#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 👇

Effects of liberal versus restrictive transfusion strategies on intermittent hypoxaemia in extremely low birthweight infants: secondary analyses of the ETTNO randomised controlled trial.

Franz AR, Engel C, Bassler D, Rüdiger M, Thome UH, Maier RF, Krägeloh-Mann I, Essers J, Bührer 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

Mother's Own Milk Provision During the First 12 Weeks of Life by Gestational Age.

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.

Cord Blood Treatment for Children With Cerebral Palsy: Individual Participant Data Meta-Analysis.

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

Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates: 2-Year Follow-Up of a Randomized Clinical Trial.

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.

Funisitis increases the risk of death or cerebral palsy in extremely preterm infants.

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

Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial.

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. 

Advancing neonatal autopsy by strengthening physician belief and fostering effective family communication.

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. Daphna how are you?

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

Ben: Don’t scare the audience off 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.

Ben: That's exactly right.

Daphna: That's our dedication to the program. No matter where we are we'll find a way to record.

Ben: We soldier on. We have a packed episode today. I wanted to address something: we have fan mail. We're not the most techie group but that's okay. On our podcast hosting site you can actually leave us fan mail. 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 thought that sounds like a great idea. they have the feature for us to get messages but we don't have a feature for them to respond. we'll do that on the air. We have two new messages that came in the past couple weeks.

The first one is a very direct question. It's asking us whether our hospital HCA Florida University NICU supports the app NICU-2-Home which is an app that we featured on Tech Tuesday. The answer is in spirit we support them but we do not use NICU-2-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 mention it at the beginning of the episode.metimes the team will let us play around with a beta version just before the episode. But these episodes are not meant to be a commercial. We don't take any money from these companies and we don't have any invested interest in them.

Daphna: For this one in particular we have the good fortune of having some of the services through ICU baby. They have their own app. I sometimes think we give families resource overload such that they use nothing. For units that may not have a regional specific [app] or are not currently using a support app introduce them. Parents love them but I worry about having multiple apps running in the same unit. Then parents end up using nothing.

Ben: We have another message from Mountain View California. This not really a question just saying “Amazing episode thanks for all you do for the community.” Thank you for that listener for this lovely message.

Daphna: We love getting feedback.

Ben: This the best. We sometimes get a lot of techy questions about fixing certain things either on the site or subscriptions. whenever we get a positive note with no strings attached it's great.

We have a busy episode today. We will have an episode of EB Neo where Dr. David Rub is going to join us to provide his commentary on the paper that was published in September of last year called “Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates: 2-Year Follow-Up of a Randomized Clinical Trial.” Stay tuned for that. I think that is all the announcements that I had for you all today.

Daphna: We were going to put a little plugin for the TECaN webinars. I'm going to do that for people who aren't aware yet. Every two years the AAP section on Neonatal-Perinatal medicine TECaN [Training and Early CAreer Neonatologist] and in general that is from what graduation to seven years out does –

Ben: I don’t think they'll officially kick you out though.

Daphna: I don't know how that works! Every two years they cycle through a different advocacy campaign which anybody can get involved in. It's really cool to know about 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 is called Together in Care: Empowering Neonatal Teams in Palliative Care. The primary offering are these free webinars focused on a variety of palliative care topics. There have been really wonderful experts. There is continuing education credit for physicians APP’s and nurses as well as MOC part two credit for live and on demand webinar attendance. The next webinar will be May 13th at 3:00 PM Eastern focused on prenatal palliative care with Dr. Steven Leuthner from the Medical College of Wisconsin. You can learn more about the campaign and register for the webinars at their website. That's https://www.tecanadvocacy.org/together-in-care.

Ben: Awesome. Okay, let's get into journal club. I'm going to start today with an interesting article that is a secondary analysis of the ETTNO trial. That paper was titled, “The Effects of Transfusion Thresholds on Neurocognitive Outcome in Extremely Low Birth Weight Infants.” The newly. published paper is titled, “Effects of liberal versus restrictive transfusion strategies on intermittent hypoxaemia in extremely low birthweight infants: secondary analyses of the ETTNO randomised controlled trial.” This was published in the Archives of Disease in Childhood a few weeks ago. We've reviewed at length the ETTNO trial me of these other transfusion trials, so I would refer you back to these episodes. The authors of this particular paper sought to explore an important secondary question arising from the original ETTNO randomized clinical trial, which was whether whether liberal red blood cell transfusion reduced intermittent hypoxemia. More broadly, whether such strategies translate into better long-term neurodevelopmental outcomes, especially in infants with higher intermittent hypoxemia burden.

I was terrified when I read the paper, because one of the things that we do in our local 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. I thought after we had “settled” this subject, maybe now we're going to find out that we shouldn't use such restrictive threshold. we'll find out what this team came across.

We know that extremely low birth weight infants, defined in the paper as babies who are born with a weight less than 1000 grams, almost uniformly develop anemia of prematurity. This a multifactorial process involving physiologic, iatrogenic, and disease-related factors. We invite you to listen to our board review questions and subjects on this matter. Historically, a substantial portion of these infants, about 50 to 80%, receive one or more red blood cell transfusion during their hospital state. This something that was brought up by the ETTNO team, and that still strikes me to this day, in their background section. Now these infants also experience intermittent hypoxemia, often due to apnea stemming from immature respiratory control. This raises the hypothesis, could red blood cell transfusion mitigate intermittent hypoxemia by improving oxygen carrying capacity and delivery to the brain? Short-term observation had suggested that transfusion might indeed transiently reduce the frequency and the depth of these episodes. But does this translate into sustained benefit over time? And more importantly, does this affect developmental outcome?

Two prior major randomized control trials were done on transfusion thresholds, the ETTNO trial and the TOP trial. Just as a reminder if you are not familiar with these papers, they really showed no benefit of liberal transfusion thresholds on neurodevelopment at 24 months corrected age. But neither trial truly had examined whether red blood cell transfusion would prevent intermittent hypoxemia or protect the brain from hypoxic injury related to both anemia and hypoxemia. this a secondary analysis of the ETTNO trial that's designed to, number one, compare the percentage of time spent in intermittent hypoxemia and the number/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 neurodevelopmental impairment. [We have] 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.

A quick reminder on the design of the ETTNO trial. It was a multicenter open label randomized parallel group study that involved 36 European NICUs. Infants less than 1 kg at birth were randomized to liberal versus restrictive transfusion strategies with different hematocrit thresholds 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’ve reviewed it at length. In this secondary analysis, [they only included] infants that had actually pulse oximetry data for over 80% of the duration of time they were looking at (babies between day eight and day 49). Of the original 1000 infants, I think 554 met this criteria. 268 were in the liberal group and 286 were in the restrictive transfusion group. The other exclusion criteria were that if the gestational age was above 29+6 weeks, major congenital anomalies, or again issues with that pulse oximetry data. The pulse oximetry stuff was fairly standard, they were using Massimo pulse oximeters. I'll let you review that.

How did they define these intermittent hypoxemia events? This was defined as a saturation below 80% lasting for more than 60 seconds. This criteria was chosen based on prior association with adverse outcomes. They looked at this analysis through various time points: postnatal day 8-21, 22-35, and day 36-49.

What were some of the 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. Number three, the interaction between the intermittent hypoxemia burden and transfusion threshold in predicting the ETTNO primary composite outcome of death or NDI at 24 months. Neurodevelopmental impairment was defined as a Bayley with an MDI of less than 85, cerebral palsy, and hearing or visual impairment.

In terms of the baseline characteristics, there were no significant differences observed between the ones who were included versus the one that were excluded in the original study.

Looking at the intermittent hypoxemia burden by transfusion strategy, across postnatal day 8-49, the median percentage of time spent in intermittent hypoxemia was about 0.91% in the liberal group versus 0.79% in the restrictive group. 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 lower pulse oximetry were also similar between the two groups. So effectively, no statistical difference between the two groups. In terms of looking at this from a shorter time point, none of these differences were statistically significant, and the burden of intermittent hypoxemia peaked between day 8-35, especially in infants with lower gestational ages.

In terms of outcome by hypoxemia exposure, in the subgroup with 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 lower MDI were not significantly different. They performed a lot of statistical analyses and logistical regression models that confirmed no interaction between the transfusion strategy and the hypoxemia burden on any of these outcomes.

So overall I felt pretty good about this. This analysis really tries to answer the question, does a liberal transfusion strategy mitigate intermittent hypoxemia over time? The answer seems to be no. In terms of earlier reporting suggesting 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 blood if they're anemic, and that helps. How do we reconcile these two issues? The authors suggest three possibilities. Number one, 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, like cardiac output, cerebral vasodilation. [Lastly, there could be] potential harm from red blood cell transfusion. They also [state] maybe it's just a transient effect that does not translate to long-term benefit.

The conclusions of the article are that among extremely low birth weight infants, liberal transfusion does not reduce the burden of intermittent hypoxemia during the critical weeks of 8-49 days postnatal life, nor do they seem to improve the outcomes at 24 months, even in those with higher exposure to hypoxemia. Liberal transfusion strategies should 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 the granularity of this answer. We're looking forward to more on this subject. Daphna, what are your thoughts?

Daphna: My first thought is how few hypoxemic episodes they collected. They collected them, but I thought the percentage of time 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'm not sure it feels like that when you're walking through the unit.

Ben: Well, you have to remember that they were really trying to look at clinically significant events. So we're looking at less than 80 for 60 seconds or more. I think these happen less often. I think we'll see a baby being in the 85 for a short while, and then climb back up. But to be in the 70’s for that long, for almost a minute with no intervention…I really hope none of our listeners see that too frequently. Because that might be scary.

Daphna: I do think we get kids who dip down, and they come right back up. I was trying to look it up, I don’t remember if there were any difference in FiO2 requirements in the two groups. They were looking at hypoxemic episodes, but I wonder were they able to wean the oxygen in some of these groups? I don't recall the answer.

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

Daphna: I've felt both scenarios, and this not based on evidence, that there are some babies who you give them this blood, and you're able to wean that oxygen. Then there are some babies where [despite that we’ve] all had this concept that it would improve hypoxemia by improving oxygen carrying capacity, [even if] you give the blood…I guess that's what they're showing, that you aren't able to wean those kids. I feel like I've had the sensation of both of those types of patients. It's nice to see the more granular data for sure.

Ben: That's exactly what the authors mentioned. 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 8-49. They're saying that what their data suggests then is that the benefits that we're talking about must be transient, and that liberal transfusion resulting in an overall mean hemoglobin increase of about 1 g/dL will not reduce intermittent hypoxemia during those days 8-49. That's really the [point] that they're making; you're getting a little bit of an effect, but are you making a big difference in terms of these severe, severe episodes? Probably not. Maybe that the baby that was stuck on 80% or having an increased FiO2 will benefit more from these transfusions, but these severe hypoxemic episodes seem to be unaffected by that.

Daphna: Thank you for that. I had an article I wanted to share. It is entitled “Mother's Own Milk Provision During the First 12 Weeks of Life by Gestational Age,” lead author Aloka Patel, senior author Tricia Johnson. This in JAMA Network Open Pediatrics. What they were looking at was, does the initiation and duration of mother’s own milk feeding vary by gestational age of birth? I think people might be surprised. The answer is yes, but by which gestational ages? This was a retrospective cross-sectional study using PRAMS data (Pregnancy Risk Assessment Monitoring System) from through the year of 2021. If you don't know what PRAMS is, it's a surveillance system established by the CDC to look at population level data about maternal characteristics, health behaviors, and health indicators in pregnant mothers and in infant health.

Women are surveyed by mail or telephone between two and six months after delivery, then these completed surveys are linked to the birth certificate data. Data in this study included birth certificates and survey information from 36 jurisdictions. That was 33 states, the District of Columbia, New York City, and Puerto Rico. To be clear, they don't look at every single pregnancy or birth, but they pull a selection randomly to look at this population data.

Outcomes included mom’s own milk feeding initiation, defined as providing any maternal breast milk, and mom’s own milk feeding continuation, defined as mom’s own milk provision at 12 weeks after delivery. This was conditional on mom’s own milk feeding initiation. They did a number of analyses, including on 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. The mom feeding duration was determined based on the survey question, how many weeks or months did you breastfeed?

They split the infants up by gestational age at birth, and they were classified into four groups. They had the extremely preterm (less than or equal to 27 weeks gestation), moderately preterm (28-33 weeks gestation), late preterm (34-36 weeks gestation), and this group that they called early-term to post-term (greater than or equal to 37 weeks). They collected a bunch of maternal characteristics; I won't go into all of them specifically but I will discuss some of the differences.

The results: in total they had just over 33,000 women (91% of the sample) which completed the survey at least 12 weeks after delivery, which I thought was phenomenal. They had a total of just over 29,000 births in the PRAMS sample. This represented about 1.5 million births in 2021, and 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. Many maternal characteristics differed by infant gestational age, but interestingly one thing that was not different was WIC use during pregnancy and prenatal care in the first trimester.

Some other differences were that mothers of the early-term to post-term groups, the oldest group of infants, were more likely to be white, 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.

Let’s get into the mom's own milk feeding. Unadjusted rates of mom's own milk feeding initiation were similar for mothers of early-term to post-term, so 88% almost across the board. The moderately preterm 88% and extremely preterm 89%, with a lower rate of mom's own milk feeding initiation observed for mothers of those late preterm infants 81.8%. For mothers who initiated mom's own milk feeding, 71% of mothers of this the oldest group (early-term to post-term infants) continued to provide milk at 12 weeks, compared with 61% of late preterm, 58% of moderately preterm, and 63% of mothers extremely preterm infants.

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 were 4.4 percentage points less likely to initiate mom's own milk feeding and 6.7% 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 rates among extremely preterm and moderately preterm infants compared with their early-term to post-term infants.

There were some significant differences by race that they described. They found significant differences in mom's own milk feeding initiation by maternal race and ethnicity, with Hispanic mothers, white mothers, and mothers of other racial groups more likely to initiate mom’s own milk feeding compared with black mothers. There was no difference in mom’s own milk feeding initiation by WIC use during pregnancy. However, for mothers who initiated mom’s own milk feeding, those who did not use WIC actually had a higher rate of mom’s own milk feeding continuation at 12 weeks, 72% versus 66%. Mothers with less than a high school diploma were least likely to initiate mom’s own milk feeding compared with mothers with higher levels of education. 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, 63% of mothers of early-term to post-term infants, 50% of the late preterm, 50% of moderate preterm, and 56% of the extremely preterm infants provided mom’s 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 mom’s own milk at 12 weeks compared with mothers of early-term to post-term infants.

The take home point is that, obviously there are a number of maternal risk factors, societal cioeconomic risk factors, that we know predict breastfeeding rates, but I think they're highlighting the really important 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 groups. I think this was really interesting. In their discussion they talk about what some of those reasons are –they may have short stays in the nursery, they may have short stays even if they are admitted to the NICU. I'm going to read this 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 at particular risk [for breastfeeding directly] due to their immature sucking ability, with weak suction patterns resulting in less robust milk transfer, which may in turn negatively impact milk supply. Their neurologic immaturity and limited ability to regulate sleep and wake cycles may result in parental perception of a late preterm infant being satiated when the infant is falling asleep. These factors may result in inadequate nutrition, dehydration, and jaundice, with higher rates of readmission in the first 2 weeks after birth for late preterm infants compared with full-term infants. Improving mom’s own milk feeding rates in this sizeable population of late preterm infants may impact both short-term and long-term clinical outcomes, which would translate to future educational and economic benefits and lower medical costs.”

I think in general, those babies tend to spend less time in the NICU, they have less time to work on breastfeeding and get that breastfeeding support. They are, hopefully, often less sick than some of the other babies in the NICU, and they may not get the most of our attention. I thought this was important for us to discuss. Thoughts.

Ben: You're harpooning on the late preterm group. But I was shocked by the early preterm group. If we had thought about this question and tried 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 and who's probably still a bit sick, compared to the full term who's at home and thriving. But the difference is not that that striking. Correct me if I misread the paper, but it doesn't seem that the mothers of early preterm infants are that leaps and bounds ahead from their full-term counterparts if you want to call them when it comes to mother's own milk feeding at 12 weeks conditional on the initiation. That to me means we should look at the barriers for our mothers in the NICU to continue to providing milk. Is it work-related stuff, that now their leave is expired, and now they have to go back to work? I don't know if this a very typical US problem, but maybe that plays a role and maybe we should look at these at these obstacles.

Daphna: I disagree with your initial point that you expected the extremely preterm moms to have higher rates of pumping. I think we really underestimate how much work it is, even if you're at home, with good resources and great support. We underestimate the stress of having your baby in the NICU on milk production. We underestimate [the result of] coming in and missing a pump because you're coming to see your baby multiple times a day and all of the other external factors that you're juggling while your baby is in the NICU. I think this fits with other NICU data on breastfeeding rates, both in and out of the NICU. I think we could do better. We just need as a society, as a system, to really support these moms.

Ben: We need to really prioritize [providing mom’s own milk]. I was not trying to dismiss the difficulty of providing breast milk for a baby in the NICU, but I was thinking from the perspective of a mother of a full-term baby that's now three months. It's easier to transition at that point, if a baby is healthy and three months old, to 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 at 10 weeks is now 32-33 weeks, the pressure unfortunately is still on. You would think that that because of that, and that hopefully breastfeeding is well established at that point, that they're able to achieve much higher rates. But no [that isn’t the case.] That is not a knock on these parents, but again like you said, on the system-wide barriers that they're experiencing in continuing something that at initiation was quite high. That is the other thing. 70% started, and then there's a big drop off. I think this where the gap is. This where the opportunity lies, in my opinion. What is happening there? It sounds like a very strong advocacy project.

Daphna: Lots of people are working on it. It's tough, especially in the US for the reasons you said. And we know how important mom's own milk is. It's like the only thing we know that works!

Ben: I think that these mothers are painfully aware of it, because of the prior 12 weeks in the NICU. This not lost on them, by any means. Okay, we're going to take a very quick break. We'll be back with our EB Neo segment.

Daphna: I am back for EB Neo. Today I am joined in the studio by Dr. David Rub, affiliate trainee at PolicyLab at Children's Hospital of Philadelphia, a fellow in the Pediatric Hospital Epidemiology and Outcomes Training Program managed by Clinical Futures at CHOP, and a neonatal-perinatal medicine fellow at CHOP. If that wasn't enough, Dr. Rub is currently completing his Master of Science in Clinical Epidemiology at the University of Pennsylvania. David, thank you for joining me today.

David: Thank you for having me.

Daphna: It's my pleasure. I'm glad that we're going to be talking about this article. I'll throw out the title: “Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates: 2-Year Follow-Up of a Randomized Clinical Trial.” This in JAMA Network Open. It is a follow-up of the IN-REC-SUR-E (intubate-recruit-surfactant-extubate) trial. But just to remind people, tell us a little bit about the original trial.

David: Sure happy to. INRECSURE, of course a play on INSURE, was a randomized clinical trial, unblinded, performed at 35 tertiary NICUs in Italy between 2015 and 2018. In this trial, they randomized 24 to 28 weekers either to standard INSURE protocol or to INRECSURE protocol. For INRECSURE, they specifically used a high frequency oscillatory ventilator and used a stepwise approach. They put the baby on the oscillator, started at a MAP of around eight, and then they went stepwise, following their oxygen saturations until they found what they consider their opening pressure. After [lung] recruitment, 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: Their primary outcome, what they were powered for, was presence or need for invasive mechanical ventilation within the first 72 hours of life. For their primary outcome, it was a positive trial. They found a significant reduction in that primary outcome. Specifically, it was about 40% in the INSURE group and 54% in the INRECSURE group. So relative risk of 0.75. What they didn't find though was, looking at their long-term outcomes, they didn't end up seeing any difference in BPD rates. In their intention to treat analysis, they did not find a difference in mortality, although they did find one in their per protocol analysis which we can talk about a little more. This study, the two year follow-up, was to see if there were any differences at two years in death after discharge or major developmental delay.

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

David: The initial trial enrolled about 200 babies. 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 137 babies total. They did a two year follow up visit with neurodevelopmental assessment, height, and growth; on some babies, they were able to get some respiratory measures and number of hospitalizations due to respiratory issues, but that was only done for about a hundred babies.

Daphna: Alright. Let's dive into the nitty gritty of the results.

David: Unlike the primary trial, they did not find a significant difference in their composite outcome of mortality after NICU discharge or major developmental delay. In the INSURE group, 13 out of the 64 had major developmental delay or died. In the INRECSURE group, 10 out of 73; no significant difference there. When we looked at their secondary outcomes, they looked at the major developmental disability alone (including CP, cognitive impairment, visual or auditory deficits) all at two years corrected postnatal age, and they didn't find anything statistically significant; the same goes for anthropomorphic measures and respiratory outcomes (recurrent respiratory infections or hospitalization secondary to respiratory causes).

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

David: I think it was an interesting primary outcome choice. There's been a lot in the literature recently about composite outcomes specifically grouping death and major developmental disability, and equating the two. I think [there is a reason to group the two] as far as a competing outcome goes, [for example] if a lot of babies are dying and then we all of a sudden see better neurodevelopmental outcomes; we're just missing the ones that would've had delays if they had survived. I think it's important to separate them out and look at the differences on their own, which they did. Overall, I don't think it necessarily moves the needle, as far as changing any management to what most of us are doing early on. There were no improvements in either neurodevelopmental outcomes or mortality.

Daphna: I wonder sometimes with these “negative” trials, this was a new maneuver. It did reduce the need for mechanical ventilation in those first 72 hours, and the babies didn't do worse. I guess that's another way that we could look at it as well.

David: One of the more interesting findings was that they had this really significant reduction in mortality they describe in their initial study. 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, because of the significant early mortality. But there were a couple interesting things in how they reported those results. One, when they did the intention to treat analysis (analyzing them as they were randomized), the results weren't statistically significant, although there was still this big signal towards reduced mortality. When they decided to reanalyze it as a per protocol analysis (meaning analyze babies as to what they got instead of what they were randomized to), there they shifted into a little bit of a statistically significant result. If you dive deeper into why these babies died and looking at those overall mortality rates, the mortality rate in the first 24 hours was actually pretty high for this group. It was about 10% in each. One thing to note is that babies in both groups actually received sustained inflations in the DR. As we've seen with the SAIL trial results, there was this big signal towards increased mortality in the groups that receive sustained inflation at birth. So that higher baseline mortality risk may be exaggerating the mortality benefit that we're seeing with INRECSURE.

The other thing is why the babies died. The big difference between the two groups was actually a really high rate of pulmonary hemorrhage in the first 24 hours in the INSURE group. I have to say is [that has] not necessarily [been] my experience as far as what I see as complications in the first 24 hours after surfactant administration. We're a LISA/MIST unit, so unless the baby needs to be intubated, we don’t them surfactant through the tube. But I almost wonder if this benefit difference is because in the INRECSURE group, you had this extended period of time where the baby had a tube in place, and you knew that it wasn't deep. So it may not have been so much the recruitment itself, but just a stable tube position. This was as opposed to the INSURE group, where you're putting in the tube quickly, not getting an x-ray to assess position, giving surfactant, and then pulling out. Was there more pulmonary hemorrhage due to a deep ET tube in the INSURE group? Just something to think about with how the results ended up shaking out in this study.

Daphna: Especially that adverse event – pulmonary hemorrhage is one of those things you really never want to have to address, but it does happen, and we know that the mortality rate is really high from pulmonary hemorrhage. So if we can avoid it at all costs, that would be the goal. Thank you for also disclosing what you guys are doing in your unit. Our unit is still using a smattering of different techniques for different babies. I'm not sure that's the right answer either. What do you think about this discussion about surfactant administration? Have we found the optimal way yet?

David: I don't know if we found the optimal way, but there's definitely this obvious push towards going as less invasive as possible. Not to bring in a new modality, but our group has started trialing SALSA (Surfactant Administration through Laryngeal or Supraglottic Airways). We've had some pretty good user experiences, and it’s been very easy to give it that way. I think, if you have the capabilities for using video laryngoscopy for giving LISA or MIST, it does seem like the evidence is there to support LISA and MIST over INSURE. But again, different units have different capabilities. Different providers are comfortable with different things. [The best for the babies is probably going to be what you feel safest and most comfortable doing].

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

David: Of course, thanks Daphna. Just one last thing I wanted to say is that they are planning a second trial comparing INRECSURE 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: Of course, thanks for having me.

Ben: We are back. Thank you Daphna for this very nice EB Neo segment. We're going to pick up right where we left off, with more review of recently published papers. I would like to turn our attention to a very compelling paper that I saw published in Pediatrics by Finch-Edmondson and colleagues called “Cord Blood Treatment for Children With Cerebral Palsy: Individual Participant Data Meta-Analysis.” It's not a subject that probably is going to be very relevant to us at the bedside in terms of how we manage our patients, but it's definitely relevant to our field and definitely relevant to our communications with parents. This study addresses one of the most 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 is a group of lifelong neurological conditions caused by non-progressive injury or issues with development in the developing brain. Traditional care involves a combination of rehabilitation, orthopedics, and assistive technologies; sadly enough, they these often have only modest gains, despite significant effort in their implementation. Stem cell therapy has emerged as a promising approach, and the field has evolved from aiming to replace damaged cells through engraftment to now focusing on properties of these stem cells on their anti-inflammatory and immune-modulating mechanisms. Therapeutic potential is thought to arise from the umbilical cord blood's paracrine signaling, its ability to modify local brain environment, and to promote endogenous repair. It's important for us to know this because, as we're going to see in the result, it plays a role in who we will see benefit most from these potential therapies.

Umbilical cord blood is the most extensively studied stem cell therapy for CP. Nearly 20 years of clinical research has been devoted to that specific type of cell lineage. Preclinical models have shown that umbilical cord blood stem cells reduce brain infarcts and neuroinflammation, and increase both neuronal and oligodendrocyte population, leading to functional improvement. These biological changes align with clinical data showing that brain connectivity improves on imaging after stem cell therapy.

A 2021 review reported that 600 children with cerebral palsy had received umbilical cord blood stem cell therapy either in single arm or control trials, with consistent evidence suggesting improved gross motor function as measured by the Gross Motor Function Measure (GMFM). However, there's significant heterogeneity across these studies – differences in the participants, differences in treatment protocols, differences in dosing, etc. – and this really has made it difficult to determine the true efficacy, dose-response relationship, and the best responders.

This a meta-analysis, [specifically a systematic review and individual participant data meta-analysis (IPDMA), meaning they] pulled individual participant data into a meta-analysis. They not just took the aggregate results from each study but looked at individual patients. Their objective was to overcome these limitations and to determine: (1) the effect of umbilical cord blood on the GMFM scale at 1, 3, 6, and 12 months, (2) to look at the impact of cell dose on treatment outcomes, (3) to look at the influence of covariates such as the age of the patient, the severity of cerebral palsy, and their the etiology, (4) to look at the safety of umbilical cord blood treatment.

In terms of the study methods, this was pre-registered systematic review and individual participant data meta-analysis that was conducted under PRISMA-IPD (Preferred Reporting Items for a Systematic Review and Meta-Analysis of Individual Participant Data) guidelines. The eligibility criteria included studies that administered autologous or allogenic umbilical cord blood via any route, and with/without the use of concomitant EPO to individuals who were diagnosed with cerebral palsy. Inclusion required baseline and follow-up GMFM at 1, 3, 6, or 12 months. The primary analysis excluded participants who received EPO alone or with umbilical cord blood (only secondary analysis included EPO with concomitant UCB), and those with multiple umbilical cord blood transfusion.

The data was collected from 11 studies (seven control trials and four single arm studies) totaling 498 participants, representing 447 unique individuals. After exclusion criteria were applied, they had 170 participants receiving umbilical cord blood only, 171 who were in the control group, and 53 patients who received umbilical cord blood with EPO. 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-severe (GMFCS classification of 4-5). 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 old as 18.9 years (adults, if you ask me). Ideologies were quite varied. 21% were stroke/IVH, 13% were HIE, and they had a whole category called “other” that composed of pathologies that we are familiar with – PVL, meningitis, and even kernicterus. 84% of the administration of umbilical cord blood was allogenic; 86% of these 84% were from unrelated donors. One of the studies administered the blood intrathecally, and all others used the IV route. The most common follow up was six months; that was assessed in 72% of the participants. Looking at the baseline differences between the participants, they saw no significant differences in demographic or clinical characteristics.

Let's look at some of the outcomes. For the primary outcome, what they found was that the administration of umbilical cord blood stem cells led to significant improvement in GMFM at six months and at 12 months post infusion, with an increase in the GMFM scale by 1.36 points at six months and 1.42 points at 12 months.

No significant improvement were seen at one or at three months. If they looked at the other group of patients that also received EPO, they saw similar results at six and 12 months. Sensitivity analysis excluding single arm or unpublished data did not change the outcome. Interestingly enough, when they looked at the dose that was used, they found that a higher dose (a higher total nucleated cell count) was associated with a greater gain in GMFM, and that was statistically significant at three months and at 12 months. Doses that were below 50 million total nucleated cells per kilo had little to no effect.

In terms of CP severity and functional response, that was very interesting. Participants with milder CP (GMFCS of one to three) showed greater improvement at three months, six months, and 12 months. They didn't see beneficial effect of the umbilical cord blood cells in those patients that had a more severe form of CP (GMFCS of four to five), irrespective of the dose.

When it came to the milder group, a higher dose was even more potent and actually led to more gains.

Now another very interesting point of this study was the age of the patient at baseline. What they found was that younger children responded better to umbilical cord blood treatment. After adjusting for the baseline GMFCS level, significant effects were found again at six months and at 12 months. Older children showed less improvement, again reinforcing potentially the benefit and the importance of this early intervention.

In terms of etiology, did babies with a certain “reason” for their cerebral palsy respond differently? They couldn't really find significant response differences between etiologies, after adjusting for CP severity. Looking at the sources of the umbilical cord blood, whether it was autologous or allogenic, didn't show any difference. But it's very important to mention that there were very little in the autologous group.

In terms of serious adverse events, the groups were comparable: 16% in the stem cell treated participants versus 13% in the controls. There was only one serious adverse event definitely related to umbilical cord blood infusion, so overall not something that that was overtly concerning, based on the number of patients that are included.

I think this study is interesting because it shows that umbilical cord blood treatment could be safe, effective, and it has an effect on improving gross motor function in some children with CP. Additionally, there seems to be a profile that favors the effect of umbilical cord blood stem cells. It seems that infants who are younger (less than five years old), who have a milder form of CP at presentation, and who are treated with higher doses of stem cells benefit more. These benefits become evident at about six to 12 months post infusion, again maybe reflecting a biological time needed for neural repair. 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 a longer period of time.

The conclusions are that the meta-analysis provides strong evidence that umbilical cord blood is clinically meaningful and a safe therapy. The identification of potentially best responders should guide future research and real-world implementation. I think it's very interesting because we counsel families frequently about the risk of CP, and I think parents are direly seeking potential therapies. I think we should not be ignorant to this to this very promising avenue of clinical research.

Daphna: Yeah, I am jumping out of my seat! I think this very exciting, very promising, and I think it's not that far away from us, right? The mean baseline age at the infusion was 54 months, but ranging from eight months to 18.9 years. We heard you say that the younger kids had more you know improvement.

Ben: This is one of the points the authors are making – if we can find the patients even earlier than that, could we even begin [treatments] much earlier? And I think that is very promising.

Daphna: I think that's super exciting. At eight months, some of those kids are still in our unit! So they're definitely in our follow-up clinics. We had that great interview with Dr. Maitre about starting to use the Hammersmith at term postmenstrual age, identifying these babies early, and maybe these therapies will become more available. I think it's really exciting. I hope it will be an opportunity that we'll start doing them in the NICU. We're not there yet, but I think we'll get there. I'm hopeful.

Ben: I am so happy you're excited!

Daphna: I'm absolutely thrilled. I think we focus a lot on trying to prevent brain injury in the NICU. Absolutely great idea. But some babies are still having brain injury, and we have to do something about it. I love that paper. Very cool. Thanks, buddy.

I have a paper that relates to cerebral palsy also, so I guess I'll do this one next. 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. The lead author is Viral Jain and senior author Namasivayam Ambalavanan.

The objective of the study was to look at if extremely preterm infants (less than 27 weeks) exposed to either histological chorioamnionitis or funisitis are at a higher risk of a combined outcome death of cerebral palsy. They looked at them independently and compared to those without these exposures.

I thought it would be nice to review the differences in this terminology. They did a great job in the background section. 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, which can be caused by intraamniotic infection, sterile intraamniotic inflammation, or other things that are part of the delivery process (epidural anesthesia and analgesia).

Histological chorioamnionitis the pathological corroboration of intraamniotic or intrauterine inflammation, which may occur with or without infection. 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. These studies suggest that it's probably inflammation that may contribute to neuronal injury. Acute histologic chorioamnionitis is characterized by the presence of neutrophilic inflammation on the chorio-amniotic fetal membranes or in the chorionic plate, while funisitis is inflammation specifically of the umbilical cord. This needs to be distinguished from chronic histologic chorioamnionitis, which refers to lymphocytic infiltration leading to inflammatory lesions in the fetal membranes, possibly due to some maternal-fetal rejection. While acute histologic chorio is evidence of an inflammatory maternal host response, funisitis in the umbilical cord reflects the fetal inflammatory response.

And I thought this was important: fetuses affected with funisitis generally are born to mothers with proven intraamniotic infection. However, funisitis may also be seen with sterile inflammation. So that's why they picked these markers specifically.

The methods: this a retrospective analysis of a prospectively collected cohort of all infants born alive at hospitals in the NICHD Neonatal Research Network between 7/1/2012 and 12/31/2019. These are little babies, born 22+0 to 26+6 weeks of gestation. Babies that were excluded were outborn, no placental pathology, congenital malformations, and genetic syndromes did not receive active treatment after birth. Also to note, funisitis data only became available after 2016. So only 2016 to 2019 did they collect funisitis data.

The primary outcome was defined as the composite outcome of death or cerebral palsy and GMFCS score greater than or equal to one at 22 to 26 months corrected age. The secondary outcomes included (1) the components of the primary outcome (so death and cerebral palsy separately), (2) death or moderate-severe neurodevelopmental impairment defined as the composite outcome of a Bayley-III cognitive score less than 85, motor score less than 85, cerebral palsy diagnosis and GMFCS level greater than or equal to two, bilateral blindness, and/or hearing impairment, (3) the individual components of moderate to severe neurodevelopmental impairment.

The study consisted of just under 7000 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 and data available for the primary outcome. After excluding infants meeting the exclusion criteria, they looked at the funisitis group. 28% of infants had funisitis, compared to 72% of controls without funisitis. Those without funisitis may or may not have histologic chorioamnionitis. Primary outcome data was available for 87% of these infants.

There were significant differences in neonatal maternal characteristics between the groups versus controls. Mothers of histologic chorioamnionitis- or funisitis-exposed infants had lower incidences of hypertension, were more likely to receive antenatal steroids, and tended to be born at a lower gestational age.

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

Daphna: Yes, very interesting. Mothers of histologic chorioamnionitis- or the funisitis-exposed infants had lower incidence of hypertension, which was also interesting. If your reason for early delivery is hypertension, then you know may not be infected. Also, they were more likely to have received antenatal steroids.

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

Daphna: Yeah. Compared to controls, infants exposed to chorioamnionitis – from now on, it's histologic chorioamnionitis, I'm not going to keep saying it! – or funisitis 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 hypertension).

There were differences by race. If we take a look at table one, black mothers were more commonly with chorioamnionitis and funisitis than controls, white mothers less commonly. There was a difference in the mode of delivery. The controls were more likely to be delivered by C-section. Those babies with prolonged rupture of membranes were much more likely to be associated with chorio and funisitis.

Into the results. 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, in multivariable analysis adjusted for potential confounders (in particular, gestational age), histologic chorioamnionitis was not associated with death or cerebral palsy. In an unadjusted analysis, there was no increase in death or cerebral palsy in those exposed to funisitis compared to those without. However, in the adjusted multivariable analysis, an increased risk of death of cerebral palsy was seen in funisitis-exposed infants (risk ratio of 1.09) and this association was primarily due to being born at an earlier gestational age.

In surviving infants, there was no association of histologic chorioamnionitis with cerebral palsy. 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, there was a lower risk of death from direct histologic funisitis exposure, but again, the prematurity. There was no association observed for cerebral palsy, death, or moderate to severe neurodevelopmental impairment, or components of neurodevelopmental impairment after adjustment.

Looking specifically at funisitis in surviving infants, infants exposed to funisitis had a significantly higher prevalence of cerebral palsy: 20% versus 25%. This was statistically significant. On multivariable 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 1.23).

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. 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 death (27 versus 22) in those exposed to funisitis on the unadjusted analysis. 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. No differences were seen for death or neurodevelopmental impairment components after adjustment.

So, the take home points are that this large 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 effects appear to be a direct adverse effect of funisitis exposure, leading to cerebral palsy in those surviving infants. Preterm birth only partially explains the increased risk at cerebral palsy. In contrast, the histological chorioamnionitis was not associated with death or cerebral palsy in preterm infants.

I thought this was interesting. We've had a number of situations in the last year with multiples who have different sides of the placenta, different umbilical cords, us trying to distinguish who has what on pathological findings, and us questioning their risks. So I thought this connection between fetal inflammation and cerebral palsy risk is interesting.

Ben: It's very interesting. It's depressing because it's not one of these entities that we know how to treat.

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

What did we miss? Maybe this this accounts for some of that.

Ben: They did a very good job in trying to explain the relationship between preterm birth, funisitis, and cerebral palsy. They're all interconnected. They have a beautiful figure showing that preterm birth contributes to cerebral palsy, but funisitis also contributes to preterm birth. So there's a lot of indirect effects here. Overall, irrespective of how you want to look at this – you can go into the granularity of looking at the relative risk for each particular effect – there's a total effect that is undeniable. It helps with counseling; I think you're absolutely right.

My last paper for today is a paper that came out last year that we never really reviewed, and that came up in the form of another article that was published in Archives in a meta-analysis. But I thought we should probably review this, as it's more relevant to our conversation. This a paper called “Azithromycin Therapy for the Prevention of Chronic Lung Disease of Prematurity (AZTEC): a multicenter, double-blind, randomized placebo-controlled trial.” It's published in the Lancet Respiratory Medicine. The trial really addresses the question, can early azithromycin therapy reduce the incidence of chronic lung disease of prematurity in extremely preterm infant?

We know bronchopulmonary dysplasia continues to be a pain in our neck, and despite all the advances in our in our field, the rates of BPD remain quite high. The pathogenesis is multifactorial. But a key inflammatory pathway for BPD involves polymorphonuclear neutrophil-driven injury to the lung parenchyma, triggering long-term remodeling and impaired lung development. We know that, in general, this theme is present all throughout the pathogenesis of BPD, which is pro-inflammatory things making the lung worse and us trying to minimize this inflammatory exposure.

One proposed contributor is pulmonary colonization with ureaplasma, a bacteria that several analyses have shown to be significantly associated with the later development of BPD. Despite this, the evidence on macrolide antibiotics as a preventive strategy does remain conflicting in the literature. 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 ureaplasma, and potentially for neonatal lung protection.

Previous meta-analyses, including one in 2014, suggested a benefit with azithromycin, but a 2021 review found no clear improvement in BPD rates. The AZTEC trial is a study that was designed in the form of a large rigorously powered multi-centered RCT to really answer the question of, should we give azithromycin to potentially reduce BPD?

The AZTEC study was a multi-center, double-blind, randomized placebo-controlled trial across 28 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 non-invasive or invasive respiratory support within the first 72 hours after birth. I guess this was used as a proxy of potential lung inflammation, because if a baby is on room air and doing great, then you don't need to do anything.

Exclusion criteria included major congenital anomalies, previous macrolide exposure, and predicted non-survival beyond 72 hours. They randomized these infants one to one. The group that was in the intervention arm received the azithromycin 20 mg/kg IV daily for three days, followed by 10 mg/kg IV daily for seven days, for a total of ten days of treatment. The placebo control received sterile water. All the participants were blinded to the study. Baseline respiratory samples from endotracheal tube or from the nasopharynx were collected before the first dose to test for ureaplasma 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. The definition is one that is fairly standard, looking at babies who had moderate chronic lung disease 21-30% FiO2 or LFNC, and severe patients being on invasive or noninvasive support at 30% FiO2. Secondary outcomes included death before 36 weeks, days on oxygen or ventilation, ureaplasma colonization, use of corticosteroids, PDA treatment, NEC, IVH, ROP, and nosocomial infection.

They screened about 1800 babies; 799 were randomized. In the final analysis 394 infants were allocated to Azithromycin, 402 allocated to placebo. The baseline characteristics were all well balanced, though there were more antenatal antibiotics that were noted in the placebo group. The median gestational age was 27 weeks. The median birth weight was 895 grams, and 89% of the babies were born at the research center that was enrolled.

In terms of the primary outcome, when we're looking at survival without moderate to severe BPD, the rates were 42% in the azithromycin group compared to 45% in the placebo group.

This was not statistically significant. Looking at subgroup analysis by ureaplasma status, gestational age (less than 28 weeks or 28-30 weeks), and inborn or outborn, there was no difference was seen in these subgroup analyses.

Looking at some of the secondary outcomes looking at death at by 36 weeks gestational age, this was 9% in the azithromycin group compared to 8% in the placebo – also not statistically significant. Looking at moderate to severe BPD, we're looking at 54% in the azithromycin group versus 51% in the placebo group. In terms of ROP, 4% in the Azithromycin group versus 7% in the placebo group; this the only one that sort of reached statistical significance.

In terms of other outcomes, there was no difference in PDA treatment, corticosteroid use, NEC, IVH, infection rates, etc. In terms of liver/renal enzyme [function], that was similar between the two groups as well. 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 azithromycin.

It's very disappointing that despite the strong biological plausibility and previous smaller studies, the AZTEC trial did not show improvement in survival without moderate to severe BPD with azithromycin. 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, as I mentioned, is a reduction in the treated ROP among survivors that was observed, although this finding requires some caution, because of the number of babies that we're talking about, and the fact that this a secondary outcome. The ureaplasma colonization rate was about 22%, which is lower than other studies. They found no treatment interaction when they isolated just the patients that were positive for ureaplasma; still no statistical significance. Very disappointing there.

The paper had a pretty striking conclusion. The interpretation of the findings in the abstract was well worded. It said, “Since prophylactic use of azithromycin did not improve survival without development of physiologically-defined chronic lung disease regardless of ureaplasma colonization, it cannot be recommended in clinical practice.”

Daphna: Darn it.

Ben: Darn it.

Daphna: It doesn't make sense. I think that's what's so frustrating. We know ureaplasma 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 it.

Ben: Yeah, it's very disappointing.

Daphna: Very disappointing.

I did have one paper left. It’s a very useful paper. 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 in Pediatric Research. It's called “Advancing Neonatal Autopsy by Strengthening Physician Belief and Fostering Effective Family Communication.” Lead author Panagiotis Kratimenos, senior author Hannah Kinney. It's really talking about how autopsy can benefit families, and maybe if we did a better job of learning about it and explaining it, more parents and more families would be interested in autopsy. This not NICU specific, but I think the points are still very valuable for our community.

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. The same trend is seen in children. Many reasons have been put forward to explain this alarming decline, including the mistaken view that autopsy has “nothing to offer” in this day of sophisticated diagnostic 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 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. Beyond advancing science, 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. By fostering open and empathetic communication, clinicians can better support families in their time of profound loss, yet also contribute to the advancement of neonatal healthcare.

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

They really go step by step about approaching the family, who asks for the autopsy, what should be addressed, what does consent look like, what do we do with the autopsy results, what about providing research consent, etc. I thought this was interesting and something that I really didn't know that much about. After autopsy, a lot of that tissue information can still be used for a very long time to gather disease-specific information. They talk a lot about barriers to providing autopsy consent, including parental or medical professional misperception, questions about disfigurement, not letting the child be in peace, this belief that autopsy would not be beneficial because the baby has already died. Other factors include socioeconomic status and the cost of autopsy. Studies consistently show that the decline in autopsies is more than attributable to the lack of opportunity and dearth of conversations with families, rather than family refusal per se. Then they go into what is the fear of autopsies? What are people worried about?

[I think if people just looked at one section of this paper, look at the section about how different cultures understand not just autopsy but death in general]. I think it will help us all go a long way in our cultural competency surrounding death and dying. I thought this was a really nice add to this paper. Then, they even give some scenarios and scripts for conversations with families, with specific terminology you can use for specific scenarios. They close the paper with a step-by-step framework in addressing autopsy with families.

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

Ben: Thank you for reviewing that. I think this idea that autopsy will have nothing to offer is a misconception is really quite pervasive.

Daphna: I do think a lot of the deaths in the NICU can be explained by the clinical presentation, so not everybody needs an autopsy. But I wonder if there are some families that might benefit from one, and as we're moving away from offering autopsy in general, they may miss that benefit.

Ben: I think that another point that the article is making is the timing. Sometimes, we try to have the autopsy conversation immediately after a patient has passed, and that's very difficult. It probably is not the best time to have that conversation. Maybe we should let the family grieve and table that conversation for the following day, or the following week if possible. It’s something that makes everything a bit more difficult, for us as well. It's a traumatic time for everybody at that point. And all because we have to fill out a form…most of the time it's because we have to fill out a form.

Daphna: For some reason, I was taught that it was almost emergent to get to get the autopsy consent. This paper very much addresses that. It's not right. Also, I think they do a nice job of outlining that for families where we can anticipate a death, this something we can discuss ahead of time.

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?! And 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, and I think this can be included in that conversation.

Ben: On this note, we will close out journal club. Thank you to everybody who is still here and listening to Journal Club. We will see you guys later this week with more content and more board review. See you guys next time. Bye