A statement published in JAMA by the US Preventive Services Task Force (USPSTF) indicates that the benefits of folic acid supplementation, first recommended in 1992 for the prevention of neural tube defects (NTDs) during pregnancy, are still substantial, and that current evidence shows minimal potential harm to the mother or fetus.1,2
The original USPSTF recommendation came in response to a finding from a 1991 study that showed that NTDs were reduced by more than 50% in women who took folic acid supplements prior to conception.3 The initial dose recommendation in 1992 was 400 μg/d, which was expanded in 2009 to 400 to 800 μg/d.4 According to an accompanying editorial in the same 2016 issue of JAMA by James Mills, MD, supplementation, when combined with the mandated fortification of all enriched cereal grains instituted in the United States in 1996, has resulted in significant reduction in NTD rates.5,6
The current revised evidence report and systematic review of literature conducted for the USPSTF1 evaluated 24 studies of folic acid supplementation published from 1984 to January of 2016. The reviewers identified 32 good-quality or fair-quality articles from a total of 5786 that provided results of primary studies or systematic reviews.
Twenty publications demonstrated clear benefits of folic acid supplementation, capturing case-controlled data from 8 data sources that reported on births occurring from 1976 to 2007 (including the Hungarian trial,7-12,13 the Hungarian cohort,14 the National Birth Defects Prevention Study,15,16 the Slone Birth Defects Study,17-19 the National Institute of Child Health and Human Development [NICHD] Neural Tube Defects Study,20 the New England study,21,22 the California Birth Defects Monitoring Program,22 and the Texas Department of Health’s Neural Tube Defect Project23). One of the most significant randomized clinical trials was conducted in Hungary with 5453 women from 1984 to 1992. This study reported 6 cases of NTDs in women who had not taken supplementation compared with no cases in the group who did.7-11
The second issue opened to review was whether there was evidence of increased risk associated with folic acid supplementation. Both the Hungarian trial and one prospective cohort study demonstrated no statistically significant increase in the risk of twin births associated with supplementation.10,25 Other risks for asthma, wheezing, and allergy were evaluated in 3 studies that failed to show consistent evidence of a link to folic acid supplementation.26-28
The authors pointed out that a potential factor in the limited risk of harm from supplementation is that so few women exceed the upper limits of dosing; the 2015 Dietary Guideline Advisory Committee reported that less than 3% of women between the ages of 14 and 50 years had a daily intake of more than 1000 μg/d from combined food and supplementation sources.29
As neural tube defects appear by the 28th day of pregnancy (when the neural tube closes), the current updated USPSTF recommendations targeted women who are “planning or capable of pregnancy,” suggesting dosages of 400 to 800 μg/d.2 These recommendations were extended to all women of childbearing years. 2
- Viswanathan M, Treiman KA, Kish-Doto J, et al. Folic acid supplementation: an evidence review for the US preventive services task force: evidence synthesis No. 145. Rockville, MD: Agency for Healthcare Research and Quality; 2017. AHRQ publication 14-05214-EF-1.
- US Preventive Services Task Force. Folic acid supplementation for the prevention of neural tube defects. JAMA. 2017;317:183-189.
- MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137.
- US Preventive Services Task Force. Folic acid for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:626-631.
- US Department of Health and Human Services. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist. 1996;61:8781-8797.
- Castillo-Lancellotti C, Tur JA, Uauy R. Impact of folic acid fortification of flour on neural tube defects: a systematic review. Public Health Nutr. 2013;16:901-911.
- Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327:1832-1835.
- Czeizel AE. Prevention of congenital abnormalities by periconceptional multivitamin supplementation. BMJ. 1993;306:1645-1648.
- Czeizel AE, Dudas I, Metneki J. Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation: final report. Arch Gynecol Obstet. 1994;255:131-139.
- Czeizel AE,Metneki J, Dudas I. The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Genet Med Gemellol (Roma). 1994;43:175-184.
- Czeizel AE. Controlled studies of multivitamin supplementation on pregnancy outcomes. Ann N Y Acad Sci. 1993;678:266-275.
- Czeizel AE. Periconceptional folic acid containing multivitamin supplementation. Eur J Obstet Gynecol Reprod Biol. 1998;78:151-161.
- Czeizel AE. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet. 1996;62:179-183.
- Czeizel AE, Dobo M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2004;70:853-861.
- Agopian AJ, Tinker SC, Lupo PJ, Canfield MA, Mitchell LE; National Birth Defects Prevention Study. Proportion of neural tube defects attributable to known risk factors. Birth Defects Res A Clin Mol Teratol. 2013;97:42-46.
- Mosley BS, Cleves MA, Siega-Riz AM, et al; National Birth Defects Prevention Study. Neural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States. Am J Epidemiol. 2009;169:9-17.
- Ahrens K, Yazdy MM, Mitchell AA, et al. Folic acid intake and spina bifida in the era of dietary folic acid fortification. Epidemiology. 2011;22:731-737.
- Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol. 2001;153:961-968.
- Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA. 1993;269:1257-1261.
- Mills JL, Rhoads GG, Simpson JL, et al; National Institute of Child Health and Human Development Neural Tube Defects Study Group. The absence of a relation between the periconceptional use of vitamins and neural-tube defects. N Engl J Med. 1989;321:430-435.
- Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA. 1989;262:2847-2852.
- Moore LL, Bradlee ML, Singer MR, Rothman KJ, Milunsky A. Folate intake and the risk of neural tube defects: an estimation of dose-response. Epidemiology. 2003;14:200-205.
- Shaw GM, Schaffer D, Velie EM, et al. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology. 1995;6:219-226.
- Suarez L, Hendricks KA, Cooper SP, et al. Neural tube defects among Mexican Americans living on the US-Mexico border: effects of folic acid and dietary folate. Am J Epidemiol. 2000;152:1017-1023.
- Vollset SE, Gjessing HK, Tandberg A, et al. Folate supplementation and twin pregnancies. Epidemiology. 2005;16:201-205.
- Crider KS, Cordero AM, Qi YP, et al. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98:1272-1281.
- Yang L, Jiang L, BiM, et al. High dose of maternal folic acid supplementation is associated to infant asthma. Food Chem Toxicol. 2015;75:88-93.
- Wang T, Zhang HP, Zhang X, et al. Is folate status a risk factor for asthma or other allergic diseases? Allergy Asthma Immunol Res. 2015;7:538-546.
- Dietary Guidelines Advisory Committee. Scientific report of the 2015 dietary guidelines advisory committee: advisory report to the secretary of health and human services. Rockville, MD: US Departments of Health and Human Services HHS) and Agriculture (USDA); 2015.