Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Systematic Review
  • Published:

Neurodevelopmental outcomes of children with congenital cytomegalovirus: a systematic scoping review

Abstract

Background

With the emergence of newborn congenital cytomegalovirus (cCMV) screening programs, more infants are being diagnosed and require long-term follow-up. The objective of the study was to summarize the literature to date on neurodevelopmental outcomes in children with cCMV with attention to study-specific definitions of disease severity (symptomatic vs. asymptomatic).

Methods

This systematic scoping review included studies of children with cCMV (≤18 years-old) measuring neurodevelopment in ≥1 domain: global, gross motor, fine motor, speech/language, and intellectual/cognitive. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. PubMed, PsychInfo, and Embase databases were searched.

Results

33 studies met inclusion criteria. Global development most frequently measured (n = 21), followed by cognitive/intellectual (n = 16) and speech/language (n = 8). Most (31/33) studies differentiated children by cCMV severity (symptomatic vs. asymptomatic), definitions of which ranged broadly. 15/21 studies described global development categorically (e.g., normal vs. abnormal). Across studies and domains, children with cCMV generally had equivalent or lower scores (vs. controls or normed measures).

Conclusions

Variation in definitions of cCMV severity and blunt categorical outcomes may limit the generalizability of findings. Future studies should utilize standardized definitions of disease severity and in-depth measurement and reporting of neurodevelopmental outcomes in children with cCMV.

Impact

  • Neurodevelopmental delays are common among children with cCMV, although gaps in the literature to have made quantification of such delays challenging.

  • Variation in definitions of asymptomatic and symptomatic cCMV as well as the use of categorical outcomes of neurodevelopment (e.g., normal vs. abnormal) limits the generalizability and clinical utility of findings.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: PRISMA flowchart of the systematic scoping review process.

Similar content being viewed by others

References

  1. Ssentongo, P. et al. Congenital cytomegalovirus infection burden and epidemiologic risk factors in countries with universal screening: a systematic review and meta-analysis. JAMA Netw. open. 4, e2120736 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fowler, K. B. et al. Racial and ethnic differences in the prevalence of congenital cytomegalovirus infection. J. Pediatr. 200, 196.e1–201.e1 (2018).

    Article  Google Scholar 

  3. Yassine, B. B., Hulkower, R., Dollard, S., Cahill, E. & Lanzieri, T. A legal mapping assessment of cytomegalovirus-related laws in the United States. J. Public Health Manag. Pract. 28, E624–E629 (2022).

    Article  PubMed  Google Scholar 

  4. Pesch, M. H. & Schleiss, M. R. Emerging concepts in congenital cytomegalovirus. Pediatrics 150, e2021055896 (2022).

  5. Villagomez, A. N. et al. Neurodevelopmental delay: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 37, 7623 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rawlinson, W. D. et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect. Dis. 17, e177–e188 (2017).

    Article  PubMed  Google Scholar 

  7. Luck, S. E. et al. Congenital cytomegalovirus: a European expert consensus statement on diagnosis and management. Pediatr. Infect. Dis. J. 36, 1205–1213 (2017).

    Article  PubMed  Google Scholar 

  8. Pesch, M. H., Kuboushek, K., Weinberg, J. B., McKee, M. & Thorne, M. Congenital cytomegalovirus infection. BMJ 373, n1212 (2021).

  9. Pesch, M. H., Saunders, N. A. & Abdelnabi, S. Cytomegalovirus infection in pregnancy: Prevention, presentation, management and neonatal outcomes. J Midwifery Womens Health 66, 397–402 (2021).

  10. Bartlett, A. W., McMullan, B., Rawlinson, W. D. & Palasanthiran, P. Hearing and neurodevelopmental outcomes for children with asymptomatic congenital cytomegalovirus infection: a systematic review. Rev. Med. Virol. https://doi.org/10.1002/rmv.1938 (2017).

  11. Pinninti, S. et al. Vestibular, gaze, and balance disorders in asymptomatic congenital cytomegalovirus infection. Pediatrics 147, e20193945 (2021).

  12. Maeyama, K. et al. Congenital cytomegalovirus infection in children with autism spectrum disorder: systematic review and meta-analysis. J. Autism Dev. Disord. 48, 1483–1491 (2018).

    Article  PubMed  Google Scholar 

  13. Slawinski, B. L. et al. Maternal cytomegalovirus sero-positivity and autism symptoms in children. Am. J. Reprod. Immunol. 79, e12840 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Arksey, H. & O’Malley, L. Scoping studies: towards a methodological framework. Int. J. Soc. Res. Methodol. 8, 19–32 (2005).

    Article  Google Scholar 

  15. Fletcher, K. T. et al. The natural history and rehabilitative outcomes of hearing loss in congenital cytomegalovirus: a systematic review. Otol. Neurotol. 39, 854–864 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Xia, W. et al. Congenital human cytomegalovirus infection inducing sensorineural hearing loss. Front. Microbiol. 12, 824 (2021).

    Article  Google Scholar 

  17. Kraaijenga, V. et al. Cochlear implant performance in children deafened by congenital cytomegalovirus—a systematic review. Clin. Otolaryngol. 43, 1283–1295 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Goderis, J. et al. Hearing loss and congenital CMV infection: a systematic review. Pediatrics 134, 972–982 (2014).

    Article  PubMed  Google Scholar 

  19. Walsh, H., Zuwala, J., Hunter, J. & Oh, Y. Congenital cytomegalovirus and human immunodeficiency virus: effects on hearing, speech and language development, and clinical outcomes in children. Front. Pediatr. 9, 771192 (2021).

  20. Puhakka, L. et al. The burden of congenital cytomegalovirus infection: a prospective cohort study of 20 000 infants in Finland. J. Pediatr. Infect. Dis. Soc. 8, 205–212 (2019).

    Article  Google Scholar 

  21. Fukushima, S. et al. Prediction of poor neurological development in patients with symptomatic congenital cytomegalovirus diseases after oral valganciclovir treatment. Brain Dev. 41, 743–750 (2019).

    Article  PubMed  Google Scholar 

  22. Yamada, H. et al. A cohort study of the universal neonatal urine screening for congenital cytomegalovirus infection. J. Infect. Chemother. 26, 790–794 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Kobas, M. et al. Clinical characteristics, audiological and neurodevelopmental outcomes of newborns with congenital cytomegalovirus infection. Swiss Med. Wkly. 148, w14627 (2018).

    PubMed  Google Scholar 

  24. Alarcon, A. et al. Clinical, biochemical, and neuroimaging findings predict long-term neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection. J. Pediatr. 163, 828–834.e821 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Pathirana, J. et al. Neurological and growth outcomes in South African children with congenital cytomegalovirus: a cohort study. PLoS ONE 15, e0238102 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Townsend, C. L. et al. Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom. Clin. Infect. Dis. 56, 1232–1239 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Pearl, K. N., Preece, P. M., Ades, A. & Peckham, C. S. Neurodevelopmental assessment after congenital cytomegalovirus infection. Arch. Dis. Child. 61, 323–326 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ivarsson, S. A., Lernmark, B. & Svanberg, L. Ten-year clinical, developmental, and intellectual follow-up of children with congenital cytomegalovirus infection without neurologic symptoms at one year of age. Pediatrics 99, 800–803 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, X. W. et al. Physical and intellectual development in children with asymptomatic congenital cytomegalovirus infection: a longitudinal cohort study in Qinba mountain area, China. J. Clin. Virol. 40, 180–185 (2007).

    Article  PubMed  Google Scholar 

  30. Giannattasio, A. et al. Outcomes of congenital cytomegalovirus disease following maternal primary and non-primary infection. J. Clin. Virol. 96, 32–36 (2017).

    Article  PubMed  Google Scholar 

  31. Griffiths, R. The abilities of babies: a study in mental measurement. JAMA 158, 88–89 (1955).

  32. Ancora, G. et al. Cranial ultrasound scanning and prediction of outcome in newborns with congenital cytomegalovirus infection. J. Pediatr. 150, 157–161 (2007).

    Article  PubMed  Google Scholar 

  33. Oosterom, N. et al. Neuro-imaging findings in infants with congenital cytomegalovirus infection: relation to trimester of infection. Neonatology 107, 289–296 (2015).

    Article  PubMed  Google Scholar 

  34. Giannattasio, A. et al. Is lenticulostriated vasculopathy an unfavorable prognostic finding in infants with congenital cytomegalovirus infection? J. Clin. Virol. 91, 31–35 (2017).

    Article  PubMed  Google Scholar 

  35. Nishida, K. et al. Prediction of neurodevelopmental impairment in congenital cytomegalovirus infection by early postnatal magnetic resonance imaging. Neonatology 117, 460–466 (2020).

    Article  PubMed  Google Scholar 

  36. Giannattasio, A. et al. Neuroimaging profiles and neurodevelopmental outcome in infants with congenital cytomegalovirus infection. Pediatr. Infect. Dis. J. 37, 1028–1033 (2018).

    Article  PubMed  Google Scholar 

  37. Maes, L. et al. Comparison of the motor performance and vestibular function in infants with a congenital cytomegalovirus infection or a connexin 26 mutation: a preliminary study. Ear Hear. 38, e49–e56 (2017).

    Article  PubMed  Google Scholar 

  38. Shan, R., Wang, X. & Fu, P. Growth and development of infants with asymptomatic congenital cytomegalovirus infection. Yonsei Med. J. 50, 667–671 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Amir, J., Atias, J., Linder, N. & Pardo, J. Follow-up of infants with congenital cytomegalovirus and normal fetal imaging. Arch. Dis. Child. Fetal Neonatal Ed. 101, F428–F432 (2016).

    Article  PubMed  Google Scholar 

  40. Numazaki, K. & Fujikawa, T. Chronological changes of incidence and prognosis of children with asymptomatic congenital cytomegalovirus infection in Sapporo, Japan. BMC Infect. Dis. 4, 22 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Noyola, D. E. et al. Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection. J. Pediatr. 138, 325–331 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Palisano, R. J., Rosenbaum, P., Bartlett, D. & Livingston, M. H. Content validity of the expanded and revised Gross Motor Function Classification System. Dev. Med. Child Neurol. 50, 744–750 (2008).

    Article  PubMed  Google Scholar 

  43. Kumar, M. L. et al. Congenital and postnatally acquired cytomegalovirus infections: long-term follow-up. J. Pediatr. 104, 674–679 (1984).

    Article  CAS  PubMed  Google Scholar 

  44. Farkas, N., Lev, D., Schweiger, A., Lerman-Sagie, T. & Malinger, G. [The importance of prenatal neuroimaging in prediction of developmental outcome of fetuses infected with cytomegalovirus]. Harefuah 149, 45–48, 61 (2010).

    PubMed  Google Scholar 

  45. Lopez, A. S. et al. Intelligence and academic achievement with asymptomatic congenital cytomegalovirus infection. Pediatrics 140, e20171517 (2017).

  46. Farkas, N. et al. Does normal fetal brain ultrasound predict normal neurodevelopmental outcome in congenital cytomegalovirus infection? Prenat. Diagn. 31, 360–366 (2011).

    Article  PubMed  Google Scholar 

  47. Bayley, N. Bayley Scales of Infant and Toddler Development (StatPearls, 2006).

  48. Dunn, L. M. & Dunn, D. M. PPVT-4: Peabody Picture Vocabulary Test (Pearson Assessments, 2007).

  49. Lee, L. L. A screening test for syntax development. J. Speech Hear. Disord. 35, 103–112 (1970).

    Article  CAS  PubMed  Google Scholar 

  50. Turriziani Colonna, A. et al. Long-term clinical, audiological, visual, neurocognitive and behavioral outcome in children with symptomatic and asymptomatic congenital cytomegalovirus infection treated with valganciclovir. Front. Med. 7, 268 (2020).

    Article  Google Scholar 

  51. Grosse, S. D., Dollard, S. C. & Ortega-Sanchez, I. R. Economic assessments of the burden of congenital cytomegalovirus infection and the cost-effectiveness of prevention strategies. Semin. Perinatol. 45, 151393 (2021).

  52. Wechsler, D. & Kodama, H. Wechsler Intelligence Scale for Children, Vol. 1 (Psychological Corporation, 1949).

  53. Alarcon, A., Martinez-Biarge, M., Cabanas, F., Quero, J. & Garcia-Alix, A. A prognostic neonatal neuroimaging scale for symptomatic congenital cytomegalovirus infection. Neonatology 110, 277–285 (2016).

    Article  PubMed  Google Scholar 

  54. Boppana, S. B. et al. Neuroradiographic findings in the newborn period and long-term outcome in children with symptomatic congenital cytomegalovirus infection. Pediatrics 99, 409–414 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Fowler, K. B. et al. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N. Engl. J. Med. 326, 663–667 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Coscia, A. et al. Risk of symptomatic infection after non-primary congenital cytomegalovirus infection. Microorganisms 8, 786 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Grue, J. The social meaning of disability: a reflection on categorisation, stigma and identity. Sociol. Health Illn. 38, 957–964 (2016).

    Article  PubMed  Google Scholar 

  58. American Psychiatric Association. Desk Reference to the Diagnostic Criteria from DSM-5 (R) (American Psychiatric Association Publishing, 2013).

  59. Green, S. E. “What do you mean ‘what’s wrong with her?’”: stigma and the lives of families of children with disabilities. Soc. Sci. Med. 57, 1361–1374 (2003).

    Article  PubMed  Google Scholar 

  60. Leyder, M. et al. Primary maternal cytomegalovirus infections: accuracy of fetal ultrasound for predicting sequelae in offspring. Am. J. Obstet. Gynecol. 215, 638.e631–638.e638 (2016).

    Article  Google Scholar 

  61. Lucignani, G. et al. A new MRI severity score to predict long-term adverse neurologic outcomes in children with congenital Cytomegalovirus infection. J. Matern. Fetal Neonatal Med. 34, 859–866 (2021).

  62. Tanimura, K. et al. Immunoglobulin fetal therapy and neonatal therapy with antiviral drugs improve neurological outcome of infants with symptomatic congenital cytomegalovirus infection. J. Reprod. Immunol. 143, 103263 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Reynolds, D. W. et al. Inapparent congenital cytomegalovirus infection with elevated cord IgM levels. Casual relation with auditory and mental deficiency. N. Engl. J. Med. 290, 291–296 (1974).

    Article  CAS  PubMed  Google Scholar 

  64. Saigal, S., Lunyk, O., Larke, R. P. & Chernesky, M. A. The outcome in children with congenital cytomegalovirus infection. A longitudinal follow-up study. Am. J. Dis. Child. 136, 896–901 (1982).

    Article  CAS  PubMed  Google Scholar 

  65. Suzuki, Y., Toribe, Y., Mogami, Y., Yanagihara, K. & Nishikawa, M. Epilepsy in patients with congenital cytomegalovirus infection. Brain Dev. 30, 420–424 (2008).

    Article  PubMed  Google Scholar 

  66. Woolger, C. in Understanding Psychological Assessment (eds Dorfman, W. I. & Hersen, M.) 219–233 (Springer, 2001).

  67. Flanagan, D., Alfonso, V., Mascolo, J. & Hale, J. The Wechsler Intelligence Scale for Children - Fourth Edition in Neuropsychological Practice (Springe, 2010).

  68. Fenson, L., Marchman, V. A. & Thal, D. MacArthur-Bates Communicative Development Inventories: User’s Guide and Technical Manual (Paul H. Brookes Publishing Company, 2007).

  69. Josse, D. Brunet-Lézine Révisé: Echelle de Développement Psychomoteur de la Première Enfance (Pearson, 1997).

  70. Green, E. et al. Griffiths Scales of Child Development 3rd Edition; Part 2: Administration and Scoring (Hogrefe, 2016).

  71. Ikuzawa, M., Matsushita, Y. & Nakase, A. Kyoto Scale of Psychological Development 2001 (Kyoto International Social Welfare Exchange Centre, 2002).

    Google Scholar 

  72. Griffith, R., Luiz, D. & Association for Research in Infant and Child Development. Griffiths Mental Development Scales, Extended Revised: GMDS-ER; Two to Eight Years (Hogrefe, the Test People, 2006).

  73. Bayley, N. Bayley Scales of Infant Development, Second Edition: Manual (The Psychological Corporation, 1993).

    Google Scholar 

  74. Wechsler, D. Manual for the Wechsler Intelligence Scale for Children-Revised (Psychological Corporation, 1974).

  75. Wechsler, D. Manual for the Wechsler Preschool and Primary Scale of Intelligence-Revised (Psychological Corporation, 1989).

    Google Scholar 

  76. Wechsler, D. Manual for the Wechsler Preschool and Primary Scale of Intelligence (Psychological Corporation, 1967).

  77. Woltmann, A. G. The Bender Visual-Motor Gestalt Test (Pearson, 1950).

  78. Gesell, A. The Mental Growth of the Pre-School Child: A Psychological Outline of Normal Development from Birth to the Sixth Year, Including a System of Development Diagnosis (Macmillan, 1925).

  79. Adams, W. & Sheslow, D. Wide Range Assessment of Visual Motor Ability (WRAVMA) (Wide Range, 1995).

    Google Scholar 

  80. Folio, M. R. & Fewell, R. R. PDMS-2: Peabody Developmental Motor Scales (Pro-ed, 2000).

  81. Stott, D. A general test of motor impairment for children. Dev. Med. Child Neurol. 8, 523–531 (1966).

    Article  CAS  PubMed  Google Scholar 

  82. Marini, A., Marotta, L., Bulgheroni, S. & Fabbro, F. Batteria per la Valutazione del Linguaggio in Bambini dai 4 ai 12 anni (Giunti OS, 2015).

    Google Scholar 

  83. Wechsler, D. WPPSI-R: Wechsler Preschool and Primary Scale of Intelligence-Revised (Psychological Corporation, 1989).

    Google Scholar 

  84. Ammons, R. B. & Ammons, C. The quick test (QT): provisional manual. Psychol. Rep. 11, 111–161 (1962).

    Article  Google Scholar 

  85. Wechsler, D. Wechsler Abbreviated Scale of Intelligence (Psychological Corporation, 1999).

  86. Dunn, L. M. & Dunn, L. M. Peabody Picture Vocabulary Yest-Revised (American Guidance Service, Incorporated, 1981).

  87. Brownell, M. N. A. Expressive One-Word Picture Vocabulary Test -- 4 (Pearson, 2011).

  88. Wechsler, D. Wechsler Preschool and Primary Scale of Intelligence–Third Edition (WPPSI-III) (Pearson Assessment, 2009).

  89. Bayley, N. Manual for the Bayley Scales of Infant Development (Psychological Corporation, 1969).

  90. Alpern, G., Boll, T. & Shearer, M. Developmental profile II. J. Read. 18, 287–291 (1980).

    Google Scholar 

  91. Roid, G. H. & Miller, L. J. Leiter International Performance Scale-Revised (Leiter-R) (Stoelting, 1997).

    Google Scholar 

  92. Kaufman, A. & Kaufman, N. Kaufman Assessment Battery for Children Interpretive Manual (American Guidance Service, 1983).

    Google Scholar 

  93. Terman, L. M. & Merrill, M. A. Stanford-Binet Intelligence Scale: Manual for the Third Revision, Form lM (Harrap, 1960).

  94. Page, M. J. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71 (2021).

Download references

Acknowledgements

The authors would like to acknowledge Marisa Conte from the Taubman Medical Library at the University of Michigan Medical School for her assistance in performing the scoping review, Scott Grosse for his feedback on table creation. The authors would also like to acknowledge Seth Dobson from Artful Analytics, LLC and Kathleen Muldoon for their input regarding figures.

Funding

M.H.P. is funded by the Eunice Kennedy Shriver National Institute for Child Health and Development, at the National Institutes of Health (5K23HD108278) and the Gerber Foundation.

Author information

Authors and Affiliations

Authors

Contributions

All authors participated in the conception, and design of the study, as well as the drafting and critical review of the manuscript for intellectual content. C.S.L. conducted the search of the literature. All authors participated in the review of articles for inclusion in the scoping review, as well as data extraction. All authors gave final approval of this version of the manuscript to be published.

Corresponding author

Correspondence to Megan H. Pesch.

Ethics declarations

Competing interests

M.H.P. serves on the Executive Committee of the National CMV Foundation (unpaid) and as a content consultant regarding congenital cytomegalovirus for MedScape/WebMD, neither of which had any input into the conceptualization or creation of this manuscript. C.S.L. and J.B.W. have no competing interests to declare.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pesch, M.H., Lauer, C.S. & Weinberg, J.B. Neurodevelopmental outcomes of children with congenital cytomegalovirus: a systematic scoping review. Pediatr Res 95, 418–435 (2024). https://doi.org/10.1038/s41390-023-02639-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-023-02639-6

This article is cited by

Search

Quick links