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Folic Acid: What is the Evidence for Recommendations and should New Zealand be fortifying our Food? Introduction Every year in New Zealand approximately 20 – 30 children are born with neural tube defects (NTDs) such as spina bifida and anencephaly (Ministry of Health, 2009). Additionally, NTDs are suggested to be the major cause of late-stage pregnancy terminations (Jamieson, 2006). Every year in the United Kingdom approximately 876 pregnancies are terminated due to NTDs after being picked up in ultrasound scans (Nichols, Curtis & Rayman, 2008). The use of preconception folic acid supplementation has been conclusively and numerously shown to be beneficial in the prevention of neural tube defects and is the main focus behind worldwide government initiatives concerning awareness, education and policy regarding folic acid supplementation and fortification (Bower, Miller, Payne & Serna, 2005; Colin, MacLennan & Broadbent, 2006; Li et al, 2003; Wald, Law, Morris, & Wald, 2001). It has also been suggested that there is evidence of folate intake helping to prevent other congenital malformations such as congenital heart defects and limb defects (Nichols et al, 2008) and may also reduce the risk of light birth weight (Charles, 2005). Although some countries such as the United States of America have introduced a mandatory food fortification policy regarding folate in staple foods such as wheat products primarily aimed at NTD reduction, New Zealand currently has no such policy (Johansson, Witthoft, Bruce & Jagerstad, 2002). However, in 1996 voluntary fortification of selected foods such as biscuits, cereals and breads has been permitted (Green, Newton & Bourn, 2003). This voluntary fortification has brought about some intense debate with the New Zealand government recently assessing the need for mandatory folate fortification although the policy reform was abandoned due to a number of reasons, including the unknown consequences of high, long-term folate intake (Jenkins, 2006). It has also been suggested that folic acid may also play a role in reducing the incidence of cardiovascular disease (CVD) by decreasing levels of serum homocysteine. Homocysteine is an amino acid which is formed during methionine metabolism and in a study by Nygard et al (1997), elevated levels of homocysteine were found in 30 – 40% of coronary artery disease patients. Hyperhomocysteinemia is a fairly common condition in which abnormal levels of homocysteine are found in the blood and has been termed as an independent risk factor for cardiovascular diseases (Au-Yeung, Yip, Siow, & Karmin, 2006; Johansson et al, 2002; Strandhagen, Landaas & Thelle, 2003). Interestingly, a study by Durga, Verhoef, Anteunis, Schouten, & Kok (2007) of 728 older men and women concluded that daily oral folic acid supplementation (800 mcg) over a three year period showed that there was a slowing effect on the decline in hearing ability compared to the control group taking an inactive placebo. The purpose of this review is to focus on and review the latest published findings relating to folic acid intakes and supplementation in order to assess New Zealand’s current guidelines for recommended daily intakes as well as assessing whether there is a need for mandatory or additional fortification of foods in New Zealand. Folate and Folic Acid The discovery of Folic acid was initially due to a woman named Lucy Wills who identified that a factor in yeast (later named folate) was found to correct macrocytic anaemia of pregnancy. The name ‘Folic acid’ was coined in 1941, when pteroyglutamic acid was isolated from spinach and comes from the Latin word for leaf which is ‘Folium’. The term ‘folic acid’ is now used to describe the synthetic form of pteroylglutamic acid which is fully oxidised and not present in natural foods, whilst the term ‘folate’ refers to the large group of compounds that have the same vitamin activity and includes natural folates and folic acid (Hoffbrand, 2001). Folate is essential for the human body as it is used in the formation of thymidylate for DNA synthesis among several other important functions, and is therefore required in higher amounts during periods of increased cell turnover; e.g. fetal development (National Health and Medical Research Council, 2006). Current recommendations regarding daily intakes for both male and female adults are 400 µg/day. Women who are pregnant have a slightly higher recommendation of 600 µg/day (National Health and Medical Research Council, 2006). There is also a separate recommendation for women who are planning on becoming pregnant with the recommendation that a folic acid supplement containing 0.8 mg be taken daily four weeks prior to and 12 weeks after conception. A further recommendation is made for women who may be at a higher risk of NTDs to take a 5 mg supplement daily for the same duration as mentioned previously (Ministry of Health, 2003). Evidence and rationale for the non-pregnant recommendations is mainly based on a study of women by O’Keefe (1995) cited in National Health and Medical Research Council (2006) which compared folate intakes of 400 µg/day compared with 200 – 300 µg/day and concluded that a higher number of subjects showing lower mean plasma folate and higher homocysteine levels were found in the lower intake group. Folate requirements have also been suggested to be quite variable as the bioavailability can also be affected by factors such as: nutrient interactions, alcohol consumption, smoking, certain drugs, and genetic variations (Ministry of Health, 2003; National Health and Medical Research Council, 2006). Importantly, it has been suggested that no negative effects have been associated with amounts of folates normally found in foods or fortified foods (National Health and Medical Research Council, 2006). However, high intakes of supplemental folic acid have been shown to cause adverse effects in people with B12 deficiency as the high levels of folic acid can exacerbate the deficiency which is a particular concern for the elderly population who are at the greatest risk of B12 deficiency (Green, Newton & Bourn, 2003). This notion however, has been argued against by Jenkins (2006) who briefly mentioned several Canadian and American studies who found no support for these claims. Masking of B12 deficiency shouldn’t be an issue now as clinical markers have been developed with sufficient sensitivity in recent years (Johansson et al, 2002). It has also been suggested that high folate intakes may accelerate the mental decline with ageing (Morris et al, 2005), however the opposite effect has also been reported by Goodwin, Goodwin & Garry (1983) and Lindeman et al (2000). In light of some of these associations New Zealand has used the estimated tolerable upper intake levels of folic acid suggested by the Institute of Medicine in the United States which states 1000 µg/day for adults and 800 µg/day for 14 – 18 year olds (Green, Newton & Bourn, 2003; National Health and Medical Research Council, 2006). This upper intake level is set as a cautious upper limit primarily due to some evidence showing that masking of B12 deficiency is possible above this level (Nichols et al, 2008). Analysis of the National Nutrition Survey from 1997 has suggested that the average intake of folate from food is around 240 µg/day for males and around 280 µg/day for females in New Zealand; with around 7% of the population having an inadequate folate intake (<200 µg/day) (Ministry of Health, 2003). Inadequate folate intake leads to a rise in homocysteine levels and megaloblastic changes in bone marrow; with further depletion, macrocytic cells are produced which develops into macrocytic anemia. Symptoms of full-blown anaemia include weakness, irritability, and fatigue among others (National Health and Medical Research Council, 2006). Naturally occurring folates are very common in foods such as fruits, nuts, seeds, and particularly green leafy vegetables. However, although natural folates are common, heat and oxidation of foods during cooking or storage may destroy up to half the amount of folate and highlights the importance and benefits of uncooked vegetables and fruits as superior sources of folate. Due to this reason folic acid is the most common folate used in the fortification of foods due to its high bio-availability as well as stability (Ministry of Health, 2003). The bio-availability of folates in food is around 50 – 60% compared with 85% for folic acid in fortified food or supplements. Accurate measurements of folate levels in foods are difficult due to the many different forms which occur; therefore food databases can be inaccurate (National Health and Medical Research Council, 2006). NTDs and Folate; Evidence for Recommendations and Mandatory Fortification In a study by Wald et al (2001) the authors analysed 13 studies of folic acid supplementation and serum folate levels as well as the results published from a large cohort study of the risks of NTDs in relation to serum folate. The authors suggested that according to their predictive model, risk reduction for NTDs could range from 23 – 52% for a 0.4 mg/day increase in folic acid, dependent on initial serum folate levels (Wald et al, 2001). A further recommendation was made for women who are planning a pregnancy to take 5 mg tablets in order to get a preventative effect of 85%, currently only women who are at high risk of NTDs are recommended to take 5 mg supplements (Wald et al, 2001). It has also been reported that folic acid supplementation may increase the amount of twin births (Wald et al, 2001) and therefore any decision on mandatory fortification needs to consider this factor as well as other potential effects. In an analysis of a large population based study looking at birth outcomes and folate supplements, Li et al (2003) concluded that a supplement dose of 400 µg/day before and during pregnancy does not increase the likelihood of multiple births and found that the rate of multiple births was actually higher in the group not taking folic acid. In 1998, the USA Food and Drug Administration introduced mandatory fortification of all cereal grain products at a level of 140 µg per 100 g, and as a result it has been suggested to have reduced NTD birth prevalence by 19% (Johansson et al, 2002). Nichols et al (2008) have suggested, after analysis of a number of studies, that fortification levels of 140 µg per 100 g are safe for elderly populations and may have caused a 5% reduction in the stroke mortality rate in North America. Another important point favouring mandatory fortification of folate is that around 35% of pregnancies in New Zealand are unplanned and survey results have shown that very few women (11%) were taking folic acid supplements prior to their unplanned pregnancy (Dobson, Devenish, Skeaff & Green, 2006). A mandatory fortification policy would effectively provide at least some periconceptional folic acid to the vast majority of women who become pregnant; planned or unplanned (Dobson et al, 2006). However, an important aspect of this is that fortification may need to be included in a staple food such as bread (cereal is most common fortified food) as it has been reported that only about 27% of women eat breakfast cereals in New Zealand (Ministry of Health, 2009) and 50% of women in a study by Bourn & Newton (2000) stated that they did not eat any fortified breakfast cereals. One issue that does not favour mandatory fortification of folate in New Zealand foods comes from a survey of 761 randomly selected men and women in an article by Bourn & Newton (2000) who state that the majority of those surveyed feel it is important to have a choice in buying foods with or without added folate. It has also been concluded by Bourn & Newton (2000) after analysing estimated intakes of food and folates that at a fortification level of 140 µg per 100 g in flour will only result in approximately 10% of women aged 25 – 44 years receiving more than 430 µg/day although this is slightly under-estimated as it does not account for all bakery products that the flour would potentially be in. Folate awareness An important aspect, and valid argument used by the supporters of mandatory fortification of folate is that there is a percentage of society who have little or no knowledge of folate and why it is important, especially concerning pregnancy. In a research article by Conlin, MacLennan & Broadbent (2006) 304 South Australian women took part in a survey designed to assess the compliance level of folate intake by pregnant women. In one question, subjects were asked how much folate should a women take when planning a pregnancy; only 18% were able to give the correct answer; furthermore the authors found that only 36% of the subjects had achieved full compliance of the recommendations, 37% achieved partial compliance, and 27% achieved no compliance at all (Conlin et al, 2006). In a study by Hilton (2007) of 88 women aged between 18 – 24 years of age, 54% were unaware of the importance of folic acid; furthermore, it was suggested that 80% of pregnancies in women in this age group are unplanned. Public health messages/programs which provide the guidelines and awareness are unlikely to be able to reach all of the target populations in society, especially those in the lower socio economic groups and with lower levels of education (Bower et al, 2005; Bruin et al, 2003). It has also been shown that although some media campaigns may be effective at promoting awareness of folate importance, many have failed however to provide certain critical details and education such as the specific timing and level of supplementation (Watson & Watson, 2001). Conclusions Based on the evidence examined, with or without mandatory fortification we believe it is essential that government health agencies continue to promote/build awareness of folic acid supplementation and why it is important when planning for a pregnancy. Furthermore it may be of benefit for these health agencies to research new methods on how to target particularly hard to reach populations such as lower socio economic groups. One of the main obstacles with supplementation is that it is difficult to ensure that women take folic acid at the critical times. Public health messages/programs which provide the guidelines are unlikely to be able to reach all of the target populations in society, especially those in the lower socio economic groups and lower levels of education. Even with fortification, supplements should still be used (Nichols, Curtis & Rayman, 2008) The issue of risk regarding intakes of folate above 1000 µg/day is still unresolved, therefore if mandatory fortification is implemented, it needs to be monitored carefully References Au-Yeung, K., Yip, J., Siow, Y., & Karmin, O. (2006). Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa b activation in macrophages. Canadian Journal of Physiology & Pharmacology, 84, 141-147. Bourn, D., & Newton, R. (2000). Estimated dietary folate intakes and consumer attitudes to folate fortification of cereal products in New Zealand. Australian Journal of Nutrition and Dietetics, 57 (1), 10-17. Bower, C., Miller, M., Payne, J., & Serna, P. (2005). Promotion of folate for the prevention of neural tube defects: who benefits? Paediatric and Perinatal Epidemiology, 19, 435-444. Bruin, K., Walle, H., Rover, C., Jeeninga, W., Cornel, M., Berg, L., et al. (2003). Influence of educational level on determinants of folic acid use. Paediatric and Perinatal Epidemiology, 17, 256-263. Charles, D., Ness, A., Campbell, D., Smith, G., Whitley, E., & Hall, M. (2005). Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review. Paediatric and Perinatal Epidemiology, 19, 112-124. Conlin, M., MacLennan, A., & Broadbent, J. (2006). Inadequate compliance with periconceptional folic acid supplementation in south Australia. Australian and New Zealand Journal of Obstetrics and Gynaecology, 46, 528-533. Dobson, I., Devenish, C., Skeaff, M., & Green, T. (2006). Periconceptional folic acid use among women giving birth at queen mary maternity hospital in Dunedin. Australian and New Zealand Journal of Obstetrics and Gynaecology, 46, 534-537. Durga, J., Verhoef, P., Anteunis, L., Schouten, E., Kok, F. (2007). Effects of folic acid supplementation on hearing in older adults. Annals of Internal Medicine, 146 (1), 1-9. Goodwin, JS., Goodwin, JM., & Garry, P. (1983). Association between nutritional status and cognitive functioning in a healthy elderly population. Journal of American Medical Association, 249 (21), 2917-2921. Hilton, J. (2007). A comparison of folic acid awareness and intake among young women aged 18-24 years. Journal of the American Academy of Nurse Practitioners, 19, 516-522. Hoffbrand, A. (2001). Historical review: the history of folic acid. British Journal of Haematology, 113, 579-589. Jamieson, D. (2006, October 23). Bakers resist folic acid plan. The Press. Retrieved April 20, 2009 from EBSCOhost database. Jenkins, R. (2006, July 28). The great folate debate. Australian Doctor. Retrieved April 20, 2009 from EBSCOhost database. Johansson, M., Witthoft, C., Bruce, A., & Jagerstad, M. (2002). Study of wheat breakfast rolls fortified with folic acid: the effect on folate status in women during a 3-month intervention. European Journal of Nutrition, 41 (6), 279-286. Lindeman, R., Romero, L., Koehler, K., Liang, H., LaRue, A., Baumgartner, R., Garry, P. (2000). Serum vitamin b12, c and folate concentrations in the new mexico elder health survey: correlations with cognitive and affective functions. American College of Nutrition, 19 (1), 68-76. Ministry of Health. (2009). Folate FAQs. Wellington, NZ: Ministry of Health. Retrieved April 20, 2009, from http://www.moh.govt.nz/moh.nsf/f872666357c511eb4c25666d000c8888/230ec4d48df28c64cc256e2e00784783?OpenDocument Ministry of Health. (2003). Food and nutrition guidelines for healthy adults: a background paper. Wellington, NZ: Ministry of Health. Morris, M., Evans, D., Bienias, J., Tangney, C., Hebert, L., Scherr, P., Schneider, J. (2005). Dietary folate and vitamin b12 intake and cognitive decline among community-dwelling older persons. Archives of Neurology, 62 (4), 641-645. Nichols, J., Curtis, E., & Rayman, M. (2008). Survey of total folate intake at conception and assessment of impact of fortification. Journal of Nutritional & Environmental Medicine, 17 (1), 44-55. Strandhagen, E., Landaas, S., & Thelle, DS. (2003). Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study. European Journal of Clinical Nutrition, 57, 1411-1417. Wald, N., Law, M., Morris, J., & Wald, D. (2001). Quantifying the effect of folic acid. The Lancet, 358, 2069-2073. Watson, M., & Watson, L. (2001). An evaluation of the impact of the folate and neural tube defects health claim pilot. Australian Journal of Nutrition and Dietetics, 58 (4),236-241. Clothing Alterations Hamilton NZ
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