Inhaled Nitric Oxide Fails to Show Clear Survival Benefit in Preterm Babies with Respiratory Failure

One of the most stubborn questions in neonatal intensive care has just been put under the microscope again, and the answer is unlikely to satisfy anyone hoping for a simple verdict. A systematic review and meta-analysis published in Pediatric Research by Jorge Luis Alvarado-Socarras, Delia E. Theurel-Martín and Edgar Fabián Manrique-Hernández of the Hospital Internacional de Colombia and Fundación Cardiovascular de Colombia examined whether inhaled nitric oxide, a gas-based therapy that has transformed the care of full-term newborns with failing lungs, actually saves lives when given to the smallest and most fragile patients: preterm infants born at 34 weeks of gestation or earlier who develop early hypoxemic respiratory failure. The team’s conclusion, drawn from nearly two decades of published evidence, is that the survival benefit of this therapy in this population remains unproven at the population level.

Inhaled nitric oxide works through an elegant piece of human physiology. Nitric oxide is a naturally produced signaling molecule that relaxes the smooth muscle lining blood vessels. When delivered through a ventilator circuit into the lungs, it acts as a selective pulmonary vasodilator, opening up the tiny vessels of the lung’s circulation precisely where air is reaching, and thereby redirecting blood toward regions that can actually exchange oxygen and carbon dioxide. In term and near-term newborns with hypoxemic respiratory failure driven by persistent pulmonary hypertension, a condition in which the lung vessels remain constricted and blood bypasses the lungs through fetal shunts, this mechanism produces dramatic improvements in oxygenation and has been shown in randomized trials to reduce the need for extracorporeal membrane oxygenation and to lower mortality. That success earned the drug its regulatory approval and made it a cornerstone of neonatal intensive care for mature infants.

Preterm infants, however, are a fundamentally different physiological challenge. In babies born at or before 34 weeks, severe hypoxemia rarely stems from a single, reversible vascular problem. Their lungs are structurally immature, often underdeveloped, and frequently damaged by the very treatments that keep them alive, including mechanical ventilation and oxygen exposure. Pulmonary hypertension in these infants can arise from multiple distinct mechanisms: maladaptation of the pulmonary vasculature, hypoplastic lungs caused by conditions such as oligohydramnios and prolonged rupture of membranes, or the evolving vascular remodeling that precedes bronchopulmonary dysplasia, the chronic lung disease of prematurity. Because the underlying biology is so heterogeneous, a therapy that dilates vessels may help some infants dramatically while doing nothing, or even harm, in others. This biological complexity is precisely why the evidence for inhaled nitric oxide in preterm babies has been inconsistent for more than two decades, with large randomized trials and individual-patient-data meta-analyses failing to demonstrate a survival advantage.

To bring clarity to this contested field, the Colombian research team conducted a systematic review following the PRISMA 2020 reporting guidelines, searching the major biomedical databases for studies published up to October 11, 2025. They included both observational studies and clinical trials that reported mortality among preterm infants with early hypoxemic respiratory failure treated with inhaled nitric oxide. Nineteen studies met the criteria for the qualitative synthesis, and six of them, encompassing a total of 556 infants, provided data suitable for quantitative pooling in a random-effects meta-analysis. The methodological quality of the included studies ranged from poor to good, and the authors were candid about the limitations, which centered on confounding, the persistent problem that sicker babies are more likely to receive the drug, and on statistical heterogeneity across studies.

The headline result was stark in its uncertainty. When the six pooled studies were combined, infants treated with inhaled nitric oxide showed no statistically significant reduction in mortality compared with those receiving standard care. The pooled relative risk was 0.65, with a 95 percent confidence interval spanning 0.29 to 1.48, an interval that comfortably includes the possibility of no effect at all, and even cannot exclude a substantial increase in risk. The I-squared statistic of 55.7 percent indicated moderate heterogeneity, meaning the individual studies disagreed with one another to a degree that complicates any single summary estimate. Importantly, the authors noted that infants who received the drug were more severely ill at baseline, a classic confounding by indication that biases observational comparisons against the treatment and makes the true effect even harder to pin down.

Yet the review’s most clinically valuable contribution may lie beyond the pooled mortality figure. The authors found that a positive oxygenation response, meaning a measurable improvement in blood oxygen levels after starting the gas, was associated with improved outcomes. In other words, the babies who respond to the drug are the babies who tend to do better, which reframes the question from whether the therapy works to which infants it works for. The magnitude and value of that response varied systematically by several clinical characteristics: gestational age, the timing of pulmonary hypertension onset, whether the diagnosis was confirmed by echocardiography, and the severity of the hypoxemia itself. These variables effectively define phenotypes, distinct clinical subgroups within the broad category of preterm respiratory failure, and the evidence suggests that treatment effect is not uniform across them.

This phenotype-driven framing aligns with a broader movement in neonatology toward precision medicine for premature lung disease. Recent work on the pulmonary vascular phenotypes of prematurity has argued that lumping all hypoxemic preterm infants together in trials guarantees diluted, uninterpretable results, because the population mixes infants whose pulmonary hypertension is transient and reversible with those whose lung disease is structural and irreversible. It also echoes findings from studies of specific subgroups, such as infants with pulmonary hypoplasia following extreme preterm premature rupture of membranes, where early functional echocardiography has been used to identify candidates likely to benefit from the therapy. A recent masked randomized controlled trial of early inhaled nitric oxide in extremely preterm infants with pulmonary hypertension, published in 2025, further underscores that the field is actively testing selective strategies rather than universal ones.

The practical implications for intensive care units are significant. In many countries, inhaled nitric oxide is expensive, requires specialized delivery equipment and monitoring, and carries known risks, including potential effects on bleeding and platelet function, which are particular concerns in fragile preterm infants vulnerable to intraventricular hemorrhage. If the therapy does not reduce mortality across the board in this population, then routine or reflexive use cannot be justified on survival grounds alone, and clinicians must weigh the costs and risks against the possibility of benefit in carefully selected patients. The review’s authors explicitly argue for a selective, phenotype-driven approach rather than routine administration to all preterm infants with hypoxemic respiratory failure, a position that is likely to inform upcoming updates to clinical guidelines, including the European consensus guidelines on the management of respiratory distress syndrome.

What the review cannot do, and the authors are careful to acknowledge this, is settle the question definitively. The evidence base remains thin: only 556 infants entered the quantitative synthesis, the studies were largely observational, and the quality limitations related to confounding and heterogeneity mean the confidence interval is wide enough to accommodate clinically meaningful benefit or harm. The authors call for well-designed randomized trials in this high-risk population, ideally ones that stratify enrollment by the very characteristics their analysis identified as effect modifiers, such as echocardiographically confirmed pulmonary hypertension and early versus late onset of disease. Until such trials are completed, the pooled estimate of a 35 percent relative reduction in risk that fails to reach statistical significance should be read not as proof of futility, but as a signal that any benefit, if it exists, is confined to identifiable subgroups.

For the families of the roughly one in ten babies born preterm worldwide, the message is one of cautious realism rather than despair. Inhaled nitric oxide remains a powerful and appropriate tool for term and near-term newborns with pulmonary hypertension, and it may still have a role for selected preterm infants whose physiology matches the responder profile. What this meticulous synthesis makes clear is that the era of one-size-fits-all rescue therapy for the smallest patients is ending, replaced by a harder but more honest question: not whether the drug works, but for whom, when, and how clinicians can tell the difference at the bedside before the first dose is given.

Subject of Research: Effectiveness of inhaled nitric oxide for reducing mortality in preterm newborns with early hypoxemic respiratory failure

Article Title: Impact on mortality of inhaled nitric oxide in newborns ≤34 weeks with early hypoxemic respiratory failure: systematic review and meta-analysis

Article References: Alvarado-Socarras, J. L., Theurel-Martín, D. E., & Manrique-Hernández, E. F. (2026). Impact on mortality of inhaled nitric oxide in newborns ≤34 weeks with early hypoxemic respiratory failure: systematic review and meta-analysis. Pediatric Research. https://doi.org/10.1038/s41390-026-05564-6

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05564-6

Keywords: inhaled nitric oxide, preterm infants, hypoxemic respiratory failure, pulmonary hypertension, neonatology, systematic review, meta-analysis, mortality, bronchopulmonary dysplasia, oxygenation response, gestational age, precision medicine