Background <p>Pregnant people have been recommended to receive influenza vaccine at any stage of pregnancy or before conception. However, a large number of pregnant people do not receive the vaccine because of safety concerns. The aim of this study was to investigate the risk of maternal influenza vaccination during the first trimester for birth defects (BDs).</p> Methods <p>A literature search of PubMed, Embase, the Cochrane Library, the Web of Science and Scopus databases was performed to identify eligible observational studies published from inception to 28th April 2023. The risk estimates were analyzed by pooling odds ratio (OR) with 95% confidence intervals (CIs). Potential sources of heterogeneity were identified by subgroup and meta-regression analysis. Several categories of sensitivity analyses were performed.</p> Results <p>31 studies involving 1,223,024 individuals were included in this study. Compared with the unvaccinated control group or those receiving influenza vaccination during second or third trimester, no increased risk of total BDs (28 studies, unadjusted OR 1.15, 95% CI 0.97–1.36; 10 studies, adjusted OR 1.03, 95% CI 0.98–1.07) or major BDs (16 studies, unadjusted OR 1.11, 95% CI 0.97–1.25; 6 studies, adjusted OR 1.03, 95% CI 0.98–1.09) was observed among those vaccinated during the first trimester. No potential risks were observed based on different vaccine type, the use of adjuvants, the assessment of BDs or control type. Results were consistent across sensitivity analyses for primary results.</p> Conclusions <p>This study provided updated evidence that influenza vaccination in early pregnancy did not increase the risk for BDs.</p>