Worldwide, hypoxic–ischemic encephalopathy (HIE) represents a burden and affects 2 million infants annually.1 The resulting neonatal encephalopathy (NE) is hard to classify after birth.2 Although over half of infants with HIE present within a mild spectrum, past clinical trials have focused exclusively on moderately and severely affected infants. The article by Akula et al. PR-2022-0126.R2 adds to the compelling evidence of data in untreated “mild” HIE that shows a range of abnormal neurological outcomes across a spectrum of highly variable assessments from 12 to 24 months through school age.3,4,5,6,7

The conundrum of mild HIE is rooted in the difficulty to define severity within 6 h that results from the evolving nature of neonatal encephalopathy in the first week after birth.8 The recognition of morbidities associated with mild HIE in the era of hypothermia reflects designation of the level of encephalopathy at less than 6 h compared with the worst stage of encephalopathy in the first week during the prior pre-hypothermia era. The lack of prior definitions for mild HIE, and variability in the assessment contributed to the differences in outcomes during recent studies.

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