Impaired implantation as a major upstream pathway of preeclampsia: a narrative synthesis of mechanistic, epidemiological and biomarker evidence

Abubakar Ibrahim¹Nik Ahmad Zuky Nik Lah^1*Engku Husna Engku Ismail¹Marina Irwan Khoo¹Lukman Yusuf¹Nik Hazlina Nik Hussain¹Anani Aila Mat Zin¹Liza Noordin¹SARIMAH ABDULLAH¹Zaleha Abdullah Mahdy²

• ¹University of Science Malaysia (USM), Penang, Malaysia
• ²Universiti Pertahanan Nasional Malaysia, Federal Territory of Kuala Lumpur, Malaysia

PreeclampsiaPreeclampsia (PE) remains a major cause of maternal and perinatal morbidity worldwide. Although abnormal placentation and shallow trophoblast invasion are well recognized, increasing evidence suggests that the origins of PE lie earlier, at the stage of implantation and decidualization. A deeper understanding of impaired implantation as the initiating event offers new opportunities for prediction, prevention, and therapy. This narrative review synthesizes mechanistic, epidemiological, and biomarker evidence accumulated over the past two years. Mechanistic studies reveal that defective decidualization and resistance to progesterone signaling impair stromal cell differentiation, angiogenic balance, and vascular remodeling. Immunological dysregulation, including maladaptive KIR–HLA interactions, CD40–CD40L pathway activation, and altered cytokine tolerance, further disrupts maternal–fetal communication. Clinical epidemiology strongly implicates implantation context: programmed frozen embryo transfer cycles lacking a corpus luteum consistently increase the risk of hypertensive disorders, highlighting the importance of peri-conception physiology. First-trimester biomarkers such as low PAPP-A, reduced PlGF, and abnormal uterine artery Doppler indices capture the early "fingerprint" of impaired implantation long before clinical disease. Emerging evidence also supports seminal plasma as a key modulator of immune priming and endometrial receptivity, with reduced exposure linked to higher PE risk. Together, these findings reframe PE not solely as a disorder of placental development in mid-gestation but as a disease with origins in implantation biology. By bringing together molecular, immunological, and clinical evidence, this review positions impaired implantation as a central trigger of PE. Recognition of implantation-era events as the upstream pathway provides a new framework for translational research, emphasizing peri-conception exposures, assisted reproduction practices, and biomarker discovery. Clinically, it highlights novel opportunities for early risk stratification and prevention strategies. This implantation-centered model may help shift the paradigm of PE from late-pregnancy diagnosis toward early-pregnancy prediction and intervention.