Half of infants evaluated for but not cooled show developmental delays at age two

Infants who are evaluated for therapeutic hypothermia but never actually receive the cooling treatment may still face significant neurodevelopmental risks, according to a prospective cohort study published in Pediatric Research. Researchers found that half of the children assessed at 24 months demonstrated sub-normative performance in at least one developmental domain, despite not meeting institutional eligibility criteria for the standard-of-care treatment for neonatal encephalopathy.

Therapeutic hypothermia is the established standard of care for moderate to severe neonatal encephalopathy, a condition marked by impaired brain function in newborns typically linked to oxygen deprivation around the time of birth. While some centers have begun considering the treatment for mild cases as well, the long-term outcomes of infants who are evaluated for cooling but do not meet eligibility criteria have remained incompletely defined.

The research team enrolled 39 infants who had been evaluated for therapeutic hypothermia based on perinatal risk factors but who did not meet their institution’s criteria for initiating the treatment. Of those enrolled, 26 completed Bayley-4 assessments at 24 months of age. Scores below 85, which represent more than one standard deviation below the normative mean, were classified as sub-normative performance.

The results were striking. Thirteen of the 26 children assessed, or 50 percent, demonstrated sub-normative performance in at least one developmental domain. Perhaps most notably, only one of those 13 children had shown an acute brain injury on magnetic resonance imaging. This finding challenges a common assumption that the absence of detectable acute injury on early brain imaging signals a low risk for later developmental problems. In other words, a normal-appearing MRI does not preclude later developmental vulnerability in this population.

The researchers also identified early postnatal metabolic and neurophysiological markers that appeared to differentiate the two groups. Compared with infants who achieved average-range performance, those with sub-normative performance had higher postnatal base deficits, measuring 10.1 versus 6 millimoles per liter, a difference that reached statistical significance with a p value of 0.04. They also had higher postnatal lactate levels, at 9.4 versus 4.9 millimoles per liter, with a p value of 0.05. Additionally, there was a trend toward less sleep-wake cycling on amplitude-integrated electroencephalography, observed in 45 percent versus 83 percent of the two groups, with a p value of 0.06 that did not reach conventional thresholds for statistical significance.

The study’s authors describe the associations between these early postnatal abnormalities and later developmental outcomes as potential rather than definitive, noting that the findings point toward a need for improved risk stratification tools rather than establishing causal pathways.

The study’s conclusions carry practical weight for neonatal care teams. Because a substantial proportion of infants evaluated for but not treated with therapeutic hypothermia demonstrated sub-normative developmental performance at age two, the authors argue that these children should receive structured longitudinal follow-up even though they were never cooled.

The findings also underscore the limits of relying on a single diagnostic modality to predict long-term outcomes. The authors emphasize that absence of acute MRI-detected injury does not preclude later developmental vulnerability, a conclusion that may prompt clinicians to weigh clinical course, metabolic data and neurophysiological monitoring more heavily when deciding which evaluated infants warrant ongoing surveillance.

Subject of Research: Neurodevelopmental outcomes at two years of age in infants evaluated for but not treated with therapeutic hypothermia for neonatal encephalopathy

Article Title: Neurodevelopmental outcomes of infants evaluated for but not treated with therapeutic hypothermia: a prospective cohort study

Article References: El-Dib, M., Sharon, D., Singh, E., Elshibiny, H., Garvey, A., Walsh, B., Erdei, C., & Inder, T. (2026). Neurodevelopmental outcomes of infants evaluated for but not treated with therapeutic hypothermia: a prospective cohort study. Pediatric Research. https://doi.org/10.1038/s41390-026-05615-y

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05615-y

Keywords: therapeutic hypothermia, neonatal encephalopathy, neurodevelopmental outcomes, Bayley-4, prospective cohort study, Pediatric Research, base deficit, lactate, aEEG, MRI brain injury, developmental follow-up, newborn brain injury