Journal Club Global from ASRM 2024: Obesity and Reproduction

Join Fertility and Sterility to discuss the effectiveness of preconception weight loss interventions in women with obesity and their impact on fertility outcomes.

Articles:

• Effectiveness of preconception weight loss interventions on fertility in women: a systematic review and meta-analysis
• A weighty issue: Views and Reviews

Discussion points:

1. What are the associations of obesity with infertility?
2. Do lifestyle interventions improve reproductive outcomes?
3. What is the mechanism and efficacy of GLP-1 agonists?
4. Should weight limits be utilized for fertility treatments?
5. Should patients attempt to lose weight prior to fertility treatments?

Discussants:

Moderators:

Good afternoon everyone and welcome to Fertility and Sterility Journal Club Global. I'm Micah Hill, the media editor for FNS, and we're very excited to have you here today for a great talk on obesity and reproduction. My co-host today is Pietro Bortoletto.

Hello, Pietro. Hi everyone, good to be back here. Feels like we always meet in the same room, same time, one year apart.

We love hosting these sessions and thanks for everyone for spending their lunchtime with us at this live event. Wanted to make a quick plug. As you've probably wondered, this is a session that's on obesity and its effect on reproduction.

We were contacted by a couple of investigators that are actually looking at this specific topic and asked if we would share this survey link. This is a two-minute survey. If you scan the QR code, they'd love to understand a little bit more about what your practice patterns look like with regard to weight loss medications, if you're a US-based fertility clinic.

So please take a scan if you're interested and fill out their survey. Thank you, Pietro. So please fill out that survey for these fellows who are doing this awesome research.

I'm going to introduce our amazing panel of experts. We have Annie Caldwell, a PhD from the University of Colorado. We're going to be discussing her paper today.

We have Karl Hansen, MD, PhD from the University of Oklahoma. Sammy Schon, MD, from the University of Michigan. Go blue.

Eric Widra, MD, Shady Grove Fertility, DC. Christina Boots, MD, Northwestern. And Rick Legro, MD, from Penn State.

So we've got the Big Ten well-represented here today. So we're actually going to start with you, Eric. So tell us a little bit as an editorial editor for Fertility and Sterility, what are the views and reviews, and why did you decide obesity and reproduction was an important topic for us? Thanks, Micah.

The views and reviews of ENR, as we talk about, are an opportunity to educate our readership in our society on emerging topics and take a more or less deep dive into the state of a particular topic. Rather than being hypothesis driven, they're topic driven, and give us an opportunity to invite experts like we have on the panel today to comment and write really cool, interesting articles. The impetus for this, for me, came from a realization that even within my own practice, there was really a frustration over management of obesity in concert with reproductive care, but also I think a knowledge gap in terms of how that field has changed.

To paraphrase one of our authors, obesity and infertility medicine have not been on a collision course. They've been tectonic plates that keep grinding against one another to varying effects, and so I thought it was a great opportunity to pull these folks together and educate us on the state of our approach to obesity in counseling patients and treating them, and what's new, and I think as you'll hear today, that world's changed, and for the better. Thanks, Eric.

We should probably set the stage before we dive into some of the data, and we've asked Dr. Shone to tell us a little bit about how obesity impacts reproduction, number one, at a high level, and this could be a whole hour of just talking about that topic. And number two, when we talk about obesity, I think we tend to gravitate and are anchored towards BMI as our quick and dirty way of discussing obesity, but really would love your input on, is this the best marker to talk about the impact of obesity and reproduction? So I think we all know that the impact of obesity on reproduction is complex, but it's also significant. As REIs, we know that it impacts every aspect of the hypothalamic-pituitary-ovarian access, clinically, it's well associated with menstrual irregularities, longer time to pregnancy, for our patients that do require fertility treatments, increased doses of medication, poor outcomes during their IVF cycles, increased risk of miscarriage, and then of course all the obstetrical outcomes, both maternal, fetal, transgenerational.

When it comes to BMI, the short answer to, is it the best metric, is no. The longer answer is, you know, I think at a population level, BMI is helpful. It's cheap.

It's reproducible. It's easy to measure. So it's an appropriate measurement for large epidemiological studies, but in an individual level, it's really lacking.

So I think it's really not a good measure of pathologic adiposity or this idea of adiposopathy or sick fat. It overestimates or underestimates based on race, sex, age, ethnicity, and it's not a great metric for people that are extremes of mean body mass as well. So I think it leaves a lot to be desired.

If you had to put your investigator hat on and you had endless amount of money and time and access to patients, what's the what's the preferred way to really investigate the link between obesity and reproduction? Should everyone be having a DEXA scan? That's what I'm doing in my studies. But I think it's more complex and I think that when you just take a metric like BMI, you overlook this idea of pathologic adiposity. You don't capture sort of impairments in metabolic dysfunction, right? And I think that's probably more telling for a lot of our patients.

When I see a patient in front of me, I say your BMI actually tells me very little about you, right? If my patient has hypertension or they have pre-diabetes, I think that's a lot more informative for counseling about their risks during pregnancy than BMI. So Annie, before we dive into your meta-analysis and systematic review, as a PhD doing research in this, do you have anything you want to elaborate on what we were just discussing? Yeah, I really agree with that. Pretty much everything you said there.

It is, you know, nice though to have something that could be a quick and dirty measure that we often get in the office like BMI is. And so I think even just starting with using waist circumference and measuring visceral adipose tissue, even if it's just through waist circumference, could be a good clinical marker that would be informative in addition to BMI, you know, before we get real fancy and actually know weight distribution. So let's jump into the evidence, Annie.

So you published this systematic review and meta-analysis looking at clinical trials in humans on this. Summarize that data for us. What did you find? Yeah, so we were able to whittle down to 16 randomized controlled trials who had randomized women to either a weight loss intervention that was lifestyle or lifestyle plus medications or medications alone.

And we found that there was first of all wide variability in all of those studies protocols and the way weight loss was approached and the way the control groups were assigned. So sometimes they're weight listed, controlled. Sometimes they're still in a, you know, healthy lifestyle informational group.

So there's a lot of heterogeneity across studies, but we did find a significant increase in pregnancy rates overall. However, there was not an increase in live birth rates. So or miscarriage between the women who had gone through a weight loss intervention and those that were in the control groups.

And then some of our sub-analyses were a little bit more interesting. We found there that women who were in a weight loss intervention that was shorter, 12 weeks or shorter, actually had higher pregnancy rates and a trend towards higher live birth rates. So, but that's a little bit counterintuitive that the shorter the intervention the better outcomes.

And I will say we've looked into a new test for publication bias and did find that that main outcome result of an increase in pregnancy might also, like it should be interpreted in light of the possibility of publication bias, I think especially of the earliest studies on this, for, you know, mostly the data including studies that had a positive result or a significant p-value to report rather than no difference. So let's get a little bit nerdy here for a second and sort of dive into the statistics and how you interpret this. Obviously, when you're statistically synthesizing data from different authors, different studies, there's a lot of challenges in that.

You're using clinical trials, so that helps with some of the confounding. But obviously that doesn't mean that the studies are all the same. So why did you choose a random effects model? And how do you deal with heterogeneity just in the study design, in the patient population, in the interventions that these primary source studies are using? Right.

Great question. So a fixed effects model which is not what we used, assumes that all of the trials are the same and all the people in the trials are similar and all of those kinds of things, and that what you're seeing is like an actual effect. The random effects model allows for heterogeneity across trials and to try to estimate if you removed that effect of the heterogeneity across trials, what the effect would be taking into account the heterogeneity.

And then you made some interesting comments on the risks of bias as you did the bias assessment on this and you said that there was low risk of selection bias, but a high risk of performance bias across these studies and several of them were at risk of attrition bias. So just for our learners out there, explain what you mean by those three biases. Yeah, so the gosh, so attrition bias means that there was greater attrition in the intervention group compared to the control group.

And then the performance bias is reflecting how closely, oh shoot, does someone, I had it. No, no, no, that's okay. So with the attrition bias, obviously when we're talking about weight loss studies, so one of your findings was that 12 weeks or less of intervention was helpful, but more than 12 weeks wasn't.

So do you think maybe that explains why? Because there's greater risk of people dropping out if it's a long intervention before treatment? That's a possibility. And then we've also considered that, so my expertise is really in these weight loss trials and we see the highest adherence and within those first three months and adherence and weight loss tend to taper off after that 12 week period. And so there might be a diminishing returns thing that's happening if you have a longer weight loss intervention where people aren't actually losing weight.

Yeah, and with performance bias, specifically with weight loss, you can't blind the patient to what they're being randomized to. And if they're being randomized to a placebo arm versus an intervention arm, you certainly, I could see, be at risk of a performance bias in these studies. Yes.

Yes, and we only had one, which was a study in China, Wang et al, and they had an obesity medication and it was a really like very well done randomized control trial where they were either getting an obesity medication or a placebo. So that one was blinded and there were, there was a really large trial sample size of 600 or so. No difference, no increase in pregnancy, live birth, or miscarriage rates between groups.

So before we move on to our next question, I just, from the clinicians up here on our panel, when you read this meta-analysis, how did you interpret this clinically and how do you counsel your patients based upon the data from these trials? Sure, I'm happy to weigh in. Can you hear me okay? Yeah, I'm happy to weigh in on that. I think this meta-analysis largely, in my mind, confirms what we've seen in the other studies individually, as well as the practice committee document that we put out a couple of years ago, and that is that when we're talking about weight loss interventions, we need to have a careful discussion with patients about what we know and what we don't know about those types of interventions, and also what we know about benefits and lack thereof in some cases.

So it, in my mind, reaffirmed what I thought was largely the situation. Yeah, I mean, I'll echo Carl. You know, the gold standard is live birth, right? Nobody really cares if they got pregnant or had a positive pregnancy test.

They want a baby. So, you know, I saw it as supporting, you know, we shouldn't be counseling patients that losing weight is going to give them a better chance for having a baby because the evidence doesn't support it. When it comes to counseling, I think one of the things that all of us are actively dealing with in the room, and I imagine a big draw for the attendees today, is the new medications that have entered the sphere of weight management, particularly the GLP-1 agonist medications.

Christine, I'd love for you to, one, start by educating the audience a little bit about what is the mechanism of action of these GLP-1 medications, but then I have a, I have literally 50 minutes of follow-up questions regarding them because I think all of us do as well. But let's start there. Well, the, these medications are actually pretty complicated and they have pleiotropic effects on multiple different organs throughout our system.

So we could have a whole hour on this too, and much of it still isn't totally understood. We believe that the primary mechanism for the, just got a lot louder, the primary mechanism for the weight loss is probably mostly targeted in the delayed gastric emptying and the effect it has on appetite suppression. But in addition to what it's doing for weight loss is also, it's targeting the islet cells in our pancreas and improving insulin secretion.

It's involved in providing anti-inflammatory effects. There's some data that shows that the thermogenesis in our brown adipose tissue is increasing. There's data in the cardiovascular literature that's showing some vasodilation, and so it's helping some cardiovascular outcomes.

There's effects on the brain and our perceptions, which I alluded to earlier, in terms of appetite suppression. So there's almost no organ it's not touching in a nutshell. And one of the things that you mentioned and probably its most powerful mechanism of action is the delayed gastric emptying.

For the average patient going through ART who's not experiencing anesthesia, that's probably not a big deal. But talk specifically about our IVF patients who will be undergoing their conscious sedation and how that gastric emptying affects your recommendations peri-conception. That's a great question.

So the anesthesia guidelines are really driving this and they came out with new guidelines probably almost exactly a year ago now that recommend that in whatever type of anesthesia event that's going to be, so whether it's a MAC that you use for an egg retrieval, if that's what you use, or a general anesthetic for a hysteroscopy, I don't use a general anesthetic for that, but you know what I mean, for a bigger surgery, that you should be stopping it seven days ahead of time so that the risk of aspiration is a lot less. I think there's still some data that needs to be explored to see if that risk is really truly there in some of these patients and certainly in some of the more moderate anesthesia. But the guidelines now are to stop at least seven days in advance, so that's certainly what we're doing in clinical practice.

And our anesthesia group locally is really focusing in on how long they've been on these medications. It sounds like the severity of the gastric emptying is an early symptom or early helpful side effect of the medication, but with prolonged usage the gastric emptying is a little bit more normalized and may be safe for them to stay on it, peri-anesthesia. But I guess the the big unknown question for us is for these patients who are actively trying to conceive, what if they get pregnant with recent exposure or concurrent exposure to these medications? What do we know and not know about pregnancy safety? There's a lot we don't know.

There is, you know, initially there's animal studies looking at the effects of GLP-1 exposure on offspring. And there are some deleterious effects of birth defects and and other things on that gamut, which has cautioned us certainly to have some amount of time of clearance before conceiving. The guidelines aren't really clear.

The FDA guidelines on terzepatide, which is zep-bound and zep-bound and manjaro, actually don't specify that. But the Canadian FDA guidelines suggest four weeks. The FDA guidelines on semaglutide, which is wagovi and ozempic, suggest eight weeks.

So we're trying to follow those guidelines in our own clinical practice. There has been some data, two studies came out in the very recent past showing, describing the outcomes of women who were taking it and then incidentally conceived. There's ongoing registry data by both the manufacturers as well, too, but this at least initial data is very reassuring.

They did not see the outcomes that were shown in some of the animal models that there were now increased risks of birth defects. I think, you know, this doesn't give us free reign to like, oh go ahead and just continue it, because I think, you know, long-term effects on not just the baby's, you know, birth defect rate, but their metabolic health from the rest of their life, you know, still very, very unknown. But I think a lot of us are trying to look at that.

For people wondering how do we come up with four weeks, six weeks, eight weeks, they look back at the pharmacodynamics studies and look at what are two half-lives beyond the medication being able to be cleared by the system. I think that's why people are centering around this. You probably need a few weeks for it to truly be out of the system.

One of the questions that I've come up with over and over again in my mind is we have this prototypical PCO patient who tends to have a higher BMI, have some of these comorbidities that may be being prescribed these medications for weight loss independent of the fertility benefit of it. We're seeing a lot of them starting to ovulate when they lose five to ten percent of their body weight. What does this mean for Clomid and Letrozole and patients who would otherwise need ovulation induction to ovulate? Do you think we could potentially be viewing these GLP-1 meds as primary fertility medications once that data matures for that subgroup? I think so.

I mean, I'd love to see just lifestyle counseling start much before they even see us for these PCOS patients that I think, you know, some really thoughtful and intentional and individualized lifestyle counseling about nutrition and activity may go a really long way and then by the time they see us, I mean, I think so. I think some of these women have tried for a long time and have really reached their lifestyle limits at which they can help themselves. So I think these medications that help them have better insulin resistance and associated weight loss show are showing that they're more likely to be more likely to ovulate and I think that's shown, you know, even in the randomized controlled trials that when you're looking at women who are anovulatory, that weight loss does seem to benefit their menstrual cyclicity and their ability to ovulate.

So I think potentially so. The tricky part is what happens when you stop the medication? And so you have to stop before you're starting to conceive and when you stop the GLP-1s, they stop working. So when I take my glasses off, I don't see anymore.

When I stop my GLP-1, it doesn't keep working. And so, you know, there's a lot of data. I don't know if you wanted me to go all the way into that, but a lot of data on rebound weight gain for these women.

So there's a lot of counseling that mental health counseling that goes into what to do when we stop these medications and how to help keep up the ovulation. This is where it gets really messy though, right? I mean, the meta-analysis shows that you ovulate more, but you don't have more babies. And it's a pretty expensive drug compared to clomiphene or letrozole.

And this is the conundrum that we face every day. And, you know, from my perspective as, you know, a clinician struggling with, you know, things like BMI limits, which I know you guys are going to touch on, it's not just, you know, does the pregnancy rate change? It's the pregnancy complications and whether my OB will ever talk to me again, you know. And so it really is a fascinating web of decisions and options that we now have.

I think this just speaks to the need to individualize it. There are some women who really want to optimize their lifestyle and their weight and feel much better about themselves before they get pregnant. And I think, you know, we just don't have that really, really long-term nuanced data that if there is weight loss before and they don't gain in the pregnancy, you know, what is the second pregnancy? Are they less heavy when they attempt their second one? I think we just don't know yet, but it is expensive and I'm not suggesting it should replace letrozole.

Oh, no, I wasn't trying to make a cheap shot. It's complicated. Yeah, just to add to that a little bit to our OBGYN colleagues and MFMs that are concerned about us helping patients achieve a pregnancy with obesity, I just remind them that patients with obesity are mostly fertile.

They're getting pregnant all the time without our permission. And so, you know, I think that's a point that needs to be driven home in some of those circumstances. But to the question about could these medications ever be a first-line treatment or how do you see them working in the care of a patient with ovulatory dysfunction? I think that depends very much on what a patient's goals are at the moment.

In other words, a patient that may not be desiring pregnancy now, but wants to pursue a weight loss intervention, may ovulate and may get pregnant once weight loss does occur. But if a patient wants to get pregnant now, the best data that we have is that they're better off pursuing first-line treatment right away. So I would do clomidoletrozole in that setting if the patient wants to be pregnant now.

So let's move the conversation on a little bit to BMI limits. So Rick, let's start with you. You have a publication in the journal that shall not be named at FNS Journal Club called Mr. Fertility Authority Tear Down That Weight Wall.

So tell us what your thought is on BMI limits for fertility treatments and ART and should it be different between the two? Yeah, so certainly that was in a European publication where their public health benefits usually cut off at 35 UK in many countries in Europe and in Australia, New Zealand, it's 32. So you can't get clomiphene citrate if your BMI is 32.1 through any publicly funded infertility treatment in New Zealand. I think that the effects of BMI on fertility outcomes are greatly exaggerated.

We're looking at relative risks that are well below two for most of the outcomes and you need huge sample sizes, as the WHI would indicate, tens of thousands to really, you know, to detect a difference. And so it's also a sliding scale, you know. It's not as if there's at 35 you have a good horrible outcomes at 34.9. It's good.

And I so I think that we it's arbitrary and I think it's also discriminatory. So for instance in New Zealand the Maori population is obese partly because of the Western diet that's been introduced and they're systematically excluded and same thing in the U.S. Those the patients with the poorest social determinants of health are the ones that are most obese and the ones that are going to be excluded from health care. So to me it seems somewhat arbitrary.

Sir, are you advocating for no BMI cutoff? No, be much higher BMI cutoff than we currently use. I would advocate and our practice is such as there's no BMI cutoff and part of it's because we don't use conscious sedation for oocyte retrievals. We use intravenous analgesia and PO valium.

So there's no anesthesiologist to tell us that someone is going to aspirate or die on the table. And again many programs USC where I trained at Duke did it way back when. So I think it's a hurdle this anesthesiology BMI 35 that I don't think is justified by the complication rate of conscious sedation in those patients.

And I think that we should be fighting back and arguing that we can do conscious sedations or other forms of analgesia to allow these patients to go through IVF. So Carl you were the good shepherd on the recent practice committee guidelines on obesity and reproduction. Tell us what what the conclusion was from the practice committee on BMI limits for fertility treatments and how did the literature and ethics of this help you arrive at that conclusion? Yeah, sure.

So when we revised this document a few years ago now, it was at an important time. It was right before the GLP-1 agonist really took off. So that's one area that we missed.

But there had been several large trials that had come out at that point that really addressed the question that we had and that is does a weight loss intervention improve outcomes? So that was an important part of that document. But the other important part was the point you're getting to and that is that our membership really wanted us to tackle the issue of BMI limits in terms of offering care and infertility practices. And as you know many practices had guidelines before that time and the majority of our membership wanted us to take a stand on it.

And so we felt it was important to do so. And I think we're bolstered by the evidence from these trials that if your outcome is a live birth and even a healthy live birth, the trials that we reviewed at the time and the trials we still have today don't show an improvement in the outcome of live birth. So that if that is your outcome that you're looking at, then a weight loss intervention did not show to improve those things and in some cases could have even had a detrimental effect in terms of time to pregnancy.

So with the BMI threshold issue itself, with the lack of any medical intervention or support for medical intervention like that, we really just stuck to ethical principles to decide and to look at the question does it make sense to withhold treatment based on BMI? And the answer is clearly that it doesn't. We treat patients all the time that have a number of medical conditions that may impact their care both before and during pregnancy. We also take care of many patients that have poor prognosis.

So decreased ovarian reserve and advanced reproductive age, for example, and so we don't withhold treatment from those individuals. Why would we think about doing that simply because of a BMI issue, so to speak? So then what we're left with is really just safety and the safety is primarily in the egg retrieval procedure itself. And we felt justified at the conclusion of that document empowering clinics to say, you know your environment, you're working with an anesthesia team.

Really the sole reason to withhold treatment to someone from a BMI standpoint should be because of safety concerns in your environment. So I practice in a mandated state and it's nice to sometimes have a bad cop that's not me. Sometimes insurances say your patient has a BMI above 35 or 40 and unless they're able to get that weight down below that threshold, we won't cover the cost of treatment for them.

Does the practice document opine on the unique aspect of mandated states and insurances having limits to limit access to care? That is not one of the conclusions of the document, although I don't remember exactly what the mandated states. But you know, I would say, you know, in our own practice, we are not a mandated state. And so there's not a lot of insurance coverage and have not had issues with BMI cut points.

But your point is well taken. In some cases that decision may be taken out of the practice's hands based on reimbursement. We should be fighting back against that, you know, if the data is not there.

I'm in a mandated state too, and I've never seen us have a BMI cut off in our coverage age and FSH. But we should be fighting back against that because there's a lot of people who have a worse prognosis. Carl, with the practice documents, are they ever taking a slant where they're actually trying to tell the insurance companies what they should be doing, saying that this should be the standard of care? Good point.

Yes, absolutely. We know that insurers many times come to our documents as what is the standard of care in a given area. And we've done that in a number of other areas in reproductive medicine.

So, for example, revision of our definition of infertility was expanded in order to be inclusive, but at the same time to help drive insurance coverage. And certainly, I feel that the document may serve in that purpose as well. So, I want to hear from each of the clinicians.

Obviously, not every practice always follows everything that's in the practice guidelines or committee opinions, and there can be a variety of reasons for that. Rick very clearly told us that they don't have any weight limits and why. So, let's just go down the table, Christina, from you.

And does your practice have weight limits? Is it different for ART versus regular infertility treatments? And if you do have limits, why? Yes, we don't have any BMI cutoffs for IUI or ovulation induction, but we do have requirements for egg retrieval and IVF. We are in a, I'm at Northwestern, and we're in a hospital system where we do our egg retrievals as technically, even though it's on campus, is an outpatient suite. And so, we have a hard cutoff of a BMI of 45 that's mandated by anesthesia.

But in higher BMIs, we can take them to the main operating room, which is a bit of a resource pull, but we can do it if we need to do it. So, we have no cutoffs in cases of medical fertility preservation. And under an infertility diagnosis, our current stance is at 50.

How challenging is it for you to get the eggs from the main OR to your lab? It's actually not bad at all. I'm happy to talk to anybody who has questions about that, but our embryologists, it's in the same building, it's just a different floor. So, our embryologists bring an incubator down, and they just take the vials and tubes and bring them back up and find the eggs up there.

That works great. We get good outcomes. Eric? Can I leave? So, we've had this conversation at SGF frequently, and as medical director, which I'm not anymore, I would start every conversation with, you guys realize that we don't have evidence to say that we should have a BMI cutoff.

It just isn't there. And the next thing is exactly what Rick said, but anesthesia. And I, you know, I agree with Carl that if you really do a risk-benefit analysis on this, it's really hard to to justify, you know, these cutoffs.

Having said that, our IVF ART cutoff is 40, and our ovulation induction cutoff is 45. One of the straw men that is often brought up is, you know, what about the the DNC or the laparoscopy for ectopic? And once again, I think if you if you really look at the numbers objectively, it's hard to justify. But as I hope most of you in the audience said, this is clinical care, and you have to make compromises with your team.

And you know, as I say to my patients who want a Saturday FET, I said, if I don't, my lab all quits because we do Saturday FETs. I don't have a practice anymore. And so you have to have anesthesia, and you have to you have to compromise to be comfortable.

We've had some really shocking comments from anesthesiologists and anesthetists that are really data-free. But yet, we have to work together. So it's a challenge.

Yeah, I was just gonna chime in. Does anyone see the absurdity between refusing to do conscious sedation, some of the BMI of 36, for an extremely low-risk procedure, and yet come to labor and delivery where 50% of the patients are obese, and super obesity too, and they're doing epidurals and general anesthesia and everything else in the book. It's like a disconnect.

So I think we do have to fight against anesthesia, and I fully agree with Eric. There's no evidence that that BMI significantly increases risk of anesthesia. In fact, I think there's evidence from Brigham and Women's Hospital that have routinely taken care of patients with BMIs of 65 and above that it is safe.

The conversion rate to a more advanced airway and complication rate is exceptionally low. But again, having the benefit of being in a in the hospital, one floor above the ICU and two floors above the main operating room style facility. Carl, what about Oklahoma? What's your cutoff? We don't have a cutoff for ovulation induction or insemination treatment cycles.

For BMI, for egg retrievals, our cutoff is 50, and that again is an anesthesia concern. We do have a team of anesthesiologists that do cover labor and delivery, and so that is helpful in that they're, as Rick mentioned, taking care of a population with obesity in many cases anyway. But the 50 is for our outpatient procedure room, which is not really a hospital setting.

Samantha, what about in Michigan? So no restriction for ovulation induction. Similarly, we are an outpatient center, and our BMI cutoff is 40. We do offer retrievals at the main hospital, and it's something that we're trying to ramp up.

We do, we send our embryology team over in a minivan with an incubator, and it works. But I think, I think, you know, building on what other people said, I think, you know, it's not only discriminatory, but in our field there are some patients who are never, they're never gonna reach a BMI below 40, or they're never gonna reach a BMI before 35, and that patient may have already lost a hundred pounds, and metabolically be in much better shape than someone with a BMI of 28, and if that patient is in their late 30s, then we're denying them their family, and that seems really counterintuitive to what we do. I have one more question for the panel before we move to questions from the audience, and if you have a question that you'd like to pose to the panel, there's gonna be microphones in the hallway, in the, in the aisleways, and if you want to line up, we'll, we'll get to you next.

We've been talking a lot about restrictions in our ability to care for these patients. I'd also like to ask the panel, what are the things that your clinics are doing proactively to help these patients lose weight? Specifically, in-house or contracted nutrition counseling services, the ability to get them plugged into a weight loss program at your local institution. Have any of you guys formalized that? Is that something that happens in a haphazard way? We'll start this way and go back.

So, a couple years ago, I actually started a multidisciplinary clinic for women with obesity and reproductive disorders, and so in our clinic, the patients are offered basically a half day of consults with an obesity medicine specialist who has a weight navigation program, so essentially, all the options for weight loss that are available through the university, be it complete meal replacement, pharmacology, etc. They meet with a nutritionist, a social worker, MFM to do their pre consult, and then myself, who works with them longitudinally and follows up with medications and treatment. That's amazing.

It's great. Yeah, but I think that we can't, you can't tell patients to lose weight and not provide them with referrals and somewhere to go. Carl? Yeah, so we do not have resources embedded within our clinic, for example, a nutritionist, dietician, that type of thing, but we do have resources both within and outside our system that we can refer patients to, including a bariatric program within our own system, and that's a little bit of variation amongst providers, honestly.

Some of our providers are more comfortable prescribing weight loss medications. Some do not, and then, of course, the outstanding question of the GLP-1 agonist that we've been talking about as well. Who's comfortable using them, and what are the next steps to introducing them more broadly into our practices? Yeah, that's a good point that I'll interject here for a second.

By a show of hands here on the panel, who is prescribing GLP-1 meds for their patients? Sort of. Interesting. Fabulous.

Eric, what is it? I'm just gonna answer to Sammy there. I think it's a waste of time to send someone with obesity for nutritional counseling, psychological counseling. There's no evidence that it's effective.

It wastes time. Choose up resources. There's no patient that comes who's obese who hasn't tried to lose weight on their own, and I think that's why I'm such an advocate for the GLP-1 agonist.

Give them something effective that actually works. The counter to that, though, is you can't just give someone a GLP agonist because when they stop it, they're gonna gain the weight back. So I feel like if you give someone a GLP agonist, but don't also plug them in with nutritional to change their behaviors, then when you stop it, you're not necessarily doing them a favor.

Well, you know, maybe it's something that they're on lifetime. Maybe they take it up to the point where they have a positive pregnancy test. I mean, I'm gonna argue these are huge molecules.

The likelihood they, we don't really know if they cross the percentage, but just from a molecular weight size, unlikely. You know, this is all created by industry to avoid malpractice or, you know, class-action suits. We need to find out, you know, how to give these drugs to women that want it.

I think it does help with some of the barriers, though, from an insurance standpoint, because a lot of them do require that. So if I can say they're already working with my nutritionist and they're already checking these boxes, then sometimes it's easier to get coverage. I also see a lot of patients that aren't trying to get pregnant right now.

So a lot of PCOS patients. And I think, again, having the tools, having a nutritionist that they can then work with during pregnancy as well, it provides a lot of support, which is helpful. And the rebound weight loss when you use a GLP-1 agonist can actually be reduced with exercise.

And so there was a trial recently that showed that if you add exercise when you're stopping the GLP or during use of the GLP, you can reduce that weight gain rebound that happens. And there was, for a long time, thoughts that women shouldn't exercise during pregnancy and maybe some of that sort of knowledge should be also re-explored in light of this. Let's open up to the audience.

Let's put our panel to the test and see what tough questions we have. If you're watching us live online, tweet out or X out to at Fertstert, and we'll look at those questions. We'll start with our illustrious editor-in-chief.

Kurt, what's your question for the panel? This was terrific. I want to stay on the same theme you guys just touched on here, which is before we can recommend GLP-1 as a fertility treatment, we have to realize we can't give it in pregnancy right now. There is a rebound effect, and Dr. Legro's own data would suggest that weight loss before pregnancy might actually increase nutritional, I mean miscarriage, and all your rebound is in the first trimester, which is going to potentially increase obstetrical complications, weight gain during pregnancy.

So, my question is, as REIs, we sometimes forget what happens to patients after they leave our office, and I wanted you guys to just pontificate a little bit on whether we're there yet and we can use this medicine. I'll tap the people who are actually prescribing them. I think this is a great question, and one that we don't know the answer to.

I know the ADA meeting this summer is trying to ask that same question, you know, and patients with diabetes who are, you know, they have this great tool to lower their glucose, and then you take it away, and their glucose spikes, you know. What's the right answer here? I don't think we know yet, so I think we have to keep studying it, and I'm going to say this a hundred times, but I think we really have to individualize it and say, okay, who's most going to benefit from this weight loss, and if it's profound, because it gets them access to IVF, then I think you should use it, and I think, you know, I think it's kind of nuts that we're prescribing it. Like, the primary care doctor could have done this five years ago before the infertility started, and so I'm hoping that there's this, you know, PSA that we can do that, but right now, I think it's reasonable.

I will say just anecdotally, you know, in the studies, for sure, there is weight gain, but not everybody regains, and I think that's where, you know, a dietician, if they're motivated, I think, you know, exercise can help. Metformin is thought to be help. I'll say anecdotally, I have some patients who say this is the first time, like, I recognized portion control, and so more intuitive eating started to come into play.

They've lost weight, so they're more active. It's not everybody, but if you have patients who are really motivated in that way, I think the rebound can probably be stunted a little bit, but I think you have to think, like, don't just give it to them for two months, so they drop 10 pounds, get into IVF knowing it's going to come back. Like, maybe that's a good reason to use it for some people, but I think we do have to be really thoughtful about it as we're prescribing that that exact phenomenon.

We don't know if that's good or bad, actually. And Kurt, I would argue, I'm not treating fertility. I'm using the indication for obesity.

You know, that's what we're treating, and as a precursor to attempting pregnancy, you know, and the FDA trials required two forms of contraception. Most women were older anyways, but, you know, I think generally, as I think we're in agreement that you're looking at a six to twelve month trial of these for really to have the significant weight loss, the 15 to 20 percent that you want, and so, you know, this isn't a three month and done thing. This isn't fentermine, you know, for a couple months.

So I do think you have to think about concomitant contraception on those patients while they're being actively treated. We have a question here. Paul.

Yes, thank you. Well, I have a very simple question. Do you think that maybe BMI is not the right metric to be used? Maybe it's too flawed.

Maybe it does not represent mortality in these patients. Yeah, so I think that BMI is flawed for anesthesia cutoffs because you're not even giving the patient an anesthesia assessment. So if you're worried about someone's airway, I think it would be lovely to at least give the patient an assessment to see if they're really at risk, because I know for us with the outpatient centers, that's our anesthesiologist's main concern, is that there might be an airway complication and they're not set up to deal with that.

But if you don't even look at the patient, I feel like it's difficult to make that argument. But could it be that BMI alone cannot actually make a difference between fat and muscle, for example, in one person? Oh, right. I mean... It's a very old metric.

It's more than 100 years old and actually was based on white males at that time. Belgian farmers. Yes, so I think that maybe this is not the right way to separate those who can have a high mortality of those who don't have one.

Totally agree. I mean, I think that's the whole point of this talk, is that obesity, we're oversimplifying it, that there's clear data that there are metabolically healthy and metabolically unhealthy obese. Those are anovulatory, those who are, those who have insulin resistance, and those who aren't.

So I think we're oversimplifying it. We have a question all the way there in the back. I'm very hopeful.

I'm from Germany. I'm very hopeful with regard to the GOP-1 agonists because it gives us an alternative to bariatric surgery and what we follow is that we have an interval of 12 months between the bariatric surgery and starting of the IVF because of the catabolic situation and burning all the fat and all the heavy metal that's sort of enclosed in the fat. Don't you think that the GOP-1 complications are, at least in little part, due to losing a lot of fat during a short span of time? And freeing all those toxic substances in it? Well, yeah, so first I would argue that that's the theory, that toxic substances are released and are harmful to health.

I mean the best evidence is the bariatric surgery trials, including the randomized trials in diabetes, in which patients are cured through bariatric surgery and have significant benefits compared to medical treatment. And if you look at what's happened with the, at least with semaglutide that we have the data, so decreased cardiovascular events, decreased mortality, decreased obstructive sleep apnea, decreased of anything associated with a cardiovascular, blood pressure, lipids. I mean, I don't think that they're releasing harmful substances from their fat.

I think that those substances are likely very biologically inert or inactive. So that hypothesis hasn't been upheld by the bariatric or the GOP-1 receptor agonist data. So you would not support that 12-month interval between surgery and IVF? No, in fact the bariatric surgery just made new guidelines.

They used to have kind of a hard, you know, one year, two years. They said when weight stabilizes, that's when patients should pursue pregnancy. And weight stabilizes a lot earlier, maybe six to eight months after a sleeve.

Certainly less than 12 months for a Roux-en-Y, which is done rarely. So there's no more of this two years after Roux-en-Y. You know, it's 12 months or eight months after a sleeve gastrectomy.

Alex, you have a question for us? Yes. It's part question, part comment. So this is a great discussion.

I had the honor, the great honor, of actually working with two of the panelists that are up on stage. So I worked for four years at the University of Oklahoma with Carl. I had that great pleasure, where the BMI, like a BMI of 40, was maybe more the norm than the exception sometimes.

And now I'm working with Eric at SGF, and I think I feel very privileged to work in a network where we have great clinical guidelines that are like mostly based on ASRM guidelines. I think that's great because it helps explain patients, our decisions, and things like that. But with a BMI cutoff, that's one area where I respectfully disagree with our guideline, and that's mostly based on the ethics of it.

And I think the ASRM practice committee document summarizes the ethical aspects very well in that pro and con table. And then, of course, when you have that safety and beneficence or non-maleficence argument in addition to the autonomy, I mean, I think as far as autonomy goes, there's no question that patients should be able to make their own informed decisions about risks. But with the beneficence and non-maleficence, I think there is the safety concern.

But on the other side, it says concern about violating the ethical principle of beneficence and non-maleficence by exacerbating underlying psychological suffering due to low self-esteem, anxiety, and this depression if treatment is denied. So I think the the mobility of that needs to be considered as well in the safety discussion. I asked to leave before, and it was tongue-in-cheek because there's so much that we do in in reproductive medicine that is a compromise or is historical.

And when you really start to peel these things apart, you find that they don't have the evidence or the science to support them. And yet, if I don't have an anesthesiologist, I've got a problem. And in a big system, it becomes even harder.

You're outpatient. The hospital's not down the street. And so while I do not want to sit here and defend cutoffs, I think that the criticisms that have been levied are absolutely correct.

You got to move the ball up the hill slowly. And I think you can look at GLPs in the same, through the same lens. We started a GLP clinic because our clinicians were uncomfortable prescribing it.

And I said to the clinicians, I said, well, if there's a new drug for oocyte production that was cheaper and better, you'd use it tomorrow, right? And so there is this inherent siloing and reluctance that we have that it takes time to fix. And so we'll continue rolling the cutoff boulder up the hill and see where we get. I mean, we've been there before with metformin, right? This is the same sort of thing, you know.

In terms of metformin, it wasn't the wonder drug we thought it was, but it's now the most prescribed drug for PCOS. Every OBGYN feels comfortable with it. And I predict one day that's the way we're going to be with GLP1 receptor agonists.

It's going to be... Except hopefully they'll work. Yeah, hopefully they'll work. And by the way, it's recommended to stop metformin if someone starts a GLP1.

At least they do it in the studies because of the increased risk of nausea and GI side effects. Yeah, just to follow up, Alex, thanks for the comment and the question. I do think it's a nuanced issue, and I could certainly see that a patient could make the decision, well, I want to take the risk.

But then the question becomes, that's not entirely your decision anymore with a system-wide issue, and it comes down to anesthesia. It comes down to your support staff. And on some level, we have to respect that in our work environment for all the reasons that Eric mentioned.

But the point is appreciated. We have time for three more questions for the folks lined up for the microphones. We'll take this question up front.

Thank you very much for the discussion. Very informative. I'm interested and curious about the intravenous analgesic that was mentioned.

What is that? We give IV Demerol. Just give an IV Demerol push, and then give a little extra if someone's in pain. And then they take Piovalium two hours before the retrieval.

And again, that's a, I don't know, does anyone do that around here now? Or does everyone have anesthesia? Demerol is a what? We didn't hear. It's a narcotic. Demerol is a narcotic.

Yeah, we do IV push in our procedure room in our clinic. Does anyone use Toradol or IV Acetaminophen? No. We use Toradol.

Yeah, we use IM Toradol sometimes if we can't use anesthesia. In the back of the room. Hello, yes, thank you for this great discussion.

And I know most of this is regarding female obesity, but could you comment also on what we're supposed to do for the male counterpart and their problems with obesity? Come to the presentation at 1.30. There's a talk on it. Not by anyone here, though. You mean there's someone else involved? But obesity, it can be associated with androgen insufficiency, abnormal semen parameters, and a host of other health impacts that, yeah, I think we're just scratching the surface of this in terms of helping our couples.

I will say what I would not recommend is recommend weight loss for the wife if the cause of infertility is male factor, but those women were included in some of the studies included in the meta-analysis. And our final question from the back. Thank you.

Thank you for the discussion. If BMI is not a good marker for us now, what about to start considering using the triglycerides and the glucose for these composed indexes that we may use now? As a comment, in our practice, we are seeing that we are able to help more the patients because we can stratify much better when a patient is just a case of BMI or a case of metabolic disease, and it's not too complicated and not too expensive. Even it's possible to do it on-site, let's say.

We do not allow this for start assessing what the panel thinks. Good. Oh, good.

I was just gonna say yes. I mean, we should be doing preconception counseling in everybody, but especially those who have a higher BMI, and I would argue that includes screening for insulin resistance and lipids, and that will help us individualize and decide who's likely to benefit the most from this. And the second comment I'll make is we're really just talking about infertility, but we're reproductive endocrinologists, and we should be helping taking care of patients with PCOS who aren't necessarily trying to get pregnant, and there's a huge role for that.

I think until you put that in your toolbox, you are probably inadequately taking care of patients with PCOS because some of them are going to really benefit from this aside from infertility. Totally agree, and just to add to that, I think when we're trying to counsel our patients about their risk during pregnancy, if someone has glucose abnormalities and hypertension and these things that can be resolved with a GLP-1, then again, I think you're not, they may not be more likely to have a live birth, but there's a chance that their pregnancy might have fewer complications. Great.

Well, I want to thank our audience, both for these incredible articles that all of you have written and for your research and helping to advance this field, and being willing to come up here and ask and answer tough questions about like why we have BMI cutoffs that are specific to our clinics and all the nuance that goes into that. I know that's not an easy thing to do in front of everyone, and I appreciate you putting yourselves out there to do that. This has been a wonderful discussion.

Pietro, do we have any journal clubs or anything else coming up from FNS? Yeah, we got two good ones. As you've probably seen over the last year, FNS has really tried to take the journal club show on the road, and we're actually going to be doing a live journal club global from the AGL meeting in New Orleans next month, and we'll actually be doing our second ever Portuguese language live journal club with some colleagues from Brazil. So stay tuned for those, and of course, if you like hearing our voices, we're on the podcast monthly, both FNS Unplugged and FNS On Air, and if you're not already following on our social media accounts, we're now on LinkedIn, Twitter, Facebook, and Instagram.

And if you're not going to hear Rick Legro's session on obesity and reproduction at 1.30 after this, stay right here in this room. For the first time ever, we are doing the best of fertility and sterility. The four editor-in-chiefs have selected their four favorite articles from the last 12 months from FNS, and we're going to hear from those authors and hear what's so incredible about their research.

Please, let's have a round of applause for our panel.