Welcome to Fertility and Sterility On Air, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussions with authors and other special features. FNS On Air is brought to you by the Fertility and Sterility family of journals, in conjunction with the American Society for Reproductive Medicine, and is hosted by Dr. Kurt Barnhart, Editor-in-Chief, Dr. Eve Feinberg, Editorial Editor, Dr. Micah Hill, Media Editor, Dr. Pietro Bortoletto, Interactive Associate-in-Chief, and Associate Editor, Dr. Kate Devine.
All right, hello everyone, and welcome back to another edition of Fertility and Sterility On Air. This is the March, 2026 episode, volume 125, number three, and I'm joined today by Kurt Barnhart and Kate Devine. Good afternoon, Eve.
This is a rare occasion for us to be recording in the afternoon. Yeah, well, I took the- If they're listening to the podcast, they'll know the difference. I don't know.
Maybe we'll sound more awake. But I appreciate your flexibility as I was flying home from the Super Bowl yesterday, so I missed our usual crack of dawn recording time for my flight. So for those of you who are Patriots fans, that was a rough game, and congrats to the Seahawks fans.
And I will say that my favorite part was the halftime show, which was absolutely magnificent to see in person. I was wondering what it must have been like in person. It was still good live entertainment? It was.
I mean, you saw everything around the edges before it came on, so we were kind of clued in that it was a real wedding by seeing the bride and groom and the bridal party, and you could see everything on the edges. But all of the celebrities were hiding in the bushes. So the only way that we really knew who was there was looking up on the big screen in the stadium where we could see what you guys were seeing on TV.
But it was fantastic. Awesome. Well, all I'd say about the Super Bowl coming from Philadelphia is, go birds.
Wrong birds, but go birds. Yeah, it was great. So I'm going to dive right in.
I have this month's seminal contribution, and the title of this is The Impact of Physical Activity and Stress on Frozen Embryo Transfer Cycles, the Step in Stress Tracking to Estimate Pregnancy Trial, or the SSTEP. And this is by Emily Jacobs with senior author Brad Van Voorhees from the University of Iowa. The study aimed to determine whether objectively measured physical activity and stress levels influence pregnancy outcome in women undergoing programmed FET cycles.
I really like this study. It was a prospective observational cohort. They started enrolling in June of 2022, continued through February of 2024.
They used the Fitbit Charge 5 wearable activity tracker, and the Fitbit provides continuous objective measurement of real-time physical activity and physiologic data. They had 96 women that they enrolled in the study, with 82 included in the final analysis. Women who were under 35 were eligible for inclusion if they were transferring a single untested blast, and women over 35 were eligible for inclusion if they were transferring a single euploid blast.
And that's because the implantation rate at the University of Iowa is the same for those two groups. All participants began to wear a Fitbit within seven days of starting oral estradiol. They were asked to wear the Fitbit continuously and only remove it for swimming, bathing, or charging.
And then each participant wore the Fitbit until conclusion of their cycle, and they defined cycle conclusion as either positive or negative beta HCG blood test. And then they ended data collection the day prior to that blood test. Patients were not given any restrictions whatsoever during the study period for either exercise or for sexual activity.
So the data collected included daily step count, daily activity zone minutes, calories burned, average heart rate, total minutes of sleep, and then total minutes spent in light, deep, and REM sleep. So the participants wore their Fitbit continuously, except for those categories above. And then to be eligible for inclusion, participants had to wear the device for at least 70% of the study period.
And they analyzed the activity across three separate windows, the entire cycle, and then pre-transfer, and then post-transfer. With regard to the measurements of stress, the authors measured stress in three different ways. So first, they measured perceived stress, and they asked patients to complete the fertility problem inventory within seven days of initial E2 administration.
And the FPI is a multi-domain measure specific to perceived infertility-related stress. Second, they measured physiologic stress, and they used salivary cortisol at three different time points, upon awakening, 30 minutes after awakening, and then again at bedtime. And they collected these two days before embryo transfer.
And then finally, they measured what they called the cortisol awakening response, which is calculating by subtracting the waking AM cortisol from the cortisol levels that are measured 30 minutes after awakening to look at that delta. With regard to sexual activity, participants tracked sexual activity, and they categorized it as penetrative with semen, penetrative without semen, and then non-penetrative, to specifically evaluate whether seminal fluid exposure influences implantation, as there are several studies in the literature that have shown an association. So what did they actually look at? The primary outcome was pregnancy, and they defined that as positive serum HCG after FET.
And then secondary outcomes, they looked at things like differences in step counts, activity intensity, calories burned, sleep, FPI stress, cortisol, sexual activity, and they compared this between pregnant and non-pregnant groups. And again, keeping in mind that HCG versus negative HCG. What did they find? I think this is sort of where the meat of the interest is.
First, there were no significant differences in physical activity before or after transfer between pregnant versus non-pregnant groups. And what I thought was most interesting was pregnant patients showed a slight increase in steps post-transfer, whereas non-pregnant patients showed a decrease. So it was statistically significant, but it was a very small effect.
There were no differences in cortisol levels or perceived stress between these two groups, which I think, again, is a really nice thing to have measured, and a really nice data point that we can use in counseling. And finally, and albeit these groups were a lot smaller, they noticed that sexual activity patterns were not associated with pregnancy outcomes. So my take-home points are kind of as follows.
First, I think the author should really be commended for this very nicely done small study. It was adequately powered to answer some of these questions about movement and sexual activity during FETs. Personally, I'd like to see future work published examining outcomes after the pregnancy test, including early pregnancy loss, ongoing pregnancy rates, and live birth rates.
And my hope is that these types of studies can be continued. And Kate and Kurt, I'm curious on each of your practice patterns. Do you restrict exercise FET preps? Do you restrict after embryo transfer? I generally don't restrict exercise during FETs.
I do restrict sexual activity for patients who are doing natural cycles in the setting of PGTM, as I want to be sure that the pregnancy results are from the unaffected embryo that we transfer and not from conception that happens without medical assistance. So I want to open it up for discussion, but I really liked this paper. That was a nice summary.
Thank you very much. I think it's practical information, relatively well done. I always wish papers followed people a little longer than just the surrogate outcomes you mentioned, but we'll get there eventually.
Recommending abstinence is a tough one, but I agree if there's a chance of pregnancy other than what we're doing, that's when we tend to restrict it. Not that that's a bad thing, but it can certainly complicate the results, especially if you're talking about genetic testing and things. Yeah, I agree with you 100% that it's a reassuring paper, most helpful for counseling.
These are questions that our patients ask us about all the time, and the data are relatively limited. They looked at a number of different parameters. I agree that following the outcomes longer would have been a nice to have, and obviously our patients also worry about how their physiologic stress may impact miscarriage, similarly exercise and their sexual activity.
We can't give them definitive information based on this here. That said, it's in keeping with what we've seen in terms of early mobilization after embryo transfer. It's just nice to be able to say even more strongly to our patients, don't stress about your stress, because at the end of the day, there's not that much you can do to modulate it and the data don't really definitively show that it's going to hurt you.
I'm going to definitely talk about this with my patients, especially those undergoing FBT. Yeah, and I'll say I really appreciate that they did both self-perceived validated scale on stress, and they also married that up with actual physiologic data. I know there's a lot of talk about stress and infertility and stress and pregnancy outcomes, and I certainly don't want to overreach these findings to say that stress measured on one day at one point in time that didn't show differences totally negates the idea that stress impacts likelihood of success, but I think these are reassuring findings.
And I think one other thing that this paper, I think, should lead us to do is to really take with a grain of salt a lot of the claims made by some of the wearable technologies that are out there and that will be continuing to be peddled to us and our patients as ways to help them become pregnant more efficiently that really show me the data. Just because their HRV happens to be favorable, we can't take that leap that that's going to get them a baby. So our patients spend enough money on this without necessarily feeling like if they don't go that extra mile, they're doing themselves a disservice.
The problem is that data is so intuitive that it's hard not to follow, but it's never really been linked to change and success. Yeah, I was going to say those extra 2,500 steps that you get in that extra mile. And then changing your behavior for one cycle doesn't negate years of what might or might not have been wrong in the first place.
Exactly. So I think you can take these with a really nice grain of salt and say that we probably don't need to restrict activity excessively. I'm not sure I'm going to tell people to walk more steps to achieve a pregnancy, but I think overall just a really nice study.
In shifting gears, Kurt, we're going to talk about obesity. So the title of your study is Male Obesity Impairs Early Embryonic Development and Increases Miscarriage Risk in Oocyte Donation Cycle. So I think this is fascinating.
I'm going to let you take it from here. This is a nice paper, a nice international collaboration out of Barcelona and in Belgium, Dr. Quintana Vey in Spain and Mina Popovich. So good, good group.
Let's dive right into it a little bit here. So overview, the question is, how much does male obesity really matter in IVF? So if you completely control for the egg quality, does the man's body weight still affect embryo development and pregnancy outcomes? So that's the underlying question here. It really was trying to use oocyte donation as a key, as a proxy to take away the egg factor so we could kind of isolate the male factor.
This was done on women with egg donors, 18 to 35, normal ovarian reserve and similar BMI across the two groups. It analyzed almost 4,000 oocyte donation ICSI cycles, including approximately 7,800 embryos across two big IVF centers. So now it's a European study, so a lot of the outcomes are time lapse.
So we'll get into that a little bit and we can have a discussion on whether we think those are relevant outcomes, but time lapse was looked at as well. We basically looked at normal weight versus obesity for basically 699 normal weight, compared that to obesity. So let's get right into the definitions here.
So in a sense, this is a cohort study. So let's go through some of the specifics. While there was a change in miscarriage, there was a change in about 9.5% in normal weight men, around 9.6% in overweight men, and a miscarriage rate in 13.5% in obese men.
Now I recognize, I get exercised about this, that this is improper English. The miscarriage wasn't in the men, obviously it was in the women, but what you're doing is stratifying it by the group of men who inseminated the oocytes. I always hate that thing about IVF women or ICSI men, that's improper use of the words.
So I'm sorry I slipped into that. Now, if you look at that, looking at characterizing it across the two groups, you get about a 67% increase odds race of miscarriage for obese versus normal weight men, odds ratio 1.67, and it was statistically significant. Now the live birth, which is also important, tended to be different, but not statistically significant.
The live birth was 46, 43, and 36. So they're not saying that it affects live birth, they're saying it affects miscarriage. That might be a statistical power thing, because obviously, as you know, we all know they're related.
So the question would be, what do you think this means in terms of a mechanism? And there is a reasonably good discussion about the mechanisms. Let me tell you a little bit more about what they found before I get into the mechanism. So they first wanted to look at embryo development, and that's where I said they used time lapse.
So they basically said they did see some delay in time lapse. I'll mention it because they say statistically they saw differences in the T2, T3, T4, T5 in the cleavage of the embryos. But again, no one has taken that step to say that that is a mechanism to live birth or miscarriage, but it is something that they noted.
But overall, the blastocysts end up to be relatively normal, 65% in normal weight and 64% in overweight. And they also suggested that looking at it, the embryos in close with the microscope, that the odds of good quality were about 20% lower embryos derived from obese men, and that just reached statistically significant. So they're talking about some developmental differences, although fertilization was the same.
And then we talk about these slight differences in miscarriages and with the same live birth rate. So the take-home messages would like to say that male obesity is associated with miscarriage, but I would be cautious about that. Let's not go a little bit too far into this.
But it does try to bring up isolating some of the findings about what it could be. Now, it is a large sample size, it is isolating the paternal contribution, it is high-resolution embryo assessment, the statistics are okay, but it is also retrospective design, it is a relatively healthy population. And interestingly, the donor egg may blunt some of the facts.
If you're really an advocate that you think it's real, the word they used was fragile eggs from somebody else, as opposed to a donor egg, the effect actually might be magnified. That's a speculation, I don't know if that's true. And the mechanism is clearly inferred, as opposed to understanding what the mechanism was.
You guys have any clues on what the mechanisms might be? They see it, there's a lot of handwaving, it's like, you know, it's an in vitro effect. So it's a non-genomic effect, they say, which is altered sperm RNA, maybe, or proteins influencing early cleavage, but that's not known, that's speculation. And they said there might be a later genomic effect or epigenomic effects, you know, as translated through DNA fragmentation or chromatin abnormalities contributing to miscarriage.
Again, that's a leap. So we don't know what it is. So I like this study because it's really kind of hypothesis generating.
I like it that they isolated the egg factor as best they could. And what they're finding is very subtle differences in the embryo, but the same number of embryos. And I'm going to just say clearly, a very subtle difference in the miscarriage.
I don't think this is really a clear demonstration of a lower miscarriage rate with, again, the same live birth rate. Great area to study. That's probably why I got into the journal, but I don't think I would counsel everybody just yet that male obesity is the cause of your miscarriage.
Recommending good health for everybody, both partners, is always a good idea. But I'm not ready to make the New York Times headline that, you know, all male partners have to lose weight before conception and take more steps. And take more steps.
Yeah, I totally agree with you. And I think that there is this healthy donor assumption. And when you have so many centers around all of Spain, I think it's a very blanket statement saying that the donor egg is presumably healthy.
And while there are potentially BMI limits on egg donors, I think that that varies widely among programs too. And so that was my biggest question about this study was, can we really say that by using a healthy donor egg that we're using a donor egg from somebody that's not overweight? And maybe there's, maybe the donors are not obese, but I'm not certain that I can say that it's 100% the male contribution from this. Well, again, it's just a way of trying to isolate it.
No, it's really hard to get fully. But I think the finding here is they're trying to say there is some basic science research that says, at least in animals, some of my friends here at Penn have said, you know, obese animals have an effect on spermatogenesis. So does it, does it have an effect clinically? If we think about when the embryonic genome activates, right? So in the first three days of development, we think that it's really more driven by the oocyte.
And then you have the embryonic genome that activates around day three and drives that embryo from day three to day five. The time points that they're looking at that they're attributing to male infertility don't seem to be consistent with that. Yeah.
And I would say the same can be, you know, said, and we should worry about potential unmeasured confounding variables as well. When we look at the clinical outcomes and the high correlation that they found between obesity in the male partner and the recipient. And they did a nice adjusted analysis for all of their outcomes that they evaluated.
That said, even though they adjusted for the BMI of the recipient, we can't say that other health factors that are correlated with high BMI in both the sperm source and the recipient would not necessarily impact the risk for miscarriage. So I took from it what you did, Kurt, that I would not put weight on male BMI and miscarriage risk. No pun intended.
I've said this before in a podcast, Micah likes it. This paper is not definitive and shouldn't make headlines, but it does need to let flow over you about the idea that, you know, this is something we should look at. And it's one of the few papers I've seen clinical outcomes isolated well.
So good talk. Yeah. Look, I agree.
Don't start blaming everybody yet. And I think like the onus is upon all of us. And actually, I think the onus is probably more upon the OBGYNs and the primary care physicians to really optimize health and counsel patients on health optimization preconception.
And so I think that, you know, I think we're starting to pay more attention to this as a nation. I think we're starting to the pendulum may start to be swinging back with the use of GLP ones. But I think if anything, it's just more of a more data to show that health contributes health of the gametes of the parents from where the gametes arise contributes to the health of the baby that's born.
There's a lot more that we can and should be doing. But I agree. Like, even though the methodology wasn't exactly what I would have loved to see, I think that the idea of preconception health is is really important.
And it's something else that we often by the time they come to see us, it's it's hard to peel that back because of the impact of age and the time frame that we're all under. But I think it is definitely part of the equation and we can't ignore it. So I'm going to go a little bit out of order only because we have another paper that I'm going to take that talks about more than just BMI.
And this paper uses the triglyceride glucose body mass index or the Taiji BMI. And this also looks at the risk of miscarriage, although in women undergoing in vitro fertilization and embryo transfer. And this is a study that was done by Ziyi Song and others from the People's Republic of China.
So the objective of this study was to explore the effects of triglyceride, fasting glucose and BMI on pregnancy outcome, especially miscarriage after IVF and embryo transfer. And this was a retrospective study from January of 2019 to December 2023 that included clinical data from over 17,000 women ages 18 to 40 undergoing IVF cycles, including fresh and subsequent FET cycles across three reproductive medicine centers in China. The main exposure was Taiji BMI.
Admittedly, I was not familiar with this, so I had to look it up. And this is a metabolic index that combines insulin resistance and adiposity into one number. So it's calculated by taking the natural log of fasting triglycerides multiplied by fasting glucose divided by two times BMI.
So for patients that are overweight but maybe have a healthier profile, their number is going to be different than patients that are metabolically unhealthy who have a low BMI. And then certainly the patients who are metabolically unhealthy and have a high BMI are going to fall into the highest index. And so what this number does is it drills down metabolic risk, looking at these very pertinent risk factors on top of BMI and incorporating BMI into a single number.
And this has been shown to have predictive value for cardiometabolic diseases. And it's used in the literature in diabetes and cardiovascular disorders quite frequently. This Taiji BMI is associated with oxidative stress, inflammatory responses and endothelial dysfunction.
And there's been some data showing vascular modeling and formation of new vascular networks or well-established physiological processes that are very important for embryo implantation and placental development. And as we know, disruptions in these processes are thought to be pathophysiological mechanisms that underlie adverse pregnancy outcomes. Correlating that, high metabolic indexes are thought to alter those vascular modeling pathways.
And so I think that that pathophysiology of how elevated Taiji BMI may affect early pregnancy is actually quite interesting. So what the authors did was they categorized patients into quartiles based on baseline Taiji BMI measured at one point before IVF start. Patients underwent ovarian stimulation with standard clinical protocols.
They underwent IVF or ICSI based on semen parameters. And then fresh embryo transfer was performed with one or two embryos based on physician judgment and clinical parameters of the embryos. FET cycles were done using natural ovulation induction or programmed cycles.
And the primary outcome was cumulative live birth rate for one egg retrieval across all fresh and subsequent FET cycles. Secondary outcomes were biochemical pregnancy rate, clinical pregnancy rate, miscarriage rate and live birth rate. And then patients were categorized into four groups on the basis of the quartiles of their Taiji BMI scores.
So they did some statistics. They looked at univariate and multivariate logistic regression. They were hoping to assess the differences in pregnancy outcome among the four groups.
And they adjusted the models for age, endometrial thickness, antral follicle counts, underlying diagnosis. And they used the lowest quartile group as the reference population. They did a restricted cubic spline to capture the dose effect connection with Taiji BMI and cumulative live birth rate.
And then they came up with this basic model for cumulative live birth rate prediction that they constructed in the effects of incorporating BMI and Taiji BMI on the model's predictive ability. And they were compared. They used some ROC curves to look at the prediction strength.
The median female age across all quartiles was 33. And patients in the highest Taiji BMI group had a longer duration of infertility and a higher proportion of secondary infertility. So what they saw was that in the fresh ET cycles, there were no significant differences in biochemical pregnancy rate, clinical pregnancy rate and live birth rate among the four quartiles.
But the miscarriage rate varied from 14 percent in quartile one to 19 percent in quartile four. So not a huge difference, but definitely moving the needle upwards on that. In frozen embryo transfer cycles, Taiji BMI was associated with higher miscarriage rates and 14 percent in quartile one to almost 23 percent in quartile four.
And along with that, lower live birth rates. The cumulative live birth rate in quartile four was 49 percent and significantly lower than in quartile one, which was 55 percent. So I really liked figure one where you can look at all of the multivariate analyses and the cubic spline results and the cubic spline really nicely shows this linearity of increasing Taiji BMI with a lower cumulative live birth rate.
You can see the slope of that line moving downward as you start to get into the higher Taiji BMI scores. So not surprisingly, female age and diminished ovarian reserve are consistently identifies it as adverse factors affecting pregnancy outcomes. So I think overall, it's a nice study.
I do think relative to our last discussion, it incrementally moves the needle beyond just thinking about body weight and miscarriage. This is the first study I've personally come across in our fields that uses Taiji BMI for risk stratification in this way. And I think from a biologic plausibility standpoint, the study intuitively makes a lot of sense.
When you have more inflammation and vascular endothelial cell dysfunction, that may alter your placental function, which may lead to poor perfusion and miscarriage rate. So I think the study is not without limitations. There's no PGT for aneuploidy that likely accounts for many of the adverse outcomes in older patients.
But I do think, you know, letting the data flow over us and really gaining a deeper understanding on what are some of the physiologic mechanisms. To me, I really liked this, that it goes beyond BMI and it looks at metabolic health. Kate, Kurt, what do you think? I thought that this was a really interesting paper.
I think we're going to be seeing more and more of these papers trying to establish the association or lack thereof between various metabolic markers that are now well validated in other medical spaces. I have seen Taiji BMI come up in some of the papers I've been asked to review and similarly had to do my deep dive of self-education on it. But, you know, there's an article in the New York Times today, you know, what does it mean to have poor metabolic health? And I think that this is something our papers are going to be asking us about more and more.
So these authors are to be commended for looking at this in a large population and as fairly early adopters of this technology. That said, you know, I think it doesn't answer the question, is it worth it for us to have all of our patients going through fertility treatment, go the extra step and not just do BMI, but do fasting blood work and have this marker evaluated for them? I think the ROC curves that they showed and the differentiation between BMI alone and Taiji BMI, I think is not totally definitive in this paper in terms of a huge added benefit. And then go the extra step.
And this is a population with an overall BMI of 22 in China. So maybe not really representative of the patients that we are most usually taking care of and maybe not representative of the patients that we have the most concerns about in terms of their metabolic health and how it how it might impact their fertility treatment outcomes. Yeah, I'll just say this because every research study is the same, right? You have to have an exposure and you have to have an outcome.
And this is intuitive. But, you know, when you start reading these papers, we don't yet know what the best metabolic exposure is. So while this is clever and it rings some bells in your brain, whenever we read these papers or write them or review them, you know, we really have to get some more maturity in the field to understand what's what's the right exposure before you can really make definitive conclusions on that.
It's related to miscarriage or not. Yeah, for sure. I'm just saying just we just we just have to have a high bar to understand it and just don't let it flow over you.
But don't accept everything as truth. Yeah, I totally agree. And maybe we're completely off the mark and we should be looking at apolipoprotein B or maybe we should be looking at other markers, fasting insulin or insulin levels.
Like, I think that there's a lot that we don't know about metabolic health. And I think that right now our field is ripe with opportunities to learn more. And I think that as we are recognizing the importance of metabolic health in many other areas, I think it's natural that it's going to have an influence on fertility.
So I think more to come on this, but I really I really enjoyed reading this. Kate, we're going to transition to you and we're going to talk about triggers, which is actually one of my favorite topics to talk about. So I'm going to let you take it from here.
But the title of this next paper is Dual Trigger versus GnRH Agonist Trigger for Elective Fertility Preservation, a Randomized Control Trial. Yeah, thanks. I really like this paper, too, as a trigger lover myself.
This is a randomized control trial, as stated in the title, and it is by first author Dunno out of a group from Spain, Belgium and Portugal, senior author Nick Palazos. So basically what this RCT evaluated was to see what the number of M2 oocytes retrieved in 109 patients undergoing elective egg freezing would do if the patients were randomized on the day of trigger to either a GnRH agonist trigger or a dual trigger with GnRH agonist plus, in this case, Avidryl. So Avidryl is the HCG source.
All patients were, as I said, randomized on the day of trigger, which was uniformly undertaken when they had three follicles of 18 millimeters or more. So they give a very nice background as to sort of the recent history of trends in triggering, especially in protocols where we have options. So those being, you know, progestin pituitary suppression, which is what was used in this trial, or a GnRH antagonist protocol.
Obviously, we're stuck with HCG trigger in agonist protocols. And so what they found in this study, and it's a relatively small study, again, 109 patients, which was likely appropriate given that they were powering their study to number of M2s. Interestingly, they also designed their sample size calculation based on a superiority design because their hypothesis was that HCG plus GnRH agonist would be superior in terms of the number of metaphase 2 oocytes.
I'm not sure that I would have necessarily made that choice. That said, in the end, given where the results fell, probably did not negatively impact the validity of the data. And so all of the patients in the study, again, used a progestin to induce pituitary suppression and they had a moderate dose of REC FSH only.
So again, just to note, slight departures from the way that we typically practice in the U.S. with mixed protocols. And it was a moderate dose of either folitropin alpha or folitropin beta or folitropin delta, so RECAvel, which is not yet approved in the United States. And what they found was that there were no statistically significant difference in any of the outcomes that they looked at.
They found that in both groups, and these were all patients that were predicted to be normal responders, so nobody with an FSH greater than 20 or an AMH greater than 3, so trying to go right down the middle there, was permitted to participate. And they found that the number of oocytes was 9.2 in the dual-trigger group and 9.6 in the antagonist-only group. They didn't find any difference in the total number of eggs nor in any of the hormonal parameters that they looked at during or following the stimulation on the day after the retrieval.
They also did not find any differences in the rate of OHSS, which was quite reassuringly zero in both groups. And so I think this is a nice study. And when I first read the title, I thought, well, that's not really what I care about.
What I really care about is, does it make a difference if you add antagonist, or rather, if you add agonist to HCG in these patients that are poor responders? And while there are randomized controlled trials on this question now, I would say we could use more data in that space. But as I read through this paper and saw that it was a paper that was specifically limited to patients that were undergoing elective egg freezing and were normal responders, I actually find this to be quite helpful, this data. And in general, I would feel comfortable using an agonist trigger in these patients anyway, and that's what I usually do.
But it's nice to have randomized controlled trial data in a well-designed study to corroborate that decision. And even though there were no cases of OHSS in this study, it was a relatively small study, and they were not powered to assess that outcome. So I would say, when in doubt, leave it out if it induces risk and does not provide any additional benefit for our patients.
I would direct the reader as well to a nice reflection that's by Messinger et al., which kind of takes what is a little bit of a detour from this particular finding. And they say that really what we should be looking at now when we are assessing studies where the distal outcome is eggs is not maturity, but what they would say are other markers of OSITE competence. And here they are suggesting AI-driven OSITE scores.
So I think reasonable people can definitely disagree about the degree of validation. And I know it's something that we were discussing even just yesterday in our editorial meeting as to whether, you know, AI outcome should be considered an outcome or rather a diagnostic test, or rather maybe even something that we still need to validate further. That said, I think Messinger et al.
are right in that really what we care about for these patients is the functional performance of these eggs. So knowing that they are mature and that, you know, in terms of the quantity of mature eggs, we didn't see a difference here. We can't assume based on that outcome that these eggs will perform equivalently well with an agonist trigger versus a dual trigger.
So, you know, I have high hopes for the eggs, but it's just one question that's not answered by this paper. What did you guys think? And will this change the way you practice at all? Yeah, I will say I rarely do both. I'm a big fan in a planned OC cycle for a loop on a lone trigger.
And I think the question that I would have liked asked and answered is, does 1K of HCG add anything to the mix? Because I think it's much more common that people use a 1K boost of HCG or a 2500 boost of HCG than doing a complete double trigger. So I personally would also really like to see the end result of what happens with those eggs. But in my brain, I'm not convinced that there's benefit of adding HCG when it comes time for embryo development.
I wish we knew. This is kind of an incremental step. And because it kind of didn't show dramatic findings, it shows that either or is okay.
But it's an incremental step. It's still a surrogate marker. We still don't have a definitive answer.
It's reassuring that as we make these steps, our logic is sound. It just doesn't definitively give you the answer yet. Well, I'm going to go ahead and just roll into the next paper then.
This was a really, really nice research letter. And it is by Mandrukov et al. This was a group that are based out of Canada.
They conducted a retrospective cohort study with transfer of 82 abnormal embryos based on Illumina NGS. Neither the patient nor the provider knew the ploidy status of the embryos at the time of transfer. So somewhat dissimilar to some of the—and Kurt, I know, nails on a chalkboard to use this term—but what have been referred to as non-selection studies in our field, these diagnostic accuracy studies where the data were collected prospectively, these were patients that underwent transfer of an embryo whereby the NGS results ultimately became known but were not known at the time of the transfer.
And so either because the patients changed their mind about wanting the testing done or something of that nature. They had 82 embryos that ultimately they learned were abnormal that were transferred blindly. What they found in this study is that there were 70 whole chromosome abnormality embryos that were transferred.
And by the way, they did not look at mosaics. All of these were results that were non-mosaic in the ploidies. And there were 12 embryos that had segmental abnormalities.
What they found—and this is a nice addition to the literature, I think—was that there were no live births resulting from any of the embryos that were transferred with whole chromosome abnormalities. So of all 70 embryos, none of them made a baby. There were miscarriages among them.
So somewhere in the range of about 20% or exactly 20% of those embryos did implant, but all of them resulted either in biochemical losses or clinical pregnancy losses. A subset of those pregnancies did undergo testing of the products of conception and also reassuring 100% of the results from the products of conception were concordant with the results of the NGS. So again, the reason that this is, you know, for those of us who like all to be right with the world like this finding is it's yet another example of 100% positive predictive value of whole chromosome aneuploidy results on NGS.
So right there in line with TEEVS and some of the other studies that we've looked at. In terms of the segmentals, the findings were different. So three live births out of the 12 segmental transfers occurred.
The rest of those were either not pregnant or miscarried. Only one of them actually was a miscarriage, and that miscarriage did not have products of conception associated with it. So small study, I think very appropriate and really perfect for a research letter, and corroborate the data that are out there that essentially whole chromosome aneuploidy non-Mosaic is a pretty reliable finding for predicting not having a live birth after an embryo transfer, whereas segmentals are a very different entity.
So now there are multiple studies in the literature that tend to accord in their finding of somewhere in the approximately 25% chance of a baby. So not from the faint of heart, and I certainly encourage more research in this area. But, you know, I think most of our centers are now considering, if not already, transferring these segmental embryos.
And if we're not, I sure hope we're not counseling patients to discard them. So I'm interested to hear what you're doing at your centers, what you thought of this paper, Curt and Eve. I like the paper for all the reasons you said.
I don't want to make too much of the findings as it is kind of a little bit of a backwards design, you know, the sample of convenience, but it does add to the literature about the negative predictive value, which is important for us to get out there. So I'm pleased that sometimes a non-methodologically rigorous study still got really valuable information like this one does. I think as a field, we've got in trouble with all genetic abnormalities are wrong, and it's taking us a while to figure out what they actually mean, you know, and we're getting closer.
I totally agree. We are not yet transferring segmental aneuploidies. I wish we would, we're just not there yet.
And I think that there are, there have been more reports of ongoing aneuploidy in some of those patients compared to the data on mosaics, which is where I think our genetics team is giving pause and waiting for more data to emerge before we start transferring those embryos. But I think that's kind of the next frontier, similar to mosaic embryos, that it may be not so much an error in mitosis or meiosis. It may actually be an interpretation of the bioinformatics of the platform that's interpreting the data that because so many of those segmental aneuploidies are actually turning out to be ongoing healthy pregnancies, that they're probably not representing a true biologic dysfunction.
But I think we at our center are just taking a little bit more of a conservative approach for right now. This is a call to action for everyone who's transferring them to please report outcomes and share with the greater community so that we can all learn more. But in the interim, I'm telling patients that currently in 2026, they're not eligible for transfer, but we are keeping a close eye on where the data goes.
Obviously, consent and counseling matters. So I don't think we have a standing policy one way or the other. You just have to have a really long conversation with your patients on what are your options and what risks are you willing to accept? Yeah, amen.
And I think that's true for everything. This discussion has flown by so fast. We have one final manuscript to talk about.
Kurt, I'm going to put you in the hot seat because I believe you were one of the authors in this Top 10 Priorities for Future Ectopic Pregnancy Research and International Consensus Development Study. And so not only did you have the pleasure of participating in the research itself, but now I'm going to ask you to present it to us. Sure.
This is an easy study to listen to. For those of you who can zone out while you're driving or whatever, this doesn't have a lot of numbers in it, but I think it's a study we should all talk about. The title of the paper is aptly called the Top 10 Priorities for Future Ectopic Pregnancy Research and International Consensus Development Study.
Had a lot of wonderful authors on it. Tara Ajith is the primary author, and one of our associate editors, Ben Moe, is the senior author. It is an international consensus that sought to redefine the research agenda in ectopic pregnancy by systematically identifying the most important unanswered research questions.
We used something called the James Lind Alliance, which is an endorsed methods that are well referenced and used before. It's an advancement of some of the other kind of Delphi consensus methods. What happens is that the group of authors, and I wasn't the primary group, but the group of authors engaged a large group of healthcare professionals, researchers, and critically people with lived experience of ectopic pregnancy as the participants, and then they asked questions and narrowed them down.
Briefly, it's 855 participants were online, and they were sent a lot more than that, just whoever chose to answer, but it encompassed 35 countries and got over 1,200 research uncertainties. So that was the first survey, just tell me what you think is an important task. Then that evidence was checked against Cochrane Guidelines and narrowed down to around 49, resurveyed by some other people, this time about 413 people, and then narrowed it down to a final consensus of number of priorities.
And then in an in-person meeting, we had 37 participants at an ESRI meeting, again, representing 10 countries, and we ranked these priorities by consensus. So it is rigorous methods as consensus meetings go, but this is a consensus meeting. The goal is to try to get a broad scope, the proverbial wide net, and not just have the same people doing research in it coming up with the same priorities.
And we did ask patients, and there were a number of patients. So what are the 10 top priorities? I think the whole group decided, we know about ectopic pregnancy now, we've done a lot about how you diagnose it, we've done a lot about how you treat it. This was more about where do you go from here, which is why I like the first one, which is, what's the minimum standard of care people with ectopic pregnancy should expect? Now, this is clearly an international issue, because it really varies on whether you go to Penn and get rigorous follow-up, or whether you go to Africa or in Asia.
And it really is very different. It's not just when you give methotrexate, but when a patient's experience can be chaotic, it's nice to get a minimal standard as the number one research priority. Number two, what are the future fertility, pregnancy, and childbirth outcomes after ectopic pregnancy? And I voted for this one high too, because it's no longer, did you just succeed in not having a patient rupture, and actually, is your tube open? It's what happens later? Is she able to undergo fertility treatment successfully? Does she need fertility treatment? Is there a difference in live birth? Is there a difference in childhood outcomes? So that clearly are unanswered questions.
Number three was more from the healthcare professional education point of view. Are we systematically teaching this along the way to everybody? Is it only REI? Should it be OBGYNs? Can family practice be able to handle this? And do patients understand? Then we get a little bit picky, can a prediction tool be developed to determine ectopic pregnancy risk and outcomes? I've managed to do a couple of research on some of these. I'm always not pleased with how good predictions are, but everybody likes the idea of prediction.
Maybe AI can help with prediction, but we put in that clearly, you can't have a one and done. You need validation of your prediction rules. It just can't be, I found a new molecule that's associated, or I found a new way of doing it.
Then we got into specific populations. So should routine testing of tubal patency and function be offered after a tubal or interstitial pregnancy? These are very specific questions. Not everybody gets an HSG or a saline ultrasound to see if the tubes are open and not after every kind of treatment.
So this was more of a, again, a health systems, if you have an ectopic pregnancy, is this a mandated or expected routine test? These are not in order. So I'm sorry, I'm jumping around. Number six goes to psychological impact of ectopic pregnancy and how can it be addressed? And of course, that's really important.
And it spans not only from the support that's needed in the time of the pregnancy, but actually after the pregnancy. I've underestimated in my practice, the risk of a miscarriage, I'm sorry, the impact of a miscarriage on my patients. It's taken me really years to understand that that can really be impactful.
And I think an ectopic pregnancy can be as well, and that's understudy. Finally, we could not talk about the effectiveness and safety treatments for non-common ectopic pregnancies. We still don't really have consensus on how to treat cervical or cesarean scar or ovarian or interstitial pregnancies.
I think that was the most obvious one, but it's still important. And then the last two are really kind of health screening problems. In other words, we've noticed the increase in cesarean section ectopic pregnancies, but does that mean someone with a prior cesarean section is high risk ectopic and needs early ultrasound? It's an unanswered question.
Or what about routine early ultrasound for people that are less risk? In our practice now, pretty much everybody gets an ultrasound early, but it's a question of whether that should be standard everywhere, like in general OBGYN practices and across the countries. And then finally, cost is a new research outcome, and we're seeing more and more of that in Fertility and Sterility and in other journals. But there should be some interest on not only does the therapy work, but is it cost effective and not just cost effective in the immediate, but cost effective in the long run with everything I said about need for future screening, whether there's fertility treatments, sort of the outcomes.
So a fun exercise. And I think the take-home points, and there's a lovely reflection by Seguinat and Heather Hipp, but anyway, it's a good read. They really point out that we've turned a corner and that we're no longer just looking at the immediate outcomes of topics.
But now we have other types of research that can be applied to this topic, and we really do need authentic patient involvement in what is the right question and how does the right methodology. So bread and butter, but it was a very well done international consensus. I'm glad it got published, and I hope it is a roadmap for future studies that can be conducted, and we will republish those studies.
I really love this paper. I have to say I've been privileged to participate in a couple of these international Delphi-type projects, and I think they have a lot of benefit, but they often focus on making recommendations in the absence of evidence. And so I like the approach that this took to really identify priorities for discovery and for future research.
So that's sometimes the background of them, but then there's a lot of expert opinion, which is also very important. We have to make decisions in the absence of evidence sometimes, but to really kind of focus in on what are the unanswered questions we need to get to to give better care, I think it's just a much more focused approach. I also really liked it, and I think that what differentiates a lot of these Delphi consensus is the inclusion of patients in the priorities too.
And I have to say what's important to patients sometimes in a very good way is surprising to me. And I think that we can't ignore the patient's voice in helping to guide what those areas of focus should be. Like what's important to a patient is often like not what I'm thinking about first and foremost.
And so I really commend you guys as a group for having that patient voice to help lend some ideas as to what else to look at. My final thought was I really enjoy these patient-focused consensus documents, and it really does lead to the conclusion that you'll have patient-oriented research. But remember, as soon as you start including non-specialists in patients, you're going to get patient-oriented outcomes.
And what's missing from this is the real molecular biology or the real discovery. So I'm not saying those are not important. I'm just saying it's usually not the focus of a consensus like this.
So I think you have to have both of those research types in parallel. That's a nice way to end another podcast where we covered quite a bit. A lot of data flowed over us, very specific data and very general data.
So I hope you enjoyed this and learned a lot. Eve, why don't you take us home? Yeah, no, I'm just going to echo that sentiment and say it was a great hour spent with both of you guys and everyone on their drive or workout or whatever you do while you listen to Fertility and Sterility On Air. So great talking to you, Kurt and Kate, and we will see everyone next month.
Bye. Thank you for listeners and please communicate with us. We always like updates on what you like and don't like about it and how we can make it better.
Thanks a lot. This concludes our episode of Fertility and Sterility On Air, brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield, Dr. Adriana Wong, Dr. Elena HogenEsch, Dr. Selina Park, Dr. Carissa Pekny, and Dr. Nicholas Raja.
