All right, ladies and gentlemen, welcome to Fertility and Sterility Journal Club Global Live from the Pacific Coast Reproductive Society 2023. It's so great to be back in person with all of you. My name is Micah Hill.
I am the media editor for Fertility and Sterility. We do these journal clubs from all over the world. Most months we have them and we're so excited to have our favorite event tonight where we have fellows debate fellows, which usually tends to be better and more lively and more interesting than the faculty because our fellows know so much.
So we're excited to learn from you tonight. So we'll start with the side who's going to argue that we should do natural FET. We'll have you introduce yourselves, please.
Hello, my name is Victoria Jang. I'm the second year REI fellow at Massachusetts General Hospital in Boston and I'm really excited to be here. Hi everyone, my name is Nirali Jain.
I'm the second year REI fellow at NYU and I am super excited to debate this program. Hi, I'm IJ Eco. I'm the second year fellow at the University of Utah in Salt Lake City and I'm just ready to talk about all the reasons natural is better.
All right, thank you natural side. Now we have our programmed side. Give us your names and where you're from, please.
Sure, my name is Nina Vyas. I'm a third year fellow at Cornell and I'm also excited. I couldn't help but say something.
My name is Maren Shapiro. I'm one of the third year fellows at UCSF and I'm ready. Hi there, my name is Grace Whiteley.
I'm one of the third year fellows from NIH. I'm very happy to be with my two program directors here and go program cycles. It's fixed.
All right, thank you so much to our fellows. So our moderator tonight is, he needs no introduction. Obviously a giant in our field and the former editor-in-chief of fertility and sterility even before we started these journal club globals a few years ago.
So Dr. Czerny, thank you for hosting this for us and I'm going to turn it over to you, sir. Okay, well we're going to start with you. Mic's on.
Okay, we're ready to keep it natural. So the first thing I would like to say is thank you PCRS, Dr. Czerny, Dr. Hill and FNS for having us today. This is going to be a really exciting debate.
We are here to really discuss natural cycle versus program cycles for endometrial preparation for frozen embryo transfers and I wanted to start off with some definitions that will help set the stage for our discussion. First I will start by defining the natural cycle FET or frozen embryo transfer. Natural cycle endometrial preparation with subsequent frozen embryo transfer utilizes a patient's natural follicular development with no subsequent additional medications.
True natural cycles usually rely on serum lab monitoring such as E2, P4 and LH, although some clinics are doing urinary monitoring throughout the cycle with the aim to quantify follicular development to detect endogenous LH surge. Timing of monitoring can be very clinic specific and can be paired with ultrasound monitoring to monitor follicular growth and blastocyst embryo transfer is typically performed six days following detection of LH surge but may vary based on embryo development day, such as earlier transfer for cleavage stage embryos. Luteal support is provided by the corpus luteum in true natural cycles, not necessitating supplemental progesterone, although patients and clinics may still prefer additional luteal support.
Now that is slightly different than what we would call modified natural cycles, which I think a lot of clinics are doing also. Modified natural cycles, in contrast, use medications to assist with either follicular development or triggering ovulation. For instance, clomid, letrozole, FSH or human menopausal gonadotropins, HMG, can be used to assist with stimulating follicular development and with addition of an ovidril or HCG trigger to initiate ovulation.
Similar serum lab and ultrasound monitoring schedules are used as true natural cycles and trigger criteria usually is set at the threshold of 16 to 18 millimeters or more. Blastocyst embryo transfers are generally performed a week following, seven days following trigger injection, but may vary based upon clinic and luteal support can vary based on clinic and follicular stimulation protocol, where progesterone is generally added following FSH or HMG stimulations, whereas clomid or letrozole stimulation cycles do not necessitate progesterone supplementation, although clinics and patients may still prefer additional luteal support. In contrast, our program cycles completely depend on exogenous medications for endometrial preparation without any associated follicular development.
An example of this type of protocol would involve GnRH access down regulation with a GnRH agonist such as Lupron with exogenous either transdermal or oral estrogens to stimulate endometrial lining growth and patients may come in for two ultrasounds such as a baseline and a final lining for which then they would look for an endometrial lining of greater than six or seven centimeters based upon the clinic before proceeding to transfer. Progesterone, usually progesterone and oil IM injections is generally started following the final lining check and will be administered daily with subsequent blastocyst embryo transfer following final lining check. Fundamentally, the major difference among these protocols is the presence or absence of a corpus luteum.
Natural and modified natural cycles depend on endogenous hormones for endometrial development and on the corpus luteum for luteal support. In contrast, programmed cycles are dependent on exogenous hormone supplementation for both endometrial development and luteal support and so no ovulatory event with subsequent corpus luteum is present. So that's the big difference and who doesn't love the corpus luteum.
Given these differences among the cycles, major benefits are present for ovulatory women when pursuing natural cycles. First, these cycles don't require pre-treatment or preparation compared to longer GnRH agonist program protocols. A huge benefit relies on the fact that women are not destined to daily Lupron or IM progesterone injections while our patients become champions of their medication regimens.
Not relying on administering challenging injections daily can decrease stress and anxiety throughout the cycle allowing patients to regain control. Additionally, the endometrial environment is closer to natural environment which my team will discuss further on possible implantation, pregnancy, and obstetrical benefits from that environment compared to program cycles. Now that we have meticulously defined these cycles, let the debate begin and to you Dr. Villas.
All right so before I get started, I just wanted to take a poll of the audience so we know kind of what we're dealing with. So for the sake of keeping things easy, I'll define majority of cycles as greater than 50 percent of the cycles that everyone does at their clinic. So by a show of hands, how many people are doing pure natural FET cycles for a majority of their cycles meaning no medication, no trigger, no luteal support? That's what we thought as well.
Okay, that's how about modified natural cycles? Any sort of modified natural cycle ovulation induction agents, trigger, luteal support, gonadotropins antagonists like we heard about yesterday? Okay, so still very few percentage of the population. And then how about majority programmed FET cycles? So we can just stop the debate now. So all of us today will make very valid points, I'm sure.
Our opposing team will attempt to convince you that natural or more likely not modified natural FET cycles have improved obstetric and therefore neonatal outcomes. We've read these studies as well and we know there's compelling points to be made there. However, during this hour our side will show that there's no clear data from any ideal study group or ideal study design yet that proves that natural or even modified natural FET cycles does have improved cycle obstetric or neonatal outcomes yet at this time.
We also believe we'll make a sound argument that performing programmed FET cycles is not only not inferior compared to natural FETs, it can have significant improvement when you're talking about structure and flow for patients, physicians, and embryologists. Let's face it, there's a reason that most of us in this audience do programmed FET cycles. So first let's talk about timing and scheduling.
For busy fertility practices and even busier embryology labs, programmed FET cycles means structure. Being able to map out your structure and your schedule for the week leads to increased optimization of workflow and therefore decreased errors in the lab. Performing natural cycles requires a fully functioning lab seven days a week.
This requires increased staffing, increased hours, which means increased cost, and also decreased quality of life. For the six of us fellows sitting up here who come from large academic institutions, we're used to seven day a week embryology labs, but for a majority of us and where we're going to practice, and many of you in the audience from smaller private or group practices, it's simply not a feasible option. There are other favorable practical points to programmed FETs.
Programmed FET cycles allow for clear treatment plans for patients who have already undergone so many hurdles and have jumped through so many hoops for their scheduling, their morning monitoring, and balancing their personal and professional lives. This is beneficial to patients and partners who travel for their care and also travel for their career. Having a schedule for this one phase of their treatment cycle may ease anxiety leading up to their embryo transfer.
Additionally for those clinics who follow a dock of the day model, scheduling an embryo transfer on the day that their physician is doing the embryo transfer can further increase patient report. Additionally for true natural FET cycles, there is an unpredictability and a lack of standardization in how we measure an LH surge. For example, three various papers show three various definitions of an LH surge.
The first by Tessard et al. in 1981 defines an LH surge as a rise of greater than 80 percent in LH level when compared to the day prior. Another paper in 2017 by Irani et al.
defines an LH surge as an LH greater than 17 followed by an E2 drop of greater than 30 percent the following day. And third there's a Gronewit et al. defines an LH surge as this is an LH greater than 10.
Missing the LH surge could lead to an inadvertent cycle cancellation or suboptimal timing of embryo transfer. My colleagues will also touch on the fact that many women we treat are not eligible for natural FET cycles. Namely, anovulatory patients are not candidates for true natural FET cycles.
Even treatment with ovulation induction agents for these anovulatory patients are reflected in heterogeneous studies with significant challenges in accurately comparing these outcomes, which we will go into further. Even NatPro, which will hopefully give us the RCT data that we so badly need to augment this conversation, is not including anovulatory patients in their recruitment. Lastly, cost.
When you break down the cost that comes with monitoring blood work and medications needed between programmed and natural FET cycles, we see some pretty interesting trends. I've also included modified natural FET cycles since that's what most of us are doing as opposed to programmed FET cycles, so we'll see all of that. So I'll bring up a slide now showing an out-of-pocket cost model, and next we'll see a fixed cost model for those of us who have just a flat fee for all FET cycles.
So in this first out-of-pocket cost model, we took an average number of visits for natural, modified, and programmed FET cycles at our three institutions. You'll see that on the top line there. We noted a higher number of visits needed for the natural and modified FET cycles compared to programmed cycles.
The prices we have listed here for ultrasound and blood work are a average of our three institutions, and also the cost of the medication is pulled from GoodRx. In this out-of-pocket model, you'll see that the cost for the modified and natural FET cycles is significantly higher. This is due to the increased number of visits needed and the higher cost of endometrin compared to ion progesterone.
This is adjusted for when you go to this fixed cost model, that we are adjusting for essentially the number of visits needed for between all three of these treatment types. However, the increased cost of medication still needed for this modified natural FET cycle does tip the scale in favor of a programmed FET cycle, although the pure natural FET cycle does end up costing a little bit less. So overall, the practical benefits of programmed FET cycles cannot be overstated, especially in light of the inconclusive evidence that my colleagues will present showing that natural FET cycles lead to any clear benefit in cycle, obstetric, or neonatal outcomes compared to programmed FET.
While our patients might like a really good schedule and decreased follicular monitoring, I think the thing that is really important to consider is whether the cycle treatment could influence implantation and early maintenance of pregnancy. Yes, there is data to support that super physiologic estrogen levels may affect endometrial receptivity in a negative way. In 2019, Quinn et al published a study looking at factors that affect successful embryo implantation.
As we all know, this process is complex and highly regulated, involving synchronization between fetal-derived tropoplastic cells and maternal uterine luminal epithelium. One particular cellular structure that we think promotes receptivity is called the uterodome, which is a hormonally regulated large cellular protrusion on the uterine epithelial surface. While data suggests that the live birth rates may be similar between natural and frozen FETs, it's important to consider what factors are affecting initial implantation in both cycle types.
Lee et al published a study in 2022 looking at what happens to these uterodomes in the cases of super physiologic estrogen exposure, as well as progesterone support in the uterus. Interestingly, the window of uterine receptivity was shown to close much, much faster at higher estrogen levels, particularly at 3 to 25 nanograms compared to the physiologic E2 levels we see in natural FET cycles. This was specific to scenarios with additional exposure to progesterone in patients that were otherwise known to have regular ovulatory cycles.
So if this is true, then we can conclude that uterine gene expression responsible for implantation is well maintained at lower estrogen concentrations and could actually become refractory when estrogen levels are higher than the body expects them to be at the time of implantation. Therefore, higher implantation rates are likely in natural cycles compared to programmed FETs. Now shifting to early maintenance of pregnancy, we have to consider the progesterone supplementation for luteal face support following transfer in program versus natural FETs.
One could argue that the support of the corpus luteum, we all love the corpus luteum, it should really be enough to support early pregnancy following natural FETs. If this was the case, we should keep natural cycles truly natural following implantation and know that this should suffice. Of course as REIs, just hoping that this works out and meets our threshold is not enough nor appropriate for a practice.
Most studies recommend the addition of vaginal progesterone following trigger or LH surge to support early pregnancy following natural cycle FET. So at the end of the day, natural cycles should have better maintenance of early pregnancy with physiologic progesterone support and this should be reinforced with a little exogenous progesterone push that we support our patients with. What does the program FET team think, Dr. Shapiro? So Dr. Villas earlier eloquently outlined all the many reasons why practically frozen cycles are better for the clinic, arguably even for the patient.
But the next question that we really have to ask ourselves that Dr. Shaw started to probe into is which type of cycle has higher pregnancy and live birth rates. I'd argue that this is the most important question. There are obviously many factors that weigh into a decision of which cycle type.
You all want to hear this, it's going to be very important. So there are obviously many factors that weigh into a decision for which cycle type to choose. Obstetric outcomes, practicality, convenience for the patient in the clinic.
But at the end of the day, what we care about most and really what our patients care about most is if they get pregnant and have a baby. So if the pregnancy rates were really different, this debate would be over. Dr. Shaw talked a lot about mechanisms for why natural cycles might potentially be better, but is there clear data that this is the case? And the answer is no.
Of all the data that's out there so far, one retrospective study found that live birth rates in program cycles were higher than natural cycles. Three favored natural or modified natural cycles, but the vast majority of the data shows no difference. Most notably, a 2017 Cochran review of four RCTs by Gobara et al found no difference in live birth rate between natural and program cycles and insufficient evidence to support one over the other.
Munst et al in 2015, Urali et al in 2016, Groenwood et al in 2017, Alargupta et al in 2018, and many others have found no convincing difference between the two. Now, my colleagues over there arguing for natural cycles may have come across a systematic review and meta-analysis by Wu et al in 2021 that showed lower live birth rates in program cycles compared to natural cycles. And if they talked about that, I wouldn't be surprised.
But there are key aspects of that study, there are the studies included in that meta-analysis that they probably won't mention, and that's that they're all European. And there's no disrespect to our European colleagues, we practice a little differently, but the big difference between FET cycles in Europe and here is that they don't use IM progesterone. So all the program cycles in those studies were done with vaginal progesterone only as luteal support.
We've all read the Divine 2021 RCT that showed a 39% decreased live birth in program cycles using vaginal progesterone alone compared to those using some form of IM progesterone. So it's not surprising that when compared to natural cycles, pregnancy rates in program cycles that only use vaginal progesterone are worse. They have suboptimal luteal support.
The standard of care in the U.S. is to use IM progesterone during program cycles, so I would argue that these European studies just aren't applicable to our U.S. protocols, and I'd caution you to really critically evaluate the protocols that they're using in the studies when you are looking at them. To prove this point, even further, a very recent large retrospective study by Wolf et al. out of Boston IVF looked at over 6,000 FET cycles and found that overall there were lower rates of live birth rate in program cycles compared to modified cycles, but 38% of their program cycles used vaginal progesterone only, and when you separate out those that use some form of IM progesterone, there were no difference in birth rates between the programmed and the natural cycles.
So far from the data that I've discussed, as long as the program cycles are using adequate IM progesterone, the pregnancy rates seem comparable. However, these studies are all done in very carefully selected optimal populations, and I think we all can agree that there are many people for whom a true natural cycle just isn't a great option. What do you do with your anovulatory patients, as Dr. Vyas pointed out, or your older women? Mercer et al.
in 2008 showed that compared to women 20 to 34 years old, women 35 to 50 years old had lower levels of urinary estrone and pregnenadiol, the main urinary metabolites of estrogen and progesterone, suggesting suboptimal luteal function in even regularly menstruating older women. With this data, would you trust the corpus luteum of a 40-year-old woman to support a pregnancy on its own? Because I don't know that I would. Moreover, a recent Swedish RCT by Wengren et al.
found that supplementing natural FETs with vaginal progesterone in the luteal phase resulted in a significantly higher live birth rate with an odds ratio of 1.6. So if you need to supplement a natural cycle with progesterone, is that corpus luteum really functioning optimally? I don't think so. Which gets us to my last point. One of the biggest issues is that in order to make a natural cycle work for the clinic and the patient, most providers modify in some way, whether with letrozole to promote follicular development, a trigger shot, luteal support, or as discussed in an oral presentation yesterday, even adding gonadotropins in antagonist.
So I ask, at what point do these modifications deviate so far from the natural protocols in studies that the results are no longer applicable? In conclusion, the current data we have does not show that one protocol is superior when it comes to pregnancy and live birth. Could there be some for whom a natural cycle makes sense? Potentially, but there are a lot of patients whose corpus lutea I wouldn't trust naturally. All right.
Well, we will continue to disagree, but I want to talk about a couple things. One is a quick aside to the breakdown of costs that was presented. We looked at endometrion as the supplemental progesterone that was used, and I think that is an option, but permetrium is also an option.
If we're going to look at the full cost spectrum, that is a cheaper alternative, and that would drive down the cost. And as Victoria mentioned, or Dr. Jiang mentioned, the way that monitoring is done can really vary from clinic to clinic. And so I think it's good to consider numbers, but appreciating that an NF3 is not the full variation of practice that we see, and we can consider how to make things more cost effective for either of the protocols.
In continuing our discussion about, again, why the corpus luteum is the best, I want you all to know there's serious consideration about having corpus luteum t-shirts. We just could not get them together in time. We want to consider the fact that frozen embryo transfers are here to stay.
In 2004, the frozen embryo transfers made up only 8% of transfers in the United States. According to the CDC, as of 2020, FETs comprised 82% of all embryo transfers. 82%.
So if we're all doing them, we need to do them right. In terms of the rise of FETs, there is a growing wealth of data that supports concerning adverse obstetric and neonatal outcomes associated with programmed cycles or corpus luteal absent cycles. And as providers, we must appropriately counsel our patients about alternatives that they have.
It doesn't mean that they have to choose those alternatives, but if an alternative exists, the patient should have the opportunity to discuss that or seek care at another clinic that's able or willing to provide that. For evidence supporting adverse obstetric outcomes, it includes a prospective observational study done in the United States in 2019 that found significantly higher rates of preeclampsia with and without severe features in programmed cycles compared to modified natural cycles, which sounds like that's what the majority of us are out in practice doing. In terms of the rates, it was 13% versus 4% for preeclampsia and 10% versus 1% for preeclampsia with severe features.
These findings remained significant after adjusting for risk factors that could be confounding, such as null parity, age, prior hypertension, BMI, history of diabetes, and then history of polycystic ovarian syndrome. Another study by Ernstadt et al. demonstrated increased risk of hypertensive disorders of pregnancy and FET cycles, and they compared both corpus luteum to those that were, they called it, it was modified.
Stimulated was the word that they used in their study. This was a Swedish study, but again, we're talking about programs versus the modified natural, and we saw that increased odds of preeclampsia, so 1.6 times or 1.8 times, respectively, compared to, for program cycles, excuse me. The same study found that there's an increased risk of postpartum hemorrhage in program cycles compared to natural and modified natural cycles, with 2.6 and 2.9 times higher odds.
And, you know, I think for a lot of us, our OB days are well behind us, and we're grateful, but we know that a lot of maternal morbidity comes from postpartum hemorrhage, and we know that a lot of maternal morbidity comes from preeclampsia, with iatrogenic preterm delivery, increased risk to the infant, increased cost to society, and these things have to be considered. It may not affect us in how we schedule our clinic that day, but they are affecting society long term. Moving away from OB outcomes to neonatal outcomes, you know that studies have found an increased risk of macrosomia from program cycles compared to natural or modified FUT cycles.
The same study by Ursa et al, which I forgot to mention, this was a quite large study, it was 10,000 cycles that were observed, and so there's a wealth of data in this database. Macrosomia was defined in this situation as 4,500 grams or more, and infants who were born from program cycles had 1.6 times or higher odds of having macrosomia, which increases the risk of the time of delivery, also possibly hypoglycemia at the time of delivery, and long-term consequences for that neonate. So while things might be easier scheduled, it doesn't mean it's the right thing, and we all know that the easy thing isn't always the right thing, and so having these discussions with our patients is important.
So I'll be interested to hear what Dr. Whiteley has to say about this topic. All right, thank you so much. So just a couple of points that I want to address before I get started is that, you know, while the studies that she quoted do report an increased odds of adverse neonatal and obstetric outcomes, I will mention that there are significant limitations to these studies, and as she did mention, most of these studies are looking at modified natural cycles versus programmed as opposed to true natural cycles versus programmed, so that's kind of been a challenge as well.
So as our proponents have very eloquently stated, you know, a large criticism of programmed embryo transfer cycles is a theoretical increased risk of adverse neonatal and obstetric outcomes, particularly hypertensive disorders of pregnancy, preeclampsia, postpartum hemorrhage in the C-section when compared to the natural cycle FET. So let's just briefly review the theories for why this might be the case. So just first and foremost, you know, we know from multiple studies, it's very well established that the incidence of preeclampsia is higher in frozen embryo transfer cycles when compared to fresh embryo transfer cycles, so that it has been postulated that the lack of secretion of the vasoactive substances relaxin and vascular endothelial growth factor in the absence of a corpus luteum may contribute to maternal vascular dysfunction and insufficient cardiovascular adaptation to pregnancy.
Another hypothesis is that superphysiologic serum estradiol levels in women undergoing a programmed FET alters gene expression, which can affect remodeling and angiogenesis, and in turn contribute to abnormal trophoblast invasion. So while there is certainly merit to both of these mechanisms, von Versen-Heunicke et al. in 2019 published that both absent or excessive number of corpus lutea is associated with altered maternal vascular health in early pregnancy, given an insufficient drop in mean arterial blood pressure compared with those that have one corpus luteum present.
So therefore, the fact that there is a lower incidence of hypertensive disorders of pregnancy in fresh embryo transfer cycles, where many corpus lutea are present, and serum estradiol levels peak far higher than levels in frozen embryo transfer cycles, may potentially question the validity of these concepts and biologic plausibility. But most importantly, there have been no randomized trials powered to compare obstetric outcomes between natural cycle and programmed frozen embryo transfer, and there is currently very poor quality evidence to support these claims. A systematic review and meta-analysis published in Human Reproduction in 2022 demonstrated an increased risk of adverse obstetric and neonatal outcomes, and I can get into those specifically, with programmed frozen embryo transfer.
However, this meta-analysis included only cohort studies and case control studies, with one retrospective review of an RCT. All 19 studies that were included in this analysis were classified as low quality or very low quality, and there was significant heterogeneity between studies, including the timing and the dosing of hormone replacement. Lastly, many variables may confound the finding of adverse neonatal and obstetric outcomes in programmed FETs in our current studies.
A larger retrospective study out of Japan in 2019 that concluded pregnancies following programmed FET were associated with a higher risk of hypertensive disorders of pregnancy, evaluated over 29,000 natural cycle FETs and 75,000 hormone replacement FETs. However, this study did not control for maternal BMI, underlying medical comorbidities, or ovulatory status in their analysis. Additionally, a registry-based cohort study that was published in Fertility and Sterility in 2021 that found programmed FET was associated with higher likelihood of hypertensive disorders of pregnancy and postpartum hemorrhage did not adjust their analysis for history of PCOS or anovulation, and no information was included on prior history of hypertension or preeclampsia in previous pregnancies.
Additionally, many studies included in the analysis that I previously mentioned did not indicate why programmed FET was chosen over natural cycle or include the indication for IVF which could influence outcomes. This begs the question, are patients that are ineligible for natural cycle FET that are allocated to a programmed FET more likely to be anovulatory with higher BMI or underlying medical comorbidities such as chronic hypertension, insulin resistance, or metabolic syndrome, putting them at increased risk of developing hypertensive disorders of pregnancy as opposed to the protocol itself? Our current body of literature has failed to adequately address and control for all the confounding variables that could potentially lead to these outcomes. As we all know, an ongoing two-arm parallel group multicenter RCT, the NATPRO trial, will randomize women to either modified natural or programmed FET and follow them for up to three FET cycles looking at the proportion of preeclampsia in women assigned to a modified natural where a corpus luteum is present compared to the proportion of preeclampsia in pregnant women assigned to a programmed FET with a corpus luteum absent.
Therefore, until we have data from a randomized control trial that demonstrates an increased risk of poor obstetric and neonatal outcomes with programmed FET, we cannot make conclusions based on poor quality retrospective data. That's it. So before we get started here, we're at the halfway point, so the fellows have laid the groundwork for their two sets of arguments.
We're going to have questions coming from three different sources. So Dr. Decherny has some questions for our fellows. They can ask questions to each other.
If you have questions in the room or a statement or comment you would like to make, please stand at the mic and we'll alternate between those and ask the questions of our fellows here. And then we have our online audience. So Ron Beasley from Poma Fertility has already posed a question.
I'll be getting to that in just a minute. So if you're online watching, you can put the comment in the chat or you can tweet us at FertSTIRT and we'll be monitoring that and ask those questions. So Dr. Decherny, I turn it over to you, sir.
I just have a few simple questions. So Grace, first. Yes.
You explained the biologic. Do you really buy those explanations? So I definitely think that the corpus luteum is important. I don't think that we've fully elucidated why.
And I think that we don't really know how relaxin and VEGF really play into outcomes. I do think it's interesting though that in fresh embryo transfer cycles, where we have such super physiologic levels of estradiol and in some cases progesterone, that we don't see increased hypertensive disorders or pregnancy. Since this is one of the large theories as to why, you know, this is the case.
And then I thought that that study was interesting. The one that I had mentioned about the 2019 study from von Versen-Heunicke that showed that basically if you have greater than three corpus lutea, you can have altered maternal vascular health because there's an insufficient drop in the mean arterial blood pressure. So I think that we don't know at this point.
I think we need to study these concepts and theories further, but yeah, I think we don't know. But there's a whole world out there that conceives without treatment and they all have corpus lutea and maybe it's the same process with those patients is what you said. It's really not an increase.
Again, I think we just, I think we don't know. I think we're kind of speculating on both sides at this point. Okay.
Ijeoma? I just go by IJ. Okay. So you presented a lot of material with a lot of variables.
How did you sort out which variables in those different papers helped you to draw your conclusions? So looking at the papers, I didn't want to, there's a lot of numbers and I'm sorry if I drowned your numbers, but looking at the confidence intervals to determine how certain things were and then looking at the populations, how they can control them. So the largest study, the Swedish study, the retrospective population-based study, they had studied them for, I think it was a five-year period of time and then looked at the kind of baseline characteristics of the individuals. And because of being Sweden, they have all of the wealth of data.
So they were able to control for a lot of baseline characteristics. And so the numbers are presented. So for example, we talked about how there are 10,000 cycles and actually the majority of them were natural, not modified.
8,000 natural and the adjusted ratio I provided was 1.8. To me, the confidence interval was 95%. It was 1.4 to 2.2. To me, I think that's significant in the range, especially in the upward, in the upper range of that. I think it's something to then consider.
While it's not the same population as the United States, I think that especially because the majority of the more natural cycles, it makes it easier to compare to the United States. And an argument was that programmed was uniquely different abroad versus in the U.S. But the fact that the end was the same in most of the end point was the same. Do you think it's important that people individualize their protocols or should they all have a fixed protocol in their practice? When you say that, you mean live birth? Yeah.
Birth rates were the same. The birth rates were the same, yes. So why do we have every paper had a slight change in the protocol? So why don't we just have a fixed protocol for all of us to use? I think the things that we're considering is not just going home with a baby, but being healthy when you take that baby home and that baby being healthy when you go home.
And so I think this paper highlighted the things that are different with the cycles, things that are risk factors for individuals in the U.S. And also, our patient populations are ready at risk for these things. They're older than a lot of the non-assisted conceptions. They're increased risk for preeclampsia, increased risk for needing a cesarean delivery, hemorrhage, et cetera.
So whatever we can do to modify things leading into that pregnancy, I think it's our onus to counsel our patients, not force, but counsel so they have an option to consider. Peter, the same question for you. So many variables.
Why not have a fixed protocol for... Actually, more confusing on your side, because the protocols are really much different. Not just interventions, but a total protocol. Why don't we all use the same protocol? The same program protocol? I think a lot of places do end up using... I think most centers who do programmed FET cycles end up having the same protocol for their patients.
And the protocol for programmed FET cycles may differ from site to site, but overall, it's some version of estradiol replacement, either transdermal or oral, and that tends to be consistent at each center. Sometimes transdermal is more expensive, so you may switch to an oral if cost or insurance doesn't cover that. And then some version of progesterone supplementation.
And I know I.J. mentioned that permethrin is a good supplement or another alternative to endometrin, but I believe that most of us prefer endometrin, given that the original studies started with endometrin, and all the ongoing studies as well do use endometrin, and that's what we're the most comfortable with in terms of outcomes. But you can switch to other types as well. But I think for program cycles in particular, working on the different variables, I believe most centers will do the same thing unless cost is a factor, and then they can switch to alternatives.
One program uses oral progesterone. Exactly. Okay, so the last question that I have, same question for each side.
So let's, you. You have to, your program chairman says that you have to use program rather than a natural cycle. What's your answer? Remember, the decision depends on your answer.
So first I would ask if it really depends on their schedule. If it's, you know, why are they making me do that? But, you know, I think it really does depend on the patient, and I would argue back to say. You would argue back.
Stand up for my patients. Yeah, I would say, you know, if this patient's having ovulatory cycles, there's no reason to subject her to those IM injections of progesterone. Have you guys seen what happens to these patients? 10 weeks of progesterone.
It's painful. So I think I would really, you know, try to stand up for what's right, and I would offer patients natural cycles if that is what is right for them. Because if a patient's coming to you, healthy ovulatory cycles, wants to do a natural cycle, has read all of IJ's great data that she's presented, on the outcomes of program versus natural FET births, I think that it could make for a really good argument for natural cycles for our patients.
Same question for you. I'd choose a program cycle. I mean, I think that you go through so much to get those embryos.
No, no, you have to do a natural cycle. I'm the program chair. What? You have to do a natural cycle.
I have to do a natural cycle. Yes, I'm telling you, I'm the program chair. I want you to do only natural cycles.
What's your answer? Only natural cycles. I don't think that's feasible for our clinic. I mean, maybe for, no, so knowing I'm at UCSF, I think it's potentially feasible.
We have a very large clinic, a very robust lab. We have the staffing to be able to do that. But if I were at a small clinic in an under-resourced area, it's 100% not feasible to do only natural cycles.
And at a time when we should be increasing access to care, I think it's, you know, maybe, maybe there's some plausibility that there's increased rates of hypertensive disorders and increased pregnancy morbidity, but we're not sure about that yet. And I think to put, I just don't think it's feasible for a lot of clinics to do that. And that's decreasing access when we really need more access.
So it depends on where I am, but. So program convenience trumps all? I think it trumps a lot of things. Yeah.
I don't think it trumps all. And I do think that the pregnancy outcomes are important that they alluded to, but I think that without convincing data, the, you know, we do a lot of things that increase our risk. There are a lot of things in IVF that increase risk for hypertension or other complications by a little bit.
And our patients take that risk on because they want a baby at the end of the day. And I think the convenience of the program cycles for clinic flow and access to care is not to be understated. And patients.
And for patients as well. Yeah. All right.
So I said we had a question from our online audience. I'm going to ask that. If anyone in the room has a question, please come up to the mic that's in the middle of the room there.
And we'll ask those. I would like to have some robust discussion from our audience as well, please. So to the fellows, Ron Beasley, the medical director of Poma Fertility asks for modified natural cycles that include progesterone supplementation.
How many days after ovulation do you suggest starting your progesterone? I think it really depends on the practice. At our, at our practice, we start progesterone the day after we do the HCG trigger and we continue progesterone until 10 weeks gestation. So it really provides that luteal support from the beginning.
If their corpus luteum is just not cutting it for them. And I know that there's data to support starting progesterone three to four days afterwards after your initial HCG trigger. But the outcomes are not as great as starting it right away.
Anyone else have a different answer or different way that you do it in your program? Do we have a question from the audience? One of the arguments in favor of giving patients large injections into their bottoms with progesterone. It seems to many of us that finding good embryos is the primary cause of infertility, creating good embryos and euploid and competent embryos. Couldn't you solve for some of the problems with access or with scheduling by using birth control pills and then aligning one's baseline to be like Monday, stopping your birth control pills on Thursday.
We do a practice where we've got about 95% modified natural FETs. Don't supplement with progesterone if their progesterone levels are fine on LD4. We're able to keep about 80, probably 90% of those transfers during the week by always starting people on a Friday or a Monday with birth control pills.
And just on the controlled cycles, if you are using it, are you guys advocating sesame oil or do you think ethyl oleate might be a nicer solution with a much smaller needle and asbestos? It's more of a comment, but I can't imagine that we'd really advocate for a clinic facility over subjecting somebody to 10 weeks of intramuscular shocks. True. Although I do think there's some patients who would argue that the vaginal progesterone is, I've had patients say that they prefer the IM injections over the vaginal progesterone.
Now that's obviously not everybody. I guess I would just push back and say, so yes, you can do a lot of things to modify natural cycles to make them more convenient, but are the studies looking at those protocols? Not yet. So I don't know that we have the data to support that those super modified cycles are really comparable.
And maybe in your clinic- Just birth control pills prior, not super modified, just birth control pills stopping on Thursdays. Even the HCG trigger to then time it subsequently, right? Because are you using an HCG trigger? Typically, we use an HCG trigger. We used to boost on gluteal day four.
Instead, we started checking progesterone levels. Even then, that falls under the category of this modified natural FBT cycle, which I think all the studies that we presented are very heterogeneous in the study population. I would just encourage for such young and brilliant providers to not make decisions based on what the majority of us do or have done for the last 20 years.
We're arguing a side. We've been assigned this side. I do think that that's a really good point, though, when you're thinking about convenience and you're thinking about scheduling, is that because we are able to modify certain aspects of natural cycles, they could actually present an opportunity for us to have a lot more heterogeneity among the studies that we perform.
Even doing research for this debate, you're looking at these papers with program cycles, and even among us discussing the program cycles that we perform at our institutions, they were widely different. Looking at the papers that were really describing Letrozole, Clomid, FSH, or HMG modified natural cycles, they had pretty consistent protocols that were actually compared among certain papers. I do think that the data could be potentially more robust if we did have more homogeneity in the protocols that we are studying, because we all know that the variation among each clinic can be really challenging when we're interpreting this really important data.
That's hopefully what we'll get with NatPro, because their two arms, the modified cycles, are monitoring no ovulation induction agent, HCG trigger, and then with or without luteal support. I think just answering that online question that we had, at MGH, we don't generally provide luteal support following Clomid or Letrozole modified natural cycles or true natural cycles, although we always use an abdryl trigger to be able to time our embryo transfer. There are some studies that show that abdryl trigger supplementation or HCG trigger supplementation following endogenous LH surge can boost that corpus luteum for the support of that pregnancy, and we will supplement with luteal support vaginal progesterone, usually Endometrin BID, two days after trigger, following FSH or HMG stimulated cycles, specifically extrapolated off of IUI data.
Looks like we have another question from our live audience. Brent Mansour at Stanford. Thank you.
This is really great. I guess my first part is a comment, which is that I think I do appreciate that the NatPro study, which we're involved in, is going to give us higher quality data to answer some of these questions, but I also want to say that I think these findings that we have now that IJ so eloquently presented are likely attenuated by the fact that in our country, because there is such access issues, that we're likely not seeing the risk in the patients that are the highest risk and the highest marginalized patients, because unfortunately they currently don't have access to fertility care. And so my question is really more for the programmed group, and I'm just wondering, thinking ahead in anticipation of the NatPro results, is there a number that would kind of change your mind? Like if preeclampsia is 1.5 times the risk, two times the risk, three times the risk, like where do we kind of say, oh, actually, maybe we should switch the protocol? And in the absence of data, if we do have a patient that has a lot of risk factors, again, just for example, preeclampsia, should that patient get a natural cycle? Because we don't know if they're at increased risk or not.
That's a great question. Thanks, Brent, making us all question ourselves. Well, actually, you have to answer a question before that.
Okay. Does your program offer both? Because this is a choice question. So for all of you, does your program, and does the patient have, can the patient participate in the choice of program versus natural? At my program, yes, you can definitely participate.
Yes, we offer both. Yeah, we offer both, and you know, patients can, we present both options. Yeah, we offer both as well.
We also offer both. We usually have patients that start with programs, and if that doesn't work out for them, then they move on for a natural cycle. Yeah, and we also offer both.
With COCs, OCPs, if they need them to lead into naturals. So, so I guess, Brent, to answer your question, it's hard to assign a number. You know, 1.5 times higher risk, 1.1 times higher risk, it's all higher risk, right? We've all done obstetrics where we know what that risk equals in reality, and it's hard to just think about a number and not about the patient themselves.
So I think if there's conclusive evidence that shows that there's any improved outcome in this RCT trial between natural and programmed cycles, that I would urge my patients to do a natural cycle. And unless there was a significant scheduling issue that they could not make it to, they were traveling, they're traveling from out of state, etc., or, you know, they're inovulatory because the NatPro doesn't necessarily, not including ovulation induction agents, so we don't quite have that data there either. So, you know, unless there's other factors that are not specifically covered by that RCT, then I'd have to consider, but if it's really black and white and there is significant benefit to doing a natural cycle, then I would urge my patients to go in that direction.
We have time for two more questions. It looks like we have our esteemed Editor-in-Chief of Fertility and Sterility Reports and PCRS extraordinaire, Dr. Paulson. Your question, sir.
I'm really appreciating the debate, and I think the literature search that you all have done is very impressive. I'm really impressed with how you are quoting all of the different literature and you're criticizing the various studies. I would point out that there's only one study that has shown that intramuscular progesterone is superior to vaginal progesterone, whereas there has been perhaps 20 or 30 years' worth of data from all over the world, Europe and everywhere, that showed that vaginal progesterone was at least as good as intramuscular, and in fact, there were suggestions in some of the previous meta-analyses that the vaginal progesterone was superior.
The Cade-Devine study was very good, but it did not show a difference in implantation rates. It showed a difference in ongoing pregnancy rates or live birth rates. That is very difficult to explain physiologically as to how that would have been.
That takes a lot of twisting of physiology. Perhaps the program cycle will not be so bad if we're not having to give somebody 10 weeks of intramuscular progesterone. Thank you.
Thank you. Dr. Kwas. Thank you for this excellent debate.
As many of you know, I've spent the last 18 months in Europe, and so I've attended a lot of conferences and similar debates. Basically, what I find interesting is that sometimes you see lectures by, for example, Anja Pinborg from Denmark, where she essentially says that natural cycles should be the standard of care, basically because of the difference in the risk of preeclampsia. One question I've asked over there that I wanted to ask here is, do we get to a point maybe where if this difference in risk is clearly established and beyond any doubt, whether we're almost medically obliged to offer a natural cycle, or whether, for example, it could happen that the family of somebody who had an IVF cycle, a programmed transfer, gets severe preeclampsia, dies, let's say, just as a provocative example.
The family sues the RAI for not offering a natural cycle. Is that something that could happen in the near future? I think if NatPro does suggest that there is a significantly increased risk of adverse neonatal and obstetric outcomes with a programmed FET, I think we'll be shifting towards more of a modified natural cycle. I just think there are significant challenges and limitations with a true natural cycle FET.
I think for the purpose of this debate, it was true natural versus programmed, but I think that there are definitely advantages to a modified natural cycle, and I think that's the way that we will shift if the NatPro findings show concern with a programmed. But it's a lot of ifs, right? Like the data's not there yet, and so we can think about these hypothetical situations, but right now, I don't know that we have the data. But the literature actually confirms what he said, that the trend is towards natural cycle.
So there probably is some truth to that. Or maybe the people that write about natural cycle are just a better writer. And I do think that even though the data is not truly confirmed and published yet with NatPro, I think as RAIs, we should do our due diligence and offer natural versus programmed cycles to patients that qualify.
I don't think we need to wait for the preeclampsia data or maternal death to actually happen to start counseling patients on their options. We have one last question from our audience, and while you're preparing for her question, if each team could just have one person get ready to give us one or two-minute closing as to why your side is the best, and then we'll take an audience vote as to who won the debate today. Thanks, you guys, and great job.
So I don't see really any downside to a natural cycle FET in someone who's young and ovulatory. I think that data is pretty obvious. But I am curious, as we're starting to do a bit more embryo banking and women are coming back to have their second or third baby from a batch of embryos that they froze when they were ovulatory, and now they're 42 to 44 and still getting periods but sometimes miss one.
What are your thoughts about, I guess that's the one group that I hesitate with the natural cycle transfer, because I do think that they're at risk of some abnormalities in their cycle, even if they aren't at the point of absolute, you know, approaching menopause. I think the, you know, the concept of being able to really assign or choose what you decide for a protocol for a patient obviously needs to be individualized, and I think that among the older populations, our clinics can potentially develop protocols that could account for that potential early recruitment that we see among that population. That if you are monitoring cycles over the course of, you know, a lot of our patients have these great apps that monitor their cycles.
They come in with a wealth of data that they collect on their personal devices. I think that there's a lot of opportunity for us to be able to really utilize modified natural cycles in those contexts, because I think it allows us to regain a little bit of control from our clinic end to be able to ensure adequate follicular development. The other aspect of it is, is that it's not necessary, and this kind of goes towards our closing remarks, is that it's obviously not one size fits all, and so even offering a natural cycle initially for that patient could allow them to be able to at least try, and then attempting a switching protocol subsequently could be a potential option for that patient.
And so, I think monitoring that patient, offering it to them, being able to have them have access to these cycles, despite how it may derail our schedules and convenience, I think could be a good option for these patients, because you never know until you try. And I want to take prerogative to go just a couple minutes over here, because we have Dr. Devine up at the microphone, who's done some of these studies, and I think has some comments that might be helpful for us. So, I just had a couple of quick comments.
You know, I, to the question of whether this is something that needs to be offered to all patients, and whether patients should have autonomy in choosing which protocol at this point in time, I think that this is an open question right now, in terms of what, whether one or the other is better, and if your center is not involved in enrolling patients in a prospective randomized controlled trial, that yes, if your center can accommodate either type of protocol, patients should be informed of the potential pluses and minuses, and offered whichever protocol they so choose. That said, I think this is an excellent opportunity to put in a plug for doing prospective randomized research. Shady Grove is the lead enrolling site for NAPRO at the current time, and for my patients, honestly, when they say, I want a natural cycle as my primary protocol, that's a hard no for me, because this is, at this time, an area where we have the potential to contribute by doing a randomized controlled trial, and if they fail in a program cycle, great, we will offer them a natural cycle for the next time, but we don't know.
There are no prospective data showing that one or the other is better, and we have the potential to answer a lot of really important clinical questions. Now, that may be further than some people want to go on the research side, for sure, but I do think that when we have a question, and it's an unanswered question, and we don't know which one is better, we should take the opportunity to enroll these patients in research studies. Thank you, Kate.
So, we're going to go in the reverse order. We'll have the program side give your closing minute argument. Thank you.
Okay. The program for embryo transfer has been the gold standard in endometrial preparation for FET, and has revolutionized how we can personalize embryo transfers for patients. Programmed FET can be offered to any patient, regardless of ovulatory status, and reduces unnecessary clinic visits, ultrasounds, lab work, in addition to unanticipated embryology workload.
Most importantly, live birth outcomes are not inferior to outcomes following a natural cycle FET. While some poor quality retrospective data shows an association between programmed FET and adverse obstetric and neonatal outcomes, these studies are small, retrospective, and many of these studies do not control for baseline maternal characteristics that could contribute to these outcomes. The natural cycle FET requires substantial monitoring and clinic visits as a protocol that risks inappropriately timing a transfer based on inconsistent guidelines for determining the LH surge.
The LH surge can be inadvertently missed, which risks cycle cancellation or suboptimal timing of an embryo transfer. While it's important to continually challenge the status quo, the programmed FET is a status quo that is here to stay. Thank you.
Natural cycle. So I think that we've spent a lot of time today trying to really discuss and better understand the benefits of each side of these protocols, and as the number of frozen embryo transfers continues to increase over time, they have to recognize that there is no one size fits all. I think that we have seen generations and generations of people reproduced through natural cycles through our entire lifespan as humans, and while our infertile population is specifically different among these people, we have to really consider at first we must do no harm as doctors.
And so if we even have whatever data that we have currently, we must be able to critically analyze this data, and if it if I were to even have the small amount of data that we have, it does show that we do have increased risk of preeclampsia, macrosomia, and poor obstetrical outcomes in that capacity. We must listen to what we have until we have more prospective trial data available to us. I would posit that at the end of the day, a natural cycle can allow for less medications, can allow for benefits of pregnancy and obstetrical outcomes, and more importantly, can allow patients to retain and reclaim their control within their cycle in the sense that they are not stressed about timings of injections, they're not destined to try to find a specialty pharmacy when they're out of town if they forget their progesterone, and they don't have those terrible estradiol stickers all over their abdomen.
And so if you think about what there are obviously always going to be patient populations that are going to uniquely benefit, such as the inovulatory population from program cycles, but we do have a lot of tools under our belt to be able to modify these cycles for not only patient convenience, ultrasound monitoring convenience, but also for access to medication convenience and being able to decrease these costs will definitely be a clinic-by-clinic standard. Clearly there is more work to be done in evaluating the impacts of these protocols among patients, and ultimately protocol recommendations should be personalized to each patient or couple to maximize healthy pregnancies, deliveries, and offsprings, and at the end of the day, that's all we ever really hope for. Thank you so much.
Thank you. So now we're going to take a vote from our live audience. This isn't which one you would choose because we saw at our pre-poll, thank you for doing that, I actually had meant to do that, that most of us are doing programs.
So this isn't about what you're doing or what you think is better, this is about which side did the better debate. Who would have made you an argument that could convince you to change to that program? And then Dr. DiCierno, Editor Emeritus, sir, you will make the call on which side won. So we're going to start with Natural.
Did Natural give the better argument today? Raise your hands. All right, good job. Good job, Natural.
And Programmed, did Programmed win the debate today? Looks the same. You can't have a tie. You have to declare a winner.
Okay, well, I would give it to this side because of grace. Not because of you, but because you come from a superior program. See, this is a great example of all studies having bias that we must consider in this decision.
But the truth is it was a tie before we even started. Thank you so much to our fellows for being willing and able to come up here. It takes a lot of bravery for anyone to do this, but especially while you're in training and with program directors and leaders and other people in the field to do this.
So thank you for doing that. For our attendees, at 5 30, the poster session is in the Valencia Ballroom. There are wonderful drinks at the pool bar.
If you want to grab one of those and head over to the poster session, please make sure that you support our fellows and their wonderful abstracts. Thank you.
