Early-pregnancy glucose–lipid signatures and metabolic heterogeneity of gestational diabetes with extension to hypertensive comorbidity in singleton and twin pregnancies: a multicenter cohort study

BACKGROUND: Early pregnancy is a critical window for metabolic adaptation, marked by coordinated regulation of glucose and lipid metabolism. Disruption of this balance may contribute to gestational diabetes mellitus (GDM), a condition increasingly recognized as metabolically heterogeneous. Whether early-pregnancy glucose-lipid indices capture this heterogeneity and extend to hypertensive disorders of pregnancy (HDP) remains unclear. METHODS: This retrospective multicenter cohort included 13,419 pregnancies (11,765 singleton and 1,654 twin pregnancies). Fasting glucose and lipid measurements obtained at 5-16 weeks of gestation were used to derive eight composite indices, including the triglyceride-glucose (TyG) index, TyG-BMI, METS-IR, SPISE, AIP, CHG, NHHR, and lnRC. Multinomial logistic regression evaluated associations with GDM subtypes (post-load, isolated fasting, and combined GDM), using normoglycemia as the reference. Extension analyses assessed GDM-HDP phenotypes (GDM-only, HDP-only, and combined GDM-HDP) relative to normoglycemic-normotensive pregnancies. Restricted cubic spline models examined dose-response relationships, and receiver operating characteristic analyses assessed discriminative performance. RESULTS: Early-pregnancy glucose-lipid indices showed a clear gradient across GDM subtypes, with progressively stronger associations from post-load GDM to isolated fasting GDM and combined GDM; adjusted odds ratios (ORs) per unit increase in TyG index were 2.54, 6.21, and 8.91, respectively. When analyses were extended to hypertensive outcomes, the strongest association was observed for combined GDM-HDP (adjusted OR, 4.81; 95% confidence interval, 3.35-6.89). Significant interaction with prepregnancy overweight status was observed for TyG-BMI, with more pronounced heterogeneity across HDP-related phenotypes, whereas associations were directionally similar across singleton and twin pregnancies after accounting for center composition. For the highest-risk phenotypes, area under the curve (AUC) values were 0.786 for combined GDM (TyG index and TyG-BMI) and 0.811 for combined GDM-HDP (TyG-BMI). A significant interaction between fasting glucose and high-density lipoprotein cholesterol was detected for both combined GDM (interaction OR 3.61) and combined GDM-HDP (interaction OR 3.79). CONCLUSIONS: Early-pregnancy glucose-lipid indices are associated with a graded pattern of metabolic heterogeneity across GDM subtypes, and a similar pattern is observed for hypertensive comorbidity. These findings are consistent with shared metabolic perturbations underlying glycemic and vascular complications during pregnancy and may inform future approaches to early-pregnancy risk assessment.