A Promising Shortcut for Premature Lungs That Turned Out Not to Work

What the Budesonide in Babies (BiB) study found when it added a steroid to surfactant for the smallest newborns

Bronchopulmonary dysplasia, usually shortened to BPD, is a chronic lung condition that affects many of the most premature babies and can mean weeks or months of extra breathing support. A large United States study called the Budesonide in Babies (BiB) trial tested a hopeful idea: adding a steroid to the lung medicine these babies already receive, to prevent BPD. The clear answer was that it did not help — and it slightly raised blood sugar.

Why premature lungs need so much help

Babies born many weeks early face the world with lungs that were never meant to breathe air yet. The tiny air sacs where oxygen enters the blood are still forming, and the lungs are easily injured by the very things that keep these infants alive — extra oxygen, breathing machines, and inflammation. When that injury adds up, the result is BPD, a chronic lung disease diagnosed when a baby still needs oxygen or breathing support at the point that would have been about 36 weeks of pregnancy [1]. The medical definition doctors still use for this was agreed upon by an expert panel more than two decades ago [2]. BPD is not rare: as hospitals have become better at helping the smallest babies survive, more of them live long enough to develop it, and the overall rate has been stubbornly hard to lower [3]. Doctors also grade how severe it is, because the most severe form is the one most likely to lead to long hospital stays and later breathing and developmental problems [4].

The long, complicated history of steroids for baby lungs

For decades, doctors have known that steroids — medicines that calm inflammation — can reduce BPD. The problem has always been the price. When strong steroids are given through a vein in the first days or weeks of life, they can lower the risk of lung disease but raise the risk of serious harms, including problems with brain development and, in the earliest days, a dangerous tear in the intestine [5][6]. Faced with this trade-off, doctors spent years trying to find a safer way to use steroids: lower doses given over a short, tapering course, an approach tested in an international study known as DART (a low-dose dexamethasone regimen) that helped babies come off the ventilator without the worst side effects [7]; and gentler steroids such as hydrocortisone, tested in the SToP-BPD study (hydrocortisone for evolving lung disease) in the Netherlands and Belgium, which did not clearly reduce death or lung disease [8]. The whole history circles one question: how do you get the good the steroid does for the lungs without the harm it can do to the rest of the body?

A clever idea: send the steroid straight to the lungs

That question led to an elegant-sounding solution. Very premature babies who struggle to breathe are often given a medicine called surfactant — a natural substance that coats the inside of the lungs and keeps the air sacs from collapsing — delivered straight down the breathing tube into the lungs. What if you mixed a steroid, budesonide, into that surfactant? The steroid would ride along to exactly where the injury starts, and, the thinking went, very little would spill over into the rest of the body. Early research was encouraging. A small pilot study suggested the mixture was feasible and might reduce chronic lung disease [9], and a later study from a single region reported a real drop in death or BPD, which excited many doctors [10]. A related approach — breathing in budesonide as a mist — was tested in a large international trial called NEUROSIS (early inhaled budesonide) and did reduce BPD in survivors [11], but a later look at those same children found a worrying hint of higher deaths, which made everyone more cautious [12]. Then a big, practical trial called PLUSS (budesonide mixed with surfactant), run across 21 hospitals in Australia, New Zealand, Canada, and Singapore, tested the surfactant mixture and did not find a clear benefit [13]. The stage was set for a definitive test.

What the BiB study did

The Budesonide in Babies trial was that test, carried out at 17 hospitals in a major United States research network between 2021 and 2024 [1]. It enrolled babies born between 22 and 28 weeks of pregnancy, or weighing between about 400 and 1000 grams (roughly 14 to 35 ounces), who were already going to receive surfactant. By the flip of a coin — and with neither the family nor the medical team knowing which treatment a baby got — half received budesonide mixed into their surfactant and half received surfactant alone, given as one or two doses in the first two days of life. The main thing the researchers measured was whether a baby had BPD or had died by the 36-week mark. This kind of blinded, randomized study is the most reliable way to know whether a treatment truly works, because it removes hope and expectation from the equation.

The study was actually stopped earlier than planned, after 641 of an intended 1160 babies, because a scheduled check showed the treatment was very unlikely to help — a decision made to avoid giving an ineffective drug to more infants [1].

What they found

The results were strikingly clear. BPD or death happened in almost exactly the same share of babies in both groups: 68.5% with the steroid mixture and 67.9% with surfactant alone [1]. Looking separately at deaths, and at lung disease among the babies who survived, showed the same thing — no real difference. In plain terms, adding budesonide to surfactant made no measurable difference to whether these babies developed chronic lung disease or survived.

There was one difference, and it was not a good one. Babies who received budesonide were more likely to have high blood sugar (about 67% versus 50%) [1]. High blood sugar is usually manageable in the nursery, but it is a sign that the steroid was not staying neatly in the lungs after all — some of it was affecting the whole body, exactly the problem the approach was meant to avoid.

Because high blood sugar can be checked with the routine heel-stick tests premature babies already have and can be treated when needed, this side effect was not dangerous for most infants in the study. But it carried a clear message. The entire reason for mixing the steroid into surfactant was to keep it in the lungs and away from the rest of the body. The rise in blood sugar showed that this plan did not fully succeed — the medicine was reaching the bloodstream — which is part of why the approach ended up offering risk without reward.

What this means for families

If your baby is in the NICU, the practical takeaway is reassuring in its own way: doctors now have solid evidence that this particular add-on treatment does not help, so there is no reason to wish your baby had received it. Two large, careful studies in different parts of the world — PLUSS and BiB — reached the same conclusion, which gives doctors real confidence [13][1]. It is worth knowing that this finding applies to babies who receive surfactant; it does not tell us about babies managed with gentler breathing support who never need surfactant. And importantly, this does not mean nothing can be done about BPD. Proven supportive care — careful use of oxygen, breathing support that avoids injury, caffeine to help babies breathe, good nutrition, and preventing infection — continues to matter, and for some higher-risk babies, doctors still carefully weigh a course of steroids given the older way, tailored to that child.

It can be hard, as a parent, to hear that a treatment was tested and did not work; it is natural to wish researchers had found a cure. But studies like this one are exactly how medicine protects children. Every baby in the trial was watched closely, and the moment the evidence showed the treatment was not helping, the study was stopped so that no further infants would receive a medicine that added a side effect without any benefit. The knowledge gained now spares countless future babies from an unhelpful exposure and helps doctors concentrate on the supportive care that genuinely improves outcomes. If you have questions about your own baby's breathing support, your NICU team can walk you through the specific plan for your child, which is always tailored to how your baby is doing rather than to a one-size-fits-all rule.

What researchers are working on next

BiB does not end the search for ways to protect fragile lungs; it clears away a shortcut that turned out to be a dead end. Researchers are now focusing on figuring out which babies are at highest risk of severe BPD, so that treatments with real side effects can be aimed only at the infants most likely to benefit, and on finding new anti-inflammatory approaches that are not steroids at all. For a condition that has been so hard to prevent [4], knowing clearly what does not work is real progress — it protects babies from an unhelpful medicine and points scientists toward better answers. Sometimes an honest "no" is exactly what moves medicine forward.

References

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  2. Jobe AH, Bancalari E. Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–1729. doi:10.1164/ajrccm.163.7.2011060 ↩
  3. Stoll BJ, Hansen NI, Bell EF, et al; NICHD Neonatal Research Network. 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 ↩
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  8. Onland W, Cools F, Kroon A, et al; STOP-BPD Study Group. Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants (SToP-BPD). JAMA. 2019;321(4):354–363. doi:10.1001/jama.2018.21443 ↩
  9. Yeh TF, Lin HC, Chang CH, et al. Early intratracheal instillation of budesonide using surfactant as vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics. 2008;121(5):e1310–e1318. doi:10.1542/peds.2007-1973 ↩
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  11. Bassler D, Plavka R, Shinwell ES, et al; NEUROSIS Trial Group. Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia. N Engl J Med. 2015;373(16):1497–1506. doi:10.1056/NEJMoa1501917 ↩
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  13. Manley BJ, Kamlin COF, Donath SM, et al; 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 ↩