In utero Zika virus exposure and neurodevelopment at 24 months in toddlers normocephalic at birth: a cohort study

Abstract

Background 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. 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. Methods We 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. Results Between 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. Conclusion In 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 registration ClinicalTrials.gov, NCT02810210. Registered 20 June 2016.

Neurodevelopmental outcome of infants without central nervous system anomalies born to symptomatic RT-PCR ZIKV positive women

“…Different from the previous study, we used infants of asymptomatic ZIKV RT-PCR and serology negative women to minimize misclassification bias; also, compared to the Bayley III scale that was used in our study, the ASQ3 has shown significant variability in sensitivity and specificity as a screening tool for neurodevelopmental anomalies but improves as the infant advances in age. Our results support the findings of Gerzson et al [17] and Grant et al [36] and highlight the importance of having an adequate unexposed control group to determine differences in outcome incidence as a critical element of causality and to reduce selection bias risk in observational studies [38].…”

“…Previous studies evaluating the neurodevelopmental outcome of normocephalic infants born to ZIKV exposed women found significant anomalies in neurodevelopment. However, these studies did not include an appropriate control group for comparison [ 12 – 15 , 30 – 32 ] or had a high risk of selection bias [ 33 – 36 ]. A study by Andrade et al [ 32 ] used a similar methodology to study exposed infants observing a higher rate of receptive language delay, but the absence of a control group limited the study; our study did not find any differences in receptive or expressive language between exposed and un exposed infants using the same Bayley III score.…”

“…Gerzson et al [ 17 ] used an appropriate control group and although limited by small sample size, did not find any difference between normocephalic exposed and unexposed infants in neurodevelopmental outcome between 18 and 29 months CA. A prospective cohort study by Grant et al [ 36 ] studied symptomatic pregnant women with ZIKV RT-PCR or serology to determine the exposure status of infants. They evaluated neurodevelopmental outcome at 24 months with the ASQ3, a screening tool for neurodevelopmental impairment, and found no differences between exposed infants and infants of symptomatic RT-PCR and serology negative women ( controls ).…”

Pregnancy and viral infections: Mechanisms of fetal damage, diagnosis and prevention of neonatal adverse outcomes from cytomegalovirus to SARS-CoV-2 and Zika virus

“…The absence of clinical and neuroradiological CZS abnormalities at birth does not exclude future functional implications for both the affected infant as well as its family, such as seizures, hearing loss, abnormal visual function, dysphagia, sleep disorders, and neurodevelopmental impairment [ 236 , 237 ]. Prevention strategies …”

Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects

“…A major concern following the in utero ZIKV exposure is whether the infants born without obvious structural brain abnormalities and/or microcephaly have impairment in development. Only a few studies compared the outcomes of the normocephalic ZIKV-exposed children with those of a neurotypical control group, or with children without ZIKV infection ( Supplementary Table S3 ) ( Cardoso et al, 2019 ; Einspieler et al, 2019 ; Valdes et al, 2019 ; Gerzson et al, 2020 ; Sobral da Silva et al, 2020 ; Familiar et al, 2021 ; Grant et al, 2021 ). Six studies did not find differences between prenatal ZIKV exposure without microcephaly and the unexposed controls ( Cardoso et al, 2019 ; Einspieler et al, 2019 ; Valdes et al, 2019 ; Gerzson et al, 2020 ; Sobral da Silva et al, 2020 ; Grant et al, 2021 ).…”