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#137 - 📑 Journal Club 53

Hello Friends 👋

We are excited to bring you a new episode of Journal Club. This week, Daphna and I cover a lot of trendy topics, including a new test for the diagnosis of preeclampsia, long-term neurodevelopmental outcomes, steroids and cerebellar growth, and more. We hope you enjoy this episode.

Happy Sunday!


The articles covered on today’s episode of the podcast can be found here 👇

Ames SG, Delaney RK, Houtrow AJ, Delgado-Corcoran C, Alvey J, Watt MH, Murphy N.Pediatrics. 2023 Jul 1;152(1):e2022060975. doi: 10.1542/peds.2022-060975.PMID: 37357731

Synnes A, Chera A, Richter LL, Bone JN, Bourque CJ, Zhang-Jiang S, Pearce R, Janvier A, Luu TM.Children (Basel). 2023 May 14;10(5):880. doi: 10.3390/children10050880.PMID: 37238428 Free PMC article.

Neel ML, Conroy S, Srinivas R, Taylor HG, Stark AR, de Silva A, Busch T, Maitre NL.Pediatr Res. 2023 May 22. doi: 10.1038/s41390-023-02656-5. Online ahead of print.PMID: 37217606

Gentle SJ, Rysavy MA, Li L, Laughon MM, Patel RM, Jensen EA, Hintz S, Ambalavanan N, Carlo WA, Watterberg K; National Institute of Child Health and Human Development Neonatal Research Network.JAMA Netw Open. 2023 May 1;6(5):e2315315. doi: 10.1001/jamanetworkopen.2023.15315.PMID: 37256621 Free PMC article. Clinical Trial.

Warmerdam LA, van Wezel-Meijler G, de Vries LS, Groenendaal F, Steggerda SJ.Neonatology. 2023 Jun 28:1-9. doi: 10.1159/000531075. Online ahead of print.PMID: 37379806 Free article.

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The transcript of today's episode can be found below 👇

Ben 0:56

Welcome Hello, everybody. Welcome back to the incubator podcast is Sunday. We have a journal club episode ready for you. How are you? Definitely.

Unknown Speaker 1:08

And doing well. We left Journal Club,

Ben 1:11

Journal Club is fun. Yeah. It seems like it's been a busy. It's been a busy season in the publication industry.

Speaker 1 1:19

Yeah, people are, I don't know, rebounding after like the few years of COVID locked down. I don't know.

Ben 1:26

There's a lot of very interesting papers and lots of opinionated paper as well. That's something that's interesting as well. But yeah, things are good. Not sure if you have any, any updates for for the audience, anything you want to talk about?

Speaker 1 1:42

No, just that I think we did this on the board review podcast, but that we are welcoming new, new trainees to the podcast who might be listening for the first time. That's all some new new first year fellows. Maybe that's true.

Ben 2:00

That's true. We tried to welcome everybody last week with an amazing interview with Dr. Schmidt. We hope that her words were inspiring. But yeah, welcome to all the new fellows. Welcome to neonatology. If you are interested in doing anything with the incubator, you can always reach out to where we're always expanding. We're always looking for people who want to work with us. So yeah, don't be shy. For sure. Okay, then I'm going to stop browsing this textbook that I'm looking for stuff in, but it's okay. All right. When textbook I'm looking at, I'll tell you offline, it's not. Alright, I'm going to start I'm starting my journal club, I start, you know, I have an interesting, two interesting papers that I want to talk about. I'm going to talk I'm going to bundle them together. Before I actually know what let's flip the switch, flip the script a little bit. Did you see that this paper came out, I wanted to shoot them just gotta mention it since since we're at the beginning of the episode. Okay. And again, it goes back to something we say all the time, which is that stuff gets published in journals, you're not following. I got this paper sent to me by our medical director, Mitch Stern, who? Yeah, cool. Thank you for sending that to me. But basically, it's a paper that was published in JAMA ophthalmology, which I don't regularly follow. And, you know, and I follow a lot of papers, but a lot of journals, but this is called prognostic value of parenteral nutrition duration on the risk of retinopathy of prematurity. And it's a retrospective study of like 11,000 kids, and I'm going to not go into the details, but it basically makes an association between parenteral nutrition for 14 days or more, and an associated increased risk of developing ROP. And they have this screening tool that they talk about in the paper called Digi rope digital opti grp 2.0, which they're using to screen for ROP with, like they're describing as having like 100% sensitivity. And, and I'm wondering if that's going to translate into some some form of criteria showing up in an AP policy statement or something along those lines. But it was interesting, there's an association that I had not perceived would be really related to the development of ROP.

Speaker 1 4:37

You're saying might it might add a new criteria for screening? Yeah.

Ben 4:44

So that I don't know and I haven't gotten I started I got the paper today. I haven't gotten into it into in details. But

Speaker 1 4:53

just it's just a it's just a reminder about inflammation in the body. Right and the way I describe it to people You're insane, like pretend like there's a fire in the kitchen. Right? Wherever the inflammation is. Yeah, but there's smoke everywhere, you know, like it's

Ben 5:08

surely feels warm in the living room. That's right.

Speaker 1 5:13

Ah, yeah. Okay. So So you mean less time on TPN? Good, I guess,

Ben 5:20

I guess or Yeah. But I mean, 14 days isn't 14 days is not a lot. But it goes, it goes back in this direction, right of? Yeah. So I haven't looked at the AMA haven't looked at anything about this paper, meaning it I, I don't want to get into confounders. And

Speaker 1 5:37

like, you're right. I mean, why did you need more than 14 days, right? Yeah, exactly how sick were you?

Ben 5:43

I got a little bit confused, because they have like all these, these, these, this new screening tool that they're developing with that anyway, so it gets tricky, but I just wanted to bring it up to people's attention. Alright, with that being said. With that being said, I'm starting with a paper that I've been meaning to review on the podcast, it's called. It's published in the journal called children coming out of Canada, first authors and signs, the amnesia VAs on the paper as well called the redefining neurodevelopmental impairment perspective of very preterm birth stakeholders. And I thought that was very interesting paper. I'm going to skip the background because I have two papers I want to present on this topic. So I'm going to try to be quick. But the question they were trying to answer was, can we identify outcome measures that are meaningful to parents of children born very preterm? And the premise of that statement is that maybe the way we measure things and what we say matters to us is not something that would matter to parents. So what they did is that they leveraged the strength of the Canadian follow up network, the CNN fun, I asked, actually, Gabriel altered who hosts the French podcast with me and they do call it the CN fun. And it's a very robust follow up network that they have in Canada. And they're looking at what severe nose or mental impairment is defined as in in their network. And that really entails usually a Bailey skills of infant and toddler development, usually the Bailey three, looking at cognitive motor language or general adaptive cognitive score below 70. They're looking also at the need for hearing aids or cochlear implants. They're looking at bilateral bilateral visual impairment, or cerebral palsy with a gross motor function classification system level three or higher. So how did they figure out what mattered to parents so they basically had 10 easy to understand clinical scenarios that were created to align with the CN fund definition of severe and other mental impairment, right. So they use their definition and they try to create some scenarios that would meet those criterias. Six scenarios captured children with a single severe impairment, cerebral palsy, like a barely three motor language or cognitive score less than 70 hearing or visual impairment. Five scenarios represented the most common combination of impairments observed in this en fund database of very preterm infants. And finally, there was an 11th scenario used as a control which basically described a typically developing child. So I'm gonna give you a few of these example because they were very well written. So there are like three sentences. The first scenario which is supposed to represent a patient with cerebral palsy is going like this, and I quote, Jamie has an 18 month old child, he can sit with support, roll and creep on his stomach, he has stiff legs will very likely use a wheelchair for longer distances at school, he can see and hear normally, he learns like other children his age and likes to play with other children, he can follow simple directions and use words like other children his age, and I think it's always interesting because we think of cerebral palsy like one entity, but we don't, it's hard sometimes to put it back in the context of everything else that could be normal about the patient. Let's, let's get let me give you two more scenarios. The one about cognitive impairment. Max is an 18 month old child he likes to play with toys for younger children tend to 12 months, he takes more time to learn new skills and needs more help doing so compared to other children his age, he can see and hear normally he walks he runs and moves like any other children his age, he can follow simple directions and use words like other children his age. So as you can see, do you want another one?

Unknown Speaker 9:39

Sure. Yeah. More example.

Ben 9:41

Another one is on language impairment. It's like it says Lina as an 18 month old child she says mama Dada and one other word which is less than is expected for her age does not point to her ears and eyes when asked. She does not use words to make her wants known but cries or grabs you instead, she can see and hear normally She walks, runs and moves like other children her age, she learns, plays and explores the environment like other children her age. So very interesting. And so for each scenario, basically what they did is that the respondents were asked whether the fictional child did or did not have a severe health condition and to rate the severity of the health state on the scale from zero being worst possible health to 10 being the best possible health. And in terms of the participation, I think you might be interested in that because they, they did something that was quite innovative they did. They did a pilot step where basically parents of children born at less than 29 weeks of gestation, attending clinic visit, between three and five years of age, at the unit of our program in Vancouver, Canada were invited to participate. And then during a second step, they did an online snowball sampling method. And respondent eligibility expanded to the Canadian and international stakeholders, which means what is that whole snowball thing that they allowed participants to enroll other participants? And they said, Hey, mom, dad, share this with your people that you think might be interested in? A snowball? Yeah, the online you

Speaker 1 11:08

know, those parents can reach other parents faster than we can

Ben 11:11

100% and you'll see the numbers. Yeah. Yeah, it's great. I thought it was so smart. So 827 So let's go some some of the results right. 827 participants responded to a total of 4553 clinical scenarios. It's interesting that in English scenarios is plural. It's like scenarios. In French you don't see scenarios you see some scenery, which is interesting, like you cactus. Anyway, interesting observation in the middle of charcoal. I'm sorry about that. 62 parents attending the neonatal follow up clinic in Vancouver completed the questionnaire, and then in the snowball step, 765 stakeholder answered the question 442 In Canada, 323 International NGOs going back to that idea that the snowball recruiting is kind of interesting. The respondents age are very, very sorry from less than 20 years old to a maximum of 65 years with 47 of the participants between the age of 30 and 40 years old. Most participants 60% of them were parents, children or family members and 28% were healthcare professionals. So let's talk a little bit about the severity rating. As expected the typically developing child when that was supposed to be the control was perceived to represent the best possible health state with a median score of 10. The scenario which described a child with cerebral palsy, and language delay was perceived to be the lowest rated health condition with a mean difference from the control of minus 4.3. Whereas the scenario describing a child with significant cognitive delay showed the smallest mean difference of minus two. For eight of the 10 scenarios, were presenting what we would define as severe neurodevelopmental impairment, fewer than 50% of the respondents perceive the health condition as severe. I mean, I think that's very interesting. Yeah. The scenario representing a child with cerebral palsy and language delay was considered severe by the largest percentage 55% and a visual impairment rated severe by 51% of respondents. This scenario representing a child with cognitive delay was classified as severe by the smallest proportion of respondents which was less than 5%. Which going back to something that Raj mentioned on the on the podcast last week, which is that she she doesn't know if we should look at cognition as closely as we are. Non parent, healthcare professional former children of children born preterm teachers, researchers, trainees answered where answers were similar to parents meaning they were concordant except for the cerebral palsy and language delay scenario, where non parents were that the scenario slightly lower than parents with a mean difference of 0.36. The respondents gender, age language of survey completion, were not associated with survey response. And so in conclusion, the authors are saying that this study shows that the assessment of severity based on clinical scenarios really differs from commonly used definition of severe no other mental impairment used in outcomes research. Secondly, what it shows is that the problem of using a composite outcome to describe neurodevelopmental impairment is really, I guess, problematic. Optimizing the way neonatal outcomes are reported is essential, and that further research is needed. So I thought, I thought that was a very interesting paper. very cleverly designed.

Speaker 1 14:37

Have you have you read pepperoni pizza and sex?

Ben 14:41


Unknown Speaker 14:42


Ben 14:43

it's very much in line it's very much in line.

Speaker 1 14:45

Yeah, and all of the data of of parents of medically complex children I mean, tend to fit with this with the with this data, but anyways, that was like a small it's like a one page Ah, maybe one and a half page by

Ben 15:03

sounds like the title of a book. But it is really short

Speaker 1 15:07

paper. It's actually it's like a story story. Since we're all I would recommend people, you'll usually get to the show notes.

Ben 15:16

I'm actually I don't know if I'm going to link it, but I'm going to do something even better, I guess is that if you are if this is remotely peeking your curiosity, Episode 57 of the podcast is the interview that we did with Doctor engineer. And she and the link to that article is actually in that episode page. So go check it out. Episode 57 of the incubator podcast, great podcast, you should listen. Yeah. Okay, one more quick paper that I wanted to mention, again, talking about neurodevelopmental outcomes. It's called Bailey trajectories predict school readiness better than single assessment and formerly very preterm preschoolers. first author is Maury. Lauren Neil, last author is Natalie met, and it's in pediatric research, it's coming out of a group in the US. And, and there's in the background of that of that paper, I would suggest, especially in your fellows, you should read it. It talks about like, I actually wrote down a few things and mentions how development is a complex construct that is partially controlled by genetic mechanisms, but its sequence can be interrupted by lack of expected environmental inputs and disrupted by neural insults, poor nutrition or atypical environmental signals. I mean, that's like to me, it's so it's so well said. Another thing that I noted from this background is mentioning how even without adverse events, development, from infancy to school age is rarely characterized as a straight line across any domain. Yet, despite this, outcomes of neonatal interventions are often assessed for efficacy at a single point in time, at two years of age, usually corrected. However, a single assessment period during assessment a single assessment during a period of maximal plasticity and vulnerability may not accurately predict long term outcomes of children in real world setting, undermining the quantification of neonatal or obstetrical intervention efficacy, limiting practitioners ability to counsel families, and inhibiting medical and social systems from matching services to need, again, are powerful assessment. They do mention some prior data showing that some studies have showed that a two year BLE score does correlate somehow with the Wechsler full scale intelligence quotient. However, it has been widely reported that the dsid sometimes can be the Bailey's can be a poor predictor of longer term outcome. So without going into further details, the question that needs to be asked is would multiple Bailey measurements taken in the first three years of life be better predictors of outcomes at four to five years? And this is something that was very curious that I was very curious about reading because I tried to do this myself. And I'll tell you why I ended up not doing it. So the study design is that they looked at infants who were born 30 weeks of gestation or less each child had to had completed one to five baby threes between the ages of six months and 35 months. Children were excluded if they had severe vision, hearing impairment, genetic disease to impact cognition, or if the caregiver did not speak English. Obviously, these have to do with the administration of the Bailey's linear regression models were used to describe association of the trajectory with preschool readiness. And they looked at the Bayley three cognition receptive and expressive language, scaled scores to predict the DS the DS, numeracy, the global cognitive assessment, the topo phonological awareness and so on. The way they did this was interesting was that initially, right? They were wondering, does multiple Bailey's make an impact both on the group level, like if we're looking at the whole population, or whether we are looking at an individual level, okay. And so when I remember when I did this, when I did this study on longterm northern mental outcome, we had a large sample of patients. And I thought maybe if we do multiple measurements, maybe that will be better predictive. But as soon as I looked for babies who had gotten multiple measurements,

Unknown Speaker 19:20

the sample size decreased Signet,

Ben 19:23

shrunk definitely a big time. So I was not surprised to see that the study that we're talking about today only included 53 infants,

Speaker 1 19:33

similar datasets that have been reported for that.

Ben 19:37

You have great idea, then you run the data, and you're like,

Speaker 1 19:40

painstakingly you collect all this data, right into spreadsheets, and then you're like,

Ben 19:47

thankfully enough, we were able to publish the data for the one measurement but yeah, but I was not able to do the study that I'm reviewing today. And over half of the mothers in that in that cohort did not have a college or A more advanced degree. So we're going to look at it in two steps. And then I'm going to give you the year. Step one is looking at individual and group average trajectories. And so what they were they were reporting is that on average, infants had 3.6 Barely scores available, the addition of a barely changed to models. Looking at long term outcomes, including only the initial scores improve the model fits for barely receptive language for expressive language and for gross motor scores, which I think is interesting. Another interesting finding is that the estimated trajectories from linear mixed models that included both the initial Bally score and change in various scores for cognition, receptive language, expressive language and gross motor predictor, predictor variables, revealed substantial variability in the individual trajectory, when contrasted to the average trajectory. What that means is that if you take them as a group, and you do the average of how the bellies are progressing, you're going to get sort of a flatline. But when you're doing individual trajectories, babies are going in opposite direction. And if you look, I think it's I forget, I think it's figure one. But if you look at the ones specifically on Bailey expressive language, you see that when you're looking at them as an entire group, the thick black line is pretty much horizontal, but individual trajectories are going in all sorts of directions. So, the step two of the project was to do a linear regression model to describe the association of estimated belly three trajectories from the first step to preschool readiness, and the results from from this this part of the analysis indicated that having both estimates for initial belly and belly change over time explained that more variability in the readiness explained more of the scores at preschool age than either variable or alone on the different Bailey domains. So for example, the model that they devised containing both the belly cognition initial score, and the change in cognition explained 63% of the variance in the GA s GCA. Score. The DGS CJ score is the differential ability scaled scale sorry, general conceptual ability. However, less than 1%, and only 26% of the variance were explained by models containing either the Bailey cognition initial score, or just the change in Bailey cognition respectively. Each model that they use differentially predicted preschool readiness outcomes. And so for example, I think people should check out the table four, because four models containing both Bailey cognition and the change in cognition as predictors, a one point higher initial Bailey score corresponded to an estimated like 6.8 point higher on the DS, CG GCA after controlling for Bailey change over one year, and similarly, a one point higher change in the cognition over one year corresponds to an estimated 18, higher DDS GC score after controlling for the initial Bailey score. So I'm not going to get into too much more detail if you're interested. It's kind of a tricky paper to go through. But the conclusions are interesting that the bill is there remind you in the conclusion that the Bailey is a developmental evaluation tool, not a direct measure of intelligence and should be interpreted cautiously. The present findings suggest that the utility of the Bailey as a predictor of future school readiness is enhanced by administering this measures across multiple follow up points, and assessing change as an additional predictor of outcomes, not just getting what the score is. But what is the change. And when you input. Like we've said, when you input, the initial bail, the score and the percentage change over time, it makes things much more predictable. Again, good luck is already hard to retain these infants in follow up, but But yeah, very interesting set of papers.

Speaker 1 23:50

Well, and that's why for most of our neonatal follow up, not all right, we have some really long term data sets of developmental follow up, which are phenomenal, like the cap trial. But you know, for us trying to really evaluate long, quote unquote long term development that whatever 18 to 24 months or 24 to 36 months is just not it's just not enough information. No, no. Okay, well, in a similar vein to your first paper, I wanted to do a quick paper, and that was actually posted by Betsy P on the founder of hope, for HIE that this was an interesting paper called perceived disability based discrimination and health care for children with medical complexity. The lead author is Stephanie Ames. And it's in pediatrics. So it's not necessarily in the neonatal population, but I still thought that there were some lessons we can take from it. There's also a thought provoking commentary on the article in the same issue of Pediatrics, anybody's interested in looking at that. But basically what they did is they conducted these kind of semi structured interviews with caregivers, caregivers of children medical complexity and disability, which they had recruited through national advocacy and research networks. The eligibility participants are parents and caregivers of a child's medical complexity who are at least one year old, and reported a disability related to physical cognitive communication and or social functioning. And the medical complexities were defined as having more than or equal to two organ systems affected. And either technology, tech dependency, functional impairment or high healthcare resource utilization. And the survey is particularly we're targeting caregivers that perceived that their child had experienced this kind of discrimination in a healthcare setting because of their disability. What is that? I mean, that's, that is a perception. Right, but I think once you hear some of the quotes, you won't be surprised.

Ben 26:05

No, no, I'm not questioning. I'm just wondering, I'm just wondering, I'm just wondering what that's what Yeah. Avoid for the course. Because I'm I guess my question is, what does that look like? Practically?

Speaker 1 26:16

Okay, I'll tell you. Yeah, okay. Um, in total, they had 30 participants from for from 15 states. And the majority of caregivers were female, 25 to 30. They ranged from 2026 to 55 years old. The majority were married 20 out of 30. And the children ranged from age 18 months to 18 years. And most caregivers reported that their children had greater than 20 healthcare encounters annually, and were insured through Medicaid. So it sounds like a pretty medically complex group. But basically, you know, they kind of did this thematic analysis. And they had these six major themes emerged to provide this kind of conceptual framework. So three major themes describe drivers of discrimination, and they included lack of clinician knowledge, clinician apathy, and clinician assumptions. And then three themes kind of described, then what were basically the consequences or the manifestations of discrimination, and they were limited access to care, substandard care, and this term dehumanization. So I'll give you some examples of these types of first, kind of the drivers of discrimination. And I have selected some that I think are most pertinent maybe to our population, though, they provide many more quotes. So things like clinical knowledge. So what I this quote, what I found is we got a lot of blanket statements about the non viability of this diagnosis and the hopelessness around the diagnosis. But none of the providers actually knew what to do or to treat the diagnosis, or knew much about the diagnosis. So they felt like the clinicians didn't really know but once they decided it was a, quote, unquote, non viable, or had a really high rate of disability, that they would give these blanket statements about what you know, like maybe non escalation of care. And they had this other driver clinician empathy for patients with disability. And examples of that were my perception is that clinicians wanted to take care of a patient that didn't have a severe special need. I don't know, sometimes it seemed like, they didn't even care to treat my daughter. They acted as if we were a waste of resources, or they were gatekeeping. They were being influenced by their perception of disability or kids with this diagnosis, they act as gatekeepers, and you're trying to do everything you can to knock that gate down. They also mentioned some of these clinical assumptions, so assumptions about patient based on diagnosis or disability rather than individualized care. The quote was, and because he doesn't make eye contact, part of the things that are diag part of his syndrome. He's not a typical child that's going to look you in the eyes when you're talking to them. And so just because he wouldn't make eye contact, they assume that he's not verbal, or if he doesn't make eye contact, they assume he doesn't understand what's going on or doesn't understand what's happening, or what they're saying. And that's really case. There was also things about assumptions regarding quality of life. So I've had a few remarks made by my doctor, basically, that it was inhumane for someone to be disabled and for you to support their life knowing that they're going to be disabled, which I can tell you right now. Now, my daughter's disabled and she's literally the happiest one year old I've ever met in my life, she smiles and plays and interacts more than any one year old I've ever met. And then finally, a lot of times these clinicians are counseling you on these decisions. And they see such a small piece of that person's life that either only see them when they're in the hospital or when they've been at their sickest. And so they see them for just a short time. So I don't think it's necessarily bad intent, they don't have a positive impression of disabilities, or medical. And then they gave some quotes about kind of the outcomes and these perceptions of discrimination, so limited access to care. And a lot of these were being made to feel unwelcome in medical practice, like an outpatient clinic, so I won't touch on the that too much. But a lot of them were like, inappropriate treatment of pain. So the most common thing we face is the disbelief of medical professionals and medical professionals about pain. Another thing, I think the assumption is pain looks like the baby will pull away pain looks like they'll cry pain looks like that. So they assume if you don't respond to pain that way, but I know it's still painful to her. And it's still aversive some of the things that they're doing. And this worry about dehumanization. So the doctors treat her like she's a vegetable or that she's invisible. They give inappropriate comments to caregivers. The doctor once told me, Well, you can read to your baby, if it makes you feel better, but she's not really learning. And she's not really responding. She responds like a dog. That's literally what he said those were his words. And finally, they mistreated her treated her like a robot every time someone walked in, they treated her like she wasn't even there. So anyways, obviously, you get what she meant, you get it, you see a reset. We know that we have wonderful empathic providers in our neonatal community, but I think our words matter, and I think these feelings of discrimination against disability happen already in the NICU. And I think there's this perception that we can't be honest with parents. But I think we could do both. I think we can be honest, without discriminating against disability. And they do underscore obviously, that there are a lot of other ways other forms of discrimination, inequities in health care, like racial, socio economic, and cultural and language barriers. But obviously, these are multiplied. If you have one of those other you know, reasons for inequity, and there's disability, they felt like they were even magnified. cumulative. So it's just it's a super minor that our words matter.

Ben 33:01

Beyond that, I think it's, I think it's not just a poor choice of words, sometimes it seems like, I think

Speaker 1 33:08

some of these are, some of these are beliefs. Right. And I think it fits perfectly with your first paper there.

Ben 33:14

But I also wonder if the issue with the with the cases that you're presenting is that as medicine has evolved, going back to something that we discuss with Satya and right where everything has such become like such a, we've become such like, like employees at a cash register, like it's like we we bill, and we do something for a purpose. Like it seems like the humanity and the care that supposed to be provided in the company, in the context of a doctor's office of hospital is being lost, because it's like, well, what am I doing here? You know, like, if it's, like, great, and you can still as a pro as a physician to provide care and humanity and that somehow, as it seems like it's completely disappeared. And sure,

Speaker 1 33:56

well, I mean, we've reviewed that paper that basically as your as your scores for like moral distress and burnout, increase your empathy decreases, you just don't have the bandwidth to it's interesting

Ben 34:09

when I was when I was at a I met with, with Rooney, one of the people who spoke as a keynote speaker was Robert groves, who's, I'm not sure he's, he has a podcast, he he's a, he's a physician, but he was talking about like the, the experience that made him decide to go into medicine, and that it was like when he was following his father one morning and he was doing like a house call. And he went to the house of like someone who was struggling with alcoholism and basically, like his dad basically sat on the floor with him and like, put his arm around his shoulder, waited for like 30 minutes and then drove him to rehab. And that this interaction was like the moment it's like, Alright, I want to go into medicine. And I feel like the paper you you presented is showing a complete lack of this aspect of care where no medications was being given no medical intervention really happened, but just this this human condition And then saying, like, oh, we have to be here for another person is completely lost. And that's very frightening. If that's if that's more than just a report and that's actually representing a trend, then that would be very, very concerning.

Speaker 1 35:12

Well, I think you're exactly right. I think sometimes what we do what we always have to offer families is connection, and empathy. And, and, and, and, like this concept of bearing witness that their kid is important. You know, I think especially in the NICU, where some of our babies don't ever leave the NICU and were some of the only people that ever know them. You know? I think that's just so valuable for our families.

Ben 35:45

This episode is so proudly sponsored by Reckitt to me Johnson. Recommend Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive and female portfolio for premature and low birth weight infants learn more at HCP dot meet Okay, okay, so I'm going back to the grind of neonatology talking about hydrocortisone. What I'm talking about a record, it's fine. No, I know. But I think I think you have a different I thought it was a good paper to review because I think it's it's not the same paper. We're not we mentioned that too. But this is called this is a paper published in JAMA Network open called heterogeneity of treatment effects of hydrocortisone by risk of bronchopulmonary dysplasia or death among extremely preterm infants in the National Institute of Child Health and Human Development, neonatal research, network trial, a secondary analysis of a randomized clinical trial. first author is our good friend, Sam, gentle Sam, how are you? And this is with authors from the NIC HD. What the, what they're looking at is they're looking at sec, they're doing a secondary analysis of the hydrocortisone trial done by the NYCEDC. Who's first author was Christie Waterberg. We did review that paper on the podcast, right. And just a quick summary of this paper briefly, right, they gave hydrocortisone four milligrams per kilo per day tapered over 10 Days to a cohort of 400 kids, a 309 year to be precise 402 Receive placebo. And they found that survival without moderate or severe BPD and 36 weeks postmenstrual. Age was not statistically significant. They looked at moderate or severe and other mental impairment that two years, and they found that this was not statistically significant. And so that really sort of made us think of steering away from hydrocortisone, really as one of these interventions. Now, one of the things that they're saying is, well, we've reviewed a paper by Eric Jensen Eric Johnson is actually also on this actual paper that said, Well, you know, the benefits of steroids and in the case of the Jensen paper reviewed a few weeks ago, dexamethasone is really related to your baseline risk, the more you at risk to begin with, the more the benefits of the dexamethasone would be beneficial over the risk. And if your risk of baseline risk of developing the disease in this case, PPD is low, then the side effects of dexamethasone are probably over taking the benefits. And so the bottom line when I'm trying to guess, in a convoluted way trying to say is what Sam gentle and the rest of the team did is trying to understand whether this was also the case for hydrocortisone. And what's interesting is that in the paper by Eric Jensen, it showed that this relationship was really true for height for dexamethasone, but not really for hydrocortisone. So they're saying does so the question they're asking is does the risk of bronchopulmonary dysplasia or death modify the effect of hydrocortisone in extremely preterm infants? We sort of went over the the hydrocortisone paper that was published in the New England Journal of Medicine. Including infants were born at a gestational age of less than 30 weeks, they were receiving mechanical ventilation at study entry between 14 and 28 days. So they were quite sick and underwent mechanical ventilation for at least seven days. And the outcomes were obviously both BPD with deficits and efficacy and no other mental outcome as a safety measure. Now in this post hoc analysis, the primary outcome for the was the recently proposed evidence based BPD great definition with the composite outcome including gridway, two and three BPD or death, so when they're looking at the risk of developing the disease, and if they're using the BPD outcome estimator that is available on the NI CHD website, and they're looking at The cumulative risk of developing grade two, grade three and F. Okay. So they ran the estimator a day of life 14, which is like right before kids got enrolled, and then the sum of an infant's risk of death and grade two or three BP was used to estimate the risk of the efficacy outcome. Okay, so without getting into further details, the population obviously is the same as the hydrocortisone trial. And some of the results are interesting. The mean estimated probability for grade two three BPD, or death on postnatal day 14 in the general population was 54%, with range going from 18 to 84%, and a median of 53%. Now compared with infants within the lower quartiles for baseline risk, so basically they divided the baseline risk into four quartiles. So either you were in q1, and your risk was like 18 to 45%, you were in q2, your risk was like 46 to 53%, you were in q3 risk was 54 65%, or you went to four and your risk was the highest, your risk was like 66 to 84%. Now the kids who in the higher quartiles were shown to have not surprisingly, lower median birth weight 800 grams in quartile one, compared to 630. In quartile four, they were also shown to have a higher median fraction of inspired oxygen on postnatal day 14, they were shown to had more median days of mechanical ventilation exposure. In the primary analysis for heterogeneity of treatment effects and the efficacy outcomes for grade two, three BPD, or death, there was no significant interaction between the baseline risk for grade two to three BPD, or death and the treatment on a relative or absolute scale, the magnitude of the effect of hydrocortisone ranged from a relative risk of 1.13 in quartile one, to 0.94 in quarter four, which basically when you're looking at this, at this curve, it looks like Well, not exactly sure how to describe it, the basically the curve is supposed to look like an inverted s, where the risk really go up if the risk of the side effects of the medication really go up if your risk is low, and the benefits really rise if your risk is high. But in this case, it's mostly flat, because it really doesn't make that much of a difference. The effect of hydrocortisone on the individual components of the composite outcome did not differ by risk quartile. Now, in the analysis of the safety outcomes of moderate or severe noted mental impairment or death, there was no significant interaction between the baseline risk and the treatment on the relative or absolute scale. And so I'm not going to read you the full conclusion as it was written the paper but the conclusion of the paper is that really, it doesn't seem like the baseline risk of grade two, three BPD, or death really modifies how effective or how much you're gaining out of the hydrocortisone. However, the key statement, I think, that I wrote down in my notes about this paper is that in the original hydrocortisone trial, the babies were at particularly high risk for BPD or death. So the samples the sample was very skewed. Remember, they all required mechanical ventilation at two weeks postnatal age to be included in the trial. So they like this post hoc analysis doesn't really include the milder cases. And so the results of this analysis don't really resolve the problem whether there are potential differences in the effect of hydrocortisone in population exposed at an earlier postnatal age, or at different risks of BPD or death. So something to take into account, but obviously an important paper that could be difficult to read because it will references. It references a separate paper as well. So anyway, I think it was quite interesting. And I think for the people who are interested in knowing when we reviewed the hydrocortisone paper I can I can I can give you that in one second. It was in Episode 51 Journal Club, Episode 51.

Speaker 1 44:13

That's it. Yeah. I think they're really trying to answer the question. I'm not sure we did. But they're trying to answer your question like, which BB would benefit most? Right? You know, if we're going to expose babies, we want to be sure that they will get something out of it, you know, yeah. And looking. Yeah, I mean, it just goes back to write more individualized medicine. Okay, well, uh, one of those lines. I have this article, the Association of dexamethasone and hydrocortisone was cerebellar growth in premature infants. Lead author Laura. Warmer, warmer dama but the paper does include dark to debrief. It's coming out of the Netherlands in the journal, neonatology. And the aim of the study was to compare cerebellar growth by looking at a variety of linear measurements on cranial ultrasound, and premature infants who received dexamethasone or hydrocortisone for chronic lung disease, lung disease, and comparing their several cerebellar growth to premature infants who did not receive any corticosteroid treatment.

Ben 45:30

So this is going Daphna.

Speaker 1 45:34

I know you don't because we fight about steroids a lot. Okay, I but it wasn't as bad as I thought it was gonna be. That's what I'll say. Okay. So the retrospective case control study. It looks at infants born at gestational age less than 29 weeks and admitted to to level three NICU. The exclusion criteria were severe congenital abnormalities and severe perinatal brain injury. So interventricular hemorrhage with a Peri ventricular hemorrhagic infarction, patients with post hemorrhagic ventricular dilatation. That required intervention if there was cystic PVL grade two or three cerebellar hemorrhage, so they included a lot of probably a lot of baby. And then infants who received both dexamethasone and hydrocortisone were excluded. So they looked at Babies who got either one course of either and infants. The other thing to note, there are a few things to know about this paper. One of the things to know is that infants who are treated in dexamethasone came from one unit and infants who were treated with hydrocortisone came from a different unit. For chronic lung disease. The controls also came from unit one where the dexamethasone treatment was done, and they did not receive any post nasal corticosteroids. I will give you the criteria for the steroid treatment. And it was the same for both units, which was the need for mechanical ventilation with a high level of supplementation oxygen and a failed extubation at least seven to 14 days after birth. And a standard course of dexamethasone was 2.3 milligrams per kilogram cumulative dose. So that this will tell you they had two different dosing regimens, also dexamethasone. So before April 18 2019, they use the dose of 2.3 milligrams per kilogram cumulative dose. After April 18 2018. They used a cumulative dose of 1.65 milligrams per kilogram, and it was administered over 16 days. Those are the cumulative doses. A standard course of hydrocortisone consisted of 72.5 milligrams per kilogram kilogram cumulative dose over 21 days. So they were using potentially higher and longer doses than some of the units.

Ben 48:11

Yeah, because we use Yeah, we use the we follow the base, I guess, on the Australian data from the dark protocol, which, which, which is basically which at the highest dose we give is in the first few days, and it's like, point one five makes per kilo, correct. So it's a much lower dose, much lower dose, okay, fine. I'm feeling a bit better by this people already. Okay.

Speaker 1 48:33

Right. And the length of treatment obviously, for both regimens is is long, like this hydrocortisone over 21 days. So, they had and you can see that obviously, with the trends in the whole community that they had decreased like their cumulative dose in 2019. So you can see that there are multiple dosing regimens, there are multiple units. So just things to keep in mind. There are also some problems I think, with the baseline characteristics and 346 infants. antenatal steroids bedded methadone were administered in approximately 85% of patients according to the national guidelines, and they were similar in both centers and in both groups, but the DEXA methods and hydrocortisone groups differed significantly from the control group and several variables. So I think that's important to note, as we evaluate this control, infants were older, they had higher birth weights, they were less likely to have a PDA they had less ventilator days and they a shorter length of stay. So in general, it was a much healthier group of babies. There was also mean there was also a difference between groups who received dexamethasone and hydrocortisone, the dexamethasone group was younger. They had a mean gestational age of 25.4 weeks, compared to 26.4 weeks mean gestational age in the hydrocortisone group. They also had smaller head circumferences and lower head circumference Z scores at birth than the height or cortisone group. Okay, those are the baseline characteristics. And I think that's important. As we review the results, there were no differences between the treatment and control groups. In the transverse see these were the kinds of measurements they did, they did the transverse cerebellar diameter, the bipedal diameter and head circumference measurements before the corticosteroid treatment was started. And they also used the corpus callosum to CGM length, which did not differ between dexamethasone and control group but was significantly larger in the hydrocortisone group compared to controls something else to note, but they found overall that the TCD, the transverse cerebellar diameter, the by bridle diameter and the CCFL, which is a corpus callosum for Stygian length, as well as the head circumference. Growth were all slower in infants with dexamethasone. However, after adjusting for the propensity score, only the transverse cerebellar diameter growth remains significantly slower and DEXA best the group, infants who received hydrocortisone had slower TCTs, the transverse cerebellar diameter and by parietal diameter, but they actually had faster corpus callosum to CGM length and head circumference growth. After propensity score adjustment, the transverse cerebellar diameter growth remained slower. And the CCFL growth was faster without differences in BPD, and head circumference growth. When you compare dexamethasone and hydrocortisone to one another, the bipedal diameter growth was slower, and the CCFL growth was faster in the hydrocortisone group. So overall, while even if you adjusted for kind of the acuity of the babies, and it looks like the cerebellar growth was still affected in babies who receive postnatal steroids, other interesting facts, and then I'll hear your thoughts the postmenstrual age, obviously, and head circumference, the square of birth positively influenced all measurements. That's not surprising. In addition, female sex was positively associated with the bipedal daily diameter, the CCFL, and head circumference measurements.

Ben 52:38

No, I mean, I think I think it's just a good. I mean, again, I think the doses were high, I think. And I think that it's just it's a reminder that this is not benign. I mean, we're so excited to get the pulmonary effects of steroids that we may tend to overlook the the delayed negative effects of steroids on the brain.

Speaker 1 52:59

Yeah, and it's always a balance, right? Yeah. Because we know that there's so many things associated long term outcomes, the long, so that's the that's the balance. Is it longer ventilator days versus the exposure to the steroid?

Ben 53:12

Yeah, yeah. Because and we know that each ventilator days associated with worse outcomes neurologically, so it's, it's really a trade off. And, and I think, I guess my takeaway from this is, don't, don't stop trying, I think sometimes you can, before we even attempt to when we can say I'm guilty of that as well. We can say okay, I'm just gonna start some steroids, but maybe give it a go before. Yeah,

Unknown Speaker 53:41

really prove prove that they need it?

Ben 53:43

That's right. That's right. Okay, I have one more paper. It's not a neonatology paper. Actually, it's more of an OB thing, but it's gonna matter for us. I was I was pulled towards this paper based on an article in The New York Times. And the New York Times Health Section had an article titled A blood test predicts preeclampsia in pregnant women. And I think that's something that we should probably be aware of as neonatologist that the paper that they're referencing is called circulating angiogenic factors level in hypertensive disorders of pregnancy. It's published in the New England Journal of Medicine evidence. It's like, almost like an off it looks like an offshoot of the New England. And anyway, first author is Ravi to Dani. And, and I think it's important for us to know about this especially I think, because this is going to be something we're going to be discussing with our OB colleagues, especially around the time of prenatal consults. Everything about this paper is very interesting. The background mentions obviously that preeclampsia is a hyper tensive disorder of pregnancy that affects approximately 5% of all pregnancies, and remains one of the leading causes of maternal and neonatal morbidity and mortality. tea in the United States. For those of you who haven't followed the news, obviously the recent reports of maternal mortality in the US has been causing a lot of stir, it's way higher than it needs to be. And preeclampsia is obviously an important morbidity that is at the could be one of the multiple morbidities at the cause of this. And they do mention that in the background, saying that the rates of hypertensive disease of pregnancy, dis hypertensive disorders of pregnancy in the US have been increasing, and again, largely to greater prevalence of chronic hypertension and other comorbidities. The goal of the study was to check whether the levels of soluble like tyrosine kinase one and placental growth factor PGF could be helping to stratify the short term risk of developing preeclampsia with severe feature in women with hypertension hospitalized in late pregnancy. So this was a multicenter, blinded, prospective study in 18 centers in the US some tertiary and some community hospital. They enrolled prospective mothers between the gestational ages of 23 to 35 weeks with hypertensive hypertensive disease of pregnancy. Interestingly enough, I think something that we need to be aware of is that multiple gestations and women on Heparin were excluded because of the potential effect on the SLM form of tyrosine kinase level. So it seems like these specific cases might make this ratio not usable. And somebody says something we deal with commonly. So

Speaker 1 56:41

something's and they're more likely to have preterm delivery. Yeah,

Ben 56:45

yeah, no. Yep. The primary outcome of the of the study was the development of preeclampsia with severe feature. secondary outcomes included a lot of things, most interestingly, maternal and fetal slash neonatal adverse outcomes. So since we're doing board review, as well, on a separate podcast, the question is what constitutes preeclampsia with severe feature, and it's basically any one of the following severe hypertension, which is a systolic above 160, or diastolic above 110. On two occasions, thrombocytopenia, platelet cyst and 100, impaired liver function, persistent, severe right upper quadrant pain, a progressive renal insufficiency, or creatinine that's rising above 1.1, pulmonary edema, new onset cerebral visual disturbance, or headaches, and any one of these following constitutes severe features. So the study was conducted between 2019 and 2021, they had a total of 1002 women 299 were included in the derivation cohort, and 715 in the validation cohort. So basically, they separated they created a derivation cohort where they found out like, what is the right number, what is the right cutoff for the test, and then they tried to validate that in the rest in the 700 other women. And they said that this, I'm not gonna go into the details of the population, but it's broadly representative of the population of pregnant women with hypertension in the US. And I think that's important as well. So in the derivation, cohort, 220, women were included, the incidence of severe preeclampsia with severe feature within two weeks was 31%. The median SFL T one to PGF ratio differed between women who developed severe preeclampsia within two weeks, which was about the level was about 200, with a range from 53 to 458. From those who did not, and there are the mean was six with an entire quartile range ranging from three to 26. And so the author said that the SFLC, one to PDF ratio, and again, just for the sake of clarity, that is the soluble form, like tyrosine kinase one over the placental growth factor, but I'm not going to see those out again. So, the SF LT one to PDF ratio of 40 or more provided prognostic performance estimated of 81% sensitivity and 81% sensitivity specificity. At this cut off, the positive predictive value was 66%. And the negative predictive value was 90% for the primary outcome, and then to make sure that this was correct, then they validated this cut off in the cohort of 715 women. So the incidence of preeclampsia with severe feature in the validation cohort was the same 33.5% close to the one in the in the derivation cohort. And the median FLT one to PDF ratio were consistently elevated in women who developed preeclampsia with severe feature, finding evidence in at all the different clinical sites. The women who developed preeclampsia with severe feature had an FLT one to PDF ratio approximately 40 times higher than those who did not. Very impressive. The comparison here is 291 versus seven, obviously, statistically significant. Based on these data. The authors concluded that nflt One to PDF ratio of 40 or more when both SF 31 en PDF are measured in picograms per milliliter, provided the prognostic performance of 94% sensitivity 75% specificity yielded a positive predictive value of 65%, and a negative predictive value of 96%. For the primary outcome, we're still restricting the analysis to women with a history of chronic hypertension, the ratio of 40 or more yielded positive and negative predictive value of 59 and 94%, respectively. A few more things and I think that's what I guess I have a few more things I'm not I'm not ready to be done yet. The receiver operating characteristic curve analyses were used to compare the predictive performance of the rate of the FLT one to PG F ratio against standard of care assessment, such as like when they measured the blood pressure, the liver function tests, the platelet counts, and so on and so forth. And the AUC of the ratio itself was 92.92. whereas all the other measurements had an AUC of about point seven, five, so it performed much better than any of the other measurements for preeclampsia with severe future. There were 288 adverse fetal and neonatal outcome, the SFLC, one to PGF ratio was 30 times higher in women with an adverse fetal and neonatal outcome compared with those without the composite adverse fetal and neonatal outcome for more prevalent in the group with an SFLC, onesie PJF ratio above 40. With the group with a ratio compared to the group with a ratio of less than 40. They were nine fetal deaths, eight of which were in the group that had a ratio superior to 41. More thing that I wanted to mention was that and that's an important that's probably one of the most important one for us is that women with an SFLC, one to PDF ratio, superior to 40, were more likely to deliver within two weeks compared with women who had a ratio below 40. So the summary is that this demographically diverse cohort of pregnant women with with hypertension in the US hospitalized between 23 and 35 weeks, the serum SFLC, one to PGF ratio of 40. Predicted or more, I guess, develop the development of preeclampsia with severe features, adverse outcomes, and delivery within two weeks of testing. The New York Times article is quite good as well. We'll link into the in the show notes, but quite a revolutionary development in Perinatology.

Speaker 1 1:02:57

Yeah, I think it's excited. Even even more so for the beat for the Dyads that it confirms preeclampsia, I think it's most exciting for babies that it could rule out preeclampsia, and may get a little bit more time.

Ben 1:03:13

Yeah. And most of our babies who are born due to preeclampsia, usually preeclampsia with severe feature. So this is like this is for a lot of our patients. And now it doesn't I mean, in the background, they do mention, we still don't have a good treatment for this, like delivery of the fetus. Yeah, but But it's interesting to look at as OB is getting a better handle on preeclampsia, it's, it's we're going to be able to, to know who's more at risk than another. Well, that then leads to maybe new development in, in management, and there'll be I'll be very interesting. So the future is exciting from that standpoint. And I think you know, what, if I remember correctly, and correct me if I'm wrong. I don't know if you have the board review books next to you. But if you go in parasitology, I think Brodkin Martin mentioned that ratio as like something that was being investigated. Really? Yeah, thanks. So

Unknown Speaker 1:04:04

I have this memory. Right here.

Ben 1:04:06

I know they're in the other room for me. But

Speaker 1 1:04:11

while I look at this, I think we did just we did review it earlier this year. And you did. Yeah. I mean, we

Ben 1:04:17

have the benefit of reviewing it frequently, but it's still it's one of the things that I used to dismiss because I'm like, well, it's not proven. It's not gonna get asked on the test. So I'm not I'm not committing this to memory, but I think it was there if I'm not mistaken.

Unknown Speaker 1:04:32

To be so hard to find.

Ben 1:04:35

It's at the end of the preeclampsia section. I think there it

Speaker 1 1:04:37

is. Okay. Yeah, recent recent investigations have found elevated ratio of soluble FLT one yes concentrations to placental growth factors associated with worse maternal and fetal outcome. A low ratio between 24 to 37 weeks can predict absence of preeclampsia within one week. Thus, measurements may Determine women at highest risk, also possible that soluble FLT one would be targeted as treatment for preeclampsia.

Ben 1:05:09

Oh, there you go. You heard it first.

Speaker 1 1:05:14

Hi. So think you know preeclampsia is still this thing that we don't understand. But this is giving I think way more hints to the pathophysiology. Yeah,

Ben 1:05:24

they do go into, I didn't want to extend the podcast too long. But they do get into that in the, in the background section of the paper, mentioning that. It has to do with vascularity, basically, right. And that and that we don't know much, but we do know that this this, this is revolving around that. So. Yeah.

Unknown Speaker 1:05:49

I have one more, but I don't know that we have the time.

Ben 1:05:52

Sure. If you want to save it for next time, that's, that's fine. Up to you. Okay.

Unknown Speaker 1:05:55

I'll save it for next time. Okay, I like this paper.

Ben 1:05:58

Do you want to tease it? Do you want to tease it for next time? Maybe you can. So next time on the journal

Speaker 1 1:06:03

is next time on the journal club. Let's say all hope is not lost for the growth restricted baby. That's what that's

Ben 1:06:12

right is the great is well done. Thanks. All right, buddy. Well, I will we have we just I just since we're teasing stuff, look at Tuesday for a Tech Tuesday episode with Blake Rutherford from an mobile app called the routines which I think you liked very much Daphna. So very cool app for discharge, planning, coordination, follow up all that stuff. So yeah, look out for that, and we'll see you around the corner. Take care, everybody. Bye, right. Thank you for listening to the incubator podcast. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address NICU You can also message the show on Instagram or Twitter, at NICU podcast or through our website at WWW dot v dash This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns. Please see your primary care professional. Thank you

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