Abstract
Preeclampsia (PE) remains a major cause of maternal and fetal morbidity and mortality worldwide, with placental dysfunction and angiogenic imbalance playing central roles in disease pathogenesis. Emerging evidence highlights epigenetic regulation and angiogenic biomarkers, including placental growth factor (PlGF), as key contributors to disease heterogeneity and risk stratification. A systematic review of studies published between 2022 and 2025 was conducted in accordance with PRISMA 2020 guidelines to synthesize current evidence on epigenetic mechanisms and biomarker potential in PE. In addition, a supplementary exploratory analysis was performed using laboratory-derived PlGF data to assess analytical variability and biological associations. Non-parametric methods were applied, including Mann-Whitney U testing to compare PlGF distributions by analytical sample classification and Kendall's tau correlation to evaluate associations with gestational age and the sFlt-1/PlGF ratio. The systematic review identified consistent epigenetic alterations involving DNA methylation, histone modifications, and non-coding RNAs across maternal and placental tissues. Supplementary analysis demonstrated significantly higher and more variable PlGF concentrations in analytically classified measured samples compared with accepted samples (P = 0.03), suggesting an influence of analytical factors on biomarker distribution. PlGF levels showed a positive association with gestational age (τ = 0.32, P = 0.04) and an inverse association with the sFlt-1/PlGF ratio (τ = -0.41, P = 0.02). These findings support PlGF as a biologically relevant marker of gestational progression and angiogenic balance while underscoring the importance of rigorous analytical quality control. Integrating epigenetic insights with robust biomarker analysis may enhance personalized risk stratification in preeclampsia.