In this episode, we discuss the use of supplemental oxygen for fetal decelerations. Then we get into part 2 of our discussion of interpreting clinical studies and when to adopt new interventions into practice, including a discussion of intranasal metoclopramide, elagolix, and a new study about an app based doula service. Finally, we answer user questions about surprise billing at the time of annual exams and the pros and cons of egg freezing.
00:00:02 Oxygen Supplementation in Labor
00:11:00 Interpreting studies part 2: intranasal metoclopramide
00:22:07 Evaluating Efficacy of Elagolix for Endometriosis
00:38:23 Doulas and Birth Outcomes
00:44:32 Listener Question: Surprise Billing
00:51:30 Listener Question: Egg Preservation
Follow us on Instagram @thinkingaboutobgyn.
In this episode, we discuss the use of supplemental oxygen for fetal decelerations. Then we get into part 2 of our discussion of interpreting clinical studies and when to adopt new interventions into practice, including a discussion of intranasal metoclopramide, elagolix, and a new study about an app based doula service. Finally, we answer user questions about surprise billing at the time of annual exams and the pros and cons of egg freezing.
00:00:02 Oxygen Supplementation in Labor
00:11:00 Interpreting studies part 2: intranasal metoclopramide
00:22:07 Evaluating Efficacy of Elagolix for Endometriosis
00:38:23 Doulas and Birth Outcomes
00:44:32 Listener Question: Surprise Billing
00:51:30 Listener Question: Egg Preservation
Follow us on Instagram @thinkingaboutobgyn.
This is Thinking About OBGYN with your hosts Antonia Roberts and Howard Harrell.
Howard:Antonia.
Antonia:Howard.
Howard:What are we thinking about on today's episode?
Antonia:Well, we're going to get into part two of our attempt at giving advice on how to read journal articles properly, and we're going to talk about some example papers today involving a study on elegolics, another one on intranasal metaclopramide or a version of reglain, and another one on a virtual doula service. But first, what's the thing we do without evidence?
Howard:Well, how about placing oxygen on a mother when there's a problem with a fetal tracing or some decelerations or something like that that we're anxious about?
Antonia:Okay, sure, yeah, I've seen this a lot in my time so far. I think at some point almost all of us have probably been taught that part of intrapartum fetal resuscitation for decelerations on the monitor or other issues with CAT2 or CAT3 tracings would be oxygen supplementation. So frequently nurses will place a non-rebrether mask on the mother and crank up the oxygen as part of this general approach to resuscitation. That might also include position changes or fluid boluses or stopping the pitocin, giving her butylene, maybe starting an amniote fusion and other such attempts to clean up the fetal tracing. But why don't you tell us why the oxygen mask is a thing we do without evidence?
Howard:Well, it's not that we should never do it or that there's that it's never the right thing to do. It's just that it isn't beneficial in most cases and might even be harmful if the mother herself isn't hypoxic. So I think we get caught up in just applying all of our interventions that we have available to us for abnormal or indeterminate fetal tracings to every patient that has one all at once, hoping that something sticks. Essentially so, as you said, this might be a fluid bolus and position change, and turning the oxytocin off or, this case, throwing some oxygen on the mom and hoping that it straightens up. And there's some sense to that, because we don't usually know in many cases the specific reason why we're seeing, let's say, repetitive late decelerations or something like that, and therefore what the specific remedy might be. And there's simply no reason, though, in this case, to give an oxygen, give oxygen supplementation to a mother who's already saturating. Well, we know what her oxygen saturation is and there's no benefit in adding oxygen to her.
Antonia:Most of the time women in labor have a continuous pulse axon. It's, that's just normal and, yeah, giving her oxygen would definitely be appropriate if she had true low oxygen saturation, so usually something below 94%. Maybe she has asthma or maybe she's preeclampic and has pulmonary edema, or maybe she has a respiratory illness like flu or COVID or something like that, and in those cases the fetal distress and the heart rate abnormalities that we see on the monitor could definitely be from fetal hypoxemia or hypoxia due to maternal hypoxia, which would be a lack of oxygen tension in her blood. So obviously we should treat that underlying cause. But for a normally oxygenating mother who still has fetal heart rate abnormalities, it's usually not something that adding extra oxygen would fix. There's usually some completely unrelated cause, like chord compression or utero placental insufficiency, for example. So super oxygenating her in those cases is just not effective at getting more oxygen to the fetus.
Howard:Hickhog, practice Bolton 106 talks about oxygen supplementation frequently being used despite any adequate data to support the practice. But they've actually updated this in the last couple of years to say definitively that there is no evidence of benefit from oxygen supplementation. The update to the Practice Bolton says that the routine use of oxygen in women who have normal saturations is not recommended.
Antonia:Yeah, and that update came after a systematic review is published of 16 trials that evaluated this practice in 2052 women, and they found no difference in umbilical artery pH or neonatal asidemia or NICU admission rates or any other clinical outcome.
Howard:There was also a study published in the Gray Journal in 2020 that gave us the results of a trial in which women at term with category two tracings in labor were randomized to 10 liters of oxygen with a face mask versus just room air. The intervention group wore the oxygen mask continually until they delivered and they looked at a lot of different outcomes, including what the tracings look like and different characteristics of the tracing. They found that for the patients who received oxygen, there was no difference in the features of the fetal monitor pre and post randomization and there was no difference in the time to resolve the decelerations or whatever was abnormal between the two groups of patients of room air versus the oxygen supplementation. So that adds to the systematic review you just mentioned, which showed no improvement in objective measures about the newborns and no improvements in the fetal tracings themselves.
Antonia:So, yeah, no clinical effects at all. Awon, which is the Association of Women's Health, obstetric and Neonatal Nurses, also released a statement in March 2022 and this was somewhat of a response to that ACOG practice advisory which is brought up. They reviewed literature up until that point, just like ACOG had, and interestingly, they did acknowledge that it hasn't been shown to benefit. But they essentially wanted to caution against swinging too far the other way, thinking that the downside would be people would never, ever, ever use oxygen for intrauterine resuscitation. So they in their statement recommend keeping it as an option for use in some patients who didn't improve despite all the other measures being used. And basically they said don't use it as a first line, but keep it in mind as maybe a second or third line.
Antonia:I'm not sure if they're thinking that that category of patients who haven't responded maybe include people who actually are desatting, actually are in respiratory compromise, and we don't realize it and so we're just thinking well, maybe they, maybe we're having a false positive normal oxygen on this false ox, or maybe we don't have the false ox on or something like that. If it's slipped off sometimes it slips off in labor. That could happen, but I think this can fall into that slippery slope of something that we do without evidence of benefit, despite that adequate trials. Because if we want to do something and we wonder, well, we've done all these other things, the tracing is still bad. What harm could it be now to put oxygen on the mother? Just throw it on?
Antonia:It's just oxygen. Maybe it might help this individual patient for some reason.
Howard:Sure, yeah, A lot of the things we talk about on here. But I think that that can be a dangerous way of thinking. In my view, A1 is clearly wrong about this and they issued this response, as you said, to the ACOG bulletin in a sort of contentious way. It's a pattern we've seen over and over again. It's why things like tokylysis or progesterone therapy for various conditions or whatever, has persisted for so long because a lot of folks in they have a paradigm in their mind that doesn't use a scientific method to make decisions. But that's also the lesson, for example, of DES.
Howard:It doesn't matter if you think that something might work by some mechanism for some individual patient. You have to prove that it does work and reserve utilization of something, an agent or intervention, until there are replicated trials that show that something is effective. It's easy to say but what's the harm, especially with oxygen or something like that? But again, that was the lesson of DES. The harm of DES wasn't even seen for decades to come, just as a potential harm of 17-hydroxyprogesterone wasn't seen until we've started to see some evidence that the offspring of children exposed to it, at least in earlier gestational ages, might have a higher rate of cancer as adults. So in the absence of a proven benefit, we should not use therapies.
Antonia:Yeah, and we do know that, for example, in neonates, hyperoxygenating them with their various resuscitation situation, that's harmful and they try to recommend dialing it down as soon as you can. So some people have speculated that even maternal oxygen might be harmful to the fetus, right, right?
Howard:yeah, well, I'll put a link to a great review article of this literature and the science that was published in 2023,. But they do discuss potential harms and the concept here is that free radical-induced oxidative cell damage can contribute to adverse outcomes, including necrotizing intercollitis and bronchopulmonary dysplasia, and they cite literature that says that resuscitation with room air as opposed to 100% oxygen with a rebreather face mask is associated with less-needle harm, including hypoxic ischemic encephalopathy and death. In other words, room air is better. This has been studied in more extensively in animal models, where some of the basic sciences of how this may work has been elucidated, and they go into this literature in some detail. But again, the point is that every intervention, even oxygen, potentially has harm. We actually understand and have some evidence that this practice is potentially harmful and, on the flip side, we have no evidence from multiple trials now that it benefits newborns in any way or that it makes the tracing look better in any way. So the practice should be abandoned and ACOG is right.
Antonia:So, in summary, people want to do something in scary situations, but every intervention is also potentially harmful, so even the most innocuous sounding things like an oxygen mask should only be done if we know they're effective.
Howard:That's a lesson of our whole podcast. Yeah.
Antonia:Yeah, that sums it all up. Okay, let's get into part two of talking about interpreting papers and studies. This time, we want to take some of the things we already discussed last time and look at a few papers briefly, using these skills, and we also want to answer about how to approach, whether we should adopt something into practice or not, because I think that's where bias can tend to drive us towards making these decisions more so than the evidence, and bias can come internally from our own desires to help people, but also externally, from the companies that are selling the intervention and also, maybe, the charismatic personalities who are representing these companies and driving our thought processes, sometimes counter to evidence.
Howard:Or even just our own, as you said with the oxygen, our own internal desire to do something, and we ignore scientific literature.
Antonia:Yeah, all right. So what was the first article you wanted to talk about?
Howard:Well, I want to highlight a real life example of deciding whether you should adopt something into practice. So this happens to all of us, maybe on a daily or weekly basis. So my clinic was recently visited by a pharmaceutical rep we don't normally allow them, but we can't stop them from walking up to the front door and they brought some information, in a summary of a clinical trial, about a new product called Gemodi. Now this is a metaclopramide nasal spray that's FDA indicated for the relief of symptoms in adults with acute and recurrent diabetic gastroparesis.
Antonia:Okay, well, acute and recurrent diabetic gastroparesis is not my bread and butter, it's an OBGYN. I don't know about you.
Howard:Well, I am diabetic, but it's not uncommon for drug reps to come by trying to cast a wide net for their products, hoping to catch all sorts of providers that might possibly encounter the drugs target patient population. But I'm pretty sure this rep was primarily trying to push it as an off-label use for nausea and vomiting.
Antonia:I haven't seen this particular product in my clinic lounge, but I have walked in there at lunch and encountered reps that are trying to talk to me about migraine meds that are specifically not meant for pregnant patients, so definitely not relevant for me, and also things like heart failure meds, definitely out of my scope, and some of those obviously were a stretch in terms of their relevance. But if I had to guess for Gemodi at your clinic, I imagine you were being shown this because you sometimes use oral metaclopramide, or Reglan is the trade name we use for nausea and vomiting during pregnancy, right?
Howard:Yeah, absolutely. And there was, I'll say, a sticky note attached to this information that said. Quote new for nausea, for nausea.
Antonia:Okay, well, so it sounds like they weren't actually stopping by to offer you health and treating the diabetic gastroparesis at all. So did you talk to this rep?
Howard:No, I don't talk to them. I actually don't know who they were. It was just left for us because we don't normally engage with drug reps in my office.
Antonia:Okay, that's probably a good policy. Well, that's good because I hope they know it's actually illegal to promote or advertise using a drug or device for anything other than its FDA approved use. So legally that would be called misbranding.
Howard:Well, it is illegal, but it happens a lot and in various shades of gray, and in some cases we've seen some high-profile settlements where companies have paid fines for doing exactly this. But nevertheless it continues, and often in subtle ways that you might not realize. Sometimes the reps will talk about another doctor they know at another insert big name clinic who's seeing great results with using drug whatever for off-label indication whatever. But that's not scientific information and it's not studied for those off-label uses for safety and efficacy. They just hope that you'll use it because whoever they name drop seems like an important person to you, because they work at wherever, and I may not mention that those folks are stock owners of the company or that they're paid by the company to do talks for them or as a consultant or something like that.
Antonia:Okay. Well, with your example here, it sounds like we're already off to a sketchy start, but let's go through the processes we talked about last time for adopting something to practice or not.
Howard:Well, in this case, if I were going to use this intranasal version of regland for nausea and vomiting during pregnancy or any other kind of nausea that maybe I would treat like post-op nausea or migraines in pregnancy we sometimes use regland for, or even symptoms of, chronic pelvic pain or premastrial dyscort disorder. I would want to see first a randomized controlled blinded trial that placebo controlled trial that showed that the drug was better than placebo for treatment of nausea and vomiting in that specific population and that it made a difference in some outcome. That was important to my patient.
Antonia:Yeah, so a drug that's been indicated and approved for gastroparesis is not going to have those kinds of studies yet. But the FDA normally would require two studies like that before they give their approval for the drug and for the indication in question. We do use drugs off label all the time because many studies are actually done after the FDA approval to guide that use. So you know, side attack for labor induction for example. It's just that the drug reps cannot be the ones to push that off label use of it. They can't be like selling you the drug with primarily for this non FDA approved indication. So were there any studies done for this intranasal drug in pregnant or gynecologic patients, perhaps after the FDA approval?
Howard:Not a single one. So the nice thing is we get to skip the whole study part that we talked about in the last episode, because there aren't studies.
Antonia:So this was a trick. Are we going to do the five step process at all today?
Howard:Well, we don't want to be too redundant, but I think if this more is a public service announcement, this is real life.
Howard:This is just something that actually happened If my office was visited by a rep suggesting an off label and unstudied use of their drug. I bet a lot of our listeners might be caught off guard by that as well as I was, and their initial reaction to something like this intranasal metaclopramide at least, might just be that, oh great, it's nice that we have another form of this drug that we already use frequently, especially a non oral drug for these patients who are really nauseous, so then they can't hold down pills. But my point is, if there isn't even a good paper or a paper to do the five step process on, that should be a huge red flag, and this happens a lot.
Antonia:Okay, yeah, and one might reasonably assume that if a company is coming to visit your clinic and promote their drug, that they would have that the drug already would have the FDA approval for what they're talking to you about, but apparently not. So apparently you have to trust trust no one and always fact check them.
Howard:Trust, don't trust and verify right.
Antonia:Right.
Howard:Well, but it's actually not even enough to have the two randomized placebo controlled trials that might lead to an FDA indication. I would suggest that's a minimum threshold before adopting a new intervention into practice. But we need more than that. Next we need a comparator trial.
Antonia:Okay, yeah, we've talked about how interesting it is that we think of the placebo controlled RCT as a gold standard, and it is for showing safety and efficacy, but it is not the gold standard for determining whether or not we adopt something into practice.
Howard:Right, exactly, so what actually changes our practice pattern would be a trial that shows that this new therapy is better than what we're currently using or safer than what we're currently using. So before I consider using a medication we talked about this was Zaranolone, for example I would want to see a head to head trial that showed that it was better again in some meaningful outcome for my patient, than any of the other number of things that I currently use. So in this case, for nausea, vomiting, that might be things like vitamin B six or doc salamine, or on Danzatron or anything else that we might use.
Antonia:Okay. So to recap, if we're considering adopting something into clinical practice, first we need to know that two at least two quality replicated RCTs against placebo have been done that show the benefit and the safety. And then we need to see at least one quality comparator trial that shows that it is superior in some meaningful way to what we're already doing. And is that it?
Howard:Well, almost. We still then need some information, formally or informally, for a cost-benefit analysis. So it's tempting to think that I could give a patient regland through a nasal spray who's vomiting and can't keep a pill down, and that'll be the instinct, I think, of a lot of OJYans who come up on this drug after being visited by this rep. Now, keep in mind that that instinct is wrong because we skipped over those first two important steps you just recapped. But let's think about the third step. If we got there, if the other study showed that, yes, it's effective for nausea, it probably is right. I don't doubt it. And yes, it works better than, I don't know, vitamin B6 or something. Well, the thing is, this medication costs $2,300 for what looks like a one-month supply.
Antonia:Okay, yikes, yeah, okay, just for comparison, almost everything else we use is gonna be available for under 10 bucks or something much cheaper than $2,300. So that would definitely require a lot of justification.
Howard:Yeah, related to this. A good example of this thought process would be the combination vitamin B6 and doxalamine tablets that are available in the form of DiClegis or Bongesta. So these medications, initially at least, were priced at over $600 when they came to market and even with steep discounting and reductions over time that have occurred, it's still over $200 a month today, with an average pregnant patient using these drugs for two to three months in the first part of the pregnancy. Now the combination of vitamin B6 and doxalamine does work better than placebo and, frankly, it works better and preferentially over many of the other anti-imetics that we just mentioned. But again, when we get to the last point, vitamin B6 and doxalamine are both over-the-counter products that can be purchased separately, and the combination for a month supply is less than 10 bucks. So there's no compelling reason to prescribe one of the trademark combo medications that are $600.
Antonia:Yeah, so drug companies love to take inexpensive drugs and then find some new delivery method or some new feature that they can put their little trademark on or patent on or something, and that would extend the patent life and makes it see, maybe slightly more convenient or better in some way. Like they could, instead of combining two separate drugs, they could come out with an extended release version that you only give once a day instead of twice a day, but then that extended release is like 10 times more expensive. So it seems like a great thing to give to your patient until you realize how much more it costs them. And just in the grand scheme like that, we're bankrupting healthcare with these sorts of lazy shortcuts.
Howard:Yeah, it's a very American thing too, okay. Well, let's move on to elagolics, and we've not really talked about this drug yet, but it is being heavily marketed right now in our field.
Antonia:Yeah, I first heard about this in residency. It's called Oralisa is one of the trade names, and Oralisa is $1,200 a month. So this is an oral GNRH antagonist which is approved for treatment of pain related to endometriosis, and it's also marketed in the form of a combination that contains ad-bac hormones, so you can get it just separately, with only the antagonists or with estrogen and progestin. So this went through the process. You would expect to get the FDA approval. These were the LRS endometriosis one and two trials. In those trials, roughly 20% of women reported improvement in their dysmenorrhea symptoms with placebo, compared to 45 and 75% respectively, reporting improvement with the low dose versus the high dose versions of this drug.
Howard:Right and this led to FDA approval. And of course we could go and look at those individual studies in detail and go through the questions we talked about in the last episode, and if we did we would discover that the trial design and the statistical methods were appropriate. We can pick at NATs a little bit, but these studies were designed obviously by the company and so sure there's a chance of some bias. But the magnitude of effect was significant enough and it's consistent with what we would expect from what we know about how this medication should work and how the pathophysiology of dysmenorrhea and endometriosis and et cetera.
Howard:So I don't doubt that this medication is highly effective compared to placebo. Remember that initial studies performed by a company, though, do tend to report an effect size that's roughly double what later studies may show that don't have the bias of being designed by the company, but I do think we can agree that this medicine is superior to placebo for treatment of endometriosis.
Antonia:Right, it's not like we just ignore studies if they were funded by the companies and haven't been replicated yet, but we interpret them with caution and then proceed while we continue watching for new updates. So in this case, even if the effect size was a little bit skewed, it's still incredibly likely to be effective, at least compared to no treatment. So have there been any more recent studies than these initial ones?
Howard:Well, there was a study in November 2023 in the Green Journal that looked at using this medication for heavy bleeding associated with fibroids. So now we're starting to see the non-endometriosis stuff to push that indication. They studied the 150 milligram dose, which is the low dose therapy, in a randomized controlled trial of 82 patients, where 28 received placebo and 54 received the active ingredient. The study was funded by the manufacturer. The authors of the study, by the way, are also stockholders in the company, so another case of a type of conflict.
Howard:Now, if we spent some time looking at the methodology of this paper and the results, like we talked about in the last episode, we would find that this study really doesn't pass muster.
Howard:This was actually over-enrolled, despite that small size. Their power analysis required only 48 patients in a two-to-one randomization, but ended up with 82. They also had a significant number of patients lost to follow-up, and this lost to follow-up group favored the active intervention, which sometimes suggests that, had those patients been included, some of the effect size would have been washed out. A study like this should be an intent to treat study, because these medications have so many side effects and patients stop using them or don't take them correctly due to side effects and so it's intent to treat, not is the way to look at this, not the people who were protocol. And despite all of this, this company-funded study that over-enrolled by nearly double and didn't do an intent to treat analysis that would have accounted for differences in those lost. To follow-up, the p-value for the primary endpoint was still only 0.035. Now the primary endpoint was a reduction in menstrual blood volume to less than 80 mLs in the last month of use, with at least a 50% reduction in menstrual blood volume from baseline to the final month.
Antonia:Okay, so it could be that ilegolix is effective for patients with heavy menstrual bleeding due to fibroids, but that conclusion shouldn't be drawn at least not definitively from this study.
Howard:Yeah, I think that's fair and this study would be a great one for Journal Club, by the way, to think about all the stuff we talked about in the last episode whether the outcome is valid and meaningful to patients, the effect of choices about inclusion and exclusion criteria, the effect of the statistical methodologies used and the choice to ignore those who were lost to follow-up.
Howard:They also use some unusual statistical techniques to even determine their p-value, and so those are other choices that the authors made, who were stockholders in the company and financially incentivized to find a p-value under.05, and they did so. A lot of thought went into this study design again to find a positive effect, and your job in Journal Club is to try to deconstruct that and understand where they might have made different choices, but they ended up with really a marginal p-value. There have been those studies prior to this, so remember. The other thing is what's already known about the topic, and they've shown that the medication does likely reduce bleeding associated with fibroids. The question is whether this current study is valid and is the finding clinically significant?
Antonia:Okay, and so far treating bleeding from fibroids is still an off-label indication for elagolic. So on some level, obviously, it makes sense that patients would have less blood loss with a GnRH antagonist just based on the mechanism Thanks, similar ultimately to Luparolide, which is the GNRH agonist that then flips into an antagonist action and that's already a well-established treatment for endometriosis and for fibroids. So we'll allow that. There's got to be some benefit to it, very likely. We already have the placebo-controlled randomized trials, although industry-funded, that show the less pain and dysperonia. So then we're leading up to how it's compared to standard treatment. Yeah, all right. So then really the next step is should we adopt this into practice? So what did we just say with the Metaclopramide example? Well, right.
Howard:So remember, we're illustrating here a sort of three-step process. So the first step was to make sure that at least a couple of placebo-controlled trials showed benefit and safety. There are significant side effects, including all the menopausal symptoms you'd expect, similar to Luparolide. That's why they have done the adbac therapy in some cases and in fact the high-dose medication is still limited to just six months of use and the low-dose medication to just two years of use because of concerns for osteoporosis. So that's a different discussion and those are things that we learn from the placebo-controlled trials. Are the side effects, but the timing of the medication is limited due to the side effects. So we have to work that into our calculus.
Howard:But remember, the next step is deciding whether something should be adopted into practice and the next step is to do a comparative trial. So some standard care options to compare elagolics against might be, say, 5 milligrams of north angiocetate or other equivalent progestinone medications, or continuous suppressive low-dose birth control pills or even Luparolide or something like that and similar. We could use similar comparators to treat dysmenorrhea or abnormal bleeding associated with fibroids, and most of those medications that I just mentioned are less than 20 bucks a month and don't have a time limitation for how long they can be used due to side effects, and most of them don't produce menopausal symptoms, luparolide, of course, being an exception, but even that is still, at this point, cheaper than elagolics.
Antonia:Yeah. So then the correct question is does elagolics treat those things better than any of those cheaper and perhaps less morbid interventions that we already have available and without a comparator trial we can't know. And it seems like if it had a big benefit to standard treatment, the company would have proudly performed a comparator trial against standard therapy to show how superior it is.
Howard:Yeah, and for all we know, they could still be in the works. These studies could be ongoing now that they've established efficacy against placebo, because that's what the FDA requires, although, frankly, it's been around long enough at this point that you would have expected to see a trial like that come out, if the company were doing one.
Howard:So I'm not too optimistic about elagolics, because Lupron, though, already failed to demonstrate superiority against birth control pills, and elagolics acts basically in the same way that Lupron does. The benefit of this new agent over Lupron is that it's oral and not an injection, but many of the same limitations occur, and depolupron was definitely better than placebo at treating fibroids and endometriosis and abnormal bleeding and pain. But I'll put a link to a double-blinded control trial, a comparator control trial from 2011,. That showed that, lo and behold, deprolupron was no better than continuous oral contraceptives at treating endometriosis related to pelvic pain. And, of course, that paper came out many, many years after Lupron had been heavily marketed to gynecologists. It's very expensive medication for that and it was no better than birth control pills.
Antonia:Yeah, that's really interesting because you think of Lupron. If you're going to basically cause menopause in someone, that's a really aggressive way to minimize the hormones that are acting on their endometriosis. But the price point of this new intervention plays off the idea that it would save patients surgery or maybe save them even the office visit of getting the Lupron injection. But that gets into another thing we talked about in the last episode of making sure that what you're claiming is supported by the data, and none of these studies so far that we've discussed on elgolix here have shown that it's any better than our normal therapies, especially at preventing surgery. So it would take a comparator trial to show that, and it would also take a comparator trial looking at something more than just subjective pain scores and subjective blood loss. So we have to think about more than just the placebo-controlled trial outcomes when we're considering practical use and especially a cost-benefit analysis.
Howard:Yeah. So I, for example, didn't use depilupron years ago when it was being marketed for this, and I've not used this new medication because it didn't pass muster of what we're talking about Now. The next step of this medication will be combining it with ad-bac therapy so that it can be used longer than two years. We're already seeing that, and that may somewhat counteract the benefit, but also would allow the medication to be taken continuously. So now you have, let's say, a 32-year-old woman who's suffering from endometriosis and the company would be happy for her to take it for the next 20 years until the patent expires, at a cost of about $300,000 over that time, compared to a cost of about $3,000 for continuous birth control pills over that time or, frankly, even surgery.
Antonia:Yeah, so you're talking about elgolix combined together with estrogen and norethin drone as like a combination? Right. The medication similar to this is relu-relugolix, and there are a lot of European trials looking at this medication for the same indications and so far nothing groundbreaking has come out of that to suggest that these truly would be superior to birth control pills, and especially not to the same degree of how much more they cost. And really, if you think about it, what they're adding back basically is a birth control pill. Yeah.
Antonia:It's oral progestin and estrogen, and at the doses that they're adding them back, it wouldn't even be enough to prevent pregnancy. So then the patients are on these birth control hormones, but then they still have to take something else for birth control.
Howard:Yeah.
Antonia:So it's silly, especially if you have a patient who doesn't want to be on hormones or something. Yeah, it doesn't make any sense to me, honestly.
Howard:Yeah Well, and this is why things like this are heavily marketed, because at their surface they don't make sense. So this is a great example and a great study again for Journal Club that gets into whether or not we should be using a new intervention. New sometimes equals better, but it's rare. Honestly, we need to know that the new is better than the old, and the only way to do that is with a comparator trial that shows either improved safety or improved efficacy or both, hopefully or something that justifies the cost of the new medication. In this case, it's likely that these medications are no better than continuous OCPs or iGestin, which is the 5 milligram north end on acetate that treating these symptoms that patients have, and, by the way, we know that it has a worse safety profile than those medications nearly 100 times the cost.
Antonia:Yeah, so the need for replicated data compared to trials is maybe the most important takeaway from this episode.
Antonia:In the last one, there's a lot of detail in analyzing a journal article that people do need to brush up on to be able to do it correctly, and there's a lot of great, very digestible resources out there.
Antonia:Obviously, your book, clinical Reasoning, is top notch for that. There are also some YouTube videos and for people who are more auditory or visual or like lazy learners, that at least can help with like single concepts Maybe not as comprehensively as how you laid it out, but anyone can at least ask these basic questions that we've just reviewed without doing any further studying on their own and see if the data answers them. But even if you believe that this company funded trial looking at elagolics for fibroids that was published in the Green Journal is a good study that found a clear benefit because you didn't know enough to deep dive into the authors tricks they might have used, even if you didn't know that, you still should already know not to use this medication if you're asking these big questions and realize there's no evidence that it's better or safer or cheaper than what we're already doing.
Howard:Right. Yeah, the rest is just marketing, and that's where most of the mistakes are made in clinical practice with adoption of new interventions, like a lot of the things, of course, we talk about. We mentioned some of the trickery used in some of the articles about the fetal pillow in the as an example in the last episode. There's an opportunity there as well for a comparator trial. A good trial would be to take the fetal pillow and compare it not to placebo, meaning noninflation, but to using other acceptable techniques like reverse reach extraction or the pet warden maneuver or a vaginal hand, and, if possible, to randomize patients to which intervention they receive. It would also look for clinically meaningful outcomes that matter to our patients, like how much blood loss was there or it was a baby admitted to the NICU or other neonatal outcomes, not simply how many seconds it took to deliver the baby.
Antonia:Right, okay, well, I think we have time for one more article, the one about the doulas, because we also want to get to a listener question. So we picked this virtual doula article from the February 2024 Green Journal called Association Between Doula Use on a Digital Health Platform and Birth Outcomes. So they concluded that virtual doula support on a digital health platform is associated with lower odds of caesarean birth and an improved birth experience, and they also added some information about outcomes, specifically in black women.
Howard:Right, and they may be on to something with the patient experience part for sure. But unfortunately again, the study design here is incapable of providing a conclusion on caesarean rates.
Antonia:Okay, I figured you'd say that, so walk us quickly through that.
Howard:Well, first of all, the study was reformed again by the company and employees or stockholders of the company, so there is a financial incentive to construct a study in some way that supports increased advocacy for payments for this service from insurers. Beyond that, though, the main issue is that this is a retrospective study of women who were given access to the product, which is called MAVEN, as part of their insurance plan through their employer or their spouse's employer, so they identified almost 9,000 pregnant patients who had access to the app and essentially compared the pregnancy outcomes of people who used the app to those who didn't use the app, and the vast majority of patients didn't use it at all, or at least didn't attend any of the appointments with a doula, but some patients used it quite a bit. So, essentially, what the study is capable of demonstrating is that people who chose to have regular appointments with a doula had a lower rate of caesarean delivery compared to those who did not choose to have regular appointments with a doula.
Antonia:Yeah, so there's always going to be a limitation in retrospective type data and in fact that conclusion seems almost intuitive. Acog already recognizes the potential value of a doula or other similar dedicated emotional support people in terms of labor outcomes, and doulas can certainly be helpful with any kind of birth if people want one, including caesarean, including postpartum recovery. There's also doulas out there for abortion. There's end of life doulas, so have emotional support for everything I say.
Howard:Can I have a doula for Mondays?
Antonia:Yeah, I want one too. We could all use a little more support for regular life struggles. Back to the labor. If you think about the kind of person who's going to be proactive in seeking a doula for any reason, they're likely doing other things as well to promote having a good outcome for themselves. So in the context of labor, a good outcome would include avoiding an unnecessary caesarean, and so that person who has a doula for pregnancy and labor may also be seeking out a practice with a known lower caesarean delivery rate. They may resist elective inductions, at least with an unfavorable cervix, or other interventions like admission for early labor, because both of those are also known to be associated with higher caesarean rates.
Howard:Yeah. So the problem is, was it the doula or was it something else? The patient who was predisposed to seeking out a doula was also doing, or combination of the factors that led to a lower caesarean rate in the study.
Antonia:Yeah, and obviously this retrospective study cannot separate out confounders like that. It's looking at self-selected, non-randomized groups and, anecdotally, I would argue that providers also manage labor a bit differently when there's a doula. So with this app, I don't know if they turn on their app and they're talking to the doula in the room, the labor room or what, or if they walked in with a really detailed birth plan, but a doctor that's taking care of a patient like that might be more likely to give the patients extra time, even in the setting of protracted labor or prolonged pushing, for example.
Howard:Right. Well, the point, though, is, if you claim that doulas cause a lower rate of caesarean delivery based upon this study or studies similar to this, well, that would be overstepping the evidence and the actual data. All this really says is that people who are interested in using doulas are the sorts of folks who have lower rates of caesarean delivery, and that's still an interesting outcome. But a randomized, controlled trial, where people were assigned to use either a doula, or, say, an in-person doula or a virtual doula service like this, versus some other intervention, like, maybe, watching a series of educational YouTube videos that provide information about labor or even just standard care, with nothing, that would be the only appropriate way to conclude whether the intervention has a direct effect on lowering rates of caesarean.
Antonia:Yeah, and I think even the part about patient satisfaction in this study was a circular argument. So they did some pretty complex appearing analyses to say that the more a patient used this app, the more satisfied they were with it. So, of course, like I use a bunch of apps on my phone, I don't use this doula app, of course, but I use the ones I like more and then I don't use the ones that I don't like. So I do need to try to cut back on my phone scrolling time anyway, but that's another story. But I'm more satisfied with the apps that I use a lot. That's the point of that, so don't need to do a statistical.
Howard:Yeah, I'm also a bit of a texting junkie, but yes, it's heavily biased. I'd say this paper is low quality and shouldn't change anyone's clinical practice, nor should it be used to advocate for payments for this particular service. That doesn't even mean that the service is bad, like folks. Don't take this as a criticism of Maven or doulas or that at all. It just means that this paper doesn't demonstrate that that service will improve outcomes for people who aren't already interested in that. So this potentially gets into medical justice. If we're not doing our due diligence to make sure that an intervention benefits more than just an exclusive, self-selected population who may already be at lower risk at baseline, we might be violating justice by advocating for it. So design the study to show what you want to show and don't make conclusions that aren't demonstrated by the data.
Antonia:Yeah, we always want to be pushing for medical resources to be used for something that either benefits a broad general population or at least benefits people that have higher risk of really significant bad outcomes. And here they did talk about the value of this doula service specifically for black people, and we know that they have higher rates of birth complications. We've talked about that before.
Howard:Higher rates of cesareans.
Antonia:Yeah, and it's still possible that it does help and that it does help black people. But it could also be the case that an alternative intervention could be just as effective and much lower cost. Like they didn't explore a series of maybe 15 or 20 minute long educational videos, and that would be a lot cheaper than an app. I also think that providers and health systems need to continue to push to institutionalize their best practices that include safely limiting interventions in labor, like ACOG already lays out in their committee opinion, because then it wouldn't be putting the onus on the patients to be have to be the proactive ones to push for things. It really should be how we treat every patient.
Howard:Yeah Well, the company has a product that they want to sell and it's up to the company that wants the money to do a study, appropriate study, and this one just isn't it. But it is very typical of the type of literature we see published almost every week in our journals and it's usually glossed over with very little critical review. But I hope what we've shown today is that it doesn't take much critical analysis. You don't have to be a statistical expert to quickly just think about the design and think about what the intention is and separate the good from the bad. You don't have to be an expert, you just have to ask the right questions.
Antonia:All right. Well, let's move on to the listener questions segment.
Howard:Speaking of questions.
Antonia:Yes, well, we have a couple. These ones are pretty exciting, so you go first.
Howard:Okay. Well, I have a question from a listener, dear Obi. I don't know how we're going to say. Like Abby, Dear Obi. I went to the doctor for my annual visit and they charged me 200 bucks for my Lexapro refill because it was out of scope for the annual visit. Signed, depressed, undressed and worth $200 less.
Antonia:Okay, I assume you made up that tagline. So you're assuming that she got an unnecessary pelvic exam?
Howard:She did. Well, this person is in her 20s and has commercial insurance with a high deductible but of course gets an annual preventative exam paid for without copay. So she goes to the doctor for what she thinks is a covered checkup without having to pay against her deductible. She gets a breast and pelvic exam that she doesn't need and then she asks for a refill of her Lexapro that her primary care provider had started for her previously, and later she finds out that this was billed as a separate in and visit and is not covered without copay. So she ends up paying the whole bill for that in M because she hasn't met her deductible for the year.
Antonia:Yeah. So her provider might consider ongoing depression treatment outside of the scope of a general well exam. So technically you could argue that it is, and so then they might code it as such without appreciating how both expensive and unexpected that little click of a button they did became for their patient. And this is something with very little transparency on both sides. I'd say that if there wasn't a very attentive discussion or assessment of depression and it literally was just fulfilling the request for the med refill, it's not really correct or fair to bill for it.
Antonia:But there's not a lot of oversight into the correct coding in a lot of clinics. So it ends up really being on the providers to know what constitutes over coding versus under coding. And unfortunately we just often have to teach ourselves this on our own time and maybe pay for the coding guides or seminars that we would do outside of normal patient care hours. We know that we can get fined and heavily penalized for over coding, so we don't want to do that. But if we under code we also will rob our own clinics of getting appropriate resources that will keep taking care of all of our patients. So for the doctor, coding it's probably not even a conscious matter of how much is going to end up in their own pocket. It's probably negligible, but it's whether or not. Just as a routine, are we doing right by both this individual patient and also by the whole clinic and the rest of our patients whenever we decide how we code for things?
Howard:Well, yeah, the hospital leadership gets a cut of this too, and I don't know if this is a privately owned practice or a corporately owned or whatever, but an unethical administrator might pressure clinicians to over code because of that revenue stream. It's a tricky balance because hospitals and large systems have to either pay extra money for a professional coder to do this correctly, which is often lower yield in clinics as opposed to inpatient settings, or save the money on the administrative staffing and pass the work down to the provider and just hope they're doing it right most of the time with the occasional random audits. And here's a fun fact I was recently told by my chart auditor that I should have billed for this exact same thing. A patient came in for her annual preventive health exam and I addressed her mood, prescribed medication and did not charge her a separate visit for that, and the auditor told me I messed up.
Antonia:Wow nice. How did you respond to that auditor?
Howard:Well, I told her that the main purpose of the annual preventative visit was to address things like mood disorders and I pointed her to the US Preventive Task Force Guidelines and the Women's Preventative Service Initiative Guidelines regarding what should be done at a women's preventative visit. And sure enough, these are the things a patient in her age group should be getting each year at that preventative health visit Alcohol use screening and counseling, anxiety screening, blood pressure screening, contraception and contraceptive care, depression screening, diabetes screening if she has risk factors, folic acid supplementation, healthy diet and activity counseling, interpersonal domestic violence screening, lipid screening if she has risk factors, obesity screening and counseling, substance use screening and assessment, tobacco screening and counseling, urinary and continent screening and then STI prevention and counseling and screening is appropriate, and immunization screening and things like that. She should also be screened for the need for BRCA or other genetic testing related to her family history and she should get a pap smear every three years as she's under age 30, as this patient was.
Antonia:Yeah, so obviously the well exam is not just pap. Breast exam bill for everything else, that's not that.
Howard:Which is what everybody thinks it is, including the coders.
Antonia:Yeah. So then it becomes a philosophical question of whether or not the screening is also treated. Is that still within your scope? In other words, maybe we screen for anxiety or depression and when we identify it, do we separately charge for treating it?
Howard:Yeah, well, you could do that. It's technically legal, but the auditor came back and agreed with me that it was also justifiable to not make a separate charge and took away her failure for me on that chart, but maybe you maybe it depends.
Howard:Maybe you refer the patient for counseling or you refer them to a mental health care provider.
Howard:Once you identify the issue, maybe you started medication and have them follow up with you. The choice to charge or not is perhaps based upon the complexity of those choices. If you spent 45 minutes with a patient in crisis dealing with depression who just happened to be scheduled for her annual preventative, well, that's a bit more complex and urgent and you really should probably charge for your time and services. But the goal of the preventative visit is screening, prevention and perhaps referring for appropriate and focused follow up of any new issues identified, all without having an extra cost associated with it, so that people come and get these services. Think about the birth control component. We do contraception and contraceptive care, but when we screen the patient to see if she needs birth control say she needs a refill or a prescription for birth control pills we don't then charge her a separate visit to prescribe the birth control. So I think this is a question of sort of ethics and is an illegally or technically gray area, but that's where we use our ethics to guide us.
Antonia:Did this listener indicate how much time in the visit was spent discussing this lexapod refill?
Howard:Yeah, it sounded like it was less than a minute or two. Just a very casual conversation about how she was doing, and sure I'll send you a refill in.
Antonia:Yeah, so okay. So billing for that just seems wrong, like what's the chance she's going to go back to that provider every year anymore? That wasn't her main purpose for coming in to lexapro refill. It was for the annual.
Howard:Yeah, so ethics or everything.
Antonia:All right. Well, I also got an interesting question I wanted to bring up on here. So, drob, should a mid 30s woman who doesn't have a partner but wants children in the future consider O-site cryopreservation? What about embryos versus just eggs? Or is this all just a marketing scam to get anxious women to pay thousands for storage fees? Asking for a friend who is always an auntie, not yet a mommy.
Howard:Okay, interesting. So I guess this one should be to deer always an auntie. So what's your answer? I feel like this could be one of those things where it's marketed obviously to anxious patients, but is also a great thing for many patients who are in that situation. Things are rarely good or bad, but the truth is somewhere in the middle. So, people, this can be fantastic for some people and maybe unnecessary for others.
Antonia:Yeah, this is so individual and it's really down to family building and there's so many options for that. So I'm just going to hit this. I'm going to review the alternatives to family building besides the cryopreservation, see where the cryopreservation fits in and then see what the professional societies say. So these are just the options that I can think of, in really no particular order and probably not all encompassing. So one thing you can do is just do nothing, wait and see what happens If you get a partner one day or whatever. Try naturally, but then be okay with possibly never having a child. So that's one option.
Antonia:Another option plan to adopt, which, besides biologically for your own body, is a very complicated process, very happy. Another option is, if you get past the age where you have any viable O-sites yourself, you could plan on using donor eggs and then either your partner's sperm or sperm from a bank, usually a healthy woman that has gone through this process for money, not as part of her own family building process, where then there was just extra. Another option is you could plan on using donor embryos, and these are often like the side product of couples who were going through IVF and then got more embryos than they ultimately were able to do transfers with, and then they have chosen to put these up for putting them up for adoption is one way to say it rather than letting them be discarded. And that doesn't mean these are free. The donor family doesn't get compensated, but the clinic and lab fees are still very high for these sometimes.
Antonia:Another option is this option that our listener asked about is go through the egg retrieval process now of your own eggs while you're in your 30s or just sometime before you have significant age-related decline and you pay for the storage and you hope that eventually one day you'll get into a situation where you could get your eggs fertilized and proceed with pregnancy that way.
Antonia:And another sub-option here to consider is because eggs alone don't have quite as good of a rate as surviving the thawing process compared to fertilized eggs or aka embryos. You could even go through the egg retrieval now and get some of the eggs fertilized, and this would depend on your situation as to whether you're going with anonymous sperm through a donor or if you already have a partner or someone in your life that would be willing to be the biological, genetic father of your kids and be involved in this, and then, I think, the most biologically complicated option, in my view, would be, at an advanced age, going through IVF later on, once you've found your partner or picked a planned sperm donor, simply because the chance of success may be much lower depending on your age at the time.
Howard:I think you've made more questions, but we'll compare those options for us then.
Antonia:Yeah. So I'm assuming she wants a child, so she doesn't want the option of being okay with never having a child and not doing anything at all. The per cycle chance of conception over age 40 just naturally trying to conceive is often quoted as less than 5%, whereas at peak fertility in the mid-20s it's 25% chance with just one intercourse. By age 50, it's still as high as 1% chance if you're not on birth control and don't have other reasons for infertility. So those are just the chances to consider. So very low chance of spontaneous conception if you get over 40 is the bottom line up front. I'm going to go ahead and skip any further commentary on adoption. I don't really have experience with this, but I know that it can be very extensive and emotionally draining and costly. So if someone is interested in it, not as a plan B for fertility but just in general, then maybe they can send us their experiences and we can talk about it. But it's probably not the best thing to do this as a plan B because it might actually be harder than the other options we're going to discuss. So then we're getting between getting egg retrieval now versus in the future using donor eggs or donor embryos or IVF. So donor eggs. If you're older and you're using donor eggs that were obtained from a healthy young donor, there's a 51% chance of a fresh transfer resulting in a live birth, regardless of how old you the patient are at the time of the pregnancy. There are still higher perinatal risks using a donor egg versus using your own egg, and that's likely multifactorial, but that would include preterm birth, low birth weights, then still birth Deterior embryos. If you're okay using being pregnant with someone that is not genetically related to you or to your partner, it is cheaper than IVF because you're skipping the whole egg retrieval and stimulation process. For yourself, it is about one third of the price and there is about 40% chance of having a live birth per attempt or per cycle. So it's not per se adoption, because as soon as this embryo has implanted into your uterus, it's fully legally yours. Once you give birth, it's yours. The genetic, the biological origins of the egg and sperm have no legal claim on this person. So that might be one pro compared to adoption. If you're okay with having a child that's not genetically yours, the genetic relation thing is just something everyone has to consider for themselves. If that is important to you, then you're looking at either egg retrieval now or going through IVF later in life, and really it is. I'll just sum it up getting an egg retrieval now to maybe go through IVF later is better than just waiting to go through IVF later. It's more cost effective, it's higher rates of success and I can break that down a little bit more. But there's been some cost breakdown studies on this in the fertility sterility journal we can link to.
Antonia:And as far as, what does ASRM and ACOG say about this? Acog doesn't directly address it. They just say expedited fertility evaluation immediately at 40 years old. So it's essentially they're in short form. Differing to ASRM is how I read that between the lines, because people at 40 years old that haven't spontaneously conceived, they're going to get escalated care pretty quickly.
Antonia:So ASRM has a 2021 guideline called Evidence-Based Outcomes After Ocite Crier Preservation for Donor Ocite IVF and for Planned Ocite Crier Preservation. So it's been since at least 2013,. They've recognized it as standard care, so not experimental, not just some gimmick to try to get more money, at least for indications like fertility preservation for people that are undergoing cancer treatment that haven't you know, they haven't started or they haven't at least completed their family building yet. And in this 2021 guideline. Finally, they also recognize just delayed childbearing and also gender transition as other indications to go through quote unquote freezing one's eggs. So they say that the evidence on the outcomes is still limited but from what has been observed so far, the live birth rates are roughly equivalent between this and someone that's going through conventional IVF at that same age. So that includes rates of embryo transfer per cycle, rates of ongoing pregnancy per embryo. They really they said there's small studies so they gave caveats on each one.
Antonia:So when it gets to age like okay, I agree that this is better than waiting till I'm 42 to start IVF. What would be the latest age to start this and how long do I have to think about this? They said the clearest threshold for difference in outcomes is getting the egg retrieval done before age 38. So before versus after, the clinical pregnancy rates were 60% versus 44% respectively. So basically, my answer to this listener is yes.
Antonia:If you're thinking that you're not going to have started your family otherwise by age 38, then and you really want genetic children, I would say by the before you get to age 38, really consider freezing your eggs. Overall the costs they're high. They're comparable to the respective IVF costs plus yearly storage of the eggs or embryos, which that ends up being about another $500, maybe up to $1,000 per year, for not per embryo or not per egg, but for your whole amount, even if you had 50 eggs or something. Of course that could change by clinic and over time, but that's going to be an almost negligible cost compared to everything else you did to go through the egg retrieval. It's still going to be cheaper than trying to start IVF after 38. So there that's my answer.
Howard:Well, and there are cheaper options. I've had a lot of patients use CNY fertility, which has offices now around the country, but they're primarily based in New York. But they are significantly cheaper. Usually I have to even a third of the price of other fertility operations. So I did look on their website. Their egg freezing packages are $4,800. And they say that compares to a national average of nearly 15,000.
Howard:And I think that they're yeah, and I've had several pregnancies. This is the maybe the new face of fertility and I think that their yearly storage fee is about $600, which again is about half of the freezer fees you see in a lot of places. So it can be done for less money. A little bit of travel in that case, and you should shop around and comparison shop. These protocols for a lot of these things are fairly standardized around the country and you can move embryos from place to place or move eggs from place to place, depending on your situation. So hopefully that answers your question. There's a lot to unpack there. We could spend a whole hour.
Antonia:Yeah, so good luck to our listener. Hopefully, whatever you choose to do, it works out the way you want it and hopefully that helps other listeners as well. But I think we need to wrap up now. We might have gone over time a bit. So the thinking about OBGYN website will have links to the things that we discussed and, of course, check out our Instagram if you haven't already. Our little ninja has been posting fun little tidbits here and there, and we will be back in a couple of weeks with something new.
Narrator:Thanks for listening. Find us online at thinkingaboutobgyncom. Be sure to subscribe Work for new episodes every two weeks.