03etiology and Pathogenesis of Neonatal Encephalopathy

4/17/14, 0:10 Etiology and pathogenesis of neonatal encephalopathy
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Official reprint from UpToDate
www.uptodate.com 2014 UpToDate
Authors
Sidhartha Tan, MD
Yvonne Wu, MD, MPH
Section Editors
Douglas R Nordli, Jr, MD
Leonard E Weisman, MD
Deputy Editor
John F Dashe, MD, PhD
Etiology and pathogenesis 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: Jan 15, 2014.
INTRODUCTION Neonatal encephalopathy is a heterogeneous syndrome characterized by signs of central nervous
system dysfunction in newborn infants. Clinical suspicion of neonatal encephalopathy should be considered in any infant
exhibiting an abnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, aspiration, feeding
difficulties [1,2], and an abnormal hearing screen.
This topic will review the etiology and pathogenesis of neonatal encephalopathy. Other clinical aspects of this syndrome
are discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)
TERMINOLOGY "Neonatal encephalopathy" has emerged as the preferred term to describe central nervous system
dysfunction in the newborn period [2,3]. The terminology does not imply a specific underlying pathophysiology, which is
appropriate since the nature of brain injury causing neurologic impairment in a newborn is poorly understood. While
neonatal encephalopathy was once automatically ascribed to hypoxia-ischemia [4], it is now known that hypoxia-
ischemia is only one of many possible contributors to neonatal encephalopathy. Whether a particular newborn's
encephalopathy can be attributed to hypoxic-ischemic brain injury is often unclear.
Some investigators require stringent criteria for using the term neonatal encephalopathy, such as two or more symptoms
of encephalopathy lasting over 24 hours [5], while others require no more than a low five minute Apgar score [6].
However, the use of Apgar scores alone is problematic, as Apgar scores may be low due to maternal analgesia or
prematurity, or can be normal in the presence of acute hypoxia-ischemic injury.
Neonatal encephalopathy usually refers to central nervous system dysfunction in term and near term infants, but for the
purposes of this review, encephalopathy of the preterm infant has also been included.
When neonatal encephalopathy is indisputably due to hypoxic-ischemic (anoxic) brain injury, it is appropriate to use the
term hypoxic-ischemic encephalopathy (HIE) [7]. Since the precise cause and temporal onset of neonatal
encephalopathy is unknown in most cases, some experts advocate calling the condition presumed HIE or apparent
HIE when the clinical features and neonatal brain injury patterns on MRI suggest that HIE is the most likely mechanism
[8]. Others favor using the non-specific term neonatal encephalopathy whenever there is doubt as to the underlying
mechanism of injury [3]. It remains to be established whether neuroimaging or other testing can one day be used as a
gold standard for determining when prenatal hypoxia, birth asphyxia, or hypoxic-ischemic brain injury is responsible for
neonatal encephalopathy. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)
There is an increased risk of cerebral palsy associated with neonatal encephalopathy but it is not an inevitable
consequence. In most cases of cerebral palsy or later developmental deficits, the cause is unknown or is related to
conditions other than prior neonatal encephalopathy. (See "Epidemiology and etiology of cerebral palsy".)

Timing of insult A common but crucial problem is the inability to time the onset, duration, magnitude, and the single
or repetitive nature of the exact insult that causes brain injury resulting in neonatal encephalopathy. This is an important
point to consider in view of neuroprotective therapies such as hypothermia. The uncertain timing and etiology of brain
injury in most cases of neonatal encephalopathy also fuels birth injury malpractice litigation. Malpractice cases, and too
often clinicians, typically focus on events around the time of delivery, which happens to be the time (hours) when the
majority of data from pregnant women are obtained, whereas the rest of pregnancy is relatively unmonitored [4].
However, it is usually unknown whether the ultimate brain injury is caused by the events only around delivery or by
cumulative insults throughout pregnancy.
The definition of asphyxia is "a condition of impaired blood gas exchange leading, if it persists, to progressive
hypoxemia and hypercapnia. Diagnosis requires a blood gas [9]. However, even with state-of-art monitoring, there is
presently no reliable measure of brain function, brain oxygenation, or cerebral blood flow during the prenatal period or
even in the intrapartum period. Therefore, the terms "birth asphyxia" and "fetal distress" are not always used
appropriately [10].
Data from studies of neonatal encephalopathy using brain MRI, near-infrared spectroscopy and electroencephalogram
monitoring suggest that the immediate perinatal period is important for evolution of brain injury in many cases [11]. One
report evaluated 351 term infants with either neonatal encephalopathy (defined as the presence of abnormal tone,
feeding difficulties, altered alertness, and at least three of several criteria suggesting possible perinatal hypoxic-
ischemia) or seizures alone during the first three days of life [12]. Brain MRI was performed in the first one to two weeks
after birth.
Clinical signs that point to an early antenatal onset of neonatal encephalopathy include intrauterine growth restriction,
small head size (if both head and body size are small then the insult could be in the first two trimesters of pregnancy),
contractures, and features suggestive of arthrogryposis. (See 'Risk factors' below.)
Criteria The American College of Obstetricians and Gynecologists (ACOG), in collaboration with the American
Academy of Pediatrics, convened a task force on neonatal encephalopathy and cerebral palsy. According to ACOG task
force, four essential criteria (table 1) are required to define an intrapartum asphyxial event sufficient to cause cerebral
palsy [13]. However, only one criterion metabolic acidosis on umbilical cord arterial blood at birth is helpful to the
clinician in the immediate postnatal period. (See "Epidemiology and etiology of cerebral palsy", section on 'Perinatal
asphyxia'.)
More importantly, for timing of the peripartum events that may be related to development of cerebral palsy, ACOG
suggests the following criteria (table 2) [10]:
There is a presumption that the absence of metabolic acidosis rules out hypoxia-ischemia [14] but this may not
necessarily be true for early antepartum episodes of hypoxia-ischemia.
In the group with encephalopathy, lesions suggestive of acute brain injury were found in 80 percent; most of the
lesions were bilateral abnormalities in basal ganglia, thalami, cortex, or white matter, although focal infarction was
detected in eight infants.
!
In the group with only neonatal seizures, acute ischemic or hemorrhagic strokes were found in 69 percent. !
Presence of a signal event immediately before or during labor !
Sudden onset of fetal bradycardia patterns !
Apgar score of 0 to 3 after five minutes !
Onset of a multisystem disorder in the first 72 hours !
Early brain imaging showing acute nonfocal cerebral abnormality !
RISK FACTORS Few studies have adequately evaluated risk factors for neonatal encephalopathy other than
hypoxia-ischemia. The studies evaluating prenatal and obstetric factors often include symptoms but not pathogenic
events that could provide information regarding the timing of the hypoxic-ischemic event. Epidemiologic population
studies of neonatal encephalopathy typically lack brain MRI data to determine the presence and degree of brain injury,
and also lack information regarding long-term outcomes. In contrast, studies of neonatal encephalopathy that do include
neuroimaging data are rarely population-based, and are underpowered to determine the effect of a broad range of
maternal antenatal risk factors.
The disparate results of these reports are likely due to several reasons, including different inclusion/exclusion criteria
among the studies and the assessment of variables that do not necessarily lead to critical brain injury (eg, shoulder
dystocia, meconium aspiration, and abnormal fetal heart rate rhythms are ominous only if associated with fetal hypoxia,
which is rare).
Antepartum Most cases of neonatal encephalopathy have their antecedents in the prenatal period. It is unknown
whether neonatal encephalopathy occurs as a result of a single insult (such as hypoxia-ischemia), multiple insults (eg,
infection plus hypoxia-ischemia), or combinations of acute or chronic conditions. In cases with multiple insults, it is
possible that the one closest to birth might be only a minor event that tips the balance to irreversible injury.
The highest quality population-based study that evaluated risk factors for neonatal encephalopathy compared 164
infants with neonatal encephalopathy and 400 randomly selected controls from term infants born in Western Australia
In a large population-based cohort of cases of neonatal encephalopathy from Western Australia, 69 percent had
only antepartum risk factors, 25 percent had both antepartum and intrapartum risk factors, 4 percent had evidence
of only intrapartum hypoxia, and 2 percent had no identified risk factors [15]. Thus, approximately 70 percent of
neonatal encephalopathy cases were associated with events arising before the onset of labor [13].
!
Similarly, in a registry of over 4100 infants with neonatal encephalopathy, 46 percent had fetal risk factors and 27
percent had maternal risk factors predating the onset of labor, while only 15 percent had a clinically recognized
sentinel event capable of causing asphyxia (35 percent if fetal bradycardia was included as an indicator) [16].
!
In a case-control study from the UK, 405 term infants with encephalopathy were compared with 239 neurologically
normal infants [17]. Overall, 7 percent of cases had only antepartum factors, 20 percent had only intrapartum
factors, 70 percent had both antepartum and intrapartum factors, and 4 percent had no identifiable risk factors for
the development of neonatal encephalopathy. Limitations of this study include potential bias related to differences
in the populations (eg, compared with controls, cases were from different years of collection, had a greater
incidence of intrauterine growth restriction and twinning, and were more likely to have mothers who were younger,
primipara, and of non-Caucasian origin), the exclusion of infection, the absence of placental data, the absence of a
diagnosis of chorioamnionitis, and inclusion of some questionable intrapartum factors such as induced labor and
variable decelerations.
!
A case-control study from Italy compared 27 term infants with neonatal encephalopathy and 100 control infants,
suggesting a combination of antepartum and intrapartum events explain moderate to severe neonatal
encephalopathy [18]. Compared with controls, neonates with encephalopathy had more frequent antepartum (74
percent versus 18 percent) and intrapartum (67 percent versus 19 percent) risk factors, including acute intrapartum
events (33 percent versus 2 percent). On the whole, 26 percent of cases of NE had only antepartum risk factors,
22 percent had only intrapartum risk factors, and , and 44 percent had a combination of the two.
!
In a case-control study in Ireland that compared 237 term infants with neonatal encephalopathy with 489 control
infants, variables independently associated with neonatal encephalopathy included meconium, oligohydramnios,
and obstetric complications, suggesting involvement of a combination of antepartum and intrapartum risk factors
[19].
!
[5]. The study identified a number of antepartum risk factors can be grouped under categories based on the maternal-
placental-fetal unit (figure 1):
Among these antepartum risk factors, intrauterine growth restriction (IUGR) was the strongest (relative risk [RR] 38.2,
95% CI 9.4-154.8) [5]. Although most babies with neonatal encephalopathy do not meet the criteria of IUGR, a small
hospital-based case-control study found that a greater proportion of infants with neonatal encephalopathy were below
the 10th percentile of growth potential compared with controls, and the difference was statistically significant [20]. These
studies suggest that there are antenatal factors contributing to the brain injury. Unfortunately, IUGR provides no clue to
the etiology (figure 2) because both external maternal and placental factors can affect fetal growth in addition to intrinsic
factors.
Placental thrombosis, infection, and disturbed uteroplacental flow have also been associated with neonatal
encephalopathy.
Most of the placental lesions result in some form of hypoxic-ischemic damage. It is suspected that both the placental
vasculopathies and inflammation can cause synergistic injury when combined with hypoxia-ischemia. Placental lesions
may underlie the finding of some studies that >41 weeks gestation is an antepartum risk factor [17].
Intrapartum Intrapartum risk factors for neonatal encephalopathy can be grouped as follows [15-17]:
Maternal !
Preconceptual factors including maternal unemployment, family history of seizures or neurologic disorder,
and infertility treatment
Maternal thyroid disease

Placental !
Severe preeclampsia
Post-dates
Abnormal appearance of the placenta
Fetal !
Intrauterine growth restriction
In a hospital-based case-control study comparing 93 cases of neonatal encephalopathy to 387 controls, placental
findings of fetal thrombotic vasculopathy, funisitis, and accelerated villous maturation were independently
associated with neonatal encephalopathy [21].
!
Another study found that the frequency of severe placental lesions was fivefold higher among 83 cases of neonatal
encephalopathy from a medicolegal registry than among 250 controls (52 to 10 percent). These lesions included
fetal thrombotic vasculopathy, chronic villitis with obliterative fetal vasculopathy, chorioamnionitis with severe fetal
vasculitis, and meconium-associated fetal vascular necrosis [22].
!
In a retrospective study of 100 term newborns who received hypothermia therapy for neonatal encephalopathy,
placental abnormalities were more common among newborns (n = 49) who did not have a sentinel event (ie, a
clinical history of disruption of blood flow to the fetus during delivery) such as placental abruption, uterine rupture,
tight nuchal cord or cord prolapse [23]. As an example, an inflammatory pathology was significantly more frequent
in infants without sentinel events (43 percent, versus 14 percent for infants with sentinel events).
!
Persistent occipitoposterior position !
Shoulder dystocia !
An acute intrapartum event, such as a placental abruption or uterine rupture, conferred a four-fold increased risk of
neonatal encephalopathy, but was present in only 8 percent of infants with neonatal encephalopathy [15]. Uterine rupture
alone is associated with only a 2 to 3 percent incidence of neonatal death but a 6 to 23 percent neonatal encephalopathy
[24,25]. In the series of 158 medicolegal cerebral palsy cases, sentinel intrapartum events were present in 11 percent
[26].
Outcomes in another study of birth sentinel events with a minimum of 12 months follow-up included death in 20 percent,
cerebral palsy in 41 percent, developmental delay in 15 percent, and normal development in 24 percent [27]. The latter
two numbers suggest that plasticity and repair responses often determine outcome to well-defined single insults.
Some of the so-called intrapartum risk factors include obstetric treatments to prevent further fetal hypoxia, such as
emergency cesarean delivery and operative vaginal delivery. These may or may not be true risk factors depending upon
the duration of the underlying insult. In addition, increased duration of second stage of labor related to shoulder dystocia
or failed vacuum may not necessarily result in critical brain injury unless accompanied by fetal hypoxia.
Some inflammatory factors, such as prolonged rupture of membranes, may exert a pathogenic influence even before
terminal labor. The importance of inflammation as a risk factor for neonatal encephalopathy is illustrated by the following
reports [28]:
Other studies have found that maternal fever, often accompanied by a diagnosis of chorioamnionitis, is associated with
low Apgar scores, neonatal seizures, and a diagnosis of "birth asphyxia" among infants who develop cerebral palsy
[32,33].
An interaction between brain injury due to inflammation and hypoxia-ischemia has been suggested by the finding in a
case-control study of an association between maternal chorioamnionitis and cerebral palsy in children with evidence of
hypoxic-ischemic brain injury [34], and by the observation of increased cytokines in the cerebrospinal fluid of patients
with neonatal encephalopathy [35].
The need for resuscitation in the delivery room is itself a poor prognostic sign as it is associated with an increased risk at
eight years of age of having a lower (<80) IQ score, even if the infant does not exhibit encephalopathy in the newborn
period (odds ratio 1.65, 95% CI 1.13-2.43) [36].
Hypoxia-ischemia can result in fetal heart rate abnormalities and umbilical acidemia, which are often cited as risk factors,
Emergency cesarean delivery, which may include failed vacuum !
Operative vaginal delivery !
Acute intrapartum events or sentinel events (eg, uterine rupture, placental abruption, cord prolapse, tight nuchal
cord, maternal shock/death)
!
Inflammatory events (eg, maternal fever, chorioamnionitis, prolonged rupture of membranes) !
In a population-based report that compared 1060 newborn cases of neonatal encephalopathy with 5330 unaffected
control newborns, independent risk factors for neonatal encephalopathy were isolated intrapartum maternal fever
(RR 3.1, 95% CI 2.3-4.2) and chorioamnionitis (RR 5.4, 95% CI 3.6-7.8) [29].
!
In a cohort study that identified 25 cases of moderate to severe neonatal encephalopathy from 8299 term births,
maternal fever had a sixfold increased risk of neonatal encephalopathy compared to a 12-fold increase for acidosis
[30]. Although there was a multiplicative increased risk with acidosis (76-fold), the effect of maternal fever seemed
to have no statistical interaction with acidosis, implying that maternal fever and acidosis represent different causal
pathways.
!
In a prospective study of infants exposed to maternal chorioamnionitis, there was a threefold increase in neonatal
depression and neonatal intensive care unit admission for newborns with elevated temperature [31].
!
more so in the legal perspective. Fetal heart rate variables are not considered as good as umbilical cord acidemia for
estimation of timing of birth insults [18,37] although both have deficiencies. The correlation of fetal heart rate
abnormalities with umbilical acidemia may have a stronger association with the presence of intrauterine vascular disease
(ie, preeclampsia, placental abruption, birth weight <10th percentile, or histologic evidence of placental infarction or
severe vascular pathology) than with acute intrapartum events [38]. Neurologic morbidities and death are significantly
more common in newborns with a pH <7.0 than in those with a pH "7.0, but the majority of acidemic neonates do not
have any major morbidity [37].
HYPOXIC-ISCHEMIC INJURY As noted earlier, it is appropriate to use the term hypoxic-ischemic encephalopathy
(HIE) when neonatal encephalopathy is due to hypoxic-ischemic brain injury. (See 'Terminology' above.)
The signs and symptoms of HIE, as well as outcome, depend upon several factors:
Hypoxia can result from ischemia (ie, a lack of sufficient blood flow to all or part of an organ), insufficient inspired
oxygen, or inadequate blood oxygen-carrying capacity (eg, inadequate oxygen in inspired air, severe anemia, carbon
monoxide poisoning). Regardless of the cause, cardiac and vascular compromise ultimately occur when hypoxia is
prolonged. The result is hypotension, ischemia, and anaerobic metabolism leading to lactic acidosis. Thus, ischemia is
both a cause and a result of hypoxia and compounds the complications of hypoxia by impairing the removal of metabolic
and respiratory by-products (eg, lactic acid, carbon dioxide).
Fetal hypoxic-ischemic brain injury and subsequent HIE can occur by one or more of the following mechanisms (table 3):
Antecedent events and risk factors Brain injury from HIE may occur before the onset of labor. Supporting evidence
comes from a neuropathologic study of 70 infants who died within seven days of birth [39]. Using criteria of low five
minute Apgar score and umbilical cord or initial blood gas pH <7.1 for asphyxia, findings consistent with brain damage
before the onset of labor were present in all asphyxiated and encephalopathic infants. In addition, the same findings
were present in 38 percent of term infants, 52 percent of preterm infants, and 1 of 12 infants without any evidence of
birth asphyxia.
This report reveals that some cases of HIE die before manifesting brain injury or clinical signs of neonatal
encephalopathy [39]. In addition, brain injury associated with HIE may be present without clinical signs of neonatal
encephalopathy. However, there are limitations to extrapolating findings from autopsy studies in that the nature of death,
failed resuscitation, and terminal drugs are not controlled for in most instances.
A major risk factor for HIE is that of multiple gestations, particularly the presence of monochorionic twins. A study of
preterm infants of multiple gestations found that the incidence of antenatal white matter necrosis on cranial ultrasound
The immediate nervous system injury sustained during the hypoxic-ischemic insult !
Physiologic properties that lead to selective vulnerabilities of certain cell populations !
The presence of endogenous protective mechanisms !
Consequences of hypoxia-ischemia that lead to secondary injuries (eg, reperfusion injury, edema, increased
intracranial pressure, abnormalities of autoregulation, and hemorrhage)
!
Maternal, via impaired oxygenation (eg, asthma, pulmonary embolism, pneumonia) or inadequate perfusion of
maternal placenta (eg, cardiorespiratory arrest, maternal hypotension, preeclampsia, chronic vascular disease)
!
Placental, via abruptio placenta, tight nuchal cord, cord prolapsed, true knot, or uterine rupture (see "Placental
pathology in cases of neurologically impaired infants")
!
Fetal, via impaired fetal oxygenation/perfusion (eg, fetomaternal hemorrhage, fetal thrombosis) !
was significantly higher in monochorionic than in dichorionic infants (30 vs 3.3 percent) [40].
In preterm infants meeting criteria for HIE, placental abruption is more likely to be identified as the antecedent event [41]
than uterine rupture and cord prolapse, which are more common sentinel events among term infants diagnosed with HIE
[27]. In preterm infants, HIE is associated with injury on 36 week MRI scan involving the basal ganglia (mostly severe),
white matter (mostly mild), brainstem, and cortex in 75, 89, 44 and 58 percent, respectively [41].
These studies emphasize the importance of early brain imaging in documenting, and possibly timing, brain lesions, as
well as the importance of postmortem examinations in cases of stillbirth and neonatal deaths. (See "Clinical features,
diagnosis, and treatment of neonatal encephalopathy".)
Level and duration of hypoxia-ischemia The level of hypoxia-ischemia that causes neonatal encephalopathy is
unknown, but animal studies provide some information. There are two experimental paradigms that present with different
pathophysiological pathways: umbilical cord occlusion and acute placental insufficiency.
The clinical corollary of umbilical cord prolapse has a more varied response, probably because of the presence of some
blood flow in the prolapsed cord. In humans, umbilical cord prolapse is an obstetric emergency except for the extreme
premature gestation mother. In a chart review of 87 cases of cord prolapse among 36,500 deliveries, the median time
from discovery to delivery was 15 minutes, with the longest being 14 hours [46]. There was no relation between time of
discovery to delivery and postnatal mortality or morbidity [46]. The longest tolerated time of umbilical cord prolapse
without major consequences three days was observed in an extremely premature infant [47], suggesting that the
duration becomes critical only near term.
Unfortunately, the onset of acute placental insufficiency states such as placental abruption in humans is almost always
unknown.
The spectrum of hypoxic-ischemic injury and outcome can be summarized as in the Figure (figure 3). The intensity of the
insult can be modified by prior events that may serve as a preconditioning stimulus. Also, there is a complex interaction
of infection with hypoxia-ischemia. As an example, preeclampsia may be a protective factor for infants born to mothers
with chorioamnionitis and at risk for cerebral palsy [52].
Occlusion of the umbilical cord results in cardiovascular compromise because of the removal of a low resistive
vascular bed
!
In sheep, fetuses can survive up to 30 minutes of occlusion with increasing brain damage observed in term sheep
compared to premature sheep fetuses [42], while 20 minute occlusion may not cause any brain injury [43]
!
In non-human primates, it was long believed that permanent neurologic injury occurred with occlusion of 12 to 17
minutes [44,45]
!
Acute placental insufficiency results in fetal compromise due to impaired ability to exchange gas and nutrients. !
A study of acute placental insufficiency (via uterine ischemia) in rabbits at 70 percent gestation found that animals
subjected to 30 minutes of global hypoxia-ischemia were no different than controls [48]. However, 40 minutes of
global hypoxia-ischemia increased fetal mortality from 0 to 25 percent, and increased marked motor deficits at birth
in the survivors from 0 to 75 percent [48]. In a population of normal fetuses, the susceptibility to injury is not
dependent solely on the duration of hypoxia-ischemia. Rabbit fetuses at 79 percent gestation undergoing additional
reperfusion-reoxygenation injury just after the cessation of hypoxia-ischemia have a greater chance of motor
deficits that in those without reperfusion-reoxygenation injury [49].
!
When experimental global hypoxia-ischemia is mild and chronic, it results in intrauterine growth restriction but may
or may not result in brain injury [50,51].
!
Vulnerable regions of developing brain Hypoxia-ischemia may have deleterious effects on vulnerable cell
populations peculiar to the developmental stage (figure 4), causing discrete injuries that could also affect seizure
threshold or cognition.
Both gray and white matter injury occur in preterm and term neonates with HIE. Early detection of recent hypoxic-
ischemic insults depends upon apparent diffusion coefficient (ADC) measurements on MRI. Beyond a week after the
onset of the insult, evidence of gray matter injury by neuroimaging is scant unless there is a significant decrease in
volume of gray matter regions or an increase in ventricular size or obvious infarcts and hemorrhage. White matter injury
is somewhat easier to detect by diffusion tensor imaging (DTI), as the fractional anisotropy of white matter bundles
normally increase with age, leading to an ability to detect minor decreases in fractional anisotropy in WM regions.
However, while DTI is performed at some tertiary centers, it is not yet widely available in clinical practice.
Mechanisms of neuronal injury Hypoxia-ischemia initially causes energy failure and loss of mitochondrial function.
This is accompanied by membrane depolarization, brain edema, an increase of neurotransmitter release and inhibition of
uptake, and an increase of intracellular calcium that sets off additional pathologic cascades [54]. These include oxidative
stress, with the production of reactive oxygen species and interaction with nitric oxide pathway to produce reactive
nitrogen species [55].
It was once believed that reactive species caused damage only if antioxidant defenses were overwhelmed, thus
upsetting the balance between oxidants and antioxidants. However, it is now realized that the interaction itself between
reactive species and antioxidant defenses ultimately causes cellular injury and death (ie, the yin-yang theory of both
being necessary) [56]. Reperfusion exacerbates the oxidative stress with a burst of reactive oxygen species.
The response of the fetus to the hypoxic-ischemic insult determines the subsequent injurious cascades and the clinical
manifestations that result. One study monitored the response of rabbit fetus brains in utero to global hypoxia using MRI
diffusion-weighted sequences and apparent diffusion coefficient (ADC) mapping as a marker of ischemic injury [57].
Fetuses that showed a precipitous drop in brain ADC at the end of 40 minutes of global hypoxia manifested hypertonia
and postural changes after birth, while those without a drop in ADC were relatively normal at birth. Thus, after the
hypoxic-ischemic insult, the initial energy failure and oxidative stress probably play a critical role in subsequent cascades
(figure 5) [49].
Excitotoxic injury Excitotoxic cellular injury occurs via excess activation of glutamate receptors, which leads to
several forms of cell death. There are four receptor types for glutamate [58], which are the N-methyl-d-aspartate
(NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and metabotropic glutamate
receptors. The metabotropic receptors are not directly coupled to ion channels.
Late oligodendroglial progenitors are vulnerable to injury in early prematurity with resulting predominant white
matter injury in premature infants [53].
!
In the term neonate with ischemic brain injury, however, certain neurons in the deep gray nuclei and perirolandic
cortex are most likely to be affected. Acute cell injury can trigger continuing loss of cells. There are neural-glial cell
interactions that can increase the brain injury. Selective damage to neurons in the subcortical gray matter can
directly contribute to long-term apoptosis in distal neuronal structures.
!
The NMDA receptors are the most avid and physiologically active. The channels activated by NMDA receptors are
voltage-dependent and calcium-permeable. Their activation causes neuron depolarization [59]. Repeated
depolarization of a neuron by unregulated glutamate release results in accumulation of intracellular calcium. During
hypoxia-ischemia, there is failure to rapidly pump synaptically released glutamate back across the cell membrane,
resulting in exposure of NMDA receptors to accumulated glutamate, which leads to lethal elevation of intracellular
calcium levels. The cascade of events initiated by this process also can induce apoptosis [60].
!
Oligodendroglia are particularly vulnerable to glutamate [61]. Preoligodendrocyte subtypes O4 and O1+ express
subunits for both the AMPA (GluR1, GluR2, GluR3, and GluR4) and kainate (KA1, GluR5/6, and GLuR7) receptors but
not NMDA receptors, whereas mature MBP+ oligodendrocytes have little to no expression of either NMDA receptors or
non-NMDA receptors.
Mature oligodendrocytes in mixed cocultures die after exposure to kainate, but AMPA receptors are the most important
mediators of cellular demise, with kainate receptors playing a smaller role [62]. In this paradigm, cell death occurs
predominantly by necrosis, not apoptosis [62]. However, there is evidence that mature oligodendrocytes expressing
myelin basic protein are resistant to excitotoxic injury produced by kainate, whereas earlier stages in the oligodendrocyte
lineage are vulnerable to this insult [63].
Nitric oxide and oxygen-free radicals Nitric oxide (NO) and oxygen-free radicals appear to play important roles
in brain injury induced by hypoxia-ischemia.
Nitric oxide can behave as an oxidant as well as an antioxidant. Under pathological conditions there is excess NO
production that results in cell toxicity through direct biochemical effects or through reactive nitrogen species that is
formed from the reaction of NO and reactive oxygen species [64].
Nitric oxide is synthesized by nitric oxide synthase (NOS) from L-arginine in the presence of essential cofactor,
tetrahydrobiopterin. Nitric oxide synthase exists in three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and
inducible NOS (iNOS).
Available evidence suggests that eNOS has a predominant protective role in hypoxia-ischemia, whereas nNOS and
iNOS have a facilitative role.
The use of specific NOS inhibitors as neuroprotectants is currently being studied.
PERINATAL STROKE Perinatal stroke is an increasingly recognized entity in term newborns with encephalopathy
and cerebral palsy. Perinatal stroke occurs about once in 4000 births. (See "Stroke in the newborn", section on
'Epidemiology'.)
The majority of infants with ischemic perinatal stroke develop neonatal seizures. Additional signs of neonatal
encephalopathy may also be present, such as lethargy, hypotonia, feeding difficulties, or apnea [68].
A specific cause for perinatal stroke is not identified in most affected newborns. Factors contributing to the risk include
maternal conditions such as prothrombotic disorder and cocaine abuse; placental complications such as preeclampsia,
chorioamnionitis and placental vasculopathy; and newborn conditions such as prothrombotic disorders, congenital heart
disease, meningitis, and systemic infection [69]. During the delivery process, an infant may develop a cervical arterial
dissection that leads to stroke.
Potential long-term sequelae of perinatal arterial stroke include cerebral palsy, cognitive deficits, hemiparesis, and
epilepsy. However, development is normal in approximately 19 to 33 percent of infants with neonatal ischemic infarction.
AMPA and kainate receptors are both coupled to sodium and potassium ion channels. Whereas NMDA receptors
are always permeable to Ca(2+), cation permeability of AMPA receptors depends on subunit composition. Ca(2+)
influx is differentially regulated by AMPA receptors compared to kainate receptors.
!
Histopathologic studies have shown that nNOS knockout neonatal animals are protected from focal hypoxic-
ischemic-induced histopathologic brain damage [65].
!
Similarly, iNOS knockout animals show a reduction of focal ischemic brain damage and locomotor deficits [66]. !
Animals lacking the eNOS gene have enlarged cerebral infarcts after ischemic injury [67]. !
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(See "Stroke in the newborn", section on 'Prognosis'.)
PROGRESSIVE ENCEPHALOPATHY One must always consider the possibility of progressive disorders in cases of
neonatal encephalopathy. These include metabolic, neurodegenerative, infectious or toxic etiologies that are rare, with a
combined incidence of approximately 6 per 10,000 live births [70], but a much higher mortality rate than the general
population [71]. A history of parental consanguinity is associated with a marked increase in the risk of progressive
encephalopathy, and thus is an important clue suggesting metabolic and neurodegenerative disease [72].
Metabolic abnormalities A large number of metabolic and genetic abnormalities may cause neonatal
encephalopathy. Inborn errors of metabolism that present in the newborn period typically share strikingly similar clinical
features, including decreased level of consciousness, seizures, poor feeding, hypotonia, and vomiting. Examples
include:
Specific disorders such as multiple sulfite oxidase deficiency may produce neuroimaging and clinical findings that very
closely mimic hypoxic-ischemic brain injury. Genetic disorders such as Prader-Willi and chromosomal abnormalities may
also present with newborn encephalopathy. However, metabolic and genetic disorders account only for a very small
proportion of cases of neonatal encephalopathy.
OTHER CAUSES Given that neonatal encephalopathy is an umbrella term that includes any type of brain injury or
insult resulting in central nervous system dysfunction, the list of brain disorders that can cause neonatal encephalopathy
is quite long [73]. As examples, brain anomalies, intracranial hemorrhage and infection can all lead to seizures and
encephalopathy in the newborn period.
Intraventricular hemorrhage in term infants may cause symptoms of neonatal encephalopathy, and is often related to
sinovenous thrombosis as opposed to the more typical intraventricular hemorrhage associated with germinal matrix
hemorrhage seen in preterm infants [74]. Intracerebral hemorrhage in a term infant is often idiopathic, but may be related
to birth trauma, congenital vascular malformation, or a clotting disorder.
Finally, a variety of maternal toxins can cause encephalopathy in the newborn period. For instance, passive addiction to
narcotics, barbiturates, alcohol, tricyclic antidepressants, and serotonin reuptake inhibitors can produce seizures and
encephalopathy in the neonate [75].
SUMMARY
Disorders of amino acid metabolism (eg, maple syrup urine disease, phenylketonuria, nonketotic hyperglycinemia)
(see "Overview of maple syrup urine disease" and "Overview of phenylketonuria")
!
Hyperammonemia (eg, urea cycle defects) (see "Urea cycle disorders: Clinical features and diagnosis") !
Neonatal hypoglycemia (see "Neonatal hypoglycemia") !
Organic acidemias (see "Organic acidemias") !
Mitochondrial disorders (see "Mitochondrial myopathies: Clinical features and diagnosis") !
Severe peroxisomal disorders (eg, Zellweger syndrome) (see "Peroxisomal disorders") !
Neonatal encephalopathy is the preferred terminology to describe central nervous system dysfunction in the
newborn period. It can result from a wide variety of conditions but often remains unexplained. The nature of brain
injury causing neurologic impairment in a newborn is poorly understood. Hypoxia-ischemia is only one of many
possible contributors to neonatal encephalopathy. Whether a particular newborn's encephalopathy can be
attributed to hypoxic-ischemic brain injury is often controversial. (See 'Terminology' above.)
!
Approximately 70 percent of neonatal encephalopathy cases are associated with events arising before the onset of !
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Topic 6205 Version 9.0
GRAPHICS
Criteria for acute intrapartum events sufficient to cause cerebral palsy
All four criteria must be met:
Evidence of metabolic acidosis: umbilical artery pH <7 and base deficit !12 mmol/L at delivery
Early onset of severe or moderate neonatal encephalopathy in infants !34 weeks of gestation
Cerebral palsy of the spastic quadriplegic or dyskinetic type
Exclusion of other identifiable etiologies (eg, trauma, coagulation disorders, infection, genetic
disorders)
Adapted from: Task force on neonatal encephalopathy and cerebral palsy, American College of Obstetricians
and Gynecologists (ACOG). Neonatal Encephalopathy and Cerebral Palsy: Executive Summary. Obstet
Gynecol 2004; 103:780.
Graphic 66304 Version 2.0
Criteria that suggest an intrapartum timing of an event that may be
related to the development of cerebral palsy but is not specifically
asphyxial
A sentinel hypoxic event occurring immediately before or during labor
A sudden and sustained fetal bradycardia or absence of fetal heart rate variability in the presence of
persistent late or variable decelerations. This usually occurs after a hypoxic sentinel event with a
normal fetal heart rate pattern prior to the event.
Apgar score of 0 to 3 after five minutes
Onset of multisystem involvement within 72 hours of birth
Early imaging studies showing evidence of an acute nonfocal cerebral abnormality
Adapted from: Task force on neonatal encephalopathy and cerebral palsy, American College of Obstetricians
and Gynecologists (ACOG). Neonatal Encephalopathy and Cerebral Palsy: Executive Summary. Obstet
Gynecol 2004; 103:780.
Timing and anatomy of risk factors for brain injury
resulting in neonatal encephalopathy
Sidhartha Tan, MD.
Anatomy and etiology of risk factors for brain injury resulting
in neonatal encephalopathy
Sidhartha Tan, MD.
Mechanisms of neonatal hypoxic-ischemic encephalopathy
Anatomical unit Examples
Maternal
Impaired oxygenation Asthma
Pulmonary embolism
Pneumonia
Inadequate perfusion of maternal placenta Cardiorespiratory arrest
Maternal hypotension
Preeclampsia
Chronic vascular disease
Placental
Abruptio placenta
Tight nuchal cord
Cord prolapsed
True knot
Uterine rupture
Fetal
Impaired fetal oxygenation/perfusion Fetomaternal hemorrhage
Fetal thrombosis
Sidhartha Tan, MD.
Outcome following neonatal hypoxic-ischemic encephalopathy
Sidhartha Tan, MD.
Timeline of neonatal hypoxic-ischemic injury
Hypoxia-ischemia may have deleterious effects on vulnerable cell populations
peculiar to the developmental stage.
WM: white matter.
Sidhartha Tan, MD.
Pathophysiology of hypoxic-ischemic encephalopathy
The downward pointing blue line represents the cascade of events that occurs with oxidative
stress, and the downward pointing black line depicts events associated with energy failure.
Sidhartha Tan, MD.

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4/17/14, 0:10 Etiology and pathogenesis of neonatal encephalopathy

4/17/14, 0:10 Etiology and pathogenesis of neonatal encephalopathy

Maternal thyroid disease

Inflammatory events (eg, maternal fever, chorioamnionitis, prolonged rupture of membranes)

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