Shall we put the world on folate?

Shall we put the world on folate?

Comment An important omission in the Series is climate change and its risks to human health. No African country has completed comprehensive assessmen...

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An important omission in the Series is climate change and its risks to human health. No African country has completed comprehensive assessments on climate change, and yet climate change will probably have adverse effects on health outcomes and thus exacerbate health inequities.10 WHO in 2008 placed climate change and health firmly on the health sector agenda.11 The time is now for African countries to act.

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*Nelson K Sewankambo, Achilles Katamba

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College of Health Sciences, Makerere University, Makere, Uganda [email protected]

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We declare that we have no conflicts of interest. 1

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Coovadia H, Jewkes R, Barron P, Sanders D, McIntyre D. The health and health system of South Africa: historical roots of current public health challenges. Lancet 2009; published online August 25. DOI:10.1016/S01406736(09)60951-X. Chopra M, Daviaud E, Pattinson B, Fonn S, Lawn JE. Saving the lives of South Africa’s mothers, babies, and children: can the health system deliver? Lancet 2009; published online August 25. DOI:10.1016/S01406736(09)61123-5.

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Abdool Karim SS, Churchyard GJ, Abdool Karim Q, Lawn SD. HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response. Lancet 2009; published online August 25. DOI:10.1016/ S0140-6736(09)60916-8. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of non-communicable diseases in South Africa. Lancet 2009; published online August 25. DOI:10.1016/S0140-6736(09)61087-4. Seedat M, Van Niekerk A, Jewkes R, Suffla S, Ratele K. Violence and injuries in South Africa: prioritising an agenda for prevention. Lancet 2009; published online August 25. DOI:10.1016/S0140-6736(09)60948-X. Chopra M, Lawn J, Sanders D, et al, for The Lancet South Africa team. Achieving the health Millennium Development Goals for South Africa: challenges and priorities. Lancet 2009; published online August 25. DOI:10.1016/S0140-6736(09)61122-3. King NMP, Henderson GE, Stein J, eds. Beyond regulations: ethics in human subjects research. London: University of North Carolina Press, 1999. Gakidou E, Lozano R, Gonzalez-Pier E, et al. Assessing the effect of the 2001–06 Mexican health reform: an interim report card. Lancet 2006; 368: 1920–35. Hughes D, Leethongdee S. Universal coverage in the land of smiles: lessons from Thailand’s 30 baht health reforms. Health Aff (Millwood) 2007; 26: 999-1008. Costello A, Abbas M, Allen A, et al. Managing the health effects of climate change. Lancet 2009; 373: 1693–733. Michael AJ, Neira M, Heymann DL. World Health Assembly 2008: climate change and health. Lancet 2008; 371: 1895–96.

Shall we put the world on folate? Later in the autumn, the Scientific Advisory Committee on Nutrition will announce its recommendation on mandatory fortification of food in the UK with folic acid. Although the Food Standards Agency Board had already agreed on mandatory fortification of a staple food with folic acid (the synthetic form of folate) in May, 2007, the committee was asked a few months later to reevaluate the recommendation in light of rising public health concerns about excessive folate intake.1 Similar discussions have been ongoing in several European countries. Some countries, including the USA, Canada, and Chile, imposed mandatory fortification of flour and grain products with folic acid about a decade ago.2 The purpose of folate fortification is to increase periconceptional folate concentrations in women of childbearing age to prevent neural tube defects and potentially other malformations (cardiac defect, or cleft lip and palate) in their babies.2 Because the prevention effort targets only women of reproductive age before conception, is it justifiable to expose the entire population to mandatorily fortified foods with an uncertain risk associated with this enrichment? Adequate folate intake is essential, because folate is a crucial cofactor in one-carbon metabolism and has an important role in DNA synthesis and replication. www.thelancet.com Vol 374 September 19, 2009

Folate deficiency is associated with high plasma concentrations of homocysteine, a potential risk factor for the development of atherosclerosis and consequently cardiovascular disease.3 Some evidence suggests that folate depletion fosters the development of cancer, particularly colorectal cancer.4 Folate might also negate the increase of breast cancer risk associated with alcohol intake.2,5 Despite the proposed beneficial effects of folate, there are rising health concerns about an excessive intake of this vitamin. High intake of folic acid might mask vitamin B12 deficiency, especially in elderly individuals.6 More recently, evidence from animal and human studies suggests that a high folate status promotes the progression of already existing preneoplasms.4,7,8 Two mechanisms could underlie this apparent cancerpromoting effect of high-dose folic acid. First, folate provides nucleotide precursors for the preneoplastic cells, which could facilitate their replication and proliferation. Second, folate as an indirect methyl donor might lead to the de-novo methylation and subsequent inactivation of tumour-suppressor genes, resulting in accelerated tumour progression.4 Other possible health implications of folate’s role in DNA methylation are not well understood. 959

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What effect did mandatory fortification with folic acid have in countries that implemented it a decade ago? The incidence rates of neural tube defects declined after fortification by about 15–50% in the USA and Canada,4 and by about 40% in Chile.9 But rates of neural tube defects in the USA and in many other countries had been falling even before mandatory fortification started.2,6 Because the mechanism by which folate might affect neural tube defects is unknown and because the development of neural tube defects is a multifactorial event,6 folate seems to be only a piece in the puzzle. The safe upper limit for folate intake as well as the safe upper folate concentration in blood are not known.10 The recommended dietary allowance for adults is 400 μg of food folate a day, which is about equivalent to 240 μg synthetic folic acid in supplements or fortified food. Women of child-bearing age planning a pregnancy should take 400 μg synthetic folic acid daily in addition to their normal dietary intake. Usually, the tolerable upper limit of folate intake for adults is set at 1 mg synthetic folic acid a day to avoid any adverse health effects.2 But how much folate is best and is it good for everyone? After mandatory fortification, the increase in additional folic acid intake in the USA has been doubled to an average of 220 μg a day instead of the predicted 100 μg a day.6 Thus many adults—except women of reproductive 960

age—reach their recommended dietary allowance of daily folate solely with the intake of mandatorily fortified food. Many countries worldwide allow voluntary fortification2 with folic acid or L-methylfolate in foods such as soft drinks, dairy products, and cereals. If those countries adopt mandatory fortification, the actual daily folate intake in many individuals might be even higher and at times exceed the upper limit because a certain proportion of people also takes folate supplements. Of concern are the trends of increasing incidence rates of colorectal cancer in several countries that had adopted mandatory fortification with folic acid, including the USA, Canada,11 and Chile.9 Because about 35% of individuals older than 50 years have colorectal adenomas,12 mandatory fortification might pose a public health challenge. Conversely, death rates from cardiovascular disease have fallen in the USA and Canada during the past decade, and are concurrent with several changes including a decline in smoking, reduction of intake of trans fatty acids, more aggressive treatment of hypertension, and folate fortification. Because the safety of folate might depend on its chemical structure (natural folate or synthetic folic acid), its dose, and the time of intervention, several long-term follow-up intervention studies assessing the safety of a high folate intake are needed before any country decides on mandatory fortification of food with folic acid. Although the importance of an adequate folate status of a woman planning to conceive is supported by epidemiological evidence, alternative strategies, such as an intervention targeting individuals at high risk or the addition of folate to oral contraceptives, might be considered rather than putting entire nations on folate. Anja Osterhues, Wolfgang Holzgreve, *Karin B Michels Division of Cancer Epidemiology, Comprehensive Cancer Center, Freiburg, University Medical Center Freiburg, Freiburg, Germany (AO, WH, KBM); and Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Woman’s Hospital, Harvard Medical School, Boston, MA 02115, USA (KBM) [email protected] We declare that we have no conflicts of interest. 1 2 3

Food Standards Agency. Nutrition—folic acid fortification. http://www. food.gov.uk/healthiereating/folicfortification (accessed Sept 1, 2009). Eichholzer M, Tonz O, Zimmermann R. Folic acid: a public-health challenge. Lancet 2006; 367: 1352–61. McNulty H, Pentieva K, Hoey L, Ward M. Homocysteine, B-vitamins and CVD. Proc Nutr Soc 2008; 67: 232–37.

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Kim YI. Folate: a magic bullet or a double edged sword for colorectal cancer prevention? Gut 2006; 55: 1387–89. Tjonneland A, Christensen J, Olsen A, et al. Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark. Eur J Clin Nutr 2006; 60: 280–86. Shane B. Folate fortification: enough already? Am J Clin Nutr 2003; 77: 8–9. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007; 297: 2351–59. Mason JB. Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons. Nutr Rev 2009; 67: 206–12.

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Hirsch S, Sanchez H, Albala C, et al. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 2009; 21: 436–39. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr 2008; 87: 517–33. Mason JB, Dickstein A, Jacques PF, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007; 16: 1325–29. Lieberman DA, Weiss DG, Bond JH, Ahnen DJ, Garewal H, Chejfec G. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 2000; 343: 162–68.

Health and climate change Expectations are running high for the UN climate change conference in Copenhagen this December. But will we get the global commitment for radical cuts in CO2 emissions that the world so urgently needs? The scientific evidence that global temperatures are rising and that man is responsible has been widely accepted since the 2007 report by the Intergovernmental Panel on Climate Change.1 There is now equally wide consensus that we need to reduce CO2 emissions to at most 50% of 1990 levels by 2050,2 if we are to have even a 50% chance of preventing temperatures exceeding preindustrial levels by more than 2°C, considered by many to be the tipping point for catastrophic and irreversible climate change. The economic argument that taking action now rather than later will be cheaper is also widely accepted after the Stern report in 2006.3 The election of President Barack Obama has shifted US policy from seeking to block an agreement to seeking to find one. So the chances of success should be good. But the politics are tough. The most vocal arguments are about equity: the rich world caused the problem: why should the poor world pay to put it right? Can the rich world do enough, through its own actions and through its financial and technological support for the poor, to persuade the poor to join in a global agreement? The present economic climate does not help, giving rich world sceptics arguments for not acting—or at least not acting now. And the sensitive issue of population stabilisation continues to slip off the agenda but is crucial to achieving real reductions in global CO2 emissions. These arguments need to be addressed head on. Climate change is global. Emissions know no frontiers. And the necessary measures should be seen not as a cost but as an opportunity. Coal-fired power stations pollute the atmosphere and worsen health. So does the internal www.thelancet.com Vol 374 September 19, 2009

combustion engine. Deforestation destroys biodiversity. Saving energy helps hard-pressed household budgets. Drought-resistant crops help poor farmers. So even without climate change, the case for clean power, electric cars, saving forests, energy efficiency, and new agricultural technology is strong.4 Climate change makes it unanswerable. The threat to health is especially evident in the poorest countries, particularly in sub-Saharan Africa, as the recent report by The Lancet and the University College London Institute for Global Health Commission shows.4 These countries are struggling to meet the Millennium Development Goals (MDGs). Their poverty and lack of resources, infrastructure, and often governance, make them far more vulnerable to the effects of climate change. Warmer climate can lead to drought, pressure on resources (particularly water), migration, and conflict. The conflict in Darfur is as much about pressure on resources as the desert encroaches as about the internal politics of Sudan. And the implications for the health of local populations are acute—on the spread and changing patterns of disease, notably water-borne diseases from inadequate and unclean supplies, on maternal and child mortality as basic health services collapse, and on malnutrition where food is scarce.5 And population stabilisation will not be achieved if, for want of resources, girls are not educated and contraceptives are unavailable.6 Climate change is causing other kinds of extreme weather events too: storms, floods, and rising sea levels affecting coastal populations and islands.7 Every such event has adverse consequences for health. The poorer the country and its infrastructure, the worse are the consequences, and the poorer the chances of meeting the MDGs.

Published Online September 16, 2009 DOI:10.1016/S01406736(09)61603-2

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