BMJ  2006;332:63-64 (14 January), doi:10.1136/bmj.332.7533.63

Editorial

Cerebral palsy and perinatal exposure to neurotropic viruses

A new study raises further questions about the role of infection

Cerebral palsy, one of the most common causes of serious long term disability, is a term covering the conditions found to have "non-progressive but often changing motor impairments secondary to lesions or anomalies of the brain arising during early development."¹ The final irreversible neurological damage frequently results from a causal pathway created by the joint effects of several factors including genetic constitution, fetal infection, preterm birth, and problems during delivery. The role of postnatal infection, such as catastrophic meningitis or encephalitis in infancy or early childhood, is usually clear, but the part played by infection in congenital or neonatal cerebral palsy is more complex and needs more investigation.² A case-control study in this issue (p 76), reporting the prevalence of neurotropic viral nucleic acids in blood spots from routine neonatal screening, if confirmed, may take us a little further.³

Several maternal viral infections, including cytomegalovirus, can be passed to the fetus at different stages in pregnancy.⁴ Estimates based on prospective studies of mothers who have had a primary cytomegalovirus infection in pregnancy suggest that 5-10% of cases of cerebral palsy, depending on the population prevalence, might be attributable to this virus.⁵ Also, evidence of the role of perinatal maternal infection in preterm pregnancy, itself a cause of cerebral palsy, is increasing. A large number of studies have found an excess of surrogate markers of perinatal infections in preterm and term babies who were later found to have cerebral palsy, although the extent to which these associations reflect direct causal effects is unclear.⁶

Gibson and colleagues report how they used the South Australia newborn screening register to retrieve the dried blood spots that had been taken from neonates who were subsequently notified to the local cerebral palsy register and from controls.³ In most developed countries these blood spots are samples taken from all babies after birth to screen for phenylketonuria. They are often retained on Guthrie cards. The South Australian study used such samples to measure the prevalence of the nucleic acids of enteroviruses; herpes simplex virus types 1 and 2; Epstein-Barr virus; cytomegalovirus; human herpesviruses 6, 7, and 8; and varicella zoster virus. The tests were not quantitative, and viral load—which may determine risk of fetal infection—was not measured.

The authors found viral nucleic acids in a high proportion of spots taken from controls: 40% tested positive for at least one. The controls had been matched to the cases by place of care, and the study included an unduly high proportion of babies born in metropolitan teaching hospitals and born preterm. Even so, the prevalence of viral nucleic acids was very much higher than expected from previous epidemiological work.

For instance, 26.7% of the control blood spots tested positive for cytomegalovirus. Studies in London teaching hospitals in the 1980s found positive cell cultures for cytomegalovirus in 3/1000 newborns, looking at samples derived from neonatal throat swabs in one study⁷ and searching for viruses in urine in another.⁸ However, as the Australian authors point out, the prevalence they report does not reflect active fetal infection; it may reflect perinatal exposure to viruses. Moreover, the results may vary with the age of the babies when tested and with methods of storage and retrieval of samples. And the high prevalence may reflect non-specific signals, given that the investigators were co-amplifying multiple viral nucleic acids in very small samples.

Despite these differences from expected absolute prevalence, the reported risks are consistent with those from previous work. The excess of positive tests for cytomegalovirus in preterm compared with term controls was significant (odds ratio 1.6). In the sample as a whole, and in babies with gestational age of 37 weeks or more, there was a significant association between a positive test for any viral exposure and cerebral palsy, but also some distinctive associations with different viruses. The authors postulate that, if the associations were causal, 4-5% of all cases of cerebral palsy in these babies might be attributable to perinatal exposure to a group of viruses including human herpesviruses 6 and 7 and varicella zoster virus.

The research group plan to follow this study with prospective and clinical investigations, looking also at interactions with other contributory factors. Overall this is an interesting and provocative contribution to the growing body of research into the role of maternal and fetal infections in cerebral palsy, even though it is based on methods that need further validation.

Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and The London, Queen Mary's School of Medicine and Dentistry, London EC1M 6BQ
(kenevalb{at}aol.com)

Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London WC1N 1EH

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Competing interests: None declared.

Research p76

References

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2. Nelson KB, Willoughby RE. Overview: infection during pregnancy and neurologic outcome in the child. Mental Retard Develop Disab Res Rev 2002;8: 1-2.
3. Gibson CS, Maclennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA. Neurotropic viruses and cerebral palsy: population based case-control study. BMJ 2006;332: 76-9.[Abstract/Free Full Text]
4. Enright AM, Prober CG. Herpesviridae infections in newborns: varicella zoster virus, herpes simplex virus, and cytomegalovirus. Pediatr Clin N Am 2004;51: 889-908.[CrossRef][ISI][Medline]
5. Stanley F, Blair E, Alberman E. Cerebral palsies: epidemiology and causal pathways. Lavenham: MacKeith Press, 2000: 55-6.
6. Jacobsson B. Infectious and inflammatory mechanisms in preterm birth and cerebral palsy. Eur J Obstet Gynecol Reprod Biol 2004;115: 159-60.[CrossRef][ISI][Medline]
7. Preece PM, Tookey P, Ades A, Peckham CS. Congenital cytomegalovirus infection: predisposing maternal factors. J Epidemiol Community Health 1986;40: 205-9.[Abstract]
8. Griffiths PD, Baboonian C, Rutter D, Peckham C. Congenital and maternal cytomegalovirus infections in a London population. Br J Obstet Gynaec 1991;98: 135-40.[ISI][Medline]

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Related Article

Neurotropic viruses and cerebral palsy: population based case-control study

Catherine S Gibson, Alastair H MacLennan, Paul N Goldwater, Eric A Haan, Kevin Priest, Gustaaf A Dekker South Australian Cerebral Palsy Research Group
BMJ 2006 332: 76-80. [Abstract] [Full Text] [PDF]