Maternal metabolomic profiling and congenital heart disease risk in offspring: A systematic review of observational studies

Aetiological understanding and screening methods for congenital heart disease (CHD) are limited. Maternal metabolomic assessment offers the potential to identify risk factors and biomarkers. We performed a systematic review (PROSPERO CRD42022308452) investigating the association between fetal/childhood CHD and endogenous maternal metabolites. Ovid-MEDLINE, Ovid-EMBASE and Cochrane Library were searched between inception and 06/09/2022. Case control studies included analysing maternal blood or urine metabolites in pregnancy or postpartum where there was foetal/childhood CHD. Risk of bias assessment utilised the Scottish Intercollegiate Guidelines Network methodology checklist and narrative synthesis was performed. A total of 134 records were screened with eight eligible studies (n = 3242 pregnancies, n = 842 CHD-affected offspring). Five studies performed metabolomic analysis in pregnancy. Metabolites distinguishing case and control groups spanned lipid, glucose and amino-acid pathways, with the development of sensitive risk prediction models. No single metabolite consistently distinguished cases and controls across studies. Three studies performed targeted analysis postnatally with altered lipid and amino acid metabolites and raised homocysteine and markers of oxidative stress identified in cases. Included studies reported small sample sizes, analysing different biosamples at variable time points using differing techniques. At present, there is not enough evidence to confidently associate maternal metabolomic profiles with offspring CHD risk. However, several identified pathways warrant further investigation.