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Researchers argue that setting an upper level of intake for folate has no scientific basis, in a new study, published in Public Health Reviews.
A briefing accompanied this roundup.
Dr Ian Johnson, Nutrition researcher and Emeritus Fellow, Quadram Institute Bioscience, said:
“The new paper by Wald and colleagues is a timely reminder that the protective effect of dietary supplementation with folates against neural tube defects has been conclusively proven, and that much more could be achieved with mandatory fortification of cereal foods. Although a theoretical case for adverse effects of fortification with folic acid can be made, the practical experience of countries such as the USA, where fortification of cereal flours with folic acid was introduced two decades ago, indicates that very significant reductions in the incidence of neural tube defects are achieved, with no evidence of harm. The UK government’s own advisory panel on nutrition has recently confirmed its longstanding advice that, with certain precautionary measures in place, mandatory fortification of cereal flours with folic acid should be introduced in Britain. It is difficult to see why this important public health measure has not yet been adopted.”
Prof. David Smith FMedSci, Professor Emeritus of Pharmacology and Founding Director of the MRC Anatomical Neuropharmacology Unit, University of Oxford, said:
“I cannot say whether the Institute of Medicine might have made an error in defining the safe upper limit of folic acid intake as 1 mg per day from the evidence at their disposal in 1998. The issue clearly needs to be re-examined in the light of current evidence. However, the IOM view is certainly not the only reason why many scientists today are concerned about mandatory folic acid fortification. The European (EFSA) and USA (NIH) authorities have both called meetings in the recent past to discuss the safety of mandatory folic acid fortification. The matter has not been resolved and that is why European governments are reluctant to take this step, in spite of the known benefit in reducing NTD pregnancies.
“Two key facts must be considered. Firstly, folic acid is a synthetic chemical that occurs rarely in nature and it is different from the natural food folates, which are in the reduced form. Humans metabolise folic acid to the reduced forms slowly and in particular many people carry genetic mutations that slow this metabolism further. As a result, in countries that have fortified most of the population carry unmetabolised folic acid in their blood. We simply do not know if this is harmful or not, but there are indications that it could be.
“Secondly, the government’s Scientific Advisory Committee on Nutrition (SACN) estimated in 2006 that mandatory folic acid fortification would reduce the number of NTD pregnancies by between 77 and 112 each year, i.e. a risk reduction of 11-18%. Thus, the introduction of fortification would expose between 580,000 and 844,000 in the population of UK to extra folic acid for each NTD pregnancy prevented. Can we be sure that in this large proportion of the population no-one would suffer harm from the folic acid? The answer must be ‘No, we cannot be sure’.
“Evidence of possible harm from folic acid is available from several peer-reviewed publications since 2007 and has recently been reviewed (see below). To summarise, firstly, in the elderly who have poor vitamin B12 status, those with high folate status in countries with fortification (USA, Australia and Chile) have been found to be at risk of cognitive impairment3. It has been estimated that the proportion of elderly in this category in the USA is about 4%, which means about 1.8 million are at increased risk of cognitive impairment in that country. Secondly, a dose-dependent effect of folic acid has been found in several studies: low doses are beneficial but higher doses are harmful, e.g. to both to mother and child during pregnancy (for example, gestational diabetes and impaired cognition in the child)6.
“The authors have ignored, or dismissed, these reports and as a result their conclusion is invalid. In my view, it is quite wrong of the authors of this paper to conclude that ‘The use of an upper intake level for folate should be abandoned’. This statement ignores much science and is potentially harmful to public health.”
1 Smith AD, Kim YI, Refsum H (2008) Is folic acid good for everyone? Am J Clin Nutr 87, 517-533.
2 Selhub J, Rosenberg IH (2016) Excessive folic acid intake and relation to adverse health outcome. Biochimie 126, 71-78.
3 Smith AD, Refsum H (2016) ‘Does high folate status impair cognition?’ Supplement to Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 36, 211-239.
4 Smith AD, Refsum H, Selhub J, Rosenberg IH (2016) Decision on folic acid fortification in Europe must consider both risks and benefits. BMJ 352, i734.
5 Reynolds EH (2017) The risks of folic acid to the nervous system in vitamin B12 deficiency: rediscovered in the era of folic acid fortification policies. J Neurol Neurosurg Psychiatry 88, 1097-1098.
6 Valera-Gran, D. (2017) Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 years of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr. 106:878-887
Dr Jaleel Miyan, Senior Lecturer in Neuroscience, University of Manchester, said:
“Wald and colleagues present a compelling analysis of the original 1991 MRC randomised, double blind control trial demonstrating that 4mg of folic acid taken as a supplement by women before pregnancy and through the first trimester of pregnancy prevented 80% of the cases of neural tube defects including the lethal versions of anencephaly and craniorachischisis, as well as the non-lethal spina bifida. The trial highlighted this vitamin deficiency as the cause of these serious developmental neurological disorders which, if addressed through supplementation, could be largely prevented.
“The problem arises in compliance and lack of planning of pregnancies as well as poor knowledge of the importance of this vitamin which needs to be taken before conception – points highlighted in the review. This is due to the fact that the period in which the neural tube forms is in the first four weeks of development, a period were most women would be unaware of pregnancy but also a period in which the fertilised egg is not connected to the maternal blood until implantation of the embryo into the uterine wall. The eggs in the ovaries need to be loaded with folate prior to ovulation in order to ensure sufficient resource for neural tube formation.
“The need for folate and the lack of impact of voluntary supplementation on the incidence of neural tube defects has stimulated 81 countries to date to introduce mandatory folic acid fortification of wheat flour and, more recently in the USA, into cornflour. However neither the European Union nor any individual country within Europe has adopted mandatory fortification. A review of mandatory fortification in the USA and other countries has found demonstrable and significant benefits not only to decreasing rates of neural tube defects but also in cardiovascular health and some decrease in cancer rates with no increase in any cancer rate reported in any country (e.g. Castillo-Lancellotti et al 2013 Public Health Nutr 16: 901-11). This should address one of the key objections to fortification raised by Cole et al (2007, JAMA 21:2351-9), Mason et al (2007, Cancer Epidemiol.Biomarkers Prev. 16:1325-9) and Hirsch et al (2009, Eur.J.Gastroenterol.Hepatol. 21:436-9) regarding increased risk of cancers with folate supplementation. In their review Wald et al provide further evidence for the lack of toxicity of folate even at high dose.
“Understanding the key role of folate in many metabolic pathways highlights the potential for many different conditions that may be associated with folate deficiency and/or folate imbalance. Most importantly folate is needed for DNA synthesis, so that a folate deficiency could result in DNA copy errors and thus increased cancer risk, contrary to the worry of fortification resulting in increased cancer risk. Methyl folate (food folate) is involved in conversion of homocysteine to methionine which goes onto to produce SAM, the essential methyl donor for DNA, protein and lipid methylation. This process is essential for switching genes on and off and activating other molecules, so folate deficiency could lead to inappropriate gene expression and a whole host of consequential birth defects. Methyl folate together with vitamin D is also essential in the synthetic pathways for the neurotransmitters dopamine, noradrenaline and adrenaline as well as serotonin, so that folate deficiency and/or vitamin D deficiency could result in autonominc dysfunction, mood disorders, depression and other neuropsychiatric conditions. Folate also feeds into energy metabolism, detoxification pathways as well as other metabolic processes making folate one of the most essential vitamins we can only get through food or supplementation. Given that modern human diet is largely deficient in folate then this, as the reviewers point out, is an essential public health matter that can easily be addressed with mandatory fortification.
“It seems absurd that we accept fortified products, largely from the USA, without local implementation. It is also somewhat curious that we worry about higher doses when, compared to the 400µg daily dose recommended for periconceptional use across developed countries, 4-5mg (10 fold higher) is the recommended, and over the counter dose, for developing countries. With no adverse effects reported across the world for folate supplementation there seems no reason for concern on fortification taking levels above assumed safe limits. Given the repeated failed attempts to get the EU to adopt mandatory fortification, the current review is timely and compelling in its arguments supporting this proven prevention of devastating neurological defects. Europe needs to take the long overdue decision to implement mandatory fortification and reduce the impact of neural tube defects.”
Prof. Tom Sanders, Professor emeritus of Nutrition and Dietetics, King’s College London, said:
“Wald et al. provide overwhelming evidence in support of the case for folic acid fortification to prevent neural tube defects as mandated in the USA and many other countries. However, it would not completely eliminate neural tube defects. Because high intakes of folic acid might harm older men and women, no European country has legislated to force food companies to fortify.
“The UK proposal by the Scientific Advisory Committee on Nutrition (SACN) in 2006 recommended the introduction of mandatory fortification of wheat flour with folic acid alongside restrictions on voluntary fortification of foods with folic acid. This proposal was met with some opposition from the food industry at the time. Consumers were also lukewarm to the proposal following a series of articles pointing out that folic acid is an unnatural form of folate, and some suggestion that it might increase risk of colorectal cancer1; and that consumers would have no choice (e.g. Joanna Blythman, Guardian, May 18 2007). The cancer issue is dealt with in some detail in the latest update by SACN in 20172.
“The review by Wald et al. concludes that there are no longer valid concerns about risk of cancer or about excessive intakes of folic acid masking vitamin B12 deficiency from the most common cause of vitamin B12 (pernicious anaemia) where there is a failure to absorb the vitamin. It is also stated that it is relatively rare for B12 deficiency to occur without megaloblastic anaemia. This is not entirely accurate as a lack of vitamin B12 in the diet affects over 50% of vegans in the UK but does not result in megaloblastic anaemia3. Although veganism is becoming more popular, an additional intake of folic acid from fortified foods would be unlikely to cause any problems in this group: vegans need to supplement their diet with vitamin B12.
“Fortification of wheat flour with folic acid as proposed by SACN would not benefit women who avoid wheat or women in ethnic minorities for whom wheat is not a staple food. Besides individuals who have coeliac disease (which may be as high as 1 in 140), there are a substantial number of women of reproductive age who avoid wheat for other reasons, some claim they are intolerant to wheat and others do it because it is fashionable in recent years. It would, therefore, be sensible to continue to allow the voluntary fortification of other cereal products such as maize, rice and breakfast cereals especially as the latter makes an important contribution to folate intake in teenage girls from low-income groups4.
“The government urgently needs to win the support for folic acid supplementation. Industrially processed wheat bread is the main source of cereals in the UK diet and is now produced in a few larger bakeries in the UK. One bakery in Kent claims to manufacture more than 30% of the processed bread on sale! In my opinion, the simplest solution would be to pass a law to make food companies add folic acid to all industrially processed bread (these already have other vitamins added). This would be an important concession to artisan and home bakers as well as to those ideologically opposed to the universal fortification of wheat.”
1 Sauer J, Mason JB, Choi S-W. ‘Too much folate – a risk factor for cancer and cardiovascular disease? Current opinion in clinical nutrition and metabolic care’. 2009;12(1):30-36. doi:10.1097/MCO.0b013e32831cec62
3 Gilsing AM, Crowe FL, Lloyd-Wright Z, et al. Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians and vegans: results from a cross-sectional analysis of the EPIC-Oxford cohort study. Eur J Clin Nutr 2010;64:933-9.
4 Holmes BA, Kaffa N, Campbell K, Sanders TA. The contribution of breakfast cereals to the nutritional intake of the materially deprived UK population. Eur J Clin Nutr 2012;66:10-7.
Prof Sir Colin Berry, Emeritus Professor of Pathology, QMUL, said:
“In this thoughtful paper on an important public health intervention, the authors identify a major problem. Some regulatory agencies use the identification of a hazard to determine policy. If regulation is hazard based (based on the possibility of harm occurring) rather than a risk/benefit evaluation, harm may follow. There are abundant data that enable a sensible risk/benefit evaluation to be made in the clinical setting about which the authors express an opinion. It is also important to note that the data base reviewed in the relevant European context appears to be incomplete. A paragraph points out that the ‘European Commission Scientific Committee on Food, put greater weight on the hypothetical possibility of harm than on the proven evidence of benefit, apparently ignoring the fact that withholding a benefit is itself a harm’.”
Prof. Mark Kilby, Professor of Fetal Medicine and spokesperson for the Royal College of Obstetricians and Gynaecologists, said:
“We welcome this important study which recommends there should be no upper limit of intake for folate. This should help to remove any final barriers to folic acid fortification of foods such as flour.
“There is clear evidence that fortification will prevent approximately half of all neural tube defects, such as anencephaly and spina bifida. There are around 1,000 diagnoses of neutral tube defects in utero in the UK, 85% of which result in an abortion. This accounts for around 1 in 200 abortions in the UK, many of which will be in the second trimester of pregnancy. In addition, a recent systematic review has demonstrated that periconceptual folic acid supplementation will reduce the risk of a baby being born small for gestational age, and therefore the theoretical risk of stillbirth.
“The authors of this paper challenge the old assumption that high levels of folic acid are toxic and may mask the neurological effects of vitamin B12 deficiency by re-analysing the evidence and demonstrating no relationship between the dose of folic acid and the development of neurological morbidity.
“The RCOG has long supported fortification of flour with folic acid as a public health measure to prevent neural tube defects in babies. This simple measure will reach women most at risk in our society who have poor dietary and socioeconomic status, as well as those women who may not have planned their pregnancy. We continue to recommend that all women take 400 micrograms of folic acid daily whilst attempting to conceive, until their 12th week of pregnancy.
“If the UK government decided to add folic acid to flour it would prevent countless family tragedies. Governments in Scotland and Wales are already united in calling for this important change.”
Dr Katie Morris, Senior Clinical Lecturer in Maternal Fetal Medicine, University of Birmingham, and Birmingham Women’s and Children’s NHS Foundation Trust, said:
“This research dispels the major barrier to flour fortification with folic acid, that there is an upper limit of folic acid intake that is safe. The authors re-evaluate the evidence for the safety concerns with folic acid fortification and consider these in the light of current medical knowledge and practice. There is no doubt that mandatory food fortification will prevent approximately half of all neural tube defects in babies. Folic acid supplementations started prior to pregnancy will always be recommended but fortification would provide an additional level of benefit to all women but importantly, the only level of protection in unplanned pregnancies or in groups less likely to take supplements e.g. socio-economically deprivation, ethnic minorities and younger women. Folic acid supplementation pre-pregnancy is also associated with reduced risks of having a small baby and a pre-term baby and thus fortification is likely to have a beneficial effect on reducing these adverse pregnancy outcomes as well. The authors’ conclusions mirror those of other experts and their call to the UK Government to fortify flour is echoed by calls from the Royal College of Obstetricians and Gynaecologists and the British and Maternal Fetal Medicine Society, to name a few.”
Dr Graham Horgan, Principal Consultant for Human Health & Nutrition, Biomathematics & Statistics Scotland, Rowett Institute of Nutrition and Health, University of Aberdeen, said:
“The reinterpretation of existing data presented in this paper is an important contribution to our understanding of the effects of folic acid. Much of the debate about fortification has involved balancing its benefits for pregnant women and their babies against the risks of increasing intakes by those who already have a high intake from supplements or voluntarily fortified products. If these risks have been overestimated, then the case for fortification needs to be reconsidered.”
Prof. Neena Modi, President of the Royal College of Paediatrics and Child Health, said:
“Folic acid taken in the early stages of pregnancy will prevent around seven of 10 neural tube defects. This new research is a game changer for fortification in allaying concerns about exceeding an upper limit of 1mg/day.
“In the early stages of pregnancy when neural tube defects arise, many women do not know they are pregnant, others may be unaware of the importance of taking folic acid, or may forget, so fortification of flour, which is harmless if consumed by children and adults, is a logical answer to a problem which can have catastrophic consequences.
“Around 80 countries already fortify foods and report significant reductions in neural tube defects. It’s a move backed by royal colleges, including the RCPCH, in addition to food manufacturers and other experts. Government now needs to implement this simple, highly effective public health measure.”
* ‘Public health failure in the prevention of neural tube defects: time to abandon the tolerable upper intake level of folate’ by Nicholas J. Wald et al. published in Public Health Reviews on Wednesday 31 January 2018.
Declared interests
Dr Ian Johnson: “I don’t have any conflict of interest to declare.”
Prof. David Smith: “I can confirm that I have no interests that might conflict with this report or my comments.”
Dr Jaleel Miyan: “I am folate spokesperson for Society for Research in hydrocephalus and spina bifida. My research is investigating the cerebral folate system and its role in brain development.”
Prof. Tom Sanders: “Scientific Governor of the British Nutrition Foundation; I chaired this report: ‘British Nutrition Foundation Task Force on Nutrition and Development – short- and long-term consequences for Health’. Wiley-Blackwell, Chichester 2013.”
Prof Sir Colin Berry: “Sir Colin consults for a number of agrochemical and pharmaceutical companies and for the MHRA. He is advises the European Risk Forum.”
Prof Mark Kilby: “No conflict of interests to declare.”
Dr Katie Morris: “I am an Executive member of the British Maternal and Fetal Medicine Society and have published a paper on folic acid supplementation and small for gestational age (‘Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small-for-gestational age neonates: a population study, systematic review and meta-analysis’, Hodgetts VA, Morris RK, Francis A, Gardosi J, Ismail KM. BJOG. 2015 Mar;122(4):478-90. doi: 10.1111/1471-0528.13202. Epub 2014 Nov 26. Review. PMID: 25424556.) I have no conflicts of interest.
Dr Graham Horgan: “Our organisation received funding from Food Standards Scotland last year to carry out the study that is referenced [20] in the paper.”
None others received.