When a Proven Treatment Meets Its Limit: Cooling Therapy and Babies Born a Few Weeks Early

What a large U.S. study of whole-body cooling in babies born at 33 to 35 weeks tells families about brain protection after a difficult birth

The Problem That Motivated the Research

Sometimes a baby is deprived of oxygen and blood flow around the time of birth — because of a problem with the placenta, the umbilical cord, or labor itself. When that happens, the brain can be injured in the hours and days that follow, a condition doctors call hypoxic-ischemic encephalopathy, or HIE. For decades there was no treatment. Then researchers discovered something remarkable: gently lowering a newborn's body temperature by a few degrees for three days could protect the brain, reducing the chance of death or lasting disability. This treatment, called therapeutic hypothermia or "cooling," was tested in several large studies in full-term babies and consistently helped [1][2][3]. A review combining many trials found that cooling lowered the death rate without leaving more survivors disabled [4], and follow-up studies showed the benefit lasted into the school years [5]. Cooling is now standard care in newborn intensive care units around the world.

But there was a catch. Almost all of those studies were done in babies born at 36 weeks of pregnancy or later — essentially full-term babies. Doctors did not know whether cooling would also help babies born just a little earlier, at 33 to 35 weeks. These babies are not extremely premature, but they are less mature, and their smaller, more fragile bodies might handle cooling differently. They can be more prone to bleeding and to problems with the intestines. Even so, because cooling helped term babies so much, many hospitals began using it for these slightly early babies too — without solid proof that it worked for them. The study described here set out to answer that open question directly [6].

How the Study Was Done

A network of U.S. research hospitals — 19 centers working together under the National Institutes of Health — ran a carefully designed experiment called a randomized clinical trial [6]. "Randomized" means that, for each eligible baby, a computer decided by chance which of two treatments the baby would receive. This is the fairest way to compare treatments, because it prevents doctors from steering sicker or healthier babies toward one group. Between 2015 and 2020, the trial enrolled 168 babies born at 33 to 35 weeks who showed signs of brain dysfunction after a difficult birth, identified within the first 6 hours of life.

Half the babies (88) received cooling: their body temperature was lowered to about 33.5 °C — roughly four degrees Celsius below normal — and kept there for 72 hours, then slowly warmed back up. The other half (80) received what doctors call targeted normothermia: their temperature was carefully kept at the normal 37 °C, with active steps taken to make sure they did not become too warm, since fever is known to be harmful to an injured brain. The two groups reached clearly different temperatures, so the comparison was a true test of cooling.

To measure how the children did, the researchers waited until the babies were 18 to 22 months old and then examined them. Specially trained examiners — who did not know which treatment each child had received, so their judgment could not be biased — checked each child's thinking and movement development using a standard assessment, along with vision and hearing. The main question was simple: how many children in each group had either died or developed moderate-to-severe disability?

What Was Found

The result was clear and, for many, surprising: cooling did not help these slightly early babies. Death or significant disability happened in about 35 of every 100 cooled babies, compared with about 29 of every 100 babies kept at normal temperature [6]. In other words, the cooled group did slightly worse, not better. When the researchers looked at deaths specifically, 22 of every 100 cooled babies died compared with 13 of every 100 in the normal-temperature group. Using their statistical methods, the researchers calculated an 87% probability that cooling actually increased the risk of death in this group of babies.

It is important to read these numbers carefully, and the researchers were careful too. Because the study included a relatively small number of babies, the findings cannot completely rule out a small benefit — but they make benefit unlikely and point, if anything, toward harm. The team also looked separately at babies with milder versus more severe brain dysfunction and found no group that clearly benefited from cooling. The authors concluded plainly that there was no evidence cooling reduces death or disability in babies born at 33 to 35 weeks [6]. This is a striking contrast with full-term babies, where the same treatment reliably helps [7][8], and it suggests that 36 weeks of pregnancy is a real turning point in how a baby's brain responds to this therapy.

The study also tracked side effects carefully. Cooled babies needed help from a breathing machine for somewhat longer — a median of about three and a half days versus two days — and a few more had problems with low blood sodium or high blood sugar [6]. On the other hand, several complications that doctors had worried about did not appear. Serious bleeding in the brain was equally uncommon in both groups, low platelet counts were similar, and major bleeding requiring a transfusion was actually a little less common in the cooled babies. No baby in either group developed the dangerous intestinal illness called necrotizing enterocolitis. So the concern raised by this study was not that cooling caused dramatic new harms, but the simpler and still important fact that cooling did not deliver the benefit it reliably provides for full-term babies.

One detail helps explain the difference in deaths between the two groups. Among the babies who died, the cause was almost always the original brain injury from lack of oxygen rather than some new problem introduced by the treatment. This suggests that, in babies born at 33 to 35 weeks, cooling simply did not protect an already-injured brain the way it does in full-term babies — not that the cooling itself created a separate danger. It is also worth understanding what the "normal temperature" group actually received, because it was not simply being left alone. Those babies were carefully kept at a normal 37 °C, and if a baby started to get too warm, the team stepped in — first with a lukewarm sponge bath and, if needed, a cooling blanket — to bring the temperature back down. Preventing fever is itself protective for an injured brain, so the comparison group was getting active, thoughtful care. This matters for families to know: choosing not to cool a slightly early baby does not mean doing nothing. It means watching the baby's temperature closely and keeping it in a healthy range.

The trial was run over five years and, while 168 babies is a substantial number for such a specialized study, it is still small enough that the results cannot completely settle every question. Researchers were careful to describe their findings in terms of probabilities rather than absolute certainty. What they could say with confidence is that they found no sign that cooling helped, and some signs that it might do more harm than good, in this particular group of babies.

What This Means for Families

If your baby was born at 33 to 35 weeks and had a difficult birth with possible brain injury, this study offers a few important takeaways. First, the best current evidence is that cooling is not the right treatment at these gestational ages, and many newborn units will now keep such babies at a carefully controlled normal temperature instead — which is itself an active, protective approach, because preventing fever matters. Second, cooling remains a proven, valuable treatment for full-term babies; this study does not change that. The finding is specifically about where the benefit of cooling begins and ends [9].

It also helps to know that diagnosing brain injury in babies born a few weeks early is genuinely harder than in full-term babies. The examination doctors use to judge how alert and responsive a newborn is was originally designed for more mature infants [10], and a slightly early baby's normal immaturity can look similar to signs of injury. This is one reason careful, repeated examination and honest conversations with your care team are so important. If you are ever unsure why a particular decision is being made, it is completely appropriate to ask your baby's doctors to walk you through the reasoning.

What Researchers Are Working On Next

Science advances by learning where treatments work and where they do not, and this study did exactly that. Researchers are now studying brain scans from these same babies — reported separately — to understand more about the injuries involved. They are also working to tell the difference between true oxygen-related brain injury and the ordinary features of being born early, so that future care can be matched more precisely to each baby. For families, the most reassuring message is that this kind of rigorous research exists to protect babies from treatments that do not help, just as earlier research established the treatments that do. Every careful study, even one with a disappointing result, makes the care of vulnerable newborns safer and wiser [6][11].

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