What is standing in the way of complete prevention of folate preventable neural tube defects?

It is well known that there is a large gap between the number of neural tube defects (NTDs) that could be prevented by folic acid and the number that are actually being prevented. Arth and colleagues demonstrate just how large that gap is (Arth et al., 2016). The question is: why are so many potentially preventable NTDs not being prevented? Campaigns recommending that women of childbearing age take folic acid supplements routinely and voluntary fortification programs have had only modest success at best (Khoshnood et al., 2015). Therefore, mandatory fortification has been instituted in almost 80 countries (Food Fortification Initiative, 2016). As Arth et al. demonstrate, many countries have not embraced the mandatory fortification approach, despite the fact that it has prevented an average of 40 to 50% of NTDs (Castillo-Lancellotti et al., 2013). Concerns regarding the safety of folic acid fortification are one reason. Two major concerns are masking vitamin B12 deficiency and increasing cancer risk. It should be noted that the amount of folic acid people receive from fortified food in the United States, where fortification of enriched cereal grain products is mandatory, is an average of 163 micrograms per day in women of childbearing age, less than half the recommended dietary allowance (Tinker et al., 2010). This is sufficient to prevent folate-related NTDs (Mosley et al., 2009) but does not appear to cause masking of the hematological signs of vitamin B12 deficiency (Mills et al., 2003). A large meta-analysis of participants in folic acid trials demonstrated that, after an average of 5 years of follow-up, the relative risk for incident cancer was 1.06 with a 95% confidence interval of 0.99 to 1.13 (Vollset et al., 2013). The authors noted that the 6% increase was not statistically significant and that trial participants were exposed to far higher doses than fortification would deliver. There was no significant increase in any individual cancers studied. Nonetheless, concerns persist regarding cancer risk (van Wijngaarden et al., 2014) and other possible but unproved risks (National Toxicology Program, 2015). It is important to note that the amount of folic acid needed to prevent NTDs is far less than the amount likely to cause adverse effects (Mills and Dimopoulos, 2015). Because NTDs are uncommon events and a small increase in cancer would affect a substantial number of people, some countries have been reluctant to require fortification. It should be noted, however, that mandatory fortification has caused a dramatic reduction in folate deficiency (Pfeiffer et al., 2012); so the benefit is not limited to a small group. Several other obstacles to mandatory fortification exist. Although European Union (EU) regulation No. 1925/2006 (European Commission, 2006) acknowledges the need for mandatory food fortification with vitamins in member states to address public health concerns, some countries resist the idea of manipulating the food supply. Merchants who want to sell their goods throughout the EU may choose not to fortify to make their products more attractive in these countries. On the other hand, widespread voluntary fortification in countries where it is permitted creates a possible problem maintaining exposure within a safe range. It has been suggested that voluntary fortification be regulated as mandatory fortification is instituted to avoid excessive exposure. Developing countries face a different set of problems with mandatory fortification. The report, “Strategic Paper: Fortification of rice and wheat flour with vitamins and minerals in the Western Pacific region” (Food Fortification Initiative, 2013), provides an excellent outline of the issues that need to be resolved before implementation. In some parts of the world, finding a food that is consumed by a large proportion of the population at risk and can be fortified may be a problem. Where grain is milled locally in small mills, getting folic acid and mixing it in the proper amount to ensure safe, effective fortification is a serious problem. Large mills are the practical place to fortify. Wheat and maize fortification are relatively easy when large mills produce most of the flour although the cost of equipment could be an obstacle. Fortifying rice is more difficult (USAID, 2008). Some techniques may produce a product that has an unacceptable taste or appearance. Coating rice may also be ineffective if the rice is washed or rinsed. Hot extrusion, the technique that produces normal looking and tasting rice that retains folic acid well, is relatively expensive and requires a major investment in processing equipment. Mandatory fortification must be mandated at the national level to ensure good coverage, facilitate quality control monitoring, and put all manufacturers on an equal footing regarding production cost. Finally, in resource poor countries, folic acid fortification must be weighed against other pressing public health needs. HIV-AIDS caused an estimated 1.5 million deaths in 2013 (Global Health Observatory data [2013] http://www.who.int/gho/hiv/epidemic_status/deaths/en/). Vitamin A deficiency was responsible for an estimated 105,000 deaths in 2013 (Stevens et al., 2015). Advocates for NTD prevention are competing with interventions to prevent other causes of death and disability. In areas where there are multiple problems related to nutritional deficiencies, strategies could be developed to fortify with other critical micronutrients such as iron or vitamin A. Fortunately, the incremental cost of adding additional micronutrients to the mix is quite small. Thus, the priority for folic acid fortification could be raised by combining it with other critical micronutrients such as vitamin A and iron depending on the country. All these obstacles must be overcome if all folate related NTDs are to be prevented. Addressing these problems will not be easy and requires the expertise of a wide range of authorities from engineers to chemists, to legislators, to public health experts. The benefits of safe, effective mandatory fortification programs in preventing NTDs are very well documented. Reducing folate deficiency anemia rates has been an important fringe benefit. Adding additional micronutrients could cause a major reduction in morbidity and mortality due to other micronutrient deficiencies. In short, preventing all folate preventable NTDs will not be easy, but it is a goal worth pursuing. This work was supported by the Intramural Research Program, NICHD, NIH. The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. James L. Mills,1 Aggeliki Dimopoulos,1 Regan L. Bailey,2 1Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 2Department of Nutrition Science, Purdue University, West Lafayette, Indiana