Extracellular Vesicle-mediated Placental Crosstalk in Early Pregnancy: Mechanisms, Biomarker Potential, and Translational Implications for Preeclampsia and Fetal Growth Restriction
Wiku Andonotopo, Dovy Djanas, Aryani Aziz, Nuswil Bernolian, Muhammad Adrianes Bachnas, Mochammad Besari Adi Pramono, Julian Dewantiningrum, Efendi Lukas, I. Nyoman Hariyasa Sanjaya, Anak Agung Gede Putra Wiradnyana, Anak Agung Ngurah Jaya Kusuma, Khanisyah Erza Gumilar, Ernawati Darmawan, Muhammad Ilham Aldika Akbar, Dudy Aldiansyah, Aloysius Suryawan, Ridwan Abdullah Putra, Theresia Monica Rahardjo, Rizna Tyrani Rumanti, Roland Frederik Lengkey, Anita Deborah Anwar, Cut Meurah Yeni, Donel Suheimi, Agus Rusdhy Hamid, Laksmana Adi Krista Nugraha, Wibisana Andika Krista Dharma, Waskita Ekamaheswara Kasumba Andanaputra
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BSTRACT
Extracellular vesicles (EVs) are increasingly recognized as mediators of maternal–fetal communication, yet their role in early placental crosstalk and adverse pregnancy outcomes remains only partially resolved. This review synthesizes current evidence on the mechanistic, biomarker, and translational relevance of placental EVs in preeclampsia and fetal growth restriction, with attention to methodological transparency and reproducibility. A systematic search of PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidance, with the timeframe restricted to 2015–2024 to ensure inclusion of fully indexed and methodologically mature studies. From 340 identified records, 35 studies met predefined eligibility criteria following duplicate removal, independent screening, and full-text assessment. Across these studies, EVs – particularly those derived from the syncytiotrophoblast – carry bioactive cargo including microRNAs, proteins, and lipids that may interact with endothelial, immune, and hemostatic pathways. A recurring, though not uniform, pattern suggests that alterations in EV composition can be detected before clinical disease, often in parallel with angiogenic imbalance and inflammatory signaling. At the same time, heterogeneity in EV isolation, characterization, and reporting (in line with evolving minimal information for studies of EV recommendations) limits direct comparability across studies. The potential of circulating EVs as minimally invasive biomarkers is supported, yet remains investigational, with inconsistent thresholds and limited external validation. Translational applications, including EV-based risk stratification or “liquid biopsy” approaches, should therefore be interpreted cautiously rather than as established clinical tools. Overall, EV-mediated signaling appears to contribute to the continuum from placental stress to maternal disease, although causal pathways remain incompletely defined. Further longitudinal and standardized investigations will be required to clarify their clinical utility. Primary and secondary evidence were interpreted with attention to evidentiary hierarchy.