CAUSES OF ABNORMAL HEMOGLOBIN CONCENTRATION RELEVANT TO PREGNANCY

Low hemoglobin concentration (anemia)
Anemia is the consequence of either less-than-optimal production of red blood cells or hemoglobin, or increased destruction or shortened life span of red blood cells. The production of red blood cells and their principal component—hemoglobin—is a complex process, one that can be adversely affected by many congenital and acquired conditions (22). In most developed countries, iron deficiency is the main cause of significant anemia during pregnancy (23), as shown by the efficacy of iron supplementation in preventing maternal anemia (evidence of benefit). In developing countries, especially where severe maternal anemia is more common, other nutritional factors and infections, including malaria, can often coexist with iron deficiency, contributing to anemia (23). In addition to poor intakes of bioavailable iron, which is a common problem in developing countries and is related to low intakes of heme iron from animal sources, hookworm infection is prevalent in many tropical areas (24). Hookworm causes upper gastrointestinal blood loss, which contributes directly to iron deficiency anemia (25).

The coexistence of multiple causes of anemia within the same individual or population makes it difficult to define anemia by using conventional biochemical markers, especially when infections are involved (26). Moreover, if multiple deficiencies contribute to the severity of anemia, supplementation with iron alone may not achieve adequate hemoglobin response. A good example is a supplementation study done by Suharno et al (27) in Indonesia, in which combined iron and vitamin A supplementation had a greater effect in correcting maternal anemia than did iron or vitamin A alone. When multiple factors contribute to the severity of anemia, iron deficiency is always a major factor (evidence of deficiency) (23). In such settings, improving iron nutrition is a necessary—but not a sufficient—measure for the reduction of anemia.

Elevated hemoglobin concentration
An elevated hemoglobin concentration is usually the result of 2 mechanisms: increased red blood cell production as a compensatory mechanism when blood oxygen carrying capacity is compromised to meet the demand of tissue (with a net increase in red cell mass), or contracted plasma volume resulting in an appearance of greater red cell volume (without a net increase in red cell mass) (28). One of the 2 most common nonpathologic reasons for elevated hemoglobin or red cell mass is residence at a higher altitude, where ambient oxygen concentration is lower. (29). The other is cigarette smoking, which causes part of the hemoglobin to become nonfunctional as a result of binding with carbon monoxide (30). Respiratory and cyanotic cardiac conditions, which compromise proper oxygenation of blood, are the principal pathologic reasons for elevated hemoglobin concentration (28). The only condition of elevated hemoglobin that is due to the production of defective red blood cells, but not subject to the control of tissue oxygen drive, is polycythemia vera (31). These conditions of increased red blood cell production share the one basic feature of increased red cell mass with normal or increased total blood volume.

When the red cell mass does not increase, the contraction of the plasma volume results in the appearance of an elevated hemoglobin concentration, or hemoconcentration (32). The most common example is acute dehydration, which can raise the hemoglobin concentration by 10–15%. Throughout normal pregnancy, blood volume expands by an average of 50% compared with the nonpregnant state (33). This rapid expansion of blood volume starts in the first trimester. Plasma volume increases more than does red blood cell mass, which produces a declining hemoglobin concentration during the first half of pregnancy. This is known as the physiologic anemia of pregnancy.

In women who have hypertensive disorders of pregnancy, particularly those with preeclampsia, blood volume does not increase, which results in a relatively higher hemoglobin concentration. In the study by Pritchard et al (34), the average hematocrit for women with preeclampsia was 0.405, compared with a mean of 0.374 for women with a normal pregnancy. This difference in hematocrit is equivalent to a 20-g/L difference in hemoglobin and shows the extent of the severe failure of plasma expansion due to preeclampsia. Several other studies showed that higher hemoglobin concentrations during pregnancy result from hypovolemia or hemoconcentration, which is usually the result of preeclampsia or pregnancy-induced hypertension (35, 36).

HEMOGLOBIN CONCENTRATION—NORMATIVE DEFINITION COMPARED WITH PHYSIOLOGIC CONSEQUENCE

Defining the normal range of hemoglobin values
The hemoglobin cutoff value commonly used to define anemia is based on the normality definition often applied to other clinical laboratory tests and in anthropometry (10). For anemia, age- and sex-specific hemoglobin distributions are based on healthy reference samples (samples from persons with disease or nutritional deficiencies identified by other laboratory criteria are excluded) (11, 12). By convention, the central 95% of the reference hemoglobin distribution was considered the normal range. The 2.5th percentile hemoglobin value (-2 SDs from the mean) was the cutoff point for low hemoglobin or anemia. Conversely, the 97.5th percentile (+2 SDs from the mean) of the same distribution was the cutoff for high hemoglobin.

Because iron deficiency is often a major cause of anemia in many parts of the world, anemia screening is commonly used as a substitute for screening for iron deficiency. However, the probability of iron deficiency in individuals who are anemic (positive predictive value) depends largely on the actual prevalence of iron deficiency in a specific population. Additionally, because many possible causes of anemia exist, such statistics-based anemia criteria provide only a guideline for establishing the probability of specific health and nutritional causes of anemia for a given population. In essence, the hemoglobin-based definition does not provide sufficient information on the meaning of, or reason for, either anemia or high hemoglobin concentrations. Usually, the further a hemoglobin value is from the central tendency of the distribution, the greater the likelihood of finding pathologic reasons to explain the abnormal value. Because of substantial normal variations in hemoglobin distribution across age, between sexes and races, and at different stages of pregnancy, the cutoff for low or high hemoglobin concentrations should be specific to sex and life cycle (11, 12). The use of inappropriate evaluative hemoglobin criteria during pregnancy can result in misinterpretation of the relation between anemia and resulting health outcomes. An example of such misinterpretation is the disregard of normal hemoglobin concentration variations related to plasma volume changes during pregnancy, which can result in a striking association between preterm births and anemia (13, 14).

Physiologic significance of anemia
Mild anemia is routinely defined as a hemoglobin value within 10 g/L of the anemia cutoff value. The World Health Organization recommends that severe anemia be defined as a hemoglobin concentration <70 href="http://www.ajcn.org/cgi/content/full/72/1/272S#R15">15). Hemoglobin concentrations below that of the mild anemia concentration and >70 g/L can be regarded as indicating moderate anemia. Some investigators have defined very severe anemia as a hemoglobin concentration <50> Hemoglobin concentrations <50> the risk of maternal and fetal mortality because of the effects of hypoxia and anemia on the cardiovascular system, which is known as high-output heart failure (16). Medical evidence shows that very severe anemia is a direct cause of maternal and child mortality. In South Asia and Africa, where severe maternal anemia is common, classifying very severe anemia as a major cause of maternal mortality along with eclampsia, obstructed birth, hemorrhage, and sepsis is appropriate. Ross and Thomas (17) estimated that =" v:shapes="_x0000_i1025" border="0" height="10" width="8">20% of maternal mortality can be attributed to severe anemia. In the less severe range, however, the evidence that anemia is a direct cause of poor reproductive outcomes is not clear. Epidemiologic studies that showed an association between maternal anemia and increased risk of poor birth outcomes did not establish a causal relation (evidence of risk only) (6–9). It is possible that a common factor can cause both anemia and poor birth outcomes.

Although oxygen carrying capacity is proportional to the circulating hemoglobin concentration, an individual with chronic anemia develops a compensatory mechanism to improve oxygen unloading to tissue from hemoglobin during the resting state. This compensatory mechanism can maintain adequate tissue oxygen delivery down to a hemoglobin concentration of 70–80 g/L (18, 19). In an exercise state, however, any loss of hemoglobin or red blood cell mass can be detected as loss in work capacity, even within a hemoglobin range of 120–130 g/L (20). From a physiologic point of view, the evidence is clear that moderate anemia is undesirable, whatever the cause. If the cause of significant anemia is iron deficiency (evidence of deficiency), prevention and correction of iron deficiency anemia are indicated. From the perspective of reproductive health outcomes, however, the evidence is not clear that anemia or iron deficiency are direct risk factors (2). Perhaps a concern more important than the health consequence of anemia is the cause of the anemia. Some major causes of anemia have many other damaging effects or health consequences beyond anemia. For example, malaria is well known to cause severe anemia in many tropical areas, particularly among primigravidae, and it also contributes to the low birth weight of infants.

In summary, sufficient evidence shows that moderate to very severe anemia can produce undesirable health consequences. From the perspective of reproductive health outcomes, only very severe anemia has clearly been shown to result in maternal mortality. The justification for controlling maternal anemia can be based on the undesirable effects of anemia other than poor birth outcomes and harmful health consequences beyond that of anemia alone.

Physiologic significance of a high hemoglobin concentration
As with defining anemia, the normative definition of high hemoglobin can be based on +2 SDs from the reference mean. For nonpregnant women, this is equivalent to a hemoglobin concentration of 155–160 g/L. Analogous with mild anemia being within 10 g/L of the cutoff, a mild-high hemoglobin concentration would be 160–170 g/L. For women, a hemoglobin concentration >170 g/L can perhaps be regarded as a moderately elevated value. During pregnancy, the upper level for defining high hemoglobin would be lower than that in nonpregnant women because of the physiologic changes in the hemoglobin concentration during pregnancy (12). Again, the meaning of the elevated hemoglobin concentration and the probability of association with adverse events depends on the specific individual or population under study.

Although much of the clinical and public health focus has been on anemia or the low end of the hemoglobin distribution, there are also problems at the high end. The most notable consequence is increased blood viscosity. The relation between hemoglobin and blood viscosity is linear when the hematocrit is <0.50 (equivalent to a hemoglobin value of 160 g/L). Above this hemoglobin concentration, the relation becomes exponential—a small increase in hemoglobin or hematocrit results in a large increase in viscosity (18). Once hemoglobin concentrations reach =" v:shapes="_x0000_i1026" border="0" height="10" width="8">180 g/L, the blood viscosity reaches a level that impairs microcirculation and an inadequate amount of oxygen is transported to tissues, similar to the situation with severe anemia. This is often manifested as peripheral cyanosis and impaired mental function resulting from compromised cerebral blood circulation (21). Additionally, because of the poor blood flow, the risk of thromboembolism increases substantially (21). A study of individuals with chronic mountain sickness (or polycythemia), which is due to a combination of high altitude residency and poor pulmonary function, showed that long-term survival with a hemoglobin >200 g/L is not possible (21).
--(Ray Yip, American Journal of Clinical Nutrition)---

RELATION BETWEEN MATERNAL ANEMIA AND IRON DEFICIENCY

Anemia as an undesirable health outcome
In maternal anemia and iron deficiency, the anemia itself is often regarded as an adverse outcome. Evidence is strong that in most undeveloped and in many developed countries, iron deficiency is the main cause of anemia in women and that iron supplementation under trial conditions prevents or corrects the anemia (3). In other words, there is evidence of a benefit or efficacy associated with iron supplementation. Consequently, large-scale iron supplementation programs during pregnancy are a common practice, although evidence of supplementation effectiveness has not been impressive (3, 4). The key argument supporting anemia as an outcome measure is related to the fact that red blood cells contain hemoglobin, which is an essential component of the respiratory system for oxygen transport. Any substantial reduction in red blood cells and hemoglobin reflects a reduced capacity of oxygen transport to tissue. Such a reduction in oxygen transport can be regarded as an adverse health outcome; thus, iron deficiency has a definite effect on health because of anemia (evidence of deficiency).

Anemia as a predictor of reproductive outcomes
In looking at pregnancy-related or reproductive outcomes, there has been a change from regarding anemia as an undesirable health outcome to regarding it as a predictor or cause of other adverse outcomes, ie, maternal and fetal mortality, preterm birth, and low birth weight. Two interesting issues have emerged from this change in perspective. One issue is that the association between mild-to-moderate anemia and other adverse reproductive outcomes is weak (evidence of risk only). Some studies found an association between anemia and adverse pregnancy outcomes, whereas other studies did not show a significant association (2). Additionally, the positive association observed in several epidemiologic studies does not establish a causal relation without the support of a plausible biological mechanism (5). Direct evidence showing that a reduction in anemia will lead to fewer adverse birth outcomes (evidence of benefit) is lacking. This leads to the question, Why provide iron supplementation if there is no evidence of beneficial reproductive outcomes? (2).

A second issue, which emerged from some of the same epidemiologic studies that found an association between anemia and a greater risk of poor birth outcomes, is that high hemoglobin values are significantly associated with poor birth outcomes (evidence of risk) (6–9). These observations raised the issue of whether we should be concerned about high hemoglobin concentrations during pregnancy. If higher than normal hemoglobin concentrations lead to poor birth outcomes, then a related question is, Should we be concerned about iron supplementation during pregnancy, given that iron supplementation can increase the hemoglobin concentration of some women? These issues are discussed below.

In examining the evidence related to high and low hemoglobin concentrations, it is important to evaluate the meaning of hemoglobin concentration. Is hemoglobin concentration a predictor or risk factor for poor pregnancy outcomes as used in epidemiologic studies (a potential cause), or is it a physiologic variable that can be regarded as an outcome in itself (a consequence)?

Significance of an abnormally low or high hemoglobin concentration during pregnancy: special consideration of iron nutrition

Iron and folate supplementation during pregnancy is commonly practiced to prevent maternal anemia, which is often caused by iron deficiency. Part of the rationale for this practice is the high iron requirement during pregnancy, almost 3 times that required for nonpregnant women of childbearing years, which is difficult to meet from dietary sources (1). Another reason for supplementation is that anemia caused by iron deficiency alone or in combination with other factors, eg, folate deficiency, vitamin A deficiency, and malaria, has been implicated as having several negative effects on maternal and fetal health. Therefore, anemia prevention through iron supplementation may help to improve reproductive outcomes.

In this supplement, Rush (2) questions the benefit of routine iron supplementation in relation to the evidence of the harm or burden of anemia on reproductive outcomes. Specifically, he notes that a high hemoglobin value during pregnancy has been associated with adverse birth outcomes. He questions whether efforts to prevent anemia through iron supplementation can put some women at risk by placing their hemoglobin in a higher range that is associated with poor pregnancy outcomes.

The purpose of this review is to look at normal and abnormal hemoglobin values in terms of their causes and consequences. This review will also reassess the evidence for iron supplementation and the strength of the evidence that implicates either a low or a high hemoglobin concentration in morbidity and mortality during pregnancy and the perinatal period. In doing this, the evidence will be categorized with respect to deficiency, risk, benefit, and feasibility to increase the effectiveness of public health programs.

Evidence of deficiency is provided by a dietary nutrient intake that is inadequate to meet the requirement estimated to be necessary to avoid a deficient state. Often, the deficient state is a clearly defined disease or nutritional disorder with specific signs and symptoms, eg, beriberi for severe thiamin deficiency. A clearly defined pathophysiologic mechanism is required for classification of a nutritional disease or disorder, and an estimated nutrient requirement has been widely used for clinical and public health purposes.

Evidence of risk is based on finding associations between nutritional factors and adverse health outcomes, often by observational studies. For example, greater saturated fat intake increases the risk of coronary heart disease. This is regarded as indirect evidence because epidemiologic findings of an association cannot distinguish whether the relation is causal. Because health and nutritional problems may coexist in a population as a result of a common risk factor, evidence of risk alone may not be sufficient to justify program action without greater proof that the association is indeed causal.

Evidence of benefit is obtained when a specific risk factor is thought to contribute to adverse health outcomes, and intervention trials show that removing the risk factor results in improved outcomes. This is regarded as direct evidence to establish a causal relation between the risk factor and poor outcome. The process to prove such evidence often involves controlled trials with proper randomization. The measured beneficial effect under controlled research conditions is known as efficacy, which is the maximum achievable effect under ideal conditions. Often, this is a necessary condition but may not be sufficient for the consideration of large-scale program action.

After the indication for program action is clear on the basis of evidence of deficiency and benefit of the intervention, evidence of feasibility is needed for initiating large-scale programs based on resource and technical capacity. One requirement for a large-scale program is evidence of effectiveness, ie, sufficient benefit under the field conditions. Often, the feasibility of a public health program is based on its cost-effectiveness compared with other programs.
---(Ray Yip, American Journal of Clinical Nutrition)---