Background Wheat flour, maize flour and rice (i.e. grains) fortification with folic acid is an important folate dietary source globally. There are no systematic reviews or meta-analyses evaluating the effect of mandatory grain fortification on folate insufficiency (using serum/plasma folate and red blood cell (RBC) folate), RBC folate levels or folate deficiency using RBC folate. This study assessed the effectiveness of mandatory grain fortification with folic acid on serum/plasma folate and red blood cell (RBC) folate levels and the risk of folate deficiency and insufficiency based on these biomarkers.

Methods We searched PubMed and Embase with assistance from a professional library informationist. We selected studies from countries with mandatory grain fortification that include folic acid in standards if they reported primary pre- and post-fortification data on folate status outcomes. We ran meta-analyses in R using random effects models with results expressed as meta-differences of means (MDM) or meta-prevalence ratios (mPR) for continuous and binary outcomes respectively. All meta-estimates were accompanied by 95% confidence intervals (CI).

Results We screened 4,311 documents, identifying 31 articles which reported folate status outcomes (22 reported mean serum/plasma or RBC folate, 18 reported prevalence of folate deficiency or insufficiency). About 19% of studies were conducted in low- or middle-income countries. Mandatory fortification improved folate status, albeit with considerable heterogeneity across studies (I2≥73%). For serum/plasma folate levels, the MDM across all studies was 15.0 nmol/L (95% CI: 9.4-20.5). For serum/plasma folate insufficiency and deficiency, the mPR (95% CI) estimates were 0.17 (0.08-0.37) and 0.08 (0.03-0.23), respectively. For red blood cell folate levels, the MDM was 329.4 nmol/L (95% CI 243.9-414.9). For RBC folate insufficiency and deficiency, mPRs (95% CIs) were 0.16 (0.08-0.30) and 0.05 (0.01-0.46), respectively.

Conclusions Mandatory grain fortification with folic acid increases blood folate levels and decreases the risk of folate insufficiency and folate deficiency.

Several co-authors are employed with Emory University and the Food Fortification Initiative. These organizations help country leaders promote, plan, implement, monitor or evaluate food fortification.

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This study was funded by The Gates Foundation (INV 028795) and the Food Fortification Initiative. Several co-authors are employed with Emory University and the Food Fortification Initiative. These organizations help country leaders promote, plan, implement, monitor or evaluate food fortification.

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