Dr. Anita Moon-Grady discusses the topic of high-output lesions. This in-depth review will provide an update on this topic for your clinical practice.
Dr. Jack Rychik discusses the topic of twin to twin transfusion syndrome. This in-depth review will provide an update on this topic for your clinical practice.
Dr. Caitlin Rollins discusses the topic of brain abnormalities in fetal congenital heart disease. This in-depth review will provide an update on this topic for your clinical practice.
Yeah, yeah. Okay. Okay. Mhm. Mhm mm. Okay. Hello. Good morning everyone. Good morning. Good afternoon and good evening. Welcome to our 12th annual Mount Sinai pediatric and congenital cardiac imaging symposium this year. Our theme is hot topics and fetal cardiology. You gotta have heart on behalf of my course, co directors, Neil Geiger and Daniel. I'd like to thank you all so much for joining us live today. We have participants from all over the world and I really do think you'll enjoy the program. We have plans. We were disappointed to have to postpone last year's conference but I'm thrilled we can all be back together. I'll be it virtually for this year's event by now. Most of you have realized that I am not truly through asana, I am kenan kenan Stern and I am humbled to have taken the reins from Truby in directing this course. I am indebted to her as well as many others, including Helen co. And many of our friends from the new york Pizza ICO Society for laying the Foundation for what is just a fabulous annual gathering of experts in pediatric congenital cardiac imaging. This conference also would not be possible without the generous support of our industry sponsors. I'd like to thank thank both Samsung and Hitachi for their extraordinary generosity. Their support has really gone a long way in helping this symposium come together this year. So please join me in thanking our industry sponsors. Just a brief overview of our program for the day. Our first session, it's not the heart or is it focuses on non primary cardiac disease and neuro development with talks on high output lesions, twin twin transfusion and brain development. Then have a session on comprehensive fetal heart care. It's more than just the heart where we will discuss the multidisciplinary fetal heart program model, an education and fetal cardiology. That session will close with a talk on disparities and Inequities and fetal heart disease. In session three. Okay, it's the heart. We will review the latest advances in fetal cardiac imaging and fetal cardiology, including early gestation imaging, radio imaging, maternal hyper oxygenation, remote monitoring and fetal telemedicine. Let's wrap up. We will have our time honored case presentations cases from across the country presented by emerging leaders in the field. That session is titled What an interesting part. A few words about a virtual format talks have been prerecorded, but Q. And A sessions will be live. You can ask your Q. And um you can ask your questions in the Q. And A box, which in turn can be up voted by other attendees, attendees will be and watch and listen mode, which means no audio or video. And our moderators and speakers will do their best to answer questions so it's likely they won't be able to get to them all. However, they will be able to respond to some that haven't gone that have gone unanswered live by using the Q. And A box and typing their response Q. And A will follow. After all the talks have played for the first three sessions, but for the case presentation session, the Q. And A will follow each individual case presents. We have programs on break time throughout the day for you to visit our virtual exhibit hall. We have several vendors including Hitachi GE Philips and Sun align who have prepared virtual exhibits for you to peruse the latest technical developments in pediatric congenital and fetal cardiac ultrasound. You can make contact with industry representatives as well there. So if that's not enough to entice you were offering raffle prizes Including Amazon gift cards ranging in value from 50 to $150 and complimentary registration to next year's conference. To those who visit all the vendor booths, There's a member to be entered in the Raffle. You have to visit all the exhibits and complete the form and you have to do so by the end of a 30 day period, which starts today. To reach the exhibit hall, please click the link on the conference sub tab, which will be open in your browser. You do not need to log out of zoom. Remember the exhibit hall will be open and available to you throughout the month of May. Finally, while you can only claim CMI for activities you live today. We do plan on making recordings available online through our partner broadcast and had details on how to access these recordings will be forthcoming. Seeing you can be claimed starting May seven throughout throughout the website where you will have to fill out a course evaluation and specific instructions or honor informational sides, which will scroll throughout the day during break time. Looking forward to next year, we will be back. It remains to be seen whether it will be virtual or in person or a hybrid of the two. And as soon as we have a date, we'll make sure to send that to you so you can mark it on your county. Also on Friday September 17, our colleagues here at Mount Sinai, an adult congenital heart disease will put on a conference. This will be a hybrid in person and virtual event done by doctors, Ali Saeedi and Barry Love. So please mark that date undercount. So once again on behalf of the organizers and course faculty thank you all so much for joining us today. Thanks again to Samsung and Hitachi and to all our exhibitors. We really hope you'll enjoy what we've prepared for you now on to the conference. Please join me in welcoming, welcoming dr jennifer Cohen and dr jennifer lamb Rockland to moderate our first session, enjoy. Hi, good morning everyone and welcome to session one non primary cardiac disease in neuro development. It's not the heart or is it? I'm jennifer Cohen. I'm a pediatric cardiologist at Mount Sinai. Good morning everybody. My name is jennifer lamb Rocklin and I'm a maternal fetal medicine specialist at maternal fetal Medicine Associates in Carnegie Hill imaging for women here in new york. And I'm excited to moderate this morning session with Dr Cohen. So our first talk today is high output lesions, human dynamic assessment and management. This talk will be given by Dr Nina Moon Grady. Dr Moon Grady is Professor pediatrics and director of the fetal cardiovascular program at UCSF. Then our second top will be twin twin transfusion syndrome, cardiac manifestations and fetal therapies. This talk will be given by Dr Jack Right chick sector Recheck is professor pediatrics. He's the associate division chief of cardiology and the director of the fetal heart program at shop. Um It is with great pleasure and honor to introduce her third speaker of the morning doctor Caitlin Roland's doctor Caitlin Rowlands is an assistant professor of neurology at Harvard Medical School. Main focus of research is trying to understand the link between neurological outcomes and congenital heart disease at the prestigious cardiac neural development neurology program at Boston Children's Hospital. This topic has been increasingly important in our consultation with patients at the time of diagnosis of CHD I'm sure we'll learn great things from Dr Roland's today. She will be ending this morning's first talk with her title talk titled The brain abnormalities in fetal CHD predicting and modifying neurodevelopmental outcomes. With that we will start our morning session. We'll play all three talks back to black back. Please ask any questions you have in the QA in section in the bottom of the screen and we'll have a question and answer session after all three talks. Let's begin with the first talk of the session. Mhm. Thank you so much for having me here today. We will start off the morning by talking about the fetal cardiac evaluation of lesions causing high output failure. I have none of the usual disclosures but I will say that I'll spend some time talking about fetal interventions not just talking about evaluation and that is because extra cardiac lesions which produce high output states including anemia, a cardiac twins, pentagonal malformation and synchro cox jail terra toma may be amenable to invasive fetal or neonatal therapy. and so for the next 15 minutes, I'll touch on the evaluation of high output failure in lesions such as trap or twin reverse arterial perfusion, psych rock, oxygen, terra toma, anemia and vein of Galen. And in this retrospective study from our center, initially designed to evaluate survival in fetuses with high drops, you'll see why I'm so interested in this. In this study, there emerged a clear demarcation between high ctr high output lesions and the low ctr low output lesions. Furthermore, cardiovascular profile scoring was predictive but only in the high output lesions and lesions amenable to and with successful fetal therapy. Had a better overall prognosis in this retrospective series. And so at our center, a cardiac evaluation has become part of the routine evaluation, not just of fetuses with suspected structural disease, but really all of the pathology that we see. So what is this functional evaluation? Well, it's really just what you might expect. It starts with systolic function evaluation, including fractional shortening, ejection, fraction cardiothoracic ratio and chamber enlargement, specifically right atrium as well as a v valve regurgitation. It also includes diastolic function assessment, a Doppler assessment of inflow venus, Doppler, XYZ and isil bulimic and relax, relaxation and Mp I time intervals a word about the doctor's diagnosis. This is really my favorite fetal vessel and people joke laugh at me for this. But um it can be sampled from the sagittal or I actually prefer the axial view in which it can be seen Jason to the stomach, but in the midline and produces a Doppler pattern very unique. Doppler pattern when normal with an S. Wave, the wave, a wave reversal, decreased pulse utility with increased a wave uh reversal culminating in uh a wave actually being below the baseline suggested of elevated venous pressure. Among other things, The Venus Doppler is though are generally not helpful if they're normal inhaled lesions, which we'll see in a moment but has also been been published. This has a physiologic origin that unfortunately I could spend my entire 15 minutes on, but I will instead direct you to this lovely article by Kiss, a route that talks about the fluid dynamics. Yeah, we also know that we can calculate cardiac output non invasively with eco by measuring the semi lunar valve cross sectional area and multiplying that by the velocity time interval and multiplying by heart rate And arrive at a combined ventricular output that increases with gestation and can be plotted in relation to gestational age or can be indexed to estimated fetal weight, in which case most fetuses will be approximately 500 million ml per minute per kilogram. I mentioned high drops. And if we think of high drops as simply the end result of the inability of the heart to deliver adequate oxygen to the tissues, it becomes clear why cardiovascular evaluation can be so helpful in patients with high output. Uh, There are a variety of different types of cardiovascular profiles. But here I'm just showing Jim Hugo's published score, which is really looking at the individual determinants of cardiac output and oxygen delivery. Using this type of score that starts with a best case of 10 and knocking points off for abnormalities in the end result of oxygen delivery. That is effusions, relaxation and compliance. And the venus. Doppler heart size as a surrogate for preload and cardiac function parameters such as contract ill itty and delivery as well as after load. A CNN umbilical artery changes. I should mention that. I don't report a score clinically but rather report the individual components uh in my program. But the idea is useful and it can be useful for serial study. So let's talk about some of these high output lesions and what they look like First. Uh this is a secret oxygen terra toma seen here at 17 weeks on ultrasound and at birth. These are 2-1-2 out of 20,000 pregnancy. So fairly rare, with a very high perinatal mortality. They can be primarily solid cystic or mixed with the solid being more at risk for high output failure and can be inter abdominal or typical. As shown in the picture. These are germ cell tumors and may have malignant components. And so they do need to be debunked early if high output is an issue, but they do need to eventually be completely removed. This is the same fetus just five weeks later, where the tumor has surpassed even the size of the fetus itself and high drops is evident in skin edema as well as pericardial effusion, cardio meagley, poor function interestingly enough. As I alluded to before the dr stenosis Doppler was normal in this patient, probably reflective of the tremendous amount of venus return that is going through this vessel psych rock, oxygen terra toma is amenable to therapy. The available therapies are expectant management, early delivery, open fetal surgery, minimally invasive fetal surgery, but fetal therapy is historically reserved for fetuses with high drops the second legion I want to talk about in the same breath as the secret oxygen territo Mazz is to reverse arterial perfusion, which occurs in approximately 1% of monte chorionic twin pregnancies. The ideology is unknown, but is thought to Represent a very early vascular event and natural history. 50 of the normal twin, the so called pump twin will die. This is what it looks like. An ultrasound mono chorionic twin pregnancy with a pump twin and the a cardiac twin with arterial perfusion to the twin rather than from the twin trap is also amenable to fetal therapy, including radio frequency ablation And in uh in the hands of experience centers over 90 survival is expected for the pump twin as opposed to that natural history. Number of 50%. We've also seen that fetal therapy for trap has been shown to normalize middle cerebral artery. Doppler pulse civility, which starts initially low resistance, suggesting cerebral hypoxia mia and reverting to normal, suggesting an improvement in cerebral oxygen delivery that is a direct result of the therapy. But there's an interventional dilemma here because sacred cox Jill terra toma as well as trap therapy is carries some risk to the mother. Uh Micro coaxial terra toma generally only offered when the fetus is hydro pick. But the high drops increases the operative risk. And trap therapy sort of the opposite dilemma that therapy is offered if the mass is over 50 of the normal twin. But the natural history is only 50 of the patients die. And so really any procedure related loss in a fetus that didn't need. The procedure would be considered really less than optimal. Okay, and so we undertook this study's a retrospective study now published several years ago from U. C. S. F. Single center experience again of 19 fetuses with known outcomes who had been evaluated at our center but did not have feel interventions is the Natural history study. And we calculated combined ventricular output uh and looked at clinical outcomes in these patients who did not have high drops When we evaluated them. This graph shows in white the patients with a good outcome and black the patients who ultimately had a poor outcome. And we also looked at combined ventricular output index as well as some of the components of the cardiovascular profile score aortic valve mitral valve and aortic valve uh valve regurgitation. And essentially what we found was that at least one of the following was present in all fetuses who had a poor outcome, either cardiothoracic ratio greater than 50% cardiovascular uh sorry, combined ventricular output that was elevated any degree of track hospital mitral regurgitation or mitral aortic valve Z score greater than two. No fetuses with good outcomes exhibited any of these findings. And this really suggested to us that a detailed cardiac evaluation could be of use in evaluation, risk stratification and counseling of these patients before the onset of high drops. And potentially could be used to guide choices about therapy. Before that increased risk to the mother and to the fetus from being operated on well, frankly hydro pick. So other lesions could potentially also be evaluated in this way, including placental Corio ngoma, although there's far less data about that Galen malformation, which is fascinating in and of itself, and the anemia for which contributor and therapy has become fairly standard. But we are now looking at this as we have opened up a stem cell therapy trial for for anemia. So this is what this might look like. Africa Policy miA has is our first target for stem cell therapy cardio Magaly preserved systolic function at least initially. But there certainly is compromised oxygen delivery. Many of these patients with Hamas, atticus alpha thalassemia present floridly hydraulic in the mid gestation. There are other types of anemia that also uh would benefit from a cardiac evaluation. Here's a patient who presented 18 weeks with again high drops, cities and cardio meagley. But with preserved systolic function and normal doctor stenosis. Doppler with abnormal in flow Doppler and elevated cardiac output. This fetus was ultimately diagnosed with anemia due to parvo virus. But the cardiac evaluation really classic for high output cardiac failure. So to come back to that stem cell trial for anemia, this is currently enrolling. If you have any questions, please don't hesitate to reach out. Um But we have seen these patients go from high output failure to normal outputs with gradual improvement in the cardio mega lee and the high drops. And have at least one patient with a normal term delivery. With a normal cardiac evaluation at birth with the last few minutes. I'll talk a little bit about intra operative monitoring. Understanding now all of the tools and the abnormalities that we see in these patients with structurally normal hearts but high output and high output failure. Inter operatively of course a human dynamic evaluation would be ideal. How do we monitor a fetus during this type of surgery? Well, um it would be nice if it would include a a full invasive set of human dynamic data. Unfortunately, this is what inter operative monitoring of the fetal cardiovascular status really looks like as the fetus inside the uterus. And here will come. Just a moment are monitoring device right there. All right. So how are we going to monitor all of those aspects of oxygen delivery and cardiovascular performance in the fetus? Well, in the same way that we do in the preoperative assessment but with continuous assessment of after load heart rate and venus duct stenosis, Dobler's and ventricular systolic function with intermittent cardiac output measurements. That may just be the doctors since the cross sectional area isn't changing of the vessel. And so monitoring cardiovascular started combined ventricular output during open fetal surgery has been published by the group at at shop. And we know that prior to anesthesia the output is normal that with the maternal incision and this is most likely not just due to the maternal incision but rather to the high dose of maternal anesthesia that is used. That may be a cardiac depressant um That the cardiac output falls quite a bit and then begins to come up post operatively. And so while this is the normal expected with fetal surgery sometimes doesn't quite go that smoothly and predictably. Here's a patient that that I was part of this surgery where we were doing intra operative monitoring for secret talks in jail territo Marie section and noted just that the systolic function didn't quite look right in this patient. And as we watched it got a little bit worse, just barely noticeable. But at that point I'm screaming for resuscitative meds and indeed the fetus went on. Here's the needle. By the time they got the needle in the heart had almost completely stopped and then a little blush of epinephrine right there and it starts to come back. So um inter operative monitoring of all of those human dynamic variables, including just the eyeball method of systolic function can really be useful because fetuses with high output going into surgery are really much more unstable than than those who have normal heart's going in. And so it helps us to be aware of this in order to act in a timely manner. So to summarize the uh evaluation and potential intervention for high cardiac output lesions, increased fetal cardiac output may lead to hydraulics, prediction of deterioration and poor outcome is becoming possible using fetal echo for outputs and cardiovascular profiling, hi drops and elevated venous pressure with decreased oxygen delivery to the to the brain may lead to neurodevelopmental consequences. But intervention can improve survival and neurodevelopmental outcomes, intervention is less risky than expectant management in some patients and Echo can really help in the risk stratification. To minimize the risk to both the fetus and the mother. Thank you very much appreciate the opportunity to speak with you today on the topic of the twin twin transfusion syndrome, cardiac manifestations and fetal therapies. Historically, the very first reporting of the presence of a twin twin transfusion is uh, we believe depicted here in this painting, Which are the Children of the mayor of Amsterdam painted in 1617. The vehicle Kindelan, which depicts what we believe are the unfortunate deaths of the twin Children Of the mayor of Amsterdam. one painted with eyes open and very pale, the other eyes open and plath oric in there, death shrouds believing that perhaps uh, this represents uh an equal exchange of blood between these two twins resulting in in their demise. Now fast forward today to 2021 we have a much clearer understanding but still as you'll, you'll hear in my presentation, a number of unknowns and yet fascinating questions that need to be answered. Turn to a transfusion syndrome today occurs in a monaco chorionic pregnancy meaning a single placenta with the presence of an inequity in fluid accumulation of poly hide remedios, la liga hydra video sequence between the shared twins within the the uterine cavity And at least 10 difference in size discrepancy between the two assist reproductive technologies has increased the number of twins in general. And GTs affects about between 15 to 20% of monte chorionic twins and untreated mortality and morbidity today is quite high. Now what causes this particular complication within the mano chorionic system is to believe to be as follows within the single placenta. There are connections Vascular connections between the two twins. 28 20 flow between those connections are dictated by there being an arterial to venous connection, say twin B to A. Or an arteriovenous in the opposite direction. These are going to develop, you know, directional flow. 8- eight connections allow for an equal liberation of that flow. So if there aren't adequate A sufficient number of 88 connections, then there should be a proper balance between the two circulations. But an inadequate number of 88 connections will result in a net flow. Depending upon the predominance of ADA V connections Between one twin and the other. And this is what we think prompts the cascade Of the 21 transfusion syndrome. It's not just a volume exchange, but a whole cascade of physiological phenomenon that occur as a consequence. There's the donor twin flow through the placenta. The donor twin manifests hyperbole mia through the loss of the blood volume. But in response there's a unique uh increase in the high vascular resistance in a vase, a constructive protective manner. This leads through release of mediators such as endo field in one and attention to an oligopoly Germany's picture and a bit of a hyper dynamic heart. As I'll show you some data about in a moment Now, what happens to the recipient twin is fascinating. Not only is the recipient receiving all this extra blood volume, but it also receives all the transferred viso active mediators, all the wrong mediators that are being released by the donor twin. The end of feeling one tension to which then result in a poly hydrangeas picture and in a select group of recipient twins, a response to this stressor, this biological storm, if you will with remodeling and the development of cardio biography in some this even development of right ventricular hypertrophy and pulmonary atresia with a result of a condition being identical in appearance in Vienna type to what we know of in general heart diseases, permanent treason attack, ventricular septum fascinating to watch this evolution take place. Now. Today we have a bit of an alphabet soup as it relates to many of these different terminologies. These are the way I look at it, are human inadequacies and fully understanding the biological spectrum of a mono chorionic pregnancy. But We're gonna talk today mostly about 20 in transfusion syndrome. There's also something the literature referred to as twin oligarchy, Germanos polly had Romney in sequence which is something that occurs without the manifestations of TTS. There's something called taps, which essentially is an anemia policy to me, a sequence with small connections being present in a very slow T. T. T. S. Type process. Importantly, one must distinguish tts from selective gr. Which one twin has inadequate placenta and cord floor abnormalities with poor growth. Typically it's partner twin. The larger will have very little if any cardiovascular manifestations. Then there's something known as trap for twin reversal, trouble profusion, which is the presence of an a cardiac a symbolic twin in which there's a pump twin and then a physiology similar to an arteriovenous malformation. We're not going to speak about trap today Again, we're going to focus our attention on TTS. It's a very reliable uh and very good way of categorizing and staging T. T. T. S. Is referred to as ghetto staging system. As you see here. What's interesting is when I first heard about the staging system, we were seeing such patients at our institution and chop Many of our patients would come in and be labelled the stage three in which this critical Doppler abnormalities. But I think many of us who do fetal cardiology appreciate that there's a lot that happens to the heart before you get to sort of this quote critical situation and that perhaps we were missing out on early signs of cardiovascular manifestations by using the Ontario staging system alone. So for example, we're going in flow across the track just valve. We know that normally there should be an E wave than a wave. But if there's alterations and compliance, the wave diminishes and you end up with fusion. This reflects hypertrophy and altered compliance. And in fact, we do see that TTS patients here. You see an example of track us to the mitral valve flow patterns the top of the donor, bottom of the recipients with single peak fusion reflecting hey, change in the compliance of the ventricle. Too subtle finding that occurs in before you get too critical. Things like the duct stenosis flow pattern. As you see here and in the donor, one will see a decrease in diastolic umbilical arterial flows, reflection of alterations in placental resistance. So ultimately, there's a whole slew of findings that one could look at purely from a cardiovascular perspective and that's demonstrated in this example here to relatively old video. But you'll see here this is a recipient with evidence of an effusion cardio. Meagley. Very poor function. Hypertrophy is a severe degree of track hospital vegetation in the context of poor function. And when you look at the short axis view the right ventricle looks like it's barely squeezing here. Here's the pulmonary artery and pulmonary valve. It's opening, but it's not opening fully. And in fact, what we see is polar insufficiency and tried desperately agitation within a context of reversal of flow in the doctors are curio sis So something has stunned this right ventricle. Some process has stunned this right ventricle. This is a fairly typical phenomenon in a severe case of TTS. So we thought it would be important to dedicate a scoring system to help us better understand The uniqueness of the cardiovascular manifestations. We came up with a 20 point composite score. We published this now quite a while ago. Back in 2007, when we looked at 150 consecutive twin pairs and looked at a variety of different cardiovascular manifestations. As you see here, About 16 had this very interesting and unique RV afloat tract obstruction abnormality. That appears to be unique to this process. Specific to this process. The score has five domains to it, The Max being 20. And we look at things such as ventricular elements, cardiac enlargement, systolic dysfunction in particular purchase fee. We look at val function, we look at things like venus. Doppler in flow patterns, whether there's a double peak or a single peak. So all of these are qualitative features without any specific measurements. To be made great vessel analysis. We look to see whether the pulmonary artery is greater than the order as it should be. But we do see that in a number of patients, even before we get to frank r bot obstruction, we can see changes in the size of the pulmonary artery, the presence or absence of poner insufficiency. All of these are on the recipient twin and in the donor twin. We look at changes in umbilical artery Doppler 20 being the maximum score, which suggests a very high burden of cardiovascular manifestations. We've now incorporated our cardiovascular score worksheet into our Seaman's single reporting. So this is uh typically reported by our coordinators and by our sin agua furs as they do the study. Now, we've looked at a variety of different other markers of cardiovascular function. And this is from a paper a couple of years back. Looking at speckle tracking my cardio tissue deformation, we looked at recipients and donors 25 pairs And looked at 25 normal gestational age matched controls. Looking at longitudinal strain. Systolic strain rate, as well as measures of pulse ability index At about 20 weeks. With a variety wide variety of Ontario staging system subjects here what you see in blue. The controls writer, the donors green. The recipients umbilical, arterial ps in the donor were higher than normal, while the emcees were lower than normal in the donor, indicating this unique set up for the donor itself. In terms of function. What you see here in green are the recipients of important diminution in percent strain in the RV and LV and the recipients. But the donors of anything, the LV was slightly higher than normal. What that tells us is that um with the presence of these altered loading conditions that in fact before any treatment, M. C. A. P. I. Is low and therefore you see a hyper dynamic volume depleted left ventricle and the donor. Whereas in the recipient, both harvey and the LV have diminished contract ill Itty. How do we treat now that we've talked about characteristics of T. T. T. S. And both donor and recipient. How do we treat uh T. T. T. S. Today very effectively Through the technologies that have been developed for placental laser photo coagulation. What I want to show you here is this diagram courtesy of Mike Bevington, who was a chop a few years back. He's now out in ST louis put together this very nice animated video that shows the progressive change in la liga hydra videos and Polly had remedios increased urinary bladder size in the recipient and the donor becoming stuck with the amniotic membrane encasing it. Now, as you come down to the placenta, you can see the connections between the arteries and the veins Between the two twins and through laser photo coagulation strategies. One can identify these connections and using a. Yeah Glaser, interrupt these connections with the placental play. That's a fascinating process. And what it does is it alters for loading conditions for the twins leading to an improvement in outcomes. What does this look like? Uh In reality? Uh here's a scope looking at um are two fetuses here. We're actually looking first at the recipient here. Just to give you a sense of what this looks like. This is a 22 weaker. We're visualizing the capillary distribution within the limbs and here you see a finger uh feet is trying to get out through the scope that's not going to happen. Um But we're going to focus our attention in a moment from the recipient of the donor. And let me give you a look at what the shrink wrapped appearance of the amniotic membrane on the donor really looks like. That'll be coming up in just a moment to hear the hand and fingers of the recipient in the polyp hydra amniotic sac. Again, this is about 21-22 weeks gestation visualization of the vasculature on the placenta. And here you see the donor stuck, shrink wrapped amniotic membrane arms folded and the cord partially compressed as well. And this is what the oligarch Germany was part of Germany of C. Cups looks like with laser for the coagulation interruption here. The changes that we see. So let me go through one particular case that uh in a very dramatic way highlighted some of the changes that can occur by eliminating these vascular connections. This is a pre lazer. Look at a recipient with a moderate degree of track hospital vegetation and RV function. That's not very good. And a fair amount of hypertrophy. Here's the RV again in its uh long axis. Looking at the pulmonary valve, the pulmonary valve is fluttering is trying to open but it's really not opening very much in the RV function. It's quite quite poor. And when we look at color, what you see in this modify three vessel tracheal view is that there's a red jet here reflecting retrograde flow and the doctor sartorius is so there's a state of functional pulmonary atresia here, laser photo coagulation is undertaken. This is what the RV looks like. One day after laser, the TR is dramatically improved. The RV function is better. And now look at the pulmonary valve, it's now opening with anti great flow across. By the way, we haven't lasered the pulmonary valve here we have laser the the vascular connections at the placental plate and we've altered the loading conditions and that's what resulted in this change. one week after laser RB. Still someone hypertrophy. But the function dramatically improved and now we have total and a great flow across the pulmonary valve and in fact total anti great float across the duck to search neurosis. one week after the laser, the dramatic improvement in the appearance and function of this recipient right ventricle. Here's another case just showing some examples of some of the dolphin changes before laser. One day after laser, One week after laser in the trickiest valve. So even within a day we begin to see an improvement in the filling characteristics reflecting an improvement in the compliance of the right ventricle dr stenosis reversal. Before the laser improvement. One day after laser normalization. One week after laser and bill call venus pulsations that were present before the laser improved dramatically. One day after laser and normalized. one week after laser. When we look at our composite reflecting the magnitude of cardiovascular manifestations, we can see that there is a decrease and the burden of cardiovascular abnormality as you go from pre to one day to one week. And then other measures such as my card of performance index, which I know our audience is familiar with is another way of quantifying global diastolic and systolic function. You see here the pre the one day and the one week for the recipient and the donor. There's a dramatic improvement in the NPC, although still not totally normal in the recipient with an increase in the Mp and the donor in the right ventricle, often reflecting the new conditions for load that exists. And here you see some of the changes in the L. V. M. P. As well, which are similar to what you see in the R. V. M. P. We've also used a strain assessments in our recipients and donors. This is a group of 25 patients looking at the pre laser In Red vs the seven days after laser in blue values for the strain percent. And what you see is that for the recipient? Elvin recipient RV. There is an improvement in function reflected in an increase on the strain going from the red to the blue. And for the donor there is a decrease again reflecting the commensurate changes in loading conditions. Were improving loading conditions for the recipient but perhaps sometimes altering in a negative way some of the loading conditions for the donor that results in some of these changes. So what I've done is I give you just a brief snapshot of many of the aspect of this fascinating condition of T. T. T. S. And what is this condition telling us? The fetal heart exhibits remarkable plasticity at this vulnerable gestational age in the second trimester. With alterations through the loading conditions and our ability to change those loading conditions dramatically improving the heart function. My card is quite sensitive to these loaded conditions and other agents that can profoundly influence structure and function exactly what these factors are still somewhat unknown and the uniqueness of fetal maya sites no doubt plays an important role here. But understanding exactly what genes are turned on and turned off and the responsiveness of the fetal meyer cardi um to these unique conditions is worthy of continued exploration and I do think that we continue this exploration. Perhaps we can better understand this phenomenon, but also understand a bit better. Perhaps some of the aspects of the development of congenital heart disease early in gestation. Thank you very much for your attention and I want to thank the organizers of the Mount Sinai conference once again for uh the opportunity to invite and have me come speak with you today. Thanks very much. I'm Caitlin Rollins. I'm the neurologist for boston Children's hospitals cardiac no development program and I also am a fetal MRI researcher. I'm going to be talking about brain abnormalities in fetal CHD predicting and modifying or developmental outcome. No developmental impairment is the most common non cardiac morbidity that Children with CHD face. The most common areas that we see impacted our attention, executive functioning, visual spatial skills, social cognition and anxiety. This is an example of what we mean by executive functioning. This is a task called the ray off stride complex figure task and Children are asked to copy the figure and then later draw it from recall. This is the image from a typical second grade student and you can see that it's really quite accurate and here's the image from a child with T. G. A. This is a very severe example but what you'll notice is that it's a very details diagram but it really misses the forest through the trees. So this is what we would often call a part oriented cognitive style. And this is a common pattern that we see in the thinking of Children with CHD. It can really impact their ability to function in school if they have a hard time seeing the big picture and get too focused on the details. This is another example of an assessment that might be used in congenital heart disease called the reading the mind in the eyes task. In this task, Children are asked to look at the facial expression just from the eyes and label it. Children who have difficulty with this task often have trouble reading social cues and that can lead to challenges and social interactions. Many different factors have been associated with neurodevelopmental outcome in CHD genetic abnormalities, complain important role as can the family environment in particular maternal education, aspects of the cardiopulmonary bypass strategy specific brain injuries such as white matter injury, hemorrhage or stroke and then postoperative complications. For example, Children who have very long lengths of stay are more likely to have developmental delay and learning difficulties down the road. In a large collaborative study that called the icon study, they looked at all known risk factors and found they only explain about 30% of the variants and neurodevelopmental outcome. In this data from the icon study in the left is the mental development index on the bailey which is the cognitive scale and on the right is the psycho motor development index of the bailey, which is the motor scale. As you can see, patient factors which included things like birth weight, mother's education and genetic abnormality explain about a quarter of the variance and outcome, operative and postoperative factors explained a relatively small proportion And then 70 of the variants remained unexplained. And this is really where fetal brain development comes in. Is that we are trying to understand whether we can explain a significant proportion of this unexplained variance by looking at what happens before birth to the brain. Now I want to take a look at how different forms of CHD can disrupt the normal fetal brain circulation and the image on the left you can see bright red, richly oxygenated blood leaving the placenta going up to the left side of the heart and then to the brain. When you look at the image in the middle, you can see there's a slight reduction in the oxygenation of the blood leaving the placenta, which likely reflects potential placental abnormalities. That blood comes up to the left side of the heart but then is directed down to the body and the blue, relatively deoxygenated nutrient deficient blood is sent to the brain. So there's a reduction in oxygen and nutrient concentration in the blood that the brain sees in utero. In T. G. A. In hypoplastic left heart syndrome. We see that blood leave the placenta go up to the heart where it undergoes, mixing moderately lowering the oxygen and nutrient content of the blood. And then rather than going up directly to the brain it flows retrograde through the doctors arterial Asus to the brain. So you see both differences in the oxygen and nutrient concentration and differences in the flow pattern to the brain and H. L. H. S. So in the first fetal MRI study in CHD, which was really a landmark study done by Catalan metropolis and her colleagues, they found that total brain volume in fetuses with CHD was reduced by 15 to 20% by 36 weeks gestation. So here you can see the fetuses who are controls in the Red Diamonds and the fetuses with CHD are the blue circles looking across the third trimester. There's a progressive relative decline in the size of the fetal brain of the CHD fetuses compared to the controls. Really quite a significant difference by the time they are near term. A second major fetal MRI study was done by mike seat and his colleagues in Toronto. So they specifically used t to mapping to study scruple oxygen delivery and consumption. And again this is a mixed cohort of CHD. So various different types on the left side of the figure here, you can see in the top portion cerebral oxygen delivery and it looks somewhat lower in the CHD fetuses compared to the controls did not quite reach significance. Below that is cerebral oxygen consumption, and you can see that that is significantly lower in the CHD fetuses. They then looked at the relationship to estimated brain weight and you can see there is a relationship a correlation between estimated brain weight and cerebral oxygen consumption. So this suggests there is an association between some of these feels terrible human dynamic factors and brain size, but it does not tell us that there's causality. So several critical gaps remained in our understanding of fetal brain development and CHD. After these two landmark studies. The first is whether there's a global effect on fetal brain versus a specific effect on vulnerable parts of brain with downstream changes. The second is to what extent fetal brain changes are related to these cerebral hemo dynamic differences versus other factors like genetics. Third, how do these fetal brain abnormalities related to neurodevelopmental outcome and addressing these questions is really critical to identify which patients are most likely to benefit from in utero therapies and also to provide insight into potential therapeutic approaches that may be most effective. So now I want to shift gears and talk a little bit about what's actually going on in the brain during pregnancy. So it's important to know the foundation for long term rural connectivity is established in the fetal period. If you look at the image on the right, I really want to focus on three parts of the fetal brain, the first part of the proliferated zones. So that's the ventricular and some ventricular zones which the arrow labeled PZ. Is pointing to just around the right way ventricle. That is very important for generating neural progenitor cells and glia. Those neural progenitor cells in glia then migrate through the next layer which is labelled IZ. The intermediate zone and that contains a scaffold which these neurons are traversing to get out to the cortical plate or the future cortex. The intermediate zone contains pre militating olympic tender sites as well as these migrating neurons and axons. Outside of that is a brighter white band labeled spc. And that's the sub plate zone that contains sub plate neurons as well as some other components. And is important for facilitating thalamic cortical connectivity and cortical cortical connectivity. So establishing connections between different parts of cortex in between the cortex and the deep grey of the thalamus. You can see the disruption to this system could really initiate a negative cascade affecting your own proliferation. Myelin nation and cerebral cortical organization with long term effects on overall brain structure. So some work has been done looking at how these different components are potentially vulnerable to hypoxia ischemia. So there's a large amount of work from premature babies as well as from animal models indicating that cream eliminating the liga dender sites undergo maturation arrest and failed to produce myelin after they're exposed to hypoxia ischemia. Similarly, the sub plate neurons in that sub plate zone show maturation all changes in response to oxygen and nutrient deprivation which may impact their functioning. Finally, the group in Washington that led by morton developed a chronic hypoxia Pitlick model where they looked at sub ventricular neuronal proliferation and neurogenesis and what they found was a reduction in that in these piglets with a corresponding reduction in cortical growth and that really mirrored what has been seen in postmortem neuropathology findings in infants with CHD. That's shown on the right there. Mhm. So in 2014 we began to launch maternal fetal brain MRI study of fetuses with isolated CHD. To see if we could identify some of these changes in vivo in this population. We performed fetal brain MRI in mid pregnancy as well as late pregnancy along with echocardiogram and Doppler. At those time points we do to your own or developmental evaluation and then we're just beginning a 6 to 8 year evaluation including MRI uh next generation genetic studies and a neuropsychological evaluation. Because at this age you can really get a detailed look at those executive functioning components visual spatial skills, social cognition elements that are really hard to assess in a young two year old. So we enrolled fetuses into four different groups to CHD groups and to control groups. The T. G. And H. L. H. S. Were analyzed as one group. As these diagnoses were thought to carry the lowest cerebral oxygen and nutrient delivery in utero. Other forms of CHD were analyzed separately. And then we enrolled to control groups. We rolled a group called the CHD related controls, which are fetuses that are healthy but have a family history most often as sibling or father with congenital heart disease, not the mother. We did not allow that and then optimal controls who were recruited through advertisements. The reason for two control groups is that in general fetal MRI participants are not representative of the general population. They tend to have higher levels of education and perhaps uh investment in the health of the pregnancy. Mhm. In terms of the inclusion and exclusion criteria, the most critical is that these are fetuses with isolated CHD no known genetic or extra cardiac anomalies or other brain anomalies. So fetal MRI presents some unique challenges in neuro imaging. First is the signal to noise ratio. It can be difficult to get a strong MRI signal through the mother's skin, fatty tissue, the muscular layers, the amniotic fluid and then again through the baby's tissues. Second, there can be uncontrollable maternal and fetal movement because we don't use sedation for these studies. So I've been incredibly lucky to work with brilliant I think electrical engineer Emily gallop or who can take an image like that scene on the left and put it together to reconstruct it in three D. Space, yielding the image on the right. Then after we get that image, we apply a segmentation algorithm which is based on the brightness and location and label it so that we're able to actually measure all of the different structures of the fetal brain. And this is manually refined but largely automatic. So what have we found so far? So first, I want to look at the comparison between the h L h S t. G. A group and the optimal controls. And what you can see here is that region is shown in blue. Are those where the CHD group is smaller than controls. And if there had been any regions that were larger in the C. H. D, those would have been labeled red, we can see that the entire brain overall is smaller in the CHD fetuses but that it is most notable in the ventricular zones, those proliferated regions as well as the someplace sub plate and intermediate zone. Mhm. When we, instead compared to the CHD related group, which as I said, we believe to be likely a better matched control group. And indeed, that did turn out to be the case that the socio demographics of the CHD related closely mirrored those of the cardiac groups. When we look at this better matched control group, what we see is actually a lower magnitude difference in general. So the blue is less dark in general and the group differences are localized only significant in the sub plate intermediate zones and then trending towards significance in the proliferated zones. So we see a much more regional vulnerability. When we look at this comparison, we then performed a two year no developmental follow up and we only did this in the CHD related controls because again the optimal controls, 97% of those women had a college education versus two thirds in the other um control group. And in the CHD. So in general, when we look at the scores in the CHT group, they are lower across the board compared to the controls most different in the expressive language and gross motor domains. And that's highly reflective of what we see in clinic, that expressive language and gross motor development are most affected in CHD. Now putting it all together, we looked at whether fetal brain MRI can add additional information in terms of explaining variants and or developmental outcome at age two. So the approach we used here was a hierarchical regression approach. So we started with fetal brain MRI the variable of interest. And then we looked sequentially at information as it would become available. So we look during the prenatal period at demographic factors. We looked at cardiac factors, we looked at birth factors and then we looked at post natal variables such as whether the child is stored, procedure in length of stay. And we looked at more variables than those listed there. It's just a key indicating the variables that were significant. What you can see is that the only variable which explains significant variance across all of the different domains of development and adaptive functioning is fetal brain MRI. And most importantly that it really explains a very significant proportion of the variance. When we look at for example, the general adaptive composite, which is a measure of everyday functioning that's very predictive of how Children will do overall long term. You can see that the fetal brain and I was the only variable to explain significant variance and it explained 21 of the variance. Now comes the really remarkable, especially when you compare these numbers to what was seen in the icon study that I showed earlier. I do want to mention. We also did use a non hierarchical approach to ensure that this hierarchical approach wasn't sort of falsely elevating the contribution of fetal brain and right. And it yielded nearly identical results. So what can we take from the data that I presented today? So first the fetal period establishes the foundation for long term neural connectivity, upon which complex cognitive and emotional processes affected in CHD rely that certain components of fetal brain critical for establishing cerebral connectivity are particularly vulnerable to hypoxia ischemia that forms of CHD that most severely reduced the fetal cerebral oxygen and nutrient delivery show the smallest spring volumes. Especially in these vulnerable regions that I showed you. The proliferated regions, the intermediate someplace zones that fetal brain size predicts neurodevelopmental outcome at two years more consistently than any other pre or postnatal factor in isolated CHD. So I think this is really an important target for future therapies to improve outcome. What remains to be determined is the interplay between fetal brain volumes and cerebral human dynamics, genetics and family environment. So all of these different factors work together and we really need large studies to try to delineate the relationships between all these different variables. So thank you so much for your interest and I look forward to answering questions. Thank you to all our speakers. Um And we're going to open up the board to uh questions. Um on a cure in a session there's uh two questions that will combine for dr wright checked to answer. Um When do you start monitoring? High risk pregnancies for T. T. T. S. From a pediatric cardiac standpoint. And what numbers on the score do you use to decide on laser therapy? And how frequently do you do you re check after therapy? Great uh good morning and afternoon and uh wherever you are. Um Thanks. Thanks for those questions. So uh I will tell you that we begin the cardiac monitoring when the patients were referred to our maternal fetal medicine doctors. You know for evaluation Uh in general, I think broadly to the community. The answer to that question is that one should probably begin the process of evaluating mantra chorionic twins at about 16-18 weeks. I think. From the medical perspective, that's that's pretty much what the general guidelines are. We know that twins can monitor chorionic twins can develop trouble early early on. It's rare for us to see serious cardiovascular manifestations at that early point. But uh progressive monitoring of these patients starting at that earliest point referral can be helpful in understanding the trajectory in terms of utilizing the score for criteria for intervention. What we apply at our institution is a combination of the Ontario station system and the cardiac score. So there's no specific single cut off for cardiac number. That makes us say we got to go to the to the intervention but rather use the two in a complementary manner. So if we have, say for example, Classic Scenario of a Cantero Stage one where cardiac manifestations are present with perhaps a score of four or five, that's an indication to go ahead and proceed interestingly in the converse presence. And I think this relates to one of the other questions that may have come up. Um if you have sort of subtle or borderline T. T. T. S. Findings and the cardiovascular score is zero, then you have to reconsider whether you actually had TTS. And that's been something we found to be very very helpful. If the recipient has little or any cardiovascular manifestations, you may be dealing with a selective big picture. More so than than a true T. T. T. S. Great. Thank you. And for Dr Moon Grady um We were wondering if you ever start maternal to Jackson and the setting of high output heart failure and if you do what your threshold is to do. So um that's a great question. Uh Did Jackson was uh used in a study that published by Jim Sciutto and others for a variety of loons? And they did. So I think it was it was a one or two point in cardiovascular profile score with the Jackson therapy. So um but other than that, I don't know. There's a lot evidence that's uh yes, when there is nothing else do I have had the Keighley started it. Um And sometimes uh you know, if there's no interventional there be available, I've definitely in the combination the beta methadone that the FMS are going to give uh and starting to Jackson um temporarily resolved effusions now, whether it's cause and effect or whether it's all due to the steroids, I don't know, but you know, if you're in that viable period, uh probably try there. There's good um pretty reasonable evidence that the fetal cardi um may actually prove contract due to changes and handling from the digoxin that we really see an older card. So yeah, it's worth a try. And uh the nine for the mother. Great, thank you. And then dr Rollins, um we were wondering your opinion on chronic maternal hyper oxygenation. There's been some recent reports on that um that it may be associated with smaller um fetal head size, which is concerning. We're sort of wondering your opinion on that. Yeah, I think that's a really um tricky question and somewhat controversial obviously, as you're sort of highlighting in the data that you mentioned showing smaller head size, I think that um the first step, ideally is that we have a better understanding of what is actually leading to the smaller brain size in these patients. Part of why I highlighted the regional differences that we see in the brain. For example, those sub plate intermediate zone and proliferated regions that are important for connectivity is because there is data that suggests that those are parts of the brain specifically vulnerable to low oxygen and nutrient delivery to hypoxia ischemia. So given that we do see greater vulnerability in those regions, that's um that is some evidence that hypoxia scheme is playing a role along with mike seeds. Data also suggests that hypoxia ischemia may be playing a role. Um That said there's also uh enormous amount of data suggesting the importance of genetic factors and giving maternal hyper oxygenation to child. Where genetic factors are really the dominant cause of their brain being small, is potentially going to have adverse effects without significant potential for benefit. So I think that the jury is really out on the kind of um a cohesive model for what's contributing to these issues. And I think that the more we can have a large collaborative studies where we can really take into account all of the different potential components and separate out fetuses with different forms of congenital heart disease. I think we'll have a better direction in terms of the most appropriate therapies for different patients. Yeah, great. Thank you. Um So another another question came in for dr recheck. What is the primary driver for development of our vot obstruction and its severity in T. T. T. S. For in other words why do some fetuses develop such severe our bot um and others don't. That's a that's a great question. And then still a puzzling one From from my perspective because it is just truly amazing. The particular signature of changes that you see uh in the recipient is so unique. I mean why is it that that some fetuses develop this RV outflow tract obstruction? Um Vienna type. It seems to me this is just my hypothesis at the moment it seems to me that there is probably a commonality of changes in after load that occur. But yet the response of the people Mayer cardio to that particular set change the loading conditions is unique and perhaps genetically based in some way. And whenever we see sort of common stressor in any biological system to get differential variable outcomes, you have to begin to think about the host and had a host response to those particular stresses. And it's not just a variability and the stresses, the variability in the host. And I think that there are just some individuals, some hearts in which given the stressor of the T. T. T. S. Phenomenon, the storm of the GPS phenomenon respond by having their right mind would fall apart and this is perhaps even more calm. We see tr we see dilation, we see dysfunction and sort of typical appearance of cardiomyopathy. But in this 10 to 15 it's almost protective actually because those that develop the PS with A. P. A. E. V. S. Don't succumb. It's it's a it's a it's a successful outcome if you will in an ironic way because they develop this congenital heart lesion and then you move forward um out of the biological storm and then we are left with the residual a as pediatric cardiologist and dealing with you know, the need to relieve the apple tract obstruction either through a balloon procedure or even surgically. Um So I think there's there's likely some host related phenomenon in some way. Maybe one's genetic basis of response to this particular storm. That leads some to develop the RV Alcatraz obstruction which ironically is protective versus some others where the heart just falls apart and then you end up with the demise. Thank you. Um I think uh Oh sorry go ahead. Um We've also development of mitral valve uh dysplasia that looks like fibrosis in a set of these patients. And so I put that together and I have quite a few autopsy spends in my collection um as well. There does seem to be um uh this vibe Roddick action in in some of these hearts. And so you know, and the feel in one we know is elevated in Yeah, the attic fluid of the recipient and that can be a pro uh fi broader agent. So I sort of, the thing I would add is that there may be um some probably host dependent reaction to these days. Oh activators that um that accelerates developed uh this fibrosis and so it both perry and uh might re valve um asia developing. Um the other thing that I found interesting is that Jack correct me, this isn't your observation, but it's like the early severe are more like go on to develop, valve are pulmonary stenosis and um and resolve all those are prior to laser. About percent of twin twin recipients were born with the outflow tract obstruction. And now with laser we've found that it can actually be reversed. So another argument that it's viso active mediators, that if you get rid of them by dick organizing that, that the fibrosis can regress. Yeah, absolutely. And Anita is uh, I've learned so much from Anita and her group in terms of how they managed as well. This is a usual useful admiration and recognition here of both of our experiences. But you know, it's interesting that we have rarely seen the mitral valve average valleys. You published on this quite a while ago fascinating phenomenon, but it does perhaps reflect the fact that there is a host uniqueness as well. But here's the thing, you know, if we could figure out a bit more about what the actual mechanism is, if it's a vibe, Roddick change in some way, you know, that bodes towards the possibility of modifying it pharmacologically, which, you know, some have thought about, you know, ace inhibition or, or council channel blockade, etcetera, Perhaps some other mechanisms in some manner. But that's really been shooting in the dark. You can get a better idea of exactly what this is. If we think it's fibra genesis in some way, there might be a more likely way in which we might be able to modify this early on. Great. Thank you so much to all our speakers. I think we'll wrap up the session um and have a break until 1130 with our exhibitors and then we'll start with session number two. Thanks everybody. Thank you everybody. Mm hmm. Right. Yeah. Yeah. Yeah. Yeah. Yeah. Mhm. Mhm. Yeah. Yeah. Mhm. Uh huh.
