Understanding the multidimensional neurodevelopmental outcomes in children after congenital Zika virus exposure.

Since 2016, international research groups have focused on assessing outcomes of children with in utero Zika virus (ZIKV) exposure. While the more severe outcomes of congenital Zika syndrome (CZS) occur in up to 10% of children with antenatal exposure, early findings among ZIKV-exposed children without CZS ages 0-5 years suggest that they may also have differences in multiple domains of neurodevelopment. Thus, longitudinal follow-up of all children with antenatal ZIKV exposure has been recommended. This review presents a summary of neurodevelopmental phenotypes of infants and children following antenatal ZIKV exposure. We present a multidimensional framework to understand child neurodevelopment from an interdisciplinary and whole-child perspective (International Classification of Functioning, Disability and Health model) and multi-domain ZIKV Outcome Toolboxes. The toolboxes are for clinicians, researchers, child educators, and others to implement longitudinal multi-domain neurodevelopmental assessments between ages 0-12 years. Recent innovations in telehealth and neuroimaging can help evaluate outcomes in ZIKV exposed children. The objective is to describe the multiple facets of neurodevelopmental focused care that can support the health, function, and well-being of children with antenatal ZIKV exposure. The research and clinical follow-up strategies are applicable to ZIKV and other congenital infectious or environmental exposures that can impact child neurodevelopment. IMPACT: International longitudinal cohort studies have revealed a range of differences in neurodevelopment among children with antenatal Zika virus (ZIKV) exposure. A multidimensional and whole-child framework is necessary to understand the neurodevelopment of children with antenatal ZIKV exposure in relation to family life, community participation, and environment. Multi-domain toolboxes that utilize parent questionnaires and child evaluations are presented. These toolboxes can be used internationally alongside telehealth, brain imaging, and other innovations to improve understanding of child outcomes.

Neurodevelopmental Outcomes of Normocephalic Colombian Children with Antenatal Zika Virus Exposure at School Entry.

The long-term neurodevelopmental effects of antenatal Zika virus (ZIKV) exposure in children without congenital Zika syndrome (CZS) remain unclear, as few children have been examined to the age of school entry level. A total of 51 Colombian children with antenatal ZIKV exposure without CZS and 70 unexposed controls were evaluated at 4-5 years of age using the Behavior Rating Inventory of Executive Function (BRIEF), the Pediatric Evaluation of Disability Inventory (PEDI-CAT), the Bracken School Readiness Assessment (BSRA), and the Movement Assessment Battery for Children (MABC). The mean ages at evaluation were 5.3 and 5.2 years for cases and controls, respectively. Elevated BRIEF scores in Shift and Emotional Control may suggest lower emotional regulation in cases. A greater number of cases were reported by parents to have behavior and mood problems. BSRA and PEDI-CAT activity scores were unexpectedly higher in cases, most likely related to the COVID-19 pandemic and a delayed school entry among the controls. Although PEDI-CAT mobility scores were lower in cases, there were no differences in motor scores on the MABC. Of 40 cases with neonatal neuroimaging, neurodevelopment in 17 with mild non-specific findings was no different from 23 cases with normal neuroimaging. Normocephalic children with ZIKV exposure have positive developmental trajectories at 4-5 years of age but differ from controls in measures of emotional regulation and adaptive mobility, necessitating continued follow-up.

Positive and negative effects of the COVID-19 pandemic on families of young children in rural Colombia and implications for child outcome research.

BACKGROUND: The COVID-19 pandemic has impacted the lives of children and families worldwide. The objective of this study is to examine exposures and impact of the COVID-19 pandemic on preschool-aged children and caregivers in the Atlántico region of Colombia. METHODS: The COVID-19 Exposure and Family Impact Scales (CEFIS) questionnaire was administered in Fall 2021 to 63 caregivers of children in Sabanalarga, Colombia enrolled in a neurodevelopment study as healthy controls. The CEFIS assesses pandemic-related exposures/events and impact; higher scores indicate greater exposure and negative impact. Descriptive and correlation analyses among exposure and impact scores were conducted. RESULTS: Caregivers reported a mean (standard deviation[SD]) of 11.1 (3.2) among 25 COVID-19-related exposures/events; most common types included stay-at-home orders, school closures, disruptions to living conditions and income loss. Total number of events was correlated with higher caregiver (P < .001) and child distress (P = .002). However, the mean (SD) impact score of 2.0 (0.6) suggests a trend toward more positive impact than negative. Caregivers reported improvements to sleep, exercise and family interactions. Some caregivers (n = 21) qualitatively reported negative effects including unemployment, fear/anxiety and inability to visit family, and positive effects such as unification, family closeness and spending more time with children. CONCLUSIONS: This study highlights the importance of comprehensively exploring positive and negative impacts of COVID-19 and families' subsequent resilience and transformation. Using tools like the CEFIS, those seeking to mitigate negative impacts can contextualize data to better understand study outcomes and tailor services, resources and policy to families' unique needs. CEFIS data likely depend on timing, economic/public health resources and cultural values; future work should prioritize understanding the generalizability of CEFIS findings across samples.

Preschool neurodevelopment in Zika virus-exposed children without congenital Zika syndrome.

BACKGROUND: Children with in utero Zika virus (ZIKV) exposure without congenital Zika syndrome (CZS) are at risk for abnormal neurodevelopment. Preschool-age outcomes for children with antenatal ZIKV exposure have not yet been established. METHODS: Children with in utero ZIKV exposure and non-exposed controls had neurodevelopmental evaluations at age 3-5 years in Sabanalarga, Colombia. Cases did not have CZS and were previously evaluated prenatally through age 18 months. Controls were born before ZIKV arrival to Colombia. Neurodevelopmental assessments included Pediatric Evaluation of Disability Inventory (PEDI-CAT), Behavior Rating Inventory of Executive Function (BRIEF-P), Bracken School Readiness Assessment (BSRA), and Movement Assessment Battery for Children (MABC). Family demographics and child medical history were recorded. RESULTS: Fifty-five ZIKV-exposed children were evaluated at mean age 3.6 years and 70 controls were evaluated at 5.2 years. Family demographics were similar between groups. BRIEF-P t-scores were higher for cases than controls in shift and flexibility domains. Cases had lower PEDI-CAT mobility t-scores compared to controls. There was no difference in MABC between groups. In 11% of cases and 1% of controls, parents reported child mood problems. CONCLUSIONS: Children with in utero ZIKV exposure without CZS may demonstrate emerging differences in executive function, mood, and adaptive mobility that require continued evaluation. IMPACT: Preschool neurodevelopmental outcome in children with in utero Zika virus exposure is not yet known, since the Zika virus epidemic occurred in 2015-2017 and these children are only now entering school age. This study finds that Colombian children with in utero Zika virus exposure without congenital Zika syndrome are overall developing well but may have emerging differences in executive function, behavior and mood, and adaptive mobility compared to children without in utero Zika virus exposure. Children with in utero Zika virus exposure require continued multi-domain longitudinal neurodevelopmental evaluation through school age.

Harnessing the power of telemedicine to accomplish international pediatric outcome research during the COVID-19 pandemic.

The COVID-19 pandemic occurred during planned neurodevelopmental follow-up of Colombian children with antenatal Zika-virus exposure. The objective of the study was to leverage the institution's telemedicine infrastructure to support international clinical child outcome research. In a prospective cohort study of child neurodevelopment (NCT04398901), we used synchronous telemedicine to remotely train a research team and perform live observational assessments of children in Sabanalarga, Colombia. An observational motor and conceptional standardized tool kit was mailed to Colombia; other materials were translated and emailed; team training was done virtually. Children were recruited by team on the ground. Synchronous activities were video-recorded directly to two laptops, each with a telehealth Zoom link to allow simultaneous evaluation of "table" and "standing" activities, and backup recordings were captured directly on the device in Colombia. The U.S. team attended live over Zoom from four states and five distinct locations, made observational notes, and provided real-time feedback. Fifty-seven, 3-4-year-old children with Zika-virus exposure and 70 non-exposed controls were studied during 10 daytrips. Direct laptop recording ensured complete record of child activities due to internet outages. Telemedicine can be used to successfully perform international neurodevelopmental outcome research in children during the COVID-19 pandemic. Telemedicine can benefit global health studies.

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

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.

Sequential Neuroimaging of the Fetus and Newborn With In Utero Zika Virus Exposure.

Importance: The evolution of fetal brain injury by Zika virus (ZIKV) infection is not well described. Objectives: To perform longitudinal neuroimaging of fetuses and infants exposed to in utero maternal ZIKV infection using concomitant magnetic resonance imaging (MRI) and ultrasonography (US), as well as to determine the duration of viremia in pregnant women with ZIKV infection and whether the duration of viremia correlated with fetal and/or infant brain abnormalities. Design, Setting, and Participants: A cohort of 82 pregnant women with clinical criteria for probable ZIKV infection in Barranquilla, Colombia, and Washington, DC, were enrolled from June 15, 2016, through June 27, 2017, with Colombian women identified by community recruitment and physician referral and travel-related cases of American women recruited from a Congenital Zika Program. Interventions and Exposures: Women received 1 or more MRI and US examinations during the second and/or third trimesters. Postnatally, infants underwent brain MRI and cranial US. Blood samples were tested for ZIKV. Main Outcomes and Measures: The neuroimaging studies were evaluated for brain injury and cerebral biometry. Results: Of the 82 women, 80 were from Colombia and 2 were from the United States. In 3 of 82 cases (4%), fetal MRI demonstrated abnormalities consistent with congenital ZIKV infection. Two cases had heterotopias and malformations in cortical development and 1 case had a parietal encephalocele, Chiari II malformation, and microcephaly. In 1 case, US results remained normal despite fetal abnormalities detected on MRI. Prolonged maternal polymerase chain reaction positivity was present in 1 case. Of the remaining 79 cases with normal results of prenatal imaging, postnatal brain MRI was acquired in 53 infants and demonstrated mild abnormalities in 7 (13%). Fifty-seven infants underwent postnatal cranial US, which detected changes of lenticulostriate vasculopathy, choroid plexus cysts, germinolytic/subependymal cysts, and/or calcification in 21 infants (37%). Conclusions and Relevance: In a cohort of pregnant women with ZIKV infection, prenatal US examination appeared to detect all but 1 abnormal fetal case. Postnatal neuroimaging in infants who had normal prenatal imaging revealed new mild abnormalities. For most patients, prenatal and postnatal US may identify ZIKV-related brain injury.