I'd like to, to introduce the, the next talk. It's gonna be by, uh, Professor Jan de Prest, uh, who's coming to us from Belgium, and he was gonna be talking to us about the feetoscopic and luminal tracheal occlusion and its role for dramic hernia, uh, diaphragmic hernias. Dr. De Press, can you hear us? Yes, thank you. Thank you very much for inviting me to, uh, participate in this. Thank you. Thank you for joining us. I would like to share an experience we had in Europe here with this antenatal intervention for diaphragmatic cornea. Um, an intervention that is tracheal occlusion, which was started in the United States but was basically converted into a fetoscopic procedure. Um, the criteria for fetal surgery were the ones that were suggested earlier on by the groups in San Francisco and later on by others, and that is, that is criteria for pulmonary hyperplasia based on lung size, which is done by a lung to head ratio measurement. Corrected for gestational age as well as the presence of liver herniation that has in the past and since confirmed by others been shown to be related to outcome and this is done also on ultrasound evaluation. This information is brought together in a clinical algorithm where at the bottom of the curve you can see the observed over expected lung to head ratio, which is a correction for gestational age and is expressed as a percentage of the normal. And there we see values of babies that have either the liver confined to the abdomen or the liver into the thorax, the white parts of the liver. And then this was, um, correlated to the outcome, as was observed in 329 cases of left-sided diaphragmatic hernia. And based on these outcomes we have like divided the population in those with severe hyperplasia with a maximum survival rate of around 20%, moderate to 50%, and mild cases with an 85% survival rate. And obviously the fetal surgery population will be the one that has a poor, an outcome that is predicted to be poor. The question for you basically is whether this is still actual. Something is happening with my slides here that I didn't anticipate, but this slide should show, but does not, as I see, um, comparative data from Children's Hospital in Philadelphia, a cohort in 2006 to 2010, as well as a cohort from Toronto. where they have shown that the outcomes are indeed dependent on the lung to head ratio. And those outcomes coincide with the observations from the past, and from that we can conclude that these selection criteria are still valid. Um, In those patients, A procedure is done around 26 to 28 weeks, at least in that initial experience. Um, a procedure that is no different than a tracheal occlusion by percutaneous, uh, fetal intubation, which is done by sono endoscopic approach, as well as a removal of the, uh, balloon. At around 34 weeks. So basically what initially was done by clipping is converted into a balloon approach. The procedure is done under local anesthesia, typically, with fetal analgesia and fetal immobilization. And basically it's a procedure that will last around 6 to 10 minutes on average. It's basically yes or no when the fetus is in a good position. This is a very reasonable procedure. Um, this is percutaneous. You see some images here from procedures that were done in Leuven, and here you see the kind of equipment that we use for that. It is cytoscopic instrumentation that is no different than what is used for cytoscopic laser surgery, a procedure that is now widely accepted. Under ultrasound guidance, the trochar will be inserted into the direction of the fetal nose and mouth. Um, I'm now missing some of the slides, but I assume that you see how this is done into the direction of the mouth. Am I still there? Yeah, can you hear me? Yes, OK, I now see this at this moment the cannula has been advanced into the amniotic cavity and the fetus will be visualized by cystoscopy. This is only of limited value because basically at that moment the ultrasonographer will guide the cannula into the direction of the mouth. Can we go to the next slide, please? There will be another clip. And once inside the mouth again, the ultrasonographer will keep the operator in the midline, and we use the palate or the midline of the palate, the uvula, and then the epiglottis, as well as the vocal cords as a landmark, and the phytoscopist, Dr. B, when you get to the slide, let me know at what point you want us to play the video. Um, each of these slides should just run the video. It won't. You just have to tell the way it works is that for us to play the video, just let me know. Say play the video and we'll roll it. Um, could you play video too? So go play video 2 now. And you should be rewind that it starts at the beginning because here the operation is virtually finished. So there is amnio infusion used. We use a saline infusion or Hartmann infusion, which is warmed up to body temperature. We don't need large volume, so that operation will not require a level one. The fidoscopist will find the vocal cords and then direct the scope into the trachea again. It's nothing more than an intubation. In an immobile, non-respiring fetus, so that is relatively easy, and a balloon will be positioned next slide please between the carina and the vocal cords. It's a sausage shaped balloon, and it will fill, as you will see here, it will fill the trachea, let's say, for at least 1/3. We try to put it as high as possible. It is a detachable balloon. And this is actually part of the problem, of course, because once you have left the balloon there now when this baby is born, this needs to be removed urgently, and that is of course a problem that may happen if preterm birth would occur in a situation where nobody is prepared for that. It is technology that we borrow from interventional radiology. It's a balloon that is in Europe on the market for that indication. It's a latex balloon, so for you this is clearly an off label use. Next slide please. So the intervention time, as you see here is very reasonable. So the majority are done in very short operating times. The outlayers on the right are the ones where you basically struggle with the fetal position. So we really won't like to have a longitudinal position of the baby preferentially because when it is in transverse, it's a very unstable lay and the fetus will be difficult to access next. Slight please. It is an invasive procedure and remarkably, when you look at these gestational ages at birth, you see that the median gestational age was 35 weeks at birth, and this was a surprise for me to see that actually after open fetal surgery we get more or less to the same average gestational age at birth. But of course those patients that will labor prematurely, the majority will do so because of ruptured membranes. Those will have a situation that is that critical because this balloon will have to be removed before birth because it's still there. When patients present with rupture of the membranes, they typically will present with amnorexis, which is fluid loss without any labor pains, and then we will admit them, give them antibiotics, and we will try to go as far as possible in pregnancy, but we will remove the balloon when there is any sign of imminent labor. At 34 weeks, the balloon will be removed if the patient has not delivered, but that will be in 75% of the population. Before that, you are faced with an emergency situation. How can the balloon be removed? We actually chose, and if you could please play the video, we actually chose the balloon because we thought that it was attractive that you could puncture this balloon by ultrasound guidance, and that is. Indeed possible. It is usually requiring an access either through the upper part of the thorax. Sometimes you can go if there is a frontal approach possible through the neck, but you can visualize the balloon reasonably well, but only in 20%. Of the cases we are able to do that by ultrasound guidance because in the majority of cases it is an unfavorable position of the baby and that we do not dare to. Can you move to the next video to do this by ultrasound guidance. In the next video we'll see the the removal of a balloon by cystoscopy. And I hope that is coming now. It is basically the same procedure as inserting the balloon. What we do is retrieve it with the forceps. We also have a puncture stylet there. If the balloon doesn't come out easily like that, we would puncture it in utero, and in our experience this has been used in in above 1 out of 2 cases. This is then the preferential approach. It is even possible to do it with ruptured membranes with prior amnio infusion. Why do we insist so much on removing the balloon prior to birth? That is mainly because we have seen that you can move to the next, next to the slide again. That is mainly because we have seen that both the survival as well as the early morbidity is better if the balloon is removed in utero at least 24 hours prior to birth. But again, there might be cases that it has to be done earlier than planned in a half critical situation. We will still first try to do it in utero, but if that doesn't work, you can resort to a procedure that you know very well. It's the removal of placental circulation. The word exit is not appropriately chosen because exit is a technique with general anesthesia. We can do this here under epidural anesthesia, so it's an operation where the obstruction in the airways is at a very well identified place. We know what we will face, and we are sure that we will get the balloon out very quickly. So we do do that under placental circulation, but without general anesthesia. In very rare cases you can pick it up after birth either by puncture percutaneously or by tracheoscopy, but that's really not the recommended way to do. In black you see the predicted survival rates based on that historical cohort that I mentioned earlier, and here you see in black the survival rates. And when you offer fetal therapy, you have an apparent increase in survival. So you see here for the group with the smallest lungs an increase from around 0 to around 20. And then in the next cohort that has a severe hypoplasia. You see also an increase, but this is of course based on a control group that was a historical group from the registry that we had available for left sided cases, we see that the increases in the average of 30 to 35%. For right sided cases, can somebody move my slides? For right sided cases, the background survival rate is lower, but the increase is very similar. And the independent predictors of survival are the initial lung size prior to the operation, the gestational age at delivery, so prematurity due to the intervention, might compromise some of the outcomes, and the ability to remove the balloon in utero at least 24 hours prior to birth. I always show these slides to slides to obstetricians for one reason or another. It doesn't show up well on my screen. There's something wrong. Um, what this slide should show, it's indeed it's that one slate 1515, great. on that slide you can see in the light blue bars the number of patients that will deliver prior to 32 weeks. It's in concordance with what I showed earlier. In those patients, despite delivery under 32 weeks. And the survival rate is as high as predicted at term without fetal therapy. So in a very sarcastic way one can say that even if this complication occurs, we don't kill babies by doing an in utero intervention. In those patients that deliver at 32 weeks or later, the survival rate is 60%, and for reasons we do not understand very well, that doesn't increase further beyond 34 weeks. But so in this group we have a survival rate of around 60%, and this is the reason why we think that we should have at all price women delivering after this operation. Beyond 32 weeks and that's the reason why we have changed our protocol a little bit and do our interventions slightly later than before now at 29 weeks. Next slide, um, there is no reason at this moment to think that we have substituted mortality by morbidity. Here you see the predicted oxygen need and in the blue bars after fetal therapy in around 100 patients in each group, day on the ventilator until full enteral feeding, days in NICU, and obviously this procedure would not change anything to the requirement of a patch repair. That of course is not addressed by the fetal intervention. This is significant, and what we see here is that there is an apparent decrease in bronchopulmonary dysplasia. This operation has not been formally tested for myelomeningocele repair or as we have for laser, so there is now a randomized trial in Europe running, tracheal occlusion to accelerate lung growth or total trial. It is actually two trials where in the severe group. A trial compares occlusion at 27 to 29 weeks. Survival is the outcome, the primary outcome variable, and that trial has started in Spain and Leuven initially, and to that has now joined London since one month. We actually also did a second trial, or we have started a second trial a bit earlier in the moderate cases in the population that in the United States at the trial at San Francisco, a population that was actually the subject of their trial, let's say about 4 or 5 years ago or a bit longer, where they have shown that fetal therapy did not benefit these patients. And why do we do this trial again? Well, because we think that the minimal invasiveness may actually avoid the complications that were seen in that trial. The average gestational age at birth in that trial was around 30 weeks, and we see that our babies are born 5 weeks later. So that's why we have also a trial in this group, and for one reason or another. The second screen doesn't show up, but in that trial, the primary outcome measure is survival without bronchopulmonary dysplasia. Other outcome measures of this trial are listed here. They are basically the same as was in the trial that Michael Harrison published a few years ago. Um, the postnatal neonatal management is standardized according to a consensus protocol that is now also the one used for a postnatal trial on HFOV. But having said that, this was required because this is a multi-center trial. It's a very pragmatical approach. We have centers that offer fetal diagnosis and would see eligible patients, and if those patients are eligible, they are first referred to a center that offers fetal therapy where they will be reevaluated if this is confirmed. The patients after consent would be randomized, and if she's randomized to expectant management during pregnancy, she will be managed at the referring center, whereas if she would require fetal intervention depending on the trial that she is in, she will be having an early or a late balloon occlusion. And she will have removal of the balloon in utero and then would be referred back to that postnatal management center to be managed according to the standardized protocol. Um, you can look up about the trial on this website. It is a website that has pages also especially for for physicians. Following a discussion you had for the MMC repair also in Europe, we wanted to do this multi-center trial at several sites, and so we had to agree on criteria for being such a center to offer fetal therapy, and this is an empirical criteria that we agreed on. You have to be offering a very active cystoscopy program, and we define that as 36 interventions per year or 3 per month as a minimum. This was based on numbers that were shown to be important for the learning curve for laser surgery, so that's the only point of reference we really have for that. But we said it should not only be a cystoscopy program but also a cystoscopy program where there is sufficient experience with this other cystoscopic procedure which is balloon occlusion, and there we said that the people that are doing this, this team, should have experience with 15 cases and at least 5 done locally. At the place where the trial is being offered, and the other 10 cases could be at a remote place where you have been trained by a uh a teacher um that is already offering this procedure for a longer time. Obviously you have to be able to guarantee a 24 hours around the clock service for balloon removal, and you have to have several team members that are familiar with this so that the patient can really rely on a safe removal of the balloon. And then of course you have to agree with this protocol. We have made for those centers in training special dummies. This is a baby, a 28 weeker baby that has a complete upper airway that looks like what you find clinically, and here you see actually friends of yours. This is Dr. Johnson while doing a fetal case, a case in Leuven, and here when he is practicing for emergency balloon. Retrieval after birth. We also have an animal model where we actually learned people to retrieve balloons in rabbits of around 600 g to have a mimic of this emergency balloon retrieval. In Europe, the trial is now taking place in those centers that is in Paris, London, that is now functional, not submitted anymore, Barcelona Leuven, and then we had a number of centers in the United States that were interested to participate, and we would really be glad because that would push the trial much further and we have been training people from Toronto. And then you have, you, I mean the people who sit there in the room with very active fetal surgery programs who have expressed interest to try to do that, to participate in this in this trial, if at least we get over the objections that are now mainly regulatory, all of Centers are actively training their cells. I mean, we have seen many of our friends already here in Leuven to be part of such procedures so that they can build up sufficient experience to start out their last 5 cases locally, then to be able to offer the trial. So this is basically what I wanted to say from Europe. Sorry, a little bit of the mishaps with the videos, but that happens probably often during these teleconferences. Perfect. Doctor Deres, thank you very much. That was great, and I apologize for those, uh, uh, don't worry, couple of slides, um, but, uh, I think you brought up a lot of great points and a lot of, uh, discussion points here. Um, Alan, I'm gonna turn it over to you and then in the meantime, I'm gonna throw up that poll we talked about and, and, and let you start the discussion. So Jan, great presentation as always. There was only one, Uh, misinformative slide in that presentation, and that was on your training program because we all know that Doctor Johnson is not trainable. I still have hope. I think he might have been the dummy. I'm not sure anyway, um, so. One major difference between Your trial and any trial on uh tracheal occlusion versus the myelomeningocele trial. is that you have popularized this over the past 10 years. And with that popularization, you've also trained a number of people and you have a number of centers in Europe that are doing tracheal occlusion and in fact around the world, a number of centers that are doing tracheal occlusion outside of the trial. So, has this impacted your effort to do a trial? Have you been able to recruit the numbers of patients that you anticipated? Um, what's your comment on the presence and availability of wide open back doors? Yes, thank you for the comment. Obviously I was trying to get around this in my presentation, but it is indeed a problem in Europe. Fortunately, the four centers now that are really propagating this trial are still operating the bulk of the patients. At this moment for the moderate trial, all these centers have signed up in written that they will not offer fetal therapy for those patients besides trial, so they're actually not allowed to do tracheal occlusion in the moderate group, and this is probably why that trial has been reasonably successful. We have now recruited 54 cases, so we're beyond the first interim analysis, which was mostly a safety analysis. And actually Professor Harrison is on that oversight committee, and he will look at the data at the beginning of January. For the severe trial we did shoot ourselves in the foot. I must agree with that. We have too long gone on with offering this procedure, still trying to figure out small improvements, while actually we didn't learn from the last 100 cases. I mean outlooks have remained the same, so we should have started the trial earlier. There were a variety of reasons why we didn't do so. One was the Local objections from the ethical committee that they said that in a population with such a poor predicted outcome it was not fair to even offer them the therapy even if it was not of proven benefit. I mean things that you certainly can argue about. And but know that this trial is established as well and approved in those 4 centers. There is an agreement that indeed the local population, everybody in Belgium and Holland, would be offered only fetal therapy within this trial. However, And this is what you allude to. There are local backdoors that I have trained personally a colleague that doesn't work too far from us and that indeed offers the procedure outside the trial, and there is nothing I can do about that. Also, some Eastern European centers don't want to refer patients with severe diaphragmatic hernia if they will not get this therapy. So indeed these are major handicaps, and that is why a multi-center trial with a larger recruitment might still recruit sufficient patients to find out, but we have no any method to enforce on other centers to stop offering this therapy besides the trial. I mean this was not probably a gentleman's agreement in the United States. You had perhaps there was some regulatory body that could enforce that, but here in Europe with all these different countries, there is certainly nobody overseeing that. Uh, but you are right, it is a problem. It was a gentleman's agreement, but it was also somewhat enforced by the payment, uh, community and that they would pay for. The procedure within the trial but not outside the trial. In Europe, it's a very complex payment environment. I don't imagine that yes indeed, and they will even not try to regulate that. I mean, as you know, even for new procedures like myelo meningocele repair, they may try to get around payment, but usually they can be forced to pay because their payment is not necessarily tied to the scientific evidence behind a certain procedure. So we have a bunch of panelists listed up there that I don't see. Is everybody, is everybody on? I see UCSF and I see Jan, but I don't see anyone else. Yeah, we forgot to invite you guys. Go ahead and open up your cameras, um, if you're on the phone and in part of this panel, because there's a bunch of, uh, expertise on this subject matter out there that, uh, would be great to have weigh in. They're all on, yeah, on the phone. on. Um, while we're waiting for everybody to boot their cameras up, could you remind Doctor Flake that none of those fetal models died during my intervention? There were no dummy deaths. They were all. So, so one of the big concerns in the United States right now is that uh there are centers that are doing tracheal occlusion outside of any trial. Uh, there are different methodologies used for the tracheal occlusion. Um, and while there has been a consortium of centers, I think that are the major centers in the US, uh, that would be qualified to do this procedure. There's been an interest. Uh, and intent, um, regulatory approval has been a problem for some of the centers. Others have already obtained regulatory approval for one for a different balloon, and etc. But so we're at different stages of the process and cases are continuing to be done outside of a clinical trial. So, is there anyone out there that doesn't think a clinical trial of this methodology is necessary at this point? Any of our groups that feel like a clinical trial is Unnecessary and even unethical that it's been a proven intervention. OK, so there's equipoise among certainly uh this very expert group of people that, uh, it has not been proven to be efficacious. Is that fair enough? Sure. OK, uh, it's interesting that you raised that because as you know, there is in the literature, uh, one, randomized trial around, uh, in the White Journal, the group of Rodrigo Ruano that is in Brazil published a uh trial where indeed fetal therapy was shown to be beneficial for severely hypoplastic cases. Um, we have looked at that, talked to our ethics committee whether we had to abort our trial. But it was judged that given that on the one hand the background survival rate in the expectant management was 0% and very consistently in that group it was judged that this was not representative for the European situation and I think for America that will be the same. And on the second and secondly is that this was on a limited number of patients and that was pooling left and right sides of the diaphragmatic hernia. In one pot and we thought that actually with this given number of patients it was not possible to make the point really that fetal therapy is beneficial and so we have continued our trial. This was our position to that. Yeah, I think I would agree that that was not an adequate trial to To prove the hypothesis one way or the other. Tony Johnson has joined us, I see, from Houston. Um, the other center in Houston now. Tony, you don't look awake. Sorry about that. Morning guys. Uh oh. So, so what about the design of your trial, Jan, and I would hope some other folks would join in here and that. Uh, you've done it, you've designed a moderate severity trial. You've changed the dates of balloon placement. And removal from the original 200 patients that you did. Um, and you have a primary endpoint that at least in the US, uh, is a very rare outcome, which is BPD in, in the relatively moderate severity group. And it's a difficult outcome to define as your primary endpoint. Um, do you think that that trial design is going to actually prove your point? of whether this is beneficial or not. Well, of course at this moment we only have the first interim analysis which was basically about safety, but when you already look at those data, there is a difference between the groups. We actually don't know which is what group, but based on gestational ages there is such an indication that, I mean, one therapy would be the occlusion group, and there you can see differences at this moment, and they are relatively important but not significant yet. But so it might be that the choice of the oxygen dependency was indeed not the most relevant one at the time of the design. It was a real concern that we would indeed increase survival at the expense of oxygen dependency, and this is why this endpoint was agreed on by all the centers that were preparing this trial and that were then agreeing also on the postnatal management protocol. And for the changing of the dates you touch a very important point. Several experiments, as well as clinical data have shown that a later tracheal occlusion. Prompts lesser lung growth than an earlier one, so it is theoretically possible that you trade off the effect of the intervention by going in later. But on the other hand, we have the clear effect of an early intervention, the risk for prematurity, and then prematurity induced problems, and that's why we try to balance that. And in this moderate group we said if we go in that late, around 30, 31 weeks, we might still have enough effect that we still improve lung growth and then as a consequence outcome. For the severe trial, you remember these were the red squares on my slides, the severe trial that is clearly that we only moved by one week, 26, 28 weeks, we went from 27 to 29 completed weeks, and based on the clinical data we had, this is a group that still will benefit from sufficient lung growth to be able to improve the prognosis. Did this answer your questions? Yes. Comments from out there. There, there's, there's questions regarding, you know, just this issue of lung growth versus lung function and really are we seeing, you know, uh, in your last sentence, uh, Jan, you said lung growth and thus lung survival or, and thus survival, I guess the question is, is that really true? Lung growth versus pulmonary function improvement, can you address that? And yes, well, actually what we did is, and I think then the people from San Francisco really have to comment on that, is what we looked at in the early neonatal life, a historical control group of expectantly managed babies versus tracheal occluded babies that were matched for severity, and it seems that the early neonatal lung function is indeed improved. And what we now look at in detail is looking at this, I mean, quantifying that better. And then try to tie that with prenatal indicators very much based on the study that was published by Dr. Roberta Keller who is working or was working at San Francisco and perhaps they can throw in there a little summary of that study because that was in that randomized trial that you had in the United States despite the fact that babies were born at 30 weeks that they apparently had an improvement of lung function as compared to the expectantly managed controls. Is that correct, Michael? Uh, yes, it is, but I think Hunman and Shin know more about that than, than I do, and Roberta is still working here, thank God. Well, you know, you know, there's all the, obviously the quantitative data, but when you talk to our, um, neonatologist Roberta, Sam Hogood, you know, the, the people that stand by the bedside and, and handbag the patients, they'll tell you there's a qualitative difference in, uh, how they, um. Are able to bag these patients right after they're delivered, um, which I think, you know, there's a lot of qualitative nature to this, uh, you know, the care of these kids, it's hard to define, um, you know, uh, probably, uh. Best sort of characterized by the group at at New York where Shin trained, and maybe you can comment a little bit on, on, you know, the qualitative part of taking care of these kids, but certainly she thinks that there is a difference in the kids that have tracheal occlusion. They're they're easier to bag. I also think a lot of it's been shown, at least from our data, was that the gas exchange may have been improved from expected, but that we still had. Very significant pulmonary hypertension. I think there's a lot of that on pulmonary hypertension. Indeed we also have the data on that is one, that overall when you compare both groups, that the degree of pulmonary hypertension, the amount of babies that have very severe pulmonary hypertension, that means defined as being resistant to the first line therapy, which is a no. And well inhaled they know and that that group benefits really from fetal therapy. Now on the other hand, and you all know that, I mean you cannot put all these eggs into one basket. I mean there are a number of babies where you see a tremendous lung size growth, but you don't see the matching vascular response and conversely, And we have been able to triage that out by prenatal measurements, and as far as we know, no, there are 3 prenatal indicators of postnatal outcome, at least if you do a tracheal occlusion, because we have most data on that, that is the degree of liver herniation. The degree of responsiveness to oxygen, that is a measure in utero of pulmonary hypertension, and the lung size, which will basically be the lung volume or the lung to head ratio. And apparently these influence the postnatal outcome, each of them independently, and the response on each of these following tracheal occlusion might be in one baby more on one than on the other side, but I think you have seen that clinically before also in the unoperated babies before birth is that some babies have relatively large lungs but they are extremely difficult in terms of hypertension and conversely. Yeah, I think that really summarizes that lung growth is not the The total picture, even the most important component of whatever you may be doing with tracheal occlusion, I think there are very important questions about the biology of tracheal occlusion still that remain unanswered, and that's one of the reasons that we need the trial. You need to accumulate enough experience with enough patience, comparing the two techniques that is appropriately stratified, etc. To really draw conclusions. I mean, I would argue, you know, when we did our tracheal occlusion trial, we got tremendous lung growth in some of the kids. We got no lung growth in other kids, and this is with complete tracheal occlusion. So there's a basic biological difference in the response of different. Lungs to tracheal occlusion. They're not all the same. Similarly, At the time of birth, the lungs that had grown the most perhaps functioned the worst. Those kids were born relatively premature, but they didn't respond to surfactant. They had poor compliance of their lungs. It was not a biologically functioning gas exchanging lung. So there's just tremendous variability in biologic factors we don't understand, and I don't think as a rule at this point. There's overwhelming data that we improve lung function with tracheal occlusion. Um, yeah, just a quick question. Uh, the, uh, pulmonary response to oxygen, are you using that clinically? Um not in the selection of patients, not in the post balloon, uh, period. But we have been using it to try to look at the pathophysiology of the intervention. There are two problems with the oxygen test. It's one, that the values, there is no reference data on normal lungs. Number 2, this test is only usable very late in pregnancy, so that from a management viewpoint, it is very difficult to use that in terms of defining options to parents. But what I see plays is that when you use it in the diaphragmatic hernia group is that you can predict indeed tremendous problems with pulmonary hypertension and that might sometimes be important for postnatal referral that some centers are better with managing these babies than others, but we don't use it at this moment clinically in that respect that we will treat patients differently. There's a, a, uh, Rodrigo, uh, Rauno, uh, you can read his comments there about a study that they did, uh, in the chat box there, uh, some interesting results. We have, uh, an unrelated question to what this particular, uh, discussion, but there was a question from, we're broadcasting this to another auditorium, and from the Sherman Auditorium, and they say, uh, besides chromosome analysis, what goes, what does the genetic workup of these patients consist of? Uh, the, uh, prenatal microarray. Who wants to address that, Jan? I was, I was trying to read the comments, and since I'm not a woman, I can only do one thing at a time. Um, could you repeat that? Yeah, the question about what type of genetic workup of these patients other than chromosome analysis, do you do a prenatal microarray? Yes, but this, this has been, I mean, for us that was even not part of the fetal therapy question. This would be part of the normal workup of patients here that come with diaphragmatic hernia per se. So yes, we do that. OK. Any, any further comments on The design of the randomized trial and will it answer A question of efficacy for tracheal occlusion. I mean, the main backside, except for the back door in Europe, is that this is a multi-center trial, but we and we have seen in your trial that indeed a single-centered trial, I mean, has many benefits, but, or at least a very limited number of centers, but this was really adapting to European reality and that is why we say this will be a trial perhaps in real life conditions. So, so let me ask you a question, Jan. How are you going to control for uh meeting criteria to enter your trial? That was one of the problems, I think, with your previous data is that if you look at your data, you had a 25% rate of primary diaphragmatic repair in your supposedly very severe group of diaphragmatic hernias with liver up and uh Yeah, 25%, and I've never seen a patient that you could primarily repair the diaphragm on in that severe group of diaphragmatic hernia patients. So it suggests that there was a problem, at least with some of your centers and case accuracy of case selection. So how are you addressing that problem in your current trial? And can we trust, can we trust the numbers we see from it, uh, that these patients have been appropriately selected for severity? Well, as I said, I mean, can the criteria be believed? I mean, our principal confirmation came from this external validation of the LHR criteria by Toronto and then in your hospital. Does a small LHR always correspond to a very large defect? Well, the answer to that apparently not. And as you know, we have also shown that in quite a number of patients that the degree of liver herniation, which probably is more or less an indicator also of the defect size, that that degree of liver herniation can be quite different from the lung size and act independently. So whether we should have found 80 or 90 or 100% batch rate, I cannot really. Say, but I think it does not necessarily mean that we have selected wrongly our patients. I mean when you look at the data, not all groups will do 100% patch repairs, even if they have measured the lung to head ratio of around 20-25%. And that's all I can say. Not being a pediatric surgeon, I don't know whether they should have done that. I cannot tell that. We have uh a few minutes left and I want to get comments from the panelists, but I also want to address the questions from the audience. Uh, another question about, um, well, first of all, what is the general risk of premature rupture of membranes? Actually, it'd be great to talk about this with all the different techniques we're talking about. Um, and I don't know, uh, if you have numbers on that, uh, before we get to the next question. Does someone want to answer that? Jan, I can tell from our side, as you've seen, I mean, it's around 15% within the first three weeks. Um, it is, uh, if you look at the 34 weeks time point, which is the important point for the balloon reversal, um, it, it's between 20% and 22%, and to that may add a few patients that will labor without ruptured membranes. So, and it is very consistent. There is some variation and the duration of the procedure is playing a role in that. Um, it is surprising that it is that high, because if you look at open fetal surgery, I mean, this is relatively comparable in terms of preterm birth. Um, we don't know the reasons for that. It is different from laser surgery, which happens at a different gestational age. So, um, it seems to be a very consistent problem that we have to solve at some stage, but at least we have not been able to solve. The great, the great unsolved problem of fetal intervention, yes, until we find another one, and I think it's important to just note that that number is also dependent on how hard you look for it and how. You know, uh, critical you are in assessing it. So there are varying rates of, uh, you know, separation of membranes and all that, but, uh, it really is dependent on You know, surveillance and looking for what's our, what's our rate of membrane separation and then Problem with open surgery, Mark, with open fetal surgery, probably about 30% of cases will develop a membrane separation, but not all of them will go on to rupture membranes. I agree with your comment, Alan. I think the way I like to think about it is the incidence of membrane trouble after intervention is 100%. And then the question is how much we detect and that that's where all these other numbers come from, but when we go through that membrane, there is some degree of disruption and this is just a problem we're going to have to solve. That I think is what cytoscopically is different. I mean, the presentation of the problem is typically amnorexis, and when you really screen for it, the degree of membrane separation, it is there, but it is not as high as after open surgery. But at the end of the day it doesn't matter if the patient starts to leak clinically or if she has membrane separation. Membrane separation for us after cystoscopy always leads to preterm labor and to clinical problems. Uh, by the way, I did forget to mention that question about the ruptured membranes did come from Brazil. I'd like to try to let you know where the what country they're coming from. We have another question about why wait till 28 or 29 weeks to do the occlusion. I can give a comment from our side. It was in that paper where we published over 200 cases. We were completely inclusive. That means if you read the tables there, you will see that the range was stretching to the left as well. There are technical limitations with the current occlusion procedure. You have a relatively small trachea, a not properly sized balloon. I mean you can get it in, but it might cause tracheal problems, and there are some case reports showing that. And also when you go earlier with the current knowledge, we know that we also, if it ruptures, it will rupture earlier and then you enter into other problems. I think from. Let's say from the pathophysiology behind tracheal occlusion, it would indeed make sense to go earlier to get a better response. That might be the case, but at this moment we are currently physically certainly limited and As you saw, we traded in on the other side, and we would rather go now at 29 weeks rather than 26 to 28. Jan, I may, I may be misinterpreting his data, but it sounds like Rodrigo Rao says that they're recently publishing their data that it is, uh, they do have better pulmonary response with earlier occlusion. Oh yes, this is certainly, I mean this is an area of controversy, but I agree completely with Rodrigo that if the earlier we go and we have also published on that where we have looked at lung volumes increase. Versus gestational age at occlusion and the lung response was definitely dependent on the time of the occlusion, the time point that the occlusion was done, so you have a better response earlier in gestation than later, as you know, in Europe there is a program where they do deliberately late occlusions, but indeed we didn't want to do it and so we have kept the middle. Here and say that the fact of having ruptured membranes and prematurity in such a significant number of cases that we have had to take that into account certainly when you do a trial. By the way, Rodrigo, we invite you to call in if you want to make a comment over the phone, uh, call in to the call-in number and you can, uh, give us your, uh, your thoughts. Uh, first of all, uh, Jan Hahnman here, um, I think first of all, tremendous, uh, I think, um, credit needs to go to you for doing something that I think. All the pediatric surgeons on this side of the Atlantic thought it was quite frankly impossible to do a percutaneous uh tracheal occlusion. Of course, people thought about it, and, and then, uh, you just did it and you showed, um, you know, we don't do it in quite the, uh, you know, I, I think, uh, 70% or more, less than 20 minutes, quite, you know, as quickly as you, but it certainly is, uh, possible, um, to do it. Uh, and then you backed it up with. I think just a tremendous volume of science. So I, I think that that is just, you know, you, you've certainly, uh, um, progressed the field uh tremendously, but just getting back to what Alan was saying about. Uh, 25% of primary repairs are, you know, all of our ultrasound folks, the guys that, you know, Roy Fly and Ruth and all those guys, they've, um, shown, uh, in, and we were just chatting about this, um, liver up versus liver down, and they found that the liver position is a stronger predictor of, of outcome than LHR even. And our, uh, study showed that no matter what the LHR, liver, uh, if you have liver down, they all do well. And so I guess I wonder if there's a correlation between. Maybe the bad LHR, liver down. And a good outcome or even primary repair. I can comment from our side. As I said, they are independent predictors when you take large numbers of patients. So we certainly cannot say that they unequivocally will do well if the liver is down or they will all do bad if the liver is up. So we have looked at that, whether you can select it as a single criteria, and the answer is at least based on our data. No 3 independent measurements all predict on their self individually, but probably combinations would be the most performant. But of course you need large data for that. The meta-analysis that we recently published on liver herniation and that was based on MRI data, that means. Probably more reliable, at least in terms of liver herniation, also has shown that it is a predictor, but it's an independent predictor. I think when we got all of our data together uh that time, when we looked at as many cases as we could gather from 5 centers in the US, the frequency of having liver down with an LHR or less than 25% observed over expected was extremely low. There were very few, there were very few of those cases. When you have liver up. At least in my experience, and a severe LHR, you have a big hole in the diaphragm. I don't know what the other pediatric surgeons here would say about the rate of primary repair with liver up and low LHR. I think the data you're um uh was the data that Tony, Tim, and, and Holly, um, gathered, and I think there were 8 patients or so. Tony, maybe you can comment that fit that criteria, and I think survival in that cohort was like 75%. I think it was 6 out of 8. Yeah, I think your memory is pretty good. And yeah, I mean, Holly Holly put it together and, and right, it was something along, it was something like that. So the data from the three centers, you know. Was pretty, you know, backed up, I think, the, the other, uh, American ultrasound data anyway. Here's a question from Andre Ivan. Uh, Andre, I don't know where you're from, but, uh, but the, the question is about open repair. Would it solve the problem of vascular kinking of the liver? With with tracheal occlusion. But one of the, maybe I can talk to that a little bit because we're still, uh, we have the experience of doing complete tracheal occlusions. And I think there is a difference between putting clips across the trachea and having a complete tracheal occlusion versus having a balloon tracheal occlusion in terms of the rate of increase of the LHR, the ultimate size of the lung. Uh, gets to, etc. And we definitely saw a number of patients that had very rapid lung growth and what we call liver lock, meaning that the lung would grow, the liver would seem to inhibit further growth, and the fetus would become distressed and have high drops related to, I think, cardiac compression from lung growth. So, the tracheal occlusion doesn't always result in liver reduction, even when you do an extreme form of tracheal occlusion, like putting clips on the trachea. I have had occasional cases indeed where the, uh, Lung growth was associated with the development of hydrops. It was much rarer than what you reported, but we recently had one or two cases with right sided diaphragmatic hernia actually. Is that indeed a tremendous or impressive lung response can be associated with tight drops of the fetus. And I can directly answer Andre's question about whether doing something open would solve, you could get around the problem of vascular kinking, and the answer to that is absolutely not, because that was our early experience before we were even thinking about occlusion or anything else. We were doing open repairs, and that was the limiting factor. We could not push the liver back down without having it kinked, so no. Well, yeah, I misinterpreted the question. It appears to be inactive and will be ended soon. If you are the host and wish this conference to continue, please press any key on your telephone touchpad. That's Big Brother talking to us. Yeah, someone's telling us to hurry up, but we're on time. We're doing OK. Um, so, yeah, that's interesting. I, that's Mike, I didn't realize that. Well, you remember the, the history, and I witnessed a good part of this, of the varying procedures to try to deal with the liver with open repair, and they, they varied from, you know, the two-step of going through the abdomen and the chest. They included putting in a huge patch so that we wouldn't, we'd allow the fetal growth to slowly reduce the liver. Uh, we did a bunch of things to try to deal with the issue of liver, uh, vascular kinking, and uh. As Mike said, none of them were successful. Those were the good old days, Alan. Oh yeah, unfortunately it didn't work. So we actually do only have about 2 or 3 minutes left. Does anyone have any, uh, last minute comments to make? Tim, do you have any comments to make, uh, Tony, anyone here want to make any last minute comments? Just the FDA. If we could figure out some way to move this process along so we can actually do the trial in the US, that's really the critical mass. I mean, Champion Holly and the team there at CHOP are trying to get this thing along because really. It's, it's holding up answering the question. It still stays out there, and I think the US group could really provide some help in completing this project, but we just got to figure out how to answer all the questions the FDA needs. Yeah, just for clarification, we've, we've done all the applications and the FDA has come back to us with requests from the company that makes the balloons to do further safety testing of one type or another, and it's, it's really been a laborious process. Don't get me started about. I don't want to get you started. You don't, you don't know anything about that, Mike. You have no experience with that every day. And I, I just wanna, as a last comment, uh, again, uh, compliment Jan on his efforts and his perseverance to get a randomized trial going. And I want to just throw out a plea to the community out there, uh, you know, these, these procedures should not be done unless you're in a startup phase and a learning phase outside of a clinical trial. We need to learn from the cases that are done. And sending patients and having them go to backdoor institutions or referring them there, I think just shouldn't be done. This is an important question and this is the only opportunity that we will have to answer it before it becomes even more widely disseminated. So, so that's my plea and the final statement. And while we're waiting for the balloon, the bulk balloon to get approved. We do have an FDA approved study to, um, uh, look at the old balloon, which is very similar, uh, just, uh, as we gain experience. So if, uh, people want to bring their patients and come out, uh, again, we're not as slick as John is, but, uh, um, uh, we'd welcome anybody to bring their patients and. Uh, just real quick, I know Jan, your phone's going to shut off in 60 seconds, but Marcelo Martinez Ferro wants to know about a selective occlusion, bronchial occlusion on the side of the defect. The experiment was done in Children's Hospital Philadelphia by a Belgian, Jean-Marc Bier, and I think Alan can report on that. OK, perfect. You've got about 10 seconds left. Well, I can say it didn't work, OK? It's, it certainly made the lung grow, but then we had trouble with mediastinal shift and other issues, uh, as I recall. And let's not forget both lungs are sicker. Yes, that's it, yeah, so you basically put pressure on the good lung, uh, when you did that, the relatively good lung, and it, uh, in some didn't improve outcome. Well, Jan, uh, I know you shut off on the computer. I don't know if you're there on the phone. Thank you so much for your talk. Sorry, you got booted out exactly. Are you there? Yes, because the phone you pay. OK, that's perfect. Yeah, we should have, so, uh, perfect. So, well, thank you so much, and, uh, it was obviously a lively discussion. I wanna thank the panelists. Uh, great discussion, controversial topic. I don't know if we've come away with any clarity at the end of this discussion. Um, I certainly have as, as someone who's naive to this. So thank you very much, and we're gonna take a fifteen-minute break and when we come back, we're gonna, um, um, have a talk of Mark Johnson on selective laser photocoagulation for twin twin transfusion. We'll see you in a few. I don't know what you're ready to hear, but I know what I'm talking. Talking about in your killing each other for drugs. Talking about police corruption. I'm born into nothing. About welfare food stamps. Talking about projects turning into co-ops. I'm talking about strangers from mid-America. $3000 a month Apartment that my mother paid $200 for. I'm not talking about prefab. Free fat Family, I'm here. Hearts and minds of people Soul. know what you're But I know what I'm talking about. I'm talking about Being able to afford the American dream, subway hikes, and not having a dollar in your pocket after having two jobs. Talking about your mother being over 65 and still having to work. I'm talking about police putting 50 shots in the wrong man. I'm talking about no more so. I'm talking about women and children being homeless. OK. We are back. I'm sitting here still, but I had this incredible urge to start doing disco dancing, uh, with that music, but I kept my control. Uh, we are back now. Um, we're gonna now turn things over a little bit of a different angle now. Um, Dr. Mark Johnson from CHOP is gonna be talking to us about selective laser photocoagulation for twin twin transfusion syndrome, and actually I'm just curious, would you say out of all of the, out of all the fetal techniques we're talking about, is that the most common? What are, what is the most common thing that we're seeing? I'd say probably right now that's the most common, um, minimally invasive technique we do. That we know of, I mean, shunts may be, we have no idea how to track those, but, uh, they're commonly done around the country, but we have no idea how many shunts are actually done, no way to track them. So we do know that there are a lot of laser centers, and we know that there are hundreds and hundreds of lasers done every year. OK. All right, um, so, uh, thank you for the talk, and then after that we'll have some discussion. to minimally invasive as opposed to open fetal surgical procedures. The first one we're going to talk about is twin twin transfusion. It's one of the most common complications in monochorionic twins. It happens in about, you can read studies that suggest 10%, 15%, as high as 20% of monochorionic twin pregnancies. It is responsible for a very large amount of the perinatal mortality. And morbidity in twins that are born. In the past, mortality was extremely high, 80 to 100% if untreated. The underlying problem is that in monochorionic twins you have two fetuses that are identical but they do not share the placental mass volume equally and inevitably one twin has a much smaller portion of the placenta than its co-twin. The second basic principle of understanding twin twin transfusion or identical twins. is that the twins are always connected by vascular anastomosis, and they can be arteries to arteries, vein to vein connections, or they can be unidirectional, where an artery will go from one twin into the placenta and then the oxygenated blood return to the co-twin. And it really depending on the type of connections, the number of connections will determine risk for having a normal twin pregnancy or developing twin twin transfusion or the development of selective intrauterine growth restriction that we'll talk about in the next session. So the current concept about why twin twin transfusion occurs is that the baby that has the smallest portion of the placenta begins to struggle in interacting with his placenta, getting enough oxygen and getting enough nutrition. That fetus will kind of respond to those challenges by releasing vasoactive substances that allow it to redistribute blood flow in its body preferentially to the heart and to the brain, the two most important organs in the body for the fetus, and by shifting that blood or the cephalization of blood to the heart and the brain, they slow down their growth, and the growth factors and the vasoactive substances that they use to modulate blood flow within their bodies. Also interact with the vascular bed of the placenta. And so over time these vasoactive substances get into the placenta and increase resistance to flow because they vasoconstrict blood flow within the placenta. And so what happens is, depending on the type and the number of connections, the fetuses can actually the resistance on the smaller twin side increases. And the smaller twins now cross over the vascular equator and try to access blood supply or the part of the placenta that is shared in this middle area by both fetuses. And so by making this shift because of increasing resistance here, they can survive, they can continue to get blood, they can continue to get oxygen. And it's not until later when resistance is really increased. And if there are more unidirectional connections from the smaller twin to the bigger twin, that you see this net shift in blood volume, which is the inevitable transfusion process. And this net shift in volume results in A number of changes that we'll talk about in just a bit. But the risks for developing twin twin transfusion, you have to really understand the vascular makeup of the angio architecture of the placenta. And Denbo back in early 2000s looked at 71 placentas using vascular injection studies. And what they found is that twin twin was really associated with multiple arterial to venous anastomosis, usually from the smaller twin to the larger twin, so that there was this net shift from one side to the other, and made the observation that there was the absence of arterial to arterial connections, and it wasn't until later that we really understood what that meant. So the risk is increased with the greater the proportion of donor to recipient one-way anastomosis and fewer compensatory recipient to donor anastomosis. He also made the observation that if you had arterial to arterial connections, it decreased the risk for twin twin transfusion, and they postulated that this equilibrated the unidirectional anastomosis, and they came up with the idea that if the smaller twin was sending blood across the vascular equator to the to the recipient twin, that these arterial to arterial connections were very sensitive to pressure. And volume so that if there was a net shift from donor to recipient, there would be a reverse shift along these AA's perfusing back into the donor side of the placenta. So they made the observation that the larger the size and the number of the donor to recipient connections, the greater the impact that these AA connections had, and they seemed to be very sensitive again to blood pressure. So the AAs would flow to the donor side to compensate for this loss in blood volume and blood pressure on the donor side. Yeah. So the bottom line concept was the donor to recipient volume transfer was unidirectional. The fall in the donor blood pressure resulted in increased reverse flow through the AAs from the recipient to the donor side to compensate for this unidirectional arterial to venous connections. They also noticed that increased arterial to arterial flow into the donor placenta probably resulted in what they termed a rescue transfusion. So it was a compensatory shift back to the donor, a rescue transfusion per se, that really allowed the donor to survive and develop despite the presence of unidirectional shifting of blood or twin twin transfusion state. But in true twin twin transfusion where you don't have the arterial to arterial connections, there is a net loss of blood volume unidirectional, and this leaves the donor very anemic, very hypovolemic, hypotensive, oliguric because they're not perfusing their kidneys like they should, activation of the renin angiotensin system, and it leaves these fetuses hypoxic. They develop anhydrammias because of the oligo. and they continue to swallow the fluid until they're eventually the stuck twin, and this leads to progressive growth restriction and intrauterine growth retardation. The recipient twin, on the other hand, is hypertensive because it's hypervolemic. It's polyuric because it's sending more blood to the kidneys. This results in polyhydramnios, and polyhydramnios was the leading cause of death in twin twin transfusion because of early ruptured membranes and preterm delivery. We also saw that this hypertensive state leads to a characteristic hypertrophic cardiomyopathy that's progressive over the course of the pregnancy that can result in heart failure, eye drops, and death of the recipient twin. So back in 1997, Ruben Quintero came up with a staging system to allow centers that were investigating treatments for twin twin transfusion to really talk to each other, and it was kind of a simple approach. Stage one was basically where the recipient had polyhydramus, defined as the deepest vertical pocket of greater than 8 centimeters. The donor had oligohydramnios with the deepest vertical pocket of 2 centimeters, but really size and fluid discrepancy only. Stage 2 was when you had polyhydramn oligohydramus size and weight discordancy, but now you observed a non-cycling, very, very small, non-filling fetal bladder. Stage 3 was defined as stage 2, plus Doppler abnormalities, blood flow abnormalities to the placenta. Stage 4 was described as high drops or one baby who was in the process of heart failure or dying. And stage 5 was when one of the singletons died. I think what we now appreciate is that Ruben's classification was actually brilliant because he was actually describing the physiologic states of twin twin transfusion. So stage 1, these findings reflected the initial phases of volume transfer from the small baby to the larger baby. Stage 2 represented the cephalization of blood flow because of the hypotension. To preferentially the heart and the brain. Stage 3 represented the increasing placental resistance because of the increasing release of vasoactive substances related to cephalization of blood flow, and stage 4 represented the cardiac failures seen in the recipient twin because of the hypertensive cardiomyopathy that occurred. So about 6 years ago, you know, a lot of this stuff that was coming out really kind of changed our understanding that twin twin transfusion is really a double-edged sword. There's the amniotic fluid problems and there's the hypertensive placenopathy issues. The amniotic fluid problem. was initially treated with amnia reduction therapy. But as we look back on who needs to be treated from who doesn't, we go back to the stages. And when we look at stage one and look at the natural history, only about 30%, 30 to 35% of stage one twin twin transfusion actually progresses to stage two or higher. And 28% will just stay at stage one throughout the whole pregnancy. About 40% progress to regress completely or go away. So in the past there's been reluctant to do anything very aggressive for stage one, and they have been managed primarily by amnia reduction. We use amnia reduction, which simply putting a needle into the amniotic space under ultrasound guidance and removing 1 to 2 to as much as 3 L of fluid. To just primarily reduce the risk of preterm delivery. But it turns out that that reduction in volume did a lot of other things. And Nick Fisk back in 1990s showed that when they put pressure transducers into the amniotic space, that the pressures in the presence of polyhydramnio with transfusion were very, very high. And this resulted in significant compression of the placenta that interfered with blood flow into the placenta. And what they found is when they did amnia reductions and decreased the amniotic fluid pressure, the oxygen in the twins, the degree of oxygen concentration went up and correlated linearly with the decrease in pressure. So they said that reduction in the severity of the polyhedramnios improved fetal hypoxia and reversed aidemia. Similarly, in the mid 90s, a group that was looking at blood flow to the uterus, were doing impedance indices and qualitative blood flow analysis before and after amnia reduction showed that amnia reduction in the setting of severe polyhydramnios not only improved uterine blood flow through the uterine arteries, but improved blood flow to the placenta, reduced vascular resistance within the placental bed. And improved overall blood delivery to the fetuses, particularly to the donor fetus. So amnia reduction changed the basic physiology of blood flow within the placenta, primarily by decreasing compression on the placental bed. But then there's the other side of the sword, which is the hypertensive placenopathy. And what we know is that with this increasing resistance in the placental bed, There is acquisition across the vascular equator, the rescue transfusion that occurs in the direction of the larger to the smaller, but over time with the net transfusion or blood loss from the donor twin to the larger twin, the smaller twin is also sending lots of growth factors, lots of cytokines, and lots of vasoactive substances to the recipient twin. That results in the high blood pressure that we see and that high blood pressure and high blood volume leads to what we have characterized as well as other centers as a progressive hypertrophic cardiomyopathy. Initially we thought this was only volume related, but it turns out that there's significant afterload pathology as well. And this appears to be due to activation of the renin angiotensin system causing peripheral vascular constriction. So now we have preload issues and after load issues that lead to a progressive thickening of the ventricles, dilation of the ventricles, stiffening of the ventricles, leakage across the valves, and over time results in heart failure, high drops, and death of the larger twin. CHOP came up with a cardiovascular score basically not for prognostic indications but basically just to characterize the changes that occur temporally over time in the setting of twin twin transfusion. And what we look at is ventricular characteristics, AV valvular function, venous Doppler characteristics, looking at growth and size of the great vessels, and in the donor twins basically looking at Doppler-vi asymmetry in the umbilical artery. And when we get a score of 0 to 4, those are early changes in the process of the hypertrophic cardiomyopathy. When we get up to scores of 15 to 20, that means there's abnormalities in essentially all of these different areas of cardiac function, and that these fetuses are at very high risk for developing high drops and dying. So when we see stage 2 or above twin twin transfusion, which we recognize as absent bladder filling or Doppler veal asymmetry abnormalities, changes in the heart with moderate to high cardiac scores, then it's been shown by experience that amnia reduction is not the best therapy. And studies have shown that laser photocoagulation is a better approach which basically separates the two fetuses by identifying the connections and lasering them closed, thereby disconnecting the two sides of the placenta. And if we could run the video. This is just a video of a laser procedure. We're starting on the donor side. You can see the kind of aiming dot for the laser. We're now on the donor side and we're crossing. This is an artery from the donor's side. We're crossing now into recipient twin territory. As we follow down, you can see a connection right here. This is a donor artery to a recipient vein coming from the other side. The other branch of this donor artery is going across the surface of the placenta, coming down, and now what you're going to start to see is recipient vessels branching in the opposite direction. And as we follow the dot down, what you're going to see right here. is an artery that now has multiple connections to the very large vessel to the right, which is marked right there, which is a recipient vein. So these are donor artery to recipient vein connections, meaning that the donor is pumping blood into the venous circulation, which is going back to the recipient twin. Uh, it's losing blood volume through these connections and increasing blood volume and pressure in the recipient. Mark, can I stop you for a second? I need some clarification for someone who's never seen this before. Can we hold the video? Yeah, can you pause the video? Um, you're pointing at these vessels and I can't see what you're talking. I don't. So when you go in, how can you tell when you're pointing to this is the donor, this is the recipient, and also how dependent on it this is this is the position of everything that you're gonna actually see these vessels, I guess. Well, position is if I had an arrow, it'd be easier. You can have an arrow and everything but a video, so that's right, you can't do it, um, so it's hard to point out the connections, but basically the principle is that we generally go into the recipient side. Of the pregnancy, where there's polyhydramnios overexpansion of the sac. OK. We go to the placental cord insertion, and then we follow the blood vessels as they cross over the surface of the placenta. And what we've learned is as they cross the placenta, they branch in a characteristic pattern. And so we follow this branching pattern down. And many times what we end up doing is coming up to the collapsed inner twin membrane. And when I talk about the collapsed inner twin membrane, remember that the donor fetus develops oligohydramnios and eventually anhydramnios, so that the sac collapsed down on them. And that's why we refer to them as stuck twins. When we identify the collapsed inner twin membrane, it serves as kind of a um a reference for us. And we can now look onto the donor side of the placenta and look for vessels that are coming from the donor side and crossing that collapsed inner twin membrane. And they're branching in the opposite direction. So it's a little trick that you can look at the branching, and you look at the vessels that cross the intertwin membrane, and you map every one of those vessels from the donor side. To where it goes into the placenta. And if an artery is coming out and connects to a vein that goes back, that's a good connection. That's one you want to leave because that's circulation from the donor. If an artery comes out but connects to a vein in the recipient's side, you know that there's blood going in that direction. So that's a bad connection that you want to get rid of, but you only want to get rid of those connections between the donor to the recipient and spare all of the connections that belong to the donor and all of the connections in the placenta that belong to the recipient. So what the dot is right now, this is a diode laser, a 600 nanometer diode laser fiber, and the dot right now is a branch from the donor artery and it's connecting to a recipient vein. Both to the upper left and lower left. And so what we're going to do is when we run the video, you'll see that we're going to come down, we're going to target those vessels, and using the laser, we're just going to photo coagulate or obliterate them. And, and I'm sorry, I want to keep going because this is fascinating to me, so I'm sorry, but when I get fascinated, I don't stop talking. So You're using a feedoscope, yes, OK, and this is, and the feetoscope has the, the laser as part of the feedoscope. Now, basically what it is, it's a 2 millimeter semi-rigid fetoscope that inserts into a sheath that has two side ports. It's connected to a remote eyepiece and a digital camera, and we have big LCD screens up on movable booms that we can watch as we do these procedures. The laser fiber goes through a superior side port and so as it comes out, it comes out just above the fetus scope. The bottom side port is hooked up to a level one infusion device so that if we want to expand fluid volume or if we encounter debris, which sometimes we do, meconium type debris, we can wash it out from the surface of the placenta. So if you continue to run this, you'll see when you hit play. So now we're targeting, you'll see the fiber come down. And you'll see the size of the fiber, and it gives you perspective of how tiny these vessels are. And so again, now we're targeting the donor artery, and there's a recipient connection right there. To the left, donor to the right. We might want to speed the video back up to 100% speed. And the key is not to laser anything that is a good connection between the donor or a good connection between the recipient. You just want to eliminate the ones that connect the one to the other. So here again was a connection between the dot on the donor artery there and the big fat recipient vein below. You can see it collapsing. Here's a tiny little branch between these two vessels, and what makes these cases challenging is that the mother is breathing, so the placenta is moving up and down. Many times, the uterus is right over the aorta, so there's pulsation, so the actual surface of the placenta is constantly moving, and it's quite often that the recipient twin will come down and help you by grabbing onto the feetoscope or kicking it or Things like that, so you have to be prepared for any kind of movement that displaces the scope or makes the firing difficult. So that's basically just an example of what we do. We go and we look, we try to follow the vessels. If we can document a true connection one side to the other, then we just eliminate them. And what that does is it leaves both fetuses with their own side of the placenta, so the donor now has to be able to live and survive on its small portion of the placenta. The recipient twin now is no longer getting blood, and so it gets rid of its excessive blood volume and pressures, and actually heart changes can actually change. So when we look at overall survivals following laser, um, Huber's group, Kurt Hecker in 2006, looked at outcomes in over 200 cases, and what they found was that at least one twin was surviving at about 84% with amnio reduction therapy in the same stage, stage 2, Stage 3s. Singleton survivals were maybe 60 to 65%, so much better survival of at least one twin, both twins surviving at about 60% as opposed to 40% with amnia reduction and overall survivals of about 72%, with an average age of delivery of about 34 weeks, whereas the average age of delivery with amnia reduction therapy prior to laser therapy was around 29 weeks, so much less prematurity, much better survivals. And additional studies came out, a number of them shortly thereafter, and looked at survival by stage. And even in stage 4, where you had a hydropic fetus who was in the middle of heart failure, you still got survival in 50% of cases of both twins. And for stage 2, which is the most common, 83% survival of at least one twin, significantly better with laser than with amnio reduction. And then with higher volume centers, more recent data shows that with experience and doing lots of cases, you can achieve as much as 93 to 94% of cases where at least one twin survives, 88% overall survival, 78% where both twins survive, and an average age of about 34 weeks. And when you look at the high volume centers around the world, this seems to be the kind of center. The ceiling, I mean, because anything above this, you still have the complication rate of preterm delivery and membrane leaking and things like that. But I think it shows that experience is important because our data is just about as good as stage one data in the earlier reports. When you look at long term neurologic consequences, with amnia reduction looking at major and minor neurologic deficits, 55% of kids after amnia reduction, 42% of kids in this study had some degree of significant neural development or cognitive delays. When you look at after laser, the numbers are less than half, and the most recent studies I've seen major neurodevelopmental delays in like 5 to 6%. And minor delays in about 7 to 8%. So not only was there better survivals, but there was less prematurity because they delivered many weeks later and the long-term neurodevelopmental and cognitive outcomes were very good. When we look at, this is a strange slide, when we looked at cardiac scores because we looked at the CHP cardiovascular scores before surgery and one week after surgery, and what we found is that in the vast majority of cases, the cardiac score significantly dropped even within 1 week to 10 days after the initial surgery. So again, the recipient twin's heart has great potential to heal. So conclusions, selective laser photocoagulation therapy increases singleton and twin survivals, increases the age of delivery, and therefore decreases neonatal morbidity and mortality and decreases long-term neurodevelopmental and cognitive morbidity as well. So with that, uh, introduction, I thought we would kind of open it up to some discussions. I'm not sure who we have on my panel here. We got, so for all of the, the faculty that are on the phone line, if you could turn on your camera, uh, we have, uh, Michael Harrison in the UCF Group, Hanneman Lee, and I think Shin is there too. Uh, Yinka, if your camera's on, you can turn it on. Doctor Cromoholm. Um, and Julie Moldenhauer and Diana Farmer, if you guys could turn on your cameras, if you could, uh, join us in this discussion, we'd appreciate it. Doc Doctor Gradios is on. Oh, great. So if he wants to turn his camera late breaking news, uh, Doctor Gradios is also here. Uh, so if he can, if you can turn on your camera, uh, Doctor Gradios, are you there? We can hear you, sort of. Um, Let me ask you a question while we're waiting for everyone to turn on their cameras. Do these, when you're going and coagulating them, um, do they ever not occlude completely and they burst and start bleeding and then I think you know in our early experience we used to use an argon laser and it's a different type of power source and there was a higher risk for rupturing vessels and getting bleeding. But, um, what I've noticed in Tim and the San Francisco group, you can chime in as well is the diode laser is much, much safer. It has Uh, a lower, uh, not as deep a penetration, and I think, um, I can't remember a case that we've had since using the diode where we've had a vessel rupture and, and never over aggressive where you've ruptured through the amnion. No, you just have to be very careful and as you see the, the vessels blanch down, you just stop, you stop and then you watch for a bit and sometimes, you know, you'll see pressure kind of. You know, start to open them back up again and then you just laser them again. But, but the diode, I think, is a much safer laser than the argon laser. And, and we saw one point in time of your video. What are we talking? Is this, is this, uh, 30 vessels? Is this 3? Is this 10 minutes? Is this 3 hours? What is the, I think it's, it's intriguing because every case is different and you know we've gone in and done cases where there might be 4 connections and we've done cases where there were 30 connections. And it all has to do with the size of the connections and you know which direction they go, um, because you know, in some cases you may have 25 connections, but most of them are going in the direction from the donor to the recipient, but there are still connections coming back. And so it's absolutely critical that you very, very carefully map and try to identify every one of those connections. Because one of the things that we all fear and worry about is if you miss a connection. Then you could either get, you know, the twin twin could continue, or you could get something called taps, which is reverse, where now a connection comes from the recipient to the donor, so they physiologically switch positions and now the donor starts receiving blood from the recipient twin or if the donor were to die. because of acute placental insufficiency, or die of placental insufficiency, and they're still connected by these vascular connections. Then when one twin dies, it could, the other twin can bleed into that twin. And it can be either neurologically injured, or that twin could die as well. So one of the, we've got some of the best experts up on the panel. Hey, Eduardo, how are you? Welcome Eduardo, can you hear us? Yeah. He's calling in now OK. So, I mean, one of the questions is, um, that I would throw out there is different techniques for mapping. Um, you know, Tim, my, my guess is your way of mapping is very similar to ours because you, you and I learn together. Um, but I'm curious as to how the, uh, Europeans map. I know that we try to get every placenta that we do laser on. We have a program where we give the patients a Styrofoam box and shipping label, and so they send their placentas back. We do injection studies and we look for missed connections. And in our series we miss connections in about 0.8% of the time. I know in the literature, however, I've read. Where people have done vascular connection, vascular injection studies and have missed vessel rates of like 10 to 15%. So there must be differences in technique, and I know that the Europeans have now started doing a trial using solemnization, which is a technique where they connect the laser sites along the surface of the placenta that probably would pick up these small connections that are left behind. Tim, so Tim, any comments why Eduardo is getting on? Um, well, I, I, I agree, it's, it's actually paramount that nothing be left behind. Um, we have a mapping, uh, strategy that involves kind of a checks and balance system. So we have, you know, two operators that have to agree on what exactly we're looking at, what type of connection. They, we have a recorder who records every single one as we move from one edge of the placenta to the other. And that's the first mapping. We don't laser anything until we've completely mapped every vessel on the placental surface. Uh, we then proceed to uh use the laser, and again, kind of checks and balances. The recorder calls out the connections that we said were present. We have to find them, confirm them before they're lasered. And we make a priority of trying to complete the laser procedure in under 5 minutes from the time the first vessel is lasered through the time the last vessel is lasered, minimizing the potential for a vascular shifts between the two circulations. And we've found that this has a significant impact on donor survival. We have, uh, any comments from the UCSF group? I, I, I got it. Um, yeah, the size or gestational dependence of the, the vessels that you Can Blade. Well, there are a number of technical issues, and you know I think we and many, many centers around the world have noticed that the complication rate is earlier if you do lasers before 18 weeks, it just seems to be a higher membrane separation rate or amniotic fluid leakage rate. We try to do our cases after 18 weeks if possible and sometimes have to temporize with amnia reductions. Which we don't like to do because of the risk of membrane separation after amnia reduction, but we will go up to 25 weeks for an anterior placenta. We'll go up to 26 weeks for a posterior placenta, but at that point, the vessels are very large and they're much more difficult to laser, especially on an anterior placenta. And so that's where our cutoffs are. Uh, I know that many centers, uh, in Europe will go up to 28 weeks or 29 weeks. Tim, what's your kind of cutoffs in your program? Uh, well, Mark, we, we haven't had that experience with the early gestation, and the earliest we would do it is 15 weeks. Uh, and the latest is, uh, you know, 27 weeks, the end of the 26th week. Um. For whatever reason, we, we have not had an increase in complication rates less than 18 weeks gestation. We have a um a question about methods. This is coming from Doctor Rata, uh, and Doctor Rata, tell me where you're from cause I don't, I'm curious, but, uh, the question is methods of optimizing the procedure and anterior placentas. Um We, there are different ways to visualize the anterior placenta. What we use is actually the same sheath that we use for the posterior placentas, which is straight, but we curve the sheath into kind of a gentle curve. So that we can get in laterally and literally look up at the placenta, and we found that to be very, very effective. There are other techniques where people will use scopes that have a 30 degree angle that looks up, and there are instruments where you can deviate the laser fiber upward. So you can, you can look up at the placenta and then using these mechanisms, you can kind of bend the laser fiber up. And then using the targeting dot, you can do the laser. Other people have used different approaches where they might do a mini laparotomy and reposition the uterus to try to come in from the back. But when we looked at our case series, our success was equivalent between anterior and posterior placentas using this curved sheath approach. Uh, we have a, a question from Hawaii, from Honolulu, from, uh, Donald, uh, Gui. Uh, he says he knows a handful of case reports that have reported identification of anastomosis and die-dye twins. Um, are these ever clinically significant? Um, I, I can't comment on that because I've never really seen a vascular communication between a dye dye. Tim, I see you nodding your head. Did you have a, well, I don't, I don't know how to explain it, but we, we have seen one case and there was a single vascular connection between the two placental discs. Uh, and that, that set of twins did have twin twin transfusion syndrome and responded to the photocoagulation of that single vascular connection. Uh, embryologically, I'm at a loss to kind of explain vascular connection. So what was, what was the type of connection? Do you remember, Tim? Uh, it was a couple of years ago, Mark, um, and I honestly don't, don't remember if either of those kids ever needs a, uh, organ transplant, you know where to go though, right? That's right. They're probably. So, so I don't know, what do you use for anterior placentas, Tim? Well, just like you, Mark, uh, we use a curved scope and positioning of the patients, so they're in a full lateral decubitus position, and we try to come in through the flank. I guess the one caveat to that is a patient with an anterior placenta that's uh less than uh 17 weeks. Sometimes with wall to wall anterior placentas, uh, you don't have a great window, you end up parallel to the surface of the placenta. So those patients, we very often will put on nifedipine and temporize for a week or two until the uterus grows and we now have a window where we can safely do the procedure. Now we have a similar approach to earlier ones where we try to temporize until the window, you know, develops that we can get in, you know, laterally on as well. So Eduardo, are you on? I think so. Welcome, El. Thank you for joining us. It's late in Europe. Thank you. What time is it there right now? It's about 95 to 9. Thank you for staying up. So Eduardo, how do you approach anterior placentas? Well, actually it's relatively similar. We place the patient a little bit lateral. We don't use very much. We tended to use very much curved scopes, but we stopped doing that. Well, it's not that we stopped, but I, if you look at the curved scope and you look at the end of the tip, you see that actually the 5 to 8 centimeters that you poke into the patient. are actually quite straight. So, uh, but the part that is outside the patient is quite curved. So actually what you see is curved, and psychologically this reassures you very much. It's actually what is in the patient is quite straight, so it doesn't make a lot of a difference. But anyway, we sometimes use curved scopes, but the best thing is I think to place the patient as lateral as you can. Sometimes we place them completely lying on their side. And playing this little trick of, I don't know whether you are using an external sheath like the candles or any external sheath or you just go directly with your scope. If you are using an external cannula, it's quite useful sometimes to withdraw your scope a little bit in the cannula. So you create some space and um and then you can press the placenta and then bend it a little, a little bit. We have a couple of videos that we show in congresses and then this helps you a little bit to see a little bit better, but of course there are cases where I agree, particularly in very early gestational ages, you just have to wait because technically it's simply impossible. Yeah, I agree with that. Yeah, well, we, we use the sheath. And we, we learned the, uh, kind of shoot through technique as we call it from uh you and Jan where you pull the scope back in and you can actually press the sheath up against or next to the vessel, um, and it, it makes it much, much safer on really acute angles upward. So that that is a very good trick to use. Yeah, because by pushing the, it's like when you would be pushing on a pillow that you create this, you force the placental surface to look a little bit more perpendicular to your scope, and then you just can fire more safely. Of course the view is quite limited, but if you are a patient, you can really go through all the surface, yeah. 11 other technique that we've found helpful is amnio infusion. Uh, with the anterior placenta, sometimes just a little bit of fluid, 500 cc's or a liter, can give you a completely different perspective, uh, with the anterior placentas. Yeah, I fully agree. I, I think you're completely right, and certainly you have to remember, sometimes there are some cases that really improved a lot with that. Yeah, I fully agree. The other thing with the anterior placenta sometimes put in, if you're using a sheath, um, 3 millimeter, 30 degree scope, uh, gives you a much crisper view. And with the angled scope you can go in with that, see exactly the whole, uh, placental surface, and then put in your feetoscope again and then, uh, ablate, uh, uh, because as Eduardo was saying, sometimes you have a very close up view of it and it's good to step back and look at the forest and then you can look at the trees again. Yeah, might help, yes. So one of the other issues, uh, Eduardo, I know you're involved in the solemnization, um, trial, I believe, um, you know, people look at vascular miss missed connections using placental injection studies, and, um, just curious, um, as to, you know, what, what is the thoughts behind that trial that's going on and And what have you found um as far as are you basically doing the lasers, then you connect the laser spots, and do you find on postnatal injection studies that really where you're connecting the dots were vessels that otherwise would have been missed because they're very small or Yeah, what's the theory behind it? Well, the reality today is that we, um, I think when we, we, we randomized some patients, but then we stopped, so our center is not participating in the Solomon trial these days. Well, as you know, Kiper Nicolaide used a very straightforward technique. He just simply draw a line. where he thought the vascular equator was, and he drew a line. Actually he was looking more at the ultrasound screen than at the endoscopic screen, possibly because of his bias as being a fetal medicine specialist. We all thought in the beginning that that was a little bit too aggressive because you are really firing a lot of surface in the placenta. So in the beginning we were trying to be very selective. So just you explained it very well in your presentation, just coagulate the vessels that are connecting the two fetuses. But the truth is is that even if you look very carefully, When you do injection studies, you sometimes discover these tiny vessels that create the taps. So I cannot speak for everybody, but I would say that after speaking with several people doing this technique, After some experience we tend to do the same. So if you see very clear the vessels, you just coagulate everything you see. But if there is a space between two vessels that you don't see very clearly what is going on there or the visualization is not good, or simply it's just a, apparently 3% or so face, you tend to draw a line there, of course explaining these things without without. A slide is quite difficult, but those of you who do fluidoscopy probably will understand me. So if there is a free space there, we'll probably draw a line. So it's not that you do a full salomon, but let's say that you do a semi-salomon in some areas of the placenta, and since we started doing that a few years ago, the truth is that we have reduced the incidence of stabs not to zero because that is impossible, but we have Reduce it very, very substantially. Yeah, so the answer is really not white, not black. We are somewhere in the middle. Perfect. I, I think that we're going to move on to the next topic and then if you guys could just stay on for the panel discussion, that will, that will be the conclusion of this event today. The last, uh, brief presentation is on selective, selective intrauterine growth restriction. In monochorionic diamnionic twins, uh, again by Doctor Johnson, and then we're gonna bring you guys back for some more discussion. OK, I just need my, uh, other presentation. Yeah, um, Stefan, bring up the last presentation. OK, it's coming up. And I'm really glad that Eduardo is here because I think he's made one of the major contributions in our understanding of selective IUGR and you'll see a lot of his data here. So when is twin twin not twin twin transfusion? Well, it's when one twin is developing more normally, doesn't have polyhydramnios necessarily, but the other twin, you have severe growth restriction, oligohydramnios, and is just a reflection of the degree of differences between the placental surfaces. So again, when we look at the choriolangiopagus, one twin has a much smaller portion of the placenta, and that there is this series of connections between the two fetuses. Increased resistance on this side of the placenta drives perhaps perfusion into the kind of vascular equator portion of the placenta and allows for the donor twin to survive or the smaller twin to survive because it can use mechanisms to access blood from the normal twin side of the placenta. Dr. Louis back in 2007, looked at 100 monochorionic diamnia placentas from pregnancies that did not go on to develop twin twin transfusion, did not have selective IUGR and had two live born infants. And what they found is that the more unequal the placental territory, meaning the smaller the placental share that the one twin had, the larger the ATA anastomoses were. The greater the net transfusion over AV anastomoses in both directions and that the larger the combined diameter of all the AA connections together resulted in a very dynamic shift of blood back and forth between the smaller twin and the larger twin side of the placenta, again reducing the impact of the placental discordance because of this rescue transfusion phenomenon. They also found that the diameter of the AA anastomosis strongly correlated with a net AV transfusion, suggesting that these AAs are flexible bidirectional anastomoses that compensate for the imbalances between the smaller and the larger AV connections that then therefore prevents the development of twin twin transfusion. And they proposed that these AAs increase the availability of oxygen and nutrition nutrients for the twin with the smaller portion of placenta because they actually perfused across this equator into this side of the placenta, thereby, again, the idea of rescue transfusion. Um, Chang looked at placental territories in IUGR fetuses, uh, and the association of Doppler abnormalities, and what they found in monochorionic twins that did not have IUGR. The difference between placental mass was minimal. The mean gestational age was almost 35 weeks. When they looked at those that had IUGR, but normal Dopplers, they started to see smaller percentages of placenta for the smaller twin. And again earlier delivery rates. And then when you looked at growth restricted fetuses with abnormal Dopplers in the umbilical artery, what we found is that these fetuses have the smallest share of placental mass, deliver much earlier, and have a much higher neonatal morbidity and mortality. And it was really this paper that Eduardo put out in 2007 that really started to increase my understanding of what was going on here, and I think this was a pivotal paper where he classified selective IUGR into three types. Type 1 is where there's positive and diastolic flow in the umbilical artery of the smaller twin, and what we find is these generally have a good outcome and a benign prognosis. The type 2 is a whole different animal where there's persistent absent to reverse end diastolic flow as the pregnancy progresses, very high risk for hypoxic degeneration and intrauterine fetal death if not recognized and delivered before these twins die. And then type 3, which is always the one thing that we looked at the Doppler studies and could never make any sense of, because as you watch the umbilical artery of the smaller twin, you can have normal and diastolic flow. That over time will decrease to absent and diastolic flow, will return to positive end diastolic flow, will return to absent and diastolic flow with periods of reverse flow that go from reverse back up to positive flow, and this cycling never made much sense at all. And so when Eduardo looked at the type 1, type 2, and type 3s, what they found was that in type 2, there was a fairly characteristic progressive deterioration of the smaller fetus that identified these fetuses when they developed severe Doppler abnormalities, meaning reverse flow. Recognizing that these fetuses are now at high risk for dying that allowed delivery and improved survival. When you look at type 3, there was no characteristic progressive deterioration. Unexpected IUFD rates was very high, and what we noticed is that the larger twin who had normal fluid, who didn't seem to have any manifestations of growth restriction or anything from the smaller baby. had about a 20% risk for PVL and neurologic damage. And he also noticed that these type 3s have the very smallest portion of placenta of all the IUGR type twins, and they also had characteristic very large AA anastomoses. When we kind of look at a type 1 selective IUGR, the first thing you notice is that the arrows delineate the connections between the two sides, and the arterial to venous from the smaller baby are the blue arrows, and the arterial to venous from the larger baby are the yellows. You can see that they're pretty much equally matched. So the difference in placental mass is almost equal or 60/40. And there's fairly balanced unidirectional connections, but notice that there are very few connections, and that's what results in type 1 selective IUGR. When you get to type 2, what you now see is much, much greater differences. This might be, say, 70, 30%, where the smaller twin has 30% of the placental mass. Again, you notice kind of balance between the unidirectional connections between both sides, but the thing to notice here is that there are very, very few of these connections, which means that the smaller twin has much less opportunity to cross this vascular equator or for this twin to provide blood to this side of the vascular equation, so limited ability for rescue transfusion. When you get to the type 3, what you notice is that they have the absolute smallest proportion of placental mass in the smaller twin, and one of the characteristic features is that there are very few connections, that many of these connections are arterial to venous from the normal twin to the smaller twin, meaning that the normal twin can profuse into the smaller twin side of the placenta. And it's very obvious that the only reason these smaller twins survive is this constant profusion or rescue transfusion from the normal twin, but Eduardo's group pointed out that they inevitably have these huge arterial to arterial connections. So if you look at placental cord insertion, one of the primary umbilical arteries goes with very little branching straight over to an umbilical artery for the smaller twin in a characteristic feature. That's right. So when we look at type 2 selective IUGR, they're fairly well characterized by a relatively consistent evolution where the IUGR fetus progressively deteriorates, kind of outgrows its placenta, and recognition of abnormal Dopplers allows early delivery and improved survival. They have similar distribution of connections between as the type ones do, but with more severe placental mass discordancy. Therefore, they feel that there's more intertwin transfusions that compensate for the insufficiency, prolong the pregnancy until the absent Doppler findings are made allowing delivery. This is different from the Type 3, which are very atypical. You can't watch the progressive deterioration. You can't time delivery because the Doppler patterns cannot tell you when the smaller twin is at risk for dying. Complications appear to be because of the large AA connections that produce the intermittent variable Doppler waveforms, and it's all due to the collision points between the two AA circulations. So when net blood flow is in this direction, The donor now has a rapid loss in blood pressure and blood volume, which now pushes blood to the normal twin, raising its blood pressure and its blood volume does increase some perfusion in its small proportion, but then just as rapidly there's reverse perfusion from the normal twin into the smaller twin. So very, very rapid changes in high blood volume between the two. That results in a very unstable hemodynamic balance that can account for that that results in episodic acute fetal to fetal transfusions between the two twins. And this is likely responsible for acute vascular overload in the small twin that appears to cause death, or recurrent hypovolemic hypotensive episodes in the normal twin that over time results in the increased brain injury, and the incident and the finding of 20 to 25% paraventricular leukomalacia in this population. And Ishi back in 2009, Looked at type 1, type 2, and type 3 with purely expected management, and with no interventions, there was a 48% loss in the normal twin, in the smaller twin, 33% in the normal twin, so very, very high mortality, very high morbidity with 37%, only 37% survival in the smaller twin. When we look at type 3, they tend to have better survivals, but again, when you look at morbidity and mortality, very high morbidity and mortality in both groups, with only a 38.5% intact survival in the normal twin and about a 60% in surviving smaller twins. So recommendations for management that have been coming out over the last several years, if you identify a type 1 selective IUGR, intervention is not warranted, survival is usually good, and you just follow these twins, and if you identify abnormal Dopplers, it's usually late in gestation and allows timing. Of delivery where you can give betamethasone and get them delivered before the smaller twin dies. In type 2, the overall prognosis is much poorer, especially for the IUGR twin. Options that are discussed are surveillance and delivery once the small twin stops linear growth and develops critical Dopplers, or if you start to see severe growth differences where the smaller twin may be 40% smaller. Than the normal twin at 20 weeks, you know that the outcome is not going to be good, and these are cases that you might manage with selective termination of the smaller twin using a selective cord occlusion approach. In the type 3s. They're so unpredictable that you can't use Doppler to manage them, and overall prognosis is poor. Doppler is not useful, and you can't predict deterioration or death of a smaller twin. In addition, there's high neurologic morbidity, particularly in the normal twin, and therefore many, many centers are now recommending early selective cord occlusion of the smaller twin. When type 3 Doppler waveforms are identified to improve the intact survival of the co-twin before 24 weeks of age. How are selective cord occlusions done? There's two techniques. One is a bipolar cord cautery, which requires amniotic fluid for you to insert the instrument, usually done under ultrasound guidance where you can grasp the cord and cauterize it. Another less invasive is using a 17 gauge radio frequency device where under ultrasound guidance you can insert this needle into the fetal abdomen just adjacent to the cord insertion site. You deploy these little metal wires and pull the needle back so that these wires surround the blood supply, and then you can do radio frequency ablation. Uh, and which is essentially cauterizes the blood supply as it enters the abdomen of the fetus. Who makes that, uh, who makes that 2.7 millimeter, uh, bipolar? Is that Boston Scientific too, or is that this is made by Everest. Everest, yeah, there are several different, uh, companies out there that make these devices. They're basically used for laparoscopy, and we just use them. In fetal surgery, going through a 3 millimeter port system, usually done on ultrasound. But what I can show you is just an example of a little more complicated. This is a monochorionic, actually monochorionic monoamniotic twin gestation. Where we did a different approach. This is we use cytoscopy because these cords are very, very tightly entwined because these two fetuses are in the same amniotic sac. The one twin was smaller and had multiple anomalies, and so what we had to use is the bipolar, which you can see here, grasp the cord, cauterization, move down the cord, do a second cauterization. You can see the amount of movement, the fact that the cords are very, very tight to each other makes it a challenging procedure. But basically you grasp and cauterize the cord in 3 different locations, being careful to pull the cautery device away from the normal twins cord because you don't want to cauterize or injure that cord. And then for monoamniotic twins with entangled cords, what you eventually will do. You will take an endoshear and cut between the three, the middle of the 3 cauterization points, uh, transsecting the cord, um, but this just shows the basic technique of, of the bipolar chord cautery. You can stop the video now. Thanks. Give me back the presentation, great. And so in our experience at CHP, um, we've done about 80 bipolar cord cauterizations and had about 86% singleton survival. We've done 15 cauteries and transsections for mono mono twins. We've done over 90 radio frequency ablations now with about an 83% singleton survival, and you've already seen our outcomes for twin twins. It's a different complication that occurs in much higher frequency than I think we previously recognized in identical twin pregnancies, and I think is kind of a new field for therapy that we're moving into, but I think it's very, very important that people recognize how to differentiate type 2s from type 3s and how to manage them using ultrasound and Dopplers. Um, that was great, and I think that, uh, we wanna definitely bring the panel back because I wouldn't wanna hear Eduardo's thoughts on what you talked about. Um, can, can all the panelists please, uh, turn on your cameras again for the final panel discussion, and then the conclusion of the event. But, uh, Eduardo, are you there? Uh, yeah, yes, yes. What are your thoughts? You watched the presentation. Do you have any? Yeah. General thoughts on or disagree or do you disagree with anything that was said? Well, actually I couldn't have explained it better, so. I was, I was kind of hoping, I was kind of hoping you could, Eduardo, because it's still kind of confusing to me, but uh yeah, I think it's beyond human understanding actually. I mean, the type 3s are an amazing challenge, and when you first described them, you know, it's like this little light went off, and then when you looked at those huge AA's, it's like the Alaskan pipeline where huge volumes and pressures of fluid are just shifting back and forth and back and forth. And when the shift is from the normal twin to the smaller twin, that's when they get their positive diastolic flow back because there's profusion into all parts of the placenta. But when it goes in the opposite direction, you lose your end diastolic flow. And now, you know, the normal twin gets this huge blood pressure increase that has to be somehow involved in the neurologic injury that it gets over time. That's what we think. Unfortunately it's very difficult to prove that, but it must be related with that. We actually have seen some cases in which you could really demonstrate this really acute transfusion between the two fetuses when one of the two goes into a sudden bradycardia for whatever reason, and we have documented that the other twin really is really flashing blood very, very quickly to the other one. And very often in these cases the cords were very close to each other and very often these are cases that even after counseling patients and sometimes we could not be in time for any therapy, so both fetuses died. But really, yeah, demonstrating that is really difficult. I think it's very likely that it has to be related with that. I think it's the best explanation we have. Now I know that you and Jan de Pres have published looking at using laser in type 3. Uh, IUGR and maybe you could comment on why people are, you recommend moving away from laser and looking at more uh direct therapy like with bipolar and RFA. Yeah, well, the truth is that in general I think it's very difficult that we will ever have a unique therapy for these pregnancies. It's just counseling, and I think there are several factors that are playing an important role. The first one is the severity. It's not the same 18 weeks at 26 weeks or 24. Of course there are legal issues as well. And in many countries also balance wishes. Some patients would prefer to go for a very active therapy with the same information, while others could prefer to wait or they can just not accept a selective fetal site. The truth is that, well, you have presented it very clearly, and if you really want a straightforward solution and reducing risks, probably the best thing from just a numerical or a statistical point of view is just going for code occlusion. But some parents for whatever reason, moral, religious, or personal reasons, don't want to take this option. And in these cases, laser could be an option. But again, it has to be very well selected. Certainly if we are having a case, as we were saying before, with an ob placenta very close to each other, cords, very large vessels, I think just trying to do a cord occlusion. Laser, sorry, trying to do a laser there can be a really a nice way of doing a very sophisticated way of doing an abortion. So I think you just have to say to the parents, unfortunately we will not be able to do it in your case. But there are other cases in which the two courts are very far away from each other. The AA might not be that large. It's a posterior placenta, so you can try, but you have to explain to patients that in 75% of cases within 48 hours the smaller twin will be dead because, as you very well explained, actually this fetus is surviving on the other one. And I think type 3 in some cases is just the latest step before going to a cardiac. It's really before losing your normal fetus, so you have so small placenta you have to live on the other one, and then when you cut that by definition, the other one will die. We try not to go to laser normally we try to counsel patients, but still some of them prefer to try, and we still do it, not very often. In most cases I would say we do occlusion, yeah. There's also been a number of examples or discussion about. Because in type 3, the severe IUGR twin may not have oligohydramnios, may actually have a deepest vertical pocket of 3 to 4 centimeters. And so going into the normal twin sack and trying to find the vascular anastomosis, you know, not only the huge AA, but all of the other anastomoses, you have to go through the inner twin membrane, which now makes them monoamniotic because it disrupts the inner twin membrane. And I know that that technically plays into against laser and more towards, you know, a cord cord cautery. That is completely right. And also there is a non-published observation that if you try, you'll find it very often. I don't know for which reason the vascular equator in these twins, it's often. In the sack of the smaller twin, which is normally the contrary to what you find in TTTS, where the vascular equator, at least in the majority of its extension, is in the sack or in the, let's say in the placental territory of the recipient or the larger twin. So it's an extra or an added difficulty. So you can go into the sack of the larger twin and then discover that only 20 to 30% of the equator is in your sack while the other part is completely hidden. Behind a membrane that is floating there because as you say very well the amniotic fluid of the smaller twin is not normal, at least it's not at least radically reduced so that can be really a nightmare of a fluidoscopic operation and it's really a challenge procedure, yeah. Any other uh comments from the audience or questions for Doctor Johnson? Um, Well, Doctor Gradios and Doctor Johnson, thank you for, for sort of closing things up on something that most of us have not very much experience in so it was great to see. Uh,
