Analysis of Biomarkers for Congenital Heart Disease Based on Maternal Amniotic Fluid Metabolomics

Abstract

Congenital heart disease (CHD) is the most common birth defect. The prenatal diagnosis of fetal CHD is completely dependent on ultrasound testing, but only ~40% of CHD can be detected. The purpose of this study is to find good biomarkers in amniotic fluid (AF) to detect CHD in the second trimester, so as to better manage this group of people and reduce the harm of CHD to the fetus. Metabolites analysis were performed in two separate sets. The discovery set consisted of 18 CHD fetal maternal AF samples and 35 control samples, and the validation set consisted of 53 CHD fetal maternal AF samples and 114 control samples. Untargeted metabolite profiles were analyzed by gas chromatography/time-of-flight-mass spectrometry (GC-TOF/MS). Orthogonal partial least square discrimination analysis (OPLS-DA) demonstrated that CHD and control samples had significantly different metabolic profiles. Two metabolites, uric acid and proline, were significantly elevated in CHD and verified in two data sets. Uric acid was associated with CHD [odds ratio (OR): 7.69 (95% CI: 1.18–50.13) in the discovery set and 3.24 (95% CI:1.62–6.48) in the validation set]. Additionally, uric acid showed moderate predictive power; the area under curve (AUC) was 0.890 in the discovery set and 0.741 in the validation set. The sensitivity and specificity of uric acid to detect CHD was, respectively, 94.4 and 74.3% in the discovery set and 67.9 and 71.9% in the validation set. The identification of uric acid as a biomarker for CHD has the potential to stimulate research on the pathological mechanism of CHD and the development of a diagnostic test for clinical applications.

Biomarkers for isolated congenital heart disease based on maternal amniotic fluid metabolomics analysis

“…However, these studies used infant or childhood serum samples as material to explore the relationship between metabolites and CHD, and it is relatively rare to study the occurrence of CHD through biological samples obtained from pregnant mothers. Previous studies reported that maternal serum [ 17 ], urine [ 18 , 19 ], and amniotic fluid (AF) [ 20 ] were used to detect metabolites by [ 1 ] H NMR or GC–MS technology. However, these methods for detecting metabolites are more limited than those detected by UHPLC‒MS.…”

“…Previous studies have used biological samples such as maternal serum [ 17 ], urine [ 18 , 19 ], and amniotic fluid (AF) [ 20 ] to detect metabolites for exploring biomarkers of congenital heart disease. However, the types of detectable metabolites are limited.…”

The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses

“…A further study used an untargeted approach to explore whether mid-pregnancy urinary metabolites could accurately discriminate CHD cases from the controls (N = 70 CHD cases and 70 controls) and found that two principal components separated the cases and the controls, with 4-hydroxybenzeneacetic acid, 5-trimethylsilyloxy-n-valeric acid, hydracrylic acid and propanedioic acid driving their differences [ 11 ]. Finally, a study in a Chinese population of metabolomic analyses using maternal amniotic fluid (N = 71 CHD cases) found that two metabolites (uric acid and proline) had higher concentrations in CHD affected pregnancies [ 12 ]. In summary, to date there have been few pregnancy metabolomic studies exploring the potential molecular causal mechanisms of CHD.…”

The relationship of maternal gestational mass spectrometry-derived metabolites with offspring congenital heart disease: results from multivariable and Mendelian randomization analyses

“…Replication of these results are warranted. A recent retrospective study in a Chinese population performed metabolomic analyses using maternal amniotic fluid and found that two metabolites (uric acid and proline) were elevated in CHD affected pregnancies 12 . In summary, there have been studies uncovering potentially important biological pathways associated with offspring CHDs.…”