- Email: [email protected]
conditions associated with cerebral palsy
Other Factors/Conditions Associated With Cerebral Palsy Susan M. Ramin and Larry C. Gilstrap, III
The cause for most cases of cerebral palsy is unknown. There are however, risk factors that have been associated with this chronic neuromuscular disease. The objective of this article is to review the maternal and fetal conditions (other than asphyxia and infection) strongly associated with increased rate of cerebral palsy. What remains to be elucidated is whether or not these associations are causative.
Copyright 9 2000 by W.B. Saunders Company erebral Palsy (CP) is a nonprogressive, chronic, neuromuscular disease, which is present early in life, 1,2 As previously alluded to, the cause in the vast majority of cases of CP is unknown. Although many cases of CP are attributed to "perinatal asphyxia," especially by the legal profession and some expert witnesses? it is seldom attributable to such. <5 Both perinatal asphyxia and infection as causes of CP are discussed elsewhere in this issue. Many of the factors and conditions associated with CP have b e e n extensively reviewed by Nelson and Ellenberg, 1,4,6-s F r e e m a n and Nelson, 5 and by Torfs and colleagues2 Some of these associations are summarized in Table 1.
C
Maternal Conditions
Using data from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, Nelson and Ellenberg v reported a significant increase in the rate of CP in newborns (total group-all birthweights) of mothers with mental retardation (relative risk [RR] 6.5; P < .01), major seizures (RR 6.7; P < .01), hyperthyroidism (RR 4.9; P < .01), and either unusual (RR 1.7; P < .05) or long (RR 1.9; P < .05) menstrual cycles. This increased rate of CP was still significant for the birthweight group of greater than From the Division of Maternal-Fetal Medicine and the Department of Obstetrics, Gynecology, and Reproductive Sciences, The University of Texas-Houston Medical School, Houston, TX. Address reprint requests to Susan M. Ramin, MD, Associate Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, The University of Texas-Houston Medical School, 6431 Fannin, Suite 3.604, Houston, TX 77030; e-maik [email protected], trn,c.edu. Copyright 9 2000 by W.B. Sau,nders Company 0146-0005/00/2403-0002~10. 00/0 doi: 1O,1053/sper. 2000. 7052
196
2,500 grams. For the total birthweight group, a history of a prior sibling with m o t o r or sensory deficits or of mental retardation was also a significant risk factor for CP. Maternal factors not associated with an increased rate of CP included either early or late registration for prenatal care, maternal education, marital status, parity, intervals between pregnancy, smoking history, or history of diabetes. Using multivariate analysis in a follow-up study from this database, Nelson and Ellenberg, s r e p o r t e d an association of p r e p r e g n a n c y maternal factors such as mental retardation, motor deficit in a sibling, seizures, hyperthyroidism, and cerebral palsy. For newborns weighing 2,500 grams or more, the 3 prepregnancy predictors for CP included maternal mental retardation, hyperthyroidism, and seizures. Maternal factors present during pregnancy that were associated with an increased rate of CP included 5 grams or more of urinary protein per 24 hours and third trimester bleeding, These investigators very aptly pointed out that n o n e of the factors studied accounted for a "large share of the outcome." Importantly, when these investigators looked at all stages "from before pregnancy t h r o u g h the nursery period," almost two-thirds of the cases of CP did not occur in the 5% of newborns with the highest risk. In other words, these risk factors were not good predictors o f outcome. In a smaller cohort o f patients from the California Child Health and Development Studies, Toffs and associates 9 r e p o r t e d a significant association (via univariate analysis) between CP and certain maternal risk factors to include long menstrual cycles, polyhydramnios, and either short or long pregnancy intervals. Thyroid medication during pregnancy was not significantly associated with CP in this study (RR 1.8; 95% confidence interval [CI] 0.2 to 12.7). W h e n mul-
Seminars in Perinatology, Vol 24, No 3 (June), 2000: pp 196-199
Other Factors Associated With Cerebral Palsy
TaMe 1. Associated Factors/Conditions for Cerebral Palsy Maternal conditions--mental retardation, albuminnria, menstrual cycles, interval between pregnancy Major/minor congenital anomalies Prematurity/low birthweight Muhifetal gestations Abnormal presentation--breech, face, or transverse Placental abnormalities Nuchal cords Data from Nelson and Ellenberg 1,4,~8and Toffs et al.9
tivariate analysis was applied to these data, abn o r m a l p r e g n a n c y intervals a n d long menstrual cycles ( > 3 6 days) r e m a i n e d as significant maternal risk factors for CP. Nelson 3 has reviewed some of the literature regarding a possible association of CP a n d fetal neurological d a m a g e with some of the recently described coagulation disorders such as factor V Leiden mutation and the antiphospholipid antibody syndrome. It would seem reasonable to postulate an association of CP with placental thrombosis or fetal strokes secondary to emboli f r o m these disorders as well as o t h e r genetic thrombophilias such as antithrombin-III, Protein C, and Protein S deficiencies. Further research is obviously n e e d e d in this area.
Congenital Malformations Nelson and Ellenberg 7 r e p o r t e d a relative risk of 3.8 (P < .01) f o r CP when m a j o r congenital malformations (excluding the central nervous system) were p r e s e n t in the newborn. T h e RR for this association was 3.9 for newborns 2,500 grams or greater. These malformations were heterogeneous. In the review by Toffs and associates, 9 b o t h severe (RR 15.6; 95% CI 8.1 to 30.0) a n d nonsevere birth defects (RR 6.1; 95% CI 3.1 to 11.8) were associated with CP. O f the total 41 children with CP in this cohort, almost three-fourths h a d either a severe (41%) or nonsevere (32%) birth defect. These defects were also h e t e r o g e n e o u s .
Prematurity/Low Birthweight Prematurity or low birthweight is o n e of the most significant risk factors for the d e v e l o p m e n t of CP. For example, in a review of 11 studies f r o m 1985 t h r o u g h 1990, Rosen a n d Dickinson ~~
197
r e p o r t e d a CP rate of 15 per 1,000 for low birthweight infants (<2,500 grams) and a CP rate of 13 to 90 per 1,000 live births for newborns weighing 500 to 1,500 grams at birth. Approximately one-third of all cases of CP occurred in low birthweight infants (36% composite rate for the 11 published reports). These investigators estimated that the risk of "intrapartum-attributed" CP was approximately 1 in 2,000 live births. In the univariate analysis of the Collaborative Perinatal Project, Nelson a n d Ellenberg 7 rep o r t e d a RR of CP of 4.9 for birthweight <2,500 g and 13.7 for birthweight <2,000 g. In the review by Torfs and colleagues, 9 the RR of CP was 4.2 for birthweight <2,000 g. Cummins a n d colleagues 1~ r e p o r t e d that newborns with birthweight <1,500 g were a " h u n d r e d times" m o r e likely to have CP than newborns weighing 3,000 to 3,500 g. T h e incidence of CP in the p r e m a t u r e or low birthweight infant varies somewhat d e p e n d i n g on the subsets of gestational age and weight studied. In a review of 381 infants (birthweight 600 to 1,250 g) who h a d neurological examinations at 36 months, Allan a n d colleagues 12 rep o r t e d a 9.5% rate of CP. In a study on the epidemiology o f CP in England and Scotland in 1984 to 1989, the prevalence of CP was 1.1 p e r 1,000 survivors with birthweights ->2,500 g comp a r e d with 78.1 p e r 1,000 for survivors weighing
<1,000 g.13 T h e r e is some controversy regarding the impact of i m p r o v e d survival of the p r e m a t u r e infant on the CP rate. For example, T o p p a n d colleagues 1~ r e p o r t e d a decrease in early neonatal deaths (282 to 239 per 1,000; P < .05) for p r e t e r m infants less than 31 weeks o v e r 2 time periods. Over the same time f r a m e there was an increase in CP in infants less than 31 weeks (85 to 123 p e r 1,000; P < .05). In contrast, Emsley and colleagues 15 r e p o r t e d no significant change in the CP rate (21% versus 18%) in survivors (23 to 25 weeks gestational age) c o m p a r i n g 2 time periods, 1984 to 1989 a n d 1990 to 1994. T h e rate of survival did increase f r o m 27% to 42%. In the investigators' opinion, there are too m a n y variables a m o n g the various published studies to date (especially considering the differences in birthweights analyzed) to implicate an increase in survival in the very p r e m a t u r e infant as causative for the increase in CP as r e p o r t e d in some of these studies.
198
Ramin and Gilstrap
Multifetal Gestations Multifetal gestation appears to be a significant risk factor for CP. For example, G r e t h e r and colleagues, a6 in a study of CP and twinning, rep o r t e d that CP was 12 times m o r e likely in twin pregnancies than singleton pregnancies. T h e rate was 12 p e r 1,000 twin pregnancies versus 1.1 p e r 1,000 singletons in their study population. Approximately 1 in 5 cases o f CP in infants <1,500 g at birth occurred in twins. Although m o r e twins h a d low birthweight, the rate of CP in twins of n o r m a l birthweight was still significantly higher than singletons. A n o t h e r important finding in their study was that the rate of CP in unlike-sex pairs versus like-sex pairs was similar. These data would suggest that there may also be an increase in CP in dizygotic twins as well as monozygotic twins. T h e rate of CP is even higher as the n u m b e r of fetuses increases. Petterson a n d colleagues av reviewed the prevalence o f CP in twins and triplets in Western Australia and r e p o r t e d a CP rate of 28 per 1,000 survivors in triplets, 7.3 in twins, a n d 1.6 in singletons. These investigators concluded that twin pregnancies resulted in CP 8 times m o r e often, and triplets 47 times m o r e often, than in singleton pregnancies. In a study f r o m Japan, Yokoyama and colleagues 18 reviewed 705 twin pairs, 96 sets of triplets, a n d 7 sets of quadruplets. The rate of CP was 0.9%, 3.1%, and 11.1% respectively in this series. In a n o t h e r report, Pharoah and Cooke m r e p o r t e d a prevalence of CP of 2.3 for singletons, 12.6 in twins, and 44.8 in triplets p e r 1000 survivors. Williams and colleagues 2~ studied the effects o f twinning, birthweight, and gestational age on the rate of CP and r e p o r t e d that all 3 were i n d e p e n d e n t risk factors. Minakami and colleagues 2~ studied adverse outcomes in twins conceived by artificial reproductive techniques (n = 136) c o m p a r e d with spontaneously conceived twins (n = 72). These investigators r e p o r t e d a lower frequency of adverse o u t c o m e s (death, CP, and mental retardation) in the f o r m e r g r o u p versus the latter g r o u p (3.3% versus S.3%).
Abnormal Presentation A b n o r m a l presentations such as breech, face, and transverse lie have b e e n r e p o r t e d to be associated with an increase rate o f CP. For exam-
ple, Toffs and colleagues 9 r e p o r t e d a relative risk of 3.8 (95% CI 1.6 to 9.1) of CP if the fetus was in an a b n o r m a l presentation. Nelson and Ellenberg 6 also r e p o r t e d an increased association of b r e e c h presentation and CP. It is important to note that it is the presentation that is the "predictor" o f CP a n d not the m e t h o d o f delivery. s In the r e p o r t of multivariate analysis of risk, Nelson and Ellenberg a r e p o r t e d that one-third of the children with CP a n d b r e e c h presentation h a d a major malformation. In a m o r e recent r e p o r t f r o m D e n m a r k , Krebs and associates 22 reviewed the relation between breech presentation a n d CP. These investigators r e p o r t e d a "borderline significant" risk of CP with b r e e c h presentation c o m p a r e d with vertex (odds ratio [OR] 1.56; 95% CI 0.9 to 2.4). However, there was no difference in the rate of CP between b r e e c h and vertex presentation by m o d e of delivery. These investigators postulated that the higher rate of CP a m o n g t e r m infants with b r e e c h presentation was m o s t likely related to a higher incidence of small for gestational age infants a m o n g the breeches.
Placental Abnormalities T h e most c o m m o n placental abnormalities associated with an increased risk of CP are premature separation of the placenta or a b r n p t i o n and bleeding. T h e relative risk of CP associated with abruption was 3.5 (P < .01) in the Collaborative Perinatal Project database. 7 Interestingly, the RR was even higher for placenta previa (RR 4.9; P < .01). Bleeding f r o m what was diagnosed as a "marginal sinus rupture" h a d a RR of 3.5 (P < .05) for CP. In California Child Health and Dev e l o p m e n t Studies database, the relative risk of CP associated with p r e m a t u r e separation of the placenta was 7.6 (95% CI 2.7 to 21.1). 9 T h e r e has b e e n recent evidence that fetal and newborn neurological d a m a g e and CP may be related to t h r o m b o p h i l i a a n d the resultant thrombosis in the placenta, possibly even involving fetal cerebral vessels, s,23-26 In a recent clinicopathologic study of 84 newborns at autopsy, Kraus and A c h e e n 27 identified 16 cases of "fetal t h r o m b o t i c vasculopathy" (FTV) in the placenta. This is characterized by "clustered fibrotic villi." Importantly, there was evidence of severe brain injury in some of the cases in which the FTV clearly p r e c e d e d the death of the fetus. These investigators suggested that parental eoagulopa-
Other Factors Associated With Cerebral Palsy
thy might be a significant u n d e r r e c o g n i z e d cause of neonatal injury.
Nuchal Cord Nelson and Grether z8 in a study of 46 children with CP from four California counties (1983 through 1985) reported a significant association of tight nuchal cord and spastic cerebral palsy (OR 18; 95% CI 6.2 to 48). This association was with spastic quadriplegia, but not with diplegia or hemiplegia.
Summary CP is relatively u n c o m m o n , occurring in 1 to 2 per 1,000 live births. T h e r e are certain risk factors that are strongly associated with higher rates of CP. Some of these include prematurity, low birthweight, congenital malformations, multifetal gestations, placental abnormalities, and the presence of a tight nuchal cord. W h e t h e r these associations are causative remains to be elucidated.
References 1. Nelson KB, EllenbergJH: Apgar scores as predictors of chronic neurologic disability. Pediatrics 68:36-44, 1981 2. American College of Obstetricians and Gynecologists: Fetal and neonatal neurologic injury. Tech Bull #163, 1992 3. Nelson KB: Medical-legal issues facing neurologists. The neurologically impaired and alleged malpractice. Neurologic Clinics 17:284-293, 1999 4. Nelson KB, Ellenberg JH: The asymptomatic newborn and risk of cerebral palsy. A m J Disease Child 141:13331335, 1987 5. Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240-249, 1988 6. Nelson KB, EllenbergJH: Obstetric complications as risk factors for cerebral palsy or seizure disorder. JAMA 251: 1843-1848, 1984 7. Nelson KB, EllenbergJH: Antecedents of cerebral palsy. I. Univariate analysis of risk. Am J Disease Child 139: 1031-1038, 1985 8. Nelson KB, EllenbergJH: Antecedents of cerebral palsy: Multivariate analysis of risk. N Engl J Med 315:81-86, 1986 9. Toffs CP, van den Berg BJ, Oechsli FW, et al: Prenatal and perinatal factors in the etiology of cerebral palsy. J Pediatr 116:615-619, 1990 10. Rosen MG, Dickinson JC: The incidence of cerebral palsy. A m J Obstet Gynecol 167:417-423, 1992
199
11. Cummins SK, Nelson KB, Grether JK, et al: Cerebral palsy in four Northern California counties, births 1983 through 1985. J Pediatr 123:230-237, 1993 12. Allan WC, Vohr B, Makuch RW, et ah Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricular hemorrhage. Arch Pediatr Adolesc Med 151:580-585, 1997 13. Pharoah PO, Cooke T,Johnson MA, et al: Epidemiology of cerebral palsy in England and Scotland, 1984-9. Arch Dis Child Fetal Neonatal Ed 79:F21-25, 1998 14. Topp M, Uldall P, Langhoff-Roos J: Trend in cerebral palsy birth prevalence in eastern Denmark: Birth-year period 1979-86. Paediatr Perinat Epidemiol 11:451-460, 1997 15. Emsley HC, Wardle SP, Sims DG, et ah Increased survival and deteriorating developmental outcome in 23 to 25 week old gestation infants, 1990-4 compared with 1984-9. Arch Dis Child Fetal Neonatal Ed 78:F99-104, 1998 16. Grether JK, Nelson KB, Cummins SK: Twinning and cerebral palsy: Experience in four northern California counties, births 1983 through 1985. Pediatrics 92:854858, 1993 17. Petterson B, Nelson KB, Watson L, et ah Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 307:1239-1243, 1993 18. Yokoyama Y, Shimizu T, Hayakawa K: Prevalence of cerebral palsy in twins, triplets and quadruplets. I n t J Epidemiol 24:943-948, 1995 19. Pharoah PO, Cooke T: Cerebral palsy and multiple births. Arch Dis Child Fetal Neonatal Ed 75:F174-177, 1996 20. Williams K, Hennessy E, Alberman E: Cerebral palsy: Effects of twinning, birthweight, and gestational age. Arch Dis Child Fetal Neonatal Ed 75:F178-182, 1996 21. Minakami H, Sayama M, Honma Y, et ah Lower risks of adverse outcome in twins conceived by artificial reproductive techniques compared with spontaneously conceived twins. Hum Reprod 13:2005-2008, 1998 22. Krebs L, Topp M, Langhoff-Roos J: The relation of breech presentation at term to cerebral palsy. Br J Obstet Gynecol 106:943-947, 1999 23. de Klerk OL, de Vries TW, Sinnige LGF: An unusual cause of neonatal seizures in a newborn infant. Pediatr 100:E8, 1997 24. Dizon-Townson DS, Meline L, Nelson LM, et ah Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 177:402-405, 1997 25. Nelson KB, Dambrosia JM, Grether JK, et al: Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 44:665-675, 1998 26. Tabbutt S, Griswold WR, Ogino MT, et ah Multiple thromboses in a premature infant associated with maternal phospholipid antibody syndrome. J Perinatol 14:6670, 1994 27. Kraus FT, Acbeen VI: Fetal thrombotic vasculopathy in the placenta: Cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 30:759-769, 1999 28. Nelson KB, Grether JK: Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal weight. A m J Obstet Gynecol 179:507-513, 1998
The cause for most cases of cerebral palsy is unknown. There are however, risk factors that have been associated with this chronic neuromuscular disease. The objective of this article is to review the maternal and fetal conditions (other than asphyxia and infection) strongly associated with increased rate of cerebral palsy. What remains to be elucidated is whether or not these associations are causative.
Copyright 9 2000 by W.B. Saunders Company erebral Palsy (CP) is a nonprogressive, chronic, neuromuscular disease, which is present early in life, 1,2 As previously alluded to, the cause in the vast majority of cases of CP is unknown. Although many cases of CP are attributed to "perinatal asphyxia," especially by the legal profession and some expert witnesses? it is seldom attributable to such. <5 Both perinatal asphyxia and infection as causes of CP are discussed elsewhere in this issue. Many of the factors and conditions associated with CP have b e e n extensively reviewed by Nelson and Ellenberg, 1,4,6-s F r e e m a n and Nelson, 5 and by Torfs and colleagues2 Some of these associations are summarized in Table 1.
C
Maternal Conditions
Using data from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, Nelson and Ellenberg v reported a significant increase in the rate of CP in newborns (total group-all birthweights) of mothers with mental retardation (relative risk [RR] 6.5; P < .01), major seizures (RR 6.7; P < .01), hyperthyroidism (RR 4.9; P < .01), and either unusual (RR 1.7; P < .05) or long (RR 1.9; P < .05) menstrual cycles. This increased rate of CP was still significant for the birthweight group of greater than From the Division of Maternal-Fetal Medicine and the Department of Obstetrics, Gynecology, and Reproductive Sciences, The University of Texas-Houston Medical School, Houston, TX. Address reprint requests to Susan M. Ramin, MD, Associate Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, The University of Texas-Houston Medical School, 6431 Fannin, Suite 3.604, Houston, TX 77030; e-maik [email protected], trn,c.edu. Copyright 9 2000 by W.B. Sau,nders Company 0146-0005/00/2403-0002~10. 00/0 doi: 1O,1053/sper. 2000. 7052
196
2,500 grams. For the total birthweight group, a history of a prior sibling with m o t o r or sensory deficits or of mental retardation was also a significant risk factor for CP. Maternal factors not associated with an increased rate of CP included either early or late registration for prenatal care, maternal education, marital status, parity, intervals between pregnancy, smoking history, or history of diabetes. Using multivariate analysis in a follow-up study from this database, Nelson and Ellenberg, s r e p o r t e d an association of p r e p r e g n a n c y maternal factors such as mental retardation, motor deficit in a sibling, seizures, hyperthyroidism, and cerebral palsy. For newborns weighing 2,500 grams or more, the 3 prepregnancy predictors for CP included maternal mental retardation, hyperthyroidism, and seizures. Maternal factors present during pregnancy that were associated with an increased rate of CP included 5 grams or more of urinary protein per 24 hours and third trimester bleeding, These investigators very aptly pointed out that n o n e of the factors studied accounted for a "large share of the outcome." Importantly, when these investigators looked at all stages "from before pregnancy t h r o u g h the nursery period," almost two-thirds of the cases of CP did not occur in the 5% of newborns with the highest risk. In other words, these risk factors were not good predictors o f outcome. In a smaller cohort o f patients from the California Child Health and Development Studies, Toffs and associates 9 r e p o r t e d a significant association (via univariate analysis) between CP and certain maternal risk factors to include long menstrual cycles, polyhydramnios, and either short or long pregnancy intervals. Thyroid medication during pregnancy was not significantly associated with CP in this study (RR 1.8; 95% confidence interval [CI] 0.2 to 12.7). W h e n mul-
Seminars in Perinatology, Vol 24, No 3 (June), 2000: pp 196-199
Other Factors Associated With Cerebral Palsy
TaMe 1. Associated Factors/Conditions for Cerebral Palsy Maternal conditions--mental retardation, albuminnria, menstrual cycles, interval between pregnancy Major/minor congenital anomalies Prematurity/low birthweight Muhifetal gestations Abnormal presentation--breech, face, or transverse Placental abnormalities Nuchal cords Data from Nelson and Ellenberg 1,4,~8and Toffs et al.9
tivariate analysis was applied to these data, abn o r m a l p r e g n a n c y intervals a n d long menstrual cycles ( > 3 6 days) r e m a i n e d as significant maternal risk factors for CP. Nelson 3 has reviewed some of the literature regarding a possible association of CP a n d fetal neurological d a m a g e with some of the recently described coagulation disorders such as factor V Leiden mutation and the antiphospholipid antibody syndrome. It would seem reasonable to postulate an association of CP with placental thrombosis or fetal strokes secondary to emboli f r o m these disorders as well as o t h e r genetic thrombophilias such as antithrombin-III, Protein C, and Protein S deficiencies. Further research is obviously n e e d e d in this area.
Congenital Malformations Nelson and Ellenberg 7 r e p o r t e d a relative risk of 3.8 (P < .01) f o r CP when m a j o r congenital malformations (excluding the central nervous system) were p r e s e n t in the newborn. T h e RR for this association was 3.9 for newborns 2,500 grams or greater. These malformations were heterogeneous. In the review by Toffs and associates, 9 b o t h severe (RR 15.6; 95% CI 8.1 to 30.0) a n d nonsevere birth defects (RR 6.1; 95% CI 3.1 to 11.8) were associated with CP. O f the total 41 children with CP in this cohort, almost three-fourths h a d either a severe (41%) or nonsevere (32%) birth defect. These defects were also h e t e r o g e n e o u s .
Prematurity/Low Birthweight Prematurity or low birthweight is o n e of the most significant risk factors for the d e v e l o p m e n t of CP. For example, in a review of 11 studies f r o m 1985 t h r o u g h 1990, Rosen a n d Dickinson ~~
197
r e p o r t e d a CP rate of 15 per 1,000 for low birthweight infants (<2,500 grams) and a CP rate of 13 to 90 per 1,000 live births for newborns weighing 500 to 1,500 grams at birth. Approximately one-third of all cases of CP occurred in low birthweight infants (36% composite rate for the 11 published reports). These investigators estimated that the risk of "intrapartum-attributed" CP was approximately 1 in 2,000 live births. In the univariate analysis of the Collaborative Perinatal Project, Nelson a n d Ellenberg 7 rep o r t e d a RR of CP of 4.9 for birthweight <2,500 g and 13.7 for birthweight <2,000 g. In the review by Torfs and colleagues, 9 the RR of CP was 4.2 for birthweight <2,000 g. Cummins a n d colleagues 1~ r e p o r t e d that newborns with birthweight <1,500 g were a " h u n d r e d times" m o r e likely to have CP than newborns weighing 3,000 to 3,500 g. T h e incidence of CP in the p r e m a t u r e or low birthweight infant varies somewhat d e p e n d i n g on the subsets of gestational age and weight studied. In a review of 381 infants (birthweight 600 to 1,250 g) who h a d neurological examinations at 36 months, Allan a n d colleagues 12 rep o r t e d a 9.5% rate of CP. In a study on the epidemiology o f CP in England and Scotland in 1984 to 1989, the prevalence of CP was 1.1 p e r 1,000 survivors with birthweights ->2,500 g comp a r e d with 78.1 p e r 1,000 for survivors weighing
<1,000 g.13 T h e r e is some controversy regarding the impact of i m p r o v e d survival of the p r e m a t u r e infant on the CP rate. For example, T o p p a n d colleagues 1~ r e p o r t e d a decrease in early neonatal deaths (282 to 239 per 1,000; P < .05) for p r e t e r m infants less than 31 weeks o v e r 2 time periods. Over the same time f r a m e there was an increase in CP in infants less than 31 weeks (85 to 123 p e r 1,000; P < .05). In contrast, Emsley and colleagues 15 r e p o r t e d no significant change in the CP rate (21% versus 18%) in survivors (23 to 25 weeks gestational age) c o m p a r i n g 2 time periods, 1984 to 1989 a n d 1990 to 1994. T h e rate of survival did increase f r o m 27% to 42%. In the investigators' opinion, there are too m a n y variables a m o n g the various published studies to date (especially considering the differences in birthweights analyzed) to implicate an increase in survival in the very p r e m a t u r e infant as causative for the increase in CP as r e p o r t e d in some of these studies.
198
Ramin and Gilstrap
Multifetal Gestations Multifetal gestation appears to be a significant risk factor for CP. For example, G r e t h e r and colleagues, a6 in a study of CP and twinning, rep o r t e d that CP was 12 times m o r e likely in twin pregnancies than singleton pregnancies. T h e rate was 12 p e r 1,000 twin pregnancies versus 1.1 p e r 1,000 singletons in their study population. Approximately 1 in 5 cases o f CP in infants <1,500 g at birth occurred in twins. Although m o r e twins h a d low birthweight, the rate of CP in twins of n o r m a l birthweight was still significantly higher than singletons. A n o t h e r important finding in their study was that the rate of CP in unlike-sex pairs versus like-sex pairs was similar. These data would suggest that there may also be an increase in CP in dizygotic twins as well as monozygotic twins. T h e rate of CP is even higher as the n u m b e r of fetuses increases. Petterson a n d colleagues av reviewed the prevalence o f CP in twins and triplets in Western Australia and r e p o r t e d a CP rate of 28 per 1,000 survivors in triplets, 7.3 in twins, a n d 1.6 in singletons. These investigators concluded that twin pregnancies resulted in CP 8 times m o r e often, and triplets 47 times m o r e often, than in singleton pregnancies. In a study f r o m Japan, Yokoyama and colleagues 18 reviewed 705 twin pairs, 96 sets of triplets, a n d 7 sets of quadruplets. The rate of CP was 0.9%, 3.1%, and 11.1% respectively in this series. In a n o t h e r report, Pharoah and Cooke m r e p o r t e d a prevalence of CP of 2.3 for singletons, 12.6 in twins, and 44.8 in triplets p e r 1000 survivors. Williams and colleagues 2~ studied the effects o f twinning, birthweight, and gestational age on the rate of CP and r e p o r t e d that all 3 were i n d e p e n d e n t risk factors. Minakami and colleagues 2~ studied adverse outcomes in twins conceived by artificial reproductive techniques (n = 136) c o m p a r e d with spontaneously conceived twins (n = 72). These investigators r e p o r t e d a lower frequency of adverse o u t c o m e s (death, CP, and mental retardation) in the f o r m e r g r o u p versus the latter g r o u p (3.3% versus S.3%).
Abnormal Presentation A b n o r m a l presentations such as breech, face, and transverse lie have b e e n r e p o r t e d to be associated with an increase rate o f CP. For exam-
ple, Toffs and colleagues 9 r e p o r t e d a relative risk of 3.8 (95% CI 1.6 to 9.1) of CP if the fetus was in an a b n o r m a l presentation. Nelson and Ellenberg 6 also r e p o r t e d an increased association of b r e e c h presentation and CP. It is important to note that it is the presentation that is the "predictor" o f CP a n d not the m e t h o d o f delivery. s In the r e p o r t of multivariate analysis of risk, Nelson and Ellenberg a r e p o r t e d that one-third of the children with CP a n d b r e e c h presentation h a d a major malformation. In a m o r e recent r e p o r t f r o m D e n m a r k , Krebs and associates 22 reviewed the relation between breech presentation a n d CP. These investigators r e p o r t e d a "borderline significant" risk of CP with b r e e c h presentation c o m p a r e d with vertex (odds ratio [OR] 1.56; 95% CI 0.9 to 2.4). However, there was no difference in the rate of CP between b r e e c h and vertex presentation by m o d e of delivery. These investigators postulated that the higher rate of CP a m o n g t e r m infants with b r e e c h presentation was m o s t likely related to a higher incidence of small for gestational age infants a m o n g the breeches.
Placental Abnormalities T h e most c o m m o n placental abnormalities associated with an increased risk of CP are premature separation of the placenta or a b r n p t i o n and bleeding. T h e relative risk of CP associated with abruption was 3.5 (P < .01) in the Collaborative Perinatal Project database. 7 Interestingly, the RR was even higher for placenta previa (RR 4.9; P < .01). Bleeding f r o m what was diagnosed as a "marginal sinus rupture" h a d a RR of 3.5 (P < .05) for CP. In California Child Health and Dev e l o p m e n t Studies database, the relative risk of CP associated with p r e m a t u r e separation of the placenta was 7.6 (95% CI 2.7 to 21.1). 9 T h e r e has b e e n recent evidence that fetal and newborn neurological d a m a g e and CP may be related to t h r o m b o p h i l i a a n d the resultant thrombosis in the placenta, possibly even involving fetal cerebral vessels, s,23-26 In a recent clinicopathologic study of 84 newborns at autopsy, Kraus and A c h e e n 27 identified 16 cases of "fetal t h r o m b o t i c vasculopathy" (FTV) in the placenta. This is characterized by "clustered fibrotic villi." Importantly, there was evidence of severe brain injury in some of the cases in which the FTV clearly p r e c e d e d the death of the fetus. These investigators suggested that parental eoagulopa-
Other Factors Associated With Cerebral Palsy
thy might be a significant u n d e r r e c o g n i z e d cause of neonatal injury.
Nuchal Cord Nelson and Grether z8 in a study of 46 children with CP from four California counties (1983 through 1985) reported a significant association of tight nuchal cord and spastic cerebral palsy (OR 18; 95% CI 6.2 to 48). This association was with spastic quadriplegia, but not with diplegia or hemiplegia.
Summary CP is relatively u n c o m m o n , occurring in 1 to 2 per 1,000 live births. T h e r e are certain risk factors that are strongly associated with higher rates of CP. Some of these include prematurity, low birthweight, congenital malformations, multifetal gestations, placental abnormalities, and the presence of a tight nuchal cord. W h e t h e r these associations are causative remains to be elucidated.
References 1. Nelson KB, EllenbergJH: Apgar scores as predictors of chronic neurologic disability. Pediatrics 68:36-44, 1981 2. American College of Obstetricians and Gynecologists: Fetal and neonatal neurologic injury. Tech Bull #163, 1992 3. Nelson KB: Medical-legal issues facing neurologists. The neurologically impaired and alleged malpractice. Neurologic Clinics 17:284-293, 1999 4. Nelson KB, Ellenberg JH: The asymptomatic newborn and risk of cerebral palsy. A m J Disease Child 141:13331335, 1987 5. Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240-249, 1988 6. Nelson KB, EllenbergJH: Obstetric complications as risk factors for cerebral palsy or seizure disorder. JAMA 251: 1843-1848, 1984 7. Nelson KB, EllenbergJH: Antecedents of cerebral palsy. I. Univariate analysis of risk. Am J Disease Child 139: 1031-1038, 1985 8. Nelson KB, EllenbergJH: Antecedents of cerebral palsy: Multivariate analysis of risk. N Engl J Med 315:81-86, 1986 9. Toffs CP, van den Berg BJ, Oechsli FW, et al: Prenatal and perinatal factors in the etiology of cerebral palsy. J Pediatr 116:615-619, 1990 10. Rosen MG, Dickinson JC: The incidence of cerebral palsy. A m J Obstet Gynecol 167:417-423, 1992
199
11. Cummins SK, Nelson KB, Grether JK, et al: Cerebral palsy in four Northern California counties, births 1983 through 1985. J Pediatr 123:230-237, 1993 12. Allan WC, Vohr B, Makuch RW, et ah Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricular hemorrhage. Arch Pediatr Adolesc Med 151:580-585, 1997 13. Pharoah PO, Cooke T,Johnson MA, et al: Epidemiology of cerebral palsy in England and Scotland, 1984-9. Arch Dis Child Fetal Neonatal Ed 79:F21-25, 1998 14. Topp M, Uldall P, Langhoff-Roos J: Trend in cerebral palsy birth prevalence in eastern Denmark: Birth-year period 1979-86. Paediatr Perinat Epidemiol 11:451-460, 1997 15. Emsley HC, Wardle SP, Sims DG, et ah Increased survival and deteriorating developmental outcome in 23 to 25 week old gestation infants, 1990-4 compared with 1984-9. Arch Dis Child Fetal Neonatal Ed 78:F99-104, 1998 16. Grether JK, Nelson KB, Cummins SK: Twinning and cerebral palsy: Experience in four northern California counties, births 1983 through 1985. Pediatrics 92:854858, 1993 17. Petterson B, Nelson KB, Watson L, et ah Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 307:1239-1243, 1993 18. Yokoyama Y, Shimizu T, Hayakawa K: Prevalence of cerebral palsy in twins, triplets and quadruplets. I n t J Epidemiol 24:943-948, 1995 19. Pharoah PO, Cooke T: Cerebral palsy and multiple births. Arch Dis Child Fetal Neonatal Ed 75:F174-177, 1996 20. Williams K, Hennessy E, Alberman E: Cerebral palsy: Effects of twinning, birthweight, and gestational age. Arch Dis Child Fetal Neonatal Ed 75:F178-182, 1996 21. Minakami H, Sayama M, Honma Y, et ah Lower risks of adverse outcome in twins conceived by artificial reproductive techniques compared with spontaneously conceived twins. Hum Reprod 13:2005-2008, 1998 22. Krebs L, Topp M, Langhoff-Roos J: The relation of breech presentation at term to cerebral palsy. Br J Obstet Gynecol 106:943-947, 1999 23. de Klerk OL, de Vries TW, Sinnige LGF: An unusual cause of neonatal seizures in a newborn infant. Pediatr 100:E8, 1997 24. Dizon-Townson DS, Meline L, Nelson LM, et ah Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 177:402-405, 1997 25. Nelson KB, Dambrosia JM, Grether JK, et al: Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 44:665-675, 1998 26. Tabbutt S, Griswold WR, Ogino MT, et ah Multiple thromboses in a premature infant associated with maternal phospholipid antibody syndrome. J Perinatol 14:6670, 1994 27. Kraus FT, Acbeen VI: Fetal thrombotic vasculopathy in the placenta: Cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 30:759-769, 1999 28. Nelson KB, Grether JK: Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal weight. A m J Obstet Gynecol 179:507-513, 1998