Michael S. Porter
Eric C. Nordby
When a newborn’s brain doesn’t receive enough oxygen or blood flow during birth, the result can be a condition called hypoxic-ischemic encephalopathy. This diagnosis brings with it medical complexities, difficult decisions, and questions that deserve clear, honest answers.
HIE represents one of the most serious challenges in newborn care. Understanding what happens, why it happens, and what can be done about it matters for anyone navigating this diagnosis.
What Is Hypoxic-Ischemic Encephalopathy and What Causes Brain Damage in Newborns?
Hypoxic-ischemic encephalopathy describes brain injury caused by oxygen deprivation. Breaking down the medical terminology helps clarify what’s happening:
Hypoxic means the brain received too little oxygen. Ischemic means the brain received insufficient blood flow. Encephalopathy means abnormal brain function.
The distinction between HIE and the broader term “neonatal encephalopathy” is more than semantic. Neonatal encephalopathy describes any newborn with signs of brain dysfunction, regardless of cause. HIE specifically refers to brain dysfunction caused by oxygen deprivation and reduced blood flow during the period around birth.
Doctors should only diagnose HIE when there’s clear evidence that oxygen deprivation caused the brain injury. This includes factors like metabolic acidosis in cord blood, low Apgar scores, signs of distress during labor, and injury to multiple organs beyond the brain.
This distinction matters because neonatal encephalopathy can result from many causes beyond oxygen deprivation, including brain malformations, stroke, metabolic disorders, genetic conditions, infections, and toxic exposures. Each cause requires different treatment approaches.
Research shows that oxygen deprivation alone causes encephalopathy in only about 7% of infants with brain dysfunction at birth. About 50% of neonatal encephalopathy cases involve HIE as at least a contributing factor. The remaining cases stem from other causes entirely.
How Common Is HIE in Newborns and Who Is Most at Risk?
The frequency of HIE varies dramatically depending on where a baby is born.
In the United States, Europe, Canada, and Australia, HIE occurs in approximately 1.5 to 2 out of every 1,000 live births. Recent data from 2012-2019 in the United States showed a consistent rate around 1.7 per 1,000 births.
These relatively low rates in developed countries represent significant progress. In the early 2000s, rates were higher. Improvements in prenatal care, fetal monitoring, and the ability to perform emergency cesarean sections when complications arise have contributed to declining incidence. By 2015, rates plateaued at these lower levels.
The picture looks starkly different in low- and middle-income countries. HIE rates in these settings range from 2.3 to over 30 per 1,000 live births. Sub-Saharan Africa experiences the highest rates, often around 15 per 1,000 or more. That’s nearly ten times the rate in wealthy countries.
Globally, an estimated 1.2 million babies develop HIE each year. About 96% of these babies are born in resource-limited settings. Perinatal asphyxia causes 23% of all newborn deaths worldwide and results in approximately 920,000 neonatal deaths annually. Another 1.1 million babies die before birth (intrapartum stillbirths) from related causes.
The disparity between rich and poor countries persists despite overall global improvements. While worldwide rates declined from 11.7 per 1,000 in 1990 to 8.5 per 1,000 in 2010, progress has slowed since 2015.
Male infants develop HIE significantly more often than female infants. This gender difference appears consistently across studies, with boys facing roughly twice the risk of girls.
How HIE Brain Injury Develops in Four Stages After Oxygen Loss
Understanding HIE requires understanding that brain injury doesn’t happen all at once. The damage unfolds in distinct phases over hours to days. This timeline is crucial because treatment targets the window between the initial injury and subsequent damage.
Primary Brain Injury Phase When Oxygen Stops Reaching the Brain
When blood flow to the brain drops severely or stops, the immediate effect is what doctors call primary energy failure. Without oxygen and glucose, brain cells can’t produce ATP, the molecule that powers cellular functions.
This energy failure happens fast. The brain tries to compensate by directing blood flow to the most critical areas like the brainstem, which controls breathing and heart rate. The cerebral cortex, thalamus, and basal ganglia receive less protection and suffer more acute damage.
In severe cases, this immediate phase causes brain cells to die through a process called necrosis. The cells essentially burst as their membranes break down. During this phase, toxic levels of calcium flood into cells, excitatory neurotransmitters accumulate outside cells where they don’t belong, and proteins that cells need stop being made.
The Latent Phase and the Critical 6-Hour Treatment Window
About 30 minutes to an hour after oxygen is restored, something unexpected happens. Brain cells appear to partially recover. Oxygen metabolism improves, and some cellular functions restart.
This latent phase, lasting roughly 6 to 15 hours, offers a deceptive calm. While the brain seems to stabilize, processes that will lead to additional injury are quietly initiating. Inflammation ramps up. The machinery of programmed cell death begins spinning into motion.
This window represents the critical period for treatment. Therapeutic hypothermia, the only proven treatment for HIE, must start within these first six hours to be effective. The intervention aims to slow brain metabolism and interrupt the cascade leading to the next phase.
Secondary Brain Injury Phase When Most Permanent Damage Occurs
Between 6 and 48 hours after the initial oxygen loss, a second wave of energy failure strikes. This secondary phase often causes more damage than the initial injury itself.
Unlike the chaotic primary injury, secondary energy failure develops methodically. Multiple destructive processes converge. Excitatory neurotransmitters like glutamate continue accumulating, overstimulating receptors and poisoning cells. Free radicals form and damage cellular structures. Inflammation spreads. Mitochondria, the power plants of cells, malfunction. Calcium keeps flooding into cells. Programmed cell death pathways activate.
The cells dying in this phase typically die through apoptosis rather than necrosis. Apoptosis is more organized. The cell’s nucleus condenses, DNA fragments, and the cell dismantles itself from within. In infant brains, apoptosis appears to cause more damage than necrosis.
The severity of this secondary failure correlates strongly with long-term outcomes. Infants whose brains show little recovery during this phase typically have poorer developmental outcomes.
Long-Term Tertiary Phase That Continues for Months After Birth
Months after the acute injury, a tertiary phase continues. Chronic inflammation persists. The brain’s ability to generate new neurons suffers. Apoptosis continues at low levels. This extended phase contributes to developmental problems that may not become apparent until later childhood.
The Sarnat Staging System for Grading Mild, Moderate, and Severe HIE
Within hours of birth, doctors assess the severity of encephalopathy using a system developed by Harvey and Margaret Sarnat. The Sarnat staging system remains the worldwide standard for classifying HIE severity.
The assessment examines six categories: level of consciousness, spontaneous activity, posture, muscle tone, primitive reflexes, and autonomic nervous system function. Based on findings across these categories, the baby receives a stage classification.
Mild HIE Symptoms and Why It May Not Be as Harmless as Once Thought
Babies with mild HIE appear hyperalert or irritable. They startle easily and may seem inconsolable. Muscle tone is normal or slightly increased. They don’t have seizures. Their pupils are dilated but reactive to light. Breathing is regular.
This stage typically resolves within 24 hours. Historically, mild HIE was thought to have a benign prognosis. Recent research challenges this assumption.
Brain MRI studies show that about two-thirds of infants with mild HIE have visible brain injury. Thirty-one percent show acute injury with restricted water diffusion, and 39% show subacute injury. Long-term follow-up reveals that 16% of children with untreated mild HIE develop disability by 18-22 months, and 40% have language deficiencies.
These findings raise important questions about whether babies with mild HIE should receive therapeutic hypothermia. Current practice varies. About 75% of UK hospitals now cool babies with mild HIE, though protocols differ. Research trials are ongoing to determine if this population benefits from treatment.
Moderate HIE Symptoms and Long-Term Outcome Statistics
Babies with moderate HIE are lethargic or obtunded, meaning they respond slowly to stimulation but do eventually respond. Muscle tone decreases. Posture shows distal flexion or complete extension rather than the normal flexed position. Seizures occur frequently. Pupils constrict but remain reactive. Breathing may be irregular or periodic.
This stage can last from 2 to 14 days, with an average duration of 5 days. Duration matters. Babies who remain in stage 2 for longer than five days typically have worse outcomes.
Between 20% and 35% of babies with moderate HIE develop long-term neurological problems. However, outcomes have improved significantly with therapeutic hypothermia. Between 25% and 75% of babies with moderate HIE will develop serious impairments or die, depending on whether they receive cooling treatment.
Severe HIE Symptoms, Mortality Rates, and Prognosis for Survivors
Babies with severe HIE are in stupor or coma. They don’t respond to stimulation. Muscles are completely floppy with no tone. Seizures are actually uncommon in severe HIE because the brain is too suppressed to generate the electrical activity that produces seizures. Pupils may be fixed and non-reactive. The baby may not breathe on their own or breathe very irregularly.
Severe HIE can last from hours to weeks. Mortality rates range from 25% to 50%. Among survivors, about 80% develop significant neurological impairments. Only 68% of babies with severe HIE survive to age three according to some studies.
The Sarnat assessment works best when performed 24 to 48 hours after birth. This timing allows the initial effects of resuscitation and acute stress to resolve while still capturing the evolution of injury.
Medical Causes and Risk Factors That Lead to HIE During Pregnancy and Birth
HIE results from events that deprive the baby’s brain of oxygen or blood flow. These events can occur before labor begins, during labor and delivery, or in the hours after birth.
Prenatal Risk Factors That Increase HIE Risk Before Labor Begins
About 69% of HIE cases involve risk factors present before labor begins. Only 4% of cases involve problems during labor alone without any preceding risk factors.
Maternal health conditions that increase HIE risk include preeclampsia, hypertension, diabetes, thyroid disease, and vascular disease. These conditions can compromise the placenta’s ability to deliver oxygen to the baby.
Placental problems represent significant risk factors. Placental abruption, where the placenta separates from the uterine wall prematurely, cuts off the baby’s oxygen supply. Placental insufficiency, where the placenta doesn’t function adequately, causes chronic oxygen deprivation.
Infections during pregnancy, including chorioamnionitis and viral illnesses, increase risk. One study found that 40% of babies with encephalopathy had chorioamnionitis, and 11% had both chorioamnionitis and a sentinel event during labor.
Fetal factors also matter. Intrauterine growth restriction, where the baby isn’t growing properly, often reflects chronic oxygen deprivation. Post-maturity, when pregnancy extends beyond 41 weeks, increases risk as the placenta ages. Fetal anemia and lung malformations compromise the baby’s ability to maintain adequate oxygenation.
Maternal substance use, including drugs and alcohol, increases HIE risk. Inadequate prenatal care correlates with higher rates, likely because conditions that increase risk go undetected and unmanaged.
Maternal age matters too. Both very young mothers (under 20) and older mothers face elevated risk. Low maternal weight (under 50 kg) and short stature (under 150 cm) also associate with increased HIE rates.
Research suggests that 5% to 20% of HIE cases result from problems during the prenatal period rather than during birth.
Labor and Delivery Complications That Can Cause HIE
About 56% of HIE cases involve oxygen deprivation during labor and delivery. These are often the cases that receive the most attention because they occur in the hospital under medical supervision.
Umbilical cord problems represent major risks. Cord prolapse, where the cord slips into the birth canal ahead of the baby, can compress against the baby and cut off blood flow. Nuchal cords, where the cord wraps around the baby’s neck, usually cause no problems but can occasionally compress during delivery. True knots in the cord can tighten during labor.
Shoulder dystocia, where the baby’s shoulder gets stuck behind the mother’s pubic bone, delays delivery and can cause profound oxygen deprivation. This complication occurs more frequently with larger babies.
Placental abruption can occur during labor as well as before. Uterine rupture, though rare, causes immediate and severe oxygen deprivation.
Abnormal fetal positioning, particularly breech presentation, increases risk. Babies presenting in non-cephalic positions face 5 to 6 times higher risk of HIE.
Prolonged labor, especially when the second stage (pushing) exceeds 60 minutes, increases risk. Paradoxically, very rapid delivery also elevates risk.
Labor augmentation, the use of medications to strengthen contractions, shows up as a risk factor in studies. Obstructed labor, where the baby can’t descend through the birth canal, causes progressive distress.
Maternal fever during labor increases risk. The mechanism isn’t entirely clear but likely involves a combination of underlying infection and the effect of elevated temperature on the baby.
Operative deliveries using forceps or vacuum extraction are associated with higher HIE rates, though it’s often unclear whether the interventions cause problems or are used because the baby is already in distress.
Inadequate or absent fetal heart rate monitoring prevents early detection of distress. When monitoring does detect problems, failure to respond appropriately, including delays in performing cesarean sections when indicated, can allow preventable injury to occur.
Postnatal Medical Problems That Can Lead to HIE in Newborns
Five to ten percent of HIE cases result from problems in the hours or days after birth rather than during the birth process.
Severe respiratory distress or respiratory failure can deprive the brain of oxygen even when the birth itself was uncomplicated. This can occur with lung disease, airway problems, or severe prematurity.
Infection, including sepsis and meningitis, can compromise oxygenation and blood flow. Severe anemia, whether from blood loss or other causes, reduces the blood’s oxygen-carrying capacity.
Low blood pressure that isn’t adequately treated can reduce blood flow to the brain. Cardiac arrest for any reason causes immediate and severe hypoxia.
Blood sugar abnormalities, both low (hypoglycemia) and high (hyperglycemia), can contribute to or worsen brain injury, though they typically don’t cause HIE by themselves.
Brain or skull trauma after birth can cause bleeding that compresses brain structures and reduces blood flow.
Baby Risk Factors Including Gender, Size, and Birth Position
Certain characteristics of the baby influence HIE risk independent of events during birth.
Male sex appears to double HIE risk compared to female sex. The mechanism behind this difference isn’t fully understood.
Large babies (macrosomia), especially those weighing over 4,000 grams, face increased risk. Large head circumference (macrocephaly) above the 97th percentile also increases risk. Conversely, very low birth weight babies and extremely premature babies face elevated risk.
Multiple gestation (twins or triplets) increases risk for each baby. Congenital anomalies also correlate with higher HIE rates.
How Doctors Diagnose HIE Using Tests, Scans, and Monitoring
Diagnosis combines clinical assessment, laboratory testing, and brain imaging. No single test confirms HIE. Instead, doctors look for a constellation of findings consistent with oxygen deprivation around the time of birth.
What Apgar Scores Reveal About Birth Asphyxia and HIE Risk
The Apgar score, created by anesthesiologist Dr. Virginia Apgar in 1952, provides a rapid assessment immediately after birth. Five criteria are evaluated:
Appearance (skin color): Blue or pale (0 points), body pink with blue extremities (1 point), completely pink (2 points)
Pulse (heart rate): Absent (0), below 100 beats per minute (1), above 100 (2)
Grimace (reflex response to stimulation): No response (0), grimace (1), cry or active withdrawal (2)
Activity (muscle tone): Limp (0), some flexion (1), active motion (2)
Respiration (breathing): Absent (0), weak or irregular (1), strong cry (2)
The score is recorded at 1 minute and 5 minutes after birth for all babies. For babies scoring 7 or below at 5 minutes or requiring resuscitation, scoring continues every 5 minutes.
Scores of 7 to 10 are normal. Scores of 4 to 6 indicate the baby needs assistance. Scores of 0 to 3 indicate critical condition requiring immediate resuscitation.
The 1-minute score reflects how the baby tolerated labor and delivery. The 5-minute score better indicates how the baby is adapting to life outside the womb. A score of 5 or less at 10 minutes is one criterion for therapeutic hypothermia eligibility.
Important limitations exist. The Apgar score alone doesn’t prove oxygen deprivation occurred or predict long-term outcomes. Many factors influence the score, including gestational age, medications given to the mother, and congenital anomalies. Resuscitation always takes priority over calculating the score.
One study comparing Apgar scoring to actual evidence of birth asphyxia (umbilical cord blood pH below 7 with seizures or abnormal tone) found that the 5-minute Apgar had 71% sensitivity and 89% specificity. This means it’s fairly good but imperfect at identifying babies who experienced oxygen deprivation.
Umbilical Cord Blood Gas Testing to Detect Oxygen Deprivation at Birth
Blood drawn from the umbilical cord immediately after birth provides objective evidence of the baby’s condition in the moments before birth. This test measures how acidic the blood is and how much oxygen and carbon dioxide it contains.
The most important measurements include pH and base deficit. pH indicates overall acidity. Base deficit measures metabolic acidosis, which accumulates when cells operate without adequate oxygen and produce lactic acid.
Normal umbilical artery blood has a pH above 7.10. Severe acidosis is generally defined as pH below 7.00. Metabolic acidosis specifically requires both pH below 7.00 and base deficit of 12 mmol/L or greater.
The distinction between respiratory and metabolic acidosis matters. Respiratory acidosis (low pH with normal base deficit) indicates temporary impaired gas exchange during delivery, which is common and usually insignificant. Metabolic acidosis (low pH with increased base deficit) indicates that the baby’s tissues didn’t receive enough oxygen for long enough to switch to anaerobic metabolism. This is much more concerning and indicates true oxygen deprivation.
Lactate levels also provide valuable information. Lactate is the direct end product when cells operate without oxygen. Some research suggests lactate measurements predict outcomes more accurately than pH.
Cord blood gas results correlate with outcomes. The lower the pH, the higher the risk of problems. Even pH levels not traditionally considered dangerous show increased risk when they drop below normal ranges.
Umbilical cord blood gas analysis is more objective and reliable than Apgar scoring for documenting birth asphyxia. A pH below 7.00 with base deficit of 16 or greater is one of the criteria that qualifies a baby for therapeutic hypothermia.
Amplitude-Integrated EEG Brain Monitoring to Assess HIE Severity
Amplitude-integrated electroencephalography (aEEG) measures brain electrical activity at the bedside. Unlike standard EEG, which requires specialized interpretation, aEEG presents simplified, compressed information that bedside clinicians can interpret.
The device attaches electrodes to the baby’s scalp and displays continuous brain wave patterns. The tracing shows background brain activity, which changes characteristically with brain injury.
Normal background activity shows continuous, somewhat irregular patterns with clear differences between sleep and wake states. Moderate abnormalities show lower amplitude or less continuity. Severe abnormalities show very low amplitude, flat patterns, or burst-suppression patterns where activity alternates with flat stretches.
aEEG detects seizures, though it can miss brief or focal seizures that more comprehensive EEG would catch. The main value of aEEG in HIE is assessing background brain activity and the presence or absence of sleep-wake cycling.
Sleep-wake cycling, where background patterns vary between active and quiet sleep, is a good sign. Absence of sleep-wake cycling correlates with worse outcomes.
In the era before therapeutic hypothermia became standard, aEEG performed within the first 6 hours predicted outcomes better than any other early test. The background pattern within the first 6 hours correlated strongly with how the baby would develop.
Studies show significant correlation between aEEG findings and the degree of HIE. One study found a correlation coefficient of 0.742 between HIE severity and aEEG background activity.
EEG findings evolve rapidly in the first 6 hours. A severely abnormal EEG in the first 24 hours, combined with low pH and a 5-minute Apgar score of 0, predicted death or severe developmental impairment with high specificity.
Today, therapeutic hypothermia is started before outcomes can be predicted with certainty. But EEG monitoring helps with treatment decisions and gives families information about prognosis, even if the information isn’t definitive.
Brain MRI Imaging to See HIE Damage and Predict Long-Term Outcomes
Brain MRI is the gold standard for assessing brain injury in HIE. The timing and patterns of injury visible on MRI provide crucial information about severity and likely outcomes.
MRI isn’t usually performed immediately after birth. The optimal timing is 4 to 10 days of life, after therapeutic hypothermia is complete but while certain types of injury patterns remain visible.
What Brain MRI Scans Show in Babies with HIE
Healthy newborn brains after 37 weeks should show specific signal patterns. The posterior limb of the internal capsule, a brain structure critical for motor function, should be bright on T1-weighted images and dark on T2-weighted images. The thalamus shouldn’t show abnormal brightness on T1 images.
HIE changes these patterns. Common findings include loss of the normal signal in the posterior limb of the internal capsule, abnormal signal in the basal ganglia and thalamus, brain swelling, loss of the distinction between gray and white matter, and cortical highlighting where the outer brain layer appears abnormally bright.
Different sequences provide different information. Diffusion-weighted imaging (DWI) is particularly sensitive to acute injury in the first week. When brain cells are damaged, water movement becomes restricted. On DWI, damaged areas appear bright. The apparent diffusion coefficient (ADC) map shows the same areas dark. Research shows that when more than 10% of the brain shows ADC values below 650, the positive predictive value for poor outcomes is 95%.
Three Main Brain Injury Patterns Seen on MRI in HIE Cases
The pattern of brain injury visible on MRI tells doctors about the type and severity of oxygen deprivation.
Watershed pattern injury affects areas at the borders between major blood vessel territories, particularly in the parasagittal cortex and underlying white matter. This pattern results from partial, prolonged oxygen deprivation rather than sudden, complete loss of oxygen. Blood pressure drops but doesn’t disappear entirely, and the areas at the edges of blood supply territories suffer most.
Children with watershed injuries typically develop spastic cerebral palsy affecting the legs (diplegia) or all four limbs (quadriplegia). Some develop hemiplegia, affecting one side more than the other. Epilepsy is relatively common. Cognitive abilities are often affected, especially perceptual reasoning and auditory working memory. The severity of watershed injury correlates with the severity of cognitive impairment. When the subcortical white matter is severely affected, outcomes are typically worse, with profound intellectual disability and severe spasticity common.
Basal ganglia and thalamus pattern injury affects deep brain structures including the putamen, ventrolateral thalamus, and posterior limb of the internal capsule. This pattern results from acute, profound oxygen deprivation—a sudden sentinel event like cord prolapse or uterine rupture.
These injuries become visible on MRI within 24 hours. Initially, swelling in the central gray matter may compress the third ventricle. By 72 hours, compression may increase depending on injury extent. Swelling typically resolves by day 5 or 6.
Children with moderately severe basal ganglia/thalamus injuries often develop extrapyramidal cerebral palsy, characterized by abnormal movements, rigidity, and problems with posture and balance. Intellectual development is frequently normal or near-normal in these children, a different pattern than watershed injuries.
Multicystic encephalopathy represents the most severe pattern. Multiple cysts form throughout the brain as damaged tissue breaks down. This pattern carries the worst prognosis, with severe quadriplegic cerebral palsy, choreoathetotic movements, progressive small head size, profound intellectual disability, difficulty swallowing, and epilepsy all common.
Best Timing for Brain MRI After HIE to Detect Injury
About two-thirds of infants with mild HIE show brain injury on MRI. Thirty-nine percent show subacute injury (abnormal signal without restricted diffusion and without brain shrinkage). Thirty-one percent show acute injury with restricted diffusion.
The timing of MRI matters. Different types of abnormalities are visible at different times. Restricted diffusion peaks in the first week and may become less apparent after that. T1 and T2 signal changes emerge over several days. Volume loss indicating chronic injury takes weeks to develop.
Performing MRI at 4 to 10 days captures acute changes while they’re still apparent but after the baby has completed therapeutic hypothermia and is medically stable enough for the scan.
One study found that injury to at least two deep gray matter regions on MRI had excellent specificity and positive predictive value for death or severe developmental problems at age two.
How MRI Results Predict Developmental Outcomes After HIE
MRI findings predict outcomes better than clinical findings alone. The extent and pattern of injury correlate with specific types of developmental problems.
Children without major visible disability after HIE but with neonatal MRI findings still face increased risk for long-term intellectual, verbal, and motor deficits. At school age, they score lower on IQ tests, particularly performance IQ, compared to population norms. Motor performance suffers across multiple domains. The watershed pattern on neonatal MRI correlates with verbal and overall IQ scores.
Therapeutic Hypothermia Cooling Treatment for HIE
Therapeutic hypothermia, also called cooling therapy, represents the only treatment proven to improve outcomes in moderate to severe HIE. Before cooling became standard care in the mid-2000s, doctors could only provide supportive care while brain injury progressed. Cooling changed that.
Clinical Trial Evidence That Cooling Treatment Reduces Death and Disability from HIE
Multiple large, well-designed trials established therapeutic hypothermia as the standard of care.
The CoolCap trial studied 234 term newborns randomized to head cooling or standard care. Death or disability occurred in 66% of babies receiving standard care compared to 55% of cooled babies.
The TOBY trial randomized 325 newborns to whole-body cooling or standard care. Death or severe disability occurred in 53% of standard care babies versus 45% of cooled babies. Survival without neurological problems increased significantly with cooling.
The NICHD trial studied 208 infants randomized to whole-body cooling at 33.5°C for 72 hours or usual care. Cooling decreased death or disability significantly, with a relative risk of 0.72.
The Infant Cooling Evaluation trial found that death or significant disability at 2 years occurred in 51% of cooled babies compared to 66% of controls.
A Cochrane systematic review analyzing 11 randomized trials including 1,505 babies confirmed that therapeutic hypothermia benefits newborns with moderate to severe HIE. Cooling reduces mortality by 25%. To prevent one death, seven babies need to be treated. Cooling reduces major developmental disability at 18 to 24 months by 23%. To prevent one case of major disability, eight babies need treatment.
Follow-up studies of cooled babies into childhood show that benefits persist. Survival improves. Cognitive outcomes improve. The benefits outweigh the risks.
Eligibility Criteria for Therapeutic Hypothermia Cooling Treatment
Strict criteria determine which babies receive therapeutic hypothermia. All three categories must be met: demographic criteria, biochemical evidence of oxygen deprivation, and clinical evidence of encephalopathy.
Demographic criteria require gestational age of at least 36 weeks, birth weight of at least 1,800 grams, and age less than 6 hours old. The 6-hour cutoff is critical because cooling must start before secondary energy failure begins.
Biochemical criteria require evidence of metabolic acidosis or a sentinel event. Acceptable evidence includes umbilical cord blood or baby’s blood drawn within the first hour showing pH of 7.0 or less OR base deficit of 16 or greater. If pH is between 7.0 and 7.15 or base deficit is between 10 and 15.9, or if no blood gas is available, the baby can still qualify if there was a clear sentinel event (cord prolapse, uterine rupture, placental abruption, or severe fetal heart rate abnormalities) AND either Apgar score of 5 or less at 10 minutes OR need for assisted ventilation for at least 10 minutes after birth.
Neurological criteria require evidence of moderate to severe encephalopathy. Seizures automatically qualify the baby. Without seizures, the baby must show moderate or severe abnormalities in at least 3 of 6 categories on modified Sarnat exam: level of consciousness, spontaneous activity, posture, tone, primitive reflexes, and autonomic nervous system function. Alternatively, amplitude-integrated EEG can show moderate to severe encephalopathy.
Babies are excluded if they have gestational age under 36 weeks, birth weight under 1,800 grams, major congenital abnormalities, imminent death, life-threatening bleeding disorders with active bleeding, significant head trauma with major bleeding in the brain, or imperforate anus (for head cooling only).
How Therapeutic Hypothermia Works to Cool the Baby’s Body and Brain
Two methods of cooling are used: whole-body cooling and selective head cooling.
Whole-body cooling uses a blanket that circulates cold water. The blanket wraps around the baby’s body and connects to a machine that maintains water temperature. The goal is to cool the baby’s core body temperature to 33 to 34°C (about 92 to 94°F). This method provides uniform cooling to all brain structures and is used in most U.S. centers because it’s easier to administer and allows better access to the scalp for EEG monitoring.
Selective head cooling uses a cap that circulates cold water around the baby’s head. The head and brain reach a cooler temperature than the body. The target rectal temperature is 34 to 35°C. The cap must be removed every 12 hours to check for skin injury. This method is used less commonly in the U.S. but remains popular in some countries.
Passive cooling may be used when immediate access to a cooling facility isn’t available or during transport. The warming device is turned off, the baby’s clothes are removed, and no blankets are used. Temperature is monitored every 15 to 30 minutes to prevent over-cooling. Passive cooling serves as a temporary measure until active cooling equipment is available.
What Happens During the 72-Hour Cooling Treatment Process
Cooling starts as soon as possible after birth, ideally within the first 6 hours. This timing targets the latent phase, before secondary energy failure begins.
The baby’s temperature is lowered to the target range and maintained there for 72 hours. Throughout this time, continuous monitoring tracks temperature, heart rate, blood pressure, breathing, and brain activity.
After 72 hours, rewarming begins slowly. The temperature increases by 0.5°C per hour. Rapid rewarming can cause complications. Depending on the cooling method, passive rewarming continues for 4 to 6 hours after active warming stops.
Medical Monitoring and Care Your Baby Receives During Cooling Treatment
Cooling affects every organ system, requiring careful monitoring and adjustment of care.
Heart and blood pressure: Heart rate normally drops during cooling, about 15 beats per minute for every degree Celsius of cooling. A heart rate of 80 to 100 beats per minute at 33.5°C is expected and not concerning. Blood pressure requires close monitoring because cooling can cause low blood pressure. Mean arterial pressure should stay above 40 mm Hg. If heart rate drops persistently below 60 beats per minute, an ECG is performed. If blood pressure remains low despite treatment, an echocardiogram evaluates heart function.
Breathing and blood gases: Blood gas measurements initially occur every 4 hours. The machine analyzing blood gases must adjust for the baby’s actual body temperature because cooler blood holds gases differently than warm blood. Oxygen levels should stay between 60 and 100 mm Hg, and carbon dioxide should stay between 38 and 45 mm Hg.
Brain monitoring: Neurological checks occur frequently, watching for seizures, changes in consciousness, and pupil responses. EEG monitoring continues at least during the initial cooling and rewarming periods. Seizures are common and require treatment. Sedation for discomfort from cooling needs to be balanced against over-sedation, which can prolong hospital stays.
Fluids and nutrition: Total fluid intake typically starts at 50 to 60 mL per kilogram per day. Electrolytes and glucose are maintained in normal ranges. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur, requiring fluid restriction. Electrolytes are checked at least daily.
Blood tests: Baseline testing includes complete blood count, coagulation studies, comprehensive metabolic panel, arterial blood gas, and troponin (a marker of heart damage). Testing repeats throughout treatment as needed.
Skin care: Skin integrity is assessed every 6 hours because cooling can cause skin injury, particularly with head cooling caps.
Infection monitoring: Cooling can suppress immune function, potentially increasing infection risk. Standard infection control precautions are followed.
Cooling Treatment Side Effects and Potential Complications to Expect
Therapeutic hypothermia is generally safe, but complications occur.
Heart effects include bradycardia (slow heart rate), which is expected, and hypotension (low blood pressure), which requires treatment. The QT interval on ECG may prolong, and in rare cases, abnormal heart rhythms can develop.
Lung effects include worsening oxygenation from pulmonary vasoconstriction and pulmonary hypertension. These effects usually resolve with rewarming. Surfactant production may be impaired. The oxygen-hemoglobin curve shifts, affecting oxygen delivery to tissues.
Blood chemistry changes include low potassium, sodium, magnesium, and phosphate levels, all of which need monitoring and correction.
Bleeding problems can occur, particularly platelet dysfunction. Mild bleeding is fairly common, but most babies still benefit from cooling despite this risk. Severe bleeding is rare.
Infection risk increases because cooling inhibits the inflammatory response. Sepsis occurs more frequently in cooled babies compared to uncooled babies in some studies.
Digestive effects include slow stomach emptying, causing feeding problems.
Drug metabolism changes occur because cooling alters how the body processes medications. Drug dosing may need adjustment.
Rewarming complications include seizures as brain metabolism speeds up, apnea, and low blood pressure as the peripheral blood vessels that constricted during cooling suddenly dilate.
Despite these potential complications, the benefits of cooling significantly outweigh the risks for babies who meet treatment criteria.
Controversial HIE Treatment Situations Where Evidence Is Unclear
Several scenarios lack definitive evidence about therapeutic hypothermia.
Mild HIE: Recent research reveals that mild HIE isn’t as benign as previously thought. Sixteen percent of children with untreated mild HIE develop disability by 18 to 22 months. Forty percent have language problems. Two-thirds show brain injury on MRI.
Whether these babies benefit from cooling remains unclear. Trials are ongoing. About 75% of UK hospitals now cool babies with mild HIE, though protocols vary. Without strong evidence either way, practice varies between centers.
Premature babies (33 to 35 weeks): A 2025 randomized trial showed no benefit and potentially worse outcomes for babies born at 33 to 35 weeks gestational age who received therapeutic hypothermia. Earlier retrospective studies raised concerns about increased side effects. Current recommendations advise against cooling for this population.
Babies in low- and middle-income countries: A meta-analysis of 10 studies in resource-limited settings showed little to no benefit in reducing death or severe disability. Cooling was associated with increased bleeding and low platelet counts.
This finding is controversial. These settings have the highest burden of HIE globally, with 96% of cases occurring in low- and middle-income countries. Many experts advocate continuing cooling despite these results, arguing that improvements in supportive care capacity may allow benefits to emerge. Others argue that resources might be better spent on preventing HIE through improved prenatal care and safer deliveries.
More intensive cooling: Can longer cooling (120 hours instead of 72) or deeper cooling (32°C instead of 33.5°C) improve outcomes? A randomized trial tested both and found no benefit at 18 months compared to standard cooling. More intensive cooling is not recommended.
Starting cooling after 6 hours: Most centers maintain a strict 6-hour window for starting treatment. Some centers have begun cooling babies up to 24 hours old. A statistical analysis suggested a 64% probability of benefit for late cooling, but this remains controversial and not standard practice. The physiology of HIE suggests treatment needs to start before secondary energy failure progresses significantly, which argues against delayed treatment.
HIE Survival Rates and Long-Term Outcomes for Children
The immediate question after an HIE diagnosis is usually about survival. The next question is about long-term development. Neither has a simple answer.
HIE Survival and Mortality Rates by Severity Level
Mortality rates range from 10% to 60% depending on severity and treatment.
Overall, approximately 20% to 50% of infants with HIE die before leaving the hospital or in early childhood. The wide range reflects different study populations and the impact of therapeutic hypothermia.
In mild HIE, mortality is very low. In moderate HIE, mortality ranges from 10% to 50% depending on whether the baby receives cooling and other factors. In severe HIE, mortality ranges from 25% to 50%, with only about 68% surviving to age three in some studies.
Therapeutic hypothermia reduces mortality by 25% overall compared to no treatment. In the era before cooling, 37% of babies with moderate to severe HIE died. With cooling, mortality dropped to 24%.
Mortality rates in the United States have declined over time. From 2010 to 2012, mortality was 11.5% to 12.3%. From 2016 to 2018, it dropped to 8.3% to 10.6%. Increased use of therapeutic hypothermia contributed to this improvement.
Developmental Disability Rates in Children Who Survive HIE
Among babies who survive HIE, 25% to 60% develop long-term neurological problems. With therapeutic hypothermia, 44% develop moderate to severe disability compared to 62% without cooling.
Despite the proven benefits of cooling, more than 40% of infants with moderate to severe HIE still die or develop significant problems including cerebral palsy, epilepsy, cognitive impairment, or vision problems.
Cerebral Palsy Rates and Types After HIE
Cerebral palsy occurs in about 19% of cooled babies compared to 30% of uncooled babies with HIE. About 14.5% of all babies born with HIE develop cerebral palsy.
The type of cerebral palsy often relates to the pattern of brain injury. Watershed injuries typically cause spastic cerebral palsy affecting the legs (diplegia) or all four limbs (quadriplegia). Basal ganglia injuries often cause extrapyramidal (dyskinetic) cerebral palsy characterized by involuntary movements and abnormal posture.
Cognitive and Learning Problems in Children Who Had HIE
Cognitive outcomes vary widely. Even children who don’t have obvious major disabilities face increased risk for problems that may not become apparent until school age.
At ages 8 to 15, children who had HIE but don’t have major disabilities scored lower on IQ tests than population norms. Performance IQ was particularly affected. The proportion with IQ below 85 was higher than expected. Motor performance was impaired across multiple domains including pure motor skills, fine motor, gross motor, and movement quality.
The pattern of neonatal brain injury predicted outcomes. Watershed injury patterns correlated with lower full-scale and verbal IQ scores. More severe watershed injury predicted worse cognitive abilities.
At age 13, children with watershed pattern injuries showed lower overall cognitive abilities, especially in perceptual reasoning and auditory working memory. Children who also had epilepsy or cerebral palsy had the lowest cognitive scores.
Behavioral and Emotional Problems After HIE
At age 3, children who had HIE showed higher rates of emotional problems even when cognitive testing was normal. Introversion occurred in 10.5% compared to 1.3% of controls. Anxiety occurred in 34.2% compared to 11.7% of controls. Depression occurred in 28.9% compared to 7.8% of controls.
Vision, Hearing, and Sensory Problems That Can Result from HIE
Blindness occurs in 7% of cooled babies compared to 14% of uncooled babies. Other vision problems occur at higher rates. Hearing problems also occur more frequently than in the general population.
When HIE-Related Developmental Problems Become Apparent
Some problems are obvious in infancy. Severe cerebral palsy, for example, becomes apparent within the first year or two. Other problems emerge later. Mild motor coordination problems might not be obvious until the child tries to write or participate in sports. Learning problems might not become apparent until school demands increase. Language delays may not be noticed until other children are speaking in complex sentences.
Follow-up studies into later childhood revealed problems that weren’t apparent at 18 to 24 months, the typical age of assessment in clinical trials.
Early Tests and Signs That Help Predict Long-Term Outcomes After HIE
No test perfectly predicts how an individual child will develop, but certain findings in the newborn period correlate with outcomes.
In the first 24 hours, a severely abnormal EEG combined with very low pH and 5-minute Apgar score of 0 predicts death or severe developmental problems with high specificity. But many babies don’t have this exact combination of findings.
MRI performed at 4 to 10 days provides strong prognostic information. Injury to at least two deep gray matter regions has excellent positive predictive value for death or severe disability at age two. The pattern and extent of injury correlate with specific types of problems.
The severity of encephalopathy in the first days of life also predicts outcomes. Babies with mild encephalopathy that resolves quickly usually do well, though recent research shows they’re not entirely without risk. Babies with moderate encephalopathy have intermediate outcomes. Babies with severe encephalopathy have high rates of death or major disability.
Duration of encephalopathy matters. Babies who remain in Sarnat stage 2 for longer than 5 days typically have worse outcomes than those whose encephalopathy resolves more quickly.
No combination of early findings perfectly predicts an individual baby’s outcome. Some babies with concerning findings do better than expected. Some with relatively mild early findings develop problems later. The unpredictability is part of what makes HIE so difficult for families.
Sentinel Events During Labor That Cause Sudden Severe Oxygen Loss
About one-third of HIE cases involve what doctors call sentinel events, specific acute problems occurring during labor or just before delivery.
Sentinel events include placental abruption (the placenta separating from the uterine wall), uterine rupture (the uterus tearing open), cord prolapse (the umbilical cord slipping into the birth canal ahead of the baby), profound bradycardia (severe drop in the baby’s heart rate), severe fetal heart rate abnormalities with deep or prolonged decelerations, shoulder dystocia (the shoulder getting stuck), and massive bleeding.
These events cause sudden, severe oxygen deprivation. The baby may have been completely healthy moments before.
Babies with sentinel events show a different pattern of brain injury on MRI compared to babies without sentinel events. They more commonly have basal ganglia and thalamus injuries rather than watershed injuries. This makes sense because sentinel events cause acute, profound oxygen loss rather than chronic, partial deprivation.
Mortality rates are higher in babies with sentinel events. Brain injury severity is worse on average.
Interestingly, when babies with and without sentinel events are matched for severity of MRI findings, their developmental outcomes at 18 months are similar. This suggests that the MRI findings predict outcomes more strongly than whether a sentinel event occurred.
Placental examination in babies with HIE often reveals chronic abnormalities even when a sentinel event occurred. The association between chronic placental problems and brain injury severity is independent of sentinel events. This suggests that chronic placental insufficiency may make babies more vulnerable to injury from acute events.
Understanding sentinel events helps doctors reconstruct the timing and mechanism of injury. For families, knowing that an identifiable event caused the injury can be both clarifying and agonizing.
When sentinel events are preventable, such as delays in performing cesarean sections after cord prolapse is diagnosed, they raise questions about the quality of care.
Other Causes of Newborn Brain Dysfunction That Are Not HIE
Not every baby born with encephalopathy has HIE. Many conditions cause newborn brain dysfunction that has nothing to do with oxygen deprivation during birth.
This distinction matters enormously. The diagnosis of HIE implies oxygen deprivation occurred around the time of birth. If encephalopathy has a different cause, that diagnosis is incorrect, and so are its implications.
Stroke
Perinatal arterial ischemic stroke occurs when a blood clot blocks a brain artery. Unlike HIE, stroke typically doesn’t associate with non-reassuring fetal heart tracings, sentinel events, low Apgar scores, or metabolic acidosis. Babies with stroke have higher initial platelet counts on average than babies with HIE.
The brain injury pattern on MRI is different, typically showing injury in the distribution of a single artery rather than the watershed or basal ganglia patterns of HIE.
Infections
Meningitis, sepsis, and congenital infections can all cause encephalopathy. Chorioamnionitis, infection of the membranes around the baby, is particularly common and can contribute to brain injury.
One study found that 40% of babies with encephalopathy had chorioamnionitis, and 11% had both chorioamnionitis and a sentinel event during labor. The role of infection in causing or contributing to encephalopathy is still being researched.
Metabolic Disorders That Can Cause Newborn Encephalopathy
Inborn errors of metabolism, mitochondrial disorders, and electrolyte abnormalities like severe low blood sugar or low calcium can cause encephalopathy. These conditions require specific testing to diagnose and specific treatments.
Genetic Conditions and Brain Malformations That Mimic HIE
Structural abnormalities of the brain, genetic syndromes, and congenital hydrocephalus can present with encephalopathy at birth. MRI typically reveals these structural problems.
Bleeding
Intracranial hemorrhage from trauma or bleeding disorders can cause encephalopathy. The bleeding is visible on imaging.
How Doctors Determine If Encephalopathy Is Actually HIE
When a baby is born with encephalopathy, doctors must consider all possible causes, not just HIE.
A detailed history helps identify risk factors for different causes. The clinical exam and Sarnat staging assess severity but don’t prove etiology. Laboratory testing screens for metabolic disorders and infection. Brain imaging, preferably MRI, shows the pattern of injury. EEG reveals brain wave patterns. Genetic testing may be needed. Examination of the placenta can provide important clues.
The ACOG-AAP task force recommends starting with the general diagnosis of neonatal encephalopathy and only sub-classifying as HIE when evidence supports oxygen deprivation as the primary cause. This evidence includes historical factors around the time of birth, MRI findings consistent with hypoxic-ischemic injury, evidence that multiple organs besides the brain were damaged, and absence of other diagnoses that better explain the findings.
Research estimates that oxygen deprivation is the sole cause of encephalopathy in only about 7% of cases. In about 50% of cases, oxygen deprivation contributes but may not be the only factor. The remaining 43% have other causes.
Misdiagnosis matters. If a baby has stroke but is diagnosed with HIE, the implications about the quality of prenatal care and delivery are wrong. If a baby has a genetic condition or metabolic disorder but is diagnosed with HIE, other family members may be affected, but genetic counseling won’t be offered because the wrong diagnosis suggests the cause was external rather than inherited.
Experimental HIE Treatments Being Researched Beyond Cooling
Therapeutic hypothermia represented a breakthrough when it became standard care in the mid-2000s. But even with cooling, more than 40% of babies with moderate to severe HIE die or develop major disabilities. Research continues on treatments that might add to cooling’s benefits.
Erythropoietin
Erythropoietin (EPO) is a hormone that stimulates red blood cell production. It also has effects on the brain separate from its effects on blood. EPO receptors exist on brain cells, and when EPO binds to these receptors, it activates pathways that protect cells from death.
Multiple mechanisms contribute to EPO’s neuroprotective effects. It inhibits apoptosis, the programmed cell death that occurs during secondary energy failure. It reduces inflammation. It may help the brain regenerate damaged areas.
Earlier trials showed that EPO improves outcomes in babies with HIE. Studies have examined EPO as a sole treatment and as an addition to therapeutic hypothermia.
Recent research suggests combining EPO with cooling is safe. The combination might improve outcomes more than cooling alone.
A large randomized trial is currently underway in Nigeria, testing whether EPO improves outcomes compared to routine care in babies with moderate to severe HIE. The trial will follow babies for two years to assess death and developmental outcomes. The hypothesis is that EPO can positively influence outcomes, particularly in resource-limited settings where access to cooling may be inconsistent.
Stem Cell Therapy Research for HIE Treatment
Stem cells represent another potential therapy. Different cell sources are being studied, including cells from the placenta and umbilical cord blood.
The mechanisms by which stem cells might help include neuroprotection, neurorestoration, anti-inflammatory effects, and cell replacement. Stem cells home to areas of injury in the brain.
Preclinical studies in piglets combine stem cell therapy with therapeutic hypothermia, reflecting standard human care. Human placental stem cells don’t cause acute reactions. The cells survive and migrate to injured brain areas.
Research is also examining whether combining stem cells with erythropoietin provides additional benefit.
Stem cell therapy remains experimental. It’s not approved for clinical use outside research trials. But protocols are being designed specifically for potential transfer to human trials.
Other Experimental Drugs Being Studied to Treat HIE
Other potential treatments being investigated include drugs that target specific mechanisms of injury: GABA receptor agonists, NMDA receptor antagonists, drugs that promote growth of new brain cells and blood vessels, glucocorticoids, and antioxidants.
A meta-analysis of trials combining various adjunctive treatments with therapeutic hypothermia found that different agents decreased length of hospital stay but didn’t reduce mortality or developmental impairment. None reduced seizures or abnormal brain imaging findings.
The challenge is that HIE involves multiple overlapping injury mechanisms occurring over different time frames. A drug targeting one mechanism may not address the others.
What Future HIE Treatment Research Is Focusing On
Future progress will likely require better understanding of which molecular targets are most important in the context of hypothermia. Cooling already targets multiple injury mechanisms. Additional treatments need to provide benefit beyond what cooling achieves.
Larger, well-designed clinical trials are needed to determine optimal doses and timing for any new therapy. The combination of cooling with therapies that offer synergistic rather than redundant neuroprotection holds the most promise.
The ultimate goal is not just survival but survival without disability. Even modest improvements in outcomes would benefit many thousands of babies globally each year.
What Life Looks Like After an HIE Diagnosis for Families
An HIE diagnosis transforms life instantly. One moment, you’re expecting to bring home a healthy baby. The next, your child is in the NICU, surrounded by machines, undergoing treatment for brain injury. The immediate crisis eventually gives way to the long-term reality of uncertainty.
The medical aspects of HIE—the Sarnat scores, the MRIs, the cooling protocols—are only part of the story. The other part is what it means to live not knowing how your child will develop, to celebrate every milestone while wondering if the next one will come, to navigate medical systems and educational systems and insurance systems, to explain to family and friends and eventually to your child what happened and why.
Some families dealing with HIE will watch their children grow into teenagers and adults with minimal or no apparent effects. Others will care for children with profound disabilities. Most will fall somewhere in between, with challenges that are significant but not devastating, with strengths in some areas and weaknesses in others, with progress that looks different than expected but is progress nonetheless.
The uncertainty is perhaps the hardest part. In the days after birth, when decisions about cooling must be made, outcomes are unpredictable. MRI provides information, but information isn’t certainty. Even as months pass and developmental patterns emerge, new questions arise. Will walking be possible? Will speech develop? Will learning differences affect school? Will seizures develop?
Understanding HIE helps families ask informed questions, make decisions based on evidence rather than fear, and recognize when something isn’t right so they can seek help. It helps them understand what treatments work, what treatments don’t, and what treatments remain unproven. It helps them evaluate information they receive from medical providers, therapists, and other families.
Knowledge doesn’t make HIE easier. But it can make the path forward clearer, the decisions more informed, and the advocacy for your child more effective.