Hello everyone and welcome to Fertility and Sterility Journal Club Global. We are live from the 77th annual Scientific Congress and Expo of the American Society of Reproductive Medicine in Baltimore, Maryland. I'm Micah Hill, your host, the Media Editor for Fertility and Sterility.
I'm joined by my co-host Pietro Bortoletto, our Interactive Associate in Chief. We are very excited today to highlight a series of articles that deal with optimal frozen embryo transfer, lessons learned from the Fertility and Sterility family of journals. And we are now a family of journals.
We have Fertility and Sterility, FNS Science, FNS Reviews, and FNS Reports. And we have three fantastic articles across that family of journals. I'm excited to be joined by six expert authors on this topic.
We have Kate Devine and Eric Widra from Shady Grove Fertility, Rachel Wynott and Brad Van Voorhis from the University of Iowa, Valerie Baker and Mindy Christensen from Johns Hopkins University. We'll start with about 30 minutes of the authors discussing their research and their papers, and then we will open up for interactive questions from our on-site audience in Baltimore and our virtual audience that is global. So Kate and Eric, let's start with you and your randomized clinical trial that you did on the route of progesterone administration.
Thank you so much, Micah, and thank you to FNS for inviting us to discuss this important topic today. As I think we all know, the utilization of frozen embryo transfer is massively on the rise for multiple reasons. When there is elevated progesterone, when our patients want to do PGTA, when they're at risk for hyperstimulation syndrome, and electively.
And for this reason, it's extremely important that we identify optimal ways to transfer embryos, both in order to optimize patients' chances of a successful and healthy live birth, and also to make sure that we are using patient-friendly regimens that are both easy to comply with, as well as optimize patients' quality of life as they go through fertility treatment and frozen embryo transfer protocol, which is extremely important. And for this reason, a number of years ago, we decided to try to answer the question as to whether vaginal progesterone only was equivalent in terms of live birth, or non-inferior to be precise, to progesterone in oil, so daily intramuscular progesterone injections. And so we completed the trial that we lovingly refer to as the SUSTAIN study to sustain pregnancy.
We can go to the next slide, please. And we also proceeded with a second comparison, a priori at the start of the study, where we compared combined progesterone regimen with daily intramuscular progesterone. So the reason that we did that was in our own retrospective analysis of our data internally, we had seen some suggestion that we might find inferior outcomes with vaginal progesterone only.
And so this was a three-armed, randomized, non-inferiority study where we compared both vaginal progesterone only to intramuscular progesterone, as well as combined vaginal progesterone with intramuscular progesterone every third day to daily intramuscular progesterone. And we completed this study, which was powered for a 10% non-inferiority margin, and actually at an alpha one-tailed of 0.025, as is typical for a non-inferiority study. And this is quite a busy slide.
I'm not sure. You might have to pull out your journal or pull up the paper on your computers to be able to look at it, but essentially this is our flow diagram as to the enrollment of subjects in one-to-one-to-one randomization to those three arms. We can go to the next slide.
And this slide shows the baseline patient characteristics. So in terms of our inclusion and exclusion criteria for this study, it was a broadly inclusive study. Subjects that had at least one high-quality blastocyst vitrified at SGF and planning frozen embryo transfer were eligible.
And actually back, it's almost hard to believe at this point, PGTA was an exclusion. When we started this study, we thought that we wanted to make the population uniform in that way, and the majority of our patients at that time were not doing PGTA. And so you can see here that there were very similar characteristics among patients that were randomized to each of the three arms, and that shows that the randomization was effective as we looked over these potential factors that could be considered covariates.
Next slide. So this is our main data figure from the paper. One thing that you'll note that's quite important is that the vaginal progesterone-only arm is much smaller than the other two arms.
We had planned an a priori analysis at 50 percent of the planned enrollment goal, having achieved their final study visit, using ongoing pregnancy as a proxy for live birth, which is of course our primary outcome. And what we found at that 50 percent time point was that actually they were statistically significantly inferior ongoing pregnancy rates, and we used a higher statistical threshold so as to avoid spurious conclusions of inferiority in the vaginal progesterone arm, since of course we very much wanted to be able to provide our patients with this potentially more patient-friendly option and to make sure that if we were concluding inferiority, we were certain. When we found that, those findings were published as an interim analysis, and randomization to that arm was stopped.
We did go ahead and continue randomizing patients to the other two arms, the progesterone and oil daily and the endometrin twice daily plus every third day progesterone and oil. And so importantly, you can click the mouse once, please. Our primary outcome of live birth did show highly statistically significantly lower live birth among patients receiving vaginal progesterone only, and no difference in terms of live birth between subjects who were randomized to the combined arm versus those who were randomized to the control arm, which was intramuscular progesterone daily.
And so we concluded based on this that while unfortunately vaginal progesterone only with the regimens used is inferior in terms of live birth from frozen blastocyst transfer and should not be used, there was a potentially more patient-friendly regimen that can be used and can provide equivalent live birth rates to our patients. You can click the mouse one more time, please. We went further and did look at a number of secondary endpoints, including chances of pregnancy as well as chances of miscarriage at various stages, biochemical pregnancy losses and clinical pregnancy losses.
And what we found was that while there was a statistically significant decrease in live birth rates with vaginal progesterone only, that did not account for the majority of the difference in terms of live birth. Rather, most of the difference in terms of live birth was attributable to pregnancy loss with a 50 percent overall total pregnancy loss rate in the group of patients who had received vaginal progesterone only. And so, you know, that leaves us wondering why might this be? You know, we know that there are many true believers and we probably will talk much about this later in the conversation today in vaginal progesterone as being sufficient for endometrial preparation for frozen embryo transfer.
I would postulate that systemic progesterone likely is truly required and optimal for frozen embryo transfer and there are some potential mechanisms that we can also discuss, including whether, you know, there are peripheral metabolites that are important when systemic progesterone is administered that aren't present with vaginal progesterone, whether there are differences in uterine contractility with vaginal versus intramuscular progesterone, and also whether there are changes in the lower genital tract that occur in early pregnancy that could account for this increased risk of miscarriage with vaginal progesterone only. Next slide. And so, this is the same data presented graphically.
We did go on to perform a per-protocol analysis as well as an intention to treat analysis in an attempt to make the last slide a little bit less busy. That slide just presented the intention to treat analysis. As you can see here, the results are nearly identical.
And so, I'd like to open up to my co-author, Eric Widra, for any comments he has on our findings as well, and I hope that we have a much wonderful discussion to follow. Thanks, Kate. When you do these trials, there's always surprises along the way.
And sometimes when you finish them, you go, oh, nobody asked us that in the beginning. It might have been interesting. The things that surprised me about this trial were, first of all, the dramatic difference in rates of pregnancy loss.
The other thing that surprised us, I think, was the number, because we did do some additional survey of patients, what they preferred or didn't prefer. There's a significant number of patients out there who actually prefer daily IM progesterone. It's almost a third, which for us was surprising as well.
As we started to present these data at different meetings and conferences, we also noted that there are differences between U.S. practices and practices in other parts of the world. When we presented this to colleagues from the U.K. and Europe, apparently they're not the same thing anymore. What we found is that the dosage of vaginal progesterone that they tend to use there is considerably higher than what is generally offered in the U.S., and it was in our trial.
And that's another question that can be reexamined if others kind of take up additional research in this area. Beyond that, I don't have anything else to add to Kate's great review of our trial, but look forward to your questions. And we certainly will be open to conversations about things like the choices that were made for the protocol and the pharmacokinetics and pharmacodynamics of vaginal and intramuscular progesterone and the myriad other protocols that could potentially be used.
We did look at serum progesterone concentrations at the time of pregnancy test and did find differences there among arms, which need to be considered as well. So one quick question before we go on to our next paper. I know you presented this at ASRM a few years ago as a prize paper there.
You've presented it a lot of places. I'm sure you've been asked about the asymmetric intervention with the vaginal arms starting their progesterone 12 hours later. So how do you answer that question? That is this a result of the 12-hour difference in progesterone start or the route of administration? Thanks.
That's an excellent question, Micah. So the reason that we chose to start the progesterone 12 hours later in the vaginal progesterone-containing arms was based, number one, as I already mentioned on some data that we had at our own center, that rates of pregnancy and live birth might be lower among patients that received vaginal progesterone only prior to FET. And some hypothesizing on our part and delving into the literature and finding that we know that the endometrium is quote-unquote advanced, that there are higher endometrial progesterone concentrations and histologic advancements in endometrium that's exposed to vaginal progesterone.
And so because of this concern that maybe, you know, they would be outside of their window of implantation if we started vaginal progesterone at the same time, we made the decision to start it 12 hours later. Again, of course, we'd love to do, you know, a 52-armed study where we could account for every potential variation in dose and timing and frequency. That said, that's not feasible.
And so we had to make some hard choices, as we always have to do when we're designing a study. That said, we, I don't want to say got lucky, but I can answer your question very well, Micah, which is to say that the both arms that contained vaginal progesterone were started 12 hours later, including the combined arm, which actually numerically performed better than the progesterone in oil, obviously statistically not significant. So the later start of the vaginal progesterone relative to the IM-only arm in the vaginal-only arm cannot account for the differences.
Otherwise, we would have seen the same thing in the combined arm. I also think, equally importantly, the differences are really attributable to increased pregnancy loss, not failure of implantation. And I think it's a tough argument to make that a 12-hour difference, you know, prior to transfer then results in a failure of pregnancy, you know, weeks later.
That's an excellent point. There's one other comment that, you know, we have implemented the combined arm as our primary protocol in practice. Of course, we allow patients to opt for intramuscular progesterone only if they prefer it, and some do, especially those coming back for baby number two who were successful with this protocol for baby number one or what have you.
That said, we did adjust the protocol somewhat in our clinical practice such that the intramuscular first dose is six days prior to transfer. So 100, we actually are quite precise because we do a lot of transfers, so they span over a long time over the day. So we say 123 plus or minus three hours of intramuscular progesterone in oil, and then they start the vaginal the next day.
So that time is now kind of standardized across protocols for us, and we've seen no difference as we've monitored it over time in terms of live birth rates between those arms. Thank you, Kate and Eric. So Rachel and Brad, they mentioned that weight was associated with serum progesterone in their study.
You've also done research on this. Tell us about your research. Great.
We're happy to do that. Thank you, Micah. At Iowa, we've been interested in the effects of obesity on reproductive outcomes, given the known detrimental effects that obesity has on outcomes from assisted reproduction.
One possible mechanism for that reduced pregnancy rates from IVF may be the effect of body weight on the pharmacokinetics of progesterone, which as we all know is a critical hormone for implantation and maintenance of pregnancy. For exogenously given progesterone, obesity could have an effect on drug delivery. Divya Shah and colleagues a number of years ago found that when obese patients were using the standard one and a half inch needle to inject IM progesterone, just over a third of patients never actually achieved an IM injection.
The needle simply wasn't long enough. So that may be one issue. Another issue is that we've shown and others have also shown that body weight and the increasing volume of distribution that accompanies that increased body weight is associated with marked differences in serum levels of many hormones, including HCG and progesterone, on the day of pregnancy test and fresh IVF cycles.
And we published this a number of years ago in Fertility and Sterility. So it's with this background of changes in pharmacokinetics of progesterone that led us to study our programmed frozen embryo transfer cycles at the University of Iowa to determine whether or not we were dosing our patients adequately with the IM progesterone. And this prompted Dr. Rachel Mejia and Dr. Rachel Wynot to conduct this retrospective study, which Dr. Wynot will now present.
If you could go to the next slide, please. So our objectives for this study was to determine if weight or BMI affects serum progesterone levels on pregnancy test day in programmed frozen embryo transfer cycles. And we also wanted to know if serum progesterone levels affected the live birth rate.
And I would like to mention at the University of Iowa, our progesterone levels are assessed by serum level on the day of pregnancy test. If the serum level is below 15 nanograms a milliliter, then the dose of IM progesterone is increased from the standard 50 milligrams up to 75 milligrams. Next slide, please.
So for our study design, we included all patients undergoing their first cryopreserved vitrified glossocyst transfer between 2015 and 2018. All patients had six milligrams of esterase per day split up into three two milligram doses. And they also started their 50 milligrams of IM progesterone in oil 120 hours prior to their transfer.
The University of Iowa program actually has a BMI cutoff of 50 kilograms a meter squared. And we included all of those patients that had weight and height available for us to be able to calculate their BMI for the study. Serum progesterone levels, as I mentioned, were measured on pregnancy test day.
And we increased their dosage if their level was less than 15 nanograms a milliliter. Next slide, please. For our results, we did compare both BMI and weight.
We did find that weight was more predictive. And so all of our future slides are going to be using kilograms and pounds. And our weight categories were chosen based off of prior research done at our institution looking at weight less than 68 kilograms, weight 68 to 90.3 kilograms, and then weight greater than 90.7 kilograms or 200 pounds.
In our demographics, we did not find any statistically significant differences between the categories except for anovulation diagnosis, which was significantly greater in those with a weight greater than 200 pounds. Next slide, please. For our results, on the left of this slide, you can see the progesterone level.
We did split it out into three groups because we do know that different institutions do use different cutoffs for their progesterone levels. We at our institution used a cutoff of 15 nanograms a milliliter. And so that was sort of our primary endpoint for our clinic.
We also looked at 15 to 19.9 and then 20 and greater. And as you can see, the high weight class, the weight greater than 200 pounds or greater than 90.7 kilograms, had a statistically significant difference of lower progesterone levels. And so 29% of those patients had levels less than 15.
45% had a serum level between 15 and 19.99. And then only 27% had a level greater than or equal to 20. Next slide, please. So we then wanted to see if this was affecting our live birth rate.
And so as I mentioned previously in our clinic, everyone starts on 50 milligrams of ion progesterone. But if this serum progesterone level on pregnancy test day is less than 15, we do increase them to 75 milligrams. And so when we look at this slide, we grouped our pregnancies into no pregnancy, abnormal pregnancy, which included all biochemical pregnancies, miscarriages, and the reason for inoctopics as well.
And the reason for combining all of those into this abnormal pregnancy category was due to low numbers. And then looking at live birth. And if you could just click once.
We actually did not see any obvious effect on pregnancy outcomes. And that is, of course, when we increased the dosage on day of pregnancy test. So our conclusions just from our small study would be that 50 milligrams of progesterone in oil seems to be adequate for allowing for implantation.
Because this was a retrospective study, we were not able to assess if not changing the dosage of intramuscular progesterone would have impacted live birth rates. So a future study looking at that would be, you know, great to have. So we know, you know, for future reference for our patients, do they need to be purchasing the more medication, injecting more of this medication.
But from our one center study, this is what we found. Great. Thank you, Brad and Rachel.
So just to follow up on that point, you know, Brad, I know you practice very evidence-based medicine. There's not really randomized controlled trials on this yet. But there is a fair amount of observational data suggesting similar findings to your study.
So in your IVF clinic, how did you make that decision or that balance on when to change your protocol based on observational data without level one data yet to support that? I guess we go a lot just on our own personal experience, analyzing our data frequently. And so we don't make changes readily. We kind of wait for the evidence to exist in the literature.
But in this case, as you say, we don't have much to go by on the literature. But there is data that suggests that pregnancy rates are lower when the progesterone level and ongoing pregnancy rates are lower with progesterone levels less than 15. So that's what prompted us to boost the dose when we find those levels.
Again, whether or not that's necessary, I guess, could be debated. And I would also like to mention that at the time of this data collection, all of the patients were using the standard one and a half inch needles. But we have changed our practice so that if patients are at a higher BMI or weight that we do consider moving them to two inch needles in order to actually get that intramuscular effect.
I think if we always waited for randomized control trials, we'd often be waiting a long time to make important changes in our practice. So thank you for that answer. So everything that we've talked about to this point has been talking about programmed frozen embryo transfers.
But there's a lot of emerging data on the importance of the corpus luteum. And we have Val and Mindy who are two researchers leading the way in that. So tell us about natural cycle FETs and the importance of the corpus luteum.
Thank you very much. You can go ahead and put up our slides. We appreciate the opportunity to speak about this topic and to share a little bit about what's out there and what we don't know so far about this question.
So we've already brought up that we're having an increasing number of frozen embryo transfers performed as we all know because of the ability for FET to facilitate PGT, elective single embryo transfer, and also has some obstetric outcomes that have been favorable such as lower risk of low birth weight and small for gestational age. But there have also been observational data in the U.S. and really throughout the world suggesting that there's a higher risk of LGA and hypertensive disorders of pregnancy. One of these was looking at pregnancy.
A couple of these have been published in FNS such as looking at pregnancy complications and perinatal outcomes with cryopreserved versus fresh. Because initially the preeclampsia risk, it wasn't clear that if it was with just IVF overall or more specifically with frozen embryo transfer. And the more recent studies that have parsed that out and looked more carefully about whether it's IVF overall or frozen transfer strongly suggested that the increased risk for hypertensive disorders of pregnancy is more in the realm of the frozen embryo transfer.
Similar study by Cindy Seitz and also from the Nordic group. So why might it be that the frozen embryo transfer is associated with a higher risk of hypertensive disorders of pregnancy? So very familiar to many of the people in this audience, when we have a natural cycle frozen embryo transfer there will of course be a dominant follicle and then a corpus luteum that is present in that cycle. In a programmed frozen embryo transfer there's no dominant follicle, no corpus luteum and we replace estradiol and we replace progesterone.
But the corpus luteum doesn't just make those two products. It also makes vasoactive substances such as relaxin and VEGF which we're currently not replacing. And perhaps those are actually important for initial placentation and early pregnancy development.
Sort of setting the stage for later pregnancy outcomes. So there have been a number of observational data suggesting that programmed FETs are associated with a higher risk of preeclampsia. One of them was an observational data that was published from data when I was at Stanford as well as with colleagues from the University of Florida.
And really this hypothesis, the credit for the initial hypothesis should go to Kirk Conrad who's a physiologist at the University of Florida. And we showed not only was there an increased risk of preeclampsia, carefully adjudicated preeclampsia in women undergoing frozen cycles with programmed versus natural, but Dr. Conrad did observational data of maternal cardiovascular adaptation to pregnancy using physiologic measures and showed pretty impressively that there were differences in how the mom began to adapt to pregnancy based on vascular markers. There's also been some other observational data.
I brought up another paper that we mentioned in the FNS article that's being presented today. And since that time there have been several other observational studies that have continued to suggest that perhaps the program cycle is associated with a higher risk of preeclampsia but maybe not so much the natural cycle. But there's a lot of caveats and we all know this.
It's so often something that looks like it might be true and observational data doesn't always pan out when a proper RCT is performed. And one of the things that many of us know is program cycles are of course more likely to be used for women who are in ovulatory. And also perhaps for women say who have resistant endometrium where the thickness of the endometrial lining is not developing as well in the natural cycle and then we would switch that person over to a program cycle.
Of course many other potential confounders that could be that could be accounting for these observations. And we don't want to necessarily just sort of swing the pendulum all the way to saying everyone should have a natural cycle because they're clearly advantages of program cycles. It's more predictable for the patient in the clinic.
We sometimes in our practice at Hopkins have patients who request that they do the program cycle because they want to have more control over when the when the transfer is going to be done. And it's also less monitoring for the patient. And then from the IBF lab perspective in fact often our lab is said well can we do more program cycles because you know we don't want to have as many on the weekends or when we can space them out better.
Because obviously with the natural cycle it's whatever day that it needs to happen that's when it needs to happen. And with the program you can have a lot more control. And then of course with the program cycle there's more flexibility if more time is needed and or higher estradiol is needed then perhaps it's physiologic to to get adequate endometrial thickness.
So so basically we we think very strongly I can click again that that there's a need for a randomized controlled trial of natural versus program cycle. And and at Hopkins as well as at other eight other sites in the U.S. where we're currently going forward with that. Well I we so we are very excited that we do have our randomized control trial called NAT Pro where we're randomizing patients to either a modified natural cycle or a programmed arm.
Our age criteria is 18 to 39 with untested PGTA embryos or 18 to 41 if they have PGTA tested embryos. And we're really excited with our recruitment so far and when we counsel patients about the study I tell them you know you're a candidate for either arm. They're equally effective as far as pregnancy rate at our center and there's not enough evidence to show that there is a risk of preeclampsia.
That's why we're doing this randomized control trial to see if there is a difference. And patients are excited to help and participate so we can answer this question. So obviously you touched on this that implementing natural cycle into a lab from an embryology workflow standpoint and clinical workflow standpoint can be challenging.
And I think some of these outcomes that we're talking about while statistically different in the observational data the absolute risk difference is relatively small. You know you may be talking about numbers needed to treat of 30 to 50. How do you sort of balance that risk with the practical things that it means to lab flow? How have you tackled that at Hopkins? Well our observational data that we published from Stanford it was actually a difference of 12 percent versus 4 percent absolute differences in the risk of preeclampsia.
And if you look in the observational data in the literature not all of that quite that magnitude. But I think it's a fair point and that's why I think until there's more definitive data we want to we want to counsel patients. We don't we don't emphasize this as a primary reason for doing the natural cycle.
But we also want to give our patients some some ability to make choices like for some and thanks to you know Dr. Devine's work you know emphasizing importance of IM progesterone for some folks that's that's really kind of a deal breaker that they would really prefer not to have to take intramuscular progesterone even though it looks like it's it's truly is needed. And then and I don't know when people do IVF somehow still want to do some part of it that's natural that they I think a lot of the demand up to this point you know the way reason we were able to collect observational data was was largely driven by patient preference which we have to consider as well. But we want to make sure that we are gathering the data that would allow us to give you know the full the full risk benefit to to patients.
Great. Thank you Val and Mindy and to all our authors. So now we get to the fun part where the audience gets to interact.
So we will open up the microphones on the floor and we will open up our virtual chat. So I encourage you to come to the microphone with any comments or questions. A quick advertisement fertility and sterility on air is our podcast that releases every month.
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So Pietro we'll start with you with our virtual audience. What's the first question from our live global audience. So we have a question for Dr. Baker and Dr. Christensen.
So we talk a little bit about the natural cycle may be an opportunity for risk reduction in women. What about the modified natural cycle where you take in ovulatory women help them to create a follicle either trigger ovulation or allow them to ovulate that follicle. Is that an opportunity for even further risk reduction in the patient population that may be at risk for preeclampsia.
That's a great question and if NIH resources were unlimited we would have definitely designed a three arm study and included an arm that was an ovulatory women with letrozole because there is still of course the presence of the corpus luteum in those in those cycles. And so I think it's a good question and we don't have any real evidence to guide us as right now as to whether that would have a lower risk. I think once we get the NAPRO data that perhaps if that suggests the corpus luteum is of is a value to the to the outcome then that that would certainly be something that could be considered if a person was not able to do a natural cycle.
And for all of our panelists please chime in on any of these questions and feel free to ask each other questions as we go. Sir on the right. Sam Zaki from Cairo, Egypt.
With regard to the first paper for those who are still insisting to take vaginal progesterone do you think if we increase the frequency would elevate the level of progesterone and overcome the lower pregnancy rate that you would expect out from having vaginal progesterone. Take that one it's the pharmacokinetic expert. Okay so you know we chose to use vaginal progesterone dosing 200 milligrams twice daily and that was based on some pharmacokinetic and pharmacodynamic data that showed adequate serum trough levels and steady state.
That said it is absolutely true that many centers including many in Europe 200 200 twice daily is considered a low dose and really 600 to 800 milligrams over the course of the day and perhaps more frequent dosing can be used. We did see in our population that there was significantly lower serum progesterone concentrations at the time of the pregnancy test among those patients who received vaginal progesterone only with a threshold of serum concentration of around nine nanograms per ml being associated with the decrease in pregnancy rate across arms and there's no interaction between the arm to which the patient was randomized and the serum progesterone concentration with regards to pregnancy. That said we the short answer to your question is that we just don't know that.
We would have to do another trial to evaluate that and there are also data out there showing that potentially vaginal progesterone combined with oral progesterone may be achieve optimal outcomes relative to intramuscular progesterone only. What we do in our center is if a patient says I simply cannot or will not take intramuscular progesterone because we don't have data showing that vaginal progesterone is adequate or optimal is that we do try to shuttle those patients towards the natural cycle and if they are anovulatory we do use letrozole in order to have that patient's endogenous progesterone present to you know optimize their endometrial receptivity. Dr. Hoyos.
Luis Hoyos from Miami. Great presentation. Just to follow up on the question if these are just natural cycles and not modified natural cycles how are you defining day zero in relationship to serum progesterone LH because that's always the part that I find difficult.
This is for the NATPROS study. So for the NATPROS study what we're monitoring the patients very closely and so for the natural cycle if they have an LH surge we identify that so if they have a follicle that's 18 millimeters and they're not having an LH surge then they'll receive an HCG or Ovidril trigger injection. If they have a follicle and their LH is you know greater than 20 or then they would still receive the trigger but then the transfer would be a day earlier.
So it would be six days after an LH surge or seven days after an evening injection of ATG. Okay so Hi everybody. This is terrific.
I'm going to ask you guys to speculate a little bit because we've made a wonderful transition about breaking down the steps of frozen transfer and I just speculate do you think it matters between this modified natural and natural like is it really HCG or LH that we need or is that an irrelevant factor? Well that is definitely a speculation since I don't have any data specifically. I mean I guess I wonder why or how the like an LH even its duration into the luteal phase doesn't stay at that level. What would be the sort of physiologic hypothesis to why that was important relative to the sort of the other vasoactive products of the of the corpus luteum? I might not be understanding your question.
That's right that's what I was asking is there you eloquently stated there's a lot more than just progesterone that's made by the corpus luteum and I'm wondering if you make a quote-unquote better corpus luteum with luteinizing hormone than you might with an HCG trigger. I'm just saying we're going to get down to that level of detail when your trial is finished. That's right and there had this has been in the looked at in only in the course of retrospective fashion and there were a few papers that suggested that the endogenous LH these were some very small studies from quite a while ago was perhaps better than than than a trigger.
On the other hand from a practical point of view already a natural cycle is more difficult than a than a program cycle to time and the Avodril or an HCG injection I should say as is a a way of of helping to programs to be able to handle that because otherwise we're asking because we have a few folks though who really just want the natural LH surge no HCG injection and so they come in daily sometimes for four days in a row and until and then if we're not sure it's truly at a level of an LH surge we found that when we were doing programs count you know is it 20 is it 25 which what's really the level of the LH surge we have to bring them in even the day after we think they're surging to to time the the transfer to figure out what what when the ovulation is occurring so it's it's partly really a practical implementation of the natural cycle. You know these are the choices we all make when we we got to put trials together of you know what are the compromises you have to make to maintain enrollment and get centers on board and uh yeah a 50 what was it a 52 arm trial that we need for Dr. Kudafaris. Thank you.
There's no question that we are paying attention to timing more and more exactly how many hours of progesterone. The word out there is it's the timing that counts not the concentration yet we are modifying how we treat because of a concentration of progesterone so I was wondering to hear from the three groups your opinion about timing not to versus concentration but how are we going to figure this out because the kinetics may be such that concentration may make a difference but maybe not so I was wondering how the three of you well you can tune you can tune in tomorrow and Dr. Doyle will be presenting our our synchrony trial which looks at timing with or without endometrial receptivity analysis and I think there'll be some great data that address that tomorrow but you know as Kate mentioned our practice now is we we're at 123 plus 123 124 123 plus or minus three and the reason that we did that and it sounds absurd it sort of is is that if we're doing 25 transcripts over the course of the day and we just tell everyone to start progesterone at 10 p.m. some people are going to get you know too long or too short most likely with respect to your question Christos I do think timing matters but I don't think it matters within that type of range at all and as Eric alluded to I hope folks will come at 10 45 tomorrow to see a randomized controlled trial of similar size showing that ERA does not seem to improve at least in an unselected population the chances of having a live birth from frozen embryo transfer of a single euploid blastocyst I think that the preponderance of evidence that's out there does show that serum progesterone concentration probably does matter in a programmed cycle that said we don't measure it routinely because when we look at our data the proportion of patients who receive intramuscular progesterone at least once every third day and then have a low serum progesterone concentration is is minuscule so we don't feel the need to do that or to supplement it but there's lots of high quality quality evidence out there particularly in programs using vaginal progesterone where you know a modification in the protocol probably does help I find based on my review of the literature when the serum progesterone concentration is low. What dose or what concentration do you use is signifying a low concentration in your program? Because we don't check it clinically we don't but within our study we did look at it and it's in the supplement for this paper but we found that there was a threshold at around nine nanograms per ml but there was a significant decrease in in the odds of of all of the outcomes we looked at.
One of the other things too is we we were all told you know years ago that with vaginal progesterone you're getting such high concentrations of progesterone in the uterus that perhaps it shouldn't matter what the circulating level is but maybe there are other sort of maternal cardiovascular effects of the circulating progesterone that actually are important and you know we don't know that yet some more speculation but that's just something I've thought about wondering if that may explain something. The point of my question in that it was a loaded question we have not paid as much attention we paid attention to the duration but maybe there is more to it than vaginal root versus transdermal PO may make a difference and I think we need to look at it regardless of how good the data are we don't have a consistent approach that was the point that was indirectly. That is a great point we have time for a few more questions and then we'll get the final comments from our authors.
Thank you Elizabeth Pritz from the Wisconsin Fertility Institute. First of all comment and then a question my comment is I did the first meta-analysis looking at what type of progesterone should be used intramuscular vaginal I did it in 2001 as a fellow and I found that intramuscular was the best however for the next 15 years I was called barbaric and so my ego would like to say thank you. Secondly I have a question about checking the progesterone levels would it make some sense just to start everyone at 75 milligrams of intramuscular progesterone and then not check afterwards particularly in Wisconsin infertility is not covered and so each test is going to be more expensive and the cost difference between 50 and 75 milligrams is minuscule.
So for the Iowa group that was actually one of our questions as well for you so we'll let you field that. So I think that's a great point we actually do increase people beyond 75 at some times because their serum progesterone levels are still low so we even have people go up to 100 and we have discussed previously you know there are programs out there that do give patients 100 milligrams just every day or so I do think that is something clinic by clinic or patient by patient that could be considered. Yeah we do 100 for that reason.
But we find a majority of patients have adequate levels on 50 and you know it'd only be in the obese patients where there's a higher rate as we showed so I don't know I 100 sounds does sound barbaric to me but. Oh great you too huh. Sorry on the left.
What do you think the mechanism is for the increase in the biochemical pregnancy rates because we saw the same thing when we did the study with the vaginal ring in stimulated cycles and we had done some of the early phase two studies with the in replacement cycles as well and saw a huge biochemical pregnancy rate. I can only hypothesize there's always the possibility that the concentrations are too low as we're addressing and then there's the other three hypothesized mechanisms that I mentioned which is you know physiologic changes in the lower genital tract and absorption in early pregnancy you know peripheral metabolites potentially that that only exist with systemic administration or changes in uterine contract to contractility. I think the first is probably the most biologically plausible in my opinion.
That said we don't have studies to to show us the answer. All right and our final live audience question please. Thank you for a great discussion again.
I wanted to ask the panel what do we know about the subcutaneous progesterone injections that that are currently under research. Do they have the potential to replace the IM formulations? So I've previously I'll just disclose I've been a consultant for a company called IPSA which has been involved in this in this work. So in the U.S. it's not available to us.
It is available in in Europe. The concentrations that would be available in the subcutaneous aqueous formulation would be would need to be given probably in a twice daily dosing to get to the IM progesterone level. But that would be another another potential way to go in terms of being able to achieve a program cycle you know.
But obviously no RCT has been done to compare the IM in oil with subcutaneous aqueous. It's one of the 52 arms but Val was the first author I believe on the trial looking at it in in you know fresh IVF which shows that it was equivalent. But we need those data for FET.
Thank you. I did have a question for the Hopkins group. For patients that are at increased risk of preeclampsia they're often placed on a baby aspirin for the duration of their pregnancy.
Do you think that that could have any I guess role for our patients going through program FET cycles? Yeah when we were designing the study we thought about that because a lot of our patients are on baby aspirin for that reason but multiple other reasons and so we are allowing patients to take baby aspirin and that's something that we'll look at in the analysis. The as you know there was just a U.S. preventive task force that came out suggesting that for women at higher risk of preeclampsia that they begin taking baby aspirin no later than 13 weeks in their in their pregnancy and they were the like first tier risk factors and second tier risk factors and we in IVF are in the second tier risk factor. So as it I think a lot of our patients will ultimately end up taking low dose aspirin perhaps at our program or but but if not then beginning at 13 weeks or and throughout the the pregnancy.
The magnitude of reduction in preeclampsia risk is probably somewhere in the range according to my MFM colleagues of like 10 to 30 percent relative reduction. So it's not as much of a you know sort of cure as we we might hope but but there that would be likely to be what what's going to be happening. Of course we're going to be collecting that in the RCT and we check in with our patients at each trimester as well as postpartum and then get all their original records so we'll we'll figure out how many of our patients have taken the low dose aspirin.
We were surprised at the breadth of criteria for instituting baby aspirin in that in that paper over 35 being one of them so that's pretty much our entire patient population over 35 and doing IVF. So it's going to be a lot of people taking aspirin. All right we are down to our final few minutes so I want to give each group 30 to 60 seconds to tell us your final thoughts.
We'll start down at the end from Iowa. So we just want to point out that in the United States women ages 20 to 34 approximately one-third of those women are meeting criterion for obesity and over 43 percent of women ages 35 to 44 meet the criterion for obesity and so we just want to highlight the importance of that specific population and making sure that we're doing research to improve the outcomes in that population. I think that it's so important that this panel represents studies that are looking not just at chances of pregnancy from the treatments that we do for our patients and obviously that's a very very important goal but as a field we need to transition to most importantly maternal and fetal health and that's what Val and Mindy are doing with the NAPRO study and perhaps less important but also our patients quality of life as they go through the treatments that we administer.
So I'm grateful to FNS for assembling this group. I just think it's important if patients ask you about the risk of preeclampsia with a natural versus a program cycle just to tell them that there's some observational studies that suggest that there could be an increased risk with a program cycle versus a natural cycle but there's not enough data for us to recommend not having a program cycle and many women have very strong preferences for one or the other as we're experiencing as we're enrolling patients in the study and many people have a strong preference to do not want to be randomized. So I think it's just really important that patients understand that there's a possible risk but there's not enough data at this point and hopefully in the next few years with the NAPRO study we'll have an answer to that question.
Petra, you've been busy moderating our online chat and listening. What's your final thought? I think people are just really excited that the next 40 years of IVF is really as a lens towards risk reduction making IVF safer. We spent the first 40 years just making sure we could do it and get it right and get patients pregnant but the next 40 years if we can really double down on making it safer for moms and for babies I think will be a productive 40 years.
Thank you all for attending. That's coming from a man married to a MFM specialist. I want to thank our panelists for coming on and putting yourself out there and talking about your research.
I want to thank the ASRM for hosting fertility and sterility. Please follow FNS on Facebook, Instagram, and Twitter. We're putting out good content about all these scientific data.
Thank you. Have a great day.
