#458 - 📑 Journal Club - The Complete Episode from August 15th 2026

The full week of Journal Club in one place. Monday, the PLaNT trial of prophylactic CPAP for late preterm infants born by cesarean, with senior author Dr. Edgardo Szyld. Tuesday, whether parental holding during therapeutic hypothermia changes feeding and length of stay. Wednesday, the Connection Study, the first live biotherapeutic product tested under an IND, and what it means for probiotics returning to the NICU. Thursday, a handheld light probe that reads bowel through the skin to catch NEC before the X-ray does. Friday, Dr. Dinushan Kaluarachchi on the respiratory severity score and what its trajectory tells us.

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First-in-human pilot study of broadband optical spectroscopy (BOS) as noninvasive surveillance for necrotizing enterocolitis (NEC). Dodd AC, Lehane AJ, Lee A, Hurlock A, Su Y, Ilahi I, Lautz TB, Backman V, Goldstein SD.J Pediatr Surg. 2026 May;61(5):162978. doi: 10.1016/j.jpedsurg.2026.162978. Epub 2026 Feb 3.PMID: 41643767

Association of parental holding during therapeutic hypothermia and NICU outcomes for infants with hypoxic-ischemic encephalopathy. Nguyen TT, Glass HC, Chan N, Taketa E, Pineda R, Cornet MC, Miller MJ.J Perinatol. 2026 Jun 22. doi: 10.1038/s41372-026-02753-3. Online ahead of print.PMID: 42332041

Live biotherapeutic product IBP-9414 (L. reuteri) in very low birth weight infants: the Connection Study. Neu J, Del Moral T, Guthrie SO, Hudak ML, Indrio F, Kim JH, Kronström A, Martin CR, Modi N, Rastad J, Schnitzer TJ, Singh R, Strömberg S, Szajewska H, Thuresson M, Caplan M.Pediatr Res. 2026 Feb 20. doi: 10.1038/s41390-026-04826-7. Online ahead of print.PMID: 41721054

Prophylactic CPAP at Cesarean Birth in Late-Preterm Newborns: A Multicenter RCT. Shah BA, DeShea L, Schmölzer GM, Josephsen JB, Fabres J, Wetzel EA, Rykovich H, Thomas A, Law B, Garrido C, Szyld E.Pediatrics. 2026 Aug 1;158(2):e2025070998. doi: 10.1542/peds.2025-070998.PMID: 42457181 Clinical Trial.

Association Between Delivery Room Continuous Positive Airway Pressure and Neonatal Outcomes in Late Preterm and Term Infants: A Systematic Review and Meta-Analysis. Chin Y, Hill M, Sett A, Thomas N, Razak A.J Paediatr Child Health. 2026 Jul 28. doi: 10.1111/jpc.70516. Online ahead of print.PMID: 42517258 Review.

Bronchopulmonary Dysplasia Definition Based on Respiratory Severity Score. Kaluarachchi DC, Peebles PJ, Lasarev MR, Guthrie SO, Laughon MM.Pediatr Pulmonol. 2026 Jul;61(7):e71750. doi: 10.1002/ppul.71750.PMID: 42478108 Free PMC article. No abstract available.

Respiratory severity score patterns by birth gestational age among a cohort of extremely preterm infants. Peebles PJ, Lasarev MR, Guthrie SO, Laughon MM, Keller RL, Kaluarachchi DC.J Perinatol. 2026 Jun 29. doi: 10.1038/s41372-026-02778-8. Online ahead of print.PMID: 42374145 No abstract available.

Respiratory severity score as a predictor for need for tracheostomy in infants with severe bronchopulmonary dysplasia. Kaluarachchi NM, Afah Annah S, Lasarev MR, Peebles PJ, Kaluarachchi DC.J Perinatol. 2026 Jun 25. doi: 10.1038/s41372-026-02720-y. Online ahead of print.PMID: 42350618 No abstract available.

Transcript

Ben Courchia, MD (00:00.574): Hello everybody, welcome back to the Incubator Podcast Journal Club. Daphna, good morning.

Daphna Yasova Barbeau, MD (00:06.356): Good morning. I'm away at surf camp — in full disclosure, I'm not doing much surfing, I'm accompanying. I've dabbled in it though.

Ben Courchia, MD (00:15.736): You don't know how to surf?

Daphna Yasova Barbeau, MD (00:20.064): Never. But people who surf say it's the best thing — everybody who does it talks about it like people who are gluten-free, like it's revolutionized everything. It really is freeing. I had the good fortune of hanging out at the beach house recording with you today. I had to last-minute deliver some cords, but I got them, so we're good to go.

Ben Courchia, MD (00:58.318): What a life. People aren't going to notice any difference — other than this big sailfish behind you. We have a very exciting week of Journal Club ahead of us. I'm going to start off with a paper that came out in Pediatrics, the journal of the American Academy of Pediatrics: "Prophylactic CPAP (Continuous Positive Airway Pressure) at Cesarean Birth in Late Preterm Newborns, a Multicenter RCT (Randomized Controlled Trial)." First author Birju Shah, senior author Edgardo Szyld. We'll have the pleasure of discussing the paper with Dr. Szyld himself at the end.

This is a paper that addresses a problem affecting everyone regardless of training level: late preterm infants, born between 34 and 36 completed weeks of gestation. They account for about 8% of all live births and make up over two-thirds of the preterm population — a proportion that continues to rise. This group accounts for the largest proportion of babies admitted to the NICU (Neonatal Intensive Care Unit), with about one-third requiring NICU care, most often for respiratory distress.

Segmented further to babies born via C-section: late preterm infants are 40 times more likely to experience respiratory distress than term infants, and that risk increases fivefold with C-section birth — classic delayed fluid clearance pathophysiology. Starting CPAP immediately after birth may reduce subsequent respiratory support, but evidence for prophylactic CPAP in the delivery room is limited.

Daphna Yasova Barbeau, MD (03:46.538): I'm realizing, since we've discussed this offline, that we've moved so far away from prophylactic, universal policies that this feels like a step back — or maybe a reassessment that some prophylactic interventions are still useful for certain subgroups.

Ben Courchia, MD (04:15.534): I actually disagree. We go to these deliveries and get a 35-weeker — for most units, the 34-to-35-week baby goes straight to the NICU anyway, which is our practice. It's the 35-to-36-weekers. How many times have we left the delivery room, come back to the unit, and thought, "they're going to call us"?

Daphna Yasova Barbeau, MD (04:54.614): That baby's going to come, and we'll have to go back, do a little CPAP, and see if they can stay.

Ben Courchia, MD (05:07.564): They call you at 20 minutes, you go, you bring the baby back a little defeated, the nurse puts them on the monitor, the prongs are off, and the kid's satting 100%. So there are these babies who may not really need NICU admission — they need a little support and help with the transition. And once you bring these 35-weekers in and get a blood culture, you've put them on a path. So what I'm interested in with this study is whether we can turn the tide.

This is an international multicenter pilot RCT evaluating whether prophylactic CPAP in the delivery room for late preterm infants born via C-section is feasible and safe, and whether it reduces the duration of respiratory support from 30 minutes after delivery through the first week of life, compared to standard care. Conducted in five tertiary centers across North and South America.

Inclusion: babies born between 34 and 36 weeks 6 days of gestation, spontaneously breathing. Babies with major congenital anomalies were excluded. The spontaneous-breathing criterion matters because these aren't babies who'd have received CPAP based on NRP (Neonatal Resuscitation Program). Infants not spontaneously breathing within five minutes were excluded.

The intervention: 20 minutes of prophylactic CPAP, PEEP (Positive End-Expiratory Pressure) set at 5 to 6 cm of water, initiated within the first five minutes after birth, via T-piece resuscitator (Neopuff) and mask. The control group received no prophylactic CPAP but could receive therapeutic CPAP if showing low saturation or labored breathing.

Primary outcome: duration of respiratory support from 30 minutes of life through the first week — any positive pressure support including CPAP. Based on prior data, mean duration of respiratory support in late preterm infants in the first week is about 50 hours; they aimed to detect a 14-hour (30%) reduction as clinically meaningful. Sixty infants per group (120 total) gave 80% power to detect an 18-hour difference at two-sided alpha 0.05.

Enrollment ran 2023–2025: 60 infants (49 mothers) received the intervention, 55 infants (45 mothers) received standard care, with balanced baseline characteristics.

Safety first: no pneumothoraces in either group, no deaths in the 30-day window.

Primary outcome: mean duration of positive pressure support in the first week didn't differ significantly — 12.3 hours (intervention) vs. 22 hours (control). Including supplemental oxygen: 15.4 vs. 30.4 hours mean; 0 vs. 1.8 hours median.

NICU admission was comparable — 50% vs. 67% — but unplanned NICU admission was significantly higher in controls, 15% vs. 7%. Surfactant use didn't differ. Therapeutic CPAP within 30 minutes: 27% of the intervention group (median 1.8 minutes) vs. 62% of controls. At 30 minutes, significantly more control infants were on respiratory support — 47% vs. 27%.

Subgroup analysis: four of five centers admitted all infants born before 35 weeks to the NICU regardless, so a planned subgroup analysis focused on 35-to-36-week-6-day infants. In that subgroup, control infants were significantly more likely to need positive pressure ventilation, CPAP, or supplemental oxygen in the first week — 46% vs. 24% — and more likely to be admitted to the NICU, 54% vs. 24%, more often unplanned, and more often for respiratory distress.

Conclusion: for spontaneously breathing late preterm infants born via C-section, prophylactic CPAP is feasible — especially on the mother's chest or close to parents in the OR — and safe, with no air leak syndromes. Overall first-week support duration didn't differ, but the intervention reduced need for support at 30 minutes and reduced unplanned NICU admission. The 35-to-36-week subgroup showed significant reductions in both first-week support and NICU admission. A larger RCT is needed. Daphna, thoughts?

Daphna Yasova Barbeau, MD (15:39.482): Physiologically it makes total sense — we're improving lung capacity while these babies clear extra fluid, and we know they're at risk for RDS (Respiratory Distress Syndrome). If the alternative is several days in the NICU, this could be a real advantage for families and babies.

Ben Courchia, MD (16:18.776): I should mention — in the supplementary material, there was an option to do this on the mother's chest, so skin-to-skin didn't need to be delayed by 20 minutes. The challenge is delivering positive pressure on the parent's chest, which in our ORs would require rearranging equipment.

Daphna Yasova Barbeau, MD (16:58.098): We'd need a dedicated CPAP setup instead of what's currently on the wall — but it could be done.

Ben Courchia, MD (17:08.368): It could. The setup they show is low-resource — two tanks, a Neopuff, and a humidifier — delivering CPAP on the mother's chest in the OR. Very neat. So without further ado, let's welcome Dr. Szyld.

Ben Courchia, MD (17:49.724): We have the pleasure of having on with us today the senior author of the PLaNT study, Dr. Edgardo Szyld. Edgardo, welcome back to the podcast.

Edgardo Szyld (18:04.790): Thank you very much for having me.

Ben Courchia, MD (18:07.324): You're professor of neonatology at Indiana University and organizer and founder of the Neonatal Resuscitation Symposium, taking place September 10–11, 2026 in Indiana. We wanted to talk about the PLaNT (Prophylactic CPAP at Late-preterm cesarean birth) study, and about the context around it. You shared with us a meta-analysis senior-authored by Abdul Razak, in the Journal of Paediatrics and Child Health, called "Association Between Delivery Room CPAP and Neonatal Outcomes in Late Preterm and Term Infants, a Systematic Review and Meta-Analysis." It reviews about six studies looking at CPAP administration for babies born at or after 34 weeks, with the primary outcome being barotrauma via pneumothorax. It found delivery room CPAP associated with potential harm in observational studies, with some confounding. That's a stark contrast to PLaNT, where pneumothorax was zero in both groups. How do you reconcile the two, especially regarding how the intervention is administered?

Edgardo Szyld (20:56.181): That's a very interesting question. With the same co-authors — Dr. Shah, Dr. Schmölzer, and myself — we performed a previous systematic review and meta-analysis for ILCOR (International Liaison Committee on Resuscitation) in 2022, on CPAP in the delivery room. Similar to this new one, we found that observational studies showed an association between CPAP use and pneumothorax — concerning, but still just an association. Looking at randomized controlled trials, there were only two, both included in our meta-analysis and this new one, and neither found any pneumothorax in a prospective RCT. So the number of patients in observational studies is huge compared to RCTs, but the RCTs are truly controlled, and show no pneumothorax.

Our PLaNT study was inspired by a small subgroup analysis from Celebi's paper, where 35 late preterm babies born by C-section showed a great benefit — reduced NICU admission — using the same intervention, 20 minutes of CPAP at 5 to 6 cm of water. People ask us, why 5 cm? Why 20 minutes? Why not more? If you have a treatment with a specific dose demonstrated to be safe and useful, why escalate the dose? Our pilot study demonstrated that was enough, and we're now working toward PLaNT 2, a larger multicenter study including 35- and 36-weekers, with the goal of reducing NICU admission.

Ben Courchia, MD (23:47.892): I'd like to drill into the design choices. The meta-analysis looks at delivery room CPAP broadly, while PLaNT is very selective — excluding vaginal births, focusing specifically on C-section babies given their elevated respiratory risk. What led to that deliberate choice of population, and what made now the right time to investigate this?

Edgardo Szyld (25:09.077): It's important to highlight we're comparing prophylactic versus therapeutic — reacting to the patient's needs. Any prophylactic intervention needs to target a higher-risk group, like vaccination. Epidemiologically, the higher-risk population is exactly what we targeted — late preterm born by C-section. We designed a pragmatic study to first test feasibility and safety in the pilot, which we demonstrated. Now we have a good efficacy signal, so we're targeting efficacy and NICU admission specifically. I would not recommend units start this intervention now — the data isn't strong enough yet, it's promising, but it's time to continue exploring, not implementing.

As for why now: our NICUs are populated largely by late preterm babies — the majority of admissions. And the C-section rate has increased significantly in recent years. More C-sections means more late preterm babies, and if we can prevent NICU admissions, we free up room for more acute babies and give this population better outcomes with earlier family bonding. It should be win-win for a short, safe intervention.

Daphna Yasova Barbeau, MD (28:04.460): I love that. My follow-up is about safety — the PLaNT study found no increase in air leaks like pneumothorax, which matters given prior studies, but it's still an uncommon problem. Do you think PLaNT 2 will enroll enough patients to have certainty that benefits outweigh pneumothorax risk?

Edgardo Szyld (28:39.317): I'd say yes. We're planning to enroll 300 patients in the next study, and combined with the first 100 from PLaNT 1, that lets us combine all RCTs in the meta-analysis, if we continue finding very few or no pneumothorax. For safety, we have stopping rules — if we'd had four pneumothoraces in the first group, we would have stopped. The DSMB (Data Safety Monitoring Board) found it safe, with zero pneumothorax, which was reassuring. For now, I can only speak to what we found in late preterm infants born by C-section: 20 minutes of CPAP at 5 to 6 cm of water was safe. I can't generalize beyond that population without doing the RCT.

Ben Courchia, MD (30:00.406): A potential critique is that we only know about the babies we X-ray — the baseline incidence is already low, and we're not investigating air leaks in every baby. What's your response to that?

Edgardo Szyld (30:33.695): We made it pragmatic and only explored symptomatic babies, because we know there are asymptomatic spontaneous pneumothoraces we don't routinely X-ray for. We didn't think it was worth exposing babies to unnecessary X-rays to find pneumothoraces that don't need treatment. After the newer NRP algorithm over the last 10 to 15 years, CPAP use in delivery rooms increased dramatically, and people may be starting to overuse it — and like any tool or drug, overuse can mean more secondary effects. That's the concern: if it's useful for preemies, people assume it should be useful for late preterm and term babies too, and we don't actually know that yet.

Daphna Yasova Barbeau, MD (31:51.341): I love that — taking a standardized approach with clear inclusion and exclusion criteria. You've mentioned the family-centered benefit of reducing NICU admissions. I wonder about the unintended consequences of parents seeing their babies receive respiratory care they may not have expected, and what that discussion should look like with families anticipating a late preterm delivery.

Edgardo Szyld (32:37.430): It's a very interesting point — our IRB (Institutional Review Board) raised this, and we also consulted our parental panels when developing the new protocol. We've been able to demonstrate we can provide CPAP on the mother's chest after C-section, without interrupting bonding and contact. We explain to families that their baby already has a higher risk of respiratory distress and possible NICU admission, and that we're offering an alternative that may prevent that — and they provide prospective consent. After the pilot, we're more convinced we can offer an even safer approach, but we're always transparent that there's an association with air leaks in observational data, even though we haven't seen it in any RCT in this population.

Ben Courchia, MD (34:04.086): Dr. Szyld, thank you so much for coming by — we'll be looking out for the publication and PLaNT 2. We'll remind everyone to register for the Neonatal Resuscitation Symposium, September 10–11, 2026 at Indiana University. Thank you for your time and your work.

Edgardo Szyld (34:34.615): Thank you for the invitation. Happy to be with you. Thank you.

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Daphna Yasova Barbeau, MD (35:15.982): Yeah, it's my turn. This is an article out of the Journal of Perinatology, lead author Tiana Nguyen, senior author Matthew Miller. I know families who've undergone therapeutic hypothermia have been awaiting this paper. It's titled "Association of Parental Holding During Therapeutic Hypothermia and NICU Outcomes for Infants with HIE (Hypoxic-Ischemic Encephalopathy)." This was a retrospective cohort study of infants diagnosed with HIE and admitted to UCSF Benioff Children's Hospital for therapeutic hypothermia between March 2017 and February 2024. The variable of interest was whether the infant was held during cooling. Why is this controversial? Babies have a lot of lines on them, central lines.

Ben Courchia, MD (36:21.268): Are you seriously asking that? There are a lot of nurses who say — well, I'll tell you why it's controversial.

Daphna Yasova Barbeau, MD (36:27.586): That's true for a lot of our babies in their first few days of life. But one concern has been whether holding changes the outcome of cooling itself — can we maintain temperature? Studies in the last few years show the blankets we have today manage temperature fluctuations during holding well. So that's exciting. They also looked at when the first hold occurred, frequency of holding, and infant characteristics — severity of encephalopathy via Sarnat exam, lab values, MRI (Magnetic Resonance Imaging) results, seizure history, respiratory support, medication need, intubation days, and G-tube (gastrostomy tube) need. NICU outcomes included time to full oral feeding, day of life at full feeding, breast milk at discharge, and length of stay. They had 440 infants with HIE across two level IV NICUs. They excluded infants who died during birth hospitalization and those transferred elsewhere — 61 excluded — leaving 379 infants, mean gestational age 39.4 weeks, mean birth weight 3.3 kilos. Of those, 28% were held during cooling, and that proportion increased over the study years, with some site variation. Among held infants, time to first hold was 1.4 days, versus about four days for those not held — which itself is a success, since babies often get rewarmed and we still miss the window to have parents hold them right after. Held infants also had a higher daily holding frequency — three times a day versus 2.5 — statistically significant.

Daphna Yasova Barbeau, MD (38:17.899): Which babies got held? Not particularly surprising: more common with higher five-minute Apgar scores (five versus four), more common with private insurance (68% versus 32%), and it varied by site. Race and ethnicity were also significantly associated — higher rates for infants identified as white or multiracial, lower for Hispanic, Asian, or Black infants. No association with gestational age, birth weight, sex, pH, base excess, MRI brain injury, or seizure history. So babies who were less sick were more likely to be held, along with factors related to family comfort and advocacy. NICU outcomes: held infants had more favorable outcomes overall, though again, this was a less-sick group at baseline. Held infants achieved full oral feeding earlier — median 2.6 days versus 3.6 days — were more likely to receive breast milk at discharge (92% versus 78%), and had a shorter length of stay (median eight days versus 11). In the unadjusted analysis, held infants reached full oral feeding sooner regardless of how it was measured — from birth (5.9 versus 8.4 days) or from feeding initiation (2.6 versus 3.8 days). In the adjusted analysis — controlling for encephalopathy severity, intubation days, insurance, race, ethnicity, admission year, and site — holding was still associated with faster feeding initiation (hazard ratio 1.4) and faster time from birth (hazard ratio 1.6), both statistically significant. Held infants were two-and-a-half times more likely to receive breast milk at discharge, with 4.9 fewer days of length of stay. Sensitivity analyses excluding race, ethnicity, and insurance kept all associations significant. So holding isn't just nice for parents and babies — it may genuinely improve NICU outcomes like getting babies home sooner. Thoughts?

Ben Courchia, MD (41:33.398): I have some questions. I don't know what to make of the fact that these are babies more likely to be held because they're likely less sick at baseline — are they doing better because they're less sick, or because they got held?

Daphna Yasova Barbeau, MD (41:43.520): They did run adjusted analyses to account for that.

Ben Courchia, MD (42:03.125): Sure — but honestly, I almost don't care, because I don't need these outcomes to tell me it's good for parents to hold their babies during therapeutic hypothermia. We know that from being physicians. My real question — full disclosure, we have no vested interest in anyone providing technological solutions for HIE — are there new tools that make holding babies during cooling more achievable?

Daphna Yasova Barbeau, MD (42:53.248): First — we agree babies should be held, but nurses at the bedside do raise real risks, like line malposition. So this data matters — yes there are risks, but concrete benefits too. There are cooling interfaces made specifically for babies, and infant blankets that help with temperature regulation. There are also different wraps, which may come down to hospital preference and whether nurses feel comfortable — which may just mean they need more training.

Ben Courchia, MD (44:06.709): So there are blankets that wrap around the baby, not just a mat with water running through it?

Daphna Yasova Barbeau, MD (44:14.518): Right — some wrap the arms and legs, some are adhesive. No head-to-head comparison for holding specifically yet, but potentially useful.

Ben Courchia, MD (44:33.567): Does wrapping the arms and legs make holding easier, in your experience?

Daphna Yasova Barbeau, MD (44:42.188): Yes, for sure — that's how nurses are used to handing babies to parents, kind of swaddled. Cooling causes some irritability, and swaddling likely makes that more comfortable. There's no study yet on swaddling babies during cooling specifically — that could be looked at. Other advances relate to securing lines — if lines are the reason we're not holding babies, maybe we need better ways to secure endotracheal tubes and lines, both for this population and for getting ELBW (Extremely Low Birth Weight) infants held sooner. Parent education and comfort matter too.

Ben Courchia, MD (45:57.302): My other question was about the exclusion criteria — excluding babies who died. What if held babies had higher mortality? That would be a significant finding. Not that it happened — I don't know the data or the authors — but do you think the study could have benefited from including that?

Daphna Yasova Barbeau, MD (46:31.660): Absolutely — that's an ongoing discussion about excluding babies who die. This was retrospective, so consent from bereaved parents is complicated but not impossible. In our experience, many bereaved families want ways to honor their babies or help future families in similar situations. I think we do bereaved families a disservice by not approaching them for research — many would say yes. We know there are benefits to holding we can't always quantify — what if we could measure them here? It might have strengthened the findings, and it raises the question of the value of these interventions even when a baby may not survive.

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Ben Courchia, MD (51:37.536): This is a paper on probiotics, published in Pediatric Research: "Live Biotherapeutic Product IBP-9414 (Limosilactobacillus reuteri) in Very Low Birth Weight Infants — the Connection Study." First author Josef Neu, second author Teresa Del Moral, with Cammy Martin and Mark Hudak also on it — big names.

Quick plug — our friend Jen Canvasser is organizing the NEC (Necrotizing Enterocolitis) Family Summit, September 1–4, 2026 in Davis, California, focused on involving families in building a world without NEC. Registration and info at necsociety.org.

This paper picks up on the ongoing probiotics conversation — since probiotics left the US market, we've seen increased NEC rates. Following confirmed cases of bacterial translocation with probiotic use, North American health authorities issued warnings about probiotic-induced sepsis. Unlike probiotics, LBPs (Live Biotherapeutic Products) are developed under regulatory oversight requiring rigorous trials and manufacturing controls to document safety, efficacy, and purity before marketing approval — a legal distinction more than a quality one. The probiotics we used before were regulated as foods or supplements, meaning nobody had to verify the label matched what was actually in the packet, or that it was made to pharmaceutical standards.

LBP status is the consequence of the FDA (Food and Drug Administration) now regulating probiotics as biologics — requiring an IND (Investigational New Drug application) just to study them in humans, a marketing license, full genomic characterization of the strain, antibiotic susceptibility profiling, a defined cell bank, and a validated potency assay. This is the pathway for probiotics to come back in the US, strain by strain. IBP-9414 contains live Limosilactobacillus reuteri (formerly Lactobacillus reuteri). This is a prospective, randomized, placebo-controlled Phase 3 trial comparing IBP-9414 with placebo in very low birth weight infants — the Connection Study — multicenter, double-blind, conducted under US IND and EU clinical trial exemption oversight across 10 countries. Primary outcomes: reduction in NEC incidence and time to SFT (Sustained Feeding Tolerance). Secondary outcomes included all-cause mortality. Eligibility: birth weight 500–1500 grams, gestational age 23–32 weeks, age ≤48 hours at enrollment. The first 300 infants had birth weights 750–1000 grams; after a pre-planned safety evaluation, enrollment broadened to include smaller babies (500–749 grams), then infants 1000–1500 grams, capped at 10% of the study population.

Enrolled infants received a single daily enteral dose of 1×10⁹ colony-forming units of powdered IBP-9414 (or sterile water placebo) within 48 hours of birth, continuing until 34 weeks 6 days postmenstrual age. The trial closed at 2,158 randomized infants — a large study, one-to-one randomization, blinded to investigators and staff, with safety assessments at 300, 600, and 1,400 participants, and an independent DMC (Data Monitoring Committee) reviewing unblinded data for safety and futility.

NEC diagnosis required either: independent evaluation of abdominal radiographs (by two blinded radiologists, with a third resolving disagreements) showing pneumatosis intestinalis and/or portal venous gas, or direct documentation of intestinal necrosis at laparotomy. SFT was defined as the first day of a 10-day period with more than 120 mL/kg/day of enteral feeds without parenteral nutrition, and mean daily weight gain over 10 g/kg. Secondary endpoints included radiograph-confirmed NEC, surgery/autopsy-confirmed NEC, all-cause mortality, weight gain during weeks three to four, hospitalization duration, and days with feeding intolerance signs. A pre-specified sensitivity analysis excluded NEC events in the first 14 days, based on expected gut colonization time.

In total, 2,158 infants were randomized; 2,117 received at least one dose and comprised the modified intention-to-treat population. Baseline characteristics were well balanced — median birth weight 850g versus 860g, median gestational age 27 weeks in both groups. Infants were treated for a median of 49 days, receiving human milk on 95% of treatment days. Primary endpoint: NEC incidence (radiograph or surgery/autopsy confirmed) was 8.7% with probiotic versus 10.2% with placebo — not statistically significant (relative risk 0.85, 95% CI 0.66–1.11, p=0.24). The pre-specified sensitivity analysis focusing on events after 14 days showed a relative risk of 0.74 — again not significant (p=0.067), close though. Treatment effects diverged after 14 days on the Kaplan-Meier curve. NEC confirmed by surgery/autopsy — unequivocal histopathological confirmation — was 0.8% with probiotic versus 1.4% with placebo, not significant overall (relative risk 0.52, p=0.126), but after 14 days, relative risk dropped to 0.29 and was statistically significant. Subgroup analyses across birth weight, gestational age, sex, and delivery method showed similar results. Time to sustained feeding tolerance: 21 days (probiotic) versus 23 days (placebo) — not significant.

Mortality — a key secondary endpoint — was reduced: 6.2% with probiotic versus 8.5% with placebo, statistically significant (relative risk 0.73, 95% CI 0.5–0.98, p=0.036). The mortality advantage strengthened after 14 days (relative risk 0.5, p=0.007). Death attributed to NEC or intestinal perforation showed a relative risk of 0.53 overall (p=0.07), dropping to 0.39 after 14 days. Excluding infants dying in the first 14 days: all-cause mortality was 2.2% (probiotic) versus 4.2% (placebo); death by NEC or perforation was 0.5% versus 1.3% (p=0.05). In infants under 1,000 grams, results were consistent — relative risk of NEC 0.87, feeding tolerance 23 versus 24 days, and mortality 6.9% versus 9.3%, statistically significant.

In the discussion, the authors note a significant 27% reduction in all-cause mortality, representing a number needed to treat of about 44 — meaning widespread use could save over a thousand patients annually in the US alone. How do we reconcile improved NEC mortality with an unclear effect on NEC incidence itself? They found a large rate of discordance between the two radiology reports for each diagnosis — an interrater reliability kappa of 0.36, well below the generally accepted adequate threshold of 0.6 — suggesting many infants reported as having NEC may have been misdiagnosed, which would dilute the apparent treatment effect.

On the 14-day cutoff: the rationale was to accommodate the known delay in microbial gut colonization, similar to time-to-effect seen with other prophylactic treatments like vaccines or statins. On combining radiograph- and surgery-confirmed NEC into one primary endpoint: surgically confirmed cases are rarer, and there's no literature-based sample size guidance for that endpoint alone — 88% of NEC cases were diagnosed clinically, so the overall NEC analysis was heavily weighted by, and dependent on, the reliability of radiographic diagnosis, which was shown to be inconsistent. The stricter surgery/autopsy-confirmed endpoint pointed to a favorable treatment effect, especially after 14 days.

On safety: the active ingredient was not detected in any blood cultures during the study using standard hospital procedures. Conclusion: although primary endpoints didn't reach statistical significance, IBP-9414 resulted in a clinically relevant reduction in all-cause mortality and in surgically/autopsy-confirmed NEC, with similar safety profiles including sepsis risk between groups.

Daphna Yasova Barbeau, MD (1:14:47.917): Such an important paper, and the discussion was especially valuable given who wrote it.

Ben Courchia, MD (1:15:02.076): The discussion is often a marker of authors' courage — either dressing things up, or genuinely tackling the hard questions their data raises, which is what they did here.

Daphna Yasova Barbeau, MD (1:15:14.926): Agreed. It's interesting that the mortality reduction is broader than just NEC — the gut microbiome affects every organ system. I'm hopeful for more studies on other long-term comorbidities tied to probiotic use in these babies. Maybe this helps convince the FDA to approve a product for babies.

Ben Courchia, MD (1:15:23.416): I think that's exactly why this was designed the way it was, going through an IND — this might be the first probiotic FDA-approved in the US, and possibly our only option going forward.

Daphna Yasova Barbeau, MD (1:15:31.544): Some standardization isn't a bad thing — nobody's arguing we should go back to over-the-counter.

Ben Courchia, MD (1:15:50.916): Agreed, but it does take a long time, and in the meantime, some babies who'd benefit aren't getting it.

Daphna Yasova Barbeau, MD (1:16:10.703): Absolutely — that's the hardest part. Every case of NEC, you wonder, could probiotics have prevented this? Tough to sit with day to day. 

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Ben Courchia, MD (1:15:40.590):  Daphna has a highly anticipated paper for us.

Daphna Yasova Barbeau, MD (1:15:50.644): The title is "First-in-Human Pilot Study of Broadband Optical Spectroscopy as Noninvasive Surveillance for Necrotizing Enterocolitis," in the Journal of Pediatric Surgery — lead author Ashley Dodd, senior author Seth Goldstein. They wanted to see if BOS (Broadband Optical Spectroscopy) — a transcutaneous, non-invasive tool previously studied in a mouse model of NEC — could identify NEC in human babies. Some background: NIRS (Near-Infrared Spectroscopy) measures venous oxygen saturation, essentially the difference between oxygenated and deoxygenated blood, using a specific near-infrared wavelength. BOS is different — it uses a much broader spectrum, 350 to 2500 nanometers. You place a probe that emits light onto the tissue of interest — here, the abdomen, to look at the intestines beneath the skin — and it reflects back a light pattern, read by a spectrometer. That gives you reflectance differences across many wavelengths, rather than one, and potentially different tissue and disease states show different reflectance patterns — disease-specific chromophores, distinguishing say tissue hypoxia from tissue necrosis, rather than just oxygenation, which NIRS is limited to and can be confounded by perfusion, inflammation, or fluid like ascites.

They enrolled premature neonates, 36 weeks gestation or fewer, excluding babies with congenital heart disease or major abdominal wall defects like gastroschisis or omphalocele, and followed them through their NICU stay. NEC was defined as Bell stage two or three, with 24 hours of documented pneumatosis or portal venous gas on X-ray. They measured four abdominal quadrants — epigastric, right lower quadrant, suprapubic, left lower quadrant — plus the outer thigh as a non-visceral control, at each encounter. Each session took one to two minutes during routine nursing care, repeated two to three times weekly, or sooner with clinical concern.

This is a machine learning paper — they trained an algorithm to distinguish well babies from NEC babies. They acquired 11,570 scans total, with 196 scans from infants diagnosed with NEC — still a small proportion. Across the study, they screened 211 infants: 50 ineligible, 25 couldn't get consent, 40 parents declined, leaving just under 100 enrolled. Corrected gestational ages ranged 25 to 36 weeks, weights 600 grams to 3,380 grams. Parental consent rates were high, with few concerns about the apparatus, no observed patient harm, and no complaints from parents or nursing staff; voluntary withdrawal was available but never requested.

BOS measurements were highly reliable and consistent — the figures look like spaghetti plots, with normalized reflectance on the vertical axis and wavelength on the horizontal. One neonate without NEC, tracked over 10 weeks, showed a very consistent pattern across wavelengths. A second figure comparing multiple neonates without NEC, matched around 1.4–1.5 kilos, showed nearly identical patterns across babies at every wavelength.

They then compared abdominal versus thigh tissue reflectance, showing predictable, distinguishable patterns by tissue type. Then: normal versus abnormal bowel. Ten infants developed NEC over the study, with an additional four having spontaneous intestinal perforation or another intra-abdominal process — characterized by abdominal distension, pneumatosis, and bloody stools, with portal venous gas in some cases. All were managed with immediate feed holding and broad-spectrum antibiotics; two of the ten required laparotomy. They demonstrated detectable spectroscopy differences between infants with severe NEC and the same infant's non-NEC baseline — unaffected readings showed higher reflectance, especially in the 780–1650 nanometer range, with severe NEC cases showing a five-to-ten-percent drop in that range.

Using a partial least squares discriminant analysis, the area under the curve was very high — nearly 100% — indicating strong separation between NEC and non-NEC scans, with sensitivity of 100%, specificity of 94%, and negative predictive value of 100%. Positive predictive value was lower, about 24%. The authors describe the model as showing outstanding sensitivity, specificity, and negative predictive value, and conclude BOS shows promise as a useful, non-invasive tool in this population — detecting early color changes in affected bowel from ischemia, not just oxygenation, aided by the fact that babies' thin skin means less overlying fat or muscle interference.

Ben Courchia, MD (1:31:57.989): Walk us through the model training? I'm kidding.

Daphna Yasova Barbeau, MD (1:32:06.339): You'd know more about that than me. But it learned well, as described. They feel BOS gives more information than NIRS alone — safe, feasible, rapid point-of-care measurements you can track over time. Small study, but exciting, especially given the loss of probiotics and rising NEC rates — this could be another non-invasive, likely not-too-expensive tool. I say that without actually knowing the cost, but it looks like a small handheld device.

Ben Courchia, MD (1:32:19.407): You have no idea — have you seen the machine? It's actually bigger than you'd think. Let me show you — the handheld probe part is small, but the whole unit looks like something out of Ghostbusters.

Daphna Yasova Barbeau, MD (1:33:09.436): That's fair, but not bad — like the size of a projector plus a handheld ultrasound probe. Just check every baby, one-to-one. I love that. Thoughts?

Ben Courchia, MD (1:33:14.957): Not ready for prime time, but exciting. What you described — it's not a clear departure from the curve, more a dampening — but this is such an early paper, more will come, maybe even a nomogram eventually. That sensitivity/specificity table is very promising. And I like that this looks at bowel color itself, rather than something we're just repurposing. Where I really want this to help is the medical NEC cases — the dead-bowel or perforation cases aren't usually where we struggle diagnostically, but there's a whole in-between group where a more sensitive signal could really help.

Daphna Yasova Barbeau, MD (1:34:48.284): Right — will it end up looking like nomograms, or will babies serve as their own controls, tracking change over time for each individual? We'll see.

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Ben Courchia, MD (1:35:20.614): We're joined by a friend of the show, Dr. Dinushan Kaluarachchi from the University of Wisconsin. Dinushan, welcome back to the podcast.

Daphna Yasova Barbeau, MD (1:35:27.578): Good morning, happy to be here.

Dinushan Kaluarachchi (1:35:47.800): Thanks for having me. It's my pleasure.

Ben Courchia, MD (1:35:51.196): We have a lot to cover. You're behind three papers on the respiratory severity score — a letter in Pediatric Pulmonology, "Bronchopulmonary Dysplasia Definition Based on Respiratory Severity Score"; a comment in the Journal of Perinatology, "Respiratory Severity Score as a Predictor for Need for Tracheostomy in Infants with Severe Bronchopulmonary Dysplasia," first-authored by your son Nathan; and a brief communication, also in the Journal of Perinatology, "Respiratory Severity Score Patterns by Birth Gestational Age Among a Cohort of Extremely Preterm Infants." We won't cover all three fully on air, but let's dig into what they add. First — for people unfamiliar, what is the respiratory severity score, how do we calculate it, and what does it mark?

Dinushan Kaluarachchi (1:37:13.268): Great question. RSS (Respiratory Severity Score) is an illness severity score for respiratory disease in preterm infants — essentially MAP (Mean Airway Pressure) times FiO2 (Fraction of Inspired Oxygen). For example, MAP of 10 and FiO2 of 40% gives you 10 × 0.4 = 4. We've used this as a predictor for CPAP failure in the first hours after birth, and in some of our clinical trials. Looking at FiO2 alone only shows one part of the picture — MAP times FiO2 gives a fuller view of respiratory status.

Ben Courchia, MD (1:38:19.100): And it's something we do intuitively at the bedside — how much pressure and oxygen we're using to keep someone stable, always aiming for the lowest support needed. Can you give people a mental map of the range? It can go very low, near zero, or up into the teens.

Dinushan Kaluarachchi (1:38:44.955): If a baby's on room air, RSS is zero; the highest we saw in our dataset was 19.2 or so.

Ben Courchia, MD (1:38:47.025): So let's talk about the Journal of Perinatology brief communication, using data from the PROP (Prematurity and Respiratory Outcomes Program) cohort to identify RSS patterns for babies born between 23 and 29 weeks across 13 sites. Figure one shows RSS by completed postmenstrual age — increasing in the first two weeks of life, then gradually decreasing, consistent with respiratory morbidity being the leading cause of mortality in that early window. Anything to add?

Dinushan Kaluarachchi (1:41:34.513): The graphs look great in color, even if printed in black and white in the journal. The idea came from noticing that studies look at FiO2 patterns or respiratory support patterns separately, but that's only one side of the picture — we wanted a global view via RSS. The PROP cohort recorded respiratory settings every day at 12 noon — very standardized — which made it a great data source for calculating RSS trends. From there, we thought about applications: entry criteria for clinical trials, family counseling, predicting tracheostomy need, and defining a BPD (Bronchopulmonary Dysplasia) grading system based on RSS at 36 weeks.

Ben Courchia, MD (1:42:54.386): On that last point — you used RSS to define BPD, comparing against the Jensen criteria. An RSS of 0.25 or less as grade one, 0.26–0.64 as grade two, above 0.65 as grade three. Clever, since other definitions use FiO2 or indirect measures of mean airway pressure across support types. And moving into tracheostomy — after 40 weeks, RSS looks like a good predictor of tracheostomy need or even mortality risk. This feels valuable for family discussions — we often believe waiting another week will change things, but sometimes the safest choice is the right one. Have you started using RSS at Wisconsin, even individually?

Dinushan Kaluarachchi (1:45:00.446): To some extent — it's an objective marker, and looking at the trend week to week shows whether things are improving or worsening. We currently use the Nationwide trach tool as well, which is great but comprehensive, making it hard to use quickly at bedside.

Ben Courchia, MD (1:45:34.237): You need fifteen minutes in a room to score a baby with that tool.

Dinushan Kaluarachchi (1:45:40.353): Right — we're hoping to develop something simpler for bedside use, incorporating RSS alongside other factors, especially developmental scores. We've had some babies who should be in the tracheostomy conversation but land in the green zone on the Nationwide tool, which doesn't feel right.

Ben Courchia, MD (1:46:12.605): For people who don't know, the Nationwide tool sorts babies into green, yellow, red — red meaning high likelihood of needing a tracheostomy, yellow meaning the course could still evolve, green meaning low near-term risk.

Dinushan Kaluarachchi (1:46:30.938): Exactly. This is hypothesis-generating data for now, but we hope to incorporate these ideas, collaborate with other sites, run a more prospective study, and eventually validate a bedside score for clinical use.

Daphna Yasova Barbeau, MD (1:47:22.562): My question across all three papers — when are you introducing RSS to families? Is it a team-based decision process? How often do you reassess with the team and family around transitions of care for these babies?

Dinushan Kaluarachchi (1:47:58.625): Great question. We discuss it during rounds and in conversations with families and colleagues, but I'll admit we don't use it extensively yet in clinical care — still developmental. Where we do use it heavily is in a different setting: some of our aerosolized surfactant trials. With multiple sites using different CPAP ranges — some starting at 4 and capping at 6, others starting at 10 — we needed consistent entry criteria and CPAP-failure thresholds for administering surfactant. That's how we started using RSS in the AERO-05 aerosolized calfactant surfactant trial, with entry criteria of RSS 1.25 up to 2.4, and specific criteria for surfactant administration on CPAP failure. It has clinical value too, and people are starting to use it, even if not yet day to day for us.

Ben Courchia, MD (1:50:46.312): Let's talk about working with your son. A lot of us have teenagers, and the idea of a meaningful collaboration is appealing. How hard was it to get this from idea to publication?

Dinushan Kaluarachchi (1:51:18.507): It was great working with Nathan — he's a junior at Middleton High School, very interested in science, writes for the school newspaper. He'd worked with a colleague's daughter on a kids' science letter for Pediatric Research, breaking down a research article, and wanted to pursue his own project. I had an undergraduate student, Samuel, working with me at the time on a related paper — presented at PAS (Pediatric Academic Societies), not yet published — and Nathan wanted his own project. We used the already-collected PROP cohort data, worked closely with Patrick Peebles and our study statistician on the approach, had several meetings to discuss and write it up. Nathan presented at Midwest SPR (Society for Pediatric Research) in Chicago and at PAS. Research letters or brief communications are great mechanisms for undergrad or high school students, or even residents — a manageable extension of a PAS abstract rather than a huge undertaking. He learned a lot, as did Samuel, and it was a great experience collaborating with both.

Ben Courchia, MD (1:53:05.832): Samuel is second author on the paper — how was working with him?

Dinushan Kaluarachchi (1:53:12.596): He made me proud — a great kid, really engaged, hands-on throughout.

Ben Courchia, MD (1:53:27.294): For people with kids around thirteen to nineteen — would you recommend looking for parent-child collaboration opportunities on meaningful scientific work, assuming both parties are interested?

Dinushan Kaluarachchi (1:53:48.084): Definitely, if the child wants to. Nathan was very motivated. You can't hand them a huge, complex project — this was an easy concept to grasp: some babies have bad lung disease that eventually needs a tracheostomy, and we need better ways to identify those patients early. That made it approachable, and the data was already available, which made the project feasible.

Ben Courchia, MD (1:54:34.420): Right — solid, pre-collected data plus graspable concepts is the key combination for anyone hoping to follow in your footsteps. Daphna, any parting thoughts?

Daphna Yasova Barbeau, MD (1:55:23.344): I really appreciate you bringing this to us — I agree with Ben, it's such an interesting way to show our kids our world. Mine's younger than yours, but I try to involve her whenever I can — it helps her understand why we go to work or take call, and lets her explore things that may or may not turn out to interest her. My question about involving your kids — how was it received by the rest of your group, your collaborators?

Dinushan Kaluarachchi (1:56:18.762): They really liked it — they'd known Nathan since he was young. He also presented at a local meeting and a regional meeting, where people talked to him and asked questions without knowing he was my son, then came back to tell me how well he explained things and how much he clearly knew.

Ben Courchia, MD (1:57:17.117): Dinushan, thank you so much for coming on and discussing your papers and this collaboration with your son. You mentioned upcoming larger studies — want to tease those before we close?

Dinushan Kaluarachchi (1:57:38.060): Sure. Two trials. One I presented at the Delphi meeting a couple of years ago, now IRB and FDA IND approved, starting this fall — late surfactant mixed with budesonide for prevention of chronic lung disease. The other, TACO and SALSA — a prophylactic surfactant trial. We completed a single-center pilot in Jordan and are analyzing that data now, planning a US pilot next. The idea: in babies born 26 to 31 weeks, use an LMA (Laryngeal Mask Airway), a supraglottic airway device, instead of a face mask for resuscitation, then give a prophylactic dose of surfactant through that device once stabilized. The standard arm is mask resuscitation with selective surfactant, usual care.

Ben Courchia, MD (1:59:07.901): That's a topic we've touched on multiple times on the podcast — very interesting. Thank you again for making the time, and best of luck with the upcoming work.

Dinushan Kaluarachchi (1:59:21.504): Thank you very much.

Ben Courchia, MD (1:59:23.114): Bye.