BMJ 2014;349:g4810 doi: 10.1136/bmj.g4810 (Published 29 July 2014)
Page 1 of 2
Editorials
EDITORIALS Folate and prevention of neural tube defects Tracking red blood cell concentrations will help guide policy decisions about fortification Robert Clarke reader in epidemiology and public health medicine, Derrick Bennett senior statistician Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
Neural tube defects are the most common disabling birth defect and can be reduced by 80% if women of childbearing age consume 400 µg of folic acid daily.1 In the United Kingdom, where roughly 800 pregnancies are affected each year, the Scientific Advisory Committee on Nutrition recommends that all women planning pregnancy should take 400 μg folic acid daily as a supplement before conception and until the 12th week of pregnancy (or 5 mg daily for women with a previous pregnancy affected by a neural tube defect).1 As half of all pregnancies are unplanned and less than a third of all women start taking folic acid before becoming pregnant,2 voluntary folic acid fortification has been permitted in the United Kingdom (and elsewhere in most European countries), and mandatory fortification has been implemented in North America, South America, and Australia 1. The relative efficacy and safety of voluntary and mandatory folic acid fortification programmes are uncertain. The study reported by Crider and colleagues in The BMJ (doi:10. 1136/bmj.g4554) was designed to determine the optimal red blood cell (RBC) folate concentrations required to prevent neural tube defects.3 The authors analysed data from two studies in non-fortified populations from two regions in China: a community intervention study testing folic acid supplementation to prevent neural tube defects that included 275 cases in 247 831 women treated with folic acid 400 µg daily;4 and a population based randomised trial to evaluate the effects of folic acid supplementation in a subset of 371 women of reproductive age who provided RBC folate concentrations after treatment with 400 µg daily.5 The results show an inverse dose-response association of neural tube defect risks with RBC folate concentrations—participants with the lowest red cell folate concentrations had the highest risk of neural tube defects (25.4 v 6/10 000 for 500 v 1200 nmol/L).3 The authors defined the threshold for optimal RBC folate concentrations for prevention of neural tube defects as 1000 nmol/L. These results are concordant with the results of a previous study by Daly and colleagues in Ireland. Their study, which included 84 cases, reported a threshold of 906 nmol/L, above which the risk of neural tube defects was minimal.6 Applying the risk model developed from the Chinese data to population RBC folate concentrations in the United States,
before and after fortification, Crider and colleagues showed that their predicted estimates for the prevalence of neural tube defects were concordant with the observed prevalence before and after fortification, confirming the validity of their model. Taken together, the Chinese, Irish, and US data indicate that RBC folate concentrations of about 1000 nmol/L or greater should be the population target for preventing neural tube defects. These findings are important and provide a clear target for RBC folate concentrations that should help guide the choice of population fortification strategies. Traditionally, RBC folate concentrations have been viewed as a better measure of folate status than serum folate concentrations, as they reflect folate status throughout the cell’s 90-120 day lifespan. However, red cell folate is unlikely to be a useful biomarker for individual women in the foreseeable future. Red cell assays are available only in specialist laboratories, whereas serum folate assays are readily available in most clinical laboratories, at least in developed countries, where they are widely used for measuring folate status in individual women. Both tests can be useful for monitoring a population’s response to changes in folate policies, and both should be included in nationally representative surveys of folate status such as the National Health and Nutrition Examination Survey in the United States.7 Data from this survey, reported by Crider and colleagues, suggest that with mandatory fortification, three quarters of the US population have adequate serum concentrations of folate and optimal RBC folate concentrations for preventing neural tube defects.3 Data from Ireland, which operates a voluntary policy, paint a less healthy picture—median serum and RBC folate concentrations in one recent survey were about 17 nmol/L and 700 nmol/L, respectively, in non-supplement users and 30 nmol/L and 1000 nmol/L in supplement users.8 Mandatory fortification in the United States (average daily dose of folic acid 0.14 mg) is associated with substantially greater population folate concentrations, which translates in to a substantially lower risk of neural tube defects.9 Moreover, voluntary folic acid fortification causes more extreme variation in folate status within populations (with low intakes in lower socioeconomic and ethnic minority groups and high intakes in users of high dose supplements).1 Consequently, the
Correspondence to: R Clarke [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g4810 doi: 10.1136/bmj.g4810 (Published 29 July 2014)
Page 2 of 2
EDITORIALS
Scientific Advisory Committee on Nutrition has called for mandatory fortification in the United Kingdom to replace voluntary fortification, together with guidance on high dose folic acid supplements, to increase the population folate concentrations while avoiding excessive intakes of folic acid.1 Large trials of folic acid supplements at doses 10 times higher than the average extra intake after fortification provide reassurance that such a policy is likely to be safe.10-12
Population surveys of RBC folate concentrations, along with the optimum threshold confirmed by Crider and colleagues, will help to guide these important policy decisions worldwide and allow public health leaders to monitor a population’s response with the ultimate goal of reducing the incidence of largely preventable neural tube defects.
3 4 5 6 7 8 9 10
Contributors: Both authors contributed to this editorial.
Crider KS, Devine O, Hao L, Dowling NF, Li S, Molloy A, et al. Population red blood cell folate concentrations for prevention of neural tube defects: a bayesian model. BMJ 2014;349:g4554. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural tube defects with folic acid in China: China-US Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 1999;341:1485-90. Hao L, Yang QH, Li Z, Bailey LB, Zhu JH, Du DJ, et al. Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial. Am J Clin Nutr 2008;88:448-57. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects: implications for prevention. JAMA 1995;274:1698-702. Clarke R, Bennett D, Parish S, Verhoef P, Dötsch-Klerk M, Lathrop M, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. Plos Med 2012;9:e10011277. Hopkins SM, McNulty BA, Walton J, Flynn A, Molloy AM, Scott JM, et al. Impact of voluntary fortification and supplement use on dietary intake of folate and status in an Irish adult population. Proc Nutr Soc 2012;71:abstract 38. Yang Q, Cogswell ME, Hamner HC, Carriquiry A, Bailey LB, Pfeiffer CM, et al. Folic acid source, usual intake, and folate and vitamin B-12 status in US adults: National Health and Nutrition Examination Survey (NHANES) 2003-2006. Am J Clin Nutr 2010;91:64-72. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37485 individuals. Arch Intern Med 2010;170:1622-31. Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E, et al. Effects of folic acid on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. Lancet 2013;381:1029-36. Clarke R, Bennett D, Parish S, Lewington S, Skeaff M, Eussen SJ, et al. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nutr 2014;100:657-66.
Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.
11
Provenance and peer review: Commissioned; not externally peer reviewed.
12
1
Cite this as: BMJ 2014;349:g4810
2
Scientific Advisory Committee on Nutrition. Folate and disease prevention. Stationery Office, 2006. Bestwick JP, Huttly WJ, Morris JK, Wald NJ. Prevention of neural tube defects: a cross-sectional study of the uptake of folic acid supplementation in nearly half a million women. PLoS One 2014;9:e89354.
For personal use only: See rights and reprints http://www.bmj.com/permissions
© BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Folate and prevention of neural tube defects Tracking red blood cell concentrations will help guide policy decisions about fortification Robert Clarke reader in epidemiology and public health medicine, Derrick Bennett senior statistician Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
Neural tube defects are the most common disabling birth defect and can be reduced by 80% if women of childbearing age consume 400 µg of folic acid daily.1 In the United Kingdom, where roughly 800 pregnancies are affected each year, the Scientific Advisory Committee on Nutrition recommends that all women planning pregnancy should take 400 μg folic acid daily as a supplement before conception and until the 12th week of pregnancy (or 5 mg daily for women with a previous pregnancy affected by a neural tube defect).1 As half of all pregnancies are unplanned and less than a third of all women start taking folic acid before becoming pregnant,2 voluntary folic acid fortification has been permitted in the United Kingdom (and elsewhere in most European countries), and mandatory fortification has been implemented in North America, South America, and Australia 1. The relative efficacy and safety of voluntary and mandatory folic acid fortification programmes are uncertain. The study reported by Crider and colleagues in The BMJ (doi:10. 1136/bmj.g4554) was designed to determine the optimal red blood cell (RBC) folate concentrations required to prevent neural tube defects.3 The authors analysed data from two studies in non-fortified populations from two regions in China: a community intervention study testing folic acid supplementation to prevent neural tube defects that included 275 cases in 247 831 women treated with folic acid 400 µg daily;4 and a population based randomised trial to evaluate the effects of folic acid supplementation in a subset of 371 women of reproductive age who provided RBC folate concentrations after treatment with 400 µg daily.5 The results show an inverse dose-response association of neural tube defect risks with RBC folate concentrations—participants with the lowest red cell folate concentrations had the highest risk of neural tube defects (25.4 v 6/10 000 for 500 v 1200 nmol/L).3 The authors defined the threshold for optimal RBC folate concentrations for prevention of neural tube defects as 1000 nmol/L. These results are concordant with the results of a previous study by Daly and colleagues in Ireland. Their study, which included 84 cases, reported a threshold of 906 nmol/L, above which the risk of neural tube defects was minimal.6 Applying the risk model developed from the Chinese data to population RBC folate concentrations in the United States,
before and after fortification, Crider and colleagues showed that their predicted estimates for the prevalence of neural tube defects were concordant with the observed prevalence before and after fortification, confirming the validity of their model. Taken together, the Chinese, Irish, and US data indicate that RBC folate concentrations of about 1000 nmol/L or greater should be the population target for preventing neural tube defects. These findings are important and provide a clear target for RBC folate concentrations that should help guide the choice of population fortification strategies. Traditionally, RBC folate concentrations have been viewed as a better measure of folate status than serum folate concentrations, as they reflect folate status throughout the cell’s 90-120 day lifespan. However, red cell folate is unlikely to be a useful biomarker for individual women in the foreseeable future. Red cell assays are available only in specialist laboratories, whereas serum folate assays are readily available in most clinical laboratories, at least in developed countries, where they are widely used for measuring folate status in individual women. Both tests can be useful for monitoring a population’s response to changes in folate policies, and both should be included in nationally representative surveys of folate status such as the National Health and Nutrition Examination Survey in the United States.7 Data from this survey, reported by Crider and colleagues, suggest that with mandatory fortification, three quarters of the US population have adequate serum concentrations of folate and optimal RBC folate concentrations for preventing neural tube defects.3 Data from Ireland, which operates a voluntary policy, paint a less healthy picture—median serum and RBC folate concentrations in one recent survey were about 17 nmol/L and 700 nmol/L, respectively, in non-supplement users and 30 nmol/L and 1000 nmol/L in supplement users.8 Mandatory fortification in the United States (average daily dose of folic acid 0.14 mg) is associated with substantially greater population folate concentrations, which translates in to a substantially lower risk of neural tube defects.9 Moreover, voluntary folic acid fortification causes more extreme variation in folate status within populations (with low intakes in lower socioeconomic and ethnic minority groups and high intakes in users of high dose supplements).1 Consequently, the
Correspondence to: R Clarke [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g4810 doi: 10.1136/bmj.g4810 (Published 29 July 2014)
Page 2 of 2
EDITORIALS
Scientific Advisory Committee on Nutrition has called for mandatory fortification in the United Kingdom to replace voluntary fortification, together with guidance on high dose folic acid supplements, to increase the population folate concentrations while avoiding excessive intakes of folic acid.1 Large trials of folic acid supplements at doses 10 times higher than the average extra intake after fortification provide reassurance that such a policy is likely to be safe.10-12
Population surveys of RBC folate concentrations, along with the optimum threshold confirmed by Crider and colleagues, will help to guide these important policy decisions worldwide and allow public health leaders to monitor a population’s response with the ultimate goal of reducing the incidence of largely preventable neural tube defects.
3 4 5 6 7 8 9 10
Contributors: Both authors contributed to this editorial.
Crider KS, Devine O, Hao L, Dowling NF, Li S, Molloy A, et al. Population red blood cell folate concentrations for prevention of neural tube defects: a bayesian model. BMJ 2014;349:g4554. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural tube defects with folic acid in China: China-US Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 1999;341:1485-90. Hao L, Yang QH, Li Z, Bailey LB, Zhu JH, Du DJ, et al. Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial. Am J Clin Nutr 2008;88:448-57. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects: implications for prevention. JAMA 1995;274:1698-702. Clarke R, Bennett D, Parish S, Verhoef P, Dötsch-Klerk M, Lathrop M, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. Plos Med 2012;9:e10011277. Hopkins SM, McNulty BA, Walton J, Flynn A, Molloy AM, Scott JM, et al. Impact of voluntary fortification and supplement use on dietary intake of folate and status in an Irish adult population. Proc Nutr Soc 2012;71:abstract 38. Yang Q, Cogswell ME, Hamner HC, Carriquiry A, Bailey LB, Pfeiffer CM, et al. Folic acid source, usual intake, and folate and vitamin B-12 status in US adults: National Health and Nutrition Examination Survey (NHANES) 2003-2006. Am J Clin Nutr 2010;91:64-72. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37485 individuals. Arch Intern Med 2010;170:1622-31. Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E, et al. Effects of folic acid on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. Lancet 2013;381:1029-36. Clarke R, Bennett D, Parish S, Lewington S, Skeaff M, Eussen SJ, et al. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nutr 2014;100:657-66.
Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.
11
Provenance and peer review: Commissioned; not externally peer reviewed.
12
1
Cite this as: BMJ 2014;349:g4810
2
Scientific Advisory Committee on Nutrition. Folate and disease prevention. Stationery Office, 2006. Bestwick JP, Huttly WJ, Morris JK, Wald NJ. Prevention of neural tube defects: a cross-sectional study of the uptake of folic acid supplementation in nearly half a million women. PLoS One 2014;9:e89354.
For personal use only: See rights and reprints http://www.bmj.com/permissions
© BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
