A Breathing Gas for the Tiniest Lungs: What the Evidence Really Shows

How researchers combined 31 studies to ask whether inhaled nitric oxide helps premature babies with serious breathing problems

Inhaled nitric oxide is a gas that widens the blood vessels in the lungs, and it can be given to newborns through their breathing support to help oxygen move more easily from the lungs into the blood. In 2025, a team of researchers gathered together 31 separate studies — involving more than 20,000 premature babies — to answer a long-standing question: does this gas actually help babies born too early who have severe breathing trouble? Their careful pooling of all the evidence found that the gas modestly reduced the chance of a serious chronic lung condition, but did not clearly help babies survive, and came with a small increase in an eye condition of prematurity [1]. This article explains what that means for families.

Why This Question Matters

Babies born many weeks early often arrive before their lungs are ready. The lungs may lack a natural substance that keeps the air sacs open, the blood vessels in the lungs may be underdeveloped, and the whole system can struggle to deliver enough oxygen. When this happens, babies need help — from extra oxygen, from machines that support their breathing, and sometimes from medicines aimed at the lungs. One of the most feared complications is a chronic lung disease called bronchopulmonary dysplasia, usually shortened to BPD. A baby is generally said to have BPD if they still need oxygen or breathing support at what would have been 36 weeks of pregnancy [1]. BPD can mean a longer hospital stay, going home on oxygen, more trips back to hospital, and breathing difficulties that last into childhood. Anything that might reduce the chance of BPD is therefore of enormous interest to families and doctors alike.

The Puzzle Doctors Have Faced for Years

Here is the frustrating part of this story, and understanding it helps make sense of why this research was needed. Inhaled nitric oxide has been a genuine success for full-term newborns. In babies born at or near their due date who have dangerously high pressure in the lung blood vessels, the gas can be close to life-saving, and health authorities in the United States formally approved it for babies born after 34 weeks [2]. It seemed natural to hope it would work the same way for smaller, more premature babies. But when researchers tested it, the benefits were far less clear. The lungs of a very premature baby are simply a different situation from the lungs of a full-term baby. By 2011, an expert panel in the United States had reviewed the evidence and advised against using the gas routinely in premature babies, because the studies did not convincingly show it helped them survive or breathe better in the long run [3]. A major review reached a similar cautious conclusion, finding no clear survival benefit and only a hint of help with lung disease in certain babies [4]. Yet in practice, when a premature baby is struggling to get enough oxygen and nothing else is working, many doctors still try the gas as a rescue treatment. That gap — between official caution and everyday practice — is exactly what the new research set out to examine.

How the Study Was Done

Rather than run a single new experiment, the researchers did what is called a systematic review and meta-analysis. In plain terms, they searched the world's medical databases thoroughly, gathered every suitable study on the question, and then used statistics to combine the results into one larger, more reliable picture. They found 31 studies that fit their criteria: 20 were randomised controlled trials — the gold-standard type of study, where babies are assigned by chance to receive the treatment or not, so the two groups are fairly compared — and 11 were observational studies that followed babies who did or did not receive the gas in ordinary care [1]. Altogether these studies included 20,080 premature babies, most of them born at or before 34 weeks. Because randomised trials give the most trustworthy answers, the researchers paid particular attention to what those trials alone showed, and they rated the strength of the evidence for each finding using a recognised grading system [5].

What They Found

The most encouraging result concerned chronic lung disease. When the researchers looked only at the randomised trials, babies who received the gas were somewhat less likely to develop BPD — roughly a nine per cent reduction in the risk, a result the team judged to be of reasonably solid quality [1]. When they combined death and BPD into a single measure, the gas again came out modestly ahead. But — and this is an important "but" for families to understand — the gas did not reduce the chance of a baby dying. Survival was the same whether or not babies received it. So the apparent benefit came entirely from fewer cases of lung disease among the babies who lived, not from saving more lives. This is a meaningful distinction: the gas should be thought of as possibly helping the lungs, not as a treatment that keeps babies alive.

The researchers also confirmed something doctors see at the bedside: shortly after the gas is started, oxygen levels in the blood tend to rise. Babies given the gas were much more likely to show a clear jump in their oxygen within half an hour [1]. Encouragingly, one longer-term sign also favoured the gas — babies who had received it were a little less likely to still need extra oxygen at one year of age. A more recent review focusing on babies with severe breathing failure reached broadly similar conclusions about lung disease [6], though a wider review of all the strategies used to prevent BPD did not single the gas out as one of the clearly effective ones [7].

What About Safety?

For the most part the news on safety was reassuring. The gas did not increase bleeding in the lungs, air leaks from the lungs, bleeding in the brain, a serious bowel condition, or several other complications of prematurity [1]. Two findings deserve mention. Babies who received the gas had a slightly higher rate of retinopathy of prematurity, an eye condition common in very premature babies — but only the milder forms; the severe kinds that need treatment were not more common. The most likely explanation is not the gas itself but the high levels of oxygen these very sick babies need, since the gas makes oxygen levels rise quickly. The researchers also noticed a very slightly smaller head size at one year in the gas group, but because tests of thinking, movement and vision showed no differences, they considered this of little importance. Longer follow-up studies of these babies have generally found no difference in development [8], and one study following children to five years of age found no effect on their development, while cautioning about survival [9].

What This Means for Families

If your baby is being considered for, or is receiving, inhaled nitric oxide, the honest summary is this: it may modestly lower the chance of chronic lung disease, it clearly helps oxygen levels in the short term, but it has not been shown to help babies survive, and it is being used in a way that goes beyond its official approval. Doctors weigh these trade-offs case by case. It is entirely reasonable to ask your baby's team why they are considering the gas, what they hope it will achieve, and how they will decide whether it is working. A thoughtful team will welcome those questions.

It also helps to understand why the answer is still not fully settled. When researchers looked at the observational studies, the results were muddier — largely because, in real life, the sickest babies are the ones most likely to be given the gas as a last resort, which can unfairly make the treatment look worse than it is [10]. This is one reason the randomised trials, which compare fairly, are trusted more. Registries confirm that the gas continues to be used in premature babies across many hospitals despite the uncertainty [11].

What Researchers Are Working On Next

The scientists behind this analysis are clear about what is still needed: large, carefully designed trials that test exactly when to start the gas, at what dose, and in which babies — especially the smallest and most premature — and that follow the children for years to check on their breathing and development [1]. Until those studies are done, inhaled nitric oxide remains a reasonable option for certain premature babies with severe breathing problems, chosen carefully rather than routinely. For families, the reassuring truth is that this is an area doctors are actively studying, precisely so that future babies can be given treatments that are known to help.

References

  1. Zhou K, Xu W, Li D, Lao C, Zou S, Liu S, Li B, Zeng F, Zhu S, Han S. Inhaled nitric oxide in preterm infants with respiratory disease: a systematic review and meta-analysis. Eur J Med Res. 2025;30(1):821. doi:10.1186/s40001-025-03008-1 ↩
  2. Kinsella JP, Steinhorn RH, Krishnan US, et al. Recommendations for the use of inhaled nitric oxide therapy in premature newborns with severe pulmonary hypertension. J Pediatr. 2016;170:312–4. doi:10.1016/j.jpeds.2015.11.050 ↩
  3. Cole FS, Alleyne C, Barks JD, et al. NIH consensus development conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. 2011;127:363–9. doi:10.1542/peds.2010-3507 ↩
  4. Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017. doi:10.1002/14651858.CD000509.pub5 ↩
  5. Higgins RD, Jobe AH, Koso-Thomas M, et al. Bronchopulmonary dysplasia: executive summary of a workshop. J Pediatr. 2018;197:300–8. doi:10.1016/j.jpeds.2018.01.043 ↩
  6. Feng Z, Wu X, Xu X, Cui Q, Wu F. Efficacy of inhaled nitric oxide in preterm infants ≤ 34 weeks: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2023;14:1268795. doi:10.3389/fphar.2023.1268795 ↩
  7. Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, et al. Interventions to prevent bronchopulmonary dysplasia in preterm neonates: an umbrella review of systematic reviews and meta-analyses. JAMA Pediatr. 2022;176:502–16. doi:10.1001/jamapediatrics.2021.6619 ↩
  8. Durrmeyer X, Hummler H, Sanchez-Luna M, et al. Two-year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants. Pediatrics. 2013;132:e695–703. doi:10.1542/peds.2013-0007 ↩
  9. Siljehav V, Gudmundsdottir A, Tjerkaski J, et al. Treating very preterm European infants with inhaled nitric oxide increased in-hospital mortality but did not affect neurodevelopment at 5 years of age. Acta Paediatr. 2024;113:461–70. doi:10.1111/apa.17075 ↩
  10. Gurram Venkata SKR, Lodha A, Hicks M, et al. Neurodevelopmental outcomes of preterm neonates receiving rescue inhaled nitric oxide in the first week of age: a cohort study. Arch Dis Child Fetal Neonatal Ed. 2024;109:211–6. doi:10.1136/archdischild-2023-325418 ↩
  11. Nelin L, Kinsella JP, Courtney SE, et al. Use of inhaled nitric oxide in preterm vs term/near-term neonates with pulmonary hypertension: results of the PaTTerN registry study. J Perinatol. 2022;42:14–8. doi:10.1038/s41372-021-01252-x ↩