Etiology and Pathogenesis of Neonatal Encephalopathy

7/23/2019 Etiology and Pathogenesis of Neonatal Encephalopathy

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12/9/2015 Etiology and pathogenesis of neonatal encephalopathy

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AuthorsSidhartha Tan, MDYvonne Wu, MD, MPH

Section EditorsDouglas R Nordli, Jr, MDLeonard E Weisman, MD

Deputy Editor John F Dashe, MD, PhD

Etiology and pathogenesis of neonatal encephalopathy

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Aug 2015. | This topic last updated: Jul 10, 2014.

INTRODUCTION — Neonatal encephalopathy is a heterogeneous syndrome char acterized 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 nervoussystem dysfunction in the newborn period [2,3]. The American College of Obstetricians and Gynecologists

(ACOG) describes neonatal encephalopathy as a clinically defined syndrome of disturbed neurologic function in the

earliest days of life in an infant born at or beyond 35 weeks of gestation, manifested by a subnormal level of

consciousness or seizures, and often accompanied by difficulty with initiating and maintaining respiration and

depression of tone and reflexes [4].

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 [5], 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 [6], while others require no more than a low five minute Apgar

score [7]. 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 (see 'Hypoxic-

ischemic injury' below), it is appropriate to use the term hypoxic-ischemic encephalopathy (HIE) [8]. Since the

precise cause and temporal onset of neonatal encephalopathy is unknown in most cases, some experts advocatecalling 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 [9]. 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".)

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

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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 [5]. 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” [10]. 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 [11].

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 [12]. 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 [13]. 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.)

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 degreeof 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.

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 focalinfarction was detected in eight infants.

In the group with only neonatal seizures, acute ischemic or hemorrhagic strokes were found in 69 percent.

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 [14]. Thus, approximately

70 percent of neonatal encephalopathy cases were associated with events arising before the onset of labor

[15].

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





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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 [6]. 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) [6]. 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

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].

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•



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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 theplacental 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 [14,16,17]:

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 [14]. 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

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

Emergency cesarean delivery, which may include failed vacuum

Operative vaginal delivery

Acute intrapartum events or sentinel events (eg, uterine rupture, placental abruption, cord prolapse, tightnuchal cord, maternal shock/death)

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








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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 cerebrospinalfluid 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, 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

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 andacidosis 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].

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)
















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 1):

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 neonatalencephalopathy [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 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".)

Acute events — Determining whether an acute hypoxic-ischemic event contributed to neonatal encephalopathy is

challenging, since there is no gold standard. The various clinical signs of hypoxic-ischemic encephalopathy,

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. A consensus statement from

the American College of Obstetricians and Gynecologists (ACOG) notes that neonatal encephalopathy related toacute hypoxia-ischemia is presumed to be associated with abnormal neonatal signs and contributing events, in

close temporal proximity to labor and delivery, that are consistent with an acute hypoxic-ischemic event [4].

Markers that are helpful for determining the likelihood that an acute peripartum or intrapartum hypoxic-ischemic

event contributed to the development of neonatal encephalopathy are as follows (table 2):

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)

Neonatal signs consistent with an acute peripartum or intrapartum 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 MRI or magnetic resonance spectroscopy consistent with hypoxia–

ischemia

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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].

Presence of multisystem organ failure consistent with hypoxic–ischemic encephalopathy•

Contributing factors consistent with an acute peripartum or intrapartum event:

A sentinel hypoxic or ischemic event occurring immediately before or during labor and delivery•

Fetal heart rate monitor patterns consistent with an acute peripartum or intrapartum event•

Brain injury patterns based on imaging studies consistent with an etiology of an acute peripartum or

intrapartum event

•

No evidence of other proximal or distal factors that could be contributing•

Developmental outcome is spastic quadriplegia or dyskinetic cerebral palsy

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 metabotropicglutamate 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 thesubcortical 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 mostimportant 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. (See "Stroke in the newborn", section on 'Prognosis'.)

PROGRESSIVE ENCEPHALOPATHY — One must always consider the possibility of progressive disorders in

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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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 "Pathogenesis, screening, and diagnosis of 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 labor (figure 1 and figure 2). These include:

Maternal factors, including unemployment, family history of seizures or neurologic disorder, infertility

treatment, and thyroid disease

•

Placental conditions, including severe preeclampsia, post-dates, and abnormal appearance of the•



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Topic 6205 Version 11.0

















GRAPHICS

Timing and anatomy of risk factors for brain injury

resulting in neonatal encephalopathy

Sidhartha Tan, MD.

Graphic 70341 Version 2.0





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

Im paired fetal oxygen at ion /perfu sion Fetomatern al h em orrh age

Fetal thrombosis

Sidhartha Tan, MD.






Markers of an acute peripartum or intrapartum hypoxic-ischemic

event

Neonatal signs consistent with an acute peripartum or intrapartum

event:

Apgar score of <5 at 5 minutes and 10 minutes

Fetal umbilical artery acidemia: fetal umbilical artery pH <7.0, or base deficit ≥12 mmol/L, or

both

Neuroimaging evidence of acute brain injury seen on brain MRI or MRS consistent with

hypoxia-ischemia

Presence of multisystem organ failure consistent with hypoxic-ischemic encephalopathy

Type and timing of contributing factors that are consistent with an

acute peripartum or intrapartum event:

A sentinel hypoxic or ischemic event occurring immediately before or during labor and

delivery:

Ruptured uterus

Severe abruptio placentae

Umbilical cord prolapse

Amniotic fluid embolus with coincident severe and prolonged maternal hypotension and

hypoxemia

Maternal cardiovascular collapse

Fetal exsanguination from either vasa previa or massive fetomaternal hemorrhage

Fetal heart rate monitor patterns consistent with an acute peripartum or intrapartum event,

particularly a category I fetal heart rate pattern on presentation that converts to one of the

following patterns:Category III pattern

Tachycardia with recurrent decelerations

Persistent minimal variability with recurrent decelerations

Timing and type of brain injury patterns based on imaging studies consistent with an etiology

of an acute peripartum or intrapartum event. Well-defined patterns on brain MRI typical of

hypoxic-ischemic cerebral injury in the newborn are:

Deep nuclear gray matter (ie, basal ganglia or thalamus) injury

Watershed (borderzone) cortical injury

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

Developmental outcome is spastic quadriplegia or dyskinetic cerebral

palsy:

Other subtypes of cerebral palsy are less likely to be associated with acute intrapartum

hypoxic-ischemic events

Other developmental abnormalities may occur, but they are not specific to acute intrapartum

hypoxic-ischemic encephalopathy and may arise from a variety of other causes

MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy





Source: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American

College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet Gynecol

2014; 123:896.






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.





Disclosures: Sidhartha Tan, MD Nothing to disclose. Yvonne Wu, MD, MPH Consultant/AdvisoryBoard: GSK [Prematurity (Monitoring of clinical trial)]. Douglas R Nordli, Jr, MD Grant/Research/ClinicalTrial Support: NIH [febrile status, SUDEP]. Consultant/Advisory Boards: Eisai [AED (zonisamide,perampanel)]. Leonard E Weisman, MD Consultant/Advisory Boards: Glaxo-Smith Kline [Malariavaccine]; NIAID [Staphylococcus aureus (Mupirocin)]. Patent Holder: Baylor College of Medicine[Ureaplasma diagnosis/vaccines/antibodies, process for preparing biological samples]. EquityOwnership/Stock Options: Vax-Immune [Ureaplasma diagnosis, vaccines and antibodies]. John F

Dashe, MD, PhD Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these areaddressed by vetting through a multi-level review process, and through requirements for references to beprovided to support the content. Appropriately referenced content is required of all authors and mustconform to UpToDate standards of evidence.

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Etiology and Pathogenesis of Neonatal Encephalopathy

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