SII serves as an independent diagnostic indicator for GDM and is regulated by placental 5-HT/NF-κB signaling.

Gestational diabetes mellitus (GDM) poses a significant threat to perinatal health. Diagnosis based solely on glycemic parameters shows limited accuracy. The Systemic Immune-Inflammation Index (SII), a quantitative marker of inflammation, may improve diagnostic precision. This study analyzed clinical data stratified by GDM and obesity status to evaluate the diagnostic utility of SII and its underlying mechanisms involving placental NF-κB and 5-hydroxytryptamine (5-HT) signaling. We observed elevated SII levels in GDM patients, which correlated positively with glucose levels and inflammatory indicators (white blood cell count, fasting blood glucose, postprandial blood glucose). Logistic regression and receiver operating characteristic analyses confirmed the diagnostic value of SII, which was further enhanced when combined with clinical covariates. Placental expression of tryptophan hydroxylase 1 (TPH1) and NF-κB was significantly increased in GDM and closely linked to SII levels. Dysregulation of placental 5-HT signaling, characterized by increased TPH1 and monoamine oxidase A (MAO-A) expression alongside reduced serotonin transporter (SERT), was associated with maternal overweight. Moreover, SII, BMI, TPH1, and NF-κB all correlated with insulin resistance (IR). These results support SII as a non-invasive diagnostic indicator for GDM and highlight the role of placental 5-HT/NF-κB signaling in its pathogenesis, providing insights for early diagnosis and targeted therapy.