Postpartum Depression: Interacting Biological Pathways and the Promising Validation of Blood-Based Biomarkers

Background/Objectives: Postpartum depression (PPD), the most common and prevalent psychiatric disorder after birth, is a prevalent yet underdiagnosed psychiatric condition that remains insufficiently understood, particularly in terms of its biological basis. While epidemiological data are extensive, few studies have systematically investigated their underlying biological mechanisms. The purpose of this study was to explore the potential links between blood biomarker levels and postpartum depressive symptoms, contributing to the development of a unified biological model of PPD. Methods: We conducted a cross-sectional study between 2023 and 2025 at a tertiary academic hospital in Timisoara, Romania, involving 860 postpartum women recruited at hospital discharge (1–2 weeks after childbirth). The participants completed the Edinburgh Postnatal Depression Scale (EPDS) and provided peripheral blood samples, which were analyzed using standardized protocols. The blood levels of pregnancy-related hormones (estrogen and progesterone), vitamin D, biochemical markers of inflammatory response (white blood cell count, C-reactive protein, fibrinogen, neutrophil count, lymphocyte count, and ferritin), anemia indicators (hemoglobin, red blood cell count, hematocrit, and ferritin), thyroid hormones (TSH, FT3, and FT4) and markers of coagulation abnormalities (D-dimer, platelets, fibrinogen, APTT, and INR) were evaluated. The data were analyzed with JASP v0.19.3. The statistical methods included multivariate linear regression, the Kruskal–Wallis and Mann–Whitney U tests, and Spearman correlation, with significance set at p < 0.05. Results: The analysis revealed that postpartum depression (PPD) is associated with distinct biological profiles, reflecting the unique hormonal and physiological changes in the peripartum period. Significant associations were identified between EPDS scores and the levels of estrogen, progesterone, thyroid hormones (TSH, FT3, and FT4), inflammatory markers (CRP and ferritin), vitamin D, and coagulation parameters (APTT and INR). These findings support the notion that PPD has a multifactorial biological basis and highlight the potential of these biomarkers as early predictors of risk. Conclusions: Integrating biochemical assessments into postpartum care may enhance early identification and inform targeted preventive interventions, such as hormone monitoring, vitamin D and iron supplementation, or thyroid function correction.