Beyond Microcephaly: Quantitative Assessment of Congenital Outcomes Following Zika Virus Infection During Pregnancy - An Updated Meta-Analysis

BackgroundZika virus (ZIKV) infection during pregnancy has been linked to severe congenital outcomes, particularly microcephaly. Since the 2015-2016 epidemic, several reviews have confirmed this association, but most focused on microcephaly and studies published until 2018. New data have since emerged, broadening the spectrum of congenital malformations and detailing the influence of gestational timing of infection. Objective: To conduct an updated systematic review and meta-analysis of studies published up to 2025, quantifying the risk of microcephaly and other congenital outcomes associated with maternal ZIKV infection, including subgroup analyses by gestational trimester and rigorous methodological quality assessment. Methods: Comprehensive searches were performed in PubMed, Scopus, Web of Science, and Lilacs databases for observational studies assessing ZIKV infection in pregnant women and congenital outcomes. Data extracted included case numbers, specific outcomes, and timing of infection during pregnancy. Random-effects meta-analyses were conducted to estimate odds ratios (OR) and risk ratios (RR), complemented by subgroup and publication bias analyses. Results: Eighteen observational studies with 4,523 exposed pregnancies and 9,710 controls were included. The combined risk of microcephaly was significantly increased (OR = 12.5; 95% CI: 7.8-20.1; I2 =62%). Other congenital anomalies, such as intracranial calcifications and ventriculomegaly, showed substantial associations (OR = 8.4; 95% CI: 4.5-15.7). Infection during the first trimester was associated with the highest risk (OR = 18.3; 95% CI: 9.7-34.6). Conclusions: This updated meta-analysis confirms the elevated risk of microcephaly and other congenital anomalies following maternal ZIKV infection, especially when infection occurs early in pregnancy. These findings underscore the need for ongoing surveillance and targeted preventive measures in endemic areas. Author summaryThis study provides a comprehensive and updated synthesis of the risk of congenital outcomes following maternal ZIKV infection, incorporating data through 2025 and evaluating multiple anomalies. By stratifying results by gestational trimester and assessing study quality, we offer detailed risk estimates to inform clinical management and policy in endemic regions.