Recommendations For Research (2023)

In conducting its critical review of the available information related to public health approaches to the prevention, detection, and management of iron deficiency anemia, the committee identified two major gaps in the research base. The first consists of information on the efficacy of routine iron supplementation during pregnancy and the second consists of several gaps in the research base for public policy decision making.

Efficacy of Routine Iron Supplementation During Pregnancy

The evidence on which to base a coherent policy of whether to routinely provide iron supplements for iron deficiency to pregnant women who are not overtly anemic—and if so, at what stage of pregnancy supplementation should begin and at what dosage—is unclear. Almost all observational studies that have related hemoglobin or hematocrit to birth-weight or duration of gestation have shown a consistent U-shaped relationship with adverse outcome at very low (<8 or 9 g/dl) or high (>13 g/dl) hemoglobin levels. These relationships are true for hemoglobin measured at any time during pregnancy, but are weakest for the relationship between a low hemoglobin concentration in the third trimester and an adverse outcome (i.e., premature birth, low-birth-weight).

The meaning of these observations is further obscured because, taken in toto, there has been no observed effect of iron supplementation on the duration of gestation or birth-weight in rigorous controlled trials (Hemminki and Starfield, 1978).

Thus, it is unclear whether an adverse prenatal outcome associated with the level of hemoglobin, low or high, can be reversed by iron supplementation or some other intervention.

High levels of hemoglobin have consistently been observed in association with a severely adverse prenatal outcome. Those who advocate universal supplementation posit that high levels of hemoglobin have little or nothing to do with iron status but rather to a unphysiologically low level of expansion of plasma volume during pregnancy. However, this has not been studied directly. Taylor and Lind (1979) demonstrated that iron supplementation has no effect on plasma volume. They found that although the red blood cell mass increased by 180 ml among controls, it increased by 349 ml among those treated with 65 mg of elemental iron daily. Thus, the hemoglobin concentration was increased, and therefore, it is unclear whether hemoglobin levels could also be raised among women with inadequate plasma volume expansion and whether it would possibly cause problems associated with a high hemoglobin concentration. Also, among women who received supplemental iron in controlled trials of iron supplementation during pregnancy, the weighted value of the mean plus two standard deviations for the hemoglobin concentration closest to term (between 36 and 40 weeks) was 14.6 g/dl (Table 3). This concentration is well above that associated with an adverse prenatal outcome and suggests the possibility that routine supplementation may possibly induce dangerous hemoglobin concentrations. It has been assumed that supplementation only affects those with low hemoglobin values and that there will not be an increase in hemoglobin concentration in those with high or fairly high hemoglobin concentrations (i.e., that there is a truncated distribution with supplementation: low values would increase, but higher values would not). On the other hand, all of the studies presented change in terms of mean and standard deviation (or standard error) and did not present any distributional data to test the assumption that there is little or no increase in high values.

Thus, a nested set of assumptions underlies a policy of routine supplementation, and all of these assumptions need to be tested by objective and careful research. The first assumption is that the adverse outcomes associated with high hemoglobin concentrations have little or nothing to do with red blood cell mass but, rather, are a function of contracted or inadequately expanded plasma volume. This assumption needs testing in an observational study that asks the following: Are high hemoglobin concentrations with adequately expanded plasma volume associated with an adverse outcome, or are only high hemoglobin concentrations associated with inadequately expanded plasma volume?

The second assumption that needs explicit study is whether routine supplementation with iron produces a change only among those with lower hemoglobin levels or affects the entire range of the distribution. If the latter is true, does it affect women with inadequately contracted plasma volume in ways that may result in hemoglobin concentrations that could be dangerous?

Finally, these preliminary studies need to be the basis for a large, well-de-signed, randomly controlled trial of routine iron supplementation in women who do not have frank iron deficiency anemia in early pregnancy. Without such a study, it cannot be concluded from data currently published in observational or experimental studies that iron supplementation is beneficial to the progress of pregnancy and that it presents no dangers to the pregnancy or in the prenatal period. So far there is little or no evidence that routine iron supplementation is of benefit to fetal growth, to the duration of pregnancy, or to indices other than the replenishment of the iron stores of the mother (not the infant). Moreover, by 6 weeks postpartum, hemoglobin levels in women who do not receive iron supplements are, on average, at their prepregnancy levels.

The need for caution is reflected by a new expert committee's report that concludes that iron supplementation for women who do not have iron deficiency anemia is unnecessary (Woolf and Washington, in press). This is, however, the conclusion of a minority of clinicians in the United States, where iron supplementation of pregnant women has been routine for years.

Without benefit of further research, the committee believes that the current routine iron supplementation practice should not be changed. The committee believes that the standard practice of routine iron supplementation during pregnancy should not be altered without evidence as firm as that required to initiate some new medical intervention or practice. The fact that iron supplementation during pregnancy has been routine in the United States for decades does not provide a body of evidence that it is, overall, advantageous; the support for the practice is based on an extrapolation from an incomplete database.

Research Base for Public Policy

Improved Data on Iron in the Food Supply

To more accurately determine the impact of iron fortification on dietary intake, the committee recommends improvement in the database on the types of iron used to fortify foods, the quantity of iron added to those foods, and the iron usage patterns by population subgroups (race, gender, and income and in relation to patterns of serum ferritin concentrations). Once the database is improved, researchers will be better equipped to estimate the iron intakes of various population subgroups. Such estimates, perhaps with the addition of projections based on recent trends, can form the basis for future recommendations for iron fortification of foods. Such data will be particularly useful for predicting which populations of consumers, if any, are at risk of excessive iron intake. Similar data also should be collected on over-the-counter supplement preparations and their use.

Expand the Sample of Infants and Minorities in National Nutrition Surveys

In preparing its screening guidelines for infants, the committee relied on NHANES data for children 2 through 5 years of age. Estimates and extrapolations for infants based on data on preschool-age children are probably not appropriate for the screening recommended at 9 months of age. In the future, nutrition surveys should include a sufficient number of infants in the survey sample size to permit estimates of iron deficiency anemia for groups of infants at 3-month age intervals from birth through 2 years of age. These data are needed to determine the appropriate cutoff values for infants with different ethnic and racial backgrounds.

Because of the differences in iron nutrition status among racial and ethnic subgroups, nutrition surveys should include larger numbers of individuals from ethnic subgroups in survey samples. For example, the sample used in NHANES III for the ''Hispanic'' population covers only Mexican Americans. Larger samples of Hispanic and other ethnic groups could be added to future survey samples (e.g., Cubans, Puerto Ricans, and those from the Caribbean). By expanding the representation of ethnic subgroups in national nutrition surveys, more data would be available to correlate dietary beliefs and practices with health status measurements.

More Information on the Prevalence of Iron Deficiency Anemia Among Adolescents

Another group for which prevalence data on iron deficiency anemia were lacking is adolescents. The committee recommends that more information be collected about the prevalence of iron deficiency anemia in adolescent males and females and about the critical determinants of iron nutrition during adolescence. Intervention programs that are designed to work for older women or poor and underprivileged mothers stand a good chance of not working for teens because of social issues pertinent only to adolescence. For adolescent males, more information on the effect of iron intake and athletic performance and endurance is needed.

New Determinants of Iron Deficiency Anemia in the First Trimester of Pregnancy

A key issue confronting the committee was the ability of clinicians and public health practitioners to identify early in pregnancy women who are at risk for developing iron deficiency anemia in the first trimester of pregnancy. Data from Scholl and colleagues (1992) indicate that the first trimester is a time of great risk for the developing fetus, with the potential for iron deficiency anemia to have a negative impact on fetal growth. The committee therefore recommends that studies be done to identify new determinants of iron deficiency anemia in pregnant women during the first trimester of pregnancy.

Conduct Cost-Benefit Studies on the Use of Serum Ferritin Concentration Determinations

Costs vary widely for the laboratory test to determine serum ferritin concentration. This is primarily based on the fact that different settings apply different overhead costs to the charge associated with this test. Administration of the basic test generally costs less than $1. The committee has recommended that laboratory determination of serum ferritin concentration be conducted to confirm the presence of iron deficiency anemia. This laboratory test is currently used in many settings as part of the prenatal laboratory profile conducted throughout the course of pregnancy. Although there is substantial agreement on the value of the use of the serum ferritin concentration determination to confirm iron deficiency anemia, at present there are few cost-benefit data to support the widespread use of the test. Additionally, the number of individuals who would benefit from this additional screening tool is not entirely clear. Therefore, the committee recommends that cost-benefit studies be conducted to determine the value of the widespread use of serum ferritin concentration tests as part of the screening protocol for evaluating iron deficiency anemia.

Sensitivities and Specificities of New Tests to Measure Iron Status

Although the state of the science for determining iron status has improved markedly, the committee recommends that more information be collected on the sensitivities and specificities of new tests for iron status, particularly in relation to different prevalences of iron deficiency anemia among at-risk population groups. For example, little information is available on the distribution of ferritin and transferrin receptors among different ethnic and racial groups. There is a need for expanded information on the predictive value of iron tests for specific at-risk groups (i.e., ferritin receptor).

Alternative Approaches to the Prevention and Detection of Iron Deficiency Anemia

Lastly, the committee found little information about the cost-benefit attributes of alternative public health approaches for preventing and detecting iron deficiency anemia. Therefore, the committee recommends that more information be collected about the costs and benefits of alternative approaches for preventing and detecting iron deficiency anemia. There is little information in the literature about the efficacy or effectiveness of alternative intervention strategies, and the committee therefore did not find it surprising that little information is available on the cost-benefit attributes of alternative public health approaches. Some straightforward studies on the cost implications of policy changes in the types of laboratory tests used to evaluate iron nutrition and the presence of iron deficiency anemia should be undertaken. Similarly, analyses of the cost implications of policy changes related to changes in cutoff values should also be conducted. The cost and effectiveness of ready-to-eat cereal fortification versus other methods of increasing iron should be of interest to WIC officials in particular. Trends in consumption patterns for major food classes should be monitored. Changes in food selection in response to dietary guidelines to reduce fat and increase nutritional quality—that is, to increase consumption of whole-grain cereals, vegetables, and beans and to decrease intake of red meat—may affect an individual's overall intake of iron, heme iron, and bioavailability (owing to the intake of phytate and other factors). Analysis of data from the 1987-1988 Nationwide Food Consumption Survey showed a weak but statistically significant negative correlation between diet quality variables defined as percentage of energy from fat and intakes of 15 nutrients below two-thirds of the Recommended Dietary Allowance. This led the authors to conclude that the adults surveyed seldom choose diets that are both high in nutrients and low in fat (Murphy et al., 1992).

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