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#301 - 📑 Journal Club - The Complete Episode from April 20th 2025




Hello friends 👋

In this Journal Club episode, Ben and Daphna review several impactful studies shaping neonatal care. They begin with a secondary analysis of the ETTNO trial, which examined whether liberal transfusion thresholds reduce intermittent hypoxemia or improve neurodevelopmental outcomes in extremely low birth weight infants. Despite prior concerns, the study found no benefit to liberal thresholds, supporting current restrictive practices. A JAMA Network Open study follows, revealing that late preterm infants are least likely to receive mother’s own milk at 12 weeks, underscoring an overlooked group in breastfeeding support efforts. Dr. David Rube joins the show to discuss a two-year follow-up of the IN-RECSURE trial, which investigated whether lung recruitment before surfactant administration leads to improved long-term outcomes—ultimately showing no difference in death or disability. The hosts also explore a meta-analysis on umbilical cord blood therapy for children with cerebral palsy, highlighting benefits in motor function for younger children with milder CP when treated at higher doses. Additional topics include the association between funisitis and cerebral palsy in extremely preterm infants and the AZTEC trial’s conclusion that azithromycin does not reduce BPD. The episode concludes with a review of best practices for discussing autopsy with families in the NICU setting.


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


Franz AR, Engel C, Bassler D, RĂŒdiger M, Thome UH, Maier RF, KrĂ€geloh-Mann I, Essers J, BĂŒhrer C, Bittrich HJ, Roll C, Höhn T, Ehrhardt H, Boettger R, Körner HT, Stein A, Neuberger P, Henriksen TB, Greisen G, Poets CF; ETTNO Investigators.Arch Dis Child Fetal Neonatal Ed. 2025 Mar 26:fetalneonatal-2024-327643. doi: 10.1136/archdischild-2024-327643. Online ahead of print.PMID: 40139741


Patel AL, Wilson J, Holmes M, Johnson TJ.JAMA Netw Open. 2025 Mar 3;8(3):e250024. doi: 10.1001/jamanetworkopen.2025.0024.PMID: 40042846 Free PMC article.


Finch-Edmondson M, Paton MCB, Webb A, Reza Ashrafi M, Blatch-Williams RK, Cox CS Jr, Crompton K, Griffin AR, Kim M, Kosmach S, Kurtzberg J, Nouri M, Ri Suh M, Sun J, Zarrabi M, Novak I.Pediatrics. 2025 Apr 11:e2024068999. doi: 10.1542/peds.2024-068999. Online ahead of print.PMID: 40210215


Gallini F, De Rose DU, Iuliano R, Romeo DM, Tana M, Paladini A, Fusco FP, Nobile S, Cota F, Tirone C, Aurilia C, Lio A, Esposito A, Costa S, D'Andrea V, Ventura ML, Carnielli V, Dani C, Mosca F, Fumagalli M, Scarpelli G, Giordano L, Fasolato V, Petrillo F, Betta P, Solinas A, Gitto E, Gargano G, Mescoli G, Martinelli S, Di Fabio S, Bernardo I, Tina LG, Staffler A, Stasi I, Mondello I, Scapillati E, Vedovato S, Maffei G, Bove A, Vitaliti M, Terrin G, Lago P, Gizzi C, Strozzi C, Villani PE, Berardi A, Cacace C, Bracaglia G, Pascucci E, Cools F, Pillow JJ, Polglase G, Pastorino R, van Kaam AH, Mercuri E, Orfeo L, Vento G; IN-REC-SUR-E Study Group; Malguzzi S, Rigotti C, Cecchi A, Nigro G, Costabile CD, Roma E, Sindico P, Venafra R, Mattia C, Conversano M, Ballardini E, Manganaro A, Balestri E, Gallo C, Catenazzi P, Astori MG, Maranella E, Grassia C, Maiolo K, Castellano D, Massenzi L, Chiodin E, Gallina MR, Consigli C, Sorrentino E, Bonato S, Mancini M, Perniola R, Giannuzzo S, Tranchina E, Cardilli V, Dito L, Regoli D, Tormena F, Battajon N, Arena R, Allais B, Guidotti I, Roversi F, Meli V, Tulino V, Casati A.JAMA Netw Open. 2024 Sep 3;7(9):e2435347. doi: 10.1001/jamanetworkopen.2024.35347.PMID: 39320892 Free PMC article. Clinical Trial.


Jain VG, Parikh NA, Rysavy MA, Shukla VV, Saha S, Hintz S, Jobe A, Carlo WA, Ambalavanan N; Eunice Kennedy Shriver NICHD Neonatal Research Network.Am J Obstet Gynecol. 2025 Feb 27:S0002-9378(25)00119-X. doi: 10.1016/j.ajog.2025.02.038. Online ahead of print.PMID: 40023378


Lowe J, Gillespie D, Aboklaish A, Lau TMM, Consoli C, Babu M, Goddard M, Hood K, Klein N, Thomas-Jones E, Turner M, Hubbard M, Marchesi J, Berrington J, Kotecha S.Lancet Respir Med. 2024 Aug;12(8):608-618. doi: 10.1016/S2213-2600(24)00079-1. Epub 2024 Apr 25.PMID: 38679042 Free article. Clinical Trial. 


Kratimenos P, Simonti G, Kinney HC.Pediatr Res. 2025 Mar 31. doi: 10.1038/s41390-025-04031-y. Online ahead of print.PMID: 40164873


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


Ben: Hello everybody. Welcome back to the Incubator podcast. We are back this Sunday with an episode of Journal Club Dafna. How are you?


Daphna: Uh, I'm doing great, buddy. Hoping to have stable internet for this conversation on my little trip away, but, um, glad


Ben: the audience like that right off the bat. The internet will be fine.


Daphna: the Internet's going to be fine, and if it isn't, they'll never hear the rest of this, so.


Ben: That's exactly right.


Daphna: Right. But here we, you know, I, that's our dedication to the program. Right. No matter where we are. We'll find a way to record.


Ben: We soldier on, um, we have a packed episode today. Um, I wanted to address something. We have fan mail. Um, I, I, we're not the most techie group, but that's okay. But basically on our uh, podcast hosting site, you can actually leave us fan mail and people have been leaving


Daphna: do. Please


Ben: Please do. Now. I was trying to reply to these people and the hosting company said, no, you cannot reply to them.

You should just try to reply to them on the air. And I was like, that sounds like a great idea. So they have the feature for us to get messages, um, but uh, we don't have, uh, a feature for them to, um. A feature for them to, to respond. So we'll do that on the air. So we have two new messages that came in the past, uh, couple weeks.

Um, the first one is a very direct question. It's asking us whether our, um, hospital, HDF Florida University NICU supports the app NICU two Home, uh, which is an app that we featured on, um, we featured on the Tech Tuesday. And the answer is, uh, I think in spirit we support them, but we do not, uh, we do not, uh, use NICU to home in our unit.

I think that's a big thing that you'll see from us in these Tech Tuesday episodes. If we are using the device, we will really mention it at the beginning of the episode. Sometimes the, the team will let us like, play around with a, with a beta just to like, before the episode. But, um, you, these episodes are really, um, they're not meant to be commercial.

We don't take any money from these companies and, um, we don't have any invested, uh, interest in, in them. So, so the answer to that question is


Daphna: I mean, and for this one in particular, we have the good fortune of, um, having some of the services through ICU baby. They have their own app, right? So I sometimes think we can give families, uh, resource overload such that they use nothing. So I think, um, for units, um, that may not have a, a regional specific or are not currently using a support app, I, yeah, introduce them.

Parents love them for


Ben: Mm-hmm.


Daphna: Uh, but I worry about having multiple apps running in the same unit. I think then parents end up using nothing.


Ben: We have another message from Mountain View, California. Uh, and this is not really a question, just saying amazing episode. Thanks for all you do for the community. So thank you for that listener, for this, uh, for this lovely message.


Daphna: We love getting feedback.


Ben: This is the best. We, we sometimes get by email a lot of techy questions about like, fixing certain things either on the site or for subscriptions and so on.

And so, so whenever we get a positive note with no, no strings attached, it's great. Um, we have a busy episode today. We will have a, an episode of EB Neo where, um, Dr. Um, David Rube is going to, um, join us to provide his commentary on the paper that was published, um, in September of last year called Lung Recruitment Before Surfactant Administration in extremely Preterm neonates two year follow up of a randomized clinical trial.

Stay tuned for that and um, I think that this is all the announcement that I had for you all today.


Daphna: We were, we were going to put a little plugin for the Tecan n webinars.


Ben: you were going to do that.


Daphna: I'm going to do, I'm going to do that for people who aren't aware yet. Every two years. The a p section on neonatal perinatal medicine, Tecan n Group training, an early career neonatologist, and in general that is, um, from what graduation to seven years out, um, does.

Ben: think they'll officially kick you out


Daphna: I don't think they gave me, I don’t know, I don’t know how that works. Um, but every two years they cycle through a different advocacy campaign, which actually anybody can get involved in. So it's really cool to, to know about either to help put together the campaign, which is a series of webinars, often followed by publication or just to log in for the webinars, the current advocacy campaign, super important.

It's called Together In Care Empowering Neonatal Teams in Palliative Care. And the primary offering is, are these free webinars focused on a variety of palliative care topics. I think they're on the, coming up on the fourth. Um, and they have been very, very good, really wonderful experts. Um, there is continuing education credit for physicians, apps and nurses, as well as MOC part two credit, um, for live and on demand webinar attendance.

The next webinar. Um, we'll be, since we're recording, May 13th at 3:00 PM Eastern, a focused on prenatal palliative care with Dr. Steven Lehner from the Medical College of Wisconsin. And you can learn more about the campaign and register for the webinars at their website. That's https://www.tecanadvocacy.org/together-in-care Um, okay. We wanted to make sure people knew about that.


Ben: Awesome. Um. Okay, let's get into, um, journal club. Um, I guess I'm going to start today, um, with, uh, an interesting article, um, that is a secondary analysis of the ETTNO trial. Um, the, the, the paper is titled The Effects of Transfusion Thresholds on Neurocognitive Outcome in Extremely Low Birth Weight Infants.

It's, um, um, the, the, the, the newly. Published paper is titled The Effects of Liberal versus Restrictive Transfusion Strategies on Intermittent Hypoxemia in Extremely Low Birth Weight Infants. And this was published in the Archives of Disease in Childhood, uh, a few weeks ago. And, um, we've reviewed at length the ETTNO trial and, uh, some of these other transfusion trials.

So I would, I would refer you back to these episodes. Uh, but the authors of this particular paper sought to explore an important secondary question arising from the original ETTNO randomized clinical trial, which was whether red, whether liberal, red blood cell transfusion, um, whether, um, those different threshold reduced intermittent hypoxemia. And more broadly, whether such strategies translate into better, long-term northern mental outcomes, especially in infants with higher, um, intermittent hypoxemia burden. And I was terrified when I read the paper because one of the things that we do mention in our local, uh, transfusion protocol is that if there is a desire to improve oxygen carrying capacity, then you shouldn't really try to follow any specific guideline.

You should make a clinical decision. And so I thought after we had sort of quote unquote settled this subject, maybe now we're going to find out that we shouldn't use such restrictive, uh, threshold. But, uh, so we'll find out what these paper, what these, um, that this team, um, uh, came across. So we know that extremely low birth weight infants, uh, define in the paper obviously.

And in general as babies who are born before, um, uh, with a weight less than a thousand grams, um, almost uniformly develop anemia of prematurity. And, um. And this is a multifactorial process involving physiologic, iatrogenic and disease related factors. Um, we invite you to, uh, listen to our, uh, board review, um, questions and, and subjects on this matter.

Um, historically, um, a substantial portion of these infants, about 50 to 80%, receive one or more red blood cell transfusion during their hospital state. This is something that was brought up by the ETTNO team, and that still strikes me to this day in their, uh, background section. Now, these infants also experience intermittent hypoxemia often due to apnea, stemming from immature respiratory control.

And this raises the hypothesis, could red blood cell transfusion mitigate intermittent hypoxemia by improving oxygen carrying capacity and delivery to the brain? Now, short-term observation had suggested that transfusion might indeed transiently reduce the frequency and the depth or of these episodes.

But does this translate into sustained benefit over time? And more importantly, does this affect developmental outcome? Now, two prior, um. Major randomized control trial were done on, on transfusion thresholds that this is the ETTNO trial, in the top trial. And really just as a reminder so that, um, if you are not familiar with these papers, it, they really showed no benefit of liberal transfusion thresholds on neurodevelopment at 24 months corrected age.

Um, but neither trial truly had. Examined whether, um, red blood cell transfusion would prevent intermittent hypoxemia or prevent or protect the brain from hypoxic injury related to both anemia and hypoxemia. So this is, um, a secondary analysis of the ETTNO trial that's designed to number one compared the percentage of time spent in intermittent hypoxemia and the number slash duration of these episodes between liberal and restrictive transfusion strategies.

And number two, to examine whether there is an interaction between transfusion thresholds and intermittent hypoxemia burden in relation to outcomes at 24 months, including death and neuro mental impairment. So obviously reviewed in a previous journal club, this relationship between intermittent hypoxemia and potentially systemic hypertension.

So I thought this was right up my alley this week, um, in reviewing this paper now. Um, a quick reminder on what the, uh, the design of the ETTNO trial was. It was a multicenter, open label, randomized parallel group study that involved 36 European NICUs. And, um, and these infants were, um, randomized to this.

This was an infant less than a kilo at birth who were randomized to liberal versus restrictive transfusion strategies with different hematocrit thresholds, uh, determined by postnatal age and their clinical condition, whether they were critical or noncritical. I'm not going to get into the details of that method.

We reviewed it at length. Now in this secondary analysis, only infants that had actually, uh, pulse oximetry data for over, um, 80% of the duration of time they were looking at, they were looking at babies between day eight and day 49. These are the babies that they included. Those were, um, eligible for participation in this, um, study.

Now of the original 1000 infants, I think 554 met this criteria. And, um, they were allocated, basically 268 was, were in the liberal group, and 286 were in the restrictive transfusion group. So, um, the other, um, exclusion criteria were that if the birth, the gestational age was, uh, above 29 plus six weeks, major congenital anomalies or again, issues with that pulse oximetry data. Um, the pulse oximetry stuff was fairly standard. They were using sort of Massimo pulse oximeters. Um, so I'll let you, um, review that. So how did they define these intermittent hypoxemia events? So this was defined as a, a saturation, um, going, um, below, um, 80% lasting for more than 60 seconds. And these criteria were chosen based on prior association with adverse outcomes.

And, um, and they looked at this analysis through various time points, postnatal day eight to 21, 22 to 35, and day 36 to 49. What were some of the, uh, primary outcomes of the study? Number one, the percentage of time spent in intermittent hypoxemia. Number two, the number and mean duration of these episode.

And number three, the interaction between the intermittent hypoxemia burden and transfusion threshold, um, in predicting the ETTNO primary composite outcome of death. Or NDI at 24 months. So far so good. Dafna. Okay. I think you're nodding along.


Daphna: I'm giving you a thumbs up, but


Ben: Thank you. Um, okay, so in terms of the results, the baseline characteristic, there were no significant, um, I'm sorry.

Uh, the, the neuro impairment stuff was defined as a, on a Bailey with an MDI of less than 85 cerebral palsy hearing or visual impairment. Um, so, so that was, that was also, uh, something of note in terms of, uh, results, uh, the baseline characteristic. There was no significant differences observed between the groups, uh, between the ones who were included versus the one that were excluded in the, um, in the original study, looking at the intermittent hypoxemia burden by, um, transfusion, uh, strategy. What we're looking at is that across postnatal day eight through 49, the median percentage of time spent in intermittent hypoxemia was, um, about 0.91% in the liberal group versus 0.79% in the restrictive group. Um, the median number of episodes was about 236 in the liberal transfusion group versus 203 in the restrictive group, and the median duration of episodes and events with, uh, lower, um, pulse oximetry were also similar between the two groups.

So effectively no statistical difference, um, between the two groups. In terms of, um, in terms of looking at this from, from a, a shorter time point, the none of these differences were statistically significant and the burden of intermittent hypoxemia. Peaked between day eight to 35, especially in infant with lower gestational age in terms of outcome by, uh, hypoxemia exposure.

So in the subgroup with, um, an above average exposure to hypoxemia the rate of death, or NDI was about 54% in the liberal group versus 50% in the restrictive group. Again, no significant difference there. Similarly, the rates of cerebral palsy and, uh, lower MDI were not significantly different, and they performed a lot of statistical analysis and a logistical regression models confirmed no interaction between the transfusion strategy and the hypoxemia burden on any of these outcome.

So overall, I felt pretty good about this. Um, this, um, this, this analysis really tries to answer the, the, the question, does a liberal transfusion strategy mitigate intermittent hypoxemia over time? And the answer seems to be no. Um, in terms of, um. Earlier report suggesting maybe a short term improvement in oxygenation following red blood cell transfusion.

I think that's the question that we all have. We know that when we have babies that have issues with hypoxemia, we can give them sometimes blood if they're anemic, and, and that helps. So how do we recon reconcile these two, um, these two issues the authors suggest, um, three possibilities. Number one, um, intermittent hypoxemia may not causally contribute  to poor outcome.

Rather it's just a marker of extreme prematurity. There may be some physiological compensatory mechanism, um, like cardiac output, cerebral vasodilation, and then, um, again, potential harm from regular cell transfusion. They're also talking about the fact that. Maybe it's just a very transient effect that does not translate over long-term, um, benefit.

So the conclusions of the article are that among, um, extremely low birth weight infant liberal transfusion does not reduce the burden of intermittent hypoxemia during the critical weeks of, uh, eight to 49 days postnatal life. Nor do they, um, seem to be improving, um, the outcomes at 24 months, even in those with higher exposure to hypoxemia.

And so liberal transfusion strategies should, um, not be used even in that case to prevent intermittent hypoxemia or to try to improve neurodevelopment in this population. Obviously, future research could be used to help, uh, the granularity of this answer. And we're looking forward to a more subject. What are your thoughts?


Daphna: Yeah, well, I, um, my first thought is how few Hypoxemic episodes they collected. Like, I mean, they collected them, but I was surprised, I thought the percentage of time. For any of the group, for the whole cohort might be higher than it was. It was a pretty low percentage of time spent in hypoxemia, which I think is great.

I think that's wonderful. Um, I'm not sure it feels like that when you're walking through the unit and for, for every patient,


Ben: Well, you have, you have to remember that, um, the, the, they were really trying to look at clinically significant events. Um, and so we're looking


Daphna: than 80


Ben: Less than 84, 60 seconds or more. I mean, thankfully those, those, I, I kind of was thinking, like, I was thinking, don't they happen more often? I think these happen less often.

I think we'll see maybe like a baby being in the 85 for a short while and then climb back up. But to be  in the, to be in the seventies for, for, for that long, for almost a minute, um, with no intervention sounds, I mean, yeah. I really hope none of our listeners see that, uh, too frequently. Because that that might be, uh, that might be scary.


Daphna: Yeah. And I do think we get kids who do, who dip down and they come right back up. As soon as


Ben: Yeah. Whoop.


Daphna: they come back up. Uh, so that's absolutely right. And I just, I'm, I was trying to look it up while you were chatting. I, I don't remember if there was any difference in FI O2 requirements, um, in the, in the two groups.

You know, we were looking at Hypoxemic episodes, but I wonder were they able to wean the oxygen in some of these groups? I don't know. I don't recall the, the answer. Um, so that


Ben: be, uh, to be perfectly frank with you, I believe that this, this data might be in the supplemental material. It's not in any of the tables on the actual paper. Um, so, uh, I might have to do some more digging to get that information. I.


Daphna: Because I, I do feel like, well, I've, I've felt both scenarios, and this is not based in evidence. This is just how I feel that there are some babies who you give them this blood and gosh, you're able to wean that oxygen. And then there are some babies where, right, we all had this, um, concept that it would improve oxygen, you know, uh, improve hypoxemia by improving oxygen, uh, carrying capacity.

And you give the blood and, and I guess that's what they're showing. You aren't able to wean those kids. Um, so, you know, I, I, I feel like I've had the sensation of, of both of those, uh, um, types of patients. Um, but it's, it's nice to see the more granular data for sure.


Ben: Yeah, and that's exactly what the authors mentioned. They, they mentioned that the randomly assigned transfusion strategy applied in the ETTNO had no impact on the percentage of time with SATs below 80 during the postnatal days, eight to 40, 49. They're saying that, um, what their data suggests then is that.

The, the benefits that we're talking about must be transient in that liberal transfusion resulting in an overall mean hemoglobin increase of about one gram per deciliter will not reduce intermittent hypoxemia during those days, eight to 49, hence. Um, and so, so that's, that's really the key that they're making about saying, well, it, it may be that you're, you're getting a little bit of a, of an effect, but are you making a big difference in terms of these severe, severe episodes?

Probably not. And maybe that the baby that was so sort of stuck on 88% really having an, an increased FI O2 will benefit more from these transfusions. But, um, these severe hypoxemic episodes seem to be on a, on, affected by that.


Daphna: Well, thank you for that.


Ben: Yeah. Welcome.


Daphna: Um, I had an article I wanted to share. Um, it is entitled Mother Zone Milk Provision during the first 12 Weeks of Life by gestational age lead author Aloka Patel, um, senior author Tricia Johnson. Um, [00:20:00] this is in a JAMA Network Open, uh, pediatrics. Um, and what they were really looking at was, does the initiation and duration of mother zone milk feeding vary by gestational age of birth?

And I, I think people might be surprised. I mean, the answer is yes, but, um, by which gestational ages? Um, so this was a retrospective cross-sectional study using, uh, prams data. That's the Pregnancy Risk Assessment Monitoring system, uh, from, uh, through, uh, the year. Year of 2021. So if you don't know what premiums is, it's a surveillance system, uh, established by the CDC to look at kind of population level data about maternal characteristics, health behaviors, health indicators, and um, in, in, uh, pregnant mothers and in infant health.

Uh, indicators, um, women are surveyed by male or telephone between two and six months after delivery. And, uh, then these completed surveys are linked to the birth certificate. Data and data in this study, um, included birth certificates and this survey information from 36 jurisdictions. That was 33 states, the District of Columbia, New York City, and Puerto Rico.

Um, so what were they looking, and sorry to make that clear. Basically they don't look at every single pregnancy or birth, but they pull a selection randomly, um, to look at this kind of population data. So outcomes included, um, mom zone, milk feeding initiation, so defined as providing any maternal breast milk and mom zone milk feeding, continuation defined as mom own milk provision at 12 weeks after delivery.

And this was conditional on moms own milk feeding initiation. So they did a, a number of analysis, some including those, those um, uh, women who never initiated breastfeeding. And those that did. A secondary outcome was mom's own milk provision at 12 weeks after delivery, like I said, not conditional on mom's own milk feeding initiation.

So the mom feeding duration was determined based on the survey question, how many weeks or months did you breastfeed? And they split the infants up by gestational age at birth, and they were classified into, um, four groups. So they had the extremely preterm, uh, less than or equal to 27 weeks gestation.

The moderately preterm 28 to 33 weeks, three weeks gestation. Late preterm 34 to 36 weeks gestation. And this group that they called early term to post term, which is basically, uh, greater than equal to 37 weeks, they have collected a bunch of maternal characteristics. I won't go into all of them specifically, um, but some of the differences.

So the results in total, uh, they had 30, just over 33,000 women, 91% of the sample, which completed the survey at least 12 weeks after delivery, which I thought was phenomenal. Um, they had a total of just over 29,000 births in the pram sample. And this misrepresented about 1.5 million births in 2021.

And this represents about 41% of the total births in the us. Overall 0.4% of infants were born extremely preterm, 1.8%, moderately preterm, 6.7% late preterm, and 91.1% were this early term to post-term group. Um, many paternal characteristics differed by infant gestational age. Um, but interesting. One thing that was not different was WIC used during pregnancy and prenatal care in the first trimester.

Some other differences. Mothers of the early term to post-term groups. The oldest group, uh, infants were more likely to be white. They were more likely to be married, to have completed college, to have a singleton and to have delivered vaginally. They were less likely to have Medicaid insurance compared with mothers of preterm infants. Okay, we'll get into the, uh, mom's own milk feeding. So unadjusted rates of mom's own milk feeding initiation were similar for mothers of early term to post term. Do you have a question?


Ben: Nope, I'm waiting. This is the, this is the, this is the, the, the best part of the paper.


Daphna: Yeah, for sure. Well, this was the unadjusted, but we'll get there. So 88%, um, almost across the board. Uh, the moderately preterm 88% and the extremely preterm, 89%, uh, with a lower rate of mom's own milk feeding initiation observed for mothers of those late preterm infants, 81.8%. And for mothers who didn’t. So that was a whole group for mothers who initiated mom's own milk feeding. Um, 71, uh, percent of mothers of this, the oldest group early term to post-term infants continued to provide milk at 12 weeks [00:25:00] compared with 61% of late preterm, 58% of moderately preterm, and 63% of mothers extremely preterm infants.

Now after adjusting for maternal characteristics compared with the early term to post-term mothers, there was no significant differences in mom's own milk feeding initiation for mothers of the moderately preterm or the extremely preterm. However, mothers of the late preterm infants, um, were 4.4 percentage points less likely to initiate mom's own mom, mom's own milk feeding and 6.7%, uh, less likely to continue providing mom's own milk at 12 weeks compared with mothers of the early term to post-term infants. There was no difference in adjusted continuation ranks among extremely preterm and the moderately preterm infants compared with their early term to post-term infants. And, um, there were some significant differences, uh, by Reese that they described. Um, they found significant differences in mom's own milk feeding initiation by maternal race and ethnicity with Hispanic and white mothers and mothers of other racial groups, more likely to initiate moms own milk feeding compared with black mothers. There was no difference in moms own milk feeding initiation by WCU during pregnancy. Um, however, for mothers who initiated moms own milk feeding, those who did not use WIC, um, actually had a higher rate of mom own milk feeding continuation at 12 weeks, 72% versus 66% mothers was less than a high school diploma.

Were least likely to initiate moms own milk feeding compared with mothers with higher levels of education. And in the supplemental analysis of overall mom's own milk provision at 12 weeks, including the mothers who did not initiate mom's own milk feeding, uh, 63% of mothers of this early term to post-term infants, 50% of the late preterm, 50% of moderate preterm, and 56% of the extremely preterm infants provided moms own milk at 12 weeks.

But after adjusting for maternal characteristics, mothers of late preterm infants were 8.5 percentage points less likely to provide moms own milk at 12 weeks compared with mothers of early term to post-term infants. So, uh, the take home point is obviously there are a number of, uh, maternal risk factors, societal, socioeconomic risk factors that we know predict, um, breastfeeding rates.

Um, but I think they're highlighting are really important. Um. Fact that the late preterm infants were consistently less likely to receive mom's own milk, feeding at birth and 12 weeks compared with even the extremely preterm or the moderately preterm, uh, groups. Um, and so I think this was really interesting.

I think it makes sense, uh, in their discussion, they talk about what some of those reasons, um, are. Um, you know, uh, they have, they may have short stays in the nursery. They may have short stays, even if they are admitted to the nicu. This late preterm groups, and I'm going to read this, you know, other little piece just from the discussion.

Late preterm infants are known to be at greater risk for neonatal morbidity, difficulty feeding and readmission compared with the full term counterparts. Specifically late preterm infants are a particular risk for breastfeeding. Um. Directly due to their immature sucking, weak suction patterns resulting in less robust milk transfer, which in turn negatively impacts milk supply.

They have neurologic immaturity, limited ability to regulate sleep and wake cycles, and may result in parental perception of a late preterm infant being satiated when the infant is falling asleep, even if the baby hasn't gotten enough to eat. Um, these factors may result in inadequate nutrition, dehydration and jaundice, higher rates of readmission, um, for late preterm infants compared with full-term infants and improving mom's own milk.

Feeding rates in the sizable population of late preterm infants, uh, may impact both short-term, long-term outcomes and would translate to future educational and economic benefits and lower medical costs. Um, I think in general, let's say for our NICU colleagues, um, those babies tend, again, tend to stay less time in the nicu.

They have less time to work on breastfeeding, get that breastfeeding support. They are hopefully often less sick than some of the other, uh, babies in the nicu and they may not get the most of our attention this late preterm group. Um, so I thought this was important for us to discuss thoughts.


Ben: Yeah, I mean, it's interesting, you're, you're sort of harpooning on the, on the late preterm group. Um. But I was kind of shocked by the, um, early preterm group, right? I mean, I would think that, um, we should have, [00:30:00] if we had thought about this question and try to answer it in a vacuum, and instead are in an ideal world, who would we expect at 12 weeks to be still supplying a ton of breast milk?

You would've expected that this would've been the mother of the 23 weeker who's probably still in the ICU, who's probably still maybe a bit sick compared to the full term, who's at home and who's now like thriving. And, and the difference is not that, that striking. I. I mean, um, it doesn't seem right and correct me if I, if I misread the paper, but like the, it doesn't seem that the, the, the, the mothers of, of early preterm infants are that leaps and bounds ahead from their sort of full term counterparts, if you want to call them when it comes to, um, m mater mother's own milk feeding at 12 weeks conditional on the initiation.

So I thought that was, that, that, and that to me probably means we should look at what are the barriers for our mothers in the NICU to continue to provide milk. Is it, is it like work related stuff that now they may be there, their whatever their, uh, their leave is, is expired and now they have to go back to work.

And I mean, I don't know if, uh, again, this is, um, a very typical US problem, but maybe that plays a role and maybe we should look at these, at these obstacles. I don't know. I.


Daphna: Yeah, I mean, I guess I, I, I may disagree with your initial point that you expected the extremely preterm moms to, to have higher rates of pumping. I, I think we really underestimate how we all do, underestimate how much work it is, even if you're at home or say myself on my brief maternity leave, how even if you're at home, good resources, great support, um, you don't have to, we did, I did have to go back to work right away, but, you know.

Whatever. I think we don't, we underestimate the stress of having your baby in the NICU on milk production. We underestimate that coming in, maybe missing a pump because you're [00:32:00] coming to see your baby multiple times a day. Um, all of the other external factors that you're start really juggling while, um, your baby's in the nicu.

Um, I think this, uh, fits with other, uh, nicu, uh, data on breastfeeding rates, uh, both, uh, in and out of the nicu. Um, uh, but I, I think, I think we could do better. We just need, as a, a society, as a system to really support these


Ben: To really prioritize it. Yeah, no, I mean, and again, I was not trying to, to dismiss the, the difficulty of, um, of providing breast milk for, um, a baby in the nicu, but I would think that, uh, I was saying it from more from, I. The perspective of a mother, of a full term baby that's now three months. It's, it's easier to transition at that point if a baby is healthy and three months and say, okay, I'm going to start doing some bottle feeding at some point, I think that's perfectly understandable.

But if you have a baby that, I don't know, at 10 weeks is now 30, 32 weeks, 33 weeks, um, the, the, the pressure unfortunately is still on. And you would think that, that, um, because of that, um, mothers would, would, and especially because of the fact that hopefully breastfeeding is well established at that point, that they're able to achieve much higher rates.

Um. But, but no, and I think that is to me, not, uh, a knock on these parents, but more, again, like you said on the, the system wide barriers that they're experiencing, um, in continuing something that at initiation was quite high. Like that is the other thing. It's not that you're saying, oh no, they're very consistent.

They, they, 70% started and was no, there's a big, big drop off. Um, and I think that this is where, I think this is where the gap is. This is where the opportunity lies in my opinion. What, what is happening there? Is it, uh, and then try to work on that. It sounds like a very strong advocacy, uh, project.


Daphna: for sure. And, and lots of people are working. I think it's, it's tough, I think in our, especially in the us I think for the reasons you said, we, I'm not sure we will get over and we know how important mom's own milk is. It's like the only thing we know that works.


Ben: Uh, and I think that these mothers are, are painfully aware of it because of their prior 12 weeks in the nicu. They're, they're not, this is not lost on them by no means. Okay. Um, we're going to take a very quick break. We'll be back with our EBNEO segment and, uh, we'll see you back in a, in a few minutes. I am back for an EBNEO. Uh, today I am joined in the studio by Dr. David Rube, an affiliate trainee in Clinical Futures, a fellow in the Pediatric Hospital Epidemiology and Outcomes Training program managed by Clinical Futures and a third year neonatal perinatal medicine fellow at the Children's Hospital of Philadelphia.


Daphna: If that wasn't enough, Dr. Rubin is currently completing his Master of Science in Clinical Epidemiology at the University of Pennsylvania. David, thank you for joining me today.


David Rube: Thank you for having me.


Daphna: Oh, it's my pleasure. Um, I'm glad that we're going to be talking about this article. Um, I'll throw out the title. It's Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates, two Year Follow of Randomized Clinical Trial.

So this is in JAMA Network Open. And it is a follow-up of the in rec. Sure. So intubate, recruit, surfactant, extubate trial. But just to remind people, tell us a little bit about the original trial.


David Rube: Sure, happy to. So INRECSURE. Um, so, you know, of course a play on INSURE, but it was a randomized clinical trial, um, unblinded that was performed at 35 tertiary NICUs in Italy, um, between 2015 and 2018. Um, and in this trial they basically, they randomized babies either to, um, standard INSURE protocol and there sort 24 to 28 weekers, um, either standard INSURE or to their INSURE protocol, um, and INSURE.

Sure. The recruitment that they did, um, specifically, uh, used a high frequency, um, oscillatory ventilator and used the, um, like a stepwise approach. Um, so they put the baby on the oscillator. They started at a map of around eight and then they went stepwise following, um, their oxygen saturations, found sort of what they consider their opening pressure and then, you know, threw a couple more steps settled on there.

And then after recruitment, after they performed the recruitment over, they delivered their surfactant and extubated the baby.


Daphna: So tell me a little bit about what they found, or I guess what they didn't find.


David Rube: Yeah, yeah, absolutely. So their primary outcome and what they were powered for was, um. Uh, presence or, uh, need for invasive mechanical ventilation within the first seven, two hours of life. Um, and actually in, for their primary outcome, it was a positive trial. So they found a significant reduction, um, in that, in that primary outcome.

Um, specifically it was about 40% in the INSURE group and 54% in the INSURE group. Um, so relative risk of 0.75. What they didn't find though was, um, looking at their long-term outcomes. So they didn't end up seeing any difference in BPD rates. Um, in their intention to treat analysis, they did not find a difference in mortality.

Um, although they did find one in their per protocol analysis, which we can talk about a little more. Um, and, and then this study now, the two year follow-up was really to look to see, um, if there were any differences at two years in death after discharge or. Um, major developmental, um, delay.


Daphna: Perfect. So tell me a little bit about the methods here.


David Rube: Great. So, um, similarly, so these babies were, it was all the same babies that were enrolled. So the initial trial enrolled about 200 babies. Um, and then at time of discharge there were 150 that were still alive, and then they followed them for two years. Their overall follow-up rate at the end of the two years was a hundred, and they, I think they had a hundred and thirty, a hundred thirty seven babies.

Um. Total at that time. And they did a two year follow up visit. So, um, they went through sort of like a neurodevelopmental assessment. Um, they also looked at, um, height  growth and, um, and some of them, they tried to get some respiratory measures and look at, you know, number of hospitalizations due to respiratory issues.

Um, but that was only done for about a hundred babies.


Daphna: All right, so let's get in. I guess let's dive into the, the nitty gritty of the results then.


David Rube: Sure. Absolutely. Um, so unlike the primary trial, so for the primary outcome in this trial, they did not find a significant difference, um, in their composite outcome of, uh, mortality after NICU discharge or major developmental delay. So the INSURE group, um, it was, there was 13 out of the 64 had. Major developmental delay or, or died in that period.

And then the indirect sugar group, it was 10 out of 70 degrees. So no significant difference there. And then when we looked at their secondary outcomes, um, they looked at the major developmental disability alone. So included cp, cognitive impairment, visual or auditory deficits, all at two years corrected postnatal age, and they didn't find any differences there either, anything statistically significant.

Um, and then the same goes for anthropomorphic measures and. Um, respiratory, um, the respiratory outcomes. So recurrent respiratory infections are hospitalization, secondary to respiratory causes.


Daphna: So what did you think about the findings? Pleased. Not pleased. What? What were you expecting?


David Rube: Yeah, I, you know, it's, um, I think one was an interesting, um, primary outcome choice. Um, and I think there's been a lot in the literature recently about composite outcomes, specifically grouping death, and, um. Major developmental disability and equating, equating the two. I, I mean, I think there's a lot of reason as far as like a competing outcome goes and, um, if a lot of babies are dying and we're all of a sudden see better neurodevelopmental outcomes that we're just missing the ones that would've had delays if they had that earlier.

But I think it's important to separate them out and which they did and look at, um, the differences on their own. Um, and then yeah, but overall, I don't think it necessarily. Moves the needle as far as changing any management to what most of us are doing. Um, um, early on, just, you know, given I, I think this point, there were no, no improvements in, in either neuro of them, mental outcomes or mortality.

Um.


Daphna: Yeah. And I, I wonder sometimes with these quote unquote negative trials, um, this was kind of a new maneuver. They were trying something new. It did reduce the need for mechanical ventilation, um, in those first 72 hours. Um, and the babies didn't do worse. I guess that's another way that we could look at it as well.


David Rube: Yeah. And. I think one of the more interesting findings was that they had this really significant reduction in mortality they, um, describe in their initial study. And, and in some of the commentary that the authors have put out, they feel like that  is part of the reason why they didn't see any improvement in their long-term.

BPD outcomes was because of the significant early mortality. Um, but let's to say there was a couple interesting things in, in how they reported that, that those results, um, so. One, when they did the intention to treat analysis. And so that's analyzing them as they were randomized. Um, the results weren't statistically significant, although there was still this big signal towards reduced mortality.

Um, and then when they decided to reanalyze it as a per protocol analysis, meaning, um, analyze babies as to what they got instead of what they were randomized to. Um, and there they sort of shifted into a little bit of a statistically significant result. Um. But if you dive deeper into why these babies died and sort of looking at those overall mortality rates, um, the mortality rate in the first 24 hours was actually pretty high.

For this group. It was about 10% in each. Um, and one thing to note is that babies in both groups actually received sustained inflations, um, in the Dr. Um, and so, and you know, as we've seen with some of the sale trial results, there was this big signal towards, um, increased mortality in the groups that receive sustained inflation at birth.

Um, so that higher baseline mortality risk may be, um, exaggerating the mortality benefit that we're seeing with the enrich maneuver. Um, the other thing is, is why the babies died. Um, and so the big difference between the two groups was actually, um, there was a really high rate of pulmonary hemorrhage. In the first 24 hours in the INSURE group.

Um, which I have to say is not necessarily my experience, um, as far as like what I see as complications in the first 24 hours after surf active administration. And, and just to say we're a, we're a Lisa missed unit. Um, so, um, you know, unless the baby needs to be intubated, and then we will, we'll be good them, um, surfactant through the tube.

But I, I almost wonder if this. Benefit difference is just that in the indirect Sure group, you had this extended period of time where the baby had a tube in place, you sort of knew that it wasn't deep. Um, so not so much the recruitment itself, but just a stable tube position as opposed to the INSURE where you're putting in the tube quickly, not getting an x-ray to assess position, giving surfactant, and then pulling out.

So. Is that maybe, was there more preliminary hemorrhage due to maybe a DPT tube in the INSURE, in the INSURE group? Um, so anyway, just something to think about with how the results ended up shaking out in this study.


Daphna: Yeah, especially that adverse event. I mean, pulmonary hemorrhage is one of those things you, you really never want to have to address, but it does, um, it does happen and we know that the mortality rate is really high from, you know, the pulmonary hemorrhage. So we, we can avoid it at all. Cause that, that would be the goal.

Um, thank you for also disclosing what you guys are doing in your unit. Um, we, our unit is still using a, uh, a smattering different, different techniques for different babies. And, uh, I'm not sure that's the right answer either. Um, but what do you think about this discussion about, uh, surfactant administration?

Have we found the optimal way yet?


David Rube: I, you know, it's interesting. I don't know if we found the optimal way, but there's definitely this, you know, obvious push towards going as less invasive as possible and part of that, you know, and to bring in a new modality. But our group has started, um, trialing salsa or the. I'm using MAA supraglottic airway for delivery of surfactant.

And we've had some pretty good, you know, from what we've seen, pretty good user experiences and very easy to give it that way. Um, but I, I think if you have the capabilities for it, and I, and I think big part is needing, really using video  laryngoscopy for giving Lisa and Mist, um, it does seem like the evidence is there to support Lisa and Mist over INSURE.

Um, but again, different units of different capabilities. Different providers are comfortable with different things, and so I think if you, the best way you know how to give it in the safest way, what you're used to is probably going to be best for the.


Daphna: I love that. I couldn't have said it better myself. So, um, David, thanks so much for joining us. Thanks for your, um, commentary on this paper. Um, and everybody can take a look again. Um, it's in JAMA Network Open. Thanks for your time.


David Rube: Of course. Thanks Abta. And just one last thing to say, they are planning a second trial comparing INSURE to Lisa, so we'll wait to see what those results


Daphna: So we'll see. The jury's still out. Thanks so much.


David Rube: course, thanks for having me.  


Ben: We are back. Thank you, um, Dafna for, um, this, uh, very nice EBNEO segment. Um, and, uh, we're going to pick up right where we left off with more review of, uh, recently published paper. I think it is my turn and I would like to turn our attention to a very.

Compelling, uh, paper that I saw published in Pediatrics by Finch, Edmondson and colleague called Cord Blood Treatment for Children with Cerebral Palsy, individual Participant Data Meta Analysis. Um, it's not a subject that probably is going to be very relevant to us at the bedside in terms of how we manage, uh, our patients, but it's, it's definitely relevant to our field and definitely relevant to our com communications with parents.

This study addresses one of the most, um, I would say intriguing and maybe hopeful areas for cerebral palsy, which is the therapeutic potential of umbilical cord blood for improving gross motor function. Now, a little bit of a review. CP obviously is a, is a, is a group of lifelong neurological conditions caused by non-progressive injury or, um, issues with development in the developing brain.

Now, traditional care involves a combination of rehabilitation, orthopedics, assistive technologies, and sadly enough. They, these often have modest gains despite, um, significant effort in their implementation. Now, stem cell therapy has emerged as a promising approach, and the field has evolved from aiming to, uh, replaced damaged cells through engraftment to now focusing on this properties of the umbilical or of these stem cells on their anti-inflammatory and immune modulating mechanisms.

So the therapeutic potential is thought to arise from the umbilical cord blood's, paracrine signaling, and its ability to modify local brain environment and to promote endogenous repair. And it's important for us to know this because as we're going to see in the result, it sort of plays a role in who we will see benefit most from these potential therapies.

Now, umbilical cord blood is the most extensively studied stem cell therapy for cp. Um, nearly 20 years of clinical research has been devoted to that specific, uh, type of cell lineage. Preclinical models have shown that umbilical cord blood, uh, stem cells reduce brain infarct and neuroinflammation, and increases both neuronal and oligodendrocyte population leading to functional improvement.

Now, these biological changes align with clinical data showing that, um, brain connectivity improves on imaging after stem cell therapy. Now. A 2021 review reported that 600 children with cerebral palsy had received umbilical cord, um, blood stem cells therapy, either in single arm or control trials with consistent evidence suggesting improved gross motor function as measured by the gross motor function measured the GMFM.

Um, however, there's significant heterogeneity across these studies, differences in the participants. There's different treatment protocols, there's different dosing, and this really has made it difficult to determine the true efficacy dose response relationship and the best responders. So basically this is a mid analysis that, um, we've, we've sort of looked at this type of data of research, um, methodology in the past.

It's, it's an individual, it's a pulling individual participant data into a meta-analysis. So they basically not just took the aggregate results from each study, but looked at individual patients and their objective was to overcome these limitations and to determine, number one, the effect of umbilical cord blood on the GMFM.

Scale at 1, 3, 6 and 12 months. Number two, to look at the impact of cell dose on treatment outcomes. Number three, um, to look at the influence of covariates such as the age of the patient, the severity of cerebral palsy and their, the etiology. And number four, to look at the safety of, uh, umbilical cord blood treatment.

So far, so good. So in terms of the study methods, um, this was, uh, pre, uh, registered systematic review and individual participant data meta-analysis that  was conducted under Prisma IPD guidelines. The eligibility criteria included studies that administered autologous or allogenic umbilical cord blood via any route, and with or without the use of concomitant, uh, e PPO to individuals who were diagnosed with cerebral palsy.

Now, inclusion required baseline and follow-up, uh, GMFM. By the way, I'm going to continue seeing GM FM because I do not feel like seeing gross motor function measure, uh, at one. At 1, 3, 6, or 12 months, the primary analysis excluded participant, uh, who received EPO alone or with the umbilical cord blood and those with multiple umbilical cord blood transfusion.

So, um, in terms of, uh, the data, the, the, the Data Inc was, um, collected from 11 studies, seven control trials for single arm study, totaling 498 participants, uh, representing 447 unique individuals. The we. Um, okay, so after exclusion criteria were applied, we had 170 participants receiving umbilical cord blood versus 171 who were in the control group, and 53 patients who received umbilical cord blood with EPO.

And those were analyzed separately. 60% of the participants in that meta-analysis were male. 90% had spastic cp, and 85% had bilateral involvement. All GMFCS levels were represented Over half were classified as moderate to severe, uh, GMFCS classification of four to five. The mean baseline age was about 55 months, but the range was very wide.

They had babies as early as eight months, and children as high as 18.9 years kind of adults. If you ask me, um. Ideologies were quite varied. Um, 21% were stroke slash um, IVH 13% were HIE and they had, um, a whole category called other, um, that composed of pathologies that we are familiar with. PVL, meningitis and even conus.

Now, 84% of the, of the administration of umbilical cord blood was allogenic, and 86% of these 84% were from unrelated donors. Um, one of the studies administered the blood intrathecal and all other use the IV route. Uh, the most common follow up point was six months. And, uh, that was assessed in, uh, 72% of the participant.

Looking at the baseline differences between, um, the participants, they saw no significant differences in demographic or clinical characteristic. So let's look at some of the, of the outcomes. So for the primary outcome. What they found is that, um,  the administration of umbilical cord blood stem cells led to significant improvement in GMFM at six months of age, at six months post infusion, I'm sorry, and at 12 months post infusion, um, with an increase in the GMFM scale by plus 1.36 points at six months and plus 1.42 points at 12 months.

No significant improvement, however were seen at one or at three months. Um, if they looked at the other group of patients that also receive epo, um, they saw similar results at six and 12 months. And sensitivity analysis excluding single arm or unpublished data, did not change the outcome. Interestingly enough, when they looked at the dose that was used, um. They found that a higher um, dose, a higher total nucleated cell count was associated with a greater gain in GMFM and that was statistically significant at three months and [00:55:00] at 12 months. And that doses that were below 50 million, uh, total nucleated cell per kilo had little to no effect. In terms of sever CP severity and functional response, that was very, very interesting.

Participants with milder CP G-M-F-C-S of one through three showed greater improvement at both three months, six months, and 12 months. And that, um, they didn't see beneficial effect of the umbilical cord blood cells in those patients that had, um, a more severe form of CP, GMFCS of level four to five, irrespective of the dose.

When it came to, um, the, the milder group, a higher dose was actually even more potent and actually led to more gains. Now another very interesting point of this study was what was the age of the patient at baseline? And what they found was that younger children responded better to umbilical cord blood  treatment.

And after adjusting for the baseline G-M-F-C-S level, significant effects were found again at six months and at 12 months and at older children showed less improvement again, reinforcing potentially the benefit and the importance of this early intervention. In terms of the ideology, did babies with certain reason for reason, quote unquote for their cerebral palsy, responded differently?

They couldn't really find significant response differences between ideologies after adjusting for CP severity, looking at the sources, um, of the umbilical cord blood, whether it was, um, autologous or allogenic. Again, that didn't show any difference, but I think it's very important to mention that there were very little.

Autologous, uh, group. So maybe take that with a great salt in terms of safety. Um, they report, um, serious adverse events. Uh, the, the groups were comparable, 16% in the stem cell treated participants versus 13% in the controls. And they said that there was only one serious adverse event definitely related to umbilical cord, um, infusion, uh, umbilical cord blood infusion.

Um, so overall, not something that that was, um, out, uh, overtly concerning based on the number of patients that are included. So, um, I think this study is interesting because it shows that umbilical cord blood treatment could be safe, it could be effective, and it. Has an effect obviously, on improving gross motor function in some children with cp and that there seems to be a profile that, um, favors the, the effect of umbilical cord blood stem cells.

It seems that infants who are younger, who are less than five years old, who have a milder form of CP at presentation and who are treated with higher doses of, um, stem cells benefit more. And that these benefits become evident at about six to 12 months post infusion. Um, again, maybe reflecting a biological time needed for neural repair because again, as we were saying in the  background, this paracrine activity is not something that can be observed immediately and maybe there's an effect that needs to be observed over, uh, a longer period of time. The conclusion are that, um, the, the meta-analysis provides some strong evidence that, um, umbilical cord blood is clinically meaningful and it's maybe a safe therapy. And, um, the identification of potentially best responders should guide, uh, future research and real world patient. I think it's very interesting because I believe that we counsel families frequently about, uh, the risk of cp and I think that, um, this is something that parents are direly seeking potential therapies and, um, I think we should not be, um, ignorant to this, uh, to this very promising, um, avenue of, uh, clinical research.


Daphna: Yeah, I am like jumping out of my seat. This is, I think this is very exciting. I think this is very promising and think it's not that far away from us, right? So I just, I mean, the mean baseline age at the infusion was this 54 months, but ranging from six months to 18.9 years. And we, we heard you say that the younger kids


Ben: Eight months.


Daphna: Yeah.

Had more, you know, improvement, so,


Ben: which, which by the way is one of the points the authors are making are if we can find the patients even earlier than that, could we even begin much earlier? And I think that is such a promising sort of,


Daphna: Yeah. I think that's super exciting. I mean, eight months, I mean, some of those kids are still in our unit, right? So that's for one, they're definitely in our follow-up clinics. Uh, we had that great interview with Dr. I always say it wrong, say it, Dr. Dr. Myth, um, about, you know, starting to use the Hammersmith in even at, uh, you know, term Postmenstrual age, um, and identifying these babies early and may these therapies, um, become more available.

Um, I think it's really exciting. I, I hope it will be a, an opportunity that, we'll, we'll start doing them in the nicu, I think. I mean, we're not there yet, but I'm, I think we'll get there. I'm hopeful.


Ben: I am so happy You are, uh, you're excited


Daphna: I'm thrilled.


Ben: It's not my paper. I didn't write that


Daphna: You didn't write, definitely


Ben: taking, I'm taking credit for it.


Daphna: No, I'm absolutely thrilled. I think, um, we focus a lot on trying to prevent brain injury in the nicu.

Yes, absolutely. A hundred percent great idea. And some babies are still having brain injury and we have to do something about it. So I am, I love that paper. Very cool. Thanks buddy. Um, I have a, a paper that relates to cerebral palsy also, so I guess I'll do this one next. Um, it is entitled Funisitis Increases the Risk of Death or Cerebral Palsy in Extremely Preterm Infants.

This comes from the American Journal of Obstetrics and Gynecology, though there are lots of neonatologists on this paper. Um, the lead author vi, uh, Jen and senior author, um, NAMA SVA Amin. Um, so they were, the objective of the study was to look at if extremely pet infants, who was those less than 27 weeks exposed to either histological, chorioamnionitis are at a higher risk of, um, a combined outcome, death of cerebral palsy.

They looked at them independently compared to those without these exposures. And I thought it would be nice to review a little bit the difference in this terminology. And they did it actually a great job in, um, the background section. So I'm going to start there. Um, as a reminder, clinical chorio is a syndrome defined by intrapartum maternal fever, combined with the presence of maternal and fetal signs of systemic inflammation, um, which can be caused by intra amniotic infection, sterile intra-amniotic inflammation, or other things that are part of the, the delivery process, epidural anesthesia and analgesia.

Now, histological chorioamnionitis is the pathological core aberration of intra amniotic or intrauterine inflammation, which may occur with or without infection. So, recent studies have indicated that sterile inflammation is more frequent than microbe associated inflammation in patients with preterm labor with intact membranes.

Preterm premature rupture of membranes at greater than 24 weeks of gestation. And an asymptomatic short cervix and suggests that it's probably inflammation that may contribute to neuronal injury. So when we're talking about acute histologic chorioamnionitis is characterized by the presence of neutrophilic inflammation on the chorio-amniotic fetal membranes, or in the chorionic plate, while funisitis inflammation specifically of the umbilical cord.

Um, these, they mentioned these need to be distinguished from chronic histologic corium neuritis, which refers to lymphocytic infiltration leading to inflammatory lesions in the fetal membranes, possibly due to some sort of maternal-fetal rejection. And while acute histologic chorio is evidence of an inflammatory, uh, kind of maternal host response, funisitis in the umbilical cord reflects the fetal inflammatory response.

And I thought this was important. Uh, fetuses affected with funisitis generally are born to mothers with proven intra amniotic infection. However, funisitis may also be seen with sterile inflammation. And so that's why they picked these outcomes specifically, or these, uh, markers specifically, um, and what they wanted, uh, to look at.

So the methods, this is a retrospective analysis of a prospectively collected cohort of all infants born alive at hospitals in the um, N-I-C-H-D Neonatal Research Network between July 1st, 2012 and December 31st, 2019. And these are little babies, 22 and oh to 26 and six seven weeks of gestation. Babies that were excluded were out born, no placental pathology, congenital malformations and genetic syndromes did not receive active treatment after birth.

Um, the only other note I want to make about the methods is that funisitis data only became available after 2016. So 2016 to 2019, they collected the funisitis data. So the primary outcome was defined as the composite outcome of death of cerebral palsy, um, and A-G-M-F-C-S, uh, system greater than, greater than or equal to one at 22 to 26 months corrected age.

The secondary outcomes included the following. The first was the components of the primary outcome, so death and uh, separately cerebral palsy. The second was death or moderate to severe neuro mental impairment defined as the composite outcome of a Bailey three score less than 85, um, sorry, cognitive score less than 85, motor score, less than 85, cerebral palsy diagnosis and G-M-F-C-S level greater than equal to two bilateral blindness and or hearing impairment.

And then the third secondary outcome was, uh, the individual components of moderate to severe neurodevelopmental impairment. So the study consisted of just under 7,000 infants. Of these, 57% of infants had histologic chorioamnionitis, 43% did not have histologic chorioamnionitis. These were the controls. About 90% of these infants had follow up, um, and data available for the primary outcome. And after excluding infants meeting the exclusion criteria, um, they looked at the funisitis group. 28% of infants had pH funisitis, um, compared to 72% of controls without funisitis. And they, those without  funisitis may or may not have histologic. Funisitis and primary outcome data was available for 87% of these infants.

There were significant differences in neonatal maternal characteristics between the groups versus controls. So mothers of histologic or neon or funisitis exposed infants had lower incidences of hypertension were more likely to receive antenatal steroids. Um, and compared to controlled infants exposed to histologic chorio or funisitis tended to be born at a lower gestational age well.


Ben: Can you say that again about the antenatal steroids? That is so bizarre,


Daphna: very interesting. So mothers of histologic, chorioamnionitis or the funisitis exposed infants had the lower incidence of hypertension. That was interesting during pregnancy. I mean, I guess, you know, if your reason for early delivery is hypertension than, you know, may not be infection. Right. Um, and they were more likely to have received antenatal steroids


Ben: which if it is a process of inflammation, you would help, you would hope that the antenatal steroids might help mitigate that inflammation, especially on the fetal side, but No. No.


Daphna: Yeah. Um, compared to controls, infants exposed to chorioamnionitis or funisitis. Uh, and I'm, it's from now on, it's his, the histologic, corium neuritis. Okay. I'm not going to keep saying it, but, um, were born at a lower gestational age. They received more antenatal antibiotics, but they were less likely to be small for gestational age, which fits with the, um, hypertension. Okay. There were differences by race. If we take a look at, um, table one, black mothers were more, more commonly with histological, chorio, and funisitis than controls. Um, uh, white mothers less commonly with Chorio or funisitis compared to controls. There was a difference in the root of delivery. Actually, the controls were more likely to be delivered by c-section.

Those babies with prolonged r membrane were much more likely to be associated with chorio and funisitis. Okay. Into the results. So, in the unadjusted analysis, there was a lower risk of death or cerebral palsy in histologic chorio exposed infants compared to controls. This was very interesting, 44% versus 41%.

However, um, in the multi-variable analysis was suggested for potential, um, confounders in particular gestational age. The histologic chorio was not associated with death or cerebral palsy. In an unadjusted analysis, there was no increase in death. Or cerebral palsy, and those exposed to funisitis compared to those without.

However, in the adjusted multi-variable analysis, an increased risk of death of cerebral palsy was seen in funisitis exposed infants, uh, uh, risk ratio of 1.09. And this association was primarily due to being born at an earlier gestational age. There was no association of histologic, so that was in the whole group.

Um, no association of histologic chorioamnionitis with cerebral palsy in surviving infants. So those babies that, that didn't die and on adjustment for potential confounders histologic chorio was associated with a lower risk of death. Mediation analysis indicated a higher risk of death from histological chorio and those babies who are earlier preterm births. So, uh, there was a lower risk of death from direct histologic funisitis exposure. But again, the prematurity, there was no association was observed for cerebral palsy, death, or moderate to severe neuro mental impairment or components of neuro Devon impairment after adjustment. Um, now they're looking specifically at funisitis, um, in surviving infants.

So those babies that didn't die, so infants exposed to funisitis had a significantly higher prevalence of cerebral palsy, 20% versus 25%. And this was statistically significant and on multi-variable analysis. After adjusting for known potential confounders, this association remained significant, indicating that funisitis was associated with a higher risk of cerebral palsy risk ratio of 1.2.

Uh, 1.23, they did another mediation analysis indicating again, that earlier birth measured by gestational age explained about 40% of the total effect of histologic funisitis on cerebral palsy. I. The remaining 60% was a potential direct adverse effect of funisitis on the development of cerebral palsy. Though this was not statistically significant, there was a lower incidence of, uh, death, um, 27 versus 22, and those exposed to funisitis on the unadjusted analysis.

Um, this association remained significant on adjustment for potential confounders. Again, the analysis indicated a higher risk of death from funisitis due to earlier preterm birth, but a lower risk of death from direct funisitis exposure. Um, no differences were seen for death or neuro volatile impairment, neuro, um, impairment, uh, components after adjustment.

So in general, the take home points is this large, uh, study showed that a higher risk of death or cerebral palsy in extremely preterm events, less than 27 weeks exposed to funisitis. This increased risk was primarily due to being born at a lower gestational age. However, surviving infants exposed to funisitis also showed an increased risk of cerebral palsy.

The major, uh, effects appears to be a direct adverse effect of funisitis exposure leading to cerebral palsy in those surviving infants. And preterm birth only partially explains the increased risk at cerebral palsy. In contrast, the histological chorio chorioamnionitis was not associated with an increase in the death of cerebral palsy and preterm infants.

Um. So I thought this was interesting. Uh, we've had a number of situations, let's say in the last year, you know, multiples who have lots of different sides of the, the placenta and different umbilical cords and trying to distinguish who has what on, on pathological findings and what are their risks. Um, so I thought this was this connection between this fetal inflammation and cerebral palsy.

Risk is interesting, I think.


Ben: Yeah. No, it's very interesting. It's depressing a little bit because it's not one of these entities that were like, oh, yeah, I know how to treat that. Like, I, I could, I could account


Daphna: can we do about it?


Ben: Yeah. And, um,


Daphna: I do think it does help us talk to parents about the risk, you know, if, if you have that, that's a known risk factor. And there are some babies who just seem to have such a. Let's say smooth clinical course. Um, and they still have this, you know, outcome of cerebral palsy, and sometimes we're scratching our heads going like, you know, what did we not see?

What did we miss? And, and maybe this is, this is accounts for some of that.


Ben: And, and they did a very good job in trying to explain a little bit the relationship between preterm birth funisitis and cerebral palsy. Obviously they're all interconnected and, and they have a beautiful figure showing that obviously, um, preterm birth contributes to cerebral palsy, but funisitis also contributes to preterm birth.

So there's a lot of indirect effects here, but overall, there is, irrespective of how you want to look at this, you can go into the granularity of looking at the, um, relative risk for each, uh, particular effect, but there's a total effect that is undeniable. Um, and, uh, yeah. So yeah. Yep. Not sure what to say about this paper, aside from, uh, dang.

Um, this is, uh, but it helps with counseling. I think you're absolutely right. All right. My last paper for today is a paper that, um, well, it's a paper that came out last year that I was realizing we never really reviewed. Um, and that came up in the form of another article that was published in the archives in a meta-analysis.

But I thought we should probably review this as it's more, uh, relevant to our conversation. This is, um, uh, a paper called Azithromycin Therapy for the Prevention of Chronic Lung Disease of Prematurity, the AZTEC trial, a multi-center double-blind randomized placebo trial. It's published in the Lancet Respiratory Medicine.

Um, and, um, the, the trial really addresses the question, can early azithromycin therapy reduce the incidence of chronic lung disease of prematurity in extremely preterm infant? So. We know bronchopulmonary pulmonary dysplasia continues to be a pain in our neck. Um, and, um, despite all the advances in our, in our field, the rates of BPD remain quite high.

Um, and the pathogenesis we know is very multifactorial. But a key inflammatory pathway, uh, for BPD involves polymorphonuclear neutrophil driven injury to the long parenchyma triggering long-term remodeling and impaired lung development. And we know that in general, this theme is present all throughout the pathogenesis of BPD, which is.

Pro-inflammatory things making their lung worse and us trying to minimize these inflammatory exposure. So one proposed contributor is pulmonary colonization with urea plasma a, uh, molecule bacteria that several analyses have shown to be significantly associated with the later development of BPD. Now, despite this, the evidence on macro antibiotics as a preventive strategy does remain conflicting in the literature.

Um. Enter. So Azithromycin is a macrolide with both anti-infective and potent anti-inflammatory properties, including reducing neutrophil chemotaxis, cytokine production, and biofilm formation. Notably, it's a medication that works quite well in the lung where it's concentrated in pulmonary tissues to levels a hundred times higher than in plasma, which makes it a very attractive candidate for the treatment of urea plasma and potentially for neonatal lung protection.

Now, previous mid analyses including one in 2014 suggested a benefit with azithromycin, but a 2021 review found no clear improvement in BPD rates. Now the AZTEC trial is a, uh, study that was designed in the form of a large, rigorously powered, multi-centered R CT to really answer the question of should we give azithromycin to reduce, uh, potentially BPD Now, um, the AZTEC study was a multi-centered, double-blind, randomized, placebo controlled trial across 28, um, tertiary NICUs in the UK.

Infants were eligible if they were born before 30 weeks of gestation. And if they had received two or more hours of, uh, non-invasive or invasive respiratory support within the first 72 hours after birth, which I guess they used as a proxy of potential lung inflammation because obviously if a baby is on room air doing great, then maybe you don't, you don't need to, um, to do anything.

Exclusion criteria included, uh, major congenital anomalies, previous macrolide exposure and predicted non survival beyond 72 hours. So they randomized these infants one to one. The group that was in the intervention arm received the azithromycin 20 milligram per kilo IV daily for three days, followed by 10 milligram per kilo daily for seven days for a total of 10 day treatment.

The placebo control received sterile water. All the, uh, participants were blinded to the study. Um, and baseline respiratory samples from the endotracheal or from the nasopharynx were collected before the first dose, uh, to test for urea plasma colonization. The primary outcome was to see if these babies would survive  without physiologically defined moderate to severe chronic lung disease at 36 weeks postmenstrual age.

Um, the, the definition is one that is fairly standard looking at babies who had, um, moderate chronic lung disease, 21 to 30% FI O2 or low flow nasal cannula and severe patients being on invasive or noninvasive support at 30%. FI O2. Secondary outcomes included death before 36 weeks, days on oxygen or ventilation, urea, plasma colonization, and the use of corticosteroids, PDA treatment neck, I-V-H-R-O-P and nosocomial infection.

So results, um. They screened about 1800 babies. 799 were randomized. And in the final analysis, basically 394 infants were allocated to Azithromycin 402, allocated to placebo. The baseline characteristics were all well balanced through, though, um, there were more antenatal, um, antibiotics that were  noted in the placebo group, the gestational age.

The median gestational age was 27 weeks. The median birth weight was 895 grams, and 89% of the babies were born at the center, uh, uh, at the research center, um, that was enrolled. Um, in terms of, um. The primary outcome. So when we're looking at survival without moderate to severe BPD, um, the, the rates were 42% in the azithromycin group compared to 45% in the placebo group.

This was not statistically significant. Um, looking at subgroup analysis by basically urea plasma status. Um, gestational age, either you were less than 28 weeks, or you were 28 to 30 weeks, whether you were born inborn or out born, no difference was seen either in these subgroup analyses. Looking at some of the secondary outcomes, looking at death at, um, by 36 weeks, uh, gestational age, this was 9% in the azithromycin group compared to 8% in the placebo.

Also not statistically significant. Looking at, um, moderate to, um, severe BPD, we're looking at 54% in the azithromycin group versus 51%, um, in the placebo group in terms of ROP, um. 4% in the Azithromycin group versus 7% in the placebo group. This is the only one that sort of, uh, reached the STA statistical significance.

Um, now in terms of other outcomes, there was no difference in PD treatment, corticosteroid use, neck IVH, infection rates, et cetera. Uh, in terms of liver slash renal enzyme that was similar between the two groups. And in terms of serious adverse events, there were seven adverse events in the azithromycin group.

Six in the placebo group. They couldn't find any QT prolongation or other safety concerns along those lines with, um, azithromycin. So, um, it's very disappointing that despite the sort of strong biological plausibility, um, and [01:21:00] previous smaller studies, the AZTEC trial did not show improvement in survival, um, without moderate to severe BPD with azithromycin.

Um, it did not impact the rates of death and did not impact the need for respiratory support. It did not impact the corticosteroid use. It did not impact inflammatory complication. The only thing that, as I mentioned, is a red reduction in the treated ROP among survivor that was observed. Although this finding actually requires some caution because, um, uh, because of the number of babies that we're talking about and that the fact that this is a secondary outcome, um, the urea plasma colonization rate was about 22%, which is lower than other studies.

Um, and they found no treatment interaction when they looked at whether maybe if we isolated then just the patients that were positive for urea plasma. Still no statistical significance. So, um, very disappointing there. In terms of the conclusion, um, I wanted to find maybe the [01:22:00] paper, because I thought that the, the paper ad, um, had a pretty, um, pretty striking sort of conclusion.

Gimme one second. I think I have it right here. Um. Yeah, so the, the interpretation of the findings in the abstract that was well, well worded, said, since prophylactic use of azithromycin did not improve survival without development of, uh, physiologically defined chronic lung disease, regardless of urea, plasma colonization, it cannot be recommended in clinical practice.


Daphna: Darn it.


Ben: Darn it.


Daphna: Oh man. It doesn't make sense. I think that's what's so frustrating. It doesn't make sense like we know. PLM is associated with preterm birth. We try to give it to moms. We try to give it to babies. It's just doesn't work. Darn


Ben: Yeah, it's very disappointing. It's very disappointing.


Daphna: very disappointing. Um, I did have one paper left. I'm not, it's a, it's a, it's a very useful paper actually. You identified this paper, so I wanted to bring people's attention to it, even if we won't have time to go through everything. This is in pediatric research. Um, it's called Advancing Neonatal Autopsy by Strengthening Physician Belief and Fostering Effective Family Communication.

Um, lead author, Ana Renos, uh, senior author Hannah Kinney. And, um, it's really talking about how autopsy can benefit families and, um. Maybe if we did a better job of learning about it and explaining it more parents, more families would be interested in autopsy. So this is not NICU specific, um, but I think the points are still very valuable for our community.

Um, and in their background, they talk a little bit about autopsy rates, and I thought this was interesting.  Autopsy rates have dropped from 19% in 1970 to a low of 7.4% in 2020. And, um, the same trend is seen in children. So that's for everybody. Uh, but we're seeing the same thing in pediatric cases. Many reasons have been put forward to explain this alarming decline, including the mistaken view that autopsy has, quote, nothing to offer in this day of sophisticated diagnostics, imaging, and state-of-the-art interventions and medicines.

Nonetheless, 40% of autopsies reveal additional findings about a patient's death beyond the clinical postmortem diagnosis. Moreover, ongoing advancements in technical tech. Technical methods have helped the progress of pathology vastly increasing the information that can be obtained from analysis of tissues collected and preserved during autopsies, such as genomics, proteomics, and metabolomics. Um, and beyond advancing science, uh, the data shows that autopsies offer profound emotional and practical benefits for families. For example, many families report a sense of closure when provided a definitive cause of death. Autopsies have been shown to alleviate parental suffering, helping parents process grieve, and ultimately come to terms with the loss of their child.

Additionally, some parents find comfort in knowing that they are adding to medical knowledge that could benefit other newborns, and then they really get into the paper by saying, by fostering open and empath, uh, empathetic communication, clinicians can better support families in their time of profound loss, yet also contribute to the advancement of neonatal healthcare.

And so basically, this is quite a long article, but I think, um, there are a lot of take home points about family communication in general, but specifically around this discussion of autopsy, which I think is, can be uncomfortable for, for all parties. And I think that's sometimes why we avoid it altogether.

Um, but they really go step by step, you know, approaching the family who asks for the autopsy, what should be addressed, what does consent look [01:26:00] like, what do we do with the autopsy results? What about providing research consent? So I thought this was interesting, something that I really didn't know that much about that.

Um, after autopsy, a lot of that information, tissue information, um, can still be used for like a very long time, um, to gather, for example, disease, um, specific information.


Ben: Hmm.


Daphna: Um, they talk a lot about barriers to providing autopsy consent, um, including kind of parental or, or medical professional misperception.

Things about like, um, disfigurement, you know, not letting the child be in peace. Um, this belief that autopsy would not be beneficial because the baby has already died. Um, and certainly other factors include socioeconomic status and the cost of autopsy.


Ben: Don't we know that?


Daphna: yeah, for sure. This is, uh, this is our problem in our own institution.

Um, but studies consistently show that the decline in autopsies is more than attributable to the lack of opportunity and dear of conversations with families rather than family refusal per se. Um. I think, uh, then they go into like, what are the, what is the fear of autopsies? What are people worried about?

And they give a beautiful, I mean, obviously everybody's relationship with their religion is different. Um, but I think if people just looked at one section and these kind of overarching, um, kind of religious specific information, um, not just about autopsy, but about death in general. Um, I think it will help us all go a long way in our, in our, in our cultural competency, um, surrounding death and dying.

So I thought this was a really nice add to this paper. Um, and then they even give kind of some scenarios and scripts for conversations with families. Um. Specific [01:28:00] terminology you can use for specific, um, scenarios that may present themselves, and then they close the paper with basically just like a step-by-step framework in addressing autopsy with families.

Um, so I'm sorry we don't have the time to read the whole thing, but I hope people will take a look at it. And I think this is one of these things we can take to the bedside right away.


Ben: Thank you for reviewing that. Yeah. I think that the, this idea that, uh, well autopsy have nothing to offer, so, so we should like that, that misconception is really, um, quite pervasive.


Daphna: Yeah. And, and I do think, I mean, a lot of the deaths in the NICU I think can be explained, uh, by the clinical presentation, right? So not everybody needs an autopsy, but, um, I wonder if there are some, some families that might benefit from one and as we're moving away from offering autopsy, that, that, that they may be missed.


Ben: That they maybe what missed?


Daphna: that might benefit. Yeah,


Ben: I think that, uh, another point that the article is making is the, the timing. Um, and I think that sometimes we try to have the autopsy conversation like immediately after a patient has passed. And, and that's very difficult. It probably is not the best time to have that conversation.

Maybe we should let the family grieve and maybe table that kind of conversation for the following day, the following week if possible. It just like, it's, it's really something that, um, makes everything a bit more difficult, especially because for us as well. I mean, I think it's a traumatic time for everybody at that point.

And, and it's like, why are we because we have to fill out a form most of the time it's because we have to fill out a form.


Daphna: you know, and I, for some reason I was kind of always taught that like. It was almost like emergent to get to get the autopsy consent. And I mean, this paper very much addresses that. It's not right.


Ben: It's not, yeah.


Daphna: one, and I think they do a nice job of outlining, like, you know, in families


Ben: Come back closer to the microphone for us.


Daphna: Sure.

Sorry, I'm rolling away. Rolling away. Um, for families where we can anticipate a death, this is something we can even discuss ahead of time. Um, which, you


Ben: Only you would say that. What a terrifying thought for me. Oh my God. If I have to bring this up to a family before the baby passes what? It's And you're not wrong. You're not wrong. You're not wrong.


Daphna: I'm not saying it's right for every scenario. I'm just saying some parents want to know what the end of life process will look like, and I, I think this can be included in that conversation. Okay.


Ben: on this note, we will close out journal club and, um, thank you to everybody who is still here at this point and, uh, listening to, uh, to Journal Club. We will see you guys later this week with more content and, uh, more board review. Um, see you guys next time. Bye.


 
 
 

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