journal 2024, volume 122, number five.

I'm joined this morning by Eve. Good morning, Eve. Good morning, Micah.

Good morning, everyone. And good morning, Kurt. How are you? I'm well this morning.

Hello, everybody. Glad to be here. And last but not least, Pietro.

Good morning, my friend. How are you? Hi, everybody. It's a fun podcast to be recording on the eve of ASRM, but we'll come out after ASRM.

In addition to all the wonderful content that's coming out at the meeting, as always, we're going to be recording live from the meeting. We have some of our best and favorite abstracts, oral presentations to be discussing, so tons of rich content coming out around the time of this podcast recording as well. Very exciting.

We're all just a few days away from flying out to Denver, and we hope to see all of you there. So let's jump right into the journal. Our Inklings this month is from Editorial Editor Dom de Ziegler.

When should ART workups be done? Following a tiered approach or all before first transfer? Normally, I don't ask questions about the Inklings. We just sort of tease them. But I'm curious, do any of you not do everything before you do an embryo transfer? In other words, is there any standard of care treatment that you're waiting for a patient to fail before you do it? Or are you doing all the workup before you do the treatment cycles? Well, Micah, I think this stems, in fact, I know this stems from the ESHRE guideline about recurrent implantation failure, where they say if you encounter recurrent implantation failure, and we could have an entire podcast on what that means and how you define it, but they say that's when you finish the workup or revisit the workup about the history and especially cavity evaluation.

So I think that's what Dom is getting at, that he thinks that that recommendation is inaccurate, and we should be doing it all up front. And I do do it all up front. I mean, I don't understand why you should withhold information for something as precious and invasive as IVF.

You want all your information up front, in my opinion. Yeah. I think there's stuff that's evidence-based that we all agree on should happen beforehand, right? We all agree the cavity should be normal and normalized, if not.

We all agree that we should make sure all of the other things that we typically check for a fertility workup are appropriate. I think the tougher question is, when do you do some of those more esoteric things, things that are a little less evidence-based? We've had stuff come and go. We've had the ERA test.

We've had the receptivas. There's reproductive immune testing. Do you wait for three euploid failed transfers to do that? Do you wait for five euploid transfers to do that? I think that's a tougher question and probably very significantly where you are in the country, how you're paying for IVF, and what ultimately your doc's recommending.

I think a lot of us are pretty evidence-based and tiered in our approach, but some are much more shotgun all of it at once, sleep no stone unturned. So a really good inkling and a really good question that I think a lot of us struggle with and a lot of patients ask us about. I'm going to present the ICMART paper later in the podcast, but I think this stems from that too.

I really think that this question, especially ESHRE doc guideline might recommend to international medicine. I mean, in the United States, who most of our podcast listeners are, but not everybody, of course, we have all the resources available to us, but there's a lot of IVF outside of the IVF, I mean, out of the United States where sometimes all you have is a 2D ultrasound that doesn't measure the cavity. And I think that's maybe what they're tilting their hat to.

Yeah, that was great. That's exactly why I asked the question, because I think our readers might read the title of this article and wonder what it's all about. And I think you both gave wonderful background as to why this is an important inkling, especially in the international front.

Moving on to the views and reviews this month from editorial editor Ruben Alvero, he's looking at LGBTQ family building progress, but lots more to do. And this is coming off of the new suite of LGBTQ practice committee documents from the ASRM. And he's building on that to try to expand that conversation.

And there's two systematic reviews, which is where I think the views and reviews really shine, is when they try to elevate the sort of quality of how they're reviewing the data by doing it systematically, and sometimes even including a meta-analysis in that. The first is on shared conception using ART in same-sex couples. And the second is on therapeutic donor insemination for LGBTQ patients.

I'm just curious, does anyone have any thoughts on these articles? Yeah, so I'll dive in here. I thought that both of them were excellent, and I think that the views and reviews on the whole is fantastic. I know we talked about a few months ago how there are some dissenters saying that the ASRM definition of infertility is not medically correct, and some of the articles touch a little bit upon that.

But where I really took issue was on that article on therapeutic donor insemination. So first and foremost, I agree that you don't necessarily need a full infertility workup prior to therapeutic donor insemination. And oftentimes when I see couples, I talk about the merits of, do we do a workup? Do we do a saline ultrasound? Donor sperm is really expensive.

One thing that I think really needs to be laid out here, though, is that there's a huge conflict of interest that's not explicitly disclosed. The author of the paper runs a large-scale fertility group that's geared towards therapeutic donor insemination in the LGBTQ population. And so I think it just, when we talk about conflicts of interest, it's not just pharmaceutical, it's not just device manufacturers.

I think you have to disclose your vantage point that you run a for-profit group that does therapeutic donor insemination in an LGBTQ population. And so I think that that just struck me as odd that that wasn't explicitly disclosed. And I felt like the tone of the article was very negative towards traditional fertility clinics, and I think that has to do with the COI.

The other thing that I want to say is I sit on the National Medical Committee for Planned Parenthood, and Planned Parenthood has over a thousand affiliate clinics throughout the United States. Planned Parenthood does therapeutic donor insemination for queer couples, too. And so there is already a huge access to care gap that Planned Parenthood is filling in this space.

So this is not a novel concept that's out there. If I can just add to that, I mean, Fertility and Sterility, I'm glad the message gets out and we're talking about this and it gives a little bit of controversy, but it does give me a little bit of dilemma as I decide what goes in and out of the journal, because it's not always science. And there's no question that, especially in this community, we've moved from science to business.

And I mean, we should be talking about it, but it's no longer the ivory tower academics saying what should be standard of care. We're driving business by business practices and by profits and by venture capital. It's a little disheartening to me that we've moved into a product as opposed to medicine.

But I just wanted to say that and our listeners should understand that and should have that point of view when they're reading articles like this. Yeah, and I think that the article said that fertility clinics force patients to undergo or require patients to undergo extensive workups prior to donor insemination in couples who are both assigned female birth. And I would argue that perhaps a study is needed to actually assess the practice patterns of fertility practices when it comes to that.

And maybe the good of this is that from this will stem a research project that surveys practices or that looks at practices, practice patterns. I will tell you, when I see two people who are assigned female at birth who want to do therapeutic donor insemination, I offer them. I say we can do this minimal monitoring, no workup.

You can start. The other thing that gets completely ignored in this article is genetic carrier screening. And I actually think that that's a very valuable piece of coming to a fertility clinic, being counseled by a physician on encouraging patients to undergo genetic carrier screening prior to selection of a sperm donor.

Psychological counseling, a lot of clinics have this embedded. They also sort of gloss over that, that outside psychologists can be used. And so I think that while it is valuable for this to be out there in the community, I also think we should take some of the lessons that have been learned from the population of donor conceived people and understand that much more counseling is needed for all couples who are using donor gametes about non-anonymity, about potential consanguinity in the future and the multitude of expertise that physicians bring to this arena.

It's not just about invasive workups. It's about counseling and thoughtful and mindful and ethical discussions about treatment that patients are going to undergo. That's well said, Eve.

So definitely check out this views and reviews. It almost sounds like there's a fertile battle that's buried within there, but certainly an area for research and an area for shared decision making between the physician and the patients. Kurt, let's get on to the original research.

The seminal article this month is looking at small copy number variations that are incidentally detected with PGT-A. What does that mean? Yeah, I learned a lot from the seminal contribution, and that's why I'm glad we're presenting it. And it's a little bit tense, but I'll try to simplify it.

But an awful lot of it is simply in the name. Confirmation of pathogenicity of small copy number variations incidentally detected via a targeted next generation sequencing based preimplantation genetic testing for aneuploid platform. That really says everything you need to know, but we have to unpack a lot of those words that were not exactly familiar to me.

So let's talk first, I guess what I need to say is what is a small copy variation? So a copy number variation are structural variations in the genome that involve differences in the number of copies of DNA in segments. So we're not talking about a whole chromosome here. We're talking about it's sometimes very small areas that are very, very difficult to gain and sometimes very large areas that are called macro that are a little bit more obvious.

They range from a few hundred base pairs, as I mentioned, to large size that can have can cover and alter genes that can also alter non coding areas of the genome and other elements of the DNA. So some of these are thought to be pathogenic and there's an evolving literature on this that some of these might actually be associated with autism, intellectual disabilities, heart defects and other congenital anomalies. So serious issues.

The problem is they're not very common and they're very hard to detect a little bit more background. If parents are looking for these things because they're affected or they've had an affected child before, really the only way to detect them was in prenatal diagnosis and searching for those in CVS and amniocentesis. So this is not a commonly diagnosed area.

So let's go back to this. So this, in essence, is a case report, but a very good case report. They're talking about a large genetics laboratory with a large scope.

So they're reporting on more than 12,000 patients between 2020 and 2022. And in those 12,000 patients, they found potentially 75. So, yes, 75 out of 12,000 small copy variations, less than 1 percent, 0.62 percent.

And these copy variations are then classified by what their potential pathogenicity is, and most of them are found to be benign or likely benign. The first categories on 40 percent were benign, another 46 were of unknown significance, and only 13 or 13.8, 14 percent were considered possibly pathogenic. So 14 percent of less than 1 percent.

But, you know, real things here. So now we know the background. Now we know.

So why is this novel? It's novel because it goes back to how we do PGT-A. And there's two types of PGT-A. Well, first of all, PGT-A with next generation sequences is the most common way we do PGT-A in the United States.

The problem is most of us don't know, you know, behind the curtain aspects of how would they do the next generation sequencing. And in reality, there's two types of next generation sequencing, something called whole genome amplification or WGA or targeted amplification. So whole genome amplification, I'm using some of the author's words on purpose here, is more common, but it's deemed by the geneticist as, quote unquote, shallow.

So in other words, they're covering the whole genome, but they're really not covering it in real depth and in real detail, whereas others advocate that a targeted approach would be better. It's selective targeting, but a much more density or specificity of what you're targeting, where you can actually look for small copy numbers as well as other things, including SNPs and others. A quote unquote can reduce the amplification error.

It can look at regions of interest and it can find the segmental aneuploidy with a higher resolution. But the other argument is it's selective. It's not the whole genome.

So you're only looking in certain areas and finding variations in that areas and might be missing other areas. Now I want to step back even farther because we're really deep here and PGT-A is not designed for this. PGT-A is designed for finding whole chromosome monosomy or triploidy.

That's what the test is. That's what it was designed to do, to remove embryos that really had a very little chance of implantation or live birth from the pool of embryos. It wasn't designed to be a true genetic test of potentially everything that can go wrong.

So what this case series is telling us is that we really are in a new area of potential genetic diagnosis based on a trophopteroderm biopsy. So in sum, this is a large case series from PGT-A with a selective PGT-A that the authors are calling highly specific. When they went back and looked at these variations, they found in over 90% of them, actually 90, almost 100% of them, that they were heritable.

In other words, they went back to the gametes and found them. By the way, 54% were maternal and the remainder were paternal. So it didn't really seem to be one way or the other.

And again, most of these were likely to be benign, although there was a number. Now, the other thing I found really interesting about this article is that all of these were reported as incidental findings to the clinical patients. So they comment a little bit about that.

What do you do with this incidental finding? So there's not a lot of follow-up on the children here, because they mentioned that most of the people, even with this incidental finding, kind of avoided transferring that embryo. We could argue whether that was a good thing or a bad thing, but they were lucky enough to have other embryos to transfer to avoid this. So it's really not clear to me and or to the office of what we do with this information.

For example, before this becomes a thing, that everybody gets this reported, there's some really important questions we have to have here. Like, do all of these get reported? Do you report the essential findings? Do you only report the ones of unknown significance? Do you only want to report the ones that are pathogenic? You know, is this supposed to replace prenatal testing for someone that has the idea of something? Does everyone need genetic counseling when they get one of these? Can the system support all of these genetic counseling potential referrals as a result of these incidental findings? Right. And let's go back to the incidents here.

We're talking about 0.15 percent. I mean, we're talking about a huge over needing to diagnose, you know, thousands of patients to find one of these potential areas. Again, this was a really good article that we all should read.

It reminds you what your platform is. It reminds you what your reporting should be. It reminds you of what your patients are seeing and what you need to see.

But it opens up more questions than it answers because of, you know, PGT-A just became a heck of a lot more complicated, especially if we're going to be held to the standard that we have to find this now, let alone the resources that it takes to find this, the amount of people that need to be screened. And then the age old argument, and you mentioned conflict of interest here. You know, this group uses this targeted sequencing and claim that it's better than whole genome sequencing.

And I don't know if that's a resolved issue as well. So I hope that we took a complicated issue to discuss about it. But look at all the questions that answers and look at how quickly this is going in terms of our need to understand this.

And I hope that we understand a little bit better. So, Micah and Eve, what do you think about this? Two main thoughts. One is I wholeheartedly agree with you in terms of the questions.

It leaves more questions than answers. And I agree when you really look at the numbers of affected individuals. And I don't have the chart in front of me.

But of the seventy five that they found, the majority were nonpathogenic or variants of unknown significance. And there was a very, very small fraction that potentially had copy number variants that were problematic with regard to things like intellectual disability or cardiac. And so there's a 13 percent.

It was no, it was six and ten thousand. Yeah, when you when you when you go down to the pathogenic variants of all the ones they find. So, you know, so only about 15 percent of the ones they found were even questionable.

But if you do that backwards, it's six and ten thousand people screened. They found something that might be pathogenic. Right.

And I think the key is might be pathogenic because don't forget, these are healthy adults who are presenting for PGT. They're not impaired adults who have medical issues where you're trying to make a rare diagnosis. And so that's the other thing.

The penetrance of these trades, the penetrance of these copy number variants is so variable that the majority of people didn't know what they had. So that's thought one. I think thought two brings up this larger question.

And we're starting to see this a lot with carrier screening. And I think how we counsel patients for PGT and for carrier screening has to shift a little bit. Previously, I had always counseled patients that carrier screening does not impact you as the carrier, but it has the ability to detect potential disease in your offspring.

Well, now they have added a lot of the genetic testing companies have added diseases to their panels that do actually have adult implications. So things like familial hypercholesterolemia, the adult carriers of those diseases have four times the risk of cardiac arrest than adult non-carriers. And so now if we are also doing PGT and we are saying that this may potentially have implications for you as the parental gamete, I think we need to counsel patients that we might be discovering things about your genetics that you may or may not have been aware of previously.

And that, I think that's an important counseling nugget. Yeah, I think that's really well said. When I read this, I wanted to take away how clinically small this finding is.

And Kurt really nailed that home. And so did you. These are not a lot of patients, but as the technology improves, the ramifications of that are important.

And that's really what this article is drilling down on. And I think this is just going to get more complicated as these companies improve their technologies. And as we understand how these genes function and work, both in the embryos themselves and as you're saying, even in the parents of these embryos.

Yeah. And as REIs, we need to own this. Like the genetics companies are running so far ahead of us.

And we have to come back to what do we want reported? What do we do about these things? When are people going to ask for it? These are medical decisions. The genetic companies are going to report everything because that's their job and they're looking to report more. So somehow we have to figure out what the breaks are and what is really necessary, because otherwise we can't do any of these tests without the legal and moral ramifications.

Right. And I was going to say the medical legal ramifications, like that terrifies me a little bit in terms of having information and not disclosing it to a patient. And at what point do we disclose it? What point do we not disclose? I think that's a whole other can of worms that we need to we need to be ahead of.

But I do agree that I feel like understanding the genetics of how PGT-A is performed, admittedly, like I didn't realize that there were two different ways of amplification between whole genome and targeted. This was new information for me. So I also learned a lot when I read this article.

But I think we all have to. And that's part of the challenge of this field is that it's moving really quickly and we have to keep up and we have to understand the tests that we're ordering for our patients. I want to put this back in perspective.

I mean, I hope everybody that's listening understands. We're arguing now about whether mosaic aneuploidy should be reported. Right.

We don't even know if that's true or not. And now we're talking about pathogenic small copy number variations that are incidentally found in six and ten thousand people. Well, but right.

Just to drive home the point again that they're calling it pathogenic, but it's in an asymptomatic carrier. And so is it truly pathogenic in that person? TBD. And maybe they just haven't lived long enough to know.

But I think it's a whole other can of worms. This sounds a lot like the conversation that maternal fetal medicine docs have with their patients when they're discussing the role of amniocentesis and CVS. It's a really powerful diagnostic tool, but comes with a small potential can of worms that may introduce more stress, anxiety than the information you glean from the test is worth.

And to kind of say it out loud, I think the overuse of PGT in all patients undergoing ART is probably becoming more and more obvious that it's less and less warranted because there is a can of worms that comes with it that we may be responsible for unpacking for patients, counseling for patients and may ultimately just generate more cost and delays in conception for that patient. So proceed with caution on PGT in all patients undergoing ART. Such a good discussion.

Definitely read this article. And for all you fellows out there, as Kurt said, we need to own this technology and this for our patients. And so make sure you become as you're going through your fellowship, be expert on how these PGT platforms work.

Eve, we're going to you next. Trends and outcomes in fresh and frozen donor oocytes. And if there's a theme in this journal, it's definitely we've already talked about it.

LGBTQ patients using donor oocytes. And we're going to get to several more articles on this. But let's start with the national trend in the U.S. and using donor oocytes.

Tell us about this article. Thanks. So this article was written by Caroline Braun from OHSU, a senior author, Jennifer Kawwass from Emory.

And I just want to give a shout out to Jen. And congratulations for being the ASRM recipient of the Ira and Esther Rosenwaks New Investigator Award. So congratulations.

And this is another great piece of work that you've done. So the objective of this manuscript is exactly as the title outlines to examine trends, characteristics and outcomes of donor oocyte embryo transfer cycles by original oocyte, fresh or frozen, and then by the resultant embryo state, frozen or fresh, to determine whether these factors are associated with clinical pregnancy, live birth and term healthy neonate deliveries. So there are four possible combinations that the authors examine.

Frozen oocyte that results in either a fresh or a frozen embryo transfer. So you can have frozen, fresh or frozen, frozen, and then fresh oocyte that results in a fresh or a frozen embryo transfer. So fresh, fresh or fresh, frozen.

They use data from the National Assisted Reproductive Technology Surveillance System, which captures upwards of 98 percent of all U.S. cycles. They analyze the data in two chunks. First was trends 2013 to 2020, and then they analyzed outcomes in 2018 to 2020, because prior to 2018, data were not included on embryos to determine if it was from a fresh or frozen oocyte.

So I'm going to go through the high level take home points, and then we can break these down into trends and outcomes. So looking at trends first, the absolute number of donor oocyte embryo transfers per year has remained steady, with the exception of decline beginning with the COVID-19 pandemic. On average, there are about 17,000 donor embryo transfers each year out of roughly 1.2 million transfer cycles, a little bit smaller than I would have anticipated.

I'm rounding a little here for simplicity, but the proportion of fresh donor egg cycles has decreased while frozen donor egg cycles have increased. Fresh donor cycles went from 80 percent to 30 percent and frozen donor from 20 percent to 70 percent. So that's a huge shift.

The proportion of frozen embryo transfers overall has increased, and I would encourage our listeners to look at figure one, which beautifully demonstrates these data. Fresh embryo transfers went from 60 percent to 20 percent and frozen went from 40 percent to 80 percent. And that's what happened around 2014.

Single embryo transfers markedly increased in this time period from roughly 37 percent in 2013 to 87 percent in 2020. So huge improvements. But I would argue we really should strive for 100 percent in this population.

Speaking of unnecessary PGT, PGT was used in 47 percent of fresh oocyte cycles and 31 percent of frozen oocyte cycles. So those are the trends, more frozen oocytes and more frozen embryos. But let's take a look at the outcomes.

And again, they really make me answer and ask the question of are we doing this the right way? I wish we had video to show Pietro's reaction when you talked about the PGT use in donor, young donor oocyte. I wish I had hair to pull out in response to that statement. My jaw nearly fell off the ground when I was reading it this weekend.

What do you mean over 40 percent of people are using PGT in a good prognosis, young age group? Why? Well, let's talk about the outcomes. And then I really want you to ask that question once we go through the outcomes, because it's it's spoiler alert. It's not indicated.

So fresh oocyte, fresh transfer had the highest pregnancy and highest live birth rate at 66 percent and 56 percent per transfer. So no PGT, fresh egg, fresh transfer. Miscarriage rates were 14 percent in this group.

That's one point for Team Fresh A.R.T., if we're keeping score. Frozen oocyte, frozen embryo had the lowest rate of pregnancy at 51 percent, 51 percent pregnancy and 41 percent live birth rate. Miscarriage rates were 19 percent in this group.

So that's presumably not all. But frozen egg, who does PGT, so worst outcomes. The good news is that there were no differences in healthy birth weight neonates between groups with a singleton pregnancy.

So you are not more likely to have a preterm delivery from a frozen compared to a fresh donor oocyte. So really, I think that the idea that fresh egg, fresh transfer has the highest pregnancy and highest live birth rate. I think that really drives home the point that PGT should not be performed in donor egg cycles and especially looking at the frozen, frozen rates.

It especially should not be performed in frozen oocyte cycles where you're then intentionally generating a frozen embryo that have the lowest success of all groups and actually like an unacceptably high miscarriage rate in that group. And I think we also have to carefully balance success and cost with ease and availability of donor oocytes. There's no question in my mind that donor egg banks are easy to use, but 10 percent absolute difference in success.

Is that worth the savings? And then it also will suffer couples who may want more than one child. You may be reducing the likelihood of having additional children down the road from purchasing a small egg lot. And so I really think it is so much easier to use a frozen donor.

But I think we have to be very transparent when counseling our patients on the risks and the success rate of the and the differences between groups. Now, well said, Eve, I was quiet and didn't pull out my hair when listening to it. But it just it just reflects two thoughts.

One, we don't realize the complexity we're adding to this process because we can. And I hope it's not profit motivated because, you know, we get paid for PGT-A. But I think it is in some degree.

But we don't need to add this technology to this. While convenience has something to do with it. Testing an embryo is, I don't know, for reassurance.

And I don't I don't necessarily buy that. And by the way, the evidence doesn't suggest it in all the trials with PGT-A that the young women don't need PGT-A and they and they lower success rates. But that's balanced by the fact that the success rate is still high.

So people don't see it in their everyday life. People are still getting pregnant. They don't see the absolute difference with until you aggregate these numbers.

So they're still motivated to add all these things on because they think it's helping. I think there's two kinds of people that ultimately arrive at donor egg and arrive at the decision of whether or not to use PGT. One of them, I think, are the patients who have experienced personal ART cycle failures, repeated implantation failures, repeated early miscarriages, multiple rounds of IVF.

And then they're finally getting to the point where their chances are about to increase and they want to maximize, at least theoretically, their chances of success with that very next embryo transfer. So PGT to them sounds very attractive, particularly when they've used PGT potentially themselves for multiple autologous cycles. And then the other group are the patients who I'm already spending all of this money on egg donation.

There's a sunk cost there. Why would I not spend a little bit more and theoretically optimize the success of this major investment? And I think for both groups, it's really hard to dissuade them from PGT. It's a conversation that can take you five minutes to say this is what PGT and PGT isn't.

But it could also be a 30 minute conversation trying to talk them out of it. And it's a really challenging one that I think all of us have dealt with before. But 40 something percent using PGT is I can't possibly be an OK number.

I'm going to disagree a little bit. We're selling PGT-A. We're not we're not talking our patients out of it.

If we said, no, we don't need PGT-A for donor eggs because it adds cost. It adds invasiveness at lower success rates. And everyone would would understand that.

We were letting the patients make that choice. And so I don't I don't think that's the case. Disagree a little bit there, Kurt.

I have that conversation every single day in my clinic. And it is, at least in my practice, it is driven by patient demand. I don't know what's out there on TikTok.

I don't know what's out there on social. But I cannot talk patients out of PGT for donor eggs in some circumstances. Some I'll grant you some.

But I think we I see it at the boards. Every answer that the new fellow is, it's the patient's choice. No, it's not the patient's choice.

It's what you recommend. It's what's right. It's what's what's what's cost effective.

It's what gives you the best outcome. If we haven't introduced a technology, well, you don't use it if you want to. You know, it's up to you.

I mean, we're the ones that are supposed to be giving advice. So we should be pushing back on that. Yeah.

And I will say I personally do with very little success. I'm just going to give a shout out to former editor in chief, Alan DeCherney, who always tells the fellows as the physician, as the REI, you're the boss. You're the ones that should be driving the the well-informed decision for the patient.

And I think that's what Kurt is getting at. By the way, Alan, congratulations on the 30th anniversary at this ASRM of the DeCherney Society. That is amazing, as he's now at his fifth major university organization as division head or chair.

So. We're going to stick with this donor theme and we're going to go on to a survey study evaluating donor gamete utilization rates, patient satisfaction and fertility treatment outcomes according to the desired race and ethnicity. So this is from Duke University.

First author Mebane and senior author Shelby Neal. The objective is exactly what the study said. They're doing a survey study to evaluate donor utilization rates.

Are the patients satisfied with what they got and what were their outcomes based upon their race and ethnicity? So this is a five year study at Duke, and it was a survey study designed to assess those questions. So over that five years, they had 450 patients that came for a consult looking for donor oocytes. And out of those 38 percent, so 170 responded to this survey.

And before we get into the details, I'm just going to say, once you start breaking down these numbers, one of the challenges of this study is just the small numbers that we get to. So they had 100 white donors who desired a white gamete who responded. 34 black, seven Asian and 13 Hispanic.

So what did they find? The findings in this study were specific to the black, non-Hispanic gamete donor patients, so those who wanted a black gamete. They overall had a lower odds of actually using donor gametes. The odds ratio was zero point one three.

They had lower satisfaction with the process, with an odds ratio of zero point one nine. And they had a lower chance of actually having a live birth if they use those donor gametes. And that was both for donor sperm or for using ART with donor oocytes.

And that odds ratio was zero point one eight. Now, I will point out that the numbers are small. And so one thing when I talk to fellows is, you know, when you have small studies, you're always setting your alpha to zero point zero five.

The authors don't state that, but that's essentially what they imply with their outcomes, that P less than zero point zero five is statistically significant. So in theory, your risk of a type one error is the same because you're setting it at point zero five. But in this case, if you had one change in the outcomes, it would move the findings to not significant.

So, for example, they had 67 percent of black patients had a baby versus 88 percent of whites, and that was statistically significant. But that was out of only 16 births. So if you move one outcome from one group to the other, it's no longer statistically significant.

So that's the risk with small studies. Your risk of type one error is increased and your risk of a type two error is increased. So in conclusion, you know, they find something that I think we all agree with, that patients who are minorities in this study, it's the black patients or those wanting a black donor gamete were less satisfied with the process.

They were less likely to actually utilize treatment and they were less likely to have a live birth. And so at the high level, I think it just highlights something that we all recognize clinically, that the availability and process of donors, especially for ethnic minorities, is a much as a challenging process. I think from a study design standpoint, there's a few things that we can talk about.

It's a small study, as I said. And so that risk of type one error, literally, if you move one patient for any of these outcomes, they're no longer statistically significant. But I think we all recognize clinically that we see this.

So I think that's just an artifact of the small sample size. They had a low response rate of 38 percent. And you might imagine that patients who are dissatisfied with the process will be more likely to respond.

So maybe they're not capturing patients who were satisfied and who it worked well. And then I think these things may be geographically different. And we'll see that when we talk about the next study that happened in New York, which had similar findings, but a different patient population where there was the disparities in the health outcomes.

So before we move on to the next study, I'm going to jump to the one that sort of dovetails on this that I have. But let's just talk about thoughts on this. Pietro, what are you thinking? I think the elephant in the room here is that there's probably a significant cultural component to the utilization of donor gametes.

I see a disproportionate number of Spanish speaking and Portuguese speaking patients in my practice. And having a donor conversation with them is often challenging for a couple of reasons. One, they probably don't have any friends or family who have done it before.

And I think that's different in your kind of middle income, white, North American patient population. Two, there's a significant amount of cost associated with the use of donor eggs that in general, these primarily Spanish, Portuguese, ethnic minority patients typically don't have the huge disposable income to be able to utilize donor gametes, particularly in a mandated state without insurance. So I'm not surprised that utilization rates are different.

But even when you've crossed those hurdles with these patients and they actually start looking around in the donor egg bank offerings, they're usually pretty disappointed with what's available. They just don't have a lot of patients that look like them, sound like them or from similar backgrounds as them. So there's multiple hurdles here for these patients.

But I think it begins with just social acceptance within their culture of using donor gametes. Yeah, that's well said. So I'm going to jump out of order and just quickly describe another research letter that is essentially looking at a similar topic.

So this one is from Cornell and it's looking at their donors. And in this study, there's 731 potential donor recipients who were screened. Again, just like the study out of Duke, the majority are white and there's a minority that are of ethnic minorities.

In this study, what they really found is that the Asian population, those wanting an Asian donor, took longer to be offered an egg and took longer to utilize the egg. So it was a month longer to be offered donor eggs, in other words, to match them to a donor that they were satisfied with and five months longer for them to utilize it. Of interest, they were able to actually break down, though, the percentage of donors that they had that was Asian.

And they actually had a larger percentage of Asian donors than they did those wanting Asian donors. And they had a larger percentage of Asian donors than they have Asians in the New York area from a population standpoint. So it wasn't from a lack of donors that was eligible.

And when they drilled down on it, really what they found is that the word Asian, obviously, we're taking the largest and most populated continent on the country and we're lumping it into one word. And they found that they had an adequate number of what you might describe as Chinese Asians. But when you started to get into Southeast Asia and Indian Asia, they didn't have enough donors.

And I think that really gets down to at some point, we just need to get an adequate donor supply for these populations. And lumping this biggest, most populous continent on the planet into one term doesn't capture well the needs of those patients that might be defined by that. All right.

So that concludes those two studies. And next, we're going to jump back to you, Eve. And we're looking at return rates and pregnancy outcomes after planned fertility delay with oocyte cryopreservation, the theme of the day.

Yeah, this is a systematic review and meta-analysis with first author Abirami Kirubarajan and senior author Sony Sierra from the University of Toronto and Trio Fertility. And apologies if I did not pronounce names correctly. But the objective of this study was to characterize the literature on social oocyte vitrification, specifically with regard to return rates, thaw rates, clinical pregnancy rates and live birth rates.

And it was a systematic review and meta-analysis that included 27 studies in patients who pursued planned oocyte freezing with over 13,000 patients in total that were included. The US and UK contributed 13 papers, while the majority the majority were from the US and UK, while Spain, Belgium, Israel, Australia, Canada, Chile, Sweden and Taiwan were the remainder. Most of these were single center retrospective cohorts.

Five were surveys and three were qualitative interviews. There was only one study where the average age at the time of retrieval was less than 35 years. And all of the other studies had average age ranges between 36 to 38 years old.

The median number of frozen oocytes per person ranged from nine to 14 as a median. And most patients only underwent a single cycle. So I think that's an important point that we'll revisit when we talk about success.

The overall return rate was 10.8 percent. And again, the interval for follow up of these studies was not explicitly stated. The median age at the time of thaw was 40.

A total of 575 live births were reported, giving an overall live birth rate of 28.9 percent. I do commend the authors on doing the study, but I have a few thoughts, some on the study themselves and some on general messaging. So I think we need more studies with a longer duration of follow up.

They don't explicitly state the time of follow up, but if the majority of the patients were 36 to 38 and then the median age at the time of thaw was 40, I would love to know how far out they collected these data. So are they just not giving patients enough time to return? And I think one of the best studies that really looked at this was the NYU study that looked at 15 years of follow up. And when there was 15 years of follow up and that one study was included in here, return rates were closer to 40 percent as opposed to 10 percent.

And so to me, I think it's very unclear if this 10 percent return rate is is really reflective of the whole population. And it's really just return rate of the patients who are returning. It's not that these patients have subsequently discarded their oocytes.

And so it's not really a final return rate for this cohort of data. And I also think that I worry a little bit that that can be misinterpreted and it could be used as an argument against employer covered planned OC cycles, which is starting to become more popular. And so I really don't want to go backwards here.

So I think that your meta analysis is only as good as the data that's inputted. I think more studies are needed with longer durations of follow up. The second is these patients froze at an older age and they froze a lower number of eggs.

And so I think, you know, if you freeze in an older age and you freeze a lower number of eggs, you will have lower success. And so I think we should be counseling patients to freeze oocytes earlier and to go through two cycles to maximize their likelihood of first and then also subsequent live birth. And again, we publish these data and a shout out to first author on that paper is Jen Bakunsen on this incredible work as her fellow research project, really showing cost effectiveness of freezing it in an earlier age and a higher number.

And so, again, I commend the authors on this work. I think that it's important. But I think, you know, it really says what's out there.

And I think we need better longer term studies that look at this over a greater duration of time. And if I'm curious to what you think about this, since you've done a lot of work in this specific area, do you think the motivations or kind of the social circumstances at the time of freezing eggs matter with regard to utilization rates down the road? Right. There's different reasons why patients freeze eggs.

You have the 36 year old who is in a long term relationship and broke up with someone who they thought was the one. And now they just want to have a plan for the future or the one who not single, not dating or not dating, not engaged anyone, but just wants to preserve the opportunity for the future. Do you think the social circumstance at the time of freezing has any correlation with long term utilization? It's a great question that I don't I don't know the answer to.

It's a good it's a good project to look at. I don't know. I have to imagine it does, because I think if we lump utilization rates together, we're probably missing some of the nuances.

They're certainly patients that we know for sure are going to be back to use those eggs. You can feel it. They're freezing because they have a DOR diagnosis, but they're getting engaged next year and want three or four kids.

I think that patient is very different than the one who's freezing midlife with with a big breakup on the heels of their decision. And I wish we could tease that out a little bit better. Yeah.

So it's a good point. There's another way to look at this is that it assures patients are when they come in to freeze their eggs. I mean, the majority of people don't use them.

I mean, life changes. There are circumstantial changes, as Pietro mentioned. And, you know, we focus on the need for everybody to do the best they can up front to maximize their pregnancy rates.

Yet the majority of people never maximize their pregnancy rates. They never use them. I don't know how to solve this issue.

I'm just pointing the other the other side of the half full glass or the half empty glass, which is that for all the egg freezing we do, the eggs aren't used. Well, and I agree with you, because even the best study shows a 40 percent utilization, which is not the majority. But I think that there is a huge difference between a 10 percent and a 40 percent utilization.

No, I'm not. Not disagreeing. I'm just just pointing, you know, flipping it over to say that we talk a lot about egg freezing for the, again, potential to someone to use it, not that somebody necessarily will.

Yeah, I think it would be really interesting to look at every person who raises oocytes in a single center program like our program and follow them longitudinally to really understand what happened. I would guess that the majority of those patients were able to conceive without medical assistance, completed their families, didn't need to use their eggs, which is fantastic. But what about the other patients? Why aren't they using them? Did they never intend to have children? Did they life circumstances changed? I don't know.

I mean, I think it's a great answer. But I think it's a social experiment that needs to be done, not not just the success of the eggs. Yeah, I agree.

Right. Right. To really understand, like, what are the what are the implications and the ramifications of what we're doing and what we're spending, arguably, a lot of time in counseling and managing these patients.

Yeah. And as you said, Eve, the most of these patients only underwent one cycle and they were older. And if you look at the Doyle model, the Harvard model, any of the available models on how many eggs you should freeze to have a live birth, they're not getting there with with one cycle.

But yet patients seem to be OK with that. And so I think it is an interesting social question as to what their actual motivation and goal is to be satisfied with this. Pietro, in the interest of time, let's have you do the POI study and endometrial receptivity or thickness for a frozen embryo transfer, because this is probably the most surprising one to me.

And then we'll close with Kurt giving us the worldwide ICMART data. Yeah, I love the research letter section in F&S. It's a really elegant way to talk about one or two key points in a very specific patient population.

I think these two research letters this month did exactly that. And shout out to the folks in Canada. Another paper from the Mount Sinai Hospital in Toronto, Canada.

This research letter is entitled Longer Duration to Optimal Endometrial Thickness in Women with Premature Ovarian Insufficiency is associated with clinical pregnancy rate in donor egg cycles by first author Dinh. So you know how we all use hormone replacement cycles in patients with POI undergoing egg donation cycles? You know how we often struggle with endometrial thickness in this patient group? And shout out to Eve, who's helped me out with a patient who I had a clinical question about earlier this year that kind of fit this exact mold. Well, the authors of this study wanted to look at this patient group specifically and examine whether patients with POI needed extended endometrial stimulation and how this extension impacted pregnancy outcomes.

They had two comparator groups. One group were AMA patients 41 and over undergoing donor egg cycles and another group undergoing autologous frozen embryo transfer. All of these patients were given esterase four milligrams twice a day for 14 days before undergoing a measurement of their endometrial thickness.

And if their thickness was less than eight millimeters, then estradiol patches at 100 micrograms every other day was added. An ultrasound was repeated in about five to seven days. Progesterone was started ultimately once a eight millimeter or more lining was achieved.

Primary outcome of the study was to was to account for the number of days to optimal endometrial thickness and the secondary outcomes were all of the obstetric outcomes. They had a very straightforward analysis. They used both Poisson and logistic GEE models, and they accounted for age, number of previous cycles and endometrial thickness at the time of decision to proceed with embryo transfer.

And in total, they had 878 cycles available for analysis arising from 387 patients. 51 of which were the POI group of interest. So what do they find? Well, interestingly, about 10 percent of POI patients during the course of their monitoring were determined to have fluid in their endometrial linings.

About 14 percent of them had sub endometrial cysts, and these are both more commonly found in this POI group than in the other two groups. But the ultimate question at hand was, what about the endometrial thickness and how long did it take to develop? Well, a higher proportion of POI patients required more than three weeks for optimal endometrial thickness compared to the other groups. And once achieved and progesterone started, they had lower clinical pregnancy rates.

Does that jive with what we what we believe, what we think, what our experience looks like? Well, I think we have to talk a little bit about the mechanism here to be able to have this discussion. We know that lack of endogenous hormone exposure negatively impacts endometrial development and kind of bringing back the point that Eve helped me out with. I had a patient earlier this year who was young, POI, new diagnosis, had not yet started on hormone replacement therapy, but hadn't had a period in over a year.

I had a really hard time getting her lining to build up. And Eve told me, sit on your hands, give her estrogen for a month, give her Provera, give her estrogen for another month, give her Provera. It may take two, three, four cycles for you to be able to get there.

But once you have that cyclic exposure to the estrogen, the lining will get there. But along the way, you may see some of that exudative fluid in the lining. You may see some subendometrial cysts, but just keep at it.

And I think that's exactly what this paper showed us, is that with a long estrogen exposure here was on the order of days to weeks longer, not months or many cycles. These patients could achieve a lining of eight millimeters, but you have to be patient. When transferred, this patient group that took longer also had a slightly lower clinical pregnancy rate, but not in a clinically dramatic way where you shouldn't offer more time for these patients.

Now, the questions that I had from this paper that weren't answered were I want to know what the what the denominator was, how many patients never ultimately made it to transfer, how many cycles were canceled, how many attempts did it take for the patient to achieve a lining that was thick enough to arise at transfer? Because I think that's sometimes helpful counseling number. I also would have loved to have seen these patients who do develop fluid in one cycle or subendometrial cysts in one cycle. Do they keep showing up? Is this a one time phenomenon early in that estrogen exposure cycle? But really helpful counseling, I think, for us who see these POI patients more and more commonly, they just got to be patient.

The lining will get there. But if it's taking longer than that three week mark, their clinical pregnancy rates may be slightly negatively affected as a result. Eve, I want to go to you first.

You've helped me out with this patient scenario recently, and I'm happy to report that that patient after three months of estrogen and provera withdrawal ultimately underwent a transfer at six and a half millimeters with a little bit of fluid and with subendometrial cysts and is discharged to her obstetrician. So in spite of all of it, we got there. So happy to hear that.

Yeah, I mean, actually, I want to give credit to Alan DeCherney, who I had called when I was recently at a fellowship and had a few hypothalamic hypogonadal patients where I just could not get the lining to develop. And Alan sort of jokingly said, you have to get their lining almost to the point of hyperplasia. And then it'll then it'll become much more receptive to estrogen.

And so there's no set protocol on how to do this. But I have found in, you know, 18 years of experience now that if you continue them on estrogen for a few weeks to months, you will eventually get a lining built up in these patients who have extremely thin linings. One other observation that I've noted is patients who have been on birth control pills from a very young age, like 13, 14, 15, and who have stayed on continuous OCPs for a long time often also have these atrophic endometriums.

And in those patients, I have similarly put them on a regimen of unopposed estrogen for a few weeks, followed by withdrawal with progesterone and have done that cyclically in order to expose their endometrium to estrogen. And it does work. And I have had good success with it.

I do I do see that fairly often in long term continuous OCP users, and it's it's described in literature as endometrial atrophy. I got one more great research letter before you let Kurt round out the story with this wonderful ICMART paper in this month's Fertility and Sterility. This one's entitled Feasibility and Efficacy of Subcutaneous Catheter for Controlled Ovarian Stimulation.

This is by first author and interactive associate Rachel Mandelbaum and senior author and F&S Reports editor Rick Paulson from the University of Southern California. So we all know that patients hate feeling like a pincushion. And we often get asked, is there a way to minimize the pokes? It's the wear and tear of being an IVF patient is all the damn needles.

Well, there are many groups that have been working on home monitoring for ultrasound, saliva and finger prick monitoring for hormone monitoring, but drug delivery is still pretty antiquated. It still requires dialing up the pen, pinching the skin and injecting and sometimes even mixing medications and dealing with kind of the burn and the uncertainty of did the shot work and did you mix it appropriately? Enter subcutaneous catheters, which are not new technology. These have been available for two decades.

This is what men and women who are diabetic utilize when they have to set up an insulin pump, a continuous glucose monitor. And they've been shown to reduce anxiety, pain and acceptability of treatment for patients who need repeated injections as part of their medical treatment. The authors of this study decided to test out a commercially available subcutaneous infusion set made by a company called Convatec in Denmark.

And the infusion that's called the Neria Guard basically includes an auto insertion device with a retractable needle that deploys a self-adhesive infusion set that contains an eight millimeter soft cannula that attaches to tubing that's compatible with a lower lock syringe. It stays on the skin for seven days. It allows for patients to self-administer meds at home, including the trigger shot.

This was a small study. They only looked at ten patients and compared their FSH and estradiol levels to a retrospective cohort that were matched on age, BMI, AMH levels and a similar constant medication dose throughout stimulation. So what did they find? They found that FSH levels did not differ and neither did peak estradiol levels.

They found that there were no malfunctions that occurred and there were no additional excuse me, that there were no additional needle injections required during the course of stimulation. However, one out of every three patients reported an adverse reaction. And for context, this is three patients out of the ten.

One included a mild allergy. One had a little bit of bruising at the site of deployment of the subcutaneous catheter and one had mild erythema that was self-resolving. 100% of patients surveyed actually found that the catheter eased anxiety, was easy to use and did not impede their daily activities.

And of three patients in this cohort of ten who underwent a subsequent cycle, they all reported preferring the catheter to the subsequent traditional needle injections that they used. While this study is not moving, I think the needle on how to deliver medications, I think it really is interesting on what are the things that we could be doing to ease the burden of being a patient, the physicality of being an IVF patient. And this is a device that I've actually looked into myself because I've had patients ask about it.

And I think in the appropriately counseled patient who needles are a major stressor, this is something that could be pretty cool, pretty innovative. And it doesn't seem to have an impact on medication dosing vis-a-vis FSH and estradiol levels, but could be a pretty cool way to explore the space a little further and make patients improve patient experience. In addition to all the wonderful things that are happening with home monitoring of hormones and ultrasound.

Great. Thank you, Pietro, for the summary of those. Encourage everyone to read the research letters.

I think Pietro and I both really love the simplified format of those, and it's a good, quick, concise way to deliver a specific finding. Kurt, let's end with the discussion on ICMART. So what's going on in the world globally with ART? My pleasure.

I'm happy that ICMART, let me spell it out for you, the International Committee for Monitoring Assisted Reproductive Technology. ICMART is publishing in F&S. They publish in F&S every other year, and they publish in human reproduction the other years with their basically worldwide ART statistics.

And what we're seeing now, just to put you all in perspective, is 2015 and 2016 data. So ICMART is a volunteer organization, WHO-backed. It is not SART.

And just before we get into the statistics, I'd let you know that this is not mandated. It's not audited. It's basically all voluntary.

However, having said that, it's amazing to see the statistics worldwide and what's going on with ART across the world and how it compares to us and others. And it's hard not to look at the tables and cheer for your country or see how things are done in different ways. So let's dive into it a little bit and let the data flow over you because I learned a lot.

We're all very USA-focused, practicing hard here. It's nice to see what's happening in the world. So again, 2015-16, not the SART data from last year or two years ago, but we're basically talking about an increase slowly, but over 2.5 million cycles up to 3 million cycles a year.

That's pretty darn impressive with 500,000 to 600,000 roughly infants born worldwide. Interestingly, just to throw some facts at you, it's around 25% are in women over 40. I'm not sure how that compares to by population, but it was interesting to see that age still is a major factor for IVF across the world.

Around 50% of the cycles are frozen embryo transfers, even five years ago. It's impressive to see that the frozen embryo transfer has revolutionized the way we practice ART. Only about 7% of the cycles are egg donation.

And drum roll, please. How many people use ICSI worldwide? Too many, Kurt. Too many.

57%. So I can't believe that 50% of cycles are male factor worldwide, but 50% of people are using for ICSI. And the cumulative delivery rate, again, self-reported is 32% to 33%.

Hear what I said, cumulative pregnancy per initiated cycle, not per cycle. There were some impressive stats too that, again, we're talking 2005 here, almost nine years ago, but the twin pregnancy rate is declining, at least in those two years. It's gone down from about 16%, then it's on its way down to a whopping 14%.

And the number of embryos transferred, at least according to self-report, is 1.7, which is actually pretty good. So I would say that worldwide things have been pretty impressive. So what did I learn? So first of all, again, this is an under-reporting, as you might imagine.

They say that probably two-thirds of the world's clinics are actually reporting to this. That's still pretty good. And China, for the first time, reported in 2015, which was very important to get them involved.

So we're talking about 79 countries. That's pretty impressive that ART is reporting 79 countries. Not all the countries report.

It's as low as one-quarter of the countries in Africa reporting, but there's very good reporting, obviously, in Australia and New Zealand, Israel, and most of Europe. And as I mentioned, China is reporting for the first time in 2015. And my goodness, are they dominating the world? So there's more than 600,000 cycles reported in one year in China.

So I'm just going to... I was fascinated by this. I'm going to go look at the table a little bit. So China has 600,000 cycles.

What do you think is the next highest country? Anyone want to guess? Japan. I didn't know Japan was so high with almost 260,000 cycles. What's the United States? 275.

It's about 84 cycles, 84,000 cycles a year. So we're way below... Again, this is 2015, 2016. We're way below the dominance in the other countries.

Now, Europe is very high, but per country, Europe is not so high. So you can look at 67,000 cycles in France and 74,000 cycles in Germany and stuff like that. But cumulative, Europe is a dominant player.

So then there's really small countries. And I got a kick out of this. So there's 39 cycles in the Dominican Republic.

39 cycles, it's amazing. But they're reporting. And I can't help but be competitive.

Iceland with 361 cycles is rapidly approaching the number of cycles in Ireland at 397. So maybe when we see this in two years, Iceland can outperform Ireland. But anyway, to be kind of serious here, there is some really good information and I'm very pleased that the world is, again, attempting to put these numbers together.

I did learn some things that I just didn't know about being US-focused. So this talks about cross-border IVF and cross-border IVF is reported at least in 18 countries. I bet it's higher than that, but at least it's reported.

This surprised me. The cross-border was 8,000 cycles just to get access to IVF and another 8,000 cycles to get access to donor egg IVF. So donor egg is still the number one driver of cross-border.

And I didn't realize Spain offers 6,000 of those 8,000 donor egg cycles. I just, I probably knew that, but just didn't pay attention to that. That explains why all the papers are coming out of donor egg with a large volume out of Spain.

So ICMART has been collecting data since 1989. And it's really impressive to see that there's 3 million cycles worldwide with 800 live births. Most of the missing countries, which I think will be improved over time is in the Middle East and Asia.

And I'll just leave it at this because I thought this was fascinating too. They make a calculation of number of cycles per million people. So this is just a metric that's kind of fun.

So overall, if you equate this, it's about 450 cycles per million people worldwide. But there's some countries that are just blowing that out of the water, which includes greater than 300 cycles per million. And those countries are many in Europe, but Israel, Belgium, and other places.

So ART is not uniform across the world is the message I'm taking, but the IVF that is being performed across the world seems to be at least those reporting of reasonable quality, reasonable safety, reasonable number of multiple births. And I would bet would only be improving. By the way, PGT-A is, looks like almost a uniquely American phenomenon when you look at the numbers here, not a worldwide phenomenon.

So put it in perspective, again, I know this is nine years behind, but it still really does give you a trend and realize that while, we might be still leading the world in technology, the world is catching up in terms of the use of ART. I think this goes back to something that Zev Rosenwaks used to tell us as fellows that 20, 30 years ago, there was probably a handful of places that you needed to travel to, to get high quality ART and have a reasonable success rate. And I think in the modern era, straightforward IVF done well, and in the appropriate patient group with a good lab really works and it works no matter where you do it.

And I think this data kind of reinforces that point that a rising tide has lifted all ships here, both nationally and globally, and patients are experiencing more and more success regardless of where they're going for their care. Right, and as I do a little bit of traveling and talk to other countries and other societies, what is our controversy, which is mostly PGT-A, is not their issue. They wanna just perform good quality IVF, but it does not gonna surprise me if PGT-A makes it to their labs eventually too.

And Kurt, thank you for summarizing this article. I think there's 75 or so supplemental tables. There's so much data here.

And a shout out to ICMART, like this isn't SART data, right? And maybe the quality, the validation, the registry, the quality assurance committees, it's not at that level, but to get this data is a massive undertaking. And there's so many interesting trends, like you said, China, adding their data, just dropping this massive amount of cycles was very insightful. The fact that they're doing very little ICSI maybe is a nod to what we should be doing in the West and in the US and the PGT differences are just staggering.

So it's just fascinating data. You could spend hours reading this article and digging into it to try to grasp and understand these trends that are happening globally. And look at it for trends.

The individual data is suspect. I mean, there's countries that are performing, you know, 300 cycles a year and claiming 70% pregnancy rates. I mean, some of this is propaganda, but the fact that people are reporting it and it's aggregated is the message to get here.

Absolutely. Fantastic discussion today. As always, we're only talking about a few of the articles.

We encourage you to get in there and read all of them. They're video articles or other very good research that's being performed. We encourage you all to join us at ASRM.

We'll be dropping the podcast, as Pietro said. We'll be having a journal club. And for the first time ever, there's a special F&S session that highlights the top papers of the year in all of the sister journals.

So we hope that you read those and learn from those. Eve, Pietro and Kurt, it was great chatting with you today. I learned a lot as always, and we'll see you next week at ASRM.

Bye everyone. See you in Denver. Thank you, Micah.

Wonderful as always. This concludes our episode of Fertility and Sterility On Air, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield and Dr. Adriana Wong.

This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource and service to its members and other practicing clinicians. While the podcast reflects the views of the authors and the hosts, it is not intended to be the only approved standard of practice or to direct an exclusive course of treatment. The opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.