School-Age Child Neurodevelopment Following Antenatal Zika Virus Exposure

Sarah B Mulkey; Regan Andringa-Seed; Elizabeth Corn; Meagan E Williams; Margarita Arroyave-Wessel; Robert H Podolsky; Colleen Peyton; Michael E Msall; Carlos Cure; Madison M Berl

doi:10.1038/s41390-025-03981-7

. Author manuscript; available in PMC: 2025 Sep 19.

Published in final edited form as: Pediatr Res. 2025 Mar 19;98(5):1856–1863. doi: 10.1038/s41390-025-03981-7

School-Age Child Neurodevelopment Following Antenatal Zika Virus Exposure

Sarah B Mulkey ^1,^2,^3,^*, Regan Andringa-Seed ¹, Elizabeth Corn ¹, Meagan E Williams ¹, Margarita Arroyave-Wessel ¹, Robert H Podolsky ⁴, Colleen Peyton ⁵, Michael E Msall ⁶, Carlos Cure ⁷, Madison M Berl ^8,⁹

^1.Zickler Family Prenatal Pediatrics Institute, Children’s National Hospital, Washington, DC

^2.Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, DC

^3.Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC

^4.Division of Biostatistics and Study Methodology, Children’s National Hospital, Washington, DC

^5.Department of Physical Therapy and Human Movement Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL

^6.Kennedy Research Center on Intellectual and Neurodevelopmental Disabilities, University of Chicago Medicine, Chicago, IL

^7.BIOMELab, Barranquilla, Atlántico, Colombia

^8.Division of Pediatric Neuropsychology, Children’s National Hospital, Washington, DC

^9.Department of Psychiatry and Behavioral Sciences, The George Washington University School of Medicine and Health Sciences, Washington, DC

Corresponding author: Sarah B. Mulkey, MD, PhD, Children’s National Hospital, Zickler Family Prenatal Pediatrics Institute, 111 Michigan Ave. NW, Washington, DC 20010, sbmulkey@childrensnational.org

Author Contributions:

Dr. Mulkey conceptualized and designed the study, obtained funding for the study, developed data collection instruments, trained the study team, reviewed study data, interpreted study data and results of data analyses, drafted the initial manuscript, and reviewed and revised the manuscript.

Ms. Andringa-Seed trained the study team, collected study data, reviewed study data, interpreted study data and data analyses, drafted the initial manuscript, and reviewed and revised the manuscript.

Ms. Corn trained the study team, collected study data, reviewed study data, interpreted study data, and reviewed and revised the manuscript.

Ms. Williams reviewed study data, interpreted study data, developed figures for the manuscript, and reviewed and revised the manuscript.

Ms. Arroyave-Wessel conceptualized and designed the study, translated data collection instruments, trained the study team, oversaw the use of telehealth for study activities, and reviewed and revised the manuscript.

Dr. Podolsky analyzed and interpreted study data, drafted initial tables for the manuscript, and reviewed and revised the manuscript.

Dr. Peyton conceptualized and designed the study, trained the study team, reviewed study data, and reviewed and revised the manuscript.

Dr. Msall conceptualized and designed the study, provided additional insight into data interpretation, and reviewed and revised the manuscript.

Dr. Cure conceptualized and designed the study, recruited study participants, oversaw data collection, reviewed study data, and reviewed and revised the manuscript.

Dr. Berl conceptualized and designed the study, trained the study team, reviewed and interpreted data and data analyses, drafted the initial manuscript, and reviewed and revised the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

PMCID: PMC12273634 NIHMSID: NIHMS2093969 PMID: 40108430

Abstract

Background:

Children exposed antenatally to Zika virus (ZIKV) during the 2015-2016 epidemic are now in school; little is known about their neurodevelopment at this age. The objective was to evaluate neurodevelopment of ZIKV-exposed Colombian children compared to non-exposed controls at ages 5-6.

Methods:

48 normocephalic children with antenatal ZIKV exposure (Cases) were recruited for a longitudinal cohort study in Atlántico, Colombia. Two age-matched control groups of 118 non-ZIKV exposed children were recruited from same communities as Cases: 63 born before ZIKV epidemic but experienced COVID-19-related school entry delays, and 55 born post-ZIKV epidemic but started school on time. Multi-domain neurodevelopment was assessed at 5-6 years using standardized measures. Standard regression and proportional odds models were used to compare outcomes. P-values were adjusted using the Benjamini-Hochberg false discovery rate (FDR) (p<0.05).

Results:

There were no differences in age at assessment between groups. Case Full-Scale IQ scores were lower than both control groups (p=.002), driven by visual reasoning (p<0.001). Controls with school entry delay had more executive control problems and lower adaptive functioning skills than Cases and Controls without school entry delay.

Conclusions:

ZIKV-exposed children have lower cognitive performance compared to controls. Early childhood experiences can affect pediatric outcomes research.

Introduction

Arboviral diseases can have teratogenic effects which impact child neurodevelopment. As evidenced by the 2015-2016 Zika virus (ZIKV) epidemic in the Americas, antenatal ZIKV exposure can have profound neurodevelopmental consequences. Congenital Zika syndrome (CZS) affects approximately 5-13% of infants with antenatal ZIKV-exposure and includes severe birth defects of microcephaly, ophthalmological and audiological pathologies, and arthrogryposis.¹ Though most infants with antenatal ZIKV exposure do not have CZS, they are still at risk for differences in early neurodevelopment.^2-9 Long-term follow-up of all children with antenatal ZIKV exposure is recommended;¹⁰ however, few ZIKV-exposed cohorts have been followed beyond three years of age.^2,5,8,11

We seek to bridge this knowledge gap and build upon serial outcome measurements in our well-characterized cohort of Colombian children with antenatal ZIKV exposure who have been followed since the prenatal period.^8,9,12,13 Early school age is a crucial time to assess cognitive and social-emotional skills vulnerable to adverse early life exposures because it is a time of emerging higher-order cognitive skills. The objective of this study was to assess neurodevelopmental outcomes of ZIKV-exposed children without CZS (Cases) at ages 5-6 years. We assessed skills across motor, receptive language, executive function, adaptive, social-emotional, and cognitive domains. Performance was compared to typically developing children without ZIKV exposure from the same communities in Colombia (Controls). We hypothesized that, similar to previous timepoints,^8,9 ZIKV-exposed children would show differences in executive function, and that other differences may emerge in language development, cognition, and motor ability at school age.

The study occurred amid the COVID-19 pandemic. The effects of school closure and limited socialization in early developmental years are still being elucidated.^14-17 Our study captured these historical effects as a part of developmental evaluations conducted between 2021 and 2023 in control cohorts of healthy, typically developing children who were different ages at the height of pandemic-related lockdown. Thus, as a secondary objective we analyzed neurodevelopmental differences with two different control groups exposed at different ages to the pandemic.

Methods

Study Population

We performed a prospective case-control study of 48 ZIKV-exposed children (Cases) and 118 children without ZIKV exposure (Controls) from the semi-rural town of Sabanalarga and the rural towns of La Peña, Aguada del Pablo, and Colombia in Department of Atlántico, Colombia. Cases were born between 08/31/2016 and 11/03/2017 and during gestation, their mothers had laboratory-confirmed ZIKV infection. The children have undergone serial evaluations since the prenatal period (Figure 1).^8,9,12,13 Cases do not have CZS, were normocephalic at birth, had normal fetal imaging, and any postnatal imaging was either normal or showed only non-specific findings.¹²

This study enrolled two control cohorts of non-ZIKV-exposed children (Control-School Entry Delay [Control-SED] and Control-No School Entry Delay [Control-NSED]). Originally, 70 non-ZIKV-exposed children (Control-SED) were enrolled as described previously from the same neighborhoods as Cases.⁹ These children were born earlier than Cases between 03/17/2015 and 03/28/2016; these dates were selected to preclude asymptomatic antenatal ZIKV exposure during at least the first half of gestation, based on timing of the ZIKV epidemic in Colombia. The 5–6-year-old evaluations for Control-SED children coincided with local closures, quarantine restrictions, and delays in schooling amid the COVID-19 pandemic (Figure 2). After behavioral observation during sessions and initial review of Control-SED outcomes data, there was concern that their performance may be impacted by COVID-19-related delays in school entry. Therefore, a second cohort of 55 non-ZIKV exposed 5-year-old children (Control-NSED) were prospectively enrolled in 2023, also from the same communities (Figure 1). Eligible Control-NSED children were born after March 23, 2018, when ZIKV levels had decreased substantially in Colombia¹⁸ and the Colombian Ministry of Health had declared the end of the ZIKV epidemic (Figure 2).¹⁹ Exclusion criteria for Control children were known exposure to infections during pregnancy (e.g., Zika, Dengue, Chikungunya); preterm birth (≤ 36 weeks); chronic medical, behavioral or psychological conditions; hearing or vision abnormalities; receiving physical, occupational or speech therapy for a developmental condition; history of seizures; or other developmental concerns as reported by caregivers.

Figure 2: — ZIKV-exposed children (Cases) were 3-4 years old during the height of the pandemic and Control-NSED were 2-3 years old with both starting school on time,¹ but the Control-SED were 5-6 years old and delayed in starting school. All groups experienced the impact of the pandemic, but at different ages.

This study received approval from the Children’s National Hospital Institutional Review Board, Washington, DC and the Institutional Review Committee and Independent Committee on Research Ethics (CIRCIE), Barranquilla, Colombia. Parents or legal guardians provided written informed consent for their child’s participation. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. This study is registered on ClinicalTrials.gov, NCT04398901.

Neurodevelopmental evaluations

All participants were evaluated between 5.0 and 6.5 years of age using the ZIKV Outcome Toolbox designed for this longitudinal study.²⁰ Cases were assessed between December 2022 and April 2023 (Figures 1 and 2). Control-SED children were seen between COVID-19 pandemic waves in October-November 2021; Control-NSED, between August-November 2023 (Figures 1 and 2).

Study visits occurred at a community center in Sabanalarga, Colombia and included caregiver-completed questionnaires and direct child assessments.⁹ Caregiver questionnaires included Spanish versions of the Behavioral Rating Inventory of Executive Function-Second Edition (BRIEF-2),²¹ Adaptive Behavior Assessment System-Third Edition (ABAS-3),²² Child Behavior Checklist (CBCL),²³ and medical history, socioeconomic, and family activity surveys. BRIEF-2 assesses executive functioning skills important for cognitive, emotional, and behavioral regulation. T-scores are generated for an overall General Executive Composite (GEC) and three subdomains that include the Emotional Regulation (ERI), Behavioral Regulation (BRI), and Cognitive Regulation Indices (CRI).²¹ Higher BRIEF-2 T-scores indicate more executive functioning problems. ABAS-3 composite standard scores were analyzed for each of three adaptive domains (Conceptual, Social, Practical) as well as for the overall General Adaptive Composite (GAC).²² CBCL assesses behavior, anxiety/depression, and social functioning. T-scores for Internalizing, Externalizing, and Total Problems were calculated.²³ Score calculations for BRIEF-2, CBCL, and ABAS-3 use normative data from the United States.^21-23

Child evaluations spanning motor, cognitive, and language domains were performed by trained research coordinators and neuropsychologists in Spanish. Children completed the Test de Vocabulario en Imágenes (TVIP, Peabody Picture Vocabulary Test)²⁴ to assess receptive vocabulary. TVIP standard scores were calculated using the composite Hispanic norms from samples in Puerto Rico and Mexico.²⁴ Fine and gross motor ability were assessed using the Movement Assessment Battery for Children-Second Edition (MABC-2).²⁵ MABC-2 sub-scores for manual dexterity, aiming and catching, and balance were analyzed in addition to the overall score, using UK norms.²⁵ The Spanish version of the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV), which renders a Full-Scale IQ (FSIQ) and five composite scores–Verbal Comprehension, Visual Spatial, Fluid Reasoning, Working Memory, and Processing Speed –was used to assess cognitive performance. Normative data were from Spain.²⁶ Two selected instruments from the Spanish language NIH Toolbox—the Flanker Inhibitory Control and Attention Test and Pattern Comparison Processing Speed Test—were administered to assess attention and processing speed and were analyzed using age-corrected standard scores from the United States.²⁷ Telehealth Zoom enabled live monitoring of study visits; child evaluations were recorded for scoring verification, as previously described.^8,28 While normative data is not matched to Spanish-speaking children living in Colombia, we utilized the same normative dataset across groups and selected the most appropriate normative data available for the tool.

Statistical analysis

Raw data were transferred from Colombia to Children’s National Hospital via secure Dropbox portal and entered into REDCap.²⁹ Demographic, socioeconomic, and participant characteristics were reported as mean for continuous variables and N (percentage) for categorical variables. Neurodevelopmental outcomes were compared between Cases and both Controls. Standard regression models were used for all outcomes having residuals that appeared close to normally distributed; these outcomes are reported as mean (95% confidence interval) in Tables 1 and 2. Proportional odds models were used when residuals did not appear close to normally distributed; these outcomes are reported as median [min, max] in Tables 1 and 2. The false discovery rate (FDR) was used to adjust for multiple testing for the overall test of differences among Case, Control-SED, and Control-NSED groups. The three groups were compared pairwise for any outcome having an FDR p-value <0.05, with the pairwise p-values being adjusted using either the Tukey-Kramer procedure (normally distributed outcomes) or the Holm procedure (other outcomes). All analyses were conducted using R 4.3.0.³⁰

Table 1:

Outcomes of child assessment measures: MABC, WPPSI, NIH Toolbox Subtests, and TVIP.

Assessment	Cases (N=48)	Control-School Entry Delay (N=63)	Control-No School Entry Delay (N=55)	p-value, FDR
WPPSI Standard Score
Full Scale IQ (FSIQ)²	65.1 (62.6 – 69.6)^a	77.4 (72.4 –82.4)^b	75.1 (69.8 – 79.9)^b	0.002
FSIQ: Number (%) Below Average	37 (77.1%)	37 (58.7%)	34 (61.8%)	--
Verbal Comprehension Index²	75.7 (70.6 – 80.5)^a	83.6 (78.8 – 88.3)^b	79.5 (74.8 – 83.3)^a,b	0.05
Visual Spatial Index²	68.0 (64.3 – 72.3)^a	80.9 (75.9 – 80.9)^b	80.1 (75.4 – 84.1)^b	<0.001
Fluid Reasoning Index²	73.2 (71.1 – 76.5)^a	80.0 (75.7 – 85.9)^b	73.6 (71.8 – 77.2)^a	0.02
Working Memory Index²	87.0 (83.8 – 91.9)	84.2 (81.5 – 87.2)	83.2 (79.6 – 84.8)	0.23
Processing Speed Index²	76.4 (73.6 – 79.5)^a	80.4 (77.6 – 84.3)^a	89.7 (82.9 – 93.2)^b	<0.001
MABC Normative Score
Overall¹	80.0 (76.6 – 83.4)^a	73.8 (70.8 – 76.8)^b	65.1 (62.0 – 68.2)^c	<0.001
Overall: Number (%) Below Average	6 (12.5%)	19 (30.2%)	30 (54.5%)	--
Manual Dexterity¹	21.7 (19.8 – 23.7)^a	19.8 (18.1 – 21.5) ^a	13.5 (11.7 – 15.3) ^b	<0.001
Aiming and Catching¹	24.4 (23.0 – 25.8) ^a	22.4 (21.2 – 23.6) ^a	19.7 (18.4 – 21.0) ^b	<0.001
Balance²	35.8 (36.8 –33.8)	33.8 (35.7 – 32.3)	33.3 (31.4 – 35.0)	0.12
TVIP Standard Score¹	101.3 (96.5 – 106.2)	94.1 (89.8 – 98.5)	94.7 (90.1 – 99.2)	0.08
TVIP - Number (%) Below Average	5 (10.4%)	11 (17.5%)	9 (16.4%)	--
NIH Toolbox Standard Score:
Pattern Comparison³	64.0 [54, 146]	54.0 [54.0, 126]	54.0 [54.0, 101]	0.07
Flanker²	91.3 (97.8 – 86.2)	95.0 (89.3 – 98.8)	94.4 (88.9 – 98.7)	0.81

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WPPSI = Wechsler Preschool and Primary Scale of Intelligence, MABC = Movement Assessment Battery for Children, TVIP = Test de Vocabulario en Imágenes Peabody. All results show estimate and 95% confidence interval. ¹ – Mean; ² – Median; ³ – Median [Min, Max] due to non-estimable lower confidence interval of median for proportional odds model. ^{a, b, c} – Groups with the same superscript letter do not differ significantly. See Supplementary Table 4 for a complete list of Tukey/Holm p-values resulting from pairwise comparison between the three groups.

Table 2:

Outcomes of parent questionnaires BRIEF-2, ABAS-3, and CBCL.

Assessment	Cases (n=48)	Control-School Entry Delay (n=63)	Control-No School Entry Delay (n=55)	p-value
BRIEF T-Score
General Executive Composite (GEC)¹	50.5 (48.1 – 52.9)^a	56.3 (54.2 – 58.5)^b	50.8 (48.6 – 53.0)^a	<0.001
GEC - Number (%) Elevated	1 (2.1%)	13 (20.6%)	3 (5.5%)	--
Behavioral Regulation Index (BRI) ¹	50.2 (47.8 – 52.6)^a	55.2 (53.1 – 57.4)^b	52.2 (50.0 – 54.5)^{a, b}	0.016
Emotional Regulation Index (ERI)¹	52.2 (49.7 – 54.7)^a	56.8 (54.6 – 59.0)^b	51.8 (49.5 – 54.1)^a	0.007
Cognitive Regulation Index (CRI) ²	49.5 (46.2 – 51.5)^a	54.6 (52.1 – 57.0)^b	48.8 (45.8 – 51.1)^a	<0.001
ABAS Standard Score¹
General Adaptive Composite (GAC)	98.6 (95.1 – 10.21)^a	91.5 (88.4 – 94.6)^b	101.3 (98.0 – 104.6)^a	<0.001
GAC - Number (%) Below Average	3 (6.3%)	10 (15.9%)	5 (9.1%)	--
Conceptual¹	96.4 (93.1 – 99.6)^{a, b}	91.3 (88.4 – 94.1)^a	101.7 (98.6 – 104.7)^b	<0.001
Practical²	101.6 (97.0 – 107.4)^a	93.4 (89.4 – 96.0)^b	101.9 (97.4 – 107.7)^a	<0.001
Social²	98.7 (95.1 – 104.7)^a	90.8 (87.4 – 94.8)^b	102.7 (96.9 – 102.7)^a	<0.001
CBCL T-Score
Total Problems¹	53.5 (50.4 – 56.6)	54.8 (52.1 – 57.5)	52.0 (49.1 – 54.9)	0.4
Total Problems - Number (%) Elevated	7 (14.6%)	18 (28.6%)	5 (9.1%)	--
Internalizing²	55.8 (51.8 – 59.8)	56.8 (54.5 – 60.4)	55.6 (51.7 – 59.3)	0.7
Externalizing²	54.2 (50.7 – 56.7)	53.0 (50.4 – 56.0)	48.8 (46.5 – 52.0)	0.07

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BRIEF = Behavior Rating Inventory of Executive Function, ABAS = Adaptive Behavior Assessment System, CBCL = Child Behavior Checklist. All results show estimate and 95% confidence interval. ¹ – Mean; ² – Median. ^{a, b, c} – Groups with the same superscript letter do not differ significantly. See Supplementary Table 4 for a complete list of Tukey/Holm p-values resulting from pairwise comparison between the three groups.

Results

Forty-eight (66%) of 70 eligible ZIKV-exposed mother-fetus/child dyads originally enrolled during pregnancy¹² were evaluated at mean (SD) age 5.9 (0.2) years (Figure 2; Table S1). Sixty-three Control-SED children were evaluated at mean (SD) age 5.9 (0.3) years and 55 Control-NSED children at 5.2 (0.2) years (Figure 2; Table S1), for a total of 118 non-ZIKV exposed Control children. Demographics, medical, and socio-economic characteristics were comparable between groups (Supplementary Tables 2-4). All participants fall in the lowest socioeconomic stratum in Colombia; this system is based on characteristics of residential housing including public service availability, topography, road type, and building characteristics.³¹

Verbal and Nonverbal Intellectual Functioning

On the WPPSI-IV, median scores in all three groups across all Indices fell into the low-average (80-89), borderline (70-79), or extremely low (60-69) ranges according to normative standards from Spain. Within this context, Cases displayed significantly lower Visual Spatial Index scores than both Control groups (Tables 1, S4, Figure 3). Cases also scored lower than Control-SED on Verbal Comprehension and Fluid Reasoning. Sometimes considered a proxy for verbal intellectual skills given the high correlation with Verbal IQ,³² there were no differences in TVIP receptive vocabulary scores between groups. Notably, this measure with normative data from a different Spanish-speaking population was solidly in the average range across groups.

Figure 3: — Abbreviations: ABAS= Adaptive Behavior Assessment System-Third Edition, BRIEF= Behavioral Rating Inventory of Executive Function-Second Edition, CBCL= Child Behavior Checklist, MABC= Movement Assessment Battery for Children-Second Edition, TVIP/PPVT= Test de Vocabulario en Imágenes/Peabody Picture Vocabulary Test, and Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) sub-scales of VCI= Verbal Comprehension Index, VSI= Visual Spatial Index, FRI= Fluid Reasoning Index, WMI= Working Memory Index, and PSI= Processing Speed Index.

The ZIKV Outcome toolbox evaluated Intellectual Reasoning by the TVIP/PPVT, VCI, and VSI, executive function by BRIEF and WMI, motor skills by MABC and PSI, adaptive skills by ABAS, and social/emotional functioning by CBCL. The gray box represents scores that fell within age expectations, while scores in the white area represent scores that are below age expectations (standard score <80). Case mean cohort scores are represented by yellow circles, Control-School Entry Delay mean cohort scores by blue circles, and Control-No School Entry Delay by green circles. Asterisks indicate an overall significant difference in scores between at least two groups within a particular outcome measure in accordance with the p-values shown in Tables 1 and 2. For pairwise comparisons of significance, see Tables 1, 2 and S4.

Social-Emotional Functioning

No CBCL parent ratings were in the clinically elevated range across internalizing and externalizing problems for all groups which were not statistically different.

Motor Functioning

MABC-2 overall scores differed between all three groups; mean scores for ZIKV-exposed Cases were highest, followed by Control-SED, and then Control-NSED children (Tables 1, S4, Figure 3). Mean overall MABC-2 scores among Cases and Control-SED were within age expectations (≥68), while the Control-NSED mean score would be considered “at risk” of movement difficulty (57-67) based on manual norms. MABC-2 scores in manual dexterity and aiming and catching domains were lower in Control-NSED compared to both Cases and Control-SED, which did not differ from each other (Tables 1, S4). Control-NSED mean manual dexterity scores would be considered to denote a significant movement difficulty based upon normative data, while those of Cases and Control-SED would be considered borderline, or “at risk” of movement difficulty. Mean aiming and catching and median balance component scores were in the normal range for all three groups. In contrast, Control-NSED scored higher in Processing Speed than Cases or Control-SED which is based on graphomotor skills.

Adaptive Functioning

ABAS-3 scores were all within age expectations; however, group comparisons showed that adaptive functioning was lower in Control-SED across all composite scores compared to Cases and Control-NSED (Tables 2, S4).

Executive functioning

Parent ratings on the BRIEF-2 across all scores were not clinically elevated. However, Control-SED children had more executive functioning problems relative to both Cases and Control-NSED (Tables 2, S4). There were no differences among groups in direct testing of executive skills. Working Memory skills fell in the low average range and NIH Toolbox median Flanker scores were also no different among groups; however, median performance was below average range.

Discussion

This study utilized a multi-domain neurodevelopmental outcome toolbox in 5-6-year-old normocephalic children with antenatal ZIKV exposure and two unexposed control cohorts of comparable ages from the same rural and semi-rural Colombian communities. To our knowledge, this is the first study to comprehensively examine neurodevelopment among school-age ZIKV-exposed children. All children experienced the COVID-19 pandemic at different ages; however, one control cohort (Control-SED) was impacted differently by starting in-person school later than typical. The study found that school-age children with antenatal ZIKV exposure without CZS have lower cognitive performance compared to non-ZIKV exposed peers regardless of school history impact from the COVID-19 pandemic.

Neurodevelopmental impact of ZIKV exposure

Maternal infection during pregnancy may increase risk for neurodevelopmental disorders in offspring, some of which may not be detectable until older stages of child development when higher order cognitive and academic skills can be reliably tested.^33,34,34,35 For this reason, we have serially followed our cohort of children with antenatal ZIKV-exposure to assess higher-order cognitive skills at school age. In this study, we observed lower cognitive function in ZIKV-exposed children (i.e., lower FSIQ) compared to both control cohorts. Scores were in the impaired range compared to normative samples, and significantly lower than their peers (Controls) who also scored lower than norms. There are likely socio-cultural differences between the children in our study and the children from Spain from which the WPPSI was normed. However, the WPPSI is a commonly used cognitive development measure in Latin America in children of this age.³⁶ Any socio-cultural differences in cases would be expected to be the same for each control group, thus also highlighting the importance of having controls from the same community and not solely relying on published normative data. While prior studies observed differences in language development in ZIKV-exposed children at younger ages,^3,7,37 we did not observe differences in receptive language skills on the TVIP nor in WPPSI Verbal Comprehension Index scores between Cases and both control groups. These findings need to be further evaluated at older ages to assess how antenatal ZIKV exposure may affect academic achievement and other emerging higher-order cognitive functions.

Mean executive function scores were within age expectations for ZIKV-exposed children. Previously observed differences in executive functioning among Cases and Controls at 3 and 4 years of age did not persist on the BRIEF.^8,9 Despite statistical differences between groups at preschool ages, the mean scores were within normal functioning at that time. Moreover, 3–4-year-old evaluations for Cases fell amid COVID-19 shutdowns which may have impacted parent ratings. However, Cases did score lower than Control-NSED on WPPSI Processing Speed Index, whose tasks integrate both motor and executive function demands. Cases, given their age-appropriate scores on the MABC, therefore may have underlying differences in executive function which impacted their performance. Our findings indicate that antenatal ZIKV exposure does not uniformly impact emerging executive functioning through age six; however, executive function is often vulnerable to late effects after early-in-life exposures and should continue to be assessed at older ages as demands for executive control increase rapidly in later elementary school and beyond.³⁸

ZIKV-exposed Cases showed comparable or better motor skills across all three domains of the MABC-2 compared to Controls at age 5-6 years. Our finding of normal mobility skills has been consistently observed in MABC-2 scores in this cohort since preschool age.^8,9 At preschool age, Cases had lower mobility scores on the caregiver-completed Pediatric Evaluation of Disability Inventory (PEDI-CAT) compared to Controls, which may indicate differences in adaptive mobility skills at home or differences in caregiver perceptions of motor ability.⁸ While the PEDI-CAT was not repeated at the 5-6 year timepoint, similar adaptive skills assessed on the ABAS were not lower in Cases. In a smaller cohort in the United States, MABC-2 scores among preschool age ZIKV-exposed children suggested lower motor performance compared to Controls.³⁹ Other studies have found that antenatal ZIKV infection appears to negatively impact motor development in the first 3 years¹¹ and lead to higher rates of long term motor delay^2,3; it is unknown if motor performance of children from these studies would have improved if followed to older ages. When looking at tasks during the child evaluations for which motor skills are important component skills involved in processing speed tasks or putting blocks together, our cases did perform below control groups. When examining WPPSI Processing Speed in particular, both motor and executive function skills contribute to task performance and thus given Cases’ lower scores, it is possible that these early differences may evolve into other more nuanced performance differences as a child’s abilities develop.

COVID-19 pandemic impact on neurodevelopment

While the primary objective of our study was to assess school-age neurodevelopment of ZIKV-exposed children, the intervening pandemic brought additional complexity and a need to consider this impact. Our approach was to enroll a second control cohort which provided insight into how the pandemic affected child neurodevelopment. Control-SED children were 5-6 years old at the height of the pandemic in Colombia and thus experienced delays to school entry and strict quarantine which limited pivotal community and learning experiences. Control-SED showed differences in executive functioning and adaptive skills relative to the other two groups; however, functioning in both domains generally fell within age expectations, suggesting that these are relative delays. Other studies have reported that COVID-19 lockdown adversely affected cognitive flexibility and working memory, and that students in online school during the pandemic demonstrated lower social adaptative skills than those that received face-to-face education.^40,41 It is possible, therefore, that differences seen on the BRIEF and ABAS in Control-SED can be attributed to this interruption in early socialization and schooling which will hopefully improve over time.

On the other hand, Control-NSED children had significantly lower mobility skills than Cases and Control-SED, particularly in the fine motor domain on MABC, and their scores fell below age expectations. It is possible that since these children were toddlers at the height of the pandemic, they may have been less exposed to typical motor development activities such as exploring one’s environment because of concern for infection and spreading of disease. Cheng et al. found that teacher ratings of motor skills of children ages 2-6 were lower during the pandemic than pre-pandemic.⁴² Kiliҫ and Koҫak also found that high proportions of children aged 6-36 months during the pandemic had delays in motor development at ages 2-5 years, particularly in fine motor skills.⁴³ Our data support this assertion, suggesting that quarantine at toddler ages may negatively impact motor development.

The COVID-19 pandemic and observed differences between control groups complicated our analysis but also allowed us to examine our data with a more rigorous standard of interpretation, as we only considered differences between Cases and Controls to be attributable to ZIKV exposure if the difference persisted between Cases and both Control cohorts. Since the pandemic likely had differing effects on children in each group; it will be important to evaluate all three cohorts at older ages of childhood to elucidate the effects of antenatal ZIKV exposure, and of the pandemic experience, on subsequent child development.

Conclusions

ZIKV-exposed children without CZS have lower cognitive performance relative to non-exposed peers at age 5-6 years. This finding highlights the importance of following children after early-in-life exposures to older ages to assess higher-order cognitive skills. Studying the intersection of the COVID-19 pandemic and antenatal ZIKV exposure provides additional insight into how both in utero viral infection and a viral pandemic impact child neurodevelopment and cognitive skills at early school age.

Supplementary Material

Supplementary Tables, S1-S4

NIHMS2093969-supplement-Supplementary_Tables__S1-S4.docx^{(29.7KB, docx)}

Impact.

Normocephalic ZIKV-exposed children have lower full-scale IQ than their unexposed peers from the same communities.
Normocephalic children with antenatal ZIKV exposure have differences in neurodevelopment that can impact them long-term.
There is a need for continued follow-up of children with antenatal ZIKV exposure to determine long-term effects on higher-order areas of cognitive function.

Acknowledgements

The authors would like to thank the children and families in this study for their continued engagement and participation across years of research and evaluation. We thank Liliana Villegas Echeverri, Daniela Rodriguez, Julieth Cajar, and Lida Utria for conducting the neuropsychological evaluations of the participants. We are also thankful for Ana Cecilia Perez, Ramiro Galindo, Javier Restrepo, Miguel Castillo, Lorenzo Cervantes, and Jose Ospino, the research study coordinators and assistants from BIOMELab in Barranquilla, Colombia, for their long-standing collaboration and dedication to this research. Finally, the authors thank Drs. Adre du Plessis, Roberta DeBiasi, and David Wessel for their support of this research and of the Congenital Infection Program at Children’s National Hospital.

Funding

Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD102445 (PI: Mulkey) and P50HD105328-01 (PI: Gaillard). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Consent Statement: Parents or legal guardians provided written informed consent for their child’s participation.

Competing interests: The authors do not have any competing interests.

Data Availability Statement

De-identified data are available from the corresponding author upon reasonable request.

References

1.Walker CL, et al. Zika virus and the nonmicrocephalic fetus: why we should still worry. Am. J. Obstet. Gynecol 220(1), 45–56 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Marbán-Castro E., et al. Neurodevelopment in Normocephalic Children Exposed to Zika Virus in Utero with No Observable Defects at Birth: A Systematic Review with Meta-Analysis. Int. J. Environ. Res. Public Health 19(12), 7319 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Blackmon K., et al. Neurodevelopment in normocephalic children with and without prenatal Zika virus exposure. Arch. Dis. Child 107(3), 244 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Grant R., et al. In utero Zika virus exposure and neurodevelopment at 24 months in toddlers normocephalic at birth: a cohort study. BMC Med. 19(1), 12 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Fernandes M., et al. Does Intra-Uterine Exposure to the Zika Virus Increase Risks of Cognitive Delay at Preschool Ages? Findings from a Zika-Exposed Cohort from Grenada, West Indies. Viruses. 15(6), 1290 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Alger J., et al. Neurodevelopmental assessment of normocephalic children born to Zika virus exposed and unexposed pregnant people. Pediatr. Res 95, 566–572 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Nielsen-Saines K., et al. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nat. Med 25(8), 1213–1217 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Mulkey SB, et al. Preschool neurodevelopment in Zika virus-exposed children without congenital Zika syndrome. Pediatr. Res 94(1), 178–184 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Mulkey SB, et al. Neurodevelopmental Outcomes of Normocephalic Colombian Children with Antenatal Zika Virus Exposure at School Entry. Pathogens. 13(2), 170 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Adebanjo T., et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb. Mortal Wkly. Rep 66(41), 1089–1099 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Hcini N., et al. Association between confirmed congenital Zika infection at birth and outcomes up to 3 years of life. Nat. Commun 12(1), 3270 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Mulkey SB, et al. Sequential Neuroimaging of the Fetus and Newborn With In Utero Zika Virus Exposure. JAMA Pediatr. 173(1), 52–59 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Mulkey SB, et al. Neurodevelopmental Abnormalities in Children With In Utero Zika Virus Exposure Without Congenital Zika Syndrome. JAMA Pediatr. 174(3), 269–276 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Kuehn LM, et al. Socioemotional Development of Infants and Toddlers During the COVID-19 Pandemic. JAMA Pediatr. 178(2), 151–159 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Rouse HL, et al. Developmental impacts of the COVID-19 pandemic on young children: a conceptual model for research with integrated administrative data systems. Int. J. Popul. Data Sci 5(4), 1651 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
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19.Ministerio de Salud y Protección Social. Colombia, primer país del continente que cierra epidemia de zika. Ministerio de Salud y Protección Social. (2016). https://www.minsalud.gov.co/Paginas/Colombia-primer-pais-del-continente-que-cierra-epidemia-de-zika.aspx
20.Mulkey SB, et al. Understanding the multidimensional neurodevelopmental outcomes in children after congenital Zika virus exposure. Pediatr. Res 96, 654–662 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Gioia GA, Isquith PK, Guy SC, Kenworthy L Behavior Rating Inventory of Executive Function^® Second Edition. (PAR, 2015). [Google Scholar]
22.Harrison PL, Oakland T ABAS-3: Adaptive Behavior Assessment System. (Western Psychological Services, Los Angeles, CA, 2015). [Google Scholar]
23.Achenbach TM, Rescorla LA Manual for the ASEBA School-Age Forms & Profiles. (University of Vermont Research Center for Children, Youth, & Families, 2001). [Google Scholar]
24.Dunn L, Lugo D, Padilla E, Dunn L Test de Vocabulario en Imagines Peabody. (American Guidance Serivce, Circle Pines, MN, 1986). [Google Scholar]
25.Henderson SE, Sugden D, Barnett AL Movement Assessment Battery for Children-2. (Pearson, 2007). [Google Scholar]
26.Wechsler D. Wechsler preschool and primary scale of intelligence—fourth edition. (Psychol. Corp., San Antonio, TX, 2012). [DOI] [PubMed] [Google Scholar]
27.Weintraub S., et al. I. NIH Toolbox Cognition Battery (CB): introduction and pediatric data. Monogr. Soc. Res. Child Dev 78(4), 1–15 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Mulkey SB, et al. Harnessing the power of telemedicine to accomplish international pediatric outcome research during the COVID-19 pandemic. J. Telemed. Telecare 30(2), 388–392 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Harris PA, et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inf 42(2), 377–381 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]
30.R Core Team. _R: A Language and Environment for Statistical Computing_. (2023). https://www.R-project.org/
31.Chica-Olmo J, Sánchez A, Sepúlveda-Murillo FH Assessing Colombia’s policy of socio-economic stratification: An intra-city study of self-reported quality of life. Cities. 97, 102560 (2020). [Google Scholar]
32.Krasileva KE, Sanders SJ, Bal VH Peabody Picture Vocabulary Test: Proxy for Verbal IQ in Genetic Studies of Autism Spectrum Disorder. J. Autism Dev. Disord 47(4), 1073–1085 (2017). [DOI] [PubMed] [Google Scholar]
33.Yates EF, Mulkey SB Viral infections in pregnancy and impact on offspring neurodevelopment: mechanisms and lessons learned. Pediatr. Res 96, 64–72 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Roth NM, et al. Notes from the field: Autism spectrum disorder among children with laboratory evidence of prenatal Zika virus exposure - Puerto Rico, 2023. MMWR Morb. Mortal. Wkly. Rep 72(29), 802–804 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Anderson P. Assessment and Development of Executive Function (EF) During Childhood. Child Neuropsychol. 8(2), 71–82 (2002). [DOI] [PubMed] [Google Scholar]
36.Williams ME,et al. Neurodevelopmental assessments used to measure preschoolers’ cognitive development in Latin America: a systematic review. J. Pediatr. Psychol 49(5), 321–339 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Peçanha PM, et al. Neurodevelopment of children exposed intra-uterus by Zika virus: A case series. PLOS ONE. 15(2), e0229434 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Anderson V., et al. Children’s executive functions: Are they poorer after very early brain insult. Neuropsychologia. 48(7), 2041–2050 (2010). [DOI] [PubMed] [Google Scholar]
39.Mulkey SB, et al. Neurodevelopmental Outcomes of Preschoolers with Antenatal Zika Virus Exposure Born in the United States. Pathogens. 13(7), 542 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Chichinina EA, Gavrilova MN Growth of executive functions in preschool-age children during the COVID-19 lockdown: Empirical evidence. Psychol. Russ 15(2), 124–136 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Günindi Y. The Effect of Online Education on Children’s Social Skills During the COVID-19 Pandemic. Int. Electron. J. Elem. Educ 14(5), 657–665 (2023). [Google Scholar]
42.Cheng SY, Tai HL, Wang TT Impact of COVID-19 Pandemic on Children’s Fundamental Motor Skills: A Study for the Taiwanese Preschoolers Teachers. Int. J. Environ. Res. Public Health 20(18), 6764 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Kılıç M, Koçak Ş Examination of psycho-motor development of children who were 6–36 months in the COVID-19 stay-at-home period. Sci. Rep 13(1), 20801 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Tables, S1-S4

NIHMS2093969-supplement-Supplementary_Tables__S1-S4.docx^{(29.7KB, docx)}

Data Availability Statement

De-identified data are available from the corresponding author upon reasonable request.

[R1] 1.Walker CL, et al. Zika virus and the nonmicrocephalic fetus: why we should still worry. Am. J. Obstet. Gynecol 220(1), 45–56 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] 2.Marbán-Castro E., et al. Neurodevelopment in Normocephalic Children Exposed to Zika Virus in Utero with No Observable Defects at Birth: A Systematic Review with Meta-Analysis. Int. J. Environ. Res. Public Health 19(12), 7319 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Blackmon K., et al. Neurodevelopment in normocephalic children with and without prenatal Zika virus exposure. Arch. Dis. Child 107(3), 244 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] 4.Grant R., et al. In utero Zika virus exposure and neurodevelopment at 24 months in toddlers normocephalic at birth: a cohort study. BMC Med. 19(1), 12 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Fernandes M., et al. Does Intra-Uterine Exposure to the Zika Virus Increase Risks of Cognitive Delay at Preschool Ages? Findings from a Zika-Exposed Cohort from Grenada, West Indies. Viruses. 15(6), 1290 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] 6.Alger J., et al. Neurodevelopmental assessment of normocephalic children born to Zika virus exposed and unexposed pregnant people. Pediatr. Res 95, 566–572 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] 7.Nielsen-Saines K., et al. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nat. Med 25(8), 1213–1217 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] 8.Mulkey SB, et al. Preschool neurodevelopment in Zika virus-exposed children without congenital Zika syndrome. Pediatr. Res 94(1), 178–184 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] 9.Mulkey SB, et al. Neurodevelopmental Outcomes of Normocephalic Colombian Children with Antenatal Zika Virus Exposure at School Entry. Pathogens. 13(2), 170 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R10] 10.Adebanjo T., et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb. Mortal Wkly. Rep 66(41), 1089–1099 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R11] 11.Hcini N., et al. Association between confirmed congenital Zika infection at birth and outcomes up to 3 years of life. Nat. Commun 12(1), 3270 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] 12.Mulkey SB, et al. Sequential Neuroimaging of the Fetus and Newborn With In Utero Zika Virus Exposure. JAMA Pediatr. 173(1), 52–59 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] 13.Mulkey SB, et al. Neurodevelopmental Abnormalities in Children With In Utero Zika Virus Exposure Without Congenital Zika Syndrome. JAMA Pediatr. 174(3), 269–276 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R14] 14.Kuehn LM, et al. Socioemotional Development of Infants and Toddlers During the COVID-19 Pandemic. JAMA Pediatr. 178(2), 151–159 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R15] 15.Rouse HL, et al. Developmental impacts of the COVID-19 pandemic on young children: a conceptual model for research with integrated administrative data systems. Int. J. Popul. Data Sci 5(4), 1651 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] 16.Almeida IL de L, Rego JF, Teixeira ACG, Moreira MR Social isolation and its impact on child and adolescent development: a systematic review. Rev. Paul. Pediatr 40 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R17] 17.Chaabane S, Doraiswamy S, Chaabna K, Mamtani R, Cheema S The impact of COVID-19 school closure on child and adolescent health: A rapid systematic review. Child Basel. 8(5), 415 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] 18.Pan American Health Organization/World Health Organization. Zika Epidemiological Report - Colombia. 7 (2017). https://www.paho.org/en/documents/zika-epidemiological-report-colombia [Google Scholar]

[R19] 19.Ministerio de Salud y Protección Social. Colombia, primer país del continente que cierra epidemia de zika. Ministerio de Salud y Protección Social. (2016). https://www.minsalud.gov.co/Paginas/Colombia-primer-pais-del-continente-que-cierra-epidemia-de-zika.aspx

[R20] 20.Mulkey SB, et al. Understanding the multidimensional neurodevelopmental outcomes in children after congenital Zika virus exposure. Pediatr. Res 96, 654–662 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R21] 21.Gioia GA, Isquith PK, Guy SC, Kenworthy L Behavior Rating Inventory of Executive Function^® Second Edition. (PAR, 2015). [Google Scholar]

[R22] 22.Harrison PL, Oakland T ABAS-3: Adaptive Behavior Assessment System. (Western Psychological Services, Los Angeles, CA, 2015). [Google Scholar]

[R23] 23.Achenbach TM, Rescorla LA Manual for the ASEBA School-Age Forms & Profiles. (University of Vermont Research Center for Children, Youth, & Families, 2001). [Google Scholar]

[R24] 24.Dunn L, Lugo D, Padilla E, Dunn L Test de Vocabulario en Imagines Peabody. (American Guidance Serivce, Circle Pines, MN, 1986). [Google Scholar]

[R25] 25.Henderson SE, Sugden D, Barnett AL Movement Assessment Battery for Children-2. (Pearson, 2007). [Google Scholar]

[R26] 26.Wechsler D. Wechsler preschool and primary scale of intelligence—fourth edition. (Psychol. Corp., San Antonio, TX, 2012). [DOI] [PubMed] [Google Scholar]

[R27] 27.Weintraub S., et al. I. NIH Toolbox Cognition Battery (CB): introduction and pediatric data. Monogr. Soc. Res. Child Dev 78(4), 1–15 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R28] 28.Mulkey SB, et al. Harnessing the power of telemedicine to accomplish international pediatric outcome research during the COVID-19 pandemic. J. Telemed. Telecare 30(2), 388–392 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R29] 29.Harris PA, et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inf 42(2), 377–381 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] 30.R Core Team. _R: A Language and Environment for Statistical Computing_. (2023). https://www.R-project.org/

[R31] 31.Chica-Olmo J, Sánchez A, Sepúlveda-Murillo FH Assessing Colombia’s policy of socio-economic stratification: An intra-city study of self-reported quality of life. Cities. 97, 102560 (2020). [Google Scholar]

[R32] 32.Krasileva KE, Sanders SJ, Bal VH Peabody Picture Vocabulary Test: Proxy for Verbal IQ in Genetic Studies of Autism Spectrum Disorder. J. Autism Dev. Disord 47(4), 1073–1085 (2017). [DOI] [PubMed] [Google Scholar]

[R33] 33.Yates EF, Mulkey SB Viral infections in pregnancy and impact on offspring neurodevelopment: mechanisms and lessons learned. Pediatr. Res 96, 64–72 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R34] 34.Roth NM, et al. Notes from the field: Autism spectrum disorder among children with laboratory evidence of prenatal Zika virus exposure - Puerto Rico, 2023. MMWR Morb. Mortal. Wkly. Rep 72(29), 802–804 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R35] 35.Anderson P. Assessment and Development of Executive Function (EF) During Childhood. Child Neuropsychol. 8(2), 71–82 (2002). [DOI] [PubMed] [Google Scholar]

[R36] 36.Williams ME,et al. Neurodevelopmental assessments used to measure preschoolers’ cognitive development in Latin America: a systematic review. J. Pediatr. Psychol 49(5), 321–339 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R37] 37.Peçanha PM, et al. Neurodevelopment of children exposed intra-uterus by Zika virus: A case series. PLOS ONE. 15(2), e0229434 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] 38.Anderson V., et al. Children’s executive functions: Are they poorer after very early brain insult. Neuropsychologia. 48(7), 2041–2050 (2010). [DOI] [PubMed] [Google Scholar]

[R39] 39.Mulkey SB, et al. Neurodevelopmental Outcomes of Preschoolers with Antenatal Zika Virus Exposure Born in the United States. Pathogens. 13(7), 542 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] 40.Chichinina EA, Gavrilova MN Growth of executive functions in preschool-age children during the COVID-19 lockdown: Empirical evidence. Psychol. Russ 15(2), 124–136 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R41] 41.Günindi Y. The Effect of Online Education on Children’s Social Skills During the COVID-19 Pandemic. Int. Electron. J. Elem. Educ 14(5), 657–665 (2023). [Google Scholar]

[R42] 42.Cheng SY, Tai HL, Wang TT Impact of COVID-19 Pandemic on Children’s Fundamental Motor Skills: A Study for the Taiwanese Preschoolers Teachers. Int. J. Environ. Res. Public Health 20(18), 6764 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R43] 43.Kılıç M, Koçak Ş Examination of psycho-motor development of children who were 6–36 months in the COVID-19 stay-at-home period. Sci. Rep 13(1), 20801 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

School-Age Child Neurodevelopment Following Antenatal Zika Virus Exposure

Sarah B Mulkey

Regan Andringa-Seed

Elizabeth Corn

Meagan E Williams

Margarita Arroyave-Wessel

Robert H Podolsky

Colleen Peyton

Michael E Msall

Carlos Cure

Madison M Berl

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Methods

Study Population

Figure 1: Timeline of longitudinal evaluations of ZIKV-exposed children and unexposed control cohorts (Control-School Entry Delay [SED] and No School Entry Delay [NSED]) from 2016 to 2023.

Figure 2: Waves of COVID-19 pandemic, school closures, and 5–6-year evaluations of Cases, Control-School Entry Delay (SED) and Control-No School Entry Delay (NSED) children.

Neurodevelopmental evaluations

Statistical analysis

Table 1:

Table 2:

Results

Verbal and Nonverbal Intellectual Functioning

Figure 3: Domains of functioning at age 5-6 years in ZIKV-Exposed Cases and Non-Exposed Control Groups.

Social-Emotional Functioning

Motor Functioning

Adaptive Functioning

Executive functioning

Discussion

Neurodevelopmental impact of ZIKV exposure

COVID-19 pandemic impact on neurodevelopment

Conclusions

Supplementary Material

Impact.

Acknowledgements

Funding

Footnotes

Data Availability Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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