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Observational Study
. 2025 Nov;114(11):2874-2884.
doi: 10.1111/apa.70186. Epub 2025 Jun 18.

Real-World Therapeutic Hypothermia for Neonatal HIE: Neurodevelopmental Outcomes and Predictors

Luca Bedetti  1 , Licia Lugli  1 , Isotta Guidotti  1 , Maria Federica Roversi  1 , Elisa Della Casa Muttini  1 , Marisa Pugliese  2 , Natascia Bertoncelli  1 , Eugenio Spaggiari  1 , Alessandra Todeschini  3 , Gina Ancora  4 , Sara Grandi  4 , Giancarlo Gargano  5 , Claudio Gallo  5 , Mario Motta  6 , Piero Catenazzi  6 , Luigi Tommaso Corvaglia  7 , Vittoria Paoletti  7 , Agostina Solinas  8 , Elisa Ballardini  8 , Serafina Perrone  9 , Sabrina Moretti  9 , Marcello Stella  10 , Alberto Berardi  1 , Fabrizio Ferrari  1
Affiliations
Observational Study

Real-World Therapeutic Hypothermia for Neonatal HIE: Neurodevelopmental Outcomes and Predictors

Luca Bedetti et al. Acta Paediatr. 2025 Nov.

Abstract

Aim: This study assessed neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) outside randomised controlled trials (RCTs). It also aimed to identify predictors of outcomes and evaluate TH practices across centres.

Methods: A prospective, area-based observational study was conducted in eight Italian NICUs (2016-2021), including neonates treated with TH for any grade of HIE. A 2-year neurodevelopmental follow-up was performed. Severe functional disability (SFD) was defined as cerebral palsy (Gross Motor Function Classification Level > 2), cognitive score < 2 SD, bilateral blindness/deafness, or epilepsy. Demographic, clinical and MRI data were analysed.

Results: Among 283 cooled infants, 11 (3.8%) died and 272 (96.2%) survived. HIE severity was mild (14.0%), moderate (76.1%) and severe (9.9%). Follow-up data were available for 232 (85.3%) survivors, with SFD diagnosed in 27 (11.6%). No infants with mild HIE developed SFD. Severe MRI anomalies were found in 51.9% of SFD cases, while 90.7% of non-SFD children had normal findings. cEEG/aEEG-confirmed seizures (OR = 12.9, CI 3.5-65.0) and severe MRI anomalies (OR = 0.24, CI 0.13-0.44) were strong SFD predictors (AUC = 0.95).

Conclusion: Mortality and SFD rates were lower than in RCTs. Seizures and severe MRI anomalies predicted poor outcomes. Further RCTs are needed to refine treatment criteria.

Keywords: brain MRI; brain cooling; cerebral palsy; hypoxic–ischemic encephalopathy; therapeutic hypothermia.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Overlapping of neurodevelopmental impairments in children with severe functional disability. Two children had severe cognitive impairment (in one case associated with epilepsy).
FIGURE 2
FIGURE 2
Sankey diagram of SFD according to the presence of seizures during TH and the five different patterns of brain MRI. SFD, severe functional disability.
FIGURE 3
FIGURE 3
Time to initiation of TH according to the severity of HIE. HIE, hypoxic–ischemic encephalopathy; TH, therapeutic hypothermia. Median time to initiation of TH in infants with mild (5.2 h, IQR 4.1–5.8), moderate (4.5 h, IQR 2.8–5.5) or severe HIE (3.2 h, IQR 2.6–3.9), p = 0.001.
See this image and copyright information in PMC

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