Maternal circulating lipid metabolic heterogeneity in preeclampsia: machine learning identifies clinically distinct subtypes

Preeclampsia is associated with dyslipidemia. Maternal circulating lipid profiles may reflect underlying placental-metabolic interactions. We aimed to identify distinct maternal circulating lipid metabolic subtypes and assess their association with clinical outcomes among preeclamptic women. A retrospective cohort study of 1,124 women with preeclampsia (2018–2022) was conducted. Third-trimester serum lipids (total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)) were analyzed. Unsupervised k-means clustering (Euclidean distance, k = 4 optimized by consensus culmulative distribution function) was used to identify subtypes. Clinical characteristics and pregnancy outcomes were compared across clusters. We identified four lipid metabolic subtypes of preeclampsia with distinct clinical profiles. Four subtypes were identified: Cluster 1 (low metabolic subtype, LMS, 33.5%), Cluster 2 (high HDL subype, HHS, 35.0%), Cluster 3 (high triglyceride subtype, HTS, 11.7%), and Cluster 4 (high metabolic subtype, HMS, 19.8%). The HTS subtype with elevated triglycerides and highest pre-pregnancy body mass index (median 23.92 kg/m 2 ), had the lowest rates of preterm birth (3.1%, p = 0.016) and low birth weight (3.8%, p < 0.001). Conversely, the HMS subtype exhibited the highest blood pressure and proteinuria levels. This study establishes lipid-driven subtypes of preeclampsia with distinct clinical trajectories, suggesting placental lipid handling may be a key modulator in disorder heterogeneity. This heterogeneity underscores the importance of lipid-based stratification for understanding placental dysfunction in preeclampsia.