Placental Age-mismatch in Early- and Late-Onset Pre-eclampsia: A Systematic Review of Multi-omics Evidence

Preeclampsia is a leading cause of maternal and perinatal morbidity worldwide. Distinction between early-onset (EOPE, <34 weeks) and late-onset (LOPE, ≥34 weeks) preeclampsia remains unclear, limiting mechanistic insight and intervention strategies. This systematic review aimed to integrate multi-omics evidence within a placental “Age-Mismatch Dyad” framework, hypothesizing that EOPE and LOPE represent distinct trajectories of placental and maternal adaptation. We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library from inception to May 2025. Two independent reviewers screened 2,120 records; 280 full texts were assessed for eligibility, and 51 studies met inclusion criteria, of which 25 were prioritized for decision-grade synthesis. Eligible studies evaluated placental single-cell or spatial atlases, circulating cfRNA and cfDNA methylation, epigenetic clocks, genetic and ancestry modifiers, and clinical outcomes or interventions. Risk of bias was assessed using RoB 2, ROBINS-I, QUADAS-2, NOS, or AMSTAR-2. EOPE was consistently associated with accelerated placental “aging,” impaired extravillous trophoblast invasion, and earlier cfRNA/cfDNA alterations, while LOPE aligned with syncytial stress and maternal cardiometabolic or ancestry-linked modifiers. cfRNA, cfDNA-methylation, and proteomic signatures provided earlier discrimination for EOPE than angiogenic ratios. Genetic ancestry and polygenic risk scores mapped preferentially to LOPE. Clinical follow-up studies demonstrated divergent long-term maternal and offspring cardiovascular risks. EOPE and LOPE represent mechanistically distinct entities with different biomarker trajectories and long-term outcomes. Despite heterogeneity in study design and limited onset-specific stratification, this review provides a roadmap for timing-aware and equitable screening and prevention strategies in preeclampsia.