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#175 - 📑 Journal Club - The latest neonatal research from Jan 14, 2024




Hello Friends 👋

We are thrilled to release our first journal club of 2024. This week, journal club covers a wide variety of topics including: 


  1. A trial on using sildenafil for brain injury in neonates with hypoxic-ischemic encephalopathy (HIE). The safety and feasibility of sildenafil as a restorative treatment are explored.

  2. The effectiveness of NIR-CIVIMAB for RSV prevention in infants. The focus is on reducing hospitalizations due to RSV-associated lower respiratory tract infections.

  3. The impact of antenatal corticosteroid treatment during late preterm periods on neonatal outcomes, especially in twin pregnancies.

  4. A study on energy drink intake before and during pregnancy and its association with adverse pregnancy outcomes.

  5. Jennifer Canvasser's meeting with the FDA regarding probiotic use in NICUs and the implications of recent FDA warnings.

  6. Research on early and exclusive enteral nutrition in preterm infants, the time taken to reach target cooling temperature in infants with HIE, and the potential role of blood transfusions in bronchopulmonary dysplasia.

These topics are critically analyzed and discussed, providing insights into current neonatal care practices and research developments.


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This week we have the pleasure of also welcoming Jenn Canvasser (@jenncanvasser) from the NEC society to summarize the takeaways from their meeting with the FDA about their recent warning on the use of probiotics in the NICU.

Check out the article directly from the NEC Society website here: https://necsociety.org/2024/01/03/nec-society-fda-meeting-on-probiotics/


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

Parental Perceptions of Informed Consent in a Study of Tracheal Intubations in Neonatal Intensive Care. Tippmann S, Schaefer J, Arnold C, Winter J, Paul NW, Mildenberger E, Kidszun A. Frontiers in Pediatrics.;11:1324948.

 

Drysdale SB, Cathie K, Flamein F, Knuf M, Collins AM, Hill HC, Kaiser F, Cohen R, Pinquier D, Felter CT, Vassilouthis NC, Jin J, Bangert M, Mari K, Nteene R, Wague S, Roberts M, Tissières P, Royal S, Faust SN; HARMONIE Study Group.N Engl J Med. 2023 Dec 28;389(26):2425-2435. doi: 10.1056/NEJMoa2309189.PMID: 38157500 Clinical Trial.

 

Wintermark P, Lapointe A, Steinhorn R, Rampakakis E, Burhenne J, Meid AD, Bajraktari-Sylejmani G, Khairy M, Altit G, Adamo MT, Poccia A, Gilbert G, Saint-Martin C, Toffoli D, Vachon J, Hailu E, Colin P, Haefeli WE.J Pediatr. 2023 Dec 21:113879. doi: 10.1016/j.jpeds.2023.113879. Online ahead of print.PMID: 38142044 Free article.

 

Razzaghy J, Shukla VV, Gunawan E, Reeves A, Nguyen K, Salas AA.Arch Dis Child Fetal Neonatal Ed. 2023 Dec 22:fetalneonatal-2023-325969. doi: 10.1136/archdischild-2023-325969. Online ahead of print.PMID: 38135494

 

Pessano S, Bruschettini M, Prescott MG, Romantsik O.Cochrane Database Syst Rev. 2023 Dec 14;12(12):CD015592. doi: 10.1002/14651858.CD015592.pub3.PMID: 38096386 Review.

 

Rao R, Comstock BA, Wu TW, Mietzsch U, Mayock DE, Gonzalez FF, Wood TR, Heagerty PJ, Juul SE, Wu YW.J Pediatr. 2023 Nov 23;266:113853. doi: 10.1016/j.jpeds.2023.113853. Online ahead of print.PMID: 38006967

 

Bahr TM, Snow GL, Christensen TR, Davenport P, Henry E, Tweddell SM, Ilstrup SJ, Yoder BA, Ohls RK, Sola-Visner MC, Christensen RD.J Pediatr. 2023 Nov 20;265:113836. doi: 10.1016/j.jpeds.2023.113836. Online ahead of print.PMID: 37992802

 

Ding M, Markon AO, Jones-Dominic OE, Purdue-Smithe AC, Rich-Edwards JW, Wolpert BJ, Chavarro JE.JAMA Netw Open. 2023 Nov 1;6(11):e2344023. doi: 10.1001/jamanetworkopen.2023.44023.PMID: 37983030 Free PMC article.

 

Zhu J, Zhao Y, An P, Zhao Y, Li S, Zhou J, Zhao H, Zhou Q, Li X, Xiong Y.JAMA Netw Open. 2023 Nov 1;6(11):e2343781. doi: 10.1001/jamanetworkopen.2023.43781.PMID: 37976061 Free PMC article.

 

Hughes BL, Clifton RG, Rouse DJ, Saade GR, Dinsmoor MJ, Reddy UM, Pass R, Allard D, Mallett G, MacPherson C, Wapner R, Metz T, Goodnight WH, Tita ATN, Costantine MM, Swamy GK, Heyborne KD, Chien EK, Chauhan SP, El-Sayed YY, Casey BM, Parry S, Simhan HN, Napolitano PG, Macones GA; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network.N Engl J Med. 2023 Nov 9;389(19):1822-1824. doi: 10.1056/NEJMc2308286.PMID: 37937785 No abstract available.


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


Ben Courchia MD (00:00.886)

Hello everybody. Welcome back to the incubator podcast. It is Sunday and we are doing our first journal club of the year. How exciting. How are you definitely.

 

Daphna Yasova Barbeau, MD (00:09.426)

Very exciting, obviously. I feel like we're always saying things are exciting, but they are, and I didn't think I was gonna say this. I miss Journal Club as well.

 

Ben Courchia MD (00:18.143)

No, we've opened many NeoReview podcasts saying we're not thrilled of doing questions. I think that has happened on multiple occasions. And I think we've opened the future local clubs where we were like, we're not ready to do this. But it's just...

 

Daphna Yasova Barbeau, MD (00:25.042)

That's true.

 

Daphna Yasova Barbeau, MD (00:30.491)

Hehehe

 

Daphna Yasova Barbeau, MD (00:33.854)

But I think it's important people know that too. We're not, everybody is really strained for time, strained for time, strained for energy, but we gotta review the evidence when we can.

 

Ben Courchia MD (00:39.69)

We don't got this together people. We're just.

 

Ben Courchia MD (00:48.226)

flying by the seat of our pants. It's not that, it's that we read the evidence and we can comprehend the evidence, but it's where we lag behind sometimes is the processing of what we read into a script, into a note that can be actually then read out on the air. That's where, so there were many times where I was doing the journal club with the highlights on the paper as I was, so like we never come on the air without having read the evidence, but.

 

Daphna Yasova Barbeau, MD (00:58.803)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (01:04.018)

That's right.

 

Daphna Yasova Barbeau, MD (01:15.178)

for sure.

 

Ben Courchia MD (01:15.818)

It would have been nicer that day if I had put the notes together. We have a lot of content to cover today, so I don't want to waste too much time venturing and you were going to make an announcement regarding our end of year giveaway.

 

Daphna Yasova Barbeau, MD (01:18.451)

Hehehe

 

Daphna Yasova Barbeau, MD (01:32.926)

That's right. Well, we had a lot, a lot of people enter a bracket into the EBNEO incubator podcast, uh, article of the year, impact article of the year. Yes. Um, so we really appreciate people who participated and we're brave enough to submit a bracket and we have a number of winners who I will find either by email or by Twitter. So I, I will find you.

 

Ben Courchia MD (01:45.342)

Impact our article of the year campaign.

 

Ben Courchia MD (02:02.262)

Check your messages.

 

Daphna Yasova Barbeau, MD (02:03.23)

Check your messages. And the things we had to give away were Beats headphones, an iPad, one of those Echo stethoscopes where you can record. And we had a little bit of swag to distribute as well. So a number of people will be getting a message and getting something exciting.

 

Ben Courchia MD (02:17.934)

Mm-hmm.

 

Ben Courchia MD (02:26.15)

Very cool. All right. We are also going to try to introduce a new segment during Journal Club. You are probably already familiar with the EBneo commentary, but we will try to give you more newsy type of content. So this week, for example, we'll have a little segment with Jen Canvasser, who will tell us a little bit about her meeting with the FDA

 

their probiotic warning. And we'll try to give you more news from the field of neonatology that may not be an actual paper, that may not be a long-form interview, just so that we keep highlighting the work that is being done by the members of our community. If you are doing something and you're like, we'd love for this to be highlighted on the show, just shoot us an email. And we'll make it. Yeah, the new news.

 

Daphna Yasova Barbeau, MD (03:18.148)

The Neo news, as it were.

 

Ben Courchia MD (03:23.05)

All right, should we get started, Daphna?

 

Daphna Yasova Barbeau, MD (03:26.29)

We must.

 

Ben Courchia MD (03:27.594)

We must. Okay, so I'm gonna start with a paper that I was really excited to see in publication. It is a paper in the Journal of Pediatrics, and the first author is Dr. Pia Wintermark, who is a neonatologist from Canada that Gabriel Altitani interviewed for the French podcast. And she is a brilliant physician scientist who studies the brain, neonatal brain development, neonatal HIE. And she published the first

 

paper on her opus of work where she is looking at the use of cell denifil for brain injury secondary to HIE. So the title of the paper is feasibility and safety of cell denifil to repair brain injury secondary to birth asphyxia. It is the SANE-01 trial, a randomized double blind placebo controlled phase 1B clinical trial. I am very excited about this paper because obviously the saga with EPO and HIE...

 

sort of came to a close last year and we're always looking for therapies and interventions that we can offer the babies and their families when they're facing with hypoxic ischemic encephalopathy. And our discussion on Sedanofil with Pia on the French podcast was very much eye opening. She writes in her introduction a lot of the things that she did mention, obviously that

 

Ben Courchia MD (04:54.49)

the treatment of neonatal encephalopathy and to try to prevent the development of brain injury. But as she mentions in the introduction, 29% of the babies who are being treated with therapeutic hypothermia still develop severe neurological sequelae. So it's not great. It's really not a great fix for this horrifying pathology. Now, what she is showing is that

 

Ben Courchia MD (05:23.082)

restorative properties by reducing the extent of brain injuries and influencing neurogenesis, neuronal architecture, and NGOgenesis. Similar benefits of the cell denifil on infarct size, apoptosis, neurogenesis, neuroinflammation, and oligodendrogenesis have been demonstrated in preclinical models of neonatal hypoxic ischemic encephalopathy. I asked her that question point blank the other day and I said, well,

 

Are we, is this going to be used for prevention? And she was saying it is for regeneration. This is going to be a treatment that potentially could fix the damage done by HIE, which is, if that turns out to be true, would be monumental. She also mentioned that sidenafel is a great drug. It's something that we are have some familiarity with because we use it obviously for babies with pulmonary hypertension. And so they're saying that it is important to investigate whether sidenafel can exert neuro-restorative effects in human neonates.

 

This paper is basically aimed at assessing the feasibility and the safety of giving sardinophil enteraly to neonates with moderate to severe neonatal encephalopathy on their developing brain despite receiving therapeutic hypothermia. So this is not obviously a substitute. The SANE-1 trial is a randomized double-blind placebo control phase 1b intervention study run in a single tertiary center in Canada.

 

They enroll babies that were 36 weeks or of age or more, weighed 1800 grams or more, and who were diagnosed with neonatal encephalopathy treated with cooling therapeutic hypothermia and who have a diagnosis that is moderate to severe neuro, um, neonatal encephalopathy on amplitude integrated EEG on admission and with HIE injury on baseline MRI. She has published a ton about early MRIs done on day one, day two, and

 

I suggest you go read these papers. We're going to try to go through this study relatively quickly. So she has a lot of papers, Pia Wintermark, check her out. The, she randomized babies two to one, Sildenafil. She was giving two mix per kilo per dose Q12 and, or, uh, and the other arm received placebo, they give this via a gastric tube beginning on day two to three of life and continued for seven consecutive days, which reminds you of the fact that this is not really preventive there. They don't really care that it's really given as early as possible.

 

Ben Courchia MD (07:51.326)

It has, it's supposed to have restorative properties. So the goal is to continue for a total of 14 dose. They assessed encephalopathy with a modified Sarnath and with amplitude integrated EEG, and they checked all sorts of labs that we all check. Troponin-1, CK, creatinine, AST, ALT, and so on and so forth. The feasibility component was defined as the ability to diagnose neonatal encephalopathy, perform the two-day MRI, randomize the treatment and treat for seven consecutive days.

 

They had obviously safety outcomes, looking at adverse events, which included death, hypotension, PPHN, worsening liver function, IVH slash intraparenchymal hemorrhage and retinopathy. They also looked at plasma concentration and they then did an exploratory analysis where they repeated the brain MRI on the surviving neonates at day 10 and day 30 of life to explore the impact of cell denifil on the brain structure and metabolism as part of safety assessments. So they measured

 

the many different factors on the MRI, which we don't really need to go into details, but the apparent diffusion coefficient, the ADC, the fractional anisotropy, the FA, the lactate and acetyl aspartate ratio, and deep gray matter area. Now, the surviving neonates were then followed up at 18 months of age, and they had a structured neurodemental assessment using the BLE. So a pretty very, very well outlined protocol. So.

 

Obviously this is safety and feasibility, so don't get too excited about the numbers. They randomized 11 neonates. Eight neonates were randomized to sedentifil, three to placebo. Most of the babies ended up receiving their first dose of sedentifil within 48 hours, at about 48 hours of life. Neonates received three to four doses while receiving therapeutic hypothermia, and the rest was done after rewarming. Neonates in the sedentifil group had lower gestational ages.

 

higher baseline troponins and higher baseline creatinine compared to the placebo group. So if anything, they were a little bit sicker. I'm gonna skip a little bit some of the safety outcome because there's not too much to write home about, but I wanted to really focus since we're trying to be mindful of time. I wanted to focus on the neuroimaging outcomes and the 18 months clinical outcome. So in terms of the neuroimaging, she commented on the baseline.

 

Ben Courchia MD (10:10.698)

imaging. So of the three neonates who received the placebo, one had watershed injury pattern and two had severe extensive brain injury on day two. So really not good prognosis. Among the neonates who were treated with Sidenofil, one had watershed injury pattern and the remaining had severe extensive brain injury on their day two MRI. The ADC values and the lactate to NAIA ratio in the thalamus were not different between the two groups at baseline. So what happens when they looked at the MRI at follow-up, day 10, day 30?

 

Looking at it from a qualitative standpoint, 71% of the neonates, so five out of seven who were treated with sidenofil, displayed partial recovery of injury on their day 30 MRI, as well as fewer cystic lesions and fewer signs of brain volume loss, defined as widening of the supratentorial ventricular system, compared to zero in the placebo group. Three babies, obviously. Let's not get too excited about that.

 

quantitatively, deep gray matter was... I'm very excited about it. I'm trying to be the voice of reason here.

 

Daphna Yasova Barbeau, MD (11:10.674)

getting excited about. Okay, you're trying to be the unbiased.

 

Ben Courchia MD (11:17.454)

Uh-huh. Quantitatively, deep gray matter was unchanged over time in the placebo group, but increased in the cell-denofil group. When they looked at the other metrics on the MRI, they were not really different between the groups at day 10 or day 30. Looking at 18 months clinical outcome, they were able to assess 9 out of 10 of the surviving neonates, and they were followed about 18.8 months. The composite outcome of death or survival to 18 months with severe

 

was 57% in the sildenafel group compared to 100% in the placebo group. So an almost like 43% difference favoring sildenafel. Among the surviving neonates, 17% in the sildenafel group developed cerebral palsy and gross motor delay compared to 100% in the placebo group. So one baby out of the six actually developed CP and gross motor delay compared to all of them in the placebo group. 33% in the sildenafel group develop global developmental delay.

 

So two out of six compared to 100% in the placebo group. In terms of motor, language, and cognitive composite scores, they were not different between the groups. And so in conclusion, they're saying that basically administering entirely sardinephil to clinically neonate with moderate to severe encephalopathy was feasible and safe. It was well absorbed during.

 

hypothermia and it's well tolerated. That's why I said you can look at the safety. There was nothing like you're gonna find out that it was well tolerated. As you probably know, if you've given cell denifil to babies, those escalation studies are now needed to define the optimal dose before large scale, randomized double blind placebo controlled phase two and three trial could be undertaken to determine the neuroprotective, neurorestorative potential of cell denifil in the context of neonatal encephalopathy. So.

 

I am obviously very excited by this study because it opens the door to now a potential new avenue for us to explore for our babies with hypoxic injury at birth. And, um, the animal data and this data are all very encouraging. We have learned from the past that we're not going to scream victory before it's all over, but I'm excited.

 

Daphna Yasova Barbeau, MD (13:19.922)

Mm-hmm. Yeah, I think this is, I mean, exciting is the word, but it's hopeful, I think, to have something on the horizon, at least that we will be working on and looking for. So, very cool. Thank you for presenting that. And you didn't mention that Dr. Wintermark will be joining us at the Delphi Conference.

 

Ben Courchia MD (13:35.454)

Yeah.

 

Ben Courchia MD (13:43.238)

Oh, I forgot to mention that. Of course. Yeah. After I finished the interview with the Gabriel's like, Gabrielle, she needs to come talk at Delphi. Like this lady is brilliant. Um, and she's so unassuming. Um, and then she opens her mouth and you're like, holy moly. And she has this vision for treatment of HIE. So it's very exciting. Yep. Delphi, September 23rd to 25th, um, limited seating, uh, agenda coming up later this month and registrations open. Very cool.

 

Daphna Yasova Barbeau, MD (13:49.766)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (13:53.861)

Yeah.

 

Daphna Yasova Barbeau, MD (14:07.86)

And registration is open.

 

Daphna Yasova Barbeau, MD (14:13.198)

Okay, my first one from the folders we say is kind of another study on NirsevimabB for prevention of hospitalizations due to RSV in infants from the Harmony study group. The lead author is Espe Grizdale, and this is published in the New England Journal of Medicine. So they wanted to look at really...

 

Ben Courchia MD (14:28.619)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (14:40.65)

the primary outcome of hospitalization for RSV associated lower respiratory tract infection. Notably, I'll mention the study was funded by Sanofi and AstraZeneca. And in addition, the follow-up for most of the infants at the time of the study was about three months. They do plan to come out with another iteration for follow-up of all infants until 12 months. So.

 

Ben Courchia MD (14:58.215)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (15:07.198)

Basically what they did, this was a placebo controlled, randomized controlled trial of infants less than 12 months of age, born at a gestational age of greater than 29 weeks, who were entering their first RSV season in France, Germany, the UK in 2022. And the infant was either randomized to receive near Civumab, the new RSV therapy vaccine or no vaccine. I guess, right.

 

Ben Courchia MD (15:32.138)

vaccine. Well, yeah.

 

Daphna Yasova Barbeau, MD (15:38.138)

Okay, so the exclusion criteria was being eligible for a Pallivizumab. So if you were like a preemie who already got your RSV prophylaxis, then you didn't qualify for the study. And that is the current clinical exclusion criteria as well. I told you the primary outcome was hospitalization for RSV-associated lower respiratory tract infection.

 

And the secondary outcome was very severe RSV associated with loror respiratory tract infection. So this was defined as a hospitalization with an O2 saturation less than 90% and that the infant required supplemental oxygen. They had just over 8,000 infants enrolled in randomized, 4,037 Nirsevimab and 4,021 to the standard care, which again was no receding nurse.

 

At randomization, the two groups were similar. However, there was a higher percentage of infants less than 37 weeks than expected in the entire group. So slightly more prematurity. But 85% of the entire group was term or greater than 37 weeks. So I won't belabor the details. I'll just jump into the data because there have been some other studies that showed similar data in terms of hospitalization.

 

3% or 11 in the intervention group, and 60 or 1.5% in the controls. They described then an efficacy of 83.2% statistically significant. And then they looked at the very severe RSV lower respiratory tract infection occurring in five infants in the intervention group. This was 0.1% as compared to 19 or 0.5% in the controls.

 

So they described the efficacy, but they describe the efficacy actually by country, which is kind of interesting. So the efficacy, 89.6% in the French group, 74.2% in the German group, and 83.4% in UK. Looking a little closer at the hospitalized infants, two out of five in the intervention group were admitted to the ICU, none of which needed mechanical intervention. Five out of 19 in the control group were also admitted to the ICU,

 

Daphna Yasova Barbeau, MD (18:04.606)

five ICU patients required intubation. They looked at a subgroup analysis and they looked at a variety of things, age of enrollment, so looking at less, were they enrolled at less than three months, three to six months or greater than six months. They looked at weight at randomization, gestational age, sex, timing of randomization, and all showed similar efficacy estimates.

 

Ben Courchia MD (18:19.905)

Thank you.

 

Daphna Yasova Barbeau, MD (18:29.982)

They also looked at hospitalization for any respiratory infection during the RSV season, which occurred at 1.1% in the intervention groups and higher, 2.4% in controls. They did look at adverse events and overall a 2% rate of adverse events in vaccinated infants. So, this is consistent with other literature so far on the EARS of the Lab.

 

Ben Courchia MD (18:49.663)

Mm.

 

Daphna Yasova Barbeau, MD (19:02.091)

Mm-hmm.

 

Ben Courchia MD (19:02.865)

That's very exciting. I have yet to give one of these doses to a patient.

 

Daphna Yasova Barbeau, MD (19:08.818)

Yeah, we just can't get our hands on it, can we? Mwahaha

 

Ben Courchia MD (19:11.858)

I can't, I can't, I just can't. I wanted to maybe give a little bit of a highlight of a few other studies since we're talking, since we're in the New England Journal of Medicine. I just wanted to highlight the fact that the two-year outcomes for the study that looked at the administration of hyperimmune globulin for congenital CMV infection, to prevent CMV infection, have come out. The original New England paper,

 

was published and was called a trial of hyperimmune globulin to prevent congenital CMV infection. This was published in 2021. Basically, they gave hyperimmune globulin to pregnant mothers that had primary CMV infection, and they randomized these patients to patients who received placebo, and then they looked at a bunch of outcomes trying to see if they were going to be able to prevent

 

a fetus or neonate with CMV infection, they were going to prevent neonatal death, they were going to prevent fetal or neonatal death from CMV infection or fetal death from that CMV infection or symptomatic CMV infection. In any case, it was a complete fluke. Nothing really worked. They were not able to make a dent and the trial was stopped early for futility. So in case you missed that trial in 2021, this is like a very cursory summary

 

the trial. And because they had planned to look at the two-year outcomes for these infants, they're coming out in the New England and they're releasing these outcomes. And these outcomes are released in the form of a correspondence, almost looks like a letter to the editor. So as you can tell, this is not going to be extremely impactful, but they did not see any difference in neurodemental outcomes between these infants at two years of age. So I guess this is putting a...

 

concluding note on that study about the use of hyperimmune globulin for prevention of CMV. I saw some other interesting articles. There was an article in JAMA Network Open called Antinatal Corticosteroid Treatment During the Late Preterm Period and Neonatal Outcomes for Twin Pregnancy. First author is, I'm going to butcher this, but it's Ji Zhu from China. And

 

Ben Courchia MD (21:35.398)

As we had seen previously, there was a paper that we had reviewed from, I think it was in the Lancet that looked at antinatal dexamethasone for late preterm birth. And this was a multi-center two-arm parallel double-blind placebo controlled trial. This was the WHO action trials. I think it made it at some point to the impact of the year article for one of these campaigns, maybe not the past year, but the previous year. And

 

And it showed that antinatal dexamethasone did not result in a reduction in neonatal death, stillbirth, or neonatal death, or severe neonatal respiratory distress. And so the question that this group out of China is asking is, what if it's a late preterm pregnancy, but they're twins? And would that potentially be a different scenario? Obviously, there's a lot of limitations from the study because it's based on a

 

It's a database, so it's a retrospective cohort study. But that being said, still includes almost like 2000 patients and what they found is that they could not identify sufficient evidence to show that dexamethasone actually made any improvement in the outcomes that they were trying to measure when it comes to lowering the risk of newborn morbidity. So the lens that showed that maybe it didn't really help for...

 

for these pregnancies and now showing that in twin pregnancies. Not so much either. Let me see. Oh, there was another article in JAMA Network Open. I don't know if you saw this one. Not really related to neonatology, but I think definitely a societal current topic. JAMA Network Open, the title is, Intake of Energy Drinks Before and During Pregnancy and Adverse Pregnancy Outcomes. First author is Ming Ding.

 

Daphna Yasova Barbeau, MD (23:20.706)

Hmm...

 

Ben Courchia MD (23:26.454)

And this too was a, this was a prospective cohort study that basically took two cohorts and they were basically sending questionnaire to these individuals that they started following for a very long time. I'm going to spare you all the detail, but what they saw was that the only real effect was that energy drink intake before the pregnancy was actually associated with an elevated risk of gestational hypertension. They measured a lot of other things.

 

but nothing really was found to be significant. But I thought that was interesting because it does correlate with a lot of data from the adult population that shows that the excessive consumption of energy drinks leads to changes in blood pressure. So it wasn't really surprising to see that result. And I think that in our space, it's kind of a nice thing to be aware of as we are doing.

 

Daphna Yasova Barbeau, MD (24:23.101)

Mm-hmm. And that consumption is increasing over all of these energy drinks.

 

Ben Courchia MD (24:27.355)

Oh, I actually, yeah, I was actually reading that in the introduction because the, I'm going to tell you exactly. Yeah. So the sales of energy drink have substantially increased by 240% in the U S and worldwide since 1987. Now, how much energy drinks were available in 1987? I don't know, but it's still, it's still impressive. And the.

 

Daphna Yasova Barbeau, MD (24:49.394)

I'm gonna go get some water.

 

Ben Courchia MD (24:54.53)

The market share for energy drinks is, they say $9.7 billion as of 2015. So, I mean, I've had a Red Bull. I mean, let's be honest, I don't drink Red Bull. It used to be more like a med school type of college situation, but yeah.

 

Daphna Yasova Barbeau, MD (25:00.498)

while.

 

Daphna Yasova Barbeau, MD (25:13.766)

In fairness, you drink five cups of coffee a day, but that's it.

 

Ben Courchia MD (25:16.566)

That's true too. Yeah, this is sort of my little review of some of the articles that I found around the internet these past few weeks. Should we take a call from Jen Canvasser who can talk to us about her recent meeting with the FDA? What do you think? All right. Let's get Jen on the line.

 

Daphna Yasova Barbeau, MD (25:42.602)

Let's do it.

 

Ben Courchia MD (00:01.133)

Jenn Canvasser, thank you so much for making time to be back on the incubator podcast with us.

 

Jennifer Canvasser (00:05.643)

Absolutely. Thanks for having me.

 

Ben Courchia MD (00:07.593)

We were saying offline, you're a veteran now of the incubator. You've been on multiple episodes. And so it's kind of nice when you come on. We don't really have to go over any technical things. You know all the tricks. We're excited to have you on because on January 3rd, the NEC Society posted on X, formerly known as Twitter, a tweet about the fact that you guys met with the FDA regarding the probiotics in the NICU. And you have there an article.

 

Daphna Yasova Barbeau, MD (00:10.825)

Mm-hmm.

 

Jennifer Canvasser (00:18.722)

Thank you.

 

Ben Courchia MD (00:37.549)

that's linked to the NECsociety.org website, which we'll link to in our show notes. But can you tell us a little bit about this meeting and what were the discussions about and what were some of your impressions afterwards?

 

Jennifer Canvasser (00:52.386)

For sure. So I think people are probably familiar, but just to give a tiny bit of background, in the fall the FDA released a series of warnings to not just clinicians, but also to families around the use of probiotics in the NICU and forced the probiotics out of, I would say, most if not all NICUs in the United States. And

 

For us, for the NEC Society, it was concerning because probiotics have been shown to be a potentially promising intervention to help prevent NEC. And so we took this opportunity to get in touch with the FDA and to, we thankfully had the opportunity to meet with them in November. So it was members of our staff team, our scientific advisory council, and our board of directors. And the goals of this meeting were to share the NEC Society's, our families, our clinicians' concerns, our experiences.

 

our questions, we have a lot of questions, and really help them understand where we're coming from, helping them to see the perspective from the patient family's point of view, what little strategies we have to prevent and to treat NAC, and how removing one potentially promising intervention and strategy is really harmful to our community and could potentially result in more babies.

 

dying and being diagnosed with NAC. So I would say the meeting overall went well because it was a great opportunity for us to be able to share again our experiences, our stories, our concerns and our questions. But I would say many, most of our questions still remain unanswered. And I think the path forward is a bit unclear right now. We're going to continue to advocate on behalf of our babies and families and continue to.

 

push the FDA to listen to our clinicians and our families and to hear where we're coming from and to partner with us. And I want to make sure that it's really clear that the FDA and the NEC society, we all want the same thing. We all want our babies to receive the safest care possible and to have the best possible outcomes and to get home with their families and thrive. And so...

 

Ben Courchia MD (02:56.949)

Mm-hmm.

 

Jennifer Canvasser (03:06.354)

I don't want anyone to think that the NEC society is against the FDA, absolutely not. We really see each other as partners in this work and we see ourselves as really uniquely positioned to advocate on behalf of our community.

 

Ben Courchia MD (03:22.185)

Yeah, I think it's more, it's not really an opposition, more of a, of a need for realignment on, on our objective so that we can all march in the same direction. You mentioned in the article that you raised the question of how feasible is it to get an IND in the context of probiotics. I just, I had the article pulled up. I'm so sorry. Like an investigational new drug application. This is what an IND stands for. Any, any constructive discussion about that? Because obviously it is.

 

It is a big task and a big to do to get a probiotic approved throughout, through this path.

 

Jennifer Canvasser (03:58.434)

So the FDA is encouraging clinicians to take that path. I'm hesitant and skeptical that is gonna be a way, a forward for this particular situation we have ourselves in just because it is so time consuming and there's so much information that is needed from the manufacturers. And so I think that will be difficult.

 

Ben Courchia MD (04:02.177)

Mm-hmm.

 

Jennifer Canvasser (04:26.846)

So I think that it's tricky. I know that that's what the FDA is encouraging. But I think there's a lot of challenges there.

 

Ben Courchia MD (04:33.945)

Fair enough.

 

Daphna Yasova Barbeau, MD (04:35.94)

Um, I, to your point, I'm wondering what those of us in the community could be or should be doing. And now that you've opened kind of these lines of communication and we can support the work that you're doing.

 

Jennifer Canvasser (04:48.418)

Thank you. I think it's really important for families to continue to receive the most as much information as possible about the their children's and their baby's care and what strategies can help to optimize outcomes. So I think that is like the message I really want to drive home is that it's still really important for families to receive as much information as possible so that they can have.

 

as the ability to feel empowered and confident to advocate for their child and their family. So I think that's one thing that clinicians can do right now is to continue to empower families with information, continue to talk amongst the community about what is happening, stay current on what the NEC society is doing to lead the advocacy work. We've posted not just the article you've mentioned, but some of us at the NEC society have posted and published.

 

independent blogs and articles on various websites. And so you can kind of get a little bit more in-depth information from those links as well. Staying current on our website, our social media, our email address, our, excuse me, our email list. I think are ways that clinicians can kind of stay in touch and figure out like where do we go from here. So yeah, those are my recommendations and just continuing to empower families with information.

 

Daphna Yasova Barbeau, MD (06:09.132)

those discussions with families, do you have a feel for how parents who may be actively admitted in it and nick you? You know, what is their sense of the problem? What do they want to know about? Are they pushing for it?

 

Jennifer Canvasser (06:20.191)

Yeah.

 

Yeah, I think it's really challenging because I think we have two sides. One is that families have more information about probiotics than ever before. And so they know that they could ask about probiotics. And I think it puts physicians in a really challenging place because families may be asking for an intervention and their hands are now tied by this externally focused thing where you can't access this potentially life-saving strategy anymore. You can't

 

access it and provide it to your families and families may be asking for it. So you might come up in that situation and that could be really challenging. On the other hand, there are some families who might be reading these headlines from the FDA in the warnings and feel really scared and skeptical. And maybe in five years from now when we do have an FDA approved probiotic, then it could have ramifications there as well. And so I think there are a lot of implications that we need to be aware of and think about. And the other thing I want to mention is

 

Some centers have reported to the NEC Society that they are seeing more babies being diagnosed or tragically dying from NAC in the last couple months. And I just want to remind centers that the NEC Society offers resources to families who've either been diagnosed or who have recently lost a child to NAC, and those are available on our website. And so that families are receiving the information that they need and can feel like they aren't alone, that there is a community out here for them to be able to access and to...

 

find a path forward.

 

Ben Courchia MD (07:53.893)

Jen, thank you so much for making time to be on with us today, and thank you for all the work that you do.

 

Jennifer Canvasser (07:58.307)

Thank you.

 

 

Daphna Yasova Barbeau, MD (26:11.046)

Oh my gosh, I love having Jen on. Every time we have Jen on, I feel, I don't know, just excitement and energy. And she's so powerful. Yeah, yeah, we're grateful that she always fits us in. She's so busy. I similarly had some papers I just wanted to touch on. There was a new Cochrane review in the neonatal space.

 

Ben Courchia MD (26:19.458)

It's always an excuse. There's always a good excuse to have Jen on the podcast.

 

Ben Courchia MD (26:25.867)

Mm-hmm.

 

Ben Courchia MD (26:31.901)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (26:37.002)

Positioning for lumbar puncture in newborn infants, lead author, Sarah Pisano. Basically they looked at RCTs and quasi-RCTs of infants up to 46 days undergoing lumbar puncture, really only able to include five studies with a total of 1,476 participants. And they were looking at basically the lateral decubitus positioning, which is probably the most common positioning versus sitting of the infant. That was four out of five studies. And the lateral decubitus versus...

 

prone positioning, which I've never seen in one of five studies. Something in the background that I thought was interesting, that they actually reported that nearly 50% of first attempts ended in failure, which I thought was an interesting statistics.

 

Ben Courchia MD (27:20.275)

Oh

 

Ben Courchia MD (27:23.87)

Let's consider the first attempt. Ha ha ha.

 

Daphna Yasova Barbeau, MD (27:27.758)

That's an interesting point, right? Does that mean you tried a few times and then you broke scrub?

 

Ben Courchia MD (27:29.666)

Cuz cuz

 

Ben Courchia MD (27:34.591)

Does the needle have to come out to be considered? Because some people, you stick and then nothing comes out, and then you try to make your way. And then it finally arrives.

 

Daphna Yasova Barbeau, MD (27:46.618)

Yeah, I think if we were purists, then it should be how many sticks, but we didn't write this. So anyways, so the long story short is, there's not as much information as somebody would like, but basically, when comparing the lateral decubitus to sitting, they actually found no difference in first attempt success.

 

Ben Courchia MD (27:51.61)

Mm-hmm. Fair enough.

 

Daphna Yasova Barbeau, MD (28:12.334)

But there was higher risk of bradycardia and desaturation in the lateral decubitus positioning. They found no difference in apnea, and they found no difference in time to perform the TAP, though that was only evaluated in two studies. And then in the lateral decubitus to prone matchup, the study that looked at prone positioning unfortunately did not evaluate bradycardia, desaturation, time to perform TAP, or apnea. But they actually found...

 

a lower chance of success at the first attempt in the lateral decubitus position as opposed to the prone positioning, which I thought was interesting. I've never seen it. If you're doing it, let us know.

 

Ben Courchia MD (28:59.315)

What were the gestational ages of these babies again?

 

Daphna Yasova Barbeau, MD (29:03.034)

So I had, they did include some premature babies, but they were not, they were not ELBWs for sure. And the majority of babies were late preterm to term infants up to 46 days of life. So they actually specifically said that, that they couldn't, this was not transferable to the very preterm population.

 

Ben Courchia MD (29:12.533)

Mm.

 

Ben Courchia MD (29:21.404)

Yeah.

 

Ben Courchia MD (29:29.922)

Fair enough. Yeah. I was listening to an episode of the well beyond medicine podcast. That's done by Nemours and they had on some, uh, startup person. Maybe it's not a startup guy. I don't know. It doesn't matter, but he had designed like a little, um, stand for babies to be placed in a standing position for lumber puncture. I thought that was quite cool. It. In the sitting position and it seemed like it was something for full term babies. Um, but I thought this was interesting as.

 

Daphna Yasova Barbeau, MD (29:36.877)

Mm, mm-hmm.

 

Daphna Yasova Barbeau, MD (29:50.826)

the in the sitting position. Right.

 

Ben Courchia MD (29:59.838)

It feels like our field is shifting towards standing or sitting lumbar puncture, sorry, for a pediatric patient. I don't know how viable that is for micro-premies, but who knows? Maybe we'll find a different position.

 

Daphna Yasova Barbeau, MD (30:12.694)

Mm-hmm, very cool, very cool. The other one I just wanted to touch on briefly was this paper, Parental Perceptions of Informed Consent and a Study of Tracheal Intubations in Neonatal Intensive Care. The lead author, Susanne Tippmann, this is from Germany. It's published in the Frontiers in Pediatrics. So this is actually a secondary analysis of an RCT that evaluated video versus direct laryngoscopy for first intubation attempt.

 

term infants. Notably, in that study, 26% were not randomized. Many clinicians had a stated preference, so they got to do what they wanted to do. But all in all, they found that first attempt success was slightly higher in the video laryngoscopy group. Adverse events were slightly higher in the direct laryngoscopy group. And esophageal intubation with desaturation never occurred in the video laryngoscopy group. It did occur in 20% of the direct laryngoscopy group.

 

So that's just a synopsis, but basically what they did in parallel was run this study on informed consent. So they were consented for this study on informed consent separately from the laryngosophy study, and they split this group for this current study into three further groups.

 

Daphna Yasova Barbeau, MD (31:40.53)

before birth or consented after birth, but before enrollment to the other study, or the third group after birth and after enrollment to the other study. So that way they could look at the different ways that parents were asked for their consent. This was just a questionnaire. They were asked about their perceptions of clinical trials and the consent process. It was fully anonymous.

 

Ben Courchia MD (32:06.118)

So, I'm so sorry, I just have to clarify something because I'm getting a little bit confused. So they had a trial that looked at video versus direct laryngoscopy and that was a trial. And then this study was looking at the way they consented the parents for that laryngoscopy trial and get their feelings about how was that process of getting consented for the study like. Is that correct?

 

Daphna Yasova Barbeau, MD (32:09.066)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (32:26.302)

Correct. And probably the last piece of information you need to know is that some of the parents for the laryngoscopy study were consented before birth, so they didn't know if their kids were going to need intubation at all. And then some of them were consented after birth but before intubation, but some were consented after intubation, like a deferred consent to participate in the study.

 

So again, those were babies who got intubated in one way or another, and then were enrolled in the study. So they were asked about their perceptions of the consent process. So one, only one parent was enrolled, consented before birth. 47% were consented after birth, but before enrollment, and 52% after birth and enrollment in the other study.

 

And then they just gave some overall perceptions. 53% or nearly 90% of parents agreed that infants should participate in clinical trials. None of the parents felt that infants who participate in clinical trials receive worse care than infants who do not participate. However, 20% of parents felt that infants who participate in clinical trials generally receive better care. So I thought that was interesting.

 

They looked at the necessity of informed consent. 85% of parents agreed that parents should be asked for their consent to participate in research studies involving their children, but not all parents. And despite it being in favor of participating in study, 10% would have preferred not to have been asked for consent at all. That doesn't change what we can do. That doesn't change what we can do, but that was interesting. I think that when...

 

Ben Courchia MD (34:03.575)

What does that mean?

 

Ben Courchia MD (34:09.807)

They said they would have rather not been consented? Wow.

 

Daphna Yasova Barbeau, MD (34:13.158)

Yeah. It's hard for us to know. I don't know. Like was this group part of the deferred consent? So it already happened to their baby. They didn't have to choose what happened. I don't know. Anyways. And then regarding that, parental perception of prospective consent versus deferred consent. The majority of parents were satisfied with both forms of informed consent, irrespective of whether it was prospective or deferred. 24 of the 29 parents...

 

Ben Courchia MD (34:23.298)

Hmm. Interesting.

 

Daphna Yasova Barbeau, MD (34:42.01)

83% who were approached prospectively found the process satisfactory, and 84% who were approached retrospectively found the process satisfactory. When asked about the best time to discuss consent with parents for emergency clinical trials, 33% said it was before birth, 67% said it was after birth. When asked the same question about non-emergency trials, 50% said it was before birth and 50% said it was after birth.

 

And then overall 86.7% of parents were satisfied with the way in which information was provided, quote unquote. While eight or 13% indicated that they were not satisfied. Of those eight parents, 50% were approached after birth and before enrollment, and 50% were approached after birth and after enrollment. But all of these eight were also disfellowsified with the modality of the consent process. So they would have liked to have been in the other group, but it was split 50-50.

 

Ben Courchia MD (35:12.703)

Interesting.

 

Ben Courchia MD (35:26.519)

Mmm.

 

Daphna Yasova Barbeau, MD (35:42.486)

So I just thought it was interesting. I think we still don't have a good grasp about the best ways to consent parents, even though we have to do it all the time.

 

Ben Courchia MD (35:42.798)

interesting.

 

Ben Courchia MD (35:53.106)

Yeah, that's a good, it's an interesting paper. Okay. The next study that I wanted to review is a study that came out in the archives of disease and childhood. It's called Early and Exclusive Enteral Nutrition in Infant-Born Preterm. I thought that was a very interesting study. First author is Jacqueline Razagi. And the last author is our good friend Ariel Salas from the University of Alabama. So the background is interesting because they're talking about feeding protocols.

 

Daphna Yasova Barbeau, MD (36:08.868)

Mm-hmm.

 

Ben Courchia MD (36:22.782)

And they're talking about the differences in feeding protocol between high-income countries and low and middle-income countries. They're saying that in low and middle-income countries, because of the constraints that they're facing, early and exclusive enteral nutrition is what they do, and it has shown to be a potential superiority over slow-feeding progression in infants born very preterm. A 2020 Cochrane review of six trials in India found that early and exclusive enteral nutrition

 

could lead to shorter hospitalization and more weight gain without increasing the risk of necrotizing enteroclitis. The question they're asking is, how generalizable is this practice? They're saying that could we and high-income countries learn from this data of low and middle-income countries, even though there might be differences in health care system and other clinical conditions at baseline, prevalence of growth restrictions, sepsis rates, et cetera, et cetera? And so what the goal of the article is, is to say,

 

What are the effects of early and exclusive enteral feeding in babies born very preterm? In that case, that means 28 to 32 weeks within an institution that's considered in a high-income country. So they're basically gonna try to apply this practice in their unit. This is an unmasked parallel group randomized control trial where you have one-to-one allocation conducted in the tertiary level regional unit in Birmingham, Alabama.

 

They included babies who were born between 28 and zero and 32 and six weeks admitted to their NICU and who could be consented within 36 hours after birth. So what exactly happened? And what does that mean like 36 hours after birth? Because then you're not starting full early enteral feed. I think they gave themselves a reasonable time to approach the parents and get the consent done. And so we'll see what in practice that looked like.

 

Basically, immediately after birth, prior to getting consent, the infants were treated according to the standard of care, which is receiving parenteral fluids based on their birth weight, which means that if they were larger infants, they would get D10. But if they were much smaller, they would get started TPN. And then immediately after they were consented, then a few things happened. The clinical team would decide whether they would then start enteral feeds at maybe 60 or up to 80

 

Ben Courchia MD (38:47.198)

after getting consent and the enteral feeding and then they would basically adjust the IV fluid volume based on what on the decision that they had made and then they would go up by 20 to 30 ml per kilo per day up to a goal of a hundred and fifty ml per kilo per day or more in the control group however nutrition they receive nutrition with maternal or donor milk which was the same as the intervention group and they started much lower they started at about 20

 

to 30 ml per kilo per day within the first 96 hours after birth, and they progressively went up on their feeds. All study participants received exclusive human milk diets for the first 14 days. And if after 14 days there was no human milk available, specifically if the mother was not providing enough milk, then they were transitioned to a preterm formula. When did they fortify? All that stuff was not defined by the study protocol. And they would.

 

discontinued the protocol if the baby developed SIP or NEC. What was the primary outcome? The primary efficacy outcome focused on the duration of full enteral feeding, defined as how many days did an infant receive enteral feeding volumes of more than 150 ml per kilo per day during the initial 28 days following birth. They had a few secondary outcomes related to growth and they had some safety outcome looking at SIP, NEC, stage two or three and death. They were able to randomize 102 infants, 74 infants.

 

of which received, they were 74 infants were actually consented within the first 24 hours. So they were really eager to get these babies started as early as possible. So let's talk about some of the results. Infant in the intervention group spent more days receiving full enteral feeds. The cumulative intake of human milk during the first week after birth was significantly higher in the intervention group. The difference

 

in the use of total parenteral nutrition within the first week after birth was not significantly different between the two groups, 4 versus 12%. I think that goes to show the level of care they receive at the University of Alabama. And it's not surprising that the babies that were started on full enteral feeds early on received more milk. Now what's interesting is how did this baby grow? How did they fare up? And they show that 89 infants underwent body composition assessment at around postnatal day 14.

 

Ben Courchia MD (41:10.286)

fat free mass for age Z scores were higher at that time in the infants who were randomized to the intervention group who were receiving full enteral feeds early on. Looking further down the road at 36 weeks post menstrual age or hospital discharge, the infants receiving early and exclusive enteral nutrition had higher length for age Z scores. Weight gain in gram per kilo per day from birth all the way through 36 weeks post menstrual age did not differ between the groups.

 

three infants in the intervention group experienced baleous emesis in the first five postnatal days, but their enteral nutrition was temporarily held for further investigation and eventually resumed. There was no significant difference in the length of stay between randomization groups. And so the authors conclude that the trial demonstrate that early and exclusive enteral nutrition in very preterm infants, in this case 28 to 32 weeks, increases the number of full enteral feeding days.

 

And that this practice may also improve fat free mass accretion, increase the length and reduce hospitalization cost. I think that was very interesting and gives us something to think about.

 

Daphna Yasova Barbeau, MD (42:17.742)

Absolutely, absolutely. Ariel and his team are always are always giving us something to think about.

 

Ben Courchia MD (42:24.274)

I know. And I love the idea that like, it really goes back to one of the missions of the incubator, which is that we can learn from everyone. And the premise of saying, this is what they do in low and middle income countries. And they might be on the right track. And maybe could we learn from this despite the differences inherent to both places? I think that's always something that piques my curiosity.

 

Daphna Yasova Barbeau, MD (42:31.667)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (42:37.054)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (42:43.726)

Absolutely. Okay. I have a paper, Time to Reaching Target Cooling Temperature and Two-Year Outcomes in Infants with Hypoxic Ischemic Encephalopathy. The lead author, Rakesh Rao from WashU in St. Louis. This was published in the Journal of Pediatrics. It's actually online ahead of print. Notably, this is a secondary analysis of the HEAL trial.

 

which you have mentioned a few times today, which as a reminder, the findings of which indicated that the use of EPO, in addition to therapeutic hypothermia, did not alter the rate of death or neurodevelopmental impairment. So they wanted to look at in that cohort if the time to reaching the target temperature is associated with death or neurodevelopmental impairment at two years of age and infants with HIE. So.

 

They had this group of infants greater than or equal to 36 weeks of gestation, diagnosed with moderate to severe HIE, and treated with therapeutic hypothermia. So they pulled the entire cohort, both who received EBO and who didn't receive EBO. And they were stratified based on the time at which target temperature was received. And they defined that as early, less than or equal to four hours of age, or late.

 

greater than four hours of age. Primary outcomes were death or neurodevelopmental impairment. The secondary outcomes included neurodevelopmental assessment with the Bayley, third edition at age two. Okay. They also looked at severity and pattern of injury on brain MRI. They did their MRIs at four to six days of age. They also looked at an ordinal outcome.

 

death, moderate or severe neurodevelopmental impairment, mild neurodevelopmental impairment, or no neurodevelopmental impairment. And they looked at a variety of short-term inpatient outcomes, seizures, inotropic support, steroids for blood pressure, pulmonary hypertension, use of nitric, ECMO, tracheostomy, NG or gastrostomy-tubic discharge, and discharged alive. So overall, in the secondary analysis, they had 500 patients.

 

Daphna Yasova Barbeau, MD (45:00.846)

21% reached their target temp within three hours, 42% within four hours, 81% within six hours of birth. The median time to reaching target temp was 4.3 hours. They looked at the target temp as like a continuous variable and plotted against the outcome of death and road volunteer impairment. And the area under the receiving operating curve was 0.54 with an optimal cut point near.

 

So that's why they stratified into those two groups at before four hours, before or equal to four hours, and then after four hours. So compared with the late target temp group, infants in the early target temp group had a higher proportion of white mothers. They were more likely to be inborn and they were more likely to have severe HIE. This was statistically significant. 28% versus 19%.

 

So I think that's important as we hear the rest of the information. Results for primary outcome of death or neurodevelopmental impairment was available for 96% of infants. This was 65 deaths, 13%. 25% had moderate to severe neurodevelopmental impairment. 11% with mild neurodevelopmental impairment and 42% with no impairment.

 

After adjusting for potential confounders, which is a lot of things, but included in cephalopathy severity, because I did tell you that the group, the early group was more likely to have severe HIE. There were no meaningful differences in the primary outcome of death or neurodivisional impairment among infants who reached a target temp before or after four hours of age.

 

Similarly, there was no difference in the four level ordinal outcome of death, moderate to severe neurovolatile impairment, mild impairment, or no impairment. And among the survivors of HIE, the unadjusted mean difference in the Bayley score were slightly different. They were lower in the late target temp group compared with the early target temp group as follows. The mean difference in cognitive score was minus 5.9. This was statistically significant.

 

Daphna Yasova Barbeau, MD (47:22.802)

the mean difference in motor score minus 4.2, statistically significant, and language score minus 6.5 with a p-value of 0.08. Again, after adjusting for potential confounders, maternal race, ethnicity, age, gestational diabetes, gestational age, HIV severity, Apgar score at 10 minutes, delivery room chest compressions, delivery room epi, recruitment site, and randomized treatment assignment, the magnitude of the group differences is attenuated, but it persists. So scores were still...

 

um lower in the late target temp group and in the early target temp group but by a small amount. They also value the brain MRIs in 95 uh 95 percent of the early target treatment group and in 94 percent in the late target not target treatment target temp group.

 

There were no significant differences in severity or pattern or brain injury between the two groups and no differences in the early neonatal complications. So I thought this was interesting study. When you look at the literature overall of the other trials, there's mixed data about, does it matter if we cool babies faster within that six or five and a half hour window?

 

So this fits with that literature, I think.

 

Ben Courchia MD (48:49.258)

Yeah, I think this is one of the things that we discussed with some of the people at the CHNC. I think there's a group of people there looking at that and trying to see, does this make a difference? I think the problem with this study, obviously, is that they're looking back at data that they collected for a different purpose. But the question then becomes if you're looking at the time to cooling as a continuous variable instead of a categorical variable, where you don't say, like, well,

 

Daphna Yasova Barbeau, MD (49:07.21)

That's right.

 

Daphna Yasova Barbeau, MD (49:13.616)

Right.

 

Ben Courchia MD (49:16.182)

before or after six hours or before or after four hours. And you say, OK, let's look at it at a continuous variable and see if cooling sooner equals better. And you design the study specifically for that. Some of the signals that the people from the CHNC we were talking to were saying that it might actually make a difference. And so I think the book is not.

 

Daphna Yasova Barbeau, MD (49:33.647)

Mm-hmm. And to pick their cutoff, to pick their cutoff, they did look at it as a continuous variable. So I thought that was interesting also.

 

Ben Courchia MD (49:40.51)

Yeah, so I think the book is not completely closed on that specific question.

 

Daphna Yasova Barbeau, MD (49:44.306)

Totally agree.

 

Though I think it would be very hard to randomize babies into.

 

Ben Courchia MD (49:54.054)

Yeah, it will be hard to randomize, but this is where you have the power of these large collaboratives where now you're starting looking at when you have so many points of data that you can actually, yeah, you can almost compensate for that. The last paper that I want to review today quickly is a paper that was published in the Journal of Pediatrics and it's called Can Red Blood Cell and Platy-Transfusions Have Pathogenic Role in Bronchopulmonary Dysplasia? First author is Timothy Barr. It comes of the Intermountain Health.

 

Daphna Yasova Barbeau, MD (49:55.635)

That's right.

 

Daphna Yasova Barbeau, MD (49:59.818)

Mm-hmm.

 

Daphna Yasova Barbeau, MD (50:05.022)

data points here.

 

Ben Courchia MD (50:22.878)

system in Utah. And basically, it's a very interesting paper that looks at what is the likelihood that red blood cell and or platelet transfusions are associated with BPD. And there's a lot of data that shows that maybe there's a pro-inflammatory pattern to transfusion that could increase your risk of BPD. And we know that pro-inflammatory offenses during the postnatal life are risk factors for the development of BPD. And we know that adult RBCs.

 

are probably some part responsible for that, that there's developmental differences between the neonatal and adult RBCs. So all that stuff is quite interesting. The study is done in the form of reviewing the transfusion database. They looked at BPD based on the Jensen criteria. They defined their transfusion practices. And what's interesting is that when they looked at the five years that they studied,

 

They had about 946 infants born before 29 weeks of gestation or weighing less than 1,000 grams. 28% of them, they were not really able to define their BPD stage. And so in the end, they only had about 670 babies that they could assign a BPD grade. 12%, no BPD. 88% developed BPD. 52% of these 88% was grade 1. 28% was grade 2. 7% was grade 3. What's interesting?

 

is that there's a positive association that's seen between the number of transfusion received and the BPD grade. The infants who developed BPD were much more likely to have received a transfusion than those who did not develop BPD. What's super interesting is that when they did these logistic regression studies, those who developed grade 3 BPD received more than twice as many red blood cell and platelet transfusions as did those who developed either grade 1 or grade 2 BPD.

 

In the unadjusted model, on average, the Jensen BPD grade increased by one for every 2.7 transfusion given. Now, it's kind of tricky, obviously. They have a large number of patients and you might say, well, maybe those babies were sicker and so on and so forth. The part of the paper that was very interesting to me is that when they reviewed every transfusion in their database, they found something interesting. And they found that 57% of the red blood cell transfusion administered and 68% of their platelet transfusion were not really compliant with their new guidelines.

 

Ben Courchia MD (52:46.25)

which were much more restrictive. And so they posed the question of saying, well, if we know that less transfusion is better, which is something that is not new from this paper, and they mentioned that in the discussion. The good thing about their paper is that they have a pool of people that have either no BPD, that have transfusion, no transfusion. So they have a variety of data point. But the question they were asking at that point was now saying, well, if we had applied

 

our new transfusion guideline, could we have reduced the amount of products these babies would have been exposed to? And I think that was very interesting. And saying that using a conservative estimate from their sensitivity analysis, they estimated that a 20 to 30% reduction in the total number of RBCs and platelet transfusion in a similar five-year period, which could have been achieved with just these new guidelines, may result in 10 to 14 fewer cases of moderate or severe cases of BPD.

 

And so I think it was very interesting to see this linkage between the changes in the practice when it comes to transfusion, which we know increase the degree of inflammation and potentially having a direct impact on their cases of BPD. So I thought that was an interesting paper. Robert Christensen is on the paper. Robin Hall's very talented group of people. So it's a great read. I suggest you check it out. We'll link it in the episode show notes. And I think that.

 

Daphna Yasova Barbeau, MD (54:14.734)

No, I was just going to say, I mean, I just shared the feeling with others that sometimes it's uncomfortable. It's uncomfortable changing to the new guidelines, right? To the lower thresholds or higher, being more conservative. I don't know how to say that. But I mean, the data is amassing about...

 

Ben Courchia MD (54:37.118)

I think when you see it from that standpoint in not just reducing the amount of transfusion product babies are exposed to, but potentially really having a reduction. And we're seeing this in the ETNO and the top trial where the babies who got more transfusion were more likely to have BPD. I think now you're starting to put things together and having a more broader overview of the problem and really the motivation really becomes stronger to say we really have to do a better job at trying to restrict how much product we expose these babies to. Fascinating study.

 

Daphna Yasova Barbeau, MD (55:03.21)

Totally agree.

 

Ben Courchia MD (55:06.81)

And I think that with that, this concludes our first Journal Club of the year. This is very exciting. We did it. Thanks everybody. Thanks to Jen Canavazer for joining us this week. And we will be back next week with another set of interview and more new episodes of the Incubator podcast coming to you in the coming week. Bye everybody.

 

Daphna Yasova Barbeau, MD (55:10.098)

We did it. Thanks everybody.

  

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