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Enrolling by invitation NCT04398901

Neurodevelopmental Outcomes in ZIKV-Exposed Children

— Observational Zika Virus Congenital Zika Syndrome Congenital Infection Child Development

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
The protocol lists: Neurodevelopmental assessments.
Who it may be relevant to
Registry conditions: Zika Virus, Congenital Zika Syndrome, Congenital Infection, Child Development. Basic parameters: 3 years — 7 years · All.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
United States, Colombia
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

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Official title

Developmental Outcome After In Utero ZIKV Exposure in Children Without Congenital Zika Syndrome

Overview

In this study the investigators will follow the neurodevelopmental outcome of children with in utero ZIKV exposure who do not have microcephaly or severe abnormalities consistent with Congenital Zika Syndrome. The ZIKV-exposed children will be compared to non-ZIKV exposed controls. Children will be assessed at age 3 and 4 years using standardized neurodevelopmental assessments. Children will also have neurodevelopmental assessment at age 5 and 7 years along with a brain MRI at age 7 years.

Detailed description

Zika-virus (ZIKV) infection in pregnancy can result in severe brain damage in 4-12% of cases. Children exposed to ZIKV in utero during the years of 2015-2017 are now in early childhood. Children with severe neurologic injury (Congenital Zika Syndrome; CZS) have a poor developmental outcome, however the developmental outcome of apparently normal infants following in utero ZIKV-exposure is not well known. The incidence of abnormal neurodevelopmental outcome in apparently normal children with in utero ZIKV-exposure is not known.

The investigators will determine if neurodevelopmental assessment scores in children exposed to ZIKV in utero who are normal appearing differ from norms. The investigators hypothesize that ZIKV-exposed normal appearing children will have lower multi-domain developmental assessment scores compared to normative samples. The investigators hypothesize that the presence of mild postnatal non-specific cranial US findings is associated with persistent lower developmental assessment scores compared to ZIKV-exposed children who had normal cranial US and quantitative imaging will find structural and functional brain differences between ZIKV-exposed children and controls..

The investigators will perform a prospective developmental outcome study at 2 sites: 1) Department of Atlántico, Colombia through collaboration with BIOMELAB, the research center of Dr. Carlos Cure, and 2) Children's National, Washington, DC.

The objective of the study is to determine whether children who were exposed to ZIKV in utero and who do not have CZS have abnormalities in neurodevelopment during early childhood and at school age.

The primary outcome at early childhood will be neurodevelopmental assessment scores at age 3 and 4 years. Scores will be compared between Zika-exposed children and controls. The primary outcome at school age will be neurodevelopmental assessment scores at age 5 and 7 years and quantitative brain MRI at 7 years.

Interventions

  • Other Neurodevelopmental assessments
    The investigators will evaluate multiple domains of neurodevelopment at age 3, 4, 5 and 7 years using parental questionnaires and child exams. At age 7 years, the children will have a non-sedated quantitative brain MRI.

Primary outcome measures

  • Neurodevelopmental assessment at age 4 years [Time frame: 4 years of age]
  • Executive function [Time frame: 5 and 7 years of age]
  • Motor function assessment [Time frame: 5 and 7 years of age]
  • Brain maturation [Time frame: 7 years of age]
Secondary outcome measures (2)
  • Motor function assessment [Time frame: 4 years of age]
  • Intellectual ability [Time frame: 5 and 7 years of age]

Eligibility criteria

Inclusion criteria

Zika-exposed cohort:

  • born to mothers with Zika lab confirmation by PCR, IgM, and/or PRNT, or mother was symptomatic for Zika but infection could not be excluded due to late testing and evaluated at Children's National, Washington, DC (USA) or at BIOMELAB, Barranquilla (Colombia)
  • normal fetal neuroimaging
  • normal birth head circumference
  • normal birth clinical exam
  • no more than mild non-specific postnatal cranial ultrasound or brain MRI findings during infancy (if performed)
  • able to be contacted for follow-up

Non-ZIKV exposed Controls:

  • healthy
  • no chronic medical conditions
  • no developmental concerns
  • born at term (>= 37 weeks)
  • birth date prior to March 31, 2016 (Colombian controls)

Exclusion criteria

Zika-exposed cohort:

  • another diagnosis that would impact neurodevelopment
  • abnormal brain MRI (non-specific mild findings are not an exclusion criteria)

Non-ZIKV exposed controls:

  • chronic medical condition with in-patient hospitalization since birth
  • under care of a medical specialty provider for a chronic medical condition
  • surgery with general anesthesia since birth (brief anesthesia for ear tubes, tonsillectomy, or other minor pediatric procedure is not an exclusion criteria)
  • history of seizure
  • abnormal vision (children wearing corrective lenses are eligible)
  • abnormal hearing affecting language development
  • developmental concerns expressed by caregiver
  • receiving physical, occupational, speech or developmental therapy
  • receiving special education services in school
  • behavioral or psychological condition
  • birth date March 31, 2016 or later (Colombian controls)
  • preterm birth (≤36 weeks)
  • planned relocation of child within 5 years and likely inability to complete study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model
Cohort

Study locations

United States · 1 center
  • Children's National Hospital — Washington D.C.
Colombia · 1 center
  • Biomelab — Barranquilla

Publications

  • Mulkey SB, Peyton C, Ansusinha E, Corn E, Arroyave-Wessel M, Zhang A, Biddle C, Gutierrez C, Sorkar A, Cure A, Cure D, du Plessis AJ, DeBiasi RL, Msall ME, Cure C. Preschool neurodevelopment in Zika virus-exposed children without congenital Zika syndrome. Pediatr Res. 2023 Jul;94(1):178-184. doi: 10.1038/s41390-022-02373-5. Epub 2022 Nov 30. PMID 36446920
  • Mulkey SB, Corn E, Williams ME, Peyton C, Andringa-Seed R, Arroyave-Wessel M, Vezina G, Bulas DI, Podolsky RH, Msall ME, Cure C. Neurodevelopmental Outcomes of Normocephalic Colombian Children with Antenatal Zika Virus Exposure at School Entry. Pathogens. 2024 Feb 13;13(2):170. doi: 10.3390/pathogens13020170. PMID 38392908
  • Corn E, Andringa-Seed R, Williams ME, Arroyave-Wessel M, Tarud R, Vezina G, Podolsky RH, Kapse K, Limperopoulos C, Berl MM, Cure C, Mulkey SB. Feasibility and success of a non-sedated brain MRI training protocol in 7-year-old children from rural and semi-rural Colombia. Pediatr Radiol. 2024 Aug;54(9):1513-1522. doi: 10.1007/s00247-024-05964-y. Epub 2024 Jul 6. PMID 38970708
  • Mulkey SB, Corn E, Williams ME, Ansusinha E, Podolsky RH, Arroyave-Wessel M, Vezina G, Peyton C, Msall ME, DeBiasi RL. Neurodevelopmental Outcomes of Preschoolers with Antenatal Zika Virus Exposure Born in the United States. Pathogens. 2024 Jun 27;13(7):542. doi: 10.3390/pathogens13070542. PMID 39057769
  • Mulkey SB, Arroyave-Wessel M, Peyton C, Ansusinha E, Gutierrez C, Sorkar A, Cure A, Samper Y, Cure D, Msall ME, Cure C. Harnessing the power of telemedicine to accomplish international pediatric outcome research during the COVID-19 pandemic. J Telemed Telecare. 2024 Feb;30(2):388-392. doi: 10.1177/1357633X211063166. Epub 2021 Dec 28. PMID 34962177
  • Mulkey SB, Williams ME, Peyton C, Arroyave-Wessel M, Berl MM, Cure C, Msall ME. Understanding the multidimensional neurodevelopmental outcomes in children after congenital Zika virus exposure. Pediatr Res. 2024 Aug;96(3):654-662. doi: 10.1038/s41390-024-03056-z. Epub 2024 Mar 4. PMID 38438554
  • Williams ME, Corn EA, Martinez Ransanz S, Berl MM, Andringa-Seed R, Mulkey SB. Neurodevelopmental assessments used to measure preschoolers' cognitive development in Latin America: a systematic review. J Pediatr Psychol. 2024 May 16;49(5):321-339. doi: 10.1093/jpepsy/jsad089. PMID 38244996
  • Mulkey SB, Andringa-Seed R, Corn E, Williams ME, Arroyave-Wessel M, Podolsky RH, Peyton C, Msall ME, Cure C, Berl MM. School-age child neurodevelopment following antenatal Zika virus exposure. Pediatr Res. 2025 Nov;98(5):1856-1863. doi: 10.1038/s41390-025-03981-7. Epub 2025 Mar 19. PMID 40108430

Identifiers

NCT: NCT04398901 · Pro00012759 · 1R01HD102445-01

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗