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Folic acid vitamin B9: Friend or foe?

Simmons, Susan, PhD, ARNP-BC

doi: 10.1097/01.NURSE.0000425875.00812.a6
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Folic acid helps prevent neural tube defects in the developing fetus, but what are the benefits and risks of bumping up folic acid levels in nonpregnant adults?

Susan Simmons is a family NP at College Park Family Care Center in Overland Park, Kan. Dr. Simmons is also a member of the Nursing2013 editorial board.

The author has disclosed that she has no financial relationships related to this article.

NURSES KNOW THAT pregnant women need to take folic acid supplements to prevent certain birth defects. But what about everyone else? Do other healthy adults need to take supplements of vitamin B9, commonly called folic acid, or do we get enough from our diet now that folic acid supplementation is mandated by law for certain foods? What are the risks, if any, from consuming too much folic acid?

A previous article, “To Be or Not to B? The Inside Scoop on Vitamin B12” (December 2012), dealt with vitamin B12 deficiency and supplementation. This article explores similar issues involving folic acid. (Although the term folic acid is used in this article, technically folates are naturally occurring substances, and folic acid is found in supplements.)1

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What's the role of folic acid?

Folic acid is a generic descriptor for over 100 coenzymes that are often called vitamers. As a coenzyme, folic acid is an important part of many cellular functions, especially the growth and repair of nervous system tissue, smooth muscle, and red blood cells.1

Folic acid is also important in maintaining normal levels of homocysteine, an amino acid that's a marker for cardiovascular disease and is associated with an increase in atherosclerosis, thrombosis, and myocardial infarction. Homocysteine is broken down by the B vitamins, especially folic acid and vitamins B12 and B6. However, lowering elevated homocysteine levels with supplemental vitamin B12, folic acid, and vitamin B6 doesn't lower the cardiovascular risk.2 Folic acid works closely with vitamin B12 to synthesize proteins and produce amino acids and genetic material. Folic acid is widely known for this last function: It prevents neural tube birth defects such as spina bifida and anencephaly.1

Extremely important in cell division, folic acid can prevent dysplasia (abnormal cell division or growth); this characteristic has prompted researchers to consider whether folic acid deficiency is linked to autoimmune diseases, cardiovascular diseases, and cancer. Patients at risk for folic acid deficiency include those with excessive alcohol intake or malnutrition.3

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Physical assessment and testing

In general, you won't find any signs or symptoms of folic acid deficiency during physical assessment unless the patient has anemia. Signs and symptoms of anemia, which are similar to those of anemia caused by B12 deficiency (with the exception of neurologic changes), include tachycardia, pallor, shortness of breath, fatigue, anorexia, and weight loss.3

Serum folate is measured to assess folic acid levels. A value of less than 4.5 nmol/L (in the absence of anorexia or fasting) is considered deficient.4 Folic acid deficiency has been rare in the United States since 1998, when certain foods, such as breads and cereals, were required to be fortified with folic acid. In that period, the overall prevalence of folic acid deficiency decreased from 16% to 0.5%.1

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Supplements versus natural folates

Because folic acid-fortified foods and supplements are readily available, the question is, How much of a good thing is too much? The higher a person's folate level, the more folic acid is left unmetabolized. This unmetabolized folic acid may interfere with folic acid's functions. The normal levels are generally assumed to be 40 to 50 nmol/L.1

Supplemental folic acid, found in both vitamins and fortified food, is a synthetic form of folate called pteroylmonoglutamic acid (PteGlu).1,5 This product is extremely stable, more bioavailable, and cheaper than folates from natural sources. (See Drawbacks of natural folate.)

PteGlu is metabolized into methylfolate, which is the normal form of the vitamin found in plasma. Unmetabolized PteGlu may mask vitamin B12 deficiency and increase the risk of insulin resistance and obesity in the offspring of pregnant women.1,6 Lifetime effects of exposure to unmetabolized PteGlu aren't known, but questions have been raised about an antifolate effect; that is, whether PteGlu might interfere with folate's beneficial effects.1

Since mandatory supplementation of foods began, potential problems have arisen, including increased cancer risk and mortality.57 In fact, many countries, including Great Britain, haven't mandated folic acid fortification because of these issues.

A less well-known form of folic acid, 5-methyltetrahydrofolate (5-MTHF), also known as folinic acid, may be beneficial for certain patients, such as those with depression or alcoholism and older patients with dementia that may be at least partially due to or affected by low folic acid levels. This form of folic acid may be less likely to mask anemia caused by vitamin B12 deficiency.8

The recommended daily requirement for folic acid for adults is 400 mcg. The amount needed increases during pregnancy and breastfeeding to 600 and 500 mcg, respectively. The safe upper limit for folic acid set by the Institute of Medicine is 1,000 mcg/day for adults.5 Be aware that folic acid can interact with other drugs and alcohol. (See Look out for interactions with folic acid.)

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Conflicting evidence on risks versus benefits

As is the case with vitamin B12, folic acid was thought to lower homocysteine levels. But after 5 years of widespread dietary supplementation with folic acid, vitamin B12, and vitamin B6, one study showed that the incidence of both cardiovascular disease and heart failure increased. On the other hand, in eight studies, stroke was shown to decrease with folic acid supplementation.1,9

Studies of patients with Alzheimer disease, vascular dementia, and depression who received folic acid supplements produced mixed results. Supplemental folic acid has also been studied in patients with autism and Down syndrome with inconsistent results.1,9,10

The effects of folic acid supplementation were most notable on the cervix and vaginal flora. Increasing folic acid intake to 1,000 to 2,000 mcg/day for about 3 months has helped to reverse cervical dysplasia. Folic acid has also decreased recurrent bacterial vaginosis, especially in Black women.1,9

Evidence on the benefit of supplemental folic acid to treat migraine and age-related hearing loss isn't conclusive. Although folic acid prevents neural tube defects in infants, too much may lead to insulin resistance, obesity, autism, and allergic asthma.1,3,5,11,12

Conflicting information raises questions about folic acid's health benefits and risks. Some studies show that when folic acid intake exceeds 800 mcg/day, cancer risk and mortality increase, especially lung cancer in current or former smokers.57 In contrast, the National Institutes of Health (NIH) in January 2010 released a statement reporting that folic acid found in green leafy vegetables and “some multivitamins” may protect against cancer in current and former smokers.13

Has the risk of colorectal cancer risen with increased folic acid supplementation? An increase in the incidence of colorectal cancer occurred around the time folic acid fortification of foods began and colonoscopy screening became more commonplace. Is the increase in colon cancer related to one or both of these factors, or some other variable?

In the Aspirin/Polyp Prevention Study, patients received both aspirin and 1 mg of folic acid for 6 years.7 This group had a 67% increase in colorectal adenomas and an increase in prostate cancer.7,12 Increasing the intake of folic acid through diet may protect against colon, breast, and possibly other kinds of cancer, but increasing intake via supplementation may be associated with an increased risk of colon cancer in countries where supplementation is mandatory such as in the United States, the Netherlands, and Chile.6,7,11

Another study showed an increase in breast cancer in women ages 55 to 74 whose supplemental intake of folic acid was greater than 400 mcg/day.5 Folic acid may accelerate tumor growth if cancer cells are already present when supplementation is begun. But if cancer isn't already present, supplementing with folic acid may decrease the risk of lung, colon, prostate, and breast cancer.5 Whether any benefit of folic acid supplementation outweighs its potential risk requires more study.1,5

Even though antifolate drugs such as methotrexate interfere with folic acid's actions, supplementation with folic acid may also cause problems. Patients using methotrexate are normally placed on folic acid supplementation due to the drug's antifolate effects. It's possible that the increased risk of acute lymphoblastic leukemia seen with methotrexate therapy may be due more to folic acid supplementation than to methotrexate use.1

In Tanzania, where the incidence of malaria is high, the use of antimalarial drugs such as hydroxychloroquine along with folic acid supplements leads to more severe forms of malaria and death from malaria.1

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The bottom line

Folic acid is essential for various actions in the body. But because of folic acid-fortified foods in the U.S. diet, we're likely to get what we need from these foods. Some people also get it in multivitamins.

All women who are trying to get pregnant, may become pregnant, or are pregnant should obtain at least 400 mcg/day of folic acid to prevent neural tube defects in the unborn child.14 But the jury is out on the benefits of bumping up folic acid levels in other healthy adults. At this time, it doesn't appear that our patients should consume more than 400 to 800 mcg/day from food and supplements. Consuming fortified breads, cereals, and meal replacements may cause an unintended overabundance of folic acid, especially in children and those who are dieting.1

Instruct your patients to read labels and add up amounts of folic acid consumed. One study found that 43% of children and 10% of adults consumed twice the upper limit per day!1 Teach patients that green leafy vegetables have more folic acid raw than when cooked because folates are easily destroyed during heating. Also explain that they can't “overdose” on folic acid consumed from natural sources.15

Patients with cervical dysplasia or recurrent bacterial vaginosis may need more folic acid, such as 1,000 to 2,000 mcg/day, as prescribed by a healthcare provider.6 Educate your patient to follow the healthcare provider's instructions explicitly, including not taking folic acid longer than prescribed and having lab work such as a complete blood cell count and folate levels as directed.

Inform patients that at this time folic acid doesn't seem to reduce the incidence of cardiovascular disease and may in fact increase the risk. Explain that some studies suggest that taking extra folic acid supplements may increase the risk of certain cancers, but that folic acid from natural sources may reduce the risk of cancer.

Folic acid supplementation is an example of too much of a good thing. Folic acid supplementation has greatly decreased birth defects, but has our increased intake of folic acid from fortified foods placed us at risk for other diseases such as cancer? Only time will tell.

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Drawbacks of natural folate

Supplemental folic acid was first produced because of concerns about birth defects and because folates that occur naturally in food tend to be unstable and can be destroyed by heat when the food is cooked. Leafy green vegetables such as lettuce and broccoli are the best source of folate, but the amount of folate depends on such variables as soil fertility, when the vegetables were picked, and how they're cooked. Folate is also found in citrus fruits and meats, but heat exposure breaks down folates.3

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Look out for interactions with folic acid

Certain medications can interfere with folate metabolism, regardless of whether the folate is from foods or supplements. Patients taking these medications may require higher daily doses than the recommended daily requirements stated in this article.

Medications interfering with folate metabolism include antimalarials, antifolates, and trimethoprim. Antifolates and antimalarials include agents such as methotrexate and hydroxychloroquine, which are often used for rheumatologic conditions such as rheumatoid arthritis, psoriasis, and lupus. Trimethoprim is found in the antibiotic sulfamethoxazole/trimethoprim. Excessive alcohol intake impairs folic acid metabolism and decreases its levels.5,16

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REFERENCES

1. Lucock M, Yates Z.Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care. 2009;12(6):555–564.
2. National Library of Medicine. MedlinePlus. Vitamin B12. 2012. http://www.nlm.nih.gov/medlineplus/druginfo/natural/926.html.
4. Schrier SL. Diagnosis and treatment of vitamin B12 and folic acid deficiency. UpToDate. 2012. http://www.uptodate.com.
5. Smith AD, Kim YI, Refsum H.Is folic acid good for everyone. Am J Clin Nutr. 2008;87(3):517–533.
6. Tom W.Folic acid and cancer risk. Pharmacist's Letter/Prescriber's Letter. 2010. 26(260109).
7. Chustecka Z.Folate supplementation linked to increased cancer incidence and mortality. Medscape Medical News. 2009. http://www.medscape.com/viewarticle/712591.
8. Fava M, Mischoulon D.Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry. 2009;70(suppl 5):12–17.
9. Gentili A, Vohra M, Vij S, Chen DK-H, Siddiqi W.Folic acid deficiency. Emedicine. 2011. http://emedicine.medscape.com/article/200184-print.
10. Ebbing M, Bleie Ø, Ueland PM, et alMortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography. JAMA. 2008;300(7):795–804.
11. Ebbing M, Bønaa KH, Nygård O, et alCancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302(19):2119–2126.
12. Whitrow MJ, Moore VM, Rumbold AR, Davies MJ.Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009;170(12):1486–1493.
13. Diet may protect against gene changes in smokers. NIH News. 2010. http://www.nih.gov/news/health/jan2010/nci-12.htm.
15. Schrier SL.Etiology and clinical manifestations of vitamin B12 and folic acid deficiency. UpToDate. 2012. http://www.uptodate.com.
16. Lucock M, Yates Z.Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care. 2009;12(6):555–564.
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