Description of the condition
Over 1.6 billion people, or a quarter of the world's population, are anaemic. The prevalence of anaemia is highest (47.4%) among preschool children, but over 40% of pregnant women, 30% of non-pregnant women and 25% of school-aged children are also affected (WHO/CDC 2008). Most anaemia occurs in developing countries, particularly in Asia, Africa and South America. At least half this burden is due to iron deficiency (Stoltzfus 2003), caused by poor dietary iron content and availability for absorption, together with increased requirements (during growth and pregnancy) and losses (especially due to intestinal parasitic infection and menstruation). Iron deficiency is thus thought to be the single most prevalent nutrient deficiency worldwide.
Iron deficiency is associated with considerable morbidity across the life cycle. In preschool children, iron deficiency anaemia appears to be associated with potentially irreversible impairments in cognitive development, and in school-aged children iron deficiency anaemia is associated with reduced school learning and educational performance (Beard 2007). Symptomatic anaemia, with fatigue, lethargy and pallor may also result in severe cases. Iron deficiency has been estimated to contribute to 0.2% of deaths in children under five, and to cost approximately 2.2 million disability adjusted life years (DALYs) annually (Stoltzfus 2004). In adolescents and adult non-pregnant women, iron deficiency is associated with impaired cognitive and physical capacity and reduced work performance. Prevention of iron deficiency anaemia during pregnancy has been associated in some studies with alleviation of low birth weight (Christian 2003), a condition which in turn is associated with reduced infant iron endowment and a subsequent increased risk of iron deficiency anaemia (Wharton 1999). Maternal iron deficiency is a global problem that may contribute to high rates of maternal depression and non-responsive care giving (Black 2011). Children can benefit from both nutritional interventions and early learning interventions that promote responsive mother-child interactions (Black 2012; Murray-Kolb 2009).
The major causes of iron deficiency include inadequate dietary iron intake due to consumption of a diet with a low overall iron content, or one that contains inhibitors of iron absorption (Nair 2009), and increased losses of iron because of chronic blood losses, most commonly due to intestinal hookworm infection (Stoltzfus 1996). Poor dietary intake and limited bioavailability (the quantity or fraction of the iron consumed that is absorbed and utilised) is considered a major contributor to the global burden of iron deficiency. Populations consuming diets that chiefly comprise cereals such as maize, wheat and rice, with an inadequate intake of iron-rich foods, in particular meat, but also legumes, nuts and other vegetables, are at high risk of iron deficiency. Cereals (including maize) contain phytates which bind to iron and prevent its absorption in the intestine (Sharpe 1950).
Iron deficiency is most likely to occur during times of increased iron requirements, and thus is seen most commonly in toddlers when rapid growth results in expansion of the blood volume and an escalation in iron requirements for production of red blood cells, during adolescence when growth and red cell production escalates again (Wharton 1999), compounded in females by the onset of menstruation with associated blood loss, and during pregnancy when women undergo expansion in blood volume, vigorous erythropoiesis and must supply iron to the developing foetus (Scholl 2000).
Diagnosis of iron deficiency and anaemia is dependent on laboratory investigation (WHO 2011a; WHO 2011b). Haemoglobin can be accurately measured using a variety of methods. Measurement of some iron indices is more specialised and in the field setting may be difficult (Lynch 2011; WHO/CDC/UNICEF 2001). Important tests for evaluating the iron status of populations include ferritin, soluble transferrin receptor (especially during concomitant inflammation and in pregnancy) and transferrin/iron binding capacity. Although bone marrow examination for macrophage iron is considered a gold standard for diagnosis of iron deficiency, it is rarely performed in field studies (WHO/CDC 2007).
Strategies to improve iron intake include improving overall dietary diversity, supplementation, point-of-use fortification of foods with micronutrient powders and fortification of staple foods with iron. Increasing the availability and consumption of a nutritionally adequate diet is the only sustainable and long-term solution, not just for overcoming iron deficiency and anaemia, but for overcoming other micronutrient deficiencies as well (FAO 2011). Food-based approaches include increasing overall food intake, increasing consumption of micronutrient-rich foods, modifying intake of dietary iron inhibitors and enhancers, using improved processing, preservation and preparation techniques, consumer education for behaviour change, improving food quality and safety and public health, and food fortification (FAO 2011).
Cereals are overwhelmingly the major source of food supplies for direct human consumption. Of the 2.4 billion tonnes of cereals currently produced, roughly 1.1 billion tonnes are destined for food use, around 800 million tonnes (35% of world consumption) are used as animal feed, and the remaining 500 million tonnes are diverted to industrial usage, seed or are wasted. With an ability to grow in diverse climates, maize – the world’s primary coarse grain – is cultivated in most parts of the world, although the vast quantity of production is concentrated in the Americas, especially the United States of America. In that country, transgenic (genetically modified) maize accounts for 85% of plantings. The major export markets have shifted increasingly to the developing countries. Currently, about 55% of world consumption of coarse grains is used for animal feed, but in many countries (mainly in sub-Saharan Africa and Latin America) they are also directly used for human consumption. At the global level, about 17% of aggregate consumption of coarse grains is devoted to food, but the share rises to as much as 80% in sub-Saharan Africa (FAO 2012).
Description of the intervention
Fortification is the addition of micronutrients to foods. Fortification is usually applied centrally, at the point of food production. Due to the relatively low cost and potential for wide distribution, fortification has been proposed as one of the most cost-effective of all health interventions. The success of fortification depends on several factors. The food 'vehicle' to which the fortificant is added must be consumed in adequate quantities by the population at risk of the micronutrient deficiency. Additionally the fortificants used must be effectively absorbed and should not diminish the taste, colour or smell of the food (WHO/FAO 2006). A variety of iron fortificants are suitable for use in flours, including ferrous sulphate, elemental iron powders, ferrous fumarate and sodium iron EDTA (Hurrell 2002; Hurrell 2010).
Maize (corn) is one of the world’s most important cereal grains. It is a dietary staple for more than 200 million people and provides approximately 20% of the world’s calories (Nuss 2010). Products of maize include corn flour, porridges, breakfast cereals, tortillas, tamales and arepas. Maize has comparable energy density to other cereal crops, and is a relatively good source of vitamin A, but also is rich in phytate, a compound that potently inhibits iron availability for absorption (McKevith 2004). In sub-Saharan Africa, Southeast Asia and Latin America, where iron deficiency is endemic, maize is a dietary staple (Nuss 2010).
Maize processing and products
A maize kernel comprises several components: the outer covering (pericarp and aleurone); the endosperm, comprising the largest fraction of the kernel; and the germ, consisting of the embryo and scutellum. Genetic background, variety, environmental conditions, plant age and geographic location can impact kernel composition within and between maize varieties (Nuss 2010). The nutritional properties of maize are located in distinct although overlapping components of the kernel. Maize contains about 72% starch, mainly found in the endosperm. The predominant source of fibre is the pericarp, although smaller amounts of fibre are also found in the endosperm. Maize contains about 10% protein, chiefly in the endosperm and germ: importantly, the essential amino acids lysine and tryptophan are only present in maize in small and inadequate quantities (FAO 1992). Quality protein maize (QPM) varieties have been developed to contain high levels of lysine and tryptophan (Prasanna 2001). Fat and lipid account for 3% to 6% of maize.
In general, maize is deficient in vitamin B12 and contains niacin in an inaccessible form, placing populations that consume high quantities of maize without sufficient dietary diversity at risk of pellagra (FAO 1992). Maize contains only modest amounts of zinc, and negligible amounts of iron, absorption of which is further diminished by the presence of phytates which bind to non-haem iron and prevent absorption: the bioavailability of iron from corn is thus estimated to be less than 2% to 5% (Beiseigel 2007). Phytases, genetically modified low phytate maize variants, and some pre-processing methods such as addition of ascorbic acid, may improve iron availability from maize (Beiseigel 2007; Hurrell 2002; Troesch 2011).
Following harvest, maize undergoes several processing steps prior to preparation of an end product. Cobs are dried, hulled and shelled to remove the kernels prior to milling (ILO 1984). Wet milling is used to obtain starch, edible corn oil, sweeteners and syrups, and animal feed products. Dry milling is used to obtain flour, meal and grits. Some maize products use whole maize while others use degerminated kernels (Codex 1985a; Codex 1985b). This is an important consideration as it may impact the overall nutritional contents. Maize meal/flour derived from dry milling is used in different ways around the world (Herbst 2001). It is used as a substitute for wheat to make corn bread, as polenta in Italy, angu in Brazil, mamaliga in Romania, mush in the United States, mealie pap in South Africa and sadza, nshima and ugali in African countries. Corn flakes are also derived from corn meal that has undergone extrusion (Nuss 2010). Fermentation of milled kernels is also commonly used in African and South American settings: derived products including bread and alcohol may have improved bioavailability of niacin; fermented maize gruel has been recommended as a fluid for replacement of electrolytes in acute diarrhoea for children in developing countries.
In many settings, maize grains undergo pre-processing prior to milling. The process of nixtamalisation refers to cooking maize grains in a dilute alkali solution (traditionally, limewater - sodium and calcium hydroxide, ash or lye). Following washing, the pericarp is removed (hulling), leaving the endosperm and germ (Katz 1974). The softened grain may then be wet-milled to produce dough 'masa', which can be used to make tortillas, tamales and arepas. Alternatively, the nixtamalised grain may be dried in ovens, ground and then prepared as nixtamalised corn flour (masa harina) that can be reconstituted at the time of use to produce the full range of corn masa products. This flour is commercially available for purchase and consumption and expedites the maize preparation process for regular consumers (Bressani 1997). Although nixtamalisation was practised for many centuries in local and home settings, it has been adapted for large-scale corn masa flour production.
Nixtamalisation gives the final product a characteristic flavour, and changes the nutritional properties of the maize. Nixtamalised maize flour contains niacin in a bioavailable form, and populations consuming maize thus produced do not develop pellagra (Bressani 1997). Due to calcium absorbed from the lime, nixtamalised maize flour has a high calcium content and can provide most of the daily calcium requirement to populations consuming this product as a staple (Wyatt 1994). Phytic acid content is reduced in nixtamalised maize products. Iron content may be slightly increased by the process; variable changes in bioavailability have been reported, with some suggesting increased availability due to reduced phytate content and others suggesting impaired bioavailability perhaps due to inhibition by calcium (Bressani 1997). Limewater-treated corn remains deficient in other B-complex vitamins and essential amino acids including lysine and tryptophan (Bressani 1990). Commercial nixtamalisation with production of nixtamalised corn flour is performed throughout the Americas, but is less commonly undertaken in Europe, Africa and India, where the prevention of pellagra is dependent on consumption of niacin from other food sources.
Precooking is another procedure applied to de-hulled and degermed corn products after milling (a separation of the kernels components hull/bran, germ and low-fat endosperm in sizes ranging from grits, to meal to flour) and is common in some South American countries. Precooked maize flour is the product obtained from white or yellow corn, composed mainly of endosperm. The maize kernel is, with this process, sequentially dehulled, degermed, precooked, dried, flaked and reduced into a fine powder (Covenin 1996; Vielma 1998)
The definitions of corn flour and cornmeal are widely varied. The United States Food and Drug Administration (FDA) defines corn flour and meal as products obtained from the grinding of dried corn grains (yellow or white). These regulations define the size (as determined by the proportion of product that can pass through test sieves of various fineness), the moisture content of each product, and the amount of fibre and fat that is retained in the product. Corn flour (white or yellow) must be able to pass through the narrowest sieves, while corn meal must be able to pass through wider sieves, but not through sieves that would permit passage of corn grits; corn meal must contain at least 1.2% fibre (FDA 2011). Maize meal and flour may also be included as part of a composite flour, in combination with other products. Composite flours are mixtures of flours from tubers rich in starch (such as yam, cassava, sweet potato), protein-rich flours (e.g. soy, peanut) and cereals (maize, rice and wheat), designed to enhance the nutritional properties of foods made from the flour (Seibel 2006). For corn meal flours, there are three sorts of maize meal at different extraction rates: dehulled, degermed maize meal 65% to 70% extraction; sifted maize meal (usually in Africa) 80% to 85% extraction and whole maize meal 90% to 95% extraction (Eustace 1982; Milazzo 1986). In some countries the yield from degerminated corn products produced for human consumption includes products such as flour, cones, meal, snack grits, brewer's grits, #8 and #4 grits. These products have a lower yield range of 65% to 70%. As edible corn yield increases there is a corresponding increase in fat and fibre content (i.e. nutritional and potentially particle size). It makes sense to determine not only the amount of corn consumed per capita but also its form or type consumed as this will impact its nutritional quality. This in turn may influence fortification decisions appropriate to each region.
Fortification of maize flour and other sub-products produced from maize has been implemented in several settings around the world. Although there is less experience with fortification of maize flour than for wheat flour, mass fortification of maize flour with iron has been a reality for many years in several countries in the Americas (Dary 2002a; Garcia-Casal 2002) and Africa (voluntary fortification has been already introduced in Ghana, Kenya, Malawi and Mauritania, with mandatory fortification in South Africa (FFI 2012).
How the intervention might work
Iron fortification aims to improve the nutritional status of populations at risk of iron deficiency and anaemia by increasing dietary content and thus iron intake. Several fortificants are available for fortification of maize flour. Selection of fortificant is a trade-off between bioavailability, maximal concentration that can be added without affecting sensory aspects, cost and availability. The bioavailability, stability and sensory effects of different iron fortificants have been described (Dary 2002a). Ferrous sulphate has high bioavailability; has been used to fortify bread, pasta and infant formula; and although it is effective when added to flour, it may adversely affect flavours, especially following storage. Ferrous fumarate is also well absorbed, has a bioavailability similar to ferrous sulphate and overcomes many of the problems associated with adverse effects on taste. Electrolytic iron compounds added to cereals have poor bioavailability, especially related to high particle size, and also produce adverse effects on taste at the higher concentrations required to achieve optimal dietary iron intake (Cook 1983; Hallberg 1982). Other iron compounds such as sodium iron EDTA (NaFeEDTA), ferrous bis-glycinate and tris-glycinate (Bovell-Benjamin 2000; Hertptramp 2004; Mendoza 2001), which protect iron from dietary inhibitors of absorption (i.e. phytates), have superior bioavailability and do not impact product taste compared to other compounds, but may be limited by their higher costs; colour and rancidity has been associated with the latter compound following storage of wheat flour. Finally, encapsulated ferrous sulphate and ferrous fumarate, in which iron is encapsulated in an oil layer, has minimal reactivity with the food matrix but offers high bioavailability; this approach is limited by the relatively high cost of the fortificant (Dary 2002b; Hurrell 2002).
The amount and final concentration of additional iron added to the food vehicle depends on the daily intake of that food by the population as well as the characteristics of the fortificant as described. Based on the expected intake of the vehicle and the bioavailability of the iron, the concentration of fortificant added can then be adjusted to achieve an appropriate daily absorption of iron (˜1 to 2 mg per day) (WHO 2009). Formal testing of the absorption of iron added to the vehicle can also be performed using isotopic testing. Iron absorption may be further improved with addition of an enhancer such as ascorbic acid (Troesch 2011), and by reducing the level of phytic acid (inhibitor) using one of a variety of techniques (Hurrell 2002).
Thus, approaches to iron fortification of staple products (including maize flour and its integration as a component in a food product) vary, with different specific vehicles employed, heterogenous types and concentrations of fortificants added to the vehicle, and different complementary strategies applied to additionally enhance iron absorption.
Risks of flour fortification with iron
Several theoretical potential adverse effects of flour fortification have been described. Secondary iron overload, associated with long-term excessive iron absorption, is usually associated with hereditary disorders such as thalassaemia, pyruvate kinase deficiency, dyserythropoietic anaemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis, sideroblastic anaemia or with acquired conditions such as sideroblastic and other dyserythropoietic anaemias, or any anaemia except for that due to blood loss, in which multiple transfusions are required (Beutler 2003). Although men and post-menopausal women do not have a mechanism for losing iron and therefore may be at greater risk of accumulating iron long-term, consumption of iron-fortified foods by them does not appear to increase their risk of iron overload (Ballot 1989; Brittenham 2004; Pouraram 2012). Hereditary haemochromatosis is characterised by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues that typically begins to be expressed in the third to fifth decades of life, but may also occur in children. Hereditary haemochromatosis due to mutations of the HFE gene is chiefly found in populations of European descent but is less common is among other ethnicities (Adams 2005). It has been speculated that fortification of staple foods with iron would restore (or partially restore) iron intake to 'recommended' levels, and thus pose a risk in predisposed individuals of iron overload that remains lower than the developed world (Brittenham 2004).
This proposed review will attempt to evaluate, based on existing research, the effectiveness of maize flour fortification with iron as a public health intervention. The World Health Organization/Centers for Disease Control and Prevention (WHO/CDC) logic model for micronutrient interventions in public health depicts the programme theory and plausible relationships between inputs and expected improvement in Millennium Development Goals (MDGs) and can be adapted to different contexts (WHO/CDC 2011). The effectiveness of maize flour fortification with iron in public health depends on several factors related to policies and legislation regulations; production and supply of the fortified rice; the development of delivery systems for the fortified maize flour; the development and implementation of external and internal food quality control systems; and the development and implementation of strategies for information, education and communication for behaviour change among consumers. A generic logic model for micronutrient interventions that depicts these processes and outcomes is presented in Figure 1.
Why it is important to do this review
Iron deficiency and anaemia remain important public health problems worldwide. One of the major limitations for development of iron fortification guidelines is a lack of a strong evidence base for this intervention (Dary 2002b). Although maize fortification with iron alone, or in combination with other micronutrients, has been implemented in many countries, to date there has been no systematic assessment of the safety and effectiveness of this intervention to inform policy making. This proposed systematic review will complement the findings of other Cochrane Reviews investigating the effects and safety of fortification of wheat flour, rice fortification (Ashong 2012), salt iodisation (Wu 2002) and fortification of condiments and seasonings (Self 2012) for preventing iron deficiency anaemia and improving health.