Fertility and Sterility On Air - TOC: July 2025

Take a sneak peak at this month's Fertility & Sterility! Articles discussed this month are:  

04:20 A Pilot Study to Investigate the Clinically Predictive Values of Copy Number Variations Detected by Next-Generation Sequencing of Cell-Free Deoxyribonucleic Acid in Spent Culture Media
 
17:16 The Impact of Microfluidics Sperm Processing on Blastocyst Euploidy Rates Compared with Density Gradient Centrifugation: A Sibling Oocyte Double-Blinded Prospective Randomized Trial
 
24:12 Prediction of Pregnancy-Related Complications in Women Undergoing Assisted Reproduction, Using Machine Learning Models
 
38:51 The Effect of Laser-Assisted Hatching on Vitrified/Warmed Blastocysts: The ALADDIN Randomized Controlled Trial
 
48:47 Assessment of Clinical Pregnancies in Up to Eight Ovarian Stimulation with Intrauterine Insemination Treatment Cycles in Those Unable to Proceed with In Vitro Fertilization
 
01:00:43 Intravaginal Exposure to Seminal Plasma After Ovum Pick-Up Does Not Increase Live Birth Rates after In Vitro Fertilization or Intracytoplasmic Sperm Injection Treatment:  A Double-Blind, Placebo-Controlled Randomized Trial
 
01:07:21 Predictive Models of Miscarriage on the Basis of Data from the Preconception Cohort Study

View this issue at https://www.fertstert.org/issue/S0015-0282(24)X0006-0

View Fertility and Sterility at https://www.fertstert.org/

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

Hello, and welcome to another episode of F&S On Air, where we are discussing the July 2025, Volume 124, Issue No. 1 of Fertility and Sterility's print journal. I am your co-host, Pietro Bordoletto, and I'm joined here with a small but mighty early morning crew, Dr. Eve Feinberg, Dr. Kate Devine.

Good morning, Kate and Eve. Good morning, Pietro. Good morning.

Happy summer. Happy summer. This is the first week of camp, I think, for a few of our kids, so we're doing an early morning recording to get them off to school.

We're missing Micah and Kurt this week, who have an off week, but will be back next month with some great content. We want to start off today's podcast by acknowledging the reviewers of the year. So every year, the editorial staff of Fertility and Sterility gets together and discusses the review process last year.

You'd be surprised by how many reviews actually happen each year. We're talking about thousands and thousands of reviews over the course of 12 months, just for Fertility and Sterility, not to mention the three sister journals. And as you all know, this happens out of the kindness of all of our hearts, where we contribute back into the society, back into the journal by reviewing articles for our peers and providing comments and making sure that they fit within the realm of what the knowable universe tells us about the field of reproductive medicine.

In this past year, there were four excellent reviewers of the year that we needed to acknowledge. Dr. Christina Boots from an EAVS program at Northwestern, an editorial board member. Dr. Marni Jacobs from San Diego, California, who's one of our methodological editors.

And as a reminder, Fertility and Sterility recently launched the methodological editor section of the editorial board. This is something that didn't used to exist, but has added, I think, a lot of value to the journal's process and the quality of articles to make sure that the science is solid, in addition to the stats. Our last two reviewers of the year are Dr. Molly Kornfield from the OHSU program with Palo Mato in Portland, Oregon.

And then finally from across the pond, Dr. Jack Wilkinson from Manchester, one of our methodological editors. Thank you to our four editors of the year, but as well as all the other reviewers who spent time devoting their time, energy and effort to improving the quality of the science in Fertility and Sterility. Now, if you haven't had a chance to look at the journal this month, there's a couple of other things that we won't get to today.

Dr. Marcelle Cedars has a views and reviews section entitled Where Will Science Take Assisted Reproduction? We talk about things like germline gene correction. We talk about in vitro gametogenesis and we talk about human and non-primate in vitro gametogenesis. There's a lot of really cool articles at this month's Fertility and Sterility that will not be covered in this podcast, but we urge every listener to go check it out.

We're going to start as we always do with the seminal contribution. These are as identified by the editorial board, our favorite and most kind of poignant, meaningful, impactful articles each issue. Kate, you have this month's entitled How Many Babies Have Been Born With the Help of ART? Thanks so much, Pietro.

Yeah, it was very privileged to have the opportunity to read in depth and discuss with both of you and with our audience today, this really important paper, I think, well-selected as seminal contribution. First author, David Adamson, joined by international coauthors representing ICMART, the International Committee on ART. And really, this is such a timely and important contribution.

What the authors aimed to do was to estimate using robust methodology, the number of babies that have been born from ART since its inception. So since 1978, Louise Brown, and going through 2018, because as you'll see, when you all read this paper in this month's F&S, the methodology used just takes quite a long time, even longer than in scenarios where we have a straightforward registry, as we do, you know, to the extent that clinics report to SART, et cetera. This paper looked to estimate not only those babies that are reported through national registries or who report directly to ICMART, but also all infants born, including infants that were born in countries that don't report at all.

So never reporting countries, as well as in countries that have either intermittently or consistently reported to ICMART, but then also have non-reporting clinics in their countries that are not included in those reports. So when you take a look, you'll see that this was a multi-step process that looked at clinical pregnancies and really rigorously, and I'm talking about 13 supplemental tables rigorously, evaluated with really well-constructed sensitivity analyses, margins of error as to how many children I should say were born in each country. So looking at their national birth rates and socio-geopolitical trends, everything you could imagine that has occurred from 1978 to 2018 on a geographical basis, how to estimate the number of children that were conceived in each country from the time that IVF was first performed in that country through 2018.

And so would certainly encourage you to take a look at the way that these authors so thoughtfully constructed these estimates, while cut to the chase in terms of the results, which was to say, I was really actually quite surprised how few infants this is. So I even asked my layperson husband to take a guess as to what he thought that number would be. He's a smart layperson and thought it would be somewhere in the realm of about 50 million.

I probably would have guessed something similar, honestly, and also would have guessed that that number should be higher if we are serving the global population appropriately. In fact, what these authors concluded was that this number is probably somewhere between 9.8 and 13 million children born from IVF from 1978 to 2018. They do acknowledge that this is likely a slight underestimate, that there may be some countries that are non-reporting and doing IVF that even with their best estimates may not have shown up on these authors' radars, but they would say that it is a slight underestimate.

And then they also acknowledge that these numbers don't include GIFT babies, which they would estimate would be somewhere in the range of about 23,000 over the first 40 years of the history of IVF. And so this paper itself is a huge contribution, but I'm even more excited to hear that these authors plan to issue this report annually. So it takes five years to come up with the most recent numbers, but we can now expect this analysis to be made available to us annually from ICMART and will be published in F&S on an annual basis, we hope and believe.

And so I think this is going to be even more important as time goes on as these authors acknowledge and discuss eloquently in their conclusion section. When we consider the rate of infertility globally, which interestingly is fairly similar in countries, regardless of race, ethnicity, socioeconomic status, in somewhere in around the 16% range over the course of the average person's lifetime, we are, as other authors have reported, likely underserving the global population of folks who need fertility care by about tenfold. And so, you know, this is, in my opinion, a tragedy and something that in the next 40 years of IVF, and this is something we've discussed on this podcast many times, we really need to be thinking about how we can equitably administer fertility care to those who need it, to make use of the technology that exists, hopefully to make use of forthcoming technologies, including automation, and really help to reach these fertility deserts, not just nationally in the United States, but globally, to help those folks who really have not been able to achieve what I think we all agree is the human right of building their families.

So I truly enjoyed reading this. I look forward to reading it every year. And I really hope to see these numbers grow, because there is a huge need for us to help more people build their families.

Even Pietro, what were your thoughts on this paper? Yeah, I mean, I think, to quote Kurt, just you have to let the data flow over you here. I think it was a tremendous piece of work that really dove into the methodologies of how they got some of these clinics to report. And I can't even imagine the undertaking of this.

I think it's heroic efforts, especially in some of these countries. So I really commend ICMART for the fabulous work that they're doing, and to the group for publishing and bringing transparency to these data. I know the listener can't see this, obviously, but there's a really stellar figure three that I think gives you a sense of what's happening globally across the different regions in the United States.

And you'll notice that everyone is trending up. We have more babies born year over year. But probably the most dramatic increases are actually happening in the Asian continent, as well as in the Middle East.

You see that these bar graphs started off really small in the 90s. But over the course of the millennia, the last decade, you've seen the numbers just absolutely skyrocket in Asia, Middle East, with, I think, for good reason. These are huge population centers, and where we've seen actually a fair amount of innovation happening within the field of REI, as it relates to IVM, and some of the best large-scale RCTs have come from these parts of the world.

So it's really cool to see, globally, ART being on the up. For sure. And Asia gives us a little bit of a tough act to follow.

So in Asia, we saw from 1990 to 2018, 8% of babies originally born, or 8% of the contribution of ART babies coming from Asia in 1990, up to a third in 2018. Whereas in North America, we saw the number decrease slightly from about 20% of all ART babies in 1990 to 18% in 2018. So not to say that the overall number is decreasing, but the proportion of the total number of babies born from ART.

So lots of reasons for that. That said, we do have a lot owed to them in terms of the research contributions, as well, as you know. Let's keep it in the ART realm, and Eve, I want to come to you next.

We have a really cool article entitled, Adding Short Duration of GnRH Antagonist and Gonadotropins to the Natural Cycle to Allow Scheduling of Transfer Day Without Compromising a Live Birth. I love the concept. I'm hoping that you will talk a little bit about the nomenclature here, because it may add a couple of things to the natural cycle.

Is it really natural, and is natural the best way to describe this kind of frozen cycle? But over to you. Yeah, thanks. And I think we can duke that out at the end.

But the first author, I want to give a shout out to one of the OB-GYN residents at Northwestern, Ali Borazjani. He was a first author on this, soon to be Cedars-Sinai Fellow, and our very own Micah Hill and Kate Devine. So the objective of this study was to evaluate whether there's a difference in live birth outcomes when comparing a modified natural cycle FET protocol using a short duration of GnRH antagonist with low dose FSH or Menopur to delay ovulation compared to, let's call it a traditional modified natural cycle protocol.

I know we've talked a lot about how our patients want natural cycle FETs, but our laboratories and our embryologists want some sense of order in the scheduling. And so this protocol actually allows for a little bit of both. It was a retrospective cohort study done at a single U.S. fertility clinic network who makes a concerted effort due to staffing to avoid weekend FETs, which Kate, I actually found that to be fascinating.

Patients are brought into the center four days prior to attempted ovulation based on historical cycle lengths. Serial ultrasound and blood work were performed until there was a dominant follicle measuring more than 17 millimeters and the endometrium was considered to be adequate. Patients are counseled if they're ready for ovulation trigger and it's a weekday, then they'll be triggered and then transferred one week later on that weekday.

If on the final monitoring day patients were having a spontaneous LH surge, they would be transferred six days later. This strategy was compared to a group of patients, it's called the study group, who were managed with the same protocol. But if the follicles was between 14 and 17 millimeters on a Friday, i.e. not ready for ovulation trigger but at risk for an LH surge, then they were instructed to begin taking a GnRH antagonist plus 75 IU add back of gonadotropins.

And the purpose of that was really just to hold them out until Monday when these patients would return and receive their trigger shot if they then met criteria. After ovulatory trigger or LH surge, micronized vaginal progesterone, 200 milligrams BID was begun three to four days prior to FET or three to four days post trigger. Primary outcome was live birth and secondary outcome was positive beta, clinical pregnancy, and spontaneous abortion.

So the key findings were that there were no differences in live birth between the groups. So in the scheduled cycle, there was a 57% live birth rate versus a natural cycle of 49.4%, so actually slightly higher but did not reach statistical significance for the scheduled group. The clinical pregnancy rate was higher in the scheduled group and the spontaneous abortion rate had no significant differences between groups.

They did a subgroup analysis looking at PGT-A, similar findings, live birth rate was unchanged. There is this slightly higher positive HCG in the scheduled group as well. And so overall, the scheduled natural cycles also have lower cancellation rates when compared to natural cycles, so 3.6% versus 8.1%. And so the authors conclude that this quote, scheduled natural cycle, FET protocol using GnRH antagonist and gonadotropins provide some flexibility in scheduling without compromising live birth outcomes.

And I agree, this may overall improve clinic workflow while maintaining the benefits of corpus luteum exposure associated with natural cycles. Overall, I think it's an interesting study and another protocol to consider that helps to balance all of these factors that we struggle with daily. I think my question for you, Kate, is cost.

So if a GnRH antagonist is $150 and 75IUs of gonadotropins is about $60, then you're potentially adding $450 in medications, the burden gets passed on to the patient to reduce the burden on the lab, like fully realizing that embryologists are expensive and necessary and staffing is a huge problem. But I'm curious how you guys think about these. And Pietro, I think you're right.

Do we need a different name for this protocol? But I think novel, interesting, well done, well written. I just am curious about some of these decisions. Yes, certainly open to any naming ideas that the two of you have rather than the scheduled natural cycle.

It's a great point, even something we struggle with very much in terms of the additional cost and burden to the patient in asking them to do this to avoid weekend scheduling. That said, we've made the decision as a practice, especially in some of our higher volume offices. So for example, in the clinic where the majority of these patients underwent their FETs, oftentimes in the weekends, we'll have 20 egg retrievals per day.

In addition to the dwindling in number, the fresh embryo transfers and those frozen embryo transfers that are not able to be moved just based on where they fall timing wise, which happened as well. And so though the embryology time required for an FET has gone down recently because of new information that has emerged about the efficacy of quick warming protocols, we still obviously take more seriously than almost anything else, the chain of custody concerns and the importance of absolute ironclad protocols for selecting the appropriate embryo for transfer. And so, to be able to offer patients an FET protocol that does not require intramuscular injections, and I know reasonable people might be able to disagree about that as well, something we'll talk about later.

We feel that it's warranted and we're very straightforward and forthcoming with the patients that there's a chance that they may need to take a few days of these additional medications. Yeah. And I guess my other question just logistically is if you're scanning them on a Friday morning and then you're saying you need medications that often have to be delivered from a specialty pharmacy.

And my understanding is you guys kind of have your own specialty pharmacy, but for the rest of the world who may not have their own specialty pharmacy, you would need medications delivered same day if you're doing that monitoring on a Friday. So I just think logistically, like that could be incredibly stressful for a patient to be told you need an additional $450 of medications so that your transfer can be on a Monday. And by the way, we're going to order these medications and you have to get them today.

Otherwise, this isn't going to work. So I think those real world practical challenges, I think I struggle with. I guess you could also offer these patients or you can counsel them a priori that, hey, if you're not running on a Friday, like you do have the option of canceling and trying again next month.

They're not on any medications, sort of no harm, no foul, except potentially cost of monitoring. I don't know. I think it's novel and it's interesting.

I'm not sure how well that would fly in our setting. I think it's a great protocol for the very specific patient in the right market where all of those stars kind of aligned. They feel so strongly about avoiding intravascular progesterone.

They have access to a pharmacy locally for same day pickup of medications. And the added cost for them is not substantial enough to make them bat their eyelashes at an extra $400, $500 worth of meds. I think it's a nice other option.

I don't think it's going to totally replace the unmedicated cycle or totally replace the medicated cycle, but it's nice to have kind of a middle ground in the middle there for patients. Yeah. But then you're also shifting your workflow to a terrible Monday.

Take your poison. It's either a terrible Monday or terrible Saturday. Yeah.

Yeah. I don't know. I really liked it though.

I don't mean to sound so negative. I actually thought it was great and it may absolutely be something that I incorporate into my practice. So I don't want to be the downer on this.

I think the more options we have to offer our patients and the more tools that we have in our toolbox, I think it makes for these really nuanced discussions and personalized approaches to medicine that we can offer to our patients and confidently say, I think these data are very convincing that we can confidently say like this does not impact your success rate. And hey, maybe a couple of extra days is actually a good thing. It's not a statistically significant difference, but it was, it certainly was not inferior.

And so, you know, I do worry sometimes if we try to trigger a little bit too early that we may be not achieving optimal endometrial thickness, or I have seen in those patients where we've checked progesterone levels, I've actually seen some pretty low progesterone levels when you trigger at a follicle size of 15. And so I wonder if, you know, that approach may actually be helping the efficacy of the cycle. It's a great point.

And just to be clear, we would never ever cancel any patient if we have to do the FET, you know, for this reason, if we have to do the FET on the weekend, we have to do the FET on the weekend. And certainly there are patients for whom these medications are even contraindicated and need true natural cycles, and we would accommodate those patients no matter what. We just don't want to also have 20 frozen embryo transfers on Saturdays and Sundays, if that can be avoided with a, with a smaller staff.

But when I presented these data at PCRS, that was the question that I got actually, what you just raised Eve, which, and I think it was from Marcelle Cedars was, you know, what, you know, obviously with a skew sample size as we had in this paper, which was one of the limitations with fewer patients in the scheduled, quote unquote, scheduled arm, you know, that said, there's there, it looks as though the patients might even do a little bit better when we pushed them through the weekend. And we think about what size follicle do patients ovulate at in true natural cycles, it's a lot bigger than what we tend to do when we're trying to control timing yet again, even in, in triggered modified natural cycles. And so is it the case that to have a little bit more follicular development makes for a higher quality corpus luteum and perhaps a better endometrial lining? You know, I think that these data kind of do beg that question.

Yeah, there was a paper from Cornell that we did on the podcast. I don't even know how many years ago at this point, but it looked at the incremental millimeter size in a Clomid IUI cycle, the incremental millimeter size of ovulatory trigger and Clomid IUI and showed that there were for every additional millimeter you gained, you gained an increase in live birth rate. And the optimal size for trigger was actually like a 22 or 23.

And I feel like typical FET protocols are triggered, modified FET protocols are trigger when the follicles over 17 or quote, the lining is adequate, which is exactly what we do. And admittedly, I wonder sometimes if people may be triggering at 15 and maybe a thinner endometrial lining on a Friday to avoid a weekend transfer. And maybe that's actually not what's best for the patient.

And so you may be avoiding a weekend in that way as well, but you may ultimately be driving up the cost by having suboptimal outcomes. So I think that that point of it too needs to be carefully considered as well. And I think we need to define, to better define what is an optimal time for trigger.

And I do think based on some data that we have that triggering too soon does not actually allow for optimal progesterone from the corpus luteum. I think you might be referring to a Romanski and Bortoletto et al paper from Cornell in 2019. Happens to be that Phil is also a middle author on this paper.

The man seems to have a shtick. Yeah. So, right.

Sorry, Pietro. I forgot that was yours, but yeah. Big shout out to Phil Romanski, who continues to put out some good work, fellowship and beyond.

The name of the theme of this July issue is really it's progesterone baby. We're going to be talking about progesterone until the cows come home, and then we're going to pivot and talk about the uterus being transplanted. But Kate, let's keep going on the progesterone theme.

You can give progesterone in many ways, but I think one of the ways that our listeners have probably not been exposed to yet is sublingual progesterone lozenges. Tell us a little bit more about that. Yeah.

So this is a retrospective cohort study out of the HRC Fertility Center with first author Rachel Mandelbaum and colleagues, including senior author Rick Paulson, with whom I have had many a debate about the best route based on current data to administer progesterone and programmed frozen embryo transfer cycles. So these authors looked at a good sample size, 1,951 programmed single euploid, good quality frozen embryo transfers, and evaluated two protocols. They looked at protocols where both arms received endometrin or micronized vaginal progesterone, 100 milligrams, three times daily.

And then in addition, in the, I guess we could call it the quote unquote control arm, they also received 50 milligrams of intramuscular progesterone daily. Whereas in the study arm or the sublingual lozenge arm, they also received 200 milligrams TID, so three times daily of sublingual progesterone. So this is a lozenge that they obtained compounded, so not commercially available on a large scale, placed under the tongue until it dissolved.

And so the authors looked at multiple primary outcomes, clinical pregnancy, which they actually defined as a positive serum HCG nine to 14 days after the embryo transfer. Ongoing pregnancy, which they defined as pregnancy progressing beyond eight weeks, live birth and miscarriage. And they looked at miscarriage at various stages, biochemical and clinical losses.

They looked at secondary outcomes, and I was excited about this, of serum progesterone concentration, both on the day before the day of embryo transfer, as well as at the time of pregnancy test. And so it's certainly a novel protocol to me. And one that I'm really excited to see, I've long wanted to see a study, a randomized controlled trial comparing oral plus vaginal to intramuscular, because I think that especially with dihydrogesterone, as is available outside of the United States, there have been some studies showing that that protocol could have some promise and be more patient friendly.

That said, I digress. I didn't know that sublingual progesterone was available, much less that the this protocol was in clinical use and clinical use to the tune of, you know, basically, as many as 1000 patients having received this protocol at HRC in from 2018 to 2023. So what the authors found was that there was no statistically significant difference in any outcome measured except the serum progesterone concentration, which we can talk about a little bit more in a moment.

So importantly, this was a retrospective study, and it was the patient and their provider that determined which protocol to use. And while many factors likely determined which protocol was used, it was clear based on the baseline characteristics, as you can see in table one of this paper, that the group receiving intramuscular progesterone was a worse prognosis group, they were older, they had more prior transfers, and they had a thinner endometria. So all of these things, of course, the authors controlled for in their analysis, as well as controlling for multiple cycles contributing by the same patient.

That said, it leaves me somewhat concerned as to whether there could have been any type of an unmeasured confounder here as well. And also wondering, you know, would we have seen the same results in a randomized controlled trial, the authors did find that there were quite high actually serum progesterone concentrations in both groups. So it was statistically lower in the group that was receiving this sublingual.

I was really, really hoping that in the group receiving the intramuscular progesterone that there would be an analysis just within that group as to whether it was associated with any of the outcomes, because we see so much data coming out of Europe, in terms of serum progesterone concentrations being associated with the outcomes of interest of this study. We'll have to stay tuned for that additional analysis because we didn't find it in this particular paper. That said, I love this paper.

I think the authors did a great job with the analysis. I think it represents a novel protocol that seems really to be quite successful. It is a lot of progesterone these patients are taking, three times a day sublingual and three times a day vaginal, quite a bit of progesterone and a lot to do.

I was also interested to see that they're giving as one of their standard protocols transfers TID vaginal progesterone as well as 50 milligrams a day intramuscular. I think that's also really more than is needed, but it did make for an apples-to-apples comparison here, for which I am grateful. I was going to say, I think the interesting point of note is the TID vaginal progesterone compared to Kate, the trial that you did that used BID vaginal progesterone.

I think it begs the other question of, is vaginal progesterone really inferior when you do TID dosing and administration? I don't know the answer to that, but I think that this was really interesting. I would love to be able to offer and get another protocol and get another administration route of progesterone. I hear that SubQ is coming on the market soon in the U.S. and that's going to be novel and exciting.

I think that the more tools that we have and the more that we have to offer, I think it really helps to just make these discussions a lot easier. Then again, are we focusing so much on progesterone levels and program cycles where we should be focusing on how do we make natural cycles easier? Should we just be relying on our corpus luteum rather than trying to figure out best ways to administer lots and lots of progesterone in program cycles? I think there's very aptly named reflections in the table of contents this month by yours truly entitled, If a Little is Great and a Lot is Better, then Way Too Much is Just About Right, which I think kind of summarizes the way that a lot of us are viewing progesterone these days. You can never have too much, maybe, question mark.

We'll talk a little bit about that in an upcoming article, but also a big shout out to first author Rachel Mandelbaum, a recent fellow graduate from the USC program who's now kind of making her way into the field as someone who's really thinking about the patient experience, trying to remove the physical burden of being a patient by coming up with novel ways of delivering medications and putting together IVF protocols so that they're a little bit more patient-friendly. Yeah, for sure, and I hope one other thing that they changed here was to stop giving somewhere in the range of 98% of their patients intramuscular estradiol. So in trying to remove intramuscular injections, I know Rachel in her practice will switch soon over to another form of estradiol.

That was exactly my point. I think as we talk about patient-friendly, I think we should perhaps think about oral or transdermal estradiol. Nice to have options of ways to deliver some of these medications.

All right, we're going to come back to me now. I have an article that talks not so much about the success of progesterone but the perinatal outcomes of progesterone, and this is specifically a natural frozen-thawed embryo transfer pregnancies. This is a cool article in that it's not a primary study, but it's actually a secondary analysis of two large RCTs, and this one comes from Elenis et al.

in Uppsala, Sweden. So we know that most natural cycles include some form of luteal phase progesterone support. Lots of studies, including in this month, show that the addition of progesterone has mostly positive results at worst neutral results on clinical pregnancy and live birth rates.

However, what's been lacking is the safety of progesterone during the early or late pregnancy, particularly with regard to obstetric and neonatal outcomes. There's not been nearly as much done in terms of shoring up that body of evidence. The recent findings that have come out, however, in small cohort studies have questioned whether or not progesterone supplementation during the early stages of pregnancy have any impact on placental and fetal development, things that may be detrimental for that developing fetus and that pregnancy in the third trimester.

So to investigate this, whether randomization to vaginal progesterone supplementation compared with no supplementation during the luteal phase of natural cycles, the authors came together and found two large RCTs, one done from 2008 to 2011 and the other done from 2013 to 2018, and 923 ovulatory women that resulted in 227 singleton live births. The intervention here was pretty straightforward, vaginal progesterone from transfer day until pregnancy ultrasound at eight weeks versus no luteal phase progesterone. The formulations for progesterone changed between the trials but were more similar than different.

The big primary outcome here was the incidence of gestational hypertensive disorders. Here they define that as preeclampsia, eclampsia, gestational hypertension, and help syndrome. The secondary outcomes were the things that you care about in an obstetric event, placenta creta, preterm birth, as well as birth weight, SGA, and APGARs.

So the big takeaway headline in terms of birth weight was that there was really small differences between the groups receiving luteal phase progesterone and no luteal phase progesterone, and 82% of people receiving luteal phase progesterone had birth weights in the normal range compared to 70% who received no luteal phase progesterone, and that was a statistically significant difference. Furthermore, as regards to gestational hypertensive disorders, there tended to be a higher trend towards hypertensive disorders in groups that received no luteal phase progesterone, 11% versus 4.4%, and here the p-value is 0.058. I'm still heading in that direction, but clearly not crossing that threshold. There were no significant differences in preterm birth, placenta creta, mode of delivery, SGA and LGA rates, and no neonatal complication differences.

There was, however, a slightly higher proportion of female infants than those born through luteal phase progesterone, which, again, chance finding, no biologic plausibility for why progesterone would affect the chromosomal sex of an embryo. And finally, just to kind of round out the story, there were no big differences in maternal deaths, stillbirth, or neonatal deaths, and again, no differences in congenital malformations or APGAR scores in both groups. So the reason why I think this was interesting to have studied is that there is some biologic plausibility for how progesterone may change things.

We know progesterone modulates the endometrial immune milieu and vascular remodeling, things that are important for placentation, fetal growth, and we know that poor fetal artery remodeling can later lead to maladaptive disorders of the placenta, resulting in hypertensive disorders. It seems to me that luteal phase support is not only beneficial for global pregnancy rates in the cycle, but in some categories here may be beneficial in risk reducing some of these obstetric and neonatal events. I think the cat's out of the bag.

I think all of us use progesterone in the natural cycle already, and I think what this study adds for us is that there continues to be a strong safety signal that the benefits far outweigh any potential concerns or risks for negative obstetric or neonatal outcomes. So I think all of us are going to continue to use progesterone, but it's nice to have some data to tell patients, oh yeah, it's actually fine. As far as we know from these two secondary analyses of two large randomized controlled trials.

Kate, Eve, did this change your mind at all about progesterone? We're still pro it. No, it didn't change my mind. I think the question that I always have is how long can luteal support be safely continued, which this article didn't really dive into, but I have a lot of patients we typically discontinue at nine weeks, and I have a lot of patients who are just insistent that they want to stay on their progesterone longer, and I do worry about additional progesterone, particularly around the time the external and internal reproductive organs are forming, and so I don't know.

I mean, I think this was common sense. We've been using progesterone for a long time. We haven't noticed detrimental outcomes, but I agree it's always nice to have a citation and the data to really show what we already know.

What do you think about in the unmedicated or quote-unquote the natural cycle, what do you think about discontinuing progesterone at the time of a positive FH on ultrasound? Too early? I mean, I don't know that you need progesterone in a true natural cycle. I don't know that we've ever really established that. I have a couple of patients who really are opposed to taking any hormones, and I have done completely natural cycles on those patients, and again, it's a very small handful.

Our typical protocol is trigger and supplement with progesterone, but it seems to work just fine, and so I think where I really worry, and I know we just talked about this, but where I really worry is in the modified cycle, are we perhaps triggering too soon, causing dysfunction that then requires progesterone supplementation, but in a true natural cycle, can we really just trust that corpus luteum is going to do what it will do, and I think the other question that I have with that is what is the upper age limit? I don't necessarily trust a corpus luteum from a 43-year-old in the same way that I would trust a corpus luteum from a 33-year-old, and so I think that there are a lot of unanswered questions that are ripe for research. I totally agree, especially with that last point about the data being lacking in terms of doing natural cycles or modified natural cycles among patients who are further into their reproductive lifespans. Particularly, I worry about patients that have started to see shortening of their cycles.

This is a study that I really think we need to do and do rigorously because we have just as many older patients demanding natural cycles, and I personally spend a lot of time trying to talk them out of it, but in the absence of really high-quality data. Do you have a cut-off level? I won't do a natural cycle on someone that has a cycle that's shorter than 26 days, and that's just hunch. It's not data-driven, but I do think that there's probably some serious dysfunction going on that is altering that cycle.

Yeah, I mean, I do something similar. I don't worry about it as much in younger patients, and or, you know, necessarily interrogate it directly for every single younger patient that has, like, a regular 26-day cycles, and maybe we should be. Again, I think the data are lacking looking at both of those variables, age as an isolated variable, cycle length as an isolated variable, and the combination of the two.

In the NAPRO study, we excluded patients who are 42 and older for that reason, but we allowed regular cycles, you know, as typically defined. So, meaning... Yeah, I think NAPRO had 24, if I'm remembering it correctly. I think your cycle could be as short as 24.

So, that may actually be good fertile ground for a subgroup analysis, looking not at the primary outcome of preeclampsia, but actually looking at likelihood of live birth in those shortened cycles. Right, certainly won't be powered for that, but it might give some signal in the hypothesis generating. So, yeah, let's do the study.

Do you think an HCG trigger modulates any of that, given its half-life and its ability to support the corpus luteum in the natural cycle, HCG-triggered natural cycle, or even a small amount of Q-weekly or twice-weekly low-dose HCG for luteal support? I mean, I do give the HCG trigger regardless, and that was the prescription in NAPRO as well, that even if it seemed as though the patient had started to mount a spontaneous LH surge, to give the trigger anyway to normalize that luteal phase support. But as Eve mentions, we may also be somehow compromising the natural corpus luteum with these modified natural cycles relative to natural. So, I certainly think in the data support, as we come full circle in this discussion, to give the supplemental progesterone if we are doing that.

And again, to answer your question, I think we don't really know. All right, you guys have asked for it, but we're finally going to move away from progesterone, and we're going to go to the uterus, and we're going to talk about two studies that have totally different takes on the uterus. Eve, tell us a little bit about this study out of Northwestern.

Yeah, so actually, I'm going to compare both of the uterine transplant studies, and I'm going to talk about them sequentially. The question that was asked and answered is actually the same, but the methodologies of how these questions were answered is actually vastly different. And I think that the nuances are really interesting, and I think it just goes to show the various brilliant minds in our field and how we can ask these questions very intelligently and how we can derive answers in different ways from the same question.

So, the first study is cost-effectiveness analysis of uterus transplantation versus gestational carrier for the treatment of absolute uterine factor in the United States. And first author is Jessica Walter, Jessie Walter from Northwestern, with senior author Heidi Harvie from Penn. And so, this study evaluates the cost-effectiveness of uterine transplant compared with GC in treating absolute uterine factor infertility for women who desire one or two live births.

And so, they created a decision analysis model, and it was created from the U.S. healthcare sector perspective, assessing both cost and quality of life adjusted years or QALYs. For our learners, a QALY is a measure used in health economics to assess the value of medical interventions, and this combines both the length of life and the quality of life into a single number. So, one QALY is one year of life in perfect health, and one QALY is length of life in years multiplied by quality of life weight.

And so, that can be anywhere from zero to one, and this quality of life weight is derived from literature, patient surveys, expert opinions, or validated instruments. And so, it's important to note that in this study, QALY was the quality of life for the parents, and this is a key difference between these two studies. So, they assumed baseline utility for an otherwise healthy patient who has uterine factor infertility of 0.87, with utility increasing if patients experience a healthy baby born at term, but a preterm birth was given a lower QALY, and this decreased further for a very preterm birth, or lowest if a uterine transplant fails to produce a live birth.

And so, the model incorporated clinical outcomes from existing literature and cost data primarily in 2020 U.S. dollars, and they looked at both scenarios for achieving one or two singleton live births. The model used up to three single embryo transfers, which again is a difference from the next study, and they incorporated probabilities of delivery complications such as preeclampsia, preterm birth, delivery methods given that uterine transplant needs to be delivered by C-section, and neonatal outcomes. They looked at GC costs based on published commercial and academic sources, and they assumed fixed costs for both GC first and second deliveries.

Uterine transplant costs were taken from cost estimates of a radical hysterectomy for the living donor, and then deceased donor costs from the organ procurement network, who has cost data availability on things like transport. Recipient costs were estimated based on those from a liver transplant, given the similar medical complexity. Post-op transplant costs for uterus transplant included 13 biopsies to assess rejection, and then the cost of prolonged immunosuppression.

So, then they connected additional analyses to compare costs and cost effectiveness with time horizon of a second singleton birth, assumed that all patients wanted a second live birth, but accounted for circumstances in which it may have been contraindicated. So, they did multiple sensitivity analyses to account for wide variation using probabilistic methods, and they used a Monte Carlo analysis with 5,000 trials, and this also is a little bit different than a deterministic sensitivity analysis that was used in the next study, we'll talk about that, and univariate testing. So, the outcomes that they measured were total cost, live birth rate, QALYs gained, and then incremental cost-effectiveness ratio, or ICER.

Here in ICER, the numerator is the incremental cost of one treatment over the incremental effectiveness often measured in QALY, so cost over QALY. So, a lower ICER is more cost-effective, and if one treatment is less costly and more effective, then we say that it dominates the other. So, the key results from this study, and they used some assumptions, and this is also another huge difference between studies, is how they calculated the assumptions for live birth rate.

So, for one singleton birth, this study assumed that the live birth rate for a gestational carrier with three embryo transfers was 94%, and I think that's fairly accurate, versus uterine transfer at 77%, based on some published literature. The cost, they said, of a gestational carrier was roughly 97,000, with a range of 57,000 to 153,000, and the cost of a uterine transplant was 116,000, with a range of 67,000 to 182,000. So, these cost variables are also really different between the study.

So, the mean QALYs for the GC was 0.93, and uterine transplant was 0.89, and so the conclusion of this study is that GC is more effective and less costly, dominating uterine transplant in the setting of one singleton live birth. When you look at two singleton live births, the likelihood of a GC having two live births was 86%, and uterus transplant was 66%, which I think is on the high side, and then the cost of a GC was 186,000, and uterine transplant was 164,000, with similar ranges, and then the mean QALYs were also higher for gestational carrier, but not by that much, so 0.92 compared to 0.88. And so, looking at two singleton live births, they concluded that uterine transplant may actually be less expensive, but offers fewer QALYs and remains not cost effective by conventional thresholds. And so, I think the limitations of this particular study is that it may not capture the full emotional and psychological value of patients wanting to experience pregnancy, and so the cost and outcomes reflect a U.S.-centric view, and they may actually not generalize globally.

And then the longer-term maternal health outcomes and child outcomes beyond two births were not evaluated, and insurance and legal access surrounding GC use and uterine transplant were not addressed. And so, the authors conclude in this study, for patients with absolute uterine factor infertility, gestational carrier is the more cost-effective strategy for both one and two live births. And so, I think that we need to think about this in terms of broader social, ethical, and access-related considerations.

The second paper, the title of that is Comparing Gestational Carrier to Uterine Transplantation in Uterine Factor Infertility, a Cost-Effectiveness Analysis. So, same question, we're going to dive into the differential methodologies, and this was first authored by Josh Combs with our very own Micah, Kate Devine, and senior author, Jeanne O'Brien. And Jeanne was one of my senior residents when I was at Northwestern.

The study analyzes the cost-effectiveness of two treatment options for absolute uterine factor infertility versus gestational carrier. And so, they did a decision tree model that was created to compare the outcomes between these two arms. In the GC arm, the individual was assumed to have undergone IVF with PGT with two euploid embryos, and they were assumed to have been created, allowing for two FET attempts.

And in defense of this, the original GC protocols did actually call for two euploid embryos, and I think it was later, sorry, the uterine transplant protocols, and I think it was later on that more and more of the teams decided that more euploid embryos were probably better to create up front. In the uterine transplant arm, they also assumed that the individual underwent IVF/PGT-A with at least two euploid embryos. The individual then underwent uterine transplant, and if failed, then they assumed that a second transplant did not occur.

If they were successful, then six months of immunosuppression followed by two FET cycles. If both FET cycles were unsuccessful, then the patient had no further treatment. If a child was born from an FET, then the individual can opt to try for another child or have a hysterectomy, and hysterectomy was performed after the last child was born.

So, all costs in this scenario were taken from published literature and were analyzed from a public payer perspective. Operative time was chosen as a surrogate for costs for the surgery since exact cost data was not available, and then operative times of 8 to 16 hours were modeled. Cost of hysterectomy, IVF/PGT-A, vitrification, subsequent FET cycles were all derived from the literature.

So, the probabilities of first and live birth from the GC arm were derived from Pertea's work and the uterine transplant arm from Johansson and others' work, and the gestational carrier was more likely to result in live birth in this analysis under all modeled circumstances. So, looking at the likelihood of live birth, and again, this is a key difference, and this really accounts for a lot of the huge differences in this study. Looking at the likelihood of one live birth with a gestational carrier, the author said 84%, and then looking at uterus transplant, this is 44%.

And then the numbers really plummet when you look at the likelihood of success of two live births. So, GC 42% compared to uterus transplant of 17%. And then they also looked at the possibility of a no-child outcome, so GC 16%, and uterus transplant 56%.

So, again, the two main outcomes of interest were QALYs and the number of live births achieved in each arm. And QALY was calculated using the lifetime utility of the child born, assuming an average lifespan of 76 years, and this was equally applied to both arms. So, again, contrast that to the prior study that looked at QALY from the parental perspective of the joy that a child brings and the years of childbearing.

And so, it's just a much shorter horizon looking at QALYs in the previous study. So, QALY losses were driven by things like major surgery, immunosuppression, and psychological burden. And an incremental cost-effectiveness ratio is calculated for both treatment arms and a willingness-to-pay threshold of $50,000 per QALY was assumed.

So, they used deterministic sensitivity analyses on each input parameter, and each was run in 10,000 iterations in which all parameters were varied simultaneously. So, I alluded to this earlier, but a deterministic sensitivity analysis differs from a probabilistic analysis in that only one or a few input parameters can be varied at one time while keeping the others constant. But in a Monte Carlo or a probabilistic model, all variables can be varied simultaneously.

So, the key finding in this study was that uterine transplant was dominated by gestational carrier for all of the input parameters, cost, operative time, graft failure, and live birth per failure, demonstrating that uterus transplant had higher cost and lower effectiveness. Direct costs were six times more expensive than a GC. This group calculated that a uterus transplant was $1.6 million compared to 240K of a gestational carrier with 23.7 for fewer QALYs.

So, GC cost was stable across all scenarios, but uterus transplant costs increased significantly with complications or graft failure. Uterus transplant was no longer absolutely dominated when live birth rate per transfer was ridiculously high of 85%, which is not yet attainable, or cost of a uterine transplant was below 13,000, or if the cost of a GC increased beyond $359,000 per live birth. So, in other words, uterine transplant only became cost effective when considering very unrealistic clinical outcomes.

So, again, the authors discussed that intangible value of experiencing pregnancy and childbirth, which cost-effectiveness analyses just don't really address. They're purely cost modeling and purely from that perspective, and you can't actually put a price on that experience. So, I think it's interesting.

I mean, both articles published in the same month arrived at the same conclusion but had major differences in the approaches that they took. The two key differences were the cost inputs and how they calculated quality of life. And so, regarding cost, I think the Combs article overestimated the cost of uterus transplant, and I think that the Walter article underestimated the cost of a gestational carrier at $97,000.

I think also it should be noted that the Combs article used billed charges, which are at least twice as high as actual costs. And so, the approaches to estimating these two factors really differed between the two papers, and I think the major difference overall that affected quality was the likelihood of live birth, which was much lower in the Combs study for both one and two children. And so, both groups acknowledge that as techniques improve and as cost is driven down, that the scale may actually tip towards cost-effectiveness of uterus transplant.

We're just not here today. So, I know that was a really long and really chunky analysis, but I'm curious on each of your thoughts. And Kate, I'm curious, as a co-author on that paper, I'm curious how you looked at the other manuscript.

Yeah, I think they did a fantastic job. I love to see, as you noted, different perspectives and different approaches to the same exact question and problem that we're facing clinically right now, which is how do we counsel these patients both in terms of cost-effectiveness and then in what we can't estimate in terms of cost, which is how important is it for these patients to actually carry and deliver? I do think that you're correct, as is the excellently written reflections piece in this month's F&S, that the Northwestern paper, Northwestern and Penn, I think pretty significantly underestimated not only the GC costs, but also the uterine transplant costs. And that to use a double lung transplant as the proxy for uterus transplant in our paper may have been an overestimate as well.

So both of those things are true. Even so, and even with all of those sensitivity analyses, I was glad to see that they agree, because I think it's pretty intuitive to all of us that at this point in the early days of uterus transplant, gestational surrogacy is going to be a more cost-effective choice for most folks. Does that mean it's the right choice for most folks? I think that's where we get into the subjectivity of what people want in their experience of parenthood.

I do think that a take-home message that you addressed early in your discussion may be the most important one, which is that patients considering either of these with absolute uterine factor should freeze a lot of high quality embryos, as many as they can, I would say early on, because who knows what their journey will entail, especially if they're going to be going towards a uterus transplant as their first approach that may or may not succeed, and that may not succeed after multiple transfers. And then they need to go to a GC at a time where they're significantly older. So if there's one piece that I take from this in terms of counseling patients is that patients with absolute uterine factor have a potentially long and torturous journey.

And so they should freeze enough embryos to make sure that they have a really high probability of having the family size that they want. And I think that is a huge part of the difference in terms of the actual probability of achieving two children between the two is the number of embryos that these patients had in the model at the front end. Yeah.

And I realized for a decision tree analysis, you can't, it's very hard to carry those out beyond three transfers as we did. We did a decision tree analysis looking at one versus two live births, considering number of frozen eggs, and your tree just gets to be too large and too difficult to manage with that many cycles. But I wholeheartedly agree.

It reminds me a little bit of my twins doing advanced math problems. They both get the right answers and the way that their minds work are very different. There's lots of different ways to do certain types of math problems.

And so looking at not just the answer, but looking at the path that you get to arrive at that answer, I think just shows how nuanced some of these cost-effectiveness analyses are. And I think really it's a great, it's a great exercise in what are the factors that we want to look at and how do we want to design a study? And I loved, I loved diving in and getting really in the weeds on how each of these different groups did each of their analyses. I thought it was fascinating.

So huge, huge kudos, Kate, to your team and huge kudos to Jessie Walter and her team. I thought these were brilliant articles and just a lot of wonderful information and good learning. And I think for our trainees who want to learn how to do decision analyses, I think the methods section of both of these papers were just incredibly well written and well thought out.

So I really enjoyed these two papers and I really enjoyed reviewing them back to back. And one more shout out I would say is to bring it back to what Pietro mentioned at the beginning of this podcast is to our reviewers, because this paper went through many, many, many revisions and sometimes that is necessary. It can be, you know, we have to power through and at the end of the day, we're making better, drawing better conclusions and more sophisticated and helpful information for folks to use clinically.

So we had great reviewers for this paper that really helped us make it better. So I don't know who you are out there, but we really appreciate your insights. It's not every month that you have the opportunity to publish two nearly identical questions being asked by two different groups of authors, but arriving at it in slightly different ways.

And I think this is a tour de force in methodology. And if you're thinking about a nice journal club presentation for your groups, fellows, I think this is a great opportunity to compare and contrast methodologies and kind of walk through the nuances of study design because arriving at different conclusions with similar inputs. I'm going to bring it home with our final article for the day.

Again, this is not a progesterone one. This is a uterus one. This is an article entitled Extended Intrauterine Balloon Stent Use to Prevent Adhesion Reformation After Hysteroscopic Adhesolysis, a Randomized Trial.

The study is done by Luo et al. from Beijing, China. Traditionally, when we manage adhesions, we typically talk about using barrier methods.

So the US IUDs are pretty common, Foley catheters in the US more common, and then gel-based alternatives in Europe, very common. But these are usually therapies that are given for about 7 to 14 days. And the author's question, is that long enough? So the authors hypothesize that prolonged mechanical separation of the uterine walls with a balloon stent specifically for 8 weeks might reduce the risk of readhesions in severe intrauterine adhesion cases.

This was a prospective single center RCT in China. 160 women between the ages of 20 to 38 with severe intrauterine adhesions as scored by the American Fertility Society scoring system greater than equal to 9. And they were randomized 1 to 1 to 8 weeks of balloon stent versus 1 week of balloon stent. And the follow-up was a second and a third look hysteroscopy at kind of standardized intervals.

Their primary outcome was adhesion recurrence at the time of the third look hysteroscopy. Their secondary outcomes were the adhesion scores, the menstrual blood loss, which is a subjective measure of volume of menstrual effluent, and the mutual thickness on ultrasound, as well as subsequent reproductive outcomes. So what do they find? The group that had a balloon for one week had a 43% recurrence rate of adhesions.

By the time you marched it out to the group that had 8 weeks of balloon, the adhesion recurrence rate at third look hysteroscopy had decreased to 17.4%. And for those doing the math at home, that's a relative risk reduction of 0.4. That's a 26% absolute risk reduction, which is pretty dramatic. In the group that had a longer balloon course, they had a lower AFS adhesion score. In the group that had a longer balloon dwell time, they had a higher rate of normal cavity.

They had improved menstrual blood loss scores and no difference in infection rate, white blood cell count rate, vaginal discharge rate. And if you're thinking about, well, does it all matter? Well, there was no difference in clinical pregnancy rates at 12 months. Both of them had about a 40% pregnancy rate over the course of the study period.

Again, the study wasn't really powered or designed to look at clinical pregnancy rate. It was powered and designed to look at the adhesion recurrence rate. And with regard to adhesion recurrence rate, I think what the study tells us is that there potentially may be some benefit to longer dwell time or mechanical barrier during the course of adhesion treatment via hysteroscopy.

Now, one kind of confounder here is that maybe one week is just too short of a time. But is eight weeks too long of a time? Is there a sweet spot in between? For any patient who has ever had a balloon, we all know that they call you because the balloon hurts. They call you because they think the balloons fall out.

They call you because the balloon hasn't, in fact, fallen out. Eight weeks is a really, really long time. I'll share with you what I do for my patients is, for patients that I'm kind of worried about, I do at least one week.

For patients that I'm a little bit more worried about, I may extend that to two weeks. And for patients that I'm really, really worried about, I actually just want to look in the cavity myself at that two-week mark with a hysteroscope, lyse any early adhesions, and do that serially until I see the adhesion stop reforming. There's great data from China that also shows that sometimes you don't even need to look.

You can simply put a saline sonogram catheter or a Foley balloon inside the uterus in the office setting, distend it to mechanically separate the walls with a little bit more magnitude, and then have that serve as kind of your early adhesiolysis in the office. Eve, you can't see Eve's face, but she's cringing, thinking about putting five to ten cc's in a Foley balloon inside the uterus in an office setting. I'm just saying, ouch.

I know. Ouch, I agree. I agree.

So, there's a bunch of different ways to sort out adhesions inside the uterus. I'd love to see a good surgical study being done in fertility and sterility. I'd love to see something that kind of questions our current way of doing things in the U.S. I think this is just another tool that we have to be able to talk to patients about.

We're really worried about adhesions. Maybe a slightly longer dwell time in that balloon may be beneficial for you. And I think this study tells us that it seems to be safe, does not increase complications with longer dwell time, but not enough data to suggest that it actually makes a big difference in clinical pregnancy rates subsequently.

But again, the study was not powered for that endpoint. Okay, Eve, what do you guys do for balloons? I take a similar approach to you, Pietro. I cannot believe that these patients could tolerate eight weeks.

I mean, so there was only nine total patients that were omitted from the per-protocol analysis because of any kind of protocol deviation, which included not being able to tolerate the full eight weeks. So it's just shocking to me. I've never seen that before.

In fact, I have many patients that can't tolerate one or two weeks. Yeah, I was going to say, usually around three to four days, you get the phone call of pain and we bring them in for balloon catheter removal. So I don't know if maybe they're using a smaller stent.

I don't know. I was astounded when I read this. I'll tell you a little bit more about how I choose my balloon.

So for my balloons where I'm worried about the cavity internally, I use a French pediatric balloon, really thin tail, really short tail, sticks and stays in the vagina nicely. For cavities where I'm worried about the lower uterine segment or the cervix, I want to use a larger 14, 16, 18 French adult balloon just because of the diameter to occupy that space is significantly better. And then Eve, I'll turn you on to this final idea.

Have the patients remove the balloon at home. I didn't used to do it, but for the last year and a half, I've been doing it. You send them home with a 10cc syringe.

You show them how to do it in the PACU. Saves a whole trip into the office to have them do it. It's really patient friendly.

I've never had a patient mess it up and we've done it hundreds of times over the last two and a half years. And it's really slick. Yeah, that's a great idea.

I think it may also give them that feeling of an element of control that if the pain gets really unbearable, they can self-manage. Yeah, totally. Well, guys, this was a lot of progesterone talk, a little bit of surgical talk at the end, and finally some really great methodological talk in the middle.

I know we wish we had Kurt and Micah here. They would have had a lot of color to the methodology discussion. We miss them, but we'll know they'll be back here next month.

That's all the time we have for today. We have so much good content to encourage everyone to check out this article online and we'll see you next time in the month of August. 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 in 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.