| Summary: | Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in <i>VEGFA, PTGS2, NOS3, TNF</i>, and <i>NOS2</i> genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester (<i>p</i> < 0.001) and had mothers with lower educational level (<i>p</i> < 0.001) and family income (<i>p</i> < 0.001). We found higher risk of CZS due the allele rs2297518[A] of <i>NOS2</i> (OR = 2.28, CI 95% 1.17–4.50, <i>p</i> = 0.015). T allele and TT/CT genotypes of the <i>TNF</i> rs1799724 and haplotypes associated with higher expression of <i>TNF</i> were more prevalent in children with CZS and severe microcephaly (<i>p</i> = 0.029, <i>p</i> = 0.041 and <i>p</i> = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in <i>NOS2</i> and <i>TNF</i> genes affect the risk of CZS and severe microcephaly.
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