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 discussions with authors and other special features. F&S On Air is brought to you by the 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, Dr. Pietro Bortoletto, Interactive Associate-in-Chief, and Associate Editor, Dr. Kate Devine.
Good morning, listeners. This is Eve Feinberg, live from ESHRE. My first guest is near and dear to my heart.
It's Dr. Alexandra Herwick, or Allie Herwick, and she is one of the fellows at Northwestern presenting some of our research at ESHRE. She is also a podcast host for the new SREI Landmark Trial podcast, so I encourage everyone to pop onto that as well and start listening. Good morning, Allie.
Good morning. Thank you so much for having me. I'm excited to be here.
Yeah, I'm so excited that you're here for a number of reasons. I think it's excellent to have fellows see not just the American Society for Reproductive Medicine meeting, but also the European Society meetings. Yeah, it honestly has been wonderful, and I feel like I've met so many incredible people, and it's good to build my network.
Yeah, no, it's great. So tell us a little bit. Obviously, I know about the work that you're presenting today, but what can you tell our listeners about your work? Yeah, the title of my research is Trends in First Cycle and Cumulative Live Birth Rates for IVF in the United States specifically.
And essentially, we did this study in combination with UNIFY, and the whole idea was that we know IVF has drastically improved over the years when you think back to the live birth rates back in like the 1980s to now. There's been many advances in the lab as well as with clinical protocols. And so specifically in the United States, there's also been changes in access with state mandates as well as employer fertility benefits now.
But it really is limited depending on where you live and then where you work. And so we wanted to show how IVF has evolved over the years to hopefully inspire policy. Yeah, and I will say, I think some of this research, at least from my perspective, was inspired by many of the claims that IVF is ineffective.
Right. And I think as we've seen the rise of restorative reproductive medicine and a lot of the studies that have come out really downplaying the success of IVF, what we did was use SART database study to examine and really tease apart like what is IVF success and how do you think about it? So tell us a little bit more about this. Yeah.
So as you alluded to, we use the SART database, but it was a retrospective cohort study. And we were essentially comparing first cycle and cumulative live birth rates from 2019 against the prior published national outcomes from 2004 to 2009. And for our study, we define like a cumulative live birth as up to three IVF cycles.
And the benchmark that we compared it to was a Luke and colleagues paper that was published in the New England Journal of Medicine back in 2012. And essentially, our cohort had over 42,000 patients who all started their first ovarian stimulation cycle in 2019. And then we followed them out for both like fresh and frozen cycles up to three cycles of IVF or up to the end of 2022, whichever one came first.
And in our inclusion criteria, we specifically included women all less than 40 years of age. And then again, they had to have undergone their first autologous IVF cycle with their own uterus in 2019. And we included 13 states plus Washington, D.C. in our analysis because we felt like it was a representative sample of the United States.
And that roughly makes about 57 percent of the United States. Yeah, it's crazy, though. So 57 percent of the U.S. ART cycles comes from 13 states alone, correct? Yes, correct.
And these are like obviously like very populated states in all four regions of the United States. But it is it is crazy to think. Yeah, I think that really speaks to some of the gaps that we have in access to care.
And so I think one of the nice things about this was we really had the ability with these state models to clean the data and really tease out good prognosis patients and look at the data in terms of what do we see in a good prognosis patient? What do we see in the average patient going through IVF? And I don't want to steal your thunder and talking about those success rates, both first cycle and cumulative. But I think it's really remarkable, actually. It definitely is.
And just like a big takeaway from the research we're presenting today is that a single IVF cycle in 2019 got patients to a live birth about as often as three cycles did back in 2004 to 2009. And so when you think about that, like we're doing one cycle and getting those live births compared to three cycles. Yeah.
Do you want to go through those numbers for our listeners? So one in your first cycle of IVF in a patient who's younger than 40, what was the single cycle success rate? In 2019, it was 56 percent, which is a wonderful percentage nowadays. And back for a cumulative like three cycles in 2005 and 2009, it was 53 percent. And that's for all ages combined.
That's for all ages combined. Correct. OK.
And then what happens when you tease out like the good prognosis patients? What do we see in that population? Yeah. So in the patients who are under 35, their first cycle rate, this is again comparing to the 2005 to 2009 cohort, went from 41 percent up to 65 percent in their first cycle. And then when you do 35 to 37 cohort, it went from 32 percent to 51 percent.
And then in our oldest population, it nearly doubled from about 22 percent up to 37 percent. Yeah, that's remarkable. And, you know, again, not to harp too much on the RRM success rates, but I think a lot of the data that they're publishing and showing is comparing it to a live birth rate of 31 percent.
So how accurate is that? Based on our data, it's not accurate at all. And in fact, when we've done even the cumulative three cycles that we looked at in every age group, there was a 12 percent increase from 2005 to 2009, regardless of like good prognosis or like older age. I think that's remarkable.
And I think that, you know, as we think about what are the take home points from this, what do you want our listeners to come away from this understanding? That's a great question. And I think, honestly, IVF is just better than it once was. And I think we're continuing to improve and evolve.
I think there are two aspects that we should think of. One is from a patient standpoint and that by getting better and being able to get better outcomes with one IVF cycle compared to three, we are helping decrease burden in some of our patients. And I want to be careful here because patients absolutely still have like the financial burden, the physical, psychological burden from roles of like assisted reproductive technologies.
And that hasn't gone away. But if you can make it less where you're doing one cycle instead of three for certain patient populations, I think overall you're decreasing that burden. It's also important to have these values because you can talk about treatment continuation with patients and the more information we have, like what are the percentages? I think that will only get better in time.
And then the other component is about policy specifically. Obviously, this is probably more applicable to the United States. But if we're able to show that IVF is, in fact, effective and we are becoming better at it, I think a lot of our insurance policies will also hopefully appreciate that and know that maybe it should be for some patients first line treatment and not at the end of like you have to do X, Y and Z before we would cover your IVF cycle.
Yeah, I think those are all excellent points. And I just want to congratulate you on work really well done and knowing what went into this on the back end, how much work you put into this project. So congratulations and I'm so excited that you're here and thank you for being on the podcast today.
Thank you for having me. I'm now with Dr. Jim Toner, who's the vice president of ASRM. Welcome, Dr. Toner.
Jim, it's nice to see you here. Nice to see you. How's your usher meeting going? It's great.
I've never been to London, enjoying the sights and sounds and catching up with friends and doing the board stuff and the exchange session yesterday. Oh, it was packed. I couldn't believe it.
I know. Just for our listeners who aren't here, ASRM did an exchange session that focused on optimizing fertility. So we had Dr. Bob Brannigan, Dr. Jim Toner and Amy Sparks and going through all of those things.
You want to tell us a little bit more about that? I will say it was standing room only, packed room. I left to run to the restroom. When I came back in, they almost wouldn't let me back in.
I had to fight to get a seat. Yeah, those are these exchange sessions are kind of fun. Three speakers, you only have 45 minutes, so everyone's going da, da, da, da, da, trying to rattle out a bunch of things.
But it was an interesting focus, I thought. It was kind of lifestyle issues that impact fertility naturally. And do they also impact fertility within the IVF, assisted reproduction sphere? there, from my perspective, some value in understanding that, because, especially for the women's perspective, by the time we tend to see them, they are dispirited, feeling pretty helpless, everything they've tried hasn't worked, but I think through understanding these factors, you know, diet, exercise, sleep, it maybe restores a little bit of agency to women and helps them feel like they can be successful and that they can be part of the team that helps them achieve the ultimate goal.
Yeah, I agree, and I think it's really nice to talk a lot about the focus on male infertility as well and lifestyle factors in the men. I think that's been under-recognized, the importance of that for so long, that I love that we're bringing that to the conversation. It's interesting, a lot of the sessions yesterday that I went to focused on lifestyle, there were a lot of sessions on GLPs, a lot of sessions on weight loss, and I think that this global recognition that the healthier you are at preconception leads to a healthier pregnancy and leads to better live birth outcomes.
I think we've intellectually known that for a long time, but I like that it's becoming more of a focus and it's nice to see that at this meeting. Yeah, I agree. You know, we focus often on just the technical aspects, here are the specific treatments we can offer, and it doubles your fecundity, it triples your, and not the day-to-day stuff that people are living.
Yeah, and I think you hit the nail on the head when you talked about having agency over it. I think our patients largely feel so helpless, like what can I do and what can I impact, and I think it's debatable whether or not what you eat can actually impact your end quality, but I think that your pregnancy weight and your pre-pregnancy weight can definitely impact your likelihood of having a healthier pregnancy. And so I think that having agency over those factors and going into pregnancy from the healthiest state that you can is good, and I love that we're focusing on that.
And people are differently positioned. Some have insurance coverage and can go straight to IVF, but for those who can't and potentially have some time, they're reluctant really to jump straight to IVF, and oftentimes these lifestyle interventions or assists might be all they need. Give them a few more months and they're pregnant naturally.
Absolutely, and I think choice in all of that too, is I would never force somebody to go through lifestyle interventions, especially at an advanced age. I think we really want to focus on those factors. But yeah, so I love that that's being discussed more.
Tell us a little bit about your upcoming presidential chain and activities that are on the horizon. Sure. Well, I certainly feel honored to be on the presidential chain.
And as it turns out, my presidency year will culminate in the meeting we'll have in 2028 in Nashville, which is the first time we've ever been to that town. But it's also the 50th anniversary of first IVF success. So it's going to be, you know, the theme of the meeting is celebratory, in a sense reflective, like look how far we've come over 50 years.
And also, you know, what's around the corner? How could this be better? And it's still remarkable to me that 50 years in, there's big unanswered questions. It's not like we've locked this down and this is the way it's done and will be forevermore, right? Yeah. I mean, I think that's been the most exciting thing for me as someone in the field for 20 years, is really seeing the evolution of how the field has grown and changed.
And I think as much as we know, there's that much more that we don't know. So that'll be sort of the theme of the meeting, patting ourselves on the back for how far we've come, but also sort of a call to action. Like it doesn't always work.
What are our other options? Right. How people build families who have challenges we've not been able to address yet. Yeah.
One of our previous guests on the podcast was Allie Herwick, who's one of the fellows at Northwestern. And we looked at cumulative live-birth success in 2019 and the subsequent years following that and showed huge increases from the prior decade. But still, I think we have a long way to go.
And so I think that that's the big question is, what can we optimize? What are the next chapters? Why are we not at 95% success rate or 100% success rate? And how do we get there? And we still haven't really made any headway with female age, right? We can't cure the fact that the eggs in a particular individual might be there, but at 45, there's so few that are still healthy enough to turn into a baby. We can't fix that, right? Not yet, at least. Right.
I mean, it's a huge... It's a huge problem, right? And I think in general, for longevity, I think there's a lot of work that's being done in the longevity space, looking at health span and lifespan. And I think ovarian span should be part of that discussion. Like, why have we evolved to live into our 70s and 80s and even 90s, but our ovaries stopped functioning at 50? And so how do we extend the ovarian lifespan for reproductive purposes, but also for health span and for prevention of menopause? And so I think those things go hand in hand.
Yeah, it'd be nice to decouple them. I'm not sure many people in their 60s want to have a child, but it'd be nice if they're not suffering from hypoestrogenism and hot fleshes and weak bones, right? So you might acknowledge that there's a window in which being a pregnant mother is safe and wise, but then a whole period of time that also needs better care. Yeah, I agree.
As somebody who no longer wants... I mean, I'm a mother. My children are going off to college. I'm not interested in having babies, but I would be very interested in having my ovaries perform a little bit better than they are today.
I'm curious. I know there's some therapies being considered, like mTOR inhibition, right? Which prevent the remaining eggs from entering folliculogenesis when they want to, if you just kind of postpone it. Maybe you can spread out the remaining eggs over 20 years and not just give them 10, right? Right.
And then there's also some exciting work that's being done by some of the basic scientists at Northwestern looking at anti-fibrotic therapy, thinking that fibrosis is a major cause of aging in multi-organ systems. And if you can prevent that fibrosis in the ovary, you may increase the elasticity and the ability of that ovary to function over a longer period of time. So I think we are inching towards that, but I think that we've come a long way in 50 years, and I would love to see where the next 20, 30, 40 years are going.
I think that's the very exciting part about our field. Another challenge we have now, it's kind of unfortunate, is the reporting of outcomes. I think we used to collaborate with the CDC for the past 30 years, functionally, and it was a very beneficial relationship.
They come at this from a different perspective than we've come at this, but they're great people with the right motivations to protect patient health, and it was a fruitful collaboration. Unfortunately, that office was let go, so SART will carry on with outcome, and we did provide outcome data even before the federal law required the creation of that federal office, but I think it's a miss, and it's a step kind of backwards. Yeah, I agree, and I think it just elevates the importance of SART.
I mean, SART's always been incredibly important, but I think it really highlights the need to self-regulate and self-report, and I think we're doing, especially going around at ASHA and listening to some of these other abstracts in some of these countries where they don't have national data collection, I think it's remarkable the efforts that SART makes and how much SART really helps to elevate our field. I agree. I think we've got the best system in the world for reporting because not only is it data collection, it's data monitoring.
The SART system has allowed us to do a whole lot of research. It's allowed us to provide to patients a predictor model based on actual data so that patients, at least in the U.S., can have a general sense of the success rate under their particular circumstances, the specific age, the specific AMH, the specific diagnosis, which is more precise than just going to clinic-specific reporting, which just generally breaks it into chunks. So it's a very good tool for patients, and it depended on collecting these data and curating them as we will continue to do.
Yeah, I think the work is tremendous. Well, I'm excited to watch you progress through the presidential chain and become the president-elect and then the president in 2028, and I'm really, truly excited for the future of our society. I am too, and thank you for the chance to have a few words.
Thanks for being here. Hi, listeners. My next speaker is Saeed Donishman, and we're talking about a really interesting poster that he's presenting.
The title of this poster is Multiple Sonographic Markers of Endometrial Receptivity Are Significantly Altered After Hormonal IUD Use Among Reproductive Age With Proven Fertility. So that's actually a really long title, but basically you looked at sonographic markers of IUD use in gestational carriers. Right, exactly right.
Yeah, so tell me a little bit more about why did you look at this? How did you do your study? That's a great question. I take care of many gestational carriers, being involved in third party reproduction, helping intended parents achieve their goals of creating their families. If you're trying to assess or evaluate the potential longer-term effects of IUD, we felt that we wanted to look at that in a population of patients who are fertile.
So which population gives us the best group to be able to assess and evaluate the longer-term effects of IUD? These are gestational carriers who've been fertile, who've had deliveries, who've had pregnancies, oftentimes more than one. Many of them come into our program, and they have to be screened to be gestational carriers. Yeah.
So when you guys screen a gestational carrier, do you do a mock cycle or how do you, what's your routine screening? So there are really three markers of endometrial function that we look at. So we typically have them come in during the follicular phase, their cycle, usually cycles somewhere between cycle days seven and 14. And then we're looking at essentially three areas of endometrial function.
We're looking at endometrial thickness, ideally eight millimeter in thickness and higher. We're looking at the pattern of the endometrium. So we want to look at a trilaminar pattern.
And then the third marker we look at is the presence of endometrial fluid or cavitary fluid, because that's been sort of negatively associated with implantation. Therefore, these three areas, if a gestational carrier comes in and she has an 8.5 millimeter trilaminar pattern with no fluid, there's no need for a mock cycle because almost every one of those gestational carriers are going to do fine in terms of having a receptive endometrium. And is that the same time that you're doing a cavity evaluation on them, like a saline ultrasound or... Exactly right.
So they come in, they spend several hours at our office, we get their blood work, their urine tests, and then we evaluate the endometrial lining with those parameters we mentioned, and then we do a saline ultrasound. So then we look at the cavity for evidence or presence of follic spiroids. So that endometrial evaluation is really important because it signifies the ability to have a receptive uterus and ultimately maximizing success rates after endometriosis.
And so tell me a little bit more. When you did this study, it was retrospective. Right.
And how did you do it? So what we did was we looked at several years worth of screening on gestational carriers. The majority of the embryo transfers were with donor-conceived embryos. So we're controlling for obviously the quality of the embryos.
These are mostly donor-conceived embryos. And then we also controlled the population because these are fertile women who are coming in to be gestational carriers. And so we looked at several years worth of data and over the course of the last 10 plus years or so, I mean, I've been taking care of gestation carriers for over 20 years, what I've noticed is that when there are problems with endometrial receptivity, meaning that when gestational carriers don't pass the screening, oftentimes it's because of endometrial function issues, presence of fluid, lack of the adequate thickness of the lining, and then lack of that trilaminar pattern.
So I had noticed that over the course of many years, but then we wanted to really formalize it with a study. And we looked at it and we looked at- And you looked at just Mirena, IUDs, not copper? So yeah, no, we looked at copper as well. So in this particular study in estuary, we looked at all gestational carriers who never had an IUD and then those who had a progestin-secreting IUD.
In a subsequent further analysis, we also divided into copper IUDs, no IUD users, and then the progestin-secreting. And so what we found was that there were several markers of endometrial function, the ones we talked about, that were significantly different in those with progestin-secreting IUDs versus no IUDs. And there was also significant differences between the copper IUD.
In other words, copper IUDs were similar to no IUD users versus the progestin-secreting IUDs, which had significant reductions in some endometrial markers. But how, you know, and looking at your, and I realize our listeners aren't looking at your poster, but looking at your poster, it looks like the upper and the lower limits of endometrial thickness. The differences were very small.
They were small, but significant. You're right. Because when you look at endometrial thickness, you're looking at like eight millimeters versus 8.4. The mean, there was differences in the mean numbers.
Obviously, our sample size was large. When we looked at the presence of endometrial fluid, you had about 4.9% endometrial fluid in non-users versus 10% in those who were users of the progestin-secreting IUD. So there were statistically significant differences, albeit small.
And so our hypothesis is that there's probably a washout period. And meaning that when you remove the IUD, there is a certain period of time that needs to pass before the effects of IUD dissipate and the endometrial function returns to normal. Yeah.
That was my next question is how do you have the data on how long it had been since the IUD was removed before they came in for their surveillance visit? Every gestational carrier has to have two natural menstrual cycles after removal of IUD before they come in for screening. So therefore, every one of them had to have two menstrual cycles. So we're talking about a three-month washout period.
But we saw that in many, the washout period was longer. It was six months. It was nine months.
It was a year. What we've done is that we're not rejecting gestational carriers who don't have the normal pattern of endometrial receptivity. What we're doing is we're just delaying their qualification or qualifying them until later on.
And we think that whilst the IUD is a terrific contraceptive device, I mean, you know, your failure rates are about one in a thousand. So we don't want to give the impression that this is going to have a long-term impact on fertility, but we want to let patients and also our colleagues know that the washout period may be different in different patients. Yeah, that's interesting.
And I think what's hard to extrapolate, and I really like this study, but I think what's hard to extrapolate is if you were to move forward with an embryo transfer, like, would these findings translate to a lower pregnancy test? And I think that's just a theoretical leap that we're making in saying that these IUDs may be detrimental. They may not be, right? Because on a natural cycle, we might see the presence of fluid or we might see a 0.4 less endometrial thickness, but is that really significant once you get to a programmed FAT cycle? I had a feeling that you were going to ask that question. Therefore, I'm ready for that question.
So what we did was, as we talked about, is we, there are certain, you know, weaknesses in the study. Number one, what is that washout period? Well, the majority of patients who came into us as transitional carers had the IUD present for about five years. The washout period, as we talked about, was about three months.
But the other question to your point is that what about actual fertility? In other words, we see some sort of changes in endometrial receptivity patterns, but does that translate into a lower fertility rate? In other words, does it translate into a lower reduction in live birth rates? Well, what we found in subsequent analysis was that there was a statistically significant difference in live birth rates post-embryo transfer in those gestational carers who came in who had an IUD that subsequently, either through further analysis, a longer washout period, maybe six months, or perhaps they had endometrial fluid initially, and then that sort of dissipated in subsequent mock cycles. Yeah, I guess my other question, I mean, one thing that I worry a lot about is the impact of a C-section on these patients. Were you able to tease out, like, is the IUD just a confounder for patients who had had a C-section? We looked at those confounders, and there wasn't a significant factor related to C-section.
In other words, when we took the C-section away as a confounder, the difference is still persistent. Yeah, that's really interesting. You're right, because with a C-section, you're talking about sometimes, you know, presence of ismosceles, and then you have endometrial factors.
It makes sense. If you look at some of the markers for endometrial receptivity and some of the sort of the DNA markers, there are some changes that happen within progestin IUD. And the other thing that happens with progestin IUD is that you have downregulation of progestin receptors within the uterus.
There was a study that was done many years ago, and what they found was when there was a presence of endometrial fluid in the follicular phase, that follicular phase endometrial fluid resolved after progestin administration or after ovulation. Right, and we see that. I mean, we see that all the time in cycles.
Right. We have the presence of fluid, we start progesterone, the fluid goes away. Right.
Like, what is the clinical significance? But what if you have a levonorgestrel secreting presence inside the uterus for many, many years? There's a potential theoretical downregulation of those progesterone receptors. So it's not the same biology and physiology with IUD users as it is with patients who have endometrial fluid sometimes because of C-section. I would argue, and again, I like to always argue, I would argue that it's not altering the stem cell population.
And so month over month, when you're talking about the cells that get downregulated, many of those cells shed on a month over month basis. But are you functionally altering the basalis cells that are responsible for regeneration of the lining? Like, intellectually, I have a hard time understanding why that would be. Therein lies the issue related to the washout period.
In other words, how long does it take for that progestin, for levonorgestrel to sort of resolve and then potentially sort of having a normal regulation of those receptors? Because in the majority of instances, we see resolution. This is not a long-term implant. Yeah, that makes perfect sense.
Yeah. I mean, I think I'm curious to see where this goes over time. I don't think that we have the answers.
I think it's certainly what sparks really good research is an interesting observation that then translates to research and clinical findings. I agree. I think more studies are needed.
Certainly, we had limitations in our particular study, like we talked about. But it's something to look at. And in the developments of the manuscript, we're going to be looking at some of the factors that we just discussed, the actual fertility rates, the live birth rates, what was the time frame that sort of that washout period, and then what was the sort of average length of time of use of the IUD? Yeah.
Well, I hope you submit that manuscript to Fertility and Sterility. Of course, we will. I think it would be great.
And thank you so much for coming on the podcast. Thank you so much. It's an honor to be here with you.
I'm now joined by Dr. Fang Gu. Welcome, Dr. Gu. Thank you.
So tell me a little bit. I know we just talked about your credentials, but for our listeners, can you tell our listeners where you practice and where you're from and who you are? Hello, everyone. I'm Fang Gu from the First Affiliate Hospital of Sun Yat-sen University in China.
Actually, I'm in the Guangdong Province, Guangzhou. Yeah, I'm practicing in a tertiary hospital, and I'm an MD and also a PhD. My major is the reproductive medicine, like all of you.
And I know you've published several papers in Fertility and Sterility in the past, which is great. And please keep sending us your work. I want to talk a little bit about what you're presenting today at ESHRE.
Yeah, I find it's good. Actually, I presented yesterday in the capital hall. I think it's a very good opportunity to present our work here to let everybody know, because actually the program cycle and the natural cycle, it's a two-dominant endometrial preparation protocol in reproductive medicine, especially in the frozen embryo transfer strategy.
And actually, I think it is very popular, and it needs some investigation to find out which protocol is optimal and more safe. Yeah, and that's why I do this. Yeah, so I will say that's a big topic of discussion in the U.S. as well.
And I think that we are seeing a lot of tension between program cycles and fresh cycles. And there's an ongoing trial in the U.S., which has not yet been released, the NAPRO study. And so we don't know the results.
And so I thought the results of your trial were really quite fascinating. Do you want to tell our listeners what the question that you asked was? What were you hoping to learn? And what did you find out through your work? My topic is to compare whether the program cycle and the mutual preparation will increase the risk of hypertensive disorders or pregnancy following the frozen embryo transfer compared with the natural cycle. Because the natural cycle, it needs an ovulation monitoring, which needs a lot of visits, clinical visits, and also it needs some average tests to find out the ovulation time.
And also the cancellation risk is high, which is not very convenient for females here. Right, right. And I will say it's our labs, like many of the IVF labs in the States, also don't like the uncertainty as to what day the embryo transfer falls out.
Yeah, exactly. Yeah, because maybe the doctors do not want to work in the weekend. And so, but if the natural cycle, we don't have a fixed time and we have to follow the ovulation time of the patient, then we need to go to work in Sunday or Saturday.
Yeah, but the program cycle is more flexible and we don't need much visit and the patients can take the pills and also the progesterone gel herself. So we save a lot of time. And that's why actually many doctors want and the patients want to use the program cycle.
However, recently there are some observational study and studies that is published in BMJ said that the program cycle will increase the risk of hypertensive disorders or pregnancy, which is, I think it's a leading cause of the maternal and perinatal mortality. And it's a very serious problem. Yeah, and that's exactly the question that we're trying to answer in the U.S. Is our natural cycles better for reducing the risk of preeclampsia? And so tell me a little bit, so how many women were recruited into the study? How many were in each arm and what did you find? Our group is 786 participants and the NC group is 395 and the PC is 397.
It's a label-randomized control trial. So you were able to randomize your patients? Yeah, and also our embryo is restricted to the eucloid embryo. Yeah, not all the embryo because we think that no pyro RCD have been focused in the eucloid embryo transfer.
And the second, we want to use the eucloid embryo transfer to exclude the confounding factors from the embryonic factors, such as the mosaism and the compliant placental disorder, which might increase the risk of hypertension disorders. Yeah, so fascinating. And what did you guys find? Well, we are surprised to find that actually in our RCT, we did not find the choice of the endometrial preparation protocol did not significantly affect the instance of HTP.
Well, but I think maybe because in China, our patients are younger, further mostly and underweight. Right, so I think your average BMI in your study was 21. Is that correct? Yeah, 21.6. Yeah, I think that is our limitation because in our PGT patients, they go to PGT, not just for PGT-A.
Most of them go for the PGT for the PGT-M or PGT-SR, and actually these patients are more healthier, and actually they do not have much fertility problems, and they are leaner. So these patients do not have a history of hypertension. So in our work, we just find that maybe the cycle itself is not predictor for developing the HTP.
Yeah. And what about successive program versus natural cycles? Were there any differences in pregnancy rates between those? The library rate in NC group is 60%. Yeah, because we all transfer the single-year library rates.
And the program cycle is a little bit lower, but there is no significant difference. It's 56.2%. Yeah, our work is negative. Our other result is negative, but we do check the blood pressure of the two protocols.
We check the blood pressure of the participants cohort, and we find that natural cycle patient has a physiological U-shape blood pressure during their pregnancy. But the program cycle, they do not have a physiological job in the first trimester, and they go up more quickly, more faster than the NC group in the late pregnancy. So I think if the participants have a clinical risk factor for the hypertension disorders, they might be more vulnerable to develop the pre-temp cell HTP finally.
Yeah, but I think it's good to present negative studies. So often, positive studies are the ones that are presented, and there are a lot of data that are out there on the differences between natural cycle and program cycles with regard to hypertensive disorders of pregnancy. But I really want to commend you for doing the study and presenting your negative findings, and I hope that that's something that you'll present and submit to Fertility and Sterility.
So we'd love to read the paper. We'd love to have the paper. Oh, thank you.
Thank you for coming on the podcast. Thank you. I'm feeling very honored to be here in London with ASRM President-elect Amy Sparks.
This is Kate Devine. I'm just generally feeling honored to be at ESHRE in London at all. How are you doing today, Amy? I'm doing great.
Thanks so much, Kate, and I really appreciate the invitation. Awesome. Well, my first question for you, even though we're here at ESHRE with all of our European colleagues, is back to the U.S. As President-elect of ASRM, give us an update.
What's new with ASRM? What's going to be new and exciting this year in Baltimore at our national meeting? Well, clearly, we're getting really excited as people are being made aware if their abstracts have been accepted and people are making plans and registering for the meeting. I think the game changer this year is that the pre-Congress event is becoming a master class, as opposed to the standard, go to a room, sit in it for four or eight hours. So you get to have a smorgasbord of opportunities where you can pick and choose what you want to attend.
And if you're presenting at this master class, you get to leave the room when you're done and go attend another session. And we're really excited about it. I am hoping by 28, we're going to move this to a two-day event.
This year, it's just on Sunday. I really encourage people to explore it. That sounds fantastic.
As somebody who has organized one of those courses in the past and been really honored to do so, it is a pretty long day. So I like the idea of it, of the modularity. What are some examples? What kinds of things will be presented? There's a lot of professional development.
There's some on AI. There's some basic science work. It's just a potpourri and people need to look at the menu and figure out what they'd like.
But you sign up for the day, so you don't have to make decisions until you get there, really. That's fantastic. Well, you heard it here.
Definitely register to come to Baltimore and don't miss the master class on Sunday. It's a choose-your-own-adventure. You can patch together your ideal curriculum.
So what could be better than that? Amy, I also wanted to talk to you a little bit about the session that you were involved in here at ESHRE, talking about lifestyle factors and how they influence ART outcomes and fertility in general. Yeah, it was a little bit of a challenging session to put together, but it ended up turning out great. Dr. Brannigan and Bob Brannigan and Jim Toner obviously did a beautiful job with their presentations.
A very recent review in fertility and sterility had been published. Jorge Chavarro is the lead author. It's a great paper.
I recommend people take a look at it because it talks about lifestyle trends and factors and how they may or may not affect fertility. They put it all together in this great table where we have a column of knowns, what's knowable, and what can't be known. Because many of these factors are just short-term events, so it's really hard to study whether it has a long-term impact on fertility.
But for me, I shared a few case studies of the really severe cases of alcohol abuse, high BMI impact on sperm production in men. And then obviously, our biggest challenge today is men thinking testosterone's a supplement when it's actually going to shut everything down, and that is a challenge. I love the way that you presented specific case reports to really illustrate how, you know, of course we don't know about moderate use, and it's also these things are very hard to know what someone's actual exposure is.
But when we have a lifestyle factor that exhibits a dose-dependent outcome, we really start to be able to say clearly, okay, this is something that is negatively impacting fertility. So I know you also talked about, you know, the extremes of BMI and severe obesity. Tell me a little bit about that case report.
Yeah, this gentleman had a BMI of 38 10 years ago and went through IVF with another partner and had about 18 million motile sperm in the ejaculate, so it was okay. He returned to us 10 years later with a BMI of 55, consuming eight sodas a day plus an energy drink, and we were looking at trying to work with a sample of about 10,000 motile sperm. So that was pretty tough.
Sent him to a urologist. Urologist didn't address the weight issue, but did start Clomid due to hypokonatism, and the couple just came through IVF this weekend, and I was pleased to report that we had gone up from our 10,000 motile sperm in the ejaculate to 240,000, so had good fertilization. I think today's day three of their embryo culture, so we'll await the outcome.
But it's just another case I had talked about was alcoholism, and it was a situation where the urologist was smart enough to say, okay, we see that you're azoospermic, basically, or had no motile sperm, maybe, and so he ran liver function tests, and they all came up abnormal. So finally, that was the tipping point to drive the patient to seek help for his alcohol abuse, and these are stories I've been keeping in my mind for decades, so it was nice to finally share some of them, but it illustrates how this is very individualized care. I mean, some patients can have extreme BMI and still have normal sperm counts, right? So you have to look at the big picture and what you can treat and what you can't.
Yeah, individualized. Both very good stories and stories that highlight how in our field and in our roles in these patients' lives, we can not only help them achieve their fertility outcomes, but also improve their overall health and their long-term, hopefully, quality of life and health span, as is the buzzword these days. Well, it's wonderful chatting with you here, Amy.
I hope that you get to enjoy London and the rest of this fantastic meeting. Thanks for being on F&S On Air. Thanks so much.
I'm returning to our audience here for Fertility and Sterility On Air, live from ESHRE in London. Very privileged to be here with Dr. Sarah Lenson. She is a professor at University of Melbourne, and she is also the co-lead of the Cochrane section on gynecology and fertility.
She's here today to talk to us about her work, rigorously evaluating the safety and efficacy of IVF add-ons. Sarah, welcome to the talk. Thanks for having me.
Thank you so much for being here. So we all loved, all of us at F&S On Air, loved your recent publication in The Lancet, where you evaluated 10 IVF add-ons, again, quite rigorously. It was almost like 10 meta-analyses in one paper.
And I know that here at this meeting tomorrow, you're also going to be talking about add-ons at the Cochrane session. So tell us a little bit more about why Cochrane is so interested in add-ons and has chosen that for their ESHRE session this year. Yeah.
So we're really grateful at Cochrane to have this standing session at ESHRE, where we know on the program, there's always going to be this kind of trusted information coming from the spirit of Cochrane, not necessarily like hammering the results of Cochrane reviews, but things that are in line with what's happening in Cochrane, like the trustworthiness crisis that we're in now in medical publishing. So tomorrow, I'm going to be talking about IVF add-ons, the paper you mentioned in terms of whether there's evidence that they can help patients get pregnant and have a baby from IVF. And I suppose the headline result is that we don't have good evidence for the most part.
Maybe not surprisingly, but still sadly. So for lots of them, we don't know if they're helping or harming. Yeah.
And it is really important, especially when we talk about, obviously, there's global variation, but the inability of many patients to afford IVF and the cost effectiveness of fertility treatment overall, obviously is harmed when we're using add-ons unnecessarily. So in terms of all of the add-ons that were evaluated in the Lancet paper, and I know I'm putting you on the spot here, but which one do you feel most passionately about should not be used outside of a research setting? I probably feel platelet-rich plasma injections into the ovaries. I feel like that's expensive, at least in Australia, it can cost $5,000 or more to pay for this procedure that has very little evidence, full stop, and definitely no evidence that it helps patients have a baby from IVF.
And there's also significant risk involved with that procedure. So there's a lot of potential risk and harm there in terms of the cost and the physical risk and no evidence. So I'd love to see big trials addressing that question.
Got it. Me too. Or just stopping using it in the meantime, I would love to see that as well.
That would be nice. And then conversely, what if any add-ons do you think are kind of worth their salt at this point based on the available evidence and the strength of the evidence? Yeah. So there was three out of the team where there was sort of like some level of evidence of possible benefit.
And one of those was ICSI or physiological ICSI, where there's been this big study from the UK, like 2,700 patients, huge trial in reproductive medicine, which showed a potential reduction in the chance of miscarriage using PIXI. So that's a strong signal from a big, well-conducted, trustworthy study from the UK, but it's just one study. And we do like, we love to see these things replicated.
That would be the ideal situation, but we're lucky to have one big trial half the time. So that's one that's on the like, maybe that could be helpful list. And just for our listeners, in terms of the benefit there, was it a benefit in terms of fertilization, blastulation, babies? What was the outcome? So we only looked at clinical outcomes rather than the kind of laboratory outcomes, I suppose.
So we just looked at pregnancy, miscarriage, live birth, and it was for miscarriage that we saw potential reduction in the risk of miscarriage with PIXI, but weirdly maybe didn't translate into an increase in live birth rate. So whether that's kind of a statistical anomaly because of the difference in the number of events or there's something else going on that's not sure. So I guess that's why we want to see another study.
I was going to say, all the more reason to try to replicate it. And what were the other two that showed a potential? Yeah, the other two were embryo glue. So again, none of this is strong evidence.
The studies are quite inconsistent. And for embryo glue, it depended on whether we use a random or fixed effects model, which is probably a bit too technical, but depending on the analysis approach we took for the meta-analysis, like under one of the approaches, it looks beneficial and under the other it didn't. So it kind of leaves it a bit unclear.
Embryo glue is beneficial. And the third one is endometrial scratching, which is like a personal bugbear of mine because we did a big study on endometrial scratching in New Zealand that I did as part of my PhD, the PIP study, which found no benefit from endometrial scratching. But when we ran the meta-analysis and we put all the studies together, even after we've excluded the untrustworthy ones, there's a signal that there's a benefit there for pregnancy and live birth.
So I had to put aside my personal conflicts, I guess, from previous research. And that's what the evidence shows. So that's why we said possibly there's a benefit from scratching.
Yeah. Really interesting. I also have in my distant past done a study on scratching that showed no benefit.
So really interesting to look at the preponderance of the data and potentially even change our views. I know that when we were speaking before we started to record, you mentioned something that I'm very excited about, which is that Cochrane is going to be taking on potentially a review looking at endometrial receptivity testing, obviously an interest area of mine as well. Tell me a little bit more about that and when can we look for that in Cochrane reviews? Yeah.
So we covered endometrial receptivity testing in this Lancer ONG paper that came out last week. So we have pretty good evidence that it doesn't help now, thanks to your research. And even from the iGenomics team did their own study themselves showing there's no benefit from endometrial receptivity testing when you analyze the data appropriately.
So there was one for which we can say, instead of saying it's unclear, which we end up saying a lot of the time for PRP for intralipid, we don't know. The evidence is so bad, we just have no idea. For endometrial receptivity testing, we have like three good trials that don't show any benefit and so we kind of more confidently say it doesn't help, don't use it, it's expensive and painful.
That's going to be the similar finding that we have in our Cochrane review. We're working on it now. I'm not sure if it's been sent through for editorial yet, but it should, I guess, depending on the Cochrane pipelines that hopefully will come out this year.
Yeah. Wow. Well, thank you for doing that work because in our field, as you've highlighted, there are so many questions that we have and that our patients have as to whether things help.
And we have to acknowledge a lot of times that we just don't know. But once we have enough data that we know, it's nice to be able to give definitive answers and move forward because sometimes less is more and sometimes we shouldn't be adding on. So I know in the Lancet, there was something of a series of patients and part of it was to increase the availability of data for patients.
Can you tell us a little bit more about that patient facing resource? Yeah. So because we have all this evidence showing we don't know if these add-ons work or perhaps we know some of them don't or maybe they harm, but we can also see a lot of misleading and over-promising information circulating on social media, on IVF clinic websites. We created this resource called Evidence-Based IVF.
It's based at the University of Melbourne. We co-developed it with a huge bunch of IVF patients to make a resource that gives them information they want about the facts behind these different options, whether there is evidence they can help or not, what they might expect it to cost, what the other practical considerations might be and the potential for side effects or harms. And it's presented in a really accessible way.
We kind of take the complicated science and give them the facts so they know this is an impartial place they can go. None of us have any kind of skin in the game in the sense get independent information and then use that to inform their decision making. So we'd really love for it to get picked up in the States.
I mean, it's based on evidence from around the world. So even though we made it in Australia, it really is globally relevant. So it's called Evidence-Based IVF and it's on the University of Melbourne website.
Awesome. Evidence-Based IVF. Well, I'm certainly going to direct my patients there because we have patients that would do anything to have a successful outcome.
So when we can, again, tell them that we would do anything too, but we don't want to charge you more and expose you to painful procedures that you don't need. So thank you so much for doing this work. Thanks so much.
Hi, everybody. I am back and here with Professor Francesca Spinella. She is a professor at St. Camillus International University of Health Sciences in Italy.
We are so privileged that she has agreed to join us on the podcast. She is coming straight to us to record having just presented her abstract. Her abstract was called Clinical Relevance of High-Level Mosaicism After PGTA.
Mosaic Segmental Aneuploidies Drive Unexpected Live Birth Outcomes. So this is such exciting abstract because Francesca and her colleagues were able to cull data globally to be able to really help guide patients who are considering transferring embryos with results that I would call, you know, intermediate results. We don't know whether these are embryos that are associated with viability or not as clearly as we do when we get that really reassuring outcome of euploid.
So Francesca, tell me about this research. Why did you decide to collaborate with this global team to try to answer this question? Thank you. First of all, thank you to invite me for this podcast.
I'm really honored for this. Actually, you know, mosaic embryo are embryo characterized by the presence of a euploid and euploid cells. And until recently, until 2015, these embryos were considered abnormal and were not transferred.
This changed when a very important paper was published by Dr. Greco and colleagues demonstrating that mosaic embryos can implant and result in healthy babies. Since then, a growing number of centers started to identify mosaic embryos and also to transfer mosaic embryos. But however, we have different results from different centers.
So our idea was to collect a lot of data from multiple centers to give clear evidence on the clinical outcome of mosaic embryos. For this reason, we founded the International Register of Mosaic Embryo Transfer, the IRMET. It was co-founded with Svetlana Madrikova, with Adrian Vesner, and with Manuel Viotti.
That was quite an esteemed group and also, I think, really important how it represents a global collaboration. Were all of the embryos in your study done with next-generation sequencing for the PGTA? Okay, I think that's an important distinction. And what I was super excited to see in this paper is that you had nearly a thousand high mosaic embryos transferred.
What did you find in terms of the outcomes from these embryos? As you say, it's so important for us to be able to counsel patients with the evidence that are available. Yes, this is very important. Actually, we have more than 4,000 mosaic embryo transfers.
In this mosaic, the majority of transferred mosaics were low-level mosaicism, while 540 were high-level mosaicism. We found that the outcome was very poor for high-level mosaics, like 19% of birth rate. However, the behavior of these high-level mosaics was not the same.
So, for example, segmental mosaics showed that a higher level of birth rate was reached at 31%. So, this means that within the group of high-level, the impact of the type of mosaicism is very important, and segmental mosaics show the more favorable outcome compared to the other. I agree with you.
Very, very important. The devil's in the details in these things. So, just to reiterate, when we're talking about the most important outcome that we all care about in this setting, which is to say live birth per transfer, you found that less than 20% of high-level whole-chromosome mosaic embryos resulted in a live birth, but 33% resulted in a live birth with segmental high mosaicism.
So, important distinction about just segmental abnormalities, perhaps in general, but certainly when we're talking about high mosaics. The other thing that I think this data has important capacity to do, since it was such a large data set of 4,200 mosaic embryos having been transferred, is to validate some of the findings of some of our other colleagues. So, what did you find in your data set among the low mosaic transfers? Did it validate what has been published in recent years with Capalbo and other groups that these embryos essentially have an equally high probability of making a baby as euploid embryos do? Actually, the paper of Capalbo is very interesting because it was a randomized controlled study, but the point is that they didn't find any difference between low-level and euploid.
Indeed, we found a significant difference between high-level and low-level, but also between low-level and euploid embryo. This difference could be due to the different approach, different methodology within the same NGS approach, but the methodology makes the difference because you can classify euploid as mosaic or mosaic as euploid, and this could be the reason for the difference. But we need more and more data.
So, the data, the previous study was based on a little bit more than 4,200 embryos. We have now 4,000 embryos. So, I think that we need to collect more and more data.
For this reason, I invite all the people that are interested or not interested in mosaic to join their method. Yeah, and another question I had about your methodology because, again, I love the way that you're being so precise in your definitions. I think we all need to do that to be able to really kind of, again, with these registries, draw meaningful conclusions.
Did you normalize the definitions across sites? For example, different centers will define mosaicism based on the percentage deviation from the standard, right? Different centers will use a different threshold. Yes. So, did you normalize the data across sites or did you use the designation that the site had already chosen locally? We normalized the result because, as I mentioned before, we collect different parameters and also the range in which each different center collects and defines mosaicism because we have two ranges, one from 20 to 80 percent and one for 30 to 70 percent.
So, we have this different category and we can now analyze the result based on the range and also based on the platform. We are also collecting the type of platform. We need to collect more data, but we already know that there is some difference in resolution.
So, they are also different in the percentage of mosaicism and also in the outcome. Got it. So, what did you use for your definition in this study? We used a threshold between 20 percent and 80 percent and the majority of the data reported was with the Illumina platform.
So, of course, a validated platform. Okay. Well, I think that's great, too, because it captures a broader swatch of the population of embryos and it's also stricter in its definition of euploidy and aneuploidy.
So, to the extent that there is live birth potential, true reproductive potential from these embryos, we're able to describe it more completely with those thresholds. So, I'm pleased that you chose them that way. Anything else that you wanted to say to our listeners in terms of the findings of this research and what you're on to next? Yes.
Actually, we are going more in-depth in our analysis. So, we want to investigate, as I mentioned before, the clinical outcome based on the different parameters that we have. So, not only in relation to the types of mosaics and the percentage of mosaics, but also in the morphology of the embryo and also on the specific characteristic of a mosaic embryo.
For example, in the presentation that I made before, we found that there is a correlation between the region of the imbalances that we found in the segmental mosaics and the outcome. So, we are now investigating more in-depth this correlation to understand if there is some specific region that can impact more on the implantation of the mosaic embryo. That's fascinating.
So, tell me more about that. Do you mean specifically which chromosome? Do you mean whether it's closer or further from the centromere? What do you mean by the region? Specific chromosome and specific position in the arm of some chromosome. So, we now are focusing our attention on chromosome 14 and chromosome 1 because we found a different birth rate depending on the region that are interested.
But this is something that needs to be further investigated. Most certainly. Well, that would be the holy grail.
No question. It feels to me that we're so far from that really being able to give explicit advice based on the region affected, but an ambitious project and one that would certainly hugely benefit patients. Yes.
Thank you. Well, thank you so much for joining us. Thank you.
It was a pleasure. Thank you. Wonderful speaking with you.
Thank you. So, welcome again to this FNS OnAir episode recorded live from ESHRE 2026. I'm Jan Kerney, Interactive Associate for Fertility and Sterility, and I'm joined by Dr. Pedro Mello, Senior Fellow in Women's and Reproductive Health at University of Oxford and Consultant Gynecologist and Sub-Specialist in Reproductive Medicine at Oxford University Hospitals and TFP Oxford Fertility.
Pedro, thank you for being here. Thank you very much for having me, Janik. Pedro, we are discussing our presentation, Letrozole versus Clinithine, with or without metformin for laboratory induction in women with polycystic ovary syndrome.
They lost in a trial. Before we talk about the study itself, could you tell us what was the question we were trying to answer and why it is important for clinicians treating women with PCOS or PMOS? Yes, absolutely. I think the first thing to say is that PCOS has been renamed to PMOS a couple of months ago after a global consensus.
And what we know is that PCOS or PMOS is the most common cause of anovulatory infertility. It accounts for about 80% of cases. And what we also know is that for a lot of these women, getting treated with ovulation induction is usually the first-line management, and also a lot of the time, the only management they need.
So getting that first intervention right is absolutely paramount. It's very important. And what we know is that since the 1960s, people have been using clomiphene, which is a drug that acts centrally in the pituitary.
It blocks estrogen receptors, and in that way, it increases FSH secretion by the anterior pituitary. And then in the early 2000s, people started using letrozole, which is a neuromatase inhibitor. It works peripherally and adipose tissue mostly.
And then in the 90s, people also started using metformin, which is a drug that increases insulin sensitization, is what it does. And to date, the most seminal trial that had been conducted on this question had been one published by Rick Legro in 2014 in the New England Journal. And essentially, at the time, the question was whether letrozole was superior to clomiphene.
And the trial did show that there was a 44% increase in live birth rates with letrozole. It was a very specific trial, though, because it was conducted in a US population. And a third of the population had a BMI over 39.
The other third had a BMI between 30 and 39. And only a minority of people had a BMI lower than 30. And in addition to that, the trial didn't quite address the question of whether metformin was beneficial or not.
So, in 2017, the NIHR in the UK determined that, actually, there was still a need to try and ascertain whether letrozole was indeed superior to clomiphene in a UK setting, and also to add the question of metformin. So, what we did was we designed the LOCI trial, which effectively was a two-by-two randomized controlled trial, where people were randomized to letrozole or clomiphene. So, that was the first question.
The second question was whether metformin was better than placebo. And the third question was whether adding metformin to letrozole actually accrued any benefit to live birth rates compared to metformin and clomiphene. So, that's the trial we conducted.
That's great. I think when I saw first the protocol, I said, okay, I'm very fan of all methodologics and designs. And I saw this and I said, okay, this is the real indication for a factorial trial, two-by-two.
But what are the risks? But what are the, for sure, the strengths are clear. We can answer two or three questions at the same time, but what are the downsides of the limitations? I think the main limitation is when there may be any sort of interaction between the different interventions that you're comparing. In other words, yes, perhaps letrozole may be superior to clomiphene for most individuals, or at least for a certain subgroup of individuals, particularly those whose BMI may be higher.
But the question then becomes, does metformin also modulate that effectiveness through its own mechanisms? And I think, so firstly, from a mechanistic standpoint, we couldn't find the justification for metformin to really modulate the effect of letrozole compared to clomiphene. And secondly, from a statistical standpoint, there are statistical methods to try and ascertain whether interaction was significant. And our p-value for that was about 0.74. So there was certainly no interaction found for our trial.
What are the main results of your trial? So the headlines are essentially, number one, that we had a pretty high live birth rate, actually. So it was 33.9% overall. And that is actually in stark contrast to the overall live birth rate that Legro and colleagues found in 2014.
So at the time, they found a live birth rate of about 23% overall. Well, we think that stems in part from the fact that our population just trended leaner, really, compared to the population that Legro examined. And I think it is important to make a caveat here, which is the fact that in the UK, we cap ovulation induction at a BMI of 35.
So people do not tend to be offered ovulation induction beyond a BMI of 35 in the National Health Service. And of course, that brings up its own questions from an ethical standpoint. And yet, it is just something that we do not do.
So that is the first result. So our live birth rate was relatively high. The second thing to say is that when we compared letrozole with clomiphene, we did not find a difference in effectiveness between the two.
So it was certainly not statistically significant in a conventional way. When we compared metformin to placebo, we also did not find a difference. So the live birth rates were very much hovering between 33% to 35%.
And when we looked at the combination question, there was also no difference between metformin with letrozole versus clomiphene with metformin in the overall population. It was a very large trial. We had a very large sample size in performing 48.
I mean, the result is quite strong. Well, yeah, I mean, it was the largest trial ever conducted on this question, actually. In fact, it has more women than all trials combined on this question up until now.
So we had 1,739 participants. So it's huge. And you'd think that it would be a trial that would be powered to answer this question robustly.
And yet we didn't find a material difference between the groups. So yeah, absolutely. We recruited across 48 centers in Scotland, England and Wales.
And yes, it was a very large trial. How should we read and understand these results compared to what Lieber et al published in 2014? Yeah, I think that's a very, very important question, because you might be tempted to look at our results, compare our results to Legro's and say, well, how come you found something completely different, really? And I think the way you square that is by looking at the populations we examined. So our population was a group of women who had a BMI on average of 28.
And again, we capped it at 35. And Legro's population had a mean BMI of 35, so seven points above ours on average. So that is quite substantial.
The second thing to say is that when we did our subgroup analyses, our pre-specified subgroup analyses, so the most important, the key subgroup analysis that we conducted was according to BMI. And what we found was that for individuals whose BMI was 30 or above, there was a 24% increase in live birth rate with letrozole with some degree of statistical confidence compared to clomiphene. So what we think is happening is there is an element of letrozole still being able to thrive in the midst of increasing adiposity, which is very much what BMI appears to be measuring in this population.
So in other words, as people's BMI increases, what appears to be happening is because letrozole exerts its effect upon adipose tissue, it's still able to do that. It's still able to inhibit the aromatase enzyme, in turn, leading to an increase in FSH levels secreted by the pituitary. Whereas clomiphene, firstly, is a very lipophilic drug, so it tends to be trapped in adipose tissue.
That's the first thing to say. And because of that, it can't reach its target, which is the pituitary. So it's not so much that as adiposity increases, letrozole becomes better.
It's more that clomiphene loses effectiveness as well. Yeah, I agree with you. I was convinced during your presentation yesterday, and I am even more now that you explained it again.
So in the future, what should we do? What should we do as researchers or as clinicians given these results? Well, I think that's really important because you might turn around and say, well, is this going to change any international guidance on the topic? Because the reality is for a long time, letrozole has been perceived as a superior drug to clomiphene. And I think there is some sense to that based on the research that has been published to date. I think there is also a powerful argument to look at phenotypes and the influence of phenotypes upon treatment outcomes.
I don't think you can say that there is a one drug that would fit everyone. I think if you think about letrozole, for example, it's a drug that it is not licensed for ovulation induction. And yet we know that it is a safe drug, generally speaking.
I don't think people will go back to saying, oh, perhaps clomiphene should be first line. But I think there is a world where in certain settings, if letrozole is not formulary, for example, to prescribe for ovulation induction in a lean population, clomiphene would be a perfectly reasonable approach. I think the other thing to say is when we looked at metformin, there was a very clear signal for improved live birth rates in people who'd had a history of one or more miscarriages, which I think is, you know, it improved live birth rates by about 57%.
So I think there is also something to tease out in those data. And I think the path forward would be very much to conduct an individual participant data meta-analysis to try and ascertain how these phenotypes influence drug response. Thank you very much for your research and for sharing your results with us.
Thank you very much. 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, Dr. Adriana Wong, Dr. Elena HogenEsch, Dr. Selena Park, Dr. Carissa Pekny, and Dr. Nicholas Raja.
