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)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(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)(2006)(2007)(2008)(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.
Keywords
Folic acid Neural tube defects Spinal dysraphism Food fortification Systematic reviewThe importance of nutrition in the aetiology of neural tube defects (NTD) was suggested by Hibbard and Smithells, who found that women deficient in folate had an increased number of abortions, placental abruptions and fetal malformations and intra-uterine growth retardation (1) . The first reports on folate deficiency and NTD, published by Smithells et al. (2,3) , showed the protective effect of folic acid on the recurrence of NTD. A randomised study by Czeizel and Dudas (4) showed a decrease in first NTD occurrence in women supplemented with twelve vitamins containing 0?8 mg of folic acid, but not in women supplemented with trace elements and a very low dose of vitamin C. A rigorous double-blind randomised controlled trial supported by the UK Medical Research Council showed that supplementing women who had a history of children with NTD with 4 mg of folic acid daily decreased recurrence by 72 % (5) . Although some studies were retrospective, their results revealed an inverse relationship between NTD and folic acid consumption of 100-400 mg/d (6,7) . Based on this information, in 1992 the US Public Health Service r...