Iron deficiency and anemia are global health problems that can cause lethargy, behavior problems, and poor cognitive development (1,2). For more than 50 years, studies have documented high prevalences of iron deficiency and anemia among rural Alaska Native individuals (3–9), particularly those living in the southwestern and northern regions where poverty rates are high and subsistence lifestyles common. Recent estimates indicate that the prevalence of iron deficiency in rural Alaska Native children exceeds national standards by 10-fold (6). Despite these previous studies, the etiology of iron deficiency and anemia in this population remains unknown, and may not be due to nutritional iron deficiency (4,5,10,11). The present study was designed to assist with generating plausible hypotheses for the etiology of iron deficiency and anemia in Alaska.
PATIENTS AND METHODS
The study cohort consisted of children and pregnant and postpartum women enrolled in the supplemental nutrition program for Women, Infants, and Children (WIC). WIC is a federally funded program administered by 90 state agencies targeting low-income nutritionally at-risk populations (http://www.fns.usda.gov/wic/aboutwic/wicataglance.htm). At-risk populations include pregnant women, postpartum women (6 months for nonbreast-feeding and 12 months for breast-feeding women), and children <5 years of age. For WIC eligibility in Alaska during 2007, the income limit for a family of 4 was <$47,767 annually (http://www.hss.state.ak.us/dpa/programs/nutri/WIC/default.htm). Alaska WIC does not provide prenatal vitamins, and no data exist on iron supplementation among pregnant women in Alaska. Alaska WIC assigns race based on the client's (or guardian's) report and allows for the assignment of more than one race per individual. Alaska Native race was assigned if Alaska Native/American Indian was the only race assigned. Overall, 4.5% of analyzed individuals had Alaska Native and at least one other race and were thus classified as a non-Native race.
The Alaska WIC program obtains blood for hemoglobin testing during the initial visit for each person enrolled. Pregnant and postpartum women were tested once during pregnancy and once postpartum. Infants were usually not tested until 9 months of age, but often during the study period this rule was not strictly enforced resulting in inclusion of some children at ages 6 to 8 months.
Hemoglobin levels were determined at community-based WIC clinics using a portable hemoglobinometer (HemoQue Inc, Lake Forest, CA). No information was available regarding standardization of machines or the methods used by WIC staff at any particular location. However, all of the WIC staff received standard training on hemoglobinometer use. Anemia was defined as having a hemoglobin level <110 g/L for children <2 years of age and pregnant women in their first or third trimester, 111 g/L for children of ages 2 to 4 years, and 105 g/L for women in their second trimester (12). Severe anemia was defined as <90 g/L for all of the evaluated groups, consistent with Alaska WIC guidelines.
The WIC database for 1999 to 2006 for all of the Alaska WIC clinics was evaluated. Available and analyzed variables included age (or pregnancy trimester/postpartum status for pregnant women), residence, race, hemoglobin level, and date of hemoglobin level. For children, hemoglobin levels obtained at ages 6 to 59 months were included. Only hemoglobin levels from 40 to 169 g/L were considered valid. Among subjects with >1 hemoglobin measurement in the database, only the first valid hemoglobin measurement was used.
Residence was categorized into 3 regional groups: rural: southwestern and northern; urban: Anchorage (Alaska's largest city), the adjacent Matanuska-Susitna region in southcentral Alaska, and interior Alaska, which is populated primarily by residents of Fairbanks (Alaska's second largest city); and coastal: the Gulf Coast and southeast Alaska. The first category contained most of Alaska's small, rural, and predominantly Yupik Eskimo communities, including all of the communities previously reported to have high iron deficiency and anemia prevalences. The second category contained most of Alaska's population and wealth and was populated predominantly by non-Native residents. The third category contained mainly small, rural, coastal communities from the Aleutian Islands and southeastern Alaska.
All of the analyses were conducted with SPSS version 13.0 statistical software (SPSS Inc, Chicago, IL). Logistic and linear regression models were constructed with region of residence, age in months, and Alaska Native race entered simultaneously. For children, sex was evaluated and did not correlate with anemia risk, so it was not considered further.
The present descriptive study consisted of an evaluation of an administrative database housed within the Alaska Department of Health and Social Services and was conducted by an employee with legal access to this database for the purpose of developing public health recommendations. No individuals were contacted. Consequently, institutional review board approval was neither sought nor obtained.
Study Population Characteristics
The WIC database had 55,083 children ages 6 to 59 months and 31,998 pregnant or postpartum women with a hemoglobin level of 40 to 169 g/L measured during 1999 to 2006. Of these, 50,964 children and 30,154 pregnant or postpartum women had residence and race recorded and these subjects formed the basis of the remaining analyses (Table 1).
Mean hemoglobin levels did not vary by month or study year either overall or when stratified by Alaska Native status. Mean hemoglobin increased with age from 117 g/L among children ages 6 to 11 months to 123 g/L among 48- to 59-month-olds. Mean hemoglobin levels were 127 g/L among first-trimester women, 119 g/L among second-trimester women, 116 g/L among third-trimester women, and 124 g/L among postpartum women.
Stratification by Age Group, Race, and Residence
Among pregnant and postpartum women, anemia prevalence was highest among women tested during the third trimester for all of the strata of race and region (Fig. 1A). Alaska Native people had the highest anemia prevalence regardless of residence, although residence in rural southwestern/northern communities conferred additional risk. By contrast, residence in rural communities did not increase risk to non-Native women. Mean hemoglobin levels were lowest and anemia prevalences were highest among women <20 years of age during all of the periods of pregnancy both overall and among those living in southwestern/northern communities. For example, for all of Alaska among those <20, 20 to 29, and ≥30 years of age, respectively, mean hemoglobin levels were 127, 128, and 127 g/L during the first trimester, 118, 120, and 119 g/L during the second trimester, 114, 116, and 116 g/L during the third trimester, and 121, 124, and 124 g/L postpartum.
Among children, those tested at ages 6 to 11 months had the highest anemia prevalence, with a steady decline in prevalence among progressively older age groups (Fig. 1B). The 2 strata with the highest anemia prevalences at all of the ages were Alaska Native and non-Native children from rural southwestern/northern regions. The decreases in anemia prevalence with progressively increasing age group occurred to the same degree across all of the strata as indicated by the relatively constant slopes of the lines. Among children from ages 6 to younger than 7 months, 122 of 494 (25%) were anemic, including 24 of 48 (50%) from rural southwestern/northern communities and 46 of 113 (41%) Alaska Native children.
For children and pregnant/postpartum women, the results for severe anemia were similar to those for anemia (Fig. 2A and B). Only 7 non-Native children and 1 non-Native pregnant or postpartum woman were identified from communities in southwestern/northern regions, so this stratum was not included in the analysis.
Among 66 of the total 121 communities in the southwestern/northern regions with at least 50 children with valid data, all but 4 had a mean hemoglobin level among children ages 6 to 59 months less than the state mean of 119 g/L. Additionally, all but 6 of these 66 communities had a higher childhood anemia prevalence than the overall state prevalence of 22%. These 6 communities were distributed across the 2 regions and had populations varying from the largest to the smallest.
During multivariate logistic regression analyses (with adjustment for age), pediatric anemia was associated independently with Alaska Native race (adjusted odds ratio [AOR] 1.4, 95% confidence interval [CI] 1.3–1.4) and southwestern/northern residence (AOR 1.9, 95% CI 1.7–2.0). When adjusted for pregnancy or postpartum status, pregnancy/postpartum anemia also was associated independently with Alaska Native race (AOR 1.5, 95% CI 1.4–1.6) and southwestern/northern residence (AOR 1.6, 95% CI 1.5–1.8). For children and pregnant/postpartum women, the results were similar when severe anemia was the outcome.
Among Alaska Native children, 35% of those living in southwestern/northern communities were anemic compared with 22% living in other regions (prevalence ratio [PR] 1.6, 95% CI 1.5–1.6), whereas among non-Native children these values were 26% and 18% (PR 1.5, 95% CI 1.2–1.7). Among Alaska Native pregnant/postpartum women, 31% of those living in southwestern/northern communities were anemic compared with 20% living in other regions (PR 1.5, 95% CI 1.4–1.7), whereas among non-Native women these values were 13% and 15% (PR 0.84, 95% CI 0.64–1.1).
Previous studies have documented that one-half to two-thirds of pediatric anemia in southwestern Alaska occurs in association with low ferritin levels (3–5,7). This indicates that in this region iron deficiency is likely the primary direct causal mechanism for most anemias among children ages 6 months through at least the early teenage years. Other studies have documented low prevalences of other causes of anemia such as intestinal parisitosis (13), elevated blood lead levels (4,14), vitamin B12 or folate deficiency (15), or hemoglobinopathies (the rate of abnormal hemoglobins among Alaska Native newborns during 2004 to 2007 was 9 per 1000 live births; Alaska Newborn Screening Program, unpublished data). The present observational study generally agrees with results from these earlier studies, and provides further insight into the potential etiologies of the prevalent iron deficiency and subsequent anemia in Alaska.
Iron deficiency may be caused by prolonged breastfeeding or use of iron-deficient formulas, including among indigenous Canadian infants (16–20). Breastfeeding prevalence at age 8 weeks in Alaska is relatively high at 70%; however, using the same categories as in the present article, the lowest prevalences exist among urban and rural Alaska Natives at 61% and 62%, respectively (Alaska Pregnancy Risk Assessment Monitoring System, unpublished data). Moreover, the Alaska WIC program supplies iron-fortified formulas to all infants who were not breast-fed. Thus, breast-feeding and formula consumption differences seem unlikely to explain the observed epidemiological patterns.
Nutritional iron deficiency could explain the anemia patterns observed in the present study. The rate of the age-related decrease in anemia in Alaska was similar to the 1.5- to 3-fold decrease in iron deficiency seen among US children from ages 1 to 2 to 3.5 years (6). The patterns of anemia during pregnancy were similar to those reported previously for iron deficiency (21). Additionally, the high anemia prevalence during infancy may reflect the documented effect of maternal anemia on fetal iron status (22).
Nutritional iron deficiency, however, cannot represent the only causal factor. Southwestern and northern Alaska Native people have a high anemia prevalence; however, these populations have iron and vitamin C intakes that exceed the US recommended dietary allowances (5,10,11), with much of the iron in a highly bioavailable form from meat and fish collected during subsistence hunting and fishing. Earlier studies in Alaska (4) and elsewhere (23) also have shown little correlation between iron intake and iron deficiency or anemia. Finally, all of the evaluated groups had a similar rate of decline in anemia prevalence with increasing age, an unlikely situation if nutritional iron deficiency, concentrated among southwestern and northern Alaska Native people, was the sole underlying etiology.
Iron deficiency and subsequent anemia may evolve among some populations as a method of decreasing infectious disease risk (24) and hence have a genetic basis. The present study found that Alaska Native race increases anemia risk among children to the same degree regardless of residence. Thus, it is possible that Alaska Native individuals have adapted to a subsistence diet high in iron-rich meat by lowering iron absorption. The decreased reliance on subsistence diets seen recently—particularly among younger people (25,26)—may then have led to iron deficiency and the high anemia prevalences seen today. This theory, however, implies that anemia and iron deficiency should be greater among Alaska Native residents outside of southwestern/northern communities because these communities are generally the most traditional with the largest reliance on subsistence diets. Additionally, southwestern/northern residence remains a risk factor even after controlling for Alaska Native race.
Numerous previous studies in Alaska (limited to date to rural southwestern Alaska Native people) and elsewhere have identified an association between Helicobacter pylori infection and iron deficiency or anemia (3,4,27–32). In contrast, a recent randomized trial of H pylori therapy to treat iron deficiency and anemia among southwest Alaska Native children of ages 7 to 11 years found little improvement in hemoglobin or ferritin levels following H pylori eradication (33). The present results support this latter study. H pylori prevalence in Alaska increases with age starting as early as age 1 year (4,34) and is endemic in rural Alaska Native but not other communities (35). Thus, if the high H pylori infection prevalence among rural Alaska Native children was the primary cause of their increased iron deficiency and anemia, the prevalence of these disorders should not decrease over time and at the same rate as among groups with lower infection prevalence. Theoretically, H pylori infection during pregnancy could lead to anemia during infancy, but few studies have evaluated H pylori effects on hematological status during pregnancy (36,37).
One potential limitation of the present study was reliance on field-based portable hemoglobinometers for the determination of hemoglobin levels. Data were not available on hemoglobinometer use, maintenance, provider training, or other variables needed to assess this possibility. Hemoglobinometers, when correctly maintained and used by trained personnel, give reliable results (38,39). The study was conducted among WIC clients and thus may not reflect the situation among unenrolled individuals. However, WIC serves a large proportion of Alaska's population: during 2002, approximately 55% of Alaska Native and 29% of non-Native children ages 6 to 59 months had a documented WIC visit. Alaska Native race was based on the self-report of WIC clients, and self-reported assignment of race may reflect cultural and historical factors as much as or more than genotype, making it difficult to reach conclusions regarding a genetic basis for anemia.
Alaska Native people living in the rural communities of southwestern and northern Alaska have substantially higher anemia and especially severe anemia prevalences than non-Native or Alaska Native people from other regions of the state. The high anemia and iron deficiency prevalences among other Native American Arctic populations (16–18) suggest that the present results may have broader significance. Previous studies in Alaska implicate iron deficiency as the major cause. Although the present study places limits on plausible hypotheses, the etiology of this iron deficiency remains unknown.
Given that the etiology remains unknown, intervention recommendations are difficult to develop. Even the standard practice of iron replacement therapy is problematic because a previous study has shown that iron deficient Alaska Native children provided with iron therapy quickly return to an iron-deficient state once iron therapy is stopped (33). Several areas for future research exist that may provide insight into causal mechanisms. Because large discrepancies exist between groups by age 6 months, future research may focus on the prenatal period or early infancy. For example, iron-deficient pregnant women may be provided iron therapy throughout pregnancy to determine whether this leads to a long-term change in the iron status of their children. Iron absorption studies could be conducted to determine whether a genetic basis exists for iron deficiency among some populations. Finally, more detailed prospective nutritional studies may identify whether children and pregnant women consuming a high iron subsistence diet have less iron deficiency and anemia than people consuming a diet considered normal in iron based on US norms.
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