Preeclampsia-associated Biomarkers and their Potential Relevance to Stillbirth Risk: A Tutorial Review

Abstract: Stillbirth remains a major global public health challenge, accounting for nearly two million deaths annually despite significant advances in antenatal and obstetric care. Reliable biomarkers for its early prediction are still lacking, highlighting the need to identify novel diagnostic strategies. Since preeclampsia and stillbirth share several underlying pathophysiological mechanisms, including placental insufficiency, impaired trophoblast invasion, endothelial dysfunction, angiogenic imbalance, oxidative stress, and systemic inflammation, biomarkers established for preeclampsia may also hold promise for stillbirth risk assessment. This tutorial review summarizes current evidence on protein- and metabolome-based biomarkers used for the early diagnosis of preeclampsia and evaluates their potential applicability for predicting stillbirth. A comprehensive literature search of Scopus, PubMed, and ScienceDirect was conducted for studies published between 2010 and 2024. Conventional fetal monitoring techniques such as ultrasonography, magnetic resonance imaging (MRI), and cardiotocography (CTG) remain valuable for assessing fetal well-being but offer limited predictive accuracy for stillbirth. Several biomarkers, including angiogenic factors (sFlt-1, PLGF, sEng), placental proteins (PP13, PAPP-A), cardiovascular markers (BNP, NT-proBNP), renal biomarkers (cystatin C), metabolic markers (uric acid), and emerging candidates such as growth differentiation factor- 15 (GDF-15), have demonstrated diagnostic value in preeclampsia. However, their clinical utility for stillbirth prediction remains insufficiently validated. Prospective studies involving dedicated stillbirth cohorts are essential to establish their predictive performance and facilitate translation into routine clinical practice.