Thinking About Ob/Gyn
A fresh and evidence-based perspective of all things related to obstetrics and gynecology. Follow us on Instagram @thinkingaboutobgyn or visit thinkingaboutobgyn.com for show notes and more.
Thinking About Ob/Gyn
Episode 9.10 Pit Breaks, Cannabis, and IUDs for Endometrial Protection
Howard and Antonia explore the evidence behind pit breaks in labor, cannabis use in pregnancy, and IUD options for hormone replacement therapy.
• Pit breaks in labor lack substantial evidence of benefit when used in active labor
• Current research suggests stopping oxytocin during active labor may slightly increase cesarean rates rather than decrease them
• Long pit breaks (up to 8 hours) in latent labor may be beneficial by allowing rest and promoting patience
• Recent systematic review shows prenatal cannabis use increases risk of low birth weight by 75%, preterm birth by 50%, and perinatal mortality by 29%
• Cannabis use during pregnancy (7.2% of pregnant women) now exceeds tobacco use
• Retrospective studies on doula care show association with better outcomes, but can't establish causation due to inherent differences in patients who seek doulas
• 52mg levonorgestrel IUDs (Mirena/Liletta) are suitable for endometrial protection during HRT, but evidence only supports use up to 5 years
• Most systematic reviews combine heterogeneous studies and shouldn't be considered level 1 evidence
We'd love to hear your questions! Send them to us through our Instagram or website thinkingaboutobgyn.com.
00:04:52 Pit Breaks in Labor
00:15:32 Examining Evidence on Oxytocin Discontinuation
00:26:08 Prenatal Cannabis Use and Adverse Outcomes
00:36:07 Doula Care Study Analysis
00:57:22 Levonorgestrel IUD Use in HRT
Follow us on Instagram @thinkingaboutobgyn.
Welcome to Thinking About OB-GYN. Today's episode features Howard Harrell and Antonia Roberts discussing pit breaks, cannabis and more.
Antonia:Howard.
Howard:Antonia.
Antonia:What are we thinking about on today's episode?
Howard:We're going to chat about just a couple of recent studies and tackle a listener question a great one. But first, what's the thing we do without evidence?
Antonia:How about pitocin breaks in labor? I don't and I don't mean just taking a bathroom break, but like a full.
Howard:A pit break, a pit stop.
Antonia:Yeah, a pit stop, like a real pit stop.
Howard:Yeah, because that's what the nurses call it. Pit break pit stop, yeah, and they do need to take a pit. Stop every now, and again.
Antonia:Yeah, everyone does.
Howard:This is cessation of oxytocin, all right, so this is going to probably be a little controversial, but I guess we're no stranger to that. A pit break is when a patient has been on some amount of oxytocin and they appear to have a stalled labor or maybe even a dysfunctional appearing contraction pattern like coupleting or something like that, and the idea is that you turn the oxytocin off for some period of time and then you restart it and somehow all that stuff gets better.
Antonia:Right. So this pause in the oxytocin could be anywhere from 20 to 60 minutes, or it could be quite a bit longer, from 20 to 60 minutes, or it could be quite a bit longer. And then typically, when it gets restarted, it might just be restarted at half the rate that it was when you stopped it, or it might even be started from scratch, like start from just the starting one or two milli units or if I don't know of too many places, but maybe some places start high dose at six, but yeah either, but still starting it at a lower rate than it was at when you stopped it.
Howard:Building back up.
Antonia:Yeah.
Howard:Yeah, and just instantly, just with the way you've explained that there's a specificity problem here, because we could stop it for 20 minutes, 40 minutes, 60 minutes, two hours, eight hours. We could start it at half the dose. We could start it at half the dose, we could start it at a lower dose and build back up. So you can think about if you were going to design a good study to answer this question. There's so many variables and we can talk about this.
Antonia:Just infinite, almost just from what you listed there.
Howard:And we can talk about this later in terms of how to design optimal studies, about some of these questions. But this is really difficult and what happens is we do a study and say, let's say, we did a perfect study and it stopped at it for 40 minutes and it started it back at half, or something like that, and that was our protocol and we found no effect. Well, what happens sometimes is people come along and say, ah, but you didn't stop it long enough or you stopped it too long, or something like that, so I only stop it for 20 minutes, or I always stop it for 90 minutes, or I never restarted at half, I restarted at three or whatever it is. And I'm just my mind is just thinking.
Howard:The burden of proof for people who do things is on the person to prove that what they're doing works. It's not by saying there's no evidence for the thing. So. It's not by saying there's no evidence for the thing, so I'm going to do it one way or the other. But in any event, whatever the protocol is, the idea is that oxytocin receptors are saturated and that by turning the oxytocin off for some period of time, you're freeing them up again, you're unsaturating them in the hopes that the uterus will be more responsive to oxytocin, or maybe in a more functional labor pattern the second time around.
Antonia:Yeah, and I do think I think a lot of people would agree that a pit break has a huge mental component as well. So if the patient and probably also their care team are getting frustrated by the lack of progress their cervix isn't dilating as fast as maybe the average labor patient would, but it's not time to go to C-section yet, like there's not an acute indication for that then sometimes they just feel better by taking a little break. They get unhooked from the Pitocin, maybe they're even allowed to have a nice snack. If they were not on a, not allowed to eat before now, just let them go ahead and eat because they're so early on, have a shower, have a nap and then jump back in a little bit more refreshed both the patient and their care team. So there, that could be a big part of it too. But is there evidence that taking this pit break improves outcomes?
Howard:This is a tough one because there are lots of recent studies that look at the idea of turning oxytocin off when a because the patient has a dysfunctional labor pattern or a dysfunctional contraction pattern or something like that, but because, well, it's so functional that oxytocin may no longer be necessary. If she can deliver without oxytocin or with a reduced oxytocin rate, it might have the benefit of decreasing hyperstimulation. Or I guess I shouldn't say that. We should say tachycystole is the modern term, but you will see that in a lot of the literature because we use that term up until about 15 years ago. And then perhaps fetal heart rate abnormalities associated with tachycystole, and some people are just interested in it because it might make the labor less painful for a patient trying to go natural. At least that's the cultural idea. So if we don't need the pit, don't use it.
Howard:And in this regard a lot of trials that have looked at turning off the oxytocin in the active phase, well, they have mixed results at best. On the whole there's no good evidence that the mode of delivery is different with or without the oxytocin discontinuation. When you're stopping it already in active labor things are going well. Some of the studies do show, as you can imagine less tachycystole, but then that hasn't necessarily translated into studies showing improved neonatal outcomes, because tachycystole doesn't mean adverse outcomes and, frankly, if a patient had tachycystole and had tachycystole, especially with adverse fetal heart tracings, we're going to deal with that in both arms of such a study, right? So didn't change neonatal outcomes.
Antonia:That's similar to another practice I've seen done. I remember seeing this in my training where if someone's in active labor and then their water is broken, they just automatically will cut the pit in half. I think their logic also was that well, we can only go to 20 and we can't go higher, so this gives us more room to not just be at 20 for a really long time. But again that I have no idea what, if any, evidence basis there was for that.
Howard:I think we're going to have to do a segment on how high oxytocin can go yeah, yeah. But coming to a theater near you, go ahead.
Antonia:Yeah, okay, so you could say that it's okay to stop the oxytocin, or at least not continue to increase it once the patient is in active labor and making good progress. So that's probably common sense, probably common sense, I think a lot of protocols already say titrate the pitocin to having that adequate contraction pattern and don't keep going up if they're already contracting as much as they need to be. So once they get into active labor, even if they were induced to get to that point, a lot of them essentially are now in a spontaneous labor process, like you couldn't stop it, even if you wanted to. But on the other hand, the pit breaks that we're talking about in this question here are often in the setting of not good progress, even an arrest of progress, and we know, from some of those other studies at least, that turning it off when there's good progress doesn't decrease the C-section rate. So does that also apply to patients who are not making good progress?
Howard:Yeah, there are some studies that suggested a lower cesarean rate if you turn the oxytocin off, but that appears to be related to cesareans done for abnormal fetal tracings, if anything, not for abnormal labor progress. And even that finding about a reduction in cesarean rate if you turn it off is not a consistent finding. It's supported by most of the studies.
Antonia:Okay. So of course reducing tachycystole and then any associated fetal responses to that is going to decrease the cesarean rate, probably more so in settings where the clinicians have a very low threshold to do cesareans anyway. So the counter argument to that is that if someone has tachycystole on pitocin it's very easy to treat just stop it and then maybe if you need to give terbutaline reposition etc, it doesn't mean that you should have never even been on pit at all, they still probably needed the pit. And then when they develop tachycystole then you stop it till it resolves and then usually you restart it once their contractions have settled out. And I think that is similar to how amnioinfusions for variable decelerations are also associated with lower cesarean rate and that by itself is a good outcome, right. But if you look at the neonatal outcomes it's not clear that they're better either way. And I don't know if they've ever compared non-intervention for variable D cells meaning no amnioinfusion but also no cesarean compared to an amnioinfusion group. Because if you do amnioinfusion and then you have a lower cesarean rate than if you don't do it, it's because you were doing more cesareans in the non-intervention group. And then if you compare that both of their neonatal outcomes are the same.
Antonia:You could argue that they're the same because you saved some in the amnioinfusion group from needing a cesarean. But if you didn't do the cesarean could you have worse neonatal outcomes. That I don't think has been studied and I don't think it would be really ethical to study it that way. But it could be that even without doing an amnio or a cesarean they'd still have the same outcomes, because we don't know. It could just be that we're only making ourselves feel better by cleaning up the tracing. We're not actually improving anything. So that's an analogy for how taking a pit break might just be making us feel better but not actually helping anything in a physical way.
Howard:Yeah, and in an institution where there's already or for an individual provider where there's already a high predilection towards cesarean, then that's going to be more impactful than in a place where folks are maybe more tolerant of category two tracings or of prolonged labors or things like that. So you also have to think about what setting the studies were done. Was it done in an institution with a cesarean rate similar to yours or an institution with a higher cesarean rate? Because let's be honest, our cesareans for category two tracings, and maybe even most of them for prolonged labors, are mostly unnecessary and don't lead to improved neonatal outcomes. And when I say mostly, like high 90s, like we can talk, think about that later.
Howard:But I think there's also the idea that less oxytocin might decrease the postpartum hemorrhage rate. But while it's true that increased oxytocin use is associated with an increased risk of postpartum hemorrhage, it doesn't appear to be causative. So I think a lot of OB-GYNs look at this the wrong way. If the patient requires more oxytocin to change your cervix, it means the uterus is, at baseline, less responsive to oxytocin, and so they're also going to be less responsive in postpartum period, so they have higher rates of hemorrhage, since control of hemorrhage is mostly mediated by oxytocin postpartum. So the patients who required less oxytocin are more responsive to oxytocin and therefore are going to be more responsive to oxytocin in the postpartum period and have less hemorrhage. So the higher rates of oxytocin necessary to achieve cervical progression is a sign that the patient is at risk for hemorrhage. But it's not something we caused by giving more oxytocin or saturating their oxytocin receptors with prolonged oxytocin. And it's not something we can fix by deliberately trying to use less oxytocin or giving a pit break that frees those receptors up again.
Antonia:Yeah, and if anything, the pit break could make that situation worse. In some of those studies where the oxytocin was turned off, I mean there would be more prolonged labors and that can increase the risk of chorioamnionitis, which also increases the risk of hemorrhage. And there was at least one study I found that shows a significantly higher risk of postpartum hemorrhage. And there was at least one study I found that shows a significantly higher risk of postpartum hemorrhage in patients. This was in patients who had their Pitocin that turned off only during pushing, so it probably wasn't even that long of a break, but they had higher postpartum hemorrhage.
Howard:And I think this demonstrates the importance of having empiric data, not a theory, because it's so easy for us to have narrative fallacies where the theory takes us down pathways, and I think we see that with a lot of practices in OB-GYN that are persistent despite lacking good scientific evidence. That said that at least a randomized controlled trial is looking at this issue of turning the oxytocin off in again when they're in active labor was or of low quality, with uncertain evidence. And then in 2021, there was a study published, so this is after the Cochran review. The study was in the British Medical Journal and it found that routinely discontinuing oxytocin in the active phase led to a small increase in cesarean rates.
Antonia:Yes, that British trial. They called it the CONDISOX trial for short, short for continued versus discontinued oxytocin stimulation of the active phase of labor, or CONDISOX. So this was a double-blinded, randomized controlled trial at nine hospitals. It was in Denmark, even though it was published in the British Medical Journal and they had 1,200 patients who had oxytocin started during early latent labor. When they got to the active phase then they were randomized to either continuing it or discontinuing it. Active phase then they were randomized to either continuing it or discontinuing it. The rate of cesarean in the discontinuation group overall was 16.6, and in the continuation group it was 14.2. When they only looked at the multiverse women who had a prior vaginal birth, so not people that were doing a TOLAC the cesarean rate was 7.5 in the discontinuation group who had it turned off in active labor and only 0.6 in those who had it continued all the way to delivery and there were no differences in the rates of neonatal outcomes.
Howard:Yeah, so doesn't support the thought that you're saving C-sections. If anything, it's the other way around. I do think that this study is the better one to look at to answer this question than the stuff that's in the Cochrane review, and it addresses a lot of the weaknesses of prior studies included in that review. Discontinuing the oxytocin once women are in active labor. Also, the outcomes were different, so they didn't have less hemorrhage, for example, by turning the oxytocin off. But more to our question, though, there are studies that look at discontinuing oxytocin when women are still in latent labor. So now we kind of have the other end of this. These were women in active labor who were doing well, and can you turn it off, and does that have a positive effect on anything?
Howard:Now let's look at the other end, where we have women who are early still in latent labor, usually obviously induced patients, and some of these do show that the rate of cesarean is decreased with discontinuation of the oxytocin and resumption for different time periods, but most effectively within an eight-hour break. So we can talk about those. There was another large study called STOP-OXI in the Lancet in 2023, conducted in France. They also looked at neonatal outcomes in two arms, including cord blood pH base, excess APGARs and acute mission rate and they found no difference in this randomized trial and in that study. The patients who got their oxytocin turned off had a 10.7% rate of cesarean delivery, while the patients who had their oxytocin continued had a 9.9% rate, but that wasn't statistically significant.
Antonia:Okay. So that study from France in 2023, that had 2,200 patients. Then the condysox one we just mentioned had 1,200. There's no other trial anywhere else about oxytocin discontinuation that has anywhere near that number of patients enrolled. But despite that, in March 2025, the Gray Journal, ajog, put up a systematic review and meta-analysis looking at this question and they claimed a reduced risk of cesarean when stopping oxytocin in active labor. So I think this is an example of that thing you hate where they include a lot of individually tiny and bad studies and then they give those so much weight that it basically drowns out those few really good studies.
Howard:Yeah, and this really shows why we need to do a whole episode sometime on how systematic reviews and meta-analyses are being perverted and provide misleading information. So they did include the two studies we just talked about in that systematic review. In fact, those two studies made up 59% of the patients included in this meta-analysis. The rest come from nine other small, low-quality studies, which the authors of the meta-analysis caution and say that these studies have issues regarding trustworthiness. Now, both of those larger studies that we've discussed show more cesareans in the discontinuation group than in the continuation group, but among the low-quality studies the trend is often reversed. But almost all of these individual small studies weren't powered sufficiently to see a difference in cesarean delivery. So this meta-analysis in particular is a reminder that a single level, one large randomized controlled trial, trumps a meta-analysis of heterogeneous studies, which is what this is an example of. So this is a great teaching point for residents and junior faculty and med students If you're trying to understand how to find an answer to a clinical question, if you understand the levels of evidence and the difference between the meta-analysis of heterogeneous and homogeneous studies and you understand the statistical problems often arising from these sort of studies, where you take heterogeneous studies and try to make the data compatible, then you would be right to say that either the 2023 study that we talked about or the 2021 study 2023 study that we talked about or the 2021 study, both of which basically have a consistent finding and which showed fewer cesareans or at least no difference in the cesarean rate, is the best clinical answer that we have, and it is level one evidence compared to this meta-analysis, which is level two evidence because, just regardless of any other reason, it is a meta-analysis of heterogeneous studies.
Howard:So this happens very frequently and, unfortunately, systematic reviews and meta-analysis are really easy to write and inexpensive and they make a great CV line item. So people do them to get publications and unfortunately, people when they go to answer a clinical question, they think, oh, I'll start with a systematic review or a meta-analysis. That's fine to do, like you could have started. I started with this meta-analysis, right? But then I look at the individual studies and you have to ask the question first, is this a meta-analysis of homogeneous or heterogeneous data? And then look at the individual studies. But I fear that many of our colleagues would just look at the meta-analysis and take whatever it says as the best answer, and that fails us very often. We're publishing way too many of these sorts of systematic reviews. They're not reliable in the way that people have been taught they are. They're usually not level one evidence they might be and when you don't understand, in fact, that this is is level two evidence, then you give up on and you ignore the level one evidence.
Howard:In this particular, when most of those other nine studies that the authors said lacked trustworthiness, they still included them, but they weren't. I think only one of them was blinded. They were, I think, all underpowered. They used vastly different protocols for what they were doing. Some were done in countries with histories of high rates of data fabrication and poor ethical and data controls data collection and we live in an age now where distinguishing good evidence from bad evidence is everything. We also live in an age where you can use PubMed to cherry pick almost any answer you want to virtually any question related to health or science.
Howard:A different author group could have taken the same 11 studies and then applied different weights to the studies or made different exclusion criteria based upon some of these trustworthiness things, or introduced elements of bias or things like that, and they could have come up with the exact opposite conclusion. And again, we see this a lot. We see meta-analyses that find opposite conclusions. So we really have to drill into our students and residents' mind that a meta-analysis is very often today not to be considered level one evidence. And the difference is again the types of studies being analyzed and whether they're heterogeneous, as they are in this case, or homogeneous.
Antonia:It's almost like if those authors of the little studies are going to they're being honest and they're saying I don't know how trustworthy these findings are. It's almost like they need to spell out don't use us in a meta-analysis. That's what they're trying to say with that statement, but people just aren't getting it. That's what they're trying to say with that statement, but people just aren't getting it. Well, let's see if we can focus in a bit more on studies about stopping it in latent labor. This is kind of part of what we're getting at here.
Antonia:So you had mentioned earlier that there was some studies that showed this seemed to lower the C-section rate if you stop it for up to eight hours. So there was one study like this in the Green Journal in March 2020, and it was looking at labor induction in nulliparous women. They found a whopping 57% lower rate of cesarean if they turn the oxytocin off for eight hours, and some more modest reductions if the pit breaks were shorter, and the reason was typically for protracted latent labor. So that's a little bit more of an example of a scenario I was thinking of when I brought this in was possibly even a nice long pit break in women who are still early on and it's just not going anywhere. So now, with that study from 2020, it sounds like that's a thing that we do with evidence, wouldn't you agree?
Howard:Maybe. Again, it depends on what we're defining and obviously when we're looking for a clinical answer or designing a study, we need a definition. I don't think eight hours is what you see happen in real life. Mostly it's 40 minutes or something like that.
Howard:So it should be noted that this was not a randomized controlled trial, but just a retrospective chart review, so there's a lot of variables that are undoubtedly not controlled. For they did note that it was not in their practice, that was not their practice to give pit breaks for patients whose membranes are already ruptured, but didn't exclude that there may have been some in the mix. But they basically just gave these patients a night off or some period of time and then restarted in the morning. And we've all done that.
Howard:I think and yeah, I think that could and should result in a lower rate of cesarean delivery, because by having this practice you're building in some patients into your care plan what kind of that mental aspect you mentioned earlier. The patients who pressed on through the night and all of a sudden find themselves on oxytocin for 16 hours or 18 hours or something with no change. They may feel discouraged. Their nurses and doctors may feel discouraged and worried about their lack of progress and so they call for a cesarean for a failed induction.
Howard:And sometimes it's pragmatic things I've got a lunch break or I've got morning before clinic or I've got after clinic and it's been X number of hours. But the patients who are willing to take a break and sleep on it and then start again in the morning, they likely have more patience and resilience in themselves and their care team likely has more patience and resilience. So this is the importance of randomization, because those factors are not accounted for in a retrospective chart review. But still, I absolutely don't doubt that just giving an additional several hours, not being in a huge rush, especially in early labor, has a positive effect. When we accept that sometimes there's no change at all for the next several hours we're giving time for the oxytocin receptors to upregulate without having an OBGYN sitting around sharpening their scalpels, putting you on some clock.
Howard:That probably doesn't even apply in a latent labor situation, so you don't necessarily need to stop the pit for that to happen. But if you're playing the long game, it probably does give the patient some comfort and rest. Maybe you need to do a balloon or something you should have done before too, and just reassess and re-tack the situation. But either way, giving laborers some more time in general in all stages of labor will result in a lower cesarean rate, and I think we did an episode a while ago on like ways to reduce your C-section rate. But really, if you just want one quick snippet, it's just be patient.
Antonia:And again, we have to remember this idea that the oxytocin receptors getting oversaturated and downregulated and like a negative feedback loop is not accurate and it's really just completely theoretical. It's not proven at all and for inductions like you just described an example of it could just as easily likely be the issue that you really needed more pit. You needed to crank it up faster, not turn it off, but that also is just as theoretical too. But either way, it's important to go with the actual clinical evidence rather than a theory of how we think the oxytocin receptors are working. So if you're someone that buys this theory that it's negative feedback and oxytocin receptors will just get oversaturated and just stop working and you need a break from pit, then you could end up in a situation where you're applying that but it's counter to what the clinical data says works.
Howard:Yeah, and both can be true.
Howard:It's a complex system.
Howard:You can both downregulate these receptors which means there is at least a theoretic reason why that happens and also, at the same time, upregulate expression of receptors in the same tissue, and you're just in a race of was one effect bigger than the other.
Howard:So this is the problem, again, with complex systems, and so you have to rely upon the actual clinical studies. I think this is one reason why, though, this patience that you need, why you shouldn't break water in early latent labor, because if you're going to pit somebody who's two or three centimeters, and they're still unchanged 12 or 14 hours later, getting towards the evening, if their water's intact, there's certainly nothing wrong at all with turning it off and giving them rest, letting them eat, starting again early the next morning, that sort of thing, or again, taking a different approach. Maybe they need a balloon or they need something else, but if it's elective, they could even go home in some situations and then just come back. But once the water's broken, there's going to be an increased risk of chorioamnionitis and sepsis and neonatal sepsis and all the urgency that follows, and so no one's really going to want to take a break at that point, and then you may back them into a C-section because you chose to break their water early.
Antonia:Then you may back them into a C-section because you chose to break their water early. Yeah, so I think we said that stopping the Pitocin when a patient is in well-progressing active labor is either of no benefit or maybe of at least a slight increased risk of harm, increased cesarean risk and a longer labor process, and does not reduce hemorrhage. So really just no argument for doing that. And we've said that being patient, especially with latent labor, and even pausing the induction altogether for up to eight hours, can be a good thing if things are otherwise looking fine, stable and they're just moving really slowly. So then now there's another situation where this is done sometimes. So what about a pit break in active labor? Maybe the water's broken already, maybe not, but there's really not good progress. Maybe they have an irregular pattern, sometimes it's only every seven or eight minutes or less, and then sometimes there's coupling contractions and then there's just really very minimal cervical dilation.
Howard:Yeah, and I think this is what I think of when people talk about this most often. So, in this context, we're not doing it because there's tachycystole. In fact, like you said, they may have a bad pattern, a slow pattern. We're not doing it because there's fetalycystole. In fact, like you said, they may have a bad pattern, a slow pattern. We're not doing it because there's fetal distress. We're not doing it because they're in early labor or because the other end, they're progressing well and we don't think they need it anymore. It's because they are in active labor but not progressing well, and we want to give the uterus a rest and make it more sensitive to oxytocin.
Antonia:In theory, yeah, so is there any evidence for this situation?
Howard:Well, unfortunately there just aren't studies that I think answer this question. We've talked about these other two clinical scenarios because sometimes people will infer benefit to pit breaks like this based upon the other data. But hopefully now folks can understand that these situations don't apply to somebody who's in active labor and not making progress. Certainly if they have their water broken. Anecdotally people may have the perception that a pit break is a good thing and they reset the clock on labor progress by turning the oxytocin off and restarting it later.
Howard:So if you have a scalpel-happy doctor and a patient who's been six or seven centimeters for four hours or has a less than perfect contraction pattern and the nurse can convince that physician to give the patient a pit break, what she's really doing is buying the patient a clock reset on the labor curve. Now they're going to get not four hours, they're going to get maybe six or something. So that's not actually changing the physiology of labor, she's just influencing the doctor's behavior in a certain way. But if the doctor understands that inductions in particular don't necessarily follow the same labor curve pattern as spontaneous labors and can patiently sit back and give the patient some more time after assessing the clinical situation again, particularly with inductions, then I would argue that going up on the oxytocin is probably the right thing to do at that point. But even if you don't, what you're doing is buying time for increased upregulation of oxytocin receptors and you're keeping the clock-watching doctor at bay.
Antonia:So at least in a certain sense these types of pit breaks in abnormal active labor could work too.
Howard:Yeah, and I think that's why so many nurses would argue that they have a strong intuition that they work. They feel like they have seen it work, but it would take a randomized controlled trial with a strict protocol to answer that question definitively, and there's nothing from the trials we've been discussing that would seem to imply that it actually works.
Antonia:Just the trials of the latent labor who get a really long break.
Howard:Sure, yeah, but you're not going to do an eight-hour break for a patient in active labor whose water's broken or anything like that.
Howard:So again, when I've seen them, they're 20 minutes or 40 minutes or maybe an hour, and that's not what these studies have really looked at. So there's something very different again about the patient in latent labor who you're inducing and their water's intact and all that. So it is a thing we do without evidence because there are no trials that says it works. Even if it does work, there's still no guidance or information on how long the break should be and things like that. So, yes, it's a thing we do without evidence and maybe something that someone should do a study on.
Antonia:Okay, so there's another free idea for you guys out there. Well, I think that's enough for that segment. Let's talk about some studies. You've got a good one, right?
Howard:Yeah, did you see this new systematic review of prenatal cannabis use and DNA outcomes published just in May 5th in JAMA Pediatrics?
Antonia:Yes, I did, and it wasn't any new information. It wasn't like a new study with new evidence, but it was a review and they compiled a lot of very compelling evidence that has been coming out over the last few years and some of which we've already discussed on prior episodes here.
Howard:Yeah, and the evidence is convincing and it's consistently very negative. So in this new review they looked at everything published up until April of 2024. So this brings the review to a total of 51 studies looking at over 21 million neonates and they found the risk of low birth was increased by 75%, preterm birth was increased by 75%, preterm birth was increased by 50%, small for gestational age was increased by 57% and perinatal mortality was increased by 29%.
Antonia:Those are all pretty bad numbers. Then there was also a more recent study that came out after their period of data collection. This one came out in October 2024, also in JAMA Pediatrics, and it looked at children's executive function and aggressive behaviors at age five following in utero cannabis exposure, and they also found negative effects on both, with potential for even longer term implications into adulthood, like academic performance and job success.
Howard:Yeah Well, I think it's timely. The use of marijuana during pregnancy has more than doubled in the last 10 to 20 years and really is accelerating, it seems. As of 2021, 7.2% of pregnant mothers use cannabis, despite recommendations from, hopefully, all their doctors and our professional societies not to use it, and there's a real disconnect. I think, where it's perceived as natural and even healthy by a lot of patients, it may be a better alternative than prescription medicines like Zofran or something for nausea or depression or anxiety or smoking cessation or chronic pain they may have. But at this point we can truly say that, yes, smoking, including vaping, is still very bad, but cannabis is even worse for your pregnancy.
Antonia:Yeah, this has been a very sobering and frustrating phenomenon to sort of observe. Very sobering and frustrating phenomenon, to sort of observe, and I think a lot of it is cultural, probably riding along with how it's been decriminalized and legalized in a lot of places. I remember this huge contrast of how it was still you can't use it at all if you're in the military and I was in the military health system and the few times we'd ever see a positive cannabis test would be like almost scandalous oh no, we got to. You're got to let your chain of command know and you're in trouble now and all of that. But now, when I'm probably not that often, but just a huge amount of patients just have it and they're just like yep, whatever, like we all do it, whole family does it, whatever. But those relative risks for those adverse outcomes, they're at least as high or higher with cannabis as compared to tobacco use. And then the data about the long-term cognitive outcomes especially is much more clear and certain with cannabis compared to tobacco.
Howard:Yeah, and more to the point, smoking during pregnancy has declined over the last 20 years. In 2021, less than 5% of women smoked during pregnancy, so that's actually now less than the percentage of women who use cannabis. In the 80s, it was something like one in four women use pregnancy. I think in the year you were born. I looked it up. It was right at 25% of women use cannabis.
Antonia:The year I was born is going to be top secret information to the podcast.
Howard:But a lady never reveals her age.
Antonia:Well, I'll give a hint that apparently the Bruce Springsteen song Born in the USA was in the top 10 when I was born.
Howard:There's going to be a spike in Googling that year. Did Born in the USA come out? Google's going to notice what's happening, but yeah, mine was Staying Alive. If people want to look it up by the BG. I still use that every time I'm doing chest compressions for CPR. I don't do chest compressions for CPR.
Antonia:You have to do the certification, but still.
Howard:But I think the point is smoking in pregnancy has not aged well, unlike us, but it's gone out of style, I think, because of public stigma against smoking during pregnancy and a lot of things in there, taking it out of how it's portrayed in television and print ads and glamorized and all that. But the exact opposite trend is now happening with cannabis and it may be a more dangerous trend, especially to unborn children.
Antonia:I remember as a kid this was very effective campaigning against tobacco just lots of billboards and TV ads about how bad smoking is and pictures of really black lungs. And even in some kind of biology class they showed us, like some cadavers, black lung. That was just like so nauseating and gross and I thought smoking so bad just from an early age. So I think we need something like that to that level for cannabis now. But it's interesting to look at some of the comments on these articles, just from just various readers.
Antonia:People that are obviously pro-cannabis will try to make arguments like, well, edibles are okay but smoking isn't. Or this form of CBD or Delta-8 or 9 are okay but THC isn't, or those types of things. And that is very reminiscent of the great lengths that tobacco companies used to go to back in the 40s and 50s to convince everyone that smoking was good. So this was before those anti-campaigns when I was a kid. So there's these people, users and probably marketers of cannabis with very strong biases. They're repeating these pro-cannabis arguments and talking points and maybe, especially for the users, don't realize that they're just supporting an industry and big cannabis. Maybe it's not exactly the same as big tobacco, it's, I think, probably more scattered, but there are still lots of people out there who stand to make lots of money of people using cannabis, even using it in pregnancy.
Howard:Yeah, and actually in many cases it is the same. Some of the biggest players are former tobacco companies who are shifting to marijuana, so that's exactly right. The same phenomenon happens with a lot of things today, but if we're in an age where we're banning food dyes that have never been linked to any adverse health comment for children, pregnant women, adults whatever in any scientific study, and it's a striking contrast to how we're so tolerant and even socially supportive of cannabis use.
Antonia:I think this podcast really is about teaching a lot of the principles in your clinical reasoning book that you've written about to our listening audience. So this cannabis issue we're talking about has a lot to do with prevailing bias and, ultimately, the purpose of any medical journal club or any scientific journal club, which what we dabble with here too, is to teach the learners and the teachers to the faculty how to spot problems, whether it's new or old literature.
Howard:Yeah, and our basic we call it the naive tendency is to agree with literature that supports our personal bias or confirms our beliefs. That's the confirmation bias. And at the same time we tend to reject new literature that disagrees with our current beliefs. We're all very educated people so we can pull out all the tools to find problems with literature when it suits us, and we can ignore those problems and even explain them away when literature doesn't support our preexisting belief. That's called motivated reasoning. So we all have personal biases like the confirmation bias. We all have professional biases and societal biases that you might call the prevailing bias. But those biases are important because we tend to only fairly critique literature when it suits us. So we have to be aware of them and have a process to avoid or counteract those biases.
Antonia:Okay, well, along that note, I've got one that'll just be like a slam dunk for you, just a big softball right down the middle.
Howard:Okay, I'm ready.
Antonia:Okay, and this is a recent one. So study in April 2025, gray Journal called Quantifying the Association Between Doula Care and Maternal and Neonatal Outcomes. This was a retrospective cohort study that looked at deliveries over a two-year period at a single institution where some patients had doulas and then the others didn't. And they just looked,831 deliveries and of those, 486 patients got doula care and the rest didn't, so it was just under 3%. They were 3% roughly versus 97% comparing their outcomes, and they concluded that those who received doula care were much more likely to have a vaginal delivery and more likely to attend their postpartum visits and have higher rates of breastfeeding and fewer preterm births. And they did attempt to adjust for race and insurance status.
Antonia:But there was a lot of other demographic information that they really couldn't include or they just maybe chose to leave out, like education level, how many other kids do they have? What's their income level, where do they live Like urban, suburban, do they have a substance abuse history? And a lot of other things like that. So now just go for it. You can take a big swing at this one.
Howard:All right, yeah, so these are exactly the sort of articles that mislead people and I'll say on the surface, there's nothing wrong with their article, right? You don't need to be an expert in statistics and uncover their perverse methodologies. It just doesn't mean what anybody thinks. It means, right. Undoubtedly, someone who approaches this article and you will approach it you'll either approach it with a belief that doulas do or do not lead to improved, meaningful outcomes, and your personal belief frankly doesn't really matter in terms of how we should think about the article and address it. So when you read an article for yourself or analyze it in a department journal club, one of the first questions you should ask is what are the authors trying to evaluate and how would the ideal study be constructed to answer that question?
Antonia:Okay, well, they're trying to evaluate whether or not having a doula improves maternal and or neonatal outcomes.
Howard:Okay, so that's easy enough. Now, how would you construct the ideal study to answer that question?
Antonia:Well, ideally you'd start from the beginning and have a prospective randomized trial where you randomly assign some patients to have a doula and others not to have one, and then try to make them as similar as possible in every other respect, as many factors as you can control, for that would affect the outcomes. Then control for those.
Howard:Right, and I'll just say briefly that's why this study doesn't have any meaning and I'm surprised in some ways that it was published in a major journal. Or maybe I shouldn't be surprised, because around 80% of all published papers will eventually be found lacking or fail replication or be superseded by new research, and that's in current large, best-in-class journals. So this is at best a preliminary finding or preliminary research that begs a randomized, controlled trial, but you can't draw a conclusion from it and you have to be disciplined about this. Now I suspect, if you believe that doulas don't improve neonatal outcomes to the degree reported in this paper, that you'll have already hit upon the idea that association doesn't equal causation, which it doesn't over 99% of the time. Over 99% of the time when you find association, there's no causal link. So that's actually a rare finding that should surprise you.
Antonia:Yeah, and just the fact that it's retrospective. Even the very most diligent retrospective studies just can't possibly adjust for all of the confounding variables, and often there's things that authors are not even aware of that could actually be the most critical variables.
Howard:Yeah, that's called a lurking variable or there's other names too, but in this case the study might have better been stated as a comparison of patients who chose doula care versus patients who did not. So the 486 women who chose to use a doula during their pregnancies and their postpartum periods are fundamentally different from the 17,345 patients who did not. They're differently motivated. They're differently educated. That doesn't mean they went to school, they just have different exposures and life educations. They have a different relationship with the medical system, perhaps different trust.
Howard:They're likely, in most cases, healthier because they're likely to be people who care about their health, and they're likely people who prioritize their health care in their pregnancy, and that's why they sought out doulas and a whole bunch of other things that we cannot even begin to account for or imagine to know. It's hardly a surprise that a person who intentionally seeks out and utilizes a doula in pregnancy would be more likely to attend her postpartum visits and more likely to breastfeed. It's also not much of a surprise that such a group would have lower cesarean delivery rates. We talked about that issue before in a prior episode, but those facts were almost certainly true before they accessed doula care, and only a randomized controlled trial would be able to show that difference. In fact, this report isn't even able to answer the question about whether or not doulas were actually a negative factor among patients who are motivated to have a vaginal birth or breastfeed. It could have actually hindered their progress.
Antonia:Yeah, because the motivation and maybe the access for seeking out the doulas in the first place presumably was the main difference between these two groups of patients. So they can't control for that. That's an inherent difference. But they did control for insurance type, which is a rough surrogate of what's their income and what's their ability to pay for a doula and just general healthcare services. But with those baseline differences in the patient's motivations and the reasons they got doulas, we haven't proven that doulas don't decrease the rate of breastfeeding or vaginal birth for those types of patients, Because without a prospective randomized trial, we don't know, maybe those highly motivated patients might have even been more successful with their goals without a doula. We don't know that this doesn't help show.
Howard:That's why you do the study.
Antonia:Yeah.
Howard:Yeah, exactly, and I'm not making the claim, that claim at all. But the point is that the current paper, the way it's designed, can't answer that most basic question in the way that they designed it and conducted it, and so it just doesn't have meaning.
Antonia:Yeah. So if they can't answer that, then there's no way that they could make this broad claim that doulas obviously improve these outcomes.
Howard:Right, and the authors don't make that claim. By the way, it's not a bad paper, right? They simply say that doula care was associated with more of these improved outcomes. But the problem is and I'm sure the authors know this the general public will cite this paper and others like it to claim that doula care definitively and directly led to these improved outcomes, not just that it was associated with improved outcomes, or that women who would like to have a doula are motivated and for all those reasons and end up with better outcomes reasons and end up with better outcomes.
Antonia:Yeah, so it's not that the authors were misrepresenting anything they didn't. But the reader doesn't typically know that 99 plus percent of all discovered associations are just coincidental. And they certainly won't know that if they're reading this through some kind of article where the article has given its own interpretation about this and said everyone needs a doula, like outrage if you don't get a doula because of this paper.
Howard:Now you mentioned that doing an RTC where you randomly assign patients to a doula, that would be a big improvement or maybe the gold standard way of looking at this, but the issue still remains about how you have a control arm. So for any RTC you conduct, the difficulty often is how you have a placebo or sham arm. There's no way to blind having a doula or not. So I'll use this comparison to take a dig at acupuncture and chiropractic studies. If you're getting acupuncture for depression, for example, I would be shocked that the acupuncture group didn't have improved outcomes of some sort compared to a no acupuncture group. And that doesn't necessarily mean that acupuncture was effective, though, because there are other therapeutic effects associated with the act of going and receiving acupuncture. So even in a randomized trial, let alone the people who choose acupuncture versus the people who don't.
Howard:Right, when you go get acupuncture, you're taking time for yourself. You're traveling to a pleasant, calming environment. You're relaxing on a bed while someone else attends to you, and you're staying there for a period of time. You're given hope and optimism in that setting, and there's warmth. You're shown kindness and gratitude by people. There's all sorts of things wrapped into an acupuncture session, besides actually having needles stuck into your skin that are potentially therapeutic for a whole range of interventions. So you can't purely compare, let's say, dry needling to acupuncture or chiropractic manipulations versus nothing or something like that, unless you add all the other things into the control group the laying down on the table, the soft lighting, the aromatherapy, whatever else is going on, the pleasant people you're interacting with, all those other things. And it's the same way with doula care. There's so much wrapped up into it that in a retrospective study even the doula care itself is going to vary from doula to doula and situation to situation. What they're actually doing with the patient is going to vary widely.
Antonia:Okay, so with the acupuncture example. So what if they did that like some kind of massage technique, where they don't actually even do anything physical like Reiki? They do touch patients, but very minimally. So let's say one group did Reiki and then the other one did Reiki plus acupuncture, so they were both going to this place laying on the table getting the same soft music in the background, and then maybe you could also throw in a third arm of no treatment at all, just for a really good comparison.
Howard:Yeah. So here's the struggle, right? How do you do this? Reiki presumes there's an invisible life force, energy that the practitioner is assessing and fixing with her hands. If you read the Wikipedia page about it, it's extremely negative and critical about how fraudulent and pseudoscientific the whole thing is. So you can read that on your own, but I'm sure our listeners will be a judge of that.
Howard:But it still has therapeutic effects, right? Even if it, even if the energy force isn't real and there's no evidence of that, there's still therapeutic effects of going there. So maybe you could try to replicate those therapeutic effects with acupuncture and Reiki. But you could carry this thought experiment about a real control group even further. So I think the way you really do control for well, you could extend this to acupuncture or Reiki. But for acupuncture is you have two groups who both get acupuncture, where they do everything else the same, but they place the needles in different places. So instead of using GV20 or HT7 or PC6 or LR3 or SP6 or ST36 or some of the spots that folks will use with their needles to treat anxiety or depression or mood disorders, then you place them in other areas where there are no mood effects claimed.
Antonia:That was a little oddly specific.
Howard:Well, we want people to know the real spots. Then you should be able to prove that by doing everything the same, but sticking that needle in a different place where there is no thought that the mood will be improved.
Antonia:Okay, yeah, so that would be the real trial someone out there would do.
Howard:And even then you have a problem with blinding. Even if the patients don't know what group they're in, because they're all getting needles in their skin, the acupuncturist will know and that will affect how they behave towards the patients, even unconsciously and we have a lot of evidence that this really happens pretty strongly, because the sham group acupuncturist will likely think this isn't going to work, maybe act less optimistic about it, maybe signal in different ways and the patients will have a different transferred experience for that reason and potentially report a different outcome with it. So this is the importance of blinding. So you still have to figure out how to blind it.
Antonia:Okay, so basically we're saying that some interventions that we would really want to study and get good evidence for are not feasible to study in a purely objective, unbiased way. So yeah, then what about back to the doula question?
Howard:Yeah, right, so it might be impossible to have an actual sham arm for that, but that's okay. Instead, you could have a comparator arm, which, honestly, is more important for interventions that we feel already work. And I don't think anyone is claiming that doula care is without benefit. That's not the point of this at all. So you might compare it to a series of educational videos, or maybe an app that combines videos and educational pieces that are tailored to the patient and maybe prompts that, maybe has an AI chat or something like that, and I know there's products like that. So maybe you compare doula to some other intervention and see if the outcomes are different.
Antonia:Yeah, that actually sounds really good and if you look at more than one comparator, that could be a really comprehensive way of trying to clarify what are the most important and effective aspects of any of these interventions. So is it the education, or the positive support and encouragement, reassurance, or maybe advocacy, the positive support and encouragement, reassurance, or maybe advocacy, or just straight up reminders remember to go to your appointment or remember to sleep or something. Where is it like the coaching in labor kind of thing, or maybe just something else? And it could be that they're within any intervention. You look at that, there's a mix of some positives and some negatives.
Howard:Yeah, and that's a problem with bundled interventions. Doulacare, by the way, is an umbrella, as you said, of very. It's a bunch of nonspecific things. There's so many ways and styles that it could be implemented and, like you said, is it the advocacy or the reassurance or what's the important part there? Maybe you help the patient a lot with one aspect and you actually harm them with another. But you won't see that in a bundled intervention. It's likely that some doula care is hugely positive and then who knows what parts are negative. So specificity is important when designing a trial.
Antonia:Yeah, it would be really nice to see it either a good qualitative or multi-comparator study that probably could help refine doula care overall. It would be really nice to see either a good qualitative or multi-comparator study that probably could help refine doula care overall, as well as other types of support services, just again by pointing out what's good and what's not good within them. Okay, so now we've talked about confounding the prevailing bias, confirmation bias and a few other ideas, without really naming that we were talking about them.
Howard:Yeah, and we do this all the time, even if we don't name them. I think we could make some nice little flip deck of some of these ideas for the Instagram that illustrate some of these concepts clinically. I'll talk to Maddie.
Antonia:Sounds good. Well, let's get to our listener question while we still have a little time. So this one I thought was great, our listener writes. So this one I thought was great, our listener writes 0B. Wondering if you have any thoughts about the duration of the levonorgestrel IUD as part of a hormone replacement therapy regimen. I know that for Mirena the duration for contraception is eight years and, if I'm not mistaken, the FDA has also given it a five-year indication for menorrhagia, which was not increased when the contraceptive duration was increased. So how long would it be safe to use Mirena as the progestin component of an HRT regimen without needing additional systemic progestin?
Howard:Signed Progestin in Provo I wonder sometimes how our listeners think about these names we make up for them.
Howard:But I assume they don't want us to use their real names.
Howard:But this is a really great question from this doctor and I had a patient like this just last week and of course we're all dealing with our younger reproductive age patients wondering how long it'll last for controlling their periods.
Howard:We have an answer about birth control that is probably going to continue to expand and in that case we don't need a study there. For bleeding we don't need a study. We can just leave it in and ask them to come back whenever their periods are becoming heavier and we can replace it and we can individualize the care for them. If their bleeding is well controlled through those years and contraception isn't an issue let's say they've had a tubal or something or a vasectomy and don't need birth control then we don't need to worry about it until they start having irregular bleeding or until that eight-year mark if contraception is in play. But when it comes to prevention of pregnancy or prevention of endometrial cancer, we do need clinical data to make those decisions and, as the listener pointed out, the Mirena and Lyletta IEDs the 52 milligram IEDs are at eight years for contraception and don't be surprised to see 10 in a little while. But what's our answer about prevention of endometrial hyperplasia in cancer for postmenopausal patients who are taking estrogen replacement?
Antonia:Yeah, yeah, you can say, come back when your bleeding's heavier. But you can't say, well, come back when you've got endometrial cancer, we'll just change it out then.
Antonia:So yeah, this is a great clinical question For our listeners who don't do this.
Antonia:It's now a relatively common practice for patients to use one of the progestin IUDs purely to protect the endometrium in the setting of using HRT, and it's not just for birth control anymore, it's not just for making their periods lighter, it's also this preventative and even in more rare cases it can have a role in fertility sparing, management of endometrial hyperplasia or early cancer. I won't talk any more about that, but I remember learning about that in training and maybe our friend Stuart someday would have comments on that too. But for the most part, using it in HRT to prevent hyperplasia or cancer is it's limited to those higher dose IUDs, the 52 milligram ones in the US, either Mirena or Lyletta. The NAMS, the North American Menopause Society, actually does have a recommendation about this and they do say the 52 milligram IUDs are suitable for endometrial protection. The ACOG endorses this as well. The British Menopause Society is also okay with this and they explicitly say if the patient has a lower dose IUD, then you need to add systemic progesterone.
Howard:Okay, yeah, so Lyletta or Mirena are the 52 milligram devices, and there was a clinical review in 2015 published in the journal Climacteric and that examined some of the key data available for this question. This data comes mainly from phase two and phase three trials of Mirena conducted in Europe where patients received either the in this case it was Mirena or oral progestins with their hormone replacement therapy, and those trials and other data from studies in paramenopausal and postmenopausal women showed that it works well at suppressing bleeding and preventing hyperplasia, but none of those were done for longer than five year periods.
Antonia:That's a bummer. That's exactly the study. You'd wish they just kept studying it out further, but I do understand. They at least have to get some five-year data first before they extend it out. But those data are why we feel reasonably safe using it, even just for the five years. So then the question now is can it last longer? If we know it lasts longer, at least for preventing pregnancy, there was a trial in the Green Journal in August 2014 that did look at cancer risk in women using the progestin IUDs in Finland.
Howard:Oh well, please tell us about it. I don't feel qualified talking about Finnish studies.
Antonia:Oh well, please tell us about it.
Antonia:I don't feel qualified talking about Finnish studies in this group of women who had the IUD that was placed for heavy bleeding.
Antonia:So in their registry they identified over 93,000 women on the IUD, and of them they identified about 2,700 total cancer cases, which was just under 3% overall of the women, which is probably about the average rate of cancer. It's not at all showing that IUD increases cancer risk or anything, but this was a. This was done over a longer term follow up of almost 10 years, and so it ended up representing over 855,000 women years of IUD use, 155,000 woman years of IUD use, and what they found in all that was that among these IUD users, the rate of cancer was half of the expected rate in a comparable group. Like age and age match, demographic matched, the women were up to age 49 when they had the device placed for their heavy bleeding, and so some of them did continue to use it through the menopausal transition, and so there's given that then there's really no reason to think the data wouldn't apply for after they completed menopause as well. So a big question is how many of these women continued to use the device after year five.
Howard:Yeah, this study seems to imply a protective effect from years five to 10. But at least in their published data it's difficult to tease out how many women were both postmenopausal and between years five and 10 using the device and what their endometrial cancer rates were. So I think that question unfortunately the question of the listener is still not answered by this finished study, which is probably the only one that's published any data even capable of offering a solution.
Antonia:Yeah, I imagine that would have been a very off-label use at the time to continue it past five years. This was back in 2014, and I think they hadn't even extended the contraceptive efficacy of it yet. So I do think it's very likely that a 52 milligram device will continue to provide some beneficial effect, at least at preventing the endometrial hyperplasia, even beyond year five. But right now we don't have any good studies to tell us that it would be as effective after year five as it was until year five, or at least as effective as systemic progestins might be. Talk about timing of IUD use in this clinical setting are not recommending using it past five years. So I think until we have some new data that clarifies this, it really would be difficult to justify or to tell patients that it's okay to use it and still be using estrogen beyond five years, or to say that it's okay to use the Skyla or Kylena instead, or to say that it's okay to use the Skylo or Kylena instead.
Howard:Yeah, and it may be that the Kylena does the job just as well. But again, if someone were to get endometrial cancer with one of these devices, it would be hard to justify the decision, given the lack of evidence of benefit. And it's probably true if you're using a Mirena at your five plus two like you just can't support it with clinical data, so hopefully more trials are coming.
Howard:It would be nice to have a small device particularly made for postmenopausal patients who want to use this for endometrial protection and obviously have data that shows that it works.
Antonia:Yeah, that would be a whole new patent, a whole new market. Well, you had this patient. You said last week what did you end?
Howard:up doing. We switched to systemic progestogens.
Antonia:All right, well, there you go. Well, I think that wraps it up. That's our time. Yeah, that wraps it up.
Howard:We'll see you guys in two weeks.
Antonia:All right, send us more questions. All right, see you then.
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