Lowered Maternal and Paternal Plasma Concentrations of Choline are Associated with the Severity of Congenital Heart Defects in the Offspring

Background/Objectives: Congenital heart defects (CHD) are the most common structural birth defects that exhibit high heritability. Emerging evidence suggested that CHD are as-sociated with disruptions in one-carbon metabolism. In a family-based trio design, we in-vestigated whether maternal, paternal, and child plasma concentrations of choline, beta-ine, and folate were associated with CHD severity. Subjects and Methods: The study in-cluded 72 children with CHD, 69 mothers and 64 fathers of the children. CHD severity was classified according to the European network of population-based registries for the epidemiological surveillance of congenital anomalies (EUROCAT) system and the Ger-man PAN study (Prevalence of Congenital Heart Defects in Newborns). Plasma and urine concentrations of choline and betaine and plasma folate vitamers were quantified using ultra-performance liquid chromatography–tandem mass spectrometry. Results: The chil-dren [mean (SD) age 3.1 (3.2) years, 59.7% males] presented with varying CHD severities according to EUROCAT (62.5% severe and 37.5% mild) and PAN classifications (45.8% severe, 30.6% moderate and 23.6% mild). Plasma concentrations of choline were < 10 µmol/L in 38 (66.7%) of the mothers and 27 (62.8%) of the fathers who provided blood samples. Maternal plasma choline concentrations < 10 µmol/L were associated with hav-ing a child with severe CHD [adjusted odds ratio (aOR) 3.7; 95% confidence intervals (95%CI) = 1.1, 12.2 compared to mothers with choline concentrations ≥ 10 µmol/L]. Low-ered paternal plasma choline concentrations were also associated with severe CHD (aOR 7.4; 95% CI = 1.7, 31.5). Plasma concentrations of choline in the children and those of be-taine and folate vitamers in parents and children were not associated with CHD severity. Conclusions: Lower plasma concentrations of choline in the parents detectable several years after conception, were related to having a child with severe CHD compared with families of children with higher plasma choline. These findings support a potential role for maternal and paternal choline metabolism in modulating CHD severity. Etiological studies aiming at prevention of prevalent congenital anomalies should focus on maternal and paternal risk factors.