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Review |

Chorioamnionitis as a Risk Factor for Cerebral Palsy:  A Meta-analysis FREE

Yvonne W. Wu, MD, MPH; John M. Colford, Jr, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Neurology and Pediatrics, University of California, San Francisco (Dr Wu); and the Division of Epidemiology, School of Public Health, University of California, Berkeley (Dr Colford).


JAMA. 2000;284(11):1417-1424. doi:10.1001/jama.284.11.1417.
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Published online

Context Chorioamnionitis has been implicated in the pathogenesis of cerebral palsy, but most studies have not reported a significant association. Cystic periventricular leukomalacia (cPVL) is believed to be a precursor of cerebral palsy in preterm infants.

Objectives To determine whether chorioamnionitis is associated with cerebral palsy or cPVL and to examine factors that may explain differences in study results.

Data Sources Searches of MEDLINE (1966-1999), Index Medicus (1960-1965), Doctoral Dissertation Abstracts On-Line (1861-1999), bibliographies, and online conference proceedings (1999) were performed for English-language studies with titles or abstracts that discussed prenatal risk factors for cerebral palsy or cPVL.

Study Selection Of 229 initially identified publications, meta-analyses were performed on studies that addressed the association between clinical (n = 19) or histologic (n = 7) chorioamnionitis and cerebral palsy or cPVL in both preterm and full-term infants. Inclusion criteria were: presence of appropriate exposure and outcome measures, case-control or cohort study design, and provision of sufficient data to calculate relative risks (RRs) or odds ratios with 95% confidence intervals (CIs). Studies evaluating risk of cerebral palsy following maternal fever, urinary tract infection, or other maternal infection were collected, but not included in the meta-analysis.

Data Extraction Information from individual studies was abstracted using standardized forms by 2 independent observers blinded to authors' names, journal titles, and funding sources.

Data Synthesis Using a random effects model, clinical chorioamnionitis was significantly associated with both cerebral palsy (RR, 1.9; 95% CI, 1.4-2.5) and cPVL (RR, 3.0; 95% CI, 2.2-4.0) in preterm infants. The RR of histologic chorioamnionitis and cerebral palsy was 1.6 (95% CI, 0.9-2.7) in preterm infants, and histologic chorioamnionitis was significantly associated with cPVL (RR, 2.1; 95% CI, 1.5-2.9). Among full-term infants, a positive association was found between clinical chorioamnionitis and cerebral palsy (RR, 4.7; 95% CI, 1.3-16.2). Factors explaining differences in study results included varying definitions of clinical chorioamnionitis, extent of blinding in determining exposure status, and whether individual studies adjusted for potential confounders.

Conclusion Our meta-analysis indicates that chorioamnionitis is a risk factor for both cerebral palsy and cPVL.

Figures in this Article

Despite improvements in perinatal medicine, the prevalence of cerebral palsy has increased over the last 2 decades,1 and the etiology of cerebral palsy remains poorly understood. Evidence suggests that 70% to 80% of cases of cerebral palsy are due to prenatal factors,2 and that birth asphyxia plays a relatively minor role.3

Chorioamnionitis, or intrauterine infection, has been implicated as a potential cause of cerebral palsy.46 Chorioamnionitis is common and often subclinical. Histologic signs of chorioamnionitis can be detected in more than 50% of women who deliver prematurely,7 and most patients have no clinical signs of infection.8 It is postulated that both subclinical and clinical chorioamnionitis can lead to a fetal inflammatory response, and that this inflammation contributes to neonatal brain injury and subsequent cerebral palsy.5,9,10 Recent reports of elevated neonatal blood11 and amniotic fluid12 cytokine levels in children with cerebral palsy support the notion that cerebral palsy is preceded by a perinatal inflammatory condition.

A number of studies have assessed the relationship between chorioamnionitis and cerebral palsy in premature infants,1220 but most have not reported a significant association. In full-term infants, the existing literature supports a relationship between chorioamnionitis and cerebral palsy,6,21 but few studies are available.

We conducted a meta-analysis to evaluate the potential association between chorioamnionitis and cerebral palsy in both full-term and preterm infants. In addition to cerebral palsy, we were interested in the outcome of cystic periventricular leukomalacia (cPVL), a powerful predictor of cerebral palsy in preterm infants. An estimated 60% to 100% of patients with cPVL go on to develop cerebral palsy.22 We performed a systematic review of the existing literature addressing all forms of chorioamnionitis as a potential risk factor for cerebral palsy or cPVL.

Study Selection

MEDLINE (1966-1999) was searched using keywords cerebral palsy and etiology with all possible suffixes included (eg, etiologies, etiologic), as well as medical subject headings cerebral palsy, etiology; periventricular leukomalacia, etiology; periventricular leukomalacia, epidemiology; and chorioamnionitis, complications. Index Medicus (1960-1965) was searched by hand for the term cerebral palsy. Doctoral Dissertation Abstracts On-Line (North American Universities, 1861-1999) was searched for keywords cerebral palsy, chorioamnionitis, maternal infection, and leukomalacia. Conference proceedings available online were searched (Society for Pediatric Research, 1999, and Child Neurology Society, 1999), as were abstracts from the January 2000 meeting of the Society for Maternal-Fetal Medicine. Bibliographies of all relevant articles were reviewed for further potential references. Only studies published in English were included.

Studies with titles or abstracts discussing prenatal risk factors for cerebral palsy or cPVL were retrieved. Any study with primary data investigating a relevant exposure and outcome was submitted for further review. A relevant exposure included any maternal infection or sign of infection during pregnancy (eg, chorioamnionitis, urinary tract infection, fever), with the exception of known congenital infections such as toxoplasmosis and cytomegaloviral infection. Relevant outcomes included cerebral palsy by any definition, cPVL, or echolucencies on neonatal ultrasound. Studies that included the ultrasonographic findings of echodensity, echogenicity, or ventriculomegaly in the definition of cPVL were excluded from the analysis. Abnormal echodensity can be a transient finding that does not invariably lead to cPVL.22 When multiple publications reported relative risks (RRs) for the same study subjects, the most recent publication was chosen.

Data Abstraction

The studies identified by the criteria described above were then reviewed independently by both authors, with all references to author names, journal title, and funding sources removed. The following inclusion criteria were applied: (1) appropriate exposure and outcome measures, as defined above; (2) case-control or cohort study design; and (3) RR or odds ratio with 95% confidence interval (CI) provided, or able to be calculated from the data presented in the article. The following data were abstracted onto standardized forms: publication year, years of study, gestational age, method of obtaining exposure information, definition of chorioamnionitis/maternal infection, definition of cerebral palsy, minimum age at diagnosis of cerebral palsy, definition of cPVL, source of cases and controls, extent of blinding, extent of controlling for potential confounding, and relevant risk ratio estimates.

Whenever possible, chorioamnionitis was categorized as clinical, histologic, and/or microbiologic. A clinical diagnosis of chorioamnionitis is usually based on criteria such as maternal fever, uterine tenderness, malodorous amniotic fluid, maternal or fetal tachycardia, and maternal leukocytosis.23 If based on such clinical criteria alone, the diagnosis was categorized as clinical chorioamnionitis. Histologic chorioamnionitis represented pathologic findings on placental histology, including inflammation of the placental membranes, fetal vasculitis, or funisitis (inflammation of the umbilical cord).24 Microbiologic chorioamnionitis was defined as retrieval of microbial organisms from the amniotic fluid or placental cultures.

If a potential confounder was matched in the study design, or included in a multivariate analysis, the resulting risk estimate was considered to be adjusted for that confounder. Whenever possible, an odds ratio was calculated and used in the summary calculations. This allowed the individual risk estimates to be as consistent as possible since most studies reported odds ratios and not RRs. The odds ratio can be interpreted as an approximation of the RR since the prevalence of cerebral palsy is low (1.5-2.5/1000 live births).25 The Woolf26 method was used in calculating a 95% CI from the raw data if available; otherwise, we calculated a 95% CI using the z score obtained from the corresponding P value.27 If a published RR or 95% CI was inconsistent with the raw data provided by the study,28,29 the effect measure was recalculated using the available data. When a zero cell was encountered,28,30 a value of 0.5 was added to each cell in the corresponding 2 × 2 table. When there was insufficient information to calculate an RR, an attempt was made to contact the original authors for further information. Raw data and RR estimates for each study are available from the corresponding author (Y.W.W.).

Statistical Analysis

In choosing from multiple effect estimates in a single study, the least adjusted estimate (ie, the estimate adjusted for the fewest number of confounding variables) was used as the primary outcome measure. Choosing the least adjusted estimate provided the maximum opportunity for comparison of consistent estimates across studies since the majority of studies only reported RRs that were uncontrolled for potential confounders. Studies with adjusted estimates were analyzed separately. In the summary estimate for either clinical or histologic chorioamnionitis, the RR for clinical chorioamnionitis was chosen over histologic chorioamnionitis, when studies provided both values, since the majority of studies involved chorioamnionitis that was defined by clinical criteria. Some studies presented multiple effect estimates for the relationship between histologic chorioamnionitis and cerebral palsy or cPVL, based on separate pathologic findings.9,18,31 For each of these studies, a single RR was calculated by combining the separate effect estimates using the Mantel-Haenszel method.32

Summary RR estimates were calculated by taking a weighted average of individual study results using a random effects model. The weight for each study is the inverse of the sum of 2 terms: the study variance and a term accounting for between-study variability.33 Homogeneity was formally tested using the general variance-based method,33 in which a conservative value of P<.10 was used to classify study results as heterogeneous. Heterogeneous studies may not measure the same underlying association between exposure and disease, so that differences in study results are unlikely to be due to random variation alone.

Finally, separate meta-analyses were performed after stratification by factors pertaining to study quality, including study design, definition of chorioamnionitis, diagnostic criteria for cerebral palsy, and extent of control for potential confounders. Differences in the stratified summary estimates were evaluated using a z score.34 Potential publication bias was evaluated with a Kendall τ test.35

A total of 229 articles were retrieved. One hundred six articles were from MEDLINE, 11 from Index Medicus, 2 from Doctoral Dissertation Abstracts On-line, 3 from conference proceedings, and 107 from bibliography review. Forty-four publications were submitted for blinded review. The remaining articles were discarded because of redundancy in data reporting,4,3640 because they did not contain original data, or because they lacked information regarding maternal infection as a risk factor for cerebral palsy or cPVL. The blinded review further excluded 14 studies because of insufficient information to calculate an RR.4154 The remaining 30 studies are summarized in Table 1.

Table Graphic Jump LocationTable 1. Summary of Study Characteristics
Premature Infants

Seventeen studies evaluated the association between clinical chorioamnionitis and cerebral palsy1220,55,56 or cPVL29,31,5760 in preterm infants, with RRs ranging from 0.95 to 7.3 (Figure 1). Ten of these 17 studies found no significant association. When the study results were analyzed using the random effects model, clinical chorioamnionitis was significantly associated with both cerebral palsy (RR, 1.9; 95% CI, 1.4-2.5) and cPVL (RR, 3.0; 95% CI, 2.2-4.0).

Figure. Chorioamnionitis and Cerebral Palsy (CP) or Cystic Periventricular Leukomalacia (cPVL) in Premature Infants
Graphic Jump Location
Asterisks indicate that P values refer to the test of homogeneity. This test evaluates the likelihood that differences between studies are due to random variation alone. If P>.10, the studies are considered homogeneous, and variability in study results is more likely to be due to chance alone.

Five studies evaluated the association between histologic chorioamnionitis and cerebral palsy in premature infants,12,1719,24 with only 1 reporting a significant association (Figure 1).19 The meta-analysis of these 5 studies produced an RR of 1.6 (95% CI, 0.9-2.7). Two studies evaluated the association between histologic chorioamnionitis and cPVL,9,31 and the summary estimate was significant (RR, 2.1; 95% CI, 1.5-2.9). When clinical and histologic chorioamnionitis were combined into a single category as a potential risk factor for cerebral palsy, the test of homogeneity suggested that the combined studies were heterogeneous (P = .07). The single study that evaluated microbiologic evidence of chorioamnionitis found no significant association with cerebral palsy.12

Stratified Analysis in Preterm Infants

A stratified analysis was performed to investigate possible sources of heterogeneity in studies of clinical chorioamnionitis in premature infants (Table 2). Both cohort studies and case-control studies produced significant summary RRs, but a stronger effect was seen in cohort studies (RR, 3.0 vs 1.8; P = .001). Studies that included only very low-birth-weight infants (<1500 g) or infants born before 32 weeks' gestation were statistically heterogeneous (P = .02).

Table Graphic Jump LocationTable 2. Summary Estimates of Clinical Chorioamnionitis and Cerebral Palsy or Cystic Periventricular Leukomalacia in Premature Infants Stratified by Study Characteristics*

Six articles provided no specific criteria for the diagnosis of clinical chorioamnionitis. The summary RR from these studies was lower than that calculated from the 7 studies with the most stringent diagnostic criteria for clinical chorioamnionitis (ie, requiring 2 clinical signs or symptoms; RR, 1.8 vs 2.9; P = .005; Table 2). Evidence for heterogeneity was found among studies without specific diagnostic criteria (P = .08). Five studies examining the risk of maternal fever alone9,18,57,61,62 were also statistically heterogeneous (P = .004).

The baseline prevalence of clinical chorioamnionitis in preterm infants estimated from control populations varied from 3%29,57,63 to 56%.14 The 7 studies reporting a relatively high (>15%) baseline prevalence were statistically heterogeneous (P = .006; Table 2). Studies that did not explicitly state that ascertainment of chorioamnionitis was performed blinded to outcome status produced a larger summary estimate than studies that blinded the exposure ascertainment (RR, 3.0 vs 1.8; P = .002).

The baseline prevalence of histologic chorioamnionitis in healthy premature control infants ranged from 33%31 to 72%.18 Of the 7 studies addressing histologic chorioamnionitis in preterm infants, only 2 studies used the same pathologic findings in defining chorioamnionitis.

The definition of cerebral palsy differed greatly among studies of premature infants (Table 2). Of the 8 studies that provided adequate information, 4 did not require a minimum age of 2 years for the diagnosis of cerebral palsy, and most did not confirm the diagnosis by an examination performed by study personnel. Some studies excluded children with congenital anomalies, while others did not specify any exclusion criteria. Cystic PVL was defined as echolucencies seen in the periventricular white matter on head ultrasound. Of the 2 studies9,64 that noted age at which ultrasounds were obtained, only 1 routinely performed follow-up scans after 2 weeks of life.9

Six studies of clinical chorioamnionitis in premature infants reported RRs controlled for gestational age.13,1719,29,58 The summary RR calculated from adjusted estimates was smaller than that derived from unadjusted estimates (RR, 1.8 vs 2.5; P = .03; Table 2). Two positive associations became insignificant after controlling for gestational age,15,58 and only 1 study provided an RR that remained significant after adjustment,57 but this study controlled only for prolonged rupture of membranes.

Full-Term Infants

For full-term infants, 2 studies of clinical chorioamnionitis and cerebral palsy yielded a summary RR of 4.7 (95% CI, 1.3-16.2).6,21 The single study examining the association between histologic chorioamnionitis and cerebral palsy in full-term infants found an RR of 8.9 (95% CI, 1.9-40).6 No studies evaluated microbiologic chorioamnionitis.

Sensitivity Analysis

The association between clinical chorioamnionitis and cerebral palsy was determined for studies including all gestational ages. The resulting summary RR differed minimally from that calculated for premature infants only, although evidence of heterogeneity was present (RR, 2.1; 95% CI, 1.5-3.0; P = .08). The addition of the single study addressing histologic chorioamnionitis in full-term infants6 did not appreciably change the association between histologic chorioamnionitis and cerebral palsy.

Publication Bias

Any meta-analysis is subject to potential publication bias (ie, nonpublication of studies that show no association between exposure and outcome). A Kendall τ test (P = .27) did not support the presence of significant publication bias. Of note, only 2 negative studies were identified among the excluded studies that lacked sufficient information to calculate an RR. One reported no association between chorioamnionitis and cPVL,43 and the other found no association between chorioamnionitis and cerebral palsy or death.45

Five studies evaluating the risk of cerebral palsy following maternal urinary tract infection during pregnancy6,15,30,62,65 found widely varying results, with RRs ranging from 0.16 to 3.9. It is likely that these studies are heterogeneous (P = .05), and therefore not evaluating the same underlying association.

Based on the available literature, chorioamnionitis appears to be associated with both cerebral palsy and cPVL in premature infants. Full-term infants exposed to chorioamnionitis also exhibit an increased risk of cerebral palsy in the 2 studies that are available. A growing body of evidence supports the notion that fetal inflammation caused by maternal infection contributes to neonatal brain injury. Experimental maternal intrauterine infection induces cytokine production in fetal rat brains,66 and maternal intrauterine infection leads to a robust fetal inflammatory response in humans.67 The cytokine hypothesis10 states that elevated blood and brain cytokine levels resulting from maternal infection lead to central nervous system damage in the fetus, and subsequent cerebral palsy. Indeed, experimental evidence indicates that inflammatory cytokines can be neurotoxic both in vitro68 and in vivo,69 and that cytokines inhibit oligodendrocytes in the developing white matter.70 In a rabbit model, experimentally induced intrauterine infection has been shown to cause fetal white matter brain lesions.71

Neonatal blood inflammatory cytokine levels are significantly higher in full-term infants who develop cerebral palsy than in controls.11 In the preterm population, a positive association has been reported between intra-amniotic fluid inflammatory cytokines and cerebral palsy72; and intra-amnionitic,12 brain,73,74 and umbilical cord75 cytokine levels are all associated with cPVL. Although these findings do not establish a causal link between cytokines and perinatal brain injury, they do provide evidence that cerebral palsy is associated with an inflammatory environment at birth.

To better understand the relationships between chorioamnionitis, inflammation, and cerebral palsy, it is crucial to develop consensus definitions of clinical and histologic chorioamnionitis. Most published reports do not apply specific diagnostic criteria for clinical chorioamnionitis, and as a group, these studies produced heterogeneous results. The results of our stratified analysis suggest that a stronger association is seen when studies use more stringent diagnostic criteria. Not surprisingly, studies evaluating the effect of fever alone were statistically heterogeneous since fever during labor may be due to epidural analgesia76 or infections other than chorioamnionitis. Studies that do not include strict clinical criteria beyond the presence of fever may lead to an overdiagnosis of chorioamnionitis, which may explain why studies reporting a relatively high prevalence (>15%) of clinical chorioamnionitis also demonstrated statistical evidence of heterogeneity.

When chorioamnionitis was diagnosed without knowledge of outcome status, a significantly lower summary RR was found. This demonstrates the importance of using blinded observers when evaluating the presence of chorioamnionitis.

The definition of cerebral palsy varied between studies; some explicitly excluded children with postnatal causes or congenital anomalies, while others did not. Although cerebral palsy can be difficult to diagnose in children younger than 2 years, 1 study made the diagnosis in infants as young as 6 months. A consensus definition of cerebral palsy is needed.

Few studies report significant associations between chorioamnionitis and cerebral palsy after adjusting for potential confounders. Although gestational age appears to be a possible confounder, it may also lie directly in the causal pathway between maternal infection and cerebral palsy. Chorioamnionitis is associated with premature delivery,7 and low gestational age is in turn associated with a host of intrinsic vulnerabilities within the brain that have been implicated in the pathogenesis of cPVL and cerebral palsy.77 Therefore, if low gestational age resulting from maternal infection in itself plays a direct role in the pathogenesis of cerebral palsy, then adjusting for its effect will falsely diminish the observed association between chorioamnionitis and cerebral palsy. Two studies of clinical chorioamnionitis in premature infants reported positive univariate associations, as well as adjusted estimates of RR15,58; both became insignificant after controlling for the effect of gestational age. It is unclear if this is because chorioamnionitis does not contribute independently to cerebral palsy, or perhaps because gestational age lies on the causal pathway.

Preeclampsia has been shown to be strongly protective against cerebral palsy in preterm infants.63,78 Failure to adjust for this potential confounder could bias the RR away from the null, giving falsely high estimates of association. The single study that adjusted for the effect of preeclampsia,58 as well as the 1 study that excluded women with preeclampsia,18 found no significant association between chorioamnionitis and cerebral palsy in premature infants. This only reinforces the need to control for the potential positive confounding effect of preeclampsia in future studies.

Other factors may interact with chorioamnionitis in the pathogenetic pathway leading to cerebral palsy. For instance, 1 study suggests that there may be a statistical interaction between birth asphyxia, or hypoxic-ischemic brain injury, and maternal infection.79 Genetic predisposition to cytokine functional polymorphisms may also play a role in determining which infants exposed to intrauterine infection go on to develop brain damage.80 Individuals with a tumor necrosis factor α promoter region polymorphism demonstrate an increased production of this cytokine, and an increased risk of preterm rupture of membranes.81 Such genetic factors may in part determine the extent of inflammation that occurs in the face of maternal infection.

All meta-analyses are subject to limitations. The biases inherent to observational studies are not eliminated in a quantitative synthesis. There may be publication bias, incomplete ascertainment of published studies, and errors in data abstraction. We did not find statistical evidence for publication bias. Blinded independent abstractors were used in an attempt to maximize accuracy in data abstraction.

The attributable risk of chorioamnionitis and spastic cerebral palsy has been reported to be as high as 12% (95% CI, 4%-20%) in normal-birth-weight children.6 For premature infants, a conservative calculation using the lower end of our 95% CI (RR, 1.4) yields an attributable risk of 28%. The total annual cost of cerebral palsy in the United States has been estimated at $5 billion.25 Even a partial reduction in the incidence of cerebral palsy could substantially reduce both financial costs and personal suffering. Would efforts to prevent chorioamnionitis and fetal inflammation lead to a decrease in the prevalence of cerebral palsy? Do the tocolytic, antibiotic, and steroid agents currently used in perinatal medicine alleviate or perhaps aggravate the fetal brain damage postulated to occur in response to maternal infection and fetal inflammation? Multicenter collaborations between obstetricians, neonatologists, and neurodevelopmental specialists are needed to address these important and complex questions.

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Verma U, Tejani N, Klein S.  et al.  Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate.  Am J Obstet Gynecol.1997;176:275-281.
de Vries LS, Regev R, Dubowitz LM, Whitelaw A, Aber VR. Perinatal risk factors for the development of extensive cystic leukomalacia.  Am J Dis Child.1988;142:732-735.
Churchill JA, Masland RL, Naylor AA, Ashworth MR. The etiology of cerebral palsy in pre-term infants.  Dev Med Child Neurol.1974;16:143-149.
Lilienfeld A, Parkhurst E. A study of the association of factors of pregnancy and parturition with the development of cerebral palsy.  Am J Hygiene.1951;53:262-282.
Gaffney G, Flavell V, Johnson A, Squier M, Sellers S. Cerebral palsy and neonatal encephalopathy.  Arch Dis Child Fetal Neonatal Ed.1994;70:F195-F200.
Canterino JC, Verma UL, Visintainer PF, Figueroa R, Klein SA, Tejani NA. Maternal magnesium sulfate and the development of neonatal periventricular leucomalacia and intraventricular hemorrhage.  Obstet Gynecol.1999;93:396-402.
Laisram N, Srivastava VK, Srivastava RK. Cerebral palsy—an etiological study.  Indian J Pediatr.1992;59:723-728.
Mayer PS, Wingate MB. Obstetric factors in cerebral palsy.  Obstet Gynecol.1978;51:399-406.
Magee JF, Rodriguez EC, Roland E, Hill A. Placental pathology in cases of cystic periventricular leukomalacia.  Mod Pathol.1996;9:4P.
Nebel W, Flowers C, Hill C.  et al.  Obstetric factors in cerebral palsy, a North Carolina study.  N C Med J.1962;23:229-235.
Brandt S, Westergaard-Nielsen V. Etiological factors in cerebral palsy and their correlation with various clinical entities.  Dan Med Bull.1958;5:47-51.
Gray PH, Hurley TM, Rogers YM.  et al.  Survival and neonatal and neurodevelopmental outcome of 24-29 week gestation infants according to primary cause of preterm delivery.  Aust N Z J Obstet Gynaecol.1997;37:161-168.
Kim JN, Namgung R, Chang W.  et al.  Prospective evaluation of perinatal risk factors for cerebral palsy and delayed development in high risk infants.  Yonsei Med J.1999;40:363-370.
Perlman JM, Risser R, Broyles RS. Bilateral cystic periventricular leukomalacia in the premature infant: associated risk factors.  Pediatrics.1996;97:822-827.
Baud O, Foix-L'Helias L, Kaminski M.  et al.  Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants.  N Engl J Med.1999;341:1190-1196.
Zupan V, Gonzalez P, Lacaze-Masmonteil T.  et al.  Periventricular leukomalacia: risk factors revisited.  Dev Med Child Neurol.1996;38:1061-1067.
Wiswell TE, Graziani LJ, Kornhauser MS.  et al.  Effects of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with high-frequency jet ventilation.  Pediatrics.1996;98:918-924.
Eastman NJ, DeLeon M. The etiology of cerebral palsy.  Am J Obstet Gynecol.1955;69:950-961.
Polivka BJ, Nickel JT, Wilkins III JR. Urinary tract infection during pregnancy: a risk factor for cerebral palsy?  J Obstet Gynecol Neonatal Nurs.1997;26:405-413.
Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies.  Lancet.1995;346:1449-1454.
Bejar RF, Vaucher YE, Benirschke K, Berry CC. Postnatal white matter necrosis in preterm infants.  J Perinatol.1992;12:3-8.
Palmer L, Blair E, Petterson B, Burton P. Antenatal antecedents of moderate and severe cerebral palsy.  Paediatr Perinat Epidemiol.1995;9:171-184.
Cai Z, Pan Z, Pang Y, Evan OB, Rhodes PG. Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration.  Pediatr Res.2000;47:64-72.
Yoon BH, Romero R, Park JS.  et al.  Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments.  Am J Obstet Gynecol.1998;179:1254-1260.
Jeohn GH, Kong LY, Wilson B, Hudson P, Hong JS. Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures.  J Neuroimmunol.1998;85:1-10.
Dommerges M, Patkai J, Renauld J, Evrard P, Gressens P. Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium.  Ann Neurol.2000;47:54-63.
Merrill JE. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological.  Dev Neurosci.1992;14:1-10.
Yoon BH, Kim CJ, Romero R.  et al.  Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits.  Am J Obstet Gynecol.1997;177:797-802.
Yoon BH. Intraamniotic inflammation and the development of cerebral palsy at three years of age.  Am J Obstet Gynecol.1999;180(suppl):S2.
Yoon BH, Romero R, Kim CJ.  et al.  High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia.  Am J Obstet Gynecol.1997;177:406-411.
Deguchi K, Mizuguchi M, Takashima S. Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia.  Pediatr Neurol.1996;14:13-16.
Yoon BH, Romero R, Yang SH.  et al.  Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia.  Am J Obstet Gynecol.1996;174:1433-1440.
Herbst A, Wølner-Hanssen P, Ingemarsson I. Risk factors for fever in labor.  Obstet Gynecol.1995;86:790-794.
Volpe JJ. Brain injury in the premature infant—from pathogenesis to prevention.  Brain Dev.1997;19:519-534.
Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?  Pediatrics.1995;95:263-269.
Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight.  Am J Obstet Gynecol.1998;179:507-513.
Dammann O, Durum SK, Leviton A. Modification of the infection-associated risks of preterm birth and white matter damage in the preterm newborn by polymorphisms in the tumor necrosis factor-locus?  Pathogenesis.1999;1:171-177.
Roberts AK, Monzon-Bordonaba F, Van Deerlin PG.  et al.  Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.  Am J Obstet Gynecol.1999;180:1297-1302.
Torfs CP, van den Berg B, Oechsli FW, Cummins S. Prenatal and perinatal factors in the etiology of cerebral palsy.  J Pediatr.1990;116:615-619.
Petridou E, Koussouri M, Toupadaki N.  et al.  Risk factors for cerebral palsy: a case-control study in Greece.  Scand J Soc Med.1996;24:14-26.

Figures

Figure. Chorioamnionitis and Cerebral Palsy (CP) or Cystic Periventricular Leukomalacia (cPVL) in Premature Infants
Graphic Jump Location
Asterisks indicate that P values refer to the test of homogeneity. This test evaluates the likelihood that differences between studies are due to random variation alone. If P>.10, the studies are considered homogeneous, and variability in study results is more likely to be due to chance alone.

Tables

Table Graphic Jump LocationTable 1. Summary of Study Characteristics
Table Graphic Jump LocationTable 2. Summary Estimates of Clinical Chorioamnionitis and Cerebral Palsy or Cystic Periventricular Leukomalacia in Premature Infants Stratified by Study Characteristics*

References

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Murphy DJ, Hope PL, Johnson A. Neonatal risk factors for cerebral palsy in very preterm babies: case-control study.  BMJ.1997;314:404-408.
Spinillo A, Capuzzo E, Orcesi S, Stronati M, Di Mario M, Fazzi E. Antenatal and delivery risk factors simultaneously associated with neonatal death and cerebral palsy in preterm infants.  Early Hum Dev.1997;48:81-91.
Polivka B. Risk Factors for Cerebral Palsy: A Multivariate Model. Columbus: Ohio State University; 1990:132.
O'Shea TM, Klinepeter KL, Dillard RG. Prenatal events and the risk of cerebral palsy in very low birth weight infants.  Am J Epidemiol.1998;147:362-369.
Bejar R, Wozniak P, Allard M.  et al.  Antenatal origin of neurologic damage in newborn infants, I: preterm infants.  Am J Obstet Gynecol.1988;159:357-363.
Roboz P. Etiology of congenital cerebral palsy.  Arch Pediatr.1962;79:233-250.
Carbine DN. Neonatal CNS Injury and Developmental Outcome After Prolonged Premature Rupture of Membranes. San Francisco, Calif: Pediatric Academic Societies; 1999.
Verma U, Tejani N, Klein S.  et al.  Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate.  Am J Obstet Gynecol.1997;176:275-281.
de Vries LS, Regev R, Dubowitz LM, Whitelaw A, Aber VR. Perinatal risk factors for the development of extensive cystic leukomalacia.  Am J Dis Child.1988;142:732-735.
Churchill JA, Masland RL, Naylor AA, Ashworth MR. The etiology of cerebral palsy in pre-term infants.  Dev Med Child Neurol.1974;16:143-149.
Lilienfeld A, Parkhurst E. A study of the association of factors of pregnancy and parturition with the development of cerebral palsy.  Am J Hygiene.1951;53:262-282.
Gaffney G, Flavell V, Johnson A, Squier M, Sellers S. Cerebral palsy and neonatal encephalopathy.  Arch Dis Child Fetal Neonatal Ed.1994;70:F195-F200.
Canterino JC, Verma UL, Visintainer PF, Figueroa R, Klein SA, Tejani NA. Maternal magnesium sulfate and the development of neonatal periventricular leucomalacia and intraventricular hemorrhage.  Obstet Gynecol.1999;93:396-402.
Laisram N, Srivastava VK, Srivastava RK. Cerebral palsy—an etiological study.  Indian J Pediatr.1992;59:723-728.
Mayer PS, Wingate MB. Obstetric factors in cerebral palsy.  Obstet Gynecol.1978;51:399-406.
Magee JF, Rodriguez EC, Roland E, Hill A. Placental pathology in cases of cystic periventricular leukomalacia.  Mod Pathol.1996;9:4P.
Nebel W, Flowers C, Hill C.  et al.  Obstetric factors in cerebral palsy, a North Carolina study.  N C Med J.1962;23:229-235.
Brandt S, Westergaard-Nielsen V. Etiological factors in cerebral palsy and their correlation with various clinical entities.  Dan Med Bull.1958;5:47-51.
Gray PH, Hurley TM, Rogers YM.  et al.  Survival and neonatal and neurodevelopmental outcome of 24-29 week gestation infants according to primary cause of preterm delivery.  Aust N Z J Obstet Gynaecol.1997;37:161-168.
Kim JN, Namgung R, Chang W.  et al.  Prospective evaluation of perinatal risk factors for cerebral palsy and delayed development in high risk infants.  Yonsei Med J.1999;40:363-370.
Perlman JM, Risser R, Broyles RS. Bilateral cystic periventricular leukomalacia in the premature infant: associated risk factors.  Pediatrics.1996;97:822-827.
Baud O, Foix-L'Helias L, Kaminski M.  et al.  Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants.  N Engl J Med.1999;341:1190-1196.
Zupan V, Gonzalez P, Lacaze-Masmonteil T.  et al.  Periventricular leukomalacia: risk factors revisited.  Dev Med Child Neurol.1996;38:1061-1067.
Wiswell TE, Graziani LJ, Kornhauser MS.  et al.  Effects of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with high-frequency jet ventilation.  Pediatrics.1996;98:918-924.
Eastman NJ, DeLeon M. The etiology of cerebral palsy.  Am J Obstet Gynecol.1955;69:950-961.
Polivka BJ, Nickel JT, Wilkins III JR. Urinary tract infection during pregnancy: a risk factor for cerebral palsy?  J Obstet Gynecol Neonatal Nurs.1997;26:405-413.
Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies.  Lancet.1995;346:1449-1454.
Bejar RF, Vaucher YE, Benirschke K, Berry CC. Postnatal white matter necrosis in preterm infants.  J Perinatol.1992;12:3-8.
Palmer L, Blair E, Petterson B, Burton P. Antenatal antecedents of moderate and severe cerebral palsy.  Paediatr Perinat Epidemiol.1995;9:171-184.
Cai Z, Pan Z, Pang Y, Evan OB, Rhodes PG. Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration.  Pediatr Res.2000;47:64-72.
Yoon BH, Romero R, Park JS.  et al.  Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments.  Am J Obstet Gynecol.1998;179:1254-1260.
Jeohn GH, Kong LY, Wilson B, Hudson P, Hong JS. Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures.  J Neuroimmunol.1998;85:1-10.
Dommerges M, Patkai J, Renauld J, Evrard P, Gressens P. Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium.  Ann Neurol.2000;47:54-63.
Merrill JE. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological.  Dev Neurosci.1992;14:1-10.
Yoon BH, Kim CJ, Romero R.  et al.  Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits.  Am J Obstet Gynecol.1997;177:797-802.
Yoon BH. Intraamniotic inflammation and the development of cerebral palsy at three years of age.  Am J Obstet Gynecol.1999;180(suppl):S2.
Yoon BH, Romero R, Kim CJ.  et al.  High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia.  Am J Obstet Gynecol.1997;177:406-411.
Deguchi K, Mizuguchi M, Takashima S. Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia.  Pediatr Neurol.1996;14:13-16.
Yoon BH, Romero R, Yang SH.  et al.  Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia.  Am J Obstet Gynecol.1996;174:1433-1440.
Herbst A, Wølner-Hanssen P, Ingemarsson I. Risk factors for fever in labor.  Obstet Gynecol.1995;86:790-794.
Volpe JJ. Brain injury in the premature infant—from pathogenesis to prevention.  Brain Dev.1997;19:519-534.
Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?  Pediatrics.1995;95:263-269.
Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight.  Am J Obstet Gynecol.1998;179:507-513.
Dammann O, Durum SK, Leviton A. Modification of the infection-associated risks of preterm birth and white matter damage in the preterm newborn by polymorphisms in the tumor necrosis factor-locus?  Pathogenesis.1999;1:171-177.
Roberts AK, Monzon-Bordonaba F, Van Deerlin PG.  et al.  Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.  Am J Obstet Gynecol.1999;180:1297-1302.
Torfs CP, van den Berg B, Oechsli FW, Cummins S. Prenatal and perinatal factors in the etiology of cerebral palsy.  J Pediatr.1990;116:615-619.
Petridou E, Koussouri M, Toupadaki N.  et al.  Risk factors for cerebral palsy: a case-control study in Greece.  Scand J Soc Med.1996;24:14-26.

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