#331 - 📑 Journal Club - The Complete Episode from July 20th 2025

Hello friends 👋

In this week’s Journal Club, Ben and Daphna dive into several impactful neonatal studies shaping today’s clinical decisions. The discussion opens with the MOCA Trial, exploring whether extending caffeine therapy in moderately preterm infants reduces hospital stays and improves outcomes. Despite reducing apnea episodes, the study highlights that extending caffeine treatment does not reduce time to discharge.

Next, the team reviews a randomized trial on late permissive hypercapnia in mechanically ventilated preterm infants, showing that targeting slightly higher CO₂ levels can shorten invasive ventilation time without worsening long-term outcomes.

Midway through the episode, we feature an EBNEO commentary with Dr. Kira McNellis on early full enteral nutrition with fortified milk in very preterm infants. She explains why fat-free mass is an important nutritional marker linked to neurodevelopment and why “negative” nutrition studies still matter for clinical practice.

Other key papers include cumulative neonatal morbidities predicting long-term neurodevelopment, the long-term academic

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

Association of a Count of Inpatient Morbidities with 2-Year Outcomes among Infants Born Extremely Preterm.

Dorner RA, Li L, DeMauro SB, Schmidt B, Zangeneh SZ, Vaucher Y, Wyckoff MH, Hintz S, Carlo WA, Gustafson KE, Das A, Katheria A; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.J Pediatr. 2025 Mar;278:114428. doi: 10.1016/j.jpeds.2024.114428. Epub 2024 Dec 4.PMID: 39643110

School outcomes after HIE: a population-based cohort study.

Rees P, Dronavalli M, Carter B, Bajuk B, Burns L, Dickson M, Eastwood J, Hossain S, Lawler K, Lee E, Munasinghe S, Page A, Uebel H, Dicair L, Green C, Gale C, Oei JL.Arch Dis Child Fetal Neonatal Ed. 2025 Jun 8:fetalneonatal-2024-328346. doi: 10.1136/archdischild-2024-328346. Online ahead of print.PMID: 40484626

Extended Caffeine for Apnea in Moderately Preterm Infants: The MoCHA Randomized Clinical Trial.

Carlo WA, Eichenwald EC, Carper BA, Bell EF, Keszler M, Patel RM, Sánchez PJ, Goldberg RN, D'Angio CT, Van Meurs KP, Hibbs AM, Ambalavanan N, Cosby SS, Newman NS, Vohr BR, Walsh MC, Das A, Ohls RK, Fuller J, Rysavy MA, Ghavam S, Brion LP, Puopolo KM, Moore R, Baack ML, Colaizy TT, Baserga M, Osman AF, Merhar SL, Poindexter BB, DeMauro SB, Kumar V, Cotten CM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.JAMA. 2025 Jun 24;333(24):2154-2163. doi: 10.1001/jama.2025.5791.PMID: 40294395 Clinical Trial.

Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease.

Musunuru K, Grandinette SA, Wang X, Hudson TR, Briseno K, Berry AM, Hacker JL, Hsu A, Silverstein RA, Hille LT, Ogul AN, Robinson-Garvin NA, Small JC, McCague S, Burke SM, Wright CM, Bick S, Indurthi V, Sharma S, Jepperson M, Vakulskas CA, Collingwood M, Keogh K, Jacobi A, Sturgeon M, Brommel C, Schmaljohn E, Kurgan G, Osborne T, Zhang H, Kinney K, Rettig G, Barbosa CJ, Semple SC, Tam YK, Lutz C, George LA, Kleinstiver BP, Liu DR, Ng K, Kassim SH, Giannikopoulos P, Alameh MG, Urnov FD, Ahrens-Nicklas RC.N Engl J Med. 2025 Jun 12;392(22):2235-2243. doi: 10.1056/NEJMoa2504747. Epub 2025 May 15.PMID: 40373211

Early full enteral nutrition with fortified milk in very preterm infants: a randomized clinical trial.

Salas AA, Gunawan E, Jeffcoat S, Nguyen K.Am J Clin Nutr. 2025 May;121(5):1117-1123. doi: 10.1016/j.ajcnut.2025.02.019. Epub 2025 Feb 21.PMID: 39986385 Clinical Trial.

Late Permissive Hypercapnia for Mechanically Ventilated Preterm Infants: A Randomized Trial.

Travers CP, Gentle SJ, Shukla VV, Aban I, Yee AJ, Armstead KM, Benz RL, Laney D, Ambalavanan N, Carlo WA.Pediatr Pulmonol. 2025 Jun;60(6):e71165. doi: 10.1002/ppul.71165.PMID: 40525736 Free PMC article. Clinical Trial.

Perinatal Urinary Tract Dilation: Recommendations on Pre-/Postnatal Imaging, Prophylactic Antibiotics, and Follow-up: Clinical Report.

Anthony Herndon CD, Otero HJ, Hains D, Sweeney RM, Lockwood GM; Section on Urology; Section on Nephrology; Section on Radiology; Section on Hospital Medicine.Pediatrics. 2025 Jul 1;156(1):e2025071814. doi: 10.1542/peds.2025-071814.PMID: 40518141 Review.

Co-Occurring Medical Conditions in Over 2300 Children With Down Syndrome at a Down Syndrome Multispecialty Clinic.

Hickey F, Maastricht L, Wolter-Warmerdam K, Daniels D, Herfindahl B, Kelminson K.J Intellect Disabil Res. 2025 Jun 4. doi: 10.1111/jir.13257. Online ahead of print.PMID: 40462648

Hours based scheduling in neonatology: a practical approach.

Stroustrup A, McNamara PJ, Tipple TE, Lakshminrusimha S.J Perinatol. 2025 Jun 19. doi: 10.1038/s41372-025-02332-y. Online ahead of print.PMID: 40537555 Review.

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Watch this week's Journal Club on YouTube 👇

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

Ben Courchia: Hello everybody, welcome back to the Incubator podcast. We are back today for a new episode of Journal Club. Daphna, good morning, how's it going?

Daphna Barbeau: I'm doing well. I'm on island mode, activated while we're recording Journal Club. But that's okay. The work continues, doesn't it?

Ben Courchia: Which island are you on?

Daphna Barbeau: No, I'm just kidding. We're in Jensen Beach, not technically on the island.

Ben Courchia: Very cool. We have a busy episode of Journal Club today. We'll have an EBNEO segment coming up this week. We're joined by Dr. Kira McNellis, who will talk to us about early full enteral nutrition with fortified milk, an article that we previously reviewed, but we'll go back into the commentary from the EBNEO team. We have some announcements. Daphna, do you want to give an update on the winners of the contest? Not that you have to give it. People should check their emails. You'll be contacted, but the prizes are going out.

Daphna Barbeau: Yeah, that's exactly right. We picked a lot. Had a lot of survey responses. We're so grateful for that. We read every single one, hoping to make some small changes to meet everybody's needs. But yeah, we gave out a lot of stuff—swag, tech stuff, free registration to Delphi, a laptop—I almost forgot our biggest prize. So definitely, if you haven't checked your email recently, check your email. Some people have already responded with their mailing address and things that we need to get you your stuff. But as always, really grateful for people who participate. Thanks, everybody.

Ben Courchia: Yeah. We're going to have some fan mail submitted to the Incubator player. I think that one of the things people sometimes ask—we have a message from Dallas, Texas, asking about links to some of the articles mentioned in the Journal Club and during the interviews. I suggest people check out the website, theincubator.org. We usually have all the information related to the different episodes accessible there. We have another message this time from Sri Lanka asking about reading transcripts. Again, this is something on the episode page people should be able to see and find. So again, all this information doesn't fit in the little box given to us on Spotify, so it's usually put on the website.

I wanted to maybe take a moment to highlight an exciting new event in the pediatric research space. We wanted to bring some attention to the inaugural Pediatric Research for the Future of Children (PRFC) forum taking place February 11 to 13, 2026 at Campus Biotech in Geneva, Switzerland. Geneva is a beautiful place—if you can go just for that alone. Organized by the European Society for Pediatric Research (ESPR) and the Society for Pediatric Research (SPR), this global forum is bringing together researchers, clinicians, and innovators committed to advancing child health through science-driven collaboration. One of the Incubator’s very own, Dr. David McCauley, is helping with the organization. The organizers are currently accepting abstract submissions for oral and poster presentations. They're especially looking for original unpublished work in five key areas: precision medicine and novel therapies in pediatrics, big data and pediatric research, child mental health and development, early life determinants of health and disease, and global pediatric research and pediatric clinician-scientist development. The abstract deadline is July 31, 2025, and everything—including the submission template—is available on the conference website at www.prfc-forum.org. We'll share this information on our social media channels as well. Definitely go check it out.

Daphna Barbeau: Yeah, sounds like it will be a very interesting conference.

Ben Courchia: Yeah, I agree. And it's quite unique to have specifically that type of conference combining two big organizations like ESPR and SPR working together on this. I think that does it for us in terms of Journal Club. Have a good day, everybody. No, I'm kidding. We are going to go right into Journal Club. I guess, per tradition, I get to go first.

Daphna Barbeau: That's right.

Ben Courchia: I wanted to start off today with a paper published in JAMA called Extended Caffeine for Apnea in Moderately Preterm Infants. The first author is Dr. Wally Carlo, who is a podcast veteran and a Delphi speaker. Check out his episode on our website and his talk on YouTube. So caffeine, as we know, is a widely used therapy, one of the most used drugs in the NICU. We use it to treat apnea of prematurity. Now, while caffeine is routinely discontinued prior to discharge, there is significant variation in clinical practice regarding the optimal timing of its discontinuation. We know that the original CAP trials looked at the administration of caffeine up until 34 weeks corrected gestational age, which is usually where most people stop. But there’s still a lot of variation as to how long we should continue caffeine treatment. Some centers, after discontinuation, observe infants for five to ten days due to its prolonged half-life, potentially delaying discharge unnecessarily. If you're studying for boards, know the half-life of caffeine—that's a very easy question to draft. Moreover, moderately preterm infants are at increased risk of apnea even after discharge, raising the theoretical possibility that continuing caffeine through hospitalization and for a period after discharge might reduce hospital stay, readmissions, or outpatient sick visits.

So this brings us to the current study, the MOCHA trial—Moderately Preterm Infants with Caffeine at Home for Apnea. Love the acronym. You can tell they worked on that. Kudos for the MOCHA acronym. The study aimed to test whether extending caffeine therapy until 28 days after discharge could decrease the number of days from randomization to discharge compared to stopping caffeine earlier as typically practiced. This was a multi-center randomized placebo-controlled trial conducted across 29 hospitals in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD Neonatal Research Network). The study included babies born between 29 and 33+6 weeks, and who were between 33 and 35+6 at the time of randomization. They also had to meet three additional criteria: they had to be receiving caffeine and about to have it discontinued, be receiving oral or tube feeding at a volume of at least 120 ml/kg/day, and be able to begin the study medication within 72 hours after stopping caffeine.

Key exclusion criteria included needing respiratory support, use of apnea monitors due to family history or parental requests, congenital heart disease, neuromuscular conditions affecting respiration, major malformations, genetic disorders, and so on. The infants were randomized in a one-to-one ratio stratified by center and gestational age. Those in the intervention group received enteral caffeine at a dose of 10 mg/kg/day. The control group received a placebo containing all the excipients but no caffeine. The treatment continued during hospitalization and for 28 days after discharge, unless the infant was still hospitalized at 44 weeks postmenstrual age, at which point they stopped; it never went beyond 44 weeks. The primary outcome was the number of days from randomization to hospital discharge up to 48 weeks. The secondary outcome was very interesting because every time Dr. Carlo runs a study, there's something interesting in the methodology. They defined something called "physiologic maturity." This was defined as being out of the incubator for at least 48 hours, successfully taking oral feeding at least 140 ml/kg/day, and being free of apnea for five consecutive days. Meeting these criteria meant the infant was called physiologically mature. Additional outcomes included postmenstrual age at discharge, hospital readmission, outpatient visits, and some serious adverse events related to arrhythmia, seizures, hospitalization, death, etc.

Going into the results: 827 infants were enrolled between February 2019 and December 2022. Four hundred sixteen were randomized to the caffeine group, 411 to the placebo group. The study was stopped by the Data and Safety Monitoring Committee due to futility, as there was less than 15% conditional power to detect a significant effect.

The median gestational age at birth was 31.1 weeks for both groups. The median birth weight was 1,580 grams in both caffeine and placebo groups. Median postmenstrual age at randomization was 34.5 weeks in the caffeine group and 34.4 weeks in the placebo group. Regarding outcomes, there were no significant differences in the primary outcome. Extending caffeine therapy did not reduce the number of days from randomization to discharge.

Caffeine did have an impact on apnea resolution. Infants in the caffeine group became apnea-free sooner, with a median of six days versus ten days in the placebo group, the adjusted difference being minus 2.7, with a 95% confidence interval ranging from minus 3.4 to minus 2. In the post-hoc analysis, only four out of 414 infants in the caffeine group experienced significant apnea after randomization, compared to 18 out of 410 in the placebo group. Secondary outcomes did not differ meaningfully. Time to physiologic maturity, discharge postmenstrual age, weight gain during hospitalization, and weight change up to eight weeks post-discharge showed no significant differences. There were no differences in hospital readmission or the number of outpatient sick visits, whether related to apnea or not. Adverse event rates, including serious events like seizures and death, were similar between groups.

The conclusion is that in moderately preterm infants with planned discontinuation of caffeine, continuation of caffeine until 28 days after discharge or 44 weeks postmenstrual age did not reduce hospital stay, hospital readmission, or sick visits. It did reduce the days to resolution of apnea, but achievement of full oral feeds delayed discharge more than apnea resolution. That last sentence is actually the key, in my opinion, to the study. Dr. Barbara Schmidt wrote a very nice editorial in JAMA as well, where she mentions exactly that. She notes that the caffeine dose was not too low, and that the open-label use of caffeine was minimal. But she says the biggest reason this study showed negative results—meaning no difference or improvement using caffeine—is probably related to the population studied. The moderately preterm infants, with a median gestational age of 31 weeks, usually have more delays to discharge related to feeding readiness than respiratory maturity. Feeding, not apnea, was the main barrier to discharge. So irrespective of that, at this time, this is the best study we have. Routine use of home caffeine therapy in this population is not supported.

The question this really leaves us with is: what will other studies show when looking at more immature infants? I think more immature infants were automatically excluded from this study, especially since many of us continue caffeine in babies who remain on some form of respiratory support, and that was one of the exclusion criteria here. So I think we’ll have to revise how we think about this, because that will mean probably stopping caffeine in babies who are still on respiratory support around 34 weeks. So anyway, that's for the next group of researchers to worry about. A very interesting study indeed.

Daphna Barbeau: Yeah, I mean, we're always wondering, like, well, I mean, we love caffeine, right? Caffeine’s worked for us. So how can we use it to our advantage? Can we give more? Can we give less? Can we give it for longer? So I think this definitely adds to our knowledge. But yeah, I agree. I still think even in the smallest babies, feeding rather than apnea is still going to be the main issue. I think we'll find the same. Very interesting. Thanks, buddy. We've been awaiting.

Ben Courchia: There are a lot of countries, especially outside the US, where they just continue caffeine moving forward and going home. So I think that's also interesting.

Daphna Barbeau: Yeah. Now, for example, there are some papers we’re not reviewing today that look at whether we can discharge babies before they’re on full feeds. That’s a different discussion than about potentially giving caffeine and going home before they’re on full feeds, like with NG tube feeding. But that’s not the standard of care around the country. It’s interesting as we try to move babies home sooner.

So I actually have another Dr. Carlo paper, so I might as well do that one next. It’s in Pediatric Pulmonology, titled Late Permissive Hypercapnia for Mechanically Ventilated Preterm Infants: A Randomized Trial. Dr. Carlo is the senior author, and Colm Travers is the lead author. This is from UAB in Birmingham. They wanted to see if targeting higher levels of pH-controlled permissive hypercapnia beyond the first week—in postnatal days seven to fourteen—reduces mechanical ventilation duration in preterm infants.

It was a single-center randomized clinical trial including preterm infants from 22+0 to 36+6 days gestational age, ventilated for clinical and radiographic RDS on postnatal days 7 to 14. They included babies who were inborn or transferred before postnatal day 7. Exclusion criteria included major congenital malformations, neuromuscular conditions affecting respiration, infants with terminal illness, or decisions to withdraw or limit care.

They stratified randomization by gestational age at birth: 22 to 25 weeks, 26 to 28 weeks, and 29 to 36 weeks. Eligible infants were randomized to either the intervention—permissive hypercapnia (I'll explain more)—or the control group, which was really the lower CO2 group. The lower CO2 group was assigned by one-to-one parallel allocation.

The two different levels of pH-controlled CO2 were based on arterial or capillary blood samples. Most babies didn’t have arterial blood monitoring. In the higher permissive hypercapnia group, they used a pH of ≥7.2 and CO2 between 60 and 75 mmHg. In the lower group, pH was ≥7.25 and CO2 between 40 and 55 mmHg. Both groups were technically permissive hypercapnia—they used either 40 to 55 or 60 to 75 CO2. Blood gas testing was done daily while on ventilator support using ABGs or CBGs. They also used transcutaneous monitors, validated against blood gases. Infants remained in their assigned group for 28 days after enrollment.

Extubation and reintubation criteria differed based on pH and CO2 targets. One extubation criterion: infants could be extubated when they had saturations of 88% with FiO2 ≤50%, conventional ventilator rate ≤20 breaths per minute, mean airway pressure (MAP) <8, amplitude <2 if on high-frequency oscillator, and were hemodynamically stable. Infants in the higher group could be extubated if they had pH ≥7.2 and PCO2 ≤75. Infants in the lower group could be extubated if they had pH ≥7.25 and PCO2 ≤55.

The reintubation criteria (which I think might have a typo) were stated as sats >88% with FiO2 ≤80 for ≥1 hour. I imagine they meant sats <88% with FiO2 >80 for ≥1 hour. Other criteria included repetitive apnea requiring bag-mask ventilation more than once per hour, clinically defined shock, sepsis needing surgery, or if the baby became hemodynamically unstable. For reintubation, infants in the higher group could be reintubated if pH <7.2 or PCO2 >75; infants in the lower group if pH <7.25 or PCO2 >55. Babies were extubated to non-invasive positive pressure ventilation.

They used an algorithm for invasive mechanical ventilation adjustments for out-of-range CO2 levels—details I won’t cover now, but it’s interesting for readers. They targeted high ventilator rates to minimize volume trauma and made decisions based on whether it was an oxygenation or ventilation problem.

Primary outcome was days alive and ventilator-free in the 28 days post-randomization, where ventilator-free meant off invasive mechanical ventilation. Secondary outcomes included hospital mortality, grade 2 to 3 BPD, postnatal steroid use, pulmonary hypertension, hemodynamically significant PDA, weight and head circumference during the 28-day period, days on respiratory support, and severe neurodevelopmental impairment. Invasive respiratory support was defined as requiring an endotracheal tube.

They enrolled 130 preterm infants: 62 randomized to higher CO2, 68 to lower CO2. Mean gestational age was 24 weeks and 5 days (±14 days), mean birth weight 657g (±198g). Exposure rates to antenatal steroids, surfactant, and mechanical ventilation before study entry were similar between groups. The lower permissive hypercapnia group had a higher rate of multiple births; other neonatal characteristics were similar. Daily pH and PCO2 were consistently higher in the higher group, significantly differing after study entry as expected.

Infants in the higher permissive hypercapnia group had significantly more days alive and ventilator-free in the 28 days after randomization: 11 ± 10 days versus 6 ± 8 days in the lower group. This was mainly due to fewer days on invasive ventilation—14 ± 10 days versus 19 ± 9 days. They had a corresponding increase in days on non-invasive respiratory support in the higher CO2 group. There was no difference in total days alive during the 28 days, but there was a difference in ventilator-free days alive, favoring the higher group.

Days on supplemental oxygen did not differ. Grade 2–3 BPD or death before discharge was not lower in the higher group (44% vs. 59%, adjusted OR 0.54). Grade 2–3 BPD among survivors at 36 weeks PMA was also not significantly different (35% vs. 50%, adjusted OR 0.56).

Risk of death before discharge didn’t differ. No differences were found in rates of hemodynamically significant PDA, pulmonary hypertension, postnatal corticosteroid treatment, necrotizing enterocolitis, late IVH, or discharge beyond 120 days. Growth indices were similar. Follow-up rate was about 80%, with no difference between groups. No significant differences in rates of severe neurodevelopmental impairment alone or combined with death. Bayley scores also did not differ.

Their overall conclusion: higher levels of pH-controlled permissive hypercapnia in infants mechanically ventilated on postnatal days 7 to 14 increased days alive and ventilator-free, but no other outcomes differed significantly.

I don’t want to minimize what they found—some babies had more than five ventilator-free days, some over a week. That’s important. Also, babies didn’t do worse in the higher hypercapnia group, which is equally important. Sometimes we worry that leaving babies hypercapnic might cause worse outcomes, especially neurodevelopmentally, but they didn’t find that.

Your thoughts? You’re our ventilator guy.

Ben Courchia: Thanks. Yeah, I think this aligns well with current practice allowing babies to tolerate higher CO2 levels. It follows data on more mature infants in the BPD phase who do better long-term with mildly higher CO2. This pattern is only strengthening. I’m happy to see this trial published and am not surprised by the results.

Daphna Barbeau: Yeah, especially regarding reintubation criteria. Sometimes we reintubated babies at much lower levels than these permissive hypercapnia targets. This study shows we can give them more time and see how they do.

Ben Courchia: Yeah, I agree. I mean, we just had on the French edition of the podcast a long conversation with Dr. Weissam Shalish from Montreal, who’s leading the APEX cohort and talking about extubation readiness and extubation criteria. And again, I think that’s a very big deal. Having clear criteria makes a lot of sense because we’re still not exactly sure what defines a successful extubation or how long we should wait before declaring it so. So yeah, I think these reintubation rates are quite good. And like we always say, if you’re not reintubating, you’re probably not extubating quickly enough.

Okay, before we take a break for our EBNEO segment, I wanted to turn and talk about a paper that made the news in the New England Journal of Medicine, titled Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. It’s a very important read for our field. I think there are a lot of lessons to take from this paper, as it will probably be a landmark publication.

It shows what many of us thought was many years away: a single-patient gene editing therapy using CRISPR delivered in vivo to treat a life-threatening neonatal metabolic disease—specifically carbamoyl phosphate synthetase 1 (CPS1) deficiency. Reading this paper feels like science fiction coming to life. CPS1 deficiency is rare and deadly—a urea cycle disorder affecting about 1 in 1.3 million births, with about half not surviving infancy. The enzyme CPS1 is crucial for eliminating ammonia. Without it, ammonia accumulates to toxic levels, causing neurological injury or death.

In this case, a male infant presented within 48 hours of life with respiratory distress and extreme hyperammonemia (>1000 µmol/L). Rapid genomic analysis revealed two truncating mutations in the CPS1 gene, confirming neonatal CPS1 deficiency. What happens afterwards is truly breathtaking. Instead of listing the child for transplant (which they did just in case), the team at CHOP and University of Pennsylvania designed a customized gene editing treatment using CRISPR-based editing. For those unfamiliar, CRISPR can change individual DNA letters without cutting the double helix. Here, adenine base editors were used to fix a nonsense mutation on the paternal allele, Q335X.

They developed a therapeutic called KJ-Guan-Aben-Simeran, or K-Abe—named after the kid, KJ. It’s an mRNA packaged in lipid nanoparticles, like the mRNA COVID vaccines, but for gene correction. It’s designed to target the liver and edit hepatocytes in vivo.

The timeline is astonishing. Look at figure 1 on page 2. From diagnosis shortly after birth, within one month they had a patient-specific cell line; by month two, CRISPR editors were screened; months three to five, mouse and primate safety studies were completed; by month six, the FDA approved the investigational new drug application; by months seven and eight, the infant received two infusions of the therapy. Before treatment, toxicology studies in mice and non-human primates showed safety: 42% corrective editing in mouse liver at the lowest primate dose with only transient, resolving liver enzyme elevations, and no significant off-target editing in over 20 candidate genes, especially in primary human hepatocytes.

The infant received two IV doses: 0.1 mg/kg initially, then 0.3 mg/kg three weeks later. Clinical improvements were dramatic. Protein intake increased above dietary allowance, nitrogen scavenger dose was halved, and importantly, the baby tolerated several viral illnesses without hyperammonemia—a major risk.

Figure 3 (page 6) shows ammonia levels dropped from pretreatment highs to sustained low-normal levels, and urinary orotic acid (a CPS1 activity biomarker) rose into or above normal, reflecting partial CPS1 function restoration.

This is the first reported use of CRISPR-based editing for CPS1 deficiency and possibly the first patient-specific in vivo gene editing therapy delivered in infancy. It was customized, developed, approved, and administered in under eight months. The therapy appears safe, effective, and tolerated so far.

Caveats: it’s an N-of-1 study. One patient, one protocol, no controls, and no liver biopsy was done, so exact gene editing levels aren’t known. Longer follow-up is needed. But to me, this is proof of concept that gene editing can be bespoke, fast, and targeted—something we dreamed of until now. For ultra-rare diseases, it opens a new treatment path—not through decades of pharma trials, but via platform technologies tailored to patients.

As authors note, this approach could become routine for hundreds of liver-based metabolic disorders. Instead of telling families no treatment is available, we might soon say we’re working on your child’s edits and will give the infusion in a few months.

Daphna Barbeau: This is incredible—earth-shattering, life-changing for some babies. And while technically no controls, I wouldn’t say no controls at all—we know the natural history for babies like this. So this is very exciting. Kudos. We have to start somewhere.

Ben Courchia: Yeah, absolutely. Alright, quick break, then back for our EBNEO segment.

Daphna Barbeau: Today I’m pleased to bring another EBNEO commentary. We love having the EBNEO team and experts come share their thoughts on high-yield articles. Their commentary is also published shortly after our discussions.

Today we discuss a potentially hot and somewhat controversial topic from The American Journal of Clinical Nutrition: Early, Full Enteral Nutrition with Fortified Milk in Very Preterm Infants: A Randomized Clinical Trial. Lead author Ariel Salas is known for innovative nutritional studies.

Joining me is Dr. Kira McNelis.

Kira McNelis: Thanks for having me.

Daphna Barbeau: You are a neonatologist at Emory University and Children’s Healthcare of Atlanta. You have a research interest in nutrition and body composition, which we’ll touch on later. And you're the recipient of the Young Investigator Award from the Imperial College London in 2024. So it's no surprise that you are our expert today on this nutritional study. Tell us about the study and what it adds to neonatal nutrition.

Kira McNelis: Dr. Salas and colleagues have done excellent nutrition research. There’s still equipoise about how fast to advance feeding and fortification. We know preterm infants are in a nutritional emergency and need rapid nutrient delivery, but the best approach is debated. This study looked at how fast we can fortify feeds.

Daphna Barbeau: Yeah, I know you used the term equipoise, but I think there’s also a fear around early advancement or fortification despite emerging safety literature. I agree this was an exciting look. Dr. Salas is always pushing boundaries to get babies hooked up faster. You made me think—before birth, babies are continuously connected to adequate nutrition via their birthing parent. After birth, we try to recreate that but aren’t always successful. What were their methods?

Kira McNelis: They conducted a randomized controlled trial including infants 29 to 33+6 weeks gestational age. While called very preterm, these babies may be considered bigger preemies. They compared early enteral feeding fortification at 4–7 days (intervention) versus delayed fortification at 7–10 days (comparison), with roughly equal allocation. It was unmasked, which is understandable since clinicians need to know feeding plans. They targeted a feeding volume advancement of 30 mL/kg/day for all infants.

Primary outcome was fat-free mass Z-score at 21 days. Secondary outcomes included weight, length, and head circumference at 21 days and at 36 weeks post-menstrual age or earlier discharge.

They enrolled 80 infants, powered to detect a 0.5 difference in fat-free mass Z-score, and performed intention-to-treat analysis. They excluded very small-for-gestational-age babies (<5th percentile), those with terminal illness, or chromosomal/congenital anomalies.

Both groups received parenteral nutrition if <1500 g at birth or dextrose-containing IV fluids if ≥1500 g while advancing feeds. The groups were well matched on birth weight and maternal comorbidities.

Daphna Barbeau: That’s great, thank you. I wanted to highlight that some of the secondary outcomes also included adverse events like necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP), death, and feeding intolerance—topics people often worry about, which you’ll cover in the results. But I want to take a moment given your nutrition expertise. Some might ask: what exactly are they measuring with body composition? Why is fat-free mass important? It’s not something commonly discussed on rounds, but it’s often seen in nutrition studies. Why should people pay attention to it?

Kira McNelis: That’s my favorite topic! I’ll keep it brief. In this and many studies, body composition was measured with air displacement plethysmography (ADP), which is FDA-approved for clinical use. If you are at one of the 100 or so NICU’s in the country that has one of these devices, you could use it in practice, though mostly it’s a research tool.

Fat-free mass is important because, in preterm infants, it’s strongly linked to neurodevelopment. Multiple studies show relationships between fat-free mass and brain size, neurodevelopmental outcomes at toddler and preschool ages, and neuronal processing speed. So it acts as an early marker—here measured at 21 days—which correlates with later neurodevelopment, allowing earlier evaluation without waiting years.

Daphna Barbeau: So what I hear is that traditional measurements like weight, length, and head circumference aren’t sufficient alone to predict the best outcomes.

Kira McNelis: Exactly. Body composition is more sophisticated. But there are challenges—such as needing the baby to be on room air to perform the test, which limits its use in very preterm infants (like 23-weekers). Also, many studies don’t have birth body composition to compare with later measurements, so they just look at one timepoint.

Daphna Barbeau: Thanks for that. You’ve convinced me this is important. So, what did the study find?

Kira McNelis: So the primary outcome was negative—no difference in fat-free mass Z-score. But there was some surveillance bias because clinicians knew which babies were in the early fortification group and adjusted feeding rates, especially days 7–10, so the total days fortified weren’t that different between groups. This is a challenge for studies like this.

However, they did find a difference in length at 36 weeks or discharge—the early fortification group was longer overall. So maybe there’s a real difference we couldn’t detect fully.

Daphna Barbeau: That’s important. Maybe the groups weren’t different enough to see the full effect.

Kira McNelis: Right. On other secondary outcomes you asked about—NEC, SIP, death, feeding intolerance—there was one death in the early group (not statistically significant), and two cases of pneumoperitoneum in the delayed group. So no detected safety difference, but a larger multicenter trial would be needed to be sure.

Daphna Barbeau: It wasn’t powered for these outcomes, but it’s good that early fortification didn’t show worse safety.

You also mentioned the type of milk—donor versus mother’s own milk—which could influence results.

Kira McNelis: Yes, important detail. They used a bovine-based fortifier. Mother’s own milk was preferred, with donor milk supplementing if needed. The transitioned off donor milk to a preterm formula after day 21 if full mom’s milk supply wasn’t available.

Donor milk and mother’s milk aren’t equivalent—donor milk usually has less protein due to lactation stage and pasteurization. The study assigned estimated protein content but didn’t directly analyze macronutrients, so some differences may exist. Also, donor milk has differences in insulin, other hormones, and bioactive factors found in mother’s milk. This is a limitation and could affect outcomes.

Daphna Barbeau: But they still found a length difference. Why is length important?

Kira McNelis: Length is a good growth indicator when body composition isn’t available. Weight is important too, but length changes may reflect nutritional effects and overall health better in some cases. So that finding is exciting and might be confirmed in larger trials.

Daphna Barbeau: Here’s a tough one: the primary outcome was measured around 35 weeks. Is that the right timing for assessing nutritional interventions?

Kira McNelis: Great question. It’s controversial. Often the timepoint is chosen for convenience and to compare to older studies. Some babies are discharged before 36 weeks, so you either lose follow-up or need very close outpatient monitoring. Longer follow-up means more confounders outside the NICU environment. There’s no perfect answer yet.

Daphna Barbeau: Fair enough. What about negative trials in nutrition? Why discuss them if there’s no positive effect?

Kira McNelis: They’re still important. We live in a fragile supply system, with shortages of injectables or fortifiers. Knowing that two protocols are roughly equivalent gives flexibility. If you have to pivot your feeding strategy due to shortages, it’s reassuring to know it’s still safe.

Daphna Barbeau: Absolutely. We’ve especially seen that recently. We’re almost out of time, but can you briefly tell us about your body composition research with large-for-gestational-age (LGA) infants?

Kira McNelis: Sure! At Emory and with my PI at Nemours Children’s in Orlando (Sree Viswanathan), we’re running an RCT using body composition, specifically fat-free mass, to guide feeding interventions. Instead of basing feeds on total body weight, we individualize based on fat-free mass. We’re studying LGA infants struggling with oral feeding, using tube feeds to support them, and looking at appetite hormones and growth through six months. It’s a personalized nutrition approach aiming to improve outcomes.

Daphna Barbeau: So that’s really cool. You’re saying that instead of using weight times a fixed volume like 150 mL/kg/day as a feeding goal, you want to evaluate a potentially better metric — especially since some of these babies might be bigger than they should be.

Kira McNelis: Yes, exactly. It’s for larger gestational age babies where I worry they might have excess fat. So the idea is to feed based on their lean mass, not total body weight, encouraging lean growth but avoiding overfeeding or growing excess fat.

Daphna Barbeau: That makes perfect sense. Especially since their oral feeding goals can sometimes be higher than expected in those first few days. I love that approach. It’s such an important question, and we look forward to seeing what you discover. Thanks so much for joining us and sharing your insights.

Kira McNelis:Thanks! I appreciate being here.

Ben Courchia: Okay, we’re back. Thanks, Daphna, for that interview. Now, let’s dive back into Journal Club. Daphna, what paper are you bringing us next?

Daphna Barbeau: Sure! This paper’s been making the rounds on social media — it’s from the Journal of Pediatrics, titled Association of Account of Inpatient Morbidities with Two-Year Outcomes Among Infants Born Extremely Preterm. The senior author is Anup Katheria, lead author Rebecca Dorner, from the NICHD team.

They wanted to investigate whether the number of neonatal morbidities is associated with death or severe neurodevelopmental impairment (NDI) among extremely preterm infants who survived to 36 weeks postmenstrual age.

It’s interesting because while we often use outcomes like head ultrasounds, we recognize multiple neonatal morbidities impact death and neurodevelopment. They aimed to examine the cumulative effect of having one, two, or multiple morbidities and identify which morbidities are most impactful.

This was a retrospective cohort analysis using prospectively collected data from 15 NICHD Neonatal Research Network centers. They included inborn infants born between 22 and 26 weeks gestation from 2014–2019 who survived to 36 weeks postmenstrual age. Infants with syndromes affecting development (like major congenital malformations or trisomies 13, 18, 21) were excluded. Surviving infants were assessed at 22 to 26+6 months corrected age using Bayley-3 and detailed neurologic exams.

The analysis focused first on identifying the three morbidities most strongly linked with death or severe NDI. They then constructed a “morbidity count” based on those three and looked at outcomes depending on how many morbidities the infant had. A multivariable analysis adjusted for known maternal and infant risk factors was also performed, with predictive modeling compared to the NICHD Extremely Preterm Birth Outcomes tool.

On to results: They had 4,692 eligible infants surviving to 36 weeks PMA; 81% (~3,700) had known 2-year outcomes. Gestational age was mostly estimated by obstetric dating (99%). 77 children stayed hospitalized beyond 120 days; 13% were lost to follow-up; 6% were lost to follow-up or had unknown neurodevelopmental impairment.

Overall, 29.8% had late death or severe neurodevelopmental impairment. About 19% had Bayley-3 motor scores <70, 18% had cognitive scores <70, 5.1% died after 36 weeks PMA, 4.1% had severe motor impairment (GMFCS 4–5), 3% were deaf, and 1.3% were blind.

In terms of neonatal morbidities, 43% had grade 2 or 3 bronchopulmonary dysplasia (BPD), 26% had late-onset infection, 24% had severe brain injury (grade 3–4 intraventricular hemorrhage), 24% had severe retinopathy of prematurity (ROP), 13% had PDA surgery or cath, 10% had necrotizing enterocolitis (NEC), and 3% had early onset infection.

The three strongest risk factors for late death or severe NDI were severe brain injury (OR 3.96), grade 2 or 3 BPD (OR 3.41), and severe ROP (OR 2.66). Increasing counts of these morbidities correlated with higher rates of late death or severe NDI:

• Death alone: 1% (none), 5.4% (1 morbidity), 10.8% (2 morbidities), 11.9% (all 3)

• Severe NDI alone: 11.8% (none), 26% (1), 46% (2), 66% (all 3)

• Combined death or severe NDI: 12.6% (none), 30% (1), 52% (2), 70% (all 3)

They also validated their predictive model with sevenfold cross-validation showing high performance. The morbidity count (severe brain injury, severe ROP, grade 2 or 3 BPD) could be a useful tool for neonatal care quality measurement, family prognostication, and potentially a new outcome measure for neonatal trials. There’s a lot more data in the paper, but I think that is the highlight.

Ben Courchia: I find this very interesting. It’s expected that more comorbidities mean worse outcomes, but it was a bit surprising that ROP made the top three. While we understand BPD and brain injury’s impacts, there’s increasing data—like a recent Journal of Pediatrics paper from Cincinnati—showing severe ROP is linked to structural brain abnormalities on MRI, including cerebellar and deep gray matter changes. We often focus on ROP from a screening and treatment standpoint, but these data suggest it may also reflect brain injury risk or be a proxy for neurological outcomes.

Daphna Barbeau: Exactly. It’s hard to tease apart cause versus effect. Some very sick babies don’t develop ROP, and some less sick babies do. Also, we often don’t know about ROP severity until late in admission, which limits early prognostic discussions with families. An important point: 40% of babies had none of these three morbidities, 35% had one, 20% had two, and only 6% had all three. That’s reassuring in some ways, but we need to focus resources on those with multiple morbidities who are at the highest risk. Ok, your turn.

Ben Courchia: Yeah, very cool. The last paper I want to discuss in this episode of Journal Club is from Archives of Disease in Childhood, titled School Outcomes After HIE: A Population-Based Cohort Study. It’s a very interesting study. Therapeutic hypothermia became standard care only between 2007 and 2009, so it’s still relatively new. Because of that, the earliest cohorts of children who received cooling are only now reaching adolescence and adulthood.

This paper offers, according to the authors, the first real chance to understand how HIE affects school performance beyond early childhood. Previous studies showed that children surviving moderate to severe HIE without major neurodevelopmental impairment may still have behavioral and cognitive challenges. However, those studies often had small sample sizes, assessed kids only at early school age, and lacked healthy control groups. Crucially, no prior studies examined educational outcomes past early childhood compared to healthy peers. So this population-based cohort study aims to fill that gap by examining school outcomes at age 8 to 9, 10 to 11, and 12 to 13 years in children with mild, moderate, or severe HIE.

This prospective population-based cohort study was conducted in New South Wales (NSW), Australia. It included all infants born at or beyond 35 weeks gestation between 2008 and 2013 diagnosed with HIE. The exposed group came from the NSW NICU dataset; controls were from the state’s perinatal data collection. Records linked to health and education databases, including the NAPLAN (National Assessment Program – Literacy And Numeracy) standardized testing database, hospital admissions, and the cerebral palsy registry.

Infants were categorized as having mild or moderate to severe HIE based on the worst recorded grade. Therapeutic hypothermia was standard for moderate to severe HIE, but discretionary in mild cases. Infants with mild HIE who developed seizures were reclassified as moderate. The primary outcome was school performance, defined by total z-scores across five NAPLAN domains assessed at grades 3, 5, and 7: reading, writing, spelling, grammar, and numeracy. Secondary outcomes were individual domain scores and meeting national minimum standards.

Between 2008 and 2013, 550 infants with HIE were included: 22% mild, 70% moderate to severe, 7% unspecified severity. In the moderate to severe group (308 infants), 80% had seizures, 82% required mechanical ventilation, and 79% received anticonvulsants. Inotropes were given to 40% (moderate-severe) and 21% (mild). Therapeutic hypothermia was used in 67% of moderate-severe cases (median 72 hours) and 61% of mild cases (median 70.5 hours).

Notably, cooling utilization rose over time — from 49.2% to 77.1% in moderate to severe HIE and from 26% to 91% in mild HIE between 2008 and 2013. Infants with moderate to severe HIE who did not receive hypothermia had much higher mortality (40.9% vs. 22%).

The final analysis included 249 surviving children with HIE and NAPLAN data plus 341,000 controls. Looking at moderate to severe HIE (386 infants), most had seizures and mechanical ventilation. At grade 3 (age 8–9), 165 children completed NAPLAN; most had cooling, and about 25% had cerebral palsy. Compared with peers, these children had lower academic scores across all five domains and were less likely to meet national benchmarks, though nearly 68% passed the full assessment. The performance gap existed regardless of cooling, but scores were generally lower in those without it. At grade 5 (age 10–11), differences persisted, especially in reading and writing, with fewer passing overall compared to grade 3, though most still met minimum standards. At grade 7 (age 12–13), scores remained lower in all domains except grammar, where pass rates were comparable. Academic trajectories showed consistent upward trends — kids with moderate to severe HIE progressed steadily through grades 3, 5, and 7, even when limited to those who had received cooling. So, while cooling helps survival and short-term outcomes, the academic gap remains stable through early adolescence.

For mild HIE, the picture is more complex due to small numbers. At grade 3, children performed similarly to peers across domains and were just as likely to pass. At grade 5, with only 28 children, some small differences appeared — slightly worse spelling and less likely to meet benchmarks in reading, writing, and numeracy, but most passed overall. These findings were not statistically robust to actually make any conclusions. At grade 7, with only 13 children, conclusions are limited.

Interestingly, the curves suggest a convergence between mild and moderate to severe HIE by grade 7, indicating potential catch-up. I found this study valuable as it looks at longer-term outcomes not previously explored. The authors conclude moderate to severe HIE is associated with lower academic attainment, but encouragingly, these children continue to progress academically over time. Most children still pass assessments, which is encouraging. I’m not familiar with Australian standards, but I assume they are comparable internationally. This is important information for families, especially those with mild HIE. Further large-scale longitudinal studies are crucial since some effects may emerge later in childhood.

Daphna Barbeau: I agree. Overall, it’s pretty encouraging. It aligns with what Betsy said about sometimes not recognizing difficulties until school age. To have moderate or severe HIE children passing with their peers is a tremendous success story. We must continue to provide resources and advocacy, as these brains still grow and develop. Support is key.

Ben Courchia: Alright, want to mention a couple quick papers before we wrap?

Daphna Barbeau: Yes, I'm going to mention a few quick papers, at least so people know that they're out. There's actually a clinical report from the AAP on perinatal urinary tract dilation, with recommendations on pre- and postnatal imaging, prophylactic antibiotics, and follow-up. I think people should take a look at that. Some of the new and pertinent points include recommendations on prenatal evaluation, using the fetal urology grading system, and guidance on follow-up for fetuses depending on whether they are low or increased risk. In addition, sometimes we don’t always know what to do with the information after we get the first postnatal renal ultrasound in babies with prenatal dilation. This report provides a paradigm for that as well, categorizing babies by risk based on the postnatal ultrasound.

• Low-risk babies: Dilation of 10 to <15 mm with central calyceal dilation

• Intermediate-risk babies: At least one of the following—dilation ≥15 mm, peripheral dilation, or ureteral dilation

• High-risk babies: Findings from the intermediate-risk category plus additional concerns such as abnormal parenchyma, abnormal bladder, or abnormal urethra

They describe how to evaluate these babies based on risk. For low-risk infants, things like VCUG and antibiotic prophylaxis are generally not indicated. For intermediate-risk infants, a VCUG may or may not be needed depending on specific findings. For high-risk infants, based on the first postnatal ultrasound, a VCUG would be needed, possibly a MAG-3 scan, inpatient consultation, and antibiotic prophylaxis is recommended. They also highlight which babies are at higher risk of UTI if they have urinary tract dilation, such as female sex, intact foreskin, distal ureteral dilation, VUR (vesicoureteral reflux), and obstructive uropathy. They also highlight that we should not be obtaining postnatal ultrasounds until at least 48 hours of life and ideally as close to discharge as possible to avoid false positives.

There was also an interesting paper in the Journal of Intellectual Disability Research about co-occurring medical conditions in children with Down syndrome, specifically from a multi-specialty clinic. Some findings were expected—feeding problems, ophthalmologic problems, celiac disease, and hyperthyroidism—but nearly 60% of the children had obstructive sleep apnea, 62% had congenital heart disease (nearly 50% of those required surgery). They also found pulmonary hypertension in 25% of patients. One novel finding was an incidence of nearly 3.5% of Wolff–Parkinson–White syndrome, which hasn’t been well described before. Definitely something for us to keep in mind.

Finally, for those following the ongoing discussion about optimizing neonatal staffing, there was a perspectives paper in the Journal of Perinatology titled "Hours-Based Scheduling in Neonatology: A Practical Approach" by lead author Annemarie Stroustrup and senior author Satyan Lakshminrusimha. The paper provides a methodology for evaluating your workforce and assigning FTEs for different roles, with separate options for academic and clinical tracks. They include a template for hours-based scheduling (Table 1) with examples for senior academic faculty, primary clinicians, and nocturnists, along with suggested FTE breakdowns. The goal is to promote transparency and give teams a framework for discussion—essentially asking, “Is this what our group looks like?”—and to help standardize neonatal workforce planning across the country. It would be great to hear what our international colleagues think about this as well. That was a whirlwind, but I wanted to mention those papers.

Ben Courchia: Thank you for sharing those! We’ll link all the papers on the Journal Club episode page. Looks like we’re way over time but had a great discussion. Congrats to all the authors who allowed us to review their work. Daphna, see you later this week for more Incubator content. Bye, everyone!