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ARTICLE |
a Departments of Neurology
b Pediatrics
d Epidemiology and Biostatistics, University of California, San Francisco, California
c Kaiser Permanente Division of Research, Oakland, California
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONAPPENDIX: EXCLUSION DIAGNOSESREFERENCES |
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PATIENTS AND METHODS. Among a cohort of 334339 infants 
36 weeks’ gestation born at Kaiser Permanente Medical Care Program in northern California in 1991–2003, we identified infants with cerebral palsy and obtained clinical data from electronic and medical charts. Risk factors for cerebral palsy among infants with different brain abnormalities were compared using polytomous logistic regression.
RESULTS. Of 377 infants with cerebral palsy (prevalence: 1.1 per 1000), 273 (72%) received a head computed tomography or MRI. Abnormalities included focal arterial infarction (22%), brain malformation (14%), and periventricular white matter abnormalities (12%). Independent risk factors for cerebral palsy were maternal age >35, black race, and intrauterine growth restriction. Intrauterine growth restriction was more strongly associated with periventricular white matter injury than with other neuroimaging findings. Nighttime delivery was associated with cerebral palsy accompanied by generalized brain atrophy but not with cerebral palsy accompanied by other brain lesions.
CONCLUSIONS. Cerebral palsy is a heterogeneous syndrome with focal arterial infarction and brain malformation representing the most common neuroimaging abnormalities in term and near-term infants. Risk factors for cerebral palsy differ depending on the type of underlying brain abnormality.
Key Words: cerebral palsy • epidemiology
Abbreviations: CP—cerebral palsy • CT—computed tomography • KPMCP—Kaiser Permanente Medical Care Program • ICD-9-CM—International Classification of Diseases, Ninth Revision, Clinical Modification • IUGR—intrauterine growth restriction • RR—relative risk • CI—confidence interval • OR—odds ratio
Cerebral palsy (CP) is a group of nonprogressive motor impairment syndromes caused by lesions of the brain arising early in development.1 The etiology of CP remains unexplained in most cases, and the prevalence of CP, between 1.0 and 2.4 per 1000 live births,2–7 has not diminished in recent decades despite advances in obstetric and neonatal care.2–4,8,9 The risk of CP among term infants in the United States may, in fact, have increased between the years 1975 and 1991, from 1.7 to 2.0 per 1000 live births.3 Based on these numbers, 
8000 children with CP are born annually in the United States.10
Because the diagnosis of CP does not specify a particular etiology or pathology, epidemiologic studies of CP have traditionally grouped children with CP into phenotypic subtypes based on the distribution of limb weakness and type of tone abnormality.7 To devise rational and improved strategies for prevention, however, it is crucial that CP be recognized as a heterogeneous group of brain disorders with potentially different risk factors and causal pathways. With the increasing availability of head computed tomography (CT) and MRI, several types of brain injury underlying CP have been described, including brain malformations, hypoxic-ischemic brain injury, focal arterial infarction, and periventricular white matter injury.6,11–14 Yet, most neuroimaging studies of CP have been hospital based and are, thus, susceptible to selection bias, and the evaluation of risk factors for CP has rarely taken into account the underlying types of brain injury present.
More than half of all children with CP are born at term,5,6 but data regarding risk factors for CP in term infants are relatively sparse compared with the large number of studies performed in premature infants. Although populations in Europe, Scandinavia, and Australia maintain active CP registries,4,6,8,15–18 few population-based studies of CP in term infants have been performed in the United States. These include the Collaborative Perinatal Project of the 1960s19, a California study in the mid-1980s20, and a study in the greater Atlanta area spanning birth years 1971–1991.3 Given the paucity of recent data, we examined demographic and neuroimaging characteristics of infants with CP identified from a cohort of term and near-term infants born in northern California during the years 1991–2002, when head MRI and CT were widely available.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX: EXCLUSION DIAGNOSESREFERENCES |
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36 weeks’ gestation born between January 1, 1991, and December 31, 2002, in the Kaiser Permanente Medical Care Program (KPMCP). The KPMCP is a large managed care organization that provides care for >3 million residents of northern California. The members of KPMCP are demographically similar to the California population, except that the very poor and very wealthy are underrepresented.21 KPMCP has 33 facilities, of which 12 have delivery rooms, and 6 have level III NICUs.
Case Identification
For all of the infants in the study cohort, we electronically searched KPMCP records for inpatient and outpatient physician diagnoses of CP (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 343.0–343.9),22 "paresis" (ICD-9-CM 342.1, 342.8, 342.9, 344.0, 344.1, 344.30–344.32, and 344.5), "gait abnormality" (ICD-9-CM 781.2), or "cerebral degeneration" (ICD-9-CM 330) before April 1, 2005. A single child neurologist (Y.W.) then reviewed medical charts to confirm the diagnosis of CP. Because chart review revealed that 0 of the initial 141 infants with an isolated diagnosis of gait abnormality met study criteria for CP, we excluded the remaining 241 infants with an isolated diagnosis of gait abnormality without reviewing their charts. Infants with an isolated diagnosis of cerebral degeneration (N = 980) were also excluded without chart review, because a review of these patients’ electronic records did not suggest CP.
We defined CP as a nonprogressive congenital motor dysfunction with examination findings of increased tone (spasticity, rigidity, and dystonia) or choreoathetosis. Hypotonic and ataxic CP were not included, because these entities are most likely etiologically distinct from spastic and dyskinetic CP. Children with a postnatal central nervous system insult occurring after 1 week of age or a neurologic condition not typically considered to be CP, such as a myopathy or neural tube defect, were also excluded a priori (see "Appendix" section for list of diagnoses).23 Because the motor impairment seen in inherited disorders, such as Angelman’s syndrome, has traditionally not been included in epidemiologic studies of CP,24 we also excluded infants with a known genetic syndrome or chromosomal anomaly.
The degree of motor disability was determined as close to age 3 years as possible. We defined "mild" disability as minimal functional limitation; "moderate" disability as diminished use of the most affected limb; and "severe" disability as the lack of any functional use of the most affected limb.5 When a young child with CP was found to be neurologically normal by 3 years of age, the CP was considered to have "resolved."25 Infants in the study population who did not have an exclusion diagnosis and who did not receive a physician diagnosis of CP, paresis, gait abnormality, or cerebral degeneration constituted the control cohort.
Covariate Data
We electronically accessed the following information from the KPMCP patient data files: infant gender, race/ethnicity (white, Hispanic, black, Asian, or other), maternal age at delivery, plurality (singleton or multiple gestation), birth weight, gestational age, time and date of birth, and whether the infant was admitted to the NICU. Infants delivered between 9 PM and 6:59 AM were considered to be born at night.26 The months of June, July, and August were defined as summer, whereas December, January, and February were considered winter months. We defined intrauterine growth restriction (IUGR) according to 3 cut points of birth weight for gestational age (<10%, <5%, or < 1%) based on the race- and gender-specific distributions of birth weight and gestational age in our study population.
Neuroimaging
We reviewed all of the head CT and MRI reports for infants with CP and grouped findings into the following: focal arterial infarction, brain malformation, periventricular white matter abnormality, generalized atrophy, hypoxic-ischemic brain injury, intracranial hemorrhage, delayed myelination, other abnormality, or normal. We defined hypoxic-ischemic brain injury as neuroradiologic evidence of parasagittal brain injury in a watershed distribution, injury of the basal ganglia or thalamus, or diffuse brain edema seen in the first days of life. Although the specificity of these findings for intrapartum hypoxia-ischemia is unknown, because we cannot directly measure intrapartum blood flow and oxygen delivery to the brain,24 these findings are often taken to imply the presence of perinatal hypoxia-ischemia in the encephalopathic neonate.27–30
Data Analysis
We calculated univariate relative risks (RR) and 95% confidence intervals (95% CIs) using the exact method and calculated multivariate odds ratios (ORs) using logistic regression. All of the variables that were associated with CP in the univariate analysis with a significance level of P < .10 were included in the multivariable model. We compared univariate ORs stratified by type of imaging abnormality using polytomous logistic regression.31 ORs are close approximations of the RR, because the outcome of CP is rare in term infants. We tested for significant changes in CP prevalence over time using the Cochran-Armitage test for trend.32 All of the analyses were performed using either Stata33 or SAS32 statistical software packages. We excluded infants with missing data on gender, ethnicity, gestational age, or birth weight from all of the analyses (N = 1005; 0.3% of potential controls). Study procedures were approved by the institutional review boards at KPMCP and at the University of California, San Francisco.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX: EXCLUSION DIAGNOSESREFERENCES |
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36 weeks’ gestation was 1.1 per 1000 live births. When infants with ataxic or hypotonic CP were also counted, the overall prevalence of all types of CP among term and near-term births was 1.4 per 1000. There was no significant trend in the prevalence of CP during the study years (z = 0.99; P = .32). The prevalence of mild, moderate, and severe CP also did not change significantly across the study years (data not shown).
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Focal arterial infarction was the most common neuroimaging finding (Table 1). Of the 121 infants with spastic hemiparesis who received a neuroimaging study, 55 (45%) had a focal arterial infarction. Brain malformations constituted the second most common type of abnormality and included schizencephaly (N = 7), hydrocephalus (N = 6), agenesis of the corpus callosum (N = 6), polymicrogyria (N = 3), lissencephaly (N = 2), holoprosencephaly (N = 2), septo-optic dysplasia (N = 2), cerebellar anomalies (N = 2), and other miscellaneous malformations (N = 9).
A significant proportion (12%) of infants with neuroimaging data exhibited a pattern of periventricular white matter injury that is more typically seen in preterm infants. In contrast, the findings considered to be specific to hypoxia-ischemia in term infants were present in only 5% of those who were imaged. Generalized atrophy, which can also be a consequence of perinatal hypoxia-ischemia, was appreciated in an additional 7% of cases.
A normal brain was seen in almost one third of infants who underwent neuroimaging (Table 1). Infants with mild or resolved CP were more likely to have a normal brain image than those with more severe degrees of motor impairment (58% vs 23%; P < .001). Of the 10 infants whose symptoms resolved by age 3 who had undergone neuroimaging (8 MRI and 2 CT), 9 had a normal scan, and the remaining infant demonstrated mild delayed myelination.
Demographic Risk Factors
Advanced maternal age (>35) was associated with an almost twofold increased risk for CP in the univariate analysis (Table 2). There was a trend toward blacks having an increased risk of CP, whereas Asians demonstrated a trend toward a decreased risk, but neither finding was statistically significant in univariable analyses. The rate of CP was not increased among infants born at night or on the weekend, and no seasonal or gender differences were seen. Although multiple gestation births were 1.7 times more likely to result in CP, this finding did not reach statistical significance (95% CI: 0.9–1.4; P = .09). Intrauterine growth restriction increased the risk of CP, with the highest risk seen in infants whose birth weights were below the first percentile for gestational age (OR: 4.5; 95% CI: 2.7–7.4). Using US birth weight and gestational age norms published by the Centers for Disease Control and Prevention to define IUGR did not significantly alter our findings. Children with CP were 8 times more likely than control children to be admitted to the NICU.
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Stratified Analyses
To better understand the relationship between risk factors and type of brain injury, we examined whether the strength of association between demographic factors and CP differed according to type of brain injury. Using polytomous logistic regression, we found that the OR for CP associated with IUGR below the first percentile was higher among children with a neuroimaging diagnosis of periventricular white matter injury (OR: 17.5; 95% CI: 6.8–45.3) than among those with other neuroimaging findings (OR: 3.5; 95% CI: 1.7–7.1; P < .01 for the difference). Among the 13 case infants with IUGR below the first percentile, 5 (38%) had periventricular white matter injury. Neuroimaging findings in the remaining children included a normal scan (N = 3), focal arterial infarction (N = 2), intracranial hemorrhage (N = 2), and brain malformation (N = 1). IUGR below the fifth percentile was also associated with risk of CP and focal arterial infarction (RR: 2.5; 95% CI: 1.3–5.5).
Neither advanced maternal age nor black ethnicity was significantly associated with a specific type of brain abnormality. However, being born at night was associated with CP in the setting of generalized brain atrophy (OR: 3.6; 95% CI: 1.4–9.3) but not with CP because of other types of brain lesions (OR: 0.9; 95% CI: 0.7–1.2; P < .01 for the difference).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX: EXCLUSION DIAGNOSESREFERENCES |
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Strengths of the study include the large population base and the significant amount of neuroimaging data available compared with most etiologic studies of CP. Several limitations also deserve mention. Neuroimaging studies were not performed in a uniform fashion, and we relied on the clinical interpretations provided by treating radiologists, only some of who are specialized in neuroradiology. Case ascertainment may not have been complete, and patients with CP were not examined to confirm the diagnosis. Although we previously described an association between chorioamnionitis and CP in a subset of 109 infants with CP who did not have a known brain malformation, genetic or congenital anomaly,34 the current study of all infants with CP in years 1991–2003 was not designed to evaluate peripartum risk factors. Thus, chorioamnionitis, which was a particularly strong risk factor for CP in infants whose imaging studies suggested hypoxic-ischemic brain injury,34 could not be evaluated in the current study, because this would require medical chart review for all infants in the birth cohort, which is not feasible.
The prevalence of CP in our population, 1.1 per 1000 live births, is similar to previous estimates in term infants.3,5,6,8 A recent study of CP among a Swedish population of infants born in 1991–1994 reported a similar proportion of hemiparesis (44%) and paraparesis (25%)6 as was seen in our population (40% and 24%, respectively). The proportion of infants with brain malformations (14%–15%) was also similar in these 2 studies. In contrast, older studies report that only 1.9% of infants with CP have a recognized brain malformation35 compared with 14% of those imaged in the current study.
We confirmed our previous finding that the prenatal risk factor of IUGR is associated with focal infarction.36 However, in this larger study with more precise definitions of growth restriction, we found that IUGR is most strongly associated with periventricular white matter injury. The underlying mechanisms by which IUGR relates to CP has been debated.7,15 The growth restriction could make the fetus more vulnerable to intrapartum hypoxic-ischemic stress,37 or the low birth weight could be merely a result of chronic intrauterine hypoxia responsible for the intrauterine white matter injury,38,39 and, thus, not directly on the causal pathway. Our finding that IUGR was most strongly associated with white matter injury and that none of the growth-restricted infants in our study cohort had neuroimaging findings suggestive of global hypoxic-ischemic brain injury supports the conclusion that most CP in growth-retarded infants is not because of intrapartum hypoxic-ischemic injury.40,41 Determining whether thrombophilias or intrauterine infections might play a role in the pathogenesis of both IUGR and periventricular white matter injury will require additional study.
One third (32%) of infants with CP who underwent neuroimaging demonstrated strong evidence for an acute brain injury occurring around the time of birth. These neuroimaging findings included acute perinatal focal arterial infarction, hypoxic-ischemic brain injury, and intracranial hemorrhage. Using predominantly clinical parameters to determine the timing of injury, Hagberg et al6 reported that a similar proportion (36%) of term infants suffered a perinatal or neonatal event responsible for the development of CP.
The nature and timing of events in the causal pathways leading to CP remain a matter of debate.7,42,43 Prenatal risk factors have been increasingly implicated as important determinants of the risk of CP and neonatal encephalopathy.2,44 Despite the dramatic decline in birth asphyxia diagnoses during the years 1991–2000 in California,45 we found that the rate of CP was unchanged in our northern California cohort during the same time period, suggesting that the clinical diagnosis of "birth asphyxia" did not contribute to the majority of CP cases. Yet, in tertiary care centers, most infants with neonatal encephalopathy show radiologic evidence of acute brain injury occurring around the time of birth.42 Perinatal complications, such as chorioamnionitis, have also been associated with CP in several studies34,46 Both prenatal and perinatal factors are likely to be important in the pathogenesis of CP, and, in some cases, the presence of prenatal risk factors may predispose infants to suffer acute brain injury during labor and delivery.
Because of the lack of racial heterogeneity, few studies have been able to examine the effects of ethnicity on risk of CP. A study of California births in 1983–1985 suggested that black ethnicity increased the risk of CP because of an increased rate of prematurity.47 We found that black ethnicity is associated with a 40% increased risk of CP among term and near-term infants. This finding concurs with a study conducted in Atlanta, which found that blacks had a 20% increased risk of CP among newborns weighing >2500 g.3 Whether this increased risk is because of socioeconomic48 or other factors has not been studied. Advanced maternal age was also a significant risk factor for CP in our cohort of term infants, as has been reported previously.5,7
Infants delivered at night have an increased risk of asphyxia-related neonatal deaths.26,49,50 Yet, to our knowledge, hour of delivery has not been significantly associated previously with CP.47,51 We hypothesized that nighttime delivery would be associated with increased risk of CP because of birth asphyxia, as evidenced by neuroimaging findings of hypoxic ischemic brain injury or generalized brain atrophy. Although we found that nighttime delivery was indeed associated with CP accompanied by generalized brain atrophy, our numbers are small, and the relationship between hour of delivery and CP requires additional confirmation in larger studies.
CP is, by definition, a heterogeneous clinical syndrome. Our results provide evidence for differences in risk factor profiles among subgroups of CP defined by the type of underlying brain injury.7,34 Only by separating infants into more homogeneous subgroups based on brain abnormalities that reflect different underlying causal pathways can we gain additional insight into the pathogenesis of this poorly understood disorder.
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APPENDIX: EXCLUSION DIAGNOSES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX: EXCLUSION DIAGNOSESREFERENCES |
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237.7x, neurofibromatosis
275.1, Wilson’s disease
277.2, Lesch-Nyhan syndrome
277.5, Mucopolysaccharidosis
331.8, Reye syndrome
331.9, cerebral degeneration, unspecified
333.6, idiopathic torsion dystonia
334.x, spinocerebellar disease, including ataxia telangiectasia
335.x, anterior horn cell disease
336.x, other diseases of spinal cord
340, multiple sclerosis
349.82, toxic encephalopathy
358.x, myoneural disorders (myasthenia gravis)
359.x, muscular dystrophies and other myopathies
741.xx, spina bifida
742.5x, spinal cord anomalies
754.59, arthrogryposis
755.55, Apert syndrome
756.16, Klippel-Feil disease
757.33, Incontinentia pigmenti, xeroderma pigmentosum
758.x, chromosomal anomalies
759.5, tuberous sclerosis
759.81, Prader-Willi syndrome
759.89, Cornelia de Lange syndrome, Lawrence Moon Biedl syndrome, Rubenstein-Taybi syndrome, Carpenter’s syndrome, cerebrohepatorenal syndrome, Cockayne’s syndrome, Menkes kinky hair disease
740.x, anencephalus
742.0, encephalocele
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ACKNOWLEDGMENTS |
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We thank Joan Verdi, Louis Henning, and Shoujun Zhao for their research assistance and Judith Grether and Karin Nelson for ongoing guidance and support.
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FOOTNOTES |
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Address correspondence to Yvonne Wu, MD, MPH, University of California, Child Neurology, 350 Parnassus Ave, Suite 609, San Francisco, CA 94143-0137. E-mail: wuy{at}neuropeds.ucsf.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX: EXCLUSION DIAGNOSESREFERENCES |
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This article has been cited by other articles:
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  D-M Walker and N Marlow Neurocognitive outcome following fetal growth restriction Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2008; 93(4): F322 - F325. [Abstract] [Full Text] [PDF]
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 S. J. Korzeniewski, G. Birbeck, M. C. DeLano, M. J. Potchen, and N. Paneth A Systematic Review of Neuroimaging for Cerebral Palsy J Child Neurol, February 1, 2008; 23(2): 216 - 227. [Abstract] [PDF]
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 E. W. Reynolds, R. M. S. Riel-Romero, and H. S. Bada Neonatal Abstinence Syndrome and Cerebral Infarction Following Maternal Codeine Use During Pregnancy Clinical Pediatrics, September 1, 2007; 46(7): 639 - 645. [Abstract] [PDF]
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 H. J. Fullerton, Y. W. Wu, S. Sidney, and S. C. Johnston Risk of Recurrent Childhood Arterial Ischemic Stroke in a Population-Based Cohort: The Importance of Cerebrovascular Imaging Pediatrics, March 1, 2007; 119(3): 495 - 501. [Abstract] [Full Text] [PDF]
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