A crisis that can reshape a child's life
When a newborn does not get enough oxygen around the time of birth, the brain can be injured. This is called neonatal encephalopathy, or NE.
It affects over a million newborns worldwide each year. Many die. Many survive with lasting disabilities, from cerebral palsy to severe learning problems.
The best tool we have is therapeutic hypothermia, which cools the baby's body just below normal for 72 hours. That cooling slows brain damage. It works, but only partially. And in low-income countries where intensive care is limited, it can even be harmful.
Researchers have been looking for something that could help beyond cooling.
Melatonin, the hormone most people know for sleep, has caught attention as a neuroprotective drug. Lab studies show it reduces inflammation and oxidative damage, two key culprits in brain injury after oxygen deprivation.
Animal models have been encouraging. Pigs, rats, and other species given melatonin after brain oxygen deprivation tend to do better than untreated animals.
The question is whether those results translate to human babies. A Cochrane review aims to be the most rigorous assessment.
Old way vs. new review
Previous smaller reviews hinted that melatonin might help. But they were not systematic, and they did not include the newest trials.
This Cochrane review followed strict methods. It searched all relevant databases through August 2025. It only included randomized controlled trials. It excluded cross-over designs and observational studies, which are less reliable for answering questions about treatment effects.
How it works, in plain English
After oxygen deprivation, a cascade of damage continues for hours or days. The damaged cells release signals that spread inflammation to nearby cells. Free radicals, highly reactive molecules, pile on more injury.
Melatonin is a natural antioxidant. It mops up free radicals. It also calms inflammation. In theory, giving melatonin during the danger window should limit how much of the brain is lost.
Think of it as fire suppression foam. The fire is already lit. You cannot undo what the first flames did. But you can slow the spread so the damaged area stays small.
The study snapshot
The review found only 4 randomized trials meeting the criteria. Together, they included 155 babies.
Two trials compared melatonin plus cooling to cooling alone. Two compared melatonin alone to standard care when cooling was not available, likely in lower-resource settings.
Follow-up varied from discharge to 18 months of age. That is short for neurodevelopmental outcomes but provides some signal.
Here's what they found
The critical outcome, which combined death and neurodevelopmental disability at 18 months, was reported by just one small pilot study of 25 babies. That is nowhere near enough data to draw conclusions.
For mortality in the first month of life, melatonin plus cooling showed a nonsignificant trend toward lower deaths. Melatonin alone without cooling had a stronger signal, with the odds of death reduced. But the certainty of this evidence was rated very low.
MRI brain findings did not differ clearly between groups.
Multiorgan dysfunction and seizure medication use, which the authors wanted to examine, were not reported in any trial.
But here is the catch.
The review's headline finding is not about melatonin working. It is about how little we actually know.
Only 155 total participants across 4 small trials. Pilot studies. Wide confidence intervals. Very low certainty evidence.
Despite years of interest and animal studies, the human evidence base is shockingly thin.
How the researchers read it
The authors are direct. They cannot draw conclusions. They call for larger randomized trials to be done urgently.
They point out that in regions without access to therapeutic hypothermia, melatonin could be especially important if it works. A treatment that is cheap, widely available, and safe would be transformative. But it needs real evidence first.
If you are a parent of a newborn with neonatal encephalopathy, standard care still applies. That means therapeutic hypothermia when available, along with intensive care support.
Melatonin is not currently standard therapy. Do not demand it or try to give supplements to a critically ill newborn on your own. The doses and timing in trials are carefully controlled.
If your baby is in a setting where cooling is not available, ask the medical team about any ongoing trials or research protocols they participate in. Some hospitals are testing melatonin in larger studies.
For expectant parents, good prenatal care remains the best protection against brain injury at birth. Regular checkups, monitoring, and skilled delivery care reduce the risk of oxygen problems.
The limits
The review includes what exists. The problem is what does not exist. Bigger trials are still missing.
The four trials used different doses, timing, and routes of melatonin delivery. That makes combining their results harder.
None of the studies tracked long-term outcomes beyond 18 months. Neurodevelopment continues unfolding throughout childhood, and some effects of early brain injury appear only later.
Larger trials are now being planned in multiple countries. Some focus specifically on settings where cooling is not available. Others test combinations of melatonin with cooling.
Until those trials report out, melatonin remains experimental for neonatal encephalopathy. The potential is real. The proof is not.
