Perinatal Asphyxia and Hypoxic-Ischemic Encephalopathy

Perinatal Asphyxia and Hypoxic-Ischemic Encephalopathy

Anne R. Hansen

Janet S. Soul

I. PERINATAL ASPHYXIA refers to a condition during the first and second stage of labor in which impaired gas exchange leads to fetal acidosis, hypoxemia, and hypercarbia. It is identified by fetal acidosis as measured in umbilical arterial blood. The umbilical artery pH that defines asphyxia is not the major determinant of brain injury. Although the most widely accepted definition of fetal acidosis is a pH <7.0, the likelihood of brain injury is relatively low with this degree of acidosis. The following terms may be used in evaluating a term newborn at risk for brain injury in the perinatal period:

A. Perinatal hypoxia, ischemia, and asphyxia. These pathophysiologic terms describe respectively, decreased oxygen (O2), blood flow, and gas exchange to the fetus or newborn. These terms should be reserved for circumstances when there are rigorous prenatal, perinatal, and postnatal data to support their use.

B. Perinatal/neonatal depression is a clinical, descriptive term that pertains to the condition of the infant on physical examination in the immediate postnatal period, i.e., in the first hour after birth. The clinical features of infants with this condition may include depressed mental status, muscle hypotonia, and/or disturbances in spontaneous respiration and cardiovascular function.
This term makes no association with the prenatal or later postnatal (i.e., beyond the first hour) condition, physical exam, laboratory tests, imaging studies, or electroencephalograms (EEGs). After the first hour or so of life, neonatal encephalopathy is the preferred descriptive term for infants with persistently abnormal mental status and associated findings.

C. Neonatal encephalopathy is a clinical and not an etiologic term that describes an abnormal neurobehavioral state consisting of an altered level of consciousness (including hyperalert state) and usually other signs of brainstem and/or motor dysfunction. It does not imply a specific etiology, nor does it imply irreversible neurologic injury because it may be caused by such reversible conditions as maternal medications or hypoglycemia.

D. Hypoxic-ischemic encephalopathy (HIE) is a term that describes clinical evidence of encephalopathy as defined earlier, with objective data to support a hypoxic-ischemic (HI) mechanism as the underlying cause for the encephalopathy.

E. Hypoxic-ischemic (HI) brain injury refers to neuropathology attributable to hypoxia and/or ischemia as evidenced by neuroimaging (head ultrasonography [HUS], magnetic resonance imaging [MRI], computed tomography [CT]) or pathologic (postmortem) abnormalities. Biochemical markers of brain injury such as creatine kinase brain bound (CK-BB) and neuron specific enolase (NSE) are not used routinely in clinical practice (see section IX.B).

The diagnosis of HIE and/or HI brain injury is not a diagnosis of exclusion, but ruling out other etiologies of neurologic dysfunction is a critical part of the diagnostic evaluation. When making a diagnosis of HIE, the following information should be documented in the medical record:

1. Prenatal history: complications of pregnancy with emphasis on risk factors associated with neonatal depression, any pertinent family history

2. Perinatal history: concerns of labor and delivery including fetal heart rate (FHR) tracing, biophysical profile, sepsis risk factors, scalp and/or cord pH (specify if arterial or venous), perinatal events such as placental abruption, Apgar scores, resuscitative effort, and immediate postnatal blood gases

3. Postnatal data

a. Admission physical exam with emphasis on neurologic exam and presence of any dysmorphic features

b. Clinical course including presence or absence of seizures (and time of onset), oliguria, cardiorespiratory dysfunction, and treatment (e.g., need for pressor medications, ventilator support)

c. Laboratory testing, including blood gases, electrolytes, evidence of injury to end organs other than the brain (kidney, liver, heart, lung, blood, bowel), and possible evaluation for inborn errors of metabolism

d. Imaging studies

e. EEG and any other neurophysiologic data (e.g., evoked potentials)

f. Placental pathology

II. INCIDENCE. The frequency of perinatal asphyxia is approximately 1.5% of live births in developed countries with advanced obstetric/neonatal care and is inversely related to gestational age and birth weight (BW). It occurs in
0.5% of live-born newborns >36 weeks’ gestation and accounts for 20% of perinatal deaths (50% if stillbirths are included). A higher incidence is noted in newborns of diabetic or toxemic mothers, those with intrauterine growth restriction, breech presentation, and newborns who are postdates.

III. ETIOLOGY. In term newborns, asphyxia can occur in the antepartum or intrapartum period as a result of impaired gas exchange across the placenta that leads to the inadequate provision of O2 and removal of carbon dioxide (CO2) and hydrogen (H+) from the fetus. There is a lack of certainty regarding the timing or severity of asphyxia in many cases. Asphyxia can also occur in the postpartum period, usually secondary to pulmonary, cardiovascular, or neurologic abnormalities.

A. Factors that increase the risk of perinatal asphyxia include the following:

1. Impairment of maternal oxygenation

2. Decreased blood flow from mother to placenta

3. Decreased blood flow from placenta to fetus

4. Impaired gas exchange across the placenta or at the fetal tissue level

5. Increased fetal O2 requirement

B. Etiologies of hypoxia-ischemia may be multiple and include the following:

1. Maternal factors: hypertension (acute or chronic), hypotension, infection (including chorioamnionitis), hypoxia from pulmonary or cardiac disorders, diabetes, maternal vascular disease, and in utero exposure to cocaine

2. Placental factors: abnormal placentation, abruption, infarction, fibrosis, or hydrops

3. Uterine rupture

4. Umbilical cord accidents: prolapse, entanglement, true knot, compression

5. Abnormalities of umbilical vessels

6. Fetal factors: anemia (e.g., from fetal-maternal hemorrhage), infection, cardiomyopathy, hydrops, severe cardiac/circulatory insufficiency

7. Neonatal factors: cyanotic congenital heart disease, persistent pulmonary hypertension of the newborn (PPHN), cardiomyopathy, other forms of neonatal cardiogenic and/or septic shock, respiratory failure due to meconium aspiration syndrome, neonatal pneumonia, pneumothorax, or other etiologies


A. Events that occur during the normal course of labor cause most babies to be born with little O2 reserve. These include the following:

1. Decreased blood flow to placenta due to uterine contractions, some degree of cord compression, maternal dehydration, and maternal alkalosis due to hyperventilation

2. Decreased O2 delivery to the fetus from reduced placental blood flow

3. Increased O2 consumption in both mother and fetus

B. Hypoxia-ischemia causes a number of physiologic and biochemical alterations:

1. With brief asphyxia, there is a transient increase, followed by a decrease in heart rate (HR), mild elevation in blood pressure (BP), an increase in central venous pressure (CVP), and essentially no change in cardiac output (CO). This is accompanied by a redistribution of CO with an increased proportion going to the brain, heart, and adrenal glands (diving reflex). When there is severe but brief asphyxia (e.g., placental abruption then stat cesarian section), it is thought that this diversion of blood flow to vital deep nuclear structures of the brain does not occur, hence results in the typical pattern of injury to the subcortical and brainstem nuclei.

2. With prolonged asphyxia, there can be a loss of pressure autoregulation and/or CO2 vasoreactivity. This, in turn, may lead to further disturbances in cerebral perfusion, particularly when there is cardiovascular involvement with hypotension and/or decreased CO. A decrease in cerebral blood flow (CBF) results in anaerobic metabolism and eventual cellular energy failure due to increased glucose utilization in the brain and a fall in the concentration of glycogen, phosphocreatine, and adenosine triphosphate (ATP). Prolonged asphyxia typically results in diffuse injury to both cortical and subcortical structures, with greater injury to neuronal populations particularly susceptible to HI insults.

C. Cellular dysfunction occurs as a result of diminished oxidative phosphorylation and ATP production. This energy failure impairs ion pump function, causing accumulation of intracellular Na+, Cl, H2O, and Ca2+; extracellular K+; and excitatory neurotransmitters (e.g., glutamate). Impaired oxidative phosphorylation can occur during the primary HI insult(s) as well as during a secondary energy failure that usually begins approximately 6 to 24 hours after the initiating insult. Cell death can be either immediate or delayed and either necrotic or apoptotic.

1. Immediate neuronal death (necrosis) can occur due to intracellular osmotic overload of Na+ and Ca2+ from ion pump failure as above or excitatory neurotransmitters acting on inotropic receptors (such as the N-methyl-D-aspartate [NMDA] receptor).

2. Delayed neuronal death (apoptosis) occurs secondary to uncontrolled activation of enzymes and second messenger systems within the cell (e.g., Ca2+-dependent lipases, proteases, and caspases), perturbation of mitochondrial respiratory electron chain transport, generation of free radicals and leukotrienes, generation of nitric oxide (NO) through NO synthase, and depletion of energy stores.

3. Reperfusion of previously ischemic tissue may cause further injury because it can promote the formation of excess reactive oxygen species (e.g., superoxide, hydrogen peroxide, hydroxyl, singlet oxygen), which can overwhelm the endogenous scavenger mechanisms, thereby causing damage to cellular lipids, proteins, and nucleic acids as well as to
the blood-brain barrier. This may result in an influx of neutrophils that, along with activated microglia, release injurious cytokines (e.g., interleukin 1-β and tumor necrosis factor α).


A. Perinatal assessment of risk includes awareness of preexisting maternal or fetal problems that may predispose to perinatal asphyxia (see section III) and of changing placental and fetal conditions (see Chapter 1) ascertained by ultrasonographic examination, biophysical profile, and nonstress tests.

B. Low Apgar scores and need for resuscitation in the delivery room are common but nonspecific findings. Many features of the Apgar score relate to cardiovascular integrity and not neurologic dysfunction resulting from asphyxia.

1. In addition to perinatal asphyxia, the differential diagnosis for a term newborn with an Apgar score ≤3 for ≥10 minutes includes depression from maternal anesthesia or analgesia, trauma, infection, cardiac or pulmonary disorders, neuromuscular, and other central nervous system (CNS) disorders or malformations.

2. If the Apgar score is >6 by 5 minutes, perinatal asphyxia is not likely.

C. Umbilical cord or first blood gas determination. The specific blood gas criteria that define asphyxia causing brain damage are uncertain; however, the pH and base deficit on the cord or first blood gas is helpful for determining which infants have asphyxia that indicates need for further evaluation for the development of HIE. In the randomized clinical trials of hypothermia for neonatal HIE, severe acidosis was defined as pH ≤7.0 or base deficit ≥16 mmol/L.

D. Clinical presentation and differential diagnosis. HIE should be suspected in encephalopathic newborns with a history of fetal and/or neonatal distress and laboratory evidence of asphyxia. The diagnosis of HIE should not be overlooked in scenarios such as meconium aspiration, pulmonary hypertension, birth trauma, or fetal-maternal hemorrhage, where HIE may be missed because of the severity of pulmonary dysfunction, anemia, or other clinical manifestations. The diagnosis of neonatal encephalopathy includes a number of etiologies in addition to perinatal hypoxia-ischemia. Asphyxia may be suspected and HIE reasonably included in the differential diagnosis when there is:

1. Prolonged (>1 hour) antenatal acidosis

2. Fetal HR <60 beats per minute

3. Apgar score ≤3 at ≥10 minutes

4. Need for positive pressure ventilation for >1 minute or first cry delayed >5 minutes

5. Seizures within 12 to 24 hours of birth

6. Burst suppression or suppressed background pattern on EEG or amplitude-integrated electroencephalogram (aEEG)

VI. NEUROLOGIC SIGNS. The clinical spectrum of HIE is described as mild, moderate, or severe (Table 55.1). EEG is useful to provide objective data to grade the severity of encephalopathy.

A. Encephalopathy. Newborns with HIE must have abnormal consciousness by definition, whether mild, moderate, or severe. Mild encephalopathy can consist of an apparent hyperalert or jittery state, but the newborn does not respond appropriately to stimuli, and thus consciousness is abnormal. Moderate and severe encephalopathy are characterized by more impaired responses to stimuli such as light, touch, or even noxious stimuli. The background pattern detected by EEG or aEEG is useful for determining the severity of encephalopathy.

B. Brainstem and cranial nerve abnormalities. Newborns with HIE may have brainstem dysfunction, which may manifest as abnormal or absent brainstem reflexes, including pupillary, corneal, oculocephalic, cough, and gag reflexes. There can be abnormal eye movements such as dysconjugate gaze, gaze preference, ocular bobbing or other abnormal patterns of bilateral eye movements, or an absence of visual fixation or blink to light. Newborns may show facial weakness (usually symmetric) and have a weak or absent suck and swallow with poor feeding. They can have apnea or abnormal respiratory patterns.

C. Motor abnormalities. With greater severity of encephalopathy, there is generally greater hypotonia, weakness, and abnormal posture with lack of flexor tone, which is usually symmetric. With severe HIE, primitive reflexes such as the Moro or grasp reflex may be diminished. Over days to weeks, the initial hypotonia may evolve into spasticity and hyperreflexia if there is significant HI brain injury. Note that if a newborn shows significant hypertonia within the first day or so after birth, the HI insult may have occurred earlier in the antepartum period and have already resulted in established HI brain injury.

D. Seizures occur in up to 50% of newborns with HIE and usually start within 24 hours after the HI insult. Seizures indicate that the severity of encephalopathy is moderate or severe, not mild.

1. Seizures may be subtle, tonic, or clonic. It can sometimes be difficult to differentiate seizures from jitteriness or clonus, although the latter two are usually suppressible with firm hold of the affected limb(s).

2. Because seizures are often subclinical (electrographic only) and abnormal movements or posture may not be seizure, EEG remains the gold standard for diagnosing neonatal seizures, particularly in HIE.

3. Seizures may compromise ventilation and oxygenation, especially in newborns who are not receiving mechanical ventilation. It is important to adequately support respiration to avoid additional hypoxic injury.

E. Increased intracranial pressure (ICP) resulting from diffuse cerebral edema in HIE often reflects extensive cerebral necrosis rather than swelling of intact cells and indicates a poor prognosis. Treatment to reduce ICP does not affect outcome.

Table 55.1. Sarnat and Sarnat Stages of Hypoxic-Ischemic Encephalopathy*


Stage 1 (Mild)

Stage 2 (Moderate)

Stage 3 (Severe)

Level of consciousness

Hyperalert; irritable

Lethargic or obtunded

Stuporous, comatose

Neuromuscular control:

Uninhibited, overreactive

Diminished spontaneous movement

Diminished or absent spontaneous movement

Muscle tone


Mild hypotonia



Mild distal flexion

Strong distal flexion

Intermittent decerebration

Stretch reflexes


Overactive, disinhibited

Decreased or absent

Segmental myoclonus

Present or absent



Complex reflexes:






Weak or absent



Strong, low threshold

Weak, incomplete, high threshold





Weak or absent

Tonic neck




Autonomic function:

Generalized sympathetic

Generalized parasympathetic

Both systems depressed




Midposition, often unequal; poor light reflex



Spontaneous; occasional apnea

Periodic; apnea

Heart rate




Bronchial and salivary secretions




Gastrointestinal motility

Normal or decreased

Increased, diarrhea




Common focal or multifocal (6-24 hours of age)

Uncommon (excluding decerebration)

Electroencephalographic findings

Normal (awake)

Early: generalized low voltage, slowing (continuous delta and theta)

Early: periodic pattern with isopotential phases

Later: periodic pattern (awake); seizures focal or multifocal; 1.0-1.5 Hz spike and wave

Later: totally isopotential

Duration of symptoms

<24 hours

2-14 days

Hours to weeks


About 100% normal

80% normal; abnormal if symptoms more than 5-7 days

About 50% die; remainder with severe sequelae

*The stages in this table are a continuum reflecting the spectrum of clinical states of newborns over 36 weeks’ gestational age.

Source: From Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976;33:696-705.

VII. MULTIORGAN DYSFUNCTION. Other organ systems in addition to the brain usually exhibit evidence of asphyxial damage. In a minority of cases (<15%), the brain may be the only organ exhibiting dysfunction following asphyxia. In most cases, multiorgan dysfunction occurs as a result of systemic hypoxiaischemia. The frequency of organ involvement in perinatal asphyxia varies among published series, depending in part on the definitions used for asphyxia and organ dysfunction.

A. The kidney is the most common organ to be affected in the setting of perinatal asphyxia. The proximal tubule of the kidney is especially affected by decreased perfusion, leading to acute tubular necrosis (ATN) with oliguria and a rise in serum creatinine (Cr) (see Chapter 28).

B. Cardiac dysfunction is caused by transient myocardial ischemia. The electrocardiogram (ECG) may show ST depression in the midprecordium and T-wave inversion in the left precordium. Echocardiographic findings
include decreased left ventricular contractility, especially of posterior wall; elevated ventricular end-diastolic pressures; tricuspid insufficiency; and pulmonary hypertension. In severely asphyxiated newborns, dysfunction more commonly affects the right ventricle. A fixed HR may indicate severe brainstem injury.

C. Pulmonary effects include increased pulmonary vascular resistance leading to PPHN, pulmonary hemorrhage, pulmonary edema due to cardiac dysfunction, and meconium aspiration.

D. Hematologic effects include disseminated intravascular coagulation (DIC), poor production of clotting factors due to liver dysfunction, and poor production of platelets by the bone marrow.

E. Liver dysfunction may be manifested by isolated elevation of hepatocellular enzymes. More extensive damage may occur, leading to DIC, inadequate glycogen stores with resultant hypoglycemia, slowed metabolism, or elimination of medications.

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Oct 27, 2018 | Posted by in PEDIATRICS | Comments Off on Perinatal Asphyxia and Hypoxic-Ischemic Encephalopathy

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