Red Blood Cell Folate and Offspring Congenital Heart Disease
- Higher periconception maternal RBC folate was significantly associated with a lower risk for offspring congenital heart disease (CHD).
- Furthermore, Mendelian randomization supported a causal role of maternal folate in reducing offspring CHD risk.
- Target RBC folate levels higher than those currently recommended for neural tube defect prevention may be advisable for primary CHD prevention if confirmed in future studies.
What is the association between periconception maternal red blood cell (RBC) folate and offspring congenital heart disease (CHD) risk?
The investigators conducted a prospective, nested, case-control study with one-sample Mendelian randomization (ClinicalTrials.gov: NCT02737644). Twenty-nine maternity institutions in 12 districts of Greater Shanghai, China were included. All 197 mothers of offspring with CHD and 788 individually matched mothers of unaffected offspring from the SPCC (Shanghai Preconception Cohort) were analyzed. Maternal RBC folate was measured before or at early pregnancy. Odds ratios (ORs) were estimated using conditional logistic regression after adjustment for covariates. Mendelian randomization was done using the methylenetetrahydrofolate reductase (MTHFR) C677T as the genetic instrument.
Case patients had lower median maternal RBC folate concentrations than control participants (714 nmol/L [interquartile range, 482-1008 nmol/L] vs. 788 nmol/L [557-1094 nmol/L]). Maternal RBC folate concentrations were inversely associated with offspring CHD (adjusted OR per 100 nmol/L, 0.93 [95% CI, 0.89-0.99]). The adjusted OR for mothers with periconception RBC folate of 906 nmol/L or more (vs. <906 nmol/L) was 0.61 (CI, 0.40-0.93). Mendelian randomization showed that each 100-nmol increase in maternal RBC folate concentrations was significantly associated with reduced offspring CHD risk (OR, 0.75 [CI, 0.61-0.92]).
The authors reported that higher maternal RBC folate is associated with reduced offspring CHD risk.
This nested, case-control study reports that higher periconception maternal RBC folate was significantly associated with a lower risk for offspring CHD. Furthermore, Mendelian randomization supported a causal role of maternal folate in reducing offspring CHD risk. These findings provide robust evidence supporting the preventive effect of periconception folic acid supplementation on CHD prevention. While further studies across different populations or ethnicities are indicated to support and verify these findings, target RBC folate levels higher than those currently recommended for neural tube defect prevention may be advisable for primary CHD prevention. Of note, evidence on adverse effects of excessive folate levels or unabsorbed folic acid on mother and fetus also needs to be assessed in future studies.
Clinical Topics: Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Prevention, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Nonstatins, Diet
Keywords: Blood Cell Count, Dietary Supplements, Erythrocytes, Fetus, Folic Acid, Heart Defects, Congenital, Maternal Behavior, Methylenetetrahydrofolate Reductase (NADPH2), Neural Tube Defects, Pregnancy, Primary Prevention, Risk
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