1932

Abstract

For three decades, the US Public Health Service has recommended that all persons capable of becoming pregnant consume 400 μg/day of folic acid (FA) to prevent neural tube defects (NTDs). The neural tube forms by 28 days after conception. Fortification can be an effective NTD prevention strategy in populations with limited access to folic acid foods and/or supplements. This review describes the status of mandatory FA fortification among countries that fortify ( = 71) and the research describing the impact of those programs on NTD rates (up to 78% reduction), blood folate concentrations [red blood cell folate concentrations increased ∼1.47-fold (95% CI, 1.27, 1.70) following fortification], and other health outcomes. Across settings, high-quality studies such as those with randomized exposures (e.g., randomized controlled trials, Mendelian randomization studies) are needed to elucidate interactions of FA with vitamin B as well as expanded biomarker testing.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-nutr-043020-091647
2022-08-22
2024-06-22
Loading full text...

Full text loading...

/deliver/fulltext/nutr/42/1/annurev-nutr-043020-091647.html?itemId=/content/journals/10.1146/annurev-nutr-043020-091647&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Agopian AJ, Tinker SC, Lupo PJ, Canfield MA, Mitchell LE. 2013. Proportion of neural tube defects attributable to known risk factors. Birth Defects Res. A 97:42–46
    [Google Scholar]
  2. 2.
    Amarin ZO, Obeidat AZ. 2010. Effect of folic acid fortification on the incidence of neural tube defects. Paediatr. Perinat. Epidemiol. 24:349–51
    [Google Scholar]
  3. 3.
    Atta CA, Fiest KM, Frolkis AD, Jette N, Pringsheim T et al. 2016. Global birth prevalence of spina bifida by folic acid fortification status: a systematic review and meta-analysis. Am. J. Public Health 106:e24–34
    [Google Scholar]
  4. 4.
    Auger N, Fraser WD, Arbour L, Bilodeau-Bertrand M, Kosatsky T. 2017. Elevated ambient temperatures and risk of neural tube defects. Occup. Environ. Med. 74:315–20
    [Google Scholar]
  5. 5.
    Bailey LB, Stover PJ, McNulty H, Fenech MF, Gregory JF 3rd et al. 2015. Biomarkers of nutrition for development—folate review. J. Nutr. 145:Suppl.1636–80
    [Google Scholar]
  6. 6.
    Bailey SWA, June E 2018. The pharmacokinetic advantage of 5-methyltetrahydrofolate for minimization of the risk for birth defects. Sci. Rep. 8:4096
    [Google Scholar]
  7. 7.
    Barboza-Argüello M, Umaña-Solís LM, Azofeifa A, Valencia D, Flores AL et al. 2015. Neural tube defects in Costa Rica, 1987–2012: origins and development of birth defect surveillance and folic acid fortification. Matern. Child Health J. 19:583–90
    [Google Scholar]
  8. 8.
    Bar-Oz B, Koren G, Nguyen P, Kapur BM. 2008. Folate fortification and supplementation—are we there yet?. Reprod. Toxicol. 25:408–12
    [Google Scholar]
  9. 9.
    Berry RJ. 2019. Lack of historical evidence to support folic acid exacerbation of the neuropathy caused by vitamin B12 deficiency. Am. J. Clin. Nutr. 110:554–61
    [Google Scholar]
  10. 10.
    Berry RJ, Bailey L, Mulinare J, Bower C. 2010. Fortification of flour with folic acid. Food Nutr. Bull. 31:Suppl. 122–35
    [Google Scholar]
  11. 11.
    Berry RJ, Carter HK, Yang Q 2007. Cognitive impairment in older Americans in the age of folic acid fortification. Am. J. Clin. Nutr. 86:265–69
    [Google Scholar]
  12. 12.
    Berry RJ, Li Z, Erickson JD, Li S, Moore CA et al. 1999. Prevention of neural-tube defects with folic acid in China. China–U.S. Collaborative Project for Neural Tube Defect Prevention. N. Engl. J. Med. 341:1485–90 Erratum 1999. N. Engl. J. Med. 341:1864
    [Google Scholar]
  13. 13.
    Black MM. 2008. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr. Bull. 29:Suppl. 2126–31
    [Google Scholar]
  14. 14.
    Blencowe H, Cousens S, Modell B, Lawn J. 2010. Folic acid to reduce neonatal mortality from neural tube disorders. Int. J. Epidemiol. 39:Suppl. 1110–21
    [Google Scholar]
  15. 15.
    Bozack AK, Hall MN, Liu X, Ilievski V, Lomax-Luu AM et al. 2018. Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh. Am. J. Clin. Nutr. 109:380–91
    [Google Scholar]
  16. 16.
    Burdge GC, Lillycrop KA. 2012. Folic acid supplementation in pregnancy: Are there devils in the detail?. Br. J. Nutr. 108:1924–30
    [Google Scholar]
  17. 17.
    Canfield MA, Ramadhani TA, Shaw GM, Carmichael SL, Waller DK et al. 2009. Anencephaly and spina bifida among Hispanics: maternal, sociodemographic, and acculturation factors in the National Birth Defects Prevention Study. Birth Defects Res. A 85:637–46
    [Google Scholar]
  18. 18.
    Carmichael SL, Rasmussen SA, Shaw GM. 2010. Prepregnancy obesity: a complex risk factor for selected birth defects. Birth Defects Res. A 88:804–10
    [Google Scholar]
  19. 19.
    CDC (Cent. Dis. Control Prev.). 1992. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morb. Mortal. Wkly. Rep. Recomm. Rep. 41:1–7
    [Google Scholar]
  20. 20.
    CDC (Cent. Dis. Control Prev.). 2010. CDC Grand Rounds: additional opportunities to prevent neural tube defects with folic acid fortification. Morb. Mortal. Wkly. Rep. 59:980–84
    [Google Scholar]
  21. 21.
    Chen LT, Rivera MA. 2004. The Costa Rican experience: reduction of neural tube defects following food fortification programs. Nutr. Rev. 62:S40–43
    [Google Scholar]
  22. 22.
    Chen MY, Rose CE, Qi YP, Williams JL, Yeung LF et al. 2019. Defining the plasma folate concentration associated with the red blood cell folate concentration threshold for optimal neural tube defects prevention: a population-based, randomized trial of folic acid supplementation. Am. J. Clin. Nutr. 109:1452–61
    [Google Scholar]
  23. 23.
    Clarke R, Birks J, Nexo E, Ueland PM, Schneede J et al. 2007. Low vitamin B-12 status and risk of cognitive decline in older adults. Am. J. Clin. Nutr. 86:1384–91
    [Google Scholar]
  24. 24.
    Clarke R, Sherliker P, Hin H, Molloy AM, Nexo E et al. 2008. Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK. Br. J. Nutr. 100:1054–59
    [Google Scholar]
  25. 25.
    Cordero AM, Crider KS, Rogers LM, Cannon MJ, Berry RJ. 2015. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. Morb. Mortal. Wkly. Rep. 64:421–23
    [Google Scholar]
  26. 26.
    Cortes F, Mellado C, Pardo RA, Villarroel LA, Hertrampf E. 2012. Wheat flour fortification with folic acid: changes in neural tube defects rates in Chile. Am. J. Med. Genet. A 158A:1885–90
    [Google Scholar]
  27. 27.
    Crider KS, Devine O, Hao L, Dowling NF, Li S et al. 2014. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ 349:g4554
    [Google Scholar]
  28. 28.
    Crider KS, Devine O, Qi YP, Yeung LF, Sekkarie A et al. 2019. Systematic review and Bayesian meta-analysis of the dose–response relationship between folic acid intake and changes in blood folate concentrations. Nutrients 11:71
    [Google Scholar]
  29. 29.
    Crider KS, Qi YP, Devine O, Tinker SC, Berry RJ. 2018. Modeling the impact of folic acid fortification and supplementation on red blood cell folate concentrations and predicted neural tube defect risk in the United States: Have we reached optimal prevention?. Am. J. Clin. Nutr. 107:1027–34
    [Google Scholar]
  30. 30.
    Crider KS, Yang TP, Berry RJ, Bailey LB. 2012. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv. Nutr. 3:21–38
    [Google Scholar]
  31. 31.
    Crider KS, Zhu JH, Hao L, Yang QH, Yang TP et al. 2011. MTHFR 677C→T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Am. J. Clin. Nutr. 93:1365–72
    [Google Scholar]
  32. 32.
    Czeizel AE, Dudás I. 1992. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 327:1832–35
    [Google Scholar]
  33. 33.
    Das JK, Salam RA, Mahmood SB, Moin A, Kumar R et al. 2019. Food fortification with multiple micronutrients: impact on health outcomes in general population. Cochrane Database Syst. Rev. 12:CD011400
    [Google Scholar]
  34. 34.
    Degerud EM, Manger MS, Strand TA, Dierkes J. 2015. Bioavailability of iron, vitamin A, zinc, and folic acid when added to condiments and seasonings. Ann. N. Y. Acad. Sci. 1357:29–42
    [Google Scholar]
  35. 35.
    De Wals P, Rusen ID, Lee NS, Morin P, Niyonsenga T. 2003. Trend in prevalence of neural tube defects in Quebec. Birth Defects Res. A 67:919–23
    [Google Scholar]
  36. 36.
    Dietrich M, Brown CJ, Block G. 2005. 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. 24:266–74
    [Google Scholar]
  37. 37.
    Dickinson CJ. 1995. Does folic acid harm people with vitamin B12 deficiency?. QJM 88:357–64
    [Google Scholar]
  38. 38.
    Duong HT, Hashmi SS, Ramadhani T, Canfield MA, Scheuerle A, Waller DK. 2011. Maternal use of hot tub and major structural birth defects. Birth Defects Res. A 91:836–41
    [Google Scholar]
  39. 39.
    Ebrahimi S, Ashkani-Esfahani S, Bagheri F. 2013. Prevalence of neural tube defects in Yasuj, Southwest Iran. Shiraz E Med. J. 14:5462
    [Google Scholar]
  40. 40.
    Engle-Stone R, Nankap M, Ndjebayi AO, Allen LH, Shahab-Ferdows S et al. 2017. Iron, zinc, folate, and vitamin B-12 status increased among women and children in Yaounde and Douala, Cameroon, 1 year after introducing fortified wheat flour. J. Nutr. 147:1426–36
    [Google Scholar]
  41. 41.
    Fazili Z, Sternberg MR, Potischman N, Wang CY, Storandt RJ et al. 2020. Demographic, physiologic, and lifestyle characteristics observed with serum total folate differ among folate forms: cross-sectional data from fasting samples in the NHANES 2011–2016. J. Nutr. 150:851–60
    [Google Scholar]
  42. 42.
    FDA (US Food Drug Adm.) Food additives permitted for direct addition to food for human consumption; folic acid. 81 Fed. Reg. 22176–83 April 15, 2016.)
  43. 43.
    FDA (US Food Drug Adm.) Food labeling: health claims and label statements; folate and neural tube defects; proposed rules. 61 Fed. Reg. 8752–81 March 5, 1996.)
  44. 44.
    FDA (US Food Drug Adm.) Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid; correction. 61 Fed. Reg 40513 Aug. 5, 1996.)
  45. 45.
    FDA (US Food Drug Adm.) Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid; final rule. 61 Fed. Reg. 8781–97 March 5, 1996.)
  46. 46.
    FDA (US Food Drug Adm.) 2018. Determining the regulatory status of a food ingredient Fact Sheet, FDA Washington, DC: https://www.fda.gov/food/food-ingredients-packaging/determining-regulatory-status-food-ingredient
    [Google Scholar]
  47. 47.
    Ferrazzi E, Tiso G, Di Martino D. 2020. Folic acid versus 5-methyl tetrahydrofolate supplementation in pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 253:312–19
    [Google Scholar]
  48. 48.
    Finer LB, Zolna MR. 2016. Declines in unintended pregnancy in the United States, 2008–2011. N. Engl. J. Med. 374:843–52
    [Google Scholar]
  49. 49.
    Finkelstein JL, Fothergill A, Johnson CB, Guetterman HM, Bose B et al. 2021. Anemia and vitamin B-12 and folate status in women of reproductive age in southern India: estimating population-based risk of neural tube defects. Curr. Dev. Nutr. 5:nzab069
    [Google Scholar]
  50. 50.
    Food Saf. Auth. Irel 2009. Currently no need for mandatory fortification—increased folate status negates mandatory folic acid fortification at this time Press Release, Food Saf Auth. Irel., Dublin: March 11. https://www.fsai.ie/details.aspx?id=7706
    [Google Scholar]
  51. 51.
    Food Stand. Aust. N. Z 2006. Mandatory folic acid fortification Rep. Food Stand. Aust. N. Z. Kingston, Aust: https://www.foodstandards.gov.au/code/proposals/documents/Short%20Guide%20_mandatory%20folic%20acid%20fortification__FINAL_%20_4_.pdf
    [Google Scholar]
  52. 52.
    Food Stand. Aust. N. Z 2007. Proposal P295: consideration of mandatory fortification with folic acid Final Assess. Rep. 7-06 Food Stand. Aust. N. Z. Kingston, Aust:.
    [Google Scholar]
  53. 53.
    Fox JT, Stover PJ. 2008. Folate-mediated one-carbon metabolism. Vitam. Horm. 79:1–44
    [Google Scholar]
  54. 54.
    French AE, Grant R, Weitzman S, Ray JG, Vermeulen MJ et al. 2003. Folic acid food fortification is associated with a decline in neuroblastoma. Clin. Pharmacol. Ther. 74:288–94
    [Google Scholar]
  55. 55.
    Friso S, Choi SW. 2002. Gene–nutrient interactions and DNA methylation. J. Nutr. 132:Suppl. 82382–87
    [Google Scholar]
  56. 56.
    Fuks F. 2005. DNA methylation and histone modifications: teaming up to silence genes. Curr. Opin. Genet. Dev. 15:490–95
    [Google Scholar]
  57. 57.
    Gabbay-Benziv R, Reece EA, Wang F, Yang P 2015. Birth defects in pregestational diabetes: defect range, glycemic threshold and pathogenesis. World J. Diabetes 6:481–88
    [Google Scholar]
  58. 58.
    Gamble MV, Liu X, Ahsan H, Pilsner JR, Ilievski V et al. 2006. Folate and arsenic metabolism: a double-blind, placebo-controlled folic acid-supplementation trial in Bangladesh. Am. J. Clin. Nutr. 84:1093–101
    [Google Scholar]
  59. 59.
    Gamble MV, Liu X, Slavkovich V, Pilsner JR, Ilievski V et al. 2007. Folic acid supplementation lowers blood arsenic. Am. J. Clin. Nutr. 86:1202–9
    [Google Scholar]
  60. 60.
    Ganji V, Kafai MR. 2009. Hemoglobin and hematocrit values are higher and prevalence of anemia is lower in the post–folic acid fortification period than in the pre–folic acid fortification period in US adults. Am. J. Clin. Nutr. 89:363–71
    [Google Scholar]
  61. 61.
    Grosse SD, Berry RJ, Tilford JM, Kucik JE, Waitzman NJ. 2016. Retrospective assessment of cost savings from prevention: folic acid fortification and spina bifida in the U.S. Am. J. Prev. Med. 50:Suppl. 574–80
    [Google Scholar]
  62. 62.
    Grosse SD, Waitzman NJ, Romano PS, Mulinare J. 2005. Reevaluating the benefits of folic acid fortification in the United States: economic analysis, regulation, and public health. Am. J. Public Health 95:1917–22
    [Google Scholar]
  63. 63.
    Grupp SG, Greenberg ML, Ray JG, Busto U, Lanctôt KL et al. 2011. Pediatric cancer rates after universal folic acid flour fortification in Ontario. J. Clin. Pharmacol. 51:60–65
    [Google Scholar]
  64. 64.
    Hao LM, Jing, Stampfer MJ, Ren A, Tian Y et al. 2003. Geographical, seasonal and gender differences in folate status among Chinese adults. J. Nutr. 133:3630–35
    [Google Scholar]
  65. 65.
    Hao L, Yang QH, Li Z, Bailey LB, Zhu J-H et al. 2008. Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial. Am. J. Clin. Nutr. 88:448–57
    [Google Scholar]
  66. 66.
    Hausman DB, Johnson MA, Davey A, Woodard JL, Poon LW et al. 2011. The oldest old: red blood cell and plasma folate in African American and white octogenarians and centenarians in Georgia. J. Nutr. Health Aging 15:744–50
    [Google Scholar]
  67. 67.
    Health Counc. Neth 2008. Towards an optimal use of folic acid Rep. 2008/02E Health Counc. Neth. The Hague:
    [Google Scholar]
  68. 68.
    Henderson AM, Aleiunas RE, Loh SP, Khor GL, Harvey-Leeson S et al. 2018. l-5-methyltetrahydrofolate supplementation increases blood folate concentrations to a greater extent than folic acid supplementation in Malaysian women. J. Nutr. 148:885–90
    [Google Scholar]
  69. 69.
    Herbert V, Zalusky R. 1962. Interrelations of vitamin B12 and folic acid metabolism: folic acid clearance studies. J. Clin. Investig. 41:1263–76
    [Google Scholar]
  70. 70.
    Hertrampf E, Cortes F, Erickson JD, Cayazzo M, Freire W et al. 2003. Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile. J. Nutr. 133:3166–69
    [Google Scholar]
  71. 71.
    Honein MA, Devine O, Sharma AJ, Rasmussen SA, Park S et al. 2013. Modeling the potential public health impact of prepregnancy obesity on adverse fetal and infant outcomes. Obesity 21:1276–83
    [Google Scholar]
  72. 72.
    Huang HY, Chen HL, Feng LP. 2017. Maternal obesity and the risk of neural tube defects in offspring: a meta-analysis. Obes. Res. Clin. Pract. 11:188–97
    [Google Scholar]
  73. 73.
    Inst. Med 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Panthothenic Acid, Biotin, and Choline Washington, DC: Natl. Acad.
    [Google Scholar]
  74. 74.
    Ionescu-Ittu R, Marelli AJ, Mackie AS, Pilote L. 2009. Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. BMJ 338:b1673
    [Google Scholar]
  75. 75.
    Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. 1999. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med. 340:1449–54
    [Google Scholar]
  76. 76.
    Jhaveri MS, Wagner C, Trepel JB. 2001. Impact of extracellular folate levels on global gene expression. Mol. Pharmacol. 60:1288–95
    [Google Scholar]
  77. 77.
    Jiang T, Christian P, Khatry SK, Wu L, West KP Jr. 2005. Micronutrient deficiencies in early pregnancy are common, concurrent, and vary by season among rural Nepali pregnant women. J. Nutr. 135:1106–12
    [Google Scholar]
  78. 78.
    Joseph KS, Kramer MS. 1996. Review of the evidence on fetal and early childhood antecedents of adult chronic disease. Epidemiol. Rev. 18:158–74
    [Google Scholar]
  79. 79.
    Kamen BA, Smith AK. 2004. A review of folate receptor α cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv. Drug Deliv. Rev. 56:1085–97
    [Google Scholar]
  80. 80.
    Kancherla V, Tsang B, Wagh K, Dixon M, Oakley GP Jr. 2020. Modeling shows high potential of folic acid–fortified salt to accelerate global prevention of major neural tube defects. Birth Defects Res 112:1461–74
    [Google Scholar]
  81. 81.
    Keats EC, Neufeld LM, Garrett GS, Mbuya MNN, Bhutta ZA. 2019. Improved micronutrient status and health outcomes in low- and middle-income countries following large-scale fortification: evidence from a systematic review and meta-analysis. Am. J. Clin. Nutr. 109:1696–708
    [Google Scholar]
  82. 82.
    Kerr SM, Parker SE, Mitchell AA, Tinker SC, Werler MM. 2017. Periconceptional maternal fever, folic acid intake, and the risk for neural tube defects. Ann. Epidemiol. 27:777–82.e1
    [Google Scholar]
  83. 83.
    Keum N, Giovannucci EL. 2014. Folic acid fortification and colorectal cancer risk. Am. J. Prev. Med. 46:Suppl. 165–72
    [Google Scholar]
  84. 84.
    Knoops KT, Spiro A 3rd, de Groot LC, Kromhout D, van Staveren WA, Tucker KL. 2009. Do dietary patterns in older men influence change in homocysteine through folate fortification? The Normative Aging Study. Public Health Nutr. 12:1760–66
    [Google Scholar]
  85. 85.
    Kubo Y, Fukuoka H, Kawabata T, Shoji K, Mori C et al. 2020. Distribution of 5-methyltetrahydrofolate and folic acid levels in maternal and cord blood serum: longitudinal evaluation of Japanese pregnant women. Nutrients 12:1633
    [Google Scholar]
  86. 86.
    Kurzius-Spencer M, da Silva V, Thomson CA, Hartz V, Hsu CH et al. 2017. Nutrients in one-carbon metabolism and urinary arsenic methylation in the National Health and Nutrition Examination Survey (NHANES) 2003–2004. Sci. Total Environ.607–608381–90
    [Google Scholar]
  87. 87.
    Lavoie A, Tripp E, Hoffbrand AV. 1974. The effect of vitamin B12 deficiency on methylfolate metabolism and pteroylpolyglutamate synthesis in human cells. Clin. Sci. Mol. Med. 47:617–30
    [Google Scholar]
  88. 88.
    Lee-Kwan SH, Moore LV, Blanck HM, Harris DM, Galuska D. 2017. Disparities in state-specific adult fruit and vegetable consumption—United States, 2015. Morb. Mortal. Wkly. Rep. 66:1241–47
    [Google Scholar]
  89. 89.
    Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB. 2016. Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J. Am. Heart Assoc. 5:e003768
    [Google Scholar]
  90. 90.
    Li YO, Diosade LL, Wesley AS. 2011. Folic acid fortification through existing fortified foods: iodized salt and vitamin A–fortified sugar. Food Nutr. Bull. 32:35–41
    [Google Scholar]
  91. 91.
    Linabery AM, Johnson KJ, Ross JA. 2012. Childhood cancer incidence trends in association with US folic acid fortification (1986–2008). Pediatrics 129:1125–33
    [Google Scholar]
  92. 92.
    Lindsey LLM, Hamner HC, Prue CE, Flores AL, Valencia D et al. 2007. Understanding optimal nutrition among women of childbearing age in the United States and Puerto Rico: employing formative research to lay the foundation for national birth defects prevention campaigns. J. Health Commun. 12:733–57
    [Google Scholar]
  93. 93.
    Liu S, Joseph KS, Luo W, León JA, Lisonkova S et al. 2016. Effect of folic acid food fortification in Canada on congenital heart disease subtypes. Circulation 134:647–55
    [Google Scholar]
  94. 94.
    Liu S, West R, Randell E, Longerich L, O'Connor KS et al. 2004. A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects. BMC Pregnancy Childbirth 4:20
    [Google Scholar]
  95. 95.
    Llanos AH, Hertrampf E, Cortes F, Pardo A, Grosse SD, Uauy R. 2007. Cost-effectiveness of a folic acid fortification program in Chile. Health Policy 83:295–303
    [Google Scholar]
  96. 96.
    Lopez-Camelo JS, Castilla EE, Orioli IM. 2010. Folic acid flour fortification: impact on the frequencies of 52 congenital anomaly types in three South American countries. Am. J. Med. Genet. A 152A:2444–58
    [Google Scholar]
  97. 96a.
    Lopez-Camelo JS, Orioli IM, da Graça Dutra M, Nazer-Herrera J, Rivera Net al 2005. Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile. Am. J. Med. Genet. A 135:212025
    [Google Scholar]
  98. 97.
    Malpeli A, Ferrari MG, Varea A, Falivene M, Etchegoyen G et al. 2013. Short-term evaluation of the impact of a fortified food aid program on the micronutrient nutritional status of Argentinian pregnant women. Biol. Trace Elem. Res. 155:176–83
    [Google Scholar]
  99. 98.
    Mannar VD, Diosady L. 2019. Quadruple fortification of salt with iodine, iron, vitamins B9 and B12 to reduce maternal and neonatal mortality by reducing anemia and nutritional deficiency prevalence. Curr. Dev. Nutr. 3:Suppl. 1P24–041-19
    [Google Scholar]
  100. 99.
    Marchetta CM, Devine OJ, Crider KS, Tsang BL, Cordero AM et al. 2015. Assessing the association between natural food folate intake and blood folate concentrations: a systematic review and Bayesian meta-analysis of trials and observational studies. Nutrients 7:2663–86
    [Google Scholar]
  101. 100.
    Martínez de Villarreal L, Villareal Pérez JZ, Arredondo Vázquez P, Hernández Herrera R, Velazco Campos MDR et al. 2002. Decline of neural tube defects cases after a folic acid campaign in Nuevo Leon, Mexico. Teratology 66:249–56
    [Google Scholar]
  102. 101.
    Mazumdar M, Hasan MOSI, Hamid R, Valeri L, Paul L et al. 2015. Arsenic is associated with reduced effect of folic acid in myelomeningocele prevention: a case control study in Bangladesh. Environ. Health 14:34
    [Google Scholar]
  103. 102.
    McGee EJT, Sangakkara AR, Diosady LL. 2017. Double fortification of salt with folic acid and iodine. J. Food Eng. 198:72–80
    [Google Scholar]
  104. 103.
    Mejia LA, Bower AM. 2015. The global regulatory landscape regarding micronutrient fortification of condiments and seasonings. Ann. N. Y. Acad. Sci. 1357:1–7
    [Google Scholar]
  105. 104.
    Metz JM, McNeil AR, Levin M. 2004. The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate. Clin. Lab. Haematol. 26:323–25
    [Google Scholar]
  106. 105.
    Millacura N, Pardo R, Cifuentes L, Suazo J. 2017. Effects of folic acid fortification on orofacial clefts prevalence: a meta-analysis. Public Health Nutr. 20:2260–68
    [Google Scholar]
  107. 106.
    Miller JW, Garrod MG, Allen LH, Haan MN, Green R. 2009. Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate. Am. J. Clin. Nutr. 90:1586–92
    [Google Scholar]
  108. 107.
    Mills JL, Carter TC, Scott JM, Troendle JF, Gibney ER et al. 2011. Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status?. Am. J. Clin. Nutr. 94:495–500
    [Google Scholar]
  109. 108.
    Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C et al. 2003. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am. J. Clin. Nutr. 77:1474–77
    [Google Scholar]
  110. 109.
    Modupe O, Krishnaswamy K, Diosady LL. 2019. Technology for triple fortification of salt with folic acid, iron, and iodine. J. Food Sci. 84:2499–506
    [Google Scholar]
  111. 110.
    Molloy AM. 2018. Should vitamin B12 status be considered in assessing risk of neural tube defects?. Ann. N. Y. Acad. Sci. 1414:109–25
    [Google Scholar]
  112. 111.
    Moretti ME, Bar-Oz B, Fried S, Koren G. 2005. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology 16:216–19
    [Google Scholar]
  113. 112.
    Morris MS, Jacques PF, Rosenberg IH, Selhub J. 2007. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am. J. Clin. Nutr. 85:193–200
    [Google Scholar]
  114. 113.
    Morris MS, Jacques PF, Rosenberg IH, Selhub J. 2010. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am. J. Clin. Nutr. 91:1733–44
    [Google Scholar]
  115. 114.
    Morris MS, Selhub J, Jacques PF. 2012. Vitamin B-12 and folate status in relation to decline in scores on the Mini–Mental State Examination in the Framingham Heart Study. J. Am. Geriatr. Soc. 60:1457–64
    [Google Scholar]
  116. 115.
    Mowla SG, Gissler M, Räisänen S, Kancherla V. 2020. Association between maternal pregestational diabetes mellitus and spina bifida: a population-based case-control study, Finland, 2000–2014. Birth Defects Res 112:186–95
    [Google Scholar]
  117. 116.
    MRC Vitam. Study Res. Group 1991. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338:131–37
    [Google Scholar]
  118. 117.
    Mukhtar A, Kramer MR, Oakley GP Jr., Kancherla V. 2017. Race and ethnicity and preconception folic acid supplement use among pregnant women in Georgia, PRAMS 2009 to 2011. Birth Defects Res 109:38–48
    [Google Scholar]
  119. 118.
    Nasri KBF, Ben Fradj MK, Touati A, Aloui M, Ben Jemaa N et al. 2015. Association of maternal homocysteine and vitamins status with the risk of neural tube defects in Tunisia: a case-control study. Birth Defects Res. A 103:1011–20
    [Google Scholar]
  120. 119.
    Natl. Inst. Health 2020. Folate: fact sheet for health professionals Fact Sheet, Natl. Inst. Health Washington, DC: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/#en12
    [Google Scholar]
  121. 120.
    Nazer HJ, Cifuentes OL. 2013. Resultados del Programa de Prevención de Defectos de Tubo Neural en Chile mediante la fortificación de la harina con ácido fólico [Effects of wheat flour fortification with folic acid on the prevalence of neural tube defects in Chile. ]. Rev. Med. Chil. 141:751–57
    [Google Scholar]
  122. 121.
    Newnham JP, Ross MG, eds. 2009. Early Life Origins of Human Health and Disease Basel, Switz: Karger
    [Google Scholar]
  123. 122.
    Obeid R, Pietrzik K, Oakley GP Jr., Kancherla V, Holzgreve W, Wieser S. 2015. Preventable spina bifida and anencephaly in Europe. Birth Defects Res. A 103:763–71
    [Google Scholar]
  124. 123.
    Odewole OA, Williamson RS, Zakai NA, Berry RJ, Judd SE et al. 2013. Near-elimination of folate-deficiency anemia by mandatory folic acid fortification in older US adults: Reasons for Geographic and Racial Differences in Stroke study 2003–2007. Am. J. Clin. Nutr. 98:1042–47
    [Google Scholar]
  125. 124.
    Paneth N, Susser M. 1995. Early origin of coronary heart disease (the “Barker hypothesis”). BMJ 310:411–12
    [Google Scholar]
  126. 125.
    Parker SE, Yazdy MM, Tinker SC, Mitchell AA, Werler MM. 2013. The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida. Am. J. Obstet. Gynecol. 209:239.e1–8
    [Google Scholar]
  127. 126.
    Peker E, Demir N, Tuncer O, Üstyol L, Balahoroğlu R et al. 2016. The levels of vitamın B12, folate and homocysteine in mothers and their babies with neural tube defects. J. Matern. Fetal Neonatal Med. 29:2944–48
    [Google Scholar]
  128. 127.
    Persad VL, Van den Hof MC, Dube JM, Zimmer P. 2002. Incidence of open neural tube defects in Nova Scotia after folic acid fortification. CMAJ 167:241–45
    [Google Scholar]
  129. 128.
    Pfeiffer CM, Hughes JP, Lacher DA, Bailey RL, Berry RJ et al. 2012. Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988–2010. J. Nutr. 142:886–93
    [Google Scholar]
  130. 129.
    Pfeiffer CM, Johnson CL, Jain RB, Yetley EA, Picciano MF et al. 2007. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988–2004. Am. J. Clin. Nutr. 86:718–27
    [Google Scholar]
  131. 130.
    Pfeiffer CM, Sternberg MR, Hamner HC, Crider KS, Lacher DA et al. 2016. Applying inappropriate cutoffs leads to misinterpretation of folate status in the US population. Am. J. Clin. Nutr. 104:1607–15
    [Google Scholar]
  132. 131.
    Pfeiffer CM, Sternberg MR, Zhang M, Fazili Z, Storandt RJ et al. 2019. Folate status in the US population 20 y after the introduction of folic acid fortification. Am. J. Clin. Nutr. 110:1088–97
    [Google Scholar]
  133. 132.
    Qi YP, Do AN, Hamner HC, Pfeiffer CM, Berry RJ. 2014. The prevalence of low serum vitamin B-12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification. J. Nutr. 144:170–76
    [Google Scholar]
  134. 133.
    Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DE. 2002a. Association of neural tube defects and folic acid food fortification in Canada. Lancet 360:2047–48
    [Google Scholar]
  135. 134.
    Ray JG, Singh G, Burrows RF. 2004. Evidence for suboptimal use of periconceptional folic acid supplements globally. BJOG 111:399–408
    [Google Scholar]
  136. 135.
    Ray JG, Vermeulen MJ, Boss SC, Cole DE. 2002b. Declining rate of folate insufficiency among adults following increased folic acid food fortification in Canada. Can. J. Public Health 93:249–53
    [Google Scholar]
  137. 136.
    Ray JG, Vermuelen MJ, Langman LJ, Boss SC, Cole DE. 2003. Persistence of vitamin B12 insufficiency among elderly women after folic acid food fortification. Clin. Biochem. 36:387–91
    [Google Scholar]
  138. 137.
    Ricks DJ, Rees CA, Osborn KA, Crookston BT, Leaver K et al. 2012. Peru's national folic acid fortification program and its effect on neural tube defects in Lima. Rev. Panam. Salud Publica 32:391–98
    [Google Scholar]
  139. 138.
    Rosenthal J, Lopez-Pazos E, Dowling NF, Pfeiffer CM, Mulinare J et al. 2015. Folate and vitamin B12 deficiency among non-pregnant women of childbearing age in Guatemala 2009–2010: prevalence and identification of vulnerable populations. Matern. Child Health J. 19:2272–85
    [Google Scholar]
  140. 139.
    Samson ME, Yeung LF, Rose CE, Qi YP, Taylor CA, Crider KS. 2022. Vitamin B-12 malabsorption and renal function are critical considerations in studies of folate and vitamin B-12 interactions in cognitive performance: NHANES 2011–2014. Am. J. Clin. Nutr. 116:7485
    [Google Scholar]
  141. 140.
    Sanabria Rojas H, Tarqui-Mamani C, Arias Pachas J, Lam Figueroa N. 2013. Impact of fortifying wheat flour with folic acid on neural tube defects in Lima, Peru. An. Fac. Med. 75:175–80
    [Google Scholar]
  142. 141.
    Santos LM, Lecca RC, Cortez-Escalante JJ, Sanchez MN, Rodrigues HG. 2016. Prevention of neural tube defects by the fortification of flour with folic acid: a population-based retrospective study in Brazil. Bull. World Health Organ. 94:22–29
    [Google Scholar]
  143. 142.
    Saubade F, Hemery YM, Rochette I, Guyot JP, Humblot C 2018. Influence of fermentation and other processing steps on the folate content of a traditional African cereal-based fermented food. Int. J. Food Microbiol. 266:79–86
    [Google Scholar]
  144. 143.
    Sayed AR, Bourne D, Pattinson R, Nixon J, Henderson B. 2008. Decline in the prevalence of neural tube defects following folic acid fortification and its cost–benefit in South Africa. Birth Defects Res. A 82:211–16
    [Google Scholar]
  145. 144.
    Scaglione F, Panzavolta G. 2014. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica 44:480–88
    [Google Scholar]
  146. 145.
    Sci. Advis. Comm. Nutr 2006. Folate and Disease Prevention Norwich, UK: H. M. Station. Off.
    [Google Scholar]
  147. 146.
    Scott JM, Weir DG. 1981. The methyl folate trap: a physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet 2:337–40
    [Google Scholar]
  148. 147.
    Selhub J, Morris MS, Jacques PF. 2007. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. PNAS 104:19995–20000
    [Google Scholar]
  149. 148.
    Senousy SM, Farag MK, Gouda AS, El Noury MA, Dabbous OA, Gaber KR. 2018. Association between biomarkers of vitamin B12 status and the risk of neural tube defects. J. Obstet. Gynaecol. Res. 44:1902–8
    [Google Scholar]
  150. 149.
    Shilatifard A. 2006. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. 75:243–69
    [Google Scholar]
  151. 150.
    Shumate C, Hoyt A, Liu C, Kleinert A, Canfield M. 2019. Understanding how the concentration of neighborhood advantage and disadvantage affects spina bifida risk among births to non-Hispanic white and Hispanic women, Texas, 1999–2014. Birth Defects Res 111:982–90
    [Google Scholar]
  152. 151.
    Smith AD, Kim YI, Refsum H. 2008. Is folic acid good for everyone?. Am. J. Clin. Nutr. 87:517–33
    [Google Scholar]
  153. 152.
    Solomon LR. 2013. Vitamin B12 and peripheral nerve function in elderly adults: “functional” B12 deficiency as a confounding variable. J. Am. Geriatr. Soc. 61:310–11
    [Google Scholar]
  154. 153.
    Stewart CP, Christian P, Schulze KJ, Arguello M, Leclerq SC et al. 2011. Low maternal vitamin B-12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal. J. Nutr. 141:1912–17
    [Google Scholar]
  155. 154.
    Stewart CP, Christian P, Schulze KJ, Leclerq SC, West KP Jr., Khatry SK. 2009. Antenatal micronutrient supplementation reduces metabolic syndrome in 6- to 8-year-old children in rural Nepal. J. Nutr. 139:1575–81
    [Google Scholar]
  156. 155.
    Stokstad EL, Reisenauer A, Kusano G, Keating JN. 1988. Effect of high levels of dietary folic acid on folate metabolism in vitamin B12 deficiency. Arch. Biochem. Biophys. 265:407–14
    [Google Scholar]
  157. 156.
    Stover PJ. 2009. One-carbon metabolism–genome interactions in folate-associated pathologies. J. Nutr. 139:2402–5
    [Google Scholar]
  158. 157.
    Tabatabaei RS, Fatahi-Meibodi N, Meibodi B, Javaheri A, Abbasi H et al. 2022. Association of fetal MTHFR C677T polymorphism with susceptibility to neural tube defects: a systematic review and update meta-analysis. Fetal Pediatr. Pathol. 41:22541
    [Google Scholar]
  159. 158.
    Tamura T, Picciano MF. 2006. Folate and human reproduction. Am. J. Clin. Nutr. 83:993–1016
    [Google Scholar]
  160. 159.
    Tice JA, Ross E, Coxson PG, Rosenberg I, Weinstein MC et al. 2001. Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for the prevention of coronary heart disease: effect of grain fortification and beyond. JAMA 286:936–43
    [Google Scholar]
  161. 160.
    Tinker SC, Cogswell ME, Devine O, Berry RJ. 2010. Folic acid intake among U.S. women aged 15–44 years, National Health and Nutrition Examination Survey, 2003–2006. Am. J. Prev. Med. 38:534–42
    [Google Scholar]
  162. 161.
    Tinker SC, Devine O, Mai C, Hamner HC, Reefhuis J et al. 2013. Estimate of the potential impact of folic acid fortification of corn masa flour on the prevention of neural tube defects. Birth Defects Res. A 97:649–57
    [Google Scholar]
  163. 162.
    Tinker SC, Gilboa SM, Moore CA, Waller DK, Simeone RM et al. 2020. Specific birth defects in pregnancies of women with diabetes: National Birth Defects Prevention Study, 1997–2011. Am. J. Obstet. Gynecol. 222:176.e1–11
    [Google Scholar]
  164. 163.
    Tinker SC, Hamner HC, Qi YP, Crider KS. 2015. U.S. women of childbearing age who are at possible increased risk of a neural tube defect–affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res. A 103:517–26
    [Google Scholar]
  165. 164.
    Tsang BL, Devine OJ, Cordero AM, Marchetta CM, Mulinare J et al. 2015. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am. J. Clin. Nutr. 101:1286–94
    [Google Scholar]
  166. 165.
    US Prev. Serv. Task Force 2017. Folic acid supplementation for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement. JAMA 317:183–89
    [Google Scholar]
  167. 166.
    van der Pols JC, Baade P, Spencer LB. 2021. Colorectal cancer incidence in Australia before and after mandatory fortification of bread flour with folic acid. Public Health Nutr 24:1989–92
    [Google Scholar]
  168. 167.
    Visentin M, Diop-Bove N, Zhao R, Goldman ID. 2014. The intestinal absorption of folates. Annu. Rev. Physiol. 76:251–74
    [Google Scholar]
  169. 168.
    Wang A, Rose CE, Qi YP, Williams JL, Pfeiffer CM, Crider KS. 2021. Impact of voluntary folic acid fortification of corn masa flour on RBC folate concentrations in the U.S. (NHANES 2011–2018). Nutrients 13:1325
    [Google Scholar]
  170. 169.
    Wang A, Yeung L, Burrows NR, Rose CE, Fazili Z et al. 2022. Reduced kidney function is associated with increasing red blood cell folate concentration and changes in folate form distributions (NHANES 2011–2018). Nutrients 14:1054
    [Google Scholar]
  171. 170.
    Wang M, Wang ZP, Gao LJ, Gong R, Sun XH, Zhao ZT. 2013. Maternal body mass index and the association between folic acid supplements and neural tube defects. Acta Paediatr. 102:908–13
    [Google Scholar]
  172. 171.
    Weir DG, Scott JM. 1999. Brain function in the elderly: role of vitamin B12 and folate. Br. Med. Bull. 55:669–82
    [Google Scholar]
  173. 172.
    Williams J, Mai CT, Mulinare J, Isenburg J, Flood TJ et al. 2015. Updated estimates of neural tube defects prevented by mandatory folic acid fortification—United States, 1995–2011. Morb. Mortal. Wkly. Rep. 64:1–5
    [Google Scholar]
  174. 173.
    Wong EC, Rose CE, Flores AL, Yeung LF. 2019. Trends in multivitamin use among women of reproductive age: United States, 2006–2016. J. Women's Health 28:37–45
    [Google Scholar]
  175. 174.
    World Health Organ 2006. Guidelines on food fortification with micronutrients Rep. 9241594012 World Health Organ. Geneva:
    [Google Scholar]
  176. 175.
    World Health Organ 2018. Fortification of rice with vitamins and minerals as a public health strategy Rep. 9789241550291 World Health Organ Geneva:
    [Google Scholar]
  177. 176.
    Wyckoff KF, Ganji V. 2007. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post–folic acid fortification period than in the pre–folic acid fortification period. Am. J. Clin. Nutr. 86:1187–92
    [Google Scholar]
  178. 177.
    Yajnik CS, Deshmukh US. 2008. Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev. Endocr. Metab. Disord. 9:203–11
    [Google Scholar]
  179. 178.
    Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S et al. 2008. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia 51:29–38
    [Google Scholar]
  180. 179.
    Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C et al. 2006. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113:1335–43
    [Google Scholar]
  181. 180.
    Yang Q, Cogswell ME, Hamner HC, Carriquiry A, Bailey LB et al. 2010. Folic acid source, usual intake, and folate and vitamin B-12 status in US adults: National Health and Nutrition Examination Survey (NHANES) 2003–2006. Am. J. Clin. Nutr. 91:64–72
    [Google Scholar]
  182. 181.
    Yang Y, Chen J, Wang B, Ding C, Liu H. 2015. Association between MTHFR C677T polymorphism and neural tube defect risks: a comprehensive evaluation in three groups of NTD patients, mothers, and fathers. Birth Defects Res. A 103:488–500
    [Google Scholar]
  183. 182.
    Yeung L, Yang Q, Berry RJ 2008. Contributions of total daily intake of folic acid to serum folate concentrations. JAMA 300:2486–87
    [Google Scholar]
  184. 183.
    Zhao R, Matherly LH, Goldman ID. 2009. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev. Mol. Med. 11:e4
    [Google Scholar]
  185. 184.
    Zhou Y, Sinnathamby V, Yu Y, Sikora L, Johnson CY et al. 2020. Folate intake, markers of folate status and oral clefts: an updated set of systematic reviews and meta-analyses. Birth Defects Res 112:1699–719
    [Google Scholar]
/content/journals/10.1146/annurev-nutr-043020-091647
Loading
/content/journals/10.1146/annurev-nutr-043020-091647
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error