MicroRNA-augmented First-trimester Precision Prediction for Placenta-mediated Disorders: A Systematic Review and Evidence-to-algorithm Translation Framework Integrating Clinical Variables and the Fetal Medicine Foundation Competing-risks Model

Placenta-mediated disorders remain major causes of maternal and perinatal morbidity because they are typically detected only after clinical trajectories are established. MicroRNAs (miRNAs), released from the placenta early in pregnancy, have emerged as promising first-trimester biomarkers, yet their integration into clinical prediction models and their mechanistic interpretation remain limited. This study systematically evaluates the evidence on first-trimester circulating miRNAs as predictors of placenta-mediated disorders and explores their potential for integration into precision risk-prediction algorithms. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. PubMed/MEDLINE, Embase, Web of Science, and clinical trial registries were searched from inception to the final search date. Eligible studies evaluated miRNAs measured at ≤14 weeks’ gestation and reported associations with placenta-mediated outcomes. Study selection, data extraction, and qualitative synthesis were performed using predefined criteria, and risk of bias was assessed using design-appropriate methods. Owing to heterogeneity in analytical platforms, normalization approaches, and outcome definitions, quantitative meta-analysis was not performed. A total of 626 records were identified, of which 31 studies met the inclusion criteria and were included in the qualitative synthesis. Across cohorts exceeding 600 pregnancies, placental-specific chromosome 19 miRNA cluster miRNAs, cardiovascular-associated miRNAs, and inflammation-related miRNAs consistently differentiated pregnancies that later developed preeclampsia, fetal growth restriction, gestational diabetes, or preterm birth. Several studies reported detection rates exceeding 80% at fixed false-positive thresholds. Mechanistic synthesis demonstrated convergence on shared biological pathways, including impaired placentation, endothelial dysfunction, immune dysregulation, and metabolic programming. Studies employing standardized reverse transcription quantitative polymerase chain reaction or next-generation sequencing platforms showed greater reproducibility and translational readiness First-trimester circulating miRNAs represent biologically plausible early indicators of placental dysfunction with potential to enhance multivariable risk-prediction models. Translation into clinical practice will require assay harmonization, external validation across populations, and careful consideration of ethical and implementation challenges.