Association between prenatal Zika virus exposure and neurodevelopmental outcomes in offspring: a protocol for a systematic review and meta-analysis of observational studies.

INTRODUCTION: Zika virus (ZIKV) infection during pregnancy has been associated with adverse birth outcomes, including congenital Zika syndrome, characterised by features such as microcephaly. However, the broader neurodevelopmental influence of prenatal ZIKV exposure, especially among offspring without congenital anomalies at birth, remains poorly understood. While previous studies, including a review, have explored neurodevelopment in ZIKV-exposed children, comparative pooled estimates between exposed and unexposed groups remain scarce. This systematic review and meta-analysis aims to evaluate the association between prenatal ZIKV exposure and neurodevelopmental outcomes in offspring without congenital anomalies at birth, using data from observational studies with defined control groups. METHODS AND ANALYSIS: We will systematically search multiple databases, including PubMed, EMBASE, Scopus, CINAHL, PsycINFO, Cochrane Library and Web of Science, alongside grey literature sources such as Google Scholar and conference proceedings. Eligible studies will include observational designs (cohort and case-control) comparing neurodevelopmental outcomes between children with and without prenatal ZIKV exposure. Primary outcomes will include gross motor, fine motor, communication, problem-solving, social-emotional and cognitive development assessed with validated tools. Three reviewers will independently screen studies, extract data and assess methodological quality using the Newcastle-Ottawa Scale and the Grading of Recommendations, Assessment, Development and Evaluation approach. A meta-analysis will be conducted where appropriate, with heterogeneity assessed using the I² statistic and further explored through subgroup and meta-regression analyses. ETHICS AND DISSEMINATION: Ethical approval is not required, as the study involves secondary analysis of publicly available data. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD420251011184.