Thrasher Research Award

Background: Congenital Zika Syndrome (CZS) is the severe neurologic outcome of fetal ZIKV-exposure in pregnancy; fortunately, the majority of ZIKV-exposed infants (95%) do not develop CZS. The risk for postnatal neurologic sequelae for infants exposed to ZIKV-in utero who do not have neurologic abnormalities at birth is not known. Through an Early Career Thrasher Award (Mulkey, #14077), we investigated the developmental outcome of a cohort of infants with ZIKV-exposure in utero who had normal fetal brain MRI and normal head size at birth. We obtained developmental assessments in 72 of 78 (92%) eligible ZIKV-exposed infants in Colombia from 4 to 18 months of age using a multi-domain questionnaire (WIDEA) and an observational motor assessment (AIMS) scored remotely on video by a neurologist (Dr. Mulkey). Figure: TOTAL WIDEA Score Over Time in ZIKV-Exposed Infants Our findings indicate a need for further study (Mulkey at al, In Prep). The total WIDEA, social cognition, and mobility domain scores deviated increasingly from norms with increasing postnatal age (Figure). The AIMS scores in ZIKV-exposed infants were similar to the normative sample over time. However, 3 infants had an AIMS score that was <2 SD’s below the norm (Z-scores: -2.57, -2.25, and -2.29). On postnatal cranial ultrasound (US), 19 of 72 (26%) infants had mild non-specific brain findings (Mulkey et al, JAMA Peds 2019). These children had a lower WIDEA mobility score than infants with normal US (P=0.05). Currently, these US findings are not a recognized sequel to ZIKV-related brain injury, yet by our results may indicate a mild ZIKV-injury with progressive functional impairment. We also have characterized a “real world” clinical-cohort of 82 US women-fetus/infant pairs with ZIKV-infection from travel and emigration at Children’s National, Washington D.C., that can further inform long-term developmental needs and support systems necessary to care for affected children (Manuscript, Under Review). The results of our Thrasher study and clinical cohort clearly indicate a need for further developmental surveillance in order to inform guidelines for the long-term evaluation of all infants and children with ZIKV-exposure. Our cohorts of 72 ZIKV-exposed Colombian children and 82 US children are uniquely able to address this knowledge gap. The sequential fetal and neonatal neuroimaging in the cohorts represents a unique feature compared to all other ZIKV-cohorts. The study is supported by a dedicated and experienced team with a remarkable 92% follow-up return rate in Colombia. Aim 1: We will evaluate multi-domain developmental scores in children exposed to ZIKV-in utero who do not have CZS. We hypothesize that ZIKV-exposed normal appearing children will have lower developmental assessment scores at 2 and 3 years of age compared to normative samples. Aim 2: We will identify factors associated with lower developmental scores in children exposed to ZIKV-in utero who do not have CZS. We hypothesize that the presence of mild postnatal non-specific cranial US findings is associated with persistent lower developmental assessment scores at age 2 and 3 years compared to ZIKV-exposed children who had normal cranial US. Other clinical and demographic factors will also be examined. Design: We will perform a prospective study of 72 in utero-ZIKV exposed children in Colombia, included in our prior studies that are normal-appearing (without CZS). A team from the USA with developmental expertise will train the Colombian team to perform developmental assessments. Child developmen