Fertility and Sterility On Air: Live from the 2025 ASRM Scientific Congress & Expo (Part 2)

Fertility & Sterility on Air is at the 2025 ASRM Scientific Congress & Expo in San Antonio, Texas (Part 2)! In this episode, our hosts Kate Devine and Eve Feinberg cover:

• The impact of cannabis on reproductive health with Jason Hedges and Jamie Lo (01:06)
  Anti-Müllerian Hormone (AMH) as a therapeutic target in women's health with David Pépin (10:18) 
• A discussion with the 2025 ASRM Distinguished Researcher Award recipient, Denny Sakkas (18:32) 
• Outcomes for patients who underwent oocyte cryopreservation at age 35 years and older: results from a large, multi-center cohort with Michelle Bayefsky (26:10) 
• The SLEEP Study: Sleep length and euploid embryo transfer protocol using the Oura Ring to assess the effect of sleep parameters on transfer outcomes with Sarah Cromack (33:48) 
• Investigating the reproductive potential of non-mosaic segmental aneuploidy: a double-blinded, multicenter non-selection study of 176 single frozen embryo transfers with Stephanie Willson and Emily Mounts (44:08)

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 discussions with authors and other special features. FNS 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. I am here with Dr. Jason Hedges and Dr. Jamie Lo from OHSU. They investigate a number of exposures, fetal exposures, and really have done a lot of work recently that's caught the attention of many of us in this field on cannabis exposure.

Dr. Lo is going to be giving an interactive session at this meeting. Welcome to FNS On Air podcast. How are you doing this morning? Good morning.

Thanks for having us. Thank you for having us. No, it's my pleasure, truly.

I think we should just dive right in. One of the things I know you've noted and why this work has been brought into focus and to attention is because of an increase in cannabis use and especially cannabis use in reproductive age people. Why do you think that the use of cannabis is rising in our country? The prevalence definitely is continuing to rise, especially during the COVID pandemic.

People are really using it for treatment for stress, anxiety, pain, sleep. A lot of the reasons for the increased prevalence is because there is increased perceptions of safety, availability of the products, and healthcare providers are reluctant to counsel patients due to the conflicting literature that's existing. There's not a real clear message on the impact it can have.

It is a lot more available. It's becoming more legalized. There's dispensaries everywhere.

In the state of Oregon, there's more dispensaries than there are Starbucks or McDonald's. That's similar to some other states. Yeah, so obviously more readily available and legalized in many, many places.

I think you're right, Dr. Lo, generally often perceived as being relatively harmless. That's an assumption I think that folks have made in the absence of data for the most part. I know that you have been helping us to understand better, both of you, what the harm is.

Tell me, what have you found in your work so far about how cannabis can adversely impact human reproduction? Yeah, and I'll speak on the female side. I think what really started this work is a lot of patients were coming to us saying, I know not to use nicotine or alcohol when I'm thinking about getting pregnant or am pregnant, but when it comes to cannabis, they weren't sure and they were asking questions. For cannabis use, prior to conception, we found that it dysregulates menstrual cycle length, it leads to anovulation, it alters female reproductive hormones, and then there's decreased rates of conception and successful pregnancy and potential increased risk for miscarriage.

During pregnancy, we found that it can abnormally impact placental perfusion, oxygenation. Also, it can lead to abnormal fetal development, especially in the brain, and this is also linked to altered offspring outcomes in terms of cognition, behavior, and decreases in brain volume postnatally as well. Similar, I'm a reproductive urologist, so a lot of my patients were presenting to me, really asking the question, does cannabis impact their male sexual functioning, reproduction, would it impact them getting their partner pregnant? I think when we started this journey investigating this, for us, it was really important because we just wanted to know what the answer would be, if it didn't have any harm or if it did.

At least in our data and what we've seen so far is that it actually kind of continual use of cannabis on the male side can definitely have a negative impact in terms of getting pregnant, it can affect hormones, and it potentially could affect offspring. So it has some real impact. What I think most important is that when we've done some of our data, it demonstrates that cessation or stopping can have a positive impact, and I think that's probably the most important thing eventually when we talk to counseling our patients.

It's super helpful to have both the male and female side represented here in terms of expertise. Tell me a little bit about your methodology. Are you mostly looking at outcomes with the exposure being self-reported use? Have you been able to assess concentration of these molecules in body fluids, urine, serum? Unfortunately, there's no good biological testing in humans, so for our human cohort studies, we do rely mostly on patient self-report and then biological confirmation, but that doesn't determine or give us information on dosage and frequency of use.

In the non-human primate model, we're able to overcome some of those limitations in human studies, and we're able to control the amount given in the exposure, so we really understand the direct effects of THC only on reproduction. And has it been similar on the male side too, mostly self-reporting? Yes, similar in humans, it's mostly self-reporting. There is no good testing like Dr. Lowe said, and so we've also looked, using the non-human primate model, looking at how it impacts on the male side, and the similar, the power of the model is the similarity in the metabolism of THC in the primate versus in humans, and so it's been a really nice model to get, I think, glean some really good information.

Yeah, I mean it's a huge resource that you guys have at OHSU, the availability of the non-human primate models, I think many scientists across the world really are certainly desirous of that resource. So thank you for putting it to good use here, looking at cannabis exposure You know, one thing that comes to mind for me in terms of what our audience might be interested in, in terms of being able to educate their patients is, what have you found in terms of dose relationship? I know you mentioned that cessation can be effective in terms of reversing some of the adverse findings, but is there, you know, we know now there's no safe amount of alcohol, right, in pregnancy for example. You know, in terms of conception, in terms of during pregnancy, how often, how much cannabis do you think is safe, or do you similarly feel that even a small amount is dangerous? So I would say similarly, we don't have any safe amount for prior to conception or during pregnancy usage.

However, what we have learned is there are a few opportunities to mitigate adverse outcomes. Obviously, you know, complete cessation is best. There's potential for reversal of adverse effects, improved fertility, improved pregnancy outcomes with abstinence.

However, that's not, you know, attainable for a lot of our patients, and so using less, so less frequent decreased doses, thinking of delivery modes that avoid toxins from cannabis smoke, so using edibles will improve outcomes. Also, a lot of our patients co-use substances with cannabis, especially nicotine and alcohol, and we know that co-use has worsened outcomes, and so decreasing to only one substance is best. Similarly on the male side, we don't know the exact impact if they use edibles twice a week or once a week, and typically when I counsel my patients, I always talk about if it's possible to cut completely out, that would be best.

We don't know the data on kind of intermittent or less amount. The more they can try to cut back, I think can be helpful at this point until we have better data. Yeah, I know it's a hard substance to cut out for many of our patients as, you know, even separate and apart from the question of addictive potential is also there's a true medical benefit for a lot of patients that use this regularly, and so sometimes we're not just talking about recreational use, obviously.

Well, I am really excited by this work. I, you know, love to have data when I counsel my patients to take something out of their life that they might feel improves their quality of life to show them that, in fact, we have data of doing this will improve your health and potentially your fertility and the health of your child or children, rather than just a tsk-tsk kind of an approach. So the work you're doing is really important, and thanks for being here this morning.

Thank you for having us. Thank you. Good morning.

I am so privileged to be here with Dr. David Pepin, who is going to be discussing his work, really, I think, fascinating and exciting work in terms of potential innovation for patients going through IVF stimulation, looking at AMH as a therapeutic target. So welcome, David. Thanks.

Thanks for inviting me, and I'm always eager to talk about AMH. Okay, great. Well, I'll let you kick it off then.

You know, this is not really a novel concept, actually. People have looked at this over time and have struggled to find a benefit. What is different about the OV586 that you are working with? So AMH is a long story, right? It's been cloned in 1986, but a lot of the work that has gone into trying to bring this to the clinic was stopped or was at a barrier because we couldn't produce enough of it, not enough that we could do in vivo studies, use it in animal models.

So I think a lot of the reason why this isn't in the clinic yet is that we have to surmount these barriers. And so OV586 is an analog of AMH, so it's a recombinant version where we've modified some of the sequence that allows us to produce large quantities of it that's highly biologically active, which we can then test in preclinical and clinical models. And we've begun to do this.

So initially we did this in mice, and what we discovered is that AMH was much more powerful than we thought. So most of what we knew about AMH before was from mouse models. So we knew it was a break to follicle development, but we just didn't realize how strong of a break it represented.

And so you can use it both ways, right? So it's a break, and then you can stop follicles from developing, but when you release the break, those follicles all go. So that's more or less what I tell my patients when we're talking about synchronizing follicles as we are preparing for IVF. So I can imagine that that's what you're thinking about in terms of an application for IVF.

So just to get a little bit more basic, first, is it acting as an agonist then prior to starting the IVF stimulation in the way you're envisioning it? Right. So we're used to using gonadotropins and playing around with the enteral follicle, trying to synchronize those, but actually everything that comes before, we're used to not being able to act upon, which is the pre-enteral follicles. So AMH is an inhibitor of pre-enteral follicle growth.

So now we get to act a little bit earlier, synchronize those follicles, release them, and then you still have to do the same stimulation, you know, FSH support and trigger, but you have a bigger cohort of pre-enteral follicles that make it to the enteral stage. Got it. Well, obviously that would be extremely helpful if we both got more follicles to develop and got them to develop more synchronously.

So we're all hopeful. Tell us what you found in your preclinical studies so far. Right.

So most of our work before or to date has been in mice. And in mice, if we synchronize those follicles, we're basically a month treatment with AMH or recombinant versions of AMH. We get about a threefold increase when we do ovarian stimulation.

This is with a mouse that has a normal ovarian reserve. If it has a diminished ovarian reserve, so if we pre-treat the mouse with large amounts of chemotherapy, we still get a better than twofold increase. And that we think would be meaningful clinically if we can achieve the same thing in humans.

But there's still a big divide between mice and humans, right? So a lot of things that we need to figure out now are what kind of dosing do we need to give to humans? For how long do we need to treat them? How long do we have to wait for these pre-enteral follicles to reach the enteral stage? To do this, we've been using non-human primate models. So we've begun to do that. We've learned a lot about the recombinant protein.

We learned that we can give it subcutaneously. This is really advantageous because a lot of the fertility medicines are self-administered. It's much easier than having to go every day to the clinic.

So that can be given subcutaneously, 24-hour half-life, very stable, very biologically active. And we did a study in monkeys where we were able to treat a couple of them for about three cycles. And we were able to show that it does not disrupt the menstrual cycle.

So those monkeys will still cycle. They're still producing normal amounts of estrogens and progesterone. And that's great because that means there's no side effects or fewer side effects, in theory, for these women that will use this drug for synchronization.

And then when you remove DMH, when you stop treatment, you can see the falcos come back through hormones like inhibitin B. So we still haven't figured out all the details of what dosing we want to give, how long do you have to treat for to get the maximal effect, when exactly should you trigger. But we have all the tools to do so now. So that's very interesting.

In the monkeys, they continue to cycle even while they're on the AMH. That's different from what you found in cats, right? So yes and no. So surprisingly, AMH doesn't stop all follicles from growing.

It's a break, but it's not an absolute break. So there's still some follicles that trickle. Those follicles don't develop normally, they're stalled.

They actually pause on their way for a number of reasons. One is the granulosa cells stop dividing and stop differentiating. But these paused follicles presumably are making these hormones because even in cats where we've had contraception for multi-years, five years, eight years, those cats still have normal amounts of reproductive hormones.

So you can have a few leftover follicles that can still support some of that hormonal production. That's fascinating. So tell me, I know that it would be a hypothesis at this point given that we haven't yet moved into humans, but based on what you've designed for your studies in monkeys for, quote-unquote, priming prior to ovarian stimulation, how long do you think that patients will need to be on this prior to starting stimulation? Yeah, I think that's a great question and it can be a little bit counterintuitive because most of the work, again, that we've done is in mice.

Mice have like a four to five-day cycle, obviously much different than a human. So if you think about the enteral follicle, FSH and LH, that's contracted. But actually the pre-enteral follicle growth, the timing of this is much more conserved across mammals.

It uses a completely different system. It's much slower. It takes months to go from pre-enteral stage to enteral.

But what we found in mice, and it's probably true of rats, cats, dogs, NHPs, and hopefully human, is that probably we're talking about a month or two. That's sufficient to pause follicles, get rid of a lot of the growing follicle pool that doesn't get replenished, and then let those follicles grow. Well that's reassuring because all of our patients want to be pregnant yesterday, so I'm glad they don't have to wait many months.

Tell me about the study design for your upcoming study in non-human primates. I mean, I think we're still discussing the details of this, but it's hard to have access to large amounts of primates, so we want to use them as well as possible. A good way to do this is to look at stimulation before and after treatment.

So do a standard cycle or placebo-controlled, look at what kind of stimulation you get for that particular monkey, and so you match that same monkey with your modified treatment, and you see, do you get an increase? Because at the population level, you would need so many monkeys to be able to do that study otherwise. That's really useful to do it within a monkey comparison. Got it.

So it's a crossover design where the monkey can serve as her own control. Okay. Well, we're really pulling for you.

As you know, we've had no major changes in the medications available for the treatment of infertility for truly decades. So this would be a game changer if it has the same results in humans as it does in mice. Obviously a long way to go there, but really exciting work, and thanks so much for joining us today.

Thanks so much. I'm here with Dr. Denny Sakkas, who is basking in the glow of his Distinguished Research Award. Congratulations, Denny.

It's a huge accomplishment, recognizing a lifetime of research contributions to our field. So first of all, thank you and congratulations. How's the meeting been for you so far? This meeting, it's interesting how it's evolved over the years, and thank you for the congratulations and obviously to SRM for the award.

It's great being recognized. It's even better from a more clinical organization to be recognized as an embryologist, and I'm sure, I think that's great for all the embryologists out there to aspire to and sort of not just work in the lab, but know that they can contribute with clinical research and translational research. So it's great.

The meeting's great. It's been very busy. It's always a good meeting.

Obviously great talks. The exhibition area is nice, but over many years, I'm sure as yourself, you make a lot of friends, and it's just great to catch up with friends and that especially. Absolutely.

It's the event of the year for many of us in that we are able to connect with others intellectually and also in our communities. Obviously a challenging time in the field of reproductive medicine in many ways. I wanted to ask you a little bit about how you've stayed committed to doing research over the course of your career.

As you said, many of us, both on the embryology side and on the clinical medicine side, the REI physicians, we get so wrapped up in our clinical work and really don't use a lot of the skills and knowledge that we learn along the way in terms of good research methodology and basic and translational science. What's driven you over all these years, and how have you continued to put out high-quality research? I'm lucky. I did my PhD in Melbourne, Australia at a time when the group with Alan Trounson, who was sort of a huge mentor for IVF and one of the originals, if you want.

I learned there the value of research and how quickly it can be translated. Obviously they had a few world firsts in those years. I think just seeing that inspired me to continue that progress.

I was lucky that I always managed to keep one foot in the IVF lab to do the work that we do to create embryos and work in the lab, which is what I really loved because you were seeing the benefits straight away, but I always like the research side. I've been lucky for many years in the different places I've worked and lucky that I've had very good support from the people I work for that allowed me to indulge my interest in having a foot in the lab and also being able to do translational and basic research, which I've always enjoyed. I couldn't agree more that luck is definitely involved in terms of having good mentorship and having good support from your employer, but of course it also takes a lot of hard work and dedication and motivation.

Again, it's a good example to just never stop thinking and learning and then you'll be productive like Dr. Sakkas or Denny. Tell me, over the course of your research career, what comes to mind in terms of what you're most proud of, your biggest contribution, if you will? Again, when I started doing that, I did my PhD on goat embryos and sheep embryos and mouse embryos, so it was sort of removed from the human side, but at that time the group was in Melbourne. We were developing a lot of the new micromanipulation techniques and I was doing quite a bit of micromanipulation.

In those days, I don't know, you're probably too young to remember, Kate, but we were doing a technique called SUSI. I was lucky because I would go and do cases in Europe and even in Australia, we had the first pregnancies with this technique, which wasn't as successful as ICSI, which this is the technique that eventually evolved to ICSI. Patients then had no choice.

The male factor patients that we treat routinely today, they really had no choice to be treated. We tried very poor insemination techniques, which failed miserably. Even SUSI in those days, where you would put one or three sperm under the zona pellucida and let them work their way out, that was fairly successful, but not as successful as ICSI, obviously, today, so I was proud of that.

Even today, there are certain papers that we've had out. Again, we have great collaborators. We do some really amazing work with a guy called Nicholas Blachter on embryo imaging, where we're learning so much about embryos, what goes on and how complicated and cunning they are in actually what they do.

There's a lot of things that I'm proud of that, again, over a few years, I've managed to do. The award, I think, is generally meant to acknowledge a lifetime's worth of research, which you've already accomplished. Of course, we look forward to decades more research and collaboration with you, Denny.

If you had any advice to the young embryologists and REIs who are now training, finishing their training, what would that be? I think be very open in your thoughts, so don't think you can do things by yourself. As intelligent as people are, I think having good collaborations, and not just even from our own field, I think reaching out into other fields, into bioengineering, into the cancer field, which is, I hate to say it, but many years ahead of us in terms of the technologies and the type of research they're adopting. If I had any advice, I would just say be very open in exploring your ideas and exploring them in other fields and not just staying mainstream in our own field.

This is a big conference, ASRM. There are many other fields out there, people doing things that are just fascinating, and I think it's always great to try to expose yourself to all those other areas. So if you're an embryologist, an REI, even as an MD, I think just look out in other fields and see what's going on there and try to incorporate that into our field because it will only benefit our field.

I love that. Collaboration is the key. I couldn't agree more, and even Denny can't do it alone.

We all need the input and help of those that have gone before us and those that are looking at things anew. So congratulations again, and thanks so much for joining us today. Thanks a lot, Kate.

Welcome back to Fertility and Sterility on Air. We are recording live from ASRM, and I'm Eve Feinberg, and I'm joined today by Michelle Bayefsky. Oh, hi, Michelle.

Thank you so much for having me. Thanks so much for coming on the podcast. We've got quite a crowd around us, and we're celebrating the 75th anniversary of Fertility and Sterility.

So for those who are live, come get some cake, enjoy, and grab some popcorn and listen as we record this podcast. So this first podcast that we're going to be, this episode we're going to be recording is on O1, Michelle's prize paper at this meeting, and the title of the paper is Outcomes for Patients Who Underwent Oocyte Cryopreservation at Age 35 and Older Results from a Large Multicenter Cohort. And as you know, we go through the abstracts, and we try to pick the ones that we think are highly relevant and may indeed change our practice pattern.

So first, I just want to congratulate you as a fellow for having prize papers. That's quite a feat. Thank you.

So tell me a little bit about why you chose to study this and what your manuscript was about. So we're interested in outcomes for patients who are older at the time of freeze, because we know in general that it's better to freeze younger if possible. We encourage our patients to do that.

Patients are going to have better outcomes, higher, you know, number of eggs and embryos and neuploidy rates. But of course, there are still many patients who either can't afford it earlier or don't think of it earlier or for whatever reason are presenting at age 35 and older. And is doing egg freezing worthwhile for them? What are their outcomes going to look like? We wanted to be able to give patients a little bit more data so that they could decide for themselves if it made sense for them.

Yeah, and I will say when we first started egg freezing, our average age was probably closer to 38. And I think that as coverage expanded, as we started to see more and more patients, that age really at our center has dropped down. But we do struggle with what, how old is too old to freeze? And, you know, sometimes I have a 42 year old patient who comes in and she wants to preserve her fertility.

And I mean, I think as everyone in this field knows, like that window for preservation has nearly closed. But I think the real question is, has it? And what did you guys, what was your hypothesis and what did your data show? We hypothesized that, well, first of all, I should just say this is a retrospective study. So the patients who ended up freezing were not surprised where patients maybe had a better than average prognosis.

So we hypothesized that there would be a range of results that younger women certainly would have better outcomes than older women. We do have, we've had at least one live birth from an IVF patient in our practice at 47 years old. So we hypothesized that it wasn't impossible for somebody to have.

So 40 fresh IVF, 47 on eggs. That's the oldest that we've ever had. So we hypothesized that there would be a range, certainly younger patients would do better than older patients.

And that's, that's basically what we found. We had more patients in the younger age groups also. So a little bit of a more robust data set for the patients closer to 35 or 38 relative to greater than 42.

But we did find that even in our greater than 42 year old age group, 12.8% of patients were able to achieve a live birth. You know, for some people, that's a high number. That's shockingly high.

And for other people, that's a low number. And if you were a patient walking in and somebody told you you had a 13% chance of having a live birth with your frozen eggs, that might not be worthwhile to you. I mean, I think it's useful because I think many programs, my own included, have age cutoffs.

Like above what point do we say that we don't feel like it's worth it for people to freeze their eggs? And admittedly, in our program, it's once you hit your 43rd birthday or 42 is our cutoff. But I guess my other question about your patients at the older end, were those aggregated eggs from multiple cycles that they had done? Or was that a single cycle, 13%? They could have done multiple cycles. They had to have frozen within a 12 month period of time because we didn't want to aggregate eggs that were actually 42 and 44.

We wanted them to be falling into one age group or another. They could have done multiple cycles, but the median number of cycles was one for all age groups, actually. Yeah, no, that's impressive.

And I think the other thing that we're not accounting for in these data, again, because of the retrospective nature, is the 42 and 43 year olds who got canceled didn't actually make it to the point of having frozen eggs. When you looked at the data, were you able to ascertain what percentage by cycle start were able to achieve a pregnancy, or was it just simply the patients who had eggs frozen? We were looking at patients who had eggs frozen and came back for thaw. So they had to at least have frozen something.

Right. So yeah, I mean, I still think, I think if you look at it from the angle of, let's take SART data for all comers at 42 and above, I mean, national averages in that age range is less than 5%. Again, SART data is per cycle start.

So I think that that probably accounts for that difference between what we see in SART and what we see from your data. But I would take the, I would take the perspective of, in the spirit of informed consent and shared decision making, that maybe we shouldn't have an upper age limit for egg freezing. Yeah, I think that's my takeaway also.

I think that patients in our oldest age group had a median AMH of 1.6 and a median number of eggs frozen of 8, which is pretty high. Yeah, that is high. The age of 42.

So to me, that means that, again, maybe these patients were better than average prognosis, and that's why those were the ones to freeze. But that also means that maybe we shouldn't have an age cutoff because there are going to be some people who have a, you know, great for them. They have a good AFC, a good ovarian reserve at an older age.

And those patients, maybe we should allow them to proceed because some portion of them will achieve the outcome that they, you know, want so, so badly. Yeah, I mean, I think it's great. And I think there was another study, and I don't remember where it came from, but that showed a much lower live birth at 42 from frozen eggs.

So I think that as we are seeing a greater range of patients, and I think especially in New York City, your patients are probably a little bit older than our patients in Chicago who are coming in. But I think that it does, it does ask and answer the question of what is the realistic probability of live birth if you can get to the point of retrieval. Right.

We did include patients across the U.S. Fertility Clinic, Fertility Network, so it wasn't only New York City patients. But yeah, I think as more time passes and as more people are coming back to use their frozen eggs, we're going to see a broader range of outcomes. Yeah, that's really interesting.

Well, thank you so much for coming on. It's been a pleasure seeing you and congratulations on being a prize paper and for sharing your work with us. Thank you so much for having me.

I am now joined by one of my absolute favorite people, Dr. Sarah Cromack from, I'd love to say from Northwestern, but really from Emory now. Yes, just graduated fellowship under your tutelage. So welcome, Sarah.

This study is near and dear to my heart being that I'm a co-investigator, but I think it's an incredible project and many congratulations for doing this as your thesis project. This is the SLEAP Study. Sarah, what does the SLEAP Study stand for? Absolutely.

So this is an acronym you and I came up with. It stands for Sleep Length and Euploid Embryo Transfer Prospective Study. I love it.

I'm not really going to admit how little I sleep and how that contributed to the study design. The genesis of the project, yes. The genesis of the project was I sleep very little and how she gets everything done.

And we wanted to study whether or not sleep would impact the likelihood of success of single euploid embryo transfer. Exactly. So when we came up with this study, they had just come out in FNS with an article about subjective sleep parameters.

And the most commonly used subjective sleep measure is something called the PSQI, the Pittsburgh Sleep Quality Inventory. And it's fairly good when you look at it, but when you actually compare subjective sleep, let's say, oh, I know I sleep seven hours, to objective measures of sleep with a wearable device or in a sleep lab, there's a big difference. And it can be, you know, up to 30 minutes, an hour, two hours.

And so we were a little bit dubious saying, hey, do those objective sleep measures because you thought you slept great compared to what we actually found out with your aura ring. We said, do these objective sleep measures match up with subjective sleep? And let's say beyond just the IVF outcomes, okay, maybe you get a few less eggs, but does it really translate to live birth outcomes? Right. Exactly.

And we pulled in Jesse Walter, who's the wearable queen and has a special interest in wearables. And then Kathy Goldstein at the University of Michigan, who's also phenomenal as part of this. Our sleep researcher.

We had our sleep researcher. So tell us a little bit about this study design. Like what did we do and how did we do it? Absolutely.

So we decided to use the aura ring, which we use number one, because we thought it would be fairly easy to recruit, which we were right. We got 150 participants in six months. And we used it because it has been very well validated in multiple clinical studies to have similar total sleep time and overall sleep wake patterns when compared to laboratory polysynagraphy, which is the gold standard of sleep measurement.

So we decided to use the aura ring and track simple objective sleep measures. So total sleep time and awakenings, as opposed to things that are less validated, like how much you're in deeper REM sleep. And we looked at before they underwent an embryo transfer.

So on the month prior to frozen transfer, through the transfer period, and then if they were pregnant up to eight weeks gestation. And going back in time, what I'm trying to remember, what was the original hypothesis? Did we think that women would do better or worse? We thought that women would do better if they had a longer sleep duration, because that's what these subjective studies had shown us with surveys, that women overall that had better PSQI maybe had a few more eggs during retrieval or had better measures of ovarian reserve. So we said, okay, maybe these women that get better sleep, they have less stress mayhaps going on in their life, other factors that might improve their success overall with transfer.

Yes. And then we prospectively followed these women. So tell us a little bit more about that.

Yeah. So we then prospectively followed the women as they were going through their transfer protocol up until after transfer every day. So we have data from for most women in the study to 60 days of sleep and looking specifically at, again, what was their average total sleep time? How efficient was their sleep? Which is total sleep time versus the time you're actually in bed.

We also looked at what is their regularity of sleep? So what is the midpoint of their sleep fall, which a normal midpoint should be between two to 4 a.m. And what was the standard deviation of their sleep midpoint? So how often were they sleeping in a similar timeframe every night? And we looked at that and compared it to specifically clinical pregnancy and live birth rates. And what was the, so the overall pregnancy rate I understand was fairly good. It was, it was.

And that was what we expected from Northwestern. We knew that our clinical pregnancy and live birth rates with a single euploid transfer and also well-selected group of women. So I'll go back and just briefly mention the exclusion and inclusion criteria.

We excluded people that were at high risk of disordered sleep. So PCOS, BMI over 40, people that were night shift workers, and we excluded people that were a high risk of a poor outcome. So if they'd had prior three or more failed transfers in attempts for that current pregnancy or if they had recurrent pregnancy loss, so more than two miscarriages.

So this is a group of women that were overall likely to be successful from transfer and at low likelihood of having a baseline disordered sleep pattern. Yeah, so not surprisingly their pregnancy rate was. The clinical pregnancy rate, the live birth rate was 63 percent and the clinical pregnancy rate was 69 percent.

Yeah, so very much in line with our data. And then we took those women and looked at them by those who got pregnant versus those that didn't get pregnant and then compared sleep. So tell us, tell us what we found.

Yeah, so when we compared sleep between the two groups we actually found that this was, ended up being a totally negative study. There was no difference in total sleep time, in sleep efficiency, in most areas of the sleep midpoint. I'll get to that really quick.

And then in the standard deviation of midpoint between the women that had no clinical pregnancy and clinical pregnancy and those that had live birth and no live birth. And that was throughout the three phases of the study. We broke it down to pre-transfer, during the transfer, and post-transfer.

And there was no difference in almost every single parameter except in the phase one. So the pre-transfer, those that had a pregnancy had a slightly earlier sleep midpoint, 2 48 a.m. compared to 3 0 7 a.m. I don't know that off the top of my head, but I'm looking at the table. I don't think that sounds like a significant difference, but you could argue that maybe they were tired and they went to bed a little bit earlier.

Overall, again, we were looking at a lot of different outcomes and so this probably wouldn't stand up to multiple hypothesis testing, which was what our amazing PhD biostatistician Margaret Banker, who helped us with all the wearable data here, told us. So overall, we found I think what's most interesting is number one, sleep did not matter. Number two, actually, women were sleeping fairly well.

Yeah, I was actually really surprised by how much our patients slept. I think it was an average of seven hours. It was, it was.

All the parameters would fall in what would someone would consider healthy sleep. So over about seven hours a night, an efficiency over 85 percent, a healthy midpoint, and a deviation of the midpoint of less than an hour. I would say like though it's a negative study, I think when I think about like why does it matter, I think it's very reassuring and I want to hear more from you in terms of how are you, now that you are in practice, how are you going to counsel patients when they ask you about what factors may or may not impact their prosnibrio transfer? Absolutely.

I think one of the things on the forefront of all of our patients' mind is what can I control in this cycle that might help? What can I eat? What can I do for exercise? I think if patients, if we told them to eat a pineapple and stand on their head for an hour, they would do it. But as you like to say, Dr. Feinberg, it's okay to have the fries. It's okay.

And so I think for me, even though it's a negative study, the outcome for our patients is really positive. It shows, again, a lot of this is out of our hands and to try to do the best you can to diminish that on stress that you feel internally about your ability to control different things. And so it's saying, you know, healthy diet is great.

Exercise is great. Sleeping as best as you can is great, but it's not going to be that thing that makes or breaks the cycle overall. Right.

I feel like our patients are so anxious overall. I can't even imagine how anxious they would be if we had told them that getting at least seven hours a night was the key to having a positive outcome. Yes.

It may have added anxiety. And what I think was one other interesting finding is we did subjectively measure people's sleep at the outset of the study with the PSQI. And over 60 percent of our participants felt their sleep was poor.

But we actually found, again, the majority of them, I think it was only about 20 percent, had what we would consider poor sleep. Right. Which is, I think that really goes to the point of using a PSQI and using subjective measures of sleep is really not an accurate way to do any meaningful sleep data study.

Exactly. Exactly. So I think the next steps with something like this, with using wearables, we'll be looking at those women that are at high risk of disordered sleep.

Dr. Jessie Walter, again, has looked at women using a wearable device with OSA. So I think maybe helping these women that are at higher risk, BMI over 40, PCOS diagnoses, is there any meaningful signal that we would get if their sleep was different? Right. Or even looking at this same study design in a PCO population and whether or not that makes a difference.

Exactly. So I just want to say congratulations. This is an incredible project for anybody, but an incredible project for a fellow to complete.

Thank you. Thank you. And we'll shout out to our amazing medical student Prita Kamat, who also was just fabulous and helped with recruitment.

That's the whole study team. So really, it was amazing. And it all came from just thinking about our own Oura Ring sleep.

So, you know, I think really interesting things were found out of that one conversation in your office. I agree. Thank you so much for coming on the podcast.

Thank you. This next abstract is investigating the reproductive potential of non-mosaic segmental aneuploid, a double-blinded multicenter non-selection study of 176 single frozen embryo transfers. And I am joined by Stephanie Wilson and Emily Mounts.

Welcome. Thank you. Thank you so much for having us.

I'm very excited to talk about this because this is something that literally comes up all the time. So Stephanie, I'd love to hear from you what prompted the study and just a little bit about the methodology that you used. If you can walk us through what your study entailed and what you were, what study question you were hoping to ask, that would be fantastic.

Yes, absolutely. So like what you mentioned, Dr. Feinberg, I think, yeah, I think that as clinicians we are very commonly faced with this scenario where maybe a patient doesn't have any quote-unquote normal embryos to transfer and has a segmental aneuploid that she's coming to you and saying, you know, what should I do with this? And just to be clear, that's a not a mosaic segmental aneuploid, but a one that is read as like two copy number aneuploid or three copy number like true segmental aneuploid. Correct, non-mosaic specifically.

Okay, so yeah, so go on. Yeah, so really, you know, the existing data is primarily retrospective research and, you know, we wanted to dive into the question of using like a gold standard study design. So we wanted to see what the true reproductive potential was of these segmental aneuploid, these non-mosaic segmental aneuploid embryos, and evaluate it with that kind of gold standard study design in a prospective way.

Yeah, so I'm looking at Dr. Barnhart, who doesn't like the term non-selection, but, you know, tell us a little bit about what you did to make this a so called non-selection study. Sure. So this was a study, our study period was from January 2020 to 2022, and essentially this was a non-selection study where we evaluated outcomes from embryo transfers of essentially unmasked PGT, like raw data that was unmasked after the transfer.

Just to clarify, when you say non-selection study, it's really more of like a blinded study in that the PGT has been done, so the biopsy has been done, the embryo has been vitrified, but you are not looking at the results of that PGT at the time when you decide which embryo is appropriate for transfer, correct? Correct, yes. So the segmental aneuploid status was not known to either the transferring provider or the patient. So yes, blinded in, you know, both aspects, and, you know, these net embryos were not deselected, I guess, or deprioritized.

So how many patients did you have in the study that transferred without knowing their PGT results? We had over 7,600 transfers that were included within the time period of those two years, 176 of which, or two percent of that pool, were then found to have segmental aneuploid on the raw PGT data. And how did their pregnancy rates compare to the pregnancy rates of patients who had euploid embryos? So oftentimes I think that maybe the most valuable counseling tool might be live birth rate for these patients. So in the segmental aneuploid positive group, the live birth rate was about 27 percent compared to 58 percent in the negative group.

And then what are some of the other findings from this study? Yeah, so, you know, I think the take home to this study is that hopefully this can allow clinics to kind of guide them into their protocols in terms of disposition of these embryos. So really we're demonstrating there's a, you know, a potential for these embryos to result in live births, result in ongoing pregnancies, but not without risk. So we did have, you know, higher rates of biochemical loss, clinical pregnancy loss, compared to their segmental aneuploid negative group.

But ultimately these do end up in live births and, you know, this supports the notion of not having to automatically discard these embryos. And then once these patients were pregnant, were their pregnancies subjected to genetic testing, either through non-invasive prenatal testing or invasive prenatal testing like amnio or CVS? Right, now that's a great question. We reviewed what was the available data in terms of, you know, standard SART follow-up.

We don't have available data on every pregnancy for this time period. We don't have any, we didn't have any postnatal complications or postnatal abnormalities that were reported, but, you know, we don't have results for every single patient that underwent it. And were you able to get any more granular data in terms of which chromosomes were more likely to lead to live birth or which chromosomes were less likely to lead to live birth? So it's, it's hard because the group of the 176 was so small and the N is small.

Interestingly, we've had, we did find a pattern of maybe the X chromosome and of the involvement with maybe poorer pregnancy outcomes, later clinical pregnancy losses, but it's hard to perform a statistical analysis on such a small number. And then with regard, just, and I know this wasn't the point of the abstract, but people ask all the time about aneuploid embryos, and I know that there were some data that came out of EVRMA a number of years ago that looked at this non-selection concept for aneuploid embryos and did not show live births with aneuploid embryos. Were you able to look at that as well to further substantiate those data? So these embryos that were transferred as part of this study were already known to be negative for whole chromosome aneuploidy.

Got it. So you've just, this study just purely looked at the segmental non-mosaic embryos. Got it.

Yeah. I mean, I guess I was just asking the bigger question of whether or not there's any newer data that has emerged arguing against or for the previous findings that whole chromosome aneuploidy does not lead to live birth. Because I know that that's something that's controversial as of late with some data coming out of the team study or data coming out of Stanford showing live birth from whole chromosome aneuploidy.

Yeah. We didn't specifically look at the aneuploidy or whole chromosome aneuploid. Everything that was included in the study was whole chromosome aneuploid negative.

Yeah. So how has this changed your practice patterns? Are you now routinely transferring these embryos within your practice? So I think it becomes a data point that we can use to counsel these patients when patients are faced with the scenario where maybe this is their last remaining embryo. Should they cycle again? We can provide them with this information that these embryos, 27% of the time, would result in a live birth.

So it's really just an additional counseling tool. We, at our clinic, we didn't automatically discard these embryos. So we didn't kind of have that clinic protocol to change.

But perhaps other clinics would be able to use this as a guideline for their protocols. Yeah. I mean, we don't automatically discard any aneuploid embryos, but we don't, as of now, we're not routinely transferring these embryos.

And so I guess part of the reason I was so interested in this study, and thank you again for coming on the podcast, is should we be counseling patients similar to how we counsel mosaic embryo transfers? Emily, I'm curious on your take on that. Like as a, you know, as somebody from the genetic side of it, how should we be thinking about these embryos? Yeah. I think that for many people in the field, this knowledge about segmental embryos has followed the same trajectory as mosaic embryos.

Although I think if we go back to when next generation sequencing started in roughly 2015, you know, most PGT labs started reporting out segmental aneuploidy as abnormal or aneuploid at that time, many times putting them in the same diagnosis box as whole chromosome aneuploids, therefore implying heavily that they have the same positive predictive value or, you know, confirmation rate, which we now know is not true. So I think the strength of this study is having this blinded data to find out the true reproductive potential of these because they were not deprioritized. They were transferred based on morphology as the best embryo available at the time, and so it allows for more evidence-based counseling around these findings.

I think most clinics now are second-guessing their practice of discarding these if they, you know, hadn't already changed that practice, but we do also know that these patients should have genetic counseling before transferring these embryos. There have been a number of case reports now of confirmations of the segmental aneuploidy being true to the fetus. Yeah, that's an important point because when we look at the data from mosaic embryo transfers, when those go on to live birth or when they go on to ongoing pregnancy, the rate of true mosaicism was very, very low.

I think it was one in a thousand that were reported. So here it does seem to be more of a real finding is what you're saying and what you're seeing. Yeah, we don't have a true sense of it yet because the ends are so much smaller with segmental aneuploidies because, again, they've been mostly not transferred in order, you know, we haven't been able to get that data, but there have been now I know of at least three or four confirmations, not just one in this study and then some other case reports, and so I do think it's something to be cautious about.

Patients should know that there is a potential for that to happen, albeit seemingly very rare, but they can be counted on the option of prenatal diagnosis. Yeah, and it's probably going to be even more nuanced than that in terms of what chromosome is affected, right? So I would be a lot more hesitant to transfer a segmental aneuploid in a chromosome that we know that could lead to a live birth as opposed to chromosomes that have different implications. Yeah, and as you know, that's going to be so difficult with segmental aneuploidy because there's an infinite number of three points and sizes, so I don't know that we'll ever be to the point where we can provide that specific level of counseling.

Right, and we have to know, though, intellectually we've been transferring segmental aneuploidies forever because when we don't do PGT, sort of like this don't ask, don't tell, we, I'm sure we've been transferring these for a long time without realizing it, right? So, yeah, well, thank you so much for coming on the podcast and taking the time and sharing your wealth of knowledge with all of us. I really appreciate it. Thank you so much for having us.

Thank you. 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. Selina Park, Dr. Carissa Pekny, and Dr. Nicholas Raja.

This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource in service to its members and other practicing clinicians. While the podcast reflects the views of the authors and the host, 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.