INTRODUCTION
In 1998 I wrote a dissertation for my B.Sc (Hons) degree in Food Science and Nutrition, entitled “Fortification of Food with Folic Acid: Prospects and Problems”. In that paper I discussed the issues surrounding the fortification of food with folic acid which had recently become compulsory in the USA. Scientific opinion at the time was in favour of such a move due to the reduction in neural tube defects in babies when folate intake is increased by 400µg per day prior to conception and for the first 12 weeks of pregnancy. It is proven that the occurrence of neural tube defects reduces by over 70% when folate intake is increased to this extent. At the time there was also a growing consensus of scientific opinion that increased folate intakes would reduce the occurrence of and mortality from vascular diseases such as atherosclerosis, myocardial infarction and stroke.
My paper examined the evidence for these claims, and also the evidence suggesting that many cancers, psychiatric disorders and adverse birth outcomes may be prevented or alleviated by folate. Critics of folic acid fortification feared that adverse effects on zinc status, people with vitamin B12 deficiency and those undergoing certain drug treatments may occur. My conclusion was that compulsory folic acid fortification in the UK would result in a significant decrease in neural tube defects, vascular disease, cervical and probably colorectal cancers and certain psychiatric disorders, and that the risks of such compulsory fortification would be negligible.
My dissertation was well received to the extent that I won the annual prize for the best student project in the biological sciences in my year.
Since 1998 and the introduction of compulsory fortification of certain foodstuffs with folic acid in the USA, a great deal more evidence has been gathered about the positive and negative effects of this move. My aim now is to examine and review the recent evidence and summarise the current state of scientific opinion on the compulsory fortification of food with folic acid.
2. FOLATE, HOMOCYSTEINE, NEURAL TUBE DEFECTS
AND VASCULAR DISEASE
A thorough review of the evidence as to the links between high levels of homocysteine in the blood being a risk factor for vascular disease can be found in Green & Jacobsen (1995), who found a “high level of association between mild to moderate hyperhomocysteinaemia and coronary artery disease, stroke, and peripheral vascular disease”. A deficiency in folic acid (or vitamin B12 or vitamin B6) results in an accumulation of homocysteine in the blood, and folic acid supplementation does reduce moderately high levels of plasma homocysteine significantly, regardless of the origin of the problem. The missing link in the research in 1998 was whether the reduction in total plasma homocysteine by folic acid supplementation actually reduced the risk of vascular disease.
So far, the results are mixed. Folic acid supplementation does decrease homocysteine levels, improves vascular function and decreases systolic blood pressure in adults and children (Bennett-Richards et al. 2002; Pena et al. 2004; Williams et al. 2005). The latter study also concluded that supplementation of 5 mg folic acid decreases blood pressure and arterial stiffness in 41 asymptomatic men with high blood pressure. However Miller et al (2010) found that overall, folic acid supplementation had no effect on cardiovascular disease or stroke. On the contrary, looking more closely at the results and comparing homocysteine levels prior to supplementation suggests potential harm in those with high homocysteine levels originally. In the meantime, folic acid supplementation should not be recommended as a means to prevent or treat CVD or stroke.
3. FOLATE AND CANCER
Concern was expressed by Smith et al (2008) that some malignancies may be propagated by excess folic acid exposure. They cite studies including Cole et al (2007) showing that persons with a history of colorectal adenomas, consuming folic acid supplements as part of a randomized control trial, had an increased risk of more severe recurrence than a placebo group. The dose administered in the trial was 1 mg (the upper safe limit). A meta-analysis carried out in 2008 (Fife et al, 2011) showed that the risk of an pre-cancerous colorectal lesion was not increased among patients who received folate supplementation for up to 3 years; however, for those who received folate for over 3 years, the risk of a lesion was increased There is also a study from Figueiredo et al (2009)suggesting that oral folic acid increases the risk of prostate cancer.
Mandatory fortification of foods with folic acid began in Canada in mid-1997. Grupp et al (2011) showed that Canadian rates of Wilms' tumour (a form of kidney cancer) declined from 1.94 to 1.43 per 100,000 children aged 0-4 (a 30% reduction) and showed no increase in any other cancers in kids aged 0-4 or 5-9.
In Spain, early supplementation with folic acid in pregnant women (before the 21st and 36th days of gestation) has been shown to result in significantly fewer nervous system tumours, particularly central nervous system tumours, than in non-supplemented women. (Ortega-Garcia et al, 2010).
Goh et al (2007) conducted a meta-analysis demonstrating that use of prenatal multivitamins by pregnant mothers was associated with a decreased risk of pediatric brain tumors by 18%, neuroblastoma by 47%, and leukemia by 36%.
Again, the overall results for cancer risk following folic acid supplementation are mixed. Rates of some cancers are reduced, others may possibly be raised.
4. FOLATE AND NEUROPSYCHIATRIC DISORDERS
In 1998 my summary was that a large proportion of psychiatric patients have a low folate status, and these patients often respond significantly less well to treatment. Folate supplementation was shown to improve mood and recovery, especially in depression, although most studies used pharmacological doses. I concluded that further trials were required to confirm wehter folate supplementation could help prevent or treat psychiatric illness.
More recently, Lazarou and Kapsou (2010) presented data on the correlation of folic acid deficiency and depression, with plausible mechanisms that may account for this association. The role of folic acid in the treatment of depression is depicted giving emphasis to the potential of folic acid to enhance patients' responsiveness to medication and the therapeutic outcome. There is still not enough data to justify prescription of folic acid as an aid in patients with severe or chronic depression or mood disorders. However, folic acid levels should be examined in individuals at increased risk for folic acid deficiency or in patients who do not respond to pharmaceutical treatment.
Christensen et al (2011) have shown that there is little evidence that folic acid + B12 supplementation improves the effectiveness of other drugs on depressive symptoms. Further research should examine whether effects might be found at higher folic acid dosages or among clinical populations.
Based on the findings of Behzadi et al (2009), folic acid seems to be an effective addition to sodium valproate in the treatment of the acute phase of mania in patients with bipolar disorder.
Ford et al (2010) showed that the daily supplementation for over two years of vitamins B(12), B(6), and folic acid does not benefit cognitive function in hypertensive older men, nor does it reduce the risk of cognitive impairment or dementia.
5. FOLATE AND PREGNANCY OUTCOME
Yang et al (2007) found that most non-pregnant women of childbearing age in the United States reported consuming less than the recommended amount of folic acid. The proportion with low daily folic acid intake was significantly higher in non-Hispanic black and Hispanic women than in non-Hispanic white women. At the present level of folic acid fortification in the USA, most women still need to take a folic acid-containing dietary supplement to achieve the Institute of Medicine recommendation.
Hossein-nezhad et al (2011) show that daily supplementation of folic acid during pregnancy could have a positive impact on the bone turnover markers in mothers and their newborns. This may suggest that both pregnant mothers and their fetuses could benefit from positive effects of folic acid taken during the whole period of pregnancy. Newborns from mothers who continued taking folic acid until the very end of their pregnancy had overall better birth outcome parameters and apgar scores compared to newborns from mothers who stopped taking a folic acid supplement at the end of the second trimester. This shows that daily supplementation of folic acid during the entire pregnancy has a positive impact on the bone turnover markers in mothers and their newborns and suggests that both pregnant mothers and their babies could benefit from positive effects of folic acid taken during the whole period of pregnancy.
5.1 Low birthweight and premature birth
5.2 Congenital defects other than neural tube defects
6. MASKING OF VITAMIN B12 DEFICIENCY
7. OTHER ADVERSE EFFECTS
7.1 Effects on zinc status
7.2 Unmetabolised folic acid in serum
40% of older adults in the US have unmetabolised folic acid in their blood serum. (Bailey et al, 2010)
7.3 Effects on patients undergoing folate-antagonist drug therapy
Low-dose methotrexate is used extensively for the treatment of rheumatoid arthritis and is also used for the treatment of other systemic rheumatic disorders and psoriasis. Its therapeutic effectiveness has not been shown to be influenced by oral administration of folate derivatives (Visser et al, 2009). A meta-analysis of nine studies indicates that folic acid supplementation reduces the toxicity of methotrexate without reducing its efficacy, (Katchamart et al, 2008).
7.4 Folate and epilepsy
8. OTHER
Ganji and Kafai (2009) found that hemoglobin values are around 2% higher in men and 2.3% higher in women and the prevalence of anemia in women is lower in the post-folic acid fortification period than in the pre-folic acid fortification period in US adults.
REFERENCES
Bailey RL, Mills JL, Yetley EA, Galiche JJ, Pfeiffer CM, Dwyer JT, Dodd KW, Sempos CT, Betz JM and Picciano MF (2010). Unmetabolised serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged greater than or equal to 60 years in the United States. American Journal of Clinical Nutrition, 92 (2), 383-9.
Bennett-Richards K, Kattenhorn M, Oakley G, Varghese Z, Rees L, Deanfield JE. 2002. Does oral folic lower total homocysteine levels and improve endothelial function in children with chronic renal failure? Circulation 105:1810–1813.
Behzadi, A. H.; Omrani, Z.; Chalian, M.; Asadi, S.; Ghadiri, M. (2009). Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double-blind randomized controlled trial. Acta Psychiatrica Scandinavica, 120, 6, 441-445
Christensen H, Aiken A, Batterham PJ, Walker J, Mackinnon AJ, Fenech M, Hickie IB (2011). No clear potentiation of antidepressant medication effects by folic acid and vitamin B12 in a large community sample. Journal Of Affective Disorders 130 (1-2), 37-45.
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Fife J, Raniga S, Hider PN, Frizelle FA (2011) Folic acid supplementation and colorectal cancer risk: a meta-analysis. Colorectal Disease; 13 2, 132-137
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. Journal of the National Cancer Institute 101(6), 432-5.
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Ganji V and Kafai MR (2009) Hemoglobin and hematocrit values are higher and prevalence of anemia is lower in the post-folic acid fortification period than in the pre-folic acid fortification period in US adults. American Journal of Clinical Nutrition, 89 (1), 363-71.
Goh YI, Bollano E, Einarson TR, Koren G. (2007) Prenatal multivitamin supplementation and rates of pediatric cancers: a meta-analysis. Clinical Pharmacology Therapy. 5, 685-691.
Green R & Jacobsen DW (1995). Clinical implications of hyperhomocysteinaemia. In Folate in Health and Disease, ed. LB Bailey, 75-122. New York: Marcel Dekker Inc.
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Katchamart W, Ortiz A, Shea B et al. (2008) Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (an update systematic review and meta-analysis). Journal of Rheumatology, 58 (6): 1197-8
Lazarou C; Kapsou M (2010). The role of folic acid in prevention and treatment of depression: an overview of existing evidence and implications for practice. Complementary Therapies in Clinical Practice, 16 (3): 161-6
Miller ER 3rd; Juraschek S; Pastor-Barriuso R; Bazzano LA; Appel LJ; Guallar E (2010) Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. American Journal of Cardiology, 106 (4): 517-27
Ortega-Garcia JA, Ferris-Tortajada J, Claudio L, Soldin OP, Sanchez-Sauco MF, Fuster-Soler JL, Martinez-Lage JF (2010). Case control study of periconceptional folic acid intake and nervous system tumors in children. Child's Nervous System; 26 12, 1727-1733.
Pena AS, Wiltshire E, Gent R, Hirte C, Cooper J. (2004). Folic acid improves endothelial function in children and adolescents with type 1 diabetes. Journal of Pediatrics 144:500–504.
Smith AD, Kim YI, Refsum H. (2008) Is folic acid good for everyone? American Journal of Clinical Nutrition. 87, 517-533.
Visser K, Katehamart W, Loza E. et al (2009). Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3t Initiative. Annals of Rheumatic Diseases, 68: 1086-93
Williams C, Kingwell BA, Burke K, McPherson J, Dart AM. (2005) Folic acid supplementation for
3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype. American Journal of Clinical Nutrition 82:26–31.
Yang QH; Carter HK; Mulinare J; Berry RJ; Friedman JM; Erickson JD (2007). Race-ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001-2002. American Journal of Clinical Nutrition, 85 (5), 1409-16
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