Clin Perinatol 32 (2005) 61 76

Birth Asphyxia and Cerebral Palsy

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

Department of Obstetrics and Gynecology, Citrus Valley Medical Center, West Covina, CA, USA b University 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 rate which 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 children 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 times the obstetrician has been targeted unfairly as the person who is responsible for a given childs 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

* Corresponding author. 959 East Walnut Street, Suite 200, Pasadena, CA 91106. E-mail address: phelanjp@earthlink.net (J.P. Phelan). 0095-5108/05/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2004.11.010 perinatology.theclinics.com

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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 newborns 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 infants brain injuries, and their long-term impact on the child. Critical to understanding the pathophysiology 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 ones 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 considered 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 be improved 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 injured during 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 [47]. 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 intrapartum 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 an umbilical 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 may not seem to be linked to subsequent neurologic deficits, nor neonatal encephalopathy [22]. In contrast, the absence of severe acidosis does not ensure a favorable neurologic 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 impairment, 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 notno 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 occurring 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 explanations include: (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 [3234]. 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 as controlled 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 by diverting 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 immatureand 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-induced splenic 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 nonasphyxiated 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 hypoxicischemic 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 the nonreactive 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 neonates 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 neonatal encephalopathy 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 neonates; 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 7.5569.9 hours]) than in the group that had acute intrapartum injury (median initial NRBC, 8.5% [range 0%156%]; median NRBC clearance time, 15.7 hours [range 0.5170.4 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 consistent 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 the newborn 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 thrombocytopenia 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 damagenot acutely injured neonateswere significantly more likely to have a platelet count that was less than 100,000/mL within 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 requirement 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 diagnosis of significant intrapartum asphyxia. Consistent with the results of Phelan and associates [42], however, Hankins et als [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 consistent, 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 has resolved, 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 composition and 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 als [23] and Hankins et als [21] methods to define fetal renal dysfunction in a heterogeneous group of asphyxiated neonates [46] and acutely asphyxiated neonates [47] were used, the Hankins method tended to classify most of the neonates as having renal dysfunction [46]. When the intrapartum FHR pattern was used, both methods identified a consistent relationship 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 invented 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 was due 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 survive, 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 preexisting neurologic impairment [5]? One cannot prevent that which has been damaged already; the obstetrician should not be faulted for this neonatal outcome. 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 numerous and have changed over the years [47]. 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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Fig. 1. The Childbirth Injury Prevention Foundations flexible method to time fetal brain injury.

injury [5]. The Foundations 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 limitation, 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

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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Table 1 The application of ACOG 163 [6] criteria to define intrapartum asphyxia Study population Acute [24] Mixed [23] Brain injured neonates 47 52 ACOG 163 criteria satisfied (%) 10 (21%) 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.

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 to 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 heart rate 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

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arose intrapartum. As with ACOG 163 criteria, the emphasis of MacLennans template [7] is on the events that surround birth, specifically the presence of metabolic acidemia and the degree of neonatal encephalopathy (see Box 2). This approach 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 identified 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 International 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 someone 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]. Volpes [53] textbook, Neurology of the Newborn , commented on an article regarding the relationship between metabolic acidosis and long-term neurologic impairment [54], and noted that approximately 85% of the asphyxiated neonates either were normal or exhibited minor deficits at 1 year of age. Moreover, the Society of Obstetricians and Gynecologists 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 Acute [50]a Mixed [51]b Essential criteria present 28/47 (60%) 40/52 (77%) 3 EC satisfied (%) 9/28 (32%) 10/40 (25%) 5 NEC satisfied (%) 1/9 (11%) 0/10 (0%) 3 EC & 5 NEC satisfied (%) 1/28 (4%) 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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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, coagulation disorders, infectious conditions, or genetic disorders Additional criteria (criteria that collectively suggest an intrapartum timing [within close proximity to labor and delivery, eg, 048 hours] but are nonspecific to asphyxial insults) A sentinel (signal) hypoxic event that occurs immediately before or during labor A 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 cerebral abnormality

significant fetal asphyxia (pH b 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 improve our 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 Opinion2003 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.

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Summary For the neonate who is suspected of having undergone a severe asphyxial episode at some time during gestation, several blood tests may assist in the determination of when and how that episode occurred. The cord blood provides 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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