Serum metabolomics in early pregnancy differentiates between gestational hypertension and preeclampsia.

BACKGROUND: Early identification of pregnancies at risk for gestational hypertension (gHTN) and preeclampsia (PE) remains a major clinical challenge. We investigated whether early‑pregnancy serum metabolomic profiles differentiate gHTN and PE prior to clinical onset. METHODS: High-resolution metabolomics (HRM) analysis was performed on 126 early-pregnancy serum samples collected at ≤ 20 weeks' gestation from 97 pregnant women enrolled in the Placental Assessment in Response to Environmental Pollution study (PARENTs) cohort at UCLA. Metabolic profiles were compared among pregnancies that later developed gestational hypertension (gHTN; n = 14 mothers, 20 samples), preeclampsia (PE; n = 9 mothers, 11 samples), and pregnancies without ischemic placental disease (non-IPD; n = 74 mothers, 95 samples). Untargeted metabolome-wide association studies (MWAS) and pathway enrichment analyses were conducted. Multivariable linear regression models adjusted for key maternal and pregnancy characteristics such as maternal age, race/ethnicity, early-pregnancy BMI, fetal sex, and parity were used to evaluate associations. RESULTS: Distinct metabolic profiles differentiated gHTN and PE from non-IPD pregnancies. Alterations in the tryptophan metabolism pathway were observed in both gHTN and PE, with a significant dose-response relationship across groups (non-IPD > gHTN > PE, p = 0.008). Key metabolites, including tryptophan and its derivatives, were progressively depleted in association with increasing disease severity. Additionally, urea cycle metabolism was altered in gHTN, with higher levels of arginine and citrulline linked to nitric oxide production and vascular tone regulation. Comparisons between PE and gHTN revealed additional differences, including lower concentration of phenylalanine and pantothenic acid in PE, suggesting distinct metabolic alteration. CONCLUSION: Early‑pregnancy metabolomic signatures reveal both shared and condition‑specific metabolic pathways underlying gHTN and PE, with tryptophan metabolism showing a dose-response relationship indicative of disease severity. These early gestational alterations may serve as biomarkers for hypertensive disorders of pregnancy (HDP), enabling closer monitoring and stratification in high-risk pregnancies. Further studies in larger cohorts are needed to validate these findings and explore therapeutic implications.