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Official reprint from UpToDate
www.uptodate.com 2014 UpToDate
Author
Yvonne Wu, MD, MPH
Section Editors
Douglas R Nordli, Jr, MD
Leonard E Weisman, MD
Deputy Editor
John F Dashe, MD, PhD
Clinical features, diagnosis, and treatment of neonatal encephalopathy
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2014. | This topic last updated: Feb 25, 2014.
INTRODUCTION AND DEFINITION Neonatal encephalopathy is a heterogeneous syndrome characterized by
symptoms of central nervous system dysfunction in newborns born at term or late preterm (!36 weeks gestation). An
infant with neonatal encephalopathy may exhibit abnormal level of consciousness, seizures, tone and reflex
abnormalities, apnea, and feeding difficulties [1,2].
Researchers have yet to adopt a consensus definition of neonatal encephalopathy. Some investigators require stringent
criteria, such as two or more symptoms of encephalopathy lasting over 24 hours [2], while others require no more than a
low 5 minute Apgar score [3].
Neonatal encephalopathy can result from a wide variety of conditions and often remains unexplained. Birth asphyxia and
hypoxic-ischemic (anoxic) encephalopathy are 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 terminology to describe central nervous system dysfunction in
the newborn period, as it does not imply a specific underlying pathophysiology [4,5].
The incidence of neonatal encephalopathy depends on how the syndrome is defined, but varies between two to nine per
1000 term births [5-7]. As the term neonatal encephalopathy has become increasingly favored, it has been shown in one
US population that the diagnosis of "birth asphyxia" has declined over the past decade [5].
This section will review the current state of knowledge regarding the diagnosis, prognosis and treatment of neonatal
encephalopathy. The pathogenesis of neonatal encephalopathy is discussed elsewhere. (See "Etiology and
pathogenesis of neonatal encephalopathy".)
CLINICAL MANIFESTATIONS AND NEONATAL ASSESSMENT The neonate who is encephalopathic may have an
abnormal state of consciousness (eg, hyperalert, irritable, lethargic, obtunded), respiratory or feeding difficulties, poor
tone or seizure activity. In the delivery room, the infant will often exhibit low Apgar scores and a weak or absent cry.
The diagnosis of neonatal encephalopathy necessitates a search for potential etiologies. A gross and histologic
examination of the placenta and cord may provide evidence of a possible cause, such as a placental vascular lesion or
infection, or a cord thrombosis [8]. A thorough maternal and family history is recommended, including a history of
thromboembolic disorders, prior pregnancy loss, maternal infection, and maternal drug use. Samples are drawn to
determine arterial cord pH and base deficit. The presence of oliguria, cardiomyopathy, or abnormal liver function tests
may suggest a global hypoxic-ischemic event. Metabolic derangements, unusual odors, dysmorphic features, and
congenital anomalies may suggest the presence of an inborn error of metabolism or genetic disorder.

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Neuroimaging Neuroimaging has become increasingly important in the evaluation of neonatal encephalopathy, and
may provide information regarding the type and timing of brain injury [9,10]. For instance, several patterns of brain injury
seen in term and late preterm infants are considered to be typical of hypoxic-ischemic brain injury. These include
parasagittal injury in the arterial watershed distribution and injury to the deep gray nuclei (lateral thalami, posterior
putamina) [4,11-14] which correspond to brain damage seen in animal models of acute total asphyxia [15].
Alternatively, a head imaging study may reveal a developmental brain malformation, focal arterial infarction, or
intraparenchymal hemorrhage, indicating a different underlying pathogenesis. In one study, 30 percent of infants with
neonatal encephalopathy demonstrated a completely normal head MRI during the newborn period, indicating a good
prognosis [13].
The findings on head CT and MRI may also provide insight into the time during which the injury occurred [16,17]. In a
study of 351 term infants with neonatal encephalopathy, MRI scans performed in the first one to two weeks of birth
suggested that the majority of infants sustained brain injury that occurred acutely in the perinatal period [16]. (See
"Etiology and pathogenesis of neonatal encephalopathy".)
Various modalities have been used to evaluate infant brains with neonatal encephalopathy, including cranial sonography
(CS), computed tomography (CT) and magnetic resonance imaging (MRI) with MR spectroscopy. Head MR imaging
techniques yield the most useful information, though the resources necessary for transporting, monitoring, and
supporting sick babies during this procedure are not always readily available. (See "Approach to neuroimaging in
children".)
Cranial sonography Cranial sonography has the advantage of being noninvasive and available at the infant's
bedside. Cranial sonography has a high sensitivity and specificity (91 and 81 percent, respectively) for locating
hemorrhages and defining ventricular size [18]. It may also detect severe parasagittal white matter damage and obvious
cystic lesions, but it does not adequately image the outer limits of the cerebral cortex [19], nor is cranial sonography a
sensitive tool for identifying milder white matter abnormalities that can be appreciated on head MRI [20]
Cranial sonography can be used to detect severe cerebral edema. Findings include increased echogenicity that causes
sulci and fissures to be obscured, blurring of other anatomical landmarks, decreased arterial pulsations, and
compression of the ventricles [21,22]. After a few days, areas of echodensity that correspond to regions of necrosis may
be present [21,22]. However, determining if early echodensities are areas of infarction or hemorrhage in the term brain is
not always possible [23].
Head CT Head CT is the most useful imaging modality for diagnosing intracranial hemorrhage and brain
calcifications. Cerebral edema, denoted by decreased attenuation of white matter and difficulty distinguishing gray from
white matter, may also be appreciated on head CT, along with cerebral atrophy, ventricular size, and severe white matter
lesions [24-27]. However, the white matter in a term newborn brain contains high water content, and therefore milder
degrees of edema and white matter injury can be difficult to appreciate on head CT. Abnormalities of the posterior fossa
are also often obscured by bony artifact.
Head MRI A number of studies have described the increasing role that MR imaging plays in the diagnosis of
neonatal encephalopathy [9,10,13,28-30]. A head MRI is the most sensitive imaging tool for detecting periventricular
white matter injury, deep gray matter lesions, arterial infarction, hemorrhage, developmental brain malformations, and
other underlying causes of neonatal encephalopathy. Deep gray matter lesions involving the bilateral basal ganglia and
thalami are particularly common findings on brain MRI in encephalopathic term infants with a recognized preceding
sentinel hypoxic-ischemic event such as placental abruption, uterine rupture, and cord prolapse [14].
The American Academy of Neurology (AAN) practice parameter suggests that a head CT be performed in cases of
neonatal encephalopathy to rule out hemorrhagic lesions [9]. However, a head MRI is recommended in order to establish
a pattern of injury and to predict neurologic outcome if the findings on head CT are inconclusive. (See 'Prognosis'
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below.)
In addition to conventional MRI, MR spectroscopy and diffusion-weighted imaging (DWI) techniques can provide useful
information regarding timing and outcome of brain injury resulting in neonatal encephalopathy [10,28,30,31].
Electroencephalography An electroencephalogram (EEG) can help to distinguish neonatal seizures from other
phenomena, and can also identify subclinical seizures. Although the 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, a continuous single 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 [32].
Diagnosis of neonatal asphyxia Hypoxic-ischemic encephalopathy (HIE, also called birth asphyxia) is a subset of
neonatal encephalopathy. It is unclear how often birth asphyxia is responsible for neonatal encephalopathy, as there is
no gold standard for determining the presence of hypoxic-ischemic encephalopathy. It is well known that the various
clinical signs of birth asphyxia, including 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. In a
population-based study of neonatal encephalopathy, only 4 percent of cases had evidence of intrapartum hypoxia in the
absence of antepartum risk factors, and 25 percent had both antepartum risk factors and intrapartum signs and
symptoms of hypoxia [2]. (See "Etiology and pathogenesis of neonatal encephalopathy", section on 'Risk factors'.)
ACOG criteria Although its true incidence is unclear, birth asphyxia is a well-known and important contributor to
neonatal encephalopathy. In order to identify cases of perinatal brain injury due to birth asphyxia, the American College
of Obstetricians and Gynecologists (ACOG) developed a consensus statement regarding the criteria needed to define an
intrapartum hypoxic-ischemic insult that is severe enough to cause a neonatal encephalopathy that subsequently leads
to cerebral palsy [17]. The following four criteria are required:
Additional criteria suggesting an intrapartum timing, but nonspecific to asphyxia, include a sentinel hypoxic event during
labor, severe electronic fetal monitoring abnormalities, Apgar score of 0 to 3 beyond five minutes, onset of multisystem
involvement within 72 hours of birth, and early imaging study showing evidence of acute nonfocal cerebral abnormality.
Limitations of ACOG criteria It has been suggested that these guidelines are somewhat arbitrary (eg, the cut-off
for cord pH), and that it may be too simplistic to think that a single set of nonspecific signs and symptoms can provide
robust criteria for distinguishing underlying causal pathways. As an example, the presence of an infectious condition
such as chorioamnionitis would preclude an intrapartum asphyxial event as being responsible for neonatal
encephalopathy and subsequent cerebral palsy, according to the ACOG guidelines. Yet a maternal infection may play a
role in causing hypoxic-ischemic brain injury in the fetus, and there is no reason to think that both cannot occur in the
same infant [33]. Of note, the etiology of cerebral palsy is multifactorial. Most cases are thought to result from prenatal
factors such as prematurity, intrauterine growth restriction, intrauterine infection, antepartum hemorrhage, severe
placental pathology, and multiple pregnancies. Perinatal hypoxia and/or ischemia likely account for only a small minority
Profound metabolic acidosis (pH less than 7.00 and base deficit !12 mmol/L) on an umbilical cord arterial blood
sample
"
Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks of gestation "
Cerebral palsy of the spastic quadriplegic or dyskinetic type "
Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious conditions, or genetic
disorders
"
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of cases of cerebral palsy. This issue is discussed in detail separately. (See "Epidemiology and etiology of cerebral
palsy".)
Until a more specific diagnostic test for hypoxic-ischemic brain injury is widely available, the attribution of neonatal
encephalopathy and cerebral palsy to birth asphyxia rests on clinical criteria as listed above. It remains to be established
whether neuroimaging or other testing can one day be used as a gold standard for determining when birth asphyxia and
hypoxic-ischemic brain injury is responsible for neonatal encephalopathy.
PROGNOSIS The likelihood and extent of brain damage is related to the degree of neonatal encephalopathy. Most
infants with mild to moderate degrees of encephalopathy develop normally, while infants with severe encephalopathy are
more likely to develop long-term neurologic morbidity [7,34-38]. Severe MRI abnormalities are usually associated with
marked EEG abnormalities and poor outcome.
Permanent neurologic sequelae can be mild, such as learning difficulties or attention deficit disorder, or may be severe
and disabling, including cerebral palsy, epilepsy, visual impairment and severe cognitive and developmental disorders.
Clinical predictors Although definitions vary, the degree of neonatal encephalopathy has been categorized by some
as follows [39]:
Term infants with mild neonatal encephalopathy in the neonatal period have a high probability of being normal at follow-
up [7,34]. 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 have a good likelihood of normal outcome
[36]. Infants with severe encephalopathy have a 75 percent risk of dying in the neonatal period, and among survivors, an
almost universal risk of sequelae exists [34,36,40,41].
Scoring systems have been devised to help predict an infant's subsequent risk for developing cerebral palsy or systemic
morbidity [39,42,43]. One of the largest studies retrospectively evaluated 365 infants with HIE and found that three
clinical parameters administration of chest compression for >1 minute, onset of regular respirations >30 minutes after
birth, and base deficit value of >16 mmol/L on any blood gas analysis within the first four hours from birth were
predictors of severe adverse outcome (death or severe disability) [43]. Severe outcome rates with none, one, two, or all
three predictors were 46, 64, 76, and 93 percent, respectively.
Seizures may be a predictor of poor outcome, but data are inconsistent.
A separate issue is that treatment with hypothermia (see 'Therapeutic hypothermia' below) may diminish the value of
clinical findings and electroencephalography (see 'EEG predictors' below) for predicting outcome among survivors of
neonatal encephalopathy [46-48]. However, in a post-hoc analysis of the NICHD trial, the clinical findings after 72 hours
of cooling were good predictors of outcome; persistence of severe hypoxic-ischemic encephalopathy at 72 hours and an
abnormal neurologic examination at the time of hospital discharge were associated with an increased risk of death or
Mild: hyperalert, hyperexcitable, normal muscle tone, no seizures "
Moderate: hypotonia, decreased movements, and often seizures "
Severe: stuporous, flaccid, and absent primitive reflexes, usually with seizures "
In a longitudinal report of 129 children ages 12 months to 16.5 years (median 6 years) who survived neonatal
encephalopathy, epilepsy developed in 13 (10 percent) [44]. Risk factors for the development of epilepsy were the
occurrence of neonatal seizures, particularly status epilepticus, and neonatal brain injury on MRI. All children with
epilepsy had unfavorable neurodevelopmental outcomes.
"
Another report analyzed data from subjects enrolled in a therapeutic hypothermia trial and compared 127 infants
who had clinical seizures during the trial with 81 infants who had no seizures [45]. After adjusting for study
treatment and severity of encephalopathy, seizures were not associated with poor outcomes at 18 months of life.
"
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disability at 18 months of age [49].
Neuroimaging predictors Neuroimaging findings can be helpful for predicting long-term outcome following neonatal
encephalopathy [10,50-52]. Abnormal signal in the posterior limb of the internal capsule appreciated on a head MRI
obtained in the first two weeks of life has been shown to predict adverse neurologic outcome [50,53]. 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 [13,14,50]. In one study, brainstem lesions on
MRI were associated with an increased risk of death [50]. Some reports suggest that a watershed pattern of brain injury
(ie, involving the boundary regions of the major cerebral vascular territories) on neonatal MRI is associated with long-
term cognitive and motor deficits, even among children without major disability such as cerebral palsy [54-56]. However,
isolated watershed distribution signal abnormalities on diffusion-weighted MRI are not invariably associated with a poor
short-term outcome [57].
Therapeutic hypothermia (see 'Therapeutic hypothermia' below) appears to decrease the degree of brain injury observed
on MRI and magnetic resonance spectroscopy [58-62]. Nevertheless, the available evidence suggests that treatment
with hypothermia does not affect the value of MRI for predicting outcome after neonatal encephalopathy [59,61,62].
Diffusion-weighted MRI can detect the presence of acute brain injury in a neonate, and thus distinguish which infants
with neonatal encephalopathy have suffered a significant brain injury that is associated with adverse outcome
[12,51,52,63].
Magnetic resonance spectroscopy can detect increased lactate and decreased N-acetyl aspartate indicating
derangements of the metabolic state of specific regions of the brain, which has also been shown to portend a worse
prognosis [28,64-66]. In cases of perinatal arterial stroke, the presence of internal capsule and basal ganglia injury has
been correlated with increased risk of hemiparesis and long-term neurologic sequelae, especially when seen in
conjunction with cortical injury [67-69].
EEG predictors Findings on electroencephalogram (EEG) and amplitude-integrated electroencephalogram (aEEG)
can also be used to help prognosticate. An EEG that shows severe background abnormalities including burst
suppression, isoelectricity or extremely low voltage portends a high likelihood of death or significant long-term neurologic
sequelae [70,71]. Since severe 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 [72].
Although severe abnormalities seen on EEG within the first 24 hours of life can be a useful predictor of outcome [73,74],
a follow-up EEG showing recovery of normal electrical activity may be associated with a much improved outcome
[74,75], indicating the importance of serial EEG examinations.
A 2012 systematic review identified 29 observational studies that evaluated 13 prognostic tests applied to term infants
with hypoxic-ischemic encephalopathy who had at least 18 months of follow-up [52]. 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.
Limited evidence suggests that aEEG is altered in the setting of hypothermia treatment [48]. In one study that compared
43 infants treated with hypothermia and 31 treated with normothermia, early (<6 hours) aEEG background abnormalities
in infants treated with hypothermia were poorly correlated with outcome. In contrast, recovery time to normal
background, and time to onset of sleep-wake cycling were more predictive of outcome in cooled infants than in non-
cooled infants. In addition, having a normal aEEG pattern within six hours of delivery predicted a normal outcome in both
cooled and non-cooled infants.
Biomarkers There are no established biomarkers for determining the extent of neonatal brain injury or predicting
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outcome in infants with neonatal encephalopathy. 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 [76]. However, all
included studies had small patient numbers and significant heterogeneity. In subsequent small 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 [77-80]. 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.
TREATMENT The 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 [81,82]. Central aspects of supportive care include the following (see 'Supportive
management' below):
Therapeutic hypothermia Treatment with hypothermia improves survival and outcome at 18 months after neonatal
asphyxia and/or neonatal encephalopathy. 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
[83]. In all the included trials, hypothermia was started within six hours after birth. Four of the trials (NICHD [84], TOBY
[85], neo.nEURO.network [86], and ICE [87]) used whole body cooling while three (CoolCap [32] and two others [88,89])
employed selective head cooling. The duration of hypothermia was 72 hours, with the exception of one small trial that
stopped cooling between 48 and 72 hours for newborns who recovered neurologically [89]. The overall methodologic
quality of the included trials was high. The following observations were noted:
A 2013 meta-analysis reached similar conclusions [90].
Data regarding the long-term safety and efficacy of therapeutic hypothermia are limited. The NICHD trial assessed
outcomes at ages six to seven years for 190 of the original 209 trial participants [91]. The proportion who died or had an
IQ score <70 was lower for children assigned to the hypothermia group compared with the control group (47 versus 62
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) "
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) [83].
"
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 hypoxic-ischemic
encephalopathy (RR 0.67, 95% CI 0.56-0.81 and RR 0.83, 95% CI 0.74-0.92, respectively) [83]. To save one
newborn from death or major disability, the number needed to treat (NNT) for those with moderate hypoxic-
ischemic encephalopathy was 6, while the NNT for those with severe hypoxic-ischemic encephalopathy 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) [83].
"
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) [83].
"
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percent) but the difference between the groups just missed statistical significance (RR 0.78, 95% CI 0.61-1.01). While
these results suggest that the benefit of therapeutic hypothermia extends later into childhood, more data are needed to
confirm long-term benefit.
Of note, secondary analyses of control infants in the NICHD and CoolCap trials found a significant association between
elevated temperature and adverse outcome [92-94]. 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.
Conclusions Hypothermia is the only effective neuroprotective therapy currently available for treatment of
neonatal encephalopathy. It is easy to administer and appears to be safe. 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 [46,95,96]. Thus, an increasing number of neonatal intensive care units in the US,
Europe, Australia, and Japan are providing therapeutic hypothermia, and national guidelines support the use of
therapeutic hypothermia for infants who meet the criteria used in the published trials [97-100].
Although direct comparisons are lacking, selective head cooling and whole body cooling appear to have similar safety
and effectiveness. Whole body cooling is preferred in most centers in the United States due to ease of administration.
Whole body cooling also provides easier access to the scalp for EEG monitoring.
Despite the promising clinical trial results, therapeutic hypothermia has limited efficacy, 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 [83]. In addition, data regarding long-term safety and efficacy of
therapeutic hypothermia beyond 18 to 24 months are limited, and the utility of this therapy has not been studied for
premature infants or infants with severe intrauterine growth restriction [101-103]. Therefore, additional neuroprotective
therapies and studies are urgently needed for neonatal encephalopathy [46].
Given the data from controlled trials and meta-analyses showing benefit for therapeutic hypothermia, our
recommendations are as follows:
Supportive management Aside from treatment with hypothermia, suggested management of HIE includes the
following recommendations:
For term or late preterm infants with neonatal encephalopathy, we suggest the use of therapeutic head cooling or
whole body cooling as early therapy (in the first six hours of life) in experienced centers. Implementation of
therapeutic hypothermia should follow published protocols employed in one of the major published trials [32,84-88].
(See 'Therapeutic hypothermia' above.)
"
When therapeutic hypothermia is not used, we suggest close monitoring of core body temperature. Although it is
unknown whether lowering body temperature to normothermic levels alters outcome in this setting, it is reasonable
to avoid hyperthermia given currently available data. (See 'Therapeutic hypothermia' above.)
"
Evaluate with an electroencephalogram (EEG) to gather information regarding diagnosis, treatment and prognosis
of neonatal encephalopathy. Serial EEGs may be helpful in further defining the prognosis. The amplitude integrated
EEG may be helpful for predicting outcome and identifying seizure activity in infants with neonatal encephalopathy.
(See 'EEG predictors' above.)
"
Obtain a head imaging study, preferably with MRI. Cranial sonography is not as sensitive as head MRI or CT.
Specific findings on head MRI can be useful for establishing the pathogenesis and prognosis of neonatal
encephalopathy. (See 'Neuroimaging' above.)
"
Treat seizures with phenobarbital, lorazepam or fosphenytoin. The optimal therapeutic agent, as well as the "
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Future prospects A variety of potential neuroprotective treatments are being studied both to prevent the cascade of
injurious effects after hypoxia-ischemia. As an example, erythropoietin has neuroprotective properties in animal models
of hypoxic-ischemic brain injury and neonatal stroke [104-107]. A preliminary randomized trial of 167 neonates with HIE
found that treatment with recombinant human erythropoietin for two weeks, starting within 48 hours of birth, was
associated with improved neurologic outcome at 18 months [108]. Confirmation of benefit in larger trials is needed.
Additional strategies that may be useful as adjuncts to hypothermia include the following [4,46,109,110]:
SUMMARY AND RECOMMENDATIONS
duration of treatment, has not been adequately evaluated. This topic is discussed in detail separately. (See
"Treatment of neonatal seizures".)
Perform a lumbar puncture to assess for intracranial bleeding or infection, especially 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: Indications, contraindications,
technique, and complications in children".)
"
Use high frequency ventilation, nitric oxide, or extracorporeal membrane oxygenation therapies, as available, for
infants with persistent fetal circulation syndrome 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.
"
Arterial blood gases and serum calcium, magnesium, glucose, and electrolytes should be assessed early in the
course and as needed. Liver enzymes and serum creatinine are measured to determine injury to other end organs.
"
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. Specific testing for ammonia, lactate and pyruvate, serum amino acids and
urine organic acids are also required to rule out a metabolic cause of neonatal encephalopathy.
"
Prevention of the build-up of superoxide radicals and other mediators of oxygen free radical-induced injury "
Reduction of glutamate receptor activation "
Prevention of intracellular calcium accumulation "
Administration of growth factors (monosialo-gangliosides, brain derived growth factor), nitric oxide synthase
inhibitors, and blockers of apoptosis
"
Reduction of secondary inflammatory reactions "
Tissue repair and regeneration "
Neonatal encephalopathy is a heterogeneous syndrome characterized by symptoms of central nervous system
dysfunction in newborns born at term or late preterm (!36 weeks gestation). Neonatal encephalopathy can result
from a wide variety of conditions and often remains unexplained. Birth asphyxia and hypoxic-ischemic (anoxic)
encephalopathy are responsible for some, but not all cases of neonatal encephalopathy. (See 'Introduction and
definition' above.)
"
The neonate who is encephalopathic may have an abnormal state of consciousness (eg, hyperalert, irritable,
lethargic, obtunded), respiratory or feeding difficulties, poor tone, or seizure activity. Neuroimaging is important in
the evaluation of neonatal encephalopathy, and may provide information regarding the type and timing of brain
injury. (See 'Clinical manifestations and neonatal assessment' above.)
"
It is unclear how often birth asphyxia is responsible for neonatal encephalopathy, as there is no gold standard for "
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REFERENCES
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determining the presence of hypoxic-ischemic encephalopathy. The various clinical signs of birth asphyxia,
including Apgar scores, low cord pH, neonatal seizures and encephalopathy, are nonspecific. To define an
intrapartum hypoxic-ischemic insult that is severe enough to cause a neonatal encephalopathy that subsequently
leads to cerebral palsy, the following four consensus criteria have been proposed (see 'Diagnosis of neonatal
asphyxia' above):
Profound metabolic acidosis (pH less than 7.00 and base deficit !12 mmol/L) on an umbilical cord arterial
blood sample

Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks of gestation
Cerebral palsy of the spastic quadriplegic or dyskinetic type
Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious conditions, or
genetic disorders

Most infants with mild to moderate degrees of encephalopathy develop normally, while infants with severe
encephalopathy are more likely to develop long-term neurologic morbidity. Severe MRI abnormalities are usually
associated with marked EEG abnormalities and poor outcome. Permanent neurologic sequelae can be mild, such
as learning difficulties or attention deficit disorder, or may be severe and disabling, including cerebral palsy,
epilepsy, visual impairment, and severe cognitive and developmental disorders. (See 'Prognosis' 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)
For term or late preterm infants with neonatal encephalopathy, we suggest the use of therapeutic head cooling or
whole body cooling as early therapy (in the first six hours of life) in experienced centers (Grade 2A). When
therapeutic hypothermia is not used, we suggest close monitoring of core body temperature and measures to avoid
hyperthermia (Grade 2C). (See 'Therapeutic hypothermia' above.)
"
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