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Updated: Sep 22, 2025
A Swine Model of Neonatal Asphyxia
Published on: October 11, 2011
Defining Longer-Term Outcomes in an Ovine Model of Moderate Perinatal Hypoxia-Ischemia
Jana Krystofova Mike1, Katherine Y Wu1, Yasmine White1
1Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
Insights
A new umbilical cord occlusion model in lambs reveals that moderate hypoxic-ischemic encephalopathy (HIE) can lead to variable outcomes, with some infants recovering fully while others develop severe deficits.
Area of Science:
- Neuroscience
- Perinatal Medicine
- Animal Models
Background:
- Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death and disability.
- Moderate HIE outcomes are unpredictable in infants, necessitating better research models.
- Current animal models often lack sufficient follow-up to capture full neurodevelopmental trajectories.
Purpose of the Study:
- To establish and validate a large animal model of moderate HIE using umbilical cord occlusion (UCO).
- To investigate neurodevelopmental outcomes and brain pathology in a 6-day follow-up period.
- To identify potential biomarkers for predicting HIE outcomes.
Main Methods:
- Near-term lambs underwent 5 minutes of asystole to induce HIE, followed by resuscitation.
- Neurobehavioral assessments were conducted over a 6-day period post-HIE.
- Brains were harvested for histological analysis to evaluate cellular damage and inflammation.
Main Results:
- Approximately 35% of lambs (UCOs) showed persistent severe motor deficits and spastic diparesis.
- The remaining lambs (UCOi) recovered normal motor activity and neurodevelopmental outcomes by day 6.
- Histological analysis revealed distinct patterns of brain injury, gliosis, and inflammation between UCOs and UCOi groups.
Conclusions:
- This 6-day UCO model effectively replicates the variable outcomes seen in moderate neonatal HIE.
- The model allows for differentiation between lambs with severe deficits and those with functional recovery.
- Further research using this model can elucidate HIE pathophysiology and aid therapeutic development.
Abstract:
Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.
