Perinatal asphyxia and hypoxic-ischemic encephalopathy

Perinatal asphyxia, a common cause of death in neonates, is caused by compromised placental or pulmonary gas exchange and can occur during the antepartum, intrapartum, or perinatal period. Persisting impairment of blood gas exchange results in oxygen deficiency, hypercapnia, and blood acidosis with potential subsequent compromise of cell function in various tissues (e.g., heart, muscle, brain). The brain is the most vulnerable organ in the context of perinatal asphyxia and the development of hypoxic-ischemic encephalopathy is a potential consequence. After rapid evaluation, eligible patients require therapeutic hypothermia over a period of 72 hours to minimize brain damage. Depressed myocardial function can exacerbate ischemia and cause subsequent short-term complications with end-organ damage in other tissues (e.g., kidneys, lung, liver, gastrointestinal tract, bone marrow). Long-term complications of perinatal asphyxia include irreversible neurological damage, cerebral palsy, and periventricular leukomalacia.

• Perinatal asphyxia is a condition characterized by fetal oxygen deprivation that occurs in close temporal proximity to birth. It may lead to impaired cell function in various tissues and result in end-organ damage (e.g., encephalopathy, renal injury).
• Neonatal encephalopathy: a syndrome of CNS dysfunction in the early newborn period characterized by an altered level of consciousness/seizures, difficulty initiating/maintaining respiration, poor tone, and/or depressed reflexes
  • Several conditions can be the cause (e.g., hypoxic-ischemic encephalopathy, inborn errors of metabolism)
  • Hypoxic-ischemic encephalopathy (HIE) is a diffuse disruption of brain function and/or structure caused by inadequate tissue oxygenation (e.g., due to cardiac arrest, trauma, drug overdose, perinatal asphyxia). It is the most common subtype of neonatal encephalopathy.

• Perinatal asphyxia accounts for ∼ 900,000 fetal deaths per year (worldwide) and is one of the main causes of early neonatal mortality. ^[1]
• Hypoxic-ischemic encephalopathy occurs in ∼ 1.5:1,000 live births in the US. ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Perinatal risk factors
  • Fetal cardiovascular abnormalities (e.g., congenital heart defects)
  • Fetal pulmonary abnormalities (e.g., decreased surfactant related to prematurity, aspiration of amniotic fluid, meconium aspiration syndrome, persistent pulmonary hypertension of the newborn)
• Antepartum risk factors (play the biggest role)
  • Placental abnormalities (e.g., fetal vascular malperfusion, thrombosis)
  • Congenital infections
  • Substance use (e.g., alcohol, cocaine, amphetamines)
  • Abnormal maternal oxygenation (e.g., due to trauma, hypotension, severe anemia)
  • Maternal conditions (e.g., diabetes mellitus, preeclampsia, congestive heart failure)
• Intrapartum risk factors
  • Traumatic delivery (e.g., shoulder dystocia, emergency cesarean delivery, failed vacuum-assisted delivery)
  • Cesarean delivery with general anesthesia
  • Impaired placental perfusion (e.g., placental abruption, abnormal uterine contractions, uterine rupture)
  • Abnormal maternal oxygenation (e.g., pulmonary edema in preeclampsia)
  • Maternal hemodynamic compromise (e.g., amniotic fluid embolus)
  • Umbilical cord prolapse, nuchal cord, umbilical cord knot

• Pathophysiology of multiorgan damage ^[3][4]
  1. Hypoxia → ↑ sympathetic activity → circulatory centralization to maintain perfusion of vital organs (e.g., brain, adrenal glands, heart) → reduced oxygen supply to peripheral organs → tissue damage (e.g. kidneys, costal diaphragm, skeletal muscle, liver)
  2. Prolonged hypoxia → compromised myocardial cell function and ischemia → ↓ myocardial contractility → ↓ cardiac output → worsening of ischemia in peripheral organs
• Pathophysiology of brain damage ^[5]
  1. Primary energy failure: antepartum/intrapartum placental dysfunction or postpartum pulmonary gas exchange impairment → insufficient oxygen supply to organ tissue → brain tissue acidosis (due to CNS susceptibility) → osmotic dysregulation in cells → cellular edema → apoptosis
  2. Latency period (lasting several hours): reperfusion and recovery of some brain cells
  3. Secondary energy failure (6–48 h after initial injury): distribution of toxic neurotransmitters, oxidative stress, inflammation → widening of affected area
  4. Brain injury (months to years after initial injury): persistent inflammation, impaired neurogenesis, reduced axonal growth → reduced neural plasticity, myelin deficits, brain cell death

Signs and symptoms of asphyxia

• Short-term asphyxia
  • Primary apnea: cyanosis (blue asphyxia)
  • ↓ Heart rate
  • Peripheral vasoconstriction maintains blood pressure and circulation
• Prolonged asphyxia
  • Secondary apnea: white asphyxia
  • ↓ Blood pressure, severely ↓ heart rate
  • ↓ Muscle tone, ↓ reflexes
• Further course of perinatal asphyxia: varies greatly and depends on the duration of oxygen deficiency
  • May require immediate neonatal resuscitation
  • Development of severe complications (e.g., hypoxic-ischemic encephalopathy, multiorgan failure)
  • Full recovery is possible

Clinical features of hypoxic-ischemic encephalopathy ^[6]

Neonatal assessment ^[7]

• General
  • Should be performed within the first 6 hours of life, in all newborns showing clinical signs of neonatal encephalopathy (e.g., difficulty initiating and/or maintaining breathing, seizures, abnormal level of consciousness) as neuroprotective treatment is time-sensitive
  • Allows estimation of the likelihood that perinatal asphyxia contributed to the development of neonatal encephalopathy
  • Neurological damage is the major concern after a hypoxic-ischemic event.
• Neonatal signs: a hypoxic-ischemic etiology of neonatal encephalopathy is most likely if one or more of these signs are present
  • APGAR score at 5 min and 10 min: < 5
  • Fetal umbilical artery pH: < 7.0
  • Arterial base deficit ≥ 12 mmol/L
  • Neuroimaging evidence of acute brain injury
  • Presence of multisystemic organ failure consistent with HIE (e.g., renal failure, hepatic injury, hematological changes)
• Additional factors
  • Birth-related events that might have lead to hypoxic-ischemic complications:
    • Uterine rupture
    • Severe abruptio placentae
    • Umbilical cord prolapse
    • Severe and prolonged maternal hypoxia and hypotension
    • Maternal cardiovascular collapse
    • Fetal exsanguination
    • Abnormal fetal heart rate monitoring during labor
  • Neuroimaging patterns consistent with neonatal hypoxic-ischemic brain injury (e.g., watershed cortical injury in MRI)
  • No evidence of other causes for neonatal encephalopathy (e.g., inborn errors of metabolism, genetic disorders)

Further diagnostic measures

• Laboratory studies
  • Umbilical arterial blood gas analysis: arterial pH, venous pH, base deficit
  • CBC: may show signs of infection, hemorrhage, or thrombocytopenia
  • Electrolytes: monitoring and treatment guidance
  • Liver function tests: evaluation of possible damage
  • Kidney function tests: evaluation of possible damage
  • Cardiac enzymes: if myocardial injury is clinically suspected
  • Coagulation tests: in case of bleeding, to exclude disseminated intravascular coagulation
  • Bacterial blood culture: to exclude neonatal sepsis
  • Lumbar puncture: if there is clinical suspicion of meningitis/encephalitis
• Imaging studies
  • Cranial MRI
    • Most sensitive tool for detecting hypoxic-ischemic injury in the brain to exclude other causes of neonatal encephalopathy
    • Patterns consistent with HIE include deep nuclear gray matter injury, parasagittal injury of the cerebral cortex, and watershed cortical injury
    • Magnetic resonance spectroscopy can be performed additionally.
  • CNS ultrasound
    • Alternative if MRI is unavailable (e.g., condition of the newborn, missing resources), but less sensitive for hypoxic-ischemic injury
    • Perfusion measurement and evaluation of morphological changes (e.g., hemorrhages, ventricular size, cerebral edema, severe white-matter damage)
  • Echocardiography
    • If myocardial injury is suspected
    • May show decreased ventricular contractility, valve dysfunction, or enlargement of the heart
• EEG
  • Conducted on the first day of life, continued monitoring for at least 24 hours
  • Evaluation of seizure activity and background electrical activity
• Biomarkers: Recent studies indicate that VEGF is significantly increased in neonates that subsequently develop encephalopathy. ^[8]

• Therapeutic hypothermia ^[9]
  • Description
    • Current standard of care for neonates with moderate to severe HIE
    • Possible as selective head cooling or systemic hypothermia
    • Treatment at 33.0–35.0°C for 72 hours
    • Within the first 6 hours of life (therapeutic window)
  • Eligibility criteria
    • Gestational age ≥ 36 weeks and ≤ 6 hours of age
      PLUS
    • pH ≤ 7 or base deficit of ≥ 16 mmol/L
    • PLUS either of the following
      • APGAR score at 10 min: ≤ 5
        OR
      • Ongoing resuscitation at 10 min
        OR
      • Clinically moderate or severe encephalopathy
• Supportive measures
  • Ensure sufficient oxygenation and ventilation (e.g., supplemental oxygen, inhaled nitric oxide, intubation).
  • Maintain adequate organ perfusion (e.g., inotropic agents).
  • Maintain electrolyte and glucose homeostasis.
  • Anticonvulsive treatment of seizures
  • Recent studies indicate a neuroprotective effect of erythropoietin in neonates with HIE. ^[10]

While maintaining adequate organ perfusion is important in children with HIE, volume overload should be avoided due to the possible subsequent development/worsening of brain edema.

CNS complications

• Cerebral palsy (most likely spastic quadriplegia or dyskinetic cerebral palsy)
• Periventricular leukomalacia (PVL)
• Epilepsy
• Specific learning disorders
• ADHD
• Intellectual developmental disorder
• Hearing and/or visual impairment

Other organ complications

• Heart: impaired myocardial contractility
• Kidneys: acute renal failure
  • Mainly conservative treatment necessary
  • Theophylline has a nephroprotective effect ^[11]
  • Dialysis in rare cases
  • Increased risk for the development of chronic kidney disease later in life
• Hematopoietic: bone marrow suppression, thrombocytopenia, disseminated intravascular coagulation
• Liver: elevated transaminase levels, hepatic injury
• Gastrointestinal tract: necrotizing enterocolitis in case of severe hypoperfusion
• Lungs: neonatal respiratory distress syndrome, pulmonary hypertension

We list the most important complications. The selection is not exhaustive.

• Mild encephalopathy: usually normal development
• Moderate to severe encephalopathy
  • Long-term neurologic manifestations
  • Severe abnormalities seen in MRI and EEG are associated with a poor outcome