In July 2013, the European Food Safety Authority (EFSA) issued a favorable opinion relating the effects of supplemental folic acid in women of childbearing age to a reduced incidence of neural tube defects (NTDs) in children.1 The European Union approved a health claim in line with EFSA’s favorable opinion that went into effect on November 18, 2014.
NTDs are birth defects in which the neural tube (the embryonic precursor to the central nervous system, including the brain and spinal cord) fails to close completely during the fourth week of embryonic development. The most common NTDs include spina bifida (an opening in one or more of the bones of the spinal column) and anencephaly (a failure of the neural tube to close at the head).2
While several authoritative bodies from other countries around the world have already recognized the beneficial role of folic acid and folates from foods and supplements in the prevention of NTDs, this is significant news in that prior to the EU approval, Europe had no officially sanctioned claim for a public health matter of such immense consequence.
“There is a previous health claim in the EU for folic acid improving maternal folate status,” observed Andrea Wong, PhD, vice president of scientific and regulatory affairs for the Council for Responsible Nutrition (CRN; Washington, DC). “The new health claim extends the previous claim to talk about the role of improved folate status in reducing the risk of NTDs.” Wong feels this is a significant step forward because the EU health claim is consistent with the message from the Institute of Medicine (IOM), Centers for Disease Control and Prevention (CDC), and other authoritative bodies in the United States and is consistent with the current FDA-approved health claim for folic acid and NTDs.
The EFSA opinion is also significant for women of childbearing age in that it serves to offer some clarity around an issue that has led to confusion for many women. In addition to specifying a supplemental amount of 400 micrograms (µg) of folic acid daily, the EFSA review further advises that this amount of supplemental folic acid needs to be consumed for at least one month before and for three months after conception in order to obtain the desired benefit of increasing maternal folate levels and thus reducing the risk of NTDs in the developing fetus. This specificity serves to reinforce the importance of consuming adequate folic acid at the appropriate time to achieve the full preventive effect, which is critical because many, if not most, women fail to consume a sufficient amount of foods that are naturally rich in folate.
The richest dietary sources of folate include dark green vegetables and legumes such as chickpeas, beans, and lentils.
Evidence of Prevention by Folate
Significant evidence exists showing that adequate folate status is associated with a reduction in the risk of NTDs.
The EFSA opinion relied heavily on a systematic review published in the Cochrane Library in 2010 and conducted by Luz Maria De-Regil from the World Health Organization and colleagues.2 The authors included five previously published studies comprising 6,105 women in drawing their final conclusions.
Overall, their analysis found a consistent protective effect of daily folic acid supplementation in preventing NTDs when compared to women in the placebo group, women in groups receiving no intervention, or those taking vitamin and mineral supplements without folic acid.
The authors further emphasize that the benefits of folic acid supplementation are dependent on the timing of the intervention and that the critical period for supplementation is before pregnancy occurs and for the first 12 weeks of pregnancy.
Of course, data from clinical trials and food fortification programs over the last decade or so have consistently shown a protective effect of achieving adequate maternal folate status before and during early pregnancy with respect to reductions in fetal NTDs. While many authoritative bodies recommend an intake of 400 µg/day during the crucial pre-conception and post-conception periods, various studies have used differing doses to show a protective effect.
In a recent paper published in the British Medical Journal, Krista Crider and colleagues from the CDC and from several institutions in China reviewed data from two Chinese studies (the Community Intervention Project and the Folic Acid Dosing Trial) as well as an Irish study (authored by Leslie Daly and colleagues, published in JAMA in 1995) and confirmed the link between higher concentrations of folate and a reduction in NTDs.3
The researchers undertook this review to work towards the elucidation of an optimal concentration of red blood cell (RBC) folate (an accurate measure of body folate status), which could be used to determine the efficacy and success of folic acid fortification and supplementation programs from a public health perspective.
Additionally, while the public health message to women of childbearing age may still center around a targeted intake—400 µg/day, as recommended by many authoritative bodies—perhaps this optimal RBC folate concentration could be a target value that clinicians could use with their patients to assess whether an individual’s folic acid intake is sufficiently high to confer maximum protection against the development of NTDs.
The Community Intervention Project in China was a prospective study consisting of 247,831 women of childbearing age, while the Folic Acid Dosing Trial consisted of 1,194 women. The Irish study was used as a comparator because this was the only published study in which the association between RBC folate concentrations and the risk of NTDs had been directly assessed.
In doing their modeling, the research group found that the estimated risk of NTDs was highest at lower RBC folate concentrations (an estimated risk of 24.5 NTDs per 10,000 births at concentrations of 500 nmol/L), while the risk was significantly lower at RBC folate concentrations above 1000 nmol/L (an estimated risk of 6 NTDs per 10,000 births). The preventive benefits seemed to level off above RBC folate concentrations of 1300 nmol/L or more.
Thus, based on their modeling, the authors proposed an estimated optimal target RBC folate concentration for women of childbearing age of 1000–1300 nmol/L. Because these assumptions held true for multiple ethnic groups (Chinese vs. Irish) consuming varied diets, the investigators believe RBC folate concentration is a generalizable and consistent predictor of the preventive benefits associated with folic acid on NTDs.
Regardless of how one looks at the issue, it’s clear that folic acid is well-supported for reducing the occurrence of NTDs.
Yunni Yi and colleagues from the UK and Germany reviewed published literature to assess the economic burden of NTDs and the impact of prevention with folic acid.4 Yi’s group reviewed 10 studies evaluating the cost-effectiveness of folic acid supplementation or food fortification for the prevention of NTDs and found that the benefit : cost ratio in favor of folic acid supplements and fortified foods is substantial. For example, in the United States, the benefit : cost ratio was 4.3 : 1 in favor of folic acid, while it was even higher in other countries, with a ratio of 11.8 : 1 in Chile and 30 : 1 in South Africa. Given that each year there are nearly 400,000 infants worldwide born with spina bifida and anencephaly, the ability to prevent a large percentage of these anomalies is significant.
Although NTDs have multiple causes, studies suggest that between 50%–70% of all NTDs may be prevented with appropriate folic acid consumption before and after conception.
Mechanisms: Folate, Methylation, and NTDs
While the development of NTDs involves many factors, the role that DNA methylation plays in the process has recently gained research importance. DNA methylation is the process of adding a methyl group (a single carbon atom bonded to three hydrogen atoms) to DNA molecules and is a process used by cells to control gene expression. Methylation is intimately involved in the early stages of embryo development. It is also clear that folates play a substantial role in the methylation of DNA.
A recently published article by Henk Blom and Yvo Smulders from VU University Medical Centre in Amsterdam reviews the evidence linking under-methylation to the development of NTDs in animal models as well as the evidence for under-methylation in mothers with pregnancies affected by NTDs.5 The researchers point to evidence where specific genotypes, including the MTHFR 677TT genotype (the methylenetetrahydrofolate reductase gene encodes the MTHFR enzyme, which is involved in the methylation of homocysteine to methionine), have been shown to result in an overall reduction of DNA methylation and lead to decreased availability of the active form of folate, 5-methyl-tetrahydrofolate. This genotype in turn has been shown to be a genetic risk factor for NTDs, providing support for the important role of under-methylation in their development.
Additional evidence is provided by animal models, including mice and chicks, where a disruption of a critical step in the methylation process resulting in under-methylation led to developmental defects, including NTDs in mice as well as cranial closure defects in chick embryos. Furthermore, studies in women pregnant with an NTD child have shown that key measurements of DNA methylation are decreased, indicating an under-methylated state.
Although more evidence is needed to continue to sift through other potential mechanisms of folate’s protective role, it follows that providing adequate folate to enhance methylation would reduce the risk of NTDs.
Folate Nutrition Labeling and Public Health Implications
With such a substantial public health impact associated with ensuring adequate intake of folic acid, it is crucial that public health authorities convey their message to women of childbearing age in a unified, singular, and clear fashion. The EU claim goes a long way in making progress towards that goal. However, recent proposed changes to Nutrition Facts and Supplement Facts labeling of food and dietary supplements in the United States have some researchers with interest in the field of maternal nutrition and folic acid concerned.
FDA’s proposed rule calls for a change in the units of measure for supplemental and food sources of folic acid from the current micrograms (µg) of folic acid to µg of dietary folate equivalents (DFE) instead.
These proposed units of measure, DFE, account for the differences in absorption between naturally occurring food sources of folate and the more absorbable synthetic folic acid used in fortified foods and supplements. While DFE are a more accurate measure of folate activity, public health advocates and researchers are concerned by the confusion that this change in labeling may cause to women looking to consume adequate folate through foods and supplements.
As an example, a label declaration of folate as 400 µg DFE (new proposed units) is only equivalent to 235 µg of added folic acid (current units). Given that the daily target recommendation of folic acid for the prevention of NTDs by public health authorities is 400 µg, it’s possible that women, confused by the new units, may take 400 µg DFE and in so doing end up getting inadequate amounts of folic acid.
“The very successful public health message to women of childbearing age for the prevention of NTDs is to consume at least 400 µg folic acid daily in addition to a healthy, folate-rich diet,” comments Martha Field, PhD of Cornell University, whose research focuses on folate and how deficiencies result in adverse disease-related outcomes. According to Field, “The change in the nutrition label from µg folic acid to DFE may create consumer confusion because it differs from the current public health message and makes the label less useful to women of childbearing age.” To this end, organizations, including CRN and the American Society of Nutrition (ASN), have submitted comments on FDA’s proposed new rule expressing similar concerns regarding the change in folate units to DFE. Both organizations have strongly encouraged FDA to retain the current µg units of measure for folic acid to avoid this confusion.
With the EU now on board with other authoritative bodies around the world regarding the profound impact of adequate folate status on NTDs, it is more important than ever to ensure that consumers clearly understand the benefits—and the risk of inadequate intake—whether this is through food fortification or supplementation programs.
- EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on the substantiation of a health claim related to increasing maternal folate status by supplemental folate intake and reduced risk of neural tube defects pursuant to Article 14 of Regulation (EC) No 1924/2006. EFSA J. 11, 3328 (2013)
- De-Regil LM, et al., “Effects and safety of periconceptional folate supplementation for preventing birth defects,” The Cochrane Database of Systematic Reviews, 2010: CD007950
- Crider K. S. et al., “Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model,” British Medical Journal. Published online July 29, 2014
- Yi Y et al., “Economic burden of neural tube defects and impact of prevention with folic acid: a literature review,” European. Journal of Pediatrics, vol. 170, no. 11 (November 2011): 1391–1400
- Blom H J et al., “Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects,” Journal of Inherited Metabolic Disease, vol. 34, no. 1 (February 2011): 75-81
Photo © iStockphoto.com/Empato. Edited by Quinn Williams.