The molecular story begins with structure. Human hemoglobin is a tetrameric protein that makes up roughly 96 percent of the dry weight of a red blood cell, and it comes in developmentally staged varieties. Fetal hemoglobin, or HbF, is built from two alpha-globin and two gamma-globin chains, giving it the designation alpha-2-gamma-2. Adult hemoglobin, HbA, swaps the gamma chains for beta chains, producing alpha-2-beta-2. The difference sounds trivial, a matter of two protein subunits, but it fundamentally alters the molecule’s biophysical behavior. HbF binds oxygen more avidly than HbA, a property that allows fetal red blood cells to snatch oxygen from maternal blood across the placenta and deliver it to developing tissues at precisely the right level, neither starving the fetus nor flooding it with excess oxygen.

What makes this system even more striking is that the switch from fetal to adult hemoglobin production runs on an internal developmental clock. It proceeds on schedule whether the fetus remains in the womb or arrives months early into a neonatal intensive care unit. At term birth, HbF typically constitutes 70 to 90 percent of total hemoglobin, with most of the remainder being HbA. In the weeks and months after birth, that balance steadily shifts as the bone marrow ramps up adult hemoglobin synthesis. But for infants born extremely preterm, this transition unfolds in the alien environment of the NICU, punctuated by blood draws, illness, and often repeated transfusions of adult donor blood, and until now clinicians have had no validated reference intervals to tell them what a normal HbF percentage should look like at any given gestational age.

That gap matters because a growing body of research has linked fetal hemoglobin levels to the outcomes that define preterm survival. Observational studies have associated a low fraction of HbF with bronchopulmonary dysplasia, the chronic lung disease of prematurity, and with retinopathy of prematurity, the disordered eye vessel growth that can threaten the vision of very preterm infants. A 2026 analysis further reported that the fetal hemoglobin fraction correlates with the risk of complications of prematurity more broadly. The logic is biologically plausible: fetal red cells carry oxygen with different kinetics and may behave differently in the microvasculature, so the composition of a preterm infant’s blood could influence how oxygen-sensitive organs develop. Yet without reference intervals, an individual laboratory value could not be confidently classified as normal or abnormal.

The Utah-led team attacked the problem with a statistical strategy that has quietly been transforming laboratory medicine. Rather than recruiting a pristine cohort of healthy volunteers, which is nearly impossible in neonatology, the researchers mined deidentified clinical records and applied the refineR algorithm, a computational method designed to extract reference intervals from real-world laboratory data. The algorithm works by identifying the apparently healthy portion of a mixed distribution, mathematically separating the central body of routine results from the pathological tail contributed by sick patients. The same team had previously used refineR to establish improved reference intervals for circulating nucleated red blood cell counts in neonates, and the approach sidesteps the selection biases that plague conventional reference interval studies.

To build the fetal hemoglobin intervals, the investigators focused on non-transfused infants spanning 23 to 40 weeks of gestation, deliberately excluding babies whose red cell populations had been altered by donor blood. This exclusion is critical, because a transfusion of adult blood instantly dilutes a preterm infant’s HbF fraction and would contaminate any attempt to define the natural developmental curve. The retrospective, deidentified records review was approved by the Intermountain Health Institutional Review Board and the University of Utah Institutional Review Board with a waiver of informed consent, and the work was conducted in compliance with federal human subjects regulations including HIPAA. Collaboration with neonatal intensive care medical directors at McKay-Dee Hospital and Utah Valley Hospital enabled collection of HbF values across the participating sites.

The resulting reference intervals, presented as curves across the gestational age spectrum from 23 to 40 weeks, give clinicians for the first time a population-based expectation for what percentage of hemoglobin should be fetal at each stage of preterm development. The clinical implications ripple outward in several directions. A HbF percentage falling below the expected interval might flag an infant at elevated risk for the oxygen-dependent complications of prematurity, prompting intensified surveillance of the lungs or retina. Conversely, the intervals provide an essential denominator for the growing interest in fetal red cell-based therapies, including a multicenter Italian randomized trial now testing cord red blood cell transfusions for severe retinopathy in preterm neonates. Interpreting any such intervention requires knowing where the natural baseline lies.

The study also highlights how much diagnostic power is locked inside routine laboratory measurements that hospitals already collect. Modern blood gas analyzers and automated hematology instruments can quantify hemoglobin derivatives and fractions at the push of a button, generating streams of data that historically were used only for individual patient decisions. Computational tools like refineR convert that accumulated clinical exhaust into population-level knowledge, a pattern now being repeated across neonatal hematology. For a field in which enrolling thousands of healthy newborns into reference studies is ethically and practically untenable, data-driven interval estimation may be the only realistic path forward, and the fetal hemoglobin curves are among its most consequential products to date.

There remain important caveats and next steps. Reference intervals describe populations, not prognoses, and the authors are careful to frame their curves as a foundation rather than a finished diagnostic test. Whether a low HbF fraction is a cause of bronchopulmonary dysplasia or retinopathy of prematurity, a marker of shared underlying vulnerability, or something in between, will require prospective studies that track infants against these new intervals over time. The investigators note that inquiries regarding data access can be addressed to the corresponding author, and the statistical code is available upon written request, inviting replication and extension by other centers. Still, the conceptual shift is hard to overstate: a molecule long celebrated for its role in the placental oxygen handshake now has a quantitative yardstick spanning the entire preterm period.

For the roughly one in ten infants born preterm worldwide, the stakes of oxygen management could hardly be higher, and fetal hemoglobin sits at the center of that physiology. By defining what normal looks like from 23 to 40 weeks of gestation, the Utah team has converted a century-old biological insight into a usable clinical benchmark. The next chapter, testing whether HbF percentage can stratify risk, guide transfusion strategy, or measure the benefit of fetal-cell therapies, now has the reference frame it needs. In the quiet arithmetic of reference intervals, neonatal medicine may have gained one of its most valuable new vital signs.

Subject of Research: Reference intervals for fetal hemoglobin percentage in preterm and term neonates from 23 to 40 weeks of gestation

Article Title: Establishing reference intervals for fetal hemoglobin percentage from 23 to 40 weeks of gestation using refineR

Article References: Zeiler, B. B., Bahr, T. M., Doyle, K., Maxfield, R. E., Stone, E. F., Addams, J. L., Ohls, R. K., & Christensen, R. D. (2026). Establishing reference intervals for fetal hemoglobin percentage from 23 to 40 weeks of gestation using refineR. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02918-0

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02918-0

Keywords: fetal hemoglobin, HbF, preterm infants, reference intervals, refineR algorithm, neonatology, neonatal intensive care, bronchopulmonary dysplasia, retinopathy of prematurity, oxygen transport, hemoglobin switching, transfusion medicine

Tracheal intubation, the placement of a tube into the windpipe to secure an infant’s airway, is among the highest-stakes procedures performed on newborns. It requires a clinician to thread a tube through the vocal cords of a patient who may weigh less than a kilogram, often while that patient is critically ill. The procedure is known to carry a substantial burden of adverse events, including oxygen desaturation, bradycardia, and in rare but devastating cases, cardiac arrest. Because newborns have a predominantly parasympathetic cardiovascular system, their hearts are especially vulnerable to vagal stimulation, which can be triggered by laryngoscopy and airway manipulation, slowing the heart rate dangerously.

Atropine works by blocking acetylcholine receptors at the muscarinic sites of the heart, effectively dampening the vagal reflexes that can cause the heart to slow. The logic behind its use during intubation has been straightforward: if airway manipulation can provoke reflex bradycardia, and if severe bradycardia can cascade into cardiac arrest, then preemptively blunting that reflex should protect the infant. That reasoning, drawn largely from pediatric anesthesia and emergency medicine, has made atropine a standard component of premedication regimens in neonatal units around the world, alongside sedatives and, in some centers, neuromuscular blocking agents.

To test that assumption at scale, a team led by Taylor Sawyer of the University of Washington School of Medicine and including co-senior authors Elizabeth Foglia and Akira Nishisaki turned to the NEAR4NEOS registry, an international collaborative that prospectively collects standardized data on every intubation attempt at participating neonatal units. The researchers analyzed 13,085 neonatal tracheal intubations performed between 2014 and 2023, making this one of the largest datasets ever assembled to examine the safety of neonatal airway management. Atropine was administered in 8,189 of those procedures, or 62.6 percent, underscoring just how deeply entrenched the practice is.

The team used multivariable logistic regression to compare outcomes between intubations in which atropine was given and those in which it was not, adjusting for confounding factors such as patient characteristics and clinical context. The primary outcome was cardiac arrest during the procedure. The result was striking: atropine use was not associated with reduced odds of cardiac arrest, with an adjusted odds ratio of 0.52 and a confidence interval spanning from 0.25 to 1.09, a range that crosses the threshold of statistical significance. In other words, the data could not demonstrate that the drug prevents the very complication it is most often given to avert.

The secondary findings were equally revealing. Atropine did deliver on one of its promised effects: it was associated with substantially lower odds of severe bradycardia, with an adjusted odds ratio of 0.33, meaning the drug cut the risk of dangerous heart rate slowing by roughly two-thirds. But that cardiac benefit came with trade-offs. Infants who received atropine had higher odds of oxygen desaturation during the procedure, with an adjusted odds ratio of 1.35, and lower odds of success on the first intubation attempt, with an adjusted odds ratio of 0.76. First-attempt success matters enormously in neonatal care, because repeated attempts prolong airway manipulation, increase physiological stress, and compound the risk of harm.

The desaturation finding has a plausible physiological explanation. Atropine increases heart rate and cardiac output, which can accelerate the consumption of oxygen reserves in an infant whose lungs are being ventilated intermittently or not at all during the attempt. A faster heart rate in a tiny preterm baby may burn through the limited oxygen buffer more quickly, causing saturation levels to fall sooner. Meanwhile, the mechanism behind the reduced first-attempt success is less clear. It may reflect confounding by indication, since clinicians may reach for atropine in sicker, more fragile infants in whom intubation is intrinsically harder, or it may reflect a genuine drug-related effect that further research will need to disentangle.

The study arrives amid a growing body of evidence questioning routine atropine in neonates. A randomized clinical trial published in The Journal of Pediatrics in 2025 by Afifi, El-Naggar, Narvey and colleagues compared atropine with placebo for nonemergent neonatal intubation and found the drug offered no clear advantage, an accompanying commentary asking pointedly whether routine pre-intubation atropine does more harm than good. Earlier work in pediatric critical care, including studies by Jones and colleagues on more than three hundred critical care intubations, had likewise suggested that atropine’s effects on rhythm disturbances during intubation are more complicated than the simple reflex-blocking model implies, and that mortality benefits observed in some pediatric cohorts appeared unrelated to the drug’s influence on bradycardia.

For clinicians, the new findings do not amount to an immediate call to abandon atropine, but they do challenge the reflexive use of the drug in every neonatal intubation. The authors themselves conclude that the association between atropine and increased desaturation and lower first-attempt success warrants further study, and the observational design of the registry analysis means that unmeasured differences between patients who received the drug and those who did not could still influence the results. Randomized trials, such as the recent placebo-controlled study, will remain essential for establishing causation. In the meantime, the results give neonatologists something they have lacked: large-scale data suggesting that the most common cardiac premedication in the NICU may not prevent the worst outcome, and may carry costs of its own.

The broader significance of the study lies in what it says about how neonatal practice evolves. Many interventions in the NICU were adopted on physiological reasoning and small studies rather than rigorous outcome data, and the NEAR4NEOS registry has become a powerful instrument for auditing those practices across hundreds of thousands of recorded procedures. Previous reports from the same collaboration have shown that premedication with sedation and neuromuscular blockade is associated with fewer adverse events, that team stress correlates with complications, and that training level affects success rates. This latest analysis adds a crucial nuance to that picture, suggesting that the individual components of premedication regimens deserve scrutiny on their own terms. As the authors and their international collaborators continue to accumulate data, the question is shifting from whether atropine blunts a reflex, which it clearly does, to whether blunting that reflex, at the cost of faster desaturation and more attempts, actually serves the smallest patients best.

Subject of Research: Atropine use and adverse events during neonatal tracheal intubation

Article Title: Association of atropine use during neonatal intubation with cardiac arrest, severe bradycardia, and other adverse events: a report from NEAR4NEOS

Article References: Sawyer, T., Narvey, M., Tyler, M. D., Abou Mehrem, A., Iben, S., DeMartino, C., Tingay, D., Hodgson, K., Kim, J., Herrick, H., Unrau, J., Puia-Dumitrescu, M., Shay, R., DeMeo, S., Assaad, M.-A., O’Shea, J., Brajkovic, I., Quek, B. H., Glass, K., … DeMartino, C. (2026). Association of atropine use during neonatal intubation with cardiac arrest, severe bradycardia, and other adverse events: a report from NEAR4NEOS. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02916-2

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02916-2

Keywords: atropine, neonatal intubation, cardiac arrest, bradycardia, oxygen desaturation, NEAR4NEOS, premedication, neonatology, NICU, patient safety, Journal of Perinatology, registry study

The underlying biology is straightforward but consequential. Bilirubin is the yellow pigment produced when the heme portion of hemoglobin is catabolized, and every molecule of bilirubin generated corresponds to one molecule of carbon monoxide released as heme oxygenase does its work. In newborns, whose livers are still maturing and whose red cell lifespan is shorter than in older children and adults, any acceleration of red cell destruction can push bilirubin concentrations upward rapidly. When bilirubin crosses the blood-brain barrier in sufficient quantities, it can cause acute bilirubin encephalopathy and permanent kernicterus, a devastating outcome that modern screening and phototherapy are designed to prevent. Identifying hemolysis early therefore gives clinicians a chance to intervene before bilirubin levels reach neurotoxic territory.

The study at the center of the dispute, conducted by Burch and colleagues, compared the direct antiglobulin test, commonly known as the DAT or Coombs test, against end-tidal carbon monoxide corrected for ambient carbon monoxide, abbreviated ETCOc, across three threshold levels. The DAT has long been the traditional tool for flagging immune-mediated hemolysis, particularly in infants whose mothers have antibodies that cross the placenta and coat the fetal red cells. It detects antibody bound to the infant’s red blood cells, which is an indirect and imperfect proxy for whether red cells are actually being destroyed at an accelerated rate. Many infants with clinically significant hemolysis test negative, and many DAT-positive infants never develop problematic bilirubin elevations.

The performance numbers cited in the correspondence are striking. Schutzman endorses the Burch group’s finding that the DAT had a sensitivity of only 13 percent for identifying hemolysis as a neurotoxicity risk factor, meaning the vast majority of hemolyzing infants went undetected by the blood test. ETCOc, by contrast, achieved a sensitivity of 88 percent at a correction threshold of 2.1 parts per million. The logic of the breath test follows directly from heme catabolism: because carbon monoxide is exhaled in proportion to bilirubin production, measuring it in the terminal portion of the infant’s exhaled breath, after subtracting background carbon monoxide in the ambient air, provides a direct physiological readout of the rate of red cell destruction. The approach has been refined over decades, and nomograms establishing reference ranges for term and late-preterm infants, including work in Chinese newborn populations, have helped define what constitutes abnormal heme catabolism in the first days of life.

Where Schutzman parts company with the original study is in its conclusion that ETCOc screening would lead to overdiagnosis, overtreatment, and higher costs. He argues that this conclusion rests on prevalence-dependent quantities, specifically the rates of indicated testing and phototherapy observed in the study cohort, and that those rates cannot be generalized to routine screening. Although all nursery admissions were nominally eligible for the Burch study, the authors themselves acknowledged that their cohort was enriched with DAT-positive and hyperbilirubinemic infants. In other words, the sample was not representative of an ordinary well-baby nursery population, and any cost or treatment projections drawn from it inherit that bias.

The magnitude of the bias, as Schutzman lays it out, is considerable. The Burch cohort showed a phototherapy rate of 9 percent, which he notes is more than fourfold the 2.1 percent rate reported in the same eight-hospital network when an unselected population of 22,455 infants was examined in earlier work by Sarathy and colleagues. That earlier study, published in Pediatrics, examined bilirubin measurement and phototherapy use after the American Academy of Pediatrics issued its 2022 newborn hyperbilirubinemia guideline, providing a large benchmark for what phototherapy utilization actually looks like across a broad, unselected nursery population. A selective sample, Schutzman contends, simply cannot support conclusions about what would happen if ETCOc were adopted for routine or universal screening.

To make the counterpoint concrete, the correspondence points to the only study to date that evaluated a large, continuous cohort of all admissions to a well-baby nursery. That investigation, by Wells and colleagues and published in the Journal of Perinatology in 2025, examined end-tidal carbon monoxide monitoring for significant hemolysis in the routine management of newborn hyperbilirubinemia. Its findings ran in the opposite direction from the overdiagnosis concern: when ETCOc was used across an unselected population, it was associated with reductions in serum bilirubin sampling, in phototherapy use, and in readmissions. The mechanistic explanation is plausible. If a breath test reliably identifies which infants are truly hemolyzing, clinicians can reserve blood draws and treatment for those who need them, while confidently observing infants whose bilirubin production is normal, rather than reflexively testing and treating based on an insensitive proxy.

The correspondence also situates the debate within a broader effort to establish a definitive reference standard for neonatal hemolysis. A 2023 review by Christensen, Stevenson, Bhutani, and coauthors asked whether any test could serve as a gold standard for diagnosing and quantifying hemolysis in neonates and infants, highlighting the inherent difficulty of the problem. Hemolysis is a dynamic process, its rate changing hour by hour in the first days of life, and no single static measurement captures it perfectly. Earlier collaborative work by Bhutani, Maisels, Schutzman, and colleagues published in Acta Paediatrica in 2018 addressed the identification of risk for neonatal hemolysis directly, helping to frame ETCOc as a physiologically grounded candidate for that role. The current exchange is thus not an isolated squabble over a single study but part of a decade-long effort to replace indirect markers with a direct measure of heme catabolism.

What hangs on this methodological dispute is far from academic. Severe neonatal hyperbilirubinemia remains one of the most common reasons for newborn readmission, and kernicterus, while rare in well-resourced settings, is entirely preventable when at-risk infants are recognized in time. A screening strategy that misses nearly nine out of ten hemolyzing infants, as a 13 percent sensitivity implies, leaves a substantial reservoir of risk undetected, particularly among infants whose hemolysis is not immune-mediated and would never be flagged by a DAT. Conversely, an approach that indiscriminately expands testing and treatment burdens families and health systems. The correspondence argues that the evidence points toward the breath test as the more faithful instrument, and that fears of overtreatment rest on a biased sample rather than on data from the populations in which routine screening would actually be deployed.

For now, the field awaits the kind of large, unselected, prospective studies that both sides agree would settle the question. The correspondence itself declares no funding, and its author discloses only an unpaid advisory role with a company in the field, Capnia, Inc., alongside affiliations with Jefferson Einstein Philadelphia Hospital, Thomas Jefferson University Hospital, and Nemours Children’s Hospital Delaware. Whether ETCOc moves from research tool to standard nursery practice will depend on whether the reductions in blood sampling, phototherapy, and readmissions seen in the Wells cohort can be replicated at scale. But the core physiological insight at the heart of the debate, that every bilirubin molecule announces itself in a puff of exhaled carbon monoxide, continues to make the breath test a compelling candidate for catching the hemolyzing newborn before jaundice becomes dangerous.

Subject of Research: Comparison of the direct antiglobulin test and end-tidal carbon monoxide measurement for detecting hemolytic hyperbilirubinemia in newborns

Article Title: Hemolytic hyperbilirubinemia

Article References: Schutzman, D. L. (2026). Hemolytic hyperbilirubinemia. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02919-z

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02919-z

Keywords: neonatal jaundice, hyperbilirubinemia, hemolysis, end-tidal carbon monoxide, direct antiglobulin test, phototherapy, newborn screening, bilirubin, kernicterus, neonatology, Journal of Perinatology, diagnostic sensitivity

The rationale for the trial rests on a well-documented clinical problem. Infants with NOWS tend to lose more weight after birth than other newborns, and earlier work by the same research group mapped early weight-loss percentile curves in opioid-exposed infants, showing that excessive weight loss is common and can trigger additional medical interventions. Because withdrawal disrupts feeding behavior, some clinicians have wondered whether high-calorie formula, which delivers more energy per milliliter than standard formula, could help these babies maintain their weight and possibly recover faster. But the idea has never been firmly established, and concerns linger about whether concentrated feeds might cause gastrointestinal upset, alter stooling patterns, or interfere with breastfeeding, which multiple studies have linked to milder withdrawal courses and shorter treatment.

To test whether such a trial is even possible, the researchers designed a double-blind randomized pilot study conducted in Connecticut and registered as NCT04419857. Between December 2020 and August 2023, they enrolled infants less than 48 hours old who had been prenatally exposed to methadone or buprenorphine, the two medications most commonly used to treat opioid use disorder in pregnancy. The babies were at risk for excessive weight loss and were being cared for under the Eat, Sleep, Console model, a function-based approach to assessing and treating NOWS that has rapidly replaced older scoring systems in many hospitals since a major randomized trial in the New England Journal of Medicine in 2023 showed it shortened hospital stays and reduced the need for medication.

Eligible infants were randomized to receive either standard-calorie or high-calorie feeds, with the feeding approach kept blinded to families and clinical staff wherever possible. The primary outcomes were deliberately pragmatic, reflecting the purpose of a pilot study: the investigators wanted to know whether they could enroll enough families, whether the randomized feeding assignments were actually followed at the bedside, and whether families stayed in the study. Adherence was measured as the proportion of feeds that followed the assigned approach, and retention was tracked both during the birth hospitalization and for two weeks after discharge, a window in which follow-up of this population is notoriously difficult.

The feasibility results were mixed in ways that are informative for anyone planning a definitive trial. Of 65 eligible infants, 35, or 53.8 percent, were randomized, a rate the authors judged comparable to other feasibility trials in similar settings. Once enrolled, families and staff largely stuck to the protocol: 84 percent of all feeds during hospitalization adhered to the randomized feeding approach, suggesting that a high-calorie feeding strategy can be implemented reliably in a real-world nursery environment. In-hospital retention reached 71.4 percent, but the picture changed sharply after discharge, with only 28.6 percent of families retained at the 14-day follow-up point. That attrition, the authors note, mirrors broader literature on post-discharge follow-up among families affected by opioid use disorder and represents the single biggest obstacle to a full-scale efficacy trial.

On the exploratory clinical outcomes, the two groups looked remarkably similar. There were no significant differences between the standard-calorie and high-calorie groups in demographic characteristics, in the maximum percentage of weight loss from birth, in the length of hospital stay, or in the frequency of stooling. The weight-loss finding, with a p-value of 0.12, and the length-of-stay finding, with a p-value of 0.88, do not rule out effects in either direction, since a pilot study of 35 infants is not powered to detect differences; rather, they establish that neither outcome showed an obvious signal of harm or benefit that would demand immediate changes to practice. The stooling comparison, which addressed concerns that concentrated feeds might slow the gut, was similarly unremarkable at p equal to 0.59.

One exploratory result stood out. Infants in the high-calorie group were more frequently receiving breastmilk at the time of discharge, a difference that reached statistical significance at p equal to 0.04. The finding runs counter to a plausible worry: that introducing fortified or high-calorie formula early might displace breastfeeding and reduce a mother’s milk supply or her confidence in nursing. Prior observational studies, including work showing that breastmilk feeding is associated with shorter treatment courses in NOWS, and clinical protocols from the Academy of Breastfeeding Medicine supporting breastfeeding in the setting of stable maternal opioid agonist treatment, have made the preservation of breastfeeding a central goal of NOWS care. The pilot’s data, while exploratory and drawn from a small sample, suggest that early high-calorie supplementation did not appear to be negatively associated with breastfeeding in this cohort.

The study also contributes to a small but growing evidence base on formula composition for opioid-exposed newborns. An earlier randomized feasibility study by Bogen and colleagues tested standard versus high-calorie formula in methadone-exposed infants, and other trials have examined energy-enriched formula in infants recovering from congenital heart surgery, another population at high risk of growth failure. Meanwhile, a systematic review of milk feed osmolality has raised general questions about the tolerability of concentrated feeds in newborns, making controlled data in the NOWS population particularly valuable. The Yale-led trial adds the important element of randomization under the modern Eat, Sleep, Console care model, which changes the context in which feeding decisions influence pharmacologic treatment and length of stay.

The authors are careful about interpretation, and appropriately so. As a pilot study, its purpose was not to prove that high-calorie feeding works or fails, but to determine whether a definitive randomized trial is achievable and to identify the design features it would need. The enrollment and adherence figures suggest the answer is a qualified yes within the hospital, while the 28.6 percent post-discharge retention signals that any future trial should invest heavily in retention strategies, an area with an established methodological literature ranging from participant-centric contact approaches to systematic reviews of retention interventions in pediatric trials. The statistical framework also had to contend with missing data, a challenge the team addressed using established methods for inference under missingness.

For clinicians caring for the rising number of infants born with opioid exposure, the practical message is one of cautious reassurance rather than a change in practice. High-calorie feeds were delivered as intended in more than four out of five feeds, did not visibly worsen weight loss trajectories, stooling, or hospital stay, and were not associated with reduced breastfeeding at discharge. For researchers, the study maps the terrain for the next step: a larger, adequately powered randomized trial with robust post-discharge follow-up to determine whether enriched nutrition can meaningfully reduce excessive weight loss in NOWS without compromising the human-milk feeding that so much evidence suggests benefits these infants. Until such a trial is completed, feeding decisions for newborns in withdrawal will continue to rest on clinical judgment, family preference, and the growing but still incomplete evidence base this pilot study has helped to build.

Subject of Research: Feasibility of high-calorie versus standard feeding in newborns with Neonatal Opioid Withdrawal Syndrome managed with Eat, Sleep, Console

Article Title: Randomized pilot study comparing standard vs high-calorie feeding in infants with Neonatal Opioid Withdrawal Syndrome

Article References: Randomized pilot study comparing standard vs high-calorie feeding in infants with Neonatal Opioid Withdrawal Syndrome. (n.d.). https://doi.org/10.1038/s41372-026-02913-5

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02913-5

Keywords: Neonatal Opioid Withdrawal Syndrome, high-calorie formula, Eat Sleep Console, randomized pilot study, breastfeeding, neonatal weight loss, methadone exposure, buprenorphine exposure, neonatal nutrition, Journal of Perinatology, clinical trial feasibility, opioid use disorder in pregnancy

The trigger for the Italian commentary was an earlier article in the same journal, in which Womack-Martenson and colleagues reported on providers’ perceptions of neonatal back transport in the United States, documenting both how often it occurs and the barriers that clinicians encounter when organizing it. Bellini and his co-authors, Maurizio Gente, Francesca Catani, and Maria del Carmen Rodriguez Perez, responded by sharing insights drawn from Italy’s own experience, where neonatal transport services have been organized at a national level for years and where the practice of returning recovering infants to referring hospitals is formally embedded in regional care networks.

The numerical core of the Italian contribution comes from a recent nationwide survey conducted by the Neonatal Transport Study Group. That survey, published in the journal Children in 2025 under the title describing the organization and activities of neonatal emergency transport in Italy, revealed that approximately 8.5 percent of all neonatal transports in the country involve back transport. This figure aligns closely with the results of a previous national survey, published in the Italian Journal of Pediatrics in 2019, which reported a rate of 9.4 percent. The near-identical values across two survey waves, conducted years apart, suggest that the frequency of back transport in Italy has remained remarkably stable over time.

That stability, the authors argue, is itself informative. It indicates that back transport is not an occasional logistical exception but a consistent, structural component of regionalized neonatal care. In a system where the sickest infants are concentrated in high-level intensive care units regardless of where they are born, a predictable fraction of those infants will eventually be well enough to continue convalescence in a level two unit nearer their families. The Italian data suggest that this fraction hovers at roughly one in twelve of all neonatal transports, a proportion large enough to warrant dedicated planning, standardized protocols, and dedicated resources rather than ad hoc arrangements.

The technical logic of back transport rests on the same principles that govern emergency retrieval, only in reverse. A convalescing infant may still require respiratory support, monitored thermal care, enteral or parenteral nutrition, and continuous observation of vital signs during the journey. The transport environment, whether a specially equipped ambulance or another vehicle configured for neonatal care, must therefore replicate a meaningful subset of the intensive care unit’s capabilities. Teams must anticipate the physiological stresses of movement, including changes in ambient pressure and vibration, the difficulty of performing procedures in a confined space, and the need to secure airways, vascular access, and equipment against the forces of acceleration and braking. Although the infant is by definition stable enough to travel, the margin for error is narrow, and the organization of the transfer determines whether the journey is a routine step in recovery or an avoidable hazard.

Bellini and colleagues emphasize that these operational realities make standardized definitions and organizational policies essential. Without a shared, precise definition of what constitutes back transport, health systems cannot measure it accurately, compare their performance across regions, or plan capacity. The Italian study group has worked for years on exactly this problem, producing national recommendations for the organization of the neonatal emergency transport service, most recently in a second edition published by the Italian Society of Neonatology in 2021. Those recommendations formalize how transport teams are staffed, how vehicles are equipped, how communication between the sending and receiving units is managed, and how the specific needs of convalescing infants differ from those of infants being retrieved in emergencies.

The Italian context is particularly instructive because of the country’s deliberate regionalization of perinatal care. Over the past decades, Italy has concentrated the care of the smallest and sickest newborns in tertiary intensive care units while maintaining a network of level two units in community hospitals. Research by the same group, published in Acta Paediatrica in 2017, examined the impact of this regionalization on transporting neonatal patients back from intensive care units to referring level two units, finding that the structure of the regional network directly shapes how often and how smoothly these return journeys happen. In a well-regionalized system, back transport is the natural mechanism by which scarce intensive care beds are freed for new emergencies while infants reconnect with their local communities and families earlier in the recovery process.

The benefits of this model extend beyond bed management. Prolonged stays in distant tertiary centers impose well-recognized burdens on families, including travel costs, separation from siblings and support networks, and the psychological strain of having a newborn hospitalized far from home. Returning a convalescing infant to a nearby unit restores proximity at a stage when bonding, breastfeeding establishment, and family participation in care become central to long-term outcomes. At the same time, the referring hospital regains the opportunity to complete the care it initiated, reinforcing clinical continuity and keeping community-level neonatal skills sharp. Back transport, in this light, is not merely a reverse ambulance ride but a deliberate act of care coordination that closes the loop opened by the original emergency retrieval.

Yet the American study that prompted the Italian response highlights that the practice faces persistent barriers. Providers reported obstacles ranging from unclear criteria for when an infant is ready to travel, to difficulties arranging appropriate vehicles and staff, to ambiguities over which service is responsible for the journey. The Italian authors’ contribution is to show that such barriers are not inevitable. A system that treats back transport as an integral, measured, and governed component of neonatal care, with national recommendations, dedicated study groups tracking activity through repeated surveys, and explicit organizational policies, can sustain a stable back transport rate over many years. The consistency of the Italian figures, at 8.5 percent in the most recent survey against 9.4 percent in the earlier one, functions as indirect evidence that institutionalized processes produce predictable practice.

The broader message for the international neonatal community is that the full lifecycle of neonatal transport, from emergency retrieval to convalescent return, should be designed, measured, and resourced as a single continuum. As regionalized perinatal networks expand in many countries, the volume of back transport will grow in proportion, and systems that lack standardized definitions and policies will accumulate the same frictions documented among American providers. The Italian experience, distilled in this correspondence, suggests a practical template: define the activity precisely, survey it nationally on a recurring basis, embed it in formal recommendations, and treat the return journey as an essential link in the chain of care rather than an afterthought. For the infants concerned, the difference between an improvised transfer and a well-orchestrated one is measured in safety, comfort, and how soon they finally arrive home.

Subject of Research: Neonatal back transport of convalescing infants within regionalized perinatal care networks

Article Title: Neonatal transport for convalescing infants

Article References: Bellini, C., Gente, M., Catani, F., Rodriguez Perez, M. D. C., & on behalf of Neonatal Transport Study Group of the Italian Society of Neonatology (2026). Neonatal transport for convalescing infants. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02909-1

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02909-1

Keywords: neonatal transport, back transport, convalescing infants, neonatal intensive care, regionalized care, Italian Society of Neonatology, Journal of Perinatology, nationwide survey, health care organization, level two units, transport teams, perinatal networks

Craniosynostosis, the premature fusion of one or more fibrous joints between the bones of the skull, affects roughly one in every 2,000 to 2,500 births in its typical forms. Because the skull must expand rapidly to accommodate a growing brain, early suture fusion forces the cranium to grow in compensatory directions, producing characteristic head shapes and, in some cases, raised intracranial pressure. Most cases are classified as primary, arising from genetic or developmental factors intrinsic to the suture itself. Secondary craniosynostosis, by contrast, is triggered by external or systemic influences, including metabolic bone disease, hyperthyroidism, or conditions that alter the biomechanical environment of the growing skull. The pattern reported in the new study appears to belong to this second category, but with features the authors say have not been documented together before.

The study population was narrowly and deliberately defined. The researchers reviewed charts of infants born at their institution between January 2020 and May 2025, including only those delivered at 22 to 28 weeks of gestation who went on to develop severe BPD and ultimately required a tracheostomy. Severe BPD is the most disabling form of chronic lung disease of prematurity, generally defined by a profound ongoing need for respiratory support well beyond the neonatal period. These infants spend months on mechanical ventilation, often at pressures far exceeding those used for typical neonatal care. Ten patients met all inclusion criteria, a small number that reflects both the rarity of this degree of respiratory morbidity and the single-center design of the review.

The most eye-catching quantitative result concerned head growth. Using standardized preterm growth charts and electronic growth chart calculators, the team tracked each infant’s head circumference percentile over time and found that the greatest four-week rise averaged 43 plus or minus 14 percentile points. That surge in head growth significantly outpaced concurrent changes in weight and length percentiles, a dissociation the authors report with a P value of 0.0023. In practical terms, these infants’ heads were growing dramatically faster than the rest of their bodies, the reverse of the growth faltering more commonly seen in chronic lung disease. The researchers also calculated a weighted mean sustained positive end-expiratory pressure of 10.6 centimeters of water across the cohort, a figure that quantifies the substantial ventilatory forces these infants’ chests and, potentially, their cranial circulation were exposed to for months.

Imaging told the rest of the story. Three-dimensional reconstructions of computed tomography scans of the head and maxillofacial region, presented in the published figures, revealed suture closure patterns described as atypical, alongside visible thickening of the calvarial bone, the dome of the skull. Calvarial thickening is not a feature of ordinary primary craniosynostosis and suggests an active bone-forming response rather than a simple failure of suture patency. The combination of rapid head circumference acceleration, abnormal suture fusion, and thickened skull bone led the authors to propose a novel phenotype of secondary craniosynostosis specific to this population of ventilator-dependent, tracheostomized infants with severe BPD.

The study was not the first to hint at this connection. The authors build on a 2023 report in the Journal of Craniofacial Surgery that described a similar phenotype of calvarial thickening and increased rates of premature calvarial suture closure in children with chronic lung disease. An earlier 2009 study had also associated rapid head growth in children following tracheostomy tube placement, suggesting that the airway intervention itself, or the underlying respiratory failure that necessitates it, may be linked to altered cranial growth dynamics. The new work sharpens the picture by focusing on a homogeneous group of extremely premature infants and by quantifying both the growth acceleration and the ventilatory pressures involved.

Why might prolonged high-pressure ventilation reshape a growing skull? The authors point to several plausible mechanisms that remain to be tested. Positive end-expiratory pressure, the pressure maintained in the airways at the end of each breath to keep the lungs open, is known from decades of neonatal physiology research to influence cerebral hemodynamics. Studies dating back to the late 1980s documented changes in cerebral blood flow velocity when positive end-expiratory pressure was adjusted in preterm infants, and more recent work has shown that ventilation mode changes can affect cerebral oxygen saturation. Sustained elevations in intracranial venous pressure or altered pulsatile forces transmitted through the dura could, in theory, alter the mechanical signaling environment of cranial sutures, which are exquisitely sensitive to tension and compression during development. Chronic hypoxia and the inflammatory milieu of severe BPD may add further systemic influences on osteoblast activity in the skull vault.

The clinical implications are potentially significant for both monitoring and intervention. Head circumference is routinely measured in neonatal follow-up care, but an accelerating head growth curve in a ventilator-dependent infant might currently be attributed to catch-up growth or, in some cases, mistaken for hydrocephalus. The new findings suggest that clinicians caring for infants with severe BPD on prolonged high-pressure support should consider cranial imaging when head growth accelerates disproportionately, since early identification of suture fusion can inform decisions about surgical release. Traditional management of single-suture craniosynostosis, as reviewed in the neurosurgical literature, ranges from observation to endoscopic strip craniectomy or open cranial vault remodeling, and the optimal approach for these medically fragile infants with thickened, abnormally remodeling skulls is entirely uncharted territory.

The authors are careful about the limits of their evidence. Ten patients from a single center, identified retrospectively, cannot establish causation, and the study lacked a comparison group of ventilated infants without severe BPD or of preterm infants managed with lower ventilatory pressures. The researchers explicitly call for prospective studies to define ventilatory exposure thresholds, clarify the underlying mechanisms, and determine the neurologic and surgical implications of this phenotype. Data availability is constrained by privacy protections inherent to such a small, reidentifiable cohort, though deidentified data may be shared upon reasonable request with institutional review board approval. The study protocol was approved by the Orlando Health Institutional Review Board, and the authors declare no competing interests.

Even with those caveats, the report opens an unexpected window onto how the environment of intensive care may leave structural marks on the developing body. The skull of an extremely premature infant is a dynamic, pliable structure whose sutures normally remain open for years to allow brain growth; the idea that months of positive-pressure breathing could accelerate bone deposition and suture fusion adds intensive care itself to the list of forces that sculpt cranial development. For the growing population of technology-dependent children who survive extreme prematurity, the findings underscore the need for long-term craniofacial surveillance and for research that treats the ventilator not merely as a life-sustaining tool but as a physiological exposure with consequences that may extend to the skeleton. As the authors conclude, only carefully designed prospective studies can determine whether this novel phenotype represents a true complication of modern neonatal intensive care and what it will mean for the neurodevelopmental and surgical futures of the children it affects.

Subject of Research: Atypical secondary craniosynostosis in ventilator-dependent premature infants with severe bronchopulmonary dysplasia

Article Title: Are premature infants with severe bronchopulmonary dysplasia at increased risk for atypical craniosynostosis?

Article References: Martin, S. G., Matrone, C., Stephens, M., Queliz Pena, T., Schreck, M., Guerrero, R. A., Zimmerman, A., Elbabaa, S. K., Jafrani, R., & Golden, B. (2026). Are premature infants with severe bronchopulmonary dysplasia at increased risk for atypical craniosynostosis?. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02907-3

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02907-3

Keywords: craniosynostosis, bronchopulmonary dysplasia, premature infants, mechanical ventilation, positive end-expiratory pressure, tracheostomy, head circumference, calvarial thickening, neonatology, craniofacial surgery, Journal of Perinatology, retrospective study

The study, led by Chelsea Hartman and Jeffrey Perlman of Weill Cornell Medicine-NewYork-Presbyterian Hospital together with colleagues at Kilimanjaro Christian Medical Centre (KCMC) in Moshi, Tanzania, set out with what the team calls a SMART aim: to reduce the rate of neonatal hypothermia by 50 percent and to raise the mean delivery room temperature of newborns by 0.6 degrees Celsius. The investigators also set out to explore whether reducing hypothermia would translate into lower early neonatal mortality, defined as death within the first seven days of life. The results exceeded the temperature goal by a wide margin, while the mortality findings delivered a more sobering lesson about the limits of single-intervention quality improvement.

The scale of the baseline problem is striking. Before any intervention, the mean neonatal temperature in the delivery room was 35.9 degrees Celsius, with a standard deviation of 0.24 degrees, well below the World Health Organization’s recommended threshold of at least 36.5 degrees Celsius. Ninety-nine percent of the newborns studied were hypothermic at birth. Sixty-six percent fell into the mild category, with temperatures between 36.0 and 36.4 degrees Celsius, while a full 33 percent were moderately hypothermic, with temperatures between 32.0 and 35.9 degrees Celsius. In other words, essentially every vulnerable baby born at the facility was losing heat faster than it could be replaced, and one in three was cold enough to face clinically significant risk.

Neonatal hypothermia is not a benign inconvenience. Newborns, and especially preterm and low-birth-weight infants, have a large surface-area-to-mass ratio, thin insulating fat layers, and immature mechanisms for generating heat, so they lose warmth rapidly through evaporation of amniotic fluid, conduction, convection, and radiation. Prior research, including systematic reviews and large cohort studies from Europe, Brazil, and South Asia, has linked admission hypothermia in very preterm infants to increased mortality, respiratory distress, and other morbidities. Studies in East Africa have repeatedly documented high prevalence, and a five-year review at Tanzanian centers underscored how gestational age, birth weight, and fetal heart rate abnormalities interact with thermal stress to shape early survival.

To attack the problem, the team applied the Model for Improvement, a widely used quality improvement framework built around iterative Plan-Do-Study-Act (PDSA) cycles. The study population consisted of neonates weighing less than 2000 grams at birth, the group at highest risk of rapid heat loss. Three sequential PDSA cycles were implemented, each refining the approach based on real-time audit data. The core interventions comprised three elements: a hypothermia prevention care bundle, in-person in-service training for delivery room staff, and a systematic audit implementation to track whether the bundle was actually being delivered as intended.

The care bundle drew on established thermal protection practices promoted by the World Health Organization and supported by randomized evidence. These include thorough drying immediately after birth to halt evaporative heat loss, delaying bathing, ensuring skin-to-skin contact where feasible, and the use of occlusive wrapping, approaches that trials in resource-poor settings have shown can meaningfully reduce heat loss even for term infants. Plastic barriers and wraps have proven particularly effective for preterm babies, and immediate kangaroo mother care has been shown in a landmark randomized trial to improve survival of low-birth-weight infants. The Tanzanian team’s contribution was not a novel technology but the disciplined packaging, teaching, and auditing of these known practices in a busy delivery room.

The impact was immediate and sustained. From the very first PDSA cycle onward, statistical process control charts showed a centerline shift in the mean delivery room neonatal temperature, rising from 35.9 degrees Celsius to 36.8 degrees Celsius, a gain of nearly a full degree that comfortably surpassed the 0.6-degree target. Simultaneously, the incidence of hypothermia shifted to 5.7 percent, and critically, all remaining cases were mild. Moderate hypothermia, which had affected a third of newborns at baseline, was eliminated entirely. In quality improvement terms, the intervention did not merely nudge the system; it moved the process to a new, stable level of performance that persisted across subsequent cycles.

The mortality data, however, tell a more complicated story. Despite the near-elimination of hypothermia at birth, early neonatal mortality rates, tracked as deaths within seven days, remained unchanged, with a control chart centerline of 12.3 percent throughout the initiative. The authors are careful and candid about this finding: because overall neonatal mortality did not fall, they conclude that there is insufficient evidence to support a causal relationship between hypothermia and early mortality in this setting. This does not mean hypothermia is harmless; rather, it reflects the reality that early deaths in this population are driven by multiple overlapping factors, including extreme prematurity, low birth weight, intrapartum complications, and fetal heart rate abnormalities, and that correcting one risk factor in isolation may not shift a composite outcome dominated by other forces.

The study nonetheless carries important lessons for the global effort to reduce newborn deaths, which still claims roughly four million lives annually by earlier estimates, with the majority occurring in low- and middle-income countries. Quality improvement initiatives in Ethiopia, India, Malaysia, and elsewhere have reported similar successes in reducing admission hypothermia using bundles, standardization, and PDSA methodology, and a Cochrane systematic review has concluded that interventions to prevent hypothermia at birth in preterm and low-birth-weight infants are effective. The Tanzanian experience adds a rigorous, chart-based demonstration that near-complete elimination of delivery room hypothermia is achievable with training, a defined bundle, and continuous audit, without expensive equipment.

For clinicians and program designers, the message is twofold. First, thermal protection is a solvable problem: a combination of drying, wrapping, warming the delivery environment, and staff engagement can move a facility from universal hypothermia to near-universal normothermia within a single improvement cycle. Second, measuring what matters requires patience and honesty; the unchanged mortality centerline is a reminder that quality improvement must be embedded in broader strategies addressing the many determinants of newborn survival. The work, funded in part by Bloomberg Philanthropies and carried out by midwives and physicians at KCMC alongside their American collaborators, stands as a template for how disciplined, data-driven care redesign can deliver dramatic physiological gains for the most vulnerable newborns, even where the ultimate outcome depends on conquering challenges far beyond the delivery room thermometer.

Subject of Research: A quality improvement initiative to reduce neonatal hypothermia at birth in Tanzania

Article Title: Reducing rates of neonatal hypothermia at birth in Tanzania: a quality improvement initiative

Article References: Hartman, C., Ngowi, E., Ahn, E., Shayo, A., Peter, N., Cypriane, J., Mlay, P., Tiwari, P., & Perlman, J. (2026). Reducing rates of neonatal hypothermia at birth in Tanzania: a quality improvement initiative. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02904-6

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02904-6

Keywords: neonatal hypothermia, quality improvement, Tanzania, delivery room, PDSA cycles, newborn thermoregulation, low birth weight, preterm infants, care bundle, Kilimanjaro Christian Medical Centre, neonatal mortality, Journal of Perinatology

Darbepoetin is a long-acting analog of erythropoietin, the hormone that signals the bone marrow to manufacture red blood cells. In extremely low birth weight infants, who are born before they can mount a robust red cell response and who lose blood through frequent laboratory testing, randomized trials have shown that darbepoetin raises hematocrits and can reduce or even eliminate the need for red blood cell transfusions. That is a major clinical win, because transfusions in preterm infants have been linked in multiple studies to complications including retinopathy of prematurity and bronchopulmonary dysplasia. But erythropoiesis-stimulating agents come with a catch: they only work if the marrow has an adequate supply of iron to load into the hemoglobin of every new cell it produces. Without sufficient iron, the drug drives the production of red cells that are small, pale, and poorly equipped to carry oxygen.

The problem facing neonatologists is that assessing iron status in a premature infant is surprisingly difficult. Serum ferritin, the most commonly used storage iron marker in adults, is highly variable in neonates born before 29 weeks of gestation and does not correlate well with functional iron availability, as earlier work by the same group demonstrated. Inflammation, transfusions, and the normal physiology of early infancy all muddy the interpretation. What clinicians really want to know is not how much iron is stored somewhere in the body, but whether the erythron, the collective machinery of red cell production, is actually getting enough iron at this moment to build hemoglobin properly. That functional question is where reticulocyte-based measurements come in.

Reticulocytes are the immature red blood cells released by the bone marrow, and because they circulate for only a day or two before maturing, they offer a real-time snapshot of erythropoietic activity. One established metric, RET-He, measures the hemoglobin content of reticulocytes in picograms. A falling RET-He signals that newly produced cells are being under-filled with hemoglobin, a classic hallmark of iron-limited erythropoiesis. The Utah team tracked RET-He alongside reticulocyte counts in both darbepoetin-treated infants and placebo recipients, and the numbers they recovered are striking. Among placebo recipients, RET-He fell over the first week from 33.6 plus or minus 0.5 picograms to 27.4 plus or minus 0.2 picograms, a statistically significant decline with a p value below 0.001. Infants receiving darbepoetin fell even further, with the difference between groups reaching p below 0.0001.

At first glance, that pattern looks alarming: the drug seems to be driving infants into deeper iron deficiency. But the researchers identified something more nuanced, a reciprocal relationship between rising reticulocyte counts and falling RET-He. As darbepoetin accelerates the marrow’s output, the pool of available iron is distributed across a rapidly expanding population of new cells, so each reticulocyte carries less hemoglobin even if total iron delivery is adequate for the infant’s needs. This dilutional effect means that a low RET-He during stimulated erythropoiesis cannot be read the same way it would be in a stable patient. A single threshold value, applied without context, risks mislabeling infants as iron deficient when their iron supply is actually keeping pace with an unprecedented demand, or conversely missing true deficiency hidden behind a vigorous marrow response.

To resolve that ambiguity, the team turned to two novel erythrocyte parameters generated by modern hematology analyzers: Micro-R, which quantifies microcytosis, the proportion of red cells that are abnormally small, and HYPO-He, which quantifies hypochromia, the proportion of cells with reduced hemoglobin concentration. Unlike RET-He, which reflects the most recent cohort of cells leaving the marrow, these metrics survey the entire circulating red cell population and capture the structural fingerprints of iron-limited cell production over a longer window. Reference intervals for Micro-R and HYPO-He in newborn infants had previously been established by members of the same group using the refineR algorithm, giving the investigators a validated framework for interpreting the values they observed during darbepoetin therapy.

The central finding of the study emerged when the two measurement families were read together. Among darbepoetin recipients whose RET-He dropped below 25 picograms, a level that would traditionally raise concern for iron deficiency, the majority, 83 percent, had Micro-R and HYPO-He measurements indicating that they were in fact iron sufficient. In other words, most of the infants flagged by the conventional marker were not truly iron limited; their low reticulocyte hemoglobin content reflected the physiology of accelerated erythropoiesis rather than a genuine shortfall in iron supply. Only a minority showed the concordant microcytosis and hypochromia that would confirm real iron-restricted red cell production. This discordance is precisely why the authors advocate using traditional and novel red cell markers in combination rather than in isolation.

The clinical implications extend beyond the neonatal unit’s fascination with laboratory parameters. Iron deficiency in early life is not a benign laboratory curiosity; iron is essential for brain development, and studies have linked iron deficiency in extremely low birth weight infants to adverse neurodevelopmental outcomes at two years of age. Overtreating with iron, on the other hand, carries its own risks, including oxidative stress and potential toxicity in infants who cannot yet regulate absorption. A monitoring strategy that reliably distinguishes true iron deficiency from the benign dilution of hemoglobin across a surging reticulocyte population would allow clinicians to target supplementation precisely, giving iron to the infants who need it and avoiding unnecessary exposure in those who do not. As restrictive transfusion guidelines become more common and erythropoiesis-stimulating agents play a growing role in keeping preterm infants transfusion-free, the stakes of getting iron assessment right only increase.

The study was conducted as a retrospective, deidentified records review approved by the Intermountain Health Institutional Review Board with a waiver of informed consent, and it was performed in accordance with federal human subjects protections. The authors, including Natalie Bishara, Timothy M. Bahr, Anne Woodbury, Robert D. Christensen, and Robin K. Ohls, report no competing interests, and both the statistical code and the underlying data are available on reasonable request. Because the analysis drew on existing trial and clinical datasets rather than a prospective interventional design, the findings will need prospective validation before they change bedside practice, and the precise algorithm for integrating RET-He, Micro-R, and HYPO-He into a clinical decision rule remains to be defined.

Even so, the conceptual shift the paper describes is likely to resonate widely. For decades, iron sufficiency has been inferred from snapshots of storage or from single thresholds applied to dynamic systems. The Utah work shows that during accelerated erythropoiesis, the very condition in which accurate iron assessment matters most, the traditional markers move in ways that can mislead, and that the structural signatures written into circulating red cells by iron-limited production offer a corrective lens. If follow-up studies confirm the approach, neonatologists may soon monitor their tiniest patients not with a single number but with a coordinated panel that reads both the tempo of red cell production and the quality of the cells being produced, ensuring that every dose of darbepoetin is matched by the iron those infants need to build oxygen-carrying blood and to protect their developing brains.

Subject of Research: Iron sufficiency assessment in premature infants treated with darbepoetin using conventional and novel erythrocyte metrics

Article Title: Assessment of iron sufficiency in premature infants treated with darbepoetin using conventional and novel erythrocyte metrics

Article References: Bishara, N., Bahr, T. M., Woodbury, A., Christensen, R. D., & Ohls, R. K. (2026). Assessment of iron sufficiency in premature infants treated with darbepoetin using conventional and novel erythrocyte metrics. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02889-2

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02889-2

Keywords: darbepoetin, premature infants, iron deficiency, RET-He, Micro-R, HYPO-He, reticulocytes, erythropoiesis, neonatology, anemia, transfusion avoidance, extremely low birth weight

Bronchopulmonary dysplasia, commonly abbreviated as BPD, is one of the most common long-term complications of extreme prematurity. It develops when the immature lungs of very preterm infants are damaged by prolonged mechanical ventilation and oxygen exposure, leading to inflammation and impaired alveolar development. Infants with moderate to severe BPD often leave the neonatal intensive care unit still dependent on supplemental oxygen, and their ongoing respiratory management requires coordination among neonatologists, pediatric pulmonologists, primary care providers, and families. Previous national surveys of experts have documented striking variability in how institutions manage the discharge of these medically complex infants, from when pulmonology consultation occurs to what written instructions families receive.

That variability is precisely what the North Carolina team set out to eliminate. During the hospitalization, infants with BPD are managed by neonatologists, but once they go home, responsibility shifts to outpatient specialists, most importantly pediatric pulmonologists. If that transition is poorly coordinated, the medical team’s inconsistent care can lead to gaps in treatment, delayed follow-up, and adverse outcomes. The researchers reasoned that a comprehensive, standardized discharge framework could reduce this risk by ensuring that every infant leaving the unit with BPD receives the same core set of services before crossing the hospital’s threshold.

The centerpiece of the intervention is the SAFER Discharge Score, an acronym that packs five essential criteria into a memorable checklist. The S stands for seeing the patient, meaning that a pulmonology consultation must take place during the hospital admission itself. The A calls for an action plan, a written document provided to the family that includes emergency contact information so caregivers know exactly what to do if respiratory symptoms deteriorate. The F requires that pulmonology follow-up be scheduled before the infant is discharged, not left to happenstance after the family arrives home. The E represents education, ensuring that caregivers receive hands-on training in managing oxygen equipment. Finally, the R mandates a repeat chest radiograph prior to discharge, giving the care team an updated picture of the infant’s lung status at the moment they leave the hospital.

Each of the five elements earns one point, allowing the team to track discharge readiness as a simple numeric score. Behind the score lies a broader set of BPD Discharge Guidelines that articulate the full process, and the implementation followed the plan-do-study-act cycle methodology familiar from quality improvement work across medicine. The project leadership designed successive plan-do-study-act cycles to test and refine the guidelines, collected monthly data, and analyzed trends over time. According to the contributions statement in the paper, the project leads conceived the intervention, designed the improvement cycles, implemented the change, and analyzed the monthly data, while senior authors provided mentorship and verified the analytical methods. The study was deemed exempt from full institutional review board review because of its retrospective design and minimal risk to participants.

The results, drawn from infants discharged between January 2021 and December 2022, show a statistically significant process change. The mean SAFER Discharge Score climbed from 3.0 before the intervention to 3.9 afterward, on a scale that tops out at 5. That near-point improvement means the typical BPD discharge moved from covering roughly three of the five essential elements to covering nearly all of them. In practical terms, far more families now left the hospital with a written action plan and emergency contacts in hand, a scheduled pulmonology appointment on the calendar, documented training on their child’s oxygen equipment, and an up-to-date chest radiograph in the medical record.

Perhaps the most clinically meaningful finding concerns timing. Before the guidelines were implemented, infants with BPD waited an average of 42.7 days after neonatal intensive care unit discharge before their first outpatient pulmonology appointment. After the intervention, that interval fell to 25.1 days, a reduction of more than two weeks. For infants whose lungs remain fragile and whose families must watch for respiratory infections that can rapidly escalate into emergencies, closing that gap matters. Earlier specialist contact means earlier medication adjustments, faster troubleshooting of home oxygen needs, and a safety net that catches deterioration before it becomes a readmission.

The study also tracked when pulmonology consultation occurred relative to discharge, another key driver of coordination. Consulting the pulmonology team while the infant is still in the unit, rather than after discharge, allows the receiving specialist to know the patient before the first clinic visit and gives families a chance to meet the team who will follow their child long term. The key driver diagram published with the study maps these interlocking elements, showing how consultation timing, caregiver education, written action plans, follow-up scheduling, and radiographic assessment feed into the shared goal of a safe and reliable transition home.

The findings align with a growing body of guidance on post-prematurity respiratory disease. The American Thoracic Society’s clinical practice guideline on outpatient respiratory management of infants, children, and adolescents with post-prematurity respiratory disease, published in 2021, emphasized structured, interdisciplinary care for these patients. Other work has documented institutional variation in home oxygen use among preterm infants and surveyed national experts about discharge practices, revealing widespread inconsistency. Prior research on children with severe bronchopulmonary dysplasia who went home dependent on ventilators has underscored how much these families depend on careful planning and rapid access to specialist expertise. The North Carolina project translates those national recommendations into a concrete, auditable bedside process.

The broader significance of the study lies in its demonstration that even complex, high-stakes care transitions can be engineered for reliability. Quality improvement science has transformed outcomes in many corners of pediatrics, and the SAFER framework offers other neonatal units a replicable template: a short, memorable checklist tied to measurable discharge criteria, tracked over time and refined through iterative testing. The authors note that the data supporting their findings are available upon reasonable request from the corresponding author, and they declare no competing interests. As more centers adopt similar structured discharge frameworks, the hope is that the weeks of vulnerability between the neonatal intensive care unit and the first pulmonology appointment will shrink for every infant with bronchopulmonary dysplasia, giving these medically fragile babies and their families a safer passage from hospital to home.

Subject of Research: Discharge guidelines and quality improvement for preterm infants with bronchopulmonary dysplasia

Article Title: Creation & implementation of discharge guidelines for preterm infants with bronchopulmonary dysplasia

Article References: Stephenson, N., Lynch, S. K., Donnelly, L. F., & Stoudemire, W. (2026). Creation & implementation of discharge guidelines for preterm infants with bronchopulmonary dysplasia. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02725-7

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02725-7

Keywords: bronchopulmonary dysplasia, preterm infants, neonatal intensive care, discharge planning, SAFER Discharge Score, quality improvement, pediatric pulmonology, care transitions, home oxygen therapy, neonatology, Journal of Perinatology, patient safety

The clinical stakes are considerable. Infants with bronchopulmonary dysplasia face elevated risks of motor delay, cerebral palsy, cognitive impairment, language difficulties, and behavioral challenges that can persist well into school age. Their prolonged hospitalizations, often stretching across many months, are characterized by exposure to invasive procedures, sedating and sometimes neurotoxic medications, extended mechanical ventilation, and the sensory environment of an intensive care unit that bears little resemblance to the womb. Yet the same extended stay also represents an extended opportunity, a window in which structured developmental care, physical therapy, occupational therapy, and family-centered interventions can be woven into daily management. The question the research addresses is whether neonatal units are systematically seizing that opportunity or leaving developmental support to happenstance and individual clinician initiative.

Neurodevelopmental therapy in the neonatal setting encompasses a broad spectrum of practices. At its most structured, it includes standardized developmental assessments performed at regular intervals, referrals to physical and occupational therapists with neonatal expertise, individually calibrated positioning and handling strategies, oral feeding support that respects the infant’s respiratory limitations, and structured programs that prepare families to continue stimulation and therapy after discharge. At its least structured, it amounts to informal bedside advice delivered when staffing allows. The literature has long suggested that early, intensive developmental intervention can improve trajectories for high-risk infants, but translating that evidence into routine practice across a heterogeneous network of intensive care units has proven difficult, and the new study illuminates precisely where the translation breaks down.

A central theme emerging from the work is the striking variability in how units that care for infants with BPD organize their developmental services. Some centers embed dedicated neurodevelopmental teams within the neonatal intensive care environment, with therapists rounding alongside neonatologists and nurses and contributing directly to individualized care plans. Others rely on consultation models in which therapists evaluate infants but remain peripheral to daily medical decision-making. Still others provide developmental programming only in fragments, dependent on the availability of personnel and the priorities of individual attending physicians. This patchwork means that two infants with comparable degrees of lung disease, admitted to different units, may receive profoundly different developmental care purely as a function of where they happen to be born.

The technical details of why this variability matters are grounded in the neurobiology of the preterm brain. The third trimester of pregnancy, which extremely preterm infants spend largely in the intensive care unit, is a period of extraordinary cerebral organization: cortical folding, myelination, synaptogenesis, and the pruning of neural circuits all proceed at a pace unmatched at any later stage of life. Sensory experience during this period literally shapes the architecture of the developing nervous system. Painful procedures, prolonged prone positioning, excessive light and noise, and handling practices that disrupt sleep can disrupt these processes, while calibrated positive sensory input, skin-to-skin contact, and supported early feeding experiences can support them. Neurodevelopmental therapy is, in this sense, not an adjunct to intensive care but an integral component of protecting the brain while the lungs are being treated.

For infants with bronchopulmonary dysplasia specifically, the developmental challenge is compounded by respiratory physiology. Many of these infants remain on oxygen support for months, and their limited respiratory reserve constrains the energy available for the motor demands of feeding, reaching, and exploratory movement. Oral feeding, one of the most complex motor tasks the newborn brain must coordinate, becomes a delicate negotiation between nutritional needs and respiratory stability. Therapists with neonatal expertise are trained to titrate intervention intensity to the infant’s physiologic tolerance, monitoring desaturation events, heart rate patterns, and behavioral stress cues to ensure that therapy strengthens rather than exhausts the child. That level of specialization is precisely what the study identifies as unevenly distributed across the units caring for this population.

The research also directs attention to the institutional and systemic factors that determine whether neurodevelopmental services flourish or falter. Adequate therapist staffing ratios, dedicated funding for developmental programs, formal training pathways in neonatal therapy, and leadership that treats brain development as a quality metric alongside survival and growth all emerge as decisive variables. Units that have made developmental care a strategic priority tend to show more consistent assessment schedules, earlier therapy initiation, and stronger family engagement. Where such infrastructure is absent, even clinicians who are personally committed to developmental principles struggle to deliver them reliably. The implication is that improving outcomes for infants with BPD is not primarily a matter of individual clinician goodwill but of building systems in which developmental care is the default rather than the exception.

Families occupy a central position in this framework, and the study’s findings carry important implications for parents navigating prolonged intensive care stays. Parents of infants with BPD frequently report anxiety about their child’s future, and they are often the first to notice subtle delays in movement, feeding, or social engagement. Structured neurodevelopmental programs that involve parents as partners, teaching positioning strategies, coaching on developmental play, and preparing families for the transition home, convert the prolonged hospitalization into a period of skill-building for caregivers as well as infants. Equally important, standardized developmental follow-up after discharge allows the early signs of cerebral palsy, cognitive delay, or language impairment to be detected and addressed during the windows in which intervention is most effective, rather than at the point of school-entry failure.

The broader significance of this work lies in its reframing of what constitutes high-quality care for bronchopulmonary dysplasia. For much of the modern neonatal era, success in managing the disease was measured in survival, oxygen weaning, and growth velocity. Those metrics remain essential, but a growing body of long-term outcome research demonstrates that pulmonary health and neurodevelopmental health are inseparable in this population: children who escape severe lung disease can still carry substantial developmental burden, and developmental interventions delivered during the intensive care stay may influence outcomes that were once assumed to be fixed. By mapping the current landscape of neurodevelopmental therapy across units that care for these infants, the study provides a baseline against which progress can be measured and a pointed reminder that the lungs and the brain of the preterm infant must be treated as one patient, not two.

Looking forward, the research suggests concrete priorities for the neonatal community: standardizing developmental assessment protocols for infants with BPD, expanding access to therapists with neonatal subspecialty training, embedding developmental outcomes into unit-level quality improvement, and ensuring equitable delivery of services so that an infant’s developmental trajectory is not determined by geography or institutional circumstance. As the cohort of BPD survivors continues to grow, the neonatal intensive care unit is increasingly being judged not only by whether its smallest patients survive, but by how fully they thrive. Neurodevelopmental therapy, integrated deliberately and systematically into the care of infants with bronchopulmonary dysplasia, may prove to be one of the most powerful tools available for shifting that balance.

Subject of Research: Neurodevelopmental therapy practices in neonatal intensive care units caring for infants with bronchopulmonary dysplasia.

Article Title: Neurodevelopmental therapy in NICUs that care for infants with bronchopulmonary dysplasia

Article References: DeMauro, S. B., Burkhardt, M., Hanin, M., Miller, A. N., House, M., Ransom, M., DuPont, T., Lagoski, M., Wood, A., Brei, B. K., Brinker, K., Wittwer, C., Gibbs, K., & on behalf of the BPD Collaborative Neurodevelopment Group (2026). Neurodevelopmental therapy in NICUs that care for infants with bronchopulmonary dysplasia. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02891-8

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02891-8

Keywords: bronchopulmonary dysplasia, neonatal intensive care, neurodevelopmental therapy, preterm infants, developmental care, neonatology, infant brain development, occupational therapy, physical therapy, family-centered care, chronic lung disease of prematurity, developmental outcomes