2024 Fetal Care Center Frontiers in Fetal Neurology Day 2 - Hour 2 Q&A

I look forward to fielding questions now. Um, hopefully easy ones, although I did hear that Doctor Nagaraj wanted some hard ones, so send those her way. Well, I will start things off. Um, I think that this is such a, this is for Doctor Naraj. This is a really difficult study to do, um, you know, uh, a series of studies, um, you know, there's so many, obviously confounders which are really hard to control. Because, um, as you pointed out, patients who are exposed to opioids often have other exposures, and it is so difficult to tease apart the impact of some of those exposures from the opioid. Uh, but this is the world we live in, and these are the children, right? So, It is what it is, but, so my question was, um, what studies have been done, um, just in general, sort of in the postnatal period and following the imaging, um, you know, of, of these kids who were prenatally exposed to opioids, um, and have any findings been found consistently in those, those children? Yeah. Uh, yeah, thanks for the question and, and, and yeah, yeah, just to address the first part, I, I, I'm just having flashbacks to, um, going through those red cap data sheets and, you know, the other exposures, a lot of these patients that choose not to answer. I'm like, how am I supposed to use that? But yeah, it's very challenging population. Um, so yeah, there are a lot of confounders, um, did, I think we did as good a job as anyone could do given the circumstances. That being said, Um, right. The question about whether or not there are studies in the postnatal period, yes, um, Stephanie Murhart, Nihal Parik, and, um, Beth Klein have, uh, done, uh, have written a few papers, uh, looking at, uh, MRI findings in fetuses in patients with prenatal opioid exposure, and they have found one. Evidence of increased white matter entry in the neonates, so little punctate white matter dots. Um, they've also described, um, decreased regional brain volume, so, um, and I think, and so I think those are the two major findings that they found, um, and then the DTI paper, I cited some literature where they described alterations in DTI parameters, so I think the, the, the short answer is yes, there have been brain abnormalities described in um In children with prenatal opioid exposure, um, but they tend to be on the mild end. A lot of things that we don't necessarily as the clinical neuroradiologist, you know, see or describe routinely. And, and, and just to. bit of an intriguing thought, which is again another study difficult to do, but we certainly use opioids for our neonates after surgical procedures and, you know, um, if needed for pain control, and many are on these opioids for some time. So I'm curious and I wonder what happens in terms of their brain anatomy and Again, difficult to address because oftentimes they have other medical comorbidities that might impact their brain anatomy, but, and there are of course some women who are on chronic opiates because of medical diseases, not because of opioid use disorder like our sickle cell anemia patients, for example. OK. So we had a question from uh Doctor Henry Akebi. I apologize if I mispronounced that. Um, can you, um, Doctor Nagaraj, uh, expand a bit on the FDRQ value on the analysis performed at BCH? With such a small sample size, the chance of false discovery would be expected to be very high. Um, I, yes, I, I, I would. So yes, I, I agree that our, our end is, is, is pretty small, um, as, as mentioned, over 50% of the patients had to be excluded from the volumetric analysis, so It does illustrate certainly the need for larger studies if we're going to, you know, validate and further understand the findings in this study, um. Uh, I mean that, that being said, um, I think that, um, I'm, I'm reassured by the fact that when I looked at the brains clinically on all the patients enrolled, the 2D measurements, so I had a, you know, a cohort of twice the size of what BCH had for their volumetric analysis, saw multiple smaller brain measurements. So, um, to me, that's, that's reassuring that I, I, I do think that the brains and the opioid exposed fetuses really are truly smaller. Um, again, as, as Charo alluded to, is it just from the opioid exposure or are there other coke confounding variables that, you know, despite our attempt to control for, we weren't able to is, is, is another question. But in real life, does it really matter? I mean, in real life, this is what these patients are living, um, the confounding variables, so perhaps it's more important to know what their real life effects upon the fetus are as opposed to knowing what the effects of isolated opiates are. So I have a question for Doctor Markham, um, specifically about cyclovira. Yes, I really feel that element, right? We want to help, we want to treat. It is such an unfortunate disease. Uh, there's so much guilt, um, surrounding, um, you know, when we, when we counsel, um, Sometimes the, the mothers feel like they did this and, and as much as we try to say that this is nothing they did and it is just unavoidable sometimes and so on, it is very difficult. So I guess the question is with Valsecovir and I was especially intrigued. You know, in those and then that one case or cases in the study with the milder anomalies, um, and as child neurologists we follow the spectrum of these, of these children, and there may be some value if we can, um, have lessen the degree of cerebral palsy, lessen the degree of epilepsy, so. The question is really the use of acyclovir and the side effects. Um, you mentioned that, well, that's such a high dose. So how can we work with the dosing? How can we work so that perhaps we should offer this to, um, you know, women, um, I mean, I think ultimately we have to provide therapeutic dosing. Um, providing non-therapeutic dosing not only still has risks, but, um, isn't going to have the benefit. So if we, we're gonna do it, we need to do it with the doses that are, are clinically studied and at least for other diseases and are accepted. Um, I mean, I think, you know, again, the risks of acyclovir are relatively low. They're not. 0, but they're relatively low. Um, if you can. Convince a patient to take these, I think it's like 8 pills a day. It's, it's a lot, uh, multiple times a day and get buy-in, which oftentimes you can in these patients because they're looking for anything they can potentially do, then, you know, again, I think we've maybe adopted it early, but that doesn't mean that it's wrong, um, because you're exactly right. Even if we're not gonna take a baby from being, um, You know, having X, Y, and Z to being completely normal, maybe we'll take that baby from having X and Y, um, and take away Z. Um, so the next question is for Doctor Nagaraj. With the ongoing, this is from Doctor Ford, with the ongoing rapid improvements in post-processing of MRI imaging to improve image quality, do you think you'll be able to go back and include the currently excluded patients in the future? Um, OK, so yeah, I, I guess the short answer to that question, so. Um, so where do I, so for the 2D measurements, we were able to include all the patients, um, enrolled in the study, and 2D measurements are what we use in clinical practice. For the 3D, um, analysis, uh, the question is, could we apply SVR. retrospectively, um, and improve image quality, I think the answer is no, we've already, they already used SVR in both, um, so as of now, No, but, uh, in the future, if we have faster imaging, I think faster imaging is, is kind of what we strive for in fetal MRI. If we acquire the images faster, we get less fetal movement and better image quality. So maybe in the future if we have faster sequences and then I'm, I'm optimistic that SVR can be um Used in routine clinical practice in the near future once the um processing pipelines have been streamlined such that the images can get to the workstation in a reasonable time frame. Um, the next question is for me, from Doctor Akemba B Akebi. We need a good animal model of congenital CMV infection in order to assess potential therapies. Is there ongoing attempts at pre-clinical studies of medication slash interventions? Uh, the short answer to that is that I don't know. Um, I focus on the clinical studies, uh, but I. I would be very surprised if there aren't, particularly given the interest around vaccines. Um, I'm sure that, you know, when we talk about development of something like a vaccine, they don't just talk about the effects of that, you know, it's not only the vaccine itself, they tend to kind of, these pharmacologic studies tend to involve all sorts of things that they're looking at. So I, I would be very surprised if there isn't something, but I'm not familiar with that. So is there at this point, um, from a clinical standpoint, is it standard that you offer valacyclovir to every, um, pregnant woman or a great question. I would not say there's any standard of care whatsoever and you have to. Remember that we kind of have different groups of people that present with concerns for CMV, so one would be the mom who says, my germy little child from daycare, uh, is coming home and there's been an outbreak of, of CMV we think at her, um. Her daycare, you know, have I been, have I been exposed before? You check her, she has not. Do you treat her so you try to prevent fetal infection if she's infected. I would say no. Nobody's really thinking about that at this point. Um, what if you have severe brain anomalies? Have we already lost our ability to make a difference? So maybe that group is exactly the one that Rebelo et al looked at, which is the babies that have more mild findings, um. And maybe we can make a difference, but there really is no standard of care at all at this point. It's all either being done in a research setting or on a, you know, case by case, very, uh, provider dependent basis. Doctor Nagaraj, you know, I, this is just a random thought that really has nothing to do with opioid exposure in pregnancy, but You know, as someone who works at a fetal center and sees your reports all the time, you often in the MRI comment on subjectively increased fluid, and I say, well, I don't really know what that means. I'm gonna see if there is objectively increased fluid. Do you know if there's standards for amniotic fluid with MRI? You know, I, I haven't, I haven't found any though I haven't looked in a while. I mean, that, that's certainly something that we could look at. Um, I mean, if, if, if there's interest like DVP on MRI like. Describing a technique correlating with the ultrasound. I know, I know I have a, a colleague, uh, at Boston or MGH who developed, you know, it's, it's another one of these, um, post-processing things where she can give, get an amniotic fluid volume from, you know, the, the like the fiesta images of the uterus, but, um, That's not ready for prime time yet. So, like a lot of these things, I mean, they're interesting and you think, cool, it would be nice to just report an amniotic fluid volume in my MRI reports, but maybe in the future. The fiesta images are my favorite, um, but it may not even need to be so, I mean, yes, the, the more. Uh, fancy you get, the better, but, you know, like you said, maybe just the deepest vertical pocket, maybe add up an AP transverse and pillow caudle, um, deepest pockets would be sufficient. Totally. No, let's, uh, I'll, I'll take a look at, yeah, yeah, we can find a fellow. Anybody who's on this line that's not here is not allowed to take that. It's our intellectual property. Um, well, if there's no other questions, I think we can end the, uh, webinar. We really appreciate everybody's, uh, attendance and attention, and I think it's been a very interesting series, um, and I hope that you all. Uh, found it to be as well and thanks to our presenters. Thank you, thank you all. Thank you.