A Breath of Extra Oxygen: Helping the Tiniest Babies Through Their First Minutes

What a new study of oxygen during delayed cord clamping means for premature babies and their families (Katheria et al., JAMA Pediatrics 2025)

Being born months too early means a baby's lungs and body are not yet ready for the sudden switch from receiving oxygen through the placenta to breathing air. In those first fragile minutes, the medical team must provide just the right amount of oxygen: too little can be dangerous, but too much can also cause harm. A new study suggests that giving extra oxygen briefly, while the umbilical cord is still attached, helped more premature babies reach safe oxygen levels quickly, without signs of harm in the short term.

Why the first few minutes are so delicate

Inside the womb, a baby never breathes air. The placenta does the work of the lungs, passing oxygen from the mother's blood into the baby's. At birth, everything must change in seconds — the lungs have to fill with air, the blood flow through them has to open up, and the baby has to start breathing. For a baby born at, say, 24 weeks, none of these systems is fully built, so this transition often needs help. One of the tools doctors use is a gentle flow of air and oxygen through a small face mask, which supports the baby's breathing and helps the lungs open.

A second, more recent change in care is that teams now often wait about a minute before clamping and cutting the umbilical cord, a practice called delayed (or deferred) cord clamping. Leaving the cord attached a little longer lets more blood flow from the placenta into the baby, and careful reviews of many studies have found that this simple step is linked to a better chance of survival for premature babies [1]. So a modern delivery of a very premature baby increasingly looks like this: the baby stays connected to the placenta for a short while, receiving breathing support at the same time.

The oxygen puzzle, and how thinking has changed over the years

Oxygen sounds like it should always be good, but for a premature baby it is more complicated. For many years, guidelines told teams to start with only a small amount of oxygen — around 21% to 30%, not far from ordinary room air — because doctors worried that high oxygen could injure a baby whose body has very little natural defense against it [2]. That caution was well founded: oxygen produces harmful byproducts, and a tiny premature baby is especially vulnerable to that kind of stress [3]. Understandably, when researchers surveyed newborn doctors in 25 countries, most said they preferred to start with lower oxygen [4].

But the story did not end there. As more data came in, a large analysis that pooled individual results from many trials found something surprising — that starting resuscitation with high oxygen was actually linked to fewer deaths among babies born before 32 weeks, compared with starting low [5]. At the same time, researchers learned that the opposite problem — too little oxygen — is genuinely dangerous. When premature babies had low oxygen levels (below 80%) at five minutes of age, they were more likely to die or to suffer bleeding in the brain [6]. Doctors were caught between two real risks, without a clear answer about which way to lean, especially now that babies spend those first minutes still attached to the cord.

There was also a hidden catch in the biology. When a baby does not get enough oxygen, the low oxygen itself can make things worse: it can dampen the baby's own efforts to breathe and can even cause the voice box to close, which blocks air from reaching the lungs [7]. On the other hand, giving a bit more oxygen early has been shown to encourage premature babies to breathe more strongly [8]. This raised a clever possibility: what if giving high oxygen while the cord is still attached could rescue the baby from low oxygen — with the placenta acting like a natural safety valve to soak up any excess before it reaches the rest of the body?

What the researchers did

To test this idea, a team led by Dr. Anup Katheria ran a study they called the DOXIE trial (its full name is the Deferred Cord Clamping With Oxygen in Extremely Low Gestation Infants trial). It took place at three hospitals in California — including Sharp Mary Birch Hospital for Women & Newborns in San Diego, the University of California San Diego, and UC Davis Children's Hospital in Sacramento — between November 2021 and October 2024 [9]. The researchers enrolled 140 babies born very early, between 22 and 28 weeks of pregnancy. Every baby received the same gentle breathing support through a face mask for about 90 seconds while the cord stayed attached. The only difference was the oxygen: by the flip of a sealed envelope, half the babies received 100% oxygen and half received 30%.

This was a carefully designed experiment. To keep the results fair, the oxygen dial was hidden under a black cover, so neither the parents nor the bedside team knew which amount any baby was getting — a method called "blinding" that prevents expectations from coloring the results. Once the cord was clamped and cut, every baby was switched to the same 30% oxygen and adjusted from there as usual. The main question the team asked was simple: how many babies reached a safe oxygen level (80%) by five minutes of age?

What they found

The extra oxygen made a clear difference in that first goal. Among babies given 30% oxygen, 28 out of 72 (about 39%) reached a safe oxygen level by five minutes. Among those given 100% oxygen, 47 out of 68 (about 69%) did — nearly a 30% improvement [9]. In plain terms, giving high oxygen during those cord-attached minutes helped many more babies avoid dangerously low oxygen early on. Interestingly, the benefit was strongest for the slightly more mature babies (26 to 28 weeks) and was less clear for the very smallest ones, so the extra oxygen may not help every baby equally.

Just as important as the benefit was the question of safety, and here the news was reassuring. The babies who received high oxygen did not show signs of getting too much: measurements of oxygen in their blood and in their brain looked the same as in the low-oxygen group. Serious brain bleeds and deaths were similar between the two groups. Some longer-term problems of prematurity, such as chronic lung disease, even appeared somewhat less common in the high-oxygen group — though because this was a small study, those particular findings are best treated as hints for future research rather than firm conclusions.

What this means for families, and what comes next

If your baby is born very prematurely, it helps to know that the team's choices about oxygen and cord timing are the product of decades of careful study, and that researchers are still actively working to get them exactly right. This study is an encouraging early step: it suggests that a short burst of higher oxygen while the cord is attached can help fragile babies through a critical moment without obvious harm. It is worth understanding, though, what the study was and was not designed to prove. It was a "pilot" — a first, smaller trial meant to show that an idea is promising and safe enough to study further. It was not large enough to prove that this approach helps babies survive or grow up healthier.

That distinction matters because earlier trials taught caution. Three recent studies that added breathing support during delayed cord clamping — including one known as the ABC3 trial [10], another comparing keeping the placental circulation intact with gently squeezing the cord [11], and a third testing breathing help before the cord was clamped [12] — did not improve their main outcomes. The DOXIE researchers suspect the missing ingredient in those studies may have been oxygen itself. International guidelines have gradually shifted, too, from insisting on low oxygen toward accepting that starting at 30% or a bit higher is reasonable [13]. Doctors also point out a practical reason the timing is tricky: it can take many seconds for a change on the oxygen dial to actually reach the baby, so a baby who needs oxygen quickly may not get enough in time if the team starts low and slowly climbs [14].

For now, the honest and hopeful summary is this: a promising idea has passed its first real test, and the researchers themselves say the next step is a larger trial, following babies over a longer time, to find out whether this early boost of oxygen truly leads to healthier children. If your family faces a very early birth, these are good questions to ask your care team — not because there is a single right answer yet, but because the answer is actively being written, and your team can explain how they weigh these choices for your baby.

References

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  2. Duff JP, Topjian AA, Berg MD, et al. 2019 American Heart Association focused update on pediatric advanced life support. Circulation. 2019;140(24):e904–e914. doi:10.1161/CIR.0000000000000731 ↩
  3. Torres-Cuevas I, Parra-Llorca A, Sánchez-Illana A, et al. Oxygen and oxidative stress in the perinatal period. Redox Biol. 2017;12:674–681. doi:10.1016/j.redox.2017.03.011 ↩
  4. Oei JL, Ghadge A, Coates E, et al. Clinicians in 25 countries prefer to use lower levels of oxygen to resuscitate preterm infants at birth. Acta Paediatr. 2016;105(9):1061–1066. doi:10.1111/apa.13485 ↩
  5. Sotiropoulos JX, Oei JL, Schmölzer GM, et al. Initial oxygen concentration for the resuscitation of infants born at less than 32 weeks' gestation: a systematic review and individual participant data network meta-analysis. JAMA Pediatr. 2024;178(8):774–783. doi:10.1001/jamapediatrics.2024.1848 ↩
  6. Jiang S, Cui X, Katheria A, et al. Association between 5-minute oxygen saturation and neonatal death and intraventricular hemorrhage among extremely preterm infants. J Perinatol. 2024. doi:10.1038/s41372-024-02194-w ↩
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  9. Katheria AC, Ines F, Lee HC, et al. Deferred cord clamping with high oxygen in extremely preterm infants: a randomized clinical trial. JAMA Pediatr. 2025;179(9):971–978. doi:10.1001/jamapediatrics.2025.2128 ↩
  10. Knol R, Brouwer E, van den Akker T, et al. Physiological versus time based cord clamping in very preterm infants (ABC3): a parallel-group, multicentre, randomised, controlled superiority trial. Lancet Reg Health Eur. 2025;48:101146. doi:10.1016/j.lanepe.2024.101146 ↩
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  13. Liley H, Weiner G, Solevåg AL, et al. Initial oxygen concentration for preterm newborn resuscitation (NLS 5400): ILCOR Consensus on Science with Treatment Recommendations. International Liaison Committee on Resuscitation; 2025. Accessed August 9, 2025. https://costr.ilcor.org ↩
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