Prenatal diagnosis of fetal lower urinary tract obstruction: Fetal...

Um, my charge this morning is to talk about the prenatal evaluation portion of babies with, uh, lower urinary tract obstructions or LUDO. There you go. There we go. So this is what we're talking about. This is a, uh, 14 week fetus at the time of an early ultrasound, and what you can see is a very large, uh, fluid filled cystic structure in the abdomen. Um, with decreased amniotic fluid, and this of course is a lower urinary tract obstruction or LO. When we talk about ludo, um, the three major causes are urethral atresia, which is a complete obstruction where the penile urethra never completely formed, and so there is no communication from the bladder neck. Through the urethra. The other most common cause is posturethral valves or PUV, which is the flap of tissue in the proximal urethra that obstructs the urine from again leaving the bladder and getting through the penile urethra. And then there's another type of obstruction which is due to a mid urethral hypoplasia where there's a very significant tapering and narrowing. Which is not a complete obstruction, but over time can become a very high grade obstruction as the pregnancy progresses because of the pelvic anatomy as it matures. The angle between the bladder neck and the urethra changes such that this area of narrowing becomes a progressive constriction and a higher grade obstruction. But what we know is that incomplete urethral obstruction, these babies will develop progressive oligohydrammias until they have anhydramus or no fluid around the baby. This will lead to physical deformations in the babies such as joint contractures and flattening of the ear and the typical potter's, uh, phenotype. And because the baby cannot expand and contract its chest, it will lead to pulmonary hypoplasia because of the interference with normal growth. And differentiation and development of the lungs and because of the obstruction and generation of pressure up to the kidneys, they developed severe hydronephrosis, dilation of the collecting system, and progressive renal fibrocystic dysplasia, resulting in renal failure after birth. And this is a typical picture of a terminated baby with the prune belly phenotype. You can see the markedly distended abdomen because of a very, very large bladder. When we look at the bladder, it's not only enlarged, but it's very, very thick walls. You can see bilateral tortuous hydroureters because of the pressure up to the kidneys, and here you can see the uh um um. Cystic dysplasia with macrocysts and basically fibrocystic dysplasia of both kidneys. So this was studied by the group out in San Francisco several decades ago, and the idea being is this an anomaly that could be potentially treated in utero. So they went to the sheep model, and what they did is they produced early obstructions by ureteral ligations in the sheep, and what they noticed is that this obstruction reduced, produced the exact same type of fibrocystic dysplasia that is seen in the human. They also noted that the earlier they created the obstruction and the longer the duration of the obstruction, the greater the damage to the kidneys. And so the next thing in their study was to say let's obstruct, but then let's reverse the obstruction to see if we can preserve the kidneys. And what they found is that if they did early mid gestational reversal of the obstruction or removal of the ligation, they could prevent the progressive dysplastic changes to the kidneys and preserve kidney function, and this gave rise to the idea of possibly putting a shunt or basically a suprapubic catheter, which is what they would do out outside of the uterus. And that this shunt could be placed under ultrasound guidance such that the proximal portion of the shunt would be within the bladder. The straight portion of the shunt would traverse the fetal bladder wall and abdomen, and that this portion of the shunt, the distal portion, would hopefully lie flat against the fetal abdomen, allowing the urine to drain from the bladder. For preventing progressive injury to the kidney, kidneys, but also restoring amniotic fluid to promote fetal lung growth and maturation. But there was very highly variable outcomes and success with early shunting, and one of the contributions we made early on was when we published this paper that looked at a stepwise approach to identifying fetuses for possible shunt therapy. And what's involved in this approach is 3 steps. First is high resolution ultrasound to really look at the anatomy of the baby, and that's important because many babies with lower urinary tract obstructions have associated anomalies like myelomeningoceles. There's a higher frequency of cardiac disease and other genetic syndromes that are important to rule out because some of those babies would not benefit from shunting because of the poor prognosis overall. Sometimes it's very difficult to perform a successful sonographic evaluation, and so in some cases we perform amnio infusions to expand the amniotic fluid space, to restore the fluid interface, giving us a much better, higher resolution image on ultrasound. It's also very important to confirm normal karyotype, um, because, uh, not an insignificant portion of these babies will have uh chromosomal abnormalities such as the major trisomies. Um, but can also have, uh, other things like uh Kleinfelter's. It's also important to confirm that it's a male fetus because when we talk about female fetuses with large, um, bladder-like structures, the majority of the time they turn out to be cloacal abnormalities, and they do not benefit from shunting, um, because it's a completely different process and, uh, underlying pathophysiology. And the last thing that we um. Uh, recommend is to actually do a renal function evaluation by draining the bladder, and the goal is to completely drain the bladder, uh, on several occasions and look at electrolytes such as sodium chloride, uh, calcium, look at osmorality, look at total proteins, and also look at uh beta 2 microglobulin uh as reflections of proximal tubular injury. And possibly direct injury to the glomerular apparatus as well. So the first step is to really look at the ultrasound very, very carefully. This is a characteristic early, um, uh, fetus with obstructive neuropathy. You can see the large fluid-filled bladder. You can see the walls are markedly thickened and ecogenic in this bladder because this bladder is developing smooth muscle hypertrophy and hyperplasia, um, because of the pressure. We can also see dilated kidneys in this case. And because this is early obstruction, we can see enlargement of the kidneys, um, increased echogenicity and dilation of the collecting system within the kidneys. So one of the things that people always look for is the classic keyhole sign, and what the keyhole is, is the dilated proximal urethra down to the level of the obstruction. This is an example of a posteri urethral valve case, and what you can see is the dilated posterior urethra and marked dilatation of the bladder because of the obstruction. It's also very important to look at the ureters because they can provide some. Diagnostic information as well. Here you can see a markedly dilated mega ureter coming from the bladder up towards the kidneys. Evaluation of the kidneys is extremely important as well. The early literature suggested that increased echogenicity was a poor prognostic sign, but I would challenge that because I believe it's more evidence of compression of the renal parenchyma. So the more compressed the renal parenchyma is, the higher echogenicity and brighter it will be on ultrasound. In many cases like this where you could see in the upper upper left corner where the kidney looks very, very bright, does not look normal. Following bladder drainage, serial bladder drainages, and allowing these kidneys to drain, you'll see re-expansion of the parenchyma, and they'll have a much more normal echogenicity. It's important to look at the degree of uh of uh pelvicassis and caleectasis as well, and the pathophyhysiology of this hydronephrosis is that if you think of the kidney as a something like a sponge that's contained within a glass fish bowl and the collecting system being a balloon full of water within that sponge structure, as you increase the size of the balloon, you compress the. The sponge tissue or renal tissue against the thick outer fish bowl, which is the serosa, and as you compress the parenchyma, you impair the very delicate vasculature that provides oxygen and nutrition and support to the tubular system in the medullary area as well as the outer cortical region that results in cell death and progressive fibrosis and eventually cystic dysplasia. Well, looking at the kidneys is very, very important, not only for the dilation and degree of compression, but also to look for early signs of cystic dysplasia, and this kidney again echogenic, but you see no really discrete cysts. This is further along in a case, and what you're starting to see is not only echogenicity, but you're also starting to pick up some areas that are suspicious and concerning for small cystic changes occurring. And later on in this case, what you could see is discrete cortical cysts developed, and when you see cortical cysts, that means that this kidney is irreversibly damaged. And is not amenable to any kind of in utero therapy because of the severity of the underlying injury. So the presence of fibrocystic dysplasia or cysts in the cortex is a very, very poor prognostic finding, but you also have to look for other things that can fool you. Here's a case of a duplicated collecting system with a dilated upper pole, and this is a, a fetus that has uh oligohydramnios and a big bladder, but when you look down at the bladder, you can look very carefully, and what you can see here is an obstructing urethrocele. An ectopic insertion of the kidney from this upper pole has resulted in formation of a large urethroce that has prolapsed down and it is obstructing the bladder outlet, resulting in this obstructive neuropathy, and these are amenable to therapy which we can talk about later in the program. Sometimes the bladder is quite large, and if you look, you can see a very dilated penile urethra, and this is an interesting case where the urethra was dilated all the way out to the tip and on high resolution gray scale ultrasound you could actually see fibrosis at the tip. Of the penis due to a disco meatal stenosis. Here's another case in a much earlier fetus that you can see the dilated penile urethra in this very echo bright area of fibrous stenosis. Other cases you might run into is a big large bladder with more of a kind of bulbous keyhole sign, and as you look at the urethra, you can follow this urethra down coronally, and if you go sagittally, what you see is this huge dilated structure. Which is the big dilated penile urethra, and this is due to anterior urethral valves, which is a more unusual and uncommon form of obstructive neuropathy, but I've probably seen about 10 cases over my career of this as well. It's also important to look at the bladder and look at the cord insertion because sometimes you can see this type of a cystic structure and notice that this is a large bladder. It's thick walled but has this cystic structure that extends from the dome of the bladder to just adjacent to the umbilical cord insertion and also note that this baby has normal amniotic fluid and what this is is actually a patent ureus. And the urachus is a tract that arises from the dome of the bladder that generally closes off early in embryonic development, but this tract goes all the way up to the umbilical cord insertion and in some cases with early obstruction notice this marked. dilated bladder with high pressure, this urea can potentially open back up and drain amniotic fluid out into the amniotic fluid space, which is one of the underlying etiologies for obstructive neuropathy with normal amniotic fluid volume. So a good clue is to look at the dome of the bladder and follow it up through the cord insertion. Another case, can I interrupt you just a moment. We had a question really on that topic. We have about 5 minutes in your presentation yet to go, but on the subject of, uh, fetuses that have normal amniotic fluid, could you maybe list the, uh, which I think you're getting into the, the key features, uh, especially in the bladder that might clue us into the fact that the bladder will not obstruct. Well, that's showing you some examples here of cases that normally amniotic. And you know, I think in cases of Peyton ureus, the bladder is very big. There are dilated ureters. There's a characteristic hydronephrosis and dilation of the intrarenal selecting system, but there's normal amniotic fluid volume, and so that's the key to try to look for the presence of things like a patent urea. Another case, um, which I've seen several of is uh a massively distended bladder with a pretty typical keyhole, um, appearance to it, um, hydronephrosis dilated, uh, collecting systems, but again, completely normal amniotic fluid volume. This finding is much more common in female fetuses, which is what gives you the clue that what this is, but I have seen at least 6 dozen. Cases of megacystis microcolon hypoparicosis syndrome in male fetuses as well, and what this is, is a basic neurologic defect in the muscles that don't allow the bladder to contract and empty and don't and impair um uh emptying of the kidneys through the uh interference with peristalsis down the uh ureters as well, um, and these kids basically uh have extremely poor survival and factors. Most of them do not survive more than a few years, but this is kind of a key that you can see it in a male, massively distended, um. But with normal amniotic fluid, if you were to drain this bladder, what you would see is after drainage, the entire bladder would still be very, very thin walled because it does not develop the hyperplasia or thickening typically seen in a complete obstruction. And basically, the amniotic fluid is just flowing into the amniotic cavity because of pressure that's generated and is actually going through a completely patent urethra. Here's another interesting case that came to us with normal amniotic fluid. This did have a thickened bladder, but a normal sized bladder. You can see that there's patency through the urethra, and what the urologist told us is that this is a pretty characteristic case of severe congenital reflux where the kidneys are just massively dilated collecting system, severe hydronephrosis, huge mega ureters. And basically this bladder is just refluxing back up to the kidneys, and yet there's normal amniotic fluid volume. So going into uh the next step, which is kotype analysis, when you're faced with anhydramnios or severe oligohydramnios, it's difficult to do amniocentesis. If you can go for it. If you can't, the alternative approaches are chloranicyla sampling, which is the way we did this two decades ago. You can also do vesselocentesis because with new technology, particularly fish, you can actually screen and confirm male carriotype and rule out major auploids. And in the past, some people advocated corticentesis to get karyotype from fetal blood, but also allows you to obtain beta 2 microglobulin values, which some reports suggest are a good marker for renal impairment as well. Um, but the last step of the evaluation is to look at underlying renal function and, uh, in the past, people would do a single drainage of the bladder. Here you can see a needle, spinal needle going in. Notice the absence of amniotic fluid. I think there's about 57 molecules of amniotic fluid right here, um, but the goal is to go into the bladder and completely drain the bladder of as much urine as possible, um, so that urine can now be analyzed. And what we look at is sodium chloride, osmolarity, calcium, beta 2 microglobulin, and total protein. And a lot of the work that we did in in Detroit helped to differentiate good prognostic values from poor prognostic values. And so basically this is what we use now, that if the urine shows values less than these, then there is potential for survival with successful shunt placement. If the values are above these cutoff thresholds. And this is a pretty good example of significant underlying renal injury and fibrous changes, and we confirmed these by looking at autopsies on fetuses that had values above these levels and not much far, not much higher above these levels, and what we found histologically was pretty significant fibrotic injury to the kidneys. Whereas patients who had elected to terminate that had values below these cutoff thresholds showed very little or very early changes that were potentially salvageable within utero therapy. But the interesting thing is that you, the reason to do serial uh studies is that the first urine specimen that you get is not really predictive or reliable. And in the past, when we just did a single bladder tap, there was highly variable outcome with shunting. But what we found is that if you do a first bladder tap, and then wait 2 days and do a second bladder tap, and then a. Two days and do a 3rd bladder tap. What you're actually sampling here is the urine that was in the bladder initially, but that urine is exposed to all kinds of degradation products and um um osmotic gradients that change the electrolyte composition. When you do the second tap, what you're now seeing is that the urine, this is the urine that was in the ureters and then the intrarenal collecting system. And then when you do the 3rd tap 2 days after that, there's actually urine that is more freshly produced by the kidney, and what we found is that the 3rd or 4th values are much, much better, have a much higher predictive value for detecting significant underlying injuries. So if you see this pattern, and let's just take Osor sodium for an example, where it initially looks poor, but after the 2nd tap, it gets better, and after the 3rd tap, it drops even further. This is an excellent candidate because we would predict with successful shunting, this would have a reasonably good prognosis, as opposed to this fetus, which was already above the cutoff threshold, it got worse and even got worse. This is a fetus that has got ongoing irreversible damage that shunting won't help or won't benefit. And so by using a normal karyotype, no other associated anomalies like a myelomeningocele or a major cardiac abnormality and good prognostic um uh urine values suggesting um non uh not severe renal injury. Uh, these are the cases that we choose for vascular amniotic shunting, which Doctor Ryan will talk about in more detail. But another benefit of draining the bladder. Is that we have seen that it can give you some idea of possible underlying etiology and what we have found that in cases of urethral atresia, after you do your complete bladder drainage and it starts to refill, we found that you see this symmetric, very thick and universal um thickening of the of the bladder wall with a. Difficical keyhole, those that we found with posturethral valves after drainage, they tend to have this more elongated bladder shape with more thickening proximal of the bladder than disli. And then what we found is that those that turned out to have the mid urethral hyperplasia or chrome belly variants, now called triads. They tended to have the typical keyhole, but as the bladder refilled, they had this really unusual appearance that we coined the snowman appearance where this would be the head, the chest, and the body of a snowman. And histologically we studied these and what we found is that there's a typical hypertrophy and thickening of the muscle wall in the lower part of the bladder, but the upper part of the bladder had a significant deficiency, and abnormal composition of the smooth muscle such that this is more of just a kind of a hernia sac off the dome of the bladder. It helps you differentiate this ideology from this ideology, from this ideology, which could be helpful for counseling the patients in the future. At this point I think I'll, I'll I'll send it off to Greg or back to Bill. Thank you very, go ahead, Greg. Thank you very much. Um, Mark. Uh, 90% of the virtual audience, uh, answered C for the last poll question. Uh, I don't know if you can see the questions there, Mark, um, now that you've stopped screen sharing, but, um, there's a lot of agreement that when referring to is it possible to obtain a fetal karyotype from the urine, uh, um, they say it's possible, but it's somewhat dependent on the volume of fluid obtained and sent to the lab. Um, And again we had about an 87% agreement on the, the, the, the other question about the sonographic appearance of the bladder and the collecting system that um that it would that the sonographic appearance can suggest the etiology obstruction um any comments about those remarks there, Mark? Well, I think, you know, the challenge with using fetal urine. Is that in the past we really couldn't, you know, reliably do fish studies or to actually culture and get karyotypes. And um it really is dependent on how much urine you get, because if you have a bladder early in obstruction and you only get 20 cc's of it, you have to send part of that to get the electrolyte and protein studies done. And so if you send only 5 or 8 cc's to the uh cytogenetics lab, there's gonna be a high incidence of failure um to get the carry type information you're after, um, as far as the last question. Um, I just showed you kind of our observations over time that there does seem to be a correlation with the shape of the bladder, uh, after you drain it and it starts to refill. It's not 100% um reliable, but it is a trend that we see. So if you drain the bladder and it's uh refills and you see that thick symmetric. Um, hyperplasia of the bladder wall, that's very, very typical of a, of a urethral atresia or a complete, uh, posturethral valve, um. And if you see that kind of snow snowman shape, um, that's more consistent with that mid urethral hyperplasia, um, and the underlying primary smooth muscle abnormality in the urinary tract. Um, histologically we saw abnormal smooth muscle all the way up from the proximal ureter ureters all the way up to the uh renal pelvis, as well as the severe abnormalities and smooth muscle development in the dome of the bladder. Um, which is why we kind of separate that category out from urethral atresia and from valves. Yeah, I wonder, can I ask a question of Mark on this one? Um, Mark, the, the, I guess the the original electrolyte cutoffs that we used were the ones you presented. Now the work from the Paris group from Francis Miller has, I think, and Humberto Nicolini has sort of emphasized the importance of using gestational age cutoffs for the electrolytes. And could you comment on that, please? Yeah, so all of the work that we did and others. The French and the Brits and uh and the Americans I'm looking at all these electrolytes, they were basically based on all of those cutoffs that I showed you um were based on your end of pain between 18 and 22 weeks. And so if you go before 18 weeks. You know, those cutoff thresholds, um, you can't use them as far as giving you good predictive value. If you go over 22 weeks, um, you can't really use those cutoffs either. And as you're showing on those graphs from uh Francois Mula, um, there is a change over gestational age. And if you do a urine urinalysis on a fetus of 17 weeks. You would have to kind of extrapolate that the cutoff value would be a bit higher. Um, and then if you were to do it on a 24 or 26 week fetus, you would have to extrapolate that those cutoff thresholds would be much lower just because of the maturation and increasing function of the kidneys with advancing gestational age. And I think your graph that you have up there right now demonstrates that very well. So all of those cutoff thresholds that I showed earlier and I believe the slide showed. Um, were based on urines that were analyzed between 18 to 22 weeks of gestation. So if you're above that, it doesn't work for 26 or 28 weekers, um, you have to adjust this, uh, way down, and I don't think we have good data that allows you to predict, um, injury at those more advanced gestational ages. Thank you. Thanks, Greg. And then you'll have about 10 minutes now for the presentation, and we can pick up with some questions for you in the uh session after the break when you're back with us. Is that all right? Sure, yeah. So Mark has given a very nice introduction to the problem. And I guess my mandate is to talk a little bit about some of the management options. And essentially we can do nothing, we can stop the pregnancy or we can intervene. Um, and in terms of intervention, we're talking about shunting or cystoscopy or even some of the open fetal surgical uh approaches. So really what I'm going to concentrate on is the role of fetal bladder shunting, the psychoamniotic shunting, or possibly the role of fetoscopy and valve ablation. Um, we have to remember that when we're doing, when we're treating these kids, our primary goal is to prevent pulmonary hypoplasia, which is secondary to the oligohydramnia. The secondary goals are preservation of renal function and preservation of bladder function. Um, but these really are secondary goals in terms of our treatment. It was the UCSF group who originally showed us the importance of shunting and followed by Charles Roddick's group. And I think we like Mark's group tend to use the Rock or the rocket shunt here. There's another Cook Harrison shunt is a more pliable shunt. It's inserted using a Selinger technique, but we've always used this one. So because it's worked well, we really have seen no reason to change, and it's a double-tailed silastic pigtail catheter that's inserted. With the coils in different directions, so theoretically the flat end is outside the baby's abdomen and it cannot grab it and pull it out, and the other end is inside the bladder as shown here. So we do these as an outpatient procedure. We give some internal analgesia, and this will differ from unit to unit. What we use is some IV remifentanyl and if necessary propofol and some local anesthetic. We do give an antibiotic. We, we tend to give a dose of indomethacin, and we may give some nifedipine immediately afterwards, but the mom usually goes home a couple of hours later. And the most important thing, as Mark alluded to, is and the infusion before you do this, because unless you put a good volume of fluid in around the fetus, you really cannot deposit the external end of the shunt, which is always the trickiest part of the procedure. Um, and this probably is the most difficult part of the whole procedure because if you have a baby with anhydramnia. Then finding a pocket where you can actually instill some fluid can be sometimes quite tricky. So what we tend to do is to put a needle into around the baby's limbs or somewhere where we can um uh where we can find a space and instill some fluid. So again, we use our color to outline the superior of the cycle, make sure we don't hit them on the way in, and then under ultrasound we will insert the shunt in the usual manner. And then here's a shunt that's in place. You can see there's still some residual hydronephrosis, but the shunt is sitting in the collapsed bladder. The other end is outside in the amniotic fluid which has recollected. And then postnatally the shunt stays there really until the baby is born, and I think we could probably argue this shunt placement here, which is one that I did, is not ideal because we would like, if possible, to insert the shunt inferior to the bladder because the higher you go, the more the risk of the bladder deflates that you're going to have some of the holes in the shunt in the in the peritoneal cavity, and you may in fact get urine leaking in and create fetal urinary ascites. So the question is whether these actually work or not. And I think we've got to be grateful to the group in Birmingham who've done a lot of the work looking at whether or not shunting is of any benefit. And they looked at the effect in terms of the prenatal or perinatal survival and postnatal survival. Now there's only a few studies really from which they could they could interpret. And if we looked at those where the outcome improved with drainage compared to those where the outcome improved with no drainage, in the group where there was a there was a um a good prognosis from the urinary electrolytes. It appeared that there was some benefit to drainage, where the good prognosis had been predicted from the electrolytes that Mark has shown us, and in the group where there was a poor prognosis, they in fact appeared to have an even better result with drainage. So it really came down to the Pluto trial, which was the only randomized trial in this area to help us decide whether in fact bladder shunting made any made any difference to these babies, and the babies who were randomized were kids where the physician was uncertain whether or not to shunt. In other words, if we knew whether shunting worked or not, then we would, we would not randomize the patients. And the the entry into the trial karyotype and urinalysis was not, were not in fact mandatory for the patients in the trial, and the amniotic fluid volume was not used as a prognostic evaluator. So these are some of the things that Mark has shown us are actually very important in evaluating these fetuses, but they were not used as part of the trial. And if we If we were uncertain as to what to do, then the patient would be randomized to either shunt or conservative management, and if we were certain what to do, they asked, could we enter those patients into a registry, and we looked at which kids had a shunt or were managed conservatively. Both groups were followed up to 5 years of age, and the end points were really perinatal mortality and renal function. And the trial was designed to collect 150 patients over approximately 4-year period and unfortunately by the end of 4 years only 31 patients had been randomized. The results are shown here and you can see that there appears to be some benefit from the shunted group compared to those who are managed conservatively, but when we look at the relative risk in the 95% confidence intervals, you can see that these cross unity and neither results in fact were shown to be significant. So the trial was stopped early because of poor recruitment, so only 20% of the planned patients were randomized over a period of 4 years. In the fetuses that were shunted, there was about a 3-fold increase in survival compared to those who were not shunted, but the numbers I would emphasize are very small, and therefore the size and direction of the effect is uncertain, and therefore the benefit, as I showed you, is unproven. All of the 12 deaths were, were from pulmonary hypoplasia, and it was inferred that some of the improved survival was probably related to a decrease in lung hypoplasia. And only 7 of the 12 live born shunted babies are alive at the age of 2, and only 2 of the shunted survivors had normal renal function. So these are fairly sobering numbers from from that trial, and all 3 conservatively managed survivors had significant renal impairments. So I think what this trial underlined was some of the difficulties we face in any kind of fetal therapy trial, because the conditions we're evaluating are pretty rare. Many may go undetected prenatally. Many parents, when faced with the realities of outcome, may choose pregnancy termination, and there's always a delay in accepting any kind of new therapy, and this reflects our bias as clinicians and the patient bias. And these are based on the small heterogeneous studies which are usually observational. And so we really lose clinical equipoise, and this, I think, hampered the recent fetoscopic laser trial in the states. It is hampering the total trials for CDH currently ongoing in Europe and here. However, I don't think we should lose heart because several trials, namely the Euro twin twin trial and the neural tubee trial. have shown us that with effort and money and time we can in fact conduct a randomized trial properly in the fetal population. This, this, I think is probably one of the most important slides to, to take away, and certainly it's one of the, one of the most important ones that parents look at when we look at the long-term outcome of babies who have been shunted. There are only 6 studies that report on these, and so the numbers are pretty small. Um, and if we look, however, there's quite a degree of consistency across all of the studies. I know Mark has been involved in the study from Detroit and and the study from Philadelphia. And he will be able to comment better, but you can see that in terms of the number of babies who survived, there's very, very similar numbers. Some of the groups report terminations of pregnancy, intrauterine deaths, and some of the groups only report neonatal deaths. And this is where there's a slight difference, for instance, in the CHO data and some of the others. But the other group that's remarkably consistent is that of these, and remember these are the best of the best group with good electrolytes. Only about 40-50% of these kids have normal renal function, and approximately 1/3 of these babies end up requiring either dialysis or transplant. So certainly in our population in Canada, when parents look at the outcome studies, many, many parents in fact will opt for a termination of pregnancy rather than shunting. So here's an example of a case of a fairly typical one that Mark had shown to us. The mum shows up at 17 weeks without anhydramus. This had been diagnosed at 14 weeks. We did a bladder tap. The electrolytes were in the upper normal range, and lo and behold, at 17 weeks there was some urinary ascites after the bladder tap. At 19 weeks we noticed the baby was peeing and filling up its sack, and by 23 weeks with no intervention, there was a recollection of amniotic fluid. So I think it shows that some of these cases can resolve spontaneously. The other way the baby can cure itself is by a spontaneous decompression of the bladder, either resulting in an asymmetrical hydronephrosis or urinary ascites, because the bladder itself ruptures. Rupture usually occurs after we drain the bladder. It's actually an unusual. Event to occur spontaneously, but very commonly will happen after we drain the bladder and always resolves after a few days. Or sometimes these can result in the development of a perinephric urinoma, as you can see here, and the kidney in fact has been compressed quite medially. Again, Mark has alluded to the importance of of cases where we should not be intervening, and we would certainly agree and the Megacystis microcolo and intestinal hyperperistalsis is a classic for this. But we have a very large bladder, and the clues are, of course, that this is a female, and that there's a normal volume of amniotic fluid, and these are cases where we really would not advocate intervening by shunting. Um, and again, the other case that of course we would not intervene in is this massively enlarged bladder secondary to a cloacal dysgenesis, and these are cases really where, where there is no role whatsoever for intervention. Um, as we're getting to the end of the time here before the break, I wanted to ask a question that came in regarding the Pluto trial before you get too far away from that. So, the uncertainty of the practitioner, whether or not to treat, why, why again were, was the practitioner uncertain whether to put a shunt in? In the Pluto trial. I think that so the practitioners fell into two groups, I guess there were the folks who believed that shunting had a definite role, in which case they would not randomize the patients, and people who believed that the answer was still too unclear, in which case the patient would be randomized. And that's what I meant when I say. We were opinionated on the basis of Of small, you know, non-randomized studies, um, which is a pity, and, and, and it happens so often in, in, in cases of fecal therapy. Yeah, so this had nothing to do with the workup or the evaluation. It had to do with the, uh, equipoise of the practitioner then. Exactly. OK, great. Thank you very much. We'll come back with some more questions. I think we're.