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Yan Xie,1 Wenni Zhou,1 Xiang Tao,2 Hui Lv,3 Zhongping Cheng1 1Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China; 2Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, People’s Republic of China; 3SG+ Bio-Testing Inc, Shanghai, 200093, People’s Republic of ChinaCorrespondence: Zhongping Cheng; Hui Lv, Email mdcheng18@tongji.edu.cn; lvhui@sgplus.cnObjective: Gestational diabetes mellitus (GDM) and preeclampsia (PE) are common pregnancy complications that share some common risk factors. GDM patients are also at high risk for PE. There are no sensitive markers for prediction, especially for the occurrence of PE in GDM patients. This study investigated plasma proteins for the prediction of PE in GDM patients.Methods: A total of 10 PE, 10 GDM, and 5 PE complicated with GDM cases, as well as 10 pregnant controls without obvious complications, were included in the nested cohort. The proteomics in the plasma collected at 12– 20 weeks of gestational age (GA) were analyzed by liquid chromatography‒mass spectrometry/mass spectrometry. Some potential markers, such as soluble transferrin receptor (sTfR), ceruloplasmin (CP), apolipoprotein E (ApoE) and inositol 1,4,5-trisphosphate receptor 1 (ITPR1), were validated using enzyme-linked immunosorbent assays.Results: Functional analysis of the plasma showed that proteasome activation, pancreatic secretion, and fatty acid degradation were activated in the GDM group, and renin secretion-, lysosome-, and proteasome pathways involving iron transport and lipid metabolism were enriched in the PE group, distinguishing PE complicating GDM.Conclusion: Through proteomics analysis of plasma in early pregnancy, PE complicating GDM may have a unique mechanism from that of PE alone. Plasma sTfR, CP and ApoE levels have potential clinical applications in early screening.Keywords: gest