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Background: Until now, it is uncertain whether lifestyle interventions during pregnancy can prevent gestational diabetes mellites (GDM) in high-risk pregnant women. Objective: This study aims at investigating the effectiveness of dietary interventions and/or exercise interventions during pregnancy for preventing GDM in high-risk pregnant women. Materials and Methods: Eligible randomized controlled trials (RCTs) were selected after a search in CENTRAL, Scopus, and PubMed. Synthesis was performed for the outcome of GDM in women with any identified GDM risk factor. Separate meta-analyses (MA) were performed to assess the efficacy of either nutrition or physical activity (PA) interventions or both combined compared with standard prenatal care for preventing GDM. Subgroup and sensitivity analyses, as well as meta-regressions against OR, were performed to assess potentional heterogeneity. Overall quality, the quality of RCTs, and publication bias were also evaluated. Results: A total of 13,524 participants comprising high-risk pregnant women in 41 eligible RCTs were analyzed for GDM. Women receiving only a nutrition intervention during pregnancy were less likely to experience GDM compared with women following standard prenatal care. Among 3109 high-risk pregnant women undergoing only dietary intervention for preventing GDM, 553 (17.8%) developed GDM; however, the result of the MA was marginally not significant (OR 0.73, 95%CI 0.51, 1.03; p-value 0.07), (Q 21.29, p-value 0.01; I2 58% (95%CI 10, 78%)). Subgroup analyses demonstrated an effect for studies that were conducted in Great Britain (OR 0.65, 95%CI 0.49, 0.81; p-value 0.003), and in Spain (OR 0.50, 95%CI 0.27, 0.94; p-value 0.03), for studies with forms of the Mediterranean diet as the intervention's component (OR 0.61; 95%CI 0.46, 0.81; p-value 0.0005), and for studies including a motivation arm in the intervention (OR 0.71, 95%CI 0.58, 0.87; p-value 0.0008). Among 2742 high-risk pregnant women being analyzed for GDM outcome after receiving only an exercise intervention, 461 (16.8%) were diagnosed with GDM. Women after receiving PA intervention were less likely to develop GDM (OR 0.64, 95%CI 0.51, 0.80; p-value < 0.0001), (Q 11.27, p-value 0.51; I2 0% (95%CI 0, 99%)). Finally, 1308 (17%) cases of GDM were diagnosed among 7673 high-risk pregnant women undergoing both diet and PA intervention. Women in the group of mixed lifestyle intervention had a significant reduction in incidence of GDM (OR 0.70, 95%CI 0.55, 0.90; p-value 0.005), (Q 50.32, p-value < 0.0001, I2 66%, (95% CI 44, 79%)). Conclusions: The results of this study support the efficacy of lifestyle interventions during pregnancy for preventing GDM in high-risk women if an exercise component is included in the intervention arm, either alone, or combined with diet. A combined lifestyle intervention including physical exercise and a Mediterranean diet accompanied by motivation support may be considered the most effective way to prevent GDM among high-risk women during pregnancy. Future research is needed to strengthen these findings. [ABSTRACT FROM AUTHOR]