Maternal serum NRF2 at 12 weeks as a biomarker for development of gestation diabetes mellitus

The main aim of this study is to evaluate value of maternal serum nuclear factor erythroid 2-related factor 2 (NRF2) levels at 12 weeks in predicting the development of gestational diabetes mellitus (GDM) at 24–28 weeks' gestation. Other maternal variables were also evaluated, and their relationships with NRF2 levels were assessed. We conducted a single-center prospective cohort study including 1,270 pregnant women who attended their first-trimester antenatal visit between October 2021 and October 2023. At 12 weeks, fasting serum was collected to measure NRF2 by enzyme-linked immunosorbent assay (ELISA) and thyroid hormones on an automated chemiluminescent platform. Clinical data included age, pre-pregnancy body mass index (BMI), blood pressure, fasting plasma glucose, and lipids. All participants underwent a 75-g oral glucose tolerance test (OGTT) at 24−28 weeks and GDM was diagnosed by International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria. Spearman correlation assessed associations between NRF2 and clinical variables. Receiver operating characteristic (ROC) analysis evaluated discrimination. Multivariable logistic regression identified independent predictors. Among 1,270 pregnant women enrolled, 177 (13.9%) developed GDM. At 12 weeks of gestation, women who later developed GDM had significantly lower serum NRF2 levels than those without GDM. They also showed higher fasting plasma glucose (FPG), mean arterial pressure (MAP), as well as lower free thyroxine (FT4) levels. ROC analysis demonstrated that serum NRF2 at 12 weeks had good predictive value for GDM, with an area under the curve (AUC) of 0.779 (95% confidence interval CI 0.745–0.812, p < 0.001). A combined model incorporating NRF2 with MAP, FT4, and FPG showed improved discrimination, with an AUC of 0.882 (95% CI 0.856−0.908, p < 0.001). In multivariable logistic regression, lower serum NRF2 (odds ratio OR = 0.948, 95% CI 0.938–0.957, p < 0.001), higher MAP (OR = 1.182, 95% CI 1.132–1.233, p < 0.001), higher FPG (OR = 3.911, 95% CI 2.471−6.190, p < 0.001), and lower FT4 (OR = 0.639, 95% CI 0.562–0.726, p < 0.001) were identified as independent predictors of GDM, whereas other baseline parameters were not significant. Decreased maternal serum NFR2 levels at 12 weeks’ gestation appear to be associated with an increased risk of developing GDM later in pregnancy. Combining this marker, together with FT4, MAP and potentially FPG may serve as a useful first-trimester screening for the risk to develop GDM.