Researchers are continuing to investigate whether enhanced folate intake from foods or

folic acid supplements may reduce the risk of cancer.

ADVERSE EFFECTS OF FOLIC ACID SUPPLEMENTS

Although folate is safe and almost free of toxicity [73], concerns that folic acid

fortification could mask symptoms of vitamin B12 deficiency and precipitate neurological

complications have been raised [74]. Other examples of potential safety issues are the

interactions with drugs, hypersensitivity reactions, increase of twinning rate and genetic

selection [73, 74].

Folic Acid and Masking of B12 Deficiency

Folic acid is generally considered to be safe [73]. Although the risk of toxicity is low,

there are some concerns about its interaction with vitamin B12 [76]. Vitamin B12 deficiency

could affect up to 10–15% of the population over 60 years of age and it is often undiagnosed.

Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated.

Folic acid supplements can correct the anemia associated with vitamin B12 deficiency.

Unfortunately, folic acid will not correct changes in the nervous system that result from

vitamin B12 deficiency. The US Institute of Medicine [77] determined that there is suggestive,

but not conclusive, evidence that folic acid, in addition to masking vitamin B12 deficiency,

precipitates or exacerbates the neurological damage caused by vitamin B12 deficiency.

This concern is related to public health fears of introducing additional folic acid to the

whole population (through food fortification), and uncertainty about unforeseen risks,

especially in vulnerable groups such as children and also the elderly in whom vitamin B12

deficiency is a particular risk.

Recent evidence suggests, however, that small doses of folic acid (200 to 400μg daily)

are unlikely to cause this problem [78] The risk of "masking" the condition increases at folic

acid intakes exceeding 1,000μg a day [78]. The Institute of Medicine [77] has in fact

established a tolerable upper intake level (UL) for folate of 1,000 µg for adult men and

women, and a UL of 800 µg for pregnant and lactating (breast-feeding) women less than 18

years of age. Therefore, supplements should not exceed the UL to prevent folic acid from

masking symptoms of vitamin B12 deficiency. In fact, evidence that such masking actually

occurs is scarce, and there is no evidence that folic acid fortification in Canada or the US has

increased the prevalence of vitamin B12 deficiency or its consequences [74].

However, it could be important to be aware of the B12 status before taking a supplement

that contains folic acid.

Folic Acid and Health: An Overview 49

Folic Acid and Anticonvulsivant Drugs

Long-term antiepileptic phenytoin therapy can result in folate deficiency, whereas

supplementation with folic acid might lower serum phenytoin. No appreciable changes in

values of phenytoin drug concentrations were found in relation to food fortification in a large

trial in Canada [79]. Furthermore, evidence does not lend support to a substantial increase in

seizure frequency in patients who are treated with oral folic acid [75].

Folic Acid and Twinning Rates

The use of multivitamin supplements containing folic acid has been associated with an

increase in twinning rates [80-82]. Twin pregnancies are at greater risk for infant morbidity

and mortality [83]. This positive association may in part be explained by residual

confounding of in-vitro fertilization and ovarian stimulation, or by the effect of other

vitamins on the multivitamins consumed [84-86]. Post fortification twinning rates were not

higher in the USA [87, 89] and similarly, in the extensive intervention study in China, folic

acid supplements showed no effect [90]. This debate is not yet closed [91].

Folic Acid and Genetic Selection

It has been hypothesized that increased amounts of folic acid during the periconceptional

period could lead to a genetic selection by improving the survival of embryos carrying the

MTHFR 677C→T mutation. This could raise homocysteine concentrations if folate intake is

subsequently restricted in the child [92, 93].

Folic Acid and Hypersensitivity Reactions

A few case reports have described hypersensitivity reactions to oral and parenteral folic

acid, but most reactions were probably due to other components of the folic acid drug [94].

Folic Acid and Methotrexate for Cancer

Methotrexate is a drug used to treat cancer which interferes with folate metabolism;

infact, it inhibits the production of tetrahydrofolate, which is the active form of folic acid.

Unfortunately it can be toxic [95-97] and Folinic acid is a form of folate that can help

"rescue" or reverse the toxic effects of methotrexate [98]. Folic acid supplements have little

established role in cancer chemotherapy [99,100]. It is important for anyone receiving

methotrexate to follow medical advice on the use of folic or folinic acid supplements.

50 Rossana Salerno-Kennedy

Folic Acid and Methotrexate for Non-Cancerous Diseases

Low dose methotrexate is also used to treat a wide variety of non-cancerous diseases

such as rheumatoid arthritis, lupus, psoriasis, asthma, sarcoidoisis, primary biliary cirrhosis,

and inflammatory bowel disease [101]. Low doses of methotrexate can deplete folate stores

and cause side effects that are similar to folate deficiency. Both high folate diets and

supplemental folic acid may help reduce the toxic side effects of low dose methotrexate

without decreasing its effectiveness [102,103]. Anyone taking low dose methotrexate for the

health problems listed above should consult with a physician about the need for a folic acid

supplement.

CONCLUSION

It is only recently that folate deficiency has been associated with the risk of neural tube

defects (NTDs), cardiovascular disease, mental disorders and some forms of cancer; there is

not sufficient data available concerning the relationship with osteoporosis.

The evidence for a reduction in risk with increased folic acid intake is powerful for

NTDs and is increasing for cardiovascular disease. There may also be benefit in terms of

prevention of colorectal cancer and Alzheimer's disease, but more clinical trials are needed.

Findings suggest that folate supplementation might decrease or increase the risk of diseases

depending on dosage and timing, but there is also an emerging picture which takes in

consideration a more complex interaction of multiple nutritional and genetic factors.

Supplements are already recommended for women during the peri-conceptional period

but, given that not all women are happy to take it and that pregnancies may also be

unplanned, there is a need to ensure adequate folate intake by some other means. Food

fortification is one method, but strategies for increasing consumption of natural food folates

could also be explored and, in particular, whether sufficient amounts can be absorbed from

these foods to protect against disease. Finally, research in relation to safety issues of folic

acid fortification is required.

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