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U.S. Preventive Services Task Force


Folic Acid for the Prevention of Neural Tube Defects

Recommendation Statement

Date: May 2009


Summary of Recommendation and Evidence


  • The USPSTF recommends that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.
    Grade: A recommendation.

Select for a Clinical Summary of this recommendation.


This recommendation statement was first published in Annals of Internal Medicine in May 2009 (Ann Intern Med 2009;150:626-31. http://www.annals.org). Select for copyright and source information.

Contents

Rationale
Clinical Considerations
Discussion
Recommendations of Other Groups
References
Members of the USPSTF

Task Force Grade Definitions

Rationale

Importance

Approximately 1 in every 1000 pregnancies is affected by a neural tube defect.

Recognition of Risk Status

Although a personal or family history of a pregnancy affected by a neural tube defect is associated with an increased risk for having an affected pregnancy, most cases occur in the absence of any positive history.

Benefits of Preventive Medication

The USPSTF found convincing evidence that supplements containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid in the periconceptional period reduce the risk for neural tube defects.

Harms of Preventive Medication

Adequate evidence suggests that folic acid from supplementation at usual doses is not associated with serious harms.

USPSTF Assessment

The USPSTF concludes that, for women who are planning or capable of pregnancy, there is high certainty that the net benefit is substantial.

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Clinical Considerations

Patient Population Under Consideration

This recommendation applies to women who are planning or capable of pregnancy, but it does not apply to women who have had a previous pregnancy affected by neural tube defects or women taking certain antiseizure medicines. Most organizations recommend that these women take higher doses of folic acid.

Assessment of Risk

The use of certain antiseizure medicines and a personal or family history of neural tube defects are well-established risk factors. Other reported risk factors include mutations in folate-related enzymes, maternal diabetes, and obesity.

Timing

Most studies indicate the need to start folic acid supplementation at least 1 month before conception and to continue daily supplements through the first 2 to 3 months of pregnancy. Studies also indicate that 50% of pregnancies in the United States are unplanned, and clinicians should therefore advise all women who are capable of pregnancy to take folic acid supplements.

Dosage

Good evidence from randomized trials in settings without fortification of food suggests that a multivitamin with 0.8 mg (800 µg) of folic acid reduces the risk for neural tube defects. Observational studies done before fortification report a reduction of neural tube defects in women taking a supplement with 0.4 mg (400 µg) of folic acid (the generally available dose). Evidence indicates that most women in the United States are not ingesting fortified foods at a level thought to provide optimal benefit. In a setting in which food is fortified with folic acid, the effective amount of additional folic acid supplementation is unclear.

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Discussion

Burden of Disease

Neural tube defects result from a malformation of the embryo's central nervous system that may result in a serious birth defect like anencephaly or spina bifida. Neural tube defects are among the most common birth defects in the United States.1 Approximately 1 in every 1000 pregnancies is affected. The Centers for Disease Control and Prevention estimates that the birth rates in 2005 for 2 of the most common neural tube defects, spina bifida and anencephaly, were 17.96 and 11.11 per 100,000 live births, respectively.2

Two well-established risk factors for neural tube defects are a history of a fetus or child with a neural tube defect or having a first-, second-, or third-degree relative with such a defect.3,4 The prevalence of defects varies by ethnicity and race: Hispanic and non-Hispanic white persons have higher rates of neural tube defects than black and Asian persons.5 Maternal medical conditions, such as diabetes and obesity, have also been associated with an increased risk. Women with epilepsy who take certain antiepileptic medications, such as valproic acid or carbamazepine, are also at increased risk.

Scope of Review

In 1992, the U.S. Public Health Service recommended the daily consumption of 0.4 mg (400 µg) of folic acid in women of childbearing age (15 to 44 years).6 In 1996, the USPSTF made a similar recommendation on the basis of several studies, including 1 large randomized, controlled trial (RCT) that demonstrated a statistically significant reduction in incidence of neural tube defects in women who took a multivitamin with 0.8 mg (800 µg) of folic acid in the periconceptional period.7,8 The USPSTF recommended that all women planning pregnancy take a daily multivitamin containing folic acid at a dose of 0.4 to 0.8 mg beginning at least 1 month before conception and continuing through the first trimester, to reduce the risk for neural tube defects (grade A recommendation). In addition, it recommended a daily multivitamin containing 0.4 mg of folic acid for all women capable of pregnancy, to reduce the risk for neural tube defects in unplanned pregnancies (grade B recommendation). The purpose of the current USPSTF review was to update the evidence on folic acid supplementation in women of childbearing age published since the 1996 USPSTF commendation. The USPSTF did not review the evidence on folic acid for women who had a history of pregnancy affected by neural tube defects nor the evidence on folic acid food fortification, counseling to increase dietary intake, or screening for neural tube defects.

Effectiveness of Preventive Medication

In addition to the RCT that was available in 1996, the USPSTF found further observational evidence published since that time that supports the hypothesis that supplementation with 0.4 to 0.8 mg (400 to 800 µg) of folic acid in the periconceptional period reduces the risk for neural tube defects in offspring.

In 2004, Czeizel and Dudás7 did a cohort study including women who were considering pregnancy and gave them multivitamins containing 0.8 mg (800 µg) of folic acid 1 month before planned conception. The authors reported a protective effect of folic acid against neural tube defects: 1 neural tube defect occurred in 3056 women who took folic acid supplements and 9 occurred in 3056 women who did not. The difference between the supplemented and unsupplemented groups was statistically significant after adjustment for birth order, chronic maternal disorders, and history of fetal death or congenital abnormality.

A meta-analysis of studies about pre- and periconceptional multivitamin use and congenital malformations also reported a protective effect of multivitamins containing folic acid against neural tube defects, with an odds ratio (OR) of 0.67 (95% CI, 0.58 to 0.77) in case-control studies and an OR of 0.52 (CI, 0.39 to 0.69) in RCTs and cohort studies. In 1995, Shaw and coworkers9 did a case-control study and reported an OR of 0.65 (CI, 0.45 to 0.94) for use of supplements containing folic acid 3 months before conception and an OR of 0.60 (CI, 0.46 to 0.79) for use 3 months after. A smaller study that adjusted for dietary folic acid intake reported an OR of 0.55 (CI, 0.25 to 1.22) for regular users and an OR of 0.92 (CI, 0.55 to 1.55) for some use of supplements containing folic acid, but neither of these findings was statistically significant.4

Data from the 2001-2002 NHANES (National Health and Nutrition Examination Survey), limited to nonpregnant female participants from age 15 to 49 years, indicate that 8% of women consumed 400 µg/d or more of folic acid from fortified foods, and 26% of women took 400 µg/d or more of folic acid through supplements within the previous month.10 Therefore, 34.3% of women of reproductive age consumed 400 µg/d or more through a combination of fortified foods and supplements. Recently, the 2007 March of Dimes Gallup survey used a random digit-dialed telephone interview of women of childbearing age to assess folic acid intake. Of this sample, 40% reported taking folic acid daily, compared with 32% in 2003, 40% in 2004, and 33% in 2005. When stratified by age, 47% of women from age 25 to 34 years reported taking a daily supplement with folic acid compared with 30% of women age 18 to 24 years.11 A recent study using NHANES data reported decreases in folic acid intake by women of childbearing age. The authors hypothesized that this was due to a reduction in fortification levels and the popularity of low-carbohydrate diets that are deficient in foods fortified with folic acid.12

Potential Harms of Preventive Medication

The USPSTF found adequate evidence that folic acid from supplementation at usual doses is not associated with serious harms. Previous concerns, discussed in the 1996 USPSTF recommendation, about potential harms related to folic acid supplementation (particularly in light of mandatory food fortification13) focused on several hypothesized areas: the masking of symptoms of vitamin B12 deficiency and consequent neurologic complications, drug interactions, allergic reactions, carcinogenic effects, and effects on the rate of twinning.14 In its current review, the USPSTF found no evidence on drug interactions, allergic reactions, or carcinogenic effects.

The USPSTF also found no clear, consistent evidence that preconceptional folic acid use results in an increased rate of twinning. Many studies with methodological problems posit an association between folic acid and twinning; however, most of these studies did not appropriately adjust for fertility interventions, an important confounder. In a 2005 retrospective cohort study, Vollset and colleagues15 suggest that the association of folic acid supplementation with twinning is the result of confounding by infertility treatment and by differential reporting of folic acid use. This study examined the association between risk for twinning in 176,042 women and exposure to a multivitamin or folic acid supplementation before or during pregnancy. After adjustment for age and parity, the authors reported an OR of 1.59 (CI, 1.41 to 1.78) for twin delivery after preconceptional folic acid supplementation. After accounting for the underreporting of folic acid use and in vitro fertilization, the OR for twin delivery after preconceptional supplementation decreased to 1.02 (CI, 0.85 to 1.24) and was no longer statistically significantly greater than the risk for women who did not take folic acid.

Another concern about folic acid supplementation includes masking of vitamin B12 deficiency. The USPSTF found no evidence to support this potential harm. Given the low prevalence of vitamin B12 depletion in young women, folic acid supplementation in women of childbearing age would not likely result in a substantial number of cases of neurologic sequelae due to masking of vitamin B12 deficiency. In a study using data from NHANES and the Hispanic Health and Nutrition Examination Survey, the Centers for Disease Control and Prevention National Center for Health Statistics reported that fewer than 1% of the total population from age 4 to 50 years had serum vitamin B12 levels less than 100 pg/mL in 1998, the level below which deficiency is likely.16 Furthermore, an ecological study comparing patients before and after folic acid fortification found no evidence of an increase in low vitamin B12 levels without anemia.17 Finally, folic acid supplementation is often given in the form of a multivitamin or prenatal vitamin that includes supplementation with B12, reducing the likelihood of its masking a deficiency in this population.

Estimate of Magnitude of Net Benefit

New evidence from observational studies provides additional support to earlier evidence from controlled trials that folic acid supplementation provides benefit in the reduction of risk for pregnancies affected by neural tube defects. The USPSTF found 4 fair- or good-quality studies published since the 1996 USPSTF commendation that reported benefits. Odds ratios for reductions in neural tube defects associated with periconceptional folic acid supplementation ranged from 0.11 to 0.65. A meta-analysis reported an OR of 0.67 in case-control studies and 0.52 in RCTs and cohort studies for neural tube defects associated with use of multivitamins containing folic acid. Adequate evidence indicates that folic acid supplementation leads to few harms. The USPSTF balanced the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit was substantial.

How Does Evidence Fit With Biological Understanding?

The function of folate is to act as a coenzyme in the metabolism of amino acids and nucleic acids.14 Its mechanism of action in the prevention of neural tube defects has not been established. However, a main function of folate is participation in one-carbon transfers, which are important in methylation reactions and in purine and pyrimidine synthesis. Folate is necessary for the regulation of DNA synthesis and function and, therefore, probably affects important events in embryogenesis that may lead to neural tube defects.

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Recommendations of Others

In 2003, an updated guideline from the American College of Obstetrics and Gynecology recommended periconceptual folic acid supplementation (0.4 mg) in a multivitamin for most women capable of pregnancy.18 For a woman planning to become pregnant and without a history of neural tube defects, the American Academy of Family Physicians (AAFP) strongly recommends prescribing folic acid supplementation of 0.4 to 0.8 mg/d. The AAFP also recommends prescribing 0.4 mg of folate supplementation to a woman of childbearing age if she is not planning a pregnancy.19 The American College of Obstetrics and Gynecology, AAFP, and most other organizations recommend 4 mg/d for women with a history of neural tube defects. "The American Academy of Pediatrics endorses the U.S. Public Health Service recommendation that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent neural tube defects," particularly for adolescent, "sexually active women who do not plan to use effective contraception or abstain from sexual intercourse."20,21 Because of teratogenesis and impaired folate metabolism associated with certain antiepileptic drugs, the American Academy of Neurology recommends folic acid supplementation of no less than 0.4 mg/d for women of childbearing age with epilepsy.22,23

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References

1. Bentley TG, Willett WC, Weinstein MC, Kuntz KM. Population-level changes in folate intake by age, gender, and race/ethnicity after folic acid fortification. Am J Public Health 2006;96:2040-7. [PMID: 17018833]

2. Mathews TJ. Trends in Spina Bifida and Anencephalus in the United States, 1991-2005. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics; 2007.

3. ACOG Committee on Practice Bulletins. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 44, July 2003. (Replaces Committee Opinion Number 252, March 2001). Obstet Gynecol 2003;102:203-13. [PMID: 12850637]

4. Thompson SJ, Torres ME, Stevenson RE, Dean JH, Best RG. Periconceptional multivitamin folic acid use, dietary folate, total folate and risk of neural tube defects in South Carolina. Ann Epidemiol 2003;13:412-8. [PMID: 12875798]

5. Botto LD, Moore CA, Khoury MJ, Erickson JD. Neural-tube defects. N Engl J Med 1999;341:1509-19. [PMID: 10559453]

6. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep 1992;41:1-7. [PMID: 1522835]

7. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5. [PMID: 1307234]

8. Screening for neural tube defects—including folic acid/folate prophylaxis. In: U.S. Preventive Services Task Force. Guide to Clinical Preventive Services, 2nd ed. Baltimore: Williams & Wilkins; 1996:467-83.

9. Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 1995;6:219-26. [PMID: 7619926]

10. Yang QH, Carter HK, Mulinare J, Berry RJ, Friedman JM, Erickson JD. Race-ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001-2002. Am J Clin Nutr 2007;85:1409-16. [PMID: 17490980]

11. Centers for Disease Control and Prevention (CDC). Use of supplements containing folic acid among women of childbearing age—United States, 2007. MMWR Morb Mortal Wkly Rep 2008;57:5-8. [PMID: 18185493]

12. Quinlivan EP, Gregory JF 3rd. Reassessing folic acid consumption patterns in the United States (1999-2004): potential effect on neural tube defects and overexposure to folate. Am J Clin Nutr 2007;86:1773-9. [PMID: 18065598]

13. Cornel MC, de Smit DJ, de Jong-van den Berg LT. Folic acid—the scientific debate as a base for public health policy. Reprod Toxicol 2005;20:411-5. [PMID: 15978774]

14. Eichholzer M, Tönz O, Zimmermann R. Folic acid: a public-health challenge. Lancet 2006;367:1352-61. [PMID: 16631914]

15. Vollset SE, Gjessing HK, Tandberg A, Rønning T, Irgens LM, Baste V, et al. Folate supplementation and twin pregnancies. Epidemiology 2005;16:201-5. [PMID: 15703534]

16. Wright JD, Bialostosky K, Gunter EW, Carroll MD, Najjar MF, Bowman BA, et al. Blood folate and vitamin B12: United States, 1988-94. Vital Health Stat 11. 1998:1-78. [PMID: 10222835]

17. Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003;77:1474-7. [PMID: 12791626]

18. ACOG Committee on Practice Bulletins. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 44, July 2003. (Replaces Committee Opinion Number 252, March 2001). Obstet Gynecol 2003;102:203-13. [PMID: 12850637]

19. American Academy of Family Physicians. Summary of Recommendations for Clinical and Preventive Services. March 2008. Accessed at http://www.aafp.org/online/en/home/clinical/exam.html Exit Disclaimer on 25 September 2008.

20. Folic acid for the prevention of neural tube defects. American Academy of Pediatrics. Committee on Genetics. Pediatrics 1999;104:325-7. [PMID: 10429019]

21. Klein JD; American Academy of Pediatrics Committee on Adolescence. Adolescent pregnancy: current trends and issues. Pediatrics 2005;116:281-6. [PMID: 15995071]

22. Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Epilepsia 1998;39:1226-31. [PMID: 9821989]

23. Yerby MS. Management issues for women with epilepsy: neural tube defects and folic acid supplementation. Neurology 2003;61:S23-6. [PMID: 14504306]

Members of the U.S. Preventive Services Task Force

Members of the U.S. Preventive Services Task Force* are Ned Calonge, MD, MPH, Chair, USPSTF (Colorado Department of Public Health and Environment, Denver, Colorado); Diana B. Petitti, MD, MPH, Vice-chair, USPSTF (Arizona State University, Phoenix, Arizona); Thomas G. DeWitt, MD (Children's Hospital Medical Center, Cincinnati, Ohio); Allen J. Dietrich, MD (Dartmouth Medical School, Hanover, New Hampshire); Kimberly D. Gregory, MD, MPH (Cedars-Sinai Medical Center, Los Angeles, California); David Grossman, MD, MPH (Group Health Cooperative, Seattle, Washington); George Isham, MD, MS (HealthPartners Inc., Minneapolis, Minnesota); Michael L. LeFevre, MD, MSPH (University of Missouri School of Medicine, Columbia, Missouri); Rosanne M. Leipzig, MD, PhD (Mount Sinai School of Medicine, New York, New York); Lucy N. Marion, PhD, RN (School of Nursing, Medical College of Georgia, Augusta, Georgia); Bernadette Melnyk, PhD, RN (Arizona State University College of Nursing & Healthcare Innovation, Phoenix, Arizona); Virginia A. Moyer, MD, MPH (Baylor College of Medicine, Houston, Texas); Judith K. Ockene, PhD (University of Massachusetts Medical School, Worcester, Massachusetts); George F. Sawaya, MD (University of California, San Francisco, San Francisco, California); J. Sanford Schwartz, MD (University of Pennsylvania School of Medicine and The Wharton School, Philadelphia, Pennsylvania); Timothy Wilt, MD, MPH (Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota).

*Members of the Task Force at the time this recommendation was finalized. For a list of current Task Force members, go to http://www.uspreventiveservicestaskforce.org/about.htm.

Disclaimer: Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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Copyright

This document is in the public domain within the United States.

Requests for linking or to incorporate content in electronic resources should be sent via the USPSTF contact form.

Source: U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;150:626-31.

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AHRQ Publication No. 09-05132-EF-2
Current as of May 2009


Internet Citation:

U.S. Preventive Services Task Force. Folic Acid for the Prevention of Neural Tube Defects: U.S. Preventive Services Task Force Recommendation Statement. AHRQ Publication No. 09-05132-EF-2, May 2009. http://www.uspreventiveservicestaskforce.org/uspstf09/folicacid/folicacidrs.htm


 


 


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