Background: Gestational diabetes mellitus (GDM) is a major pregnancy complication linked to subclinical inflammation. However, the predictive value of first-trimester upstream cytokines like interleukin-6 (IL-6) versus downstream acute-phase proteins like C-reactive protein (CRP) remains poorly defined. This prospective study evaluated the association of first-trimester maternal serum IL-6 and CRP levels with subsequent GDM risk.
Methods: A total of 300 pregnant women (<14 weeks of gestation) were enrolled in Khorramabad, Iran. Baseline serum IL-6 and CRP concentrations were quantified using automated assays. Participants were prospectively followed until 24 to 28 weeks, when GDM was diagnosed via a standard 75-g oral glucose tolerance test. Multivariable logistic regression adjusted for clinical confounding covariates.
Results: Of the 300 participants, 129 women (43.0%) developed GDM. These women exhibited significantly higher first-trimester median levels of both CRP (10.5 mg/L vs. 6.1 mg/L, p = 0.004) and IL-6 (3.8 pg/mL vs. 2.9 pg/mL, p = 0.010) compared to controls. In multivariable logistic regression, IL-6 was the sole independent predictor of GDM (Odds Ratio = 1.10, p < 0.001). Conversely, CRP (p = 0.767), maternal age (p = 0.114), and body mass index (p = 0.761) lost statistical significance. Additionally, a positive family history of diabetes demonstrated a profound univariate risk profile (79.4% GDM incidence vs. 25.6% without, p < 0.001).
Conclusion: First-trimester maternal serum IL-6 is a powerful, independent predictor of GDM that statistically outperforms downstream hepatic markers like CRP.
Mechanistic and Translational Relevance: Early IL-6 elevation reflects an upstream molecular insult driving insulin resistance, likely by impairing insulin receptor substrate phosphorylation before overt hyperglycemia develops. Identifying this inflammatory nexus during the first trimester shifts the paradigm from late-gestation reaction to early-pregnancy prevention, offering a proactive window for targeted preventive therapeutics to preserve beta-cell kinetics and improve perinatal metabolic outcomes.