Severe alloimmunization is surrounded by vague information and confusion, but this episode will prepare patients and providers for available treatment. Patients with previous fetal death, previous IUT before 24 weeks, or with a titer of 256 or higher may be diagnosed with severe disease. Remember, options do exist for severe situations, and prevention and monitoring are the key elements to having a healthy baby. This episode discusses IVIG and plasmapheresis, early MCA Scans and early IUTs, and phenobarbital.
Severe alloimmunization is surrounded by vague information and confusion, but this episode will prepare patients and providers for available treatment. Patients with previous fetal death, previous IUT before 24 weeks, or with a titer of 256 or higher may be diagnosed with severe disease. Remember, options do exist for severe situations, and prevention and monitoring are the key elements to having a healthy baby. This episode discusses IVIG and plasmapheresis, early MCA Scans and early IUTs, and phenobarbital.
Episode themes:
IVIG: Intravenous Immunoglobulin: An infusion of mostly IgG immunoglobulins that is made by extracting the immunoglobulins from the plasma of ~1,000 donors. It is thought to lessen the mother’s antibody response and delay fetal anemia. It can also be given after birth to newborns to treat hyperbilirubinemia.
Phenobarbital: An oral medication given to an alloimmunized mother before baby’s birth to improve baby’s liver function, allowing the baby to more efficiently break down bilirubin and reducing the need for exchange transfusion after birth.
Plasmapheresis: The process of removing the plasma from the body whereby the blood is removed and run through a machine that separates the plasma from the red blood cells. The plasma is discarded and the red blood cells are returned to the body with fewer antibodies (which live in plasma).
Allo Hope Terminology Library https://allohopefoundation.org/library/terminology/
Guests: Dr. Ken Moise https://partnersincare.health/directory/kenneth-moise
Dr. Thomas Travett http://www.georgiaperinatal.com/dr-trevett/
Links mentioned in this episode:
PETIT study on IVIG:l https://pubmed.ncbi.nlm.nih.gov/29902448/
Ruma et al. on plasmapheresis & IVIG: https://www.sciencedirect.com/science/article/abs/pii/S0002937806022058
Trevett et al. on phenobarbital: https://www.ajog.org/article/S0002-9378(04)00938-X/fulltext
Jansen nipocalimab clinical trials for severe disease patients:
https://clinicaltrials.gov/ct2/show/NCT03755128
https://clinicaltrials.gov/ct2/show/NCT03842189
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 https://www.mediaclub.co.
Bethany Weathersby:
The information shared on the Allo Podcast is not intended as medical advice.
Molly Sherwood:
Your medical care decisions should be made in consultation with your physician who is familiar with your specific case.
Molly Sherwood:
Hi, welcome to the Allo Podcast from the Allo Hope Foundation. I'm Molly Sherwood.
Bethany Weathersby:
And I'm Bethany Weathersby.
Molly Sherwood:
Are you ready to sit still for this recording, Bethany?
Bethany Weathersby:
I think I can do it. I think I can do it. I just had a Zoom meeting and I am excited about what we're talking about.
Molly Sherwood:
I am too, but it is hard to sit still for this whole time, which is like...
Bethany Weathersby:
Yeah.
Molly Sherwood:
Oh, this reminds me of your family photo, your awesome family photo, that you posted over the weekend. And Nora was really struggling to sit... It was Nora?
Bethany Weathersby:
No. She was just laid back with, of course, she has a dress on. Her legs are just spread and I'm like, oh no, I have to teach her how to sit like a lady. She was lounging back. And then August was screaming. And Callum, the four year old, was trying to parent August. And so, he was like just wrapping his arms around him.
Molly Sherwood:
Manhandling him?
Bethany Weathersby:
Yeah. Which made August scream louder. And that was the photo.
Molly Sherwood:
I love it. I just love authentic family photos.
Bethany Weathersby:
I do too. I prefer to post those actually because it's more real and just shows this is what life with young children is really like.
Molly Sherwood:
I think so too. As a Christmas gift, which was a while ago, my husband gave me a planned family photo shoot and promised not to complain. So, that was a really excellent gift.
Bethany Weathersby:
I would love that.
Molly Sherwood:
I know.
Bethany Weathersby:
That's great.
Molly Sherwood:
I don't think he really fulfilled that part of the bargain, but he really tried. Because I made him change a couple times. But anyway, we did it. And my middle son, Hayes, who's three, we were in the middle of it. We were doing some candid photos, but then the photographer was like, "Um, could you help him?" And I look over and he had completely pulled down his pants and underwear and bent over doing a tripod. He was doing downward dog, full moon [inaudible 00:01:39] the camera. I do have a picture of it, but I just don't think that would fly on social media.
Bethany Weathersby:
But why were the pants down? What was happening there?
Molly Sherwood:
I don't know.
Bethany Weathersby:
Did he need to potty or?
Molly Sherwood:
No.
Bethany Weathersby:
Oh my gosh.
Molly Sherwood:
He did not.
Bethany Weathersby:
He was just feeling uninhibited about that photo shoot.
Molly Sherwood:
He really, really was.
Bethany Weathersby:
Anyway.
Molly Sherwood:
Okay. We love to goof around because we're hilarious people. But today is super important because it's an interesting topic. It's sort of mysterious. There's lots of misconceptions about it. We're going to talk about severe disease and preventative treatments for HDFN, which are applicable in severe disease. There's some controversy around it, but I think largely just due to the lack of awareness. We have to figure that we're already talking about a rare disease and then we're talking about the subgroup of people who have severe disease. So, we're leaning on just a small amount of evidence about these options. But we want everyone to know that these options do exist for these situations. And I definitely want people to come away from this episode knowing how to identify when somebody might be in need of these treatments. So, these aren't going to be applicable to everybody, but it's just important to know.
Bethany Weathersby:
Yes, absolutely. You probably won't need it, but if you do, it is the difference between life and death. Having this information and knowing what your care plan should look like really, really matters. And so, that's why we want to get this out there. And I know in my personal experience, it has affected our whole lives and our entire family because our daughter died of severe HDFN. And yes, we were told things that were not true, a lot, from our providers at the time.
Bethany Weathersby:
And for instance, Lucy was given an 80% survival rate. And we were reassured that she would be fine because it was my first sensitized pregnancy. And then she died. And she wasn't fine. And then my next baby, we were told, this baby will have a 0% survival rate if she has your husband's blood type. And she did have that blood type and she was born healthy at 38 weeks with the right treatment. And so, that just is an example of the confusion around this topic.
Molly Sherwood:
I know. There are so many misconceptions. I feel like a lot of it might be, like we talked about, it's so rare that if a doctor has happened... Maybe a doctor has happened to see one case and that case had a great outcome and was super low impact or unaffected, then a doctor might say, oh, it's going to be totally fine. Everything is fine.
Bethany Weathersby:
Right.
Molly Sherwood:
Or the flip side could happen. And so, it's just so hard. At least we can maybe do our job of assimilating a bunch of information, and then we can give...
Bethany Weathersby:
Well-rounded, I guess, expectations and what to look for.
Molly Sherwood:
Yeah. Definitely.
Bethany Weathersby:
For sure.
Molly Sherwood:
Okay. Let's talk about... You've probably heard all of them yourself, even in your own pregnancies. What are some of the common misconceptions, at least specific to severe disease?
Bethany Weathersby:
Right. I have heard these myself and then also, many patients have told me and you that they've heard these as well. So, here's just a list of some of them. You can't have severe disease in your first sensitized pregnancy. Part of the problem with mine was that I had a very high titer, I had anti-Kell and it was not taken seriously because it was my first sensitized pregnancy. And so, yes, most of the time, that first one is mild and can progress and become more severe later in other pregnancies, but not always.
Bethany Weathersby:
Okay. Another one is, nothing can be done to treat fetal anemia before 18 weeks. Another one is if you have a severely affected baby or you lose a baby to HDFN, that's it. You can't have any more healthy babies after that. Another one is the preventative treatments don't work or they are experimental or too risky, insurance won't pay. So I think those are...
Molly Sherwood:
And that is the hard part too, the insurance thing. But hopefully we'll talk about some tips because that is an uphill battle, but it's possible.
Bethany Weathersby:
Yes. So, hopefully we can clear up some of these misconceptions.
Molly Sherwood:
Yeah. I think so too. I'm excited about this one because it's so empowering to know about these options even if you don't end up needing them.
Molly Sherwood:
So, just to give that reminder, most alloimmunized pregnancies don't require intervention, IUTs. We talked about that in the IUT episode. And when we're talking about severe disease, there's not really a super formal definition, but in general, it means just having fetal anemia starting in the early second trimester, just pretty early. So, the definition that's been used in a clinical trial that's ongoing right now, which we'll talk about later, is developing anemia and needing an IUT before 24 weeks.
Bethany Weathersby:
Good to know. And we are so grateful to have the input of two experts in the field, Dr. Ken Moise and Dr. Thomas Trevett.
Molly Sherwood:
Yeah. These guys are on our medical advisory board and also every time I look at the literature in this condition, pretty much one of their names is on it.
Bethany Weathersby:
Right, right.
Molly Sherwood:
And so, that's the case. Actually we're going to talk about a few publications throughout this episode. And they're authors. One or both of them are authors on all of them. So, they are just super specialized in this disease and excellent practitioners, as you know firsthand.
Bethany Weathersby:
Yes. I do. Yes. They treated me in my last three pregnancies. And those babies are healthy and energetic now. And screaming in all the family photos. So, since Dr. Moise has been treating alloimmunized women for decades, we asked him how common severe early anemia is.
Dr. Ken Moise:
I would say of all the cases I see, it's probably 10% at most. And again, I'm getting a select referral population. But to have disease, as you did, say before 18 weeks, it's maybe 5 to 10% of these alloimmunized pregnancies. And usually, it's further down a woman's reproductive life. So, that first pregnancy has moderate, mild to moderate disease and it's the next pregnancy where things get more severe when the titer goes up.
Bethany Weathersby:
So, that leads to my next question, which was is it possible for women to have severe disease with their very first sensitized pregnancy?
Dr. Ken Moise:
I have seen it. It's not typical, but some women, we call hyper responders, have very robust immune systems.
Molly Sherwood:
Okay. This is super helpful information, but we also have to decide what to do with it. We don't want to be fearful because chances are this won't be the path that an alloimmunized pregnancy takes. Something that requires extremely early intervention. But we want our community to know how to look for it and what their options are for these special cases. And just to feel empowered to have discussions about their treatment plan that is safe.
Molly Sherwood:
So, it's funny because, again, Dr. Moise says that there's an assumption that the first pregnancy will always be mild to moderate and that's totally normal to make a generalized statement about something. You can't couch every single sentence you say, but then when you asked him for more information, he shares actually it is rare but possible. So, all the more reason to just be aware of these things in any case and then decide what's right for a patient or for yourself.
Bethany Weathersby:
Yes, absolutely. And I think if my MFMs with my first sensitized pregnancy had a better understanding of severe disease, they probably wouldn't have assumed that everything was fine because it was the first sensitized pregnancy and that could have saved my daughter's life.
Bethany Weathersby:
So, let's talk about the special case that is severe disease. Yesterday, I was thinking through it. What makes it severe? You already touched on that, but it's really all about the timing. If a baby gets anemic in the third trimester, it's much safer and easier to treat. You can deliver or do a safe IUT. But what makes it severe is how early this anemia is coming on and there are fewer treatment options than to treat that fetal anemia.
Bethany Weathersby:
So, we asked Dr. Moise what was the earliest disease that he has seen? Earliest fetal anemia?
Dr. Ken Moise:
So, we believe the antibodies begin to cross around 12 weeks. And the earliest anemia I've diagnosed, at least by MCA because it's almost impossible to get into a blood vessel at 15 weeks, is 15 weeks. I would say 15 weeks is probably the threshold of treatment and diagnosis.
Bethany Weathersby:
So, it is possible to treat fetal anemia earlier than 18 or 20 weeks?
Dr. Ken Moise:
Absolutely. I think you can do intra peritoneal transfusions before 20 weeks, for sure. We know that the standard intravascular transfusion before 22 weeks is about a 20% mortality. It's just a technical challenge to get a needle into a blood vessel that's the size of the needle. So, trying to avoid that and using intra peritoneal needle transfusion as a bridging therapy makes sense.
Molly Sherwood:
That's such an interesting visual to imagine.
Bethany Weathersby:
Right.
Molly Sherwood:
It's crazy.
Bethany Weathersby:
I was just thinking that. How is that possible that they... How? It's amazing.
Molly Sherwood:
And you know what else that he said very early on, as an aside, but I just want to throw it out there because it's a question we get a lot. He shares that we believe that antibodies cross the placenta beginning around 12 weeks. And that's something that I know you and I end up sharing with patients often because we often get this question about whether their antibodies caused an early miscarriage. I know both you and I have experienced early miscarriage before and so many women and mothers and hopeful mothers. And we believe and the research shows and what we know now that there's not a relationship with this condition in an early miscarriage. So, I just want to throw that out there because it reminded me when he said it.
Bethany Weathersby:
In a first trimester miscarriage.
Molly Sherwood:
In a first trimester miscarriage. Sorry.
Bethany Weathersby:
Okay.
Molly Sherwood:
Because we know that the antibodies are not crossing the placenta and not affecting the baby.
Bethany Weathersby:
Right.
Molly Sherwood:
So, back to the severe anemia. He's sharing about the risks of an early intra peritoneal transfusion. And so, thankfully what we're going to talk about is that there are some ways that have been demonstrated to delay the need for IUT, which just helps you be that much safer if you can manage to push it back so that you have a slightly bigger baby to do an IUT. So, those treatments are plasmapheresis and IVIG. So, here he is discussing those a little bit.
Dr. Ken Moise:
And if we go back, if the titer is really high, back at 10 to 12 weeks, we should be doing things like plasmapheresis or IVIG to gain some time. We know those techniques only buy time until we do the transfusions, but if we can get them past that 20, 22 week window, the likelihood of a successful procedure goes remarkably higher. So, we want to buy time. So, the right answer in the high titer, bad history patient is at 10 to 12 weeks, that's when we start plasmapheresis plus minus IVIG to try to get them to 20, 22 weeks and do that first transfusion and then we can stop those therapies.
Bethany Weathersby:
What is plasmapheresis and what is IVIG?
Dr. Ken Moise:
Plasmapheresis is not used that much, but it's a technique where you're put on a machine that separates your blood, takes out the liquid part of the blood, gives you back your red blood cells and your platelets and simply removes the plasma which contains the antibody. And so, after several procedures, your titer will drop dramatically, even in half or more, which is good. You have less antibody to cross to the baby. What we know is if we stop at that point, your body will say, wait a minute, you took away my antibody. Now I'm going to make even more. And the old literature would talk about a rebound phenomenon where the titer goes even higher. So, we usually always combine plasmapheresis with IVIG to quiet down the immune system so you don't get that rebound effect. And then we keep you on IVIG until the MCA dopplers show the baby is anemic.
Bethany Weathersby:
That was super interesting to hear about plasmapheresis especially. It sounds so crazy. Removing the liquid from your body and then taking the plasma out and then giving you your red blood cells back.
Molly Sherwood:
Sorcery.
Bethany Weathersby:
Yeah. Right. And I've had plasmapheresis with my surviving three babies and it was a big loud machine that my blood would go through and you can actually see it in this kind of tumbler thing, like a washing machine or something. And it separates the blood and the plasma and then this bag of plasma just fills up more and more and then they give you back your red blood cell portion of your blood.
Molly Sherwood:
Wow.
Bethany Weathersby:
It's crazy.
Molly Sherwood:
It's so interesting because as you were describing it, I was thinking that if this were around at the time of exorcisms, people totally would've used it as an exorcism device to take all of the bad stuff out.
Bethany Weathersby:
Right. That's what you're doing. That's what you're doing. You're taking the bad antibodies out. And the problem is our bodies are so good at keeping us safe from illness and disease. So we remake antibodies well and that's what he was talking about afterwards. Sometimes there's this rebound where your titer can go up again and that is what the IVIG is for after the plasmapheresis. It helps keep that titer down. And IVIG is intravenous immunoglobulin, which is a product made from thousands of people's antibodies concentrated into a liquid that's given through an IV. And it's not red cell antibodies like Kell or D. It's not that type so you don't have to worry about that. But that's given every week.
Molly Sherwood:
That's so interesting. So, is the idea... Well, maybe we don't know this, but is the idea that reintroducing other good antibodies will suppress our bodies' reaction of being like, whoa, I have no antibodies left, I need to make a bunch of new stuff?
Bethany Weathersby:
So, that's what I asked because my mind was blown when I first learned that. Because it worked so well for me. It worked to keep my baby safe. And they told me that it distracts your immune system. It's flooded with antibodies and so it's paying less attention to the baby. That's what I was told. I don't know if that's real.
Molly Sherwood:
I can buy that. That makes sense to me.
Bethany Weathersby:
When I asked Dr. Moise, just in our private session when I was his patient, I said, how does it actually keep my baby safe? And he said it works in one or more of these three ways, which is it suppresses the antibody and lowers the titer. Or it prevents the antibodies from going through the placenta and getting to the baby as well. Or it helps the baby fight off the antibodies that are attacking.
Molly Sherwood:
Wow.
Bethany Weathersby:
He was like, we don't know everything about it but we do know and the studies show that it can prevent or delay fetal anemia.
Molly Sherwood:
And the studies do show and we will talk about that and I know he will too. But maybe part of the confusion or the misconception is, like you're saying, the mechanism is not super well understood. But also we're talking about the rarest of the rare. Nobody can expect to see a beautiful huge study on the safety and effectiveness of this. But we do have some good studies and they've come to be recommended now in the clinical guidelines for this. So, you asked him about this previously. Why is there a little bit of controversy?
Bethany Weathersby:
There seems to be a lot of controversy surrounding those treatments, plasmapheresis and IVIG. I've been told that their experimental, insurance won't cover the cost, no evidence that they work, it's unnecessary and it's not an option unless your baby dies and then you can maybe use the treatments with your next baby. Why are we hearing those things?
Dr. Ken Moise:
I think until the Peditra was published just a few years ago, which was a group of us internationally got together and pulled our anecdotal experiences together and polled those and some sophisticated statistics were done to show that in fact it worked, particularly if you started earlier. That IVIG with a plus or minus plasmapheresis prolonged the pregnancy with a better outcome. So, the baby wasn't as anemic when you finally did do a transfusion and you did it four to six weeks later. I think that's the best data out there. But until we had that group of about, I think it's about 50 patients that we polled at many different international centers, there really wasn't a good paper with a lot of patients to point to it.
Dr. Ken Moise:
But most people don't recognize that paper. But I think it is a sentinel paper to say that there is merit to this treatment in the severe disease. And I've not had a problem when I provide these papers to insurance companies to get coverage. Even though IVIG's incredibly expensive, I've always been able to get it covered. We usually attach the paper with a cover letter and we've been able to talk to the medical director and get it covered.
Molly Sherwood:
That's a great nugget too about submitting for insurance coverage because I know a lot patients ask us about that. So, that's good to know. So we'll definitely link to that study in the show notes.
Bethany Weathersby:
Also, I just wanted to say, and also it's helpful if they can print that study off and take it to their MFM.
Molly Sherwood:
Oh, totally.
Bethany Weathersby:
To discuss these treatments with their doctor because, like you said, it's so rare to even need these that a lot of doctors have not used them.
Molly Sherwood:
Sure.
Bethany Weathersby:
And so, bringing in the actual study to discuss it with your MFM is such a great idea.
Molly Sherwood:
I want to talk about the PETIT. How does he say it?
Bethany Weathersby:
He says PETIT.
Molly Sherwood:
PETIT. P-E-T-I-T. It's in caps. PETIT study. And then also I was going to talk about, there's a 2007 paper that I think is a great resource that you originally used because you said this is the paper you said you kept in your pocket for the [inaudible 00:16:36] of hope.
Bethany Weathersby:
I did. I read it over and over again. It gave me so much hope.
Molly Sherwood:
I hope I can do it justice then by trying to talk about that.
Bethany Weathersby:
It sounds so nerdy. Doesn't that sound nerdy?
Molly Sherwood:
It's so nerdy. Totally nerdy. I love it though. Love the nerdiness. At least I know if this is boring, you'll at least like it, what I have to say about this paper.
Bethany Weathersby:
Oh no, I'm into it. I'm so into it.
Molly Sherwood:
So, I looked up the PETIT study to just share about it and of course his memory is perfectly accurate. So, what makes the study so awesome is that they collaborated across 12 fetal centers in four countries. There's a bunch of authors on this paper.
Bethany Weathersby:
Wow.
Molly Sherwood:
And they had a intervention and a control group, which is really hard to do in obstetrics, in rare disease. This whole constellation of things has to happen to build a study like this.
Molly Sherwood:
So, they had a group of 24 women who received IVIG and then a matched control group of 28 women. And matched control just means that you selected to make the group as comparable as possible as your treatment group so that when you compare the two, you can hope that there aren't other things confounding the results. And one thing that I love about this study that is so cool, they actually stacked the odds against themselves in their IVIG group. They selected actually women with historically more severe disease than the control group. These women had experienced more fetal death. Their anemia in their previous pregnancies, sorry. Their babies' anemia in their previous pregnancies occurred on average of three weeks earlier than the control group even.
Bethany Weathersby:
Wow. Okay.
Molly Sherwood:
And these women in the IVIG group had an average of five IUTs in their previous pregnancies.
Bethany Weathersby:
Oh my goodness.
Molly Sherwood:
And the control group was four. So, of course, all the women in this study have had severe disease already in the past. But the treatment group that received IVIG had even worse of a hand to be dealt.
Molly Sherwood:
So, what they found was that only one of the IVIG pregnancies did the baby develop high drops. Whereas six of the non-IVIG fetuses did, which is great. And also the after birth exchange transfusion rate was significantly lower for the babies in the IVIG group, which they weren't really expecting these findings. Because what we talked about was the goal is to just delay treatment, it's not to just absolve any issues entirely. We know that's unlikely. But they found these results, which is so encouraging.
Bethany Weathersby:
Wow.
Molly Sherwood:
And then they also saw, as an aside, they did an assessment additionally of women who had received their IVIG prior to 13 weeks gestation, starting at that earlier time. And the anemia started to develop on average of 25 days later in those pregnancies than in their previous pregnancy. So, they did find in that paper the importance of starting IVIG earlier.
Bethany Weathersby:
That's what we did with mine. But we can talk about that later. But, yeah. So, the goal was to be there first before the antibodies and get that IVIG going before the baby becomes anemic. And that was really helpful.
Molly Sherwood:
That's a great visual. Get there first. Get ahead of it.
Molly Sherwood:
And then before that study came out, because it's a pretty new study, then we talked about the 2007 paper, the Ruma et al paper, and that's the one that you kept in your pocket. And so that one...
Bethany Weathersby:
Yes.
Molly Sherwood:
You already know it like the back of your hand. So maybe you should be saying this.
Bethany Weathersby:
I do. No, no. You are the research queen.
Molly Sherwood:
That study was on nine women. So, fewer women. Seven of them had a loss in the past from this condition and two of them had super high titers. So, these fetuses received IVIG and plasmapheresis treatment. All of them survived. They all required IUTs, but it was delayed. And the mean age at delivery was 34 weeks, which is wonderful for a disease this severe. And titers were significantly reduced after plasmapheresis and then stayed that way as they continued with IVIG therapy.
Molly Sherwood:
So, I understand why you kept that in your back pocket, it's very encouraging.
Bethany Weathersby:
Yes. It really was. Because we had been told we could not have any surviving babies if they had Josh's blood type, which of course, they all happened to have his blood type.
Molly Sherwood:
Of course.
Bethany Weathersby:
But this just gave me so much hope and also direction for where to go. Because we were like, how can we possibly have the family that we really wanted? And this was like, well, these people did it this way and it worked great.
Molly Sherwood:
Yeah.
Bethany Weathersby:
And that led me to reach out to Dr. Moise and that's where it all started.
Molly Sherwood:
Now, I do want to know though about the actual experience you have. What are the side effects of the treatments if you get them?
Bethany Weathersby:
Yes. So, first of all, I did want to say that in my case, it was even better. I don't know if that's because there was plasmapheresis combined with IVIG. So, Lucy, my first sensitized pregnancy, my first baby with HDFN, she was severely anemic at 17 weeks. So, her hematocrit was six and her MOM was 2.5 at 17 weeks.
Molly Sherwood:
Which is just unheard of. Crazy.
Bethany Weathersby:
Right. So, you can imagine that the anemia was there much earlier than that, affecting her earlier. And then she died at 19 weeks. So, then Nora, my next baby, she did not become anemic until 24 weeks. So, compared to 17, that's a big difference. And she wasn't that anemic. Her MOM was 1.55, I think, and her hematocrit was 26 as compared to Lucy's 6.
Bethany Weathersby:
So, you can just see what a difference it made. And then also the boys who came after Nora, same thing. They needed their first IUT at 28 weeks and then 25 weeks.
Molly Sherwood:
That's amazing.
Bethany Weathersby:
I know. So, I just wanted to give that little input.
Molly Sherwood:
I'm glad you said that.
Bethany Weathersby:
So, the side effects. There weren't that many side effects for me with the plasmapheresis. It was just, pun is not intended here, but it was just kind of draining.
Molly Sherwood:
Oh my God. That's so good. How did that not make it into our notes for this?
Bethany Weathersby:
I don't know.
Molly Sherwood:
What if you hadn't given that joke. I'd have been so sad.
Bethany Weathersby:
I just can't think of any better word to describe how I felt afterwards. So, literally felt drained. And that's because other important things are found in your plasma, like calcium or certain blood clotting factors. And so, those are removed with the antibodies.
Bethany Weathersby:
Anyway. But the nurse doing the plasmapheresis will monitor your calcium level and your blood clotting factors and all of that. And then just give you a supplement or an IV if you need more.
Bethany Weathersby:
So, anyway. No worries about that. But it was just kind of draining. And then of course, you have to have a permacath for the plasmapheresis, which is... It's this big double lumen, kind of like a port, but it's coming out of your skin. And then you can hook two tubes up to it. And so, that's how they pull the blood out and then push the blood back in at the same time.
Molly Sherwood:
And I remember seeing pictures of yours. Is it always up kind of in your, I don't know, under your clavicle?
Bethany Weathersby:
So, it was literally in your jugular. And the tube goes down to the opening of your heart, actually. I remember the surgeon telling me that right before he put it in and I was thinking [inaudible 00:23:14].
Molly Sherwood:
Could you wait until after, please?
Bethany Weathersby:
Yeah.
Molly Sherwood:
After.
Bethany Weathersby:
Right. For me, that was really painful and really just irritating, this thing dangling out of your jugular. And I hated that. I hated it so much. I do think some women have been able to do... I feel like one had it in her arm, but it's called something else and my brain's not super good right now. So, that was the only side effects of the plasmapheresis.
Bethany Weathersby:
And then IVIG had a lot more side effects for me. And most women do have some type of side effects from IVIG. I felt like I had a horrible flu, debilitating migraines, exhaustion, weakness, nausea and vomiting, muscle pain, skin rash. And then of course, I had a port which is also in your jugular, but it's under the skin so they can access it to do the IVIG every week. And that was also not fun or pleasant to have inserted in my body. It was just uncomfortable.
Bethany Weathersby:
But I will also say that it's totally worth it. All of this... I felt, during the treatments, I felt so good because I could do something to keep my baby safe. And it just felt like this is actually easier than how it was with Lucy where we were just waiting around not doing anything and she was getting so sick and then she died.
Molly Sherwood:
Sure.
Bethany Weathersby:
But there are things to help with the side effects. For the IVIG, they should give a pre-med before the infusion of, I think it's Benadryl, to prevent reactions and then Tylenol and there are certain medications to help with your migraines if that happens and nausea. So, yes. Always just ask your doctor what your options are for treating these side effects if they become really debilitating.
Bethany Weathersby:
And then also when you're having that IVIG infusion, really drink a lot of water. A lot of fluids helps. And also the slower they run the infusion, usually the fewer side effects the patient has. And I've seen a lot of women say that's how it went for them. And that certainly was how it was for me. If they ran it too fast, I had terrible side effects afterwards.
Molly Sherwood:
So, what's too fast and what's ideal, do you feel like?
Bethany Weathersby:
I can't remember. I can't remember the rate.
Molly Sherwood:
Yeah.
Bethany Weathersby:
And it's different for every patient, but I know that...
Molly Sherwood:
Or just the total number, the amount of time you were sitting there.
Bethany Weathersby:
So, for me, it was almost an eight hour infusion.
Molly Sherwood:
Wow. Okay.
Bethany Weathersby:
But I was able to have a home care nurse come to my house and do the infusion at home once a week. So, that was really, really helpful.
Molly Sherwood:
That is super helpful. And I guess maybe sometimes it goes more quickly if people are at an infusion center and it's typical to try to turn patients over quickly. So, you probably do have to be vocal if you are looking for something slowly, just to make sure.
Bethany Weathersby:
Yes. For sure.
Molly Sherwood:
So, I want to know in reality what a treatment plan looks like. Caveat being, of course, you and I cannot create a person's treatment plan.
Bethany Weathersby:
Right.
Molly Sherwood:
We can't tell somebody that this is right for them, but just an idea of something to picture and then patients and practitioners will work together to decide if something like this is appropriate.
Bethany Weathersby:
So, for me, and Dr. Moise and Dr. Trevett, they're at different centers. They are in different states, but they both followed this plan. So, this is what we did for my three surviving babies. We started very early in the pregnancy with just a regular ultrasound to, first of all, make sure the baby had a heartbeat and was growing appropriately. And then they could get a really accurate due date from that scan. Those early scans provide the most accurate due date.
Bethany Weathersby:
So, all of these treatments, the timing of them is super important and the timing is based on your estimated due date. So, that was really important, that early dating scan. I think it was between five and eight weeks or something.
Bethany Weathersby:
And then that's when we would set up the treatments too around that time. And then usually I had the permacath and/or the port surgically placed around 9 or 10 weeks. And then we started the plasmapheresis treatments. So, that's just three plasmapheresis treatments every other day. So, it's for instance, Monday, Wednesday, Friday. And then right after that Friday plasmapheresis treatment, the very next day, we start the IVIG infusion. And the first one is called a loading dose and they do two actually. So, they'll do it on that Saturday and then another one on Sunday.
Molly Sherwood:
Okay.
Bethany Weathersby:
And after that, it's just IVIG once every week. The dose for that IVIG was one gram per kilogram of weight. So, it is based on the patient's weight.
Molly Sherwood:
Okay. And then you do those until the baby requires their first IUT?
Bethany Weathersby:
Yes. That is the plan that we followed. I know that some doctors... I think the old way to do it was to stop the IVIG once they got to, I don't know, 20 weeks or viability around 24 weeks. But my doctors said it was much safer to do the IVIG treatments than in IUT, if possible. So, we did the IVIG every week until that first IUT was needed and then we stopped the IVIG and then just treated with IUTs until delivery.
Bethany Weathersby:
But I have seen several patients do IVIG their entire pregnancy and never need an IUT. They do it all the way to delivery.
Molly Sherwood:
Wow.
Bethany Weathersby:
It's amazing.
Molly Sherwood:
That is amazing.
Bethany Weathersby:
Yeah.
Molly Sherwood:
So, I'm thinking back. So, you're saying just three plasmapheresis treatments in one week, early on, around 10 weeks of your pregnancy.
Bethany Weathersby:
Yeah.
Molly Sherwood:
Right? A Monday, Wednesday, Friday thing. Then you're loading dose back to back IVIG starting that weekend. Couple days later.
Bethany Weathersby:
Yes.
Molly Sherwood:
Right.
Bethany Weathersby:
Well, the day after the plasmapheresis.
Molly Sherwood:
The day after the last plasmapheresis.
Bethany Weathersby:
Yeah.
Molly Sherwood:
Then weekly IVIG thereafter. And in your experience, maybe until the first IUT, but you've seen some variation there.
Bethany Weathersby:
Yes. And then I will say that with Dr. Trevett, with my last two babies, we saw that their MOMs were starting to rise around I think 18 weeks. And my titer had gone up some, so he actually did another three rounds of plasmapheresis to bring it back down. And it worked with both of them. It brought down the MOM and the titer and then they went a while until they needed that first IUT.
Bethany Weathersby:
So, every doctor... Your own doctor should tailor it to your case. But that's what we did and that's what their typical treatment is, Dr. Moise and Dr. Trevett.
Molly Sherwood:
That's so interesting. It's really like an art.
Bethany Weathersby:
It is. Yes.
Molly Sherwood:
Just to map it out and find what's right.
Bethany Weathersby:
And I do want to say that Dr. Moise and Dr. Trevett are always open to speak with other MFMs about these treatments and answer any questions that your doctor has regardless of where you are currently in the world. They speak to doctors all over the world and answer any questions that they have. So, a lot of patients just share Dr. Moise's email with their MFM and then ask them to discuss it with him and that can be really helpful, I think.
Molly Sherwood:
Yeah. That is super helpful. And maybe we should link... We could at least link to our medical advisory board page, which they're both on and people can find out how to contact them, should they want to.
Bethany Weathersby:
That's a good idea.
Molly Sherwood:
Okay, we'll do that.
Molly Sherwood:
All right. One more preventative treatment that's used in a different way that I wanted to touch on briefly is phenobarbital. And I have not had it, so I'm just going to try to describe it and you can tell me if this is right. So, the idea is this medication is given to the mother several days before delivery. It helps the baby better metabolize high bilirubin after birth. And Dr. Trevett published a study with Dr. Moise talking about the efficacy of phenobarbital, which I took a look at and I will talk about it. But first I want to hear what Dr. Trevett has to say about using phenobarbital in pregnancy.
Dr. Thomas Trevett:
We found back in 2004, based on the experience that Dr. Ken Moise had in his prior patients, that giving a medication called phenobarbital in the last week of the pregnancy to the mom is able to decrease the likelihood of severe complications related to the high bilirubin levels that almost all babies who get transfusions in utero end up having after birth. So, we know that there's a very high turnover rate of the blood cells that are given during the transfusion. And by turnover rate, I mean they break down very easily in the baby's bloodstream both after transfusion and after birth. And so, what that results in is a very high level of the breakdown products of the red blood cell, which is called bilirubin. And high levels of bilirubin can build up in the baby's system and cause significant problems for the baby's early brain development.
Dr. Thomas Trevett:
And many times, if that happens, they have to go on bilirubin therapy, which is essentially putting them under lights which help get rid of the bilirubin from their system. And in the worst case scenario, they have to actually have something called an exchange transfusion, which is similar to plasmapheresis, but they're extracting the bilirubin from the baby's blood.
Dr. Thomas Trevett:
What we've found is giving phenobarbital in that last week of pregnancy crosses into mom's system and then crosses into the baby's system and it stimulates the baby's liver to improve its ability to deal with the high levels of bilirubin.
Molly Sherwood:
Okay. So, what he's talking about is when a baby's red blood cells are actively being broken down, which is what's happening with this disease, a byproduct of that breakdown is bilirubin. And so, that's why a lot of our babies after birth have high bilirubin and need to be under lights or need exchange transfusions or top up transfusions after birth. And so, the idea which he demonstrated in his study, which we'll also link to, is to give the moms oral phenobarbital, they did 30 milligrams three times a day, after their last IUT to help strengthen the baby's liver function to help them metabolize the extra bilirubin.
Molly Sherwood:
And so, in his study, it was a retrospective study, meaning he was looking back at medical records over time to see what happened. And so, this study was over the course of between 1985 and 2003.
Bethany Weathersby:
Whoa.
Molly Sherwood:
So, he looked at 30 years of data and came up with 71 patients in this study, which again goes to show how rare this is. You have to look at enormous hospital systems data for 30 years to find 71 patients. Anyway.
Molly Sherwood:
So, he separated it into two groups, those who had received oral phenobarbital and those who had not. And so, those who had received phenobarbital antenatally, meaning when you're still in the mother's stomach, was associated with a decreased rate of exchange transfusion. So, only 9% of the babies whose moms had taken phenobarbital before birth needed an exchange transfusion after birth versus 52% in those who had not.
Bethany Weathersby:
Wow.
Molly Sherwood:
That is pretty significant difference.
Bethany Weathersby:
That's huge.
Molly Sherwood:
I know. Such a good study.
Bethany Weathersby:
Yeah. So I, again, have personal experience with this drug and my three youngest babies all had HDFN and only two of them had the phenobarbital.
Bethany Weathersby:
So, with Nora, with my pregnancy with Dr. Moise, we did 10 days of phenobarbital leading up to delivery and she had no issues with high bilirubin after birth. She was born at 38 weeks, so that also helps the baby. The further along the baby is, the better developed their liver is. So, I know that helped her as well.
Bethany Weathersby:
But she had five IUTs and no bilirubin issues after birth. And of course, we monitored closely for the whole week after birth, but she was able to avoid NICU time and she came home from the hospital in my arms two days after birth. So, that was amazing.
Bethany Weathersby:
And then my last baby, August, and that was being treated by Dr. Trevett, we did the 10 days of phenobarbital leading up to the delivery. And he was born at 37 weeks and one day. He had seven IUTs and again was able to avoid the NICU and he did need, I think, two days of lights. But his bilirubin never got super high, so that was wonderful.
Bethany Weathersby:
And my middle son, between those two, Callum, we did not get to do the phenobarbital because he was born by emergency C-section right before an IUT. So, he was born at 34 weeks and did not have the phenobarbital and really struggled with high bilirubin. He had a transfusion right after birth. He had full bili lights, the phototherapy, right after birth. And his bilirubin levels were still very high. So, then they did IVIG to treat that high bilirubin and all of that combined.
Molly Sherwood:
IVIG in him, which is different.
Bethany Weathersby:
Yes. Yes.
Molly Sherwood:
We need to talk about that in another episode, for sure.
Bethany Weathersby:
Yes, for sure. Yeah. All of those things were needed to keep his bilirubin below brain damage levels. And several days. He had three days of IVIG and even more phototherapy. So, in my case, the phenobarbital really seemed to help the babies need less intervention after birth.
Bethany Weathersby:
One of the main questions I had for my doctors when they suggested taking phenobarbital was, well, what are the risks? It's always good to weigh the benefit versus the risk of anything that we do treatment wise. So, I asked Dr. Trevett that during our interview and so let's listen to that clip right now.
Dr. Thomas Trevett:
What I always tell my patients is that once they start on the phenobarbital, they should probably be very cautious about driving because phenobarbital is a sedative. It was used historically as an anti-seizure medication because it is a sedative, a neurologic depressant similar to alcohol. It doesn't have the properties of the dangerous effects of alcohol, but it has a similar effect on the central nervous system as a slight depressant. And it makes people a little bit sleepy. So, I always tell people, you really have to be careful because some people do get very sleepy on this medication. Most women do not. But there aren't any other real serious side effects of using the phenobarbital.
Bethany Weathersby:
Great. Good to know. So, just watch for feeling a little sedated or tired for the pregnant woman. But that was always reassuring to me that in his opinion, there weren't major risks for the baby. Definitely talk to your doctor about the possibility of using phenobarbital if you are interested.
Bethany Weathersby:
And there is one last preventative treatment I want to just touch on really quickly. And it's currently in the trial phase, so we can't make any statements for sure yet on what it does or if it works. But just wanted to let you know that this is in the trial phase and it's Janssen Pharmaceuticals. Currently, it's in the phase two trial being tested on alloimmunized women with severe disease. And the drug is called M281 or nipocalimab. And it was created to block the transmission of the maternal antibodies during pregnancy from going through the placenta to the baby and also to reduce the amount of maternal antibodies in general.
Bethany Weathersby:
So, the trials are testing to see if it's safe and to see if it works right now. So, we will definitely keep everyone updated on those trials. And I do know that there will be a phase three trial coming up soon. So, we will also try to include a link to that study.
Bethany Weathersby:
So, if you do have severe disease and are interested in possibly participating in this trial, then definitely check out the link and then also talk to your MFM about it.
Molly Sherwood:
So, how do we wrap this up? This is a lot. It's so hard.
Bethany Weathersby:
It is a lot.
Molly Sherwood:
Because there's so much to talk about, but we just want everyone to know so that they can triage and work through it and figure out what might be right for them.
Molly Sherwood:
So, okay. We're talking about severe disease here, which is loosely defined as requiring an IUT in your early second trimester. So, how do you know if you might be one of these people? Usually the criteria might be if you've already had a loss due to alloimmunization in the past or had a pregnancy that required IUTs early on. And also, if you've had a very high titer and you know your baby has the antigen, you may develop severe disease. You may not, but you may. And so, a high titer is also especially important for anti-Kell, but also anti-C and anti-D have [inaudible 00:38:16] demonstrated. I think the three of them are the most likely to result in severe disease.
Molly Sherwood:
So, in our treatment algorithm, we consider somebody a candidate for IVIG, of course, they have to work with their doctor and think through their specific case, if they've had a previous fetal death, if they've had an IUT in the past at sooner than 24 weeks or with a titer that's 256 or higher. So, that's just something to consider when you're trying to frame how applicable these things are.
Bethany Weathersby:
Right. I do want to point out really quickly.
Molly Sherwood:
Yeah.
Bethany Weathersby:
I think you said if you know the baby has the antigen. And I wanted to say that a lot of times you don't know if your baby is antigen positive or negative, so you have to start these treatments before you can know. Unless the baby's father is homozygous.
Molly Sherwood:
Right.
Bethany Weathersby:
Then you will know the baby definitely has the antigen, but in my case, my husband is heterozygous, so each baby had a 50-50 chance of having the Kell antigen. So, the earliest we could find that out was 14, 15 weeks through the cell free fetal DNA test. And these treatments have to start... We started them around 10, 11 weeks and the studies say they work better if IVIG has started earlier than 13 weeks.
Bethany Weathersby:
So, yes, this also is for people with heterozygous, I guess, partners or baby's daddy is heterozygous.
Molly Sherwood:
That's a great clarification. Right. Because sadly, at the time, if you need to make the decision about this early intervention, early preventative treatment, you may not know if the baby's antigen positive.
Bethany Weathersby:
Right. But you can always start the treatments and then when you find out if baby is negative, just stop the treatments.
Molly Sherwood:
Right. Okay. Yeah. That's a great caveat. I'm glad you said that. And also, it's tricky because a lot of times, women find out they have antibodies and they are not seen by their high risk doctor until they're 18 weeks, which is common and okay if you have very low titers, but it is important right away to figure out, at the very least, your titer so you make this assessment in time.
Bethany Weathersby:
Yes. And that's a simple blood test that your midwife or your OB can do easily.
Molly Sherwood:
Tell us about some tips for entering a pregnancy like this.
Bethany Weathersby:
So, if you've had a history of, like we said, severe disease and you are thinking about another pregnancy, it's great to set up a preconception appointment with your MFM to discuss all of this. Go in with all of your questions written down, every question you could think of. And ask him or her all of the questions, write down or record the answers, and then come up with a treatment plan that you and your MFM feel comfortable with. And I did that before each of these last three pregnancies and it just gave us confidence to move forward. We felt really good about the plan. It's super helpful.
Bethany Weathersby:
And then also, if your MFM is not on board with these treatments, it's good to know that before you get pregnant again. And if you want to, we say shop around, that's great. See different doctors and just find the right fit for you and your pregnancy.
Bethany Weathersby:
Then once you're pregnant, get started scheduling these treatments as soon as possible because the insurance approval timeline is insane. It just takes, usually, takes a really long time to get this approved by insurance. So, again, the timing is important. When you start these treatments is very important. So, that's why you should just get started as early as possible getting the treatments set up and getting them approved by insurance.
Bethany Weathersby:
And then again, like Dr. Moise mentioned, this can be hard sometimes to get it approved by your insurance, especially the IVIG, which is very expensive. But if they deny coverage, just go back again, submit again, ask your MFM for help. And a lot of times the MFM just has to bring in the right info and the right studies, like Dr. Moise said, to get it covered.
Bethany Weathersby:
So, all three of my babies, all three times, we were denied coverage and we have really good insurance specifically for pregnancy issues. And we were denied every time and had to go back several times until they were all approved.
Molly Sherwood:
What are some of the things that you've said that you feel [inaudible 00:42:08] get that coverage eventually.
Bethany Weathersby:
Right, actually... So, my doctors were communicating with the insurance company and then I had to call many times and just explain my baby's life depends on these treatments. And then again, my baby's life depends on the timing of these treatments. I need this to be rush order. We need to get this through. Again, also asking the person for their names. Okay, what's your name? Writing it down so that later if something doesn't match up or somebody has a question about that conversation, you can say, no, I talked to Jimmy on this day and he said this. And that's really helpful.
Bethany Weathersby:
So, yes, those are some of the things I said. And then also I wanted to say that it is harder for women in the UK to have these treatments approved, but I do know women who had their IVIG treatments approved by the NHS and were covered and worked beautifully in each case.
Bethany Weathersby:
I also want to add that women with extremely high titers and aggressive antibodies can have healthy babies and multiple pregnancies in most cases. So, please don't be discouraged. If you do have severe disease, I want you to feel hopeful and know what to do in order to have a healthy baby. And the main thing is finding the right team of doctors and having the right treatments.
Molly Sherwood:
I hope any practitioners listening to this also find this super helpful.
Bethany Weathersby:
Yeah.
Molly Sherwood:
And I know that they have a lot of resources at their fingertips too.
Bethany Weathersby:
Yes.
Molly Sherwood:
And also, it feels like an appropriate podcast topic to touch on something that I know you and I care about a lot, which is the extreme psychosocial, just mental health burden that women go through. Just even thinking about everything that you're talking about, having gone through, coordinating so much, managing insurance, so many visits to the doctor, having a permacath, dealing with side effects. It can be really crushing. And also, even the labor that goes into learning about these things and advocating. It's very common in rare disease that the patient has to take it into their own hands and work collaboratively with their care team because not every doctor can be expected to know about these obscure things, but then that burden is on the patient and it unfortunately has to be that way sometimes. And that's a big deal. It's really hard.
Molly Sherwood:
And we see that and we see it all the time in our patients, and I wish we could take it away, but at least, hopefully our listeners know that they're not alone. And also, you know what's interesting is that a lot of these women who have become alloimmunized have already been through a lot. Usually, you've already been pregnant before or you've had an occasion where you've needed a transfusion. Maybe you've had a miscarriage or a traumatic birth or a C-section. There's so many things that make somebody more likely to be alloimmunized to begin with, that it sort of selects for women who have already been through a lot. So, it's just a big deal. It's a lot to go through. And even though it's so hard, there's a group of women in this world who are doing it too. And we see you and all of the feelings you might have about this are valid and real and we know this is hard.
Bethany Weathersby:
Great point. Really glad that you brought that up. And it's so true. It's really hard and these patients are not alone. So, we hope that this can give you a bit more clarity about severe disease so you can feel confident when discussing your care plan.
Bethany Weathersby:
If you, your partner, or someone close to you is experiencing HDFN, we are here for you. We have a great resource library on our website at Allohopefoundation.org. That's Allo spelled A-L-L-O hopefoundation.org.
Molly Sherwood:
Thanks for listening.
Molly Sherwood:
The Allo Podcast is a production of the Allo Hope Foundation. It was researched and written by Bethany Weathersby and me, Molly Sherwood. It is produced and edited by CJ Housh and Eric Hurst of Media Club. The Allo Podcast is sponsored by Janssen Pharmaceutical companies of Johnson & Johnson.