What a Tiny Blood Sample Might One Day Tell Doctors About a Newborn's Brain After a Difficult Birth

A family-friendly guide to Montaldo et al.'s 2026 study in JAMA Network Open, which compared gene patterns in the blood of babies with mild or more serious oxygen-related brain injury and healthy newborns

When a baby's brain is short of oxygen around birth, doctors have only a few hours to judge how serious the injury is and whether cooling treatment will help. A study of 112 newborns in the United Kingdom and Italy found that a tiny blood sample taken in the first hours of life showed different gene patterns in babies with mild injury, more serious injury and no injury. It is a promising early step towards an objective test, not a test doctors can use yet.

This article explains that study, published in 2026 by Montaldo and colleagues [1], and what it may mean for families. If your baby has been cared for because of a difficult birth, we hope it helps you understand the questions doctors are working on and why your baby's follow-up appointments matter.

Why the first six hours after birth matter so much

Sometimes, during labour or delivery, a baby's brain does not get enough oxygen or blood flow. The brain injury that can follow is called hypoxic-ischaemic encephalopathy, usually shortened to HIE ("hypoxic" means low oxygen, "ischaemic" means reduced blood flow, and "encephalopathy" means the brain is not working normally). Brain problems around birth of this kind are one of the leading causes of death in young children worldwide, although global deaths fell by almost a third between 1990 and 2021 [2]. Lack of oxygen is the most common cause, and doctors now have one proven treatment, although there is still room to do better [3].

For about 50 years, doctors have judged how serious HIE is by carefully examining the baby. This approach goes back to a 1976 study of 21 newborns by two doctors named Sarnat, who described three stages of the condition, now usually called mild, moderate and severe [4]. The examination looks at things like how alert the baby is, how floppy their muscles are, and whether they have seizures.

The treatment is called therapeutic hypothermia, or "cooling": the baby's body is kept at about 33.5 °C, a little below normal body temperature, for three days to protect the brain. A large study in hospitals of a United States newborn research network showed that cooling reduced the chance of death or serious disability in babies with moderate or severe HIE [5]. When researchers later combined 11 such studies including 1,505 babies, they found that for roughly every seven babies cooled, one more baby survived without major disability. That evidence applies when cooling starts within six hours of birth [6].

Babies with mild HIE were not included in those studies, and for a long time doctors believed they would be fine. Newer research has made the picture less clear. In one study that followed babies with mild HIE closely, about 1 in 6 babies with mild HIE who were not cooled had some disability at around 18 to 22 months [7]. Another study found that two-year-olds who had mild HIE scored a little lower on thinking skills than other children [8], and a study of teenagers found some had difficulties with attention and school [9]. Understandably, many hospitals started cooling babies with mild HIE too, even though there was no clear proof that it helps them [10]. A small trial called COMET (Cooling in Mild Encephalopathy), carried out in six specialist newborn units in the United Kingdom and Italy, found that cooling did not improve brain scan measurements in babies with mild HIE, although the babies who were cooled had been somewhat sicker at the start [11]. You can read more about that trial in our article on cooling for mild HIE.

All of this leaves doctors with a hard problem. The examination in the first hours is difficult, signs can be subtle and can change, and the decision about cooling has to be made quickly.

Reading the body's messages: what "gene expression" means

Every cell in the body carries the same set of genes, which work like an instruction book. But cells do not use every instruction at once. Depending on what is happening, some genes are turned up and others turned down. When a gene is in use, the cell makes copies of it in a molecule called RNA. By reading the RNA in a blood sample, scientists can see which instructions the blood cells are using at that moment. This is called a "gene expression" profile.

This idea has already been useful in other areas of children's medicine. Patterns of just a few genes in blood can help tell bacterial infections apart from viral ones in feverish children [12], and similar patterns can help diagnose Kawasaki disease, an illness that inflames blood vessels [13]. In newborns, blood taken at birth showed gene changes in babies who went on to develop a serious infection, even before they became unwell [14]. The same research team had already found gene changes in the blood of babies with moderate or severe HIE [15][16], but nobody had looked at babies with mild HIE.

What the researchers did

The researchers studied 112 babies born at full term [1]. Forty had mild HIE and were taking part in the COMET trial; 33 had moderate or severe HIE (29 moderate and 4 severe) and were all cooled at a hospital in Naples, Italy; and 39 were healthy newborns from the same Italian hospital. Specially trained and certified assessors examined every baby with HIE in the first six hours of life.

Each baby gave a very small amount of blood, about half a millilitre, which is roughly a tenth of a teaspoon. The first sample was taken within six hours of birth and before any cooling started; on average the babies were less than two hours old. A second sample was taken at about three days of age. The researchers then read the RNA in each sample and compared the three groups.

What they found

Soon after birth, babies with mild HIE had a distinct gene pattern. Compared with healthy babies, 981 genes were turned up or down in the mild group, and 622 in the moderate or severe group. Strikingly, only 37 of these changed genes were the same in both groups. In other words, mild HIE did not look like a smaller version of moderate or severe HIE; it looked different.

The kinds of genes involved also differed. In babies with moderate or severe HIE, groups of genes linked to the immune system, the body's defence network, stood out strongly. In babies with mild HIE, the genes that stood out were mostly those cells use to repair themselves, manage their energy and keep their normal processes running.

By three days of age, the pattern in babies with mild HIE had largely settled back towards that of healthy babies: relative to healthy babies, only one gene changed significantly over those three days in the mild group, compared with 30 in the moderate or severe group. Babies with moderate or severe HIE still showed changes, especially in immune-related genes.

The two groups of babies with HIE also did very differently later on. Among the 33 babies with moderate or severe HIE, 11 died or had moderate or severe disability by 18 to 22 months. Among the 40 babies with mild HIE, none had moderate or severe disability, 3 had mild disability and, sadly, 1 baby died.

Important things to keep in mind

This was a careful study, but it has limits, and the researchers are open about them. The study was fairly small, with only four babies with severe HIE. The two HIE groups came from different studies and different years, and their samples were processed on different machines in different laboratories; the team used statistical methods to correct for this, but some differences could still come from the process rather than the babies. All the babies with moderate or severe HIE were being cooled when their second sample was taken, which may itself affect the blood. Blood also reflects what is happening throughout the body, not just in the brain.

Most importantly, the study did not test how accurately the gene patterns could tell one group from another, and it has not yet been repeated in a separate group of babies. So there is no blood test for HIE that your baby's doctors can order today.

What this means for your baby and family

If your baby has HIE, decisions about cooling will still be based on a careful examination by your baby's team, together with other tests. This study does not change that. What it does suggest is that mild HIE is a real, measurable condition, not just a baby who is slightly unsettled, which supports doctors taking it seriously.

It also carries a reassuring message: as a group, babies with mild HIE showed a blood pattern that settled quickly. But the researchers are clear that this does not guarantee every child will develop without difficulties, and that babies with mild HIE should still have follow-up appointments as they grow [1]. Those check-ups are the best way to spot any needs early and get support in place.

What researchers are working on next

The researchers say their findings now need to be confirmed in larger groups of babies. Sensible next steps would include narrowing the pattern down to a small number of genes, processing all samples in the same way, and testing whether the pattern predicts how children are doing as they grow. Scientists have already shown that a gene-based blood test for infection can be built into a small, fast device that gives results in under half an hour [17], so a rapid bedside test is not out of reach. Other teams are studying the chemicals found in babies' urine after HIE [18], and in the future, combining several kinds of measurement may give doctors and families clearer answers in those first crucial hours.

References

  1. Montaldo P, Herberg J, Uppal S, et al. Whole-Blood Gene Expression and Hypoxic-Ischemic Encephalopathy at Birth. JAMA Netw Open. 2026;9(8):e2629378. doi:10.1001/jamanetworkopen.2026.29378 ↩
  2. Tan S, Mageziyi S, Long L, Dilimulati N, Hui Z, Rejiafu N. Analysis of global, regional, and national burdens of neonatal encephalopathy from 1990 to 2021: insights from the Global Burden of Disease Study 2021. Front Public Health. 2025;13:1627448. doi:10.3389/fpubh.2025.1627448 ↩
  3. Chakkarapani E, de Vries LS, Ferriero DM, Gunn AJ. Neonatal encephalopathy and hypoxic-ischemic encephalopathy: the state of the art. Pediatr Res. 2025;98(7):2444-2458. doi:10.1038/s41390-025-03986-2 ↩
  4. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696-705. doi:10.1001/archneur.1976.00500100030012 ↩
  5. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584. doi:10.1056/NEJMcps050929 ↩
  6. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013;2013(1):CD003311. doi:10.1002/14651858.CD003311.pub3 ↩
  7. Chalak LF, Nguyen KA, Prempunpong C, et al. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. Pediatr Res. 2018;84(6):861-868. doi:10.1038/s41390-018-0174-x ↩
  8. Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-Year Neurodevelopmental Outcomes After Mild Hypoxic Ischemic Encephalopathy in the Era of Therapeutic Hypothermia. JAMA Pediatr. 2020;174(1):48-55. doi:10.1001/jamapediatrics.2019.4011 ↩
  9. Halpin S, McCusker C, Fogarty L, et al. Long-term neuropsychological and behavioral outcome of mild and moderate hypoxic ischemic encephalopathy. Early Hum Dev. 2022;165:105541. doi:10.1016/j.earlhumdev.2022.105541 ↩
  10. Kumar V, Singla M, Thayyil S. Cooling in mild encephalopathy: Costs and perils of therapeutic creep. Semin Fetal Neonatal Med. 2021;26(3):101244. doi:10.1016/j.siny.2021.101244 ↩
  11. Montaldo P, Cirillo M, Burgod C, et al. Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial. JAMA Netw Open. 2024;7(5):e249119. doi:10.1001/jamanetworkopen.2024.9119 ↩
  12. Herberg JA, Kaforou M, Wright VJ, et al. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA. 2016;316(8):835-845. doi:10.1001/jama.2016.11236 ↩
  13. Wright VJ, Herberg JA, Kaforou M, et al. Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature. JAMA Pediatr. 2018;172(10):e182293. doi:10.1001/jamapediatrics.2018.2293 ↩
  14. An AY, Acton E, Idoko OT, et al. Predictive gene expression signature diagnoses neonatal sepsis before clinical presentation. EBioMedicine. 2024;110:105411. doi:10.1016/j.ebiom.2024.105411 ↩
  15. Montaldo P, Kaforou M, Pollara G, et al. Whole Blood Gene Expression Reveals Specific Transcriptome Changes in Neonatal Encephalopathy. Neonatology. 2019;115(1):68-76. doi:10.1159/000492420 ↩
  16. Montaldo P, Burgod C, Herberg JA, et al. Whole-Blood Gene Expression Profile After Hypoxic-Ischemic Encephalopathy. JAMA Netw Open. 2024;7(2):e2354433. doi:10.1001/jamanetworkopen.2023.54433 ↩
  17. Pennisi I, Rodriguez-Manzano J, Moniri A, et al. Translation of a Host Blood RNA Signature Distinguishing Bacterial From Viral Infection Into a Platform Suitable for Development as a Point-of-Care Test. JAMA Pediatr. 2021;175(4):417-419. doi:10.1001/jamapediatrics.2020.5227 ↩
  18. Valerio E, Stocchero M, Pirillo P, et al. Neurosteroid pathway derangement in asphyctic infants treated with hypothermia: an untargeted metabolomic approach. EBioMedicine. 2023;92:104636. doi:10.1016/j.ebiom.2023.104636 ↩