#334 - Neonatal Neurology - A Year in a Review (ft the Newborn Brain Society)

Hello friends 👋

In this episode of The Incubator Podcast, Daphna is joined by Dr. Pia Wintermark and Dr. Eleanor Molloy for a deep dive into the most impactful neonatal neurology studies of the past year. The discussion begins with a critical look at therapeutic hypothermia for mild hypoxic-ischemic encephalopathy (HIE) and preterm infants, highlighting recent pilot trials that challenge the practice of expanding cooling beyond established guidelines. They dissect key findings from multicenter studies, examining safety, feasibility, and the unintended consequences of “therapeutic creep.”

The conversation then shifts to the importance of precise terminology and standardized data collection in neonatal encephalopathy research. Pia and Eleanor explain why clearer definitions, genetic testing, placental pathology, and harmonized registries are essential for improving outcomes and guiding future clinical trials.

Finally, the team explores new and emerging interventions, including the feasibility of intranasal human milk as a stem cell therapy and the potential neuroprotective role of caffeine in neonatal hypoxia-ischemia models.

This episode offers a concise but comprehensive look at what’s shaping neonatal neurocritical care—from refining existing therapies to exploring innovative approaches that could change practice in the years ahead.

----

Short Bios:

Dr. Pia Wintermark: Dr. Pia Wintermark is the Chair of the Quality Improvement and Research Committee of the Newborn Brain Society. She is a tenure-track Associate Professor and clinician-scientist at McGill University. She leads the NeoBrainLab, a research program focused on high-resolution neonatal brain imaging, fundamental studies in neonatal neuroscience, and clinical trials in neonatal neurocritical care.

Dr. Eleanor Molloy: Dr. Eleanor Molloy is the Professor and Chair of Paediatrics and Child Health in Trinity College Dublin, Ireland. She is a paediatrician and neonatologist based in Children’s Health Ireland at Crumlin & Tallaght and the Coombe Hospital. She qualified in Medicine in UCC (1993) and received her PhD from UCD in 2003. Her research group is concerned with interdisciplinary child health research and the promotion of Paediatric Translational projects to improve child health and she is co-director of the Trinity research in childhood centre (TRICC) with> 100 principal investigators.

She is co-lead for the Health Research Board funded In4Kids the national paediatric clinical trials network aiming to facilitate access to clinical trials for children in Ireland. The Molloy translational research laboratory  in TCD evaluates new methods to modify the immune responses newborn infants with brain injury through their childhood to find new therapies to improve their outcome by modifying persistent dysfunctional inflammation.

Internationally she has served as the Secretary & President of the Irish American Paediatric Society and as the Irish representative on the European Board of Paediatrics: European Union of Medical Specialists (UEMS), Confederation of European Specialists in Paediatrics (CESP), Board member of the European Society for Paediatric Research and Newborn Brain Society. She was awarded Honorary Fellowship at the American Paediatric Society, a Professorial Fellowship by Trinity College and is the Associate Editor in chief for the journal “Paediatric Research” on behalf of the International Paediatric Research Foundation since 2015.She has supervised more than 20 PhD and MD thesis students and have over 300 peer reviewed publications. She is interested in collaborative research encompassing consensus definitions of terminology related to neonatal sepsis and measuring core outcomes so that research data can be shared to improve outcomes for children.  She is developing programmes in multiorgan care as well as functional motor care from the newborn period to adulthood following neonatal brain injury,  sepsis  and cerebral palsy in partnership with families and with funding from Science Foundation Ireland and the Health Research Board.

----

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

Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial.

Montaldo P, Cirillo M, Burgod C, Caredda E, Ascione S, Carpentieri M, Puzone S, D'Amico A, Garegrat R, Lanza M, Moreno Morales M, Atreja G, Shivamurthappa V, Kariholu U, Aladangady N, Fleming P, Mathews A, Palanisami B, Windrow J, Harvey K, Soe A, Pattnayak S, Sashikumar P, Harigopal S, Pressler R, Wilson M, De Vita E, Shankaran S, Thayyil S; COMET Trial Group.JAMA Netw Open. 2024 May 1;7(5):e249119. doi: 10.1001/jamanetworkopen.2024.9119.PMID: 38709535 Free PMC article. Clinical Trial.

Whole-Body Hypothermia for Neonatal Encephalopathy in Preterm Infants 33 to 35 Weeks' Gestation: A Randomized Clinical Trial.

Faix RG, Laptook AR, Shankaran S, Eggleston B, Chowdhury D, Heyne RJ, Das A, Pedroza C, Tyson JE, Wusthoff C, Bonifacio SL, Sánchez PJ, Yoder BA, Laughon MM, Vasil DM, Van Meurs KP, Crawford MM, Higgins RD, Poindexter BB, Colaizy TT, Hamrick SEG, Chalak LF, Ohls RK, Hartley-McAndrew ME, Dysart K, D'Angio CT, Guillet R, Kicklighter SD, Carlo WA, Sokol GM, DeMauro SB, Hibbs AM, Cotten CM, Merhar SL, Bapat RV, Harmon HM, Sewell E, Winter S, Natarajan G, Mosquera R, Hintz SR, Maitre NL, Benninger KL, Peralta-Carcelen M, Hines AC, Duncan AF, Wilson-Costello DE, Trembath A, Malcolm WF, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.JAMA Pediatr. 2025 Apr 1;179(4):396-406. doi: 10.1001/jamapediatrics.2024.6613.PMID: 39992674 Free PMC article. Clinical Trial.

Causes and Terminology in Neonatal Encephalopathy: What is in a Name? Neonatal Encephalopathy, Hypoxic-ischemic Encephalopathy or Perinatal Asphyxia.

Branagan A, Molloy EJ, Badawi N, Nelson KB.Clin Perinatol. 2024 Sep;51(3):521-534. doi: 10.1016/j.clp.2024.04.015. Epub 2024 May 23.PMID: 39095093 Review.

Data Collection Variability Across Neonatal Hypoxic-Ischemic Encephalopathy Registries.

Peeples ES, Mietzsch U, Molloy E, deVeber G, Mohammad K, Soul JS, Guez-Barber D, Pilon B, Chau V, Bonifacio S, Afifi J, Craig A, Wintermark P; Newborn Brain Society Guidelines and Publications Committee.J Pediatr. 2025 Apr;279:114476. doi: 10.1016/j.jpeds.2025.114476. Epub 2025 Jan 23.PMID: 39863078 Free article.

Feasibility of intranasal human milk as stem cell therapy in preterm infants with intraventricular hemorrhage.

Hoban R, Gallipoli A, Signorile M, Mander P, Gauthier-Fisher A, Librach C, Wilson D, Unger S.J Perinatol. 2024 Nov;44(11):1652-1657. doi: 10.1038/s41372-024-01982-8. Epub 2024 Apr 30.PMID: 38688998 Clinical Trial.

Perinatal Caffeine Administration Improves Outcomes in an Ovine Model of Neonatal Hypoxia-Ischemia.

Mike JK, White Y, Ha J, Iranmahboub A, Hawkins C, Hutchings RS, Vento C, Manzoor H, Wang A, Goudy BD, Vali P, Lakshminrusimha S, Gobburu JVS, Long-Boyle J, Fineman JR, Ferriero DM, Maltepe E.Stroke. 2024 Nov;55(11):2705-2715. doi: 10.1161/STROKEAHA.124.048264. Epub 2024 Oct 21.PMID: 39429154 Free PMC article.

----

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

Daphna Barbeau: Sophia, Eleanor, thank you so much both for joining me today.

Pia Wintermark: Hi Daphna, how are you doing?

Daphna Barbeau: Doing well. Very pleased to have you both in the studio to discuss the  very important topic about the neurology year in review. We've had quite a busy year, I think, of articles. What do you all think?

Pia Wintermark: It was unto truth.

Daphna Barbeau: Well, let's not leave people waiting. We can jump right in, but just so people know how this year-in-review is going to go, you've selected some randomized clinical trials, as well as a second segment talking about the need for definitions and data collection, so some articles based around that. And then some pilot studies of new treatments that are of interest, burgeoning aspects in our field. So I really appreciate the outline. I think this is going to really set the stage for everybody listening.

So let's go ahead and get started. The first article you selected was Whole Body Hypothermia versus Targeted Normothermia for Neonates with Mild Encephalopathy: A Multi-Center Pilot Randomized Clinical Trial. This is coming from the Comet Trial Group and it was in JAMA Network Open. Tell me a little bit about this important article.

Pia Wintermark: So this one we were thinking is important because they tackle a growing dilemma in neonatal neurocritical care. The question was: should we cool babies with mild hypoxic-ischemic encephalopathy, or are we doing more harm than good? The background is therapeutic hypothermia is the gold standard for moderate or severe HIE. But for now, there is still the debate—should we cool the mild ones? Looking through what's published, they concluded that 80% of mild cases are now also cooled in high-income countries, despite no real trial showing that it's effective.

So they decided to test whether whole body hypothermia for 48 or 72 hours is safe, feasible, and potentially beneficial. They used MRI markers as the outcome. It was a three-arm, open-label, multi-center pilot RCT. They enrolled 101 neonates with mild HIE and normal EEG. There were two kinds: those early enough that they were not cooled—these were randomized to either normothermia or 72 hours hypothermia; and those already cooled but with normal EEG—could we do hypothermia for 48 hours or 72 hours?

The outcome was MRI findings. They succeeded in enrolling 101 neonates with approximately the same number in the three groups. They found that thalamic N-acetyl aspartate was lower in both hypothermia groups, suggesting hypothermia may be dangerous in this case. But overall, MRI injury was minimal and there was no significant difference between the groups. Seizures were similar, but adverse events were more common in cooled infants.

They conclude that this study, at least for now, doesn't support cooling for mild HIE.

Strengths: it’s the first randomized study for mild HIE; rigorous MRI methods and masked assessment; used thalamic-NAA which has been related to outcomes; and proved you can enroll these babies in a trial.

Limitations: pilot trial, so not designed to assess long-term outcome; division between infants already cooled vs. not cooled – the cooled babies may have been cooled based on an abnormal EEG, and so they may have been sicker at baseline; measured NAA in the thalamus but most babies had white matter injury; variations in MRI readings; when looking at NAA-to-creatinine ratio, there were no difference between groups; and unclear sedation policies, which might influence adverse event reporting.

So overall—a good trial, important question, still some limitations. More trials are needed. I wouldn’t conclude it’s dangerous yet.

Daphna Barbeau: It feels like this was the year of validating some “scope creep” in the world of therapeutic hypothermia. Our next paper is a nod to that as well. I agree with you. I think we were hopeful there would be tremendous outcome improvement cooling those mild babies, as many of us have been doing—hoping that if it’s working for one group it might work for another. We were seeing some difference in outcomes in those mild kids, but this didn’t quite give us the answer we were hoping for. Eleanor, any thoughts?

Eleanor Molloy: No, I think it's really nice to have more definitive evidence about the mild group, but I do see there are more trials planned in this area, so it will be really interesting to see. In the other trials, they’re really looking at multi-organ outcomes and maybe we’ll see long-term outcomes down the road.

Daphna Barbeau: Yeah, I agree—it will give us a more well-rounded picture. This is an important topic to discuss with you both as experts about re-demonstrating study outcomes. At one point in time in science, we had tons of papers about the same study. Then we moved to: if we show it once, do we have to show it again? But there’s probably somewhere in between for validation of study findings. When do you think enough is enough?

Pia Wintermark: That’s a hard question. The important thing is the selection of the population. This is why we are coming to the definition discussion later—because you can’t just group babies after the fact. For mild cases, you probably need big numbers to prove whether it’s effective or not. We definitely need more numbers to conclude without these limitations—but make sure you compare mild to mild.

Eleanor Molloy: And you’re going to see as well that babies with neonatal encephalopathy are so heterogeneous, with lots of different causes. It’s a real umbrella term. But we do come to that later in definitions, so I probably shouldn’t preempt that section.

Daphna Barbeau: That’s right, you’re setting the stage for where we’re going next. But before we get there, another hot topic: Whole Body Hypothermia for Neonatal Encephalopathy in Preterm Infants, 33 to 35 Weeks Gestation. This was out of the NICHD and released in JAMA Pediatrics. The first paper looked at milder, less sick infants—now we’re moving to smaller, younger infants. Again, both groups where we were seeing worldwide practice shifts, including some of those babies under therapeutic hypothermia treatment. Tell us about the earlier group.

Eleanor Molloy: Another “therapeutic creep” paper. They looked at 33- to 35-weekers and randomized them to therapeutic hypothermia versus normothermia. They were pretty strict about normothermia, which was nice. They had 19 US centers, recruiting 168 babies. The primary outcome—composite of death and disability at 18 to 22 months—showed no benefit for therapeutic hypothermia. Because numbers were small, they did a Bayesian analysis and found a 74% probability of death or disability if cooled, and an 87% probability of increased death for cooling. This suggests we should pause before cooling this type of baby. The study was rigorous—nicely matched groups, controlled temperatures, certified examiners, blinded assessments.

Limitations: moderate sample size; some loss to follow-up (more in normothermic group); intervention unblinded to clinicians, but follow-up assessors were blinded.

Their conclusion is that there is no benefit for hypothermia in infants of 33 to 35 weeks with moderate or severe HIE, and possible increased death or impairment. This might discourage further studies in this group.

Daphna Barbeau: Yeah, I think this was another paper where we were hopeful again—because other pilot studies showed at least safety in this group. We were hoping to see long-term outcome benefits. But seeing increased morbidity and especially mortality was disappointing to the community. This certainly created hesitation—especially in centers that were cooling some 35-weekers and creeping into the 33–34-weekers, even though major trials enrolled very few 35-weekers. They were always a group we weren’t quite sure about. How do you think this has changed practice in your areas, especially for 35-weekers that many centers were already routinely cooling?

Pia Wintermark: I think the debate is probably closed for the 33- and 34-weekers. But as you say, there has been a lot of discussion about the 35-weekers. I think it’s like the mild group—it’s the one where the therapeutic creep happened. So it would be hard if you have a 35-weeker or 35 + 6/7 and you do not cool. I think the debate is still going on, but it’s moving toward not cooling them.

Eleanor Molloy: I suppose it’s looking at the numbers, because they actually went to 35 + 6 days in this study—so nearly 36 weeks. Possibly we should look in more detail, maybe in prospective studies, at that group of babies. But at the moment, I think this clearly says we shouldn’t really cool them under 36 weeks. It fits with some of the work in premature babies where we assumed cooling would work and have shown no benefits. So it does fit with other literature.

Daphna Barbeau: We’ve been talking a lot about the 35-weekers. I think the group that was more striking was the 34 + 0 to 34 + 6/7 group, because they did an analysis splitting the cohort into the 33rd, 34th, and 35th weeks. Each group was small because the overall study was small, and splitting by gestational age made them even smaller. But what was so striking was the death rate in the 34-week group—8/26 (31%) in the hypothermic group compared to 2/32 (6%) in the normothermic group. I think that’s what’s really giving the community pause.

The paper also brought up discussions about things we know in HIE and therapeutic hypothermia that aren’t always controlled for in studies—like babies getting too hot or too cold. It’s another reminder that, whether or not babies are receiving cooling, keeping them within a safe range is important. Preventing deviations could improve outcomes regardless of cooling.

Pia Wintermark: I also think it’s interesting because when the study started, we were afraid there would be more bleeding in the brain, which was a reason not to offer therapeutic hypothermia. But that part was not confirmed—it was the same outcome as term babies for that, so bleeding wasn’t the biggest concern after all.

Daphna Barbeau: You’re absolutely right. We thought IVH or coagulopathy might turn the tables, but it looks like that’s not the biggest issue. Very interesting.

Okay, that takes us to our next theme—the idea of definitions and the need for further data collection. You’re highlighting the paper Causes and Terminology in Neonatal Encephalopathy: What Is in a Name—Neonatal Encephalopathy, Hypoxic Ischemic Encephalopathy, or Perinatal Asphyxia? This is from the Newborn Brain Society Guidelines and Publications Committee, in the Journal of Pediatrics. You alluded to this earlier, Eleanor—we’re not even sure what to call it. These umbrella terms may encompass babies who may not benefit from therapeutic hypothermia. How do we make those distinctions? Tell us about the paper.

Eleanor Molloy: This is a review article. Looking back, the original Sarnat papers in 1976 used the term “neonatal encephalopathy.” Since therapeutic hypothermia came on the scene, papers started using “HIE” more often. Now the literature is a mix, sometimes describing slightly different babies, which makes systematic reviews and research harder. Karen Nelson, the senior author, has always said to look at the cause. Neonatal encephalopathy is a good umbrella term at birth, but we should try to find the cause. With advances in genomics, understanding metabolic disease, and placental pathology, we’re realizing many babies have identifiable causes—just not always apparent on day one.

The paper suggests starting with the term “neonatal encephalopathy” on day one, gathering evidence as we decide on cooling, examining the placenta, deciding whether to do genetic or metabolic testing, and then refining the diagnosis. Hypoxic ischemic encephalopathy being one possible outcome. The ACOG and AAP definition describes neonatal encephalopathy as abnormal consciousness with difficulty initiating respiration, then subdivides it into hypoxic-ischemia when that’s the main cause, as a diagnosis of exclusion. Epidemiological work by Nadia Badawi shows that only about 4% of babies in her study had purely intrapartum hypoxia as the cause. Many had maternal conditions, abnormal placenta, or other factors.

The framework they propose includes evaluating growth in utero and at birth, placental pathology (including chorioamnionitis), congenital malformations (heart defects, diaphragmatic hernia, etc.), and infection (bacterial, viral, CMV, Zika, COVID). Genetic causes via neuro-genetic panels are also important. I'm going to highlight one paper, a Chinese study, where they picked 133 neonates with neonatal encephalopathy and they reckoned that 68 definitely had HIE because they had a sentinel event; but they found 29% had a positive results on next generation sequencing. We should also look for metabolic disorders (look for hypoglycemia, metabolic acidosis, organomegaly) and perinatal stroke (many of these babies have abnormalities in the placenta). They also touch on chemicals and/or environmental toxins, though no confirmed link yet, and note poverty and socioeconomic factors as major influences. The paper concludes with a push for standardized definitions and diagnostic criteria, acknowledging these will evolve over time.

Daphna Barbeau: I love that. We often steer away from reviews on the podcast because they can be hard to navigate, but you did a great job highlighting the sections. It’s a wonderful, easy-to-read paper—everything from the Newborn Brain Society is like that. I had an attending who would always say, encephalopathy is the clinical picture, and HIE is only one cause. We haven’t fully elucidated the others, and there are mimickers. For those of us interested in HIE and cooling, it might explain why some babies are sicker than expected for their insult, or why others do extraordinarily well—or poorly—unexpectedly. It could be genetic or intrauterine environment factors, like a “two-hit hypothesis” we see in other diseases. We’re all looking for that prognostic calculator for parents, but maybe it’s these other questions that are preventing it. Pia, your thoughts?

Pia Wintermark: I agree. After reading this review, you’d want to offer genetic testing to all HIE babies. It might show more concomitant issues than we think. Like you, I’ve been puzzled by two babies with the same story and completely different outcomes. And for trials, proper definitions are key—how can you compare trials if the enrolled babies aren’t the same?

Daphna Barbeau: Exactly. Maybe future trials with more testing will allow subgroups and outcome comparisons. I think standardized genetic panels could make ordering and collection easier, helping distinguish groups moving forward. Exciting developments. There are also papers coming soon looking at sentinel events and lab markers to identify babies who aren’t following the typical HIE trajectory—so we can look for other causes.

Eleanor Molloy: One thing I didn’t mention—apart from defining things clearly—is that knowing the cause can change treatment. For example, chorioamnionitis could change antibiotic management. Metabolic babies might have treatable disorders. Early gene therapies, like for SMA, could be applied. Immunotherapeutics may depend on etiology. This could stop us treating everyone as if they’re the same.

Pia Wintermark: And as Eleanor mentioned, the placenta is so important. It should always be examined in HIE babies. It’s improved in recent years, but it’s still not always done—and it’s an easy one to add.

Daphna Barbeau: It’s low-hanging fruit. Communication with our obstetric colleagues is key—they may have information that doesn’t make it to us, even if we’re in the delivery room. We should be going back to look for clues and improving that communication in high-risk cases. Ironically, I think our EMR-to-verbal-to-EMR systems are sometimes making communication worse, not better. That’s my takeaway for our huddles.

Eleanor Molloy: Sometimes we think, “there's a definite sentinel event, there's a shoulder dystocia.” I say, that's fine. But when I do go and check the placenta, this is a baby who was already compromised and therefore they had a shoulder dystocia because they were actually not able to flex and have normal tone at delivery. Pia and your suggestion of doing everyone's placenta and considering genomics for everyone is really important because sometimes we make assumptions about the cause. And it's really helpful for the parents and for the delivery staff to know that this was a baby who already needed support.

Pia Wintermark: I think it always helped the mom, you know, because the moms always feel guilty. If you can say it's the placenta it was the fault of nobody and nobody can influence that, you know.

Daphna Barbeau: Yeah, and I think it actually, I think it may actually encourage better collaboration with our obstetrics colleagues, right? I think there's sometimes, like you said, everybody's looking for fault. Like who can we say was at fault? And that's not the goal. The goal is how can we give this baby the best outcome possible? How can we prevent it in future babies? And I think by, you know, probably our obstetric colleagues don't even understand how this is changing on our end and saying, now we know which babies may tolerate labor more poorly, which babies we need to act on maybe a category two tracing, early category three tracing instead of waiting for a real compromise. Why do some babies tolerate shoulder dystocia and some don't? Why does a smaller baby get a shoulder dystocia and the bigger baby didn't get a shoulder dystocia. So I think having that multidisciplinary approach will be really valuable. And I think us collecting some of that information will have better buy-in with our obstetric colleagues. And I totally agree with you. Anything we can do for families to help them understand what happened, because that's really the minority of patients I feel like now where we can say, you know, this is what happened to help them, to assuage any guilt or shame related.

Well, I could talk about that all day. So let's get on to our next paper. This one's entitled Data Collection Variability Across Neonatal Hypoxic Ischemic Encephalopathy Registries. This is also coming from the Newborn Brain Society Guidelines and Publications Committee, the Journal of Pediatrics. So tell us what we learned here.

Pia Wintermark: So this one exactly was another work, you know, after the definition one that we decided to look at. And it was a bit eye-opening, you know, to run this international study and just to see how inconsistent our data systems are when it comes to neonatal HIE. So the question that was asked with this article is if we are not measuring the same thing, how can we truly improve outcome of these babies? And so it was to explore global HIE registry. And so as we all know, many places have local registry where we collect data of this baby, we do some research. It's usually one center, two centers group. But then they are grouped all around the world and everybody is collecting to try to improve the outcome of this baby. So the idea was can we get access to all these registries, not the data obviously, but just what is collected inside these different registries and see if they differ, how they differ, and then also ask the question to all these registries: would you be interested possibly one day to put everything together so that we can compare around the world, and not only locally at your place what you're doing? So we succeeded by getting 22 registries across 14 countries. The idea was really to go beyond North America and everywhere where possibly we could find a registry. Then we compared all these elements and sent a survey at the end to explore their definition of HIE, because we noticed not everybody had the same criteria to enter patients in the database, and if they would be happy at some point to harmonize or collect together the data.

It was quite impressive because every registry had a different size, from 59 elements to 450 data elements, mostly a median of 106. They had very few data points in common, which was mostly gestational age and Apgar score. But for example, lab values, follow-up data — because there is a lot of variation around the world in how it's done — obviously were not consistent.

In fact, only four data elements had exactly the same definition and were collected the same way across all these registries. That speaks to the fact that data formatting and classification had huge variation. Still, everybody in these registries mentioned that they would be happy to at least to collect the same core elements, so that they could compare with other places in the world.

I think the strength of this was that it was a combined effort of different registries. We tried to be as systematic and rigorous as possible, grouping by thematic areas to see what was in common. Participation was limited. In low-resource settings, we didn’t get many registries — probably because few exist, or some don’t exist at all. Most registries came from places that offered cooling. If you’re not offering cooling, you probably don’t have a registry. Some differences in terminology made it difficult too.

I think it was a wake-up call to say maybe first we should agree on what basic elements we should all collect for those with registries or who want to follow these babies. Then we can start collecting more broadly. There has been a second step to the study — bringing people together to discuss and debate what those core elements should be. There should be a next paper coming soon with the core elements after a lot of debate and feedback from the NBS community, PAS, and others. There will also be optional elements you can collect if you want. We have recently launched — though it’s a work in progress — a plan to retrospectively collect 2024 data from everyone willing to share their data using these core elements. So far, at least 50 sites around the world have agreed to participate.

Obviously, it’s a big organizational task and will move slowly, but hopefully in a few years when we do another round of this, we can provide an update.

Daphna Barbeau: Well, love that. First, I just want to highlight what you're doing. I think sometimes research can be quite competitive instead of collaborative. But if we really want to get a clinical change to the bedside as quickly as we can for babies, then it will rely on bringing together all these brilliant minds across the world. To the Newborn Brain Society's credit, I think it's probably the most international collaborative group out there. It really adds power to what everybody's doing and saying, like, if you're measuring something I'm not measuring, then maybe I should be looking at that. That's how we get enough numbers to make meaningful change, especially when sometimes we can't do a truly randomized control trial. It just seems like in this day and age, with the technology and communication we have, there's really no excuse for teams not to be collaborating. So I think that is tremendous.

I was hoping you could highlight — what were the most consistent fields and what were the least consistent fields? What had a lot of overlap, and what were the more discrepant areas?

Pia Wintermark: The most consistent was the general characteristics — gestational age, weight. What was surprising is that some of the most inconsistent areas were how brain imaging is collected, even though it’s one of the key outcomes for these babies. These children can have multi-system organ failure, and there was lots of variation in how this is recorded — probably because there’s a lot of variation in how these babies are treated. We ran a parallel survey, and it showed that cardiovascular management varied enormously. We’ve heard about this at PAS. The same applies across all systems; for example there is also variation in sedation and anti-seizure management. There’s no evidence-based consensus for many of these because to create it you’d need to run large, systematic trials, which is hard. Maybe another way is to do comparative effectiveness trials — like in preterm infants — by grouping sites that do the same thing. If we could put everybody together who works on the same things, I think we could reach more conclusions and build the evidence.

Daphna Barbeau: Yeah, I love another thing you highlight — we feel like we get therapeutic hypothermia, we know what to do, it’s standardized. But you're right, there are so many aspects of management that vary across institutions and locations: fluid management, pressors, sedation, hemodynamics, electrolyte management. We still have a lot to study in the area of therapeutic hypothermia and HIE to optimize outcomes. For certain groups of babies, it works really well — it’s one of the greatest treatment effects in the last two decades — but there are still ways we can improve care for each baby.

Actually, before we move on — how can people get involved with the Newborn Brain Society if they're not already involved?

Pia Wintermark: You can become a regular member — that’s the first step. Then, when we launch initiatives like the current one, we welcome more participating sites. Just becoming a member connects you to the Newborn Brain Society, its regular webinars, and its conferences. There are plenty of ways to get involved. The goal is to improve care for these babies by bringing together everyone interested in this field.

Eleanor Molloy: I suppose the aim is to be more multidisciplinary and to have all the therapists and neonatal nurses and everyone involved, and parents are very involved in the Newborn Brain Society. So it's really just to say the next meeting face to face is actually in Naples. So yeah, we have to go there, it's very tough. But there's a lot of them. If someone wants to just have a sneak peek at what it's like, I think if you go to the Thursday seminars—every Thursday there's a seminar—it’s worth maybe looking at a few of those and seeing if you want to become a member. And then there are loads of opportunities to be in all the different committees and to just become part of them. So it's very open, I think, isn’t it, Pia?

Pia Wintermark: We try to get a large representation from everywhere in the world.

Daphna Barbeau: I love that. So there's still a call, I guess, if people want to get their registries included—if they're already collecting data, that's excellent. We'll make sure people can contact you that way. It's really easy to sign up; you just do a quick registration form. There's a yearly fee for being a member. It's very cost effective—I think it's a hundred dollars in the States, and they even have some different discounts for low- and middle-income countries, which is excellent. The INBBC 2026, like you said, is in Naples, Italy, February 8th through the 10th, 2026. It looks like we’re still collecting abstract submissions and the program is up, so lots of things to look at on the website—which is newbornbrainsociety.org.

Okay, well, as always, I'm keeping us from moving on time, but let's go to the third theme today: the study of new treatments. I'm so excited about reviewing these papers again, because I really think that there are some exciting opportunities here. The first paper you're going to highlight is Feasibility of Intranasal Human Milk as Stem Cell Therapy in Preterm Infants with Intraventricular Hemorrhage. This was in the Journal of Perinatology. So tell us about this exciting intervention.

Pia Wintermark: Yeah, so I think we wanted to highlight this because it was a fascinating idea—using the parents' own milk as stem cell therapy for brain injury in preterm babies. Obviously, it was a phase one trial. They wanted to see if it’s feasible to give fresh human milk through the nose, and if it can target the brain of premature neonates with intraventricular hemorrhage.

It’s still one of the important complications of prematurity and a cause of long-term abnormal neurodevelopmental outcome. Supportive care has been there all along, but it doesn't prevent something new—and who knows, maybe you could repair the brain by just giving your milk to your baby.

They evaluated if it’s feasible, safe, and acceptable in the NICU. It was a prospective, non-randomised, non-blinded feasibility study. They enrolled 37 newborns under 33 weeks of gestation, collected freshly expressed parent milk (ideally within three hours), and gave it nasally. Ideally, a baby was supposed to receive it twice a day, approximately 1.6 milliliters per day until day 28 of life. They assessed safety and acceptability, and they analyzed a subset of milk samples to see the stem cell type and viability.

The results showed that most infants could receive this treatment for at least three days, with a median of seven days. Initially they wanted to do 28 days, but it was shorter. They didn’t see major safety issues. Staff surveys showed that the intervention was easy to fit into routine care—though, as usual with something new, a few providers were a bit anxious.

Interestingly, analysis of the milk confirmed that there were stem cells present that could potentially repair the brain, but the level varied between different milk samples, especially after the first week of birth. We know milk composition varies from one mom to another, and that was true for stem cells as well.

Strengths: this was the first time human milk was given intranasally, and if it works, it would be so easy to do—very different from harvesting stem cells, which requires precise quantities and lab processes. They tried it in a real-world clinical setting and showed they could recruit and complete the study.

Limitations: small sample size, no measure of efficacy, pandemic-related difficulties, and no consistent brain imaging. Long-term follow-up is also lacking. It would have been nice to have ultrasounds before and after, and perhaps MRIs at some point. I guess they’ll do that in the next phase. But this is a fascinating, promising study of something new that might be easily implementable to support fragile premature babies in the NICU.

Daphna Barbeau: I love that. This isn’t an evidence-based comment, but I think breast milk is magic. The more we evaluate it, the more it may become evidence-based. For us in the States, the challenge will certainly be getting fresh milk at bedside, which other countries with better social support can do more easily.

Potentially, if this shows therapeutic benefit, it could be a reason to change that. When I think about what scope creep we can do with this, it’s very exciting. Dr. Hoban’s group is having follow-up of those babies, so we’re looking forward to more results. What is the next step for intranasal human milk?

Pia Wintermark: I don't know—they didn’t mention, but I’m guessing maybe a phase two. What would be really important is making sure every baby in the trial receives the same amount every day and finding a way to make the treatment consistent, because there’s variation in the milk and in the number of treatment days. That consistency would help build the case.

More milk analysis would also help. And as we give some babies PHM, maybe we could extend and test this in other populations—like HIV-exposed babies. I also think it would promote bonding, since parents would feel useful if their milk could repair the brain. Definitely looking forward to the next steps.

Daphna Barbeau: Yeah, I agree. When parents can see their milk going straight from the breast to pump to their baby—in whatever format, whether enterally, as milk drops for oral motor practice, or intranasally—it really empowers them. It would be interesting to study whether that changes milk production. From my own experience, I think it would. That alone can change outcomes for babies. Very exciting. Eleanor, your thoughts?

Eleanor Molloy: I think it’s very exciting and a very easy intervention to give. I think it will be potentially useful, but we probably need more patients before it can become routine practice. I’d love to see the immune composition of the milk as well—to see what the active ingredients are.

Daphna Barbeau: Very exciting. All right, I want to make sure we have enough time to get to our last highlighted study, Perinatal Caffeine Administration Improves Outcomes in an Ovine Model of Neonatal Hypoxia Ischemia. Again, we’re looking for things we’re already doing in the NICU and seeing if they can help other populations. This paper came out in Stroke, which is a reminder that exciting neonatal papers can appear in journals outside our usual cohort. Let’s hear about this one.

Eleanor Molloy: This one’s very interesting because we’re all familiar with caffeine for apnea of prematurity, and in the preterm population there have been suggestions of neuroprotection and renal protection—it has nice multi-organ effects. But we just don’t have the doses absolutely correct to support that.

Mike et al., from Emin Maltepe’s group, looked at caffeine in more detail in a lamb model. They had previously reviewed what drugs work in animal models from small to large animals, and caffeine emerged as more effective than therapeutic hypothermia and others. That’s why they did this study. They started by giving the ewes caffeine pre-delivery. They showed good placental transport of caffeine. Traditionally we’ve told people not to have a lot of caffeine before delivery, but this suggests the opposite. The lambs then had global severe HIE induced by umbilical cord compression.

Postnatally, the lambs were given caffeine—20 mg/kg followed by 10 mg/kg (standard preterm doses). A small cohort received a very high dose of 60 mg/kg followed by 30 mg/kg.

Overall, the low-dose group had much improvement in many aspects: decreased inflammatory markers, improved neurodevelopmental outcomes, decreased gray matter injury, and better outcomes in many brain regions. They also found these effects to be stronger than those seen with azithromycin, without causing immunosuppression—which is important, because we don’t want to suppress the immune response entirely. They showed decreased cell death by apoptosis within the brain, with lower Caspase-3 markers. Interestingly, the high-dose caffeine group had worse outcomes in nearly every aspect. This mirrors some human data where 60 mg/kg doses didn’t help and sometimes worsened outcomes. This could be particularly useful in low- and middle-income countries because caffeine is inexpensive. The study has a nice graphical abstract showing the protocol and results in one picture. It’s a very interesting and exciting area, and it corroborates other research suggesting caffeine is protective.

Daphna Barbeau: Yeah, I think it's an example of “more is not always better,” but rather finding the right dose. This is actually a really interesting article for us to review this summer in the States when—this is when we're recording—just maybe a week after the NIH in the United States said that they're no longer seeking proposals exclusively for animal models. That’s really going to prohibit some of this testing, and I think maybe some people don't understand the importance of animal models to help us even decide what to test on humans.

I think this is really exciting work. The lamb model has been used in neonatology for generations of neonatologists and has really helped us elucidate not just the pathology, but also the physiology, which we have then translated to babies. Caffeine is another place where we're trying to see where else we can use it and who else we can use it on—especially for its neuroprotective effects. Pia, your thoughts?

Pia Wintermark: I think it's interesting, and I think this study was part of an initiative from the Gates Foundation that brought together all the people working on different treatments. They decided to create a way to test them first in small organelles, then small animals like rats, and now big animals. I think there is also a group in the UK, from Nicky Robertson, that is part of this. I think this pipeline to test different treatments is an interesting way to go faster—testing different cocktails and all that. I think it’s a great initiative. And yes, exactly as with the previous one—caffeine—we use it all the time. So if it works, then it's easy to disseminate.

Daphna Barbeau: I love that. Well, I want to thank you both for your expertise, for all of the hard work you do in your professional lives—which includes your collaboration on the Newborn Brain Society—and for highlighting these really important articles. I hope people have learned a lot. We will leave in the show notes all of the links to the articles and ways for them to get engaged with the Newborn Brain Society, as well as ways to get in contact with the two of you if they have more thoughts about some of these articles. Can you leave us any closing thoughts as we finish out our neurology year in review?

Pia Wintermark: I would just say thank you for organizing and leading this. I love to hear the podcast, so I was really honored to be on it. Thank you, Daphna.

Daphna Barbeau: Thank you. The honor is all ours.

Eleanor Molloy: Yeah, and thank you so much for all your work on the podcast, because yes, I am a huge fan as well. It’s great to listen to and to see you putting everything into context. Actually, my only other comment is that, as well as talking about the brain, the effects of all these drugs on the whole body are really interesting. I suppose we'll see what the future holds there as well. Thank you very much.

Daphna Barbeau: Yeah, so I think that's a call to action for people who are still looking for research projects or to change their research—there’s still lots to solve in neonatology. Thank you both for highlighting this important work and areas where questions are still unanswered. Thank you so much.