Folic Acid, Neural Tube Defects, and Congenital Heart Defects

Neural tube defects (NTDs) are among the most common major malformations in the United States. Daily folic acid supplementation in the periconceptional period significantly reduces the risk of neural tube defects.  However, most women do not receive the recommended daily intake of folate from diet alone; thus, it is recommended that all women of childbearing age should take supplemental folic acid.

Since half of all pregnancies in the US are unplanned, the US Preventive Services TAsk Force recommends that all women who are capable of getting pregnant should take a daily supplement or multivitamin containing 0.4 to 0.8 mg (400 to 800 mcg) of folic acid.  In terms of preventing neural tube defects, the critical period for supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy.

Folic Acid and Congenital Heart Defects

While the initial impetus to fortify grains with folic acid and to recommend folic acid supplementation during pregnancy was driven by a desire to lower risk for neural tube defects, there is increasing evidence to indicate that periconceptual use of folic acid may have other benefits.

For example, periconceptual use of folic acid has been shown to decrease risk for congenital heart defects (CHDs).  There is considerable variation in the magnitude of the effect across studies, with some studies suggesting a greater than 50% reduction in risk (Obeid et al, 2019); however, a recent meta-analysis estimated that periconceptual folate supplementation was associated with an approximately 20% reduction in risk of CHDs (Cheng et al, 2022).  Similar to what has been observed for NTDs, the reduction in risk is most evident when folic acid supplementation is initiated before conception.

Folate Levels Predict Risk for Neural Tube Defects

The concentration of folate in red blood cells (RBC) is thought to be a more accurate measurement of folate status.  While RBC folate levels fluctuate according to diet and folate supplementation, RBC folate levels are a better indicator of tissue stores of folate and may therefore be less susceptible to rapid changes in the diet as compared to serum folate levels.

Only two studies have examined the association between maternal RBC folate concentrations during pregnancy and risk for NTD risk.  Both studies observed that higher RBC folate concentrations in early pregnancy were associated with a lower NTD risk.  While there is no established cut-off value for RBC folate concentrations, Crider and colleagues observed that with a RBC folate concentration of 500 nmol/L the estimated risk of a neural tube defect was 25.4 (20.8 to 31.2) per 10?000, whereas at a RBC folate concentration of 1200 nmol/L the estimated risk was more than fourfold lower at 5.8 (4.6 to 7.1) per 10?000.

The risk was substantially attenuated at estimated red blood cell folate concentrations above 1000 nmol/L (for example, 6 neural tube defects per 10?000 births at 1180 (1050 to 1340) nmol/L). Our results indicate that a red blood cell folate concentration of roughly 1000-1300 nmol/L might achieve optimal prevention of folate sensitive neural tube defects, with a resulting overall risk of neural tube defects of about 6 per 10?000. This range could be useful in the development and monitoring of folic acid fortification programs.

The World Health Organization (WHO) recommends that ed blood cell folate concentrations should be above 400 ng/ml (or 906 nmol/L) in women of reproductive age to achieve the greatest reduction of NTDs.  Current recommendations indicatie supplementation with 400 mcg to 800 mcg of folate; typically we do not assess serum or RBC folate levels proximate to the time of conception.

More Folic Acid May Be Required to Reduce Risk for CHDs    

Evidence for the prevention of CHDs using prenatal folate supplementation is not as strong as that observed for the prevention of NTDs.  One possible explanation is that a higher dose of folic acid may be required to reduce risk of CHDs than for NTDs.   A recent study from China looked at risk of congenital heart defects and folate status, using RBC folate concentrations as a more accurate measurement of folate status (Chen et al, 2022).  

In this nested case control study, 197 mothers with offspring with a CHD were compared to 788 individually matched mothers of unaffected offspring from the SPCC (Shanghai Preconception Cohort).  Maternal RBC folate was measured before or during the early stages of pregnancy. 

Mothers who had a child with a congenital heart defect had lower maternal RBC folate concentrations than the controls (mothers of children without CHD).  Mean maternal folate levels were 714 nmol/L [interquartile range, 482 to 1008 nmol/L] in the cases versus 788 nmol/L [557 to 1094 nmol/L]) in the unaffected controls. 

Maternal RBC folate concentrations were inversely associated with risk for offspring CHD. The adjusted odds ratio (OR) for mothers with periconception RBC folate concentrations of 906 nmol/L or more (vs. <906 nmol/L) was 0.61. Furthermore, each 100-nmol increase in maternal RBC folate concentration was associated with a reduction in offspring risk for CHD (OR, 0.75 [CI, 0.61 to 0.92]).

Should We Measure RBC Folate Levels Prior to Conception?

This is the first study to look at RBC folate concentrations and risk of congenital heart defects. The finding that higher periconceptual folate levels are associated with decreased risk of CHDs is consistent with previous studies examining risk of neural tube defects.  

Despite the unequivocal benefits of folic acid supplementation and recommendations urging all women of reproductive age to take folic acid supplements, preconceptual use of folic acid has not increased substantially.  The authors note that in a previous cross-sectional study in Chinese women, only 42.6% of women took the recommended 400 mcg of folic acid daily before pregnancy.  In this study, mean RBC folate levels were suboptimal in 90.1% of women planning for pregnancy.  In the United States, Tinker and colleagues observed that  22.8% of reproductive aged women had suboptimal RBC folate concentrations. 

Ruta Nonacs, MD PhD

References

Chen H, Zhang Y, Wang D, Chen X, Li M, Huang X, Jiang Y, Dou Y, Wang Y, Ma X, Sheng W, Jia B, Yan W, Huang G; SPCC (Shanghai Preconception Cohort) Group. Periconception Red Blood Cell Folate and Offspring Congenital Heart Disease : Nested Case-Control and Mendelian Randomization Studies. Ann Intern Med. 2022 Aug 23. 

Cheng Z, Gu R, Lian Z, Gu HF. Evaluation of the association between maternal folic acid supplementation and the risk of congenital heart disease: a systematic review and meta-analysis. Nutr J. 2022 Mar 26;21(1):20. 

Obeid R, Holzgreve W, Pietrzik K. Folate supplementation for prevention of congenital heart defects and low birth weight: an update. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S424-S433. 

Tinker SC, Hamner HC, Qi YP, et al. 2015. U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res. A Clin. Mol. Teratol. 103: 517–526.