© 2022 Elsevier LtdIntroduction: The purpose of the present study was to compare maternal serum betatrophin levels during the first trimester from healthy pregnancies to those complicated by gestational diabetes mellitus (GDM). Methods: In this prospective study, 320 pregnant women were evaluated in their first trimester, and 145 pregnant women who met the inclusion criteria were divided into the following two groups according to GDM screening results: GDM (n:20) and non-diabetic healthy control (n: 125). Samples of maternal serum fasting insulin, fasting blood glucose, hemoglobin (HB)A1c, and betatrophin levels obtained from the women's blood samples between 11+0/7 -13+6/7 gestational weeks during first trimester nuchal translucency screening. 75-g oral glucose tolerance test protocol was preferred for GDM scanning between 24+0/7 -28+0/7 gestational weeks. Results: Maternal age and first-trimester body mass index (BMI) were higher in the GDM group than in the control group. Gestational age at blood draw was similar between the groups. First-trimester fasting insulin, fasting glucose, hemoglobin (Hb)A1c, thyroid-stimulating hormone, triiodothyronine (sT3), and thyroxine (sT4) were statistically similar between groups. First trimester Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was 2.67 ± 1.42 in the GDM group and 2.12 ± 1.61 in the control group and not statistically different. Maternal age and BMI adjusted first-trimester maternal serum betatrophin levels were 11.58 ± 6.40 ng/mL in the GDM group and 31.11 ± 3.00 ng/mL in the control group and was statistically lower in the GDM group (p < 0.001). Discussion: Our results indicated that first trimester maternal serum betatrophin levels are decreased in pregnancies complicated by GDM and first trimester betatrophin levels could be an early screening tool for GDM to allow better pregnancy management.