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SAM foreign to prevent hypertensive disorders of pregnancy, slash preeclampsia and its associated complications like fetal growth restriction and preterm birth. Figo and a variety of meta analyses and of course ACOG and SMFM all recommend starting low dose aspirin before 16 weeks in gestation. Whether that's a universal recommendation, which some advocate for, or following a risk based protocol, which is what currently ACOG is endorsing. Now this is interesting because Figo recommends using 100 to 150 milligrams daily, not the 81. So let's just agree to disagree. That depends on who you read and it's very varied across the globe. Actually, I Posted this in our Instagram page. The table out of this new publication that showed the variety of different opinions on doses for low dose aspirin in pregnancy and when to stop. Some stop at 34, some stop at 36. ACOG says continue until delivery. Varied, varied, varied. I can tell you that 81 milligrams and below is the minority of the recommendation. The minority, the majority say 100 to 150 or 162. In other words, two baby aspirins, which as you all know from previous episodes that I've done. I'm a big fan of the. That definitely works, especially in high risk patients. And you know, we can discuss that at another time. We've done that many times before. Those in that high risk category. If we're gonna risk stratify, higher dose seems to be the way to go. And once again, just as a freebie clinical pearl, it seems to be that stopping at 36 weeks is coming back in vogue. I know that those previous episodes, previous publication that have shown that stopping it like at 28 to 30 weeks also is protective. But those used the thermo Fisher like blood test using the ratio of soluble lactyros and Kinase 1 and placental growth factor to risk stratify. And if those had a negative ratio defined as under 40, then they were stopped, aspirin was stopped and they did not develop preeclampsia at any different rate as those who continued. All right, so you can risk stratify using a thermal Fisher test, or you can continue until about 36 weeks and then stop it. The idea is you maximize benefits at the same time reducing the potential risk for bleeding. All right, so yes, it's super controversial. We've tackled that many, many, many times. And you all know I'm a big fan of higher dose aspirin with the caveat that you can either reduce down to 81mg after 34 or 36 weeks or just stop it altogether, which once again is coming back into vogue. Okay, so now that we've said all that, remember our question that we're tackling here and somebody has. If somebody has an NSAID allergy, how do you do desensitization in pregnancy? Ideally do it before they get pregnant, but again, somebody doesn't have access to care until they get pregnant. Can you do this safely during gestation? And the answer is absolutely, unequivocally, yes. Just like you do the same. Just like you can do the same for penicillin for syphilis treatment. All right, so we're going to get into this protocol again out of Singapore. Not huge numbers, but it worked. This was a cross sectional study. All women were pregnant. They all presented for care and said, look, it looks like I've got some moderate to high risk factors for preeclampsia. That's based on physician assessment and a self reported history of NSAID hypersensitivity. So these weren't skin tested, they weren't challenged. It's like they report a history. We're going to use that knowing of course that maybe some didn't, but whatever. I mean, this is self reported history of NSAID hypersensitivity and then putting them through a very easy to adopt outpatient clinic protocol. That's very easy. Very, very easy. Using little aliquots, increasing increments of milligrams of aspirin to introduce to the patient. Now read you the protocol in just a minute over a setting of like two to two and a half hours, right? Eight different incremental doses until they hit either 100 or 150 milligrams based on the clinician preference notice. 100 or 150. Nobody stopped at 81. I'm just saying just take that for what it is. Now, just like with blood transfusion, where premedication is not necessary, that's all tradition. These providers also did not give any pre medication to these patients before the challenge. So no Benadryl, no other antihistamine, no leukotriene modifying meds. They just said, hey, you're gonna be good, don't worry about it. We're gonna slowly introduce this thing and then if you need something, then we can give you like an antihistamine for rescue or epinephrine if you like, you know, become short of breath or something. But we'll deal with that as we go. Okay, so now listen to this y', all, because this is fascinating. Remember, this can be done over a couple of hours. Well, actually like two to two and a half hours, something like that. So here's a protocol. Let me read it directly from the methods. Then we'll take a little break and then we will come back to see what happened. All right? Quote we administered up to eight sequential doses of aspirin. That is 1mg, 2, 4, 8, 16, 32, 37 and then 50mg. This was orally. Each dose was given at 20 minute intervals, two to reach a final dose, as we've already stated, of either 100 or 150 milligrams based on the obstetrical provider's preference. Okay, but nobody stopped at 81. So remember, the doses that were used here was 1, 2, 4, 8, 16, 32, 37. That was interesting. And then 50 milligrams, all increasing until they hit the total of 100 or 150. Okay, fine. So they keep going. We assessed the maternal blood pressure, pulse oxygen saturation following each dose and monitored the patient for an hour after the last dose for any adverse reactions and uterine contractions. Those who were successfully desensitized were instructed to continue aspirin daily without interruption. Here it is, guys. Listen to this. Until 36 weeks, or at the onset of labor, if that happened prior, end quote. Notice again, this trend. They stopped it at 36. Okay, now this is Singapore. I know it's not us, but you stop it when you go into labor or at 36 weeks and then it's over. Okay? So just to let you know, again, a lot of controversy on that of when to stop, but likely springing back to what it was before, again, just FYI. So why don't we take a quick break here now that we've read that protocol of eight sequential doses 20 minutes apart to introduce up to a total maximum cumulative dose of either one, 100 or 150 milligrams. 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And we are back. Now before I get into the summary results here, I do want to just briefly, even though I've already mentioned it, just briefly talk about table S1 in this article. That's supplement one, okay, because that's what I posted with the appropriate reference on our Instagram page. So interesting. Okay, because this table is a quote, cross sectional survey of recommendations on the use of aspirin in pregnancy for the prevention of preeclampsia. End quote. There's like 18 or 19ish different societies or expert groups including ACOG, FIGO, the World Health Organization. Let's see here. Society of Obstetrics Gynecology Canada, the International Society for the Study of Hypertension Working Group, yada yada, keeps on, keeps on going. The Japanese society, so I'll say like 18 to 19 different ones. The dose of aspirin, guys, spans the gamut of 75 up to the 162 milligram dose. No universal agreement. And I know I've talked about that many times, but it's interesting to see when you see it all in one table. And I'm glad these authors did this. Varied. Super varied. Anyway, just thought I'd throw that out there. Okay, so now back to the results here. Now remember as we stated a little while ago, unfortunately it's not like 500 patients. It's kind of small. I'm going to prepare you. Let me just tell you, it's kind of small, but also NSAID allergy, not that common out there in the community and this span, listen to this, guys, almost three years. It was like January 2021 to November 2024. All right, so you got those three years set for an N of 34 pregnant women. 34, 34. Not a lot. I get it. But the fact that this worked and is super easy to adopt is the main take home issue here. All right, now, the median age of these 34 women was 34. And the median duration of NSAID hypersensitivity was around 11 years. All right, there. Oh, I had, I've had this for like 11 years. I can't take any NSAID. So it's been around for a while. Okay, now of these 10 women had coexisting asthma. So 10 out of 34. So almost a third of them had coexisting asthma, five had atopic dermatitis, four had chronic spontaneous urticaria, and another four had allergic rhinitis. All of those things, remember, are kind of tied together. All right, now 33 of those 34, so like 97% reported hypersensitivity reactions to at least two different types of NSAIDs, with the most common symptom being angioedema. How about that? So like the real stuff, not like, oh, I take it, I get a little itchy, which is important to know. But we're talking about real issues here, like angioedema, right? So 33 of the 34 said, yep, this is what happens. And they either said angioedema or symptoms compatible with that diagnosis. Now, there were none with a history of NSAID exacerbated respiratory disease, anaphylaxis, or severe cutaneous adverse reactions like Steven Johnson syndrome and toxic epidermal necrolysis, which is good because you don't want to give somebody a little desensitization and then they bubble up their skin and you're like, ah, that would be kind of bad. So toxic epidermal necrolysis was not included in the list of self reported issues here. Remember, this was all patient self reported reported of NSAID allergy, but of those, 33 reported angioedema, which kind of sucks. So these are real things that potentially could be problematic. All right, so we have a total of 34 pregnant women, all with self reported issues here and all who took this desensitization protocol. Now, if you're asking about what about gestational ages, let me tell you that quickly and then we're going to go into the results here. All of These patients, all 34, underwent desensitization at a median gestation age. Okay, so that's just the median, median gestational age of around 13.5 weeks. Now, of these, 16, so 16 of the 34 developed periorbital angioedema, with two additionally exhibiting urticaria. Now, the median time interval from the administration of the first dose of aspirin in this desensitization protocol to the onset of the hypersensitivity was like four hours. So it's a good idea. Remember, that's why after the last dose is done, up to the 100, 150 milligrams, you got to watch them for that hour to try to get to, you know, at least a four hour time frame. So even though the protocol can be done like in two and a half hours, you got to watch them for about at least another hour to get to that three and a half to the four hour mark, just to make sure. Okay, so this is something that happens relatively quickly. If something is going to happen, not going to happen days later. Now the authors continue. Quote. Seven, that's 20.6%. Seven women developed symptoms after receiving a cumulative aspirin dose of 100 milligrams and 9. So 26% after the 150 milligrams. Now here's the important part, guys, because you're like, ugh, 20% had some kind of effect. But wait a minute, here's the important point. Quote. All mucocutaneous reactions were mild. And, and we did not observe episodes of anaphylaxis, bronchial or gastrointestinal symptoms, and other serious adverse events. None of the participants required im, epinephrine or hospital admission, end quote. So you get angioedema. That's the puffiness of subcutaneous tissue. Your lips get all big, the cheeks get big, the eyes get all puffy, they close. Looks terrible. And it is, but it's different than anaphylaxis. I mean, I don't want to minimize angioedema. Angioedema is horrible. Fine, it looks terrible, could cause some morbidity for the patient, but it's not anaphylaxis. All right? Now angioedema and anaphylaxis can be intimately related. So see the connection here, guys? They are different but related. And so if you see angiodema, you're like, oh my God. The next thing to fall, the next shoe to drop is going to be anaphylaxis. So you got to be very careful here. But in this case, in this little case series, no patient had severe anaphylaxis. Now I Know that makes you uncomfortable. If treating the patient in your location is something like, I'm not digging that, then send it to the allergist. We have a multidisciplinary team including obstetrics, gynecology, family medicine, sports medicine, cardiology in our practice. So, you know, it's pretty comfortable for us. I mean, we do a lot of sedation procedures. The family medicine side does colonoscopies in a clinic setting under light sedation. So we can kind of rescue these. But that's based on your own practice location and style and protocols. All right, so having said that, let's continue here with the results and then we're going to wrap it up. Quote, altogether, 94% of pregnant women, that's 32 of the 34. So 94% of the pregnant women continue taking aspirin daily after desensitization. This included 14 of the 16 individuals who experienced the hypersensitivity reactions, all of whom managed their symptoms with antihistamines for a median duration of about seven days. So let's stop there for a minute. So 32 of the 34 continued it after their discontinuation. Others like, meh, I'm kind of done, but 94% is pretty good. The point is they can continue if they choose to do so. And including a 14 of the 16 who had the initial reactions, they continue taking it. They're like, hey, I mean, I took a little bit of Benadryl at home and I got over it. And that duration was about seven days. Okay, so they continue and they're going to start wrapping this up. Quote, of the 32 participants, 17 were on 150 milligram aspirin dose, while the remaining 15 were on 100 milligrams. The latter group included three individuals who required a dose reduction from 150 due to persisting angioedema, which resolved after dose adjustment. End quote. All right, so if you can get to the 150 grade. Now we're back off to the lower limit for these authors of 100mg. Here it is. Aspirin adherence was 100% assessed through a combination of directed questioning, patient reported compliance, and prescription fulfillment tracking at each clinic visit. Now, of course, it's, I mean, yeah, it's 100% compliance as far as you know, because it wasn't directly observed medical dispensation. So, yeah, I mean, yes, I took it. Yes, I fulfilled it. Just because you fulfilled the prescription doesn't mean you take it. But nonetheless, at least they tried. The short of it is is that using this protocol of oral aspirin desensitization in 20 minute intervals with slightly increasing doses up until 100 150mg resulted in no severe adverse reaction. Some minor temporary issues like swelling of the subcutaneous tissue around the face, some angioedema, but nobody went to the hospital and nobody died. That's pretty darn reassuring. So the authors concluded our data suggests that aspirin desensitization can be successfully performed during pregnancy, enabling women with NSAID induced angioedema or urticaria to tolerate up to 150 milligrams of aspirin following oral desensitization in the early second trimester. End quote. So I get what you're saying. I know that you're likely not going to do this. But if somebody asks, hey, in patients who have NSAID allergy, and right now we only got one truly recommended universal worldwide option here for pharmacological prophylaxis for hypertensive disorders of pregnancy, which is aspirin, what do we do with these? Well, you can say, take your chance and see how they do, or you can say there is a protocol for oral aspirin desensitization up to 150mg and seem to be tolerated very well, with the catch that these are very small numbers and it's kind of a preliminary report and it needs to be replicated in a larger number. But yes, this can absolutely, absolutely be done, as the authors state, and they're going to start wrapping this up. Quote, these preliminary results support the role of desensitization in avoiding the unnecessary withholding of aspirin in pregnant women with NSAID hypersensitivity and so have significant implications for antenatal care, particularly in settings with a high prevalence of preeclampsia. I love it. I like it. I agree with it. And something to consider. Podcast family. We have covered a new publication that's not even officially out yet. The title is Low Dose Aspirin Desensitization during Pregnancy in Individuals at Risk for Preeclampsia. And this comes out of the gray journal, the first listed author. I can't say it, but I'm gonna spell it. D A S H R A A T H. So Dathrath, as far as I can know, as far as I can tell. So Dathrath. Anyway, as always, we're thankful for you. We're glad you're part of our podcast community. Now. Let's take it home. Podcast family, we really are thankful for you. We hope you enjoyed this episode. We'll see you next time on Clinical Pearls.