What is Hypoxic-Ischemic Encephalopathy (HIE) in a premature newborn?

What is Hypoxic-Ischemic Encephalopathy (HIE)?

Hypoxic-ischemic encephalopathy (HIE) is a brain injury in newborns caused by inadequate blood flow and oxygen delivery to the brain during the perinatal period, occurring in term and near-term infants (≥36 weeks gestational age) at a rate of 1.5 per 1000 live births in developed countries, with significantly higher rates of 3-10 per 1000 in low- and middle-income countries. 1, 2, 3

Pathophysiology in Premature vs. Term Infants

Premature infants face distinct vulnerabilities compared to term infants:

• Preterm newborns have unique pathophysiological factors including difficulty maintaining adequate cerebral perfusion pressure, with 24-40% of infants weighing less than 1000g experiencing hypotension in the first day of life 4

• The immature brain has poorly developed autoregulation mechanisms, with a narrower and lower autoregulation pressure range that decreases with gestational age 4

• Anatomical vulnerabilities in preterm infants include incomplete arterial ingrowth into deep white matter and fragile germinal matrix vasculature near the caudothalamic groove that is prone to hemorrhage and hypoperfusion 4

• The germinal matrix (a transient neural cell proliferative zone) involutes in the third trimester, making preterm infants particularly susceptible to intraventricular hemorrhage (IVH) when combined with lack of cerebrovascular resistance 4

Clinical Presentation and Timing

HIE manifests with specific temporal patterns:

• Approximately 90% of infants with HIE experience seizure onset within the first 2 days after birth, strongly suggesting perinatal asphyxia as the underlying cause 1, 5

• HIE is the dominant cause of neonatal seizures, accounting for 46-65% of all neonatal seizure cases 1, 5

• Clinical manifestations include varying degrees of encephalopathy (classified as mild, moderate, or severe based on Sarnat staging), seizures, altered consciousness, and potential progression to cerebral palsy, epilepsy, and neurodevelopmental impairment 1, 2, 3

Phases of Brain Injury

HIE progresses through distinct pathophysiological phases:

• Primary phase: Initial energy failure and cell metabolism dysfunction occurring during the hypoxic-ischemic event 2, 6

• Latent phase: Brief period of apparent recovery following the initial insult 2

• Secondary phase: Delayed energy failure occurring 6-48 hours after the initial insult, characterized by increased cytotoxicity, apoptosis, activated microglia, and inflammation 2, 6

• Tertiary phase: Persistent brain injury with reduced neural plasticity and ongoing neuronal loss that can continue for months to years 2, 6

Diagnostic Approach

Systematic evaluation identifies the cause in approximately 95% of cases:

• MRI with diffusion-weighted imaging is the gold standard for detecting hypoxic-ischemic injury and provides superior sensitivity compared to other modalities 1, 5

• Head ultrasound serves as initial bedside imaging if the infant is unstable or MRI is unavailable, identifying intraventricular hemorrhage, hydrocephalus, and white matter changes, though it has low sensitivity for hypoxic-ischemic injury 1

• CT has limited but specific role in detecting hemorrhagic lesions in encephalopathic infants with birth trauma history, low hematocrit, or coagulopathy 1

• Continuous video-EEG monitoring is essential to recognize seizures and assess prognosis, as many seizures are subclinical without clinical manifestations 1

Treatment

Therapeutic hypothermia is the only evidence-based treatment:

• Cooling to 33-34°C for 72 hours must be initiated within 6 hours of birth in infants ≥36 weeks gestational age with moderate-to-severe HIE 4, 1

• Hypothermia reduces mortality from 35% to 27% and permanent neurological disability from 48% to 27% in eligible infants 1

• Treatment protocol requires: strict temperature control, 72-hour duration, slow rewarming over at least 4 hours, and multidisciplinary intensive care with respiratory support, continuous monitoring, and antiseizure medications as needed 4, 1

• Hypothermia should be administered under clearly defined protocols similar to those used in published clinical trials, in facilities with capabilities for multidisciplinary care and longitudinal follow-up 4

Critical Management Pitfalls

Avoid these common errors:

• Do not use 100% oxygen to initiate resuscitation in term and late-preterm newborns, as it is associated with excess mortality; instead, begin with 21% oxygen (room air) 4

• Rapid volume expansion in premature infants increases risk of intraventricular hemorrhage; administer volume expanders slowly if needed 4

• Hypothermia is not indicated for mild HIE based on current evidence, though these infants may still develop neurodevelopmental deficits and require close monitoring 7

• Hypothermia provides only partial neuroprotection; 40-50% of treated infants still experience death or disability, highlighting the need for adjunctive therapies currently under investigation 2, 8

Prognosis

Long-term outcomes depend on severity and treatment:

• 15-20% of infants with HIE die in the early neonatal period, while survivors face risks of cerebral palsy, epilepsy, visual and hearing impairment, cognitive impairment, and behavioral disorders 3

• Absence of major cerebral lesions on MRI is highly predictive of normal neurological outcome, making neuroimaging valuable for prognostication 1

• Infants initially presenting with mild encephalopathy may develop more significant brain injury later in life, with progressive tissue loss documented on serial imaging 7