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PEDIATRICS Vol. 110 No. 4 October 2002, pp. 832-833

COMMENTARY

Maternal Infections Are Depressing

Abbreviations: NE, neonatal encephalopathy • CP, cerebral palsy

Neonatal encephalopathy (NE) is the best very early predictor for term infants of later cerebral palsy (CP), the most common acquired disorder of movement and tone in children.¹ Although CP was once attributed to adverse perinatal events, population-based studies identify antenatal rather than intrapartum antecedents.^1,2 Recent studies suggest that the disease process may be active postnatally.^3,4

Half of all CP occurs in children born at term. The few studies available strongly support the association of maternal intrauterine infection with CP in term infants.⁵ There is an even stronger association (10 of 10 studies of term infants) for maternal fever or clinical chorioamnionitis and NE manifested by depressed transition, altered tone, need for respiratory support or seizures.⁶ While more intensively studied, the association of maternal infection with CP is equivocal for infants born prematurely, perhaps because of our lack of a normal control population and difficulty in adjusting for the degree of immaturity and comorbid conditions.^5,6

In 1998, Nelson et al³ published a case-control study notable for 3 findings: 1) the association of maternal infection (clinically diagnosed or based on histologic evidence of placental inflammation) with NE, 2) the association of both infection and NE with later development of CP, and 3) evidence that affected newborns had very high blood concentrations of inflammatory cytokines. The association of high blood levels of cytokines with later CP has been reproduced in another cohort of term infants.⁴

In this issue, Shalak et al⁷ refine this further by measuring at various times the association of cytokines with proximal neurologic outcomes in critically ill term newborns born to infected mothers. Two chemokines, interleukin-8 and RANTES, were elevated and then cleared after clamping of the cord, suggesting origin from the placenta. Interleukin-6 peaked after birth, suggesting endogenous production by the neonate. The prevalence of neonatal depression and tone abnormalities showed a similar decay from time of birth. Hypotonia correlated with postnatally produced interleukin-6 levels. All 3 cytokines were most elevated in those infants with hypoxic-ischemic encephalopathy, consistent with detection of multiply elevated cytokine concentrations in term infants who later progressed to CP.

Given these findings, should we be intervening to block the proinflammatory cytokine cascade associated with infection and NE? No. Although this article posits that inflammatory cytokines may directly damage cellular constituents of the brain, the function of cytokines in the CNS is highly complex, depends on developmental stage, and differs from that elsewhere in the body.⁷ Inflammatory cytokines, such as TNF, can be neuroprotective as well as neurotoxic and serve a physiologic role in brain plasticity. Meddling with imperfectly understood processes risks causing harm—"brain-sparing" cytokines interleukin-10 and TGF-ß are associated with neurologic disease when given exogenously.⁸

The key point here is that we need to recalibrate as clinicians. Maternal or placental infection increases the risk of moderate to severe NE, not just sepsis. Our clinical evaluations of NE should include consideration of maternal infection, examination of the placenta, and use of neonatal markers of infection/inflammation.

Rodney E. Willoughby, Jr, MD

Department of Pediatrics
Johns Hopkins School of Medicine
Baltimore, MD 21287-4933

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FOOTNOTES

Received for publication Jul 22, 2002; Accepted Jul 22, 2002.

Address correspondence to Rodney E. Willoughby, Jr, MD, Pediatrics Infectious Diseases, Johns Hopkins Hospital, 600 N Wolfe St/Park 256, Baltimore, MD 24287-4933. E-mail: rwilloug{at}jhmi.edu

REFERENCES

1. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med.1986; 315 :81 –86[Abstract]
2. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral palsy. J Pediatr.2000; 112 :515 –519
3. Nelson KB, Dambrosia JM, Grether JK, Phillips TM. Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol.1998; 44 :665 –675[CrossRef][Web of Science][Medline]
4. Foster-Barber A, Ferriero DM. Neonatal encephalopathy in the term infant: neuroimaging and inflammatory cytokines. Ment Retard Dev Disabil Res Rev.2002; 8 :20 –24[CrossRef][Web of Science][Medline]
5. Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy. JAMA.2000; 284 :1417 –1424[Abstract/Free Full Text]
6. Willoughby RE Jr, Nelson KB. Chorioamnionitis and brain injury. Clin Perinatol.2002 . In press
7. Shalak LF, Laptook AR, Jafri HS, Ramilio O, Perlman JM. Clinical chorioamnionitis, elevated cytokines, and brain injury in term infants. Pediatrics.2002; 110 :673 –680[Abstract/Free Full Text]
8. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neuroscience.2001; 2 :734 –744[CrossRef][Web of Science][Medline]

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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