Studying the heterogeneity of gestational diabetes mellitus: cardio-metabolic alteration and treatment response in a multi-ethnic population in Singapore (GDM-CARE): a study protocol

INTRODUCTION: Gestational diabetes mellitus (GDM) is a transient hyperglycemic condition identified during pregnancy in women without a history of chronic diabetes. GDM prevalence varies in different populations and is high among pregnant women of Asia-Pacific islanders compared with others like Europeans. GDM mothers could be categorized into different glycemic intolerance phenotypes involving various combinations of insulin sensitivity and insulin resistance, that could lead to different short-term and long-term maternal and offspring outcomes, independent of known risk factors of GDM. We hypothesize that identification of these heterogenous phenotypes offers better opportunities for more effective and precise treatments in preventing GDM-related adverse outcomes. The GDM-CARE study aims to evaluate glycemic profiling recorded via a continuous glucose monitoring (CGM) device and cardio-metabolic biomarkers alteration that determine different GDM phenotypes and their specific treatment responses. METHODS AND ANALYSIS: The GDM-CARE study enrollment began in 2022. Research visits will be conducted at three time points: baseline (5-13 weeks of gestation), visit 1 (15-30 weeks of gestation), and visit 2 (34-36 weeks of gestation, only for GDM participants). Blood and fecal samples, medical record, anthropometric and blood pressure measurements will be collected, CGM will be worn for 7-14 days, and questionnaires will be completed. The effect size across five groups would be more than 0.60, targeting 800 subjects to be recruited. The sample size of 200 GDM and overweight/obese subjects can detect a difference of 0.3 effect size across five groups with 80% power, 0.5% type-I error and 10% drop-out rate. Student's t-test, Mann-Whitney U test, chi-square test, and Fisher's exact test will be applied, based on the distribution or scale of the variables. The effects sizes will be reported as estimates (β) or relative risk with a 95% confidence interval (CI), using multiple linear regression or Modified Poisson Regression, after adjusting for key confounders. The two-sided p value will be set at significance if less than 0.05. DISCUSSION: We anticipate that our study would enable us to: (1) differentiate GDM phenotypes with various combinations of insulin resistance and β-cell dysfunction by applying glycemic profiling, cardio-metabolic profiling, and metabolites profiling; (2) study the GDM phenotype-specific treatment response.