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 11.8 MTHFR, Bed Rest, and More!
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We take on four stubborn myths in modern obstetrics and follow the evidence instead of the vibes, from thrombophilia testing to bed rest to seizure prophylaxis. We also spotlight a patient-empowering insulin strategy that may improve gestational diabetes outcomes faster than usual care.
• distinguishing recurrent pregnancy loss evaluation from venous thromboembolism testing
• focusing thrombophilia workups on antiphospholipid antibody syndrome when criteria are met
• explaining why MTHFR variants and PAI-1 polymorphisms do not belong in routine panels
• unpacking how social media and narrative fallacies keep low-value tests alive
• reviewing the AWARE trial and why activity restriction lacks benefit and carries harms
• clarifying reasonable pregnancy activity modifications versus false labor prevention claims
• assessing late preterm antenatal corticosteroids for twins and the hypoglycemia signal
• discussing inertia of practice and why weak evidence becomes hard to undo
• breaking down patient-led insulin titration for gestational diabetes and why it may reduce macrosomia
• evaluating laboring down and long-term pelvic floor outcomes plus statistical pitfalls
• answering a listener question on Keppra alternatives to magnesium for preeclampsia seizures
Be sure to check out thinking about obgyn.com for more information, and be sure to follow us on Instagram.
0:00 Welcome And What We’re Reviewing
0:28 Thrombophilia Testing After Miscarriage
3:51 What Belongs In A VTE Panel
5:55 MTHFR And PAI1 Myth Busting
13:36 Activity Restriction And The AWARE Trial
23:27 Practical Counseling Without False Promises
27:08 Late Preterm Steroids For Twins
32:53 Patient-Led Insulin Titration In GDM
38:38 Laboring Down And Pelvic Floor Outcomes
47:51 Keppra Versus Magnesium For Preeclampsia
1:00:25 Wrap Up And Where To Follow
Follow us on Instagram @thinkingaboutobgyn.
Welcome And What We’re Reviewing
SPEAKER_01Welcome to Thinking About OBGYN. Today's episode features Howard Harrell and Antonia Roberts discussing new studies.
SPEAKER_02Howard?
SPEAKER_00Antonia?
SPEAKER_02What are we thinking about on today's episode?
Thrombophilia Testing After Miscarriage
SPEAKER_00Well, some recent new articles in the last two or three months of the Green Journal, and then we do have an interesting question from a listener that we'll get to. But first, what's the thing we do without evidence?
SPEAKER_02Okay. How about when people check MTHFR mutation or PAI1 as part of a thrombophilia workup?
SPEAKER_00Okay, sure. So I think this question for OBGYNs at least has two parts to consider when we hear this or when we think of thromophilia workup. So first we have this long history really of doing thromophilia workups for patients who've had recurrent miscarriage or with other obstetric challenges, like maybe a history of abruption or early severe preeclampsia or things like that. And then secondly, there's just that workup that anybody might do, a hematologist, internal medicine doctor, anybody, for a person who's had a history of thromboembolism. And then I guess the question is too, are those two things the same?
SPEAKER_02Well, I think a lot of us in OBGYN do confuse them because there is a little bit of overlap. So just as a brief refresher, both for myself and the listeners, as far as I know, the only thrombophilia that can cause the pregnancy losses or those other morbidities you listed, like early onset severe preeclampsia, is antiphospholipid antibody syndrome, which is essentially like an autoimmune in the pathophysiology, but all other thrombophilias just cause deep vein thromboses, which is still bad, but really is not related to having those recurrent miscarriages. So for people who meet that miscarriage criteria, obviously it's not just one early miscarriage, but there's specific details that the ASRM lays out. So for people who meet that criteria, the only thrombophilia we should be checking is the antiphosphilipid antibody syndrome. And then the rest of that recurrent miscarriage workup is for other things like structural and genetic and hormonal, et cetera. So on the other hand, when people have a history of a DVT, they should be having a more comprehensive thrombophilia panel checked when it's relevant to. So I'll add, I don't think I even realized this till after residency that outside of the OBGYN context, it may not be relevant for someone who has that personal or family history of a DVT to have any kind of thrombophilia testing at all. That information does affect a lot of things that we do, like prescribing birth control, surgical planning sometimes, and then our level of DVT prevention that we employ in pregnancy. So essentially, we almost always have a reason to test our patients with that certain history for thrombophilias. But outside of that, there may not be a reason to. And actually, the current guidelines from the American Society of Hematology and ACOG emphasize selective testing only when the results will alter or direct the clinical management of the patient. So let's talk about patients who have had a thromboembolism first.
SPEAKER_00Okay. So yeah, so I think this normally would include testing for factor V Laden, either with a PCR-based test or for the G1691A mutation, or a functional activated protein C resistance assay, and then a PCR-based test identify mutation in the prothrombin gene. This is the G20210A mutation. And then a measurement of protein C functional activity and a measurement of free protein S antigen or total protein S antigen activity. And then an antithrombin 3 deficiency test, which is a measurement of the anti-thrombin functional activity. So those are all inherited genetic factors. Then, as you mentioned, there's also acquired factors, specifically the antiphospholipid syndrome. And so for this, you would get the lupus anticoagulant and the anticardiolipin antibodies, IgG and IgM, and the antibeta-2 glycoprotein antibodies, IgG and IgM. And of course, if any of those happen to be positive, because there's so many false positives, you want to repeat those at 12 weeks and exclude transient antibodies or just false positive results. And that testing, as you mentioned, should only be done if the patient already meets clinical criteria for the antiphospholipid syndrome, which includes three miscarriages under 10 weeks or an unexplained mid-trimester loss. Obviously, if you know from genetic testing why the 14-week loss happened or something like that, you don't meet the criteria for it. I'll say the other thing that's weird about that criteria that's debatable is whether or not having had any prior normal pregnancies should change your qualifications for the criteria. So you can imagine that somebody who's had six normal pregnancies, but also in the course of their reproductive years had three miscarriages and their pregnancies had no hypertension or other problems. They obviously don't have antiphosolipid syndrome. But what about one normal pregnancy or one pregnancy with pre-eclampsia and four losses? So there's some grayness in there, and use your clinical judgment.
MTHFR And PAI1 Myth Busting
SPEAKER_02Okay. Well, I didn't hear you say anything in there about the methylene tetrahydrofolate reductase polymorphisms or plasminogen activator inhibitor type one.
SPEAKER_00Do we have a co-host today?
SPEAKER_02Yes, we have uh my our youngest co-host.
SPEAKER_00Well listeners to the podcast will be used to a few baby settings over the years. So if you hear a baby, just have joy in your heart.
SPEAKER_02Yes.
SPEAKER_00But also, I feel like you're showing off by tell saying the whole word. So I'm just gonna say MTHFR and PAI1.
SPEAKER_02I yeah, I just had to have my tongue twister for the day. So, okay. So MTHFR, PAI1. Either way, you didn't mention those at all in the thromophilia workup or the antipospholipid workup or recurrent miscarriage workup, but they are still popularly ordered. I I feel like I've seen it in almost every patient that's already had this workup done. And it must be the rage on social media.
SPEAKER_00Well, the American Society of Hematology specifically mentions that they have refrained from recommending those labs as part of the thromophilia workup because MTHFR polymorphisms have not been associated with venous thromboembolism, and plasminogen activator inhibitor type 1, PAI 1, has not been conclusively associated with venous thromboembolism. They do word it differently, not at all and not conclusively. So to answer your question, those two labs should not be included in a workup for venous thromboembolism. And that document we'll put a link to is really interesting. It also includes specific things. Should you test a woman whose mother had this mutation or that, who's considering birth control, there's a lot of specific recommendations in there for someone who wants to take a look.
SPEAKER_02I do feel like OBGOINs bear some responsibility for commonly ordering these tests, and it probably bleeds over into the idea that MTHFR mutations or the PAI1 polymorphisms were associated with spontaneous abortion risk due to microscopic thrombi. I think this is also why so many women have learned that they have MTHFR mutations, or we should say variants, because so many of them have been tested after a miscarriage.
SPEAKER_00Yeah, that's a good point. Or why are we even calling them mutations as to imply pathology? So the American Society of Reproductive Medicine, ASRM, as you mentioned, they have a practice committee opinion on the evaluation of tr of treatment and evaluation of recurrent pregnancy loss, and we can link to that as well. And they do, as you mentioned, recommend testing for antiphospholipid syndrome if you've met that clinical criteria. But as far as inherited thrombophilias, they recommend no testing for patients with recurrent pregnancy loss for inherited thromophilias because high-quality prospective cohort studies have failed to find an association between those thrombophilias and recurrent pregnancy loss.
SPEAKER_02Yeah, and this is nothing new. We've known all of this at least for 10 to 15 years. I'm guessing people probably try to imagine how the antiphospholipid antibody syndrome causes pregnancy loss, and the mechanism of how it causes that is not firmly established. It's possible that inflammation plays a role. But if people think it must be because it's a thrombophilic state and all these blood clots are clogging up the placental vessels, if they think about it that way, then they'll think that, well, all thrombophilias must do the same thing and they must be equally risky here for pregnancy loss, regardless of what the actual clinical evidence shows.
SPEAKER_00Yeah, a narrative fallacy, and that's one of the many dangers of narrative fallacies is that you extend one fallacy to other domains. So, right, the antifluslovid syndrome may not work through a thrombophilic mechanism, but how many residents have been taught that by their MFM on their high-risk OB rotation or their REI? And yeah, we've known this for a long time. Back when the Choosing Wisely campaign came out, this was one of the things that like they said not to do from our societies. This has been a long time. But this is that knowledge to action gap that Emily and I talked a bit about on the last episode, where famously it can take up to 17 years for evidence to reach the bedside. And I wonder if that is even true anymore, where in cases like this, the MTHFR mutation has so many, so much momentum and legs, if you will, on social media that people are still pursuing it.
SPEAKER_02Yeah, it's like it has just taken off a life on its own, basically. That that was a great episode, by the way. And I guess it did used to be standard practice, maybe 15 years ago or so, to test for all these thrombophilias for recurrent pregnancy loss. So maybe that 17 years should be coming, if not for all of this new momentum, as you said. It seems like MTHFR testing is as popular as ever. People are learning about it on social media now, they're coming in, they're asking for it, and then a lot of their providers are just caving and ordering it.
SPEAKER_00Yeah, you can even find just labs that will do this for you. Click the link below for 20% off, or a functional medicine provider who's consumed by MTHFR variations being the rage. But over the last 15 years or so, ACOG, the American Society of Humatology, as I mentioned, the Choosing Wisely Initiative, the American College of Medical Genetics, they've all come out recommending against testing folks for MTHFR mutations. These mutations likely have no clinical meaning whatsoever, but they're very common. About 25% of Hispanic patients and maybe 15% of Caucasians will carry the homozygote mutation for the C6717 variant. And maybe 60% of the populations have at least one of the variants of the A and C mutations, heterozygote or homozygote. And so again, do you even consider that pathogenic? It's just a common variant, and we've not clinically tied it to any disease process that matters, particularly in an age of folate supplementation in the normal diet and foodstuffs that we consume, where you might find some problem in folate-deficient folks?
SPEAKER_02Aaron Ross Powell Well, to be clear, these variants, especially these variants that affect more than half the population, are not risk factors for venous thromboembolism, despite what we might learn in biochem about the pathways and how we might theoretically draw that connection. It's not an actual risk. There's no evidence that they're associated with miscarriage or stillbirth. And there's no increased risk for neural tube defects, even though these mutations are involved in the folate pathway. Anyone that's getting 400 micrograms daily of folic acid in their diet before pregnancy will not have an increased risk of neural tube defects, regardless of which of the MTHFR genotypes they might have. And the American Heart Association also says there's no increased risk of myocardial infarctions or stroke.
Activity Restriction And The AWARE Trial
SPEAKER_00Right. But on social media, our patients are being told that the type of folate they take will matter depending upon if they have these deficiencies or that it causes tongue ties. And there's a whole world out there of MTHFR tongue tie and pot syndrome connections that have been established. And so when you see that sort of stuff, just know that you're looking at gross misinformation. So Okay. Well, let's move on to the aware trial, which is in the this month's April 2026 Green Journal.
SPEAKER_02I knew you'd like this one when I saw it.
SPEAKER_00Well Yeah. Well, I was excited. So we've we we talk all the time about this inertia in practice or the knowledge to action gap that that we talked about last episode, or just in general, the persistence of false beliefs, especially those that are more culturally rooted or things that just seem to make sense empirically to people, like MTHFR must affect folate metabolism and must increase the risk of neural tube defects. It just makes sense. But one of those certainly is activity restriction during pregnancy or even bed rest. And we've talked a lot about that over the years. We've also talked about the fact that the majority of OB providers, midwives, still make some comments about activity restriction, some recommendations to their patients, even if it's not to the point of strict bed rest. But many folks still recommend bed rest for some indications.
SPEAKER_02Yeah, and it really is easy to tell people things like, why don't you just take it easy if they're coming in because they're having contractions and they're not in preterm labor, and they say, Well, I've been overdoing it. And then you say, Well, just rest up now. And then it feels like you've solved the problem. And then conversely, every other pregnant woman believes that walking or doing squats or having intercourse is gonna put her into labor. So obviously, restricting those sorts of activities must help prevent preterm labor or otherwise just be good for pregnant women. So these recommendations have all the trappings that you just discussed. It's something that's been out there in our culture for generations, and it seems to make sense in some way that activity could be associated with uterine contractility, especially when women will say they notice their Braxton Hicks contractions tend to be more bothersome when they're walking and quiet down when they do less.
SPEAKER_00Yeah. But maybe they were going to quiet down anyway, even if they didn't do less. And maybe more importantly, okay, maybe that's true, but those types of contractions aren't associated with or a cause of preterm labor. But yeah, this is the perfect storm for the persistence of false beliefs, where something makes sense, it has some anecdotal experience that rings true for so many people. It's just a thing everybody knows.
SPEAKER_02Well, this aware study is the lead article in this month's Green Journal, and I think they did it as your birthday present.
SPEAKER_00Thank you.
SPEAKER_02So there's an editorial that accompanies the article. The author of this editorial summarizes the findings in this study and also the literature that's already out there, and he mentions that there is no known activity that will cause preterm birth or miscarriage or any other pregnancy adverse outcomes. He also mentioned something that we've talked about before, which is this idea of guilt sanctioning. So if patients are told they should limit activity and then they have a negative outcome, then perhaps unintentionally they've been assigned this guilt because they're gonna look back and wonder if that one time that they were dealing with a screaming toddler and had to lift them up to get them off this furniture they had climbed too high on, or maybe that one time they worked an extra shift over the holidays might have then been the reason why they ultimately had their baby early or miscarried or whatever their outcome was. So he encourages us to be honest with our patients that we have no scientific evidence that activity restriction would be helpful for any of those things. And yet he still admits that maybe we don't have the perfect trial for it yet, since most of the data is retrospective, including this aware study too. But it does agree with prior studies. So we already have studies that show that inpatient versus outpatient management of a shortened cervix has no difference. And several studies have shown no benefit to activity restriction in relation to preterm labor or preterm birth. But again, most of them are retrospective.
SPEAKER_00Right. Well, this is at least a prospective cohort, but it wasn't randomized. And this was done as part of the maternal fetal medicine unit network, and they had patients wear pedometers as a surrogate for how much activity they had, and they wore them throughout their pregnancy after a certain gestational age and measured how many steps they took per day. And they defined patients as sedentary if they had fewer than 3,500 steps per day. And there was a lot of data collected about these patients because this information was collected as part of a couple of studies that were looking at preterm labor prevention interventions. So they knew a lot about these patients so they could control for a lot of variables. And ultimately they concluded that there was no statistically significant difference in latency from time of enrollment to delivery between the patients who had less activity, fewer than 3,500 steps, or more activity. In fact, among patients with a short cervix in the second trimester, which of course would be that little high risk group that you identify and you're really telling them, gosh, take it easy, those who had sedentary activity had an increased risk of preterm birth before 34 weeks of gestation and an increased risk of delivery at an earlier gestational age. And that too is actually consistent with data from other studies. So I would be a bit more aggressive than the editorialist was, and it's a good editorial, please read it. But I would suggest that the only data we have, in fact, is that activity restriction is associated with an increased risk of preterm delivery. We certainly know it's associated with an increased risk of thromboembolism and bone demineralization and economic hardships for the family and a bunch of other things, and guilt sanctioning, but we just have no evidence that it's positive or healthy for any aspect of pregnancy.
SPEAKER_02Yeah, I think this editorialist is trying to be fair and open-minded, and that's probably why they asked him to write it and not you. Okay. But but he does make a good point that there are basically three possibilities. So the first possibility is there's some unknown confounders, and so perhaps patients who had reduced activity were already at a higher baseline risk for preterm birth, and that's why they either had this either self-imposed or physician-imposed activity restriction that led them to be less active, but they were already at baseline higher risk for preterm birth. But he does point out that the authors looked at a whole bunch of confounders and found nothing to indicate that that would be true. So the second possible explanation is there could have been a relationship with the data where the patients who were having more contractions self-imposed their own activity restriction. And therefore the preterm labor is what caused the activity restriction rather than the other way around. And then, of course, the third possibility is that it reduced activity does somehow increase the risk of preterm birth.
SPEAKER_00Well, right. And of course, he's absolutely correct. And if I were putting money on this about what the absolute truth of the matter is, I guess it would be that second one that people who start having more contractions walk less and take it easy. But uh the walking less, though, doesn't do anything, so they end up delivering preterm anyway. So it's still an indictment of activity restriction as a means of dealing with it, I suppose. But this is reminiscent of all of the pelvic restrictions and things we've put on patients with uregonycological procedures over the years, where the anatomic outcomes are as good, if not better, in the patients who don't have restrictions. So we still need the right study. The point, though, is that we should not be telling people to have activity restrictions when we only know of harm associations and we have no compelling evidence that there's any benefit. So this aware study just adds to the knowledge basis that activity restriction is not helpful. I don't need the harm to be. There. I don't need it to be that it actually cause is a cause of preterm birth, as the study might imply. And of course, as he points out, this study can't be used to make that conclusion, and that's fair. But it is a cause of increased venous thromboembolism and of guilt sanctioning and of economic disruption to the family and of loss of muscle and bone mass and a whole bunch of other things that are negative enough not to recommend it to patients who don't benefit from it.
SPEAKER_02And we've known that there's no benefit to activity restriction in pregnancy for a very long time, but that knowledge is just not sufficiently translated into clinical practice. And certainly it hasn't changed the cultural beliefs that activity is a cause of labor, and that activity restriction therefore is useful to prevent early delivery or even pregnancy loss.
Practical Counseling Without False Promises
SPEAKER_00Sure, not just preterm labor. And we see patients all the time who are ER follow-ups for first trimester bleeding, and they've been seen by the ER provider and they had an ultrasound and they were told they had a subchronic hemorrhage or something like that. And they've been told not to have sex and they've been given a work excuse and told not to work until they come see us and then we give them the clearance to go back to work. Again, the implication of that action is that sexual intercourse or orgasm or work will add to the pressure of the bleed and cause miscarriage or is a cause of miscarriage or something like that. And we know those things aren't true.
SPEAKER_02But before we move on, I just want to make like a common sense distinction here. There are lots of activities that are just going to become very uncomfortable or impractical for pregnant patients that I think reasonably sh still should be avoided, just so the patient's not having to deal with like a strained back or really bad foot pain from really bad swelling in her feet because she's been standing for 12 hours or passing out, for example. And then also you run in start to run into work scheduling issues when once they're getting close to their due date. So just for my own example, like I I stopped doing major surgeries and taking overnight call about a week before my induction that was scheduled that term. Because I was getting sweaty and overheated, basically anything, any surgery that took more than 20 minutes and getting a lot slower. Like I couldn't sprint as well to an emergency on call. So and even before that, a lot of my nurses wouldn't let me do heavy lifting of patients, like when we're transferring them in the OR from one bed to another. And I was fine with that. I was very thankful for that actually, just to avoid the back strain or to avoid a heavy patient like pressing on my belly as I got further along. So I still do support some activity restrictions or modifications in pregnancy, but I try to clarify that it this has nothing to do with preventing labor or anything like that. It's just more about having some mercy for the mom herself and how she's feeling and just the back pain and foot swelling and all of that.
SPEAKER_00Right. And for an obstetrician, of course, it's always going to be a gamble if you book yourself out to be on call and you go into labor before your due date and there's no one to cover your call or you're on labor, you're on call and you go into labor and you gotta scramble to cover your shift. So that's definitely fair.
SPEAKER_02Yeah. And like who's gonna deliver your baby when you're the you're the You will. Yeah. You'll deliver your own baby, your own call.
SPEAKER_00You admit yourself and you do it.
SPEAKER_02Yeah. Yeah. But I probably, even with all that, I probably walked around even more towards the end just to keep myself moving and actually ease the discomfort. It was just certain things like the heavy lifting that that I cut back on, and I'm very happy to recommend that to patients. Like if they're saying, like I I do a lot of heavy lifting and my boss won't give me a break and say, okay, sure. But yeah, that's different from what the way aware study is about and what we're talking about here.
SPEAKER_00Yeah, all sorts of patients have very demanding physical jobs that require a lot of heavy lifting and a lot of things. And mechanically, they may not be able to do that job while they're pregnant. And so it's not about preventing preterm labor or miscarriage or anything else. They may need notes that allow them to take potty breaks or to sit more or things like that. So anybody who gains 40 pounds of weight all of a sudden and has their back arched out in a weird way as their center of gravity moves forward is going to have struggles doing a lot of their normal activities, and we can help them with that. It does create sort of an ethical thing about disability, though, and some patients will want disability, saying they're disabled to do their job. And you have to be careful about that because historically people have used the idea of activity being a source of pregnancy loss, pre-eclampsia, preterm labor, things like that to give people disability. And some of that might actually be fraudulent. So you can still do it in many circumstances, but be clear about what you're saying.
Late Preterm Steroids For Twins
SPEAKER_02Okay, well, let's move on. So there was another original study in that same edition of the Green Journal. It's a study of antenatal corticosteroids and neonatal outcomes in patients with twin gestations at risk for late preter birth. So we've talked a couple times before about the literature around the late antenatal corticosteroids, and the data for that is less than compelling. The original study had found a very minimal benefit that may not have been very clinically important, and then subsequent studies have found no benefit, yet the recommendation has still stuck around. And this was all in singleton pregnancies. So this one now is a study that enrolled twin pregnancies between 34 weeks to 36 weeks, six days, and they administered beta-methasone to a group of them at risk of preterm birth, and then compared that to a group who did not receive beta-methasone.
SPEAKER_00Yeah, it's been 10 years since the OPS trial. That was 2016 when it was published, and that has led to the now common practice of late preterm steroid administration. So as you mentioned, those findings, which were minimal at best, it was less need for supplemental oxygen for a couple of hours in babies born by cesarean and only in one gender. It was this really marginal benefit in a marginal subset. But that led to this practice. And there had also been some concern in the original study about neonatal hypoglycemia, but that wasn't replicated in some of the subsequent data and the follow-up of those babies was okay. So we haven't seen real harm from it. But twins obviously are an interesting group because about 60% of them will be born before 37 weeks. And you could see where people would just routinely give beta-methasone to all twins if they thought this was a compelling thing to do because more than half of them are going to be delivered before 37 weeks. That's not a recommendation, but you can see where the stretch would go. And so if there was a benefit to this group of patients, that would be a great area to study and a group to pursue. So now this again was not a randomized controlled trial, but rather was a multi-center retrospective cohort study, so that has its own set of problems. Nevertheless, when they controlled for as much as they possibly could and tried to compare these two groups, there was no difference in the composite outcome of respiratory morbidity in those fetuses exposed to steroids versus those who were not. There was a difference in some of the individual components of that index. So this is a composite with several individual components. And specifically the need for mechanical ventilation and supplemental oxygen was improved in the steroid group. But overall, most of these newborns had CPAP. And of course, the lack of randomization makes it hard for us to know if the centers that tended to give steroids were also more likely to not use mechanical ventilation and more likely to use CPAP for respiratory issues, which would probably be the more evidence-based way of doing things compared to the centers where the physicians who didn't use steroids maybe were more prone to mechanical ventilation. And maybe that's the difference. So the only fair thing to say is that the composite index was no different. All of these interventions added together were no different. What was also different, though, was the rate of admission to the NICU for the diagnosis of hypoglycemia. So in the steroid group, this was 10.3% versus 5.2% in the no-steroid group. So that's more reminiscent of the original ALPS trial. Now, more infants than that had hypoglycemia, but these were just the group of infants who were the only reason that they were in the NICU was for hypoglycemia, nearly double the rate, in fact, of ICU admission for hypoglycemia in those exposed to steroids.
SPEAKER_02Well, the truth is this study was not powered sufficiently to answer many of the questions they sought to answer. And in the end, they conclude, of course, that there's a need for ongoing research. That's like the perennial thing at the end of every study.
SPEAKER_00Aaron Powell When you didn't find anything, that's what you said. Yeah.
SPEAKER_02So they talk a lot about the ALPS trial, but they don't reference the subsequent follow-up studies that have failed to validate those findings. So I think if nothing else, the study is more evidence that the findings of the ALP trial may represent a false discovery that still has yet to be replicated.
SPEAKER_00Aaron Powell Well, in the last episode, Emily brought up the idea that whatever the current standard is, whatever wherever you gain the entrenched practice, that's going to be very important because the whole point about inertia of practice is that it's very difficult to move away from what's already being done for a whole variety of reasons. We have to be careful about adopting new interventions without good evidence because then they become the standard, the entrenched practice. And then even when new evidence comes along later that says it doesn't work, we don't move away. In the case of late antenatal steroids, we've adopted that into practice based upon weak and mixed results of one study. And now with several subsequent data sets not replicating those findings, well, no one wants to stop doing it because it is this because of this inertia of practice idea. On the other hand, had we been more disciplined and awaited for more data and subsequent replication of those findings, then we certainly wouldn't have started doing it based upon any of the follow-up studies, including this one, I think. So this just underscores the need to be very diligent about why we start doing anything initially to begin with, because it's very hard to stop doing it once it's already been adopted into practice and seems like the standard of care.
Patient-Led Insulin Titration In GDM
SPEAKER_02Right. Okay, let's move on again. There's another article in the April 2026 Green Journal that I thought you would like. It's the one about patient-led insulin titration for glycemic management with gestational diabetes.
SPEAKER_00Yeah, that was a great article. And to be honest, I assumed everyone was already doing what the article advocates for. One of the co-authors of that paper is Stephen Gabby, who is a type 1 diabetic and who revolutionized the care of diabetes during pregnancy.
SPEAKER_02Aaron Powell Do you guys just have this little type 1 diabetes obstetrician club?
SPEAKER_00Aaron Powell We do. And if you don't, it's none of your business.
SPEAKER_02Okay, fine. Spike club.
SPEAKER_00Yeah.
SPEAKER_02Okay. Well, explain to us then what they did in this paper.
SPEAKER_00Aaron Ross Powell Well, there are lots of ways of dosing insulin at the starting point when a patient needs insulin. And the truth is for a highly insulin-resistant diabetic like a type 2 diabetic, you can easily do weight-based dosing and be okay. But most patients in pregnancy, they'll you'll start with a lower dose, a just true gestational diabetic, of a long-acting insulin like Gargine, Lantis, or one of the biosimilars, and then increase it by some amount to achieve the desired effect, which is usually to have a fasting blood glucose between 75 and 95. And it's usually the fastings that go first. A lot of the postprandials you can clean up with diet and things like that. So you're usually working on this fasting number first. In this study, they did a non-blinded but randomized control trial where patients were assigned to start at 10 units nightly and then go up or down if needs be by two units a night until they achieved fastings between 75 and 95. So if they overshot and were low, they could back off two units. But if they were above 95, just add two more tonight. And then the control group were patients who had weekly adjustments made by their providers after reviewing their glucose.
SPEAKER_02Okay, so you already do what the intervention arm was doing.
SPEAKER_00Yes, and with all sorts of diabetics, not just gestational diabetics. My pre-gestational diabetics I'll do this with as well. A lot of them come in, they're pregnant, and they have subpar care, and of course you're trying to get them as adjusted rapidly as possible. Patients need to be empowered to control their own blood sugars. And I think that's the hallmark of diabetes care that really started with Elliot Jocelyn decades ago. I can explain to the patient how I plan to adjust their insulin in response to what their blood sugars are going to be, and I can educate them. And they're quite capable of making these adjustments for themselves, and they're going to be more compliant and more knowledgeable about their disease.
SPEAKER_02Yeah, and I can see how even weekly, a lot of them are scheduled every two weeks. And then if they have high sugars, then they're not doing anything until they see their doctor in two weeks. That's just that much longer. So what did they find in this study?
SPEAKER_00Well, of course, ultimately patients ended up at the same place. So in other words, their average glucose was the same prior to delivery in both these groups, but they got there much more quickly when they made the adjustments on their own. And again, this seems like a self-obvious truth. The question is, does it have any more meaning than that? So they also found a much lower risk of macrosomia and in larger gestational age infants, so you know the estimates and the actual birth weights, in the patients who did the self-adjustment. In fact, the effect size is quite surprising. 37% of the traditional group had macrosomia compared to just 6.9% of the patient-led titration group. And actual weighed babies, large registral age birth weight, was 34.6% in the traditional group compared to 3.3% in the patient-led titration group.
SPEAKER_02That's basically a tenfold difference.
SPEAKER_00Yeah. And I'd love to see that replicated. That's almost hard to believe. I'd love to see that replicated in another study. The weakness of this paper really is that there were only 29 and 27 patients in the two groups. But if this is true or even some trend to that large of a difference, it does go a long way to advancing care for gestational diabetes because previously we failed to see robust improvements in fetal macrosomia in particular with insulin as a control for diabetes. We've seen most of it in diet and exercise, but once you initiate insulin therapy, the benefit tends to go away. And now, of course, I wonder if that's because the people who were diet and controlled, you've told that you've educated them about their diet and you've asked them to exercise. And do if they get sugars controlled, they've done that quickly. They've gone home and adjusted what they eat and they've achieved euglycemia very quickly, whereas we have been, as you said, slowly rolling on the insulin therapy. And so maybe that's a difference. I would love to see this replicated.
SPEAKER_02Yeah, and even if a future study doesn't show as significant of a difference in the macrosomia or large gestational age babies, it still makes a lot of sense to empower patients to adjust their own insulin. Clearly, it didn't seem like there's any harms here.
SPEAKER_00Right. And I think non-diabetic doctors, people other than me and Stephen Gabby, have always been afraid of insulin. And that there's been this very conservative approach where insulin doses are increased by maybe only 10% at a time. And then that might only be happening every week or ever even two weeks, depending on how often you see them. And these patients should be able to achieve good glucose control very rapidly if they're just empowered to do it. And that's what this study affirms.
Laboring Down And Pelvic Floor Outcomes
SPEAKER_02All right, let's move on again. So you and Emily in that last episode briefly talked about laboring down. And another aspect of this that sometimes we hear about is the effect on the pelvic floor. And at least on social media, and there's a YouTube, like a pregnancy postpartum fitness channel that I like, but it also talks about this too. The implication is that laboring down is somehow better for the pelvic floor than immediate pushing because overall there's slightly less pushing. I think you guys had said seven minutes on average, less pushing if you labor down. So I think that the theory is laboring down allows for everything, the whole pelvic floor and everything to stretch out more slowly. And then perhaps that gives less tissue damage and less tears and therefore less long-term pelvic floor issues. But there was a paper in the February 26 Green Journal that compared three-year outcomes of second stage pushing time on postpartum pelvic floor morbidity. So this study had randomized about 2,400 patients to immediate pushing versus waiting for 60 minutes after they achieved full dilation. And then these patients all had pelvic floor assessments at week one, then week six post delivery, and then again around three years later. And each time the patients filled out pelvic floor symptom questionnaires and also had some objective exams.
SPEAKER_00Yeah, and they were all, I think, epiduralized too. So what did they find? This sounds exciting.
SPEAKER_02Yeah, so yeah, so they had epidurals. They found that there was no difference at two to three years between the two groups in relationship to either their POP Q measures, which is the objective measure physical exam, and to most of the pelvic floor symptom questionnaires.
SPEAKER_00Most?
SPEAKER_02Yeah, most. So not all. So they compared 10 different pelvic floor symptom and quality of life questionnaire scores at baseline and again at two to three years. So none of them were statistically significantly different except for a subscore on the PFDI 20 questionnaire, Krady. So none of them were statistically significantly different except for a subscore on the PFDI 20 questionnaire called Krady for short. Now, the important thing here is that there was no difference in the scores at three years, and there was no difference in these scores initially, but the change in baseline for each group is what was is significantly different. So plus there was no multiple comparators adjustment. So it's unclear if this is clinically significant at all or just an artifact in the data. But essentially they had 20 different data points because they looked at the change from the group's own baseline, which is what was different, compared to the actual difference between the two groups, which was not different.
SPEAKER_00Yeah, it's confusing. But the questions on that subscore that Crady is the colorectal anal distress inventory questions, these are questions that ask the patients if they feel the need to strain too hard to have a bowel movement, if they feel like they've not completely emptied their bowels at the end of a movement, if they usually lose stool with well-formed stools, or if they usually lose stools with diarrhea, or if they usually lose gas from the rectum, it's beyond their control. And they also ask if they've have pain when they have bowel movements or a sense of urgency to rush to the bathroom to have a bowel movement, or if they've noticed any prolapse of their bowel from their anus.
SPEAKER_02Right. So those are eight questions regarding specifically colorectal type symptoms. And you can score anywhere between zero and 32 total, depending on how you answer those eight questions. So the immediate pushing group had a baseline score of 15.8, and the delayed pushing group had a baseline score of 19 on average. So at baseline, those who were randomized to delayed pushing were already slightly higher on this Krady, but it wasn't statistically significantly different than the 15.8. So then at three years, the immediate pushing group had an average of 19.2, which was the same as the baseline score of the delayed pushing group. But now the delayed pushing group at three years was at 14.9, so it's almost like they flip-lapped. So that means that the immediate pushing group, their score went up by 2.4 points on average, and the delayed pushing group went down by 5.7 points on average. And it was not statistically significant when the two groups were compared to each other, but that change in their own baselines was what was viewed as statistically significant.
SPEAKER_00Do you think in years future your kids will go back and try to find themselves on which podcast episodes they were on? That'd be a cool activity. They had 20 different data points in. That analysis and they found one of the 20 was statistically significant, but they didn't do a multiple comparators analysis. And that's interesting because the chance of finding or the likelihood that at least one out of 20 is 5%, right? It's that's what a p-value is. So you almost expect when you compare 20 slices of the same data that you're going to find one of those things being statistically significant at least. And that's what happened here. So from a purist perspective, this is not an important finding.
SPEAKER_02Right. So so this probably means nothing, but this is the sort of thing that you'll see highlighted online where people will claim that delayed pushing results in less bowel issues in the future. But that's not what the authors even conclude, and that's not what the data indicates.
SPEAKER_00Right. You also have to think about what's the theory here. Does this make sense not just from a pure numbers perspective? In the delayed pushing group, the fetal head was on the pelvic floor, stretching everything out for an average of 30 minutes longer than for those patients who immediately push. And those patients who waited also had a longer duration of active pushing. That was interesting, despite laboring down. But they had similar rates of vaginal and operative delivery. And I think what's going on here is something that's relatively common with multiple data slicing like this. And it's just, let's call it a statistical artifact. For whatever reason, though, by chance, perhaps, those assigned to the delayed pushing group tended to overestimate by a little bit their baseline symptoms. And those in the immediate pushing group, maybe they slightly underestimated, and you'll see this is where you get differences in groups. I talk about this in clinical reasoning. Then you have what's called regression to the mean. And when these symptoms were reassessed later, both groups regressed to their own mean a bit. So the change in that looked significant. So the important metric here to understand is that at baseline and at three years, neither group reported, compared to each other, statistically significant differences in any of these survey items. And of course, nor were there any observed objective differences in their pop cue assessments. And so that's similar to other findings that have looked extensively in the past at GI symptoms. So it would be a surprise compared to what we already know if this somehow found that there was a change in GI symptoms compared to what we've already known from other literature. So this is a negative study.
SPEAKER_02Well, especially because they pushed for longer. Yeah, right. It just wouldn't even make sense to conclude somehow less straight on the pelvic floor. But it it seems like people out there like to analyze some of this data to that, to death. And probably if especially if they're looking for a certain answer already, they're going to hunt for it.
SPEAKER_00Yeah, that's the risk of bias in study. So one thing that you would do before you started a study like this, or really before you read such a paper, is decide what am I going to see that's clinically significant that's going to affect how I practice. If there's a tremendous difference in the pelvic four outcomes of patients who've had delayed pushing versus immediate pushing, you won't have to torture the data to see it. There'll be a very significant difference, a significant magnitude of effect and effect size, and it'll be obvious in the data, and you'll be able to draw a very easy conclusion from it. So be leery of people who make large conclusions like you might see on social media about this study from this overly tortured data that is just seeing noise for signal or signal for noise. It's very problematic.
SPEAKER_02All right. Well, do we still have time for our listener question?
SPEAKER_00Let's do it if the baby's okay.
SPEAKER_02Okay. I think the baby wants to hear it. So the listener writes We occasionally have patients who have contraindications to magnesium sulfate and need to use alternative agents for seizure prophylaxis in preecnampsia. Of course, we also sometimes use antiepileptic medications for people who have refractory seizures. I understand that alternative therapies to magnesium have been historically used in Europe for a long time. However, there seems to be an increasing trend of using Kepra as the leading alternative to magnesium sulfate, and now I'm seeing it being used instead of mag, even in patients who don't have a contraindication. So what am I missing? Signed, I dream of seizures and cesareans.
SPEAKER_00This must be a resident then. So well, I don't think that the listener is missing anything. If a person doesn't have a contraindication to magnesium sulfate for seizure prophylaxis, then that's what they should be on. And I'll put a link to a great recent review article that was in the Gray Journal on eclampsia that's co-authored by Baja Sabai that's really worth reading. And it certainly paints the picture for what our current state of knowledge is and where we're going and where the research opportunities are. And of course, he discusses prevention and treatment of seizures in this monograph.
SPEAKER_02Yes. And in there he says there's substantial evidence regarding the use of magnesium sulfate to prevent convulsions in women with preacleamphea with severe features. And he states specifically that it's been found to be superior to phenytoin, diazepam, and nemodopene for prevention, and that it is the drug of choice for prevention of a seizure, cutting the risk of seizure by more than half with a reduction in maternal death. He also says it's the drug of choice for preventing recurrent seizures in a patient who actually has eclampsia. And that again has been shown to lower the risk of maternal death, and it is still superior to diazepam and phenytoin and to this sort of cocktail that's popular in Europe. Usually that's a mixture of claripromazine, promethazine, and pethidine.
SPEAKER_00And for the occasional woman who sees is despite having adequate magnesium sulfate concentrations on board, meaning you've got it and you've given it twice, or you've done the second dose, then they recommend in the article Lorazepam, four milligrams IV over three to five minutes. So no Kepra so far. I think that this has become the standard of care the world over, and you would only be limited in doing this if you didn't have magnesium sulfate available to you. So I guess the listener has set up a scenario, though, where somebody might have a contraindication to the use of magnesium sulfate, and that's where Kepra might be a concern.
SPEAKER_02Right. So the big one that would come to mind is myasthenia gravis. I think I've encountered this one time in my whole life. It's not that common. Maybe in a maybe in a higher volume place, you see a little bit more of it.
SPEAKER_00I've had a couple of patients, but they didn't have preeclampsia, so it wasn't a concern.
SPEAKER_02Yeah. So magnesium is strictly contraindicated for them because it decreases the amount of acetylcholine released by the motor nerve impulse and reduces the sensitivity of the motor end plane to acetylcholine. For those patients, giving magnesium can then precipitate a severe myosinic crisis and respiratory failure. Others might be relative contraindications or precautions, like if let's say they have significant renal impairment. But usually then we just so we still give magnesium, but we reduce the dose and monitor the levels more closely. And maybe in patients with, let's say, they have a heart block or some prior significant myocardial damage. We'd also be more cautious with magnesium because it can affect cardiac conduction. I've never honestly encountered this kind of a labor. And in my setting, I would definitely consult a specialist or maybe transfer the patient if I did encounter it. But theoretically, those would be the only other scenarios. And of course, if someone has pulmonary edema, they should not be on mag.
SPEAKER_00Okay. But this is where I guess the consideration would be to should we can't use mag, should we use an alternative agent? And that's why this comes up. We should state, first of all, listening to what the question was, that every professional society in the world that has a statement about this says that magnesium sulfate is a superior choice and should be used for seizure prophylaxis. But if you couldn't, what might you use? And so the listener specifically mentioned Kepra. And this I think is popular because it doesn't have respiratory or cardiac toxicity, the some of the key things you were mentioning that you might see in a world where magnesium was being considered. But whether it works to prevent seizures is a completely different question. So there was a paper published in a low-quality journal in 2016 out of India that was a retrospective observational study. And this paper is what is sometimes cited in support of using Kepra. But the truth is, in that paper, it was just a case series really, they started 47 of 50 patients on magnesium sulfate, and they used Kepra in three patients who had elevated creatinine. Then they had to discontinue magnesium in nine of those 47 patients due to oliguria or rising creatinine or some other magtoxicity that they encountered. And so in those patients, of those nine, they started five of them on Kepra. Two of the 38 patients who stayed on magnesium subsequently had seizures. And then they added Kepra to those two patients after they had seizures. They gave a one gram loading dose of Kepra, followed by 500 milligrams IV twice a day. And the only patient who seized of those 10 total patients who received Kepra was the one who seized first on magnesium, and then they added Kepra, and then she actually died in the study.
SPEAKER_02This isn't a study.
SPEAKER_00Right. Yeah, this isn't a study. This is a glorified case series. But you see the damage here where people say, oh, you had these patients and the ones on magnesium, two of them seized, and none of the ones who were initially started on Kepra had seizures. Well, only three of them started on Kepra initially. I mean, that that's insane.
SPEAKER_02Aaron Powell So this has no qualities at all of adding to any kind of scientific understanding of whether or not Kepra could prevent seizures as effectively, if not better, than magnesium.
SPEAKER_00Aaron Powell Absolutely right. But after that, there have been also some incidental reports. That was 2016. There have been some incidental reports of Kepra being used in patients with myocenia gravis. And you see how this happens, right? Oh gosh, we can't give this MG patient mag. What should we do? And you go to PubMed and you search for this and you find a recent article and you read the abstract of it and you decide just, okay, well, Kepra sounds like something somebody's done, so I'm going to do it. And then you do it on an N of one or two, and they don't have seizures, and then you write a case report. And this is how low-quality evidence mills work, right? But it's a huge leap to go even then from we're going to do the best we can in a patient who can't have magnesium, and we're just guessing what might help with no evidence in a patient with MG to from that to, I'm just going to start using Kepra on everybody because magnesium sulfate has a nasty side effect profile, and I worry about the renal and cardiac implications of it, so let's use Kepra instead of magnesium sulfate. And much the same story would be true of phenytoin and benzodiazepines and other alternatives. All of these drugs, I'm sure, do likely work. Phenotone and diazepine and pneumotopine have all been compared, though, had to magnesium sulfate, and they probably prevent seizures compared to placebo. Probably asterisk. But they're inferior to magnesium sulfate. And so Kepra is just the one that doesn't have high quality trials, or frankly, even a low quality trial. It's just an unknown.
SPEAKER_02Okay, but there is a trial underway, right?
SPEAKER_00Aaron Powell Well, yeah. According to clinicaltrials.gov, there's a trial underway in Nebraska just recently. I don't know if they're even enrolling, that intends to be a randomized controlled trial comparing magnesium sulfate to Kepra for seizure prophylaxis. They estimate in their study that they need 1,240 patients to find a statistically significant difference between an equally allotted magnesium to Kepra group. And of course, that means they expect this to take six or seven years at a minimum to find 1,240 patients with preoclampsia with severe features at their institution to do this trial with. So it'll be a minute.
SPEAKER_02It is really interesting how people will change their clinical practices based on basically no evidence or even a just based on the promise of a trial that's still years away from being completed.
SPEAKER_00Yeah. And you don't know how this comes about. Do they hear people at meetings talking about this new thing that they've heard about and or the people working on the study excited about this new study? That happens. I remember many years ago hearing a very influential figure in OBGYN come to a talk and he was talking off-cuff about doing a trial very similar to this, except it was going to look at nephetipine for seizure prophylaxis. And I say that and it might have been libetolol. It was one of the two, but I think it was nepetopine. And it makes sense, napetopene's calcium channel agonist, magnesium is has effects on calcium in a similar but different mechanism. But he was talking about how the theory of which whether it was libatolol or nepetapine, the hypothesis about how it would affect cerebral perfusion in the same way that magnesium sulfate did, and you can also make libetolol make sense for that, right? And that it would have this dual purpose of both preventing seizures and lowering blood pressure. And he was going around doing meetings talking about how excited he was that this trial was getting underway and they were going to finally get rid of magnesium and all this stuff. And then the temptation here is to put the cart in front of the horse. Here's this very well-known luminary in the field of OEGON talking about a study he's going to do. Now, that was over 20 years ago, and you can imagine that the reason why we're not using Nephetopine or Lebetolol, whichever one it was for seizure prophylaxis today, is because the study found it didn't work, right? But boy, you would have been you would have been like, yeah, I'm going to start doing this when you heard him talk about it. I remember it. I remember feeling that way, like, oh, this is exciting, it's revolutionary, and this is going to change what we've done. And it makes some physiologic sense because of the effects on cerebral perfusion and cerebral blood vessels and things like that. But the lesson here is you've got to wait for the evidence.
SPEAKER_02Well, so would you use Capra in a patient with myasthenia gravis who had severe preclampsia?
SPEAKER_00I'm not sure that I would. It almost seems like that there's actually considerably more evidence for phenytoin. And right, phenytoin doesn't work as well as magnesium sulfate, sure, but does it work better than placebo? I think it does. Benzodiazepines probably work better than placebo, but there's just no evidence for Kepra. It's just silly. And maybe in time it'll pan out, and we'll all be using it in ten years. But as of right now, it's derelict.
SPEAKER_02I guess we'll wait for that child for Nebraska.
SPEAKER_00Well, we'll have the author on in ten years to talk about it when it's published, if it finds a conclusion. And I'll apologize publicly, but it doesn't matter if he's right or wrong. And I know who the author is, and he's smart and he's contributed a lot to this field and has a lot of understanding about it. He's one of the reasons why I use nephetipine as my medicine for discharge of preeclamptics rather than levatololol. And he showed he did studies that showed a lower readmission rate. I think he is an emerging leader in this area. But so was the guy 20 years ago, right? And so you just have to wait for the data and not just go with it.
Wrap Up And Where To Follow
SPEAKER_02So All right. Well, why don't we wrap it up?
SPEAKER_00Yeah. Well, you have kept that baby fairly quiet, and and the listeners can go back and search for the little Easter eggs of her making some noises. But we'll see everybody in a couple of weeks.
SPEAKER_01Thanks for listening. Be sure to check out thinking about obgyn.com for more information, and be sure to follow us on Instagram. We'll be back in two weeks.