Dan Swarr, MD - 2024 Fetal Care Center Navigating Perinatal Care for Trisomy 13 & 18

Awesome. Thanks so much. Uh, it's my pleasure to introduce, uh, Doctor Daniel Suar. He is a neonatologist and geneticist at Cincinnati Children's Hospital, um, and comes with unique expertise because he's actually double boarded in, in both neonatology, uh, and genetics. Um, so he's here to start off, uh, with a little bit of a natural history and, uh, information to kind of provide the foundation for the rest of the day. Great. Well, thanks everyone for inviting me, the organizers. It's a great honor to be here today and talk a little bit and hopefully set the stage for what we're gonna talk about for the rest of the afternoon. Um, so that's my really goal today. We don't have too much time together, but, uh, try to provide an objective review of the literature, um, for the pre and postnatal outcomes of fetuses and children diagnosed with trisomy 13 or 18. Um, we're gonna be pretty limited in the, the, there's a huge number of papers, particularly over the past 10 years or so that have really come out. We're, we're gonna focus on a couple, and in particular, we're gonna try to focus on some of our local data since we've been able to publish that in a couple, in the past couple of years. Um, and hopefully, this will provide a big overview of the, the details that we're gonna hear about from all the experts across the various disciplines that are related to this condition. So just to give a little bit of historical context, um, trisomy 13 and 018 were actually described in back to back case reports in The Lancet, Lancet in 1960. Um, and then a few years after that, uh, Weber et al. published a relatively large series, at least for that time period, uh, uh, case series of the two conditions. And not surprise or somewhat surprisingly to me at least, some of the numbers that they reported in their initial case series back in 1907 aren't dramatically different than some of the survival data that I'm going to present a little bit later from much more recent cohort. So, in their initial large case series, about 28% of the infants had died by 4 weeks of age and 87% had died by their first birthday. I mean just keep those numbers a little bit in mind when we look at some of the newer data. Um, this paper from Doctor Carey, who we're lucky enough to have here today, summarized um uh the literature over the 80s and 90s. And you can see here on the bottom, the median survival, um, and this is for trisomy 18, range from 2.5 days to uh 2 weeks depending on which study you looked at. Um, and, and they kind of weren't dramatic, other than these kind of outcome studies weren't dramatic changes in kind of the management where they're happening during this period. However, I think there's been a lot of changes really over the past 5 to 10 years in particular. Um, and this paper here, um, that Doctor Carey also wrote, um, in 2012 in Current Opinion of Pediatrics looked at some of the approaches and described what he termed at that time conventional approach and Maybe not, that's kind of no longer the best term as, as we've changed so much in how we approach these inferences we'll hear today. But, uh, conventional or at least historical approach to management of these inferences typically to really only offer comfort care in the withholding of technological support such as mechanical ventilation or surgery. Um, and certainly that was the approach that was advocated throughout the, uh, 1980s, 1990s, and And, uh, and even up into the 2000s was a very commonly held view, um, among neonatologists when surveyed, at least based on this 2008 study to have referenced here, but certainly perspectives are changing and, and some newer surveys of neonatologists suggest that that's the case. Um, and as we've seen certainly here, the medical interventions that we're offering these infants, um, and children who have a diagnosis of trisomy 13 and 018. Um, have changed dramatically over the past, um, 5 to 10 years in terms of what we're offering in terms of delivery room resuscitation, and the care that we provide in the NICU, including surgical care that we're gonna hear more about from Doctor Yinsky and others today. Um, and some of the stated rationales for the historical or conventional approach, um, as it's called, were due to the high rates of medical morbidity and mortality that we're all familiar with, and the diagnosis is perceived as quote unquote lethal or resulting in a very poor, very poor quality of life, and as a result, Medical interventions wouldn't either not be beneficial or cause the child and their extended family harm. Um, and often, as we've, I'm sure all probably heard, uh, the concept of futility is sometimes are often invoked in those discussions. Um, for those of you who haven't read this paper by Annie Han VA, I highly recommend it if you have any interest in this topic. Um, she really kind of breaks down a lot of the points of discussion, um, and particularly related to the ethics of providing care, uh, for children with trisomy 13 and 18, and it's just an excellently written paper. And she discusses a lot the concept of futility, which is, is something that does get invoked in counseling. Um, but that's a, you know, pretty challenging, um, subject, especially when you talk about quantitative futility or qualitative futility. So quantitative futility simply would mean that the medical intervention that you're discussing doesn't work at all. Um, and, you know, in some instances that might be true, um, but, you know, in other, for other things like providing mechanical ventilation is certainly gonna treat apnea. And so it doesn't necessarily mean it's the right treatment, you know, actually offer, um, but using the term futility probably wouldn't apply in that, in that, um, situation. Quality of life arguments often come up, um, in things like qua qualitative futility of the intervention, quote unquote, not being worth it. But obviously, those are highly subjective and they're gonna vary very much from family to family. And then best interest in resource allocation arguments are discussed in this paper, and again, it's an excellent read for those of you who haven't come across that before. So, I'm gonna talk about two studies for the remainder of the talk. The first is, um, a relatively large and well-done study that was done in Ontario, Canada, that was published in JAMA in 2016. Um, and then I'm also gonna discuss a little bit smaller study, but, uh, a study that was done here that represents our local data and I'd say the results are overall fairly similar. Um, and the Nelson paper in particular, I think was a landmark study, um, because there's a lot of similar outcome studies that came. Around the same time as this study or shortly after, um, and I think it really highlighted or, or kind of brought a lot of attention to the kind of changing practices that are occurring both locally, nationally, and internationally for children with trisomy 13 and 18. So this study was a retrospective cohort study. Um, it's been a pretty large period of time, so there's gonna be a lot of practice changes that occurred over this time, but interestingly, the authors did not see a change in survival over time. Um, the date span 1991 to 2012. And um it was a large, uh, administrative database study done in using a single-payer system in Canada. They had 174 infants with trisomy 13 and 20454 infants with trisomy 18. Um, and their incidence was 6 per 100,000 live births for trisomy 13 and 8.8 per 100,000 live births, uh, for trisomy 18, and I'll compare that to our local data a little bit later. And what's, there's two things that you really notice with their survival curves, um, The first is that there's obviously a steep drop off um in survival in the first month and really in the first week of life. But then after that, um, the survival actually plateaus pretty significantly, especially once you get out to about 6 months of age. And you really see that kind of plateau continues long term. So here they showed survival out to 15 years, excuse me, the 15-year survival curves, and you can really see again after that first year of life, things really plateau. And I'll show that in a little bit different on the next slide, uh, quantitatively. So, for trisomy 13, in their study, interestingly, this is a little bit opposite of what many other studies, including our study have found, but in their study, trisomy 13, um, uh, did a little bit better. Um, and of those infants who are alive at 30 days, the 1-year survival was almost 50%, just under 50% at 47%. And of those who are alive at 6 months of age, their 10-year survival was uh right around 50%. They're interestingly again, they trisomy 18 numbers were. Slightly lower. The um infants who are alive at 30 days had a 1-year survival of 36% and those alive at 6 months of age had a 10-year survival of 60%. Um, we'll talk a little bit about this in subsequent talks, but, um, and again, this has certainly changed over time, but the number of, uh, surgical procedures being offered to infants with both trisomy 13 has, it really increased kind of both locally and nationally and internationally. You can see of the, if you remember, there are 174 infants with trisomy 13 in this study, 41 received surgical procedures that include major cardiac uh surgical procedures, um. Uh, gastro GI procedures that include things like G tube, but other gastrointestinal surgeries and tracheostomy placement, among others. And um I'm sure Doctor Gaginsky had talked about this in greater detail, but, um, and, and of course, there's selection bias in, in which infants or, uh, children are receiving surgeries. So many of the infants or children who are receiving surgeries are gonna be the ones who have already survived that first month or first several months of life that are the most critical or the purest of highest mortality. Um, and there's certainly, uh, you know, mortality associated or, or following the surgical procedures, um, though a significant number of them survived for many years after the surgery. And, you know, because this is an administrative database, their data doesn't sort out what was related to or potentially unrelated to the surgery in terms of the cause of mortality. So we did a similar study here where we looked at our cohort. Um, what's a little unique for those who don't know how neonatology is organized in the Greater Cincinnati area, our neonatology department covers all of the level 1 and level 2 nurseries in addition to the NICUs. Um, and so, um, by putting IRBs in place at all of those, uh, various healthcare systems, we were able to capture certainly all of the live births. And then Leanra worked very diligently to do our best to try to capture, uh, prenatal cases as well, um, by reaching out to the genetic counselors at all of the associated, um, MFM groups. So, I put all in quotes. Um, I'm cer certainly if there was, um, a pregnancy affected by trisomy 13 or 18 that Didn't end up getting cared for by one of the MFM specialists in the area, um, and, uh, resulted in early loss, we could have missed those types of cases, but I think given the coverage that we have in Cincinnati, we're able to cover most of, uh, the both prenatal and postnatal cases of trisomy 13 in the greater Cincinnati area. Um, we did the study a couple of years ago now, so the dates that we did for the chart review. spanned uh January 1st, 20 2012 to December 31st, 2018. And we had 125 fetuses or infants with either trisomy 13 or 2018. And our live birth rate was roughly uh about twice of what they reported in the Nelson et al study from Canada. So our trisomy 13 um live birth rate was 1 per 10,000, which if you remember was about 0.6 per 10,000 for the Canadian study. And 1.86 per 10,000, which is um a little bit more than double the rate of 0.88 per 10,000 for the Canadian study. Um, the rates of spontaneous loss in our study were about 6.5%, um, for, uh, pregnancies prior to 20 weeks' gestation, and then around 19%, um, for pregnancies after 20 weeks gestation. So about a quarter of those, um, pregnancies, uh, uh, ended in a loss. And then the elective termination rate was 7, just around 17%. 58% of the pregnancies did end in a live birth, and the rates of cesarean section were around 49%. Preterm labor was uh 14%. And then of those, um, these are not mutually exclusive, of course. Delivery for maternal indications was 16.7% in delivery for fetal well-being was the same as 16.7%. Most of these were prenatal diagnosis, so, um, around 81% of the diagnoses were made prenatally, most of which were done by amniocentesis or confirmed with amniocentesis, though a few with, uh, CVS. And then, um, in 50 cases, in 50 of the pregnancies, sulfur fetal DNA was performed. Um, notably, it was, um, um, reported as high risk in 92%, but it is worth noting that 4 out of the 50 had a low risk, um, self-free fetal DNA test report despite having a diagnosis of trisomy 13 or 18. I think all of, uh, the, the false negatives were with trisomy 18. Um, and then postnatal diagnosis, 24 of the cases had a postnatal diagnosis. Um, 12 of those did have non-invasive testing that was high risk, um, prior to delivery. Um, 2 of the postnatal diagnoses had a low-risk cell-free fetal DNA testing, um, and then the remainder had either declined or failed testing. So just to give you an idea of the flow of the infants kind of through our healthcare system, um, with a prenatal or postnatal diagnosis of trisomy 13. We had a total of 38 diagnosis of trisomy 13 and um you can see the breakdowns of the pregnancy outcomes. 25 of those resulted in a, a live born infant. The majority of them delivered at level 3 or level, uh, a hospital that had a level 3 or level 4 nursery available, so a NICU. Um, though not all of those, um, actually about half of those only actually went to the NICU. The other half were cared for in the mother-baby unit at those facilities. And then a smaller percentage, um, ended up delivering at, at our nurse, at one of the hospitals that held only a level 1 or level 2 nursery. Um, that would be facilities like Bethesda North or UC Westchester. And then here's a similar breakdown for the infants with um trisomy 18. Again, so you can see there's uh, you know, a reasonable number who are delivering at a facility that didn't have a NICU and of those that delivered at the larger facilities, um, you know, only part of those infants are actually getting admitted to our NICUs. Um, and the, the rates of discharge home are also here. So there's a significant number of infants who do go to our NICU who are discharged home. And here's our survival data. You're gonna see looks, uh, you know, uh, qualitatively looks very similar to what you saw for the Canadian study. The only major difference is that our outcomes were flipped in the sense that trisomy 18, um, had better survival rates in, in our local cohort compared to the Nielsen study, though there's a lot of other studies that show that same phenomena with trisomy 18 having, uh, higher survival rates. Um, our median survival for trisomy 13 was 7 days with uh obviously huge range. Um, we had, uh, there's one child who is 637 days at the time the data is collected and still alive. In trisomy 18, the median survival was approximately a month with again a very large range. Um, uh, that very large number there in days is about 7.5 years, so a child is still alive at 7.5 years at the time the data was collected. Um, but you see the same phenomena that we talked about earlier with the Nelson et al data where there's a very sharp drop-off, um, in the first few days of life in terms of, um, survival and mortality, um, and particularly in the, in the first month of life, but after that, things really flatten off. So, um, many of the infants who are passing away in the first year of life are passing away in the first few days. Um, and then after that, um, uh, things plateau significantly. And in our data, Similar to what Nelson and all reported, of the 27 infants who are alive in a month, um, approximately 50% are alive at 1 year of age. And this is 5-year survival data. Again, you see that there's a precipitous drop off very early in life, but things flatten off significantly after that. Factors in our study that are associated with mortality, again, this is gonna be limited by the relatively small nature or rela relatively small number of patients that we had in the study and the relatively rare nature of the disease. Um, but we observed, um, that trisomy 13, um, the initial goals of care and then probably not surprisingly, extremely low birth weight or extreme prematurity were the only factors that we could find associated with survival. Um, surprisingly, and this may potentially be just related to the numbers that we had available that weren't any obvious major differences between some of the more common congenital anomalies we see in, um, duration of survival. Um, so here, I showed you the data for trisomy 13 versus 18. Um, this is defined, uh, we defined goals of care as the initial goals of care and knowing that a lot of families do change their goals of care throughout their course in the NICU. Um, so this is based on their kind of initial goals and also it's worth noting that, um, goals of care doesn't necessarily mean what type of care or, or support services that they received in the NICU. So, If your goals was to receive full intensive care as indicated, it doesn't necessarily mean that you received surgery or mechanical ventilation. It was just that you wanted that if it was medically appropriate. Um, that group is shown here in green, and I'll show you the numbers in a little bit, but that was about half the kids. Um, and then the comfort care is shown in red and non-invasive support, um, we define it more carefully in the paper if you're interested. But that essentially means families that chose things like um non-invasive respiratory support like high flow nasal cannula or standard flow nasal cannula or NG feeds as a means to kind of support and provide kind of medical care with the duration of potentially extending life, um, but not to opt for invasive measures like mechanical ventilation or, uh, surgical procedures. There's some overlap with uh the comfort care group, um, and we go into a little bit more in the paper for people that are interested. Um, just to give you a breakdown of kind of what, um, medical care, uh, were received by children in our cohort, um, I just highlight a few, we go into great depth in the paper breaking this all down and kind of, uh, you know, very significant detail. But mechan about 25% of the children across the two groups, a little bit more in trisomy 13, a little bit fewer in trisomy 18 received mechanical ventilation. Um, we'll talk about surgical procedures later in the afternoon, but about a quarter in our study, a little bit more for trisomy 18 and a little bit less for trisomy 13, received any type of surgical intervention. And if you're interested in the paper, we break down exactly what those surgeries are and, and uh how many infants received them. Um, obviously, some of the infants received multiple surgical procedures. And then our breakdown between the families who chose comfort care versus the families who chose invasive interventions was about 50/50 with uh only around 10% choosing the sort of intermediate non-invasive pathway. So I'll finish up there and I'm happy to take any questions either now or at the end of the session, but just to conclude and kind of introduce the rest of the talks for the session, um, fetuses and infants with trisomy 18 and 13 and 18 are at relatively high risk of intrauterine fetal demise or, or spontaneous loss. If you remember, the total for those two categories is around 25%. Um, and have a high rate of neonatal morbidity and mortality, particularly within that first week of life, even, um, when they receive kind of quote unquote full medical interventions or neonatal intensive care. However, a growing body of evidence suggests that both medical and surgical interventions can increase survival rates. Um, knowing that these infants, unfortunately do have higher rates of morbidity and mortality associated with those procedures, though that's not particularly well defined and certainly needs more research that I think we're gonna hear about from Doctor Carey at the end. Um, and then long-term survival with either diagnosis is possible and I think it's an important thing to consider. Um, in our counseling, particularly when we're talking about families who might choose a comfort care approach, knowing that even with a comfort care approach, long-term survival could be a potential outcome. Um, and evolving our approaches to management of children have really evolved rapidly. I particularly, particularly over the past 5 to 10 years, and, and I think it'll be great to hear from our specialists in surgery and cardiology in particular as we go through the session today about how that care that we're delivering has really changed over the past, um, uh, 5 to 10 years. Um, counseling at all stages of care, um, including decision about whether to pursue medical intervention such as cardiac surgery should be tailored to each family and child, and really in, in the current environment should be multidisciplinary, and this is where, uh, you know, a team like our fetal care team really shines where we can bring together multiple specialists, data-driven with a growing number of publications that have come out, particularly in the past 5 or 10 years. Um, and really focusing on, um, kind of adapting multiple risk factors that may change the baby's prognosis such as gestational age, birth weight, and the complexity of the one or more surgical anomalies that they may have. And counseling is gonna need to continue to involve cause I think the amount of data and studies that are coming out, um, particularly hopefully with some of the more perspective studies that Doctor Carey is gonna talk about at the end of the session, I think it can really change. Um, the way that we view and understand these diagnoses and how to best, um, approach them. And then, um, Doctor McCaffrey again wrote a really nice paper on this topic. Again, if you haven't seen it, um, as, as he puts it, a plea for truth, transparency, and recognition of our prejudices regarding the decisions we make when caring for these children. I think that's just some food for thought for all of us as we talk about. Um, all the exciting advances that we're gonna hear about through the rest of the afternoon. So with that, I'll finish up and answer any questions you have, um, in the chat. Thanks so much, Doctor Suar. Uh, just a reminder, if you're tuned in, you can submit, uh, questions, uh, via the chat and then we'll, uh, ask those for you. Um, Doctor Suar, I'm still trying to understand this history that we have from the Nelson paper that the survival didn't really change, uh, over almost two decades. Uh, but now we have the opportunity and ability to provide more complex medical care. Um, how does it all fit in in terms of what the survival, um, will ultimately be for these children? Is it a mix of the underlying comorbidities? Is it a mix of family choice? Uh, what's, what's next? Yeah, it's a great question. I think Dr. Carey is going to talk about a perspective study that's being proposed proposed that I think will help address those a little bit because both our study and really many of the other studies out there are retrospective studies that have done chart review or administrative database review. And so I think it's, it's difficult to tease apart some of those issues. Clearly in our data, there is an association between kind of the initial goals of care that the family chose and kind of duration of survival or, you know, you know, the length of the, the child's life, but I think it's really hard. Those are obviously heavily confounded. The decisions that people are going to make are going to be heavily based on, um, you know, the comorbidities, so things like prematurity, you know, what congenital anomalies are present or not present. And so I think it's really hard to tease apart from a retrospective study like the data we have of, of how those things play together and whether the families who are making the decisions to pursue more intensive care or because they're term baby with fewer or no major congenital anomalies or don't have a major surgical issues or major cardiac issues. Um, Versus, you know, the things that we're doing are actually extending their life. And so I think it's kind of difficult to tease apart from the data that we have. And, and there's, you know, conflicting literature out there in terms of what interventions or whether which interventions we actually have extend life versus kind of these associations that we've observed in the retrospective studies. I don't see any questions from the audience yet, but I also have a question. I think something that I've seen in many different, um, retrospective studies really about trisomy 13 and 18 is that there is a correlation between patients who have a prenatal diagnosis having a shorter survival than patients who receive a postnatal diagnosis. And I imagine there's a number of factors that go into that. But do you have any ideas or comments on kind of that trend? My guess, and this is not certainly not based on data, but more just based on anecdotal experience is a lot of that has time to the, the time that the family has to prepare and kind of think about what they want to do and when that's happening, you know, happening during the pregnancy versus happening in the NICU. Uh, you know, I think particularly in the cases that I've had or especially when they've had reassuring sul-free fetal DNA testing, the postnatal diagnosis is so much harder because they've, you know, You that they're already stressed out about it and then they get this devastating diagnosis. And so I think that period of time where they're just dealing with the, the, the shock and upset of dealing with that difficult diagnosis. You know, Takes up a significant amount of the time that, you know, is happening in the NICU in terms of, you know, what's next and what medical decisions we're making and whether or not we're kind of pursuing a surgery or pursuing other medical treatment options. And so I think probably a lot of that is related to just the time that the family has during the prenatal period to process that information and decide kind of what care decisions they want for their child.