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sounding board

Can We Prevent Cerebral Palsy?

Karin B. Nelson, M.D. Improvements in obstetrical and neonatal care have led to marked declines in rates of injury and death in mothers and infants. The risk of neurologic disability in infants and children has been reduced through such interventions as the administration of folate to women who are pregnant, immunizations, avoidance of exposure to certain toxic agents, and the proper use of helmets and car seats for infants and older children. Advances in medicine have led to an expectation that we should be able to prevent cerebral palsy, which is the most common form of chronic motor disability in children. But what is the evidence that we, in developed countries, can do so? Cerebral palsy is a group of conditions that are characterized by chronic disorders of movement or posture; it is cerebral in origin, arises early in life, and is not the result of progressive disease. The condition is frequently accompanied by seizure disorders, sensory impairment, and cognitive limitation. Cerebral palsy is heterogeneous in both its manifestations and its causation. In this article I briefly review the evidence that supports or fails to support the hypothesis that cerebral palsy can be prevented by means now available, with attention to the quality of this evidence.1 An important indicator of success in the prevention of cerebral palsy would be a decrease in its prevalence. The only population-based study conducted in the United States to track trends in the occurence of cerebral palsy concluded that contrary to initial expectations with improvements in perinatal medicine including the use of fetal monitoring and cesarean section the prevalence of cerebral palsy has not decreased.2 The results of studies conducted in other countries are in agreement with that conclusion, except for one recent study of infants of low birth weight.3 For overall births and within major subgroups defined according to birth weight and gestational age, industrialized nations have not yet succeeded in reducing the frequency of cerebral palsy. Although, a recent study indicates that injections of progesterone can reduce the risk of recurrent preterm delivery,4 the prevention of prematurity, which is an important factor associated with the development of cerebral palsy, has not yet been shown to be feasible. In the United States, the rates of preterm births (at less than 37 weeks of gestation) and very preterm births (at less than 32 weeks) have remained virtually unchanged since 1990.5

some probable successes

It is likely that some success has been achieved in preventing cerebral palsy when its development is related to specific antecedent factors, although there are no documented studies of high medical quality to establish this. Some prevention is afforded in the mother by avoidance of exposure to methyl mercury, immunization against rubella, and iodine supplementation in areas where cretinism is endemic, and in the child by control of hyperbilirubinemia, avoidance of exposure to benzyl alcohol, and immunization against measles for the prevention of acquired motor and other disabilities. However, these causes of cerebral palsy are uncommon in developed countries, where their elimination has not reduced the incidence of this disorder. The incidence of familial forms of cerebral palsy, which have been found chiefly in inbred communities, might be decreased by the avoidance of consanguineous unions. Although rigorous evidence is lacking, Stanley et al.6 consider that both screening for toxoplasmosis in areas where the infection is endemic and the delivery of very preterm infants in a tertiary center can offer some protection against the development of cerebral palsy. The optimal data in support of various preventive strategies would come from randomized, controlled clinical trials, yet such data are lacking for interventions that might reduce the rate of cerebral palsy. According to systematic reviews of randomized clinical trials,7 current evidence fails to support a reduction in the incidence of cerebral palsy in premature

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infants through the administration to pregnant women of antenatal steroids, magnesium sulfate, and thyroid hormone (for those who are hypothyroid). Current evidence also fails to support a reduction in this incidence through the administration to premature infants of surfactant, vitamin K, and phenobarbital or through interventions to treat the twin-to-twin transfusion syndrome. Clinical trials of some of these interventions are currently under way. But what about term infants? Although term infants are at relatively low absolute risk, term births constitute the large majority of all births, as well as approximately half of all births of children with cerebral palsy.

interventions based on potential causes

Although the frequency of cerebral palsy has not declined, and although there are relatively few specific, modifiable risk factors for cerebral palsy, attention to some factors that are associated with an increased risk of cerebral palsy might help to prevent its development.
perinatal stroke

to fetal distress associated with placental vasculopathy no study has yet investigated whether surgical delivery increases or decreases the risk of stroke in the infant. In the extensive literature on thromboembolic disorders in pregnancy, there has been little discussion of the effect of these disorders or of their treatment on the long-term outcome for the infant. Trials of preventive therapies that target fetal or infant stroke would be challenging, given the relatively low incidence of the outcome, the difficulty of identifying perinatal stroke in infants who are asymptomatic in the neonatal period, and the absence of evidence that anticoagulant therapy provided to pregnant women who are at risk for thromboembolic disease can lessen the risk of stroke in the infant.
intrauterine exposure to infection

The increased use of neuroimaging procedures in the evaluation of symptomatic neonates has led to the identification of arterial ischemic stroke before birth or within the first month after birth in approximately 1 in 4000 term infants.8 In other infants, the occurrence of perinatal stroke has been recognized retrospectively, when neuroimaging was performed after the earliest months of life because of the development of hemiparesis or seizure.9 In many, but not all, neonates who have strokes, cerebral palsy later develops. No estimate is available of the proportion of cases that result from early stroke, but stroke is probably the most common cause of hemiparetic cerebral palsy and of some proportion of cases of spastic quadriplegic cerebral palsy. Among the factors that contribute to the vulnerability of the fetus or infant to stroke and to the subsequent development of cerebral palsy are inherited or acquired thrombophilia in the mother or infant, placental thrombosis, infection, and the use of intravascular catheters.10 Surgery is, in general, a risk factor for thrombosis. The risk of stroke in the mother increases by a factor of three or four with cesarean delivery.11,12 Although a relatively high proportion of infants with perinatal stroke were delivered by cesarean section probably a response

A diagnosis of chorioamnionitis (placental infection) during pregnancy is associated with an increased risk of cerebral palsy in infants who weigh 2500 g or more at birth.13,14 In very premature infants, the association of infection with cerebral palsy has been less consistent and, when present, less strong.14,15 Intrauterine exposure to infections other than toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (the so-called TORCH) infections, has been estimated13 to result in about 12 percent of cases of otherwise unexplained spastic cerebral palsy in nonmalformed singleton infants of normal birth weight. Clinical definitions of chorioamnionitis are imprecise, and for the same specimen, there is often disagreement between the histologic indicators and the clinical diagnosis.16 Randomized trials of the use of antibiotics during pregnancy have been designed to investigate the outcomes of pregnancy or birth and have not been large enough or followed children long enough to examine whether such therapy can reduce the risk of cerebral palsy. Because of the possibility of harmful consequences of the widespread administration of antibiotics during pregnancy,16 an evaluation of the safety and efficacy of their use in pregnancy would require randomized clinical trials that included the evaluation of longterm neurologic outcomes.
multiple pregnancy

The incidence of cerebral palsy is higher among twins and triplets than among singletons. Studies have found that twins make up about 10 percent of total cases, and one study found that 4.5 percent

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were among infants of normal birth weight.17 The increase in risk associated with multiple gestations is chiefly related to the higher rate of premature delivery in such pregnancies and to the risk of adverse neurologic outcomes associated with the intrauterine death of one twin or one triplet. The death of one twin along with an adverse neurologic outcome in the surviving infant often occurs in the twin-to-twin transfusion syndrome. Randomized studies that are under way to compare approaches for the management of the twin-to-twin transfusion syndrome (e.g., amnioreduction, laser coagulation, and septostomy) are not designed to investigate long-term neurologic outcomes. There is no good evidence that any known intervention in a multiple pregnancy can reduce the risk of cerebral palsy in the surviving infant after the death of another fetus.
birth asphyxia

The presence of birth asphyxia is commonly inferred on the basis of clinical findings such as low Apgar scores, acidosis, and neonatal seizure, although these findings are not specific to asphyxia. For example, intrauterine exposure to infection and maternal fever is associated with low Apgar scores, and markers of infection are common antecedents of low Apgar scores.16 Neuroimaging may provide information on the timing of an insult and help to characterize any resultant abnormality, but in most instances neuroimaging does not help to identify the cause of the insult. Different pathways to harm may require different strategies for treatment or prevention. Complications that can cause an acute interruption in the delivery of oxygen to the fetus, such as placental abruption, a tight or prolapsed nuchal cord, maternal shock, or a large placental infarct, were identified in the birth records of children of normal birth weight who had cerebral palsy and a control group of children in a large, populationbased study.18 Of eight complications examined in the study, only a tight nuchal cord was more common in children with cerebral palsy than in children in the control group, and it was associated with spastic quadriplegic cerebral palsy and often accompanied by dyskinesia, but was not associated with hemiplegic or diplegic cerebral palsy. About 6 percent of the cases of otherwise unexplained spastic cerebral palsy were attributable to a potentially asphyxiating complication during birth.19 The chief indicator of possible asphyxial events during labor that is widely used is the fetal heart rate,

evaluated either by auscultation or by electronic fetal monitoring. Electronic fetal monitoring was designed to provide an early warning that permits caregivers to recognize the onset of asphyxial injury to the fetus. Does its use prevent cerebral palsy? Randomized, controlled clinical trials of the efficacy of electronic fetal monitoring during labor, as compared with auscultation, have been systematically reviewed.18 In nine studies of satisfactory quality, a total of 18,561 women with high-risk or low-risk pregnancies underwent delivery at seven clinical centers in the United States, Europe, and Australia. In the largest of the studies, conducted in Dublin, Ireland, a nonsignificantly higher rate of cerebral palsy was observed among children born to the group of women randomly assigned to the use of electronic fetal monitoring.20 In a study conducted in the United States,21 there was a significantly higher rate of cerebral palsy among premature infants whose births had been monitored electronically. Meta-analyses of randomized studies of electronic fetal monitoring during labor18 did not show a decrease in cerebral palsy with its use or less frequent occurrence of low Apgar scores, admission to a neonatal intensive care unit, or death. Electronic monitoring was associated with an increase of 40 percent in cesarean deliveries. In a casecontrol study that examined the association of abnormalities revealed by electronic fetal monitoring during labor with the later development of cerebral palsy,22 even though abnormalities were more frequent during birth among children who later received a diagnosis of cerebral palsy, three quarters of these children had no such abnormalities. The false positive rate was 99.8 percent. Among infants with fetal abnormalities on electronic monitoring, the rate of cerebral palsy in those delivered surgically was not lower than the rate in those delivered vaginally. When adverse events occur during delivery, they can be sudden, unpredictable, and catastrophic. Interventions that are aimed at preventing cerebral palsy as a consequence of adverse events during labor, including interventions based on findings on electronic fetal monitoring, have not been shown to be capable of achieving this goal. Reviewing pooled data from nine industrialized countries, Clark and Hankins concluded that despite a 5-fold increase in the rate of cesarean section based, in part, on the electronically derived diagnosis of fetal distress, cerebral palsy prevalence has remained stable23 (Fig. 1).

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Cases of Cerebral Palsy (per 1000 live births)

Cerebral palsy in developed countries 10 8 6 4 2 0

Cesarean sections in the United States

20 15 10 5 0

1970

1975

1980

1985

1990

1995

2000

Figure 1. The Prevalence of Cerebral Palsy and the Rate of Cesarean Delivery in Developed Countries. Pooled data are from Australia, Canada, Denmark, England, Ireland, Norway, Scotland, Sweden, and the United States. Adapted from Clark and Hankins,23 with the permission of the publisher.

Cesarean Sections (% of all deliveries)

25

from those used for very premature infants, but for both groups large base populations will be needed to ensure sufficient numbers of subjects. Although cerebral palsy, especially in cases related to birth asphyxia, is not known to be preventable by means now available, lawsuits brought against obstetricians for not preventing its development are a major contributor to the high cost of malpractice insurance and the disruptive consequences of the climate of litigation.26 The courts often permit unsupported expert opinion to supersede the consistent evidence of randomized, clinical trials, meta-analyses, casecontrol studies, and population-based time trends. Can we now prevent cerebral palsy? Apart from our ability to avoid exposure to a few associated risk factors in a small minority of cases, there is little evidence at present that we can.
From the Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Md.
1. Harris RP, Helfand M, Woolf SH, et al. Current methods of the

Although it seems intuitively reasonable that a speedy delivery might occasionally rescue an infant from potential harm, there is no evidence of good quality that surgical delivery can prevent cerebral palsy. Cesarean section during active labor, which may be performed on the basis of intrapartum electronic monitoring, has been associated with an increased risk of hemorrhage, infection, thromboembolic events, and air or amniotic-fluid embolization in the mother.24,25 Interventions that have been assumed to be capable of saving an occasional infant may, if undertaken on the basis of clinical observations such as findings on electronic monitoring, increase the risks to mothers; as Clark and Hankins note, operative intervention based on electronic fetal monitoring has probably done more harm than good.23

implications
The known causes of cerebral palsy account for only a minority of the total cases. Even for most of those cases, however, evidence of the preventability of the disorder is lacking. For future research that may make cerebral palsy preventable, we need new hypotheses, animal models that will take into account the complexity often encountered clinically, and careful clinical research. Trials of preventive interventions will require strategies for term infants that are somewhat different

U.S. Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:Suppl:21-35. 2. Winter S, Autry A, Boyle C, Yeargin-Allsopp M. Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 2002;110:1220-5. 3. Surman G, Newdick H, Johnson A. Cerebral palsy rates among low-birthweight infants fell in the 1990s. Dev Med Child Neurol 2003;45:456-62. 4. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-85. 5. MacDorman MF, Minino AM, Strobino DM, Guyer B. Annual summary of vital statistics 2001. Pediatrics 2002;110:1037-52. 6. Stanley FJ, Blair E, Alberman E. Cerebral palsies: epidemiology and causal pathways. Clinics in Developmental Medicine no. 151. London: Mac Keith Press, 2000. 7. The Cochrane Collaboration home page. (Accessed August 28, 2003, at http://www.cochrane.org.) 8. Lynch JK, Nelson KB. Epidemiology of perinatal stroke. Curr Opin Pediatr 2001;13:499-505. 9. Golomb MR, MacGregor DL, Domi T, et al. Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. Ann Neurol 2001;50:163-8. 10. Andrew ME, Monagle P, deVeber G, Chan AKC. Thromboembolic disease and antithrombotic therapy in newborns. Hematology (Am Soc Hematol Educ Program) 2001:358-74. 11. Lanska DJ, Kryscio RJ. Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis. Stroke 2000;31: 1274-82. 12. Ros HS, Lichtenstein P, Bellocco R, Petersson G, Cnattingius S. Pulmonary embolism and stroke in relation to pregnancy: how can high-risk women be identified? Am J Obstet Gynecol 2002;186:198203. 13. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997;278:207-11. [Erratum, JAMA 1998;279:118.] 14. Walstab J, Bell R, Reddihough D, Brennecke S, Bessell C, Beischer N. Antenatal and intrapartum antecedents of cerebral palsy: a case-control study. Aust N Z J Obstet Gynaecol 2002;42:138-46. 15. Grether JK, Nelson KB, Walsh E, Willoughby RE, Redline RW.

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Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med 2003;157:26-32. 16. Willoughby RE Jr, Nelson KB. Chorioamnionitis and brain injury. Clin Perinatol 2002;29:603-21. 17. Petterson B, Nelson KB, Watson L, Stanley F. Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 1993;307:1239-43. 18. Thacker SB, Stroup D, Chang M. Continuous electronic heart rate monitoring for fetal assessment during labor. Cochrane Database Syst Rev 2001;2:CD000063. 19. Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol 1998;179:507-13. 20. Grant A, OBrien N, Joy MT, Hennessy E, MacDonald D. Cerebral palsy among children born during the Dublin randomised trial of intrapartum monitoring. Lancet 1989;2:1233-6. 21. Shy KK, Luthy DA, Bennett FC, et al. Effects of electronic fetalheart-rate monitoring, as compared with periodic auscultation, on

the neurologic development of premature infants. N Engl J Med 1990;322:588-93. 22. Nelson KB, Dambrosia JM, Ting TY, Grether JK. Uncertain value of electronic fetal monitoring in predicting cerebral palsy. N Engl J Med 1996;334:613-8. 23. Clark SL, Hankins GD. Temporal and demographic trends in cerebral palsy fact and fiction. Am J Obstet Gynecol 2003;188: 628-33. 24. Lilford RJ, van Coeverden de Groot HA, Moore PJ, Bingham P. The relative risks of caesarean section (intrapartum and elective) and vaginal delivery: a detailed analysis to exclude the effects of medical disorders and other acute pre-existing physiological disturbances. Br J Obstet Gynaecol 1990;97:883-92. 25. Jackson N, Paterson-Brown S. Physical sequelae of caesarean section. Best Pract Res Clin Obstet Gynaecol 2001;15:49-61. 26. Mello MM, Studdert DM, Brennan TA. The new medical malpractice crisis. N Engl J Med 2003;348:2281-4.
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