Abstract
BackgroundIn utero exposure to Zika virus (ZIKV) is known to be associated with birth defects. The impact of in utero ZIKV exposure on neurodevelopmental outcomes in early childhood remains unclear. The objective of this study was to determine the impact of in utero ZIKV exposure on neurodevelopment at 24 months of age among toddlers who were born normocephalic to women who were pregnant during the 2016 ZIKV outbreak in French territories in the Americas.MethodsWe conducted a population-based mother-child cohort study of women whose pregnancies overlapped with the 2016 ZIKV epidemic in Guadeloupe, Martinique, and French Guiana. Infants were included in this analysis if maternal ZIKV infection during pregnancy could be determined, the newborn had a gestational age ≥ 35 weeks, there were no abnormal transfontanelle cerebral ultrasound findings after delivery or no abnormal ultrasound findings on the last ultrasound performed during the third trimester of the mother’s pregnancy, there was an absence of microcephaly at birth, and the parent completed the 24-month neurodevelopment assessment of the infant at 24 months (± 1 month) of age. ZIKV exposure of the toddler was determined by evidence of maternal ZIKV infection during pregnancy. Neurodevelopment assessments included the Ages and Stages Questionnaire (ASQ) for five dimensions of general development—communication, gross motor, fine motor, problem solving, and personal-social skills; the Modified Checklist for Autism on Toddlers (M-CHAT) for behavior; and the French MacArthur Inventory Scales (IFDC) for French language acquisition.ResultsBetween June 2018 and August 2019, 156 toddlers with and 79 toddlers without in utero ZIKV exposure completed neurodevelopment assessments. Twenty-four (15.4%) ZIKV-exposed toddlers and 20 (25.3%) ZIKV-unexposed toddlers had an ASQ result below the reference − 2SD cut-off (P = 0.10) for at least one of the five ASQ dimensions.ConclusionIn one of the largest population-based cohorts of in utero ZIKV-exposed, normocephalic newborns to date, there were minimal differences apparent in neurodevelopment outcomes at 24 months of age compared to ZIKV-unexposed toddlers at 24 months of age.Trial registrationClinicalTrials.gov, NCT02810210. Registered 20 June 2016.
Highlights
In utero exposure to Zika virus (ZIKV) is known to be associated with birth defects
Inclusion in analysis Toddlers were included in this analysis if all of the following criteria were met: maternal ZIKV infection during pregnancy could be determined; the newborn had a gestational age of 35 weeks or more; there were no abnormal transfontanelle cerebral ultrasound findings after delivery up to 2 months of age or, in the absence of a transfontanelle cerebral ultrasound after delivery, no abnormal ultrasound findings on the last ultrasound performed during the third trimester of the mother’s pregnancy; there was an absence of microcephaly at birth, defined as a head circumference above − 2SD below the mean according to sex and gestational age on the INTERGROWTH-21st chart; and the parent completed the neurodevelopment assessment of the toddler at 24 months (± 1 month) of age
A toddler was considered exposed to ZIKV if the mother had Reverse transcriptase polymerase chain reaction (RT-PCR) (RealStar Zika Virus RT-PCR Kit 1.0, Altona Diagnostics) positive result for ZIKV in blood, urine, or both at any stage during her pregnancy; if the toddler had anti-ZIKV Immunoglobulin M (IgM) (EuroImmun ELISA or in-house MAC-ELISA in French Guiana [16]) in the cord blood or blood taken within the first 10 days of life; or if the toddler had anti-ZIKV Immunoglobulin G (IgG) (EuroImmun ELISA or in-house MAC-ELISA in French Guiana [16]) in the blood beyond 12 months of age and the date of birth was posterior to the end of the ZIKV epidemic: 11 September 2016 in French Guiana, 25 September 2016 in Guadeloupe, and 16 October 2016 in Martinique
Summary
In utero exposure to Zika virus (ZIKV) is known to be associated with birth defects. The impact of in utero ZIKV exposure on neurodevelopmental outcomes in early childhood remains unclear. Adverse neurodevelopment findings in infants exposed in utero to ZIKV with and without CZS have recently been documented in the USA [7], Brazil [8,9,10,11], and Colombia [12] Within these prospective studies assessing neurodevelopment outcomes, there has been minimal use of comparative and appropriate control groups. This is a critical consideration, given that neurodevelopment in early childhood is known to be influenced by both genetic and environmental factors, including substance abuse during pregnancy, maternal age [13], sociodemographic determinants [14], prematurity or low birth weight, maternal and early infant nutritional status [15], and sex of the infant in the case of language acquisition [13]
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