Fetal Surgical Intervention for Myelomeningocele: Fetal Surgery 2012

You and I think um I, I think I would tend to agree with giving steroids in in large uh predominantly microsystem. That aren't hydraulic. Well, I think the proof is the fact that there's been just in all these places just 1 or 2 or 3. Uh, fetal surgical resections for CCAs in the last 5 years. So the horses out of the barn, steroids are effective, but there's no need to do a trial. Well, I, we, before we started giving steroids a lot, we had also reduced how many of these we were doing just by waiting until we saw cardiac changes. But I agree, I think the risk of giving steroids is so low that, uh, and the potential benefit is so high that it's going to be hard to make a case to randomize patients, especially if it could be beneficial. You any comments from the studio or anyone out there who have Melanie, do you have a comment or no? Well, my main question is, um, with the counseling, with informed consent, when you don't have a randomized trial, how much, how, what is entailed in the counseling? How much, how much informed consent can these families really get prior to these procedures? Well, I think all you can do with non-directive, uh, informed. Uh, counseling is to give them the, the facts of your experience and OK. What, uh, you have to offer. I, I don't, you know, this is not an endeavor where you have 1000 patients and that you can do, You can base all of your counseling on randomized trials with the exception of perhaps the myelo meningocele experience. So, we counsel patients, I think, uh, we spend a huge amount of time doing it and we counsel them as accurately as we can, uh, regarding the risks, the benefits, and the outcomes that we've had up to, up to that point. And then, you know, it's, it's their decision to make. I think gestational age plays an important part in this too, because a lot of the work that Tim and we've carried on looking at the growth pattern of these tumors is that they tend to kind of plateau and stop growing between 24 and 26 weeks. So, you know, if you have, uh, uh, a tumor that's, you know, rapidly growing by watching the CVR carefully. You know that's going to be an aggressive tumor, and if you treat it before 24 weeks, and they stop growing, that, that's pretty convincing. You know, evidence to me that the steroids have had a pretty significant effect, and that's what we've seen in a large number of cases. Now, if you give steroids after 26 weeks, how do you differentiate that the steroids had the impact versus the natural physiology of these tumors that tend to plateau between 24 and 26 weeks. So, I think gestational age plays a role in all of this as well. I really agree with that, and that's been what we've struggled with many times. I agree that if you see someone or a fetus at about 23 weeks, just like the case Alan presented, I think it makes every sense to give up steroids. When you see them at 23, 24 weeks, or, or, or rather 25, 26, 27 weeks, and the CVR is just about, you know, 2.5, and, and you think they're really getting to that point and there's no evidence of cardiac dysfunction. That's the group that we have watched closely in the past, even without steroids. But right now, again, as has been said by others, by the time they get to us, they've gotten steroids already, you know, anyway, because the word is already out. There was a question from your group, I think, about the timing of the second dose of steroids. Um, No, Mark. I think you, you know, you have to look for a response. So, if you give a, a two course, you know, of betamethasone and a week later, the tumor has continued to grow, um, I think that, that would be reason enough to try a second dose. Um, I don't know what the other groups think. Some people say you should wait two weeks, but if you have a 2.5 CVR tumor and it's continuing to grow, uh, how long do you wait before the second course? UCSF got an opinion. You usually have an opinion about everything. Well, Hanman and Chin give you something. Yeah, 1 to 2 weeks seems reasonable. That's usually what we do, you know, we always, it's always a matter of debate at our meetings, but, you know, that's generally the time course for us. Yeah, and what's the most, uh, what's the, how many, uh, doses of steroids are folks willing to give? This is uh usually a battle between perinatologists and surgeons. Well, I think if you, I think if you've given two courses and the tumor continues to grow, it's a non-responsive tumor. And at that point, I think you have to do something more definitive. I think that's right, Mark. Have we ever given? Yeah, in fact, we just gave more to this last one. We have a patient that just delivered a fetus at, uh, 31 weeks by a C-section because, um, uh, the, the fetus had a, oops, had a, um, uh, C chem with a CVR of almost 4 that didn't respond to 2 rounds, and actually a, a third round of steroids. What just happened there? Looks like it's abandoned ship, abandoned ship. Come back here, Mike. We're hearing voice only. All right. So, we, we beat steroids, uh, pretty well here. Um, so, what about, what about the, uh, you know, I gave sort of the overview there and I mentioned some indications for open fetal intervention. Um, are there other things we should be doing? Uh, you know, we've had that list for a long time. Uh, we really haven't expanded upon it. Things like, uh, fetal intervention for obstructive neuropathy, fetal intervention for, uh, uh, hydrocephalus. You know, are there. Anatomic, uh, anomalies that would be better treated than they currently are by. Open fetal surgery or other approaches. Well, while the thoughts still, still hot, I, I wanted to ask Shin how, uh, how they, they managed that last CCA fetus at 31 weeks gestation. Was it via an exit to CAM resection? Um, we gave it, we gave it a lot of thought. This mom actually was a non-responder. We offered her, uh, open fetal surgery, and she actually declined, um, and then, uh, ended up being admitted at about 28 weeks for painful contractions. Um, we had discussed an exit, and with the group, really the, the thought was that, um, we would offer it, uh, if the baby made it to about 32 weeks. Um, and unfortunately, the mom ended up having a, um, Ruptured membranes and, uh, um, the OB team was concerned about her painful contractions. She has a previous C-section, so they didn't want her to labor too much. They weren't interested in doing a, a VBAC. So she ended up having a C-section last night. I was at the bedside, um, when she, uh, delivered, and then in the delivery room so that we could do a decompressive thoracotomy if needed. So how's the kid doing? Doing OK, actually, um, intubated on about 50%, um, gas exchange is pretty good, but I'm planning on taking it out, um, pretty soon, depending on how the baby does. That's interesting for a CPR of 4. It calls into question then when should we be doing an exit if a kid with a CVR of 4 is doing fine after a C-section. We, we've never done one here, um, you know, since I've been here, but. Um, You know, I don't recall any of our kids, um, you know, we, we would take the quick kids quickly to the OR, but we haven't required an exit to an eCO, um, or resection or resection. I think it's very hard to predict which kids will benefit from an exit procedure. Uh, I don't think there are clear CVR criteria or otherwise. Uh, I think there are certainly differences in CPAP tumors. Some are very firm and, uh, you know, uh, noncompressible, and I think those kinds of tumors, if, uh, you have massive mediastinal shift and contralateral lung compression will need emergency decompression or you can't ventilate. That just makes sense. And, so, the, I think there are some kids that clearly need an exit procedure, will benefit from an exit procedure. We've had a number of them at CHOPP that we've done exit procedures and thought that, uh, they were fully justified in having that, and it was the safest, most controlled way to manage their delivery. We've done others at CHOP that I think probably, uh, could have easily been ventilated, you know, without the exit procedure, because the, the, uh, CPAPs were more compressible. The, uh, contralateral lung was able to be ventilated. So, I think it's very hard to predict. Um, and I think it's probably been overutilized in the past somewhat. On the other hand, I think, uh, You know, if you have marked mediastinal shift, contralateral lung compression, I think, uh, you know, to err on the safe side, we would still recommend an exit procedure. That has been our practice here in Houston as well. And, and just in addition to some of the cystic lesions we've actually seen, you know, those that we've done a trial of ventilation at the time of exit, and you can actually see the massive expansion of the mass once it's been exteriorized again, just to prove the point. So I think, you know, it's to make that call, but we also believe that the safest approach in, in some of those cases is the exit to resection. Um, we can go, we can come back to these, but I wanna get to questions from the audience. Uh, Doctor Radhakrishnan from Bangalore, India has a question regarding your experience with continence in your SCT, your fetal, uh, surgery SCT patient. It's actually been very good. Now, we've had, uh, I think we've had, we're actually trying to write this up now. We've had, uh, at least 7 patients in our experience that have had, uh, urogenital anomalies related to probably developmental compression from the SCT. These are sort of atypical cloacal anomalies. We've had a urethral, um, uh, atresia. We've had a number of significant, uh, urinary, uh, malformations associated with massive SCTs. Um, Aside from that, uh, the kids have had very good interectal continence, and, uh, most of them have had good urinary continence as well, and we, we, uh, Uh, get formal urologic consultation on all the kids and we do, uh, follow up with ultrasonography of the bladders and various other urologic testing. And so, Uh, I think, as a rule, type one SCTs, um, can be expected to have good anorectal function. Type two and three SCTs are the ones where you get pelvic outlet compressions and sometimes associated urogenital anomalies and secondary, uh, dysfunction. You can obviously have obstructive neuropathy related to an SCT with neurogenic bladder, uh, if you have, you know, a, a severe, Uh, form of that. So, so, with those exceptions, other than those exceptions, I think you can expect to have good anorectal function. And urologic function. Anyone else have experience with that? We reported our experience uh with a fairly large series of SCTs, many of whom had undergone fetal surgery, not many, excuse me, some of whom. And in addition to everything that that Alan had mentioned, the type 2 and the type 3s are also at risk for acute renal injury, um, and many of these, uh, uh, uh, now children are having chronic renal insufficiency from injury that occurred in utero from, uh, either complete or near complete, uh, bladder outlet obstruction from a type 2 or type 3. So in addition to neurogenic bladder, some urethral atresias. Uh, there can be injury to the kidneys as well. I think the issue though is that um a lot of what the uh long term follow up is, is really um largely unknown um just because it's so, such a rare disease and it's hard to get true long term follow up and continence issues uh really you need to study them, you know. Past their toddler years, so I think it is challenging to know what the true long-term outcome is. And we've actually seen um uh some late recurrences uh with malignancy uh in the teen years. So I think these, these cases really need to be followed closely for, you know, many, many years. And, and then in the big, big view, a newborn or a fetus who has a large SCT who undergoes resection, as Hanman said, really needs, uh, you know, serial urodynamic follow-up because there can be, uh, subtle abnormalities too. And Alan, this is a good one for, uh, Thinking about, uh, less invasive ways to go after it, because, uh, after all, it's just a, a, uh, a blood flow issue. Now, so, Um, I don't know if anyone has any experience. I know the Europeans had experience in the past with various ways to plug up those vessels. Uh, we tried the radio frequency thing, and that is not something to do, um, but there should be a non-invasive way to plug up those vessels. Any thoughts? Yinka Yinka, aren't you working on this? No, I mean, we have done some work in, in animals too. Again, I, I think Alan has spoke, spoken about this a few times. Trying different uh modalities, especially RFAs, etc. and the, the extent of injury is just much more than you can monitor by ultrasound, and I think that's really the major, major concern. The concern obviously with, with deploying, um, agents intravascularly to occlude it, I mean this is one of the most vascular lesions there are with, with a lot of. You know, arteriovenous, um, infections and, and unless you can really limit your area of deployment, whatever you deploy runs the risk of embolizing all over the whole body and, and I think that's been the major issue here. The, the concept of having a single middle sacral artery that's, that's, that's, uh, perfused on this thing for those who've operated on these large tumors, you know, that's definitely not the case. I mean, there's blood supply from so many different areas that just targeting one vessel is not sufficient. I think, I think this discussion can be extended to CCAs as well, or CPAMs, and there have been a number of efforts to, uh, sclerose CPAMs and even a misguided effort to use an RFA and a CPAP. I think, you know, the RFA technology. It's clearly a problematic because of the, the fluid content of the fetus, all right? Um, so, you've got a fetus that's 80, 90% water and you really can't control the heat energy of an RFA in that kind of a, a, uh, environment. The, uh, issues with embolization with ethanolamine or other substances, Uh, are clearly related to the fact that you can't keep it in the tumor. It, it, uh, particularly SCTs have large arteriovenous communications. And I know of a case, uh, a clear case in which ethanolamine was put into the, uh, inflowing vasculature to the tumor and came out the outflow of the tumor and resulted in immediate thrombosis within the vasculature, emboli circulating in the heart and going to various places. So, Uh, it doesn't stay in the tumor. So, I think, uh, that's hazardous. And not to mention the effects, potential effects on fetal development, neurologic development, etc. of having ethanolamine in your circulation. None of those things have ever been experimentally assessed or looked at. The other thing that's been tried, I think, in Europe is laser energy, and my understanding of the experience with that. Uh, is that they actually tried to at least uh. And one experience is that they tried to occlude the venous outflow of the tumors by superficial laser circumferentially around the tumor as opposed to trying to stop the inflow of the tumors. I think trying to stop inflow in these tumors is problematic just because there's so many, so much collateralization, and as was mentioned, it's not the middle sacral, it's also both hypogastrics, and if you occlude one major blood supply, it'll develop other major blood supplies soon thereafter. So, I don't know of a good answer to your question, Mike. I think there, I agree there has to be an energy type or a methodology out there now or in the future that would be appropriate for this, but I don't think it's been identified yet. So Alan I think uh one of the the comments that you raised uh really bring home the notion of the need for animal investigation or some kind of investigation prior to attempting what are a variety of random. Really, you know, human experimentation issues in patients first, and that I think there is potential for some of these more minimally invasive techniques. I actually think that there is the potential to refine radio frequency ablation and that that is still something worth investigating, but I don't think doing it first in humans is the right answer or with some of the other one-off techniques that you've described. You know, I didn't agree more. As someone who has absolutely no experience in fetal surgery, I have a question for you. One of the things that we're investigating is the use of CyberKnife for solid tumors in, uh, in children. Well, it's already been investigated in adults. We're interested in investigating for hepatoblastoma in children in an animal model. It would be interesting to use something like this which causes no uh surrounding collateral damage because each beam comes from a different angle so the mother should have absolutely no injury from these external beams. The only problem is the fetus is moving, um, so if you could go in through fetal intervention to put in a fiducial. And that's it. You put in the fiduciial, uh, close, you're done, and then you can do external beamer. You could do, um, cyberknife therapy to any solid organ. Uh, it'd be an interesting thing to try in an animal model, uh, which, which we have the capability. Explain a fiduciial to me. So in a, in it's a great question. So, um, your vocabulary always just blows me away. I, you, you knew I was really smart, right? Yeah, I said that to try to impress you. A fiducial is, um. In in CyberKnife for, for neurosurgery is very easy because it doesn't move. So you lay the patient down and it, they, they don't move, they're fixed into a position and it and it targets the tumor. In a moving organ such as the lung, uh, what we do, uh, we, we, what they do, what can be done is you go in, open or laparoscopically and put in a tiny little piece of metal. Uh, it's a little device that the beam recognizes, and that's what the beam targets. So if it's moving all over the place, the beam will find it and and attack that tissue that you set parameters around that fiducial. So it's a way to target a a moving target and it may be something interesting to try in a in a fetus because it's so noninvasive. It sounds very interesting actually. It's an interesting thought, although the difference in the Radiation that's given in that methodology is that you're really trying to target rapidly dividing cells. It's, it's not, um, ablating blood flow, which is the goal in fetal intervention. So but, but that something to think about, but goals of therapy are a little different. Yeah. You know, 11 technology that is coming on board, and I think the Japanese are way ahead of us on this is MR guided high frequency ultrasound, which can pinpoint within a 1 millimeter and can coagulate vessels. And for something like SCT which likely would require repeated treatments because of the uh Collateralization that that Alan made a comment about. I, I think in the US there's only about 5 of these devices available, and it's approved by the FDA to treat uterine fibroids. Um, I don't know if any of you have one of these devices at your institutions. We don't. Is that haifu? Is that the haifu? Yes, you know, Tim, I totally agree. When I visited Tosho in, in, uh, Japan, they were doing experiments looking at, um, uh, using haifu to ablate, uh, renal arteries in rabbits. Um, and it's, it's great technology, and, you know, the collateral injury is very, very small, and as you said, they can really localize on the millimeter level. Um, the thing I wanted to bring up is just, you know, we, we talk about. Energy devices and deployment in these masses, and I think looking at SET and C camera just two really different situations. One's an enclosed space in which, uh, you know, we're we're talking about a space occupying lesion and and and creating necrosis which in my mind would would make things worse before they got better, and SETs make a lot more sense in terms of sort of an open space in which you could cause necrosis without the same problem. Yeah, that's a good point. You're going to have swelling with tissue necrosis, and that's always been a concern with any of the vascular ablative technologies. But the argument that people make in that regard then is actually going in before you get the eye drops, which now begs the point again, should you even be intervening in the first place if the patient is not hydropic, right. Well, the, some of the successes that have been claimed for sclerosis of, uh, CCAs have been that circumstance. They. That's my point. They treat non-hydropic patients and claim success and survival. How to make an asymptomatic patient better. Right. Bettina Peck had some experience with uh Haifu, collaborated with the Haifu folks working on your uterine fibroids in San Francisco a few years ago and in animal models, and the, the challenge that occurred at the time and the technology may have proved was damage of the tissues en route to the tissue that you were treating. Um, uh, being unable to sort of focus into a deeper, uh, tissue area, but I think the addition of MR Tim to that technology, MR guided, uh, could really, uh, be beneficial. So that, that may be the answer for us all in the future, but that's a pretty high tech intervention. Yeah, I, I don't think I'm gonna convince my hospital to buy one for we lost you. Tim, can you hear us? Yeah, I can hear you. OK, sorry, we lost you for a second there. OK. Uh, um, I don't, Alan, you had a question that was interesting that you had written down as a point. You know, usually when we do these events, about 50% of the viewing audience is international. And for some reason, on this event, those numbers are off. Uh, we only have about 25% of the viewing audience is international. So relating to one of the points that you had brought up before in in your um documents, are we, is this really, uh, are we really seeing this internationally, um, and for those of you who of the 25% that are, uh, here from other countries. Are you, are you considering starting a fetal treatment in your countries, um, and, and if so, how far along are you and what is the, what is the limitation? It's just a very interesting, uh, different breakdown than we've seen in uh uh previous events. I think it's a, it's a great question and It's a, it's a complex answer because I think you have political issues, you have resource issues, you have, uh, uh, philosophical issues that differ between country to country. For instance, there are some societies in which termination is the favored and predominant, uh, uh, approach to myelomeningocele, for instance, and that obviously has an impact on whether or not you want to start an open fetal surgery program for myelomeningocele. There are other countries that simply don't have the sophistication or resources to develop an open fetal surgery program, and it does take sophistication and it does take major resources and institutional support, etc. to start a fetal surgical program and maintain one. So there are a variety of reasons philosophically. I think the Europeans in general have been opposed to open fetal surgery as something that's invasive and high risk for the mother. And you know, rarely warranted. Uh, so, so there have been a lot of reasons that it's been, and it was developed obviously at UCSF and in this country. And so there are a variety of reasons why it's been predominantly localized to the US. I think that's changing, particularly with the myelomeningocele study. I think the Europeans in particular have taken a second look at whether open fetal surgery is a legitimate. Thing to do and in fact, a number of centers have opened in Europe, so I think the biggest Uh. Uh, influence for change has been this, the mom study, which we'll talk about extensively next, that, that shows a clear cut. Uh, well proven indication for, so let me take everything that you just said and apply it to the United States now. Melanie's mind on your head. All right, let's, I'm gonna talk about a place like us, OK? It's very intriguing for us. We have a great fetal treatment center. We're doing no fetal surgery. Um, what? Uh, if you can take a 10 day answer and try to make it into a, a couple of minutes, how does a place get started? Why, how do you, uh, what do you tell a program that is intrigued by the concept of starting fetal surgery? Uh, what does it take? What are the limitations? What are the cautions that you would give to them, uh, about starting such a center? Well, I think that's a great question for our panelists. So let's open it up. Because it's a tough question, and I think we all probably have different attitudes about it. So Doctor Adzik, do you wanna start with that? Well, I, I guess we, we could talk about this in the context of MMC because that, that's really the volume driver now, and, and there's a lot of interest now, and I know that the three mom sites had a lot of interest, uh, post Mom's trial, Vanderbilt, UCSF, and Shop. Our, our approach, at least for MMC, um, that we thought that at least 3 conditions were important. First, that. The visiting team would bring patients in this case to CHOP who are candidates for fetal MMC repair so that team could see about the entire process from the counseling, which is very intense to our plans at least for long term follow up. So that's the first point. The, uh, second point is that it should be a truly multidisciplinary effort and therefore, the visiting team needs to include pediatric surgeons and pediatric neurosurgeons and obstetricians, and maternal fetal medicine specialists and anesthesiologist and a coordinator. So the whole team needs to come, and we've put this into practice. This, this process can't be learned by a single healthcare provider, just, just showing up to, to watch a case. Uh, it just won't work that way. And third, my, my own bias and our center's bias is that the, uh, new center needs to demonstrate a commitment to following their patients, uh, both mother and child in the long term, uh, be committed to research, um, in this area, uh, clinically at least, perhaps basic science as well, and that requires a substantial institutional commitment. And then the final thing is you, you have to figure out whether or not there's sufficient volume there to, to really warrant it because you get rusty. You need volume. That's my opinion. That's actually interesting because one of the uh Uh, people from the audience wrote that that was their limitation in getting a program started is they just were afraid they didn't have enough volume. I think that's probably a pretty common concern. Any, you know, Tim, you, you, you're a great example. You went from a place that had a thriving fetal treatment center in fetal surgery and, and moved to a new place. What were some of your challenges in getting the program started up there? Well, I, I think Scott touched on some of them. I think the most important thing is that you need real institutional commitment. And uh when I went from CHOP to Cincinnati, um, Cincinnati put up $10 million to build a program. Uh, they built an inpatient unit. They bought all the ultrasound machines, uh, gave us the resources to recruit expertise and, and at every level and in, in many disciplines, and I think that's why it was successful because they had, uh, fought through this before. Uh, they even approached me and were willing to put the resources into place to, to really build a, a program that could be successful and recognize that you can't do that on a catchment area, uh, that immediately surrounds your hospital. You really have to have a regional, at least regional, uh, catchment to make it viable. Uh, and I think, uh, all the points that Scott had made, I, I agree with. I think. It's, it's not sufficient to have a single individual with expertise. You really have to have a team, and you have to have the institutional support behind that. So, so based on that, and Scott, I want to go back to you. Let's say there's 3 centers in one city that want to do fetal treatment. Now you're diluting out all the volume. That's got to be a problem, especially in a big city like Philadelphia or Boston or a place where there's multiple, uh, large centers. Um, I'm not sure that that's the city you're really referring to. I, I think you're referring to the city where, where the guy sitting with the blue background is in. Yinka, what do you, what do you think about that? That's actually, that's a, that's a great example. That's a great question. So Yinka, how does that happen? You got Competing centers, they're both trying to do the same thing. Mm. How does that happen? That's, that's a long story. Uh, but, but I mean that is a challenge, and, and I think it touches on all the points that have been stated. Same thing also to to realize is that while no matter how big the city is, and while, of course, your initial catchment is the city in which you're based, most of these anomalies are so rare that you really need to have a much more You know, a very broad catchment area and so you're actually, it's not even so much it's bad enough having them within the same city, but I think also within the same region is going to be key because these are not very common conditions. Obviously some parts of the country have different rates of termination than others, you know, the quote unquote Bible Belt down in the south, etc. so some anomalies are probably going to be more rampant or less terminated than in other parts of the country, but it still comes down to the same, I think every center needs to be sure that They will have the volume to sustain it, that they do have the expertise, have the institutional commitment. I mean, all the points that Scott has mentioned. Well, I think the expertise is a major issue as well. Uh, let's face it, there's not a lot of expertise in fetal medicine, uh, spread around the world. Uh, it's a highly specialized area. There aren't a lot of MFMs even that focus on the fetal side of, uh, maternal fetal medicine. You could almost call it maternal focused medicine in most cases. So finding adequate and not just adequate expertise, but the level of expertise required to run a quality fetal treatment center, your imaging expertise, for instance, you know, your, your prenatal diagnosis and the quality of that is absolutely essential. If, if you don't have that component, you're going to make terrible mistakes and have, you know, a poor outcome on many of your patients. So, it's, it's not an easy thing to assemble. Um, and it's hard to acquire de novo, uh, in a center. So I think that's one of the, the real limitations. I think the point was made earlier on too, how in Europe there's, there isn't, you know, as much interest or at least, uh, not much has been done in terms of open field surgery. And it goes back to the same issue. While this was developed here in the US by Mike Harrison and a lot of it started out of UCSF, there are very few pediatric surgeons in Europe that are actually engaged in this arena. And I think so having a multidisciplinary fiddle center in Europe or other parts of the world is really not as common or probably, you know, even nonexistent except for a few pockets that we know, you know, that some of them on this on this conference as well. But I think in the US we've been fortunate with with the efforts that have been created that there are more pediatric surgeons that are actually involved and of course with that again as being As it's really important, you know, it can be a solo, um, objective. It has to be a multidisciplinary, multi-specialty effort, and, and I think that's important to have expertise in all aspects to really have the best opportunity for success. I, you know, 11 point that I, I think wasn't made, um, for, for these programs to be successful, I think they, they need to have grounding in less advanced techniques. Before just jumping to doing something like myo meningocele. And I think that's a mistake that's been made or about to be made at some places where, without having, uh, laid the foundation for excellent prenatal imaging, uh, less invasive approaches, shunts, speedoscopic interventions, exit procedures to make the jump with their entire team. So you don't have the nurses who are up to speed, you don't have the MFMs who are up to speed. Uh, with open fetal surgery, uh, they, they don't even get a chance to kind of traverse the learning curve with less, uh, sophisticated, uh, interventions such as pedoscopic surgery. So Tim, I think that's a really great point, and I am reminded of an article that was published in the New England Journal, probably 3 or 4 years ago now. I can't remember, describing an exit procedure for a large, um. Uh, neck mass and the tragedy of that article that was published in the New England Journal that it was absolutely not an exit procedure. It was just a regular C-section with no attention to, um, uterine hemostasis or uh relaxation that and with operations sort of done, you know, in the middle of prior to trying to clamp the cord while this mother was. Uh, being delivered and it, and it was published as an exit procedure was absolutely wrong. Um, there was, uh, clearly no editorial, uh, oversight, and this was the first procedure that was done, you know, exit procedure that was done at Mass General. So there's a lot of misinformation out there about what this is and it's concerning, I think, Todd, the, um. One of the reasons that you may not have the significant international component on. Conference that you've had with others is that the target audience here and for what you've usually done has been. Uh, surgeons, pediatric surgeons by and large, and this field is, uh, very, uh, differently viewed through the lens of our internal fetal medicine colleagues and in other countries fetal. Uh, care, if you will, is largely delivered by that group. So there's many components that play into who is looking at the fetus and through what lens, right? You know that is a great segue. So the, the, we've had a few questions from the audience, uh, Dr. Farmer Visa, what you just said, and, and, um. People are saying, OK, well then looking at who our audience is, I think it's a small percentage of people that are actually practicing fetal surgery and mostly are people that are interested or want to know more about it. And really the question is not can or should we be doing it, but who do we refer, how, when do we refer? And you know, Alan, when you were here giving the lung lesion thing, that was the question that kept coming to you was, we got babies. How, what do we do? Do we call you? Do we send them to you? Who do we send? So I think what we really need to start doing is, is educating uh when to refer and who should be referred throughout the country and I think that's what a lot of the audience is looking to hear. We have at least 2 people from Canada really curious about the referral indications and we can go and focus in on those when we go through each of the topics today, uh, about referrals. Does anyone want to make a comment about that? What have you found, uh, about the, the education or understanding about referrals? Have they been appropriate? Well, I think it is based on education, and so you really, you need to understand the path of physiology, the way. That, uh, these lesions can behave to understand the potential for problems that they, uh, can have. And so, uh, I, my simple answer of when to refer is simply when you don't have the expertise or don't have comfort with managing the patient, uh, in your own center. Um, and, you know, there are centers with expertise in all of these problems that, um, You know, are available for referral from any part of the country, at least in the US. I know you guys other comments? No. No, Alan, I think you did a good job, at least with the CCAM talking about the CVR as a means of assessing, but I think, you know, what the audience probably wants to know in addition is what CVR should you get concerned about, you know, as when to refer, and I think it was mentioned in your talk, 1.6, at least those are the ones that would get into trouble. We try to do the same thing with SATs to, you know, trying to determine the tumor fetal ratio. They can try to give obstetricians an idea as to how big is big enough to be concerned that these patients need to go to a referral center where you can predict that this is the fetus that's likely to get into trouble both from the fetal and maternal standpoint and have them at a center that can, that can take care of that. I think as you've said, there are many centers all over the US that are spread out and capable of doing this, but for the audience to really realize what are the critical points where, you know, if you, if you do find this. Um, if you, if you, if this is what you observe in your fetus at this point, please by all means send them to another level of care. Well, and there are a lot of places that don't measure a good CVR, right? I mean, you know, if you don't have the capability in your center to monitor these, these tumors, if you can't follow echocardiography on a, on a solid vascular SCT, uh, and follow the, the hemodynamic parameters to, to, uh, observe for evolution of high output physiology, etc. then you really shouldn't be managing that patient. And, uh, you know, so, I think it depends on your baseline expertise. It depends on whether or not you're, you're comfortable and have an understanding of the pathophysiology of that lesion. There are some places obviously that are much more sophisticated than others. But, you know, if you don't understand it or you can't monitor it or you're just You know, concerned about it, you should refer them to a place that, that, uh, manages these problems. But I also think that raises an interesting point, Alan, and you know, I think centers like all of us here really do understand, you know, these lesions, and part of our responsibility, I think, is to educate our colleagues that are out there in the communities, and I think, you know, educational programs and. Outreach and going to meetings and having special, you know, pre-meeting conferences, things like that it's kind of one of our responsibilities because until people are aware and understand the problem, understand the. Indications for referral, what to look for. They're just in there in the dark and they really don't know what to do with these patients or how to counsel these families. So part of our responsibility, I see it is trying to raise awareness and teach people a little bit more than they have right now so they understand the issues and referral patterns better. One of the things I might add is that I think our patients are driving some of the change in the approach to fetal problems, and that I think that's a good thing and I think that the educational efforts that have been put forth on some of the really excellent websites now that are available at most of the centers represented here uh do a tremendous service in terms of educating. Patients. And the patient becomes the person who is most interested in the fetal anomaly. So, they seek out learning opportunities, and they are now starting to demand Uh, different and multidisciplinary approaches to their problem, whereas I think in times past there could be a very. A limited discussion that was a personal conversation with an obstetrician and a patient that often reflected the, the obstetrician's personal knowledge base, which, which frankly could, could be limited relative to these rare and unusual things. So that is to say, in times past, it was possible that you could have a single person making a diagnosis, which might or might not be accurate. Uh, performing some treatment which might or might not have been appropriate and then potentially terminating the pregnancy or being responsible for the outcome, all done in a vacuum. And I think our patients have become more sophisticated and are not willing to accept that anymore and are asking for multidisciplinary opinions, seeking other things, and I think that the, the continued effort to make information available to patients is one of the things that has helped move this field forward. I think one of the things that we tend to emphasize is partnership with the local referring MDs, the OBs and the MFMs, uh, because so often, this is a diagnosis-specific need for referral, and some cases don't need to travel. I mean, I'm sure all of the centers that are on the conference call really are seeing patients from great distances, and they don't always have to make that journey. And it's hard to expect the generalists in the community to be up to speed in everything that we do on a day to day basis. And so I think forming partnerships with, with these physicians, uh, can improve the, the quality of the care that can be delivered and the timeliness of referral when it's appropriate. Good, just one more thing to put a plug in as we're trying to work more to educate the pediatric surgeons is, uh, um, I mean, as you know, the American Pediatric Surgical Association is trying hard to reach out and actually one of the, um, I think the pre-conference ideas for, for next year is, is really what the. Pediatric surgeon needs to know about fetal diagnosis and fetal surgery, uh, about, about prenatal counseling and, and, uh, and fetal surgery. So it's again another means of getting out there to pediatric surgeons that are not primarily involved in, in centers like this, but need to know what they, uh, how they should be involved and, and when and, uh, and how to, to refer this patient. You know, I was just thinking about how, what distinguishes centers that seem to be able to accomplish this and I hadn't thought about this before, but it's, it's almost, it's not a question of expertise because many centers have the right expertise in individuals. It's how they talk to each other and how they break down the cultural barriers. So it really makes a huge difference, as Diana said, about whether you're doing things from an obstetric point of view, from a pediatric surgery point of view, from a neonatology point of view. It's how they get together and focus on a patient. It's almost never, it's always a team. And, and so, I mean, it sounds funny, but it's, it's really the teamwork that makes the thing go. Yeah, I think that's, that's very true. Not, not only when things start as they did at UCSF, but for new centers coming on now, uh, Mike, uh, knows, uh, Franny Moore because we were exposed to him in medical school. And he, uh, wrote, I have it here on my computer, new procedures are developed in the centers where the people are, the people that is, who feel a personal motivation to develop them. Whether the innovation be a new drug, a new treatment, a new hormone, a new operation, or just a new philosophy of medicine, it usually starts in a unicentric way, but you, you need that commitment from the institution and you need the passion for the leaders of the program to get something started. And there's no one who has a, a better view of that than you, Mike. Uh, and I see Doctor McKenzie there. She should know all about Frances D. Morris. She trained at the Brigham Hospital. The bridge builder. Yeah, I love Franny. That's great. Uh, It, we have a, a few questions from the audience. Um, there's a, a question about a rare thing that we may find. A question from Hyderabad, India. Doctor Ratha says, how do you calculate CVR on a bilateral CPAP? And I assume that's rare enough that it's probably not ever been discussed. Well, what is it? 1 to 3% of CPAMs are, are bilateral or multilobar. Well, 11 thing you, you may want to think about is oftentimes you'll get that referral, and it won't be a bilateral CPAM or CCAM. It'll be a chaos case. So, you know, most chaos cases come to us and referred as bilateral CCAMs. So that the first thing to think about, and I see everybody nodding their heads because that's the truth. Or you can have mixtures of lesions as well, a sequestration on one side, a CPM on the other. You know, ragmatic hernia is often thought to be CAMs, but our normal, you know, the, the pathophysiology associated with a large CVR on a unilateral tumor would be very different than. You know, the pathophysiology of bilateral tumors, and so I don't know that the CVR measurement even applies in that circumstance. Because it's, it's going to be a different path of physiology, I guess if it were a mediastinal shift in one direction, you would measure the CVR of the, you know, greatest mass effect is trying to, to predict the onset of high drops because the onset of high drops is related to compression of the heart and mediastinal shift. We have a, a question from Saudi Arabia, um, from Doctor Paul. And it's a it's actually a great question. And, all right, we got a situation here where there's very few centers that are doing this, uh, and, but the problems are out there. Most people need help. How much are we utilizing systems like this telemedicine, uh, uh, advances and we've got this technology now. Are you consulting patients? Are you looking at, uh, fetal MRIs virtually? Are you using the new technology to help guide these countries all over the world with their patients? Is anyone doing that? We actually have some medicine um endeavors that are in place, not so much so international, uh, but those are also important in, in the works as well. But I think part of it again is understanding the. The, I mean, obviously it's easy to talk to another physician and give your impression about a case that you've been, that you've been asked to review. Yeah. In terms of the formal lines of, of uh responsibility for that patient and the care of that patient is, is what's to be determined. The major aspect of it really is, is what's the quality of what you're getting to see on the images that have been sent over to you and I think many times that's the limitation, but obviously I think this is something that, that needs to be used more in the future. So Todd, I think you raise uh a great question, and I think that certainly fetal diagnosis is an area, uh, where telemedicine kinds of techniques can be very useful if you think about it, very few of us in the first phase are performing physical examinations on the patients that we see. There's a great deal that can be done related, uh, through, uh, history taking and, uh, image evaluation. The, you know, I've moved to an area that serves a very rural based, uh, population, and we have used a uh fairly robust telemedicine program to serve many of these patients and with, uh, sort of high definition uh connections into many of these locations and without a doubt, uh, the same. Technologies if you will that help us communicate with our rural colleagues would be very appropriate to helping folks in a global situation as well, and I do think that fetal diagnosis certainly we could help many people around the world just with image interpretation. But the quality of the images is essential. I mean, I think we all get frequent requests to consult on cases outside the US, um, with, uh, You know, images sent by email, etc. Sometimes that's feasible and understandable. Sometimes you simply have inadequate information to, to make a good judgment. I think there's obviously a huge role for improved technology and establishing links with other centers in the future. Right now I don't think any of our centers are really actively doing that on a on a routine basis. We have a, so Melanie, I'm gonna get to you because we have about less than 10 minutes just to go over where we stand, issues with fetal surgery in general before we get into each specific disease. So if there's anyone that has questions, send them in now because we have a few minutes left. Melanie, I think one thing we did in Ohio, we've been around for about 10 years and we worked with Tim Crumbleholm to form a collaborative of all the centers doing fetal diagnosis and treatment in Ohio. And now he's gone he's left us, but you know we still have that connection. I think so many this field is is so predominantly for people that can afford it, people that can go to the centers, people they can reach out. I think we really need to work on that, developing these, these referral centers, their expertise so they can send you the images so they can work with the families. Because they really can't oftentimes they can't afford to go out of their town where they're they're predominantly diagnosed. That's a great question. What do you Is there a system in place for for patients if we have patients to send or someone has a patient to send, uh, that's gonna be their issue, the travel, the stay, the cost of that. Do you, is there systems in place in each of your centers? Um, I know that it's been asked a lot before. Certainly at CHOP, we have extensive capability to assist patients both in transportation, and lodging, and, um, everything that they require for the 3 or 4 or 5 month, uh, ordeal that, uh, is involved with fetal intervention. So, um, you know, Ronald McDonald houses, uh, various other, uh, resources that are available to help families, uh, Come from wherever they live to stay for a while at shop, I'm sure most of the other places have similar sorts of arrangements. Yeah, we, we have a, uh, a philanthropic fund that really, uh, takes care of travel arrangements, hotel accommodations for the duration of these patients, and we had a commitment from the hospitals that we would never turn anyone away because of inability to pay. Uh, the unique nature of the kind of things that are done in all of these centers makes it very challenging for them to just go down the street and, and. Get a procedure. Uh, so there, there's really an ethical component to that question as well. So we, we feel the same way too. There was a, uh, a question from Mumbai, uh, India from, uh, Doctor, uh, Parik, um. It, the, the question is, where can we get information? Uh, even myself as, you know, someone who's, you know, hosting the show but knows very little about fetal surgery, tried to do as much research as I could and there's not much out there. Um, I went to each of your hospital websites and was reading about what I could find, um, but is there a collaborative that we could, uh, what's, is there something in process where people can learn more about it? Um, I mean, Google's made the answer easy for all of us. You Google, you see who comes to the top, and you go to their website and you read about the procedures, and usually they get the referral. So. Um, I, I guess, you know, Doctor Pree, I don't know if there's anything specific, but I can tell you, I can tell you that myself, I went to these, the individual, uh, representatives you see here. I went to their websites, and a lot of them have very good videos and, and explanations about, uh, when to refer and, and these types of questions. Anyone wanna make a comment on that? Is he ask, are you asking from the patient perspective or the physician perspective? That's a great question because certainly the websites have a tremendous amount of information, and I think at this point good information for patients to educate themselves about these various lesions. Obes he's referring to. OK, so, you know, we published extensively in the literature. It's out there. There's a lot of information on the pathophysiology of all the lesions that we're talking about. So there's certainly a literature base to draw from. There is also the opportunity. You know, to, uh, call us directly and talk to us if you have, uh, questions on patients. And, um, Mark gets all, you know, calls all the time regarding patients from a variety of places, um, from other OBs that uh want more information. So, there, there are direct lines to all of us if you want to discuss a patient with us, um. And uh need more information. Actually, I'm, I'm gonna ask each of you if you wouldn't mind, uh, at the end of your panel, if you could just write a quick, uh, name of your hospital and what, what a phone number contact people could call if they had, uh, specific questions for your institution, that'd be great for people to have, uh, and write down. I know we would like to have that. So there's also, there's also collaborative groups like the Euro fetus Group and the North American Fetal Therapy Network or NAFNET. You can go to those websites and there are links to, like, the NFNT center to all of the fetal therapy centers that are members of NFNET. If you go to Eurofeetus, there are connections there to different centers. So, again, it's a good place to go to start and then kind of work your way through the information that is linked there. OK. So, maybe we can find that, uh, is there a link already that we could post here? We'll find it. We'll find it at the break, um, and Doctor Pree, I hope that answered your question. Uh, any other, um, Questions or comments before we take a break? Any last minute things you wanted to address from your list here? Did we get to everything? Just, uh, one more thing about lung lesions somebody brought up bilateral, uh, CAM decams, and, um, I just would, uh, say that in those patients, uh, you should, um, just. Think about at some point the entity of pleuropulmonary blastoma, which we've seen a couple of cases of, and they're incredibly rare. There's about 300 cases worldwide. My colleague, uh, Doug Minotti has a particular interest in these patients. He is working with the person who runs the registry, uh, in, um, uh, Minnesota. I think, uh, he started the interest when he was with Yinka uh in Houston. They had a case, but Um, when you have bilateral, uh, lesions or, uh, multilobar lesions, uh, I would say that it's still way more likely to be a CCA CA, uh, but, um, you certainly have to think about pleuropulmonarylastoma because the, uh, natural history is very different. Well, and that's one of the, uh, problems with pleuropulmonary blastoma is you can't differentiate it by imaging studies from CPAM, CCA. And we've had, uh, at least three, I think 4 at CHOP in our series of, uh, lung lesions. Um, so, it seems, it seems more frequent than, Uh, people suggest it's, um, I think most Beatle centers have at least 2 or 3 of them on their list. One final comment maybe about CVR because there seems to be a lot of interest and discussion about that. But CVR is just not a single measurement. It's a powerful tool that you can follow these lesions. So, yes, you can use them for prognostic, you know, to give a family what, what risk group you fall into. But really, it's a, it's a valuable tool so that when we see these patients weekly or twice weekly, by calculating the CVR in a consistent way, you can really track. The growth rate of these things and helps to say, wow, this is kind of a slow grower, medium grower, fast grower and help to kind of, um, really say how often do you have to be followed, when have you plateaued? Uh, because if your CVR is unchanged for two or three visits, then you've probably reached that crucial plateau phase and you can maybe back off your surveillance a bit for the family. And maybe after plateau, you can give them a little bit more reassurance that things are going to be better. Uh, in the last couple of minutes, there's a couple of questions, um, about training for, I, I've asked you this myself. Uh, someone wants to get trained in fetal surgery, uh, you know, there's a big wide, uh, range of what that really means. Um, the question was, uh, is this only limited to pediatric surgeons or is there training programs for OBGYNs to, to learn fetal surgery? What is the system? How does that happen? Who do they call and, and is it even in place? Well, there are no accredited training programs, uh, for becoming a fetal surgeon or a fetal interventionalist. Uh, for the most part, it's an apprentice type system. You have to, uh, join a fetal treatment program in one way or the other, and Uh, you know, undergo, get the experience and the training. There are some non-accredited fetal fellowships. Um, I know Tim had one in Cincinnati. We have one at, at CHP, um, that, uh, you know, are limited in number and have limited, uh, um, numbers of spots, but You know, is 11 potential route to get there. You know, it's inherently obvious that if you're going to, uh, resect a CCAM tumor or, uh, do a sacrococcygeal teratoma, that you need to be a pediatric surgeon. Um-hum. That's what we do. Right. Right? So, this is not a, a, uh, intervention that is, uh, appropriate for anything but a multidisciplinary approach. Um-hum. OK? There are, uh, roles for, MFMs, there are roles for pediatric surgeons. There are roles for neurosurgeons, uh, in a true fetal treatment program. And, you know, arguing about who does what is generally fairly nonproductive. Um. Um-hum. So, it's, it's, it should be a multidisciplinary effort and you need all components of it to make it successful. But there's also a large range of therapies available. Some of them are ultrasound guided. That's right. You know, shunt procedures where those, the lead in that has been taken by MFMs and OBs around the world. The Europeans, for example, are very fetoscopic and ultrasound orientated, um, which is a lot of our training, my training. Um, so things like shunts you can learn through one of these mentorships where you go to a program and really learn. The diagnosis, the selection criteria, and how to do the procedures, because technically while they seem straightforward, there's always a steep learning curve. And by getting mentored, you know, you don't have the same learning curve because you're learning from people that have gone through that. Um, fetoscopic procedures, well, you know, we, all of us pediatric surgeons, obstetricians, we're all trained in doing laparoscopy. This is just one step beyond laparoscopy. And so I think that's why fetoscopic surgical interventions have really taken off. Yeah. Because there's a slow, the lower learning curve. However, there is a learning curve. And if you look at centers outcome data for things like selective laser, there's a clear, uh, learning curve there. So you really need to go and work with people who really have a lot of experience, have been doing this for a lot of years, learn the tricks, learn not to make the mistakes that we all made in the early days. But really what we focus, it seems, on this part of the program is open fetal surgery, and that's so highly restricted. That it's really a whole different beast. So it's a new concept. We'll have team fellowships instead of one person, the whole group goes over together. Much fun. Well, but we'll, we'll discuss fetoscopy a lot as the, as the program moves forward here. So, well, uh, any last comments or questions from the panelists before we go to break? Just one quick thing to what's been talked, what's been said about training. You know, Mike said earlier on too that one of the major aspects of this whole endeavor is having people work together. Uh, pediatric surgeons and MFMs are typically trained in silos that kind of rise up and, and then meet at the point of setting up a fetal center and, you know, and then things have to mesh together, which doesn't always happen. One thing we've tried to do with that is actually we've just set up a, a perinatal surgery fellowship with the whole idea of training an MFM and a pediatric surgeon, training together, working together again with this apprenticeship system work, but in a, already setting up that collaborative experience while they're still in training, and we hope that hopefully that would. You know, pretend for better interactions as as things move forward. Yeah, great, thank you. If there's no other comments, we are going to head to break exactly at the minute on time. I think that's the first time in history that's ever happened. Uh, we're gonna take a 10 minute break and then we're gonna come back with an overview on, uh, myelo meningocele by Doctor Adsik. Uh, so, uh, we'll see you. What's that? What video? Oh, we're gonna show you a brief video, uh, giving an overview about the fetal treatment center at CHOP, and, uh, enjoy that during the break and then we'll see you in about 10 minutes. We'll see you in a little bit. For most of human history, the fetus has been really shrouded in mystery in multiple layers of the maternal abdomen obscuring anything that was wrong with the fetus. With the emergence of prenatal diagnostic techniques, particularly with the advent of maternal fetal ultrasound, we could view into the womb for the first time. We could see things we've never seen before and as those fetuses were followed, it became more clear what. May or may not happen to them. There were a certain category of birth defects that were for the most part lethal. Where when the baby was born, we were too late to do anything about it. That was really the impetus to try to knock on the door sooner. Perhaps we can treat this new group of highly selected unborn patients who have severe diseases that are progressive during the pregnancy. Maybe we could treat them before birth, and that was a very radical and controversial concept. At 20 weeks, I had the level 2 ultrasound and everything was fine. About 5 weeks later, I went for a regular checkup with my OB and he said, you know, you're measuring a couple weeks ahead of schedule. Let's just get an ultrasound and just make sure everything's going OK. And that's when we found out that I was carrying a very, very sick baby. I think about fetal surgery work being presented at national international meetings and essentially being laughed out of the room. Most people thought we were crazy because there had to be at least 100 reasons why you couldn't operate on a fetus. There was also a lot of skepticism about whether or not this was really beneficial. That's frequently the case with something. That's new and it was our obligation to not only convince the world, convince ourselves, but all that work had to be done prior to starting it clinically. We had to know that if we offered anything before birth, it had to be safe for mom. We had to go into the experimental laboratory and work principally with fetal sheep to develop the animal models and the techniques that we hoped someday could be used clinically. We showed that those anatomic abnormalities cause the same. Sort of organ damage that was seen in human fetuses and we showed in the animal model again that it could be corrected before birth. Then we had to apply this cautiously in the clinical realm, isolated cases, being brutally honest with the families about what we could and could not do, what our hopes were and what our fears were, and people began to believe, oh. In certain select instances, it's not crazy to operate on the baby before they're born. When they told us what fetal surgery meant, it was very surreal. It was something out of a sci-fi movie. We sat down with the doctors and they gave us their conclusions on what they believed Addison's condition was that that she had a mediastinal teratoma, which is a large tumor in her chest that had compacted her heart and her lungs. So she actually was in heart failure. We were told it was a fifty-fifty chance of survival through the surgery and we felt that was enough to proceed. We spent a lot of time talking about the risks and the benefits and the fact that we have failures as well as successes. They couldn't have been more professional and caring and. And making us feel like we were making the right decision and no matter what decision we made, they would have been fully supportive of. The Center for Fetal Diagnosis and Treatment at CHOP is one of a handful of centers throughout the United States and in fact the world and undoubtedly the largest. CHOP was really the ideal place to develop a center. CHOPP is an unbelievable place, so. Layers and layers of expertise. What we know and are able to tell families because we've lived it is an amazing resource for families. And with the opening of the Garbose Family Special Delivery Unit, we have continually improved the outcome of mother and baby. The SDU at CHOP is the first of its kind where you deliver the fetus in a children's hospital where Uh, all of the services that that fetus needs are immediately available. Doctor Isaac described some of the early procedures to us and how much had changed, and just, just from where he was and where he had come to when he operated on Addison was, was, was an amazing change, an amazing improvement, and I expect it to continue. Babies are still dying. We don't understand enough. But our lab here is entirely focused on learning everything we possibly can about the mysteries of the fetus. There's incredible research endeavor that is always knocking on the next door, from maternal safety imaging techniques to open fetal surgery to now minimally invasive fetal surgery and ultimately to stem cell and gene therapy. In the next 5 years we'll be treating a child with sickle cell disease in utero. With a single injection of cells, we're going to see kids who had diagnoses that there was no hope for. We're going to see these kids actually surviving and living great lives because of these interventions that they're doing. And because of the research that they're doing, we see teenagers now when before we saw fetuses, and that work would not have been possible without the support from donors. Philanthropy is an opportunity to have tremendous impact. And what better thing to fund than babies? I mean, because you're funding a cure for a lifetime. Truly, they're saving lives and and making families whole and, and happy. The ultimate payoff is seeing a mom come back with her child and how normal they are and how active they are and how smart they are. Addison is everything a 3 year old little girl should be. She is nosy, she doesn't listen. She smiles, she's happy, she likes wearing her dresses. Addison is a delight. People say to me she's so happy and she has just got such a bright love of life. And you watch her grow and you watch her smile and you watch how she changes and as she's conquered the obstacles in her way. And you, you're, you're amazed. When she was born and so sick, I never would have imagined that she would be doing as well as she is today. And if the Center for Fetal Diagnosis and Treatment was not there or if we were not made aware of it, Addison would not be here today. People that know her, they look at her and they can't believe it, and all you can do is you sit there and you say, look at her now. Look at me now. You got me now, you're at now. Look at me now. Hey, look at me now. right. Look at me now. Me now. Look at me now. Look at me now. See me now. Look at me now. Look me now. Look at me now. Bye guys. Say bye. Untitled, untitled music music music music. 2 and closes on 1. OK, and welcome back. We are here for part two of the uh current concepts and controversies in fetal treatment, and we're going to move right into the current status of open fetal surgery for myelomeningocele. And, uh, we're gonna have, uh, we have Doctor Scott Adzik, who's going to, who's one of our panels for the first session is going to be giving us a brief overview on where we're at with Milo Meningose. Doctor Adzik is surgeon in Chief, Department of Surgery, um, uh, General Thoracic and fetal Surgery Director, uh, Center for Fetal Diagnosis and Treatment, the C. Everett Koop Endowed Chair. Uh, pediatric surgery professor of pediatrics, OP, uh, in GYN at the Perlman School of Medicine at the University of, uh, Philadelphia, uh, uh, at University of Pennsylvania. We really appreciate you being here today, uh, Doctor Adzik, and I'm gonna open up the mic to you now. Great, thanks, Todd. Um, this is a wonderful forum to, to have discussion and saves plane fares and time in airports. We're going to talk about fetal surgery for mild meningocele or MMC for short, which, uh, for those who don't know, is the most severe form of spina bifida. Uh, it's a pretty common birth defect. Estimates are spina bifida affects about 1500 babies born each year in the US. That's about 30 babies per week, about 5 or 6 per day. And the two hallmarks of this malformation are we learned in medical school, there's a failure of closure of the neural tube by 4 to 6 weeks gestation, so that, as this illustration shows, part of the spinal cord and spinal nerves, uh, protrude through an opening in the back and are exposed to amniotic fluid in the in utero environment. The second hallmark is the Arnalia malformation, particularly hindbrain herniation, where the hindbrain and these malformations descends into the, the upper portion of the cervical spinal canal, and this, in turn, uh, leads to hydrocephalus and brain damage. So I can advance these, I guess, huh? I can. The natural history of meningocele is shown here. Um, it corresponds in part, uh, to the anatomic level of the defect, the proximal extent, and this includes hydrocephalus, hindbrain herniation, motor and cognitive impairments, bladder and bowel incontinence, uh, lifelong quality of life issues. The outcomes with standard conventional care after birth are that roughly 14% die by age 5, mostly due to symptomatic brain stem compression due to hind brain herniation. About 85%, uh, require shunts, with about half of those shunts developing complications like infection or, or occlusion within one year of age. Uh, 33% have an IQ less than 80. Only about half can live independently as adults. The rationale for fetal surgery for my meningocele is based on a two hit hypothesis. First, the failure of neurulation. The second hit is secondary damage acquired in utero from amniotic fluid and or meconium and or hydrodynamic forces within the, Neurolacode or the fetus is back rubbing against the uterine wall. There, there's a little story behind this that involves, uh, UCSF and Martin Muley, who's one of our panelists. Uh, in the early 90s, Martin and Claudia Muy came to UCSF to do a research fellowship in fetal diagnosis and treatment with Mike Harrison and me and Alan Flake. And Martin had an interest in spina bifida, and he read an abstract, written by a pathologist named Grover Hutchins from Johns Hopkins. And that abstract cited an autopsy series of human fetuses with spina bifida, and he had examined the exposed neural plaque code and showed that there was apparent damage in utero to the exposed spinal cord, uh, that related to the gestational age of the fetus, uh, greater gestational age, uh, more injury. And so we decided to take this to the laboratory. At that time, we were doing a lot of work, uh, in fetal sheep. And what Martin and Claudia Muhly did was to, in mid gestation, fetal sheath, remove all the hard tissue, soft tissue to expose the uninjured spinal cord at mid gestation. And this shows a photograph of meningocele creation in fetal sheep at 75 days gestation where term is 145 days. Uh, I, I can't, oh, we don't have the photographs. That's a shame. Well, basically, the skin of the lumbar area of the fetal lamb is excised. Uh, the paraspinal muscle is excised, uh, to mimic what we see clinically because there's a deficiency in paraspinal musculature. A complete laminectomy at L1 to L5 is performed. Uh, I'm not seeing the photographs here. Are you seeing them there? No. No, we're not. We're trying to. We're working on. We're, we're working on trying to find them. It's not, uh, crucial. Um, and then, so a complete laminectomy is done, and now, and then, uh, the fetus was put back into the uterus and about three months thereafter was born, and you can see on the left, the newborn lamb with the mild meningocele, it's wool, wool bearing. It looks strikingly like what you see clinically in a human newborn with mild meningocele. And if you look, look at this lesion under the microscope, the spinal cord is largely destroyed. If you do neurologic testing on these sheep, the dressing covers the mild meningocele lesion. Uh, they're paralyzed from the waist down, uh, and are insensate. So mid gestational spinal cord exposure leads to a humanlike my meningocele, or MMC at the time of birth. The next step was to create the lesion, uh, go back in 4 to 6 weeks to, uh, cover the lesion, do a repair. And, uh, then, uh, look, look at the functional results of the sheep at the time of birth, and this showed that in utero coverage, a mild meningocele rescues neurologic function at birth, and here's the. Uh, this was a publication 17 years ago. Nature Medicine. And there's a video I, I hope it works, um, that we'd retrieved from the UCSF archives. uh oh, that's not a good sign. Its archives that shows, and I don't hear the audio here because Martin Muley is moderating. It shows a lamb that. Well, at first we were very surprised to see that these were just cute little and almost normal lambs. First of all, they had a heel back wound, um, and the lambs had a near normal neurologic function. They were able to stand up. They were able to walk. They even climbed upstairs and came downstairs, and, uh, very interestingly, they were not incontinent of stool and not incontinent of urine. Somatosensory evoked potentials were measured and demonstrated conclusively that the repaired animals had sensory function in their hind limbs. Microscopic studies were also performed on these lambs. They showed that the spinal cord was deformed in some cases, but the interesting result was that there was minimal loss of neural tissue in the part of the cord that was exposed and repaired. So the basic result of the study was that the repaired spinal cord was intact. So we can go on to the next slide because I can't control it here. There we go. So, and the same, uh, sort of principles were confirmed in non-surgically induced models. The, uh, curly tailed mouse model that Martin Gilley's group worked on, uh, Enrico Danzer in Alan Flake's lab at SH developed a retinoic acid induced model that showed the same findings, basically. About the mid 90s or so, numerous groups were thinking about repairing my meningocele before birth clinically. Uh, this, this was a big step from going after life threatening malformations to one that was devastating, but not truly life or death. This shows our rationale for early gestational repair at 19 to 25 weeks gestation. 95 or 96. I think all this is pretty self-evident. The downside to doing an early gestational repair, though, were, were, were potential risk of premature birth and death and, of course, maternal complications, which I'll get into in more detail. And of the 1st 50 or so fetal my meningo cell repairs that we did at CHOP, there were 3 deaths due to premature birth. And this shows a publication in The Lancet of an early gestational repair around the same time clinical work is being done at UCSF, and, uh, a lot of, uh, clinical cases were being done at Vanderbilt. One of the serendipitous findings was that the hindbrain herniation, which is apparent on the left hand side, a sagittal view of a 22 week gestation fetus, and I can't point it out, but there is hindbrain herniation there, was reversed, uh, as seen on this MRI, uh, at the time of birth in a fetus who underwent in utero repair. Subsequent work, uh, in SHEP by Diana Farmer and Rusty Jennings at UCSF and then by Sarah Bouchard at CHOP, showed the mechanism, how this occurs. And with mild meningocele on the left, the cerebral spinal fluid, uh, which spaces the brain inside and out and the spinal cord runs out through the back. Uh, the hindbrain comes down and gets wedged in the upper portion of the cervical spinal canal, interferes with cerebral spinal fluid flow, leading to hydrocephalus. And if this is repaired or closed before birth, you not only prevent amniotic fluid from coming in, but cerebral spinal fluid from coming out. I guess you could view this as a pressure column being reestablished in the spinal canal and the hindbrain goes back up, whereas this is not the case if you wait until the time of birth for repair. To do the operation, Alan Flakes, some of his videos showed this, uh, nicely for open fetal surgery, maternal general anesthesia, maternal laparotomy. We use a transverse approach. Uh, this shows the uterine stapling device in place. This is straightforward to place. Uh, you place two full thickness stays, sutures under sonographic guidance. Use the cautery to go down through the myometrium and through the membranes in a completely relaxed uterus and then insert the stapler. This shows a stapled hysterotomy. You can see the white absorbable staples. Uh, you can see the my meningocele lesion. I see the uterus, and on the left is a needle for injection of muscle relaxant and narcotic as an additional fetal anesthetic besides maternal general anesthesia. Fetal echocardiographic monitoring is important. Uh, I think, uh, one of the hallmarks is you need a fetal cardiologist there in the operating room to monitor the heart and the function and the rate, not, not only umbilical arterial wave, wave forms. Jack Rek and his team does that for us at CHOP. Many times it has changed intraoperative management because we've had to look for potential problems with umbilical cord profusion, uterine arteries, positioning, too, too deep anesthesia. The arachnoid skin, uh, junction is incised. This operation can be done under, uh, 3 or 4 times loop magnification or with the operating microscope. Dura is closed if it's present, myofascial flaps are raised, and then the skin is closed. This shows various views, uh, from, from Mark Johnson's collection of my meningoceles. You can see various size sacks to a no sac with a mild, uh, or a, uh, molluskschisis. And this is what the postnatal back looks like if the baby, Reins, uh, in utero for weeks. In about 15% of our cases since the stop of the MOMS trial, we've had to use an Alloderm patch because there's been insufficient skin, and that appears to be a little more prevalent in myelischesis cases, but the numbers are small. This shows our results prior to the MOM's trial at SHOP, uh, 50 cases, upper anatomic level of TA to as low as S1. Gestational age at time of surgery, just shy of 23 weeks. At delivery about 34 1/2 weeks. Uh, 3 deaths due to very premature, Birth, partial or complete reversal of hind brain herniation in all cases. Information about ventricular size, the cortical index, which was improved by ultrasound, the shunt rate by one year of age, 40%, which is a figure to keep in mind in light of the MMS trial results that I review. All these babies were born in Philadelphia, so a neurologic assessment could be performed. 2/3 were two or more levels, uh, better functionally than the anatomic, Level urodynamic data is still incomplete. Long term function is, is an unresolved question. Ooh. Um, this slide did show, uh, the results that Natalie Rintoul looked at in terms of looking at 300 or so babies found in the CHOP spina bifida clinic who were treated after birth and showed basically that the incidence of a shunt, uh, postatally was about 85% as opposed to 40% for those treated before birth. The OB complications is very important, uh, at CHP. Uh, chorioamniotic separation is usually a sonographic finding, but, but in, uh, 4% of cases it was a global separation requiring admission for bed rest and monitoring. Preterm labor requiring magnesium sulfate in 6%, maternal transfusion in 4%, postoperative oligohydramnios in 6%. Mean postoperative hospital stay was about 5 days. Uh, no, no ICU stays. And, uh, delivery before the planned C-section date at 36 weeks was, uh, in 44% of the cases, and in that group, uh, the mean gestational age, at delivery was 32 weeks. Mean gestational age for the entire group, 34 1/2 weeks. No uterine dehiscan at the time of delivery, but, of course, these are like classic cesarean section, uh, scars, and the mother requires a C section in the fetal surgery pregnancy, as well as for all subsequent pregnancies, which is a big commitment. The CHP experience for follow up for those, uh, I guess, nearly 60 children treated before the MOMS trial has been coordinated by Mark Johnson, and he and, and the group showed that there was a decreased need for a VP shunt and reduced hydrocephalus and shunt related morbidity. Reversal of hind brain herniation reduces the CRI2 related accumulative mortality and morbidity. And improves neuro functional outcome and ambulatory status. For instance, at age 5, these children, 83% were in the average or high average range on neurodevelopmental tests. So this data was accumulating while we were doing, uh, the MOMS trial. So here are the potential benefits and risks of fetal myelomeningo cell repair, which I think I've outlined. Um, but it was time, and I think, to consider doing a randomized prospective trial. There were 3 centers really doing this, many other centers who had an interest, and we really didn't, uh, know what, what, what the benefit risk ratio was. So it was probably the only time. Uh, in the evolution of this therapy to do a randomized, uh, prospective trial. This is called the MOMS Trial Management of mom and Inosele study, MOMS for, uh, short, um, and, uh, it was sponsored, uh, not completely paid for, but sponsored by the NIH, by the NICHD. The goal of the trial was to compare the safety and efficacy of in utero repair of open neural tube defects with that of standard postnatal repair. I'm, I'm, I'm getting some echoing back. Is that OK? Uh Alan. Are you guys there? Yeah, are your speakers on? I don't think there was just some echoing coming back. I wanted to make sure that wasn't a problem for you. We hear you clearly. OK. So around the year 2000 or so, there, there were those three, centers, uh, doing meningo cell repairs. Um, when you think about doing a randomized prospective trial, it's difficult for, say, a medication, much more difficult for an operation, and then an order of magnitude more difficult for a fetal surgery operation. Uh, we were very challenged by this in terms of standardization. And from my point of view, getting consensus was perhaps the most difficult thing I've been involved in in my career. Prospective randomized trial for clinical centers. Liz, Tom, George Washington ran the data and study coordinating center where all the data went, so the investigators were blinded as to results, and through the International Fetal Medicine and Surgery Society study, there was no back door. Other centers who could do fetal therapy in the US agreed not to do it during the duration of the trial, and if this back door hadn't been closed, uh, I think the trial would have been unsuccessful. And I'll go through, um, Income variables. Inclusion criteria are shown here. My meningocele, uh, myeloningocele starting at T1 to as low as S1, approximately, with evidence of hindbrain herniation by MRI. Singleton pregnancy, less than 26 weeks gestation, normal karyotype. Since the NIH was partially funding this, uh, the patients had to be a resident of the US and at least 18 years of age. So, if there was massive fetal ventriculum megaly, could still be a candidate. If there was bilateral club feet, could still be a candidate. The exclusion criteria shown here, additional fetal abnormalities, a variety of maternal risk factors, including a risk for preterm labor, insulin dependent diabetes, and, uh, morbid obesity with a body mass index of greater than equal to 35 or any, any other maternal contraindications to elective operations. Did my slides go, oh, there, there we go. Uh, the geographic triage of patients is shown here, uh, patients from the west to UCSF, from the Midwest and the south to Vanderbilt, and from the Midwest and the northeast to CHP. I actually came up with this idea during our, um, conferences based on the 2000 presidential election with electoral college votes, and then Liz, Tom, uh, fine tuned this with actual birth rates. The evaluation at the mom's center was quite comprehensive, as shown here, uh, two day process. For the mother carrying a fetus with a mom meningocele who might be a fetal surgery candidate at less than 24 weeks gestation, her choices included termination of the pregnancy or near term cesarean section with postnatal mom meningocele repair, or entering the MOM's trial if she was a candidate. Randomization to newborn discharge is shown here. The prenatal group admitted, repaired, remained near the center until delivery, and then delivery by C-section at 37 weeks if undelivered. The postnatal group would return home, have surveillance ultrasounds once a month, return at 37 weeks to the MOM center for delivery by cesarean and postnatal closure within 48 hours by the same neurosurgical team at each of the three clinical sites. To a license was standardized. Primary outcome measure one was death or the need for ventricular decompressive shunting by one year of age as defined by objective criteria, and there was an independent committee of neurosurgeons who, uh, determined whether or not criteria had been met. Criteria for shunts was defined by one of the UCSF, pediatric neurosurgeons, very important. Primary outcome measure two, the reviewers wanted curiously two primary outcomes. This was a composite outcome that Liz Tom came up with, which was a combination of mental development and index and the difference between the motor level and the lesion level. Secondary outcome variables, maternal, neonatal, infant, as you would expect. Follow-up exams were performed by what I call SWAT teams, pediatricians and psychologists who would come into the three centers and do the evaluations at 1 year of age and at 2.5 years of age, independent of the investigators, and they were blinded with regard to the infant's treatment assignment. The oversight was strict. There was a blue ribbon oversight committee at each of the three clinical sites that would review randomized cases on a monthly basis. The local IRBs, of course, uh, the steering committee that was chaired by Mary Dalton and involved the three principal. 4 principal investigators, the Data Safety and monitoring Committee and the maternal Fetal Medicine Network Advisory board. I should note that the PIs for this study were at Vanderbilt, Joe Brunner, and then, uh, Ed Yang, and then John Brock, um, the, at, uh, UCSF, Mike Harrison, and then Diana Farmer, and, uh, I was the PI, uh, at CH. The MOUS trial was stopped, stopped on December 7, 2010 by the Data Safety Monitoring Board because due to the efficacy of prenatal surgery, both at 1 year of age follow up and 2 1/2 years of age follow-up, and at that time, 183 patients had been randomized, and, uh, the 12 month follow up had been in 158 patients and the 30 month follow-up in 136 patients. We still don't know the urologic results were still blinded as far as those results, because that was started, uh, during the MMS trial. New England Journal of Medicine publication in March of 2011. The take home lesson for primary outcome variable one is that shunts were placed in 40% of the prenatal surgery group compared to 82% of the postnatal surgery group. The outcome of the children at 2.5 years of age, the primary outcome score was highly significant. But it, it wasn't weighted at all in terms of the neurodevelopmental index at 2 1/2 years of age. It was strictly the difference between the motor function and anatomic levels, and this, this was true for the Bailey's psychomotor development index, the Peabody Developmental motor scales, uh, the WIFEM scores for mobility, and the walking status. 42% of babies in the prenatal surgery group could walk independently, whereas only 21% in the postnatal surgery group. This was despite the fact that there were anatomically higher mild meningocele lesions in the prenatal surgery group by, uh, serendipity. Uh, lesions that were L3 or lower on sonography, 68% in the prenatal surgery group, 84% in the postnatal surgery group. So, the prenatal surgery results were better in terms of motor level, despite being more severe cases, if you will. This shows the outcome variables in terms of radiologic findings, better for prenatal surgery, for hind brain herniation, brain stem kinking, syringomyelia, location of the fourth ventricle, and so forth. Maternal outcome is very important, mimicked what I showed you for that CHOP preliminary data pre moms. Things to point out are, uh, blood transfusion at the time of delivery, 9% in the fetal surgery group. Status of the hysterotomy site at time of delivery, intact in about 2/3, because it was inspected in all cases, very thin and 1/4, an area of dehiscence of the scar in 9% and complete dehiscence, um, in one case without rupture. Fetal or neonatal outcomes. Perinatal death, 22 deaths in each group. uh, gestational age at birth just beyond 34 weeks in the prenatal surgery group beyond 37 weeks in the postnatal surgery group. Of note, 13% of the babies in the prenatal surgery group were, were born at less than 30 weeks gestation, and Mark Johnson has looked at the full delivery cohort now, which is a complete data set, and that rate is 11%. So about 1 in 10 were born at less than 30 weeks gestation. Uh, the, as far as new, newborn complications go, the only one that was statistically significant was the presence of, uh, respiratory distress syndrome, um, much higher in the prenatal surgery group than the postnatal surgery group. So the conclusions are the prenatal repair of my meningocele is not a cure. Uh, there was a lot of talk about that before the MOMS trial in terms of miracles and things of that sort. Well, it's, it's not a cure. It's not a cure, but it did reduce the need for ventricular shunting to treat hydrocephalus and improve motor outcomes, including the ability to walk at 30 months of age. But it's associated with significant maternal and neonatal risks, including premature birth and uterine scar issues. So what's next? Well, this should be a focus, I would hope for the panel discussion. We need to complete the MOMS trial data set, which is probably about 12 to 18 months away, plus the urology study. Uh, Doctor Mark Johnson has looked at the full delivery cohort, and he can address this more, but longer operating room times correlated with increased risk for preterm birth, as did oligohydramnios postoperatively. Longer OR times may be a surrogate for surgical team performance. We need more information when the one year cohort is, uh, complete for prenatal predictors. Perhaps there are those fetuses with severe ventriculomegaly who might not be good candidates for fetal repair because they may end up with a shunt no matter what. The same thing may be true for tapes. We need to look at maternal morbidity, future pregnancy and psychology. All, all, all, all those results are pending. We have the ideal chance to look at cost, prenatal versus postnatal, perhaps in the 1st 5 years of life. A group from Washington University at the last MFM, um, SMFM meeting used the financial model and the mom's trial information, uh, to show that over $3 million would be saved, uh, for 100 babies treated before birth. Uh, Julie Moldenhauer and others have been involved in the NIH sponsored maternal, See repair task force guidelines for new for new centers and competencies, so that's worthy of discussion. We're in the midst of the MMS2 study, follow-up at ages 6 to 8 in the school age group to see if these results are durable, and we need to explore earlier and minimally invasive intervention using tissue engineering techniques. This shows our results at CHOPPS since the end of the MOMS trial, um, December 7, 2010 until recently. We've had a lot of referrals, uh, 359, 202 after screening were evaluated on site. And note that only 60 fetal, uh, fetal surgical repairs of mom meningocele were performed, which is only 30% of the on-site evaluation. So, 70% were either ruled out on maternal or, Fetal criteria, or in some cases elected that this was not for them if they were candidates. Postnatal surgery total 92. Uh, half of those have been done at shop, and 7 of those would have been fetal surgery candidates, but the mothers decided that this wasn't for them. Termination of pregnancy in 62 cases. Uh, 10 of those cases were fetal surgery candidates. The other 52 were not, and the family decided to abort. There were three, evaluations where there was a normal fetus. There was one case that had fetal surgery elsewhere who we turned down as a candidate using mom's trial criteria, and there was one case of in utero fetal demise. One interesting point is fetal surgery exclusion for the absence of hindbrain herniation on MRI, looking at the analysis versus using ultrasound alone. Uh, the absence of hindbrain herniation, which usually signifies a closed defect with a thick membrane in which there's no cerebrospinal fluid leak, who would not be a candidate for fetal surgery is important. But of these cases, with hind brain herniation clear, with absence of hind brain herniation clear by fetal MRI, by very sophisticated ultrasound, hind brain herniation was a positive call in 5 of those cases, and it was an equivocal call in 4 of these cases. So, I think the important lesson here is in terms of preoperative evaluation, uh, fetal MRI, uh, should, should be mandatory in my opinion. What about fetoscopic me meningo repair? Are you using 3 or 4? Ports. Well, this is an appealing concept to mitigate maternal morbidity, but the Achilles' heel is that 3 or more ports leads to fixation of the membranes and tearing with uterine growth. Premature birth 3 to 6 weeks after surgery and delivery before 30 weeks gestation as a rule. And based on results that are available, at least now, with fetostoscopic repair, largely in Europe, compared to open fetal myel meningocele repair, fetoscopic repair has higher rates of fetal death, premature rupture of membranes, chorioamnionitis, oligohydramnius, premature delivery, and persistent hindbrain herniation. So until this problem of 3 or 4 ports is solved, um, I, I think that, uh, fetoscopic repair should be on the back burner. What about tissue engineering approaches? Well, Miho Wat Nabi, who is one of the research fellows working with Alan Flake in the lab, is working on, Enrico Danzer's mild meningocele retinoic acid induced fetal RAP model, as shown in the left upper panel. Characteristic. You can see the, the tail there. Uh, and you, you, you using a Hydrogel scaffold, closing the defect at E18. This is the appearance at the time of birth, where the concept is to seal the lesion before birth, to prevent amniotic fluid and meconium exposure before birth and to prevent a cerebrospinal fluid, uh, leak. We're pursuing this as well. In, uh, fetal sheep using ultraviolet light activated underwater adhesive like glues, biologic glues, such that mussel shells produce nano textured biogradable elastomers using gecko technology and also cell sheet technology. So this should be an area of discussion during the panel because I know that Diana Farmer, and others are working in this area as well. And this shows, uh, I guess we won't see the video, but it shows a fetal sheet my meningo cell closure with a geltin Hydrogel scaffold, and then we can call up the video, and that'd be, Sort of fun. This is Alan Flake and Miha Wat and I'm, I, I, I'll be putting a seal in. So the concept eventually would be to have injectable tissue engineered components. That could be placed under ultrasound guidance by needle like an amniocentesis or through a single fetoscopic port to seal the defect, prevent amniotic fluid exposure, prevent CSF leak, and perhaps this could be done even earlier in gestation. My bias is the earlier the better, so it would be wonderful if this could be done at 15 to 16 weeks gestation. I think that's the last slide. Oh, well, the, the linchpin of this presentation, of course, is the, uh, MMS trial, uh, and many thanks to these, uh, groups, many, many names. What an incredible trial that this was, and at the sites, uh, the, the 3 clinical sites in George Washington as well as the NICHD where Kathy Spong played a crucial role. And many thanks to the women, their children, and families, the IFMSS, the SMFM, the fetal therapy community, and the perinatal community. That's it. All right. Thank you, Doctor Adzik. That was, uh, perfect. That was fantastic, and I think we have a lot of, uh, discussion points to go over. So that was a, a phenomenal talk. Thank you very much. Um, we'd like to know, uh, bring on the, the faculty to start going over some questions and discussion over some controversial points. Uh. So, uh, Mike Harrison and your group at UCSF Hae Min Lee and Xin, uh, can you guys, uh, load up your, turn on your camera, and, uh, Yinka, uh, from Texas Children's, go ahead and turn on your camera. We see, uh, Doctor Diana Farmer from UC Davis. Welcome back again. Uh, Doctor, uh, Tim Crummelholm from Denver Children's, go ahead and turn on your camera. We also now have Doctor Kelly Bennett from Vanderbilt. Uh, go ahead and turn on your camera. Uh, Doctor, uh, Julie Moldenhauer from CHOP. Hello and welcome. Thanks for joining us. And, uh, Martin Muli from Zurich, uh, is should be on the line too. If everyone can turn on their cameras, we're gonna have a, it looks like Brady Bunch here. We're a big party going on. So, um, Alan, a lot of issues were brought up, um, and, uh, between you and Doctor Adzik and Doctor Johnson, if you have, uh, points to bring up, I also wanna introduce Doctor Roger Hudgins. Uh, Doctor Hudgins is our, uh, chief of pediatric neurosurgery here at Akron Children's Hospital and, uh, is gonna be giving us the neuro, the pediatric neurosurgeon perspective and his opinion on all this as well. So, uh, welcome, Doctor Hudgins. Thanks for joining us. Um. So, um, well, first of all, I think it looks more like Hollywood Squares out there than the Brady Bunch. Who got the middle square? It's Mike UCSF group. OK, um, I, I, I wanna say this is a, a hand assembled panel because, uh, we have representation from all of the moms, uh, groups. We have some new American centers, uh, only new from the perspective of MMC, but, uh, Tim has, uh, started doing the procedure. Uh, the Texas Children's Group has, uh, started doing the procedure. Um, and we have a new European center. Martin Muhly's, uh, joining us from Zurich, and also Jan de Prest has, uh, has started to initiate a center in Europe. And so, There's a, there's a spectrum of center experience, a spectrum of. Uh, stages of center development here that I think will add to the discussion. We also brought in, uh, Julie Moltenhauer, who has a lot of firsthand, um, Experience with the thought process of trying to develop guidelines for centers of myelomeningocele, and I think that's probably where I would like to start the discussion since we ended the discussion in the open fetal surgery with, you know, how do you develop the fetal surgery center, uh, what's required, etc. and I think, uh, that's a natural lead-in into a discussion on, uh, what's required for a myelomeningocele center, what should be in place. Um, What are your opinions on that, Julie? Why don't you start us off? Sure, so, um, last fall, probably in October, the first meeting, um, was held, and, um, the folks at the NIH sponsored a group of us. There were folks from the, the fetal therapy community, um, many professional societies, and members also from, um, insurance companies that were present. It was really just a think tank to open up the discussion. How do we move forward and sort of transition, uh, fetal MMC repair from the three groups that participated in the MOMS trial to a more broad. Uh, group and so from that came a second meeting where at this juncture it was solely the representatives from multiple professional societies. There's 12 in total and we came up with basically a set of sort of guidelines. To move forward on it's, it's still not yet published, um, and it has really taken a lot of time to get everybody on the same page as far as moving forward and coming to a general consensus as you can imagine, but the, the bottom line really was is that having a, uh, an established fetal fetal center um performing the surgery where there were um. You know, a multidisciplinary approach at each center, including, uh, maintaining the mom's trial criteria, intraoperative procedures and postoperative care, uh, was also, uh, one of the big key points. And then to also how do we move forward in maintaining, um, outcomes data and, um, benchmarking progress as this is sort of transitioning to multiple centers, uh, across the country. Yeah, I realize you can't go into too much detail as it has not yet been published, but um There was a lot of discussion surrounding the issues of volume requirements. And I think that's uh particularly important in view of the numbers that Scott showed in the post-mom era of requiring 3 or 4 referrals really for a single appropriate case of myelo meningocele. So, um, Can you give us a general idea of, of the consensus on that at least? So I think the gist is that there's no real consensus on a specific number. So is it 10? Is it 25? Is it 50? Um, I think the consensus more was towards, you know, if you're doing 100 but you're having, you know, a 20% perinatal loss rate, that that's probably not a good statistic. 5 and you have good 5 good outcomes, that's a marker for, you know, a center that's doing a good job. And so really, uh, outcomes data is the driving force for what is an adequate number. And so reporting of results is obviously the key to that is it, uh, is there a mechanism envisioned for reporting of results and, uh, some quality control over sinners? Obviously the big concern is whether the results of the mom mom's trial can be propagated in less experienced sinners. Yeah, so I mean right now we're in the process of putting together a national registry. We had a FEA MMC consortium meeting that happened in October just before the NAFNET steering committee meeting on a Friday afternoon, and the hope is to have this become an ongoing meeting as we're moving forward and creating a national registry. Um, we're interested in hearing, you know, what folks have to say about what our tracking points and monitoring points, but really the gist of it is is that we are going to try to move forward and have a national registry that everybody who's performing MMC repairs can contribute to and that we will use this as benchmarking and quality data. Any thoughts on this from the other panel members? There must be. So when is this gonna come out? When's the publication gonna come out? Uh, hopefully in the next month. And where is it gonna come out? Um I know the answers. Yeah, well, it's gonna be in a couple different journals that are specific to. Fenotherapy, so. She'd have to kill us if she told us, Scott. He's already tried to, I think. So Tim, you've, you've started a new center out there. um, what are your thoughts about it? How do we, how do we maintain the right number of centers, reasonable quality control, all those difficult questions. Well, I, I, I think it's extraordinarily hard to control, Alan. I think all we can, uh, at the current state of things is to make. Best recommendations about what are the criteria that you should have to set up a program like this? What kind of experience, what kind of expertise, uh, not just having an MFM and a neurosurgeon, but every aspect of a fetal center, uh, that's necessary to care for these, these moms and their babies. Um, I think the consensus, uh, uh, statement that Julie alluded to is going to be a good first step. Um, but I honestly feel that one of our societies, whether it's SMFM or the IFMSS, uh, needs to step up and take a leadership role in setting the bar a little bit higher, because, uh, as you can imagine, the consensus statement is fairly, uh, generic, and the bar was set fairly low. Uh, and that's one concern that I have with. Uh, centers with without sufficient, um, oversight, without sufficient support, uh, maybe, uh, entering into some very deep water. I read it. You can tell it's a. Later in the evening in Europe, I guess we have a blackout on our European uh yeah. Panel members, but they're there. I know they are, and it looks like Jan de Pres has also joined us. So we have two new European centers out there. We'll get to to Europe before too long, um. So it is very difficult to regulate and control centers that come on board. One of the concepts that's been propagated is that there should be mentorship of new centers from old centers and that there should be some sort of a a training phase and follow through of support and education for the centers that begin this work. Um, any thoughts on that process and the appropriate, uh, Ways to do that. Well, you, you might, you might make a comment about uh what we've done with Jan and with Martin and with the Michigan folks and with the Oshner folks. Mark, that's Mark. Well, basically, uh, with selected centers that we have a history with admittedly, um, and with individuals that we know well and have existing. Fetal treatment programs or existing programs in myelo meningocele. We've made an effort to both uh bring them to our center to observe uh cases, their entire teams, anesthesia, OB, pediatric surgery, etc. Um, we've developed relationships between members of our team with members of their team, so it's a totally open door. They have access to our protocols, access to our equipment lists, access to everything that we do at CHOP, um, to make this successful. And uh then on their startup phase uh at their institution, uh, Mark and I have gone to assist Jan De Prest. I've been over to help Martin Muli with his initial uh cases. Um, and I think it's an important uh transition from. Uh, starting on your own to feeling comfortable on your own, uh, to have an actual member of an experienced team, um, there to observe and to, uh, comment and to troubleshoot. And to have uh debriefings afterwards about what you did right, what you did wrong, what you can improve in the future. So, so that's. I think a relatively good model to get. Uh, centers that have the, the framework in place, uh, up and running, but, uh, it again depends on having an appropriate framework in place and, uh, individuals there that can pull it off. I think another, another important part of it is, you know, the way that we've done this is that we have the team come up for the entire two day evaluation and they see, you know, everything that goes into counseling a patient, not only all the imaging stuff, but the different counseling from the subspecialists, including the. MFM people, the genetics people, the surgeons, the neurosurgeons, the pediatric surgeons, you know, it's really a 2.5 day process and, uh, a lot of programs see what's involved and a number of them kind of just put up their hands and say, well, I, I see this is more complicated than we anticipated, and there are people that have backed away from it. So I think, you know, being there, seeing what's involved, going to the OR. Seeing the the multiple teams that are doing multiple different things at one time, it's like a a a well choreographed um ballet or something in many centers, once they see the whole process, realize that maybe their center don't have that level of expertise or or or. Um, institutional support that they can really pull it off and have backed away. So I think going to a center, seeing what's going on is an important, you know, process for anybody who's thinking about developing a, a, a program and get Mike's view on that and Tim's view and. Um, I, I think we have Jan on the phone as well, and he just made a comment, uh, texted a comment. So Jan, are you there and can you speak? We can't see you for some reason. Yes, indeed, uh, thank you, thank you for having me. Well, I can only add to that that personally, uh, our team also learned a lot, not only from the surgical technique, but also from the whole perioperative management of the mom, which for us was completely new. It is a tremendous enterprise we realized as well, and there the coaching, not only by the pediatric surgeon but also by the MFM specialists was extremely important because this was really something we were not used to. This is very critical care for the mother, and their direct coaching has been extremely helpful. And one of the major advantages of, uh, going to Leuven was also the availability of Belgian beer, which was a major incentive for the transatlantic flights and a known tocolytic. Martin, are you there? Can you comment on your European perspective there, and, and unfortunately, there's this black panel, and this has nothing to do with the fact that it's night in Europe. It's rather got to do with the fact that you guys seem to be having a firewall that hinders true beauty travel over the ocean. We didn't think you would notice that we did that. Yeah, it's, it's actually intentional, Martin. We have Jan, we have Jan's picture now, but you're still blacked out. But go ahead and talk to us. OK, no, no problem. What I want to say to you is that I totally agree, of course, with what has been said on how fetal surgery should spread over the world, and I'd just like to make a comment regarding our experience with the CHOP team. And from our prospect, this is an ideal way to learn. We've had this pretty exclusive partnership from scratch that of course originated in the collaborations that we had many, many years ago, and now the circle has closed, so to speak. And when we started the enterprise clinically, that was back in 2010. Alan Flake was there. We've been discussing the cases beforehand with the CHOP team, of course, also with Scott, and then he came over and we had a very comfortable situation because we could feel this is the great big expertise present physically, and that does make a difference. And we've now been doing 5 cases so far. And there was a constant briefing and debriefing process, and we've been learning a lot in terms of preoperative, postoperative management, but in particular, and this regards me as the responsible fetal surgeon, in particular with regard to the surgical technique, and it is. For me, it is absolutely unimaginable how somebody who has no training, who has no expertise, who has not such a fabulous physical assistance of a of an expert at the table, can do the job professionally and safely. So my comment is that is perhaps not one of the models, but most likely the only correct model to spawn fetal surgery to other centers. Because this assures quality, and this is the only thing we, we have to do to be correct vis a vis of our patients and their families. Uh that's uh Swiss beer is very good too, Martin, so the uh, I guess the one of the requirements is good beer wherever I travel to. Well, absolutely, but you know, we're we're pretty comprehensive in our concepts. This is not just the fetus, the mom, the family, the team, but this also comprehends the surrounding positive factors that make traveling, assisting, supervising worthwhile. So that's why you come so often to Zurich. So, comments from uh uh UCSF. Any thoughts on this? What's that? Diana is really the one who dealt with this most of the time. Diana, well, I think the, uh, the point you raised about education are critical, and I think there are a variety of ways to educate folks. I think the, um, experience of having someone with the team is really key, and I think Simon you visited the group in Minnesota that, uh, was getting started, and we, I would just echo. France at that time was the same. Many centers well thought they might want to do this once they appreciate um the full bread that's really required to do it in a safe manner, um, make may make the decision not to do it and that has been the case. Again, we all are aware that there have been maternal deaths around the world from this intervention, and I think anyone who undertakes this must be prepared to feel confident that if they had a maternal death, that they had everything in place to avoid that. Yeah, I don't know of any, uh, maternal deaths with open fetal surgery, Diana, do you? Yes, there was a paternal death with open fetal surgery in, I believe it, uh, Mike, it was the South American arena. There have been 3 There've been three? South America. Well, I think that just points out the need for, uh, preparation and expertise and guidance in this endeavor. I think it's a, a tragic, tragic thing and something that at least in early on, we always said we would uh quit the endeavor if we ever had a maternal death. So, um, so we're, we're in South America, so I know not to go there. Um, I was at the cytoscopy group in Ireland, and it was discussed there in the specific, uh, there was one in Colombia, and I think there were two in Argentina, but the specifics about them weren't available. Yeah, well, that's one of the things we we probably will never hear about them except by word of mouth. That's right. You know, I think that that is, that is why a society like IFMSS, these things should be discussed at that society. It must be possible to get details because there might have been avoidable factors, but most likely not. But then the word needs to be spread. This is not how you can do this. I think there are almost, uh, definitely avoidable factors. I mean, if you consider the US experience with open fetal surgery, um, we've had no maternal deaths. We've had no in the past many years serious maternal complications unless someone on my panel. Disagrees. I think it's been a very, very safe endeavor for mothers. Um, so I think if you, if you prepare appropriately, take the appropriate precautions, screen your mothers correctly. It should almost never happen that you have a serious maternal. Event. But you know, I'd like to ask the question. Do we know what the causes were for these apparently 3 mothers to die? No, we don't, we don't have the specifics, Martin, but, but I think one thing is clear, is that unlike, you know, the tremendous experience with fetal surgery in Leuven with Jan and your experience in Switzerland, these were in centers with far less experience with any kind of fetal intervention and not the same kind of teams that you already have in place before you embarked on doing mild meningocele surgery. Well, let's go on with a with a related topic then, which I think um. Obviously moms has set a standard. It's set a standard for fetal and maternal outcomes, and You know, there's the issue of, in a way it's stifle, it's stifling progress and innovation in the field if you, uh, you know, consider, uh, new centers living up to the mom's standard and doing things according to the mom's protocol as a sort of a requirement. So. What are, what are your views on innovation, innovation such as minimally invasive approaches? We heard a little bit of that from Scott, uh, and certainly the current unpublished for the most part, experience with fetoscopic treatment of myelo meningocele has been, uh, disappointing, and the results don't hold up to the mom's results. Um, but how did, how do you introduce, uh, innovation in this field? Where it's the appropriate way to do it, uh, in an ethical way. Cause you've got a lot of groups out there that are proposing, uh, fetoscopic approaches, tissue engineering approaches, um, some of which are actually being implemented on patients at the moment. So, What are your thoughts? Start with. Mike Well, Mike's the Mike's the innovator and he's always uh objected to anything that stifles innovation, so yeah, and, and recently, Alan, I've been very worried about, uh, uh, stifling innovation from a whole bunch of points of view, not the least of which is regulatory. So we have not had to in this field deal with the FDA and that regulatory. System, but it sounds like we're going to in the future. So there are two problems I see with the, with the trials. One is the trial effect that, um, that it's pretty hard to get around that is you, patients do better if they're at a fancy center, uh, that they're doing the trials, that's one. That skews the results. And the second one you've already talked about is the most important is if you have a long trial, you completely stifle innovation during that time. And the MOMS is a great example of that, uh. I don't know how many years it took, but, but during that time, no one could even think about a new approach. So. It's a problem. And probably the only solution I see, Alan, is what you've done is you just keep working away on new ideas in the laboratory and you wait until you get a chance to do it appropriately in in a person. Well, and the introduction of it almost has to be a trial compared to the current standard of moms. Which is You know, you know how trials go, right? They're very difficult to design as we just saw. Very difficult to execute. So, and it's even more, here's another problem for many things in fetal intervention. It's exceedingly, it's getting more and more difficult to do the first human case. It's there's no real, uh, criteria for it, uh, and, and in our environment, it's just getting to be a bigger and bigger and bigger risk. To the center and to the doctors. And I think it's easier in places like South America and Europe and Southeast Asia where they can proceed even without appropriate preparation or experimental work or otherwise. No question, Ellen, this is exactly what I think too. And, and Mike, why is it so difficult in the United States to start a new center? Perhaps I missed that one. It's not, it's not so difficult to start a new center. There are a number of new centers that have been started. I, I think, uh, I think in the United States, um, a lot of this, um, probably unfortunately in terms of innovation has. Been legislated by third party payers because I know that. When we've talked about whether or not patients who wouldn't have been candidates in the MOM's trial. Um, you know, if you slightly broaden some aspects of inclusion criteria, uh, you know, third party payers may not pay for it, and they may not pay for, you know, more than just the, the surgery itself, um, so that's, that's a big, I think, uh, driver of, of these unfortunately in the United States, and, you know, the other thing I, I just, uh, you know, if the MM study had, uh, two primary outcome variables. I think the mom's trial had two protagonists, Scott, and Diana, sort of an observer for this. It was just phenomenal leadership on their part to get this done. Because uh the amount of work that I saw from sort of an observer standpoint was, was, uh, really tremendous. And I think that, uh, Scott and Diane really give them the credit for it. So it's come to my attention that Kelly Bennett is out there from Vanderbilt somewhere, and, and I don't see her image, uh, or even her name. Are you there, Kelly? Yes, I am. I'm here. We're, we're sorry to ignore you. I just, uh, uh, can you turn on your camera, perhaps? Yes. Is your camera on? I have on, but it doesn't seem to be coming up. OK. If you click the start my webcam, try it again, maybe it'll pop up. In the, in the meantime, if you have any comments on what we've already talked about, um, I, I think, you know, our experience at Vanderbilt has been very much the same as as Chops in that, uh, people that we've hosted in terms of, uh, having them visit the team from, from Yale and Brown, and we had a group from France come, uh, Texas Children's has come, and you know, very much the same experience in terms of, uh, the effort that goes into developing such a multidisciplinary team. Uh, the, the difficult, difficulty of bringing that expertise to another center because in fact it is very much a team effort and you know it's not one individual that makes this surgery a success. And I think as everybody's aware, each individual case does bring nuances that you problem solve as you work through any individual case. So I think, you know, it's much like CHOP and UCSF, we've, we've seen the same thing that people are not as thank you. We still don't have your image up. We'll keep working on it. Um, Tim, do you have any thoughts on introducing, uh, innovation in, in this field? How, how the right way to do it is. Well, I, from my view, I, I sort of see the, the MOM's trial as not an impediment to innovation, but a spur to it. Um, I think that 5 years from now, we won't be doing open fetal surgery for this, and that we'll have a single port early gestation, uh, bioengineering solution. Um, and the thing that's gonna drive that are the complications from mom that were demonstrated in the mom's trial and the risks from a neonatal perspective. And while the mom's trial was a phenomenal achievement, and really I, I congratulate everybody who was involved with it, it still, uh, gives one pause when you're counseling moms about the obstetrical risks, about the neonatal risk. And it's not 100%, you know, we go from 82% to 40% need for shunt placement. Um, maybe we can do significantly better if we can achieve this at 15 or 16 weeks gestation. And Scott's points about the multiple port fetoscopic approach, I couldn't agree with more. You know, that's just not the right way to approach this. Um, but I think in the right hands, in the right centers, there will be therapeutic innovations. And eventually there will probably need to be some sort of trial with using the moms as a benchmark, but I, I think it's going to be a tremendous spur to innovation and developing new techniques so that we can achieve better results with less invasive approaches. Uh, there's no question that it's, it's not a solved problem and there's lots of uh impetus to improve upon the current approach, um. So I, I agree with you in that sense. Uh, the, the difficulty I have is the current problems with trying to do a new technology, such as a tissue engineered scaffold placement in utero and trying to get regulatory approval for that, trying to ethically implement it in a group of patients. Um, in, in our scenario, that's, that's actually quite problematic. I totally agree, Alan. I think that there's going to be a big, uh, problem in the future because more and more of our interventions are going to involve, uh, uh, innovative devices or substances like the muscle glue or those things. And the, and the regulatory pathway for those things is becoming more difficult all the time. Absolutely. Jan, you had something to. Well, we were at when we started the program under your supervision, we had this question here locally, having never offered open surgeries except for around the perinatal period for exit procedures. There was a huge resistance to to to start with this open program, and our ethics committee really insisted that we try to come up with a good argument why not to do it cytoscopically. So as Scott analyzed, I mean, cytoscopy currently with the available information and we really dig down in all the individual case reports and series that were available, is that indeed it does not mimic the surgery. It is having a 30-40% failure rate of achieving the surgical goals and then ending up anyway with preterm delivery, much more higher numbers and earlier than in open surgery that we could convince. The people who are sending patients to this program to keep on going with the open surgical approach, but at the same time we have said, look here, we are open if peer reviewed experience that comes available in the next 1 year, 2 years, 3 years from that center in Germany, if that comes up with reasonable results, that means similar efficacy, similar efficacy, same safety. And at least an equal outcome in terms of gestational age at birth, then we would consider that. But then we feel at that time that a nose to nose trial or head to head trial, we'll have to compare the two approaches, that at least if we stick with the same surgical procedure. How and at what time an alternative single port approach will come into reality that really will be dependent on on those experimental data supporting that approach. But you see here, we are permanently evaluating that, and we are certainly open to a cytoscopic approach because 1 out of 3 mothers here in the program declines because it is open. And that's whether we want it or not, whether that is the doctor who refers who plays a role. I don't know what it is, but we know missed opportunities for those fetuses to benefit from surgery. I want we would like to do it. Can I someone make a comment, yeah, and then I want to ask Dr. Hodgins a question. So go ahead. Yes, I'd like to make a comment concerning. The fetoscopic approach. One crucial thing from a neurosurgical standpoint, and I dare to throw it in because I am personally active in that field and I do the neurosurgery part also in the fetal surgery setting. is that it is not just sufficient to cover the lesion. This is maybe sufficient in the case of a myeloschisis where there's no cyst. And protruding, but in the classical situation of a cystic myelomeningocele, it is absolutely indispensable to remove the cyst, to excise those tissues that don't belong there, and to then only realize appropriate coverage. And people doing the fetoscopic approach must absolutely consider and realize this surgical step, otherwise the operation is ill done. It's ill conceived and not professionally done, and my feeling is that some of the people doing the feetoscopic approach. are not only not surgeons, but in particular they are not neurosurgeons, and some of the clues to the success of this operation are missing there and that is part of the problem. And the feetoscopic approach cannot just be putting there a tissue engineered or a bioengineered or whatever thing to cover up the lesion in cases of the classical myelomeningocele. That's not sufficient and to do the proper operation fetoscopically. As you mentioned, Tim, with a single port setting is a huge challenge. Perhaps if you can combine that with some miraculous robotics coming out from your single port and doing the correct operation, that's perhaps feasible. I don't believe. that this is going to be the case in 5 years from now, but perhaps in 10 years from now, but we should stick just with, with, with, with a basic knowledge how the neurosurgical part has to be done for the operation to be correct and successful. All right, we have a neurosurgeon waiting to come here. So we should take advantage of that. Yeah, this is great. I appreciate that. I appreciate the plug for my specialty, uh, here, but, uh, uh, it's, it's really, uh, uh, an honor for me to be here and be, have the, the, uh, the possibility to discuss this. We're really the world's experts. But I don't know if anybody watches college football, but I feel a little bit like, uh, Lee Corso on game day, and, uh, not so fast, my friends. Um, I think there's still some things, uh, out there that, that we need to solve before we kind of move along here. One of the things actually, um, uh, that I have a question I have for the, the mom's participants is. In looking at the data, it says that 51% of the prenatally repaired uh uh children met shunt criteria, yet only 31% received or 31 received a shunt. So if you do the math there, I don't know exactly what that end would be, but it comes to about 65% that those babies that were repaired prenatally. Could have had a shunt and maybe should have had a shunt but didn't have a shunt. So my question is, what happened there and what does that mean? So I can speak to that a little bit and appreciate that uh comment. One of the challenges when we put this trial together, um, and really War Peacock at the time was my neurosurgical consultant who helped with the original concept of trying to develop a reasonable primary endpoint. Uh, the problem was that the variability in the neurosurgical community or the placement of shunt in, at least in this country, and particularly in California, was absolutely enormous. And, Was influenced a lot by individual neurosurgical preference. There were those who felt strongly that every single child should have a prophylactic shunt placed at the time of closure of the myelomeningocele defect. There were those who felt that the complications associated with shunt placement are are significant enough that you should avoid placement of a shunt until the latest possible time. And this variability across the country, uh, persists in terms of neurosurgical, um, practice. So the reason that the shunt criteria was developed. Uh, and really with the guidance of work was to try to standardize an image-based way to evaluate this outcome across. The multiple patients, there is a tremendous amount of diversity, as you know, in the way the spina bifida lesions present. There's variability in the association of the chia malformation with the height of the, the location of the lesion on the back. So this is a pretty variable disease to which uh we try to apply a randomized trial and the development of the shunt criteria was an effort to try to standardize what has been the variable indications for shunts across the world. But, uh, you know, maybe I'm misunderstanding, but I would have thought that the same criteria would apply for both the post and the prenatally treated uh children. Yet in the post-treated children of 74 that met criteria for shunting, 66%, 66 were shunted. So 66 of 74. Yet in the pre. It was 31 of 51, so there's a, there's a big discrepancy. Were the mothers, the families of those children that were prenatally treated more motivated to not have a shunt? Because I will tell you that out here in the community, that's the word. Is that these prenatally treated uh families are really motivated to not have a Chiari malformation, not have a shunt, and, and, and so forth. So who, who made that decision if they met criteria for a shunt but then did not have a. Unplaced. So, um, I can, uh, answer that. The decision of whether or not they met, met criteria was made by an independent, a neurosurgical review panel made up of, uh, separate neurosurgeons that were not part of the, any of the individual centers. The decision to actually place a shunt was made by the patient's doctor. So this is why there's such a discrepancy. People went back home to where they came from and were managed by their home neurosurgeon. Now, an effort was made to, uh, have consultation with the trial neurosurgeons about what the indication was, but really mostly to try to collect the data. But there are two separate evaluation groups. The need for a shunt was divided, was decided by this independent neurosurgical review committee, and the, uh, the meeting shunt criteria, and the actual placement of the shunt was done by the patient's individual doctor. Well, you know, again, um, in my personal experience, I've seen a couple of these children, I would come around and find them in the spina bifida clinic after their repair, and quite often fontanelle full, uh, head circumference growing very rapidly, large ventricles on an ultrasound, and the family's telling me that they didn't want, didn't need a shunt. And, and I would tell you that I think that the families directed a good part of this. There's some discrepancy here, at least in my mind, that needs to be explained. Well, 11 thing that might help is that Liz, Liz Tom gave me information about that discrepancy between meeting criteria and actually getting a shunt, and so she, she sent, sent me a message that, that I can read. Um, and it has to do with the criteria in which, uh, it has to do with head, head, head size, basically, which is criteria number 3 on the slide. And she wrote, if the head circumference was large, greater than the 95th percentile, or increasing, or the ventricles were increasing, it had to be at least two of these three within that criteria 3, but there were no accompanying symptoms, that is a bulging fontanelle or split sutures or a sunsetting sign or for those babies less than one week of age, apnea, bradycardia, lethargy, then quite often the neurosurgeons didn't place a shunt. The vast majority of patients where shunt criteria were met, but no shunt was placed, were in that criterion only. If revised shunt criteria based on a modified criteria 3 are used, then there's a very close match between shunt, shunt criteria and shunt actual, actually in both groups, prenatal and postnatal. So she, she writes, and this is a biostatistician saying this, clearly the neurosurgeons were not, quote, shunt happy, close quotes. The primary outcome was death or shunt or meeting criteria for a shunt, and if we look at death or shunt, or meeting the revised criteria for a shunt, um, in the prenatal surgery group, the, the outcome is 46% and the postnatal surgery group it's, uh, 86%. Now, we'll have a chance to when the one year cohort is complete. And it'll be the responsibility of one of the three neurosurgeons at one of the three clinical sites to write that up and, And meet some of your questions. Those are good questions. We have, uh, uh, questions from the audience. Uh, Doctor, uh, Ambre, uh, Gabriella Ambrese, uh, says, do you use antibiotics, uh, in the surgery for the fetus? Yes. OK. Uh, and then how, how certain is the reversal of hindbrain herniation with fetal repair of MMC? Check, check the slide. It has all the information. Uh, but, uh, uh, it's pretty certain. Yeah. OK. Just to refresh people's memory. I mean, that's, that's been probably the most, uh, uh, consistent and reproducible finding of fetal closure of myelomaningocele is reversal of the hind brain herniation to one degree or another. But if this questioner wants detailed information, it's right in the chart. OK, well, actually it's exactly on time. Does anyone wanna make any last comments, uh, before we take a break here? Uh, any comments or questions, uh, Kelly, uh, or Julie, uh, any comments or, um. Jan or uh Martin or Mike, anyone you want to make a comment, Tim? I'd like to thank you guys for having me and us in this panel. I find it very interesting, and I think this is a very good forum to exchange important stuff in a relatively informal, um, fashion. So thank you very much indeed, and I think this could be repeated. I just have one question. Are all of the clinical centers represented here using Still using the mom's criteria for inclusion, exclusion, workups, uh, role of the fetal cardiologist, use of prenatal MRI in terms of the commitment to follow up. At at Vanderbilt, yeah, for sure, yeah, we are at Vanderbilt as well, and including everything you mentioned, our only exception is that we are sending our patients home. That's the only difference. So, so for all of your patients, they all have a fetal MRI pre-op. That's right. And for all of your patients, you have a fetal cardiologist in the room? Correct. And you're, you're totally committed to long term follow up of the patients despite them going back to their parents' native center? Well, they do get delivered at their center, but we do have the patients consenting to the data registry so that we can have them send us their neonatal information. So, we have been collecting that all, ever since the, um, mom's trial ended. OK. Go, the one thing, uh, at UCSF and really it was, uh, Diana who instituted this before she left, is that we, uh, monitor the temperature, um, we put a temp probe, uh, within the uterus, um, because we found that, uh, the variability of the fluid, uh, being administered, um, uh, can cause fetal temperature variation. So we found that to be useful, um, uh. So what, what have you found? So you had this probate in there. Can't you trust the level one? I guess not. Um, well, uh, you know, I think, uh, usually you can, but, um, sometimes, uh, you know, the, the scrubs will draw up some, we don't use a level one, we, we infuse, uh, with, um, syringes, um, uh, that we draw, uh, for sort of, um, you know, personalized control of the amount of fluid given. And, uh, sometimes it'll sit around. So we found that, um, in particular, when there's a decrease in temperature, uh, you may get, uh, um, uh, flow disturbances, decrease in diastolic flow, um, and so we've, uh, kept a real close eye on the temperature. I don't know if it really does much, but I got, um, the case that we discussed when I called you intraoperatively once about the baby that had sort of unexplained, Um, bradycardia was how we discovered that in our hospital, they had changed the standard temperature of, uh, what they, when we asked for warm saline, they had turned down the devices, uh, hospital wide and that's how we discovered it. Wow. So why, why did you guys give up the level one? Yeah. Cause you used to use it and it's great. Maybe they didn't use it. Didn't you guys use level one way back when? Uh, we used a different kind of, uh, when we were doing, um, fetoscopic surgery, we used an infusion pump device that was similar to a level one, but for our open fetal cases, we used, uh, warm saline, uh, administered directly. But wouldn't it be solved if you just use the lower one? We, you know, we did, we actually talked about that, and, um, uh, I can't remember the exact reason, but, um, uh, you know, I'm sure it works, but there was some rationale that, uh, uh, I can't remember right now, and so we've just do it the old fashioned way, but it's a good point that you can't, you know, you don't wanna generate, you don't wanna create cardioplasia. Yeah, yeah. Yeah, we, we, we, we'll try to bring you guys up to speed before the next webinar. OK. It's uh, very fancy technology at this level one. Yeah, right. You know, I'd just like to make a comment to, to bring us back to what Scott said as a conclusion, which is that we don't cure this disease, and I'm just wondering, just looking at it from a distance now, whether our sites are not too low. It'd be interesting to see what the neurosurgeons say, but the reason to think about other ways to go after this and to be able to do it earlier is maybe you can get dramatically better results. These results. Just between us, are not that good. You know, we need to do better. And to do better, I think we're going to have to do something different. Oh, absolutely. You know, the, the idea of an ultrasound guided, you know, uh, procedure at 15 weeks or something would be the, you know, ideal way to, to take care of the second hit, right? But, Uh, and I think it's, yeah, I think there's still a fair amount of the basic biology of the, uh, lesion itself that we don't understand from a neurodevelopmental point of view. The, the first hit, the, the problem with neurulation is an area of active investigation and, and in many centers. I agree with Mike that I think that a tragedy of the trial was that it slowed innovation for a much longer time than we expected because the trial just took longer to perform than we thought. The pace of innovation now after the trial compared to what happened in the last 9 years really speaks to that, and I think there's room for basic biology here. I think there are stem cell solutions or other bioengineering solutions that are important, but these kids. Don't walk what, you know, universally what the trial showed us, however, which is so exciting is that there is hope there, you know, frankly, for centuries before the mom trial, people thought that this, there was nothing to do for this disease. There was very little research done in the last. You know, 50 decades on this disorder, and I think fetal surgery has made a tremendous contribution to having people look at this again with the notion that, in fact, there is plasticity, there is the opportunity to do something for this really quite prevalent, uh, birth defect. So I think innovation is the answer and the future, and I think the, uh, fetal trial, uh, helped bring this disease to the forefront. Here, here. All right. And with that, I'm gonna bring this session to a close. Uh, fantastic panel, fantastic discussion. I, uh, wanna thank everyone.