OBJECTIVE: Women with gestational diabetes mellitus (GDM) often develop a metabolic memory that increases the risk of future metabolic disorders, even after blood glucose levels normalize following clinical intervention. However, the impact of this metabolic memory on susceptibility to SARS-CoV-2 remains unclear. Therefore, we aim to investigate the potential association between metabolic memory in GDM and susceptibility to SARS-CoV-2 infection. METHODS: We conducted a prospective cohort study with 1,675 pregnant women, including 197 (11.8%) with GDM. Postpartum SARS-CoV-2 infections were tracked via telephone follow-up and categorized into negative and positive groups. Logistic regression was used to explore risk factors for SARS-CoV-2 infection. Peripheral blood samples were collected from 30 GDM and 30 normal glucose-tolerant (NGT) pregnant women in three trimesters (T1, T2, T3) for longitudinal untargeted metabolomics to identify GDM and SARS-CoV-2-associated metabolites. Limma package was applied to find differential metabolites (DEMs) associated with SARS-CoV-2 infection and GDM. RESULTS: Among 1,675 women, 1,348 (80.5%) tested positive for SARS-CoV-2. GDM post-partum women had higher SARS-CoV-2 infection rates (88.3% vs. 79.4%, P = 0.003) than NGT women. GDM was associated with SARS-CoV-2 infection (T2: OR [95% CI]: 2.17 [1.26-3.54], P = 0.005
T3: OR [95% CI]: 1.70 [1.03-2.82], P = 0.040). Compared to the SARS-CoV-2 negative group, the positive group exhibited elevated levels of allantoic acid, LPE (0:0/22:6), LPC (15:0/0:0), 1-linoleoyl-sn-glycero-3-phosphorylcholine in T1 and T2, before clinical intervention. In T3, allantoic acid remained elevated post-intervention. A similar increase as described above was observed in the GDM compared to the NGT group. CONCLUSION: Compared to NGT, women with GDM are at a higher risk of postnatal SARS-CoV-2 infection. Metabolic memory from GDM may heighten susceptibility to SARS-CoV-2.