Project Details

Early Career

Status: Funded - Open

Neurologic outcome of apparently normal newborns from Zika virus positive pregnancies

Sarah Mulkey, MD, PhD


BACKGROUND: Zika (ZIKV) infection in pregnancy can result in a range of neurologic disease severity in exposed fetuses. Fetuses exposed to Zika infection that do not develop overt brain abnormalities by birth, may still be at risk for postnatal neurologic sequelae.

GAP: It is not known if normal neuroimaging in the third trimester fetus exposed to ZIKV infection is associated with normal neurodevelopment in infancy.

HYPOTHESIS: Our overarching hypothesis is that infants with ZIKV exposure in utero who have normal fetal brain MRI and normal fetal head size will still be at significant risk for abnormal neurodevelopment in infancy.

METHODS: We performed a longitudinal study of neurodevelopmental outcome through the first 18 months of age in infants whose mothers had ZIKV infection in pregnancy. The study cohort was enrolled from a prospective fetal to newborn neuroimaging study (Mulkey et al, JAMA Peds 2019) in Barranquilla, Colombia and in Washington, DC, USA. Eligible infants had normal fetal MRI and US, normal head size at birth and normal newborn brain MRI and/or cranial US with normal or no more than non-specific mild changes. Following in person staff training by the study neurologist, infant development was assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) and the Alberta Infant Motor Scale (AIMS) at 4 to 18 months of age. AIMS were not used for infants >15 months due to age limit of test when children are walking. The AIMS assessments were video-recorded and scored centrally by the study neurologist. Infants had 1 or 2 neurodevelopmental assessments during the follow-up period. Results in the cohort were converted to Z-scores relative to normative samples. We also compared neurodevelopment between infants with normal and mildly abnormal neuroimaging.

RESULTS: 72 of 78 (92%) study infants without congenital Zika syndrome had neurodevelopmental tests. Forty assessments were done at a mean age of 174.5 +/- 27 days and 66 at the mean age of 411.3 +/- 96 days. Thirty-four infants were assessed twice. The total WIDEA score and the domains of self-care, communication, social cognition, and mobility in ZIKV-exposed cases differed from the comparable age norms. In particular, the total WIDEA score, social cognition domain score, and mobility domain score grew more abnormal with increasing postnatal age. The AIMS scores in the ZIKV-exposed infants with assessment age <15 months however, were similar to the normative sample over time. Three infants had an AIMS score from 10-12.5 months of age that was <2 SD’s below the norm (Z-scores: -2.57, -2.25, and -2.29). The z-score of the total WIDEA for these three infants was -1.36, -1.72, and -1.84, respectively. On postnatal neuroimaging, 19 infants had a non-specific finding of lenticulostriate vasculopathy, choroid plexus cysts, or subependymal cysts. These children had an increased, but not statistically significant, odds of a low AIMS score (OR=4.25, 95%CI 0.63-28.6) at 12 months of age.

IMPACT: This study found that normocephalic newborns without congenital Zika syndrome are at risk for neurodevelopmental decline in the first 18 months of age. Ongoing neurodevelopmental surveillance is necessary to monitor outcomes and provide optimal therapy for infants identified with developmental delays.

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Mulkey, Sarah B., Gilbert Vezina, Dorothy I. Bulas, Zarir Khademian, Anna Blask, Youssef Kousa, Caitlin Cristante, Lindsay Pesacreta, Adre J. du Plessis, and Roberta L. DeBiasi. "Neuroimaging Findings in Normocephalic Newborns With Intrauterine Zika Virus Exposure." Pediatric neurology 78 (2018): 75-78.

Mulkey, Sarah B., Dorothy I. Bulas, Gilbert Vezina, Yamil Fourzali, Armando Morales, Margarita Arroyave-Wessel, Christopher B. Swisher et al. "Sequential neuroimaging of the fetus and newborn with in utero Zika virus exposure." JAMA pediatrics 173, no. 1 (2019): 52-59.