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Perinatal Asphyxia

Lisa M. Adcock

Lu-Ann Papile

I. PERINATAL ASPHYXIA

refers to a condition of impaired gas exchange that leads, if persistent, to fetal hypoxemia and hypercarbia. It occurs during the first and second stage of labor and is identified by fetal acidosis, as measured in umbilical arterial blood. The umbilical artery pH that defines asphyxia of a sufficient degree to cause brain injury is unknown. Although the most widely accepted definition is a pH 36 weeks' gestation and accounts for 20% of perinatal deaths (50% if stillborns are included). A higher incidence is noted in term infants of diabetic or toxemic mothers, infants with intrauterine growth restriction, breech presentation, and postdates infants.

III. ETIOLOGY.

In term infants, 90% of asphyxial events occur in the antepartum or intrapartum period as a result of impaired gas exchange across the placenta that leads to the inadequate provision of oxygen (O2) and removal carbon dioxide (CO2) and H+ from the fetus. The remainder of these events occurs in the postpartum period and is 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.

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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 perinatal hypoxia-ischemia include the following:

1. Maternal factors: hypertension (acute or chronic), infection, diabetes, hypotension, vascular disease, drug use, and hypoxia due to pulmonary, cardiac, or neurologic disease.

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

3. Uterine rupture.

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

5. Abnormalities of umbilical vessels.

6. Fetal factors: anemia, infection, cardiomyopathy, hydrops, severe cardiac/ circulatory insufficiency.

7. Neonatal factors: severe neonatal hypoxia due to cyanotic congenital heart disease, persistent pulmonary hypertension of the newborn (PPHN), cardiomyopathy, other forms of neonatal cardiogenic and/or septic shock.

IV. PATHOPHYSIOLOGY

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, maternal alkalosis due to hyperventilation.

2. Decreased O2 delivery to the fetus as a result of the reduction of placental blood flow.

3. Increased O2 consumption in both mother and fetus.

B.

During labor complicated by a hypoxic-ischemic challenge, the following changes may occur:

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).

2. With prolonged asphyxia cerebral blood flow becomes dependent on systemic BP (loss of cerebral vascular autoregulation). A decrease in CO leads to hypotension and impaired cerebral blood flow resulting in anaerobic metabolism and eventual intracellular energy failure due to an increase in the utilization of glucose in the brain and a fall in the concentration of glycogen, phosphocreatine, and adenosine triphosphate (ATP).

3. Hypoxia-induced vascular dilatation increases glucose availability, at least transiently; and anaerobic metabolism produces lactic acid.

C.

Cellular changes occur due to 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 amino acid (EAA) neurotransmitters (e.g., glutamate). Impairment of oxidative phosphorylation can occur during the primary asphyxial episode as well as during a secondary energy failure that usually occurs approximately 6 to 24 hours after the initiating insult. Cell death can be either immediate or delayed, and either apoptotic or necrotic.

1. Immediate neuronal death can occur due to intracellular osmotic overload of Na+ and Ca2+, as seen with excessive EAA acting on inotropic glutamate receptors (such as the N-methyl-D-aspartate [NMDA) receptor])

2. Delayed neuronal death 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; or depletion of energy stores.

3. EAA also can activate α-3-hydroxy-5-methyl-isoxazole (AMPA) receptor channels, leading to oligodendrocyte progenitor cell death.

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4. Reperfusion of previously ischemic tissue may cause injury as 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 [IL-1 β] and tumor necrosis factor α [TNF-α]).

V. DIAGNOSIS

A. Perinatal assessment of risk

includes awareness of preexisting maternal or fetal problems that may predispose to perinatal asphyxia (see preceding list) and of changing placental and fetal conditions (see Chap. 1) ascertained by ultrasonographic examination, biophysical profile, nonstress tests, measurement of urinary estriol.

B. Clinical presentation

can be variable. Common clinical scenarios include a postdates infant with asphyxia, meconium aspiration, pulmonary hypertension, pneumothorax, or birth trauma.

C. 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 function.

1. In addition to perinatal asphyxia, the differential diagnosis for a term infant with an Apgar score ≤3 for >5 minutes includes depression from maternal anesthesia or analgesia; trauma; metabolic or infectious insults; neuromuscular disorders; and central nervous system (CNS), cardiac, or pulmonary malformations

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

D.

Umbilical cord or first blood gas determination.

The specific blood gas criteria that define asphyxia causing brain damage are uncertain.

1. In a population-based cohort of 17,000 term infants, the average umbilical cord arterial pH was 7.24 ± 0.07 and BE was -5.6 ± 0.3 mmol/L. Umbilical arterial pH 8.5 µg/L) plus elevated CK-BB, or elevated CK-BB and low cord blood arterial pH had sensitivity of 71% each and specificity of 95% and 91% respectively in predicting moderate to severe encephalopathy.

C. Renal evaluation

1. Blood urea nitrogen (BUN) and serum creatinine (Cr) may be elevated in perinatal asphyxia. Typically elevation is noted 2 to 4 days after the insult.

2. Fractional excretion (FE) of Na+ or renal failure index may help confirm renal insult (see Chap. 31).

3. Urine levels of β-2-microglobulin have been used as an indicator of proximal tubular dysfunction, although not routinely. This low molecular weight protein is freely filtered through the glomerulus and reabsorbed almost completely in the proximal tubule.

4. Renal sonographic abnormalities correlate with the occurrence of oliguria.

X. CRANIAL IMAGING

A. Cranial sonographic

examination is less useful than other imaging modalities in assessing edema, subtle midline shift, superficial cortical or posterior fossa hemorrhage, and ventricular compression.

B. Computed tomography (CT)

may be useful for determining the extent of cerebral edema, especially when performed 2 to 4 days after the insult.

C. Magnetic resonance imaging (MRI).

T1- and T2-weighted MRI has been considered the best modality for imaging the neonatal brain; however, standard MRI may not detect hyoxic-ischemic changes during the first few days after the insult. High signal on T2-weighted images represents vasogenic edema.

1. Diffusion-weighted images (DWI) can show abnormalities within hours of the insult that may yield prognostic information. By detecting differences in rates

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of diffusion of water protons, DWI reveals restricted water diffusion, reflecting cytotoxic edema that is not apparent on conventional MRI. However, DWI does not distinguish cytotoxic edema from cell death, especially in global diffuse injuries, during the first hours following a hypoxic-ischemic insult.

2. Localized magnetic resonance spectroscopy (MRS), also called proton-MRS or 1H-MRS, measures the relative concentrations of various metabolites in tissue. Elevated lactate and abnormal ratios of choline to total creatine and N-acetylaspartate (NAA) to total creatine have been described following neonatal hypoxic-ischemic brain injury and may yield prognostic information.

XI. EEG

is used both to evaluate for seizure activity and also to define abnormal background activity such as burst-suppression, continuous low voltage, or isoelectric patterns. When expertise in interpretation of neonatal EEGs is not readily available, amplitude integrated EEG (aEEG) has been used to evaluate for seizures and to define abnormal background patterns. This method consists of a single-channel EEG from biparietal electrodes. There is selective filtering of specific channels (15 Hz), then integration of the signal amplitude and semilogarithmic recording of the processed signal.

XII. PATHOLOGIC FINDINGS OF BRAIN INJURY

A.

Specific neuropathology may be seen after moderate or severe asphyxia.

1. Focal or multifocal cortical necrosis affecting all cellular elements can result in cystic encephalomalacia and/or ulegyria (attenuation of depths of sulci) due to loss of perfusion in one or several vascular beds.

2. Watershed infarcts occur in boundary zones between cerebral arteries, particularly following severe hypotension. They reflect poor perfusion of the vulnerable periventricular border zones in the centrum semiovale and produce predominantly white matter injury. In the term infant, this typically results in bilateral parasagittal cortical and subcortical white matter injury or injury to the parieto-occipital cortex.

3. Selective neuronal necrosis is the most common type of injury seen following perinatal asphyxia. It is due to differential vulnerability of specific cell types; for example, neurons are more easily injured than glia. Specific regions at increased risk are CA1 region of hippocampus, Purkinje cells of cerebellum in term infants, and brainstem nuclei. Necrosis of thalamic nuclei and basal ganglia (status marmoratus) can be considered a subtype of selective neuronal necrosis.

B.

Neuropathology may reflect the type of asphyxial episode, although the precise pattern is not predictable.

1. Prolonged partial episodes of asphyxia tend to cause diffuse cerebral (especially cortical) necrosis. Expected clinical findings usually include seizures and paresis.

2. Acute total asphyxia tends to spare the cortex although affecting primarily the brainstem, thalamus, and basal ganglia. Expected clinical findings usually include disturbances in consciousness, respiration, HR, BP, and temperature control; disorders of tone and reflexes; cranial nerve palsies.

3. Partial prolonged asphyxia followed by a terminal acute asphyxial event (combination) is probably present in most cases.

XIII. TREATMENT

A. Perinatal management of high-risk pregnancies

1. Fetal HR and rhythm abnormalities may provide supporting evidence of asphyxia, especially if accompanied by presence of thick meconium. However, they provide no information concerning duration or severity of an asphyxial event.

2. Measurement of fetal scalp pH is a better determinant of fetal oxygenation than Po2. With intermittent hypoxia-ischemia, Po2 may improve transiently whereas the pH progressively falls. Fetal scalp blood lactate has been suggested as easier and more reliable than pH, but has not gained wide acceptance.

3. Close monitoring of progress of labor with awareness of other signs of in utero stress.

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4. The presence of a constellation of abnormal findings may indicate the need to mobilize the perinatal team for a newborn that could require immediate intervention. Alteration of delivery plans may be indicated and guidelines for intervention in cases of suspected fetal distress should be designed and in place in each medical center (see Chap. 1).

B. Delivery room management

(see Chaps. 4, 17, and 24).

The initial management of the hypoxic-ischemic infant in the delivery room is described in Chapter 4.

C. Postnatal management of neurologic effects of asphyxia

1. Ventilation. CO2 should be maintained in the normal range. Hypercapnia can cause cerebral acidosis and cerebral vasodilation. This may result in more flow to uninjured areas and relative ischemia to damaged areas (“steal phenomenon”). Excessive hypocapnia (CO2 7 days have poorer outcomes. In one study, half of the 42 surviving infants who had Sarnat stage 2 encephalopathy had normal neurodevelopment at 1 year of age; approximately 10% had a normal neurologic exam and mild developmental delay and one-third were diagnosed with CP.

c. Stage 3 HIE: 50% to 89% die and all survivors have major neurodevelopmental impairment.

d. Prognosis is considered to be good if an infant does not progress to and/or remains in stage 3 and if total duration of stage 2 is 3 days, the rates of CP and epilepsy were 46% and 40% respectively.

3. The detection of low voltage activity, electrocerebral inactivity or burst-suppression patterns on EEG is a better prognostic indicator of poor outcome than is the finding of epileptiform activity. In particular, 93% of neonates with extreme burst suppression activity have poor outcomes. Persistent burst suppression is associated with an 86% to 100% risk of death or severe neurodevelopmental sequelae.

4. Normal findings on DWI MRI between 2 and 18 days of age are associated with normal neuromotor outcome at 12 to 18 months. Abnormalities of deep gray matter that are detected early have the worse motor and cognitive outcomes. In one study, abnormal DWI of the basal ganglia noted within 10 days of a hypoxic-ischemic insult was associated with a 93% risk of abnormal neurodevelopmental outcome at 9 months to 5 years.

Suggested Readings

ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy. Neonatal encephalopathy and cerebral palsy: Defining the pathogenesis and pathophysiology. Washington, DC: American College of Obstetricians and Gynecologists, 2003.

Blackmon LR, Stark AR. Hypothermia: A neuroprotective therapy for neonatal hypoxic-ischemic encephalopathy. Pediatrics 2006;117:942-948.

Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 2006;91:F127-F131.

Higgins RD, Raju TNK, Perlman J, et al. Hypothermia and perinatal asphyxia: Executive summary of the National Institute of Child Health and Human Development Workshop. J Pediatr 2006;148:170-175.

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