Experts urge addition of folic acid to flour to halt “avoidable tragedy” of birth defectsBMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k477 (Published 31 January 2018) Cite this as: BMJ 2018;360:k477
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Gareth Iacobucci  reiterates the argument put forward by Wald and colleagues  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) .
We do not wish to undermine the obvious benefits of folic acid in NTD prevention, but feel that the article by Wald et al  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 . 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 . Is exposure to this unnatural vitamer harmful?
2. The impact on anti-folate pharmacotherapy 
3. The risk of cancer , , twin births , insulin resistance , cognitive decline in the presence of elevated folate and low B12 , and epigenetic interactions 
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  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 – email@example.com
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Competing interests: No competing interests