BACKGROUND: Recent studies support that osteocalcin (OC), apart from its skeletal role, is implicated in glucose homoeostasis. Aims of this study were to examine the first-trimester maternal serum concentrations of OC in pregnancies that developed gestational diabetes mellitus (GDM) and to create a first-trimester prediction model for GDM.DESIGN: Case-control study in a prospective cohort of pregnant women. Maternal serum levels of OC were measured in 40 cases that developed GDM and 94 unaffected controls. First-trimester biophysical parameters, biochemical indices, maternal-pregnancy characteristics, and OC concentrations were assessed in relation to GDM occurrence.RESULTS: In the GDM group, first-trimester OC serum levels were increased compared to the control group (mean = 8·81 ng/mL, SD = 2·59 vs. mean = 7·34 ng/ml, SD = 3·04, P = 0·0058). Osteocalcin was independent of first-trimester biophysical and biochemical indices. Osteocalcin alone (OR = 1·21, CI: 1·02-1·43, P = 0·023) was a significant predictor of GDM [Model R(2) = 0·04, area under the curve (AUC) = 0·61, CI: 0·55-0·72, P < 0·001]. The combination of maternal and pregnancy characteristics with OC resulted in an improved prediction model for GDM (Model R(2) = 0·21, AUC = 0·80, CI: 0·71-0·88, P < 0·001). The combined model yields a sensitivity of 72·2% for 25% false-positive rate.CONCLUSIONS: First-trimester maternal serum levels of OC are increased in GDM pregnancies. Osteocalcin combined with maternal and pregnancy characteristics provides an effective screening for GDM at 11-14 weeks.