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Birth Asphyxia and Cerebral Palsy

Jeffrey P. Phelan, MD, JDa,*, Gilbert I. Martin, MD b,Lisa M. Korst, MD, PhDc

a  Department of Obstetrics and Gynecology, Citrus Valley Medical Center, West Covina, CA, USA bUniversity of California Irvine, Citrus Valley Medical Center, West Covina, CA, USA

c Department of Pediatrics and Obstetrics and Gynecology, USC Keck School of Medicine,

 Los Angeles, CA, USA

The global cerebral palsy (CP) rate (ie, the rate of all types of CP) is estimated

to be approximately 1 to 2 cases per 1000 live births [1]. CP that is due to

hypoxic ischemic encephalopathy (HIE) in the singleton term infant is even rarer,

with a reported prevalence of approximately 1 in 12,500 live births [2], a ratewhich has declined steadily over the last several decades [2,3]. Notwithstanding

this decline and the rarity of this form of CP, there is a lasting financial and

emotional toll on the families that try to raise a CP-afflicted child and on society

through increases in government expenditures to assist in the care of these chil-

dren and the disruption of the family unit through higher rates of divorce.

At the same time, there has been a societal presumption that most, if not 

all, cases of HIE-induced CP occur during the 3 hours that are related to

the events of labor and delivery; society has tended to overlook the remaining

7000 hours of the pregnancy. As a result of this societal perspective, often timesthe obstetrician has been targeted unfairly as the person who is responsible for a

given child’s neurologic injuries. Nevertheless, numerous physicians and

researchers have attempted to unravel the HIE-induced CP mystery [4,5]. To

date, their efforts primarily have been limited to trying to classify fetal outcome

 based on birth-related end points [4], rather than looking at the continuum of 

life [5].

One aspect of the HIE-induced CP mystery is that its rarity has precluded

in-depth studies into its pathogenesis. Until recently, little information has been

available [5] to study these infants much beyond the moment of birth. As a

0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.clp.2004.11.010 perinatology.theclinics.com

* Corresponding author. 959 East Walnut Street, Suite 200, Pasadena, CA 91106.

 E-mail address: phelanjp@earthlink.net (J.P. Phelan).

Clin Perinatol 32 (2005) 61–76

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result, many of the approaches to time or date of fetal brain injury have focused

 primarily on birth-related end points, such as the newborn’s umbilical artery pH

that is measured at the time of birth [4,6,7]. Rather, the entire pregnancy, labor,delivery, and well beyond birth require examination to understand fully the

 pathophysiologic mechanisms that are responsible for an infant’s brain injuries,

and their long-term impact on the child. Critical to understanding the patho-

 physiology of HIE-induced CP is the ability to maintain an open mind when

analyzing studies, and not to prejudge them merely because they do not feed

one’s biases or are not considered mainstream at the time. As many of us may

recall, the use of diethylstilbestrol (DES) to prevent pregnancy loss was con-

sidered mainstream obstetric care for a period of time until young women began

to present with vaginal carcinoma that was linked to DES exposure in utero [8].Moreover, scientists know that under the HIE-induced CP umbrella, many

children manifest their asphyxial injury in several ways.

Scientists who have studied asphyxiated neonates realize that, often times,

these babies were injured under vastly differing circumstances. For example,

some may have been injured in the past and yet survived in utero to be liveborn;

some may have been injured acutely intrapartum and likely would have died

without intervention. Thus, injured neonates may differ in their presentation

 because of differences in the timing, mechanism, or severity of the asphyxial

episode. Therefore, our clinical understanding of this condition may not beimproved by analyzing asphyxiated neonates as one group or under one

umbrella. Phelan and Ahn [9] distinguished clinical patterns that were associated

with term neonates who had permanent brain injury by using the intrapartum

fetal heart rate (FHR) pattern. Although this classification cannot determine the

exact moment when fetal brain injury occurred, this classification system does

 permit one to identify three groups of fetuses who were injured during different 

time intervals and often, in different ways. For example, Phelan and Ahn [9]

showed that some infants were injured before presenting in labor, some were

injured acutely during labor and delivered emergently, and some were injuredduring labor over some prolonged period of time before delivery. For that matter 

and with the addition of life expectancy, the following issues or questions are

the basis of each and every case of a brain-damaged baby:

When did the asphyxial event begin? What caused it to happen? When did the brain injury occur?

In an effort to answer these questions, this article is designed to update our knowledge of, and our experience with, hematologic markers that are related

to HIE-induced CP. These include umbilical artery pH, nucleated red blood cells

(NRBC), platelet counts, liver function tests, renal function studies, organ

dysfunction, and the effectiveness of various methods to time fetal brain injury

[4–7]. This article is intended solely for educational purposes and is to be used

to enhance our understanding of the pathophysiologic mysteries that are asso-

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ciated with HIE-induced CP. It is our hope that this article will assist all of us to

reduce, if not, eliminate this tragic neurologic disorder.

Umbilical artery pH

A profound metabolic acidemia or mixed acidemia at birth, as reflected by

an umbilical artery pH of less than 7.00 and a base deficit of 12 or greater,

although often a direct result of an hypoxic event, usually reflects the impact 

of a slow heart rate (b 100 beats per minute) at the time of birth [10] and seems

to be a poor predictor of long-term neurologic impairment  [11]. For example,

Myers [12] demonstrated that animals whose blood pH was maintained at 7.1 showed no hypoxic brain injury, and that fetuses who had a pH of less than

7.00 could survive several hours before they died. Thus, the initial abnormal pH

that surrounds a given birth may not be, in and of itself, indicative of an intra-

 partum injury.

When one considers how obstetric practice has changed over the past several

decades with respect to fetal acid/base assessment, one has to wonder what role,

if any, fetal acid/base assessment has in current, let alone, future obstetric care.

In the past, fetal acid/base status was believed to be a critical component of 

labor management. This clinical practice stemmed from the work of Saling [13].In his studies, Saling found that infants who had a pH of less than 7.2 were

more likely to be physiologically depressed at delivery. Conversely, a normal

fetal outcome was more likely to be associated with a nonacidotic fetus

(pH 7.20) [14]. Even at the peak of its popularity, fetal scalp blood sampling

was used in a limited number of pregnancies [15]. Notwithstanding, in 1994,

Goodwin and associates [16] concluded that fetal scalp blood sampling ‘‘. . .has

 been virtually eliminated without an increase in the cesarean rate for fetal

distress or an increase in indicators of perinatal asphyxia. [Its continued role]

in clinical practice is questioned.’’As an alternative to fetal scalp sampling, clinicians who have been concerned

about fetal acid/base status often turned to the presence of FHR accelerations

to assure themselves of a healthy fetus. In key studies, Phelan [17] and Skupski

et al [18] demonstrated that labor stimulation tests, such as scalp or acoustic

stimulation, that induced FHR accelerations were significantly more likely to

indicate a normal fetal acid/base status and a favorable fetal outcome. If the fetus

failed to respond with a FHR acceleration to the sound or scalp stimulation in the

 presence of a ‘‘pathologic’’ FHR pattern, there was a higher probability that 

the fetus would have a pH less than 7.20 [17].As with fetal scalp blood sampling, umbilical cord blood gas data do not 

seem to be useful in predicting long-term neurologic impairment. Of 314 infants

who had severe umbilical artery acidosis with long-term follow-up that were

identified in the world literature, 27 (8.6%) children subsequently were found

to be brain-damaged [11]. In the Fee et al [19] study, for example, minor 

developmental delays or mild tone abnormalities were noted at the time of 

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hospital discharge in 9 of 110 (8%) singleton term infants. When 108 of these

infants were examined on long-term follow-up, all were considered to be

neurologically normal. None of these infants, including a neonate who had anumbilical artery pH of 6.57 at birth, demonstrated major motor or cognitive

abnormality. In contrast, of the 113 neonates who had severe acidosis in the

Goodwin et al [20] study, 98 (87%) newborns had normal outcomes. Among the

remaining 15 infants, 5 neonates died and 10 infants were brain-damaged. In a

series of 46 neonates who had neonatal encephalopathy without long-term

follow-up [21], severe metabolic acidosis was not encountered in all of the

infants. Of interest, Dennis [22] commented in his series of patients that ‘‘the

very acidotic children did not perform worse than [the nonacidotic children]’’.

Thus, the finding of severe fetal acidosis on an umbilical arterial cord gas maynot seem to be linked to subsequent neurologic deficits, nor neonatal

encephalopathy [22].

In contrast, the absence of severe acidosis does not ensure a favorable neu-

rologic outcome. For example, Korst and associates [23,24] previously showed

that neonates who had sufficient intrapartum asphyxia to produce persistent 

 brain injury did not have to sustain severe acidosis (umbilical arterial pH 7.00).

When their two studies are combined, 42 (60%) fetuses did not have severe

acidosis but all were neurologically impaired. Of 94 infants who did not have

reported permanent brain damage, Dennis and associates [22] also noted that children who did not have acidosis seemed to fare worse than acidotic children.

Thus, it seems that factors other than the presence of severe acidosis probably

are responsible for fetal brain injury. Thus, to understand the role of neonatal

metabolic acidosis and its relationship, if any, to long-term neurologic impair-

ment, studies will need to be done to compare those infants who have severe

metabolic acidemia at birth who do and do not have permanent brain damage.

Severe acidosis, rather than fetal brain damage, continues to be used as an

end point in the study of intrapartum asphyxia [25] and to define whether a

fetus has sustained intrapartum brain damage [4,6,7]. This remains intriguing, because according to Schifrin [26], ‘‘there is no pH value that separates cleanly

those babies who have experienced intrapartum injury from those who have

not—no prognosis can be made or refuted on the basis of a single laboratory

study.’’ The lack of a consistent relationship between the presence or absence of 

fetal acidosis suggests that the pathophysiologic mechanisms that are responsible

for fetal brain damage seem more likely to be related to the adequacy of cerebral

 perfusion [5]. Thus, as has happened with fetal scalp blood sampling, the use of 

umbilical cord blood gases to define or time fetal brain damage or the quality of 

care may not have a role in the contemporary or future practice of obstetrics.

Nucleated red blood cells

The presence of NRBCs, also known as normoblasts, in the cord blood and

the neonatal circulation seems to be one of the most valid indicators of pre-

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vious hypoxemia. More than 60 years ago, Anderson [27] noted that ‘‘. . .in

stillbirths and [neonatal deaths] within 10 days of life, a higher NRBC

count was observed’’. Anderson also observed that ‘‘a decided increase of  NRBC. . . point[ed] to pathologic states or events in the newborn infant occur-

ring during the course of delivery [which] applies especially to asphyxia and

its associated hemorrhages.’’ Anderson [27] also reported that ‘‘NRBC counts

closely approaching or identical with that of the normal adult [a zero NRBC

count]. . .[was] consistent with a normal easy delivery.’’ It was not until nearly

30 years later that Fox [28], after his studies of the histopathology of the

 placenta, proposed that the number of NRBCs provided ‘‘a rough guide to the

degree of oxygen deprivation’’ that a patient has suffered. Fox [28] also noted

that the probability of asphyxia, as he defined it, was six to seven times higher when a high NRBC count was found in the placenta. As such, Fox [28] was

one of several investigators who suggested that asphyxia induced an increase in

the number of NRBCs in the circulating blood of newborns. Some of the most 

intriguing data in support of this proposition came from Soothill et al [29],

who noted the same relationship between the number of NRBCs and the severity

of fetal hypoxemia.

Although a few NRBCs may be found in the circulating blood of newborns,

it is unusual to see more than 10 such cells per 100 white blood cells [30,31].

When that ratio is exceeded, the most frequent nonasphyxial explanationsinclude: (1) prematurity (b 28 weeks’ gestation), (2) Rh sensitization, (3) twin– 

twin transfusion syndrome, (4) ABO incompatibility, (5) intrauterine fetal growth

restriction, and (6) uncontrolled diabetes mellitus. Several factors that once

were considered to contribute to an elevation of the NRBC count are no longer 

considered influential [32–34]. For example, fetal anemia (hematocrit  b 40.0%)

that is identified at or around the time of birth was not associated with an

elevation in the NRBC counts among asphyxiated [32] and nonasphyxiated

[33] newborns. Similarly, prematurity, unless the fetus was less than 28 weeks’

gestation, was not a factor in the elevation of NRBC. Other conditions, such ascontrolled diabetes mellitus, hypertensive disease of pregnancy, and maternal

obesity, also did not seem to influence the NRBC count  [34].

 Nonetheless, normal nonasphyxiated neonates may have an elevated NRBC

count  [35,36]; however, Buonocore and associates [37] observed that neonates

who had elevated NRBCs at around the time of birth were significantly more

likely to have neurologic impairment at 3 years of age. Buonocore et al [37]

concluded that NRBC counts ‘‘[were] helpful in identifying perinatal hypoxia

and in predicting neurodevelopmental outcome.’’

The underlying theory is that the fetus responds to oxygen deprivation bydiverting blood from less vital organs to the brain, heart, and adrenal glands

and by stimulating production and release of erythropoietin. The erythropoietin,

in turn, speeds up erythropoiesis as a means of improving fetal oxygenation. This

stepped-up process results in an increased proportion of immature—and thus,

 NRBCs. In the rat model, Blackwell and associates [38] exposed pregnant rats

to 2 hours of acute hypoxia. Beginning at 12 hours and continuing through

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24 hours after  exposure to acute hypoxia, a significant increase in NRBCs was

observed [38]. The greater-than-average representation of NRBCs in the blood of 

asphyxiated newborns may reflect hurried erythropoiesis and asphyxia-inducedsplenic injury [39] that impairs the ability of that organ to ‘‘clear’’ immature, and

otherwise suboptimal, red blood cells.

Phelan et al [30] and Korst et al [31] demonstrated that neurologically

impaired neonates had significantly greater NRBCs than did normal nonas-

 phyxiated newborns. Additionally, these investigators showed that there were

distinct patterns that involved maximal NRBC values and clearance times that 

seemed to be associated with the FHR pattern and the timing of fetal hypoxic-

ischemic injury. The clearance time is referred to as the length of time from birth

to the disappearance of NRBCs from the peripheral circulation. Children in thenonreactive group were far more likely than those in the group that was injured

intrapartum to maintain NRBCs in their peripheral circulation for more than

80 hours [30,31,34].

It must be emphasized that a single NRBC value cannot be used to time fetal

 brain injury. This is due, in part, to the fact that normal, nonasphyxiated neo-

nates also may have an elevated NRBC count  [35] and there is some overlap in

values among various FHR subgroups [36]. These observations are in keeping

with the Neonatal Encephalopathy Committee Opinion in 2003 [4], ‘‘although

nucleated red blood cells. . .

may be elevated in some newborns with neonatalencephalopathy and subsequent neurologic dysfunction, the clinical utility of 

these measurements to determine the timing of neurologic injury should be

considered investigational.’’ When the initial NRBC count and the clearance

time are combined, however, the Committee [4] went on to add that ‘‘. . . NRBC

counts are elevated among neonates with fetal asphyxial injury. [NRBC] counts

appear to be more elevated and to remain elevated longer in newborns with

antepartum injury than in infants with intrapartum injury.’’

As their experience and data expanded, Phelan and associates [34] published

a follow-up study on the NRBC values in term, neurologically-impaired neo-nates; they were able to corroborate their earlier observations [30,31]. In that 

study, they compared the NRBC counts and clearance times of neonates who had

acute intrapartum and preadmission neurologic injuries [34]. The neonates who

had preadmission brain damage were 7.1 times more likely to have an NRBC

count that was at least 26% ( P b.001) and 13.4 times more likely to have a

clearance time of 80 hours or longer ( P b.0001). For example, the initial NRBC

values and clearance times were significantly higher in the group that had

 preadmission neurologic injuries (median initial NRBC, 25% [range 0%–732%];

median NRBC clearance time, 132.9 hours [range 7.5–569.9 hours]) than inthe group that had acute intrapartum injury (median initial NRBC, 8.5% [range

0%–156%]; median NRBC clearance time, 15.7 hours [range 0.5–170.4 hours]).

Some infants who have a nonreactive FHR pattern from admission to delivery

will have few or no NRBCs in their cord blood or peripheral circulation. These

observations suggest that an NRBC count in excess of 26% [21] is less consis-

tent with an acute intrapartum injury and more consistent with a preadmission

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insult  [34]. This suggests that some central nervous system (CNS) insults have

occurred so long before delivery that there has been sufficient time before

delivery to clear the normoblasts. Additionally, the initial NRBC count in thenewborn usually is the peak NRBC value or is close to that maximum value.

This also may explain some of the overlap that is seen in NRBC values among

 permanently brain-damaged newborns.

Platelets

Hematologic dysfunction can occur as a result of sustained acidosis, hypoxia,

and hypotension, and may be manifest by overt disseminated intravascular coagulation. Decreased platelet values seem to be more evident in cases of 

 preadmission injury. For example, Korst et al [40] demonstrated in 129 term,

 brain-injured infants who were classified in the three FHR groups that the

nonreactive group was eight times more likely than neonates in the Hon and

acute groups to have an initial platelet count of less than 150 (1000/ mL).

Moreover, the mean platelet values for these groups illustrated that decreased

 platelets also are more common in the nonreactive group. Further investigation

of patterns of fetal brain injury, the extent of intracerebral bleeding, and the

extent of systemic vascular endothelial damage are necessary to clarify the physiologic processes that lead to the altered platelet counts.

After the Korst et al [40] study was published, Hankins and associates [21]

suggested that acutely asphyxiated neonates who had neonatal encephalopathy

would develop thrombocytopenia (platelet count  b 100,000/ mL) within 5 days

of birth. In that study, they found that 28% of their subjects had thrombo-

cytopenia in the early neonatal period. Subsequently, Phelan and associates [41]

studied a heterogeneous group of asphyxiated neonates and found that neonates

who had preadmission brain damage—not acutely injured neonates—were

significantly more likely to have a platelet count that was less than 100,000/ mLwithin 5 days of birth. These results suggested that a decrease in the neonatal

 platelet count to less than 100,000/ mL within 5 days of birth may be inconsistent 

with the theory that the neonate was asphyxiated acutely.

Neonatal organ dysfunction

Multi-system organ dysfunction has long been considered a clinical require-

ment to support the claim that a neonate had been asphyxiated. The underlying premise is that asphyxiated neonates will, if the fetus has sufficient time, divert 

or shunt blood away from organs, such as the kidneys, liver, intestines, and bone

marrow, preferentially to the fetal brain in an effort to preserve CNS function.

But, as demonstrated by Phelan and associates [42], neonates who have acute

asphyxial brain damage do not always demonstrate multi-system organ

dysfunction. In a later publication, Hankins et al [21] broadened the requirements

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of organ dysfunction as previously expressed in the Phelan article [42] and

suggested that ‘‘the absence of organ dysfunction is inconsistent with the diag-

nosis of significant intrapartum asphyxia.’’ Consistent  with the results of Phelan and associates [42], however, Hankins et al’s [21] study demonstrated

that, even with this inclusive definition, a percentage of neonates did not seem to

have organ dysfunction. This suggests that acute fetal neurologic injury can

happen so quickly that there may not be sufficient time for shunting blood to

occur  [42]. Thus, the absence of organ dysfunction should be considered consis-

tent, in selected circumstances, with an acute fetal neurologic insult.

Liver function tests

One of the fetal responses to hypoxia is increased shunting of blood through

the ductus venosus; subsequent hepatic hypoxia can occur with elevations of 

liver transaminases. Levels of serum glutamic-oxaloacetic transaminase (SGOT)

and glutamic-pyruvic transaminase (SGPT) are considered to be some of the

more specific parameters of liver cell injury. They have been suggested as a

routine and rapid laboratory test for establishing the presence of hepatic cellular 

damage following an asphyxial event if centralization of the fetal circulation has

occurred [43]. Because this injury is highly reversible after the hypoxia hasresolved, one would expect that fetuses who have preadmission injury may have

normal liver transaminases. Fetuses who undergo acute injury may not proceed

with the physiologic process of centralizing their circulation, and thus, they also

may exhibit normal SGOT and SGPT levels [21,42]. Here, the circumstances

that surround the timing of the injury must put the liver function tests in the

 proper context. There are two definitions for hepatic dysfunction: SGOT or 

SGPT 1.5 times the upper limit of normal for the laboratory [21] or SGOT or 

SGPT of 100 U/L [23].

Renal function

The combination of ischemia and hypoxemia can cause renal damage. This

is manifested in decreased renal function and by the presence of oliguria,

hematuria, and proteinuria. Related hematologic markers that may be useful in

determining the physiologic impact of asphyxia on the kidneys are serum

creatinine and sodium. Because there is a wide variation in renal compositionand output in the immediate neonatal period and because some neonates may

show initially high concentrations of serum creatinine due to events and

treatment immediately surrounding the birth and immediate neonatal care, a

 persistently elevated serum creatinine concentration of at least 1.2 mg/dL after 

 birth seems to be consistent with hypoxic renal damage [44,45]. Hankins and

associates [21] broadened the clinical requirements to define renal dysfunction.

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But, when Korst et al’s [23] and Hankins et al’s [21] methods to def ine fetal

renal dysfunction in a heterogeneous group of asphyxiated neonates [46] and

acutely asphyxiated neonates [47] were used, the Hankins’ method tended toclassify most of the neonates as having renal dysfunction [46]. When the

intrapartum FHR pattern was used, both methods identified a consistent rela-

tionship among FHR groups [46]. Earlier resolution of creatinine levels to

normal may occur and are likely to reflect less severe injury and less profound

centralization of the fetal circulation.

Decreased sodium levels may be noted as a likely result of the syndrome of 

inappropriate antidiuretic hormone or renal dysfunction [48], and in cases of 

severe asphyxia, may be manifest for several days.

Timing fetal brain injury

For centuries, scientists have attempted to determine the timing of fetal brain

injury. At first, attention was focused on the several hours during which a patient 

was in labor. It was for this reason that electronic fetal monitoring was in-

vented and has become an integral part of our obstetric care over the past 4 to

5 decades. The operant presumption has been that the FHR patterns would

alert the obstetrician in sufficient time to prevent fetal brain injury that wasdue to HIE. What went wrong? Was there a failure of fetal monitoring or was

it something else? First, our fetal monitoring forefathers underestimated the

number of infants who were injured before labor and overestimated the number 

who were injured during labor  [5]. At best, the fetal monitor permitted us to

 prevent intrapartum deaths [49]; as a result, some neonates were able to sur-

vive, albeit, in an impaired state. One must ask whether the birth of such children

was a failure of fetal monitoring or a failure to recognize a fetus who had pre-

existing neurologic impairment  [5]? One cannot prevent that which has been

damaged already; the obstetrician should not be faulted for this neonataloutcome. This begs the question of whether the failures of fetal monitoring are

related to the current approaches to the interpretation of fetal monitoring [50]

or to the presumption that the use of the fetal monitor should result in the

 prevention of CP through earlier detection and timely intervention? Before one

can prevent a neurologic insult, one must be able to identify which fetus is at 

risk for that brain damage and then make a determination of whether that insult 

 potentially was preventable. Notwithstanding, law does impose an obligation to

mitigate any resultant harm.

Thus, techniques to define acute intrapartum fetal brain injury are numerousand have changed over the years [4–7]. The approach that is used at the

Childbirth Injury Prevention Foundation is based on the concept that fetuses will

manifest their injuries in consistent ways as reflected on the fetal monitor strip

[5]. For example, Phelan and Ahn [9] showed that when these fetuses are so

classified, they do manifest distinct intrapartum FHR patterns that are linked to

hematologic markers in the neonatal period and specific patterns of fetal brain

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injury [5]. The Foundation’s method to time fetal brain injury uses a flexible

approach that relies on the admission FHR pattern; the characteristics of fetal

movement on admission; and the subsequent changes in the FHR pattern, if any, during labor and delivery [5]. Then, neonatal hematologic observations

are used to link them to the intrapartum FHR pattern (Fig. 1). The reason for 

this quality management approach is to permit the obstetrician an opportunity

to risk-assess each labor at the time of admission and then to be able to identify

changes, if any, in fetal status during that labor. This approach is not limited to

the findings that surround the moment of birth, such as umbilical artery cord

gases and Apgar scores, but focuses on the continuum of life and the transition

from fetal to neonatal life and beyond [5].

Other methods that are used to time fetal brain injury rely heavily on the

observations that surround the moment of birth [4,6,7]. As a result of this limi-

tation, many fetuses who are injured during labor will be missed and will not 

included in these timing schemes. The American College of Obstetricians and

Gynecologists (ACOG) 163 criteria [6] to determine whether an intrapartum

injury occurred during the intrapartum period are listed in Box 1. Subsequent 

Fig. 1. The Childbirth Injury Prevention Foundation’s flexible method to time fetal brain injury.

Box 1. The American College of Obstetricians and Gynecologists

criteria to define intrapartum asphyxia

Arterial pH of less than 7.00

Apgar score of up to 3 for longer than 5 minutes

Neonatal neurologic sequelae

Multi-organ system dysfunction

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research demonstrated that many neonates who were neurologically injured as a

result of HIE were not detected with the use of these criteria [23,24]. For example, Korst et al [24] applied the ACOG 163 criteria to a homogeneous

group of neonates who had acute intrapartum asphyxia that was sufficient to

 produce permanent brain injury (Table 1). In a similar study of a heterogeneous

group of neonates who had permanent brain damage that was due t o HIE,

Korst et al [23] applied the ACOG 163 criteria to 52 neonates (see Table 1).

The International Consensus criteria that are illustrated in Box 2 [7] seem to

 be an extension of the ACOG 163 criteria [6]. On the surface, this method seems

to be superior to ACOG 163 criteria in the determination of whether an insult 

Box 2. The International Consensus criteria to define an acute

intrapartum hypoxic event

Essential criteria

Evidence of metabolic acidosis in intrapartum fetal umbilical

arterial or very early neonatal blood samples (pH b 7.00 and

base deficit 12 mmol/L)Early onset of severe or moderate encephalopathy in infants

who are at least 34 weeks’ gestation

Cerebral palsy of the spastic quadriplegic or dyskinetic type

Nonessential criteria

A sentinel (signal) hypoxic event that occurs immediately before

or during labor

A sudden, rapid, and sustained deterioration of the fetal heartrate pattern, usually after the hypoxic sentinel event where

the pattern was previously normal

Apgar scores of 0 to 6 for longer than 5 minutes

Early evidence of multi-system involvement.

Early imaging evidence of acute cerebral edema

Table 1

The application of ACOG 163 [6] criteria to define intrapartum asphyxia

Study population Brain injured neonates ACOG 163 criteria satisfied (%)Acute [24] 47 10 (21%)

Mixed [23] 52 5 (10%)

 Abbreviations: ACOG, American College of Obstetricians and Gynecologists; acute, reactive FHR on

admission followed by a sudden, rapid, and sustained deterioration of the FHR that lasted until

delivery; mixed, a heterogeneous group of neonates with 3 types of FHR patterns that were associated

with permanent brain injury due to hypoxic ischemic encephalopathy.

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arose intr apartum. As with ACOG 163 criteria, the emphasis of MacLennan’s

template [7] is on the events that surround birth, specifically the presence of 

metabolic acidemia and the degree of neonatal encephalopathy (see Box 2). Thisapproach suggests, in part, that all children who are injured during labor will

manifest their injury in such a manner. When these criteria are present, does this

mean that the odds of the injury being intrapartum are greater?

Once again, the three essential and five nonessential criteria were applied to

homogeneous [51] and heterogeneous [52] groups of neonates who had

 permanent brain injury that was due to HIE (Table 2). Few infants were iden-

tified using these criteria. For example, these criteria were able to identify 1 of 

28 (4%) children in the acute group [51] and none in the heterogeneous group

[52]. This suggests that many children who have intrapartum injuries are not identified using this method. These findings also suggest that the use of this

approach may not help clinical researchers to identify and potentially prevent 

 permanent brain injury that is due to HIE.

The next in the series of attempts to determine the timing of fetal brain injury,

the Neonatal Encephalopathy Committee Opinion of 2003 [4], used the Inter-

national Consensus criteria [7] and ACOG 163 criteria [6] to form the foundation

for a ‘‘new’’ approach. A clear benefit of the new opinion [4] was that some-

one finally addressed the issue that many fetal brain injuries were unrelated to

HIE; they added a fifth clause that excluded these infants from the analysis(Box 3). As with the other approaches, the emphasis was on the events that 

surrounded birth, including metabolic acidemia on an umbilical artery cord gas

and the presence of neonatal encephalopathy. The ongoing dilemma with this

approach is the requirement of metabolic acidemia to determine whether an

insult occurred intrapartum. The likelihood of permanent neurologic impairment 

in neonates who have severe acidosis at birth is uncommon and is estimated to

 be approximately 8% to 9% [11]. Volpe’s [53] textbook, Neurology of the New-

born, commented on an article regarding the relationship between metabolic

acidosis and long-term neurologic impairment  [54], and noted that ‘‘approxi-mately 85% of the asphyxiated neonates either were normal or exhibited minor 

deficits at 1 year of age.’’ Moreover, the Society of Obstetricians and Gyne-

cologists of Canada [55] demonstrated that the application of guidelines to define

Table 2

The application of the International Consensus criteria to define an acute intrapatum hypoxic event 

Study population

Essential criteria

 present 

3 EC

satisfied (%)

5 NEC

satisfied (%)

3 EC & 5 NEC

satisfied (%)

Acute [50]a  28/47 (60%) 9/28 (32%) 1/9 (11%) 1/28 (4%)

Mixed [51] b 40/52 (77%) 10/40 (25%) 0/10 (0%) 0/40 (0%)

 Abbreviations: EC, essential criteria; NEC, nonessential criteria.a  Reactive FHR on admission followed by a sudden, rapid, and sustained deterioration of the

FHR that lasts until delivery. b A heterogeneous group of neonates with three types of FHR patterns that are associated with

 permanent brain injury that is due to HIE.

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‘‘significant fetal asphyxia’’ (pHb 7.00, base deficit  N 16 mmol/L, neonatal

encephalopathy, Apgar score of less than 3 for longer than 5 minutes, and

seizures with neonatal encephalopathy), would have missed 53 of 60 (88%)

of the babies who had asphyxial newborn encephalopathy, including 23 of 

29 (79%) who had seizures, 3 of 6 (50%) who were in a coma, and 3 of 6 (50%)

who died [54]. These findings suggest that a different approach to evaluate

neonates who are suspected of HIE should be undertaken. This would improveour understanding of the pathogenesis of HIE-induced CP and would enable us

to identify and better treat all of the neonates who are afflicted with this tragic

condition. Although no studies have specifically investigated the Neonatal

Committee Opinion–2003 method to time fetal brain injury, this approach seems

to be too restrictive to assist families of children who have CP in understanding

what happened to their child.

Box 3. The Neonatal Encephalopathy Committee Opinion in 2003

criteria to define an acute intrapartum hypoxic event as sufficient

to cause cerebral palsy

Essential criteria (must meet all four)

Evidence of a metabolic acidosis in fetal umbilical cord

arterial blood obtained at delivery (pH b 7 and base deficit

12 mmol/L).

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, co-

agulation disorders, infectious conditions, or genetic disorders

 Additional criteria (criteria that collectively suggest an

intrapartum timing [within close proximity to labor and delivery,

eg, 0–48 hours] but are nonspecific to asphyxial insults)

A sentinel (signal) hypoxic event that occurs immediately before

or during laborA sudden and sustained fetal bradycardia or the absence of

FHR variability in the presence of persistent, late or variable

decelerations, usually after a hypoxic sentinel event when

the pattern was previously normal

Apgar score of 0 to 3 beyond 5 minutes

Onset of multi-system involvement within 72 hours of birth

Early imaging study showing evidence of acute nonfocal cere-

bral abnormality

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Summary

For the neonate who is suspected of having undergone a severe asphyxialepisode at some time during gestation, several blood tests may assist in the

determination of when and how that episode occurred. The cord blood pro-

vides valuable data with the arterial pH, NRBC, and platelet levels. The NRBC

count, SGOT, SGPT, serum creatinine, and serum sodium levels should be

monitored for several days. In the context of the prenatal and intrapartum history

and the clinical condition of the neonate, these hematologic markers may provide

 physicians with information regarding the timing and severity of the fetal

asphyxial insult.

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