Fertility and Sterility On Air - Unplugged: July 2025

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals!

Topics this month include: whether drug-free in vitro activation with immediate autotransplantation improved reproductive outcomes in patients with poor ovarian response and premature ovarian insufficiency (2:13); resident management of pregnancy of unknown location (16:42); integration of mental health treatment into the care of Mullerian agenesis (26:38), and a narrative review of blastocyst development as a surrogate for pregnancy outcomes (36:27).

F&S Science: https://www.fertstertscience.org/article/S2666-335X(25)00040-0/abstract
Consider this: https://www.fertstert.org/news-do/beta-book-beta-overlooked-exploring-systems-pul-surveillance-residency
F&S Reports: https://www.fertstertreports.org/article/S2666-3341(25)00057-1/fulltext
F&S Reviews:  https://www.fertstertreviews.org/article/S2666-5719(25)00008-8/fulltext

View the sister journals at:

• https://www.fertstertreviews.org
• https://www.fertstertreports.org
• https://www.fertstertscience.org

Welcome to Fertility and Sterility On Air, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussion with authors, and other special features. F&S On Air is brought to you by the Fertility and Sterility family of journals in conjunction with the American Society for Reproductive Medicine.

Hi everyone, and welcome to another episode of F&S Unplugged. I'm your co-host Pietro Bordoletto, and I'm joined by the three titans of reproductive medicine. One Daylon James, one Molly Kornfield, and one Blake Evans of noted Oklahoma City Thunder fandom.

Congratulations, Blake. Hey, I'm not going to lie. If you weren't going to mention it, I was going to.

I am on top of the world right now. If anyone knows, I'm a massive NBA Thunder fan. And the parade actually just wrapped up, like, right down the street from my office.

You can hear helicopters going. There's hundreds of thousands of people. It's really, really exciting.

As a Thunder fan, NBA fan, pumped. Put us on the map. Is that why you made us push this recording back by three hours today, Blake? Just level with the listener.

Yeah, that's why I was sweating profusely when we sat down to record. I ran here from the parade. I dig it.

Well, congrats to the Oklahoma City Thunder. Big week for you all. Yes.

Yeah, I finally can sleep. I'll be honest. These playoffs have shaved years of my life off.

But I'm so pumped. It was a real fun experience. My family and I had to watch it, go to the games, wear ticket holders.

And so it was a great time. Go Thunder. Go Thunder.

Speaking of Thunder, we usually relegate Daylon to, like, the middle or the end. But I think F&S Science is really bringing the Thunder and the Lightning this month. I heard something about drug-free in vitro activation of follicles.

Daylon, tell us more. Yes. Well, I mean, this is an intro laced with all kinds of God references there.

The Titans. I wouldn't call myself a Titan. I would say more of like a demigod there.

But maybe between the Thunder and the Lightning, a storm type, Zeus-y. Not really Zeus. Too big time.

But this story is certainly magical and the stuff of gods. It's a bit of a throwback for me, a nostalgia trip, because I was first introduced to this idea when I transitioned my lab to reproductive biology back in 2013. And this at the time, you know, my lab was focused on, in part, on fertility preservation and ovarian tissue transplantation.

And this at the time was a truly disruptive idea that had entered the zeitgeist. It was a bit of a combination of the, you know, legendary titanic status of Aaron Hsueh. Excuse the pronunciation.

It's hard for me with the H and the S right next to each other. But he's a living legend in reproductive endocrinology. And this upstart, Kazuhiro Kawamura from Japan, who is a young physician scientist, who, together with Aaron Hsueh, demonstrated the proof of concept of in vitro activation, whereby women with primary ovarian insufficiency had part of their ovarian cortex excised, fragmented and incubated in this AKT activating cocktail, and then auto transplanted, resulting in follicle growth, oocyte aspiration, IVF, all the way to live birth for one of these patients.

And at the time, my incipient efforts to, like, optimize ovarian tissue transplantation, in that case, in the context of fertility preservation, made this news really a particular interest to my lab. But it was also widely discussed. I don't know if you guys remember.

I mean, we were just young guns back then, maybe not even specialized. But this was widely discussed amongst REIs as it expanded the scope of tissue auto transplantation to a much broader group of patients, right? Talking to anyone POI or even poor responders. But the follow up studies with larger cohorts of women showed that while the birth outcomes were feasible and reproducible, there was another patient who had live birth, at least one.

They were rare. The outcomes were not really high at high efficiency. Since then, I hadn't heard much about IVA.

But ART patients, I'm guessing, I mean, I wonder, I'll say, they're very resourceful as a group. And often as the outcomes, you know, as they struggle more, they go deep, deep into the literature. So I'm asking you guys, here we are more than a decade later, do your patients ever talk about IVA? Or do you guys ever think about this at all? I get patients asking me left and right about HIPPO signaling, Daylon.

I can't tell you how often patients come and ask. Yeah, daily. Nightly and ever so rightly.

The HIPPO signaling part of this, it's interesting. And this is part of the story, as you alluded to there with the drug free activation. The initial efforts use this AKT cocktail, but it was AKT stimulation as well as HIPPO signal activation.

For the listener at home, what's AKT? AKT is an effector of PA3 kinase signaling involved in this mTOR pathway, the so-called, you know, longevity pathway that a lot of, you know, people who want to live forever and have a lot of money are trying to hack this with rapamycin. It's involved, it's ubiquitous almost, you would say, and involved in cell proliferation, but also implicated in cancer proliferation. So AKT stimulation in this exogenous fashion would seem like kind of a liability to some.

And that's why this story was kind of, I would say, news, although it had already been demonstrated that you didn't need the AKT signaling. And you didn't need any kind of exogenous activation at all, because as I was getting to, the HIPPO signaling is activated just when you disrupt the tissue. You chop it up, and HIPPO signaling just spontaneously arises intrinsically.

So when they ask you about HIPPO signaling, you can say, yes, sure, HIPPO signaling may have an influence, but it's really downstream of this mechanical disruption of the tissue, which is thought to maybe liberate, in terms of teleologically, it's thought to perhaps liberate the follicles from that quiescence in some molecular fashion downstream of HIPPO. But getting back to the story, the idea there was very big. And I think, as I said, the scope seemed to expand.

And everyone was thinking, remember, like endometrial scratch, right? Or there's a lot of ideas that come and go. Don't say that. He has suppressed it.

That was a guttural, that came straight from the belly of the beast there. Can I hear it again? I unmuted myself to let out a distasteful ugh. Yeah, well, it may go with the way of ERA or endometrial scratch.

I don't want to say ERA as a concept doesn't have legs, but sometimes it's the execution. And here was the question here. Was it just the execution? Could you improve and maybe get beyond these poor outcomes? As the father of transplantation once said, Thomas Earl Starles, another pronunciation challenge there, R-Z-L, I mean, come on.

What he said was, what was inconceivable yesterday and barely achievable today often becomes routine tomorrow. So to the latter end there. The story from F&S Science, which has actually Kazuhiro Kawamura on the author list, but is led by Bozhena Saar-Ryss and Shevach Friedler.

I think I did pretty good with the pronunciation on those. Those are two REIs from Tel Aviv who led this study. And this study, what it aims to do is check in on that.

Is this routine now? Have we advanced the tech to make it feasible, at least at a scale? So they checked in on this using IVA, same protocol as I said before, with a new cohort of 21 women who were in two groups, either primary ovarian insufficiency or poor responders. There were 14 POI, seven poor responders, and these were defined by ESHRE and Bologna criteria, respectively. And all of the patients had this procedure, ovarian cortex retrieved, fragmented into these one to two millimeter pieces, and then transplanted back around 10 to 12 fragments into pockets either in the ovarian fossa or between the cortex and the medulla.

And in cases where the ovarian tissue was totally fibrose and there was no avascular, they would put it beneath the serosa, the fallopian tubes. Patients were followed up to measure the response and recovery of function for up to a year. And when they saw that, they were stimulated with oocyte retrieval and IVF to follow.

The long story short here is that there was a response, although perhaps not surprisingly, the poor responders did better than the POI patients, right? So of seven poor responders, four showed an increase in AMH, so more than half. But all of them, seven out of seven, were able to retrieve mature oocytes. All seven had frozen embryo transfers, good quality embryos.

Of the 14 POI patients, by contrast, only one showed an increase in AMH. But seven of those 14, half of them got mature eggs, and five of the 14 were able to transfer good quality frozen embryos. The downside here is of the seven poor responders and five POI patients, only one from each group had a clinical pregnancy and only the one poor responder had a live birth.

So it's a bit of a disappointment. It looks like the same kind of outcomes by percentage as have been shown previously, with the one side that there is no, it's drug free. So just the mechanical disruption is enough.

That seems to be demonstrated, but not really efficiently. So it doesn't look like IVA will be, you know, a la Thomas Earl Starzl. It doesn't look like IVA is going to be routine anytime soon.

But there are useful tidbits, I think, in the details here. One is the relatively poor outcomes from 12 total transfers suggests that there's other factors involved, right? These were good quality embryos, but there was no PGT. And these were many patients, you know, they were under 40, but POI, poor response, suggesting poor quality eggs, perhaps, maybe other factors, uterine factors or systemic, I don't know.

Second, there was this whole facet of the study related to vascular perfusion. I didn't go into it because the results were kind of negative. I was hoping you were going to talk about that because I know that's kind of your thing.

Well, this is my, what I've long thought is that it's hard, right? Because you've got all the negative influence, inflammation, ischemia, which is in large part neutralizing any of the benefit you're getting from this HIPPO signal activation and rejuvenation of these, you know, quiescent follicles. So it really muddies the waters here. So there really needs to be something done about that.

Read my papers. Although I don't think it's really practical in a clinical context now to rescue the vascular function. And just even theoretically, it seems like a heavy lift.

And then finally, I think it was interesting to see the timelines between poor responders and POI patients, right? So 56, this is the median time to resumption of function, 56 days for the poor responders and almost double that, 108 days for the POI patients, which makes sense. But I think it helps to calibrate the timeline for like de novo follicle activation and maturation for more autotransplantation in the context of cancer survivors. But also it suggests that if you do fresh tissue transfer with no cryopreservation, there's more survival of more advanced stage follicles that never crash, so to speak, with that freeze thaw.

And therefore, you kind of hit the ground running. So this, you know, fresh transfer paradigm in the context of IVA, which I don't think is ready for prime time, but one benefit is that not having to ever freeze the tissue, I think allows you to rescue some pre-antral stage follicles. Whereas in the past, I think you had to start from like maybe secondary.

So a lot here, I think for F&S science story, this is one that really invites a lot of scrutiny. As you said, Pietro, there's the whole vascular angle that bears scrutiny. But more than anything for me, this is a really strong, I don't want to call it a negative result, but this is what we need in science more.

It's like, here, let's check in on this. Let's do maybe more carefully designed study with broader patients and control for certain things we didn't control for before and see what happens. And when it's a negative result, publish it and let us see, you know, where we're still struggling.

So that's the best takeaway for me here is that we're not ready for prime time. We're pretty static, in fact, but I think we have a little clearer resolution on what the obstacles are. So a great story from F&S science.

Maybe your patients can be talking about HIPPO again someday soon, guys. Daylon, I have a question for you. I'm putting my surgeon hat on here.

I know that there's a couple of different techniques or approaches to returning the ovarian tissue back into the body for transplantation. The peritoneal pocket approach, the lining underneath the cortex approach, and sometimes even the putting it in the forearm or armpit approach. I know in this study, the authors described kind of having two different methods within the ovary, within the peritoneal pocket.

How much do you think the method of transplantation affects these kind of vascular considerations that we're worried about and the success of IV as a technique? Yeah, I think that it's a big point. It's an important point and a critical factor. I mean, first you want to have a highly vascularized area that's going to maximize the recovery of the tissue.

And I know we did it at our center under the forearm or armpit. I don't think we did that. But the forearm was really eye-catching, but I don't think really practical.

You want a site that is amenable to expansion of the follicles. There's a lot of steric hindrance in the process. And in fact, transplanting to heterotopic sites leads to smaller follicles, so to speak.

It could be that they're transplanted or it could be the restrictions of the site. But from our studies, we found that you'll be looking for size as an indicator of when you're approaching maturity. But you need to recalibrate because we'd have follicles that were M2 as early in our mouse models.

We were recovering mature follicles that were from 3, 4 millimeters in size and highly variable. So I think that there's a lot about the transplantation site. I think what we've learned, though, more is that it's really plastic.

You want to do something that's convenient. I think what's typically done clinically is now not typically. There's a lot of orthotopic transplants still to the site.

But I think when it's done, it's still relatively rare, sadly, or maybe happily because it's unnecessary. But in just the abdominal, peritoneal, and abdominal cavity, that's really amenable to monitoring and accessible to laparoscopy. I think it's more practical considerations you need to keep in mind here.

How are you going to get those eggs out? How are you going to make that minimally invasive for the patient? Remember, IVF patients, ART patients go through a lot, but this is extra. With the re-implantation, there's a lot of risk involved there. And most of the time, you can expect a negative outcome.

So the fortitude and courage of the patients involved here, you want to really make it as easy as possible for them, just in terms of how disruptive it is to their life. Cool. Thanks for that, Phelan.

I'm going to bring us back over to Consider This Now. We're going to talk about something that's same, same, but different. And in fact, it's actually just totally different.

There's not a really good segue here. But an article that kind of caught my attention called The Beta Book or Beta Overlooked, colon, Exploring Systems of Pregnancy of Unknown Locations Surveillance in Residency. This is first author Jordan Fletcher, senior author Sarah Horvath, coming from a group from Penn State, University of Michigan, and UCLA.

The reason for this publication in Consider This is all of us who have gone through residency have managed some form of a beta book, a quant book, a beta list, which is a centralized tool that's anecdotally employed to organize and surveil patients who have either a known ectopic or pregnancy of unknown location until there's a definitive diagnosis, treatment, and follow-up. And it's not really known how often this kind of program or this exposure exists in OB-GYN residencies and how effective it is of a tool for management and building comfort in trainees so that they have that skill set post-training. So the primary objective for this study was to describe the beta book's use, operational differences in surveillance between residency programs, and to just analyze some resident metrics like satisfaction, perceived competence, and then some actual competence.

The way that they did this was they first reached out to program directors and they focused only on the state of Pennsylvania. The reason they focused only on Pennsylvania is that there's a large number of OB-GYN residency programs in the state that vary substantially in size and type, meaning you have university, community-based, and then hybrid programs. The program directors were asked to fill out a survey talking about the use of the beta book, resident involvement, type of faculty oversight, amongst other things.

And then afterwards, the residents themselves were asked to fill out a survey within their program. And they looked at differences between PD and resident answers, and they also looked at resident-specific variables. So what did they find? So as a whole, 17 programs existed in the state.

14 of those program directors returned surveys and distributed the secondary resident survey, which is a nice response rate for anyone who's ever done a survey study. They found that most programs use a beta book. About 93% have some form of a beta book.

And about 85% of them have it as an actual list within the electronic medical record. Interestingly, almost a third of programs reported the beta book was overseen by subspecialists. So this meant RAIs and complex family planning docs.

And the majority of program directors were satisfied with the structure of this beta book, but a third were not, interestingly. All the program directors stated that the graduating residents were fully competent to manage the beta book and do this independently after training. Now, for the resident portion of the survey, unfortunately, the response rate was much lower.

This was 18%. 61 out of the 316 residents completed the survey. They said... Too busy to do surveys.

Yeah, they don't have time for that. They can barely log their cases. They can't log a log book with HCGs.

Been there. So here I think where it's interesting, I compared it to my own experience. They found that the average beta book size was highly variable between programs.

16% of residents cared for on average 26 to 40 patients who are actively on the beta book. And 23% of residents reported spending four or more hours per week on pregnancy of unknown location management within their GYN service. I don't know how that jives with Blake and Molly, your experience, but 26 to 40 patients on a beta list is crazy.

That's quite a bit. That certainly seems more than my experience. Yeah, my med school had like a massive beta book, kind of like that amount.

It felt that long. And the GYN team ran it every single day. Our residency here in Oregon, it's a much smaller beta list.

It's usually less than 10. And you only manage it on the family planning rotation, which about half of them do here. And I just think that's not enough exposure.

And you only do that rotation once, whereas if every year you come through your guide rotation, you do it again as a team, I think you're going to get better at it. It's ultimately not that hard, but it takes a lot of repetition. That's how we managed it at my program.

So I did residency at the Brigham Mass General Program. Each hospital had their own beta list. It was primarily managed by the GYN attending of the week with the GYN service team of the week.

So you kind of got the exposure over and over again over the course of four years, which was nice. And you got to see how different specialists and subspecialists managed the beta list, which there are some nuances depending on their comfort levels, which was helpful. From a satisfaction perspective, they asked the residents how satisfied they were with the structure of their beta book.

About 80% were satisfied and 75% were satisfied with the faculty oversight and the time devoted to it. So I think the current setup is a good one. Now, the final question was the perceived versus actual competence.

So most residents, like I told you, feel very comfortable with management of pregnancy of a known location. They actually also sent them a series of multiple choice questions taken from the prologues to assess actual competence of the residents filling out the survey, which I thought was kind of a nifty way to trust but verify. And they showed that there were no major differences there across perceived and actual competence.

I think this is something that is nuanced but not hard and in the best of circumstances is pretty formulaic. And something that someone who is a non-physician could probably manage primarily with physician oversight, which is what I think happens in a lot of practices once you leave the academic setting. So all in all, I think the study is not revolutionizing how we manage pregnancy on a location, but I think it's really interesting for how we train our residents and our fellows in the management of pregnancy on a location.

The beta book still has a role. Seems like it seems to be a good method for keeping track of pregnancies, teaches trainees appropriately on how to manage these pregnancy of unknown locations. I'm sure there are bells and whistles that an EMR can improve, and there's more people that you can bring into the fold to make sure follow-up happens and patients get the care that they deserve and need.

But really cool little study and consider this that was of interest, hopefully, to all of our listeners. Molly, Blake, thoughts on the outcome findings of the study? When I saw the title, for some reason, I thought it was going to be one of those AI studies. So I thought they were going to be using AI to manage the beta book, which liability-wise was making me a little bit nervous, but I'm glad it wasn't that.

But maybe an idea for the future. Yeah, I think that's a good idea. It's nice that they made this into a paper or consider this article.

We really manage these all the time as our AIs. Admittedly, we don't have a version of a beta book in our program, and if you have Epic, they have little sticky notes, I guess you could call them, that pop up. It's just specific to the provider that's reading it.

And we'll list out all the trends of the HCGs, and our patients are so good with follow-up to where we're not calling them like, hey, you missed your HCG appointment today, but they're going to show up or have it done. So these are all coming to our inbox, and then we'll just trend them on our little sticky notes. But we manage these so frequently.

So I think it's kudos to the authors of this paper. Outsider take here. This maybe is in need of a paradigm shift, right? And just bear with me for a moment here.

If you read Brave New World, there's this part of it where they have massive filing cabinets to keep track of all the babies, the alphas and the betas and whatnot. And it's so futurist, but it's an anachronism reading it now, because of course you have computers. And the idea here that I'm positing is maybe we need a definitive diagnosis for ectopic.

Would that maybe help instead of monitoring? You're talking about the Holy Grail, Daylon, a biomarker for ectopic that is better than beta HCG, that is better than a beta HCG trend, that is better than a beta HCG and a progesterone. I know there are really smart people, including our editor-in-chief at Fertility and Sterility, Kurt Barnhart, who have sought this elusive creature. But I think with the tech that we have these days, I think we're probably getting closer than ever to potentially having a useful biomarker or even a more algorithmic approach to diagnosis and management that eliminates some of this human error.

That may be a really good first intermediate step. So stay tuned. Maybe we'll see some of that come up in Fertility and Sterility.

Well, it would start with you, Pietro. I was kind of burying the lead there. Be the change you wish to see in the world, Daylon.

This is the project you started when we were working together, and it has evolved now to a very similar approach. And it's not a biomarker, it's a signature, Pietro. That's what I was getting at.

Maybe we need a more holistic view. But as you said, we'll see. Early stage, early days.

Stay tuned. Molly, we're going to go back over to you to F&S Reports. I am so delighted that you chose an article on malaria anomalies, something that are near and dear to my heart.

I mean, it's always nice when we highlight articles that come out within the F&S family of journals, but also on this podcast. Tell me why we need to integrate mental health with the diagnosis and care for patients with MRKH. I chose this one just for you, Pietro.

So I'm stepping a little bit on Blake's toes with this one. So F&S has been featuring these mini review articles and has quite a few lately. And so I picked one of those to discuss this month.

I think it's a great way to kind of update your knowledge a smaller amount of time and then digging into a totally full review. I think probably for the authors, it's a little hard to write a mini review because you can't just put everything in like you can with a narrative or a scoping review. But for this article, a mini review may have just been the best format because there was kind of a paucity of data on the topic, because I imagine they actually did put every study in here.

But I thought this was really compelling. So the title of the article is, The Need to Integrate Mental Health Treatment into the Care of Mayer–Rokitansky–Küster–Hauser, also known as MRKH. The authors are Teni Davoudian and Emily Hills, both at Baylor College of Medicine.

And full disclosure, Teni is an incredible psychologist who used to be in our division out in Oregon. And so I would always refer my patients with MRKH to her. And so now I'm excited to see what she has been writing up over at Baylor.

So MRKH, also known as Mullerian agenesis, is a congenital disorder leading to absence of a functional uterus and cervix. The mini review states that qualitative research really supports that patients with MRKH report feeling that their providers are unsupportive and lack expertise in their condition, and that when providers remark how rare their condition is, it leads to feeling further isolation. And so I think that's a really important point in our field.

I don't think we actually think it's that rare. We're all managing patients with this and similar conditions in our practice. But I can imagine how, especially socially, these patients may feel really isolated.

And so all this kind of qualitative research about the significant mental health burden that comes with this diagnosis really necessitates the need for a mini review to provide a little education to us as providers. So the author has noted four critical psychological time points for MRKH patients. First is when many of us, I think, are most attuned when we make the diagnosis, which is such a big diagnosis to make.

That's when we're offering the most support. And these are adolescents, so they're really vulnerable to mental health issues at that age. And the second time point is when those individuals want to start pursuing sexual activity and are deciding on what treatment they're going to do to allow to potentially pursue this.

The third is when they're in their first intimate relationship. And then the fourth time point is when they're interested or thinking about pursuing fertility. Common feelings that have been expressed are grief, helplessness, shame, and social isolation, bringing up that isolation piece again.

This is so rare. No one else is going through this. And these are really heightened during adolescence, but can really persist into adulthood as well.

Something one of my partners taught me that I just want to bring up here, there's actually a lot more to sexual dysfunction in patients with MRKH. And it's not just because they don't have or they necessarily don't have a full-length vagina for penetration. It's usually due to a combination of some of the anatomical challenges, but also they have limitations in arousal, lubrication, and orgasm.

Beyond that, overall, infertility due to the inability to carry a pregnancy really carries the greatest emotional impact for these patients. So the sexual dysfunction as well as the infertility are some of the barriers and challenges. The recommendations that the authors propose are to be sure to incorporate mental health treatment into care for malaria and agenesis, which we all are familiar with from the guidelines in ACOG and ASRM around this.

But we all know there's a lot of barriers to accessing good mental health care. In a perfect world, all of our MRKH patients would live next to a specialized center with a physician and a mental health team that all understand their condition really well and the challenges they have and would know all the right treatments and get them recommended. But in reality, we know these specialized centers are really few and far between and most don't have an embedded mental health provider who's specifically informed on these diagnoses.

And in addition, these providers also really need to have a lens that incorporates the patient's sociocultural aspects of care as well. The authors said that in some cultures, physicians and or patients might only want to undergo vaginal dilation after marriage, and some providers might only offer this after marriage. So a lot of other factors at play that I hadn't even thought of.

There's a huge role for support groups, particularly in the age of the internet. And there's actually a table in the mini-review, a table for Daylon, who loves a table, that has a list of patient advocacy foundations that do offer support groups. And so I'll definitely be touching on these and sharing them with my patients to find out, hey, you're not actually that rare.

There's other people out there going through this too. And then just my own two cents that I thought I'd plug here in the podcast. I think we all kind of need to update our education about MRKH based on the emerging kind of diversity of gender and sexual expression in our population and in our patients.

I think traditionally the doctor kind of meets the patient and says, okay, now we're going to do vaginal dilation and then you can have sex. But I think that's a really narrow understanding of sexual expression, how people have sex. And I've had patients who say to me, you know what, penetrative vaginal intercourse is just not that important to me and not that important to my partners.

And so for those patients, they don't have to pursue dilation. There's no medical need to pursue that. And so I think figuring out what's important to your patient, where are they at with sexual expression, where are they at with intimacy is really essential to finding the best treatment for them.

And it seems to be a little bit of a disconnect between my patients and their parents as well, because Gen Z and Gen Alpha patients, they have a really much more nuanced understanding and experience of sexuality than their parents or their doctors. So I think any of our REI or mixed clinics where we're working, where we're diagnosing and caring for these patients, we need, we ideally do need to have a proficient mental health provider to provide not just the initial, but the longitudinal care for these patients. It's such an access to care issue.

I would love to see, you know, beyond these support groups, which I'm really excited to learn more about, is there an option for virtual care where one really great mental health provider who really understands MRKH can provide care all over the country to these patients? But I wanted to talk to you guys, what do you think of this mini review? And then do you guys have embedded mental health support in your clinic for these patients or for all your patients? How does that work? Yeah, that was a great summary. We do have several reproductive counselors that we work with. They're not embedded into our clinic necessarily, but we have a list that we'll provide to our patients, but none of which are including these in this paper.

So I think that's something that I admittedly don't really think about when I'm seeing my malarian anomaly patients as the mental health aspect of things. And so I like this review because it really helps as a provider to just keep that in your mind when you're talking to them because it's not entirely about reproduction. And even though I'm not going to be counseling them about all these mental health aspects, having them aware that, hey, here's some resources for you, I think that's super helpful.

I think the, well, as you were kind of talking about the article, there are two things that kind of struck me. One is I take care of probably an outsized amount of malarian anomaly patients just by nature of saying that I like taking care of these patients. I end up seeing a lot, which is lovely.

But I'm very, very rarely the first one making the diagnosis at MRKH for these patients. These patients are getting diagnosed at 10, 11, 12, 13, 14 by their pediatricians, by an emergency room visit, sometimes their parent's OBGYN. So for me, I'm catching them where they've had an opportunity to understand the disease a little bit more, understand the implications of the disease and just be able to wrap their head around what it means for them from a sexual function and reproductive perspective.

But what I think this highlights is that even though they've made the diagnosis and it was many years ago, it still has trickled down effects into their reproductive years that can't go undiscussed. You have to check in and you have to talk to them about how does this diagnosis affecting you, your relationships, your desire to have relationships, your planning for family building in kind of creative and non-traditional ways. I think it's really, really important to have someone in your community, ideally within your practice that you have a relationship with who understands some of that nuance.

I would say most mental health professionals that we interface with in REI land are really good at third party. They're really good at grief. They're really good at loss.

But this is a little bit of its own beast from a topic area. It's really cool that people like Dr. Davoudian are kind of talking about this and writing about this. I know that she's now embedded in Texas Children, so she probably sees an outsized amount of MRKH patients.

So kudos to her for publishing this. It's super helpful for all of us who take care of malaria and anomaly patients. One fun anecdote that I heard from Sam Pfeiffer, who's the chief architect, if you will, of the MAC 2021, was that as they were going through the new classification system, there was a really strong desire to get away from eponyms and call this Mullerian agenesis.

There was actually pretty significant pushback from the patient and advocacy community. Something about having MRKH as your letters that you've kind of associated your diagnosis with, your community with, felt really personal to them. They actually did not like the change to Mullerian agenesis, despite it being a little bit more clean, elegant, and useful from a research perspective.

So always interesting to still see MRKH being used, despite Mullerian agenesis being the preferred scientific classification term. Interesting. I wonder if we ever deviate from PCOS, if that'll be the same.

Oh, you lead the charge, I'll follow. Because every single patient who ever has an ovarian cyst has PCOS. I know this is completely unrelated, but we're talking about acronyms here.

Ain't that the truth. Blake, why don't you bring us home with F&S Reviews this month and tell us a little bit about what you're seeing in the journal. All right.

Thanks, Pietro. So I'm going to talk about blastocyst development, something near and dear to our hearts. And this, I will say, I always say go back and review these and read these articles.

But this one particularly is good for fellows. It really goes into depth about blastocyst development, genomic activation, and when that occurs in the cleavage stage embryos. It talks a lot about culture media conditions, changes in conditions, and just a lot of the studies that pertain to those.

So these reviews are always presenting a challenge for me to try and make this concise as a review as I can for you all on the podcast. But I say this because it's like a 35-page paper, and I think it is something that's really good for fellows to go back and read. So just I wanted to mention that.

So the title of this is Blastocyst Development and Assisted Reproductive Technologies, A Narrative Review Evaluating Its Role as a Surrogate Marker for Pregnancy Outcomes and Live Birth Success by Authors Dean Morbeck and Michael Diamond of Melbourne, Australia, and Augusta, respectively. There is an urgent global need to improve IVF success rates. This is no surprise to us and also a need to expand access to services.

Specific to the IVF lab, challenges such as standardization and shortages of trained embryologists definitely hinder the quality and limited service availability. Meanwhile, in addition to this, high costs associated with IVF procedures create disparities in access to care, which is exacerbated by a shortage of RAIs. Technological innovation in the IVF lab provides one strategy for addressing these challenges by developing tools to standardize and optimize protocols and therefore improve access and also extend fertility care workforce.

However, product approval relies on demonstrating comparable pregnancy rates, requiring extensive patient involvement and time-consuming trials, which may be further hindered by patient reluctance to participate in these trials. So to expedite device development for fertility treatments, the adoption of an intermediate endpoint capable of accurately assessing the risk and efficiency holds promise in shortening approval timelines. So in light of all of these considerations, this review explores blastocyst development as a potential surrogate marker for pregnancy.

It also examines the correlation between blast development and implantation potential. It also evaluates how culture conditions and other factors affect outcomes, discuss the evidence supporting an absence of adverse effects of embryo culture on perinatal and offspring health. So I'm going to talk a little bit about this review.

Admittedly, it's not a novel concept, but it is a great review nonetheless, and it's certainly food for thought whenever we're considering blastocyst development. So this review incorporates three decades of research of clinical experience and human ART, critically evaluating the strength of evidence supporting blast development as a surrogate marker. So one of the first things they look at with blast development is the usable blastocyst rate.

They discuss how this provides a robust measure of overall laboratory performance, but admittedly it needs a standardized definition to be a trusted surrogate marker. And they discuss how a lot of publications use percentage of top-quality blastocysts with a grade A intercell mass and or grade A trophectoderm as percent of top-quality blastocysts. They also discuss the speed and the morphologic quality of the blast.

So are you having a blastocyst that's on day five or is it on day seven? Because there's certainly differences in outcomes there, and they talk about how blastocyst development has been repeatedly demonstrated to be strongly correlated with the chance of live birth. They also discuss Euploidy rates could also serve as surrogate endpoints, but the focus of this was mainly for noninvasive measures, and so the authors don't delve too much into PGT with regards to outcomes. They also talk about different culture conditions.

Different culture conditions, they say, is one of the most studied laboratory interventions in IVF with regards to embryo development. However, they discuss that assessing the risk associated with embryo culture and laboratory interventions in the context of neonatal outcomes is an important area of research that needs more focus. They also discuss certain laboratory interventions such as type of culture media, extended cultures to the blastocyst stage, or embryo cryo.

These have been associated with neonatal outcomes. However, the results remain inconclusive with some studies, such as reporting higher live birth rate with certain culture medias, while others find no significant impact. And then they discuss with regards to embryo culture.

While suboptimal culture conditions may influence peri-implantation embryo viability and embryo progression, evidence suggests that laboratory factors don't significantly impact health to the offspring conceived through ART. So, again, I know I'm just very narrowly overviewing what these authors are talking about. This is a ton of information to unpack, and it's more of just a really broad review that I, again, encourage you all to go back and read over.

But looking at the results, they say, while blast development demonstrates promising correlations with pregnancy outcomes, there are still gaps between blast formation and pregnancy success. It's not just the blast formation. But, of course, we have to consider embryonic factors beyond morphologic assessment, maternal factors, endometrial receptivity, paternal contributions, and also various clinical and laboratory variables.

Blastocyst development rate is sensitive to suboptimal conditions, they say, occurring after embryonic genome activation, which they discuss usually at the cleavage stage, and correlating strongly with both aneuploidy and implantation potential. So, a couple of concluding thoughts with this. This review suggests that blast development can serve as a valuable surrogate for establishing equivalency of pregnancy and live birth rates with ART protocols.

Blast development rates show consistent statistical inference with pregnancy outcomes. Specifically, reduced blast rates correlate with reduced pregnancy rates, while equivalent or increased rates associated with equivalent pregnancy rates. And, lastly, using blast development as a surrogate endpoint for regulatory approval of new devices and protocols could accelerate innovations in ART while maintaining safety standards, particularly for automation technologies aimed at improving laboratory standardization and efficiency.

So, not a novel idea, so to speak, just more food for thought. What do you guys think? We do a lot of fresh transfers in our practice. So, you know, reading through this, I'm like, yes, that makes sense, that makes sense.

If you see embryos where you don't have anything to transfer on day five, but now you've got an embryo on day six or on day seven, and when you're counseling a patient particularly on an embryo that's from day seven, still can result in a pregnancy. But keeping all of this in mind that they're discussing in this article, I think, is helpful. So, what do you guys think? You guys have any thoughts on this? I gravitated towards the very last paragraph of this review.

And I, to quote one Jimmy Ruffin of Motown fame, he said, what becomes of the broken hearted? I want to know what becomes of the patient who doesn't make blastocysts well. And this is me putting my Cornell hat on. This is me putting your hat on, Blake in Oklahoma.

Molly, I'm not sure how much fresh transfer you guys are doing on the West Coast, but I suspect it's less than Blake and Cornell in my Boston experience. I think blastocyst transfer is stellar. And blastocyst development is a really useful marker.

But we have to take a step back and think, we know that there's probably 11 to 14 million IVF conceived children born so far in the world. The vast majority of them are fresh transfers. And the vast majority of them are day three fresh transfers.

It really is only in the last five to 10 years where we've made this blastocyst push. And we're going to be catching up soon, if not already caught up. But I really worry about what becomes of the patients who don't make blasts and clinics that are dogmatic about blast culture.

It's more of a comment, less of a question. I'll shut up now. No, it's a valid comment.

And we've talked before about how geographics play a role. And we talk about every podcast pretty much. We're all in very different areas of the country.

And insurance plays a role too. And going from trained at NIH in DC, Maryland area where a lot of IVF is covered, and then you go to Oklahoma where hardly anything is covered, it really shifts how you counsel patients. And I always will tell patients there's a difference in wanting to do PGT and having embryos to be able to do PGT.

And so we will very commonly do something that I didn't do in fellowship, but they'll take like progesterone after their egg retrieval, just in case we're recommending a transfer for those who on day two embryo check, you're like, I don't think we're going to have anything to biopsy. So let's transfer what we've got. And so it's not uncommon for us to do a day three transfer of poor quality embryos, and they result in pregnancies.

And we wouldn't do it if they didn't, right? But it's like, hey, it's either we progesterone blast, see if we have anything to biopsy, or we can transfer what we have and see if you have a pregnancy. But also if it's coming completely out of pocket, you can see how a lot of patients will say, yeah, let's go ahead and just transfer what we've got. So not uncommon in Oklahoma, be honest.

Yeah, well said. Yeah, I like this paper because it kind of allows me to use blastocystin. I think there's been so much talk about cumulative pregnancy rate, cumulative live birth rate, and focusing on that with our kind of our research.

But I think if for the study that Daylon presented, for example, for really diminished ovarian reserve, even POI patients where your pregnancy and live birth rates are so low, it's going to be hard to obtain statistical significance between study groups. And so if we are allowed to use blast as a proxy, and this is saying that that's an appropriate proxy, I think from a research perspective, that's really nice. And it kind of opens up more doors that have kind of closed with this focus on cumulative pregnancy rate.

You also make a great point. You know, whenever I design a retrospective study, I'm really focused on the blastocystin and the blastulation outcome. And there are some patients who end up may, are you excluding them? Are you including them? What are you doing with these day three transfers? And often those are a poor prognosis group, but there are also a really interesting group.

And where are we missing them in our studies if we're focusing on blastulation? So no good answer there, but yeah. Yeah, they can end up in your numerator if they don't start in your denominator. And I think there's a lot of clinics that just don't give people an opportunity.

To get in. My counterpoint there is that while I do appreciate that there are some patients left behind with this focus on blastulation, I think, Molly, what you just said should be emphasized that sometimes a focus on the majority can also have a great benefit to the minority in unexpected ways. And more information is always better in just the economy of the process, efficacy and outcomes generally.

But for me, what really stuck out is how hard, and Blake, all credit to you in tackling this monumental review. I mean, I kind of gave up and started skimming halfway through because it is massive. And it's tough to integrate all of these different parameters over the course of so many years into one synthesis in terms of like conclusive judgment.

So what I counterintuitively hear, and maybe I throw some shade on reviews for a similar reason in the past, but it's more just my insistence on having control of the system. I think nowadays we're much better situated to glean some real insight with large centers that do everything embryoscope. Like the information that's going to come out of these live imaging, the predictive value of that, I think, is on an upward curve right now.

And we haven't really appreciated the benefits that that's going to provide, that this live imaging and morphometrics is going to provide for all patients and perhaps even, perhaps even, which I know maybe is a stretch, but even, you know, day three, maybe looking at the first few cleavage stages. And people talk about these ducks, and I know that's kind of like a huge red herring, but maybe there'll be some information in the timing or the morphokinetics along some other lines at the earlier cleavage stages. So I'm really excited for, I hate to, you know, AI, blah, blah, blah, but I'm more excited just for the information actually, you know, being distilled to some real clinical value, which I think is imminent.

Where I think this article shines is it's the one you print out, you hand to your lab director, you hand to your medical director, and you both give it a read-through and make sure that your lab is thinking about blastulation in a evidence-based way and not missing out on the utility of that as a useful marker in your laboratory and to track clinical success. And like Molly said, to talk about it as a research metric. So big, heavy lift to put together a review like this.

Always cool to see something so well thought out and organized, published. Kudos to Dean Morbeck and Michael Diamond on that one. Guys, that's all the time we have for today.

We try to bring you our favorite articles from the sister journals, but this is certainly not all of the articles in the sister journals. Do go check out F&S Reports, Reviews, and Science online, and then stop by and consider this on the firststert.org main page. Until we meet again next time, that's all for me.

Blake, Daylon, and Molly. Thunder up. Titans.

Go Thunder. World champs. Get over it, bro.

No comment. And goodbye. This concludes our episode of Fertility and Sterility on Air, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine.

This podcast is produced by Dr. Molly Kornfield and Dr. Adriana Wong. This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource and service to its members and other practicing clinicians. While the podcast reflects the views of the authors and the hosts, it is not intended to be the only approved standard of practice or to direct an exclusive course of treatment.

The opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.