Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles.
Gareth Iacobucci [1] reiterates the argument put forward by Wald and colleagues [2] that the time has come to abandon the tolerable upper intake level of 1mg folic acid to prevent neural tube defects (NTD).
The discovery that folate prevents many NTDs is undoubtedly one of the finest examples of recent preventative medicine. The work of Smithells and colleagues from 1965, and through the 70s and 80s [3-7], established the protective effect of folate against NTD. These data were supported by the MRC’s randomised double-blind prevention trial, which demonstrated a 72% reduction of NTD recurrence using 4mg of synthetic folic acid (PteGlu) [8].
We do not wish to undermine the obvious benefits of folic acid in NTD prevention, but feel that the article by Wald et al [2] filters out significant concern that has emerged since the initial use of folic acid as a fortificant at a population level, and particularly in regards to the amount and type of vitamer the population is exposed to.
Considerable attention is given to the US Institute of Medicines perspective on the upper limit of folate, and the potential for neurological damage in patients who have a vitamin B12 deficiency [9]. This IOM report dates back to 1998, the inception point for mandatory fortification in the US. A number of reports have been published since this time identifying other issues that might be cause for concern. Although not a comprehensive list, these include:
1. 400µg of synthetic PteGlu is efficiently metabolised into natural 5methyl-H4folate - higher doses see unmetabolised PteGlu appear in the blood plasma [10]. Is exposure to this unnatural vitamer harmful?
2. The impact on anti-folate pharmacotherapy [11]
3. The risk of cancer [12], [13], twin births [14], insulin resistance [15], cognitive decline in the presence of elevated folate and low B12 [16], and epigenetic interactions [17]
4. Attenuation of natural killer cell cytotoxicity and potential antimetabolite activity [18, 19].
A balanced perspective needs to be put forward to address all concerns, including ones that are more recent than the original 1998 IOM report. Folate metabolism is complex. Questions remain about the timing of folate exposure in certain groups, and the dose. In 1999 the lead author wrote a short piece for eBMJ [19] alluding to potential concerns regarding mandatory fortification in the US, twenty years later, the content of that original article remains equally germane.
Women of reproductive age are the target, elevating PteGlu intake above 1mg/day spills over to the entire population, including children. Of course, folate should be deployed to reduce these devastating malformations, but we need to ask questions about how much is efficacious. Could there be problems with too much unmetabolised PteGlu entering the circulation, and what are the biological implications of a lifetime’s exposure to elevated PteGlu.
To conclude, with such considerations we find it difficult to accept that, as stated by Wald et al, “concern about higher exposure to folic acid is unjustified”. The philosophical arguments and socio-political comments offered up are best tempered by a broader exposition of the science; both positive and negative outcomes that have been reported post 1998. The authors suggest that only “unequivocal evidence of harm” could weigh against implementation of fortification. We suggest that only when the unequivocal absence of harm is demonstrated should higher levels of PteGlu be added to the UK diet.
Mark Lucock*1, Jeong-Hwa Choi2, Martin Veysey3, Emma Beckett1,4
1 School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW 2258, Australia
2 Department of Food Science and Nutrition, Keimyung University, Daegu 42601, Korea.
3 Hull-York Medical School, University of York, Heslington, York, UK
4 School of Medicine and Public Health, University of Newcastle, Ourimbah, NSW, Australia
*Corresponding author – mark.lucock@newcastle.edu.au
References
1. Lacobucci G. Experts urge addition of folic acid to flour to halt “avoidable tragedy” of birth defects. BMJ Jan 2018;360:k477 doi: 10.1136/bmj.k477
2. Wald NJ, Morris JK, Blakemore C. Public health failure in the prevention of neural tube defects: time to abandon the tolerable upper intake level of folate. Public Health Rev Jan 2018. doi:10.1186/s40985-018-0079-6.
3. Hibbard ED, Smithells RW. Folic acid metabolism and human embryopathy. Lancet 1965;1:1254.
4. Smithells RW, Sheppard S, Schorah CJ. Vitamin deficiencies and neural tube defects. Arch Dis Child 1976;51:944–9.
5. Smithells RW, Sheppard S, Schorah CJ et al. Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet 1980;1:339–40.
6. Smithells RW, Seller MJ, Harris R et al. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983;1:1027–31.
7. Smithells RW, Sheppard S, Wild J et al. Prevention of neural tube defect recurrences in Yorkshire: final report. Lancet 1989;2:498–9.
8. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131–7.
9. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press; 1998. https://www.ncbi.nlm.nih.gov/books/NBK114310.
10. Lucock MD, Wild J, Smithells RW, et al. In vivo characterization of the absorption and biotransformation of pteroylmonoglutamic acid in man: a model for future studies. Biochem Med Metab Biol 1989;42:30-42.
11. Arabelovic S, Sam G, Dallal GE et al. Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with rheumatoid arthritis. J Am Coll Nutr 2007;26:453-455.
12. Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L, Bunout D. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 2009;21:436-439.
13. Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302:2119-26.
14. Nazer HJ, Aguila RA, Cifuentes OL. The frequency of twin pregnancies increased in a Chilean hospital associated with periconceptional flour folic acid supplementation. Rev Med Chil 2006;134:48-52.
15. Yajnik CS, Deshpande SS, Jackson AA, et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia 2008;51:29-38.
16. Morris MS, Selhub J, Jaques PF. M.S. Morris, J. Selhub, P.F. Jacques, Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham heart study. J Am Geriatr Soc 2012;60:1457-1464.
17. Beckett E, Veysey M, Lucock M, et al. Maternal folate and DNA methylation in offspring. The Handbook of Nutrition, Diet and Epigenetics. 2017; Editors: Patel V, Preedy V. SpringerLink, USA; DOI - 10.1007/978-3-319-31143-2_3-1
18. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006;136:189-194.
19. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci USA 2009;106:15424-49.
20. Lucock M. Food fortification with folic acid. eBMJ 23rd July 1999; http://www.bmj.com/rapid-response/2011/10/28/food-fortification-folic-acid
Competing interests:
No competing interests
23 February 2018
Mark D Lucock
Associate Professor in Human Molecular Nutrition
Jeong-Hwa Choi, Martin Veysey, Emma Beckett
University of Newcastle, Australia
School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW 2258, Australia
Re: Experts urge addition of folic acid to flour to halt “avoidable tragedy” of birth defects
Gareth Iacobucci [1] reiterates the argument put forward by Wald and colleagues [2] that the time has come to abandon the tolerable upper intake level of 1mg folic acid to prevent neural tube defects (NTD).
The discovery that folate prevents many NTDs is undoubtedly one of the finest examples of recent preventative medicine. The work of Smithells and colleagues from 1965, and through the 70s and 80s [3-7], established the protective effect of folate against NTD. These data were supported by the MRC’s randomised double-blind prevention trial, which demonstrated a 72% reduction of NTD recurrence using 4mg of synthetic folic acid (PteGlu) [8].
We do not wish to undermine the obvious benefits of folic acid in NTD prevention, but feel that the article by Wald et al [2] filters out significant concern that has emerged since the initial use of folic acid as a fortificant at a population level, and particularly in regards to the amount and type of vitamer the population is exposed to.
Considerable attention is given to the US Institute of Medicines perspective on the upper limit of folate, and the potential for neurological damage in patients who have a vitamin B12 deficiency [9]. This IOM report dates back to 1998, the inception point for mandatory fortification in the US. A number of reports have been published since this time identifying other issues that might be cause for concern. Although not a comprehensive list, these include:
1. 400µg of synthetic PteGlu is efficiently metabolised into natural 5methyl-H4folate - higher doses see unmetabolised PteGlu appear in the blood plasma [10]. Is exposure to this unnatural vitamer harmful?
2. The impact on anti-folate pharmacotherapy [11]
3. The risk of cancer [12], [13], twin births [14], insulin resistance [15], cognitive decline in the presence of elevated folate and low B12 [16], and epigenetic interactions [17]
4. Attenuation of natural killer cell cytotoxicity and potential antimetabolite activity [18, 19].
A balanced perspective needs to be put forward to address all concerns, including ones that are more recent than the original 1998 IOM report. Folate metabolism is complex. Questions remain about the timing of folate exposure in certain groups, and the dose. In 1999 the lead author wrote a short piece for eBMJ [19] alluding to potential concerns regarding mandatory fortification in the US, twenty years later, the content of that original article remains equally germane.
Women of reproductive age are the target, elevating PteGlu intake above 1mg/day spills over to the entire population, including children. Of course, folate should be deployed to reduce these devastating malformations, but we need to ask questions about how much is efficacious. Could there be problems with too much unmetabolised PteGlu entering the circulation, and what are the biological implications of a lifetime’s exposure to elevated PteGlu.
To conclude, with such considerations we find it difficult to accept that, as stated by Wald et al, “concern about higher exposure to folic acid is unjustified”. The philosophical arguments and socio-political comments offered up are best tempered by a broader exposition of the science; both positive and negative outcomes that have been reported post 1998. The authors suggest that only “unequivocal evidence of harm” could weigh against implementation of fortification. We suggest that only when the unequivocal absence of harm is demonstrated should higher levels of PteGlu be added to the UK diet.
Mark Lucock*1, Jeong-Hwa Choi2, Martin Veysey3, Emma Beckett1,4
1 School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW 2258, Australia
2 Department of Food Science and Nutrition, Keimyung University, Daegu 42601, Korea.
3 Hull-York Medical School, University of York, Heslington, York, UK
4 School of Medicine and Public Health, University of Newcastle, Ourimbah, NSW, Australia
*Corresponding author – mark.lucock@newcastle.edu.au
References
1. Lacobucci G. Experts urge addition of folic acid to flour to halt “avoidable tragedy” of birth defects. BMJ Jan 2018;360:k477 doi: 10.1136/bmj.k477
2. Wald NJ, Morris JK, Blakemore C. Public health failure in the prevention of neural tube defects: time to abandon the tolerable upper intake level of folate. Public Health Rev Jan 2018. doi:10.1186/s40985-018-0079-6.
3. Hibbard ED, Smithells RW. Folic acid metabolism and human embryopathy. Lancet 1965;1:1254.
4. Smithells RW, Sheppard S, Schorah CJ. Vitamin deficiencies and neural tube defects. Arch Dis Child 1976;51:944–9.
5. Smithells RW, Sheppard S, Schorah CJ et al. Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet 1980;1:339–40.
6. Smithells RW, Seller MJ, Harris R et al. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983;1:1027–31.
7. Smithells RW, Sheppard S, Wild J et al. Prevention of neural tube defect recurrences in Yorkshire: final report. Lancet 1989;2:498–9.
8. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131–7.
9. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press; 1998. https://www.ncbi.nlm.nih.gov/books/NBK114310.
10. Lucock MD, Wild J, Smithells RW, et al. In vivo characterization of the absorption and biotransformation of pteroylmonoglutamic acid in man: a model for future studies. Biochem Med Metab Biol 1989;42:30-42.
11. Arabelovic S, Sam G, Dallal GE et al. Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with rheumatoid arthritis. J Am Coll Nutr 2007;26:453-455.
12. Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L, Bunout D. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 2009;21:436-439.
13. Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302:2119-26.
14. Nazer HJ, Aguila RA, Cifuentes OL. The frequency of twin pregnancies increased in a Chilean hospital associated with periconceptional flour folic acid supplementation. Rev Med Chil 2006;134:48-52.
15. Yajnik CS, Deshpande SS, Jackson AA, et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia 2008;51:29-38.
16. Morris MS, Selhub J, Jaques PF. M.S. Morris, J. Selhub, P.F. Jacques, Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham heart study. J Am Geriatr Soc 2012;60:1457-1464.
17. Beckett E, Veysey M, Lucock M, et al. Maternal folate and DNA methylation in offspring. The Handbook of Nutrition, Diet and Epigenetics. 2017; Editors: Patel V, Preedy V. SpringerLink, USA; DOI - 10.1007/978-3-319-31143-2_3-1
18. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006;136:189-194.
19. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci USA 2009;106:15424-49.
20. Lucock M. Food fortification with folic acid. eBMJ 23rd July 1999; http://www.bmj.com/rapid-response/2011/10/28/food-fortification-folic-acid
Competing interests: No competing interests