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Review of AMA Recommendations on Folic Acid Supplementation

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This report responds to Resolution 526 (A-98), which was introduced by the Section on Medical Schools and adopted by the House of Delegates, and Resolution 506 (I-98), which introduced by the Medical Student Section and referred to the Board of Trustees. Resolution 526 asked that the American Medical Association (AMA) update Council on Scientific Affairs (CSA) Report 5 (I-95), entitled "Folic Acid Relationship to Spinal Closure Birth Defects and Adult Vascular Disease"; recognize recent new understanding of the role of folic acid in preventing neural tube defects (NTD), cardiovascular disease, and colorectal cancer; and review the revised recommendations on Dietary Reference Intakes, especially for dietary folate and supplemental folic acid, issued by the Institute of Medicine Food and Nutrition Board. Resolution 506, asks "That the AMA encourage research efforts to identify and monitor those populations potentially at risk for masking Vitamin B₁₂ deficiency through routine folic acid supplementation of enriched food products." 

Introduction and Overview 

At about the time CSA Report 5 (I-95) was released, the Food and Drug Administration (FDA)^1,2 recommended that enriched cereal grains be fortified with folic acid to reduce the incidence of NTD, such as spina bifida and anencephaly. The recommendation became effective January 1, 1998. In implementing this proposal, the FDA chose to follow its Advisory Committee's recommendations for a fortification level of 140 µg of folic acid per 100 g of enriched cereal grain. This level represents amounts that are 2 to 4 times that needed to restore amounts of folate lost during milling and refining. This fortification level was established based on the results of food consumption surveys and a goal of having 95% of the population not exceed a daily total folate intake of 1 mg. 

Because the oral bioavailability of folate is 50% less than that of folic acid, and because folic acid supplements up to 1 mg are available for purchase without a prescription, the Centers for Disease Control and Prevention Working Group on Folic Acid used a boundary maximum of 1 mg of folic acid, rather than total folate, in their modeling efforts to estimate an optimal level of fortification. An optimal level was defined as one that would prevent the maximum number of NTDs, yet still assure that 95% of the population would not exceed a daily consumption of 1 mg of folic acid. The Working Group estimated that a fortification level of 140 mg of folic acid per 100 g of cereal grain would assure that 33% of women of reproductive age in the United States would achieve a daily folic acid consumption of at least 400 mg. This value is a small increase over the current fraction of the population of childbearing women (about 30%) who achieve this level of consumption through the use of multivitamin supplements. This small increase would effectively prevent 4% to 20% of NTDs. In contrast, a folic acid cereal grain fortification level of 350 mg per 100 g cereal would increase the proportion of women of childbearing age consuming the recommended level of 400 mg of folic acid to nearly 50%, thereby preventing an estimated 27% to 48% of NTDs preventable by folic acid, while still satisfying population criteria for preventing daily intake in excess of 1 mg folic acid. 

While even higher levels of folic acid intake among a larger proportion of women of childbearing age would further decrease NTD risk, fortified foods are consumed by the entire population, including children and the elderly, and not just the targeted group. The inherent concern is the potential for adverse effects in non-targeted groups. Another potential problem is the increase in risk for people with low vitamin B₁₂ status for the neurological complications of undiagnosed pernicious anemia. Further, the long-term effects of high doses of folates are unknown. The FDA recommendation of a relatively low fortification level of folic acid is considered an optimal one and takes into account the need to maximize the reduction in risk for NTD while at the same time minimizing safety concerns. 

Recent studies ^3-7 have shed light on the interaction among folic acid, vitamins B₁₂ and B₆ and homocysteine concentrations, and the risk of Alzheimer and vascular disease, including multi-infarct dementia, coronary artery disease, cerebrovascular disease and peripheral arterial disease. Other published data ^8-11 indicate that low folic acid status increases the risk for colorectal neoplasia and other gastrointestinal diseases, which suggests a potential benefit of increased consumption of folic acid for a larger segment of the population. 

Methods 

The MEDLINE database was searched for English-language articles published between 1995 and the present, limited to those discussing human subjects, using "folic acid" as the major heading and "adverse effects," "contraindications," "poisoning," and "toxicity" as subheadings. Based on recent concerns that high intake of folic acid may mask vitamin B₁₂ deficiency, and to further explore the metabolic interrelationships between folic acid, vitamin B₆, and vitamin B₁₂, a secondary search was conducted using the strategy: "vitamin B₁₂ and folic acid and (pyridoxine or pyridoxal or pyridoxamine). Two additional searches were conducted using the terms "folic acid and Alzheimer disease" and "folic acid and colorectal cancer." Other sources of information included review of references listed in relevant publications, search of the World Wide Web, and consultation with experts. Approximately 70 documents were retrieved for analysis. 

Folic Acid and Neural Tube Defects 

The average US diet provides from 50 to 500 µg of absorbable folate per day, mostly from green leafy vegetables and meat. However, the bioavailability of folate occurring naturally in a mixed diet varies, and supplemental folic acid is about twice as bioavailable as folate in food.¹² As of January 1998, all enriched cereal grain sold in the United States is fortified with 140 µg of folic acid per 100 g of grain.² It is estimated that this amount will increase folic acid intake by approximately 100 µg daily. However, this level of fortification may not be sufficient to prevent the majority of NTD, which occur very early in pregnancy (3 to 4 weeks after conception), before most women realize they are pregnant.¹³ Additionally, women who have had a previous child with NTD are at greater risk for having a subsequent child with NTD and a higher supplementation of folic acid--from 4 to 5 mg daily--is recommended in these cases.^14-15 

The US Public Health Service ^16,17 stresses the importance of folic acid as a preventive measure against NDT and recommends that all women who are capable of becoming pregnant consume 0.4 mg of folic acid daily, while limiting total consumption to less than 1.0 mg daily. It is estimated that if all women of reproductive age were to consume 0.4 mg of folic acid daily, the incidence of NTD would be reduced by up to 70%. The 1998 report ¹⁸ from the Institute of Medicine on Dietary Reference Intakes (formerly known as recommended dietary allowances ¹⁹), also includes a recommended intake of 400 µg of folic acid daily (from supplements and/or fortified foods, in addition to a varied diet) for women who might become pregnant. The report emphasizes the need for extra folic acid prior to conception and during the first month of pregnancy, when the neural tube develops. 

Findings from one recent study shed new light on the relationship between folic acid and NTD. Steegers-Theunissen et al ²⁰ studied maternal blood and amniotic fluid concentrations of folic acid, vitamins B₆ and B₁₂, and homocysteine in relation to NTD. Concentrations of the various substances were measured in maternal blood and amniotic fluid of 27 women carrying fetuses with an NTD and 31 women carrying healthy fetuses. The mean homocysteine concentration was higher in the amniotic fluid of the study group than in the controls. There were no significant differences between the groups in mean concentration of any of the vitamins or homocysteine in maternal blood, suggesting that the cause of NTD could reside in a derangement of primary or secondary maternal or fetal homocysteine metabolism. 

Relationship of Folic Acid, Vitamins B₆, B₁₂ and Homocysteine 

Detailed information and discussion about the metabolic interrelationships among folic acid, vitamins B₆ and B₁₂, and homocysteine were presented in CSA Report 5 (I-95). Therefore, only a brief overview is given here. The amino acid homocysteine is dependent on vitamins B₆, B₁₂ and folic acid for metabolism.²¹ In the presence of inadequate intake of any of these co-enzymes, elevated blood homocysteine concentration results, implying a functional relationship to hyperhomocysteinemia. Elevated homocysteine concentrations have been linked to cardiovascular disease (CVD), stroke, cancers, and dementing disorders. ^12,22 

Plasma homocysteine is a sensitive biomarker of folate deficiency, with a strong inverse relationship: the lower the homocysteine concentration, the higher the folate level;²³ and hyperhomocysteinemia has been implicated as an independent risk factor for cardiovascular⁶ and Alzheimer disease.⁷ Because homocysteine metabolism is reliant on enzymatic action derived from folate and vitamin B₁₂ co-factors (tetrahydrofolate and cyanocobalamin, respectively), there is a ready biochemical explanation for these associations, although the precise mechanisms are not clearly understood.²⁴ 

Folic Acid and Vitamin B₁₂ Deficiency 

A major concern about fortification of grains and other foods with folic acid, and the recommended increased Dietary Reference Intake of this vitamin, is the potential to mask anemia caused by vitamin B₁₂ deficiency states.^5,25 Masking of a deficiency can delay diagnosis and has particular implications for older adults. Due to absorption problems, the elderly have a higher prevalence of vitamin B₁₂ deficiency that, if untreated, can lead to irreversible neurological damage.²¹ Other high risk groups for vitamin B₁₂ deficiency are patients with acquired immunodeficiency syndrome, those taking medications over long periods for ulcers, and those who have had stomach or small bowel resection.¹⁴

In a review article, Campbell¹⁰ points out that routine hematologic indices have a low sensitivity for vitamin B₁₂ deficiency, in paricular in patients who receive folic acid supplements. Thus, it is important for physicians to be especially vigilant in these cases. Undiagnosed pernicious anemia is prevalent in about 2% of the elderly and is more common among women, both black and white.⁴ This cohort would be at possible risk for undetected cobalamine deficiency if large amounts of folate were consumed. In general, while there is a potential risk that folate supplementation can mask cobalamine deficiency, data suggesting that folate supplements are unsafe are not based on controlled studies. On the other hand, increased folate intake could potentially benefit the elderly because of its inverse association with homocysteine. As has been noted, elevated homocysteine concentrations are independent risk factors for coronary heart disease (CHD) and stroke.²¹ 

Potential Risk Factors for Cardiovascular Disease 

In a recent large prospective (14-year) cohort study on women,²⁶ the 20% who had the highest intake of folate from multivitamin consumption had a significantly lower incidence of mortality and morbidity from CHD, compared to those in the lowest quintile. Findings from this study suggested that folate and vitamin B₆ intake above the recommended dietary allowance might be an important primary preventive strategy against CHD in women. One cross-sectional population study ²⁷ found that plasma homocysteine correlated with known risk factors for arteriosclerosis, including smoking, elevated serum cholesterol, limited physical activity, and so on. 

Several epidemiological studies confirm a relationship between elevated homocysteine and atherosclerosis, as well as thromboembolic disease. Shimakawa et al ²⁸ analyzed dietary intake of folate, vitamin B₆ and vitamin B₁₂ in a case-control study of 660 middle-aged individuals to ascertain whether vitamin intake is a determinant of plasma homocysteine concentration. The cases were 322 men and women with carotid artery atherosclerosis. An inverse relationship was found between homocysteine and each of the vitamins, all three of which are involved in homocysteine metabolism. Interestingly, in both cases and controls, those using supplemental vitamins had lower concentrations of homocysteine.

In another major epidemiological study on men and women aged 25 to 65 years,²⁹ homocysteine concentrations among cases diagnosed with coronary atherosclerosis (with occlusion > 90% in one artery and > 40% in a second artery) were compared to controls who had < 50% occlusion in only one artery. Findings from this study support a positive association between coronary artery occlusion and plasma homocysteine, with a strong relationship between degree of occlusion and concentration of homocysteine. Numerous other authors ^30-35 have similarly noted the relationship between plasma homocysteine and morbidity and mortality from CHD. 

In a prospective study of 21,000 men, Wald et al ³⁶ analyzed data from 229 men without a history of ischemic heart disease at study entry, who subsequently died. These were compared to age-matched controls in a nested case-control design. Conclusions from this study were that the association between homocysteine concentration and ischemic heart disease is probably a causal one and that a general increase in folate consumption, which would lower homocysteine concentrations, would be expected to reduce mortality from heart disease. 

Elevated homocysteine concentrations have also been implicated as a risk factor for deep venous thrombosis (DVT).⁷ In a case-control format, Den Heijer and colleagues ^37,38 determined the plasma homocysteine concentrations of 269 patients with DVT and the same number of controls. More than twice as many of the cases had elevated homocysteine concentrations compared to the controls, 28 and 13, respectively (p=.001). It is unclear whether homocysteine is just a marker for imminent CVD or whether it is a toxic metabolite involved in the atherosclerotic process. Some studies have shown that homocysteine acts as a toxin to the vascular endothelium, that it facilitates oxidation of the low density lipoprotein molecule and thus encourages formation of atherosclerotic plaques.^15,39 

Findings from recent studies support the view that, with intervention through supplementation, food fortification, and improved nutritional intake of vitamin B₆ and folate, cadiovascular morbidity and mortality will continue to decline. What remains to be determined is whether interventions to lower plasma homocysteine concentrations are effective in lowering the risk of vascular disease. This question will be elucidated when the results of ongoing multi-center trials become available. 

Potential Risk Factors for Alzheimer Disease 

Several recent reports ^7,40-42 describe an association between homocysteine and Alzheimer disease (AD). Clarke and colleagues ⁷ via a case-control study design examined homocysteine concentrations in patients whose diagnosis of AD was confirmed pathologically. This precluded the explanation that the association was related to the misdiagnosis of AD instead of vascular dementia. Findings showed a 2-fold increased risk of developing AD for patients in the top third of the serum homocysteine distribution. In this study, there was an inverse correlation between serum folate and vitamin B₁₂ concentrations and the risk for AD, which supports the homocysteine hypothesis. In considering the mechanistic relationship between homocysteine and AD, it is hypothesized that homocysteine and its metabolite, homocysteic acid, have acute toxic effects on neurons.⁴¹ Another consideration is the finding that the Î4 allele of apolipoprotein E (apoE), a risk factor for AD, is also a risk factor for CVD, and the presence of both may interact in the etiology of AD.^43,44 

Folate and Colorectal Cancer 

Recent studies explored the relationship between folic acid and the risk of colorectal cancer. Lashner et al ⁴⁵ examined the effect of folic acid supplements on the risk of cancer or dysplasia in patients with ulcerative colitis. In a case-control study, patients who had taken daily folate supplements had a lower risk of neoplasia with a dose-response effect. Another case-control investigation ¹¹ based on 236 cases with adenomatous polyps or cancer and 409 controls surveyed the patients using a food frequency questionnaire to determine nutrient intake. Folate was the most protective micronutrient, with women in the highest intake group being only half as likely to develop adenomas. Ma et al ⁸ similarly found an association between low plasma folate status and increased risk for colorectal cancer. 

Nutrition Recommendations: Summary of Current Concepts 

Folate. The Institute of Medicine (IOM)¹⁸ has increased the Dietary Reference Intake for folate to 400 µg of food folate daily for women who might become pregnant to reduce the risk of NTD. This may be obtained from fortified grains, vitamin supplements, or in combination. The IOM has also recommended this allowance for all adults because low folate intake is associated with heart disease and cancer. The maximum daily tolerable folate intake recommendation is set at 1,000 µg. These latest recommendations have been increased from the previous IOM Report (1989), which recommended concentrations of 200 µg for men and 180 for women. The majority of recent studies suggest that the latest IOM recommendation is an optimal concentration, effectively preventing NTD, while minimizing the potential negative effects of large amounts of folate-that of masking vitamin B₁₂ deficiency. Additionally, studies have shown an optimal cut-off concentration of serum folate to be effective in reducing homocysteine concentrations, beyond which no further benefit is derived. 

Vitamin B₁₂. Adults aged 50 years and older need to maintain vitamin B₁₂ concentrations, in addition to folate, and should get this vitamin from fortified foods and/or supplements. Between 10% to 30% of older people lose the ability to absorb vitamin B₁₂ from food as it occurs naturally; therefore supplementation or fortification is needed. Deficiency of this micronutrient can lead to gastrointestinal and neurological problems. The IOM recommendations are for people aged 50 years and older to reach a daily intake or eat fortified foods to meet the target of 2.4 µg of vitamin B₁₂. Since folate supplementation can mask the symptoms associated with B₁₂ deficiency, it is important to maintain adequate concentrations of this vitamin independent of folate. 

Vitamin B₆. Research shows that vitamin B₆ can lower homocysteine concentrations and thereby decrease the risk for CHD and other diseases. However, it is unclear whether increasing B vitamin intake directly lowers the incidence of CVD and colorectal cancer. Consumption of too much vitamin B₆ can cause sensory neuropathy, accompanied by pain and numbness in the limbs. An upper limit of 100 mg per day has been set for this nutrient.¹⁹ 

Conclusion 

With regard to NTD, government recommendations agree with those of the IOM on the specific level of folic acid intake required to prevent a majority of NTD. From 0.4 mg to less than 1 mg constitutes optimal amounts with regard to prevention and safety. The literature supports an association between homocysteine and CVD, colorectal cancer, and other diseases that is reversible with folate and/or vitamins B₁₂ and B₆ supplementation. However, further studies are needed to examine possible causal relationships among vitamin intake, homocysteine and associated diseases, and to address the question of appropriate levels of supplementation as well as whether genetic or other environmental factors play a role in hyperhomocysteinemia. Ultimately, prospective studies are needed to answer these questions as well as to determine the precise micronutrient needs of different populations at risk for specific diseases. Research also needs to address nutrient requirements for preventive measures, versus treatment of deficiency states. 

RECOMMENDATIONS

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegats as AMA policy at the 1999 AMA Annual Meeting. 

1. The AMA encourages the Centers for Disease Control and Prevention (CDC) to continue to conduct surveys to monitor nutritional intake and the incidence of neural tube defects (NTD).   
2. The AMA continues to encourage broad-based public educational programs about the need for women of child-bearing potential to consume adequate folic acid through nutrition, food fortification, and vitamin supplementation to reduce the risk of NTD.   
3. The AMA encourages the CDC and the National Institutes of Health to fund basic and epidemiological studies and clinical trials to determine causal and metabolic relationships among homocysteine, vitamins B₁₂ and B₆, and folic acid, so as to reduce the risks for and incidence of associated diseases and deficiency states.   
4. The AMA encourages research efforts to identify and monitor those populations potentially at risk for masking vitamin B₁₂ deficiency through routine folic acid supplementation of enriched food products.   
5. The AMA urges the Food and Drug Administration to increase folic acid fortification to 350 µg per 100 g of enriched cereal grain.   
6. The AMA encourages the FDA to require food, food supplement, and vitamin labeling to specify milligram content, as well as RDA levels, for critical nutrients, which vary by age, gender, and hormonal status (including anticipated pregnancy).