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This episode is brought to you by. Prime Obsession is in session. And this summer, Prime Originals have everything you want. Steamy romances, irresistible love stories, and the book to screen favorites you've already read twice off campus. Elle every year. After the love hypothesis, Sterling point and more slow burns, second chances, chemistry you can feel through the screen. Your next obsession is waiting. Watch only on Prime
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Girl. Winter is so last season. And now spring's got you looking at pictures of tank tops with hungry eyes. Your algorithm is feeding you cutoffs. You're thirsty for the sun on your shoulders that perfect hang on the patio. Sundress those sandals you can wear all day and all night. And you've had enough of shopping from your couch. Done. Hoping it looks anything like the picture when you tear open that envelope. It's time for a little in person spring treat. It's time for a trip to Ross. Work your magic.
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All right, let's be honest. Vomiting sucks. It sucks whether you're pregnant or not. But it sucks even more when you're pregnant. I mean, that feeling that your guts are coming out of your oropharynx, not the favorite. And it's terrible. Not only is this a medical and an electrolyte and a physiologic problem, I mean, it's a psychological problem. I mean, this wears people out. Repetitive retching is a quick way to burn your morale and wear you down. So if you can't figure it from our wonderful background sound here, this poor woman puking is that. We're gonna talk about a new trial called the Vomit TR Trial, y'. All. I'm not being insensitive. It is actually called the Vomit trial. V O M I T. It actually stands for validating the effects of ondansetrone and mirtazapine in treating hyperemesis gravidarum. This was out of Denmark. This originally was released, y', all, ahead of print at the end of 2025. Literally, the end. It was on December 30, 2025, and I had this in my queue and. And of course, in typical fashion, something else came out and I wanted to cover that, so I kept bumping it and bumping it. But now that this is officially out in June of 2026 in the gray journal, I can't put it off anymore. So we're going to talk about the vomit trial. Validating the effects of ondansetron. That's Zofran and Mirtazapine, an atypical antidepressant in treating hyperemesis gravidarum. This study is very reassuring in the use of atypical medications to treat tackle this horrible condition of hyperemesis. However, even though it is very, very reassuring, let me say it right now, there is a big limitation with this study and it's not my interpretation of this. The authors are very clear in saying, hey, let's interpret this correctly. This is. Let me just, let me just give you jump ahead here and give you the finding. This is reassuring. This is good news for Mirtazapine when nothing else has worked in combination and or in lieu of on Dansetron. However, there is this blank as a limitation. I'm gonna tell you what that is here. So this used two kind of humorous items in the study. One is the PUKE score. Remember, that stands for the pregnancy unique quantification of emesis. That is a standardized way, uniform way to track nausea, vomiting and hyperemesis in pregnancy called the PUKE score and the vomit trial. Is this not clever or what? I mean, sounds like it is just being highly insensitive to the condition, but it's really not. The PUKE score and the vomit trial, that's where we're going in this episode from the Gray Journal now officially out June of 2026. We will be right back. We're just trying to fulfill our life calling and our mission. This is Dr. Chapa's OB GYN no Spin podcast. Well, podcast family, we really are learning a lot about hyperemesis. Now we have two genes. I'm sure there's more, but we definitely have two. We've located two genes that are specifically associated with the causation of recalcitrant nausea and vomiting in pregnancy. One is GDF15 and then the other is IGF BP7. That's insulin growth factor binding protein number seven. So we do have these two loci, GDF15 and EGF B as in boy, P as in protein number seven, that both play important roles in placentation, appetite and even in cachexia that are linked to hyperemesis grevidarum. So we've covered this in the past. We've talked about hyperemesis on several episodes in the past. And we really are making big headway here in terms of etiology and causation. So maybe at one point there'll be a way to tackle through some kind of gene therapy or specific blocking molecule, the effects of GDF15 and IGF BP7 as two potential causative cures for this condition. But we're not there yet. Of course, we've got some known risk factors, personal history of Hyperemesis, even family history of hyperemesis is a big deal. Motion sickness is a risk factor for hyperemesis, and especially if there's nausea with migraine, those are all at increased risk for hyperemesis, gravidarium onset. Okay, so we know that there's risk factors. We know what the potential causes are. But until we have great specific targeted therapy, we're left with the usual, like Zofran and B6 and Unisom and, you know, doxylamine, and the list that we've covered many times before on this show. However, mirtazapine as an atypical antidepressant is not typically one of the first ones we give. Now, to be very clear here, I'm not advocating that everybody with nausea, vomiting get mirtazapine as first line. It's not first line. However, this is a valuable option for those where Zofran maybe doesn't work as well and they're still miserable, and especially in those who have some concomitant anxiety and or depression, whether that's preexisting or they feel that way because they can't stop puking, Mirtazapine may have role you all. This is an acogs clinical expert series that came out on inpatient management of hyperemesis gravidarum. And in that previous expert series that we covered, the authors state, quote, mirtazapines antiemetic. And here it is, guys, watch this. And weight gain effects. You see that? So it caused a little bit of appetite stimulation. So mirtazapines antiemetic and weight gain effects, in addition to its role as an antidepressant and in anxiolytic, make it a reasonable option for the management of refractory cases of hyperemesis gravidarum. End quote. That is out of ACOG's Clinical Expert Series. I mean, man, look at all the bang that you get for a buck. Okay? You get antiemetic properties, you get weight gain effects, you get antidepressant effects and anxiolysis. My goodness. I mean, we should put this thing in the water. Okay? It's great. It's a joke. But mirtazapine, of course, always has some side effects, as they always do. And some of this can have some sedation because it's still histamine. Like, we're going to talk about the mechanism of action in a minute. But it does work. When we get into this vomit trial that divided patients into three arms, you get mirtazapine, you get Zofran, and you get nothing. Yeah, There was an arm that was placebo. Kind of sucks if you get the placebo arm, but it is what it is. So it was very well designed. However, the big limitation here that we can get to in a minute is that. Let me just say it and you all can figure it out. This was around Covid ish time. What do you think happened? Well, of course, all studies had poor recruitment numbers because of COVID And so that affected the ultimate study number, which affects power, which affects the reliability of what they found, which is reassuring. I mean, the results, the conclusion is reassuring. Hey, this thing does work there. I've spilled it for you already. It does work. However, there was a problem with the power of the study because they had to mess around with the numbers. Okay, I'm gonna explain that in a minute. And this is not my interpretation of this. The authors say we messed around with the numbers because we had such poor recruitment because people were afraid of COVID Rightfully so. And that is a big issue here, that the power is a little hokey, but nonetheless, we've known that mirtazapine is an option. So this isn't the first one to say mirtazapine is an option. We've known that. We've known that for a long time, just like we've known that Thorazine, okay, an antipsychotic that also works. Thorazine is also great for hiccups, by the way. Thorazine, which is chlorpromazine, absolutely works. So there's all these other agents that be used here, but not typically as. First line. Now let me get into quickly the mechanism of action of mirtazapine and why this works. It is an antidepressant, but it works on a lot of different channels. Okay, first of all, it has serotonin and histamine receptor ability. So that's one line. That's why it's an antidepressant. So serotonin and histamine receptors are hit. And like Zofran, like ondansetron, Mirtazapine is a potent 5ht3 receptor antagonist. Okay, so that's how it shares a similarity to Zofran. But unlike Zofran in it also has affinity for the 5 HT2a and 5 HT2c receptors that are involved in appetite regulation. In other words, the mechanism of vaccine of mirtazapine is Zofran plus. Okay, so they work in similar channels, but Zofran can just take away your nausea. Mirtazapine is like, hey, I'll take away your nausea. And make you a little hungry at the same time because it can modulate appetite. Okay, so that's the big plus here. Plus, unlike other antiemetics, Mirtazapine is also a potent antihistamine that has affinity for the H1 receptor. So you get all these different mechanism of action here where this thing has multiple effects. Not only is it an antidepressant, not only is it a weight modulator, an appetite regulator, it also is an antiemetic and it's a mild anxiolytic. So you get a lot of different effects, effects from mirtazapine. That brings us to the vomit trial. Yeah, unfortunate name. I get it and I mentioned it in the intro. It is the validation of ondansetron and mirtazapine for the treatment of hyperemesis. Remember, this is a Dutch study, remember, one to one to one. So it's a very well designed. You get mirtazapine, you get zofran, you get placebo. But the catch is that we've already said this was from 2019, remember COVID 19. So. So 2019 through 2022. And that's why the final n, the final number, guys of pregnant women who were involved with this was 59. 59. That's not a lot. Now, they did go through a standardized quantification scale called the Puke Scale. It's pregnancy unique quantification of emesis 24. And the short of it is you want to see a change in your number based on your therapy. We've talked about the PUKE score in the past. Everyone, very quickly, just in terms of the study design and the methods here. Remember, we've already said it's randomized to 1 to 1 to 1 for mirtazapine, ondansetron or placebo. 59 pregnant women who all had hyperemesis gravidarum, they had to have a puke 24 initial score greater than or equal to 13 or a score of 7 if it was accompanied by more than 5% weight loss. So this is not just nausea and vomiting. These women did have hyperemesis gravidarum. Now, the tablets were administered twice a day for the first week. That was on dansetron or Zofran, 8 milligrams in the morning and the evening. Mirtazapine, that's only given once a day. So they had 15 milligrams in the evening and then the placebo dose in the morning. So it had to match the Zofran group. And then of course, the placebos. Well, those were placebos. Now, in the Second week, they could have a dose escalation of double the dose of mirtazapines. So that was 30 milligrams. Or they could have 4, 8 milligrams of Zofran daily. Okay, so the first week standard, and then in the second week they could have an escalated dose. All groups. So either in the mirtazapine, either in the placebo, or in the Zofran group, they were all permitted to have oral reglan 10mg up to three times daily and as rescue medication. And that's good because, you know, the whole idea of having a placebo army like, wait, you're gonna get me admitted and not give me anything? No, no. It was possible for them to have oral metaclopramide as rescue as well. The primary outcome was the change in the PUKE score at day two. Now, to be clear, remember, they followed these patients up to two weeks. It was a two week total follow up. But the primary outcome was, did you get better initially? Because that's what we want, right? We don't want you better in 10 days, we want you better initially. So it was a change in the Puke24 score from baseline to day two across all three groups. Now, at day two, the Mirtazapine group had a mean point greater reduction in the PUK score than did placebo. And ondansetron did as well, but it had less of a drop in the PUK score than mirtazapine. Mirtazapine group had a 1.86 point drop, whereas on dansetron was only a 0.5 point reduction. Now, this was also significant all the way to day 14. Mirtazapime. Here it is, guys. Appeared superior at two weeks with a 2.43 point reduction over placebo, whereas on Dansetron was only 0.64. So short of it is mirtazabine seemed to win obviously over placebo, and it seemed to win overall dance intron. Although that could be a power issue because it was a problem with the power of this study. We'll talk about that in just a little bit. Now, one catch. Because nothing is free. The mirtazabine group, and I've got to be clear here, nothing is free. They did have slightly more, quote, unquote, adverse symptoms. Okay, now, and that's a big deal because while you can take away your nausea, you know you want to be zonked either. But thankfully, there was no severe adverse reactions and the most common side effects and in the mirtazabine group were fatigue at 48%, which makes sense because it's a histamine kind of agent. Dizziness at 24%, headache at 24%, while aldansetron was associated mainly with constipation and headaches. So, you know, this isn't like they're not capable of working, but you got to tell them because it's an antidepressant, there's some anti histamine effects. Fatigue and a little bit of dizziness can be a side effect, although, you know, you can take away nausea. So just want to be clear that in this study that only had 59 patients, yes, mirtazabine seemed to do well, but it did have slightly more increased side effects than did Zofran. So this trial showed that puke scores did in fact improve with mirtazapine not just at day two, but all the way through day 14. Although the power calculation here wasn't exactly what they wanted to. They wanted to have a planned 180 participants, guys, they wanted 1, 8 0. But because of COVID and difficulty with recruitment, they only ended up with 59 patients. So that, that, that's the big issue here, guys. This is the big elephant in the room is that they had compromised power. And there's nothing that I have found about myself. You know, it's not like I did a power calculation. The authors are very open, hey, we had compromised power here because we had difficulty recruiting. So while this study is very reassuring that mirtazabine validates its use for hyperemesis, you got to interpret that very carefully because it didn't reach their full power expectation.
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So the take home message here is, yes, mirtazapine, as we've already known because it was in ACOG's Clinical Expert Series on inpatient management of hyperemesis a couple of years before this came out. Yes, mirtazapine absolutely works. And it could work as well as on Danzetron, even though it didn't reach statistical significance. So the idea is don't be afraid of Mirtazamine. If you got to use it, that's fine. And no, there has not been a link to adverse neonatal malformations. No fetal malformations with use in the first trimester. That was actually covered in Aix, CoG's clinical expert series that we've already talked about. And there's a small little paragraph in there and it says, quote, studies have not shown an increased risk of major congenital malformations with mirtazabine use, including. Here it is, guys. Here's a take home pearl in the first trimester, end quote. So don't worry about it. It's not going to cause the kid to have some other, you know, a horned head or three eyeballs. The whole question is, well, does it somehow affect, you know, their neurocognition? We don't have that data either. Doesn't seem, doesn't seem to. There. Doesn't seem to have any, you know, long term neurodevelopmental issues. What's bad is maternal dehydration and malnutrition in the first trimester. That's the big confounding factor there. That's what can give the child, you know, a negative effect in terms of neurodevelopment if mom isn't getting proper nutrition and there's ketone bodies and persistent dehydration. Okay? So yes, mirtazapine use in the first trimester seems to be just fine. So as these authors say, because this was Covid and they had some difficulty with recruiting, the power calculation here wasn't great. So they did have to do some messing with the numbers. And that's the issue here, is that while this study is very reassuring, they didn't really get to where they were going because they had compromised power. So let me read this to you exactly, and then you draw your own conclusion. Okay? I have no problem using mirtesamine. I've done it for many, many years. Just like I've used Thorazine for this. You just got to be careful that you don't add up your polypharmacy effects. You don't want a patient to have, you know, extra pyramidal symptoms. And I educate all my patients about that. But I'd rather get them treated and be a little sedated if that's a side effect rather than not being able to have anything po. So in this final paragraph, right before the conclusion, the authors say, quote, the compromised power is partly due to COVID 19, but other factors also added to the difficulties. They go on to say the patient population is challenging and reasons for declining participation in this trial included unwillingness to consent to trial medication and declining because the potential participants were too debilitated to engage in a clinical trial. End quote. The synopsis, the choppa synopsis of that is, man, I don't want to go into some trial. I may get a placebo. Just, I just want to feel better. And I don't want to wait for 14 days. Just give me meds now. So I mean, that we get that right. That's not hard to understand. So for a variety of reasons, they didn't get to their true patient n, which again, led to compromised power. So, yes, that's one of the complications here is that when you have compromised power, you put you at risk of certain types of error. Specifically, it increases the risk of a type 2 error, which could be the case especially for ondansetron, because, you know, ondansetron didn't do as well as mirtazapine. But that could be a sample size issue. But nonetheless, this still gives very confident and very reassuring information. As the authors state, quote, the present results are likely to be incorporated in future treatment recommendations, despite the limited number of participants in the trial. End quote. Now they're talking about their own group there and what are they going to do with the findings from this study? So don't be afraid to go outside of the box when she's not getting better. So remember, first thing, of course, doxylamine, B6, ginger, all of that is acog indoors for nausea, vomiting. When they cross over to hyperemesis, then you've got to take out the big guns. And of course, Zofran is just fine. No issues with that. But things like mirtazapine definitely do have a role when it's necessary, but not as first line, just again when necessary. Mirtazapine I've used again for several years, and I think it's just fine. The brand name for that, if you're like, why does that sound familiar? That is Remeron. Remeron. That's how I trained it when I was at Parkland. But the generic is Mirtazapine. So, yes, don't fear Remeron. It does have a role, not as first line, but just when needed. It also has a long half life, so you only can. You can only take it once a day. It's not necessary to take it more than once. And most people started around 15 milligrams, traditionally taken at night. So when they wake up in the morning, you've got most of the effect on board. And some of the sedation should actually help the patient sleep. Through the night. Okay. Maximum usually is around 45 milligrams or so, but in general, you can start at 15 milligrams of remeron at night to help with some sedation and hopefully get medication on board for the morning. So, Podcast family, very quick. I just wanted to give you an update of what just came out in the Gray Journal. As of June of 2026, this is the VOM trial. Mirtazapine on Dansetron and placebo for hyperemesis gravidarium. Small number out of Denmark. It had issues with recruitment, it had issues with power, but it already validates what we've already known. This isn't the first paper that said that this potentially could be used. Podcast family, as always, we're thankful for you. We're glad you're part of our podcast community. And now that we've done all that, Michael, let's take it home. This is Dr. Chapa's obgyn no spin podcast.