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

Abstract

IMPORTANCEThe 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 PARTICIPANTSThis 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 InitialDevelopmental 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). RESULTSOf 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 age 2 = 0.006; P < .003) and self-care domain score (coefficients: age = -0.238 vs age 2 = 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 cra...

Zika virus infection leads to mitochondrial failure, oxidative stress and DNA damage in human iPSC-derived astrocytes

“…Moreover, could infants born healthy from ZIKV-infected mothers have future complications? 79 ZIKV infection has been shown to have long-term neuropathological and behavioral consequences in mice 29 . Astrocytes control redox homeostasis in the adult CNS, and their depletion can lead to motor deficits and neuronal loss caused by oxidative stress 80 .…”

The Impact of Maternal Infection on the Neonate

“…The major neuronal migration is occurring before the 25th week of gestation, making exposure to the virus in the first and second trimesters the most devastating. Infants with ZIKV exposure and no apparent congenital syndrome are also at risk for abnormal neurodevelopmental outcomes, as evidenced in a recent study of 70 infants followed to age 18 months [46]. These infants had confirmed exposure to ZIKV but no findings to support CZS, and despite the normal head circumference, had subsequent neurodevelopmental deficits develop over the first year of life [46].…”

“…Infants with ZIKV exposure and no apparent congenital syndrome are also at risk for abnormal neurodevelopmental outcomes, as evidenced in a recent study of 70 infants followed to age 18 months [46]. These infants had confirmed exposure to ZIKV but no findings to support CZS, and despite the normal head circumference, had subsequent neurodevelopmental deficits develop over the first year of life [46]. As studies continue and longer-term outcomes become known, it is critically important to follow any infant with ZIKV exposure closely.…”

Teratogen update: Zika virus and pregnancy

“…In a recent study (Mulkey et al, 2020), 70 infants without evidence of congenital Zika syndrome born to Colombian mothers with Zika virus infection during pregnancy underwent neurodevelopmental assessments between 4 and 8 months of age (57%) and between 9 and 19 months of age (86%). These assessments showed scores decreased from normative scores as the children grew older, suggesting that long-term developmental monitoring is needed for infants born to mothers with prenatal Zika infection, even among those babies that appear normal at birth.…”