Early Prediction of Gestational Diabetes Mellitus and Insulin Therapy Requirement Using First-Trimester PAPP-A and Free β-hCG MoMs Levels: A Retrospective Case–Control Study

<b>Objectives:</b> To evaluate the association between gestational diabetes mellitus (GDM), including insulin-dependent GDM with pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) and free beta human chorionic gonadotropin (free β-hCG) MoM levels, and to assess their potential as predictive risk factors. <b>Methods:</b> This retrospective study included 2588 women with singleton pregnancies who underwent combined first-trimester screening, along with the 50 g glucose challenge test (GCT) and a 100 g oral glucose tolerance test (OGTT) between 24 and 28 weeks of gestation. Patients were initially divided into four groups based on the glucose screening results, and PAPP-A and free β-hCG MoMs were compared between these groups. GDM cases managed by diet were then compared with those requiring insulin therapy. <b>Results:</b> Of the study population, 132 women (5.10%) were diagnosed with GDM, 112 (84.8%) managed their glycemia with dietary changes, while 20 (15.2%) required insulin therapy. PAPP-A levels were significantly lower in the GDM group compared to the control group (<i>p</i> < 0.001). In addition, the insulin-dependent GDM group had significantly lower PAPP-A levels than the diet-controlled group (<i>p</i> < 0.001). No significant differences were observed in the free β-hCG MoM levels between the groups (<i>p</i> = 0.292). Receiver operating characteristic analysis identified 0.815 as the optimal PAPP-A cut-off value for predicting GDM, with a sensitivity of 61.4%, specificity of 61.6%, and an area under the curve (AUC) of 0.649 (95% CI: 0.595-0.703). For insulin-dependent GDM, the same threshold yielded an AUC of 0.621 (95% CI: 0.563-0.679), with a sensitivity of 58.6% and a specificity of 59.7%. <b>Conclusions:</b> Low serum PAPP-A MoM levels are significantly associated with the development of GDM, including insulin-dependent cases. Although PAPP-A alone may not be a definitive predictive marker for GDM, low levels could support the recommendation for early screening as part of a broader diagnostic approach.