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Perinatal asphyxia in term and late preterm infants

Perinatal asphyxia in term and late preterm infants
Literature review current through: May 2024.
This topic last updated: Aug 23, 2023.

INTRODUCTION — Perinatal asphyxia is caused by a lack of oxygen to organ systems due to a hypoxic or ischemic insult that occurs within close temporal proximity to labor (peripartum) and delivery (intrapartum). In the neonate, the lack of oxygen may lead to multi-organ failure with brain involvement as the major organ of concern (hypoxic-ischemic encephalopathy [HIE]). In most cases of HIE, there is concomitant hypoxic-ischemic injury to other major organ systems, including the heart, kidney, lung, and/or liver.

This topic will review the clinical manifestations and management of neonates with perinatal asphyxia. The clinical features, evaluation, and management of HIE are discussed in greater detail separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

TERMINOLOGY — Terms that are used in this topic include:

Perinatal asphyxia – Condition of impaired gas exchange or inadequate blood flow that leads to persistent hypoxemia and hypercarbia that occurs in temporal proximity to labor (peripartum) and delivery (intrapartum)

Hypoxemia – Abnormally low blood oxygen levels in the blood

Hypoxia – Abnormally low blood oxygen levels in the body tissue

Ischemia – Reduction or complete cessation of blood flow to an organ, which compromises both oxygen delivery (hypoxia) and substrate delivery to an organ

DEFINITION OF PERINATAL HYPOXIC-ISCHEMIC EVENT — The American College of Obstetricians and Gynecologists published an executive summary that outlines neonatal signs and contributing factors used to establish acute hypoxic-ischemic events in term and late preterm infants (gestational age [GA] ≥35 weeks) that would likely result in hypoxic-ischemic encephalopathy (HIE) (table 1) [1].

Neonatal signs consistent with an acute perinatal hypoxic-ischemic event include:

Apgar score of <5 at 5 minutes and 10 minutes

Fetal umbilical artery pH <7.0, or base deficit ≥12 mmol/L, or both

Brain injury seen on brain magnetic resonance imaging (MRI) or MR spectroscopy consistent with acute hypoxia-ischemia

Presence of multisystem organ failure consistent with hypoxic-ischemic encephalopathy (HIE)

In this summary, contributing factors (type and timing) consistent with an acute perinatal event include:

A sentinel hypoxic or ischemic event occurring immediately before or during labor and delivery, such as ruptured uterus or severe abruptio placentae. (See "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences" and "Placental pathology: Findings potentially associated with neurologic impairment in children", section on 'Acute disorders that may be associated with perinatal asphyxia'.)

Fetal heart rate monitor patterns consistent with an acute peripartum or intrapartum event (eg, conversion of category I fetal heart rate [normal pattern] to a category III pattern [absent variability with recurrent late or variable decelerations or bradycardia or sinusoidal pattern]). (See "Intrapartum fetal heart rate monitoring: Overview", section on 'Category III FHR pattern'.)

The timing and type of brain injury patterns based on imaging studies that are typical of hypoxic-ischemic injury in the term and late preterm newborn. This includes MRI demonstrating deep nuclear gray matter (basal ganglia or thalamus), watershed (borderzone) cortical and white matter injury, or both ("near-total" pattern of injury). (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Brain MRI'.)

No evidence of other proximal or distal factors that could be contributing to encephalopathy.

EPIDEMIOLOGY — Reported incidence rates of perinatal asphyxia vary depending on the definition used and population studied [2-4]. In a study from a single center in Switzerland, the estimated incidence of severe perinatal asphyxia ranged from 5 to 8 per 1000 live births over the study period (2004 to 2014) [2]. The incidence of hypoxic-ischemic encephalopathy (HIE) was approximately 1 per 1000 live births. In this study, severe perinatal asphyxia was defined as fulfilling three of the following criteria: five-minute Apgar score ≤5, pH ≤7, base deficit ≥16 mmol/L, lactate ≥12 mmol/L, and/or moderate to severe encephalopathy.

In a population-based study from Sweden that analyzed data from >3 million singleton live births from 1988 through 2018, the incidence of perinatal asphyxia was 11 per 1000 live births [4]. In this study, perinatal asphyxia was defined as one- or five-minute Apgar score ≤3, encephalopathy, or neonatal seizures.

The risk of perinatal asphyxia is considerably higher in resource-limited countries and is an important contributor to infant mortality [5,6].

CLINICAL MANIFESTATIONS OF INITIAL PERINATAL ASPHYXIA INSULT — Data regarding the direct effects on perinatal asphyxia on major organ systems are limited and based on observations of infants with hypoxic-ischemic encephalopathy (HIE) prior to the routine use of therapeutic hypothermia. The initial physiologic response to perinatal asphyxia is redistribution of blood flow from the nonvital organs (eg, skin and splanchnic area) to the vital organs (brain, heart) [7]. In most infants with moderate to severe HIE, there is evidence of dysfunction in at least one other organ system. However, systemic effects of perinatal asphyxia may be present even in the absence of encephalopathy. Therefore, all major organ functions are evaluated after a well-documented perinatal event, including cases in which there is an absence of findings associated with encephalopathy. (See 'Initial steps' below.)

Encephalopathy — The brain is the major organ of concern following a perinatal hypoxic-ischemic event. The risk factors, pathophysiology, clinical presentation, evaluation, and management (therapeutic hypothermia) of HIE are discussed in detail separately. (See "Etiology and pathogenesis of neonatal encephalopathy" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

Respiratory failure — Respiratory failure is frequently seen in infants with severe perinatal asphyxia and is most commonly the result of an underlying or concomitant disorder such as sepsis, pneumonia, or meconium aspiration syndrome (MAS) [8]. Perinatal asphyxia is also associated with persistent pulmonary hypertension of the newborn (PPHN) [7,9,10]. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Following perinatal asphyxia, apnea or hypoventilation may occur due to HIE and seizures. In severe cases, death may occur with terminal apnea if the infant is not successfully resuscitated.

A chest radiograph, pulse oximetry, and capillary blood gases are generally sufficient to assess the pulmonary status of the infant with perinatal asphyxia and to determine underlying etiologies for respiratory distress (eg, pneumonia, MAS, pulmonary edema). In addition, echocardiography may be helpful in making the diagnosis of PPHN. (See "Overview of neonatal respiratory distress and disorders of transition", section on 'Diagnostic approach' and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Diagnosis'.)

Infants with respiratory failure require intubation and mechanical ventilation during the first hours of life. Infants who are treated with hypothermia also are typically intubated and mechanically ventilated. (See 'Respiratory support' below and "Overview of mechanical ventilation in neonates".)

Cardiovascular manifestations — After a significant hypoxic-ischemic insult, reduced cardiac output and hypotension are commonly observed due to ventricular dysfunction and/or poor vascular tone [11,12]. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

In newborns with severe ventricular dysfunction due to perinatal asphyxia, a tricuspid regurgitation murmur may be heard on cardiac auscultation. This is due to transient papillary muscle dysfunction from the ischemic insult; it typically diminishes over the first few days after birth. (See "Common causes of cardiac murmurs in infants and children", section on 'Tricuspid regurgitation'.)

Electrocardiogram (ECG) may demonstrate ischemic changes (eg, ST depression and T-wave inversion). Echocardiography may demonstrate ventricular dysfunction [13]. Echocardiography can also identify infants with PPHN. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Echocardiography'.)

Cardiac markers are often used to assess myocardial damage, though these tests are nonspecific.

Troponin is a marker of myocardial injury that can be detected in the blood within two to four hours after an ischemic injury [14]. Troponin may remain detectable for up to 21 days [15]. The association between elevated troponin and long-lasting cardiac depression is uncertain.

Serum B-type natriuretic peptide (BNP) levels may be elevated in neonates with high ventricular filling pressures due to ventricular dysfunction and/or PPHN.

Acute kidney injury — Oliguria as a manifestation of kidney dysfunction is common after perinatal asphyxia [7]. It is due to either reduced cardiac output or acute kidney injury secondary to tubular necrosis. Impaired kidney function is detected by an elevation in serum creatinine (SCr).

In one study of 144 term infants with HIE, 70 percent had evidence of kidney impairment (defined as urine output <1 mL/kg per hour [oliguria] for 24 hours and an SCr level > 1.13 mg/dL [100 micromol/L] or oliguria for >36 hours or SCr 1.41 mg/dL [125 micromol/L] or any SCr level that increased postnatally) [7]. (See "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis".)

Serial measurements of SCr and electrolytes and ongoing accurate monitoring of urine output are required to assess and follow the effect of asphyxia on renal function.

Depending on the degree of kidney impairment further management, including adjusting fluid and electrolyte management and drug dosing for medications that are renally excreted and in very severe cases kidney replacement therapy, may be warranted. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Management' and 'Drug monitoring and dosing' below.)

Liver injury — Elevation of liver enzymes (eg, serum alanine transaminase level >100 units/L) is common in infants with perinatal asphyxia [7,16]. Impaired liver function may also manifest as direct (conjugated) hyperbilirubinemia, hypoalbuminemia, coagulopathy, and poor metabolism of drugs that rely on hepatic metabolism or biliary excretion. Long-term effects of neonatal liver hypoxia-ischemia are unknown. (See 'Drug monitoring and dosing' below.)

Gastrointestinal manifestions

Feeding intolerance – A reduced tolerance of enteral feedings in infants with perinatal asphyxia is common due to the redistribution of blood flow away from the splanchnic circulation to vital organs such as the brain. Therefore, either no or only minimal enteral feeding is provided to infants with perinatal asphyxia, particularly during therapeutic hypothermia [17]. (See 'Nutrition' below.)

Necrotizing enterocolitis – Perinatal asphyxia is associated with increased risk of necrotizing enterocolitis in the term and near-term infants [18,19]. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis", section on 'Term infants'.)

Hematologic manifestations

Thrombocytopenia and abnormal coagulation — Thrombocytopenia and prolonged coagulation times (ie, prolonged prothrombin time [PT] and activated partial thromboplastin time [aPTT]) are common after a severe asphyxia event due to several factors:

Disseminated intravascular coagulation occurs after perinatal asphyxia resulting in ongoing consumption of clotting factors and platelets [20-23]. (See "Disseminated intravascular coagulation in infants and children", section on 'Other etiologies in neonates'.)

Bone marrow suppression contributing to thrombocytopenia.

Impaired hepatic production of clotting factors due to hepatic injury.

Acute blood loss — Severe antenatal or peripartum/intrapartum blood loss due to hemolysis, massive feto-maternal transfusion, or blood loss during placental abruption may be the cause of perinatal asphyxia. Severe anemia at birth needs immediate treatment. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Acute blood loss'.)

Hypo- and hyperglycemia — In neonates with perinatal asphyxia, there is an initial stress-induced hyperglycemia that is followed by a sharp drop in blood glucose levels due to increased glucose consumption. Hypoglycemia is also more common in infants with severe liver damage due to inadequate glycolysis. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Neonatal hyperglycemia".)

INITIAL STEPS

Clinical stabilization — at delivery — At birth, an initial assessment is made for cardiorespiratory stability. The management in the delivery room for infants who fail to meet criteria for routine care (absence of good tone, crying or breathing without difficulty) and who require further resuscitative measures is summarized in the figure (algorithm 1) and discussed separately. (See "Neonatal resuscitation in the delivery room", section on 'Infants requiring delivery room resuscitation'.)

Evaluation

Goal — The goal of a concurrent initial evaluation during stabilization is to determine the presence and extent of end-organ damage, identify a possible etiology or concomitant condition that require specific therapy, the need for therapeutic hypothermia, and to obtain a baseline to compare changes in organ function over time. The general assessment is based on physical findings, laboratory testing, imaging, and monitoring of brain function (which is discussed separately). (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Evaluation'.)

General assessment — General assessment consists of an evaluation of the neonate’s respiratory status (evidence of respiratory distress [labored breathing/tachypnea] and need for respiratory support), cardiac status (eg, hypotension or need for inotropic blood pressure support), neurologic status (hypotonia and the presence of seizures), and basic laboratory evaluation. Urinary output is also monitored.

Basic laboratory tests — Routine laboratory testing includes:

Blood gas analysis – Arterial or venous blood gases are obtained to assess gas exchange (oxygenation and ventilation) and acid-base disturbances. Indication for therapeutic hypothermia is based on a sample of umbilical cord blood or any blood obtained within the first hour after birth and after resuscitation with a pH of ≤7.0 or a base deficit of ≥16 mmol/L along with evidence of hypoxic-ischemic encephalopathy. (See 'Therapeutic hypothermia' below.)

Complete blood count (CBC) – CBC are obtained to identify patients with anemia, which may have contributed to asphyxia, thrombocytopenia (increased risk of bleeding), and/or elevated white count (suggestive of infection). It has been suggested that elevated nucleated red blood cell (NRBC) counts in cord blood is a marker of fetal hypoxia and perinatal brain injury [24-26]. (See 'Hematologic manifestations' above.)

Glucose – Infants with perinatal asphyxia are at-risk for abnormal glucose levels (hypoglycemia and hyperglycemia), which may require interventions to normalize blood glucose levels. (See "Management and outcome of neonatal hypoglycemia" and "Neonatal hyperglycemia".)

Kidney function studies – Initial testing for kidney function includes serum creatinine (SCr), BUN, and electrolytes to identify infants with acute kidney injury (decrease in glomerular filtration rate), which may result in electrolyte abnormalities due to renal dysfunction and fluid overload. (See 'Acute kidney injury' above and "Neonatal acute kidney injury: Evaluation, management, and prognosis".)

Liver function studies – Initial hepatic testing includes measuring total and conjugated bilirubin, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Perinatal asphyxia is associated with hepatic damage confirmed by an elevated ALT and AST, which may increase the risk of hyperbilirubinemia. (See 'Liver injury' above.)

Cardiac evaluation – Electrocardiogram (ECG) is performed to detect myocardial ischemia. Echocardiography should be performed if there is clinical concern for depressed ventricular function and/or persistent pulmonary hypertension. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation", section on 'Laboratory and imaging tests' and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Echocardiography'.)

Sepsis evaluation – (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests'):

Blood cultures are performed in all infants with perinatal asphyxia because serious infections (eg, sepsis) is a major complication [27].

Although cerebral spinal fluid samples may yield important information including meningitis, infants are often too sick to undergo lumbar puncture.

Cranial ultrasound – Cranial ultrasound is performed to exclude subdural or intraventricular hemorrhage. Daily imaging with cranial ultrasound is performed after birth to detect ischemic lesions in particular to the deep grey matter, which may not be seen earlier than 24 hours after the insult [28,29].

Additional testing — Based on the clinical status of the infants and initial evaluation, additional testing may be performed:

Chest radiography – For infants with respiratory distress, chest radiography is performed to identify other concomitant conditions (eg, pneumonia, meconium aspiration syndrome, pulmonary congestion, or persistent pulmonary hypertension of the newborn). (See 'Respiratory failure' above.)

Abdominal ultrasound – For patients with severe anemia, abdominal ultrasound is performed to detect any evidence of hepatic injury or adrenal hemorrhage. In addition, for neonates with persistent thrombocytopenia, ultrasound evaluation of major vessels may be helpful in detecting an underlying thrombosis.

Cardiac evaluation – For infants with evidence of cardiac injury (hypotension, need for inotropic support, abnormal ECG), additional evaluation may include echocardiography, troponin, and serum B-type natriuretic peptide (BNP) levels. (See 'Cardiovascular manifestations' above.)

Coagulation studies – Infants with evidence of liver dysfunction and/or overt bleeding symptoms should have coagulation tests performed, including prothrombin time (PT) and activated partial thromboplastin time (aPTT).

Inborn errors of metabolism – In infants with neonatal encephalopathy due to moderate perinatal asphyxia, or in infants without an obvious sentinel event, testing for inborn errors of metabolism include blood ammonia levels to identify an underlying urea cycle deficiencies and qualitative urine organic acid to identify elevated levels of sulfite seen in neonatal encephalopathy due to sulfite oxidase deficiency and molybdenum cofactor deficiency. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Hyperammonemia' and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Seizures' and "Etiology and prognosis of neonatal seizures", section on 'Cofactor and vitamin deficiencies'.)

MANAGEMENT

Therapeutic hypothermia — Therapeutic hypothermia is the only proven neuroprotection intervention for hypoxic-ischemic encephalopathy (HIE) and has become the standard of care in most high-resource settings. This is discussed in detail separately.

Effects of therapeutic hypothermia on other organ systems — Therapeutic cooling is typically maintained at a rectal temperature of 33 to 35°C (91.4 to 95.0°F) for 72 hours. Hypothermia can have clinical effects on other major organ systems affected by perinatal asphyxia (eg, kidney, heart, liver, gastrointestinal tract, lungs). It is imperative for the clinical team to understand the impact of cooling on the function of the major organ systems that have already undergone injury from perinatal asphyxia [30,31]:

Respiratory effects – Partial pressure of carbon dioxide (pCO2) decreases by 3 to 4 percent for every 1°C drop in temperature below 37°C. This is due to reduced CO2 production as metabolism declines and increasing of CO2 in blood as body temperature is lowered [32]. In blood gas samples, there is a concomitant increase in pH with the lower pCO2. It remains uncertain what the optimal target ranges should be for pCO2 and pH during therapeutic hypothermia. In our center, pCO2 levels are set for 50 mmHg (6.7 kPa) to avoid hypocapnia.

Blood gas analysis is performed at 37°C. The actual pCO2 at 33.5°C is obtained by multiplying the pCO2 value measured at 37°C by a correction factor of 0.8. As an example, a blood gas measurement of pCO2 at 37°C of 50 mmHg represents an in-vivo value of 40 mmHg.

A single center study reported lower pulse oximetry during hypothermia compared with normal body temperatures [33]. These results suggested that therapeutic hypothermia shifts the oxygen-hemoglobin dissociation curve to the left, resulting in lower partial pressure of oxygen (PaO2), which could lead to underestimation of hypoxemia. Further studies are needed to confirm these findings.

Cardiovascular effects – Cardiac output falls due to a reduction in heart rate (sinus bradycardia) and stroke volume. However, there appears to be no significant change in the risk of hypotension due to the initial perinatal asphyxia. This is most likely due to peripheral vasoconstriction that occurs with cooling. A systematic review suggested that therapeutic hypothermia provides a cardioprotective effect [34].

Metabolism and glucose metabolism – The metabolic rate declines linearly with decreasing temperature. As the metabolic rate declines, glucose utilization, insulin release, and insulin sensitivity may decrease. This can result in an increase in glucose levels. In a prospective cohort of term infants with neonatal encephalopathy in which 44 of 45 neonates received therapeutic hypothermia, 16 episodes of hypoglycemia and 18 episodes of hyperglycemia were detected by continuous interstitial glucose monitoring [35]. In this observational study, after adjusting for hypoxia–ischemia severity, hyperglycemia was associated with worse global brain function (monitored by amplitude-integrated electroencephalography) and seizures. However, because of the observational nature of the study, no causal relationship between episodes of hyperglycemia and abnormal brain function could be established, as it is possible that hyperglycemia is a marker for multi-organ injury, including the brain.

Coagulopathy and thrombocytopenia – Limited data suggest that there is no additional effect of hypothermia on the increased risk of coagulopathy induced by perinatal asphyxia, but cooling is associated with an increased risk of thrombocytopenia [36]. However, coagulopathy requiring intervention remains a common occurrence during therapeutic hypothermia so that ongoing monitoring of clotting factors (eg, plasma fibrinogen) and liver function is needed.

Liver and kidney function – Based on animal data, therapeutic hypothermia does not appear to increase the risk of liver or kidney injury [37]. Limited clinical data have suggested that cooling may improve liver and kidney outcome, but these results need to be confirmed with additional trials and follow-up of larger number of patients [12,34]. Hypothermia decreases hepatic metabolism and thereby function, which impacts drug dosing for medications that are dependent on hepatic metabolism and excretion. (See 'Drug monitoring and dosing' below.)

Intestinal function – Hypothermia does not appear to increase the risk of necrotizing enterocolitis and may provide potential benefit for preventing additional ischemic intestinal injury. However, administration of morphine for sedation/analgesia during therapeutic hypothermia may further reduce intestinal motility. As a result, full enteric feeding is typically deferred during therapeutic hypothermia, but "minimal enteral feeding" may be provided. (See 'Nutrition' below.)

Monitoring

Clinical monitoring — Routine monitoring for neonates with perinatal asphyxia, particularly those managed with therapeutic hypothermia, consists of:

Continuous heart rate and respiratory monitoring (including respiratory rate and pulse oximetry).

Blood pressure monitoring (either with an intraarterial catheter or with frequent noninvasive measurements).

Continuous electroencephalography (EEG), with standard or amplitude-integrated EEG.

Cerebral oximetry with near-infrared spectroscopy (if available).

Daily cranial ultrasound.

Laboratory monitoring, including:

Blood gas analysis, glucose, and complete blood count (CBC), obtained several times a day during the first three days after resuscitation and then daily until values have normalized. For infants who do not qualify for therapeutic hypothermia, most abnormalities will have normalized by the third day.

SCr, total and conjugated bilirubin, liver enzymes (ALT and AST), and CRP, obtained daily. In addition, coagulation tests (PT and aPTT) should be monitored in infants with liver dysfunction and/or overt bleeding.

Drug monitoring and dosing — Levels of many drugs will be elevated by perinatal asphyxia because the pharmacokinetics for these drugs are altered due to reduced kidney excretion and hepatic metabolism/excretion [38]. This effect may be aggravated or enhanced by therapeutic hypothermia. Monitoring drug levels is generally appropriate for drugs with potentially harmful side effects (eg, aminoglycosides, vancomycin, certain antiseizure medications) [39-42]. Refer to individual drug monographs within UpToDate for additional details regarding the need for dosing adjustment based on kidney or hepatic impairment.

Supportive care based on organ system — Supportive care measures are provided for all infants with perinatal asphyxia both before, during, and after therapeutic hypothermia, and for those infants in whom cooling is not performed.

Neuroprotective management — Neuroprotective measures and seizure management are discussed separately. (See "Treatment of neonatal seizures".)

Respiratory support — Respiratory support is needed for most infants with perinatal asphyxia and for all infants treated with therapeutic hypothermia [9]. The goal of supportive care is to maintain adequate oxygenation and ventilation, especially during sedation needed for hypothermia, and avoid episodes of hyperoxia, hypoxia, hypercapnia, and hypocapnia. In our center, target ranges for preductal oxygen saturation is >95 percent and the temperature-corrected target for partial pressure of carbon dioxide (pCO2) is 35 to 45 mmHg.

Most infants receiving therapeutic hypothermia will need intubation and mechanical ventilation for optimal respiratory support [9] as the need for sedation (eg, with morphine) during cooling impairs the respiratory drive of the neonate. However, some patients may only require nasal continuous positive airway pressure (nCPAP). (See "Overview of mechanical ventilation in neonates" and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn".)

As previously discussed, blood gas values need to be interpreted differently during therapeutic hypothermia as the pCO2 decreases by 3 to 4 percent for every 1°C drop in temperature [9,32]. Although it remains uncertain what the optimal values for pCO2 and pH are during therapeutic hypothermia, we target pCO2 levels of 50 mmHg (6.7 kPa) to avoid hypocapnia. Generally, a correction factor of 0.8 is used to calculate the in vivo pCO2 at 33.5°C, as the test is performed at 37°C. (See 'Therapeutic hypothermia' above.)

Persistent pulmonary hypertension of the newborn (PPHN) is a known complication associated with perinatal asphyxia. In these patients, administration of inhaled nitric oxide (iNO) may be needed, which can also be administered during therapeutic hypothermia. (See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Inhaled nitric oxide (iNO)'.)

Cardiovascular support — Infants with ventricular dysfunction and/or shock often require inotropic agents to support cardiac function and maintain perfusion. Sympathomimetic stimulation by catecholamine agents such as dobutamine and dopamine improves myocardial contractility and may have an additional beneficial effect on peripheral vascular beds.

Dopamine is the most commonly used agent, including in our center. Dobutamine is an excellent alternative. In some cases, milrinone may be useful as it increases contractility and reduces afterload without a significant increase in myocardial oxygen consumption. However, hypotension may be a side effect of milrinone, and additional vasoconstrictive agents may be needed. (See "Neonatal shock: Management", section on 'Vasoactive agents'.)

For infants with severe hypotension not responding to high doses of inotropes, hydrocortisone (1.25 mg/kg per dose, 4 doses per 24 hours) is typically used, especially if there is evidence or concern for adrenal insufficiency [43]. A clinical trial in 35 infants has reported low-dose hydrocortisone (0.5 mg/kg per dose given every six hours) was more effective than placebo in raising blood pressure and decreasing inotrope dosing, suggesting that lower doses of hydrocortisone might also be effective in increasing blood pressure [44]. Nevertheless, we continue to use the standard higher dose until there is confirmation that the lower dose of hydrocortisone is equally as effective. (See "Neonatal shock: Management", section on 'Suspected adrenal insufficiency'.)

Empiric antibiotic therapy — Empiric antibiotics are provided until culture results are known because these patients are at-risk for serious infection [45]. Antibiotic dosing should be adjusted to account for changes due to liver and/or kidney dysfunction [39,46,47]. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

Fluid and electrolyte management — Infants with perinatal asphyxia are at-risk for fluid and electrolyte abnormalities due to acute kidney injury and the syndrome of inappropriate antidiuretic hormone (SIADH), which is frequently associated with brain injury [48]. Adjustments of fluid and electrolyte management are made in response to the changes in the clinical status of the patient with ongoing monitoring of fluid balance, including monitoring net fluid intake, weight, and respiratory status and frequent assessment of blood electrolytes. Electrolyte levels should be maintained in the normal range during cooling by adjusting fluid therapy. (See "Fluid and electrolyte therapy in newborns".)

In the first day of life, infants generally are maintained on intravenous fluids of 10 percent dextrose without additional sodium and potassium at a rate of 30 to 60 cc/kg per day. This degree of fluid restriction is to avoid the risk of water retention associated with SIADH, which commonly occurs in neonatal perinatal asphyxia. Infants with severe kidney failure also are prone to develop fluid overload and may require fluid restriction.

If there is evidence of fluid overload resulting in a decline/compromise in pulmonary function, we administer a trial dose of loop diuretic (eg, furosemide 1 mg/kg per dose) to correct hypervolemia [31]. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Fluid management'.)

Nutrition — Nutritional management is highly variable as there is little evidence to guide optimal nutritional support during hypothermia [49]. Many centers defer full enteral feeding until the period of therapeutic hypothermia is completed due to concern of reduced intestinal function. Minimal enteral feeding (sometimes called "trophic feeds") and parenteral nutrition (PN) are provided for nutrition support. The amount and composition of intravenous fluids may need to be adjusted based on changes in the monitored levels of electrolytes, triglycerides, and glucose. Clearance of intravenous lipids from PN may be reduced due to hepatic impairment. (See "Parenteral nutrition in infants and children".)

However, practice is not standardized and some centers may provide enteral feeds during therapeutic hypothermia. In a clinical trial involving 80 neonates undergoing therapeutic hypothermia for HIE who were randomly assigned to early feeding (ie, started during therapeutic hypothermia) or delayed feeding (started after therapeutic hypothermia), rates of feeding intolerance with similar in both groups (26 versus 31 percent, respectively) [50].

Glucose levels should be monitored several times daily and glucose infusion rates adjusted to maintain glucose levels between 72 to 145 mg/dL (4 to 8 mmol/L) since inappropriately low or high glucose levels can adversely impact neurologic outcomes [51]. (See "Management and outcome of neonatal hypoglycemia" and "Neonatal hyperglycemia".)

Hyperbilirubinemia — For neonates with perinatal asphyxia who have clinically significant unconjugated hyperbilirubinemia, the risk of bilirubin-induced neurotoxicity is increased due to reduced ability to conjugate bilirubin for biliary excretion and increased permeability of the blood-brain barrier in the setting of acute HIE. Thus, when determining the threshold for treatment, lower thresholds are used in for these patients than are used in newborns without neurotoxicity risk factors. The treatment thresholds are summarized in the figure (figure 1) and discussed in greater detail separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management", section on 'Thresholds for treatment'.)

Coagulopathy and thrombocytopenia

Coagulopathy – For infants with significant coagulopathy (eg, severely prolonged aPTT and PT times) or overt bleeding, we provide fresh frozen plasma to replace clotting factors that may be either be consumed (disseminated intravascular coagulation) or be low due to impaired hepatic function. This is discussed in greater detail separately. (See "Disseminated intravascular coagulation in infants and children", section on 'Transfusion of platelets and/or plasma'.)

Thrombocytopenia – In critically ill neonates, platelets transfusions are provided for platelet count <50,000/microL, as discussed in detail separately. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion'.)

Acute kidney injury — Management and prevention of neonatal acute kidney injury are discussed in detail separately. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Management' and "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Preventive measures'.)

OUTCOME — Outcomes for infants with perinatal asphyxia depend primarily on the severity of brain injury. Survival and long-term neurodevelopmental outcomes for infants with perinatal asphyxia have improved with the advent of therapeutic hypothermia. It remains uncertain whether therapeutic hypothermia has similar benefit for other organ systems (eg, heart, kidney, and liver).

SUMMARY AND RECOMMENDATIONS

Definition – Perinatal asphyxia is caused by a lack of oxygen to organ systems due to a hypoxic or ischemic insult that occurs within close temporal proximity to labor (peripartum) and delivery (intrapartum). In the neonate, the lack of oxygen leads to multi-organ failure. The brain is the major organ of concern (hypoxic-ischemic encephalopathy [HIE]). The criteria used to define an acute peripartum or intrapartum hypoxic-ischemic event are summarized in the table (table 1). (See 'Terminology' above.)

Epidemiology – Reported incidence rates of perinatal asphyxia vary depending on the definition used and population studied. In resource-abundant settings, the incidence is approximately 5 to 10 per 1000 live births. The risk is considerably higher in resource-limited countries. (See 'Epidemiology' above.)

Clinical manifestations

Encephalopathy – Most infants with perinatal asphyxia have moderate to severe HIE, which is discussed in detail separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

Respiratory failure – Respiratory failure is frequently seen in infants with severe perinatal asphyxia and is most commonly the result of an underlying or concomitant disorder (eg, sepsis, pneumonia, meconium aspiration syndrome). Perinatal asphyxia is also associated with persistent pulmonary hypertension of the newborn (PPHN). (See 'Respiratory failure' above.)

Cardiovascular manifestations – After a significant hypoxic-ischemic insult, reduced cardiac output and hypotension are commonly observed due to ventricular dysfunction and/or poor vascular tone. Electrocardiogram (ECG) may demonstrate ischemic changes (eg, ST depression and T-wave inversion). Echocardiography may demonstrate ventricular dysfunction. (See 'Cardiovascular manifestations' above and "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

Acute kidney injury (AKI) – Oliguria and elevated serum creatinine are commonly observed. (See 'Acute kidney injury' above and "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis".)

Liver injury – Hypoxic-ischemic liver injury is manifested by increase in liver enzymes (alanine transaminase level [ALT] and aspartate aminotransferase [AST]), direct (conjugated) hyperbilirubinemia, hypoalbuminemia, and coagulopathy. (See 'Liver injury' above.)

Gastrointestinal manifestations – Feeding intolerance is a common in neonates with perinatal asphyxia. In addition, affected infants are at increased risk for necrotizing enterocolitis. (See 'Gastrointestinal manifestions' above and "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)

Hematologic manifestations – Hematologic manifestations include coagulopathy and thrombocytopenia. In some cases, acute blood loss may be the underlying cause of perinatal asphyxia (eg, feto-maternal transfusion, blood loss from placental abruption). (See 'Hematologic manifestations' above.)

Clinical stabilization and evaluation – Initial management of an infant following a perinatal hypoxic-ischemic event includes:

Cardiorespiratory stabilization in the delivery room, as summarized in the figure (algorithm 1) and discussed in detail separately. (See "Neonatal resuscitation in the delivery room".)

Evaluation of the extent of end-organ involvement. (See 'Evaluation' above.)

Determination of whether the neonate is a candidate for therapeutic hypothermia, as summarized in the table (table 2) and discussed in detail separately.

Therapeutic hypothermia – Therapeutic hypothermia is the only proven neuroprotection intervention for HIE and has become the standard of care in most high-resource settings. This is discussed in detail separately.

Supportive care – Supportive care measures are provided for all infants with perinatal asphyxia before, during, and after therapeutic hypothermia, and for those infants in whom cooling is not performed. This includes:

Respiratory support – Mechanical ventilator support is needed for most infants with perinatal asphyxia, particularly those treated with therapeutic hypothermia. The goal of respiratory support is to maintain adequate oxygenation and ventilation and avoid episodes of hyperoxia, hypoxia, hypercapnia, and hypocapnia. (See 'Respiratory support' above and "Overview of mechanical ventilation in neonates" and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn".)

Cardiovascular support – Infants with ventricular dysfunction and/or shock often require inotropic agents to support cardiac function. Dopamine is the most commonly used agent. (See 'Cardiovascular support' above and "Neonatal shock: Management".)

Empiric antibiotics – Empiric antibiotics are administered until culture results are known. (See 'Empiric antibiotic therapy' above and "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

Fluid and electrolyte – Infants with perinatal asphyxia are at-risk for fluid and electrolyte abnormalities due to AKI and the syndrome of inappropriate antidiuretic hormone (SIADH). Fluid and electrolytes should be adjusted in response to the changes in the clinical status of the patient with ongoing monitoring of net fluid intake and output, daily weight, respiratory status, and blood electrolytes. (See 'Fluid and electrolyte management' above and "Fluid and electrolyte therapy in newborns".)

Nutrition – Optimal nutritional support during hypothermia is uncertain. Many centers defer full enteral feeding until the period of therapeutic hypothermia is completed due to concern of reduced intestinal function. Nutrition support typically consists of minimal enteral feeding ("trophic feeds") in combination with parenteral nutrition. However, practice is not standardized and some centers may provide enteral feeds during therapeutic hypothermia. (See 'Nutrition' above and "Parenteral nutrition in infants and children".)

Glucose levels should be monitored several times daily and glucose infusion rates adjusted to maintain glucose levels between 72 to 145 mg/dL (4 to 8 mmol/L) since inappropriately low or high glucose levels can adversely impact neurologic outcomes [51]. (See "Management and outcome of neonatal hypoglycemia" and "Neonatal hyperglycemia".)

Drug dosing – For infants with AKI and/or hypoxic-ischemic liver injury, drug dosing for certain medications may need to be adjusted depending on the severity of organ dysfunction. (See 'Drug monitoring and dosing' above.)

Prognosis – Outcomes for infants with perinatal asphyxia depend primarily on the severity of brain injury. Survival and long-term neurodevelopmental outcomes for infants with perinatal asphyxia have improved with the advent of therapeutic hypothermia, as discussed separately.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ann R Stark, MD, who contributed to an earlier version of this topic review.

  1. Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet Gynecol 2014; 123:896. Reaffirmed 2020.
  2. Endrich O, Rimle C, Zwahlen M, et al. Asphyxia in the Newborn: Evaluating the Accuracy of ICD Coding, Clinical Diagnosis and Reimbursement: Observational Study at a Swiss Tertiary Care Center on Routinely Collected Health Data from 2012-2015. PLoS One 2017; 12:e0170691.
  3. Dzakpasu S, Joseph KS, Huang L, et al. Decreasing diagnoses of birth asphyxia in Canada: fact or artifact. Pediatrics 2009; 123:e668.
  4. Razaz N, Norman M, Alfvén T, Cnattingius S. Low Apgar score and asphyxia complications at birth and risk of longer-term cardiovascular disease: a nationwide population-based study of term infants. Lancet Reg Health Eur 2023; 24:100532.
  5. Lawn JE, Cousens S, Zupan J, Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: when? Where? Why? Lancet 2005; 365:891.
  6. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2016; 388:3027.
  7. Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2004; 89:F152.
  8. Lista G, Pogliani L, Fontana P, et al. Cardiovascular and respiratory status in mechanically ventilated asphyxiated term infants: comparison between hypothermic and control group. Acta Biomed 2004; 75:107.
  9. Szakmar E, Jermendy A, El-Dib M. Respiratory management during therapeutic hypothermia for hypoxic-ischemic encephalopathy. J Perinatol 2019; 39:763.
  10. Agarwal P, Shankaran S, Laptook AR, et al. Outcomes of infants with hypoxic ischemic encephalopathy and persistent pulmonary hypertension of the newborn: results from three NICHD studies. J Perinatol 2021; 41:502.
  11. Van Bel F, Walther FJ. Myocardial dysfunction and cerebral blood flow velocity following birth asphyxia. Acta Paediatr Scand 1990; 79:756.
  12. Polglase GR, Ong T, Hillman NH. Cardiovascular Alterations and Multiorgan Dysfunction After Birth Asphyxia. Clin Perinatol 2016; 43:469.
  13. Kluckow M. Functional echocardiography in assessment of the cardiovascular system in asphyxiated neonates. J Pediatr 2011; 158:e13.
  14. Abiramalatha T, Kumar M, Chandran S, et al. Troponin-T as a biomarker in neonates with perinatal asphyxia. J Neonatal Perinatal Med 2017; 10:275.
  15. Bertinchant JP, Larue C, Pernel I, et al. Release kinetics of serum cardiac troponin I in ischemic myocardial injury. Clin Biochem 1996; 29:587.
  16. Tarcan A, Tiker F, Güvenir H, Gürakan B. Hepatic involvement in perinatal asphyxia. J Matern Fetal Neonatal Med 2007; 20:407.
  17. Oliveira V, Singhvi DP, Montaldo P, et al. Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK. Arch Dis Child Fetal Neonatal Ed 2018; 103:F388.
  18. Chu A, Chiu HK. Necrotizing Enterocolitis in the Full-Term Infant. Pediatr Ann 2015; 44:e237.
  19. Al Tawil K, Sumaily H, Ahmed IA, et al. Risk factors, characteristics and outcomes of necrotizing enterocolitis in late preterm and term infants. J Neonatal Perinatal Med 2013; 6:125.
  20. Christensen RD, Baer VL, Yaish HM. Thrombocytopenia in late preterm and term neonates after perinatal asphyxia. Transfusion 2015; 55:187.
  21. Boutaybi N, Steggerda SJ, Smits-Wintjens VE, et al. Early-onset thrombocytopenia in near-term and term infants with perinatal asphyxia. Vox Sang 2014; 106:361.
  22. Bauman ME, Cheung PY, Massicotte MP. Hemostasis and platelet dysfunction in asphyxiated neonates. J Pediatr 2011; 158:e35.
  23. Suzuki S, Morishita S. Hypercoagulability and DIC in high-risk infants. Semin Thromb Hemost 1998; 24:463.
  24. Buonocore G, Perrone S, Gioia D, et al. Nucleated red blood cell count at birth as an index of perinatal brain damage. Am J Obstet Gynecol 1999; 181:1500.
  25. Christensen RD, Henry E, Andres RL, Bennett ST. Reference ranges for blood concentrations of nucleated red blood cells in neonates. Neonatology 2011; 99:289.
  26. Christensen RD, Lambert DK, Richards DS. Estimating the nucleated red blood cell 'emergence time' in neonates. J Perinatol 2014; 34:116.
  27. Hakobyan M, Dijkman KP, Laroche S, et al. Outcome of Infants with Therapeutic Hypothermia after Perinatal Asphyxia and Early-Onset Sepsis. Neonatology 2019; 115:127.
  28. Eken P, Jansen GH, Groenendaal F, et al. Intracranial lesions in the fullterm infant with hypoxic ischaemic encephalopathy: ultrasound and autopsy correlation. Neuropediatrics 1994; 25:301.
  29. de Vries LS, Cowan FM. Evolving understanding of hypoxic-ischemic encephalopathy in the term infant. Semin Pediatr Neurol 2009; 16:216.
  30. Wood T, Thoresen M. Physiological responses to hypothermia. Semin Fetal Neonatal Med 2015; 20:87.
  31. Sarkar S, Barks J. Management of neonatal morbidities during hypothermia treatment. Semin Fetal Neonatal Med 2015; 20:97.
  32. Groenendaal F, De Vooght KM, van Bel F. Blood gas values during hypothermia in asphyxiated term neonates. Pediatrics 2009; 123:170.
  33. Afzal B, Chandrasekharan P, Tancredi DJ, et al. Monitoring Gas Exchange During Hypothermia for Hypoxic-Ischemic Encephalopathy. Pediatr Crit Care Med 2019; 20:166.
  34. van Wincoop M, de Bijl-Marcus K, Lilien M, et al. Effect of therapeutic hypothermia on renal and myocardial function in asphyxiated (near) term neonates: A systematic review and meta-analysis. PLoS One 2021; 16:e0247403.
  35. Pinchefsky EF, Hahn CD, Kamino D, et al. Hyperglycemia and Glucose Variability Are Associated with Worse Brain Function and Seizures in Neonatal Encephalopathy: A Prospective Cohort Study. J Pediatr 2019; 209:23.
  36. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; :CD003311.
  37. Satas S, Løberg EM, Porter H, et al. Effect of global hypoxia-ischaemia followed by 24 h of mild hypothermia on organ pathology and biochemistry in a newborn pig survival model. Biol Neonate 2003; 83:146.
  38. Favié LMA, de Haan TR, Bijleveld YA, et al. Prediction of Drug Exposure in Critically Ill Encephalopathic Neonates Treated With Therapeutic Hypothermia Based on a Pooled Population Pharmacokinetic Analysis of Seven Drugs and Five Metabolites. Clin Pharmacol Ther 2020; 108:1098.
  39. Bijleveld YA, de Haan TR, van der Lee JH, et al. Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia. Br J Clin Pharmacol 2016.
  40. van den Broek MP, Groenendaal F, Toet MC, et al. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin Pharmacokinet 2012; 51:671.
  41. van den Broek MP, Rademaker CM, van Straaten HL, et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed 2013; 98:F341.
  42. van den Broek MP, van Straaten HL, Huitema AD, et al. Anticonvulsant effectiveness and hemodynamic safety of midazolam in full-term infants treated with hypothermia. Neonatology 2015; 107:150.
  43. Gyurkovits Z, Maróti Á, Rénes L, et al. Adrenal haemorrhage in term neonates: a retrospective study from the period 2001-2013. J Matern Fetal Neonatal Med 2015; 28:2062.
  44. Kovacs K, Szakmar E, Meder U, et al. A Randomized Controlled Study of Low-Dose Hydrocortisone Versus Placebo in Dopamine-Treated Hypotensive Neonates Undergoing Hypothermia Treatment for Hypoxic-Ischemic Encephalopathy. J Pediatr 2019; 211:13.
  45. Rao R, Lee KS, Zaniletti I, et al. Antimicrobial therapy utilization in neonates with hypoxic-ischemic encephalopathy (HIE): a report from the Children's Hospital Neonatal Database (CHND). J Perinatol 2020; 40:70.
  46. Bijleveld YA, de Haan TR, van der Lee JH, et al. Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia. Antimicrob Agents Chemother 2018; 62.
  47. Bijleveld YA, Mathôt R, van der Lee JH, et al. Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia. Clin Pharmacol Ther 2018; 103:458.
  48. Diederen CMJ, van Bel F, Groenendaal F. Complications During Therapeutic Hypothermia After Perinatal Asphyxia: A Comparison with Trial Data. Ther Hypothermia Temp Manag 2018.
  49. Ojha S, Dorling J, Battersby C, et al. Optimising nutrition during therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed 2019; 104:F230.
  50. Hu Y, Chen F, Xiang X, et al. Early versus delayed enteral nutrition for neonatal hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia: a randomized controlled trial. Ital J Pediatr 2022; 48:146.
  51. Parmentier CEJ, de Vries LS, van der Aa NE, et al. Hypoglycemia in Infants with Hypoxic-Ischemic Encephalopathy Is Associated with Additional Brain Injury and Worse Neurodevelopmental Outcome. J Pediatr 2022; 245:30.
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