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Neurodevelopmental Abnormalities in Children With In Utero Zika Virus Exposure Without Congenital Zika Syndrome

Educational Objective
To investigate whether infants without congenital Zika syndrome but who were exposed to Zika virus in utero have normal neurodevelopmental outcomes until 18 months of age.
1 Credit CME
Key Points

Question  Do newborns with in utero Zika virus exposure, normal fetal imaging result, and average head circumference measurement at birth have normal neurodevelopmental outcomes?

Findings  In this cohort study of 70 Colombian infants with in utero Zika virus exposure but without congenital Zika syndrome at birth, multidomain neurodevelopmental assessment scores deviated from normal scores as the children became older.

Meaning  Findings from this study suggest long-term neurodevelopmental monitoring should be performed for all infants with Zika virus exposure to ascertain the neurodevelopmental implications of the virus that may manifest with older age.


Importance  The number of children who were born to mothers with Zika virus (ZIKV) infection during pregnancy but who did not have apparent disability at birth is large, warranting the study of the risk for neurodevelopmental impairment in this population without congenital Zika syndrome (CZS).

Objective  To investigate whether infants without CZS but who were exposed to ZIKV in utero have normal neurodevelopmental outcomes until 18 months of age.

Design, Setting, and Participants  This cohort study prospectively enrolled a group of pregnant women with ZIKV in Atlántico Department, Colombia, and in Washington, DC. With this cohort, we performed a longitudinal study of infant neurodevelopment. Infants born between August 1, 2016, and November 30, 2017, were included if they were live born, had normal fetal brain findings on magnetic resonance imaging and ultrasonography, were normocephalic at birth, and had normal examination results without clinical evidence of CZS. Seventy-seven infants born in Colombia, but 0 infants born in the United States, met the inclusion criteria.

Exposures  Prenatal ZIKV exposure.

Main Outcomes and Measures  Infant development was assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) and the Alberta Infant Motor Scale (AIMS) at 1 or 2 time points between 4 and 18 months of age. The WIDEA and AIMS scores were converted to z scores compared with normative samples. Longitudinal mixed-effects regression models based on bootstrap resampling methods estimated scores over time, accounting for gestational age at maternal ZIKV infection and infant age at assessment. Results were presented as slope coefficients with 2-tailed P values based on z statistics that tested whether the coefficient differed from 0 (no change).

Results  Of the 77 Colombian infants included in this cohort study, 70 (91%) had no CZS and underwent neurodevelopmental assessments. Forty infants (57%) were evaluated between 4 and 8 months of age at a median (interquartile range [IQR]) age of 5.9 (5.3-6.5) months, and 60 (86%) underwent assessment between 9 and 18 months of age at a median (IQR) age of 13.0 (11.2-16.4) months. The WIDEA total score (coefficients: age = –0.227 vs age2 = 0.006; P < .003) and self-care domain score (coefficients: age = –0.238 vs age2 = 0.01; P < .008) showed curvilinear associations with age. Other domain scores showed linear declines with increasing age based on coefficients for communication (–0.036; P = .001), social cognition (–0.10; P < .001), and mobility (–0.14; P < .001). The AIMS scores were similar to the normative sample over time (95% CI, –0.107 to 0.037; P = .34). Nineteen of 57 infants (33%) who underwent postnatal cranial ultrasonography had a nonspecific, mild finding. No difference was found in the decline of WIDEA z scores between infants with and those without cranial ultrasonography findings except for a complex interactive relationship involving the social cognition domain (P < .049). The AIMS z scores were lower in infants with nonspecific cranial ultrasonography findings (–0.49; P = .07).

Conclusions and Relevance  This study found that infants with in utero ZIKV exposure without CZS appeared at risk for abnormal neurodevelopmental outcomes in the first 18 months of life. Long-term neurodevelopmental surveillance of all newborns with ZIKV exposure is recommended.

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Article Information

Accepted for Publication: September 4, 2019.

Published Online: January 6, 2020. doi:10.1001/jamapediatrics.2019.5204

Correction: This article was corrected on March 2, 2020, to remove a key that had been incorrectly included in Figure 1.

Corresponding Author: Sarah B. Mulkey, MD, PhD, Division of Fetal and Transitional Medicine, Children’s National Hospital, 111 Michigan Ave NW, Washington, DC 20010 (

Author Contributions: Dr Mulkey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs DeBiasi and Cure are co–senior/last authors.

Concept and design: Mulkey, Arroyave-Wessel, Russo, Msall, du Plessis, DeBiasi, Cure.

Acquisition, analysis, or interpretation of data: Mulkey, Peyton, Bulas, Fourzali, Jiang, Russo, McCarter, Msall, DeBiasi.

Drafting of the manuscript: Mulkey, DeBiasi.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Mulkey, Jiang, McCarter.

Obtained funding: Mulkey, DeBiasi.

Administrative, technical, or material support: Arroyave-Wessel, Bulas, Russo, Msall, DeBiasi.

Supervision: Mulkey, McCarter, du Plessis, DeBiasi, Cure.

Conflict of Interest Disclosures: Dr Mulkey reported receiving grants from the Thrasher Research Fund during the conduct of the study. Drs Mulkey and DeBiasi reported providing technical expertise to the Zika studies by the Centers for Disease Control and Prevention outside the submitted work. Dr Fourzali reported receiving other compensation from the Children’s National Hospital outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded in part by a grant from the Thrasher Research Fund (Drs Mulkey [principal investigator], du Plessis, and DeBiasi); awards UL1TR001876 and KL2TR001877 from the National Institutes of Health National Center for Advancing Translational Sciences (Dr Mulkey); and grant HRSA/MCHB T73 MC11047 from the Leadership Education in Neurodevelopmental and Related Disorders Training Program (Dr Msall).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed herein are those of the authors and do not reflect the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

Additional Contributions: We thank the women, infants, and their families who participated in the assessments and Children’s National Hospital for supporting the congenital Zika program. The following members of the BIOMELAB team in Barranquilla, Colombia, ensured the success of this study: Yazmin Martinez and Jose Ospino, primary research coordinators, as well as Edna Acosta, Yhina Samper, Donella Santiago, Alsira Diaz, Donella Santiago, and Ana Cecilia Perez. Gilbert Vezina, MD, Children’s National Hospital, provided interpretation of the fetal and neonatal imaging. Youssef A. Kousa, DO, PhD, Children’s National Hospital, served as a resource for his research in the congenital Zika program, and Armando Morales, MD, Sabbag Radiologos, served as a resource for his work in fetal and neonatal neuroimaging. Christopher Swisher, BS, and Caitlin Cristante, BS, Children’s National Hospital, provided research coordination. E. Morales-Monforte, PhD, Hospital Sant Joan de Deu Barcelona, provided a written Spanish-language AIMS (Alberta Infant Motor Scale) training class. These individuals received no additional compensation outside of their usual salary for their contributions.

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