Version May 2024
INTRODUCTION AND DEFINITION — Neonatal encephalopathy is a heterogeneous, clinically defined syndrome characterized by disturbed neurologic function in the earliest days of life in an infant born at or beyond 35 weeks of gestation, manifested by a reduced level of consciousness or seizures, often accompanied by difficulty with initiating and maintaining respiration, and by depression of tone and reflexes [1].
This section will review the diagnosis, treatment, and prognosis of neonatal encephalopathy. The pathogenesis of neonatal encephalopathy is discussed elsewhere. (See "Etiology and pathogenesis of neonatal encephalopathy".)
ETIOLOGY — Neonatal encephalopathy can result from a wide variety of conditions. Hypoxic-ischemic encephalopathy (HIE) or birth asphyxia is responsible for some, but not all, cases of neonatal encephalopathy. Given that the underlying nature of brain injury causing neurologic impairment in a newborn is often poorly understood, "neonatal encephalopathy" has emerged as the preferred term to describe the clinical syndrome of central nervous system dysfunction in the newborn period because it does not imply a specific underlying etiology or pathophysiology. (See "Etiology and pathogenesis of neonatal encephalopathy".)
Determining whether an acute hypoxic-ischemic event contributed to neonatal encephalopathy is challenging, since there is no gold standard test for diagnosis. The various clinical signs of HIE, including low Apgar scores, low cord pH, neonatal seizures, and encephalopathy, are nonspecific and may occur in the absence of global hypoxic-ischemic brain injury or long-term neurologic sequelae. However, when clinical symptoms suggest that HIE is the most likely cause of neonatal encephalopathy, a diagnosis of "presumed HIE" is often appropriate while awaiting additional test results, and while instituting neuroprotective therapies designed specifically to treat HIE. [2]. (See "Etiology and pathogenesis of neonatal encephalopathy", section on 'Risk factors' and 'Markers of acute hypoxia-ischemia' below.)
EPIDEMIOLOGY — The incidence of neonatal encephalopathy depends on how the syndrome is defined, but published estimates vary between 2 and 9 per 1000 term births [3-6]. As the term "neonatal encephalopathy" became increasingly favored, it was shown in one US population that the diagnosis of "birth asphyxia" declined between the years 1991 and 2000 [3]. In a 2010 review, the estimated incidence of neonatal encephalopathy was 3.0 per 1000 live births (95% CI 2.7-3.3), while the estimated incidence of hypoxic-ischemic encephalopathy (a subset of neonatal encephalopathy) was 1.5 per 1000 live births (95% CI 1.3-1.7) [7]. Although ascertainment and use of therapeutic hypothermia increased in the ensuing years, a 2023 analysis of a US population found that the population incidence of perinatal hypoxic-ischemic encephalopathy had remained stable [8].
Antepartum and intrapartum risk factors for neonatal encephalopathy are reviewed separately. (See "Etiology and pathogenesis of neonatal encephalopathy", section on 'Risk factors'.)
CLINICAL PRESENTATION — The neonate who is encephalopathic may have an abnormal state of consciousness (eg, hyperalert, irritable, lethargic, or obtunded), diminished spontaneous movements, respiratory or feeding difficulties, poor tone, abnormal posturing, absent primitive reflexes, or seizure activity. In the delivery room, the infant will often exhibit low Apgar scores and a weak or absent cry. The severity of neonatal encephalopathy can be classified as mild, moderate, or severe according to these clinical findings (see 'Clinical predictors' below). Newborns presenting with moderate to severe neonatal encephalopathy often require immediate resuscitation.
EVALUATION — The diagnosis of neonatal encephalopathy necessitates a search for potential etiologies. In a consensus statement, the American College of Obstetricians and Gynecologists (ACOG) recommends a comprehensive evaluation in all cases of neonatal encephalopathy [1]. This evaluation should include an assessment of neonatal clinical status and consideration of all factors potentially contributing to neonatal encephalopathy, including maternal medical history, obstetric antecedents, intrapartum factors (including fetal heart rate monitoring results and acute sentinel events), and placental pathology.
The presence of oliguria, cardiomyopathy, or abnormal liver function tests may suggest a global hypoxic-ischemic event. Neuroimaging plays a key role in the evaluation of neonatal encephalopathy and may provide information regarding the nature, pattern and severity of brain injury [9,10]. A thorough maternal and family history is recommended, including a history of thromboembolic disorders, prior pregnancy loss, maternal infection, and maternal drug use. Metabolic derangements, unusual odors, dysmorphic features, and congenital anomalies may suggest the presence of an inborn error of metabolism or genetic disorder.
Rapid assessment — A rapid clinical assessment of term newborns presenting with neonatal encephalopathy (table 1) is necessary to determine eligibility for therapeutic hypothermia, which is typically started within six hours of birth. (See 'Therapeutic hypothermia' below.)
Markers of acute hypoxia-ischemia — Neonatal encephalopathy is most likely due to acute hypoxia-ischemia when one or more of following conditions are present (table 2) [1]:
●Neonatal signs consistent with an acute peripartum or intrapartum hypoxic-ischemic event:
•Apgar score of <5 at 5 minutes and 10 minutes
•Fetal umbilical artery pH <7.0, or base deficit ≥12 mmol/L, or both
•Acute brain injury seen on brain magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS) consistent with hypoxia-ischemia, including deep nuclear gray matter or watershed (borderzone) injury
•Presence of multisystem organ failure consistent with hypoxic-ischemic encephalopathy (HIE)
●Additional factors consistent with an acute peripartum or intrapartum hypoxic-ischemic event:
•A sentinel hypoxic or ischemic event occurring immediately before or during labor and delivery, such as ruptured uterus or severe abruptio placentae
•Fetal heart rate monitor patterns consistent with an acute peripartum or intrapartum event, such as a category III pattern
•No evidence of other proximal or distal temporal factors that could be contributing to the encephalopathy
Fetal heart rate monitor patterns are reviewed separately. (See "Intrapartum fetal heart rate monitoring: Overview".)
Investigations — The following tests and investigations are recommended to evaluate the etiology of neonatal encephalopathy:
●Cord blood samples to determine umbilical arterial and venous pH and base deficit.
●A gross and histologic examination of the placenta and umbilical cord may provide evidence of a contributing cause, such as a placental vascular lesion or infection/inflammation, or an umbilical cord thrombosis [11].
●A complete blood count and differential to evaluate for possible infection, hemorrhage, and/or thrombocytopenia.
●Arterial blood gases, serum calcium, magnesium, glucose, and electrolytes to guide management. These should be assessed early in the course and as needed.
●Liver enzymes and serum creatinine are measured to identify injury to other end organs.
●Bacterial blood cultures to rule out sepsis, and viral cultures if there is a specific concern.
●Coagulation tests such as prothrombin time (PT), partial thromboplastin time (PTT), and D-dimer should be performed if there is bleeding or oozing to rule out disseminated intravascular coagulopathy.
●Electroencephalography (EEG) to determine whether there are clinical or electrographic seizures and to evaluate the background electrical activity, since these findings can impact the treatment and prognosis of neonatal encephalopathy. EEG is usually obtained on the first day of life (prior to or during treatment) and EEG monitoring is continued for at least 24 hours or longer if electrographic seizures are present. The amplitude integrated EEG is a helpful bedside tool that can screen for seizure activity in infants with neonatal encephalopathy and provide additional bedside information regarding background electrical activity. (See 'EEG' below and 'EEG predictors' below and "Clinical features, evaluation, and diagnosis of neonatal seizures".)
●Brain MRI at four to seven days of age. Specific findings on brain MRI can be useful for determining the pathogenesis and prognosis of neonatal encephalopathy. Cranial sonography is not as sensitive as MRI. Head CT in the acute neonatal period has poor sensitivity for injury detection; CT also imposes excessive and avoidable radiation exposure. (See 'Neuroimaging' below.)
●Specific testing for inborn error of metabolism, including ammonia, lactate and pyruvate, serum amino acids, and urine organic acids to rule out a metabolic cause of neonatal encephalopathy.
●Genetic testing (eg, cytogenetics and comparative genomic hybridization [CGH] microarray) is suggested if the child is dysmorphic or exhibits congenital anomalies.
●Lumbar puncture, if there is concern for intracranial infection (eg, fever, elevated white blood cell count, rash, positive blood culture, and/or maternal herpes lesion or documented infection), since meningitis can mimic the signs and symptoms of neonatal encephalopathy. Antibiotics are started until infection is ruled out, and acyclovir is initiated if herpes simplex virus is suspected. (See "Lumbar puncture in children".)
Neuroimaging — We recommend a brain MRI for infants with neonatal encephalopathy to establish the presence and pattern of injury, and to predict neurologic outcome. Typically, brain MRI is performed at four to seven days of age when any diffusion-weighted imaging abnormalities are still apparent, and after the infant has completed therapeutic hypothermia.
Neuroimaging plays a key role in evaluating infants with neonatal encephalopathy. Brain MRI yields the most useful information (see 'Brain MRI' below), and neonatal brain MRI is the standard of care at tertiary care centers in the United States and other developed countries. However, the resources necessary for transporting, monitoring, and supporting sick babies during this procedure, and the highly specialized expertise needed to interpret neonatal brain MRI studies, may not be readily available at all hospitals. Cranial ultrasound has low sensitivity for hypoxic-ischemic brain injury due to HIE and is rarely helpful in the evaluation of newborns with neonatal encephalopathy unless there is a concern for large intracranial hemorrhage.
Head CT has little to no role in the neuroimaging of infants with neonatal encephalopathy, given the excessive radiation exposure and the lower sensitivity compared with MRI [10]. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'CT safety considerations'.)
Brain MRI — A brain MRI is the most sensitive imaging tool for detecting cortical and white matter injury, deep gray matter lesions, arterial infarction, hemorrhage, developmental brain malformations, and other underlying causes of neonatal encephalopathy [9,10,12-15].
●Patterns suggestive of hypoxic-ischemic brain injury – Certain distributional patterns of brain injury seen in term and late preterm infants are considered to be typical of hypoxic-ischemic brain injury (image 1). These are [16]:
•Injury to the deep gray nuclei (especially the posterior putamina and anterolateral thalami) [12,17-20], which also corresponds to brain damage seen in animal models of acute total asphyxia [21]. In one study of 48 term neonates with encephalopathy who likely suffered acute and total oxygen deprivation due to a sentinel event, this pattern of deep gray injury on brain MRI was present in 74 percent [20]. Brainstem injury may also be common in these circumstances [2,22].
•Parasagittal injury of the cerebral cortex and subcortical white matter in the arterial watershed distribution. This occurs more commonly in the setting of mild hypoxia or ischemia of prolonged or chronic duration, though parasagittal watershed injury can also be seen in the setting of an acute sentinel event [23].
●Patterns suggestive of other causes of brain injury – By contrast, some patterns of brain injury seen on brain MRI suggest that peripartum global hypoxia-ischemia did not play a role in causing neonatal encephalopathy. These include:
•Focal arterial infarction
•Venous infarction
•Isolated intraparenchymal or intraventricular hemorrhage
•Kernicterus
•MRI patterns suggesting metabolic encephalopathies
The presence of a brain malformation such as lissencephaly would suggest that the neonatal encephalopathy is a result of abnormal brain development, as opposed to an acute brain injury occurring around the time of birth. In some cases, findings of both an acute brain injury and old injury and/or brain dysgenesis can be seen, suggesting a mixed pathogenesis.
Magnetic resonance spectroscopy — In addition to conventional MRI, magnetic resonance spectroscopy (MRS) can provide useful complimentary information regarding the nature and prognosis of brain injury underlying neonatal encephalopathy [9,13]. To evaluate the presence of hypoxic-ischemic brain injury, it is most useful to obtain spectra from locations that are particularly susceptible to injury. Therefore, two regions of interest are commonly evaluated: the deep gray nuclei (putamen and/or thalamus) and the posterior white matter. An elevated ratio of lactate to n-acetyl aspartate (NAA) in the deep gray nuclei has been shown to be a useful indicator of hypoxic-ischemic injury and a predictor of poor outcome [24,25].
Cranial ultrasound — Cranial ultrasound has the advantage of being noninvasive and usually available at the infant's bedside. Cranial ultrasound has a high sensitivity and specificity (91 and 81 percent, respectively) for locating hemorrhages and assessing ventricular size [26]. It may detect severe parasagittal white matter damage, cerebral edema, and obvious cystic lesions, but it does not adequately image the outer limits of the cerebral cortex [27], nor is cranial ultrasound a sensitive tool for identifying the majority of white matter abnormalities, which are best detected by brain MRI [28].
EEG — Electroencephalography (EEG) can help to distinguish neonatal seizures from other phenomena and can also identify subclinical seizures. Although EEG is not helpful for determining the cause of neonatal encephalopathy, it can provide evidence for the presence and severity of encephalopathy, as well as provide prognostic information. (See 'Prognosis' below.)
Amplitude integrated EEG using a continuous, single- or dual-channel recording of background cerebral electrical activity, is easy to use and interpret at the bedside, and has been used to distinguish mild from severe neonatal encephalopathy in large clinical trials and to diagnose neonatal seizures [29].
TREATMENT — Therapeutic hypothermia is the treatment of choice (in the first six hours of age) for neonatal encephalopathy that meets criteria for presumed hypoxic-ischemic encephalopathy (HIE) (see 'Indications' below), and is available in experienced centers. (See 'Therapeutic hypothermia' below.)
The supportive management of moderate and severe neonatal encephalopathy should take place in a neonatal intensive care unit. Major goals include the maintenance of physiologic homeostasis and treatment of the outward manifestations of brain injury [30,31]. Central aspects of supportive care include the following (see 'Supportive management' below):
●Maintenance of adequate ventilation (avoidance of hypoxemia or hyperoxia)
●Maintenance of sufficient brain and organ perfusion (avoidance of systemic hypotension or hypertension; avoidance of hyperviscosity)
●Maintenance of normal metabolic status (eg, normoglycemia, nutritional status, pH)
●Control of seizures
●Control of brain edema (avoidance of fluid overload)
Therapeutic hypothermia — Therapeutic hypothermia, maintained for 72 hours at 33 to 35°C (91.4 to 95.0°F) and started within the first six hours after delivery, is the only proven neuroprotective therapy for treatment of neonatal encephalopathy (table 1).
Given the data from controlled trials and meta-analyses (see 'Effectiveness' below) showing benefit from therapeutic hypothermia, we suggest the use of therapeutic whole body or head cooling as early therapy (starting in the first six hours of life) for term or late preterm infants with neonatal encephalopathy who meet strict criteria and are treated at experienced centers capable of providing comprehensive care [32]. Implementation of therapeutic hypothermia should follow published protocols employed in one of the major published trials. (See 'Implementation' below.)
There is a consensus among experts that therapeutic hypothermia should be more widely available, based upon the benefit and safety of hypothermia, and the lack of other effective treatments [33-35]. Thus, hypothermia has become the standard of care in most neonatal intensive care units in the United States, Europe, Australia, and Japan, and national guidelines support the use of therapeutic hypothermia for infants who meet the criteria used in the published trials [36-39].
Indications — In general, eligibility criteria for therapeutic hypothermia require the following (table 1) [32]:
●Gestational age ≥36 weeks and ≤6 hours of age (some centers include gestational age ≥34 or 35 weeks, although supportive data are lacking).
●One of the following:
•Metabolic or mixed acidosis with a pH of ≤7.0 or a base deficit of ≥16 mmol/L in a sample of umbilical cord blood or any blood obtained within the first hour after birth
•A 10-minute Apgar score of ≤5
•Ongoing resuscitation (eg, assisted ventilation, chest compressions, or cardiac medications) initiated at birth and continued for at least 10 minutes
●Moderate to severe encephalopathy on clinical examination - Therapeutic hypothermia has only been shown to improve outcomes in infants with moderate to severe encephalopathy.
Whether this treatment improves outcomes in infants with milder degrees of encephalopathy is unknown. Studies suggest that newborns with mild encephalopathy can also exhibit brain injury [40,41]; however, the safety and efficacy of therapeutic hypothermia for mild encephalopathy has not yet been established in clinical trials [42,43].
Because the original clinical trials used different definitions of moderate to severe encephalopathy, there is practice variation as to how this inclusion criterion is defined. Most centers use a modified Sarnat exam (table 3), with or without additional information on the presence of seizures. The Sarnat exam rates the severity of abnormalities in level of consciousness, spontaneous activity, tone, posture, primitive reflexes, and autonomic function [44].
Effectiveness
●Benefit in high-income countries – Treatment with hypothermia improves survival and outcome at 18 months for infants with neonatal encephalopathy in high-income countries who meet specified criteria for presumed moderate to severe HIE. This conclusion is supported by a 2012 meta-analysis of seven randomized controlled trials of therapeutic hypothermia involving 1214 newborns with moderate to severe neonatal encephalopathy [45]. In all the included trials, hypothermia was started within six hours after birth. The overall methodologic quality of the included trials was high. The following observations were noted:
•At age 18 months, therapeutic hypothermia compared with usual care led to a significant reduction in the composite primary outcome of death or major neurodevelopmental disability (48 versus 63 percent, risk ratio [RR] 0.76, 95% CI 0.69-0.84) [45].
•In subgroup analysis, the benefit of therapeutic hypothermia for reducing death or major neurodevelopmental disability was statistically significant for newborns with both moderate and severe HIE (RR 0.67, 95% CI 0.56-0.81 and RR 0.83, 95% CI 0.74-0.92, respectively) [45]. To save one newborn from death or major disability, the number needed to treat (NNT) for those with moderate HIE was 6, while the NNT for those with severe HIE was 7.
•The reduced risk of death or major neurodevelopmental disability was seen with both total body cooling and selective head cooling (RR 0.75, 95% CI 0.66-0.85 and RR 0.77, 95% CI 0.65-0.93, respectively) [45].
•Therapeutic hypothermia increased survival with a normal neurologic outcome at 18 months (40 versus 24 percent, RR 1.63, 95% CI 1.36-1.95) [45].
A 2013 meta-analysis reached similar conclusions [46].
Data regarding the long-term safety and efficacy of therapeutic hypothermia suggest that the benefit extends later into childhood. The NICHD trial assessed outcomes at ages six to seven years for 190 of the original 209 trial participants [47]. The proportion who died or had an intelligence quotient (IQ) score <70 was lower for children assigned to the hypothermia group compared with the control group (47 versus 62 percent), but the difference just missed statistical significance (RR 0.78, 95% CI 0.61-1.01). In the TOBY trial, with outcome data available for 280 of the original 325 subjects available, the proportion of children who survived to ages six or seven years with an IQ score of ≥85 was significantly higher for the hypothermia group compared with the control group (52 versus 39 percent, RR 1.31, 95% CI 1.01-1.71) [48]. However, suboptimal cognitive outcomes after therapeutic hypothermia may still occur [49-51].
Therapeutic hypothermia is the only proven neonatal intervention for neonatal encephalopathy that reduces the risk of cerebral palsy [52]. However, therapeutic hypothermia only provides partial neuroprotection, as illustrated by the 2012 meta-analysis of the major trials, in which nearly one-half of all infants who were treated with hypothermia either died or had major neurodevelopmental disability at 18 months [45]. In addition, the utility of this therapy has not been determined for infants with severe intrauterine growth restriction, mild encephalopathy, or prematurity [53-56]. Therefore, additional neuroprotective therapies and studies are urgently needed for neonatal encephalopathy [35].
The utility of delaying initiation of therapeutic hypothermia to 6 to 24 hours after birth is unclear, as data are limited. One controlled trial randomly assigned 168 term infants with HIE to therapeutic hypothermia for 96 hours starting at 6 to 24 hours after birth or to noncooling [57]. At 18 to 22 months of age, hypothermia was associated with a nonsignificant trend towards a reduction in the composite outcome of death or moderate to severe disability compared with noncooling (24.4 versus 27.9 percent, absolute risk reduction 3.5 percent, 95% CI -1 to 17 percent). Therefore, there is uncertainty regarding the true effectiveness of delayed onset therapeutic hypothermia.
●No apparent benefit in low- and middle-income countries – Randomized trial evidence suggests that therapeutic hypothermia as practiced in high-income countries is not beneficial and may cause harm when used for neonatal encephalopathy in low- and middle-income countries (LMIC). The multicenter HELIX trial, performed in tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh, randomly assigned 408 term infants with moderate or severe neonatal encephalopathy who were within six hours of birth to whole body hypothermia using a servo-controlled cooling device or to usual care (control group) [58]. At 18 to 22 months, the composite outcome of death or moderate or severe disability was similar for the therapeutic hypothermia and control groups (50 versus 47 percent, risk ratio [RR] 1.06, 95% CI 0.87-1.30), while death alone was increased for the hypothermia group (42 versus 31 percent, RR 1.35, 95% CI 1.04-1.76). Several secondary outcomes were also worse in the hypothermia group.
The negative findings of the HELIX trial contrast with findings of trials done in high-income countries, which showed that hypothermia improved survival and outcome at 18 months for infants with neonatal encephalopathy and moderate to severe HIE. The reasons for the discrepant results are not clear, but differences in the populations studied may be a factor. Unlike infants in high-income countries, most of the infants in the HELIX trial were born outside of the hospital, and the quality of preadmission care could not be evaluated [58]. In addition, HELIX included a higher proportion of infants who were small for gestation age or low birth weight, had clinical seizures at enrollment, or had MRI markers suggesting a longer duration of hypoxic-ischemic injury [58,59].
Implementation — Hypothermia should be started within the first six hours after delivery and continued for 72 hours at target temperature (table 1). The rectal temperature should be maintained at 33 to 35°C (91.4 to 95.0°F), with target temperature typically set at 33.5°C. Although direct comparisons are lacking, selective head cooling and whole-body cooling appear to have similar safety and effectiveness. However, whole-body cooling is preferred to head cooling in most centers in the United States due to ease of administration. Whole-body cooling also provides easier access to the scalp for electroencephalography (EEG) monitoring. Cooling can be started and maintained during neonatal transport if there is need to transfer the infant to a specialized center [60,61].
Hypothermia for 72 hours with the rectal temperature maintained at 33 to 35°C (91.4 to 95.0°F) is the strategy used by the randomized trials that established the efficacy of this intervention. Four trials (NICHD [62], TOBY [63], neo.nEURO.network [64], and ICE [65]) used whole-body cooling to a goal rectal temperature of 33.5°C or 92.5°F (range 33 to 34°C [91.4 to 93.2°F]). Three trials (CoolCap [29] and two others [66,67]) employed selective head cooling, with a rectal temperature maintained in the two larger head cooling trials at 34 to 35°C (93.2 to 95.0°F) [29,66].
The duration of hypothermia in the trials was 72 hours, with the exception of one small trial that stopped cooling between 48 and 72 hours for newborns who recovered neurologically [67]. In a subsequent randomized controlled trial of 364 neonates with HIE that was stopped early for futility and evidence of increased mortality in the experimental arms, the strategy of longer (120 hours) or deeper (32°C [89.6°F]) hypothermia, or both, did not reduce early neonatal death or death or disability at age 18 months compared with hypothermia for 72 hours at 33.5°C (92.3°F) [68,69].
Adverse effects — Therapeutic hypothermia is generally well-tolerated, but short-term adverse effects in the randomized trials included sinus bradycardia and thrombocytopenia [46]. Subcutaneous fat necrosis, with or without hypercalcemia, has been observed as a potential rare complication [70,71].
Supportive management — Aside from treatment with therapeutic hypothermia, suggested management of neonatal encephalopathy includes the following recommendations:
●Treat seizures with phenobarbital, lorazepam, fosphenytoin, or levetiracetam. The optimal therapeutic agent, as well as the duration of treatment, has not been adequately evaluated. This topic is discussed in detail separately. (See "Treatment of neonatal seizures".)
●Use high frequency ventilation, inhaled nitric oxide, or extracorporeal membrane oxygenation therapies, as available, for infants with persistent pulmonary hypertension to maintain oxygenation.
●Replace volume and use inotropic agents as required to maintain blood pressure and adequate cerebral perfusion. However, systemic hypertension and volume overload, which can worsen cerebral edema, should be avoided.
●Early treatment may be crucial to outcome if a metabolic disorder is suspected. Feeds should be stopped, acidosis and hypoglycemia corrected, and specific treatment such as vitamin supplementation or hemodialysis considered after consultation with a geneticist or a specialist in pediatric metabolism.
●Maintain euglycemia [72,73].
General supportive measures for infants with a perinatal hypoxic-ischemic event are reviewed in detail separately. (See "Perinatal asphyxia in term and late preterm infants", section on 'Supportive care based on organ system'.)
When therapeutic hypothermia is not used, we suggest close monitoring of core body temperature and avoidance of hyperthermia. Although it is unproven whether lowering body temperature to normothermic levels alters outcome in this setting, secondary analyses of control infants in the NICHD and CoolCap trials found a significant association between elevated temperature and adverse outcome [74-76]. These observational data do not establish causality, and additional studies are needed to determine whether reducing temperatures to normothermic levels will improve neurologic outcomes in infants who do not receive therapeutic hypothermia.
Future prospects — A variety of potential neuroprotective treatments are being studied to prevent the cascade of injurious effects after hypoxia-ischemia [77,78]. As an example, erythropoietin has neuroprotective properties in animal models of hypoxic-ischemic brain injury and neonatal stroke [79]. However, a placebo-controlled randomized trial of 500 infants undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy found that erythropoietin did not reduce the risk of death or neurodevelopmental impairment [80]. Infants in the trial who received erythropoietin also experienced more serious adverse events during the neonatal period; therefore, high doses of erythropoietin should not be given to infants undergoing therapeutic hypothermia for HIE. Lower-quality evidence suggests possible neuroprotective effect of monotherapy with erythropoietin (ie, without hypothermia) [81], but larger trials are needed to confirm benefit, which could apply to situations where cooling is not an option (eg, in low- and middle-income countries [58]) or where cooling is not proven to be effective (eg, mild HIE).
PROGNOSIS — The likelihood and extent of brain damage is related to the severity of encephalopathy. Most infants with mild encephalopathy develop normally, although many will have evidence of brain injury on MRI [40,82]. Infants with moderate to severe encephalopathy are more likely to develop long-term neurologic morbidity [5,83-87]. Severe brain MRI abnormalities are usually associated with marked electroencephalogram (EEG) abnormalities and poor outcome.
Range of outcomes — Therapeutic hypothermia reduces death and disability among infants with neonatal encephalopathy, but outcomes remain suboptimal. In a systematic review of 1214 neonates with hypoxic-ischemic encephalopathy (HIE) who were treated with therapeutic hypothermia, nearly one-half either died or had major neurodevelopmental disability at 18 months, while 40 percent had a normal neurologic outcome [45].
Among survivors, permanent neurologic sequelae of neonatal brain injury can be mild, such as learning difficulties or attention deficit disorder, or may be severe and disabling, such as cerebral palsy, epilepsy, visual impairment, or severe cognitive and developmental disorders. One report of 110 survivors of neonatal encephalopathy found that subnormal intelligence quotient (IQ) scores at six to seven years of age were present in more than 25 percent of children overall; an IQ score <70 among survivors with and without cerebral palsy was found in 96 and 9 percent, respectively [49]. Cerebral palsy develops in approximately 13 percent [88].
Although there is an increased risk of cerebral palsy associated with neonatal encephalopathy, it is not an inevitable consequence. In most cases of cerebral palsy or later developmental deficits, the cause is related to conditions other than prior neonatal encephalopathy. (See "Cerebral palsy: Epidemiology, etiology, and prevention".)
Clinical predictors — Although definitions vary, a more severe degree of neonatal encephalopathy, as categorized by modified Sarnat criteria (table 3), and the presence of seizures are associated with increased risk of adverse outcome.
Term infants with mild neonatal encephalopathy have a higher probability of being normal at follow-up [5,83]. Infants with moderate encephalopathy have a 20 to 35 percent risk of later sequelae from the insult, although those whose neurologic examinations are completely normal within one week and whose brain MRI show no evidence of injury have a good likelihood of normal outcome [85,89]. In the era before the advent of therapeutic hypothermia, infants with severe encephalopathy had a 75 percent risk of dying in the neonatal period, and among survivors, an almost universal risk of sequelae [83,85,90,91].
Neonatal seizures are also a predictor of poor outcome [92-94].
Neuroimaging predictors — Brain MRI and magnetic resonance spectroscopy (MRS) are strongly predictive of long-term outcome following neonatal encephalopathy [95-98]. Typically, brain MRI is performed after the infant is rewarmed, at 4 to 7 days of age when any diffusion-weighted imaging abnormalities can still be seen. Neonatal brain MRI and MRS are validated and well-accepted biomarkers of HIE severity, neurologic outcome [12,99-103], and treatment response following hypothermia [104-109].
●Lesion location and pattern – Abnormal signal in the posterior limb of the internal capsule appreciated on a brain MRI obtained in the first two weeks of life has been shown to predict adverse neurologic outcome [95,110]. In term infants with neonatal encephalopathy, lesions affecting bilateral basal ganglia and thalami that are detected by MRI in the first weeks of life have been associated with poor neurologic outcomes and death [12,20,95]. In one study, brainstem lesions on MRI were associated with an increased risk of death [95].
Some reports suggest that a watershed pattern of brain injury (ie, involving the boundary regions of the major cerebral vascular territories) on neonatal brain MRI is associated with long-term cognitive, language, and motor deficits, even among children without major disability such as cerebral palsy [23,99,111,112]. However, isolated watershed distribution signal abnormalities on diffusion-weighted brain MRI are not invariably associated with a poor short-term outcome [113].
●Diffusion imaging – Diffusion-weighted MRI can detect the presence of acute brain injury; that is, injury that occurred within 7 to 10 days prior to the study. Thus, diffusion-weighted images can distinguish which infants with neonatal encephalopathy have suffered a significant brain injury that is associated with adverse outcome within a window of time that often includes the time of delivery [19,96,97,114].
●Impact of therapeutic hypothermia – In one study performed prior to the advent of therapeutic hypothermia, 30 percent of infants with neonatal encephalopathy demonstrated a completely normal head MRI during the newborn period, indicating a good prognosis [12]. In infants with HIE who are treated with therapeutic hypothermia (see 'Therapeutic hypothermia' above), the rates of normal brain MRI are even higher, ranging from 41 to 54 percent [104,105,115]. Of note, the available evidence suggests that treatment with hypothermia does not affect the value of MRI for predicting outcome after neonatal encephalopathy [104,105,107].
●MRI scoring systems – In a report of 117 infants (gestational age ≥36 weeks) with HIE who received therapeutic hypothermia, a deep learning model predicted adverse motor outcomes at 12 to 24 months based on three factors: putamen/globus pallidus injury on T1 MRI; gestational age; and cord pH [116]. Note that several MRI scoring systems are published [117,118] but are mainly used for research; none is optimal for predicting neurodevelopmental outcomes [119,120].
●MRS – MRS can detect increased lactate and decreased N-acetyl aspartate (NAA) concentrations, which indicate derangements of the metabolic state of specific regions of the brain and portend a worse prognosis [13,121-123]. A prospective multicenter study using 3 Tesla MRI found that thalamic NAA concentrations measured within 14 days after birth predicted adverse neurodevelopmental outcomes at two years with a sensitivity and specificity of 100 and 97 percent, respectively [124]. Earlier reports had suggested a lower predictive value for MRS. In a 2010 meta-analysis of single-center studies, elevated Lac/NAA ratios in the thalamus or basal ganglia demonstrated a pooled sensitivity of 82 percent and specificity of 95 percent for neurodevelopmental outcome [24], and a 2013 systematic review found that MRS was not as predictive of outcome as other MRI parameters [97].
EEG predictors — Findings on EEG and amplitude-integrated electroencephalography (aEEG) can provide useful prognostic information in neonatal encephalopathy. Therefore, most centers that treat infants with moderate to severe encephalopathy will perform EEG monitoring for at least 24 hours, or longer if electrographic seizures are seen [125]. Other cooling centers perform continuous EEG monitoring throughout cooling and rewarming to evaluate for presence of subclinical seizures and to assess change in EEG background over time [126]. An EEG that shows severe background abnormalities including burst suppression, isoelectricity or extremely low voltage portends an increased likelihood of death or significant long-term neurologic sequelae [127-130]. Since severe brain MRI abnormalities are usually associated with marked EEG abnormalities and poor outcome, the EEG may be especially helpful as a prognostic tool in the setting of moderate MRI abnormalities [131,132].
A 2012 systematic review identified 29 observational studies that evaluated 13 prognostic tests applied to term infants (n = 1306) with HIE who had at least 18 months of follow-up [97]. When obtained within the first week after birth, the best performing prognostic tests were aEEG (pooled sensitivity and specificity, 0.93 and 0.90) and routine EEG (pooled sensitivity and specificity, 0.92 and 0.83). However, the confidence intervals for these data were wide because of small patient numbers in the included studies.
In infants with neonatal encephalopathy undergoing therapeutic hypothermia, a persistently abnormal aEEG at 48 hours of age is more predictive of adverse outcome than an abnormal aEEG at an earlier age. A 2017 meta-analysis included nine studies with individual patient data that evaluated the prognostic accuracy of aEEG at various time points (6, 24, 48, or 72 hours) after birth in term babies (n = 520) with neonatal encephalopathy treated with therapeutic hypothermia [133]. The main finding was that a persistently severely abnormal aEEG at ≥48 hours was predictive of an adverse neurodevelopmental outcome (ie, death or moderate to severe disability) at one year or more. In the pooled data, an abnormal aEEG at 48 hours had a good sensitivity (85 percent) and specificity (93 percent), while an abnormal aEEG at 6 hours had a good sensitivity (96 percent) but a poor specificity (39 percent).
Biomarkers — There are no established biomarkers for determining the extent of neonatal brain injury or predicting outcome in infants with neonatal encephalopathy. However, several studies have found that elevated levels of serum tau protein are associated with worse outcomes in HIE [134-136].
In a systematic review published in 2009, serum interleukin-1B, serum interleukin-6, cerebrospinal fluid neuron-specific enolase (NSE), and cerebrospinal fluid interleukin-1B (all measured before age 96 hours) were putative predictors of abnormal outcomes at age ≥12 months in survivors [137]. However, all included studies had small patient numbers and significant heterogeneity. In subsequent small and uncontrolled reports of term newborns with neonatal encephalopathy who were treated with hypothermia, levels of serum S100b, NSE, neuronal glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) correlated with neurologic outcomes [138-141]. Given the shortcomings of these data, further studies are needed to determine if any of these biomarkers is useful for the early assessment of infants with neonatal encephalopathy.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neonatal encephalopathy".)
SUMMARY AND RECOMMENDATIONS
●Neonatal encephalopathy is a heterogeneous, clinically defined syndrome characterized by disturbed neurologic function in the earliest days after delivery in an infant born at or beyond 35 weeks of gestation, manifested by a subnormal level of consciousness or seizures, often accompanied by difficulty with initiating and maintaining respiration and with depression of tone and reflexes. Neonatal encephalopathy can result from a wide variety of conditions. Acute hypoxic-ischemic events are responsible for some, but not all, cases of neonatal encephalopathy. (See 'Introduction and definition' above.)
●Term newborns presenting with neonatal encephalopathy may require immediate resuscitation and should be triaged as quickly as possible to determine eligibility for therapeutic hypothermia, which must be started within six hours of birth. (See 'Clinical presentation' above and 'Rapid assessment' above.)
●All infants with neonatal encephalopathy should have a comprehensive evaluation (table 1), including an assessment of neonatal clinical status and all potentially contributing factors, such as maternal medical history, obstetric antecedents, intrapartum factors (including fetal heart rate monitoring results and issues related to delivery), and placental pathology. Neuroimaging, especially brain MRI, often provides information regarding the nature, pattern, and extent of brain injury. (See 'Evaluation' above.)
●A number of markers are helpful for determining the likelihood that an acute peripartum or intrapartum hypoxic-ischemic event contributed to the development of neonatal encephalopathy (table 2). (See 'Markers of acute hypoxia-ischemia' above.)
●For term or late preterm infants with moderate to severe neonatal encephalopathy (table 3) who are within the first six hours after delivery, we recommend therapeutic hypothermia with head cooling or whole-body cooling (table 1) (Grade 1B). This recommendation applies to experienced centers in high-income settings and may not apply to low-income settings where the benefit is uncertain.
Therapeutic hypothermia includes either head or whole-body cooling and is maintained for 72 hours at 33 to 35°C (91.4 to 95.0°F). (See 'Therapeutic hypothermia' above.)
●The management of moderate and severe neonatal encephalopathy should take place in a neonatal intensive care unit. Central aspects of supportive care include the following (see 'Treatment' above and 'Supportive management' above):
•Maintenance of adequate ventilation (avoidance of hypoxemia or hyperoxia)
•Maintenance of sufficient brain and organ perfusion (avoidance of systemic hypotension or hypertension; avoidance of hyperviscosity)
•Maintenance of normal metabolic status (eg, normoglycemia, nutritional status, pH)
•Control of seizures
•Control of brain edema (avoidance of fluid overload)
•Close monitoring of core body temperature and measures to avoid or minimize hyperthermia
●Most infants with mild encephalopathy develop normally, while infants with moderate to severe encephalopathy are more likely to develop long-term neurologic morbidity. Severe brain MRI abnormalities are usually associated with marked electroencephalogram (EEG) abnormalities and poor outcome. Permanent neurologic sequelae can be mild, such as specific learning difficulties or attention deficit disorder, or may be severe and disabling, such as cerebral palsy, epilepsy, visual impairment, and severe cognitive and developmental disorders. (See 'Prognosis' above.)
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