Do the benefits of folic acid fortification outweigh the risk of masking vitamin B12 deficiency?BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k724 (Published 01 March 2018) Cite this as: BMJ 2018;360:k724
- James L Mills, senior investigator1,
- Anne M Molloy, associate professor, emeritus2,
- Edward H Reynolds, former consultant neurologist3
- 1Epidemiology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
- 2School of Medicine, Trinity College Dublin, Ireland
- 3Maudsley and King’s College Hospitals, London, UK
- Correspondence to: J L Mills , E H Reynolds
Yes—James L Mills, Anne M Molloy
Worldwide we are preventing only about 10% of the neural tube defects that can be avoided by folate.1 The EU and some of the world’s largest countries have not adopted mandatory fortification, the only population strategy definitively shown to reduce the incidence of these devastating birth defects.1 Some have argued that fortification will benefit only a small number of children at the expense of an unproved risk to a much larger number of elderly people. But arguments focusing on this unresolved issue overlook another compelling reason for mandatory fortification.
Folate deficiency is a far more common problem than neural tube defects and has been almost eliminated by mandatory folic acid fortification in the US. Before mandatory fortification, the prevalences of low serum (<10 nmol/L) and red cell folate (<340 nmol/L) were 24% and 3.5%, respectively, in a representative sample of the US population. After fortification these figures were both ≤1%.2 This translates into millions of cases of folate deficiency corrected or averted. Not only does this avoid the morbidity caused by folate deficiency anaemia, it reduces medical costs for healthcare visits, laboratory testing, and treatment.
Folate deficiency is common in many parts of the world. Chinese3 and Indian4 studies report a high population rate of anaemia. Even in the UK, one large population study reported that about 10% of people aged 65-74 and 20% of those >75 years old were at high risk of folate deficiency.5 Fortification is an excellent way to overcome this problem because folic acid is considerably more bioavailable and stable than food folate.6 Moreover, higher folate concentrations have been associated with lower risk of colorectal cancer and with improved cognition in elderly people,78 although it remains to be determined if these associations are causal.
In contrast to the well documented major public health benefit of preventing folate deficiency anaemia in large numbers of people, the risk of neurological problems is small and unproved for levels of folic acid used in mandatory fortification programmes. Although vitamin B12 deficiency anaemia can be masked by high dose folic acid, this has not been shown to be a problem since fortification in the US.9 The incremental intake of folic acid from fortification is probably much too small to cause masking.
The theory that high dose folic acid can cause or worsen neurological problems in those who are vitamin B12 deficient is based on old studies with serious limitations. All of these studies were observational. Comparative control groups taking vitamin B12 were not studied, raising the question noted by the authors in one commonly cited observational study10: were the neurological problems due to the “tremendous variability inherent in the disease as it relates to remissions and relapses.”
None of the major reviews carried out by the leading public health experts in the US and Europe have accepted as fact the theory that high dose folic acid (>5 mg/day) can exacerbate or precipitate neurological damage in patients with vitamin B12 deficiency.61112 The most conservative conclusion is that it is plausible but unproved. To address the issue of masking B12 deficiency, an upper limit on folic acid intake has been recommended.
In conclusion, mandatory fortification has done far more than prevent neural tube defects. It has prevented millions of cases of folate deficiency without any proved adverse effects. Instituting mandatory fortification in countries where it has not been introduced would prevent many more devastating birth defects and cases of folate deficiency.
No—Edward H Reynolds
There is no doubt that periconceptional folic acid supplements reduce the risk of neural tube defects.1314 In the roughly 80 countries that have instituted mandatory fortification of cereal grains with folic acid, rates of neural tube defects have fallen by 20%-60%. Given that rates have not fallen significantly in areas without mandatory fortification,15 proponents argue for wider adoption. However, folic acid fortification is not without its risks for a much larger proportion of the population. Excessive folic acid may increase the risk of neurological complications in patients with pernicious anaemia.1016 Low serum vitamin B12 concentrations have been reported in about 10% of older people,17 and the risk of folic acid fortification in this elderly population is being misunderstood and neglected.
More than masking
Folic acid supplementation can mask the diagnosis of vitamin B12 deficiency in a minority of patients, but this is a small part of a wider more serious problem. Advocates of fortification have overlooked that inappropriate excess folic acid in pernicious anaemia can eventually lead to relapse of the anaemia, usually after temporary and sometimes suboptimal remission, as well as neurological deterioration. At five and 10 years of follow-up relapse of the anaemia is as common as neurological relapse.1018
Temporal dissociation between the haematological and neurological signs can occur in both vitamin B12 and folate deficiency.19 Similarly, haematological and neurological remissions and relapses can be dissociated in vitamin B12 deficiency associated with excess folate, creating the opportunity for “masking” during haematological remission before a relapse. The higher the folic acid level the greater the risk of relapse, but the duration of exposure of the nervous system and the blood is also important.20
Although expert committees suggested that 1mg folic acid per day is the safe upper limit for the nervous system, they did not consider haematological relapse and duration of exposure.20 Among patients with pernicious anaemia treated with <1 mg folic acid, none of 25 developed neurological deterioration after 5-19 days, whereas six of 12 treated for 90-930 days did.21 Patients with neurological complications of vitamin B12 deficiency had the highest folate levels.21
Problems after fortification
In countries with fortification, older people with low vitamin B12 levels and high folate have also been shown to be at greater risk of cognitive impairment. In a study of 1459 healthy people aged over 60 years, high serum folate was associated with both anaemia and cognitive impairment in those with low vitamin B12 levels but not in participants with normal vitamin B12 levels.22 Furthermore, total homocysteine and methylmalonic acid concentrations decreased with increasing folate in participants with low serum vitamin B12 levels, whereas the opposite occurred in those with normal vitamin B12 levels.22 In a study of 1354 elderly people those with high red cell folate levels and low vitamin B12 levels were three times more likely to have impaired cognitive performance than those with normal folate.23 Metabolic evidence of vitamin B12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin levels, was more pronounced in older adults with high plasma folate.24
In 549 elderly people studied over eight years those with plasma vitamin B12 levels in the bottom two quintiles predicted slow cognitive decline; the rate of decline was accelerated in those who also had high plasma folate.25 Similarly, in elderly people with the transcobalamin 776GG genotype, which affects uptake of vitamin B12, the risk of peripheral neuropathy was three times that of those with the CC genotype; the risk associated with the GG genotype was doubled in those whose folate was twice the recommended allowance (odds ratio 6.9 versus 3.3).26 After fortification was introduced in the US the prevalence of low vitamin B12 levels increased even in the absence of macrocytosis or anaemia.27
Because of preoccupation with masking some neglected lessons of the past are being gradually rediscovered in the era of fortification.28 There is consistent clinical, experimental, and biochemical evidence that excess folate in the presence of vitamin B12 deficiency can be directly harmful to the nervous system and blood. Administration of folic acid increases the demand for vitamin B12. Both may influence epigenetic mechanisms.19
Fortification exposes elderly people at increasing risk of vitamin B12 deficiency17 to prolonged excess folate without any neurological monitoring. Fortification undoubtedly reduces neural tube defects. But vitamin B12 deficiency in pregnancy is also common in many countries29 and is also a risk factor for neural tube defects. Such defects attributable to B12 deficiency have tripled in Canada, which has folate fortification.30 Fortification with both folic acid and vitamin B12 would increase the benefits and reduce the risks.
Competing interests: All authors have read and understood BMJ policy on declaration and declare the following: JLM is supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The views presented do not necessarily represent those of the US government. EHR was a member of the COMA 2000 UK Committee on folic acid fortification.
Provenance and peer review: Commissioned; externally peer reviewed.