Chorioamnionitis and Cerebral Palsy in Term and Near-Term Infants

ORIGINAL CONTRIBUTION

Yvonne W. Wu, MD, MPH Context Half of all cases of cerebral palsy (CP) occur in term infants, for whom risk Gabriel J. Escobar, MD factors have not been clearly defined. Recent studies suggest a possible role of chorioamnionitis. Judith K. Grether, PhD Objective To determine whether clinical chorioamnionitis increases the risk of CP in Lisa A. Croen, PhD term and near-term infants. John D. Greene, MA Design, Setting, and Patients Case-control study nested within a cohort of 231582 Thomas B. Newman, MD, MPH 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 EREBRAL PALSY (CP), A GROUP organization providing care for more than 3 million residents of northern California. of nonprogressive motor im- Case patients were identified from electronic records and confirmed by chart review pairment syndromes caused 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). by lesions of the brain aris- Controls (n=218) were randomly selected from the study population. ingC early in development,1 occurs in 1 to 2.4 per 1000 live births.2-5 Al- Main Outcome Measure Association between clinical chorioamnionitis and increased risk of CP in term and near-term infants. though premature infants are at particularly high risk, more than half of all Results Most CP cases had hemiparesis (40%) or quadriparesis (38%); 87% had children with CP are born at term.5 been diagnosed by a neurologist and 83% had undergone neuroimaging. Chorioam- Population-based studies suggest that nionitis, 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 despite advancements in obstetrical and ratio [OR], 3.8; 95% confidence interval [CI], 1.5-10.1; P=.001). Independent risk neonatal care, the prevalence of CP in factors identified in multiple logistic regression included chorioamnionitis (OR, 4.1; 95% term infants has remained constant in CI, 1.6-10.1), intrauterine growth restriction (OR, 4.0; 95% CI, 1.3-12.0), maternal recent decades.2-4,6,7 black ethnicity (OR, 3.6; 95% CI, 1.4-9.3), maternal age older than 25 years (OR, Chorioamnionitis, or inflammation 2.6; 95% CI, 1.3-5.2), and nulliparity (OR, 1.8; 95% CI, 1.0-3.0). The population- of the placental membranes, may in- attributable fraction of chorioamnionitis for CP is 11%. crease the risk of CP by 2- to 12-fold Conclusion Our data suggest that chorioamnionitis is an independent risk factor for in term infants.8-12 However, previous CP among term and near-term infants. studies are limited by small size,9,10 and JAMA. 2003;290:2677-2684 www.jama.com adjusted relative risk estimates are either not significant10 or not presented fore, we examined the association be- boards at the KPMCP and at the Uni- for term infants.8,12 Whereas birth as- tween chorioamnionitis and CP, as well versity of California, San Francisco. phyxia was previously thought to be the as the role that “birth asphyxia” plays most common etiology of CP, clinical in this relationship, in a large cohort of Setting signs attributed to birth asphyxia, such term infants in the Northern Califor- The KPMCP is a large managed care or- as low Apgar scores and neonatal en- nia Kaiser Permanente Medical Care ganization that provides care for more cephalopathy, may in some cases be due Program (KPMCP), most of whom had 9,13-15 to chorioamnionitis. Previous stud- undergone neuroimaging studies. Author Affiliations: Departments of Neurology (Dr ies lacking neuroimaging data8-10 have Wu), Pediatrics (Drs Wu and Newman), and Epide- been unable to elucidate the complex METHODS miology and Biostatistics (Dr Newman), University of California, San Francisco; Kaiser Permanente Divi- relationships between chorioamnion- This case-control study is nested within sion of Research, Oakland, Calif (Drs Escobar and Croen itis, birth asphyxia, and CP. There- the cohort of all singleton term and and Mr Greene); and California Department of Health Services, Sacramento (Dr Grether). near-term (36 or more weeks’ gesta- Corresponding Author and Reprints: Yvonne W. Wu, tion) infants born in 1991 to 1998 at MD, MPH, Division of Child Neurology, Box 0136, Uni- See also pp 2669 and 2730 the KPMCP. All study procedures were versity of California, San Francisco, 500 Parnassus Ave, and Patient Page. MUE #411, San Francisco, CA 94143 (e-mail: wuy approved by the institutional review @peds.ucsf.edu).

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All children were older than 2 years Box. International Classification of Diseases, Ninth Revision, at the onset of the study. Since CP can Clinical Modification (ICD-9-CM) Codes for Conditions be definitively diagnosed at age 2 Not Considered Cerebral Palsy years,18 those children who met case eli- 237.7x Neurofibromatosis gibility criteria after age 2 years were 275.1 Wilson disease considered “definite” cases. Children 277.2 Lesch-Nyhan syndrome with CP but who were lost to fol- 277.5 Mucopolysaccharidosis low-up between ages 15 and 24 months 331.8 Reye syndrome were considered “probable” cases, and 331.9 Cerebral degeneration, unspecified also included in the study. Infants who 333.6 Idiopathic torsion dystonia met inclusion criteria but who were lost 334.x Spinocerebellar disease, including ataxia telangiectasia 335.x Anterior horn cell disease to follow-up before age 15 months were 336.x Other diseases of spinal cord excluded, since early motor abnormali- 340 Multiple sclerosis ties suggestive of CP may resolve by 349.82 Toxic encephalopathy childhood.19 358.x Myoneural disorders (eg, myasthenia gravis) Because we were interested in perina- 359.x Muscular dystrophies and other myopathies tal risk factors for unexplained CP, chil- 741.xx Spina bifida dren with postnatal brain injury or 742.5x Spinal cord anomalies known developmental abnormalities 754.59 Arthrogryposis were excluded. Criteria for exclusion 755.55 Apert syndrome were a central nervous system insult oc- 756.16 Klippel-Feil disease curring after 1 week of age; a known de- 757.33 Bloch-Sulzberger disease (incontinentia pigmenti), xeroderma pigmento- sum velopmental or genetic abnormality, such 758.x Chromosomal anomalies as a brain malformation or chromo- 759.5 Tuberous sclerosis somal anomaly; evidence of a congeni- 759.81 Prader-Willi Syndrome tal viral infection; and presence of a con- 759.89 Other specified anomalies, including Cornelia de Lange syndrome, Lawrence dition that is not considered to be CP,20 Moon Biedl syndrome, Rubenstein-Taybi syndrome, Carpenter syndrome, ce- including neural tube defects and ar- rebrohepatorenal syndrome, Cockayne syndrome, Menkes kinky hair disease throgryposis (BOX). We randomly selected 2 controls per case from the study population. We used electronic records to determine the than 3 million residents (30% of the normality (ICD-9-CM code 781.2). A length of follow-up at the KPMC for all population) in northern California. The single pediatric neurologist (Y.W.) who control children. members of the KPMCP are demo- was blinded to the presence of chorio- graphically similar to the general Cali- amnionitis then reviewed the outpa- Data Abstraction fornia population, except that the very tient medical records to confirm the di- A trained medical record abstractor re- poor and very wealthy are underrep- agnosis of CP. viewed obstetric and neonatal charts resented.16 Of its 33 facilities, 12 have We defined CP as a nonprogressive without knowledge of neurologic delivery rooms and 6 have level III neo- congenital motor dysfunction with find- outcome. Chorioamnionitis was con- natal intensive care units. ings of spasticity, rigidity, or choreo- sidered present if a treating physician athetosis. Inclusion criteria were 36 or made a diagnosis of chorioamnionitis Participants more weeks’ singleton gestation, non- or endometritis based on clinical symp- Among all singleton live births of 36 or progressive motor dysfunction, exami- toms. Histologic chorioamnionitis was more weeks’ gestation born between nation findings of increased tone or defined as microscopic evidence of in- January 1, 1991, and December 31, choreoathetosis, and moderate to se- flammation in the placental mem- 1998, we electronically searched the vere disability. Moderate disability was branes or umbilical cord. Intrauterine KPMCP patient database for inpatient defined as diminished use of the most growth restriction was defined as birth and outpatient physician diagnoses affected limb, and severe disability re- weight less than the 10th percentile for of CP (International Classification of ferred to the lack of any functional use gestational age based on race- and sex- Diseases, Ninth Revision, Clinical of the most affected limb.5 Hypotonic specific normative data compiled from Modification17 [ICD-9-CM] codes CP in the absence of increased tone was California births.21 343.0-343.9), paresis (ICD-9-CM codes not included because this entity is most “Birth asphyxia” is a vague and con- 342.1, 342.8, 342.9, 344.0, 344.1, likely etiologically distinct from spas- troversial term that denotes a clinical 344.30-344.32, and 344.5), or gait ab- tic and dyskinetic CP. diagnosis lacking specificity for any

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single underlying pathological condi- minish the association between cho- Description of Cases tion. To study the significance of this rioamnionitis and CP. Instead, we tested After excluding 97 children with CP for diagnosis as it is used in practice, we the hypothesis that these factors may reasons such as mild disability or the abstracted this terminology as it was in some cases be due to chorioamni- presence of a developmental anomaly used by treating physicians. That is, we onitis by looking for associations be- (Figure), the remaining 109 children considered birth asphyxia to be pre- tween chorioamnionitis and these clini- with unexplained moderate to severe sent if a treating physician diagnosed cal markers in infants with CP. STATA CP comprised the final cases. The vast an infant clinically with either birth as- version 7 (StataCorp LP, College Sta- majority (93%) of these children had phyxia or hypoxic-ischemic encepha- tion, Tex) was used for all analyses; been followed up for at least 2 years, lopathy, regardless of whether true hy- PϽ.05 was used to determine statisti- and 87% had been diagnosed by a neu- poxia-ischemia was present. cal significance. rologist as having CP (TABLE 1). Most In contrast, we use the term “hypoxic- cases had hemiparesis (40%) or qua- ischemic brain injury” to refer either to RESULTS driparesis (38%). Two hundred eigh- the neuroradiological findings of brain Of the 231582 infants in the study teen controls were selected. injury in the parasagittal watershed dis- population, the electronic search for rel- Magnetic resonance imaging or com- tribution, basal ganglia, or thalami, or evant physician diagnoses revealed 618 puted tomography of the head had been to diffuse brain edema observed in the children with possible CP (FIGURE). performed in 83% of children with CP first days of life. Although the specific- Chart review confirmed the diagnosis (n=75 and n=16, respectively). The ity of these findings for hypoxia- of CP in 206 children. The prevalence most common abnormalities were fo- ischemia is unknown because there is of CP was 0.9 per 1000 live births (ap- cal infarct, white matter abnormalities no way to directly measure intrapar- proximately 1/1100), which is consis- sparing the cortex, hypoxic-ischemic tum blood flow and oxygen delivery to tent with previous population-based es- brain injury, and generalized atrophy the brain,22 these findings are often taken timates of CP in term infants.3,5,6,28 (Table 1). to imply the presence of perinatal hypoxia-ischemia in neonates with encephalopathy.23-26 Figure. Selection of Study Cases

Data Analysis 246 009 Infants in Birth Cohort ∗ We calculated univariate odds ratios 14 427 Excluded 10 148 Gestational Age <36 wk (ORs) and 95% confidence intervals 6087 Multiple Births (CIs) using the exact method, and compared univariate ORs stratified by type 231 582 in Study Population of imaging abnormality using polyto- 2256 Had Exclusion Diagnosis mous logistic regression.27 We calcu-

lated multivariable ORs by perform- 228 708 Had No Electronic 618 Potential Cases Submitted ing a backward stepwise logistic Diagnosis of CP, Plegia, for Chart Review or Gait Abnormality regression, with PϽ.10 used as the cut- 509 Excluded ∗ off for retention in the model. Odds ra- 97 Had CP 218 Study Controls tios are close approximations of the 63 Mild Severity 24 Developmental Anomaly† relative risk since the outcome of CP 15 Genetic Syndrome or Chromosomal Anomaly 8 Ataxic CP is rare in term infants. 1 Congenital CMV Potential confounders found to be 412 Did Not Have CP by Study Criteria 266 Had Orthopedic Abnormality significantly associated with CP on uni- 46 Had Hypotonia Only variate analysis were included in the 46 Had Acute or Progressive Neurologic Abnormality multivariable model, as were risk fac- 28 Postnatal Cause 11 CP But Lost to Follow-up at Age <15 mo tors that were considered a priori to be 6 Motor Abnormalities Resolved by Age 2 y potential confounders. Factors that 5 Had Arthrogryposis were not considered to be etiologic, 4 Miscellaneous‡

such as low Apgar scores, emergent ce- 109 Study Cases sarean section, neonatal seizures, and a diagnosis of “birth asphyxia,” were not CP indicates cerebral palsy; CMV, cytomegalovirus. included in the model. These abnor- *Infants could be excluded for more than 1 reason. †Developmental anomalies included brain malformation (n=18), severe dysmorphic features (n=3), mul- malities are likely to be markers of the tiple congenital anomalies (n=2), and gastroschisis (n=1). underlying brain injury leading to CP, ‡Miscellaneous reasons included alternating hemiplegia (n=2), infant died in the neonatal period (n=1), and twin gestation (n=1). and adjusting for them could falsely di-

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hours compared with Ͻ24 hours), nul- represent a significant risk factor in uni- Table 1. Clinical Characteristics of 109 Term or Near-Term Infants With Unexplained liparity, and IUGR also were associated variate analysis, it was found to be inde- Congenital Cerebral Palsy (CP) with CP (TABLE 2). The OR of chorio- pendently associated with CP after Characteristic No. (%)* amnionitis and CP did not differ signifi- adjustment for confounders. This dis- CP classification cantly between mothers who received in- crepancy may be explained in part by the Definite (Ͼ2 y of follow-up) 101 (93) trapartum antibiotics and those who fact that black mothers were on average Probable (15-24 mo 8 (7) of follow-up) were not given antibiotics (OR, 6.8 [95% younger than their white counterparts. CP diagnosed by a neurologist 95 (87) CI, 1.2-70] vs 2.6 [95% CI, 0.5-13.0]; Younger maternal age conferred a pro- CP type Spastic 99 (91) P=.37), though our numbers were small. tective effect, and without adjustment Choreoathetotic 8 (7) A histologically confirmed diagno- for this confounder, maternal age would Rigid 1 (1) Limb involvement sis of chorioamnionitis was made in 5 act to suppress the effect of ethnicity on Hemiparesis 44 (40) of 19 children (26%) with CP vs 1 of 9 risk of CP. Of note, none of the black Quadriparesis 41 (38) Paraparesis 15 (14) (11%) control children (P=.36). Five women in the case or control groups had Unclear 8 (7) of 6 mothers with histologic evidence chorioamnionitis. Severity of motor dysfunction† of placental inflammation lacked any Moderate 67 (61) Severe 38 (35) clinical signs of chorioamnionitis, while Stratified Analyses Equivocal 4 (4) 6 of 8 mothers diagnosed clinically with The relationship between chorioamni- Neuroimaging findings (n = 91) Focal infarction 29 (32) chorioamnionitis had no placental in- onitis and CP varied according to sub- White matter abnormalities 10 (11) flammation. Since placental examina- type of CP. In addition, the OR of cho- Hypoxic-ischemic injury 8 (9) Generalized atrophy 7 (8) tions were not performed in the vast rioamnionitis for CP was higher among Intracranial hemorrhage 7 (8) majority of study participants, histo- children with a neuroimaging diagno- Other abnormality‡ 11 (12) logic chorioamnionitis was not in- sis of hypoxic-ischemic brain injury than No abnormality 23 (25) cluded in further analyses. among those with other neuroimaging *Children with CP for whom no data were available regarding specific clinical characteristics were not in- Several factors that we considered to findings (univariate OR, 17.2 [95% CI, cluded in the corresponding row. †Severity of disability was determined at age 2-3 y when- be clinical markers of fetal distress and 3.3-88] vs 3.2 [95% CI, 1.2-8.1]; P=.04). ever possible. brain dysfunction, rather than causes, Multivariable analyses stratified by CP ‡Abnormalities not easily classified into the categories listed above include prominent ventricles (n = 2), intraparen- were strongly associated with CP, in- subtypes were performed when num- chymal calcifications (n = 2), white matter abnormalities with occipital encephalomalacia (n = 1), diffuse brain- cluding 5-minute Apgar score less than bers were adequate (TABLE 4). The ad- stem infarction (n = 1), arachnoid cyst (n = 1), 7, the clinical diagnosis of “birth as- justed OR of chorioamnionitis for CP was communicating hydrocephalus (n = 1), mildly de- creased size of posterior fossa structures (n = 1), sub- phyxia,” and neonatal seizures (Table particularly high among children with arachnoid hemorrhage (n = 1), and polycystic brain (n = 1). 2). As hypothesized, however, these quadriplegic CP, and among those with same findings were associated with cho- neuroimaging findings of hypoxic- rioamnionitis among the children with ischemic brain injury. Chorioamnion- Twenty-six of the 35 infants (74%) CP (5-minute Apgar score Ͻ7 [OR, 5.3; itis was not an independent risk factor with hemiplegic CP who received an im- 95% CI, 1.4-19.5], birth asphyxia [OR, for CP resulting from focal infarction. In- aging study of the head were diagnosed 4.9; 95% CI, 1.3-18.1], and neonatal sei- stead, when we performed the multi- with a focal infarct. Patients who under- zures [OR, 5.6; 95% CI, 1.5-21.3]). variable analysis restricted to the 29 chil- went a magnetic resonance imaging scan None of the 9 control children born to dren with focal infarction, preeclampsia were more likely to be diagnosed with a mothers with chorioamnionitis dem- (OR, 3.4; 95% CI, 1.0-11.8) and intra- perinatal stroke than were those who un- onstrated these or other neonatal com- uterine growth restriction (OR, 4.3; 95% derwent only a computed tomography plications, although 2 infants had brief CI, 1.0-18.3) were the only significant scan (36% vs 13%, respectively; P=.07). temperature elevations immediately af- risk factors retained in the model. Only 6 of 24 infants (25%) diagnosed ter birth. Children with apparent CP but who clinically with birth asphyxia who un- were followed up for less than 15 derwent neuroimaging studies demon- Multivariable Analysis months were excluded from the study. strated findings specific for hypoxic- Chorioamnionitis remained an indepen- When the 13% of control children who ischemic brain injury. All children with dent risk factor for CP in the multivari- were lost to follow-up prior to 15 hypoxic-ischemic brain injury had spas- able model (OR, 4.1; 95% CI, 1.6- months were also excluded, the rela- tic quadriplegia. 10.1). Other risk factors included tionship between chorioamnionitis and intrauterine growth restriction (OR, 4.0; CP did not change appreciably. Univariate Analysis 95% CI, 1.3-12.0), maternal age older Chorioamnionitis was diagnosed in 14% than 25 years (OR, 2.6; 95% CI, 1.3-5.2), COMMENT of cases and 4% of controls (OR, 3.8; 95% black race (OR, 3.6; 95% CI, 1.4-9.3), and We found that clinical chorioamnion- CI, 1.5-10.1; P=.001). Maternal fever, nulliparity (OR, 1.8; 95% CI, 1.0-3.0) itis is independently associated with a prolonged rupture of membranes (Ն36 (TABLE 3). Although black race did not 4-fold increased risk of CP in term in-

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fants. A history of birth asphyxia was ports.9,29-31 However, the diagnosis of The association between maternal fe- also strongly predictive of CP, a find- birth asphyxia often was made in the ver and CP was first reported in 1955.32 ing that is supported by recent re- setting of clinical chorioamnionitis. Subsequently, 2 of the 3 available stud-

Table 2. Univariate Risks For Cerebral Palsy in Singleton Term Infants No./Total (%)*

Cases Controls Variable (n = 109) (n = 218) OR (95% CI) P Value Maternal age, y Ͻ25 20/108 (18) 60/218 (28) Reference 25-35 66/108 (61) 119/218 (54) 1.7 (0.9-3.2) .09 Ͼ35 22/108 (20) 39/218 (18) 1.7 (0.8-3.7) .15 Maternal race White 52/109 (48) 125/218 (57) Reference Black 11/109 (10) 12/218 (6) 2.2 (0.8-5.8) .07 Hispanic 19/109 (17) 33/218 (15) 1.4 (0.7-2.8) .30 Asian 13/109 (12) 32/218 (15) 1.0 (0.4-2.1) .93 Other 4/109 (4) 5/218 (2) 1.9 (0.4-9.3) .34 Unknown 10/109 (9) 11/218 (5) 2.2 (0.8-6.0) .09 Nulliparity 52/106 (49) 80/215 (37) 1.6 (1.0-2.7) .04 Prepartum complications History of infertility 3/106 (3) 8/215 (4) 0.7 (0.1-3.2) .68 Intrauterine growth restriction 11/105 (10) 6/207 (3) 3.9 (1.3-13.3) .01 Gestational diabetes 10/106 (9) 10/215 (5) 2.1 (0.8-5.9) .10 Preeclampsia/pregnancy-induced hypertension 6/106 (6) 10/215 (5) 1.2 (0.4-3.9) .70 Intrapartum complications Clinical chorioamnionitis 15/106 (14) 9/215 (4) 3.8 (1.5-10.1) .001 Histologic chorioamnionitis 5/19 (26) 1/9 (11) 2.5 (0.2-135) .36 Maternal fever (temperature Ն100.0°C) 21/106 (20) 15/215 (7) 3.3 (1.5-7.2) .001 Highest documented maternal temperature, °C Ͻ37.8 85/106 (80) 200/215 (93) Reference 37.8-38.1 10/107 (9) 6/215 (3) 3.9 (1.2-13.5) .01 Ͼ38.1 11/107 (10) 9/215 (4) 2.9 (1.0-8.1) .02 Rupture of membranes Ͻ24 h 84/98 (86) 189/202 (94) Reference 24-35.9 h 5/98 (5) 8/202 (4) 1.4 (0.4-5.0) .55 Ն36 h 9/98 (9) 5/202 (2) 4.1 (1.2-15.8) .02 Delivery variables Breech presentation 5/106 (5) 5/215 (2) 4.1 (0.4-9.2) .31 Cesarean delivery (urgent or emergency) 38/106 (36) 17/215 (8) 6.5 (3.3-13.1) Ͻ.001 Forceps used 6/106 (6) 2/215 (0.9) 6.4 (1.1-65.1) .02 Vacuum used 16/106 (15) 17/215 (8) 2.1 (0.9-4.7) .05 Meconium (mild or trace) 13/106 (12) 31/215 (14) 0.8 (0.4-1.7) .60 Meconium (moderate or severe) 24/106 (23) 20/215 (9) 2.9 (1.4-5.8) .001 Tight nuchal cord 3/106 (3) 6/215 (3) 1.0 (0.2-4.9) Ͼ.99 Infant characteristics Male sex 57/107 (53) 115/211 (54) 1.0 (0.6-1.6) .84 Gestational age, mean (SD), wk 39.5 (1.5) 39.6 (1.3) NA .84 Birthweight, mean (SD), g 3331 (608) 3477 (463) NA .02 5-Minute Apgar score Ͻ7 26/107 (24) 2/211 (0.9) 33.5 (8.0-294) Ͻ.001 Cord pH Ͻ7.0† 14/42 (33) 0/28 (0) NA Ͻ.001 Admitted to neonatal intensive care unit 52/107 (48) 17/210 (8) 10.7 (5.5-21.3) Ͻ.001 Diagnosis of “birth asphyxia”‡ 27/107 (25) 0/211 (0) NA Ͻ.001 Neonatal seizures 31/107 (29) 3/211 (1) 42.6 (10.3-372) Ͻ.001 Abbreviations: CI, confidence interval; NA, not applicable; OR, odds ratio. *Only the study participants with data available for the specified risk factor are included in each row. †Odds ratio and upper confidence limit cannot be calculated due to zero cells. Lower confidence limit = 3.5. ‡Diagnosis of birth asphyxia or hypoxic-ischemic encephalopathy made by a treating physician. Odds ratio and upper confidence limit cannot be calculated due to zero cells. Lower confidence limit = 18.4.

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ies were unable to confirm this asso- How chorioamnionitis might lead to ating or exacerbating brain injury from ciation in term infants after adjusting CP is poorly understood; most likely, hypoxia-ischemia. Chorioamnionitis for confounders.10,12 However, chil- several mechanisms act together to leads to an elevation of inflammatory dren with CP of all causes were ana- cause fetal brain injury. Hypothesized cytokines in the fetus.33 In animal mod- lyzed together in these studies. We mechanisms include (1) elevated lev- els, the inhibition of these cytokines (in- found that children with CP due to a els of fetal cytokines in the presence of terleukin 1 and tumor necrosis factor developmental or genetic abnormality maternal infection cause direct injury ␣) has been shown to reduce the ex- represented 19% of all children with CP. to the fetal brain (ie, the fetal inflam- tent of brain injury following hypoxia- Our data suggest that when these chil- matory response)33,34; (2) inflamma- ischemia.38-40 Although chorioamnion- dren are excluded from the analysis, tion of the placental membranes leads itis may potentiate hypoxic-ischemic chorioamnionitis is indeed associated to interruption of placental gas ex- brain injury in neonates, it also is pos- with an increased risk of CP. change and blood flow, resulting in hy- sible that inflammation produces a pat- poxic-ischemic brain injury in the fe- tern of brain injury that mimics the tus35; (3) maternal fever raises the core neuroradiological findings of hypoxic- Table 3. Multivariable Risks of Prenatal and temperature of the fetus, which in turn ischemic brain injury in term infants. Perinatal Risk Factors for Unexplained may be harmful to the developing brain, The term “birth asphyxia” is impre- Cerebral Palsy in Term Infants especially in the setting of cerebral is- cise and misleading, as it implies the exis- P 35-37 Variable OR (95% CI)* Value chemia ; and (4) maternal intrauter- tence of hypoxic-ischemic brain injury. Maternal race ine infection leads to direct infection of Our results suggest that chorioamnion- White Reference the fetal brain or meninges, although itis may be a cause of the neonatal syn- Black 3.6 (1.4-9.3) .01 9,14 Hispanic 2.0 (0.9-4.1) .07 this is seen rarely. drome that often is referred to as birth Asian 0.9 (0.4-1.9) .78 The finding of a particularly strong asphyxia. Indeed, intrapartum fever has Maternal age Ͼ25 y 2.6 (1.3-5.2) .01 association between chorioamnionitis been found to represent a significant risk Nulliparity 1.8 (1.0-3.0) .04 Clinical chorioamnionitis 4.1 (1.6-10.1) .002 and CP among the 6% of children who factor for signs of birth asphyxia, such Intrauterine growth 4.0 (1.3-12.0) .01 sustained hypoxic-ischemic brain in- as low Apgar scores and neonatal en- restriction jury was unexpected and based on small cephalopathy.9,13-15 In our study, only Abbreviations: CI, confidence interval; OR, odds ratio. *Included in the logistic regression model: maternal age, numbers. However, this finding sup- 25% of children diagnosed with birth as- maternal race, nulliparity, sex, clinical chorioamnionitis, intrauterine growth restriction, preeclampsia, and ports the second hypothesis, ie, that phyxia demonstrated neuroradiologi- tight nuchal cord. chorioamnionitis plays a role in initi- cal findings suggesting hypoxic- ischemic injury. Although the diagnosis of birth asphyxia was a strong predictor Table 4. Multivariable Odds Ratios of Clinical Chorioamnionitis for Cerebral Palsy, Stratified of CP in our population, it is important by Type of Cerebral Palsy and Type of Brain Abnormality on Imaging to emphasize that apparent birth as- Variable No. (%) OR (95% CI) P Value phyxia may be a marker of multiple po- Limb involvement Hemiparesis 44 (40) 2.9 (0.9-9.4) .07 tential pathways leading to injury of the Quadriparesis 41 (38) 9.7 (3.4-27.8) Ͻ.001 developing brain. For this reason, “neo- Paraparesis* 15 (14) NA NA natal encephalopathy” is emerging as the Severity of disability preferred term for describing the status Moderate 67 (61) 4.3 (1.5-12.3) .01 of neurologically depressed new- Severe 38 (35) 7.5 (2.4-23.4) .001 borns,41-43 given that it does not imply a Type of neuroimaging abnormality† specific underlying pathogenesis. Focal infarction‡ 29 (27) NA NA Focal infarction was a common cause No abnormality 22 (20) 6.1 (1.5-24.2) .01 of hemiplegic CP in our patients, a find- White matter abnormalities§ 10 (9) NA NA ing that is consistent with other re- ࿣ “Hypoxic-ischemic injury” 7 (6) 17.5 (3.3-93.4) .001 ports.44,45 It is hypothesized that the Generalized atrophy 7 (6) 7.2 (1.2-43.9) .03 naturally occurring prothrombotic state Abbreviations: CI, confidence interval; NA, not available; OR, odds ratio. *Odds ratio for chorioamnionitis and cerebral palsy cannot be calculated due to a zero cell. of pregnancy, combined with a heredi- †Only infants with information available regarding neuroimaging results and maternal chorioamnionitis are included in this table. tary or acquired thrombophilia and the ‡Odds ratio, 95% CI, and P value not available because the variable was dropped from the model. When the multi- presence of a right-to-left shunt, all con- variable analysis was restricted to children with focal infarction, the significant risk factors retained in the model were preeclampsia (OR, 3.4; 95% CI, 1.0-11.8; P = .05) and intrauterine growth restriction (OR, 4.3; 95% CI, 1.0-18.3; tribute to the relatively high incidence P = .05). of thromboembolic stroke in the new- §Odds ratio, 95% CI, and P value not available because the variable was dropped from the model. When the multi- 46 variable analysis was restricted to children with white matter abnormalities only, intrauterine growth restriction was born period. Among children with fo- the only risk factor retained in the model (OR, 7.0; 95% CI, 1.2-40.3; P = .03). ࿣Other obstetric complications present in this group include placental abruption (n = 1), fetal intolerance of labor in the cal infarction in our study, preeclamp- setting of bicornuate uterus and uterine fibroids (n = 1), and emergency cesarean delivery for intolerance of labor sia was identified as a risk factor in the (n = 2). multivariable model. It is unclear

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whether preeclampsia and perinatal term infants. Recent studies have found 7. Suzuki J, Ito M. Incidence patterns of cerebral palsy in Shiga Prefecture, Japan, 1977-1991. Brain Dev. thromboembolic stroke represent out- that neonatal serologic markers of in- 2002;24:39-48. comes that both stem from a common flammation are associated with future 8. Nelson KB, Ellenberg JH. Antecedents of cerebral 56,57 palsy, I: univariate analysis of risks. AJDC. 1985;139: underlying prothrombotic condi- CP. If these inflammatory markers 1031-1038. tion47-49 or whether they are causally re- are mediators of perinatal brain injury 9. Grether JK, Nelson KB. Maternal infection and ce- lated via vasculopathy and clot forma- associated with chorioamnionitis, strat- rebral palsy in infants of normal birth weight [pub- lished correction appears in JAMA. 1998;279:118]. tion within the placenta. egies for protecting the developing brain JAMA. 1997;278:207-211. The incidence of CP in term infants from such perinatal inflammation may 10. Walstab J, Bell R, Reddihough D, Brennecke S, Bes- sell C, Beischer N. Antenatal and intrapartum ante- has not previously been reported to vary be beneficial for preventing CP. cedents of cerebral palsy: a case-control study. Aust by ethnicity, although few studies are We conclude that chorioamnionitis N Z J Obstet Gynaecol. 2002;42:138-146. 3,5,50 11. Wu YW, Colford JM. Chorioamnionitis as a risk available. In contrast, we found that confers a 4-fold overall increased risk factor for cerebral palsy: a meta-analysis. JAMA. 2000; among singleton term births, black eth- of CP in term infants, and that future 284:1417-1424. 12. Nelson KB, Ellenberg JH. Antecedents of cere- nicity was associated with a 3.6-fold in- etiologic studies of CP will be strength- bral palsy: multivariate analysis of risk. N Engl J Med. creased risk of CP, after adjusting for ened if children are stratified by type 1986;315:81-86. confounders. Our results also support of CP and neuroimaging findings. 13. Badawi N, Kurinczuk JJ, Keogh JM, et al. Intra- partum risk factors for newborn encephalopathy: the previous findings that chorioamnion- Western Australian case-control study. BMJ. 1998; Author Contributions: Dr Wu, as principal investiga- 317:1554-1558. itis may increase the risk of CP among tor of this study, had full access to all of the data in 51 14. Perlman JM. Maternal fever and neonatal de- whites but not blacks. Whether these the study and takes responsibility for the integrity of pression: preliminary observations. Clin Pediatr (Phila). ethnic differences are due to genetic or the data and the accuracy of the data analyses. 1999;38:287-291. Study concept and design: Wu, Escobar, Grether, 15. Lieberman E, Lang J, Richardson DK, Frigoletto other factors deserves further investi- Croen, Newman. FD, Heffner LJ, Cohen A. Intrapartum maternal fever gation. Acquisition of data: Wu, Escobar, Greene. and neonatal outcome. Pediatrics. 2000;105:8-13. Analysis and interpretation of data: Wu, Escobar, Our study is limited by multiple com- 16. Krieger N. Overcoming the absence of socioeco- Grether, Newman. nomic data in medical records: validation and appli- parisons and by the possibility that Drafting of the manuscript; obtained funding; study cation of a census-based methodology. Am J Public supervision: Wu, Newman. other confounders may have been over- Health. 1992;82:703-710. Critical revision of the manuscript for important in- 17. Practice Management Information Corporation looked. In addition, due to small sub- tellectual content: Wu, Escobar, Grether, Croen, (PMIC). International Classification of Diseases, Ninth group sample sizes, our stratified analy- Greene, Newman. Revision, Clinical Modification. 5th ed. Los Angeles, Statistical expertise: Wu, Greene, Newman. Calif: PMIC; 1999. ses produced ORs with wide CIs. Administrative, technical, or material support: Wu, 18. Kuban KC, Leviton A. Cerebral palsy. NEnglJMed. Children with CP were not examined Escobar, Croen. 1994;330:188-195. Funding/Support: This study was funded by the United 19. Nelson KB, Ellenberg JH. Children who “out- by study investigators to confirm their Cerebral Palsy Foundation. Dr Wu is a recipient of the grew” cerebral palsy. Pediatrics. 1982;69:529-536. diagnoses, and the lack of standardiza- Neurological Sciences Academic Development Award 20. Badawi N, Watson L, Petterson B, et al. What con- grant 5 K12 NSO1692. tion in both the type and timing of neu- stitutes cerebral palsy? Dev Med Child Neurol. 1998; Role of Sponsor: The United Cerebral Palsy Founda- 40:520-527. roimaging studies could lead to poten- tion had no involvement in, or control over, the con- 21. State of California Department of Health. Intra- tial bias in the ascertainment of brain duct of the study, the decision to publish, or the con- uterine Growth and Neonatal Risk in California. Sac- tent of this article. ramento: State of California Dept of Health; 1976. imaging abnormalities. Selection bias Acknowledgment: We thank Rowena Alison, Petra 22. Blair E. A research definition for “birth as- also may have occurred given the in- Liljestrand, PhD, Janet Lee, MS, Barry Malin, MPP, Lori phyxia”? Dev Med Child Neurol. 1993;35:449-452. Panossian, MS, and Saikumar Mamidipudi, MD, for 23. Roland EH, Poskitt K, Rodriguez E, Lupton BA, Hill complete follow-up, though restrict- their research assistance. We are also indebted to A. Perinatal hypoxic-ischemic thalamic injury: clinical ing both case and control infants to Donna Ferriero, MD, for her careful review of the features and neuroimaging. Ann Neurol. 1998;44: manuscript. those with 15 or more months’ fol- 161-166. 24. Pasternak JF, Gorey MT. 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