top of page

#005 - 📑 Journal Club 3

The articles reviewed in this week's episode can be found here 👇

New Hour-Specific Serum Bilirubin Nomogram.

Changes in PDA Treatment Strategy and Respiratory Outcomes

Outcomes of Extremely Premature Infants Comparing PDA Management Approaches.

Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen

Towards a Rational Approach to Patent Ductus Arteriosus Trials: Selecting the Population of Interest.

MRI biomarkers in very preterm infants: relationships to perinatal factors.

Should Vitamin A Injections to Prevent Bronchopulmonary Dysplasia or Death Be Reserved for High-Risk Infants?

Information order for periviable counseling: Does it make a difference?

Perinatal Counseling at the Margin of Gestational Viability: Where We’ve Been, Where We’re Going, and How to Navigate a Path Forward.

Multicenter validation of the nSOFA score for prognosis in the neonatal intensive care unit.

Rates and Determinants of Mother’s Own Milk Feeding in Infants Born Very Preterm.

Outcomes of Very Preterm Infants Conceived with Assisted Reproductive Technologies.

Implementation of a Standardized Neonatal Intubation Training Package.

Development, Reliability, and Testing of a New Rating Scale for Neonatal Encephalopathy.

Neonatal Morbidities in Infants Born Late Preterm at 35-36 Weeks of Gestation: A Swedish Nationwide Population-based Study.


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


bpd, babies, pda, neonatal, paper, weeks, interesting, trials, infants, author, outcomes, study, vitamin, question, maternal, risk, article, treatment, intubation, neonates


Daphna, Ben

Ben 00:41

And we're live. Welcome to another episode of the incubator. Daphna, how are you this morning?

Daphna 00:47

I'm doing great. Had a long service week. But other than that, excited to talk about all these articles you were right with the journal was packed.

Ben 00:58

Yeah, you had a busy service week, you had a not just busy service week, you had an impressive service week,

Daphna 01:05

procedure filled procedure filled.

Ben 01:08

I heard through the grapevine that you you gave a back to back exchange transfusion on two consecutive days on the same patient. Is that a thing?

Daphna 01:15

That is correct, but I think it highlights our first paper, I guess we can just get into it.

Ben 01:24

That's right, the Journal of Pediatrics this month, between what's been published online and what's been published in print is just packed packed, packed with highly relevant neonatology articles. And we just hope we're going to have enough time to cover all of these, you know. So the first article is a very relevant one it came out, I don't know when it came out, came out, May 14, it was accepted may 14 2021. And it is called a new our specific serum bilirubin. nomogram for neonates above 35 weeks of gestation. And this was published by the folks at Intermountain Health in Utah, including Timothy Barr, with last author, Vinod boustani. So we have new kutani diagrams. So for the people who may not have read the paper just yet, this is a take on the 1999 nomogram. That was published by Bhutan. And this was from data collected over a 15 year period of universal bilirubin screening. And they were able to reconstruct a new Britanny diagram, this paper is very interesting. It includes a ton of babies, I think, between the babies that were screened, and the babies that were ended up being included in their analysis, I think it was 397,395 Total serum Bailey values for primary analysis. So that is when you talk about normative data. Yeah, that's, that's it right there. And, and what was interesting was that, obviously, they talked about a lot of the different differences between sex between ethnic background and, and what I also appreciated was that if you look at this paper, you can see that they have superimposed the old kutani diagram over the new one. Yeah, I thought that was helpful. That was very helpful, it ended to, I think, the three things that people will notice is that number one, the new diagram, give us actually an look into that black box, that used to be times zero 12 hours, we now have normal values for zero to 12 hours, which is interesting, because for the low intermediate for the low, and for the to the to initial lines, the low and high intermediate risk zones, we see that it's just the slope is just upwards, while for the high risk zone, it actually starts higher and dips in and then increases again, the high risk and high intermediate risk zones remain pretty much higher than the previous nomogram. And the low intermediate risk zone actually is higher initially, but then plateaus below where the 99 diagram is, I hope this makes any sense to everybody listening, obviously, look at the diagram. But But yeah, this is this is actually very, very exciting to have another take on something that has been as well established that as the Bhutan diagram.

Daphna 04:29

Yeah, I think they deserve recognition for you know, like you said, it was well established, we were using it, but for the same team to go back and reevaluate it, I think is is impressive, I think, you know, we need to see that in research and validation of things that we're using every single day. So yeah, props to the team for for doing doing the work and we'll see, you know, will this work? Are we going to integrate it now into you know, Billy Cool. How will this look moving forward? I don't know yet.

Ben 05:05

Right? And, and it's important for us to remind everybody who's listening that this is the boochani diagram, which gives you these risk stratification zones. This is not the exchange transfusion thresholds. It is not the phototherapy thresholds, it's really the risk zones to, to actually, yeah, for follow up. And what's interesting is that I'm going to quote the paper here, because the authors make a note of this. And they're saying, by making use of a different population of neonates from a different geographic location, and with 140 times the amount of data, we created a normal gram with remarkable overall similarity to the 99 version. I thought that was interesting, because we tend to, we'll see in other papers that we're going to discuss today, sometimes we think that all data is bad data. But here you can see that the normal graph, even though it was built with less patients, and more than 20 years ago, it still pretty much is quite valid. I mean, the lines are not that far off.

Daphna 06:08

Yeah, that's exactly right. The you know, the, they are different, but not impressively. So. And I don't think it'll change our practice very much. So. So you're right, it's nice to see that validation.

Ben 06:24

Are the things that they've mentioned in their discussion was that the other gaps that the new normal Graham filled, including clarifying that there is no difference in serum bilirubin values between male and female neonates, they've confirmed that in their data, they clarified that there's higher serum belly values among late preterm versus term neonates. And they clarify that neonates of black race have lower initial belly values and those of Asian race have higher initial Billy values. And I thought that was interesting, because it made me think about patients in a more granular way.

Daphna 06:59

Well, I think that's so much. And you know, since we've been doing the podcast for the last few weeks, I think that's where medicine is moving, right? Individualized Care. And that's particularly true for a bunch of papers that we're talking about today. So, you know, why would Billy Rubin be any different?

Ben 07:18

Absolutely. And I think if you go in that in that journal article, in the at the end, the last diagram is actually a four figure picture that looks at many different things in terms of comparing males with females having a diagram for for, for black neonates, and one for Asian neonates. And I think, depending on the ethnic background and risk factors being different, I think this is helpful to actually personalize a little bit to care for these patients. So that we don't I mean, if the bilirubin levels may behave differently, depending on the background of each patient, and we should be aware of that to make the proper decision. By the way, we're going to remind everybody that we're going to have in the shownotes, all the different links to the different papers, their references and the timestamps so that you can actually go back and look and find what are we talking about? But that's, but that's really it. I thought that was a that was a pretty soon if there was a very significant paper to be published, obviously. And, and you actually got to use it this week.

Daphna 08:28

All week? Yes, that's

Ben 08:30

right. Okay, so that's paper. Number one, which paper do you want us to, to move on to next?

Daphna 08:37

Well, I think that we have a group grouping of papers regarding I think everybody's favorite topic, the PDA. So I think I think we'll probably do quite some extensive discussion on on the PDA and I think the this boil spoiler alert. I'm not sure we've answered any questions that we're trying to answer.

Ben 09:03

Um, I want to, I want to start with a paper that came out of my fellowship institution. There's a paper in this in this month's edition that's called the changes in patent ductus arteriosus treatment strategy and respiratory outcomes in premature infants. It's first authored by the pica Rolandi and senior author is Nelson quarry, who I've had the pleasure of working with and who's one of the brightest men I know. So, the group at the University of Miami decided to evaluate whether a change in patent ductus arteriosus management strategies over time had an impact on respiratory outcomes in premature infants. And to make this simple, they've defined two epochs from 2005 to 2007. That was epoch one, and then 2011 2015. That was epoch two, and this represents the shifts in the management of PDA at the institution where they were in the epoch one more time More aggressive and treated PDA more aggressively. And then in the second epoch, they were more liberal and just not treating PDAs. And what they found between the two epochs was that, obviously, they documented that that PDAs were treated more, that they were treated less 54% of the time in epoch two compared to 90%, and epoch one. But their multivariable logistic regression analysis demonstrated that infants in epoch two, with larger PD with later PDA diagnosis, and less frequently a treatment had greater odds of bronchopulmonary, dysplasia, composite of BPD or death and more treatment with postnatal steroids. So, obviously, showing that being more hands off may not be such a good thing. What were your thoughts on that?

Daphna 10:42

Well, I think it's just interesting. We talked about pendulum swinging in care, right. So this is true at a lot of institutions probably worldwide. And we'll talk about that in just a second. But, you know, there were a number of papers who found really no difference, or no improvement in outcomes with treatment of PDAs at a variety of characteristics of types of PDAs. And, and so there's really been a shift, I think, in our practice from from being very intervention driven, and just kind of tolerating PDAs. That being said, you know, we'll discuss this, but there's a lot of crossover and babies who were in most of the trials who are not randomized to intervention who ended up getting getting treated anyways. And so, you know, now we're, we have now we have the data and, you know, in this EMR heavy time period, we can really look at, you know, maybe more granularly look at the data and see, you know, how did those changes in practice affect outcomes. So I'm glad that we have a few papers to, to discuss. I think one of the one of the big points is that in, in, in the paper, both of papers will talk about that, that those crossover babies who, you know, were not randomized to receive intervention, but so many of them do receive intervention Do you know, we just can't, so we can get to that point where you can't sit on your hands anymore, and you feel like you have to do something, and I would have liked to see more of data about those babies, you know, sort of Harrison between not between epochs, but and inter, you know, the babies who were in the same epoch, but got treated and didn't treat get treated.

Ben 12:42

So I think you're pointing at something very interesting. In the case of the study from University of Miami, this was prospectively collected data but but retrospectively reviewed. So it goes without saying that they did not have good control, they did not prospectively control who was going to get treated or not, they did have a significant number of babies, I think about 309, and epoch one, 400, and epoch two, and the babies were rather small 25.8 weeks plus minus two, and epoch 220 6.2, plus minus two. So I think what I really liked about the paper was that it really gives it addresses what we've all sort of been feeling, which is, with this hands off approach, we are missing something that is not impacting babies altogether, the same way. And and it may not be this all or none approach. from a, from a scientific standpoint, in terms and in terms of bringing evidence to the bedside, it's a bit more difficult to interpret this data carefully, mostly because of the fact that it was retrospectively reviewed data. I think the biggest issue with this is that they did not at least provide us with data regarding the closure rates of there. So it's hard to say whether it is the treatment that is 100% effective that is causing these differences, or maybe some of these babies were treated with something other than ligation actually continue to have open PDAs. And maybe that's still not addressed. But it doesn't really matter at that point. Because, number one, this was not the intent of the study. It's providing a question and I think the editors of the Journal did a very good job at bundling all these articles together because some of them answer each other's questions and and they also bring up new questions. So I thought it was a very interesting idea because again, this paper said there's more BPD so without spending too much time on this paper, if we move on to to the next to the next one, I'll have to find it. Give me one second.

Daphna 14:51

Our lists are long today or notes.

Ben 14:54

There's so many so

Daphna 15:04

Well, you're looking for this one the targeted by echocardiographic treatment of the ductus arteriosus and preterm infants by ibuprofen or the trial Cappy trial.

Ben 15:15

That was that was actually yeah, I mean, that one, but I was actually looking for was that we'll go ahead and talk about this one. I guess it's it isn't there's no, I wanted to talk about the other one. I'm so sorry.

Daphna 15:28

Well, I think we'll have to talk about both.

Ben 15:30

So the reason I wanted to talk about the other one, which is called outcomes of extremely premature infants, comparing piton, ductus arteriosus management approaches, it was published this month, it's by Gabrielle Altet. first author, last author is Olga Bessel. And these are folks from Canada. What was very interesting is that they wanted to evaluate the change in the proportion of death, slash BPD, among preterm infants following a policy change from strict non intervention to standard treatment, which is almost the same as the one as far as what the University of Miami did, except that this was a multicenter trial where they actually identified one unit and left them with a more conservative approach, and then identify the second unit that had a more more up to date approach of just not treating the PDAs at all. And what was very interesting is that study included 12 150 infants, and the sites that they used were comparable. And they looked at this evidence from, I think it was around, they did the policy change in 2013. And they followed the babies. So basically, from two years before 2011, to 2017. And what they found was that for babies who were older than 26 weeks, they found that there was no real difference in the outcomes. But for babies who were less than 26 weeks, they found that BPD increased by 31%. And they didn't find so that so I thought that was very interesting, because they pointed out the same result that the University of Miami paper found, but we're able to identify that gestational age was a key difference factor in getting those outcomes.

Daphna 17:11

And that makes sense, because the you know, the Miami group had had a lower head of lower, you know, very pre premature babies. You know, the mean gestational age was 25 weeks. So that subset of the Canadian group was similar, I think to the Miami group, and again, just underscores the fact that we can't treat all preterm babies the same way. And perhaps with the especially PDA treatment, that we really have to start to stratify babies based on those other confounding factors, you know, gestational age, and other other comorbidities, too. And I think that's, that's really the crux of the issue with the PDA question. There. There are too many confounding factors. We also, you know, we haven't all agreed upon what makes a PDA AHIMA, you know, hemodynamically, significant. We haven't all agreed upon, what are the clinical features that are most concerning, even though I think we all in practice, have some, you know, have some findings that make us more more worried or less worried about the PDA impacting care? And but, you know, I think, as we start to describe those a little bit better that we can do the research, right, we can all be speaking the same language when we talk about babies.

Ben 18:43

You're absolutely right. I think it also shows that if you look at the paper from the University of Miami, on its on its own, it has. There's some questions that are need to be answered, obviously, when it comes to how can we interpret the information, but you can see that publishing observational data is very important, because even if we can pinpoint exactly what are the causes behind the observation, these observations are real, and they underscore issues. And then you see that these can be answered by a different group that was able to actually shed light on that on that area. So I liked how it it shows that we all need to collaborate and share our experiences, even if we don't sometimes have a good explanation for them. And you can start seeing because I do think that the group from Canada showed that 26 weeks seems to be a cut off where we're seeing more or less effects, but there may be other aspects of the PDA that we're still like you said, hemodynamic significance and so on.

Daphna 19:42

Yeah, and I think, you know, we there's so many of these database studies, right where we pull 10s of 1000s of babies and obviously that comes with its own problem and risk but I think this is a perfect example where You know, the studies are especially valuable because we just need to look at more babies and get more granular about about.

Ben 20:08

So I'm gonna, I'm gonna let you then talk about that third paper, because the yes, there is a third paper about PDA this one. Go ahead.

Daphna 20:17

So we introduced it briefly the trial copy trial. Dr. Jean Christophe Rosa. Yeah, from the University Hospital in Nantes, France. And so they enrolled babies under 28 weeks of gestation with a large PDA. So they were very specific about their echo measurements for PDA. And very early in admission, so between six to 12 hours after birth, and they were randomized to either ibuprofen or placebo by 12 hours of age. And so this was randomized, but it was intention to treat because they were allowed to

Ben 21:08

cross over

Daphna 21:09

a significant amount of babies. So, for example, in their babies who weren't treated, the placebo group over 60% Were still quote unquote, rescued, with ibuprofen therapy. And so they looked, so their outcome question was different. And they wanted to look at survival without cerebral palsy using the Amul T's Tyson classification, at two years of age corrected and also using as queues. And so obviously, their groups were different in the amounts of ibuprofen used, but again, a high proportion of babies were still eventually treated with ibuprofen. And so they, they did see some differences, that, and let me pull that up, but that they're not everything reached statistical significance. But there were some differences in neurodevelopmental outcomes in the babies who received treatment that I think are, you know, for parents and for children in school or not, you know, not unimportant. So number of children with total ASQ scores less than 186. Um, did not approach did not meet statistical significance, but very much approached it mean fine motor skills, mean problem solving abilities. So that did approach statistical significance. And problem problem solving abilities below threshold approached significance in the babies who received or who were randomized to receiving ibuprofen. So those outcomes were slightly better, and babies who received ibuprofen. But again, this is another place where I'd like to see more of the data about the babies who were bailed out of their placebo groups, and to and to run the same statistical, you know, analysis on the outcomes for those for those babies. So I'm glad that I'm glad actually, that we had all of these trials to look at at the same time, because I think it begs the bigger question about, you know, how do we proceed with studying the the PDA?

Ben 23:54

Yeah, I mean, they were they were very rigorous in getting targeted echoes between six to 12 hours of life. And I think they defined the large PDA as 2.2 millimeters

Daphna 24:05

2.26. That's right, great points.

Ben 24:09

And, and so that was very, that was very rigorous. I was a bit puzzled by the target primary outcome of cerebral palsy. That is something I had not seen before. We're more used to seeing more immediate morbidity such as death BPD, and so on. But that was an interesting outcome and the fact that their conclusion conclusions was that early, early targeted echocardiography for ibuprofen for early targeted echo PDA did not change the rate of survival without cerebral palsy. So there's there's a, I think, there's a lot of questions that are left answered, because this seems to make the case that there's really no difference between the two groups and so maybe prevent withholding ibuprofen for these babies may just be a valid option, considering the other two papers we just reviewed, Said. More hands approach has not been benefiting us, especially in lower gestational age. And just for I don't know if we've mentioned this, but this was a study that enrolled about 300. And something infants less than 28 weeks across, I think 11 centers. So that was very, I was very good quality sort of data. Data is simple.

Daphna 25:21

A lot of work, a lot

Ben 25:22

of work. But yeah, I mean, I was very interested in the this, there was a very nice editorial this month, by a few Felco fosh. Who, who, and by Daniel Rios and Patrick McNamara, talking about these trials of PDA treatment. Obviously, a thief is a an active member of the neonatal Twitter community, I recommend everybody should follow him. But their editorial was called towards a rational approach to picking ductus arteriosus trials, selecting the population of interest. And, and they made some very strong statements, I think, in that editorial. Because it was not really directed, it was really written in relation to this article by by Rosae, and Associates, but it talks about the issues related to PDA trials in general. And he was making the point that you were making that we're not really able to identify what is truly hemodynamically significant PDA I know that him and McNamara had the identified this the score that they they've published before in the Journal of Pediatrics, about hemodynamically significant PDA. I thought it was, it was very strong for them in the editorial to say, and I'm quoting, we propose a moratorium on quote unquote problem, pragmatic randomised trials that enroll patients based on either P diameter alone, or imprecise measurements such as the left atrium to aortic ratio, saying that these these, these measurements provide a false understanding of what hemodynamic significance is, and may provide clinicians with the wrong interpretation when it comes to treatment and outcome.

Daphna 27:06

Yeah, I think one of the other points that they made that we haven't discussed yet is, you know, we talked about a lot of the babies in the control groups who were bailed out and still treated, but we didn't talk about all the babies in the control groups who don't receive, you know, medication or ligation, and they still close. And so we, you know, so I think we have to look at those groups of babies individually to start to do the comparison. So I also think there's a place potentially for, you know, these big trials to give us some more of that data.

Ben 27:43

And he was making the point of us focusing on treatment, right, we're focusing on giving ibuprofen, giving into medicine, whatever. But they right in their, in their editorial, another major methodological concern in current trials is the high rate of open label treatment in the placebo arm, particularly, particularly when coupled with relatively poor efficacy of the intervention drug to close PDAs in the intervention arm, sort of what we alluded to, in the initial paper, also from University of Miami, where we don't really know how many PDS have closed. And they quote, for example, by day 14, the rate of PDA closure was 54% in the placebo arm compared to with 75% in the intervention arm. And so that was that was obviously a very significant finding. The study was designed to compare patients where early shunt elimination was achieved with a matched control group with prolonged exposure to Dr shunting. But such physiologic separation did not occur. And I thought that was such a good statement. Because it's the physiologic effects of having the PA open that are of concern, not really what medications we give them. And if we're not able to control that through medications or through treatment, then are we really studying what we're aiming to study? And it's back to more questions about the PDA. Obviously,

Daphna 28:50

that's more more even more questions than questions answered. But I'm glad they bundled the papers and gave us the opportunity to talk about them. And it did, you mentioned something that does kind of bring up a good point if we're ready to move on. And you had said that most PDA papers weren't focusing on neurodevelopmental outcomes, that they're mostly focused on BPD. And I thought this paper about diffuse white matter abnormalities, you know, may speak to some of that.

Ben 29:27

Yeah, absolutely. So let me just pull that up. Yeah. So I think we're going to move on from the PDA discussion, that at least, I'm going to say it's in all humbleness. I'm going to say that the one thing I'm taking away from this month's edition is that is 26. Week, cut off is very interesting to me, because I'm going to take that into to the bedside and manage things a bit differently based on that, that that whole discussion between the University of Miami paper between the Canadian work and between this this French group and 26 weeks seems to be a cutoff where we need to treat babies a bit more differently. That was very interesting. Anyway, the paper you're referring to is called perinatal risk and protective factor in the development of diffuse white matter abnormalities on term equivalent age and magnetic resonance imaging and infants born very preterm who first daughter is now Pareek. And last author is Dr. Isla pani for the Cincinnati infant neurodevelopmental early prediction study investigators. So tell us tell us about this.

Daphna 30:29

So they looked at almost 400 babies born in less than 32 weeks through this multicenter trial with a mean gestational age of about 29 weeks. So, you know, are kind of moderately preterm babies. And what they wanted to look at was a variety of neonatal complications, as well as some kind of perinatal factors and the subsequent finding of diffuse white matter abnormalities on the term corrected MRI, which, again, we're talking about term corrected MRIs, which not all institutions are, are doing. So you know, as that practice is falling out of, or has fallen out of favor, you know, I'm intrigued by some of these kinds of observational studies that you know, may or may make as may make us reconsider the utility of some of those practices. So, I will mention that this group has done a lot of work on diffuse white matter abnormality, and that they have previously shown that this type of injury predicted poor long term neurodevelopmental outcomes on are on a range of areas cognitive language and motor deficits at two to three years corrected age. So, the major findings were that there was greater volumes of diffuse white matter abnormality in babies who had suffered pneumothorax had severe bronchopulmonary dysplasia, severe retinopathy of prematurity, and male sex. And then the following factors were associated with decreased risk. Interestingly, postnatal dexamethasone therapy for severe BPD, and they did use the dark protocol, and duration of caffeine therapy for severe BPD. And exclusive maternal milk knew at the time of discharge, I'd like to point out that they didn't find differences in the following, which I thought was interesting. So they didn't see differences in the white matter abnormalities for babies who did or did not receive anti needles, steroid therapy or anti natal magnesium therapy. And, interestingly, when we talk about inflammation over the course of a NICU stay, there was no difference in babies where there was concern for chorioamnionitis also no changes based on Apgar score, or some of the other things that we can we are typically concerned about, mostly as it relates to ivh. But hypotension, PDA, sepsis, antibiotic use, or, you know, the need for surgery. So we always are talking about how are neurodevelopmental outcomes affected by the use of things like anesthesia. So no changes in those major comorbidities, or neck or sip? Or, you know, prolonged TPN? So what do you think?

Ben 33:46

Well, number one, I was I was not really surprised by the by the outcomes that are negative, negatively affecting the MRI, I think pneumothorax BPdc, VRRP. I was I was expecting, and I was very surprised. I was surprised by the items that were protective. Number one, Dart I was not expecting that. And I don't know if this is going to make me order more dexamethasone. But it shouldn't I shouldn't think this is a dose response effect. But anyway, the one that I was very curious about was the caffeine. Because caffeine has been such an important topic of discussion. Especially recently, there's been more and more papers asking about how long should we keep caffeine on board? We keep it until 34 weeks, because that's what the initial trial had done. But we don't really know if we should extend it. We don't know what what are the effects of extending caffeine beyond that point. Some people are saying should we even stop it before 34 weeks if there's no need for it? And so, in the article, they said that the average length of use of caffeine was 62 days between zero and 89 days. And so it left me wanting to know more a little bit about this. I wish I hope that they can. You can go deeper into it and tell us because I've been asking myself that question during rounds? Should I stop caffeine at 34? Wait, should I stop it sooner Should I keep it going, and this makes me makes me happy about continuing caffeine. Because you see that it does have some protective effect on the brain. And obviously, I was not surprised by the maternal milk diet. And, and so that makes it even one more, one more item to, to continue encouraging your administration of maternal milk.

Daphna 35:27

Sure. And, you know, and that may be confounded by other things, you know, that we can't, we can't see, you know, kangaroo care or other parental involvement in the unit. But, but, you know, they, they hypothesize, you know, some sort of immunologic or, you know, anti inflammatory process. But again, it was interesting that some of the other things that are certainly immunologic or inflammatory, like, you know, sepsis, or choreo, weren't related. And those are certainly things that we have previously felt to impact brain development in the family, preterm baby, and again, validates the findings that severe ROP and severe BPD were the strongest predictors. And, and again, it's probably not a chicken or egg phenomenon. It's probably a kind of an ongoing state of increased oxygen need, and radicals and that affects everything.

Ben 36:39

Absolutely. Because ROP and DPD are not acute, acute complications or prematurity, they're chronic, chronic issues that have been that are developing over a significant amount of time. So it's like you said, it's not really surprising. pneumothorax actually is an acute complication. That was impressive that a single event like this can have these types of repercussions. Yeah, but absolutely.

Daphna 37:01

Well, I wonder if that takes us to our other BPD paper regarding vitamin A.

Ben 37:07

Another another big one. The title of the article is should vitamin A injections to prevent BPD or death be reserved for high risk patient high risk infants question mark reanalysis of the NI CHD neonatal Research Network randomised trial. first author is Matthew Rizvi. And obviously its last author is Dr. Bell. And this is for the new Nero Research Network. When the conclusion of an abstract starts by contrary to expectation you have. But the crux of the paper, the objective was to determine whether infants at high risk of BPD or death benefit from vitamin A therapy and those at lower risks. What they did is that they took the 9697 trial that was that was done on vitamin A, that had identified vitamin A as a as an independent risk modifier for BPD. And tried to look at these patients based on their risk BPD risk stratification to see who would benefit the most. And what they found was that the relative the relative risks for vitamin A therapy on BPD was very different based on the on the predicted risk of BPD at baseline. So I'm going to quote the results the effect of vitamin A therapy on BPD, or death dependent on the infant's risk of the primary outcome. For example, relative risk of point seven, three, for infants with 25% predicted risk, and relative risk of point nine, six for the infant's with 75% risk. And obviously, we want the relative risk to be lower to see a stronger effect of vitamin A on BPD. So for the babies who had the higher risk of BPD 75%, their benefits from vitamin D was lower than the babies who had a lower predicted risk. And so it shuffles everything, because you and I both know that our at our previous institutions, we modified we we went through several iterations of our vitamin A protocol initially given to every baby that was born below certain birth weights, because they were at high risk of BPD, then we did a sort of tailored approach where we looked at based on their BPD risk factors if it was 50% or above, and we would give them vitamin D. And now this is begging the question out, do we have we identified our populations completely, completely wrong? Because if and, and have an end to their I mean, our previous institution, we were still in touch with them. And if they see that paper, and they've asked the same question, do we need to now revise our protocol? So yeah, and I

Daphna 39:39

mean, notably, the the vitamin A therapy was associate associated with decreased use of oxygen at 36 weeks, but not really other respiratory support. So you know, maybe there's something there but it wasn't the group of babies we were looking to protect, right. We were looking at the most severe babies, the highest risk For the first, you know, week of life to start vitamin A therapy, and it just goes to show the importance of validating our work. And I think in other facets of science, you know, we do it over and over and over again until people say, Why are we still repeating this? You know, it's a it's, it's, we every, it's always consistent. But medicine has, I think, moved away from validation trials. And so I think we have two papers this this month that, you know, look back at older trials, and I really, I respect the teams for doing that, and putting putting out data that might be contradictory. Just so so people have the information when they're trying to make their their protocols and policies. I don't know what to do with the information yet?

Ben 40:54

Well, I think it's it's, I'm not exactly sure what we're going to do about this, to be honest with you, I'm curious to see what other centers are going to, or other centers are going to address. But I think it's pointing out to the fact that we've been treating BPD as if everybody has the same disease. And we're trying to be giving this cocktail of items that we each one has a little bit of a contribution to better outcomes and hoping that something sticks. But when you look back, the big question that this paper asks is, why is that? Why is it that if you have a lower risk, that makes no sense, from a statistical standpoint, that if your baseline risk of developing a disease is lower than you would benefit more from an intervention, there was this great article by Jensen from chop in the Journal of Pediatrics, I think last year, that looked at the identifying the drugs for BPD, that are worth using, what is the number needed to treat and he was saying, we need to look at the baseline risk of the control groups. And based on that decide, calculate our number needed to treat because it's all depends on the baseline frequencies. So that doesn't make sense. So when you look at the at the paper, and you look at some of the explanations, I think they hide they nailed it on the head. And I'm going to quote and I'm going to read from the paper because I highlighted that section. And and I think it just answers that question. It says our findings have important implications for both the clinical use of vitamin A therapy and the design of studies related to BPD, BPD, and death have multiple ideologies, a single interventions is single intervention may not affect all factors causing either of these outcomes, because vitamin A therapy resulted in similar decrease in vitamin A deficiency for all infants, regardless of their risk of BPD. Or death, we speculate that the proportion of BPD related to vitamin A deficiency may be greatest in the lower risk infants, that is high risk infants develop BPD or die due to a preponderance of other risk factors for these outcomes. And so that's absolutely right. We know that vitamin A deficiency could be one of the root causes of BPD. But for them to be a major factor in the development of BPD, you have to be maybe not so prone to other risk factors. And so I think I think they're absolutely right, I think, but it's still leaves a lot of questions unanswered. The other thing that they mentioned, obviously, is that they're not really looking at the other ways vitamin A may may affect other organs, organs, such as eyes and cardiovascular system. That's very important to mention that because you're only looking at BPD. But yeah, I mean, I think people should be aware of this trial and what we're supposed to do now. Yeah, it's expensive. It's an im injection. Nobody likes the vitamin A, especially the baby was always on shortage. It's a mess and know

Daphna 43:38

why. And I think that's it, you know, we know that it's is a chronic disease. And so it's not going to be one intervention that saves all of our babies from from BPD. We know that the longer they need respiratory support, the longer they need respiratory support. And so it's, it's, it's an ongoing question. But certainly, I think one that begs that we talk about BTB. PD, maybe more extensively in our in our prenatal counseling, because it does impact. You know, I think the NICU admission significantly, and it impacts quality of life significantly. And so maybe we talk about Perry variable counseling a little bit.

Ben 44:26

You're like on the ball today, with transitions, you're moving so smooth. From one paper to the next. Well, we're

Daphna 44:33

afraid we won't get to everything. So

Ben 44:36

we definitely want to wait, I mean,

Daphna 44:39

we're going to try so I think the next article we'll talk about is information order for Perry Bible counseling, does it make a difference? Lead author of Ciobanu McDonnell. And so I thought this was an interesting paper that, you know, at least should touch on, they looked at a study of 800 In 39, women of notably childbearing age, but not, not women that were in the acute, period. So these women were not in preterm labor were not at risk for preterm delivery, but they were of childbearing age. And so they felt that given the ethical concerns about studying these women in a in a kind of acute situation, that they that they chose not to study women who are getting actual perinatal counseling, but women who could potentially be getting perinatal counseling at some time. So just something to keep with a grain of salt. But in general of that group, I'll tell you right off the bat that 66% chose intensive care and 34 Choose comfort care in the scenario of a hypothetical scenario of them coming in and you know, some sort of preterm labor or maternal indication for preterm delivery of a 22 weaker. And so there are a few things I'd like to point out. So they used pictographs. So we always talk about the best way to present information to families. And that may not be the same for every family. But, you know, I would ask people to just take a look at the pictographs. Because I think it does help families understand the numbers that we're talking about. And those

Ben 46:30

pictographs I mean, they're pretty basic, but they're little red rectangles with little baby icons, maybe 10 to 15 on a horizontal line, and there's maybe 10. It's a grid, basically, of 10 by 15. And it's just like little baby icons, and they're colored differently to represent proportion. So I think it's supposed to be 100 babies, under Brandon. Thank you.

Daphna 46:55

So yeah, 100 100 little babies. And then they actually showed two pictographs. One that showed, well, three pictographs, one that showed survival rates only for 22 weekers, one that showed survival rates coupled with a little bit of information regarding a NICU admission, such as the need for ongoing painful procedures, and the average length of stay, and the third pictograph demonstrated of 22 weekers, who survived, what does what proportion of them have moderate to severe disability, and the spelled out what that might look like so significant motor disability, inability, potentially, to communicate, so that they could describe that a little bit. And I thought, to begin with that this is valuable, right, because we threw so much information at parents during this time. And, you know, how can we make it as simple as possible, and I thought that pictographs were useful? And how can you know that our words matter? And in how we describe some of these findings, but that was not their question. Their question was, if the order in which we provide the information, changes, choices. So first, I'll start with they did look at if we describe the NICU course, did it change decision rates, and I think a lot of us do this, especially in the extremely, you know, in the very parry variable range. And that, unfortunately, probably represents some of our own biases about, you know, the implications of of resuscitation at certain gestational ages. And that's probably different for everybody. But I think some people try to capture the pain and suffering associated with a NICU admission. And that we'll touch on on a later point about what kind of driving force was most important to parents. But the description of NICU care and talking about painful procedures and length of stay actually had no change in decision rates, which I thought was interesting. And then there are subsequent points, or parents, or moms, potential mommies whose were viewed the survival pictograph. First, were more likely to choose intensive care than participants who reviewed the disability pictograph first. They were also more likely to choose intensive care when in the description of options that was the first treatment choice listed then when Comfort Care was listed first, and so they really shuffled the deck in how There are a variety of arms introducing information. And so I thought that was really interesting.

Ben 50:09

Yeah, I mean, I think it was a very interesting paper, number one, number one, because it touches on decision making processes and psychology, which I'm fond of. And something we discussed with Matt trouba, who is a, an adult intensive care physician who's going to be on the podcast next week. So tease for next week right there. But there was a few things, obviously, with this paper that that are both an issue but really aren't. Number one, the fact that these mother these women were not pregnant, makes you wonder, it's always very easy to be rational when you're not really pregnant. But obviously, you cannot do this study on pregnant women who are either in threatened preterm labor or anything like that it would be completely unethical. But what's not surprising, though, is that the psychology behind this decision making process has been very well described. And this whole idea of loss aversion. That is that has been documented by the likes of Kahneman and others. Existence. So it's very interesting to see that it does. It's something for us to be, yeah, it holds true. And it's something for us to be aware of, what do we start off with our words matter, the order of which we present information matters. And it matters for a very important decision. I mean, these decisions are life have lifelong ramifications, whether parents are going to welcome a child that has a very high likelihood of being disabled in the future is an important one. So we need to be very careful in how we present information and try not to bias parents one way or another so that they can make the best decision.

Daphna 51:40

Yes, there are other there are other findings were probably for those of us who have been doing, you know, doing this not not totally surprising, but higher religiosity, but not necessarily higher service attendance to, you know, religious services showed higher rates of choices towards intensive care. Of course, in the kind of guiding value system for the woman sanctity, the sanctity of life versus quality of life, very much influenced decisions. And I think that's important, because I think it goes to show that we can't always do prenatal counseling, the way we try to do it, you know, in 1010 minutes, it really would be helpful to have the opportunity, it is valuable to get to know that mother if you have an opportunity to and we don't always have the opportunity, but to see her a few times and find out, you know, what, what are and there are a few questions we can ask to say, you know, what are the kind of the guiding principles in your life, what's most important to you? And perhaps we can help unburdened families by saying, Well, if this is what's important to you, then then this decision may fit with that. And I think that is one way that we can take some of our own bias out of out of perinatal counseling. So I was really glad for the for the article, and we had the chance to discuss it.

Ben 53:09

And it leads I'm gonna do a nice segue myself right now to the to the next article, which is called perinatal counseling at the margin of gestational viability, where we've been where we're going and how to navigate a path forward by Marian Arnold's and Naomi Leventhal, I think this goes over the evolution of perinatal counseling and how the edges of viability have moved. And because we're a little bit short on time, I just want to go straight to the figure, because they have an amazing figure that basically describes the pathway to address the antenatal period and the antenatal consult, where you're supposed to elicit values describe anticipated prognosis for survival and potential for complication, partner with expectant parents and offer guidance. I thought that was very interesting. And under that, for example, it says explain options saying we have decisions, we have a decision to make, share the decision, but it helps to hear what I'm thinking. And then there was the last section of that pathway, which has allow for information processing and follow ups as needed, which is exactly what you were just pointing out to. So for example, they give examples of closing the loop. Quote, I'm going to let the OB team know what we've discussed. Check back in quote, I'm circling back to see if you have any more questions. And last one, incorporate new information, quote, it's been a few days since we last talked now that you've had the steroid shot, etc, etc. So obviously, these are big discussions with big ramifications in terms of the decision being made. So obviously, parents need probably lots of buffer periods to think things over discuss it with important people in their lives, and then we have to have the availability to circle back to them as much as possible. Obviously, if a baby is born preterm, we may not always have that, but it's even more reason for us to be involved earlier rather than later.

Daphna 54:52

Well, you know, it takes more time. Obviously, it takes a lot more effort, but it's definitely I think the right thing to do. You did say we were we were running short on time, but I think we had a few more articles we just mentioned.

Ben 55:09

Yes. So people should check out that figure from the perinatal counseling at the margin available. That's a good one. Okay, go ahead.

Daphna 55:15

Well, I think we wanted to talk about, let me pull it up here. This preprint article multicenter validation of the neonatal sequential organ failure assessment score for prognosis in the neonatal intensive care unit, lead author, James, when, from the University of Florida, and so have to

Ben 55:43

do with the fact that you did a fellowship?

Daphna 55:46

Well, it has to do with the fact that this is one of those large data base trials, but I can tell you from personal experience that Dr. Wynn pored over that data, I mean, I think he looked at every single baby individually. And so I don't think that comes across in the paper. And, you know, it's, it's so hard for us to, to see the background, right of all the work that we're doing, when we're pulling from large, large databases, and this was a multicenter trial, including schools in Chicago, the university, Chicago and Northwestern. But again, I think he looked at 20,000 patients, that's right, 20,000 patients, but I firmly believe he looked at almost every single baby individually. And so what the team developed was a severity score, based on a variety of factors. And they do provide a link to their calculator. So anybody can see it. It's quite easy to use, it's just easy to search for on And the factors that go into the calculator baby intubated, yes or no steroids, yes or no. What is the platelet count? What is the number of isotopes? What is the fit required and the current saturation? And so I think none of those things are individually surprising that they may factor into a score that is intended to predict mortality. But taken together, they showed validation that it had good predictive value. Certainly over the course of time, the older the baby was in postnatal age, and certainly in increasing gestational age. So I thought this was really interesting, right? We're always trying to trying to decide, you know, which is the baby that will make it and which baby will not make it. And you know, this doesn't give us any definitive answers. But certainly, I think it provides a framework for our monitoring of babies, for our discussions with parents. And I think very much the trend of these numbers, I think are valuable. The other thing that the team has done is they've actually put the score into their EMR. And so that just like any other vital sign, it reads out, continuous and sofa scores. And so I thought that was an interesting way to use the data so that somebody didn't have to go in and calculate it, even though the calculator is very easy to use.

Ben 58:46

Yeah, I mean, if you so the N sofa stands for neonatal sequential organ failure assessment. And it is very simple. As you said, I always value simple tools. And I would recommend people check out both the calculator as you mentioned, but also the original paper that describes the end sofa. It was published in JAMA in February on February 4 2021. And the article is called is called evaluation of the neonatal sequential organ failure assessment and mortality risk in preterm infants with late onset infection. So that was, so that's yeah, so that was a very good article as well.

Daphna 59:24

And I think Do we have time for one more? Yeah. I think you know, we had both to discuss this the rates and determinants of mother's own milk feeding in infants born very preterm by for lead author, Dr. Terrell from the Canadian neonatal network in the Canadian preterm birth network. So they looked at 6400 BV is less than 33 weeks and their outcome variable was breast milk any amount at discharge, which mirrors major Neonatal Intensive Care marker here in the United States. So they looked at a variety of NICUs. And the average across NICUs, 70% of babies received mother's own milk. And they looked at a variety of maternal and neonatal variables. And some of the major findings, which, you know, are not surprising. And we've seen in other studies, that rates increased significantly, almost linearly with increases in gestational age from 65%, at 25 weeks, up to about 72%, to the 29 to 32. weaker, and they don't go into very much about why that might be. But I can only imagine that the length of the NICU stay, and that's been shown in other articles, impacts you know, the mother's ability to keep up with the with the pumping, and certainly the more critically ill baby who is not receiving milk, and maybe another impact factor for moms to keep pumping, I'll touch on some of the other data. And then we can talk about some of those things. maternal milk at discharge was increased actually in prime hips. And older moms, interestingly, in male sex, and then, for whatever reason, maternal receipt of magnesium

Ben 1:01:26

of the baby, no sex of the baby, right? male sex of the baby.

Daphna 1:01:34

The things which has been shown in other studies that maternal diabetes, smoking and then have lower rates of maternal milk at discharge, they also found that higher parity, so the more babies Mommy has had, was actually associated with with lower rates. And previous studies, you know, we have found that mothers who have breastfed previously had higher rates of breastfeeding in the NICU. And they didn't they didn't look at that question specifically about moms who had breastfed before, but with higher parity. And then I think the most valuable thing that we could probably take away is that fee, receipt of maternal maternal maternal mom's own milk by three days of life was associated with higher rates of discharge. And so it really, I think, validates that we need to be advocates for babies and for moms, to get them the resources to start pumping as soon as you know, physically and emotionally possible. Obviously, mothers with a premature and critically ill neonates are at risk for delayed like to Genesis. So the stress delivery by C section separation, their own medical problems. There's so many reasons why moms may or may not be able to really provide milk by three days of life. But it just I think shows in so many studies show the benefits of you know, moms don't milk, that we really have to treat it as a medication, we have to study it like a medication and really be advocates for how we can support moms with breastfeeding. What I will point out is this is interesting. This was obviously done in Canada where parental leave and health care's is quite different than ours here in the States. But the findings actually are, are not that different. So I thought that was interesting.

Ben 1:03:36

Yeah, that was that was a very interesting paper. I was surprised by the I mean, the smoking thing was was it's been described before, but it's still something that puzzles me. Alright, let's I would like to go through a few more articles, even if we cannot go in depth, at least just to point out to to the listeners, that there is that evidence out there. The one I wanted to just at least briefly mentioned it was recently published. It's called outcomes a very preterm infant conceived with assisted reproductive technologies by Feynman first author and doctors stir is the last author. This is a group out of California. And their goal was to compare mortality and early respiratory outcomes a very preterm infants can see the AR t VS spontaneously. And they found that there was there was at the one year mortality of so they looked at infants born less than less than 32 weeks and they were able to get 54 cases of AR t they match these with one to two ratio to controls and they were matched by gestational age and multiple gestation. primary outcome was one year mortality and then there was other secondary outcomes. But the bottom line is infant one year mortality was not different based on mode of conception. Infants with conceived by assisted reproductive technology were less likely To receive respiratory support or supplemental oxygen at all time points, but this relationship only reached significance for receipt of oxygen at 28 days. And so I thought that was very interesting because I was always under the bias perception that babies were born via assisted reproductive technologies did worse. And so this was very well done in terms of matching, but it shows that actually, there was not much difference. So that was an interesting paper, people should check it out. The is there another people you want to kind of go into the next one?

Daphna 1:05:30

We'll just run down the list, I guess.

Ben 1:05:32

I guess there was another paper called implementation of a standardized neonatal intubation training package by Dr. O'Shea, and last author, Dr. Andrew Brunton from Glasgow in the UK. So I thought that was very interesting, because it was a QI project that looked between 2017 and 2018. And then, and basically, the it was two phases, obviously. So that was the first phase second phase 2018 to 2020. What they looked at was the integration of the implementation of an intubation kit, with a video, video laryngoscope and other items to see if they could improve the success rate of trainees during intubation. It covered about 300 procedures. And what they showed was that they were really able to boost the success rate of junior trainees on their first attempt that intubation from 37% to more than 60%. I thought that was very significant. And that was a very significant paper for several reasons. Number one, because it shows that this can be done, number one, and number two, I think as residents, especially in the US are rotating less and less through the NICU. And as we intubate less than as babies, we have much less opportunities to train residents and trainees towards intubation. So we need to make every instance count. And it's by having these types of setup that we can potentially give the opportunity to residents to succeed at this procedure. And maybe spark like Michael NaVi said last week sparked the interest of a resident in the field. And so I think these are things that we should really take seriously and not just dismissed, because it seems very obvious, obviously, that if you have a laryngoscope, and you have this whole preparation in place, then yes, success rates are going to be higher. But beyond the success rate, I think it's what comes with the confidence that this can provide a trainee when you succeed on the first intubation.

Daphna 1:07:20

Yeah, and we always we always do these type of papers under the guise of, you know, improving learner outcomes. But the fact of the matter is data on even experienced incubators in the NICU is that, you know, they're not always successful. And so are there ways that we can make every intubation more successful, I think is something we have to look at and video assisted intubation is certainly one way we can do it. It's one way we can involve more members of the team. Other than just the person intubating. We can show the anatomy, we can look for other kinds of anomalies in minor anomalies in the airway for each baby, especially those babies that are needing to be intubated, re intubated many times so

Ben 1:08:07

there was another article quickly that's called developmental reliability and testing of a new rating scale for neonatal encephalopathy. last author is Dr. ivanti Fernandez from Spain, and basically describes a new scale for measuring neonatal encephalopathy considering our busy week made us also use the encephalopathy scale. I thought that was interesting. I just looked at the scale. It's pretty thorough. It includes various items. And the scale is at the end of the paper. It includes alertness, spot, postures, continuous motor activity, motor response, Mio tariku, reflexes, reading pattern, clinical seizures. So that's going to be interesting to see when that skill is going to get tested against some of the things that we're currently using. Something to check out. What are the paper did I noticed that there was a very interesting paper from the Swedish National nationwide population based study called neonatal morbidities and infants born late preterm at 35 to 36 weeks of gestation, a Swedish nationwide population based study. last author is Jenny bolc. I want to give a shout out to Stefan Johansson, who is a friend of ours on Twitter who is very active. And this study looked at to assess the risk for neonatal morbidities among infants born late preterm at 35 to 36 weeks, early term and late term compared with full term infants. And, obviously, the findings were not very surprising infants born late preterm are at increased risk of neonatal morbidities although the absolute risks for severe neonatal morbidities are low. And, again, I always like a good graph, but figure the figure provided in the graph looks at multiple different morbidities Apgar score of zero to three at five minutes meconium, aspiration, respiratory morbidity, metabolic morbidities and so on. And you have these curves by gestational age that show you that really being born before term is not a good thing. And and so we have to make an effort To try to either convey that to our obese and make because sometimes, you know what it made me think is that sometimes if an OB tells me that they're going to have to deliver somebody a bit early 35 weeks, I'm like, Ah, no big deal, right? I feel like we can totally handle this. But then you look at these graphs, and it's like, yeah, it's no big deal for me, because I can manage the patient fairly safely. But it's not fair for these families. And for these children, if we can avoid it, it's a good reminder that we should try to aim for for term. And I really liked that figure. It was a nice, a nice, a nice reminder. I think

Daphna 1:10:28

so there's a good reason we evolutionarily cook that long, basically.

Ben 1:10:33

That is correct nature, that it correctly. Is there anything else that you wanted to go over? Oh, my God. I mean, like we said, it's packed packed with articles.

Daphna 1:10:43

Yeah, well, I mean, we had to apologize if we didn't get to touch on, you know, we were trying to cover as many neonatal papers as we can. I think I think we get to almost all of them.

Ben 1:10:58

I think you're right. I think you're right. So

Daphna 1:11:00

thanks, everybody for hanging with us.

Ben 1:11:04

We again, there's going to be the links and the titles of the articles in the in the show description. And should we talk about our guest for next week, do it. So next week, we'll have an interview. Again, we're alternating between journal clubs and interviews. And we're trying to cover that's also something that I wanted to mention, we're trying to cover individual journals and journal club and not try to try to go over papers from multiple different journals so that you can have a feeling that we've gone over an actual journal, and you can actually devote your time to other journals. So we hope that you like it. If you have any feedback, let us know. Next week, we're hosting Matt shuba, who's an adult intensive care physician from Cleveland, who is the sort of founder and who published the Zen intensivist manifesto. And so he'll tease he's going to talk to us about what is intensive ism. And how do we approach intensive care in a more mindful fashion?

Daphna 1:12:00

Yeah, we had a lot of fun recording it. So hopefully you guys have a lot of fun listening.

Ben 1:12:05

Absolutely. Well, definitely. Thank you so much. See you next see you. I'll see you this week at work. We'll see you next week on the next episode.

Daphna 1:12:12

All right, have a good one.

Ben 1:12:14

Thank you for listening to this week's episode of the incubator. 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.


bottom of page