News Release

Heterogeneous development of children with Congenital Zika Syndrome-associated microcephaly

Peer-Reviewed Publication


Gauging outcomes for Zika-affected babies, two years later

image: Hammersmith Infant Neurological Examination scores for children with Congenital Zika Syndrome associated microcephaly. A) The main section–neurological exam; B) The second section–motor milestone; and C) The third section—child behavior. view more 

Credit: Aguilar Ticona et al, 2021, PLOS ONE (CC-BY 4.0,

At age two, children who were born with neurological abnormalities due to congenital Zika Virus (ZIKV) have a range of neurodevelopmental profiles that can be tracked using a routine neurological assessment, according to a new study published this week in the open-access journal PLOS ONE by Dr. Albert Ko of Yale University, US and Dr. Federico Costa of The Federal University of Bahia, Brazil, and their colleagues.

Children exposed to ZIKV in utero can develop distinct neurological abnormalities, such as microcephaly, and central nervous system malformations. Previous studies have found neurodevelopmental delays of around 20 months in young children with congenital Zika syndrome (CZS)-associated microcephaly. However, cases have also been reported describing babies with normal neurodevelopment despite equivalent presentation with CZS-associated microcephaly at birth.

In the new study, researchers followed 42 CZS-affected children between the ages of 25 and 32 months from a Microcephaly Outpatient Clinic in Brazil. A total of 19 of the enrolled children (45.2%) were male, the median age at evaluation was 28 months, and all children had a head circumference more than 2 standard deviations below average. Participants were evaluated on their neurological and neurodevelopment, using Hammersmith Infant Neurological Examination (HINE) and the Bayley Scales of Infant and Toddler Neurodevelopment (Bayley-III) respectively.

In general, the children demonstrated severe language, cognitive and motor delays, as measured by Bayley-III, and severe neurological symptoms, as recorded by the HINE. However, the HINE and Bayley-III raw scores effectively captured heterogeneity in these symptoms. Greater head circumference at follow-up was associated with higher cognitive (β = 1.27; 95% CI = 0.01–2.53) and motor raw scores (β = 2.03; 95% CI = 0.25–3.81). Better HINE scores were also correlated with higher Bayley-III cognitive and motor raw scores, even after controlling for other factors. The study was the first to associate HINE—a short and easy neurological examination tool—with cognitive and motor development in children with CZS. The authors conclude that HINE may be a useful tool to characterize long-term outcomes, and capture the clinical heterogeneity, of children with CZS-associated microcephaly.

The authors add: “Children with CZS-associated microcephaly demonstrate severe neurodevelopmental impairments. However, they have heterogeneous development patterns and it is necessary to understand the differences between these children to provide a better health intervention.”


Citation: Aguilar Ticona JP, Nery N Jr, Doss-Gollin S, Gambrah C, Lessa M, Rastely-Júnior V, et al. (2021) Heterogeneous development of children with congenital Zika syndrome-associated microcephaly. PLoS ONE 16(9): e0256444.

Author Countries: Brazil, United States of America

Funding: The study was supported by grants from the National Institutes of Health (NIAID R01 AI052473 (AK), R25 U01AI088752 (AK), FIC R01 TW009504 (AK), R25 TW009338 (AK), F31 AI114245 (AK), R01 AI121207(AK)) (, Wellcome Trust (102330/Z/13/Z (FC); 218987/Z/19/Z (FC)) (, Bahia State Research Support Foundation (FAPESB) ZIKA-FAPESB T.O. n° PET0021/2016 (, São Paulo Research Foundation (FAPESP) under Project 2016/20045-7 (LCSF) (, the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 734584 (DBA) ( and the Coordination for the Improvement of Higher Education (CAPES) from Brazil ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

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