Zika exposure during pregnancy and the risk of hospitalisation and death due to community-acquired pneumonia in early childhood: a nationwide registry-based cohort study in Brazil

Background Childhood pneumonia remains a leading cause of morbidity and mortality worldwide. Prenatal Zika virus (ZIKV) infection has been associated with severe outcomes such as Congenital Zika Syndrome (CZS), linked to excess hospitalisations. However, the long-term respiratory consequences of prenatal ZIKV exposure across the full clinical spectrum, including children without CZS, remain poorly understood. We aimed to examine the association between prenatal ZIKV exposure and community-acquired pneumonia-related hospitalisation or death during childhood. Methods We conducted a population-based cohort study of live-born singletons in Brazil (January 2015–November 2018). We applied three complementary approaches under a triangulation framework, to strengthen confidence in the observed associations: IPTW-weighted Cox regression, a within-sibling stratified Cox model, and a negative control outcome analysis. Separate analyses compared ZIKV-exposed children with and without CZS to unexposed children. Findings We included 4,108,409 unexposed children, 3900 ZIKV-exposed without CZS, and 1786 with CZS. Female sex accounted for 48.8%, 46.7%, and 53.1% across the three groups; the majority in each were of Brown/ Pardo maternal race/ethnicity (64.6%, 67.8%, and 72.4%). By 42 months, cumulative incidence of pneumonia-related hospitalisation or death was 15.6% (95% CI 13.7–17.5) among children with CZS, versus 3.9% (95% CI 3.2–4.7) among ZIKV-exposed children without CZS and 4.6% (95% CI 4.6–4.7) among unexposed children. In IPTW-weighted models, CZS was associated with a fourfold increased risk (aHR 4.12, 95% CI 3.64–4.66), consistent with the sibling comparison (aHR 4.15, 95% CI 1.62–10.64). Prenatal ZIKV exposure without CZS was not associated with the outcome across any approach. Negative control analyses suggested limited residual confounding. Interpretation Children exposed to ZIKV in utero without CZS had a risk of pneumonia-related morbidity and mortality comparable to unexposed children, a reassuring finding for most exposed children. An increased risk was associated with prenatal ZIKV exposure only among children with CZS. These findings underscore the need for long-term follow-up and targeted respiratory prevention strategies for children with CZS. Funding Wellcome Trust, Royal Society, and CNPq.