Fertility and Sterility On Air - Unplugged: September 2024

In this month's Fertility & Sterility: Unplugged, we take a look at articles from F&S's sister journals! Topics this month include: radiofrequency ablation of fibroids (3:00), an opinion piece on testing embryos to reduce type 1 diabetes risk (17:42), preeclampsia risk with abnormal semen analysis (29:34), and a review of PCOS and miscarriage (44:33).

F&S Reports: https://www.fertstertreports.org/article/S2666-3341(24)00078-3/fulltext

Consider This: https://www.fertstert.org/news-do/preimplantation-genetic-testing-type-1-diabetes

F&S Science: https://www.fertstertscience.org/article/S2666-335X(24)00055-7/abstract

F&S Reviews: https://www.fertstertreviews.org/article/S2666-5719(24)00035-5/abstract#:~:text=Some%20studies%20have%20suggested%20an,receptivity%2C%20and%20the%20uterine%20environment

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. FNS 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 FNS Unplugged. I'm one of your many fabulous co-hosts. I'm Pietro Bortoletto, but you know that from the sound of my voice.

I'm joined with the typical legs of the, I'm not supposed to call them a tripod anymore. I think Daylon nicks that. I'll call them members of the Marvel Universe.

I don't know. What's another? I'll just call them Blake, Molly, Daylon. What's up, guys? Hey.

Hey, what's up? Wanted to give a special shout out to all of the fellows interviewing for REI Fellowship. By the time they hear this, I guess they'll probably be about done. Anyways, you guys are awesome.

Stick to it. Excited to see the outcome of this year's match. We've all had the experience recently where we've been interviewing people for fellowship spots, and it's been both flattering and amazing to hear from you all that you listen to the podcast.

You care about the podcast and you even catch it when Molly, for example, like last month's podcast did not present an article. Molly is fine. Molly was here, but we just had not a lot of time to present that month, and we had lots of science to discuss, so we decided to take it down the road to this month.

So for the concerned fellow listener, Molly was fine, and Molly's here with us. Hi, Molly. I'm okay.

I'm not being silenced by my co-host. We just ran out of time. We'll get to the article this week.

There's the podcast Deep State had a hit out on Molly. This is an aside. I just have something to mention, but how does someone score the 100th percentile multiple years on CREOGs? You guys are just crazy smart out there.

Oh, you read my application, Blake? No, no, no. That's not you. I didn't know that was making its rounds again.

It was not you, but seriously, some of these applicants are impressive. You guys are awesome. You make me feel really, really subpar with my 99th percentile CREOG score.

Yeah, there it is. All right, enough about CREOG scores. That's a different podcast.

Shout out to the CREOGs over coffee crowd. I heard my residents talking about it this week. Let's get into some science.

Molly, you didn't have the chance to present last month. Let's start with you. Why don't you kick us off? My article this week from F&S Reports is Transvaginal radiofrequency ablation: a therapeutic option for managing symptomatic uterine fibroids in women with reproductive desires by first author Marin Martinez, Eugenia and last author Perez Medina, Tirso.

They're all out of Madrid, Spain. So this is my second time in a row talking about fibroids. And as we all know, fibroids are a really big issue in our field.

We know they're common. They affect as many as 70 to 80 percent of people with uteruses by the time they reach menopause. And they can have really significant impacts on quality of life due to heavy menses and bulk symptoms and real significant impacts on fertility related to distortion of the uterus.

And as for what to do with fibroids, while a hysterectomy is, of course, definitive treatment for our patients desiring fertility, many will pursue a myomectomy, which can come with some risks, including just to name a few, blood loss at time of surgery, intra and extra uterine adhesions and the potential need for future cesarean section of delivery. So there's of course interest, significant interest in fertility sparing approaches to fibroid management that may be other than myomectomy, including radiofrequency ablation. So radiofrequency ablation relies on applying electrical current into the center of the fibroid, which leads to necrosis and cell death of the fibroid and the body then resorbs the necrotic tissue and the fibroids can be reduced by as much as 60 to 80 percent of their size over the year following treatment.

The authors of this study described that there's pretty limited data on outcomes, specifically reproductive outcomes, fertility sparing cases, following this treatment, and so they really sought to describe symptom control and outcomes at their center following radiofrequency ablation. So this study was a prospective cohort of 27 patients at this one center who underwent radiofrequency ablation of fibroids and who desired fertility. They then followed the 27 patients over the course of two years following the ablation, and the inclusion criteria for the study were FIGO type 3, 4, 5, and 6 fibroids, maximum volume could not exceed 145 cubic centimeters, and they could include FIGO type 0, 1, and 2 as well if they were considered high complexity and couldn't be managed by hysteroscopy alone.

And in some of the cases they actually use radiofrequency ablation to shrink those type 0 to 2 fibroids in order to facilitate hysteroscopic removal which was an interesting approach. The authors actually used a vaginal approach to administer the radiofrequency ablation and that's different from what I've seen in our practice where I've seen people use a laparoscopic approach. They used a vaginal approach with a technique that I imagine is pretty similar to how you do an egg retrieval with a transvaginal ultrasound providing ultrasound guidance and using a needle guide to target the fibroids.

And then they actually used IV contracts to confirm that at least 80% of the vascularization of the fibroids had been destroyed and confirmed that the treatment was complete. They then followed the patients, they did a symptom severity scale questionnaire both pre-procedure and then at one, six, and 12 months. They advised patients wait six months to try to conceive, which is pretty similar to what most of us are recommending after a myomectomy.

And then the question is what did they find? How did it affect symptoms and how did it affect reproductive outcomes? So of the 27 patients they looked at, two thirds underwent the procedure for menorrhagia, one third were referred by a fertility clinic, and all of those one third also reported menorrhagia. So all the patients had menorrhagia and one third were coming from a fertility clinic. The patients actually were able to get back to work much faster than with patients who had an open myomectomy, so returned to work at three to five days after surgery.

Much earlier than with an open myomectomy where they might be out for multiple weeks and a bit earlier than a laparoscopic myomectomy where I usually tell my patients to take a couple weeks off. Common minor symptoms included fever, fatigue, pain, abnormal bleeding, and expulsion of necrotic fibroid tissue through the vagina, which certainly sounds like it would be alarming if it happened at home. And then at six months, when they followed up on those patients, the fibroids were reduced in size by 62%, so consistent with that previously seen 60 to 80%.

And symptoms on the symptom scale, which ranged from zero to 40, 40 being the worst, decreased from a median of 30 down to a median of 13. All of the 27 patients did report improvements in bleeding, and three of the cases still also underwent a hysteroscopic resection of the fibroid that had now been reduced in size. Of note, two out of the 27 patients were not considered to have an adequate response to treatment.

In one of the patients, a large fundal fibroid actually grew in size and then was eventually resected surgically and was actually pathologically found to be an adenoma, not a myomioma. And then in the other patient, despite initial improvement, they then had worsening pain and bleeding and did undergo a surgical myomectomy 21 months later. And of note, both of those patients did end up with laparotomies.

So of 27 patients, two ended up with laparotomies to really treat their condition. Of the remaining 25 women, 19 who had a successful procedure did pursue conception attempts, and 14 of those 19, or 73%, were successful and had a live birth. So of the patients who pursued conception, 73% had a live birth.

Now of the remaining six, one was continuing to attempt natural conception and the remaining five are pursuing ART at that point. Of pregnancies that were achieved, 17% ended in a first trimester loss and 82% went to full term. And notably, there were actually no cases of uterine rupture or IUFD in this cohort, or fetal demise in this cohort.

There was one case of highly attached placenta. I imagine that's something along the placenta accreta spectrum, so highly attached placenta that led to hemorrhage in a patient who also had a history of five hysteroscopies prior to the ablation, so multiple risk factors. And then another patient had a placental polyp, which required a hysteroscopic reception in the postpartum period.

So two kind of concerning placental histories. I think what really intrigued me about this study is that they administered the radiofrequency ablation vaginally in our hospital. I've just seen it done.

It's not a surgery that I've done myself, but I've seen our MIG surgeons do it in many cases, and they've done it laparoscopically. So I like that this could be an outpatient option and uses the skills and equipment that I have access to as an REI and that I feel really skilled at as an REI, so it's really a nice set of skills. I was hopeful that this could offer a shorter time to pregnancy, as it's always hard to have that six-month waiting period after a myomectomy.

I know some people do a little longer, some people do a little bit shorter, kind of depends on the case sometimes too. And these authors, the patients were waiting six months after radiofrequency ablation as well. And so for older patients, that's a long time to wait.

I'd also be really interested in if there was any impact on ovarian reserve that was studied as part of this cohort, potentially related to unintentional thermal spread and any impact on the vasculature, uterus, and surrounding structures. And with surgical myomectomy, we have all kind of theoretically worried about impact on ovarian reserve. The studies I've seen have actually not shown it's particularly concerning, it's just something we always think more conceptually about.

But I would be interested for radiofrequency ablation, is there more thermal spread than we're thinking there is. And I think there's definitely a good number of postpartum complications that are probably related more to the patient's pathology at baseline, but also these multiple uterine procedures they've had as being patients who have fibroids. I think it's probably comparable to the amount of complications we see in fertility patients who've had a surgical myomectomy, but I think we definitely need larger data sets to really tease out the difference.

And I did do a PubMed search just to kind of update my own knowledge on what else is out there on this topic. I hadn't looked in a year or two. And I think this study, despite only being 27 patients, despite being a smaller study, really does add to the limited body of literature on this topic.

There's more out there though and I last looked, which is great. There is an ongoing prospective cohort study that compares radiofrequency ablation to surgical myomectomy. So not randomized, but prospective.

And they actually did publish a little bit higher miscarriage rate than you would expect for the age of patients are 41%, although their myomectomy group also had a high miscarriage rate of 43%, so might have been more patient population. And then of note in that study, the radiofrequency ablation group did have a 30 week fetal demise and a uterine rupture at 10 weeks gestation. So two pretty serious complications.

So it may be that with our catchment of 27 patients in this Madrid study, they didn't find that. So for now, I'm probably still choosing surgical myomectomy for the majority of my patients. I'm definitely a late adapter.

But I think in the author's words, this is definitely promising. I'm intrigued by this. I would be totally open to training on its use in our clinic and particularly the potential to facilitate a hysteroscopic myomectomy that might otherwise not be possible.

So I want to know, what do you guys think of this article? Do you have much experience with radiofrequency ablation of fibroids? If so, is it macroscopic? Have you seen transvaginal? Are you doing them yourself? Are you referring out? And then how would you kind of choose, are you referring a patient for surgical myomectomy or radiofrequency ablation? Daylon, you want to take the lead on this one? Listen, I got something to say about this totally not clinical. And that's a very selfish take, which is that whenever I'm in a meeting, in these reproductive meetings with a bunch of clinicians, and there's like an awkward moment, right? We're supposed to be social. I'm not good at it.

So, you know, my fault, sure. But in that awkward moment, I'll just be like, yo, tell me your craziest fibroid story. And then I just tuck in for like half an hour and I'm just, you know, regaled.

So selfishly, if this, you know, transvaginal radiofrequency thing takes off, I think it's going to take the fun out of those awkward moments. Well said, Daylon. I'll opine here, Molly, because I have strong thoughts on fibroid management and surgery.

And I think for the listener who's unfamiliar with radiofrequency ablation, there are two FDA-approved devices in the United States. The Assessa, which is the laparoscopic version that I think Molly's familiar with, and then the Sonata system that is transcervical, ultrasound-guided ablation device. Both of them work on the principle of coagulative necrosis, where you're trying to cook the fibroid, increase the temperature that denatures proteins, and that tissue essentially breaks down within itself.

I think therein lies the fundamental problem. It's not an extirpative procedure. You're not physically removing a fibroid and cutting tissue, but you're leaving tissue in there that's been cooked.

And I think intellectually, kind of down in your gut, you're like, it's probably bad to leave dead tissue within the myometrium. There's probably some negative impact on the surrounding normal endometrium from inflammation, from it acting like culture media and increasing the risk of infection. Does it weaken the surrounding myometrium? All of those, I think, is probably why you see some of these adverse pregnancy events from it.

And I think you nailed it on the head, where I think one way for us to build confidence and build data with this procedure is use it as a tool to facilitate a proper myomectomy, to reduce the risk of a myomectomy. The fibroid is just so big, there's no way that I could do this hysteroscopically. I'd have to do it open.

Well, can I get it to hysteroscopic by pre-treating it with radiofrequency ablation and giving it three to six months? Maybe. That may be a way towards just building comfort, building data, and ultimately getting the gunky stuff out of the uterus, out of the myometrium afterwards. That, to me, I think is probably the most promising first use of it.

But I think you need data like this to show us that, well, maybe it's not as bad as we think and it's actually okay. I think there's definitely some signal here that there's some adverse obstetric outcomes that in the patient who's desiring future fertility, it kind of lump it right now like UAE. If you're thinking about getting pregnant, you probably shouldn't embolize your uterus.

And I think if you're thinking about getting pregnant, I don't know that the data is mature enough to say that you shouldn't be trying to induce coagulative necrosis within your fibroids and leaving them there. But those are my two cents. Yeah, that's been my similar train of thought, too.

We've had some of our surgical reps talk about the Assessa, and one of our MIG surgeons is, in fact, doing a study right now with that. But, again, enrolling patients from our clinic is like, oh, they want to get pregnant. So I don't know that the words cell necrosis and cell death and pregnancy should go hand-in-hand or future fertility being the same train of thought.

So I was reassured to see these findings, of course, smaller sample size overall. And, of course, we're going to need a lot more before we really feel good about this. But I was reassured.

In fact, I sent this article to our MIG surgeon once I saw this because she has always asked about, well, do we have patients who want to enroll in it? What do they think about it? So, you know, we know we've talked previously on the podcast. We know that fibroids decrease pregnancy rates just by being there. But what we don't know is cutting into the uterus and burrowing out this fibroid, then sewing it back in multilayers at a time and saying, aha, it's out.

Now your pregnancy rates are going to be better. That's what's unclear based off of the available data, because fibroids are hard to study, right? I mean, they're different sizes, different positions in the uterus, different BMI on the patient. I mean, there's several different factors that go into it.

But fibroids are just different number, different shapes, different sizes, different locations. And so all of those things together make fibroids a little hard to study. So going back to the study, though, it was nice to see that they had certain size cutoffs and certain types of fibroid cutoffs.

But at the end of the day, I think we just need bigger studies, more data to to be more reassuring. But it was I think this is a great study overall, though. I think there's a very small critical mass of REIs that offer this procedure.

I can think of one or two people that are REI centric that offer it. Most of it's living in the hands of generalists and MIGS folks. I think you'll see very slow adoption into the fertility community until that changes.

And I think ultimately we're convinced that it's safe and effective and better than myomectomy. But I'm glad this article is published. I'm glad it's published in F&S Reports.

It's open access. So if you're listening and wondering, like, oh, I'd like to learn more, pop on the F&S Reports website. You'll have direct access to the PDF, which is great.

All right. Hopefully that scratched the itch for our listener who missed Molly last month. I'm going to keep it rolling and talk a little bit about a Consider This article that kind of tickled my fancy last month.

So I think our listeners are familiar with type one diabetes. It is one of those terrible diseases that people are often bored with that increases the risk of a host of complications, such as cardiovascular disease, chronic kidney disease, neuropathy, just to name a few. And the CDC estimates that there's around one point seven million adults in the U.S. that are living with type one diabetes.

And the cost of the health system for those folks is upwards of 14 billion dollars annually. So that kind of qualifies satisfies the requirement of if we're thinking about what diseases are worth preventing, it's the ones that affect people early in life that have substantial impact on longevity of life as well as quality of life, but also have a substantial public health burden. So this article is interesting because this article is written by Dr. Nathan Treff, who is a individual with type one diabetes himself.

And he's been public about this. We've talked about this on the F&S Journal Clubs with him before. But he's also the founder of a company called Genomic Predictions that offers something called polygenic risk scoring or PGT-P for embryos.

And the concept here is that we know type one diabetes is a polygenic disorder. There's not a specific gene that causes type one diabetes, but there are specific loci that are kind of known to be associated with it. And we know that there's a genetic heritability to type one diabetes.

So individuals who have a sibling with type one diabetes have up to an 85 percent chance of developing the disease if they share a specific high risk HLA genotype with that sibling. So you can see pretty clearly that if you have type one diabetes or have a strong family history of type one diabetes, it could be very interesting to have a test to screen embryos to reduce that risk. The current data that's out there suggests that there is an opportunity for risk reduction.

Current research with PGT-P looking at polygenic risk scores has shown anywhere from 45 to 72 percent relative risk reduction in type one diabetes prevalence, depending on that a prior risk level in the family. And what this article is intending to do is kind of make the case for we can prevent passing on recessive conditions. We can prevent passing on dominant conditions.

Why not type one diabetes, a polygenic condition? People with type one diabetes also suffer from infertility. They may be using IVF and if they're using IVF with PGT, which is increasingly more common, do we have a burden to talk to patients about the technology that exists that could potentially risk reduce that in the next generation? And I think this is a really challenging question, challenging for our field, because I think there's the yuck factor from people who are not super savvy with polygenic risk scores, right? Is this Gattaca? That's always the thing that you hear about in the media. You can select against deleterious traits.

We can also select for non deleterious traits. And I think that's a little bit of the yuck factor. But two is also the question of is the data mature enough for us to really believe that we can truly reduce the risk of type one diabetes relatively? Absolutely, you're not reducing absolute risk by 45 to 72 percent.

We're talking about relative risk reductions here. Is that true and how can you prove it? And ultimately, the definitive way to prove it is that you have to do it and then you have to follow people over the course of a lifetime. And it's a really tough study to pull off.

Right. You'll never actually get it done. So you have to extrapolate from complex models, from twin studies.

You have to use biobank data from the UK biobank, from the all of us study in the United States. And probably the ultimate biggest problem with this is that all of this biobank data is coming from a very select group of individuals around the world, mostly Caucasians, Europeans, people with kind of that background. If you're a Asian, if you're African-American, if you are, you name it, but not Caucasian, the data that informs the polygenic risk scores that was fed into the biobanks doesn't really apply to you.

And the utility of some of these polygenic risk scores quickly loses its value. That's probably a temporary problem. I think as we collect more whole genome data from patients of diverse backgrounds, that will probably get better.

And whether or not that makes the polygenic risk score predictive value better or worse, I think is a TBD thing. But I think this is a thing that our field is actively grappling with. Full disclosure, at Boston IVF, we do work with genomic predictions and we do offer polygenic risk scoring for patients who are interested.

I don't think we've had a patient who has taken us up on it since we've been offering it. But I think a lot of that is because it's new and there's not a lot of familiarity with it from a patient's perspective, a genetic counselor perspective, but also even a physician and lab perspective. But I'll shut up for a second.

I think we could talk about the subject for a long time. I think we've had in the podcast before. But Blake, Molly, Daylon, are you guys interfacing with polygenic risk scores in your clinics? Has this come up personally or from patients for you? Well, I'll just start from like a non-practicing clinical view.

Just historically, I think it's remarkable and goes hand in glove with ART, the way our capacity has increased over the course of a really short amount of time. Whereas like 10 years ago, I can remember, 23&Me or any of these services came out, and there was this notion of having them instruct you as to your XYZ risk. And that was deemed to be irresponsible, more because the capacity wasn't there.

You were misinforming people or raising a lot of alarms where it wasn't appropriate. But now we've evolved to a point where the capacity is there. These predictions, they have real value and are really important in terms of the outcome and changing the lives of the families affected.

So it's, I think, moved beyond a question of technical capability, and now it's a societal issue of whether we're comfortable with doing this, bearing in mind that there's no this, not that, in my opinion. I think once you allow for the deleterious, the information is in the hands of the patient, right? It's their information. And it's going to soon be a matter of interface as easy as Google to plug your information in and get all the information you want out of it.

So I think this is a real societal question as to what we collectively and as individual health care providers, I think it's going to ultimately come to what the health care provider is comfortable with in facilitating. And I think we know from the history of sex selection, now family balancing, or whatever euphemism it took to make it palatable. I think that it's a question of how soon we're going to be able to reconcile.

And that's kit and caboodle. We're going to be able to reconcile this kind of polygenic risk scoring. One other argument that you hear with polygenic risk scores is that we already have a huge, we have a supply and demand problem where there's a lot more demand for services and just not enough supply to keep up with it.

And if we are now introducing patients into the mix who don't have infertility, but are using services to avoid passing on conditions to the next generation, what does that do for the patients who truly need IVF for its foundational purpose, which is overcoming infertility? I'm sensitive to that argument, having worked in a mandated and a non-mandated state. And I think, Blake, we were just talking beforehand, what the wait list looks like in Oklahoma, in Mali, what the wait list looks like in Washington, or in Oregon, excuse me. I'm sensitive to what an influx of people into the system who don't have infertility, but want to use this to help conceive what that could do.

I don't think we have a good answer for it yet. I think as a group, and I say group loosely, I think that includes culturally, society, individuals, physicians, we have to kind of decide like, is this how we view the next iteration of the application of this incredible technology that is IVF? And if so, how do we do it in a way that's data-driven, ethically sound, and allows us to continue to also take care of patients who need this for IVF 1.0 reasons, which was overcoming infertility. And I think this will be, going back to what you said, Daylon, more of a societal issue.

I think that's going to be always there. And especially, I'm just thinking in terms of in this political climate that we're unfortunately in with Roe versus Wade being overturned, and then you add this into it. Doing IVF is going to be even probably more of a controversial issue if you're saying, well, we're only selecting embryos that are not affected by type 1 diabetes.

So I think that's going to raise even more eyebrows because we're already at the point where we're saying, you can't say an aneuploid embryo is a human life and has the same rights as a human life, which is unfortunately the way a lot of people view it, or a lot of these politicians trying to put restrictions on IVF. But I see this as introducing a little bit more complexity into that situation as it becomes more mainstay. Yeah, this topic hasn't come up a lot with my patients in Oregon.

I think our population tends to be a little more low intervention. But I know that in some clinics, patients are asking about this all the time, and it's a big issue. And I think, yeah, I think if I were asked about it, you're really balancing the potential benefit of this with the risks of IVF to the parents and then the risks of an IVF pregnancy, which is a higher risk of pregnancy if it's a family that otherwise wouldn't need IVF.

And I think there are interesting ethical questions and concerns around a chronic manageable condition. Now, I don't have type one diabetes and I don't have a child with type one diabetes. And I know that's probably an incredibly can be very stressful and very challenging.

And so I can't speak for that population. I think it's some of the questions that come up with PGTM as well, in terms of what conditions are we testing for with PGTM versus not balancing risks and benefits. Probably my biggest issue with this, and I think it's the last comment told me because we really could spend an hour on the topic, is there's a potential that as you screen for more than one polygenic condition, that you're going to get a diverse set of information for that embryo.

And while the type one diabetes relative risk reduction may look good, the BRCA or the hereditary cancer syndrome, or excuse me, no, because that's a single gene, but schizophrenia, that may be markedly increased in that embryo. And how do you as a parent select an embryo that, you know, has a lower risk of one thing, a higher risk of something? How does that affect your ability to raise the child? How do you over or under medicalize that child's life in teenage years? Those are, I think, some of the stickier issues that I think need to be sorted out. And they're very real.

And I think when I have that conversation with patients, a lot of them are like, oh, actually, it'd be better to not know, because there's only so much we want to know. And maybe blinding is the way forward there, but TBD. Glad this article is out there.

I think it prompted a discussion for us. I'm sure that the lay public and the community will have some thoughts on it. So thanks to Nathan and the team for sending it to consider this.

Daylon, why don't you tell us a little bit about what's coming out in F&S Science this month? Yeah, this is an appropriate segue, I guess, in terms of, like, the idea of, I don't want to call it too much information. There's never too much information. But I think it reflects multiple challenges with assisted reproduction, which since day one, I think, has been a bit of a, I mean, it is a bypass of physiological process in many ways.

And it's been a part of medicine for so long that we rarely reflect, I would argue, on what a monumental hack IVF is. While it's taken for granted, like, there's no medium besides the modern world where gametes expelled or extracted from the body could come back together and reconstitute a healthy pregnancy. I mean, like caveman days.

Like, not kidding. You told me a caveman performed a minor brain surgery, you had fossil evidence. I'd be like, maybe.

But you told me they performed IVF. No way. But the hacks, you know, at this point are so baked in to modern IVF that sometimes we have to consider what is being bypassed and what the physiological and reproductive consequences of that hack entail.

And this is really well illustrated by the increased risk of preeclampsia in program cycles that has been pretty well documented at this point. And the logic, just to review being there, I think the consensus logic being that the program cycles lack the entire complement of the basal active and other factors presented by the corpus luteum in a natural cycle in this absence can affect implantation and subsequent many other hypertensive or circulatory aspects of the pregnancy. Now the risk is minimal.

But like many things in ART, this evolving, continuously evolving epidemiological landscape, it demands attention from you guys. I mean, you poor things, you got to be vigilant. So a question to the panel.

Do you incorporate this relatively new information about increased incidence of preeclampsia into your patient counseling? If so, how do you counsel the patients undergoing program cycles for frozen embryo transfer nowadays? I'm probably pretty avant-garde about this topic because I think it's, I have an MFM wife at home and we talk about this a lot. And I have had the benefit of working in two practices that are predominantly transferring in the natural cycle. So I don't have to convince patients that the natural cycle is just as effective as the programmed or artificial cycle.

I think the evidence has shown uniformly that they are the same. It's the embryo that's the star of the show. You just have to get the uterus prepared and there are a couple of different ways to prepare it.

I think the, so my default has always been less is more and the natural cycle is the less is more approach, particularly in an ovulatory patient. I think the trickier part is what do you do in the patient who is oligoovulatory or anovulatory? Is there a true risk reduction there to get that patient ovulating with the help of letrozole or Clomid that will bend the arc of the universe away from preeclampsia, away from these placentally mediated disorders? And I think for the IVF naive patient who's never been pregnant before, there's probably a small amount of risk reduction. But the minute you have the patient in front of you who's showing up to ART, who's pre-diabetic hypertensive, has a borderline BMI or has had a pregnancy already affected by preeclampsia growth restriction the first time and now is coming to you to help get pregnant for the second time.

I think that's where the opportunity probably lies for risk reduction for that patient. And that's the patient where I have the conversation where, hey, there's some data that is maturing regarding the safety of these different frozen embryo transfer options. If you had the option to pick one today, I'd like you to give you a sense for what the lay of the land looks like so you make a really fully informed decision.

So I do have that conversation in select patients and hoping to have it more broadly once there's data to say that I should have that conversation more broadly. Blake, Molly, do you guys do anything differently? I don't have as extensive as a conversation with my patients, but I mean, that's everything you said is spot on. But I, as one of the enrolling sites for the NAPRO study, I basically just kind of pitch it, summarized how PHR did and said, can you help us find out a conclusive answer and enroll in this study? Patients are fortunately really excited and willing to enroll in this study.

How many have you enrolled? Because Boston IVF is also a site. I think we're around 90, 95. That's amazing.

That's huge. We started enrolling over the summer and we just broke a dozen. Hoping to enroll more, but I think this is probably the one of the more important questions that our field is going to answer in the next year or so is what does this study show? Yeah, this will be a very, or it is a very highly anticipated study.

And it's really cool to be a part of one of the several sites enrolling patients. So to be determined, Daylon, to circle back to your question. I'll be a bit more aggressive than Blake is I think it's actually not going to show a difference.

I think it's an unselected patient population that's already ovulatory. Rare outcomes are rare. You're probably not going to really move the needle.

And I think if the study had been centered around inovulatory patients and giving them electrosol versus the artificial cycle, that's probably where you're going to see some benefit. But that's my two cents. I don't have any clinical data or any interim analysis data to inform that.

That's just my gut. Well, you heard it here first, guys, and we're going to come back for the steel cage match debate between Pietro and Blake at a later date. But, you know, I'm reserving my bets on that one.

And to be honest, this is what I love about this field. And this is why I appreciate you practitioners, the best of you, who I have the pleasure of sharing company with here virtually. You're not just like considering each patient in a very nuanced way and a patient-centric individualized view, but you're actually asking the questions, right? To further inform not just that patient, but the field.

And that's the thing about ART, right? The latency between research and practice is relatively short. It evolves very quickly, dynamically. And this is perhaps evidence to that.

I wouldn't call it distressing, but something to keep our attention to. It's a related, kind of related story from F&S Science I have for you guys this month, where we've got another parameter entering the chat. And that, unexpectedly, is male factor.

Specifically, lead author, Ling Guo, and senior author, Yan Li, from Shandong University in China, they showed a significant increase in preeclampsia in pregnancies generated from male patients with oligoacinospermia, so low count, low motility. Which is totally not intuitive to me. This study was actually derived from a primary multi-standard study published in New England Journal of Medicine that was a big deal about three years ago, showing that PGTA did not improve live birth rates relative to traditional IVF.

In the present analysis, which is a sub-analysis excluding patients where sperm parameters weren't known, they took 1,131 women, again, carefully curated, all of whom underwent transfer of a single frozen embryo fertilized by ICSI of note here. The natural programmed and stimulated cycles were all included, although pretty equally represented in each group, but also it's just something to keep your eye on. And those two groups that were compared are males with normal spermia, of which there were 726, and the oligoacinospermic group, which had 405 patients, so good numbers here.

The superficial analysis right off the bat showed a significant increase in preeclampsia with a p-value of 0.035. And after a bunch of adjustment for confounders, that p-value remained significant, barely at 0.047. So, I mean, given the numbers here, I think you got to expand a little bit, maybe look at a more refined patient population, focusing on perhaps cycles individually in subgroups. But still, I have to ask, I mean, what do you make of this? First of all, there have been a handful of studies that have linked sperm parameters to embryo quality, miscarriage, even preeclampsia. And also other studies showing no relationships.

So we have evidence on both sides. But this, in my view, is worth a close look for at least two reasons, and maybe you guys have more. One, it derives from this carefully curated data set generated in the context of a multicenter, randomized control trial.

So these numbers, I think, are solid. And two, and perhaps more importantly, it highlights a potential increased risk among a patient group, this oligoacetylspermic group, with a condition that's pretty common. You know, a lot of patients presenting with this.

Again, not like anyone should rush to incorporate this kernel into their patient counseling as they would, you know, the risk of programmed and preeclampsia. But nevertheless, you know, with the new data and these new studies coming out, it must inform your worldview. Maybe you're sorry that you listened to me all this time.

I know a lot of people have already gone to sleep here listening through the waves. But I have to ask, what are your thoughts on this study, guys? Wide awake. Wide awake.

So I think this is a great study. I think it's fascinating findings. And, you know, we, as providers, finding things that can reduce morbidity and improve outcomes is something we always are striving to do.

So if this is a known risk factor, do we now have all male patients taking a baby aspirin as well, in addition to their partner? When trying to conceive, as we are now recommending a lot of our patients to do before around 12 weeks of pregnancy. So where do we go with this? Hard to say. But knowing what these risk factors are and how to mitigate them, I think, is really important.

So I think this certainly opens that door. I think it's also important to just put a little asterisk next to this. This is a secondary analysis of an RCT that was powered for a different primary outcome.

Right. So the solidness of the RCT is solid for the primary outcome, assuming you're adequately powered and randomization worked. I think when you're doing a secondary analysis, you have to take that finding with a grain of salt.

I also like to point out that even though not statistically significantly different between the two groups, there were more program cycles in the male factor group. And so that could be skewing things a little bit. However, I think sometimes we are probably overstating the role of program versus natural cycles in preeclampsia.

I think we've all really like hung our hats on that. We're so excited about it. And I think that we're missing stuff.

So I'm glad that people are looking into male factor. I've always had a sneaking suspicion about male factor. And then my study idea that I can't figure out how to get it done with the studies we have.

So maybe a fellow listening can pick this up. I think testes sperm might be associated with preeclampsia more. So different topic, but I'd love to see someone tease that out.

And the perfect control group there is vasectomy, testes after vasectomy, because they don't have male factor infertility. So someone do that study. Give me a call and get the results.

But yeah, definitely exciting findings taken with a grain of salt, as with all these kind of population or, as you said, secondary analysis studies. Yeah, I think it's I'm glad you guys brought those points of view, because something like this is it's actionable, if true. And we really need to be sure about it.

So those caveats should be taken into careful consideration. For me, unlike the relationship of program cycles to preeclampsia, where there's a logic and a mechanism that makes sense to me, it's hard for me to intuit that connection in terms of the contribution of the sperm to implantation. Not to say it's not plausible.

I mean, it could affect embryo development. It could affect a lot of parameters of the embryo. And that could carry through to the implantation process.

I'm not ruling it out. But as a scientist, you don't just like to see the correlation, but you like to see the dots connected. And I think it remains to be seen whether we can find those dots in this case.

My MD brain wants the connection to be abnormal sperm, sperm issue, DNA fragmentation, whatever that is, that leads to abnormal placental development. But I don't think a PhD brain would necessarily have enough to make that connection. And we do know that in animal models, we see more imprinting errors with IVF.

So I have to wonder, is it something related to epigenetics or imprinting? So I don't know what you think about that, Daylon. Well, a plug for the MD brain. That's, I think, exactly the thinking of the PhD brains out there, that it's DNA fragmentation and or epigenetic factors that may contribute to embryo development and or placental development.

So, hey, don't underestimate the MD brain. Yeah, you have to say it because every time we're talking about male factor, is it the symptom or is it the cure or the disease that is potentiating some of this effect, right? Is it the ICSI to overcome the oligosthenospermia that's driving some of this effect? Or is it the true underlying oligosthenospermia, which you need ICSI to help overcome? Zymote sperm prep for all, right? That's just going to cure all. This episode brought to you by Zymote.

Blake Evans is a stockholder. I am not, in fact, but joking around, guys. Just joshing you.

Just joshing. All right, let's bring the podcast home. Let's review some things from F&S Reviews.

All right, going to bring it home. So, going to talk about a condition some of you might have heard of, polycystic ovary syndrome. This paper is entitled Polycystic Ovary Syndrome and Miscarriage, something you guys also have probably heard a lot of, and narrative reviews.

So, first author Leanne M. Bui and senior author Anna Sokalska out of San Jose, California and Stanford, respectively. PCOS, as we all know, is the most common endocrine disorder affecting women of reproductive age, around 1 in 10 women. It's extremely common.

Although PCOS is often identified when presenting for oligomenorrhea or infertility care, PCOS, as we know, is linked to several metabolic conditions, like insulin resistance, cardiovascular disease, diabetes mellitus. In addition to many well-known obstetrical risks, preterm birth, small for gestational age, preeclampsia, diabetes, which may predispose poor reproductive outcomes. So, in this case, we're wanting to investigate miscarriage.

However, the data is lacking and conflicting. So, this study reviews the current literature on obesity, insulin resistance, hyperinsulinemia, several different factors in how it relates to PCOS and miscarriage. What did the authors do? They looked at a total of 148 studies that were included.

It did include both naturally conceived pregnancies, as well as ART pregnancies. They reviewed the current literature on obesity, insulin resistance, thrombophilia, hyperandrogenism, IVF outcomes, endometrial receptivity, oxidative stress, chronic inflammation, many, many things, which I'm going to briefly study. They looked at a previous meta-analysis, and they looked at the prevalence of miscarriage in women with PCOS compared to controls.

And they found anywhere from about 40 to 50% higher risk compared to controls. Some studies cited nearly a three-fold increased risk of miscarriage in women with PCOS. However, the authors discussed that some of these studies being limited by reporting bias, small sample sizes, or having stated moderate to high risk of bias in general.

And so, also given the high risk prevalence of elevated BMI, or the high prevalence of elevated BMI in women with PCOS, in addition to numerous other features, such as insulin resistance, for example, this may account for these contradictory findings. This next study that they talked about I liked, and was done to kind of help tease out this information. To assess whether PCOS is an independent risk factor for early pregnancy loss, Lu et al.

conducted a case-control study where he compared lean PCOS patients, and then factored for age, BMI, embryo, scored match, and healthy non-PCOS women. And they found that in comparison to the controls, that the lean PCOS women had an increased pregnancy loss rate and decreased live birth rate, suggesting that PCOS, independent of BMI, influences reproductive outcomes. And the authors cited similar findings in women who looked at just those exact factors, but also specifically in obese patients with and without PCOS.

So, suggesting that PCOS may in fact be an independent risk factor for miscarriage aside from weight. The authors also evaluated the current literature with regards to many of the factors I mentioned earlier, insulin resistance, thrombophilia, hyperandrogenism, IVF outcomes, which I'm going to very briefly summarize those there. I'm copying and pasting from every podcast we do, go back and read up on all this.

These review papers are extremely informative. There's a lot of information that you can just sink your teeth into, but I want all of our listeners to go back and listen. So, first, we're going to just basically the summary for each of these.

Insulin resistance was found to be more common in women with recurrent pregnancy loss compared to those of a normal obstetrical history. But ultimately, they said that a lack of study specifically aimed to find an association between pregnancy loss and insulin resistance in women with PCOS. Thrombophilia, while numerous studies were found in women with PCOS and having thrombotic events as well, they ultimately said that specific data on miscarriage is lacking in women with PCOS.

And you can almost kind of copy and paste that same summary with each of these, but I'm going to briefly go over them. So, they discussed that the ideology behind hyperandrogenism and miscarriage is based on limited studies that demonstrate that androgens may in fact lead to endometrial or placental dysfunction by dysregulating genes associated with decidualization, placentation, and angiogenesis. And so for that cause, I think that maybe this leads to miscarriage subsequently in these PCOS patients.

And we look at egg and embryo quality. So, Youngheim et al., previously she did a meta-analysis and found ultimately no difference in implantation, clinical pregnancy rates, miscarriage-relied birth rates in obese women versus normal weight women who used eggs or oocytes from normal weight donors, which suggests that there could be some obesity-related egg quality issue and not necessarily a uterine factor. And maybe this is underlying the observed difference in reproductive outcomes.

So, the authors discussed that this may be thought to result from high follicular fluid of insulin levels, free fatty acids, inflammatory markers that may negatively impact oocyte development. And there's other studies that found that non-obese PCOS women, in comparison to non-obese, non-PCOS controls, had smaller oocyte diameter, lower M2 numbers, but this study ultimately didn't address miscarriage rates. So, overall, they discussed that there is a lack of data regarding pregnancy loss in women with PCOS in relation to egg quality and or embryo quality.

Lastly, they cite that there is insufficient data to provide a known association with endometrial receptivity and also oxidative stress. They have sections where they look at each of these as well. So, a lot of lacking data, as you can see from a lot of these summaries I've just gone through.

So, in conclusion, the authors discuss that the available evidence points to an increased risk of miscarriage in PCOS. Although linked to metabolic abnormalities associated with poor outcomes, as we discussed previously, the association between PCOS and pregnancy loss is very likely multifactorial. And while there are studies that have explored PCOS-specific risk-mitigating interventions, the authors discuss several, like metformin, vitamin D, antioxidants, data still remains limited and inconclusive, basically.

They conclude that they're unable to provide evidence-based recommendations regarding which of these interventions may be the most beneficial based off of a patient-specific PCOS phenotype. So, what do you guys think? A lot of information here, as always. I always promise a lot of information in these review studies.

It's kind of hard to dial it down to a short summary, but PCOS, as you know, is just extremely common. And if there are ways to help improve outcomes in our patients, then, of course, we'd love to do that. But what do you guys think of this study? Actually, this topic came up this morning.

So, we were doing resident teaching, and the resident was teaching the junior residents about the RPL workup. And one of the things she mentioned is, could we be sending a PCOS workup in patients with RPL? I think that's right. Very intelligent.

Very thoughtful. Very modest. Very demure.

Maybe not cutesy. Maybe not cutesy. But definitely demure.

But the question was a good one, which is, I think PCOS is not a monolith, right? There's not just one type of PCOS. And there's the PCOS where you have some pretty abnormal androgens and the metabolic syndrome, and there's some PCOS that's pretty vocal to the ovary without some of those systemic effects. And I think until we get better at parsing out PCOS phenotypes biochemically, I think we're still going to be at a loss for what truly is and isn't impacted by PCOS.

Yeah, also to consider along the same lines that it's such a broad constellation of symptoms and compartments that are affected, any one of which, I would argue, you might link to repeated pregnancy loss or miscarriage. So it's difficult when the monolith is not well defined or is a spectrum instead of a monolith. And each one of those elements may have a link.

So it's difficult to parse up because these things often co-migrate, right? So much like what we said about fibroids at the beginning of this podcast, there are different sizes, different locations, a lot of different things to consider. Hard to study, right? So the authors point out in this study, similar to PCOS, so there's a lot of different phenotypes. There's the lean and then there's the obese phenotype.

There's the ovulatory versus non-ovulatory. There's some with insulin resistance versus non. So there's a lot of phenotypes.

So hard to parse out all of these different things and find ultimately one specific recommendation based off of that. Also, not for nothing, we got two charts. I love a chart or table.

And one table is four pages. So, I mean, it just speaks to the fact that this link, we kind of collectively intuit it, right, that there is a link. But it's just so complicated.

And the spectrum of humanity is so broad and diverse that I don't know what it's going to take to finally crack the nut there. I think the answer is probably in genome sequencing. I think we're looking at downstream consequences of disease that we can measure biochemically.

I think the answer for truly genotyping some of this is going to come from genome sequencing. I think once that becomes more readily available and less expensive and we actually have the clinical outcomes to correlate with what we're seeing in the genotypes, then I think that's probably where we come up with some of the answers for these non-structural diseases like PCOS. But that's my two cents.

But there are smart people out there working on it. I'd love to have an intervention that works. I mean, we'd all love to have interventions that work to prevent miscarriage.

But in the PCOS population, it's tough. And I think a lot of people have their hearts set on metformin. That, unfortunately, just has not panned out.

So, I don't think I'll be able to afford to whole genome sequence my entire PCOS population just yet. But exciting next steps. All right.

Well, I think we've covered a pretty wide array of topics today, and we included Molly. So, I'm going to go ahead and consider the podcast a success. This is us signing off.

Until next time, we will see you next month as we approach the ASRM annual meeting. Hopefully, we'll have some special podcast content from that meeting. Be on the lookout for an invitation to come join us in the podcast booth if you're presenting.

If you have a prize paper, if you're going to be at the meeting, we'd love for you to come say hi. But that's all the time we have for today. Thank you, and we'll see you next time.

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.