MANDATORY FOLIC ACID FORTIFICATION SUMMARY OF EMERGING EVIDENCE ON HEALTH OUTCOMES

KEY POINTS Based on all available scientific evidence, adding folic acid to bread in Australia and New Zealand is safe for the whole population. Food Standards Australia New Zealand (FSANZ) is continuing to carefully monitor, review and report on scientific research on folic acid and health outcomes. Since the mandatory requirement was developed in 2007, no new evidence has emerged that changes FSANZs original conclusion that mandatory fortification with folic acid is safe. Folic acid is added to flour in many countries, with two thirds of the worlds population having access to folic acid fortified flour. For over 10 years, the United States and Canada have had mandatory fortification of flour with folic acid and have found this to be an effective way of reducing neural tube defects (NTDs).

FOLIC ACID AND HEALTH OUTCOMES There are studies currently looking at the possible protective and adverse effects of folic acid on types of health conditions, including cancer, stroke, mental function in the elderly, and some types of other birth defects. However, the only proven scientific evidence is that folic acid protects against NTDs. FSANZ has continued to review the results of randomised controlled trials as they are reported. These have included a number of large trials administering folic acid with other B vitamins to test the hypothesis that folic acid will reduce the incidence of heart disease and stroke. A number of these large randomised trials are testing doses of folic acid up to twenty times (2000-5000g) higher than the average amount being added under mandatory fortification. The average folic acid added through mandatory folic acid fortification will be 150g. This is a brief review of the emerging evidence on folic acid and health outcomes since the development of the Standard in 2007.

FOLIC ACID AND BIRTH OUTCOMES Neural Tube Defects There is convincing evidence that increasing intakes of folic acid can reduce the incidence of NTDs. The level of fortification in Australia is expected to prevent between 14 and 49 NTDs in the 300-350 affected pregnancies each year when combined with existing voluntary fortification permissions and current levels of supplement usage.

In New Zealand mandatory fortification is expected to prevent between 4 to14 NTDs per year in the 70-75affected pregnancies each year when combined with existing voluntary fortification permissions and current levels of supplement usage. FSANZ estimates the cost saving from the yearly prevention of NTDs in Australia to be $AUD125 million and $NZD39 million New Zealand (including still births and terminations). Emerging evidence suggests that deficient or inadequate maternal vitamin B12 status is also associated with a significantly increased risk for NTDs (Molloy et al, 2009). This highlights that other factors, in addition to folic acid, may also be important in preventing NTDs.

Twinning The observation of increased twinning was made some years ago and was noted in FSANZs Final Assessment Report. The genetics of various diseases and their possible interaction with folic acid or any other compound is still unknown.

Spontaneous Preterm Birth Pre-conception folate (folic acid) supplementation was recorded in a cohort of 34,480 pregnant women participating in a Down syndrome screening study (Bukowski et al., 2009). The authors report that pre-conceptional folate supplementation for 1 year or more was associated with a 70% decrease in risk of spontaneous preterm delivery between 20 and 37 weeks compared to women not taking a folate supplement. As this study is an observational study the results may be subject to confounding factors.

Congenital Heart Defects A time trend analysis in Canada (Lonescu-Ittu et al., 2009) reported that in the 7 years following mandatory folic acid fortification implementation there was a significant decrease of 6% each year in the prevalence of severe congenital birth defects. It should be noted that other risk factors for severe congenital heart defects were not measured which may confound the results. The authors also had to rely on data from the US to establish a lag time between the announcement of the policy and its implementation, as there was a lack of this data in Canada.

FOLIC ACID AND CANCER RISK The risk of folic acid promoting cancer was canvassed exhaustively by FSANZ during the standards development process. Based on all of the available evidence, FSANZ concluded that there is no apparent risk to public health and safety, including cancer. FSANZ consulted with scientific experts both nationally and internationally who supported this conclusion. However, FSANZ is continuing to monitor and assess any new evidence that might arise and have formed a group of experts to assist with this. Below is a brief summary of studies investigating folic acid intake and cancer risk published since the development of the standard.

Colon Cancer Prior to gazettal of the FSANZ Standard, the results of Lonn et al (2006) were known. This study reported a non-significant increase in total cancer, colo-rectal, breast and prostate cancers. Another large cardiovascular trial did not report any cancer data. Since then, 4 large cardiovascular trials (up to 12,000 people randomised for up to 7 years) have reported their cardiovascular outcomes but only one has reported any data for colorectal cancer to date. In this study there was a non-significant decrease in colo-rectal cancer in those receiving folic acid and B vitamins (Zhang et al, 2008). A large study (8,000 people) examining the effect of folic acid on stroke rates, which includes participants from Australia and New Zealand ,is scheduled to complete data collection in mid-2009. Three smaller trials have been conducted (100- 1000 people). Of these, the two trials in people with colon adenomas (Cole et al, 2007 Logan et al 2008) have reported lower rates of colo-rectal cancer in those receiving folic acid. Without knowing what the as-yet unreported data from the large cardiovascular trials is, it is not possible to conclude whether folic acid is associated with a decrease, an increase or has no effect on colo-rectal cancer incidence.

Colo-rectal adenoma studies Cole et al (2007) reported a small, non-significant increase in the recurrence of colon adenomas associated with folic acid intakes. There was a higher increase in advanced adenoma which was significant only in the subset who chose to continue to participate for 4-6 years. It was noted that those given folic acid had had larger adenomas removed before the trial started and so may have been more prone to having additional adenomas than the people in the placebo group. A 2008 study from the UK in 939 men and women who had had all bowel polyps removed, found a slightly higher rate of new adenomas (not significant) but no difference in the rate of advanced adenomas in those given folic acid compared to placebo (Logan et al, 2008). In these two studies, there was a lower rate of colo-rectal cancer in those who received folic acid than those who received placebo (up to 27% lower). In contrast, a small trial investigating folic acid supplementation and the recurrence of colorectal adenomas in 94 subjects with adenomatous polyps (Jaszewski et al., 2008) reported a significant reduction in the recurrence of adenomas in the subjects receiving the folic acid supplement (5mg/day) compared to the placebo. This was only observed in subjects under the age of 70 years.

Time Trend Studies Mason et al (2007) reported increased rates of colorectal cancer rates in the United States and Canada between 1986-2002. They suggest this trend may be due to folic acid fortification which was mandated in 1996 and fully in place in 1998 in the United States.

In contrast, in 2007, the United States National Cancer Institute reported no significant change in cancer trends coinciding with the introduction of mandatory folic acid fortification, when they analysed the same dataset as Mason et al., 2007. (http://progressreport.cancer.gov/doc_detail.asp?pid=1&did=2007&chid=73&coid=720&m id=#trends). A study in Chile analysed hospital discharge data for colon cancer during the periods of 1992-6 and 2002-4 concluding that the higher rate of discharge in the second period coincided with the introduction of folic acid fortification in 2000 (Hirsch et al., 2009). However the study does not include data from the period when folic acid fortification was introduced. The International Classification of Disease coding also changed at that time and this might affect the validity of the results. In Australia and New Zealand, the Department of Health and Ageing has engaged the Australian Institute of Health and Welfare to implement the Australia Health Ministers Advisory Council endorsed monitoring framework for the mandatory fortification of food with folic acid. The purpose of this work is to coordinate monitoring of folate levels in the Australian and New Zealand populations to establish baseline data and enable assessment of the effectiveness of mandatory fortification with folic acid. It is also intended to monitor for adverse health effects.

Prostate cancer The focus of the Cole et al (2007) study was the recurrence of colorectal adenomas, however an increase in the incidence of prostate cancer was observed. This mainly occurred in the folic acid supplement group, where 24 cases were reported compared to only 9 cases in the placebo group. A more recent report by Figueirdo et al (2009) provides further detail on the male subjects investigated in the Cole et al (2007) study. This current study followed 643 (baseline) men over 10 years. It should be noted that there was a large drop out after the sixth year of study. During this time only one more case of prostate cancer was noted in the folic acid group and none in the placebo group. Lonn et al (2006) reported a much smaller, non-significant increase in prostate cancer in those randomised to folic acid and other B vitamins. Lonn et al (2006) used a higher dose of folic acid than did Cole et al (2007). Given the number of large trials that have not yet described their prostate cancer outcomes these results should be interpreted with caution. A number of trials are underway to test the hypothesis that higher intakes of folic acid might reduce the risk of cardiovascular disease, which are also collecting information on side effects, such as cancer.

Breast cancer Overall the combined studies suggest a non significant slight reduction in breast cancer. As noted above, Lonn et al (2006) reported a non-significant increase in breast cancer in those who received folic acid plus other B vitamins. This trial had only a small number of women. In 2008, Zhang et al reported a non-significant decrease in breast cancer in women randomised to folic acid and other B vitamins in a trial of 5,400 US women followed for 7 years. No other study has reported any data relating to breast cancer to date.

FOLIC ACID AND HEART DISEASE Stroke and Heart disease A meta-analysis by Bazzano et al (2006) found no significant effect on cardiovascular disease. A meta-analysis of trials published prior to April 2007 reported a significant 18% reduction in stroke (Wang et al, 2007) in those randomised to folic acid. However several trials that were much larger than any included in these meta-analyses have been published since then and have not reported the same level of effect on stroke. In addition, several large trials investigating folic acid and cardiovascular disease are currently taking place that are yet to publish their results. These randomised controlled trials will also provide more useful data to confirm or refute the possible association with various cancers and folic acid intakes.

UNMETABOLISED FOLIC ACID Unmetabolised folic acid in plasma and immune system During the standards development process, FSANZ investigated the potential for unmetabolised folic acid circulating in the blood to be a health risk. FSANZ concluded that the link between unmetabolised circulating folic acid and adverse health effects has not been substantiated. Consequently, the health significance of this remains uncertain. The study by Sweeney et al (2009) investigated circulatory unmetabolised folic acid in 70 adults and 20 new born babies following widespread uptake of voluntary fortification permissions for folic acid. . Low levels of unmetabolised circulating folic acid were present in the majority of subjects. The authors conclude that mandatory fortification would further increase these levels. They note that the health consequences of unmetabolised circulating folic acid are unknown but suggest the potential for folic acid to mask pernicious anaemia and possibly accelerate the growth of existing cancers. The study by Troen et al. (2006) describes a relationship between the presence of unmetabolised folic acid and one particular type of cell involved in immunity and which can kill cancer cells. As the test of immunity and unmetabolised folic acid levels were done on the same sample of blood, it is not possible to determine which occurred first.

FOLIC ACID AND RHEUMATOID ARTHRITIS Arabelovic et al. (2007) examined the amount of methotrexate used by 36 patients with rheumaroid arthritis between 1988-1997 and noted an increase in dosage. There are other important considerations when assessing the usefulness of drugs, such as side effects. For example, van Ede et al. (2001) randomised 434 patients with rheumatoid arthritis to receive either placebo or 1-2 mg folic acid per day in addition to their methotrexate in a doubleblind study. After 48 weeks, 38% of those receiving placebo had discontinued taking methotrexate owing to side effects whereas only 17% of those receiving folic acid had to cease taking methotrexate. This study also reported that methotrexate dosage was higher in those receiving folic acid compared to placebo.

FOLIC ACID AND COGNITIVE FUNCTION Durga et al. (2007) tested vitamin B12 with or without 800g folic acid versus placebo in 818 people who did not have vitamin B12 deficiency over 3 years. Those who received vitamin B12 plus folic acid had less cognitive loss (a good outcome) that those who received vitamin B12 alone. The possibility that folic acid may affect neurological function in people with vitamin B12 deficiency dates back to the 1940s when pernicious anaemia was being treated with liver (it was before vitamin B12 had been purified; we now know that liver contains vitamin B12). Patients with pernicious anaemia given 15-20 mg folic acid, without liver, experienced a progression of their neurological problem (Meyer, 1947). One interpretation of this finding is that vitamin B12 deficiency will continue to progress unless vitamin B12 is given; another hypothesis is that very high doses of folic acid exacerbates the consequence of vitamin B12 deficiency. As there has never been a properly conducted controlled trial, the hypothesis (folic acid exacerbates the neurological effects of vitamin B12 deficiency) continues to be cited.

References
Aisen PS, Schneider LS, Sano M et al. (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer Disease. A randomized controlled trial. JAMA.,300:1774-83. Albert CM, Cook NR, Gaziano JM et al. (2008) Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease. A randomized trial. JAMA., 299:2027-36. Arabelovic, S., Sam, G., Dallal, G.E., Jacques, P.F., Selhub, J., Rosenberg, I.H., Rosenberg, I.H. and Roubenoff, R. (2007) Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with higher methotrexate dosing in patients with rheumatoid arthritis. J. A. Coll. Nutr., 26(5):453-55. Bazzano LA, Reynolds K, Holder KN, He J. (2006) Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA., 13;296(22):2720-6. Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH et al. (2009) Preconceptional folcate supplementation and the risk of spontaneous preterm birth: a cohort study. Plos Med. Cole BF, Baron JA, Sandler RS et al. (2007) Folic acid for the prevention of colorectal adenomas. A randomized controlled trial. JAMA., 297:2351-9. Durga J, van Boxtel MPJ, Schouten EG et al. (2007) Effect of 3-years folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet., 369:208-216 Ebbing M, Bleie , Ueland PM et al. (2008) Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA., 300:795-804. Ebbing M, et al. (2009) Treatment with folic acid and vitamin B12 increased cancer incidence, cancer mortality and all cause mortality in ischemic heart disease patients. Abstract from the 7th International Conference on Homocysteine Metabolism, Prague. Fernandez-Miranda C, Yebra M, Aranda JL et al. (2007) Effect of folic acid treatment on carotid intima-media thickness of patients with coronary disease. Int J Cardiol;118:345-9. Ford AH, Flicker L, Thomas J et al. (2008) Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psychiatry., 69:1203-9. Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA. (2009) Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst., 18;101(6):432-5. Flicker L, Vasikaran SD, Thomas J et al. (2006) Efficacy of B vitamins in lowering homocysteine in older men: maximal effects for those with B12 deficiency and hyperhomocysteinemai. Stroke., 37:547-9 Hodis HN, Mack WJ, Dustin L et al. (2009) High-dose B vitamin supplementation and progression of subclinical atherosclerosis. A randomized controlled trial. Stroke;40:730-6. Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L, Bunout D. (2009). Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol. 21(4):436-9. Jaszewski R, Misra S et al. (2008) Folic acid supplementation inhibits recurrence of colorectal adenomas: A randomized chemoprevention trial. World J Gastroenterol., 14(28): 4492-4498. Kim Y-I. Baik HK, Fawaz K, et al. (2001) Effects of folate supplementation on two provisional molecular markers of colon cancer : A prospective, randomized trial. Am J Gastroenterol., 96:184-95. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH et al. (2005) Secondary prevention with folic acid; results of the Goes extension study. Heart., 91:1213-4.

Logan RA, Grainge MJ, Shepherd VC et al. (2008) Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology., 134:29-38. Lonescu-Ittu R, Marelli AJ, Mackie AS and Pilote L. (2009) Prevalence of sever congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. BMJ. 338;1673. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr. (2006) Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med.,17;355(7):746. Mason, J.B., Dickstein, A., Jacques, P.F., Haggarty, P., Selhub, J., Dallal, G. and Rosenberg, I.H. (2007) A temporal association between folic acid and fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epi. Biomarkers & Prevention., 16(7):1325-29. Meyer, L.M. (1947) Folic acid in the treatment of pernicious anaemia. Blood., 2:50-62. Molloy AM, Kirke PN, Troendle JF, Burke H, Sutton M, Brody LC, Scott JM, Mills JL. (2009) Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic Acid fortification. Pediatrics.,123(3):917-23. NHMRC. Clinical Practice Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer. Adopted December 2005. http://www.nhmrc.gov.au/publications/synopses/cp106/cp106syn.htm Quinlivan, E.P. and Gregory, J.F. (2003) Effect of food fortification on folic acid intake in the United States. Am. J. Clin. Nutr., 77(1):221-25. Paspatis GA, Karamanolis DG. (1994) Folate supplementation and adenomatous colonic polyps. Rectum., 37:1340-1. Dis Colon

SACN (2008). Draft minutes. Additional meeting to discuss folic acid and CRC risk, 21st January, 2008. SACN/07/min/02. http://www.sacn.gov.uk/pdfs/sacn_08_01_21.pdf Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. (2005) Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA., 293:1082-8. Schernhammer, E., Wolpin, B., Rifai, N., Cochrane, B., Manson, J.A., Ma, J., Giovannucci, E., Thomson, C., Stampfer, M.J. and Fuchs, C. (2007) Plasma folate, vitamon B6, vitamon B1 and homocysteince and pancreatic cancer risk in four large cohorts. Cancer Res., 67(11):5553-60. SEARCH Study Collaborative Group. (2007) Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J., 154:815-823. Sweeney...BMC Public Health advance online publication Troen, A.M., Mitchell, B., Sorensen, B., Wener, M.H., Johnston, A., Wood, B., Selhub, J., McTiernan, A., Yasiu, Y., Oral, E., Potter, J.D and Ulrich, C.M. (2006) Unmetabolised fa in plasma is associated with reduced natural killer cell cytoxicity among postmenopausal women. J Nutr., 136(1):189-94. Toole JF, Malinow MR, Chambless LE et al. (2004) Lowering homocysteine in patients with ischaemic stroke to prevent recurrent stroke, myocardial infarction and death. JAMA., 291:565-75. van Ede, A.E., Laan, R.F.J.M. and Rood, M.J. et al. (2001) Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis. Arthritis & Rheumatism, 44:1515-24. van Uffelen JGZ, Chinapaw MJM, van Mechelen W, Hopman-Rock M. (2008) Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial. Br J Sport Med., 42:344-351. Wang, X., Qin, X., Demirtas, H., Li, J., Mao, G., Huo, Y., Sun, N., Liu, L., Xu, X.(2007) Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. The Lancet., 369(9576):1876-1882.

Zhang SM, Cook NR, Albert CM et al. (2008) Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women. A randomized trial. JAMA., 300:2012-21. Zhu S, Mason J, Shi Y et al. (2003) The effect of folic acid on the development of stomach and other gastrointestinal cancers. Chinese Med J., 116:15-9.