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Reply to: Placental infection and risk of cerebral palsy in very low birth weight infants
The Journal of Pediatrics Volume 129, Number 5
Editorial correspondence
777
Table. Antenatal factors among patients with cerebral palsy and control subjects
Factors Chorionitis (all) Chorionitis with neonatal seizures Choriomtis without neonatal seizures Maternal infection (all) Maternal infection with neonatal seizures Maternal infection without seizures
Case patients (N= 59)
Control subjects (N = 234)
No.
%
No.
%
Odds ratio (95% confidence interval)*
10 2 8 22 7 15
17 3 14 37 12 25
8 0 8 40 1 39
3 0 3 17 0.4 17
5.8 (2.2-15.4) 12.2 (1.2-119) 4.4 (1.6-12.4) 2.9 (1.5-5.4) 31.4 (3.8-260) 1.7 (0.9-3.4)
*Odds ratios calculated by univariate analysis; 0.5 added to each cell when a zero value is present in a cell.
by neonatal seizures was not associated with increased risk of CP overall." We did not examine the contribution of neonatal seizures to the association between chorionitis and preterm CP in our original report, but have reanalyzed our data and present the findings in the Table. In our study population, chorionitis both with and without neonatal seizures was associated with an increased risk of CP. It is interesting to note, however, that the overall prevalence of chorionitis differs considerably between the two studies--56% versus 6% in our study. There axe at least two possible explanations for this that may also explain the inconsistency in the findings. First, chorionitis may occur much more frequently among a U.S. population, or alternatively, the diagnosis may be made more frequently either because of more intense investigation of pregnant women or the use of different diagnostic criteria. In our study we applied strict criteria in the diagnosis of chorionitis requiting at least two of the following: clinical, microbiologic, or histologic evidence of chorionitis. We then investigated a further category--maternal infection that included subjects with evidence of genital Iract infection who did not fulfill the criteria for the diagnosis of chorionitis and women with evidence of urinary tract infection, pyelonephritis, or other pyrexial illnesses. As the Table shows, the association between maternal infection and an increased risk of CP in the absence of neonatal seizures is not significant at the 5% level. In contrast there is a strong association between maternal infection foUowed by seizures and CP. The apparent differences in the findings of the two studies may be related to differences in the definition of chorionitis. This highlights the importance of agreed criteria for diagnostic groups in this type of study so that findings can be pooled or compared. In conclusion, current evidence indicates that maternal infection/chorionitis may have an important role in the origin of preterm CP. The underlying mechanisms whereby maternal infection leads to fetal brain damage and the possible preventive slrategies are yet to be explored.
Deidre J. Murphy, MB Bristol, United Kingdom Ann Johnson, MD NPEU Oxford, United Kingdom 9/35/76809
REFERENCES
1. Grether JK, Nelson KB, Stanley Emery E 1II, Cummins SK. Prenatal and perinatal factors and cerebral palsy in very low birth weight infants. J Pediatr 1996;128:407-14. 2. Murphy DJ, Sellers S, MacKenzie IZ, Yudldn PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346:1449-54.
Reply To the Editor: We are very interested to know that our British colleagues find, as we did, 1 that the combination of material chorioamnionitis and neonatal seizures identifies very low birth weight infants who are at greatly increased risk of cerebral palsy. The observations that nonplacental maternal infection was also associated with increased risk, as previously reported, 2 and that the neonatal seizures may also indicate heightened risk in infants exposed to nonplacental maternal infection, are also of much interest. These findings add to accumulating evidence that chorioamnionitis and some of its subcategories, and perhaps maternal infection at other loci, are related to risk of adverse outcome in premature infants.3-7 Previous studies8' 9 and recent experience in the California cohort (unpublished observations) suggest that maternal infection may be a risk factor for cerebral palsy in term infants as well. The difference in prevalence of chorioamnionitis in the British and American studies is indeed noteworthy. The prevalence of chorioamnionitis is known to differ considerably in different populations and to be much higher in preterm than in term births. It is likely that chorioamnionitis is markedly underascertained clinically and that differences in definitions influence differences in reported prevalences. If chorioamnionitis can be important to fetal outcome, as now appears probable, we certainly agree that improved criteria for the clinical and histologic diagnoses of this condition must be developed. Improved definitions also will be needed in investiga-
778
Editorial correspondence
tions of the roles of specific microorganisms, locus and duration of infection, and the possibility of useful therapy, With regard to preec]ampsia and risk of cerebral p-,dsy, the obse~,atton in California is of a much more potent "protective" effect than is noted for Oxford ((xlds ratio 0.08 in Califot~ttia sttldy, 0.4 in Oxford), which polenlially leaves room for an effect of magnesium. We look forward to observations in other data sets from places where magnesium sulfate is ,and is not adnfinistered lbr preec]ampsia. We thank Drs. Murphy and Johnson for their letter, which adds to our growing conviction that there is a need for further investigation of fine possible contribution of placental and other maternal infection to longqenn ,]eurologic disability in the child. Judith K. Grethe~; PhD Karin B. Nelson, MD National Institute of Neurological Disorders and Stroke Nalion~d Institutes t~" Health Bethesda, MD 20892-9130 9/35/768O8 REFERENCES
1. Grether JK, Nelson KB, E]rtery ES ILI. Cummins SK, Prenat~d and perinatal factors and cerebral palsy in very low birth weight irtfants. J Ped iatr 1996; L28:407-14.
The Journal of Pediatncs Novembei" 1996
2. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of anteqatal and intrapartum risk faeL tors for cerebral palsy in very preterm singleton babies. Lancet 1995 ;346: I a49-54. 3. Nelson KB, EIlenbereo JH. Predictors of low and very low birth weight and the relation of these to cerebral palsy. JAMA 1985:254:1473-79. 4. Cooke RW[. Cerebral p',:dsy in very low birthwcight tnfams, Arch Dis Child 1990;65:201-6. 5. Bejar R, Wozniak P, Allard M, et al. Antcnatal origin of neurologic damage in newborn infants: I. prcterm infants. Am J Obstet Gyneco] 1988;159:357-63. 6. Faix RG, Do,m SM. Association of septic shock caused by early-onset group B streptococcal sepsis and periventricular leukomalacia in the pretcrm infeaat. Pediatrics 1985;76:415-9. 7, Perlman J. Bilateral cystic periventricuLar lcukomalacia in the premature infant: associated risk factors. Pediatrics 1996; 97:822-7, 8. Eastman N J, DeLeon M. The etiology of cerebral palsy. Am J Obstct Gynecol 1955:69:950-61. 9~ Nelson KB, Ellenberg JI--I,Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med 1986;315:81-6.
Editorial correspondence
777
Table. Antenatal factors among patients with cerebral palsy and control subjects
Factors Chorionitis (all) Chorionitis with neonatal seizures Choriomtis without neonatal seizures Maternal infection (all) Maternal infection with neonatal seizures Maternal infection without seizures
Case patients (N= 59)
Control subjects (N = 234)
No.
%
No.
%
Odds ratio (95% confidence interval)*
10 2 8 22 7 15
17 3 14 37 12 25
8 0 8 40 1 39
3 0 3 17 0.4 17
5.8 (2.2-15.4) 12.2 (1.2-119) 4.4 (1.6-12.4) 2.9 (1.5-5.4) 31.4 (3.8-260) 1.7 (0.9-3.4)
*Odds ratios calculated by univariate analysis; 0.5 added to each cell when a zero value is present in a cell.
by neonatal seizures was not associated with increased risk of CP overall." We did not examine the contribution of neonatal seizures to the association between chorionitis and preterm CP in our original report, but have reanalyzed our data and present the findings in the Table. In our study population, chorionitis both with and without neonatal seizures was associated with an increased risk of CP. It is interesting to note, however, that the overall prevalence of chorionitis differs considerably between the two studies--56% versus 6% in our study. There axe at least two possible explanations for this that may also explain the inconsistency in the findings. First, chorionitis may occur much more frequently among a U.S. population, or alternatively, the diagnosis may be made more frequently either because of more intense investigation of pregnant women or the use of different diagnostic criteria. In our study we applied strict criteria in the diagnosis of chorionitis requiting at least two of the following: clinical, microbiologic, or histologic evidence of chorionitis. We then investigated a further category--maternal infection that included subjects with evidence of genital Iract infection who did not fulfill the criteria for the diagnosis of chorionitis and women with evidence of urinary tract infection, pyelonephritis, or other pyrexial illnesses. As the Table shows, the association between maternal infection and an increased risk of CP in the absence of neonatal seizures is not significant at the 5% level. In contrast there is a strong association between maternal infection foUowed by seizures and CP. The apparent differences in the findings of the two studies may be related to differences in the definition of chorionitis. This highlights the importance of agreed criteria for diagnostic groups in this type of study so that findings can be pooled or compared. In conclusion, current evidence indicates that maternal infection/chorionitis may have an important role in the origin of preterm CP. The underlying mechanisms whereby maternal infection leads to fetal brain damage and the possible preventive slrategies are yet to be explored.
Deidre J. Murphy, MB Bristol, United Kingdom Ann Johnson, MD NPEU Oxford, United Kingdom 9/35/76809
REFERENCES
1. Grether JK, Nelson KB, Stanley Emery E 1II, Cummins SK. Prenatal and perinatal factors and cerebral palsy in very low birth weight infants. J Pediatr 1996;128:407-14. 2. Murphy DJ, Sellers S, MacKenzie IZ, Yudldn PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346:1449-54.
Reply To the Editor: We are very interested to know that our British colleagues find, as we did, 1 that the combination of material chorioamnionitis and neonatal seizures identifies very low birth weight infants who are at greatly increased risk of cerebral palsy. The observations that nonplacental maternal infection was also associated with increased risk, as previously reported, 2 and that the neonatal seizures may also indicate heightened risk in infants exposed to nonplacental maternal infection, are also of much interest. These findings add to accumulating evidence that chorioamnionitis and some of its subcategories, and perhaps maternal infection at other loci, are related to risk of adverse outcome in premature infants.3-7 Previous studies8' 9 and recent experience in the California cohort (unpublished observations) suggest that maternal infection may be a risk factor for cerebral palsy in term infants as well. The difference in prevalence of chorioamnionitis in the British and American studies is indeed noteworthy. The prevalence of chorioamnionitis is known to differ considerably in different populations and to be much higher in preterm than in term births. It is likely that chorioamnionitis is markedly underascertained clinically and that differences in definitions influence differences in reported prevalences. If chorioamnionitis can be important to fetal outcome, as now appears probable, we certainly agree that improved criteria for the clinical and histologic diagnoses of this condition must be developed. Improved definitions also will be needed in investiga-
778
Editorial correspondence
tions of the roles of specific microorganisms, locus and duration of infection, and the possibility of useful therapy, With regard to preec]ampsia and risk of cerebral p-,dsy, the obse~,atton in California is of a much more potent "protective" effect than is noted for Oxford ((xlds ratio 0.08 in Califot~ttia sttldy, 0.4 in Oxford), which polenlially leaves room for an effect of magnesium. We look forward to observations in other data sets from places where magnesium sulfate is ,and is not adnfinistered lbr preec]ampsia. We thank Drs. Murphy and Johnson for their letter, which adds to our growing conviction that there is a need for further investigation of fine possible contribution of placental and other maternal infection to longqenn ,]eurologic disability in the child. Judith K. Grethe~; PhD Karin B. Nelson, MD National Institute of Neurological Disorders and Stroke Nalion~d Institutes t~" Health Bethesda, MD 20892-9130 9/35/768O8 REFERENCES
1. Grether JK, Nelson KB, E]rtery ES ILI. Cummins SK, Prenat~d and perinatal factors and cerebral palsy in very low birth weight irtfants. J Ped iatr 1996; L28:407-14.
The Journal of Pediatncs Novembei" 1996
2. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of anteqatal and intrapartum risk faeL tors for cerebral palsy in very preterm singleton babies. Lancet 1995 ;346: I a49-54. 3. Nelson KB, EIlenbereo JH. Predictors of low and very low birth weight and the relation of these to cerebral palsy. JAMA 1985:254:1473-79. 4. Cooke RW[. Cerebral p',:dsy in very low birthwcight tnfams, Arch Dis Child 1990;65:201-6. 5. Bejar R, Wozniak P, Allard M, et al. Antcnatal origin of neurologic damage in newborn infants: I. prcterm infants. Am J Obstet Gyneco] 1988;159:357-63. 6. Faix RG, Do,m SM. Association of septic shock caused by early-onset group B streptococcal sepsis and periventricular leukomalacia in the pretcrm infeaat. Pediatrics 1985;76:415-9. 7, Perlman J. Bilateral cystic periventricuLar lcukomalacia in the premature infant: associated risk factors. Pediatrics 1996; 97:822-7, 8. Eastman N J, DeLeon M. The etiology of cerebral palsy. Am J Obstct Gynecol 1955:69:950-61. 9~ Nelson KB, Ellenberg JI--I,Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med 1986;315:81-6.