A Gentler Way to Give Premature Babies Their First Breathing Medicine: What Happens Two Years Later?

What a follow-up study of the CaLI trial found when researchers checked in on babies who received surfactant through a soft tube instead of a breathing machine

Many babies born very early need a medicine called surfactant to help their lungs stay open. Researchers recently followed 147 of these babies for two years after they received that medicine in one of two different ways, to see whether the gentler method left them developing just as well — or even better — than the older approach. The results were reassuring, though not yet a clear final answer.

Why This Question Matters: A Difficult Trade-Off Parents and Doctors Have Long Faced

A 2026 follow-up study — the one this article is about — checked in on 147 of these babies at age two to see how they were developing.[1] To understand why that check-up mattered so much, it helps to know how doctors arrived at today's gentler way of giving surfactant in the first place. Babies born more than ten weeks early often cannot yet make enough of a natural substance called surfactant, which keeps the tiny air sacs in the lungs from collapsing with every breath. Without it, breathing becomes exhausting and dangerous, so doctors give these babies surfactant directly into their lungs soon after birth. For decades, the only way to do this was to place a breathing tube down the baby's throat and connect it to a ventilator — a machine that breathes for the baby. That approach works, but it comes with a well-known downside: babies who spend time on a ventilator, even briefly, are more likely to develop chronic lung disease of prematurity, also called bronchopulmonary dysplasia — a condition doctors now define by how much breathing support a baby still needs at around 36 weeks after conception, and which leaves the lungs stiff and underdeveloped for months or years after birth.[2] Starting in the 2010s, doctors in Europe began trying something different: threading a much thinner, softer tube through the baby's vocal cords while the baby kept breathing on their own with the help of a simple air-pressure device called CPAP, which holds the airway open without fully taking over breathing. This gentler technique, called less invasive surfactant administration, or LISA, let babies receive the medicine without ever needing a ventilator. A large 2021 review of the early evidence found that babies given surfactant this way were less likely to die or develop chronic lung disease than babies who received it the traditional way.[3] A major international study confirmed this benefit in a bigger group of babies, and when researchers checked back in on those children two years later, the ones who had received the gentler method needed fewer hospital visits for breathing problems, with no sign that the technique had harmed their development.[4][5] A German research group reported similar encouraging development scores in some of the earliest, most fragile babies who received the gentle technique, and doctors' professional societies later published shared guidelines spelling out exactly how the procedure should be performed safely from hospital to hospital.[6][7] What nobody had carefully tested, though, was whether the timing of another very common newborn medicine — caffeine, which is used to help premature babies breathe more regularly — made a difference when combined with this gentler surfactant technique. That is the question a group of California researchers set out to answer, and the study covered in this article is what they found two years after the babies in their study were born.

The Study: Following 147 Babies for Two Years

Researchers at three children's hospitals in California — Loma Linda University Children's Hospital, UC Irvine Medical Center, and Sharp Mary Birch Hospital for Women & Newborns in San Diego — enrolled 180 babies born between 24 and almost 30 weeks of pregnancy in a study called the CaLI trial (short for Caffeine and Less Invasive Surfactant Administration).[1] Every baby in the study received caffeine within the first two hours after birth. Half of the babies were then randomly assigned to receive surfactant through the gentle thin-tube method while staying on CPAP; the other half stayed on CPAP alone, without receiving surfactant right away (they could still receive it later if their doctors judged they needed it). The first results from this study, published a few years ago, showed that the thin-tube group needed a breathing tube less often in their first three days of life and had less chronic lung disease.[8] The study reported here went back to check on these same children when they turned two years old — an age when doctors can meaningfully test how a child is thinking, moving, seeing, and hearing. Trained evaluators, who did not know which treatment each child had originally received, assessed 147 of the 180 children (about 82%) using a detailed hands-on developmental test as well as a questionnaire that parents filled out about their child's skills.

What the Researchers Found

The main question was whether children who received the gentle thin-tube surfactant were less likely to have died or to show a significant delay in thinking, movement, vision, or hearing by age two. About 23 out of 100 children in the thin-tube group had died or shown such a delay, compared with about 33 out of 100 children in the CPAP-only group — a difference that looks meaningful on paper but was small enough, given the size of this study, that it could have happened by chance rather than being a true effect of the treatment. On detailed hands-on testing, children in the thin-tube group scored a few points higher, on average, on both thinking (cognitive) and movement (motor) skills than children in the other group, though again the difference was not large enough to rule out chance. No babies in the thin-tube group died, compared with four babies in the CPAP-only group — a striking difference, though the study was too small to say for certain that the treatment itself explains it. One result did stand out as a clear, statistically meaningful finding: on the parent-completed questionnaire, children who had received the thin-tube surfactant were more likely to score in the typical range for fine motor skills — things like using their hands and fingers — than children in the other group. Reassuringly, the study found no differences at all in how often either group of children needed breathing medicines, steroid treatments, or hospital stays for breathing problems after they went home, and no sign that the procedure itself — which does involve briefly looking into the baby's throat with a small instrument — caused any lasting harm.

What This Means for Families

If your baby needed surfactant and received it through this gentler thin-tube method alongside early caffeine, this study offers real reassurance: two years later, these children were, on every measure researchers looked at, doing at least as well as — and numerically often a bit better than — children who did not receive surfactant this way, with no evidence of harm from the procedure itself. What this study cannot yet tell any individual family is whether the gentle method definitely improves a child's long-term development, because the group studied was not large enough to prove that the encouraging trends were real and not chance. Families should also know that one of the more hopeful findings — better fine motor scores — came from a parent questionnaire rather than from the more detailed hands-on testing, which did not show a significant difference in the same skill area; researchers are honest that these two types of testing do not always agree, and that this particular result needs to be confirmed with more testing as these children grow. If your NICU team used this thin-tube approach with your baby, this research supports what many parents are hoping to hear: there is no evidence it caused any developmental setback, and there are promising, if not yet fully proven, signs of benefit.

What Researchers Are Working on Next

Because this study followed a relatively small group of babies from just three hospitals, the researchers themselves say a bigger, multi-hospital study is needed to find out for certain whether combining early caffeine with the gentle thin-tube surfactant method truly improves long-term development, or whether the encouraging numbers seen here were simply good luck in a small group. Researchers also want to understand why the parent questionnaire and the hands-on developmental test told slightly different stories about fine motor skills, and they plan to keep following these same children as they grow older, since some development-related questions cannot be fully answered until children reach school age. For now, this study adds an important, carefully checked piece to a growing body of evidence that the gentler way of giving premature babies their surfactant is, at the very least, just as safe for their development as the older method — and it does so using the same rigorous kind of two-year check-up that doctors first used decades ago to prove that caffeine itself — now one of the most common medicines given to premature babies — was both safe and helpful for the developing brain.[9][10]

References

  1. Dorner RA, Morales A, Banerji A, Uy C, Ines F, Finer N, Vaucher Y, Katheria AC. Two-Year Outcomes of Less Invasive Surfactant Administration Among Preterm Neonates: A Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open. 2026;9(3):e263852. doi:10.1001/jamanetworkopen.2026.3852 ↩
  2. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants: An Evidence-Based Approach. American Journal of Respiratory and Critical Care Medicine. 2019;200(6):751-759. doi:10.1164/rccm.201812-2348OC ↩
  3. Abdel-Latif ME, Davis PG, Wheeler KI, De Paoli AG, Dargaville PA. Surfactant Therapy via Thin Catheter in Preterm Infants With or At Risk of Respiratory Distress Syndrome. Cochrane Database of Systematic Reviews. 2021;(5):CD011672. doi:10.1002/14651858.CD011672.pub2 ↩
  4. 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 ↩
  5. Dargaville PA, Kamlin COF, Orsini F, et al. Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants. JAMA. 2023;330(11):1054-1063. doi:10.1001/jama.2023.15694 ↩
  6. Mehler K, Broer A, Roll C, et al. Developmental Outcome of Extremely Preterm Infants Is Improved After Less Invasive Surfactant Application: Developmental Outcome After LISA. Acta Paediatrica. 2021;110(3):818-825. doi:10.1111/apa.15565 ↩
  7. Reynolds P, Bustani P, Darby C, et al. Less-Invasive Surfactant Administration for Neonatal Respiratory Distress Syndrome: A Consensus Guideline. Neonatology. 2021;118(5):586-592. doi:10.1159/000518396 ↩
  8. Katheria A, Ines F, Banerji A, et al. Caffeine and Less Invasive Surfactant Administration for Respiratory Distress Syndrome of the Newborn. NEJM Evidence. 2023;2(12). doi:10.1056/EVIDoa2300183 ↩
  9. Schmidt B, Roberts RS, Davis P, et al; Caffeine for Apnea of Prematurity Trial Group. Caffeine Therapy for Apnea of Prematurity. New England Journal of Medicine. 2006;354(20):2112-2121. doi:10.1056/NEJMoa054065 ↩
  10. Schmidt B, Roberts RS, Davis P, et al. Long-Term Effects of Caffeine Therapy for Apnea of Prematurity. New England Journal of Medicine. 2007;357(19):1893-1902. doi:10.1056/NEJMoa073679 ↩