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.