Reduced serum acetyl-L-carnitine is associated with hypertensive disorders in women with gestational diabetes mellitus: a multi-omics study.

BACKGROUND: Gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP) are common metabolic complications during pregnancy. GDM is an independent risk factor for HDP, while HDP is a major contributor to maternal and perinatal morbidity and mortality. Reliable early tools for identifying women with GDM who are at risk of subsequently developing HDP remain limited. This study aimed to integrate metabolomic, lipidomic, and clinical data to identify reproducible candidate biomarkers associated with subsequently diagnosed HDP in women with GDM and to characterize the accompanying metabolic and lipidomic alterations. METHODS: In this prospective exploratory biomarker study, a discovery cohort (n = 128) and a validation cohort (n = 55) were recruited. Serum samples collected at 24-28 weeks of gestation were analyzed using untargeted and targeted metabolomics. Lipidomics was performed to complement the metabolomic analysis and characterize lipid-related alterations. A combined predictive model was constructed using logistic regression, and its predictive performance was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Untargeted metabolomics identified lower serum acetyl-L-carnitine (ALC) in the GDMHDP group than in the GDM group, and this difference was confirmed by targeted LC-MS/MS in the validation cohort. The combined ALC-diastolic blood pressure (DBP) model achieved an area under the curve (AUC) of 0.907 in the discovery cohort and 0.886 in the validation cohort. Adding ALC to DBP improved discrimination and reclassification in both cohorts. Multi-omics analysis showed complementary and partly distinct lipid associations with ALC and DBP. Lower ALC was associated with selected ceramide and monolysocardiolipin species, as well as with lipid patterns consistent with altered fatty-acid handling, whereas DBP showed a partly distinct pattern of lipid correlations. CONCLUSIONS: Reduced serum ALC at 24-28 weeks of gestation was reproducibly associated with GDM complicated by HDP. Combining ALC with DBP improved discrimination between GDMHDP and uncomplicated GDM, suggesting complementary metabolic and hemodynamic information. Given the modest number of GDMHDP cases and the single-center design, these findings should be interpreted as exploratory and hypothesis-generating; they support further evaluation of ALC as a candidate metabolic marker but require confirmation in larger independent cohorts.