Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children


We report neurodevelopmental outcomes in 216 infants followed since the time of PCR-confirmed maternal Zika virus (ZIKV) infection in pregnancy during the Rio de Janeiro epidemic of 2015–2016 (refs. 1,2). Neurodevelopment was assessed by Bayley Scales of Infant and Toddler Development, third edition (Bayley-III; cognitive, language and motor domains) in 146 children and through neurodevelopment questionnaires/neurological examinations in 70 remaining children. Complete eye exams (n = 137) and hearing assessments (n = 114) were also performed. Below-average neurodevelopment and/or abnormal eye or hearing assessments were noted in 31.5% of children between 7 and 32 months of age. Among children assessed by Bayley-III, 12% scored below –2 s.d. (score <70; a score of 100 ± 2 s.d. is the range) in at least one domain; and 28% scored between −1 and −2 s.d. in any domain (scores <85–70). Language function was most affected, with 35% of 146 children below average. Improved neurodevelopmental outcomes were noted in female children, term babies, children with normal eye exams and maternal infection later in pregnancy (P = 0.01). We noted resolution of microcephaly with normal neurodevelopment in two of eight children, development of secondary microcephaly in two other children and autism spectrum disorder in three previously healthy children in the second year of life.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2: Bayley-III assessments in 146 children between the ages of 7 and 32 months.
Fig. 3: Gestational age at time of maternal Zika virus infection in 244 pregnancies.

Data availability

The data sets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.


  1. 1.

    Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary report. N. Engl. J. Med. (2016).

  2. 2.

    Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro. N. Engl. J. Med. 375, 2321–2334 (2016).

  3. 3.

    Moore, C. A. et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 171, 288 (2017).

  4. 4.

    Kapogiannis, B. G., Chakhtoura, N., Hazra, R. & Spong, C. Y. Bridging knowledge gaps to understand how Zika virus exposure and infection affect child development. JAMA Pediatr. 171, 478 (2017).

  5. 5.

    Honein, M. A. et al. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA 317, 59–68 (2017).

  6. 6.

    Rice, M. E. et al. Vital signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection – U.S. territories and freely associated states, 2018. MMWR Morb. Mortal. Wkly Rep. 67, 858–867 (2018).

  7. 7.

    Pacheco, O. et al. Zika virus disease in Colombia—preliminary report. N. Engl. J. Med. (2016).

  8. 8.

    Barcellos, C. et al. Increased hospitalizations for neuropathies as indicators of Zika virus infection, according to health information system data, Brazil. Emerg. Infect. Dis. 22, 1894–1899 (2016).

  9. 9.

    Nogueira, M. L. et al. Adverse birth outcomes associated with Zika virus exposure during pregnancy in São José do Rio Preto, Brazil. Clin. Microbiol. Infect. 24, 646–652 (2018).

  10. 10.

    Meneses, J. et al. Lessons learned at the epicenter of Brazil’s congenital Zika epidemic: evidence from 87 confirmed cases. Clin. Infect. Dis. 64, 1302–1308 (2017).

  11. 11.

    Melo, A. S. et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 73, 1407–1416 (2016).

  12. 12.

    van der Linden, V. et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth – Brazil. MMWR Morb. Mortal. Wkly Rep. 65, 1343–1348 (2016).

  13. 13.

    Reynolds, M. R. et al. Vital signs: update on Zika virus-associated birth defects and evaluation of all U.S. infants with congenital Zika virus exposure – U.S. Zika Pregnancy Registry, 2016. MMWR Morb. Mortal. Wkly Rep. 66, 366–373 (2017).

  14. 14.

    Moura da Silva, A. A. et al. Early growth and neurologic outcomes of infants with probable congenital Zika virus syndrome. Emerg. Infect. Dis. 22, 1953–1956 (2016).

  15. 15.

    Bayley, N. Comparisons of mental and motor test scores for ages 1–15 months by sex, birth order, race, geographical location, and education of parents. Child Dev. 36, 379–411 (1965).

  16. 16.

    Ballot, D. E. et al. Use of the Bayley Scales of Infant and Toddler Development, third edition, to assess developmental outcome in infants and young children in an urban setting in South Africa. Int. Sch. Res. Notices 2017, 1631760 (2017).

  17. 17.

    Anderson, P. J. et al. Underestimation of developmental delay by the new Bayley-III Scale. Arch. Pediatr. Adolesc. Med. 164, 352–356 (2010).

  18. 18.

    Vohr, B. R. et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J. Pediatr. 161, 222–228.e3 (2012).

  19. 19.

    Lopes Moreira, M. E. et al. Neurodevelopment in infants exposed to Zika virus in utero. N. Engl. J. Med. 379, 2377–2379 (2018).

  20. 20.

    Cherry, J., Demmler-Harrison, G. J., Hotez, P. J., Kaplan, S. L. & Steinbach, W. J. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases (Saunders, 2018).

  21. 21.

    da Cunha, R. D. E. S., Lamy Filho, F., Rafael, E. V., Lamy, Z. C. & de Queiroz, A. L. G. Breast milk supplementation and preterm infant development after hospital discharge: a randomized clinical trial. J. Pediatr. 92, 136–142 (2016).

  22. 22.

    Vianna, P. et al. Zika virus as a possible risk factor for autism spectrum disorder: neuroimmunological aspects. Neuroimmunomodulation 25, 320–327 (2018).

  23. 23.

    Muenchhoff, M. & Goulder, P. J. R. Sex differences in pediatric infectious diseases. J. Infect. Dis. 209 (Suppl. 3), S120–S126 (2014).

  24. 24.

    Halai, U.-A. et al. Maternal Zika virus disease severity, virus load, prior dengue antibodies, and their relationship to birth outcomes. Clin. Infect. Dis. 65, 877–883 (2017).

  25. 25.

    Zin, A. A. et al. Screening criteria for ophthalmic manifestations of congenital Zika virus infection. JAMA Pediatr. 171, 847–854 (2017).

  26. 26.

    Tsui, I. et al. Eye findings in infants with suspected or confirmed antenatal Zika virus exposure. Pediatrics 142, e20181104 (2018).

  27. 27.

    Rossetto, J. D. et al. Visual function assessment in children with congenital Zika virus infection. J. AAPOS 22, e60 (2018).

  28. 28.

    Ventura, C. V. et al. Risk factors associated with the ophthalmoscopic findings identified in infants with presumed Zika virus congenital infection. JAMA Ophthalmol. 134, 912–918 (2016).

  29. 29.

    Ventura, C. V. et al. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arq. Bras. Oftalmol. 79, (2016).

  30. 30.

    Yepez, J. B. et al. Ophthalmic manifestations of congenital Zika syndrome in Colombia and Venezuela. JAMA Ophthalmol. 135, 440–445 (2017).

  31. 31.

    Lanciotti, R. S. et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg. Infect. Dis. 14, 1232–1239 (2008).

  32. 32.

    von der Hagen, M. et al. Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev. Med. Child Neurol. 56, 732–741 (2014).

  33. 33.

    Bayley, N. Bayley Scales of Infant and Toddler Development: Administration Manual (Harcourt Assessment, 2006).

  34. 34.

    Madaschi, V., Mecca, T. P., Macedo, E. C. & Paula, C. S. Bayley-III Scales of Infant and Toddler Development: transcultural adaptation and psychometric properties. Paidéia (Ribeirão Preto) 26, 189–197 (2016).

  35. 35.

    Souza, C. T. et al. Assessment of global motor performance and gross and fine motor skills of infants attending day care centers. Rev. Bras. Fisioter. 14, 309–315 (2010).

  36. 36.

    Johnson, S., Moore, T. & Marlow, N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? Pediatr. Res. 75, 670–674 (2014).

  37. 37.

    Jary, S., Kmita, G. & Whitelaw, A. Differentiating developmental outcome between infants with severe disability in research studies: the role of Bayley Developmental Quotients. J. Pediatr. 159, 211–4.e1 (2011).

  38. 38.

    Haataja, L. et al. Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J. Pediatr. 135, 153–161 (1999).

  39. 39.

    Romeo, D. M. M. et al. Neuromotor development in infants with cerebral palsy investigated by the Hammersmith Infant Neurological Examination during the first year of age. Eur. J. Paediatr. Neurol. 12, 24–31 (2008).

  40. 40.

    Romeo, D. M., Ricci, D., Brogna, C. & Mercuri, E. Use of the Hammersmith Infant Neurological Examination in infants with cerebral palsy: a critical review of the literature. Dev. Med. Child Neurol. 58, 240–245 (2016).

Download references


This study was supported by the Departamento de Ciência e Tecnologia do Ministério da Saúde do Brasil (DECIT/25000.072811/2016-19, to P.B. and M.E.M.); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES 001/88887.116627/2016-01 to PB); Brazilian National Council for Scientific and Technological Development (CNPq/441098/2016-9 to M.E.M. and CNPq307282/2017-1 to P.B.); Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, No. E-18/2015TXB to M.E.M., No. 239224/E-032018 to M.E.M. and No. E-26/202.862/2018 to P.B.); Fondation Christophe e Rodolphe Mérieux to P.B.; ZikAlliance, 734548 to P.B.; the Thrasher Research Fund (No. 20164370 to K.N.S. and K.A.); the Bill and Melinda gates Foundation Grand Challenges Explorations (No. OPP112887 to P.B.M.); the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (No. AI28697 to K.N.S., No. AI1259534-01 to K.N.S. and G.C., No. AI140718-01 to K.N.S. and P.B.); the National Eye Institute (NEI) of the National Institutes of Health (No. AI129847-01 to K.N.S., I.T. and P.B.); the United Kingdom’s Department for International Development (to M.E.M.); and the ZikaPlan (Preparedness Latin American Network, to M.E.M.). We thank the women who enrolled in this study, the Fiocruz Zika Field Team who rendered our work possible, and P.F. Augusto and C.B. de Souza (Federal University of São Paulo), who assisted with neurodevelopmental assessments.

Author information

K.N.-S., P.B., C.R.G., J.P.P. and M.E.M. conceived and designed the study. K.N.-S., P.B, T.K., Z.V., L.D., M.P., L.M.A.d.C., S.M.P., A.A.Z., I.T., T.R.S.S., D.C.d.C., R.P.C., J.M., A.B.R., R.H.H., C.Y.P.A., F.F.G., J.P.P., S.L.G. and M.E.M. were responsible for data collection and accuracy checking of data. K.N.-S., P.B, T.K. and Z.V. were responsible for data analysis. K.N.-S., P.B, T.K., Z.V., K.A., C.R.G., L.D., A.A.Z., I.T., C.E., P.B.M., J.D.C., Z.X., G.C. and M.E.M. were responsible for interpreting the data. K.N.-S., P.B, Z.V., T.K. and M.E.M. drafted the manuscript. All authors critically revised the manuscript and gave final approval of the version to be published.

Correspondence to Karin Nielsen-Saines or Maria Elisabeth Moreira.

Ethics declarations

Competing interest

The authors declare no competing interests.

Additional information

Peer review information: Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2.

Reporting Summary

Source data

Source Data Fig. 1

Statistical Source Data

Source Data Fig. 2

Statistical Source Data

Source Data Fig. 3

Statistical Source Data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading