CDC, and it met with representatives of federal agencies to determine how such guidelines might affect these agencies' activities.
This committee report summarizes information related to public health measures for the prevention, detection, and management of iron deficiency anemia, presents recommended guidelines related to this area as they apply in primary health care and public health clinic settings, and makes recommendations for research. The report identifies and addresses aspects that differ between the two target populations (infants and children, and women of childbearing age), as well as those common to both groups, and briefly considers family-oriented approaches. This report is intended to provide a frame of reference for health professionals and to assist the CDC with preparing national guidelines for the prevention and control of iron deficiency anemia. A fuller exposition of the information that informed the committee's deliberations is found in the appendixes to this report and in the references.
In approaching its task, the committee considered several issues: the importance of iron deficiency anemia as a public health problem on the basis of prevalence estimates and health effects, the availabilities and efficacies of different public health approaches for prevention and detection, and the positive and negative implications of alternative approaches for the population at risk and the general population.
Two approaches can be taken to address public health problems: a population-based approach and an individual-based approach. When applied to reducing the prevalence of iron deficiency anemia, the population-based approach seeks to lower the population's risk by enriching and fortifying the food supply and by altering individual food choices through education and information programs. The individual-based approach seeks to identify those at the highest risk and to treat them by providing both supplements and education to increase the iron contents of their diets. The two approaches are complementary means of achieving lower rates of iron deficiency anemia.
After considering the alternative public health approaches and their consequences, the committee concluded that one major assumption had to be made before guidelines could be formulated: Iron enrichment and fortification of the U.S. food supply shall remain at current levels. In view of concerns about the adverse health effects attributable to the consumption of large amounts of iron, the committee believes that increasing the amount of fortification or the range of fortified products for the general population is not an appropriate public health strategy for preventing iron deficiency anemia (however, it may prove desirable to consider iron fortification of other foods specifically targeted at certain subgroups [e.g., infants]). Nor does the committee believe that currently available data allow it to recommend that the amount of fortification be lowered at this time. This situation may change as the nutrition and public health
communities better Understand the implication of the results of serum ferritin levels from the third National Health and Nutrition Examination Survey (NHANES III).
These conclusions were made on the basis of two observations. First, the prevalence of iron deficiency anemia among young children has been declining, and the decline is attributed to the use of iron-fortified formula and cereal, appropriate supplementation of breastfed infants, and later introduction of cow's milk to infants' diets than had been typical in the past. Second, preliminary data from the most recent national survey (NHANES III) indicate that average levels of serum ferritin, a marker of iron stores, have increased among adult males. If more detailed analyses confirm this observation, higher levels of iron enrichment and fortification of the general food supply would not be warranted because of the potential harm to those at risk of developing hemochromatosis.
The committee then considered the second available approach—that of screening individuals at risk to identify and treat those affected. This individual-based approach is appropriate because of the availability of tests with acceptable sensitivities and specificities, the prospect of the more widespread availability of new tests that detect iron depletion before the development of symptoms, and the availability of inexpensive iron supplements. The database supporting the beneficial effects of treating iron deficiency anemia in childhood is substantial, but the committee questioned the adequacy of the database demonstrating benefits from routine iron supplementation during pregnancy. This last issue is discussed more fully in the committee's recommendations for research.
Subsequent sections of the report discuss four major issues that the committee considered:
- defining iron deficiency anemia and the effects of different criteria on its estimated prevalence,
- determining the prevalence of iron deficiency anemia and considering its public health importance,
- developing methods for delivering iron to children and women, and
- determining the efficacy and safety of different interventions.
These issues and the committee's conclusions follow.
Anemia is defined as a hemoglobin concentration (or hematocrit) that is below the 95 percent confidence interval (i.e., below the 2.5th percentile) for healthy, well-nourished individuals of the same age, sex, and stage of pregnancy (LSRO, 1984). The cutoff values are from the population surveyed in NHANES II after exclusion of individuals with a high probability of iron deficiency (Table 1).
TABLE 1 Cutoff Values for Iron Deficiency Anemia in Children, Women of Childbearing Age, and Pregnant Womena
Iron deficiency anemia refers to an anemia that is associated with additional laboratory evidence of iron depletion as a result of one or more of the following tests results: low serum ferritin concentration, low transferrin saturation, or an elevation in the erythrocyte protoporphyrin level.
Iron deficiency without anemia represents a relatively mild iron deficiency that is diagnosed on the basis of a combination of biochemical indicators of iron status but in which the hemoglobin concentration remains within the normal range. Although no single indicator of iron status is diagnostic of functional iron deficiency, a low serum ferritin concentration indicates that iron reserves are depleted.
Hematologic Indicators Of Iron Nutrition
Measurement of hemoglobin and hematocrit levels is used to screen for anemia and putative iron deficiency because they are easy and inexpensive to measure and reflect the largest iron compartment in the body. However, individuals with mild degrees of iron deficiency are missed by such screenings because of the overlap in values between normal and iron deficient individuals. Hemoglobin and hematocrit values vary by age, sex, and stage of pregnancy. Hemoglobin values normally are lower in children than in nonpregnant adults. During puberty, the average hemoglobin concentration of males rises above that of females—a gender difference sustained throughout the reproductive years. During pregnancy, hemoglobin values gradually fall to a low point in the second trimester, largely because of a normal expansion in blood volume. From the end of the second trimester to term, the concentration of hemoglobin rises again. The average hemoglobin concentration of healthy blacks is lower than that of other races, by about 0.3 g/dl in young children and 0.8 g/dl in adults, as recorded in the NHANES II database.
Determination of the serum ferritin concentration is the only commonly used laboratory test that allows the evaluation of iron reserves. A serum ferritin concentration of less than 10 mg/liter in infants and children and less than 12 µg/liter in adults by itself indicates depleted iron stores. In combination with low hemoglobin or hematocrit levels, a serum ferritin concentration of less than 15 µg/liter in infants and children or less than 20 µg/liter in adults indicates iron deficiency anemia (LSRO, 1984). The serum ferritin concentration is elevated in the presence of infection and should be measured when the person is free of infectious disease (i.e., for at least 2 weeks).
Erythrocyte protoporphyrin accumulates in red blood cells when insufficient iron is available to form heme, the iron-containing portion of hemoglobin. Erythrocyte protoporphyrin levels are elevated in individuals with iron deficiency anemia or lead poisoning, as well as in those with infections or inflammatory conditions of more than 1 week in duration. In an otherwise healthy individual, anemia accompanied by an elevated protoporphyrin level is most commonly indicative of iron deficiency anemia.
Other laboratory tests used for the diagnosis of iron deficiency anemia include mean corpuscular volume (MCV), serum iron concentration and iron-binding capacity, and transferrin receptor concentration. A low MCV is most commonly associated with iron deficiency anemia or thalassemia trait; a high MCV but low hemoglobin is inconsistent with a diagnosis of iron deficiency and is more likely anemia caused by folate or vitamin B12 deficiency.
The ratio of serum iron to iron-binding capacity (transferrin saturation) is decreased in individuals with iron deficiency. This measure is less frequently used than in the past because the samples used for measurements can be easily contaminated and its reproducibility is relatively poor.
Transferrin receptor concentration is a promising new indicator that should shortly become available for widespread use. The transferrin receptor concentration is elevated in individuals with iron deficiency anemia but not in those with inflammatory disease, a useful feature (Ferguson et al., 1992). For nutritional survey purposes, the combination of transferrin receptor, serum ferritin, and hemoglobin concentration determinations is likely to provide an excellent depiction of iron status (Cook et al., 1993).
Prevalence of Anemia as a Public Health Problem
Current information on the prevalence of iron deficiency anemia in the United States comes from data collected between 1976 and 1980 as part of NHANES II. In NHANES II, the prevalence of iron deficiency anemia (determined by MCV, transferrin saturation, and erythrocyte protoporphyrin) was about 9 percent (those below the 95 percent confidence interval; i.e., below the 2.5th percentile) in children 12 to 24 months of age (LSRO, 1984). For nonpregnant women of childbearing age, the prevalence of iron deficiency anemia found in NHANES II was 5 percent. Throughout the 1980s, the preva-
lence of iron deficiency anemia in infants and preschool-age children declined, on the basis of prevalence data collected under the CDC Pediatric Surveillance System, from 7 to 3 percent (Yip et al., 1987a,b). Preliminary data from NHANES III collected between 1988 and 1991 appear to confirm this trend (preliminary analysis of data on hemoglobin and serum ferritin concentration measures only), with a prevalence at or below 3 percent for both black and white children 1 to 5 years of age; the prevalence among Mexican American infants, but not young children, may be somewhat higher (A.C. Looker, National Center for Health Statistics, personal communication, June 1993).
For women of childbearing age, data do not show a similar drop in the prevalence of iron deficiency anemia. NHANES II and preliminary NHANES III data show that 4 to 10 percent of U.S. women of childbearing age have iron deficiency anemia on the basis of two or three abnormal values for the surveyed indicators of iron status (see above). The estimated prevalence is lower in non-Hispanic white women than in black women and women in one Hispanic sub-group. Women between 15 and 19 years of age have a prevalence of iron deficiency anemia similar to that of women between 20 and 44 years of age. For women between 20 and 44 years of age, a higher prevalence of iron deficiency anemia is associated with poverty, low educational attainment, and high parity (LSRO, 1984).
No national population survey data on iron deficiency anemia are available for pregnant women. However, data on low-income women are available from the CDC Pregnancy Nutrition Surveillance System, and the national WIC evaluation. The 1990 CDC survey reported prevalences of iron deficiency anemia of 10, 14, and 33 percent in the first, second, and third trimesters of pregnancy, respectively, for all pregnant women of all races (Kim et al., 1992). Black women exhibited a significantly higher prevalence of iron deficiency anemia than did women of other races. CDC data show that the prevalence of iron deficiency anemia in the low-income population has remained stable since 1979, a finding that the committee found particularly troubling.
Data from the 1985 National WIC Evaluation were consistent with most past studies—a significant negative relationship of initial hemoglobin with birth-weight (-23.6 g birth-weight per 1 g/dl increase in hemoglobin concentration [p<0.01] and a 0.96 percent increase in the rate of birth-weight under 2,500 g for each increase of 1 g/dl of initial hemoglobin [p<0.05]) (Rush et al., 1988). When these results were reexamined more closely for this report, there was no evidence of adverse relationship between a hemoglobin level under 10 g/dl or over 14 g/dl with adverse prenatal outcomes among whites. Among blacks, high hemoglobin (>14 g/dl) was associated with low-birth-weight in both first and second trimester participants, and low hemoglobin (<10 g/dl) was associated with low-birth-weight in first trimester participants, but numbers were small. For the much larger group of second trimester participants, there was no association of low hemoglobin with low-birth-weight (D. Rush, Tufts University, personal communication, June 1993).
The committee's opinion, based on the findings presented above and the information cited in the references to this report, is that the measures now in place are successfully addressing the problem of iron deficiency anemia among infants and young children. The preliminary finding that the prevalence of iron deficiency anemia is somewhat higher among children in one Hispanic sub-group, if confirmed, suggests a time lag in effectively reaching groups made up of recent immigrant populations. In the case of women, the prevalence of iron deficiency anemia persists at a level of 4 to 10 percent, and better information is needed to know why this is so. There is a need, in general, to have better data on specific population groups to define meaningful cutoff points for iron deficiency anemia in people of different racial and ethnic groups and to target interventions more effectively. These needs are further explained in the section on recommendations for research at the end of the committee's report.
Implications of Research on Excess Iron Intake
A recent article by Salonen and colleagues (1992) has renewed interest in the role of iron in chronic disease. In the study of Salonen and colleagues, the central question was relatively straightforward: Is excess body iron, as indicated by the plasma ferritin concentration, a significant positive risk factor for myocardial infarction? The committee determined that it would be necessary to review the role of iron in relation to chronic disease (cancer, atherosclerosis, and neurodegenerative disorders) postulated as resulting from excess iron through iron-catalyzed, biologically undesirable reactions. The information considered by the committee in pursuit of this question is contained in the paper by committee member John L. Beard, which appears in Appendix C to this report.
The committee determined that data are insufficient for a satisfactory test of the hypothesis of Salonen et al. (1992) in the U.S. population or to link excess iron intake to an increased risk of other chronic diseases. A follow-up analysis of NHANES I data (Sempos et al., under review) found no increased relative risk of myocardial infarction associated with excessive dietary iron intake or high levels of transferrin saturation, hemoglobin, or hematocrit (serum ferritin concentration were not measured) in people of all age, gender, and ethnic groups that were studied. Other analyses (Cooper et al., 1993; Daviglus et al., 1993; Dunn et al., 1993; Rimm et al., 1993; Stampfer et al., 1993) reached essentially the same negative conclusion.
In addition to the potential direct effects of high dietary iron intakes, large doses of supplemental iron may have an effect on the levels of other minerals (i.e., zinc, manganese, and copper) in plasma. Although there is a substantial research base on the interaction between iron and other minerals, it remains uncertain whether recommendations for the use of supplemental iron for the prevention of iron deficiency anemia may have a significant effect on other
minerals consumed in the diet or taken in the form of supplements for other purposes (see Appendix B).
Developing Recommended Screening and Intervention Guidelines
The committee wishes to emphasize that the draft guidelines developed through its deliberations and contained in this report are based on current recommendations of expert groups for preventing and treating iron deficiency anemia among the populations under study (AAP, CON, 1993; IOM, 1990b, 1992b; LSRO, 1989), the collective expertise and experience of the committee's members, and its review of the scientific literature. The committee was not charged with nor had the resources to systematically evaluate the guidelines it produced for the screening, prevention, and treatment of iron deficiency anemia in this report as part of its program of work. Because the CDC plans to use the committee's draft recommendations to develop guidelines for public health clinics and clinicians in private practice nationwide, the committee recommends that the proposed procedure be evaluated, particularly with respect to costs and benefits, before implementation in the public and private sectors.
Such standards for basic requirements for screening have recently been outlined by Rush (1993) for a proposed nationwide screening program for the elderly.
- Any screening procedure must have an acceptable level of sensitivity and specificity relative to some definite diagnostic procedure. Sensitivity (the ability to identify true cases) is important when an undetected case might have dire consequences, such as irreversible damage to the individual. Specificity (the ability of the screening procedure to classify correctly those without the condition) is important to avoid labeling someone with an incorrect presumptive diagnosis (false positive). Such false-positive diagnoses might both overburden the health care system and cause unnecessary anxiety, worry, expense, and bother for individuals who are not at risk.
- The screening procedure for a presymptomatic diagnosis (as opposed to case finding for symptomatic disease) must give an adequate advantage in time (the lead time) over waiting for the individual to appear for care because of symptoms.
- There must be a proven therapy for the disorder, and earlier treatment (the lead time) must confer benefits over treatment at the time symptoms might otherwise have led to presentation for care.
- Finally, individual screening and therapy must offer benefits—both for the public health and the nation's economy—over other possible strategies such as universal or community prevention programs.
The committee believes that the research base for the hematologic tests suggested in its recommended guidelines for screening prevention, and treatment of iron deficiency anemia meet the above criteria.
Additional standards for evaluating the committee's recommended guidelines are found in recent reports by the Institute of Medicine's Division of Health Care Services (IOM, 1990a, 1992a). The Committee on Clinical
Practice Guidelines has produced several reports on the development and evaluation of clinical practice guidelines. The committee recommends that the draft guidelines proposed in this report be further evaluated by the CDC against the eight attributes for clinical practice guidelines recommended by that Committee on Clinical Practice Guidelines (see Table 3-1 in that committee's full report [IOM, 1992a]).
Intervention Strategies: Efficacy and Safety
The methods for delivering iron to children and women can be categorized as either population based or as medicinal or therapeutic. The present population-based approach has two components—providing education to promote the consumption of iron-rich foods and increasing the iron content of the food supply. The therapeutic approach for delivering iron is through the voluntary or prescribed use of supplemental iron preparations.
Enrichment and Fortification
Enrichment of white bread and flour with iron (among other nutrients) is mandatory when the term enrichment is used in labeling and fortification of both standardized and nonstandardized foods has taken place. Fortification of ready-to-eat cereals gradually has increased, with many products now supplying 45 percent or more of the U.S. Recommended Daily Allowance for iron in a 1-ounce (28-g) serving, the amount required for a cereal to be eligible for purchase with food vouchers distributed in the U.S. Department of Agriculture's Special Supplemental Food Program for Women, Infants, and Children (WIC). The WIC program is targeted to low-income infants, children, and pregnant and lactating women, but it appears to have had the unintended effect of increasing the iron contents of products purchased by the broad array of consumers. The extent to which fortification of cereals with iron may have contributed to the increasing ferritin levels of men or the lower prevalence of anemia in the general population of young children is unknown.
Fortification with iron of foods consumed solely by infants—formula and infant cereals—allows for a clearly targeted intervention and is judged to have been effective. Appendix D outlines the trends in consumption of iron from the above sources, the current regulatory framework for enrichment and fortification, and the use and efficacy of iron-fortified infant cereals and meat in delivering iron to infants and children.
Education and Dietary Change
The most prevalent example of nutrition education for dietary change is embodied in the publication Nutrition and Your Health: Dietary Guidelines for
Americans (DHHS/USDA, 1991). Although there is no recommendation specific to iron, the first guideline, ''Eat a Variety of Foods,'' specifically discusses ways to increase dietary consumption of iron through the consumption of iron-rich foods. The use of the dietary guidelines has become a universal component of all nutrition education programs. However, changes in diet brought about by educational efforts alone are very difficult to evaluate and quantify. Program evaluations generally neglect to include an examination of dietary change (Dwyer, 1982). Also, most evaluations are related to a combination of nutrition education and the delivery of food or supplemental iron—nutrition education and supplemental food (food stamps, WIC, or school lunch) or nutrition education and iron supplements (WIC, prenatal intervention studies [CDC-Ohio intervention in progress]).
A study of the dietary intake of preschool-age children showed that those who were provided supplemental food and nutrition education through the WIC program had significantly higher intakes of energy, ascorbic acid, and iron than nonparticipants (Brown and Tieman, 1986). Data from the 1985 National WIC Evaluation showed that program participants had significantly higher intakes of thiamin, niacin, vitamin B6, ascorbic acid, and iron than nonparticipants (Rush et al., 1988). However, there was no residual long-term impact on dietary intake resulting from earlier enrollment in the program.
Supplementation for Infants and Children
It appears that the use of nonfood supplemental iron is generally unnecessary for most infants and children. However, supplemental iron as ferrous sulfate drops is recommended for preterm infants who are fed breast milk. Iron-fortified infant formula supplies adequate iron for formula-fed preterm infants. Iron-fortified infant formula, iron-fortified infant cereal, and meat are good dietary sources of iron for infants and children (See also Appendix D).
It appears that supplemental iron for infants is safe at prescribed doses. However, all supplemental iron preparations should be kept out of the reach of children to avoid poisoning. (See Appendix B for additional information.)
Supplementation for Women
Recommendations for the prescription of iron supplements have little prospect for success in preventing iron deficiency anemia unless they are accompanied by compliant behavior. Research shows that compliance is generally very inconsistent even for relatively simple drug regimens (Haynes et al., 1979). Although drug compliance is often poor even for individuals with life-threatening conditions such as diabetes, epilepsy, and organ transplantation, research shows that compliance is worse when the individual has no obvious illness, such as hypertension. The observed compliance with supplemental iron regi-