Fertility and Sterility On Air - Unplugged: November 2025

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals! Topics this month include: (03:00) prevalence of endometrial hyperplasia and carcinoma among patients with PCOS; differences in trophectoderm gene expression among euploid blasts during extended in vitro culture (13:16), comparison of embryo transfer techniques and pregnancy outcomes (28:58), and exploring the association of ectopic pregnancy with embryonic competence (39:19).

F&S Reports: https://www.fertstertreports.org/article/S2666-3341(25)00101-1/fulltext   
F&S Science: https://www.fertstertscience.org/article/S2666-335X(25)00067-9/abstract
F&S Reviews: https://www.fertstertreviews.org/article/S2666-5719(25)00002-7/fulltext
Consider this: https://www.fertstert.org/news-do/beyond-tubal-factors-rethinking-ectopic-pregnancy-through-embryonic-competence-and

View the sister journals at:

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

Welcome to Fertility & Infertility Unplugged, the podcast where you can stay up-to-date on the latest global research in reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussions with the authors, and other special features. Fertility & Infertility Unplugged is brought to you by the Fertility & Infertility journal family, in conjunction with the American Society for Reproductive Medicine, and is hosted by Dr. Molly Kornfield, Dr. Blake Evans, Dr. Daylon James, and Dr. Pietro Bortoletto.

Hello, listeners, welcome to a new episode of F&S Unplugged, here at the American Society for Reproductive Medicine's annual meeting in San Antonio, Texas, and for me personally, here at the American Association of Gynecological Laparoscopists in Vancouver. And a big shout-out to Columbia University in the UK, the faculty, and colleagues who hosted me at the F&S Journal last year when I was in town. It was really cool to hear that you listened to the podcast and stopped reading the spring journal; it gave me a little pang of sadness, but it's really cool to know that you're enjoying this content in podcast form.

I would have recovered if I hadn't introduced my co-hosts, Molly, Blake, and Daylon. Guys, how are you? Yeah, I came in hot, warmed up in the bedroom and snacking in the lab, friends. I understood maybe 50% of it.

Yes, I don't really know what you said, but it's great to see you all. It was so much fun seeing you all in person at ASRM, except for Daylon. I missed you, Daylon.

Our annual reminder that I'm a little taller than Pietro. I always forget it. When I see you in person, I'm just reassured that I am a little taller.

That's because you were wearing cowboy boots, so if you were wearing cowboy boots at the gala, you would have had an inch or two more than what you saw on Pietro. I don't know if that matters. It's true, it's fair.

Anyway, we're here. We're here. Guys, let's go.

What articles are you most excited about in your journals this month? We don't have a set order. But who's most excited about science coming out of their SNSF domain? Molly, I see a hand reaching out. I'm excited about this journal this month.

I'm really excited to have found this journal. I think I missed it when I looked at the most recent issue for the last show, so I'm glad I found it this time. This journal is about the prevalence of endometrial hyperplasia and carcinoma in women with polycystic ovary syndrome.

The first author is Ravi Agarwal and the last is Sharon Weiner. Wait a minute. Is that the Ravi Agarwal from the University of Southern California and my former resident at Brigham and Women's Hospital, Ravi Agarwal? It's the same person.

It was the University of the South that did this study. Or Ravi. I have some stories about him after you shared his research.

I can't dwell on that. Ravi continued to be a productive actor and published this journal. As we say every week, PCOS is a common condition that affects 5 to 10% of women of reproductive age.

One of the most serious risk factors for PCOS is the increased risk of endometrial hyperplasia and endometrial cancer due to exposure to estrogen that does not counteract oligomenorrhea or amenorrhea. As we know, endometrial hyperplasia is divided into two subtypes: non-atypical endometrial hyperplasia and endometrial hyperplasia with atypia, or endometrial interepithelial neoplasia, both abbreviated as EIN. For EIN, 43% of cases will be diagnosed as endometrial, and 33% of these will become cancerous within one year.

Previous studies have shown that women with PCOS are three times more likely to develop endometrial cancer than the general population, but the prevalence in the PCOS population has not been examined. Our general guidelines state that women with PCOS should not undergo this procedure, particularly if they have other risk factors such as prolonged menstruation, menstrual bleeding, or obesity. The authors aimed to determine the prevalence of endometrial hyperplasia and cancer in women with a newly diagnosed PCOS.

They therefore designed a cross-sectional study of 219 women newly diagnosed with PCOS at a hospital in a large urban city. The diagnosis was determined using the Rotterdam criteria, and they also investigated other endometric causes. Their clinic has a unique practice that made this study possible.

Every patient with a new PCOS diagnosis receives an endometrial biopsy at that time. So I thought that there might be people who have a lower biopsy rate in their clinic who are getting a PCOS biopsy. That's how they were able to obtain this cross-sectional data.

Of the 208 women diagnosed with PCOS, 30% had an abnormal endometrial biopsy. Non-atypical hyperplasia was present in 9%, EIN in 15%, and endometrial cancer in 6%. All these diagnoses are highly significant. The population they studied, which we have studied previously, is a higher-risk population; all the patients had PCOS in their late 30s. It is also a more underserved population, as most patients lacked access to routine care, and over 80% were Hispanic.

Women with PCOS and positive pathology results were an older group with more severe pathology. For non-atypical hyperplasia, EIN, and cancer, the ages were 30, 31, and 32, respectively, compared to 28 in the normal group. However, this is still a very young group, so the average age for people with a new diagnosis of endometrial cancer was 32, compared to 28 in the normal group.

So age wasn't a huge factor. There was no difference between the minimum BMIs of the groups, and the proportion of obesity was quite similar between the groups, which was surprising. I think there was a higher BMI overall in this group, but the group with the highest BMI had the greatest risk for cancer or non-atypical hyperplasia.

Consistent with previous studies, those with cancer had lower parity. The authors proposed that because pregnancy is protected against hyperplasia and endometrial cancer, the presence of undiagnosed hyperplasia for many years, which can lead to cancer, may also be a risk factor for not getting pregnant. They observed a trend with the A1C level, although BMI did not correlate with the severity of the pathological diagnosis.

Endometrial cancer, for example, had an A1C of 6.5%, while normal pathology had an A1C of 5.2%. The most complex and interesting aspect of this study is that the highest testosterone concentrations were found in those with normal endometrial biopsies. The free count was 9 in the normal groups, compared to 8, 7, and 5 in the non-atypical hyperplasia groups, and in the cancer groups, respectively.

It's the same kind of trend. The lower the testosterone, the higher the risk for developing endometrial cancer. I think that's something I've always known, but haven't seen in the literature.

I think that inherently, the person with the worst PCOS and the most hyperandrogenism, along with the highest testosterone, will have the best pathological outcomes. But what we see in practice is that patients with the highest testosterone have slightly fewer lines. I really liked this study.

The prevalence of abnormal pathology was much higher than I expected, acknowledging that this was a high-risk population. The number needed to treat was 1 in 3 to find an abnormal pathology condition, which is truly alarming. In my own practice, I tend to have a low threshold for biopsy.

I know that some of my colleagues might use endometrial length and blood patterns to determine whether or not to perform a biopsy. I don't think there's a clear-cut answer. I know that in my residency clinic, where patients didn't have much access to care and had more difficulties with follow-up, we were very quick to perform biopsies, like in this clinic where they diagnosed the biopsy of the day.

Even though the patients were very young with few risk factors, they simply had an abnormal condition. But I think we also need to be aware of this very aggressive approach to biopsy in this population. It's a good thing.

We had an abnormal pathology rate of 1 in 3, but the biopsy subjects patients to a procedure that can increase their discomfort or even trauma around seeking medical care. So I think doing these biopsies upfront is totally fine, but you need to talk to your patients about pain management options and, hey, would you like to come back next week and do it with different options to improve their pain or even do it under anesthesia? But I think the most interesting finding is this discovery about testosterone.

You know, the authors indicate that historically, people thought higher androgens would increase the risk because of adipose and peripheral conversion of androgen to estrogen, but they note another study that has findings similar to what they have today, where androgens were somewhat protective against pain. And so I think there might be this type of patient with PCOS. I think we have these patients where they have quite bad PCOS, quite high BMIs, and their BMIs are never as high as they should be.

"Oh, I'm just at 6.5, I'm just at 6.9, what's going on here?" And this could actually be a lower-risk group for hyperplasia or cancer. At this point, I'm still biopsying these patients, like everyone else in this BMI range with oligomanorrhea and other risk factors, but this could actually be a lower-risk group. What are your thoughts on this? What are your thoughts on the findings, the rise in abnormal pathology or the rise in testosterone, with higher testosterone and more normal pathology? Despite what I thought of Dr. Agarwal as an intern on the pedagogy floor, this is actually a very well-done study, which may have influenced me to be a little more proactive about biopsying these patients.

I generally use the "finger rule" if they only obey every... or obey less than every 3 months, despite their BMI and other risk factors. I recommend a biopsy or at least a discussion with them. This, I think, adds a bit of nuance to it, and I think helpfully—and I really like that you calculated the number of treatments needed for the earpiece; it's a very good way to conceptualize how helpful this can be for this specific group of patients.

I calculated it, and that made me adjust my bowel biopsy a bit to be more aggressive. I was honestly quite worried to see those numbers, and I agree with Pietro; I think we should perhaps be a little more optimistic about the biopsy. I don't know if "optimistic" is the right word.

We're doing this a lot more and listening a lot more because these are even patients who didn't necessarily have risk factors; they just had PCOS, so these aren't even the patients I would consider biopsying. And seeing so many patients with abnormal pathology was quite frightening, to be honest. So I agree, I think that as a practice owner, we need to consider whether we should be doing more biopsies, and more studies are needed with more numbers as well, of course, but this is very important data.

And I think that for their overall health, I want to know if they have hyperplasia, I want to know if they have cancer, but in terms of doing what's best for their fertility, if hyperplasia or cancer is present, it's pretty inevitable that their endometriosis will also be receptive and that a childhood implantation will occur. So for all the reasons, all the right reasons, being concerned about their health, being concerned about the effectiveness of their fertility treatment, I think that biopsying a little more aggressively might be a good next step. I like that.

Thanks Molly, and big hugs to Ravi for releasing this really cool document. Dalon, what's going on in science these days? Well, there's a lot of talk about the term "Black Box." I like that.

It's famous in science, but also in culture. Of course, we all know it's an inscrutable phenomenon, almost bordering on magic, because it's so inscrutable. It defies observation, it takes on a fantastical air.

In F&S science, however hackneyed the analogy may be, I think there's no better way to understand implantation. That's what I'm going to talk about today in F&S science. And the story of the inscrutability of implantation—we're obviously talking about uterine implantation here.

I think it's even more expansive with the methods we've developed and deployed to shed light on this black box, to escape the analogy. Here, I'm talking about blastoids, gastroloids, human embryonic models that allow for complete modeling of pre-implantation, pre-implantation, biological implantation. And at the same time, there are these imaging models and single-cell OMIX resolution analyses that, quite literally, open up the inside of cells and embryos.

And, as inspiring as all this knowledge is, and as fertile as the groundwork is for hypothesis generation and translation studies, the current impact on clinical practice isn't very widespread, I think—at least not to the extent we see with other emerging technologies, like genomics or micromanipulation. I mean, it's not exactly a new technology, but it's the ART (Artificial Research and Technology) point of the sword for many of these technologies. But, of course, these things take time, and you need, I think, the key to accelerating translation is to have these bridging applications, to improve practice, and also, on the other hand, to validate these in vitro models, to validate their relevance to the fundamental truth of human biology.

So, we need these references, essentially. We need to use human materials, which I think is a point of emphasis in the field of research today, because we're currently trying to restrict, most aggressively, in vitro tissue research, but there's a long history of trying to restrict primary human research. I mean, there are many good reasons for this, but it's essential for progress, and for all the reasons I've mentioned.

Today, I have an example, I would say, of one of these throttling applications. It's a story from the Valencian Infertility Institute in Valencia, Spain. It was almost a bit Italian, if I must say.

You know what, my friend, I don't need you, my partner, to speak all your languages. This isn't a linguistics podcast, okay? We're talking about science. I can adopt any accent I want.

Proceed. Thank you very much. So, the first author to enter here.

Now I'm even afraid to say his name. No kidding, Pietro. I'm going to Americanize him.

I'll do it. Maria José de los Santos. How are you? He's crying.

Say the name of the first author, especially the second, hyphenated by his last name. No, I'm with the first. I'm with the first author.

This is just my policy. There are too many names. Look at the article and read all the names.

In fact, after I say "my peace," your boy will say all the names he has. So, Professor de los Santos' group, they were looking at the differential gene expression. And they were trying to link this differential gene expression to this notion of being healthy with an implant, versus not. That makes sense, right? It's clinically practical.

It's a good function, a good diagnostic tool. So, to address this, they obtained 15 blastocyst uploids from couples adopting Ixie and PGT-A, supernumerary blastocysts, presumably after they had completed their cycles. And they cultured them in these chamber slides, for the embryos that were attached or unattached to the culture surface of the chamber slide.

Then, based on a subset of these cultures, they had 5 and 5 of each. So, out of the 15 total embryos, they compared 5 and 5 unattached and attached embryos using RNA-Seq, a global transcriptome profile of each whole embryo, and I think that's key here. So, there was an intercellular mass component, as well as trophectoderm derivatives.

And by looking at these two groups, attached versus unattached, they found many factors expressed differently, as you can imagine, including those related to cell adhesion and metabolism. Perhaps particularly among the unattached embryos, there was a signature of reduced energy metabolism and innate immune activation, which I suppose might make sense in terms of a crisis state. But I wouldn't argue that this in itself represents a change of perspective in clinical diagnoses, so I encourage listeners to pay attention. The key to this story—I don't mean a change of perspective, but what's important—is to go back to the idea of ​​the applications of restraint.

Here we have a use case that I think has potential for development. It might not be practical at the moment, but the focus here is to use the trophectoderm transcriptomic signature as a proxy for implantation potential. And trophectoderm biopsy is a common element.

We're almost at the end of all the cycles at this point. It's crazy if you ask me, but there you have it. And the cost and resolution are improving.

So we can imagine a next-level PGT—I don't know, Molly, you're so good with acronyms, you have to come up with something related to karyotyping and global transcriptomic analysis. Bam, bam, bam, something snappy, we'll label it, we'll be rich, and then all our problems will be solved. Anyway, this next level, PGT, Molly, can measure not only karyotyping but also the transcriptome.

And so, while this might be overkill in most cases, I think patients with an implantation error can have a test to determine if it's an intrinsic or extrinsic factor in terms of causality. I mean, maybe it won't change the results, but maybe it will. Maybe it will change your approach.

Anyway, maybe there was a time before you considered this analysis in your clinics, but while we're talking about experimental approaches, do you do anything experimental? I mean, sure, but I'd also like to ask, do you do anything experimental in your clinics? For example, Pietro, you might remember endometrial co-culture, do you remember that? I learned a thing or two about that during my time at Cornell. Yeah, I don't know. It probably kind of rolled out by then, but do you get correlations, or do you get vanilla to vanilla? I mean, you do your job, I understand, but is there anything beneficial in terms of your approach? I think a lot of what we do, I mean, it's not experimental in relation to ASRM, but it's outside of what is, you know, like using growth hormones during our poor prognosis patients, and it's not in the rules to do that, but many of us are comfortable going a little bit outside the boundaries, but in terms of really experimental, like what's happening in this study or mitochondrial transfer, things like that, we're pretty much inside the boundaries, I would say.

Yes, I think that when having a risk-benefit discussion with the patient—and when I say benefits, we usually have a caveat, saying there's a lack of clear benefits based on the data—but is there this add-on? I think you can call it an add-on, or an experimental medication, or something we add. It's something we don't typically do, I think. Depending on the clinic you're at, there are some clinics where you feel more comfortable being experimental. But having this conversation with the patient, saying, look, there's data that shows this may have benefits. The data isn't really that reassuring, but this intervention is probably not hate-caused, it's inexpensive, and so we can give it, knowing these caveats. But there are definitely different practices in the country where they feel very comfortable doing things that are argumentatively quite risky and expensive, with Very few benefits, so I'm not going to go into those details. I think we can all name a few of our leaders, but yes, I would say experimental for reasons that are clear, that's clear. And I think, you know, as far as the approach and treatment are concerned, which is really a party, you could say, for the scientific approach to ART, and I see it even in group meetings, you know, we're talking about difficult cases, and now, with the lower cost of genomics and sequencing, many of these cases, almost as a curiosity point of view, we'll be in meetings and we'll say, well, you know, sequence it, let's look and see if there are, you know, our whole exome sequence, let's see if there are clear genetic abnormalities, you know. And I think more and more groups are doing that, and from a diagnostic point of view, and again, the question is, is this really going to change the failure rate? for these patients, but I think the totality of our knowledge is increasing, and the sophistication and intersection of all these data points, as well as, you know, machine learning—I can't wait to say it, but there's the truth—I think maybe we're going to have a deeper understanding of all the different infertility pathologies, and as you just pointed out, Blake, it's very personalized, all these approaches, and, you know, as Molly also said, the treatment cycle isn't exactly the same as the next, so you have to experiment a little bit or at least explore the boundaries of your standard vanilla practice. I'm really impressed to hear that you're fun; I enjoy doing a podcast with young REIs.And that's what the three of you are. I'm really comfortable in the gray area of ​​data, at least personally, and I've made an effort in recent years to really educate myself about reproductive immunology and what exists and what doesn't.

And my view is that reproductive immunology is dashing, but it's also a bit punk rock. It's a kind of countercultural medicine. It questions existing dogma, it refuses to accept necessary explanations for things, and I think it emphasizes the complexity of immunology for patients.

She deserves a voice, and she deserves to have someone wait for her. So I'm a little surprised by reproductive immunology, and like all of us, I hope we'll have more information to support what we're doing. But I remind everyone that a lack of information doesn't mean a lack of effects.

And everything we do today in healthcare started with a taste and a feeling, and it was taboo until it wasn't anymore. And I think we know that there's a very vibrant immune system in every organ of our body, and that there are autoimmune conditions in every organ of our body, and it's naive to think that the uterus is a privileged structure that, for example, is immune to autoimmune dysfunction. So I think we're just scratching the surface.

So we all need to feel more comfortable than the people in gray, because I think most of our patients deserve it. I like that, Pietro. He's the Sid Vicious of REI.

Rather, literally. Dylan, I have a question for you. This article made a big assumption.

They classified the embryos as attached or unattached, and they divided the embryos into these two groups. Can we say what the implanted embryo looks like in vitro, or do we use our best evidence to say it looks like an attached embryo? Is this a good way to classify these two groups? Yes, look. The details are here.

I don't want to go too far. If I were to be honest, I'd say it's not really an implementation model. It's not really a development or implementation model.

Attached embryos are a model of implantation. There's a lot missing here. I'm not saying it's truly a model of implantation or not.

What's interesting is the idea of ​​a transcriptomic analysis to find out what's happening here. Here, they made an observation that correlated with the transcriptomic signature. That's the key.

The key here is that you can have an objective measurement that can be used for diagnosis. In the use case I'm describing, we're talking about material that has been mostly eliminated. Trophectoderm analysis is a common practice.

On the other hand, the biopsy of the emerging trophectoderm is often a false positive. The trophy is progressing. The aneploid in the trophy is not correlated with ICM status in many cases.

One could therefore argue that the transcriptomic signature of how the trophy behaves is more valuable than the karyotype if it allows you to eliminate embryos. Or at least add another dimension. That's where I'll stop.

Thanks for putting the key to the work, Pietro. They're doing hard work in Valencia. It's not embryo modeling, but I think they're taking the first steps towards translating this into common use.

Well said, Daylon. Big round of applause in Valencia. In Spain, they have a lot of incredible research because they can do outdoor cultivation.

We couldn't do that in many places around the world. I'm eager to see what else they do. Blake, please come back to us.

I will, yes. I've come to all of you for the F&S reviews this month. We'll be talking about embryo transfer techniques, some of which I haven't heard of.

Have you ever heard of a clinical transfer technique? I'm familiar with clinical transfer, yes. You can learn about it without the ultrasound consultation and simply by going to Feel. Yes.

Have you ever done a transfer like that? I'd say all the transfers I've done as a colleague have been clinical embryo transfers. I started doing ultrasound embryo transfers as an attendant in my previous practice. Oh, wow, okay.

So, you might want to focus on that a little. But I'm going to... This review wanted to... No, it didn't want to. It looked, in fact, at clinical touch compared to the most common approach today, so 2D ultrasound, transabdominal, 3D ultrasound and 4D ultrasound as well.

She examined the effectiveness of each of them and conducted a systematic review and meta-analysis of these techniques. This is from a group in the UK. I'll try to give you the name of the group.

Youssef Bibijouan, the author of James Duffy. I'm so sorry. I mispronounced your name.

I'm certain I said it. As I mentioned, this study compared different techniques for embryo transfers during IVF or for embryo transfers. It was published very recently, just a few months ago.

With 3D and 4D ultrasound, some clinics are using it and want to see if they get improved results compared to standard 2D ultrasound. So, basically, most women who have IVF and embryo transfer use 2D transabdominal ultrasound. Historically, and Pietro, you can chime in too, I've never used the clinical touch technique, but as Pietro mentioned a while ago, it's the use of tactile feedback.

So, you don't use ultrasound; it's the use of tactile sensation. And once you have the embryo catheter in place for IVF, advancing it 1-2 cm, you transfer the embryo. They wanted to compare this approach by looking at previous studies, going back to 2002—that was the earliest I could see from this meta-analysis. They looked at data from 25 different randomized controlled trials in 16 countries.

Nearly 9,000 embryo transfers were included, and they compared five techniques: 2D transabdominal ultrasound, 2D transvaginal ultrasound, 3D transabdominal ultrasound, and 4D transvaginal ultrasound. Have you ever performed a transvaginal ultrasound during an embryo transfer? I haven't. I've heard of people performing a transrectal ultrasound during an embryo transfer, which, again, is a perfectly viable way to visualize the pelvis, even though it's different from what we do.

Have you ever performed a transvaginal ultrasound during an embryo transfer? I think we're all eager to do it. We were able to see the abdomen, so we didn't end up doing it, but we were all prepared. However, we hadn't done it in our practice.

I think we were going to do a vaginal examination, then a guide wire, or even insert the catheter, then the ultrasound, but we didn't. I don't know if my partners did it. I understand.

Yes, I didn't do it personally; I was just curious if you had been part of one. The key outcomes they examined in this study were live birth rates, clinical birth rates, illness rates, and ectopic birth rates. So, the main findings, looking at the results, showed that clinical touch was consecutively inferior to 2D transvaginal ultrasound for both live birth rates and clinical birth rates, despite the statistically significant difference they noted.

So, I know that one of Micah Hill's points, if you listen to one of his pet peeves, is that if you use words like "trend" or "pattern" or words that indicate a higher or lower percentage, but it's not clinically significant, then, in fact, you're saying that it wasn't clinically significant. So, that's something I took into account while being trained under him. So, when comparing 2D ultrasound or all the modalities we mentioned, there was no significant difference between live birth, clinical birth, clinical disease, or ectopic birth rates.

The most advanced technique, therefore, when viewing a 4D transvaginal ultrasound—so, in fact, you're viewing a live 3D image, I suppose that's the best way to describe it—has not shown a clear advantage over our typical 2D transabdominal ultrasound methods. The certainty of the evidence was assessed as moderate, with some concerns about the limited number of studies on 3D and 4D ultrasounds. I would personally say that the limited number of studies on 3D and 4D ultrasounds—I looked at the included studies and I was able to see a total of one study of 3D transabdominal ultrasound and a total of one study of 4D transabdominal ultrasound—is a concern.

So, these are certainly very limited figures in this regard. Therefore, there are messages to take into account. What does this mean? 2D ultrasound guidance remains the gold standard for embryo transfers.

So, what we do is work, which is reassuring to know. There is no strong evidence that more advanced imaging models, such as 3D or 4D ultrasound, improve outcomes. And the historical or traditional clinical touch was no longer effective.

Again, this is not statistically significant. That was their point of view. It was just as effective as what you meant, what the authors meant, and there was no clear correlation between the results and the imaging models.

You're not supposed to touch the fades, guys. Yes, yes, I know. I know, but it's reassuring to know too, if you touch the fades or sometimes when you have the ultrasound where you think you're in the right position and you move a little, I'm a little further away than I thought with the catheter.

It's not the end of the world. It's not a significant difference in terms of effects. So, at least it's reassuring.

And then, of course, as always with these review studies, the authors note that more quality testing is needed, especially with 3D and 4D ultrasounds, particularly because there was only one student for each. So, anyway, I found it, in general, not frightening, but reassuring that what we're doing is the most effective way to approach and perform our embryo transfers. So, do you have any other insights you gained from this study? I have a question, which is more of a suggestion: they should compare it to a subset, a small subset of Pietro's Clinical Touch, and see how it compares.

That could make the knife move and prove it's safe. But, actually, no, laughing, one point of curiosity: you work in these large practices with many authors, I've always found that a bit odd, I think, curious. You have several patients, you share, you do transfers for patients who aren't yours, but, on your transfer day, that's all there is to it.

So, how come? I mean, the date is there, clearly, but nobody talks about it. Look, compare the success rates between different people who were making the transfers, because it seems to be a very deliberate place where nobody talks about it. We all talk about our success rates, but there must be a difference between operators in terms of transfers, in terms of success, right? Yes, it's part of our QC and it's been in our economic practice and now in our private hybrid practice, it's that, you know, you look at the results of your patients who are pregnant, which may be more related to your protocols and your, you know, have they had a hysteroscopy, how is it in their system, all that, and the quality there, and you also look at the rates, you just have to look at the euploid embryos, you can look at the age, the three days per age, that sort of thing, but it's part of the QI-QC and if someone is below a certain threshold, then they might get pregnant by a more senior doctor for a little while and then, once they are above the threshold, they get pregnant by someone else.

At least in the practices I've worked with, it's fairly standard. It must be difficult when you get down to the technical details. Oh, my God.

I think it's interesting, you know, just thinking about the scaling and personalized medicine, and, you know, these studies, in certain populations, clinical touch is probably as good as 2D, and you're absolutely right about certain operators. Among my colleagues, some of us, I think, are much more intuitive when we're working with a complex brain, and some of us are more into the ultrasound. And like, hey, can I see the brain and the speculum and use that to guide me? And we all have different ways of solving problems, and so, I think the operator would be really important, and I think the patient population would be important too.

So, for really high BMI patients, or those with a lot of fibroids, I think you'll most likely need ultrasound guidance, or more likely, maybe it's for you, for the benefit of 3D and 4D and vaginal imaging and all that. So, you know, just one study, but in the future, it would be cool to do that. The point is well taken, I suppose, but if nothing else, you take from the study's perspective that there are enough modalities that the differences between operators aren't, like, they're rendered insignificant because there's an option for every person who has a particular preference.

So, if I ever become a REI, take care. I remind the audience and the headphones that every time you perform an IUI, you're performing a clinical touch. Hmm.

That's profound. That's profound, I know. Thank you.

That's great. Okay, let's take this at home and not necessarily talk about an article in the traditional sense, but rather a response to authors. Yes, we absolutely have letters to the editor on fertility and sterility, and we consider this a common place for these letters to the editor responding to papers published within the F&S family. I have a paper to consider entitled "Beyond Tubal Factors: Rethinking Ectopic Pregnancy Through Embryonic Competence and Endometrial Interaction" by authors Anastasia Salame and Houman Fatemi.

This is in response to an article published on fertility and sterility that highlighted the top 10 priorities for future research on ectopic pregnancy. It's one of those international consensus studies. And it's not just about criticizing the top 10 priorities, but about pointing to a potentially new mechanism to explain why ectopic pregnancy exists and to discuss why we should consider evaluating it further.

We know that ectopic pregnancy is rare, and that 1 to 2% is generally the number considered. In studies of ectopic pregnancy, some data suggest it's 8 to 10%, depending on the population. And we've generally thought that ectopic pregnancies are the result of something happening to the fallopian tube. The tube may have been injured, punctured, infected, etc.

It's the tube, the baby, and we take the tube and fix everything. What these authors are saying—and they make a very interesting point here—is that attributing most ectopic pregnancies to just one factor is probably unrealistic, given that we see a reduction in ectopic pregnancies when using direct intrauterine embryo transfers under ultrasound guidance or with clinical guidance. So, what is the ectopic pregnancy rate with U-point transfer? The most recent data is 1.19%. That's really small, isn't it? So, these authors propose that a considerable proportion of ectopic pregnancies must be attributed to aneploid. Therefore, if embryo-endometrium crosstalk is essential for implantation, and healthy embryos are generally accepted by the uterine cavity for implantation, while abnormal embryos are generally rejected, instead of explaining why a genetically normal embryo travels the entire length of the fallopian tube to the uterus, it doesn't make sense. What they are arguing is that an embryo cannot have crosstalk with the endometrium, which is ready to receive it, and its ability to remain there has increased. This is not a valid idea. People studied ectopic pregnancies in the 80s and 90s during the karyotype era, but we haven't really replicated these studies in a more modern era where we have the ability to perform more nuanced sequencing of these products of conception to understand them. Aneuploidy, but also polymorphisms in these implantations. I think it would be a potentially interesting study if you could register patients who have ectopic pregnancies and glue that tissue and put it through a sequence in non-euploid embryos. It would be really cool to see if there are more aneuploid implantations or if there's a SNIP that appears more often than not. It's certainly difficult to get the numbers; multicenter is probably the way, but for me, it resonated. It feels good. We know that the embryo and endometrial crescents are important, and a bad embryo does it less efficiently. It feels good that these embryos can end up somewhere. So, a shout-out to the authors who read this book and thought about publishing it in Consider This. If you find yourself in the same position and are thinking of publishing something in response, we'd love to see that submission in the Consider This section. Guys, we've gone beyond our welcome. We talked about good science, and we talked about my former intern, Ravi. We talked about the clinical touch. Thank you all for being here and until next time, Molly, Blake.And Daylon, we'll see you again soon. It's great to see you. We'll see you next time, and a hello to all our listeners. We really appreciate you, and it was fun to meet up with the people at ASRM and the people who come and say thank you for making the podcast. We appreciate it, and insights into changes in beliefs, critiques, gentle critiques—we appreciate them. This concludes our episode of Eternal Fertility and Sterility, 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.