Folic acid
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Folic acid

Folic acid and folate (the anion form) are forms of a water-soluble B vitamin. These occur naturally in food and can also be taken as supplements. Folate gets its name from the Latin word folium, leaf. more...

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History

A key observation of researcher Lucy Wills nearly 70 years ago led to the identification of folate as the nutrient needed to prevent the anemia of pregnancy. Dr. Wills demonstrated that the anemia could be corrected by a yeast extract. Folate was identified as the corrective substance in yeast extract in the late 1930s and was extracted from spinach leaves in 1941.

Biological roles

Folate is necessary for the production and maintenance of new cells. This is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to replicate DNA and synthesize RNA. It also helps prevent changes to DNA that may lead to cancer. Both adults and children need folate to make normal red blood cells and prevent anemia.

Biochemistry

In the form of a series of tetrahydrofolate compounds, folate derivatives are coenzymes in a number of single carbon transfer reactions biochemically, and also is involved in the synthesis of dTMP (2'-deoxythymidine-5'-phosphate) from dUMP (2'-deoxyuridine-5'-phosphate).

The pathway in the formation of tetrahydrofolate (FH4) is the reduction of folate (F) to dihydrofolate (FH2) by folate reductase, and then the subsequent reduction of dihydrofolate to tetrahydrofolate (FH4) by dihydrofolate reductase.

Methylene tetrahydrofolate (CH2FH4) is formed from tetrahydrofolate by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate (CH3–FH4) can be made from methylene tetrahydrofolate by reduction of the methylene group, and formyl tetrahydrofolate (CHO-FH4, folinic acid) is made by oxidation of the methylene tetrahydrofolate.

In other words:

F → FH2 → FH4 → CH2=FH4 → 1-carbon chemistry

A number of drugs interfere with the biosynthesis of folic acid and tetrahydrofolate. Among them are the dihydrofolate reductase inhibitors (such as trimethoprim and pyrimethamine, the sulfonamides (competitive inhibitors of para-aminobenzoic acid in the reactions of dihydropteroate synthetase) and the anticancer drug methotrexate (inhibits both folate reductase and dihydrofolate reductase).

Recommended Dietary Allowance for folate

The Recommended Dietary Allowance (RDA) is the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97 to 98 percent) healthy individuals in each life-stage and gender group. The 1998 RDAs for folate are expressed in a term called the Dietary Folate Equivalent (DFE). This was developed to help account for the differences in absorption of naturally-occurring dietary folate and the more bioavailable synthetic folic acid. The 1998 RDAs for folate expressed in micrograms (µg) of DFE for adults are:

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Use of dietary supplements containing folic acid among women of childbearing age—United States, 2005
From Morbidity and Mortality Weekly Report, 9/30/05 by L.L.M. Lindsey

Neural tube defects (NTDs) are serious birth defects of the spine (spina bifida) and brain (anencephaly), affecting approximately 3,000 pregnancies each year in the United States (1). Daily periconceptional consumption of 400 [micro]g of folic acid, as recommended by the Public Health Service (PHS) since 1992, reduces the occurrence of NTDs by 50%-70% (2). The Food and Drug Administration ordered mandatory fortification with folic acid of U.S. cereal grain products, beginning in 1998. However, despite a 26% reduction in NTDs, not all women of childbearing age receive adequate levels of folic acid from their diets (1). Therefore, increasing the number of women who take dietary supplements containing 400 [micro]g of folic acid daily remains an important component of NTD prevention (3). This report summarizes results from the 2005 March of Dimes Gallup survey, which determined a decrease in the proportion of childbearing-aged women who reported taking folic acid in dietary supplements daily, * from 40% in 2004 to 33% in 2005, returning to a level consistent with that reported during 1995-2003 (Figure). These results emphasize the need for innovative programs to increase folic acid consumption to further reduce NTDs.

The Gallup survey has been conducted since 1995 using a random-digit-dialed telephone interview of a proportionate stratified sample. Response rate for the 2005 survey was 32%, with 2,647 women aged 18-45 years responding; response rates for previous surveys ranged from 24% to 52%. Statistical estimates were weighted to reflect the total population of women aged 18-45 years in the contiguous United States who resided in households with telephones. The margin of error for estimates based on the total sample was [+ or -] 2%. To assess awareness of folic acid, respondents were asked, "Have you ever heard, read, or seen anything about folic acid?" To assess knowledge about folic acid, respondents were asked, "What have you heard, read, or seen about folic acid?" In addition, the survey asked questions regarding motivating factors and barriers to taking folic acid.

In the 2005 survey, 33% of women of childbearing age reported taking folic acid daily, compared with 40% in 2004. This decrease was consistent across most demographic characteristics, with nonwhite, young, less educated, and lower-income women the least likely to report taking folic acid daily (Table 1). The percentage of women reporting awareness of folic acid increased from 78% in 2004 to 84% in 2005, an all-time high for the survey. However, the percentage of women knowing that folic acid prevents birth defects remained unchanged at 25%, and the percentage of women knowing that folic acid should be taken before pregnancy decreased from 12% in 2004 to 7% in 2005, the lowest percentage since 1997 (Figure).

Twenty-six percent of women aged 18-45 years reported dieting during the preceding 6 months, relatively unchanged from 24% in 2004 (4). Of the women reporting dieting, 37% were taking folic acid daily and were nearly 30% more likely to be taking folic acid than nondieters (odds ratio [OR] = 1.27; 95% confidence interval [CI] = 1.13-1.41). Dieters were 50% more likely than nondieting women to believe that folic acid is important for women of childbearing age (OR = 1.50; CI = 1.34-1.68). Twenty-seven percent of dieting women reported being on low-carbohydrate diets, down substantially from 48% in 2004. Of the women on low-carbohydrate diets, 37% reported taking folic acid daily, down from 49% in 2004 (Table 2). In addition, 37% of women on other diets reported taking folic acid daily, down from 40% in 2004. Whereas in 2004 women on low-carbohydrate diets were 50% more likely to take folic acid daily than women on other diets, in 2005 folic acid consumption was similar among women in the two dieting groups (OR = 1.00; 95% CI = 0.81-1.24. Although in 2004, low-carbohydrate dieters were 30% more likely to believe that folic acid is important for women of childbearing age than women on other diets, in 2005, no difference was evident between women in these dieting groups (OR = 0.95; 95% CI = 0.76-1.18).

Women were asked questions to determine why they do or do not take vitamin or mineral supplements. Women who did not report taking supplements were asked, "Why do you not take any vitamin or mineral supplements on a daily basis?" The most common barriers women noted were forgetting to take supplements (28%), perceiving they do not need them (16%), and believing they get needed nutrients and vitamins from food (9%).

In 2005, to determine what might motivate women not taking vitamins or supplements to begin taking folic acid daily, respondents were asked, "For what specific need would you start taking a vitamin or mineral supplement?" The most common reported needs were being sick or in poor health (20%), a doctor's recommendation (20%), the need for energy (9%), being pregnant (8%), being deficient in any vitamins or minerals (7%), balancing the diet (6%), and keeping bones strong (6%). In addition, 11% cited no specific need that would motivate them to begin taking a vitamin or supplement. Among women who reported not consuming a vitamin or mineral supplement daily, 31% indicated they had received a doctor's recommendation. Older women were more likely to report receiving a doctor's recommendation (aged 35-45 years, 38%; 25-35 years, 38%; 18-24 years, 24%).

Editorial Note: From 2004 to 2005, the percentage of women of childbearing age taking folic acid daily decreased from 40% to 33%. At least two possible explanations exist for this decline. First, 2004 survey results might have indicated a true increase in women's reported behavior that was not sustained; hence, in 2005, folic acid consumption returned to a level consistent with survey results since 1995. The reasons for such an increase in 2004 remain unclear. A second possible explanation is that the 2004 survey data were an anomaly and did not accurately reflect women's daily use of folic acid. The same sampling design and methodology have been used each year; however, multiple factors could have produced anomalous findings (e.g., nonrespresentative sampling or low response rates).

The 2005 findings indicated that only 33% of women of childbearing age reported consuming folic acid daily. Data from NHANES indicate no change during 1991-2000 in reported consumption of 400 [micro]g of folic acid daily among nonpregnant women aged 15-44 years (CDC, unpublished data, 2005). Given that reported folic acid consumption through supplementation has changed minimally during the preceding decade, new programs are needed. As one example, CDC is developing a program focused on ensuring that young women achieve optimal nutrition by encouraging that women in college consume a daily multivitamin containing 400 [micro]g of folic acid. Fortification of food is a second approach demonstrated to reduce occurrence of NTDs (1). A recent report indicated a significant decrease in the prevalence of NTDs after implementation of folic acid fortification, reiterating the important role of fortification in reducing NTDs (5). Another report indicated an increase in blood folate levels for all segments of the U.S. population since fortification (6). Given the reported success of fortification and given that only one third of women report folic acid supplement use, another approach to reducing NTDs might be to develop programs that encourage women to consume folic acid from fortified foods. These foods, especially breakfast cereals, might be an easy alternative to ensure that women consume 100% of the recommended daily amount of folic acid every day.

The reduction in the proportion of women who reported being on low-carbohydrate diets is consistent with other reports indicating a diminishing trend in use of low-carbohydrate diets (7). The slowing of this trend could facilitate NTD prevention because more women might be consuming foods fortified with folic acid (e.g., breads), which are the largest contributor of folate to diets in the United States (8).

The findings in this report are subject to at least two limitations. First, the low response rate for this survey might have produced biased results. Second, because the majority of respondents to the survey were white, had at least some college, and had a median household income of approximately $50,000, the survey might not reflect the total U.S. population of women of childbearing age.

With 67% of women not consuming a vitamin containing folic acid daily, innovative programs are needed to prevent NTDs. These programs must effectively address motivations and barriers regarding folic acid consumption to meet the national health objective for 2010 of increasing to 80% the proportion of women consuming 400 [micro]g of folic acid daily (objective no. 16-16a) (9).

References

(1.) CDC. Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000. MMWR 2004;53: 362-5.

(2.) Medical Research Council Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-7.

(3.) CDC. Recommendation for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992;41 (No. RR-14).

(4.) CDC. Use of vitamins containing folic acid among women of childbearing age--United States, 2004. MMWR 2004;53:847-50.

(5.) Williams LJ, Rasmussen SA, Flores A, Kirby RS, Edmonds LD. Decline in the prevalence of spina bifida and anencephaly by race/ ethnicity: 1995-2002. Pediatrics 2005;116:580-6.

(6.) Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr 2005;82:442-50.

(7.) The NPD Group. Dieting trends--United States, 2004-2005. Dieting Monitor 2005;2(8).

(8.) Dietrich M, Brown CJP, Block G. The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J Am Coll Nutr 2005;24:266-74.

(9.) US Department of Health and Human Services. Healthy people 2010: understanding and improving health. 2nd ed. Washington, DC: US Department of Health and Human Services; 2000. Available at http://www.health.gov/healthypeople.

* Women who reported taking a multivitamin, prenatal vitamin, or a folic-acid-only supplement in response to the question "What type of vitamin or mineral supplements do you take?" were coded as taking a vitamin containing folic acid (consistent with all previous surveys).

Reported by: LLM Lindsey, PhD, CDC Foundation, Atlanta, Georgia. JR Petrini, PhD, March of Dimes Birth Defects Foundation, White Plains, New York. H Carter, MPH, C Prue, PhD, J Mulinare, MD, Div of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities; CDC.

COPYRIGHT 2005 U.S. Government Printing Office
COPYRIGHT 2005 Gale Group

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