Dr. Eyal Krispin - Twin Twin Transfusion Syndrome The Disease, Solutions and Challenges

Go ahead and get started. Good morning, everyone. I have the pleasure of introducing Dr. Iowl-Krispin, who agreed to talk with us this morning and shares like a piece. Dr. Kiswin joined the Boston Children's Hospital Maternal Field Care Center in 2022, where he's continued to advance diagnostics and management of patients requiring fetal intervention, as we all know. He previously did residency training of Tetris and Gennatology at Rebin Medical Center in Israel before working on faculty at Tel Aviv University, then he went on to complete fetal surgery fellowship at Texas Children's Hospital and joined and brought his knowledge to us from there. In addition to his clinical accolades, he's a prolific researcher in the field of praynatology and fetal intervention, having published over 60 peer-reviewed journal articles. Thank you, Dr. Kiswin, for offering to share your knowledge and experience about twin-to-in transfusion syndrome with us this morning. Okay, good morning, everyone. Thanks for this introduction. So I'm gonna talk about a field that is a little bit out of your usual scope, I guess, but hope you'll find it interesting. So twin-to-in transfusion syndrome. When we talk about twin pregnancies, we talk about two types of twins in general. We have identical twins and non-identical twins or dizygotic twins, the non-identical twins or monosigotic twins. And when we focus on monosigotic twins, most of them share one placenta. They can be in two separated amniotic sacs, what we call monocorionic diamniotic. Theoretically, they can also be in two separated sacs and have two separated placenta. That's what we call dichorionic diamniotic. I personally think that this percentage is a little lower than what is expressed in the literature, but we also have the more rare type in which they share one placenta and one amniotic sac. And we're gonna focus today only about identical twins sharing one placenta. And then when they share one placenta, there are specific complications that go along with it. The most common one is twin-to-in transfusion syndrome that we see in about 12 to even 15% of those pregnancies. The second most common one is selective fibrogorceric syndrome. And then we have other complications, such as higher frequencies of congenital anomalies and trap and taps, which we won't talk about today, but as you can see, these are very complicated pregnancies with very high rates of issues going throughout the pregnancy. This image of a placenta died for arteries and vein on the chorionic plate practically represent the entire pathophysiology of TTTS. So what you can see here, you can see in one end cord insertion, that would be one of the twins in the other one, another cord insertion, you can see that in this specific specimen, the cord insertion of one was kind of central and the other one was marginal at the edge of the placenta. But the distribution of the vessel, it's kind of like two trunks of a tree going into the placenta. And this is usually how I explain it to the patient to trunks of a tree. And then the roots of those trees are meeting on the placenta. Those are the roots. The vessels that are dyed here in blue, those would be the arteries and you can see how they go over the others, which are the veins. And you can see those areas around this middle line, which we call the vascular equator, where those vessels meet. And they can meet as an artery to artery, an artery to vein and also vein to vein. And those are the anastomosis. So we see in any monocoreonic pregnancy, in any pregnancy that share one placenta, we see those vascular connections. But what happens exactly in TTS? So in TTS, what happens is that those AV artery to vein and anastomosis are unbalanced in a way that there is a net transfer of fluid from one to into the other. And I'm saying fluid and not blood because it's not that we're getting at the end, one twin that is anemic and the other one that is polycytemic. We're getting one that is over hydrated and the other one dehydrated. So in TTS, the main issue is that those connections are not balanced and there is a net transfer from one to the other. This causes a chain of vasoactive mediator in each of those twins. In the donor which is now dehydrated, there is an activation of the Rene and Jotin-Zenaldosteron system that ends up with this twin to be producing less and less urine, ending up being with oliguria and anuria eventually not producing any urine. And amniotic fluid is basically baby's urine starting 16 weeks and on. So as this disease progressed, less and less urine, less and less amniotic fluid, we see this sac becomes smaller and smaller. On the recipient side, the opposite occurs with the A and P, atrial-naturatic peptide and polyurei eventually and more and more fluid around this fetus. So the first is those connections. The second is the vasoactive mediators and we also know in terms of the connections that specifically in twin to in transusion syndrome, we see less of the AA, artery to artery anastomosis that we see in other monocorionic plates, believing that these kind of protect or cause this sort of balance between the twin. So less of the AA anastomosis. And what happens eventually, if we can look at those arrows here at the bottom, first there is kind of flow back and forth some of them in a balanced way, but if this disease happens, there's an unbalanced flow from one that we call the donor to the recipient and gradually less and less fluid on the donor sac until a point that the donor sac becomes completely with no amniotic fluid. And this is what we call a stuck twin, that the twin just cocoons under those membranes. On the other side, there is a lot of fluid on the recipient side. Without intervention, this disease has very poor outcome. And we're talking about 90% of losing the entire pregnancy. The first question that we ask ourselves is can we predict which of those pregnancies will go down the road of TTTS? And there are a few parameters that we can notice as early as the first trimester, first ultrasound, if we see a significant difference in the sizes of them, what we call the CRL, the crown romp length. If we see right from the get code, this cordon amniotic fluid amounts, NT, that's the nukele turns loosens C, all kinds of ultrasound measurements that we're taking for those twins. Both in the first trimester, but also later on, can imply with pretty good chances that this disease will happen. Regardless, those pregnancies require very close monitoring and starting 16 weeks usually, we recommend every other week ultrasound, which is quite different from single tone regular pregnancies that are not seen that often. And the reason is that this disease can come as a surprise, everything can look normal and then two weeks after something deteriorated significantly. The classical classification of TTS established a long time ago at 1999, it's called the Quintero classification and it's practically five stages. The first stage is when we see differences in amniotic fluid between the two. And this is all ultrasound measurements. So we see in one twin, what we call polyhydramene, as we can measure more than eight centimeters of fluid. And we wanna see in the other twin, the donor twin less than two centimeters of fluid, that would be stage one. So if we get nine and three, that wouldn't define a stage one. We have to have both of these. Stage two is when the donor twin becomes an array, doesn't produce any urine and cannot even feel its own bladder. So we can demonstrate the bladder on the donor twin. Stage three is when we start seeing abnormal Doppler flows, meaning abnormal flow patterns in specific vessels that were measuring the umbilical artery and the ductus venoses. And this is mainly related to the diastolic flow in the umbilical artery, where we see instead of forward flow during diastyl, we see absent of forward flow or even reverse flow and in the ductus venoses, the A waves, the waves that we see during the contractions of the atrium. So every time we're looking at a vessel's Doppler, we're thinking where is that vessel heading to? When we're looking at the umbilical artery, this one is heading to the placenta. So we know that it represents the placenta resistance. When we're looking at the ductus venoses, this one goes to the right atrium. So we know it is representing the cardiac function. Stage four is when we start seeing hydropsines, that would be in the recipient twin that starts accumulating fluid in different locations. And stage five is when we're too late and one or both twins have demised. And a few images how this looks in practical by ultrasound. So the images here on the top, those would be for the recipient twin. We can see a large bladder. We can see a lot of fluid in this measurement, nine centimeters. The donor twin, the other twin we can see here, still seeing a bladder. However, it's smaller than the bladder of the recipient twin. We see very small amounts of amniotic fluids. And you can even notice that the echo genicity of the fluid for the donor twin looks different than the one of the recipient twin, thinking that the fluid there is more concentrated and looks a little bit different by ultrasound. Stage two is again, we see a lot of fluid for the recipient, a large bladder on the recipient twin. And then very low amounts of amniotic fluid and here between the umbilical arteries, we were expecting to see a bladder, which we cannot see in this image. Stage three, adding those Doppler's abnormalities. And this is a represent, this represents the umbilical artery. So a normal umbilical artery flow would have a peak in the systole and then also a positive flow during diastole. In this image, you can see that the flow is went down to zero. So what we call absent end diastolic flow during the diastole. So that would be defining a stage three. And stage four, and a part, well, you can see here another image of those Doppler's, that still puts us as stage three, but that would be the doctors' phenoses, which is completely abnormal in this image, and specifically this part here, that is called the A-waves that should have been positive again in our negative. But what is important here is the stage four that we see signs of hydropsychomolation of fluid in this image both under the skin in the belly. So that would put us at stage four. And as I mentioned before, without intervention, we're looking at a very poor outcome. And what are the treatments that we can offer for those patients? So in the past, what was offered was either amnioreduction, meaning just draining the excessive amount of amniotic fluid from the recipient side, or what is called as septostomy, which is just causing a, creating a hole in the membrane here between the twins, allowing the fluid from the recipient side to go through that hole to the donor side. But as you can imagine, both of these treatments don't solve the problem, it's practically giving Tylenol to a very significant disease in the background because the problem is not with the fluids, the problem is with those connections on the placenta. And that's the reason that today, we're not really offering those treatments only in extreme situations that we can either not offer the laser treatment, which I'll talk about now, or we're looking at the edges of the gestational ages. So what do we offer? We offer the fetoscopic laser photococulation and there aren't many treatments in the fetal intervention field that has been proven by randomized control studies, but this one has, and we know that with fetoscopic laser photococcal population that is offered for stage two and above of TTS, we're changing the natural history of this disease significantly and we're looking at, instead of looking at about 90% chance of losing the entire pregnancy, we're looking at 90% chances of having at least one, twin alive at birth, and about 70% chances of having both of them alive at birth. And this is quite a significant change that we can offer our patients. And let's start with a little, with a little image here, video here. Any two, get rid of this. Is there a pointer? Okay. So this is the case that we've done here. It kind of goes fast, but what you can see, we are at the area, looking at the placenta and at the area of those vascular connections. And you can see sometimes those connections seems as very thin vessels and sometimes they are very thick vessels. And we can see whether we're coagulating let me hold it right here. So you can see one vessel coming from up here. And we know that it's coming from up there because look how it's splitting like branches of a tree. So it just shows us where it's coming from. While the other one is coming from below. So one would be from the recipient, the other one would be from the donor. We know whether these are arteries or veins, AV and estimosis, both by how they look, meaning the color, the arteries would have deoxygenated blood coming from the fetus towards the placenta. So they look a little darker or bluish while the veins look bright red. And then, so basically we're looking for those connections, where targeting them with our laser and then we are connecting between them. And I'll get back to this part to where we're collecting, connecting between them. But in general, when we're talking about laser, the evolution of this procedure or surgery was that at first, the first treatment was just to go in, locate where the membrane goes and just go with a straight line throughout this membrane, separating the two, twins into two separated percentile. And that was called the non-selective approach. What we do currently, we target those connections, we try to find what we call the vascular equator, because sometimes the vascular equator doesn't go in line with the membrane. The vessels of one twin can go actually outside the membrane while the other twin go inside the membrane. So we have to target and locate where those connections are. When we find them, we coagulate them. And then usually what we do, we just connect between them on areas that don't have connections on, but we think might have smaller connections that we cannot visualize by our instruments. However, and this is what's called solidification, I'll get back to this at the end of the talk, but the most important thing is finding those connections knowing that one comes from one twin, the other comes from the other twin. And sometimes it's not easy to find them and not easy to see them. But once we do, we take them, we make sure that we take them throughout the membrane from one edge to the other. And that's another example of a recent case that we had here. The baby's in the way here a little bit, but you can see how the vessel spreads. So this is what helps us know where they're coming from. And we can follow them back towards the ombilical accord of one twin of the other twin, but you can see how they split like branches of a tree and that's why we know we are at the end of them. And then for example, this is a down here. Okay. Hopefully I can get it now. Okay, well, let's just keep going. But you can see how one ends and then you see another one starting and this is where the vascular connections are. In this specific case, we had many connections going back and forth. Let me run this a little faster. You can see sometimes the connections are very, are through very small vessels. We call those spiders. And you see how many were in this specific case. And then we're just connecting them with a straight line after we got all of the connections. We're just going with a straight line connecting them and practically decolonizing the placenta into two separated placentas. We still have quite a lot of challenges with this procedure. Prior bleeding, if the pregnant person had prior bleeding, she says that she had some vaginal bleeding. She was diagnosed with a hematoma or something. We know that if there is even one drop of blood in that amniotic fluid, we might not be able to see anything. So that's one challenge. Some places still do what's called die amniacinthesis that they use color when they do amniacinthesis to differentiate between the two sacs. So they put color in one sac, take the fluid out and then go to the other sac, make sure that there is no fluid in no color. And that's how they know that they took samples from two sacs. If they put that drop of die, we can't see anything. Anterior placenta. So imagine the uterus as this room. If the placenta is posterior, it will be on the floor. So if we come in from the top, we see we look right through and we look right down to the placenta. But if the placenta is anterior, it would be on this ceiling. And then we have to come in from a window, from the side and look upwards. And this makes the procedure more complicated and challenging. And sometimes there is no window that we can go through and we cannot go through a placenta. So that's another challenge. If the cords are very close to each other, we see very large vessels connecting directly between the cords and we cannot coagulate them with laser or they might just burst if we try to do that. And another challenge, sometimes those ladies come with a very short cervix. Just because of the excessive amount of amniotic fluid they had 19 week uterus can be like a nine months uterus. And then the cervix is already short and that just increases the risk of rupture of membranes and preterm delivery. So we still have a lot of challenges. In the second part of my talk, I wanna talk a little bit about studies that we've done specifically in that field of TTS. The first study that I wanna talk about, it's not ours but it's an important one. So I wanna mention it because I mentioned that we offered the intervention for stage two and above. And there's a question, what do we do with stage one? Shouldn't we offer an intervention as well? And other things that we try to target on our study were the pre-off assessment. I mentioned that the Quintero staging are from 1999 and you can imagine how the ultrasound field have changed since then and how many more details we can notice today. So discussing about maybe alternative ways to diagnose or look at this disease not through the Quintero staging and then also predicting outcomes. The patients want to know with the surgery how many babies will they take home? Will they have one baby? Will they have two babies? Will they not? So this is a very important part that in our counseling before going into the surgery, they wanna know how is this gonna look like? Interior placenta, what do we do in those situations that we cannot access the uterus through a window, as I mentioned, if there is no window, if the placenta covers the entire interior part, what do we do in those situations? And what do we do with the complications that we see because we see rather high rates of complications and the most common complication get into it later is what we call choreomniotic separation and septostomy. So how can we reduce the rates of those complications? And lastly, what do we do at the edges? What do we do in very early TTTS and what do we do in very late TTTS? Classically, the treatment is offered at 16 to 26 weeks, but we know that very early, if we do the treatment, we get very high rates of complications. And what do we do if we get that even earlier than that? Or what do we do if we get it after 26 weeks? So these are the studies that we wanna do to look into. First about stage one TTTS. In general, it's always a balance here, whether we should go in with the procedure or just sit on it and see how things progress. We know that with the procedure, we get a risk of complication, which would be mainly rupture of membranes and premature delivery. Without doing anything, we're looking at a risk of a significant deterioration and getting into those 90% chance of losing the pregnancy. And there was a very good randomized control study who looked specifically on stage one TTTS. And the bottom line was that if those are gonna be stage one that will not progress, then it's better not to treat them. But if they will progress, it would have been better to treat them to begin with, which is kind of logical. But in terms of number, we're looking at about 40% chance of stage one to either remain as a stage one or even become better than that. 60% chance of progressing. And it's very difficult to say which one, which will be progressing and which one will remain as such. So the bottom line or the conclusion of this study was that if you can do a close monitoring of those patients, then it's better just to wait and see. However, those patients, they even rule area, if you cannot offer immediate intervention, if you're gonna see them only in a week or two weeks, then offering treatment is definitely reasonable and definitely something that they can benefit from. And then we have a specific parameters that we will definitely go and do the surgery in stage one. That would be if the patient is already symptomatic. Sometimes those patients are symptomatic in a way that they have so much fluid in the uterus, they're contracting, they're uncomfortable lying on their back or they have a short cervix already. So that would be an indication for stage one. But what this study wanted to demonstrate is what do we do with those asymptomatic stage one TTTS? So again, we're offering the treatment to any TTTS stage two and above, but we can also operate to stage one in specific situations. About going back to the diagnosis and the limitation of the quintero diagnosis, there have been many attempts since 1999 to incorporate other parameters, ultrasound parameters mainly, into the diagnosis of TTTS. And most of them focused on cardiac parameters, fetal echo, but they have not become the mainstay or the choice for staging, mainly because they were not associated with overall outcome. Meaning you could get to some staging system that shows you certain deterioration by cardiac parameters, but they couldn't demonstrate this correlation with prognosis. In quintero stages, as simple as they are, we know that stage one is better than stage two, stage two is better than stage three in terms of the overall survival rates. But in those other predicting ultrasounds, they couldn't show it in a very clear way. Not only that, they are technically challenging. They require fetal echo, which is way more complicated than the parameters I mentioned for quintero, and could be evaluated only in specific centers. So we looked for other parameters that might be relevant and might show some better predicting, predictive value. And we looked at, so we always measure the blood flow in the MCA, in the middle of cerebral artery, usually we're measuring it to diagnose fetal anemia, because we know that in fetuses that are anemic, the pixistolic velocity or the highest flow would be very high in anemic fetuses. And so what we went and looked at those parameters and saw that we can look at a specific parameters called the pulsatility index, which is practically a calculation between the systole and the diastole. And we demonstrated that in specific cases, if we get a very low of the pulsatility index parameter, we can demonstrate very different rates of survival for the donor. So we recommended adding this parameter to the evaluation, and what you can see here, I know that it's a little bit specific, but what you can see here that with this additional parameter, we showed that if it exists, then the rates of survival are significantly lower for the donor twin, for the smaller twin. And we did recommend incorporating this into the evaluation of TTTS. So another parameter that we can look at and discuss survival rates. And then we thought, okay, so we have this parameter that are offered different parameters. How can we incorporate all those parameters to come up with sort of a calculator to the parents and tell them eventually, what are the chances for them to have a dual survival? And what we did in this study, we found a list of six parameters that showed in different studies, and in our data, some difference in survival, and created a calculator giving each of them a relevant weight into eventually what would be the chances of having both twins alive after laser. So you can see here that the parameters that we incorporated are relatively simple. The donor below 10th percent, I mean, very small donor, or a very large discorgency in the size of the twins, about 25%, and then a few more Doppler parameters, the PI below 10th percent, I would show you from the prior study, the anterior placenta, which also had some significant weight here. And then we were able to calculate for each of them what would be the weight of it and came up with this calculator, showed also that it has a very high sensitivity and specificity. And as a practical example, if we have one case that doesn't present with any of these six parameters, we can tell the parents that the overall chance of having a dual survival would be 80%. However, if the case presents with an anterior placenta, with those two abnormal Doppler parameters, that in this specific case, we can tell them that there is only one percent chance of having dual survival. So many times we go into the surgery, knowing that we will only be able to save one twin. And we consult the patients accordingly. So many times we go into the surgeries, aiming to save one of them, and not to save both of them, knowing that without intervention, we will lose the entire pregnancy. And these calculators help us in those consultations, because we can give them an actual tool and show them what are the actual numbers that we're predicting. Next issue, the anterior placenta that I mentioned before. So, anterior placenta, as I said, it's right in front. We can't go through the placenta with our instruments. So we need to go from the side and then look upwards. As you can see, those images here. So the scope goes from the edge and then looking upwards. But when we look upwards, we get an upward angle towards what we want to see, because you see it's almost parallel to what is actually happening. And there were different suggestions to how to solve this problem. How to solve the problem of having a scope that comes kind of parallel to where you want to treat. Some offered a 30 degree angle of the scope with also an option to kind of tilt the edge of the laser towards those 30 degrees. And remember that we have only one channel. We don't have two tools. We have one channel. And through that channel, we have the camera and the laser. So different suggestions. Others offered, go with a 70 degree look and then remember where it is, come back, and try to find that spot again and kind of blindly take it. And then there are also some curved scopes that give you some angle. So you won't be very parallel. And what we showed was that in some situations, all of these treatments will still give you a suboptimal solution because you either don't have a, an opening, a window with no vessels or that you'll be very parallel to those vessels. And the suggestion was that to do a preliminary step with maternal laparoscopy and then tilt the uterus a little bit and go into the uterus from the posterior part. And this is how it practically looks like. So laparoscopy to maternal abdomen. And then you can see how we go in with that needle targeting towards the posterior part of the uterus, which you'll see in a moment. And then coming in actually not from the side upwards, but from the posterior. That's how we're getting into the posterior part of the uterus. So tilting the uterus and then allowing our instruments to go to the posterior part of the uterus, once we're in that right spot, we're removing the gas and proceeding with the surgery that is in the uterus. And what we demonstrated in that study that we've done, that not only that you're not getting any differences in the rates of complications, meaning that mainly the gestational age at delivery, which was comparable to the other techniques, we showed that there was a significantly higher rates of inability to complete solumant technique. And what that means practically is inability to visualize all the connections in the standard fetoscopic for anterior placenta compared to those laparoscopy assisted procedures which we were able to practically take all the connections and demonstrate them. So that's one solution that we can offer to selected cases that we feel that the placenta is covering. And we don't have a safe window to go through and we can offer this laparoscopic surgery. And then a few more words about complications. So the most common complication that we see with our surgeries is what we call coriognatic separation. And that is practically tempting of the membranes from the uterine wall. The membranes are adjacent attached to the inside of the uterine wall. And when we come in with our instruments from the outside, they might just tend to it similar to if you have a wallpaper on your wall and you're drilling from the outside, you can go through it, but you might also tend to it out. And this way of tempting out the membranes is associated with complications down the road mainly with premature up to off membranes. So coriognatic separation, the second one, septostomy, is then we incidentally get a hole between the membranes, between the twins because of the instruments that we're using, because of the laser that sometimes interest the membranes. And then we practically get both twins in one sac instead of having them in two separated amniotic sacs. And that's what we call septostomy. And this is also associated with complications down the road. These are a few images that you can see here. That's by ultrasound. So that's the membrane here that is supposed to be going attached to the uterine wall. But tinted when we went in. And this is a septostomy that you can see kind of hole. It's a little hard to see, but hole between the, between the separating membrane of the two. And basically what we showed in this study that. If you do get a complication, other coriognatic separation, septostomy, or both, you get high rates of premature deliveries, early or gestational age at delivery. And naturally, if you get both of these complications together, you get the worst outcome. So our aim and focus is still on trying to find ways to minimize the rates of a coriognatic separation. And for that, we need to think of ways to actually incur the membranes into the uterine wall before those entries. And this is our main focus right now. And the last study that I wanted to show you is about those edges, about those cases that we see happening either very early in pregnancy or very late in pregnancy. Everybody agrees that if it happens between 16 to 26 weeks, you should do something. But what happens if you diagnose the surgery, the TTS, if you diagnose it very early or very late? Not only that, we know that lasers that are done very early, 16 to 17 to 18 weeks are associated with higher rates of complications, such as premature up to of membranes, coriognatic separation. We know that very late, we have higher fetal vernix that we can't clearly see the fluid. The fluid is very hasty. We know that very late, the vessels have a very large caliper, and we can't coagulate them sometimes. Or the uterus is so large that our instruments cannot even reach from one end to the other. So these are still challenges, but what we did in that study, we did a delphime methodology that we went and asked, practically, asked experts what would they do in those situations until, and there's a way to do it to get a consensus eventually. And I wanted to show you some of the important findings that we got from this study. The first is that it's okay to offer laser before 16 weeks. If you see a very advanced disease, stage three, stage four, at 15 weeks, then you can definitely offer laser as well. On the other hand, if you see TTS between 16 and 18 weeks, probably not wise to rush into it because of the rates of complications. So unless you feel that you have to rush into it because of significant anomalies in the Doppler's or significant maternal symptoms, better to just wait and sit on it a little longer. So these statements kind of change a little bit the way that we look and treat very early TTS. As for the later part, and also here, if it was not accepted to offer laser after 26 weeks, now we can definitely offer it up to 28 weeks, knowing that it might be associated with better outcomes compared to just expect and management. The last thing I wanted to talk about that we were also involved in study for is solomonization. Solomonization came from this name, came from solomons, judgment about this. Probably you all know this story about that baby, separating the baby and the mother who chose that baby. And King Solomon knew that the one who didn't want to cut the baby into two was the actual mother. So that's where the name came from. But practically what that means is separating the placenta into two parts. And taking those connections between the twins and then going with a straight line to connect those dots and creating two separated placenta. So the original study showed that if you do that, if you connect those dots and separate into two placentas, you get lower rates of complications and by complications, I mean, between anemia polycytemia. I don't want to get into that too much, but sometimes after laser, if some of those connections are left open, we see gradual flow of blood from one to the other. And then we get this situation that one of them is anemic and the other one is polycytemic. And this study showed that if you do the solomonization, if you connect those dots, you will get lower rates of those complications. And after this study, everybody started doing that. Everybody started connecting the dots, connecting the line. This means putting a lot of energy on the placenta because it's not just choosing specific locations and putting the coagulating them with laser. It's going straight from one end to the other with laser. And then we showed that maybe it's not wise to get that because we saw pretty significantly higher rates of placenta interruptions in those situations that offered laser. And I can show you some examples here from actual cases that we had. You can see this hole here on the membrane under the placenta, both here. That's where the actual laser went through. And this can happen a few weeks after even with sudden bleeding into the amniotic fluid and signs of placenta, a drop. So knowing those risks now, we kind of modified the way that we treat those patients and we do what's called modified solomonization, which we practically choose whether to connect or not. The instruments that we're using today are better than the ones that were used a few years back. We have better resolutions. We see an area that is completely bare doesn't have any connections on it. There is no reason for us to put the laser energy on it and increase the race, the race of complications. So just to summarize the research work that we've done on the field of CTTS. We've added some additional parameters to evaluate the severity of of the disease. And we came up with this predicting model calculator to allow the parents. Some more information about the chances of survival. We offered alternative treatments to cases of anterior placenta that we can't go through the side and look upwards. That would be a laparoscopic assisted. And we analyzed the complications specifically, coriarmia, exeparation and septostomy. We offer now treatment for early and late TTS as well and changed a little bit the practice in terms of solomonization. That's it. Thank you and happy to take any questions. Well, thanks so much for that great talk. Let me start by for those on zoom. There's several dozen people on zoom type into Q&A if you have a question. As I'll give you some time to start doing that, I can read them on my phone. So as they're doing that, I just want to say how humbling this is. You started by saying this a little bit out of our wheelhouses. People who used to take care of babies after they come out in all of our specialties. And what I have found over the last year or two is how a little high-know or even knew from medical school about percentile anatomy biology and really complex interplay between twins. And even remember, Diamond, all that stuff. We learned that in medical school, but we don't think about that. We're just used to it. I'm just having this a baby with usually we've known about their prenatal anomaly. And we've been doing through our advanced field care center before you and Shami came. We've been seeing families for decades and working with our imaging specialists to make diagnosis and give counseling. And then the baby comes out and we either rush them to your intake or anomaly or take care of them in the ICU or whatever need be. But I've been stunned by how much happens before that point and how many babies don't make it to us. As I've been watching what you all have been doing, the number of lives that have been saved. People may not know here. It's been kind of quite launched the field surgery we've been doing. But we've done over we you've done over what three dozen now up till most 40. Almost 40 39 or something. A fetal procedure is here at Boston Children's Hospital and it's impressive. And as we've gone through this as an institution, there's been a lot of while and we don't do this. And this is all new. And the fact of matter is this stuff is not new. We don't do this, but they do. And they've been doing it for a long time. And they're really, really good at it. If you go in and I would recommend anybody without being too disruptive to go in and watch these procedures. And some of you have. And when I on shami do a twin twin transfusion, it's like walking and watching one of us take a appendix out. It's completely scripted. They know exactly what they're doing. It's high risk for all the reasons that that they state. But they're, but they're very experienced at doing this and the difference that makes it incredible. So I'm sure those questions I have some, but I would turn it over to others for technical ethical and procedural questions people might have questions. We'll start here. I'll thank you and I want to start with, with perhaps very naive question. What I, what I learned today at the outset was that there are normally on the surface you described arterial to arterial connections or Venus to Venus connections. And actually they were protective. And so then I thought, well, my goodness, then as you divide these. Your obviously obliterating some of those connections and loss of those protective connections. Is that a, is that a problem or they just don't exist when there's a twin twin transfusion? Yeah, that's a great question. In specific situations, for example, when we know that one twin is significantly smaller than the other one, we know that the smaller twin is smaller because it has a smaller portion of the placenta. It has imagined the placenta as a pizza or a pie. It has just one slice of that pizza while the other one has the entire pizza. And that's why it's smaller. But by those connections, it's actually borrowing parts of the placenta from the other twin. So we know that if we will end up taking those connections, we actually reduce the chances of that smaller twin to survive. However, we do still offer that and recommend that because we know that without doing that, we'll lose both of them. So sometimes we take those connections, knowing that we're increasing the chances of immediately losing the smaller twin or the one of the twins. Just because we know that without intervention, we will lose both of them at the end. So yeah, those AA connection sometimes support one of the twins borrow parameters from the other side of the placenta, but we just have to compromise and take them. Thank you so much for the clarity in an evolving area. Two quick questions for time. You mentioned there's perturbation of the ren and NGTAS, NGTENSEN system. Has there ever been any either inter-amniotic medication administration or maternal medication administration to target that access? And then my other question was just on just not the survival, but the neurologic improvement after these procedures. Yeah, two good questions. So as for the treatment, the problem is that if we will treat one of them, we will cause the opposite on the other one. And since they are connected, even if we will end up treating them directly in tributaryne, the medication will go to the other one and do the opposite. So we can't really offer that if we'll treat the mom, it will go through the uterus to both. As for neurological outcomes, the one thing that I like about this treatment, I mean, we have different treatments in the field of fetal intervention and we're kind of limited with our outcomes, but in TTS, if the procedure goes well and babies survive and delivered in a good gestational age, we have two healthy babies. That is the bottom line. We don't see significant neurological morbidities significantly higher than other monochronic normal twins. Of course, there are situations that they end up delivering early and then you get return complications or if we lost one of them, but in general, the outcomes, the neurological outcomes are very reassuring. And on the other hand, if we end up losing one of them before laser, then we have very high rates of either losing the other one or having some significant neurological morbidity to the surviving twin. Thanks for your talk. Great question. Yeah. We're talking about blood vessels and blood flow and identifying these blood vessels as like the critical part of the operation can't help to think about like, is it possible to use? You know, nowadays we use these different cameras with sort of wavelengths that can capture different sort of fluorophores like in a sign and green, for example, like I don't know if you've heard about spy fight. We use that all the time to look at blood vessels within tissue, something you call so et cetera, et cetera. Could that be applicable here to be able to distinguish these arterio arteriovenous be able to tease them out. Make sure you got them all. I don't know. Yeah, great question. And so that would be great if we could have a map of those connections before going in both knowing where we should target and making sure that we took all the connections. And there are a few attempts to do that. We're limited because these are pregnant women and we can't use different types of X-rays. But by ultrasound, there were attempts to kind of map those vessels. And we are currently working on an MRI study to try and show those connections and demonstrate them and demonstrate them. But you know, if you have any other ideas of things to ways to do that, you know, we always. What I'm talking about is an intravenous injection that the patient gets in a lights up to blood vessels and this special camera picks it up as it shows up only the blood vessels interruptively. So it's not an image modality. Well, it's fairly benign to the substance. It's interesting, but I think once we're inside, we're already visualizing them. We're actually visualizing them. So I'm not sure what the added value would be because we can we can just look at them and see them with our camera. But are there some that are deeper within surface that you can't see or would it help you distinguish? Because those are some of the things we've seen is depending on the inflow outflow of an organ, you can see the veins, you can actually see the arteries based on the timing of the contrast as it flows in and then it flows out. So you see, you actually can see the flow in real time. Yeah, that's something interesting to look into with the only thing. That's great idea. The first thing is, you know, we need to inject it, you know, this die to the to the umbilical cord to start circulating through the placenta. And do it to the mom. Yeah, yeah, therefore directly you need to inject it to the court. That that increase risk of injections to the court and then would like to FDA. And also, the problem is say that you will notice them if you can't reach them and coagulate them eventually, then what would be the added value? Because you at the end, you need to reach them to coagulate them. Yeah, the one instance I could think of from your talk that might help is in the late term when it's difficult to see because there's so much vernex. I would encourage you to go and watch this five five, which is used almost every day in the OR. For much of many different things we do, but particularly for our complex, the staff deal work. Ben and for Oconsomala use it all the time and what going and watching them sing how well it feels like the vessels, it might give you guys some ideas. I think it's a great, introduce very sort of watch us and just does something and we learn. We're at a time I actually have a bunch of questions, but I'm going to ask you privately because we're well over time and we will certainly have more opportunities to learn from you. Just as a sneak preview, although the 40 cases or so that have been done have all been placental or or cord or amniotic band type surgery. Surgery and the fetus is about to start here at Boston Children's Hospital. I was watching some practice yesterday and so we're waiting for right patient. So we'll be getting it through the more advanced field intervention soon, but it is incredible for us to learn how you're. It's actually talked sort of not just not only about normal child versus demise in pediatric surgery. We sometimes have really high risk sort of yes or no outcomes, but but to go completely normal or. BADL is quite a dramatic difference that and you guys talk about this every day so thanks for teaching us. Thank you very much.