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Impact of folic acid fortification of flour on neural tube defects: a systematic review

  • Cecilia Castillo-Lancellotti (a1), Josep A Tur (a1) and Ricardo Uauy (a2)
Abstract
Objective

To review the impact of folic acid fortification of flour on the prevalence of neural tube defects (NTD).

Design

Systematic review of the literature on MEDLINE via PubMed, Scopus, OvidSP and LILACS (Latin American and Caribbean Health Sciences Literature) reporting the impact of folic acid fortification of flour on the prevalence of NTD in 2000–2011. Focusing on Santiago of Chile's birth defects registry (1999–2009) and the monitoring of flour fortification, we analysed the prevalence (NTD cases/10 000 births) pre and post flour fortification and the percentile distribution of folic acid content in flour (2005–2009). We explored the potential association between median folic acid in flour (mg/kg) and the prevalence of NTD.

Setting

Chile, Argentina, Brazil, Canada, Costa Rica, Iran, Jordan, South Africa and the USA.

Subjects

Live births and stillbirths.

Results

Twenty-seven studies that met inclusion criteria were evaluated. Costa Rica showed a significant reduction in NTD (∼60 %). Prevalence in Chile decreased from 18·6 to 7·3/10 000 births from 1999 to 2007 and showed a slight increase to 8·5 in 2008–2009, possibly due to changes in fortification limits. When we related the prevalence of NTD with levels of flour fortification, the lowest prevalence was observed at a folic acid level of 1·5 mg/kg.

Conclusions

Fortification of flour with folic acid has had a major impact on NTD in all countries where this has been reported. Chile showed a 55 % reduction in NTD prevalence between 1999 and 2009. There is a need to constantly monitor the levels of flour fortification to maximize benefits and prevent the potential risk of folic acid excess, moreover to be vigilant for any new adverse effects associated with excess.

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Corresponding author
*Corresponding author: Email dracastillo@gmail.com
References
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1.Hibbard, ED & Smithells, RW (1965) Folic acid metabolism and human embryopathy. Lancet 285, 1254.
2.Smithells, RW, Sheppard, S & Schorah, CJ (1976) Vitamin deficiencies and neural tube defects. Arch Dis Child 51, 944950.
3.Smithells, RW, Sheppard, S, Schorah, CJet al. (1981) Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 56, 911918.
4.Czeizel, AE & Dudas, I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamins supplementation. N Engl J Med 327, 18321835.
5.MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131137.
6.Werler, MM, Shapiro, S & Mitchell, AA (1993) Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 269, 12571261.
7.Shaw, GM, Schaffer, D, Velie, EMet al. (1995) Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 6, 219226.
8.Public Health Service of the United States (1992) Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep 41, 17.
9.Food and Drug Administration (1996) Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Final Rule. 21CFR Parts 136, 137, and 139. Federal Register 61, 87818789.
10.Flour Fortification Initiative (2004) Fortification Status January 2012. http://www.sph.emory.edu/wheatflour//globalmap.php (accessed January 2012).
11.Wolff, T, Witkop, CT, Miller, Tet al. (2009) Folic acid supplementation for the prevention of neural tube defects: an update of the evidence for the US Preventive Services Task Force. Ann Intern Med 150, 632639.
12.Lumley, J, Watson, L, Watson, Met al. (2011) Withdrawn: periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev issue 4, CD001056.
13.Goh, YI, Bollano, E, Einarson, TRet al. (2006) Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 8, 680689.
14.Instituto de Salud Pública Chile (2005) Programa de Fortificación de Harinas. http://www.ispch.cl/programa-de-fortificacion-de-harinas (accessed January 2011).
15.Honein, MA, Paulozzi, LJ, Mathews, TJet al. (2001) Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285, 29812986.
16.Ray, JG, Vermeulen, MJ, Boss, SCet al. (2002) Declining rate of folate insufficiency among adults following increased folic acid food fortification in Canada. Can J Public Health 93, 249253.
17.De Wals, P, Rusen, ID, Lee, NSet al. (2003) Trend in prevalence of neural tube defects in Quebec. Birth Defects Res A Clin Mol Teratol 67, 919923.
18.Chen, LT & Rivera, MA (2004) The Costa Rican experience: reduction of neural tube defects following food fortification programs. Nutr Rev 62, Suppl. 1, S40S43.
19.Simmons, CJ, Mosley, BS, Fulton-Bond, CAet al. (2004) Birth defects in Arkansas: is folic acid fortification making a difference? Birth Defects Res A Clin Mol Teratol 70, 559564.
20.Hertrampf, E & Cortés, F (2004) Folic acid fortification of wheat flour: Chile. Nutr Rev 62, Suppl. 1, S44S48.
21.De Wals, P, Tairou, F, Van Allen, MIet al. (2007) Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 357, 135142.
22.Sayed, AR, Bourne, D, Pattinson, Ret al. (2008) Decline in the prevalence of neural tube defects following folic acid fortification and its cost–benefit in South Africa. Birth Defects Res A Clin Mol Teratol 82, 211216.
23.Chen, BH, Carmichael, SL, Selvin, Set al. (2008) NTD prevalences in central California before and after folic acid fortification. Birth Defects Res A Clin Mol Teratol 82, 547552.
24.Pacheco, SS, Braga, C, Souza, AIet al. (2009) Effects of folic acid fortification on the prevalence of neural tube defects. Rev Saude Publica 43, 565571.
25.López-Camelo, JS, Castilla, EE, Orioli, IMet al. (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, 24442458.
26.Collins, JS, Atkinson, KK, Dean, JHet al. (2011) Long term maintenance of neural tube defects prevention in a high prevalence state. J Pediatr 159, 143149. e2.
27.Amarin, ZO & Obeidat, AZ (2010) Effect of folic acid fortification on the incidence of neural tube defects. Paediatr Perinat Epidemiol 24, 349351.
28.Barboza, MP & Umaña, LM (2011) Impacto de la fortificación de alimentos con ácido fólico en los defectos del tubo neural en Costa Rica. Rev Panam Salud Publica 30, 16.
29.Abdollahi, Z, Elmadfa, I, Djazayery, Aet al. (2011) Efficacy of flour fortification with folic acid in women of childbearing age in Iran. Ann Nutr Metab 58, 188196.
30.Mathews, TJ, Honein, MA & Erickson, JD (2002) Spina bifida and anencephaly prevalence United States, 1991–2001. MMWR Recomm Rep 51, 911.
31.Meyer, RE & Siega-Riz, AM (2002) Sociodemographic patterns in spina bifida birth prevalence trends – North Carolina, 1995–1999. MMWR Recomm Rep 51, 1215.
32.Williams, LJ, Mai, CT, Edmonds, LDet al. (2002) Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology 66, 3339.
33.Mersereau, P, Kilker, K, Fassett, Eet al. (2004) Spina bifida and anencephaly before and after folic acid mandate – United States, 1995–1996 and 1999–2000. MMWR Morb Mortal Wkly Rep 53, 362365.
34.Canfield, MA, Collins, JS, Botto, LDet al. (2005) Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study. Birth Defects Res A Clin Mol Teratol 73, 679689.
35.López-Camelo, JS, Orioli, IM, da Graça Dutra, Met al. (2005) Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile. Am J Med Genet A 135, 120125.
36.Williams, LJ, Rasmussen, SA, Flores, Aet al. (2005) Decline in the prevalence of spina bifida and anencephaly by race/ethnicity: 1995–2002. Pediatrics 116, 580586.
37.Besser, LM, Williams, LJ & Cragan, JD (2007) Interpreting changes in the epidemiology of anencephaly and spina bifida following folic acid fortification of the US grain supply in the setting of long-term trends, Atlanta, Georgia, 1968–2003. Birth Defects Res A Clin Mol Teratol 79, 730736.
38.De Wals, P, Tairou, F, Van Allen, MIet al. (2008) Spina bifida before and after folic acid fortification in Canada. Birth Defects Res A Clin Mol Teratol 82, 622626.
39.Calvo, EB & Biglieri, A (2008) Impact of folic acid fortification on women's nutritional status and on the prevalence of neural tube defects. Arch Argent Pediatr 106, 492498.
40.Boulet, SL, Yang, Q, Mai, Cet al. (2008) Trends in the postfortification prevalence of spina bifida and anencephaly in the United States. Birth Defects Res A Clin Mol Teratol 82, 527532.
41.Orioli, IM, Lima do Nascimento, R, López-Camelo, JSet al. (2011) Effects of folic acid fortification on spina bifida prevalence in Brazil. Birth Defects Res A Clin Mol Teratol 91, 831835.
42.Ministry of Health (1999) Technical Standard for the Wheat Flour Fortification with Vitamins and Minerals. Chile: MINSAL.
43.Kelly, AE, Haddix, AC, Scanlon, RMet al. (1996) Cost-effectiveness of strategies to prevent neural tube defects. In Cost-effectiveness in Health and Medicine, pp. 312349 [MR Gold, JE Siegel, LB Russell et al., editors]. New York: Oxford University Press.
44.Grosse, SD, Waitzman, NJ, Romano, PSet al. (2005) Reevaluating the benefits of folic acid fortification in the United States: economic analysis, regulation, and public health. Am J Public Health 95, 19171922.
45.Llanos, A, Hertrampf, E, Cortes, Fet al. (2007) Cost-effectiveness of a folic acid fortification program in Chile. Health Policy 83, 295303.
46.Cabrera, RM, Shaw, GM, Ballard, JLet al. (2008) Autoantibodies to folate receptor during pregnancy and neural tube defect risk. J Reprod Immunol 79, 8592.
47.Richardson, BC (2002) Role of DNA methylation in the regulation of cell function: autoimmunity, aging and cancer. J Nutr 132, Suppl. 8, S2401S2405.
48.Al-Gazalo, LI, Padmanabhan, R & Melnyk, S (2001) Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect. Am J Med Genet 103, 128132.
49.Blom, HJ, Shaw, GM & den Heijer, M (2006) Neural tube defects and folate. Nat Rev Neurosci 7, 724731.
50.Ray, JG, Vermeulen, MJ, Boss, SCet al. (2002) Increased red cell folate concentrations in women of reproductive age after Canadian folic acid food fortification. Epidemiology 13, 238240.
51.Hertrampf, E, Cortés, F, Erickson, JDet al. (2003) Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile. J Nutr 133, 31663169.
52.Daly, S, Mills, JL, Molloy, AMet al. (1997) Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350, 16661669.
53.Wald, NJ, Law, MR, Morris, JKet al. (2001) Quantifying the effect of folic acid. Lancet 358, 20692073.
54.Berry, RJ, Li, Z, Erickson, JDet al. (1999) Prevention of neural-tube defects with folic acid in China. China–US Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 341, 14851490.
55.Guinotte, CL, Burns, MG, Axume, JAet al. (2003) Methylenetetrahydrofolate reductase 677C→T variant modulates folate status response to controlled folate intakes in young women. J Nutr 133, 12721280.
56.Botto, LD & Yang, Q (2000) 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151, 862877.
57.Cabrera, RM, Hill, DS, Etheredge, AJet al. (2004) Investigations into the etiology of neural tube defects. Birth Defects Res C Embryo Today 72, 330344.
58.Waller, DK, Shaw, GM, Rasmussen, SAet al. (2007) Prepregnancy obesity as a risk factor for structural birth defects. Arch Pediatr Adolesc Med 161, 745750.
59.Nazer, J, López-Carmelo, J & Castilla, E (2001) Estudio de 30 años de vigilancia epidemiológica de defectos de tubo neural en Chile y en Latinoamérica. Rev Med Chile 129, 531539.
60.Hertrampf, E & Cortés, F (2004) Folic acid fortification of wheat flour: Chile. Nutr Rev 62, Suppl. 1, S44S48.
61.Castillo, C, Tur, JA & Uauy, R (2010) Flour fortification with folic acid in Chile. Unintended consequences. Rev Med Chil 138, 832840.
62.Cuskelly, G, McNulty, H & Scott, JM (1999) Fortification with low amounts of folic acid makes a significant difference in folate status in young women: implications for the prevention of neural tube defects. Am J Clin Nutr 70, 234239.
63.Daly, S, Mills, JL, Molloy, AMet al. (1997) Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350, 16661669.
64.Wald, NJ, Law, M & Hoffbrand, AV (2004) Folic acid fortification in the prevention of neural tube defects. Am J Clin Nutr 80, 16651666.
65.Thompson, MD, Cole, DE & Ray, JG (2009) Vitamin B-12 and neural tube defects: the Canadian experience. Am J Clin Nutr 89, issue 2, S697S701.
66.Dary, O (2009) Nutritional interpretation of folic acid interventions. Nutr Rev 67, 235244.
67.Hao, L, Yang, Q-H, Li, Zet 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, 448457.
68.Quinlivan, EP & Gregory JF, III (2007) 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 86, 17731779.
69.Daly, LE, Kirke, PN, Molloy, Aet al. (1995) Folate levels and neural tube defects: implications for prevention. JAMA 274, 16981702.
70.Kim, YI (2007) Folate and colorectal cancer: an evidence-base critical review. Mol Nutr Food Res 51, 267292.
71.Selhub, J, Morris, MS, Jaques, PFet al. (2009) Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr 89, issue 2, S702S706.
72.Mason, JB (2009) Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons. Nutr Rev 67, 206212.
73.Moore, LL, Bradlee, ML, Singer, MRet al. (2003) Folate intake and the risk of neural tube defects: an estimation of dose–response. Epidemiology 14, 200205.
74.Kim, YI (2008) Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev 17, 22202225.
75.Cole, BF, Baron, JA, Sandler, RSet al. (2007) Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297, 23512359.
76.Mason, JB, Dickstein, A, Jacques, PFet al. (2007) A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 16, 13251329.
77.Morris, MS, Jacques, PF, Rosenberg, IHet al. (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, 17331744.
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