What are Some Risk Factors for Hypoxic-Ischemic Encephalopathy Outcomes?

Patient Presentation
An 18-month-old male came to clinic for his health maintenance visit. His parents were very pleased with his growth and his development. He was running, climbing, saying many words and occasionally would put 2 words together. He was scribbling, feeding himself and was very sociable with people.

The past medical history was remarkable for being a full-term male with moderate hypoxic-ischemic encephalopathy at birth (i.e. hypotonicity, decreased activity, intermittent bradycardia and periodic breathing), presumably due to a tight nucal cord, that was treated with hypothermia. He did not have any identified neonatal seizures. Since discharge from the neonatal intensive care unit the toddler had been meeting or exceeding his developmental milestones. He continued to not have any evidence of seizures, and he was still being followed by the neonatal followup program.

The pertinent physical exam showed an interactive male who appropriately vocalized some mild distress with examination.
His growth parameters were in the 25-75%. He had some mild eczema but the rest of the examination was normal.

The diagnosis of a healthy male was made. The pediatrician reviewed the developmental screening including autism screening which was normal for his age. “Given that he has not had any problems to date, his overall prognosis looks very good, but as you know there can still be other problems such as learning or attentional problems that we may not see yet. That is why the neonatal program and I keep asking you all the developmental questions and we are going to continue to follow him. You should watch him and if you or other people like his daycare professionals have questions let us know. But you should also treat him like the wonderful young boy he is and enjoy him for who he is,” the pediatrician counseled.

“Neonatal encephalopathy, manifesting as altered responsiveness, seizures, apnea and abnormal muscle tone and reflexes, resulting from hypoxic-ischemic injury is termed hypoxic-ischemic encephalopathy (HIE).” Neonatal encephalopathy can be associated with other problems including stroke, hemorrhage, infection, pre-term brain injury and hypoglycemia as some examples. Sometimes more than one of these entities occurs simultaneously such as hypoglycemia and HIE. HIE can result in long-term neurological problems including motor, behavioral, and cognitive problems that can become apparent even years later. HIE occurs in 1-3/1000 live births. Causes of HIE can be broadly separated into two general types:

  • Acute catastrophic asphyxia is associated with about 25% of cases and is associated with placental abruption, uterine rupture, cord prolapse, fetal entrapment and cord problems
  • Chronic which appears to be associated with about 66% of cases where they are “repeated but relatively short periods of deep hypoxia” and is associated with the “direction function of the inherent intermittent “asphyxia” of labor.”
  • Another ~10% of moderate to severe HIE appears to have problems preceding labor onset with abnormal fetal heart rate and associated preceding fetal compromise.

Although labor contractions cause intermittently impaired uteroplacental perfusion, authors note the “In face, it appears that the fetus is spectacularly good at defending itself against hypoxia, and injury only occurs in a very narrow window between intact survival and death.”

Optimal treatment for HIE continues to evolve especially based on animal models. Hypothermia initiated within 6 hours of birth can improve outcomes in various studies. Hypothermia of ~3°C for approximately 72 hours is often used. Treatment of other problems such as concommitent hemodynamic and respiratory instability, neonatal seizures and possible neonatal infection also make balancing the physiological needs of treatment more difficult.

Learning Point
Predictions of clinical outcome for an individual or groups of individuals can be difficult as treatment changes over time and there are many parameters which cannot be easily measured or accounted for. However, clinicians discussing treatment with families are aware of some of the increased risks. Clinical examination can assist with diagnosis and also prognosis. Unsurprisingly, infants with a clinical examination that progressively deviates from normal are more severely affected and generally have poorer prognoses. The Sarnat and Thompson scores are two such scoring systems. These systems evaluate various neurological system components including consciousness, types of movement or positioning, tone, and autonomic nervous system functions (i.e. heart rate, respiration, pupils). Evolution of the neurological examination over the time of the hypothermia treatment period appears to help predict long term outcome better than the initial stage of HIE. Other risk factors include: lower Apgar score for longer periods of time (often 10 minute Apgar is used in studies), more hemodynamic/respiratory instability for longer periods of time, abnormal metabolic parameters (e.g. anemia, hypocarbia, glycemic control, lactate, and pH), certain electroencephalography patterns, and neuroiimaging injury patterns (e.g. deep brain structures affected such as the basal ganglia and thalamus, or watershed injury patterns).

HIE is not a good diagnosis to have and infants with moderate to severe HIE even with hypothermic treatment have a 48% chance of major neurological problems or death. Long term sequelae can include blindness, cerebral palsy, deafness, developmental delay, epilepsy, and intellectual impairment. Cognition appears to be a important marker of long-term problems for children. But cognitive problems may be present even without motor problems and some cognitive problems are more difficult to identify until later in life such as attentional issues, learning disabilities, memory and behavioral/social interaction problems.

Questions for Further Discussion
1. What are some seizure patterns/classifications? A review can be found here

2. What are some etiologies for intellectual disability? A review can be found here

3. What causes respiratory failure? A review can be found here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Traumatic Brain Injury and Brain Diseases.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Gunn AJ, Thoresen M. Neonatal encephalopathy and hypoxic-ischemic encephalopathy. Handb Clin Neurol. 2019;162:217-237. doi:10.1016/B978-0-444-64029-1.00010-2

Goswami I, Guillot M, Tam EWY. Predictors of Long-Term Neurodevelopmental Outcome of Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia. Semin Neurol. 2020;40(03):322-334. doi:10.1055/s-0040-1702939

Nguyen T, Wusthoff CJ. Clinical manifestations of neonatal seizures. Pediatrics International. 2021;63(6):631-635. doi:10.1111/ped.14654

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa