3
Prevention of Iron Deficiency

Fernando E. Viteri, M.D., Sc.D.

University of California at Berkeley

Iron is an essential nutrient. Iron deficiency in humans has wide-ranging negative consequences, including impaired physical growth, compromised cognitive development, short attention span and impaired learning capacity, reduced muscle function and energy utilization, decreased physical activity and lower work productivity, lowered immunity, increased infectious disease risk, impaired fat absorption (most probably including fat-soluble vitamin A), increased lead absorption with all its negative consequences, and poorer pregnancy outcomes (Alaudin, 1986; Chandra, 1990; Dallman, 1974, 1986; Enwonwu, 1989; Husaini et al., 1990; Judisch et al., 1986; Li et al., 1994; Lozoff et al., 1992; Pollitt et al., 1982; Scrimshaw and SanGiovanni, 1997; Viteri and Torun, 1974; Walter, 1992). Iron deficiency also impairs the transformation of the thyroid hormones, T4 to T3, in peripheral tissues, the production and metabolism of epinephrine and norepinephrine, and leads to difficulty in maintaining body temperatures upon exposure to cold (Beard, 1990).

Functional consequences of severe iron-deficiency anemia during pregnancy include increased rates of premature delivery, perinatal complications in mother and newborn, low birthweight, low iron stores, and indications of iron deficiency and anemia in the newborn or in later infancy. Of great concern is the finding that some of the negative effects on cognitive and affective function of iron deficiency in infancy may persist, even after ion deficiency and anemia have been corrected (Lozoff et al., 1992). The majority of studies also report adverse consequences from mild to moderate iron deficiency and anemia.

The standard WHO criteria for anemia are shown in Table 3-1 (NSS1). These criteria indicate that the iron deficiency is of sufficient severity to interfere with hemoglobin formation, but iron has many other functions that are



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--> 3 Prevention of Iron Deficiency Fernando E. Viteri, M.D., Sc.D. University of California at Berkeley Iron is an essential nutrient. Iron deficiency in humans has wide-ranging negative consequences, including impaired physical growth, compromised cognitive development, short attention span and impaired learning capacity, reduced muscle function and energy utilization, decreased physical activity and lower work productivity, lowered immunity, increased infectious disease risk, impaired fat absorption (most probably including fat-soluble vitamin A), increased lead absorption with all its negative consequences, and poorer pregnancy outcomes (Alaudin, 1986; Chandra, 1990; Dallman, 1974, 1986; Enwonwu, 1989; Husaini et al., 1990; Judisch et al., 1986; Li et al., 1994; Lozoff et al., 1992; Pollitt et al., 1982; Scrimshaw and SanGiovanni, 1997; Viteri and Torun, 1974; Walter, 1992). Iron deficiency also impairs the transformation of the thyroid hormones, T4 to T3, in peripheral tissues, the production and metabolism of epinephrine and norepinephrine, and leads to difficulty in maintaining body temperatures upon exposure to cold (Beard, 1990). Functional consequences of severe iron-deficiency anemia during pregnancy include increased rates of premature delivery, perinatal complications in mother and newborn, low birthweight, low iron stores, and indications of iron deficiency and anemia in the newborn or in later infancy. Of great concern is the finding that some of the negative effects on cognitive and affective function of iron deficiency in infancy may persist, even after ion deficiency and anemia have been corrected (Lozoff et al., 1992). The majority of studies also report adverse consequences from mild to moderate iron deficiency and anemia. The standard WHO criteria for anemia are shown in Table 3-1 (NSS1). These criteria indicate that the iron deficiency is of sufficient severity to interfere with hemoglobin formation, but iron has many other functions that are

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--> more sensitive to iron depletion. Approximately 73 percent of the body's iron is normally incorporated into hemoglobin and 12 percent in the storage complexes ferritin and hemosiderin. A very important 15 percent, however, is incorporated into a variety of other iron-containing compounds essential to cell function. WHO data indicate global rates for iron deficiency anemia in developing countries of 51 percent for children 0—4 years of age, 46 percent for school-age children, 42 percent for women, and 26 percent for men (NSS1) (see Table 3-1 for the WHO diagnostic criteria for iron-deficiency anemia). Even in the United States, the NHANES II survey found an overall 7 percent prevalence of actual anemia in women 15–44 years of age, but with the highest burden in minority and poverty groups (WHO/UNICEF/UNU, in press). Diagnosis Of Iron Deficiency And Anemia In the absence of pathological iron losses, iron requirements are greatest during periods of growth (e.g., childhood); pregnancy; and, in women of reproductive age, because of menstruation. Documented associations between iron deficiency and ferropenic anemia include smaller babies, higher rates of stillbirth and perinatal mortality, more premature deliveries, and newborns with lower iron stores. An infant's risk of developing iron deficiency begins in utero, because premature delivery deprives the baby of the accumulation of iron near the end of pregnancy and smaller babies generally have less body iron (Widowson and Spray, 1951; Rosso, 1990). Unfortunately, the iron in breast milk cannot prevent the exhaustion of iron reserves in the first 4–6 months brought about by rapid growth. Poor weaning practices and inadequate feeding during childhood contribute further to the persistence or development of iron deficiency. When growth rates diminish, risk of iron deficiency is reduced unless there is abnormal blood loss to parasitic infection; menstruating women, however, continue to be at risk. In this group, about 20 percent have skewed menstrual blood (iron) losses in the upper ranges of the normal distribution that cannot be covered by their usual dietary intake, and over 50 percent have inadequate or depleted prepregnancy iron reserves (Cook et al., 1986; Custer et al., 1995; Franzetti et al., 1984; Hallberg and Rossander-Hulten, 1991). Because of the high iron requirements of pregnancy, iron deficiency is the rule, particularly in teenage gestations and in women with frequent pregnancies. The stages in the development of iron deficiency are the depletion of iron stores, as indicated by low plasma ferritin; interference with biochemical processes, indicated by low transferrin saturation and elevated free erythrocyte protoporphyrin and serum transferrin receptors; and, finally, anemia, as indicated by low hemoglobin. It should be noted that although transferrin receptors appear promising as an indicator, standard cutoffs and interpretation of values from different commercial assays are yet to be developed. Up to an anemia prevalence

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--> of 50 percent, the proportion of individuals with biochemical iron deficiency is about double those with actual anemia (WHO/UNICEF/UNU, in press). Above 50 percent, it can be assumed that nearly all of the population described is iron deficient. The significance of this finding is that these subclinical degrees of iron deficiency can interfere with cognitive, immune, and muscle function. Pregnancy presents challenges in the diagnosis of both anemia and iron deficiency because of the normal and variable hemodilution, which lowers hemoglobin concentration to varying degrees, and the hormonal changes and the frequency of infection, both of which modify the indicators (Cook et al., 1994; Hytten, 1985; Puolakka et al., 1980; Romslo et al., 1983). Serum transferrin receptor levels appear especially useful in diagnosing iron deficiency in pregnancy (Carriaga et al., 1991). The lack of appropriate hemodilution in chronic undernutrition may mask the true level of anemia in the face of iron deficiency and decreased circulating hemoglobin mass (Rosso, 1990). Prepregnancy iron nutrition and hemoglobin level markedly influence the development of gestational anemia (Kauffer and Casanueva, 1990). There is thus a need to consider interventions that will improve prepregnancy iron reserves and provide extra amounts of iron, in addition to that in the diet, during gestation (Sloan et al., 1992; Viteri, 1994a,b, in press a,b). After initial diagnosis of the prevalence of anemia and, ideally, the Hb distribution within a population, with emphasis on at-risk groups, the diagnosis of iron deficiency can be refined and verified by further biochemical tests. The Hb response to iron administration is best measured as part of ongoing surveillance of an adequate sample of the population. These additional steps could be implemented simultaneously. The surveillance system should be based on serial hemoglobin determinations in samples of population groups at risk (ideally also including serum ferritin) and periodic assessments at sentinel epidemiological sites. TABLE 3-1 Cutoff Values for the Diagnosis of Anemia (WHO)   Hemoglobin <     Age/Gender Group g/l mmol/l Hematocrit < l/l Children       6 months–5 years 110 6.83 0.33 5–11 years 115 7.13 0.34 12–14 years 120 7.45 0.36 Nonpregnant women (>15 years) 120 7.45 0.36 Pregnant womena 110 6.83 0.33 Men (≥ 15 years) 130 8.07 0.39 a The CDC proposes a cutoff point of 105 g/l during the second trimester. Severe anemia in pregnancy: Hb levels < 70 g/l; very severe anemia: < 40 g/l.

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--> The general diagnosis of anemia should lead to a causal analysis. The necessary interventions and community participation toward the common aim of controlling iron deficiency and anemia must be the objective (WHO, 1991). The higher the anemia prevalence rates in a population, the greater the proportion arising from iron deficiency. There are also many different kinds of hemoglobinopathies, however; the most frequent is Hb-C, Hb-S and the thalassemias (alpha and beta; major, intermedia and minor, based on the degree of anemia they produce). The heterozygous A-S Hb affects up to 30 percent of some African populations (8 percent in African Americans). This genotype has essentially no hematological consequences, in contrast with the Hb S-S, which produces severe hemolytic and thrombotic crises (1 in 400 African Americans) and requires specialized medical attention. Hb-C produces mild anemia and affects about 4 percent of African Americans. The S-C Hb condition is associated with more severe anemia and is easily diagnosed. It affects about 1 in 850 African Americans. These hemoglobinopathies may explain failures of response to nutritional interventions in individuals, but they should not be a cause for modifying iron fortification or supplementation programs for populations at risk. The thalassemias are a different problem because they produce anemia brought about by a failure in Hb production and chronic hemolysis. Children affected by thalassemia major generally have Hb levels below 60 g/l; those with thalassemia intermedia have Hb levels between 60 and 95 g/l, and those with thalassemia minor have Hb levels between 95 and 135 g/l. The more severe the anemia, the greater the stimulus to absorb iron and the greater the tendency to become iron-loaded, particularly because the only therapy customarily available for thalassemia anemia is repeated transfusions (justified only in thalassemia major or in special cases of thalassemia intermedia). The thalassemias are distributed primarily in populations of Mediterranean origin and of tropical or subtropical African, Middle Eastern, and Asian origin, generally areas where malaria has been endemic. In populations seriously affected by the thalassemias the concomitant iron deficiency of dietary and pathological origin (e.g., hookworm infection), as well as the risk of iron overload, must be evaluated and the programs adjusted accordingly (Charoenlarp et al., 1988). Box 3-1 presents the suggested minimum information needed to make a tentative diagnosis of iron deficiency, estimate its public health significance, and plan the most appropriate interventions. Causes Of Iron Deficiency Iron nutritional status depends on long-term iron balance. It is favored by the ingestion of sufficient iron in food (native, or added through fortification) in a bioavailable form or through iron supplementation. Regulation of iron absorption is crucial in favoring absorption in iron deficiency and in avoiding iron excess.

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--> Balance is adversely affected by the amount of iron lost through gut mucosal turnover and skin desquamation; intestinal excretion; menstruation; the pregnancy-delivery-lactation cycle; and pathologic blood losses, mainly from excessive menstrual flow, hookworm and schistosomiasis, gastrointestinal bleeding from ulcerations, hemorrhoids, diarrhea, and other occult blood losses (Bothwell et al., 1979). BOX 3-1 Anemia and Iron Deficiency as a Problem of Public Health Importance: Minimal Indicators of Iron Deficiency (in order of decreasing reliability) Anemia prevalence in the population: Iron deficiency is considered to be about 2 to 2.5 times the rate of anemia. This estimate applies when malaria is not endemic in the region and there are no reasons to suspect widespread hemoglobinopathies. Category of public health significance Prevalence of anemia in any at-risk group (%) High >20 Medium 12.0–19.9 Low 5.0–11.9 Records of anemia in health centers and clinics, as well as among hospital inpatient and outpatient pregnant women, women of childbearing age, and children between 6 and 36 months of age. If a categorization of severity is needed, the above-indicated prevalences would hold for these groups. For preschool-age children, schoolchildren, adolescents, and adult men, prevalences of 12 percent would be considered of ''high public health significance." Any prevalence above 6 percent should be considered of public health significance in these groups. Informed opinion of physicians or health personnel on the frequency of anemia (by measurement of Hb or Hct) or the presence of pale individuals (severe anemia), ideally individuals that have proved responsive to iron treatment. A hemoglobin determination in 100-200 pregnant women at any time during the third trimester. Enroll clinics, hospitals, and traditional birth attendants. Use CDC cutoff values corrected for altitude. Rapid survey of clinical paleness in vulnerable groups. Valid only if found in >5 percent of such groups. Negative surveys cannot rule out anemia as a problem. Proxies: Hookworm infection is endemic. Vegetarian diets are followed by choice or because of food availability. Multiple pregnancies and teenage pregnancies. Data from neighboring areas or from areas of similar human and geoecological characteristics in the country or region.

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--> In a healthy steady state, iron losses are fairly constant and iron balance depends mainly on the regulation of iron absorption: upward in iron deficiency and downward in iron sufficiency. The greater capacity to absorb iron in iron-deficiency situations is the most important short-term factor in the body's effort to maintain iron homeostasis. The amount of bioavailable iron in food is very important in the long term (Cook, 1990; Hulten et al., 1995). There are no effective mechanisms for excreting the excess iron. Parenterally administered iron, including repeated blood transfusions, chronically excessive medicinal iron intake, or elevated iron absorption caused by impaired downward regulation of iron absorption (people homozygous for the hemochromatosis gene, some types of thalassemia, and hemosiderosis trait in some Black populations) lead to excess iron accumulation. Food iron is present in most diets in a proportion of 6 mg/1,000 calories and is composed of two different pools: heme and nonheme iron (Hallberg and Bjorn-Rassmussen, 1972; Layrisse et al., 1969). The heme iron pool includes all food compounds that have iron as part of heme molecules. Dietary heme iron is provided by animal blood, flesh, and viscera; the most important is hemoglobin in blood and myoglobin in muscle. In general, heme iron absorption is not modified by most inhibitors and enhancers of iron absorption. Exceptions are dietary protein, which increases heme iron absorption, and food calcium and manganese, which inhibit it. It must be clearly understood that these interactions occur while digestion and absorption of iron are taking place (within 2 hours of meal ingestion), and that only partial inhibition is produced by dairy products and other calcium-rich foods consumed in a varied meal, reducing iron absorption by 30 percent, at most (Gleerup et al., 1995; Hallberg et al., 1993). At the same time, heme iron absorption is also regulated upward and downward, but to a lesser extent than absorption of nonheme iron. In normal individuals, heme iron absorption fluctuates between 15 and 30 percent, but can increase up to about 50 percent in iron-deficient anemic subjects and can decrease to about 5–8 percent when the amount of heme iron is around 50 mg (Cook, 1990; Layrisse et al., 1973; Viteri et al., 1978). The nonheme iron pool is made up of all other sources of iron. Nonheme iron is often bound in seeds, to phytic acid, and in other vegetable tissues to phenolic compounds. Nonheme iron is also present in heme-iron-containing and other animal tissues and in animal products such as milk and eggs. In contrast with heme iron, nonheme iron absorption is affected by many dietary components. Heme-iron-containing proteins and ascorbic, malic, tartaric, and succinic acids and some fermentation products are enhancers of nonheme iron uptake. Meat and alcohol also enhance nonheme iron absorption by promoting gastric acid production. Inhibitors include phytic acid and other polyphosphates, fibers, calcium, manganese, polyphenols such as tannins, and other compounds present in foods and beverages, especially tea, coffee, chocolate, and herbal infusions that produce polymers and insoluble, unabsorbable iron chelates.

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--> Nonheme iron constitutes over 90–95 percent of dietary iron, particularly in the developing world. The absorption of nonheme iron can vary from 1 to 30 percent or more, depending on the presence of enhancers or inhibitors of absorption, and especially on the iron status of the individual (Bothwell et al., 1979; Cook, 1990; Layrisse et al., 1969). The latter is the most important factor in controlling iron absorption. In general, with meals of intermediate and high bioavailability, iron absorption can be as high as 5 mg of iron daily in iron deficiency. This is reduced to about 2–3 mg/day when diets are of poor bioavailability. As iron reserves increase, iron absorption decreases. When serum ferritin reaches 50–60 µg/l, equivalent to about 500 mg of iron reserves, iron absorption from daily meals of intermediate and high iron bioavailability allows the absorption of only about 1 mg of food iron/day, which is equivalent to the replacement of average obligatory losses, not including menstruation (Hulten et al., 1995). There is no published information of this kind for daily meals with poor bioavailability, but extrapolations suggest that this amount of iron would be absorbed with iron reserves of only about 140 mg. Cook (1990) has also summarized the importance of iron nutritional status on heme and nonheme iron absorption in a single meal containing both kinds of iron (see Table 3-2). The percentage of heme and nonheme iron absorbed increased by a multiple of 2.4 to 8.4 among iron-deficient, compared with normal, men. If the meal contained only nonheme iron, the percentage of absorption would be reduced to one-half that presented in Table 3-2. Several important conclusions can be derived from the above: Dietary composition appears to be particularly important when iron reserves are low or in the presence of iron deficiency. Downward regulation of iron absorption is very effective, even when the diet is rich in heme iron and of a composition that favors iron absorption. Therefore, the development of iron-overload conditions from dietary iron intake in normal individuals is highly improbable. Poor-quality diets would not satisfy the iron needs of a large percentage of menstruating women and would not allow the accumulation of iron reserves beyond about 150 mg, which is below the ideal for women entering pregnancy. TABLE 3-2 Percentage of Iron Absorption Source of Iron Normal Men Normal Women Iron-Deficient Subjects Heme 20 31 47 Nonheme 2.5 7.5 21   SOURCE: Cook, 1990.

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--> For simplicity, diets have been classified as of high, intermediate, and low bioavailability, depending on the proportion of heme iron and the presence of inhibitors and enhancers of nonheme iron absorption. Their respective bioavailabilities have been averaged at 15, 10, and 5 percent, respectively. A woman of childbearing age with requirements of absorbed iron at the median of 1.25 mg/day, and consuming a diet of poor bioavailability, would need to ingest 25 mg of iron in order to achieve adequate intake. This would mean that she would have to ingest 4,170 calories daily of an average diet containing 6 mg of iron/1,000 cal compared with an average energy intake of 2,100 cal/day by this population. If the diet is of intermediate (10 percent) bioavailability, only 50 percent of women would be able to maintain a normal iron status and about 20 percent would develop anemia. Only a very small proportion would be able to build adequate iron reserves for pregnancy. The majority of these women would rapidly develop iron deficiency and gestational anemia during pregnancy. Most of the iron compounds used for the fortification of foods become part of the nonheme dietary iron pool, and their absorption is similar to that of the other components of the pool and subject to inhibitors and enhancers (Bothwell et al., 1979). Exceptions to this rule are soluble iron chelates, which are 2 to 5 times more efficiently absorbed than the dietary nonheme iron pool in the presence of inhibitors, and purified bovine Hb, which becomes part of the heme-iron pool when used as a fortificant. The bioavailability of soil iron, which contaminates many staples and vegetables, is largely unknown, although it is generally considered low. The absorption of iron compounds administered as 30–120 mg boluses for supplementation or therapeutic purposes presents a different picture. When given without food, absorption declines logarithmically with logarithmic dose increments, but it remains at about 6 to 8 percent, even after apparent repletion of iron stores, possibly because of mass action (Bothwell et al., 1979; Grebe et al., 1975; Hallberg and Sölvell, 1967; Viteri et al., 1978). Svanberg (1975), however, found only 2 percent absorption of supplemental iron in late pregnancy. This steady absorption from large doses of iron explains why, in mg of iron absorbed, higher iron intakes allow higher, but less efficient, iron absorption. Animal studies have demonstrated that iron absorption is particularly inefficient when supplemental or therapeutic iron is administered at short intervals (several times a day, daily, or even every 2 or 3 days). This "mucosal block" to iron absorption caused by repeated iron administration has been well documented in several animal species (Fairweather-Tait et al., 1985; Hahn et al., 1943; Stewart et al., 1950; Viteri et al., 1995a; Wright and Southon, 1990). In humans, the absorption data are not as clear, but they suggest that for less than 1 week of daily iron supplementation, or even with 2 to 4 daily doses, the blockage is minor, if it operates at all, among nonanemic and normal or mildly iron-deficient subjects (Cook and Reddy, 1995; Höglund, 1969; Norrby, 1974;

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--> O'Neil-Cutting and Crosby, 1987; Reizenstein et al., 1975;. Rush et al., 1966; Smith and Pannacciulli, 1958; Solomons, 1995). Iron blockage in the human under different iron nutritional conditions has not been fully explored. In a detailed study by Hallberg (1970), the absorption efficiency of administering 37 or 74 mg up to 4 times a day was highly variable. On average, iron absorption was around 8–9 percent. Finally, in considering iron regulation and metabolism with the aim of preventing iron deficiency, interactions with other nutrients are important in their effect on the absorption and utilization of iron. Copper is involved in oxidoreduction of iron in the process of absorption, transport, storage, and mobilization; folate and vitamin B12 are involved in nucleic acid synthesis of all cells and clearly in erythropoiesis, thus modifying iron utilization; vitamins B6 and B2 are specifically required in the process of heme synthesis; and amino acids are required for protein synthesis in general, and for hemoglobin synthesis in particular. Vitamin A is involved in mobilization of iron reserves, in Hb synthesis, and appears to favor iron absorption in the presence of inhibitors (Hodges, et al., 1978; Layrisse et al., 1997; Mejia et al., 1979). Low dietary iron intakes—particularly where much of the iron is in non-heme form—combined with the increased iron needs of growth or pregnancy, and even the small chronic iron losses of mildly excessive menstrual flow, increase the risk of developing iron deficiency and anemia. These risks are often further exacerbated in developing countries by parasitic infections. Endemic malaria increases the prevalence and aggravates the severity of anemia, particularly among young children and pregnant women, and produces iron sequestration and some iron losses (Brabin, 1992). As with other hemolytic processes, folate and vitamin B12 requirements are also elevated by malaria (Fleming, 1990). Hookworm disease is a serious cause of intestinal blood loss (Layrisse and Roche, 1964; Roche and Layrisse, 1966). Infection with Schistosomia haematobium causes blood loss in the urine and can result in intestinal bleeding (Scrimshaw et al., 1968). Iron Excess Objections to the strategies for the control of iron deficiency have sometimes been raised by hematologists in developed countries. They cite the danger of possibly accelerating or inducing iron excess and overload conditions in some clinical conditions, as well as claims for its involvement in a variety of cancers and heart disease in their countries (Halliwell et al., 1992; Herbert, 1992; Lauffer, 1992; Stevens et al., 1994). These issues cannot be ignored in this paper. Nevertheless, in the face of the widespread iron deficiency and ferropenic anemia in the great majority of populations in the developing world and in groups at risk for iron deficiency everywhere, this should not be an issue (ACC/SCN, 1997; Gillespie, 1996) as long as monitoring of interventions is in place to avoid

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--> excessive administration of iron in therapeutic and chronic supplementation programs (a minimal requirement in any nutrition intervention program). Food iron (including that included in iron-fortified food) poses no threat to these populations. The recessive genetic disorder, hemochromatosis, is particularly prevalent in white populations of European descent, especially those of Celtic origin. Regions with particular haplotypes have been identified in central Sweden and in northeast Italy. In the U.S. Caucasian population, the homozygous state is never less than 0.1 percent and may be as much as 0.5 percent in some population groups (Lynch, 1995). Hemochromatosis exists at a possible rate of about 1 percent among African-Americans, but its etiology needs further clarification (Wurapa et al., 1996). A recent preliminary report by the Centers for Disease Control and Prevention (CDC) indicates that a prevalence among Hispanics in San Diego, California, is similar to that seen among non-Hispanic American whites (CDC, 1996). The consequences of iron excess are mainly liver cirrhosis and increased liver cancer. Heart failure from myocardial dysfunction and diabetes brought about by pancreatic disease are suggested rare consequences, but this remains highly controversial (Lynch, 1995). The adoption of general iron fortification of foods in the developing world, where iron deficiency is highly prevalent, has been slowed further by fears of accelerating iron overload conditions in genetically prone individuals, even though this is a relatively rare clinical problem. It is not a reason to withhold the benefits of iron fortification as a public health measure from the overwhelming majority of the population (Ballott et al., 1989a). This fear has been based on concern in industrial countries, where iron deficiency is less of a problem. Prevention Of Iron Deficiency in At-Risk Groups Control measures for iron deficiency and anemia should not be considered in isolation, but rather as part of integrated approaches to combat micronutrient malnutrition and within the general objectives of alleviating critical poverty; achieving sustainable food security; and improving the economic, health, overall nutritional, and educational status of the population. This obvious statement is emphasized to stress that no single approach to dealing with iron deficiency and anemia will work for all populations and in all settings. The approach taken in this paper is to evaluate successful interventions for iron from a lifestyle perspective. Table 3-3 presents a summary of successful interventions that, based on experience, can be implemented in the short, medium or long term for different categories of target individuals. The implementation of medium- and long-term strategies can be accelerated under favorable circumstances. Once established, process and impact evaluations should be performed periodically within a defined surveillance system to determine if there is a need for continuation, modification, or even suspension of a given strategy.

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--> Infancy The first preventive measure against infant iron deficiency is assuring adequate body iron at birth by avoiding gestational iron deficiency and other conditions leading to low birthweight and premature delivery (Colomer et al., 1990; De Benaze et al., 1989; Puolakka et al., 1980; Scholl and Hediger, 1994; Scholl et al., 1992). The importance of prepregnancy iron nutrition in preventing gestational iron deficiency has not been sufficiently recognized. Current intrauterine devices (IUD) increase menstrual flow in many women (INACG, 1981), but IUDs can be effectively used in combination with some form of iron supplementation. Birth spacing and delaying pregnancy beyond the teen years allow the deposition or recovery of iron reserves after the pubertal growth spurt or a previous pregnancy (Beard, 1994; Bothwell et al., 1979; INACG, 1981). A second critical measure for improving the iron stores of the newborn is delayed ligation of the umbilical cord. Ligation of the umbilical cord after it stops pulsating (about 30–60 seconds after delivery) increases the infant's blood volume about 60 ml, providing approximately 34 mg of iron, which equates to between 25 and 30 percent of the newborn's total circulating iron (Burman, 1969; Lanzkowsky, 1976). These additional 34 mg of iron are equivalent to what a healthy, exclusively breast-fed baby would absorb in 5 months. In theory, this delayed ligation will determine whether a 6-month infant is iron deficient or not. In the first 4–6 months, breast-feeding is an important contribution to the maintenance of better iron nutrition in infants. Research has clearly shown that exclusively breast-fed infants have greater iron stores than infants who are formula-fed (Saarinen et al., 1977). The amount of iron in human milk is very small (< 0.6 mg/l), and its bioavailability, once thought to be around 50 percent (McMillan et al., 1976; Saarinen et al., 1977), has recently been shown to average 11 percent (Davidsson et al., 1994 a,b). Even though exclusively breast-fed infants generally enter into iron deficit after about 6 months, their non-breast-fed counterparts are usually iron deficient sooner. The universal promotion of exclusive breast-feeding for 4 to 6 months is thus a key element in maintaining adequate iron nutriture. Infants beyond about 6 months of age need an additional source of iron beyond that provided by breast milk. A large body of evidence documents that iron deficiency and anemia in older infants and young children can be prevented by appropriate complementary feeding. When breast-feeding is not possible, iron-fortified milk preparations are needed (Walter et al., 1990, 1993a). Another alternative after about 6 months of age is preventive iron supplementation. In this age group, once iron deficiency is present, anemia develops quickly and therapy with oral iron is needed to rapidly improve the infant's hematological status and avoid possible permanent developmental deficits. The

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