Update on Prevention of Folic Acid-Preventable Spina Bifida and Anencephaly

Transcription

1 Ó 2008 Wiley-Liss, Inc. Brief Report Update on Prevention of Folic Acid-Preventable Spina Bifida and Anencephaly Karen N. Bell 1 and Godfrey P. Oakley Jr. 2 * 1 Department of Epidemiology, Rollins School of Public Health of Emory University, Gloucester, Massachusetts 2 Department of Epidemiology, Rollins School of Public Health of Emory University, Atlanta Georgia Received 4 May 2008; Revised 28 June 2008; Accepted 16 July 2008 BACKGROUND: The number of countries fortifying wheat and maize flour with folic acid has increased in the past 2 years. Folic acid prevents most cases of spina bifida and anencephaly by raising serum folate levels among women capable of bearing children, as does encouraging women to consume folic acid supplements prior to pregnancy. METHODS: The progress in preventing these serious birth defects can be measured by tracking the number of countries now fortifying and program coverage in each. Country estimates of the number of pregnancies affected by spina bifida and anencephaly are calculated using a prefortification birth prevalence baseline and estimates of the proportion prevented by wheat and maize flour fortified with folic acid. RESULTS: Current fortification programs are preventing about 22,000, or 9% of the estimated folic acid-preventable spina bifida and anencephaly cases. This represents an annual global decrease of about 6,600 folic acid-preventable spina bifida and anencephaly cases since CONCLUSIONS: The pace of preventing these serious birth defects can be accelerated if more countries require fortification of both wheat and maize flour and if regulators set fortification levels high enough to increase a woman s daily average consumption of folic acid to 400 mcg. Birth Defects Research (Part A) 85: , Ó 2008 Wiley-Liss, Inc. Key words: spina bifida; anencephaly; birth defect surveillance; flour fortification INTRODUCTION In 2006 we published an article that described a method for tracking the global prevention of spina bifida and anencephaly with fortification of wheat flour (Bell and Oakley, 2006). Since then, the goal of total prevention of folic acid-preventable spina bifida and anencephaly (FAPSBA) has come closer as more countries adopt requirements that wheat flour be fortified with folic acid (Maberly et al., 2008). While methods for estimating the amount of prevention are not fully developed, available data enable us to update the global progress made in the past 2 years toward increasing consumption of folic acid through wheat, and in some cases, maize flour fortification. This article describes methods for estimating the prevention of FAPSBA and estimates the numbers of cases prevented for each country in which fortified flour is consumed. The Flour Fortification Initiative (FFI) reported that the number of countries with national requirements for wheat flour fortification rose to 54 in 2007, with still more countries permitting fortified flour to be sold (Maberly et al., 2008). An estimated 27% of the world s population now has access to flour fortified with iron Disclosure: Professor Oakley is a co-inventor (while at CDC) of a patent that covers adding folic acid to contraceptive pills and could be compensated if CDC receives fees. He has been and may be a consultant to Ortho McNeil on this issue. Funding for this study was provided in part by The Global Alliance for Improved Nutrition (GAIN), Geneva, Switzerland. This organization had no involvement in the study design, or the collection, analysis, interpretation of data, or the writing of the report. Grant sponsor: Global Alliance for Improved Nutrition (GAIN), Geneva, Switzerland. *Correspondence to: Godfrey Oakley, Dept. of Epidemiology, Rollins School of Public Health of Emory University, 1518 Clifton Rd. NW, Atlanta, GA gpoakley@mindspring.com. Published online 9 December 2008 in Wiley InterScience ( wiley.com). DOI: /bdra Birth Defects Research (Part A): Clinical and Molecular Teratology 85: (2009)

2 FOLIC ACID-PREVENTABLE SPINA BIFIDA AND ANENCEPHALY 103 and/or folic acid. Our analysis of the updated FFI data shows that millers in 67 countries currently fortify wheat flour with folic acid, 47 of them in response to national mandates or regional requirements and the rest on a voluntary or pilot project basis. Six countries fortify both wheat and maize flour with folic acid. Australia, New Zealand, and Ireland may soon implement mandatory folic acid fortification. METHODS Our global prevention model assumes that approximately 75% of the cases of spina bifida and anencephaly (FAPSBA) can be prevented by daily folic acid consumption of 400 mcg or more. We further assume that a roughly linear inverse relationship exists between increasing erythrocyte folate levels and folic acid consumption on the one hand and decreasing NTD risk on the other. This relationship is based on published analyses and controlled studies that estimated the maximum possible reduction in overall NTD risk at between 60 85% (Daly et al., 1995, 1997; Wald et al., 1998, 2001). We also considered evidence from observational studies that documented reductions in NTD risk that have occurred with increases in folic acid consumption and/or erythrocyte folate levels (Berry et al., 1999; Dietrich et al., 2005; Hertrampf et al., 2003; Wald et al., 2001). If a 75% reduction in NTD birth prevalence is applied to the March of Dime s baseline global rate of 2.45 NTDs per 1,000 live births, the remaining rate of 0.6 is consistent with rates observed in women consuming the recommended 400 mcg or more of folic acid daily. We developed the term prevention factor to approximate the proportion (FAPSBA) that can be prevented in a population by increasing daily amounts (expressed in quartiles with ranges) of folic acid up to and over the amount 400 mcg required to prevent most cases of folate-responsive spina bifida and anencephaly. Consequently we estimate that 25% of the cases can be prevented by consuming close to 100 mcg; 50% by 200 mcg; 75% by consuming 300 mcg; and 100% by consuming 400 mcg daily. While oversimplified in many respects, we decided that these prevention factors are good enough to use with the available global data on birth prevalence of NTDs, known to be subject to enormous variation in accuracy, quality, and collection methods (Botto et al., 2006; Hobbs et al., 2001). As described in the first tracking article 2 years ago, our model of how much (Y 5 number of cases) FAPSBA is actually being prevented through flour fortification in a given country incorporates several variables: (A) the proportion of FAPSBA that can be prevented by daily average consumption of folic acid from fortified wheat and/or maize flour in a particular country; (B) the estimated number of pregnancies affected by FAPSBA; and (C) the estimated proportion of women capable of bearing children who consume the fortified flour. Variable A is based on wheat flour fortification levels and amounts of flour fortified as of 2007 or 2008 from the downloadable database on the FFI website ( edu/wheatflour/countrydata.php), and in some cases, wheat and maize data supplied by the Micronutrient Initiative (Ranum and Wesley, 2008; Wesley and Ranum, 2004). The resulting model, expressed as Y 5 A 3 B 3 C, estimates country-specific numbers of FAPSBA cases that are being prevented through flour fortification, compared to the baseline estimates published in the 2006 March of Dimes global birth defects report (Christianson, 2006). RESULTS Table 1 displays the estimated annual prevention of FAPSBA pregnancies through flour fortification with folic acid. Country-specific NTD prevalence rates prior to fortification are assumed to be the same as those reported in the March of Dimes report, but the annual number of cases is calculated from 2008 estimates of the birth rate, and then applied to midyear population estimates published by the international division of the U.S. Census Bureau. Wheat and maize flour consumption data are from 2002 Food and Agriculture (FAO) Food Balance Sheets, the latest available. Our latest global estimate of the number of FAPSBA cases is 243,691, or 75% of the number of NTD-affected pregnancies estimated to occur each year if no country had mandatory folic acid fortification. As shown in Table 2, only six countries fortify both wheat and maize flour, and approximately 60 additional countries fortify wheat flour. We applied the same prevention factors established in our prior study for each range of daily folic acid consumption to estimate the proportion of FAPSBA that have been prevented, that is, 25% if mcg of folic acid are consumed; 50% if mcg; 75% if mcg; and 100% if more than 350 mcg (Bell and Oakley, 2006). Figure 1 maps the countries where millers fortify wheat (and sometimes maize) flour with folic acid. The color shadings from light to dark aqua correspond to increasing proportions of FAPSBA prevented in each country fortifying wheat and/or maize flour. In most countries, regulators do not set fortification levels high enough to provide most women with 400 mcg daily of folic acid, the amount recommended by the U.S. Public Health Service to reduce the risk of NTDs (Centers for Disease Control and Prevention, 1992). We estimate that in 2008, of the approximately 243,691 FAPSBA, current fortification programs are preventing about 22,134, or about 9.08% of the global total. Figure 2 displays the progress in global estimated prevention over the past 2 years, a reduction of about 6,600 FAPSBA cases. DISCUSSION Our first global estimate of FAPSBA prevented through folic acid flour fortification identified 39 countries that mandate or encourage the fortification of wheat flour; this updated estimate includes 68 countries and takes maize flour fortification into account where it is consumed on a large scale. The magnitude of prevention as measured by the absolute number of cases prevented increased substantially by 30% in 2 years, even though the global proportion of prevented cases rose by only 3.2 percentage points, from 6.8 to 9%. This increase in prevention was primarily a result of wheat fortification being initiated in many additional countries, including some with a relatively high baseline prevalence of NTD births such as South Africa and Pakistan. In fact, investigators in South Africa, using a hospital-based surveillance system, recently reported a decrease of 30.5% in the

3 104 BELL AND OAKLEY Table 1 Estimated Annual Prevention of NTD Births with Fortified Wheat and Maize Flour, 2008 Country Estimated annual prevalence of NTD births y Folic acidpreventable NTDs (FAPSBA) { Daily grams fortified flour consumed Daily mcg folic acid consumption from wheat and/ or maize flour k % of FAPSBA that complete fortification Program will prevent } coverage # Folic acid fortification level for wheat maize, ppm** FAPSBA prevented yy South Africa* 1,784 1, , % 100% 1.4,2 1,338 Kyrgyzstan % 100% Turkmenistan % 100% Iran 2,225 1, % 100% 1.5 1,669 Azerbaijan % 10% Chile % 100% Morocco 1,610 1, % 100% 1.4 1,208 Cyprus % 40% 25 4 Uzbekistan 1,495 1, % 30% Uruguay % 100% Argentina 1,394 1, % 100% 2.2 1,045 Egypt 3,976 2, % 20% Kazakhstan % 50% Tajikistan % 71% Pakistan 9,036 6, % 25% 1.5 1,694 Georgia % 0% Israel % 20% Afghanistan 3,000 2, % 30% Bahrain % 100% Yemen 1, % 100% Mongolia % 11% U Arab Em % 100% Fiji % 100% Oman % 100% Qatai % 100% Cuba % 100% Kuwait % 100% Ukraine % 20% Saudi Arabia % 100% Canada % 100% China 23,705 17, % 1% Gaza Strip % 100% l 66 United States 6,032 4, % 100% 1.5 2,262 St.Vinc & Gren % 100% Jordan % 100% Barbados % 100% Jamaica % 100% Belize % 100% Brazil* 5,849 4,387 88, % 100% 1.5, 1.5 2,193 Dominica % 100% India 119,889 89, % 2% 1.5 1,079 Malaysia 1, % 20% Costa Rica* , % 100% 1.8, Guyana % 100% Grenada % 100% Mexico* 5,509 4,132 67, % 100% 0.6, 0.4 1,033

4 FOLIC ACID-PREVENTABLE SPINA BIFIDA AND ANENCEPHALY 105 Table 1 Estimated Annual Prevention of NTD Births with Fortified Wheat and Maize Flour, 2008 (continued) Country Estimated annual prevalence of NTD births y Folic acidpreventable NTDs (FAPSBA) { Daily grams fortified flour consumed Daily mcg folic acid consumption from wheat and/ or maize flour k % of FAPSBA that complete fortification Program will prevent } coverage # Folic acid fortification level for wheat maize, ppm** FAPSBA prevented yy Sudan 3,036 2, % 35% Bolivia % 100% Panama % 100% Nepal 4,151 3, % 20% Dom. Republic* , % 100% 1.8, Lesotho % 100% Haiti % 100% Peru 1, % 100% Zambia* , % 60%, Paraguay % 100% 3 73 Honduras % 100% El Salvador % 100% Guatemala % 100% Uganda* 1,964 1,473 11, % 50% 2.52,1 184 Nicaragua % 100% Colombia 1,788 1, % 100% Indonesia 3,199 2, % 100% Congo DRC 5,720 4, % 70% Côte d lvoire 1,700 1, % 100% Malawi % 10% Vietnam % 15% 2 28 Ecuador % 100% Total # NTDs annually prevented in fortifying countries, ,134 or 9.08% Global estimate of annual folic acid-preventable NTDs 243,691 *Maize flour is fortified, source Fortification Handbook update by Peter Ranum and Annie Wesley, March y Calculated from NTD prevalences in 2006 March of Dimes report with U.S. Census estimates of births in { Assumed to be 75% of annual NTD prevalence in population that does not consume folic acid. From Food Balance Sheets, 2002, in grams of wheat and/or mage flour FAO does not have later estimates. k Calculated from grams of wheat 3 fortification levels for wheat flour plus grams of maize flour 3 fortification level for maize. } Prevention percentage: % annual NTDs prevented through flour fortification, as function of folic acid consumption and prefortification annual estimate of NTDs, using model in this article. # FF1 estimates of % of population consuming fortified wheat flour, 2007 or **Fortification Handbook update by Peter Ranum and Annie Wesley, March yy # of NTDs prevented by wheat and maize flour fortification, calculated as product of folic acid-preventable NTD estimate 3 prevention percentage 3 program coverage.

5 106 BELL AND OAKLEY Table 2 Countries Fortifying Wheat and Maize Flour with Folic Acid, 2008 Folic acid fortification* Number of countries Country name Fortifies wheat and maize flour 6 Costa Rica, Dominican Republic, Brazil, Uganda, South Africa, Mexico Fortifies only maize flour 1 Zambia Fortifies only wheat flour 61 Afghanistan, Argentina, Azerbaijan, Bahrain, Barbados, Belize, Bolivia, Canada, Chile, China, Colombia, Congo DRC, Côte d Ivoire, Cuba, Cyprus, Dominica, Ecuador, Egypt, El Salvador, Fiji, Gaza Strip, Georgia, Grenada, Guatemala, Guyana, Haiti, Honduras, India, Indonesia, Iran, Israel, Jamaica, Jordan, Kazakhstan, Kuwait, Kyrgyzstan, Lesotho, Malawi, Malaysia, Mongolia, Morocco, Nepal, Nicaragua, Oman, Pakistan, Panama, Paraguay, Peru, Qatar, Saint Vincent and the Grenadines, Saudi Arabia, Sudan, Tajikistan, Turkmenistan, U Arab Em, Ukraine, United States, Uruguay, Uzbekistan, Vietnam, Yemen *Source: Ranum and Wesley (2008), Fortification Handbook Update and Flour Fortification Initiative website. birth prevalence of NTDs (Sayed et al., 2008). Another factor contributing to this FAPSBA prevention increase is the addition of folic acid from fortified maize flour in our model; for example, this increased the estimated prevention significantly in Brazil. Our method for tracking the prevention of FAPSBA depends on datasets that may contain significant errors, especially when individual countries are concerned. For example, the March of Dimes estimates of the birth prevalence of NTDs for each country are based primarily on surveillance systems, which in many countries are hospital-based and poorly funded. Birth prevalence estimates may also be low in countries where a high proportion of affected pregnancies are terminated. We decided to rely on 2002 FAO food balance sheet estimates for wheat and maize flour consumption to calculate folic acid consumption for this update and the initial baseline estimate, in part because the FAO has been revising its methodology for food balance sheets. However, errors in flour consumption estimates are unlikely to affect the results of our FAPSBA tracking estimates, because we used them primarily to calculate per capita folic acid consumption and then rank countries in four large groupings that correspond to the proportion of the recommended daily amount (400 mcg) for women of reproductive age. The information on wheat and maize flour fortification programs may also be subject to errors, especially where program coverage is concerned. Both groups generating this data, The FFI and The Micronutrient Initiative, caution that they may be incomplete and that updates are made as new information is reported or collected. An ideal model for estimating FAPSBA prevention would be based on women s blood folate measurements, which better reflect the risk of a pregnancy affected by Figure 1. Prevention of FAPSBA with fortification of wheat and maize flour.

6 FOLIC ACID-PREVENTABLE SPINA BIFIDA AND ANENCEPHALY 107 require wheat flour to be fortified with folic acid. Second, the amount of folic acid added to all types of fortified flour must be high enough to supply the average women with 400 mcg of folic acid daily. More than half of all fortifying countries fall considerably short of this goal. Third, country fortification programs must be expanded, with mandates if necessary, and they must be feasible, to reach all women capable of bearing children. Two large countries, China and India, have begun small pilot programs to fortify wheat flour with folic acid. Their expansion would contribute enormously to prevention of FAPSBA. Figure 2. Estimated number of FAPSBA cases prevented from wheat and maize flour fortification, 2006 and [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com.] an NTD, as we have noted above in the Methods section. Blood folate levels rise proportionately to folic acid consumption in the ranges of folic acid contributed by fortification; these increases in median consumption would consequently result in decreasing rates of NTD-affected pregnancies to the levels close to 0.6 per 1,000 live births observed by Berry et al. in 1999 in the large-scale China study and the 0.8 estimated by Daly et al. in 1997 for daily consumption of 400 mcg of folic acid. Blood folate measurements, if collected prior to and following flour fortification, would provide excellent information about the amount of FAPSBA risk reduction in individual countries, and would be an excellent tracking method. Even though our current model has many weaknesses, it does permit periodic charting of NTD prevention from a baseline that may fairly represent the numbers of children born with spina bifida and anencephaly in many countries of the world. CONCLUSIONS Seventeen years after folic acid was unequivocally shown to prevent spina bifida and anencephaly, we estimate that only about 10% of the birth defects in the world that can be prevented by folic acid are actually being prevented. There is an urgent need to implement programs that will prevent all the deaths and disabilities caused by FAPSBA. The pace of prevention of FAPSBA depends on the following actions by regulators in every country. First, folic acid fortification of flour must be required for wheat flour, and also for maize flour if it is an important staple. More than 150 countries do not REFERENCES Bell KN, Oakley GP, Jr Tracking the prevention of folic acidpreventable spina bifida and anencephaly. Birth Defects Res A Clin Mol Teratol 76: Berry RJ, Li Z, Erickson JD, et al Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention [corrected; erratum to be published]. New Engl J Med 341: Botto LD, Lisi A, Bower C, et al Trends of selected malformations in relation to folic acid recommendations and fortification: an international assessment. Birth Defects Res A Clin Mol Teratol 76: Centers for Disease Control and Prevention Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 41:1 7. Christianson A, Modell B March of Dimes Global Report on Birth Defects: The Hidden Toll of Dying and Disabled Children. White Plains: March of Dimes. Daly LE, Kirke PN, Molloy A, et al Folate levels and neural tube defects. Implications for prevention. JAMA 274: Daly S, Mills JL, Molloy AM, et al Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350: Dietrich M, Brown CJ, Block G The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J Am Coll Nutr 24: Hertrampf E, Cortes F, Erickson JD, et al Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile. J Nutr 133: Hobbs CA, Hopkins SE, Simmons CJ Sources of variability in birth defects prevalence rates. Teratology 64Suppl 1:S8 S13. Maberly G, Grummer-Strawn L, Jefferds M, et al Trends in wheatflour fortification with folic acid and iron worldwide, 2004 and MMWR 57:8 10. Ranum P, Wesley A World Cereal Fortification Standards and Practices, Micronutrient Initiative Fortification Handbook. Ottawa, Canada: Micronutrient Initiative. atlanta08/micountrytable2008bgainmodifications.doc Sayed AR, Bourne D, Pattinson R, et al Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa. Birth Defects Res A Clin Mol Teratol 82: Wald NJ, Law M, Jordan R Folic acid food fortification to prevent neural tube defects. Lancet 351:834; author reply Wald NJ, Law MR, Morris JK, et al Quantifying the effect of folic acid. Lancet 358: Wesley A, Ranum P Fortification Handbook. In: Wesley A, Ranum P, editors. Vitamin and mineral fortification of wheat flour and maize meal: The Micronutrient Initiative. Ottawa, Canada.