Neurodevelopmental Outcomes in ZIKV-Exposed Children

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Child Development; Congenital Zika Syndrome; Zika Virus; Congenital Infection
• Intervention / Treatment: Other: Neurodevelopmental assessments

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.

• Study Type: Observational
• Enrollment (Anticipated): 204

Contacts and Locations

Study Locations

• Colombia
  • Atlantico
    • Barranquilla, Atlantico, Colombia
      • BIOMELAB
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 6 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Zika-exposed children at 3-4 years of age (will be enrolled and studied up to age 8 years) Non-exposed controls at 4 to 5 years of age

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Colombia ZIKV-exposed; Seventy children in Colombia were previously enrolled as part of a fetal-neonatal neuroimaging study in 2016-2017 and were from Department of Atlantico, Colombia on the Caribbean coast. Eligible children had prior normal fetal MRI and fetal US, normal birth head circumference, normal clinical exam, no more than mild non-specific postnatal imaging findings, and are thus without findings of CZS.	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.
Colombia Non-ZIKV exposed control; The investigators will enroll 70 non-ZIKV exposed children, age 4 to 5 years, in Department of Atlántico, Colombia with birth dates prior to March 31, 2016. Based on the arrival of ZIKV to Colombia in November 2015, this date would ensure a control cohort without congenital ZIKV exposure in the first half of gestation and unlikely during any of the pregnancy.	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.
United States ZIKV-exposed; The US cohort either presented during pregnancy or after birth and sought clinical care with the Children's National Congenital Zika Program in Washington, DC and were ZIKV-exposed.	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.
United States Non-ZIKV exposed control; The investigators will enroll 32 non-ZIKV exposed children, age 4 years, in Washington, DC.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurodevelopmental assessment at age 4 years	PEDI-CAT score	4 years of age
Executive function	BRIEF-2 score	5 and 7 years of age
Motor function assessment	MABC-2 score	5 and 7 years of age
Brain maturation	Quantitative brain MRI volumetric measurement	7 years of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor function assessment	MABC-2 score	4 years of age
Intellectual ability	Age-appropriate Wechsler	5 and 7 years of age

Collaborators and Investigators

• Sponsor: Children's National Research Institute
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH); Thrasher Research Fund
• Investigators: Principal Investigator: Sarah B Mulkey, MD, PhD, Children's National Research Institute

Publications and helpful links

General Publications

• Mulkey SB, DeBiasi RL. Do Not Judge a Book by Its Cover: Critical Need for Longitudinal Neurodevelopmental Assessment of In Utero Zika-Exposed Children. Am J Trop Med Hyg. 2020 May;102(5):913-914. doi: 10.4269/ajtmh.20-0197. No abstract available.
• Mulkey SB, Bulas DI, Vezina G, Fourzali Y, Morales A, Arroyave-Wessel M, Swisher CB, Cristante C, Russo SM, Encinales L, Pacheco N, Kousa YA, Lanciotti RS, Cure C, DeBiasi RL, du Plessis AJ. Sequential Neuroimaging of the Fetus and Newborn With In Utero Zika Virus Exposure. JAMA Pediatr. 2019 Jan 1;173(1):52-59. doi: 10.1001/jamapediatrics.2018.4138.
• Mulkey SB, Arroyave-Wessel M, Peyton C, Bulas DI, Fourzali Y, Jiang J, Russo S, McCarter R, Msall ME, du Plessis AJ, DeBiasi RL, Cure C. Neurodevelopmental Abnormalities in Children With In Utero Zika Virus Exposure Without Congenital Zika Syndrome. JAMA Pediatr. 2020 Mar 1;174(3):269-276. doi: 10.1001/jamapediatrics.2019.5204. Erratum In: JAMA Pediatr. 2020 Mar 1;174(3):305.
• Mulkey SB, Ansusinha E, Cristante C, Russo SM, Biddle C, Kousa YA, Pesacreta L, Jantausch B, Hanisch B, Harik N, Hamdy RF, Hahn A, Chang T, Jaafar M, Ambrose T, Vezina G, Bulas DI, Wessel D, du Plessis AJ, DeBiasi RL. Complexities of Zika Diagnosis and Evaluation in a U.S. Congenital Zika Program. Am J Trop Med Hyg. 2021 Apr 19;104(6):2210-2219. doi: 10.4269/ajtmh.20-1256.

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2020
• Primary Completion (Anticipated): May 31, 2023
• Study Completion (Anticipated): June 30, 2025

Study Registration Dates

• First Submitted: May 19, 2020
• First Submitted That Met QC Criteria: May 19, 2020
• First Posted (Actual): May 21, 2020

Study Record Updates

• Last Update Posted (Actual): August 29, 2022
• Last Update Submitted That Met QC Criteria: August 26, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: ZIKV
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Disease; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Syndrome; Zika Virus Infection
• Other Study ID Numbers: Pro00012759; 1R01HD102445-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Undecided at this time

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No