• Elizabeth Centeno Tablante, Helena Pachón, Heather M Guetterman, and Julia L Finkelstein.
• Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA.
• Cochrane Db Syst Rev. 2019 Jul 1; 7 (7): CD012150CD012150.

BackgroundFolate 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.ObjectivesTo 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 MethodsWe 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 CriteriaWe 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 AnalysisTwo review authors independently assessed study eligibility, extracted data, and assessed risk of bias.Main ResultsWe 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' ConclusionsFortification 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.

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