Folic Acid and Prevention of Spina Bifida and Anencephaly

10 Years After the U.S. Public Health Service Recommendation

Introduction

Prepared by
J. David Erickson, D.D.S., Ph.D.
Division of Birth Defects and Developmental Disabilities
National Center on Birth Defects and Developmental Disabilities

The material in this report originated in the National Center on Birth Defects and Developmental Disabilities, José F. Cordero, M.D., Director, and the Division of Birth Defects and Developmental Disabilities, Joseph Mulinare, M.D., M.S.P.H., Acting Director.

In September 1992, the U.S. Public Health Service (USPHS) recommended that all women capable of becoming pregnant should consume 400 µg of folic acid/day on an ongoing basis to reduce their risk for having a pregnancy affected by spina bifida and anencephaly (i.e., neural tube defects [NTDs]) (1). The recommendation was preceded a year earlier by a CDC recommendation for women at high risk (i.e., those women who have had an earlier pregnancy affected by an NTD). The 1991 CDC recommendation stated that women at high risk should plan subsequent pregnancies and consume 4,000 µg/day of folic acid from the time they begin trying to become pregnant through the first trimester of pregnancy to reduce their risk (2). The 1992 USPHS recommendation specified that women at high risk should follow the general population recommendation for consumption of 400 µg/day when not trying to become pregnant (1).

Both of these recommendations were based on scientific evidence that increased folic acid consumption reduced the risk for having a pregnancy affected by an NTD. In 1983, a nonrandomized but controlled trial that studied multivitamins containing folic acid determined that folic acid might prevent NTDs (3). In 1991, the British Medical Research Council (MRC)-sponsored randomized controlled trial indicated that folic acid alone could reduce the risk for NTD-affected pregnancies among women who had had an earlier NTD-affected pregnancy (4). In 1992, a randomized controlled trial in Hungary reported the protective effect of folic acid-containing multivitamins against first occurrences of NTDs (5). These two controlled and randomized studies, together with consistent results from multiple observational studies, prompted the 1992 USPHS recommendation.

The 1992 USPHS recommendation stated that increased folic acid consumption could be achieved in three ways: by increasing consumption of foods rich in naturally occurring folates, by increasing use of folic acid-containing dietary supplements, and by fortification of a staple foodstuff (e.g., flour). In 1998, a report from the Food and Nutrition Board of the Institute of Medicine (IOM) stated that women of reproductive age should consume 400 µg/day of folic acid from dietary supplements or from fortified foods, in addition to eating a healthy diet containing natural folate compounds (6).

Since 1992, efforts have been made to increase daily use of dietary supplements containing 400 µg of folic acid by women of reproductive age. Additionally, in 1998, the Food and Drug Administration began requiring the fortification of enriched cereal grain products with folic acid at the level of 140 µg/100 grams of grain (fortification was optional during March 1996--December 1997). This level of fortification was chosen to assist women of reproductive age in increasing their folic acid consumption by an average of 100 µg of folic acid daily.

This issue of the MMWR Recommendations and Reports presents data to assess the impact of efforts to prevent NTDs through increased folic acid consumption. Blood folate levels for U.S. women of reproductive age from the National Health and Nutrition Examination Survey (NHANES) for the combined years of 1999 and 2000 were substantially higher than those determined for the NHANES III samples collected during 1988--1994 (7). Because substantial increases have not occurred in the reported use of folic acid-containing dietary supplements during 1995--2002 (8), the assumption is that the majority of this rise in blood folate levels is the result of consumption of fortified cereal grain products (e.g., bread and pasta) and from fortified ready-to-eat breakfast cereals. In addition to an increased availability of folic acid derived from fortified flour, a substantial number of ready-to-eat cereals have had increases in their folic acid content (CDC, unpublished data, 2002). Certain subgroups of the population have experienced more limited increases in blood folate levels than has the general population of reproductive-age women. One group of women attending family planning clinics in Georgia had a median serum folate level of 8.9 ng/mL, compared with the NHANES 1999--2000 median of 13.0 ng/mL (9). The reasons for this difference are unknown but could include a lower level of folic acid consumption among subgroups of the U.S. population. If so, such subgroups could possibly benefit from targeted interventions to promote increased folic acid consumption from breakfast cereals and dietary supplements. In China, an intensive campaign to encourage use of folic acid supplements among women planning to start a pregnancy was highly successful in reducing NTDs among the population (10).

NTD rates have declined by approximately 20%--30% since the institution of folic acid-fortified cereal grains (11--13). This decrease is expected on the basis of predicted increases in folic acid consumption from fortified cereal grains (100 µg/day) (14). In contrast, the decrease in NTD rates is not the 50%--70% decrease predicted by USPHS in 1992 (1), if all women of reproductive age were to consume 400 µg of folic acid/day. The decrease is also lower than what could be predicted on the basis of the substantial rise in blood folate levels among U.S. women of reproductive age. Spina bifida rates in North Carolina appear to have decreased less among disadvantaged segments of the population (12). Possibly, women who are most at risk for having NTD-affected pregnancies do not consume as much fortified food products; they do not have the same level of access to other sources of folic acid and could benefit from targeted interventions; or they do not absorb as much folic acid as do women who are at lower risk.

In 1995, approximately 52% of reproductive-age women were aware of the term folic acid, and this increased to 80% in 2002 (8). However, just 20% of women participating in a 2002 March of Dimes survey knew that folic acid could prevent certain birth defects, and the proportion who stated that they took a vitamin supplement containing folic acid daily increased from 25% in 1995 to only 31% in 2002 (8). These findings indicate that educational efforts directed at women of reproductive age might have had an impact on knowledge and to a lesser extent on behavior. According to polls taken by multiple groups, including the March of Dimes (8), women of reproductive age state that the recommendation of a physician or other health-care provider would positively influence their decision to take folic acid-containing dietary supplements. However, only a minority of women who are currently using a supplement identify their physician as a source of information. A study in Florida (CDC, unpublished data, 2002) reported that approximately 90% of physicians who responded to a survey knew that folic acid can prevent NTDs but that a more limited proportion could identify the recommended daily dose of 400 µg for the general population; furthermore, an even more limited proportion could state the recommended dose of 4,000 µg for women at high risk. This indicates a need for more educational efforts directed at physicians and other health-care providers.

Among women who are at high risk for an NTD-affected pregnancy because they have had an NTD-affected pregnancy or have spina bifida themselves, approximately 33% reported regular use of a supplement, and only 48% indicated that they believed that folic acid is effective in reducing the risk for an NTD (CDC, unpublished data, 2002). A Texas case-control study reports that 56% of women who have had an infant with an NTD recall receiving postpartum advice to use folic acid, compared with 26% of mothers in the control group. Women who received advice were more likely to use supplements regularly than women who did not (41% versus 22%) (15).

These reports reflect the encouraging progress made to increase folic acid consumption by women of reproductive age and reduce the proportion of babies born with NTDs. However, more work needs to be done to reach the goal of preventing all NTDs that could be avoided if all women who become pregnant were to follow the 1992 USPHS recommendation. In addition to the work that needs to be done to prevent NTDs, as discussed in the articles in this report, the policies related to folic acid consumption need to be reviewed and evaluated, and more research is required to improve understanding regarding the causes of NTDs. The Food and Drug Administration mandate to fortify flour and other cereal grain products has had a positive impact on the folate status of the U.S. population. Nevertheless, more birth defect prevention could possibly be achieved by a higher level of grain fortification or by fortification of additional types of foods. Physicians and scientists need a better understanding of what proportion of NTD cases that now occur result from inadequate folic acid consumption and what proportion result from causes unrelated to folic acid. Thus, more research is needed to better understand the biological mechanism by which folic acid prevents NTDs and the causes of those cases that are not connected with folic acid consumption.

References

1. CDC. Recommendations 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).
2. CDC. Effectiveness in disease and injury prevention: use of folic acid for prevention of spina bifida and other neural tube defects, 1983--1991. MMWR 1991;40:513--6.
3. Smithells RW, Nevin NC, Sellar MJ, et al. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983;1:1027--31.
4. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131--7.
5. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832--5.
6. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B₆, folate, vitamin B₁₂, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press, 1998.
7. CDC. Folate status in women of childbearing age by race/ethnicity---United States, 1999--2000. MMWR 2002 (in press).
8. March of Dimes Birth Defects Foundation. Folic acid and the prevention of birth defects: a national survey of pre-pregnancy awareness and behavior among women of childbearing age, 1995--2002. Conducted by the Gallup Organization. White Plains, NY: March of Dimes Foundation, May 2002. Publication no. 31-1677-02.
9. CDC. Than L, Watkins M, Daniel, KL. Serum folate levels among women attending family planning clinics---Georgia, 2000. MMWR 2002;51(No. RR-13):3--7.
10. Berry RJ, Li Z, Erickson JD, et al. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. New Engl J Med 1999;341:1485--90.
11. Mathews TJ, Honein MA, Erickson JD. Spina bifida and anencephaly prevalence---United States, 1991--2000. MMWR 2002;51(No. RR-13):8--10.
12. Meyer RE, Siega-Riz AM. Sociodemographic patterns in spina bifida birth prevalence trends---North Carolina, 1995--1999. MMWR 2002;51(No. RR-13):11--14.
13. Williams LJ, Mai CT, Edmonds LD, et al. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the Unites States. Teratology 2002;66:33--9.
14. Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect of folic acid. Lancet 2001;358:2069--73.
15. Canfield MA, Anderson JL, Waller DK, Palmer SE, Kaye CI. Folic acid awareness and use among women with a history of a neural tube defect pregnancy---Texas, 2000--2001. MMWR 2002;51(No. RR-13):15--18.

 

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