Can a simple carbon monoxide reader replace a needle procedure to monitor for anemia? Can a drug stop antibodies from crossing the placenta entirely? We look to the cutting edge of medical treatment for disease that brought these women together.
Over the Past 2 seasons Bethany and Molly have discussed the lack of consistent, accessible treatment and the current ways we can treat an alloimmunized mom and her children with HDFN, but on this episode with Dr. Moise we discuss a bright future. Can a simple carbon monoxide reader replace a needle procedure to monitor for anemia? Can a drug stop antibodies from crossing the placenta entirely? We look to the cutting edge of medical treatment for disease that brought these women together.
Guest: Dr. Kenneth J Moise Jr, M.D. Dell Medical School – UT Austin
Director, Comprehensive Fetal Care Center Dell Children’s Medical Center
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Research for this episode provided by Bethany Weathersby and Molly Sherwood of the Allo Hope Foundation. Find more information at https://allohopefoundation.org
The Allo Podcast is produced and edited by Media Club.
Molly Sherwood:
The information shared on The Allo Podcast is not intended as medical advice. Your medical care decisions should be made in consultation with your physician who is familiar with your specific case.
Bethany Weathersby:
Hi, welcome to The Allo Podcast from the Allo Hope Foundation. I'm Bethany Weathersby.
Molly Sherwood:
And I'm Molly Sherwood. And it is super difficult to follow the last episode that we just had. I think normally we banter about a random story or something that we were talking about before we recorded, but talking about anything other than Rose's story seems just silly. I know listening back to it, I listened to it recreationally and for editing because we listen back to it to edit and everything. But the second it was released to us to edit, I was just listening in my car for fun right away. Because I love hearing her voice. Her voice is so soothing to me, and the way she describes things is so powerful. Do you remember something she said in the episode was that when she finally felt this sense of relief, I think that she was in Dr. Moise's care, she said, "It felt like I picked something up and put it down." And the way that she demonstrated that visual was so, so cool. It was awesome. So anyway, I know a lot of listeners from Rose's story are going to be wondering what they can do to be a part of change, and so we're going to talk about that at the end of this episode, which is a great way to close out the season, I think.
Bethany Weathersby:
And also we felt like today's episode would be the perfect follow up to Rosa's story because we're kind of looking at maternal Alloimmunization and HDFN through a more international lens, kind of. Stepping back and seeing the whole HDFN community of patients and researchers and providers worldwide and asking what can we learn from each other? And not only that, but what can we do to help each other as well? And then what can you, the listener do to play a part in promoting awareness and proper care for families affected by this disease? So yeah, like you said, kind of the perfect way to finish out our second season of The Allo Podcast. Plus, Molly, you and I get to nerd out to our heart's content on this episode, right?
Molly Sherwood:
Our favorite. So you wrote the intro to the script and you wanted me in this moment to say abso-effing-lutely. And I do agree with that sentiment, but I'm struggling with how to say that. But abso-effing-lutely. I agree.
Bethany Weathersby:
Yeah. Because I know that's how you feel about research.
Molly Sherwood:
That's how I feel. So today's right up my alley because we're going to be talking about the most recent updates and advancements in the management of Alloimmunization and HDFN. And this season has been so special because it's given us some incredible stories that I think in some ways are a better teacher than what research can offer, but research is a huge contributor to progress in healthcare and to our understanding of disease and adoption of change. So it's super encouraging to know that things are actively being done and there are people who know that this is something that we need to understand more of. So who better to interview for this episode than a man who has published over 300 times and literally written textbooks about this disease and his highest achievement, Rose's personal chauffeur, Dr. Moise.
Dr. Ken Moise:
Yeah, who would've known.
Bethany Weathersby:
Welcome.
Dr. Ken Moise:
Yeah. Well, thanks for inviting me. This is going to be great. I'm looking forward to this.
Molly Sherwood:
We have been too. And I think before we dive in, something I want to comment on that I observed between the two of you is the really special friendship that you've built over the years. Can you guys talk about how that started?
Bethany Weathersby:
Okay. Well, that's funny because I wanted to know. I've just never heard your take on when we met, Dr. Moise, because well, on my end, I just found you on the internet and then emailed you and you didn't know who I was and I was just desperate for help. Do you remember that?
Dr. Ken Moise:
It's been a while, but it comes back. Yeah, I do. But you were just one of many people that emailed me at the time until I got to actually meet you in person. And then I met this powerful woman who had advocated for herself so well to try to have a baby. Who had been told not to have a baby, right? Not to ever have a baby.
Bethany Weathersby:
Right.
Dr. Ken Moise:
And that your family was over with and this was all you were going to ever have.
Bethany Weathersby:
Yeah. So I emailed you out of the blue and you called me back within 30, 45 minutes. You called me on my cell phone and I could not believe it. That was such a powerful conversation for me because it ended with me having this sense of hope that I had not had before. That's what I needed the very most at that moment was just hope that maybe I could pursue this and that there was treatment available for this and there were experts who knew how to handle this type of pregnancy. And that was so powerful for me and I really can't ever express what you mean to me and my family. My children are alive because of you. And also ... Okay, I'm trying not to get emotional, but I feel like it's coming. Okay. I'm already getting emotional, but I do this a lot with Dr. Moise. I think he's used to it. But you really did heal my heart and you pieced our family back together in a really miraculous way that we did not think was possible. And so thank you for that. And also, you did so much for Rose, and I also want to thank you for what you did for Rose and Lucas and Bruce. You could have easily said, "No. That's an impossible ask.", when I came to you with that request. And I also can't express what that meant to me.
Dr. Ken Moise:
I couldn't say no. I mean, here was a young lady who had lost two children and you all were supporting her to get here, thank goodness, because God love you, getting her through the visa process was such a endeavor. But little did I know that I would be her Uber to get her wisdom teeth removed. I didn't sign up for that part, but it worked out okay.
Molly Sherwood:
Full service.
Dr. Ken Moise:
Yeah, it was full service really. And then at some point when she lost the Ronald McDonald House combination, I just happened to have an extra house on my property and so Rose moved into my former mother-in-law's house. And probably the hardest part of taking care of Rose was going to the grocery store every Sunday with her, because I hate going to the grocery store. I hate it. It is my passion not to go to a grocery store. But I would take Rose there and her eyes would be as big as saucers looking at all this food and fresh produce, and she always would make me go back through the aisles to find things she could not. That was the hardest part. Taking care of her medically was easy.
Molly Sherwood:
Only you would say that. Yeah. Rose was very critical of some of our food. She thought our food was all way too sugary. She was like, "Your bread tastes like sugar and why do you have cookies?" They don't have cookies. They have digestive biscuits. That's their cookies. So she's like, "Do you have digestive biscuits?" And I'm like, "I have no idea. I've never looked for digestive biscuits."
Bethany Weathersby:
You guys had a really sweet relationship that just means so much to her, I know.
Dr. Ken Moise:
Yeah. I felt like she was an adopted daughter after a while. We've been through so much here for six months with Lucas both in utero then after he was born. And yeah, it was an experience for me. I'll never forget it. We dropped her off at the airport and I went to go. Aaron stayed with her, my daughter. And I went over to park in the cell lot to wait for them to check in, and I happened to go in this little convenience store and it was just fortuitous because it was these little license plates. And the first one I saw was Lucas. I couldn't believe it. Little Texas license plate. So I bought it right away and we sent it to him. So he has a Texas license plate.
Molly Sherwood:
Oh my God.
Bethany Weathersby:
So sweet.
Dr. Ken Moise:
Because he's a native born Texan, right? Yeah.
Molly Sherwood:
Yes he is.
Bethany Weathersby:
We're just so glad Dr. Moise is here with us. So let's dive in. We have a lot to cover.
Dr. Ken Moise:
Let's do it.
Molly Sherwood:
So let's start. We're going to talk about research coming out of the Netherlands, which they publish probably the most prolifically on this disease. Do you agree, Dr. Moise? And so we're going to talk about some updates from them. We're going to talk about a new medical treatment that may become available soon, and we're going to talk about what this disease looks like in Africa. So those are the main buckets for today. So the plan is I'm going to bring up these things and then just throw it to you guys to talk about. So that's the plan.
Bethany Weathersby:
Sounds good.
Dr. Ken Moise:
Yep.
Molly Sherwood:
Cool. The first one I wanted to bring up is from the researchers in Leiden who we admire very much, and they put out awesome work on this disease. So they actually just published something related to a question that moms ask us all the time, which is, I already had an infected pregnancy. I already needed IUTs. What's going to happen in my next pregnancy? And so they did a study on subsequent alloimmunized pregnancies, which is what happens in a pregnancy where the mom needed an IUT before? What's going to happen next time? And they did this in anti-D and anti-Kell pregnancies over an 18 year period. And so they had 69 women get pregnant again, and most of them, all but 10, did need IUTs again. And what's interesting is that on average, they needed them three weeks earlier than in their previous allo pregnancy. Does that line up with what you've seen Dr. Moise?
Dr. Ken Moise:
Absolutely. And typically we tell patients it's going to come on earlier and that we need to start our surveillance earlier than what happened in the previous pregnancy. But every now and then we're surprised as the study found, I think it was 14% didn't need any transfusions, which we don't quite understand too much. And I think some of them required them later than the previous pregnancy. So there's a lot about the immune system we don't understand to be able to predict the outcome in the next pregnancy so we have to follow those very carefully.
Bethany Weathersby:
That also surprised me when I read this. I was kind of shocked. Like wow, that's I guess more than I expected would go on to not need IUTs. Thinking to my pregnancies, I've had four Kell pregnancies. Lucy died, but then the next, baby Nora, her first IUT was at 24 weeks with the help of plasmapheresis and IVIG. And then the baby after that, same treatments, plasmapheresis, IVIG, and his first IUT was at 28 weeks. Same titer. And it was just a shock to me.
Dr. Ken Moise:
Yeah, there's some variables we just don't understand about the level of antibody or how it crosses. And then I always say, remember the baby's not an innocent bystander. It actually takes the red blood cells out of circulation, so it's a participant in its disease. All those variables are just poorly understood.
Molly Sherwood:
By the way, those babies, the ones that didn't need IUTs, all had anti-D, not anti-Kell, which I thought was ... I guess it wasn't terribly surprising. I just wanted to comment on that.
Dr. Ken Moise:
Yeah, I think the other important point, Molly, is they all were antigen positive. So obviously if you have a heterozygous partner and you carry a negative baby, no matter what your titer is, it's not going to have a problem. But in that study, all of them were antigen positive, so they should have been sick or most them were.
Bethany Weathersby:
Did they have IVIG? How was their treatment different in different pregnancies or did they all have similar treatments?
Dr. Ken Moise:
Some of them did. Some of the ones that presented earlier had IVIG. I think one was on the nipo trial and they excluded that patient, but they looked at the data with and without IVIG and it wasn't any different. We know IVIG can prolong the pregnancy by three weeks in general. I think they looked at that and broke it down, but some of the babies were treated or the moms were treated with IVIG.
Bethany Weathersby:
I'm surprised because I feel like I would really skew the results, but I could be basing that on my own. I mean, I think it was an eight week delay for me with the onset of fetal anemia for my babies. That's the difference that IVIG made for them.
Molly Sherwood:
Yeah, that is interesting.
Dr. Ken Moise:
In general, if you look at the PETIT trial, it's two to three weeks, but again, I think depends a lot on when you start it. So you have to start it fairly early, like 10 or 12 weeks when the antibody's just beginning to cross the placenta. I think sometimes we are using it too late and obviously it has less effect because the antibody's already crossed to the baby. So I think that's an important point to make.
Molly Sherwood:
You know what else I want to call out, which is a good segue to the next study we're going to talk about is when they were referring to the babies that didn't need IUTs, of course, those babies did tend to be, I think delivered a little bit earlier. Then they would start to develop signs of anemia at like 35, 36 weeks and they would say, "Oh, let's just deliver this baby." So they said all neonates required phototherapy in that group, which is given prophylactically after a pregnancy complicated by allo antibodies. And I thought that was so cool because we don't always see that in the US. We don't always see babies just getting thrown under lights right when they're born knowing they're going to potentially have HDFN. So I wanted to call that out because I really like that they do it that way.
Dr. Ken Moise:
I've talked to Enrico. They're pretty aggressive with phototherapy. I mean, why not start it? It's pretty innocuous and then take it away if you don't need it. So they start it pretty early. Yeah.
Bethany Weathersby:
And why do you think we don't do that here in the US, Dr. Moise?
Dr. Ken Moise:
I'm not sure. Obviously there's some logistics in getting the lamps there and all, and they may have limited resources of lamps sometimes. But to me, just bringing in at least the lamps on top of the baby would be pretty simple and then wait and watch the bilirubin trend and see where it goes.
Molly Sherwood:
I feel like part of it also is it seems like folks for high bili unrelated to HDFN, they don't necessarily routinely check bili right at birth. Because I don't remember what the AAP guidelines say, but it's later. It's like six to 12 hours after birth or something.
Dr. Ken Moise:
Yeah, I think there should be good communication between the OB/MFM and the neonatologist to tell them this baby's coming. We always get a cord bili, and if you have a cord bili of three or more, your baby's going to have a high bili once it's on its own. And so that sort of tips them off that, wow, this baby's going to have some bilirubin problems. So a good communication in passing the bat between the neonatologist and the MFM or OB I think is paramount here.
Molly Sherwood:
I think so too. And we have fantasies about what we can do to help with that transition for moms, like creating a fetal health record, even if the mom fills it out herself and brings it with her to her delivery and just kind of helping to aid with that transition. Because it is super important that things don't fall through the cracks. This is a great lead-in though to the next paper from Leiden. They just published this year also a paper on a review of the history and treatment, but mostly the neonatal management that they do for HDFN. And it's a really concise, neat and tidy paper that Bethany, you said was super engaging even to read. You were talking about that before.
Bethany Weathersby:
Yeah, I love this paper. I keep going back to it and reading it for fun.
Molly Sherwood:
They do a great job summarizing the history and the pregnancy treatment of the disease, which isn't even the goal of this paper, but then they go on to explain how they manage it. And so they break it into two phases, early phase and late phase. Which kind of reminds me of what Bethany, you gave an awesome analogy ... For all I know maybe this came from Dr. Moise, so I'm not sure where to give credit. But remember you gave an analogy?
Bethany Weathersby:
I think it just came from my brain.
Molly Sherwood:
Nice. Okay. Original content here from Bethany.
Bethany Weathersby:
I see these things in ... I visualize them, and so I see them in a scenario or-
Molly Sherwood:
Classic educator here.
Bethany Weathersby:
Yeah. Elementary educator. That's where my brain is at. The bilirubin to me feels like a tsunami. It's like right away it's coming ashore. You've got to run. It's hitting. You've got to be aware immediately. And then the delayed onset anemia feels like a volcano that's already ruptured and the lava is slowly creeping down the mountain side. It's coming. You can't really stop it, but it's slow. And so something you also have to be aware of. But right now when you first have a newborn baby, the thing to really be aware of is that tsunami of bilirubin.
Molly Sherwood:
Okay. So early phase, hyper bili, tsunami. That's what we're equating together. And so they measure bili right at birth, just like you said, Dr. Moise, and then every three to four hours. And okay, this is a random nugget that I thought was so cool and I want to hear what you guys think about it. They were able to comment on how the disease presents differently based on the antibody the mom has. So for them if the mom has anti-D or little C, they're like, "Get that baby under the lights right now." But if the baby has anti-E or anti-big C, then they say those babies need to be under lights, but maybe not to the extent that it would sacrifice important skin to skin time. And then this I thought was so interesting, and I did not know this, but it kind of makes sense. They say that Kell actually tends to have lower BI levels because physiologically, it's not necessarily the breakdown of mature blood cells that's as big of a problem in Kell as it is the inhibition of making new ones. So they even have studied this, and they say that in Kell pregnancies, those babies with HDFN needed less phototherapy, 2.4 versus 4.1 days, and less exchange transfusions, 6% versus 62%, compared to anti-D. So what do you guys think about that?
Dr. Ken Moise:
Well, it's fascinating because, and this is going to predate both of you, but when we used to do bilirubin levels in amniotic fluid, it used to be called delta D450, to decide when the baby was getting sick, it worked great for anti-D, but it didn't work very well for Kell, which would go right along with this. So the bili levels were much lower in the babies who are anemic from Kell and we had to change our numbers. And I remember stories of patients calling me saying, "My doctor doesn't know about MCAs yet and keeps doing Delta Ds and they're normal." And I went, "You need to do an MCA." So it goes right along with what we used to know years ago when we did amniocentesis to follow these diseases that Kell's a double hit. There is some hemolysis, but it's not to the same degree as D, but it's a bone marrow suppression that happens with Kell. So yeah, it makes sense they wouldn't need exchanges quite as quickly for their bilirubin issues.
Bethany Weathersby:
And could we say the level of hemolysis ... Well, I guess maybe the aggression of hemolysis would be the same. It's just that with anti-D, the baby's creating more blood to be destroyed. Is that right? Than the baby with Kell.
Dr. Ken Moise:
Yeah, because again, as we said, it's suppression of the bone marrow so they're not making enough red cells, and then the ones it does make are affected by the maternal antibody. So there's probably not globally as much bilirubin produced. Yeah. No, that makes sense.
Molly Sherwood:
This is kind of interesting. Not to say of course, that you shouldn't be monitoring a Kell baby as closely as a D baby, but they're just talking about priority in the first hours, I think.
Okay. So then they section it over to the late phase, which is late anemia presenting in these babies. And they say that babies ought to be monitored weekly for hemoglobin and reticulocyte count initially for the first six weeks and then as applicable until around three months of age. And that's consistent with what we've said in previous episodes. And I think that's also what Dr. Moise, you give patients when they take some paperwork and hand to their post-birth neonatologist, right?
Dr. Ken Moise:
Yeah. And I think another statistic I found fascinating because they follow their babies so closely is that 80% of the babies that had transfusions needed a top-up transfusion later on, but 60% of the babies who didn't get treated with transfusions still had ongoing homolysis after they were born and eventually needed top-up transfusions. So you're not out of the woods just because you didn't have transfusions. You still need to be followed pretty carefully after your baby's born.
Bethany Weathersby:
Wow. And you're talking about transfusions in utero?
Dr. Ken Moise:
Yes. So 80% of the ones that had in utero transfusions ended up with top-ups, but 60% of the babies who didn't need in utero transfusions still needed top-ups later in pediatric life.
Bethany Weathersby:
Right. That's a lot. Wow. How many babies are not followed weekly with those blood tests just because they didn't have IUTs?
Dr. Ken Moise:
That's a great question. I don't know the answer. I think that what we are seeing, and Bethany, you and I talk about this all the time, is the AAP is really good at putting out guidelines, they just updated them last year, on how to manage bilirubin, but then they're silent on anything after that. We need an algorithm for our neonatologist and pediatric specialists to know what to do with these kiddos afterwards. Most of them are not aware of what to do.
Bethany Weathersby:
Yeah, we're seeing that too on the patient side for sure. Something I liked about the wording here was that they say weekly blood draws for six weeks and then at your discretion after that. And I feel like that is more palatable to the pediatrician than weekly blood tests until the baby's out of the woods. I don't know. We've just seen a lot of patients have to push for that care and then often they get a unfavorable response from their provider because they feel like it's overkill. But I think that maybe if they're coming to them and saying, "Let's just do six weeks weekly and then we can go from there," I think it would be more widely accepted. What do you guys think?
Dr. Ken Moise:
Well, I think you can individualize to some extent. When I talk to pediatricians and pediatric hematologists, we talk about reticulocyte counts and if they're going up and the hemoglobin is stable, then the baby's recovering, particularly after IUTs. We'd like a 2% number for two weeks, but I think it can vary. But I think as long as your hemoglobin is stable or going up and your reticulocyte count is going up, you can individualize to that particular baby and how it's responding. What's interesting is I've asked the hematologist to draw some DATs on those babies and even with their reticulocyte count going up, the DAT is still positive. So that antibody is hanging around from the mom for three or four months. It's still there from what they achieved from being exposed in utero.
Bethany Weathersby:
Yes. My pediatric hematologist actually checked my baby's DAT as part of their blood work towards the end because they just felt more confident discharging them knowing that my antibodies weren't in their system. And that also gave us peace of mind to be totally done. There's no antibodies to destroy what they are making.
Molly Sherwood:
Can you explain the utility of the reticulocyte count for our listeners too?
Dr. Ken Moise:
The reticulocyte count is just to measure the young red blood cells coming out of the bone marrow, and I think it reflects the baby's response to anemia. So we know at least in the IUT babies that their bone marrow goes to sleep, if you would. We're not quite sure why. Some people believe it's related to the different type of hemoglobin we put in the babies. So we put adult hemoglobin in fetuses. They're supposed to have fetal hemoglobin. But whatever we suppress their bone marrow. So when you look at them, say after the third transfusion, there are no reticulocytes left. It's all donor cells. And at birth it's the same. There's no reticulocytes. So until you start seeing those, you know their bone marrow hasn't started to recover yet. And when that happens, when the reticulocyte count goes up, the bone marrow is starting to work again and that's a good sign that the baby's turned the corner and it's headed off to a normal life.
Molly Sherwood:
Yeah. That's an awesome indicator. I feel like sometimes we forget to talk about it. Okay, one more thing I wanted to bring up from this study that Bethany and I thought was really interesting is that they introduced this tiered model for the cutoffs at which they would do a transfusion for these babies. And they do comment just like you did, Dr. Moise, that internationally there is no consensus on cutoff values or dosage or transfusion rates, but for them they have a hemoglobin threshold depending on the baby's age. So it's 10.4 or lower in the first week of life, 8.8 in the second week, and 7.2 from week three onwards. So what do you guys think about that tiered model?
Dr. Ken Moise:
Well, I think that makes some sense. You don't want to over transfuse the baby. If you keep putting blood in the baby as top-up transfusions, you continue to suppress the bone marrow. So you want to let the baby on its own have its bone marrow wake up so that's why they've proposed these levels. Now, know these aren't evidence based. I've talked to the Leiden group and they're shooting from the hip about what a baby will tolerate. Some babies don't tolerate those levels. So the mom will report the baby's sleeping all the time or it's not feeding anymore. That baby still needs to go in and probably need a top-up, even though it may not be as low as some of these levels. But most babies are going to tolerate, in essence, a hematocrit of 21% several weeks out. So you don't want to jump in and give blood too quickly, but you don't want to let the baby get sick either and stop eating. So you have to, again, individualize a bit. But I like the fact that they have some numbers because most hematologists, again, kind of shoot from the hip and do what they want. And that may be to the detriment of that bone marrow waking up by giving too much blood too quickly.
Bethany Weathersby:
Yeah, I loved this piece because it's something that we've seen again in the patient population is these babies often are premature, and so they're dealing with a lot. They're learning how to breathe on their own, regulate body temperature, learning how to feed, and then dealing with this HDFN as well and it's a lot to deal with as a tiny new human. And they seem to do better with a higher transfusion threshold when they're super young. And it didn't make sense, I think to have one threshold regardless of age. And I know with my own son, Callum, he was born at 34 weeks, so again, he was dealing with a lot. He was struggling with oxygen, DSATs, and his feeding and he was dropping, but his hematocrit was like 25 and they thought we should let it go lower because we don't want to transfuse too soon. But we realized, no, I think he needs this to progress. And so right after that transfusion, he started eating better and he didn't have the oxygen DSATs anymore, and then he was discharged from the NICU just a couple days later.
Dr. Ken Moise:
That makes sense. Makes sense. I don't know. Are we going to talk about EPO at all? Because that's the new boy on the block to help with all this problem.
Molly Sherwood:
Oh yeah, go for it. We should talk about that.
Dr. Ken Moise:
So Leiden again, God love Leiden, has just completed a randomized trial. I think it's been accepted for publication in Lancet. I've not seen it yet. But it showed that if you put the baby on EPO, which is erythropoietin, it's the hormone that drives the bone marrow, it comes from the kidney. But we do know how to make it genetically. You can get that bone marrow to come back quicker. And in their study that I heard about, the baby still needed top-up transfusions, but not as many and not as quickly. So they're beginning to use that more. What I've recently found out is there's two forms. One is a little bit more expensive. I forget the name of it, but it's once weekly and then the cheaper one is three times a week. And I know they were using that with Rose and baby Lucas, but she was having to come in three times a week to give shots, which is a lot. And they're subcutaneous shots. It's just under the skin. But in the trial out of Leiden, they used it once a week and it was showing clear evidence of improving the recovery time for the bone marrow. And so I think that's going to be the new paradigm for these kids with the hypo proliferative anemia, is to put them on weekly EPO shots to help them recover quicker, which makes sense.
Molly Sherwood:
That would be awesome. Especially because I know we're going to talk in this episode about countries with limited access to IUTs and access to blood. And so other treatments like that that can prevent a baby from needing a transfusion would be huge. And Lucas did not need a transfusion after birth, right? He never needed one.
Dr. Ken Moise:
No. He was put on EPO pretty quickly and he never needed any kind of top-ups, which was surprising because he had very few reticulocytes at the time of birth. So some promise there. Yeah.
Molly Sherwood:
Yeah. That's so exciting.
Bethany Weathersby:
All right. Dr. Moise, here's a question. One thing I really loved about this study was their look back at the history of HDFN. It just reminded me that we haven't even known about this disease for 100 years. We have known about it less than 100 years. We couldn't even treat or prevent this disease until this 1960s. And so it makes sense that we are going to be having these new innovations and new advancements and I don't know, it just seems like those take so long to trickle down to the actual patients. And I'm wondering why that is, even though we know that this is a somewhat newly discovered disease. And so wouldn't it make sense that it is advancing quickly and shouldn't we be more open to those advancements?
Dr. Ken Moise:
Yeah, great question, Beth. I think that probably for common diseases, we see new therapies coming out more quickly, and I hate to say this, but it may be for financial remuneration that the pharmaceutical companies can do these big clinical trials quicker and they're going to get more bang for their buck on return on investment when they pick a disease that's common. Hypertension, depression, any of those things. This is a rare disease, and so it's going to be much slower, number one, to do a study as we may talk about in a minute, but more importantly, then to get people to accept this. So I think it's our job on the academic side to try to educate the community mostly through publications, to be quite honest, as to what's new on the block? How do you incorporate it? I can't tell you how many calls I'm getting about free DNA right now. They just don't trust it. Because-
Bethany Weathersby:
But the data's out there, right? Hasn't it been published?
Dr. Ken Moise:
Right. But they still don't trust it. They still don't trust it.
Bethany Weathersby:
Why is that? Just because it's new to them?
Dr. Ken Moise:
Well, I've asked that question and I said, "But you trust all the other genetic tests you do." And they went, "Well, I know, but it's ..." So what it came down to when I started asking the question was, "Well, we just accept all these other genetic tests, but in the free DNA tests for blood typing of the baby, it's too new. We don't have enough data to tell us it works." I said, "Look at Europe. They've been doing it for 15 years." "Well, that's Europe. It's not the United States." You get that line all the time too. But it's a technology that does work. It just takes time for people to get a comfort level to change their practice. Even with publications and evidence-based medicine and randomized trials. It just takes time to incorporate into their practice. But it's mostly education and the patients being empowered to ask about it, right?
Bethany Weathersby:
Yes. And this is, again, bringing me back to this study. The thing that I really noticed was when there was a nurse, I believe she was in the UK, and she discovered that babies with jaundice were responding better when they were exposed to sunlight. And so then that led to the development of phototherapy treatment and then all of these other countries adopted that treatment. But the US, it took about two decades from what ... I probably need to recheck and reread. But from what I'm remembering, it was so slow and I thought about how many babies in those 20 years or so died because they didn't have access to that therapy. Think about how common a high bilirubin is after birth. I don't know.
Dr. Ken Moise:
I think we're better today at accepting European studies. I think the Europeans have done a much better job of how they do their studies and how they publish their studies. I know in the United States we have an FDA that's very strict. The EU or EMA it's called actually as the equivalent of the FDA in Europe is getting stricter. It wasn't as strict before. So people sort of doubted some of those studies. I think that's probably part of the unwillingness to accept data coming out of Europe. You ultimately have to repeat it in the states before you get FDA and other people to accept it, to be honest.
Molly Sherwood:
We need to see for ourselves first. That's how we work. Hey, while you're talking about cell-free DNA, let's just touch on that. So you're referring to cell-free fetal DNA, which we spell out as cffDNA, or sometimes just cfDNA. Can you talk about that a little bit more?
Dr. Ken Moise:
Yeah, absolutely. First, full disclosure, I'm an advisor to the company that offers it in the US. BillionToOne is the company. The test is called Unity, and it's a free DNA test that is done between 10 and 12 weeks for most of the major red cell problems like D, big C, little C, E, J, K, A, Kell. And so they've developed a pretty robust assay using sequencing, which is even better than what the Europeans do. They use PCR. And their initial paper just was published a few months ago, looked at 1400 internal samples. Now, the critique is they sort of spiked the samples to make it look like maternal blood. And in 1400 samples, they got it right 100% of the time, which is impressive, for all these antigens.
Molly Sherwood:
What does that mean? They spiked the samples?
Dr. Ken Moise:
So they took a maternal blood sample and they took a fetal sample of known fetal blood type, and they put a little bit in the maternal sample to be equivalent to what you'd expect if you drew blood from a mother.
Molly Sherwood:
Oh, I see, I see.
Dr. Ken Moise:
They call it a contrived sample, which is an interesting name, but it mimics what you would see in real life and comes very proximate to it so you can do it a large number of samples. Because they know all these samples make up. So they have to find mothers that were negative, take their blood and babies that were positive and they knew that and spike them together if you would. But in 1400 samples, they didn't miss it ever, which is impressive. Now, you tell that to clinicians and they go, "Yeah, but that's not real life. That's kind of cooking the books."
So they're now prospectively collecting samples of patients that have the assay's been sent in and then they're checking the babies after they're born. And it's going to take a little while to get all those samples in, but eventually ... And I've asked clinicians, how many do you need? And they said maybe 250. Once those samples come in and they show they're not making any mistakes, then I think people will embrace this technology and I suspect it'll be in the next year or two and as more of us write about it, I think it'll become more and more accepted.
Molly Sherwood:
And the impact of that would be huge because we'd be able to not have to do amniocentesis, at least in the moms who have those antibodies, which are the most common ones anyway. And hopefully we could stop having to worry about testing dad, which is another nuisance. It's hard logistically to do and it gets ordered incorrectly all the time. But if we could get rid of those two things, that would really streamline the way that we screen for this disease.
Dr. Ken Moise:
I've been asked to write a review for one of our journals, and you're right, either dad may not be available, you're not sure who the dad is, or what we run into quite a bit in our population is dad's not insured and you can't put dad's sample on mom's insurance. Maybe she qualifies for Medicaid because she's pregnant. He doesn't have Medicaid, and you can't put that sample on mom's insurance, so you can't get it done. So you're right, a free DNA test would be paid for and be much easier to do. My desire is to see fewer people who obviously everybody wants to avoid amniocentesis, is to not just do serial MCAs with a negative baby. Because I've heard horror stories of babies that are antigen negative who have some spuriously high MCA and dose to cordocentesis and maybe even gets a transfusion and the baby's negative and didn't need any of that risky behavior. So I think it takes all that off the table, which is fantastic. Because remember, MCAs have a false positive rate of 12% from the original study. So they can be wrong. They can be wrong.
Bethany Weathersby:
And something that we see often as well is antigen negative baby, and yet the mother is still subjected to regular titer blood draws and titer checks, and then if the titer is high, there's all this fear and confusion and what do we do now and doubting of the antigen test and it causes a lot of stress.
Dr. Ken Moise:
Yeah, I agree. And I think we need to embrace the technology and feel comfortable with it and move on to your point and not do all these additional tests that will give you false positive results. I've seen titers go up in women who carry negative babies. I can't explain it, but it happens sometimes. And you would think the titer wouldn't change, but sometimes it does, but it's not a good indicator of whether she carries an antigen positive or negative baby.
Bethany Weathersby:
And one last benefit I want to add to the cell-free fetal DNA test is that you get results earlier than the amniocentesis and this test can be done ... Is it 10 weeks? Nine weeks?
Dr. Ken Moise:
10 to 12 weeks, yeah.
Bethany Weathersby:
10 to 12 weeks. And then if you're doing an amnio, that's like 16 weeks?
Dr. Ken Moise:
Right. And I think to your point, along that same line, if you had a patient you would consider an IVIG plasmapheresis, you can order that at 10 weeks, get a result back within a week or 10 days and decide do I need to move forward with some aggressive immunotherapy or not based on this baby's antigen status.
Bethany Weathersby:
That is so helpful. Yeah.
Molly Sherwood:
I'm really encouraged listening to all of this. It's just exciting to know that there may be a future that's something more streamlined and that is not delivered with so many caveats and explanations like we usually have to do.
Dr. Ken Moise:
Well, here's the best part of the story. It'll take a while too, but the day will come, Europeans do this now, where if you're, say RH negative, you'll get this test done before you get your RhoGAM shot at 28 weeks. And statistically 40% of women don't need that shot. So why use it up? Why expose a woman to a blood product? So in Europe now, in many countries, they do this test at 28 weeks. If it's negative, baby's negative, they don't give RhoGAM. And in fact, in the Netherlands, they don't even check the baby's blood type at delivery. They're done. They believe in this test so much that they don't check cord blood. They don't give RhoGAM after delivery. They just say, "We're done with you."
Bethany Weathersby:
Right. And how many years have they had this test, did you say?
Dr. Ken Moise:
I think it was 2006 they started doing that. Yeah.
Bethany Weathersby:
Wow, okay.
Dr. Ken Moise:
It's been a while. And they feel very comfortable with that.
Molly Sherwood:
This reminds me also of something that you've floated to us lately about options that are non-invasive to monitor these babies. Didn't you say there's some research going on in Utah about babies? It's like an exhalation study for babies with HDFN?
Dr. Ken Moise:
Yeah. Bethany asked me to find a neonatologist who knows something about this disease, and I couldn't find one in the US. Every neonatologist-
Molly Sherwood:
That's crazy.
Dr. Ken Moise:
There's an expert on HDFN. And I'm like, "No, they know how to deal with bilirubin and that's about it." So I found someone. This amazing gentleman named Bob Christiansen at the University of Utah has been working in this disease. He's a neonatologist and a pediatric hematologist, and he's been doing this work with exhaled carbon monoxide. Not dioxide, monoxide. That bad stuff you put monitors in your house looking for. And it turns out when you break down hemoglobin, you create a heme molecule and a carbon monoxide molecule and you exhale it. It's in your breath. And so he actually has a meter that works to pick this up in babies and actually has shown that it's better than just checking bilirubins as to who's going to need lights, who's going to need phototherapy.
Molly Sherwood:
That's so crazy.
Dr. Ken Moise:
It's a little nasal cannular. You put the baby's nose and you just measure on this little meter in 10 minutes and it tells you if the baby's lights and cells or not. And so I said, "Well, that's so cool. Could we do that in pregnancy?" And he said, "Well, interesting you say that. We've done it in four women. And sure enough, when their babies are hemolyzing in utero, the mom exhales more carbon monoxide on our meters." And I went, wow, think about this for developing countries that don't have to do MCAs. Or what about false positive MCAs? So we're looking into that. We're going to try to see if we can use this meter and assess women before IUTs who we know their babies are sick. We'll get some results and see what their carbon monoxide levels are. And then once the baby's out, like a day or two after delivery, we'll do it again to see what their baseline is. And hopefully these would be non-smokers because carbon monoxide goes up when you smoke so we don't want smokers in pregnancy anyway. But it may be a very cheap and dirty way to follow these pregnancies.
Molly Sherwood:
That's awesome.
Dr. Ken Moise:
Yeah. So I'm excited about it and here's the funny part. AAP has approved this meter. It's an FDA approved meter.
Molly Sherwood:
What? For this?
Dr. Ken Moise:
To determine homolysis in newborns. Yeah.
Bethany Weathersby:
That's amazing.
Dr. Ken Moise:
It's approved by AAP. So I asked my neonatologist locally when I was trying to put this research protocol together, "What do you know about this?" He says, "Absolutely nothing."
Bethany Weathersby:
Oh my goodness.
Molly Sherwood:
That's too bad.
Bethany Weathersby:
We've got to get it out there. We've got to them using it.
Dr. Ken Moise:
Another unsung secret about new data, new stuff that we need to be looking at this new technology. Yeah.
Bethany Weathersby:
Question just because I'm curious. So is this similar? I mean, I'm thinking of bilirubin is a byproduct of the destruction of red blood cells. So is carbon monoxide also then a byproduct?
Dr. Ken Moise:
Yes, it's further up the chain.
Bethany Weathersby:
Okay. And are there a lot of other byproducts and what are they?
Dr. Ken Moise:
So biliverdin end up being bilirubin. So your heme goes to carbon monoxide and biliverdin, which goes to bilirubin. And so it's in the chain of breaking down the molecule of hemoglobin. You produce carbon monoxide, you produce bilirubin. So it's right there associated with the breakdown of hemoglobin. So this particular meter's been used in sickle cell patients and in other patients with hemolytic anemias to show that their levels are high because it's an indirect measure of the breakdown of the heme product. So it makes sense that if a fetus is in utero breaking down hemoglobin, its carbon monoxide is going to cross through the placenta to the mother and she's going to exhale it over and above her own, and therefore it may be elevated and be a predictor of fetal homolysis in utero.
Bethany Weathersby:
That's incredible.
Dr. Ken Moise:
Should be cool. Yeah, I'm excited about it.
Molly Sherwood:
That is so cool. So this is reminding me ... I'm thinking back to our last episode of last season, which was past, present, future, and we had a clip in there from you, Dr. Moise, saying that you are hoping that the future of this disease is that it can be treated medically rather than through invasive procedures like IUTs or even some of the examples we've given so far in this episode. But we wanted to ask you for an update on the progress of nipocalimab, which is a candidate being studied right now to help prevent or delay the need for IUTs.
Dr. Ken Moise:
I think the answer to this disease, and Bethany, you and I talked about this about the whole African scene, is prevention makes sense. In developing countries, the advent of rhesus immune globulin in the late '60s has so changed the number of women, but we're still going to see people who fail rhesus immune globulin. Someone doesn't give it right, or they forget to give it. We don't have an immune globulin for Kell or for little C and don't foresee us having that anytime soon. So we're still going to have HDFN in the future. So the question is, okay, for those cases, if we don't want to do IUTs, how do we treat them? And Janssen Pharmaceutical, which is a subsidiary of Johnson and Johnson has developed this antibody, this monoclonal antibody, so it's a synthetic antibody, that blocks the receptor at the placental level to keep the bad antibody from crossing to the baby.
That's the simplistic concept. It also turns out this same receptor is responsible for how much antibody floats around in your bloodstream. And so by giving this medication, you drop mom's titer. So you win on both ends. You drop the circulating titer that could cross the placenta and you block the placenta too. So a double approach to a therapeutic approach.
Phase two. So just to step back for a second for our listeners, there are three phases, actually there are four, but there are three major phases to approving a drug in the United States. You have to do what's called preclinical studies. That's animal studies to show the drug's safe. Typically in some form of primate. Then you do phase one, which is you give the drug to healthy human volunteers. I don't know who these people are, but they take the drug and they get paid to do it, and they check all this blood work on them.
And if you show no badness, you move to phase two, which is where nipocalimab currently has completed phase two, and that's where you give it to patients with the disease. And you do two things. You say, is it safe? Does it work? And how much do you have to give? Because you're trying to figure out the dose of the drug that's effective. That's phase two. And phase three unfortunately for requirements by the FDA, is you have to do, typically it's two randomized trials where you give some of the patients a placebo, which is sugar water if you would. And some give the drug and you look at the outcome. In rare diseases like this, the FDA will accept one randomized trial in phase three and say you still have to get placebo and compare it to the effect of the drug. Because we know that even in placebo in a lot of diseases ... Doesn't make sense to me for this one, but in a lot of diseases there is a placebo effect. That is you believe you're getting better even though the drug isn't working.
And so to take that away, these randomized trials are done between placebo and drug to say, is the drug really effective in producing outcome? This is even done in cancer therapy. Believe it or not, they give cancer patients placebos versus new drugs to see if they work. So phase two was just completed. I think we finished it first part of 2023, and the data's analyzed. It's been presented in some verbal presentations. We're trying to ... In fact, this morning I was working on the manuscript yet again. So I'm not at liberty to produce all the numbers, but I can tell you what's out there. And that's that in very sick patients, so with 13 patients who had either lost a baby or had transfusions before 24 weeks. So that was the criteria to get in, and it was only D and Kell that were allowed in. So it had to have a pretty bad history. In 54% of them, they received no transfusions at all. They got to 32 weeks without transfusions.
Molly Sherwood:
Wow. That's awesome.
Dr. Ken Moise:
And we would expect them all based on what we've been discussing today, to have worsening disease or equivalent disease, but in more than half of the patients, they escaped having transfusions and almost every one of them had a live baby with one exception. So that's really important to say a big difference in outcome. So based on that data, Janssen is in the midst of putting together the phase three trial, which again will be drug versus placebo. What they've decided to do is do what's called a two to one randomization. So you're twice as likely to get the drug as you are to get placebo. So two thirds of the patients will get the drug, one third will get the placebo.
The criteria are pretty broadened now. They're not the really bad patients that we picked for phase two. They're patients with any IUT, one or more, any IUT. And they've included D, C, Kell, Duffy. And so pretty broad criteria to get into the trial. Knowing though that the trial's what we call blinded, so the investigator doesn't know and the patient doesn't know what they're getting. And then we follow them very carefully through the pregnancy. Just like we would do any alloimmunized pregnancy with serial MCAs. They need transfusions, they'll be at a center with experience in doing transfusions. The company will pay for them to travel to those centers to get the transfusions if they need it. I think they're planning to enroll 120 patients worldwide before they break the code. So the FDA's making them do all 120 before they break the code to see if it works or not. So that's hopefully going to start really soon. In the next month or two, actually, we'll have some US centers opening up.
Bethany Weathersby:
And can you explain to us what you mean by break the code? Because I think this is fascinating.
Dr. Ken Moise:
So in a placebo controlled trial to meet the FDA requirements, your investigators and your patients are not allowed to know what they're getting. Again, to take into account that placebo effect I mentioned. In rare situations where the patient has a complication, you can find out what they're getting. It won't be the need for IUT. You won't be able to break the code. Typically, in a blinded trial, the investigator has no idea what the outcome is till the end of the trial and then the groups are exposed and you say, okay, here's what happened in the placebo group. Here's what happened in the treated group. Now let's look at the difference in outcomes. So that's when the code is broken. Only our research pharmacies will know what they're giving us. And it'll look the same in the same bag of fluids as to whether it's the drug or the placebo.
And in fact, I understand they want to put a brown paper bag over the top of it in addition to it. So we have no idea what the patient's getting. We can't follow their titers. We will know that their free DNA is positive to get into the trial. They have to have a certain significant titer to the different antibodies I mentioned. But we can't follow their titers to know what happens. We can follow their MCAs every week, but we can't follow their titers. Because as I mentioned, the titer's going to go down with the drug.
Bethany Weathersby:
So that would be negative of-
Molly Sherwood:
Oh, I see.
Dr. Ken Moise:
That would break the code. That would break the code.
Molly Sherwood:
Right.
Bethany Weathersby:
Okay. So once you're to the point where you can break the code because you're seeing success with this drug, do they still continue doing the placebo?
Dr. Ken Moise:
Yeah, great question. So there are in these types of trials, things called interim analysis where they break the code halfway through and a special committee breaks the code and looks at it and says, "Okay, we have to stop the drugs either not working or the drug's working really well." Okay. That's called an interim analysis. And it's a special committee does that. The FDA would not allow an interim analysis. They felt that all 120 patients had to be in the study before they looked at results. So there will not be an interim analysis in this particular study.
Bethany Weathersby:
And then I also wanted to just go back to Agne's episode, and we got permission from Janssen for her to share her full story. And so she was in the trial and we see the whole story play out and her results and everything.
Dr. Ken Moise:
Is that the Lithuanian patient?
Bethany Weathersby:
Yes. She's the one you said her titers are in the millions, I believe.
Dr. Ken Moise:
Yeah, now it is. Yeah. No, she sent me the baby's picture. Yeah. Unfortunately for Agnes, one of the entry criteria for phase three is that you can't have received the drug in the past. Several of the patients have asked about that and Janssen's not allowing them back in at this point until phase three is done, and then it would be a different story. So they have to wait until phase three is done.
Bethany Weathersby:
Okay. So let's talk about really quick, what are some important things for patients to be aware of as they think about this phase three trial? Well, number one, you can't do plasmapheresis and IVIG in combination with this trial. So if you are enrolled as a participant in this phase three trial, that takes those options off the table for you. Plasmapheresis and IVIG, not an option. So that's very important to understand, especially knowing that there is a placebo arm to this trial. So 33% chance you could get placebo, which is no drug at all. And then also important to know that you will be getting very close monitoring and good care and access to intrauterine blood transfusions if you need them. Travel expenses and lodging expenses should be covered by Janssen Pharmaceuticals for trial participants. Another important thing is that you need to apply early in your pregnancy to participate in this trial. So if you are thinking about this option even before you're pregnant, go ahead and bring it up with your MFM. Start asking questions, start gathering information so that you can make a good decision in time to participate if that's what you would like to do.
Dr. Ken Moise:
Just think the gestational age is going to be probably the most limiting factor. So if someone is 20 weeks gestation, they don't qualify. They're going to need to be between 14 and 15 weeks so we have time to get the free DNA test back. Even if they have a homozygous partner, they still require the free DNA. Different chemistries, EKG, physical exam. All that needs to be done. And the limiting factor is going to be the free DNA coming back quickly, usually, hopefully within a week, to get them in because they need to get the drug by 16 and six sevenths weeks. So they have to get the drug by the end of the 16th week technically. And so if they're in a more advanced pregnancy, they wouldn't qualify for the trial. So early seeking information makes sense. Yeah.
Molly Sherwood:
I just want to make it super clear that nobody asked us to give this information today. Bethany and I and Dr. Moise want to share it to our audience because we think it's relevant to a lot of our listeners. And so we wrote this script and Bethany's talking through things that she thinks are really important considerations as a patient.
Bethany Weathersby:
Yes. And just going off of what many, many patients have asked me about this trial. Because these are the things I think most of them are thinking about and considering and so it's good to have all the information possible. And then of course, if you want to learn more and we didn't touch on something that you need to know, you can look back at our webinar that we did, and that's a lot more in depth, so be sure to look at that.
Molly Sherwood:
We'll just link that in the show notes. Also, let's link the clinical trial listing, because that has a list of all the sites too for the study.
Bethany Weathersby:
And I wanted to add the phase two trial is the one that Agne participated in, and you can go back and listen to her episode if you haven't heard it. She has extremely severe disease. She had lost three babies and had no living children going into this trial with her fourth pregnancy, and then now she has a healthy three ... Maybe she's four. But anyway, healthy daughter. That was such an incredible story, and so that could also help you just understand more about the patient perspective on participating in this trial. And again, this will be the phase three trial coming up, so it's slightly different. But yeah, Agne had a wonderful experience.
Molly Sherwood:
Hey, what years are the phase three trials supposed to be open for?
Dr. Ken Moise:
Well, I mean the plan is until they enroll 120 patients. They're looking at quite a few centers around the world. Like 30 or 40 centers. Phase two had I think 14 centers. And again, because the criteria is so much different, there are going to be many more people that qualify. I think they're shooting for a three year duration. Because remember, if we enrolled everybody tomorrow, they still have to deliver and we have to follow their babies. And so there's a lag time between entry and outcomes. I would say they're shooting for three years. That's what they're trying to do. Phase two was 2019 to 2022, but it only involved 13 patients and with very strict criteria. And we had COVID in the middle of that too, which slowed things down.
Bethany Weathersby:
Well, this is just very exciting. This is a huge light, honestly, I think in the future for me as a patient, just thinking about the possibilities.
Molly Sherwood:
Let's talk Africa. You should tee us up, Bethany.
Bethany Weathersby:
Okay, let's do it. Okay. Let's talk about a continent that I love dearly and hold closely to my heart because I grew up there. Africa. Our whole Allo Hope team has just been drawn to the patients in Africa over the past few years for lots of reasons. Well, number one, because this is a preventable, treatable, temporary disease and a lot of patients in Africa are not receiving that prevention. They're not receiving the right care and they're losing their babies and having a whole lot of devastating consequences. We just feel like there's a lot of potential in Africa to advance the treatment and the outcomes for this disease. And also the people that we've met are so lovely and we've just fallen in love with them. Over my past 10 years of patient advocacy, I have become friends with a lot of women in Africa, a lot of other patients, and it has been really difficult to I guess support them because I felt like I couldn't really help them in their pursuit of better care. I felt very helpless. And so, I mean, I could just encourage them and support them emotionally, but now in the past year or two, we have actually been able to infiltrate and start helping them receive the care that they need to have healthy pregnancies and healthy babies and that is so exciting to us.
Molly Sherwood:
Just this year, we found this study that was put out by a group of doctors in Ethiopia and they were doing IUTs, and we were so excited because I haven't seen much of any ... I mean, we just talked about Rose's story. That was not really a realistic possibility in Kenya, getting an IUT. And so we had this study in our back pocket, which came out, I think it was in April of 2023. And we were like, how cool is this? And then you had the opportunity, Bethany, to really utilize that knowledge and translate that into another living baby.
Bethany Weathersby:
Yes. Well, years before I met Rose, I met Essie online and we just developed a friendship and she told me she had lost two babies to HDFN and it was heartbreaking and I really could not do anything for her in Africa. I remember saying, "Is there any way you could just come to the US for care?" Of course she couldn't. I mean, that's just a huge ask. And so she and I just went back and forth similarly to Agne, how we just were brainstorming constantly, how can she have a living baby. And so when we found this study showing that they're doing successful IUTs in Ethiopia, we were just so encouraged. And long story short, Essie got pregnant, we were able to get her over to Ethiopia and she received IUTs from that team of doctors who were incredible. Just the kindest, most generous men and skilled at what they do and using resources that they have available to do this really hard work over there. Essie now has a healthy baby girl as a result. So years in the making, but she got that baby here alive. Oh, it's amazing.
Molly Sherwood:
It's incredible. It's incredible. They have really minimal resources over there. Especially one thing we've learned about that's a huge issue is access to blood. Because they can identify, oh yeah, this baby needs an IUT now, but it doesn't mean they can just do it. They have to wait for the blood to be available, which can sometimes take a week or more. And even that's in quite a streamlined system in Ethiopia actually. So I do want to talk about just the hurt that this continent, or at least from what we've seen in multiple countries in Africa is going through to try to manage these pregnancies and prevent them. But I want to give a little quote to paint that picture from this study. And we'll link to the study in the bottom of the show notes anyway. And they did have live birth after IUT of 90.5%, which is a tiny bit lower than we've seen in other centers, but for the resources they have, it's incredible.
But what they say ... It's great. What they say is, "ISO immunization remains ..." And ISO immunization is ... Some other countries use that instead of Alloimmunization, but same thing. "Remains a significant factor in perinatal morbidity and continues to compromise women's obstetric care in Sub-Saharan Africa due to the poor antenatal practices for all RH negative women, failure to recognize sensitizing events in pregnancy and to treat them appropriately, failure and absence of facilities to determine the degree of fetomaternal bleeding and the unaffordability of anti-D immunoglobulin."
So I just want us to talk about the extent of the problem. I think Rose's story was a great testament to that, but this disease is not rare in Africa. I mean in the US it happens in less than 1% of pregnancies or around 1%, but in other countries, the Alloimmunization rate like women who have antibodies is much higher. So there's been a study in Sudan of women who are pregnant with their second or later child. They've had a previous pregnancy before. 10.8% of those had red cell antibodies. In Uganda, 9.8%. And that's just any pregnant women, even with their first pregnancy. And also in Nigeria 5.8%. So this is a huge continental problem.
Bethany Weathersby:
With almost no access to treatment for these women.
Molly Sherwood:
So yeah, let's talk about why. What is the issue with accessing Rh immunoglobulin, which is the main way to prevent this?
Dr. Ken Moise:
Many of these countries can't afford to purchase what we all know as RhoGAM. It should be called Rhesus immune globulin, but it's made by Kedrion. It's quite expensive, and so they can't purchase it or bring it into their country. When I talked to Rose, she had to buy her own. She actually literally went to a pharmacy and purchased her own medication. So I just think it's been a priority issue with these countries and their healthcare systems of not making a public health initiative. First of all, you have to find out your Rh negative. Not every woman in these countries even gets blood typing done. Rose knew. She told me when she was a blood donor in high school, she learned she was Rh negative, but that's pretty unusual. So you first start with who's Rh negative, turns out about eight to 10% of the population of these countries is in fact Rh negatives, 15% in the US, but it's still fairly high at eight to 10% Rh negative.
And then they have to know their Rh negative first and get educated they need this. Then they have to go buy it themselves. And my understanding is that the most widely available product for whatever reason, probably because of cost, is something called Rh Clone, which is a monoclonal antibody made in India that is questionably effective. I do believe there's a study coming out in Lancet soon to question its efficacy in these patients. And I know in Rose's story, she received it multiple times and still was sensitized. So it may not be as effective as what we call polyclonal product that comes from plasma. And these countries just don't have programs set up to harvest plasma from either donors or sensitized women to make their own approved polyclonal RhoGAM type product. So they're currently buying this monoclonal product from India, which is questionably effective. So it's a matter of availability and the issue of public health and how they're managing these Rh negative women.
Molly Sherwood:
And the monoclonal RhoGAM is not approved for use in the US or in Europe, right?
Dr. Ken Moise:
That's right. There's been lots and lots of work done on monoclonal or if you would, synthetic rhesus immune globulin and all of the studies have failed. And that replicating what nature has done with polyclonal plasma, those studies have been ineffective. And so everybody's searching for that magic bullet to make a synthetic rhesus immuno globulin, but no one has succeeded to date, yet this Indian company is selling their product to the African countries as the only product available.
Molly Sherwood:
And you know what is just ... This is what really makes me upset when I think about it, is that a lot of women are scrounging together a third of their monthly income to be able to pay for one dose of this. It's crazy. What are we do? This is terribly depressing now.
Bethany Weathersby:
No, it's a good insight to see what they have to do. Go ahead.
Molly Sherwood:
No. I don't know. I don't know what to say. It's an unfortunate picture.
Dr. Ken Moise:
Well, I think what you all are doing is educating folks and opening this Pandora's box and realizing it's a two-pronged approach. It's first improving the education of these women to know their blood type and to need it, then to hopefully help them get the right rhesus immune globulin. And then finally, those who fail, and there will be failures as we talked about, do they have access to facilities and expertise to have their babies treated with 90 plus success rates to have good outcomes? And so I think it's a multifaceted approach to try to change this aspect of their healthcare system. They get some good projects. The Eldon people that make the EldonCard, which comes out of Sweden, is a little tiny bedside point of care testing with a couple of drops of blood. They've done studies in Pakistan and other places where you can train non-healthcare workers to determine blood types of people within a few minutes with a drop of blood. And I know they're doing some work in Kenya, I believe. They're starting to do some work there. We're trying to educate patients.
Molly Sherwood:
To your point, I mean Bethany and I, a lot of what we're immersed in is treatment after these women develop this disease. But in Africa, prevention is king right now. It's so important. So maybe what we should do is transition to sharing what folks can do to support people all over the world affected by this disease or who could be affected by this disease. And I also think it's a great way to close out the season because I know that a lot of our topics and stories have been so powerful, people are going to be wondering, what's my role in this?
Bethany Weathersby:
Okay, so what can we do about this? How can we contribute? How can the listener pitch in? There's a lot of options. You can read about the global shortage of Rh immune globulin and amplify the voices of organizations serving this cause by following them on social media or donating to them. We'll post some links in the show notes. The one that is immediately coming to mind is Rhesus Solution Initiative in Nigeria. They are amazing. They're doing incredible work, educating young girls and women about the importance of knowing their blood type and what to do next. And they're also giving care to Rh negative pregnant women. And that's one that comes to mind. But yeah, we'll post some links to that. You can also become a recurring donor for the Allo Hope Africa program. And we need about $12,000 a year to sustain this program.
And this is a new program we just launched this year, and we are already seeing results coming out of this program. It's incredible. We're connecting with doctors and nurses and patients and blood people, and it's just an amazing program. So we need this funding to continue this program in Africa. And by the way, Rose is now working as the Allo Hope Foundation ambassador in Kenya. She's doing incredible work and she's personally counseling alloimmunized women every day. She's traveling to their local hospitals to see them. She's even communicating with their doctors and helping facilitate the best care for them and helping facilitate donor blood when they urgently need it. She's making all these connections. And so this funding for this program will help us pay for women to get accurate lab testing. Also, women who think that they might have this condition but they're not sure because they haven't received accurate results or they just can't afford to have the test in the first place.
And then anyone who becomes a recurring donor of $50 a month or more, they will receive email updates from Rose about the progress that she is seeing in the Allo Hope Africa initiative. And that's really special to see how your contribution is affecting real live women and babies that are affected by this disease. You can also just do a one-time donation to Allo Hope. We're running Lucy Stocking fundraiser. We run the Lucy Stocking Fundraiser at the end of every year, and it begins on Giving Tuesday and it's such a special event because it not only raises money to continue this great work that the foundation is doing, but it also helps women honor their HDFN babies. So follow us on Facebook and Instagram and keep an eye out for those posts about the Lucy Stocking fundraiser. We also collect donations year round, of course, on our website.
And then if you also want to host a stocking fundraiser for your child, just email us at info@allohopefoundation.org. Another way to give back is to donate blood or donate plasma. Even if you have antibodies, there are special red cell programs that you can participate in. And then of course, promoting awareness of this disease by talking about it with friends and family. Talk about it with your provider or your nurse. A lot of times they're super curious about it. It's a very interesting disease. Ask your doctors about this at your next appointment. Share on social media. Learn about this disease and advocate. Dr. Moise, is there anything we didn't talk about that you want to touch on before we go?
Dr. Ken Moise:
You and I, Bethany, talked about this the other night. I've been doing fetal medicine for some 30 years now, and I've seen some ... I remember seeing my first transfusion when I was a senior resident in 1985, and I watched my attending do an intraperitoneal transfusion under fluoroscopy, not ultrasound. And I just thought it was the coolest thing. And I said, "I need to do this. This is what I want to do when I grow up." And in the last 30 years, I've watched a lot of new therapies come on board for the unborn baby. Things like laser for twin, twin and myelomeningocele repair for spina bifida to have some children be able to walk. But of all the different things that we've come up with to help the fetus, this is the one that's been the most successful. And transfusions have resulted in more live babies than any other fetal procedure we do.
And what I think has drawn me to this particular area and why I've spent most of my life doing research in it, taking care of patients with HDFN is that their babies are normal. There's no structural problem. There's no genetic problem. These are normal unborn children. They just happen to be the wrong blood type. And to Bethany's earlier comments when we started today, holding someone's hand through this very difficult time when there's a tremendous amount of guilt of attacking their own baby through their antibodies that they had nothing to do with making and have nothing to do with controlling has been very rewarding to know that we can help them get through this short time in pregnancy and end up with a normal child. That's been my mission, that's been my calling, and I hope to pass up Baton on to the next generation. But thanks for having me today.
Bethany Weathersby:
And thank you so much for all the work you do for patients like us. It's incredible. We're so grateful for you.
Molly Sherwood:
We are. I'm not talking because I'm going to be crying. I cried enough in Rose's episode. I was listening back to it, and every time I talked to that episode, I was crying. Oh my gosh. It was terrible.
Bethany Weathersby:
And as we wrap up the season, I just want to say thank you to all of our amazing guests who shared their stories and their expertise with us. Brittany, Katie, Amber, Emily, Agne, and Rose. We were so honored to get to interview you and hear your stories. And of course, our amazing maternal fetal medicine specialists, Dr. Kara Markham and Dr. Ken Moise, thank you so much for all that you've done in the field and for your contributions to this podcast. We are so grateful for you.
Molly Sherwood:
The listener feedback we get is a huge contributor to whether or not we decide to do another season. And the listeners have been so kind. And people reach out to us on Facebook or through email or through Instagram and share about the way that the podcast has given them a feeling of closeness and support and empowerment. And it has been so wonderful to see the way that this has been received by listeners. And so even though every time we do this, we're like, are we going to do this again? It feels like we have to do this again. So we can't wait until season three.
Bethany Weathersby:
We got to do it.
Molly Sherwood:
People just have to be stuck with us being weirdos in our closets.
Dr. Ken Moise:
So whether you're a patient, provider or otherwise affected by antibodies in pregnancy, we're here for you. We have great resources on our website at allohopefoundation.org. That's A-L-L-O, hopefoundation.org. See you.
Bethany Weathersby:
The Allo Podcast is a production of the Allo Hope Foundation. It was research and written by Molly Sherwood and me, Bethany Weathersby. It's produced and edited by CJ Housh and Eric Hurst of Media Club. The Allo Podcast is sponsored by Janssen Pharmaceutical companies of Johnson and Johnson. And get the word out there. I've got to stop talking you guys.
Molly Sherwood:
I thought that was great. That was great.
Bethany Weathersby:
I'm so tired I can't make it make sense.
Molly Sherwood:
Make it make sense. That was awesome.