1. Higher maternal levels of red blood cell (RBC) folate are associated with a reduced risk of offspring congenital heart disease (CHD).
2. Every 100-nmol increase in maternal RBC folate concentration was significantly associated with reduced CHD risk.
Evidence Rating Level: 1 (Excellent)
Study Rundown: CHD is the most common congenital defect worldwide. Current strategies in managing CHD include prenatal and postnatal screening for diagnostic management and surgery. Although, substantial efforts are currently required to identify major modifiable risk factors. Maternal folate supplementation is well-established to protect against neural tube defects and is a crucial nutrient for embryonic development. Critically, there is a gap in knowledge as to understanding the significant associations between folic acid supplementation and CHD. There is also a gap in knowledge as to understanding whether the biomarker, RBC folate, is associated with fetal heart development. Overall, this study found that higher maternal RBC folate is associated with a reduced risk for offspring CHD. This study was limited by occasionally missed diagnoses of asymptomatic or minor CHD cases, as well as RBC folate concentrations potentially not being directly comparable to previous studies using different measurement assays. There was also unmeasured and residual confounding. Nevertheless, these findings are significant, as they demonstrate that higher maternal RBC folate is associated with reduced offspring congenital heart disease risk, which can lead to changes in current recommendations for levels of folate supplementation.
Relevant Reading: Summary for Patients: Maternal Folate Level and Congenital Heart Disease
In-Depth [case-control study]: This prospective, nested, case-control study and 1-sample Mendelian randomization was conducted at 29 maternity institutions in 12 districts of Shanghai, China. The study included 197 mothers of offspring with CHD and 788 individually matched mothers of unaffected offspring. Patients with abnormal prenatal ultrasound scans in the second trimester were eligible for the study. Patients with simple patent foramen ovale, patent ductus arteriosus closed within 3 months of age, physiologic pulmonary branch stenosis resolved at postnatal follow-up, and atrial septal defect closed within 3 months of age were excluded from the study. The primary outcome measured was the association of continuous maternal RBC folate concentration with subsequent offspring CHD risk. Outcomes in the primary analysis were assessed via 1-sample Mendelian randomization using the MTHFR-C677T variant as the instrument variable, which is a well-established functional polymorphism related to folate metabolism. Based on the primary analysis, the case patients had lower median maternal RBC folate concentrations than control participants (714 nmol/L [interquartile range, 482 to 1008 nmol/L] vs. 788 nmol/L [557 to 1094 nmol/L]). After analysis, it was determined that maternal RBC folate concentrations were inversely associated with offspring CHD (adjusted Odds Ratio [OR] per 100 nmol/L, 0.93; 95% Confidence Interval [CI], 0.89 to 0.99). The Mendelian randomization showed that each 100-nmol increase in maternal RBC folate concentrations was significantly associated with reduced offspring CHD risk (OR, 0.75; 95% CI, 0.61 to 0.92). Overall, this study demonstrates that higher maternal RBC folate levels are associated with reduced risk for offspring CHD, suggesting that there should be higher target RBC folate levels than currently recommended.
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