Supplementary Material for: Fifteen years of neonatal Therapeutic Hypothermia: clinical trends show unchanged post-rewarming outcomes despite reduction in HIE severity

INTRODUCTION Hypoxic-ischemic encephalopathy (HIE) affects 1-2 per 1000 births and is associated with mortality and long-term neurodevelopmental challenges. At present, therapeutic hypothermia (TH) is the only neuroprotective intervention for these infants. This study examines whether HIE severity, clinical management during TH and post-rewarming outcomes have changed since its introduction 15 years ago.

METHODS Neonatal characteristics, HIE severity, management during TH and post-rewarming MRI of all infants with HIE undergoing TH between 2008-2023 were compared across three five-year epochs. Linear regression was used to estimate annual changes over time.

RESULTS In total, 252 infants underwent TH. Median GA (39.5 weeks), birth weight (3376 grams) and time to start TH (4.25 hours) remained stable over time. Apgar score at 5 minutes (p=0.031) and lowest pH <1h postpartum (p=0.020) increased over time. Thompson score at 1-3h decreased across epochs (p=0.046). There was an increase in percentage with normal-mild aEEG background patterns on admission (p=0.041) and a decrease in aEEG-confirmed seizures (p<0.001) and anti-seizure medication (p<0.001). Inotropic support decreased (p=0.007), and use of invasive mechanical ventilation decreased over the last five years. Mortality (28.6%) and post-rewarming composite adverse outcome (i.e. neonatal mortality and/or adverse MRI score) (37.9%) remained unchanged. Number of infants seen at 2-year follow-up increased (p<0.001).

CONCLUSION Over the last 15 years we treated more infants with milder HIE, as indicated by lower Thompson and milder aEEG scores, and the need for invasive cardiorespiratory support declined. However, there were no improvements in composite adverse outcome (mortality and/or adverse MRI score).