Developmental outcomes in children exposed to Zika virus in utero from a Brazilian urban slum cohort study

Abstract

Background The prevalence of developmental alterations associated with in-utero Zika virus (ZIKV) exposure in children is not well understood. Furthermore, estimation of the Population Attributable Fraction (PAF) of developmental alterations attributed to ZIKV has not been performed due to lack of population-based cohorts with data on symptomatic and asymptomatic ZIKV exposures and an appropriate control group. The aim of this study was to characterize neurodevelopmental outcomes of children at 11 to 32 months of age with intrauterine ZIKV exposure and estimate the PAF of alterations secondary to ZIKV exposure. Methodology/Principal findings We performed a cohort of biannual community-based prospective serosurveys in a slum community in Salvador, Brazil. We recruited women participating in our cohort, with a documented pregnancy from January 2015 to December 2016 and children born to those mothers. Children were classified as ZIKV exposed in utero (born from women with ZIKV seroconversion during pregnancy) or unexposed (born from women without ZIKV seroconversion or that seroconverted before/after pregnancy) by using an IgG monoclonal antibody blockade-of-binding (BoB). We interviewed mothers and performed anthropometric, audiometric, ophthalmological, neurologic, and neurodevelopmental evaluations of their children at 11 to 32 months of age. Among the 655 women participating in the cohort, 66 (10%) were pregnant during the study period. 46 (70%) of them completed follow-up, of whom ZIKV seroconversion occurred before, during, and after pregnancy in 25 (54%), 13 (28%), and 1 (2%), respectively. The rest of women, 7 (21.2%), did not present ZIKV seroconversion. At 11 to 32 months of life, the 13 ZIKV-exposed children had increased risk of mild cognitive delay (RR 5.1; 95%CI 1.1–24.4) compared with the 33 children unexposed, with a PAF of 53.5%. Exposed children also had increased risk of altered auditory behavior (RR 6.0; 95%CI 1.3–26.9), with a PAF of 59.5%. Conclusions A significant proportion of children exposed in utero to ZIKV developed mild cognitive delay and auditory behavioral abnormalities even in the absence of gross birth defects such as microcephaly and other neurodevelopmental domains. Furthermore, our findings suggest that over half of these abnormalities could be attributed to intrauterine ZIKV exposure.

Neurodevelopment in Children Exposed to Zika Virus: What Are the Consequences for Children Who Do Not Present with Microcephaly at Birth?

“…Our overall results are consistent with another Brazilian study, which analyzed a smaller sample and reported a difference between groups concerning the cognitive domain but not for the motor and language domains [ 8 ]. Pursuing a more detailed comparison between groups, we analyzed the outcomes of the BSIDIII subtests using balanced scores for receptive and expressive communication as well as gross and fine Motor; the frequency of delays in these subtests did not differ significantly between the exposed and unexposed groups.…”

“…The short-term risks of congenital ZIKV infections are already known and the impairment of neurodevelopment is evident in children with moderate to severe microcephaly [ 4 , 5 , 6 ]. However, the risk of developmental delays in children with evidence of maternal ZIKV infection during pregnancy born without microcephaly remains unknown [ 7 , 8 , 9 ].…”

Congenital Zika Infection and the Risk of Neurodevelopmental, Neurological, and Urinary Track Disorders in Early Childhood. A Systematic Review

“…The recent study of Ticona et al (2021) [ 35 ] investigated the relationship between the in-utero Zika virus exposure and the prevalence of developmental alterations in early childhood. It was observed that from a group of women living in a slum community in Brazil, both the asymptomatic and symptomatic Zika virus infection during the antenatal period is associated with mild neurodevelopmental abnormalities in children asymptomatic at birth.…”

“…Of course, microcephaly of any type is considered a major driver of neurology and neurodevelopment delays [ 43 ]. However, the fact that neurodevelopmental and neurological disorders were observed also in children born asymptomatically indicates that the exposed children without CZS appeared at risk for neurodevelopmental disorders in all of the domain disorders, such as motor, cognition, and mainly in language [ 20 , 27 , 32 , 35 ]. Furthermore, normocephalic children should also be under frequent follow-up, due to an increased risk of developing microcephaly after birth [ 26 ].…”

Social determinants associated with Zika virus infection in pregnant women

“…[9,10]. Intrauterine exposure to ZIKV can result in Congenital Zika Syndrome (CZS), which includes a range of physical and neurological impairments, such as microcephaly [9][10][11].…”