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Chorioamnionitis was associated with an increased risk of cerebral palsy in singleton children born at term
OBSTETRICS
Chorioamnionitis was associated with an increased risk of cerebral palsy in singleton children born at term WuYW, Escobar GJ,Grether JK,Croen LA,Greene JD, NewmanTB.Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003; 290: 2677^2684.
OBJECTIVE To evaluate the association between clinical chorioamnionitis and cerebral palsy (CP) in singleton infants born at or near term.
DESIGN Case-control study.
SETTING Health management organization in the USA.
SUBJECTS Cases were 109 children, born as singletons at 36 weeks gestation in 1991^1998, who had unexplained moderate to severe spastic or dyskinetic cerebral palsy and had been followed to at least 15 months of age (93% beyond 2 years). Controls were 218 children meeting the same criteria, but without cerebral palsy, plegia, or gait abnormality. Excluded were children with postnatal brain injury, developmental or genetic abnormality, congenital viral infection, or a condition other than CP.
METHODS Children with CP were identi¢ed from the organization’s electronic records and con¢rmed by chart review (including neuroimaging in 83% of cases) by a child neurologist, who was blinded to the presence of chorioamnionitis during pregnancy. Controls were randomly selected from the organization’s database. The presence of chorioamnionitis was ascertained from medical records, based on clinical ¢ndings, by a researcher blinded to CP status.
60
Evidence-based Obstetrics and Gynecology (2004) 6, 60 ^ 61 doi:10.1016/j.ebobgyn.2004.04.013
MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI) for CP in infants from pregnancies with clinical chorioamnionitis, compared to infants from pregnancies without chorioamnionitis, adjusted for other risk factors, such as maternal age, race, and parity, and intrauterine growth restriction. MAIN RESULTS Clinical chorioamnionitis was diagnosed in 14% of cases and 4% of controls (p=0.001). Also signi¢cantly associated with CP were maternal fever, prolonged rupture of membranes (436 hrs), and intrauterine growth restriction. By multivariable analysis, the OR of chorioamnionitis for CP was 4.1 (1.6^10). The association between chorioamnionitis and CP was stronger for children with quadriplegia (38% of cases, OR 9.7, CI 3.4^28) or severe disability (35% of cases, OR 7.5, CI 2.4^23). There was also a strong association in children diagnosed by neuroimaging with hypoxic-ischemic injury (6% of cases, OR 17.5, CI 3.3^93), but no signi¢cant association in children diagnosed with focal infarction (27% of cases) or white matter abnormalities (9% of cases). The attributable risk fraction of chorioamnionitis for CP in singleton nearterm infants is calculated to be 11% overall and 27% for spastic quadriplegia. CONCLUSION In children born as singletons at or near term, the risk of moderate to severe cerebral palsy was increased four-fold in those whose mothers had a clinical diagnosis of chorioamnionitis during pregnancy.
1361^259X/$ - see front matter Published by Elsevier Ltd.
Commentary This population-based study within a large health-maintenance organization provides new evidence that chorioamnionitis is associated with, and is probably a cause of, cerebral palsy (CP) in term and near-term infants. Singleton infants born at 36 weeks gestation or later had a 4.1-fold increase in odds of CP if there was a clinical diagnosis of chorioamnionitis (p=0.001) and a 9.7-fold increase in odds of CP involving all four limbs (spastic quadriparesis, po0.001). The association was independent of other observed predictors of CP. These observations are comparable with those of two previous reports.1,2 The authors of the present study estimated that about11% of otherwise unexplained CP may be related to chorioamnionitis, a figure also comparable with a previous estimate.1 As examined in other studies, the association of chorioamnionitis with CP in very preterm infants is apparently weaker and less consistent than in term and near term infants. There may be racial differences in susceptibility, as chorioamnionitis appears to increase risk of CP in Caucasian but not in African-American children, as observed by the present authors and in a study of very preterm children.3 Most cases of hemiplegic CP (74%) occurred in children whose neuroimaging studies indicated focal infarction of brain.Thus, if a term infant has hemiplegic CP, it is more likely than not that that child has had a stroke. As in previous studies, maternal fever and prolonged rupture of membranes were associated with risk of CP. It was not stated whether children exposed to chorioamnionitis more often than those unexposed had low Apgar scores, acidosis, and neonatal seizures, but it was implied that they did, as in other studies: ‘Our results suggest that chorioamnionitis may be the cause of the neonatal syndrome that often is referred to as birth asphyxia.’ Neonatal depression and seizures should lead to a search for evidence of infection in mother, placenta, or infant.
Importantly, the association of chorioamnionitis with CP was especially strong (OR 17.5, CI 3.3^93.4) in children whose brain imaging studies were interpreted to indicate ‘hypoxic-ischemic brain injury’. Does this mean that in£ammation and hypoxia must occur together to cause brain injury? Or is the brain imaging pattern commonly attributed to hypoxia or ischemia no more etiologically specif|c than the clinical syndrome of ‘birth asphyxia’? It is important to pursue this question because, although the f|nal cellular pathways of injury and imaging appearance might be similar in these two etiologies, strategies for prevention of brain injury would be quite di¡erent. Finally, it must be acknowledged that, as the authors stated, ‘There are currently no evidence-based strategies for preventing CP in term infants.’ It cannot be assumed, without clinical trials, that wider use of antibiotics could prevent CP in the presence of chorioamnionitis, and that such treatment would provide more benefit than harm to mothers and infants.
Karin B. Nelson MD National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
Literature cited 1. Grether JK, Nelson KB. Maternal infection and risk of cerebral palsy in infants of normal birthweight. JAMA 1997; 278: 201^211. 2. Walstab J, Bell R, Reddihough D et al. Antenatal and intrapartum antecedents of cerebral palsy: a case-control study. Aust NZ J Obstet Gynaecol 2002; 42: 138 ^146. 3. Grether JK, Nelson KB, Walsh E, et al. Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med 2003; 157: 26 ^32.
Evidence-based Obstetrics and Gynecology (2004) 6, 60 ^ 61
61
Chorioamnionitis was associated with an increased risk of cerebral palsy in singleton children born at term WuYW, Escobar GJ,Grether JK,Croen LA,Greene JD, NewmanTB.Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003; 290: 2677^2684.
OBJECTIVE To evaluate the association between clinical chorioamnionitis and cerebral palsy (CP) in singleton infants born at or near term.
DESIGN Case-control study.
SETTING Health management organization in the USA.
SUBJECTS Cases were 109 children, born as singletons at 36 weeks gestation in 1991^1998, who had unexplained moderate to severe spastic or dyskinetic cerebral palsy and had been followed to at least 15 months of age (93% beyond 2 years). Controls were 218 children meeting the same criteria, but without cerebral palsy, plegia, or gait abnormality. Excluded were children with postnatal brain injury, developmental or genetic abnormality, congenital viral infection, or a condition other than CP.
METHODS Children with CP were identi¢ed from the organization’s electronic records and con¢rmed by chart review (including neuroimaging in 83% of cases) by a child neurologist, who was blinded to the presence of chorioamnionitis during pregnancy. Controls were randomly selected from the organization’s database. The presence of chorioamnionitis was ascertained from medical records, based on clinical ¢ndings, by a researcher blinded to CP status.
60
Evidence-based Obstetrics and Gynecology (2004) 6, 60 ^ 61 doi:10.1016/j.ebobgyn.2004.04.013
MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI) for CP in infants from pregnancies with clinical chorioamnionitis, compared to infants from pregnancies without chorioamnionitis, adjusted for other risk factors, such as maternal age, race, and parity, and intrauterine growth restriction. MAIN RESULTS Clinical chorioamnionitis was diagnosed in 14% of cases and 4% of controls (p=0.001). Also signi¢cantly associated with CP were maternal fever, prolonged rupture of membranes (436 hrs), and intrauterine growth restriction. By multivariable analysis, the OR of chorioamnionitis for CP was 4.1 (1.6^10). The association between chorioamnionitis and CP was stronger for children with quadriplegia (38% of cases, OR 9.7, CI 3.4^28) or severe disability (35% of cases, OR 7.5, CI 2.4^23). There was also a strong association in children diagnosed by neuroimaging with hypoxic-ischemic injury (6% of cases, OR 17.5, CI 3.3^93), but no signi¢cant association in children diagnosed with focal infarction (27% of cases) or white matter abnormalities (9% of cases). The attributable risk fraction of chorioamnionitis for CP in singleton nearterm infants is calculated to be 11% overall and 27% for spastic quadriplegia. CONCLUSION In children born as singletons at or near term, the risk of moderate to severe cerebral palsy was increased four-fold in those whose mothers had a clinical diagnosis of chorioamnionitis during pregnancy.
1361^259X/$ - see front matter Published by Elsevier Ltd.
Commentary This population-based study within a large health-maintenance organization provides new evidence that chorioamnionitis is associated with, and is probably a cause of, cerebral palsy (CP) in term and near-term infants. Singleton infants born at 36 weeks gestation or later had a 4.1-fold increase in odds of CP if there was a clinical diagnosis of chorioamnionitis (p=0.001) and a 9.7-fold increase in odds of CP involving all four limbs (spastic quadriparesis, po0.001). The association was independent of other observed predictors of CP. These observations are comparable with those of two previous reports.1,2 The authors of the present study estimated that about11% of otherwise unexplained CP may be related to chorioamnionitis, a figure also comparable with a previous estimate.1 As examined in other studies, the association of chorioamnionitis with CP in very preterm infants is apparently weaker and less consistent than in term and near term infants. There may be racial differences in susceptibility, as chorioamnionitis appears to increase risk of CP in Caucasian but not in African-American children, as observed by the present authors and in a study of very preterm children.3 Most cases of hemiplegic CP (74%) occurred in children whose neuroimaging studies indicated focal infarction of brain.Thus, if a term infant has hemiplegic CP, it is more likely than not that that child has had a stroke. As in previous studies, maternal fever and prolonged rupture of membranes were associated with risk of CP. It was not stated whether children exposed to chorioamnionitis more often than those unexposed had low Apgar scores, acidosis, and neonatal seizures, but it was implied that they did, as in other studies: ‘Our results suggest that chorioamnionitis may be the cause of the neonatal syndrome that often is referred to as birth asphyxia.’ Neonatal depression and seizures should lead to a search for evidence of infection in mother, placenta, or infant.
Importantly, the association of chorioamnionitis with CP was especially strong (OR 17.5, CI 3.3^93.4) in children whose brain imaging studies were interpreted to indicate ‘hypoxic-ischemic brain injury’. Does this mean that in£ammation and hypoxia must occur together to cause brain injury? Or is the brain imaging pattern commonly attributed to hypoxia or ischemia no more etiologically specif|c than the clinical syndrome of ‘birth asphyxia’? It is important to pursue this question because, although the f|nal cellular pathways of injury and imaging appearance might be similar in these two etiologies, strategies for prevention of brain injury would be quite di¡erent. Finally, it must be acknowledged that, as the authors stated, ‘There are currently no evidence-based strategies for preventing CP in term infants.’ It cannot be assumed, without clinical trials, that wider use of antibiotics could prevent CP in the presence of chorioamnionitis, and that such treatment would provide more benefit than harm to mothers and infants.
Karin B. Nelson MD National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
Literature cited 1. Grether JK, Nelson KB. Maternal infection and risk of cerebral palsy in infants of normal birthweight. JAMA 1997; 278: 201^211. 2. Walstab J, Bell R, Reddihough D et al. Antenatal and intrapartum antecedents of cerebral palsy: a case-control study. Aust NZ J Obstet Gynaecol 2002; 42: 138 ^146. 3. Grether JK, Nelson KB, Walsh E, et al. Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med 2003; 157: 26 ^32.
Evidence-based Obstetrics and Gynecology (2004) 6, 60 ^ 61
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