Extra Folic Acid Provides Prenatal Protection

Young David's life is difficult. He was born with spina bifida, one of a group of conditions known as neural tube defects (NTDs). In David's case, the tube enclosing his spinal cord failed to close at the base of his spine. As a consequence, his legs are paralyzed and he has no bladder control. His incontinence is managed by an implanted catheter, a tube that collects urine in a bottle attached to his wheelchair. The catheter causes frequent urinary tract infections that resist treatment.

Some other NTDs, such as anencephaly (a very small brain or no brain at all), are fatal early on; others, while not fatal, involve extreme mental and physical impairment. Within the last 15 years, we have learned that most NTDs are preventable. The remedy turns out to be one of the B vitamins--folate. If a mother's body is properly nourished with high levels of folate at the time of conception and in the first few months of pregnancy, the risk of giving birth to a child with NTDs is greatly reduced.

Women who seek medical advice before they conceive or while still in the early stages of pregnancy are told to take 400 mcg of folic acid a day. This is more than double the Recommended Dietary Allowance (RDA) for nonpregnant women, which is 180 mcg/day. At the higher level of supplementation, several intervention studies show a significant reduction in the occurrence of NTDs--as much as 60 to 70 percent.¹

NTDs develop only 18 to 30 days after conception--before a woman may even know she's pregnant. Thus, a woman's folate status needs to be good before conception. Most women don't seek medical advice before conception, so they don't know if their folate levels are optimal. In many cases, they are not. It is for these reasons that the U.S. Food and Drug Administration (FDA), in accord with recommendations from the Public Health Service in Washington, D.C., and the Centers for Disease Control and Prevention Folic Acid Working Group in Atlanta, mandated that, beginning in January 1998, grain products sold in the United States had to be fortified with folic acid: 140 mcg of folic acid per 100 grams of grain product.

This program is intended to improve the folate status of women of childbearing age. By reducing NTDs, folic acid fortification also has the potential to prevent much misery. Even so, not everyone is in favor of it. Why? There are two objections. One is that 140 mcg of folic acid per 100 g of cereal product is not enough to prevent NTDs and that the fortification level should be higher. The other argues that folate supplementation may mask another B vitamin deficiency; namely, vitamin B12. Let's look at both sides of the debate.

Fortification Concerns * Fortification levels are too low: To consume 400 mcg of folic acid in grain products fortified at the mandated level would require a person eat close to 300 g of grain each day. That translates to nearly a pound of bread (taking its moisture content into account), or two-thirds of a pound of pasta (dry weight). This is decidedly more than most women eat--though some breakfast cereals are currently fortified with 400 mcg of folic acid per serving. Of course, fortified cereal grain products would not be the only source of folate in a woman's diet. The U.S. Department of Agriculture (USDA) estimates that most women get 200 mcg of folate from their daily diet. However, folate from food may not be as effective as supplemental folic acid (a synthetic form of the vitamin).

One study shows that consuming 400 mcg of folate each day from foods failed to raise red blood cell folate concentrations to protective levels, while 400 mcg of supplemental folic acid did.² Several possible explanations come to mind. The polyglutamate form of folate that naturally occurs in food may be less available than the synthetic form; cooking or storage may destroy vitamins and cause intakes to be lower than estimated; or the amount needed to prevent NTDs is higher than 400 mcg and women who took the 400-mcg supplement received additional folate from their diets.

Based on these study results, the mandated fortification level of folic acid likely is not sufficient to protect the fetuses of all pregnant women. Why not increase the level of fortification? The answer lies in folic acid's relationship to vitamin B12, which is the basis of the second concern regarding fortification.

* Supplemental folate masks vitamin B12 deficiency: The FDA is mandated to set fortification levels that are safe for all population groups. Although folic acid is not toxic, high levels may not be safe for the elderly. Ten to 20 percent of the elderly are diagnosed as having low levels of vitamin B12,³ and B12 deficiency may go unrecognized if folic acid intake is high. Therefore, the FDA selected a fortification level that keeps total folate intake under 1 mg/day. It is thought that folate intakes under 1 mg/day do not mask vitamin B12 deficiency, but no one knows for sure.

Vitamin B12 deficiency is a serious condition. If not corrected in time, it leads to irreversible neurological damage. Many factors can cause B12 deficiency--insufficient B12 intake, poor B12 absorption caused by an absence of "intrinsic factor" (a substance made by stomach cells that is essential for B12 absorption), or poor absorption because of insufficient stomach acid. The most recognizable sign of B12 deficiency is macrocytic anemia (oversized, immature red blood cells), indicated by a high mean-corpuscular volume (MCV), a measurement done in routine blood tests.

Here's the problem: If folic acid intake is high, macrocytic anemia won't develop. No red flag will be raised by blood test results warning "B12 deficiency possible! Investigate further!" Not having macrocytic anemia is good. The problem is that if B12 deficiency goes undetected and uncorrected, it can lead to psychoneurological damage. For this reason, restricting folic acid intake is often suggested.

And The Answer Is ... One possible solution to this serious dilemma lies not in restricting folic acid intake, but in developing better techniques to recognize B12 deficiency. Total serum B12, a classic indicator of B12 status, is criticized for its lack of sensitivity. Methylmalonic acid is a metabolic intermediate that is normally low in blood and becomes elevated when there is B12 deficiency. Measuring methylmalonic acid levels is thought by some researchers to be a good indicator of B12 deficiency,⁴ yet not all agree.⁵

Another partial solution is to fortify grain products with B12 as well as folic acid. This would protect people whose B12 deficiency is caused by insufficient intake. It could also help those who have atrophic gastritis and produce insufficient stomach acid. (Such individuals can absorb the crystalline form of B12 found in supplements but not the protein-bound form found in foods.⁶) People who do not produce intrinsic factor, a protein needed for B12 absorption, still need B12 therapy by injection (which effectively bypasses the absorption issue). So, why hasn't the FDA considered B12 supplementation? That question has yet to be answered.

Although the fortification program is intended to increase folate intake of women of child-bearing age, other groups will benefit from the higher levels as well. Increased folate may protect both women and men from vascular diseases such as atherosclerotic heart disease and cerebrovascular stroke. When folate (or B12 or vitamin B6) is in short supply, a metabolic pathway can become blocked and lead to a build-up of homocysteine, a recognized risk factor in vascular disease.⁷ (See also NSN, May 1996, p. 20, and Aug. 1996, p. 6.) Large daily folate supplements (e.g., 5 mg) can reduce plasma homocysteine concentrations.⁸

The elderly may benefit most of all from folate's effect on homocysteine. A subset of the Framingham Heart Study research team concentrated on 747 participants ages 67 to 96 who filled out usable food-frequency questionnaires and had blood measures of B vitamins and homocysteine. Estimated test results showed that the new fortification level would reduce the number of elderly consuming less than 200 mcg folate/day from 17 to 7 percent, and the percentage consuming less than 400 mcg/day from 65 to 46 percent.⁹ These numbers would be even more favorable with higher levels of fortification.

So far, there have been no randomized, controlled trials to determine whether lowering homocysteine will reduce vascular disease risk, but the evidence strongly suggests it might. People with elevated plasma homocysteine would be wise to take a folate-containing multivitamin supplement.

Will folate supplementation have adverse effect beyond masking B12 deficiency? There is no indication to date that the newly mandated levels of folic acid will have any side effects. Earlier suggestions that folic acid supplementation adversely affects zinc status are untrue.¹⁰

Fortifying cereal-grain products with folate may be a step in the right direction, though the new level probably will not protect all women from ever giving birth to a child with an NTD. When better B12 deficiency tests are developed, FDA may dare to raise folate's fortification level. In the meantime, women intending to get pregnant or who discover they are pregnant should still take vitamin supplements. In fact, it is prudent for any woman of child-bearing age to take a multivitamin containing both folate and B12. Elderly people and anyone else with elevated plasma homocysteine should also consider taking supplements that include folate and vitamins B12 and B6. And everyone should eat foods that contribute to good folate status.

Stephanie Briggs, Ph.D., is a nutritional biochemist with more than 20 years experience in laboratory research. She is also a freelance writer.

REFERENCES
1. Rieder, M. "Prevention of neural tube defects with periconceptional folic acid." Clin Perinatol, 21: 483-502, 1994.

2. Cuskelly, G., McNulty, H., et al. "Effect of increasing dietary folate on red-cell folate: Implications for prevention of neural tube defects," Lancet, 347: 657-59, 1996.

3. Lindenbaum, J., Rosenberg, I., et al. "Prevalence of cobalamin deficiency in the Framingham elderly population," Am J Clin Nutr, 60: 2-11, 1994.

4. Savage, D., Lindenbaum J., et al. "Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies," Am J Med, 96: 239-46,1994.

5. Chanarin, I. & Metz, J. "Diagnosis of cobalamin deficiency: The old and the new," Br J Haematology, 97: 695-700, 1997.

6. Suter, P., Golner, B., et al. "Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis," Gastroenterology, 101: 1039-45, 1991.

7. Graham, I., Daly, L., et al. "Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project," JAMA, 277: 1775-81, 1997.

8. Landgren, F., Israelsson, B., et al. "Plasma homocysteine in acute myocardial infarction: Homocysteine-lowering effect of folic acid," J Intern Med, 237: 381-88, 1995.

9. Tucker, K. Mahnken, B., et al. "Folic acid fortification of the food supply: Potential benefits and risks for the elderly population," JAMA, 276: 1879-85, 1996.

10. Kauwell, G., Bailey, L., et al. "Zinc status is not adversely affected by folic acid supplementation and zinc intake does not impair folate utilization in human subjects," J Nutr, 125: 66-72, 1995.

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