Folic acid fortification for Europe?BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h6198 (Published 24 November 2015) Cite this as: BMJ 2015;351:h6198
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Dr. Smith and colleagues make some statements regarding our editorial that require clarification. They interpret our statement that, “No important adverse effects have been identified to date, probably because a modest level of fortification has proved very effective in preventing these devastating birth defects”, to mean that we are claiming that it is safe because it is effective for one condition. This interpretation is incorrect. Food fortification in the US has resulted in an estimated average exposure of approximately 200 µg of folic acid per day. This is half the recommended dietary allowance (RDA). We were indicating that it is not surprising that no adverse effects have been demonstrated from such a modest dose. As they point out, the WHO states that even high folic acid exposure, in contrast to the small amount fortification delivers, “has not reliably been shown to be associated with negative effects”. Thus, the postulated adverse effects, if any, are unproven.
The reduction in neural tube defect rates produced by fortification has been shown to be proportional to the underlying rate  and reported reductions vary depending on the completeness of ascertainment. Many areas in Europe are not covered by monitoring programs; not all programs identify prenatally lost or terminated cases ; and the rates vary considerably. Thus, some areas would benefit more than others. It is also worth noting that neural tube defect rates have increased during bad economic times; so benefits are likely to be greater in times of economic difficulty.
Smith and colleagues point out that fortification will expose the general population to folic acid, implying that this is undesirable. The US experience showed that fortification resulted in very large benefits to the general population. The prevalence of folate deficiency as measured by red cell folate dropped from 3.5% before fortification to ≤1% after fortification, decreasing morbidity and medical costs. A similar analysis could be done in Europe to see how many people would benefit from fortification.
In contrast to this proved benefit, the adverse effect of high folate levels on cognitive function claimed by Smith et al. has not been proved. They cite the evidence for a detrimental effect of folic acid in B12 deficient elderly people but do not mention the evidence against it. Clarke et al. tested this specific hypothesis and found that participants who had low vitamin B12 concentrations had the same increase in risk for cognitive decline if they had high folate (odds ratio 1.50, CI 0.91-2.46) or low folate (odds ratio 1.45, CI 1.19-1.76). A second study examined cognitive decline during a ten year period and found that while lower holotranscobalamin was related to increased risk for cognitive decline, there was no interaction with folate. Thus, participants who had low vitamin B12 and high folate concentrations were at no greater risk than those who had low vitamin B12 and low folate concentrations.
It should be noted that the relationship between folate, vitamin B12 and cognitive decline is far from established.[11-13] In contrast to the Morris paper  cited by Smith et al. showing an increased rate of cognitive decline in those with high folate intakes, The Women’s Health Initiative Memory Study  found that women who reported folate intakes below the RDA were at increased risk for cognitive impairment or dementia later in life, suggesting that food fortification could reduce the risk for cognitive impairment over the long term.
As has been stated previously, the phenomenon Smith et al. report  is very likely the result of people who have untreated vitamin B12 deficiency taking multivitamin supplements. Such people would absorb the folic acid, resulting in high folate concentrations, but could not absorb the vitamin B12. Those who had the most severe deficiency would have the lowest B12 concentrations and would be at high risk for cognitive disturbances. Several of their findings support the hypothesis that the low B12-high folate observation is due to untreated B12 deficiency. Only 4% of the study subjects fell into this group; folate and B12 were highly positively correlated in the population overall; and high folate was protective against cognitive decline in those who were not B12 deficient. Thus, the folic acid exposure is not relevant to the problem.
It should be noted that our research showed that the proportion of vitamin B12 deficient patients presenting without anemia did not increase following food fortification in the US, providing some reassurance that the risk of masking B12 deficiency was not being increased.
Concerning cancer risk, Smith et al. cite the same meta-analysis we cited in the editorial. We also noted that a six percent increase, if real, could have a public health effect. However, the study found that there was no significant increase; the six percent increase reported was simply the point estimate. The subgroup analyses cited by Smith et al. do not take into account the multiple comparisons problem. For example the association between folic acid-MTHFR genotype and cancer mortality was the only finding with a p value below 0.05 in the 18 comparisons made in the folic acid subgroup analysis and would not be significant after any Bonferroni correction.
We also noted that the most relevant cancer rates have dropped significantly in the US since fortification began. Many factors influence these rates other than folic acid exposure, but it is encouraging that the increase Smith et al. hypothesize might have occurred was not found.
In summary, fortification with folic acid has greatly reduced both neural tube defect rates and folate deficiency. The dose needed to accomplish these goals is modest and no adverse effects have been convincingly demonstrated to date.
1. Choumenkovitch SF, Selhub J, Wilson PWF, et al. Folic acid intake from fortification in United States exceeds predictions. J Nutr 2002;132:2792-8.
2. WHO. Guideline: Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects. Geneva: World Health Organization; 2015. http://www.ncbi.nlm.nih.gov/books/NBK294192/pdf/Bookshelf_NBK294192.pdf
3. Berry RJ, Li Z, Erickson JD, et al. Prevention of neural-tube defects with folic acid in China. NEJM 1999;341:1485-90.
4. Mills JL, Signore C. Neural tube defect rates before and after food fortification with folic acid. Birth Defects Res A Clin Mol Teratol 2004;70:844–5.
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6. European Surveillance of Congenital Anomalies (EUROCAT) www.eurocat-network.eu/
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8. Pfeiffer CM, Hughes JP, Lacher DA, et al. Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. J Nutr 2012;142:886-93.
9. Clarke R, Sherliker P, Hin H, et al. Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK. Brit J Nutr 2008;100:1054-9.
10. Clarke R, Birks J, Nexo E, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr 2007;86:1384-91.
11. van der Zwaluw NL, Dhonukshe-Rutten RAM, van Wijngaarden JP, et al. Results of 2-year vitamin B treatment on cognitive performance: Secondary data from an RCT. Neurology 2014;83:2158-66.
12. Dangour AD, Allen E, Clarke R, et al. Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial. Am J Clin Nutr 2015;102:639-47.
13. Raman G, Tatsioni A, Chung M, et al. Heterogeneity and lack of good quality studies limit association between folate, vitamins B-6 and B-12, and cognitive function. J Nutr 2007; 137:1789-94.
14. Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol 2005;62:641-5.
15. Agnew-Blais JC, Wassertheil-Smoller S, Kang JH, et al. Folate, vitamin B-6, and vitamin B-12 intake and mild cognitive impairment and probable dementia in the Women’s Health Initiative Memory Study. J Acad Nutr Diet 2015;115:231-41.
16. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007;85:193-200.
17. Berry RJ, Carter HK, Yang Q. Cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007;86:265-7.
18. Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003;77:1474-7.
19. Ebbing M, Bønaa K, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302:2119-26.
Competing interests: No competing interests
Re: Folic acid fortification for Europe? A decision on folic acid fortification in Europe must consider risks as well as benefits
We are concerned about the following statement in a recent Editorial on the safety of folic acid fortification: “No important adverse effects have been identified to date, probably because a modest level of fortification has proved very effective in preventing these devastating birth defects.” It is unusual in medicine to claim that a treatment is safe just because it is effective in treatment or prevention of one condition; what is required is objective evidence on overall safety and side effect profile in all people exposed to the “treatment”, not only those that benefit. It appears that the WHO has also not fully assessed the possible harmful effects of folic acid since, in their guideline on folate and neural tube defects, they state: “high folic acid intake has not reliably been shown to be associated with negative health effects”.
Incidentally, the effectiveness of mandatory fortification in Europe would not be as great as claimed by the Editorial, which stated that half of all neural tube defects (NTDs) can be prevented. This claim is misleading in the European context, because the effectiveness of fortification depends on the baseline prevalence of NTDs, with a smaller reduction in countries with low prevalence. The accompanying report found a prevalence of NTDs in Europe of 9.1 per 10,000 births. In 8 states of the USA the prevalence before fortification was 10.7, while after fortification it had fallen to 7.0. It is not likely that, if fortification is introduced, the prevalence in Europe will decline to much below 7 per 10,000 because only a certain proportion of NTDs are caused by low folate status and a floor effect has been noticed.
Regarding possible adverse effects, for each neural tube defect pregnancy prevented, mandatory fortification of flour products with folic acid will expose several hundred thousand Europeans to folic acid, a synthetic form of folate not widely found in nature. Increasing evidence suggests that certain subgroups of the population may suffer harm from exposure to high levels of folic acid. Some of the most consistent evidence concerns elderly members of the population. In Chicago, elderly people who consumed > 349 g of total folate per day (half of which was folic acid from supplements) had a faster rate of cognitive decline over 6 y than those who consumed < 221 g of folate per day. Furthermore, those who consumed daily supplements containing > 400 g folic acid showed significant cognitive decline compared with non-supplement users. Another study found that after mandatory fortification in the USA, those with poor vitamin B12 status but high serum folate (> 59 nmol/L), showed an increased risk of anaemia and/or of cognitive impairment, which appears to be related to the presence of unmetabolized folic acid in the circulation. In Australia, a similar effect on cognition was found: elderly people with high red blood cell folate (1,594 nmol/L) and low vitamin B12 status (< 250 pmol/L) showed an increased risk of cognitive impairment. It was notable in this study that even those with low-normal B12 (median 383 pmol/L) but high red blood cell folate had an increased risk of impairment. The prevalence in Europe of elderly with low-normal vitamin B12 status is likely to be quite significant and so this subgroup would be at risk of cognitive impairment if they are also exposed to high folate levels. In surveys across Europe, typically 6-10% of those aged ≥60 y are vitamin B12 deficient (plasma vitamin B12 < 150 pmol/L) and the prevalence of deficiency increases with age. Furthermore, an additional to 20-30% has marginal status (plasma vitamin B12: 148–221 pmol/L)[11-14].
Concerning possible adverse effects of folic acid, the Editorial says that the literature on folic acid and cancer is inconsistent. We would like to point out that an often cited meta-analysis including almost 50,000 individuals in folic acid trials, found a 6% increased risk of cancer in those taking folic acid, but that this risk did not quite reach significance (RR 1.06, 95% CI 0.99-1.13). What we do not know is whether this meta-analysis was sufficiently powered to show a significant association of 6%, which is a very relevant increase in cancer risk, given the high prevalence of cancer. A second problem is that several relevant subgroups were not examined. In the Norwegian trials, it was found among patients who took folic acid that those who had the 677TT genotype of MTHFR had a greater risk of dying from cancer than those with the CC genotype. An observational study also reported that women with the 677TT genotype and high serum folate had a higher risk of breast cancer than those with lower folate. Another example of the importance of subgroups is that people with different genotypes of the 19bpdel polymorphism in DHFR show different associations between folate and cancer and also between folate and cognition (reviewed in reference).
Although high blood levels of folate may in part be due to the consumption of fortified ready-to-eat breakfast cereals and/or supplements, there is no doubt that mandatory fortification in the USA led to a marked increase in the prevalence of high serum levels. A similar effect is likely in Europe if fortification is introduced. In view of the evidence outlined above that high folate levels may not be harmless, we believe that the European authorities should carefully consider all the evidence concerning benefits and risks before making a recommendation for mandatory folic acid fortification.
1. Mills JL, Dimopoulos A. Folic acid fortification for Europe? BMJ (Clinical research ed) 2015;351:h6198.
2. WHO. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects. Guideline. Secondary Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects. Guideline 2015. http://www.who.int/nutrition/publications/guidelines/optimaserum_rbc_wom....
3. Heseker HB, Mason JB, Selhub J, et al. Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid. Br J Nutr 2009;102(2):173-80.
4. Khoshnood B, Loane M, Walle H, et al. Long term trends in prevalence of neural tube defects in Europe: population based study. BMJ (Clinical research ed) 2015;351:h5949.
5. Williams J, Mai CT, Mulinare J, et al. Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995-2011. MMWR Morbidity and mortality weekly report 2015;64(1):1-5.
6. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr 2008;87(3):517-33.
7. Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol 2005;62(4):641-5.
8. Morris MS, Jacques PF, Rosenberg IH, et al. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007;85(1):193-200.
9. Morris MS, Jacques PF, Rosenberg IH, et al. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr 2010;91:1733-44.
10. Moore E, Ames D, Mander A, et al. Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. Journal of Alzheimer's disease : JAD 2014;39:661-68.
11. Wang HX, Wahlin A, Basun H, et al. Vitamin B12 and folate in relation to the development of Alzheimer's disease. Neurology 2001;56(9):1188-94.
12. Obeid R, Schorr H, Eckert R, et al. Vitamin B12 status in the elderly as judged by available biochemical markers. Clin Chem 2004;50(1):238-41.
13. Clarke R, Sherliker P, Hin H, et al. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, Holotranscobalamin. Clin Chem 2007;53(5):963-70.
14. Loikas S, Koskinen P, Irjala K, et al. Vitamin B12 deficiency in the aged: a population-based study. Age Ageing 2007;36.
15. Vollset SE, Clarke R, Lewington S, et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. Lancet 2013;381(9871):1029-36.
16. Ebbing M, Bonaa KH, Nygard O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. Jama 2009;302(19):2119-26.
17. Ericson UC, Ivarsson MI, Sonestedt E, et al. Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele. Am J Clin Nutr 2009;90(5):1380-89.
18. Selhub J, Rosenberg IH. Excessive folic acid intake and relation to adverse health outcome. Biochimie 2016;(in press).
19. Pfeiffer CM, Caudill SP, Gunter EW, et al. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr 2005;82(2):442-50.
A David Smith, Department of Pharmacology, University of Oxford, Oxford, UK
Helga Refsum, Institute of Nutrition, University of Oslo, Oslo, Norway
Jacob Selhub, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA
Irwin H Rosenberg, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA
Competing interests: No competing interests