Plasma metabolomic and lipidomic profiles accurately classify mothers of children with congenital heart disease: an observational study.

Introduction: Congenital heart disease (CHD) is the most common congenital anomaly, representing a significant global disease burden. Limitations exist in our understanding of aetiology, diagnostic methodology and screening, with metabolomics offering promise in addressing these.

Objective: To evaluate maternal metabolomics and lipidomics in prediction and risk factor identification for childhood CHD.

Methods: We performed an observational study in mothers of children with CHD following pregnancy, using untargeted plasma metabolomics and lipidomics by ultrahigh performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). 190 cases (157 mothers of children with structural CHD (sCHD); 33 mothers of children with genetic CHD (gCHD)) from the children OMACp cohort and 162 controls from the ALSPAC cohort were analysed. CHD diagnoses were stratified by severity and clinical classifications. Univariate, exploratory and supervised chemometric methods were used to identify metabolites and lipids distinguishing cases and controls, alongside predictive modelling.

Results: 499 metabolites and lipids were annotated and used to build PLS-DA and SO-CovSel-LDA predictive models to accurately distinguish sCHD and control groups. The best performing model had an sCHD test set mean accuracy of 94.74% (sCHD test group sensitivity 93.33%; specificity 96.00%) utilising only 11 analytes. Similar test performances were seen for gCHD. Across best performing models, 37 analytes contributed to performance including amino acids, lipids, and nucleotides.

Conclusions: Here, maternal metabolomic and lipidomic analysis has facilitated the development of sensitive risk prediction models classifying mothers of children with CHD. Metabolites and lipids identified offer promise for maternal risk factor profiling, and understanding of CHD pathogenesis in the future.