Fortification of wheat and maize flour with folic acid for population health outcomes

Elizabeth Centeno Tablante, Helena Pachón, Heather M Guetterman, Julia L Finkelstein, Elizabeth Centeno Tablante, Helena Pachón, Heather M Guetterman, Julia L Finkelstein

Abstract

Background: Folate is a B-vitamin required for DNA synthesis, methylation, and cellular division. Wheat and maize (corn) flour are staple crops consumed widely throughout the world and have been fortified with folic acid in over 80 countries to prevent neural tube defects. Folic acid fortification may be an effective strategy to improve folate status and other health outcomes in the overall population.

Objectives: To evaluate the health benefits and safety of folic acid fortification of wheat and maize flour (i.e. alone or in combination with other micronutrients) on folate status and health outcomes in the overall population, compared to wheat or maize flour without folic acid (or no intervention).

Search methods: We searched the following databases in March and May 2018: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In Process, Embase, CINAHL, Web of Science (SSCI, SCI), BIOSIS, Popline, Bibliomap, TRoPHI, ASSIA, IBECS, SCIELO, Global Index Medicus-AFRO and EMRO, LILACS, PAHO, WHOLIS, WPRO, IMSEAR, IndMED, and Native Health Research Database. We searched the International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing or planned studies in June 2018, and contacted authors for further information.

Selection criteria: We included randomised controlled trials (RCTs), with randomisation at the individual or cluster level. We also included non-RCTs and prospective observational studies with a control group; these studies were not included in meta-analyses, although their characteristics and findings were described. Interventions included wheat or maize flour fortified with folic acid (i.e. alone or in combination with other micronutrients), compared to unfortified flour (or no intervention). Participants were individuals over two years of age (including pregnant and lactating women), from any country.

Data collection and analysis: Two review authors independently assessed study eligibility, extracted data, and assessed risk of bias.

Main results: We included 10 studies: four provided data for quantitative analyses (437 participants); five studies were randomised trials (1182 participants); three studies were non-RCTs (1181 participants, 8037 live births); two studies were interrupted time series (ITS) studies (1 study population of 2,242,438, 1 study unreported). Six studies were conducted in upper-middle-income countries (China, Mexico, South Africa), one study was conducted in a lower-middle-income country (Bangladesh), and three studies were conducted in a high-income country (Canada). Seven studies examined wheat flour fortified with folic acid alone or with other micronutrients. Three studies included maize flour fortified with folic acid alone or with other micronutrients. The duration of interventions ranged from two weeks to 36 months, and the ITS studies included postfortification periods of up to seven years. Most studies had unclear risk of bias for randomisation, blinding, and reporting, and low/unclear risk of bias for attrition and contamination.Neural tube defects: none of the included RCTs reported neural tube defects as an outcome. In one non-RCT, wheat flour fortified with folic acid and other micronutrients was associated with significantly lower occurrence of total neural tube defects, spina bifida, and encephalocoele, but not anencephaly, compared to unfortified flour (total neural tube defects risk ratio (RR) 0.32, 95% confidence interval (CI) 0.21 to 0.48; 1 study, 8037 births; low-certainty evidence).Folate status: pregnant women who received folic acid-fortified maize porridge had significantly higher erythrocyte folate concentrations (mean difference (MD) 238.90 nmol/L, 95% CI 149.40 to 328.40); 1 study, 38 participants; very low-certainty evidence) and higher plasma folate (MD 14.98 nmol/L, 95% CI 9.63 to 20.33; 1 study, 38 participants; very low-certainty evidence), compared to no intervention. Women of reproductive age consuming maize flour fortified with folic acid and other micronutrients did not have higher erythrocyte folate (MD -61.80 nmol/L, 95% CI -152.98 to 29.38; 1 study, 35 participants; very low-certainty evidence) or plasma folate (MD 0.00 nmol/L, 95% CI -0.00 to 0.00; 1 study, 35 participants; very low-certainty evidence) concentrations, compared to women consuming unfortified maize flour. Adults consuming folic acid-fortified wheat flour bread rolls had higher erythrocyte folate (MD 0.66 nmol/L, 95% CI 0.13 to 1.19; 1 study, 30 participants; very low-certainty evidence) and plasma folate (MD 27.00 nmol/L, 95% CI 15.63 to 38.37; 1 study, 30 participants; very low-certainty evidence), versus unfortified flour. In two non-RCTs, serum folate concentrations were significantly higher among women who consumed flour fortified with folic acid and other micronutrients compared to women who consumed unfortified flour (MD 2.92 nmol/L, 95% CI 1.99 to 3.85; 2 studies, 657 participants; very low-certainty evidence).Haemoglobin or anaemia: in a cluster-randomised trial among children, there were no significant effects of fortified wheat flour flatbread on haemoglobin concentrations (MD 0.00 nmol/L, 95% CI -2.08 to 2.08; 1 study, 334 participants; low-certainty evidence) or anaemia (RR 1.07, 95% CI 0.74 to 1.55; 1 study, 334 participants; low-certainty evidence), compared to unfortified wheat flour flatbread.

Authors' conclusions: Fortification of wheat flour with folic acid may reduce the risk of neural tube defects; however, this outcome was only reported in one non-RCT. Fortification of wheat or maize flour with folic acid (i.e. alone or with other micronutrients) may increase erythrocyte and serum/plasma folate concentrations. Evidence is limited for the effects of folic acid-fortified wheat or maize flour on haemoglobin levels or anaemia. The effects of folic acid fortification of wheat or maize flour on other primary outcomes assessed in this review is not known. No studies reported on the occurrence of adverse effects. Limitations of this review were the small number of studies and participants, limitations in study design, and low-certainty of evidence due to how included studies were designed and reported.

Conflict of interest statement

Elizabeth Centeno Tablante: has no affiliation with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review. Helena Pachón: works for the Food Fortification Initiative which receives funding from private, public and civic sector organisations to support its mission of providing technical assistance to countries in the area of food fortification. Heather Guetterman: has no affiliation with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review. Julia Finkelstein: has no affiliation with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review.

Figures

1
1
Adapted from WHO/CDC 2011.
2
2
Flow diagram.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1. Analysis
1.1. Analysis
Comparison 1 Maize flour or maize flour products fortified with folic acid alone versus no intervention, Outcome 1 Erythrocyte folate concentrations (nmol/L).
1.2. Analysis
1.2. Analysis
Comparison 1 Maize flour or maize flour products fortified with folic acid alone versus no intervention, Outcome 2 Serum folate concentrations (nmol/L).
2.1. Analysis
2.1. Analysis
Comparison 2 Maize flour or maize flour products fortified with folic acid plus other vitamins and minerals versus unfortified maize flours or maize flour products (not containing folic acid nor any other vitamins and minerals), Outcome 1 Erythrocyte folate concentrations (nmol/L).
2.2. Analysis
2.2. Analysis
Comparison 2 Maize flour or maize flour products fortified with folic acid plus other vitamins and minerals versus unfortified maize flours or maize flour products (not containing folic acid nor any other vitamins and minerals), Outcome 2 Serum folate concentrations (nmol/L).
3.1. Analysis
3.1. Analysis
Comparison 3 Wheat flour or wheat flour products fortified with folic acid alone versus unfortified wheat flours or wheat flour products (not containing folic acid nor any other vitamins and minerals), Outcome 1 Erythrocyte folate concentrations (nmol/L).
3.2. Analysis
3.2. Analysis
Comparison 3 Wheat flour or wheat flour products fortified with folic acid alone versus unfortified wheat flours or wheat flour products (not containing folic acid nor any other vitamins and minerals), Outcome 2 Plasma folate concentrations (nmol/L).
4.1. Analysis
4.1. Analysis
Comparison 4 Wheat flour or wheat flour products fortified with folic acid plus other vitamins and minerals versus unfortified wheat flours or wheat flour products (not containing folic acid nor any other vitamins and minerals), Outcome 1 Anaemia (as defined by trialists), randomised studies.
4.2. Analysis
4.2. Analysis
Comparison 4 Wheat flour or wheat flour products fortified with folic acid plus other vitamins and minerals versus unfortified wheat flours or wheat flour products (not containing folic acid nor any other vitamins and minerals), Outcome 2 Haemoglobin concentrations (in g/L), randomised studies.

References

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Brito 2015 {published data only}
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Bronberg 2016 {published data only}
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Callaghan‐Gillespie 2017 {published data only}
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Carlsson 2002a {published data only}
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Carlsson 2002b {published data only}
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CIGNIS 2010 {published data only}
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Colman 1974b {published data only}
    1. Colman N, Larsen JV, Barker M, Barker EA, Green R, Metz J. Prevention of folate deficiency by food fortification. V. A pilot field trial of folic acid fortified maize meal. South African Medical Journal 1974;48(41):1763‐6.
Colman 1974c {published data only}
    1. Colman N, Green R, Stevens K, Metz J. Prevention of folate deficiency by food fortification. VI. The antimegaloblastic effect of folic acid‐fortified maize meal. South Africa Medical Journal 1974;48(42):1795‐8.
Colman 1975a {published data only}
    1. Colman N, Green R, Metz J. Prevention of folate deficiency by food fortification. II. Absorption of folic acid from fortified staple foods. American Journal of Clinical Nutrition 1975;28(5):459‐64.
Colman 1975b {published data only}
    1. Colman N, Barker EA, Barker M, Green R, Metz J. Prevention of folate deficiency by food fortification. IV. Identification of target groups in addition to pregnant women in an adult rural population. American Journal of Clinical Nutrition 1975;28(5):471‐6.
Colman 1982 {published data only}
    1. Colman N. Addition of folic acid to staple foods as a selective nutrition intervention strategy. Nutrition Reviews 1982;40(8):225‐33.
DAZ 2004 {published data only}
    1. Folic acid deficiency: enriched flour for an improved folic acid supply. Deutsche Apotheker Zeitung 2004; Vol. 144, issue 39:105‐7.
Doyle 1995 {published data only}
    1. Doyle W. Folic acid in prevention of neural tube defects. Lancet 1995;345:389‐90.
Fleischman 2011 {published data only}
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Freire 2000 {published data only}
    1. Freire WB, Hertrampf E, Corets F. Effect of folic acid fortification in Chile: preliminary results. European Journal of Pediatric Surgery 2000;10(1):42‐3.
Ganes 2002 {published data only}
    1. Ganes S, Astrup AV, Stender S. Folic acid fortification of flour. Ugeskrift for Laeger 2002;164(35):4087‐8.
Gardiner 2009 {published data only}
    1. Gardiner HM, Fouron JC. Folic acid fortification and congenital heart disease. BMJ 2009;338(7705):1144.
Glosz 2016 {published data only}
    1. Glosz CM, Reaves S, Manary M, Papathakis P. Assessment of micronutrient status in pregnant Malawian women before and after treatment for moderate malnutrition. FASEB Journal 2016;30(Suppl 1):892.9.
Hansen 2001 {published data only}
    1. Hansen M, Samman S, Madsen LT, Jensen M, Sorensen SS, Sandstrom B. Folic acid enrichment of bread does not appear to affect zinc absorption in young women. American Journal of Clinical Nutrition 2001;74(1):125‐9.
Hirsch 2011 {published data only}
    1. Hirsch S, Pia de la Maza M, Barrera G, Leiva L, Bunout D. Folic Acid and Colon Cancer: impact of wheat flour fortification with folic acid. San Diego: Elsevier Academic Press Inc, 2011.
Hurrell 2015 {published data only}
    1. Hurrell RF. Flour fortification as a strategy to prevent anaemia. British Journal of Nutrition 2015;114(4):501‐2.
Jacobson 1995 {published data only}
    1. Jacobson B. Folic acid and the prevention of neural tube defects. Chapati flour should be fortified as well. BMJ 1995;311(6999):256.
Janmohamed 2016 {published data only}
    1. Janmohamed A, Karakochuk CD, Boungnasiri S, Chapman GE, Janssen PA, Brant R, et al. Prenatal supplementation with Corn Soya Blend Plus reduces the risk of maternal anemia in late gestation and lowers the rate of preterm birth but does not significantly improve maternal weight gain and birth anthropometric measurements in rural Cambodian women: a randomized trial. American Journal of Clinical Nutrition 2016;103(2):559‐66.
Jian 2013 {published data only}
    1. Jian H, Jing S, Junsheng H, Wenxian L, Chunming C. Effects of fortified flour consumption on serum folate and homocysteine in childbearing‐aged women in high prevalence regions of neurotube defect. Annals of Nutrition and Metabolism 2013;63:1530.
Jiang 2011 {published data only}
    1. Jiang Z, Liang Q, Wang Y, Zheng X, Pei L, Zhang T, et al. Metabonomic study on women of reproductive age treated with nutritional intervention: screening potential biomarkers related to neural tube defects occurrence. Biomedical Chromatography 2011;25(7):767‐74.
Johansson 2002 {published data only}
    1. Johansson M, Witthoft CM, Bruce A, Jagerstad M. Study of wheat breakfast rolls fortified with folic acid ‐ The effect on folate status in women during a 3‐month intervention. European Journal of Nutrition 2002;41(6):279‐86.
Jooma 2004 {published data only}
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Kelly 1997 {published data only}
    1. Kelly P, McPartlin J, Goggins M, Weir DG, Scott J M. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. American Journal of Clinical Nutrition 1997;65(6):1790‐5.
Kirby 2000 {published data only}
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Landim 2016 {published data only}
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Langman 2005 {published data only}
    1. Langman LJ, Ray JG, Mamdani MM, Cole DEC. Absence of effect of folic acid flour fortification on anticonvulsant drug levels. Therapeutic Drug Monitoring 2005;27(2):232.
Margo 1975 {published data only}
    1. Margo G, Barker M, Gernandes‐Costa F, Colman N, Green R, Metz J. Prevention of folate deficiency by food fortification. VII. The use of bread as a vehicle for folate supplementation. The American Journal of Clinical Nutrition 1975;28(7):761‐3.
McNulty 2001 {published data only}
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Metz 1986 {published data only}
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Mirarefin 2007 {published data only}
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Monch 2015 {published data only}
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Nackers 2010 {published data only}
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Northrop‐Clewes 2013a {published data only}
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Northrop‐Clewes 2013b {published data only}
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Paniz 2015 {published data only}
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Pouraram 2015 {published data only}
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Ray 2005 {published data only}
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SAJCN 2003 {published data only}
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Tinker 2013 {published data only}
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van den Wijngaart 2013 {published data only}
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Wald 2002 {published data only}
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Walker 1983 {published data only}
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Source: PubMed

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