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.
RBC 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 than serum folate levels. While RBC folate levels do fluctuate according to diet and folate supplementation, RBC folate levels are a better indicator of tissue stores of folate over the previous 3 to 4 months and may therefore be less susceptible to day-to-day changes in folate intake than 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.
This study concluded that a RBC folate concentration of roughly 1000-1300 nmol/L might achieve optimal prevention of folate sensitive neural tube defects, with an estimated 87.9% reduction in the risk for NTD.
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; however, we typically we do not assess serum or RBC folate levels proximate to the time of conception to confirm adequate supplementation.
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 further reduction in offspring risk for CHD.
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 where RBC folate levels of 906 nmol/L or more were associated with an 87.9% reduction in the population risk for NTD (0.8 vs. 6.6 cases per 1000).
The current study found a 51.3% reduction in the estimated population risk for CHD when women attained RBC folate levels between 906 and 1132 nmol/L (vs. <226 nmol/L: 6.6 vs. 13.5 per 1000 births), with an additional 4.7% reduction in risk with RBC levels of 1360 nmol/L or more. The effect of RBC folate levels seemed to flatten out at higher levels, suggesting an approximate threshold with regard to offspring CHD risk. This finding is consistent with RBC folate concentrations and risk for NTDs, where RBC folate levels above 1300 to 1500 nmol/L provided little additional benefit.
Expanding on the evidence base for recommendations and guidelines about primary prevention of birth defects, the authors propose that higher target RBC folate levels than currently recommended might be advisable for periconception women to achieve the effect of primary CHD prevention. However, they note that before any changes to practice guidelines can be implemented, we must have a better understanding of the adverse effects of excessive folate levels or unabsorbed or unmetabolized folic acid on the mother and the developing fetus.
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.
As part of preconception counseling, the American College of Obstetricians and Gynecologists recommends that clinicians discuss diet and the importance of folic acid supplementation prior to pregnancy. At the first prenatal visit, blood testing includes a complete blood cell count and screening for rubella immunity, hepatitis B, syphilis and HIV.
In our area of New England, many pregnant women will receive blood tests for thyroid disease and vitamin D levels. Screening for thyroid disease is recommended in high-risk patients; however, universal screening is not standard of care. While studies indicate that vitamin D supplementation may decrease risk for some adverse outcomes in pregnancy, checking vitamin D levels is not universally recommended.
While the above findings may suggest that it would also be useful to measure RBC folate concentration and this could lead to decreased risk for NTDs and heart defects, it may be difficult to institute routine screening of folate status. More specifically, the first prenatal visit typically occurs between 6 and 12 weeks of gestation. At this point, the neural tube and heart have already formed, and supplementing with folic acid at this point would not have any impact on the risk of malformation.
Ruta Nonacs, MD PhD
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.