A Hopeful Idea, Honestly Tested: Adding a Steroid to a Premature Baby's First Lung Treatment

What the large international PLUSS study found about budesonide mixed with surfactant for very premature babies

Babies born more than three months early often need help breathing, and many go on to develop a chronic lung condition called bronchopulmonary dysplasia, or BPD. Researchers hoped that adding a small dose of a common anti-inflammatory steroid, budesonide, to the lung medicine these babies already receive might protect their lungs without the risks that come from giving steroids throughout the body. A large, carefully designed study of more than a thousand babies, called PLUSS, tested this idea and found that adding the steroid did not make a meaningful difference — but it also did not cause new harm [1].

Why this question matters to families

When a baby is born extremely early — before 28 weeks of pregnancy — the lungs are among the least finished organs. With modern intensive care most of these babies survive, but more than half develop BPD, a condition in which the delicate, still-growing lung becomes inflamed and scarred so that it cannot do its job easily [2]. Children who have had BPD are more likely to struggle with breathing illnesses in early childhood, to need extra hospital visits, and to face challenges in development. Despite many advances in newborn care, the number of babies who develop BPD has stayed stubbornly high over the years, which is why doctors keep searching for new ways to prevent it [3]. Today, doctors judge how serious a baby's BPD is by how much breathing help the baby still needs at around the time they would have been due to be born — a more meaningful measure of the lungs' health than simply counting days on extra oxygen [4].

The problem with steroids

Steroids are powerful medicines that calm inflammation, and doctors have known for a long time that they can reduce lung damage in premature babies. The difficulty is that the way steroids have traditionally been given — as injections or by mouth, so the medicine travels through the whole body — can harm the developing brain. Careful reviews of many studies found that giving these whole-body steroids in the first days of life lowered lung disease but raised the risk of cerebral palsy, a movement disorder [5]. Because of that, doctors became cautious, generally reserving these steroids for later and only for the babies who clearly needed them [6].

To keep the helpful effect while avoiding the harm, researchers tried delivering the steroid straight into the lungs as a fine mist that the baby breathes in. One large study showed this reduced lung disease but raised a worrying hint that slightly more babies might die — a concern that did not go away when the children were followed up years later [7] [8]. That left an appealing alternative: mix a single small dose of steroid into surfactant, the slippery natural substance that premature lungs lack and that doctors already squirt directly into the windpipe in the first hours of life. The surfactant would carry the steroid exactly where it was needed and nowhere else.

The early signs of promise

This carrier idea was not pulled from thin air. A small pilot study and then a larger trial, both in sicker babies who were on breathing machines and needed a lot of extra oxygen, suggested that mixing budesonide into surfactant cut the combined risk of death or BPD by more than a third [9] [10]. Those results were encouraging enough that a few hospitals around the world began doing it routinely. But the studies were small and included only a narrow group of the sickest babies, so no one could be sure the benefit was real or that it would hold up across the wider range of premature babies that doctors actually care for. A bigger, more rigorous test was needed, and that test was PLUSS.

How the study worked

PLUSS was run in 21 newborn intensive care units across four countries — Australia, New Zealand, Singapore, and Canada — and enrolled 1,059 babies born before 28 weeks [1]. Each baby was assigned by chance, like flipping a coin, to receive either surfactant with budesonide mixed in, or surfactant alone. Neither the parents nor the doctors caring for the baby knew which one had been given, a method called "blinding" that keeps the comparison fair and prevents expectations from coloring the results. To make sure the findings would apply to as many babies as possible, the study did not limit itself to only the sickest infants; it included babies on gentle breathing support as well as those on breathing machines. The steroid dose was the same one used in the earlier promising trials, and it could be given through whichever gentle technique a unit normally used to deliver surfactant, including the modern thin-tube method [11].

The main thing the researchers measured was how many babies were alive and free of BPD at the point when a premature baby's lungs are formally assessed, around what would have been 36 weeks of pregnancy. Doctors judged BPD using an up-to-date method based on how much breathing help a baby still needs at that age [4].

What they found

The answer was clear and a little disappointing: adding the steroid did not help. About 26 out of every 100 babies who got the steroid–surfactant mixture were alive and free of BPD, compared with about 23 out of every 100 who got surfactant alone — a difference small enough that it could easily be due to chance [1]. The two pieces of that result, how many babies survived and how many of the survivors had BPD, each pointed the same way: no meaningful difference. Tellingly, babies who received the steroid were no less likely to need whole-body steroids later on, which is one of the main things the gentler approach was supposed to avoid [1].

The study also looked carefully at other important outcomes — serious bleeding in the brain, a serious eye condition of prematurity, bloodstream infections, a dangerous bowel condition, and problems with a heart blood vessel — and found no real differences between the two groups. The length of time on a breathing machine and the length of the hospital stay were essentially the same [1].

The reassuring part

Even though the steroid did not help, the study delivered genuinely good news on safety. Babies who received budesonide did not have more of the serious problems doctors worry about with steroids. A temporary rise in blood sugar was slightly more common but not clearly so, and serious bowel injury was no more frequent [1]. Most importantly, there was none of the troubling increase in deaths that had appeared with the breathed-in steroid approach, suggesting that delivering the medicine this particular way does not carry that danger [8].

What this means for your baby

If your baby is in the NICU, the practical takeaway is this: a hopeful idea was put to a fair and thorough test, and on average it did not improve lung outcomes, so most doctors will not add budesonide to surfactant as a routine prevention step [1]. This does not mean steroids have no place in your baby's care. Doctors still use them thoughtfully and selectively for babies whose lungs are not improving, weighing the benefits and risks for each individual child rather than giving the medicine to every baby [6]. A study that finds "no benefit" is not a failure — it protects future babies from a treatment that does not work and frees the medical team to focus on approaches that do. It is also worth knowing that this kind of large, blinded, randomized study is the most reliable way medicine has to tell whether a treatment truly helps. Earlier, smaller studies had suggested the steroid mixture worked, and it would have been easy to keep using it on that basis; PLUSS shows the value of testing hopeful ideas thoroughly before they become routine. If you ever feel uncertain about a decision in your baby's care, asking the team to walk you through the evidence behind it is always reasonable, and a good NICU team will welcome the conversation.

What researchers are working on next

The PLUSS team is not finished. They plan to follow these children as they grow to see whether any difference in development or breathing appears later in childhood, the way longer-term follow-up turned out to be crucial for the breathed-in steroid studies [8]. Researchers are also asking whether a small group of the very sickest babies might still benefit, since those were the babies in the earlier hopeful trials [10]. And the gentle, thin-tube method of getting medicine into a premature baby's lungs that PLUSS used so widely is now a proven delivery system, ready to carry better treatments once researchers find them [11]. The search for a safe way to protect these fragile lungs goes on, now guided by one more large, honest piece of evidence.

References

  1. Manley BJ, Kamlin COF, Donath SM, et al; for the PLUSS Trial Investigators. Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial. JAMA. 2024;332(22):1889–1899. doi:10.1001/jama.2024.17380 ↩
  2. Thébaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019;5(1):78. doi:10.1038/s41572-019-0127-7 ↩
  3. Stoll BJ, Hansen NI, Bell EF, et al. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 2015;314(10):1039–1051. doi:10.1001/jama.2015.10244 ↩
  4. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751–759. doi:10.1164/rccm.201812-2348OC ↩
  5. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021;10:CD001146. doi:10.1002/14651858.CD001146.pub6 ↩
  6. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021;11:CD001145. doi:10.1002/14651858.CD001145.pub5 ↩
  7. Bassler D, Plavka R, Shinwell ES, et al. Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia. N Engl J Med. 2015;373(16):1497–1506. doi:10.1056/NEJMoa1501917 ↩
  8. Bassler D, Shinwell ES, Hallman M, et al. Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia. N Engl J Med. 2018;378(2):148–157. doi:10.1056/NEJMoa1708831 ↩
  9. Yeh TF, Lin HC, Chang CH, et al. Early Intratracheal Instillation of Budesonide Using Surfactant as a Vehicle to Prevent Chronic Lung Disease in Preterm Infants: A Pilot Study. Pediatrics. 2008;121(5):e1310–e1318. doi:10.1542/peds.2007-1973 ↩
  10. Yeh TF, Chen CM, Wu SY, et al. Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016;193(1):86–95. doi:10.1164/rccm.201505-0861OC ↩
  11. Dargaville PA, Kamlin COF, Orsini F, et al. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA. 2021;326(24):2478–2487. doi:10.1001/jama.2021.21892 ↩