Brain injuries are among the leading causes of death and long-term disability in infants, with neonatal hypoxic-ischemic encephalopathy (HIE) and perinatal arterial ischemic stroke (PAIS) being two of the most common conditions. Together, these conditions contribute to a significant burden of neurological and developmental complications that affect both the infants themselves and their families.
HIE occurs when a newborn suffers from a lack of oxygen and blood flow to the brain, often during or shortly after birth, leading to severe brain damage. It is a major cause of death in neonates and accounts for about 22% of infant deaths worldwide, affecting one to three in every 1,000 live births each year. PAIS, although slightly less common, is another critical neonatal brain injury that results from a clot blocking a major blood vessel in the brain. Both conditions share overlapping symptoms such as brain injury and seizures, which complicate diagnosis and treatment.
Despite sharing some clinical features, the underlying mechanisms of HIE and PAIS are quite distinct. Understanding these differences, as well as how these two conditions might co-occur in some infants, is crucial for improving clinical outcomes. A recent study, published in the journal Pediatric Research, has contributed valuable insights into how often PAIS occurs in infants diagnosed with HIE and how this co-occurrence affects their long-term health.
Mechanisms of Brain Injury: HIE vs. PAIS
The two conditions—HIE and PAIS—both lead to brain injury but through different mechanisms:
- HIE occurs when there is a global reduction in blood and oxygen flow to the brain, typically caused by complications during birth, such as cord prolapse, placental abruption, or prolonged labor. The lack of oxygen triggers a cascade of biochemical and cellular events that lead to brain cell death, inflammation, and long-term neurological damage. The standard treatment for HIE is therapeutic hypothermia or brain cooling, which aims to slow the rate of damage caused by the oxygen deprivation by lowering the infant’s body temperature.
- PAIS, on the other hand, is caused by an ischemic stroke, where a clot blocks one of the major blood vessels supplying the brain. This blockage interrupts the blood supply to specific regions, causing localized damage. The blockage may result from a variety of factors, including clotting disorders, vascular malformations, or infections during pregnancy.
While these conditions differ in their causes, both can result in similar clinical signs, such as seizures and encephalopathy (brain dysfunction). However, the severity and nature of the brain damage can vary depending on the type and location of the injury.
Study Setup: Investigating the Co-Occurrence of HIE and PAIS
The recent study, led by Jessica Wisnowski, Ph.D., and her colleagues, used data from the HEAL Trial, a large multi-center clinical trial designed to investigate new treatments for HIE. The study aimed to explore how often PAIS occurs in infants diagnosed with moderate to severe HIE and how this co-occurrence affects short-term and long-term outcomes.
The study included 473 infants who were diagnosed with moderate or severe HIE within six hours of delivery. These infants were enrolled in the HEAL Trial, a clinical trial focused on therapeutic hypothermia for treating HIE, and had undergone brain MRI scans to assess brain injury. The researchers analyzed the MRI scans to identify any evidence of PAIS and compared clinical characteristics, such as seizure occurrence, encephalopathy severity, and neurodevelopmental outcomes, between infants with and without PAIS.
Key Findings from the Study
The study’s results provided several important insights:
- 4% of infants with moderate to severe HIE showed MRI evidence of PAIS.
- Three out of four infants with PAIS also showed signs of HIE-pattern brain injury, which means they experienced a combination of both ischemic and hypoxic-ischemic damage.
- Seizures were more common in infants with PAIS, suggesting that the additional vascular injury may exacerbate neurological instability.
- Infants with PAIS were more likely to experience persistent moderate or severe encephalopathy even five days into treatment compared to those without PAIS, suggesting that the combination of both injuries leads to a more severe and prolonged course of brain dysfunction.
- Despite the interesting findings, the number of infants with PAIS was relatively small—only 21 out of 473—which limited the ability to detect statistically significant differences in the long-term neurodevelopmental outcomes at two years of age.
The small sample size of infants with PAIS presented a challenge in drawing definitive conclusions about the long-term outcomes. However, these findings highlight the potential complexity of treating neonates with both HIE and PAIS, as the presence of both conditions can complicate diagnosis, treatment, and prognosis.
Potential Explanations for the Co-Occurrence of HIE and PAIS
Researchers have speculated on several potential explanations for the co-occurrence of HIE and PAIS, as both conditions share some common risk factors:
- Shared Risk Factors: Conditions such as chorioamnionitis (inflammation of the membranes surrounding the fetus) and placental disease (e.g., placental insufficiency or preeclampsia) are known to increase the risk of both HIE and PAIS. These conditions disrupt blood flow to the fetus and may predispose infants to both brain injuries.
- ECMO as a Risk Factor: Some infants with HIE are treated with extracorporeal membrane oxygenation (ECMO), a life-saving treatment that temporarily takes over the heart and lung function. However, ECMO itself is a known risk factor for stroke, including PAIS. This could explain why infants with HIE are more likely to experience both conditions.
- Complications During Labor: The occurrence of PAIS during labor and delivery could lead to a more difficult and prolonged birth, which increases the likelihood of oxygen deprivation and HIE. In such cases, the infant may experience both ischemic and hypoxic-ischemic injuries as a result of the complex interplay between these factors.
Clinical Implications and Future Directions
This study emphasizes the need for early detection and comprehensive diagnostic strategies to identify all potential causes of brain injury in neonates. While brain MRI has become an essential tool in diagnosing and evaluating HIE and PAIS, it is important to consider both conditions in infants undergoing therapeutic hypothermia. Detecting the presence of PAIS in infants with HIE could lead to more tailored interventions that address the unique challenges posed by these combined injuries.
As the study authors point out, large-scale studies are crucial for improving our understanding of neonatal brain injury and developing more effective interventions. These studies can help determine the optimal treatments for infants suffering from both HIE and PAIS, as well as guide clinicians in making more accurate predictions about long-term outcomes.
Conclusion: Advancing Neonatal Brain Injury Research
The research conducted by Dr. Wisnowski and her colleagues offers valuable insights into the complexities of neonatal brain injuries. By investigating how HIE and PAIS can co-occur, the study helps refine our understanding of these conditions and paves the way for better diagnostic tools and treatment strategies. While much progress has been made, there is still much to learn about the precise mechanisms that link these two devastating conditions, and further research is needed to improve the prognosis for affected infants.
As the study highlights, brain MRI is a critical tool in identifying the full spectrum of brain injuries in neonates undergoing therapeutic hypothermia for HIE. Researchers and clinicians alike hope that continued advancements in neonatal care and brain injury research will lead to better outcomes for infants affected by these leading causes of death and disability, ultimately reducing the burden of these conditions on children and families around the world.
Reference: Fernando F. Gonzalez et al, Perinatal arterial ischemic stroke diagnosed in infants receiving therapeutic hypothermia for hypoxic-ischemic encephalopathy, Pediatric Research (2024). DOI: 10.1038/s41390-024-03531-7