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- [00:02]
A
Welcome to this week's bonus episode of Blood Podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Laura Michaels discusses beta thalassemia minor is associated with high rates of worsening anemia in pregnancy with Dr. Ariella Langer and longitudinal profile of estrogen related thrombotic biomarkers after cessation of combined hormonal contraceptives with Dr. Mark Blondin.
- [00:32]
B
Hello, everyone. Welcome to the Blood Podcast. I'm Laura Michaels and I'm here with Dr. Arielle Langer and Dr. Mark Blondin, both of whom are authors of submissions for our compendium on maternal health. Welcome, Dr. Langer.
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C
Thank you so much for having me.
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B
I'm interested a little bit in the beta thalassemia minor study. What drove you folks to look at anemia in pregnancies?
- [00:59]
C
In this study, so I can in my mind see the exact face of the patient that made me want to do this research project. I had a young woman come into clinic to see me. I have a focus on women's health, so I see a lot of pregnant patients as well as a lot of heavy menstrual bleeders. So, second one, not the topic for today, but this young woman came in in her first pregnancy and she was billed as having beta thalassemia minor, but her hemoglobin was in the eights. And this was just totally absent from my training. I just had no. I just stood there and I was very worried I was missing something. I was worried she wasn't iron deficient, her B12 was fine. And then I looked and she wasn't hemolyzing. And I just was sitting there scratching my head and I thought, like, what did I miss in training that I had no idea that she could be this anemic? And what are we supposed to be doing? And all those questions, should I be transfusing her? Like, is this going to lead to issues? And this particular patient was actually a physician herself still in residency. And so had all the questions that I had and I didn't have the answers. And so, you know, we made our best of that care and made sure that fetal growth was okay. But it really lit a fire in me because then when I went back with the humility we all sometimes have to have and, like, looked at the literature and looked at the textbooks, it wasn't there. And so I really actually had a scenario that I knew there wasn't a known answer to about whether or not she was an outlier or representative. And that really made me want to dive in and figure it out.
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B
That's so interesting. So we don't typically think about beta thalassemia minor as having a huge amount of effect on patients lives, but it looks like from your study that indeed anemia does occur in pregnancy on a relatively frequent basis.
- [02:47]
C
I think that's exactly part of how this caught me off guard so much in taking care of that patient. And then after that patient, before I was able to conduct the study, saw quite a few more patients. We're all taught beta thalassemia, you know, we sometimes call it minor, we sometimes call it treat, and we really think about it as not really a true disorder. And I think for the majority of the time that was totally relevant, but it was part of why I also thought it was important to have some data to speak to the space and to set some expectations. Because while thalassemia intermediate and major are rare, thalassemia minor in the grand spectrum of things really actually isn't that rare. And so keeping that in mind, looking at the study, I was seeing enough patients that I suspected I was correct. I suspected that it was the case that. I'm sorry, I feel like this is way too wordy of an answer.
- [03:37]
B
No, no, it's fine.
- [03:39]
C
Thinking about it, when I started to see enough patients in clinic where we really saw that this was something that was happening, not obscurely, not that one patient that lit the spark for me as a rarity, but actually happening with some regularity, I really realized that maybe it was incident. And then in our research, we actually found that very much to be the case that the patient coming in with the hemoglobin in the eights wasn't an outlier. In fact, we found that a hefty proportion of our patients were having that. In fact, nearly a third of them were dropping down into that range by the third trimester. So I felt like that really changed the frame for me about whether or not this is something that's really a carrier state.
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B
Yeah. So you looked at about 350 people or 350 pregnancies.
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C
The denominator in our study is the pregnancies, not the patients. And so that is one of the things, and thank goodness for statisticians to help us with making that distinction and making sure that our statistics were done right in the times we looked at statistical significance because we had to to account for the fact that this is representing some women more than once who are of course going to have correlation. But 347 pregnancies that we had in about 240 women and then what was.
- [04:55]
B
The incidence of anemia and did it vary across the months of gestation?
- [05:03]
C
One of the interesting things that we found was the variability, including the recovery. So we wanted to make sure that we weren't introducing a lot of bias into our measurements. So we were very regimented. We took one value, the first appearing in the first or second trimester, and then the first value appearing in the third trimester and the first in each time point so that our more anemic patients might have repeated measurements so we wouldn't bias our results that way. And so we found that only about 7% of patients were in that hemoglobin under 9 bucket in the first or second trimester. But that went up to, as I mentioned, it was 31% in that third trimester. Interestingly, when they presented actually to labor and delivery, that number dropped down again. So this is presentation not after delivery, but at that first cbc, at check in, and that was down to again, about 7% of the patients. And so I think one of the interesting things that this brings up for some of my basic science colleagues to investigate is what is the mechanism that we're seeing? Because I think for me, the explanation I thought was gonna be the answer was that this was an exaggerated version of dilutional anemia of pregnancy. But that doesn't entirely match with this idea that the patients were not as severely anemic when they actually show up in labor.
- [06:20]
B
One of the things I thought was interesting was how many women had their anemia addressed with iron supplementation. Now, of course, it's easy to mistake it if you just rely on an mcv, but to me it was really interesting, especially because you don't really want to iron overload beta thal people. Right. If I remember that correctly, in beta.
- [06:41]
C
Thalassemia minor, we think that most people have intact iron metabolism, so that they're not necessarily going to over absorb and lose that hepcidin regulatory axis at the same time. We know that from other epidemiologic work that there are lower rates of iron deficiency in this population. And so I think that always asks this question of is there maybe something there about their iron regulation that's different? And iron supplementation isn't especially pleasant. Right. Like all the side effects of iron heartburn, nausea, constipation are already side effects of pregnancy. So we don't really need to pile that on for people if we don't have a benefit expected for them. But what I think you're referring to is we didn't try to capture oral Iron. Cause it's so ubiquitous and reviews and medical records aren't good at capturing it. We actually looked at folks who were getting IV iron, and we looked and saw what proportion of those were given to patients who had iron deficiency. And for those in the maternal health space, we know that there is some debate about exactly what the right definition of iron deficiency is in pregnancy. But we tried to be generous and in assuming that when it was given, it was the right direction. And so we used a ferritin cutoff of 50. So one of the ways we are more sort of assuming more iron deficiency, more iron demands in pregnancy, or if it was documented at a transferrin saturation under 20. So either of those metrics, we said, okay, there's lots of people would say that's an appropriate use of iron. But for us with those metrics there, almost half of the women who got IV iron actually weren't iron deficient, to your point. And I think that that's interesting because the common mistake of thinking someone who has a microcytic anemia is iron deficient is super understandable. But these are people actually had it measured, shown that the driver was an iron deficiency and still got iron iv. And so I think that's also a potential harm here if you don't understand that thalassemia minor could cause this degree of anemia, that people are just doing whatever they can because they, they can't understand what's happening.
- [08:43]
B
Absolutely. Did you see any difference or any notable findings in the fetal outcomes or birth weights?
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C
We didn't. And that was actually another finding I thought was really helpful to be able to share with our ob GYN colleagues and the patients themselves, all of the outcomes that we can measure, whether it was low birth weight and fetal anomalies. We didn't see any difference in terms of outcomes. We could. We didn't see more prematurity. And so all of that stuff is really reassuring because one of the big concerns, if you are very anemic, is growth going to be diminished in utero? And we don't have any signal for that in this. And so that was pretty reassuring. In terms of thinking about the fetal and neonatal outcomes, is there anything that.
- [09:27]
B
Makes your data set less generalizable either regionally or globally, or, you know, urban, rural or. I'm just wondering how, how, how much we can take these data as generalizable.
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C
I think that there are a couple of things to point out. One of the entry criteria for the study was that you had to deliver within the Mass General Brigham Network which means that if you did a home delivery, which inherently selects for more, well, people, we didn't capture you at all. That was systematically excluded. And so that's one potential source of bias. Although home births aren't a huge proportion locally as part of our local healthcare culture. The other thing is that the network includes a bunch of small community affiliates, too, including affiliates that are out in some of the more rural parts of Western Massachusetts. So demographically, certainly Massachusetts doesn't capture the entire United States or the globe, but we do have a lot of different types of hospitals that are within the data set and locations. In terms of being in the Boston area versus being further out, I will say an important thing to point out is that this study only looked at beta thalassemia minor. And so I can't really claim scientifically credibly about whether or not this really applies to alpha thalassemia minor, which is often lumped together. But it has some differences. And one of the differences in why your question brought this up is because in terms of people's ethnic backgrounds, the distributions are very different. So alpha thalassemine being something that is much more common in folks who are Asian, South Asian or Southeast Asian heritage, versus looking at this population, which skews heavily towards people from Southern Europe and the Middle east, that's fascinating.
- [11:16]
B
Where do you see this research going next?
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C
There are two different things. One, it made me wonder about how much this applied to other congenital forms of anemia. So we're currently finishing up a study looking at a similar question in hereditary spherocytosis and trying to understand, is the pattern the same, particularly this pattern of worsening in the beginning of the third trimester and then recovering somewhat? And so that's one piece thinking about how much does this apply to other types of congenital anemias that are physiologically quite distinct? And the other is, I hope that there's a basic science colleague out there somewhere who's thinking about the question of how that globin regulation is there. And what about anemia and pregnancy, we've assumed versus really understanding. And then the last thing is, for some of the women involved, one important finding that we did have here is that maternal outcomes did have one important difference. There is this signal here for increased rates of postpartum hemorrhage. And it's hard to say because this is an observational, retrospective study about what was driving that. But amongst the things to keep in mind is there's a lot of data about the risks of postpartum hemorrhage being Higher for women who enter delivery anemic, specifically this cutoff of about 10. And we think that that's probably a rheologic phenomenon about not having enough red cell mass to push platelets and coag factors in opposition to endothelium. And so that's the why. But whether or not that's the mechanism here, I think it is an important signal to think about not only counseling patients and obese, but whether or not there is someone who can come up with a treatment that's effective to raise counts to avoid that risk.
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B
That is so interesting. Dr. Langer, thank you so much for taking the time with us and for this work that you've led. Appreciate your time.
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C
Thank you so much for having me.
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A
Welcome, Dr. Blondin. The title of your research is Longitudinal Profile of Estrogen Related Thrombotic Biomarkers After Cessation of Combined Hormonal Contraceptives. Tell us a little bit about your research and what were your goals for this article.
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D
The background and the goal of this research was really born on the clinical ward. I'm an angiologist working in Geneva and I treat women with baby thromboembolism. And I'm also caring for in patients to avoid the development of venous thromboembolism. And one of the open questions that we had identified is how to deal with estrogen containing contraceptives either in women who've had, let's say, deep vein thrombosis and are in the acute phase of treatment, or in women who are hospitalized or are planned to have surgery and are users of estrogen containing contraceptives. And one of the key variables that we had identified is the lack of knowledge of how long the risk of thrombosis related to the Pill would actually last once a user has stopped the Pill. And that is a key variable because it will actually inform our decisions on what to tell women who develop thrombosis. And in terms of their management of the pillar, should they stop it right away at the time of vt? Can they go on until the end of anticoagulation? Or should we go for an intermediate solution, which I think is the best one? So that was the key questions we wanted to ask ourselves. We looked at different options to answer this question. The best option would be to do a clinical cohort and gather VT events. But that would translate into very, very large observational study. And we have this chance in hormone associated VT that we have identified surrogate biological markers for the risk of estrogen for vt. And so with these Biomarkers which mimic the risk of vt. We've done a biological study in Geneva. So what we've done is we identify women who were planning on stopping their estrogen containing contraceptive, enroll them mainly through social media, and then we made several blood draws to look at the longitudinal profile of these surrogate marker for VT in women who spontaneously decided to stop their pill.
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A
What were the key findings that you feel are imparted in this article for the readers?
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D
So the key finding of our research was that the prothrombotic environment secondary to the estrogen disappears actually fairly rapidly once woman stops taking the hormone. We were expecting that this prothrombotic risk would last several weeks, perhaps six weeks after cessation of the pill. But actually what we've seen is that already after two weeks most of these prothrombotic risk, according to the measures of these surrogate biomarkers, disappeared, with about 3/4 of this increase in risk disappearing at two weeks. And so what it means, it's like very likely a woman who stops her pill or her vaginal ring would actually go back to the baseline risk for woman who doesn't take a contraceptive around two weeks, perhaps four weeks, but very, very rapidly.
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A
The implications of these findings, how does that affect women going forward?
- [16:57]
D
The question of clinical implication of our findings is crucial here. As I said, we had designed this study based on a clinical question. So going back to the women after we've had the finding, what I think is important is that we can now pretty much safely inform women who are in the acute phase of a deep vein thrombosis or pulmonary embolism and who are users of estrogens that establish they can remain on the estrogen quite safely, that's based on past research published in blood, but that they should probably get off the estrogen about a month prior to the time when anticoagulation is planned to be taken off. And just that month interval between the stop of the pill until the stop of the anticoagulation means that there won't be any effect of the pillar once the lady comes out of the anticoagulation. So that's one of the clinical implications that we use in clinical practice here in Geneva. Another clinical implication is around the management of these hormones for planned surgery. There's a bit of heterogeneity in practices overall in the world as to whether we should stop temporarily contraceptive before planned major surgery or not. But it is recommended by some of the international societies or who, for instance, and if one decides to interrupt the contraception, then probably just a two week window before the surgery is enough. Interrupting contraceptive for a long period of time obviously exposes women to a greater risk of either abnormal menstrual bleeding or definitely pregnancy.
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A
What does the future look like regarding this?
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D
So the future overall for hormone associated VTE looks like a big question mark because I think there's a lot that we still need to understand. I think the main focus currently is to try to get the safest preparations as possible with regards to this key side effect, which is thrombotic side effects. So what we've shown in our study is that this effect doesn't last long once a woman stops the pill. But I think where the field should be going is trying to identify really the safest preparation. And we have for instance, newer estrogenic preparations that are on the market and that need to be carefully evaluated and also a better personalized prediction on which women is more likely to get this side effect than someone else. Currently we're using very broad variables such as obesity, family history of vt, et cetera, but I think we could get more detailed personalized prediction for individual patients.
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A
Is there anything you would like to share before we end this interview?
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D
So I'd like to acknowledge my co authors on this paper and particularly all the participants who joined this effort and came back regularly for the blood draw. We cannot do research without participants. I'm really thrilled that we were able to complete this study.
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B
We'd like to thank Dr. Langer and Dr. Blondin for participating in the Blood Podcast today as part of the Maternal Health Initiative here at the American Society of Hematology.
- [20:30]
A
Thank you for listening to this bonus episode of the Blood Podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.