Risk Factors
There are several known risk factors for the development of cerebral palsy, but there are probably also other risk factors that are as yet unknown. Any perinatal trauma experience that has the potential to damage white matter in the brain is a possible risk factor for the disease. One of the most common risk factors is low birth weight, which is highly associated with preterm birth (i.e., low gestational age) and often linked to multiple gestations. The disorder known as periventricular leukomalacia is perhaps the leading cause of cerebral palsy and is defined as the loss of white matter around the lateral ventricles in the brain. Perinatal hemorrhage and ischemic stroke are also major risk factors, as they both lead to reduced blood flow to the brain. Asphyxia at or around the time of birth is another well-researched risk factor. Maternal infection during pregnancy or labor and acquired infection (such as meningitis) just after birth may also lead to cerebral palsy. Finally, there is some evidence that being male is a risk factor for the disease.
1. Prediction of the development of cerebral palsy from perinatal risk factors
Perinatal data of 29 cerebral palsy (CP) children and 237 control children were analyzed to identify etiological and predictive factors for cerebral palsy. Obstetrical and neonatal factors associated with CP in the low-birth-weight group were sex (male) and place of birth, and in the normal-birth-weight group they were prolonged delivery, meconium staining of the amniotic fluid, an Apgar score of less than 4 at 1 minute, the first respiration occurring only after 3 minutes, and the first cry taking place after 7 minutes. The following neonatal signs and symptoms were strongly associated with CP in the both birth weight groups; convulsion, hypotonia, hypertonia, absence of the Moro reflex, tremor, and apnea. A linear discriminant function was developed from the above neonatal signs and symptoms. The use of three factors, convulsion, hypotonia, and apnea efficiently discriminated between the CP and control children and they would be used as good predictive factors for cerebral palsy.
[Saito, T., Fujii, T. & Tango, T. (1983). Prediction of the development of cerebral palsy from perinatal risk factors. Brain & Development, 5(1), 1-8.]
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2. Why is there a modifying effect of gestational age on risk factors for cerebral palsy?
OBJECTIVE: To investigate risk factors for cerebral palsy in relation to gestational age. DESIGN: Three case-control studies within a geographically defined cohort. SETTING: The former Oxfordshire Health Authority. PARTICIPANTS: A total of 235 singleton children with cerebral palsy not of postnatal origin, born between 1984 and 1993, identified from the Oxford Register of Early Childhood Impairment; 646 controls matched for gestation in three bands: <or=32 weeks; 33-36 weeks; >or=37 weeks. RESULTS: Markers of intrapartum hypoxia and infection were associated with an increased risk of cerebral palsy in term and preterm infants. The odds ratio (OR) for hypoxia was 12.2 (95% confidence interval 1.2 to 119) at <or=32 weeks and 146 (7.4 to 3651) at >or=37 weeks. Corresponding ORs for neonatal sepsis were 3.1 (1.8 to 5.4) and 10.6 (2.1 to 51.9). In contrast, pre-eclampsia carried an increased risk of cerebral palsy at >or=37 weeks (OR 5.1 (2.2 to 12.0)) but a decreased risk at <or=32 weeks (OR 0.4 (0.2 to 1.0)). However, all infants <or=32 weeks with maternal pre-eclampsia were delivered electively, and their risk of cerebral palsy was no lower than that of other electively delivered <or=32 week infants (OR 0.9 (0.3 to 2.7)). Nearly 60% of <or=32 week controls were delivered after spontaneous preterm labour, itself an abnormal event. CONCLUSION: Inflammatory processes, including pre-eclampsia, are important in the aetiology of cerebral palsy. The apparent reduced risk of cerebral palsy associated with pre-eclampsia in very preterm infants is driven by the characteristics of the gestation matched control group. Use of the term "protective" in this context should be abandoned.
[Greenwood, C., Yudkin, P., Sellers, S., Impey, L. & Doyle, P. (2005). Why is there a modifying effect of gestational age on risk factors for cerebral palsy? Archives of Disease in Childhood. Fetal and Neonatal Edition, 90(2), F141-6.]
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3. Chorioamnionitis an cerebral palsy in term and near-term infants
ONTEXT: Half of all cases of cerebral palsy (CP) occur in term infants, for whom risk factors have not been clearly defined. Recent studies suggest a possible role of chorioamnionitis. OBJECTIVE: To determine whether clinical chorioamnionitis increases the risk of CP in term and near-term infants. DESIGN, SETTING, AND PATIENTS: Case-control study nested within a cohort of 231 582 singleton infants born at 36 or more weeks' gestation between January 1, 1991, and December 31, 1998, in the Kaiser Permanente Medical Care Program, a managed care organization providing care for more than 3 million residents of northern California. Case patients were identified from electronic records and confirmed by chart review by a child neurologist, and comprised all children with moderate to severe spastic or dyskinetic CP not due to postnatal brain injury or developmental abnormalities (n = 109). Controls (n = 218) were randomly selected from the study population. MAIN OUTCOME MEASURE: Association between clinical chorioamnionitis and increased risk of CP in term and near-term infants. RESULTS: Most CP cases had hemiparesis (40%) or quadriparesis (38%); 87% had been diagnosed by a neurologist and 83% had undergone neuroimaging. Chorioamnionitis, considered present if a treating physician made a diagnosis of chorioamnionitis or endometritis clinically, was noted in 14% of cases and 4% of controls (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.5-10.1; P =.001). Independent risk factors identified in multiple logistic regression included chorioamnionitis (OR, 4.1; 95% CI, 1.6-10.1), intrauterine growth restriction (OR, 4.0; 95% CI, 1.3-12.0), maternal black ethnicity (OR, 3.6; 95% CI, 1.4-9.3), maternal age older than 25 years (OR, 2.6; 95% CI, 1.3-5.2), and nulliparity (OR, 1.8; 95% CI, 1.0-3.0). The population-attributable fraction of chorioamnionitis for CP is 11%. CONCLUSION: Our data suggest that chorioamnionitis is an independent risk factor for CP among term and near-term infants.
[Wu, Y. W., Escobar, G. J., Grether, J. K., Croen, L. A., Greene, J. D. & Newman, T. B. (2003). Chorioamnionitis an cerebral palsy in term and near-term infants. JAMA: The Journal of the America Medical Association, 290(20), 2677-84.]
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4. Causes of cerebral palsy
Risk factors for cerebral palsy in term or near-term children include intrauterine exposure to infection or inflammation and disorders of coagulation. Interruption of the oxygen supply during birth contributes approximately 6% of spastic cerebral palsy. Low Apgar score, need for resuscitation, and seizures are nonspecific indicators of neonatal illness that do not identify cause. Although not entirely consistent, current evidence suggests that in utero infection may predispose very preterm and more mature infants to cerebral palsy and that antenatal exposure to steroids may be somewhat protective. Recognition of a broader set of causal possibilities encourages hope for new strategies for the prevention of cerebral palsy.
[Nelson, K. B. & Grether, J. K. (1999). Causes of cerebral palsy. Current Opinions in Pediatrics, 11(6), 487-91.]
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5. Risk factors for cerebral palsy
Cerebral palsy is a major cause of crippling in children, but it's etiology is poorly understood. This case control study was done to assess some of the identified risk factors for cerebral palsy, 125 cerebral palsy cases selected from hospital clinic and 125 age and sex matched neighbourhood controls, all aged less than 5 years and residing in Delhi (India) were studied. Information regarding antenatal, natal and postnatal period was collected by mother's interview, and wherever available, from hospital records with the study subjects. Most common type of cerebral palsy was spastic (88%). Quadriplegia was the commonest topographical subtype (86.4%). Birth asphyxia was found to be present in only 25.6% of cases. The commonest risk factor amongst cases was low birth weight (28.8%). The multivariate odds ratios (confidence limits) for the risk factors found to be significantly associated with cerebral palsy were 36.1 (7.76-160) for birth asphyxia, 13.8 (4.95-38.3) for low birth weight, 37.4 (4.47-313) for neonatal convulsion, 23 (4.7-112) for neonatal jaundice, 14.4 (3.69-56.4) for neonatal infection, 24.9 (2.78-223) for instrument assisted delivery and 15.4 (1.57-152) for antepartum hemorrhage. Precipitate labour, caesarean section, twins, toxemia, breech delivery and head injury were not found to be significantly associated with cerebral palsy. Thus birth asphyxia, low birth weight, neonatal convulsions, neonatal jaundice, neonatal infection, instrument assisted delivery and antepartum hemorrhage are significant risk factors for cerebral palsy.
[Suvanand, S., Kapoor, S. K., Reddaiah, V. P., Singh, U. & Sundaram, K. R. (1997). Risk factors for cerebral palsy. Indian Journal of Pediatrics, 64(5), 677-85.]
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6. Risk factors for adverse outcome in preterm infants with periventricular hemorrhagic infarction
OBJECTIVE: Our objective was to identify risk factors that were associated with mortality and adverse neurologic outcome at 18 months of age in preterm infants with periventricular hemorrhagic infarction. METHODS: This was a retrospective cohort study of all preterm infants who were <37 weeks' gestation, had periventricular hemorrhagic infarction, and were admitted between 1995 and 2006. Ultrasound scans were reviewed for grading of germinal matrix hemorrhage, localization and extension of the infarction, and other abnormalities. Several clinical factors were scored. Outcome measures were mortality, cerebral palsy, and Gross Motor Function Classification System level. Odds ratios were calculated by univariate and multivariate logistic regression analyses. RESULTS: Of 54 infants, 16 (30%) died. Twenty-five (66%) of 38 survivors developed cerebral palsy: 21 mild (Gross Motor Function Classification System levels 1 and 2) and 4 moderate to severe (levels 3 and 4). Several perinatal and neonatal risk factors were associated with mortality. After multivariate logistic regression, only use of inotropic drugs and maternal intrauterine infection were predictors of mortality. In survivors, only the most extended form of periventricular hemorrhagic infarction was associated with the development of cerebral palsy but not with severity of cerebral palsy. Cystic periventricular leukomalacia and concurrent grade 3 germinal matrix hemorrhage were associated with more severe cerebral palsy. CONCLUSIONS: In preterm infants with periventricular hemorrhagic infarction, mortality occurred despite optimal treatment and was associated with circulatory failure and maternal intrauterine infection. In survivors, motor development was abnormal in 66%, but functional abilities were good in the majority. Extension and localization of the periventricular hemorrhagic infarction were not related to functional outcome.
[Roze, E., Kerstjens, J. M., Maathuis, C. G., ter Horst, H. J. & Bos, A. F. (2008). Risk factors for adverse outcome in preterm infants with periventricular hemorrhagic infarction. Pediatrics, 122(1), e46-52.]
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7. Sex and the pathogenesis of cerebral palsy
Cerebral palsy (CP) and related developmental disorders are more common in males than in females, but the reasons for this disparity are uncertain. Males born very preterm also appear to be more vulnerable to white matter injury and intraventricular hemorrhage than females. Experimental studies in adult animals and data from adult patients with stroke indicate that sex hormones such as estrogens provide protection against hypoxic-ischemic injury, and the neonatal brain is also influenced by these hormones. However, hormonal influences on the fetus and neonates are substantially different from those on adults. Recent data from neonatal rodents subjected to hypoxia-ischemia also demonstrate differences between males and females. Knockout of the gene for poly (ADP-ribose) polymerase (PARP-1), a major step in the cascade of injury, protected male but not female mouse pups from hypoxic-ischemic injury. Other reports demonstrated major differences between male and female neurons grown separately in cell culture, suggesting that sex differences in the fetal or neonatal period result from intrinsic differences in cell death pathways. This new information indicates that there are important neurobiological differences between males and females with respect to their response to brain injuries. This information is relevant to understanding the pathogenesis of CP as well as to the design of future clinical trials of potential neuroprotective strategies.
[Johnston, M. V. & Hagberg, H. (2007). Sex and the pathogenesis of cerebral palsy. Developmental Medicine and Child Neurology, 49(1), 74-8.]
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8. Does asphyxia cause cerebral palsy?
The incidence of cerebral palsy is 1 per 1,000, whereas the proportion caused by perinatal asphyxia is only 8% to 10%. The purpose of this article is to review the relationship between asphyxia and cerebral palsy. Only a minority of cases, those involving severe pathological fetal academia, are consistently associated with neonatal encephalopathy and an increased risk of cerebral palsy.
[Pschirrer, E. R. & Yeomans, E. R. (2000). Does asphyxia cause cerebral palsy? Seminars in Perinatology, 24(3), 215-20.]
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9. Perinatal risk factors and motor deficiency due to cerebral palsy
Despite improvement in perinatal care, the prevalence of cerebral palsy has not decreased in France, Sweden, the United Kingdom or Australia. Based on a review of recent publications, the course of cerebral palsy can be partially explained by the increase in risk among very low birthweight and very pre-term infants whose survival is now better. Until recently, many publications have supported the hypothesis that asphyxia at birth was the major cause of cerebral palsy. However, these results have been widely questioned; the role of asphyxia remained unclear. In 1993 and 1994, several publications showed that there is a significant relationship between asphyxia and cerebral palsy, but that the role of asphyxia was overestimated in the past. The role of maternal and antenatal risk factors must also be taken into account. The prevention of cerebral palsy must be undertaken very early in pregnancy.
[Rumeau-Rouquette, C. & Breart. (1996). Perinatal risk factors and motor deficiency due to cerebral palsy [French]. Journal de Gynecologie, Obstetrique et Biologie de la Reproduction (Paris), 25(2), 119-23.]
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10. Asphyxia-related risk factors and their timing in spastic cerebral palsy
OBJECTIVE: To investigate the association of asphyxia-related conditions (reducing blood flow or blood oxygen levels in the fetus) with spastic cerebral palsy (CP) considering different gestational age groups and the timing of risk. DESIGN: Population-based case-control study. SETTING: Danish Cerebral Palsy Register in eastern Denmark and Danish Medical Birth Register. POPULATION OR SAMPLE: 271 singletons with spastic CP and 217 singleton controls, frequency matched by gestational age group, born 1982-1990 in eastern Denmark. METHODS: Data were abstracted from medical records, and a priori asphyxia-related conditions and other risk factors were selected for analysis. Each factor was classified according to the time at which it was likely to first be present. MAIN OUTCOME MEASURES: Spastic CP. RESULTS: Placental and cord complications accounted for the majority of asphyxia conditions. In multivariate analysis, placental infarction was significantly associated with a four-fold increased risk for spastic quadriplegia and cord around the neck was significantly associated with a three-fold increased risk for spastic CP overall. The combination of placental infarction and being small for gestational age (SGA) afforded an especially high risk for spastic quadriplegia. Placental and cord complications were present in 21% of cases and 12% of controls. CONCLUSIONS: The risk for spastic quadriplegia from placental infarction may be linked in some cases with abnormal fetal growth (17% of all children with spastic quadriplegia and 3% of control children both had an infarction and were SGA) — suggesting an aetiologic pathway that encompasses both factors. The risk for spastic CP from cord around the neck is not accounted for by other prepartum or intrapartum factors we examined. Considering the relative timing of risk factors provides a useful framework for studies of CP aetiology.
[Nielsen, L. F., Schendel, D., Grove, J., Hvidtjorn, D., Jacobsson, B., Josiassen, T., Vestergaard, M., Uldall, P. & Thorsen, P. (2008). Asphyxia-related risk factors and their timing in spastic cerebral palsy. BJOG: An International Journal of Obstetrics and Gynaecology, 115(12), 1518-28.]
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11. Antenatal risk factors for cerebral palsy
Two of every 1000 live-born children develop cerebral palsy (CP). The aetiology of CP is often unclear and because CP is a symptom complex rather than a disease, clinically defined at 4-5 years of age, it is not surprising that there are considerable problems associated with epidemiological studies of its aetiology. The only reason for the CP concept is that it emanates from an insult to a growing, developing brain and a dynamic clinical picture from static pathology. Evidence suggests that 70-80% of CP cases are due to prenatal factors and that birth asphyxia plays a relatively minor role (<10%). Some antenatal risk factors are repeatedly observed to be related to CP: low gestational age, male gender, multiple gestation, intrauterine viral infections and maternal thyroid abnormalities. Recently, intrauterine infection/inflammation with a maternal response (consisting of chorioamnionitis) and a fetal inflammatory response (consisting of funicitis or elevated interleukin-6 in fetal plasma) has been found to be related to white matter injury and CP. Some risk factors are associated with CP at all gestational ages whereas others mostly affect term or preterm infants, e.g. intrauterine growth restriction seems to be a risk factor in term infants. There also seems to be an association between autoimmune and coagulation disorders and CP.
[Jacobsson, B. & Hagberg, G. (2004). Antenatal risk factors for cerebral palsy. Best Practice & Research: Clinical Obstetrics & Gynaecology, 18(3), 425-36.]
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12. Maternal infection and cerebral palsy in infants of normal birth weight
CONTEXT: Exposure to maternal or placental infection is related to risk of preterm birth and, in premature infants, of brain lesions predictive of cerebral palsy (CP). Few studies have investigated whether maternal infection is associated with risk of CP in children of normal birth weight. OBJECTIVE: To investigate maternal infection during the admission for delivery as a possible risk factor for CP in infants born weighing 2500 g or more. DESIGN: Population-based case-control study. SETTING: All hospitals in 4 northern California counties, 1983 through 1985. PARTICIPANTS: A total of 46 children with disabling spastic CP who had no recognized prenatal brain lesions and 378 randomly selected control children weighing 2500 g or more at birth and surviving to age 3 years. MAIN OUTCOME MEASURES: Disabling spastic CP and signs of neonatal morbidity. RESULTS: Maternal fever exceeding 38 degrees C in labor was associated with increased risk of unexplained CP (odds ratio [OR], 9.3; 95% confidence interval [CI], 2.7-31.0), as was a clinical diagnosis of chorioamnionitis. One or more indicators of maternal infection were present in 2.9% of control children, 22% of children with CP (OR, 9.3; 95% CI, 3.7-23.0), and 37% of those with the spastic quadriplegic subtype of CP (OR, 19.0; 95% CI, 6.5-56.0). Newborns exposed to maternal infection, both cases and controls, had 5-minute Apgar scores below 6 more often than those unexposed. Among children with CP, those born to infected women were more often hypotensive, needed intubation, had neonatal seizures, and received a clinical diagnosis of hypoxic-ischemic encephalopathy. CONCLUSION: Intrauterine exposure to maternal infection was associated with a marked increase in risk of CP in infants of normal birth weight. Maternal infection was also linked with low Apgar scores, other evidence of hypotension [corrected] and need for resuscitation, and neonatal seizures-signs commonly attributed to birth asphyxia.
[Grether, J. K. & Nelson, K. B. (1997). Maternal infection and cerebral palsy in infants of normal birth weight. JAMA: The Journal of the America Medical Association, 278(3), 207-11.]
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