eMedicine Specialties > Neurology > Pediatric Neurology

Hypoxic-Ischemic Brain Injury in the Newborn

Author: Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Coauthor(s): Dennis WW Shaw, MD, Professor, Department of Radiology, Department of Radiology, University of Washington School of Medicine; Consulting Staff, Children's Hospital and Regional Medical Center of Seattle
Contributor Information and Disclosures

Updated: Apr 4, 2006

Introduction

Background

In the immediate newborn period, many factors can produce neurologic symptoms mimicking those of HIE, including prepartum and postpartum ischemia/hypoxemia, genetic factors, metabolic disease, and maternal and fetal drug use. Because the relationship between asphyxia and HIE cannot always be established, the term newborn encephalopathy (NE) was proposed as an alternative to remove the medicolegal implications of HIE. Newborn NE is a clinically defined syndrome of disturbed neurologic function in full-term infants that attempts to correlate symptoms in the neonatal period that have some relationship with neurologic outcomes in childhood. NE symptoms may or may not be causally linked to hypoxemia/ischemia. Far from fixing the problem, use of the term NE just removes from obstetric practitioners the unfair blame they receive for poor neonatal outcomes.

The National Collaborative Perinatal Project (NCPP), a prospective study of more than 50,000 pregnancies and 40,000 infants, was conducted to analyze the features of NE. Its results showed that the following were associated with increased morbidity on follow-up examination: decreased activity after the first day of life, need for incubator more than 3 days, feeding problems, poor suck, and respiratory difficulties.

Other factors not mentioned in the description of NE syndrome have been associated with postneonatal morbidity. Examples are static motor deficits (cerebral palsy [CP]), mental retardation, and epilepsy. These factors include neonatal seizures, low 10-minute Apgar scores, stupor, and coma.

Pathophysiology

General principles of perinatal ischemia and hypoxemia

In fetal life, hypoxic-ischemic disturbances are primarily a consequence of hypoperfusion because the arterial partial pressure of oxygen (PaO₂) normally is low. Despite this, severe hypoxemia can occur, leading to myocardial dysfunction with subsequent cerebral hypoperfusion or loss of cerebrovascular autoregulation. This cerebral hypoperfusion in turn may lead to neuronal ischemia.

Primary perinatal hypoxemia

In utero hypoxemia is usually the result of placental insufficiency, and infants who have experienced in utero hypoxemia often have clinically significant respiratory or cardiac failure after birth. By comparison, postnatal hypoxemia is the result of either respiratory or cardiac insufficiency, alone or in combination. Primary perinatal hypoxemia can derange the already fragile cerebrovascular autoregulation of the neonatal brain (see Pressure-passive cerebral circulation). This may explain why severe surfactant deficiency syndrome is associated with certain patterns of neuronal damage, such as periventricular leukomalacia (PVL).

Perinatal ischemia

Severe cardiac contractile dysfunction due to either major cardiac malformations or severe hypoxemia leads to cerebral hypoperfusion and loss of cerebrovascular regulation. Circulatory insufficiency can result from severe prenatal or postnatal hemorrhage or neonatal sepsis. In response to hypoxic-ischemic insults, circulatory rearrangement of the cardiac output occurs, with shunting of blood flow away from the liver, kidneys, gut, lungs, and skeletal muscle into the heart, brain, and adrenal glands of the infant. This shunting explains the coexistence of liver and kidney failure in cases of severe HIE-NE. This initial reaction to systemic hypoxia and ischemia in the newborn is one of lowering the heart rate and increasing blood pressure to maintain a near-normal cardiac output.

With progression of the hypoxic-ischemic state, the heart rate, blood pressure, and cardiac output decrease substantially; systemic metabolic acidosis increases partly because of the production of lactic acid.

In the neonatal period, autoregulation of cerebral circulation is impaired. This autoregulation is further impaired by both hypoxemia and hypercarbia, which leaves the cerebral circulation in a pressure-passive state. In this state, cerebral perfusion changes as intravascular pressure changes. The immature cerebral arteries have a limited ability to adapt to hypotensive episodes. This occurrence may be especially important in the genesis of the parasagittal pattern of cerebral injury observed after hypotension. The other extreme of the range of arterial pressure may also be problematic because the decreased upper limit of autoregulation may increase the risk of periventricular and intraventricular hemorrhage.

Poor perfusion of the depths of the sulci

In the neonatal period, relatively underperfusion affects the depths of the sulci, creating a zone of increased susceptibility to hypotensive insults. This effect may lead to gyri that resemble mushrooms owing to atrophy of their base near the deep parts of the sulci.

Excitatory neurotransmitter toxicity (excitotoxicity)

A large body of evidence indicates that certain excitatory neurotransmitters (ie, amino acids, especially glutamate) are excessively released at the synaptic cleft during conditions of hypoxia-ischemia. These excitotoxins may play a critical role in the neuronal damage observed during low-energy states. The evidence linking excitotoxins to ischemic cell death include the following: (1) Synaptic activity is necessary for hypoxic cell death. (2) Specific glutamate antagonists prevent hypoxic cell death. (3) Glutamate exposure mimics hypoxic cell death. (4) Glutamate accumulates extracellularly in vivo during hypoxia (because of increased release and decreased uptake). (5) The topography of neuronal death with hypoxia is similar to that of glutamate synapses. The regional distribution of glutamatergic neurons may explain some of the patterns of injury seen in the cerebrum after hypoxia-ischemia. Hypoglycemia and hyperthermia may potentiate the deleterious effect of ischemia on the CNS.

Increased sensitivity of white matter to ischemic damage in premature neonates (excitotoxicity)

A sensitivity to hypoxic-ischemic damage has been observed in premature infants. This pattern of brain damage has been traditionally attributed to developmental changes in the arterial watershed zones in immature fetuses (and premature infants). Over the past decade, the trajectory of these vessels producing a periventricular watershed zone has been questioned. On the contrary, new information shows that the oligodendrocyte and its precursors are susceptible to injury in the fetus. Some of that finding may be related to immature handling of oxygen radicals.

Mortality/Morbidity

See Prognosis.

Clinical

History

Overall, a patient with a history of problems during labor and delivery followed by difficulties during resuscitation in the delivery room (eg, low Apgar scores at 10 minutes, delayed respiratory effort), with subsequent development of a severely depressed level of consciousness (eg, stupor or coma), especially in association with ventilatory disturbances (eg, apnea, respiratory failure) and seizures, is likely to have long-term neurologic morbidity.

• Full-term infants
  • Many clinical features of neonatal HIE are nonspecific; as such, the diagnosis must be made with caution and only after careful examination of historical, physical-neurologic, and laboratory data. Antepartum factors that may be associated with neonatal HIE include the following:
    • Maternal diabetes
    • Pregnancy-induced hypertension
    • Intrauterine growth retardation (IUGR)
    • Maternal hypotension-shock
    • Severe bleeding
    • Placental insufficiency
    • Abruptio placentae
    • Cord prolapse
    • Prolonged expulsive period
    • Dystocia
  • NE is a clinically defined syndrome of disturbed neurologic function in full-term infants. It includes decreased activity after the first day of life, need for an incubator after 3 days, feeding problems, poor suck, and respiratory difficulties. These criteria for NE were used in the analysis of the NCPP.
  • In the NCPP, neonatal seizures were associated with high rates of mortality and morbidity, including CP, mental retardation, and epilepsy. In the same cohort, the number of days of neonatal seizures also was correlated with neurologic disability. The timing of neonatal seizures was associated with risk of death, not with risk of long-term motor deficits.
  • A history of low Apgar scores at 1 and 5 minutes is commonly used as an indicator of HIE and subsequent morbidity, but this index has several drawbacks (see Physical).
  • A history of birth trauma, especially in association with problems in the expulsive period of delivery (eg, severe dystocia), may play a role in HIE-NE. Nonetheless, when analyzed properly, obstetric complications (eg, birth trauma, dystocia, cord prolapse) are not useful in predicting the outcome of the newborn unless they are followed by low late Apgar scores, signs of NE, depressed level of consciousness, or neonatal seizures.
  • Extracorporeal membrane oxygenation (ECMO) is associated with clinically significant morbidity in term neonates with serious pulmonary disease.
• Preterm infants
  • In premature neonates, the patient's history is essential for diagnosis.
  • PVL is the most typical lesion in the preterm infant with NE. PVL is associated with the following historical findings: maternal hypotension, twin pregnancy, fetal or maternal arrhythmia, severe postnatal respiratory or cardiac disease associated with hypotension (<30 mm Hg), acidosis, and heart failure. Premature newborns who are small for their gestational age are particularly vulnerable to PVL. PVL has also been noted in small premature infants who had no evidence of hypotension.

Physical

A full-term newborn with clinically significant intrapartum hypoxic-ischemic insults, enough to cause permanent neurologic sequelae should have abnormal findings on neurologic examination in the first week of life. However, an infant with significant prepartum injury to the brain in this period may be entirely asymptomatic in the neonatal period.

• Renal, cardiac, and pulmonary systems: Renal, cardiac, and pulmonary dysfunction often occur after a presumed hypoxemic insult. The true frequency of the co-occurrence of neurologic and other systemic (eg, renal, cardiac, pulmonary, liver) dysfunction is difficult to establish.
• Apgar scores: Apgar scores at 1 and 5 minutes are commonly used to predict late morbidity, despite their poor correlation with long-term outcomes.
• Mental status
  • As the patient wakes up, spontaneous movements and eye opening demonstrate his or her level of arousal.
  • Constant crying and irritability is evidence of an excessively aroused or hyperalert state.
  • Stupor and coma are poor prognostic signs in the absence of alternative reversible causes, such as high phenobarbital levels (>30-50 mcg/mL).
  • The patient's level of consciousness should be recorded as his or her best motor response.
  • The examiner also should detail the type of movement (eg, withdrawal, triple flexion, localization of pain) elicited as the patient's reaction to the stimulus.
• Cranial nerves
  • Lack of reflex activity mediated by the cranial nerves can indicate brainstem dysfunction.
  • Full-term infants should blink and sustain eye closure in response to a sustained light stimulus. Repeated flashes of light should produce habituation (eg, attenuated blinking) after 3-4 stimuli. Virtually all full-term newborns can track a ball of red wool, and the movement of stripes of at least one eighth of an inch or bigger can elicit opticokinetic nystagmus. Objects and pictures with round contours and facial appearances also make good targets for tracking in the newborn. Tracking is possible in infants with complete destruction of the occipital cortex by virtue of a subcortical pulvinar-collicular system. Retinal hemorrhages are commonly observed in the neonate after vaginal delivery. Pupillary reflexes are reliably present at term.
  • Neurologic examination may be difficult in the small and frail premature infant, but weakness of the lower extremities sometimes reflects the neuropathologic substrate of PVL. Over time, the patient with periventricular white-matter lesions develops spastic diplegia affecting the lower extremities more than the upper extremities.
  • Blinking to light starts at 26 weeks gestational age, sustained eye closure to light is seen around 32 weeks, and 90% of newborns track a ball of red wool by 34 weeks. Opticokinetic reflexes can be seen at 36 weeks. The pupil starts reacting to light around 30 weeks, but the light reflex is not consistently assessable until the gestational age of 32-35 weeks. Extraocular movements can be elicited by performing the doll's-eye maneuver at 25 weeks and by performing caloric stimulation at 30 weeks.
  • In infants aged 32-34 weeks, suck and swallow are reasonably coordinated with breathing, but the actions are not perfected until after term.
  • Patients with mild HIE-NE often have mydriasis. Progression of the disease may produce miosis (even in the dark) responsive to light, and in severe cases (stage 3 of Sarnat classification), the pupils are small or midpositioned and poorly reactive to light, reflecting sympathetic or parasympathetic dysfunction.
  • The lack of pupillary, eye movement, corneal, gag, and cough reflexes may reflect damage to the brainstem, where the cranial-nerve nuclei are located. Decreased respiratory drive or apnea can be from lesions of the respiratory center, which overlap with vagal nuclei (ambiguous and solitaire) or medullary reticular formation. Ventilatory disturbances in HIE may manifest as periodic breathing apnea (similar to Cheyne-Stokes respiration) or just decreased respiratory drive.
• Motor function
  • Begin the motor examination of an infant with suspected HIE-NE by qualitatively and quantitatively observing his or her posture and spontaneous movements. Asymmetry in the amount of movement and posture is a subtle sign of hemiparesis, but it may be the only focal feature of the examination. Slight stimulation (eg, gently touching the patient) can increase motor activity in the term neonate and may be helpful in demonstrating asymmetrical hemiparesis.
  • Eliciting the Moro reflex may be an excessive stimulus and mask a subtle asymmetry in limb movement. Asymmetry in the Moro reflex is seen in peripheral lesions (eg, those due to brachial plexus injury).
  • Total absence or paucity of spontaneous movements, especially if associated with no reaction to painful stimuli and generalized hypotonia indicates brainstem dysfunction or severe, diffuse, or multifocal cortical damage.
  • Specific patterns of motor weakness indicate cerebral injury patterns. Patients with parasagittal injury tend to have proximal-greater-than-distal and upper extremity–more-than–lower extremity weakness. A unilateral, focal infarct, especially one involving the middle cerebral artery, causes contralateral hemiparesis and focal seizures. Patients with selective neuronal necrosis may have severe hypotonia, stupor, and coma.
  • Motor examination of a newborn with large unilateral lesions may reveal mild hemiparesis and seizures in as many as 80%. The seizures often are partial (focal) and contralateral to the cortical lesion. Neonates with severe bilateral infarcts may have quadriparesis. Moro and tonic neck reflexes do not habituate, reflecting the lack of cortical modulation, which attenuates the response after repeated trials or sustained stimulus. Newborns with diencephalic lesions cannot regulate their temperature and have problems with sleep-wake cycles. The long-term sequelae of focal or multifocal cerebral necrosis include spastic hemiparesis and quadriparesis (eg, bilateral hemiparesis), cognitive deficits, and seizures.
  • Foot-ankle dorsiflexion or triple flexion (eg, foot-ankle dorsiflexion, knee and hip flexion) after plantar stimulation reflects only an intact spinal cord and sensory and motor nerves. Extensor movements (eg, arm elevation above the level of the shoulders) are more sophisticated motor actions than the dorsiflexion or triple flexion and require some cortical function.
  • A tonic neck reflex is performed by turning the patient's head to 1 side. The patient appears to be observing the arm and leg extension on the side to which the head is turned and flexion on the opposite side. The tonic neck reflex posture should go away after several seconds, and its persistence is a sign of cortical dysfunction.
  • Spasticity is a velocity-dependent increase in tone that is generally most prominent with limb extension in muscle groups with antigravitational action (arm flexion, plantar extension). This sign can be seen over time in infants with corticospinal tract damage caused by a hypoxic-ischemic insult. In the neonatal period, spasticity is commonly noted first and is most prominent in the distal parts of the extremities. All fingers are flexed with the thumb under the second to fifth fingers, a pattern commonly referred to as cortical thumbs. Fewer than 5-10 beats of ankle clonus may be present in healthy neonates, but infants with damage to the corticospinal tract may have sustained ankle clonus.
  • Hip abduction may be seen with increased tone and even with decerebrate posturing. Another manifestation of CNS dysfunction in the neonatal period is increased axial extensor tone with arching of the back and neck extension or opisthotonus. Many infants simultaneously have decreased axial flexor tone (eg, major head lag on arm traction maneuver) and increased axial extensor tone. In many cases, limb and axial hypotonia are present for several months before increased axial extensor tone or limb spasticity can be detected.
• Seizures
  • HIE is often reported to be the most frequent cause of neonatal seizures. They usually occur 12-24 hours after birth and are difficult to control with anticonvulsants. Large, unilateral infarcts occur with neonatal seizures in as many as 80% of patients. Seizures are often partial (focal) and contralateral to the cortical lesion. About two thirds of newborns with cerebral venous infarcts have seizures. Those with multiple or diffuse lesions and cerebral venous infarcts often have multifocal or migratory seizures. Seizures are observed during physical examination and may confirm the diagnosis. Observation often reveals clonic rhythmic contractions. When holding the limb affected by clonic seizures, the examiner's hand shakes or feels limb movement. Limb flexion or extension does not suppress the clonic activity, as it does in jitteriness and clonus.
  • Tonic unilateral or focal seizures consistently have an EEG signature. In the seizures, unilateral arm and leg posturing is often accompanied by ipsilateral trunk flexion. Generalized tonic posturing (eg, extension of the upper and lower extremities or extension of the legs and flexion of the arms) is related to an EEG seizure in 15% of affected neonates. Tonic seizures can be seen in neonates with local anesthetic intoxication. Although generalized tonic posturing is infrequently associated with electrical seizures, it is not a benign sign. Of neonates with tonic posturing and an abnormal EEG background, 13% have normal development. Mizrahi and Kellaway (1987) suggested the name brainstem release phenomena because tonic posturing and some subtle seizurelike motor automatisms (see below) are probably the result of primitive brainstem and spinal motor patterns liberated because the lack of inhibition from damaged forebrain structures.
  • Subtle seizures may be a part of the HIE-NE picture. Subtle manifestations of neonatal seizures are confirmed on EEG and include apnea; tonic eye deviation; sustained eye opening; slow, rhythmic, tongue thrusting; and boxing and swimming movements. Most still accept that some subtle seizures may be correlated with EEG results. However, publications since the late 1980s have shown that seizures are not as frequent as previously thought and that they are unusual in patients close to term. Several other patterns of subtle neonatal seizures are described without EEG confirmation. The lack of an EEG signature does not exclude CNS pathology because neonates with HIE often have motor automatisms without EEG seizures.
  • Seizures may be difficult to clinically diagnose in the premature neonate. Subtle seizures associated with ictal EEG changes are not rare in premature infants. The subtle patterns of neonatal seizures in the premature infant include sustained eye opening, oral-buccal-lingual movements (smacking, drooling, chewing), pedaling movements, grimacing, and autonomic manifestations.
• Grading systems for HIE
  • Several systems have been created to measure the severity and monitor the progress of the encephalopathic signs and symptoms in neonates after a presumed hypoxic-ischemic insult. These systems have some usefulness, but they are criticized because they were validated with retrospectively collected data. Most of these systems fail to consider the predictive values of each component separately. Some systems also fail to account for toxic, infectious, or metabolic factors masquerading as, or superimposed on, HIE.
  • Sarnat and Sarnat system: The system Sarnat and Sarnat created in 1976 is still one of the most popular and the basis for most modern systems. The authors advise that drugs and other conditions that may produce neonatal neurologic alterations similar to those of HIE-NE should be excluded. Their system also uses EEG to help predict the outcome.
    • Stage 1: Stage 1 relies on the finding of an early syndrome characterized by hyperalertness (eg, decreased sleep) and sympathetic activation (eg, eyes wide open, decreased blinking, mydriasis), excessive reaction to stimuli, weak suck with normal tone, and EEG findings. This stage lasts less than 24 hours, and patients who remain in stage 1 have normal neurologic outcomes.
    • Stage 2: Patients progressing to stage 2 have mild hypotonia, are lethargic or obtunded (eg, delayed and incomplete response to sensory stimuli), clinical seizures, parasympathetic activation with miosis (even on the dim light), slowed heart rate ( <120 bpm), increased peristalsis, and copious secretions. Early on, EEG shows relatively low-voltage amplitude (<25 µV in the slow theta and delta range). On the second day, the EEG demonstrates a bursting pattern during wakefulness or obtundation (which worsens during sleep) and multifocal, low-frequency (1- to 1.5-Hz) EEG seizures with a central or temporal predominance. If the EEG recovers within 5 days, it becomes completely normal. If the recovery takes more than 5 days, low-amplitude slowing is noted.Stage 2 lasts 2-14 days. Clinical and EEG recovery within 5 days is associated with a good prognosis. Periodic EEG may indicate a poor prognosis if interburst intervals are totally isoelectric or if the bursting frequency is less than every 6 seconds, with a bursting pattern (every 3-6 seconds) lasting more than 7 days.
    • Stage 3: Stage 3 is characterized by stupor with response to only strong stimuli, with withdrawal or decerebrate posturing, severe hypotonia (eg, flaccidity) and suppression of deep tendon reflexes, primitive (eg, Moro, tonic neck, suck) reflexes, and brainstem (eg, corneal, oculocephalic, gag) reflexes. Clinical seizures are less frequent in stage 3 than in stage 2. The patient has generalized sympathetic or parasympathetic autonomic dysfunction with abnormal respiration and small or midposition pupils that are poorly reactive to light. EEG shows a deepened periodic pattern with increased amplitude and decreased frequency of bursts (every 6-12 seconds). Further worsening of the picture leads to a very-low-voltage or isoelectric EEG.
  • Lipper postasphyxial index: Findings on neurologic examination can be scored by using the Lipper postasphyxial index, in which points are assigned to normal findings. The index, when calculated in the first 48 hours of life, is correlated with neurodevelopmental outcomes at 1 year of age.
• Miller system: Most recently, Miller and collaborators from the University of California at San Francisco validated a simple scoring system based on the typical signs and symptoms of NE. The maximum score from the first 3 days of life is used for prognostication. In their study, no scoring was done when the subjects were sedated or paralyzed. Table 1. Scoring in the Miller System to Stage HIE

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  Table

  Sign or Symptom	Score = 0	Score = 1
  Feeding	Normal	Gavage feeds, gastrostomy tube, or feeding by mouth not tolerated
  Alertness	Alert	Irritable, poorly responsive, or comatose
  Tone	Normal	Hypotonia or hypertonia
  Respiratory status	Normal	Respiratory distress (need for CPAP or mechanical ventilation)
  Reflexes	Normal	Hyperreflexia, hyporeflexia, or absent reflexes
  Seizure	None	Suspected or confirmed clinical seizure

  Sign or Symptom	Score = 0	Score = 1
  Feeding	Normal	Gavage feeds, gastrostomy tube, or feeding by mouth not tolerated
  Alertness	Alert	Irritable, poorly responsive, or comatose
  Tone	Normal	Hypotonia or hypertonia
  Respiratory status	Normal	Respiratory distress (need for CPAP or mechanical ventilation)
  Reflexes	Normal	Hyperreflexia, hyporeflexia, or absent reflexes
  Seizure	None	Suspected or confirmed clinical seizure

  Note.—Total score = 0-6. CPAP = continuous positive airway pressure.

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