Maternal HIF1A-IGFBP2 dysregulation links endometriosis to gestational diabetes: a prospective cohort study

Endometriosis (EM) may be associated with adverse pregnancy outcomes, but its relationship with gestational diabetes mellitus (GDM) and circulating metabolic biomarkers remains incompletely defined. This study evaluated temporal associations and exploratory discrimination of circulating HIF1A and IGFBP2 with maternal glycemia and criteria-defined GDM.

This prospective single-center cohort included 200 pregnant women with laparoscopically diagnosed EM and 200 controls without known or clinically detected EM. Serum HIF1A and IGFBP2 were measured at enrollment (6-7 weeks of gestation) and again during mid-pregnancy (24-28 weeks). Early measurements preceded the later GDM assessment; the mid-pregnancy blood sample and the 75-g OGTT were both obtained within the 24-28-week window. GDM was defined using IADPSG fasting-glucose and 75-g OGTT thresholds applied directly to the raw glucose data. Spearman rank correlation, age- and BMI-adjusted logistic regression, exploratory ROC analysis with 2,000 stratified bootstrap resamples, and bootstrap optimism correction were performed.

Criteria-defined GDM occurred in 69/200 women with EM (34.5%) and 27/200 controls (13.5%; RR 2.56, 95% CI 1.71-3.81; P<0.001). HIF1A and IGFBP2 concentrations were lower in the EM group at both pregnancy time points. Within the EM cohort, Spearman rank correlations with mid-pregnancy fasting blood glucose were -0.68 for early-pregnancy HIF1A, -0.50 for early-pregnancy IGFBP2, -0.54 for mid-pregnancy HIF1A, and -0.89 for mid-pregnancy IGFBP2 (all P<0.001). In adjusted logistic models, lower early HIF1A, early IGFBP2, mid-pregnancy HIF1A, and mid-pregnancy IGFBP2 were associated with GDM, with ORs of 0.922, 0.920, 0.798, and 0.941, respectively. Individual-marker AUCs were 0.844 and 0.688 in early pregnancy and 0.871 and 0.889 in mid-pregnancy. Combined-model AUCs were 0.856 and 0.888, with optimism-corrected AUCs of 0.845 and 0.882.

In this cohort, EM was associated with a higher frequency of criteria-defined GDM and lower circulating HIF1A and IGFBP2 concentrations. These biomarkers showed promising exploratory internal diagnostic performance, but the findings are observational and require external validation.