Hypoxic-Ischemic Encephalopathy in Preterm Infants: Why It’s Different and Often Missed

Preemie

Hypoxic Ischemic Encephalopathy (HIE) is a form of brain damage caused by oxygen deprivation around the time of birth. Hypoxic-Ischemic Encephalopathy in preterm infants is an under-recognized and potentially a devastating condition.

The incidence of HIE in preterm infants is likely higher than current statistics suggest. One of the reasons is that preterm HIE often hides in plain sight, as the physiological immaturity of a preemie masks the classic HIE symptoms. Thus standard diagnostic tools (such as neurological exams) are harder to interpret, causing HIE to be overlooked or its symptoms to be attributed to other common complications of prematurity.

A journal review from 2016 attempted to highlight the differences in HIE between term and preterm infants and advocated that this area is still poorly studied.1

The preterm infant’s brain undergoes rapid, critical development after birth, making it uniquely vulnerable compared to term infants. While HIE in term infants most commonly damages deep brain structures such as the basal ganglia (important for motor control and coordination) and the thalamus (a key relay station for sensory information), the preterm brain is more susceptible to a different pattern of injury.

This vulnerability is due to the fact that the preterm brain contains fragile, immature cell populations that are still developing and are critical for future brain function, including:

  • Pre-oligodendrocytes (pre-OLs) / oligodendrocytes progenitor cells: These are the “precursor” cells that will eventually mature into oligodendrocytes, which are responsible for producing myelin. Myelin acts like insulation around the axon of the brain, which are the long strands of nerve cells that send electrical signals to other cells. This insulation is essential for fast and efficient brain signal transmission.2 Because pre-OLs are so crucial for future brain wiring, they are “highly susceptible to hypoxia” from HIE.1
  • Subplate neurons: These are among the first brain cells to form and mature. They help establish connections between the brain’s outer layer (cortex) and deeper structures, making them essential for proper brain development.3

The paper also states that there are higher rates of adverse neurological outcomes (such as cerebral palsy) in preterm infants compared to term infants.1 This higher rates come from the fact that the injury strikes at the very foundational building blocks (pre-OLs and subplate neurons) of the developing brain, disrupting future development on a large scale. In contrast, to-term babies with HIE have injuries to already-established neuronal structures.

Due to the potential higher rates and devastating effects, researchers are advocating for clearer definitions of “preterm HIE” so doctors can identify it more consistently.1 This is the essential first step toward better monitoring and future treatments. Researchers are also developing early warning models to predict the onset of neonatal HIE and, hopefully, to discriminate which neonates require therapeutic hypothermia within the first six hours of life.4

REFERENCES

  1. Gopagondanahalli, K. R., Li, J., Fahey, M. C., Hunt, R. W., Jenkin, G., Miller, S. L., & Malhotra, A. (2016). Preterm Hypoxic-Ischemic Encephalopathy. Frontiers in pediatrics, 4, 114. https://doi.org/10.3389/fped.2016.00114
  2. Kuhn, S., Gritti, L., Crooks, D., & Dombrowski, Y. (2019). Oligodendrocytes in Development, Myelin Generation and Beyond. Cells, 8(11), 1424. https://doi.org/10.3390/cells8111424
  3. Ohtaka-Maruyama C. (2020). Subplate Neurons as an Organizer of Mammalian Neocortical Development. Frontiers in neuroanatomy, 14, 8. https://doi.org/10.3389/fnana.2020.00008
  4. Lacan, L., et al. (2024). Early automated classification of neonatal hypoxic-ischemic encephalopathy − An aid to the decision to use therapeutic hypothermia. Clinical Neurophysiology, 166, 108-116.