Elsevier

The Journal of Pediatrics

Volume 181, February 2017, Pages 267-271.e1
The Journal of Pediatrics

Original Articles
Congenital Cytomegalovirus among Children with Cerebral Palsy

https://doi.org/10.1016/j.jpeds.2016.10.024Get rights and content

Objectives

To determine the proportion of children with cerebral palsy (CP) and cytomegalovirus (CMV) DNA detected retrospectively in their newborn screening cards (NBSC), to compare the proportion of children with CMV DNA in their NBSC across spastic subtypes of CP, and to compare the sex and other characteristics of children with CP and CMV detected on their NSBC with those in whom CMV DNA was not detected.

Study design

Retrospective observational study. Data were extracted from patient records on children with CP (birth years 1996-2014) from 2 Australian state CP registers and state-wide paediatric rehabilitation services with consent. NBSCs were retrospectively analyzed for CMV DNA by nested polymerase chain reaction (PCR) using primers against gB. Positive samples were validated using real time PCR for CMV UL83.

Results

Of 401 children recruited, 323 (80.5%) had an available NBSC. Of these, 31 (9.6%; 95% CI, 6.8-13.3) tested positive for CMV DNA by nested PCR for CMV gB, of whom 28 (8.7%; 95% CI, 6.1-12.2) also had CMV DNA detected by real-time PCR for CMV UL83. Detection of CMV DNA was significantly associated with epilepsy, but not with clinical or epidemiologic characteristics, including sex and pattern of spasticity.

Conclusions

CMV viremia in the newborn period, indicating congenital CMV infection, is highly prevalent among children with CP. Further research is needed to investigate the mechanisms and contribution of congenital CMV to the causal pathways to CP.

Section snippets

Methods

Parents or guardians of children (aged less than 18 years) with CP (birth years 1996-2014) from the NSW and ACT CP registers, or the state-wide disability services provider Cerebral Palsy Alliance, or the CP outpatient clinic at the Children's Hospital at Westmead, provided informed consent for NBSC testing for cCMV and extraction of registry data. This study was approved by the NSW Population and Health Services Research Ethics Committee (EC00410), the Cerebral Palsy Alliance Human Research

Results

A total of 401 individuals with CP were recruited, of whom 323 (80.5%) had an available NBSC (Figure; available at www.jpeds.com). Of these, 31 (9.6%; 95% CI, 6.8-13.3) tested positive for CMV DNA (cCMV-positive cases) in NBSC by nested PCR for CMV gB, of whom 28 (8.7%; 95% CI, 6.1-12.2) had CMV DNA also detected by real time PCR for CMV UL83.

We next compared the characteristics of participants using extracted registry data, according to their NBSC test result for CMV DNA. There were 140 female

Discussion

This retrospective study identified that 9.6% (95% CI, 6.8%-13.3%) of children with CP had CMV DNA detected in their NBSC, confirming cCMV infection. This proportion is markedly higher than the proportion of children with CMV detected in the newborn period in the general community (approximately 0.6%).2, 16 It is also 6 times greater than the proportion of children with CP who have cCMV reported as an attributable cause to the ACPR (1.5%),9 and in a recent retrospective study of Caucasian

References (24)

  • I. Dakovic et al.

    Clinical features of cerebral palsy in children with symptomatic congenital cytomegalovirus infection

    Eur J Paediatr Neurol

    (2014)
  • J. Howard et al.

    Utility of newborn screening cards for detecting CMV infection in cases of stillbirth

    J Clin Virol

    (2009)
  • Y. Suzuki et al.

    Epilepsy in patients with congenital cytomegalovirus infection

    Brain Dev

    (2008)
  • M.C. Cheeran et al.

    Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention

    Clin Microbiol Rev

    (2009)
  • A. Kenneson et al.

    Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection

    Rev Med Virol

    (2007)
  • S.C. Dollard et al.

    New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection

    Rev Med Virol

    (2007)
  • M.J. Cannon et al.

    Washing our hands of the congenital cytomegalovirus disease epidemic

    BMC Public Health

    (2005)
  • S.C. Munro et al.

    Symptomatic infant characteristics of congenital cytomegalovirus disease in Australia

    J Paediatr Child Health

    (2005)
  • F. Stanley et al.

    Causal pathways initiated preconceptionally or in early pregnancy. Cerebral palsies: epidemiology and causal pathways

    (2000)
  • D.W. Kimberlin et al.

    Valganciclovir for symptomatic congenital cytomegalovirus disease

    N Engl J Med

    (2015)
  • P. Brasil et al.

    Zika virus infection in pregnant women in Rio de Janeiro—preliminary report

    N Engl J Med

    (2016)
  • H. Smithers-Sheedy et al.

    Congenital cytomegalovirus is associated with severe forms of cerebral palsy and female sex in a retrospective population-based study

    Dev Med Child Neurol

    (2014)
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    Funded by National Health and Medical Research Council (Dora Lush Public Health Scholarship 1055901 [to H.S.-S.] and Career Development Fellowship 1087062 [to C.R.-G.]), Rebecca L. Cooper Medical Research Foundation ([to H.S.-S., C.J., A.K., N.B], Cerebral Palsy Alliance Research Foundation [to H.S.-S., C.R.-G., C.J., A.K., N.B.], Sydney Medical School Foundation [to H.S.-S., C.J.]. The authors declare no conflicts of interest.

    *

    Current affiliation: Westmead Institute for Medical Research, Westmead, New South Wales, Australia.

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